4-aminopiperidine and their use as a medicine
First Claim
Patent Images
1. A compound of the formula in racemic, enantiomeric form or all combinations of these forms, whereinR1 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.
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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.
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Citations
10 Claims
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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 whereinZ23 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. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10)
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;
- (CH2)m-Y-Z11 or
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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 whereinX1 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, aminoX3 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.
- (CH2)m-Y-Z11 and —
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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.
- (CH2)m-Y-Z11 and —
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5. A compound of claim 1 wherein R2 is selected from the group consisting of —
- C(Y)NHX1, —
C(O)X2 and SO2X3X1 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, orX3 is —
(CH2)pZ25, Z25 is phenyl unsubstituted or substituted by at least one alkoxy or —
CF3.
- C(Y)NHX1, —
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6. A compound of claim 1 wherein R3 is selected from the group consisting of hydrogen, alkyl, alkenyl.
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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.
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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.
- C(Y)NHX1 or —
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9. A compound of claim 1 wherein R3 is hydrogen or methyl.
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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.
Specification