# US 9,750,738 B2 · Arylpiperazine opioid receptor antagonists

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- Number: US 9,750,738 B2
- Document ID: US9750738B2
- Status: Granted
- Kind: B2
- Application number: 14/968,258
- Filed: 2015-12-14
- Published: 2016-04-07
- Granted: 2017-09-05
- Earliest claimed: 2010-02-24
- Assignees: Research Triangle Institute
- Applicants: Research Triangle Institute
- Inventors: Frank Ivy Carroll; Juan P. Cueva; James B. Thomas; S. Wayne Mascarella; Scott P. Runyon
- Web page: https://patentgrep.com/patent/US9750738B2

## CPC

- A61K 31/495: having six-membered rings with two {or more} nitrogen atoms as the only ring heteroatoms, e.g. piperazine {or tetrazines}(A61K31/48 takes precedence {; with three nitrogen atoms A61K31/53})
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61P 1/14: Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/06: Antihyperlipidemics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 7/04: Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 9/12: Antihypertensives
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 15/08: for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/08: Antiepileptics; Anticonvulsants
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/20: Hypnotics; Sedatives
- A61P 25/22: Anxiolytics
- A61P 25/24: Antidepressants
- A61P 25/30: for treating abuse or dependence
- A61P 25/32: Alcohol-abuse
- A61P 25/34: Tobacco-abuse
- A61P 25/36: Opioid-abuse
- A61P 27/02: Ophthalmic agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 241/04: having no double bonds between ring members or between ring members and non-ring members
- C07D 295/096: with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

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

## Claims

### Claim 1

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 OH, OC1-6 alkyl, C2-8 alkyl, C1-8 haloalkyl, C2-8 alkenyl, C2-8 alkynyl, aryl substituted by one or more Y1 groups, CH2-aryl wherein the aryl group is substituted by one or more Y1 groups, OCOC1-8 alkyl, COC1-8 alkyl, CONH2, NHCHO, NH2, NHSO2C1-8 alkyl, or NHCO2C1-8 alkyl;
Y3 is hydrogen, Br, Cl, F, 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,
wherein at least one of R1, R2, R3 and R4 is other than hydrogen;
each Y1 is, independently, hydrogen, OH, Br, Cl, F, CN, CF3, NO2, N3, OR8, CO2R9, C1-6 alkyl, NR10R11, NHCOR12, NHCO2R12, or CONR13R14, 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
wherein n is 3,
wherein n is 0, 1, 2 or 3,
wherein n is 2 or 3,
wherein n is 1, 2 or 3,
wherein n is 0, 1, 2 or 3, —CH2CH2—X—R6, or
R6 is 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 Y1 groups, CH2-aryl substituted by one or more Y1 groups, 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 Y1 groups;
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, CH2OR30, or CH2-aryl substituted by one or more Y1 substituents;
each R21 is, independently, hydrogen, C1-8 alkyl, CH2-aryl substituted by one or more Y1 substituents, 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 Y1 substituents;
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 or S, wherein when Z is 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;
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The method of claim 1, wherein
R is OH, OC1-3 alkyl, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, aryl substituted by one or more Y1 groups, CH2-aryl wherein the aryl group is substituted by one or more Y1 groups, OCOC1-4 alkyl, COC1-4 alkyl, CONH2, NHCHO, NH2, NHSO2C1-4 alkyl, or NHCO2C1-4 alkyl; and
Y3 is hydrogen, Br, Cl, F, CF3, NO2, OR8, CO2R9, C1-3 alkyl, NR10R11, NHCOR12, NHCO2R12, CONR13R14 or CH2(CH2)n,Y2.

### Claim 3 (depends on 1)

The method of claim 1, wherein
R is OH, OCH3, or OCF3; and
Y3 is hydrogen.

### Claim 4 (depends on 1)

The method of claim 1, wherein
R1, R2, R3 and R4 are each, independently, hydrogen, methyl or ethyl; and
at least one of R1, R2, R3 and R4 is other than hydrogen.

### Claim 5 (depends on 1)

The method of claim 1, wherein
R1, R2, R3 and R4 are each, independently, hydrogen or methyl; and
at least one of R1, R2, R3 and R4 is methyl.

### Claim 6 (depends on 1)

The method of claim 1, wherein
R is OH, OCH3, or OCF3;
Y3 is hydrogen;
R1 R2, R3 and R4 are each, independently, hydrogen, methyl or ethyl, wherein at least one of R1, R2, R3 and R4 is other than hydrogen; and
R5 is —(CH2)n-phenyl, wherein n is 3.

### Claim 7 (depends on 1)

The method of claim 1, wherein R5 is

### Claim 8 (depends on 1)

The method of claim 1, wherein the opioid receptor antagonist is represented by the formula:
or a pharmaceutically acceptable salt thereof.

### Claim 9

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 OH, OC1-6 alkyl, C2-8 alkyl, C1-8 haloalkyl, C2-8alkenyl, C2-8 alkynyl, aryl substituted by one or more Y1 groups, CH2-aryl wherein the aryl group is substituted by one or more Y1 groups, OCOC1-8 alkyl, COC1-8 alkyl, CONH2, NHCHO, NH2, NHSO2C1-8 alkyl, or NHCO2C1-8 alkyl;
Y3 is hydrogen, Br, Cl, F, 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,
wherein at least one of R1, R2, R3 and R4 is other than hydrogen;
each Y1 is, independently, hydrogen, OH, Br, Cl, F, CN, CF3, NO2, N3, OR8, CO2R9, C1-6 alkyl, NR10R11, NHCOR12, NHCO2R12, or CONR13R14, 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, N3C1-6 alkyl, or CH2(CH2)nY2′;
each Y2′ is, independently, hydrogen, CF3, or C1-6 alkyl;
R5 is
wherein n is 3,
wherein n is 0, 1, 2 or 3,
wherein n is 2or 3,
wherein n is 1, 2 or 3,
wherein n is 0, 1, 2 or 3,
—CH2CH2—X—R6, or
R6 is C2-8alkenyl, C1-4 alkyl substituted C4-8cycloalkyl, C1-4alkyl 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 Y1 groups, CH2-aryl substituted by one or more Y1 groups, 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 Y1 groups;
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, CH2OR30, or CH2-aryl substituted by one or more Y1 substituents;
each R21 is, independently, hydrogen, C1-8 alkyl, CH2-aryl substituted by one or more Y1 substituents, NR31R32, NHCOR33, NHCO2R34, CONR35R36,CH2(CH2)nY2,or C(═NH)NR37R38;
R30 is hydrogen C1-8 alkyl, C2-8 alkenyl, C,2-8 alkenyl, CH2O2C1-8 alkyl, CO2C1-8 alkyl, or CH2-aryl substituted by one or more Y1 substituents;
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 or S wherein when Z is 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;
or a pharmaceutically acceptable salt thereof.

### Claim 10 (depends on 9)

The method of claim 9, wherein
R is OH, OC1-3 alkyl, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkenyl, C2-4 alkynyl, aryl substituted by one or more Y1 groups, CH2-aryl wherein the aryl group is substituted by one or more Y1 groups, OCOC1-4, alkyl, COC1-4 alkyl, CONH2, NHCHO, NH2, NHSO2C1-4 alkyl, or NHCO2C1-4 alkyl; and
Y3 is hydrogen, Br, Cl, F, CF3, NO2, OR8, CO2R9, C1-3alkyl, NR10R11, NHCOR12, NHCO2R12, CONR13R14 or CH2(CH2)nY2.

### Claim 11 (depends on 9)

The method of claim 9, wherein
R is OH, OCH3, or OCF3; and
Y3 is hydrogen.

### Claim 12 (depends on 9)

The method of claim 9, wherein
R1, R2, R3 and R4 are each, independently, hydrogen, methyl or ethyl; and
at least one of R1, R2, R3 and R4 is other than hydrogen.

### Claim 13 (depends on 9)

The method of claim 9, wherein
R1, R2, R3 and R4 are each, independently, hydrogen or methyl; and
at least one of R1, R2, R3 and R4 is methyl.

### Claim 14 (depends on 9)

The method of claim 9, wherein
R is OH, OCH3, or OCF3;
Y3 is hydrogen;
R1, R2, R3and R4 are each, independently, hydrogen, methyl or ethyl, wherein at least one of R1, R2, R3 and R4 is other than hydrogen; and
R5 is —(CH2)n-phenyl, wherein n is 3.

### Claim 15 (depends on 9)

The method of claim 9, wherein R5 is

### Claim 16 (depends on 9)

The method of claim 9, wherein the opioid receptor antagonist is represented by the formula:
or a pharmaceutically acceptable salt thereof.

### Claim 17

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 OH, OC1-6 alkyl, C2-8 alkyl, C1-8 haloalkyl, C2-8alkenyl, C2-8 alkynyl, aryl substituted by one or more Y1 groups, CH2-aryl wherein the aryl group is substituted by one or more Y1 groups, OCOC1-8 alkyl, COC1-8 alkyl, CONH2, NHCHO, NH2, NHSO2C1-8 alkyl, or NHCO2C1-8 alkyl;
Y3 is hydrogen, Br, Cl, F, 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,
wherein at least one of R1, R2, R3 and R4 is other than hydrogen;
each Y1 is, independently, hydrogen, OH, Br, Cl, F, CN, CF3, NO2, N3, OR8, CO2R9, C1-6 alkyl, NR10R11, NHCOR12, NHCO2R12, or CONR13R14, 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, C1-8alkyl, 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
wherein n is 3,
wherein n is 0, 1, 2 or 3,
wherein n is 2 or 3,
wherein n is 1, 2 or 3,
wherein n is 0, 1, 2 or 3,
—CH2CH2—X—R6, or
R6 is C2-8alkenyl, C1-4 alkyl substituted C1-4 cycloalkyl, C1-4alkyl 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 Y1 groups, CH2-aryl substituted by one or more Y1 groups, or CO2C1-8 alkyl;
R18 is hydrogen, C1-8 alkyl, C2-8 alkenyl, C3-8alkynyl, CH2CO2C1-8 alkyl, CO2C1-8 alkyl or CH2-aryl substituted by one or more Y1 groups;
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, C1-6alkyl, 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, CH2OR30, or CH2-aryl substituted by one or more Y1 substituents;
each R21 is, independently, hydrogen, C1-8 alkyl, CH2-aryl substituted by one or more Y1 substituents, 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 Y1 substituents;
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 or S wherein when Z is 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 X2together form ═O, ═S, or ═NH;
or a pharmaceutically acceptable salt thereof.

### Claim 18 (depends on 17)

The method of claim 17, wherein
R is OH, OC1-3 alkyl, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, aryl substituted by one or more Y1 groups, CH2-aryl wherein the aryl group is substituted by one or more Y1 groups, OCOC1-4 alkyl, COC1-4 alkyl, CONH2, NHCHO, NH2, NHSO2C1-4 alkyl, or NHCO2C 1-4 alkyl; and
Y3 is hydrogen, Br, Cl, F, CF3 NO2, OR8, CO2R9, C1-3alkyl, NR10R11, NHCOR12, NHCO2R12, CONR13R14 or CH2(CH2)nY2.

### Claim 19 (depends on 17)

The method of claim 17, wherein
R is OH, OCH3, or OCF3; and
Y3 is hydrogen.

### Claim 20 (depends on 17)

The method of claim 17, wherein
R1, R2, R3 and R4 are each, independently, hydrogen, methyl or ethyl; and
at least one of R1, R2, R3 and R4 is other than hydrogen.

### Claim 21 (depends on 17)

The method of claim 17, wherein
R1, R2, R3 and R4 are each, independently, hydrogen or methyl; and
at least one of R1, R2, R3 and R4 is methyl.

### Claim 22 (depends on 17)

The method of claim 17, wherein
R is OH, OCH3, or OCF3;
Y3 is hydrogen;
R1, R2, R3and R4 are each, independently, hydrogen, methyl or ethyl, wherein at least one of R1, R2, R3 and R4 is other than hydrogen; and
R5 is —(CH2)n-phenyl, wherein n is 3.

### Claim 23 (depends on 17)

The method of claim 17, wherein R5 is

### Claim 24 (depends on 17)

The method of claim 17, wherein the opioid receptor antagonist is represented by the formula:
or a pharmaceutically acceptable salt thereof.

### Claim 25

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 OH, OC1-6 alkyl, C2-8 alkyl, C1-8 haloalkyl, C2-8 alkenyl, C2-8 alkynyl, aryl substituted by one or more Y1 groups, CH2-aryl wherein the aryl group is substituted by one or more Y1 groups, OCOC1-8 alkyl, COC1-8 alkyl, CONH2, NHCHO, NH2, NHSO2C1-8 alkyl, or NHCO2C1-8 alkyl;
Y3 is hydrogen, Br, Cl, F, 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,
wherein at least one of R1, R2, R3 and R4 is other than hydrogen;
each Y1 is, independently, hydrogen, OH, Br, Cl, F, CN, CF3, NO2, N3, OR8, CO2R9, C1-6 alkyl, NR10R11, NHCOR12, NHCO2R12, or CONR13R14, 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, R12R13 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
wherein n is 3,
wherein n is 0, 1, 2 or 3,
wherein n is 2 or 3,
wherein n is 1, 2 or 3,
wherein n is 0, 1, 2 or 3,
—CH2CH2—X—R6, or
R6 is C2-8 alkenyl, C1-4 alkyl substituted C4-8 cycloalkyl, C1-4alkyl 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;
R17is hydrogen, C1-8 alkyl, CO2C1-8 alkylaryl substituted by one or more Y1 groups, CH2-aryl substituted by one or more Y1 groups, 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 Y1 groups;
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, CH2OR30, or CH2-aryl substituted by one or more Y1 substituents;
each R21 is, independently, hydrogen, C1-8 alkyl, CH2-aryl substituted by one or more Y1 substituents, 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 Y1 substituents;
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 or S, wherein when Z is 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 X2together form ═O, ═S, or ═NH;
or a pharmaceutically acceptable salt thereof.

### Claim 26 (depends on 25)

The method of claim 25, wherein
R is OH, OC1-3 alkyl, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, aryl substituted by one or more Y1 groups, CH2-aryl wherein the aryl group is substituted by one or more Y1 groups, OCOC1-4 alkyl, COC1-4 alkyl, CONH2, NHCHO, NH2, NHSO2C1-4 alkyl, or NHCO2C 1-4 alkyl; and
Y3 is hydrogen, Br, Cl, F, CF3, NO2, OR8, CO2R9, C1-3 alkyl, NR10R11, NHCOR12, NHCO2R12, CONR13R14 or CH2(CH2)nY2.

### Claim 27 (depends on 25)

The method of claim 25, wherein
R is OH, OCH3, or OCF3; and
Y3 is hydrogen.

### Claim 28 (depends on 25)

The method of claim 25, wherein
R1, R2, R3 and R4 are each, independently, hydrogen, methyl or ethyl; and
at least one of R1, R2, R3 and R4 is other than hydrogen.

### Claim 29 (depends on 25)

The method of claim 25, wherein
R1, R2, R3 and R4 are each, independently, hydrogen or methyl; and
at least one of R1, R2, R3 and R4 is methyl.

### Claim 30 (depends on 25)

The method of claim 25, wherein
R is OH, OCH3, or OCF3;
Y3 is hydrogen;
Rl, R2, R3 and R4 are each, independently, hydrogen, methyl or ethyl, wherein at least one of R1, R2, R3 and R4 is other than hydrogen; and
R5 is —(CH2)n-phenyl, wherein n is 3.

### Claim 31 (depends on 25)

The method of claim 25, wherein R5 is

### Claim 32 (depends on 25)

The method of claim 25, wherein the opioid receptor antagonist is represented by the formula:
or a pharmaceutically acceptable salt thereof.