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Details for Patent: 5,843,977

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Details for Patent: 5,843,977

Title: [(3-heteroaryl-1-pyrrolidinyl) alkoxy]-3,4-dihydro-1(2H)-naphthalenones and related compounds 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): Strupczewski; Joseph T. (Flemington, NJ), Bordeau; Kenneth J. (Kintnersville, PA)
Assignee: Hoechst Marion Rosueel, Inc. (N/A)
Filing Date:Jun 06, 1995
Application Number:08/467,795
Claims:1. A compound having the formula: ##STR133## wherein, either one of X.sub.y or X.sub.z is --C(.dbd.O)-- and the other is --CH.sub.2 --;

R'.sub.5 is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, or bromine;

X is --O--, --S--, ##STR134## R.sub.2 is selected from the group consisting of lower alkyl, aryl lower alkyl, aryl, cycloalkyl, aroyl, alkanoyl, and phenylsulfonyl groups, wherein 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;

Y is lower alkyl, 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 ##STR135## where Z.sub.1 is lower alkyl, --OH, lower alkoxy, --CF.sub.3, --NO.sub.2, --NH.sub.2 or halogen;

in which aryl is phenyl or ##STR136## where R.sub.5 is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, trifluoromethoxy;

all geometric, optical, and stereoisomers thereof, or a pharmaceutically acceptable acid addition salt thereof.

2. A pharmaceutical composition which comprises the compound of claim 1 and a pharmaceutically acceptable carrier therefor.

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

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

5. 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.

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

7. A compound of the formula: ##STR137## wherein either one of X.sub.y or X.sub.z is --C(.dbd.O)-- and the other is --CH.sub.2 --;

R'.sub.5 is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, or bromine;

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;

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

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

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

--CHR.sub.24 --CR.sub.23 R.sub.24 --C.dbd.C--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 ##STR138## 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, wherein aryl is as defined hereinafter;

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)alkoxy (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.18)alkanoyloxy (C.sub.1 -C.sub.6)alkyl or ##STR139## where Z.sub.1 and p are as previously defined, wherein aryl is as defined hereinafter;

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;

with the proviso that R.sub.23 is not hydrogen, (C.sub.1 -C.sub.18) linear alkyl, phenyl, or ##STR140## when R.sub.27 is hydrogen and R.sub.24 is hydrogen, (C.sub.1 -C.sub.18)linear alkyl, phenyl, or ##STR141## with the proviso that R.sub.24 is not hydrogen, (C.sub.1 -C.sub.18) linear alkyl, phenyl, or ##STR142## 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 ##STR143## or when R.sub.1 is --CHR.sub.24 --CH.dbd.CHR.sub.24 -- or --CHR.sub.24 --C.dbd.C--CHR.sub.24 --;

aryl is phenyl or ##STR144## 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;

all geometric, optical, and stereoisomers thereof, or a pharmaceutically acceptable acid addition salt thereof.

8. An antipsychotic composition, which comprises the compound of claim 7 in an amount sufficient to produce an antipsychotic effect and a pharmaceutically acceptable carrier.

9. A method of treating psychoses, which comprises administering to a mammal a psychoses-treating amount of the compound of claim 7.

10. An analgesic composition, which comprises the compound of claim 7 in an amount sufficient to produce a pain-relieving effect and a pharmaceutically acceptable carrier.

11. A method of alleviating pain, which comprises administering to a mammal a pain-relieving effective amount of the compound of claim 7.

12. A depot pharmaceutical composition, which comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound of claim 7, wherein the compound contains an acylated hydroxy group, or an acylated amino group.

13. The depot pharmaceutical composition of claim 12, 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.

14. The composition of claim 12, which contains a pharmaceutically acceptable oil.

15. The composition of claim 14, 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.

16. The composition of claim 13, which contains a pharmaceutically acceptable oil.

17. The composition of claim 16, 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.

18. A method for providing a long acting antipsychotic effect, which comprises injecting into a mammal an amount of the composition of claim 12 sufficient to produce a long acting antipsychotic effect.

19. A method for providing a long acting antipsychotic effect, which comprises injecting into a mammal an amount of the composition of claim 13 sufficient to produce a long acting antipsychotic effect.

20. A method for providing a long acting antipsychotic effect, which comprises injecting into a mammal an amount of the composition of claim 17 sufficient to produce a long acting antipsychotic effect.

21. A compound of the formula: ##STR145## wherein, either one of X.sub.y or X.sub.z is --C(.dbd.O)-- and the other is --CH.sub.2 --;

R'.sub.5 is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, or bromine;

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 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, trifluoromethyl, 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 --, where n is 0, 1, 2 or 3; or

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

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

--CHR.sub.24 --CR.sub.23 R.sub.24 --C.dbd.C--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 ##STR146## 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, wherein aryl is as defined hereinafter;

R.sub.24 is hydrogen, (C.sub.1 -C.sub.18) linear alkyl, phenyl, (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)alkoxy(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.18)alkanoyloxy(C.sub.1 -C.sub.6)alkyl or ##STR147## where Z.sub.1 and p are as previously defined, wherein aryl is as defined hereinafter;

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;

aryl is phenyl or ##STR148## 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;

all geometric, optical, and stereoisomers thereof, or a pharmaceutically acceptable acid addition salt thereof.

22. An antipsychotic composition, which comprises the compound of claim 21 in an amount sufficient to produce an antipsychotic effect and a pharmaceutically acceptable carrier.

23. A method of treating psychoses, which comprises administering to a mammal a psychoses-treating amount of the compound of claim 21.

24. An analgesic composition, which comprises the compound of claim 21 in an amount sufficient to produce a pain-relieving effect and a pharmaceutically acceptable carrier.

25. A method of alleviating pain, which comprises administering to a mammal a pain-relieving effective amount of the compound of claim 21.

26. A depot pharmaceutical composition, which comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound of claim 21, wherein the compound contains an acylated hydroxy group, or an acylated amino group.

27. The depot pharmaceutical composition of claim 26, 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.

28. The composition of claim 26, which contains a pharmaceutically acceptable oil.

29. The composition of claim 28, 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.

30. The composition of claim 27, which contains a pharmaceutically acceptable oil.

31. The composition of claim 30, 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.

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

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

34. A method for providing a long acting antipsychotic effect, which comprises injecting into a mammal an amount of the composition of claim 33 sufficient to produce a long acting antipsychotic effect.

35. A depot pharmaceutical composition, which comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound having the formula: ##STR149## wherein, wherein, either one of X.sub.y or X.sub.z is --C(.dbd.O)-- and the other is --CH.sub.2 --;

R'.sub.5 is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, or bromine;

X is --O--, --S--, ##STR150## R.sub.2 is selected from the group consisting of lower alkyl, aryl lower alkyl, aryl, cycloalkyl, aroyl, alkanoyl, and phenylsulfonyl groups, wherein 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;

Y is lower alkyl, 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.dbd.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.dbd.C--CH.sub.2 --CH.sub.2 --, or

--CH.sub.2 --CH.sub.2 --C.dbd.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 ##STR151## where Z.sub.1 is lower alkyl, --OH, lower alkoxy, --CF, --NO.sub.2, --NH.sub.2 or halogen;

in which aryl is phenyl or ##STR152## where R.sub.5 is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, 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 be acylated with a (C.sub.4 -C.sub.18)alkoxycarbonyl group;

all geometric, optical, and stereoisomers thereof, or a pharmaceutically acceptable acid addition salt thereof.

36. The depot pharmaceutical composition of claim 35, 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.

37. The composition of claim 35, which contains a pharmaceutically acceptable oil.

38. The composition of claim 37, wherein the oil is selected from the group consisting of coconut oil, peanut oil, sesame oil, cotton seed oil, corn oil, soybean oil, olive oil, and synthetic esters of fatty acids and polyfunctional alcohols.

39. The composition of claim 36, which contains a pharmaceutically acceptable oil.

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

41. A method for providing a long acting antipsychotic effect, which comprises injecting into a mammal an amount of the composition of claim 35 sufficient to produce a long acting antipsychotic effect.

42. A method for providing a long acting antipsychotic effect, which comprises injecting into a mammal an amount of the composition of claim 36 sufficient to produce a long acting antipsychotic effect.

43. 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.
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