4-Aminopiperidine and their use as a medicine
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Accused Products
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
26 Claims
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1. Compounds of general formula
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14)
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2. Compounds of general formula I according to claim 1, characterized in that
i) the substituent or substituents which can be carried by the aryl radicals represented by Z11, and Z12 and heteroaryl represented by Z12 are chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, alkylthio, — - CF3, —
OCF3, phenyl, phenoxy, aminosulphonyl radicals;
ii) the substituent or substituents which can be carried by the heterocycloalkyl radical represented by Z12 are chosen independently from the oxy and alkyl radicals;
iii) the substituent or substituents which can be carried by the aryl and heteroaryl radicals represented by Z22 are chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkenyl, alkoxy, alkylthio, CF3, OCF3, nitro, cyano, azido, aminosulphonyl, piperidinosulphonyl, mono- or di-alkylamino, —
C(O)—
O-alkyl, —
C(O)-alkyl, or phenyl, phenoxy, phenylthio, benzyloxy radicals, the phenyl radical being able to be substituted;
iv) the substituent or substituents which can be carried by the aryl radicals represented by Z23 and Z24, cycloalkyl and heteroaryl represented by Z24 are chosen independently from the 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, alkylsulphonyl, mono- or di-alkylamino, amino, aminoalkyl, pyrrolyl, pyrrolydinyl or the phenyl, phenoxy, phenylthio, benzyl, benzyloxy radicals the aryl radical of which is optionally substituted by one or more alkyl, CF3 or halo radicals;
v) the substituent or substituents which can be carried by the aryl and heteroaryl radicals represented by Z25 are chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF3, OCF3, nitro, cyano, —
NH—
C(O)-alkyl, alkylsulphonyl, amino, mono- and di-alkylamino, phenyl, pyridino radicals;
vi) the substituent which can be carried by the alkyl radical represented by R3 is the cyano radical. vii) the substituent or substituents which can be carried by the aralkyl radical represented by R3 are chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF3, OCF3, OCHF2, SCF3, SCHF2, nitro, cyano, —
C(O)O-alkyl, alkylsulphonyl, thiadiazolyl radicals, or the phenyl and phenoxy radicals the phenyl radical of which is optionally substituted by one or more halo radicals.viii) the substituent or substituents which can be carried by the heteroarylalkyl radical represented by R3 are chosen independently from the fluoro, chloro, bromo or nitro radicals.
- CF3, —
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3. Compounds of general formula I according to claim 1 or 2 in which:
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R1 represents a linear or branched (C1-C6)alkyl radical, the —
CH2)m—
Y—
Z11 or —
(CH2)m—
Z12 radical in whichZ11 represents a (C1-C6)alkyl, Z12 represents bis-phenyl, (C3-C7)cycloalkyl, (C3-C7)heterocycloalkyl optionally substituted, or aryl or heteroaryl optionally substituted by one or more substituents chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy radicals, or Z12 represents Y represents the oxygen atom, or R1 represents a radical of formula R2 represents a radical of formula —
C(Y)NHX1, —
C(O)X2 or SO2X3 in whichX1 represents a linear or branched (C1-C15)alkyl radical, or —
(CH2)pZ22 in whichZ22 represents cyclohexenyl, bis-phenyl, (C3-C7)cycloalkyl, (C3-C7)heterocycloalkyl, mono- or di-alkylamino, —
C(O)—
O-alkyl, or aryl or heteroaryl optionally substituted by one or more radicals chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, alkylthio, CF3, OCF3, nitro, cyano, azido, piperidinosulphonyl, —
C(O)—
O-alkyl, —
C(O)-alkyl, or phenyl radicals,or Z22 represents a radical of formula X2 represents a linear or branched (C1-C10)alkyl, alkynyl, —
(CH2)m—
W—
(CH2)q—
Z23 or —
(CH2)p—
U—
Z24 radical in whichW represents SO2, U represents a covalent bond, Z23 represents an aryl radical;
Z24 represents cyclohexenyl, bis-phenyl, (C3-C7)cycloalkyl optionally substituted by an aminoalkyl, or aryl or heteroaryl radical optionally substituted by one or more radicals chosen from fluoro, chloro, bromo, iodo, alkyl, alkoxy, —
CF3, —
OCF3, SCF3, hydroxy, —
O—
C(O)-alkyl, mono- or di-alkylamino, aminoor Z24 represents a radical of formula or X2 represents X3 represents a —
(CH2)pZ25 radical in which Z25 represents an aryl radical optionally substituted by one or more identical or different radicals chosen from alkoxy and CF3,R3 represents the hydrogen atom, an alkyl, alkenyl, heteroarylalkyl radical optionally substituted or a radical of formula —
C(Y)—
NHX1, —
C(O)X2 or SO2X3 in whichX1 represents a —
(CH2)pZ22 radical in whichZ22 represents an aryl radical optionally substituted by one or more radicals chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF3, nitro, phenoxy radicals;
X2 represents the vinyl radical substituted by a phenyl, the phenyl radical being itself optionally substituted by one or more halo, or —
CH2)p—
U—
Z24 radicals in whichZ24 represents alkyl, (C3-C7)cycloalkyl, (C3-C7)heterocycloalkyl, bis-phenyl, amino, mono or di-alkylamino, or aryl or heteroaryl optionally substituted by one or more radicals chosen from alkoxy, bromo, chloro, fluoro, hydroxy, CF3, nitro, amino, mono- and di-alkylamino, pyrrolyl, or X2 represents a radical of formula X3 represents a linear or branched (C1-C10)alkyl radical, the vinyl radical substituted by a radical (the phenyl radical being itself optionally substituted), CF3, or —
(CH2)pZ25 in whichZ25 represents aryl or heteroaryl optionally substituted by one or more substituents chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF3, nitro, —
NH—
C(O)-alkyl, mono- and di-alkylamino radicals.
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4. Compounds of general formula I according to any of the preceding claims, wherein R1 represents a linear or branched (C1-C6)alkyl radical, the —
- (CH2)m—
Y—
Z11 or —
(CH2)m—
Z12 radical in whichZ11represents a (C1-C6)alkyl, Z12 represents naphthyl, morpholino, bis-phenyl, pyrrolidinyl substituted by the oxy radical, or the phenyl, piperazinyl, pyridinyl and indolyl radicals which are optionally substituted by one or more substituents chosen independently from the bromo, fluoro, chloro, alkyl, alkoxy, —
CF3, —
OCF3 radicals;
or Z12 represents Y represents the oxygen atom, or R1 represents a radical of formula given below;
- (CH2)m—
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5. Compounds of general formula I according to any of the preceding claims, wherein R2 represents a radical of formula —
- C(Y)NHX1, —
C(O)X2 or SO2X3 in whichX1 represents a linear or branched (C1-C10)alkyl, or —
(CH2)pZ22 radical in whichZ22 represents cyclohexyl, cyclohexenyl, bis-phenyl, morpholino, piperidino, mono- or di-alkylamino, —
C(O)—
O-alkyl, or phenyl, naphthyl or furyl optionally substituted by one or more radicals chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, alkylthio, CF3, —
OCF3, nitro, cyano, azido, piperidinosulphonyl, —
C(O)—
O-alkyl, —
C(O)-alkyl or phenyl radicals,or Z22 represents a radical of formula X2 represents an alkyl, alkynyl, —
(CH2)m—
W—
(CH2)q—
Z23 or —
(CH2)pZ24 radical in whichW represents SO2;
Z23 represents the phenyl radical;
Z24 represents cyclohexenyl, bis-phenyl, cyclohexyl optionally substituted by an aminoalkyl, or phenyl, naphthyl, benzothienyl, thienyl or indolyl radical optionally substituted by one or more radicals chosen from fluoro, chloro, bromo, iodo, alkyl, alkoxy, —
CF3, —
OCF3, —
SCF3, hydroxy, —
O—
C(O)-alkyl, —
NH—
C(O)-alkyl, mono- or di-alkylamino, amino, orZ24 represents a radical of formula or X2 represents X3 represents a —
(CH2)pZ25 radical in which Z25 represents the phenyl radical optionally substituted by one or more identical or different radicals chosen from alkoxy and CF3,
- C(Y)NHX1, —
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6. Compounds of general formula I according to any of the preceding claims, wherein R3 represents the hydrogen atom, an alkyl, alkenyl or furyl-methyl radical substituted by one or more nitro radicals, or a radical of formula —
- C(Y)—
NHX1, —
C(O)X2 or SO2X3 in whichX1 represents a —
(CH2)pZ22 radical in whichZ22 represents the phenyl or naphthyl radical optionally substituted by one or more radicals chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF3, nitro, phenoxy radicals, X2 represents the vinyl radical substituted by a phenyl radical itself optionally substituted by one or more halo, or —
(CH2)p—
U—
Z24 radicals in whichZ24 represents alkyl, cyclohexyl, tetrahydrofuryl, bis-phenyl, amino, mono or di-alkylamino, or phenyl, indolyl, thienyl, pyridinyl, benzothienyl and furyl optionally substituted by one or more radicals chosen from alkoxy, bromo, chloro, fluoro, amino, mono- and di-alkylamino, nitro, hydroxy, pyrrolyl or X2 represents a radical of formula X3 represents a linear or branched (C1-C10)alkyl radical, the vinyl radical substituted by a phenyl, CF3, or —
(CH2)pZ25 radical in whichZ25 represents a phenyl, naphthyl, thienyl, pyrazolyl or thiazolyl radical optionally substituted by one or more substituents chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF3, nitro, —
NH—
C(O)-alkyl, mono- and di-alkylamino radicals;
- C(Y)—
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7. Compounds of general formula I according to any of the preceding claims, wherein R1 represents the —
- (CH2)mZ12 radical in which m=2 and Z12 represents bis-phenyl or the radical indolyl substituted by one or more substituents chosen independently from the alkyl and alkoxy radicals.
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8. Compounds of general formula I according to any of the preceding claims, wherein R2 represents the radicals of formula —
- C(Y)NHX1 and —
C(O)X2 in whichY represents S;
X1 represents a phenyl radical optionally substituted by one or more azido radicals, X2 represents —
(CH2)pZ24 in whichp is equal to 1, 2 or 3, Z24 represents cyclohexyl, or phenyl or benzothienyl optionally substituted by one or more radicals chosen from fluoro, chloro, bromo, iodo or —
CF3.
- C(Y)NHX1 and —
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9. Compounds of general formula I according to any of the preceding claims, wherein R3 represents the hydrogen atom or the methyl radical.
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10. Process for the preparation, in liquid phase, of compounds of formula I according to claim 1, characterized in that it comprises
the reducing amination of the following N-substituted piperidone - in which R represents the methyl or Boc radical, in the presence of an amine of formula R1NH2 in which R1 has the meaning indicated in claim 1, in order to obtain the compound of formula 1
which compound of formula (1) is reacted withA) either a compound of formula X1NC(Y) in which X1 and Y have the meaning indicated in claim 1, in order to obtain a compound of formula (2)
which compound of formula (2) represents the corresponding compound of formula (I) in which R3 represents Me or Boc and which, when R3 represents Boc, can be subjected to an acid treatment in order to obtain the corresponding compound of formula (I) in which R3 represents the hydrogen atom,which compound of formula (I) thus obtained can be reacted with a compound of formula X1NC(Y), X2CO2H or X3SO2Cl in which X1, Y, X2 and X3 have the meaning indicated in claim 1, in order to obtain the corresponding compound of formula I in which R2 represents a radical of formula —
C(Y)NHX1 and R3 the —
C(Y)—
NHX1, —
C(O)X2 or SO2X3 radical respectively;
B) or a compound of formula X2CO2H in which X2 has the meaning indicated in claim 1, in order to obtain a compound of formula (3) which compound of formula (3) represents the corresponding compound of formula (I) in which R3 represents Me or Boc and which, when R3 represents Boc, can be subjected to an acid treatment in order to obtain the corresponding compound of formula (I) in which R3 represents the hydrogen atom, which compound of formula (I) thus obtained can be reacted with a compound of formula X1NC(Y), X2CO2H or X3SO2Cl in which X1, Y, X2 and X3 have the meaning indicated in claim 1, in order to obtain the corresponding compound of formula I in which R2 represents a radical of formula —
C(O)X2 and R3 the —
C(Y)—
NHX1, —
C(O)X2 or SO2X3 radical respectively.
- in which R represents the methyl or Boc radical, in the presence of an amine of formula R1NH2 in which R1 has the meaning indicated in claim 1, in order to obtain the compound of formula 1
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11. Preparation process, in solid phase, for compounds of formula I according to claim 1, characterized in that it comprises
the reducing amination of the ketonic resin - in the presence of an amine of formula R1NH2 in which R1 has the meaning indicated in claim 1, in order to obtain the compound of formula (4)
which compound of formula (4) is reacted withA) either a compound of formula X1NC(Y) in which X1 and Y have the meaning indicated in claim 1, in order to obtain a compound of formula (5)
followed by cleavage of the resin in order to obtain the corresponding compound of formula (I) in which R3 represents the hydrogen atom,B) or a compound of formula X3SO2Cl in which X3 has the meaning indicated in claim 1, in order to obtain a compound of formula (6)
followed by cleavage of the resin in order to obtain the corresponding compound of formula (I) in which R3 represents the hydrogen atom,C) or a compound of formula X2CO2Cl in which X2 has the meaning indicated in claim 1, in order to obtain a compound of formula (7)
followed by cleavage of the resin in order to obtain the corresponding compound of formula (I) in which R3 represents the hydrogen atom;
D) or a compound of formula X2CO2H in which X2 has the meaning indicated in claim 1, in order to obtain a compound of formula (7) as defined above, followed by cleavage of the resin in order to obtain the corresponding compound of formula (I) in which R3 represents the hydrogen atom.
- in the presence of an amine of formula R1NH2 in which R1 has the meaning indicated in claim 1, in order to obtain the compound of formula (4)
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12. Preparation process, in solid phase, for compounds of formula I according to claim 1, characterized in that it comprises
the reducing amination of the ketonic resin - in the presence of an amine of formula R1NH2 in which R1 has the meaning indicated in claim 1, in order to obtain the compound of formula (8)
which compound of formula (8) is reacted withA) either a compound of formula X1NC(O) in which X1 has the meaning indicated in claim 1, in order to obtain a compound of formula (9)
which compound (9) thus formed is reacted with a compound of formula R3X in which R3 is as defined in claim 1 and X represents Br or I, followed by cleavage of the resin in order to obtain the corresponding compound of formula (I);
B) or a compound of formula X3SO2Cl in which X3 has the meaning indicated in claim 1, in order to obtain a compound of formula (10)
which compound (10) thus formed is reacted with a compound of formula R3X in which R3 is as defined in claim 1 and X represents Br or I, followed by cleavage of the resin in order to obtain the corresponding compound of formula (I);
C) or a compound of formula X2CO2Cl in which X2 has the meaning indicated in claim 1, in order to obtain a compound of formula (11)
which compound (11) thus formed is reacted with a compound of formula R3X in which R3 is as defined in claim 1 and X represents Br or I, followed by cleavage of the resin in order to obtain the corresponding compound of formula (I);
D) or a compound of formula X2CO2H in which X2 has the meaning indicated in claim 1, in order to obtain a compound of formula (11) as defined above, which compound (11) thus formed is reacted with a compound of formula R3X in which R3 is as defined in claim 1 and X represents Br or I, followed by cleavage of the resin in order to obtain the corresponding compound of formula (I).
- in the presence of an amine of formula R1NH2 in which R1 has the meaning indicated in claim 1, in order to obtain the compound of formula (8)
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13. As medicaments, the products of formula I according to claims 1 to 9, as well as the addition salts with pharmaceutically acceptable mineral or organic acids of said products of formula I.
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14. Pharmaceutical compositions containing, as active ingredient, at least one of the medicaments according to claim 13, in combination with a pharmaceutically acceptable support.
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2. Compounds of general formula I according to claim 1, characterized in that
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15. Use of compounds of general formula Ia
- View Dependent Claims (16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26)
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16. Use of products of general formula Ia according to claim 15, characterized in that
i) the substituent or substituents which can be carried by the aryl radicals represented by Z11 and Z12 and heteroaryl represented by Z12 are chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, alkylthio, — - CF3, —
OCF3, phenyl, phenoxy, aminosulphonyl radicals;
ii) the substituent or substituents which can be carried by the heterocycloalkyl radical represented by Z12 are chosen independently from the oxy and alkyl radicals;
iii) the substituent or substituents which can be carried by the aryl and heteroaryl radicals represented by Z22 are chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkenyl, alkoxy, alkylthio, CF3, OCF3, nitro, cyano, azido, aminosulphonyl, piperidinosulphonyl, mono- or di-alkylamino, —
C(O)—
O-alkyl, —
C(O)-alkyl, or phenyl, phenoxy, phenylthio, benzyloxy radicals, the phenyl radical being able to be substituted;
iv) the substituent or substituents which can be carried by the aryl radicals represented by Z23 and Z24, cycloalkyl and heteroaryl represented by Z24 are chosen independently from the 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, alkylsulphonyl, mono- or di-alkylamino, amino, aminoalkyl, pyrrolyl, pyrrolydinyl or the radicals phenyl, phenoxy, phenylthio, benzyl, benzyloxy radicals the aryl radical of which is optionally substituted by one or more alkyl, CF3 or halo radicals;
v) the substituent or substituents which can be carried by the aryl and heteroaryl radicals represented by Z25 are chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF3, OCF3, nitro, cyano, —
NH—
C(O)-alkyl, alkylsulphonyl, amino, mono- and di-alkylamino, phenyl, pyridino radicals;
vi) the substituent which can be carried by the alkyl radical represented by R3 is the cyano radical. vii) the substituent or substituents which can be carried by the aralkyl radical represented by R3 are chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF3, OCF3, OCHF2, SCF3, SCHF2, nitro, cyano, —
C(O)O-alkyl, alkylsulphonyl, thiadiazolyl radicals, or the phenyl and phenoxy radicals the phenyl radical of which is optionally substituted by one or more halo radicals.viii) the substituent or substituents which can be carried by the heteroarylalkyl radical represented by R3 are chosen independently from the fluoro, chloro, bromo or nitro radicals.
- CF3, —
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17. Use of compounds of general formula Ia according to any of claims 15 to 16 in which R1a represents a linear or branched (C1-C6)alkyl radical, the —
- (CH2)m—
Y—
Z11 or —
(CH2)m—
Z12 radical in whichZ11 represents a (C1-C6)alkyl, Z12 represents bis-phenyl, (C3-C7)cycloalkyl, (C3-C7)heterocycloalkyl optionally substituted, or aryl or heteroaryl optionally substituted by one or more substituents chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy radicals, or Z12 represents Y represents the oxygen atom, or R1a represents a radical of formula
- (CH2)m—
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18. Use of compounds of general formula Ia according to any of claims 15 to 17 in which R2a represents a radical of formula —
- C(Y)NHX1, —
C(O)X2 or SO2X3 in whichX1 represents a linear or branched (C1-C15)alkyl radical, or CH2)pZ22 in which Z22 represents cyclohexenyl, bis-phenyl, (C3-C7)cycloalkyl, (C3-C7)heterocycloalkyl, mono- or di-alkylamino, —
C(O)—
O-alkyl, or aryl or heteroaryl optionally substituted by one or more radicals chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, alkylthio, CF3, OCF3, nitro, cyano, azido, piperidinosulphonyl, —
C(O)—
O-alkyl, —
C(O)-alkyl, or phenyl radicals,or Z22 represents a radical of formula X2 represents a linear or branched (C1-C10)alkyl, alkynyl, —
(CH2)m—
W—
(CH2)q—
Z23 or —
(CH2)p—
U—
Z24 radical in whichW represents SO2, U represents a covalent bond, Z23 represents an aryl radical;
Z24 represents cyclohexenyl, bis-phenyl, (C3-C7)cycloalkyl optionally substituted by an aminoalkyl, or aryl or heteroaryl radical optionally substituted by one or more radicals chosen from fluoro, chloro, bromo, iodo, alkyl, alkoxy, —
CF3, —
OCF3, SCF3, hydroxy, —
O—
C(O)-alkyl, mono- or di-alkylamino, aminoor Z24 represents a radical of formula or X2 represents X3 represents a —
(CH2)pZ25 radical in which Z25 represents an aryl radical optionally substituted by one or more identical or different radicals chosen from alkoxy and CF3,
- C(Y)NHX1, —
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19. Use of compounds of general formula Ia according to any of claims 15 to 18 in which R3a represents the hydrogen atom, an alkyl, alkenyl, heteroarylalkyl radical optionally substituted or a radical of formula —
- C(Y)—
NHX1, —
C(O)X2 or SO2X3 in whichX1 represents a —
(CH2)pZ22 radical in whichZ22 represents an aryl radical optionally substituted by one or more radicals chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF3, nitro, phenoxy radicals;
X2 represents the vinyl radical substituted by a phenyl, the phenyl radical being itself optionally substituted by one or more halo, or —
(CH2)p—
U—
Z24 radicals in whichZ24 represents alkyl, (C3-C7)cycloalkyl, (C3-C7)heterocycloalkyl, bis-phenyl, amino, mono or di-alkylamino, or aryl or heteroaryl optionally substituted by one or more radicals chosen from alkoxy, bromo, chloro, fluoro, hydroxy, CF3, nitro, amino, mono- and di-alkylamino, pyrrolyl, or X2 represents a radical of formula X3 represents a linear or branched (C1-C10)alkyl radical, the vinyl radical substituted by a radical (the phenyl radical being itself optionally substituted), CF3, or —
(CH2)pZ25 in whichZ25 represents aryl or heteroaryl optionally substituted by one or more substituents chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF3, nitro, —
NH-C(O)-alkyl, mono- and di-alkylamino radicals.
- C(Y)—
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20. Use of compounds of general formula Ia according to any of claims 15 to 19 in which R1a represents a linear or branched (C1-C6)alkyl radical, the —
- (CH2)m—
Y—
Z11 or —
(CH2)m—
Z12 radical in whichZ11 represents a (C1-C6)alkyl, Z12 represents naphthyl, morpholino, bis-phenyl, pyrrolidinyl substituted by the oxy radical, or the phenyl, piperazinyl, pyridinyl and indolyl radicals which are optionally substituted by one or more substituents chosen independently from the bromo, fluoro, chloro, alkyl, alkoxy, —
CF3, —
OCF3 radicals;
or Z12 represents Y represents the oxygen atom, or R1a represents a radical of formula given below;
- (CH2)m—
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21. Use of compounds of general formula Ia according to any of claims 15 to 20 in which R2a represents a radical of formula —
- C(Y)NHX1, —
C(O)X2 or SO2X3 in whichX1 represents a linear or branched (C1-C10)alkyl, or —
(CH2)pZ22 radical in whichZ22 represents cyclohexyl, cyclohexenyl, bis-phenyl, morpholino, piperidino, mono- or di-alkylamino, —
C(O)—
O-alkyl, or phenyl, naphthyl or furyl optionally substituted by one or more radicals chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, alkylthio, CF3, OCF3, nitro, cyano, azido, piperidinosulphonyl, —
C(O)—
O-alkyl, —
C(O)-alkyl or phenyl radicals,or Z22 represents a radical of formula X2 represents an alkyl, alkynyl, —
(CH2)m—
W—
(CH2)q—
Z23 or —
(CH2)pZ24 radical in whichW represents SO2;
Z23 represents the phenyl radical;
Z24 represents cyclohexenyl, bis-phenyl, cyclohexyl optionally substituted by an aminoalkyl, or phenyl, naphthyl, benzothienyl, thienyl or indolyl radical optionally substituted by one or more radicals chosen from fluoro, chloro, bromo, iodo, alkyl, alkoxy, —
CF3, —
OCF3, SCF3, hydroxy, —
O—
C(O)-alkyl, —
NH—
C(O)-alkyl, mono- or di-alkylamino, amino, orZ24 represents a radical of formula or X2 represents X3 represents a —
(CH2)pZ25 radical in which Z25 represents the phenyl radical optionally substituted by one or more identical or different radicals chosen from alkoxy and CF3,
- C(Y)NHX1, —
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22. Use of compounds of general formula Ia according to any of claims 15 to 21 in which R3a represents the hydrogen atom, an alkyl, alkenyl or furyl-methyl radical substituted by one or more nitro radicals, or a radical of formula —
- C(Y)—
NHX1, —
C(O)X2 or SO2X3 in whichX1 represents a —
(CH2)pZ22 radical in whichZ22 represents the phenyl or naphthyl radical optionally substituted by one or more radicals chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF3, nitro, phenoxy radicals, X2 represents the vinyl radical substituted by a phenyl radical itself optionally substituted by one or more halo, or —
(CH2)p—
U—
Z24 radicals in whichZ24 represents alkyl, cyclohexyl, tetrahydrofuryl, bis-phenyl, amino, mono or di-alkylamino, or phenyl, indolyl, thienyl, pyridinyl, benzothienyl and furyl optionally substituted by one or more radicals chosen from alkoxy, bromo, chloro, fluoro, amino, mono- and di-alkylamino, nitro, hydroxy, pyrrolyl or X2 represents a radical of formula X3 represents a linear or branched (C1-C10)alkyl radical, the vinyl radical substituted by a phenyl, CF3, or —
(CH2)pZ25 radical in whichZ25 represents a phenyl, naphthyl, thienyl, pyrazolyl or thiazolyl radical optionally substituted by one or more substituents chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF3, nitro, —
NH—
C(O)-alkyl, mono- and di-alkylamino radicals;
- C(Y)—
-
23. Use of compounds of general formula Ia according to any of claims 15 to 22 in which R1a represents the —
- (CH2)mZ12 radical in which m=2 and Z12 represents bis-phenyl or the radical indolyl substituted by one or more substituents chosen independently from the alkyl and alkoxy radicals.
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24. Use of compounds of general formula Ia according to any of claims 15 to 23 in which R2a represents the radicals of formula —
- C(Y)NHX, and —
C(O)X2 in whichY represents S;
X1 represents a phenyl radical optionally substituted by one or more azido radicals, X2 represents —
(CH2)pZ24 in whichp is equal to 1, 2 or 3, Z24 represents cyclohexyl, or phenyl or benzothienyl optionally substituted by one or more radicals chosen from fluoro, chloro, bromo, iodo or —
CF3.
- C(Y)NHX, and —
-
25. Use of compounds of general formula Ia according to any of claims 15 to 24 in which R3a represents the hydrogen atom or the methyl radical.
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26. Use according to claims 15 to 25 for the preparation of a medicament intended to treat acromegalia, hypophyseal adenomas or endocrine gastroenteropancreatic tumors including carcinoid syndrome.
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16. Use of products of general formula Ia according to claim 15, characterized in that
Specification
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Current AssigneeIpsen Pharma Sas (Ipsen Sa)
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Original AssigneeSociete de Conseils de Recherches et d'Applications Scientifiques
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InventorsGonzalez, Jerome, Moinet, Christhope, Thurieau, Christophe
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Granted Patent
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Time in Patent OfficeDays
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Field of Search
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US Class Current514/253.01
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CPC Class CodesA61P 1/00 Drugs for disorders of the ...A61P 1/02 Stomatological preparations...A61P 1/12 AntidiarrhoealsA61P 1/18 for pancreatic disorders, e...A61P 11/00 Drugs for disorders of the ...A61P 13/12 of the kidneysA61P 15/00 Drugs for genital or sexual...A61P 17/06 AntipsoriaticsA61P 19/00 Drugs for skeletal disordersA61P 19/08 for bone diseases, e.g. rac...A61P 19/10 for osteoporosisA61P 25/04 Centrally acting analgesics...A61P 25/06 Antimigraine agentsA61P 25/28 for treating neurodegenerat...A61P 3/04 Anorexiants; Antiobesity ag...A61P 3/10 for hyperglycaemia, e.g. an...A61P 35/00 Antineoplastic agentsA61P 35/02 specific for leukemiaA61P 43/00 Drugs for specific purposes...A61P 5/00 Drugs for disorders of the ...A61P 5/02 : of the hypothalamic hormone...A61P 5/04 : for decreasing, blocking or...A61P 5/08 : for decreasing, blocking or...A61P 5/16 : for decreasing, blocking or...A61P 5/46 : for decreasing, blocking or...A61P 5/48 : of the pancreatic hormonesA61P 9/00 : Drugs for disorders of the ...A61P 9/10 : for treating ischaemic or a...C07D 211/58 : attached in position 4C07D 401/12 : linked by a chain containin...C07D 401/14 : containing three or more he...C07D 405/14 : containing three or more he...C07D 409/14 : containing three or more he...C07D 417/14 : containing three or more he...