4-Aminopiperidine and their use as a medicine

• US 20040006089A1
• Filed: 05/23/2002
• Published: 01/08/2004
• Est. Priority Date: 12/14/1999
• Status: Active Grant

• Current Assignee: Ipsen Pharma Sas (Ipsen Sa)
• Original Assignee: Societe de Conseils de Recherches et d'Applications Scientifiques
• Inventors: Gonzalez, Jerome, Moinet, Christhope, Thurieau, Christophe
• Granted Patent: US 7,115,634 B2
• Time in Patent Office: Days
• US Class Current: 514/253.01
• 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. Compounds of general formula

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.

3. Compounds of general formula I according to claim 1 or 2 in which:

R₁ represents a linear or branched (C₁-C₆)alkyl radical, the —

CH₂)_m—

Y—

Z₁₁ or —

(CH₂)_m—

Z₁₂ radical in which

Z₁₁ 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 which

X₁ 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 which

W 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, amino

or 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 which

X₁ represents a —

(CH₂)_pZ₂₂ radical in which

Z₂₂ 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 which

Z₂₄ 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 which

Z₂₅ 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.

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 which

Z₁₁represents 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;

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 which

X₁ represents a linear or branched (C₁-C₁₀)alkyl, or —

(CH₂)_pZ₂₂ radical in which

Z₂₂ 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 which

W 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, or

Z₂₄ 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,

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 which

X₁ represents a —

(CH₂)_pZ₂₂ radical in which

Z₂₂ 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 which

Z₂₄ 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 which

Z₂₅ 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;

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.

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 which

Y represents S;

X₁ represents a phenyl radical optionally substituted by one or more azido radicals,

X₂ represents —

(CH₂)_pZ₂₄ in which

p 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.

9. Compounds of general formula I according to any of the preceding claims, wherein R₃ represents the hydrogen atom or the methyl radical.

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 with

A) 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.

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 with

A) 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.

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 with

A) 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).

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.

14. Pharmaceutical compositions containing, as active ingredient, at least one of the medicaments according to claim 13, in combination with a pharmaceutically acceptable support.

15. Use of compounds of general formula I_a

16. Use of products of general formula I_a 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.

17. Use of compounds of general formula I_a according to any of claims 15 to 16 in which R_1a represents a linear or branched (C₁-C₆)alkyl radical, the —

(CH₂)_m—

Y—

Z₁₁ or —

(CH₂)_m—

Z₁₂ radical in which

Z₁₁ 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 R_1a represents a radical of formula

18. Use of compounds of general formula I_a according to any of claims 15 to 17 in which R_2a represents a radical of formula —

C(Y)NHX₁, —

C(O)X₂ or SO₂X₃ in which

X₁ 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 which

W 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, amino

or 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,

19. Use of compounds of general formula I_a according to any of claims 15 to 18 in which R_3a 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 which

X₁ represents a —

(CH₂)_pZ₂₂ radical in which

Z₂₂ 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 which

Z₂₄ 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 which

Z₂₅ 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.

20. Use of compounds of general formula I_a according to any of claims 15 to 19 in which R_1a represents a linear or branched (C₁-C₆)alkyl radical, the —

(CH₂)_m—

Y—

Z₁₁ or —

(CH₂)_m—

Z₁₂ radical in which

Z₁₁ 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 R_1a represents a radical of formula given below;

21. Use of compounds of general formula I_a according to any of claims 15 to 20 in which R_2a represents a radical of formula —

C(Y)NHX₁, —

C(O)X₂ or SO₂X₃ in which

X₁ represents a linear or branched (C₁-C₁₀)alkyl, or —

(CH₂)_pZ₂₂ radical in which

Z₂₂ 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 which

W 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, or

Z₂₄ 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,

22. Use of compounds of general formula I_a according to any of claims 15 to 21 in which R_3a 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 which

X₁ represents a —

(CH₂)_pZ₂₂ radical in which

Z₂₂ 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 which

Z₂₄ 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 which

Z₂₅ 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;

23. Use of compounds of general formula I_a according to any of claims 15 to 22 in which R_1a 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.

24. Use of compounds of general formula I_a according to any of claims 15 to 23 in which R_2a represents the radicals of formula —

C(Y)NHX, and —

C(O)X₂ in which

Y represents S;

X₁ represents a phenyl radical optionally substituted by one or more azido radicals,

X₂ represents —

(CH₂)_pZ₂₄ in which

p 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.

25. Use of compounds of general formula I_a according to any of claims 15 to 24 in which R_3a represents the hydrogen atom or the methyl radical.

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.