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Details for Patent: RE37729

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Details for Patent: RE37729

Title: 4-Heteroaryl-1-piperidinealkylamines and derivatives thereof and their therapeutic utility
Abstract:Heteroarylpiperidines, pyrrolidines, and piperazines are useful as antipsychotic and analgesic agents. The compounds are especially useful for treating psychoses by administering to a mammal a psychoses-treating effective amount of one of the compounds. Depot derivatives of the compounds are useful for providing long acting effects of the compounds. The compounds are also useful as analgesics by administering a pain-relieving effective amount of one of the compounds to a mammal.
Inventor(s): Glamkowski; Edward J. (Warren, NJ), Chiang; Yulin (Convent Station, NJ), Strupczewski; Joseph T. (Flemington, NJ), Bordeau; Kenneth J. (Kintnersville, PA), Nemoto; Peter A. (Evanston, IL), Tegeler; John J. (Bridgewater, NJ)
Assignee: Aventis Pharmaceuticals Inc. (Bridgewater, NJ)
Filing Date:Feb 03, 1999
Application Number:09/240,842
Claims:1. A compound of the formula: ##STR133##

wherein,

X is --O--, --S--, --NH--, or --N(R.sub.2)--;

R.sub.2 is selected from the group consisting of lower alkyl, aryl lower alkyl, aryl, cycloalkyl, aroyl, alkanoyl, alkoxycarbonyl, and .[.phenysulfonyl.]. .Iadd.phenylsulfonyl .Iaddend.groups;

aryl is as defined hereinafter;

p is 1 or 2;

Y is hydrogen, lower alkyl, hydroxy, chlorine, fluorine, bromine, iodine, lower alkoxy, trifluoromethyl, nitro, or amino;

R.sub.1 is --CR.sub.24 R.sub.27 --(CR.sub.23 R.sub.24).sub.n --CR.sub.24 R.sub.27 -- wherein n is 0, 1, 2, or

--CHR.sub.24 --CH.dbd.CH--CHR.sub.24 --,

--CHR.sub.24 --C.ident.C--CHR.sub.24 --,

--CHR.sub.24 --CH.dbd.CH--CR.sub.23 R.sub.24 --CHR.sub.24 --,

--CHR.sub.24 --CR.sub.23 R.sub.24 --CH.dbd.CH--CHR.sub.24 --,

--CHR.sub.24 --C.ident.C--CR.sub.23 R.sub.24 --CHR.sub.24 --, or

--CHR.sub.24 --CR.sub.23 R.sub.24 --C.ident.CHR.sub.24 --,

the --CH.dbd.CH-- bond being cis or trans;

R.sub.23 is hydrogen, (C.sub.1 -C.sub.18)linear alkyl, phenyl, hydroxy, (C.sub.1 -C.sub.18)alkoxy, aryloxy, aryl(C.sub.1 -C.sub.18)alkyloxy, (C.sub.1 -C.sub.18)alkanoyloxy, hydroxy(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.18)alkoxy(C.sub.1 -C.sub.6)alkyl, .[.phenyl(C.sub.1 -C.sub.6)alkoxy,.]. aryl(C.sub.1 -C.sub.18)alkyloxy(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.18)alkanoyloxy(C.sub.1 -C.sub.6)alkyl, or ##STR134##

where Z.sub.1 is lower alkyl, --OH, lower alkoxy, --CF.sub.3, --NO.sub.2, --NH.sub.2, or halogen, and p is as previously defined; and

R.sub.24 is hydrogen, (C.sub.1 -C.sub.18)linear alkyl, phenyl, hydroxy(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.18)alkoxy(C.sub.1 -C.sub.6)alkyl, phenyl(C.sub.1 -C.sub.6)alkyloxy, aryl(C.sub.1 -C.sub.18)alkyloxy(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.18)alkanoyloxy(C.sub.1 -C.sub.6)alkyl, or ##STR135##

where Z.sub.1 is as previously defined, and p is as previously defined;

R.sub.27 is hydrogen or R.sub.24 and R.sub.27 taken together with the carbon to which they are attached form C.dbd.O or C.dbd.S; and

R.sub.18 and R.sub.19 are independently selected from the group consisting of:

hydrogen,

(C.sub.1 -C.sub.18 straight or branched chain)alkyl,

--C(.dbd.O)--O--(C.sub.1 -C.sub.18)alkyl,

--C(.dbd.O)--(C.sub.1 -C.sub.18)alkyl,

.[.--C(--O--)-pyridyl.]. .Iadd.--C(.dbd.O)-pyridyl,.Iaddend. ##STR136##

where NR.sub.18 R.sub.19 taken together form a ring structure selected from the group consisting of piperidinyl, morpholinyl, and piperazinyl;

where the piperidinyl or piperazinyl ring is optionally substituted by ##STR137##

where X, Y, and .[.P.]. .Iadd.p .Iaddend.are as previously defined; where

R.sub.4 is hydrogen, lower alkyl, lower alkoxy, hydroxy, tri(C.sub.1 -C.sub.6)alkylsilyloxy, hydroxy lower alkyl, alkanoyloxy lower alkyl, amino, mono- or dialkylamino, (C.sub.1 -C.sub.18)acyl amino, (C.sub.1 -C.sub.18)alkanoyl, trifluoromethyl, chlorine, fluorine, bromine, --O--C(.dbd.O)--(C.sub.1 -C.sub.18.[.).]. straight or branched chain)alkyl or --C(.dbd.O)-aryl;

where R.sub.28 is hydrogen, (C.sub.1 -C.sub.6) alkyl, aryl(C.sub.1 -C.sub.6) alkyl, phenyl, or substituted phenyl;

in which aryl is phenyl or ##STR138##

wherein R.sub.5 is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, or trifluoromethoxy;

and, any hydroxyl group attached to an aliphatic or aromatic carbon atom, or any primary or secondary nitrogen atom may be acylated with a (C.sub.4 -C.sub.18) .[.carboxylic.]. .Iadd.alkanoyl .Iaddend.group, in addition, any nitrogen atom may alternatively .[.by.]. .Iadd.be .Iaddend.acylated with a (C.sub.4 -C.sub.18)alkoxycarbonyl group; .Iadd.and.Iaddend.

m is 1, 2, or 3;

.[.with the proviso that when X is --O-- and Y is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, bromine, iodine, or a hydroxyl group, R.sub.18 and R.sub.19 are not lower alkyl;

with the proviso that R.sub.18 and R.sub.19 are not hydrogen when R.sub.1 is (CH.sub.2).sub.2-5 --, X is --O--, and Y is 6-F;.].

.Iadd.with the proviso that R.sub.23 is not hydrogen, (C.sub.1 -C.sub.18)linear alkyl, phenyl, or .Iaddend. ##STR139##

.Iadd.when R.sub.27 is hydrogen and R.sub.24 is hydrogen, (C.sub.1 -C.sub.18)linear alkyl, phenyl, or .Iaddend. ##STR140##

.Iadd.with the proviso that R.sub.24 is not hydrogen, (C.sub.1 -C.sub.18)linear alkyl, phenyl, or .Iaddend. ##STR141##

.Iadd.when R.sub.27 is hydrogen and n is 0; or when R.sub.27 is hydrogen and R.sub.23 is hydrogen, (C.sub.1 -C.sub.18)linear alkyl, phenyl, or .Iaddend. ##STR142##

.Iadd.or when R.sub.1 is --CHR.sub.24 --CH.dbd.CH--CHR.sub.24 -- or --CHR.sub.24 --C.ident.C--CHR.sub.24 --;

with the exception that the above provisos do not apply when R.sub.2 is alkoxycarbonyl; .Iaddend.all geometric, optical, and stereoisomers thereof, or a pharmaceutically acceptable acid addition salt thereof.

2. The compound of claim 1, wherein X is --N(R.sub.2)--.

3. The compound of claim 2, wherein R.sub.2 is (C.sub.1 -C.sub.18)alkanoyl or (C.sub.1 -C.sub.18)alkoxycarbonyl.

4. The compound of claim 1, wherein R.sub.18 and R.sub.19 are hydrogen.

5. The compound of claim .[.4.]. .Iadd.32.Iaddend., which is 2-[4-[(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]ethyl]amine and its pharmaceutically acceptable acid addition salts..[.

6. The compound of claim 4, which is 2-[4-(6-fluoro-1, 2-benzisoxazol-3-yl)-1-piperidinyl]propyl]amine..].

7. The compound of claim 4, which is 3-[4-(6-fluoro-1, 2-benzisoxazol-3-yl)-1-piperidinyl]-2-hydroxy-1-propylamine and its pharmaceutically acceptable acid addition salts.

8. The compound of claim 1, wherein R.sub.18 is hydrogen and R.sub.19 is --(C.dbd.O)pyridyl.

9. .[.The compound of claim 8,.]. .Iadd.A compound .Iaddend.which is .Iadd.selected from .Iaddend. N-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-3-pyridineca rboxamide and its pharmaceutically acceptable acid addition salts.

10. The compound of claim 1, wherein R.sub.18 is hydrogen and R.sub.19 is ##STR143##

11. The compound of claim 1, wherein NR.sub.18 R.sub.19 form .[.a.]. .Iadd.an optionally substituted .Iaddend.piperidinyl ring.

12. The compound of .[.11.]. .Iadd.69.Iaddend., which is .Iadd.selected from .Iaddend.1,2-bis-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethane and its pharmaceutically acceptable acid addition salts.

13. The compound of claim .[.11.]. .Iadd.69.Iaddend., which is .Iadd.selected from .Iaddend. 1,2-bis-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-hydroxypropan e and its pharmaceutically acceptable acid addition salts.

14. (S)-3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-methylpropyl methyl carbamate and its pharmaceutically acceptable acid addition salts.

15. An antipsychotic composition, which comprises the compound of claim 1 in an amount sufficient to produce an antipsychotic effect and a pharmaceutically acceptable carrier.

16. A method of treating psychoses, which comprises administering to a mammal a psychoses-treating amount of the compound of claim 1.

17. An analgesic composition, which comprises the compound of claim 1 in an amount sufficient to produce a pain-relieving effect and a pharmaceutically acceptable carrier.

18. A method of alleviating pain, which comprises administering to a mammal a pain-relieving effective amount of the compound to claim 1.

19. A depot pharmaceutical composition, which comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound of claim 1, wherein the compound contains an acylated hydroxy group, or an acylated amino group.

20. The depot pharmaceutical composition of claim .[.8.]. .Iadd.19.Iaddend., wherein the hydroxy group is acylated .Iadd.with a (C.sub.4 -C.sub.18)alkanoyl group.Iaddend., or the amino group is acylated with a (C.sub.4 -C.sub.18)alkanoyl group or a (C.sub.4 -C.sub.18)alkoxycarbonyl group.

21. The composition of claim 19, which contains a pharmaceutically acceptable oil.

22. The composition of claim 21, wherein the oil is selected from the group consisting of coconut oil, peanut oil, sesame oil, cottonseed oil, corn oil, soybean oil, olive oil, and esters of fatty acids and polyfunctional alcohols.

23. The composition of claim 20, which contains a pharmaceutically acceptable oil.

24. The composition of claim 23, wherein the oil is selected from the group consisting of coconut oil, peanut oil, sesame oil, cottonseed oil, corn oil, soybean oil, olive oil, and esters of fatty acids and polyfunctional alcohols.

25. A method for providing a long acting antipsychotic effect, which comprises injecting into a mammal an amount of the composition of claim 19 sufficient to produce a long acting antipsychotic effect.

26. A method for providing a long acting antipsychotic effect, which comprises injecting into a mammal an amount of the composition of claim 20 sufficient to produce a long acting antipsychotic effect.

27. A method for providing a long acting antipsychotic effect, which comprises injecting into a mammal an amount of the composition of claim 24 sufficient to produce a long acting antipsychotic effect..Iadd.

28. A compound of the formula: ##STR144##

wherein,

X is --O--, --S--, --NH--, or --N(R.sub.2)--;

R.sub.2 is selected from the group consisting of lower alkyl, aryl lower alkyl, aryl, cycloalkyl, aroyl, alkanoyl and phenylsulfonyl groups;

aryl is as defined hereinafter;

p is 1 or 2;

Y is hydrogen, lower alkyl, hydroxy, chlorine, fluorine, bromine, iodine, lower alkoxy, trifluoromethyl, nitro, or amino, when p is 1, except that

Y is lower alkoxy, hydroxy or halogen, when p is 2 and X is --O--;

in which (R.sub.1) is R.sub.20, R.sub.21 or R.sub.22, wherein:

R.sub.20 is --(CH.sub.2).sub.n --, where n is 2, 3, 4 or 5;

R.sub.21 is

--CH.sub.2 --CH.dbd.CH--CH.sub.2 --,

--CH.sub.2 --C.ident.C--CH.sub.2 --,

--CH.sub.2 --CH.dbd.CH--CH.sub.2 --CH.sub.2 --,

--CH.sub.2 CH.sub.2 --CH.dbd.CH--CH.sub.2 --,

--CH.sub.2 --C.ident.C--CH.sub.2 --CH.sub.2 --, or

--CH.sub.2 --CH.sub.2 --C.ident.C--CH.sub.2 --,

the --CH.dbd.CH-- bond being cis or trans;

R.sub.22 is R.sub.20 or R.sub.21 in which one or more carbon atoms of R.sub.20 or R.sub.21 are substituted by at least one C.sub.1 -C.sub.6 linear alkyl group, phenyl group or ##STR145##

where Z.sub.1 is lower alkyl, --OH, lower alkoxy, --CF.sub.3, --NO.sub.2, --NH.sub.2, or halogen, and p is as previously defined; and

R.sub.18 and R.sub.19 are independently selected from the group consisting of:

hydrogen,

(C.sub.1 -C.sub.12 straight or branched chain)alkyl,

--C(.dbd.O)--O--(C.sub.1 -C.sub.12)alkyl,

--C(.dbd.O)--(C.sub.1 -C.sub.12)alkyl, and

where NR.sub.18 R.sub.19 taken together form a ring structure selected from the group consisting of piperidinyl, morpholinyl, and piperazinyl;

in which aryl is phenyl or ##STR146##

wherein R.sub.5 is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, or trifluoromethoxy;

with the proviso that when X is --O-- and Y is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, bromine, iodine, or a hydroxyl group, R.sub.18 and R.sub.19 are not lower alkyl;

with the proviso that R.sub.18 and R.sub.19 are not both hydrogen when R.sub.1 is --(CH.sub.2).sub.2-5 --, X is --O--, and Y is 6-F;

all geometric, optical, and stereoisomers thereof,

or a pharmaceutically acceptable acid addition salt thereof..Iaddend..Iadd.

29. A pharmaceutical composition which comprises a compound of claim 28 and a pharmaceutically acceptable carrier..Iaddend..Iadd.

30. The compound of claim 28, wherein X is --N(R.sub.2)--..Iaddend..Iadd.

31. The compound of claim 30, wherein R.sub.2 is (C.sub.2 -C.sub.12)alkanoyl..Iaddend..Iadd.

32. The compound of claim 28, wherein R.sub.18 and R.sub.19 are hydrogen..Iaddend..Iadd.

33. The compound of claim 28, wherein NR.sub.18 R.sub.19 form a piperidinyl ring..Iaddend..Iadd.

34. An antipsychotic composition, which comprises the compound of claim 28 in an amount sufficient to produce an antipsychotic effect and a pharmaceutically acceptable carrier..Iaddend..Iadd.

35. A method of treating psychoses, which comprises administering to a mammal a psychoses-treating amount of the compound of claim 28..Iaddend..Iadd.

36. An analgesic composition which comprises the compound of claim 28 in an amount sufficient to produce a pain-relieving effect and a pharmaceutically acceptable carrier..Iaddend..Iadd.

37. A method of alleviating pain, which comprises administering to a mammal a pain-relieving effective amount of the compound of claim 28..Iaddend..Iadd.

38. A depot pharmaceutical composition, which comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of the formula: ##STR147##

wherein,

X is --O--, --S--, --NH--, or --N(R.sub.2)--;

R.sub.2 is selected from the group consisting of lower alkyl, aryl lower alkyl, aryl, cycloalkyl, aroyl, alkanoyl, alkoxycarbonyl, and phenylsulfonyl groups;

aryl is as defined hereinafter;

p is 1 or 2;

Y is hydrogen, lower alkyl, hydroxy, chlorine, fluorine, bromine, iodine, lower alkoxy, trifluoromethyl, nitro, or amino, when p is 1, except that

Y is lower alkoxy, hydroxy or halogen, when p is 2 and X is --O--;

in which (R.sub.1) is R.sub.20, R.sub.21 or R.sub.22, wherein:

R.sub.20 is --(CH.sub.2).sub.n --, where n is 2, 3, 4 or 5;

R.sub.21 is

--CH.sub.2 --CH.dbd.CH--CH.sub.2 --,

--CH.sub.2 --C.ident.C--CH.sub.2 --,

--CH.sub.2 --CH.dbd.CH--CH.sub.2 --CH.sub.2 --,

--CH.sub.2 CH.sub.2 --CH.dbd.CH--CH.sub.2 --,

--CH.sub.2 --C.ident.C--CH.sub.2 --CH.sub.2 --, or

--CH.sub.2 --CH.sub.2 --C.ident.C--CH.sub.2 --,

the --CH.dbd.CH-- bond being cis or trans;

R.sub.22 is R.sub.20 or R.sub.21 in which one or more carbon atoms of R.sub.20 or R.sub.21 are substituted by at least one C.sub.1 -C.sub.6 linear alkyl group, phenyl group or ##STR148##

where Z.sub.1 is lower alkyl, --OH, lower alkoxy, --CF.sub.3, --NO.sub.2, --NH.sub.2 or halogen, and p is as previously defined; and

R.sub.18 and R.sub.19 are independently selected from the group consisting of:

hydrogen,

(C.sub.1 -C.sub.12 straight or branched chain)alkyl,

--C(.dbd.O)--O--(C.sub.1 -C.sub.12)alkyl,

--C(.dbd.O)--(C.sub.1 -C.sub.12)alkyl, and

where NR.sub.18 R.sub.19 taken together form a ring structure selected from the group consisting of piperidinyl, morpholinyl, and piperazinyl;

in which aryl is phenyl or ##STR149##

wherein R.sub.5 is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, or trifluoromethoxy;

and, any hydroxyl group attached to an aliphatic or aromatic carbon atom, or any primary or secondary nitrogen atom may be acylated with a (C.sub.4 -C.sub.18)alkanoyl group; in addition, any nitrogen atom may alternatively be acylated with a (C.sub.4 -C.sub.18)alkoxycarbonyl group; and

with the proviso that when X is --O-- and Y is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, bromine, iodine, or a hydroxyl group, R.sub.18 and R.sub.19 are not lower alkyl;

with the proviso that R.sub.18 and R.sub.19 are not both hydrogen when R.sub.1 is --(CH.sub.2).sub.2-5 --, X is --O--, and Y is 6-F;

with the proviso that when R.sub.18 and R.sub.19 are both hydrogen, R.sub.1 is not R.sub.20 or R.sub.21 when X is --O-- and Y is hydrogen;

wherein the compound contains an acylated hydroxy group, or an acylated amino group, and further wherein the hydroxy group is acylated with a (C.sub.4 -C.sub.18)alkanoyl group, or the amino group is acylated with a (C.sub.4 -C.sub.18)alkanoyl group or a (C.sub.4 -C.sub.18)alkoxycarbonyl group;

all geometric, optical, and stereoisomers thereof,

or a pharmaceutically acceptable acid addition salt thereof..Iaddend..Iadd.

39. The composition of claim 38, which contains a pharmaceutically acceptable oil..Iaddend..Iadd.

40. The composition of claim 39, wherein the oil is selected from the group consisting of coconut oil, peanut oil, sesame oil, cottonseed oil, corn oil, soybean oil, olive oil, and esters of fatty acids and polyfunctional alcohols..Iaddend..Iadd.

41. A method for providing a long acting antipsychotic effect, which comprises injecting into a mammal an amount of the composition of claim 38 sufficient to produce a long acting antipsychotic effect..Iaddend..Iadd.

42. A method for providing a long acting antipsychotic effect, which comprises injecting into a mammal an amount of the composition of claim 40 sufficient to produce a long acting antipsychotic effect..Iaddend..Iadd.

43. A compound of the formula: ##STR150##

wherein,

X is --O--, --S--, --NH--, or --N(R.sub.2)--;

R.sub.2 is selected from the group consisting of lower alkyl, aryl lower alkyl, aryl, cycloalkyl, aroyl, alkanoyl, alkoxycarbonyl, and phenylsulfonyl groups;

aryl is as defined hereinafter;

p is 1 or 2;

Y is lower alkyl, hydroxy, chlorine, fluorine, bromine, iodine, lower alkoxy, trifluoromethyl, nitro, or amino, when X is --S--, --NH--, or --N(R.sub.2)--;

Y is lower alkyl, trifluoromethoxy, nitro, or amino when X is --O--;

R.sub.1 is --CR.sub.24 R.sub.27 --(CR.sub.23 R.sub.24).sub.n --CR.sub.24 R.sub.27 -- wherein n is 0, 1, 2, or 3; or

--CHR.sub.24 --CH.dbd.CH--CHR.sub.24 --,

--CHR.sub.24 --C.ident.C--CHR.sub.24 --,

--CHR.sub.24 --CH.dbd.CH--CR.sub.23 R.sub.24 --CHR.sub.24 --,

--CHR.sub.24 --CR.sub.23 R.sub.24 --CH.dbd.CH--CHR.sub.24 --,

--CHR.sub.24 --C.ident.C--CR.sub.23 R.sub.24 --CHR.sub.24 --, or

--CHR.sub.24 --CR.sub.23 R.sub.24 --C.ident.CHR.sub.24 --,

the --CH.dbd.CH-- bond being cis or trans;

R.sub.23 is hydrogen, (C.sub.1 -C.sub.18)linear alkyl, phenyl, hydroxy, (C.sub.1 -C.sub.18)alkoxy, aryloxy, aryl(C.sub.1 -C.sub.18)alkyloxy, (C.sub.1 -C.sub.18)alkanoyloxy, hydroxy(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.18)alkoxy(C.sub.1 -C.sub.6)alkyl, aryl(C.sub.1 -C.sub.18)alkyloxy(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.18)alkanoyloxy(C.sub.1 -C.sub.6)alkyl, or ##STR151##

where Z.sub.1 is lower alkyl, --OH, lower alkoxy, --CF.sub.3, --NO.sub.2, --NH.sub.2, or halogen, and p is as previously defined; and

R.sub.24 is hydrogen, (C.sub.1 -C.sub.18)linear alkyl, phenyl, hydroxy(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.18)alkoxy(C.sub.1 -C.sub.6)alkyl, phenyl(C.sub.1 -C.sub.6)alkyloxy, aryl(C.sub.1 -C.sub.18)alkyloxy(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.18)alkanoyloxy(C.sub.1 -C.sub.6)alkyl, or ##STR152##

where Z.sub.1 is as previously defined, and p is as previously defined;

R.sub.27 is hydrogen or R.sub.24 and R.sub.27 taken together with the carbon to which they are attached form C.dbd.O or C.dbd.S; and

R.sub.18 and R.sub.19 are independently selected from the group consisting of:

hydrogen,

(C.sub.1 -C.sub.18 straight or branched chain)alkyl,

--C(.dbd.O)--O--(C.sub.1 -C.sub.18)alkyl,

--C(.dbd.O)--(C.sub.1 -C.sub.18)alkyl,

--C(.dbd.O)-pyridyl, ##STR153##

where NR.sub.18 R.sub.19 taken together form a ring structure selected from the group consisting of piperidinyl, morpholinyl, and piperazinyl;

where the piperidinyl or piperazinyl ring is optionally substituted by ##STR154##

where X, Y, and p are as previously defined; where

R.sub.4 is hydrogen, lower alkyl, lower alkoxy, hydroxy, tri(C.sub.1 -C.sub.6)alkylsilyloxy, hydroxy lower alkyl, alkanoyloxy lower alkyl, amino, mono- or dialkylamino, (C.sub.1 -C.sub.18)acyl amino, (C.sub.1 -C.sub.18)alkanoyl, trifluoromethyl, chlorine, fluorine, bromine, --O--C(.dbd.O)--(C.sub.1 -C.sub.18 straight or branched chain)alkyl or --C(.dbd.O)-aryl;

where R.sub.28 is hydrogen, (C.sub.1 -C.sub.6) alkyl, aryl(C.sub.1 -C.sub.6) alkyl, phenyl, or substituted phenyl;

in which aryl is phenyl or ##STR155##

wherein R.sub.5 is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, or trifluoromethoxy;

and, any hydroxyl group attached to an aliphatic or aromatic carbon atom, or any primary or secondary nitrogen atom may be acylated with a (C.sub.4 -C.sub.18)alkanoyl group; in addition, any nitrogen atom may alternatively be acylated with a (C.sub.4 -C.sub.18)alkoxycarbonyl group; and

m is 1, 2, or 3;

with the proviso that when X is --O-- and Y is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, bromine, iodine, or a hydroxyl group, R.sub.18 and R.sub.19 are not lower alkyl;

with the proviso that R.sub.18 and R.sub.19 are not hydrogen when R.sub.1 is --(CH.sub.2).sub.2-5 --, X is --O--, and Y is 6-F;

all geometric, optical, and stereoisomers thereof,

or a pharmaceutically acceptable acid addition salt thereof..Iaddend..Iadd.

44. The compound of claim 43, wherein X is --N(R.sub.2)--..Iaddend..Iadd.

45. The compound of claim 44, wherein R.sub.2 is (C.sub.2 -C.sub.18)alkanoyl or (C.sub.1 -C.sub.18)alkoxycarbonyl..Iaddend..Iadd.

46. The compound of claim 43, wherein R.sub.18 and R.sub.19 are hydrogen..Iaddend..Iadd.

47. The compound of claim 43, wherein R.sub.18 is hydrogen and R.sub.19 is --(C.dbd.O)-pyridyl..Iaddend..Iadd.

48. The compound of claim 43, wherein R.sub.18 is hydrogen and R.sub.19 is .Iaddend. ##STR156## .Iadd.

49. The compound of claim 43, wherein NR.sub.18 R.sub.19 form an optionally substituted piperidinyl ring..Iaddend..Iadd.

50. An antipsychotic composition, which comprises the compound of claim 43 in an amount sufficient to produce an antipsychotic effect and a pharmaceutically acceptable carrier..Iaddend..Iadd.

51. A method of treating psychoses, which comprises administering to a mammal a psychoses-treating amount of the compound of claim 43..Iaddend..Iadd.

52. An analgesic composition, which comprises the compound of claim 43 in an amount sufficient to produce an pain-relieving effect and a pharmaceutically acceptable carrier..Iaddend..Iadd.

53. A method of alleviating pain, which comprises administering to a mammal a pain-relieving effective amount of the compound of claim 43..Iaddend..Iadd.

54. A depot pharmaceutical composition, which comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound of claim 43, wherein the compound contains an acylated hydroxy group, or an acylated amino group..Iaddend..Iadd.

55. The depot pharmaceutical composition of claim 54, wherein the hydroxy group is acylated with a (C.sub.4 -C.sub.18)alkanoyl group, or the amino group is acylated with a (C.sub.4 -C.sub.18)alkanoyl group or a l (C.sub.4 -C.sub.18)alkoxycarbonyl group..Iaddend..Iadd.

56. The composition of claim 34, which contains a pharmaceutically acceptable oil..Iaddend..Iadd.

57. The composition of claim 56, wherein the oil is selected from the group consisting of coconut oil, peanut oil, sesame oil, cottonseed oil, corn oil, soybean oil, olive oil, and esters of fatty acids and polyfunctional alcohols..Iaddend..Iadd.

58. The composition of claim 55, which contains a pharmaceutically acceptable oil..Iaddend..Iadd.

59. The composition of claim 58, wherein the oil is selected from the group consisting of coconut oil, peanut oil, sesame oil, cottonseed oil, corn oil, soybean oil, olive oil, and esters of fatty acids and polyfunctional alcohols..Iaddend..Iadd.

60. A method for providing a long acting antipsychotic effect, which comprises injecting into a mammal an amount of the composition of claim 54 sufficient to produce a long acting antipsychotic effect..Iaddend..Iadd.

61. A method for providing a long acting antipsychotic effect, which comprises injecting into a mammal an amount of the composition of claim 55 sufficient to produce a long acting antipsychotic effect..Iaddend..Iadd.

62. A method for providing a long acting antipsychotic effect, which comprises injecting into a mammal an amount of the composition of claim 59 sufficient to produce a long acting antipsychotic effect..Iaddend..Iadd.

63. A compound of the formula: ##STR157##

wherein,

X is --O--, --S--, --NH--, or --N(R.sub.2)--;

R.sub.2 is selected from the group consisting of lower alkyl, aryl lower alkyl, aryl, cycloalkyl, aroyl, alkanoyl and phenylsulfonyl groups;

aryl is as defined hereinafter;

p is 1 or 2;

Y is hydrogen, lower alkyl, hydroxy, chlorine, fluorine, bromine, iodine, lower alkoxy, trifluoromethyl, nitro, or amino, when p is 1, except that

Y is lower alkoxy, hydroxy or halogen, when p is 2 and X is --O--;

in which (R.sub.1) is R.sub.20, R.sub.21 or R.sub.22, wherein:

R.sub.20 is --(CH.sub.2).sub.n --, where n is 2, 3, 4 or 5;

R.sub.21 is

--CH.sub.2 --CH.dbd.CH--CH.sub.2 --,

--CH.sub.2 --C.ident.C--CH.sub.2 --,

--CH.sub.2 --CH.dbd.CH--CH.sub.2 --CH.sub.2 --,

--CH.sub.2 CH.sub.2 --CH.dbd.CH--CH.sub.2 --,

--CH.sub.2 --C.ident.C--CH.sub.2 --CH.sub.2 --, or

--CH.sub.2 --CH.sub.2 --C.ident.C--CH.sub.2 --,

the --CH.dbd.CH-- bond being cis or trans;

R.sub.22 is R.sub.20 or R.sub.21 in which one or more carbon atoms of R.sub.20 or R.sub.21 are substituted by at least one C.sub.1 -C.sub.6 linear alkyl group, phenyl group or ##STR158##

where Z.sub.1 is lower alkyl, --OH, lower alkoxy, --CF.sub.3, --NO.sub.2, --NH.sub.2 or halogen, and p is as previously defined; and

R.sub.18 and R.sub.19 are independently selected from the group consisting of:

(C.sub.13 -C.sub.18 straight or branched chain)alkyl,

--C(.dbd.O)--O--(C.sub.13 -C.sub.18)alkyl,

--C(.dbd.O)--(C.sub.13 -C.sub.18)alkyl, and

--C(.dbd.O)-pyridyl, ##STR159##

where NR.sub.18 R.sub.19 taken together form a ring structure selected from the group consisting of piperidinyl, morpholinyl, and piperazinyl;

where the piperidinyl or piperazinyl ring is substituted by ##STR160##

where X, Y, and p are as previously defined; where tri(C.sub.1 -C.sub.6)alkylsilyloxy, hydroxy lower alkyl, alkanoyloxy lower alkyl, amino, mono- or dialkylamino, (C.sub.1 -C.sub.18)acyl amino, (C.sub.1 -C.sub.18)alkanoyl, trifluoromethyl, chlorine, fluorine, bromine, --O--C(.dbd.O)--(C.sub.1 -C.sub.18 straight or branched chain)alkyl or --C(.dbd.O)-aryl;

where R.sub.28 is hydrogen, (C.sub.1 -C.sub.6) alkyl, aryl(C.sub.1 -C.sub.6) alkyl, phenyl, or substituted phenyl;

in which aryl is phenyl or ##STR161##

wherein R.sub.5 is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, or trifluoromethoxy;

and, any hydroxyl group attached to an aliphatic or aromatic carbon atom, or any primary or secondary nitrogen atom may be acylated with a (C.sub.4 -C.sub.18)alkanoyl group; in addition, any nitrogen atom may alternatively be acylated with a (C.sub.4 -C.sub.18)alkoxycarbonyl group; and

m is 1, 2, or 3;

all geometric, optical, and stereoisomers thereof,

or a pharmaceutically acceptable acid addition salt thereof..Iaddend..Iadd.

64. A pharmaceutical composition which comprises a compound of claim 63 and a pharmaceutically acceptable carrier therefor..Iaddend..Iadd.

65. The compound of claim 63, wherein X is --N(R.sub.2)--..Iaddend..Iadd.

66. The compound of claim 63, wherein at least one of R.sub.18 and R.sub.19 is --(C.dbd.O)-pyridyl..Iaddend..Iadd.

67. The compound of claim 63, wherein R.sub.18 is hydrogen and R.sub.19 is .Iaddend. ##STR162## .Iadd.

68. The compound of claim 63, wherein NR.sub.18 R.sub.19 form a substituted piperidinyl ring..Iaddend..Iadd.

69. An antipsychotic composition, which comprises the compound of claim 63 in an amount sufficient to produce an antipsychotic effect and a pharmaceutically acceptable carrier..Iaddend..Iadd.

70. A method of treating psychoses, which comprises administering to a mammal a psychoses-treating amount of the compound of claim 63..Iaddend..Iadd.

71. An analgesic composition, which comprises the compound of claim 63 in an amount sufficient to produce a pain-relieving effect and a pharmaceutically acceptable carrier..Iaddend..Iadd.

72. A method of alleviating pain, which comprises administering to a mammal a pain-relieving effective amount of the compound to claim 63..Iaddend..Iadd.

73. A depot pharmaceutical composition, which comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound of claim 63..Iaddend..Iadd.

74. The depot pharmaceutical composition of claim 73, wherein the hydroxy group is acylated with a (C.sub.4 -C.sub.18)alkanoyl group, or the amino group is acylated with a (C.sub.4 -C.sub.18)alkanoyl group or a (C.sub.4 -C.sub.18)alkoxycarbonyl group..Iaddend..Iadd.

75. The composition of claim 73, which contains a pharmaceutically acceptable oil..Iaddend..Iadd.

76. The composition of claim 75, wherein the oil is selected from the group consisting of coconut oil, peanut oil, sesame oil, cottonseed oil, corn oil, soybean oil, olive oil, and esters of fatty acids and polyfunctional alcohols..Iaddend..Iadd.

77. The composition of claim 74, which contains a pharmaceutically acceptable oil..Iaddend..Iadd.

78. The composition of claim 77, wherein the oil is selected from the group consisting of coconut oil, peanut oil, sesame oil, cottonseed oil, corn oil, soybean oil, olive oil, and esters of fatty acids and polyfunctional alcohols..Iaddend..Iadd.

79. A method for providing a long acting antipsychotic effect, which comprises injecting into a mammal an amount of the composition of claim 73 sufficient to produce a long acting antipsychotic effect..Iaddend..Iadd.

80. A method for providing a long acting antipsychotic effect, which comprises injecting into a mammal an amount of the composition of claim 74 sufficient to produce a long acting antipsychotic effect..Iaddend..Iadd.

81. A method for providing a long acting antipsychotic effect, which comprises injecting into a mammal an amount of the composition of claim 78 sufficient to produce a long acting antipsychotic effect..Iaddend.
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