Derivatives piperidinecarboxylic acids, pharmaceutical compositions containing them, method of stimulation of secretion of growth hormone

 

(57) Abstract:

The invention relates to 1,4 - and 1,3-disubstituted piperidines that have activity, stimulating the secretion of growth hormone by the pituitary gland of a mammal, and can find application in medicine. 3 ad and 1 C.p. f-crystals, 1 table.

The technical field to which the invention relates.

The present invention relates to new compounds, in particular to 4,4-disubstituted and 3,3-disubstituted piperidine compounds of, for containing compositions and to their use for the treatment of pathological diseases caused by growth hormone deficiency.

The level of technology

Growth hormone is a hormone that stimulates the growth of all tissues, are able to grow. In addition, it is known that growth hormone affects several metabolic processes, for example, stimulates protein synthesis and the mobilization of free fatty acids and causes the switching energy metabolism to fatty acid metabolism. The growth hormone deficiency can cause a number of severe pathological disorders, such as dwarfism.

Growth hormone is secreted by the pituitary gland. Its secretion is under strict direct or indirect control of the series g (GHRH) and inhibited by somatostatin. In both cases, the hormones are secreted by the hypothalamus, but their action is mediated primarily through specific receptors localized in the pituitary gland.

Also described other compounds that stimulate the secretion of growth hormone by the pituitary gland. For example, arginine, L-3,4-dihydroxyphenylalanine (L-DOPA), glucagon, vasopressin, RASAR (pituitary peptide that activates adenylate cyclase), agonists of muscarinic receptors and synthetic Hexapeptide, GHRH (peptide that stimulates growth hormone), cause the secretion of endogenous growth hormone, acting either directly on the pituitary gland, either by acting on the secretion of GHRH and/or somatostatin from the hypothalamus.

Diseases or conditions where it is desirable to increase the level of growth hormone, protein nature of growth hormone does not allow you to use nothing but parenteral administration.

In addition, other existing right natural regulators of secretion, for example, GHRH and RAZAR are sufficiently long polypeptides, and for this reason, preferably parenteral administration.

Previously it was proposed that the use of certain compounds to increase levels of growth hormone in mammals, for example, in patents EP 38072,WO 9613265, WO 9622997, WO 9635713, WO 9638471, WO 9632943, WO 9700894, WO 9706803, WO 9709060, WO 9707117, WO 9711697, WO 9722620, WO 9723508, WO 9724369 and WO 9734604.

For the composition of the compounds that cause the secretion of growth hormone, important as their activity, stimulating the secretion of growth hormone, and their bioavailability. Thus, the aim of the present invention are novel compounds having properties stimulating the secretion of growth hormone. Moreover, the aim of the invention are also novel compounds having properties stimulating the secretion of growth hormone (controls the secretion of growth hormone), which are specific and/or selective and have no or essentially have no side effects, such as, for example, the effect on the secretion of LH, FSH, TSH, ACTH, vasopressin, oxytocin, cortisol and/or prolactin. The aim of the invention are also compounds with good bioavailability when administered orally.

Brief description of the invention

In accordance with the present invention offers new compounds that act directly on pituitary cells in normal experimental conditions in vitro, inducing the secretion of their growth hormone.

Compounds that promote the secretion of growth hormone, magutse secretion of growth hormone at the level of the pituitary gland.

Moreover, the compounds of the present invention, promotes the secretion of growth hormone, you can also type in vivo to increase the secretion of endogenous growth hormone.

Description of the invention

Thus, in a broad sense, the present invention relates to a compound of General formula I

where

R1represents hydrogen or C1-6-alkyl, optionally substituted by one or more aryl or hetaryl;

a and d are independently 0, 1, 2 or 3;

b and C are independently 0, 1, 2, 3, 4, or 5, provided that b + C is 3, 4 or 5;

D represents

R2-NH-(CR3R4)e-(CH2)f-M-(CHR5)g-(CH2)h-,

where R2, R3, R4and R5independently represent hydrogen or C1-6alkyl, optionally substituted by one or more halogen, amino, hydroxyl, aryl or hetaryl; or

R2and R3or R2and R4or R3and R4can optionally form a -(CH2)i-U-(CH2)j- where i and j are independently equal to 1 or 2, and U represents-O-, -S - or a valence bond;

h and f are independent is UP>6=CR7, Allen, gitarren, -O - or-S-;

R6and R7independently represent hydrogen or C1-6alkyl, optionally substituted by one or more aryl or hetaryl;

G represents-O-(CH2)k-R8,

J represents-O-(CH2)l-R13,

where R8, R9, R10, R11, R12, R13, R14, R15, R16and R17independently represent hydrogen, halogen, aryl, hetaryl, C1-6alkyl or C1-6alkoxy;

k and l are independently 0, 1 or 2;

E is a-CONR18R19, -COOR19, -(CH2)m-NR18SO2R20, -(CH2)m-NR18COR20, -(CH2)m-OR19, -(CH2)m-R20, -CH(R18R19, -(CH2)m-NR18-CS-NR19R21or -(CH2)m-NR18-CO-NR19R21; or

E is a-CONR22NR23R24where R22represents hydrogen, C1-6-alkyl, optionally substituted by one or more aryl or hetaryl, or aryl or hetaryl, optionally substituted by one or more C1-or hetaryl, or C1-7-acyl; and R24represents hydrogen, C1-6-alkyl, optionally substituted by one or more aryl or hetaryl; or aryl or hetaryl, optionally substituted by one or more C1-6-alkyl; or

R22and R23together with the nitrogen atoms to which they are attached, may form a heterocyclic system optionally substituted by one or more C1-6-alkyl, halogen, amino, hydroxyl, aryl or hetaryl; or

R22and R24together with the nitrogen atoms to which they are attached, may form a heterocyclic system optionally substituted by one or more C1-6-alkyl, halogen, amino, hydroxyl, aryl or hetaryl; or

R23and R24together with the nitrogen atom to which they are attached, may form a heterocyclic system optionally substituted by one or more C1-6-alkyl, halogen, amino, hydroxyl, aryl or hetaryl;

where m is 0, 1, 2 or 3,

R18, R19and R21independently represent hydrogen or C1-6-alkyl, optionally substituted with halogen, -N(R25R26where R25and R26independently predstavlyayushix or aryl;

or R19represents a

where

Q represents-CH< or -- N<,

K and L are independently-CH2-, -CO-, -O-, -S-, -NR27- or a valence bond, where R27represents hydrogen or C1-6-alkyl;

n and o are independently 0 to 1, 2, 3, or 4

R20represents a C1-6alkyl, aryl or hetaryl;

or its pharmaceutically acceptable salt;

provided that

if M is a valence bond, E is a-CONR22NR23R24.

In a more specific embodiment, the present invention relates to a compound of General formula I

where

R1represents hydrogen or C1-6-alkyl, optionally substituted by one or more aryl or hetaryl;

a and d are independently 0, 1, 2 or 3;

b and C are independently 0 to 1, 2, 3, 4, or 5, provided that b + C is 3, 4 or 5,

D represents

R2-NH-(CR3R4)e-(CH2)f-M-(CHR5)g-(CH2)h-,

where R2, R3, R4and R5independently represent hydrogen or C1-6alkyl, neo is 2 and R3or R2and R4or R3and R4can optionally form a -(CH2)i-U-(CH2)j- where i and j are independently equal to 1 or 2, and U represents-O-, -S - or a valence bond;

h and f are independently 0, 1, 2 or 3;

g and e are independently 0 or 1;

M represents-CR6=CR7, Allen, gitarren, -O - or-S-;

R6and R7independently represent hydrogen or C1-6-alkyl, optionally substituted by one or more aryl or hetaryl;

G represents-O-(CH2)k-R8,

J represents-O-(CH2)l-R13,

where R8, R9, R10, R11, R12, R13, R14, R15, R16and R17independently represent hydrogen, halogen, aryl, hetaryl, C1-6-alkyl or C1-6-alkoxy;

k and l are independently 0, 1 or 2;

E is a-CONR18R19, -COOR19, -(CH2)m-NR18SO2R20, -(CH2)m-NR18COR20, -(CH2)m-OR SIG19, -(CH2)m-OCOR20, -CH(R18R19, -(CH2)m-NR18-CS-NONR22NR23R24where R22represents hydrogen, C1-6-alkyl, optionally substituted by one or more aryl or hetaryl, or aryl or hetaryl, optionally substituted by one or more C1-6-alkyl; R23represents a C1-6-alkyl, optionally substituted by one or more aryl or hetaryl, or1-7-acyl; and R24represents hydrogen, C1-6-alkyl, optionally substituted by one or more aryl or hetaryl; or aryl or hetaryl, optionally substituted by one or more1-6-alkyl; or

R22and R23together with the nitrogen atoms to which they are attached, may form a heterocyclic system optionally substituted by one or more C1-6-alkyl, halogen, amino, hydroxyl, aryl or hetaryl; or

R22and R24together with the nitrogen atoms to which they are attached, may form a heterocyclic system optionally substituted by one or more C1-6-alkyl, halogen, amino, hydroxyl, aryl or hetaryl; or

R23and R24together with the nitrogen atom to which they are attached, may form a heterocyclic system, neobyazatel">where m is O, 1, 2 or 3,

R18, R19and R21independently represent hydrogen or C1-6-alkyl, optionally substituted with halogen, -N(R25R26where R25and R26independently represent hydrogen or C1-6-alkyl; hydroxyl, C1-6-alkoxy, C1-6-alkoxycarbonyl, C1-6-alkylcarboxylic or aryl;

or R19represents a

where

Q represents-CH< or -- N<,

K and L are independently-CH2-, -CO-, -O-, -S-, -NR27- or a valence bond, where R27represents hydrogen or C1-6-alkyl;

n and o are independently 0, 1, 2, 3, or 4

R20represents a C1-6alkyl, aryl or hetaryl;

or its pharmaceutically acceptable salt.

In addition, the compounds of formula I can include any of their optical isomers, in the form of separated, pure or partially purified optical isomers or racemic mixtures. In the presence of one or more chiral carbon atoms, such chiral center or centers may be R and/or S-configuration, or a mixture of R and S configurations.

Moreover, the compounds of formula I mo Malaysia, what possible stereoisomers (E or Z isomers) included in the scope of the invention, if the specific geometric isomer not specified.

In one embodiment of the invention the compound of formula I, R1represents hydrogen. In another embodiment, the compound of the formula I R1represents a C1-6-alkyl, such as C1-4-alkyl, in particular methyl.

In another embodiment, the compound of formula I and is equal to 1.

In yet another embodiment, the compound of the formula I d is equal to 1.

In another embodiment, the compound of the formula I b is 1.

In yet another embodiment, the compound of the formula I b is 2.

In another embodiment, the compound of the formula I b is equal to 3.

In yet another embodiment, the compound of formula I is 1.

In another embodiment, the compound of formula I is 2.

In yet another embodiment, the compound of formula I is 3.

In a specific embodiment, the compound of formula I (b+C is 4.

In another embodiment, the compound of the formula I D is a

R2-NH-(CR3R4)e-(CH2)f-M-(CHR5)g-(CH2)h-,

where R2, R3, R4and R5independently represent hydrogen or C

R2and R3or R2and R4or R3and R4can optionally form a -(CH2)i-U-(CH2)j- where i and j are independently equal to 1 or 2, and U represents-O-, -S - or a valence bond,

h and f are independently 0, 1, 2 or 3;

g and e are independently 0 or 1;

M represents-CR6=CR7, Allen, gitarren, -O - or-S-; where R6and R7independently represent hydrogen or C1-6-alkyl. In one embodiment, R2represents hydrogen. In the second variant, R3represents hydrogen. In the third embodiment, R3represents a C1-6-alkyl, in particular methyl. In another embodiment, R4represents hydrogen. In another embodiment, R4represents a C1-6-alkyl, in particular methyl. In another embodiment, R3and R4form a -(CH2)i-U-(CH2)j-. In yet another variant of i is 1. In another embodiment, i is 2. In another embodiment, j is 1. In another embodiment, j is 2. In yet another embodiment, U is a valence bond. In another embodiment, R3and R4form a -(CH2)3-. In another embodiment, h is 0. In another embodiment, f is 0. In each the one embodiment, M represents-CR6=CR7, Allen, -O - or-S-. In another embodiment, R6and R7are both hydrogen or one of R6and R7represents methyl and the other represents hydrogen. In another embodiment, M represents an E-isomer-CR6=CR7-. In another embodiment, M represents-CH=CH-. In another embodiment, M represents- (CH3)=CH-. In another embodiment, M is arisen, in particular phenylene.

In yet another embodiment, the compounds of formula I D is a

R2-NH-(CR3R4)e-(CH2)f-M-(CHR5)g-(CH2)h-,

where R2, R3, R4and R5independently represent hydrogen or C1-6alkyl, optionally substituted by one or more halogen, amino, hydroxyl, aryl or hetaryl; or

R2and R3or R2and R4or R3and R4can optionally form a -(CH2)i-U-(CH2)j- where i and j are independently equal to 1 or 2, and U represents-O-, -S - or a valence bond,

h and f are independently 0, 1, 2 or 3;

g and e are independently 0 or 1;

M represents a valence bond. In one embodiment, R3represents a C1-6-alkyl, in particular methyl. In another embodiment, R4represents hydrogen. In another embodiment, R4represents a C1-6alkyl, in particular methyl. In another embodiment, R3and R4form a -(CH2)i-U-(CH2)j-. In yet another variant of i is 1. In another embodiment, i is 2. In another embodiment, j is 1. In another embodiment, j is 2. In yet another embodiment, U is a valence bond. In another embodiment, R3and R4form a -(CH2)3-. In another embodiment, h is 0. In another embodiment, f is 0. In another embodiment, f is 1. In another embodiment, g is 0. In yet another embodiment, e is 0. In another embodiment, e is 1. In a preferred embodiment, the compounds of formula I D is a (1E)-4-amino-4-methylpent-1-enyl,

(1E)-4-amino-2,4-dimethylpent-1-enyl, (1E)-3-(1-aminocinnamate)prop-1-enyl, 1-amino-1-methylethyl or 3-aminomethylphenol.

In yet another embodiment, the compounds of formula I G is a-O-(CH2)k-R8,

where R8, R9, R10, R11and R12independently represent hydrogen, halogen, aryl, hetaryl,1-6-alkyl or C1-6alkoxy; k is 0, 1, and the. the more one embodiment, one of R8, R9, R10, R11and R12independently represents a phenyl, and the other is hydrogen, in particular R10represents phenyl. In another embodiment, R8represents phenyl. In yet another embodiment, k is 1. In another embodiment, G is phenyl, 1-naphthyl or 2-naphthyl, preferably phenyl or 2-naphthyl. In another embodiment, G is benzyloxy. In another embodiment, G is 1H-indole. In another embodiment, G is-biphenyl-4-yl.

In the above compound of the formula I G preferably represents 2-naphthyl, benzyloxy, 1H-indole or a biphenyl-4-yl.

In another embodiment, the compounds of formula I, J is a

where R13, R14, R15, R16and R17independently represent hydrogen, halogen, aryl, hetaryl, C1-6-alkyl or C1-6alkoxy. In another embodiment, J is a

In a specific embodiment, J is a

In a preferred embodiment, R13, R14, R15, R16and R17all represent hydrogen.

In yet another embodiment, the compounds of formula I E is a-C the performance represent hydrogen or C1-6-alkyl, optionally substituted with halogen, -N(R25R26where R25and R26independently represent hydrogen or C1-6-alkyl; hydroxyl, C1-6-alkoxy, C1-6-alkoxycarbonyl, C1-6-alkylcarboxylic or aryl. In a specific embodiment, E is a-CONR18R19. In another embodiment, R18and R19independently represent hydrogen or C1-6-alkyl. In a specific embodiment, one of R18and R19represents hydrogen and the other are the stands. In another embodiment, E is a-COOR19. In a specific embodiment, R19represents a C1-6-alkyl, in particular ethyl.

In another embodiment, E is a-CONR22NR23R24where R22represents hydrogen, C1-6-alkyl, optionally substituted by one or more aryl or hetaryl, or aryl or hetaryl, optionally substituted by one or more C1-6-alkyl; R23represents a C1-6-alkyl, optionally substituted by one or more aryl or hetaryl, or C1-7-acyl; and R24represents hydrogen, C1-6-alkyl, optionally substituted by one or more aryl or hetaryl; or aryl, or the atoms of nitrogen, to which they are attached, may form a heterocyclic system optionally substituted by one or more C1-6-alkyl, halogen, amino, hydroxyl, aryl or hetaryl; or

R22and R24together with the nitrogen atoms to which they are attached, may form a heterocyclic system optionally substituted by one or more C1-6-alkyl, halogen, amino, hydroxyl, aryl or hetaryl; or

R23and R24together with the nitrogen atom to which they are attached, may form a heterocyclic system optionally substituted by one or more C1-6-alkyl, halogen, amino, hydroxyl, aryl or hetaryl. In another embodiment, R22represents hydrogen. In another embodiment, R22represents a C1-6-alkyl, such as1-4-alkyl, in particular methyl. In an additional embodiment, R23represents a C1-6-alkyl, such as C1-4-alkyl, in particular methyl. In another embodiment, R23represents a C1-7-acyl, such as2-4-acyl, in particular acetyl. In yet another embodiment, the compounds of formula I R24represents hydrogen. In another embodiment, the compounds of formula I R24 represents hydrogen, and R23and R24represents a C1-6-alkyl, such as C1-4-alkyl, in particular methyl. In another embodiment, R22and R23together with the nitrogen atoms to which they are attached, may form a heterocyclic system optionally substituted by one or more C1-6-alkyl, halogen, amino, hydroxyl, aryl or hetaryl. This heterocyclic system comprising R22and R23may be aromatic or non-aromatic and may be selected from, for example, pyrazole, pyridazine, triazine, indazole, phthalazine, cinnoline, pyrazolidine or pyrazoline. In another embodiment, R22and R24together with the nitrogen atoms to which they are attached, may form a heterocyclic system optionally substituted by one or more1-6by alkyl, halogen, amino, hydroxyl, aryl or hetaryl. This heterocyclic system comprising R22and R24may be aromatic or non-aromatic and may be selected from, for example, pyrazole, pyridazine, triazine, indazole, phthalazine, cinnoline, pyrazolidine or pyrazoline. In another embodiment, R22and R23together with the nitrogen atoms to which they C1-6-alkyl, halogen, amino, hydroxyl, aryl or hetaryl. This heterocyclic system comprising R22and R23may be aromatic or non-aromatic and may be selected from, for example, pyrazole, pyridazine, triazine, indazole, phthalazine, cinnoline, pyrazolidine or pyrazoline. In an additional embodiment, the compounds of formula I R23and R24together with the nitrogen atom to which they are attached, may form a heterocyclic system optionally substituted by one or more C1-6-alkyl, halogen, amino, hydroxyl, aryl or hetaryl. This heterocyclic system comprising R22and R23may be aromatic or non-aromatic and may be selected from, for example, aziridine, Dityatin, pyrrole, imidazole, pyrazole, isoindole, indole, indazole, purine, pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, indoline, isoindoline or research. In a specific embodiment, R23and R24together with the nitrogen atom to which they are attached, form pyrrolidin.

When R22and R23form a heterocyclic system, R23and R24can also simultaneously substituted by one or more aryl or hetaryl, or aryl or hetaryl, optionally substituted by one or more C1-6-alkyl.

When R22and R24form a heterocyclic system, R23and R24can also be used to form a heterocyclic system, or R23may be C1-6-alkyl, optionally substituted by one or more aryl or hetaryl, or C1-7-acyl.

In the above compound of the formula I E preferably represents (methylamino)carbonyl, N,N-dimethyldithiocarbamic, etoxycarbonyl or (pyrrolidin-1-yl)aminocarbonyl.

Especially preferred group of compounds of formula I are compounds having the formula Ia

where R1, D, G, E, J, a and d take the values described above.

Another especially preferred group of compounds of formula I are compounds having the formula Ib

where R1, D, G, E, J, a and d take the values described above.

Preferred compounds of formula I of the invention are:

Methylamide 1-{(2R)-2-[N-((2E)-5-amino-5-metrex-2-enoyl)-N-methylamino]-3-(2-naphthyl)propionyl}-4-benzylpiperidine-4-carboxylic acid

Metiram is slots

Methylamide 1-{(2R)-2-[N-((2E)-5-amino-5-metrex-2-enoyl)-N-methylamino]-3-(biphenyl-4-yl)propionyl}-4-benzylpiperidine-4-carboxylic acid

Methylamide 1-{(2R)-2-[N-((2E)-5-amino-3,5-dimethylhex-2-enoyl)-N-methylamino]-3-(biphenyl-4-yl)propionyl}-4-benzylpiperidine-4-carboxylic acid

Methylamide 1-((2R)-2-{N-[(2E)-4-(1-aminocinnamate)but-2-enoyl]-N-methylamino}-3-(biphenyl-4-yl)propionyl)-4-benzylpiperidine-4-carboxylic acid

2-Amino-N-[(1R)-2-[4-benzyl-4-(N’,N’-dimethylthiocarbamyl)piperidine-1-yl]-((1H-indol-3-yl)methyl)-2-oxoethyl]-2-methylpropionamide

2-Amino-N-{(1R)-2-[(3R)-3-benzyl-3-(N’,N’-dimethylthiocarbamyl)-piperidine-1-yl]-1-benzoyloxymethyl-2-oxoethyl 2-methyl-propionamide

2-Amino-N-[(1R)-2-[(3R)-3-benzyl-3-(N’,N’-dimethylthiocarbamyl)-piperidine-1-yl]-1-((1H-indol-3-yl)methyl)-2-oxoethyl]-2-methylpropionamide

Ethyl ester of 1-{(2R)-2-[N-((2E)-5-amino-5-metrex-2-enoyl)-N-methylamino]-3-(biphenyl-4-yl)propionyl}-4-benzylpiperidine-4-carboxylic acid

Ethyl ester of 1-{(2R)-2-[N-((2E)-5-amino-3,5-dimethylhex-2-enoyl)-N-methylamino]-3-(biphenyl-4-yl)propionyl}-4-benzylpiperidine-4-carboxylic acid

Ethyl ester of 3-{(2R)-2-[N-((2E)-5-amino-3,5-dimethylhex-2-enoyl)-N-methylamino]-3-(2-naphthyl)propionyl}-4-benzylpiperidine-4-carboxylic acid

Ethyl ester of (3S)-1-[(2R)-2-((2E)-5-amino-5-metrex-2-anolamine)-3-(1H-indol-3-yl)propionyl]-3-benzylpiperidine-3-carboxylic acid

Ethyl ester of (3S)-1-[(2R)-2-((2E)-5-amino-3,5-dimethylhex-2-anolamine)-3-(1H-indol-3-yl)propionyl]-3-benzylpiperidine-3-carboxylic acid

Ethyl ester of (3S)-1-[(2R)-2-(3-(aminomethyl)benzoylamine)-3-(1H-indol-3-yl)propionyl]-3-benzylpiperidine-3-carboxylic acid

N-{(1R)-2-[4-benzyl-4-(N’,N’-dimethylthiocarbamyl)piperidine-1-yl]-1-((2-naphthyl)methyl)-2-oxoethyl}-N-methylamide (2E)-5-amino-5-metrex-2-ene acid

N-[(1R)-2-[3-benzyl-3-(N’,N’-dimethylthiocarbamyl)-piperidine-1-yl]-1-((1H-indol-3-yl)methyl)-2-oxoethyl]amide of (2E)-5-amino-5-metrex-2-ene acid

N-{(1R)-2-[3-benzyl-3-(N’,N’-dimethylthiocarbamyl)-piperidine-1-yl]-1-((2-naphthyl)methyl)-2-oxoethyl}-N-methylamide (2E)-5-amino-5-metrex-2-ene acid

{(1R)-2-[3-benzyl-3-(N’,N’-dimethylthiocarbamyl)piperidine-1-yl]-1-(benzoyloxymethyl)-2-oxoethyl}amide of (2E)-5-amino-5-DIN-1-yl]-1-((2-naphthyl)methyl)-2-oxoethyl}-2-methylpropionamide

2-Amino-N-{(1R)-2-[3-benzyl-3-(N’,N’-dimethylhydrazine-bonyl)piperidine-1-yl]-1-((biphenyl-4-yl)methyl)-2-oxoethyl}-2-methylpropionamide

2-Amino-N-{(1R)-2-[3-benzyl-3-(N’,N’-dimethylhydrazine-bonyl)piperidine-1-yl]-1-((1H-indol-3-yl)methyl)-2-oxoethyl}-2-methylpropionamide

2-Amino-N-{2-[3-benzyl-3-(N’-methylhydrosiloxane)-piperidine-1-yl]-1-((benzoyloxymethyl)-2-oxoethyl}-2-methylpropionamide

2-Amino-N-{(1R)-2-[3-benzyl-3-(N’-methylhydrosiloxane)piperidine-1-yl]-1-((1H-indol-3-yl)methyl)-2-oxoethyl}-2-methylpropionamide

(Pyrrolidin-1-yl)amide is 1-[(2R)-2-(2-amino-2-methylpropionamide)-3-(lH-indol-3-yl)propionyl]-3-benzylpiperidine-3-carboxylic acid

2-Amino-N-{(1R)-2-[3-benzyl-3-(N,N’,N’-trimethylhydrazine-carbonyl)piperidine-1-yl]-1-((1H-indol-3-yl)methyl)-2-oxoethyl}-2-methylpropionamide

and their pharmaceutically acceptable salts.

A common way

The schema I see the end of the description.

The methodology used in this invention and illustrated in the above scheme I, based on the peptide addition reactions of, well known in the prior art, and in no way should rassmatrivalis the unity to the carboxylic acid using the consolidating agent, such as carbodiimide and gidroksibenzotriazola (HOAt) to give the amide. Before the next attach a suitable protective group such as tert-butyloxycarbonyl (Vos) may be removed using methods well known in the field, resulting in a receive connection (2). It is also possible to avoid the use of protecting groups. Thereafter, the compound (2) is attached to the carboxylic acid of formula D-COOH using the consolidating agent, thus obtaining the compound (3).

Scheme II, see the end of the description.

Compounds of General structure I, with the end of hydrazine, can be obtained as shown in scheme II. The methodology used in this invention and illustrated in scheme II, based on the peptide addition reactions of, well known in this area, and in no way should be construed as limiting the invention in any respect. In the first stage of mono-, di - or tri-substituted hydrazine or hydrazone (4) interacts with the appropriately protected amino acid with the formation of compound (5) using a suitable connecting reagent, such as hydrochloride, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, 1-hydroxybenzotriazole Il is varicela, such as dimethylformamide or dichloromethane. After that, amide (5) and carboxylic acid are combined with the consolidating agent, thus obtaining the compound (6). After this connection (6) attached to the carboxylic acid of formula D-COOH using the consolidating agent, thus obtaining the compound (7). In the method before the next attach a suitable protective group such as tert-butyloxycarbonyl (Vos) may be removed using methods well known in the field. It is also possible to avoid the use of protecting groups. Protect and unprotect from the corresponding amino acids can be performed using methods well known in the field and are described, for example, in T. W. Green (Protective Groups in Organic Synthesis, 2. Ed., John Wiley and Sons, New York, 1991).

The compounds of formula I exhibit an increased resistance to proteolytic degradation by the action of enzymes, because they are unnatural compounds, in particular, because of the natural amide bond substituted unnatural mimetics amide bonds. Increased resistance to proteolytic degradation compounds of the invention compared with the known peptides, causing the release of the hormone, as expected, the improvement is adequate literary publications.

In the above structural formulas and the text of the description, the following terms shall have the following value.

Group C1-6-alkyl, C1-6-alkylene, C1-4-alkyl or C1-4-alkylen described above include alkyl or alkylene group specified length or linear or branched or cyclic configuration. Examples of linear alkyl are methyl, ethyl, propyl, butyl, pentyl and hexyl and the corresponding divalent derivatives, such as ethylene. Examples of the branched alkyl is isopropyl, sec-butyl, tert-butyl, isopentyl and isohexyl and their corresponding divalent derivatives, such as isopropylene. Examples of cyclic alkyl is C3-6-cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl and their corresponding divalent derivatives, such as cyclopropyl.

C1-6-Alkoxygroup described above, include CNS group specified length or linear or branched or cyclic configuration. Examples of linear alkoxy are methoxy, ethoxy, propoxy, butoxy, pentox, hexose. Examples of branched alkoxy are isopropoxy, second-butox is iloxi, cyclopentyloxy, cyclohexyloxy.

C1-7-Acyl groups described above include acyl groups of a specified length or linear or branched or cyclic configuration. Examples of linear acyl is formyl, acetyl, propionyl, butyryl, valeryl etc., Examples of branched atilov are isobutyryl, isovaleryl, pivaloyl, etc. Examples of cyclic atilov are cyclopentanecarbonyl, cyclohexylcarbonyl and so on

In the context of the present invention, the term "aryl" includes part of a monovalent carbocyclic aromatic ring, being either monocyclic, bicyclic or polycyclic, e.g. selected from the group consisting of phenyl and naphthyl, optionally substituted by one or more C1-6-alkyl, C1-6-alkoxy, halogen, amino or aryl.

In the context of the present invention, the term "Allen" includes part of a divalent carbocyclic aromatic ring, being either monocyclic, bicyclic or polycyclic, e.g. selected from the group consisting of phenylene and naphthylene, optionally substituted by one or more C1-6-alkyl, C1-6-alkoxy, halogen, amino and aziklicescoe aromatic ring, being either monocyclic, bicyclic or polycyclic, e.g. selected from the group consisting of pyridyl, 1-N-tetrazol-5-yl, thiazolyl, imidazolyl, indolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, teinila, chinoline, pyrazinyl or isothiazoline, optionally substituted by one or more C1-6-alkyl, C1-6-alkoxy, halogen, amino or aryl.

In the context of the present invention, the term "heterocyclic system" includes part of an aromatic as well as non-aromatic ring, which may be either monocyclic, bicyclic or polycyclic, and to keep his ring structure at least one, e.g. one, two or three atoms(MOU) nitrogen and optionally one or more, e.g. one or two other heteroatoms, for example, sulfur atoms or oxygen. Preferably the heterocyclic system is selected from pyrazole, pyridazine, triazine, indazole, phthalazine, cinnoline, pyrazolidine, pyrazoline, aziridine, Dityatin, pyrrole, imidazole, pyrazole, isoindole, indole, indazole, purine, pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, indoline, is soedineniya of the present invention can contain one or more asymmetric centers, chiral carbon atoms), and this means that the stereoisomers, in the form of separated, pure or partially purified, stereoisomer or their racemic mixtures are included in the scope of the invention.

Compounds of the present invention may not necessarily be in the form of pharmaceutically acceptable salts, such as pharmaceutically acceptable acid additive salts of compounds of formula I, which include salt, obtained by the interaction of the compounds of formula I with an inorganic or organic acid, such as hydrochloric, Hydrobromic, sulfuric, acetic, phosphoric, lactic, maleic, almond, phthalic, citric, glutaric, gluconic, methansulfonate, salicylic, succinic, tartaric, toluensulfonate, triperoxonane, sulfamic or fumaric acid and/or water.

The compounds of formula I can be introduced in the form of a pharmaceutically acceptable acid salt additive or, if possible, in the form of a salt of an alkali metal or alkaline earth metal or salt (lower)alkylamine. It is believed that such salt forms have activity approximately of the same order as the forms in the form of free bases.

In another embodiment, the present invention relates to pharmaceutical whom mleay salt together with a pharmaceutically acceptable carrier or diluent.

Pharmaceutical compositions containing the compound of the present invention can be obtained by conventional methods, such as described in Remington's Pharmaceutical Sciences, 1985 or in Remington: The Science and Practice of Pharmacy, 19th Edition (1995). The composition can be in conventional forms, for example capsules, tablets, aerosols, solutions, suspensions or compositions for local administration.

Used by pharmaceutical carrier or diluent may be a conventional solid or liquid carrier. Examples of solid carriers are lactose, white earth, sucrose, cyclodextrin, talc, gelatin, agar, pectin, Arabic gum, magnesium stearate, stearic acid or lower alkalemia cellulose ethers. Examples of liquid carriers are purified syrup, peanut oil, olive oil, phospholipids, fatty acids, amines, fatty acids, polyoxyethylene or water.

Similarly, the carrier or diluent may include any known in the field of material that provides for delayed release, such as glycerol monostearate or glycerol distearate, separately or in mixture with wax.

If you are using a solid carrier for oral administration, the drug may bite pills or lozenges. The amount of solid carrier may vary within wide limits, but should normally be in the range of from about 25 mg to about 1 g If you use a carrier liquid, the drug may be in the form of a syrup, emulsion, hard gelatin capsule or sterile water for injection such as aqueous or non-aqueous liquid suspension or solution.

A typical tablet which can be prepared by traditional methods tabletting may include:

For nasal administration of the drug may contain the compound of formula I dissolved or suspended in a liquid carrier, in particular an aqueous carrier, for use in aerosol form. The carrier may contain additives such as solubilizing agents, for example, propylene glycol, surfactants, amplifiers suction, such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives, such as parabens.

As a rule, the compounds of the present invention is prepared in the form of a unit dosage form comprising 50-200 mg of active ingredient together with a pharmaceutically acceptable carrier in a single dose.

Acceptable dose of the compounds according to this sordos, with the introduction of patients, such as people, as a medicine.

In the following embodiment, the present invention relates to pharmaceutical compositions in unit dosage form comprising as active ingredient from about 10 to about 200 mg of the compounds of General formula I or its pharmaceutically acceptable salt.

It has been shown that compounds of General formula I possess the ability to stimulate the secretion of growth hormone in vivo. Therefore, these compounds can be used to treat conditions requiring a high level of growth hormone in plasma, such as having a place for people with growth hormone deficiency or older people or cattle.

Thus, in the particular embodiment, the present invention relates to pharmaceutical compositions for the stimulation of growth hormone from the pituitary, and this composition comprises as active ingredient a compound of General formula I or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier or diluent.

In the following embodiment, the present invention relates to a method of stimulation of growth hormone is uly I, or its pharmaceutically acceptable salt.

In yet another embodiment, the present invention relates to the use of compounds of General formula I or its pharmaceutically acceptable salt for a medicinal product for the stimulation of growth hormone from the pituitary gland.

Professionals are well aware of how diverse and plural is the current and potential use of growth hormone in humans. Thus, compounds of General formula I can enter with the purpose of stimulation of growth hormone from the pituitary, and this should lead to effects similar to the effects in the use of the growth hormone. The compounds of formula I are useful for the stimulation of growth hormone in the elderly; prevention of catabolic side effects of glucocorticoids; prevention and/or treatment of osteoporosis; treatment of chronic fatigue syndrome (CFS), treatment of acute fatigue and loss of muscle mass after surgery, stimulation of the immune system, acceleration of wound healing, accelerating bone repair of fractures, accelerating healing of complicated fractures, e.g. osteogenesis using distractie, treatment of secondary depletion of fractures, treatment of growth retardation, treatment of growth retardation of thrombocytopenia, treatment of Crohn's disease, treatment of incomplete bowel syndrome, chronic obstructive pulmonary disease (COPD), treatment of complications associated with transplantation, treatment of physiological short stature, including children with growth hormone deficiency and nizkoroslosti associated with chronic illness, treatment of obesity and is associated with obesity, stunted growth, treatment of anorexia, treatment of growth retardation associated with Prader-Willi syndrome and Turner syndrome; increase in the rate of growth of the patient with the syndrome of partial insensitivity to growth hormone, accelerating the recovery and reducing hospitalization of burn patients; treatment of intrauterine stunted growth, skeletal dysplasia, of hypercortisolism and Cushing's syndrome; induction pulsating allocation of growth hormone replacement growth hormone in stressed patients, treatment of osteochondrodysplasia, Noonan syndrome, schizophrenia, depressions, Alzheimer's disease, delayed wound healing and psychosocial deprivation, treatment of pulmonary dysfunction and depending on ventilation, treatment of heart failure or related to dysfunction of the blood vessels, treatment attenuated cardiac function, treatment or prevention of a heart attack m & e the treatment of adults in chronic dialysis attenuation reduction of protein catabolism as a result of significant surgical operation, reducing cachexia and protein loss due to chronic diseases, such as cancer or AIDS; treatment of hyperinsulinemia including nesidioblastosis (hyperplasia of pancreatic islets), an additional treatment for ovulation induction; to stimulate the development of the thymus and prevent age-related weakening of the functions of the thymus, the treatment of patients with immunosuppression, the treatment of sarcopenia, treatment of AIDS-related wasting, improving muscle strength, mobility, maintenance of skin thickness, homeostasis metabolism, renal homeostasis in disease of old age, stimulation of osteoblasts, bone remodeling and cartilage growth, regulating food intake, stimulation of the immune system in bedroom animals and treatment of disorders of aging in animals, stimulation of growth in cattle and wool growth in sheep, treatment of the metabolic syndrome (syndrome X), treatment of insulin resistance, including NIDDM type II, in mammals, for example humans, improve sleep quality and correction of the relative hyposomatotropism aging due to high increase in REM phase of sleep and reduce latency, REM sleep I dose should vary depending on the compounds of formula I, the method of administration and the desired therapy. However, to achieve efficient extraction of endogenous growth hormone in patients and animals is usually injected dose level between 0,0001 and 100 mg/kg of body weight per day. Moreover, the compounds of formula I have no or essentially no side effects with the introduction of the above levels, doses, and side effects such as, for example, the secretion of LH, FSH, TSH, ACTH, vasopressin, oxytocin, cortisol and/or prolactin. Usually, dosage forms suitable for oral, intranasal, pulmonary or cutaneous injection, include from about 0.0001 to about 100 mg, preferably from about 0.001 to about 50 mg of the compounds of the formula I mixed with a pharmaceutically acceptable carrier or diluent.

The pharmaceutical composition of the invention optionally can include a compound of formula I in combination with one or more compounds exhibiting different activity, for example, antibiotics or with other pharmaceutically active material.

The route of administration may be by any method, which effectively transports the active compound to the appropriate or desired site of action, such as oral, in the introduction.

In addition to the pharmaceutical use of the compounds of the formula I, they may be suitable as a tool for studies of the regulation of growth hormone secretion in vitro.

The compounds of formula I may also be suitable as a tool to assess the ability of the pituitary to secrete growth hormone in vivo. For example, in serum samples taken before and after administration of these compounds to man, may be determined by the level of growth hormone. Comparison of the growth hormone level in each serum sample should determine the ability of the pituitary gland of the patient to secrete growth hormone.

The compounds of formula I can be introduced commercially important species of animals to increase the rate and extent of growth and to increase the production of milk.

Additional use of compounds of the formula I, which regulates the secretion of growth hormone, is their combination with other regulators of secretion, such as GHRH (2 or 6), GHRH and analogs, growth hormone and its analogs or somatomedins, including IGF-1 and IGF-2.

Pharmacological methods

The efficiency and the degree of activity of compounds of the formula I in relation to the secretion of growth hormone can be assessed in vitro in primary cultures of rat pituitary, and Takai modification of the method of O. Sartor et al., Endocrinology 116, 1985, pp.952-957. Male albino rats Sprague-Dawley (250+/-25 g) were obtained from M llegaard, Lille Skensved, Germany. The rats were kept in group cages (four animals per cage) in rooms with a 12-hour cycle of light. The room temperature varied from 19 to 24°C and humidity from 30% to 60%.

Rats were killed and dissected hypophysis. Removed rear and middle lobe, and the remaining tissue was immediately placed in a cooled ice buffer for selection (Wednesday Gey (Gibco 041-04030) containing addition of 0.25% D-glucose, 2% nonessential amino acids (Gibco 043-01140) and 1% bovine serum albumin (BSA) (Sigma A-4503)). The tissue was cut into small pieces and transferred into a buffer for selection, additionally containing 3.8 mg/ml trypsin (Wortington #3707 TRL-3) and 330 mg/ml Gnkazy (Sigma D-4527). This mixture is incubated at 70 rpm for 35 min at 37°C in an atmosphere of O2/CO295/5%. Then the fabric was three times washed in the above buffer. Then using a standard Pasteur pipette, tissue was divided into single cells. After dispersion, the cells were filtered through a nylon filter (160 mm) to remove undigested tissue. Cell suspension 3 times washed with buffer to allocate, optionally containing trypsin inhibitor (0.75 mg/ml, Worthingto-3375), 4 mm glutamine (Gibco 043-N), of 0.075% sodium bicarbonate (Sigma S-8875), 0,1% non-essential amino acids, and 2.5% fetal bovine serum (FCS, Gibco 011-06290), 3% horse serum (Gibco 034-06050), 10% fresh rat serum, 1 nm T3(Sigma T-2752) and 40 mg/l dexamethasone (Sigma D-4902) pH of 7.3, to a density of 2×105cells/ml Cells were sown in tablets for micrometrology (Nunc, Germany), 200 ml per well, and cultured for 3 days at 37°C and 8% CO2.

Testing connection

After cultivation, the cells were washed twice with buffer for stimulation (balanced salt Hanks solution (Gibco 041-04020), optionally containing 1% BSA (Sigma A-4503), of 0.25% D-glucose (Sigma G-5250) and 25 mm HEPES (Sigma H-3375) pH 7,3) and plaincourault for 1 hour at 37°C. the Buffer was replaced with 90 ml of buffer for stimulation (37°C). Added to ten ml of the tested compounds and the plates were incubated for 15 min at 37°C and 5% CO2. Wednesday decantation and analyzed for the content of 6N using the testing system rGH SPA.

All compounds were tested at doses varying from 10 PM to 100 mm. A plot of the dose-response constructed using the hill equation (Fig P, Biosoft). Efficiency (maximum allocation 6R, Emax) expressed in % of Emax6HR>P CLASS="ptx2">The metabolic stability of compounds of the formula I can be estimated using the techniques described below.

Compounds are dissolved in water at a concentration of 1 mg/ml 25 ml of this solution was added to 175 ml of the appropriate enzyme solution (which gives the ratio of enzyme:substrate (weight/weight) of approximately 1:5). The solution is kept at 37°C for the night, 10 ml portions of solutions with varying degrees of destruction analyzed by comparing with the zero sample using mass spectrometry with the injection jet of electroepilation (ESMS) with the installed ion monitoring of the molecular ion. If the signal was reduced by more than 20% compared with the zero sample, the remaining solution was analyzed using HPLC and mass spectrometry to determine the exact extent and site of destruction.

To test the ability of different solutions to cause the destruction of the peptides in the stability tests included several standard peptides (ACTH 4-10, angiotensin 1-14 and glucagon).

Standard peptides (angiotensin 1-14, ACTH 4-10 and glucagon) were obtained from Sigma, MO, USA.

All enzymes (trypsin, chymotrypsin, elastase, aminopeptidase M and carboxypeptidase Y and C) were obtained stasis in 100 mm ammonium bicarbonate pH 8.0 (all at a concentration of 0.025 mg/ml).

A mixture of carboxypeptidase: carboxypeptidase Y and 50 mm ammonium acetate pH 4.5 (all at a concentration of 0.025 mg/ml).

A solution of amino peptidases M: aminopeptidase M (0.025 mg/ml) in 100 mm ammonium bicarbonate pH 8.0.

Mass spectrometric analysis was performed using two different mass spectrometers. Sciex API III triple quadrupole LC-MS instrument (Sciex instruments, Thomhill, Ontario) equipped with electrospray ion source and plasma-desorption unit Bio-Ion 20 (Bio-Ion Nordic AB, Uppsala, Sweden).

Quantitative determination of compounds (before and after destruction) was performed using device API III, using odnawialny monitoring of the investigated molecular ion in a jet injection of the analyte. The current fluid (Meon:water 1:1) at a rate of 100 ml/min was controlled by block HPLC ABI 140V (Perkin-Elmer Applied Biosystems Divisions, Foster City, CA). Instrument parameters were set in accordance with standard operating conditions and monitoring SIM was conducted using the most intense molecular ion (in most cases, it corresponded to the molecular ion with a double charge).

Identification of products of destruction included, in addition, the use of plasma-desorbs is ICOI device. The precision determined at this mass is typically better than 0.1%.

Separation and disintegration products was performed using column 4,6×105 mm reversed-phase HPLC HY-TACH-18 (Hewlett-Packard Company, Palo Alto, CA) with standard separating gradient of acetonitrile: TFUCK. As the HPLC system used NRM (Hewlett-Packard Company, Palo Alto, CA).

Any new property or a combination of the features described here are considered as an integral part of the present invention.

Examples

The method of obtaining compounds of formula I and compositions containing them is illustrated further by the following examples, which however shall not be construed as limiting.

Structures of the compounds are confirmed by either high performance liquid chromatography (HPLC), nuclear magnetic resonance (NMR, Bruker 400 MHz) or liquid chromatography-mass spectrometry (LC-MS). The NMR shifts (d) are presented in parts per million (M. D.) and presents only the individual peaks. So pl. is the melting point and is expressed in °C. Column chromatography was carried out using the methods described in W. C. Still et al., J. Org. Chem. 1978, 43, 2923-2925, on silica gel 60 Merck (Art 9385). Compounds used as is obtained using known methods. Apply a solution of methanol/ammonium is a 10% solution of ammonia in methanol.

HPLC-analysis:

Method A1

The RP-analysis was performed using UV detection at 214, 254, 276, and 301 nm on a column of silica TR 4.6 mm × 250 mm 5m C-18 (The Seperations Group, Hesperia), which was suirable at a speed of 1 ml/min at 42°C. the Column was balanced with 5% acetonitrile in buffer containing 0.1 M ammonium sulfate, pH of which was brought to 2.5 to 4 M sulfuric acid. After injection the sample was suirable gradient of acetonitrile from 5% to 60% in the same buffer during 50 minutes

Method B1

The RP-analysis was performed using UV detection at 214, 254, 276, and 301 nm on a column of silica TR 4.6 mm × 250 mm 5m C-18 (The Seperations Group, Hesperia), which was suirable at a speed of 1 ml/min at 42°C. the Column was balanced 5% (acetonitrile + 0.1% TFUC) in aqueous solution TFUK in water (0.1 per cent). After injection the sample was suirable gradient from 5% to 60% (acetonitrile + 0.1% TFUC) in the same aqueous buffer for 50 minutes

MAM-MS-analysis:

MAM-MS analyses were performed using a PE Sciex API 100 LC/MS System using Waters® 3 mm × 150 mm 3,5 m C-18 Symmetry column and spraying of positive ions with a flow rate of 20 ml/min Column of the CRT at a flow rate of 1 ml/min

Legend:

TLC: thin layer chromatography

DMSO: dimethyl sulfoxide

Min: minutes

h: hours

BOC: tert-Butyloxycarbonyl

DMF: dimethylformamide

THF: tetrahydrofuran

EDAC: N-ethyl-N-dimethylaminopropylamine hydrochloride

HOAt: 1-hydroxy-7-asobancaria

DIA: diisopropylethylamine

TFUCK: triperoxonane acid

Blocks for the synthesis of:

N-methylated amino acids, used in the following examples were obtained as described in Can. J. Chem. 1977, 55, 906.

Example 1

Methylamide 1-{(2R)-2-[N-((2E)-5-amino-5-metrex-2-enoyl)-N-methylamino]-3-(2-naphthyl)propionyl}-4-benzylpiperidine-4-carboxylic acid

Stage And

N-tert-Butyloxycarbonyl-4-benzylpiperidine-4-carboxylic acid

Ethyl ester of N-tert-butyloxycarbonyl-4-benzylpiperidine-4-carboxylic acid (obtained as described Gilligan et al., J. Med. Chem., 1994, 364-370 using as alkylating agent methyl benzyl) (11,0 g; 32 mmol) was heated under reflux for 7 h in a mixture of ethanol (190 ml) and aqueous sodium hydroxide (18% 190 ml). The volume is designed for people who were extracted with ethyl acetate (2 × 250 ml). The combined organic phase was evaporated to obtain 8.6 g of N-tert-butyloxycarbonyl-4-benzylpiperidine-4-carboxylic acid.

1H-NMR: d (CDCl3) 1,45 (s, N); 1,5 (m(ush.); 2H) ; 2,08 (m(ush.); 2H); 2,88 (m(ush.); 2H); 2,89 (s, 2H); 3,95 (m(ush.); 2H); 7,09-7,30 (5 arene. N).

Stage

tert-Butyl ether 4-benzyl-4-methylcarbamoylmethyl-1 - carboxylic acid

N-tert-Butyloxycarbonyl-4-benzylpiperidine-4-carboxylic acid (3.0 g; 9.0 mmol) was dissolved in methylene chloride (25 ml) was added EDAC (1.8 g; 9.0 mmol) and HOAt (1.3 g; 9.0 mmol). The mixture was stirred for 15 min, then was added methylamine (33% in ethanol; 2,3 ml; 18 mmol) and DIEA (1.6 ml; 9.0 mmol) and the mixture was stirred over night. Added methylene chloride (100 ml) and the mixture was washed with saturated aqueous sodium bicarbonate solution (50 ml) and aqueous acidic solution of sodium sulfate (10%, 50 ml), dried (MgSO4) and was evaporated in vacuum. The residue was chromatographically on silica (90 g) using as eluent a mixture of aqueous ammonia/ethanol/methylene chloride (1:7:92) to give 2.8 g of tert-butyl methyl ether 4-benzyl-4-methylcarbamoylmethyl-1-carboxylic acid.

1H-NMR: d (CDCl3) of 1.44 (s, N); 1.55V (m(ush.); 2H); 1,98 (m(ush.); 2H); 2,70 (d, 3H); 2,98 (m(ush.); 2H)Jn-4-carboxylic acid

Tert-butyl ether 4-benzyl-4-methylcarbamoylmethyl-1-carboxylic acid (2.8 g) was dissolved in a mixture of TFWC and methylene chloride and was stirred for 40 min. the Solvent was removed in vacuo, the residue was dissolved in water (30 ml) and the pH was brought to 13 with aqueous sodium hydroxide (1 n). The aqueous phase was extracted with methylene chloride (3×75 ml), the combined organic phases were dried (MgSO4) and was evaporated in vacuum to obtain 1.50 g of methylamine 4-benzylpiperidine-4-carboxylic acid.

1H-NMR: d (CDCl3) 1,80 (TD; 2H); 2,14 (d(ush.), 2H); 2,70 (d, 3H); of 2.81 (s, 2H); 2,85 (dt; 2H); is 3.21 (dt, 2H); 5.25 in (t, 1H); 7,00-7,35 (5 arene. N).

Stage D

Methylamide 4-benzyl-1-((2R)-2-methylamino-3-(2-naphthyl)Pro-pional)piperidine-4-carboxylic acid

(2R)-2-tert-Butyloxycarbonyl-N-methyl-3-(2-naphthyl)-propionic acid (709 mg of 2.15 mmol), HOAt (293 mg, 2.25 mmol) and EDAC (412 mg; 2.25 mmol) was dissolved in methylene chloride (5 ml) and was stirred for 15 minutes was Added to methylamide 4-benzylpiperidine-4-carboxylic acid (500 mg; 2.25 mmol) and deja (0.35 ml) and the mixture was stirred over night. Added methylene chloride (30 ml) and the mixture was washed with saturated aqueous sodium bicarbonate solution (20 ml) and aqueous acidic solution of sodium sulfate (10%, 20 W in ethyl acetate as eluent to obtain 810 mg methylamide 4-benzyl-1-((2R)-2-(N-tert-butyloxycarbonyl)-3-(2-naphthyl)propionyl)piperidine-4-carboxylic acid, which was dissolved in TFWC/methylene chloride (8+8 ml) and was stirred for 40 min at room temperature. The solvent was removed in vacuo, the residue neutralize with saturated sodium bicarbonate solution and was extracted with ethyl acetate (50 ml). The organic phase was dried (MgSO4) and was evaporated to obtain 729 mg methylamide 4-benzyl-1-((2R)-2-methylamino-3-(2-naphthyl)propionyl)piperidine-4-carboxylic acid.

Stage E

Methylamide 4-benzyl-1-((2R)-2-methylamino-3-(2-naphthyl)Pro-pional)piperidine-4-carboxylic acid (360 mg; 0.82 mmol) conjugatively with (2E)-5-(tert-butyloxycarbonyl)-5-methyl-2-hexenoic acid using the same methods of conjugation, as in stage D. Removing the N-terminal BOC group was carried out as in stage D, but at -10°C. the Crude product was purified on RP-18-Seppak® (5 g; Waters) with a gradient from 0.1% TFUK in water/acetonitrile 100/0 to 0.1% TFUK in 60/40 water/acetonitrile to obtain 306 mg of the compound indicated in the title, in the form of triptoreline.

1H-NMR: (Meon) (selected peaks for the main rotamer) of 1.30 (s, 3H); 1,31 (a, 3H); 2,10 (AB-syst, 2H); to 2.55 (s, 3H); of 5.81 (m, 1H).

HPLC: Rt= 31,88 min (A1)

Rt= 33,30 min (B1)

ESMS: m/z: 569,4 (M+H)+.

Example 2

The compound was obtained as in example 1, using (2E)-5-(tert-butyloxycarbonyl)-5,3-dimethyl-2-hexenoic acid instead of (2E)-5-(tert-butyloxycarbonyl)-5-methyl-2-hexenoic acid at a stage that is

HPLC: Rt= 33,70 min (A1)

Rt= 34,22 min (B1)

ESMS: m/z: 583,4 (M+H)+.

Example 3

Methylamide 1-{(2R)-2-[N-((2E)-5-amino-5-metrex-2-enoyl)-N-methylamino]-3-(biphenyl-4-yl)propionyl}-4-benzylpiperidine-4-carboxylic acid

The compound was obtained as in example 1 using (2R)-2-(tert-butyloxycarbonyl)-N-methyl-3-(4-biphenyl)propionic acid instead of (2R)-2-(tert-butyloxycarbonyl)-N-methyl-3-(2-naphthyl)propionic acid in stage D.

HPLC: Rt= 34,53 min (A1)

Rt= 36,15 min (B1)

ESMS: m/z: 595,4 (M+N)+.

Example 4

Methylamide 1-{(2R)-2-[N-((2E)-5-amino-3,5-dimethylhex-2-enoyl)-N-methylamino]-3-(biphenyl-4-yl)propionyl}-4-benzylpiperidine-4-carboxylic acid

The compound was obtained as in example 1 using (2R)-2-(tert-butyloxycarbonyl)-N-methyl-3-(4-biphenylyl)propionic acid instead of (2R)-2-(tert-butyloxycarbonyl)-N-methyl-3-(2-naphthyl)propionic acid at the stage D is arylamino)-5-methyl-2-hexenoic acid at a stage that is

HPLC: Rt= to 35.15 min (A1)

Rt= 36,83 min (B1)

ESMS: m/z: 609,4 (M+H)+.

Example 5

Methylamide 1-((2R)-2-{N-[(2E)-4-(1-aminocinnamate)but-2-enoyl]-N-methylamino}-3-(biphenyl-4-yl)propionyl}-4-benzylpiperidine-4-carboxylic acid

The compound was obtained as in example 1 using (2R)-2-tert-butyloxycarbonyl-N-methyl-3-(4-biphenylyl)propionic acid instead of (2R)-2-tert-butyloxycarbonyl-N-methyl-3-(2-naphthyl)propionic acid in stage D and using (2E)-4-(1-(tert-butyloxycarbonyl)cyclobutyl)but-2-envoy acid instead of (2E)-5-(tert-butyloxycarbonyl)-5-methyl-2-hexenoic acid at a stage that is

HPLC: Rt= to 35.15 min (A1)

Rt= 36,68 min (B1)

ESMS: m/z: 607,4 (M+H)+.

Example 6

2-Amino-N-[(1R)-2-[4-benzyl-4-(N’,N’-dimethylhydrazine-bonyl)piperidine-1-yl]-1-((lH-indol-3-yl)methyl)-2-oxoethyl]-2-methylpropionamide

tert-Butyl ether 4-benzyl-4-(N’,N’-dimethylhydrazine-carbonyl)piperidine-1-carboxylic acid

To a solution of 1-tert-butyl ester 4-benzylpiperidine-1,4-dicarboxylic acid (0.75 g, 2,35 mmol) (obtained as described Gilligan et al., J. Med. Chem., 1994, 364-370) in methylenchlorid)carbodiimide (0.45 g, of 2.35 mmol) and the mixture was stirred for 30 minutes and Then was added N’,N’-dimethyl (0,27 ml of 3.53 mmol) and diisopropylethylamine (0,52 ml of 3.06 mmol) and the mixture was stirred for 2 days. Added methylene chloride (100 ml), the mixture was washed with saturated aqueous sodium bicarbonate solution (20 ml), water (20 ml), dried (MgSO4), filtered and concentrated in vacuum. The resulting oil was chromatographically on silica (40 g) using heptane/ethyl acetate (1:2) to obtain the 0,76 g tert-butyl ester 4-benzyl-4-(N’,N’-dimethylthiocarbamyl)-piperidine-1-carboxylic acid as a colourless oil.

HPLC: Rt= 9,66 min (N8)

LC-MS: Rt= 9,29 min, m/z: 362,0 (m+1).

N,N-Dimethylhydrazide 4-benzylpiperidine-4-carboxylic acid

To a solution of tert-butyl methyl ether 4-benzyl-4-(N’,N’-dime-Tilgathpilneser)piperidine-1-carboxylic acid (0,76 g, 2.02 mmol) in methylene chloride (2 ml) PRL 0°With the added triperoxonane acid (5 ml) and the mixture was stirred for 60 minutes the Reaction was stopped with ethanol (20 ml), the mixture was concentrated in vacuo and was purified three times with methylene chloride to obtain N,N-dimethylhydrazide 4-benzylpiperidine-4-carboxylic acid in quantitative yield.

To a solution of 2-tert-butoxycarbonylamino-3-(lH-indol-3-yl)-propionic acid (from 0.37 g, 1.2 mmol) in methylene chloride (15 ml) and dimethylformamide (5 ml) was added 1-hydroxy-7-asobancaria (0.16 mg, 1.20 mmol) and hydrochloric acid salt of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (to 0.23 g, 1.20 mmol) and the mixture was stirred for 30 minutes and Then was added N’,N’-dimethylhydrazide 4-benzylpiperidine-4-carboxylic acid (0.26 g, 1.0 mmol) and diisopropylethylamine (to 0.69 ml, 4.0 mmol) and the mixture was stirred over night. Added methylene chloride (100 ml), the mixture was washed with saturated aqueous sodium bicarbonate solution (20 ml), water (20 ml), dried (MgSO4), filtered and concentrated in vacuum. The resulting oil was chromatographically on silica (40 g) using methylene chloride/(10% ammonia in methanol) (9:1) obtaining of 0.43 g of tert-butyl methyl ether (2-(4-benzyl-4-(N’,N’-dimethylhydrazine-carbonyl)piperidine-1-yl)-1-(lH-indol-3-ylmethyl)-2-oxoethyl)carbamino acid as a colourless oil.

HPLC: Rt= 10,45 min (N8)

LC-MS: Rt= 9,92 min, m/z: 548,2 (m+1).

N’,N’-dimethylhydrazide 1-(2-amino-3-((lH-indol-3-yl)propionyl)-4-benzylpiperidine-4-carboxylic acid

To a solution of tert-butyl averti (0.40 g, 0.73 mmol) in methylene chloride (3 ml) at 0°With the added triperoxonane acid (3 ml) and the mixture was stirred for 30 minutes the Reaction was stopped with ethanol (20 ml), the mixture was concentrated in vacuo and was purified three times with methylene chloride to obtain 0,63 g N’,N’-dimethylhydrazide 1-(2-amino-3-((1H-indol-3-yl)propionyl)-4-benzylpiperidine-4-carboxylic acid as a colourless oil.

HPLC: Rt= 7,52 min (N8)

LC-MS: Rt= to 7.61 min, m/z = 448,4 (m+l).

tert-Butyl methyl ether (1-(2-(4-benzyl-4-(N’,N’-dimethylthiocarbamyl)piperidine-1-yl)-1-(lH-indol-3-ylmethyl)-2-oxo-ethylcarbamate)-1-methylethyl)carbamino acid

To a solution of tert-butyloxycarbonyl-2-methylpropionic acid (0.18 g, 0.88 mmol) in methylene chloride (10 ml) was added 1-hydroxy-7-asobancaria (0,12 mg, 0.88 mmol) and hydrochloric acid salt of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.12 g, 0.88 mmol) and the mixture was stirred for 30 minutes and Then was added N’,N’-dimethylhydrazide 1-(2-amino-3-((1H-indol-3-yl)propionyl)-4-benzylpiperidine-4-carboxylic acid (0,46 g, 0.73 mmol) and diisopropylethylamine (0,50 ml of 2.92 mmol) and the mixture was stirred over night. Added methylene chloride (100 ml), the mixture was washed with a saturated aqueous solution of bicarbonate on what was referable on silica (40 g) using methylene chloride/(10% ammonia in methanol) (9:1) to obtain 0.31 g of tert-butyl methyl ether (1-(2-(4-benzyl-4-(N’,N’-dimethylamide-pinocarvone)piperidine-1-yl)-1-(1H-indol-3-ylmethyl)-2-oxo-ethylcarbamate)-1-methylethyl)carbamino acid as a colourless oil.

HPLC: Rt= of 10.25 min (N8)

LC-MS: Rt= 9,66 min, m/z = 663,2 (m+1).

2-Amino-N-[(1R)-2-[4-benzyl-4-(N’,N’-dimethylthiocarbamyl)piperidine-1-yl]-1-((lH-indol-3-yl)methyl)-2-oxoethyl]-2-methylpropionamide

To a solution of tert-butyl methyl ether (1-(2-(4-benzyl-4-(N’,N’-dimethylthiocarbamyl)piperidine-1-yl)-1-(lH-indol-3-ylmethyl)-2-oxoethylidene)-1-methylethyl)carbamino acid (0.29 grams, 0.46 mmol) in methylene chloride (3 ml) at 0°With the added triperoxonane acid (3 ml) and the mixture was stirred for 30 minutes the Reaction was stopped with ethanol (20 ml), the mixture was concentrated in vacuo and was purified three times with methylene chloride to obtain 0.25 g of 2-amino-N-[(1R)-2-[4-benzyl-4-(N’,N’-dimethylthiocarbamyl)piperidine-1-yl]-1-((1H-indol-3-yl)methyl)-2-oxoethyl]-2-methylpropionamide in the form of a white amorphous powder.

HPLC: Rt= 24,56 min (A1), Rt= 24,95 min (B1), Rt= 7,73 min (N8).

LC-MS: Rt= 7,74 min, m/z = 533,4 (m+1).

Example 7

2-Amino-N-[(1R)-2-[(3R)-3-benzyl-3-(N’,N’-dimethylthiocarbamyl)-piperidine-1-yl]-1-benzoyloxymethyl-2-oxo-ethyl)-2-methyl-propionamide

This compound was obtained using the method of example 6.

ESMS: m/z: 524,4 (M+N)+

the Tyl)-2-oxoethyl]-2-methylpropionamide

This compound was obtained using the method of example 6.

ESMS: m/z: 533,4 (M+N)+

HPLC: Rt: 27,60 min (A1)

HPLC: Rt: 26,84 min (B1)

Example 9

Ethyl ester of 1-{(2R)-2-[N-((2E)-5-amino-5-metrex-2-enoyl)-N-methylamino]-3-(biphenyl-4-yl)propionyl}-4-benzylpiperidine-4-carboxylic acid

LC-MS: Rt= 12,11 min, m/z: 610,4 (M+N)

HPLC: Rt= 42,075 min (A1)

HPLC: Rt= 44,383 min (B1)

Example 10

Ethyl ester of 1-{(2R)-2-[N-((2E)-5-amino-3,5-dimethylhex-2-enoyl)-N-methylamino]-3-(biphenyl-4-yl)propionyl}-4-benzylpiperidine-4-carboxylic acid

LC-MS: Rt= 12,36 min, m/z: 624,4 (M+N)

HPLC: Rt= 42,785 min (A1)

HPLC: Rt= 45,148 min (B1)

Example 11

Ethyl ester of 1-{(2R)-2-[N-((2E)-5-amino-5-metrex-2-enoyl)-N-methylamino]-3-(2-naphthyl)propionyl}-4-benzylpiperidine-4-carboxylic acid

LC-MS: Rt= 11,92 min, m/z: 584,4 (M+N)

HPLC: Rt= 39,893 min (A1)

HPLC: Rt= 42,046 min (B1)

Example 12

Ethyl ester of 1-{(2R)-2-[N-((2E)-5-amino-3,5-dimethylhex-2-enoyl)-N-methylamino]-3-(2-naphthyl)propionyl}-4-benzylpiperidine-4-Carbo/P>

HPLC: Rt= 42,780 min (B1)

Example 13

Ethyl ester of (3S)-1-[(2R)-2-((2E)-5-amino-5-metrex-2-anolamine)-3-(1H-indol-3-yl)propionyl]-3-benzylpiperidine-3-carboxylic acid

LC-MS: Rt= 10,07 min, m/z: 559,4 (M+N)

HPLC: Rt= 35,585 min (A1)

HPLC: Rt= 37,441 min (B1)

Example 14

Ethyl ester of (3S)-1-[(2R)-2-((2E)-5-amino-3,5-dimethylhex-2-anolamine)-3-(1H-indol-3-yl)propionyl]-3-benzylpiperidine-3-carboxylic acid

LC-MS: Rt= 10,42 min, m/z: 573,2 (M+N)

HPLC: Rt= 36,680 min (A1)

HPLC: Rt= 38,563 min (B1)

Example 15

Ethyl ester of (3S)-1-[(2R)-2-(3-(aminomethyl)benzoylamine)-3-(1H-indol-3-yl)propionyl]-3-benzylpiperidine-3-carboxylic acid

LC-MS: Rt= 10,24 min, m/z: 567,4 (M+N)

HPLC: Rt= 36,118 min (A1)

HPLC: Rt= 38,052 min (B1)

Example 16

N-{(1R)-2-[4-Benzyl-4-(N’,N’-dimethylthiocarbamyl)-piperidine-1-yl]-1-((2-naphthyl)methyl)-2-oxoethyl]-N-methylamide (2E)-5-amino-5-metrex-2-ene acid

LC-MS: Rt= 8,82 min, m/z: 598,4 (M+N)

HPLC: Rt= 30,858 min (A1)

HPLC: Rt= 31,198 min (B1)

ESMS: m/z: 573,2 (M+N)+

Example 18

N-{(1R)-2-[3-Benzyl-3-(N’,N’-dimethylthiocarbamyl)-piperidine-1-yl]-1-((2-naphthyl)methyl)-2-oxoethyl}-N-methyl-amide of (2E)-5-amino-5-metrex-2-ene acid

ESMS: m/z: 598,4 (M+N)+

Example 19

{(1R)-2-[3-Benzyl-3-(N’,N’-dimethylthiocarbamyl)piperidine-1-yl]-1-(benzoyloxymethyl)-2-oxoethyl}amide of (2E)-5-amino-5-metrex-2-ene acid

LC-MS: Rt= 8,77 min, m/z: 564,2 (M+N)

HPLC: Rt= 29,829 min (A1)

HPLC: Rt= 29,250 min (B1)

Example 20

2-Amino-N-{2-[3-benzyl-3-(N’,N’-dimethylthiocarbamyl)piperidine-1-yl]-((2-naphthyl)methyl)-2-oxo-ethyl}-2-methyl-propionamide

LC-MS: Rt= 4,77 min, m/z: 544,4 (M+N)

HPLC: Rt= 30,900/31,586 min (A1)

HPLC: Rt= 30,188/30,727 min (B1)

Example 21

2-Amino-N-{(1R)-2-[3-benzyl-3-(N’,N’-dimethylhydrazine-bonyl)piperidine-1-yl]-1-((biphenyl-4-yl)methyl)-2-oxoethyl}-2-methylpropionamide

LC-MS: Rt= 4,98 min, m/z: 570,4 (M+N)

HPLC: Rt= 33,839/34,313 min (A1)

HPLC: Rt= 33,297/33,640 min (B1)

Example 22

2-Amino-N-{(1R)-2-[3-benzyl-3-(N’,N’-THE ASS="ptx2">LC-MS: Rt= 4,32 min, m/z: 533,4 (M+N)

HPLC: Rt= 25,946/27,231 min (A1)

HPLC: Rt= 25,822/26,685 min (B1)

Example 23

2-Amino-N-{2-[3-benzyl-3-(N’,N’-dimethylthiocarbamyl)piperidine-1-yl]-1-(benzoyloxymethyl)-2-oxoethyl}-2-methyl-propionamide

LC-MS: Rt= 4,33/min 4.75V; m/z: 510,4 (M+N)

HPLC: Rt= 30,737/30,945 (A1)

HPLC: Rt= 26,809/27,307 (B1)

Example 24

2-Amino-N-{(1R)-2-[3-benzyl-3-(N’,N’-dimethylhydrazine-bonyl)piperidine-1-yl]-1-(benzoyloxymethyl)-2-oxoethyl}-2-methylpropionamide

LC-MS: Rt= 4,25/5,27 min; m/z: 519,4 (M+N)

HPLC: Rt= 24,994 min (A1)

HPLC: Rt= 25,742 min (B1)

Example 25

(Pyrrolidin-1-yl)amide 1-[(2R)-2-(2-amino-2-methylpropionamide)-3-(1-H-indol-3-yl)propionyl]-3-benzylpiperidine-3-carboxylic acid

The mixture of diastereomers

The diastereoisomer I:

LC-MS: Rt= 4,40 min; m/z: 559,4 (M+N)

HPLC: Rt= to 26.04 min (A1)

HPLC: Rt= 25,79 min (B1)

The diastereoisomer II:

HPLC: Rt= 27,38 min (A1)

Example 26

2-Amino-N-{(1R)-2-[3-benzyl-3-(N,N’,N’-trimethylhydrazine-carbonyl)piperidine-1-yl]-1-(Areaer I:

LC-MS: Rt= 5,07 min; m/z: 547,4 (M+N)

HPLC: Rt= 32,16 min (A1)

The diastereoisomer II:

LC-MS: Rt= 5,24 min; m/z: 547,4 (M+H) HPLC: Rt= 33,60 min (Al) Compounds of examples 9-26 were obtained using the methods of examples 1-6.

Example 27

Data in vitro by stimulating the secretion of growth hormone activity of the compounds of Examples 1-26.

Data are presented as values EC50and Emaxand obtained according to the methods described previously in the present description of the invention, in comparison with known peptide secretion stimulator of growth hormone GHRP-6. The obtained data are presented in the table.

The data presented in the table clearly show that all the compounds of the present invention have significant activity against the stimulation of growth hormone secretion and that the effectiveness of a number of compounds (including the compounds of examples 3, 5, 22 and 25), at least approximately equal to or even greater than the activity of GHRP-6.

1. Derived piperidinecarboxylic acid, selected from the following compounds:

Methylamide 1-{(2R)-2-[N-((2E)-5-amino-5-metrex-2-enoyl)-N-methylamino]-3-(2-naphthyl)propionyl}-4-benzylpiperidine--3-(2-naphthyl)propionyl}-4-benzylpiperidine-4-carboxylic acid

Methylamide 1-{(2R)-2-[N-((2E)-5-amino-5-metrex-2-enoyl)-N-methylamino]-3-(biphenyl-4-yl)propionyl}-4-benzylpiperidine-4-carboxylic acid

Methylamide 1-{(2R)-2-[N-((2E)-5-amino-3,5-dimethylhex-2-enoyl)-N-methylamino]-3-(biphenyl-4-yl)propionyl}-4-benzylpiperidine-4-carboxylic acid

Methylamide 1-((2R)-2-{N-[(2E)-4-(1-aminocinnamate)but-2-enoyl]-N-methylamino}-3-(biphenyl-4-yl)propionyl)-4-benzylpiperidine-4-carboxylic acid

2-Amino-N-[(1R)-2-[4-benzyl-4-(N’,N’-dimethylthiocarbamyl)piperidine-1-yl]-1-((1H-indol-3-yl)methyl)-2-oxoethyl]-2-methylpropionamide

2-Amino-N-{(1R)-2-[(3R)-3-benzyl-3-(N’,N’-dimethylthiocarbamyl)-piperidine-1-yl]-1-benzoyloxymethyl-2-oxoethyl}-2-methylpropionamide

2-Amino-N-[(1R)-2-[(3R)-3-benzyl-3-(N’,N’-dimethylthiocarbamyl)-piperidine-1-yl]-1-((1H-indol-3-yl)methyl)-2-oxo-ethyl]-2-methylpropionamide

Ethyl ester 1-{(2R)-2-[N-((2E)-5-amino-5-metrex-2-enoyl)-N-methylamino]-3-(biphenyl-4-yl)propionyl}-4-benzylpiperidine-4-carboxylic acid

Ethyl ester 1-{(2R)-2-[N-((2E)-5-amino-3,5-dimethylhex-2-enoyl)-N-methylamino]-3-(biphenyl-4-yl)propionyl}-4-benzylpiperidine-4-carboxylic acid is of IMT}-4-benzylpiperidine-4-carboxylic acid

Ethyl ester 1-{(2R)-2-[N-((2E)-5-amino-3,5-dimethylhex-2-enoyl)-N-methylamino]-3-(2-naphthyl)propionyl}-4-benzylpiperidine-4-carboxylic acid

Ethyl ester of (3S)-1-[(2R)-2-((2E)-5-amino-5-metrex-2-anolamine)-3-(1H-indol-3-yl)propionyl]-3-benzylpiperidine-3-carboxylic acid

Ethyl ester of (3S)-1-[(2R)-2-((2E)-5-amino-3,5-dimethylhex-2-anolamine)-3-(1H-indol-3-yl)propionyl]-3-benzylpiperidine-3-carboxylic acid

Ethyl ester of (3S)-1-[(2R)-2-(3-(aminomethyl)benzoylamine)-3-(1H-indol-3-yl)propionyl]-3-benzylpiperidine-3-carboxylic acid

N-{(1R)-2-[4-benzyl-4-(N’,n’-dimethylthiocarbamyl)-piperidine-1-yl]-1-((2-naphthyl)methyl)-2-oxoethyl}-N-methylamide (2E)-5-amino-5-metrex-2-ene acid

N-[(1R)-2-[3-benzyl-3-(N’,N’-dimethylthiocarbamyl)-piperidine-1-yl]-1-((1H-indol-3-yl)methyl)-2-oxoethyl]amide of (2E)-5-amino-5-metrex-2-ene acid

N-{(1R)-2-[3-benzyl-3-(N’,N’-dimethylthiocarbamyl)-piperidine-1-yl]-1-((2-naphthyl)methyl)-2-oxoethyl}-N-methylamide (2E)-5-amino-5-metrex-2-ene acid

{(1R)-2-[3-benzyl-3-(N’,N’-dimethylthiocarbamyl)piperidine-1-yl]-1-(benzoyloxymethyl)-2-oxoethyl}amidror)piperidine-1-yl]-1-((2-naphthyl)methyl)-2-oxoethyl}-2-methylpropionamide

2-Amino-N-{(1R)-2-[3-benzyl-3-(N’,N’-dimethylthiocarbamyl)piperidine-1-yl]-1-((biphenyl-4-yl)methyl)-2-oxoethyl}-2-methylpropionamide

2-Amino-N-{(1R)-2-[3-benzyl-3-(N’,N’-dimethylthiocarbamyl)piperidine-1-yl]-1-((1H-indol-3-yl)methyl)-2-oxoethyl}-2-methylpropionamide

2-Amino-N-{2-[3-benzyl-3-(N’-methylhydrosiloxane)piperidine-1-yl]-1-(benzoyloxymethyl)-2-oxoethyl}-2-methylpropionamide

2-Amino-N-{(1R)-2-[3-benzyl-3-(N’-methylhydrosiloxane)piperidine-1-yl]-1-((1H-indol-3-yl)methyl)-2-oxoethyl}-2-methylpropionamide

(Pyrrolidin-1-yl)amide 1-[(2R)-2-(2-amino-2-methylpropionamide)-3-(1H-indol-3-yl)propionyl]-3-benzylpiperidine-3-carboxylic acid

2-Amino-N-{(1R)-2-[3-benzyl-3-(N,N’,N’-Trimethylhydrazinium)piperidine-1-yl]-1-((1H-indol-3-yl)methyl)-2-oxoethyl}-2-methylpropionamide

and their pharmaceutically acceptable salts.

2. Pharmaceutical composition for stimulating the secretion of growth hormone, comprising as active ingredient the compound under item 1 or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier or diluent.

3. The connection to the supply activity.

4. The method of stimulation of secretion by the pituitary gland of a mammal growth hormone, including the introduction of a given mammal an effective amount of the compounds on p. 1, or its pharmaceutically acceptable salts, or pharmaceutical compositions under item 2.



 

Same patents:

The invention relates to the use of compounds of formula I to obtain medical drug suitable for the treatment of asthma, seasonal or chronic allergic rhinitis, sinusitis, conjunctivitis, food Allergy, scombroid poisoning, psoriasis, urticaria, pruritus, eczema, rheumatoid arthritis, inflammatory bowel disease, chronic obstructive pulmonary disease, thrombosis and otitis and preferably asthma, seasonal and chronic allergic rhinitis

The invention relates to new imidazole derivative of the formula (I):where R1represents phenyl or pyridinyl, substituted by substituents selected from the group comprising (1) phenyl, (2) furyl, thienyl, (3) halogen, (4) halogen(lower)alkyl, (5) lower alkylthio, (6) nitro, (7) lower alkenyl, optionally substituted phenyl, (8) lower quinil, optionally substituted phenyl, (9) lower alkoxy, optionally substituted cyclo(lower)alkyl or phenyl, (10) lower alkyl, optionally substituted, phenyloxy or (11) amino, optionally substituted protected carboxyla; R2represents lower alkyl; R3represents halogen or lower alkyl; R4represents (1) lower alkenyl, optionally substituted phenyl, (2) phenyl, optionally substituted lower alkyl or lower alkenyl, (3) lower alkyl or (4) thienyl, optionally substituted with halogen; a represents a lower alkylene and L represents a simple bond, a lower albaniles or lower alkylene, optionally substituted phenyl or pyridinyl, or-X-CH2- where X represents O or NR5where R5represents hydrogen or n is

The invention relates to imidazole derivative of the formula (I), where X, Y, R, R2, R3and R4such as defined in the claims

The invention relates to indole derivative of General formula I:

where R1represents hydrogen, halogen, methoxy; R2represents hydrogen, halogen, methyl, ethyl, methoxy; R3represents carboxy, tetrazolyl or CONHSO2R4in which R4represents methyl, ethyl, phenyl, 2,5-dimethylisoxazole, trifluoromethyl; T represents-CH2- or-SO2-; and ring a is 3-chlorophenyl, 4-chlorophenyl, 3-triptoreline, 3,4-dichlorophenyl, 3,4-differenl, 3-fluoro-4-chlorophenyl, 3-chloro-4-forfinal, 2,3-dichloride-5-yl; or their pharmaceutically acceptable salts or esters, as well as pharmaceutical compositions containing them

The invention relates to imidazole derivative of formula (1), where X, Y, R, R2, R3and R4such as defined in the claims

The invention relates to new derivatives of azetidine formula

in which R denotes an element of the formula

R1denotes a methyl radical or ethyl, R2denotes a naphthyl radical, hinely, phenyl, possibly substituted by one or more halogen atoms, alkyl radicals, alkoxyl, hydroxyl, etc.,, R3and R4identical or different, represent a phenyl radical, possibly substituted by one or more halogen atoms, alkyl, alkoxyl, formyl, trifluoromethyl, etc.,, R5denotes an alkyl radical or phenyl, substituted by one or more halogen atoms, R6and R7identical or different, denote a hydrogen atom or an alkyl radical, or R6and R7together with the nitrogen atom to which they are connected, form piperidinyl or pieperazinove cycle, substituted alkyl, R’6and R’7identical or different, denote a hydrogen atom or an alkyl radical, or R’6and R’7together with the nitrogen atom to which they are connected, form a pyrolidine or pieperazinove cycle, possibly substituted by one alkyl radical, cycloalkyl, -ALK-O-ALK, hydroxyalkyl, or R6and R7together with the nitrogen atom to which they are connected, form a loop imidazole, piperazinone, thiomorpholine, etc., R8denotes alkyl, R9denotes a hydrogen atom, an alkyl radical or an alkyl, substituted dialkylamino, phenyl, etc.,, R10and R11identical or different, denote a hydrogen atom or alkyl, R12and R13together with the nitrogen atom to which they are connected, form a loop of the research, a R16and R17together with the nitrogen atom to which they are connected, form a loop of piperidine, R’ denotes a hydrogen atom or the radical-CO-ALK, ALK denotes an alkyl or alkylene, and alkyl or alkylene radicals or their parts and CNS radicals or their parts are straight or branched chain, containing from 1 to 6 carbon atoms, and their optical isomers and their salts with mineral or organic acid

The invention relates to a derivative phthalazine General formula (I) or their pharmaceutically acceptable salts, or hydrates, where R1and R2are the same or different from each other and each represents a halogen atom, a C1-C4alkyl group which may be substituted by a halogen atom, a hydroxyl group or a C1-C4alkoxygroup, which may be substituted by a halogen atom, or cyano; X represents a cyano, a halogen atom, hydroxyimino, optional O-substituted C1-C4alkyl group, or a heteroaryl group selected from thiazoline, thienyl, pyrazolidine, triazolinones and tetrazolyl groups that may be substituted WITH1-C4alkyl group; Y represents a cyclic amino group (i) - (v) described in paragraph 1 of the claims; (vi) etinilnoy or ethyl group substituted WITH1-C4alkyl group, which, in turn, replaced by a number of deputies referred to in paragraph 1 of the claims; (vii) optionally substituted phenyl group; (viii) pyridyloxy or thiazolidine group

The invention relates to derivatives of 6-sulfamoylbenzoic-4-carboxylic acid of formula (1), where R1, R2, R3and R4such as defined in the claims

The invention relates to new indole derivative of the formula I

where two of R1a, Rlb, Rlc, Rldindependently from each other denote H, F, I, Cl, Br, (C1-C4)alkyl, phenyl, phenyl-(C1-WITH4)alkyl, (C1-C4)alkoxy, phenyl-(C1-C4)alkoxy, phenyloxy, HE, -NR5aR5b, -SOn-R6c, n is 1-2, and are the same or different, and two other mean N; where all residues R5a, R5b, R6cif present in the molecule more than once, are independent from each other and may be each the same or different; one of R2and R3means -(CH2)p-CO-R8and the other denotes H, F, Cl, Br, or -(CH2)p-CO-R8; p is 0, 1 or 2; R8means-NR9R10, -OR10; A represents the bivalent residue of(C1-C4)alkyl, which is saturated or which contains a triple bond, or -(C1-C4)alkyl-CO-NH-, where the nitrogen is associated with R4; R4means phenyl, which is substituted by one residue R15bor pyridyl, which is unsubstituted or substituted14on the nitrogen atom; all their stereozoom

The invention relates to new arylpiperazine derivative of General formula I

< / BR>
and their pharmaceutically acceptable salts, esters, where Y is O; Q is CH; X, Z and Z' each independently represent CH or N; m=0-1; n=0-4; R1and R2independently selected from H, F, Cl, Br, OCH3OC2H5, OCH2CF3CH3WITH2H5, CF3isopropylate; R3represents H; R4and R5represent H or phenyl, except that R1represents H, R2represents H, Cl or CF3, R3, R4and R5=N, Y=0, and Q=CH, if m=0 and n=1; and also except that R1represents H, R2is OCH3, R3, R4and R5=H, Y=0, Q=CH, if m=0 and n=2

The invention relates to new derivatives of piperidine-ketocarboxylic acids of the formula (I), where R1- COR4or SO2R4, R4means of alkenyl, substituted phenyl or pyridine, naphthyl, honokalani, chinoline, benzothiophene, dihydroxyphenyl or pyridyl, substituted with allmineral, R2- C1-C6-alkyl which can be substituted by phenyl or pyridium, R3group-OR6or other6where R6means hydrogen, C1-C6-alkyl, which may be a phenyl, pyridine or morpholinium, their tautomeric and isomeric forms, and salts

The invention relates to an inhibitor of the activity of esterified cholesterol transport protein (HETB), comprising as active ingredient a compound represented by the formula (I), where R is a straight or branched alkyl group; a lower halogenating group; substituted or unsubstituted cycloalkyl group; substituted or unsubstituted cycloalkylcarbonyl group; substituted or unsubstituted aryl group, or substituted or unsubstituted heterocyclic group, X1X2X3and X4may be the same or different and each represents a hydrogen atom, halogen atom, lower alkyl group, lower halogenating group; a lower alkoxygroup; a cyano; a nitro-group; Y represents-CO -, and Z represents a hydrogen atom or mercaptohexanol group, or its pharmaceutically acceptable salt, or hydrate, or MES

The invention relates to nitrogen-containing compounds that may constitute the active ingredient of the pharmaceutical composition active as an antagonist neirokinina, and more particularly to a derivative of arylpyrimidines and pharmaceutical compositions containing these compounds

The invention relates to the derivatives of acanaloniidae formula (I)

or their pharmaceutically acceptable acid additive salts, where R1means a hydrogen atom or hydroxyl; R2means a hydrogen atom or methyl, X is-O - or-CH2-

The invention relates to the derivatives of acanaloniidae formula (I)

or their pharmaceutically acceptable acid additive salts, where R1means a hydrogen atom or hydroxyl; R2means a hydrogen atom or methyl, X is-O - or-CH2-

The invention relates to the derivatives of acanaloniidae formula (I)

or their pharmaceutically acceptable acid additive salts, where R1means a hydrogen atom or hydroxyl; R2means a hydrogen atom or methyl, X is-O - or-CH2-

The invention relates to new derivatives of nitrogen-containing heterocyclic compounds of the formula

or their pharmaceutically acceptable salts, where R1represents H, COCOR2, COOR3or SO2R3, R2is1-6alkyl, C1-6alkenyl,5-7cycloalkyl, 2-thienyl, 3-thienyl, phenyl or substituted phenyl, R3is phenylalkyl,represents a saturated five-membered nitrogen-containing heterocyclic ring with one nitrogen atom or benzododecinium saturated six-membered nitrogen-containing heterocyclic ring;is oxazol, oxadiazole or thiazole, And is associated with carbon atom of the five-membered heteroaromatic rings and represents COO(CH2)mAr,where R1has the values listed above or is CONR4(CH2)mAr or (CH2)mO(CH2)nAr and R1cannot be COCOR2or SO2R3, R4represents H or<

The invention relates to a new compound - camsylate amlodipine of formula (I)

The compound of formula (I) receive treatment amlodipine by camphorsulfonate in an organic solvent

The invention relates to physiologically active compounds and relates to CIS-diamino(2,2,6,6-tetramethylpiperidine-4-yl)tetrachlorethene (IV) dihydrate and method of its production, which is in interaction hydrochloride 4-amino-2,2,6,6-tetramethylpiperidine with tetrachloroplatinate potassium or sodium, followed by separation of the target product
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