# US 7,612,056 B2 · Substituted diaza-spiro-[4.5]-decane derivatives and their use as neurokinin antagonists

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- Number: US 7,612,056 B2
- Document ID: US7612056B2
- Status: Granted
- Kind: B2
- Application number: 11/547,705
- Filed: 2005-04-04
- Published: 2007-11-01
- Granted: 2009-11-03
- Earliest claimed: 2005-04-04
- Assignees: Jenssen Pharmaceutica N.V.
- Inventors: Frans Eduard Janssens; Bruno Schoentjes; Sophie Coupa; Alain Philippe Poncelet; Yvan René Ferdinand Simonnet
- Web page: https://patentgrep.com/patent/US7612056B2

## CPC

- C07D 471/10: Spiro-condensed systems
- A61P 1/02: Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/06: Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
- A61P 1/08: for nausea, cinetosis or vertigo; Antiemetics
- A61P 1/12: Antidiarrhoeals
- A61P 1/14: Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- 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 11/00: Drugs for disorders of the respiratory system
- A61P 11/02: Nasal agents, e.g. decongestants
- A61P 11/06: Antiasthmatics
- A61P 11/14: Antitussive agents
- A61P 13/00: Drugs for disorders of the urinary system
- A61P 13/02: of urine or of the urinary tract, e.g. urine acidifiers
- A61P 13/10: of the bladder
- A61P 15/06: Antiabortive agents; Labour repressants
- A61P 15/10: for impotence
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 17/04: Antipruritics
- A61P 17/06: Antipsoriatics
- A61P 19/04: for non-specific disorders of the connective tissue
- A61P 19/06: Antigout agents, e.g. antihyperuricemic or uricosuric agents
- 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 25/16: Anti-Parkinson drugs
- 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 25/28: 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 37/00: Drugs for immunological or allergic disorders
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

This invention concerns substituted diaza-spiro-[4.5]-decane derivatives having neurokinin antagonistic activity, in particular NK1 antagonistic activity, a combined NK1/NK2 antagonistic activity, a combined NK1/NK3 antagonistic activity and a combined NK1/NK2/NK3 antagonistic activity, their preparation, compositions comprising them and their use as a medicine, in particular for the treatment and/or prophylaxis of schizophrenia, emesis, anxiety and depression, irritable bowel syndrome (IBS), circadian rhythm disturbances, pre-eclampsia, nociception, pain, in particular visceral and neuropathic pain, pancreatitis, neurogenic inflammation, asthma, chronic obstructive pulmonary disease (COPD) and micturition disorders such as urinary incontinence. The compounds according to the invention can be represented by general Formula (I) and comprises also the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the N-oxide form thereof and prodrugs thereof, wherein all substituents are defined as in Claim 1.

## Claims

### Claim 1

A compound according to the general Formula (I) wherein:
R2 is Ar2;
X is a covalent bond;
Q is O;
R1 is Ar1-alkyl;
n is an integer, equal to 1;
m is an integer, equal to 1;
Z is a covalent bond;
j, k, p, q are integers, independently from each other, equal to 1 or 2; provided that (j+k) and (p+q) are each equal to 3 or 4 and provided that when (j+k) is equal to 3, then (p+q) is equal to 4; or when (j+k) is equal to 4 then (p+q) is equal to 3;
t=0 or 2; and if t=2, each T is taken together to form a radical of formula ═CH—CH ═CH—CH═;
each Alk represents, independently from each other, a covalent bond; a bivalent straight saturated hydrocarbon radical having from 1 to 6 carbon atoms;
Y is a bivalent radical of formula —C(═O)—, —SO2—;
L is alkyl, alkyloxy, Ar3 and Het2;
Ar1 is phenyl;
Ar2 is phenyl substituted with 2 alkyl radicals;
Ar3 is phenyl, optionally substituted with 1 substituent that is alkyl and halo;
Het2 is a monocyclic heterocyclic radical that is tetrahydrofuranyl, furanyl or thienyl;
alkyl is a straight saturated hydrocarbon radical having from 1 to 6 carbon atoms or a cyclic saturated hydrocarbon radicals having from 3 to 6 carbon atoms; each hydrocarbon radical optionally substituted on one or more carbon atoms with at least one radical that is halo.

### Claim 2 (depends on 1)

The compound according to claim 1 wherein the spiro-moiety has the Formula (f11), and “a” denotes the piperidinyl-moiety of Formula (I) and “b” denotes the Alk-Y-Alk-L-moiety of Formula (I):

### Claim 3 (depends on 1)

The compound according to claim 1 wherein R1 is Ar1methyl and attached to the 2-position or R1 is Ar1 and attached to the 3-position.

### Claim 4 (depends on 1)

The compound according to claim 1 wherein the R2—X—C(═Q)-moiety is 3,5-di-(trifluoromethyl)phenylcarbonyl.

### Claim 5 (depends on 1)

The compound according to claim 1 wherein Y is —C(═O)—.

### Claim 6 (depends on 1)

The compound according to claim 1 wherein Alk is a covalent bond or —CH2—.

### Claim 7 (depends on 1)

The compound according to claim 1 wherein L cyclopropyl, phenyl, tetrahydrofuryl, furanyl or thienyl.

### Claim 8

A compound that is

### Claim 9 (depends on 1)

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a compound according to claim 1.

### Claim 10 (depends on 1)

A process for preparing a pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a compound according to claim 1, comprising intimately mixing a pharmaceutically acceptable carrier with a compound of claim 1.

### Claim 11

A process for preparing a compound according to Formula (I):
the pharmaceutically acceptable acid or base addition salts thereof, the stereochemic ally isomeric forms thereof, or the N-oxide forms thereof wherein:
R2 is Ar2;
X is a covalent bond;
Q is O;
R1 is Ar1-alkyl;
n is an integer, equal to 1 ;
m is an integer, equal to 1 ;
Z is a covalent bond;
j, k, p, q are integers, independently from each other, equal to 0, 1, 2, 3 or 4; provided that (j+k) and (p+q) are each equal to 3 or 4 and provided that when (j+k) is equal to 3, then (p+q) is equal to 4; or when (j+k) is equal to 4 then (p+q) is equal to 3;
t=0 or 2; and if t=2, each T is taken together to form a radical of formula ═CH—CH═CH—CH═;
each Alk represents, independently from each other, a covalent bond; a bivalent straight saturated hydrocarbon radical having from 1 to 6 carbon atoms;
Y is a bivalent radical of formula —C(═O)— or —SO2—;
L is alkyl, alkyloxy, Ar3, or Het2;
Ar1 is phenyl;
Ar2 is phenyl substituted with 2 alkyl substituents;
Ar3 is phenyl, optionally substituted with 1 substituent that is alkyl or halo;
Het2 is a monocyclic heterocyclic radical that is tetrahydrofuranyl; furanyl, or thienyl; and
alkyl is a straight saturated hydrocarbon radical having from 1 to 6 carbon atoms or a cyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms; each hydrocarbon radical optionally substituted on one or more carbon atoms with at least one halo;
comprising
a) reductively N-alkylating an intermediate compound of Formula (II) with an intermediate compound of Formula (III) to obtain a final compound according to Formula (Ia), in a reaction-inert solvent and optionally in the presence of a reducing agent;
or b) reductively N-alkylating an intermediate compound of Formula (IV) with an intermediate compound of Formula (III) to obtain a final compound according to Formula (Ib), in a reaction-inert solvent and optionally in the presence of a reducing agent;
or c) reacting an intermediate compound of Formula (III) with a carboxylic acid compound of Formula (V) to obtain a final compound according to Formula (Ic), in a reaction-inert solvent and optionally in the presence of a base;
and (d) optionally, converting compounds of Formula (I), into each other following transformation, and optionally, converting the compounds of Formula (I), into a therapeutically active non-toxic acid addition salt by treatment with an acid, or into a therapeutically active non-toxic base addition salt by treatment with a base, or conversely, converting the acid addition salt form into the free base by treatment with alkali, or converting the base addition salt into the free acid by treatment with acid; and, optionally, preparing stereochemically isomeric forms or N-oxide forms thereof.

### Claim 12 (depends on 11)

The process according to claim 11, wherein the Alk-Y-Alk-L-moiety in the compounds of Formulas (III), (Ia), (Ib) and (Ic) is benzyl.