US 3,961,062 AGrant
Pharmaceutical Composition Containing 1-(Imidazole-1-Yl)-Isoquinolines and Method of Treating Hyperlipemia
Issue Date:1976-06-01
•18 Claims
Abstract
This application discloses pharmaceutical compositions containing, and a method of treatment with, 1-(1-imidazolyl)-isoquinolines of the general formula I and their physiologically tolerated salts, ##SPC1## In which R.sub.1, R.sub.2 and R.sub.3 represent hydrogen, alkyl of 1 to 4 carbon atoms or phenyl, R.sub.1, R.sub.2 and R.sub.3 may be identical or different, R.sub.4 represents hydrogen, alkyl of 1 to 4 carbon atoms, phenyl or chlorine, and R.sub.5 represents hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 5 to 8 carbon atoms, phenyl or chlorine.
Metadata
Assignee
- Hoechst Aktiengesellschaft
Inventors
- Ulrich Lerch
- Ernold Granzer
Application Information
Application Number:US 5620481
Filing Date:1975-03-26
Priority Date:1973-03-26
Art Unit:125
Classifications
IPC:
A61K 3147
Field of Search:
424258
Patent Drawings
This patent does not have any drawings.
Description
EXAMPLE 1:
3-Chloro-1-(1-imidazolyl)-4-phenylisoquinoline hydrochloride
a. 3-Chloro-4-phenyl-2H-isoquinoline-1
22.9 g. (0.11 mole) of phosphorus pentachloride were introduced into a suspension of 23.7 g (0.1 mole) of 2-oximo-3-phenyl-indanone-1 in 200 ml of carbon tetrachloride while stirring and in such a manner that the solvent was brought to boiling. After having stirred for 4 hours at room temperature, a mixture of 20 ml of methanol and 5 ml of water was added dropwise and the whole was allowed to stand for 24 hours. The reaction mixture was evaporated under reduced pressure and the residue was heated with 100 ml of methanol for 1 hour under reflux. After cooling, the product was filtered off with suction, washed with a small amount of methanol and recrystallized from methanol. Colorless crystals were obtained. M.p. 276.degree. to 278.degree. C.
b. 1,3-Dichloro-4-phenylisoquinoline
100 g (0.39 mole) of crude 3-chloro-4-phenyl-2H-isoquinoline-1 were heated for 4 hours to 150.degree. C in an autocalve in a mixture of 400 ml of POCl.sub.3 and 5Ml of concentrated hydrochloric acid. After concentration of the reaction solution under reduced pressure, the remaining oil was poured on ice and brought to crystallization by the addition of seed crystals. After recrystallization from petroleum ether (60.degree. to 90.degree. C), the product was found to melt at 94.degree. to 95.degree. C.
1,3-Dichloro-4-phenylisoquinoline could also be prepared by heating equal quantities by weight of 3-chloro-4-phenyl-2H-isoquinoline-1 and phosphorus pentachloride for 4 hours to 140.degree. to 150.degree. C and removing at the same time by distillation the phosphoroxy chloride that had formed. The excess of phosphorus pentachloride was hydrolyzed with ice, the product was dissolved in chloroform, washed with water and, after removal of the solvent it was recrystallized from petroleum ether.
c. 3-Chloro-1-(1-imidazolyl)-4-phenyl-isoquinoline
15 g (0.5 mole) of an 80% suspension of sodium hydride in mineral oil were introduced, while stirring, into a solution of 37.5 g (0.6 mole) of imidazole in 250 ml of absolute 1,2-dimethyoxyethane. The whole was heated for 30 minutes to the boil and then a solution of 109.6 g (0.4 mole) of 1,3-dichloro-4-phenylisoquinoline in 100 ml of absolute 1,2-dimethoxyethane was added dropwise. The mixture was then boiled for 3 hours under reflux, the solvent was distilled off under reduced pressure and the residue was dissolved in a mixture of methylene chloride and water. The organic phase was washed with water, the sol-was removed under reduced pressure and the product was recrystallized from toluene. M.p. 165.degree. to 168.degree..
Hydrochloride:
40 g of the base were dissolved in a small amount of warm methylene chloride and the solution was diluted with a four-fold quantity of benzene. Upon addition of ethereal HCl and trituration, the hydrochloride precipitated. Recrystallization in methylene chloride/benzene. M.p. > 195.degree. C
Phosphate:
A concentrated solution of the base in acetone was combined with a solution of the 1.1-molar amount of crystallized phosphoric acid in a small amount of acetone. The phosphate crystallized upon standing. M.p. 175 to 177.degree. C.
e. 3-Chloro-1-(1-imidazolyl)-4-phenylisoquinoline
2.74 g (10 mmoles) of 1,3-dichloro-4-phenylisoquinoline abd 2.04 g (30 mmoles) of imidazole were heated for 3 hours to 150.degree. C in 5 ml of dimethyl-formamide. Working up was effected as described uner 1d.
f. 3-Chloro-1-(imidazolyl)-4-phenylisoquinoline
2.74 g (10 moles) of 1,3-dichloro-4-phenylisoquinoline, 1.02 g (15 mmoles) of imidazole and 2.7 g (15 mmoles) of tri-n-butylamine were heated for 18 hours in 5 ml of dioxane under reflux. Working was carried out as described under 1c.
g. 3Chloro-1-(1-imidazolyl)-4-phenylisoquinoline
2.74 g (10 mmoles) of 1,3-dichloro-4-phenylisoquinoline, 1.02 g (15 mmoles) of imidazole and 5 ml of pyridine were heated for 8 hours under reflux and, after cooling, distributed between benzene and water. The residue which remained behind after evaporation of the organic phase was chromagtographed on silica-gel. As solvent, a mixture of chloroform and methanol 95:5 was found to be suitable.
EXAMPLE 2:
3-Chloro-1(1-imidazolyl)-isoquinoline
Reaction analogous to that of 1c., from 1,3-dichlorosioquinoline. M.p. 160.degree. to 161.degree. C.
Hydrochloride: M.p. 251.degree. C.
EXAMPLE 3:
3-Chloro-1-(2-methylimidazole-1-yl)-4-phenylisoquinoline
Reaction analogous to that of 1c. with 2-methylimidazole. M.p. 167.degree. to 168.degree. C.
Hydrochloride: M.p. 231.degree. to 232.degree. C.
EXAMPLE 4:
3-Chloro-1-(4-phenylimidazole-1-yl)-4-phenylisoquinoline hydrochloride
Reaction analogous to that of 1c, with 4(5)-phenylimidazole. M.p. 255.degree. to 257.degree. C.
EXAMPLE 5:
3-Chloro-(2-phenylimidazole-1-yl)-4-phenylisoquinolineoxalate
870 mg (29 mmoles) of an 80% suspension of sodium hydride in mineral oil were added portionwise to 4.3 g (30 mmoles) of 2-phenylimidazole in 50 ml of absolute dioxane and the whole was heated to 50.degree. to 60.degree. C until the evolution of hydrogen was finished. Then, 7.1 g (26 mmoles) of 1,3-dichloro-4-phenyl-isoquinoline were added and, after having evaporated the solvent, the reaction mixture was heated for 7 hours to 140.degree. - 150.degree. C. The reaction mixture was distributed between chloroform and water. The organic phase was dried and evaporated. The product was purified by column chromatography on silicagel with chloroform/ethyl acetate 8:2. It was dissolved in isopropanol and the oxalate was precipitated with a solution of 1.6 g. of oxalic acid in isopropanol. Finally, it was recrystallized from ethanol. M.p. 192.degree. to 194.degree. C (decomp.).
EXAMPLE 6:
3-Chloro-1-(4,5-dimethylimidazole-1-yl)-4-phenylisoquinoline
Reaction analogous to 5, with 4,5-dimethylimidazole. M.P. 164.degree. to 165.degree. C.
Hydrochloride: M.p 264.degree. to 265.degree. C.
EXAMPLE 7:
3-Chloro-1-(4,5-diphenylimidazole-1-yl)-4-phenylisoquinoline
Reaction analogous to 5, with 4,5-diphenylimidazole. M.p. 195.degree. to 196.degree. C.
EXAMPLE 8:
1-(1-Imidazolyl)-4-cyclohexylisoquinoline
a. 4-Cyclohexyl-3,4-dihydro-2H-isoquinoline-1-one
195 g (0.71 mole) of N-(2-cyclohexyl-2-phenyl-ethyl)-carbamide acid ethyl ester were introduced, while stirring, to 1800 g of polyphosphoric acid, at 130.degree. C, in such a manner that the internal temperature was 130.degree. to 140.degree. C. The temperature was kept for 30 minutes at 140.degree. C. After cooling to about 70.degree. C, the reaction mixture was poured on ice and allowed to stand overnight. The product was filtered off with suction and distributed between water and chloroform. The organic phase was washed with water and saturated sodium bicarbonate solution, dried and evaporated. The residue was recrystallized from ethanol. M.p. 156.degree. to 157.degree. C.
b. 4-Cyclohexyl-2H-isoquinoline-1-one
50 g of 4-cyclohexyl-3,4-dihydro-2H-isoquinoline-1-one and 20 l g of methanol-wet 30% Pd/C were heated while to 220.degree. C in a stream of argon. Thin-layer chromatographic analysis revealed that the reaction was practically completed after 75 minutes. The product was dissolved in chloroform, the catalyst was separated and the organic phase was evaporated. After recrystallization from acetone, colorless crystals were obtained. M.p. 111.degree. to 112.degree. C
c. 1-Chloro-4-cyclohexylisoquinoline
40.7 g (0.18 mole) of 4-cyclohexyl-2H-isoquinoline-1-one and 340 g (2 moles) of phosphoroxy chloride were heated for 5 hours under reflux. The excess POCl.sub.3 was removed under reduced pressure, the residue was poured on ice and the product was extracted with benzene. The organic phase was washed with water, dried with magnesium sulfate and evaporated. The residue was recrystallized from petroleum ether with the aid of active carbon. M.p. 53.degree. to 55.degree.C.
d. 1-(1-Imidazolyl)-4-cyclohexylisoquinoline.
3.4 g (50 mmoles) of imidazole were allowed to react with 1.9 g (49 mmoles) of sodium amide in 50 ml of absolute dioxane until the evolution of ammonia was finished. Then 9 g (37 mmoles) of 1-chloro-4-cyclohexyl-isoquinoline were added and the solvent was evaporated. The reaction mixture was heated for 3 hours to 140.degree. C, distributed between methylene chloride and water and the organic phase was evaporated after having been dried over magnesium sulfate. The oily crude product was taken up in 30 ml of ether and crystallized upon trituration. M.p. 92.degree. to 93.degree. C, hydrochloride M.p. 228.degree. to 229.degree. C.
EXAMPLE 9:
1-(4-phenylimidazole-1-yl)-4-cyclohexyl-isoquinoline
Reaction analogous to 5, with 4(5)-phenyl-imidazole and 1-chloro-4-cyclohexylisoquinoline, M.p. 169.degree. to 170.degree. C.
Dihydrochloride: M.p. 192.degree. to 194.degree. C.
EXAMPLE 10:
4-Ethyl-1-(1-imidazolyl)-isoquinoline hydrochloride
a. e-Ethyl-3,4-dihydro-2H-isoquinoline-1-one:
Reaction analogous to 8a, from N-(2-phenylbutyl)-carbamic acid ethyl ester, B.p..sub.0.9 159.degree. to 164.degree. C.
b. 4-Ethyl-2H-isoquinoline-1-one:
Reaction analogous to 8 b from 4-ethyl-3,4-dihydro-2H-isoquinolinel-one, M.p. 133.degree. to 134.degree. C.
c. 4-Ethyl-1-chloroisoquinoline:
Reaction analogous to 8 c, but from 4-ethyl-2H-isoquinoline-1-one, B.p..sub.0.1 98.degree. to 100.degree. C.
d. 4-Ethyl-1-(1-imidazolyl)-isoquinoline hydrochloride:
Reaction analogous to 8d., from 4-ethyl-1-chloroisoquinoline, M.p. 208.degree. to 290.degree. C.
EXAMPLE 11:
4-n-Butyl-1-(1-imidazolyl)-isoquinoline
a. 4-n-Butyl-23,4-dihydro-2H-isoquinoline-1-one:
Reaction analogous to 8a., from N-(2-phenyl-n-hexyl)-carbamic acid ethyl ester, B.p..sub.0.6 164.degree. to 168.degree. C.
b. 4-n-Butyl-2H-isoquinoline-1-one:
Reaction analogous to 8b., from 4n-butyl-3,4-dihydro-2H-isoquinonline, M.p. 92.degree. to 95.degree. C.
c. 4-n-butyl-1-chloroisoquinoline:
Reaction analogous to 8c., from 4-n-butyl-2H-isoquinoline-1-one, B.p..sub.0.1 110.degree. to 112.degree. C.
d. 4-n-butyl-1-(1-imidazolyl)-isoquinoline-hydrochloride:
Reaction analogous to 8d., from 4-n-butyl-1-chloroisoquinoline. M.p. 206.degree. to 207.degree. C.
EXAMPLE 12:
4-n-Butyl-1-(4-phenyllmidazole-1-yl)-isoquinoline-hydrochloride
Reaction analogous to 8d., from 4-n-butyl-1-chloroisoquinoline and 4(5)-phenylimidazole.
M.p. 166.degree. to 167.degree. C.
EXAMPLE 13:
4-n-Hexyl-3,4-dihydro-2H-isoquinonline
a. 4-n-Hexyl-3,4-dihydro-2H-isoquinoline-1-one:
Reaction analogous to 8a, from N-(2-phenyl-n-octyl)-carbamic acid ethyl ester, B.p..sub.0.5 170.degree. to 175.degree. C.
b. 4-n-Hexyl-2H-isoquinoline-1-one:
Reaction analogous to 8b., from 4-n-hexyl-3,4-dihydro-2H-isoquinoline-1-one, M.p. 82.degree. to 85.degree. C.
c. 1-Chloro-4-n-hexylisoquinoline:
Reaction analogous to 8c., from 4-n-hexyl-2H-isoquinoline-1-one, B.p..sub.0.1 119.degree. to 123.degree. C.
d. 4-n-Hexyl-1-(1-imidazolyl)-isoquinoline-hydrochloride:
Reaction analogous to athat of 1-chloro-4-n-hexylisoquinoline, M.p. 167.degree. to 168.degree. C.
EXAMPLE 14:
1-(2-Methylimidazole-1-yl)-4-phenylisoquinoline-hydrochloride
Reaction analogous to 8d., from 1-chloro-4-phenylisoquinoline and 2-methylimidazole, M.p. 243.degree. to 244.degree. C.
EXAMPLE 15:
1-(1-Imidazolyl)-4-phenylisoquinoline-oxalate
9.15 g (30 mmoles) of 3-chloro-1-(1-imidazolyl)-4-phenylisoquinoline in 100 ml of ethanol and 4.8 ml of triethylamine were hydrogenated at 60.degree. C in a hydrogenating apparatus in the presence of 1 g of 10% Pd/BaSO.sub.4. After about 3 hours, 1 mole of hydrogen was taken up and the hydrogenation stopped. After separation of the catalyst, the mixture was concentrated and the residue was taken up in ethyl acetate and water. The aqueous phase was again extracted with ethyl acetate and the combined ethyl acetate solutions were washed with water and dried over NaSO.sub.4. The oxalate was precipitated with a solution of 3.0 g (33 mmoles) of oxalic acid in ethyl actate. Decomposition 220.degree. C.
EXAMPLE 16:
3-Ethyl-1-(1-imidazolyl)-isoquinoline-hydrochloride
a. 3-Ethylisoquinoline-1-one
88.3 g (0.87 mole) of triethylamine in 100 ml of absolute acetone were added dropwise to 128 g (0.73 mole) of 2-ethylcinnamic acid in 1200 ml of absolute acetone. The whole was stirred for 10 minutes and 94.6 g (0.87 mole) of chloroformic acid ethyl ester in 100 ml of absolute acetone were added dropwise with stirring. After 1 hour, a concentrated solution of 65 g (1 mole) of sodium azide in a small amount of water was added dropwise and stirring was continued for 30 minutes. The major part of the solvent was removed at room temperature under reduced pressure and the residue was poured onto ice. Extraction was effected with methylene chloride and the organic phase was washed with water and dried carefully over MgSC.sub.4. This solution of the acid azide was added dropwise into 350 ml of boiling diphenyl ether, during which time the methylene chloride was simultaneously distilled off. The whole was further heated for 1 hour under reflux and then the solvent was removed under reduced pressure. The residue was recrystallized from ethanol. M.p. 139.degree. to140.degree. C.
b. 3-Ethyl-1-chlorisquinoline:
14 g (81 mmoles) of 3-ethylisoquinoline-1-one were heated under reflux in 50 ml of POCl.sub.3 until thin-layer chromatagraphic analysis of the reaction mixture showed the end of the reaction. The mixture was concentrated under reduced pressure. The residue was poured onto ice and rendered alkaline with dilute sodium hydroxide solution. The product was extracted with methylene chloride and distilled after drying. B.p..sub.0.1 101.degree. to 104.degree. C.
c. 3-Ethyl-1-(1-imidazolyl)-isoquinoline:
Reaction analogous to 8d., with 3-ethyl-1-chlorosioquinoline, M.p. 85.degree. to 86.degree. C; hydrochloride: M.p. 224.degree. to 225.degree. C.
EXAMPLE 17:
3-Ethyl-4-chloro-1-(1-imidazolyl)-isoquinoline
a. 3-Ethyl-1,4-dichlorosioquinoline:
15 g (87 mmoles) of 3-ethylisoquinoline-1-one and 35.2 g (174 mmoles) of phosphorus pentachloride were heated for 4 hours to 110.degree. - 120.degree. C. Then, hydrolysis was carried out dropwise with ethanol, while cooling and the reaction mixture was distributed between water and benzene. After drying and evaporation of the organic phase, there remained a yellowish oil which was reacted without further purification.
b. 3-Ethyl-4-chloro-1-(1-imidazolyl)-isoquinoline
Reaction analogous to 8d., from 3-ethyl-1,4-dichloroisoquinoline, M.p. 115.degree. C.
Phosphate M.p. 148.degree. to 149.degree. C.
EXAMPLE 18:
1-(1-imidazolyl)-3-phenyl-isoquinoline
a. 3-Phenyl-2H-iisoquinoline-1-one:
Reaction analogous to 15a., from 2-phenyl-cinnamic acid. M.p. 195.degree. to 196.degree. C.
b. 1-Chloro-3-phenylisoquinoline:
Reaction analogous to 15 b., from 3-phenyl-2H-isoquinoline-1-one, M.p. 76.degree. C.
c. 1-(1-imidazolyl)-3-phenyl-isoquinoline:
Reaction analogous to 8d., from 1-chloro-3-phenyl-isoquinoline, M.p. 141.degree. to 142.degree. C.
Oxalate M.p. 189.degree. to 190.degree. C.
EXAMPLE 19:
4-Chloro-1-(1-imidazolyl)-3-phenylisoquinoleine
a. 1,4-Dichloro-3-phenylisoquinoline:
Reaction analogous to 16 a. from 3-phenyl-2H-isoquinoleine-1-one, M.p. 159.degree. C.
b. 4-Chloro-1-(1-imidazolyl)-3-phenylisoquinoline:
Reaction analogous to 8d., from 1,4-dichloro-3-phenyl-isoquinoline, M.p 189.degree. C.
Oxalate M.p. 181.degree. to 182.degree. C.
Claims
We claim:
1. A pharmaceutical composition having hypolipemic and hypoglycemic activity consisting essentially of a physiologically tolerable carrier and, as the essential active compound, about 3 to 200 mg/kg per daily dosage unit of a 1-(1 -imidazolyl)-isoquinoline of the formula ##SPC6## or a physicologically tolerated salt thereof, wherein R.sub.1, R.sub.2, and R.sub.3, which may be the same or different, are hydrogen, alkyl of 1 to 4 carbon atoms, or phenyl, but R.sub.2 and R.sub.3 are not both alkyl; R.sub.4 is hydrogen, alkyl of 1 to 4 carbon atoms, phenyl, or chlorine; and R.sub.5 is hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 5 to 8 carbon atoms, phenyl, or chlorine, but R.sub.4 and R.sub.5 are not both t-alkyl.
2. The composition defined in claim 1 in which the active compound is 3-chloro-1-(1-imidazolyl)-4-phenylisoquinoline or a physiologically tolerated salt thereof.
3. The composition defined in claim 1 in which the active compound is 3-chloro-1-(4,5-dimethylimidazolyl-1-yl)-4-phenylisoquinonline or a physiologically tolerated salt thereof.
4. The composition defined in claim 1 in which the active compound is 3-chloro-1(4,5-diphenylimidazole-1-yl)-4-phenylisoquinoline or a physioligcally tolerated salt thereof.
5. The composition defined in claim 1 in which the active compound is 3-chloro-1-(1-imidazolyl)-isoquinoline or a physiologically tolerated salt thereof.
6. The composition defined in claim 1 in which the active compound is 4-n-butyl-1-(1-imidazolyl)-isoquinoline or a phyisologically tolerated salt thereof.
7. The composition defined in claim 1 in which the active compound is 4-ethyl-1-(1-imidazolyl)-isoquinoline or a physiologically tolerated salt thereof.
8. The composition defined in claim 1 in which the active compound is 4-phenyl-1-(1-imidazolyl)-isoquinoline or a physiologically tolerated salt thereof.
9. The composition definded in claim 1 in which the active compound is 3-chloro-1-(2-methylimidazole-1-yl)-4-phenylisoquinoline or a physiologically tolerated salt thereof.
10. A method for the treatment of hyperlipemia in a patient which comprises administering to said patient a daily dosage of about 3 to 200 mg/kg of an active compound of the formula ##SPC7## or a physiologically tolerated salt thereof, wherein R.sub.1, R.sub.2, and R.sub.3, which may be the same or different, are hydrogen, alkyl of 1 to 4 carbon atoms, or phenyl, but R.sub.2 and R.sub.3 are not both t-alkyl; R.sub.4 is hydrogen, alkyl of 1 to 4 carbon atoms, phenyl, or chlorine; and R.sub.5 is hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 5 to 8 carbon atoms, phenyl, or chlorine, but R.sub.4 and R.sub.5 are not both t-alkyl.
11. The method defined in claim 10 in which the active compound is 3-chloro-1-(1-imidazolyl)-4-phenylisoquinoline or a physiologically tolerated salt thereof.
12. The method defined in claim 10 in which the active compound is 3-chloro-1-(4,5-dimethylimidazolyl-1-yl)-4-phenylisoquinoline or a physiologically tolerated salt thereof.
13. The method defined in claim 10 in which the active compound is 3-chloro-1-(4,5-diphenylimidazolyl-1-yl)-4 -phenylisoquinoline or a physiologically tolerated salt thereof.
14. The method defined in claim 10 in which the active compound is 3-chloro-1-(1-imidazolyl)-isoquinoline or a physiologically tolerlated salt thereof.
15. The method defined in claim 10 in which the active compound is 4-n-butyl-1-(1-imidazolyl)-isoquinoline or a physiologically tolerated salt thereof.
16. The method defined in claim 10 in which the active compound is 4-ethyl-1-(1-imidazolyl)-isoquinoline or a physiologically tolerated salt thereof.
17. The method defined in claim 10 in which the active compound is 4-phenyl-1-(1-imidazolyl)-isoquinoline or a physiologically tolerated salt thereof.
18. The method defined in claim 10 in which the active compound is 3-chloro-1-(2-methylimidazole-1-yl)-4-phenylisoquinoline or a physiologically tolerated salt thereof.
Patent Citations (1)
| Patent | Date | Inventor | Cited By |
|---|---|---|---|
| FR7,445M | 1970-01-01 |