# US 2013/0158029 A1 · Sigma receptor inhibitors

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- Number: US 2013/0158029 A1
- Document ID: US20130158029A1
- Status: Published application
- Kind: A1
- Application number: 13/699,341
- Filed: 2011-05-26
- Published: 2013-06-20
- Earliest claimed: 2010-05-27
- Assignees: Laboratorios Del Dr. Esteve, S.A.
- Inventors: Monica Garcia López; Antoni Torrens Jover; José Luis Diaz Fernández; Ana Maria Caamaño Moure
- Web page: https://patentgrep.com/patent/US20130158029A1

## CPC

- C07D 231/12: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/10: Laxatives
- A61P 1/12: Antidiarrhoeals
- 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 9/06: Antiarrhythmics
- 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 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 25/06: Antimigraine agents
- A61P 25/08: Antiepileptics; Anticonvulsants
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/22: Anxiolytics
- A61P 25/24: Antidepressants
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 25/30: for treating abuse or dependence
- A61P 25/32: Alcohol-abuse
- A61P 25/34: Tobacco-abuse
- A61P 25/36: Opioid-abuse
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 231/14: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The invention refers to compounds of general formula (I) having pharmacological activity towards the sigma receptor, to processes of preparation of such compounds, to pharmaceutical compositions comprising them, and to their use for the treatment and or prophylaxis of a disease in which the sigma receptor is involved.

## Claims

### Claim 1

A compound of general formula (I):
wherein
R1 represents substituted or unsubstituted, aromatic or non-aromatic heterocyclyl; substituted or unsubstituted aryl; or substituted or unsubstituted cycloalkyl;
R2 and R3, identical or different, represent a hydrogen atom; F; Cl; Br; I; CF3; OH; SH; NH2; CN; substituted or unsubstituted alkyl; substituted or unsubstituted alkenyl; substituted or unsubstituted alkoxy; substituted or unsubstituted cycloalkyl; substituted or unsubstituted aryl; substituted or unsubstituted, aromatic or non-aromatic heterocyclyl; substituted or unsubstituted cycloalkylalkyl; substituted or unsubstituted arylalkyl; substituted or unsubstituted, aromatic or non-aromatic heterocyclylalkyl; a (C═O)—R7 group; a (C═O)—O—R8 group; a S(O)t—R9 group; or a (C═)—NR10R11 group;
R4 and R5, identical or different, represent a hydrogen atom; substituted or unsubstituted alkyl; substituted or unsubstituted alkenyl; substituted or unsubstituted alkoxy; substituted or unsubstituted cycloalkyl; substituted or unsubstituted aryl; substituted or unsubstituted, aromatic or non-aromatic heterocyclyl; substituted or unsubstituted cycloalkylalkyl; substituted or unsubstituted arylalkyl; substituted or unsubstituted, aromatic or non-aromatic heterocyclylalkyl; a (C═O)—R7 group; a (C═O)—O—R8 group; a S(O)t—R9 group; or a (C═O)—NR10R11 group;
or
together form, with the nitrogen atom to which they are attached, a substituted or unsubstituted, aromatic or non-aromatic heterocyclyl group;
X represents an oxygen atom or a CH—R12 group wherein R12 is selected from H, CH3, SH, OH, NH2, CF3, Cl, F, Br, I, and CN;
m is 1, 2, 3 or 4;
n is 1, 2, 3 or 4;
t is 1, 2 or 3; and
R7, R8, R9, R10 and R11, identical or different, represent a hydrogen atom; substituted or unsubstituted C1-6 alkyl; substituted or unsubstituted C2-6 alkenyl; substituted or unsubstituted C1-6 alkoxy; substituted or unsubstituted cycloalkyl; substituted or unsubstituted aryl; substituted or unsubstituted, aromatic or non-aromatic heterocyclyl; substituted or unsubstituted cycloalkylalkyl; substituted or unsubstituted arylalkyl; substituted or unsubstituted, aromatic or non-aromatic heterocyclylalkyl;
or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein R1 is 5- to 10 membered substituted or unsubstituted, aromatic or non-aromatic heterocyclyl group which preferably contains N, O or S as ring member; a 5 to 10 membered substituted or unsubstituted aryl group; or a 5 to 10 membered substituted or unsubstituted cycloalkyl group.

### Claim 3 (depends on 2)

The compound according to claim 2, wherein R1 is substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphtyl, substituted or unsubstituted thiophene, substituted or unsubstituted benzothiophene, substituted or unsubstituted benzofuran, substituted or unsubstituted pyridine or substituted or unsubstituted quinoline.

### Claim 4 (depends on 3)

The compound according to claim 3, wherein R1 is selected from the group consisting of: 2-thienyl, 3-thienyl, 2,5-dichloro-3-thienyl, 2,3-dichloro-5-thienyl, 2,3-dichloro-4-thienyl, 2-benzothienyl, 3-benzothienyl, 4-benzothienyl, 5-benzothienyl, 7-benzothienyl, 2-benzofuryl, 5-benzofuryl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 5-quinolyl, 6-quinolyl, 3,4-difluorophenyl, 3,4-dichlorophenyl, cyclopentyl, cyclohexyl, 7-hydroxy-2-naphtyl, 6-hydroxy-2-naphtyl, 5-hydroxy-2-naphtyl, 6-fluoro-2-naphtyl, 6-methoxy-2-naphtyl, 6-bromo-2-naphtyl, 6-hydroxymethyl-2-naphtyl, 6-fluoromethyl-2-naphtyl, 7-hydroxy-1-naphtyl, 6-hydroxy-1-naphtyl, 5-hydroxy-1-naphtyl, 5-fluoro-1-naphtyl, 5-bromo-1-naphtyl and 1-naphtyl.

### Claim 5 (depends on 1)

The compound according to claim 1, wherein R2 and R3 is independently H or substituted or unsubstituted C1-6 alkyl group.

### Claim 6 (depends on 5)

The compound according to claim 5, wherein R2 is methyl and R3 is H, or R2 and R3 are simultaneously H or methyl.

### Claim 7 (depends on 1)

The compound according to claim 1, wherein R4 and R5 form together with the nitrogen atom to which they are attached a substituted or unsubstituted heterocyclyl group.

### Claim 8 (depends on 7)

The compound according to claim 7, wherein R4 and R5 form together a morpholine-4-yl group, a piperidine group, pyrrolidine group or a piperazine-4-yl group.

### Claim 9 (depends on 1)

The compound according to claim 1, wherein each m and n independently represent 1 or 2.

### Claim 10 (depends on 1)

The compound according to claim 1 selected from the group consisting of:
4-(2-((1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazol-3-yl)methoxy)ethyl)morpholine,
4-(2-((5-methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yl)methoxy)ethyl)morpholine,
4-(3-(1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazol-3-yl)propyl)morpholine,
4-(3-(5-methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yl)propyl)morpholine,
4-(2-(2-(1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazol-3-yl)ethoxy)ethyl)morpholine,
4-(2-((1-cyclohexyl-5-methyl-1H-pyrazol-3-yl)methoxy)ethyl)morpholine,
4-(3-(1-cyclohexyl-5-methyl-1H-pyrazol-3-yl)propyl)morpholine,
1-(3,4-dichlorophenyl)-5-methyl-3-((2-(pyrrolidin-1-yl)ethoxy)methyl)-1H-pyrazole,
1-(2-((1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazol-3-yl)methoxy)ethyl)piperidine,
1-(4-(2-((1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazol-3-yl)methoxy)ethyl)piperazin-1-yl)ethanone,
(2S,6R)-4-(2-((1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazol-3-yl)methoxy)ethyl)-2,6-dimethylmorpholine,
4-(2-((5-methyl-1-(quinolin-3-yl)-1H-pyrazol-3-yl)methoxy)ethyl)morpholine,
4-(4-(1-(3,4-dichlorophenyl)-5-methyl H-pyrazol-3-yl)butyl)morpholine,
4-(3-(5-methyl-1-(quinolin-3-yl)-1H-pyrazol-3-yl)propyl)morpholine,
4-(2-((1-(3,4-dichlorophenyl)-1H-pyrazol-3-yl)methoxy)ethyl)morpholine,
4-(2-((1-(3,4-dichlorophenyl)-4,5-dimethyl-1H-pyrazol-3-yl)methoxy)ethyl)morpholine,
4-(3-(1-(quinolin-3-yl)-1H-pyrazol-3-yl)propyl)morpholine,
4-(4-(1-(3,4-dichlorophenyl)-1H-pyrazol-3-yl)butyl)morpholine,
4-(4-(5-methyl-1-(quinolin-3-yl)-1H-pyrazol-3-yl)butyl)morpholine,
4-(3-((1-cyclohexyl-5-methyl-1H-pyrazol-3-yl)methoxy)propyl)morpholine,
4-(2-((1-cyclopentyl-5-methyl-1H-pyrazol-3-yl)methoxy)ethyl)morpholine,
1-(4-(2-((1-cyclohexyl-5-methyl-1H-pyrazol-3-yl)methoxy)ethyl)piperazin-1-yl)ethanone hydrochloride,
(3S,5R)-1-(2-((1-cyclohexyl-5-methyl-1H-pyrazol-3-yl)methoxy)ethyl)-3,5-dimethylpiperazine hydrochloride,
4-(2-(2-(1-cyclohexyl-5-methyl-1H-pyrazol-3-yl)ethoxy)ethyl)morpholine hydrochloride,
4-(2-((1-cyclohexyl-1H-pyrazol-3-yl)methoxy)ethyl)morpholine hydrochloride,
4-(2-((1-cyclohexyl-4,5-dimethyl-1H-pyrazol-3-yl)methoxy)ethyl)morpholine hydrochloride,
1-(4-(2-((1-cyclohexyl-1H-pyrazol-3-yl)methoxy)ethyl)piperazin-1-yl)ethanone,
1-(4-(3-((1-cyclohexyl-1H-pyrazol-3-yl)methoxy)propyl) piperazin-1-yl)ethanone,
1-(4-(4-((1-cyclohexyl-1H-pyrazol-3-yl)methoxy)butyl)piperazin-1-yl)ethanone,
1-(4-(4-((1-cyclohexyl-5-methyl-1H-pyrazol-3-yl)methoxy)butyl)piperazin-1-yl)ethanone,
1-(4-(3-((1-cyclohexyl-5-methyl-1H-pyrazol-3-yl)methoxy)propyl)piperazin-1-yl)ethanone,
1-(4-(2-((1-(3,4-dichlorophenyl)-1H-pyrazol-3-yl)methoxy)ethyl)piperazin-1-yl)ethanone
1-(4-(3-((1-(3,4-dichlorophenyl)-1H-pyrazol-3-yl)methoxy)propyl)piperazin-1-yl)ethanone,
1-(4-(4-((1-(3,4-dichlorophenyl)-1H-pyrazol-3-yl)methoxy)butyl)piperazin-1-yl) ethanone,
1-(4-(3-((1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazol-3-yl)methoxy)propyl)piperazin-1-yl)ethanone,
1-(4-(3-((1-(3,4-difluorophenyl)-1H-pyrazol-3-yl)methoxy)propyl) piperazin-1-yl)ethanone,
1-(4-(3-((1-(3,4-difluorophenyl)-5-methyl-1H-pyrazol-3-yl)methoxy)propyl)piperazin-1-yl)ethanone,
1-(4-(2-((1-(3,4-difluorophenyl)-5-methyl-1H-pyrazol-3-yl)methoxy)ethyl)piperazin-1-yl)ethanone,
1-(4-(2-((1-(3,4-difluorophenyl)-1H-pyrazol-3-yl)methoxy)ethyl)piperazin-1-yl)ethanone,
4-(2-((1-(3,4-difluorophenyl)-5-methyl-1H-pyrazol-3-yl)methoxy)ethyl)morpholine,
4-(2-((1-(3,4-difluorophenyl)-1H-pyrazol-3-yl)methoxy) ethyl)morpholine,
4-(3-((1-(3,4-difluorophenyl)-5-methyl-1H-pyrazol-3-yl)methoxy)propyl)morpholine,
1-(4-(2-((1-cyclohexyl-5-methyl-1H-pyrazol-3-yl)methoxy)ethyl)piperazin-1-yl)propan-1-one,
1-(4-(2-((1-cyclohexyl-5-methyl-1H-pyrazol-3-yl)methoxy)ethyl)piperazin-1-yl)-2-methylpropan-1-one,
1-(4-(2-((1-cyclohexyl-1H-pyrazol-3-yl)methoxy)ethyl)piperazin-1-yl)propan-1-one,
1-(4-(2-((1-cyclohexyl-1H-pyrazol-3-yl)methoxy)ethyl)piperazin-1-yl)-2-methylpropan-1-one,
1-(4-(2-((1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazol-3-yl)methoxy)ethyl)piperazin-1-yl)propan-1-one,
1-(4-(2-((1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazol-3-yl)methoxy)ethyl)piperazin-1-yl)-2-methylpropan-1-one,
1-(4-(2-((1-(3,4-dichlorophenyl)-1H-pyrazol-3-yl)methoxy)ethyl)piperazin-1-yl)propan-1-one, and
1-(4-(2-((1-(3,4-dichlorophenyl)-1H-pyrazol-3-yl) methoxy)ethyl)piperazin-1-yl)-2-methylpropan-1-one,
or a pharmaceutically acceptable salt, prodrug or solvate thereof.

### Claim 11 (depends on 1)

A process for the preparation of a compound of formula (I) as defined in claim 1, or a salt, isomer or solvate thereof, which is:
a) a process which comprises the reaction of a compound of formula (II)
with a compound of formula (III)
in which LG represents a leaving group;
b) a process which comprises the oxidation of a compound of formula (II) to afford a compound of formula (VII)
followed by the reaction of the compound of formula (VII) with a phosphonium salt of formula (VIII)
to afford a compound of formula (IX)
and reduction of the compound of formula (IX);
c) a process which comprises the oxidation of a compound of formula (II) to afford a compound of formula (VII)
followed by the reaction of the compound of formula (VII) with a suitable phosphonium salt and subsequent acid hydrolysis to afford a compound of formula (XI)
reduction of the compound of formula (XI) and subsequent reaction with a compound of formula (III)
in which LG represents a leaving group;
d) a process which comprises reaction of 3-acetyl-6-methyl-pyran-2,4-dione with magnesium and subsequent reaction with a compound of formula (V):
to afford a compound of formula (XV)
and reduction of the compound of formula (XV) and subsequent reaction with a compound of formula (III)
in which LG represents a leaving group;
e) a process which comprises the oxidation of a compound of formula (II) to afford a compound of formula (VII)
followed by the reaction of the compound of formula (VII) with a phosphonium salt of formula (XVII)
to afford a compound of formula (XVII)
and reduction of the compound of formula (XVIII).

### Claim 12 (depends on 1)

A medicament comprising at least one compound of formula (I) as defined in any of claim 1, or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof and a pharmaceutically acceptable excipient.

### Claim 13 (depends on 1)

A method for the manufacture of a medicament comprising combining the compound as defined in claim 1 with a pharmaceutically acceptable excipient.

### Claim 14 (depends on 1)

A method for the treatment and/or prophylaxis of a sigma receptor-mediated disease or condition, comprising administering to a patient a therapeutically amount of the compound as defined in claim 1.

### Claim 15 (depends on 14)

The method according to claim 14, wherein the disease comprises diarrhea; lipoprotein disorders; migraine; obesity; elevated triglyceride levels; chylomicronemia; dysbetalipoproteinemia; hyperlipoproteinemia; hyperlipidemia; mixed hyperlipidemia; hypercholesterolemia; hypertriglyceridemia; sporadic hypertriglyceridemia; inherited hypertriglyceridemia; dysbetalipoproteinemia; arthritis; hypertension; arrhythmia; ulcer; learning, memory and attention deficits; cognition disorders; neurodegenerative diseases; demyelinating diseases; addiction to drugs and chemical substances including cocaine, amphetamine, ethanol and nicotine; tardive dyskinesia; ischemic stroke; epilepsy; stroke; stress; cancer; psychotic conditions; inflammation; or autoimmune diseases.

### Claim 16 (depends on 14)

The method according to claim 14, wherein the disease is pain.

### Claim 17 (depends on 1)

Compound of general formula (I) as defined in claim 1 for use as a pharmacological tool.

### Claim 18 (depends on 14)

The method according to claim 14, wherein the disease is depression, anxiety or schizophrenia.

### Claim 19 (depends on 16)

The method according to claim 16, wherein the pain is neuropathic pain, inflammatory pain or other pain conditions involving allodynia and/or hyperalgesia.

### Claim 20 (depends on 5)

The compound according to claim 5, wherein R2 and R3 are independently H or methyl.