# US 7,410,970 B2 · Substituted 1,4,-di-piperidin-4-yl-piperazine derivatives and their use as neurokinin antagonists

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- Number: US 7,410,970 B2
- Document ID: US7410970B2
- Status: Granted
- Kind: B2
- Application number: 10/527,821
- Filed: 2003-10-07
- Published: 2006-07-27
- Granted: 2008-08-12
- Earliest claimed: 2002-10-08
- Assignees: Janssen Pharmaceutica NV
- Inventors: Frans Eduard Janssens; François Maria Sommen; Benoît Christian Albert Ghislain De Boeck; Joseph Elisabeth Leenaerts; Yves Emiel Maria Van Roosbroeck; Gaston Stanislas Marcella Diels
- Web page: https://patentgrep.com/patent/US7410970B2

## CPC

- C07D 401/14: containing three or more hetero rings
- 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 1/14: Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- A61P 3/02: Nutrients, e.g. vitamins, minerals
- A61P 3/04: Anorexiants; Antiobesity agents
- 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 13/10: of the bladder
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- 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 17/16: Emollients or protectives, e.g. against radiation
- 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 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- 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 27/02: Ophthalmic agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/16: for influenza or rhinoviruses
- A61P 31/18: for HIV
- A61P 31/22: for herpes viruses
- A61P 35/00: Antineoplastic agents
- A61P 37/04: Immunostimulants
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61P 39/00: General protective or antinoxious agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 211/58: attached in position 4
- C07D 405/14: containing three or more hetero rings
- C07D 409/14: containing three or more hetero rings
- C07D 413/14: containing three or more hetero rings
- C07D 417/14: containing three or more hetero rings
- C07D 471/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The invention concerns substituted 1,4-di-piperidin-4-yl-piperazine derivatives having neurokinin antagonistic activity, in particular NK1 antagonistic activity, their preparation, compositions comprising them and their use as a medicine, in particular for the treatment of emesis, anxiety, depression, pain, pancreatitis and IBS.

## Claims

### Claim 1

A compound according to the general Formula (I)
the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, wherein:
n is an integer equal to 1;
m is an integer equal to 1;
p is an integer equal to 1;
Q is O or NR3;
X is a covalent bond or a radical of formula —O—, —S— or —NR3—;
each R3 independently from each other, is hydrogen or alkyl;
each R1 independently from each other, is selected from the group consisting of Ar1, Ar1-alkyl and di(Ar1)-alkyl;
q is an integer equal to 0 or 1;
R2 is selected from the group consisting of alkyl, Ar2, Ar2-alkyl, Het1 or Het1-alkyl;
Y is a covalent bond or a bivalent radical of formula —C(═O)— or —SO2—;
each Alk represents, independently from each other, a covalent bond; a bivalent straight or branched, saturated or unsaturated hydrocarbon radical having from 1 to 6 carbon atoms; or a cyclic saturated or unsaturated hydrocarbon radical having from 3 to 6 carbon atoms; each radical optionally substituted on one or more carbon atoms with one or more alkyl, phenyl, halo, cyano, hydroxy, formyl and amino radicals;
L is selected from the group of hydrogen, alkyloxy, Ar3-oxy, alkyloxycarbonyl, mono- and di(alkyl)amino, mono- and di(Ar3)amino, mono- and di(alkyloxycarbonyl)amino, Ar3, Ar3-carbonyl, Het2 and Het2-carbonyl;
Ar1 is phenyl, optionally substituted with 1, 2 or 3 substituents each independently from each other selected from the group consisting of halo, alkyl, cyano, aminocarbonyl and alkyloxy;
Ar2 is naphthalenyl or phenyl, each optionally substituted with 1, 2 or 3 substituents, each independently from each other, selected from the group consisting of halo, nitro, amino, mono- and di(alkyl)amino, cyano, alkyl, hydroxy, alkyloxy, carboxyl, alkyloxycarbonyl, aminocarbonyl and mono- and di(alkyl)aminocarbonyl;
Ar3 is naphthalenyl or phenyl, optionally substituted with 1, 2 or 3 substituents each independently from each other selected from the group consisting of alkyloxy, alkyl, halo, hydroxy, pyridinyl, morpholinyl, pyrrolidinyl, imidazo[1,2-α]pyridinyl, morpholinylcarbonyl, pyrrolidinylcarbonyl, amino and cyano;
Het1 is a monocyclic heterocyclic radical selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl; or a bicyclic heterocyclic radical selected from the group of quinolinyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl and benzothienyl; each heterocyclic radical may optionally be substituted on any atom by a radical selected from the group consisting of halo and alkyl;
Het2 is a monocyclic heterocyclic radical selected from the group consisting of pyrrolidinyl, dioxolyl, imidazolidinyl, pyrrazolidinyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, imidazolidinyl, tetrahydrofuranyl, 2H-pyrrolyl, pyrrolinyl, imidazolinyl, pyrrazolinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl and triazinyl; or a bicyclic heterocyclic radical selected from the group consisting of benzopiperidinyl, quinolinyl, quinoxalinyl, indolyl, isoindolyl, chromenyl, benzimidazolyl, imidazo[1,2-α]pyridinyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl and benzothienyl; each radical optionally substituted with one or more radicals selected from the group consisting of Ar1, Ar1alkyl, halo, hydroxy, alkyl, piperidinyl, pyrrolyl, thienyl, oxo, alkyloxy, alkyloxyalkyl and alkyloxycarbonyl; and
alkyl is a straight or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms or a cyclic saturated hydrocarbon radicals having from 3 to 6 carbon atoms; optionally substituted on one or more carbon atoms with one or more radicals selected from the group consisting of phenyl, halo, cyano, oxo, hydroxy, formyl and amino radicals.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein the compound of Formula I is {4-[4-(1-benzoylpiperidin-4-yl)-piperazin- 1-yl]-2-benzyl-piperidin-1-yl }-(3,5-bistrifluoromethylphenyl)methanone:

### Claim 3 (depends on 1)

The compound according to claim 1, characterized wherein
Q is O;
X is a covalent bond;
each R1 is Ar1 or Ar1-alkyl;
q is 0 or 1;
R2 is Ar2;
Y is a covalent bond or a bivalent radical of formula —C(═O)— or —SO2—;
each Alk represents, independently from each other, a covalent bond; a bivalent straight or branched, saturated or unsaturated hydrocarbon radical having from 1 to 6 carbon atoms; or a cyclic saturated or unsaturated hydrocarbon radical having from 3 to 6 carbon atoms; each radical optionally substituted on one or more carbon atoms with one or more phenyl, halo, cyano, hydroxy, formyl and amino radicals;
L is selected from the group of hydrogen, alkyloxy, Ar3-oxy, alkyloxy-carbonyl, mono- and di(alkyl)amino, mono-and di(Ar3)amino, Ar3 and Het2;
Ar1 is phenyl, optionally substituted with 1, 2 or 3 alkyl radicals;
Ar2 is phenyl, optionally substituted with 1, 2 or 3 alkyl radicals;
Ar3 is phenyl, optionally substituted with 1, 2 or 3 substituents each independently from each other selected from the group of alkyloxy, alkyl, halo, hydroxy, pyridinyl, morpholinyl, pyrrolidinyl, imidazo[1,2-α]pyridinyl, morpholinylcarbonyl, pyrrolidinylcarbonyl, amino and cyano;
Het2 is a monocyclic heterocyclic radical selected from the group of pyrrolidinyl, piperidinyl, morpholinyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, isoxazolyl, thiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; or a bicyclic heterocyclic radical selected from the group of benzopiperidinyl, quinolinyl, quinoxalinyl, indolyl, chromenyl and benzimidazolyl; each radical optionally substituted with one or more radicals selected from the group of Ar1, Ar1alkyl, halo, hydroxy, alkyl, piperidinyl, pyrrolyl, thienyl, oxo and alkyloxycarbonyl; and
alkyl is a straight hydrocarbon radical having 1 to 6 carbon atoms, optionally substituted with one or more halo radicals.

### Claim 4 (depends on 1)

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

### Claim 5 (depends on 1)

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

### Claim 6 (depends on 1)

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

### Claim 7 (depends on 6)

The pharmaceutical composition according to claim 6, wherein the pharmaceutical composition is an oral dosage form suitable to be orally administered.

### Claim 8 (depends on 1)

A process for the preparation of a composition as claimed in claim 1, wherein a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of a compound as claimed in claim 1.

### Claim 9 (depends on 1)

A process for the preparation of a compound of claim 1, wherein
a) a final compound of Formula (I) is obtained by reductive N-alkylation of an intermediate of Formula (II) wherein R1, R2, X, Q, m, n and p are defined as in claim 1, with an N-substituted piperdinone of Formula (III) wherein R1, Alk, Y, L and q are defined as in claim 1, in a reaction-inert solvent and in the presence of a reducing agent; or
b) a final compound of Formula (Ia) is obtained by acylation of a final compound of Formula (I′) wherein R1, R2, X, Q, m, n, p and q are defined as in claim 1, with an acyl compound of Formula (V) wherein Alk and L are defined as in claim 1 and W1 is a leaving group, in a reaction-inert solvent and in the presence of a base; or
c) a final compound of Formula (Ia) is obtained by a base-catalyzed nucleophilic addition reaction of a final compound of Formula (I′) wherein R1, R2, X, Q, m, n, p and q are defined as in claim 1, with a carboxylic acid of Formula (VI) wherein Alk and L are defined as in claim 1, or its ester, in a reaction-inert solvent and in the presence of a base; or
d) a final compound of Formula (Ib) is obtained by a base-catalyzed nucleophilic addition reaction of a final compound of Formula (I′) wherein R1, R2, X, Q, m, n, p and q are defined as in claim 1, with a compound of Formula (VII) wherein Alk and L are defined as in claim 1 and W2 is a leaving group, in a reaction-inert solvent and in the presence of a base; or
e) a final compound of Formula (Ic) is obtained by reductive amination/alkylation of a final compound of Formula (I′) wherein R1, R2, X, Q, m, n, p and q are defined as in claim 1 with a compound of Formula (VIII) wherein Alk and L are defined as in claim 1 and W3 is a leaving group, in a reaction-inert solvent and in the presence of a base; and
f) optionally converting a compound of claim 1 into an acid addition salt by treatment with an acid, or into a base addition salt by treatment with a base, or conversely, converting an acid addition salt form into the free base by treatment with alkali, or converting a base addition salt into the free acid by treatment with an acid; or preparing the N-oxide and/or steroechemically isomeric forms thereof.

### Claim 10 (depends on 1)

A process for the preparation of a compound of Formula (XIII), wherein a compound of Formula (XI), wherein A is an aryl or heteroaryl, Z is Z1 as defined below wherein each variable is defined as in claim 1, Hal is an halogen and r is an integer ranging from 1 to a number equal to the number of available carbon atoms in the aryl or heteroaryl-moiety A, is reacted with an unsaturated heteroaryl Het of Formula (XII) in the presence of catalytic amounts of Pd(OAc)2 and 1,3-bis diphenylphosphinopropane, in the presence of a suitable base, preferably Cs2CO3 or K(AcO) and in a reaction-inert polar solvent.

### Claim 11 (depends on 10)

The process according to claim 10, wherein Hal is bromo or iodo, A is phenyl or pyridinyl, Z is Z1 and Het imidazo[1,2-α]pyridinyl, pyrrolyl or thienyl.

### Claim 12 (depends on 1)

A method of treating a warm-blooded animal suffering from emesis, depression, anxiety disorder, pain, pancreatitis, micturition disorder, or iffitable bowel syndrome comprising administering to said animal a therapeutically effect amount of a compound according to claim 1.

### Claim 13 (depends on 12)

The method of claim 12, wherein the micturition disorder is overactive bladder.

### Claim 14 (depends on 12)

The method of claim 12, wherein the animal suffers from emesis.

### Claim 15 (depends on 12)

The method of claim 12, wherein the animal suffers from depression.

### Claim 16 (depends on 12)

The method of claim 12, wherein the animal suffers from anxiety disorder.

### Claim 17 (depends on 12)

The method of claim 12, wherein the animal suffers from pain.

### Claim 18 (depends on 12)

The method of claim 12, wherein the animal suffers from pancreatitis.

### Claim 19 (depends on 12)

The method of claim 12, wherein the animal suffers from micturition disorder.

### Claim 20 (depends on 12)

The method of claim 12, wherein the animal suffers from irritable bowel syndrome.