Derivatives of 4-aminopiperidine and their use a medicament

• US 20050239796A1
• Filed: 05/04/2005
• Published: 10/27/2005
• 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: Moinet, Christophe, Gonzalez, Jerome, Thurieau, Christophe
• Granted Patent: US 7,393,861 B2
• Time in Patent Office: Days
• US Class Current: 514/253.10
• 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

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;

ii) the substituents carried by the heterocycloalkyl represented by Z₁₂ are independently oxy or alkyl;

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;

vii) the substituents carried by aralkyl represented by R₃ are independently selected from the group consisting of fluoro, chloro, bromo, iodo, alkyl, alkoxy, —

CF₃, —

OCF₃, —

OCHF₂, —

SCF₃, —

SCHF₂, nitro, cyano, —

C(O)O-alkyl, alkylsulfonyl, thiadiazolyl, phenyl and phenoxy optionally substituted by at least one halo and

viii) the substituents carried by heteroarylalkyl represented by R₃ are independently selected from the group consisting of fluoro, chloro, bromo and nitro.

3. A compound of claim 1 wherein

R₁ is selected from the group consisting of (C₁-C₆)alkyl, —

(CH₂)_m—

Y-Z₁₁ and —

(CH₂)_m-Z₁₂,

Z₁₁ is (C₁-C₆)alkyl,

Z₁₂ is selected from the group consisting of bis-phenyl, (C₃-C₇)cycloalkyl, (C₃-C₇)heterocycloalkyl optionally substituted, aryl or heteroaryl optionally substituted by at least one member selected from the group consisting of fluoro, chloro, bromo, iodo, alkyl and alkoxy,

or Z₁₂ is

Y is oxygen,

or R₁ is

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, (C₃-C₇)heterocycloalkyl, mono- or di-alkylamino, —

C(O)—

O-alkyl, 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,

or Z₂₂ is

X₂ is selected from the group consisting of (C₁-C₁₀)alkyl, 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

or Z₂₄ is

or X₂ is

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, heteroarylalkyl optionally substituted, —

C(Y)—

NHX₁, —

C(O)X₂ and SO₂X₃ in which

X₁ is —

(CH₂)_pZ₂₂,

Z₂₂ is aryl unsubstituted or substituted by at least one member selected from the group consisting of fluoro, chloro, bromo, iodo, alkyl, alkoxy, —

CF₃, nitro and phenoxy;

X₂ is vinyl substituted by phenyl, unsubstituted or substituted by at least one member selected from the group consisting of halo or —

(CH₂)_p—

U-Z₂₄,

Z₂₄ is selected from the group consisting of alkyl, (C₃-C₇)cycloalkyl, (C₃-C₇) heterocycloalkyl, bis-phenyl, amino, mono or di-alkylamino, and aryl and heteroaryl unsubstituted or substituted by at least one member selected from the group consisting of alkoxy, bromo, chloro, fluoro, hydroxy, —

CF₃, nitro, amino, mono- and di-alkylamino and pyrrolyl,

or X₂ is selected from the group consisting of

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

CF₃ and —

(CH₂)_pZ₂₅

Z₂₅ is aryl or heteroaryl unsubstituted or substituted by at least one member selected from the group consisting of fluoro, chloro, bromo, iodo, alkyl, alkoxy, —

CF₃, nitro, —

NH—

C(O)-alkyl and mono- and di-alkylamino.

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 naphthyl, morpholino, bis-phenyl, pyrrolidinyl substituted by oxy and 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;

or Z₁₂ is

Y is oxygen,

or R₁ is

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, bis-phenyl, morpholino, piperidino, mono- or di-alkylamino, —

C(O)—

O-alkyl, 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

Z₂₄ is

or X₂ is

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, or furyl-methyl substituted by at least one member selected from the group consisting of nitro, —

C(Y)—

NHX₁, —

C(O)X₂ and SO₂X₃,

X₁ is —

(CH₂)_pZ₂₂

Z₂₂ is phenyl or naphthyl unsubstituted or substituted by at least one member selected from the group consisting of fluoro, chloro, bromo, iodo, alkyl, alkoxy, —

CF₃, nitro and phenoxy,

X₂ is vinyl substituted by phenyl unsubstituted or substituted by at least one member selected from the group consisting of halo, or —

(CH₂)_p—

U-Z₂₄,

Z₂₄ is selected from the group consisting of alkyl, cyclohexyl, tetrahydrofuryl, bis-phenyl, amino, mono- or di-alkylamino, and phenyl, indolyl, thienyl, pyridinyl, benzothienyl and furyl, all unsubstituted or substituted by at least one member selected from the group consisting of alkoxy, bromo, chloro, fluoro, amino, mono- and di-alkylamino, nitro, hydroxy and pyrrolyl

or X₂ is selected from the group consisting of

X₃ is (C₁-C₁₀)alkyl, vinyl substituted by phenyl, —

CF₃, or —

(CH₂)_pZ₂₅,

Z₂₅ is selected from the group consisting of phenyl, naphthyl, thienyl, pyrazolyl and thiazolyl, all unsubstituted or substituted by at least one member selected from the group consisting of fluoro, chloro, bromo, iodo, alkyl, alkoxy, —

CF₃, nitro, —

NH—

C(O)-alkyl and mono- and di-alkylamino.

7. A compound of claim 1 wherein R₁ is —

(CH₂)_mZ₂ 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 process for the liquid phase preparation of a compound of claim 1, comprising

reducing amination of a N-substituted piperidone of the formula

wherein R is methyl or Boc, in the presence of an amine of the formula R₁NH₂ in which R₁ is as defined in claim 1, to obtain a compound of the formula

which compound is reacted with

A) either a compound of the formula X₁NC(Y) in which X₁ and Y have the meaning of claim 1, to obtain a compound of the formula

which compound is the corresponding compound of formula (I) in which R₃ is Me or Boc and which, when R₃ is Boc, can be subjected to an acid treatment to obtain the corresponding compound of formula (I) in which R₃ is hydrogen,

which compound of formula (I) thus obtained can be reacted with a compound of the formula X₁NC(Y) or X₂CO₂H or X₃SO₂Cl in which X₁, Y, X₂ and X₃ have the meaning of claim 1, to obtain the corresponding compound of formula I in which R₂ is —

C(Y)NHX₁ and R₃ is —

C(Y)—

NHX₁, —

C(O)X₂ or —

SO₂X₃, respectively;

B) or a compound of the formula X₂CO₂H in which X₂ has the meaning of claim 1, to obtain a compound of the formula

which compound of formula (3) is the corresponding compound of formula (I) in which R₃ is Me or Boc and which, when R₃ is Boc, can be subjected to an acid treatment to obtain the corresponding compound of formula (I) in which R₃ is hydrogen,

which compound of formula (I) thus obtained can be reacted with a compound of the X₁NC(Y), X₂CO₂H or X₃SO₂Cl which X₁, Y, X₂ and X₃ have the meaning of claim 1, to obtain the corresponding compound of formula I in which R₂ is —

C(O)X₂ and R₃ is —

C(Y)—

NHX₁, —

C(O)X₂ or SO₂X₃ respectively.

11. A solid phase preparation process for a compound of claim 1, comprising

reducing the amination of the ketonic resin

in the presence of an amine of the formula R₁NH₂ in which R₁ has the meaning of claim 1, to obtain a compound of the formula

which compound of formula (4) is reacted with

A) either a compound of the formula X₁NC(Y) in which X₁ and Y have the meaning of claim 1, to obtain a compound of the formula

followed by cleavage of the resin to obtain the corresponding compound of formula (I) in which R₃ is hydrogen,

B) or a compound of the formula X₃SO₂Cl in which X₃ has the meaning of claim 1, to obtain a compound of the formula

followed by cleavage of the resin to obtain the corresponding compound of formula (I) in which R₃ is hydrogen,

C) or a compound of the formula X₂CO₂Cl in which X₂ has the meaning of claim 1, to obtain a compound of the formula

followed by cleavage of the resin to obtain the corresponding compound of formula (I) in which R₃ is hydrogen;

D) or a compound of the formula X₂CO₂H in which X₂ has the meaning of claim 1, to obtain a compound of formula (7) as defined above, followed by the cleavage of the resin to obtain the corresponding compound of formula (I) in which R₃ is hydrogen.

12. A solid phase preparation process for a compound of claim 1, comprising

reducing amination of the ketonic resin

in the presence of an amine of the formula R₁NH₂ in which R₁ has the meaning of claim 1, to obtain a compound of the formula

which compound of formula (8) is reacted with

A) either a compound of the formula X₁NC(O) in which X₁ has the meaning of claim 1, to obtain a compound of the formula

which compound (9) is reacted with a compound of the formula R₃X in which R₃ is defined as in claim 1 and X is Br or I, followed by cleavage of the resin to obtain the corresponding compound of formula (I);

B) or a compound of the formula X₃SO₂Cl in which X₃ has the meaning of claim 1, to obtain a compound of the formula

which compound (10) is reacted with a compound of the formula R₃X in which R₃ is defined as in claim 1 and X is Br or I, followed by cleavage of the resin to obtain the corresponding compound of formula (I);

C) or a compound of the formula X₂CO₂Cl in which X₂ has the meaning of claim 1, to obtain a compound of the formula

which compound (11) is reacted with a compound of the formula R₃X in which R₃ is defined as in claim 1 and X is Br or I, followed by cleavage of the resin to obtain the corresponding compound of formula (I);

D) or a compound of the formula X₂CO₂H in which X₂ has the meaning of claim 1, to obtain a compound of formula (11) as defined above,

which compound (11) is reacted with a compound of the formula R₃X in which R₃ is defined as in claim 1 and X is Br or I, followed by cleavage of the resin to obtain the corresponding compound of formula (I).

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

13. (canceled)

15. A method of treating a disease involving a receptor of somatostatin in warm-blooded animals comprising administering to warm-blooded animals in need thereof an amount of a compound of the formula

16. The method of claim 15, wherein

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

CF₃, —

OCF₃, phenyl, phenoxy and aminosulfonyl;

ii) the substituents carried by the heterocycloalkyl represented by Z₁₂ are oxy or alkyl;

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

CF₃, —

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

C(O)—

(O)-alkyl, —

C(O)-alkyl, and phenyl, phenoxy, phenylthio and benzyloxy with the phenyl unsubstituted or substituted;

iv) the substituents carried by aryl represented by Z₂₃ and Z₂₄, cycloalkyl and heteroaryl represented by Z₂₄ are selected 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 and phenyl, phenoxy, phenylthio, benzyl and benzyloxy, the aryl of which is unsubstituted or substituted by at least one member selected from the group consisting of alkyl, —

CF₃ and halogen,

v) the substituents carried by aryl and heteroaryl represented by Z₂₅ are 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 substituent carried by alkyl represented by R₃ is cyano,

vii) the substituents carried by aralkyl represented by R₃ are selected from the group consisting of fluoro, chloro, bromo, iodo, alkyl, alkoxy, —

CF₃, —

OCF₃, —

OCHF₂, —

SCF₃, —

SCHF₂, nitro, cyano, —

C(O)O-alkyl, alkylsulfonyl, thiadiazolyl and phenyl and phenoxy unsubstituted or substituted by at least one halogen and

viii) the substituents carried by heteroarylalkyl represented by R₃ are selected from the group consisting of fluoro, chloro, bromo or nitro.

17. The method of claim 15, wherein R_1a is (C₁-C₆)alkyl, —

(CH₂)_m—

Y-Z₁₁ and —

(CH₂)_m-Z₁₂,

Z₁₁ is (C₁-C₆)alkyl,

Z₁₂ is bis-phenyl, (C₃-C₇) cycloalkyl, (C₃-C₇)hetero-cycloalkyl optionally substituted and aryl or heteroaryl unsubstituted or substituted by at least one member selected from the group consisting of fluoro, chloro, bromo, iodo, alkyl and alkoxy,

or Z₁₂ is

Y is oxygen,

or R_1a is

18. The method of claim 15 wherein R_2a is selected from the group consisting of —

C(Y)NHX₁, —

C(O)X₂ and —

SO₂X₃ in which

X₁ is (C₁-C₁₅)alkyl, or —

(CH₂)_pZ₂₂,

Z₂₂ is selected from the group consisting of cyclohexenyl, bis-phenyl, (C₃-C₇)cycloalkyl, (C₃-C₇)heterocycloalkyl, mono- or di-alkylamino, —

C(O)—

O-alkyl and aryl or 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 and phenyl,

or Z₂₂ is

X₂ is selected from the group consisting of (C₁-C₁₀)alkyl, alkynyl, —

CH₂)_m—

W—

(CH₂)_q-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 unsubstituted or substituted by an aminoalkyl and aryl or 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 and amino,

or Z₂₄ is

or X₂ is

X₃ is —

(CH₂)_pZ₂₅, Z₂₅ is aryl optionally substituted by at least one alkoxy or CF₃.

19. The method of claim 15 wherein R_3a is selected from the group consisting of hydrogen, alkyl, alkenyl, heteroarylalkyl optionally substituted, —

C(Y)—

NHX₁, —

C(O)X₂ and SO₂X₃,

X₁ is —

(CH₂)_pZ₂₂,

Z₂₂ is aryl unsubstituted or substituted by at least one member selected from the group consisting of fluoro, chloro, bromo, iodo, alkyl, alkoxy, —

CF₃, nitro and phenoxy,

X₂ is vinyl substituted by phenyl unsubstituted or substituted by at least one halogen, or —

(CH₂)_p—

U-Z₂₄,

Z₂₄ is selected from the group consisting of alkyl, (C₃-C₇)cycloalkyl, (C₃-C₇)heterocycloalkyl, bis-phenyl, amino, mono or di-alkylamino and aryl or heteroaryl unsubstituted or substituted by at least one member selected from the group consisting of alkoxy, bromo, chloro, fluoro, hydroxy, CF₃, nitro, amino, mono- and di-alkylamino and pyrrolyl,

or X₂ is selected from the group consisting of

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

CF₃ and —

(CH₂)_pZ₂₅,

Z₂₅ is aryl or heteroaryl unsubstituted or substituted by at least one member selected from the group consisting of fluoro, chloro, bromo, iodo, alkyl, alkoxy, —

CF₃, nitro, —

NH—

C(O)-alkyl and mono- and di-alkylamino.

20. The method of claim 15 wherein R_1a 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 naphthyl, morpholino, bis-phenyl, pyrrolidinyl substituted by oxy and phenyl, piperazinyl, pyridinyl and indolyl unsubstituted or substituted by at least one member selected from the group consisting of bromo, fluoro, chloro, alkyl, alkoxy, —

CF₃ and —

OCF₃;

or Z₁₂ is

Y is oxygen,

or R_1a is

21. The method of claim 15 wherein R₂, 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, bis-phenyl, morpholino, piperidino, mono- or di-alkylamino, —

C(O)—

O-alkyl 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 and phenyl,

or Z₂₂ is

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

(CH₂)_m—

W—

(CH₂)_q-Z₂₃ and —

(CH₂)_p-Z₂₄,

W is SO₂;

Z₂₃ is phenyl;

Z₂₄ is selected from the group consisting of cyclohexenyl, bis-phenyl, cyclohexyl optionally substituted by 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

Z₂₄ is

or X₂ is

X₃ is —

(CH₂)_pZ₂₅, Z₂₅ is phenyl unsubstituted or substituted by at least one alkoxy or CF₃.

22. The method of claim 15 wherein R_3a is selected from the group consisting of hydrogen, alkyl, alkenyl, furyl-methyl substituted by at least one member selected from the group consisting of nitro, —

C(Y)—

NHX₁, —

C(O)X₂ and SO₂X₃

X₁ is —

(CH₂)_pZ₂₂,

Z₂₂ is phenyl or naphthyl unsubstituted or substituted by at least one member selected from the group consisting of fluoro, chloro, bromo, iodo, alkyl, alkoxy, —

CF₃, nitro and phenoxy,

X₂ is vinyl substituted by phenyl unsubstituted or substituted by at least one halo, or —

(CH₂)_p—

U-Z₂₄,

Z₂₄ is selected from the group consisting of alkyl, cyclohexyl, tetrahydrofuryl, bis-phenyl, amino, mono or di-alkylamino, and phenyl, indolyl, thienyl, pyridinyl, benzothienyl and furyl unsubstituted or substituted by at least one member selected from the group consisting of alkoxy, bromo, chloro, fluoro, amino, mono- and di-alkylamino, nitro, hydroxy and pyrrolyl

or X₂ is selected from the group consisting of

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

CF₃ and —

(CH₂)_pZ₂₅,

Z₂, is selected from the group consisting of phenyl, naphthyl, thienyl, pyrazolyl and thiazolyl, all unsubstituted or substituted by at least one member selected from the group consisting of fluoro, chloro, bromo, iodo, alkyl, alkoxy, —

CF₃, nitro, —

NH—

C(O)-alkyl and mono- and di-alkylamino.

23. The method of claim 15 wherein R_1a is —

(CH₂)_mZ₁₂, m=2 and Z₁₂ is bis-phenyl or indolyl substituted by at least one alkyl or alkoxy.

24. The method of claim 15 wherein R_2a is —

C(Y)NHX₁ or —

C(O)X₂,

Y is S;

X₁ is phenyl unsubstituted or substituted by at least one azido,

X₂ is —

(CH₂)_pZ₂₄,

p is 1, 2 or 3,

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

CF₃.

25. The method of claim 15 wherein R_3a is hydrogen or methyl.

26. The method of claim 15 wherein the disease treated is selected from the group consisting of acromegalia, hypophyseal adenomas and endocrine gastroenteropancreatic tumors including carcinoid syndrome.