(en)The present invention relates to compounds of formula (I)

ArCH.sub.2 R.sup.1 (I)

or a monomethyl or monoethyl ether thereof (the compound of formula (I) including these ethers may contain no more than 29 carbon atoms in total); ethers, esters thereof; acid addition salts thereof; wherein Ar is a fused tricyclic aromatic ring system containing a maximum of 14 ring atoms and at least one heteroatom or a fused pentacyclic ring system with at least 4 aromatic rings containing a maximum of 22 ring atoms and at least one heteroatom; or a substituted derivative thereof; for either the tricyclic or pentacyclic ring system there is a maximum of one heteroatom for each ring present but preferably only one or two of the rings contain a heteroatom; the rings forming the tricyclic or the pentacyclic ring system contain five or six atoms; the heteroatoms are conveniently nitrogen, phosphorus, oxygen, sulfur or selenium; suitably the heteroatom is oxygen, sulfur or nitrogen; the tricyclic or the pentacyclic ring system should be planar or deviate only slightly from planarity; suitably the ring system is aromatic or contains one non-aromatic ring; preferably the ring system is aromatic; nitrogen atoms contained in five-membered rings are substituted by hydrogen, methyl or ethyl;
R 1 contains not more than eight carbon atoms and is a group ##STR1## wherein m is 0 or 1; R 5 is hydrogen;
R 6 and R 7 are the same or different and each is hydrogen or C 1-5 alkyl optionally substituted by hydroxy;
R 8 and R 9 are the same or different and each is hydrogen or C 1-3 alkyl; ##STR2## is a five or six-membered saturated carbocyclic ring; R 10 is hydrogen, methyl or hydroxymethyl;
R 11 , R 12 and R 13 are the same or different and each is hydrogen or methyl;
R 14 is hydrogen, methyl, hydroxy, or hydroxymethyl.

1.ApplicationNumber: US-39971689-A
1.PublishNumber: US-5017600-A
2.Date Publish: 19910521
3.Inventor: BAIR; KENNETH W.

4.Inventor Harmonized: BAIR KENNETH W(US)

5.Country: US
6.Claims:
(en)The present invention relates to compounds of formula (I)

ArCH.sub.2 R.sup.1 (I)

or a monomethyl or monoethyl ether thereof (the compound of formula (I) including these ethers may contain no more than 29 carbon atoms in total); ethers, esters thereof; acid addition salts thereof; wherein Ar is a fused tricyclic aromatic ring system containing a maximum of 14 ring atoms and at least one heteroatom or a fused pentacyclic ring system with at least 4 aromatic rings containing a maximum of 22 ring atoms and at least one heteroatom; or a substituted derivative thereof; for either the tricyclic or pentacyclic ring system there is a maximum of one heteroatom for each ring present but preferably only one or two of the rings contain a heteroatom; the rings forming the tricyclic or the pentacyclic ring system contain five or six atoms; the heteroatoms are conveniently nitrogen, phosphorus, oxygen, sulfur or selenium; suitably the heteroatom is oxygen, sulfur or nitrogen; the tricyclic or the pentacyclic ring system should be planar or deviate only slightly from planarity; suitably the ring system is aromatic or contains one non-aromatic ring; preferably the ring system is aromatic; nitrogen atoms contained in five-membered rings are substituted by hydrogen, methyl or ethyl;
R 1 contains not more than eight carbon atoms and is a group ##STR1## wherein m is 0 or 1; R 5 is hydrogen;
R 6 and R 7 are the same or different and each is hydrogen or C 1-5 alkyl optionally substituted by hydroxy;
R 8 and R 9 are the same or different and each is hydrogen or C 1-3 alkyl; ##STR2## is a five or six-membered saturated carbocyclic ring; R 10 is hydrogen, methyl or hydroxymethyl;
R 11 , R 12 and R 13 are the same or different and each is hydrogen or methyl;
R 14 is hydrogen, methyl, hydroxy, or hydroxymethyl.

7.Description:
(en)This is a divisional of copending application Ser. No. 07/132,724, filed on Dec. 11, 1987, now U.S. Pat. No. 4,816,071, which is a continuation of Ser. No. 06/801,085, filed Nov. 22, 1985, now abandoned, which is a continuation-in-part of Ser. No. 06/673,355, filed Nov. 20, 1984, now abandoned.


The present invention relates to heteropolycyclic alkanol derivatives which have been found to have biocidal activity. More specifically the invention concerns aminoalkanol derivatives containing a heteropolycyclic ring system, methods for the synthesis thereof, novel intermediates therefor, pharmaceutical formulations thereof and the use thereof as biocidal agents particularly antitumor agents.
Accordingly, in a first aspect, the present invention provides a compound of the formula (I)

ArCH.sub.2 R.sup.1 (I)

or a monomethyl or monoethyl ether thereof (the compound of formula (I) including these ethers may contain no more than 29 carbon atoms in total); ethers, esters thereof; acid addition salts thereof; wherein Ar Is a fused tricyclic aromatic ring system containing a maximum of 14 ring atoms and at least one heteroatom or a fused pentacyclic ring system with at least four aromatic rings containing a maximum of 22 ring atoms and at least one heteroatom; either ring system optionally substituted by one or two substituents (the substituents will contain not more than four carbon atoms in total when taken together being the same or different and are selected from halogen; cyano; C 1-4 alkyl or C 1-4 alkoxy, each optionally substituted by hydroxy or C 1-2 alkoxy; halogen substituted C 1-2 alkyl or C 1-2 alkoxy; a group S(O) n R 2 wherein n is an integer 0, 1 or 2 and R 2 is C 1-2 alkyl optionally substituted by hydroxy or C 1-2 alkoxy; or the ring system is optionally substituted by a group NR 3 R 4 containing not more than 5 carbon atoms wherein R 3 and R 4 are the same or different and each is a C 1-3 alkyl group or NR 3 R 4 forms a five- or six-membered heterocyclic ring optionally containing one or two additional heteroatoms).
For either the tricyclic or pentacyclic ring system there is a maximum of one heteroatom for each ring present but preferably only one or two of the rings contain a heteroatom.
The rings forming the tricyclic or pentacyclic ring system contain five or six atoms. The heteroatoms are conveniently nitrogen phosphorus oxygen, sulfur or selenium;.suitably the heteroatom is oxygen, sulfur or nitrogen The ring system should be planar or deviate only slightly from planarity. Suitably the tricyclic or the pentacyclic ring system is aromatic or contains one non-aromatic rIng. Preferably the ring system is aromatic. Nitrogen atoms contained in five-membered rings are substituted by hydrogen, methyl or ethyl.
R 1 contains not more than eight carbon atoms and is a group ##STR3## wherein m is 0 or 1;
R 5 is hydrogen;
R 6 and R 7 are the same or different and each is hydrogen or C 1-5 alkyl optionally substituted by hydroxy;
R 8 and R 9 are the same or different and each is hydrogen or C 1-3 alkyl; ##STR4## is a five- or six-membered saturated carbocyclic ring;
R 10 is hydrogen, methyl or hydroxymethyl;
R 11 , R 12 and R 13 are the same or different and each is hydrogen or methyl;
R 14 is hydrogen, methyl, hydroxy, or hydroxymethyl.
Specific ring systems included within the scope of the present invention include tricyclic ring systems such as ##STR5## wherein Z is a heteroatom, and pentacyclic ring systems containing four 6-membered carbocyclic aromatic rings and a 5-membered aromatic ring containing one heteroatom; preferably the heteroatom in either ring system is O, S, NH, NCH 3 or NEt; ##STR6## preferably any of the ring systems is optionally substituted by one substituent.
Ar is suitably ##STR7## wherein Z=O, S, NH, NCH 3 , NEt; suitably ArCH 2 R 1 or a monomethyl or monethyl ether thereof contains not more than 28 carbon atoms in total; suitably R 1 is ##STR8## wherein
R 16 is CH 2 OH, CH(CH 3 )OH or CH 2 CH 2 OH,
R 17 is hydrogen, C 1-3 alkyl or CH 2 OH,
R 18 is hydrogen or methyl.
Preferably Ar is ##STR9## preferably R 16 is CH 2 OH or CH(CH 3 )OH; R 17 is hydrogen, methyl, ethyl or CH 2 OH.
Most preferably R 1 is a diol of the structure ##STR10## wherein R 19 is hydrogen or methyl and R 20 is hydrogen, methyl or ethyl, preferably methyl.
Acid addition salts included within the scope of the present invention are those of compound of formula (I) and ethers and esters thereof.
Esters and nonpharmaceutically useful salts of the compounds of the formula (I) are useful intermediates in the preparation and purification of compounds of the formula (I) and pharmaceutically useful acid addition salts thereof and are therefore within the scope of the present invention. Thus acid addition salts of the compounds of the formula (I) useful in the present invention include but are not limited to those derived from inorganic acids, such as hydrochloric, hydrobromic, sulfuric and phosphoric acids, and organic acids such as isethionic (2-hydroxyethylsulfonic), maleic, malonic, succinic, salicylic, tartaric, lactic, citric, formic, lactobionic, pantothenic, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, naphthalene-2-sulfonic, and ascorbic acids, and amino acids such as glycine.
Acid addition salts particularly useful as biocidal agents are those that are pharmacologically and pharmaceutically acceptable. Thus, suitable acid addition salts include but are not limited to those derived from hydrochloric, methanesulfonic, ethanesulfonic, isethionic, lactic, and citric acids.
The preferred pharmacologically and pharmaceutically acceptable salts are those that are soluble in solvents suitable for parenteral administration, for example, hydrochlorides, methanesulfonates and isethionates.
Esters of compounds of formula (I) are derived from acids known to those skilled in the art to be suitable for ester formation, and are conveniently those derived from C 1-6 alkanoic acids or alkanoic acid derivatives, for example acetic acid, propionic acid, n-butyric acid and iso-butyric acid. The esters may be formed from all or only some of the hydroxy groups contained in the compounds of formula (I). Specific compounds within the scope of formula (I) include;
2-[(1-Dibenzothiophenylmethyl)amino]-2-methyl-1,3-propanediol,
2-[(2-Dibenzothiophenylmethyl)amino]-2-methyl-1,3-propanediol,
2-[(4-Dibenzothiophenylmethyl)amino]-2-methyl-1,3-propanediol,
2-[(1-Dibenzofuranylmethyl)amino]-2-methyl-1,3-propanediol,
2-[(2-Dibenzofuranylmethyl)amino]-2-methyl-1,3-propanediol,
2-[(Naphtho[2,3-b]thiophen-4-ylmethyl)amino]-2-methyl-1,3-propanediol,
2-Methyl-2-[(naphtho[2,1-b]thiophen-5-ylmethyl)amino]-1,3-propanediol,
2-Methyl-2-[(naphtho[2,1-b]thiophen-2-ylmethyl)amino]-1,3-propanediol,
2-Methyl-2-[(naphtho[1,2-b]thiophen-2-ylmethyl)amino]-1,3-propanediol,
2-Methyl-2-[(naphtho[1,2-b]thiophen-5-ylmethyl)amino]-1,3-propanediol,
2-Methyl-2-[(naphtho[1,2-b]furan-2-ylmethyl)amino]-1,3-propanediol,
2-Methyl-2-[(naphtho[2,1-b]furan-2-ylmethyl)amino]-1,3-propanediol,
2-[(9-Acridinylmethyl)amino]-2-methyl-1,3-propanediol and
2-[(Acenaphtho(1,2-b]quinolin-10-ylmethyl)amino]-2-methyl-1,3-propanediol;
ethers, esters thereof; acid addition salts thereof.
Of these specific examples of compounds of formula (I), the most preferred compound is 2-[(naphtho[2,3-b]thiophen-4-ylmethyl)amino]-2-methyl-1,3-propanediol or 2-[(1-dibenzothiophenylmethyl)amino]-2-methyl-1,3-propanediol; ethers, esters thereof; acid addition salts thereof.
The compounds of formula (I) and their ethers, esters and salts thereof may be prepared by any method known in the art for the preparation of compounds of analogous structure. Thus, the compounds of formula (I) may, for example, be prepared by any of the methods defined below.
1. The reduction of a compound of formula (II) ##STR11## Wherein R 2 -R 4 and R 6 -R 14 are as hereinbefore defined or a suitably protected derivative thereof followed by deprotection where appropriate.
The conditions and reagents for such a reaction are well known to those skilled in the art, and any such conditions/reagents may be employed. The conversion of (II) or suitably protected derivatives thereof may be carried out by a reducing agent followed by deprotection if necessary. The reduction is conveniently carried out by a metal hydride such as lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, or by catalytic hydrogenation, conveniently by hydrogen in the presence of a metal catalyst such as palladium or platinum or equivalent reagents as outlined by J. March, Advanced Organic Chemistry, 2nd ed., pages 819-820, McGraw Hill, New York 1977. The reduction is suitably carried out with the compound of formula (II) in solution in an inert solvent or mixture of solvents compatible with the reducing agent, at a non-extreme temperature, for example, between 0° and 80° C., conveniently at room temperature.
In the case of lithium aluminum hydride and like reagents, suitable solvents include ethers (for example tetrahydrofuran, diethyl ether and 1,2-dimethoxyethane) optionally in the presence of a hydrocarbon cosolvent (for example toluene, benzene or hexane).
In the case of sodium borohydride and like reagents, suitable solvents include alcohols (for example ethanol, methanol or isopropanol) optionally in the presence of a hydrocarbon cosolvent (for example toluene, benzene or hexane) or an ether cosolvent (for example diethyl ether or tetrahydrofuran).
In the case of sodium cyanoborohydride and like reagents, suitable solvents include those described for sodium borohydride and in the presence of an acid conveniently glacial acetic acid or ethanolic hydrochloric acid as outlined in, for example R. Hutchins et al., Organic Preparations and Procedures International 11, 201 (1979).
In the case of catalytic hydrogenation, suitable solvents include alcohols (for example methanol and ethanol) optionally in the presence of a hydrocarbon cosolvent (for example toluene or benzene) or ether cosolvent (for example diethyl ether or tetrahydrofuran) in the presence of an acid (for example glacial acetic acid or ethanolic hydrochloric acid) or in glacial acetic acid.
Protected derivatives of compounds of formula (II) are conveniently used when lithium aluminum hydride is employed as the reducing agent. Convenient protecting groups are compatible with the reducing agent utilized and are readily removed under nondestructive conditions, for example benzyl, tetrahydropyranyl and isopropylidene ethers.
It is often convenient not to isolate the compound of the formula (II) but to react a compound of the formula (III) with a compound of the formula (IV): ##STR12## wherein Ar and R 2 -R 4 and R 6 -R 14 are as defined in (I), and reduce the compound of the formula (II) so formed in situ. The reaction of the compounds of the formulae (III) and (IV) is again suitably carried out using conditions and reagents which are well known to those skilled in the art, for example in the presence of an acid, such as a sulfonic acid, i.e., p-toluenesulfonic acid, in an appropriate inert solvent, such as an aromatic hydrocarbon, suitably toluene, with azeotropic removal of water followed by treatment with the reducing agent in an appropriate solvent, suitably ethanol or methanol. Alternatively, (II) formed under equilibrium conditions in appropriate solvents can be reduced in situ with an appropriate reducing agent, suitably sodium cyanoborohydride. The compound of formula (III) may be in the form of a protected aldehyde, for example an acetal, which liberates the aldehyde function under the reaction conditions.
In turn, a compound of formula (III) can be synthesized by reacting the appropriate heteropolycyclic ring with a formylating agent such as that generated by the reaction between SnCl 4 and Cl 2 CHOCH 3 or equivalent reagents, for example, according to the method of A. Rieche et al., Chem. Ber. 93, 88 (1960) or with other standard formylating reagents/procedures known to the art, for example, the Gatterman-Koch reaction (CO/HCl/AlCl 3 /CuCl), the Gatterman reaction (HCN/HCl/ZnCl 2 ), and the Vilsmeier reactio (POCl 3 /PhN(Me)CHO, or POCl 3 /Me 2 NCHO) (J. March, vide supra, pages 494-497).
The compounds of the formula (III) may also be prepared from an appropriate heteropolycyclic ring substituted by a suitable functional group such as (but not limited to) esters, CH 2 OH, CHBr 2 , CH 3 , COCH 3 , COOH, or CN, and converting this functional group to an aldehyde group by methods well known to those skilled in the art.
Where the heteropolycyclic ring bears substituents, the compound of formula (III) may be prepared by a variety of methods known in the art of organic chemistry depending on the nature of the substituent on the heteropolycyclic ring. For example, if the substituent(s) is a halogen, the starting materials may be prepared by direct treatment of the heteropolycyclic ring with a halogenating agent (e.g., Cl 2 , Br 2 , or SO 2 Cl 2 ) or indirectly by such routes as the Sandmeyer reaction (H. H. Hodgson, Chem. Rev. 40, 251 (1947). If the substituent(s) is alkyl, the heteropolycyclic ring may be reacted with the appropriate reagents under Friedel-Crafts reaction conditions (G. A. Olah, Friedel Crafts and Related Reactions, Vols. 1-3, Interscience, New York, N.Y., 1963-1965).
In appropriate cases, the compounds of the formula (IV) and ethers thereof also may be prepared by methods known in the art, for example, by the reaction of a compound of the formula (V) ##STR13## (or ethers thereof) wherein R 7 -R 9 and R 11 -R 14 and m are as hereinbefore defined with an appropriate aldehyde conveniently acetaldehyde or formaldehyde in B. M. Vanderbilt and H. B. Hass, Ind. Eng. Chem. 32, 34 (1940)) followed by reduction (as outlined in J. March, vide supra, pages 1125-1126), conveniently by hydrogen and a metal catalyst (for example, a platinum containing catalyst) in an appropriate solvent, conveniently glacial acetic acid.
2. The reduction of a compound of the formula (VI) ##STR14## wherein Ar and R 2 -R 14 are as hereinbefore defined and the hydroxy groups are optionally protected, followed by deprotection of the hydroxy groups where appropriate. The reduction may be carried out by standard reducing agents known for carrying out this type of reduction (as outlined in J. March, vide supra page 1122) for example a hydride reagent such as lithium aluminum hydride in an inert solvent, such as an ether, i.e., tetrahydrofuran, at a non-extreme temperature, for example, at between O° and 100°C. and conveniently at the reflux temperature of the ether. The compound of the formula (VI) may be formed by the reaction of the appropriate acid (ArCOOH) or a suitable reactive acid derivative thereof (as outlined in J. March, vide supra, pages 382-390), for example an acid halide in an inert solvent with an amine of the formula (IV) in which the hydroxy groups are optionally protected for example when the compound of the formula (IV) is a diol, by an isopropylidene group. The compound of the formula (VI) so formed is suitably reduced in situ and deprotected if necessary to give a compound of formula (I). The compounds of the formula ArCOOH can be prepared by methods well known to those skilled in the art.
3. The reaction of a compound ArCH 2 L (wherein Ar is as hereinbefore defined and L is a leaving group) with a compound of the formula (IV) as hereinbefore defined. Suitable leaving groups are those defined by J. March, vide supra, pages 325-331, and include halogens such as chlorine and bromine and sulfonic acid derivatives such as p-toluenesulfonate. The reaction is suitably carried out in an appropriate solvent, such as a dipolar aprotic solvent or alcohol at a non-extreme temperature, for example 50-100°. The compounds of the formula ArCH 2 L can be prepared by methods well known to those skilled in the art.
There is therefore provided, as a further aspect of the invention, a method for the preparation of a compound of formula (I) comprising any method known for the preparation of analogous compounds, in particular those methods defined in (1) to (3) hereinabove.
The compounds of this invention have biocidal activity, e.g., are toxic to certain living cells which are detrimental to mammals, for example pathogenic organisms and tumor cells. While the compounds herein have biocidal activity, it should be appreciated that the range and level of activity may vary from compound to compound, and therefore the compounds are not necessarily equivalent.
This toxicity to pathogenic organisms has been demonstrated by activity against viruses (e.g., Herpes simplex 1/vero), fungi (e.g., Candida albicans), protozoa (e.g., Eimeria tenella and Trichomonas vaginalis), bacteria (e.g., Mycoplasma smegmatis and Streptococcus pyogenes), and helminths (e.g., Nippostrongylus brasiliensis). The antitumor activity of compounds of formula (I) has been demonstrated in a number of recognized screens and primarily by activity against ascitic P388/0 leukemia.
Preferred compounds of the formula (I) are those which have antitumor activity. The activity against ascitic tumors, including P388/0, is evidenced by reduction of tumor cell number in mammals (for example, mice bearing ascitic tumors) and consequent increase in survival duration as compared to an untreated tumor bearing control group. Antitumor activity is further evidenced by measurable reduction in the size of solid tumors following treatment of mammals with the compounds of this invention compared to the tumors of untreated control tumor bearing animals. Compounds of formula (I) are active against murine tumors such as lymphocytic leukemia P388/0 lymphocytic leukemia L1210 melanotic melanoma B16, P815 mastocytoma, MDAY/D2 fibrosarcoma, colon 38 adenocarcinoma, M5076 rhabdomyosarcoma and Lewis lung carcinoma.
Activity in one or more of these tumor tests has been reported to be indicative of antitumor activity in man (A. Goldin et al., in Methods in Cancer Research ed. V. T. DeVita Jr. and H. Busch, 16 165, Academic Press, N.Y. 1979).
There are sublines of P388/0 which have been made resistant to the following clinically useful agents; cytosine arabinoside, doxorubicin, cyclophosphamide, L-phenylalanine mustard, methotrexate, 5-fluorouracil, actinomycin D, cis-platin and bis-chloroethylnitrosourea. Compounds of this invention show potent activity against these drug-resistant tumors using the procedure for P388/0 above.
Compounds of formula (I) have also been found to be active against human tumor cells in primary cultures of lung, ovary, breast, renal, melanoma, unknown primary gastric pancreatic mesothelioma myeloma and colon cancer. As used herein "cancer" is to be taken as synonymous with "malignant tumor" or more generally "tumor" unless otherwise noted. This is a procedure in which the prevention of tumor cell colony formation, i.e., tumor cell replication, by a drug has been shown to correlate with clinical antitumor activity in man (D. D. Von Hoff et al., Cancer Chemotherapy and Pharmacology 6, 265 (1980); S. Salmon and D. D. Von Hoff, Seminars in Oncology, 8, 377 (1981)).
Compounds of formula I which have been found to have antitumor activity intercalate in vitro with DNA (this property is determined by viscometric methods using the procedure of W. D. Wilson et al., Nucleic Acids Research 4, 2697 (1954)) and a log P as calculated by the method of C. Hansch and A. Leo in Substituent Constants for Correlation Analysis in Chemistry and Biology, John Wiley and Sons, New York, 1979, lying in the range between -2.0 and +2 5.
As has been described above, the compounds of the present invention are useful for the treatment of animals (including humans) bearing susceptible tumors. The invention thus further provides a method for the treatment of tumors in animals, including mammals.,especially humans, which comprises the administration of a clinically useful amount of compound of formula (I) in a pharmaceutically useful form, once or several times a day or other appropriate schedule, orally, rectally, parenterally, or applied topically.
In addition, there is provided as a further, or alternative, aspect of the invention a compound of formula (I) for use in therapy, for example as an antitumor agent.
The amount of compound of formula (I) required to be effective as a biocidal agent will, of course vary and is ultimately at the discretion of the medical or veterinary practitioner. The factors to be considered include the condition being treated, the route of administration, the nature of the formulation the mammal's body weight, surface area age and general condition and the particular compound to be administered. A suitable effective antitumor dose is in the range of about 0.1 to about 120 mg/kg body weight, preferably in the range of about 1.5 to 50 mg/kg, for example 10 to 30 mg/kg. The total daily dose may be given as a single dose, multiple doses, e.g., two to six times per day, or by intravenous infusion for a selected duration. For example, for a 75 kg mammal, the dose range would be about 8 to 9000 mg per day, and a typical dose would be about 2000 mg per day. If discrete multiple doses are indicated, treatment might typically be 500 mg of a compound of formula (I) given 4 times per day in a pharmaceutically useful formulation.
While it is possible for the active compound (defined herein as compound of formula (I), or ether, ester, or salt thereof) to be administered alone, it is preferable to present the active compound in a pharmaceutical formulation. Formulations of the present invention, for medical use, comprise an active compound together with one or more pharmaceutically acceptable carriers thereof and optionally other therapeutical ingredients. The carrier(s) must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The present invention, therefore, further provides a pharmaceutical formulation comprising a compound of formula (I) (in the form of the free base, ether, or ester derivative or a pharmaceutically acceptable acid addition salt thereof) together with a pharmaceutically acceptable carrier therefore.
There is also provided a method for the preparation of a pharmaceutical formulation comprising bringing into association a compound of formula (I), an ether, ester, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier therefore.
While the antitumor activity of the compounds of formula (I) is believed to reside in the free base, it is often convenient to administer an acid addition salt of a compound of formula (I).
The formulations include those suitable for oral, rectal or parenteral (including subcutaneous, intramuscular and intravenous) administration. Preferred are those suitable for oral or parenteral administration.
The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active compound into association with a carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active compound into association with a liquid carrier or a finely divided solid carrier or both and then, if necessary, shaping the product into desired formulations.
Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets or lozenges, each containing a predetermined amount of the active compound; as a powder or granules; or a suspension in an aqueous liquid or non-aqueous liquid such as a syrup an elixir, an emulsion or a draught.
A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active compound in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered active compound with any suitable carrier.
A syrup may be made by adding the active compound to a concentrated, aqueous solution of a sugar, for example sucrose, to which may also be added any accessory ingredients. Such accessory ingredient(s) may include flavorings, an agent to retard crystallization of the sugar or an agent to increase the solubility of any other ingredient, such as a polyhydric alcohol for example glycerol or sorbitol.
Formulations for rectal administration may be presented as a suppository With a conventional carrier such as cocoa butter.
Formulations suitable for parenteral administration conveniently comprise a sterile aqueous preparation of the active compound which is preferably isotonic with the blood of the recipient. Such formulations suitably comprise a solution of a pharmaceutically and pharmacologically acceptable acid addition salt of a compound of the formula (I) that is isotonic with the blood of the recipient. Thus, such formulations may conveniently contain distilled water, 5% dextrose in distilled water or saline and a pharmaceutically and pharmacologically acceptable acid addition salt of a compound of the formula (I) that has an appropriate solubility in these solvents, for example the hydrochloride, isethionate and methanesulfonate salts, preferably the latter.
Useful formulations also comprise concentrated solutions or solids containing the compound of formula (I) which upon dilution with an appropriate solvent give a solution suitable for parental administration above.
In addition to the aforementioned ingredients, the formulations of this invention may further include one or more accessory ingredient(s) selected from diluents, buffers, flavoring agents, binders, surface active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.


The following examples are provided by the way of illustration of the present invention and should in no way be construed as a limitation thereof.
GENERAL COMMENTS
All solvents were reagent grade and used without further purification with the following exceptions. THF was dried by distillation from Na/K alloy under nitrogen (N 2 ) and used immediately. Toluene (PhCH 3 ) was distilled from CaH 2 under N 2 and stored over 3A molecular sieves. Chemicals used were reagent grade and used without purification unless noted. The full name and address of the suppliers of the reagents and chemicals is given when first cited. After this, an abbreviated name is used.
Preparative HPLC was carried out on a Water's Prep LC/System 500A machine using two 500 g silica gel (SiO 2 ) cartridges unless otherwise noted. Plugs of SiO 2 used for purifications were "flash chromatography" SiO 2 (Merck & Co., Inc., Merck Chemical Division, Rahway, N.J. 07065, Silica Gel 60, 230-400 mesh). In this procedure, an appropriate volume sintered glass funnel was filled approximately 3/4 full with the SiO 2 and packed evenly by tapping the outside of the funnel. A piece of filter paper was then placed on top of the SiO 2 and a solution of the material to be purified applied evenly to the top. Gentle suction through a filter flask moved the eluting solvent through the plug rapidly. The appropriate size fractions were combined as needed and further manipulated.
General procedures are described in detail. Analogous procedures show melting point (mp), recrystallization solvents, and elemental analyses (all elements analyzing within a difference of ≦0.4% of the expected value). Any changes to the procedure such as solvent reaction temperature reaction time or workup are noted.
NMR ( 1 H, 13 C) IR and MS data of all new products were consistent with the expected and proposed structures. The positions assigned to structural isomers were unequivocally determined by a number of NMR techniques. All final products were dried in a vacuum oven at 20 mm Hg pressure at the temperature indicated overnight (12-16 h). All temperatures are in degrees Celsius. Other abbreviations used are: room temperature (RT), absolute (abs.), round bottom flask (RB flask), minutes (min), hours (h).
EXAMPLE 1
2-[1-Dibenzothiophenylmethyl)amino]-2-methyl-1,3-propanediol hydrochloride
To a RB flask equipped with magnetic stirring bar, condenser, thermometer, Dean-Stark trap, N 2 inlet line with bubbler was added dibenzothiophene-1-carbaldehyde (M. L. Tedjamulia et al., J. Het. Chem. 21, 321 (1984), 10.0 g, 65.7 mmol), 2-amino-2-methyl-1,3-propanediol (Aldrich Chemical Co., P. O. Box 2060, Milwaukee, Wis. 53201, 6.91 g, 65.7 mmol, p-toluenesulfonic acid monohydrate (Aldrich, 0.1 g) and PhCH 3 (300 mL). The mixture was stirred at reflux with removal of H 2 O for 3 h (or until no more H 2 O collects). Most of the PhCH 3 was then removed by distillation (200 mL). The mixture was then cooled in an ice bath and diluted with abs. EtOH (200 mL) and cooled. Solid NaBH 4 (MCB Manufacturing Chemists, Inc., 2909 Highland Ave., Cincinnati, Ohio 45212, 2.49 g, 65.7 mmol) was added in one portion to the mixture. The ice bath was then removed, the reaction allowed to warm to room temperature and then stirred overnight. The solvent was then removed from the reaction mixture by rotary evaporation to give a crude solid. This was shaken vigorously with warm H 2 O (500 mL) and allowed to cool to RT, filtered and washed with additional H 2 O and placed in a vacuum oven overnight (80°). The crude solid was transferred to flask and dissolved in a mixture of CH 3 OH and gaseous HCl dissolved in abs. EtOH, filtered and diluted to 2 L with Et 2 O. The white solid was recrystallized two additional times from CH 3 OH/Et 2 O (400 mL/600 mL), filtered and washed with additional Et 2 O (300 mL) and placed in a vacuum oven at 80° overnight to give a total of 7.38 g (33.2% yield) of 2-[(1-dibenzothiophenylmethyl)amino]-2-methyl-1,3-propanediol hydrochloride, mp 236-237°, (C,H,N,Cl,S). Other compounds Which were isolated as their methanesulfonates were produced by treating the crude free base with methanesulfonic acid (99.5%, Morton Thiokol, Inc.- Alfa Products, P.O. Box 299, 152 Andover Street, Danvers, Mass. 01923), followed by crystallization as described above. For other preparations alternative solvents such as abs. EtOH and i-PrOH were used in combination with Et 2 O or hexane as the crystallization solvents.
EXAMPLE 2
2-[(2-Dibenzothiophenylmethyl)amino]-2-methyl-1,3-propanediol hydrochloride
Using the procedure outlined in Example 1, dbenzothiophene-2-carbaldehyde E. Campaigne and J. Ashby, J. Het. Chem. 6, 517 (1969)) and 2-amino-2-methyl-1,3-propanediol (Aldrich) gave a 33.1% yield of 2-[(2-dibenzothiophenylmethyl)amino)-2-methyl-1,3-propanediol hydrochloride, mp 194-194.5°, (C,H,N,Cl,S), (CH 3 OH/Et 2 O).
EXAMPLE 3
2-[(4-Dibenzothiophenylmethyl)amino]-2-methyl-1,3-propanediol hydrochloride
Using the procedure outlined in Example 1, dibenzothiophene-4-carbaldehyde (M. L. Tedjamulia et al., J. Het. Chem. 20, 861 (1983)) and 2-amino]-2-methyl-1,3-propanediol (Aldrich) gave a 38.2% yield of 2-[(4-dibenzothiophenylmethyl)amino-2-methyl-1,3-propanediol hydrochloride, mp 209-210° (C,H,N,Cl,S), (EtOH/Et 2 O).
EXAMPLE 4
2-](1-Dibenzofuranylmethyl)amino]-2-methyl-1,3-propanediol
4A. Dibenzofuran-1-carbaldehyde
Dibenzofuran (Aldrich) was formylated using the procedure of A. Rieche et al., Chem. Ber. 93, 88 (1960). The crude product isolated in 83% yield contained mainly dibenzofuran-2-carbaldehyde and a lesser amount of dibenzofuran-1-carbaldehyde. A large proportion of dibenzofuran-2-carbaldehyde was removed by recrystallization of the crude product from 95% EtOH. The filtrate was concentrated and chromatographed on SiO 2 using PhCH 3 as the eluting solvent. The first aldehyde fractions contained dibenzofuran-1-carbaldehyde; later fractions contained the remaining dibenzofuran-2-carbaldehyde. The fractions containing the 2-aldehyde were crystallized from CH 2 Cl 2 /hexane to give a 43.2% overall yield of dibenzofuran-2-carbaldehyde, mp 71-73°, (C,H). The fractions containing the 1-aldehyde were also crystallized from CH 2 Cl 2 /hexane to give a 3.8% yield of dibenzofuran-1-carbaldehyde, mp 66-68°, (C,H).
4B. 2-[(1-Dibenzofuranylmethyl)amino]-2-methyl-1,3-propanediol hydrochloride
Using the procedure outlined in Example 1, dibenzofuran-1-carbaldehyde (4A) and 2-amino-2-methyl-1,3-propanediol (Aldrich) gave a 41.4% yield of 2-[(1-dibenzofuranylmethyl)amino]-2-methyl-1,3-propanediol hydrochloride, mp 237-238°, (C,H,N,Cl), (CH 3 OH/Et 2 O).
EXAMPLE 5
2-[(2-Dibenzofuranylmethyl)amino]-2-methyl-1,3-propanediol hydrochloride
Using the procedure outlined in Example 1, dibenzofuran-2-carbaldehyde (J. Garmatter and A. E. Siegrist Helv. Chim. Acta 57,945 (1974)) and 2-amino-2-methyl-1,3-propanediol (Aldrich) gave a 56.4% yield of 2-dibenzofuranylmethyl)amino]-2-methyl-1,3-propanediol hydrochloride, mp 199-201°, (C,H,N,Cl), (EtOH/Et 2 O).
EXAMPLE 6
2-[(Naphtho(2,3-b]thiophen-4-ylmethyl)amino]-2-methyl-1,3-propanediol
6A. Naphtho[2,3-b]thiophen-4-carbaldehyde
Naphtho[2,3-b]-thiophene (H. G. Pars Pharmaceutical Laboratories, Inc., 763 Concord Ave., Cambridge, Mass. 02138) was formylated using the procedure of A. Rieche et al., Chem. Ber. 93, 88 (1960) to give a mixture of crude naphtho[2,3-b]-thiophen-4-carbaldehyde and naphtho[2,3-b]thiophen-9-carbaldehyde in a 4:1 ratio respectively (by 1 H NMR) in 61.6% yield. The mixture could not be separated by chromatography or fractional crystallization. Reduction of the mixture with NaBH 4 in THF gave a mixture of the corresponding alcohols. After preparative HPLC using PhCH 3 as the eluting solvent and the shave/recycle technique, 4-hydroxymethylnaphtho-[2,3-b-]thiophene was obtained isomerically pure. This material was oxidized using BaMnO 4 to give after workup and crystallization (CH 2 Cl 2 /hexane) 2.95g (82.7% yield) of naphtho[2,3-b]-thiophene-4-carbaldehyde, mp 113°, (C,H,S).
6B. 2-[(Naphtho(2,3-b]thiophen-4-ylmethyl)amino]-2-methyl-1,3-propanediol hydrochloride·0.05 H 2 O
Using the procedure outlined in Example 1, naphtho[2,3-b]thiophen-4-carbaldehyde (6A) and 2-methyl-2-amino-1,3-propanediol (Aldrich) gave a 56.6% yield of 2-[(naphtho[2,3-b]thiophen-4-ylmethyl)amino]-2-methyl-1,3-propanediol hydrochloride·0.05 H 2 O, mp 205-207° (dec), (C,H,N,Cl,S) (EtOH/Et 2 O).
EXAMPLE 7
2-Methyl-2-[(naphtho[2,1-b]thiophen-5-ylmethyl)amino]-1,3-propanediol
7A. Methyl 5-formylnaphtho[2,1-b]thiophene-2-carboxylate
Methyl naphtho[2,1-b-]thiophene-2-carboxylate (E. Campaigne and R. E. Cline, J. Org. Chem. 21, 39 (1956) was formylated using the procedure of Rieche et al., Chem. Ber. 93, 88 (1960) to give a 52.4% yield of methyl 5-formylnaphtho-[2,1-b]thiophene-2-carboxylate, mp 196-198°, (C,H,S), (CH 2 Cl 2 /hexane).
7B. Naphtho[2,1-b]thiophene-5-carbaldehyde
To a RB flask equipped with magnetic stirring bar, condenser and N 2 inlet line with bubbler was added methyl 5-formylnaphtho-[2,1-b]thiophene-2-carboxylate (7A, 9.75g, 36 mmol), KOH (85%, Mallinckrodt Co., St. Louis, Mo. 63147, 18.0 g, 320 mmol), CH 3 OH (40 mL) and H 2 O (80 mL). The mixture was refluxed for 1.5 h, cooled and neutralized with 3 N HCl (500 mL). A yellow solid formed which was filtered and washed with H 2 O (3×300 mL) and dried in a vacuum oven overnight to give crude 5-formylnaphtho-[2,1-b]thiophene-2-carboxylic acid in quantitative yield. This material was then slurried with quinoline (Mallinokrodt, 60 mL) and cuprous oxide (MCB, 6.2 g, 43.3 mmol) and heated to 185° in an oil bath for 1 h. The reaction mixture was allowed to cool to RT then partitioned between Et 2 O (500 mL) and concentrated HCl (200 mL) containing saturated NH 4 Cl (100 mL). The layers were separated and the aqueous layer extracted with additional Et 2 O (500 mL). The Et 2 O layers were combined and washed in succession with 1 N HCl (300 mL), H 2 O (2×300 mL) and saturated NaCl solution (2×300 mL), dried (MgSO 4 ), filtered and concentrated to give a light brown crude solid. After chromatography on SiO 2 using CHCl 3 /hexane as the eluting solvent and crystallization (CHCl 3 /cyclohexane) there was obtained 4.98 g (65.2% yield) of naphtho[2,1-b-]thiophene-5-carbaldehyde mp 101-102° (C,H,S).
7C. 2-Methyl-2-[(naphtho[2,1-b]thiophen-5-ylmethyl)amino]-1,3-propanediol hydrochloride
Using the procedure outlined in Example 1, naphtho[2,1-b]-thiophene-5-carbaldehyde (7B) and 2-methyl-2-amino-1,3-propanediol (Aldrich) gave an 80.9% yield of 2-methyl-2-[(naphtho[2,1-b]thiophen-5-ylmethyl)amino]-1,3-propanediol hydrochloride, mp 208.5-210° (dec) (C,H,N,Cl,S), (i-Pr-OH/Et 2 O).
EXAMPLE 8.
Methyl-2-[(naphtho[2,1-b]thiophen-2-ylmethyl)amino]-1,3-propanediol hydrochloride
Using the procedure outlined in Example 1, naphtho[2,1-b]-thiophene-2-carbaldehyde (K. Clarke et al., J. Chem. Soc. C 537 (1969)) and 2-methyl-2-amino-l,3-propanediol (Aldrich) gave a 75.2% yield of 2-methyl-2-[(naphtho-[2,1-b]thiophen-2-ylmethyl)amino]-1,3-propanediol hydrochloride, mp 189-190°, (C,H,N,Cl,S), (EtOH/Et 2 O).
EXAMPLE 9
2-Methyl-2-[(naphtho[1,2-b]thiophen-5-ylmethyl)amino]-1,3-propanediol hydrochloride
Using the procedure outlined in Example 1, naphtho[1,2-b]-thiophene-2-carbaldehyde (M. L. Tedjamulia et al., J. Het. Chem. 20, 1143 (1983)) and 2-methyl-2-amino-1,3-propanediol (Aldrich) gave a 53.3% yield of 2-methyl-2-[(naphtho[1,2-b]thiophen-yl-methyl)amino]-1,3-propanediol hydrochloride, mp 224-224.5°, (C,H,N,Cl,S), (CH 3 OH/Et 2 O).
EXAMPLE 10
2-Methyl-2-[(naphtho[2,1-b]thiophen-5-ylmethyl)amino]-1,3-propanediol
10A. Methyl 5-formyl-naphtho[1,2-b]thiophene-2-carboxylate
Using the procedure outlined in Example 7A, methyl naphtho[1,2-b]-thiophene-2-carboxylate (E. Campaigne and R E Cline, J. Org. Chem. 21, 39 (1956) gave a 61.0% yield of methyl 5-formylnaphtho(1,2-b-]thiophene, 2-carboxylate mp 207.5-208.5°, (C,H,S), (CH 2 Cl 2 /hexane).
10B. Naphtho[1,2-b-]thiophene-5-carbaldehyde
Using the procedure outlined in 7B, methyl naphtho[1,2-b]-thiophene-2-carboxylate (10A) gave a 61.9% yield of naphtho[1,2-b]thiophene-5-carbaldehyde, mp 96-96.5°, (C,H,S), (CH 2 Cl 2 /hexane).
10C. 2-Methyl-2-[(naphtho[2,1-b]thiophen-5-ylmethyl)amino]-1,3-propanediol hydrochloride
Using the procedure outlined in Example 1, naphtho[1,2-b]thiophene-5-carbaldehyde (10B) and 2-methyl-2-amino-1,3-propanediol (Aldrich) gave a 61.3% yield of 2-methyl-2-[(naphtho[1,2-b]thiophen-5-ylmethyl)amino]-1,3-propanediol hydrochloride, mp 196-198° (dec), (C,H,N,Cl,S), (EtOH/Et 2 O).
EXAMPLE 11
2-Methyl-2-[(naphtho[2,1-b]thiophen-5-ylmethyl)amino]-1,3-propanediol
11A. Naphtho[1,2-bifuran-2-methanol
To a RB flask equipped with magnetic stirring bar reflux condenser N 2 inlet line with bubbler was added ethyl naphtho(1,2-b]-furan-2-carboxylate (H. G. Pars Pharmaceutical Laboratories Inc. 6.85 g, 28.5 mmol), lithium borohydride (Aldrich 0.62 g, 28.5 mmol) and dry THF (400 mL). The mixture was stirred at reflux for 6 h and then poured into H 2 O (1 L). The reaction mixture was acidified with 1N HCl and the resulting white solid was filtered, washed with additional H 2 O (500 mL) then dissolved in CH 2 CL 2 (500 mL), dried (Na 2 SO 4 ), filtered, concentrated to 200 mL and diluted to 500 mL with hexane. The resulting material was filtered washed with hexane (100 mL), and placed in a vacuum oven overnight (80°) to give a total of 4.8 g (69.7%) of naphtho[1,2-b]furan-2-methanol, mp 105.5-107°, (C,H).
11B. Naphtho[1,2 -b]furan-2-carbaldehyde
To a RB flask equipped with magnetic stirring bar, reflux condenser, N 2 inlet line with bubbler was added naphtho[1,2-b]furan-2-methanol (11A 4.8 g, 24.2 mmol), barium manganate (Aldrich, 12.4 g, 48 mmol) and dry CH 2 Cl 2 (500 mL). The mixture was refluxed for 6 h, filtered and the resulting dark yellow solution filtered through a small plug of SiO 2 to remove inorganic salts and polar materials. The solvent was then removed by rotary evaporation and the crude material recrystallized using CH 2 Cl 2 /pentane to give after drying 4.02 g (84.7% yield) of phenanthro[1,2-b]furan-2-carbaldehyde, mp 123°, (C,H).
11C. 2-Methyl-2-[(naphtho[1,2-b]furan-2-ylmethyl)amino]-1,3-propanediol hydrochloride
Using the procedure outlined in Example 1 naphtho[1,2-b-]-furan-2-carbaldehyde (11B) and 2-methyl-2-amino-1,3-propanediol (Aldrich) gave a 43.4% yield of 2-methyl-2-[(naphtho[1 2-b]furan-2-ylmethyl)amino]-1,3-propanediol hydrochloride, mp 197-199° (dec), (C,H,N,Cl), (EtOH/Et 2 O).
EXAMPLE 12
2-Methyl-2-[(naphtho[2,1-b]furan-2-ylmethyl)amino]-1,3-propanediol hydrochloride
Using the procedure outlined in Example 1, naphtho[2,1-b]furan-2-carbaldehyde (G. Giovanninetti et al., Farmaco, Ed. Sci. 36, 94 (1981) and 2-methyl-2-amino-1,3-propanediol (Aldrich) gave a 43.4% yield of 2-methyl-2-[(naphtho-[2,1-b]furan-2-ylmethyl)amino]-1,3-propanediol hydrochloride, mp 228-230° (dec), (C,H,N,Cl), (EtOH/Et 2 O).
EXAMPLE 13
2-[(9-Acridinylmethyl)amino]-2-methyl-1,3-propanediol dihydrochloride
Bromination of 9-methylacridine (Lancaster Synthesis, Ltd., P. O. Box 1000, Industrial Drive, Wyndham, N.H. 03087) by the procedure of A. Campbell et al., J. Chem. Soc. 1145 (1958) gave 9-bromomethylacridine. To a RB flask equipped with magnetic stirring bar, condenser, and N 2 inlet line with bubbler was added 9-bromomethylacridine (10.5 g, 38.58 mmol), 2-amino-2-methyl-1,3-propanediol (Aldrich, 4.06 g, 38.58 mmol), anhydrous K 2 CO 3 (Mallinckrodt, 10.50 g, 76.0 mmol) and abs. EtOH (250 mL). The mixture was refluxed for 4 h, cooled and filtered. The solvent was then removed by rotary evaporation. The crude product was dissolved in CH 3 OH (200 mL) filtered again and diluted to 2 L with Et 2 O. The dark colored crude product was then recrystallized one additional time from CH 3 OH/Et 2 O and then twice from CH 3 OH to give 3.46 g (24.3% yield) of 2-[(9-acridinylmethyl)amino]-2-methyl-1,3-propanediol dihydrochloride·0.6 H 2 O, mp 210-211° (dec), (C,H,N,Cl).
EXAMPLE 14
2-[(Acenaphtho[1,2-b]quinolin-10-ylmethyl)amino]-2-methyl-1,3-propanediol
14A. Acenaphtho[1,2-b] quinoline-10-methanol
To a RB flask equipped with magnetic stirring bar, reflux condenser, N 2 inlet line with bubbler was added ethyl acenaphtho[1,2-b]quinoline-10-carboxylate (H. G. Pars Pharmaceutical Laboratories, Inc., 6.75 g, 23 mmol and dry THF (400 mL). The mixture was stirred at reflux for 3 h and then poured into H 2 O (1 L). The reaction mixture was acidified with 1 N HCl and the resulting white solid was filtered washed with additional H 2 O (500 mL) then dissolved in CH 2 Cl 2 (500 mL), dried (Na 2 SO 4 ), filtered, passed through a small plug of SiO 2 using CH 2 Cl 2 as the eluting solvent. The appropriate fractions were combined and the volume reduced to 100 mL and diluted to 400 mL with hexane. The resulting material was filtered, washed with hexane (100 mL) and placed in a vacuum oven overnight. A total of 5.52 g (81.6% yield) of acenaphtho[1,2-b]quinoline-10-methanol mp 215-218° was obtained which analyzed correctly (C,H,N) for the assigned structure.
14B. Acenaphtho[1,2-b]quinoline-10-carbaldehyde
To a RB flask equipped with magnetic stirring bar, reflux condenser, N 2 inlet line with bubbler was added acenaphtho[1,2-b]quinoline-10-methanol (14A, 2.25 g, 8 mmol), barium manganate (Aldrich, 4.0 g, 16 mmol) and dry CH 2 Cl 2 (1 L). The mixture was refluxed for 24 h, filtered and the resulting dark yellow solution filtered and the solvent removed by rotary evaporation to give a dark green solid. This material was dissolved in a mixture of EtOAc (700 mL) and THF (200 mL) and passed through a small plug of SiO 2 using EtOAc as the eluting solvent. The appropriate fractions were combined and the solvent removed by rotary evaporation to give a 71.7% yield of acenaphtho[1,2-b]quinoline-10-carbaldehyde, mp 245-246°, (C,H,N).
14C. 2-[(Acenaphtho[1,2-b]quinolin-10-ylmethyl)amino)-2-methyl-1,3-propanediol Dihydrochloride·1.25 H 2 O
Using the procedure outlined in Example 1, acenaphtho[1,2-b]quinoline-10-carbaldehyde (14B) and 2-methyl-2-amino-1,3-propanediol (Aldrich) gave a 55.7% yield of 2-[(acenaphtho[1,2-b]quinolin-10-ylmethyl)amino)-2-methyl-1,3-propanediol dihydrochloride·1.25 H 2 O, mp 242-245° (dec) (C,H,N,Cl), (CH 3 OH/Et 2 O).
Antitumor Screening Results
Methods for evaluating the antitumor activity of these compounds are essentially those used in the Tumor Panel by the Developmental Therapeutics Program, Division of Cancer Treatment, National Cancer Institute, A. Goldin, et al., Methods in Cancer Research, Vol. XVI, p. 165, Academic Press (1979). Some modifications, in dose level and schedule have been made to increase the testing efficiency.
EXAMPLE 15
Lymphocytic Leukemia P388/0 Test
CD2-F 1 mice, of the same sex, weighing 20±3 g, are used for this test. Control and test animals are injected intraperitoneally with a suspension of -10 6 viable P388/0 tumor cells on day 0. In each test, several dose levels which bracket the LD 20 of the compound are evaluated; each dose level group contains six animals. The test compounds are prepared either in physiologic saline containing 0.05% Tween 80 or distilled water containing 5% dextrose and are administered intraperitoneally on days 1, 5, and 9 relative to tumor implant. Doses are on a mg/kg basis according to individual animals' body weights. The day of death for each animal is recorded, the median identified for each group and the ratios of median survival time for treated (T)/control (C) groups are calculated. The criterion for activity is T/C×100≧120%. Results of P388/0 testing are summarized in Table I.

TABLE I______________________________________ Optimal T/C × 100%Compound Dose (Excluding 30 Day LD.sub.20of Formula (mg/kg) Survivors) (mg/kg)______________________________________ 1 240 +140 240 2 225 +130 200 3 275 +155 200 4B 225 +140 200 5 225 +120 225 6B 150 +125 15010C 150 +125 11513 440 +130 490______________________________________

EXAMPLE 16
Formulation Examples

______________________________________A. TABLET______________________________________Compound of Formula I 500.0 mgPregelatinized Corn Starch 60.0 mgSodium Starch Glycolate 36.0 mgMagnesium Stearate 4.0 mg______________________________________

The compound of formula (I) is finely ground and intimately mixed with the powdered excipients, pregelatinized corn starch and sodium starch glycolate. The powders are wetted with purified water to form granules. The granules are dried and mixed with the magnesium stearate. The formulation is then compressed into tablets weighing approximately 600 mg each.

______________________________________B. TABLET______________________________________Compound of formula (I) 500.0 mgCorn Starch 70.0 mgLactose 83.8 mgMagnesium Stearate 4.2 mgPolyvinylpyrrolidone 14.0 mgStearic Acid 28.0 mg______________________________________

The compound of formula (I) is finely ground and intimately mixed with the powdered excipients, corn starch and lactose. The powders are wetted with a solution of polyvinylpyrrolidone dissolved in a mixture of purified water and denatured alcohol to form granules. The granules are dried and mixed with the powdered stearic acid and magnesium stearate. The formulation is then compressed into tablets weighing approximately 700 mg each.

______________________________________C. CAPSULES______________________________________Compound of formula (I) 500.0 mgCorn Starch 50.0 mgMagnesium Stearate 3.0 mg______________________________________

The finely divided compound of formula (I) is mixed with powdered corn starch and wetted with denatured alcohol to densify the powder. The dried powder is mixed with stearic acid and filled into hard-shell gelatin capsules.

______________________________________D. SYRUP______________________________________Compound of formula (I) 250.0 mgEthanol 250.0 mgGlycerin 500.0 mgSucrose 3,500.0 mgFlavoring Agent q.s.Coloring Agent q.s.Preserving Agent 0.1%Purified Water q.s. to 5.0 mL______________________________________

The compound of formula (I) is dissolved in the ethanol, glycerin, and a portion of the purified water. The sucrose and preserving agent are dissolved in another portion of hot purified water, and then the colouring agent is added and dissolved. The two solutions are mixed and cooled before the flavoring agent is added. Purified water is added to final volume. The resulting syrup is thoroughly mixed.

______________________________________E. IV INJECTION______________________________________Compound of formula (I) 5.0 mgGlycerin q.s. for isotonicityPreservative 0.1%Nydrochloric Acid or as needed forSodium Hydroxide pH adjustmentWater for Injection q.s. to 1 mL______________________________________

The compound of formula (I) and preservative is added to the glycerin and a portion of the water for injection. The pH is adjusted with hydrochloric acid or sodium hydroxide. Water for injection is added to final volume and solution is complete after thorough mixing. The solution is sterilized by filtration through a 0.22 micrometer membrane filter and aseptically filled into sterile 10 mL ampules or vials.