US 6,207,680 B1Granted

Heteroarylpiperidines and their use as antipsychotics and analgesics

AssigneeAventis Pharmaceuticals Inc.

InventorsEdward J. Glamkowski, Yulin Chiang, Joseph T. Strupczewski, Kenneth J. Bordeau, Peter A. Nemoto, John J. Tegeler

Life of this patent

Estimating the term…

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.

Claims65

Dependent claims

A compound having the formula:

wherein,
X is —O—, —S—,
R2 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 alkoxy, hydroxy or halogen when p is 2 and X is —O—;
in which 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, phenyl group or
where Z1 is lower alkyl, —OH, lower alkoxy, —CF3, —NO2, —NH2 or halogen, and p is as previously defined;
where R12 is selected from the group consisting of:
hydrogen,
where R13 is selected from the group consisting of hydrogen and (C1-C12) alkyl groups;
where R14 is selected from the group consisting of hydrogen and (C1-C12) alkyl groups;
where NR15R16 taken together form a ring structure selected from the group consisting of piperidinyl, morpholinyl and piperazinyl;
where R17 is selected from the group consisting of lower alkyl and aryl groups;
in which aryl is phenyl or
where R5 is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, or trifluoromethoxy;
all geometric, optical, and stereoisomers thereof;
or a pharmaceutically acceptable acid addition salt thereof.

25 more elements

A compound of the formula:

wherein,
X is —O—, —S—, —NH—, or —N(R2)—;
R2 is selected from the group consisting of lower alkyl, aryl lower alkyl, aryl, (C3-C10)cycloalkyl, aroyl, (C2-C18) alkanoyl, (C1-C18)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;
R1 is —CR24R27—(CR23R24)n—CR24R27—, where n is 0, 1, 2 or 3;
or
—CHR24CH═CH—CHR24—,
—CHR24—C≡C—CHR24—,
—CHR24—CH═CH—CR23R24—CHR24—,
—CHR24—CR23R24—CH═CH—CHR24—,
—CHR24—C≡C—CR23R24—CHR24—, or
—CHR24—CR23R24—C≡C—CHR24—,
the —CH═CH— bond being cis or trans;
R23 is hydrogen, (C1-C18) linear alkyl, phenyl, hydroxy, (C1-C18)alkoxy, aryloxy, aryl(C1-C18)alkyloxy, (C1-C18)alkanoyloxy, hydroxy(C1-C6)alkyl, (C1-C18)alkoxy(C1-C6)alkyl, aryl(C1-C18)alkyloxy(C1-C6)alkyl, (C1-C18)alkanoyloxy(C1-C6)alkyl or
where Z1 is lower alkyl, —OH, lower alkoxy, —CF3, —NO2, —NH2 or halogen, and p is as previously defined, wherein aryl is as defined hereinafter;
R24 is hydrogen, (C1-C18) linear alkyl, phenyl, hydroxy (C1-C6)alkyl, (C1-C18)alkoxy (C1-C6)alkyl, phenyl(C1-C6)alkyloxy, aryl(C1-C18)alkoxy(C1-C6)alkyl, (C1-C18)alkanoylcxy(C1-C6)alkyl or
where Z1 and p are as previously defined, wherein aryl is as defined hereinafter;
R27 is hydrogen or R24 and R27 taken together with the carbon to which they are attached form C═O or C═S;
with the proviso that R23 is not hydrogen, (C1-C18)linear alkyl, phenyl, or
when R27 is hydrogen and R24 is hydrogen, (C1-C18)linear alkyl, phenyl, or
with the proviso that R24 is not hydrogen, (C1-C18)linear alkyl, phenyl, or
when R27 is hydrogen and n is 0, or when R27 is hydrogen and R23 hydrogen, (C1-C18)linear alkyl, phenyl, or
or when R1 is —CHR24—CH═CH—CHR24— or —CHR24—C≡C—CHR24—;
R12 is selected from the group consisting of:
hydrogen,
alkyl,
—C(═O)—(C1-C18 straight chain or branched)alkyl,
—C(═O)—NR13R14,
—C(═O)—NR15R16,
—S(═O)2—R17, and
where R13 is selected from the group consisting of hydrogen and (C1-C18)alkyl groups;
where R14 is selected from the group consisting of hydrogen and (C1-C18)alkyl groups;
where NR15R16 taken together form a ring structure selected from the group consisting of piperidinyl, morpholinyl and piperazinyl;
where R17 is selected from the group consisting of (C1-C18)alkyl and aryl groups;
where R4 is hydrogen, lower alkyl, lower alkoxy, hydroxy, tri(C1-C6)alkylsilyloxy, hydroxy lower alkyl, alkanoyloxy lower alkyl, amino, nitro, mono- or dialkylamino, (C1-C18)acyl amino, (C1-C18)alkanoyl, trifluoromethyl, chlorine, fluorine, bromine, —O—C(═O)—(C1-C18 straight or branched chain)alkyl or —C(═O)— aryl;
where m is 1, 2, or 3;
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;
and, any hydroxyl group attached to an aliphatic or aromatic carbon atom, or any primary or secondary nitrogen atom may be acylated with a (C4-C18)alkanoyl group;
in addition, any nitrogen atom may alternatively be acylated with a (C4-C18)alkoxycarbonyl group;
all geometric, optical, and stereoisomers thereof, or a pharmaceutically acceptable acid addition salt thereof.

40 more elements

A compound of the formula:

wherein,
X is —O—, —S—, —NH—, or —N(R2)—;
R2 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(R2)—;
Y is lower alkyl, trifluoromethyl, nitro, or amino when X is —O—;
R1 is —CR24R27—(CR23R24)n—CR24R27—, where n is 0, 1, 2 or 3;
or
—CHR24CH═CH—CHR24—,
—CHR24—C≡C—CHR24—,
—CHR24—CH═CH—CR23R24—CHR24—,
—CHR24—CR23R24—CH═CH—CHR24—,
—CHR24—C≡C—CR23R24—CHR24—, or
—CHR24—CR23R24—C≡C—CHR24—,
the —CH═CH— bond being cis or trans;
R23 is hydrogen, (C1-C18) linear alkyl, phenyl, hydroxy, (C1-C18)alkoxy, aryloxy, aryl(C1-C18)alkyloxy, (C1-C18)alkanoyloxy, hydroxy(C1-C6)alkyl, (C1-C18)alkoxy(C1-C6)alkyl, aryl(C1-C18)alkyloxy(C1-C6)alkyl, (C1-C18)alkanoyloxy(C1-C6)alkyl or
where Z1 is lower alkyl, —OH, lower alkoxy, —CF3, —NO2, —NH2, or halogen, and p is as previously defined, wherein aryl is as defined hereinafter;
R24 is hydrogen, (C1-C18) linear alkyl, phenyl, hydroxy(C1-C6)alkyl, (C1-C18)alkoxy(C1-C6)alkyl, phenyl(C1-C6)alkyloxy, aryl(C1-C18)alkoxy(C1-C6)alkyl, (C1-C18)alkanoyloxy(C1-C6)alkyl or
where Z1 and p are as previously defined, wherein aryl is as defined hereinafter;
R27 is hydrogen or R24 and R27 taken together with the carbon to which they are attached form C═O or C═S;
R12 is selected from the group consisting of:
hydrogen,
alkyl,
—C(═O)—(C1-C18) straight chain or branched)alkyl,
—C(═O)—NR13R14,
—C(═O)—NR15R16,
—S(═O)—R17, and
where R13 is selected from the group consisting of hydrogen and (C1-C18)alkyl groups;
where R14 is selected from the group consisting of hydrogen and (C1-C18)alkyl groups;
where NR15R16 taken together form a ring structure selected from the group consisting of piperidinyl, morpholinyl and piperazinyl;
where R17 is selected from the group consisting of (C1-C18)alkyl and aryl groups;
where R4 is hydrogen, lower alkyl, lower alkoxy, hydroxy, tri(C1-C6)alkylsilyloxy, hydroxy lower alkyl, alkanoyloxy lower alkyl, amino, nitro, mono- or dialkylamino, (C1-C18)acyl amino, (C1-C18)alkanoyl, trifluoromethyl, chlorine, fluorine, bromine, —O—C(═O)—(C1-C18 straight or branched chain)alkyl or —C(═O)—aryl;
where m is 1, 2, or 3;
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;
and, any hydroxyl group attached to an aliphatic or aromatic carbon atom, or any primary or secondary nitrogen atom may be acylated with a (C4-C18)alkanoyl group;
in addition, any nitrogen atom may alternatively be acylated with a (C4-C18),)alkoxycarbonyl group;
all geometric, optical, and stereoisomers thereof, or a pharmaceutically acceptable acid addition salt thereof.

36 more elements

A compound of the formula:

wherein,
X is —O—, —S—, —NH—, or —N(R2)—;
R2 is selected from the group consisting of lower alkyl, aryl lower alkyl, aryl, (C3-C10)cycloalkyl, aroyl, (C2-C18)alkanoyl, (C1-C18)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;
R1 is —CR24R27—(CR23R24)n—CR24R27—, where n is 0, 1, 2 or 3;
or
—CHR24CH═CH—CHR24—,
—CHR24—C≡C—CHR24—,
—CHR24—CH═CH—CR23R24—CHR24—,
—CHR24—CR23R24—CH═CH—CHR24—,
—CHR24—C≡C—CR23R24—CHR24—, or
—CHR24—CR23R24—C≡C—CHR24—,
the —CH═CH— bond being cis or trans;
R23 is hydrogen, (C1-C18) linear alkyl, phenyl, hydroxy, (C1-C18)alkoxy, aryloxy, aryl(C1-C18)alkyloxy, (C1-C18))alkanoyloxy, hydroxy(C1-C6)alkyl, (C1-C18)alkoxy(C1-C6)alkyl, aryl(C1-C18)alkyloxy(C1-C6)alkyl, (C1-C18)alkanoyloxy(C1-C18)alkyl or
where Z1 is lower alkyl, —OH, lower alkoxy, —CF3, —NO2, —NH2, or halogen, and p is as previously defined, wherein aryl is as defined hereinafter;
R24 is hydrogen, (C1-C18) linear alkyl, phenyl, hydroxy(C1-C6)alkyl, (C1-C18)alkoxy(C1-C6)alkyl, phenyl(C1-C6)alkyloxy, aryl(C1-C18)alkoxy(C1-C6)alkyl, (C1-C18)alkanoyloxy(C1-C6)alkyl or
where Z1 and p are as previously defined, wherein aryl is as defined hereinafter;
R27 is hydrogen or R24 and R27 taken together with the carbon to which they are attached form C═O or C═S;
R12 is
where R4 is hydrogen, lower alkyl, lower alkoxy, hydroxy, tri(C1-C6)alkylsilyloxy, hydroxy lower alkyl, alkanoyloxy lower alkyl, amino, nitro, mono- or dialkylamino, (C1-C18)acyl amino, (C1-C18)alkanoyl, trifluoromethyl, chlorine, fluorine, bromine, —O—C(═O)—(C1-C18 straight or branched chain)alkyl, or —C(═O)—aryl;
where m is 1, 2, or 3;
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;
and, any hydroxyl group attached to an aliphatic or aromatic carbon atom, or any primary or secondary nitrogen atom may be acylated with a (C4-C18)alkanoyl group;
in addition, any nitrogen atom may alternatively be acylated with a (C1-C18))alkoxycarbonyl group;
all geometric, optical, and stereoisomers thereof, or a pharmaceutically acceptable acid addition salt thereof.

25 more elements

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

wherein,
R2 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 alkoxy, hydroxy or halogen when p is 2 and X is —O—;
in which (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, phenyl group or
where Z1 is lower alkyl, —OH, lower alkoxy, —CF3, —NO2, —NH2 or halogen, and p is as previously defined;
where R12 is selected from the group consisting of:
hydrogen,
where R13 is selected from the group consisting of hydrogen and (C1-C12)alkyl groups;
where R14 is selected from the group consisting of hydrogen and (C1-C12)alkyl groups;
where NR15R16 taken together form a ring structure selected from the group consisting of piperidinyl, morpholinyl and piperazinyl;
where R17 is selected from the group consisting of lower alkyl and aryl groups;
in which 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;
and, any hydroxyl group attached to an aliphatic or aromatic carbon atom, or any primary or secondary nitrogen atom may be acylated with a (C4-C18)alkanoyl group;
in addition, any nitrogen atom may be acylated with a (C4-C18)alkoxycarbonyl group;
all geometric, optical, and stereoisomers thereof, or a pharmacuetically acceptable acid addition salt thereof.

25 more elements

Dependencies are inferred from the claim text.

Facts

Application: 08/468,993Filed 6 Jun 1995 · division
Priority: 19 May 1989
Granted: 27 Mar 2001
Term ends: Not estimatedThe source records don’t support an estimate.

Classification33 codes

C07D 231/56
Condensed with carbocyclic rings or ring systems: benzopyrazoles; Hydrogenated benzopyrazoles
A61P 23/00
Anaesthetics
A61P 25/00
Drugs for disorders of the nervous system
A61P 25/04
Drugs for disorders of the nervous system: centrally acting analgesics, e.g. opioids

Family

Application07/354,411Parent of this continuation · filed 19 May 1989
Application07/456,790Parent of this continuation · filed 29 Dec 1989
Application07/619,825Parent of this continuation · filed 29 Nov 1990
Application07/944,705Parent of this continuation-in-part · filed 5 Sep 1991
Application07/788,269Parent of this continuation-in-part · filed 5 Nov 1991
Application07/969,383Parent of this continuation-in-part · filed 30 Oct 1992
Application08/144,265Parent of this continuation-in-part · filed 28 Oct 1993
Application08/329,000Parent of this division · filed 25 Oct 1994
US 5,776,963 AParent of this division
Application08/329,000Parent of this continuation-in-part
US 5,364,866 AParent of this continuation-in-part
Application07/944,705Parent of this continuation
US 5,633,265 ARelated patent
US 6,207,680 B1This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

Facts

Application

08/468,993Filed 6 Jun 1995 · division

Priority

19 May 1989

Granted

27 Mar 2001

Term ends

Not estimatedThe source records don’t support an estimate.

Classification33 codes

C07D 231/56
Condensed with carbocyclic rings or ring systems: benzopyrazoles; Hydrogenated benzopyrazoles
A61P 23/00
Anaesthetics
A61P 25/00
Drugs for disorders of the nervous system
A61P 25/04
Drugs for disorders of the nervous system: centrally acting analgesics, e.g. opioids

Family

Application07/354,411Parent of this continuation · filed 19 May 1989

Application07/456,790Parent of this continuation · filed 29 Dec 1989

Application07/619,825Parent of this continuation · filed 29 Nov 1990

Application07/944,705Parent of this continuation-in-part · filed 5 Sep 1991

Application07/788,269Parent of this continuation-in-part · filed 5 Nov 1991

Application07/969,383Parent of this continuation-in-part · filed 30 Oct 1992

Application08/144,265Parent of this continuation-in-part · filed 28 Oct 1993

Application08/329,000Parent of this division · filed 25 Oct 1994

US 5,776,963 AParent of this division

Application08/329,000Parent of this continuation-in-part

US 5,364,866 AParent of this continuation-in-part

Application07/944,705Parent of this continuation

US 5,633,265 ARelated patent

US 6,207,680 B1This patent

From the US filing history. Foreign family members aren’t listed.