(en)[Problems] A compound, which is useful as an active ingredient of a pharmaceutical composition, for example, a pharmaceutical composition for treating chronic renal failure and/or diabetic nephropathy, is provided.
[Solving Means] The present inventors have conducted extensive studies on a compound having an EP4 receptor antagonistic activity, and confirmed that the amide compound of the present invention has an EP4 receptor antagonistic activity, thereby completing the present invention. The amide compound of the present invention has an EP4 receptor antagonistic activity, and can be used as an active ingredient of a pharmaceutical composition for preventing and/or treating various EP4-related diseases, for example, chronic renal failure and/or diabetic nephropathy, and the like.

1.ApplicationNumber: US-99238809-A
1.PublishNumber: US-8598355-B2
2.Date Publish: 20131203
3.Inventor: NOZAWA EISUKE
IBUKA RYOTARO
IKEGAI KAZUHIRO
MATSUURA KEISUKE
ZENKOH TATSUYA
SEO RYUSHI
WATANUKI SUSUMU
KAGEYAMA MICHIHITO

4.Inventor Harmonized: NOZAWA EISUKE(JP)
IBUKA RYOTARO(JP)
IKEGAI KAZUHIRO(JP)
MATSUURA KEISUKE(JP)
ZENKOH TATSUYA(JP)
SEO RYUSHI(JP)
WATANUKI SUSUMU(JP)
KAGEYAMA MICHIHITO(JP)

5.Country: US
6.Claims:
(en)[Problems] A compound, which is useful as an active ingredient of a pharmaceutical composition, for example, a pharmaceutical composition for treating chronic renal failure and/or diabetic nephropathy, is provided.
[Solving Means] The present inventors have conducted extensive studies on a compound having an EP4 receptor antagonistic activity, and confirmed that the amide compound of the present invention has an EP4 receptor antagonistic activity, thereby completing the present invention. The amide compound of the present invention has an EP4 receptor antagonistic activity, and can be used as an active ingredient of a pharmaceutical composition for preventing and/or treating various EP4-related diseases, for example, chronic renal failure and/or diabetic nephropathy, and the like.

7.Description:
(en)CROSS REFERENCES TO RELATED APPLICATIONS
This application is a 371 of International Patent Application No. PCT/JP2009/058821, filed on May 12, 2009, and claims priority to Japanese Patent Application No. 2008-127424, filed on May 14, 2008.
TECHNICAL FIELD
The present invention relates to an amide compound which is useful as an active ingredient of a pharmaceutical composition, for example, a pharmaceutical composition for treating chronic renal failure and/or diabetic nephropathy.
BACKGROUND ART
Prostaglandin E2 (hereinafter referred to as “PGE2”) is known as one of the metabolites in an arachidonic acid cascade. The PGE2 exhibits various activities, for example, a pain inducing and increasing action, a pro-inflammatory action, an anti-inflammatory action, an uterine contractile action, a digestive peristalsis promoting action, an awaking action, a gastric acid secretion inhibiting action, a hypotensive action, a platelet aggregation inhibition action, a bone resorption-promoting action, an angiogenic action, and the like.
There exist four subtypes, EP1, EP2, EP3, and EP4, for the PGE2 receptors, which have a wide distribution in various tissues. The activation of the EP1 receptor is believed to cause the increase in intracellular Ca 2+ . The EP3 receptor is one of the receptors having different routes for second-messenger systems. The activation of the EP2 and EP4 receptors is believed to cause the activation of adenylate cyclase, and thus to increase the intracellular cAMP level. In particular, it is believed that the EP4 receptor is related to relaxation of smooth muscles, promotion or inhibition of an inflammatory reaction, lymphocyte differentiation, hypertrophy or proliferation of mesangial cells, secretion of gastrointestinal mucus, and the like.
An inhibitor of a PGE2 receptor, that is, a PGE2 antagonist has a binding activity to the PGE2 receptor. That is, the PGE2 antagonist exhibits a PGE2 antagonistic activity or a PGE2 inhibitory activity. Accordingly, the PGE2 antagonist is expected to be a drug for treating diseases caused by PGE2. Among these, the EP4 receptor antagonist is expected to be an agent for treating EP4-related diseases, for example, renal disease, inflammatory diseases, various pains, and the like, in human and animals. In addition, the antagonist selective to the EP4 receptor is preferred from the viewpoint that it can avoid the side-effects based on the subtypes of other EP1, EP2, and EP3.
As an EP4 receptor antagonist, a compound represented by the following formula is known (Patent Document 1).









(For the symbols in the formula, refer to this publication.)
Further, as an EP4 receptor ligand, a compound represented by the following formula is known (Patent Document 2).









(For the symbols in the formula, refer to this publication.)
Further, as an EP4 receptor antagonist, a compound represented by the following formula is known (Patent Document 3). In this connection, this document was published after the priority date of the present application.









(For the symbols in the formula, refer to this publication.)
Further, as an EP4 receptor antagonist, a compound represented by the following formula is known (Patent Document 4).









(For the symbols in the formula, refer to this publication.)
Further, as an EP4 receptor antagonist, a compound represented by the following formula is known (Patent Document 5).









(For the symbols in the formula, refer to this publication.)
Further, as an EP4 receptor antagonist, a compound represented by the following formula is known (Patent Document 6).









(For the symbols in the formula, refer to this publication.)
Further, as EP4 receptor ligands, compounds represented by the following formulae are known (Patent Document 7).









(For the symbols in the formulae, refer to this publication.)
Further, as an EP3 and/or EP4 receptor antagonist, a compound represented by the following formula is known (Patent Document 8).









(For the symbols in the formula, refer to this publication.)
Further, as an EP4 receptor blocker, a compound represented by the following formula is known (Patent Document 9).









(For the symbols in the formula, refer to this publication.)
Further, as an EP4 receptor antagonist, a compound represented by the following formula is known (Patent Document 10). In this connection, this document was published after the priority date of the present application.









(For the symbols in the formula, refer to this publication.)
Further, as an EP4 receptor antagonist, a compound represented by the following formula is known (Patent Document 11). In this connection, this document was published after the priority date of the present application.









(For the symbols in the formula, refer to this publication.)
RELATED ART DOCUMENTS
Patent Documents


Patent Document 1: Pamphlet of International Publication No. WO 2007/121578
Patent Document 2: Pamphlet of International Publication No. WO 2007/143825
Patent Document 3: Pamphlet of International Publication No. WO 2008/104055
Patent Document 4: Pamphlet of International Publication No. WO 2005/021508
Patent Document 5: Pamphlet of International Publication No. WO 2005/105732
Patent Document 6: Pamphlet of International Publication No. WO 2005/105733
Patent Document 7: Pamphlet of International Publication No. WO 2008/017164
Patent Document 8: Pamphlet of International Publication No. WO 03/016254
Patent Document 9: Pamphlet of International Publication No. WO 2005/061475
Patent Document 10: Pamphlet of International Publication No. WO 2008/123207
Patent Document 11: Pamphlet of International Publication No. WO 2009/005076


SUMMARY OF THE INVENTION
Problems that the Invention is to Solve
A compound which is useful as an active ingredient of a pharmaceutical composition, for example, a pharmaceutical composition for treating chronic renal failure and/or diabetic nephropathy is provided.
Means for Solving the Problems
The present inventors have conducted extensive studies on a compound having an EP4 receptor antagonistic activity, and have found that a compound of the formula (I) exhibits excellent effectiveness, thereby completing the present invention.
That is, the present invention is related to the compound of the formula (I) or a salt thereof, and a pharmaceutical composition comprising the compound of the formula (I) or a salt thereof and a pharmaceutically acceptable excipient.









(wherein
Ring D is a group of the formula (II), the formula (III), the formula (IV), the formula (V), or the formula (VI),









Ring D 1 is a monocyclic or bicyclic nitrogen-containing hetero ring which may be substituted with phenyl,
Ring D 2 is aryl, a hetero ring, or C 3-10 cycloalkyl,
R 41 , R 42 , R 43 and R 44 are the same as or different from each other, and are each —X 2 —B 4 ,
R 45 is —X 1 —B 5 ,
R 46 is —H, halogen, C 1-6 alkyl which may be substituted with one or more halogens, or —O—C 1-6 alkyl,
V and W are the same as or different from each other, and are CH or N, provided that there is no case where V and W are N at the same time,
X 1 is a bond, C 1-6 alkylene, (C 1-6 alkylene)-CONH—, (C 1-6 alkylene)-O—, (C 1-6 alkylene)-O—(C 1-6 alkylene), or C 2-6 alkenylene,
X 2 is a bond, C 1-6 alkylene, (C 1-6 alkylene)-CONH—, (C 1-6 alkylene)-O—, (C 1-6 alkylene)-O—(C 1-6 alkylene), C 2-6 alkenylene, —O—, —S—, —NH—, —N(C 1-6 alkylene)-, —N(C 1-6 alkylene)-(C 1-6 alkylene), or —O—(C 1-6 alkylene),
B 4 is aryl, a hetero ring, or C 3-10 cycloalkyl, each of which may be substituted with the same or different 1 to 5 groups selected from R 4 ,
R 4 is a group consisting of halogen, —OH, —O—(C 1-6 alkyl), —O—(C 1-6 alkylene)-O—(C 1-6 alkyl), aryl which may be substituted, a hetero ring which may be substituted, (C 1-6 alkylene)-aryl, (C 1-6 alkylene)-hetero ring, —O—(C 1-6 alkylene)-aryl, and —O—(C 1-6 alkylene)-hetero ring,
B 5 represents (i) a bicyclic hetero ring which may be substituted with one or more groups selected from the group consisting of halogen and C 1-6 alkyl, or (ii) monocyclic aryl, a monocyclic hetero ring, or C 3-10 monocyclic cycloalkyl, each of which is substituted with the same or different 1 to 5 groups selected from R 5 ,
R 5 is a group consisting of halogen, —OH, —O—(C 1-6 alkyl), —O—(C 1-6 alkylene)-O—(C 1-6 alkyl), aryl which may be substituted, a hetero ring which may be substituted, (C 1-6 alkylene)-aryl, (C 1-6 alkylene)-hetero ring, —O—(C 1-6 alkylene)-aryl, and —O—(C 1-6 alkylene)-hetero ring: provided that when X 1 is a bond, methylene, or ethylene, Y is CH, R 2 is methyl, Ring E is phenylene, Z is a bond, and R 3 is —CO 2 H; R 5 is a group consisting of —OH, —O—(C 1-6 alkyl), —O—(C 1-6 alkylene)-O—(C 1-6 alkyl), aryl which may be substituted, a hetero ring which may be substituted, (C 1-6 alkylene)-aryl, (C 1-6 alkylene)-hetero ring, —O—(C 1-6 alkylene)-aryl, and —O—(C 1-6 alkylene)-hetero ring,
Ring E is phenylene or C 5-7 cycloalkanediyl,
R 1 and R 2 are the same as or different from each other, and are H or C 1-6 alkyl, provided that when R 5 is a bicyclic hetero ring which may be substituted, R 2 is —H,
Y is CH or N,
Z is a bond or C 1-6 alkylene, and
R 3 is —CO 2 H or a biological equivalent thereof,
provided that when Ring D is phenyl which may be substituted or pyridyl which may be substituted, Y is CH, and Z is a bond, R 3 represents a group other than —CO 2 H, tetrazolyl, and sulfonamide).
In this connection, unless otherwise specifically described, when a symbol in a chemical formula in the present specification is used in other chemical formulae, the symbol represents the same meaning.
Furthermore, the present invention relates to a pharmaceutical composition for preventing or treating chronic renal failure and/or diabetic nephropathy, which contains the compound of the formula (I) or a salt thereof. In this connection, this pharmaceutical composition includes an agent for preventing or treating chronic renal failure and/or diabetic nephropathy, which contains the compound of the formula (I) or a salt thereof.
Furthermore, the present invention relates to use of the compound of the formula (I) or a salt thereof for the manufacture of a pharmaceutical composition for preventing or treating chronic renal failure and/or diabetic nephropathy, the compound of the formula (I) or a salt thereof for use in the prevention and treatment of chronic renal failure and/or diabetic nephropathy, and a method for preventing or treating chronic renal failure and/or diabetic nephropathy, comprising administering an effective amount of the compound of the formula (I) or a salt thereof to a subject. In this connection, the “subject” is a human or a non-human animal in need of the prevention or treatment, and in a certain embodiment, is a human in need of the prevention or treatment.
Effects of the Invention
The compound of the formula (I) or a salt thereof has an EP4 receptor antagonistic activity, and can be used as an active ingredient of a pharmaceutical composition for preventing and/or treating chronic renal failure and/or diabetic nephropathy.


MODE FOR CARRYING OUT THE INVENTION
Hereinbelow, the present invention will be described in detail.
In the present specification, the “alkyl” includes linear alkyl and branched alkyl. Thus, the C 1-6 alkyl is a linear or branched alkyl having 1 to 6 carbon atoms, and specifically, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, or the like. In a certain embodiment, it is methyl, ethyl, n-propyl, or isopropyl, in a further embodiment, methyl, or ethyl, and in yet another embodiment, methyl.
The “alkylene” is a divalent group formed by removing any one of the hydrogen atoms of the “alkyl” above. Thus, the C 1-6 alkylene is a linear or branched alkylene having 1 to 6 carbon atoms, and specifically, for example, methylene, ethylene, trimethylene, or the like, and in a further embodiment, methylene.
The “alkenylene” is a divalent group in which any one or more single bonds in the “alkylene” above are double bonds, and thus, the C 2-6 alkenylene is linear or branched alkenylene having 2 to 6 carbon atoms, and specifically, for example, vinylene, propenylene, isopropenylene, or the like, and in a further embodiment, vinylene.
The “halogen” means F, Cl, Br, or I.
Thus, the “C 1-6 alkyl which may be substituted with one or more halogens” is, in addition to C 1-6 alkyl which is not substituted with halogen, C 1-6 alkyl which is substituted with one or more halogens which are the same or different, and specifically, for example, trifluoromethyl, fluoromethyl, difluoromethyl, 2-fluoroethyl, 3-fluoropropyl, or the like.
The “cycloalkyl” is a saturated hydrocarbon ring group, which may be bridged or may be condensed with a benzene ring. Thus, the C 3-10 cycloalkyl is a saturated carbon ring having 3 to 10 carbon atoms, and specifically, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecanyl, norbornyl, bicyclo[2.2.2]octyl, adamantyl, indanyl, 1,2,3,4-tetrahydronaphthyl, or the like. In a certain embodiment, it is C 3-6 cycloalkyl, and in yet another embodiment, C 5-6 cycloalkyl. The “monocyclic cycloalkyl” means a monocyclic saturated hydrocarbon ring group, and thus, the C 3-10 monocyclic cycloalkyl is specifically, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or the like. The “cycloalkanediyl” is a divalent group formed by removing any one of the hydrogen atoms of the “cycloalkyl” above. Thus, the C 5-7 cycloalkanediyl is specifically, for example, cyclopentane-1,3-diyl, cyclohexane-1,3-diyl, cyclohexane-1,4-diyl, cycloheptane-1,3-diyl, or cycloheptane-1,4-diyl, and in a certain embodiment, cyclohexane-1,4-diyl.
The “aryl” is a C 6-14 mono- to tricyclic aromatic hydrocarbon ring group, and includes a partially hydrogenated ring group thereof. It is specifically, for example, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl, or the like. In a certain embodiment, it is phenyl or naphthyl, and in a further embodiment, phenyl. The “monocyclic aryl” means a monocyclic aromatic hydrocarbon ring group, and specifically, for example, phenyl.
The “hetero ring” means a ring group containing i) a monocyclic 3- to 8-membered ring containing 1 to 4 hetero atoms selected from oxygen, sulfur, and nitrogen, and in a certain embodiment, a 5- to 7-membered hetero ring, and ii) a bi- to tricyclic hetero ring containing 1 to 5 hetero atoms selected from oxygen, sulfur, and nitrogen, which is formed by condensation of the monocyclic hetero ring and one or two selected from a monocyclic hetero ring, a benzene ring, C 5-8 cycloalkane, and C 5-8 cycloalkene. The ring atom, sulfur or nitrogen, may be oxidized to form an oxide or a dioxide.
Examples of the “hetero ring” include the following groups.
(1) Monocyclic Saturated Hetero Ring Group
i) those containing 1 to 4 nitrogen atoms, specifically azepanyl, diazepanyl, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrazolidinyl, piperazinyl, and the like;
ii) those containing 1 to 3 nitrogen atoms and 1 to 2 sulfur atoms and/or 1 to 2 oxygen atoms, specifically a thiomorpholinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, morpholinyl, and the like;
iii) those containing 1 to 2 sulfur atoms, specifically tetrahydrothiinyl and the like;
iv) those containing 1 to 2 sulfur atoms and 1 to 2 oxygen atoms, specifically oxathiolane and the like; and
v) those containing 1 to 2 oxygen atoms, specifically oxiranyl, dioxolanyl, oxolanyl, tetrahydropyranyl, 1,4-dioxanyl, and the like;
(2) Monocyclic Unsaturated Hetero Ring Group
i) those containing 1 to 4 nitrogen atoms, specifically pyrrolyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, dihydrotriazinyl, azepinyl, and the like;
ii) those containing 1 to 3 nitrogen atoms and 1 to 2 sulfur atoms and/or 1 to 2 oxygen atoms, specifically thiazolyl, isothiazolyl, thiadiazolyl, dihydrothiazinyl, oxazolyl, isoxazolyl, oxadiazolyl, oxadinyl, and the like;
iii) those containing 1 to 2 sulfur atoms, specifically thienyl, thiepinyl, dihydrodithiinyl, dihydrodithionyl, and the like;
iv) those containing 1 to 2 sulfur atoms and 1 to 2 oxygen atoms, specifically dihydrooxathiinyl and the like; and
v) those containing 1 to 2 oxygen atoms, specifically furyl, pyranyl, oxepinyl, dioxolyl, and the like;
(3) Condensed Polycyclic Saturated Hetero Ring Group
i) those containing 1 to 5 nitrogen atoms, specifically quinuclidine, 7-azabicyclo[2.2.1]heptyl, 3-azabicyclo[3.2.2]nonanyl, and the like;
ii) those containing 1 to 4 nitrogen atoms, and 1 to 3 sulfur atoms and/or 1 to 3 oxygen atoms, specifically trithiadiazaindenyldioxoloimidazolidinyl and the like; and
iii) those containing 1 to 3 sulfur atoms and/or 1 to 3 oxygen atoms, specifically 2,6-dioxabicyclo[3.2.2]oct-7-yl and the like;
(4) Condensed Polycyclic Unsaturated Hetero Ring Group
i) those containing 1 to 5 nitrogen atoms, specifically indolyl, isoindolyl, indolinyl, indolidinyl, benzimidazolyl, quinolyl, tetrahydroquinolyl, isoquinolyl, tetrahydroisoquinolyl, indazolyl, imidazopyridyl, benzotriazolyl, tetrazolopyridazinyl, carbazolyl, quinoxalinyl, dihydroindazolyl, benzopyrimidinyl, naphthyridinyl, quinazolinyl, cinnolinyl, and the like;
ii) those containing 1 to 4 nitrogen atoms, and 1 to 3 sulfur atoms and/or 1 to 3 oxygen atoms, specifically benzothiazolyl, dihydrobenzothiazolyl, benzothiadiazolyl, imidazothiazolyl, imidazothiadiazolyl, benzoxazolyl, benzoxadiazolyl, and the like;
iii) those containing 1 to 3 sulfur atoms, specifically benzothienyl, benzodithiinyl, and the like;
iv) those containing 1 to 3 sulfur atoms and 1 to 3 oxygen atoms, specifically benzoxathiinyl, phenoxadinyl, and the like; and
v) those containing 1 to 3 oxygen atoms, specifically benzodioxolyl, benzofuranyl, isobenzofuranyl, chromenyl, benzodihydrofuranyl, and the like.
The “nitrogen-containing hetero ring” means, among the aforementioned hetero rings, a ring group selected from i) and ii) of (1), i) and ii) of (2), i) and ii) of (3), and i) and ii) of (4), and the like. In a certain embodiment, it is a ring group having a bond on the nitrogen atom constituting the ring.
Specific examples of the “monocyclic or bicyclic nitrogen-containing hetero ring” in Ring D 1 include pyrrole, pyrrolofuran, pyrrolothiophene, indole, benzimidazole, indazole, and 4,5,6,7-tetrahydroindole.
Specific examples of the “hetero ring” in Ring D 2 include benzothiophene, 4,5,6,7-tetrahydrobenzothiophene, and pyridine.
Specific examples of the “hetero ring” in B 4 include quinolyl, isoquinolyl, oxazole, thiazole, and indole.
Specific examples of the “hetero ring” in R 4 include pyridine, thiazole, oxazole, and imidazole.
Specific examples of the “bicyclic hetero ring” in B 5 include quinoline, isoquinoline, benzofuran, benzothiophene, benzoxazole, benzothiazole, indole, quinoxaline, naphthylidine, quinazoline, cinnoline, and benzimidazole. In a further embodiment, the examples include quinoline, isoquinoline, benzofuran, benzothiophene, benzoxazole, and benzothiazole.
Specific examples of the “monocyclic hetero ring” in B 5 include thiazole, oxazole, pyridine, thiophene, furan, pyrrole, imidazole, triazole, oxadiazole, thiadiazole, pyrazine, pyrimidine, pyridazine, piperidine, pyrrolidine, azepan, tetrahydropyran, tetrahydrothiopyran, and piperazine. In a further embodiment, the examples include thiazole, oxazole, pyridine, thiophene, piperidine, and tetrahydropyran.
Specific examples of the “hetero ring” in R 5 include piperidine, piperazine, morpholine, thiomorpholine, pyridine, thiazole, oxazole, and imidazole. In a further embodiment, the examples include piperidine.
Further, the ring above is described as the name of the ring itself, or a monovalent ring thereof, but if necessary, it may be a monolvalent, divalent, or higher valent ring group formed by removing hydrogen atom(s) at an arbitrary position.
The “—CO 2 H or a biological equivalent thereof” means —CO 2 H, or another atom or atom group which has an electronic or steric configuration equivalent to —CO 2 H, can release acidic protons, and has common biological properties. Examples thereof include —CO 2 H, hydroxamic acid (—CO—NH—OH, —CO—NH—O—C 1-6 alkyl), sulfonamide (—NH—SO 2 —C 1-6 alkyl), acylcyanamide (—CO—NH—CN), acyl sulfonamide (—CO—NH—SO 2 —C 1-6 alkyl), —SO 2 —NH—CO—C 1-6 alkyl, or tetrazolyl, oxadiazolonyl, oxadiazolethionyl, oxathiadiazolyl, thiadiazolonyl, triazolethionyl, hydroxyisoxazolyl, and the like, in a further embodiment, the examples include —CO 2 H, acyl sulfonamide (—CO—NH—SO 2 —C 1-6 alkyl), hydroxamic acid (—CO—NH—OH, —CO—NH—O—C 1-6 alkyl), and tetrazolyl, and in yet another embodiment, the examples include —CO 2 H. Further, C 1-6 alkyl in the biological equivalent of —CO 2 H may be substituted with —OH or —O—C 1-6 alkyl.
In the present specification, the expression “may be substituted” means unsubstituted or substituted with the same or different 1 to 5 substituents. In this connection, when there is a plurality of substituents, these substituents may be the same as or different from each other.
Examples of the acceptable substituent in “aryl which may be substituted” and the “hetero ring which may be substituted” in R 4 and R 5 include halogen, C 1-6 alkyl which may be substituted with one or more halogens, —O—(C 1-6 alkyl which may be substituted with one or more halogens), and —OH.
Further, R 46 in the formula (II) is a substituent which substitutes the hydrogen atoms on the atom constituting the ring, and for example, when V or W represents CH, the hydrogen atom of the CH may be substituted with R 46 . Thus, the expression “V or W is CH” means a case where the hydrogen atom is substituted with R 46 , that is, V or W may be C(—R 46 ).
Certain embodiments of the compound of the formula (I) or a salt thereof are presented below.
(1) A compound or a salt thereof, in which Ring D is a group of the formula (II).
(2) The compound or a salt thereof, in which R 46 is —H, fluoro, chloro, methyl, or trifluoromethyl. In another embodiment, the compound or a salt thereof, in which R 46 is fluoro, chloro, methyl, or trifluoromethyl. In yet another embodiment, the compound or a salt thereof, in which R 46 is trifluoromethyl. In yet another embodiment, the compound or a salt thereof, in which R 46 is substituted on the atom constituting the ring represented by V or W (that is, R 46 is substituted at the 5- or 6-position of the indole). In yet another embodiment, the compound or a salt thereof, in which R 46 is substituted on the atom constituting the ring represented by V (that is, R 46 is substituted at the 5-position of the indole). In yet another embodiment, the compound or a salt thereof, in which R 46 is fluoro, chloro, methyl, or trifluoromethyl substituted on the atom constituting the ring represented by V. In yet another embodiment, the compound or a salt thereof, in which R 46 is trifluoromethyl substituted on the atom constituting the ring represented by V.
(3) The compound or a salt thereof, in which V is CH and W is CH. In another embodiment, the compound or a salt thereof, in which V is N and W is CH. In yet another embodiment, the compound or a salt thereof, in which V is CH and W is N.
(4) The compound or a salt thereof, in which X 1 is C 1-6 alkylene or (C 1-6 alkylene)-O—. In another embodiment, the compound or a salt thereof, in which X 1 is methylene. In yet another embodiment, the compound or a salt thereof, in which X 1 is —CH 2 CH 2 —O—.
(5) The compound or a salt thereof, in which B 5 is a bicyclic hetero ring which may be substituted with one or more groups selected from the group consisting of halogen and C 1-6 alkyl. In another embodiment, the compound or a salt thereof, in which B 5 is quinolyl, isoquinolyl, benzofuryl, or benzothienyl, each of which may be substituted with one or more groups selected from the group consisting of halogen and C 1-6 alkyl. In yet another embodiment, the compound or a salt thereof, in which B 5 is quinolyl, isoquinolyl, benzofuryl, or benzothienyl. In yet another embodiment, the compound or a salt thereof, in which B 5 is quinolyl. In yet another embodiment, the compound or a salt thereof, in which B 5 is isoquinolyl. In yet another embodiment, the compound or a salt thereof, in which B 5 is benzofuryl. In yet another embodiment, the compound or a salt thereof, in which B 5 is benzothienyl. In yet another embodiment, the compound or a salt thereof, in which B 5 is quinolin-2-yl. In yet another embodiment, the compound or a salt thereof, in which B 5 is quinolin-3-yl. In yet another embodiment, the compound or a salt thereof, in which B 5 is quinolin-5-yl. In yet another embodiment, the compound or a salt thereof, in which B 5 is quinolin-6-yl. In yet another embodiment, the compound or a salt thereof, in which B 5 is quinolin-7-yl. In yet another embodiment, the compound or a salt thereof, in which B 5 is quinolin-8-yl. In yet another embodiment, the compound or a salt thereof, in which B 5 is isoquinolin-1-yl. In yet another embodiment, the compound or a salt thereof, in which B 5 is isoquinolin-3-yl. In yet another embodiment, the compound or a salt thereof, in which B 5 is isoquinolin-5-yl. In yet another embodiment, the compound or a salt thereof, in which B 5 is isoquinolin-7-yl. In yet another embodiment, the compound or a salt thereof, in which B 5 is monocyclic aryl, a monocyclic hetero ring, or C 3-10 monocyclic cycloalkyl, each of which is substituted with group(s) selected from R 5 . In yet another embodiment, the compound or a salt thereof, in which B 5 is a phenyl substituted with halogen(s). In yet another embodiment, the compound or a salt thereof, in which B 5 is a monocyclic hetero ring substituted with aryl. In yet another embodiment, the compound or a salt thereof, in which B 5 is thiazolyl substituted with phenyl. In yet another embodiment, the compound or a salt thereof, in which B 5 is pyridyl substituted with phenyl.
(6) The compound or a salt thereof, in which Ring E is 1,4-phenylene or cyclohexane-1,4-diyl. In another embodiment, the compound or a salt, in which Ring E is 1,4-phenylene. In yet another embodiment, the compound or a salt in which Ring E is cyclohexane-1,4-diyl.
(7) The compound or a salt thereof, in which R 1 is —H.
(8) The compound or a salt thereof, in which R 2 is —H or methyl. In another embodiment, the compound or a salt in which R 2 is —H.
(9) The compound or a salt thereof, in which Y is CH.
(10) The compound or a salt thereof, in which Z is a bond.
(11) The compound or a salt thereof, in which R 3 is —CO 2 H. In another embodiment, the compound or a salt, in which R 3 is a biological equivalent of —CO 2 H.
(12) The compound or a salt thereof which has a combination of two or more of the groups described in (1) to (11) above.
The present invention includes the compound or a salt thereof which has a combination of two or more of the groups described in (1) to (11) above, as described in (12), and as specific examples thereof, the following embodiments are also exemplified.
(13) The compound or a salt thereof, in which Ring D is a group of the formula (II).
(14) The compound or a salt thereof of (13), in which V is CH and W is CH.
(15) The compound or a salt thereof of (14), in which Ring E is 1,4-phenylene or cyclohexane-1,4-diyl, Z is a bond, and R 3 is —CO 2 H.
(16) The compound or a salt thereof of (15), in which R 1 is —H and R 2 is —H or methyl.
(17) The compound or a salt thereof of (16), in which Y is CH and R 2 is —H.
(18) The compound or a salt thereof of (17), in which X 1 is —CH 2 CH 2 —O— and B 5 is phenyl substituted with halogen(s).
(19) The compound or a salt thereof of (18), in which E is 1,4-phenylene.
(20) The compound or a salt thereof of (18), in which E is cyclohexane-1,4-diyl.
(21) The compound or a salt thereof of (17), in which X 1 is methylene.
(22) The compound or a salt thereof of (21), in which E is 1,4-phenylene.
(23) The compound or a salt thereof of (21), in which E is cyclohexane-1,4-diyl.
(24) The compound or a salt thereof of (22) or (23), in which B 5 is a bicyclic hetero ring which may be substituted with one or more groups selected from the group consisting of halogen and C 1-6 alkyl.
(25) The compound or a salt thereof of (24), in which B 5 is quinolyl, isoquinolyl, benzofuryl, or benzothienyl, each of which may be substituted with one or more groups selected from the group consisting of fluoro, chloro, and methyl.
(26) The compound or a salt thereof of (25), in which B 5 is quinolyl which may be substituted with fluoro(s). In another embodiment, the compound or a salt thereof of (25), in which B 5 is quinolin-2-yl which may be substituted with fluoro(s). In yet another embodiment, the compound or a salt thereof of (25), in which B 5 is quinolin-3-yl. In yet another embodiment, the compound or a salt thereof of (25), in which B 5 is quinolin-5-yl. In yet another embodiment, the compound or a salt thereof of (25), in which B 5 is quinolin-6-yl. In yet another embodiment, the compound or a salt thereof of (25), in which B 5 is quinolin-7-yl. In yet another embodiment, the compound or a salt thereof of (25), in which B 5 is quinolin-8-yl.
(27) The compound or a salt thereof of (25), in which B 5 is isoquinolyl. In another embodiment, the compound or a salt thereof of (25), in which B 5 is isoquinolin-1-yl. In yet another embodiment, the compound or a salt thereof of (25), in which B 5 is isoquinolin-3-yl. In yet another embodiment, the compound or a salt thereof of (25), in which B 5 is isoquinolin-5-yl. In yet another embodiment, the compound or a salt thereof of (25), in which B 5 is isoquinolin-7-yl.
(28) The compound or a salt thereof of (22) or (23), in which B 5 is a monocyclic hetero ring which is substituted with 1 to 5 groups selected from R 5 , and R 5 is aryl.
(29) The compound or a salt thereof of (28), in which B 5 is thiazolyl and R 5 is phenyl.
(30) The compound or a salt thereof of (28), in which B 5 is pyridyl and R 5 is phenyl.
Furthermore, specific examples encompassed by the compound of the formula (I) or a salt thereof include the following examples.
4-[({[5-chloro-1-(quinolin-2-ylmethyl)-1H-indol-7-yl]carbonyl}amino)methyl]benzoic acid, trans-4-[({[5-methyl-1-(quinolin-2-ylmethyl)-1H-indol-7-yl]carbonyl}amino)methyl]cyclohexane carboxylic acid, trans-4-[({[5-fluoro-1-(quinolin-2-ylmethyl)-1H-indol-7-yl]carbonyl}amino)methyl]cyclohexane carboxylic acid, 4-[({[1-(quinolin-2-ylmethyl)-5-(trifluoromethyl)-1H-indol-7-yl]carbonyl}amino)methyl]benzoic acid, trans-4-[({[1-(quinolin-2-ylmethyl)-5-(trifluoromethyl)-1H-indol-7-yl]carbonyl}amino)methyl]cyclohexane carboxylic acid, trans-4-[({[5-chloro-1-(isoquinolin-3-ylmethyl)-1H-indol-7-yl]carbonyl}amino)methyl]cyclohexane carboxylic acid, trans-4-[({[1-(isoquinolin-3-ylmethyl)-5-(trifluoromethyl)-1H-indol-7-yl]carbonyl}amino)methyl]cyclohexane carboxylic acid, trans-4-{[({5-chloro-1-[(2-phenyl-1,3-thiazol-4-yl)methyl]-1H-indol-7-yl}carbonyl)amino]methyl}cyclohexane carboxylic acid, 4-{[({5-chloro-1-[2-(4-chlorophenoxy)ethyl]-1H-indol-7-yl}carbonyl)amino]methyl}benzoic acid, trans-4-{[({5-chloro-1-[2-(4-chlorophenoxy)ethyl]-1H-indol-7-yl}carbonyl)amino]methyl}cyclohexane carboxylic acid, 4-{[({1-[(2-phenyl-1,3-thiazol-4-yl)methyl]-5-(trifluoromethyl)-1H-indol-7-yl}carbonyl)amino]methyl}benzoic acid, trans-4-{[({1-[(2-phenyl-1,3-thiazol-4-yl)methyl]-5-(trifluoromethyl)-1H-indol-7-yl}carbonyl)amino]methyl}cyclohexane carboxylic acid, trans-4-{[({1-[(5-phenylpyridin-2-yl)methyl]-5-(trifluoromethyl)-1H-indol-7-yl}carbonyl)amino]methyl}cyclohexane carboxylic acid, 4-{[({1-[2-(4-chlorophenoxy)ethyl]-5-(trifluoromethyl)-1H-indol-7-yl}carbonyl)amino]methyl}benzoic acid, trans-4-[({[1-(isoquinolin-3-ylmethyl)-5-methyl-1H-indol-7-yl]carbonyl}amino)methyl]cyclohexane carboxylic acid, trans-4-[({[5-fluoro-1-(isoquinolin-3-ylmethyl)-1H-indol-7-yl]carbonyl}amino)methyl]cyclohexane carboxylic acid, trans-4-[({[6-fluoro-1-(isoquinolin-3-ylmethyl)-1H-indol-7-yl]carbonyl}amino)methyl]cyclohexane carboxylic acid, trans-4-[({[1-(1-benzofuran-2-ylmethyl)-5-chloro-1H-indol-7-yl]carbonyl}amino)methyl]cyclohexane carboxylic acid, trans-4-[({[1-(1-benzofuran-2-ylmethyl)-5-(trifluoromethyl)-1H-indol-7-yl]carbonyl}amino)methyl]cyclohexane carboxylic acid, trans-4-[({[(5-chloropyridin-2-yl)methyl]-5-(trifluoromethyl)-1H-indol-7-yl}carbonyl)amino]methyl}cyclohexane carboxylic acid, and trans-4-{[({1-[(5-chloro-1-benzofuran-2-yl)methyl]-5-(trifluoromethyl)-1H-indol-7-yl}carbonyl)amino]methyl}cyclohexane carboxylic acid, and salts thereof.

Furthermore, specific examples encompassed by the compound of the formula (I) or a salt thereof also include the following compounds.
4-{(1S)-1-[({1-[2-(4-chlorophenoxy)ethyl]-1H-indol-7-yl}carbonyl)amino]ethyl}benzoic acid, 4-[2-({1-[2-(4-chlorophenoxy)ethyl]-1H-indol-7-yl}carbonyl)-1-methylhydrazino]benzoic acid, trans-4-[({[5-chloro-1-(quinolin-2-ylmethyl)-1H-indol-7-yl]carbonyl}amino)methyl]cyclohexane carboxylic acid, trans-4-[({[1-(4-chlorobenzyl)-5-(trifluoromethyl)-1H-indol-7-yl]carbonyl}amino)methyl]cyclohexane carboxylic acid, trans-4-[({[1-(4-chlorobenzyl)-5-methyl-1H-indol-7-yl]carbonyl}amino)methyl]cyclohexane carboxylic acid, 4-[({[5-methyl-1-(quinolin-2-ylmethyl)-1H-indol-7-yl]carbonyl}amino)methyl]benzoic acid, 4-[({[1-(1-benzofuran-2-ylmethyl)-1H-indol-7-yl]carbonyl}amino)methyl]benzoic acid, trans-4-[({[1-(1-benzofuran-2-ylmethyl)-1H-indol-7-yl]carbonyl}amino)methyl]cyclohexane carboxylic acid, trans-4-[({[1-(1-benzothiophen-2-ylmethyl)-1H-indol-7-yl]carbonyl}amino)methyl]cyclohexane carboxylic acid, 4-[1-methyl-2-({1-[(2-phenyl-1,3-thiazol-4-yl)methyl]-1H-indol-7-yl}carbonyl)hydrazino]benzoic acid, 4-{[({5-chloro-1-[(2-phenyl-1,3-thiazol-4-yl)methyl]-1H-indol-7-yl}carbonyl)amino]methyl}benzoic acid,
and salts thereof.


With regard to some of the compounds of the formula (I) or salts thereof, tautomers or geometrical isomers thereof can be existed, depending on the kinds of the substituents. In the present specification, the compound of the formula (I) or a salt thereof may be described in only one form of isomers, but the present invention includes other isomers, isolated forms of the isomers, or a mixture thereof.
Furthermore, some of the compounds of the formula (I) or salts thereof, may have asymmetric carbon atoms or asymmetries, and correspondingly, the optical isomers thereof can be existed. The present invention includes the isolated form of the optical isomer of the compound of the formula (I) or a salt thereof or a mixture thereof.
Additionally, pharmaceutically acceptable prodrugs of the compound of the formula (I) or a salt thereof are also included in the present invention. The pharmaceutically acceptable prodrug refers to a compound having a group which can be converted into an amino group, a hydroxyl group, a carboxyl group, or the like, by solvolysis or under a physiological condition. Examples of the groups for forming a prodrug include those as described in Prog. Med., 5, 2157-2161 (1985) or “Pharmaceutical Research and Development” (Hirokawa Publishing Company, 1990), vol. 7, Drug Design, 163-198.
Furthermore, the salt of the compound of the formula (I) is a pharmaceutically acceptable salt of the compound of the formula (I), and some of the compounds of the formula (I) may form an acid addition salt or a salt with a base, depending on the kinds of the substituents. Specifically, examples thereof include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyl tartaric acid, ditolyl tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid, and the like, and salts with inorganic bases such as sodium, potassium, magnesium, calcium, aluminum, and the like, and with organic bases such as methylamine, ethylamine, ethanolamine, lysine, ornithine, and the like, salts with various amino acids such as acetyl leucine and the like or derivatives of amino acids, ammonium salts, and others.
Additionally, the present invention also includes various hydrates or solvates, and polymorphism of the compound of the formula (I) and a salt thereof. Furthermore, the present invention also includes the compounds labeled with various radioactive or non-radioactive isotopes.
(Production Processes)
The compound of the formula (I) or a salt thereof can be prepared by applying various known synthetic methods, using the characteristics based on their basic structures or the kinds of the substituents. At this time, depending on the types of the functional groups, it is in some cases effective from the viewpoint of the preparation techniques to protect the functional group with an appropriate protecting group (a group which is capable of being easily converted into the functional group), during the steps from starting materials to intermediates. Examples of the protecting group include the protective groups as described in “Greene's Protective Groups in Organic Synthesis (4th edition, 2006)”, edited by P. G. M. Wuts and T. W. Greene, and the like, which may be appropriately selected and used depending on the reaction conditions. In these methods, a desired compound can be obtained by introducing the protecting group to carry out the reaction, and then, if desired, removing the protecting group.
Additionally, the prodrug of the compound of the formula (I) or a salt thereof can be prepared by introducing a specific group during the steps from starting materials to intermediates, in the same manner as for the above protecting groups, or by further carrying out the reaction using the obtained compound of the formula (I) or a salt thereof. The reaction can be carried out by applying a method known by a person skilled in the art, such as general esterification, amidation, dehydration, and the like.
Hereinbelow, typical production processes of the compound of the formula (I) will be described. Each of the production processes can also be carried out with reference to the documents appended to the description herein. In this connection, the production process of the compound of the formula (I) is not limited to the examples as shown below.
(Production Process 1)









The present production process is a method for obtaining the compound of the formula (I) by reacting a compound 1a with a compound 1b.
The reaction is carried out using an equivalent amount of the compound 1a and the compound 1b or an excessive amount of either thereof, by stirring under cooling to under heating, preferably at −20° C. to 60° C., usually for 0.1 hour to 5 days, in a solvent which is inert to the reaction, in the presence of a condensing agent. Here, the solvent is not particularly limited, but examples thereof include aromatic hydrocarbons such as benzene, toluene, xylene, or the like, halogenated hydrocarbons such as dichloromethane (DCM), 1,2-dichloroethane (DCE), chloroform, or the like, ethers such as diethyl ether, tetrahydrofuran (THF), dioxane, dimethoxyethane (DME), and the like, N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), ethyl acetate, acetonitrile, water, or a mixture thereof. As the condensing agent, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridin-1-ium-3-oxide hexafluorophosphate (HATU), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI.HCl), dicyclohexylcarbodiimide (DCC), 1,1′-carbonyldiimidazole (CDI), diphenylphosphoric azide, phosphorus oxychloride, a condensing agent-carrying polystyrene resin, for example, a PS-carbodiimide (Argonaut Technologies, Inc., USA), or the like may be preferably used in some cases, but is not limited thereto. It may be preferable in some cases for the reaction to use an additive such as, for example, 1-hydroxybenzotriazole (HOBt) and the like, and it may be advantageous in some cases for the smooth progress of the reaction to carry out the reaction in the presence of, for example, an organic base such as triethylamine, N,N-diisopropylethylamine (DIPEA), N-methylmorpholine, and the like, or an inorganic base such as potassium carbonate, sodium carbonate, potassium hydroxide, and the like. Also, it is preferable to use an isocyanate-carrying polystyrene resin, for example, PS-Isocyanate (Argonaut Technologies, Inc., USA) and the like, in order to remove an excessive amine after completion of the reaction. In addition, a quaternary ammonium salt-carrying polystyrene resin, for example, MP-Carbonate (Argonaut Technologies, Inc., USA) and the like can be used, in order to remove excessive carboxylic acid and the aforementioned additives, and the like, after completion of the reaction.
Furthermore, a method, in which the compound 1a is lead into a reactive derivative thereof, and then the reactive derivative is reacted with the compound 1b, can also be used. Here, examples of the reactive derivative of the compound 1a include acid halides obtained by the reaction with a halogenating agent such as phosphorus oxychloride, thionyl chloride, and the like, mixed acid anhydrides obtained by the reaction with isobutyl chloroformate or the like, active esters obtained by condensation with HOBt or the like, and others. The reaction of these reactive derivatives and the compound 1b can be carried out under cooling to under heating, preferably at −20° C. to 60° C., in a solvent which is inert to the reaction, such as halogenated hydrocarbons, aromatic hydrocarbons, ethers, and the like.
Furthermore, by subjecting to a hydrolysis condition, the compound in which R 3 is a carboxylic ester can be derived to the compound of the formula (I) in which R 3 is a carboxylic acid can be obtained. Similarly, by subjecting the compound of the formula (I) in which R 3 is a substituent having a protecting group to a suitable deprotection condition, the compound of the formula (I) having a substituent from which the protecting group is removed as R 3 can be derived.
(Production Process 2)









(In the formula, Ring F represents a monocyclic or bicyclic hetero ring or monocyclic aryl, U represents a leaving group, and U′ represents —B(OH) 2 or —B(OL)OL′. Here, L and L′ are the same as or different from each other and represent C 1-6 alkyl, or L and L′ may be combined to represent C 2-6 alkylene.)
The compound (I-b) of the present invention can be obtained by a coupling reaction of the compound (I-a) and the compound 2a.
Examples of the leaving group represented by U include halogen, methanesulfonyloxy, p-toluenesulfonyloxy, and trifluoromethanesulfonyloxy groups, and the like.
This reaction is carried out using an equivalent amount of the compound (I-a) and the compound 2a or an excessive amount of either thereof, by stirring the mixture at room temperature to under heating with reflux in a solvent which is inert to the reaction, usually for 0.1 hour to 5 days, in the presence of a base and a palladium catalyst. This reaction is preferably carried out under an inert gas atmosphere. The solvent as used herein is not particularly limited, but examples thereof include aromatic hydrocarbons, ethers, halogenated hydrocarbons, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, DMF, DMSO, water, and a mixed solvent thereof. As the base, an inorganic base such as sodium carbonate, potassium carbonate, sodium hydroxide, and the like can be used. As the palladium catalyst, tetrakis(triphenylphosphine) palladium, dichlorobis(triphenylphosphine) palladium, palladium chloride-1,1′-bis(diphenylphosphino)ferrocene, or the like can be used. Further, “Metal-Catalyzed Cross-Coupling Reactions” edited by A. d. Meijere and F. Diederich, 1st Edition, VCH Publishers Inc., 1997, or “Jikken Kagaku koza (Courses in Experimental Chemistry) (5th Edition)” edited by The Chemical Society of Japan, vol. 13 (2005) (Maruzen) can be referenced to.
(Starting Material Synthesis)
Starting Material Production Process 1









A starting material compound 1b-1 can be prepared by using a compound 3a as a starting material, depending on the type of the substituent, by either of the route A and route B above. Route A is a method in which the compound 3b is reduced into a compound 3d, which is subjected to azidation and reduction to an amino group, thereby preparing the starting material compound 1b-1. On the other hand, Route B is a method in which the, compound 3b is subjected to oximation, followed by reduction, thereby preparing the starting material compound 1b-1.
Starting Material Production Process 2









The compound 1a-1 can be prepared by an N-alkylation reaction and ester hydrolysis of a compound 4a and a compound 4b. The compound (I-a) can be prepared by an amidation reaction of the compound 1a-1 and the compound 1b.
The compound of the formula (I) is isolated and purified as their free compounds, salts thereof, hydrates, solvates, or polymorphic substances. The salt of the compound of the formula (I) can be prepared by subjecting to a conventional salt formation reaction.
Isolation and purification can be carried out by employing general chemical operations such as extraction, fractional crystallization, various types of fractional chromatography, and the like.
Various isomers can be prepared by selecting a suitable starting compound or separated by making use of the difference in the physicochemical properties among the isomers. For example, the optical isomers can be obtained by means of general optical resolution methods of racemic compounds (for example, by fractional crystallization introducing the compound into diastereomer salts with optically active bases or acids, chromatography using a chiral column or the like, and others), or can also be prepared from a suitable optically active starting compound.
The pharmacological activity of the compound of the formula (I) or a salt thereof was confirmed by the following test.
Test Example 1
Evaluation Test of Rat EP4 Receptor Affinity
Cell Culturing and Transfection
Using a 10 cm collagen-coated dish (Asahi Glass), HEK293 cells were cultured in D-MEM culture medium, the culture medium was removed at a confluence (90 to 100% density state) and washed with a phosphate buffer saline (PBS), and then the cells were detached with N,N,N′,N′-tetrakis(carboxymethyl)ethylenediamine (EDTA). The number of the cells were counted and seeded on a 15 cm collagen-coated dish to a confluence of 70%. On the next day, to an Opti-MEM culture medium at 1.2 mL/dish was added Lipofectamine 2000 (Invitrogen) at 60 μL/dish, followed by leaving to stand at room temperature for 5 minutes. A plasmid in which rat EP4 (Sequence Number 1) had been inserted into a TA cloning site of pcDNA3.1-V5-His-topo was added thereto at 15 μg/dish. After leaving to stand at room temperature for 30 minutes, the resultant was added to the dish and cultured for 20 to 24 hours. The cell culture was carried out in a CO 2 incubator (37° C., 5% CO 2 ).
Preparation of Membrane Fraction
The culture medium was removed by suction, 10 mL of cooled PBS was added thereto per 15 cm dish, and the cells were scraped using a cell scraper (Sumitomo Bakelite). They were washed with cooled PBS (1,200 rpm, 4° C., 5 min), and then suspended in 6 mL of cooled 20 mM Tris-HCl (pH 7.4; Nakalai Tesque Inc., including 5 mM EDTA (Nakalai Tesque Inc.) per dish and the resultant was homogenized using a Polytron and the homogenate was centrifuged (26,000 rpm, 20 min, 4° C.). The obtained precipitate was resuspended in cooled 20 mM Tris-HCl and homogenized again using a Polytron, and the homogenate was centrifuged (26,000 rpm, 20 min, 4° C.). The obtained precipitate was resuspended in 50 mM HEPES (pH 7.5; Dojindo Laboratories) at 1 mL per dish, homogenized using a Polytron, and freeze-stored at −80° C. as a membrane fraction. At this time, a part thereof was used for the measurement of the protein concentration. Measurement of the protein concentration was carried out in duplicate using a Bio-Rad Protein assay kit (Bio-Rad Laboratories) in accordance with the appended standard Protocol.
Binding Assay
[ 3 H]PGE2 50 μL (final concentration 0.3 nM; Perkin Elmer), 100 μL (20 μg/well) of a membrane fraction prepared from the rat EP4 expression cell and 50 μL of a test compound were mixed in a 96-well microplate (Sumitomo Bakelite), incubated at room temperature for 1 hour, filtered by suction on a UniFilter-96 GF/B (Perkin Elmer) using a FilterMate Harvester (Perkin Elmer), and then washed three times with 300 μL/well of a cooled assay buffer. Dilution of [ 3 H]PGE2 and the membrane fraction was carried out using an assay buffer (50 mM HEPES, 10 mM MgCl 2 ), and dilution of the test compound and the unlabeled PGE2 was carried out using DMSO and an assay buffer. Further, in the case of the addition of a human serum albumin (HSA), dilution was carried out using an assay buffer containing 4% HSA (final concentration 1%; Sigma). The UniFilter-96 GF/B was treated preliminarily by washing twice with 200 μL/well of a cooled assay buffer. The UniFilter-96 GF/B after filtration was dried in a dryer overnight, 50 μL/well of MicroScint20 (Perkin Elmer) was added thereto, and then the radioactivity was measured using a TopCount (Perkin Elmer). For measurement of the non-specific binding, an unlabeled PGE2 (final concentration 1 μM; Cayman) was added. All of the measurements were carried out in duplicate, and the specific binding amount was determined by subtracting the non-specific binding amount from the total binding amount. The Ki value was calculated according to the general methods.
The Ki values of several compounds of the formula (I) are shown in Table 1. In the connection, Ex represents the below-described Example Compound number.







TABLE 1




Ex
Ki (nM)










3
0.76


4
0.82


6
31


23
0.35


32
12


52
1.8


53
1.4


57
0.85


69
1.4


96
1.7


115
1.0


124
1.4


132
2.6


137
9.1


140
0.61


143
1.0


146
1.8


159
2.1


164
6.3


187
0.75


188
1.2


206
1.2


207
1.1


208
1.8


209
1.9


210
1.3


211
1.7


212
2.4


213
2.0


214
2.2


215
2.6


216
16


217
3.0


218
2.9


219
3.3


220
16


222
2.8


223
3.5


224
2.1


225
2.1


226
2.8


227
1.7


228
2.1


229
3.9


231
1.4

































































Test Example 2
Evaluation Test of EP4 Receptor Antagonistic Activity by Measurement of cAMP Amount in Human Jurkat Cells
Cell Culturing
Jurkat cells (derived from human leukemia T lymphoma) were cultured with RPMI1640 (added with 10% fetal bovine serum) using a F75 flask. After proliferation to semiconfluency, indomethacin having a final concentration of 5 μM was added thereto, and the cells were further cultured for 18 hours. The cells were collected in a 15-mL Spitz tube, prepared to be 1×10 6 cells/mL using a Cell Banker (Mitsubishi Kagaku Iatron), and stored at −80° C. until used for assay. The cells were cultured in a CO 2 incubator (37° C., 5% CO 2 ).
HTRF Assay
A cAMP HiRange kit (Cisbio international) was used for cAMP measurement. A test compound, PGE2, and the cells were diluted and prepared with an assay buffer. The test compound was prepared to have a 3-fold concentration relative to the final concentration, PGE2 was prepared to be 300 nM, and the Jurkat cells frozen stored were prepared to be 1×10 6 cells/mL by thawing them at 37° C. To a 384-well U-bottom black microplate (Corning) were added the test compound, the cells, and PGE2 in this order in each in an amount of 5 μL, followed by shaking with a plate shaker and incubating at room temperature for 30 minutes. After incubation, 5 μL of a d2 reagent which had been diluted 0.6-fold with a lysis buffer was added to each well, followed by shaking with a plate shaker. Subsequently, 5 μL of an europium cryptate reagent which had been diluted 0.6-fold with a lysis buffer was added to each well, followed by shaking with a plate shaker and incubating at room temperature for 60 minutes under light shielding. After incubation, the fluorescence of the cryptate at 620 nm and the fluorescence of the d2 at 655 nm were measured using ARVO1420 (PerkinElmer). The cAMPs of 280, 70, 17.5, 4.38, 1.09, 0.27, and 0.068 nM were measured simultaneously for creating a standard curve. All measurements were performed in quadruplicate, and inhibitory rates were calculated by determining the cAMP amount of each test sample to the value obtained by subtracting the cAMP amount of the group without addition of PGE2 from the cAMP amount of the group with addition of PGE2 of 100 nM. IC 50 values were calculated by a Logistic regression method.
In this connection, as the “assay buffer” and “lysis buffer” above, those as shown below were used:
Assay buffer; 1×HBSS (Hanks buffered salt solution, Nissui Pharmaceutical Co., Ltd.), 20 mM HEPES (pH 7.4, Nakarai Tesque), 0.5 mM IBMX (3-isobutyl-1-methylxanthine, WAKO), 0.02% CHAPS (Sigma), 0.1% Bovine serum albumin (Sigma), 2 μM Indomethacin (Sigma)
Lysis buffer; 50 mM NaPO 4 , 0.8 M KF, 1% Triton X-100, 0.2% Bovine serum albumin
As the results of evaluation, the compounds of Example 3, Example 53, Example 57, and Example 124 showed IC 50 values of 0.11 nM, 0.094 nM, 0.037 nM, and 0.15 nM, respectively.
Test Example 3
Evaluation Test of Rat EP4 Receptor Antagonistic Activity by Measurement of cAMP Amount
rEP4 cAMP HTRF Assay
CHO cells in which rat EP4 had been forced to be expressed were seeded in 96-well plates at 2×10 4 cells/100 μL and cultured overnight. The culture medium was replaced with 2 μM Indomethacin/0.1% BSA/alpha-MEM, and further, after 60 minutes, replaced with 1 mM IBMX/2 μM Indomethacin/0.1% BSA/alpha-MEM. After 10 minutes, the test compound was added, and further, after 10 minutes, PGE2 was added at a final concentration of 100 nM. The cells were cultured and reacted in a CO 2 incubator (37° C., 5% CO 2 ). After 30 minutes, the culture medium was removed and 100 μL/well of 0.2% Triton X-PBS was added for lysis of the cells. The cAMP contained in this cell lysis solution was measured with a cAMP HiRange kit (Cisbio international). The cell lysis solution was disperesed at 10 μL each into a 384-well U-bottom black microplate (Corning), and a d2 reagent and an europium cryptate reagent were added in this order to each well, each in an amount of 5 μL. It was incubated at room temperature for 60 minutes under light shielding. After incubation, the fluorescence of the cryptate at 620 nm and the fluorescence of the d2 at 655 nm were measured using ARVO1420 (PerkinElmer). The cAMPs of 280, 70, 17.5, 4.38, 1.09, 0.27, and 0.068 nM were measured simultaneously for creating a standard curve. The inhibitory rates were calculated by determining the cAMP amount of each test sample to the value obtained by subtracting the cAMP amount of the group without addition of PGE2 from the cAMP amount of the group with addition of PGE2 of 100 nM. IC 50 values are calculated by a Logistic regression method.
As the results of evaluation, the compounds of Example 3, Example 53, Example 57, and Example 124 showed IC 50 values of 0.99 nM, 0.90 nM, 0.76 nM, and 1.1 nM, respectively.
Test Example 4
Evaluation Test of In Vivo Rat EP4 Receptor Antagonistic Activity
A solution of PEG 400:20% Tween 80:aqueous 1 M NaHCO 3 solution=1:4:5 of a test compound was orally administered to a SD rat (male, 6-week old) under non-fasting conditions, and after 1 hour, ONO-4819 was administered subcutaneously to the back of the rat. After 30 minutes, Lipopolysaccharide (LPS, 0.01 mg/kg) was administered to the tail vein without anesthesia, and after 60 minutes, 0.5 mL of heparin blood was collected from the fundus under ether anesthesia. The blood sample was centrifuged (3000 rpm, 10 minutes) to separate the plasma, and then the TNF-α concentration in the rat plasma was measured by an ELISA kit (see Hepatology Research Journal, vol. 21, 252-260, 2001). A value obtained by subtracting the TNF-α concentration of the group treated with ONO-4819 from the TNF-α concentration of the group not treated with ONO-4819 was taken as 100%, and the inhibitory rates to the value were calculated for the test compounds.
The inhibitory rates of several compounds of the formula (I) are shown in Table 2. In this connection, Ex represents the below-described Example compound number.







TABLE 2




Inhibitory
Dose

Ex
rate (%)
(mg/kg)









23
51
0.01

53
45
0.01

57
113
0.03

96
57
0.01

115
60
0.03

124
105
0.03

143
70
0.03

146
88
0.01

159
68
0.03

187
58
0.03

188
88
0.01

206
72
0.01

207
83
0.03

208
35
0.01

210
67
0.03

211
43
0.01

212
52
0.01

213
75
0.01

214
62
0.01

215
71
0.01

224
71
0.003

225
77
0.003











































Test Example 5
Test to Investigate the Effect on Urine Albumin in Streptozotocin (STZ)-Induced Diabetic Rats
Eight-week old male Wistar (Crj) rats were divided into groups with unbiased urinary albumin excretion (UAE) in advance, and STZ (50 mg/kg) was intravenously administered thereto. From the next day of the administration of STZ, the test compound was continuously orally administered, and urine was periodically collected in a metabolism cage for 24 hours to measure the UAE. In this way, the effect of the test compound on improvement of early nephropathy in diabetic model rats can be confirmed.
Test Example 6
Test to Investigate the Effect on the Renal Function of 5/6 Nephrectomy Chronic Renal Failure (5/6 Nx) Rats
8-Week-old Wistar male rats were used for the test. Two-thirds of the left kidney was incised under pentobarbital anesthesia, and after 1 week, the entire right kidney was extracted. After 2 weeks from extraction of 5/6 of the kidney, the protein excretion amounts in urine were measured by 24-hour urine collection in metabolic cages, and were divided into groups so that there was no difference in each group. Thereafter, over 6 to 8 weeks, 5 mL/kg of the test compound which had been suspended in 0.5% MC was administered orally. The same amounts of the solvent (0.5% MC) were administered orally to the sham group which had undergone only laparotomy and the 5/6 Nx-control group. 24-Hour urine collection was carried out every two weeks.
By measuring the protein excretion amounts in urine, plasma creatinine, plasma urea nitrogen, and creatinine clearance, the effect of the test compound on the improvement of chronic renal failure can be confirmed, and in this test, it was confirmed that compounds exhibiting effectiveness exist.
Furthermore, the selectivity of the compound of the formula (I) or a salt thereof on four subtypes of the PGE2 receptor (EP1, EP2, EP3, and EP4) was evaluated. Specifically, for the receptor of each subtype derived from the rats, inhibition of the cAMP amounts was evaluated by adding the test compounds, respectively, in the same manner as in Test Example 3. As a result, it was shown that the compound of the formula (I) or a salt thereof has a selective antagonistic activity or an EP4 receptor.
From the results of the above-described tests, it was confirmed that the compound of the formula (I) or a salt thereof has an EP4 receptor antagonistic activity, and can be used as an active ingredient of a pharmaceutical composition for preventing or treating various EP4-related diseases, and the like. Examples of the EP4-related diseases include renal diseases (for example, acute nephritis, recurrent hematuria, persistent hematuria, chronic nephritis, rapidly progressive nephritis, acute renal failure, chronic renal failure, diabetic nephropathy, Bartter's syndrome, and the like), inflammatory skin diseases (for example, sunburn, burns, eczema, dermatitis, and the like), ischemic heart diseases caused by arteriosclerosis (for example, myocardial infarction, angina, and the like), cerebrovascular disorders caused by arteriosclerosis (for example, stroke, stroke including lacunar infarction, cerebral thrombosis, cerebral hemorrhage, subarachnoid hemorrhage, cerebral infarction, and the like), peptic ulcer diseases (for example, gastric ulcer, duodenal ulcer, and the like), malignant cancer and metastasis thereof (for example, colon cancer, breast cancer, and the like), and the like, or the analogous diseases in humans and animals, and in a certain embodiment, renal diseases such as chronic renal failure, diabetic nephropathy, and the like.
Furthermore, the compound of the formula (I) or a salt thereof can be used as a compound having a diuretic action. By having a diuretic action, the compound of the formula (I) or a pharmaceutically acceptable salt thereof can be used as an agent for treating and/or preventing various types of edema (for example, cardiac edema, cerebral edema, and the like), hypertension such as malignant hypertension, and the like, a premenstrual syndrome, urinary calculus, a poor urine disease caused by an acute or chronic disease, hyperphosphatemia, and the like.
A pharmaceutical composition containing one or more kinds of the compound of the formula (I) or a salt thereof as an active ingredient can be prepared in accordance with a generally used method, using an excipient usually used in the art, that is, a pharmaceutical excipient, a pharmaceutical carrier, or the like.
The administration can be carried out in any form of oral administration via tablets, pills, capsules, granules, powders, liquid preparations, or the like; or parenteral administration via injections such as intraarticular, intravenous, or intramuscular injections, suppositories, eye drops, eye ointments, percutaneous liquid preparations, ointments, percutaneous patches, transmucosal liquid preparations, transmucosal patches, inhalations, and the like.
As the solid composition for oral administration, tablets, powders, granules, or the like are used. In such a solid composition, one or more kinds of active ingredients are mixed with at least one inert excipient. According to a conventional method, the composition may contain inert additives such as a lubricant, a disintegrator, a stabilizing agent, and a solubilizing agent. As occasion demands, the tablets or the pills may be coated with a sugar coating, or a film of a gastric or enteric material.
The liquid composition for oral administration includes pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, or the like, and contains a generally used inert diluent such as purified water or ethanol. In addition to the inert diluent, this liquid composition may contain an auxiliary agent such as a solubilizing agent, a moistening agent, and a suspending agent, a sweetener, a flavor, an aroma, and an antiseptic.
The injections for parenteral administration include sterile aqueous or non-aqueous liquid preparations, suspensions and emulsions. The aqueous solvent includes, for example, distilled water for injection and physiological saline. Examples of the non-aqueous solvent include alcohols such as ethanol. Such a composition may further contain a tonicity agent, an antiseptic, a moistening agent, an emulsifying agent, a dispersing agent, a stabilizing agent, or a solubilizing agent. These are sterilized, for example, by filtration through a bacteria retaining filter, blending of a bactericide, or irradiation. Additionally, these can also be used by preparing a sterile solid composition, and dissolving or suspending it in sterile water or a sterile solvent for injection prior to its use.
The agent for external use includes ointments, plasters, creams, jellies, cataplasms, sprays, lotions, eye drops, eye ointments, and the like. The agents contain generally used ointment bases, lotion bases, aqueous or non-aqueous liquid preparations, suspensions, emulsions, and the like.
As the transmucosal agents such as an inhalation, a transnasal agent, and the like, those in the form of a solid, liquid, or semi-solid state are used, and can be prepared in accordance with a conventionally known method. For example, a known excipient, and also a pH adjusting agent, an antiseptic, a surfactant, a lubricant, a stabilizing agent, a thickening agent, or the like may be appropriately added thereto. For their administration, an appropriate device for inhalation or blowing can be used. For example, a compound may be administered alone or as a powder of formulated mixture, or as a solution or suspension in combination with a pharmaceutically acceptable carrier, using a conventionally known device or sprayer, such as a measured administration inhalation device, and the like. A dry powder inhaler or the like may be for single or multiple administration use, and a dry powder or a powder-containing capsule may be used. Alternatively, this may be in a form such as a pressurized aerosol spray which uses an appropriate propellant, for example, a suitable gas such as chlorofluoroalkane, carbon dioxide, and the like, or other forms.
In oral administration, the daily dose is preferably from about 0.001 to 100 mg/kg, in an embodiment, from 0.1 to 30 mg/kg, and in another embodiment, from 0.1 to 10 mg/kg, per body weight, administered in one portion or in 2 to 4 divided portions. In the case of intravenous administration, the daily dose is suitably administered from about 0.0001 to 10 mg/kg per body weight, once a day or two or more times a day. Additionally, a transmucosal agent is administered at a dose from about 0.001 to 100 mg/kg per body weight, once a day or two or more times a day. The dose is appropriately decided in response to the individual case by taking the symptoms, the age, and the gender, and the like into consideration.
Although it varies depending on the administration way, dosage form, administration site, the kinds of excipient and additive, the pharmaceutical composition of the present invention includes from 0.01 to 100% by mass, in an embodiment, from 0.01 to 50% by mass, of one or more of the compound of the formula (I) or a salt thereof as an active ingredient.
The compound of the formula (I) or a salt thereof can be used in combination with various agents for treating or agents for preventing the above-described diseases for which the compound of the formula (I) or a salt thereof is considered to be effective. The combined preparation may be administered simultaneously, or separately and continuously or at a desired time interval. The preparations to be co-administered may be prepared separately, or may be a pharmaceutical composition containing various agents for treating or agents for preventing the above-described diseases for which the compound of the formula (I) or a salt thereof is considered to be effective and the compound of the formula (I) or a salt thereof.
Examples
The production processes of the compound of the formula (I) or a salt thereof will be described below in more detail based on Examples. In this connection, the present invention is not limited to the compounds described in the following Examples. Furthermore, the production processes for the starting compounds will be described in Production Examples, and the production processes for the known compounds will be described in Reference Examples. Further, the production processes for the compound of the formula (I) or a salt thereof are not limited only to the production processes of the specific Examples as below, but the compound of the formula (I) or a salt thereof can be prepared by any combination of the production processes or the methods that are apparent to a person skilled in the art.
Production Example 1
To a mixture of 5-chloro-1H-indole-7-carboxylic acid (500 mg), triphenylphosphine (1.01 g), ethanol (235 mg) and toluene (20 mL) was added dropwise diethyl azodicarboxylate (2.2 M toluene solution, 1.74 mL) at room temperature. After stirring for 2 hours at room temperature, the reaction mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain ethyl 5-chloro-1H-indole-7-carboxylate (550 mg) as a white solid.
Production Example 2
To a mixture of ethyl 5-(1-hydroxyethyl)thiophene-2-carboxylate (1.01 g), diphenylphosphorylazide (1.67 g), and toluene (10 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (905 μL) under ice-cooling, followed by stirring for 30 minutes. The reaction mixture was warmed to room temperature, followed by stirring for 15 hours. The reaction liquid was washed with water and 1 M hydrochloric acid in this order, and dried over anhydrous sodium sulfate. Then, after concentration under reduced pressure, the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain ethyl 5-(1-azidoethyl)thiophene-2-carboxylate (1.03 g) as a colorless oily substance.
Production Example 3
To a mixture of ethyl 5-(1-azidoethyl)thiophene-2-carboxylate (1.03 g), THF (20 mL), and water (4 mL) was added triphenylphosphine (2.35 g) at room temperature. This mixture was stirred at 60° C. for 3 hours. After leaving the reaction mixture to be cooled at room temperature, the mixture was concentrated under reduced pressure and azeotroped with toluene. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) concentrated, and a 4 M hydrogen chloride-ethyl acetate solution (1.5 mL) was added to the obtained residue. After stirring for 3 minutes, the mixture was concentrated again under reduced pressure. Diisopropyl ether was added thereto and the precipitated white solid was collected by filtration to obtain ethyl 5-(1-aminoethyl)thiophene-2-carboxylate hydrochloride (979 mg) as a white solid.
Production Example 4
To a mixture of ethyl 1,2,3,4-tetrahydroquinoline-8-carboxylate (1.1 g) and DMF (9.0 mL) was added sodium hydride (55% dispersion in paraffin liquid, 280 mg) at 0° C., followed by stirring at room temperature for 30 minutes. To the reaction mixture was added a solution of 1-(bromoethyl)-4-chlorobenzene (1.2 g) in DMF (2.0 mL) under ice-cooling, followed by stirring at room temperature for 3 days. To the reaction mixture was added sodium hydride (55% dispersion in paraffin liquid, 280 mg), followed by stirring for 1 day. To the reaction mixture were added water and ethyl acetate, and a liquid-separation operation was carried out. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain ethyl 1-(4-chlorobenzyl)-1,2,3,4-tetrahydroquinoline-8-carboxylate (510 mg).
Production Example 5
To a mixture of methyl 3-amino-2-hydroxybenzoate (700 mg) and THF (21 mL) was added 4-chlorophenylisothiocyanate (717 mg), followed by stirring at room temperature overnight. To the reaction mixture were sequentially added copper iodide (0.87 g) and triethylamine (641 μL), followed by stirring at 60° C. overnight. The reaction mixture was concentrated under reduced pressure and methanol was added thereto, the mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. To the residue was added ethyl acetate (20 mL), the insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1), and then triturated with n-hexane-ethyl acetate (10:1, 11 mL) to obtain methyl 2-[(4-chlorophenyl)amino]-1,3-benzoxazole-7-carboxylate (270 mg) as a pale yellow solid.
Production Example 6
To a mixture of methyl 1H-indole-7-carboxylate (100 mg) and DMF (1 mL) was added potassium tert-butoxide (75 mg) at room temperature, followed by stirring for 5 minutes. To the reaction mixture was added 4-(bromomethyl)benzonitrile (131 mg), followed by stirring at room temperature for 2 hours. Water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine in this order, and dried over anhydrous sodium sulfate, and then the solvent was evaporated to obtain crude methyl 1-(4-cyanobenzyl)-1H-indole-7-carboxylate (211 mg). To a mixture of crude methyl 1-(4-cyanobenzyl)-1H-indole-7-carboxylate (211 mg), THF (10 mL), and methanol (5 mL) was added a 1 M aqueous sodium hydroxide solution (2.5 mL), and the obtained mixed liquid was stirred at 60° C. overnight. After leaving to be cooled to room temperature, the solvent was evaporated under reduced pressure, and to the obtained residue was added ethyl acetate, followed by extraction with water. The aqueous layer was neutralized by adding 1 M hydrochloric acid (2.5 mL), and extracted with ethyl acetate. This organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated to obtain crude 1-(4-carbamoylbenzyl)-1H-indole-7-carboxylic acid (230 mg). To a mixture of crude 1-(4-carbamoylbenzyl)-1H-indole-7-carboxylic acid (229 mg), methyl (S)-4-[1-aminoethyl]benzoate hydrochloride (123 mg), and HOBt (23 mg) in DMF (3 mL) was added EDCI.HCl (150 μL), followed by stirring at room temperature for 3 hours. Water was added thereto, followed by extraction with ethyl acetate-diethyl ether. The organic layer was washed with water and saturated brine in this order, and dried over anhydrous sodium sulfate. After evaporating the solvent, to the obtained residue was added methanol. The precipitated solid was collected by filtration and dried to obtain methyl (S)-4-[1-({[1-(4-carbamoylbenzyl)-1H-indol-7-yl]carbonyl}amino)ethyl]benzoate (142 mg).
Production Example 7
A mixture of 1-(4-chlorobenzyl)-1,2,3,4-tetrahydroquinoline-8-carboxylic acid (310 mg), methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (240 mg), EDCI.HCl (210 mg), HOBt (160 mg), pyridine (0.25 mL), and DMF (3.00 mL) was stirred at room temperature for 3 days. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain methyl 4-[(1S)-1-({[1-(4-chlorobenzyl)-1,2,3,4-tetrahydroquinolin-8-yl]carbonyl}amino)ethyl]benzoate (129 mg).
Production Example 8
To a mixture of methyl trans-4-acetylcyclohexane carboxylate (0.5 g) and pyridine (5.0 mL) was added hydroxylamine hydrochloride (0.57 g) under ice-cooling, followed by stirring at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure. To the residue were added ethyl acetate and a 10% aqueous citric acid solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was combined, and washed with a 10% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution, water, and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain methyl trans-4-(N-hydroxyethanimidyl)cyclohexane carboxylate (0.45 g).
Production Example 9
To a mixture of methyl trans-4-(N-hydroxyethanimidyl)cyclohexane carboxylate (0.44 g) and ethanol (8.0 mL) were added concentrated aqueous ammonia (2.0 mL) and an ethanol suspension (6.0 mL) of Raney nickel (2.0 mL), followed by stirring at room temperature for 12 hours under a hydrogen atmosphere at 3.4 atm. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. To the residue was added diethyl ether, a 4 M hydrogen chloride-dioxane solution (1.0 mL) was added thereto under ice-cooling, and the precipitated solid was collected by filtration and washed with diethyl ether to obtain methyl trans-4-(1-aminoethyl)cyclohexane carboxylate hydrochloride (0.42 g).
Production Example 10
To 5,6,7,8-tetrahydro-2H-[1]benzothieno[2,3-d][1,3]oxazine-2,4(1H)-dione (1.5 g) and potassium carbonate (1.4 g) was added DMF (15 mL), and methyl iodide (1.2 m) was added thereto under ice-cooling, followed by stirring at room temperature for 6 hours. Methyl iodide (0.61 mL) was added thereto, followed by stirring at room temperature overnight, water (15 mL) was added to the reaction mixture, and the solid was collected by filtration, washed with water, and dried under reduced pressure to obtain 1-methyl-5,6,7,8-tetrahydro-2H-[1]benzothieno[2,3-d][1,3]oxazine-2,4(1H)-dione (1.3 g).
Production Example 11
To 1-methyl-5,6,7,8-tetrahydro-2H-[1]benzothieno[2,3-d][1,3]oxazine-2,4(1H)-dione (0.50 g) was added ethanol (20 mL), and triethylamine (0.44 mL) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride were sequentially added, followed by heating with reflux for 18 hours. The reaction mixture was cooled to room temperature, and a 10% aqueous citric acid solution (15 mL) was added thereto. To a mixture was added ethyl acetate, followed by washing with water, and the obtained organic layer was dried over anhydrous sodium sulfate. After filtering and concentrating under reduced pressure, the residue was purified by silica gel column chromatography (hexane/ethyl acetate: 90/10-75/25) to obtain methyl 4-[(1S)-1-({[2-(methylamino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)ethyl]benzoate (0.42 g).
Production Example 12
To methyl 4-[(1S)-1-({[2-(methylamino)-4,5,6,7-tetrahydro-1-benzothien-3-yl]carbonyl}amino)ethyl]benzoate (0.41 g) was added 1,3-dimethyl-2-imidazolidinone (4.0 mL), and potassium carbonate (0.30 g) and 1-(bromomethyl)-4-chlorobenzene (0.34 g) were added thereto under ice-cooling, followed by stirring at 50° C. overnight. The reaction mixture was cooled to room temperature, and then water (50 mL) was added thereto, followed by extraction with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate: 15/1-4/1) to obtain methyl 4-{(1S)-1-[({2-[(4-chlorobenzyl)(methyl)amino]-4,5,6,7-tetrahydro-1-benzothiophen-3-yl}carbonyl)amino]ethyl}benzoate (0.15 g).
Production Example 13
To a mixture of methyl 5-bromo-1-(4-chlorobenzyl)-1H-indole-7-carboxylic acid (300 mg), trimethylboroxin (100 mg), potassium carbonate (165 mg), and 1,4-dioxane (9 mL) was added tetrakis(triphenylphosphine) palladium (0) (46 mg) at room temperature. This mixture was stirred under heating with reflux for 15 hours. The reaction mixture was left to be cooled to room temperature, and water was added thereto, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain methyl 1-(4-chlorobenzyl)-5-methyl-1H-indole-7-carboxylate (60 mg).
Production Example 14
To a mixture of (3-oxo-1,3-dihydro-2-benzofuran-1-yl)(triphenyl) phosphonium bromide (5.1 g) and tetrahydrofuran (50 mL) were added potassium tert-butoxide (1.3 g) and 5-chloro-2-nitro benzoaldehyde (1.0 g) at room temperature under an argon atmosphere, followed by stirring for 5 minutes. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 3-(5-chloro-2-nitrobenzylidene)-2-benzofuran-1(3H)-one (808 mg).
Production Example 15
A mixture of 3-(5-chloro-2-nitrobenzylidene)-2-benzofuran-1(3H)-one (808 mg), reduced iron (750 mg), ammonium chloride (72 mg), water (2.5 mL), and ethanol (25 mL) was stirred at 80° C. for 4 hours. The reaction mixture was filtered using Celite and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 3-(2-amino-5-chlorobenzylidene)-2-benzofuran-1(3H)-one (466 mg).
Production Example 16
1-(6-Bromopyridin-3-yl)ethanone (5.00 g), propane-1,3-diylbis(diphenyl phosphine) (1.546 g), DMF (55 mL), methanol (30 mL), and triethylamine (10.5 mL) were mixed, and the inside of the reaction vessel was degassed and replaced with argon. Palladium acetate (II) (842 mg) was added thereto, and then the inside of the reaction vessel was replaced with carbon monoxide and stirred at 70° C. for 2 days. After leaving to be cooled to room temperature, the reaction mixture was diluted with a mixed liquid of diethyl ether-ethyl acetate, and washed with water and saturated brine in this order. The organic layer was dried over anhydrous sodium sulfate, then the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain methyl 5-acetylpyridine-2-carboxylate (1.16 g).
Production Example 17
To a solution of 3-(2-amino-5-chlorobenzylidene)-2-benzofuran-1(3H)-one (466 mg) in ethanol (3.5 mL) was added a 1 M aqueous sodium hydroxide solution (3.4 mL) at room temperature, followed by heating with reflux for 45 minutes. The reaction mixture was acidified by adding of 1 M hydrochloric acid under ice-cooling, and stirred at room temperature for 1 hour. The resulting precipitate was separated by filtration and the filtrate was extracted with diethyl ether. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 2-(5-chloro-1H-indol-2-yl)benzoic acid (395 mg).
Production Example 18
To a mixture of 2-(5-chloro-1H-indol-2-yl)benzoic acid (217 mg), DMF (4.0 mL), and THF (1.0 mL) was added sodium hydride (55% dispersion in paraffin liquid, 77 mg) at room temperature under an argon atmosphere, followed by stirring for 5 minutes. At room temperature, methyl iodide (0.50 mL) was added thereto, followed by stirring for 12 hours. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain methyl 2-(5-chloro-1-methyl-1H-indol-2-yl)benzoate (270 mg).
Production Example 19
To a mixture of methyl 4-propionyl benzoic acid (0.50 g) and pyridine (5.0 mL) was added hydroxylamine hydrochloride (0.54 g) under ice-cooling, followed by stirring at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, to the residue were added ethyl acetate and a 10% aqueous citric acid solution and the aqueous layer was extracted with ethyl acetate. The organic layer was combined, and washed with a 10% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution, water, and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and to the residue was added ethanol (15 mL). To the reaction mixture were added a suspension of Raney nickel (2.0 mL) in ethanol (15 mL), and concentrated aqueous ammonia (3.0 mL), followed by stirring at room temperature for 14 hours under a hydrogen atmosphere of 3 atm. The insoluble materials in the reaction mixture were separated by filtration through Celite, and the filtrate was concentrated under reduced pressure. To the residue was added diethyl ether (10 mL), and a 4 M-hydrogen chloride/dioxane solution (1.0 mL) was added thereto under ice-cooling. The precipitated crystal was collected by filtration and washed with diethyl ether to obtain methyl 4-(1-amino propyl)benzoic acid hydrochloride (0.51 g).
Production Example 20
To a mixture of methyl 5-acetylpyridine-2-carboxylate (1.00 g), THF (24 mL), and methanol (12 mL) was added sodium borohydride (110 mg), followed by stirring at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and then to the obtained residue was added a saturated aqueous sodium chloride solution. After extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated and then dried under reduced pressure to obtain methyl 5-(1-hydroxyethyl)pyridine-2-carboxylate (897 mg).
Production Example 21
A mixture of methyl 5-(1-hydroxyethyl)pyridine-2-carboxylate (895 mg) and dichloromethane (10 mL) was ice-cooled, and triethylamine (1.72 mL) and methanesulfonyl chloride (765 μL) were added thereto. The mixture was stirred under ice-cooling for 3 minutes, and then stirred at room temperature for 30 minutes. To a mixture was added water, followed by extraction with chloroform. This organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure to obtain a pale yellow oily residue (1.457 g). This residue was mixed with DMF (5 mL) and sodium azide (965 mg), followed by stirring at 60° C. for 1 hour. The mixture was left to be cooled to room temperature, and water was added thereto, followed by extraction with a mixed liquid of ethyl acetate-diethyl ether. The organic layer was washed with water and saturated brine in this order, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain methyl 5-(1-azidoethyl)pyridine-2-carboxylate (828 mg).
Production Example 22
To a mixture of 3-hydroxy-4-methyl benzoic acid (3.0 g), potassium carbonate (10.9 g), and acetonitrile (60 mL) was added ethyl iodide (4.8 mL) under ice-cooling, followed by stirring at 60° C. overnight. Thereafter, ethyl iodide (4.8 mL) was added thereto, followed by stirring at 70° C. for 3 days. In addition, ethyl iodide (4.8 mL) and potassium carbonate (5.5 g) were added thereto, followed by stirring overnight. To the reaction mixture was added water (100 mL), followed by extraction with ethyl acetate, and the obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane:5/95) to obtain ethyl 3-ethoxy-4-methylbenzoate (4.0 g).
Production Example 23
Methyl (S)-4-(1-acetamideethyl)benzoic acid (4.40 g) and concentrated sulfuric acid (15 mL) were mixed at room temperature, stirred until it became homogeneous, and then ice-cooled. To this was added dropwise a mixed liquid of fumed nitric acid (3 mL) and concentrated sulfuric acid (2 mL) over 30 minutes while the internal temperature was kept at 10° C. or lower. After completion of dropwise addition, the mixture was stirred at room temperature for 5 hours. The reaction liquid was poured into ice water, followed by stirring and then extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain methyl (S)-4-(1-acetamideethyl)-3-nitro benzoate (4.83 g).
Production Example 24
Under a hydrogen atmosphere, a mixture of methyl (S)-4-(1-acetamideethyl)-3-nitro benzoate (4.83 g), ethyl acetate (30 mL), and 10% palladium/carbon (500 mg) was stirred at room temperature for 18 hours. After the reaction, the catalyst was removed by filtration and the solvent was evaporated under reduced pressure. To the obtained residue was added ethyl acetate, followed by heating with reflux. This was left to be cooled to room temperature, and then the precipitate was collected by filtration to obtain methyl (S)-3-amino-4-(1-acetamideethyl)benzoate (3.31 g).
Production Example 25
To a mixture of ethyl 3-ethoxy-4-methylbenzoate (2.0 g), N-bromosuccinimide (1.9 g) and ethyl acetate (40 mL) was added 2,2′-azobis(2-methylpropionitrile) (15 mg), followed by stirring for 14 hours under heating with reflux. The mixture was left to be cooled, hexane was added thereto, the precipitated solid was separated by filtration, and the obtained filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane:5/95) to obtain ethyl 4-(bromomethyl)-3-ethoxybenzoate (2.4 g).
Production Example 26
To a mixture of 4-chloro-1H-pyrrole-2-carboxylic acid (0.20 g) and DMF (2.0 mL) was added potassium tert-butoxide (0.31 g) under ice-cooling, followed by stirring at room temperature for 15 minutes. To the reaction mixture was added 1-bromomethyl-4-chlorobenzene (0.29 g) under ice-cooling, followed by stirring at room temperature for 14 hours. To the reaction mixture was added water at room temperature, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 4-chloro-1-(4-chlorobenzyl)-1H-pyrrole-2-carboxylic acid (0.06 g).
Production Example 27
To a mixture of sodium nitrite (193 mg) and concentrated sulfuric acid (2 mL) was added dropwise a solution of methyl (S)-3-amino-4-(1-acetamideethyl)benzoate (600 mg) in acetic acid (6 mL), followed by stirring at room temperature for 30 minutes. To the ice-cooled solution of copper chloride (I) (550 mg) in concentrated hydrochloric acid (6 mL) was added dropwise the above-described reaction mixture, followed by stirring at room temperature for 5 hours. The reaction liquid was poured into ice water, followed by extraction with chloroform. The organic layer was washed with water and then dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain methyl (S)-4-(1-acetamideethyl)-3-chlorobenzoate (465 mg).
Production Example 28
To a mixture of methyl 4-formyl-3-methoxybenzoate (3.30 g) and THF (30 mL) was added dropwise methyl magnesium bromide (3 M diethyl ether solution, 3.60 mL) under ice-cooling. After dropwise addition, the mixture was stirred for 1 hour under ice-cooling. A saturated aqueous ammonium chloride solution was added thereto to stop the reaction, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, and then dried over an aqueous anhydrous sodium sulfate solution. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain methyl 4-(1-hydroxyethyl)-3-methoxybenzoate (1.92 g).
Production Example 29
To a mixture of 1-(4-bromophenyl)-1-cyclopropylmethane amine (1.08 g) and THF (10 mL) were added triethylamine (1 mL) and di-tert-butyl dicarbonate (1.25 mL), and the mixture was stirred at room temperature for 16 hours. The solvent was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl[(4-bromophenyl)(cyclopropyl)methyl]carbamate (1.36 g).
Production Example 30
To a mixture of methyl 4-(1-hydroxyethyl)-3-methoxybenzoate (1.92 g), diphenylphosphorylazide (2.76 g), and toluene (20 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (1.5 mL) at room temperature, followed by stirring at room temperature for 2 days. To this mixture were added THF (10 mL), water (5 mL), and triphenylphosphine (3.0 g) at room temperature, and the mixture was stirred at 60° C. for 3 hours. The mixture was left to be cooled to room temperature, and the solvent was evaporated under reduced pressure, followed by extraction with ethyl acetate. To this organic layer was added a 1 M aqueous hydrochloric acid solution (50 mL), and a desired product was extracted in the aqueous layer. To this aqueous layer was added a 1 M aqueous sodium hydroxide solution (60 mL), and then a desired product was extracted with ethyl acetate three times. The combined organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and to the obtained residue (748 mg) was added a 4 M hydrogen chloride 1,4-dioxane solution (4 mL), followed by stirring for 3 minutes and concentrating under reduced pressure. To this residue was added ethyl acetate, followed by stirring at room temperature for 10 minutes, and then the precipitate was collected by filtration to obtain methyl 4-(1-aminoethyl)-3-methoxybenzoate hydrochloride (439 mg).
Production Example 31
A mixture of methyl (S)-4-(1-acetamideethyl)-3-chlorobenzoate (464 mg) and 2 M hydrochloric acid (12 mL) was stirred at 100° C. for 2 days. After leaving to be cooled to room temperature, the mixture was concentrated under reduced pressure, further azeotroped with ethanol, and dried to obtain (S)-4-(1-aminoethyl)-3-chlorobenzoic acid hydrochloride (428 mg).
Production Example 32
To a mixture of sodium hydride (0.29 g, 55% dispersion in paraffin liquid) and DMF (10 mL) was added methyl 4H-furo[3,2-b]pyrrole-5-carboxylate (0.5 g) under ice-cooling, followed by stirring for 10 minutes and further 1-(bromomethyl)-4-chlorobenzene (0.81 g) was added thereto, followed by stirring at room temperature for 4 hours. To the reaction mixture was added a 10% aqueous citric acid solution (10 mL), followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate: 5/1-3/1) to obtain 4-(4-chlorobenzyl)-4H-furo[3,2-b]pyrrole-5-carboxylic acid (0.35 g).
Production Example 33
Methyl 4-{[(tert-butoxycarbonyl)amino](cyclopropyl)methyl}benzoate (793 mg), methanol (5 mL), and 4 M hydrogen chloride/dioxane (5 mL) were mixed, followed by stirring at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and then to the residue was added ethyl acetate. The precipitated solid was collected by filtration and dried under reduced pressure to obtain methyl 4-[amino(cyclopropyl)methyl]benzoate hydrochloride (561 mg).
Production Example 34
A mixture of 7-bromo-5-methoxy-1H-indole (1.2 g) and THF (12 mL) was stirred at −78° C. under an argon atmosphere. To the reaction mixture was added dropwise an n-butyllithium n-hexane solution (1.65 M, 9.6 mL) at −50° C. or lower. The reaction mixture was stirred for 0.5 hour under ice-cooling. The reaction mixture was cooled to −78° C., and dry ice (10 g) was added thereto, followed by slowly warming to room temperature. The reaction mixture was poured into a 10% aqueous citric acid solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (THF/hexane=20→60%) to obtain 5-methoxy-1H-indole-7-carboxylic acid (0.60 g).
Production Example 35
To ethyl 4-(bromomethyl)-3-ethoxybenzoate (2.4 g) was added DMF (24 mL), and sodium azide (0.54 g) was added thereto, followed by stirring at room temperature overnight. To the reaction mixture was added water (50 mL), followed by extraction with ethyl acetate, and the obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. To the residue were added THF (21 mL), and water (4.0 mL), and then added triphenylphosphine (6.6 g), followed by stirring at room temperature for 1 hour, and further at 75° C. for 1 hour. The reaction mixture was ice-cooled, adjusted to pH 2 by adding a 1 M aqueous hydrochloric acid solution, and washed with diethyl ether. The aqueous layer was neutralized with saturated aqueous sodium bicarbonate, followed by extraction with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Under ice-cooling, to the residue were added ethyl acetate (4.0 mL) and then 4 M hydrogen chloride ethyl acetate solution (4.0 mL), and the precipitated solid was collected by filtration, washed with ethyl acetate, and then dried at 60° C. under reduced pressure to obtain ethyl 4-(aminomethyl)-3-ethoxybenzoate hydrochloride (1.1 g).
Production Example 36
Under an argon atmosphere, to an ice-cooled mixture of nitrosonium tetrafluoroborate (355 mg) and dichloromethane (15 mL) was added methyl (S)-3-amino-4-(1-acetamideethyl)benzoate (650 mg), and the reaction mixture was stirred at room temperature for 20 hours. To this was added 1,2-dichlorobenzene (15 mL), dichloromethane was evaporated under reduced pressure and then the mixture was stirred at 160° C. for 2 hours. After cooling to room temperature, a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with chloroform.
The organic layer was dried over anhydrous sodium sulfate and then solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol) to obtain methyl (S)-4-(1-acetamideethyl)-3-fluorobenzoate (266 mg).
Production Example 37
To a mixture of methyl 4-cyano-2-methylbenzoate (3.0 g) and methanol (60 mL) was added dichlorocobalt hexahydrate (8.1 g) under ice-cooling, followed by stirring. To a mixture was slowly added sodium borohydride (3.9 g), followed by stirring at room temperature for 2 hours. Under ice-cooling, to the reaction mixture was added saturated aqueous ammonia (20 mL), followed by stirring at room temperature for 30 minutes. This solution was filtered through Celite and washed with methanol. The filtrate was concentrated under reduced pressure, and to the obtained residue was added 1 M hydrochloric acid (50 mL), followed by washing with diethyl ether. The aqueous layer was adjusted to pH 8 by adding saturated aqueous sodium bicarbonate, and further adjusted to pH 10 by adding a 1 M aqueous sodium hydroxide solution. The mixture was extracted by adding chloroform, and the organic layer was dried over anhydrous magnesium sulfate. A 4 M hydrogen chloride dioxane solution (10 mL) was added thereto, followed by concentration under reduced pressure. The solid was washed with diethyl ether, then collected by filtration, and dried at 60° C. under reduced pressure to obtain methyl 4-(aminomethyl)-3-methylbenzoate hydrochloride (3.0 g).
Production Example 38
To 1-(biphenyl-4-ylmethyl)-1H-indole-7-carboxylic acid (0.20 g), methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride, and HATU was added DMF (4.0 mL), followed by adding diisopropylethylamine (0.26 mL) under ice-cooling and then stirring at room temperature for 22 hours. Again, the mixture was ice-cooled, a 10% aqueous citric acid solution (4.0 mL) was added thereto, and the precipitated solid was collected by filtration, washed with water, and dried at 60° C. under reduced pressure to obtain methyl 4-[(1S)-1-({[1-(biphenyl-4-ylmethyl)-1H-indol-7-yl]carbonyl}amino)ethyl]benzoate (0.30 g).
Production Example 39
To a mixture of cis-4-(butoxycarbonyl)cyclohexane carboxylic acid (3.3 g) and thionyl chloride (13 mL) was added DMF (2 drops), followed by stirring at 50° C. for 0.5 hours. The reaction mixture was concentrated under reduced pressure and azeotroped with toluene to obtain a residue. A mixture of copper iodide (5.2 g) and THF (13 mL) was stirred at an internal temperature of −40° C. under an argon atmosphere. To the reaction mixture was added dropwise a diethyl ether solution (1.1 M, 55 mL) of methyl lithium at an internal temperature of −30 to −40° C. over about 15 minutes, followed by stirring at the same temperature for 1 hour. The reaction mixture was cooled to an internal temperature of −60° C., and the THF solution (10 mL) of the above-described residue was added dropwise thereto at an internal temperature of −50 to −60° C. over about 5 minutes. The mixture was stirred at the same temperature for 0.5 hours, and methanol (15 mL) was added dropwise thereto, followed by warming to room temperature. To the reaction mixture were added a saturated aqueous ammonium chloride solution and ethyl acetate, and the aqueous layer was extracted with ethyl acetate. The organic layer was combined, washed with a saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous magnesium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain butyl cis-4-acetylcyclohexane carboxylate (2.2 g).
Production Example 40
To 5-methyl-1H-indole-7-carboxylic acid (1.1 g), potassium carbonate (1.3 g) was added DMF (22 mL), and then methyl iodide (1.3 mL) was added thereto under ice-cooling. After stirring at room temperature overnight, the reaction mixture was adjusted to pH 3 by adding a 10% aqueous citric acid solution. The mixture was extracted with ethyl acetate, and the obtained organic layer was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate: 95/5-85/15) to obtain methyl 5-methyl-1H-indole-7-carboxylate (1.2 g).
Production Example 41
To a mixture of ice-cooled methyl 6-hydroxypyridine-2-carboxylate (800 mg), DME (10.5 mL), and DMF (2.6 mL) was added sodium hydride (55% oil dispersion, 240 mg), followed by stirring for 10 minutes. To this was added lithium bromide (910 mg), and then the mixture was stirred at room temperature for 15 minutes and further 4-chlorobenzylbromide (2.15 g) was added thereto. This mixture was stirred at 65° C. for 20 hours. Water was added thereto, followed by extraction with ethyl acetate-diethyl ether, and the organic layer was washed with water and saturated brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain methyl 1-(4-chlorobenzyl)-6-oxo-1,6-dihydropyridine-2-carboxylate (270 mg; Example 41a) and methyl 6-[(4-chlorobenzyl)oxy]pyridine-2-carboxylate (448 mg; Example 41b), as a colorless oily substance, respectively.
Production Example 42
A mixture of methyl 5-bromo-1H-indole-7-carboxylate (300 mg), 1-methyl-2-pyrrolidinone (6 mL), sodium methanesulfinate (600 mg), and copper iodide (I) (1.10 g) was stirred at 150° C. for 17 hours under an argon atmosphere. The reaction mixture was left to be cooled to room temperature, ethyl acetate was added thereto, and then the insoluble materials were removed by filtration. To this filtrate was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine in this order, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain methyl 5-(methanesulfonyl)-1H-indole-7-carboxylate (91 mg).
Production Example 43
To a mixture of tert-butylcarbamate (5.60 g) and n-propanol (50 mL) were added a 0.5 M aqueous sodium hydroxide solution (94 mL) and tert-butyl hypochlorate (5.32 mL), followed by stirring at room temperature for 20 minutes. To the reaction mixture was added dropwise an n-propanol (50 mL) solution of (DHQD)2Phal (766.5 mg) under ice-cooling. In addition, at the same temperature, an n-propanol (80 mL) solution of methyl 4-vinyl benzoate (2.5 g) was added dropwise over 30 minutes, and then potassium osmate dihydrate (253.8 mg) was added thereto. The reaction mixture was stirred for 1 hour under ice-cooling, and then stirred at 4° C. overnight. The reaction mixture was concentrated under reduced pressure, and to the residue was added water (250 mL). The aqueous layer was extracted with ethyl acetate (100 mL×3). The organic layer was combined, washed with a 1 M aqueous hydrochloric acid solution (200 mL) and saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate=3:1) to obtain methyl 4-{(1R)-1-[(tert-butoxycarbonyl)amino]-2-hydroxyethyl}benzoate (850 mg) as a white solid.
Production Example 44
To methyl 1-(4-bromobenzyl)-1H-indole-7-carboxylate (0.63 g), 4,4,4′,4′,5,5,5′,5′-octamethyl 2,2′-bi-1,3,2-dioxaborolane (0.56 g), potassium acetate (0.27 g), bis(triphenylphosphine) palladium (II) dichloride (39 mg), and triphenylphosphine (29 mg) was added toluene (6.0 mL), followed by stirring at 110° C. under an argon atmosphere. After stirring for 5 hours, the reaction mixture was purified by silica gel column chromatography (hexane-ethyl acetate=20/1-10/1) to obtain methyl 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-1H-indole-7-carboxylate (0.45 g).
Production Example 45
To a mixture of 7-bromoinden-1-ol (1.06 g), triphenylphosphine (1.86 g), 4-chlorophenol (911 mg), and toluene (30 mL) was added dropwise diethyl azodicarboxylate (2.2 M toluene solution, 3.3 mL) at room temperature. After dropwise addition, the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and then the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 7-bromo-1-(4-chlorophenoxy)indane (306 mg).
Production Example 46
To a mixture of 7-bromo-1H-pyrrolo[3,2-c]pyridine (0.16 g) and THF (6.0 mL) were added di-tert-butyl dicarbonate (0.26 g) and N,N-dimethyl-4-aminopyridine (0.010 g) at room temperature, followed by stirring at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=0 to 25%) to obtain tert-butyl 7-bromo-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (0.22 g).
Production Example 47
To a mixture of 7-bromoindole (3.3 g) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone (33 mL) were added 2-phenyloxirane (2.5 mL) and cesium carbonate (11 g) at room temperature, followed by stirring at 80° C. for 12 hours. To the reaction mixture were added ethyl acetate and water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain 2-(7-bromo-1H-indol-1-yl)-1-phenylethanol (5.1 g).
Production Example 48
A mixture of tert-butyl 7-bromo-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (0.20 g), 1,3-bis(diphenylphosphino)propane (0.028 g), palladium acetate (0.015 g), DMF (4.0 mL), methanol (6.0 mL), and triethylamine (0.28 mL) was stirred at 80° C. for 2 days under carbon monoxide atmosphere. The reaction mixture was left to be cooled and replaced with argon. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then filtered. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=30 to 60%) to obtain methyl 1H-pyrrolo[3,2-c]pyridine-7-carboxylate (0.081 g).
Production Example 49
To a mixture of 4-[(1S)-1-({[1-(4-chlorobenzyl)-1H-indol-7-yl]carbonyl}amino)ethyl]benzoic acid (250 mg) and DMF (5 mL) was added 1,1′-carbonyldiimidazole (187 mgl) at room temperature, followed by stirring for 5 minutes, and then 3-(aminosulfonyl)propylacetate (209 mg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (173 μL) were added in this order, followed by stirring for 3 days. The reaction mixture was ice-cooled, and 10% aqueous citric acid (30 mL) was added thereto, followed by stirring for 30 minutes. The precipitated solid was collected by filtration and washed with cold ethanol (4 mL) to obtain 1-(4-chlorobenzyl)-N-[(1S)-1-(4-{[(3-acetoxypropyl)sulfonyl]carbamoyl}phenyl)ethyl]-1H-indole-7-carboxamide (210 mg) as a pale yellow solid.
Production Example 50
To methyl 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-1H-indole-7-carboxylate (0.30 g), pyridin-2-yltrifluoromethanesulfonate (0.35 g), tripotassium phosphate (0.49 g), palladium(II) chloride (27 mg), and biphenyl-2-yl(dicyclohexyl)phosphine (0.11 g) were added dioxane (12 mL) and water (3.0 mL), followed by stirring at 100° C. for 4 hours. The reaction mixture was purified by silica gel column chromatography (hexane/ethyl acetate=5/1-4/1) to obtain methyl 1-(4-pyridin-2-yl benzyl)-1H-indole-7-carboxylate (0.15 g).
Production Example 51
To 2-(7-bromo-1H-indol-1-yl)-1-phenylethanol (0.70 g) were added DMF (7.0 mL), tert-butyl(chloro)dimethylsilane (0.47 g), and imidazole (0.23 g), followed by stirring at room temperature for 25 hours. To the reaction mixture was added a 10% aqueous citric acid solution (15 mL), followed by extraction with ethyl acetate, and the obtained organic layer was washed with brine. After drying over anhydrous sodium sulfate and concentrating under reduced pressure, the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=99/1-90/10) to obtain 7-bromo-1-(2-{[tert-butyl(dimethyl)silyl]oxy}-2-phenylethyl)-1H-indole (0.92 g).
Production Example 52
To 7-bromo-1-(2-{[tert-butyl(dimethyl)silyl]oxy}-2-phenylethyl)-1H-indole (0.91 g) was added dehydrated THF (30 mL), and an n-butyl lithium hexane solution (1.6 M, 5.2 mL) was added thereto at −78° C. while replacing with argon. The mixture was warmed from −78° C. to −5° C., followed by stirring for 30 minutes. The reaction mixture was again cooled to −78° C., and dry ice was added thereto, followed by stirring to room temperature. To the mixture was added diethyl ether, followed by washing with a 1 M aqueous sodium hydroxide solution. The obtained aqueous layer was adjusted to pH 3 with a 10% aqueous citric acid solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) to obtain 1-[(E)-2-phenyl vinyl]-1H-indole-7-carboxylic acid (0.34 g).
Production Example 53
To methyl 1H-indole-7-carboxylate (1.5 g) was added DMF (15 mL), and potassium tert-butoxide (1.5 g) was added thereto under ice-cooling, followed by stirring for 10 minutes. 4-(Bromomethyl)biphenyl (2.8 g) was added thereto, followed by stirring at room temperature for 19 hours. The reaction mixture was again ice-cooled, and a 10% aqueous citric acid solution (20 mL) was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=97/3-95/5) to obtain methyl 1-(biphenyl-4-ylmethyl)-1H-indole-7-carboxylate (2.5 g).
Production Example 54
To methyl 1-(biphenyl-4-ylmethyl)-1H-indole-7-carboxylate (2.5 g) were added methanol (20 mL), THF (20 mL), and a 1 M aqueous sodium hydroxide solution (10 mL), followed by stirring at 60° C. for 16 hours. To the reaction mixture was added a 10% aqueous citric acid solution (20 mL), followed by extraction with ethyl acetate, and the organic layer was washed with brine. After dehydration over anhydrous sodium sulfate, filtering and concentrating under reduced pressure, the obtained residue was added with diisopropylether, solidified, and collected by filtration. This solid was purified by silica gel column chromatography (chloroform/methanol=99/1-97/3) to obtain 1-(biphenyl-4-ylmethyl)-1H-indole-7-carboxylic acid (0.99 g).
Production Example 55
To (6-piperidin-1-ylpyridin-3-yl)methanol (0.61 g) was added methylene chloride (6.0 mL), and thionyl chloride (1.0 mL) was added dropwise thereto under ice-cooling. In addition, a catalytic amount of DMF was added thereto, followed by stirring at room temperature for 2 hours. Methylene chloride (5.0 mL) and thionyl chloride (1.0 mL) were added thereto, followed by stirring at 60° C. overnight. The reaction mixture was concentrated under reduced pressure, and DMF (10 mL) was added thereto. Then, methyl 1H-indole-7-carboxylate (0.56 g) and potassium tert-butoxide (1.3 g) were added thereto under ice-cooling, followed by stirring at room temperature for 3 hours. The reaction mixture was extracted by adding ethyl acetate and water, and the organic layer was washed with brine, dried over anhydrous sodium sulfate, then filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5-70/30) to obtain methyl 1-[(6-piperidin-1-ylpyridin-3-yl)methyl]-1H-indole-7-carboxylate (0.12 g).
Production Example 56
To methyl 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-1H-indole-7-carboxylate (0.15 g), 1,1′-bis(diphenylphosphino)ferrocene palladium (14 mg), cesium fluoride (0.17 g), and 3-bromopyridine (79 mg) was added dioxane (4.5 mL), followed by stirring at 100° C. for 21 hours under an argon atmosphere. The reaction mixture was purified by silica gel column chromatography (hexane/ethyl acetate=2/1-1/1) to obtain methyl 1-(4-pyridin-3-yl benzyl)-1H-indole-7-carboxylate (0.13 g).
Production Example 57
To a mixture of (1-phenylpiperidin-4-yl)methanol (958 mg), methyl 1H-indole-7-carboxylate (590 mg), and toluene (20 mL) was added (tributylphosphoranylidene)acetonitrile (1.0 g) at room temperature. The mixture was stirred at 100° C. for 1 day. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain methyl 1-[(1-phenylpiperidin-4-yl)methyl]-1H-indole-7-carboxylate (163 mg).
Production Example 58
4-Phenyl thiophene-2-methanol (0.21 g), toluene (2.0 mL), and a catalytic amount of pyridine were added, and thionyl chloride (0.16 mL) was added dropwise thereto under ice-cooling. After stirring at room temperature for 3 hours, the reaction mixture was concentrated under reduced pressure, azeotroped with toluene, and dried at 60° C. under reduced pressure to obtain 2-(chloromethyl)-4-phenylthiophene (0.22 g).
Production Example 59
To a mixture of methyl 4-bromo-1-(4-chlorobenzyl)-1H-pyrrole-2-carboxylate (0.72 g) and DMF (21 mL) were added phenylboric acid (0.30 g), sodium carbonate (0.58 g), water (3.0 mL), and tetrakis(triphenylphosphine) palladium (0.13 g), followed by stirring at 100° C. for 24 hours. To the reaction mixture were added ethyl acetate and water, and the insoluble materials were separated by filtration through Celite. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=0 to 10%) to obtain methyl 1-(4-chlorobenzyl)-4-phenyl-1H-pyrrole-2-carboxylate (0.26 g).
Production Example 60
To a mixture of tert-butyl 4-{[7-({(1S)-1-[4-(methoxycarbonyl)phenyl]ethyl}carbamoyl)-1H-indol-1-yl]methyl}piperidine-1-carboxylate (1.67 g), and THF (20 mL) was added a 4 M hydrogen chloride ethyl acetate solution (2.0 mL) at room temperature, followed by stirring for 1 hour. The reaction mixture was stirred at 60° C. for 6 hours. The reaction mixture was concentrated under reduced pressure. The residue was washed with ethyl acetate and diethyl ether, collected by filtration, and dried under reduced pressure to obtain methyl 4-[(1S)-1-({[1-(piperidin-4-ylmethyl)-1H-indol-7-yl]carbonyl}amino)ethyl]benzoate hydrochloride (1.46 g).
Production Example 61
To a mixture of methyl 4-[(1S)-1-({[1-(piperidin-4-ylmethyl)-1H-indol-7-yl]carbonyl}amino)ethyl]benzoate hydrochloride (150 mg) and dichloromethane (2.0 mL) were added sodium triacetoxyborohydride (210 mg) and benzaldehyde (70 mg) at room temperature, followed by stirring for 3 days. To the reaction mixture was added water. In addition, the mixture was alkalified by adding a 1 M aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain methyl 4-{(1S)-1-[({1-[(1-benzyl piperidin-4-yl)methyl]-1H-indol-7-yl}carbonyl)amino]ethyl}benzoate (121 mg) as a white solid.
Production Example 62
To methyl 1-(1,3-benzoxazol-2-ylmethyl)-1H-indole-7-carboxylate (0.22 g), methanol (2.0 mL), and THF (2.0 mL) was added a 1 M aqueous sodium hydroxide solution (1.0 mL), followed by stirring at 70° C. for 14 hours. The reaction mixture was ice-cooled, a 10% aqueous citric acid solution (5.0 mL) was added thereto, and the precipitated solid was collected by filtration, and washed with water and diethyl ether/hexane (1/1) to obtain 1-{2-[(2-hydroxyphenyl)amino]-2-oxo ethyl}-1H-indole-7-carboxylic acid (0.18 g).
Production Example 63
To a mixture of methyl 4-{[(1H-benzimidazol-2-ylcarbonyl)amino]methyl}benzoate (230 mg), potassium carbonate (257 mg), and DMF (4.6 mL) was added p-chlorobenzylbromide (191 mg), followed by stirring at room temperature for 2.5 days. To the reaction mixture was added water (30 mL), followed by extraction with ethyl acetate (30 mL). The organic layer was sequentially washed with saturated aqueous sodium bicarbonate and saturated brine, and dried over anhydrous magnesium sulfate. After filtration and concentration, the obtained residue was washed with methanol (2 mL) to obtain methyl 4-[({[1-(4-chlorobenzyl)-1H-benzimidazol-2-yl]carbonyl}amino)methyl]benzoate (269 mg) as a white solid.
Production Example 64
To a mixture of ethyl 5-chloro-1H-indole-7-carboxylate (3.0 g) and acetic acid (30 mL) was added sodium cyanoborohydride (2.5 g), followed by stirring at room temperature for 19 hours. The reaction mixture was concentrated under reduced pressure, and the residue was adjusted to pH 8 by adding saturated aqueous sodium bicarbonate. After extraction with chloroform, the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was added with diethyl ether/hexane (1/5), solidified, and collected by filtration. To this solid was added ethyl acetate (10 mL), and 4 M hydrogen chloride ethyl acetate (10 mL) was added thereto, followed by concentration under reduced pressure. To the residue was added diethyl ether/hexane mixture (1/5), and the solid was collected by filtration and dried under reduced pressure to obtain ethyl 5-chloroindoline-7-carboxylate hydrochloride (1.6 g).
Production Example 65
A mixture of ethyl 1-[(5-bromopyridin-2-yl)methyl]-5-chloro-1H-indole-7-carboxylate (0.30 g), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (88 mg), sodium tert-butoxide (0.12 g), piperidine (84 mg), tris(dibenzylideneacetone)dipalladium (0) (70 mg), and dehydrated toluene (6.0 mL) was bubbled with argon for 10 minutes, followed by stirring at 110° C. for 2 hours. The reaction mixture was filtered through Celite and washed with diethyl ether. To this filtrate was added saturated aqueous sodium bicarbonate, followed by extraction with diethyl ether, and the organic layer was washed with saturated brine. After drying over anhydrous sodium sulfate, filtering and concentrating under reduced pressure, the residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to obtain ethyl 5-chloro-1-[(5-piperidin-1-ylpyridin-2-yl)methyl]-1H-indole-7-carboxylate (0.23 g).
Production Example 66
A mixture of 2-fluoro-5-(trifluoromethyl)benzonitrile (1000 mg), 5-chloro-1H-indole (800 mg), potassium carbonate (1.8 g), and DMSO (10 ml) was stirred at 100° C. for 14 hours. The reaction mixture was cooled to room temperature, and water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 2-(5-chloro-1H-indol-1-yl)-5-(trifluoromethyl)benzonitrile (1.66 g).
Production Example 67
To a mixture of 2-(5-chloro-1H-indol-1-yl)-5-(trifluoromethyl)benzonitrile (1.66 g) and ethylene glycol (18 mL) was added a 1 M aqueous sodium hydroxide solution (26 mL) at room temperature, followed by stirring at 180° C. for 16 hours. The reaction mixture was cooled to room temperature and neutralized by adding 1 M hydrochloric acid (26 mL), followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 2-(5-chloro-1H-indol-1-yl)-5-(trifluoromethyl)benzoic acid (1.67 g).
Production Example 68
To a mixture of ethyl 1-(1,2,3,4-tetrahydroisoquinolin-7-ylmethyl)-5-(trifluoromethyl)-1H-indole-7-carboxylate (0.14 g) and ethyl acetate (10 mL) was added manganese dioxide (0.30 g) at room temperature. The reaction liquid was stirred for 6.5 hours under the condition for heating with reflux. In addition, to the reaction liquid were added toluene (10 mL) and manganese dioxide (0.30 g) at room temperature, followed by stirring at 110° C. for 1 day and then at 130° C. for 1 day. The reaction liquid was left to be cooled to room temperature, and filtered using Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=75:25-30:70) to obtain ethyl 1-(isoquinolin-7-ylmethyl)-5-(trifluoromethyl)-1H-indole-7-carboxylate (85 mg).
Production Example 505
To a mixture of 4-bromo-3-chloro-2-methyl aniline hydrochloride (1.0 g), sodium acetate (0.5 g), and acetic acid (15 mL) was added N-iodosuccinimide (1.0 g) under water-cooling. The reaction mixture was stirred at room temperature for 3.5 hours. To the reaction mixture were added ethyl acetate and water, and alkalified by adding potassium carbonate. Then, a liquid-separation operation was carried out, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0-90:10) to obtain 4-bromo-3-chloro-6-iodo-2-methylaniline (1.3 g).
Production Example 506
To a mixture of N-[2-methyl-3-(trifluoromethyl)phenyl]acetamide (6.2 g) and acetic acid (40 ml) was added an acetic acid solution (10 ml) of bromine (1.8 ml) under water-cooling. The reaction liquid was stirred at room temperature overnight and then at 50° C. for 2 hours. In addition, to the reaction liquid was added bromine (1.5 ml) under water-cooling, followed by stirring at 50° C. for 1 day. In addition, to the reaction liquid was added bromine (2.0 ml) under water-cooling, followed by stirring at 50° C. for 1 day. In addition, to the reaction liquid was added bromine (2.0 ml) under water-cooling, followed by stirring at 50° C. for 1 day. In addition, to the reaction liquid was added bromine (2.0 ml) under water-cooling, followed by stirring at 50° C. for 4 days. The reaction liquid was poured into ice water (about 200 g), ethyl acetate was added thereto, followed by neutralization with potassium carbonate. A liquid-separation operation was carried out, and the organic layer was washed with an aqueous sodium thiosulfate solution and saturated brine in this order, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure to obtain N-[4-bromo-2-methyl-3-(trifluoromethyl)phenyl]acetamide (9.0 g).
Production Example 507
To a mixture of tert-butyl 5-bromo-7-(bromomethyl)-6-chloro-1H-indole-1-carboxylic acid (7.2 g) and acetonitrile (50 mL) was added 4-methyl morpholine-4-oxide (2.7 g) at room temperature. The reaction mixture was stirred at 50° C. for 7 hours and then at 70° C. overnight. The reaction mixture was concentrated under reduced pressure, ethyl acetate and water were added thereto, and a liquid-separation operation was carried out. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0-90:10) to obtain tert-butyl 5-bromo-6-chloro-7-formyl 1H-indole-1-carboxylic acid (2.9 g).
Production Example 508
To a mixture of tert-butyl 5-bromo-6-chloro-7-formyl 1H-indole-1-carboxylic acid (2.9 g), sodium dihydrogen phosphate (2.0 g), 2-methyl-2-butene (2.6 g), water (10 mL), and 1,4-dioxane (30 mL) was added sodium chlorite (1.8 g) under ice-cooling. The reaction mixture was stirred under ice-cooling for 1 hour, and then at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and ethyl acetate and water were added thereto, and a liquid-separation operation was carried out. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure to obtain 5-bromo-1-(tert-butoxycarbonyl)-6-chloro-1H-indole-7-carboxylic acid (3.1 g).
Production Example 509
To a mixture of 5-bromo-1-(tert-butoxycarbonyl)-6-chloro-1H-indole-7-carboxylic acid (0.3 g), water (2.0 mL), and methanol (6.0 mL) was added potassium carbonate (0.6 g) at room temperature. The reaction mixture was stirred at 70° C. for 5.5 hours. The reaction mixture was concentrated under reduced pressure, and ethyl acetate and water were added thereto, followed by acidification with 1 M hydrochloric acid. Then, a liquid-separation operation was carried out, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure to obtain 5-bromo-6-chloro-1H-indole-7-carboxylic acid (0.22 g).
Production Example 510
To a mixture of N-[4-bromo-2-methyl-3-(trifluoromethyl)phenyl]acetamide (9.0 g) and ethanol (40 mL) was added concentrated hydrochloric acid (40 mL) at room temperature. The reaction mixture was stirred at 100° C. for 4 hours. The reaction mixture was left to be cooled to room temperature, and ethyl acetate and water were added thereto, followed by alkalification with potassium carbonate. Then, a liquid-separation operation was carried out, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate 90:10-60:40) to obtain 4-bromo-2-methyl-3-(trifluoromethyl) aniline (6.9 g).
Production Example 511
To a mixture of 4-amino-3-bromo-5-iodobenzonitrile (1.0 g), copper iodide (60 mg), and triethylamine (10 mL) was added bistriphenylphosphine palladium dichloride (0.22 g) under an argon atmosphere, and degassed twice with argon. Ethynyl trimethylsilane (0.47 mL) was added thereto under ice-cooling, followed by stirring at room temperature for 24 hours. The insoluble materials in the reaction mixture were separated by filtration through Celite, and the filtrate was concentrated under reduced pressure. To the residue were added a 10% aqueous citric acid solution and ethyl acetate, and the insoluble materials were separated again by filtration. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, water, and saturated brine, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:chloroform=2:1) to obtain 4-amino-3-bromo-5-[(trimethylsilyl)ethynyl]benzonitrile (0.81 g).
Production Example 512
To a mixture of 4-amino-3-bromo-5-[(trimethylsilyl)ethynyl]benzonitrile (0.80 g) and tetrahydrofuran (3.0 mL) was added a 1 M tetrabutyl ammonium fluoride-THF solution (3.0 mL) under ice-cooling, followed by stirring at room temperature for 0.5 hour. To the reaction mixture was added water under ice-cooling, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/hexane=30-50%) to obtain 4-amino-3-bromo-5-ethynylbenzonitrile (0.57 g).
Production Example 513
To a mixture of tert-butyl 5-bromo-7-methyl-6-(trifluoromethyl)-1H-indole-1-carboxylic acid (1.2 g) and carbon tetrachloride (20 mL) were added N-bromosuccinimide (0.70 g) and 2,2′-azobis(2-methylpropionitrile) (20 mg) at room temperature. The reaction mixture was stirred at 90° C. for 18 hours. The reaction mixture was left to be cooled to room temperature and filtered through Celite to remove the insoluble materials. The filtrate was evaporated under reduced pressure, and to the residue was added acetonitrile (20 mL), followed by addition of 4-methyl morpholine-4-oxide (0.50 g) under ice-cooling. The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was evaporated under reduced pressure, ethyl acetate and water were added thereto, and a liquid-separation operation was carried out. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0-90:10) to obtain tert-butyl 5-bromo-7-formyl-6-(trifluoromethyl)-1H-indole-1-carboxylic acid (0.26 g).
Production Example 514
To a mixture of 4-amino-3-bromo-5-ethynylbenzonitrile (0.57 g) and 1-methyl-2-pyrrolidinone (12 mL) was added tert-butylcarbamate (0.57 g) under ice-cooling, followed by stirring at room temperature for 24 hours. To the reaction mixture was added a 10% aqueous citric acid solution under ice-cooling, followed by extraction with ethyl acetate. The organic layer was washed with water, a saturated aqueous sodium hydrogen carbonate solution, water, and saturated brine, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to obtain 7-bromo-1H-indole-5-carbonitrile (0.55 g).
Production Example 515
To a mixture of methyl trans-4-[({[5-bromo-6-chloro-1-(isoquinolin-3-ylmethyl)-1H-indol-7-yl]carbonyl}amino)methyl]cyclohexane carboxylate (0.28 g), sodium formate (0.10 g), and DMSO (5.0 mL) was added tetrakis(triphenylphosphine) palladium (20 mg) at room temperature. The reaction mixture was stirred at 70° C. for 2 hours and then at 90° C. for 3 hours. In addition, to the reaction mixture were added sodium formate (0.10 g) and tetrakis(triphenylphosphine) palladium (40 mg) in this order at room temperature, followed by stirring overnight at 90° C. To the reaction liquid were added ethyl acetate and water, and the insoluble materials were removed by filtration through Celite. The filtrate was subjected to a liquid-separation operation, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol:chloroform=0:100-5:95) to obtain methyl trans-4-[({[6-chloro-1-(isoquinolin-3-ylmethyl)-1H-indol-7-yl]carbonyl}amino)methyl]cyclohexane carboxylic acid (0.14 g).
Production Example 516
To a mixture of methyl trans-4-[({[5-bromo-6-(trifluoromethyl)-1H-indol-7-yl]carbonyl}amino)methyl]cyclohexane carboxylic acid (75 mg), triethylamine (0.1 mL), and methanol (5.0 mL) was added 10% palladium-carbon (80 mg) under ice-cooling. The reaction liquid was stirred at room temperature for 1 day under 1-atom hydrogen. The insoluble materials of the reaction liquid were removed by filtration through Celite, and evaporated under reduced pressure. To the residue was added ethyl acetate and water, and a liquid-separation operation was carried out. The organic layer was washed with a 5% aqueous citric acid solution and saturated brine in this order, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=80:20-50:50) to obtain methyl trans-4-[({[6-(trifluoromethyl)-1H-indol-7-yl]carbonyl}amino)methyl]cyclohexane carboxylic acid (41 mg).
The Production Example compounds shown in Tables below were prepared in the same manner as in Production Examples above, using the respective corresponding starting materials. The structures of the Production Example compounds are shown in Table 3 to Table 136 and the production processes, and the physical data of the Production Example compounds are shown in Tables 201 to 211.
Example 1
To a solution of methyl 4-[(1S)-1-({[1-(4-chlorobenzyl)-1,2,3,4-tetrahydroquinolin-8-yl]carbonyl}amino)ethyl]benzoate (129 mg) in THF (2.0 mL) and methanol (1.0 mL) was added a 1 M aqueous sodium hydroxide solution (1.0 mL) at room temperature, followed by stirring for 2 days. The reaction mixture was neutralized by adding 1 M hydrochloric acid (1.0 mL) at room temperature, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate). The resulting product was dissolved in ethyl acetate (2.0 mL), and to the solution was added a 4 M hydrogen chloride ethyl acetate solution (2.0 mL) at room temperature, followed by stirring for 1 day. The solvent was evaporated under reduced pressure, and the residue was washed with ethyl acetate, collected by filtration, and dried under reduced pressure to obtain 4-[(1S)-1-({[1-(4-chlorobenzyl)-1,2,3,4-tetrahydroquinolin-8-yl]carbonyl}amino)ethyl]benzoic acid hydrochloride (97 mg).
Example 2
To a mixture of 1-(4-chlorobenzyl)-1H-indole-7-carboxylic acid (0.20 g), methyl 4-(aminomethyl)-3-chlorobenzoate hydrochloride (0.18 g), and HATU (0.32 g) in DMF (4.0 mL) was added diisopropylethylamine (0.29 ml) under ice-cooling, followed by stirring at room temperature for 14 hours. After ice-cooled again, a 5% aqueous citric acid solution (8.0 mL) was added thereto, and the precipitated solid was collected by filtration, sequentially washed with water and diisopropylether, and dried at 60° C. under reduced pressure. To the obtained solid were added methanol (3.0 mL), THF (3.0 mL), and a 1 M aqueous sodium hydroxide solution (2.0 mL), followed by stirring at 60° C. for 2 hours. The reaction mixture was left to be cooled, a 10% aqueous citric acid solution (5.0 mL) was added thereto, and the precipitated solid was collected by filtration, washed with water, and dried at 60° C. under reduced pressure to obtain 3-chloro-4-[({[1-(4-chlorobenzyl)-1H-indol-7-yl]carbonyl}amino)methyl]benzoic acid (0.24 g).
Example 3
To methyl 4-[(1S)-1-({[1-(biphenyl-4-ylmethyl)-1H-indol-7-yl]carbonyl}amino)ethyl]benzoate (0.30 g) were added methanol (4.0 mL), THF (4.0 mL), and a 1 M aqueous sodium hydroxide solution (3.0 mL), followed by stirring at 65° C. for 2 hours and then at room temperature for 3 days. To the reaction mixture was added a 10% aqueous citric acid solution (4.0 mL), and the precipitated solid was collected by filtration, washed with water and a mixture of diethyl ether/hexane (1/1), and dried at 60° C. under reduced pressure to obtain 4-[(1S)-1-({[1-(biphenyl-4-ylmethyl)-1H-indol-7-yl]carbonyl}amino)ethyl]benzoic acid (0.25 g).
Example 4
To a mixture of 4-{(1S)-1-[({1-[(6-chloropyridin-3-yl)methyl]-1H-indol-7-yl}carbonyl)amino]ethyl}benzoic acid (0.15 g), phenylboronic acid (84 mg), tripotassium phosphate (0.22 g), palladium (II) chloride (9.2 mg), and biphenyl-2-yl(dicyclohexyl) phosphine (36 mg) were added dioxane (6.0 mL), water (1.5 mL), followed by stirring at 100° C. for 1 hour. The reaction mixture was adjusted to pH 3 by adding a 10% aqueous citric acid solution. The mixed liquid was filtered through Celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/THF=2/1-1/1) to obtain 4-{(1S)-1-[({1-[(6-phenylpyridin-3-yl)methyl]-1H-indol-7-yl}carbonyl)amino]ethyl}benzoic acid (66 mg).
Example 5
To 4-{(1S)-1-[({1-[(6-chloropyridin-3-yl)methyl]-1H-indol-7-yl}carbonyl)amino]ethyl}benzoic acid (95 mg) were added ethanol (2.0 mL) and piperidine (65 μL), followed by stirring at room temperature overnight. After concentration under reduced pressure, DMSO (1.0 mL), piperidine (65 μL), and potassium tert-butoxide (61 mg) were added thereto, followed by stirring at 80° C. for 2 hours. To the reaction mixture was added a 10% aqueous citric acid solution (10 mL), followed by extraction with ethyl acetate. The obtained organic layer was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=99/1-95/5) to obtain 4-{(1S)-1-[({1-[(6-ethoxypyridin-3-yl)methyl]-1H-indol-7-yl}carbonyl)amino]ethyl}benzoic acid (9.0 mg).
Example 6
To a mixture of 1-(4-chlorobenzyl)-N-[(1S)-1-(4-{[(3-acetoxypropyl)sulfonyl]carbamoyl}phenyl)ethyl]-1H-indole-7-carboxamide (200 mg), THF (3 mL), and methanol (3 mL) was added a 1 M aqueous sodium hydroxide solution (1.7 mL), followed by stirring at room temperature overnight. The reaction mixture was adjusted to pH 4 by adding 1 M hydrochloric acid (1.7 mL), and further, water (20 mL) was added thereto, followed by stirring at room temperature for 30 minutes. The precipitated solid was collected by filtration, washed with water (4 mL), and then washed with cold ethanol (3 mL) to obtain 1-(4-chlorobenzyl)-N-[(1S)-1-(4-{[(3-hydroxypropyl)sulfonyl]carbamoyl}phenyl)ethyl]-1H-indole-7-carboxamide (80 mg) as a pale yellow solid.
The Example compounds shown in Tables below were prepared in the same manner as in Examples above, using the respective corresponding starting materials. The structures of the Example compounds are shown in Table 137 to Table 200 and the production processes and the physical data of the Example compounds are shown in Table 212 to Table 223.
Furthermore, other embodiments of the compound of the formula (I) or a salt thereof are shown in Tables 224 to 228. These compounds can be easily prepared by the preparation methods above, the methods described in Examples, the methods apparent to a skilled person in the art, or modified methods thereof.
In addition, the following abbreviations are used in Tables below.
Pr: Production Example number (a case where in Production Example, “/Cl” is described after Production Example number means that the Production Example compound was isolated as a hydrochloride), Ex: Example number (a case where in Example, “/Cl” is described after Example number means that the Example compound was isolated as a hydrochloride), No: Compound number, Structure: Structural formula (Ac: acetyl, TMS: trimethylsilyl, TBS: tert-butyl dimethylsilyl), Syn: Production process (among Examples or Production Examples above, the Production Example number or Example number produced in the same manner is shown. For example, it represents that the compound of Production Example 69 was prepared in the same manner as for the compound of Production Example 38), Data: Physicochemical data (values measured with NMR-C: δ (ppm) in 1 H NMR in CDCl 3 , NMR-D: δ (ppm) in 1 H-NMR in DMSO-d 6 , FAB+: FAB-MS (cation), FAB−: FAB-MS (anion), ESI+: ESI-MS (cation), ESI−: ESI-MS (anion), APCI+: APCI-MS (cation), EI: ELMS (cation), CI+: CI-MS (cation), APCl/ESI+: APCI-MS (cation), or ESI-MS (cation), mp: melting point (° C., dec: decomposition)).








TABLE 3





Pr
Structure





1














2














3/Cl














4














5














6











































TABLE 4



Pr
Structure



7












8












9/Cl












10












11










































TABLE 5





Pr
Structure





12














13














14














15














16











































TABLE 6





Pr
Structure





17














18














19/Cl














20














21














22













































TABLE 7





Pr
Structure





23














24














25














26














27














28













































TABLE 8





Pr
Structure





29














30/Cl














31/Cl














32














33/Cl














34













































TABLE 9





Pr
Structure





35/Cl














36














37/Cl














38














39














40













































TABLE 10





Pr
Structure





41a














41b














42














43









































TABLE 11





Pr
Structure











44














45














46














47














48













































TABLE 12



Pr
Structure








49












50












51












52












53














































TABLE 13





Pr
Structure











54














55














56














57













































TABLE 14





Pr
Structure











58














59














60/Cl














61











































TABLE 15



Pr
Structure








62












63












64/Cl












65












































TABLE 16





Pr
Structure











66














67














68














69













































TABLE 17





Pr
Structure











70














71














72














73














74















































TABLE 18





Pr
Structure











75














76














77














78













































TABLE 19





Pr
Structure











79














80














81














82














83













































TABLE 20



Pr
Structure








84












85












86












87












88












































TABLE 21



Pr
Structure








89












90












91












92












































TABLE 22





Pr
Structure











93














94














95














96













































TABLE 23





Pr
Structure











97














98














99














100













































TABLE 24





Pr
Structure











101














102














103














104













































TABLE 25





Pr
Structure











105














106














107














108











































TABLE 26



Pr
Structure



109












110












111












112












113








































TABLE 27



Pr
Structure



114












115












116












117












118








































TABLE 28



Pr
Structure



119












120












121/Cl












122












123








































TABLE 29



Pr
Structure



124












125












126












127






































TABLE 30



Pr
Structure



128












129












130












131








































TABLE 31





Pr
Structure





132














133














134














135







































TABLE 32



Pr
Structure



136












137












138












139






































TABLE 33



Pr
Structure



140












141












142












143






































TABLE 34



Pr
Structure



144












145












146












147






































TABLE 35



Pr
Structure



148












149












150












151












152








































TABLE 36



Pr
Structure



153












154












155












156






































TABLE 37



Pr
Structure



157












158












159












160








































TABLE 38





Pr
Structure





161/Cl














162














163














164







































TABLE 39



Pr
Structure



165












166












167












168








































TABLE 40





Pr
Structure





169














170














171














172









































TABLE 41





Pr
Structure





173














174














175














176







































TABLE 42



Pr
Structure



177












178












179












180








































TABLE 43





Pr
Structure





181














182














183














184







































TABLE 44



Pr
Structure



185












186












187/Cl












188/Cl












189










































TABLE 45





Pr
Structure





190














191














192














193














194











































TABLE 46





Pr
Structure





195














196














197














198









































TABLE 47





Pr
Structure





199














200














201














202







































TABLE 48



Pr
Structure



203












204












205












206








































TABLE 49





Pr
Structure





207














208














209














210









































TABLE 50





Pr
Structure





211/Cl














212














213














214









































TABLE 51





Pr
Structure





215














216














217














218









































TABLE 52





Pr
Structure





219














220














222














223









































TABLE 53





Pr
Structure





225














226














227














228









































TABLE 54





Pr
Structure





229














230














231














232









































TABLE 55





Pr
Structure





233














234














235














236









































TABLE 56





Pr
Structure





237














238














239














240









































TABLE 57





Pr
Structure





241














242














243














244









































TABLE 58





Pr
Structure





245














246














247














248









































TABLE 59





Pr
Structure





249














250














251














252









































TABLE 60





Pr
Structure





253














254/Cl














255














256









































TABLE 61





Pr
Structure





257














258














259














260









































TABLE 62





Pr
Structure





261














262














263







































TABLE 63





Pr
Structure





264














266














267














268









































TABLE 64





Pr
Structure





269














270














271














272









































TABLE 65





Pr
Structure





273














274














275














276









































TABLE 66





Pr
Structure





277














278














279














280







































TABLE 67



Pr
Structure



281












282












283












284






































TABLE 68



Pr
Structure





285












286












287












288







































TABLE 69



Pr
Structure



289












290












291












292






































TABLE 70



Pr
Structure



293












294












295






































TABLE 71





Pr
Structure





296














297














298














299









































TABLE 72





Pr
Structure





300














301














302














303









































TABLE 73





Pr
Structure





304














305














306














307









































TABLE 74





Pr
Structure





309














309














310














311














312











































TABLE 75





Pr
Structure





313














314














315














316














317











































TABLE 76





Pr
Structure





318














319














320














321









































TABLE 77





Pr
Structure





322














323














324







































TABLE 78





Pr
Structure





325














326














327







































TABLE 79





Pr
Structure





328














329














330







































TABLE 80





Pr
Structure





331














332














333







































TABLE 81





Pr
Structure





334














335














336





































TABLE 82



Pr
Structure



337












338












339












340






































TABLE 83



Pr
Structure



341












342












343












344








































TABLE 84





Pr
Structure





345














346














347














348









































TABLE 85





Pr
Structure





349














350














351














352









































TABLE 86





Pr
Structure





353














354














355














356









































TABLE 87





Pr
Structure





357














358














359














360









































TABLE 88





Pr
Structure





361














362














363














364









































TABLE 89





Pr
Structure





366














367














368







































TABLE 90





Pr
Structure





369














370














371







































TABLE 91





Pr
Structure





372














373














374







































TABLE 92





Pr
Structure





375














376














377





































TABLE 93



Pr
Structure



378












379












380












381








































TABLE 94





Pr
Structure





382














383














384














385









































TABLE 95





Pr
Structure





386














387














388





































TABLE 96



Pr
Structure



389












390












391












392








































TABLE 97





Pr
Structure





393














394














395














396







































TABLE 98



Pr
Structure



397












398












399












400






































TABLE 99



Pr
Structure



401












402












403




































TABLE 100



Pr
Structure



404












405












406






































TABLE 101





Pr
Structure





407














408














409














410







































TABLE 102



Pr
Structure



411












412












413












414






































TABLE 103



Pr
Structure



415












416












417












418






































TABLE 104



Pr
Structure



419












420












421




































TABLE 105



Pr
Structure



422












423












424












425






































TABLE 106



Pr
Structure



426












427












428












429






































TABLE 107



Pr
Structure



430












431












432




































TABLE 108



Pr
Structure



433












434












435




































TABLE 109



Pr
Structure



436












437












438




































TABLE 110



Pr
Structure



439












440












441












442






































TABLE 111



Pr
Structure



443












444












445












446






































TABLE 112



Pr
Structure



447












448












449












450






































TABLE 113



Pr
Structure



451












452












453






































TABLE 114





Pr
Structure





454














455














456














457









































TABLE 115





Pr
Structure





458














459














460














461














462









































TABLE 116



Pr
Structure



463












464












465












466






































TABLE 117



Pr
Structure








467












468












469












470










































TABLE 118



Pr
Structure



471












472












473












474






































TABLE 119



Pr
Structure



475












476












477












478






































TABLE 120



Pr
Structure



479












480












481












482








































TABLE 121





Pr
Structure





483














484














485














486









































TABLE 122





Pr
Structure





487














488














489














490







































TABLE 123



Pr
Structure



491












492












493












494






































TABLE 124



Pr
Structure



495












496












497












498






































TABLE 125



Pr
Structure



499












500












501












502






































TABLE 126



Pr
Structure



503












504












505












506








































TABLE 127





Pr
Structure





507














508














509














510














511











































TABLE 128





Pr
Structure





512














513














514














515














516











































TABLE 129





Pr
Structure





517














518














519














520














521











































TABLE 130





Pr
Structure





522














523














524














525







































TABLE 131



Pr
Structure



526












527












528












529








































TABLE 132





Pr
Structure





530














531














532














533














534









































TABLE 133



Pr
Structure



535












536












537












538






































TABLE 134



Pr
Structure



539












540












541












542






































TABLE 135



Pr
Structure



543












544












545












546






































TABLE 136



Pr
Structure



547












548












549






































TABLE 137





Ex
Structure





1/Cl














2














3














4







































TABLE 138



Ex
Structure



5












6












7












8








































TABLE 139





Ex
Structure





9














10














11














12









































TABLE 140





Ex
Structure





13














14














15














16









































TABLE 141





Ex
Structure





17














18














19














20









































TABLE 142





Ex
Structure





21/Cl














22














23














24









































TABLE 143





Ex
Structure





25














26














27














28









































TABLE 144





Ex
Structure





29














30














31














32









































TABLE 145





Ex
Structure





33














34














35














36








































TABLE 146




Ex
Structure




37













38













39













40







































TABLE 147




Ex
Structure




41













42













43













44







































TABLE 148




Ex
Structure




45













46













47













48







































TABLE 149




Ex
Structure




49













50













51













52







































TABLE 150




Ex
Structure




53













54













55













56






































TABLE 151



Ex
Structure



57












58












59












60







































TABLE 152




Ex
Structure




61













62













63













64







































TABLE 153




Ex
Structure




65













66













67













68







































TABLE 154




Ex
Structure




69













70













71













72







































TABLE 155




Ex
Structure




73













74













75













76







































TABLE 156




Ex
Structure




77













78













79













80







































TABLE 157




Ex
Structure




81













82













83













84






































TABLE 158



Ex
Structure



85












86












87












88







































TABLE 159




Ex
Structure




89













90













91













92







































TABLE 160




Ex
Structure




93













94













95













96







































TABLE 161




Ex
Structure




97













98













99













100







































TABLE 162




Ex
Structure




101













102













103













104







































TABLE 163




Ex
Structure




105













106













107













108







































TABLE 164




Ex
Structure




109













110













112













113







































TABLE 165




Ex
Structure




114













115













116













117






































TABLE 166



Ex
Structure



118












119












120












121







































TABLE 167




Ex
Structure




122













123













124













125






































TABLE 168



Ex
Structure



126












127












128












129






































TABLE 169



Ex
Structure



130












131












132












133







































TABLE 170




Ex
Structure




134













135













136













137







































TABLE 171




Ex
Structure




138













139













140













141







































TABLE 172




Ex
Structure




142













143













144













145







































TABLE 173




Ex
Structure




146













147













148













149







































TABLE 174




Ex
Structure




150













151













152





































TABLE 175




Ex
Structure




153













154













155






































TABLE 176





Ex
Structure





156














157














158














159









































TABLE 177





Ex
Structure





160














161














162














163









































TABLE 178





Ex
Structure





164














165














166














167









































TABLE 179





Ex
Structure





168














169














170







































TABLE 180





Ex
Structure





171














172














173







































TABLE 181





Ex
Structure





174














175














176







































TABLE 182





Ex
Structure





177














178














179







































TABLE 183





Ex
Structure





180














181














182





































TABLE 184



Ex
Structure



183












184












185/Cl






































TABLE 185





Ex
Structure





186














187














188














189









































TABLE 186





Ex
Structure





190














191














192














193









































TABLE 187





Ex
Structure





194














195














196







































TABLE 188





Ex
Structure





197














198














199







































TABLE 189





Ex
Structure





200














201














202







































TABLE 190





Ex
Structure





203














204














205





































TABLE 191



Ex
Structure



206












207












208












209






































TABLE 192



Ex
Structure



210












211












212




































TABLE 193



Ex
Structure



213












214












215












216






































TABLE 194



Ex
Structure



217












218












219












220






































TABLE 195



Ex
Structure



221












222












223












224






































TABLE 196



Ex
Structure



225












226












227












228






































TABLE 197



Ex
Structure



229












230












231












232






































TABLE 198



Ex
Structure



233












234












235












236






































TABLE 199



Ex
Structure



237












238












239




































TABLE 200



Ex
Structure



240












241




































TABLE 201




Pr
Syn
Data




1
Pr 1
ESI+: 224


2
Pr 2
CI+: 226


3/Cl
Pr 3
FAB+: 200


4
Pr 4
ESI+: 330


5
Pr 5
ESI+: 303


6
Pr 6
ESI+: 456


7
Pr 7
ESI+: 463


9/Cl
Pr 9
ESI+: 186


10
Pr 10
FAB+: 238


11
Pr 11
ESI+: 373


12
Pr 12
ESI+: 497


13
Pr 13
ESI+: 314


14
Pr 14
ESI+: 302


15
Pr 15
ESI+: 272


16
Pr 16
ESI+: 180


17
Pr 17
ESI+: 272


19/Cl
Pr 19
ESI+: 194


20
Pr 20
ESI+: 182


21
Pr 21
ESI+: 207


23
Pr 23
ESI+: 267


24
Pr 24
ESI+: 237


25
Pr 25
ESI+: 289


27
Pr 27
ESI+: 256


30/Cl
Pr 30
ESI+: 210


31/Cl
Pr 31
ESI−: 198


32
Pr 32
ESI+: 276


34
Pr 34
ESI−: 190


35/Cl
Pr 35
ESI+: 224


36
Pr 36
ESI+: 240


37/Cl
Pr 37
FAB+: 180


38
Pr 38
ESI+: 489


39
Pr 39
ESI+: 227


40
Pr 40
ESI+: 190


41a
Pr 41a
ESI+: 278


41b
Pr 41b
ESI+: 278


42
Pr 42
ESI+: 254


43
Pr 43
ESI+: 296


44
Pr 44
ESI+: 392


46
Pr 46
ESI+: 297


47
Pr 47
EI: 315, 317


48
Pr 48
ESI+: 177


49
Pr 49
ESI+: 596


50
Pr 50
ESI+: 343


51
Pr 51
EI: 431


52
Pr 52
ESI−: 262


53
Pr 53
EI: 341


54
Pr 54
ESI−: 326


55
Pr 55
ESI+: 350


56
Pr 56
ESI+: 343


57
Pr 57
ESI+: 349


60/Cl
Pr 60
ESI+: 420


61
Pr 61
ESI+: 510


62
Pr 62
ESI−: 309


63
Pr 63
ESI+: 434


64/Cl
Pr 64
ESI+: 226


65
Pr 65
ESI+: 398


66
Pr 66
EI: 320


67
Pr 67
ESI−: 338


68
Pr 68
ESI+: 399


69
Pr 38
ESI+: 447


71
Pr 54
ESI+: 286


72
Pr 54
ESI+: 289


73
Pr 53
ESI+: 300


74
Pr 54
ESI+: 286


75
Pr 53
ESI+: 317


76
Pr 54
ESI+: 303


77
Pr 7
ESI+: 422


78
Pr 54
ESI+: 302


79
Pr 53
ESI+: 348


80
Pr 54
ESI+: 320


81
Pr 38
ESI+: 451


82
Pr 5
ESI+: 351
































































































TABLE 202




Pr
Syn
Data




83
Pr 54
ESI+: 323


84
Pr 7
ESI+: 484


85
Pr 38
ESI+: 485


86
Pr 5
ESI+: 317


87
Pr 54
ESI+: 303


88
Pr 38
ESI+: 464


89
Pr 38
ESI+: 465


90
Pr 38
ESI+: 487


91
Pr 7
ESI+: 441


92
Pr 4
ESI+: 316


93
Pr 54
FAB+: 302


94
Pr 38
ESI+: 330


95
Pr 7
ESI+: 463


96
Pr 7
ESI+: 484


97
Pr 7
ESI+: 470


98
Pr 7
ESI+: 413


99
Pr 54
ESI+: 316


100
Pr 11
ESI+: 369


101
Pr 38
ESI+: 477


102
Pr 38
ESI+: 492


103
Pr 53
ESI+: 365


104
Pr 54
ESI+: 337


105
Pr 12
ESI+: 493


106
Pr 54
ESI+: 300


107
Pr 7
FAB+: 427


108
Pr 21
ESI+: 221


109
Pr 38
ESI+: 439


110
Pr 7
ESI+: 462


111
Pr 7
ESI+: 496


112
Pr 7
ESI+: 481


114
Pr 7
FAB+: 447


115
Pr 38
ESI+: 439


116
Pr 1
EI: 257


117
Pr 1
EI: 207


118
Pr 38
ESI+: 461


120
Pr 53
EI: 331


121/Cl
Pr 3
ESI+: 181


122
Pr 54
FAB−: 302


123
Pr 38
ESI+: 465


124
Pr 38
FAB+: 433


125
Pr 7
ESI+: 448


126
Pr 7
ESI+: 482


127
Pr 53
FAB+: 349


128
Pr 7
ESI+: 498


129
Pr 7
ESI+: 518


130
Pr 54
FAB+: 321


131
Pr 38
FAB+: 482


132
Pr 53
FAB+: 399


134
Pr 53
ESI+: 278


135
Pr 53
ESI+: 278


136
Pr 54
FAB+: 371


137
Pr 54
ESI−: 248


138
Pr 54
ESI+: 250


139
Pr 7
ESI+: 532


140
Pr 7
ESI+: 515


141
Pr 7
ESI+: 447


143
Pr 38
ESI+: 431


144
Pr 38
ESI+: 437


145
Pr 7
ESI+: 481


146
Pr 7
ESI+: 477


147
Pr 7
ESI+: 528


148
Pr 40
EI: 168


149
Pr 7
ESI+: 473


150
Pr 38
ESI+: 423


151
Pr 25
EI: 245


152
Pr 54
ESI+: 292


153
Pr 40
ESI+: 208


154
Pr 38
FAB+: 453


155
Pr 1
ESI+: 220


156
Pr 40
ESI+: 344


157
Pr 38
ESI+: 411


158
Pr 38
ESI+: 411
































































































TABLE 203




Pr
Syn
Data




159
Pr 7
ESI+: 473


160
Pr 7
ESI−: 488


161/Cl
Pr 35
FAB+: 184


162
Pr 53
CI+: 378


163
Pr 54
ESI−: 314


164
Pr 38
ESI+: 451


165
Pr 38
ESI+: 477


166
Pr 7
ESI+: 467


167
Pr 7
ESI+: 484


168
Pr 40
ESI+: 208


169
Pr 54
EI: 349


170
Pr 38
ESI+: 511


171
Pr 38
ESI+: 463


172
Pr 53
ESI+: 332


173
Pr 53
ACPI+: 317


174
Pr 54
ESI+: 304


175
Pr 54
ESI+: 303


176
Pr 7
ESI+: 451


177
Pr 7
ESI+: 465


178
Pr 7
ESI+: 457


179
Pr 7
ESI+: 471


180
Pr 7
ESI+: 504


181
Pr 7
ESI+: 464


182
Pr 7
ESI+: 470


183
Pr 53
ESI+: 332


184
Pr 54
ESI+: 304


185
Pr 7
FAB+: 521


186
Pr 7
FAB+: 507


187/Cl
Pr 31
ESI+: 184


188/Cl
Pr 27
ESI+: 198


189
Pr 53
EI: 341


190
Pr 7
ESI+: 465


191
Pr 7
ESI+: 457


192
Pr 7
ESI+: 471


193
Pr 38
FAB+: 447


194
Pr 54
ESI+: 328


195
Pr 53
ESI+: 307


196
Pr 53
ESI+: 344


197
Pr 54
ESI+: 293


198
Pr 38
ESI+: 454


199
Pr 38
ESI+: 460


200
Pr 38
ESI+: 495


201
Pr 53
ESI+: 317


202
Pr 54
ESI+: 303


203
Pr 7
ESI+: 465


204
Pr 7
ESI−: 514


205
Pr 53
ESI+: 335


206
Pr 54
ESI+: 321


207
Pr 53
ESI+: 335


208
Pr 54
ESI+: 321


209
Pr 53
EI: 313


210
Pr 8
ESI+: 242


211/Cl
Pr 3
ESI+: 228


212
Pr 38
ESI+: 495


213
Pr 7
ESI+: 464


214
Pr 7
APCI+: 482


215
Pr 7
APCI+: 488


216
Pr 7
APCI+: 482


217
Pr 38
ESI+: 463


218
Pr 7
APCI+: 488


219
Pr 38
ESI+: 483


220
Pr 38
ESI+: 469


222
Pr 53
ESI+: 331


223
Pr 54
ESI+: 317


225
Pr 53
ESI+: 301


226
Pr 54
ESI+: 287


227
Pr 54
FAB−: 298


228
Pr 38
ESI+: 461


229
Pr 38
ESI+: 467


230
Pr 38
ESI+: 447


231
Pr 38
ESI+: 453


232
Pr 53
ESI+: 310
































































































TABLE 204




Pr
Syn
Data




233
Pr 54
ESI+: 296


234
Pr 38
ESI+: 461


235
Pr 38
ESI+: 478


236
Pr 38
ESI+: 484


237
Pr 38
ESI+: 470


238
Pr 38
ESI+: 464


239
Pr 53
ESI+: 307


240
Pr 41a
ESI−: 262


241
Pr 41b
ESI−: 262


242
Pr 38
ESI+: 457


243
Pr 54
ESI+: 293


244
Pr 38
ESI+: 451


245
Pr 38
ESI+: 471


246
Pr 38
ESI+: 457


247
Pr 7
ESI+: 454


248
Pr 7
ESI+: 425


249
Pr 7
ESI+: 425


250
Pr 38
ESI+: 448


251
Pr 38
ESI+: 468


252
Pr 38
ESI+: 488


253
Pr 38
ESI+: 474


254/Cl
Pr 43
ESI+: 196


256
Pr 7
ESI+: 463


257
Pr 56
ESI+: 343


261
Pr 54
ESI+: 329


262
Pr 38
ESI+: 490


263
Pr 38
ESI+: 490


266
Pr 53
EI: 300


268
Pr 7
ESI+: 493


269
Pr 54
ESI+: 287


270
Pr 38
ESI+: 448


271
Pr 53
EI: 389


272
Pr 53
ESI+: 301


273
Pr 54
ESI+: 287


274
Pr 54
ESI−: 360


275
Pr 38
ESI+: 523


276
Pr 38
ESI+: 448


277
Pr 54
ESI+: 329


278
Pr 38
ESI+: 490


279
Pr 53
ESI+: 378


280
Pr 54
ESI+: 364


281
Pr 38
ESI+: 425


282
Pr 38
ESI+: 475


283
Pr 38
ESI+: 481


284
Pr 7
ESI+: 525


285
Pr 7
FAB+: 501


286
Pr 7
ESI+: 518


287
Pr 7
ESI+: 538


288
Pr 7
APCI/ESI+: 524


289
Pr 53
ESI+: 347


290
Pr 54
ESI+: 333


291
Pr 38
ESI+: 494


292
Pr 38
ESI+: 480


293
Pr 38
ESI+: 486


294
Pr 54
ESI+: 336


295
Pr 38
ESI+: 497


296
Pr 54
ESI+: 329


297
Pr 53
ESI+: 317


298
Pr 54
ESI+: 303


299
Pr 53
ESI+: 301


300
Pr 38
ESI+: 464


301
Pr 54
ESI+: 335


302
Pr 38
ESI+: 448


303
Pr 38
ESI+: 434


304
Pr 54
ESI+: 287


305
Pr 7
ESI+: 496


306
Pr 38
ESI+: 490


307
Pr 53
ESI+: 287


308
Pr 7
FAB+: 439


309
Pr 54
ESI+: 273


310
Pr 53
EI: 348


311
Pr 56
ESI+: 349































































































TABLE 205



Pr
Syn
Data









312
Pr 53
ESI+: 333

313
Pr 7
ESI+: 434

314
Pr 54
ESI+: 319

315
Pr 54
ESI+: 335

316
Pr 38
ESI+: 496

317
Pr 38
ESI+: 488

318
Pr 54
ESI+: 335

319
Pr 38
ESI+: 496

320
Pr 44
ESI+: 392

321
Pr 7
ESI+: 480

322
Pr 50
EI: 348

323
Pr 53
EI: 347

324
Pr 38
ESI+: 489

325
Pr 54
ESI+: 334

326
Pr 38
ESI+: 495

327
Pr 54
ESI+: 335

328
Pr 38
ESI+: 496

331
Pr 4
EI: 352

333
Pr 53
ESI+: 365

334
Pr 54
ESI+: 339

335
Pr 54
ESI+: 337

336
Pr 7
ESI+: 520

337
Pr 7
FAB+: 490

338
Pr 7
FAB+: 500

339
Pr 7
EI: 450

340
Pr 7
ESI+: 484

341
Pr 53
ESI+: 274

342
Pr 7
ESI+: 456

343
Pr 7
ESI+: 490

344
Pr 7
ESI+: 498

345
Pr 7
ESI+: 466

346
Pr 7
ESI+: 472

347
Pr 54
EI: 259

348
Pr 38
FAB+: 421

349
Pr 53
ESI+: 307

350
Pr 38
ESI+: 472

351
Pr 53
EI: 305

352
Pr 54
ESI+: 292

353
Pr 53
ESI+: 399

354
Pr 53
ESI+: 345

355
Pr 54
ESI+: 371

356
Pr 38
ESI+: 453

357
Pr 7
ESI+: 532

358
Pr 7
ESI+: 518

359
Pr 7
ESI+: 524

360
Pr 53
EI: 301

361
Pr 54
ESI+: 288

362
Pr 38
ESI+: 449

363
Pr 54
ESI+: 293

364
Pr 38
ESI+: 454

366
Pr 54
ESI+: 331

368
Pr 53
ESI+: 331

369
Pr 54
ESI+: 303

370
Pr 7
ESI+: 433

371
Ex 4
ESI+: 329

372
Pr 7
ESI+: 450

373
Pr 38
ESI+: 476

374
Pr 38
ESI+: 482

375
Pr 53
ESI+: 332

376
Pr 53
ESI+: 323

377
Pr 53
ESI+: 283

378
Pr 38
ESI+: 473

379
Pr 54
ESI+: 269

380
Pr 7
ESI+: 310

381
Pr 53
EI: 321

382
Pr 54
ESI+: 318

383
Pr 38
ESI+: 479

384
Pr 54
ESI+: 309

385
Pr 38
ESI+: 456

386
Pr 38
ESI+: 430

387
Pr 38
ESI+: 416

388
Pr 38
ESI+: 422



































































































TABLE 206



Pr
Syn
Data









389
Pr 54
FAB−: 306

390
Pr 38
ESI+: 455

391
Pr 63
ESI+: 451

392
Pr 53
EI: 392

393
Pr 53
ESI+: 301

395
Pr 54
ESI+: 287

396
Pr 54
ESI+: 370

397
Pr 53
ESI+: 323

398
Ex 4
ESI+: 363

399
Pr 38
ESI+: 517

400
Pr 7
ESI+: 434

401
Pr 38
ESI+: 523

402
Pr 38
ESI+: 510

403
Pr 54
ESI+: 309

404
Pr 38
ESI+: 516

405
Pr 38
ESI+: 470

406
Pr 38
ESI+: 462

407
Pr 53
ESI+: 304

408
Pr 53
EI: 349

409
Pr 54
ESI+: 290

410
Pr 38
FAB+: 445

411
Pr 7
ESI+: 437

412
Pr 7
ESI+: 443

413
Pr 38
FAB+: 439

414
Pr 53
EI: 391

415
Pr 54
ESI+: 322

416
Pr 38
ESI+: 469

417
Pr 38
ESI+: 475

418
Pr 66
EI: 286

419
Pr 67
ESI−: 304

420
Pr 54
FAB−: 362

421
Pr 38
ESI+: 511

422
Pr 38
ESI+: 517

423
Pr 53
ESI+: 318

424
Pr 54
ESI+: 304

425
Pr 7
ESI+: 451

426
Pr 7
FAB+: 487

427
Pr 7
FAB+: 453

428
Pr 38
ESI+: 412

429
Pr 7
ESI+: 459

430
Pr 38
ESI+: 403

431
Pr 38
ESI+: 397

432
Pr 53
ESI+: 347

433
Pr 54
ESI+: 319

434
Pr 7
ESI+: 439

435
Pr 7
ESI+: 456

436
Pr 7
ESI+: 466

437
Pr 7
ESI+: 472

438
Pr 7
ESI+: 480

439
Pr 7
ESI+: 412

440
Pr 38
ESI+: 461

441
Pr 38
ESI+: 497

442
Pr 53
ESI+: 397

443
Pr 38
ESI+: 516

444
Pr 38
FAB+: 503

445
Pr 54
ESI+: 369

446
Pr 38
ESI+: 522

447
Pr 38
FAB+: 497

448
Pr 53
APCI/ESI+: 431

449
Pr 53
APCI/ESI+: 425

450
Pr 54
APCI/ESI+: 403

451
Pr 54
APCI/ESI+: 397

452
Pr 38
APCI/ESI+: 550

453
Pr 38
APCI/ESI+: 556

454
Pr 38
APCI/ESI+: 550

455
Pr 53
APCI/ESI+: 412

456
Pr 54
APCI/ESI+: 384

457
Pr 7
APCI/ESI+: 531

458
Pr 32
ESI+: 371

459
Pr 53
ESI+: 383

460
Pr 53
ESI+: 399

461
Pr 54
ESI+: 355



































































































TABLE 207



Pr
Syn
Data









462
Pr 54
ESI+: 371

463
Pr 7
ESI+: 508

464
Pr 53
ESI+: 383

465
Pr 7
ESI+: 524

466
Pr 53
APCI/ESI+: 399

467
Pr 54
APCI/ESI+: 371

468
Pr 7
APCI/ESI+: 524

469
Pr 7
ESI+: 524

470
Pr 32
ESI+: 371

471
Pr 7
ESI+: 524

472
Pr 53
ESI+: 399

473
Pr 53
ESI+: 399

474
Pr 53
ESI+: 399

475
Pr 54
ESI+: 371

476
Pr 54
ESI+: 371

477
Pr 7
ESI+: 524

478
Pr 7
ESI+: 524

479
Pr 53
ESI+: 503

480
Pr 33
ESI+: 403

481
Pr 53
APCI/ESI+: 349

482
Pr 53
ESI+: 335

483
Pr 53
ESI+: 331

484
Pr 54
APCI/ESI+: 321

485
Pr 54
ESI+: 317

486
Pr 53
APCI/ESI+: 354

487
Pr 53
APCI/ESI+: 388

488
Pr 54
ESI+: 321

489
Pr 38
APCI/ESI+: 474

490
Pr 54
ESI+: 371

491
Pr 7
ESI+: 524

492
Pr 7
ESI+: 470

493
Pr 7
ESI+: 474

494
Pr 54
ESI+: 371

495
Pr 54
APCI/ESI+: 326

496
Pr 54
APCI/ESI−: 358

497
Pr 7
APCI/ESI+: 479

498
Pr 7
APCI/ESI+: 513

499
Pr 54
ESI+: 355

500
Pr 7
ESI+: 508

501
Pr 7
ESI+: 524

502
Pr 53
ESI+: 422

503
Pr 54
FAB−: 392

504
Pr 7
ESI+: 547

505
Pr 505
EI: 345

506
Pr 506
ESI+: 298

507
Pr 507
FAB+: 358

508
Pr 508
FAB−: 372

509
Pr 509
FAB−: 272

510
Pr 510
EI: 253

511
Pr 511
APCI/ESI+: 293

512
Pr 512
APCI/ESI+: 221

513
Pr 513
FAB+: 392

514
Pr 514
APCI/ESI+: 223

515
Pr 515
ESI+: 490

516
Pr 516
ESI+: 383

517
Pr 511
EI: 315

518
Pr 512
ESI+: 244

519
Pr 514
EI: 243

520
Pr 46
FAB+: 343

521
Pr 25
FAB+: 421

522
Pr 505
EI: 379

523
Pr 511
EI: 349

524
Pr 512
EI: 277

525
Pr 514
EI: 277

526
Pr 46
FAB+: 377

527
Pr 7
ESI+: 427

528
Pr 53
ESI+: 568

529
Pr 53
FAB−: 501

530
Pr 34
APCI/ESI−: 185

531
Pr 1
APCI/ESI+: 215

532
Pr 33
APCI/ESI+: 403

533
Pr 508
FAB+: 408

534
Pr 509
EI: 307

536
Pr 53
ESI+: 568





































































































TABLE 208



Pr
Syn
Data









537
Pr 515
ESI+: 490

538
Pr 53
APCI/ESI+: 356

539
Pr 54
APCI/ESI+: 328

540
Pr 7
APCI/ESI+: 481

541
Pr 53
ESI+: 602

542
Pr 68
APCI/ESI+: 399

543
Pr 54
APCI/ESI+: 371

544
Pr 7
APCI/ESI+: 524

545
Pr 53
ESI+: 524

546
Pr 53
ESI+: 524

547
Pr 53
ESI−: 400

548
Pr 54
ESI−: 372

549
Pr 7
ESI+: 527








































TABLE 209



Pr
Syn
Data



8
Pr 8
NMR-C: 8.42-8.31 (1H, brs), 3.68 (3H, s), 2.33-2.23 (1H,



m), 2.19-2.02 (3H, m), 1.97-1.89 (2H, m), 1.86 (3H, s),



1.58-1.25 (4H, m)

18
Pr 18
NMR-D: 7.97-7.93 (1H, m), 7.76-7.70 (1H, m),



7.67-7.62 (1H, m), 7.59 (1H, d, J = 2.1 Hz), 7.55-7.52 (1H, m),



7.51 (1H, d, J = 8.7 Hz), 7.18 (1H, dd, J = 2.1, 8.7 Hz), 6.37 (1H,



s), 3.60 (3H, s), 3.47 (3H, s)

22
Pr 22
NMR-C: 7.55 (1H, dd, J = 7.7, 1.5 Hz), 7.47 (1H, d, J = 1.5 Hz),



7.26 (1H, s), 7.17 (1H, d, J = 7.7 Hz), 4.36 (2H, q, J = 7.1 Hz),



4.10 (2H, q, J = 7.1 Hz), 2.27 (3H, s), 1.44 (3H, t, J = 7.1 Hz),



1.39 (3H, t, J = 7.1 Hz)

26
Pr 26
NMR-C: 7.30 (2H, d, J = 8.5 Hz), 7.06 (2H, d, J = 8.5 Hz),



7.02 (1H, d, J = 2.0 Hz), 6.85 (1H, d, J = 2.0 Hz), 5.45 (2H,



s)

28
Pr 28
NMR-C: 7.68-7.64 (1H, ddd, J = 1.5, 1.5, 7.8 Hz),



7.55-7.52 (1H, t, J = 1.5 Hz), 7.44 (1H, d, J = 7.8 Hz), 5.19-5.08 (1H,



m), 3.92 (3H, s), 3.92 (3H, s), 2.53 (1H, brs), 1.52-1.47 (3H,



m)

29
Pr 29
NMR-C: 7.49-7.41 (2H, m), 7.25-7.15 (2H, m), 4.98 (1H,



brs), 4.02 (1H, brs), 1.41 (9H, s), 1.10-0.97 (1H, m),



0.64-0.50 (2H, m), 0.46-0.28 (2H, m)

33/Cl
Pr 33
NMR-D: 8.80 (2H, brs), 8.05-7.97 (2H, m), 7.76-7.66 (2H,



m), 3.87 (3H, s), 3.74-3.64 (1H, m), 1.37-1.23 (1H, m),



0.74-0.58 (2H, m), 0.56-0.35 (2H, m)

45
Pr 45
NMR-C: 7.45-6.88 (7H, m), 5.75-5.5 (1H, m),



3.36-3.21 (1H, m), 3.05-2.94 (1H, m), 2.45-2.23 (2H, m)

58
Pr 58
NMR-D: 7.90 (1H, d, J = 1.7 Hz), 7.71-7.62 (3H, m),



7.46-7.37 (2H, m), 7.34-7.26 (1H, m), 5.06 (2H, s)

59
Pr 59
NMR-C: 7.56-7.47 (2H, m), 7.40-7.25 (5H, m),



7.25-7.16 (2H, m), 7.13-7.06 (2H, m), 5.55 (2H, s), 3.80 (3H, m)

70
Pr 53
NMR-C: 7.71 (1H, d, J = 8.0 Hz), 7.39 (1H, s), 7.31 (2H, d, J = 4.3 Hz),



7.26-7.11 (3H, m), 6.98 (2H, d, J = 8.0 Hz),



5.80 (2H, s), 4.32 (2H, q, J = 7.1 Hz), 1.36 (3H, t, J = 7.1 Hz).

113
Pr 54
NMR-D: 7.94 (1H, dd, J = 1, 8 Hz), 7.68 (1H, dt, J = 1, 8 Hz),



7.64-7.57 (2H, m), 7.52-7.57 (2H, m), 7.16 (1H, dd, J = 2,



9 Hz), 6.38 (1H, s), 3.48 (3H, s)

119
Pr 53
NMR-D: 8.27 (1H, s), 7.85 (1H, d, J = 3.2 Hz), 7.64 (1H, d, J = 1.5 Hz),



7.31 (2H, d, J = 8.8 Hz), 6.89 (1H, d, J = 3.2 Hz),



6.78 (2H, d, J = 8.8 Hz), 5.65 (2H, s), 4.19 (2H, q, J = 7.0 Hz),



1.15 (3H, t, J = 7.0 Hz)

133
Pr 54
NMR-D: 13.42 (1H, brs), 8.27-8.19 (1H, m), 7.82 (1H, d, J = 3.4 Hz),



7.77-7.67 (1H, m), 7.31 (2H, d, J = 8.8 Hz),



6.91-6.82 (3H, m), 5.74 (2H, s)


































































TABLE 210



Pr
Syn
Data



142
Pr 16
NMR-C: 8.04-7.97 (2H, m), 7.45-7.35 (2H, m), 5.12 (1H,



brs), 4.10 (1H, brs), 3.91 (3H, s), 1.41 (9H, s),



1.13-1.00 (1H, m), 0.66-0.50 (2H, m), 0.49-0.32 (2H, m)

255
Pr 20
NMR-C: 7.37-7.31 (1H, m), 7.22-7.08 (2H, m), 5.33 (1H, dd,



J = 2.8, 7.0 Hz), 3.28-3.15 (1H, m), 2.94-2.82 (1H, m),



2.47-2.21 (2H, m), 2.17-2.06 (1H, m)

258
Pr 34
NMR-C: 7.98-7.94 (1H, m), 7.58-7.54 (1H, m),



7.47-7.42 (1H, m), 7.26-7.21 (2H, m), 6.92-6.86 (2H, m), 6.26 (1H, dd,



J = 1.8, 5.7 Hz), 3.28-3.16 (1H, m), 3.01-2.90 (1H, m),



2.42-2.26 (2H, m)

259
Pr 7
NMR-C: 7.84-7.73 (3H, m), 7.50-7.41 (2H, m),



7.24-7.08 (5H, m), 6.67-6.59 (2H, m), 5.81-5.75 (1H, m), 4.67 (1H, dd,



J = 6.5, 14.5 Hz), 4.32 (1H, dd, J = 4.6, 14.5 Hz), 3.94 (3H,



s), 3.23-3.11 (1H, m), 2.98-2.87 (1H, m), 2.32-2.20 (2H, m)

260
Pr 53
NMR-D: 7.81 (1H, d, J = 7.2 Hz), 7.62 (1H, d, J = 3.4 Hz),



7.40 (1H, d, J = 7.2 Hz), 7.07 (1H, t, J = 7.2 Hz),



6.81-6.71 (4H, m), 6.65 (1H, d, J = 3.4 Hz), 5.49 (2H, s),



4.01-3.96 (2H, m), 3.75 (3H, s), 3.62-3.57 (2H, m), 3.39-3.25 (3H, m)

264
Pr 54
NMR-D: 7.77 (1H, d, J = 7.6 Hz), 7.57 (1H, d, J = 2.9 Hz),



7.47 (1H, d, J = 7.6 Hz), 7.06 (1H, t, J = 7.6 Hz), 6.84 (2H,



d, J = 8.5 Hz), 6.77 (2H, d, J = 8.5 Hz), 6.62 (1H, d, J = 2.9 Hz),



5.91 (2H, s), 4.01-3.96 (2H, m), 3.61-3.56 (2H, m),



3.26 (3H, s)

267
Pr 7
NMR-D: 8.91 (1H, d, J = 8.3 Hz), 7.90 (2H, d, J = 8.3 Hz),



7.68 (1H, d, J = 6.9 Hz), 7.51 (2H, d, J = 8.3 Hz), 7.47 (1H,



d, J = 3.2 Hz), 7.20 (1H, d, J = 6.9 Hz), 7.06 (1H, d, J = 6.9 Hz),



6.78 (2H, d, J = 8.8 Hz), 6.69 (2H, d, J = 8.8 Hz),



6.57 (1H, d, J = 3.2 Hz), 5.43-5.31 (2H, m), 5.21-5.11 (1H, m),



4.01-3.94 (2H, m), 3.85 (3H, s), 3.63-3.57 (2H, m), 3.27 (3H,



s), 1.34 (3H, d, J = 6.8 Hz)

329
Pr 53
NMR-D: 7.74-7.78 (1H, m), 7.54-7.48 (1H, m), 7.43 (1H, d,



J = 2.9 Hz), 7.10 (1H, t, J = 7.6 Hz), 6.57 (1H, d, J = 2.9 Hz),



4.23 (2H, d, J = 7.4 Hz), 3.96-3.79 (5H, m), 2.63-2.41 (2H,



m), 1.72-1.57 (1H, m), 1.37 (9H, s), 1.23-1.14 (2H, m),



1.06-0.92 (2H, m)

330
Pr 53
NMR-C: 7.32-7.25 (2H, m), 7.10-7.04 (2H, m),



6.98-6.96 (1H, m), 6.87-6.83 (1H, m), 5.47 (2H, s), 3.77 (3H, s)

332
Pr 54
NMR-D: 7.78-7.73 (1H, m), 7.55-7.49 (1H, m), 7.41 (1H, d,



J = 3.2 Hz), 7.07 (1H, t, J = 7.8 Hz), 6.54 (1H, d, J = 3.2 Hz),



4.32 (2H, d, J = 7.3 Hz), 3.96-3.77 (2H, m), 2.64-2.38 (2H,



m), 1.82-1.67 (1H, m), 1.37 (9H, s), 1.27-1.14 (2H, m),



1.08-0.93 (2H, m)

































































TABLE 211



Pr
Syn
Data



367
Pr 54
NMR-D: 12.4-12.3 (1H, brs), 7.77 (1H, d, J = 2.2 Hz),



7.59 (2H, d, J = 7.7 Hz), 7.42-7.31 (5H, m), 7.27 (1H,



d, J = 1.7 Hz), 7.21-7.13 (2H, m), 5.57 (2H, s)

394
Pr 54
NMR-D: 13.3-13.1 (1H, brs), 8.55 (1H, d, J = 2.4 Hz),



7.92 (1H, dd, J = 8.4, 2.4 Hz), 7.87 (1H, d, J = 2.3 Hz),



7.66 (1H, d, J = 3.3 Hz), 7.43 (1H, d, J = 2.3 Hz),



6.66 (1H, d, J = 3.3 Hz), 6.60 (1H, d, J = 8.4 Hz),



5.77 (2H, s)

535
Pr 7
NMR-C: 9.22-9.00 (1H, brs), 7.99 (1H, s), 7.39-7.34 (1H,



m), 6.56-6.50 (1H, m), 5.96-5.85 (1H, m), 3.84 (3H, s),



3.40-3.29 (2H, m), 2.31-2.18 (1H, m), 2.08-1.95 (2H, m),



1.92-1.79 (2H, m), 1.67-1.53 (1H, m), 1.52-1.35 (2H, m),



1.11-0.94 (2H, m)





































TABLE 212




Ex
Syn
Data




1/Cl
Ex 1
ESI+: 449


2
Ex 2
FAB−: 451


3
Ex 3
FAB−: 473


4
Ex 4
ESI+: 476


5
Ex 5
ESI+: 444


6
Ex 6
FAB+: 554


7
Ex 3
ESI+: 433


8
Ex 3
ESI+: 442


9
Ex 3
ESI+: 408


10
Ex 3
ESI+: 437


11
Ex 3
ESI−: 468


12
Ex 3
ESI+: 471


13
Ex 3
ESI+: 450


14
Pr 38
ESI+: 457


15
Ex 3
FAB+: 451


16
Ex 3
ESI+: 473


17
Ex 3
ESI+: 413


18
Ex 3
ESI+: 483


19
Ex 3
ESI+: 456


20
Ex 3
ESI+: 456


21/Cl
Ex 3
ESI+: 449


22
Ex 3
FAB+: 399


23
Ex 3
ESI+: 464


24
Ex 3
ESI+: 479


25
Ex 3
ESI+: 434


26
Ex 3
ESI+: 468


27
Ex 3
ESI+: 453


28
Ex 3
ESI+: 425


29
Ex 3
FAB+: 399


30
Ex 3
FAB+: 433


31
Ex 3
ESI+: 463


32
Ex 3
ESI+: 425


33
Ex 3
ESI+: 447


34
Ex 3
ESI+: 434


35
Ex 3
ESI+: 468


36
Ex 3
ESI+: 484


37
Ex 3
ESI+: 490


38
Ex 3
FAB+: 451


39
Ex 3
FAB+: 419


40
Ex 3
FAB+: 468


41
Ex 3
ESI+: 501


42
Ex 3
ESI+: 518


43
Ex 3
ESI+: 433


44
Ex 3
ESI+: 417


45
Ex 3
ESI+: 467


46
Ex 3
ESI+: 463


47
Ex 3
ESI+: 514


48
Ex 3
FAB−: 421


49
Ex 3
ESI+: 459


50
Ex 3
ESI+: 439


51
Ex 3
FAB+: 409


52
Ex 3
ESI+: 459


53
Ex 3
ACPI+: 476


54
Ex 3
ESI+: 397


55
Ex 3
ESI+: 397


56
Ex 3
ESI+: 453


57
Ex 3
ESI+: 470


58
Ex 3
ESI+: 437


59
Ex 3
ESI+: 463


60
Ex 3
FAB+: 497


61
Ex 3
ESI+: 437


62
Ex 3
ESI+: 451


63
Ex 3
ESI+: 443


64
Ex 3
ESI+: 457


65
Ex 3
ESI+: 490


66
Ex 3
ESI+: 450


67
Ex 3
ESI−: 454


68
Ex 3
FAB+: 507


69
Ex 3
FAB+: 493


70
Ex 3
ESI+: 451


71
Ex 3
ESI+: 443


72
Ex 3
ESI+: 457


73
Ex 3
ESI+: 451


74
Ex 3
ESI+: 502


75
Ex 3
ESI+: 450


76
Ex 3
ESI+: 439


77
Ex 3
APCI+: 468


78
Ex 3
APCI+: 474


79
Ex 3
FAB+: 449


80
Ex 3
APCI+: 468


81
Ex 3
APCI+: 474


82
Ex 3
FAB+: 433









































































































TABLE 213



Ex
Syn
Data









83
Ex 3
FAB+: 440

84
Ex 3
FAB+: 446

85
Ex 3
FAB+: 481

86
Ex 3
ESI+: 449

87
Ex 3
ESI+: 469

88
Ex 3
ESI+: 455

89
Ex 3
ESI+: 447

90
Ex 3
ESI+: 447

91
Ex 3
ESI+: 453

92
Ex 3
ESI+: 433

93
Ex 3
ESI+: 439

94
Ex 3
ESI+: 464

95
Ex 3
ESI+: 470

96
Ex 3
ESI+: 456

97
Ex 3
ESI+: 443

98
Ex 3
ESI+: 411

99
Ex 3
ESI+: 411

100
Ex 3
ESI−: 435

101
Ex 3
ESI+: 457

102
Ex 3
ESI+: 443

103
Ex 3
ESI+: 450

104
Ex 3
ESI+: 440

105
Ex 3
FAB+: 434

106
Ex 3
ESI+: 454

107
Ex 3
ESI+: 474

108
Ex 3
ESI+: 460

109
Ex 3
ESI+: 422

110
Ex 3
ESI+: 449

112
Ex 3
ESI+: 473

113
Ex 3
ESI+: 479

114
Ex 3
ESI+: 434

115
Ex 4
ESI+: 476

116
Ex 3
ESI+: 476

117
Ex 3
ESI+: 434

118
Ex 3
ESI+: 511

119
Ex 3
ESI+: 476

120
Ex 3
ESI+: 509

121
Ex 3
FAB+: 487

122
Ex 3
FAB+: 504

123
Ex 3
FAB+: 524

124
Ex 3
FAB+: 510

125
Ex 3
ESI+: 476

126
Ex 3
ESI+: 411

127
Ex 3
ESI+: 467

128
Ex 3
FAB+: 461

129
Ex 3
ESI+: 480

130
Ex 3
ESI+: 466

131
Ex 3
ESI+: 472

132
Ex 3
ESI+: 483

133
Ex 3
ESI+: 434

134
Ex 3
ESI+: 476

135
Ex 3
ESI+: 482

136
Ex 3
ESI+: 450

137
Ex 3
FAB+: 425

138
Ex 3
FAB+: 420

139
Ex 3
ESI+: 420

140
Ex 3
ESI+: 466

141
Ex 3
ESI+: 486

142
Ex 3
ESI+: 436

143
Ex 3
ESI+: 470

144
Ex 3
FAB+: 476

145
Ex 3
FAB+: 442

146
Ex 3
FAB+: 476

147
Ex 3
ESI+: 482

148
Ex 3
ESI+: 482

149
Ex 3
ESI+: 474

150
Ex 3
ESI+: 475

151
Ex 3
ESI+: 481

152
Ex 3
ESI+: 482

153
Ex 3
FAB+: 484

154
Ex 3
FAB+: 452

155
Ex 3
FAB+: 458

156
Ex 3
ESI+: 496

157
Ex 3
ESI+: 518

158
Ex 3
ESI+: 504

159
Ex 3
ESI+: 510

160
Ex 3
FAB+: 419

161
Ex 3
ESI+: 407

162
Ex 3
ESI+: 458

163
Ex 3
ESI+: 439

164
Ex 3
ESI+: 435

165
Ex 3
ESI+: 440














































































































TABLE 214




Ex
Syn
Data




166
Ex 3
ESI+: 436


167
Ex 3
ESI+: 459


168
Ex 3
ESI+: 420


169
Ex 3
ESI+: 416


170
Ex 3
ESI+: 402


171
Ex 3
ESI+: 408


172
Ex 3
ESI+: 441


173
Ex 3
ESI+: 437


174
Ex 3
ESI+: 468


175
Ex 3
ESI+: 462


176
Ex 3
ESI+: 442


177
Ex 3
ESI+: 465


178
Ex 3
ESI+: 420


179
Ex 3
ESI+: 502


180
Ex 3
ESI+: 503


181
Ex 3
ESI+: 448


182
Ex 3
ESI+: 456


183
Ex 3
ESI+: 423


184
Ex 3
ESI+: 509


185/Cl
Ex 1
ESI+: 496


186
Ex 3
ESI+: 429


187
Ex 3
ESI+: 425


188
Ex 3
ESI+: 431


189
Ex 3
ESI+: 437


190
Ex 3
FAB+: 473


191
Ex 3
FAB+: 439


192
Ex 3
ESI+: 455


193
Ex 3
ESI+: 461


194
Ex 3
ESI+: 497


195
Ex 3
ESI+: 503


196
Ex 3
ESI+: 445


197
Ex 3
ESI+: 425


198
Ex 3
ESI+: 442


199
Ex 3
ESI+: 383


200
Ex 3
ESI+: 389


201
Ex 3
ESI+: 398


202
Ex 3
ESI+: 452


203
Ex 3
ESI+: 458


204
Ex 3
FAB+: 466


205
Ex 3
FAB+: 398


206
Ex 3
ESI+: 447


207
Ex 3
ESI+: 483


208
Ex 3
ESI+: 502


209
Ex 3
ESI+: 508


210
Ex 3
ESI+: 489


211
Ex 3
ESI+: 483


212
Ex 3
ESI+: 536


213
Ex 3
ESI+: 542


214
Ex 3
APCI/ESI+: 536


215
Ex 3
APCI/ESI+: 517


216
Ex 3
ESI+: 494


217
Ex 3
APCI/ESI+: 510


218
Ex 3
ESI+: 510


219
Ex 3
ESI+: 510


220
Ex 3
ESI+: 510


221
Ex 3
ESI+: 510


222
Ex 3
ESI+: 510


223
Ex 3
ESI+: 510


224
Ex 3
ESI+: 456


225
Ex 3
ESI+: 460


226
Ex 3
APCI/ESI+: 460


227
Ex 3
APCI/ESI+: 465


228
Ex 3
APCI/ESI+: 499


229
Ex 3
ESI+: 494


230
Ex 3
ESI+: 510


231
Ex 3
ESI+: 533


232
Ex 3
ESI+: 554


233
Ex 3
ESI+: 476


234
Ex 3
ESI+: 554


235
Ex 3
ESI+: 476


236
Ex 3
APCI/ESI+: 467


237
Ex 3
APCI/ESI+: 510


238
Ex 3
ESI+: 588


239
Ex 3
ESI+: 510


240
Ex 3
ESI+: 510


241
Ex 3
ESI+: 513



































































































TABLE 215



Ex
Syn
Data









3
Ex 3
NMR-D: 12.9-12.8 (1H, brs), 8.88 (1H, d, J = 7.9 Hz),



7.88 (2H, d, J = 8.4 Hz), 7.73-7.68 (1H, m), 7.59-7.52 (3H, m),



7.49 (2H, d, J = 8.4 Hz), 7.45-7.38 (4H, m), 7.36-7.29 (1H,



m), 7.24-7.19 (1H, m), 7.08 (1H, dd, J = 7.4, 7.4 Hz),



6.91 (2H, d, J = 8.2 Hz), 6.63 (1H, d, J = 3.1 Hz), 5.60-5.48 (2H,



m), 5.20-5.10 (1H, m), 1.28 (3H, d, J = 7.1 Hz)

4
Ex 4
NMR-D: 8.91 (1H, d, J = 7.8 Hz), 8.17 (1H, d, J = 2.1 Hz),



8.02-7.95 (2H, m), 7.87 (2H, d, J = 8.3 Hz), 7.75-7.67 (2H,



m), 7.62 (1H, d, J = 3.1 Hz), 7.50-7.36 (5H, m),



7.27-7.18 (2H, m), 7.10 (1H, dd, J = 7.6, 7.6 Hz), 6.65 (1H, d, J = 3.3 Hz),



5.67-5.49 (2H, m), 5.18-5.07 (1H, m), 1.27 (3H, d, J = 7.0 Hz)

6
Ex 6
NMR-D: 12.06-11.94 (1H, brs), 8.83 (1H, d, J = 7.8 Hz),



7.88 (2H, d, J = 8.4 Hz), 7.70 (1H, d, J = 7.8 Hz), 7.53 (1H,



d, J = 3.2 Hz), 7.47 (2H, d, J = 8.4 Hz), 7.23-7.15 (3H, m),



7.12-7.05 (1H, m), 6.78 (2H, d, J = 8.4 Hz), 6.62 (1H, d, J = 3.2 Hz),



5.52 (1H, d, J = 18.0 Hz), 5.46 (1H, d, J = 18.0 Hz),



5.11-5.00 (1H, m), 4.75-4.62 (1H, br), 3.62-3.41 (4H,



m), 1.90-1.78 (2H, m), 1.25 (3H, d, J = 7.1 Hz)

23
Ex 3
NMR-D: 12.4-12.3 (1H, brs), 10.9 (1H, s), 7.80 (2H, d, J = 8.9 Hz),



7.76-7.73 (1H, m), 7.52-7.46 (2H, m),



7.29-7.24 (2H, m), 7.15 (1H, dd, J = 7.4, 7.4 Hz), 6.98 (2H, d, J = 8.9 Hz),



6.92-6.87 (2H, m), 6.60 (1H, d, J = 3.2 Hz), 4.68 (2H,



t, J = 5.2 Hz), 4.21 (2H, t, J = 5.2 Hz), 3.31 (3H, s)

53
Ex 3
NMR-D: 12.0-11.8 (1H, brs), 8.31-8.25 (1H, m), 8.19 (1H,



d, J = 8.5 Hz), 7.92-7.85 (2H, m), 7.78 (1H, d, J = 2.1 Hz),



7.73-7.67 (1H, m), 7.65 (1H, d, J = 3.3 Hz), 7.56-7.49 (1H,



m), 7.10 (1H, d, J = 2.1 Hz), 6.69-6.62 (2H, m), 5.84 (2H,



s), 2.78 (2H, t, J = 6.2 Hz), 1.96-1.84 (1H, m),



1.67-1.56 (2H, m), 1.48-1.35 (2H, m), 1.14-0.87 (3H, m),



0.72-0.57 (2H, m)

54
Ex 3
NMR-D: 12.9-12.7 (1H, brs), 8.32 (1H, d, J = 8.1 Hz),



7.87 (2H, d, J = 8.3 Hz), 7.39 (2H, d, J = 8.3 Hz), 7.29 (2H, d, J = 8.5 Hz),



7.05 (2H, d, J = 8.5 Hz), 6.83 (1H, s), 6.79 (1H,



s), 5.47-5.36 (2H, m), 5.11-5.01 (2H, m), 2.01 (3H, s),



1.41 (2H, d, J = 7.0 Hz)

57
Ex 3
NMR-D: 12.9-12.7 (1H, brs), 8.98-8.90 (1H, m), 8.18 (1H,



d, J = 8.6 Hz), 7.93-7.86 (2H, m), 7.81 (1H, d, J = 2.1 Hz),



7.75-7.62 (4H, m), 7.59-7.53 (1H, m), 7.20 (1H, d, J = 2.1 Hz),



7.13 (2H, d, J = 8.2 Hz), 6.72 (1H, d, J = 8.4 Hz),



6.67 (1H, d, J = 3.2 Hz), 5.83 (2H, s), 4.25 (2H, d, J = 5.7 Hz)



mp: 243-244 (dec)




































































TABLE 216



Ex
Syn
Data









96
Ex 3
NMR-D: 11.9-11.8 (1H, brs), 8.17-8.10 (2H, m), 7.91 (1H,



d, J = 8.4 Hz), 7.87 (1H, d, J = 7.8 Hz), 7.73-7.67 (1H, m),



7.55-7.45 (3H, m), 6.97-6.93 (1H, m), 6.58-6.50 (2H, m),



5.81 (2H, s), 2.84-2.76 (2H, m), 2.39 (3H, s),



1.95-1.84 (1H, m), 1.65-1.54 (2H, m), 1.47-1.38 (2H, m),



1.19-0.87 (3H, m), 0.73-0.56 (2H, m)



mp: 244-245 (dec)

115
Ex 4
NMR-D: 13.1-12.6 (1H, brs), 8.84 (1H, d, J = 7.9 Hz),



8.72 (1H, d, J = 2.1 Hz), 7.86-7.78 (3H, m), 7.76-7.70 (1H, m),



7.63 (2H, d, J = 7.4 Hz), 7.54-7.35 (6H, m), 7.24-7.18 (1H,



m), 7.13-7.06 (1H, m), 6.64 (1H, d, J = 3.1 Hz), 6.57 (1H,



d, J = 8.2 Hz), 5.72-5.58 (2H, m), 5.12-5.01 (1H, m),



1.21 (3H, d, J = 7.1 Hz)

124
Ex 3
NMR-D: 12.0-11.8 (1H, brs), 8.41-8.34 (1H, m), 8.21 (1H,



d, J = 8.5 Hz), 8.13 (1H, s), 7.92-7.83 (2H, m), 7.76 (1H, d,



J = 3.2 Hz), 7.73-7.76 (1H, m), 7.56-7.49 (1H, m),



7.37-7.31 (1H, m), 6.85 (1H, d, J = 3.2 Hz), 6.73 (1H, d, J = 8.5 Hz),



5.91 (2H, s), 2.88-2.76 (2H, m), 1.96-1.82 (1H, m),



1.67-1.53 (2H, m), 1.48-1.34 (2H, m), 1.16-1.02 (1H, m),



1.02-0.85 (2H, m), 0.74-0.57 (2H, m)



mp: 242 (dec)

132
Ex 3
NMR-D: 12.9-12.7 (1H, brs), 8.97 (1H, d, J = 7.9 Hz),



7.90 (2H, d, J = 8.3 Hz), 7.73-7.65 (2H, m), 7.54-7.48 (3H, m),



7.24-7.18 (1H, m), 7.09-6.98 (2H, m), 6.57 (1H, d, J = 3.1 Hz),



6.56-6.49 (1H, m), 5.39-5.14 (3H, m), 3.46-3.36 (4H,



m), 1.59-1.43 (6H, m), 1.39 (3H, d, J = 7.0 Hz)

137
Ex 3
NMR-D: 12.1-11.9 (1H, brs), 8.31-8.22 (1H, m),



7.71-7.64 (1H, m), 7.52 (1H, d, J = 3.1 Hz), 7.27 (2H, d, J = 8.5 Hz),



7.16-7.09 (1H, m), 7.05 (1H, t, J = 7.5 Hz), 6.86 (2H, d, J = 8.5 Hz),



6.61 (1H, d, J = 3.1 Hz), 5.56 (2H, s),



3.06-2.94 (2H, m), 2.44-2.37 (1H, m), 1.90-1.76 (2H, m),



1.57-1.33 (5H, m), 1.21-1.06 (2H, m)

140
Ex 3
NMR-D: 12.85-12.75 (1H, br), 9.03 (1H, d, J = 7.9 Hz),



7.91-7.83 (3H, m), 7.68 (1H, d, J = 7.9 Hz), 7.53 (2H, d, J = 8.3 Hz),



7.51-7.43 (6H, m), 7.26 (1H, d, J = 7.5 Hz),



7.11-7.05 (1H, m), 6.57 (1H, d, J = 3.4 Hz), 5.46 (1H, d, J = 15.7 Hz),



5.39 (1H, d, J = 15.7 Hz), 5.27-5.17 (1H, m), 1.38 (3H,



d, J = 7.0 Hz)

143
Ex 3
NMR-D: 12.85-12.77 (1H, brs), 9.17 (1H, s),



8.99-8.93 (1H, m), 8.06 (1H, d, J = 7.7 Hz), 7.79 (1H, d, J = 2.3 Hz),



7.77-7.59 (6H, m), 7.21-7.16 (3H, m), 7.05 (1H, s),



6.65 (1H, d, J = 3.3 Hz), 5.79 (2H, s), 4.36-4.30 (2H, m)





































































TABLE 217



Ex
Syn
Data



146
Ex 3
NMR-D: 11.92 (1H, s), 9.20 (1H, s), 8.36-8.27 (1H, m),



8.05 (1H, d, J = 8.4 Hz), 7.77 (1H, d, J = 2.0 Hz),



7.75-7.66 (2H, m), 7.65 (1H, d, J = 3.1 Hz), 7.63-7.56 (1H, m),



7.08 (1H, d, J = 2.0 Hz), 6.96 (1H, s), 6.64 (1H, d, J = 3.1 Hz),



5.80 (2H, s), 2.90-2.82 (2H, m), 2.00-1.90 (1H, m),



1.71-1.62 (2H, m), 1.50-1.41 (2H, m), 1.20-0.94 (3H, m),



0.76-0.62 (2H, m)



mp: 221

149
Ex 3
NMR-D: 11.9 (1H, s), 8.38-8.31 (1H, m), 7.89-7.82 (2H,



m), 7.68 (1H, dd, J = 7.7, 1.2 Hz), 7.53 (1H, d, J = 3.0 Hz),



7.49-7.41 (3H, m), 7.19-7.15 (1H, m), 7.09-7.03 (1H, m),



6.81 (1H, s), 6.60 (1H, d, J = 3.0 Hz), 5.71 (2H, s),



3.05-2.97 (2H, m), 2.06-1.95 (1H, m), 1.82-1.62 (4H, m),



1.42-1.06 (3H, m), 0.92-0.77 (2H, m)

155
Ex 3
NMR-D: 11.98-11.88 (1H, brs), 8.48-8.41 (1H, m),



7.92-7.84 (2H, m), 7.66 (1H, dd, J = 1.0, 7.9 Hz), 7.63 (1H, s),



7.52-7.44 (4H, m), 7.18 (1H, dd, J = 1.0, 7.9 Hz),



7.08-7.02 (1H, m), 6.57 (1H, d, J = 3.4 Hz), 5.52 (2H, s),



3.13-3.05 (2H, m), 2.11-2.00 (1H, m), 1.85-1.70 (4H, m),



1.51-1.38 (1H, m), 1.25-1.10 (2H, m), 0.98-0.84 (2H, m).

159
Ex 3
NMR-D: 11.97-11.90 (1H, brs), 9.20 (1H, s),



8.45-8.39 (1H, m), 8.14-8.11 (1H, brs), 8.05 (1H, d, J = 8.2 Hz),



7.78-7.57 (4H, m), 7.33 (1H, s), 7.03 (1H, s), 6.83 (1H, d, J = 3.2 Hz),



5.87 (2H, s), 2.93-2.86 (2H, m), 2.00-1.89 (1H, m),



1.70-1.62 (2H, m), 1.50-1.42 (2H, m), 1.20-0.92 (3H, m),



0.77-0.66 (2H, m)



mp: 260

164
Ex 3
NMR-D: 12.9-12.8 (1H, brs), 9.14 (1H, d, J = 8.1 Hz),



7.93 (2H, d, J = 8.3 Hz), 7.66-7.61 (1H, m), 7.57 (2H, d, J = 8.3 Hz),



7.28 (1H, d, J = 3.3 Hz), 7.21-7.15 (1H, m),



7.09-7.01 (1H, m), 6.47 (1H, d, J = 3.3 Hz), 5.28-5.15 (1H, m),



4.29-4.06 (2H, m), 3.29-3.13 (2H, m), 2.96-2.84 (1H, m),



1.61-0.94 (13H, m)

169
Ex 3
NMR-D: 12.9-12.7 (1H, brs), 8.47 (1H, d, J = 8.2 Hz),



7.93-7.85 (5H, m), 7.74 (1H, s), 7.54-7.49 (2H, m),



7.47 (1H, s), 7.45 (1H, s), 7.10-7.06 (1H, m), 6.95-6.90 (1H, m),



6.10-6.06 (1H, m), 5.47 (2H, s), 5.18-5.09 (1H, m),



1.45 (3H, d, J = 7.1 Hz)

174
Ex 3
NMR-D: 11.9 (1H, s), 8.74 (1H, d, J = 2.3 Hz),



8.29-8.22 (1H, m), 7.89 (1H, dd, J = 8.1, 2.4 Hz), 7.73-7.59 (3H, m),



7.52 (1H, d, J = 3.3 Hz), 7.49-7.34 (3H, m), 7.17-7.02 (2H,



m), 6.63 (1H, d, J = 3.3 Hz), 6.56 (1H, d, J = 8.1 Hz),



5.72 (2H, s), 2.96-2.87 (2H, m), 2.09-1.97 (1H, m),



1.81-1.52 (4H, m), 1.37-1.04 (3H, m), 0.90-0.73 (2H, m)



































































TABLE 218



Ex
Syn
Data



182
Ex 3
NMR-D: 12.9-12.8 (1H, brs), 8.51 (1H, d, J = 7.8 Hz),



7.93-7.83 (5H, m), 7.70 (1H, d, J = 2.1 Hz), 7.56-7.42 (5H,



m), 6.99 (1H, s), 6.72-6.69 (1H, m), 5.59 (2H, s),



5.24-5.09 (1H, m), 1.48 (3H, d, J = 7.1 Hz)

187
Ex 3
NMR-D: 12.9-12.8 (1H, brs), 9.15-9.08 (1H, m), 7.82 (2H,



d, J = 8.3 Hz), 7.74-7.69 (1H, m), 7.57 (1H, d, J = 3.3 Hz),



7.48-7.39 (4H, m), 7.34-7.30 (1H, m), 7.24-7.06 (3H, m),



6.62 (1H, d, J = 3.3 Hz), 6.22 (1H, s), 5.76 (2H, s),



4.54 (2H, d, J = 6.0 Hz)

188
Ex 3
NMR-D: 12.0-11.9 (1H, brs), 8.50-8.41 (1H, m),



7.72-7.66 (1H, m), 7.56 (1H, d, J = 3.4 Hz), 7.51-7.46 (1H, m),



7.42 (1H, d, J = 8.2 Hz), 7.24-7.03 (4H, m), 6.61 (1H, d, J = 3.0 Hz),



6.35 (1H, s), 5.78 (2H, s), 3.13-3.06 (2H, m),



2.12-2.01 (1H, m), 1.85-1.68 (4H, m), 1.50-1.36 (1H, m),



1.25-1.09 (2H, m), 0.99-0.84 (2H, m)

201
Ex 3
NMR-D: 12.3 (1H, s), 10.3 (1H, s), 7.74 (2H, d, J = 8.8 Hz),



7.35 (2H, d, J = 8.4 Hz), 7.09 (2H, d, J = 8.4 Hz),



6.98 (1H, s), 6.77 (1H, s), 6.68 (2H, d, J = 8.8 Hz), 5.43 (2H, s),



3.17 (3H, s), 2.04 (3H, s)

202
Ex 3
NMR-D: 12.94-12.78 (1H, brs), 9.28-9.18 (1H, m),



7.94-7.87 (3H, m), 7.86-7.80 (2H, m), 7.73 (1H, d, J = 8.4 Hz),



7.66 (1H, d, J = 7.8 Hz), 7.53-7.43 (5H, m), 7.32-7.25 (1H,



m), 7.19 (1H, s), 7.14-7.09 (1H, m), 5.81 (2H, s), 4.58 (2H,



d, J = 6.0 Hz).

204
Ex 3
NMR-D: 12.93-12.76 (1H, brs), 9.05 (1H, d, J = 8.1 Hz),



7.90 (2H, d, J = 8.1 Hz), 7.86-7.78 (3H, m), 7.71 (1H, d, J = 8.6 Hz),



7.66 (1H, d, J = 7.8 Hz), 7.55 (2H, d, J = 8.1 Hz),



7.51-7.44 (3H, m), 7.31-7.25 (1H, m), 7.23 (1H, s),



7.14-7.08 (1H, m), 5.75 (1H, d, J = 15.7 Hz), 5.71 (1H, d, J = 15.7 Hz),



5.29-5.19 (1H, m), 1.52 (3H, d, J = 7.0 Hz).

206
Ex 3
NMR-D: 12.0-11.9 (1H, brs), 8.40 (1H, t, J = 5.6 Hz),



7.77 (1H, d, J = 7.8 Hz), 7.68 (2H, dd, J = 6.9, 6.9 Hz), 7.58 (1H,



d, J = 3.1 Hz), 7.33-7.15 (3H, m), 7.08-7.01 (1H, m),



6.95 (1H, s), 6.63 (1H, d, J = 3.1 Hz), 5.89 (2H, s),



3.14-3.03 (2H, m), 2.13-1.99 (1H, m), 1.86-1.64 (4H, m),



1.49-1.33 (1H, m), 1.25-0.82 (4H, m)

207
Ex 3
NMR-D: 12.3-12.2 (1H, brs), 10.8 (1H, s), 7.93-7.87 (2H,



m), 7.83-7.80 (1H, m), 7.69 (2H, d, J = 8.9 Hz), 7.56 (1H,



d, J = 3.1 Hz), 7.54-7.50 (1H, m), 7.49-7.44 (3H, m),



7.22-7.16 (1H, m), 6.83 (2H, d, J = 8.9 Hz), 6.79 (1H, s),



6.67 (1H, d, J = 3.3 Hz), 5.75 (2H, s), 3.08 (3H, s)
































































TABLE 219



Ex
Syn
Data



208
Ex 3
NMR-D: 12.9-12.7 (1H, brs), 9.16 (1H, t, J = 5.9 Hz),



7.90-7.79 (4H, m), 7.78 (1H, d, J = 2.2 Hz), 7.64 (1H, d, J = 3.1 Hz),



7.49-7.42 (3H, m), 7.37 (2H, d, J = 8.2 Hz), 7.26 (1H,



d, J = 2.2 Hz), 6.89 (1H, s), 6.61 (1H, d, J = 3.4 Hz),



5.67 (2H, s), 4.46 (2H, d, J = 5.9 Hz)

209
Ex 3
NMR-D: 12.0-11.8 (1H, brs), 8.48 (1H, t, J = 5.6 Hz),



7.91-7.80 (2H, m), 7.75 (1H, d, J = 2.0 Hz), 7.63 (1H, d, J = 3.2 Hz),



7.50-7.40 (3H, m), 7.14 (1H, d, J = 2.0 Hz), 6.84 (1H,



s), 6.61 (1H, d, J = 3.2 Hz), 5.70 (2H, s), 3.04-2.94 (2H, m),



2.08-1.90 (1H, m), 1.82-1.57 (4H, m), 1.41-1.03 (3H, m),



0.90-0.73 (2H, m)



mp: 237

210
Ex 3
NMR-D: 12.1-11.9 (1H, brs), 8.77 (1H, t, J = 5.6 Hz),



7.71 (1H, d, J = 2.1 Hz), 7.51 (1H, d, J = 3.3 Hz), 7.30-7.22 (2H,



m), 7.14 (1H, d, J = 2.1 Hz), 6.89-6.81 (2H, m), 6.53 (1H,



d, J = 3.3 Hz), 4.62 (2H, t, J = 5.3 Hz), 4.15 (2H, t, J = 5.3 Hz),



3.14-3.06 (2H, m), 2.19-2.04 (1H, m), 1.95-1.73 (4H,



m), 1.60-1.43 (1H, m), 1.34-1.14 (2H, m), 1.04-0.88 (2H,



m)

211
Ex 3
NMR-D: 13.0-12.8 (1H, brs), 9.37 (1H, t, J = 6.0 Hz),



7.93 (2H, d, J = 8.3 Hz), 7.73 (1H, d, J = 2.0 Hz), 7.56-7.46 (3H,



m), 7.27-7.19 (3H, m), 6.73-6.65 (2H, m), 6.53 (1H, d, J = 3.1 Hz),



4.61-4.50 (4H, m), 3.91 (2H, t, J = 5.1 Hz)

212
Ex 3
NMR-D: 9.26 (1H, t, J = 5.9 Hz), 8.13 (1H, s),



7.87-7.79 (4H, m), 7.75 (1H, d, J = 3.3 Hz), 7.54-7.50 (1H, m),



7.48-7.42 (3H, m), 7.38 (2H, d, J = 8.2 Hz), 6.93 (1H, s),



6.81 (1H, d, J = 3.2 Hz), 5.73 (2H, s), 4.50 (2H, d, J = 5.8 Hz)



mp: 248

213
Ex 3
NMR-D: 12.0-11.7 (1H, brs), 8.57 (1H, t, J = 5.5 Hz),



8.10 (1H, s), 7.90-7.82 (2H, m), 7.74 (1H, d, J = 3.3 Hz),



7.49-7.42 (3H, m), 7.40 (1H, s), 6.89 (1H, s), 6.81 (1H, d, J = 3.1 Hz),



5.76 (2H, s), 3.03 (2H, t, J = 6.2 Hz), 2.05-1.93 (1H,



m), 1.82-1.71 (2H, m), 1.71-1.60 (2H, m), 1.43-1.29 (1H,



m), 1.20-1.04 (2H, m), 0.91-0.77 (2H, m)



mp: 241

214
Ex 3
NMR-D: 12.07-11.83 (1H, brs), 8.72 (1H, d, J = 2.1 Hz),



8.46 (1H, t, J = 5.5 Hz), 8.12 (1H, s), 7.97-7.90 (1H, m),



7.72 (1H, d, J = 3.1 Hz), 7.63 (2H, d, J = 7.2 Hz),



7.50-7.42 (2H, m), 7.42-7.33 (2H, m), 6.82 (1H, d, J = 3.1 Hz),



6.72 (1H, d, J = 8.2 Hz), 5.77 (2H, s), 2.98-2.89 (2H, m),



2.07-1.96 (1H, m), 1.79-1.69 (2H, m), 1.63-1.51 (2H, m),



1.36-1.22 (1H, m), 1.17-1.04 (2H, m), 0.88-0.73 (2H, m)



mp: 235 (dec)


































































TABLE 220



Ex
Syn
Data



215
Ex 3
NMR-D: 9.42 (1H, t, J = 6.0 Hz), 8.07 (1H, s), 7.92 (2H, d,



J = 8.2 Hz), 7.60 (1H, d, J = 3.2 Hz), 7.54-7.45 (3H, m),



7.21 (2H, d, J = 9.0 Hz), 6.72 (1H, d, J = 3.2 Hz), 6.69 (2H,



d, J = 9.0 Hz), 4.66-4.50 (4H, m), 3.92 (2H, t, J = 5.0 Hz)



mp: 208-210

216
Ex 3
NMR-D: 12.2-11.7 (1H, brs), 8.51-8.40 (1H, m), 8.13 (1H,



s), 7.75-7.64 (2H, m), 7.37 (1H, s), 7.34 (1H, d, J = 7.8 Hz),



6.83 (1H, d, J = 3.1 Hz), 6.45 (1H, d, J = 7.8 Hz), 5.71 (2H,



s), 3.02-2.85 (2H, m), 2.14-1.98 (1H, m), 1.91-1.78 (2H,



m), 1.67-1.51 (2H, m), 1.36-1.10 (3H, m), 0.92-0.73 (2H,



m)

217
Ex 3
NMR-D: 12.1-11.7 (1H, brs), 8.53 (1H, d, J = 2.0 Hz),



8.43 (1H, t, J = 5.3 Hz), 8.14 (1H, s), 7.95 (1H, d, J = 8.4 Hz),



7.85 (1H, d, J = 3.2 Hz), 7.81 (1H, d, J = 8.1 Hz),



7.73-7.65 (2H, m), 7.57-7.51 (1H, m), 7.35 (1H, s), 6.87 (1H, d, J = 3.2 Hz),



5.86 (2H, s), 2.92 (2H, t, J = 6.0 Hz),



2.04-1.92 (1H, m), 1.79-1.64 (2H, m), 1.58-1.44 (2H, m),



1.26-0.98 (3H, m), 0.82-0.66 (2H, m)

218
Ex 3
NMR-D: 12.3-11.5 (1H, brs), 8.91-8.80 (1H, m),



8.45-8.34 (2H, m), 8.15 (1H, s), 7.92 (1H, d, J = 8.5 Hz), 7.81 (1H, d,



J = 3.1 Hz), 7.58-7.48 (1H, m), 7.36 (1H, s), 7.30 (1H, d, J = 8.7 Hz),



7.24 (1H, s), 6.88 (1H, d, J = 3.1 Hz), 5.89 (2H,



s), 2.95-2.81 (2H, m), 2.00-1.87 (1H, m), 1.72-1.60 (2H,



m), 1.51-1.38 (2H, m), 1.16-0.92 (3H, m), 0.77-0.60 (2H,



m)

219
Ex 3
NMR-D: 12.4-11.4 (1H, brs), 9.04-8.97 (1H, m),



8.46-8.31 (2H, m), 8.14 (1H, s), 7.83 (1H, d, J = 8.0 Hz), 7.70 (1H, d,



J = 3.1 Hz), 7.60 (1H, dd, J = 4.2, 8.3 Hz), 7.42-7.28 (2H,



m), 6.85 (1H, d, J = 3.1 Hz), 6.36 (1H, d, J = 7.0 Hz),



6.27 (2H, s), 2.70-2.59 (2H, m), 1.88-1.76 (1H, m),



1.63-1.47 (2H, m), 1.33-1.21 (2H, m), 0.98-0.76 (3H, m),



0.58-0.42 (2H, m)

220
Ex 3
NMR-D: 9.64 (1H, s), 8.72 (1H, d, J = 6.4 Hz),



8.39-8.27 (2H, m), 8.25-8.14 (2H, m), 7.70 (1H, d, J = 3.2 Hz),



7.65-7.57 (1H, m), 7.39-7.35 (1H, m), 6.90 (1H, d, J = 3.2 Hz),



6.60 (1H, d, J = 7.1 Hz), 6.21 (2H, s), 2.57-2.50 (2H, m),



1.90-1.79 (1H, m), 1.65-1.54 (2H, m), 1.31-1.18 (2H, m),



0.96-0.78 (3H, m), 0.56-0.40 (2H, m)

221
Ex 3
NMR-D: 9.07 (1H, d, J = 3.5 Hz), 8.82 (1H, d, J = 8.8 Hz),



8.37-8.29 (1H, m), 8.18 (1H, s), 7.98 (1H, d, J = 8.5 Hz),



7.85-7.78 (1H, m), 7.69 (1H, d, J = 3.1 Hz), 7.65-7.58 (1H,



m), 7.39-7.36 (1H, m), 6.89 (1H, d, J = 3.1 Hz), 6.32 (1H,



d, J = 7.1 Hz), 6.23 (2H, s), 2.55-2.50 (2H, m),



1.92-1.74 (1H, m), 1.65-1.51 (2H, m), 1.27-1.15 (2H, m),



0.95-0.75 (3H, m), 0.56-0.36 (2H, m)




































































TABLE 221



Ex
Syn
Data



222
Ex 3
NMR-D: 12.6-11.2 (1H, brs), 8.93-8.85 (1H, m),



8.42-8.35 (1H, m), 8.32 (1H, d, J = 9.5 Hz), 8.14 (1H, s), 7.93 (1H, d,



J = 8.7 Hz), 7.80 (1H, d, J = 3.2 Hz), 7.55 (1H, dd, J = 4.3,



8.3 Hz), 7.43 (1H, s), 7.39-7.30 (2H, m), 6.86 (1H, d, J = 3.2 Hz),



5.85 (2H, s), 2.95-2.81 (2H, m), 2.01-1.91 (1H, m),



1.76-1.64 (2H, m), 1.56-1.42 (2H, m), 1.21-1.09 (1H, m),



1.09-0.95 (2H, m), 0.81-0.66 (2H, m)

223
Ex 3
NMR-D: 12.0-11.7 (1H, brs), 9.13 (1H, s), 8.44 (1H, d, J = 5.7 Hz),



8.41-8.34 (1H, m), 8.16-8.11 (1H, m), 7.86 (1H, d,



J = 8.6 Hz), 7.81 (1H, d, J = 3.2 Hz), 7.75 (1H, d, J = 5.7 Hz),



7.49 (1H, s), 7.39-7.31 (2H, m), 6.86 (1H, d, J = 3.2 Hz),



5.84 (2H, s), 2.94-2.84 (2H, m), 2.02-1.90 (1H, m),



1.75-1.63 (2H, m), 1.55-1.44 (2H, m), 1.21-0.95 (3H, m),



0.80-0.65 (2H, m)

224
Ex 3
NMR-D: 12.0-11.8 (1H, brs), 9.20 (1H, s), 8.20-8.11 (1H,



m), 8.04 (1H, d, J = 8.1 Hz), 7.69-7.65 (2H, m),



7.61-7.56 (1H, m), 7.51-7.45 (2H, m), 6.96-6.93 (1H, m), 6.88 (1H,



s), 6.54 (1H, d, J = 3.1 Hz), 5.78 (2H, s), 2.92-2.82 (2H, m),



2.38 (3H, s), 1.98-1.88 (1H, m), 1.73-1.60 (2H, m),



1.53-1.40 (2H, m), 1.20-1.08 (1H, m), 1.08-0.93 (2H, m),



0.80-0.60 (2H, m)



mp: 251-252 (dec)

225
Ex 3
NMR-D: 12.2-11.5 (1H, brs), 9.22 (1H, s), 8.30-8.21 (1H,



m), 8.06 (1H, d, J = 8.1 Hz), 7.76-7.56 (4H, m), 7.50 (1H,



dd, J = 2.6, 9.3 Hz), 6.97 (1H, s), 6.94 (1H, dd, J = 2.6, 9.3 Hz),



6.64 (1H, d, J = 3.1 Hz), 5.80 (2H, s), 2.91-2.81 (2H,



m), 2.02-1.89 (1H, m), 1.74-1.60 (2H, m), 1.55-1.40 (2H,



m), 1.20-0.94 (3H, m), 0.79-0.61 (2H, m)



mp: 233

226
Ex 3
NMR-D: 12.1-11.7 (1H, brs), 9.25 (1H, s), 8.45-8.37 (1H,



m), 8.08 (1H, d, J = 8.1 Hz), 7.77-7.58 (4H, m), 7.51 (1H,



d, J = 3.2 Hz), 7.03 (1H, s), 6.95 (1H, dd, J = 8.7, 10 Hz),



6.64 (1H, d, J = 3.2 Hz), 5.66 (2H, s), 2.86-2.77 (2H, m),



2.02-1.90 (1H, m), 1.74-1.63 (2H, m), 1.57-1.46 (2H, m),



1.19-0.95 (3H, m), 0.80-0.64 (2H, m)



mp: 197

227
Ex 3
NMR-D: 8.59 (1H, t, J = 5.6 Hz), 7.75 (1H, d, J = 2.1 Hz),



7.64 (1H, d, J = 3.2 Hz), 7.52-7.46 (1H, m), 7.45-7.39 (1H,



m), 7.25-7.12 (3H, m), 6.61 (1H, d, J = 3.2 Hz),



6.39-6.34 (1H, m), 5.77 (2H, s), 3.13-3.03 (2H, m), 2.08-1.96 (1H,



m), 1.84-1.65 (4H, m), 1.48-1.33 (1H, m), 1.22-1.11 (2H,



m), 0.96-0.81 (2H, m)



mp: 228-230


































































TABLE 222



Ex
Syn
Data



228
Ex 3
NMR-D: 12.1-11.8 (1H, brs), 8.70 (1H, t, J = 5.5 Hz),



8.14-8.09 (1H, m), 7.76 (1H, d, J = 3.3 Hz), 7.53-7.47 (1H, m),



7.46-7.39 (2H, m), 7.26-7.13 (2H, m), 6.81 (1H, d, J = 3.2 Hz),



6.42-6.37 (1H, m), 5.84 (2H, s), 3.16-3.06 (2H, m),



2.10-1.99 (1H, m), 1.83-1.64 (4H, m), 1.48-1.33 (1H, m),



1.22-1.07 (2H, m), 0.98-0.83 (2H, m)



mp: 209

229
Ex 3
NMR-D: 12.2-11.7 (1H, brs), 8.49-8.36 (2H, m),



8.14-8.07 (1H, m), 7.79 (1H, dd, J = 2.5, 8.4 Hz), 7.69 (1H, d, J = 3.2 Hz),



7.37-7.33 (1H, m), 6.81 (1H, d, J = 3.2 Hz), 6.65 (1H,



d, J = 8.5 Hz), 5.73 (2H, s), 2.97-2.83 (2H, m),



2.13-2.00 (1H, m), 1.89-1.78 (2H, m), 1.64-1.51 (2H, m),



1.34-1.10 (3H, m), 0.91-0.73 (2H, m)



mp: 224-226 (dec)

230
Ex 3
NMR-D: 12.3-11.4 (1H, brs), 8.32-8.28 (1H, m),



8.27-8.22 (1H, m), 8.13-8.06 (2H, m), 8.00-7.93 (1H, m),



7.84-7.72 (2H, m), 7.66 (1H, d, J = 5.6 Hz), 7.62 (1H, d, J = 3.2 Hz),



7.34-7.29 (1H, m), 6.78 (1H, d, J = 3.2 Hz), 6.38 (2H, s),



2.49-2.41 (2H, m), 1.88-1.73 (1H, m), 1.60-1.48 (2H, m),



1.27-1.13 (2H, m), 0.92-0.71 (3H, m), 0.51-0.34 (2H, m)

231
Ex 3
NMR-D: 8.71-8.60 (1H, m), 8.14-8.10 (1H, m), 7.75 (1H,



d, J = 3.3 Hz), 7.58 (1H, d, J = 2.1 Hz), 7.48 (1H, d, J = 8.8 Hz),



7.45-7.42 (1H, m), 7.24 (1H, dd, J = 2.2, 8.8 Hz),



6.82 (1H, d, J = 3.3 Hz), 6.35-6.32 (1H, m), 5.85 (2H, s),



3.11-3.00 (2H, m), 2.06-1.94 (1H, m), 1.84-1.59 (4H, m),



1.44-1.29 (1H, m), 1.19-1.03 (2H, m), 0.95-0.77 (2H, m)



mp: 211-213

232
Ex 3
NMR-D: 12.0-11.8 (1H, brs), 9.26 (1H, s), 8.51-8.40 (1H,



m), 8.13-8.05 (2H, m), 7.79-7.55 (4H, m), 6.97 (1H, s),



6.67 (1H, d, J = 3.2 Hz), 5.71-5.51 (2H, m), 3.13-2.95 (1H,



m), 2.47-2.35 (1H, m), 2.03-1.80 (1H, m), 1.75-1.36 (4H,



m), 1.13-0.90 (3H, m), 0.82-0.58 (2H, m)

233
Ex 3
NMR-D: 12.2-11.7 (1H, brs), 9.31 (1H, s), 8.53-8.41 (1H,



m), 8.14 (1H, d, J = 8.0 Hz), 7.83-7.52 (5H, m), 7.17 (1H,



d, J = 8.5 Hz), 7.05 (1H, s), 6.72 (1H, d, J = 3.2 Hz),



5.78-5.56 (2H, brs), 3.21-2.76 (2H, brs), 2.08-1.95 (1H, m),



1.87-1.47 (4H, m), 1.21-1.00 (3H, m), 0.89-0.68 (2H, m)




























































TABLE 223



Ex
Syn
Data



234
Ex 3
NMR-D: 12.0-11.8 (1H, brs), 8.48-8.40 (1H, m), 8.23 (1H,



d, J = 8.6 Hz), 8.09 (1H, s), 7.97-7.90 (2H, m),



7.78-7.70 (1H, m), 7.62 (1H, d, J = 3.2 Hz), 7.59-7.52 (1H, m),



6.71 (1H, d, J = 8.6 Hz), 6.68 (1H, d, J = 3.2 Hz), 5.66 (2H, s),



3.08-2.89 (1H, brs), 2.48-2.34 (1H, brs), 2.01-1.88 (1H, m),



1.79-1.30 (4H, m), 1.13-0.91 (3H, m), 0.84-0.56 (2H, brs)

235
Ex 3
NMR-D: 12.1-11.7 (1H, brs), 8.43-8.35 (1H, m), 8.23 (1H,



d, J = 8.6 Hz), 8.00-7.88 (2H, m), 7.79-7.49 (4H, m),



7.14 (1H, d, J = 8.5 Hz), 6.73 (1H, d, J = 8.6 Hz), 6.69 (1H, d, J = 3.2 Hz),



5.67 (2H, s), 3.14-2.34 (2H, brs), 2.04-1.88 (1H,



m), 1.80-1.40 (4H, m), 1.18-0.95 (3H, m), 0.83-0.60 (2H,



m)

236
Ex 3
NMR-D: 12.5-11.8 (1H, brs), 9.18 (1H, s), 8.38-8.32 (1H,



m), 8.25 (1H, d, J = 1.6 Hz), 8.05 (1H, d, J = 7.5 Hz),



7.77 (1H, d, J = 3.2 Hz), 7.75 (1H, s), 7.73-7.67 (1H, m),



7.64-7.58 (1H, m), 7.43 (1H, d, J = 1.6 Hz), 7.08 (1H, s),



6.81 (1H, d, J = 3.2 Hz), 5.86 (2H, s), 2.94-2.82 (2H, m),



2.01-1.90 (1H, m), 1.74-1.61 (2H, m), 1.55-1.43 (2H, m),



1.21-0.94 (3H, m), 0.80-0.62 (2H, m)

237
Ex 3
NMR-D: 11.95-11.84 (1H, brs), 9.22 (1H, s), 8.42 (1H, d, J = 5.7 Hz),



8.40-8.34 (1H, m), 8.16-8.12 (1H, m), 8.00 (1H,



d, J = 8.5 Hz), 7.80 (1H, d, J = 3.2 Hz), 7.64 (1H, d, J = 5.8 Hz),



7.37-7.33 (1H, m), 7.29 (1H, s), 7.26-7.23 (1H, m),



6.88 (1H, d, J = 3.2 Hz), 5.86 (2H, s), 2.95-2.82 (2H, m),



2.01-1.88 (1H, m), 1.72-1.61 (2H, m), 1.52-1.41 (2H, m),



1.21-0.94 (3H, m), 0.78-0.63 (2H, m)















































TABLE 224





















No
R A
R B
X
Y



1
H
CH 3





















2
H
CH 3





















3
H
CH 3





















4
H
CH 3





















5
H
CH 3





















6
H
CH 3





















7
H
CH 3





















8
H
CH 3



























































TABLE 225





















No
R A
R B
X
Y



9
H
F





















10
H
F





















11
H
F





















12
H
F





















13
H
F





















14
H
F





















15
H
F





















16
H
F



























































TABLE 226





















No
R A
R B
X
Y



17
H
CN





















18
H
CN





















19
H
CN





















20
H
CN





















21
H
CN





















22
H
CN





















23
H
CN





















24
H
CN



























































TABLE 227





















No
R A
R B
X
Y



25
H
CN





















26
H
CN





















27
H
CN





















28
F
H





















29
F
H





















30
F
H





















31
F
H





















32
F
H



























































TABLE 228





















No
R A
R B
X
Y



33
F
H





















34
F
H





















35
F
H





















36
F
H





















37
F
H





















38
F
H





















39
CF 3
Br




















































INDUSTRIAL APPLICABILITY
The compound of the formula (I) or a salt thereof has an EP4 receptor antagonistic activity, and can be used as an active ingredient of a pharmaceutical composition for preventing and/or treating chronic renal failure and/or diabetic nephropathy.
SEQUENCE LISTING FREE TEXT
The following sequence numeral list <400> has a description of nucleotide sequence of rat EP4 (Sequence Number 1).