Heteroarylpiperidines, pyrrolidines and piperazines and their use as antipsychotics and analgesics
DC CAFCFirst Claim
Patent Images
1. A compound of the formula:
-
whereinX is —
O—
or —
S—
;
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 alkoxy, hydroxy and halogen when p is 2 and X is —
O—
;
(R1) is R20, R21, or R22, wherein;
R20 is —
(CH2)n—
where n is 2, 3, 4 or 5;
R21 is —
CH2—
CH═
CH—
CH2—
, —
CH2—
C≡
C—
CH2—
, —
CH2—
CH═
CH—
CH2—
CH2, —
CH2—
CH2—
CH═
CH—
CH2—
, —
CH2—
C≡
C—
CH2—
CH2—
, or —
CH2—
CH2—
C≡
C—
CH2—
, the —
CH═
CH—
bond being cis or trans;
R22 is R20 or R21 in which one or more carbon atoms of R20 or R21 are substituted by at least one C1-C6 linear alkyl group, pheny group or where Z1 is lower alkyl, —
OH, lower alkoxy, —
CF3, —
NO2, —
NH2 or halogen;
R is hydrogen, lower alkyl, lower alkoxy, hydroxyl, carboxyl, chlorine, fluorine, bromine, iodine, amino, lower mono or dialkylamino, nitro, lower alkyl thio, trifluoromethoxy, cyano, acylamino, trifluoromethyl, trifluoroacetyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, formyl, —
C(═
O)-alkyl, —
C(═
O)—
O-alkyl, —
C(═
O)-aryl, —
C(═
O)-heteroaryl, —
CH(OR7)-alkyl, —
C(═
W)-alkyl, —
C(═
W)-aryl, and —
C(═
W)-heteroaryl;
or —
CH(OR7)-alkyl;
wherein alkyl is lower alkyl;
aryl is phenyl or wherein R5 is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, or trifluoromethoxy;
heteroaryl is wherein Q3 is —
O—
, —
S—
, —
NH—
, or —
CH═
N—
;
W is CH2 or CHR8 or N—
R9;
R7 is hydrogen, lower alkyl, or acyl;
R8 is lower alkyl;
R9 is hydroxy, lower alkoxy, or —
NHR10; and
R10 is hydrogen, lower alkyl, C1-C3 acyl, aryl, —
C(═
)-aryl or —
C(═
O)-heteroaryl, where aryl and heteroaryl are as defined above;
andm is 1, 2, or 3;
all geometric, optical and stereoisomers thereof, or a pharmaceutically acceptable acid addition salt thereof.
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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 amounts of one 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.
16 Citations
147 Claims
-
1. A compound of the formula:
-
wherein X is —
O—
or —
S—
;
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 alkoxy, hydroxy and halogen when p is 2 and X is —
O—
;
(R1) is R20, R21, or R22, wherein; R20 is —
(CH2)n—
where n is 2, 3, 4 or 5;
R21 is —
CH2—
CH═
CH—
CH2—
,—
CH2—
C≡
C—
CH2—
,—
CH2—
CH═
CH—
CH2—
CH2,—
CH2—
CH2—
CH═
CH—
CH2—
,—
CH2—
C≡
C—
CH2—
CH2—
, or—
CH2—
CH2—
C≡
C—
CH2—
,the —
CH═
CH—
bond being cis or trans;
R22 is R20 or R21 in which one or more carbon atoms of R20 or R21 are substituted by at least one C1-C6 linear alkyl group, pheny group or where Z1 is lower alkyl, —
OH, lower alkoxy, —
CF3, —
NO2, —
NH2 or halogen;
R is hydrogen, lower alkyl, lower alkoxy, hydroxyl, carboxyl, chlorine, fluorine, bromine, iodine, amino, lower mono or dialkylamino, nitro, lower alkyl thio, trifluoromethoxy, cyano, acylamino, trifluoromethyl, trifluoroacetyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, formyl, —
C(═
O)-alkyl, —
C(═
O)—
O-alkyl, —
C(═
O)-aryl, —
C(═
O)-heteroaryl, —
CH(OR7)-alkyl, —
C(═
W)-alkyl, —
C(═
W)-aryl, and —
C(═
W)-heteroaryl;
or —
CH(OR7)-alkyl;
wherein alkyl is lower alkyl;
aryl is phenyl or wherein R5 is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, or trifluoromethoxy;
heteroaryl is wherein Q3 is —
O—
, —
S—
, —
NH—
, or —
CH═
N—
;
W is CH2 or CHR8 or N—
R9;
R7 is hydrogen, lower alkyl, or acyl;
R8 is lower alkyl;
R9 is hydroxy, lower alkoxy, or —
NHR10; and
R10 is hydrogen, lower alkyl, C1-C3 acyl, aryl, —
C(═
)-aryl or —
C(═
O)-heteroaryl,where aryl and heteroaryl are as defined above;
andm is 1, 2, or 3;
all geometric, optical and stereoisomers thereof, or a pharmaceutically acceptable acid addition salt thereof. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 80, 81, 82, 83, 84, 85, 86)
wherein X is —
O—
or —
S—
;
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 alkoxy, hydroxy and halogen when p is 2 and X is —
O—
,(R1) is R20, R21, or R22, wherein;
R20 R21 is —
CH2 —
CH═
CH—
CH2—
,—
CH2—
C≡
C—
CH2—
,—
CH2—
CH═
CH—
CH2—
CH2 —
,—
CH2—
CH2—
CH═
CH—
CH2—
,—
CH2—
CH≡
C—
CH2—
CH2—
, or—
CH2—
CH2—
C≡
C—
CH2—
,the —
CH═
CH—
bond being cis or trans;
R22 is R20 is R21 in which one or more carbon atoms of R20 or R21 are substituted by at least one C1-C6 linear alkyl group, phenyl group or wherein Z1 is lower alkyl, —
OH, lower alkoxy, —
CF3, —
NO2, —
NH2 or halogen; and
R and m are as defined hereinafter;
m is 1, 2, or 3; and
when m is 1, 2, or 3, R is hydrogen, lower alkyl, lower alkoxy, hydroxyl, carboxyl, chlorine, fluorine, bromine, iodine, amino, lower mono or dialkylamino, nitro, lower alkyl thio, trifluoromethoxy, cyano, acylamino, trifluoromethyl, trifluoroacetyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, formyl, —
C(═
O)-alkyl, —
C(═
O)—
O-alkyl, —
C(═
O)-aryl, —
C(═
O)-heteroaryl, —
CH(OR7)-alkyl, —
C(═
W)-alkyl, —
C(═
W)-aryl, and —
C(═
W)-heteroaryl;
alkyl is lower alkyl;
aryl is phenyl or where R5 is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, trifluoromethoxy;
heteroaryl is Q3 is —
O—
, —
S—
, —
NH—
, —
CH═
N—
;W is CH2 or CHR8 or N—
R9;
R7 is hydrogen, lower alkyl, or acyl;
R8 is lower alkyl;
R9 is hydroxy, lower alkoxy, or —
NHR10; and
R10 is hydrogen, lower alkyl, C1-C3 acyl, aryl, —
C(═
O)-aryl or —
C(═
O)-heteroaryl,where aryl and heteroaryl are as defined above; and
as claimed in claim 1 with the proviso that when m is 3, R is not —
C(═
O)-heteroaryl or —
C(═
W)-heteroaryl;all geometric, optical and stereoisomers thereof, or a pharmaceutically acceptable acid addition salt thereof.
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81. A compound as claimed in claim 1 87, which is (E)-1-[4-[[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-butenyl]oxy]-3-methoxyphenyl]ethanone, or a pharmaceutically acceptable acid addition salt thereof.
-
82. A pharmaceutical composition, which comprises a compound as claimed in any one of claims 1-81 1-75 and 77-81, and a pharmaceutically acceptable carrier therefor.
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83. An antipsychotic composition which comprises a compound as claimed in any one of claims 1-81 1-75 and 77-81, in an amount sufficient to produce an antipsychotic effect, and a pharmaceutically acceptable carrier therefor.
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84. A method of treating psychoses, which comprises administering to a mammal a psychoses-treating effective amount of a compound as claimed in any one of claims 1-81 1-75 and 77-81.
-
85. An analgesic composition which comprises a compound as claimed in any one of claims 1-81 1-75 and 77-81, in an amount sufficient to produce a pain-relieving effect, and a pharmaceutically acceptable carrier therefor.
-
86. A method of alleviating pain, which comprises administering to a mammal a pain-relieving effective amount of a compound as claimed in any one of claims 1-81 1-75 and 77-81.
-
78. A compound of the formula:
-
wherein p is 1 or 2;
Y is hydrogen, Cl, Br, or F, when p is 1;
Y is lower alkoxy, hydroxy, or halogen when p is 2;
n is 2, 3, or 4;
R is hydrogen, C1-C3 alkyl, C1-C3 alkoxy, hydroxyl, alkanoyl, Cl, F, Br, I, amino, C1-C3 mono or dialkyl amino, acylamino, —
NO2, —
OCF3, —
CF3, alkyl-C(═
O)—
, CF3—
C(═
O)—
, or —
CH(OR7)-alkyl;
alkyl is lower alkyl R7 is hydrogen, lower alkyl-C(═
O)—
, or CF3—
C(═
O)—
;
and m is 1, 2, or 3;
R is hydrogen, C1-C3 alkyl, C1-C3 alkoxy, hydroxyl, alkanoyl, Cl, F, Br, I, amino, C1-C3 mono or dialkyl amino, acylamino, —
NO2, —
OCF3, —
CF3, alkyl-C(═
O)—
, CF3—
C(═
O)—
, or —
CH(OR7)-alkyl;
alkyl is lower alkyl;
R7 is hydrogen, lower alkyl, lower alkyl-C(═
O)—
, or CF3—
C(═
O)—
;
and m is 1, 2, or 3;
all geometric, optical and stereoisomers thereof or a pharmaceutically acceptable acid addition salt thereof.
-
-
79. A compound of the formula:
-
wherein p is 1 or 2; Y is hydrogen, Cl, Br, or F, when p is 1;
Y is lower alkoxy, hydroxy, or halogen when p is 2;
n is 2, 3, or 4;
R is hydrogen, C1-C3 alkyl, C1-C3 alkoxy, hydroxyl, acyl, alkanoyl, Cl, F, Br, I, amino, C1-C3 mono or dialkyl amino, acylamino, —
NO2, —
OCF3, —
CF3, alkyl-C(═
O)—
, CF3—
C(═
O)—
, or —
CH(OR7)-alkyl;
alkyl is lower alkyl;
R7 is hydrogen lower alkyl, or lower alkyl-C(═
O)—
, or CF3—
C(═
O)—
;
and m is 1, 2, or 3;
all geometric, optical and stereoisomers thereof or a pharmaceutically acceptable acid addition salt thereof.
-
-
87. A compound of the formula
-
104. A compound of the formula
-
132. A compound of formula
Specification