Tetrahydroisoquinoline basic ethers and pharmaceutical compositions and methods employing them

• US 4,113,869 A
• Filed: 08/02/1976
• Issued: 09/12/1978
• Est. Priority Date: 08/09/1975
• Status: Expired due to Term

• Current Assignee: Beecham Group PLC (GlaxoSmithKline PLC)
• Original Assignee: Beecham Group PLC (GlaxoSmithKline PLC)
• Inventors: Gardner, Derek Victor
• Primary Examiner(s): Daus, Donald G.
• Assistant Examiner(s): Rivers, Diana G.
• Application Number:
  US05/710,446
• Time in Patent Office: 771 Days
• Field of Search: 260/288 D, 260/287 D, 260/283 SA, 260/289 D, 260/247.5 GP, 424/258, 424/248.56
• US Class Current: 514/307
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 25/26 Psychostimulants, e.g. nicotine, cocaine
• CPC Class Codes: C07D 217/02 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
• CPC Class Codes: C07D 217/04 with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
• CPC Class Codes: C07D 217/14 other than aralkyl radicals
• CPC Class Codes: C07D 217/24 Oxygen atoms

Abstract

Compounds of the formula (II): ##STR1## and salts thereof wherein R₁ is a C_1-6 alkyl, C_3-6 cycloalkyl phenyl, naphthyl, aralkyl, substituted phenyl or substituted naphthyl group; R₂ is a group: ##STR2## wherein R₆ is a hydrogen atom or a C_1-6 alkyl group, R₇ is a hydrogen atom or a C_1-6 alkyl, phenyl, tolyl, or benzyl group or R₆ is linked to R₇ so that the NR₆ R₇ moiety is a 5-,6- or 7- membered ring, R₈ is a hydrogen atom or a C_1-4 alkyl group or is joined to R₆ to form part of a morpholino ring and R₉ and R₁₀ are each hydrogen atoms or C_1-4 alkyl groups; R₃ is a hydrogen atom or a C_1-6 alkyl or a trifluoromethyl group; R₄ is a hydrogen atom or a C_1-6 alkyl, benzyl or phenyl group or an acyl group containing from 2 to 7 carbon atoms and R₅ is a hydrogen atom or a -C_1-6 alkyl group; have been found to be mood modifying agents and anorexia agents.

Claims

1. A compound of the formula (II):

##STR32## or a pharmaceutically acceptable salt or optically active isomer thereof, wherein R₁ is phenyl or naphthyl, or phenyl or naphthyl each substituted by one or two halogen atoms, trifluoromethyl, C_1-4 alkyl, hydroxy, C_1-4 alkoxy, nitro, amino, methylamino, dimethylamino, diethylamino, carboxy, methoxycarbonyl, ethoxycarbonyl, cyano, carboxamido, sulphonamido, trifluoromethoxy, trifluoromethylthio or acyl of 2 to 7 carbon atoms;

R₂ is a group;

##STR33## in which R₆ is a hydrogen or methyl, R₇ is hydrogen or methyl, ethyl or benzyl;

R₃ is hydrogen or C_1-6 alkyl or trifluoromethyl;

R₄ is hydrogen or C_1-6 alkyl, benzyl or phenyl or acyl of from 2 to 7 carbon atoms; and

R₅ is hydrogen or C_1-6 alkyl.

2. A compound according to claim 1 wherein R₁ is a phenyl or naphthyl group or a phenyl group substituted by a fluorine, chlorine or bromine atom or a methyl, methoxy or trifluoromethyl group.

3. A compound according to claim 1 wherein R₂ is a group of the sub-formula (a), (b), (c) or (d):

##STR34##

4. A compound according to claim 1 wherein R₃ is a hydrogen atom.

5. A compound according to claim 1 wherein R₄ is a methyl group.

6. A compound according to claim 1 wherein R₅ is a hydrogen atom.

19. A compound according to claim 1 in the form of an acid addition salt.

20. A pharmaceutical composition which comprises an anti-depressantly effective amount of a compound as claimed in claim 1 together with a pharmaceutically acceptable carrier.

21. A pharmaceutical composition which comprises an anorexically effective amount of a compound as claimed in claim 1 together with a pharmaceutically acceptable carrier.

22. A pharmaceutical composition according to claim 20 adapted for oral administration to humans.

23. A pharmaceutical composition according to claim 21 adapted for oral administration to humans.

24. An anorexia inducing pharmaceutical composition according to claim 23 containing from 0.5 mg. to 50 mg. of active compound.

25. A mood modifying pharmaceutical composition according to claim 22 containing from 0.05 mg. to 50 mg. of active compound.

26. A method of reducing depression which comprises administering to a depressed human an anti-depressantly effective amount of a compound according to claim 1.

27. A method of reducing appetite which comprises administering to a human an anorexically effective amount of a compound according to claim 1.

7. A compound of the formula (III):

##STR35## and pharmaceutically acceptable salts thereof wherein R₁₁ is a hydrogen, fluorine or chlorine atom or a nitro, trifluoromethyl methyl or methoxy group and R₁₂ and R₁₃ are each a hydrogen atom or a methyl or ethyl group.

8. A compound according to claim 7 wherein R₁₁ is a 4-fluorine or 4-chlorine atom or a 4-trifluoromethyl group.

9. A compound according to claim 7 wherein R₁₁ is a 3-trifluoromethyl group.

10. A compound according to claim 7 wherein R₁₂ and R₁₃ are each methyl groups.

11. A compound of the formula (IV):

##STR36## and pharmaceutically acceptable salts thereof wherein R₁₁ is a hydrogen, fluorine or chlorine atom or a nitro, trifluoromethyl or methoxy group and R₁₂ and R₁₃ are each a hydrogen atom or a methyl or ethyl group.

12. A compound according to claim 11 wherein R₁₁ is a 4-fluorine or 4-chlorine atom or a 4-trifluoromethyl group.

13. A compound according to claim 11 wherein R₁₁ is a 3-trifluoromethyl group.

14. A compound according to claim 11 wherein R₁₂ and R₁₃ are each methyl groups.

15. A compound of the formula (V):

##STR37## and pharmaceutically acceptable salts thereof wherein R₁₂ and R₁₃ are each a hydrogen atom or a methyl or ethyl group.

16. A compound according to claim 15 wherein R₁₂ and R₁₃ are each methyl.

17. A compound of the formula (VI):

##STR38## and pharmaceutically acceptable salts thereof wherein R₁₂ and R₁₃ are each a hydrogen atom or a methyl or ethyl group.

18. A compound according to claim 17 wherein R₁₂ and R₁₃ are each methyl.

28. The compound 7-(dimethylaminoethyloxy)-2-methyl-4-(4-trifluoromethylphenyl)-1,2,3,4-tetrahydroisoquinoline.

29. The compound 2-methyl(-7-(methylaminoethyloxy)-4-phenyl-1,2,3,4-tetrahydroisoquinoline.

30. The compound 2,3-dimethyl-7-dimethylaminoethyloxy-4-phenyl-1,2,3,4-tetrahydroisoquinoline.

31. The compound 7-(3-dimethylamino-2-hydroxypropyloxy)-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline.

32. The compound (+)-7-dimethylaminoethoxy-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline

33. The compound (-)-7-dimethylaminoethoxy-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline.