1.ApplicationNumber: US-3691169D-A
1.PublishNumber: US-3691169-A
2.Date Publish: 19720912
3.Inventor: ALLAN POE GRAY

4.Inventor Harmonized: GRAY ALLAN POE()

5.Country: US
6.Claims:
(en)2-(Alkylthioalkyl)-1,2,3,4-tetrahydroisoquinolines such as 2-(3ethylthiopropyl)-1,2,3,4-tetrahydroisoquinoline exhibit cardiovascular activity and are useful in the preparation of Nalkylsulfinylalkyl-1,2,3,4-tetrahydroisoquinolines.

7.Description:
(en)D United States Patent [15] 3,6 Gray [45] Sept. 12, 1972 2-(ALKYLTHIOALKYL)-1,2,15,4- [56] References Cited TETRAHYDROISOQUINOLINES UNITE D STATES PATENTS [72] Inventor: Allan Poe Gray, Chittenden, Vt. Assign: New" ubontorks Inc. 3,308,128 3/ 1967 Robinson ..260/283 S [22] Filed: Sept. 3, 1970 Primary Examiner-Donald G. Daus [2n AWL N05 69,450 Attorney-Roenig, Senniger, Powers and Leavitt Related [1.8. Application Data [57] ABSTRACT [62] Division of Ser. No. 680,354, Nov. 3, l967, 2-( Alkylthioalkyl)-l ,2,3,4-tetrahydroisoquinolines Pat. No. 3,549,640. such as 2-( 3-ethylthiopropyl)-l,2,3,4- tetrahydroisoquinoline exhibit cardiovascular activity ((ZII. d m usgfu] i th eparation of N-alkylsulfinylalk 1. 3,44 d I [58] Field of Search ..260/283 S y 2 etrahy rmsoqumo mes l2 (Ilalms, No Drawings 2-(ALKYLTHIOALKYU- l ,2,3 ,4- TETRAHYDROISOQUINOLINES CROSS-REFERENCE TO RELATED APPLICATION This application is a division of my copending application Ser. No. 680,354, filed Nov. 3, 1967, for N-Alkylsulfinylalkyl-and Sulfonylalkyl-l ,2 ,3 ,4- Tetrahydroisoquinolines, now US. Pat. No. 3,549,640. This invention relates to compositions of matter classifled in the art of chemistry as tetrahydroisoqulnollnes having an aliphatic sulfur-containing substituent attached to the ring nitrogen atom.
The invention sought to be patented in its composition aspect, is described as residing in the concept of a chemical compound having the generalized structure:
H t-n wherein A contains up to seven carbon atoms and is selected from the group consisting of alkylene; alkenylene; alkyleneoxycarbonyl; or alkyleneamino', X is selected from the group consisting of thio, sulfmyl or sulfonyl; R contains up to seven carbon atoms and is selected from the group consisting of alkyl. alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, alkaryl, aralltyl, amino, aminoalkyl, alkylamino, dialkylamino, alkylaminoalkyl, dialkylaminoalkyl, amidino, aminothiocarbonyl, alkylthiocarbonyl, cyano or alkylsulfonyl; R represents a member selected from the group consisting of hydrogen or alkyl; and R" represents a member selected from the group consisting of lower alkyl, lower alkoxy, aminoalkyl, lower dialkylamino, acetamino, halo, e.g., chloro, bromo, fluoro, iodo; haloalkyl, e.g., chloromethyl, trifluoromethyl; or methylenedioxy, i.e., two R" s form O-CH,O wherein the oxygen atoms are attached to the aromatic ring at adjacent positions, and n has a value of from zero to 2.
As used herein, the term lower alkyl" means alkyl radicals having one to four carbon atoms, inclusive, either straight or branched chain, among which are, for purposes of illustration, but without limiting the generality of the foregoing, methyl, ethyl, n-propyl, nbutyl, isopropyl, isobutyl, secondary-butyl, and tertiary-butyl.
Preferred compositions encompassed by this invention are those represented by the aforementioned formula wherein A contains from two to six carbon atoms and R, R and R" each contain up to seven carbon atoms. Also preferred compositions are those wherein R and R" represents hydrogen, X represents thio, sulfinyl, or sulfonyl, A represents an alkylene group and R represents alkyl. Particularly preferred compositions are those wherein the ring nitrogen and the sulfur atoms are separated by at least three carbon atoms, i.e., A has at least three unbranched carbon atoms, and the total number of carbon atoms in A and R is from five to seven.
The invention sought to be patented in the process of preparation aspects is described as residing in the concept of embodying such a molecular structure in tangible form by linking a sulfur-containing organic moiety and a tetrahydroisoquinoline through its nitrogen atom 'by one or more processes. For example the compositions can be formed by (l) the reaction of a Z-(haloalkyl)-l ,2,3,4-tetrahydroisoquinoline with a thiol to give a 2-(thioalkyl)-l,2,3,4-tetrahydroisoquinoline (2) oxidizing the 2-(thioalkyl)-l ,2,3,4-tetrahydroisoquinoline to a Z-(sulfmylalkyD-l ,2,3,4-tetrahydroisoquinoline, or (3) oxidizing the 2-(thioalkyl)-l ,2,3 ,4- tetrahydroisoquinoline to the corresponding Z-(sulfonylalkyl l ,2,3,4-tetrahydroisoquinoline.
The invention sought to be patented, in the process of using aspect, is described as residing in the concept of using the tangible embodiment of a composition of matter identified as a tetrahydroisoquinoline with a sulfur-containing substituent on the nitrogen atom by administering to warm blooded animals such composition as the essential active ingredient of a pharmaceutical formulation. it has been observed that the tangible embodiments of the invention possess the inherent applied use characteristics of increasing blood pressure and producing favorable cardiovascular effects as hereinafter evidenced by clinical evaluation. in addition to increasing blood pressure, the novel compositions of this invention have also been found to have vasodilator activity.
The tangible embodiments of the composition aspect of the invention in their free base form are, for the most part, liquids having low aqueous solubility and are soluble in polar solvents such as lower aliphatic alcohols. Examination of the compounds produced according to the herein described process reveals physical characteristics such as infrared spectra which confirm the molecular structure hereinbefore set forth. The aforementioned physical characteristics, taken together with analytical data the nature of the starting materials and the mode of synthesis positively confirm the structure of the compositions sought to be patented.
lt will be apparent from the definition of AXR in the aforementioned formula that it is intended to include specifically or as equivalents, such representative radicals as the thioalkyl groups, e.g., methylthiomethyl, methylthiopropyl, ethylthiopropyl, propylthiopropyl, methylthioisopropyl, butylthiopropyl, cyclohexylthiobutyl, cyclohexylthioisobutyl, phenylthiopropyl, naphthylthiopropyl, and the like.
Other representative radicals include the aminoalkylthioalkyl groups, e.g., aminomethylthiopropyl, aminopropylthiopropyl, methylaminoethylthiopropyl, dimethylaminopropylthiopropyl, diethylaminopropylthiopropyl, and the like; the amidinothioalkyl groups, e.g., amidinothiopropyl, amidinothiobutyl, and the like: the thiocyanoalkyl groups, e.g., thiocyanoethyl, thiocyanopropyl, thiocyanobutyl, thiocyanopentyl, thiocyanoisobutyl, and the like.
Synthesis of the novel tetrahydroisoquinolines of the present invention may be effected by a variety of processes as hereinafter indicated in the examples. For instance, the 2-(alkylthioalkyl)- l ,2,3 ,4- tetrahydroisoquinolines are prepared by refluxing the appropriate alkylthioalkyl halide with tetrahydroisoquinoline. Alternatively, a 2-(haloalkyl)- tetrahydroisoquinoline hydrochloride can be prepared and then reacted with the appropriate alkylthiol in the presence of an acid acceptor. The sulf'myl and sulfonyl 3 derivatives are prepared by oxidation of the corresponding thio compound. The generalized processes for the preparation of the thio compositions can be illustrated as follows: (a)
Y-A-B-R NH N-ASR Hrs-1|) il-n] RSH H5) u-m wherein A, n, R, R and R" are as previously defined and Y represents halogen, e.g., chloro, bromo, iodo, or R'" --SO,-- wherein R'" is lower alkyl or aryl.
Thereafier, the thio composition (I) is oxidized to the corresponding sulfinyl or sulfonyl derivative.
in the above described synthesis. it will be apparent to those skilled in the art of chemistry that the proportion of reactants, duration of reaction, solvents, acid acceptors, catalysts and the like can be varied depending on the type of reactant.
From the specific reaction conditions given in the Examples, it will be obvious to those skilled in the art of chemistry that the reagents and conditions which can be employed in the inventive process will depend to a great extent on the nature of the thiol as well as the particular tetrahydroisoquinoline.
In general, a temperature range from about 0 C. to about the reflux temperature of the solvent has been found to be satisfactory Temperatures above and below the aforementioned range can also be employed but are less preferred. A preferred range is from about 25 C. to about 150 C.
It is also preferred, although not necessary, that the reaction of the tetrahydroisoquinoline and thiol compound be conducted in an inert solvent. in general, the choice of solvent will largely be dependent upon its inability to undergo reactions with either the starting materials or reaction products, its ease of separation from the reaction product, as well as economic considerations.
A variety of inert solvents can be employed in the practice of the instant process, i.e., saturated aliphatic hydrocarbons, aromatic hydrocarbons, aliphatic alcohols, and the like. Typical solvents which can be employed include benzene, toluene, xylene, ethanol, tertiary butanol, secondary butanol, 2-propanol, tertiary amyl alcohol, methyl isobutyl carbinol, acetone, acetonitrile, dirnethylformamide, and the like. Preferred solvents are those completely miscible with the reactants and which can be readily separated.
Pressure is not necessarily critical and the process can be conducted at atmospheric, subatmospheric or superatmospheric pressures.
The contact time necessary to effect the novel process of the present invention need only be of such duration as to insure optimum conversion of the reactants to the corresponding Z-substituted tetrahydroisoquinoline compound. Reaction times of several hours are thoroughly practicable. Shorter or longer periods can also be feasibly employed depending upon the temperature (higher temperatures usually permit the use of shorter reaction times), and the manner in which the process is conducted.
Oxidation of the 2-(aliphaticthioalkyl)- 1 ,2,3,4- tetrahydroisoquinoline to the corresponding sulfinyl or sulfonyl compounds can be conveniently effected by known prior art. procedures. For example, 2-(3- ethylthiopropyl 1 ,2,3,4-tetrahydroisoquino1ine can be oxidized easily to 2-(3-ethylsuliinylpropyl)-1,2,15,4- tetrahydroisoquinoline with peracetic acid. Other peroxides can also be employed.
Preparation of the 2-alkylsulfonylaIkyl)-1,2,3,4- tetrahydroisoquinolines are likewise prepared by the oxidation of the 2-( alkylthioalkyl)-1 ,2,3 ,4- tetrahydroisoquinolines with an appropriate oxidizing agent such as hydrogen peroxide and the like.
As previously indicated, the starting materials for the preparation of the novel composition of this invention are the tetrahydroisoquinolines and the thiols. These reactants are known compounds or can be prepared by the methods indicated in the examples.
The manner of making and using the compositions and processes of the invention is further illustrated by the following examples, which set forth one mode contemplated for carrying out the invention so as to enable any person skilled in the art of chemistry to make and use the same.
EXAMPLE 1 2-( 3-Methylthiopropyl )-l ,2,3 ,4-tetrahydroisoquinoline A solution of 16.2 g. (0.13 mole) of 3- methylthiopropyl chloride and 34.6 g. (0.26 mole) of tetrahydroisoquinoline in 100 ml. of benzene was heated at reflux on a steam bath for hours during which a crystalline precipitate slowly formed. The precipitate was filtered off (tetrahydroisoquinoline hydrochloride, 14.7 g., 67 percent yield) and the filtrate was concentrated in vacuo. Distillation and redistillation of the residue afforded 11.5 g. (40 percent) of 2-(3-methylthi0propyl)-1,2,3 ,4- tetrahydroisoquinoline as a yellow oil, b.p. 138-l40 (0.5 mm.), n D 1.5608.
Analysis. Calculated for C l-l NS: N, 6.33. Found: N(basic), 6.14.
Treatment of an ether solution of the base with ethereal hydrogen chloride and recrystallization from ethanol gave 2-( 3-methylthiopropyl l ,2,3 ,4- tetrahydroisoquinoline hydrochloride in the form of small, colorless needles, mp. l84186.
Analysis. Calculated for C13H ClNS: C, 60.56; H, 7.82; CI, 13.75. Found: C, 60.14; H, 7.73; Cl(ionic), 13.78.
EXAMPLE 2 2-( 3-Ethylthiopropyl 1 ,2,3,4-tetrahydroisoq uinoline A. A solution of 215 g. (1.6 moles) tetrahydroisoquinoline and 126 g. (0.8 mole) of trimethylene chlorobromide in 1,300 ml. of benzene was stirred at room temperature for hours. The precipitate of 130 g. of tetrahydroisoquinoline hydrobromide was filtered off and the filtrate was extracted with dilute hydrochloric acid. The aqueous extract was made alkaline with solid potassium carbonate and the precipitated oil taken into ether. Drying and removal of the ether and distillation of the residue yielded 89 g. (53 percent) of 2-(3-chloropropyl)- tetrahydroisquinoline, b.p. 131-137 (3 mm.), n D 1.5463.
Analysis. Calculated for C,,H ,C1N: N, 6.68. Found: N(basic),6.63.
2-( 3 -Chloropropyl )-tetrahydroisoquinoline hydrochloride, prepared in ether and recrystallized from isopropyl alcohol-ether, showed m.p. 187187.5
Analysis. Calculated for C H cl Nz C, 58.54; H, 6.96; Cl(ionic), 14.40. Found: C, 58.27; H, 7.21; Cl(ionic), 14.40.
B. To a cooled solution of 18.7 g. (0.81 g. atom) of metallic sodium in 300 ml. of ethanol was added 29.9 g. (0.48 mole) of ethanethiol. The solution was allowed to come to room temperature and 79.3 g. (0.32 mole) of 2-( 3-chloropropyl )-tetrahydroisoquinoline hydrochloride dissolved in 150 ml. of methanol was added dropwise with stirring over a period of minutes. A white precipitate formed during the addition. The reaction mixture was stirred at room temperature for 0.5 hour and at reflux for one hour. About 100 ml. of solvent was distilled out of the reaction mixture which was then poured into 1 liter of water and extracted with ether. The ether solution was extracted with dilute hydrochloric acid. A hydrochloride salt precipitate formed during the extraction. The aqueous mixture was made alkaline and extracted with ether. Drying and removal of the ether and distillation of the residual oil gave 61.5 g. (81 percent) of 2-( 3ethylthiopropyl)- l,2,3,4-tetrahydroisoquinoline, b.p. l50l56 (0.4 mm.), r1 1) 1.5521.
Analysis. Calculated for C H NS: N, 5.95. Found: N(basic), 5.87.
2-( 3 -Ethylthiopropyl l ,2,3,4-tetrahydroisoquinoline hydrochloride, recrystallized from isopropyl a1 cohol, formed colorless plates, m.p. 200.5202.
Analysis. Calculated for C H CINS: C, 62.02; H,
8.24; CI, 13.04. Found: C, 61.85; H, 8.16; Cl(ionic), 13.00
EXAMPLE 3 2-(3-Ethylsulfinylpropyl)-1,2,3 ,4- tetrahydroisoquinoline To an ice cold solution of 23.5 g. (0.1 mole) of the base produced in Example 28 and 6 m1. of glacial acetic acid in 50 m1. of acetonitrile was added, dropwise with stirring, a solution of 19 g. of commercial 40 percent peracetic acid (0.1 mole) in 25 m1. of
EXAMPLE 4 2-( 3-Propylthiopropyl l ,2 ,3 ,4-tetrahydroisoquinoline To a stirred, ice cold solution of 16.1 g. (0.7 3. atom) of metallic sodium in 250 ml. of ethanol was added 31.2 g. (0.41 mole) of l-propanethiol. The solution was allowed to come to room temperature and a solution of 67.5 g. (0.27 mole) of the hydrochloride salt prepared in Example 28 in m1. of methanol was added dropwise with stirring. Stirring was continued and the reaction mixture was heated at reflux on a steam bath for 2.5 hours. The reaction mixture was concentrated to about one-half its original volume, poured into 700 ml. of water and extracted with ether. The ether solution was extracted with dilute hydrochloric acid. The aq ueous acid solution was made basic with aqueous sodium hydroxide and extracted with ether. The ether was dried and evaporated and the residual oil distilled to give 60.1 g. (90 percent) of 2-(3-propylthiopropyl)- l,2,3,4-tetrahydroisoquinoline, b.p. l67 (0.2 mm.).
Analysis. Calculated for C, .,l-l, NS: N, 5.62. Found: N(basic), 5.67
2-(3-propylthiopropyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride, recrystallized from isopropyl alcohol-ether, formed colorless plates, m.p. -197.
Analysis. Calculated for c u cms C, 63.02; H, 8.46; Cl, 12.40. Found: C, 62.79; H, 8.49; Cl(Schi'miger), 12.51.
EXAMPLES 5-6 1n the following examples the analogous compounds were prepared as indicated. The methods employed were the same as those set forth for the preceding examples. The physical constants and other analytical data are set forth in Table 1 below:
TABLE 1 Percent Start materl fi Method from example example Physical constants Example Compound Z-(propylthioethyD-l s a PE a y ochloride salt. {2-(methylthioeth t1) Hydrochloride 8 EXAMPLE 7 2-( Methylthiomethyl)-l ,2,3,4-tetrahydrois0quinoline To a solution of l06g. (0.8 mole) of tetrahydroisoquinoline in 250 ml. of benzene warmed to 35 was added dropwise with stirring, 38.6 g. (0.4 mole) of chloromethyl methyl sulfide. A white precipitate formed during the addition. The reaction mixture was stirred at room temperature 6 hours and allowed to stand for an additional 18 hours. The reaction mixture was filtered to give 57.5 g. percent) of tetrahydroisoquinoline hydrochloride and the filtrate was extracted with dilute hydrochloric acid. The aqueous acid layer was made basic with 20 percent sodium hydroxide and extracted with ether. Drying and removal of the ether left a yellow oil which was twice distilled to yield 29.8 g. (39 percent) of 2- (methylthiomethyl )-l ,2,3 ,4-tetrahydroisoquinoline, b.p. l20-l22 l .0 mm.), n"D 1.5819.
Analysis. Calculated for C,,H,,,NS: S, Found: S(Schoniger),l6.28.
2-( Methylthiomethyl )-l ,2,3 ,4-tetrahydroisoquinoline hydrochloride, recrystallized from ethanol-ether, formed colorless plates, m.p. l54-l 57.
Analysis. Calculated for C H CINS: C, 57.50; H, 7.02; Cl, 15.43. Found: C, 57.61; H, 7.20; Cl(Sch6niger), l5.32.
2-( Methylthiomethyl)-l ,2,3,4-tetrahydroisoquinoline methanesulfonate, recrystallized from ethanolether, formed small, colorless needles, m.p. l l6-l l8.
Analysis. Calculated for C H NO S S, 22.|6. Found: S(Sch6niger), 22.24.
EXAMPLE 8 2-( 3-Ethylsulfinylpropyl)-6-methyl-l 2,3,4- tetrahydroisoquinoline In a manner similar to that set forth in Example 2A 2- (3-chloropropyl )-6-methyll ,2,3,4-tetrahydroisoquinoline is prepared from the reaction of 6-methyltetrahydroisoquinoline (l.6 moles) and trimethylene chlorobromide (0.8 mole), thereafter the hydrochloride salt is formed, recrystallized and dissolved in methanol. To a cooled solution of 18.7 grams (0.81 g. atom) of metallic sodium in 300 ml. of ethanol is added 29.9 grams (0.48 mole) of ethanethiol. The solution is allowed to reach room temperature and the 2-( chloropropyl )-6-methyll ,2,3,4-tetrahydroisoquinoline hydrochloride (0.32 mole) dissolved in methanol is added dropwise. Thereafter the reaction mixture is stirred at reflux for about one hour. After distilling off a portion of the solvent, the reaction mixture is poured into water and extracted with ether. The ether solution is then extracted with dilute HCl, the aqueous mixture made alkaline and extracted with ether. Drying and removal of the ether and distillation of the residue gives 2-( S-ethylthiopropyl )-6-methyl-l ,2,3 ,4- tetrahydroisoquinoline. Elemental and infrared analysis confirms the structure.
To an ice cold solution of 0.1 mole of the 2-(3- ethylthiopropyl )-6-methyil ,2,3,4-tetrahydroisoquinoline and 6 ml. of glacial acetic acid in 50 ml. of acetonitrile is added, dropwise with stirring, a solution of I) grams of commercial 40 percent peracetic acid (0.l mole) in 25 milliliters of acetonitrile. The reaction mixture is stirred at room temperature for 1 hour,
poured into 150 ml. of water, made basic with dilute aqueous ammonia and extracted with ether. The ether solution is washed with dilute potassium carbonate solution, dried and treated with ethereal hydrogen Other procedures which were employed to evaluate the effect of the tetrahydroisoquinoline are set forth in the examples.
Preliminary toxicity studies on 2-( 3-ethylsulfmylchloride. The resulting precipitate is recrystallized 5 pr0pyl)-l.2.3.4-tetrahydroisoquinoline were confrom isopropyl alcohol to yield 2-(3-ethylsulfinylducted following the usual, well defined, and stanpropyl)-6-methyll,2,3,4-tetrahydroisoquinoline dardized procedures as described in the pamphlet Aphydrochloride. Elemental and infrared analysis conpraisal of the Safety of Chemicals in Foods, Drugs and firms the structure. Cosmetics," published in 1959 by the association of Food and Drug Officials in the United States. (Hogen, EXAMPLES Acute Toxicity," page l7; Fitzhugh, Sabacute Tox- In the following examples the analogous compounds ici y. p g n lh gh. hr nic ral T xicity." are prepared as indicated. The methods l y d ar page 36). Sixty day subacute toxicity tests in Wistar the same as those set forth in the preceding example. rats 1 50 and 150 mg/kg of body weight per day) and The starting materials and final products are set forth in sh g 3 0 and 90 mg/kg of body weight Table ll below: per day) indicated no significant biochemical or TABLE 11 Method of Example Compound Starting material example 1L... 2-(3-ethylthiofropyl)A-methyl-1,2,3,4-tstrahydroisoqulnollno 4-muthyl-l,2,3,t-tutrah (lrolsoquiuolino 8 l0... 2-(3-rnethylth opropyll-B-methoxy-l,2,3,4-tetrahydrolsoquiuollmti-mothoxy-l,2,3,4-tutr tytlrmsoqulnoliuu.. it 11 2-(3-prop lthlopropyD-T-chloro-l,2,8,4-tetrahydroisoquinolino 7-cliloro-l,2,3,4-tutrul1ydrolsoquinoliuu ii 12 2-(3-ethy thlopropyD-B-trlfluoromethyl-l,ZAALetruhyrlroisoquinollne. 6-trilluoromuthyl-1,2,3,4-totruhytlroisoquiuoliiw... H
The manner of using the invention ht t b histalogical evidence of toxicity. The composition was patented in its process aspect will now be described. Quite unexpectedly, it has been discovered that the tangible embodiments of this invention exhibit favorable cardiovascular effects in warm blooded animals. it has been observed that these compositions are useful as therapeutic agents for increasing systolic blood pres sure, with little or no concurrent increase in diastolic blood pressure. Hence, the compositions are useful as valuable therapeutic agents in the alleviation and control of low systolic blood pressure as would be associated with shock and other disorders. Additionally it has been observed that the compositions of of this invention are particularly unique in that while the blood pressure is increased there is no concurrent decrease in blood flow in the peripheral vascular system. In fact, an increase in blood flow rate in the peripheral vascular system has been observed when the tetrahydroisoquinoline was administered.
Various well known procedures were carried out to ascertain the cardiovascular effect of 2-( 3ethylsulfinylpropyl) l ,2,3,4-tetrahydroisoquinoline. In the preliminary tests 2-(3-ethylsulfinylpropyl)-l,2,3,4- tetrahydroisoquinoline was administered to anesthetized and unanesthetized dogs as the hydrochloride.
in the case of unanesthetized dogs, the systolic blood pressure was measured indirectly by using a tail cuff technique with the pressure recorded on a Beckman Continuous Systolic Monitor. Systolic and diastolic pressures of three dogs were also obtained with the electrosphygmograph cuff attachment to the physiograph, utilizing pressures from both the brachial and tail arteries.
Cardiac output was obtained by the dye-dilution method utilizing Cardio-Green dye and a Waters Densitometer. Dye injections were made through a catheter inserted through the right jugular vein and positioned near, or in the right atrium. Arterial sample for dye was from the left carotid artery.
The Shipley-Wilson rotameter was utilized to measure the rate of blood flow through the femoral artery.
administered to the dogs orally in capsules, once daily, 5 days per week. The rats received the same composition orally in drinking water 7 days per week.
The effective dosage of the compounds of this invention depends upon the individual characteristics of each case. in general, however, it has been observed that an effective concentration of the tetrahydroisoquinolines will usually range from about 0.10 to about milligrams per kilogram of body weight of the warm blooded animal. A preferred range is from about 0.25 to about 50 milligrams per kilogram of body weight. The tetrahydroisoquinolines can be formulated into capsules, tablets, injectable solutions, and the like. Tablets and capsules can be formulated with the usual ingredients and excipients such as starch, methylcellulose, natural gums, dibasic calcium phosphate, lubricants, dispersing agents and the like.
In some instances it may be preferred to administer the tetrahydroisoquinolines by infusion, such as with plasma, at a constant rate over an extended period of time. In such cases, the effective concentration can be adjusted to provide the desired dosage levels.
The following examples set forth the manner of using the tetrahydroisoquinolines of this invention for increasing the blood pressure in warm blooded animals.
EXAMPLE 13 Effect of Tetrahydroisoquinolines on Systolic Blood Pressure a. An unanesthetized dog having a control blood pressure of l /70 was injected intravenously with 0.5 mglltg of 2-(3-ethylsulfinylpropyl)-l,2,3,4- tetrahydroisoquinoline hydrochloride and observed for l hour. immediately following the injection, the person holding the dog noted a forceful pounding of the heart. This was accompanied by an increase in heart rate from a control level of 126 to l68. The heat rate then returned to the control level of 126 by the end of 30 minutes. The systolic blood pressure immediately increased from 180 to 220-230 and had almost returned to control level by the end of 1 hour. No increases in diastolic pressure were observed.
b. A second unanesthetized dog which was very calm and had a control blood pressure of 120/70 which changed to 150/66 30 minutes after intravenous administration of 1 mg/kg of 2- (3-ethylsufinylpropyl l ,2,3 ,4-tetrahydroisoquinoline hydrochloride. Heart rate increased from 72 to 100. Little or no gross stimulation occurred. On another day this same dog was injected intravenously with 0.5 mg/kg of 2-(3-ethylsulfinylpropyl l ,2,3,4-tetrahydroisoquinoline hydrochloride. From a control pressure of 122/60 the pressure increased to 130/65 7-10 minutes after injection. A maximal increase to 145/73 occurred 43 minutes after injection. One and onehalf hours after injection the pressure was almost back to control levels.
EXAMPLE 14 Effect of Tetrahydroisoquinolines on Cardiac Output The effect of 2-(3ethylsulfinylpropyl)-1,2,3,4- tetrahydroisoquinoline on cardiac output was determined in a pentobarbitalized dog. The dosage was I mglkg of body weight administered intravenously as the hydrochloride. The cardiac output was obtained by the dye-dilution method utilizing Cardio Green dye and a Waters Densitometer. Dye injections were made through a catheter inserted through the right jugular vein and positioned near, or in the right atrium. Arterial sampling for dye was from the left carotid artery. The results of this experiment is given in Table III. Each value in the table represents data from one dye-dilution curve. The values for controls are averages of the number in parentheses and were taken during the few minutes immediately preceding administration of the tetrahydroisoquinoline.
TABLE I" Mean Total Cardiac Arterial Perhe- Heart Output Blood ral Rate Stroke Time (liters! Pressure Resista- (beats! Volume (mins) min) (mm Hg) nce" min) (ml) Control (2) 2.81 140 3.02 144 19.5 2-3 4.95 142 1.72 198 25.0 12-13 5.07 143 1.69 204 24.9 29-30 4.48 140 1.87 240 18.2 45-46 3.18 130 2.45 228 14.0
(1)= pressure (mm Hg)! cardiac output (mllsec) EXAMPLE 15 Effect of Tetrahydroisoquinolines On Blood Flow The Shipley-Wilson rotameter was utilized to measure the rate of blood flow through the femoral artery in the subject anesthetized dogs. Injection of 1 mg of 2- (3-ethylsulf1nylpropyl l ,2,3 ,4-tetrahydroisoquinoli ne hydrochloride into the tubing leading directly to the femoral artery resulted in an increase in flow of l to 2 minutes duration. This increased flow was apparently due to vasodilation since the blood pressure (recorded from the same tubing leading directly to the artery) was not increased. in two anesthetized dogs femoral blood flow was recorded and 0.5 to 1.0 mg/kg of the same tetrahydroisoquinoline hydrochloride was injected intravenously. increases in flow of 3 to 5 minutes duration were observed. These changes were not due to any increase in blood pressure. In one of these dogs an additional intravenous injection of 10 mg/kg of the tetrahydroisoquinoline caused evidence of prolonged vasodilation.
Simple substituents on the tetrahydroisoquinoline moiety of the compounds of the present invention do not adversely affect the pharmacological properties thereof, and are to be regarded as the full equivalents of the compounds of the invention wherein the tetrahydroisoquinoline moiety is unsubstituted. For example, the molecule may also contain substitutents wherein R or R" groups are other than hydrogen. Such additions to the molecular structure of the inventive concept herein described are, therefore, equivalents of the subject matter sought to be patented.
As previously indicated, the aforementioned general formula defines the compounds of the present invention as the free base form thereof. inasmuch as the physical embodiments of the inventive concept have pharmacological utility, for such use the compounds will usually be administered in the form of their pharmaceutically acceptable acid addition salts, these salts are the full equivalents of the free base forms thereof. The acid addition salts can be prepared by reacting the corresponding free bases in a conventional manner with an inorganic acid such as hydrochloric, hydrobromic, sulfuric and phosphoric; or an organic acid, such as methanesulfonic, ethanesulfonic, ethanedisulfonic, cyclohexylsulfamic, formic, maleic, citric, tartaric and tannic acids. The compounds can also be administered in the form of their quarternary ammonium salts formed by the reaction with a lower alkyl halide.
In addition to their use as the essential active ingredient in pharmaceutical formulations, the novel compositions of this invention can be employed in a variety of other fields. For example, the tetrahydroisoquinoline compounds of this invention are useful as intermediates in the synthesis of other chemical compounds.
What is claimed is:
l. A compound selected from the group consisting of tetrahydroisoquinolines having the formula:
wherein A is an alkylene group having at least one and not more than seven carbon atoms, R is an alkyl group having at least one and not more than seven carbon atoms, R is selected from the group consisting of hydrogen and lower primary and secondary alkyl groups, R" is selectedfrom the group consisting of lower alkyl, lower alkoxy, halo and methylenedioxy groups; n has a value of zero through two; provided that when R" is methylenedioxy, then R", means a single methylenedioxy group attached to adjacent carbon atoms and H means H and the pharmaceutically acl3 ceptable acid addition salts of said tetrahydroisoquin- Ollie compound as set forth in claim 1 wherein A is a propylene group, R is a methyl group, R is hydrogen and n is 0.
3. A compound as set forth in claim 1 wherein A is a propylene group, R is a propyl group, R is hydrogen and n is 0.
4. A compound as set forth in claim 1 wherein A is an ethylene group, R is a propyl group, R is hydrogen and n is 0.
5. A compound as set forth in claim 1 wherein A is an ethylene group, R is a methyl group, R is hydrogen and n is 0.
6. A compound as set forth in claim 1 wherein A is a methylene group, R is a methyl group, R is hydrogen and n is 0.
7. A compound as set forth in claim 1 wherein A is a I4 propylene group, R is an ethyl group, R is hydrogen, R" is methyl and n is l.
8. A compound as set forth in claim 1 wherein A is a propylene group, R is an ethyl group, R is a methyl group and n is 0.
9. A compound as set forth in claim 1 wherein A is a propylene group, R is a methyl group, R is hydrogen, R" is methoxy and n is l.
10. A compound as set forth in claim 1 wherein A is a propylene group, R is a propyl group, R is hydrogen, R" is chloro and n is I.
11. A compound as set forth in claim 1 wherein A is a propylene group, R is an ethyl group, R is hydrogen, R" is trifluoromethyl and n is l.
12. A compound as set forth in claim 1 wherein A is a propylene group, R is an ethyl group, R is hydrogen, and n is 0.
l i l 1F PO-WJO UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 1,691 ,169 Dated September 12 1972 luventor(s) Allan Poe Gray It is certified that error appears in the aboveidentified patent and that said Letters Patent are hereby corrected as shown below:
T Front page data element [73] Assignee: "Neisler "I Laboratories, Inc." should be Mallinokrodt Chemical Works".
Column l line ll, "in vacuo should be "in vacuo" line 5 4 "ClEH should be c H Col. 5 line 23, "of minutes" should be' of 26 minutes"; line E5, "13.00" should be "13.00.". Column 6, line M5, "C H CINS" should be "C H CINSW. Column 8, line 22, "(Schonig er') should be "(Schoniger')"; line 32,
h U Q 7| H I "o h iw S ShOJld be C H NO S Column 10, line 35, "heat" should be "heart". Column ll, the title for" the fourth column of Table III reading "Total Perhe-ral. Resistance "should be "Total Peripheral Resistance Column 12, line 67, H 1; should be "H Signed and sealed this 8th day of May 1973.
(SEAL) Attest:
EDWARD M. FLETCHER,JR. ROBERT GOTTSCHALK Attesting Officer Commissioner of Patents