4-aminopiperidine and their use as a medicine

• US 7,115,634 B2
• Filed: 12/13/2000
• Issued: 10/03/2006
• Est. Priority Date: 12/14/1999
• Status: Expired due to Term

• Current Assignee: Ipsen Pharma Sas (Ipsen Sa)
• Original Assignee: Societe de Conseils de Recherches et d'Applications Scientifiques
• Inventors: Moinet, Christophe, Gonzalez, Jérôme, Thurieau, Christophe
• Primary Examiner(s): Saeed, Kamal A.
• Application Number:
  US10/130,924
• Publication Number:
  US 20040006089A1
• Time in Patent Office: 2,120 Days
• Field of Search: 546/196, 546/197, 514/320
• US Class Current: 514/320
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 1/12 Antidiarrhoeals
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: 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
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 5/02 : of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
• CPC Class Codes: A61P 5/04 : for decreasing, blocking or antagonising the activity of the hypothalamic hormones
• CPC Class Codes: A61P 5/08 : for decreasing, blocking or antagonising the activity of the anterior pituitary hormones
• CPC Class Codes: A61P 5/16 : for decreasing, blocking or antagonising the activity of the thyroid hormones
• CPC Class Codes: A61P 5/46 : for decreasing, blocking or antagonising the activity of glucocorticosteroids
• CPC Class Codes: A61P 5/48 : of the pancreatic hormones
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 211/58 : attached in position 4
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 405/14 : containing three or more hetero rings
• CPC Class Codes: C07D 409/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings

Abstract

A subject of the present application is new derivatives of 4-aminopiperidines of formula
in which R₁, R₂ and R₃ represent various radical, and their preparation processes by synthetic methods in parallel in liquid and solid phase. These products having a good affinity with certain sub-types of somatostatin receptors, they are particularly useful for treating the pathological states or diseases in which one (or more) somatostatin receptors are involved.

Claims

1. A compound of the formula

in racemic, enantiomeric form or all combinations of these forms, wherein

R₁ is —

(CH₂)_m-Y-Z₁₁ or

—

(CH₂)_m-Z₁₂,

Z₁₁ is (C₁-C₆)alkyl or optionally substituted aryl,

Z₁₂ is bis-phenyl optionally substituted aryl or -optionally substituted heteroaryl,

R₂ is selected from the group consisting of —

C(Y)NHX₁, —

C(O)X₂ and SO₂X₃;

R₃ is selected from the group consisting of hydrogen, an optionally substituted alkyl, alkenyl and alkynyl,

X₁ is selected from the group consisting of (C₁-C₁₅)alkyl, alkenyl, alkynyl, —

(CH₂)_m-Y-Z₂₁ and —

(CH₂)_pZ₂₂,

Z₂₁ is (C₁-C₆)alkyl

Z₂₂ is selected from the group consisting of cyclohexenyl, indanyl, bis-phenyl, (C₃-C₇)cycloalkyl and (C₃-C₇)heterocycloalkyl, aryl and heteroaryl optionally substituted

X₂ is selected from the group consisting of alkenyl optionally substituted by phenyl optionally substituted, alkynyl, —

(CH₂)_m-W-(CH₂)_q-Z₂₃ and —

(CH₂)_p-U-Z₂₄ wherein

Z₂₃ is (C₁-C₆)alkyl or aryl optionally substituted;

Z₂₄ is selected from the group consisting of cyclohexenyl, bis-phenyl, (C₃-C₇)cycloalkyl optionally substituted, (C₃-C₇)heterocycloalkyl, cyano, amino, mono and di-alkylamino, aryl and heteroaryl optionally substituted,

X₃ is selected from the group consisting of (C₁-C₁₀)alkyl, alkenyl optionally substituted by phenyl optionally substituted, —

CF₃, and

—

(CH₂)_pZ₂₅,

Z₂₅ is aryl optionally substituted,

Y is oxygen or sulfur,

W is oxygen or sulfur or SO₂;

U is a covalent bond or oxygen;

n is an integer from 0 to 4;

m is an integer from 1 to 6;

p is an integer from 0 to 6;

q is an integer from 0 to 2,

and their addition salts with pharmaceutically acceptable acids.

2. A compound of claim 1 wherein

i) the substituents carried by aryl represented by Z₁₁ and Z₁₂ and heteroaryl represented by Z₁₂ are independently selected from the group consisting of fluoro, chloro, bromo, iodo, alkyl, alkoxy, alkylthio, —

CF₃, —

OCF₃, phenyl, phenoxy and aminosulfonyl;

iii) the substituents carried by aryl and heteroaryl represented by Z₂₂ are independently selected from the group consisting of fluoro, chloro, bromo, iodo, alkyl, alkenyl, alkoxy, alkylthio, —

CF₃, —

OCF₃, nitro, cyano, azido, aminosulfonyl, piperidinosulfonyl, mono- or di-alkylamino, —

C(O)—

O-alkyl, —

C(O)-alkyl, phenyl, phenoxy, phenylthio and benzyloxy, the phenyl optionally substituted;

iv) the substituents carried by aryl represented by Z₂₃ and Z₂₄, cycloalkyl and heteroaryl represented by Z₂₄ are selected independently from the group consisting of fluoro, chloro, bromo, iodo, alkyl, alkoxy, alkylthio, —

CF₃, —

OCF₃, —

OCHF₂, —

SCF₃, nitro, cyano, azido, hydroxy, —

C(O)O-alkyl, —

O—

C(O)-alkyl, —

NH—

C(O)-alkyl, alkylsulfonyl, mono- or di-alkylamino, amino, aminoalkyl, pyrrolyl, pyrrolidinyl, phenyl, phenoxy, phenylthio, benzyl and benzyloxy, the aryl is optionally substituted by at least one member selected from the group consisting of alkyl, CF₃ and halo;

v) the substituents carried by aryl and heteroaryl represented by Z₂₅ are independently selected from the group consisting of fluoro, chloro, bromo, iodo, alkyl, alkoxy, —

CF₃, —

OCF₃, nitro, cyano, —

NH—

C(O)-alkyl, alkylsulfonyl, amino, mono- and di-alkylamino, phenyl and pyridino;

vi) the substituents carried by alkyl represented by R₃ is cyano;

3. A compound of claim 1 wherein

R₁ is selected from the group consisting of —

(CH₂)_m-Y-Z₁₁ and —

(CH₂)_m-Z₁₂,

Z₁₁ is (C₁-C₆)alkyl,

Z₁₂ is selected from the group consisting of bis-phenyl, optionally substituted aryl and heteroaryl optionally substituted by at least one member selected from the group consisting of fluoro, chloro, bromo, iodo, alkyl and alkoxy,

Y is oxygen,

R₂ is selected from the group consisting of —

C(Y)NHX₁, —

C(O)X₂ and SO₂X₃ wherein

X₁ is (C₁-C₁₅)alkyl, or —

(CH₂)_pZ₂₂,

Z₂₂ is selected from the group consisting of cyclohexenyl, bis-phenyl, (C₃-C₇)cycloalkyl, and (C₃-C₇)heterocycloalkyl, aryl and heteroaryl-unsubstituted or substituted by at least one member selected from the group consisting of fluoro, chloro, bromo, iodo, alkyl, alkoxy, alkylthio, —

CF₃, OCF₃, nitro, cyano, azido, piperidinosulfonyl, —

C(O)—

O-alkyl, —

C(O)-alkyl, or phenyl,

X₂ is selected from the group consisting of alkynyl, —

(CH₂)_m-W-(CH₂)_q-U-Z₂₃ and —

(CH₂)_p-U-Z₂₄,

W is SO₂,

U is a covalent bond,

Z₂₃ is aryl;

Z₂₄ is selected from the group consisting of cyclohexenyl, bis-phenyl, (C₃-C₇)cycloalkyl optionally substituted by an aminoalkyl, aryl and heteroaryl unsubstituted or substituted by at least one member selected from the group consisting of fluoro, chloro, bromo, iodo, alkyl, alkoxy, —

CF₃, —

OCF₃, —

SCF₃, hydroxy, —

O—

C(O)-alkyl, mono- or di-alkylamino, amino

X₃ is —

(CH₂)_pZ₂₅, Z₂₅ is aryl optionally substituted by at least one member selected from the group consisting of alkoxy and —

CF₃,

R₃ is selected from the group consisting of hydrogen, alkyl, alkenyl.

4. A compound of claim 1 wherein R₁ is [(C₁-C₆)alkyl,] —

(CH₂)_m-Y-Z₁₁ and —

(CH₂)_m-Z₁₂,

Z₁₁ is (C₁-C₆)alkyl,

Z₁₂ is selected from the group consisting of morpholino, bis-phenyl, pyrrolidinyl substituted by oxy, phenyl, piperazinyl, pyridinyl and indolyl, all unsubstituted or substituted by at least one member selected from the group consisting of bromo, fluoro, chloro, alkyl, alkoxy, —

CF₃ and —

OCF₃;

Y is oxygen.

5. A compound of claim 1 wherein R₂ is selected from the group consisting of —

C(Y)NHX₁, —

C(O)X₂ and SO₂X₃

X₁ is (C₁-C₁₀)alkyl, or —

(CH₂)_pZ₂₂,

Z₂₂ is selected from the group consisting of cyclohexyl, cyclohexenyl and bis-phenyl, morpholino, piperidino, and phenyl, naphthyl and furyl unsubstituted or substituted by at least one member selected from the group consisting of fluoro, chloro, bromo, iodo, alkyl, alkoxy, alkylthio, —

CF₃, —

OCF₃, nitro, cyano, azido, piperidinosulfonyl, —

C(O)—

O-alkyl, —

C(O)-alkyl, —

C(O)-alkyl and phenyl,

or Z₂₂ is

X₂ is selected from the group consisting of alkyl, alkynyl, —

(CH₂)_m-W-(CH₂)_q-Z₂₃ and —

(CH₂)_pZ₂₄,

W is SO₂;

Z₂₁ is phenyl;

Z₂₄ is selected from the group consisting of cyclohexenyl, bis-phenyl, cyclohexyl optionally substituted by an aminoalkyl, and phenyl, naphthyl, benzothienyl, thienyl and indolyl unsubstituted or substituted by at least one member selected from the group consisting of fluoro, chloro, bromo, iodo, alkyl, alkoxy, —

CF₃, —

OCF₃, —

SCF₃, hydroxy, —

O—

C(O)-alkyl, —

NH—

C(O)-alkyl, mono- or di-alkylamino and amino, or

X₃ is —

(CH₂)_pZ₂₅, Z₂₅ is phenyl unsubstituted or substituted by at least one alkoxy or —

CF₃.

6. A compound of claim 1 wherein R₃ is selected from the group consisting of hydrogen, alkyl, alkenyl.

7. A compound of claim 1 wherein R₁ is —

(CH₂)_mZ₁₂ in which m=2 and Z₁₂ is bis-phenyl or indolyl substituted by at least one member selected from the group consisting of alkyl and alkoxy.

8. A compound of claim 1 wherein R₂ is —

C(Y)NHX₁ or —

C(O)X₂,

Y is S;

X₁ is phenyl optionally substituted by at least one azido,

X₂ is —

(CH₂)_pZ₂₄,

p is 1, 2 or 3,

Z₂₄ is cyclohexyl, or phenyl or benzothienyl optionally substituted by at least one member selected from the group consisting of fluoro, chloro, bromo, iodo, —

CF₃.

9. A compound of claim 1 wherein R₃ is hydrogen or methyl.

10. A pharmaceutical composition having an affinity for somatostatin receptors comprising an effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.