UA72462C2 - Compounds with properties of releasing the growth hormone and a pharmaceutical composition based thereon - Google Patents

Abstract

The invention relates to novel compounds, compositions containing them, and their use for treating medical disorders resulting from a deficiency in growth hormone.

Description

The present invention relates to novel compounds, compositions containing them, and their use for the treatment of medical disorders caused by growth hormone deficiency.

Growth hormone is a hormone that stimulates the growth of all tissues capable of growth. In addition, it is known that growth hormone exhibits a number of effects on metabolic processes, for example, stimulation of protein synthesis and mobilization of free fatty acids, and also switches energy metabolism from carbohydrate metabolism to fatty acid metabolism. Growth hormone deficiency can cause a number of serious medical disorders, such as dwarfism.

Growth hormone is secreted by the pituitary gland. Secretion is under strict direct or indirect control of a number of hormones or neurotransmitters. Growth hormone secretion can be stimulated by growth hormone-releasing hormone (GHR) and inhibited by somatostatin. In both cases, hormones are secreted from the hypothalamus, but their action is mediated primarily through specific receptors located in the pituitary gland. Other compounds have also been described that stimulate the release of growth hormone from the pituitary gland. For example, arginine, --3,4-dihydroxyphenylalanine (I-Oora), glucagon, vasopressin, RASAR (pituitary adenylate cyclase activating peptide), muscarinic receptor agonists, and the synthetic hexapeptide SNER (growth hormone-releasing peptide) release endogenous growth hormone as a result direct action on the pituitary gland or due to the effect on the release of SNEN and/or somatostatin from the hypothalamus.

In the case of disorders or conditions in which elevated levels of growth hormone are desired, the proteinaceous nature of growth hormone makes all routes of administration, except parenteral, unsuitable. In addition, other natural direct-acting secretory stimulators, for example, ONKN and RASAR, are longer polypeptides, so parenteral administration is preferred.

The use of certain compounds to increase growth hormone levels in mammals has previously been suggested,

Example, in ER 18072, ER 83864, UMO 8302272, Mo 8907110, UMO 8901711, MO 8910933, UMO 8809780, Mo 9118016, Mo 9201711, UUO 9304044 , MMO 9700894, UMO 9722620, UMO 9723508, UMO 9740023 and UMO 98106531.

The composition of growth hormone-releasing compounds is of great importance due to their ability to release growth hormone, as well as their bioavailability. Therefore, the purpose of this invention is to create new compounds that have the ability to release growth hormone. In addition, it is an object of the invention to create new growth hormone-releasing compounds (stimulators of growth hormone secretion) that are specific and/or selective and have no or virtually no side effects, such as, for example, the release of luteinizing hormone (LH), follicle-stimulating hormone (FSH), thyroid-stimulating hormone (THH), adrenocorticotropic hormone (ASTH), vasopressin, oxytocin, cortisol and/or prolactin. The goal is also to create compounds that have good oral bioavailability.

According to the present invention, new compounds are proposed that act directly on pituitary cells under normal conditions of the ip myo experiment, causing them to release growth hormone.

These growth hormone-releasing compounds can be used ip miigo as unique research tools to determine, among other things, the mechanism of regulation of growth hormone secretion at the level of the pituitary gland.

In addition, the growth hormone-releasing compounds of the present invention may also be administered ip to enhance the release of endogenous growth hormone.

According to this, the present invention relates to a compound of the general formula (c)

M M in vany i and no 1

Vk (9) Ov--y formula in which

IN! means hydrogen or C 1-6 alkyl,

B2 means hydrogen or C-C-alkyl,

Yi means in 10 shi k 9

What's the matter?

Y or --M o

Kk (at 12 p.m

Kk and holes where B" means hydrogen or C-C-alkyl, p is O or 1, a, 5, i, and y are independently 0, 1, 2, C or 4, g is 0 or 1, the sum of -5ana is equal to 0, 1,2, Z or 4,

VU, VO, B"! and B!2 independently of each other mean hydrogen or C-C-alkyl,

O means "M-B"Z or bonds o where o is equal to 0, 1 or 2, t means -M(B"Z)(B'U) or hydroxyl,

BZ, B": and B!E independently of each other mean hydrogen or C3-to-alkyl,

B" means hydrogen, aryl or hetaryl, b means -O-(CHg)- B", in"

G-Z v" d" v" s yiv vp ' M " v" My v" v" ve

Kk 18 sok u y , Y tv 5 , where B", B'8, BZ, Vo and B! independently of each other mean hydrogen, halogen, aryl, hetaryl, C1-C-alkyl or C-6-Alkoxy,

K is equal to 0, 1 or 2,

In means -O-(CHg)-B22, in? in c" in: I-th c ' M Y 22 22 22

AK M 2 in p y; in

Oh dear

AND ' BUT. 5 5 'where B22, BZ, ID, AD" and 29 independently of each other mean hydrogen, halogen, aryl, hetaryl, C1-C6-alkyl or C1-C6-Alkoxy,

Y is equal to 0, 1 or 2, and is equal to 0, 1 or 2, p is equal to 0, 1 or 2, c is equal to 0, 1 or 2, and is equal to 0 or 1, e is equal to 0, 1, 2 or 3,

It is equal to 0 or 1,

IN? means hydrogen or C 1-6 alkyl optionally substituted with one or more hydroxyl, aryl or hetaryl,

B and B" independently of each other are hydrogen or C 1-6 alkyl optionally substituted with one or more halogen, amino, hydroxyl, aryl or hetaryl,

VAZ means hydrogen or C 1-6 alkyl optionally substituted with one or more halogen, amino, hydroxyl, aryl or hetaryl,

B and B" or he and 28 or EE" and 28 can optionally form -(CHg)-O-(CHg), where and and ) independently of each other are equal to 1, 2 or 3, and ) means -O- , -5- or valence bond,

M means arylene, hetarylene, -O-, -5- or -СВ82/-СВ28-,

IN? and 228 independently of each other represent hydrogen or C 1-6 alkyl optionally substituted with one or more aryl or hetaryl, or a pharmaceutically acceptable salt thereof.

In addition, the compounds of formula I may include any of their optical isomers, in the form of separated, pure or partially purified optical isomers or racemic mixtures thereof. In the case of the presence of one or more chiral carbon atoms, such chiral center or centers can be in the K- and/or 5-configuration, or be a mixture of K and 5.

In addition, compounds of formula I may have one or more carbon-carbon double bonds with the possibility of geometric isomers, and it is assumed that possible stereoisomers (E- or 2-isomers) should be included in the scope of this invention, unless a specific geometric isomer.

In one embodiment of the compound of formula I B! means C1-6-alkyl, such as C1-6-alkyl, in particular methyl. In the second embodiment of B! means hydrogen.

In another embodiment of the compound of formula I, 22 means C1-6-alkyl, such as C1-6-alkyl, in particular, methyl.

In yet another embodiment of the compound of formula I, G means

In oh

Kk ge

Sh- )v and M at 12 is

KO

Kk where B" means hydrogen or C-C-alkyl, p is O or 1,

a, 5, i, and y are independently equal to 0, 1, 2, C or 4, d is equal to 0 or 1, the sum of di-5ana is equal to 0 1, 2, C or 4,

ВУ, ВО, В"! and В"2 independently of each other mean hydrogen or C-C-alkyl,

O means "M-V"Z or 14

Kk ra o where o is equal to 0, 1 or 2, t means -M(B"5) (VU) or hydroxyl,

BZ, B!5 and B!5 independently of each other mean hydrogen or C1-6-alkyl,

B" means hydrogen, aryl or hetaryl. In one embodiment, P" means hydrogen. In the second version of the embodiment, B" means C1-6-alkyl, such as C1-4-alkyl, in particular, methyl. In the third version of the embodiment, p is equal to 0.

In another embodiment, 4 is equal to 0. In yet another embodiment, 4 is equal to 1. In another embodiment, 5 is equal to 0. In yet another embodiment, 5 is equal to 1. In another embodiment, Her is equal to 0. In yet another embodiment, Her is equal to 1. In another embodiment, y is equal to 0. In yet another embodiment, y is equal to 1. In another embodiment, r is equal to 0. In yet another embodiment, r is equal to 1. In another embodiment, РЕ? means hydrogen. In another embodiment of R? means C1-6-alkyl, such as C1-4-alkyl, in particular methyl. In another embodiment, B'E stands for hydrogen. In yet another embodiment, B'!9 means C1-6-alkyl, such as C1-6-alkyl, in particular, methyl. In another embodiment, B"! represents hydrogen. In yet another embodiment, B"! means

C 1-6 alkyl, such as C 1-4 alkyl, in particular methyl. In another embodiment, E is hydrogen. In yet another embodiment, 72 is C 1-6 alkyl, such as C 1-4 alkyl, particularly methyl. In another embodiment, O means "M-V!Z". In yet another embodiment, VZ stands for hydrogen. In yet another embodiment, "Z" means C1-6-alkyl, such as C1-6-alkyl, in particular, methyl.

In yet another embodiment, O means 14 in ra, o

In yet another embodiment, B"" is hetaryl, particularly thiazolyl. In yet another embodiment, B" is hydrogen. In yet another embodiment, o is 0. In another embodiment, o is 1. In yet another embodiment, T is hydroxyl. In another embodiment, T is -M(B')(B'Y). In another incarnation of BV!" means C1-6-alkyl, such as C1-4-alkyl, particularly methyl. In another embodiment, B15 means C1-6-alkyl, such as C1-4-alkyl, particularly methyl.

In another version of the embodiment of the compound of the formula I, G means 9 units of units, where 9, 5, Her, and independently of each other are equal to 0, 1, 2, C or 4, h is equal to 0 or 1, the sum of 5anti equals 0, 1,2, C or 4,

ВУ, ВО, В"! and В"2 independently of each other mean hydrogen or C-C-alkyl,

O means "M-B!Z or 14 of them ra o where o is equal to 0, 1 or 2, t means -M(B'U)(B'U) or hydroxyl,

BZ, B", and B" are independently hydrogen or C1-6 alkyl, B" is hydrogen, aryl or hetaryl. In one embodiment, 4 is 0. In the second embodiment, d is 1. In the third embodiment, 5 is 0. In another embodiment, 5 is 1. In yet another embodiment, y is 0. In another embodiment, y is 1. In yet another embodiment y is equal to 0. In another embodiment, y is equal to 1. In yet another embodiment, r is equal to 0. In another embodiment, r is equal to 1. In yet another embodiment, P? means hydrogen. In another embodiment

AND? means C3-C6-alkyl, such as C1-4-alkyl, in particular methyl. In another embodiment, "9 is hydrogen. In yet another embodiment, B'E is C1-6 alkyl, such as C1-4 alkyl, particularly methyl. In another embodiment, B"! means hydrogen. In another incarnation of V! means C1-6 alkyl, such as C1-4 alkyl, particularly methyl. In another embodiment, V! means hydrogen. In yet another embodiment, K12 means C1-6 alkyl, such as C1-6 alkyl, in particular methyl. In another embodiment, 0 means "M-B'Z. In yet another embodiment, KZ means hydrogen. In yet another embodiment, B1Z means C1-6 alkyl, such as C1-4 alkyl, particularly methyl. In another embodiment, O means 14 in ra o

In yet another embodiment, B" is hetaryl, particularly thiazolyl. In yet another embodiment, E"" is hydrogen. In yet another embodiment, o is 0. In another embodiment, o is 1. In yet another embodiment, T is hydroxyl. In another embodiment T stands for -M(B')(B'Y, In yet another embodiment, B! stands for C 1-6 alkyl, such as C 1-6 alkyl, particularly methyl. In another embodiment, B: stands for C 1-6 alkyl, such as C1---alkyl, in particular, methyl.

In the combination of the above formula | better if Y means 4-hydroxy-4-(2-thienyl)piperidino-, (3-hydroxycyclohexyl)imino-, 4-(M,M-dimethylamino)-piperidino-, M-methyl-M-(1-methylpiperidine) -4-yl)amino-, 4- ((M,M-dimethylamino)-methyl)piperidino-, 4-methylpiperazino-, (2,2,6,6-tetramethylpiperidin-4-yl)amino-, 4- hydroxypiperidino -, (35)-3-((M,M-dimethylamino)methyl)piperidino-, (25)-2((M,M-dimethylamino)methyl)pyrrolidino group.

In yet another embodiment of the compound of formula I, C means в" в' в" в" m в в? в where В", В'8, ВЗ, Во and В! independently of each other means hydrogen, halogen, aryl, hetaryl, C1-C6-alkyl or C1-C6-alkyl. In the first embodiment, K"" means hydrogen. In the second embodiment, KZ means hydrogen. In a third embodiment, K"" means hydrogen. In another embodiment, KZ means aryl, in particular, phenyl. In yet another embodiment, 220 means hydrogen. In another embodiment, B! means hydrogen. In the compound of the above formula | C preferably means 2-naphthyl or biphenyl-4-yl.

In another version of the embodiment of the compound of formula I, Y means in? 2 in2 or chews in b" 5 in where 82, BZ, B, de and E independently of each other mean hydrogen, halogen, aryl, hetaryl, C1-6- alkyl or C1-6- alkoxy. In one version of the embodiment of RK? means hydrogen. In the second embodiment, KZ means hydrogen. In the third embodiment, 22" means hydrogen. In another embodiment, 22" is halogen, particularly fluorine. In yet another embodiment, 25 is hydrogen. In another embodiment, P29 is hydrogen. In a compound of formula I above, Y is preferably phenyl, 4-fluorophenyl, or 2-thienyl.

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

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

In another version of the embodiment of the compound of formula I, c is equal to 0.

In another version of the embodiment of the compound of formula I, a is equal to 0.

In yet another version of the embodiment of the compound of the formula | M represents arylene or -CHB2/-СВ28-, where B" and 28 independently of each other represent hydrogen or C1-6-alkyl, optionally substituted with aryl or hetaryl. In one embodiment, M represents arylene, in particular, phenylene. In another embodiment, M means -"СВ2/-СВ28-", where

B" and b28 are independently hydrogen or C1-6 alkyl. In another embodiment, B" is hydrogen. In yet another embodiment, B27 means C1-6 alkyl, in particular, methyl. In another embodiment, 228 is hydrogen. In another embodiment, M means the E-isomer -СВ2/-СВ25-. In the compound of the above formula I, M preferably means ethenylene, 1,3-phenylene or 1,2-propenylene.

In another version of the embodiment of the compound of formula I, e is equal to 0.

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

In another variant, the embodiment of the compound of formula I is equal to 0.

In yet another embodiment of the compound of formula I, 7 is 1.

In another embodiment of the compound of formula I! R? and B" independently of each other mean hydrogen or

C-C alkyl. In one embodiment, P: means hydrogen. In the second embodiment, RU means C1-C6 alkyl, in particular, methyl. In the third embodiment, KE" means hydrogen. In another embodiment, EK" means C1-6-alkyl, in particular, methyl.

In another variant of the embodiment of the compounds of the formula I R and B" or R: and R3 or R" and EZ can optionally form -(CHg)-0-(CHg);, where and and | are independently equal to 1 or 2, and ) means -O-, -5- or a valence bond.

In another version of the embodiment of compounds of the formula I RU and B" form -(CHg)-O-(CHg) g, where and and ) independently of each other are equal to 1, 2 or 3, and ) means -O-, -5- or valence bond. In one embodiment, the sum of ih) is 3. In the second embodiment, О means a valence bond. In a separate embodiment, (SVUVUU) means cyclobutyl.

In another version of the embodiment of the compounds of the formula I P and B" form -(CHg)-Ш-(CHag), where and and | independently of each other are equal to 1 or 2, and ! means -O-, -5- or valence bond. In one embodiment, the sum of it) is 3. In the second embodiment, ) means a valence bond. In a separate embodiment, (СВ5В7) means cyclobutyl.

In yet another embodiment of the compound of formula I, RU means hydrogen. In the second embodiment, BZ means C 1-6 alkyl, in particular, methyl.

In a separate embodiment, the present invention relates to a compound of the general formula

Gee! (c) i iy (c)

Ye Yang M

M M

VA rai t tu M s | and 1 n Ge) Ov-y formula in which

IN! means hydrogen or C 1-6 alkyl,

B2 means C-C-alkyl,

Г means a 9 o

Kk dv

Kk

C) and 5

Shsh-)v

ИЙ or --ЙКХ Ge) in and at 12 ' ( Kh

Kk

In VV! where B" means hydrogen or C1-6-alkyl, p is O or 1, a, 5, y, and are independently equal to 0, 1, 2, C or 4, g is equal to 0 or 1, the sum of dig-5- -1-y equals 0, 1, 2, C or 4,

ВУ, ВО, В"! and В"2 independently of each other mean hydrogen or C-C-alkyl,

O means "M-V"Z or 14

E ra o where o is equal to 0, 1 or 2, t means -M(B"5) (VU) or hydroxyl,

BZ, B!5 and B!5 independently of each other mean hydrogen or C1-6-alkyl,

B!" means hydrogen, aryl or hetaryl, b means 37

And 18 in" in" E or in. in" in where B", B'8, VZ, Vo and B! independently of each other means hydrogen, halogen, aryl, hetaryl, C1-6-alkyl, or C1-6-alkyl,

U means 22 i 23 » 23 22 v v E v 26. v v" ' 5 v? where 22, BZ, B, where and 26 independently of each other mean hydrogen, halogen, aryl, hetaryl, C1-C-alkyl or C-6-Alkoxy, a is 0, 1 or 2, p is 0, 1 or 2, c is 0, 1 or 2, a is 0 or 1, e is 0, 1, 2 or 3,

It is equal to 0 or 1,

VAZ means hydrogen or C-6-alkyl optionally substituted with one or more hydroxyl, aryl or hetaryl,

AND? and B" are independently hydrogen or C 1-6 alkyl optionally substituted with one or more halogen, amino, hydroxyl, aryl or hetaryl,

VAZ means hydrogen or C 1-6 alkyl optionally substituted with one or more halogen, amino, hydroxyl, aryl or hetaryl,

B and B" or P and E8 or БЕ" and 8 can optionally form -(CHg)-0O-(CHg)-, where and and | are independently equal to 1, 2 or 3, and ) means -0-, -5- or a valence bond,

M means arylene or -СВ2/-СВ28-,

IN? and 228 independently of each other represent hydrogen or C 1-6 alkyl optionally substituted with one or more aryl or hetaryl, or a pharmaceutically acceptable salt thereof.

The best compounds of the formula | according to the invention are the following: /M-(1А8)-1-(М4-(1А8)-1-benzyl-2-(4-

((dimethylamino)methyl)piperidin-1-yl)-2-oxoethyl|-M-methylcarbamoyl)-2-(2-naphthyl)ethyl)-M-methylamide (2E)-5-amino-5-methylhex-2- enoic acid

And M and on ru I sleep, about M. sleep,

M-AC1 A)-1-14-(1 A)-1-benzyl-2-((35)-3-(dimethylaminomethyl)piperidin-1-yl)-2-oxoethyl|-M-methylcarbamoyl)u-2 -(2-naphthyl)ethyl)-M-methylamide (2E)-5-amino-5-methylhex-2-enoic acid: M soma i sn, o no» sn,

M-A(18)-1-74-(C1 A)-1-benzyl-2-((35)-3-(dimethylaminomethyl)piperidin-1-yl)-2-oxoethyl|-M-methylcarbamoyl)-2 -(2-naphthyl)ethyl)-M-methylamide (2E)-4-(1-aminocyclobutyl)-but-2-enoic acid vi i s Y x M ech ni g m sn, o mon»

CH,

M-AC1 A)-1-44-(1 A)-1-benzyl-2-((25)-2-((dimethylamino)methyl)pyrrolidin-1-yl)-2-oxoethyl|-M-methylcarbamoyl) -2-(2-naphthyl)ethyl)-M-methylamide (2E)-5-amino-5-methylhex-2-enoic acid: M - on LV IV. sn, o m" sn» sn.

M-AC1 A)-1-44-(1 A)-1-benzyl-2-((25)-2-((dimethylamino)methyl)pyrrolidin-1-yl)-2-oxoethyl|-M-methylcarbamoyl) -2-(2-naphthyl)ethyl)-M-methyl-3-(methylamino)-methyl)benzamido: M and M sn, sn, o m7sn sn,

М-А(Ц1 А)-1-1(4Ч-К1 А)-1-benzyl-2-(4-(dimethylamino)piperidin-1-yl)2-oxoethyl|-M-methylcarbamoyl)-2-(2 - naphthyl)ethyl)-M-methylamide (2E)-5-amino-5-methylhex-2-enoic acid

A M and on rya sn, 0 "SN, i sn,

M-methyl-M-C1 A)-1-(M-methyl-M-C1 A)-1-N-methyl-M-(1-methylpiperidin-4-yl)ucarbamoyl|-2-phenylethyl)carbamoyl)- 2-(2-naphthyl)ethylamide (2E)-5-amino-5-methylhex-2-enoic acid: M -- on p sn, o sn,

3-aminomethyl-M-((1 2)-1-14-(1 8)-1-benzyl-2-(4-methylpiperazin-1-yl)-2-oxoethyl|-M-methylcarbamoyl)-2-( 2- naphthyl)ethyl)-M-methylbenzamide

It's a dream

KIM with ten,

MA A)-1-(4H-(1B)-1-benzyl-2-(4-methylpiperazin-1-yl)-2-oxoethyl|-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-

M-methylamide of (2E)-5-amino-5-methylhex-2-enoic acid is not snv o | st o : M vu m 8) M sn that "sn

M-methyl-M-((1 A)-1-/M-methyl-M-|(18)-2-phenyl-1-(2,2,6,6-tetramethylpiperidin-4-ylylcarbamoyl)ethyl| Carbamoyl)-2-(2-naphthyl)ethyl)amide (2E)-5-amino-5-methylhex-2-enoic acid

NS CH,

I M 3 nok rt,

Sn o

3-aminomethyl-M-methyl-M-(1 2)-1-(/M-methyl-M-(1 8)-2-phenyl-1-((2,2,6,6-tetramethylpiperidine-4- Ilucarbamoyl)ethyl|carbamoyl)-2-(2-naphthyl)ethyl)-benzamide not 0 t: stO0 "sn, x M

МН сн, 0 сн, no

M-methyl-M-((1 A)-1-(M-methyl-M-C1 A)-2-phenyl-1-((2,2,6,6-tetramethylpiperidin-4-ylcarbamoyl)ethyl|carbamoyl )-2-(2-naphthyl)ethylamide (2E)-5-amino-3,5-dimethylhex-2-enoic acid ne ns sn.sH Ot: с o "ХМ осн, ro prachn 7 и n сн, 0 sleep, no

M-(128)-1-74Ch-((12K)-1-benzyl-2-(4-methylpiperazin-1-yl)-2-oxoethyl|-M-methylcarbamoyl)-2-(2-naphthyl) ethyl)-

M-methylamide (2E)-4-(1-aminocyclobutyl)but-2-enoic acid oldyle

And M

Sun and Sun, oh M.! what a dream

MA A)-1-(4H-(1B)-1-benzyl-2-(4-methylpiperazin-1-yl)-2-oxoethyl|-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-

M-methylamide (2E)-5-amino-3,5-dimethylhex-2-enoic acid сх ; M from Shay

M-AC1 A)-1-(4Ch-(1B)-1-benzyl-2-(4-methylpiperazin-1-yl)-2-oxoethyl|-M-methylcarbamoyl)-2-(biphenyl-4-yl) )ethyl)-M-methylamide (2E)-4-(1-aminocyclobutyl)-but-2-enoic acid x M sn in sn. about him

MA A)-1-4(4Ch-K1B)-1-benzyl-2-(4-hydroxypiperidin-1-yl)-2-oxoethyl|-M-methylcarbamoyl)-2-(biphenyl-4-yl)ethyl )-M-methylamide (2E)-5-amino-5-methylhex-2-enoic acid nomen, Article 0

M sm, 0 on

M-(128)-1-74-K1 2K)-1-benzyl-2-(4-hydroxypiperidin-1-yl)-2-oxoethyl|-M-methylcarbamoyl)y-2-(biphenyl-4-yl) )ethyl)-M-methylamide (2E)-5-amino-3,5-dimethylhex-2-enoic acid: M nom B g m sn, o on

M-A(C1 A)-1-(4Ch-K1 A)-1-benzyl-2-(4-pdroxypiperidin-1-yl)-2-oxoethyl|-M-methylcarbamoyl)-2-(2-naphthyl) ethyl)-

M-methylamide (2E)-5-amino-5-methylhex-2-enoic acid not sn, o) СН» o tu M sn, o on

M-A(C1 A)-1-(4Ch-K1 A)-1-benzyl-2-(4-pdroxypiperidin-1-yl)-2-oxoethyl|-M-methylcarbamoyl)-2-(2-naphthyl) ethyl)-

M-methylamide (2E)-5-amino-3,5-dimethylhex-2-enoic acid ns sn.sH, o sne 0 : M sn, o on

M-(128)-1-74-(12K)-1-benzyl-2-(4-hydroxypiperidin-1-yl)-2-oxoethyl|-M-methylcarbamoyl)y-2-(2-naphthyl) ethyl)-M-methylamide (2E)-4-(1-aminocyclobutyl)but-2-enoic acid

AH po x M s Di She AS sn. about him

MA A)-1-4(4-K1B)-1-(4-fluorobenzyl)-2-(4-pdroxypiperidin-1-yl)-2-oxoethyl|-M-methylcarbamoyl)-2-(2-naphthyl )ethyl)-M-methylamide (2E)-5-amino-5-methylhex-2-enoic acid

And M

Same on om How st, oh he

IS

M-(1 2)-1-74-K1 2)-1-(4-fluorobenzyl)-2-(4-pdroxypiperidin-1-yl)-2-oxoethyl|-M-methylcarbamoyl)-2-(2- Naphthyl)ethyl)-M-methylamide (2E)-5-amino-3,5-dimethylhex-2-enoic acid no snu.sn; o sn, o x M

A, sn, 0 on

IS

MA A)-1-4(4H-(1B)-1-benzyl-2-(4-hydroxy-4-(2-thienyl)piperidin-1-yl)-2-oxoethyl|-M-methylcarbamoyl)- 2-(2-Naphthyl)ethyl)-M-methylamide (2E)-5-amino-5-methylhex-2-enoic acid: M сх на пр у сн, 0 8 он

MA A)-1-(4Ch-K1 AB)-1-(3-hydroxycyclohexylcarbamoyl)-2-phenylethyl|-M-methylcarbamot)-2-(2-naphthyl)ethyl)-

M-methylamide (2E)-5-amino-5-methylhex-2-enoic acid

A M s nya rr ron sleep. at

MAC1 8-1-14Ch-(1 A)-1-benzyl-2-(4-dimethylamino)piperidin-1-yl)-2-oxoethyl|-M-methylcarbamoyl)-2-(2-naphthyl)ethyl)- M-methylamide (2E)-4-(1-aminocyclobutyl)but-2-enoic acid

M sleep, oh "I sleep,

MA A)-1-(4-K(2B8)-2-(4-hydroxypiperidin-1-yl)-2-oxo-1-((2-thienyl)umethyl)ethyl|-M-methylcarbamoyl)-2- (2-naphthyl)ethyl)-M-methylamide (2E)-5-amino-5-methylhex-2-enoic acid

: M sh nah shiy, sn. oh heaven 5-7

M-(1 28)-1-74-K(2 B)-2-(4-hydroxypiperidin-1-yl)-2-oxo-1-((2-thienylmethyl)ethyl|-M-methylcarbamoyl)-2 -(2-Naphthyl)ethyl)-M-methylamide (2E)-5-amino-3,5-dimethylhex-2-enoic acid not sn.ENU o Sn" (c) on

KA IAADKO Sun and Sat. at 477 5th

М-А(Ц1 А)-2-(biphenyl-4-yl)-1-1х4-(2А)-2-(4-hydroxypiperidin-1-yl)-2-oxo-1-((2-thienylmethyl) (2E)-5-amino-5-methylhex-2-enoic acid ethyl|-IM-methylcarbamoyl)ethyl)-M-methylamide

And M

Eh vl te sn, oh and the 8th

M-(18)-2-(biphenyl-4-yl)-1-14-K18)-2-(4-hydroxypiperidin-1-yl)-2-oxo-1-((2-thienylmethyl)ethyl |-M-methylcarbamoyl)ethyl)-M-methylamide (2E)-5-amino-3,5-dimethylhex-2-enoic acid xx - M va ee sn, 0 - 8-7

M-(1 28)-1-74Ch-K(1 2K)-1-benzyl-2-(4-hydroxypiperidin-1-yl)-2-oxoethyl|-M-methyl-carbamoyl)-2-(biphenyl- 4-yl)ethyl)-M-methylamide (2E)-5-methyl-5-(methylamino)hex-2-enoic acid

SN, oh and not in Mod-on sn, g sn. dream o ((18)-1-479Ch-(1 2)-1-benzyl-2-(4-hydroxypiperidin-1-yl)-2-oxoethyl|-M-methylcarbamoyl)-2-(biphenyl-4-yl) ethyl)amide of (2E)-4-(1-aminocyclobutyl)but-2-enoic acid

A : m : Y

And M

NA froze m

N

0) he and their pharmaceutically acceptable salts.

General methods

The methods illustrated in Schemes I-III below should in no way be construed as limiting the present invention in any way, and should be considered only as a guide as to how the compounds of the present invention may be prepared.

Scheme sy kA h 0 esterification / v/v reduction vos-M sh- 5 Х 0 VOS--M ---- ( h on ( iy U nig NI ve You Snu u A

Oxidation of zinc and amination of wax-k -- 64-02 pk ( o bN ( o o kV ka 9 kov in removal

In the protective group of the group I vob--m nn НМ 16 46

Amines of type 9

Kk and Iv

NM

16 ( x Piy 15 in r! Kk can be synthesized from a BOC-protected amino acid (see scheme I). The acid is converted into an ester by conducting a reaction with or without the use of a reagent such as, for example, 1-hydroxybenzotriazole, 1- hydroxy-7-azabenzotriazole or 3-hydroxy-1,2,3-benzotriazol-4(ZH)-one, and a reagent such as, for example, the hydrogen chloride salt of M-(3-dimethylaminopropyl)-M'-ethylcarbodiimide or diisopropylcarbodiimide, and a catalyst such as N,M-dimethylaminopyridine. The ester can be reduced with a suitable reagent such as isobutylaluminum hydride in a suitable solvent such as, for example, toluene, dichloromethane, ether, or tetrahydrofuran to give the BOC-protected aldehyde or alcohol. If alcohol is obtained, then the alcohol can be oxidized to the corresponding aldehyde by a suitable technique, such as, for example, using dimethylsulfoxide / oxalyl chloride / triethylamine or dimethylsulfoxide / sulfur trioxide / pyridine, pyridinium dichromate or x pyridinium chlorchromate.

Reductive amination with the appropriate amine M(B5)(B"E) and a suitable reagent, such as sodium cyanoborohydride or sodium triacetoxyborohydride, in a suitable solvent, such as, for example, alcohols, can give a BOC-protected amine. If at least one of EB": or B! means hydrogen, then the amino group can be protected in a manner known to those skilled in the art, and described in the literature, for example, T.M. UMIeu, Mem Mogk, before the next stages. Removal of the VOC-protecting group can be carried out in a manner known to specialists in this field and described in T.UU.sgeepe,

R.S.M. Mushiv, Rgoiesiime dgoire ip ogdapis zupiSheviv, 279 eyiop, UMieu, Mem Mogk, such as, for example, using hydrogen chloride in ethyl acetate or trifluoroacetic acid in dichloromethane. Scheme I

Are you there? в в - о) в protective group треко я на я на Яв 13 В! AND; in

In m a conditions of connection and, . "m a

B' 2.) removal of protective 12, J 11 to 11 in groups in (si o 9

U be G-ya (o) o protective oh Fa | Kk 1 M 4 no NM M ia connection conditions | | ' - 5 6 « - - : b -ya bo Ov-u V i (is! 2.) removal of protective 12 I group Kk M protective group (o)

A yan ZD v van what are the conditions of connection --- PL S I A A A - - --....--..zh 2.) removal of the protective group (c) (to her V ko n sinyu 8, ra M. is in days m SHHA i » oo fu o a 12, u

There is Mr

Compounds of the formula I type can be synthesized by conducting an amine coupling reaction of the type 9 e co 4 4

Met )v

Example 12: B and a suitable protected acid with or without the use of a coupling reagent such as, for example, 1-hydroxybenzotriazole, 1-hydroxy-7-azabenzotriazole or 3-hydroxy-1,2, 3-benzotriazol-4(3)-one, and a reagent such as, for example, the hydrogen chloride salt of M-(3-dimethylaminopropyl)-M'-ethylcarbodiimide or diisopropylcarbodiimide, in a suitable solvent such as M,M-dimethylformamide or dichloromethane ( see diagram II). Removal of the nitrogen-attached protecting group can be accomplished with an acid in a manner known to one skilled in the art and described in the literature, for example in

T.M. Ssgeepe, R.S.M. Mshiiv, Rgoiesiime dgoirv ip ogdapis zupinev, 274 eaiiop, Umieu, Mem Mogk. The coupling reaction of the product with a suitable protected acid is carried out with or without the use of a reagent capable of entering into coupling reactions, such as, for example, 1-hydroxybenzotriazole, 1-hydroxy-7-azabenzotriazole or /3-hydroxy-1,2,3-benzotriazole -4(3)-one, and a reagent such as, for example, the hydrogen chloride salt of M-(3-dimethylaminopropyl)-M'-ethylcarbodiimide or diisopropylcarbodiimide, in a suitable solvent such as M,M-dimethylformamide or dichloromethane. Removal of the protecting group attached to the nitrogen can be carried out with the help of an acid in a manner known to a person skilled in the art and described in the literature, for example, in T.MM. eyyiop, UMieu, Mem MogK.

The coupling reaction of the product with a suitable protected acid is carried out with or without the use of a reagent capable of entering into coupling reactions, such as, for example, 1-hydroxybenzotriazole, 1-hydroxy-7-azabenzotriazole or 3-hydroxy-1,2,3-benzotriazole- 4(3)-one, and a reagent such as, for example, the hydrogen chloride salt of M-(3-dimethylaminopropyl)-M'-ethylcarbodiimide or diisopropylcarbodiimide, in a suitable solvent such as M,M-dimethylformamide or dichloromethane. All protecting groups can be removed in a manner known to one skilled in the art and described in the literature, for example in

T.M. Stgeepe, R.S.M.MUiyiv, Rgoiesiime dgoimrz ip ogdapis zupipeviv, 279 eyiop, UMieu, Mem Mogk. PI scheme

Ko 8 a in the protective group-) gi on v

I 3 c) | 9 and i

NM Ge) conditions of connection of M (c) - 5 -5-25------ ( x 2.) removal of protective back group OBU 12 ry in V ruk gey 9 10 1) (and in Cl protective group. » on (a vo Ge! re o i I M V conjugation conditions NM i t. (x 2.) removal of protective Kk (c) OBU v' V group re group (0) uh dec v vann go Tone conjugation conditions nytaaaaaaaaodzhyaanaanaayaanalyaayalVzhShyaaldlzhnazhavannat ny 8 10 2.) removal of the protective group in which

Fo ii va. uk dec | I.!

KO fbvedlu M i, ki

Kk o (in KA

Compounds of the formula I type can be synthesized by carrying out the coupling reaction of an amine of the type c

NM (in;

and a suitable protected acid with or without the use of a reagent capable of entering into coupling reactions, such as, for example, 1-hydroxybenzotriazole, 1-hydroxy-7-azabenzotriazole or 3-hydroxy-1,2,3- benzotriazol-4(3)-one, and a reagent such as, for example, the hydrogen chloride salt of M-(3-dimethylaminopropyl)-M'-ethylcarbodiimide or diisopropylcarbodiimide, in a suitable solvent such as M,M-dimethylformamide or dichloromethane (see (PP scheme).Removal of the nitrogen-attached protecting group can be accomplished with an acid in a manner known to a person skilled in the art and described in the literature, for example in

T.M.sgeepe, R.S.M.M yiv, Rgoiesiime dgoyrz ip ogdapis zupipeviv, 279 eayiop, UMieu, Mezh Mogk. The coupling reaction of the product with a suitable protected acid is carried out with or without the use of a reagent capable of entering into coupling reactions, such as, for example, 1-hydroxybenzotriazole, 1-hydroxy-7-azabenzotriazole or /3-hydroxy-1,2,3-benzotriazole -4(3)-one, and a reagent such as, for example, the hydrogen chloride salt of M-(3-dimethylaminopropyl)-M'-ethylcarbodiimide or isopropylcarbodiimide in a suitable solvent such as M,M-dimethylformamide or dichloromethane. Removal of the protecting group attached to the nitrogen can be carried out with the help of an acid in a manner known to a person skilled in the art and described in the literature, for example, in T.MM. eyyiop, UMyeu, Mem MogK.

The coupling reaction of the product with a suitable protected acid is carried out with or without the use of a reagent capable of entering into coupling reactions, such as, for example, 1-hydroxybenzotriazole, 1-hydroxy-7-azabenzotriazole or 3-hydroxy-1,2,3-benzotriazole- 4(3)-one, and a reagent such as, for example, the hydrogen chloride salt of M-(3-dimethylaminopropyl)-M'-ethylcarbodiimide or diisopropylcarbodiimide, in a suitable solvent such as M,M-dimethylformamide or dichloromethane. All protecting groups can be removed in a manner known to one skilled in the art and described in the literature, for example in

T.M.sgeepe, R.(3.M.Mutsiv, Rgoiesiime dgoyrz ip ogdapis zupipeviv, 274 eyiop, UMieu, Mem MogK.

Compounds of the formula | show improved resistance to proteolytic degradation by enzymes because they are unnatural, in particular because natural amide bonds are substituted unnatural analogs of amide bonds. The increased resistance to proteolytic degradation of the compounds of the invention compared to known hormone-releasing peptides is expected to improve their bioavailability compared to peptides offered in the prior art.

In the above structural formulas and in the text of this description of the invention, the following terms have the following meanings:

The C-C alkyl, C-C alkylene, C-4 alkyl or C-4 alkylene groups defined above shall include such alkyl or alkylene groups of the indicated length having a linear, branched, or cyclic configuration.

Examples of linear alkyl are methyl, ethyl, propyl, butyl, pentyl and hexyl and their corresponding divalent moieties such as ethylene. Examples of branched alkyl are isopropyl, sec-butyl, tert-butyl, isopentyl and isohexyl and their corresponding divalent moieties such as isopropylene. Examples of cyclic alkyl are C3-6-cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl and their corresponding divalent moieties such as cyclopropylene.

The above-defined C 1-6 -alkyl groups must include such alkyl groups of the specified length, which have a linear, branched, or cyclic configuration. Examples of a linear alkyl group are methoxy, ethoxy, propoxy, butoxy, pentoxy, and hexoxy. Examples of a branched alkyl group are isopropoxy, sec-butoxy, tert-butoxy, isopentoxy, and isohexoxy. Examples of a cyclic alkyl group are C1-6 cycloalkyl groups, such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy groups.

In the context of this invention, the term "aryl" shall include monovalent carbocyclic aromatic ring moieties that are monocyclic, bicyclic or polycyclic, for example, selected from the group consisting of phenyl and naphthyl, optionally substituted with one or more C 1 -C 6 alkyl, C---an alkyl group, a halogen, an amino group or an aryl group.

In the context of this invention, the term "arylene" shall include divalent carbocyclic aromatic ring moieties that are monocyclic, bicyclic or polycyclic, for example, selected from the group consisting of phenylene and naphthylene, optionally substituted with one or more C 1 -C 6 -alkyl; C is an alkyl group, a halogen, an amino group or an aryl group.

In the context of the present invention, the term "hetaryl" shall include monovalent heterocyclic aromatic ring moieties that are monocyclic, bicyclic, or polycyclic, for example, selected from the group consisting of pyridyl, 1-H-tetrazol-5-yl, thiazolyl, imidazolyl, indolyl , pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, quinolinyl, pyrazinyl or isothiazolyl, optionally substituted with one or more C 1-6 alkyl, C 1-6 alkyl, halogen, amino or aryl.

In the context of this invention, the term "hetarylene" shall include divalent heterocyclic aromatic ring moieties that are monocyclic, bicyclic, or polycyclic, for example, selected from the group consisting of pyridindiyl, 1-H-tetrazoldiyl, thiazoldiyl, imidazoldiyl, indoldiyl, pyrimidindiyl, thiadiazoldiyl .

In the context of the present invention, the term "heterocyclic system" shall include both aromatic and non-aromatic ring moieties, which may be monocyclic, bicyclic or polycyclic, and contain at least one, for example one, two or three nitrogen atom(s) in their ring structure , and optionally one or more, for example, one or two, other heteroatoms, for example, oxygen or sulfur atoms. The heterocyclic system is preferably selected from pyrazole, pyridazine, triazine, indazole, phthalazine, cynoline, pyrazolidine, pyrazoline, aziridine, dithiazine, pyrrole, imidazole, pyrazole, isoindole, indole, indazole, purine, pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline , piperidine, piperazine, indoline, isoindoline or morpholine, optionally substituted by one or more C 1 -C 6 -alkyl, C 1 -C 6 -alkyl, halogen, amino or aryl.

The term "halogen" shall include chlorine (CI), fluorine (P), bromine (Bi) and iodine (1).

In the context of the present invention, the term "stimulator of growth hormone secretion" shall include any compound that has the ability to directly or indirectly induce (ie, stimulate or increase) the release of growth hormone from the pituitary gland. The term "stimulator of growth hormone secretion" includes peptides capable of releasing growth hormone, peptidomimetics capable of releasing growth hormone, and compounds of a non-peptide nature capable of releasing growth hormone.

The compounds of the present invention may optionally be in the form of a pharmaceutically acceptable salt, such as pharmaceutically acceptable acid addition salts of compounds of formula I, which include those obtained by reacting a compound of formula 1/ with an inorganic or organic acid such as hydrochloric acid, hydrobromic, sulfuric, acetic, phosphoric, lactic, malic, maleic, mandelic, phthalic, citric, glutaric, gluconic, methanesulfonic, salicylic, succinic, tartaric, toluenesulfonic, trifluoroacetic, sulfamic or fumaric acids and/or water.

Compounds of formula I may be administered in the form of a pharmaceutically acceptable acid addition salt or, where applicable, an alkali metal, alkaline earth metal or lower alkylammonium salt. Such salt forms are believed to exhibit approximately the same order of activity as the free base forms.

In another aspect, the present invention relates to a pharmaceutical composition comprising as an active ingredient a compound of general formula I or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent.

Pharmaceutical compositions containing a compound of the present invention can be prepared by conventional techniques, for example, as described in Ketipdiopje Rpagtasetschiis! Zsiepse5, 1985 or in Ketipoop:

Tnpe Zsiepse apa Rgasiise oi Rpagtasu, 197 eaiyiop (1995). The compositions can be obtained in conventional forms, for example, capsules, tablets, aerosols, solutions, suspensions or means for local application.

The pharmaceutical carrier or diluent used may be a conventional solid or liquid carrier. Examples of solid carriers are lactose, kaolin, sucrose, cyclodextrin, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, stearic acid or ethers of cellulose and lower alcohols. Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene or water.

Likewise, the carrier or diluent may include any sustained release material known to those skilled in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.

If a solid carrier is used for oral administration, the drug may be tableted, placed in a hard gelatin capsule in the form of a powder or granules, or may be in the form of a lozenge or lozenge. The amount of solid carrier can vary widely, but will typically range from about 25 mg to about 1 g. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule, or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.

A typical tablet that can be manufactured using conventional tableting techniques may contain:

Core:

Active compound (in the form of a free compound or its salt) 10 mg

Colloidal silicon dioxide (aerosil) 1.5 mg

Cellulose, microcryst. (Amise!i) 7Omg

Modified cellulose resin (As-b0i-

ОЙ) 7.5 mg

Magnesium stearate

Coating:

NRMS, approximately 9mg "Mumasei 9-40 T, approximately 0.9mg x Acylated monoglyceride used as a plasticizer for film coating.

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

It was demonstrated that compounds of the general formula | have the ability to release endogenous growth hormone ip mimo. Thus, the compounds can be used to treat conditions that require elevated plasma levels of growth hormone, such as in human growth hormone deficiency, or in elderly patients, or in livestock.

Therefore, in a certain aspect, the present invention relates to a pharmaceutical composition for stimulating the release of growth hormone from the pituitary gland, which includes as an active ingredient a compound of the general formula I or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent.

In another aspect, the present invention relates to a method of stimulating the release of growth hormone from the pituitary gland, which comprises administering to a subject in need thereof an effective amount of a compound of general formula I or a pharmaceutically acceptable salt thereof.

In yet another aspect, the present invention relates to a method of treating growth retardation associated with asthma, which comprises administering to a subject in need thereof an effective amount of a stimulator of growth hormone secretion or a pharmaceutically acceptable salt thereof. In a certain aspect, the present invention relates to a method of treating growth retardation associated with asthma, which comprises administering to a subject in need thereof an effective amount of a compound of general formula I or a pharmaceutically acceptable salt thereof.

In yet another aspect, the present invention relates to a method of treating growth retardation associated with juvenile rheumatoid arthritis or cystic fibrosis, which comprises administering to a subject in need thereof an effective amount of a stimulator of growth hormone secretion or a pharmaceutically acceptable salt thereof. In one embodiment, the present invention relates to a method of treating growth retardation associated with juvenile rheumatoid arthritis, which comprises administering to a subject in need thereof an effective amount of a growth hormone release stimulator or a pharmaceutically acceptable salt thereof. In a second embodiment, the present invention relates to a method of treating growth retardation associated with cystic fibrosis, which comprises administering to a subject in need thereof an effective amount of a growth hormone release stimulator or a pharmaceutically acceptable salt thereof. In a separate embodiment, the present invention relates to a method of treating growth retardation associated with juvenile rheumatoid arthritis, which comprises administering to a subject in need thereof an effective amount of a compound of general formula I! or a pharmaceutically acceptable salt thereof. In a separate embodiment, the present invention relates to a method of treating growth retardation associated with cystic fibrosis, which comprises administering to a subject in need thereof an effective amount of a compound of general formula I or a pharmaceutically acceptable salt thereof.

In yet another aspect, the present invention relates to the use of a compound of general formula I! or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for stimulating the release of growth hormone from the pituitary gland.

It is well known to those skilled in the art that the current and potential applications of human growth hormone are many and varied. Yes, compounds of the formula | may be administered to stimulate the release of growth hormone from the pituitary gland and therefore have effects or applications similar to growth hormone itself. Compounds of the formula | are suitable for: stimulation of the release of growth hormone in the elderly, prevention of catabolic side effects of glucocorticoids, prevention and treatment of osteoporosis, treatment of chronic fatigue syndrome (CE5), treatment of acute fatigue syndrome and muscle loss after elective surgery, stimulation of the immune system, acceleration wound healing, acceleration of growth of bone fractures, acceleration of healing of complicated fractures, such as in traction osteogenesis, treatment of wasting secondary to fractures, treatment of growth retardation, treatment of growth retardation caused by renal disorder or failure, treatment of cardiomyopathy, treatment of wasting, etc. associated with chronic liver disease, treatment of thrombocytopenia, treatment of growth retardation associated with Crohn's disease, treatment of short bowel syndrome, treatment of wasting associated with chronic obstructive pulmonary disease (COPD), treatment of transplant-associated complications, treated treatment of physiologically short stature, including children with growth hormone deficiency and short stature associated with a chronic disease, treatment of obesity and growth retardation associated with obesity, treatment of anorexia, treatment of growth retardation associated with Prader-Willi syndrome and syndrome

Turner, increasing growth rate in a patient with partial GH intolerance, accelerating recovery and reducing the number of burn patients requiring hospitalization, treatment of intrauterine growth retardation, skeletal dysplasia, hypercorticism and Cushing's syndrome, induction of pulsatile GH release, reimbursement growth hormone in patients who have experienced stress, treatment of osteochondrodysplasias, Noonan syndrome, schizophrenia, depression, Alzheimer's disease, delayed wound healing and psychosocial deprivation, treatment of catabolism associated with impaired pulmonary function and respiratory dependence, treatment of heart failure and related disorders of vascular function, treatment of impaired cardiac function, treatment or prevention of myocardial infarction, reduction of blood pressure, protection against impaired ventricular function or prevention of reperfusion cases, treatment of adults, patients on chronic dialysis, weakening of protein cat abolic reactions after major surgery, reduction of cachexia and protein loss caused by chronic disease such as cancer or AIDS, treatment of hyperinsulinemia including pancreatic islet hyperplasia, adjuvant treatment to induce ovulation, stimulation of thymus growth, and prevention of age-related thymic decline, treatment of immunocompromised patients, treatment of sarcopenia, treatment of AIDS-related wasting, improvement of muscle tone, mobility, maintenance of skin thickness, treatment of metabolic homeostasis and renal homeostasis in the frail elderly, stimulation of osteoblasts, bone remodeling and cartilage growth tissues, regulation of food intake, stimulation of the immune system in companion animals and treatment of age-related disorders in companion animals, promotion of cattle growth and stimulation of wool growth in sheep, increase of milk production in cattle, treatment of metabolic syndrome (syndrome in X), treatment of insulin resistance, including non-insulin-dependent diabetes mellitus (MIOM), in mammals, e.g., humans, treatment of cardiac insulin resistance, improvement of sleep quality, and correction of relative hyposomatotropism of physiological aging caused by a significant increase in the fast phase (CEM ) of sleep and a decrease in the latent phase of REM sleep, treatment of hypothermia, treatment of frailty associated with aging, treatment of congestive heart failure, treatment of hip fractures, treatment of immune deficiency in individuals with a reduced ratio of T4/T8 cells, treatment of muscle atrophy, treatment of m of musculoskeletal disorders in the elderly, increased activity of protein kinase B (PCB), improvement of general lung function and treatment of sleep disorders.

In the context of the present invention, the term "treatment" shall also include prophylactic treatment.

In yet another aspect, the present invention relates to the use of a stimulator of growth hormone secretion or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of growth retardation associated with asthma. In one particular embodiment, the invention relates to the use of a compound of general formula I or a pharmaceutically acceptable salt thereof for the treatment of stunting associated with asthma.

In a second specific embodiment, the invention relates to the use of growth hormone-releasing peptides, growth hormone-releasing peptidomimetics, or growth hormone-releasing compounds of a non-peptide nature, or a pharmaceutically acceptable salt thereof, for the treatment of growth retardation associated with asthma.

Another aspect of the present invention relates to the use of a stimulator of growth hormone secretion or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of growth retardation associated with juvenile rheumatoid arthritis or cystic fibrosis. In one embodiment, the invention relates to the use of a growth hormone secretion stimulator or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of growth retardation associated with juvenile rheumatoid arthritis. In the second embodiment, the invention relates to the use of a growth hormone secretion stimulator or its pharmaceutically acceptable salt for the manufacture of a medication intended for the treatment of growth retardation associated with cystic fibrosis. In one specific embodiment, the invention relates to the use of a compound of general formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of growth retardation associated with juvenile rheumatoid arthritis. In the second specific embodiment, the invention relates to the use of a compound of the general formula | or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of growth retardation associated with cystic fibrosis. In another specific embodiment, the invention relates to the use of growth hormone-releasing peptides, growth hormone-releasing peptidomimetics, or growth hormone-releasing compounds of a non-peptide nature, or a pharmaceutically acceptable salt thereof, for the treatment of growth retardation associated with juvenile rheumatoid arthritis. In yet another specific embodiment, the invention relates to the use of growth hormone-releasing peptides, growth hormone-releasing peptidomimetics, or growth hormone-releasing compounds of a non-peptide nature, or a pharmaceutically acceptable salt thereof, for the treatment of growth retardation associated with cystic fibrosis .

For the above indications, the dosage may vary depending on the stimulator of growth hormone secretion used, for example, on the compound of formula I used, on the route of administration, and on the desired therapeutic effect. However, in general, daily doses ranging from 0.0001 to 100 mg/kg of body weight are administered to patients and animals to ensure effective release of endogenous growth hormone. In addition, the compounds of formula I have no or practically no side effects when administered in the doses indicated above, and such side effects are, for example, the release of luteinizing hormone (LH), follicle-stimulating hormone (FH), thyroid-stimulating hormone (THH), adrenocorticotropic hormone (ASTH), vasopressin, oxytocin, cortisol and/or prolactin. Of course, dosage forms suitable for oral, nasal, pulmonary or transdermal administration include from about 0.0001 mg to about 100 mg, preferably from about 0.001 mg to about 50 mg, of a compound of formula I mixed with a pharmaceutically acceptable carrier or diluent.

The dose of the compounds of the present invention is conveniently 0.01-500mg/day, for example from about 5 to about 5Omg, for example in doses of about 10mg, when administered to patients, for example humans, as a medicinal product.

Optionally, the pharmaceutical composition according to the invention may include a compound of formula I in combination with one or more compounds exhibiting other types of activity, for example, an antibiotic or other pharmacologically active material.

The route of administration can be any route that effectively delivers the active compound to the appropriate or desired site of action, such as oral, nasal, pulmonary, transdermal, or parenteral, with oral being the preferred route.

In addition to the pharmaceutical use of the compounds of formula I, they can be useful tools for research on the regulation of growth hormone release.

Compounds of the formula | can also be used as means for ip beyond the assessment of the ability of the pituitary gland to release growth hormone. For example, serum samples taken before and after administration of these compounds to humans can be analyzed for growth hormone content. Comparing the level of growth hormone in each serum sample will directly determine the ability of the patients' pituitary gland to release growth hormone.

Compounds of the formula | can be administered to commercially important animals to increase their growth rate and degree, and to increase milk and wool production.

Another way to use the compounds of formula I, which have the ability to stimulate the release of growth hormone, is to combine them with other stimulators of secretion, such as SNKR (2 or 6), ONKR and its analogs, growth hormone and its analogs, or somatomedins, including ISBE- 1 and IE-2.

Pharmacological methods

Compounds of the formula | can be subjected to an ip myo assay to determine their potency and ability to release growth hormone in primary rat pituitary cultures, and such assays can be performed as described below.

Isolation of rat pituitary cells is a modification of the technique of O. zZapog eii ai., Epdoshypoiodu, 116, 1985, pp. 952-

957. Male Zrgadoe-Oameu albino rats (250225 grams) were purchased from MoPedaaga, Se 5Kepzmeid, Oeptagk.

Rats were housed in group cages (four animals/cage) and placed in rooms with a 12-h light cycle. The room temperature varied between 19-24"С, and humidity - 30-6095.

The rats were decapitated and the pituitary glands were dissected. The intermediate lobes of the pituitary gland were removed, and the rest of the tissue was immediately placed in an ice-cold isolation buffer (Gay's medium ((irso 041-04030) supplemented with 0.2595 U-glucose, 295 substituted amino acids (sirso 043-01140) and 195 bovine serum albumin ( VZA) (bBidta A-4503)).The tissue was cut into small pieces and transferred to the buffer for isolation with an admixture

C, mg/ml of trypsin (MMogpipdiop 3707 TI -3) and 30 mg/ml of the drug UOMase (Zidta 0-4527). This mixture was incubated at 7b0 revolutions/min. within 35 minutes at 37"С in an atmosphere of O2/СО»2 95/595. The tissue was then washed three times in the buffer specified above. Individual cells were then suctioned from the tissue with the help of an ordinary cotton swab. After dispersing, the cells were filtered through a nylon filter (160 mm) to remove non-hydrolyzed tissue. The cell suspension was washed 3 times with isolation buffer supplemented with a trypsin inhibitor (0.75 mg/ml, Umogiipdaiop 52829) and finally resuspended in OMEM culture medium (Ssirso 041-01965) supplemented with 25 mM HERE5 (Zidta H-3375), 4 mM glutamine (Sirso 043-05030Н), 0.07590 sodium bicarbonate (bidta 5-8875), 0.190 substitute amino acid, 2.595 bovine fetal serum (EC5, sirso 011-06290), 395 horse serum (sirso 034-06050), 1095 fresh rat serum . Cells were seeded on plates for microtitration (Mips, Oeptagk), 200 ml/well, and cultivated for 3 days at 37"С and 895 СО".

Compound testing

After cultivation, cells were washed twice with stimulation buffer (balanced salt solution

Hanks (sbirso 041-04020) with an admixture of 195 VBA (Zidta A-4503), 02595 U-glucose (Zidta 5-5250) and 25 mM

NEREZ5 (bidta H-3375) pH 7.3) and preincubated for 1 hour at 37"C. The buffer was replaced with 9 Oml of stimulating buffer. Ten ml of the solution of the tested compound was added and the tablets were incubated for 15 minutes at 37"C and 595С. The medium was decanted and analyzed for the content of growth hormone (GH) using the HON 5RA test system.

All compounds were tested in doses from 10pM to 100mM. The dose-response relationship was constructed using the Hill equation (Reed P, Viozhoi), Efficiency (maximum release of growth hormone, Emax) was expressed in 95

Emayes for ONER-6. Activity (ESvo) was defined as the concentration inducing half of the maximal stimulation of growth hormone release.

Evaluation of the metabolic stability of compounds of formula I can be carried out according to the procedure described below:

The compounds are dissolved in water at a concentration of mg/ml. 25 ml of this solution is added to 175 ml of the corresponding enzyme solution (which gives an enzyme:substrate ratio (w/w) of approximately 1:5). The solution is left overnight at 37"C. 10 ml of different cleavage solutions were analyzed in comparison with a blank sample by mass spectrometry with flow injection and electrospraying (ЕЗМ5) with selective ion monitoring of a molecular ion. If the signal intensity decreased by more than 2095 compared to the zero sample, then the remainder of the solution was subjected to analysis by the method of high performance liquid chromatography (HPLC) and mass spectrometry to accurately determine the area (areas) and the degree of degradation.

Several standard peptides (ACTH 4-10, angiotensin 1-14 and glucagon) were included in the stability tests to test the ability of different solutions to cleave the peptides.

Standard peptides (angiotensin 1-14, ACTH 4-10, and glucagon) were purchased from Ziedt (MO, OA).

All enzymes (trypsin, chymotrypsin, elastase, microsomal aminopeptidase and carboxypeptidases MU and B) were purchased from Voephipdeg Mappeit ztrHN (Mappeit, Segtapu).

A mixture of pancreatic enzymes: trypsin, chymotrypsin and elastase in 100 mM ammonium bicarbonate rna,o (all concentrations 0.025mg/ml).

A mixture of carboxypeptidases: carboxypeptidases M and B in 50 mM ammonium acetate RNAe,5 (all concentrations 0.025 mg/ml).

Microsomal aminopeptidase solution: microsomal aminopeptidase (0.025 mg/ml) in 100 mM ammonium bicarbonate.

Mass spectrometric analysis was carried out using two different mass spectrometers: a triple quadrupole device 5sieh ARII for liquid chromatography in combination with mass spectrometry (IS-M5) (bsieh ipzigitep, Tpoppiii, Opiagio), equipped with an ion source with electrospraying, and the device determining the flight time of Vio-Iop 20 with plasma desorption (Vio-Iop Mogais AV, Orrzaia, Zmedep).

Quantitative analysis of compounds (before and after degradation) was carried out on an ARI IP device using selective ion registration of a single molecular ion under analysis with flow injection of the material under analysis. Liquid consumption (MeOH: water 1:1) in 10 Oml/min. was controlled using a device for high-performance liquid chromatography AVI 1408 (Regkip-EIteg Arriiea Viozuvietv Oimiviopv,

Eozieg Sypu, SA). The instrument was set to standard operating conditions with selective ion recording monitoring of the molecular ion with the highest intensity (in most cases this corresponded to the doubly charged molecular ion).

In addition, mass spectrometry with plasma desorption (ROM5) was used to identify the fission products with the application of the sample on a target with a nitrocellulose coating and using the standard parameters of the instrument. The accuracy of mass determination by this method was generally better than 0.19.

Separation and isolation of cleavage products was carried out using a reversed-phase column for high-performance liquid chromatography (HPLC) NU-TASN S-18 4.6x105 mm (Nemley-Raskaga Sotrapu,

Raiu AGo, SA) with a standard acetonitrile:trifluoroacetic acid separation gradient. A system for high-performance liquid chromatography (HPLC) HRI109OM (Nemley-Raskaga Sotrapu, Raio Ap,

SA).

selectively registered (5IM) (a.o.m. carboxypeptidase enzymes

Standards.id///// 17777771

ASTNAYAO 77777771 bench Her

Glucagon 77777711 3488/87І1,81І1111117-11111ц11111111

Insulin (B23-29)./ | .yuryur/р/ю/ю/ю/р/о859ИМ3О6 /Й777777777711111111711111111111111

Angotensin/-s44 | 1760/8810 HER ANVR2 7777/1777 81744096 HER ANVR 7777/7777 87264374 | 77777111 i: Stable (decrease in 5IM signal less than 2095 after 24h in digestion solution) Unstable (decrease in 5IM signal more than 2095 after 24h in digestion solution)

Any novel feature or combination of features described herein is considered essential to the present invention.

EXAMPLES

Further, the preparation of compounds of formula I and preparations containing them is illustrated by the following examples, which, however, should not be considered limiting.

The structures of the compounds were confirmed by the methods of elemental analysis (EA), nuclear magnetic resonance (NMR) or mass spectrometry (MS). NMR shifts (4) are given in parts per million (ppm) and for selected peaks only. T.p. (tr) means the melting point and is given in "S. Chromatography on a column was carried out according to the method described by MUM.S.5I ei aiYi., 9U.Ogd. Spet., 1978, 43, 2923-2925, on silica gel 60. Compounds, used as starting materials were known compounds or compounds that can be easily obtained by methods known to reg 5e.

Analysis by the method of high performance liquid chromatography:

Method A1.

Reversed phase (RR) analysis was carried out using UV detection at 214, 254, 276 and ЗО1 nm on a column with silicon oxide 218ТР54 4.6bmmx250mm 5m C-18 (Pe Zeragayop Ogotsshr, Nezregia), which was eluted at Tml/min. at 42"C. The column was equilibrated with 595 acetonitrile in a buffer consisting of 0.1M ammonium sulfate adjusted to pH 2g.5 with 4M sulfuric acid. After introduction, the sample was eluted with a gradient of acetonitrile from 595 to 6095 in the same buffer for 5 min.

Method B1.

Reverse phase (ER) analysis was performed with UV detection at 214, 254, 276 and 301 nm on a column with silicon oxide 218TR54 4.6bmmx250mm 5m C-18 (Pe Zeragayop Sgoshr, Nezregia), which was eluted at Tml/min. at 42"C. The column was equilibrated with 595 (acetonitrile 0.195 trifluoroacetic acid) in an aqueous solution of trifluoroacetic acid in water (0.195). After introduction, the sample was eluted with a gradient (acetonitrile 0.190 trifluoroacetic acid) from 595 to 6095 in the same aqueous buffer for 50 min.

Abbreviation:

TLC: thin layer chromatography

DMSO: dimethylsulfoxide min.: minutes h.: hours

Vos: tert-butoxycarbonyl

DMF: dimethylformamide

THF: tetrahydrofuran

EBAS: M-ethyl-M'-dimethylaminopropylcarbodiimide hydrochloride

NOAC 1-hydroxy-7-azabenzotriazole

DIEA: action of isopropylethylamine

TFOC: trifluoroacetic acid

Building blocks:

M-Methylated amino acids used in the following examples were prepared as described in Sap. uU.Spet., 1977, 55, 906. tert-Butyl complex ester of 3-hydroxy-1,1-dimethylproylcarbamic acid: sn, OnUs sn, by oiochor ne H

At 0"C, ethyl chloroformate (1.1 ml, 11.5 mmol) was added dropwise to a solution of 33-tert-butoxycarbonylamino-3-methylbutanoic acid (2.50 g, 11.5 mmol) and triethylamine (1.92 ml, 13.8 mmol) in tetrahydrofuran (100 ml). The solution was stirred for 40 minutes at 0"C. The resulting precipitate was collected on a filter and washed with tetrahydrofuran (20 ml). The liquid was immediately cooled to 0°C. A 2M solution of lithium borohydride in tetrahydrofuran (14 mL, 28.8 mmol) was added dropwise. The solution was stirred at 0°C for 2 hours and then warmed to room temperature over a period of 4 hours. It was cooled to 00.

Methanol (5 ml) was carefully added. 1N hydrochloric acid (100 ml) was added. The solution was extracted with ethyl acetate (2x100ml, 3x50ml). The combined organic layers were washed with a saturated solution of sodium bicarbonate (10 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was subjected to chromatography on silicon oxide (110 g) with ethyl acetate/heptane 1:2, obtaining 1.84 g of tert-butyl ester of 3-hydroxy-1,1-dimethylpropylcarbamic acid.

1IN-NMR (SOSI»z): a 1.33 (s, 6H), 1.44 (s, 9H), 1.88 (t, 2H), 1.94 (ext., 1H), 3.75 (sq., 2H), 4.98 (width, 1H).

3-(tert-Butoxycarbonylamino)-3-methylbutanal: sn, On sn. n neo o n.e N

DMSO (1.22 ml, 17.2 mmol) was added to a solution of oxalyl chloride (1.1 ml, 12.9 mmol) in dichloromethane (15 ml) at -78 °C. The mixture was stirred for 15 min at -78 °C. During the period of 15 min. a solution of tert-butyl ester of 3-hydroxy-1,1-dimethylpropylcarbamic acid (1.75 g, 8 mmol) in dichloromethane (1 Oml) was added dropwise. The solution was stirred at -78"C for another 15 min. Triethylamine (6 b, 00 ml, 4 mmol) was added. The solution was stirred at -78 "C for 5 min., and then heated to room temperature. The solution was diluted with dichloromethane (100 ml) and extracted with 1N hydrochloric acid (100 ml). The aqueous phase was extracted with dichloromethane (5 Oml). The combined organic layers were washed with saturated sodium bicarbonate solution (100 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by column chromatography on silicon oxide (140 g) with ethyl acetate/heptane (1:3), obtaining 1.10 g

3-(tert-butoxycarbonylamino)-3-methylbutanal.

MHz-"H-NMR (SOCI3): a 1.39 (s, 6H), 1.45 (s, 9H), 2.85 (d, 2H), 4.73 (lat., 1H), 9, 80 (Vol. 1H).

Ethyl-(2E)-5-(tert-Butoxycarbonylamino)-5-methylhex-2-enoate: sn. He sn, o neo i di chen n.s N Z

Triethylphosphonoacetate (1.9 bml, 9.mmol) was dissolved in tetrahydrofuran (30 ml). Potassium tert-butoxide (1.10 g, 9, mmol) was added. The solution was stirred for 40 minutes. at room temperature. A solution of 3-(tert-butoxycarbonylamino)-3-methylbutanal (1.10 g, 5.5 mmol) in tetrahydrofuran (bml) was added. The solution was stirred at room temperature for 75 minutes. It was diluted with ethyl acetate (100 ml) and 1N hydrochloric acid (100 ml). The phases were separated. The aqueous phase was extracted with ethyl acetate (2x50 ml).

The combined organic phases were washed with saturated sodium bicarbonate solution (bOml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by silica column chromatography (90 g) using ethyl acetate/heptane (1:14) to give 1.27 g of ethyl-(2E)-5-(tert-butoxycarbonylamino)-5-methylhex-2-enoate.

IN-NMR (SOSI"): a 1.30 (s, 6H), 1.46 (s, 9H), 2.62 (d, 2H), 4.27 (sq, 2H), 4.42 (width ., 1H), 5.88 (d.1H), 6.94 (td1H), (2E)-5-(tert-Butoxycarbonylamino)-5-methylhex-2-enoic acid: sn, where sn. iv) non-K. That's what he is

Ethyl-(2E)-5-(tert-butoxycarbonylamino)-5-methylhex-2-enoate (1.233g, 4.54mmol) was dissolved in dioxane (20ml). Lithium hydroxide (0.120 g, 5.00 mmol) was added as a solid. Water (1 Oml) was added until a clear solution was obtained. The solution was stirred for 1 hour. at room temperature. The solution was diluted with water (70 ml) and extracted with tert-butyl methyl ether (2x100 ml). The aqueous phase was acidified with 1H sodium bisulfate solution (pne-1) and extracted with tert-butyl methyl ether (3x7Oml). The organic phases were combined and dried over magnesium sulfate. The solvent was removed in vacuo to give 1.05 g of (2E)-5-(tert-butoxycarbonylamino)-5-methylhex-2-enoic acid. The crude product was used in further synthesis.

NMR (DMSO ab): 4 1.15 (s, 6H), 1.35 (s, 9H), 2.53 (d, 2H), 5.75 (d, 1H), 6.57 (width ., 1H), 6.75 (td, 1H), 12.15 (s, 1H). 1-Aza-spiro/3.3Z|heptan-2-one: other (c)

Methylenecyclobutane (40.0g, 0.587mol) was dissolved in diethyl ether (250ml). Chlorosulfonyl isocyanate (2 bml, 0.294 mol) was added dropwise at -40°C. The reaction mixture was heated to 10°C. An exothermic reaction and the formation of a precipitate are observed. The reaction mixture was cooled to -20"C. It was stirred for 1 hour, during this time it warmed up to room temperature. A saturated aqueous solution of sodium sulfite (100 ml) was added dropwise. The reaction mixture was vigorously stirred for 1 hour. A second portion of a saturated aqueous solution was added dropwise. sodium sulfite (100 mL). Solid sodium bicarbonate was added to pH 7. Dichloromethane (500 mL) was added. The phases were separated. The organic layer was dried over magnesium sulfate. The solvent was removed in vacuo to give 2.50 g of 1-aza-spiro|3.3)heptane- 2-one. 1IN-NMR (SOSI): a 1.75 (m, 2H), 2.26 (m, 2H), 2.39 (m, 2H), 2.96 (s, 2H), 6 ,55 (width, 1H). tert-Butyl ether of 2-oxo-1-azaspiro(3.3Z|)heptane-1-carboxylic acid

M o "ho ko sn?

A solution of di-tert-butyl dicarbonate (55.7 g, 0.211 mol) in dichloromethane (100 mL) was added dropwise to a solution of 1-aza-spiro(3.Z|heptan-2-one), triethylamine (3 mL, 0.255 mol) and 4- of dimethylaminopyridiene (2.6g, 0.021mol) in dichloromethane (100ml). The reaction mixture was stirred for 16h at room temperature. It was washed with 1095 aqueous ammonium chloride solution (100ml), water (100ml) and saturated aqueous sodium bicarbonate (100ml) The organic layer was dried over magnesium sulfate, and the solvent was removed in vacuo to give 48.24 g of crude 2-oxo-1-azaspiro|3.1-heptane-1-carboxylic acid tert-butyl ether, which was used in the next step without purification.

IN-NMR (SOCI3): a 1.55 (s, 9H), 1.78 (m, 1H), 1.92 (m, 1H), 2.18 (m, 2H), 2.90 (m, 2H), 3.04 (s, 1H). (1-"tert-Butoxycarbonylamino)cyclobutyl)acetic acid: sn, o o o i s c o n with H 1 H aqueous solution of lithium hydroxide (227 ml, 227 mmol) was added to a solution of tert-butyl ether 2-oxo-1-azaspiro (3.3Z |)heptane-1-carboxylic acid (48g, 0.227mmol) in tetrahydrofuran (200ml). The reaction mixture was stirred for 2 hours. Diethyl ether (200 ml) and water (200 ml) were added. The mixture was stirred for 16 hours. The organic layer was isolated. The aqueous phase was extracted with diethyl ether (200 ml). The aqueous phase was acidified with a 1095 aqueous solution of sodium bisulfate to pH 33. The resulting precipitate was collected on a filter, washed with water and dried under vacuum, obtaining 38.84 g of (1-(tert-butoxycarbonylamino)cyclobutyl)acetic acid.

IN-NMR (SOS33): a 1.45 (s, 9H), 1.85 (m, 1H), 1.95 (m, 1H), 2.25 (m, 4H), 2.87 (m, 2H), 5.15 and 6.20 (both widths, 1H in total). (2E)-4-(1-tert-Butoxycarbonylamino)cyclobutyl)but-2-enoic acid: sn. o | c) neo hom ZON (2E)-4-(1-(tert-Butoxycarbonylamino)cyclobutyl)but-2-enoic acid was synthesized starting from (1-(tert-butoxycarbonylamino)cyclobutyl)acetic acid, similarly to the synthesis of (2E) )-5-(tert-butoxycarbonylamino)-5-methylhex-2-enoic acid, starting with 3-tert-butoxycarbonylamino-3-methylbutanoic acid. 1IN-NMR (SOSI): a 1.43 (s, 9H), 1.84 (m, 1H), 1.95 (m, 1H), 2.10 (m, 2H), 2.20 (m , 2H), 2.70 (m, 2H), 4.75 (width, 0.5H), 5.90 (m, 1H), 6.35 (width, 0.5H), 6.95 ( m, 1H).

Ethyl ether of (2E)-5-tert-butoxycarbonylamino-3,5-dimethylhex-2-enoic acid: ve ok Z tob on,

Diacetonamine hydrogenoxalate (30.0 g, 14 mmol) was suspended in tetrahydrofuran (400 mL). An aqueous solution of sodium hydroxide (1N, 14 bml) was added. Di-tert-butyldicarbonate (38.3g, 175mmol) was dissolved in tetrahydrofuran (1000ml) and added dropwise to the reaction mixture. The reaction mixture was stirred for 2 hours. at room temperature. Sodium hydroxide (1H, 14 mmol) was added and the reaction mixture was stirred for 12 hours. at room temperature. Water (200 ml) and ethyl acetate (200 ml) were added.

The aqueous phase was extracted with ethyl acetate (4 x 200 ml). The combined organic phases were dried over magnesium sulfate and the solvent was removed in vacuo. The residue was purified by flash chromatography on silicon oxide (200 g), using ethyl acetate/heptane (1:3) as an eluent, obtaining 28.4 g of tert-butyl ether (1,1-dimethyl-3-oxobutyl)carbamic acid.

Triethylphosphonoacetate (4.7 g, 20.9 mmol) was dissolved in tetrahydrofuran (Zbml). Potassium tert-butoxide (2.3 g, 20.9 mmol) was added and the reaction mixture was stirred for 40 min. at room temperature. Tert-butyl ether (1,1-dimethyl-3-oxobutyl)carbamic acid (2.5 g, 11.6 mmol) was dissolved in tetrahydrofuran (15 ml) and added dropwise to the reaction mixture, which was heated to boiling under reflux for 12 hours. Ethyl acetate (100ml) and hydrochloric acid (1N, 100ml) were added and the phases were separated. The aqueous phase was extracted with ethyl acetate (3x50Oml). The combined organic phases were washed with an aqueous solution of sodium bicarbonate (saturated, 100 ml), dried (magnesium sulfate) and evaporated in vacuo.

The residue was purified by flash chromatography on silicon oxide (120 g), using ethyl acetate/heptane (1:2) as an eluent, obtaining 2.0 g of (2E)-5-tert-butoxycarbonylamino-3,5-dimethylhex-2-enoic acid ethyl ether .

IN-NMR (SOSIZz): a 1.25 (t, ZN), 1.30 (s, 6Н), 1.44 (s, 9Н), 2.21 (s, ZN), 2.58 (s, 2H), 4.14 (sq, 2H), 4.48 (s, 1H), 5.65 (s, 1H). (2E)-5-tert-Butoxycarbonylamino-3,5-dimethylhex-2-enoic acid:

ns o M Zo ZON

(2E)-5-tert-butoxycarbonylamino-3,5-dimethylhex-2-enoic acid ethyl ester (1.95g, 6.83mmol) was dissolved in 1,4-dioxane (25ml) and water (15ml). Lithium hydroxide (0.18 g, 7.52 mmol) was added and the reaction mixture was stirred for 12 hours. at room temperature. Water (150 ml) and tert-butyl methyl ether (150 ml) were added. The aqueous phase was diluted with a 1095 aqueous solution of sodium bisulfate to pH 1.5 and extracted with tert-butyl methyl ether (3x10Oml). The combined organic phases were dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from heptane (20 ml), obtaining 0.6 g of (2E)-5-tert-butoxycarbonylamino-

C3,5-dimethylhex-2-enoic acid.

IEN-NMR (SOCI3): a 1.29 (s, 6H), 1.44 (s, 9H), 2.23 (s, ЗН), 2.62 (s, 2H), 4.45 (s, 1 N), 5.66 (s, 1 N). (2E)-5-(M-(tert-Butoxycarbonyl)-M-methylamino)-5-methylhex-2-enoic acid ne o m he on sn. . (2E)-5-(tert-Butyloxycarbonylamino)-5-methylhex-2-enoic acid (5.00g, 20.bmmol) was dissolved in tetrahydrofuran (/Oml). Methyl iodide (10.3 mL, 164 mmol) was added and the solution was cooled to 0°C. Sodium hydride (6095 in oil) (2.07 g, 61. mmol) was added portionwise and the solution was stirred at room temperature for four days. Ethyl acetate ( /Oml) and water (bOml) and the solvent was removed in vacuo. The crude product was dissolved in water (40ml) and ether (40ml). The organic phase was washed with saturated aqueous sodium bicarbonate solution (30ml). The aqueous phases were mixed and 595% aqueous citric acid was added to pHZ. The aqueous phase was extracted with ethyl acetate (4x50ml). The organic phase was washed with water (2x40ml), aqueous sodium thiosulfate solution (595, 40ml), water (40ml), dried over Md5O4 and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate (45ml) and washed with an aqueous solution of sodium bisulfate (1095,

ХхЗОмл), dried over Md5Ox and concentrated in a vacuum, obtaining 4.00 g of (2E)-5-(M-(tert-butoxycarbonyl)-M-methylamino)-5-methylhex-2-enoic acid. 1IN-NMR (SOSI"): b 1.38 (s, 6H), 1.45 (s, 9H), 2.80 (d, 2H), 2.85 (s, ЗН), 5.88 (d , 1H), 7.01 (sq., 1H).

Example 1.

MA A)-1-(4Ch-K1 A)-1-benzyl-2-(4-((dimethylamino)methyl)piperidin-1-yl)-2-oxoethyl|-M-methylcarbamoyl)-2-(2- Naphthyl)ethyl)-M-methylamide (2E)-5-amino-5-methylhex-2-enoic acid and M shen nia V sh sh sn. oh M.

SN. tert-Butyl ether of 4-(dimethylcarbamoyl)piperidine-1-carboxylic acid

СХ neo m сн 3 сн, | 6) 1-(tert-Butoxycarbonyl/piperidine-4-carboxylic acid (8.0 g, 35 mmol) was dissolved in dichloromethane (70 mL) and N,M-dimethylformamide (35 mL). 1-Hydroxy-7-azabenzotriazole ( 4.75g, 35mmol). The solution was cooled to 0"C. The hydrogen chloride salt of M-(3-dimethylaminopropyl)-M'-ethylcarbodiimide (6.69g,

C5mmol). The reaction mixture was stirred for 20 min. at 0"C. A 5.6M solution of dimethylamine in ethanol (37ml, 209mmol) was added. The reaction mixture was stirred for three days, during which time it warmed to room temperature. It was diluted with ethyl acetate (400ml) and washed with 1095 aqueous sodium bisulfate solution (400ml) . The aqueous phase was extracted with ethyl acetate (2 x 200 ml). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution (300 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (SO 00 Hg) using dichloromethane as an eluent. /methanol 20:11, and obtaining 4.56 g of tert-butyl ether of 4-(dimethylcarbamoyl)piperidine-carboxylic acid.

IN-NMR (SOSI"): b 1.47 (s, 9H), 1.70 (m, 4H), 2.60-2.90 (m, ZN), 2.96 (s, ZN), 3 .08 (c, ЗН), 4.17 (m, 2Н).

4-((dimethylamino)methyl)piperidine-1-carboxylic acid tert-butyl ether

СХ neo M сн, сн,

At 0"C, a solution of 4-((dimethylamino)methyl)-piperidine-1-carboxylic acid tert-butyl ether (4.56g, 18mmol) in tetrahydrofuran (30ml) was added dropwise to a suspension of sodium borohydride (1.61g, 4mmol) in tetrahydrofuran (3 mL). The reaction mixture was stirred for 20 min at 0"C. It was added drop by drop

OS is a solution of iodine (4.51 g, 1.8 mmol) in tetrahydrofuran (3 mL). The reaction mixture was heated to boiling under reflux for 1 h. It was cooled to 4"C. Methanol (200 ml) was added dropwise.

The solvent was removed in vacuo. The residue was dissolved in a 2095 aqueous solution of sodium hydroxide (200 ml) and tert-butyl methyl ether (150 ml). The phases were separated. The aqueous phase was extracted with tert-butyl methyl ether (3x100 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo.

The crude product was purified by flash chromatography on silicon oxide (100 g), using dichloromethane/methanol/2595 aqueous ammonia (100:10:1) as eluent, and 4.07 g of tert-butyl ether 4-((dimethylamino)methyl)piperidine- 1-carboxylic acid. 1IN-NMR (SOCI3): b 1.22 (m, 2H), 1.44 (s, 9H), 1.85 (d, 2H), 2.09 (m, 1H), 2.61 (s, 6H), 2.65 (m, 2H), 2.78 (t, 2H), 4.05 (d, 2H).

M, M-Dimethyl-M-((piperidin-4-yl)umethyl)amine »

M dream

IN

M

N

A 3M solution of hydrogen chloride in ethyl acetate (120 mL, 15 mmol) was added to a solution of 4-((dimethylamino)methyl)piperidine-1-carboxylic acid tert-butyl ether (2.0 g, 14 mmol) in ethyl acetate (500 mL).

The reaction mixture was stirred for 30 minutes. at room temperature. The solvent was removed in vacuo, yielding 2.3 g of the crude dihydrochloride salt of M,M-dimethyl-M-((piperidin-4-ylylmethyl)amine), which was used in the next step without purification.

IN-NMR (SOSI", sample values): b 1.48 (m, 2H), 1.92 (s, 6H), 3.22 (d, 2H).

M-((1 A)-1-benzyl-2-(4-((dimethylamino)methyl)-piperidin-1-yl)-2-oxoethyl|-M-methylcarbamic acid tert-butyl ether

Kt

Ta : S : M sleep sky M she

At 0"C, the hydrogen chloride salt of M-(3-dimethylaminopropyl)-M-ethylcarbodiimide (1.158 g, 6.04 mmol) was added to a solution of (2K)-2-(M-(tert-butoxycarbonyl)-M-methylamino)-3- of phenylpropionic acid (1.69g, 6.04mmol) and 1-hydroxy-7-azabenzotriazole (0.822g, 6.04mmol) in dichloromethane (25ml) and N,M-dimethylformamide (12ml).

The reaction mixture was stirred for 20 min. at 0"C. A solution of the crude dihydrochloride salt of M,M-dimethyl-M-((piperidin-4-yl)umethyl)amine (1.3 g, 6.04 mmol) in M,M-dimethylformamide (1 Oml) was added alternately and dichloromethane (ml) and ethyldisopropylamine (b, 2ml, 36.25mmol). The reaction mixture was stirred for 16 hours, during which time it warmed to room temperature. It was diluted with ethyl acetate (100ml) and washed with a saturated aqueous solution of sodium bicarbonate (100ml). The organic layer dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (100g) using dichloromethane/methanol/2595 aqueous ammonia (200:10:1) as eluent to give 1.22g of tert-butyl ether M-MK1A8)-1-benzyl.2-(4-((dimethylamino)methyl)-piperidin-1-yl)-2-oxoethyl|-M-methylcarbamic acid.

IN-NMR (SOSI»z, sample values): b 1.28, 1.11, 1.37 and 1.38 (all s, total 9H), 4.00 (m, 1H), 4.57 (m , 1H), 4.97 and 5.26 (both t, 1H in general), 7.1P-7.40 (m, 5H).

MO:404|Ma1G. (28)-1-(4-(Dimethylamino)methyl)piperidin-4-yl)-2-(methylamino)-3-phenylpropan-1-one

Yaru

A M sn,

SVY sn, Fr

At 0"C, trifluoroacetic acid (20 ml) was added to a solution of tert-butyl ether M-(1B)-1-benzyl-2-(4-((dimethylamino)methyl)-piperidin-1-yl)-2-oxoethyl| -M-methylcarbamic acid (1.22 g, 3.02 mmol) in dichloromethane (20 ml). The reaction mixture was stirred for 1 hour at 0"C. Solvents were removed in vacuo.

The residue was redissolved in dichloromethane (7/Oml) and the solvent was removed in vacuo. This procedure was repeated twice. The crude product was purified by flash chromatography on silica (100 g) using dichloromethane/methanol/2595 aqueous ammonia (100:10:1) as eluent to give b509mg /(2K)-1-(4- ((dimethylamino)methyl) piperidin-4-yl)-2-(methylamino)-3-phenylpropan-1-one.

IN-NMR (SOSI", sample values): b 0.91 and 1.47 (m and d, in general 1Н), 1.27 (m, 1Н), 4.62 (t, 1Н).

Tert-butyl ether M-(18)-1-194-((1 2)-1-benzyl-2-(4-((dimethylamino)-methyl)piperidin-1-yl)-2-oxoethyl|-

M-methylcarbamoyl)-2-(2-naphthyl)ethyl)-M-methylcarbamic acid des and

With what st o : sn, o

OKA And me

A mole and not a dream, O CHI U zi Men,

GU x /

Hu

At 0"C, the hydrogen chloride salt of M-(3-dimethylaminopropyl)-M'-ethylcarbodiimide (416 mg, 2.17 mmol) was added to a solution of (2EK)-2-(M-(tert-butoxycarbonyl)-M-methylamino)-3- (2-Naphthyl)-propionic acid (715 mg, 2.17 mmol) and 1-hydroxy-7-azabenzotriazole (296 mg, 2.17 mmol) in dichloromethane (20 mL) and M,M-dimethylformamide (1 O mL). The reaction mixture was stirred for 20 min. . at 0"C. A solution of (28)-1-(4-((dimethylamino)methyl)piperidin-1-yl)-2-(methylamino)-3-phenylpropan-1-one (659 mg, 2.17 mmol) in dichloromethane (1 Oml) was added alternately ) and M,M-dimethylformamide (ml) and ethyldiisopropylamine (0.5 bml, 3.2 bmmol). The reaction mixture was stirred for 16 hours, during which time it warmed up to room temperature. it was diluted with ethyl acetate (100 ml) and washed with a saturated aqueous solution of sodium bicarbonate (100 ml). The aqueous solution was extracted with ethyl acetate (3x50ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (80 g), using ethyl acetate/heptane/triethylamine (1:1:0.08) as an eluent, and 1.05 g of tert-butyl ether M-(18)- 1-74-(1 2)-1-benzyl-2-(4-((dimethylamino)-methyl)piperidin-1-yl)-2-oxoethyl|-M-methylcarbamoyl)y-2-(2-naphthyl) ethyl)-M-methylcarbamic acid.

IN-NMR (SOSI", sample values): b 1.24 and 1.42 (both s, total 9H), 5.04, 5.28, 5.44, 5.54, 5.73 (m, dd , dd, dd and m, in general ZN). (28)-M-(1 A)-1-Benzyl-2-(4-((dimethylamino)methyl)piperidin-1-yl)-2-oxoethyl|-M-methyl-2-(methylamino)-3- (2-naphthyl)propionamide sn» o

A M cher So sn. about M. sleep,

At 0"C, trifluoroacetic acid (138 ml) was added to a solution of tert-butyl ether M-((18)-1-14-((1 M)-1-benzyl-2-(4-((dimethylamino)-methyl) -piperidin-1-yl)-2-oxoethyl|-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamic acid (1.05g, 1.71mmol) in dichloromethane (13ml). The reaction mixture was stirred within 50°C at 0"C. Solvents were removed in vacuo. The residue was dissolved in dichloromethane (50 mL) and the solvent was removed in vacuo. This procedure was repeated twice. The crude product was purified by flash chromatography on silicon oxide (80 g) using dichloromethane/methanol/2595 aqueous ammonia as an eluent to give 846 mg of (2K)-M-(18)-1-benzyl-2-(4-((dimethylamino) methyl)piperidin-1-yl)-2-oxoethyl|-N-methyl-2-(methylamino)-3-(2-naphthyl)propionamide.

IN-NMR (SOCI), sample values: b 0.60 (m, 1H), 4.38 (t, 1H), 5.72 and 5.79 (both t, total 1H).

Tert-butyl ether /(3E)-4-IM-(1 2)-1-14Ch-(1 2)-1-benzyl-2-(4-hydroxy-piperidin-1-yl)-2-oxoethyl|- M-methylcarbamot)-2-(2-naphthyl)ethyl)-M-methyl-carbamoyl|-1,1-dimethylbut-3-enylcarbamic acid and i c with "sn,

At 0"C, the hydrogen chloride salt of M-(3-dimethylaminopropyl)-M'-ethylcarbodiimide (112 mg, 0.58 mmol) was added to a solution of (2E)-5-(tert-butoxycarbonylamino)-5-methylhexene-2-enoic acid (142 mg , 0.58mmol) and 1-hydroxy-7-azabenzotriazole (79mg, 0.5dmmol) in dichloromethane (10ml) and N,M-dimethylformamide (5ml).

The reaction mixture was stirred for 20 min. at 0"C. A solution of (2K)-M-(18)-1-benzyl-2-(4- ((dimethylamino)-methyl)piperidin-1-yl)-2-oxoethyl|-M- methyl-2-(methylamino)-3-(2-naphthyl)-propionamide (30Omg,

0.5d8mmol) in dichloromethane (ml) and M,M-dimethylformamide (5ml) and ethyldiisopropylamine (0.1Oml, 0.58mmol).

The reaction mixture was stirred for 3 days, during which time it was heated to room temperature. it was diluted with ethyl acetate (7Oml) and washed with a saturated aqueous solution of sodium bicarbonate (7Oml). The aqueous phase was extracted with ethyl acetate (33x50 ml). The combined organic layers were dried over magnesium sulfate.

The solvent was removed in vacuo. The crude product was purified by flash chromatography on silicon oxide (70Og), using dichloromethane/methanol/2595 aqueous ammonia (200:10:1) as an eluent, and 31 mg of tert-butyl ether K(ZE)-4-YM-(1 8 -1-1M-(1 A)-1-benzyl-2-(4-hydroxy-piperidin-1-yl)-2-oxoethyl|-M-methylcarbamoyl)-2-(2-naphthyl)ethyl)-M- methylcarbamoyl|-1,1-dimethylbut-3-enylcarbamic acid.

IN-NMR (SOCIz, sample values): b 1.28 and 1.30 (both s, total 6H), 1.42 (s, 9H), 2.23, 2.27, 2.38, 2.A3 , 2.51, 2.52, 2.81 and 2.82 (all s, total 12H), 5.56, 5.76 and 5.90 (m, m and dd, total 2H), 6.17 and 6.19 (both dd, in total 1H), 6.94 (m.1nH).

At 0"C, trifluoroacetic acid (bml) was added to a solution of tert-butyl ether

I A)-1-benzyl-2-(4-hydroxy-piperidin-1-yl)-2-oxoethyl|-M-methylcarbamoyl)-2-(2-naphthyl)ethyl)-M-methylcarbamoyl|-1,1 -dimethylbut-3-enyl)/carbamic acid (212mg, 0.29mmol) in dichloromethane (bml).

The reaction mixture was stirred for 20 min. at 0"C. it was diluted with dichloromethane (30 ml). A saturated aqueous solution of sodium bicarbonate (30 ml) was added dropwise. Solid sodium bicarbonate was added until r-7 was established. The phases were separated. The aqueous phase was extracted with dichloromethane (3x50 ml). The combined the organic phases were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (20g) using dichloromethane/methanol/2595 aqueous ammonia (100:10:1) as eluent to afford 5 mg of the title compound . 2.83 (all c, total 12H), 5.58, 5.79 and 5.92 (m, m and dd, total 2H), 6.16 and 6.19 (both d, total 1H), 7, 00 (m, 1N).

TOP: 39.23 min. (A1) 41.55 min. (B1)

MS: 640.4 (MAG.

For biological tests, the compound was converted to its acetate salt by lyophilization with 0.5 M acetic acid (40 ml).

Example 2

M-A(18)-1-74-(C1 A)-1-benzyl-2-((35)-3-(dimethylaminomethyl)piperidin-1-yl)-2-oxoethyl|-M-methylcarbamoyl)-2 -(2-naphthyl)ethyl)-M-methylamide (2E)-5-amino-5-methylhex-2-enoic acid I B sa U x t-shcs sn, 9 7 vn, Z i NI H x I ; тя я ух No and We M - sn, o ( more x-- Z m ST, art

3-Ethyl ether of 1-tert-butyl ether (ZK)-piperidine-1,3-dicarboxylic acid o and

ZK

"What? o plon, sn, (8)-Ethylnipetcotate tartrate (10.0g, 32.5mmol) was suspended in tetrahydrofuran (9Oml). A 1N solution of sodium hydroxide in water (98 ml, 98 mmol) was added. A solution of di-tert-butyl dicarbonate (7.10 g, 32.5 mmol) in tetrahydrofuran (9 mL) was added. The reaction mixture was stirred for 1 hour. at room temperature. Ethyl acetate (400 ml) was added. The reaction mixture was washed with 1095% aqueous solution of sodium bisulfate (400 ml). The aqueous solution was extracted with ethyl acetate (2 x 200 ml). The combined organic layers were washed with a saturated aqueous solution of sodium bicarbonate (200 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silicon oxide (90 g), using ethyl acetate/heptane 1:4 as an eluent, and 4.13 g of 1-tert-butyl ether (ZK)-piperidine-1 was obtained. 3-dicarboxylic acid. 1IN-NMR (SOCI3): 6 1.27 (t, ЗН), 1.48 (s, 9Н), 1.54 (m, 1Н), 1.62 (m, 1Н), 1.73 (m, 2H), 2.05 (m, 1H), 2.45 (m, 1H), 2.181 (m, 1H), 2.98 (width, 1H), 3.93 (m, 1H), 4.14 (qv, 1H).

Tert-butyl ether (3K)-3-formylpiperidine-1-carboxylic acid o; su"

M oo

N Sen

From sn, C 1.2M solution of diisobutylaluminum hydride in toluene (30.8 ml, 36.9 mmol) was added at -78"С to a solution of 1-tert-butyl ether (3EK)-piperidine-1,3-dicarboxylic acid 3-ethyl ether (4.13g, 16.1mmol) in diethyl ether (30ml). The reaction mixture was stirred for 2.5h at -78°C. Water (9.bml) was added dropwise. The reaction mixture was warmed to room temperature. The precipitate was removed by filtration throughout the celite layer. Celite was washed with tert-butyl methyl ether (3x100ml). The liquid phases were combined and dried over magnesium sulfate. The solvent was removed in vacuo, obtaining 1.94 g of crude tert-butyl ether (3EC)-3-formylpiperidine-i-carboxylic acid, which was used in the next step without further purification. 1IN-NMR (SOSI"): b 1.45 (s, 9H), 1.67 (m, 2H), 1.95 (m, 1H), 2.43 (m, 1H), 3.10 (m , 1H), 3.32 (dd, 1H), 3.52 (d, 1H), 3.66 (m, 1H), 3.95 (m, 1H), 9.69 (s, 1H).

Tert-butyl ether (35)-3-(dimethylaminomethyl)piperidine-1-carboxylic acid "CH, su

M sn, oo nen

From sleep Z

A solution of crude tert-butyl ether (3K)-3-formylpiperidine-1-carboxylic acid (1.94g, 9.mmol) in dichloromethane (80ml) was prepared. A 5.6 M solution, dimethylamine in ethanol (3.2 ml, 18.2 mmol) and molecular sieves were added in turn. Sodium triacetoxyborohydride (5.78 g, 27.3 mmol) was added to this mixture. Acetic acid (1.04 mL, 18.2 mmol) was added. The reaction mixture was stirred for 1 hour. at room temperature. A 1N aqueous solution of sodium hydroxide (7Oml) and tert-butyl methyl ether (7Oml) were added. The phases were separated. The aqueous solution was extracted with tert-butyl methyl ether (3x70 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silicon oxide (40 g), using dichloromethane/methanol/259% aqueous ammonia (100:10:1) as an eluent, and 86 mg of tert-butyl ether (35)-3-(dimethylaminomethyl)piperidine-1 was obtained -carboxylic acid.

1H-NMR(SOCI3):5 1.10 (m, 1H), 1.45 (s, 9H), 1.45 (m, 1H), 1.64 (m, 2H), 1.85 ( m, 1H), 2.10 (m, 2H), 2.20 (s, 6H), 2.50 (width, 1H), 2.79 (m, 1H), 3.95 (m, 2H) .

M,M-Dimethyl-M-(ZA)-piperidin-3-yl)umethyl)amine se i sn,

Tert-butyl ether (35)-3-(dimethylaminomethyl)piperidine-1-carboxylic acid (1.25g, 5.15mmol) was dissolved in ethyl acetate (30ml). A 2.7 M solution of hydrogen chloride in ethyl acetate (/5 ml, 203 mmol) was added.

The reaction mixture was stirred for 45 minutes. at room temperature. The solvent was removed in vacuo, yielding 97 mg of the crude dihydrochloride salt of M,M-dimethyl-M-(ZA)-piperidin-3-yl)umethyl)amine, which was used for the next step without further purification.

IN-NMR (CO3O): b 1.42 (m, 1H), 1.86 (m, 1H), 2.00 (m, 2H), 2.38 (m, 1H), 2.85 (t, 1H), 2.95 (s, 6H), 2.98 (m, 1H), 3.16 (m, 2H), 3.42 (m, 1H), 3.53 (m, 1H).

M-(18)-1-benzyl-2-((35)-3--(dimethylaminomethyl)-piperidin-1-yl)-2-oxoethyl|-M-methylcarbamic acid tert-butyl ether 9

Not 00 M

M in sleep, Fr

MU sleep,

At 0"C, the hydrogen chloride salt of M-(3-dimethylaminopropyl)-M'-ethylcarbodiimide (870 mg, 4.54 mmol) was added to a solution of (2K)-2-(M-(tert-butoxycarbonyl)-M-methylamino)-3- of phenylpropionic acid (1.27g, 4.54mmol) and 1-hydroxy-7-azabenzotriazole (617mg, 4.54mmol) in dichloromethane (20ml) and M,M-dimethylformamide (10ml). The reaction mixture was stirred for 20min at 0" WITH. A solution of crude dihydrochloride /N,M-dimethyl--((ZA)-piperidine-3-ylylmethyl)amine (97 mg, 4.54 mmol) in dichloromethane (20 mL) and N,M-dimethylformamide (1 mL) and ethyldiisopropylamine ( 3.9 ml, 22.7 mmol). The reaction mixture was stirred for three days, during which time it warmed to room temperature. Ethyl acetate (300 ml) was added. The solution was washed with a saturated aqueous solution of sodium bicarbonate (300 ml). The aqueous phase was extracted with ethyl acetate (2 x 200 ml). The combined organic layers were dried over magnesium sulfate.

The solvent was removed in vacuo. The crude product was purified by flash chromatography on silicon oxide (90 g), using dichloromethane/methanol/2595 aqueous ammonia (100:10:1) as eluent, and 1.69 g of tert-butyl ether M-(1A)-1-benzyl- 2-((35)-3-(dimethylaminomethyl)-piperidin-1-yl)-2-oxoethyl|-M-methylcarbamic acid.

IEN-NMR (SOCIz, sample values): b 1.20, 1.24, 1.31 and 1.32 (all s, total 9H), 2.12, 2.13 and 2.18 (all s, total 6H), 2.81 (m, ЗН), 4.97 and 5.30 (both m, in general 1H), 7.05-7.35 (m, 5H). (28)-1-((35)-3-(Dimethylamino)methyl)piperidin-1-yl)-2-methylamino-3-phenylpropan-1-one sn» Ho;

NM

M so, sn,

At 0"C, trifluoroacetic acid (25 ml) was added to a solution of M-(12)-1-benzyl-2- ((35)-3-(dimethylaminomethyl)-piperidin-1-yl)-2-oxoethyl tert-butyl ether |-M-methylcarbamic acid (1.69g, 4.2mmol) in dichloromethane (25ml). The reaction mixture was stirred for 30 minutes at 0"C. The solvent was removed in vacuo.

The residue was dissolved in dichloromethane (100 ml) and the solvent was removed in vacuo. This procedure was repeated twice. The crude product was purified by flash chromatography on silica (90 g), using dichloromethane/methanol/2590° aqueous ammonia (1001011) as eluent, and 115 g of (22)-1-((35)-3- ((dimethylamino)methyl)piperidine was obtained -1-yl)-2-methylamino-3-phenylpropan-1-one.

IN-NMR (SOSI), sample values: b 0.38, 1.11, 1.37 and 1.65 (all m, total 4H), 2.11, 2.19, 2.25 and 2.31 (all s, 9H in total), 4.37 and 4.53 (both m, 1H in total), 7.10-7.35 (m, 5H),

Tert-butyl ether М-А(18)-1-1М-(1А)-1-benzyl-2-((35)-3-((dimethylamino)methyl)piperidin-1-yl)-2-oxoethyl |-M-methylcarbamoyl)-2-(2-naphthyl)ethyl)-M-methylcarbamic acid with I M volo titre c sn, o : m sn,

At 0"C, the hydrogen chloride salt of M-(3-dimethylaminopropyl)-Me-ethylcarbodiimide (379 mg, 1.9 mmol) was added to a solution of (2K)-2-(M-(tert-butoxycarbonyl)-M-methylamino)-3 -(2-naphthyl)propionic acid (651mg, 1.98mmol) and 1-hydroxy-7-azabenzotriazole (269mg, 1.98mmol) in dichloromethane (10ml) and M,M-dimethylformamide (ml). The reaction mixture was stirred for 20min . at 0"C. A solution of (28)-1-((35)-3-((dimethylamino)methyl)-piperidin-1-yl)-2-methylamino-3-phenylpropan-1-one (60 mg, 1.98 mmol) in dichloromethane (1 mL) and ethyldisopropylamine (0.5 mL, 2.97 mmol). The reaction mixture was stirred for three days, during which time it warmed to room temperature. Ethyl acetate (100 ml) was added. The solution was washed with a saturated aqueous solution of sodium bicarbonate (100 ml). The aqueous phase was extracted with ethyl acetate (3x50ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo.

The crude product was purified by flash chromatography on silicon oxide (90 g), using dichloromethane/methanol/2595 aqueous ammonia (100:10:1) as eluent, and 1.18 g of tert-butyl ether M-(C1 A)-1-( M-

I A)-1-benzyl-2-((35)-3-((dimethylamino)methyl)-piperidin-1-yl)-2-oxoethyl|-M-methylcarbamoyl)-2-(2-naphthyl)ethyl) -M-methyl-carbamic acid.

IN-NMR (SOSI", sample values): b 0.45 and 0.71 (both m, total 1H), 1.03, 1.05, 1.15, 1.20, 1.28, 1.36 and 1.42 (all s, total 9H), 2.12, 2.15, 2.23, 2.26, 2.29, 2.85 (all s, total 5H), 5.05, 5.44 , 5.58, 5.71, 5.85 and 6.00 (all s, generally 2H), 7.10-7.80 (m, 12H). (28)-M-(1 A)-1-Benzyl-2-((35)-3-((dimethylamino)methyl)piperidin-1-yl)-2-oxoethyl|-M-methyl-2-(methylamino )-3-(2-naphthyl)propionamide g sn o x M sn, o ms sn,

At 0"C, trifluoroacetic acid (20 ml) was added to a solution of tert-butyl ether M-(18)-1-1M-C1 A)-1-benzyl-2-((35)-3-((dimethylamino)methyl) -piperidin-1-yl)-2-oxoethyl|-M-methylcarbamoyl)-2-(2-naphthyl)ethyl)-M-

of methylcarbamic acid (1.18g, 1.92mmol) in dichloromethane (20ml). The reaction mixture was stirred for 500 minutes. at 0"C. The solvent was removed in vacuo. The residue was dissolved in dichloromethane (8 Oml) and the solvent was removed in vacuo. This procedure was repeated twice. The crude product was purified by flash chromatography on silica (40 g) using dichloromethane/methanol/2595 as eluent. aqueous ammonia (100:10:1), and 788 mg of (2K)-M-(18)-1-benzyl-2-((35)-3-(dimethylamino)methyl)piperidin-1-yl)-2- oxoethyl|-N-methyl-2-(methylamino)-3-(2-naphthyl)propionamide.

IN-NMR (SOSI»z, sample values): b 2.01 and 2.25 (both s, total 9H), 3.72 (m, 2H), 3.95 and 4.27 (both m, together 1H ), 5.77, 5.86 and 6.03 (t, m and dd, in general 1H), 7.10 and 7.85 (m, 12H).

Tert-butyl ether ((3E)-4-(M-((1 2)-1-14Ch-(1 28)-1-benzyl-2-((35)-3-((dimethylamino)methyl)piperidine- 1-yl)-2-oxoethyl|-M-methylcarbamoyl)-2-(2-naphthyl)ethyl)-M-methylcarbamoyl|-1,1-dimethylbut-3-enyl)carbamic acid ver o sn, o mn» sn ,

At 0"C, the hydrogen chloride salt of M-(3-dimethylaminopropyl)-Mie-ethylcarbodiimide (105 mg, 0.55 mmol) was added to a solution of (2E)-5-(tert-butoxycarbonylamino)-5-methylhex-2-enoic acid ( 13bmg, 0.55mmol) and 1-hydroxy-7-azabenzotriazole (74mg, 0.55mmol) in dichloromethane (5ml). The reaction mixture was stirred for 20 min at rt. A solution of (2k)-M-K18)-1 was added alternately -benzyl-2-((35)-3-((dimethylamino)methyl)piperidin-1-yl)-2-oxoethyl|-M-methyl-2-(methylamino)-3-(2-naphthyl)propionamide (281 mg , 0O.55mmol) in dichloromethane (5ml) and ethyldisopropylamine (0.094ml, 0.55mmol). The reaction mixture was stirred for 16 hours, during which time it warmed to room temperature. It was diluted with ethyl acetate (7Oml) and washed with a saturated aqueous solution of sodium bicarbonate ( 70ml). The aqueous phase was extracted with ethyl acetate (3x50ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo.

The crude product was purified by flash chromatography on silicon oxide (40 g), using dichloromethane/methanol/2595 aqueous ammonia (100:10:1) as an eluent, and 398 mg of tert-butyl ether (ZE)-4-(M- (1 8 )-1-0M-C1 A)-1-benzyl-2-((35)-3-(dimethylamino)methyl)piperidin-1-yl)-2-oxoethyl|-M-methylcarbamoyl)-2-(2- naphthyl)ethyl)-N-methylcarbamoyl)-1,1-dimethylbut-3-enylcarbamic acid.

IN-NMR (SOCIz, sample values): b 1.44 (c, 9H), 5.58, 5.75 and 5.86 (all m, 2H), 6.09 and 6.17 (both d, total 1H), 6.84 (m, 1H), 7.10-7.80 (m, 12H).

At 0"C, trifluoroacetic acid (7 ml) was added to a solution of tert-butyl ether

I A)-1-benzyl-2-((35)-3-((dimethylamino)-methyl)piperidin-1-yl)-2-oxoethyl|-M-methylcarbamoyl)-2-(2-naphthyl)ethyl) -N-methylcarbamoyl)|-1,1-dimethylbut-3-enylcarbamic acid (398mg, 0.54mmol) in dichloromethane (7ml). The reaction mixture was stirred for 40 min. at 0"C. The solvent was removed under vacuum.

The residue was dissolved in dichloromethane (20 ml) and the solvent was removed in vacuo. This procedure was repeated twice. The crude product was purified by flash chromatography on silicon oxide (40 g) using dichloromethane/methanol/259% aqueous ammonia (100:10:1) as eluent to give 150 mg of the title compound.

IN-NMR (SOSI", sample values): b 1.08, 1.12, 1.14 and 1.15 (all c, total 6H), 5.46, 5.59, 5.75 and 5.94 (all m, in total 2H), 6.15 (m, 1H), 6.93 (m, 1H).

TOP: 27.55 min. (A1), 23 min. (B1)

RH-MS: 640.4 (Mt |" at 8.54 min.

For biological tests, the title compound was converted to its acetate salt by lyophilization from 0.5M acetic acid (40 mL).

Example C

M-(18)-1-K1 2)-1-Benzyl-2-((35)-3-(dimethylaminomethyl)piperidin-1-yl)-2-oxoethyl|-M-methylcarbamoyl)-2-(2- naphthyl)ethyl)-M-methylamide (2E)-4-(1-aminocyclobutyl)but-2-enoic acid vi i Si x Mi i i i 8 sleep. o mb sn,

Tert-butyl ether (1-(2E)-3-(M-(1 2)-1-1M-(1 A)-1-benzyl-2-((35)-3-, (dimethylamino)methyl)piperidine -1-yl)-2-oxoethyl|-M-methylcarbamoyl)-2-(2-naphthyl)ethyl)-M-methylcarbamoyl|allylucyclobutyl)carbamic acid layer LI CA

Z I xx M ne M z oi g i sn, 0 i sn,

At 0"C, the hydrogen chloride salt of M-(3-dimethylaminopropyl)-M'-ethylcarbodiimide (85 mg, 0.44 mmol) was added to a solution of (2E)-5-(tert-butoxycarbonylamino)-5-methylhex-2-enoic acid (113 mg . A solution of (2EK)-M-(18)-1-benzyl-2-((35)-3- ((dimethylamino)methyl)piperidin-1-yl)-2-oxoethyl|-M-methyl-2 -(methylamino)-3-(2-naphthyl)propionamide (228 mg,

0.44mmol) in dichloromethane (10ml) and ethyldiisopropylamine (0.07ml, 0.44mmol). The reaction mixture was stirred for 16 hours, during which time it warmed to room temperature. It was diluted with ethyl acetate (70 ml) and washed with a saturated aqueous solution of sodium bicarbonate (70 ml). The aqueous phase was extracted with ethyl acetate (3x50ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo.

The crude product was purified by flash chromatography on silica (40 g) using dichloromethane/methanol/2595 aqueous ammonia (100:10:1) as eluent to give 314 mg of tert-butyl ether (1-(2E)-3-(M- ((18)-1-479-(1 2)-1-benzyl-2-((35)-3-(dimethylamino)methyl)piperidin-1-yl)-2-oxoethyl|-M-methylcarbamoyl)-2 -(2-naphthyl)ethyl)-M-methylcarbamoyl|allyl-cyclobutyl)carbamic acid.

IEN-NMR (SOCI), sample values: b 1.40 (m, 9H), 4.22 and 4.57 (both m, total 2H), 5.60, 5.75, 5.85 and 5, 90 (dd, dd, m and m, in total 2Н), 6.10 and 6.19 (both d, in total 1Н), 6.73 and 6.87 (both m, in total 1Н), 7.22, 7, 42 and 7.76 (all m, 12H in total).

At 0"C, trifluoroacetic acid (20 ml) was added to a solution of tert-butyl ether (1-C2E)-3-|M-C1 A)-1- (M-(1 8)-1-benzyl-2-((35 )-3-((dimethylamino)methyl)piperidin-1-yl)-2-oxoethyl|-M-methylcarbamoyl)-2-(2-naphthyl)ethyl)-M-methylcarbamoylallylucyclobutyl)carbamic acid (314 mg, 0.42 mmol) in dichloromethane (7 ml). The reaction mixture was stirred for 20 min at 0"C. The solvent was removed in vacuo. The residue was dissolved in dichloromethane (20 ml) and the solvent was removed in vacuo. This procedure was repeated twice.

The crude product was purified by flash chromatography on silica (40g) using dichloromethane/methanol/ammonia (100:10:1) as eluent to give 180mg of the title compound.

IN-NMR (SOS with, sample values): b 0.40 and 0.74 (both m, total 2H), 3.73 and 4.22 (both m, total 2H), 5.57, 5.77 and 5.91 (all m, total 2H), 6.15 and 6.24 (both d, total 1H), 6.85 and 6.96 (both m, total 1H), 7.22, 7.92 and 7 .74 (all m, 12H in total).

TOP: 28.03 min. (A1) 29.92 min. (B1)

MS: 652.4 (MAG.

For biological tests, the title compound was converted to its diacetate salt by lyophilization from 0.5M acetic acid (40ml).

Example 4

M-A(18)-1-74-(C1 A)-1-Benzyl-2-(25)-2-(dimethylamino)methyl)pyrrolidin-1-yl)-2-oxoethyl|-M-methylcarbamoyl)- 2-(2-naphthyl)ethyl)-M-methylamide (2E)-5-amino-5-methylhex-2-enoic acid

A M n y: y y Kr sn. oh mon;

I sn, 2-Ethyl ether of 1-tert-butyl ether (25)-pyrrolidine-1,2-dicarboxylic acid

So that's 9

And he sleeps. WITH

M-tert-butoxycarbonylproline (24.38g, 113mmol) was dissolved in dichloromethane (bOml). Ethanol (7.9 mL, 135 mmol) and 4-dimethylaminopyridine (1.52 g, 12.5 mmol) were added. The solution was cooled to 0"C. The hydrogen chloride salt of M-(3-dimethylaminopropyl)-M'-ethylcarbodiimide (23.88g, 125mmol) was added. The reaction mixture was stirred for 16h, during which time it warmed to room temperature. Ethyl acetate (400ml) was added. It was washed with 1095 aqueous sodium bisulfate solution (300ml). The aqueous phase was extracted with ethyl acetate (3x200ml). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution (300ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silicon oxide (400 g), using ethyl acetate (14) as an eluent, and 17.11 g of 2-ethyl ether of 1-tert-butyl ether (25)-pyrrolidine-1,2-dicarboxylic acid was obtained.

IN-NMR (SOSIz): b 1.28 (m, ZN), 1.43 and 1.46 (both s, total 9H), 2.95 (m, ZN), 2.22 (m, 1H), 3.50 (m, 2H), 4.18 and 4.30 (m and dd, in general ZN).

M-t-Butoxycarbonyl-(5)-prolinal

Co

M oo wo---sun, sun,

At -787C, a 1.2 M solution of diisobutylaluminum hydride (31.7 ml, Zdmmol) in toluene was added dropwise to a solution of 2-ethyl ether of 1-tert-butyl ether (25)-pyrrolidine-1,2-dicarboxylic acid (4.02 g, 16 .5 mmol) in diethyl ether (15 ml). The reaction mixture was stirred for at -78"C. Water (9.9 ml) was added dropwise. The reaction mixture was heated to room temperature. The mixture was filtered through a layer of Celite. The Celite was washed with tert-butyl methyl ether (3x10 Oml). The combined organic layers were dried over magnesium sulfate. Solvent was removed in vacuo, obtaining 2.34 g of crude M-t-butoxycarbonyl-(5)-prolinal, which was used in the next stage without further purification.

IN-NMR (SOSIz): b 1.42 and 1.47 (both s, in general 9Н), 1.70-2.20 (m, AN), 3.20-4.30 (m, ZN), 9 .45 and 9.55 (both s, 1H in total).

Tert-butyl ether (25)-2-(dimethylamino)methyl)pyrrolidine-1-carboxylic acid c, chi

I sleep, we sleep"

Crude M-t-butyloxycarbonyl-(5)-prolinal (2.34g, 11.7mmol) was dissolved in dichloromethane (90ml).

A 5.6 M solution of dimethylamine in ethanol (4.19 ml, 23.5 mmol) was added. Molecular sieves of 0.4 nm (10.0 OGg) were added.

Sodium triacetoxyborohydride (7.47 g, 35.2 mmol) and glacial acetic acid (1.34 mL, 23.5 mmol) were added alternately. The reaction mixture was stirred for three days. it was filtered through a layer of celite. Celite was washed with methanol (150 ml). A 1N aqueous solution of sodium hydroxide (150 ml) and tert-butyl methyl ether (150 ml) were added. The phases were separated. The aqueous phase was extracted with tert-butyl methyl ether (3x100 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo.

The crude product was purified by flash chromatography on silica (90 g) using dichloromethane/methanol/2595 aqueous ammonia (100:10:1) as eluent to give 1.29 g of tert-butyl ether (25)-2-(dimethylamino)methyl ) of pyrrolidine-1-carboxylic acid. 1IN-NMR (SOCI3): b 1.48 (s, 9H), 1.90 (m, 4H), 2.15 and 2.23 (AB, 2H), 2.26 (s, 6H), 3, 31 (width, 2H), 3.85 (width, 1H).

M-Dimethyl-M-((25)-pyrrolidin-2-ylylmethyl-amine sn

M.

M sn, a 2.71 M solution of hydrogen chloride in ethyl acetate (75 mL, 202 mmol) was added to a solution of (25)-2-(dimethylamino)methyl)pyrrolidine-1-carboxylic acid tert-butyl ether (1.29 g, 5.65 mmol) in ethyl acetate (ZOml).

The reaction mixture was stirred for 30 minutes. at room temperature. The solvent was removed in vacuo, obtaining 1.36 bg of the crude dihydrochloride salt of M-dimethyl-M-((25)-pyrrolidin-2-yl)umethyl-amine, which was used in the next step without further purification. 1IN-NMR (SOCI3): b 1.90 (m, 2H), 2.17 (m, 1H), 2.40 (m, 1H), 2.90 (m, 2H), 3.14 (s, 6H), 3.55 (m, 2H), 4.35 (m, 1H).

Tert-butyl ether //M-K18)-1-benzyl-2-(25)-2-((dimethylamino)methyl)-pyrrolidin-1-yl)-2-oxoethyl|-M-methylcarbamic acid sn, o

AND

Nv. 0 M

M po i o sn, o u» sn.

At 0"C, the hydrogen chloride salt of M-(3-dimethylaminopropyl)-M'-ethylcarbodiimide (1.30 g, 6.76 mmol) was added to a solution of (2K)-2-(M-(tert-butoxycarbonyl)-M-methylamino)- 3-phenylpropionic acid (1.89g, 6.76bmmol) and 1-hydroxy-7-azabenzotriazole (0.92g, 6.76bmmol) in dichloromethane (10ml). The reaction mixture was stirred for 20 minutes at 0"C. A solution of the crude dihydrochloride salt of M-dimethyl-M-((25)-pyrrolidin-2-yl)umethylamine (1.36 g, 6./bmmol) in dichloromethane (10 ml) and M,M-dimethylformamide (10 ml) was added alternately. ) and ethyldiisopropylamine (5.75 ml, 33.8 mmol). The reaction mixture was stirred for 16 hours, during which time it warmed up to room temperature. It was diluted with ethyl acetate (100 ml) and washed with a saturated aqueous solution of sodium bicarbonate (100 ml). The aqueous phase was extracted with ethyl acetate (3x80ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silicon oxide (90 g), using dichloromethane/methanol/2595 aqueous ammonia (100:101) as eluent, and 2.26 g of tert-butyl ether M-K1 A)-1-benzyl-2- (25)-2-((dimethylamino)methyl)-pyrrolidin-1-yl)-2-oxoethyl|-M-methylcarbamic acid.

IN-NMR (SOS c, sample values): b 1.20, 1.33 and 1.37 (all c, total 9H), 2.22 and 2.28 (both c, total bH), 2.82 and 2.84 (both s, in general ЗН), 4.25 (m, 1H), 4.80, 5.11 and 5.30 (dc, t and m, in general 1H), 7.10-7.30 ( m, 5H).

Sg2Nza5MzOz 389.51 calcd. С 67.83; H 9.06; M10.79

C 67.39 was found; H 9.13; M 10.73 (28)-1((25)-2-((Dimethylamino)methyl)pyrrolidin-1-yl)y-2-methylamino-3-phenylpropan-1-one sn 9

NM

M and;

S r

And sleep

At 0"C, trifluoroacetic acid (dml) was added to a solution of tert-butyl ether M-C1 2)-1-benzyl-2-(25)-2-((dimethylamino)methyl)pyrrolidin-1-yl)-2-oxoethyl |-M-methylcarbamic acid (2.26 g, 5.80 mmol) in dichloromethane (3 mL). The reaction mixture was stirred for 20 min at 0"C. The solvent was removed in vacuo.

Dichloromethane (/0ml) was added and the solvent was removed in vacuo. This procedure was repeated twice.

The crude product was purified by flash chromatography on silicon oxide (90 g), using dichloromethane/methanol/2590° aqueous ammonia (100:10:1) as an eluent, and 1.24 g of (28)-1(25)-2-(dimethylamino )methyl)pyrrolidin-1-yl)-2-methylamino-3-phenylpropan-1-one.

IN-NMR (SOSI", sample values): b 2.33 (s, ЗН), 2.43 (s, 6Н), 3.25 (m, ЗН), 4.17 (m.1Н), 7, 25 (m, 5N).

Tert-butyl ether M-(1B)-1-44-(1A)-1-benzyl-2-(25)-2-((dimethylamino)methyl)pyrrolidin-1-yl)-2-oxoethyl|- M-methylcarbamoyl)-2-(2-naphthyl)ethyl)-M-methylcarbamic acid

Kk): M neo Zg M sn, 0 ' m7bch» i sn,

At 0"C, the hydrogen chloride salt of M-(3-dimethylaminopropyl)-M'-ethylcarbodiimide (530 mg, 2.76 mmol) was added to a solution of (2K)-2-(M-(tert-butoxycarbonyl)-M-methylamino)-3- (2-naphthyl)propionic acid (911mg, 2.76mmol) and 1-hydroxy-7-azabenzotriazole (37b6mg, 2.7bmmol) in dichloromethane (5ml). The reaction mixture was stirred for 20min at 0"C. A solution of (2K)-1-(25)-2-((dimethylamino)methyl)pyrrolidine-1yl)-2-methylamino-3-phenylpropan-1-one (800mg, 2.76bmmol) in dichloromethane (5ml) was added alternately. ) and M,M-dimethylformamide (ml) and ethyldiisopropylamine (0.71 ml, 4.15 mmol). The reaction mixture was stirred for three days, during which time it warmed to room temperature. It was diluted with ethyl acetate (100 ml) and washed with a saturated aqueous solution of sodium bicarbonate (100 ml). The aqueous phase was extracted with ethyl acetate (3x7Oml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silicon oxide (90 g) using dichloromethane/methanol/2595 aqueous ammonia (200:10:1) as eluent to give 1.37 g of tert-butyl ether M-(18)-1-714- (1 2)-1-benzyl-2-((25)-2- ((dimethylamino)-methyl)pyrrolidin-1-yl)-2-oxoethyl|-M-methylcarbamoyl)-2-(2-naphthyl)ethyl )-M-methylcarbamic acid. 1IN-NMR (SOSI", sample values): b 0.64 (m, 1H), 1.10, 1.29, 1.36 and 1.47 (all s, total 9H), 4.99, 5, 09, 5.45 and 5.53 (t, t, m and t, in general 2H), 7.10-7.90 (m, 12H). (28)-M-(1 2)-1-Benzyl-2-((25)-2-((dimethylamino)methyl)pyrrolidin-1-yl)-2-oxoethyl|-M-methyl-2-(methylamino )- 3-(2-naphthyl)propionamide; M ek; dream oh "shk sn,

At 0"C, trifluoroacetic acid (10 ml) was added to a solution of tert-butyl ether M-(18)-1-1M-C1 A)-1-benzyl-2-(25)-2-((dimethylamino)methyl)- pyrrolidin-1-yl)-2-oxoethyl|-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamic acid (1.37g, 2.28mmol) in dichloromethane (100ml). stirred for 75 min. at 0"C. The solvent was removed in vacuo. The residue was dissolved in dichloromethane (70 mL) and the solvent was removed in vacuo. This procedure was repeated twice. The crude product was purified by flash chromatography on silicon oxide (90 g), using dichloromethane/methanol/2595 aqueous ammonia (100:10:1) as an eluent, and 692 mg of (2K)-M-(18)-1-benzyl-2- (25)-2-(dimethylamino)methyl)pyrrolidin-1-yl)-2-oxoethyl|-N-methyl-2-(methylamino)-3-(2-naphthyl)propionamide.

IN-NMR (SOSI»z, sample values): b 1.85 and 2.01 (both s, in general ЗН), 2.20 and 2.31 (both s, in general бН), 3.65 and 3.80 (both t, 1H), 4.04 and 4.45 (both m, in general 1H), 5.60 and 5.91 (those dd, in general 1H), 7.10-7.90 (m, 12H).

Tert-butyl ether "ZE)-4-(M-(1 2)-1-14-((1 A)-1-benzyl-2-((25)-2-((dimethylamino)methyl)pyrrolidine-1 -yl)-2-oxoethyl|-M-methylcarbamoyl)-2-(2-naphthyl)ethyl)-M-methylcarbamoyl|-1,1-dimethylbut-3-enyl/ucarbamic acid kto tu o sn, o ms; dream

At 0"C, the hydrogen chloride salt of M-(3-dimethylaminopropyl)-Mie-ethylcarbodiimide (132 mg, 0.69 mmol) was added to a solution of (2E)-5-(tert-butoxycarbonylamino)-5-methylhex-2-enoic acid ( 168mg, 0.69mmol) and 1-hydroxy-7-azabenzotriazole (94mg, 0.69mmol) in dichloromethane (5ml). The reaction mixture was stirred for 20 min at rt. A solution of (2k)-M-K18)-1 was added alternately -benzyl-2-(25)-2-((dimethylamino)methyl)pyrrolidin-1-yl)-2-oxoethyl|-M-methyl-2-(methylamino)-3-(2-naphthyl)propionamide (345mg,

0.b9mmol) in dichloromethane (100ml) and M,M-dimethylformamide (5ml) and ethyldiisopropylamine. The reaction mixture was stirred for 1 hour, during which time it warmed to room temperature. It was diluted with ethyl acetate (7/00 ml) and washed with a saturated aqueous solution of sodium bicarbonate (700 ml). The aqueous phase was extracted with ethyl acetate (3x50ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silicon oxide (40 g), using dichloromethane/methanol/2595 aqueous ammonia (100:10:1) as an eluent, and 491 mg of tert-butyl ether K(ZE)-4-( M-(18)-1-14-(C12)-1-benzyl-2-(25)-2-((dimethylamino)methyl)pyrrolidin-1-yl)-2-oxoethyl|-M-methylcarbamoyl) -2-(2-naphthyl)ethyl)-N-methylcarbamoyl|-1,1-dimethylbut-3-enyl/ucarbamic acid. 1IN-NMR (SOSI", sample values): b 0.55 (m, 1Н), 1.11, 1.12 and 1.17 (all s, total 6Н), 2.25 (s, 6Н), 2 .45 (с, ЗН), 2.85 (с, ЗН), 4.02 (m, 1Н), 5.48 (dd, 1Н), 5.80 and 5.93 (m and dd, in total 1Н) , 6.10 and 6.18 (both d, in general 1H), 6.87 and 7.00 (both m, in general 1H), 7.10-7.90 (m, 12H).

TOP: 27.97 min. (A1) 27.80 min. (B1)

MS: 626.4 (MA1G"

For biological tests, the title compound was converted to its diacetate salt by lyophilization from 0.5M acetic acid (40ml).

Example 5

M-A(18)-1-74-(C1 A)-1-Benzyl-2-(25)-2-(dimethylamino)methyl)pyrrolidin-1-yl)-2-oxoethyl|-M-methylcarbamoyl)- 2-(2-naphthyl)ethyl)-M-methyl-3-(methylamino)methyl)benzamide zva, z

AND

We are those a ee or thing t "M Kora ra

With in

SV whose dream at

I have-

And ks, and with r"

May dream

Tert-butyl ether M-(3-(M-(1 2)-1-14-(1 A)-1-benzyl-2-(25)-2-((dimethylamino)methyl)pyrrolidin-1-yl) -2-oxoethyl|-M-methylcarbamoyl)-2-(2-naphthyl)ethyl)-M-methylcarbamoyl|benzyl)-M-methylcarbamic acid ran 1 31 mish I H ny" ter o B; sv E vo g

State University of

We sleep

At 0"C, the hydrogen chloride salt of M-(3-dimethylaminopropyl)-Mie-ethylcarbodiimide (132 mg, 0.69 mmol) was added to a solution of 3-(M-(tert-butoxycarbonyl)-M-methylamino)benzoic acid (183 mg, 0 .69 mmol) and 1-hydroxy-7-azabenzotriazole (94 mg, 0.69 mmol) in dichloromethane (5 ml). The reaction mixture was stirred for 20 min at 0"C. A solution of (2K)-M-((1 2)-1-benzyl-2-(25)-2-((dimethylamino)methyl)pyrrolidin-1-yl)-2-oxoethyl|-M-methyl- 2-(methylamino)-3-(2-naphthyl)propionamide (345 mg, O0.b9 mmol) in dichloromethane (1 Oml) and

M,M-dimethylformamide (5 ml) and ethyldiisopropylamine (0.118 ml). The reaction mixture was stirred for 16 hours, during which time it warmed up to room temperature. It was diluted with ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate (7/Oml). The aqueous phase was extracted with ethyl acetate (3x50ml).

The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silicon oxide (40 g), using as an eluent dichloromethane/methanol/2595 aqueous ammonia (100:10:1), and received 524 mg of tert-butyl ether M-13-|(M-(1 A) -1- (M-(18)-1-benzyl-2-((25)-2-((dimethylamino)methyl)pyrrolidin-1-yl)-2-oxoethyl|-M-methylcarbamoyl)-2-( 2- naphthyl)ethyl)-M-methylcarbamoyl|benzyl)-M-methylcarbamic acid.

IN-NMR (SOSIz, sample values): b 0.72 (m, 1H), 1.45 (width, 9H), 3.18 (width, 6H), 4.05 (m, 1H), 4 .32 and 4.40 (both widths, in general 2H), 5.60 (dd, 1H), 5.95 (m, 1H), 6.80-6.90 (m, 16H).

At 0"C, trifluoroacetic acid (/ml) was added to a solution of tert-butyl ether M-(3-|M-(1 A)-1-1M-

And A2)-1-benzyl-2-(25)-2-((dimethylamino)-methyl)pyrrolidin-1-yl)-2-oxoethyl|-M-methylcarbamoyl)-2-(2-naphthyl)ethyl)- M-methylcarbamoyl|benzyl)-M-methylcarbamic acid (523mg, 0.70mmol) in dichloromethane (7ml). The reaction mixture was stirred for 25 min. at 0"C. The solvent was removed in vacuo. The residue was dissolved in dichloromethane (FOml) and the solvent was removed in vacuo. This procedure was repeated twice.

The crude product was purified by flash chromatography on silica (40g) using dichloromethane/methanol/259o5 aqueous ammonia (100:10:1) as eluent to give 43 mg of the title compound.

IN-NMR (SOSI", sample values): b 0.87 (m, 1H), 1.22 (m, 1H), 1.45 (m, 1H), 1.67 (m, 1H), 4, 09 (m, 1H), 5.53 and 5.90 (dd and m, in general 2H), 6.80-7.90 (m, 16H).

TOP: 28.43 min. (A1) 63 min. (In 1)

MS: 648.4 (MAG

For biological tests, the title compound was converted to its diacetate salt by lyophilization from 0.5M acetic acid (40ml).

Example 6

MA A)-1-44-(1 A)-1-Benzyl-2-(4-(dimethylamino)piperidin-1-yl)-2-oxoethyl|-M-methylcarbamoyl)-2-(2-naphthyl)ethyl )-M-methylamide (2E)-5-amino-5-methylhex-2-enoic acid: M сн, о «сн, и сн,

The title compound was prepared as described in Example 1 using the hydrochloride salt of 4-(dimethylamino)piperidine, (2EK)-2-(M-(tert-butoxycarbonyl)-M-methylamino)-3-phenylpropionic acid, (28 )-2-(M-(tert-butoxycarbonyl)-M-methylamino-3-(2-naphthyl))propionic acid and (2E)-5-(butoxycarbonylamino)-5-methylhex-2-enoic acid.

IN-NMR (SOS with, sample values): b 1.40 (s, 6H), 2.00 (s, 6H), 4.42-4.85 (2H), 5.45-5.90 (m , 2H), 6.28 (dd, 1H), 6.85 (m, 1H), 7.10-7.85 (m, 12H).

MS (ER): t/2 626.2 (M-H)"

Example 7

M-Methyl-M-C1 A)-1-(M-methyl-M-(1KE)-1-|M-methyl-M-(1-methylpiperidin-4-yl)ucarbamoyl|-2-phenylethyl)carbamoyl) -2-(2-naphthyl)ethylamide (2E)-5-amino-5-methylhex-2-enoic acid

Iv SN. i) ex sun yy sun about sleep

The title compound was prepared as described in Example 1 using 1-methyl-4-(methylamino)piperidine, (2K)-2-(M-(tert-butoxycarbonyl)-M-methylamino)-3-phenylpropionic acid, (2K)-2-(M-(tert-butoxycarbonyl)-M-methylamino-3-(2-naphthyl))propionic acid and (2E)-5-(butoxycarbonylamino)-5-methylhex-2-enoic acid.

IN-NMR (SOSI", sample values): b 5.50-6.08 (m, 2H), 6.20-6.70 (m, 2H), 7.10-7.85 (m, 12H) .

Example 8

3-Aminomethyl-M-(1 2)-1-14-(1 A)-1-benzyl-2-(4-methylpiperazin-1-yl)-2-oxoethyl|-M-methylcarbamoyl)-2-(2 - naphthyl)ethyl)-M-methylbenzamide

O I sleep, o : M "suku MU sleep. about M

From S. "sn.

The title compound was prepared as described in Example 1 using M-methylpiperazine, (28)-2-(M-(tert-butoxycarbonyl)-M-methylamino)-3-phenylpropionic acid, (2K)-2-( M-(tert-butoxycarbonyl)-

M-methylamino-3-(2-naphthyl))propionic acid and 3-(tert-butoxycarbonylamino)methyl)benzoic acid.

IN-NMR (SOSI", sample values): b 3.30 (m, 1H), 3.50 (dd, 1H), 3.75 (m, 1H), 3.95 (s, 2H), 5, 78 (t, 1H), 3.88 (m, 1H), 7.00-7.80 (16H).

TOP: 24.55 min. (A1) 26.52 min. (B1)

MS (ER): t/2 606.4 (MANI.

Example 9

M-(1 2)-1-14-(1 K)-1-Benzyl-2-(4-methylpiperazin-1-yl)-2-oxoethyl|-M-methylcarbamoyl)-2-(2-naphthyl)ethyl )-

M-methylamide (2E)-5-amino-5-methylhex-2-enoic acid com a pi mV I sn, o g. Sm sn.

The title compound was prepared as described in Example 1 using M-methylpiperazine, (28)-2-(M-(tert-butoxycarbonyl)-M-methylamino)-3-phenylpropionic acid, (2K)-2-( M-(tert-butoxycarbonyl)-

M-methylamino-3-(2-naphthyl))propionic acid and /(2E)-5-(butoxycarbonylamino)-5-methylhex-2-enoic acid.

IN-NMR (SOSI", sample values): b 1.24 (s, 6H), 1.65 (s, ZN), 2.35 (s, ZN), 2.80 (s, ZN), 5, 68 (dd, 1H), 5.78 (dd, 1H), 6.18 (dd, 1H), 6.95 (m, 1H), 7.15-7.80 (m, 12H).

TOP: 25.03 min. (A1) 27.50 min. (B1)

MS (ER): t/2 598.4 (MANI.

Example 10

M-Methyl-M-((1 A)-1--/M-methyl-M-((1 8)-2-phenyl-1-(2,2,6,6-tetramethyl-piperidin-4-ylcarbamoyl) )ethyl|carbamoyl)-2-(2-naphthyl)ethyl)amide (2E)-5-amino-5-methylhex-2-enoic acid ns sn,

Holi; m " nm y: t Y sn, sn, o

The title compound was prepared as described in Example 1 using 4-amino-2,2,6,6-tetramethylpiperidine, (2K)-2-(M-(tert-butoxycarbonyl)-M-methylamino)-3- phenylpropionic acid, (2K)-2-(M-(tert-butoxycarbonyl)-M-methylamino-3-(2-naphthyl))propionic acid and (2E)-5-(butoxycarbonylamino)-5-methylhex-2-enoic acid acid

IN-NMR (SOSI", sample values): b 1.25 (s, 6H), 1.40 (two s, 6H), 1.52 (two s, 6H), 2.92 (s, ЗН), 3.02 (two s, 3H), 5.10 (dd, 1H), 5.50 (dd, 1H), 6.15 (d, 1H), 6.75 (m, 1H), 7.00- 8.00 (m, 12H).

TOP: 29.27 min. (A1) 31.67 min. (B1)

MS (ER): t/2 654.8 (MANI.

Example 11

3-Aminomethyl-M-methyl-M-((1 A)-1-(M-methyl-Mm-(1 A)-2-phenyl-1-(2,2,6,6-tetramethylpiperidin-4-yl) (ucarbamoyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)-benzamide not

And M

"bitch M lm sn, o sn.

The title compound was prepared as described in Example 1 using 4-amino-2,2,6,6-tetramethylpiperidine, (2K)-2-(M-(tert-butoxycarbonyl)-M-methylamino)-3- phenylpropionic acid, (2K)-2-(M-(tert-butoxycarbonyl)-M-methylamino-3-(2-naphthyl))propionic acid and 3-(tert-butoxycarbonylamino)methyl)benzoic acid.

IN-NMR (SOSI", sample values): b 3.60-3.85 (m, 2H), 3.90-4.30 (m, 1H), 5.25-5.95 (m, 2H) , 6.70-7.90 (m, 16nH).

TOP: 29.27 min. (A1) 31.55 min. (B1)

MS (ER): t/2 662.4 (MANI.

Example 12

M-Methyl-M-((1 A)-1--M-methyl-M-C18)-2-phenyl-1-(2,2,6,6-tetramethyl-piperidin-4-ylylcarbamoyl)ethyl| carbamoyl)-2-(2-naphthyl)ethylamide (2E)-5-amino-3,5-dimethylhex-2-enoic acid and

Y shchi sn, about / sn. o p. o sbuz i 5 t -M-sn, o ih Hi i u

AND

The title compound was prepared as described in Example 1 using 4-amino-2,2,6,6-tetramethylpiperidine, (2K)-2-(M-(tert-butoxycarbonyl)-M-methylamino)-3- phenylpropionic acid, (2K)-2-(M-(tert-butoxycarbonyl)-M-methylamino-3-(2-naphthyl))propionic acid and (2E)-5-(butoxycarbonylamino)-3,5-dimethylhex-2 -enoic acid.

IN-NMR (SOSI", sample values): b 3.92-4.30 (m, 1Н), 5.05-5.88 (m, ЗН), 7.00-7.80 (m, 12Н) .

TOP: 29.80 min. (A1) 32,43 (B1)

MS (ER): t/2 668.4 (MANI.

Example 13

MA A)-1-(4-(1 A)-1-Benzyl-2-(4-methylpiperazin-1-yl)-2-oxoethyl|-M-methylcarbamoyl)-2-(2-naphthyl)ethyl)-

M-methylamide (2E)-4-(1-amino-cyclobutyl)but-2-enoic acid

AH | with

And my dream

The title compound was prepared as described in Example 1 using M-methylpiperazine, (28)-2-(M-(tert-butoxycarbonyl)-M-methylamino)-3-phenylpropionic acid, (2K)-2-( M-(tert-butoxycarbonyl)-

M-methylamino-3-(2-naphthyl))propionic acid and (2E)-4-(1-(butoxycarbonylamino)cyclobutyl)but-2-enoic acid.

IN-NMR (SOSI), selective peaks: b 1.62 (s, ЗН), 2.35 (s, ЗН), 2.80 (s, ЗН), 5.70 (dd, 1Н), 5, 80 (dd, 1H), 6.22 (d, 1H), 6.98 (m; 1H), 7.15-7.80 (m, 12H).

TOP: 25.88 min. (A1) 28.65 min. (B1)

MS (ER): t/2 610.4 (MANI.

Example 14

MA A)-1-(4-(1 A)-1-Benzyl-2-(4-methylpiperazin-1-yl)-2-oxoethyl|-M-methylcarbamoyl)-2-(2-naphthyl)ethyl)-

M-methylamide (2E)-5-amino-3,5-dimethylhex-2-enoic acid ah - y un r val y chu g nay sn. about K i on

And in en

The title compound was prepared as described in Example 1 using M-methylpiperazine, (28)-2-(M-(tert-butoxycarbonyl)-M-methylamino)-3-phenylpropionic acid, (2K)-2-( M-(tert-butoxycarbonyl)-

M-methylamino-3-(2-naphthyl))propionic acid and (2E)-5-(butoxycarbonylamino)-3,5-dimethylhex-2-enoic acid. 1IN-NMR (SOCI", sample values): b 1.18 (s, 6H), 1.68 (s, ЗН), 1.95 (s, ЗН), 2.30 (s, ЗН), 2, 85 (c, ЗН), 3.40 (dd, 1Н), 3.54-3.75 (m, 2Н), 5.68-5.85 (m, ЗН), 7.15-7.80 ( m, 12H).

TOP: 25.70 (A1) 28.27 min. (B1)

MS (ER): t/2 612.4 (MANI.

Example 15

M-AC1 A)-1-14Ch-(1 A)-1-Benzyl-2-(4-hydroxypiperidin-1-yl)-2-oxoethyl|-M-methylcarbamoyl)-2-(biphenyl-4-yl) ethyl)-M-methylamide (2E)-4-(1-aminocyclobutyl)but-2-enoic acid

OA p kim y nach V (sn, o on

This compound was prepared as described in Example 1, but using as starting materials 4-hydroxypiperidine, (2K)-2-(M-tert-butoxycarbonyl-M-methylamino)-3-phenylpropionic acid and (2K)-2-( M-tert-butoxycarbonyl-M-methylamino)-3-(biphenyl-4-yl)propionic acid and (2E)-4-(1-(tert-butoxycarbonylamino)cyclobutyl)but-2-enoic acid.

MS (ER): 6374 (MAN)

TOP: p-33.58 min. (A1)

TOP: p-34.95 min. (B1)

Example 16

MA A)-1-4(4Ch-K1 A)-1-Benzyl-2-(4-hydroxypiperidin-1-yl)-2-oxoethyl|-M-methylcarbamoyl)-2-(biphenyl-4-yl)ethyl )-M-methylamide of (2E)-5-amino-5-methylhex-2-enoic acid is not me D st o a M e Y IF sn, 0 ; he

This compound was prepared as described in Example 1, but using as starting materials 4-hydroxypiperidine, (2K)-2-(M-tert-butoxycarbonyl-M-methylamino)-3-phenylpropionic acid and (2K)-2-( M-tert-butoxycarbonyl-M-methylamino)-3-(biphenyl-4-yl)upropionic acid and (2E)-5-tert-butoxycarbonylamino-

B-methylhex-2-enoic acid.

MS (ER): 625.4 (MAN)

TOP: p-32.65 min. (A1)

TOP: p-34.02 min. (B1)

Example 17

M-(1 2)-1-14-(1 2K)-1-Benzyl-2-(4-hydroxypiperidin-1-yl)-2-oxoethyl|-M-methylcarbamoyl)y-2-(biphenyl-4- yl)ethyl)-M-methylamide (2E)-5-amino-3,5-dimethylhex-2-enoic acid ns sn.sHn, o CH, (6)

MAZH kim v shk go sn, o on

AND

This compound was prepared as described in Example 1, but using as starting materials 4-hydroxypiperidine, (2K)-2-(M-tert-butoxycarbonyl-M-methylamino)-3-phenylpropionic acid and (2K)-2-( M-tert-butoxycarbonyl-M-methylamino)-3-(biphenyl-4-yl)upropionic acid and (2E)-5-tert-butoxycarbonylamino-

C3,5-dimethylhex-2-enoic acid.

MS (ER): 639.4 (MAN)

TOP: p-33.29 min. (A1)

TOP: p-36,4 Ohv. (B1)

Example 18

M-(1 28)-1-74Ch-K(1 K)-1-Benzyl-2-(4-hydroxypiperidin-1-yl)-2-oxoethyl|-M-methylcarbamoyl)y-2-(2- naphthyl )ethyl)-M-methylamide (2E)-5-amino-5-methylhex-2-enoic acid and M and IF sn. about him

This compound was prepared as described in Example 1, but using as starting materials 4-hydroxypiperidine, (2K)-2-(M-tert-butoxycarbonyl-M-methylamino)-3-phenylpropionic acid and (2K)-2-( M-tert-butoxycarbonyl-M-methylamino)-3-(2-naphthyl)propionic acid and (2E)-5-tert-butoxycarbonylamino-5-methylhex-2-enoic acid.

MS (ER): 599.4 (MAN)

TOP: p-29.88 min. (A1)

Example 19

MA A)-1-4(4-K1 A)-1-Benzyl-2-(4-hydroxypiperidin-1-yl)-2-oxoethyl|-M-methylcarbamoyl)y-2-(2-naphthyl)ethyl) -M-methylamide of (2E)-5-amino-3,5-dimethylhex-2-enoic acid

This compound was prepared as described in Example 1, but using as starting materials 4-hydroxypiperidine, (2K)-2-(M-tert-butoxycarbonyl-M-methylamino)-3-phenylpropionic acid and (2K)-2-( M-tert-butoxycarbonyl-M-methylamino)-3-(2-naphthyl)propionic acid and (2E)-5-tert-butoxycarbonylamino-

C3,5-dimethylhex-2-enoic acid.

MS (ER): 613.4 (MAN)"

TOP: p-30.58 min. (A1)

Example 20

MA A)-1-4(4-K1 A)-1-Benzyl-2-(4-hydroxypiperidin-1-yl)-2-oxoethyl|-M-methylcarbamoyl)y-2-(2-naphthyl)ethyl) -M-methylamide (2E)-4-(1-aminocyclobutyl)but-2-enoic acid

GU Her I sv Her and Al M A I zu z

Sn, o I ki on nak hi

This compound was prepared as described in Example 1, but using as starting materials 4-hydroxypigaeridine, (2K)-2-(M-tert-butoxycarbonyl-M-methylamino)-3-phenylpropionic acid and (2K)-2-( M-tert-butoxycarbonyl-M-methylamino)-3-(2-naphthyl)propionic acid and (2E)-4-(1-(tert-butoxycarbonylamino)cyclobutyl)but-2-enoic acid.

MS(ER):611 (MN)

TOP: p-30.82 min. (A1)

Example 21

M-(1 2)-1-74-K1 2K)-1-(4-fluorobenzyl)-2-(4-hydroxypiperidin-1-yl)-2-oxoethyl|-M-methylcarbamoyl)-2-(2- Naphthyl)ethyl)-M-methylamide (2E)-5-amino-5-methylhex-2-enoic acid: M sn, 0 on

THAT

This compound was prepared as described in Example 1, but using as starting materials 4-hydroxypiperidine, (22)-2-(M-tert-butoxycarbonyl-M-methylamino)-3-(4-fluorophenyl)propionic acid and (2K) )- 2-(M-tert-butoxycarbonyl-M-methylamino)-3-(2-naphthyl)propionic acid and (2E)-5-tert-butoxycarbonylamino-5-methylhex-2-enoic acid.

MS (ER): 617.4 (MAN)"

TOP: p-30.27 min. (A1)

TOP: p-31.6 Ohv. (B1)

Example 22

MA A)-1-44-K1 AB)-1-(4-fluorobenzyl)-2-(4-hydroxypiperidin-1-yl)-2-oxoethyl|-M-methylcarbamoyl)-2-(2-naphthyl)ethyl )-M-methylamide (2E)-5-amino-3,5-dimethylhex-2-enoic acid calcd.; s ee ray ns o sn.sn, 9 g sv o n - ia YAKA M A. mia 7 Shchi Tse shi s o it on

MYH x- x

This compound was prepared as described in Example 1, but using as starting materials 4-hydroxypiperidine, (22)-2-(M-tert-butoxycarbonyl-M-methylamino)-3-(4-fluorophenyl)propionic acid and (2K) )- 2-(M-tert-butoxycarbonyl-M-methylamino)-3-(biphenyl-4-yl)propionic acid and (2E)-5-tert-butoxycarbonylamino-3,5-dimethylhex-2-enoic acid.

MS (ER): 631.4 (MAN)

TOP: p-30.98 min. (A1)

TOP: p-32.38 min. (B1)

Example 23

M-(128)-1-74-K1K)-1-Benzyl-2-(4-dimethylamino)piperidin-1-yl)-2-oxoethyl|-M-methylcarbamoyl)y-2-(2-naphthyl )ethyl)-M-methylamide (2E)-4-(1-aminocyclobutyl)but-2-enoic acid

Let and ; sleep 6; ra r r a Ж я ств b. sati sleep, re E

SU sn, 5.

The title compound was prepared as described in Example 1, but using 4-M,M-dimethylpiperazine, (2K)-2-(M-(tert-butoxycarbonyl)-M-methylamino)-3-phenylpropionic acid, (2K )-2-(M-(tert-butoxycarbonyl)-M-methylamino)-3-(2-naphthyl))propionic acid and (2E)-4-(1-(tert-butoxycarbonylamino)cyclobutyl)but-2-enoic acid acid

IN-NMR (SOSI), sample peaks: b 1.90 (s, ZN), 2.38 (s, ZN), 2.45 and 2.47 (two s, ZN), 2.78 and 2, 80 (two s, ZN), 6.32 (dd, 1H), 6.90 (m, 1H), 7.15-7.84 (m, 12H).

TOP: 26.72 min. (A1)

MS (ER): 638.4 MANI"

Example 24

MA A)-1-(4-K(28)-2-(4-Hydroxypiperidin-1-yl)-2-oxo-1-((2-thienyl)umethyl)-ethyl|-M-methylcarbamoyl)-2 -(2-naphthyl)ethyl)-M-methylamide (2E)-5-amino-5-methylhex-2-enoic acid ns sn, (c) Sv o C rarch im tyu sn. o - ov-y

This compound was prepared as described in Example 1, but using as starting materials 4-hydroxypiperidine, (2EK)-2-(M-tert-butoxycarbonyl-M-methylamino)-3-(2-thienyl)upropionic acid and (2K) )-2-(M-tert-butoxycarbonyl-M-methylamino)-3-(2-naphthyl)propionic acid and (2E)-5-tert-butoxycarbonylamino-5-methylhex-2-enoic acid.

MS (ER): 605.4 (MAN)

TOP: p-29.07 min. (A1)

Example 25

MA A)-1-(4-K(28)-2-(4-Hydroxypiperidin-1-yl)-2-oxo-1-((2-thienyl)umethyl)-ethyl|-M-methylcarbamoyl)-2 -(2-naphthyl)ethyl)-M-methylamide (2E)-5-amino-3,5-dimethylhex-2-enoic acid with a M on pp sn, o I and

This compound was prepared as described in Example 1, but using as starting materials 4-hydroxypiperidine, (2EK)-2-(M-tert-butoxycarbonyl-M-methylamino)-3-(2-thienyl)upropionic acid and (2K) )-2-(M-tert-butoxycarbonyl-M-methylamino)-3-(2-naphthyl)propionic acid and (2E)-5-tert-butoxycarbonylamino-5-methylhex-2-enoic acid.

MS(ER):619.4(MaH)"

UPPER: n-29.76 bkhv. (A1)

Example 26

M-(1 2)-2-(Biphenyl-4-yl)-1-1M-(2)-2-(4-hydroxypiperidin-1-yl)-2-oxo-1-((2-thienylmethyl)ethyl |d|-M-methylcarbamoyl)ethyl)-M-methylamide (2E)-5-amino-5-methylhex-2-enoic acid in cho; dy yak nyu sn, Yi ksi t ON i T

Ton Mi a a V

We are on it,

This compound was prepared as described in Example 1, but using as starting materials 4-hydroxypiperidine, (2EK)-2-(M-tert-butoxycarbonyl-M-methylamino)-3-(2-thienyl)upropionic acid and (2K) )-2-(M-tert-butoxycarbonyl-M-methylamino)-3-(biphenyl-4-yl)upropionic acid and (2K)-5-tert-butoxycarbonylamino-

B-methylhex-2-enoic acid.

MS (ER): 631.2 (MAN)"

TOP: p-32,20 min. (A1)

Example 27

M-(1B82-(Biphenyl-4-yl)-1-14-(18)-2-(4-hydroxypiperidin-1-yl)-2-oxo-1-((2-thienylmethyl)ethyl|- M-methylcarbamoyl)ethyl)-M-methylamide (2E)-5-amino-3,5-dimethylhex-2-enoic acid and 7 rei nyu sn, Te Yitsyi ryk ai o a i ! Yi te aya k shi Yi We! dream at 17 and 5

This compound was prepared as described in Example 1, but using as starting materials 4-hydroxypiperidine, (2EK)-2-(M-tert-butoxycarbonyl-M-methylamino)-3-(2-thienyl)upropionic acid and (2K) )-2-(M-tert-butoxycarbonyl-M-methylamino)-3-(biphenyl-4-yl)upropionic acid and (2E)-5-tert-butoxycarbonylamino-

C3,5-dimethylhex-2-enoic acid.

MS (ER): 465.4 (MAN)"

TOP: p-32.89 min. (A1)

Example 28

MA A)-1-4(4Ch-K1 A)-1-Benzyl-2-(4-hydroxypiperidin-1-yl)-2-oxoethyl|-M-methylcarbamoyl)-2-(biphenyl-4-yl)ethyl )-M-methylamide (2E)-5-methyl-5-(methylamino)hex-2-enoic acid sn, (c; d

KM in Mon

Her sleep, h sleep, st o:

This compound was prepared as described in Example 1, but using as starting materials 4-hydroxypiperidine, (2K)-2-(M-tert-butoxycarbonyl-M-methylamino)-3-phenylpropionic acid and (2K)-2-( M-tert-butoxycarbonyl-M-methylamino)-3-(biphenyl-4-yl)upropionic acid and (2E)-5-(M-(tert-butoxycarbonyl)-

M-methylamino)-5-methylhex-2-enoic acid.

MS: t/2 639.4 (Ma-H)-

TOP: Method A1: Ki-32.94x8v.

Example 29 (18)-1-74-C12)-1-Benzyl-2-(4-hydroxypiperidin-1-yl)-2-oxoethyl|-M-methylcarbamoyl)-2-(biphenyl-4-yl) ethyl)amide of (2E)-4-(1-aminocyclobutyl)but-2-enoic acid

AL; with Y : M. on and r 6) on

TOP: Ke31.55 min. (A1)

E-33.11 min. (B1)

PH-MS: 623.6 (MANI.

Claims (17)

1. The compound of the general formula and; 2 IF) (ba Y IF) H 5 K (SNAba M s (SV) 1 vi IF) Ov, in which B' is hydrogen or C-C-alkyl, B2 is hydrogen or C-C-alkyl, Y represents 9 in 10 A o h M in Y in (Oy (F. 12 |! in 11 A where B: represents hydrogen or C-C-alkyl, p takes the value 0 or 1, a, 5, Her, and independently of each other take the values 0, 1, 2, З or 4, г takes the value 1, the sum of 'yagya5 and y is equal to 1, 2, З or 4, VU, ВО, В!! and В!2 independently of each other represent hydrogen or C1-C6-alkyl, O represents "M-B"Z or 14 A ra (c) where o takes the value 0, 1 or 2, T represents -M(B") (BZ) or hydroxyl , BZ, B Her 2!E independently of each other represent hydrogen or C.-C-alkyl, B!" represents hydrogen, aryl or hetaryl, or Y represents: C 10 A in web- -- M o y 1211 AB where a, 5, Her, and independently take the values 0, 1, 2, З or 4, г takes the value 0 or 1, the sum of 5 is not equal to 0, 1,2, З or 4, VU . or B 4 ra where o takes the value 0, 1 or 2, T represents -M(B":)(B'E) or hydroxyl, BZ, B and bE independently of each other represent hydrogen or C-C-alkyl , B!" represents hydrogen, aryl or hetaryl, C represents -O-(CHag) B", in 17 in 18 17 17 18 A A 17 he) A and 18 in" d - in" V schi in sm i in" in 17 M 17 --sh 18 uv zhu And I from Z or 5 from de B", VIV, Viz, to and B"! independently of each other are hydrogen, halogen, aryl, hetaryl, C1-6-alkyl or C1-6-alkoxy, K takes the value 0, 1 or 2, U is -O-(CHag)-B22, ve in 2o 22 23 A A 22 in je n and 23 in' de in B in" cm and Z in? in" M 22 what 23 U is connected with Z or 5 with de B, A, dya, de and 26 independently of each other are hydrogen, halogen, aryl, hetaryl, C-C-alkyl or C-C-Alkoxy, Y takes the value 0, 1 or 2, and takes the value 0, 1 or 2, p takes the value 0, 1 or 2, c takes the value 0, 1 or 2, and takes the value 0 or 1, e takes the value 0, 1, 2 or Z, Y takes the value 0 or 1, B? represents hydrogen or C1-C6-alkyl, optionally substituted by one or more hydroxyl, aryl or hetaryl, B? and B" independently of each other are hydrogen or C 1-6 alkyl optionally substituted by one or more halogen, amino, hydroxyl, aryl or hetaryl, VAZ is hydrogen or C1-6-alkyl optionally substituted by one or more halogen, amino group, hydroxyl, aryl or hetaryl, B and B" or PE? and P8, or B" and 28 may optionally form -( CHg)-O-(CHg)/-, where and and | independently of each other take the values 1, 2 or 3, and 7 represents -O-, -5- or a valence bond, M represents arylene, hetarylene, -O-, -5- or -С82/-СИД28- , In? and 228 independently of each other represent hydrogen or C1-C6 alkyl optionally substituted with one or more aryl or hetaryl, or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, which differs in that K! is C-C alkyl. 3. A compound according to any of the previous clauses, which differs in that B? is C 1-6 alkyl. 4. A compound according to any of the previous points, which differs in that And is a verb? do o a M )v Y vi (Oy o 12 |! v B 1 where B: represents hydrogen or C-C-alkyl, p takes the value 0 or 1, a, 5, Her, and independently of each other take the values 0, 1, 2, C or 4, r takes the value 1, the sum of r 5 and y takes the value 1, 2, C or 4, VU, VO, B!! and B!2 independently of each other represent hydrogen or Si -in-alkyl, O represents "M-B"C or B 4 ra where o takes the value 0, 1 or 2, T represents -M(B":)(B'E) or hydroxyl, BZ, B: and B!E are independently hydrogen or C 1-6 alkyl, and B! is hydrogen, aryl or hetaryl. 5. A compound according to any of claims 1-3, which is distinguished by the fact that И is Shi y y y! 2 in! 1 where a, 5, Her, and y independently of each other take the values 0, 1, 2, З or 4, г takes the value 0 or 1, the sum of г 5 and y takes the values 0, 1,2, З or 4, VU , WHO, D!! and V! independently of each other represent hydrogen or C1-6-alkyl, O represents "M-B!Z" or "(c)" where o takes the value 0, 1 or 2, T represents -M(B)(B' C) or hydroxyl, VZ, B! and 2!E are independently hydrogen or C 1-6 alkyl, and B! is hydrogen, aryl or hetaryl. 6. A compound according to any of the previous items, which differs in that C represents 17 c! 18 in! 18 in 17 B 21 eco 19 о A or ; where are B", BB, D"", D2o and E?! independently of each other are hydrogen, halogen, aryl, hetaryl, C1-6-alkyl or C1-6-alkyl. 7. A compound according to any of the previous items, which differs in that U represents 22 v! 23 A 22 in 26 23 r A A zhu in! or Z where 822, BZ, ID, AD" and 26 independently of each other represent hydrogen, halogen, aryl, hetaryl, C1-6-alkyl or C1-6-alkyl. 8. A compound according to any of the previous clauses, which differs in that M represents arylene or -СВ2"-С28-, where В?" and E28 are independently hydrogen or C 1-6 alkyl optionally substituted with aryl or hetaryl. 9. The compound according to any of the previous items, which differs in that B and B" independently of each other represent hydrogen or C-C-alkyl. 10. A compound according to any one of claims 1-8, which differs in that Re and ВЕ" form -(CHg)-0-(CHg)g, where and and and) independently of each other take the value 1, 2 or 3 , and OO represents -O-, -5- or a valence bond. 11. A compound according to any of the previous items, which differs in that C is hydrogen or C 1-6 alkyl. 12. The compound according to any of the previous items, which differs in that it is selected from MA A)-1-(4Ch-K1B)-1-benzyl-2-(4-((dimethylamino)methyl)piperidine-1- yl)-2-oxoethyl|-M-methylcarbamoyl)-2-(2-naphthyl)ethyl)-M-methylamide (2E)-5-amino-5-methylhex-2-enoic acid ns sn, O t CHnzU o ; achu is M nn and Ve sn. o M 3 - CH, M-A(18)-1-74-C1 A)-1-benzyl-2-(35)-3-(dimethylaminomethyl)piperidin-1-yl)-2-oxoethyl|-M -methylcarbamoyl)-2-(2-naphthyl)ethyl)-M-methylamide (2E)-5-amino-5-methylhex-2-enoic acid B: schi Y; M dream at SN. M-(C1H)-1-74-C1B)-1-benzyl-2-((35)-3-(dimethylaminomethyl)piperidin-!-yl)-2-oxoethyl|-N-methylcarbamoyl)-2- (2-Naphthyl)ethyl)-M-methylamide (2E)-4-(1-aminocyclobutyl)but-2-enoic acid ЧК : и Ї KIM sleep o with CH, М-(Ц1 Я)-1-74-Ц1 B)-1-benzyl-2-((25)-2-((dimethylamino)methyl)pyrrolidin-1 -yl)-2-oxoethyl|-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-M -methylamide (2E)-5-amino-5-methylhex-2-enoic acid ns sn, O t Sn o ;achuFe " M snu o CH, M-(18)-1-74-C1 A)-1-benzyl -2-(25)-2-((dimethylamino)methyl)pyrrolidin-1-yl)-2-oxoethyl|-M-methylcarbamoyl)-2-(2-naphthyl)ethyl)-M-methyl-3-(( methylamino)-methyl)benzamide At 7 p.m. who is not yy sn. dream at SN. MA A)-1-44Ch-K1 B)-1-benzyl-2-(4-(dimethylamino)piperidin-1-yl)-2-oxoethyl|-M-methylcarbamoyl)-2-(2-naphthyl)ethyl) -M-methylamide (2E)-5-amino-5-methylhex-2-enoic acid is not CH, (9) : CH» about ;achu is | M we and dream. o m" OH" CH, M-methyl-Mm-(18)-1-(M-methyl-M-(1 AB)-1-IM-methyl-M-(1 -methylpiperidin-4-yl)- carbamoyl|-2-phenylethyljarbamoyl)-2-(2-naphthyl)ethylamide (2E)-5-amino-5-methylhex-2-enoic acid oo «« sn, ma ; M na hu NI m sn. o sn, Z -aminomethyl-M-(1 2)-1-44-K1 2)-1-benzyl-2-(4-methylpiperazine-1 4lu-2-oxoethyl|-M-methylcarbamoyl-2-(2-naphthyl)ethyl) -M-methylbenzamide O tsno ano DV ev sno o shku; with "sn, M-AC1 A)-1-(4-K1 B)-1-benzyl-2-(4-methylpiperazine-1 -1)-2-oxoethyl|-M-methylcarbamoyl)-2-(2- naphthyl)ethyl)-M-methylamide (2E)-5-amino-5-methylhex-2-enoic acid; -methyl-M-((1A)-2-phenyl-1-(2,2,68,6b-tetramethylpiperidin-4-yl)carbamoyl)ethylcarbamoyl-2-(2-naphthyl)ethyl)amide (2E)- 5-amino-5-methylhex-2-enoic acid and NE CH. ns sn (9) : sn. about MN Z Z : | CH with M; M M K! NA tr 7 | N SNU sleep. o 3-aminomethyl-M-methyl-Mm-((1 A)-1-(/M-methyl-M-|(1 A8)-2-phenyl-1 -(2,2,6,6-tetramethylpiperidine- 4-ylcarbamoyl)ethylcarbamoyl)-2-(2-naphthyl)ethyl)-benzamide not О т сн, 9 сн, ; M NA mg i MN sn. O sn, not M-methyl-M-((1 A)-1-/M-methyl-M-((1 A)-2-phenyl-1 -(2,2,68,6b-tetramethylpiperidine-4- yl)carbamoyl)ethylcarbamoyl-2-(2-naphthyl)ethylamide of (2E)-5-amino-3,5-dimethylhex-2-enoic acid Sleep о сн, not М-АЦ1 А)-1-(4-К1 В)-1-benzyl-2-(4-methylpiperazine-1 -1)-2-oxoethyl|-M-methylcarbamoyl)-2-(2- naphthyl)ethyl)-M-methylamide (2E)-4-(1-aminocyclobutyl)-but-2-enoic acid 24 Y : Y ; M nm hu TK m sn. o shku; with "sn, M-AC1 A)-1-(4-K1 B)-1-benzyl-2-(4-methylpiperazine-1 -1)-2-oxoethyl|-M-methylcarbamoyl)-2-(2- naphthyl)ethyl)-M-methylamide (2E)-5-amino-3,5-dimethylhex-2-enoic acid ns snUsSNU o OH» (9) M AD " M NA g m snu o shku; With "sn, MA A)-1-44-K1 A)-1-benzyl-2-(4-hydroxypiperidin-1 -yl)-2-oxoethyl|-M-methyl-carbamoyl-2-(biphenyl-4- yl)ethyl)-M-methylamide (2E)-4-(1-aminocyclobutyl)but-2-enoic acid benzyl-2-(4-hydroxypiperidin-1-yl)-2-oxoethyl|-M-methylcarbamoyl)-2-(biphenyl-4-yl)ethyl)-M-methylamide (2E)-5-amino-5-methylhex -2-enoic acid no A AL : M nm ku sf M sna o On MA A)-1-44-K1 A)-1-benzyl-2-(4-hydroxypiperidin-1 -yl)-2-oxoethyl|- M-methyl-carbamoyl)-2-(biphenyl-4-yl)ethyl)-M-methylamide (2E)-5-amino-3,5-dimethylhex-2-enoic acid ; MA A)-1-44-K1 A)-1-benzyl-2-(4-hydroxypiperidin-1 yl)-2-oxoethyl|-Mi-methylcarbamoyl)-2-(2-naphthyl)ethyl)-m-methylamide (2E)-5-amino-5-methylhex-2-enoic acid; M nm x g M sleep. o OH MA A)-1-44-K1 A)-1-benzyl-2-(4-hydroxypiperidine-1 -yl)-2-oxoethyl|-M-methylcarbamoyl)-2-(2-naphthyl)ethyl)-M-methylamide of (2E)-5-amino-3,5-dimethylhex-2-enoic acid; M NA g m d. o OH MA A)-1-(4-(1 A)-1-benzyl-2-(4-hydroxy (2E)-4-(1-aminocyclobutyl)but-2-enoic acid 2 X: y Y KM sn. o on MA A)-1-4(4Ch-(K1 2)-1-(4-fluorobenzyl)-2-(4-hydroxypiperidin-1-i1)-2-oxoethyl|-M-methylcarbamoyl-2-(2 - naphthyl)ethyl)-M-methylamide (2E)-5-amino-5-methylhex-2-enoic acid in D and Y; M sna o OH E MA A)-1-4(4Ch-(K1 2)-1-(4-fluorobenzyl)-2-(4-hydroxypiperidine-1 4lu-2-oxoethyl|-M-methylcarbamoyl-2-( 2-naphthyl)ethyl)-M-methylamide (2E)-5-amino-3,5-dimethylhex-2-enoic acid Я | M on НИ M sleep. o ОН E M-АЦ1 А)-1-14-( 1 A)-1-benzyl-2-(4-hydroxy-4-(2-thienyl)piperidin-1-yl)-2-oxoethyl|-M-methylcarbamoyl-2-(2-naphthyl)ethyl)-M- methylamide (2E)-5-amino-5-methylhex-2-enoic acid NOSE sleep about, | СНз о : M N lnu M 2 | / X sleep o 5 OH M-(1 A)-1-794Ch-K1 2)-1 -(3-tihydroxycyclohexylcarbamoyl)-2-phenylethyl|-M-methylcarbamoyl)-2-(2-naphthyl)ethyl)-M- methylamide ( of 2E)-5-amino-5-methylhex-2-enoic acid o MA A)-1-4(4-(1 B)-1-benzyl-2-(4-dimethylamino)piperidin-1 -yl)-2-oxoethyl|-M-methylcarbamoyl-2-(2-naphthyl) ethyl)-M-methylamide (2E)-4-(1-aminocyclobutyl)-but-2-enoic acid in Х M Х Х Х Х Х сн. o MON" CH, M-(18)-1-7h-K(22)-2-(4-hydroxypiperidin-1-yl)-2-oxo-1-(2-thienylmethyl)ethyl|-M- methylcarbamoyl)-2-(2-naphthyl)ethyl)-M-methylamide (2E)-5-amino-5-methylhex-2-enoic acid OH : M snu o te 5th M-(1 8)-1-7h-K(2 2)-2-(4-hydroxypiperidin-1-yl)-2-oxo-1 -((2-thienylmethyl) ethyl|-M-methylcarbamoyl)-2-(2-naphthyl)ethyl)-M-methylamide (2E)-5-amino-3,5-dimethylhex-2-enoic acid 1 OH xx ' M nm g M snu o t 5-/М-А(Ц1А)-2-(biphenyl-4-yl)-1--4-(2А)-2-(4-hydroxypiperidin-1-l)-2-oxo-1-(2 -thienyl)umethyl)ethyl|-IM-methylcarbamoyl)ethyl)-M-methylamide (2E)-5-amino-5-methylhex-2-enoic acid t OH : M nm U NI M sn. 5th M-A(C1 A)-2-(biphenyl-4-yl)-1-4M-C1 A)-2-(4-hydroxypiperidin-1-l)-2-oxo-1 -( 2-thienyl)umethyl)ethyl|-IM-methylcarbamoyl)ethyl)-M-methylamide (2E)-5-amino-3,5-dimethylhex-2-enoic acid ns snUENz o de OH acha a: M nom i; sleep o B MA A)-1-44-K1 A)-1-benzyl-2-(4-hydroxypiperidin-1-yl)-2-oxoethyl|-M-methyl-carbamoyl-2-(biphenyl-4-yl) ethyl)-M-methylamide (2E)-5-methyl-5-(methylamino)hex-2-enoic acid sn. O t sno Al ; M Ker M uten sn SN Z sn. o 3 C (18)-1-474-(1 2)-1-benzyl-2-(4-hydroxypiperidin-1 4lu-2-oxoethyl|-M-methylcarbamoyl-2-(biphenyl-4-yl)ethyl) amide of (2E)-4-(1-aminocyclobutyl)but-2-enoic acid and their pharmaceutically acceptable salts. 13. A pharmaceutical composition containing as an active ingredient a compound according to any one of claims 1-12 or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent. 14. A method of stimulating the release of growth hormone from the pituitary gland of a mammal, which is characterized by the fact that the indicated mammal is administered an effective amount of the compound according to any of claims 1-12 or its pharmaceutically acceptable salt, or the composition according to claim 13. 15. A method of manufacturing a medicinal product for the treatment of growth retardation associated with asthma, characterized in that an effective amount of the compound according to any one of claims 1-12 or a pharmaceutically acceptable salt thereof is combined together with a pharmaceutically acceptable carrier or diluent. 16. A method of manufacturing a medicinal product intended for stimulating the release of growth hormone from the pituitary gland of a mammal, characterized in that an effective amount of the compound according to any of claims 1-12 or a pharmaceutically acceptable salt thereof is combined together with a pharmaceutically acceptable carrier or diluent. 17. A method of manufacturing a medicinal product intended for the treatment of growth retardation associated with juvenile rheumatoid arthritis, characterized in that an effective amount of the compound according to any one of claims 1-12 or a pharmaceutically acceptable salt thereof is combined with a pharmaceutically acceptable carrier or thinner