US 2016/0095854 A1 · ARYLPIPERAZINE OPIOID RECEPTOR ANTAGONISTS

Abstract

Provided are opioid receptor antagonists represented by the formula (I): where R, Y3, R1, R2, R3, R4 and R5 are as defined herein.

Claims9

Dependent claims

1-26:

(canceled)

A method of antagonizing opioid receptors, comprising administering to a subject in need thereof an effective amount of an opioid receptor antagonist represented by the formula (I):

wherein
R is hydrogen, OH, OC1-6 alkyl, C1-8 alkyl, C1-8 haloalkyl, C2-8 alkenyl, C2-8 alkynyl, aryl substituted by one or more groups Y1, CH2-aryl wherein the aryl group is substituted by one or more groups Y1, OCOC1-8 alkyl, COC1-8 alkyl, CONH2, NHCHO, NH2, NHSO2C1-8 alkyl, or NHCO2C1-8 alkyl;
Y3 is hydrogen, Br, Cl, F, CN, CF3, NO2, OR8, CO2R9, C1-6 alkyl, NR10R11, NHCOR12, NHCO2R12, CONR13R14 or CH2(CH2)nY2;
R1, R2, R3 and R4 are each, independently, one of the following structures:
or R1 and R2, R2 and R3 and/or R3 and R4 are bonded together to form a cyclo alkyl group or a bridged heterocyclic ring;
each Y1 is, independently, hydrogen, OH, Br, Cl, F, CN, CF3, NO2, N3, OR8, CO2R9, C1-6 alkyl, NR10R11, NHCOR12, NHCO2R12, CONR13R14, or CH2(CH2)nY2, or two adjacent Y1 groups form a —O—CH2—O— or —O—CH2CH2—O— group;
each Y2 is, independently, hydrogen, CF3, CO2R9, C1-8 alkyl, NR10R11, NHCOR12, NHCO2R12, CONR13R14, CH2OH, CH2OR8, COCH2R9,
each n is, independently, 0, 1, 2 or 3;
each o is, independently, 0, 1, 2 or 3;
each R8, R9, R10, R11, R12, R13 and R14 is, independently, hydrogen, C1-8 alkyl, CH2-aryl wherein the aryl group is substituted by one or more substituents OH, Br, Cl, F, CN, CF3, NO2, N3, C1-6 alkyl, or CH2(CH2)nY2′;
each Y2′ is, independently, hydrogen, CF3, or C1-6 alkyl;
R5 is
R6 is C1-8 alkyl, C2-8 alkenyl, C1-4 alkyl substituted C4-8 cycloalkyl, C1-4 alkyl substituted C4-8 cycloalkenyl, or thiophene;
X is a single bond, —C(O)— or —CH(OR15)—;
R15 hydrogen, C1-6 alkyl, —(CH2)q-phenyl or —C(O)—R16;
R16 is C1-4 alkyl or —(CH2)q-phenyl;
each q is, independently, 1, 2 or 3;
R17 is hydrogen, C1-8 alkyl, CO2C1-8 alkylaryl substituted by one or more groups Y1, CH2-aryl substituted by one or more groups Y1, or CO2C1-8 alkyl;
R18 is hydrogen, C1-8 alkyl, C2-8 alkenyl, C3-8 alkynyl, CH2CO2C1-8 alkyl, CO2C1-8 alkyl or CH2-aryl substituted by one or more groups Y1;
R19 is a group selected from the group consisting of structures (a)-(p):
Q is NR21, CH2, O, S, SO, or SO2;
each Y4 is, independently, Br, Cl, F, CN, CF3, NO2, N3, OR22, CO2R23, C1-6 alkyl, NR24R25, NHCOR26, NHCO2R27, CONR28R29, or CH2(CH2)nY2;
or two adjacent Y4 groups form a —O—CH2—O— or —O—CH2CH2—O— group;
p is 0, 1, 2, or 3;
R20 is hydrogen, C1-8 alkyl, C2-8 alkenyl, C2-8 alkenyl, CH2OR30, or CH2-aryl substituted by one or more substituents Y1;
each R21 is, independently, hydrogen, C1-8 alkyl, CH2-aryl substituted by one or more substituents Y1, NR31R32, NHCOR33, NHCO2R34, CONR35R36, CH2(CH2)nY2, or C(═NH)NR37R38;
R30 is hydrogen C1-8 alkyl, C2-8 alkenyl, C2-8 alkenyl, CH2O2C1-8 alkyl, CO2C1-8 alkyl, or CH2-aryl substituted by one or more substituents Y1;
R22, R23, R24, R25, R26, R27, R28, R29, R31, R32, R33, R34, R35, R36, R37 and R38 are, independently, hydrogen, C1-8 alkyl, CH2-aryl substituted by one or more substituents OH, Br, Cl, F, CN, CF3, NO2, N3, C1-6 alkyl, or CH2(CH2)nY2′;
Z is N, O or S, wherein when Z is O or S, there is no R18;
X1 is hydrogen, C1-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl;
X2 is hydrogen, C1-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl;
or X1 and X2 together form ═O, ═S, or ═NH,
with the proviso that when R5 is
then at least one of R1, R2, R3 and R4 is other than hydrogen as defined above;
or a pharmaceutically acceptable salt thereof.

32 more elements

A method of treating drug addiction, drug abuse, depression, anxiety, schizophrenia, obesity and eating disorders, comprising administering to a subject in need thereof an effective amount of an opioid receptor antagonist represented by the formula (I):

wherein
R is hydrogen, OH, OC1-6 alkyl, C1-8 alkyl, C1-8 haloalkyl, C2-8 alkenyl, C2-8 alkynyl, aryl substituted by one or more groups Y1, CH2-aryl wherein the aryl group is substituted by one or more groups Y1, OCOC1-8 alkyl, COC1-8 alkyl, CONH2, NHCHO, NH2, NHSO2C1-8 alkyl, or NHCO2C1-8 alkyl;
Y3 is hydrogen, Br, Cl, F, CN, CF3, NO2, OR8, CO2R9, C1-6 alkyl, NR10R11, NHCOR12, NHCO2R12, CONR13R14 or CH2(CH2)nY2;
R1, R2, R3 and R4 are each, independently, one of the following structures:
or R1 and R2, R2 and R3 and/or R3 and R4 are bonded together to form a cyclo alkyl group or a bridged heterocyclic ring;
each Y1 is, independently, hydrogen, OH, Br, Cl, F, CN, CF3, NO2, N3, OR8, CO2R9, C1-6 alkyl, NR10R11, NHCOR12, NHCO2R12, CONR13R14, or CH2(CH2)nY2, or two adjacent Y1 groups form a —O—CH2—O— or —O—CH2CH2—O— group;
each Y2 is, independently, hydrogen, CF3, CO2R9, C1-8 alkyl, NR10R11, NHCOR12, NHCO2R12, CONR13R14, CH2OH, CH2OR8, COCH2R9,
each n is, independently, 0, 1, 2 or 3;
each o is, independently, 0, 1, 2 or 3;
each R8, R9, R10, R11, R12, R13 and R14 is, independently, hydrogen, C1-8 alkyl, CH2-aryl wherein the aryl group is substituted by one or more substituents OH, Br, Cl, F, CN, CF3, NO2, N3, C1-6 alkyl, or CH2(CH2)nY2′;
each Y2′ is, independently, hydrogen, CF3, or C1-6 alkyl;
R5 is
R6 is C1-8 alkyl, C2-8 alkenyl, C1-4 alkyl substituted C4-8 cycloalkyl, C1-4 alkyl substituted C4-8 cycloalkenyl, or thiophene;
X is a single bond, —C(O)— or —CH(OR15)—;
R15 hydrogen, C1-6 alkyl, —(CH2)q-phenyl or —C(O)—R16;
R16 is C1-4 alkyl or —(CH2)q-phenyl;
each q is, independently, 1, 2 or 3;
R17 is hydrogen, C1-8 alkyl, CO2C1-8 alkylaryl substituted by one or more groups Y1, CH2-aryl substituted by one or more groups Y1, or CO2C1-8 alkyl;
R18 is hydrogen, C1-8 alkyl, C2-8 alkenyl, C3-8 alkynyl, CH2CO2C1-8 alkyl, CO2C1-8 alkyl or CH2-aryl substituted by one or more groups Y1;
R19 is a group selected from the group consisting of structures (a)-(p):
Q is NR21, CH2, O, S, SO, or SO2;
each Y4 is, independently, Br, Cl, F, CN, CF3, NO2, N3, OR22, CO2R23, C1-6 alkyl, NR24R25, NHCOR26, NHCO2R27, CONR28R29, or CH2(CH2)nY2,
or two adjacent Y4 groups form a —O—CH2—O— or —O—CH2CH2—O— group;
p is 0, 1, 2, or 3;
R20 is hydrogen, C1-8 alkyl, C2-8 alkenyl, C2-8 alkenyl, CH2OR30, or CH2-aryl substituted by one or more substituents Y1;
each R21 is, independently, hydrogen, C1-8 alkyl, CH2-aryl substituted by one or more substituents Y1, NR31R32, NHCOR33, NHCO2R34, CONR35R36, CH2(CH2)nY2, or C(═NH)NR37R38;
R30 is hydrogen C1-8 alkyl, C2-8 alkenyl, C2-8 alkenyl, CH2O2C1-8 alkyl, CO2C1-8 alkyl, or CH2-aryl substituted by one or more substituents Y1;
R22, R23, R24, R25, R26, R27, R28, R29, R31, R32, R33, R34, R35, R36, R37 and R38 are, independently, hydrogen, C1-8 alkyl, CH2-aryl substituted by one or more substituents OH, Br, Cl, F, CN, CF3, NO2, N3, C1-6 alkyl, or CH2(CH2)nY2′;
Z is N, O or S, wherein when Z is O or S, there is no R18;
X1 is hydrogen, C1-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl;
X2 is hydrogen, C1-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl;
or X1 and X2 together form ═O, ═S, or ═NH,
with the proviso that when R5 is
then at least one of R1, R2, R3 and R4 is other than hydrogen as defined above;
or a pharmaceutically acceptable salt thereof.

32 more elements

A method of treating alcohol addiction, nicotine addiction, cocaine addiction and methamphetamine addiction, comprising administering to a subject in need thereof of an effective amount of an opioid receptor antagonist represented by the formula (I):

wherein
R is hydrogen, OH, OC1-6 alkyl, C1-8 alkyl, C1-8 haloalkyl, C2-8 alkenyl, C2-8 alkynyl, aryl substituted by one or more groups Y1, CH2-aryl wherein the aryl group is substituted by one or more groups Y1, OCOC1-8 alkyl, COC1-8 alkyl, CONH2, NHCHO, NH2, NHSO2C1-8 alkyl, or NHCO2C1-8 alkyl;
Y3 is hydrogen, Br, Cl, F, CN, CF3, NO2, OR8, CO2R9, C1-6 alkyl, NR10R11, NHCOR12, NHCO2R12, CONR13R14 or CH2(CH2)nY2;
R1, R2, R3 and R4 are each, independently, one of the following structures:
or R1 and R2, R2 and R3 and/or R3 and R4 are bonded together to form a cyclo alkyl group or a bridged heterocyclic ring;
each Y1 is, independently, hydrogen, OH, Br, Cl, F, CN, CF3, NO2, N3, OR8, CO2R9, C1-6 alkyl, NR10R11, NHCOR12, NHCO2R12, CONR13R14, or CH2(CH2)nY2, or two adjacent Y1 groups form a —O—CH2—O— or —O—CH2CH2—O— group;
each Y2 is, independently, hydrogen, CF3, CO2R9, C1-8 alkyl, NR10R11, NHCOR12, NHCO2R12, CONR13R14, CH2OH, CH2OR8, COCH2R9,
each n is, independently, 0, 1, 2 or 3;
each o is, independently, 0, 1, 2 or 3;
each R8, R9, R10, R11, R12, R13 and R14 is, independently, hydrogen, C1-8 alkyl, CH2-aryl wherein the aryl group is substituted by one or more substituents OH, Br, Cl, F, CN, CF3, NO2, N3, C1-6 alkyl, or CH2(CH2)nY2′;
each Y2′ is, independently, hydrogen, CF3, or C1-6 alkyl;
R5 is
R6 is C1-8 alkyl, C2-8 alkenyl, C1-4 alkyl substituted C4-8 cycloalkyl, C1-4 alkyl substituted C4-8 cycloalkenyl, or thiophene;
X is a single bond, —C(O)— or —CH(OR15)—;
R15 hydrogen, C1-6 alkyl, —(CH2)q-phenyl or —C(O)—R16;
R16 is C1-4 alkyl or —(CH2)q-phenyl;
each q is, independently, 1, 2 or 3;
R17 is hydrogen, C1-8 alkyl, CO2C1-8 alkylaryl substituted by one or more groups Y1, CH2-aryl substituted by one or more groups Y1, or CO2C1-8 alkyl;
R18 is hydrogen, C1-8 alkyl, C2-8 alkenyl, C3-8 alkynyl, CH2CO2C1-8 alkyl, CO2C1-8 alkyl or CH2-aryl substituted by one or more groups Y1;
R19 is a group selected from the group consisting of structures (a)-(p):
Q is NR21, CH2, O, S, SO, or SO2;
each Y4 is, independently, Br, Cl, F, CN, CF3, NO2, N3, OR22, CO2R23, C1-6 alkyl, NR24R25, NHCOR26, NHCO2R27, CONR28R29, or CH2(CH2)nY2,
or two adjacent Y4 groups form a —O—CH2—O— or —O—CH2CH2—O— group;
p is 0, 1, 2, or 3;
R20 is hydrogen, C1-8 alkyl, C2-8 alkenyl, C2-8 alkenyl, CH2OR30, or CH2-aryl substituted by one or more substituents Y1;
each R21 is, independently, hydrogen, C1-8 alkyl, CH2-aryl substituted by one or more substituents Y1, NR31R32, NHCOR33, NHCO2R34, CONR35R36, CH2(CH2)nY2, or C(═NH)NR37R38;
R30 is hydrogen C1-8 alkyl, C2-8 alkenyl, C2-8 alkenyl, CH2O2C1-8 alkyl, CO2C1-8 alkyl, or CH2-aryl substituted by one or more substituents Y1;
R22, R23, R24, R25, R26, R27, R28, R29, R31, R32, R33, R34, R35, R36, R37 and R38 are, independently, hydrogen, C1-8 alkyl, CH2-aryl substituted by one or more substituents OH, Br, Cl, F, CN, CF3, NO2, N3, C1-6 alkyl, or CH2(CH2)nY2′;
Z is N, O or S, wherein when Z is O or S, there is no R18;
X1 is hydrogen, C1-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl;
X2 is hydrogen, C1-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl;
or X1 and X2 together form ═O, ═S, or ═NH,
with the proviso that when R5 is
then at least one of R1, R2, R3 and R4 is other than hydrogen as defined above;
or a pharmaceutically acceptable salt thereof.

32 more elements

A method of treating diabetes, diabetic complications, diabetic retinopathy, sexual/reproductive disorders, epileptic seizure, hypertension, cerebral hemorrhage, congestive heart failure, sleeping disorders, atherosclerosis, rheumatoid arthritis, stroke, hyperlipidemia, hypertriglycemia, hyperglycemia, hyperlipoproteinemia, substance abuse, drug overdose, compulsive behavior disorders and addictive behaviors, comprising administering to a subject in need thereof an effective amount of an opioid receptor antagonist represented by the formula (I):

wherein
R is hydrogen, OH, OC1-6 alkyl, C1-8 alkyl, C1-8 haloalkyl, C2-8 alkenyl, C2-8 alkynyl, aryl substituted by one or more groups Y1, CH2-aryl wherein the aryl group is substituted by one or more groups Y1, OCOC1-8 alkyl, COC1-8 alkyl, CONH2, NHCHO, NH2, NHSO2C1-8 alkyl, or NHCO2C1-8 alkyl;
Y3 is hydrogen, Br, Cl, F, CN, CF3, NO2, OR8, CO2R9, C1-6 alkyl, NR10R11, NHCOR12, NHCO2R12, CONR13R14 or CH2(CH2)nY2;
R1, R2, R3 and R4 are each, independently, one of the following structures:
or R1 and R2, R2 and R3 and/or R3 and R4 are bonded together to form a cyclo alkyl group or a bridged heterocyclic ring;
each Y1 is, independently, hydrogen, OH, Br, Cl, F, CN, CF3, NO2, N3, OR8, CO2R9, C1-6 alkyl, NR10R11, NHCOR12, NHCO2R12, CONR13R14, or CH2(CH2)nY2, or two adjacent Y1 groups form a —O—CH2—O— or —O—CH2CH2—O— group;
each Y2 is, independently, hydrogen, CF3, CO2R9, C1-8 alkyl, NR10R11, NHCOR12, NHCO2R12, CONR13R14, CH2OH, CH2OR8, COCH2R9,
each n is, independently, 0, 1, 2 or 3;
each o is, independently, 0, 1, 2 or 3;
each R8, R9, R10, R11, R12, R13 and R14 is, independently, hydrogen, C1-8 alkyl, CH2-aryl wherein the aryl group is substituted by one or more substituents OH, Br, Cl, F, CN, CF3, NO2, N3, C1-6 alkyl, or CH2(CH2)nY2′;
each Y2′ is, independently, hydrogen, CF3, or C1-6 alkyl;
R5 is
R6 is C1-8 alkyl, C2-8 alkenyl, C1-4 alkyl substituted C4-8 cycloalkyl, C1-4 alkyl substituted C4-8 cycloalkenyl, or thiophene;
X is a single bond, —C(O)— or —CH(OR15)—;
R15 hydrogen, C1-6 alkyl, —(CH2)q-phenyl or —C(O)—R16;
R16 is C1-4 alkyl or —(CH2)q-phenyl;
each q is, independently, 1, 2 or 3;
R17 is hydrogen, C1-8 alkyl, CO2C1-8 alkylaryl substituted by one or more groups Y1, CH2-aryl substituted by one or more groups Y1, or CO2C1-8 alkyl;
R18 is hydrogen, C1-8 alkyl, C2-8 alkenyl, C3-8 alkynyl, CH2CO2C1-8 alkyl, CO2C1-8 alkyl or CH2-aryl substituted by one or more groups Y1;
R19 is a group selected from the group consisting of structures (a)-(p):
Q is NR21, CH2, O, S, SO, or SO2;
each Y4 is, independently, Br, Cl, F, CN, CF3, NO2, N3, OR22, CO2R23, C1-6 alkyl, NR24R25, NHCOR26, NHCO2R27, CONR28R29, or CH2(CH2)nY2,
or two adjacent Y4 groups form a —O—CH2—O— or —O—CH2CH2—O— group;
p is 0, 1, 2, or 3;
R20 is hydrogen, C1-8 alkyl, C2-8 alkenyl, C2-8 alkenyl, CH2OR30, or CH2-aryl substituted by one or more substituents Y1;
each R21 is, independently, hydrogen, C1-8 alkyl, CH2-aryl substituted by one or more substituents Y1, NR31R32, NHCOR33, NHCO2R34, CONR35R36, CH2(CH2)nY2, or C(═NH)NR37R38;
R30 is hydrogen C1-8 alkyl, C2-8 alkenyl, C2-8 alkenyl, CH2O2C1-8 alkyl, CO2C1-8 alkyl, or CH2-aryl substituted by one or more substituents Y1;
R22, R23, R24, R25, R26, R27, R28, R29, R31, R32, R33, R34, R35, R36, R37 and R38 are, independently, hydrogen, C1-8 alkyl, CH2-aryl substituted by one or more substituents OH, Br, Cl, F, CN, CF3, NO2, N3, C1-6 alkyl, or CH2(CH2)nY2′;
Z is N, O or S, wherein when Z is O or S, there is no R18;
X1 is hydrogen, C1-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl;
X2 is hydrogen, C1-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl;
or X1 and X2 together form ═O, ═S, or ═NH,
with the proviso that when R5 is
then at least one of R1, R2, R3 and R4 is other than hydrogen as defined above;
or a pharmaceutically acceptable salt thereof.

32 more elements

Dependencies are inferred from the claim text.

Facts

Application

14/968,258Filed 14 Dec 2015

Priority

24 Feb 2010

Published

7 Apr 2016

Term ends

Not estimatedThe source records don’t support an estimate.

Classification34 codes

A61K 31/495
Having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins: having six-membered rings with two or more nitrogen atoms as the only ring…
A61K 31/496
Having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines: non-condensed piperazines…
A61P 1/14
Drugs for disorders of the alimentary tract or the digestive system: prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics,…
A61P 3/00
Drugs for disorders of the metabolism

Family

Application61/307,534Us provisional application · filed 24 Feb 2010

Application61/316,423Us provisional application · filed 23 Mar 2010

Application13/574,179Division · filed 19 Jul 2012

Application14/968,258Division

US 2012/0295919 A1Published application

US 9,273,027 B2Related patent

US 9,750,738 B2Related patent

US 2016/0095854 A1This patent

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

Arylpiperazine opioid receptor antagonists

Life of this patent

Abstract

Claims9

Arylpiperazine opioid receptor antagonists

Life of this patent

Abstract

Claims9