USRE37729EExpiredUtility
4-Heteroaryl-1-piperidinealkylamines and derivatives thereof and their therapeutic utility
Est. expiryMay 19, 2009(expired)· nominal 20-yr term from priority
Inventors:Edward J. GlamkowskiYulin ChiangJoseph T. StrupczewskiKenneth J. BordeauPeter A. NemotoJohn J. Tegeler
A61P 25/04A61P 25/00A61P 29/00A61P 25/18C07D 471/04C07D 403/12C07C 255/54C07D 261/20C07D 207/08C07D 413/12C07F 7/1804C07C 233/25C07D 413/14C07C 45/71C07D 417/14C07C 45/673C07D 417/04C07D 277/82C07C 323/22C07C 233/33C07C 45/45C07D 231/56C07D 401/14C07D 275/06C07D 401/04C07D 413/04C07D 401/12A61P 23/00C07D 275/04A61K 31/41A61K 31/495
39
PatentIndex Score
0
Cited by
38
References
81
Claims
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.
Claims
exact text as granted — not AI-modifiedWe claim:
1. A compound of the formula:
wherein,
X is —O—, —S—, —NH—, or —N(R 2 )—;
R 2 is selected from the group consisting of lower alkyl, aryl lower alkyl, aryl, cycloalkyl, aroyl, alkanoyl, alkoxycarbonyl, and phenysulfonyl 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 1 is —CR 24 R 27 —(CR 23 R 24 ) n —CR 24 R 27 — wherein n is 0, 1, 2, or
—CHR 24 —CH═CH—CHR 24 —,
—CHR 24 —C≡C—CHR 24 —,
—CHR 24 —CH═CH—CR 23 R 24 —CHR 24 —,
—CHR 24 —CR 23 R 24 —CH═CH—CHR 24 —,
—CHR 24 —C≡C—CR 23 R 24 —CHR 24 —, or
—CHR 24 —CR 23 R 24 —C≡CHR 24 —,
the —CH═CH— bond being cis or trans;
R 23 is hydrogen, (C 1 -C 18 )linear alkyl, phenyl, hydroxy, (C 1 -C 18 )alkoxy, aryloxy, aryl(C 1 -C 18 )alkyloxy, (C 1 -C 18 )alkanoyloxy, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 18 )alkoxy(C 1 -C 6 )alkyl, phenyl(C 1 -C 6 )alkoxy, aryl(C 1 -C 18 )alkyloxy(C 1 -C 6 )alkyl, (C 1 -C 18 )alkanoyloxy(C 1 -C 6 )alkyl, or
where Z 1 is lower alkyl, —OH, lower alkoxy, —CF 3 , —NO 2 , —NH 2 , or halogen, and p is as previously defined; and
R 24 is hydrogen, (C 1 -C 18 )linear alkyl, phenyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 18 )alkoxy(C 1 -C 6 )alkyl, phenyl(C 1 -C 6 )alkyloxy, aryl(C 1 -C 18 )alkyloxy(C 1 -C 6 )alkyl, (C 1 -C 18 )alkanoyloxy(C 1 -C 6 )alkyl, or
where Z 1 is as previously defined, and p is as previously defined;
R 27 is hydrogen or R 24 and R 27 taken together with the carbon to which they are attached form C═O or C═S; and
R 18 and R 19 are independently selected from the group consisting of:
hydrogen,
(C 1 -C 18 straight or branched chain)alkyl,
—C(═O)—O—(C 1 -C 18 )alkyl,
—C(═O)—(C 1 -C 18 )alkyl,
—C(—O—)-pyridyl —C(═ O )- pyridyl,
where NR 18 R 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
where X, Y, and P p are as previously defined; where
R 4 is hydrogen, lower alkyl, lower alkoxy, hydroxy, tri(C 1 -C 6 )alkylsilyloxy, hydroxy lower alkyl, alkanoyloxy lower alkyl, amino, mono- or dialkylamino, (C 1 -C 18 )acyl amino, (C 1 -C 18 )alkanoyl, trifluoromethyl, chlorine, fluorine, bromine, —O—C(═O)—(C 1 -C 18 ) straight or branched chain)alkyl or —C(═O)-aryl;
where R 28 is hydrogen, (C 1 -C 6 ) alkyl, aryl(C 1 -C 6 ) alkyl, phenyl, or substituted phenyl;
in which aryl is phenyl or
wherein R 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 4 -C 18 ) carboxylic alkanoyl group, in addition, any nitrogen atom may alternatively by be acylated with a (C 4 -C 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 18 and R 19 are not lower alkyl;
with the proviso that R 18 and R 19 are not hydrogen when R 1 is (CH 2 ) 2-5 —, X is —O—, and Y is 6-F;
with the proviso that R 23 is not hydrogen, ( C 1 -C 18 ) linear alkyl, phenyl, or
when R 27 is hydrogen and R 24 is hydrogen, ( C 1 -C 18 ) linear alkyl, phenyl, or
with the proviso that R 24 is not hydrogen, ( C 1 -C 18 ) linear alkyl, phenyl, or
when R 27 is hydrogen and n is 0 ; or when R 27 is hydrogen and R 23 is hydrogen, ( C 1 -C 18 ) linear alkyl, phenyl, or
or when R 1 is —CHR 24 —CH═CH—CHR 24 — or —CHR 24 —C≡C—CHR 24 —;
with the exception that the above provisos do not apply when R 2 is alkoxycarbonyl; 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 2 )—.
3. The compound of claim 2 , wherein R 2 is (C 1 -C 18 )alkanoyl or (C 1 -C 18 )alkoxycarbonyl.
4. The compound of claim 1 , wherein R 18 and R 19 are hydrogen.
5. The compound of claim 4 32 , 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 18 is hydrogen and R 19 is —(C═O)pyridyl.
9. The compound of claim 8 , A compound which is selected from N-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-3-pyridinecarboxamide and its pharmaceutically acceptable acid addition salts.
10. The compound of claim 1 , wherein R 18 is hydrogen and R 19 is
11. The compound of claim 1 , wherein NR 18 R 19 form a an optionally substituted piperidinyl ring.
12. The compound of 11 69 , which is selected from 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 69 , which is selected from 1,2-bis-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-hydroxypropane 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 19 , wherein the hydroxy group is acylated with a ( C 4 -C 18 ) alkanoyl group , or the amino group is acylated with a (C 4 -C 18 )alkanoyl group or a (C 4 -C 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.
28. A compound of the formula:
wherein,
X is —O—, —S—, —NH—, or —N ( R 2 ) —;
R
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 1 ) is R 20 , R 21 or R 22 , wherein:
R 20 is — ( CH 2 ) n —, where n is 2 , 3 , 4 or 5 ;
R
21
is
—CH
2
—CH═CH—CH
2
—,
—CH
2
—C≡C—CH
2
—,
—CH
2
—CH═CH—CH
2
—CH
2
—,
—CH
2
CH
2
—CH═CH—CH
2
—,
—CH
2
—C≡C—CH
2
—CH
2
—, or
—CH
2
—CH
2
—C≡C—CH
2
—,
the —CH═CH— bond being cis or trans;
R
22
is R
20
or R
21
in which one or more carbon atoms of R
20
or R
21
are substituted by at least one C
1
-C
6
linear alkyl group, phenyl group or
where Z
1
is lower alkyl, —OH, lower alkoxy, —CF
3
, —NO
2
, —NH
2
, or halogen, and p is as previously defined; and
R
18
and R
19
are independently selected from the group consisting of:
hydrogen,
( C 1 -C 12 straight or branched chain ) alkyl,
—C (═ O ) —O— ( C 1 -C 12 ) alkyl,
—C (═ O )—( C 1 -C 12 ) alkyl, and
where NR
18
R
19
taken together form a ring structure selected from the group consisting of piperidinyl, morpholinyl, and piperazinyl;
in which aryl is phenyl or
wherein R
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
18
and R
19
are not lower alkyl;
with the proviso that R 18 and R 19 are not both hydrogen when R 1 is —( CH 2 ) 2-5 —, X is —O—, and Y is 6 - F;
all geometric, optical, and stereoisomers thereof,
or a pharmaceutically acceptable acid addition salt thereof.
29. A pharmaceutical composition which comprises a compound of claim 28 and a pharmaceutically acceptable carrier.
30. The compound of claim 28 , wherein X is —N( R 2 )—.
31. The compound of claim 30 , wherein R 2 is ( C 2 -C 12 ) alkanoyl.
32. The compound of claim 28 , wherein R 18 and R 19 are hydrogen.
33. The compound of claim 28 , wherein NR 18 R 19 form a piperidinyl ring.
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.
35. A method of treating psychoses, which comprises administering to a mammal a psychoses- treating amount of the compound of claim 28 .
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.
37. A method of alleviating pain, which comprises administering to a mammal a pain- relieving effective amount of the compound of claim 28 .
38. A depot pharmaceutical composition, which comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of the formula:
wherein,
X is —O—, —S—, —NH—, or —N ( R 2 ) —;
R
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 1 ) is R 20 , R 21 or R 22 , wherein:
R 20 is — ( CH 2 ) n —, where n is 2 , 3 , 4 or 5 ;
R
21
is
—CH
2
—CH═CH—CH
2
—,
—CH
2
—C≡C—CH
2
—,
—CH
2
—CH═CH—CH
2
—CH
2
—,
—CH
2
CH
2
—CH═CH—CH
2
—,
—CH
2
—C≡C—CH
2
—CH
2
—, or
—CH
2
—CH
2
—C≡C—CH
2
—,
the —CH═CH— bond being cis or trans;
R
22
is R
20
or R
21
in which one or more carbon atoms of R
20
or R
21
are substituted by at least one C
1
-C
6
linear alkyl group, phenyl group or
where Z
1
is lower alkyl, —OH, lower alkoxy, —CF
3
, —NO
2
, —NH
2
or halogen, and p is as previously defined; and
R
18
and R
19
are independently selected from the group consisting of:
hydrogen,
( C 1 -C 12 straight or branched chain ) alkyl,
—C (═ O ) —O— ( C 1 -C 12 ) alkyl,
—C (═ O )—( C 1 -C 12 ) alkyl, and
where NR
18
R
19
taken together form a ring structure selected from the group consisting of piperidinyl, morpholinyl, and piperazinyl;
in which aryl is phenyl or
wherein R
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 4 -C 18 ) alkanoyl group; in addition, any nitrogen atom may alternatively be acylated with a ( C 4 -C 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
18
and R
19
are not lower alkyl;
with the proviso that R 18 and R 19 are not both hydrogen when R 1 is —( CH 2 ) 2-5 —, X is —O—, and Y is 6 - F;
with the proviso that when R
18
and R
19
are both hydrogen, R
1
is not R
20
or R
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 4 -C 18 ) alkanoyl group, or the amino group is acylated with a ( C 4 -C 18 ) alkanoyl group or a ( C 4 -C 18 ) alkoxycarbonyl group;
all geometric, optical, and stereoisomers thereof,
or a pharmaceutically acceptable acid addition salt thereof.
39. The composition of claim 38 , 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, cottonseed oil, corn oil, soybean oil, olive oil, and 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 38 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 40 sufficient to produce a long acting antipsychotic effect.
43. A compound of the formula:
wherein,
X is —O—, —S—, —NH—, or —N ( R 2 ) —;
R
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 2 ) —;
Y is lower alkyl, trifluoromethoxy, nitro, or amino when X is —O—;
R 1 is —CR 24 R 27 —( CR 23 R 24 ) n —CR 24 R 27 — wherein n is 0 , 1 , 2 , or 3 ; or
—CHR
24
—CH═CH—CHR
24
—,
—CHR
24
—C≡C—CHR
24
—,
—CHR
24
—CH═CH—CR
23
R
24
—CHR
24
—,
—CHR
24
—CR
23
R
24
—CH═CH—CHR
24
—,
—CHR
24
—C≡C—CR
23
R
24
—CHR
24
—, or
—CHR
24
—CR
23
R
24
—C≡CHR
24
—,
the —CH═CH— bond being cis or trans;
R 23 is hydrogen, ( C 1 -C 18 ) linear alkyl, phenyl, hydroxy, ( C 1 -C 18 ) alkoxy, aryloxy, aryl ( C 1 -C 18 ) alkyloxy, ( C 1 -C 18 ) alkanoyloxy, hydroxy ( C 1 -C 6 ) alkyl, ( C 1 -C 18 ) alkoxy ( C 1 -C 6 ) alkyl, aryl ( C 1 -C 18 ) alkyloxy ( C 1 -C 6 ) alkyl, ( C 1 -C 18 ) alkanoyloxy ( C 1 -C 6 ) alkyl, or
where Z
1
is lower alkyl, —OH, lower alkoxy, —CF
3
, —NO
2
, —NH
2
, or halogen, and p is as previously defined; and
R 24 is hydrogen, ( C 1 -C 18 ) linear alkyl, phenyl, hydroxy ( C 1 -C 6 ) alkyl, ( C 1 -C 18 ) alkoxy ( C 1 -C 6 ) alkyl, phenyl ( C 1 -C 6 ) alkyloxy, aryl ( C 1 -C 18 ) alkyloxy ( C 1 -C 6 ) alkyl, ( C 1 -C 18 ) alkanoyloxy ( C 1 -C 6 ) alkyl, or
where Z
1
is as previously defined, and p is as previously defined;
R
27
is hydrogen or R
24
and R
27
taken together with the carbon to which they are attached form C═O or C═S; and
R
18
and R
19
are independently selected from the group consisting of:
hydrogen,
( C 1 -C 18 straight or branched chain ) alkyl,
— C (═ O )— O —( C 1 -C 18 ) alkyl,
— C (═ O )—( C 1 -C 18 ) alkyl,
—C (═ O )- pyridyl,
where NR
18
R
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
where X, Y, and p are as previously defined; where
R 4 is hydrogen, lower alkyl, lower alkoxy, hydroxy, tri ( C 1 -C 6 ) alkylsilyloxy, hydroxy lower alkyl, alkanoyloxy lower alkyl, amino, mono - or dialkylamino, ( C 1 -C 18 ) acyl amino, ( C 1 -C 18 ) alkanoyl, trifluoromethyl, chlorine, fluorine, bromine, —O—C (═ O )—( C 1 -C 18 straight or branched chain ) alkyl or —C (═ O )- aryl;
where R 28 is hydrogen, ( C 1 -C 6 ) alkyl, aryl ( C 1 -C 6 ) alkyl, phenyl, or substituted phenyl;
in which aryl is phenyl or
wherein R
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 4 -C 18 ) alkanoyl group; in addition, any nitrogen atom may alternatively be acylated with a ( C 4 -C 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
18
and R
19
are not lower alkyl;
with the proviso that R 18 and R 19 are not hydrogen when R 1 is — ( CH 2 ) 2-5 —, X is —O—, and Y is 6 - F;
all geometric, optical, and stereoisomers thereof,
or a pharmaceutically acceptable acid addition salt thereof.
44. The compound of claim 43 , wherein X is —N( R 2 )—.
45. The compound of claim 44 , wherein R 2 is ( C 2 -C 18 ) alkanoyl or ( C 1 -C 18 ) alkoxycarbonyl.
46. The compound of claim 43 , wherein R 18 and R 19 are hydrogen.
47. The compound of claim 43 , wherein R 18 is hydrogen and R 19 is — ( C═O )- pyridyl.
48. The compound of claim 43 , wherein R 18 is hydrogen and R 19 is
49. The compound of claim 43 , wherein NR 18 R 19 form an optionally substituted piperidinyl ring.
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.
51. A method of treating psychoses, which comprises administering to a mammal a psychoses- treating amount of the compound of claim 43 .
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.
53. A method of alleviating pain, which comprises administering to a mammal a pain- relieving effective amount of the compound of claim 43 .
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.
55. The depot pharmaceutical composition of claim 54 , wherein the hydroxy group is acylated with a ( C 4 -C 18 ) alkanoyl group, or the amino group is acylated with a ( C 4 -C 18 ) alkanoyl group or a l ( C 4 -C 18 ) alkoxycarbonyl group.
56. The composition of claim 34 , which contains a pharmaceutically acceptable oil.
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.
58. The composition of claim 55 , which contains a pharmaceutically acceptable oil.
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.
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.
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.
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.
63. A compound of the formula:
wherein,
X is —O—, —S—, —NH—, or —N ( R 2 ) —;
R
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 1 ) is R 20 , R 21 or R 22 , wherein:
R 20 is — ( CH 2 ) n —, where n is 2 , 3 , 4 or 5 ;
R
21
is
—CH
2
—CH═CH—CH
2
—,
—CH
2
—C≡C—CH
2
—,
—CH
2
—CH═CH—CH
2
—CH
2
—,
—CH
2
CH
2
—CH═CH—CH
2
—,
—CH
2
—C≡C—CH
2
—CH
2
—, or
—CH
2
—CH
2
—C≡C—CH
2
—,
the —CH═CH— bond being cis or trans;
R
22
is R
20
or R
21
in which one or more carbon atoms of R
20
or R
21
are substituted by at least one C
1
-C
6
linear alkyl group, phenyl group or
where Z
1
is lower alkyl, —OH, lower alkoxy, —CF
3
, —NO
2
, —NH
2
or halogen, and p is as previously defined; and
R
18
and R
19
are independently selected from the group consisting of:
( C 13 -C 18 straight or branched chain ) alkyl,
—C (═ O ) —O— ( C 13 -C 18 ) alkyl,
—C (═ O )—( C 13 -C 18 ) alkyl, and
—C ( ═O )- pyridyl,
where NR
18
R
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
where X, Y, and p are as previously defined; where tri ( C 1 -C 6 ) alkylsilyloxy, hydroxy lower alkyl, alkanoyloxy lower alkyl, amino, mono - or dialkylamino, ( C 1 -C 18 ) acyl amino, ( C 1 -C 18 ) alkanoyl, trifluoromethyl, chlorine, fluorine, bromine, —O—C (═ O )—( C 1 -C 18 straight or branched chain ) alkyl or —C (═ O )- aryl;
where R 28 is hydrogen, ( C 1 -C 6 ) alkyl, aryl ( C 1 -C 6 ) alkyl, phenyl, or substituted phenyl;
in which aryl is phenyl or
wherein R
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 4 -C 18 ) alkanoyl group; in addition, any nitrogen atom may alternatively be acylated with a ( C 4 -C 18 ) alkoxycarbonyl group; and
m is 1 , 2 , or 3 ;
all geometric, optical, and stereoisomers thereof,
or a pharmaceutically acceptable acid addition salt thereof.
64. A pharmaceutical composition which comprises a compound of claim 63 and a pharmaceutically acceptable carrier therefor.
65. The compound of claim 63 , wherein X is —N( R 2 )—.
66. The compound of claim 63 , wherein at least one of R 18 and R 19 is — ( C═O )- pyridyl.
67. The compound of claim 63 , wherein R 18 is hydrogen and R 19 is
68. The compound of claim 63 , wherein NR 18 R 19 form a substituted piperidinyl ring.
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.
70. A method of treating psychoses, which comprises administering to a mammal a psychoses- treating amount of the compound of claim 63 .
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.
72. A method of alleviating pain, which comprises administering to a mammal a pain- relieving effective amount of the compound to claim 63 .
73. A depot pharmaceutical composition, which comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound of claim 63 .
74. The depot pharmaceutical composition of claim 73 , wherein the hydroxy group is acylated with a ( C 4 -C 18 ) alkanoyl group, or the amino group is acylated with a ( C 4 -C 18 ) alkanoyl group or a ( C 4 -C 18 ) alkoxycarbonyl group.
75. The composition of claim 73 , which contains a pharmaceutically acceptable oil.
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.
77. The composition of claim 74 , which contains a pharmaceutically acceptable oil.
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.
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.
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.
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.Cited by (0)
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