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US3870722A - 2-Methyl-3-substituted-4-aryl isoquinolines - Google Patents

2-Methyl-3-substituted-4-aryl isoquinolines Download PDF

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US3870722A
US3870722A US412132A US41213273A US3870722A US 3870722 A US3870722 A US 3870722A US 412132 A US412132 A US 412132A US 41213273 A US41213273 A US 41213273A US 3870722 A US3870722 A US 3870722A
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phenyl
butyl
tert
methyl
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William J Houlihan
Jeffrey Nadelson
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Sandoz AG
Sandoz Wander Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/24—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring

Definitions

  • This invention pertains to 2-methyl-3-substituted-4- aryl isoquinolines. More particularly, it concerns 2- methyl-3-substituted-4-phenyl-1,2,3,4- tetrahydroisoquinolines, acid addition salts thereof, and processes for their preparation.
  • tetrahydroisoquinolines of this invention may be represented by the following strucutral formula:
  • R and R are each independently methyl or ethyl, or
  • R and R together represent (CH n represents 4, 5, or 6, and R and R each independently represent hydrogen, halo of atomic weight 19-36, trifluoromethyl, lower alkyl, ie. alkyl of 1-4 carbon atoms, e.g. methyl, ethyl, propyl, isopropyl, butyl, and the like, and lower alkoxy, ie.
  • alkoxy having 1-4 carbon atoms such as methoxy, ethoxy, isopropoxy, and the like, provided that R, and R may not represent alkyl at the 8position, and provided further that two trifluoromethyl groups or two tertiary butyl groups or a trifluoromethyl and a tertiary butyl group are not on adjacent carbon atoms.
  • Compounds (1) are prepared by treating a corresponding compound (11) with formic acid and formaldehyde for about 12-24 hours at a temperature of about 70-1 C., conveniently at the reflux temperature of the system. Conventional solvents may be used but are unnecessary.
  • Compounds (111) may be converted into compounds (11) by hydrogenating the former with a platinum metal catalyst, such as platinum oxide in inert solvent, such as loweralkanoic acid, e.g. acetic acid, at a temperature of from about 2060C., preferably about 25-35C., at 25-100 psi until about two equivalents of hydrogen are absorbed. Neither time temperature of reaction, pressure nor the solvent used is critical.
  • a platinum metal catalyst such as platinum oxide in inert solvent, such as loweralkanoic acid, e.g. acetic acid
  • the compounds of formula (111) may be prepared according to the following reaction scheme:
  • Compounds (111) may be prepared from compounds (IV) by hydrogenating the latter at 25-100 p.s.i. in inert alcohol solvent, e.g. lower alkanols such as etha- N-CH 3 4 time, temperature, pressure nor solvent utilized is criti- 80-I C., for about one-half to 3 hours.
  • inert alcohol solvent e.g. lower alkanols such as etha- N-CH 3 4 time, temperature, pressure nor solvent utilized is criti- 80-I C., for about one-half to 3 hours.
  • the reaction cal in obtaining compounds (III). time and temperature are not critical.
  • novel compounds of formula (IV) may be ob- As will be appreciated by persons skilled in the art, tained according t0 the following reaction scheme: compounds (V) and (VI) may also exist in tautomeric form and the exact form of the compounds and the amount of compound in each tautomeric form will de- R 0 35 x pend upon such factors as pH, temperature, solvent,
  • the compounds of formula (VI) may be obtained ac- (Iv) cording to the following reaction scheme from compounds VII and compounds vm ,l 3 R o 05 l N 2; 3 5 mrc- CB 1. (VIII) where X, R through R and the provisos are as set out where above. R through R and the provisos are as set out above regarding compounds (VI), and
  • Y represents halo of atomic weight 35-80.
  • the compounds (V) may be prepared according to The compounds of formula (VII) may be obtained the following reaction scheme: from the compounds of the formula n 0 P R o unfit-0H 5 v N a 0 an Rh H (VI) (v) where R, through R and respecting compounds (V) the provisos are as set out above, and provided further R 5 0 3 that R, and R may not represent alkyl at a position NH CH ortho to the carbon bonded to the amide group on an i compounds (VI), provided further that two trifluoro- 3 methyl groups or two tertiary butyl groups or a trifluoromethyl and a tertiary butyl group are not on adjacent carbon atoms.
  • Compounds (V) are thus prepared from compounds (VI) by treating the latter with polyphosphoric acid at a temperature of about -120C., preferably about where R, and R and the provisos are as set out above for compounds (VI), by treatment with a lithiating agent, particularly an alkyl or aryl lithium compound; n-butyl lithium is especially preferred.
  • a lithiating agent particularly an alkyl or aryl lithium compound; n-butyl lithium is especially preferred.
  • This reaction may be performed in solvent and for a period of time similar to that described above in connection with the process for obtaining compounds (VI).
  • the temperature of the reaction is preferably from about l to +1 0C.
  • Compound (VII) is normally not isolated from the reaction mixture and may be used directly in the process for preparing compounds (Vl) above.
  • the compounds (IX) are preparable from compounds of the formula OK t where R, and R are as set out above, provided that R and R may not represent alkyl at a position ortho to the carbon bonded to the acid group, and provided further that two trifluoromethyl groups or two tertiary butyl groups or a trifluoromethyl and a tertiary butyl group are not on adjacent carbon atoms, in a standard manner by halogenating compounds (X) with halogenating agents such as thionyl chloride, and aminating the resulting acid halide with tert.butylamine.
  • R and R are as set out above, as are the provisos respecting compounds (XI), and provided that regarding compounds (XII) R and R do not represent alkyl at a position ortho to the carbon bonded to the amido group, and provided further that two trifluoromethyl groups or two tertiary butyl gorups or a trifluoromethyl and a tertiary butyl group are not on adjacent carbon atoms.
  • compound (Xll) is heated in inert hydrocarbon or halogenated hydrocarbon solvent, e.g. benzene, toluene, pentane, odichlorobenzene and the like.
  • inert hydrocarbon or halogenated hydrocarbon solvent e.g. benzene, toluene, pentane, odichlorobenzene and the like.
  • the reaction may be carried out at a temperature of about 200C., and conveniently at the reflux temperature of the solvent utilized.
  • Compounds (XII) are prepared from compounds (XIII) in inert hydrocarbon or ether solvent, e.g. benzene, toluene, ethyl ether, tetrahydrofuran and the like.
  • the reaction is a two step reaction involving lithialithiation of the compound (XIII) to obtain a dilithio intermediate thereof, which in turn is treated with benzaldehyde to obtain compounds XII).
  • the lithiation is preferably performed at a temperature between about -60 and +l0C. for about 1 to 3 hours whereas'the second step, generally performed without separation of the dilithio intermediate, is performed between l0 and +l0C. for about 1-3 hours.
  • the products of each of the reactions described above may be recovered by conventional techniques such as crystalization, filtration, trituration, and the like.
  • Compounds (I), (II) and (111) may exist in the form of their acid addition salts. Said salts and their respective free bases may be converted from one to the other by conventional techniques and are chemically interchangeable for purposes of the above described process.
  • the compounds of formula (I) exist in racemic form or in the form of optically active isomers. The separation and recovery of the respective isomers may be readily accomplished employing conventional techniques, and such isomers are included within the scope of the invention.
  • the compounds of formula (I) are useful because they possess pharmacological activity in animals as hypolipidemic agents, particularly as hyperlipoproteinemic agents, as indicated by the fall in cholesterol and/or triglyceride levels in male albino Wistar rats weighting 110-130g. initially.
  • the rats are maintained on drug-free laboratory chow diet for seven days and then divided into gorups of 8 to 10 animals. Each group, with the exception of the control, is then given orally 6-25 mg/kg of body weight per diem of the compound for 3-6 days.
  • the animals are anesthetized with sodium hexobarbital and bled from the carotid arteries. Serum or plasma samples are collected, and 1.0 ml.
  • the compounds are indicated as being useful as hypocholesterolemic agents in the treatment of hypocholesteremia.
  • the compounds of formula (I) may be combined with a pharmaceutically acceptable carrier or adjuvant, and may be administered orally in such forms as tablets, capsules, elixers, suspensions and the like, or parenterally in the form of an injectable solution or suspension.
  • a pharmaceutically acceptable carrier or adjuvant such forms as tablets, capsules, elixers, suspensions and the like, or parenterally in the form of an injectable solution or suspension.
  • the dosage will vary depending upon the mode of administration utilized and the particular compound employed.
  • the compounds of formula (I) may be similarly administered in the form of their nontoxic pharmaceutically acceptable acid addition salts.
  • Such salts possess the same order of activity as the free base, are readily prepared by reacting the base with an appropriate acid and accordingly are included within the scope of the invention.
  • Representative of such salts are the mineral salts, such as hydrochloride, hydrobromide, sulfate, phosphate and the like and the organic acid salts, such as the succinate, benzoate, acetate, p-toluenesulfonate, benzenesulfonate and the like.
  • the compounds of formula (I) exist as optical isomers. In come cases, greater pharmacological activity or other beneficial attribute may be found for a particular isomer and in such instances administration of such isomer may be preferred.
  • the compounds (I) are administered at a daily dosage of from about 05-100 mg/kg of animal body weight, preferably orally and in divided doses, 2 to 4 times a day or in sustained release form.
  • the total daily dosage is from about 30-1000 mg. per day.
  • Dosage forms suitable for internal use comprise from about 7.5 mg. to about 500 mg. of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier or diluent.
  • Tablets containing 50 mg. of active ingredient and 250 mg. of lactose may be prepared by conventional techniques and are useful in treating lipemia at a dose of one tablet 2 to 4 times a day.
  • N-tert. butyl-a-phenyl-o-toluamide When the above process is carried out and in place of N-tert. butyl-a-phenyl-o-toluamide there is used a. 6-chloro-N-tert.butyl-a-phenyl-o-toluamide, b. N-tert.butyl-4-methyl-a-phenyl-o-toluamide, c. N-terLbutyl-a-phenyl-S-triflu0romethyl-otoluamide, or d. 4-methoxy-N-tert.butyl-a-phenyl-o-toluamide,
  • the resulting white solid is filtered and recrystallized from ethanolethyl ether, washed with water, dried, and filtered and the filtrate treated with gaseous HCl.
  • the resulting white solid is filtered and recrystallized from ethanol-ethyl ether (1:1 to give 3-tert.butyl- 4-phenyl isoquinoline hydrochloride; m.p. 236238C.
  • hydrochloride a 2 -tert.butyl-8-chloro-2-methyl-4-phenyll ,2,3 ,4
  • the title compound of this example is effective when orally administered to an animal suffering from lipemia at a dosage of 200 mg. twice per day.
  • R represents where R and R are each, independently, methyl or ethyl, or R and R together represent (CH where n represents 4, 5, or 6,
  • R and R each, independently, represent hydrogen, halo of atomic weight 19-36, trifluoromethyl, lower alkyl, or lower alkoxy, provided that R and R may not represent alkyl at the 8-position, and provided further that two trifluoromethyl or two tertiary butyl groups or a trifluoromethyl and a tertiary butyl group are not on adjacent carbon atoms and the pharmacologicaliy acceptable acid addition salts thereof.

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

2-Methyl-3-substituted-4-aryl isoquinolines, e.g. 2-methyl-3tertiary butyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline, prepared from corresponding 2-des-methyl isoquinoline intermediates, are useful as hypolipidemic agents.

Description

United States Patent [191 Houlihan et al.
[ 1 2-METHYL-3-SUBSTlTUTED-4-ARYL ISOQUINOLINES [75] Inventors: William J. Houlihan, Mountain Lakes; Jeffrey Nadelson, Lake Parsippany, both of NJ.
[73] Assignee: Sandoz-Wander, lnc., Hanover, NJ.
[22] Filed: Nov. 2, 1973 [2]] App]. No.: 412,132
[52] U.S. CL... 260/283 R, 260/283 SY, 260/286 R, 260/289 R, 260/343.3, 260/515 R, 260/52] R, 260/558 R, 260/559 R, 424/258 [51] Int. Cl C07d 33/34 [58] Field of Search 260/283 R, 289 R [56] References Cited UNITED STATES PATENTS 3,666,763 5/1972 Gelhe et a] 260/289 R l lMar. 11,1975
OTHER PUBLICATIONS Gardent et al.; Chem. Abstracts, Vol. 64, 1966; p. 19555a.
Helsley 260/289 R Diana 260/289 R Primary Examiner-Donald G. Daus Assistant ExaminerMary C. Vaughn Attorney, Agent, or Firm-Gerald O. Sharkin; Robert C. Honor 5 Claims, N0 Drawings 1 2-METHYL-3-SUBSTITUTED-4-ARYL ISOQUINOLINES This invention pertains to 2-methyl-3-substituted-4- aryl isoquinolines. More particularly, it concerns 2- methyl-3-substituted-4-phenyl-1,2,3,4- tetrahydroisoquinolines, acid addition salts thereof, and processes for their preparation.
The tetrahydroisoquinolines of this invention may be represented by the following strucutral formula:
R and R are each independently methyl or ethyl, or
R and R together represent (CH n represents 4, 5, or 6, and R and R each independently represent hydrogen, halo of atomic weight 19-36, trifluoromethyl, lower alkyl, ie. alkyl of 1-4 carbon atoms, e.g. methyl, ethyl, propyl, isopropyl, butyl, and the like, and lower alkoxy, ie. alkoxy having 1-4 carbon atoms, such as methoxy, ethoxy, isopropoxy, and the like, provided that R, and R may not represent alkyl at the 8position, and provided further that two trifluoromethyl groups or two tertiary butyl groups or a trifluoromethyl and a tertiary butyl group are not on adjacent carbon atoms.
The compounds of formula (I) are preparable from compounds of the formula (II) according to the following reaction scheme:
H0001! R 1 HCHO (II) (I) where R, through R and the provisos are as set out above.
Compounds (1) are prepared by treating a corresponding compound (11) with formic acid and formaldehyde for about 12-24 hours at a temperature of about 70-1 C., conveniently at the reflux temperature of the system. Conventional solvents may be used but are unnecessary.
The compounds of formula (11) are prepared by hydrogenation of corresponding isoquinoline intermediates Of formula ([11) according to the following reaction scheme:
1; R N-H (III) (II) where R through R and the provisos are as set out above.
Compounds (111) may be converted into compounds (11) by hydrogenating the former with a platinum metal catalyst, such as platinum oxide in inert solvent, such as loweralkanoic acid, e.g. acetic acid, at a temperature of from about 2060C., preferably about 25-35C., at 25-100 psi until about two equivalents of hydrogen are absorbed. Neither time temperature of reaction, pressure nor the solvent used is critical.
The compounds of formula (111) may be prepared according to the following reaction scheme:
and l X represents halo of atomic weight about 3580. Compounds (111) may be prepared from compounds (IV) by hydrogenating the latter at 25-100 p.s.i. in inert alcohol solvent, e.g. lower alkanols such as etha- N-CH 3 4 time, temperature, pressure nor solvent utilized is criti- 80-I C., for about one-half to 3 hours. The reaction cal in obtaining compounds (III). time and temperature are not critical.
The novel compounds of formula (IV) may be ob- As will be appreciated by persons skilled in the art, tained according t0 the following reaction scheme: compounds (V) and (VI) may also exist in tautomeric form and the exact form of the compounds and the amount of compound in each tautomeric form will de- R 0 35 x pend upon such factors as pH, temperature, solvent,
etc. For simplicity, compounds (V) and (VI) will be de- R R N picted by use of the structures shown, but it will be un- A derstood that the corresponding tautomeric forms and R 9 1 their use and production are also contemplated by the 1 invention.
The compounds of formula (VI) may be obtained ac- (Iv) cording to the following reaction scheme from compounds VII and compounds vm ,l 3 R o 05 l N 2; 3 5 mrc- CB 1. (VIII) where X, R through R and the provisos are as set out where above. R through R and the provisos are as set out above regarding compounds (VI), and
Y represents halo of atomic weight 35-80.
Compounds (VII) and (VIII) are first reacted in inert solvent such as hydrocarbon solvents, c.g. benzene or toluene, or ethers such as ethyl ether or tetrahydro furan, at a temperature of from about 60 to about 10C. The preferred temperature range is about to 50C. and the reaction may be run for l-l0 hours. The resulting product is then hydrolyzed by conven- Compounds (IV) are accordingly obtained by treating a compound of formula (V) with halogenating agent such as PCI POCI SOCI PBr PBr and SOBr and the like optionally in solvent such as aromatic hydrocarbon solvent, e.g. benzene or toluene, for about 30-90 minutes at a temperature of about 80l C., conveniently at the reflux temperature of the system. Neither time, temperature nor solvent are 40 't' 1. en ca tional techniques to provide compounds (VI).
The compounds (V) may be prepared according to The compounds of formula (VII) may be obtained the following reaction scheme: from the compounds of the formula n 0 P R o unfit-0H 5 v N a 0 an Rh H (VI) (v) where R, through R and respecting compounds (V) the provisos are as set out above, and provided further R 5 0 3 that R, and R may not represent alkyl at a position NH CH ortho to the carbon bonded to the amide group on an i compounds (VI), provided further that two trifluoro- 3 methyl groups or two tertiary butyl groups or a trifluoromethyl and a tertiary butyl group are not on adjacent carbon atoms.
Compounds (V) are thus prepared from compounds (VI) by treating the latter with polyphosphoric acid at a temperature of about -120C., preferably about where R, and R and the provisos are as set out above for compounds (VI), by treatment with a lithiating agent, particularly an alkyl or aryl lithium compound; n-butyl lithium is especially preferred. This reaction may be performed in solvent and for a period of time similar to that described above in connection with the process for obtaining compounds (VI). The temperature of the reaction is preferably from about l to +1 0C. Compound (VII) is normally not isolated from the reaction mixture and may be used directly in the process for preparing compounds (Vl) above.
The compounds (IX) are preparable from compounds of the formula OK t where R, and R are as set out above, provided that R and R may not represent alkyl at a position ortho to the carbon bonded to the acid group, and provided further that two trifluoromethyl groups or two tertiary butyl groups or a trifluoromethyl and a tertiary butyl group are not on adjacent carbon atoms, in a standard manner by halogenating compounds (X) with halogenating agents such as thionyl chloride, and aminating the resulting acid halide with tert.butylamine.
The compounds (X) are prepared according to the following reaction scheme:
R 0 RI; g o
(XIII) R5 0 R5 V 0 (xx) (x) Compounds (XI) may be prepared according to the following reaction scheme:
IHR a R on E (XII) (n) where R represents lower alkyl, as defined above, or phenyl, and
R and R are as set out above, as are the provisos respecting compounds (XI), and provided that regarding compounds (XII) R and R do not represent alkyl at a position ortho to the carbon bonded to the amido group, and provided further that two trifluoromethyl groups or two tertiary butyl gorups or a trifluoromethyl and a tertiary butyl group are not on adjacent carbon atoms.
According to the above process, compound (Xll) is heated in inert hydrocarbon or halogenated hydrocarbon solvent, e.g. benzene, toluene, pentane, odichlorobenzene and the like. The reaction may be carried out at a temperature of about 200C., and conveniently at the reflux temperature of the solvent utilized.
The compounds of formula (XII) are obtainable from compounds (XIII) according to thefollowing reaction scheme:
(1) lithiation where R,,, R and R and the provisos are as set out above for compounds (XII).
Compounds (XII) are prepared from compounds (XIII) in inert hydrocarbon or ether solvent, e.g. benzene, toluene, ethyl ether, tetrahydrofuran and the like. The reaction is a two step reaction involving lithialithiation of the compound (XIII) to obtain a dilithio intermediate thereof, which in turn is treated with benzaldehyde to obtain compounds XII). The lithiation is preferably performed at a temperature between about -60 and +l0C. for about 1 to 3 hours whereas'the second step, generally performed without separation of the dilithio intermediate, is performed between l0 and +l0C. for about 1-3 hours.
Unless specifically indicated otherwise, the products of each of the reactions described above may be recovered by conventional techniques such as crystalization, filtration, trituration, and the like.
Certain of the compounds of formulae (VIII) and (XIII) are known and may be prepared according to methods disclosed according to the literature. The compounds of formulae (VIII) and (XIII) not specifcally disclosed may be preparedby methods analogous to those in the literature from known compounds.
Compounds (I), (II) and (111) may exist in the form of their acid addition salts. Said salts and their respective free bases may be converted from one to the other by conventional techniques and are chemically interchangeable for purposes of the above described process. The compounds of formula (I) exist in racemic form or in the form of optically active isomers. The separation and recovery of the respective isomers may be readily accomplished employing conventional techniques, and such isomers are included within the scope of the invention.
The compounds of formula (I) are useful because they possess pharmacological activity in animals as hypolipidemic agents, particularly as hyperlipoproteinemic agents, as indicated by the fall in cholesterol and/or triglyceride levels in male albino Wistar rats weighting 110-130g. initially. The rats are maintained on drug-free laboratory chow diet for seven days and then divided into gorups of 8 to 10 animals. Each group, with the exception of the control, is then given orally 6-25 mg/kg of body weight per diem of the compound for 3-6 days. At the end of this period, the animals are anesthetized with sodium hexobarbital and bled from the carotid arteries. Serum or plasma samples are collected, and 1.0 ml. samples of the serum are added to 9.0 ml. redistilled isopropanol. Two autoanalyzer cupsful of a mixture of zeolite-copper hydroxide and Lloydds reagent [Kessler, G., and Lederer, H., 1965, Technicon Symposium, Mediad Inc., New York (345-347)] are added, and the mixture is shaken for 1 hour. Cholesterol and triglyceride levels are determined simultaneously on the same sample by Technicon N-24 A (cholesterol) and N-78 (triglyceride) methodology. The mean serum cholesterol levels are than computed and the hypocholesterolemic activity is expressed as the fall in cholesterol levels as a percentage of the control level. The change in serum triglyceride levels induced by the drug is computed as a percentage of the control triglyceride levels.
In particular, the compounds are indicated as being useful as hypocholesterolemic agents in the treatment of hypocholesteremia.
For such usage, the compounds of formula (I) may be combined with a pharmaceutically acceptable carrier or adjuvant, and may be administered orally in such forms as tablets, capsules, elixers, suspensions and the like, or parenterally in the form of an injectable solution or suspension. The dosage will vary depending upon the mode of administration utilized and the particular compound employed.
As indicated above, the compounds of formula (I) may be similarly administered in the form of their nontoxic pharmaceutically acceptable acid addition salts. Such salts possess the same order of activity as the free base, are readily prepared by reacting the base with an appropriate acid and accordingly are included within the scope of the invention. Representative of such salts are the mineral salts, such as hydrochloride, hydrobromide, sulfate, phosphate and the like and the organic acid salts, such as the succinate, benzoate, acetate, p-toluenesulfonate, benzenesulfonate and the like.
As noted above, the compounds of formula (I) exist as optical isomers. In come cases, greater pharmacological activity or other beneficial attribute may be found for a particular isomer and in such instances administration of such isomer may be preferred.
In general, satisfactory results in alleviating lipemia may be obtained when the compounds (I) are administered at a daily dosage of from about 05-100 mg/kg of animal body weight, preferably orally and in divided doses, 2 to 4 times a day or in sustained release form. For most larger mammals (e.g. primates) the total daily dosage is from about 30-1000 mg. per day. Dosage forms suitable for internal use comprise from about 7.5 mg. to about 500 mg. of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier or diluent.
Tablets containing 50 mg. of active ingredient and 250 mg. of lactose may be prepared by conventional techniques and are useful in treating lipemia at a dose of one tablet 2 to 4 times a day.
EXAMPLE 1 N-turt.butyl-a-phenyl-o-toluamide To a flask equipped with a stirrer, dropping funnel, condenser and gas inlet tube maintained under a nitrogen atmosphere there is added at room temperature ;67.5 g. (0.5 mole) N-methyl benzamide and 1200 ml.
dry tetrahydrofuran. The reaction flask is immersed in an ice bath and cooled to an internal temperature of 5C. Stirring is initiated and 688 ml. of 1.6 M. n-butyl lithium (1.1 mole) in hexane is added dropwise over about 1 hour maintaining temperature below 8C. The resulting dilithio salt is stirred at 5C. for an additional hour and then a solution of 58.5 g. (0.55 mole) of benzaldehyde in 500 ml. tetrahydrofuran is added dropwise in about 1 hour maintaining the temperature between -1 0 and +10C. The resulting mixture is stirred at 5C. for 1 hour longer and 300 ml. of saturated ammonium chloride is added maintaining the temperature at about 10C. The layers are separated and the organic phase dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give a-hydroxy-N-methyl-aphenyl-o-toluamide.
A mixture of 76.5 g. of a-hydroxy-N-methyl-a-phenyl-o-toluamide and (0.314 mole) ml. 0- dichlorobenzene is heated at reflux for 18 hours. The mixture is cooled and filtered and the resulting solid triturated with cold ether to give 3-phenyl phthalide.
When the above detailed procedure is carried out and in place of N-methyl benzamide there is used a. o-chloro-N-phenyl benzamide,
b. N-methyl-p-toluamide,
c. N-methyl-m-trifluoromethyl benzamide, or
d. p-methoxy-N-methyl benzamide, there is obtained through the corresponding intermediate a-hydroxy-aphenyl-o-toluamide,
a. 7-chloro-3-phenyl phthalide,
b. 5-methyl-3-phenyl phthalide,
c. 6-trifluoromethyl-3-phenyl phthalide, or
d. 5-methoxy-3-phenyl phthalide, respectively.
A mixture of 55.2 g. of 3-phenyl phthalide (0.263 mole), 600 ml. ethanol and 5.9 g. of 10% Pd/C is hydrogenated at room temperature and 50 psi until 1 equivalent of H is absorbed. The catalyst is removed by filtration and the solvent removed in vacuo and the residue triturated in petroleum ether to give til-phenylo-toluic acid; m.p. l01104C.
To a mixture of 49.8 g. (0.235 mole) a-phenyl-otoluic acid, 300 ml. ether and 10 ml. pyridine, add dropwise with stirring 25 ml. (0.35 mole) of thionyl chloride. The resulting mixture is stirred 21 hours at room temperature then filtered and the solvent removed in vacuo. The resulting acid chloride is dis- When the procedure described in the above two paragraphs is carried out and in place of 3-phenyl phthalide there is used a. 7-chloro-3-phenyl phthalide,
b. 5-methyl-3-phenyl phthalide,
c. 6-trifluoromethyl-3-phenyl phthalide, or
d. 5-methoxy-3-phenyl phthalide, there is obtained through the corresponding acid and acid halide,
a. 6-chloro-N-tert.butyl-a-phenyl-o-toluamide,
b. N-tert.butyl-4-methyl-a-phenyl-o-toluamide,
c. N-tert.butyl-a-phenyl-5-trifluoromethyl-otoluamide, or
d. 4-methoxy-N-tert.butyl-a-phenyl-o-toluamide, re-
spectively.
EXAMPLE 2 N-tert.butyl-oz-phenyl-a-pivaloyl-o-toluamide To a flask equipped with a stirrer, dropping funnel, condenser and gas inlet tube and maintained under a nitrogen atmosphere there is added at room temperature 59 g. (0.221 mole) of N-tertbutyl-a-phenyl-otoluamide in 1000 ml. dry tetrahydrofuran. The flask is immersed in an ice bath and cooled to an internal temperature of 5C. Stirring is initiated and 336.5 mi. (0.490 mole) of n-butyl lithium in hexane) is added dropwise in about 1 hour maintaining the temperature below 8C. The resulting solution is stirred 2 hours at room temperature, cooled to 5C., and 26.6 g. (0.221 mole) of pivaloyl chloride in 250 ml. of dry tetrahydrofuran is added dropwise maintaining temperature below 8C. After addition, the mixture is stirred 2 hours at room temperature and hydrolyzed with 150 ml. of saturated ammonium chloride, the resulting solution is filtered and the layers separated. The organic layer is dried over magnesium sulfate, filtered and evaporated in vacuo. The residue is triturated with ether to give N-tert.butyl-a-phenyl-a-pivaloyl-otoluamide; m.p. l57-161C.
When the above process is carried out and in place of N-tert. butyl-a-phenyl-o-toluamide there is used a. 6-chloro-N-tert.butyl-a-phenyl-o-toluamide, b. N-tert.butyl-4-methyl-a-phenyl-o-toluamide, c. N-terLbutyl-a-phenyl-S-triflu0romethyl-otoluamide, or d. 4-methoxy-N-tert.butyl-a-phenyl-o-toluamide,
there is obtained a. 6-chloro-N-tert.butyl-a-pivaloyl-a-phenyl-otoluamide, b. N-tert.butyl-4-methyl-a-pivaloyl-oz-phenyl-otoluamide, c. N-tert.butyl-a-pivaloyl-a-phenyl-S-trifluoromethyl-o-toluamide, or d. 4-methoxy-N-tert.butyl-a-pivaloyl-a-phenyl-otoluamide, respectively. When the above process is carried out and in place of pivaloyl chloride there is used 2,2-dimethylbutanol chloride or l-methyl cyclohexanecarbonylbromide, there is obtained e. a-(2,2-dimethylbutanoyl)-N-tert.butyl-a-phenylo-toluamide, or f. N-tert.butyl-a-( l-methyl cyclohexanoyl)-a-phenylo-toluamide, respectively.
EXAMPLE 3 3-tert.butyl-4-phenyl isocarbostyril in portions 79 g. (0.225 mole) of N-tert.butyl-aphenyl-a-pivaloyl-o-toluamide is added to 1 130 mg. of polyphosphoric acid heated to C. The mixture is stirred 1 1/2 hours at 90C. and poured onto ice with stirring. The resulting solid is filtered and washed thoroughly with water. The solid is recrystallized from chloroform: ethyl ether (1:1) to give 3-tert.butyl-4-phenylisocarbostyril; m.p. 284-286C.
When the above process is carried out and in place of N-tert. butyl-a-phenyl-oz-pivaloyl-o-toluamide there is used a. 6-chloro-N-tert.butyl-a-pivaloyI-a-phenyl-otoluamide,
b. N-tert.butyl-4-methyl-a-pivaloyla-phenyl-otoluamide,
c. N-tert.butyl-a-pivaloyl-a-phenyl-5-trifluoromethyl-o-toluamide, or
d. 4-methoxy-N-tert.butyl-a-pivaloyl-a-phenyl-otoluamide,
e. a-(2,2-dimethylbutanoyl)-N-tert.butyl-a-phenylo-toluamide, or
f. N-tert.butyl-a-(1-methy1 cyclohexanoyU-a-phenylo-toluamide, there is obtained a. 3-tert.butyl-8-chloro-4-phenyl isocarbostyril,
b. 3-tert.butyl-6-methyl-4-phenyl isocarbostyril,
c. 3-tert.butyl-4-phenyl-7-trifluoromethyl isocarbostyril,
d. 3-tert.butyl-6-methoxy-4-phenyl isocarbostyril e. 3-(2,Z-dimethylbutyl)-4-phenyl isocarbostyril, or
f. 3-l(1-methyl cyc1ohexyl)-4-pheny1 isocarbostyril,
respectively.
EXAMPLE 4 3-tert.butyl-l-ch1oro 4-phenyl isoquinoline A mixture of 11 g. (0.04 mole) of 3-tert. butyl-4- phenyl isocarbostyril and 40 ml. of phosphorous oxychloride is refluxed for 1 hour. The excess solvent is removed in vacuo and ice is added to the residue and stirred. The resulting solid is filtered and washed with water and recrystallized from ethanol to give 3- tert.butyl-1-chloro-4-phenyl isoquinoline; m.p. 139-140C.
When the above process is carried out and in place of phosphorous oxychloride there is used phosphorous pentachloride or thionyl chloride, the identical product is again obtained.
When the above process is carried out and in place of 3-tert. butyl-4-phenyl isocarbostyril there is used a. 3-tert.butyl-8-chloro-4-phenyl isocarbostyril,
b. 3-tert.butyl-6-methyl-4-phenyl isocarbostyril,
c. 3-tert.buty1-4-phenyl-7-trifluoromethyl isocarbostyril,
d. 3-tert.butyl-6-methoxy-4-phenyl isocarbostyril e. 3-(2,2-dimethylhutyl)-4-phenyl isocarbostyril, or
f. 3-l(l-methyl cyclohcxyl)-4-phenyl isocarbostyril,
d. isoiso- EXAMPLE 3-tert.butyl-4-phenyl isoquinoline hydrochloride A mixture of 21.7 g. (0.073 mole) of 3-tert.butyl-lchloro-4-phenyl isoquinoline, 4.09 g. (0.073 mole) potassium hydroxide, 1.09g palladium on carbon and 1 liter of ethanol is hydrogenated at room temperature and 50 psi until 1 equivalent of hydrogen is absorbed. The catalyst is filtered off and washed with ethanol, combined ethanol portions are evaporated in vacuo. The residue is dissolved in ethyl ether, washed with water, dried, and filtered and the filtrate treated with gaseous HCl. The resulting white solid is filtered and recrystallized from ethanolethyl ether, washed with water, dried, and filtered and the filtrate treated with gaseous HCl. The resulting white solid is filtered and recrystallized from ethanol-ethyl ether (1:1 to give 3-tert.butyl- 4-phenyl isoquinoline hydrochloride; m.p. 236238C.
When the above process is carried out and in place of 3-tert. butyl-l-chloro-4-phenyl isoquinoline there is used a. 3-tert.butyl-l,8-dichloro-4-phenyl isoquinoline,
b. 3-tert.butyl-l-chloro-6-methyl-4-phenyl isoquinoline,
c. 3-tert.butyl-1-chloro-4-phenyl-7-trifluoromethyl isoquinoline,
cl. 3-tert.butyl-l-chloro-6-methoxy-4-phenyl isoquinoline,
e. 3-(2,2-dimethylbutyl)-l -chloro-4-phenyl isoquinoline, or
f. 3-( l-methylcyclohexyl)- l -chloro-4-phenyl isoquinoline,
there is obtained as the hydrochloride a. 3-tert.butyl-8-chloro-4-phenyl isoquinoline,
b. 3-tert.butyl-6-methyl-4-phenyl isoquinoline,
c. 3-tert.butyl-4-phenyl-7-trifluoromethyl isoquinoline,
d. 3-tert.butyl-6-methoxy-4-phenyl isoquinoline,
e. 3-(2,2-dimethylbutyl)-4-phenyl isoquinoline, or
f. 3-(1-methylcyclohexyl)-4-phenyl isoquinoline, re-
spectively.
EXAMPLE 6 3-tert.butyl-4-phenyl-l ,2,3,4-tetrahydroisoquinoline A mixture of 28.5 g. (O.ll mole) of 3-tert. butyl-4- phenyl isoquinoline, 2.85 g. platinum oxide and 300 ml. of acetic acid is hydrogenated at room temperature and 50 psi until two equivalents of hydrogen are absorbed. The catalyst is filtered off and the acetic acid is evaporated in vacuo. The residue is dissolved in ether, washed with 50% sodium hydroxide, water and saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated. The residue is crystallized from petroleum ether to give 3-tert.butyl-4- phenyl-l ,2,3,4-tetrahydroisoquinoline; m.p. 79-8lC.
When the above process is carried out and in place of 3-tert. butyl-4-phenyl isoquinoline there is used a. 3-tert.butyl-8-chloro-4-phenyl isoquinoline,
b. 3-tert.butyl-6-methyl-4-phenyl isoquinoline,
c. 3-tert.butyl-4-phenyl-7-trifluoromethyl isoquinoline,
d. 3-tert.butyl-6-methoxy-4-phenyl isoquinoline,
e. 3-(2,2-dimethylbutyl)-4-phenyl isoquinoline, or
f. 3-( l -methylcyclohexyl)-4-phenyl isoquinoline, there is obtained a. 2-tert.butyl-8-chloro-4-phenyl-1,2,3 ,4-
tetrahydroisoquinoline, b. 3-tert.butyl-6-methyl-4-phenyll ,2,3,4-
tetrahydroisoquinoline, c. 3-tert.butyl-4-phenyl-7-trifluoromethyl-l ,2,3 ,4-
tetrahydroisoquinoline,
3-tert.butyl-6-methoxy-4-phenyl-1,2,3 ,4- tetrahydroisoquinoline, e. 3-(2,2-dimethylbutyl)-4-phenyll ,2,3,4-
tetrahydroisoquinoline, or f. 3-( l-methylcyclohexyl)-4-phenyl-l ,2,3,4-
tetrahydroisoquinoline, respectively.
EXAMPLE 7 3-tert.butyl-2-methyl-4-phenyl-1,2,3,4- tetrahydroisoquinoline hydrochloride A mixture of 4.50 g. (0.017 mole) of 3-tert.butyl-4- phenyl-l,2,3,4-tetrahydroisoquinoline, 4.5 g. of formic acid and 6.3 g. of 37% aqueous formaldehyde is refluxed i8 hours. The cooled mixture is treated with 2N hydrochloric acid and ether. The layers are separated and the organic phase is washed with 2N hydrochloric acid. The aqueous phases are combined and made basic with 50% sodium hydroxide and extracted with chloroform. The chloroform extracts are dried and evaporated, the residue dissolved in ether and treated with gaseous hydrogen chloride to give 3-tert.butyl-2- methyl-4-phenyl-l ,2,3,4-tetrahydroisoquinoline hydrochloride, m.p. 192-195C.
When the above detailed procedure is carried out and in place of 3-tert.butyl-4-phenyl-l,2,3,4- tetrahydroisoquinoline, there is used a. 2-tert.butyl-8-chloro-4-phenyl-l ,2,3,4-
tetrahydroisoquinoline,
3-tert.butyl-6-methyl-4-phenyl-l ,2,3,4- tetrahydroisoquinoline,
c. 3-tert.butyl-4-phenyl-7-trifluoromethyl-l ,2,3 ,4-
tetrahydroisoquinoline,
3-tert.butyl-6-methoxy-4-phenyl-l ,2,3,4- tetrahydroisoquinoline,
e. 3-( 2,2-dimethylbutyl )-4-phenyl-l ,2,3 ,4-
tetrahydroisoquinoline, or
f. 3-( 1-methylcyclohexyl)-4-phenyl-l ,2,3,4-
tetrahydroisoquinoline there is obtained as the hydrochloride a. 2 -tert.butyl-8-chloro-2-methyl-4-phenyll ,2,3 ,4
tetrahydroisoquinoline,
3-tert.butyl-2,6-dimethyl-4-phenyl-1,2,3,4-
tetrahydroisoquinoline; m.p. 8889C. as free base,
c. 3-tert.butyl-2-methyl-4-phenyl-7-trifluoromethyl- 1,2,3 ,4-tetrahydroisoquinoline,
d. 3-tert.butyl-6-methoxy-2-methyl-4-phenyl-1,2,3,4-
tetrahydroisoquinoline; m.p. 72.573.5C. as free base,
e. 3-(2,2-dimethylbutyl)-2-methyl-4-phenyl-l,2,3,4-
tetrahydroisoquinoline, or
f. 3-( 1-methylcyclohexyl)-2-methyl-4-phenyl- 1,2,3,4-tetrahydroisoquinoline; m.p. 67-75C., respectively.
The title compound of this example is effective when orally administered to an animal suffering from lipemia at a dosage of 200 mg. twice per day.
What is claimed is:
l. A compound of the formula where R represents where R and R are each, independently, methyl or ethyl, or R and R together represent (CH where n represents 4, 5, or 6,
and R and R each, independently, represent hydrogen, halo of atomic weight 19-36, trifluoromethyl, lower alkyl, or lower alkoxy, provided that R and R may not represent alkyl at the 8-position, and provided further that two trifluoromethyl or two tertiary butyl groups or a trifluoromethyl and a tertiary butyl group are not on adjacent carbon atoms and the pharmacologicaliy acceptable acid addition salts thereof.
2. The compound of claim 1 which is 3-tert.butyl-2- methyl-4-phenyl-l ,2,3,4-tetrahydroisoquinoline.
3. The compound of claim 1 which is 3-tert.butyl-2- methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline hydrochloride.
4. The compound of claim 1 which is 3-tert.butyl-2,6- dimethyl-4-phenyl-l ,2,3,4-tetrahydroisoquinoline.
5. The compound of claim 1 which is 3-tert.butyl-6- methoxy-2-methyl-4-phenyll ,2,3 ,4- tetrahydroisoquinoline.

Claims (5)

1. A COMPOUND OF THE FORMULA
1. A compound of the formula
2. The compound of claim 1 which is 3-tert.butyl-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline.
3. The compound of claim 1 which is 3-tert.butyl-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline hydrochloride.
4. The compound of claim 1 which is 3-tert.butyl-2,6-dimethyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline.
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3989704A (en) * 1973-10-30 1976-11-02 Sandoz, Inc. 3-Substituted-4-aryl isoquinolines
US4113869A (en) * 1975-08-09 1978-09-12 Beecham Group Limited Tetrahydroisoquinoline basic ethers and pharmaceutical compositions and methods employing them
US4340600A (en) * 1980-05-22 1982-07-20 Smithkline Corporation Renal dilating methods and compositions using 4-(3,4-dihydroxyphenyl)-1,2,3,4-tetrahydroisoquinolines
US4461912A (en) * 1981-12-18 1984-07-24 Sankyo Company Limited Phenylacetic acid derivatives, their preparation and compositions containing them
EP0481383A1 (en) * 1990-10-16 1992-04-22 Takeda Chemical Industries, Ltd. Heterocyclic amine derivatives, their production and use
US5446071A (en) * 1994-11-18 1995-08-29 Eli Lilly And Company Methods for lowering serum cholesterol

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3666763A (en) * 1970-01-06 1972-05-30 Hoffmann La Roche 4-phenyl isoquinolines and process for preparing same
US3745162A (en) * 1970-08-31 1973-07-10 Robins Co Inc A H 1,2,3,4-tetrahydroisoquinoline-2-(thio)-carboxamides
US3753994A (en) * 1970-08-10 1973-08-21 Sterling Drug Inc 1,1'-azinobis(1,2,3,4-tetrahydroisoquinolines)

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3666763A (en) * 1970-01-06 1972-05-30 Hoffmann La Roche 4-phenyl isoquinolines and process for preparing same
US3753994A (en) * 1970-08-10 1973-08-21 Sterling Drug Inc 1,1'-azinobis(1,2,3,4-tetrahydroisoquinolines)
US3745162A (en) * 1970-08-31 1973-07-10 Robins Co Inc A H 1,2,3,4-tetrahydroisoquinoline-2-(thio)-carboxamides

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3989704A (en) * 1973-10-30 1976-11-02 Sandoz, Inc. 3-Substituted-4-aryl isoquinolines
US4113869A (en) * 1975-08-09 1978-09-12 Beecham Group Limited Tetrahydroisoquinoline basic ethers and pharmaceutical compositions and methods employing them
US4340600A (en) * 1980-05-22 1982-07-20 Smithkline Corporation Renal dilating methods and compositions using 4-(3,4-dihydroxyphenyl)-1,2,3,4-tetrahydroisoquinolines
US4461912A (en) * 1981-12-18 1984-07-24 Sankyo Company Limited Phenylacetic acid derivatives, their preparation and compositions containing them
EP0481383A1 (en) * 1990-10-16 1992-04-22 Takeda Chemical Industries, Ltd. Heterocyclic amine derivatives, their production and use
US5198462A (en) * 1990-10-16 1993-03-30 Takeda Chemical Industries, Ltd. Heterocyclic amine, derivatives, their production and use
US5300646A (en) * 1990-10-16 1994-04-05 Takeda Chemical Industries, Ltd. Heterocyclic amine derivatives, their production and use
US5446071A (en) * 1994-11-18 1995-08-29 Eli Lilly And Company Methods for lowering serum cholesterol

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