Spirobiindane, methods for their production (options)

 

(57) Abstract:

The proposed spirobiindane formula I or II where R1represents aryl-(C1-C6alkyl), C3-C7-cycloalkyl-(C1-C6-alkyl), aryl-(C0-C5alkyl)-K-(C1-C6-alkyl), C3-C7-cycloalkyl-(C0-C5alkyl)-K-(C1-C5-alkyl), where K is O, S(O)m, aryl denotes phenyl, pyridyl and indolyl which may be substituted by 1-2 halogen atoms; R2is hydrogen, R3aand R3bare hydrogen, a halogen atom, a C1-C5by alkyl; R4and R5are hydrogen, C1-C6-alkyl, substituted by 1-3 hydroxy groups; R6is hydrogen; a represents a group -(CH2)x-C(R7)(R7a)-, where x = 0 or 1, R7and R7arepresent1-C6-alkyl; and one of b, D, E, F is C(R8)(R10), O, S = O, S(O)m, NR9and b, D, E or F may be absent, thus forming a 5-, 6-membered ring, R8and R10represent hydrogen, R9is R'2; SO2R'2C(O)R'2C(O)OR'2, SO2(CH2)q-aryl, where R'2may b the sludge; q=0, 1; m = 0, 1, or 2; n = 1; G, H, I and J represent the carbon atoms or sulfur so that at least one is a heteroatom and one of G, H, I and J may not necessarily be absent, which ensures the formation of 5-membered heterocyclic or 6-membered aromatic ring, and its pharmaceutical salts and individual diastereoisomer. The method of obtaining the compounds of formula I or II involves the interaction of compounds 4 or 4A with the compound of formula noos-And-NR4R5or noos-And-N(R4)L, where L represents a protective group, which is then removed (if present). The method of obtaining the compounds of formula I or II by reacting the compounds of formula (2) or (2A) with the compound of the formula (12) or (12A), where L represents a protective group, which is then removed. The method of increasing the content of endogenous growth hormone in humans and animals, the pharmaceutical composition for increasing the endogenous production or secretion of growth hormone in man or animal. 5 S. and 6 C.p. f-crystals, 1 table.

The growth hormone, which is isolated from the pituitary gland, stimulates the growth of all body tissues that are able to grow. In addition, it is known that growth hormone has the following main steps in metabolic process is korost utilization of carbohydrates in the cells of the body.

3. Increases the activation of free fatty acids and the use of fatty acids for energy production.

Insufficient secretion of growth hormone can lead to various diseases, as for example to the dwarf.

To release growth hormone known different ways. For example, such chemical compounds as arginine, L-3,4-dihydroxyphenylalanine (L-DORA), vasopressin, glucagon and insulin, causing hypoglycemia, as well as manifestations of such activities as drowsiness and physical activity indirectly by inducing the secretion of growth hormone from the pituitary gland due to the impact in any way on the hypothalamus and, perhaps, or reducing the secretion of somatostatin, or increasing the secretion of the known factors that increase the release of growth hormone (GPF), or unknown endogenous hormone that stimulates growth hormone, or it all together.

In cases where it is desirable to increase the levels of growth hormone, the problem is usually allowed, providing exogenous growth hormone or introducing GPF or peptide compound which stimulates the production and/or secretion of growth hormone. In any case, the peptide nature of the connection requires that it was introduced by John the tea to the high cost of the product and include risk transfer to the recipient growth hormone diseases, associated with the source of the pituitary gland. Recently became available growth hormone obtained by recombinant methods, which although it eliminates the risk of transmission of disease, still does not reduce the extremely high cost of the product, which can be entered either by injection or as a nasal spray.

Were developed by other compounds that stimulate the secretion of endogenous growth hormone, such as analog peptidyl connection related GPF, or peptides of U.S. patent 4411890. These peptides, although much smaller than the growth hormones is still exposed to the action of various proteases. As for most peptides, their potential bioavailability after oral administration is low. The considered compounds are ones counterparts, promoting the secretion of growth hormone, which is stable in different physiological environments and which can be introduced parenterally, through the nose or mouth.

The present invention encompasses some spiraeoideae, which have the ability to stimulate the secretion of natural or endogenous growth hormone. Thus, these compounds can be used to treat conditions that require the Yu growth hormone, or to animals used for food purposes, where the stimulation of growth hormone leads to growing a larger, more productive animals. Thus, the aim of the present invention is the description of helical compounds. Another objective of the present invention is the description of methods for obtaining such compounds. Another goal is the description of the use of such compounds to enhance the secretion of growth hormone in humans and animals. And another goal is to describe compositions containing spiraeoideae for use in the treatment of humans and animals to increase the secretion of growth hormone. Other objectives will become apparent when reading the following descriptions.

New spiraeoideae of the present invention is best described by the following structural formulas I and II:

< / BR>
< / BR>
R1represents C1-C10alkyl, aryl, aryl(C1-C6alkyl) and C3-C7cycloalkyl(C1-C6alkyl or C1-C5alkyl-K-(C1-C5-alkyl), aryl (C0-C5alkyl)-K-(C1-C5alkyl), C3-C7cycloalkyl- (C0-C5alkyl)-K-(C1-C5alkyl), where K is O, S(O)mN(R2)C(O), C(O)N(R2mR2a, 1-3 OR2aor C(O)OR2aand aryl groups can be substituted by phenyl, phenoxy, aloevera, 1-3 C1-C6the alkyl, 1-3 Halogens, 1-2 OR2methylenedioxy, S(O)mR2, 1-2 CF3, OCF3, nitro, N(R2)(R2), N(R2)C(O)R2C(O)OR2C(O)N(R2)(R2), SO2N(R2)(R2)

N(R2)S(O)2aryl or N(R2)SO2R2;

R2represents hydrogen, C1-C6alkyl, C3-C7cycloalkyl, and if two C1-C6alkyl groups are present on one atom, they may be not necessarily connected with the formation of C3-C8cyclic ring, optionally containing oxygen, sulfur or NR2a;

R2arepresents hydrogen or C1-C6alkyl;

R3aand R3bindependently represent hydrogen, halogen, C1-C6alkyl, OR2, cyano, OCF3methylenedioxy, nitro, S(O)mR, CF3or C(O)OR2and if R3aand R3bare anthopology, they can be connected with the formation of C5-C8aliphatic or aromatic ring, optionally containing 1 or 2 heteroatoms selected from oxygen, sulfur or nitrogen;

the l, where the substituents may be 1 to 5 Halogens, 1 to 3 hydroxy, 1 to 3 C1- C10alkanoyloxy, 1-3 C1-C6alkoxy, phenyl, phenoxy, 2-furyl, C1-C6alkoxycarbonyl, S(O)m(C1-C6alkyl); or R4and R5taken together form -(CH2)rLa(CH2)s- where Lais C(R2)2, O, S(O)mor N(R2), r and s are independently equal to 1-3, and R2has the previously indicated meaning;

R6represents hydrogen or C1-C6alkyl;

A represents A

< / BR>
or

< / BR>
where x and y independently represent 0-3;

Z is N-R2or O;

R7and R7aindependently represent hydrogen, C1-C6alkyl, OR2, trifluoromethyl, phenyl, substituted C1-C6alkyl, where the substituents are imidazolyl, phenyl, indolyl, p-hydroxyphenyl, OR2, 1-3 fluoro, S(O)mR2C(O)OR2C3-C7cycloalkyl, N(R2)(R2), C(O)N(R2)(R2); or R7and R7acan be independently connected to one or both of R4and R5groups with the formation of alkilinity bridges between the terminal nitrogen and the alkyl part of R7or R7agroups, and the bridge can content is so one or two of B, D, E, or F may not necessarily be missing, which will ensure the formation of 5-, 6 - or 7-membered ring; and provided that B, D, E and F can be C(R8)(R10or C= O only if one of the remaining B, D, E and F is O, S(O)mor NR9B and D or D and E taken together may represent CR8=CR10provided that one of the other B and E or F at the same time is O, S(O)mor NR9;

R8and R10independently represent hydrogen, R2OR2, (CH2)qaryl, (CH2)qC(O)OR2, (CH2)qC(O)(CH2)qaryl or (CH2)q(1H-tetrazol-5-yl), and aryl may be optionally substituted by 1-3 Halogens, 1-2 C1-C8the alkyl, 1-3 OR2or 1-2 C(O)OR2;

R9is R2, (CH2)qaryl, C(O)R2C(O)(CH2)q- aryl, SO2R2, SO2(CH2)qaryl, C(O)N(R2)(R2), C(O)N(R2)-(CH2)qaryl, C(O)OR2, 1-H-tetrazol-5-yl, SO3H , SO2N(R2)aryl, or SO2N(R2)(R2), and (CH2)qmay be optionally substituted WITH 1-21-C4the alkyl, and R2and aryl can optionally be substituted by another 1-3 OR2a, O(CH2)qB>the aryl, 1-5 halogen, 1-3 C1-C4the alkyl, 1,2,4-triazolium, 1-H-tetrazol-5-yl, C(O)NHSO2R2a, S(O)mR2aTHAT IS , C(O)NHSO2(CH2)qthe aryl, SO2NHC(O)R2a, SO2NHC(O)(CH2)qthe aryl, N(R2)C(O)N(R2a)-(R2a), N(R2a)C(O)N(R2a)(CH2)qthe aryl,

N(R2a)(R2a), N(R2a)C(O)R2aN(R2a)C(O)(CH2)qthe aryl, OC(O)N(R2a)(R2a), OC(O)N(R2a)(CH2)qthe aryl or SO2(CH2)qCONH-(CH2)wNHC(O)- R11where w is 2 to 6, a R11is Biotin, aryl or aryl substituted 1 or 2 OR2by 1-2 halogen, azido or nitro;

m = 0,1 or 2;

n = 1 or 2;

q = 0, 1, 2, 3 or 4; and

G, H, I and J represent atoms of carbon, nitrogen, sulfur or oxygen, so that at least one heteroatom and one of G, H, I or J may not necessarily be absent, which ensures the formation of 5 - or 6-membered heterocyclic aromatic ring;

and its pharmaceutically acceptable salts and individual diastereoisomer.

In the above formulas and forth throughout the description the terms have the following meanings.

These alkyl groups include alkyl groups specified length, rasaki alkyl groups include: methyl, ethyl, propyl, ethinyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, hexyl, isohexyl, alkyl, propenyl, butenyl, butadienyl etc.

These alkoxygroup include alkoxygroup specified length, branched or unbranched, which may optionally contain a double or triple bond. Examples of such alkoxygroup include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentox, isopentane, hexose, isohexane, allyloxy, propenyloxy, isobutyryloxy, 2-hexenoate etc.

The term "halogen" includes atoms of Halogens: fluorine, chlorine, bromine and iodine.

The term "aryl" includes phenyl and naphthyl and the aromatic residues of 5 - and 6-membered rings with 1-3 heteroatoms, or a condensed 5 - or 6-membered bicyclic ring containing 1-3 heteroatom selected from nitrogen, sulfur or oxygen. Examples of such aromatic heterocyclic rings include pyridine, thiophene, benzothiophene, tetrazole, N-methylindol, dihydroindol, indazole, N-formylindole, benzimidazole, thiazole, furan, diamidin and thiadiazole.

Some of videopreteen terms may occur more than once in the above formula, and in this case, ka is the first invention are

< / BR>
where R1represents C1-C10alkyl, aryl(C1-C4alkyl), C3-C6cycloalkyl(C1-C4alkyl), (C1-C4alkyl)-K-(C1-C4alkyl), aryl(C0-C5alkyl)-K-(C1-C4alkyl), or (C3-C7cycloalkyl)(C0-C5alkyl)-K-(C1- C4alkyl), where K is O, S(O)m, -CR2=CR2- , or N(R2)C(O), where R2and alkyl groups may be substituted further 1-7 halogen, S(O)mC1-C4the alkyl, OR2and aryl groups may be further substituted C1-C4the alkyl, 1 to 2 halogen, 1 to 2 OR2, CF3, OCF3methylenedioxy, S(O)mR2, SON(R2)(R2), N(R2)SO2R2or C(O)OR2; R2represents hydrogen, C1-C6alkyl or C3-C7cycloalkyl, and, if two C1-C6alkyl groups are present on one atom, they may be not necessarily connected with the formation of C4-C6-cyclic ring, which optionally comprises 1-2 heteroatom selected from oxygen, sulfur or NR2a;

R2arepresents hydrogen or C1-C6alkyl;

R3aand R3bindependently represent hydrogen, halo2;

R4and R5independently represent hydrogen, C1-C6alkyl, substituted C1-C6alkyl, where the substituents can be from 1-5 halogen, 1-2 hydroxy, 1-2 C1-C6alkanoyloxy, 1-2 C1-C6-alkyloxy, or S(O)m(C1-C4alkyl);

A represents A

< / BR>
or

< / BR>
where x and y are independently 0, 1 or 2;

R7and R7aindependently represent hydrogen, C1-C4alkyl, or substituted C1-C4alkyl, where the substituents can be 1-3 fluorine, imidazolyl, phenyl, indolyl, or S(O)m- C1-C4alkyl C(O)R2or R7and R7acan be independently connected to one or both of R4and R5groups with the formation of alkilinity bridges between the terminal nitrogen and the alkyl part of R7or R7agroups, where the bridge contains 1-3 carbon atoms;

B, D and F independently represent C(R8)(R10), C=O, S(O)mor NR9so one of B, D or F may not necessarily be absent, which ensures the formation of 5 - or 6-membered ring, and provided that one of B, D and F is C(R8)(R10), or C=O only if one of the other B, D and F groups is O, S(O)m>the Rhyl, (CH2)qC(O)OR2, (CH2)qC(O)O(CH2)qaryl, (CH2)q(1H-tetrazol-5-yl), where the aryl may be optionally substituted by 1 to 3 halogen, 1 to 2 C1-C4the alkyl, 1-3 OR2or 1-2 C(O)OR2;

R9is R2, (CH2)qaryl, C(O)R2C(O)(CH2)q-aryl, SO2R2, SO2(CH2)qaryl, C(O)N(R2)(R2), C(O)N(R2)-(CH2)qaryl, 1-H-tetrazolyl-5-yl, , SO2N(R2) - aryl, SO2N(R2)(R2), where (CH2)qmay be optionally substituted by 1-2 C1-C2the alkyl, and R2may be optionally substituted by 1-2 OR2a, O(CH2)qthe aryl, 1-2 C(O)OR2aC(O)N(R2a)- (R2a), S(O)mR2a, 1-H-tetrazol-5-yl, C(O)NHSO2R2aC(O)NHSO2(CH2)qthe aryl, (R2a)C(O)N(R2a)(R2a), or N(R2a)C(O)N(R2a)(CH2)qthe aryl, where aryl may be optionally substituted by 1-3 OR2aby 1-2 halogen, 1-2 C1-C4the alkyl, C(O)OR2aor 1-H-tetrazol-5-yl; SO2(CH2)wCONH(CH2)w- NHC(O)R11where w is 2 to 6, a R11is Biotin, aryl or aryl substituted 1 or 2 OR2aby 1-2 halogen, azido or nitro;

rimidine;

and its pharmaceutically acceptable salts and individual diastereoisomer.

Another group of preferred compounds are realized when in the compound III is absent F.

Other preferred compounds of the present invention have structural formula IV

< / BR>
where R1represents C1-C10alkyl, aryl(C1-C4alkyl), C5-C6cycloalkyl(C1-C4alkyl), (C1- C4alkyl)-K-C1-C2alkyl-, aryl(C0- C2alkyl)-K-(C1- C2alkyl), or C3- C6cycloalkyl(C0-C2alkyl)-K-(C1-C2alkyl),

where K represents O or S(O)mand aryl may be further substituted with 1-2 C1-C4-alkyl, 1-2 halogen, OR2C(O)OR2, CF3or S(O)mR2;

R2represents hydrogen, C1-C4alkyl, cyclo C3-C6alkyl, and, if two C1-C4the alkyl are present on one atom, they may be not necessarily connected with the formation of C5-C6cyclic ring, optionally containing heteroatoms of oxygen or NR2a; R2arepresents hydrogen or C1-C4alkyl;

R3aand R3bindependently represent water which SUB>alkyl, or CF3;

R4and R5independently represent hydrogen, C1-C4alkyl, or substituted C1-C4alkyl, where the substituents may be 1-2 hydroxy or S(O)m(C1-C3alkyl);

A represents A

< / BR>
where x = 0 or 1;

R7and R7aindependently represent hydrogen or C1-C3-alkyl, or R7and R7acan be independently connected to one or both of R4and R5groups with the formation of alkalinous bridge between the terminal nitrogen and the alkyl part of R7and R7agroups with the formation of 5 - or 6-membered rings containing terminal nitrogen;

B and D independently represent C(R8)(R10), C=O, O, S(O)mor NR9provided that one of B and D can be C(R8)(R10or C=O only if different from B and D represents O, S(O)mand NR9;

R8and R10independently represent hydrogen, R2OR2or (CH2)qaryl, where aryl may optionally be substituted by 1-2 halogen, 1-2 C1-C4the alkyl, OR2or 1-2 C(O)OR2;

R9represents C(O)R2C(O)(CH2)qaryl, SO2R2, SO(CH2)qaryl, C(O)N(R2)(R2), or C(O)N(R2)(CH may be optionally substituted by 1-2 OR2a, O(CH2)qthe aryl, C(O)OR2aC(O)N(R2a)(R2a), S(O)mR2a, 1-N-tetrazol-5-yl, C(O)NHSO2aR2aor N(R2a)C(O)N(R2a)-(R2a), and aryl may be optionally substituted by 1-2 OR2aby 1-2 halogen, 1-2 C1-C2the alkyl C(O)OR2a, 1-N-tetrazol-5-yl, and S(O)mR2a; or SO2(CH2)qCONH(CH2)wNHC(O)R11where w is 2 to 6, a R11may not necessarily represent Biotin, aryl, and aryl may be optionally substituted by 1-2 OR2by 1-2 halogen, azido, nitro;

m = 0, 1, or 2;

q = 0, 1, 2, or 3;

aryl is phenyl, naphthyl, pyridyl, indolyl, thienyl or tetrazolyl; and

pharmaceutically acceptable salts thereof and individual diastereoisomer.

The most preferred compounds of the present invention has the formula V

< / BR>
where R1choose from:

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
R3arepresents hydrogen or fluorine;

D is O, S, S(O)mN(R2), NSO2(R2), NSO2(CH2)qOH, NSO2(CH2)taryl, NC(O)(R2), NSO2(CH2)qCOOR2N-SO2(CH2)qC(O)N(R2)(R2)

N-SO2(CH2
R2represents hydrogen or C1-C4alkyl;

m = 1 or 2;

t = 0, 1, or 2;

q = 1, 2, or 3:

w = 2 to 6;

and their pharmaceutically acceptable salts and individual diastereoisomer.

The most preferred compounds of the present invention, promoting the secretion of growth hormone, include the following:

1. N-[1(R)-[(1,2-dihydro-1-methanesulfonamide[3H - indole-3,4'-piperidine] -1'-yl)carbonyl]-2-(1H-indol-3-yl)- ethyl]-2-amino-2-methylpropanamide;

2. N-[1(R)-[(1,2-dihydro-1-metacarbonate[3H - indole-3,4'-piperidine] -1'-yl)carbonyl]-2-(1H-indol-3-yl)- ethyl]-2-amino-2-methylpropanamide;

3. N-[1(R)-[(1,2-dihydro-1-benzosulfimide[3H - indole-3,4'-piperidine]-1'-yl)carbonyl]-2-(1H-indol-3-yl)- ethyl]-2-amino-2-methylpropanamide;

4. N-[1(R)-/(3,4-dihydro-Spiro/2H-1-benzopyran-2,4'-piperidine/-1'- yl)carbonyl/-2-(1H-indol-3-yl)ethyl/-2-amino-2-methylpropanamide;

5. N-/1(R)-/(2-acetyl-1,2,3,4-tetrahydrofuro/isoquinoline - 4,4'-piperidine/-1'-yl)carbonyl/-2-(indol-3-yl)ethyl/-2-amino-2 - methylpropanamide;

6. N-/1(R)-/(1,2-dihydro-1-methanesulfonamido/3H - indole-3,4'-piperidine] -1'-yl)carbonyl/-2-(phenylmethoxy)- ethyl/-2-amino-2-methylpropanamide;

7. N-/1(R)-/(1,2-dihydro-1-methanesulfonamido/3H - indole-3,4'-piperidine] -1'-)carbonyl/-2-(phenylmethoxy)- ethyl/-2-amine is bonil/-2-(2', 6'-differgenerations) ethyl/-2-amino-2-methylpropanamide;

9. N-/1(R)-/(1,2-dihydro-1-methanesulfonyl-5-pterospora/3H - indole-3,4'-piperidine] -1'-yl)carbonyl/-2-(phenylmethoxy) ethyl/-2-amino-2-methylpropanamide;

10. N/1(S)-/(1,2-dihydro-1-methanesulfonamido/3H - indole-3,4'-piperidine]-1'-yl)carbonyl/-2-(feniletilic)- ethyl/-2-amino-2-methylpropanamide;

11. N-/1(R)-/(1,2-dihydro-1-methanesulfonamido/3H - indole-3,4'-piperidine]-1'-yl)carbonyl/-3-(phenylpropyl)-2 - amino-2-methylpropanamide;

12. N-/1(R)-/(1,2-dihydro-1-methanesulfonamido/3H - indole-3,4'-piperidine]-1'-yl)carbonyl/-3-cyclohexylprop)-2 - amino-2-methylpropanamide;

13. N-/1(R)-/(1,2-dihydro-1-methanesulfonamido/3H - indole-3,4'-piperidine]-1'-yl)carbonyl/-4-phenylbutyl/-2 - amino-2-methylpropanamide;

14. N-/1(R)-/(1,2-dihydro-1-methanesulfonamido/3H - indole-3,4'-piperidine] -1'-yl)carbonyl/-2-(5-fluoro-1H-indol-3-yl)ethyl/-2 - amino-2-methylpropanamide;

15. N-/1(R)-/(1,2-dihydro-1-methanesulfonyl-5-pterospora/ 3H-indole-3,4'-piperidine] -1'-yl)carbonyl/-2-(5-fluoro-1H-indol-3-yl) ethyl/-2-amino-2-methylpropanamide;

16. N-/1(R)-/(1,2-dihydro-1-(2-etoxycarbonyl)methylsulfonylamino/ 3H-indole-3,4'-piperidine] -1'-yl)carbonyl/-2-(1H-indol-3-yl) ethyl/-2-amino-2-methylpropanamide;

17. N-/1(R)-/(1,2-dihydro-1,1-dioxaspiro/ 3H-benzothiophen-3,4'-piperidine]-1'-yl)carb is>Representative examples of the items below

< / BR>
N-/1(R)-/3,4-dihydro-4-oxaspiro/2H-1-benzopyran-2,4'- piperidine/-1'-yl)carbonyl/-4-phenylbutyl/-2-amino-2-methylpropanamide

< / BR>
N/1(S)-/(1,2-dihydro-1-methanesulfonyl/3H-indole - 3,4'-piperidine/-1'-yl)carbonyl/-2-(feniletilic)ethyl/- 2-amino-2-methylpropanamide

< / BR>
N-/1(R)-/(1,2-dihydro-1-methanesulfonyl/3H-indole - 3,4'-piperidine/-1'-yl)carbonyl/-2-(phenylmethoxy)ethyl/- 2-amino-2-methylpropanamide.

In the present description, the abbreviations have the following meanings:

BOC - tert-butyloxycarbonyl,

THIEF - benzotriazol-1 yloxy Tris/dimethylamine/phosphonium - hexaphosphate,

CBZ - benzyloxycarbonyl,

DCC - dicyclohexylcarbodiimide,

DMF - N,N-dimethylformamide,

EDC - 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide,

FAB-MS - mass spectrometry fast atom bombardment,

GHRP - peptide that stimulates growth hormone

HOBT - hydroxybenzotriazol,

LAH - sociallyengaged,

HPLC - high performance liquid chromatography,

MHz - megahertz = MHz,

MPLC - liquid chromatography medium pressure,

NMM is N-methylmorpholine,

NMR - nuclear magnetic resonance = NMR,

OXONE - peroxy the er - serine,

TFA - triperoxonane acid,

THF is tetrahydrofuran,

TLC - thin layer chromatography = TLC,

TMS tetramethylsilane was = TMS.

Compounds of the present invention contain at least one asymmetric center, which is marked with an asterisk in the structural formula I and II above. In the molecule may be more asymmetric centers, depending on the nature of the various substituents in the molecule. For each asymmetric center can produce two optical isomers and it should be assumed that all such optical isomers, as separated, pure or partially purified optical isomers, racemic mixture, or diastereoisomeric mixtures thereof, are included in the scope of the present invention. In that case, if the asymmetric center marked with an asterisk were found to be more active and thus more preferred isomer is represented by formula Ia. This preferred absolute configuration applies to both formula I and II. If R2Deputy represents hydrogen, a special configuration of the asymmetric center corresponds to the configuration in the D-amino acid. In most cases, it is also designated as R-configuration, although this will vary according C2">

< / BR>
Compounds of the present invention are usually isolated in the form of their pharmaceutically acceptable salts accession acids, for example salts derived from inorganic or organic acids. Examples of such acids can serve as hydrochloric, nitric, sulfuric, phosphoric, formic, acetic, triperoxonane, propionic, maleic, succinic, malonic, methansulfonate, etc. in Addition, some compounds containing an acid function, such as carboxy, can be identified in the form of inorganic salts, in which the counterion may be selected from sodium, potassium, lithium, calcium, magnesium, etc. and organic bases.

The compounds I and II of the present invention can be obtained by sequential or convergent synthesis. Detailed diagrams of the successive synthesis of compounds I and II are presented in the following schemes reactions.

Protected amino acid derivatives 1 in many cases commercially available, if the protective group L is, for example BOC or CBZ group. Other protected amino acid derivative 1 can be obtained well-known from the literature of ways, many of spiroperidol and spiroxazine (n = 2) of formula 2 and 2a are known from literaturerosie, sulfonylamine, etc. In another embodiment, various phenyl - or heteroarylboronic spirobiindane and spiroxazine (n = 2) can be obtained according to literature methods, using the intermediate phenyl and heteroarylboronic.

In the schemes, the following schemes 1, synthetic methods are illustrated only for spiroperidol, though experts recognize this fact, as illustrated by the transformation can be performed with products of higher homologous series, leading to the formation of compounds of formulas I and II, where n = 2.

Intermediate compounds of formulas 3 and 3A can be synthesized in accordance with scheme 1, is given at the end of the description. The combination of spiroperidol formulas 2 and 2A to protected amino acids of formula 1, where L represents a suitable protective group usually perform in such an inert solvent as dichloromethane, using such provides reaction reagents, as DCC and EDC in the presence of HOBT. In another embodiment, the reaction mix can be accomplished by such reagents as BOP in an inert solvent, for example dichloromethane. Department of unwanted side products and purification of the intermediate compounds carry out chromatography on with the x2">

Turning 3 and 3A in the intermediate compounds 4 and 4a can be implemented in accordance with scheme 2, shown at the end of the description. Benzyloxycarbonyl group can be removed by various methods known in the art; for example, catalytic hydrogenation with hydrogen in the presence of palladium or platinum catalyst in such proton solvent like methanol. In cases where catalytic hydrogenation is contraindicated because of the presence of other potentially reactive groups, delete benzyloxycarbonyl group by treatment with a solution of hydrogen bromide in acetic acid. The removal of the BOC protective groups are in a solvent such as methylene chloride or methanol, a strong acid like hydrochloric or triperoxonane acid.

Conditions required to remove the other protective groups which may be present can be found in Greene, N. Wuts, P. G. M. Protective Groups Organic Synthesis, John Wiley and Sons, NY, 1991.

Intermediate compounds of formulas 5 and 5b, where A represents A methylene or substituted methylene group, can be obtained in accordance with scheme 3, shown at the end of the description, due to the combination of intermediate 4 and 4a with the amino acids of formula 6 and again in the ini and amino acids 6 are well-known amino acids, or amino acids, which are easy to synthesize well-known specialists of ways. In another embodiment, the reaction mix can be realized by such a reagent combinations, like a THIEF, in which the inert solvent like dichloromethane. In addition, if R4or R5represent hydrogen, then the amino acid of formula 7 is used in the reaction combinations, where L represents a protective group, as described previously, to obtain 5a and 5c. Remove protection from 5a and 5c (L = protective group) can be performed under conditions known in the art.

Compounds of formulas I and II, where R4and/or R5represents hydrogen, can be further transformed into new compounds I and II (preferred side chain R7= CH2-CH/OH/CH2X, where X= H or OH) which are substituted on the amino group, as indicated in figure 4, is given at the end of the description. Reductive amination of I and II aldehyde carried out under conditions known in the art; for example, catalytic hydrogenation with hydrogen in the presence of platinum, palladium or Nickel catalysts, or for the account of such chemical reducing agents, as cyanoborohydride sodium in such an inert solvent as methanol or ethanol. Alkylation up by the formulas I and II, where A is N(R2)- (CH2)z-C(R7)(R7a)-(CH2)ymay be obtained in accordance with scheme 5, provided at the end of the description, due to the interaction of 4 or 4a with reagents 8, where X is easily tsepliaeva group, for example Cl, Br or I, imidazole. In another embodiment, 4 and 4a can be subjected to interaction with the isocyanate of formula 9 in such inert solvent like 1,2-dichloroethane. If R4or R5is hydrogen in the final product, reagents 8 and 9 must contain deleted L protective group instead of R4or R5.

The compounds I and II of the present invention can also be obtained in the usual way, as shown in reaction schemes 6, 7 and 8, provided at the end of the description.

Protected amino acid derivatives 10 are in many cases commercially available, if M = methyl, ethyl or benzyl esters. Other protected ether complex amino acids can be obtained by classical methods known in the art. Some of these methods include the reaction of the protected amino acids with diazoalkanes and removing the protective group L, the reaction of amino acids with the corresponding alcohol in the presence of a strong acid, podollan on circuits 11, 12 and 13, provided at the end of the description.

Intermediate compounds 11 and 11a can be obtained in accordance with scheme 6, reaction of a combination of amines with 10 amino acids 6 and/or 7, where L represents a protective group as shown in scheme 3. If urea bond is present in 11 or 11a, it can be entered in accordance with scheme 5.

The transformation of ester 11 and 11a in the intermediate acid 12 or 12a can be done in a number of ways known in the art, as shown in figure 7; for example, methyl and ethyl esters can hydrolyze hydroxide lithium proton solvent, such as aqueous methanol. In addition, removing the benzyl group can be accomplished near reductive methods including hydrogenation in the presence of a platinum or palladium catalyst in such proton solvent like methanol. Allyl ester can be split tetrakis-triphenylphosphonium catalyst in the presence of 2-amoxicillinbuy acid in various solvents, including ethyl acetate and dichloromethane (see J.Org. Chem. 1982, 42, 587).

Acid 12 or 12a can then be turned into 5 and 5a and 5b and 5c, as shown in scheme 8. The combination of spiroperidol formula 2 and 2a with the such as dichloromethane, through this combination of reagent, as dicyclohexylcarbodiimide (DCC) and EDC in the presence of 1-hydroxybenzotriazole (HOBT). In another embodiment, the combination can also be accomplished by combining such agent, as benzotriazol-1-yloxytris/dimethylamine/fosfodiesterasa ("BOP") in such an inert solvent like dichloromethane. Conversion of 5a and 5c in the first and second reach, removing the protective group L. If R4and/or R5is H, a nitrogen atom can optionally add a substituted alkyl group in accordance with scheme 4.

In scheme 9, is provided at the end of the description, presents the production of oxidized spiroindanyloxymorphone intermediate compounds in which R3aand R3bboth represent hydrogen. Hydroporinae protected spyroidea 13 with subsequent oxidative treatment pyridinylamino results of serontonin 14.

Turning spirostanol in intermediate benzolactams presented in figure 10, provided at the end of the description. Processing of serontonin nitric acid in such an inert solvent as chloroform (Schmidt reaction), is one of the many appropriate literary methods such transformations. In this case, when then these intermediate the protection can be removed and put in connection, accelerating the secretion of growth hormone, as shown in schemes 1 and 8, using a common intermediate compound 2.

Alkylation 15 and 16 alkylhalides in a solvent such as DMF in the presence of NaH results 17 and 18 (R2= C1-C4alkyl).

If L represents a suitable protective group such as benzyl group, amides, you can restore sociallyengaged to amines 19 and 21. These amines in which R2=H, can then be alkilirovanii, areleaving, allievate or subjected to interaction with substituted sulfanilamide or isocyanates, using conditions known in the art, to obtain the compounds 20 and 22. The removal of the protective group (L) by hydrogenolysis using a palladium catalyst leads to the production of intermediate compounds that can enter into compounds that accelerate the secretion of growth hormone of the present invention using the reaction presented in schemes 1 and 8, in which the share of intermediate compound 2.

In another embodiment, 1,2,3,4-tetrahydrofuro/isoquinoline-4,4'-piperidine/ ring can be obtained according to scheme 12. Ozonolysis of protected serondela with the subsequent processing of dimate the I and acylation gives amine 25. Aminosidine group (L) was defined previously.

Cyclic analogs of formula 26 where X, Y represent H, H; OH, H; H, OH; and = O, can be obtained by methods described in literature and known to experts. For example, according to scheme 13 Spiro/2H-1-benzopyran-2,4'-piperidinyl/ analogue can be obtained from substituted or unsubstituted 2-hydroxyacetophenone and suitably protected 4-piperidone, as indicated Kabbe, H. J. Synthesis 1978, 886-887 and there in the links. 2-Hydroxyacetophenone, in turn, are either commercially available or can be obtained by methods known from the literature specialists. Such methods are described Chang, C. T. et al., in J. Am. Chem. Soc. 1961, 3414-3417, Elliott. J. M. et al., in J. Med. Chem. 1992, 36, 3973-3976. Removing the protective groups described in Protective Groups in Organic Synthesis, Creene, T. W. , Wats, P. G., John Wiley and Olojson, R. A. et al., J.Org. Chem. 1984, 49, 2081-2082, reveals amines, which can be introduced into compounds that accelerate the secretion of growth hormone in accordance with schemes 1 and 8, in which the share of intermediate compound 2.

< / BR>
The ketone functionality in compounds of the General structure 27 can be restored to the alcohol using sodium borohydride or can be fully recovered prior to analysis, using conditions the th of concentrated hydrochloric acid and subsequent hydrogenation leads to the production of compounds of General formula 29. Amine of formula 27, 28 or 29 can then enter in the connection, accelerating the secretion of growth hormone, due to the reactions presented in schemes 1 and 8, using the shared connection of the formula 2. In another embodiment, the ketone is often possible to recover after the introduction of the compounds of formula 1.

Obtaining chiral analogs of hidroxizina/2H-1-benzopyran-2,4'-piperidine/ can be carried out using optically active reducing agents and crystallization diastereoisomeric salts.

Compounds of formulas I and II of the present invention is obtained from a variety of substituted natural and unnatural amino acids, such as represented by formula 30 and 6 and 7, where A represents -(CH2)x-C(R7)(R7a)-(CH2)y. Many of these acids are described in U.S. patent 5206237.

These intermediate compounds in racemic form carried out by classical methods familiar to specialists /Williams, R. M. Synthesis of Optically Active-Amino Acids" Pergamon Precc: Oxford, 1989, Vol. 7).

There are several methods of separation (DZ)-amino acids.

< / BR>
One of the common methods is the separation of amino or carboxyamide intermediates due to crystallization of salts obtained which can be attached to the optically active acids, using the previously described reactions. A breakdown of the individual diastereoisomers either chromatography or by crystallization with subsequent hydrolysis of chiral amides results in separated amino acids. Similarly, aminosidine intermediate compounds can be converted into a mixture of chiral diastereoisomeric esters and amides. Separation of a mixture using the methods previously described and hydrolysis individual diastereoisomers results in (D) and (L) amino acids. Finally, enzymatic methods of separation of N-acetyl derivative (DZ)-amino acids represented by Whitesides with TCS. in J. Am. Chem. Soc., 1989, 111, 6354-6364.

If you want to synthesize these intermediate compounds in optically pure form, you can use some common methods of obtaining, which include:

(1) asymmetric electrophilic amination of chiral enolates (J. Am. Chem. Soc., 1986, 108, 6394-6395, 6395-6397 and 6397-6399), (2) asymmetric nucleophilic amination of optical active carbonyl derivative (J. Am. Chem. Soc. , 1992, 114, 1906, Tetraheoron Lett. 1987, 28, 32), (3) diastereoselective alkylation of chiral glycerinated synthons (J. Am. Chem. Soc. , 1991, 113, 9276; J. Org. Chem., 1889, 54, 3916), (4) diastereoselective nucleophilic which of the derivatives properley dehydrolinalool (Asymmetric Synthesis Chiral Catalysis; Morrison, J. D. Ed; Academic Press; Orlabdo FL, 1985, Vol. 5), and (6) the enzymatic synthesis of (Angew. Chem. Ed. Engl., 1978, 17, 176).

So, for example, alkylation of enolate of diphenyloxazole 31 (J. Am. Chem. Soc., 1991, 113, 9276) zanamivirabdomen in the presence of athribis/(trimethylsilyl)/amide proceeds calmly to obtain 32, which in turn target (D)-2-amino-5-phenylpentane acid 33, removing the N-tert-butyloxycarbonyl group triperoxonane acid, and Giriraja over PdCl2the catalyst (see scheme 14 provided in the end of the description).

Intermediate compounds of formula 30, which are derivatives of O-benzyl-(D)-serine 34, conveniently be obtained using known procedures, from an appropriately substituted benzylamino and N-protected (D)-serine 34. Convenient to protective groups served as BOC and CBZ. Benzylidene 34 can be accomplished in a number of ways well known in the literature, including the removal of protection by two equivalents of sodium hydride in such an inert solvent as DMF followed by treatment with one equivalent of any benzylchloride (Synthesis, 1989, 36), as shown in figure 15, is provided at the end of the description.

O-Alkyl-(D)-serine derivatives also get using the schema alkylation, n is uly 35, include acid catalyzed benzylidene carboxyamide intermediate obtained from 34, reagents of formula ArCHOC(=NH)CCl3/O. Jonemitsu Chem. Pharm. Bull, 1988, 36, 4244. In another embodiment, in the alkylation of chiral glycinato (J. Am. Chem. Soc., 1991, 113, 9276; J. Org. Chem., 1989, 54, 3916) ArCH2OCH2X, where X represents tsepliaeva group, get 35. In addition, D, L, -O-aryl(alkyl)serine and you can get and split the previously described ways.

Alkylation of N-protected-(D)-cysteine 36 is performed by the method described for the synthesis of (D)-serine derivative, and is illustrated next to R1a-X, where X is tsepliaeva group, such as halides and methyloxirane, as presented in figure 16, is provided at the end of the description.

Oxidation of the cysteine derivative 37 to sulfoxide 38 (n=1) and sulfone 30 (n= 2) can be done using many oxidizing agents. (Review of the oxidation of sulphides, see Org. Prer. Proced. Int., 1982, 14, 45). Periodate sodium (J. Org. Chem., 1967, 32, 3191) is often used for sulfoxidov and acidic potassium persulfate (OXONE) (Tetrahedron Lett., 1981, 22, 1287) is used to produce sulfones.

So, various substituted amino acids can be introduced into the connection, accelerating videoengine, which contain sulfoxide or sulphonic functional group, can be obtained from cysteine accelerating the secretion of connections using periodate sodium OXONE. In another embodiment, it is possible to use hydrogen peroxide as oxidizing agent at the last stage of the synthesis according to scheme 17, provided at the end of the description. Sulfoxides 40 (n=1 ) and sulfonovy 40 (n=2) analogues can be separated using preparative thin-layer chromatography.

Remove aminosidine groups can be done in a number of ways known in the art; these methods are described in "Protective Groups in Organic Synthesis", T. W. Greene, N 4 1981.

The compounds of formula 1, where R4and R5each represent hydrogen, can be subjected to reductive alkylation with an aldehyde in accordance with the above methods, or alkylation by various epoxides. The products obtained in the form of salts of hydrochloric or triperoxonane acids, usually purified by HPLC with reversed phase or by recrystallization.

Spirobiindane formula 41 can be obtained in several ways, including the following synthesis.

< / BR>
Spirobiindane formula 42, where L represents a specific protective

The nitrogen indoline 42, where L represents a protective group as methyl or benzyl, can be subjected to interaction with a variety of electrophilic compounds to obtain spiroperidol formula 43, where R9may provide different functionality. The connection 42 can be subjected to interference, for example, isocyanates such an inert solvent as dichloromethane to obtain derivatives of urea; chloroformate, in such an inert solvent as dichloromethane to obtain carbamates; anhydrides anhydrides or illimitable to obtain amides; sulphonylchloride to order sulfonamides, sulphonylchloride for receiving sulfonamides (see diagram 18 provided at the end of the description).

In addition, the nitrogen indoline 42 recovery can be alkilirovanii aldehydes under conditions known in the art. If the aldehyde used in the reaction of reductive amination is Glyoxylic acid of formula HCOCOOM, where M represents a protective group, M can be removed from the product and get further derivatives. In another embodiment, 42 can be subjected to interaction with epoxides to obtain 43, where R9is-hydroxyzi the SUB> represents phenyl or substituted phenyl, heteroaryl or substituted heteroaryl, interacting 42 with tortenelem or targettraining reagent. These reactions are described in detail H. Ong. et al., J. Med. Chem., 1983, 23, 981-986.

Spiroperidol intermediate 43 (L = Me or Bn), where R9represents hydrogen, or most of the previously described derivatives can be demetilirovanie or dibenzylamine to obtain 44, where R9represents hydrogen, or most of the previously described derivatives, in accordance with the circuit 19 provided in the end of the description. For compounds of formula 43, where L = Me, demethylation can be accomplished in various ways known in the art. For example, demethylation 43 can be done through interaction with cyanogenmod and potassium carbonate in such an inert solvent as dichloromethane to obtain cyanamide, which can be restored to obtain 44 by processing sociallyengaged in boiling under reflux tetrahydrofuran, or boiling a strong acid, such as hydrochloric acid, or with such a Grignard reagent, as methylmagnesium. In another embodiment, demethylation 43 can be made by way of ACE-Cl, as disclosed what their benzyl group can perform the restoration methods including hydrogenation in the presence of a platinum or palladium catalyst in such proton solvent like methanol. In another embodiment, dibenzylamine 43, L = Bn, it is possible to implement ACE-Cl method disclosed in R. Olofson et al., J. Org. Chem., 1984.

Spiroheterocyclic compounds 45 can be obtained in a number of ways, including the syntheses presented in figure 20, is provided at the end of the description.

Allylic oxidation of the protected piperidine 47 carried out by classical methods known in the art (Rabjohn, N Org. React. 1976, 24, 261). The obtained allyl alcohol is treated with thionyl chloride in such an inert solvent as benzene to obtain the corresponding chloride 48. If D = O or S, alkylation lead in DMF or acetone as solvent and potassium carbonate as the base, and if D = NR9(where R9= H, alkyl, aryl, acyl, sulfonyl; carbamate), the reaction is carried out with sodium hydride as the base in such an inert solvent as THF, to obtain predecessor cyclization 49. If L represents a protective group, compound 49 can be cilitate in a number of ways known in the art. For example, declinatio 49 can be realized by the interaction of the hydride tributyl inania 46 (D = NR9) can be obtained by the methods provided in schemes 18 and 19. If D = S, the connection 46 can oxidize to sulfoxide 47 (n = 1), and sulfonate 47 (n = 2), many oxidizing agents (see diagram 21 provided at the end of the description). For example, periodate sodium is often used for synthesis of sulfoxidov, and OXONE used for the synthesis of sulfones. After removal of the protective groups receive Amin 45, which then can be included in the connection, accelerating the secretion of growth hormone in accordance with the reactions presented in schemes 1 and 8, using a common intermediate compound 2.

Spirobiindane formulae 50 and 51 can be obtained in the reactions presented in scheme 22, provided at the end of the description.

Phthalimide formula 53, where R11has values such as alkyl, aryl (CH2)q-aryl; or represent a protective group, either commercially available or can be synthesized from the corresponding phthalimido ways known in the art (for example, Bewster et al., in J. Org. Chem., 1963, 28, 501; Mcalees et al., J. Chem. Soc., 1977, 2038). Phthalimide 53 can be alkilirovanii in the presence of such grounds, as potassium hydride, bis/(trimethylsilyl)/lithium amide or potassium-protected bis-2-heloizahelena, where L represents a protective polyurethane foam can be removed with methods, as described earlier, to obtain the compounds of formula 50. The recovery of the lactam of formula 50 hydrides such as sociallyengaged, results in connection 51.

It should be noted that the procedure of the above reaction schemes can be varied to facilitate the reaction or to avoid the formation of undesirable side products.

Compounds that promote the secretion of growth hormone, formulas I and II can be used in vitro as unique tools for understanding how the regulation of growth hormone secretion at the level of the pituitary. This includes the use in the evaluation of many factors, which are known or assumed to affect the secretion of growth hormone (e.g., height, gender, nutrition, glucose, amino acids, fatty acids), as well as the state of hunger or satiety. In addition, the compounds of the present invention can be used to assess how other hormones change activity allocation growth hormone. So, for example, has found that somatostatin inhibits the release of growth hormone. Other hormones that play an important role that should be explored in relation to their effect on the secretion of growth hormone, vklyuchayuthie corticoide, epinephrine and norepinephrine; the hormones of the pancreas and gastrointestinal tract, such as insulin, glucagon, gastrin, secretin; these vasoactive peptides as bombezin, neurokinin; thyroid hormones like thyroxine and thiiodothyronine. Compounds of formulas I and II can also be used to study the possible negative or positive effects of some pituitary hormones such as growth hormone and endorphin peptides, pituitary to modify the allocation of growth hormone. The greatest scientific value lies in the use of these compounds to clarify the mechanism by which the secretion of growth hormone on the sub-cellular level.

The compounds of formula I and II can be entered animals, including humans, for the isolation of growth hormone. So, for example, the compounds can be entered in the commercial interest of animals like pigs, sheep, cattle, etc., to accelerate their growth and rate of weight gain, improve feed efficiency and increase milk production in these animals. In addition, these compounds can enter humans in vivo as a diagnostic tool to determine whether the weave selected before and after such an introduction, you can analyze the content of growth hormone. Comparison of quantities of growth hormone in each of these samples can be used to directly measure the ability of the patient's pituitary gland to allocate growth hormone.

Accordingly, the present invention includes within its scope pharmaceutical compositions containing as active ingredient at least one compound of formula I together with a pharmaceutical carrier or diluent. Optionally, the active ingredient of the pharmaceutical compositions contain an anabolic agent in addition to at least one of the compounds of formula I, or a different composition with another activity, such as antibiotics, growth-promoting, or agent for the treatment of osteoporosis, or in combination with a corticosteroid to minimize the catabolic side effects, or with other pharmaceutically active materials, if this combination enhances efficacy and minimizes side effects.

Agents, promoterwise growth and anabolic agents include, but are not limited to, TRH, called diethylstilbestrol (des), estrogen agonists, theophylline, anabolic steroids, enceinte USA 4036979, for example, avenox, or peptides disclosed in U.S. patent 4411890.

Another use of compounds that accelerate the secretion of growth hormones, the present invention is the combination with other compounds that accelerate the secretion of growth hormones, such as peptides that promote the secretion of growth hormone GHRP-6, GHRP-1, as disclosed in U.S. patent 4411890 and in publications WO 89/07110, WO 89/07111 and B-HT920, as well as hexarelin and the recently discovered GHRP-2 as described in WO 93/04081, or the hormone that stimulates the secretion of growth hormone (GHRH, also designated as GRF) and its analogs or growth hormone and its analogs, or somatomedin, including IGF-1 and IGF-2 or-adreline agonists, such as clonidine or serotonin 5HTID agonists, such as sumatriptan, or agents which inhibit somatostatin or its release such as physostigmine and pyridostigmine.

As is well known in the art, the known and potential use of growth hormone are diverse and numerous. Thus, the introduction of the compounds of the present invention to stimulate the excretion of endogenous growth hormone can have the same effect as growth hormone itself. These different uses of growth hormone may be summarized as follows: stimulation vydelenijami effects from the use of glucocorticosteroids, the treatment of osteoporosis, stimulation of the immune system, acceleration of wound healing, accelerating splicing bones after a fracture, treatment of slow growth, the treatment of acute or chronic renal failure, treatment of physiologically low growth, including growth hormone deficiency in children, treatment of low growth associated with chronic illness, treatment of obesity and the slowdown associated with obesity, treating growth deceleration associated with Prader-Willi syndrome and Turuer's; accelerating the recovery and reducing hospitalization time for patients with burns or after such serious surgery, as surgery on the stomach; treatment of intrauterine growth deceleration, skeletal dysplasia, hypercortisolism and Cushing's syndrome; replacement of growth hormone in patients in stressful situations; treatment of osteochondrodysplasias, Noonans syndrome, sleep disorders, Alzheimer's disease, delayed wound healing and psychosocial deprivation; treatment of dysfunction of the lungs and respiratory dependency; attenuation of protein catabolic response after a major operation; treating malabsorption syndrome, reducing cachexia and protein loss due to chronic conditions such as cancer or AIDS, Ussuriiskii, including nesidioblastosis; concomitant treatment for induction of ovulation and for the prevention and treatment of gastric ulcers and duodenal ulcers; stimulation of development of the thymus and to prevent reduction of the function of the thymus; concomitant therapy for patients on chronic hemodialysis; treatment of patients with immunosuppression and to enhance antibody response following vaccination; increasing muscular strength, mobility, maintenance of skin thickness, metabolic homeostasis, renal homeostasis in painful elderly; stimulation of osteoblasts, the restoration of bone tissue and the growth of cartilage; the treatment of such neurological diseases as caused by peripheral and medicines neuropathy, syndrome, Guillian-Barre, amyotrophic lateral sclerosis, cerebrovascular disorders and diseases associated with demyelination; stimulation of the immune system in animals and treatment of disorders associated with age in animals; the acceleration of growth in livestock and stimulation of wool growth in sheep.

Professionals should be clear that there are a number of compounds that are currently used in attempts to treat diseases or therapeutic indications listed above. The combination of these is growth hormone of the present invention introduces additional, complementary and often synergistic properties to enhance the growth, anabolic and other desirable properties of these various therapeutic agents. In these combinations of therapeutic agents and compounds that accelerate the secretion of growth hormone, the present invention can independently be present in doses ranging from one-hundredth to one of dose levels which are effective when these compounds and compounds that accelerate the secretion of use separately.

Combined therapy for inhibiting bone resorption, prevent osteoporosis and accelerate the healing of bone fractures can be illustrated through a combination of bisphosphonates and joints, accelerating the secretion of growth hormone of the present invention. The use of bisphosphonates for these purposes described, for example, Hamdy, N. A. T., Role of Bisphosphonattes in Metabolic Bone Diseases, Treuds in Endocrinol. Metab. 1993, 4, 19-25. Bisphosphonates for such applications include alendronate, tiludronate, dimethyl-ARD, risedronate, etidronate, MIND-175, clodronate, pamidronate and VM-210995. In accordance with their effectiveness daily dose levels with oral bisphosphonates is from 0.1 mg to 5 g, and the levels of daily doses of the compounds that accelerate the secretion of the hormone Rosa osteoporosis.

Compounds of the present invention can be administered orally, parenterally (for example intramuscularly, intraperitoneally, intravenously or subcutaneously by injection or implant), through the nose, vaginally, rectally, sublingually or casual, and they can be prepared in the form of dosage forms appropriate for each route of administration.

Solid dose forms for oral administration include capsules, tablets, pills, powders and granules. In these dose forms, the active compound is mixed with at least one inert pharmaceutically acceptable carrier such as sucrose, lactose or starch. These dose forms can also comprise, as is common practice, additional substances other than inert diluents, such as moving, such as magnesium stearate. In the case of capsules, tablets and pills dose forms may also contain buferiruemoi agents. Tablets and pills can also be prepared with gastric coverings.

Liquid dose forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs containing inert diluents which are usually used for such purposes, for example, is you, emulsifiers and suspendresume agents, and sweetening, flavoring agents and fragrances.

The preparations of the present invention for parenteral administration include sterile aqueous or nonaqueous solutions, suspensions or emulsions. Examples of nonaqueous solvents or carriers include propylene glycol, polyethylene glycol, vegetable oils such as olive oil and corn oil, gelatin and organic esters for injection, such as etiloleat. These dose forms may also contain an adjuvant such as preservatives, wetting agents, emulsifying agents and dispersing agents. They can be sterilized, for example, by filtration through a retaining bacteria filter, due to the introduction in the composition of sterilizing agents, by irradiation of the compositions, or by heating the compositions. They can also be prepared in the form of sterile solid compositions which can be dissolved in sterile water or some other sterile environment for injection immediately before use.

Compositions for rectal or vaginal injection are preferably suppositories which may contain, besides the active substance, such excipient the Denia also preferably prepared with standard excipients well known to specialists.

The dose of the active ingredient in the compositions of the present invention may vary; however, it is necessary that the amount of active ingredient is to get a suitable dose form. Select the doses depend on the desired therapeutic effect, the route of administration, duration of treatment. Typically, the level of dose is in the range from 0.0001 to 1000 mg/kg body weight daily for patients and animals, for example mammals, to obtain efficient production of growth hormone.

The following examples are offered only to illustrate and not to limit the disclosed invention.

Example 1

N-/1(R)-/(2', 3'-Dihydro-2-oxaspiro/piperidine-4,4'- (1H)-quinoline/-1 yl)carbonyl/-2-(indol-3-yl)ethyl/-2-amino - 2-methylpropanesulphonic

Stage A: 1'-(tert-butyloxycarbonyl)-3,4-dihydro - 3-oxaspiro/1H-inden-1,4'-piperidine

To a solution of 661 mg (2,31 mmol) 1'-(tert - butyloxycarbonyl) Spiro/1H-inden-1,4'-piperidine/ (obtained according to the method of Chambers et al, J. Med. Chem. 1992, 35, 2036) in 5.0 ml THF added 5.8 ml (1.0 M THF, 2.9 mmol) 9-BBN. The reaction mixture is heated at 70oC up until according to TCX is not that all starting material had been consumed. The resulting solution was concentrated, and about 1 g (19.2 mmol) of PCC. The reaction mixture is heated to room temperature, and then refluxed for 30 minutes. The resulting solution was diluted with ether and filtered through filter cake, consisting of a mixture of celite and Florisil. In the purification using flash chromatography (silica gel, hexane/ethyl acetate, 4:1) receive 326 mg (47%) specified in the title compound.

1H NMR (200 MHz, CDCl3): 7,75 - of 7.60 (m, 2H), 7,50 - 7,44 (m, 2H), 4,30 - to 4.15 (m, 2H), 2,85 (dt, 2H), 2.63 in (s, 2H), 1,98 (dt, 2H), 1,53 - of 1.40 (m, 2H), 1,49 (s, 9H).

Stage B: Spiro/1H-inden-1,4-piperidine/-3(2H)-he trifurcated

A solution of the intermediate obtained in stage A in a mixture of 1:1: 0,5 triperoxonane acid, dichloromethane and anisole is stirred for 1 hour and then concentrated and azeotropic distillation from toluene to obtain the title compound.

1H (200 MHz, CDCl3): 7,81 - of 7.70 (m, 1H), 7,62 was 7.45 (m, 2H), 7,22 - to 7.15 (m, 1H), 3.72 points - to 3.58 (m, 2H), 3,29 totaling 3.04 (m, 2H), 2,70 (s, 2H), 2,47 (dt, 2H), 1.85 to about 1.75 (m, H).

Stage C: Triptorelin-2,3-dihydrospiro/inden - 1,4'-piperidine/

To a solution of 1.0 g (3,21 mmol) of the intermediate obtained in stage b In 3.0 ml of dichloromethane add 0,945 ml (6,74 mmol) of triethylamine and 50 mg of DAMP, and finally, 0,501 ml (at 20 ml of dichloromethane. The resulting solution was washed with water, dried over magnesium sulfate and concentrated. In the purification using flash chromatography (silica gel, hexane/ethyl acetate 2:1) receive 568 mg (1,91 mmol).

1H NMR (200 MHz, CDCl3): 7,79 - to 7.64 (m, 2H), 7.5 to 7,41 (m, 2H), 4.75 in with 4.65 (m, 1H), 4,22 - 4,08 (m, 1H), 3,37 (dt, 1H), 2,92 (dt, 1H), 2,70 (s, 2H), 2,08 (dt, 2H), 1,71 - 1,6 (m, 2H).

Stage D: Triptorelin-3', 4'-dihydro-2-oxaspiro/piperidine-4,4'(1H)-quinoline/

To a solution of 218 mg (3,36 mmol) of sodium azide in 0,285 ml of water and 1.5 ml of chloroform at 0oC add 0,105 ml of sulfuric acid. The reaction mixture was stirred for 2.5 h, and then the layers separated, and CHLOROFORMATES layer is dried over sodium sulfate. Then a solution of hydrazine powered acid are added to a solution of 400 mg (1,34 mmol) of the intermediate obtained in stage A. To this solution add 0,400 ml) and sulfuric acid for 5 minutes, the reaction mixture is stirred for 20 minutes, and then for 45 minutes at 45oC, and finally for 16 hours at room temperature. The layer of sulfuric acid added to ice, and then alkalinized 50% sodium hydroxide. The aqueous layer was extracted with ethyl acetate, an ethyl acetate extracts are dried over sodium sulfate and concentrated. In the clearing stands the receive 50 mg (0,160 mmol) of material with a high value of RF and 16 mg (0,051 mmol) low RF value.

1H NMR (200 MHz, CDCl3high RF): 8.9-8.7 (Shir.s, 1H), 7.40-7.21 (m, 2H), 7.18-7.04 (m, 1H), 6.90-6.86 (m, 1H), 4.52-4.36 (m, 1H), 3.97-3.83 (m, 1H), 3.52 (dt, 1H) 3.22 (dt, 1H), 2.79 (s, 2H), 2.12-1.66 (m, 4H).1H NMR (200 MHz, CDCl3low RF): 8.12 (DD, 1H), 7.60-7.52 (m, 1H), 7.45-7.35 (m, 2H), 6.95 (Shir.s, 1H), 4.56-4.43 (m, 1H), 4.03-3.96 (m, 1H), 3.64-3.62 (m, 2H), 3.49-3.35 (m, 1H), 3.11 (dt, 1H), 2.20-1.80 (m, 4H).

Stage E: 3',4'-Dihydro-2-oxaspiro/piperidine-4,4'- (1H)-quinoline/

A solution of 49 mg (of) 0.157 mmol) of material with high RF from step B in methanol/water 4: 1 with an excess of potassium hydroxide is stirred over night. The resulting solution was concentrated and to the residue is added water and ethyl acetate. The layers separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers dried over sodium sulfate and concentrated to obtain 31 mg (0,143 mmol) specified in the title compound.

Stage F: N/R)-/(2',3'-dihydro-2-oxo,Spiro/piperidine-4,4' -(1H)-quinoline/-1 yl)carbonyl/-2-(indol-3-yl)ethyl/-1-//1,1 - dimethylthiocarbamyl/amino/-2-methylpropanamide

To a solution of 29 mg (0,134 mmol) of the intermediate obtained in stage C, 65 mg (0,167 mmol) 2-amino-N-/-(1R)-/2',3'-dihydro-2-oxaspiro/piperidine-4,4'(1'H)- quinoline/-1-yl)-carbonyl/-2-(1H-indol-3-yl )ethyl-2-methylpropanamide and 24 mg (0,174 mmol) HOBT in dichloromethane added 33 mg (0,174 m is pushing A) with one exception: when the chromatographic treatment using dichloromethane/acetone. Get to 34.8 mg (0,059 mmol) specified in the title compound.

Stage G: N-/1(R)-/(2', 3'-Dihydro-3-oxaspiro/piperidine-4,4'(1H)- quinoline/-1 yl)carbonyl/-2- (indol-3-yl)ethyl/-2-amino-2-methylpropanesulphonic

Specified in the title compound (7.2 mg, of 0.013 mmol) is obtained from the intermediate obtained in stage D (14 mg, is 0.023 mmol) according to the method of example 1 (stage C) with one exception: cleaners containing hydrochloride salt is obtained from the purified free amine, adding in this case, 4 N. HCl in dioxane.

1H NMR (400 MHz, CD3OD, 2:1 mixture of rotamers): 8.34 (d, 2/3H), 8.27 (d, 1/3H), 7.59 (d, 2/3H), 7.55 (d, 1/3H), 7.38 (d, 1/3H), 7.33 (d, 2/3H), 7.25 (d, 1/3H), 7.18-6.98 (m, 4H), 6.85 (d, 1/3H), 6.80 (d, 2/3H), 6.68 (d, 2/3H), 5.23-5.17 (m, 1H), 4.22-4.19 (m, 2/3H), 4.09-3.95 (m, 1/3H), 3.62-3,59 (m, 1/3H), 3.36-3.17 (m, 2 2/3H), 3.08 (dt, 1/3H), 2.75 (dt, 1/3H), 2.69 (dt, 2/3H), 2.48 (DD, 2H), 1.93-1.75 (m, 2/3H), 1.60 (s, 3H), 1.58 (s, 2H), 1.40-1.32 (m, 1H), 1.51 (s, 1H), 1.10 (m, 1/3H), 1.02 (m, 2/3H), 0.90 (m, 2/3H), 0.22 (dt, 2/3H). FAB-MS: m/e 490 (M+1).

Mass spectrum by fast atom bombardment: m/e 490 (M+1).

Example 2

N-/1(R)-/(2', 3'-Dichloro-1-oxaspiro/piperidine-4,4'- (1H)-isoquinoline/-1 yl)carbonyl/-2-(indol-3-yl)ethyl/-2 - amino-2-methylpropanesulphonic

Stage A: /3',4'-Dihydro-1-oxaspiro/piperidine - 4,4'(1H)-isoquinoline/

Specified in the title compound (11.3 mg, being 0.036 mmol) Paluch (stage D).

1H NMR (200 MHz, CDCl3): to 8.12 (DD, 1H), 7,60-7,52 (m, 1H), 7,45 - 7,35 (m, 2H), 6,95 (Shir.s, 1H), 4,56 - 4,43 (m, 1H), 4,03-of 3.96 (m, 1H), 3,64-3,63 (m, 2H), 3,49-to 3.35 (m, 2H), 3,11 (dt, 1H), 2,20-of 1.80 (m, 4H).

Stage B: N-/1(R)-/(2,3'-Dihydro-1-oxaspiro/piperidine-4,4' (1H)-isoquinoline/-1 yl)carbonyl/-2-(indol-3-yl) ethyl/-2-//1,1-dimethylthiocarbamyl/-amino/-2-methylpropanamide

Specified in the title compound (13,6 mg, is 0.023 mmol) is obtained from the intermediate from step A (10.0 mg, to 0.032 mmol) and 2-amino-N-/1(R)-/2',3'-dihydro-2-oxaspiro/piperidine-4,4' (1 N)-quinoline/-1-)carbonyl/-2-(1H-indol-3-yl)ethyl-2-methylpropanamide (to 21.6 mg, by 0.055 mmol) by the method of example 13 (stage D).

Stage C: N-/1(R)-/(2',3'-Dihydro-1-oxaspiro/piperidine-4,4' (1H)-isoquinoline/-1 yl)carbonyl/-2-(indol-3-yl)ethyl/-2-amino-2 - methylpropanesulphonic

A solution of 10.1 mg (0,017 mmol) of the intermediate obtained in stage B, 1.5 N. HCl in ethyl acetate is stirred overnight and then concentrated and azeotrope is distilled from methanol to obtain 8,3 mg (0.015 mmol) specified in the title compound.

1H NMR (400 MHz, CD3OD, 2:1 mixture of rotamers): 7.94 (d, 1/3H), 7.87 (d, 2/3H), 7.62-7.53 (m, 2H), 7.40-7.33 (m, 2 1/3H), 7.18-7.10 (m, 3H), 6.75 (d, 2/3H), 5.22-5.18 (m, 2/3H), 5.15 (t, 1/3H), 4.27-4.23 (m, 2/3H), 4.14-4.10 (m, 1/3H), 3.68-3.61 (m, 1H), 3.25-3.18 (m, 4H), 3.10 (dt, 2/3H), 2.87 (dt, 1/3H), 2.70 (dt, 2/3H). FAB-MS: m/e 490 (M+1).

Mass spectrum by fast atom bombardment: m/e 490 (M+1).

Example 3

N-/1(R)-/(4H-1-Oxaspiro/3H-2-benzopyran-3,4'-piperidine/-1'-yl) carbonyl/-2-(indol-3-yl)-ethyl/-2-amino-2-methylpropanesulphonic

Stage A: Spiro/3H-2-benzopyran-3,4'-piperidine/-1(4H)-he

To a suspension of 10% palladium on coal (5 mg) in 5 ml of ethanol was added 1'-benseler/3H-2-benzopyran-3,4'-piperidine/-1(4H)-he/ (20 mg, 0,059 mmol) (Hashigaki et al., Chem. Pharm. Bull., 32, pp. 3561-3568 (1984)). The hydrogenation is carried out at room temperature and a pressure of 1 ATM. The reaction mixture is stirred for 2 hours at room temperature until, while according to TLC, the reaction does not end there. The catalyst was removed by vacuum filtration through celite 545 and the filtrate concentrated to obtain the target product (12,4 mg, 98.5 per cent).

Mass spectrum by fast atom bombardment calculated for C13H15NO2217, found 218 (M+H, 100%).

Stage B: N-/1(R)-/(4H-1-Oxaspiro/3H-2-benzopyran - 3,4'-piperidine/-1'-yl )carbonyl/-2-(indol-3-yl )- ethyl/-2-//(1,1-dimethylethylene)carbonyl/amino/ 2-methylpropanamide

A solution of the intermediate from step A (12 mg, by 0.055 mmol) and (R)-//2-//(1,1-dimethylmethoxy)carbonyl/- amino/-2,2-dimethyl-1-oxoethyl/amino/-1H-indol-3-prolactin (8,8 mg, 0,084 mmol) and EDC (22 mg, 0.12 mmol). The reaction mixture was stirred at room temperature for 1 hour before until according to TLC, the reaction is not completed. The resulting solution was washed with a saturated solution of nitriloside and dried over anhydrous magnesium sulfate. Then the obtained solution is filtered and concentrated. In the purification using chromatography on silica gel get mentioned in the title compound (15 mg, 47%). Mass spectrum by fast atom bombardment calculated for C33H40N4O6: 589. Found 589 (M+H, 39%) (489 M+H, 100, 42%, the loss of the tert-Boc group).

Stage C: N-/1(R)-/(4H-1-oxaspiro/3H-2-benzopyran - 3,4'-piperidine/-1'-yl)carbonyl/-2-(indol-3 - yl)ethyl/-2-amino-2-methylpropanesulfonate

A solution of the intermediate from step B (12 mg, 0.02 mmol) in 3 ml of methanol is cooled to 0oC. While mixing, slowly add concentrated hydrochloric acid (3 ml). The reaction mixture is stirred for 30 minutes, until according to TLC analysis, the reaction is not completed. Then the resulting solution was repeatedly concentrated from toluene. Salt of hydrochloric acid is used further without additional purification (10,15 mg, 96%).

1H NMR (400 MHz, CD3OD): p (m, 2H), 4.191-4.114 (m, 1/3H), 3.637-3.587 (m, 1H), 3.344-3.299 (m, 1H), 3.188-3.124 (m, 1H) 3.030 (s, 2/3 H), (dt 2.81 Hz, 9.4 Hz, 1/3 H), 2.536 (kV, 1H), 2.301 (t, 1/3 H), 1.590, 1.571 (2s, 6H), 1.539-1.483 (m, 2/3H), 1.275 (s, 6H), 1.259-1.206 (m, 2/3H), (m, 1H), 0.633-0.545 (m, 1/3H), -0.277 -0.361 (m, 1/3H).

FAB-MS calc. for C28H32N4O4488; found 489 (M+H, 65%).

Mass spectrum by fast atom bombardment calculated for C28H32N4O4: 488 found 489 (M+H, 65%).

Example 4

N/R)-/(4', 5'-Dihydro-4'-oxaspiro/piperidine-4,6'- /6H/thieno[2,3-b] thiopyran/-1-yl)carbonyl/-2-(indol-3-yl)- ethyl/-2-amino-2-propanedithiol

Stage A: N-/1(R)-/(4',5'-dihydro-4'-oxaspiro/piperidine - 4,6'/6H/thieno-2,3-b-thiopyran/-1-yl)carbonyl/-2- (indol-3-yl)ethyl/-2-//(1,1-dimethylethylene)carbonyl/-amino/-2-propanamide

Receive by way of example 3, step C. Use: Spiro/piperidine-4,6'-/6H/thieno[2,3-b] thiopyran/-4'(5'H)-one - hydrochloride (10 mg, 0,044 mmol) (EP publication 90313629), (R)-//2-//(1,1-dimethylmethoxy)carbonyl/amino/- 2,2-dimethyl-1-oxoethyl/amino/-1H-indole-3-propanoic acid (20 mg, 0,051 mmol), NOT (1 EQ.), N-methylmorpholin (0.01 ml, 0,093 mmol) and EDC (20 mg, 0.10 mmol). The reaction time is 5 hours yield: 22 mg (98%).

1H NMR (400 MHz, CDCl3): the product exists as a mixture of two conformers (2:1): 8.240 (s, 2/3 H), 8.063 (C, 1/3 H), 7.680 (d, 2/3 H), 7.628 (d, 1/3 H), 7.416-6.962 (m, 5 567 (m, 8 1/3H), 1.503, 1.454, 1.427, 1.409 (4C, 12H), 1.278-1.217 (m, 2H), 0.708-0.628 (m, 2/3H).

Mass spectrum by fast atom bombardment: calculated:31H38N4O5S2610, found: 611 (M+H, 32%).

Stage B: N-/1(R)-/(4', 5'-dihydro-4'-oxaspiro/piperidine-4,6'-/6H/thieno-2,3-b thiopyran/-1-yl)-carbonyl/-2-(indol-3-yl)ethyl/-2-amino-2-propanedithiol

Receive by way of example 15, step C. the Intermediate compound from the previous step (200 mg, 0,033 mmol) and 3 ml of methanol. The reaction time is 1.5 hours. The output of 12.2 mg (69%).

1H NMR (400 MHz, CD3OD): the product exists as a mixture of two conformers(2:1): 7.562-7.022 (m, 6H), 5.513-5.446 (m, 6 2/3H), 5.099-5.003 (m, 1H), covered 4.914-4.726 (m, 2/3H), 4.178 (d, 1H), 3.624 (d, 1H), 3.337-3.043 (m, 2 2/3H), 2.760-2.660 (m, 1H), 2.324 (d, 1H), 2.234 (d, 1H), 1.597, 1.587, 1.574, 1.510 (4C, 4H), 1.364-1.225 (m, 3H), 0.562-0.482 (m, 2/3H), -0.311 -0.391 (m, 2/3H).

Mass spectrum by fast atom bombardment calculated for C26H30N4O3S2510, found 611 (M+H, 51%).

Example 5

N-/1(R)-/(3-Hydrosphere/1H-isobenzofuran-1,4'-piperidine/-1'-yl) carbonyl/-2-(indol-3-yl)ethyl/-2-amino-2-methylpropanesulphonic

Stage A: N-/1(R)-/(3-Hydrosphere/1H-isobenzofuran-1,4-piperidine/-1'-yl)carbonyl/-2-(indol-3-yl)ethyl/-2- //1,1-dimethylthiocarbamyl/amino/-2-methylpropanamide
(10 mg, 0,044 mol) (Bauer, et. al. , U.S. patent 3985889), (R)-//2-//(1,1-dimethylmethoxy)carbonyl/aminona/- 2,2-dimethyl-1-oxoethyl/amino/-1H-indole-3-propanoic acid (20 mg, 0,051 mmol), NOT (1 EQ.), N-methylmorpholin (0.01 ml, 0,093 mmol) and EDC (20 mg, 0.10 mmol). The reaction time is 5 hours. Yield 21 mg (81%). The product exists as two conformers (1:1):

1H NMR (CDCl3): 8.096 (s, 1H), 7.689 (t, 1H), 7.341 (d, 1H), 7.244-6.611 (m, 6H), 5.288-5.202 (m, 1/2H), 4.945 (Shir.s, 1/2H), 4.161 (d, 1/2H), 4.003 (d, 1/2H) 3.338 (d, 1/2H), 3.280-3.115 (m, 2H), 3.005-2.861 (m, 1H), 2.751 (d, 1/2H), 2.416 (d, 1/2H), 1.787 - 1.549 (m, 3 1/2H), 1.491, 1.461, 1.421, 1.410 (4C, 12H), 1.281-1.212 (m, 3H), 0.857 (t, 6H).

Mass spectrum by fast atom bombardment calculated for C32H40N4O5560, found: 561 (M+H, 33%).

Stage B: N-/1(R)-/(3-Hydrosphere/1H-isobenzofuran - 1,4'-piperidine/-1'-yl)carbonyl/-2-(indol-3 - yl)ethyl/-2-amino-2-methylpropanesulphonic

Get to the method of example 3, step C. Use intermediate connection with the previous stage (20 mg, 0.04 mmol) and 3 ml of methanol. The reaction time is 1 hour. The output of 18.2 mg (93.5 per cent).

1H NMR (400 MHz, CD3OD): the product exists as a mixture of two conformers(1:1): 7.621-6.568 (m, 8H), 5.198-5.136 (m, 1H), covered 4.856 (Shir.s, 1H), 4.098-4.045 (m, 1H), 3.611-3.499 (m, 1H), KZT 3,348-3.110 (m, 5 1/2H) 2.987-2.903 (m, 2 1/2H), 2.618 (d, 1/2H), 2.508 (d, 1/2 H), 1.691-1.473( m, 8H), 1.271 (Shir.s, 2 1/2H), 0.081 - 0.O3461, found 461 (M+H, 96%).

Example 6

N-/1(R)-/(3,4-Dihydro-6-methyl-4-oxaspiro/2H-1 - benzopyran-2,4'-piperidine/-1'-yl)carbonyl/-2- (indol-3-yl)- ethyl/-2-amino-2-methylpropanesulphonic

Stage A: N-/1(R)-/(3,4-Dihydro-6-methyl-4-oxaspiro/2H - 1-benzopyran-2,4 '-piperidine-1'-yl)-carbonyl/-2-(indol-3-yl)ethyl/-2-//(1,1-dimethylethylene) carbonyl/amino/-2-methylpropanamide

Receive by way of example 3, step C. Use: 3,4-dihydro-6-methylspiro/2H-1-benzopyran-2,4'-piperidine/- 4-anhydrobiotic (20 mg, 0,058 mmol) (Hashigaki et. al. Chem. Pharm. Bull, 32, pp 3561-3568 (1984)), (R)-//-2-//(1,1-dimethylmethoxy)carbonyl/amino/-2,2-dimethyl-1 - oxoethyl/amino/-1H-indole-3-propanoic acid (32 mg, 0,082 mmol), NOT (1 EQ.), N-methylmorpholin one (0.03 ml, 0.28 mmol) and EDC (40 mg, 0.21 mmol). The reaction time is 8 hours. Yield 34 mg (86%).

1H NMR (400 MHz, CDCl3): the product exists as a mixture of two conformers (2:1): 8.154 (s, 2/3H), 8.088 (s, 1/3H), 7.626 (d, 2/3H), 7.591-7.060 (m, 6H), 6.725-6.688 (m, 2/3H), 5.265 - 5.168 (m, 2/3H), 4.985-4.900 (m, 2/3H), 4.289-4.178 (m, 2/3H), 3.469 (s, 2/3H), 3.229-3.064 (m, 2 2/3H), 2.730 (t, 2/3H), 2.562 (s, 2 1/3H), 2.251 (d, 2 1/3H), 2.158 (d, 2/3H), 2.068 (d, 2/3H), of 1,680-1.541 (m, 3H), 1.502, 1.475, 1.454, 1.427, 1.402 (5s, 15H), 1.292-1.226 (m, 3H), 0.616-0.532 (m, 1/3H), -0.495 -0.590 (m, 1/3H).

Mass spectrum by fast atom bombardment calculated for C34H42N4O6602, found 603 (M+H,3-yl)ethyl/-2-amino-2-methylpropanesulphonic

Receive by way of example 3, step C. Use intermediate connection with the previous stage (20 mg, 0,029 mmol) and 3 ml of methanol. The reaction time is 3 hours. The output of 17.5 mg (96,5%).

1H NMR (400 MHz, CDCl3): the product exists as a mixture of two conformers(2: 1): 7.550-6.768 (m, 7 1/3H), 5.089-5.016 (m, 2H), covered 4.872-4.679 (m, 1H), 4.144-4.093 (m, 1H), 3.569-3.485 (m, 1H), 3.321-3.081 (m, 2 1/3H), 2.716-2.600 (m, 1 1/3H), 2.253, 2.236, 2.222, 2.196, 2.190, 2.155 (6C, 4H), 1.569, 1.541 1.475 (3C, 7H), 1.388-1.237 (m, 3 2/3H), 0.881-0.808 (m, 2H), 0.434-0.420 (m, 2/3H), 0.427-0.436 (m, 2/3H).

Mass spectrum by fast atom bombardment calculated for C29H34N4O4504; found 503 (M+H, 97%).

Example 7

N-/1(R)-/(3,4-Dihydro-4-oxaspiro/2H-1-benzopyran - 2,4'-piperidine/-1'-yl)carbonyl/-4-phenylbutyl-2-amino-2 - methylpropanesulphonic

Stage A: (R)-//2-//(1,1-Dimethylethylene)carbonyl)amino/-2,2-dimethyl-1-oxoethyl/ amino/-4 - phenylbutanoate acid fenilmetilovy ester

The dichloromethane solution of 2(R)-amino-4-phenylbutanoate acid phenylmethylene ester/salt toluenesulfonic acid (6.0 g, 13 mmol) is extracted with dilute sodium hydroxide solution. The organic layer is dried over magnesium sulfate and evaporated to obtain a residue. Added to a solution of N-tert-butyloxycarbonyl remediat over night at room temperature. The resulting mixture was poured into a mixture of brine and 3 N. HCl and extracted with ethyl acetate. The organic extract is dried, evaporated and purified using flash chromatography elwira 40% ethyl acetate in hexane to obtain the target product (vs. 5.47 g, 91%).

1H NMR (400 MHz, CDCl3): 7,34-7,07 (m, 10H), 5,15 (l, JAB=12 Hz, 1H), 5.08 to (l, JBA=12 Hz, 1H), 4,86 (Shir.s, 1H), 4,67-to 4.62 (m, 1H), 2,61 of $ 2.53 (m, 2H), 2,18 with 2.14 (m, 1H), 2,01 is 1.96 (m, 1H), 1,47 (s, 3H), USD 1.43 (s, 3H), of 1.41 (s, 9H).

Stage B: (R)-//2-//(1,1-Dimethylethylene)carbonyl- /amino/-2,2-dimethyl-1-oxoethyl/amino/-4-phenylbutanoate acid

The intermediate connection with the previous stage (lower than the 5.37 g of 11.8 mmol) hydronaut at room temperature and a pressure of 1 ATM, using 10% palladium on coal as a catalyst (0.5 g), for 2 hours. The catalyst is filtered off through celite, the solution is evaporated to obtain the title compound (4,22 g, 100%).

1H NMR (200 MHz, CD3OD): 7,804-7,143 (m, 5H), 4,402-4,359 (m, 1H), 2,672 (dt, 2 Hz, 6 Hz, 2H), 2,126 - at 2,004 (m, 2H), 1,483-1,444 (2C, 5H), 1,423 (s, 9H), 1,422 (s, 3H).

Stage C: N-/1(R)-/(3,4-Dihydro-4-oxaspiro/2H-1 - benzopyran-2,4'-piperidine/-1'-yl)carbonyl/- 4-phenylbutyl-2-//(1,1-dimethylethylene)carbonyl/amino/-2-methylpropanamide

A solution of Spiro/2H-1-benzopyran-2,4'-piperidine/-4(3H)-it (20 mg, 0,0776 mmol who eat add NOWT (1 EQ.), N-methylmorpholine (0.1 ml, 0.90 mmol) and EDC (33 mg, 0,17 mmol). The reaction mixture was stirred at room temperature for 3 hours before until according to TLC, the reaction is not completed. The resulting solution was washed with a saturated solution of nitriloside and dried over anhydrous magnesium sulfate. The resulting solution was filtered and concentrated. After chromatographic purification on silica gel get mentioned in the title compound (41,6 mg, 95.5 percent).

1H NMR (400 MHz, CDCl3): the product exists as a mixture of two conformers(1:1): 7.853-6.925 (m, 9H), 4.936-4.868 (m, 2H), 4.355-4.265 (MT, 1H), 3.605-3.565 (m, 1/2H), 3.388-3.318 (m, 1H), 3.022-2.965 (m, 1H), 2.686-2.608 (m, 3H), 2.067-1.948 (m, 2 1/2H), 1.871-1.810 (m, 1H), 1.580 (Shir.s, 2H,), 1.503, 1.488, 1.455, 1.411, 1.403 ( 5s, 15H), 1.292-1.227 (m, 2H).

Stage D: N-/1(R)-/(3,4-Dihydro-4-oxaspiro/2H-1 - benzopyran-2,4'-piperidine/-1'-yl)carbonyl/- 4-phenylbutyl-2-amino-2-methylpropanesulphonic

A solution of the intermediate from the previous stage (40 mg, 0,071 mmol) in ethyl acetate cooled to 0oC. Then bubbled through a solution of gaseous hydrogen chloride for 2 minutes. The reaction mixture is stirred for 15 minutes before until according to TLC, the reaction is not completed. The resulting solution was concentrated, and the salt of hydrochloric acid (to 33.8 mg, 95, the e mixture of two conformers(1:1): 8.271-8.229 (m, 1H), 7.799 (DD, 1 3/4 Hz, 7.84 Hz, 1H), 7.545 (kV, 1H) 7.289-7.006 (m, 7H), 4.737-4.703 (m, 1H), 4.277 (d, 1/2H), 4.186 (d, 1/2H), 3.555-3.292 (m, 1 1/2H), 3.187-3.068 (m, 1H), 2.809-2.724 (2m, 2H), 2.633-2.563 (m, 1H), 2.085-1.927 (m, 3 1/2H), 1.645, 1.639, 1.616 (3C, 6H), 1.677-1.603 (m, 3H), 1.316-1.279 (m, 2H).

Example 8

N-/1(R)-/(3,4-Dihydro-4-oxaspiro/2H-1-benzopyran - 2,4'-piperidine/-1'-yl)carbonyl/-2-(phenylmethoxy)ethyl/-2 - amino-2-methylpropanesulphonic

Stage A: N-/1(R)-/(3,4-Dihydro-4-oxaspiro/2H-1 - benzopyran-2,4'-piperidine/-1'-yl)carbonyl/- 2-(phenylmethoxy)ethyl/-2-//(1,1-dimethylethylene)carbonyl/amino/-2 - methylpropanamide

A solution of Spiro/2H-1-benzopyran-2,4'-piperidine/-4-(3H)she (20 mg, 0,776 mmol) and (R)-//2-//(1,1-dimethylethylene)- carbonyl/amino/-2,2-dimethyl-1-oxoethyl/amino/-3- (phenylmethoxy)-3-propanoic acid (32 mg, of 0.085 mmol) in dichloromethane cooled to 0oC, and then add N-methylmorpholine (0.1 ml, 0.90 mmol) and EDC (33 mg, 0,171 mmol). The reaction mixture was stirred at room temperature for 4 hours before until according to TLC, the reaction is not completed. The resulting solution was then washed with a saturated solution of nitriloside, and dried over anhydrous magnesium sulfate. The resulting solution was then filtered and concentrated. After chromatographic purification on silica gel get mentioned in the title compound (40,8 mg, o 580 (M+H, 23%); (found 480 (M+H - 100, 57%, the loss of the tert-BOC protective group).

Stage B: N-/1(R)-/(3,4-Dihydro-4-oxaspiro/2H-1 - benzopyran-2,4'-piperidine/-1'-yl)carbonyl/- 2-(phenylmethoxy)ethyl/-2-amino-2-methylpropanesulphonic

Receive by way of example 3, step D. Use intermediate connection with the previous stage (35 mg, 0.061 mmol) and ethyl acetate (10 ml). The reaction time is 1 hour. The output from 30.2 mg (97%).

1H NMR (400 MHz, CD3OD): the product exists as a mixture of two conformers(1:1): 7.800-7.792-(m, 1H), 7.533-7.578 (m, 1H), 7.395-7.285 (m, 5H), 7.088-7.015 (m, 2H), 5.551-5.107 (m, 1H), covered 4.921-4.816 (m, 1H), 4.535-4.518 (2C, 1 1/2H), 4.295 (d, 1H), 3.911-3.803 (m, 1H), 3.717-3.703 (2C, 1 1/2H), 3.499-3.400 (m, 1H), 3.309-3.291 (4C, 3 1/2H), 3.211-3.051 (m, 1H), 2.789 (kV, 1/2H), 2.633-2.513 (AB kV, 1H), 2.060 (t, 1H), 1.897 (d, 1/2H), 1.821-1.725 (m, 1/2H), 1.626-1.567 (6s, 6H), 1.564-1.410 (m, 1/2H), 1.301 (Shir.with, 1 1/2H).

Mass spectrum by fast atom bombardment calculated for C27H33N3O5479; found 480 (M+H, 100%).

Example 9

N-/1(R)-/(6-Chloro-3H-4-oxaspiro/1H-hinzelin-2,4'- piperidine/-1'-yl)carbonyl/-2-(indol-3-yl)ethyl/-2-amino-2 - methylpropanesulphonic

Stage A: N-/1(R)-/(6-Chloro-3H-4-oxaspiro/1H-hinzelin-2,4' -piperidine/-1'-yl)carbonyl/-2-(indol-3-yl)ethyl/-2-//(1,1 - dimethylethylene)carbonyl/amino/-2-methylpropanamide

Get in the way when is methylethoxy) carbonyl/amino/-2,2-dimethyl-1-oxoethyl/amino/-1H-indole-3-propanoic acid (81 mg, 0.21 mmol), HOBT (1 EQ.), N-methylmorpholin (1 EQ. and EDC (80 mg, 0.42 mmol). The reaction time is 3 hours. The output of 64.5 mg (60%). Mass spectrum bombarded with fast electrons, calculated for C32H39N6O5Cl 623, found 624 (M+H, 29%).

Stage B: N-/1(R)-/(6-Chloro-3H-4-oxaspiro/1H-hinzelin-2,4'-piperidine/-1'-yl) carbonyl/-2-(indol-3-yl)ethyl/-2-amino-2-methylpropanesulphonic

Receive by way of example 7, step D. Use intermediate connection with the previous stage (50 mg, 0.08 mmol). Reaction time: 1 hour. Yield 40 mg (89.5 per cent). Mass spectrum by fast atom bombardment calculated for C27H31N6O3Cl 523, found 523 (M+H, 71%).

Example 10

N-/1(R)-/(1,4-Dihydro-4-phenyl-1-oxaspiro/3H-2-benzopyran-3,4' -piperidine/-1'-yl )carbonyl/-2-(indol-3-yl)- ethyl/-2-amino-2-methylpropanesulphonic

Stage A: 1,4-Dihydro-4-perspira/3H-2-benzopyran - 3,4'-piperidine/-1-he

Receive by way of example 3, step A, from 1'-benzyl - 1,4-dihydro-4-perspire(3H-2-benzopyran-3,4'-piperidine)-1 - anhydroglucitol (8 mg, 0.019 mmol) and 5 ml of ethanol. The reaction time is 45 minutes. The output of 5.5 mg (98.5 per cent). Mass spectrum by fast atom bombardment calculated for C19H19NO2293, found 294 (M+H, 93%).

Stage B: N-/1(R)-/(1,4-Digital/amino/-2-methylpropanamide

Receive by way of example 3, step B. Use intermediate connection with the previous stage (5 mg, of 0.017 mmol), (R)-//2-//(1,1-dimethylmethoxy)carbonyl/amino/- 2,2-dimethyl-1-oxoethyl/amino/-1H-indole-3-propanoic acid (12 mg, 0,030 mmol), HOBT (1 EQ.), N-methylmorpholin (1 EQ.) and EDC (12 mg, to 0.060 mmol). The reaction time is 5 hours. The output of 9.2 mg (86%).

1H NMR (400 MHz, CD3OD): the product exists as a mixture of two conformers(1: 1): 8.185-8.072 (m, 1 1/2H), 7.885 (s, 1/2H), 7.710 - 6.813 (m, 12H), 5.331-5.309 (m, 1/2H), 5.198-5.111 (m, 1/2H), 4.710-4.605 (m, 1/2H), 4.300-4.235 (m, 1/2H), 3.876 (d, 1/2H), 3.719-3.617 (m, 1H), 3.355-3.046 (m, 1 1/2H) 2.746 (kV, 1/2H), 2.006-1.960 (m, 1H), 1.678-1.574 (m, 2H), 1.438, -1.368 (m, 6H), 1.257, 1.240, 1.227, 1.208, 1.186 (5C, 5H).

Stage C: N-/1(R)-/(1,4-Dihydro-4-phenyl-1-oxaspiro- /3H-2-benzopyran-3,4'-piperidine/-1'-yl)- carbonyl/-2-(indol-3-yl)ethyl/-2-amino-2-methylpropanesulphonic

Receive by way of example 7, step D. Use intermediate connection with the previous stage (9 mg, 0.015 mmol) and 10 ml of ethyl acetate. Reaction time 1 hour yield 8 mg (97%).

1H NMR (400 MHz, CDCl3): the product exists as a mixture of two conformers(2: 1): 8.347-8.333 (m, 1H), 8.043 (t, 1/2H), 7.662-6.869 (m, 12 1/2H), 5.355-5.315 (m, 1/2H), 5.108-5.061 (m, 1/2H), covered 4.897-4.768 (m, 1/2H), 4.174-4.103 (m, 1/2H), 3.717-3.526 (m, 1H), 3.387-3.237 (m, 2H), 3.179-3.067 (m, 1H), 2.660 (kV, 1/2H), 2.044-1.981 (m, 1H), 1.655-1.212 (m, 11H), ANO for C34H36N4O4564, found 565 (M+H, 25%).

Example 11

N-/2(R)-/(3,4-Dihydro-4-oxaspiro/2H-1-benzopyran - 2,4'-piperidine/-1'-yl)carbonyl/-2-(indol-3-yl)ethyl-2-amino - 2-methylpropanesulphonic

Stage A: N-/1(R)-/(3,4-Dihydro-4-oxaspiro/2H-1 - benzopyran-2,4'-piperidine/-1'-yl)carbonyl/-2- (indol-3-yl)ethyl/-2-//(1,1-dimethylethylene)- carbonyl/amino/-2-methylpropanamide

This intermediate compound is obtained from (R)- //2-//(1,1-dimethylmethoxy)carbonyl/amino/-2,2-dimethyl-1 - oxoethyl/amino/-1H-indole-3-propanoic acid (903 mg, 2.3 mmol) and Spiro/2H-1-benzopyran-2,4'-piperidine/-4(3H)-one - hydrochloride (535 mg, 2,11 mmol) (Elliot. J. et. al. J. Med. Chem. 1992, 35, 3973-3976), according to the method of example 25 stage A (1.25 g, 100%).

1H NMR (400 MHz, CDCl3) compound exists as a mixture of conformers (ratio 2: 1): 8.42, 8.31 (2c, 1H), 7.79, 7.75 (d, 1.6 Hz, 7.8 Hz, 1H), 7.66, 7.56 (2D, 8.0 Hz, 7.6 Hz, 1H), 7.47-6.78 (m, 8H), 5.37-5.15 (m, 1H), 4.98, 4.94 (2 Shire.s, 1H), 4.24, 4.18 (2 Shire.with 1H), 3.40, 3.32 (2 Shire.d, 2H), 3.23-3.02 (m, 3H), 2.73 (dt, 3 Hz, 13 Hz, 1H), 2.47 (d, 2 Hz, 1/3H), 2.17 (d, 16.6 Hz, 2/3H), 2.08 (q, j 16.7 Hz, 2/3H) 1.84 (Shir.s, 2H), 1.70-1.60 (Shir. DD, 1H), 1.3-1.2 (Shir.DD, 1H), 0.56 (dt, 4.6, 13.8 Hz, 2/3H), -0.55 (dt, 4.6, 13.8 Hz, 2/3H). FAB-MS:

Mass spectrum by fast atom bombardment calculated for C33H40N4O6588 found 595 (M+Li, 100%).

Stage B: N-/1(R)-/(3,4-Di is ORed

To a stirred solution of the intermediate obtained in stage A (1.0 g, 1.7 mmol) in 5 ml of methanol, add 5 ml of concentrated hydrochloric acid. The reaction mixture was stirred at room temperature for 1 hour, and add 20 ml of toluene, and the resulting mixture is evaporated in vacuum. This procedure is repeated twice to obtain the title compound (0.87 g, 98%).

1H NMR (400 MHz, CD3OD): compound exists as a mixture of two conformers (ratio 2:1): 7.76-6.90 (m, 10H), 5.11 (DD, 5,11 Hz, 1H), 4.16, 4.11 (DD, 2.0 Hz, 14 Hz, 1H), 3.60, 3.33 (MD, 14 Hz, 1H), 3.25-3.10 (m, 2H), 2.92-2.67 (m, 2H), 2.30-2.17 (AB, centered at w.23, 16.7 Hz, 2H), 2.85-2.80 (Shir. d, 1/3H), 1.60 1.59 (2s, 6H), 1.70-1.50 (m, overlapped), 1.40-1.30 (MT, 1H), 0.47 (dt, 5.5, 13.5 Hz, 2/3H), -0.38 (dt, 5.5, 13.5 Hz, 2/3H).

Mass spectrum by fast atom bombardment calculated C28H32N4O4488 found 489 (M+H, 100%).

Example 11A

N-/1(R)-/(3,4-Dihydro-4(RS)-hydroximino/2H-1 - benzopyran-2,4'-piperidine/-1'-yl)carbonyl/-2-(indol-3-yl)- ethyl-2-amino-2-methylpropanamide

To mix the solution specified in the title of example 11 compound (55 mg, 0.09 mmol) in 5 ml of methanol at 0oC add sodium borohydride (16 mg, 0.4 mmol) in several portions. After 30 minutes of paramasivan wiroa 10% methanol in dichloromethane to obtain specified in the title compound (35 mg, 78%).

1H NMR (400 MHz, CD3OD): compound exists as a mixture of two diastereoisomers (1: 1), and each isomer exists as two conformers (ratio 2: 1): 7.89-6.66 (m, 9H), 5.14-5.06 (m, 1H), 4.52-4.45 (DD, 1H), 4.22-4.10 (MT, 1H), 3.58-3.44 (MD, 1H), 3.25-3.14 (m, 2H), 3.10 - 2.59 (dt, 1H), 2.02 (DD, 6.2, 14.7 Hz, 1/3H), 1.79-1.74 (DD, 1/3H), 1.60-1.40 (m, 3H), 1.37, 1.31, 1.28, 1.28, 1.26 (4C, 6H), 1.3-1.05 (m, overlapped), 0.71, 0.49 (d, 5.6, 13.5 Hz, 2/3H), -0.20, -0.47 (dt, 4.6, 13.5 Hz, 2/3H).

Mass spectrum by fast atom bombardment calculated for C28H34N4O4490, found 491 (M+H, 100%).

Example 12

N-/1(R)-/(3,4-Dihydro-Spiro/2H-1-benzopyran-2,4'- piperidine/-1'-yl)carbonyl/-2-(indol-3-yl)ethyl/-2-amino-2 - methylpropanesulphonic

Stage A: 3,4-Dihydrospiro/2H-1-benzopyran-2,4'-piperidine/

To a stirred solution of Spiro/2H-1-benzopyran-2,4'- piperidine/-4(3H)-anhydroglucitol (53 mg, 0.21 mmol) in 5 ml of methanol at 0oC add sodium borohydride (38 mg, 1 mmol) in several portions. After 30 minutes the mixture is evaporated and then treated with concentrated hydrochloric acid (2 ml) for 30 minutes. The obtained residue hydronaut due palladium on coal (10%, 10 mg), H2(1 ATM) in ethanol for 2 hours. The catalyst is filtered off, getting clean ex is B>OD): 7,07 (appears as a doublet, 2H), 6,84 (appears as a triplet 7 Hz, 2H), 7,07-was 7.08 (m, 4H), 2,82 (t, 7 Hz, 2H), 2,02 (Shir. d, 14,5 Hz), 1,90-of 1.85 (m, 4H), E1 mass spectrum: calculated for C13H17NO 203, found 203 (M+, 45%).

Stage B: N-/1(R)-/(3,4-Dihydro-Spiro/2H-1-benzopyran-2,4'- piperidine/-1'-yl)carbonyl/-2- (indol-3-yl)ethyl/-2-//(1,1-dimethylethylene)- carbonyl/amino/-2-methylpropanamide

This intermediate compound is obtained from the product from step A and (R)-//2//(1,1-dimethylmethoxy)carbonyl/amino/-2,2 - dimethyl-1-oxoethyl/amino/-1H-indole-3-propanoic acid in accordance with the standard methods of a combination of peptides.

1H NMR (400 MHz, CDCl3), the compound exists in the form of conformers (ratio 2:1): 8.04, 8.02 (2s, 1H), 7.70, 7.61 (2D, 8 Hz, 1H), 7.49-6.66 (m, 1H), 4.92 (Shir.s, 1H), 4.30-4.20 (m, 1H), 3.4-3.1 (m, 4H), 2.85-2.45 (m, 3H), 1.68 (t, 7.6 Hz, 1H), 1.49, 1.45, 1.44, 1.43, 1.41 (5C, 12H), 1.30-1.21 (m, 3H), 1.11-1.07 (DD, 2.5, 14 Hz, 1/3H), 0.68 (DD, 4.5 Hz, 13 Hz, 1/3H), -0.33 - -0.43 (dt, 1/3H).

Mass spectrum by fast atom bombardment calculated for C33H42N4O5: 574, found 575 (M+H, 35%).

Stage C: N-/1(R)-/(3,4-Dihydro-Spiro/2H-1-benzopyran - 2,4'-piperidine/-1'-yl )carbonyl/-2-(indol - 3-yl)ethyl/-2-amino-2-methylpropanesulphonic

Specified in the title compound is obtained from promezhutochnoye exists as a mixture of conformers (ratio 2: 1): 8.31, 8.21 (2D, 6.6 Hz, 2/3H), 7.58, 7.52 (2D, 7.8 Hz, 1H), 7.37 (d, 8.2 Hz, 1H), 7.15-6.60 (m, 6 1/3H), 5.17-5.13 (m, 1H), 4.14 (Shir.d, 13.2 Hz, 1H), 3.35-3.10 (m, 3H), 2.90-2.45 (m, 3H), 1.70 (t, 6.9 Hz, 1H), 1.60 (s, 6H), 1.60-1.40 (m, overlapped), 1.40 - 1.20 (m, 2H), 1.11 (Shir.d, 12.7 Hz, 2/3H), 0.57 (dt, 4.3, 13 Hz, 2/3H), -0.31 (dt, 4.3, 13, 2/3H).

Mass spectrum by fast atom bombardment calculated for C28H34N4O3474, found 475 (M+H, 60%).

Example 13

N-/1(R)-/(3,4-Dihydro-6-methanesulfonamido-4-oxaspiro/2H - 1-benzopyran-2,4'-piperidine/-1'-yl)carbonyl/-2- (indol-3-yl)ethyl/-2-amino-2-methylpropanesulphonic

Specified in the title compound is obtained from (R)- //2-//(1,1-dimethylmethoxy)carbonyl/amino/-2,2-dimethyl-1 - oxoethyl/amino/-1H-indole-3-propanoic acid and 3,4-dihydro - 6-methanesulfonamido-4-oxo-Spiro/2H-1-benzopyran-2,4'- piperidine/ by way of example 10, stages A and B.

N-/1(R)-/(3,4-Dihydro-6-methanesulfonamido-4-oxaspiro/2H - 1-benzopyran-2,4'-piperidine/-1'-yl)carbonyl/-2- (indol-3-yl)ethyl/2-//(1,1-dimethylethylene)carbonyl/amino/- 2-methylpropanamide

1H NMR (400 MHz, CDCl3): compound exists as a mixture of conformers (ratio 2:1): 8.60, 8.36 (2 Shir.c, 1H), 7.63-6.81 (m, 8H), 5.20 (Shir.c, 1H), 5.10-5.02 (Shir.m, 1H), 3.45-3.30 (Shir.m, 1H), 3.25 - 3.10 (Shir.m, 2H), 2.97, 2.95 (2s, 3H), 2.75-2.56 (m, 1H), 2.28 (PTS.Shir.s, 1H), 2.18 (d, 16.6 Hz, 1H), 2.05 (d, 16.6 Hz, 1H), 1.86-argirova fast atoms, calculated for C34H43N5O8S 681 found 688 (M+Li, 40%).

N-/1(R)-/(3,4-Dihydro-6-methanesulfonamido-4-oxo-Spiro/2H-1-benzopyran - 2,4'-piperidine/-1'-yl)carbonyl/-2- (indol-3-yl)ethyl/-2-amino-2-methyprednisolone

1H NMR (400 MHz, CD3OD), the compound exists as a mixture of conformers (ratio 2: 1): 7.63-6.92 (m, 8H), 5.14-5.08 (m, 1H), 4.18-4.08 (MT, 1H), 3.62-3.51 (MT, 1H), 3.25-3.10 (m, 2H), 2.91, 2.89 (2s, 3H), 2.78-2.67 (d, 2 Hz, 15 Hz, 2H), 2.27 (q, j 16.7 Hz, 1H), 2.19 (d, 16.6 Hz, 1H), 1.86-1.80 (m, 1/3H), 1.80-1.50 (m, overlapped), 1.60, 1.59, 1.48 (3C, 6H), 1.40-1.30 (m, 1H), 0.47 (dt, 4.8 Hz, 13 Hz, 2/3H), -0.39 (dt, 4.8 Hz, 13 Hz, 2/3H).

Mass spectrum by fast atom bombardment calculated for C29H35N5O6S 581, found 582 (M+H, 75%).

Example 14

N-/1(R)-/(3,4-Dihydro-4(RS)-hydroxy-6-methanesulfonylaminoethyl/2H-1 - benzopyran-2,4'-piperidine/-1'-yl) carbonyl/-2-(indol-3-yl)ethyl/-2-amino-2-methylpropanamide

Specified in the title compound is obtained from the connection specified in the title of example 13, by way of example 11A.

1H NMR (400 MHz, CD3OD), the compound exists as a mixture of 2 diastereoisomers (1:1), and each isomer exists in two conformations: 7.62-7.50 (m, 1H), 7.42-7.29 (m, 2H), 7.17-6.98 (m, 4H) 6.68 (d, 8.7 Hz, 1H), 5.15-5.05 (m, 1H), 4.75-4.65 (m, 1/3H), 4.57 (1, 7 Hz, 9 Hz, 1/3H), 4), 1.86 (DD, 6.0, 13.7, 1/2H), 1.70-1.35 (m, 3H), 1.33, 1.32, 1.31, 1.28, 1.24 (5C, 6H), 1.33-1.29 (m, overlapped), 1.06 (Shir.d, 13 Hz, 1/3H), 0.71 (dt, 4.6 Hz, 13 Hz, 1/3H), 0.49 (dt, 4.6 Hz, 13 Hz, 1/3H), -0.21 (dt, 4.6 Hz, 13 Hz, 1/3H), -0.49 (dt, 4.6 Hz, 13 Hz, 1/3H).

Mass spectrum, with fast atom bombardment calculated for C29H37N5O6S 583, found 584 (M+H, 20%).

Example 15

N-/1(R)-/(2-Acetyl-1,2,3,4-tetrahydrofuro/isoquinoline-4,4'- piperidine/-1'-yl)carbonyl/-2-(indol-3-yl)ethyl/-2 - amino-2-methylpropanesulphonic

Stage A: 1,3-Dihydro-1,3-dihydrexidine/4H-2-benzopyran-4,4'- piperidine/-1'-carboxylic acid 1,1-dimethylethylene ester

Through the mix a solution of Spiro/1H-inden-1,4'-piperidine/- 1'-carboxylic acid 1,1-dimethylethylamine complex ether (800 mg, 1.8 mmol) and 50 ml of methanol at -78oC purge air to ozone until the solution becomes blue. The resulting mixture is left at this temperature for 20 minutes, then rinsed with nitrogen. Add dimethyl sulfide (3 ml) and the resulting mixture is warmed to room temperature and stirred for two hours. After evaporation of the solvent to obtain the crude product (940 mg), used without further purification.

Stage: 1,2,3,4-Tetrahydrofuro/isoquinoline-4,4'- piperidine/-1'-carbonneutral, saturated ammonia in one day, and evaporated to remove ammonia. The residue is again dissolved in 3 ml of methanol, and add cyanoborohydride sodium (50 mg, excess). The resulting mixture is stirred over night. After evaporation and purification receive Amin.

1H NMR (400 MHz, CD3OD): 7,35-of 6.96 (m, 4H), of 4.00 (s, 2H), 3,14 (s, 2H), 3,90 (Shir. s, 2H), 2.05 is (Shir.s, 2H), 1,95 (Shir.t, 2H), 0.69 (d, 2H), 1,49 (s, 9H).

Stage C: 2-Acetyl-1,2,3,4-tetrahydrofuro/isoquinoline - 4,4'-piperidine/-1'-carboxylic acid 1,1-dimethylethylene ester

The intermediate compound from step A (16 mg) is treated with 2 ml of pyridine and 2 ml of acetic anhydride for 2 hours, then the reaction mixture is evaporated in vacuo to obtain the title compound (12 mg).

1H NMR (400 MHz, CDCl3), the compound exists as a mixture of 3:1 rotamers: 7.36-7.05 (m, 4H), 4.72 (s, 2/4H), 4.65 (s, 6/4H), 4.10 - 4.00 (Shir.d, 12.8 Hz, 2H), 3.85 (Shir.C, 3/4H), 3.65 (s, 1/4H), 3.11 (t, 13.1 Hz, 3/4H), 3.00 (t, 13.1 Hz, 1/4H), 2.19 (s, 3/4H), 2.18 (s, 9/4H) 2.00-1.80 (m, 2H), 1.65-1.47 (m, 2H, overlapped), 1.47 (s, 9/4H), 1.45 (s, 27/4H).

Stage D: 2-Acetyl-1,2,3,4-tetrahydrofuro/isoquinoline - 4,4'-piperidine/

Through a solution of the intermediate obtained in stage C (12 mg) in 5 ml of ethyl acetate at 0oC bubbled HCl (about connection.

1H NMR (400 MHz, CD3OD): 7,47-7,19 (m, 4H), 4,79 (s, 2H), 3.96 points (s, 2H), 3,36 (Shir. D., of 6.7 Hz, 2H), 2,30-of 2.24 (m, 1H), of 2.21 (s, 3H), of 1.76 (d, 13H).

Mass spectrum by fast atom bombardment calculated for C15H20S2O 244, found 245 (M+H, 100%).

Stage E: N-/1(R)-/(2-Acetyl-1,2,3,4-tetrahydrofuro/ isoquinoline-4,4'-piperidine/-1'-yl)carbonyl- /-2-(indol-3-yl)ethyl/-2-//(1,1-dimethylethylene) carbonyl/amino/-2-methyl-propanamide

Specified in the title compound is obtained from the intermediate from step D in the way described earlier.

Example 16

N-/1(R)-/1,2-Dihydro-1-methanesulfonamido/3H-indole-3,4'-piperidine/- 1'-yl)carbonyl/-2-(2', 6'-differgenerations)ethyl/-2 - amino-2-methylpropanesulphonic

Stage A: Methyl- (R)-//2-//(1,1-dimethylmethoxy)carbonyl/ amino/-2,2-dimethyl-1-oxoethyl/amino/- 3-/(2',6'-differenl)methoxy/propanoic acid

Suspension not containing oil of sodium hydride (obtained from 60% oil dispersion of sodium hydride as a result of washing hexane (3 x), 1.2 g, 30.0 mmol) in 30 ml of N,N-dimethylformamide is added to N-tert-butoxycarbonyl- (D)-serine (of 3.07 g, 15.0 mmol) in 10 ml of N,N - dimethylformamide at room temperature. When the evolution of gas ceases, add 2,6-differenziale (2,68 g, 12.9 mmol). After 18 cha is ing the mixture is stirred for further 1 hour, and then poured into water and extracted with ethyl ether. The organic layer is washed successively with water (5×), brine and dried over sodium sulfate, filtered and concentrated. The residue is dissolved in 20 ml of chloroform and at room temperature add BOC--methylalanine, EDC, HOBT and Et3N. After 3 hours the reaction mixture was poured into water and extracted with methylene chloride. The organic layer is dried over sodium sulfate and concentrated. Specified in the title compound is obtained after chromatographic purification (hexane/ethyl acetate 3:1) to obtain 2.37 g (35%).

1H NMR (300 MHz, CDCl3, mixture of rotamers): 7,27 (m, 1H), 7,02-to 6.88 (m, 2H), 4.95 points (m, 1H), 4.72 in (dt, 8,3 Hz, 1H), 4,58 (Shir.s, 2H), 3,90 (m, 1H), 3,78 (s, 1H), 3,69 (s, 3H), of 1.48 (s, 3H), 1,45 (s, 3H), of 1.41 (s, 9H).

Stage B: N-/1(R)-[(1,2-Dihydro-1-methylsulfonylamino[3H - indole-3,4'-piperidine] -1'-yl)carbonyl] - 2-(2', 6'-differgenerations)ethyl]-2-amino - 2-methylpropanesulphonic

To a solution of the intermediate obtained in this example, at stage A (2.37 g, from 5.29 mmol) in 30 ml of methanol is added lithium hydroxide (340 mg, 8.1 mmol) in 3 ml of water. After 2 hours under stirring at room temperature the reaction mixture was concentrated and then diluted with water, extracted with ethyl ether. Organogenesis layer is dried over sodium sulfate, filter and concentrate to obtain 2,18 g (95%) acids. Specified in the title compound is obtained from acid (78 mg, 0.18 mmol) and 1,2-dihydro-1-methylsulfonylamino/3H-indole-3,4'-piperidineacetate (50 mg, 0,164 mmol) by the method of example 20, step (using the hydrochloride in ethyl ether instead triperoxonane acid) to obtain 48 mg (44%).

1H NMR (400 MHz, CD3OD, mixture of rotamers): 7.39 (m, 2H), 7.22 (m, 1 1/2H), 7.03 (m, 1/2H), 5.14 (DD, of 13.7 Hz, 1H), 4.66 (d, 16 Hz, 2H), 4.49 (m, 1H), 4.09 (m, 1H), 3.92 (Shir.s, 2H), 3.76 (m, 2H), 3.25 (m, 1H), 2.97 (s, 3/2H), 2.96 (s, 3/2H), 2.87 (m, 1H), 1.95 (m, 1H), 1.76 (m, 3H), 1.61 (s, 3/2H), 1.57 (s, 3 3/2H), FAB-MS: 565 (M+1).

Mass spectrum by fast atom bombardment: 565 (M+1).

Example 17

N-[(R)-[(1,3-Dihydro-1-methylsulfonylamino[3H-indole - 3,4'-piperidine] -1'-yl)carbonyl]-3-cyclohexylprop]-2 - amino-2-methylpropanesulphonic

Stage A: tert-Butyloxycarbonyl-(D)-hexahydronaphthalen

A solution of tert-butyloxycarbonyl-(D)-homophenylalanine (100 mg, 0,358 mmol) in 1 ml acetic acid hydronaut over PtO2at a pressure of 1 atmosphere for 16 hours. The resulting mixture was filtered through celite and the resulting filtrate concentrated and azeotropic distillation with toluene.

1H NMR (400 MHz, CDCl3): to 5.03 (d, 8 Hz, 1H), 4,22 (m, 1H), equal to 1.82 (m, 1H), 1,64 (the l-1-oxoethyl]amino]-4-cyclohexylmethanol acid

A solution of BOC-D-homophenylalanine in acetic acid hydronaut over PtO2at a pressure of 1 atmosphere for 16 hours. The resulting mixture was filtered through celite and concentrated. To this residue (44 mg) in 15 mol. DMF add benzylbromide (198 ml) and K2CO3(970 mg) at room temperature. After stirring overnight the mixture was poured into 200 ml of ether and washed with water. The organic phase is dried over magnesium sulfate, filtered and concentrated. The residue is purified using flash chromatography (silica gel, 7.5% ethyl acetate in hexano) to obtain 534 mg (95%) of intermediate compounds. A solution of 534 mg of this material in 10 ml of a mixture of 1:1 TFA/CH2Cl2stirred for 1 hour, and then otparivat and azeotropic distillation from toluene. The residue is dissolved in 10 ml of CH2Cl2and cooled to 0oC. BOC--methylalanine (362 mg), EDC, HOBT and NMM add, and all this stirred over night. The resulting solution was poured into 250 ml ethyl acetate and washed successively 1 N. NaHSO4(aq.), water and saturated sodium bicarbonate. The organic phase is dried, filtered and concentrated. In the chromatographic purification using flash chromatography (silica gel, ethyl acetate /hexane) receive 638 mg of UCU, H), 4,59 (m, 1H), 4,87 (m, 1H), 5,18 (m, 2H), of 6.96 (m, 1H), 7,35 (m, 5H).

Mass spectrum by fast atom bombardment calculated C26H40N2O5460, found 461,5 (M+H).

Stage C: N-[1(R)-[(1,2-Dihydro-1-methylsulfonylamino[3H-indole-3,4'-piperidine-1'- yl)carbonyl] - 3-cyclohexylprop] -2-amino-2-methylpropanesulphonic

The mixture 638 mg of the intermediate obtained in stage B, and 100 mg of 10% Pd on coal mix in the atmosphere2within 4 hours. The resulting mixture was filtered through celite and the resulting filtrate concentrated. Portion 87 mg of this residue is dissolved in 2 ml of CH2Cl2and 49.8 mg of 1,2-dihydro-1-methylsulfonylamino/3H-indole-3,4'- -piperidinedione, EDC and HOBT is added and stirred for 16 hours. The resulting solution was poured into 200 ml ethyl acetate and washed successively 1 N. NaHSO4(aq.), water and saturated aqueous sodium bicarbonate. The organic phase is dried, filtered and concentrated. In the purification using flash chromatography (silica gel, 60% ethyl acetate/hexane) obtain 55 mg (47%) of intermediate compounds. All the resulting material was dissolved in 2 ml of a mixture of 1:1 TFA/CH2Cl2, stirred for half an hour. The solution otparivat, and the remainder of ociaie dissolved in CH2Cl2, treated with HCl in ether and concentrated to obtain the title compound.

1H NMR (400 MHz, CD3OD): 0.93 (m, 2H), 1.15-1.3 (m, 6H), 1.55 - 1.8 (m, 1H), 2.06 (dt, to 15.4 Hz, 1H), 2.88 (m, 1H), 2.97 (m, 1H) 3.35 (m, 2H), 3.8-4.1 (m, 3H), 4.51 (m, 1H), 4.83 (m, 1H), 7.06 (q, 7 Hz, 1H), 7.22 (m, 2H), 7.37 (d, 8 Hz, 1H).

Mass spectrum by fast atom bombardment calculated for C27H42N4O4S 518, found 519,7 (M+H).

Example 18 (method 1)

N/[1(R)-[(1,2 - Dihydro-1-methanesulfonamide[3H-indole-3,4'-piperidine] -1'-yl) carbonyl] -2-(phenylmethoxy)- ethyl]-2-amino-2-methylpropanesulphonic

Stage A: 1,2-Dihydro-1-methanesulfonamide[3H-indole - 3,4'-piperidine] hydrochloride

To a solution of 1.20 g (5.8 mmol) of 1'-methyl-1,2-dihydrospiro/3H-indole-3,4'-piperidine (obtained by the method of H. Ong. et al., J. Med. Chem. 1983, 23, 981-986) in 20 ml of dry dichloromethane at 0oC add triethylamine (of 0.90 ml, 6.4 mmol) and methanesulfonamide (0,49 ml of 6.35 mmol) and stirred for 30 minutes. The reaction mixture is poured into 15 ml of saturated aqueous sodium bicarbonate solution, and extracted with dichloromethane (2 x 10 ml). The combined organic extracts washed with brine (20 ml), dried over anhydrous potassium carbonate is filtered, and the solvent is removed when PON is deployed without additional purification.

To a solution of above crude product in 20 ml of dry 1,2-dichloroethane at 0oC add 1.0 ml (9.3 mmol) of 1-chlorocinnamate, then stirred at room temperature for 30 minutes, and, finally, by boiling under reflux for 1 hour.

The reaction mixture is concentrated to approximately 1/3 of the volume, and then diluted with dry methanol (20 ml) and refluxed for one and a half hours. The reaction mixture is cooled to room temperature and concentrated to approximately half volume. The precipitate is filtered off and washed with a small amount of cold methanol. The result is 1.0 g piperidine HCl salt as a white solid. The obtained filtrate is concentrated and add a small amount of methanol and then ether. The precipitate is again filtered off, washed with cold methanol and dried. The result is the addition of 0.49 g of the target product. Full output 1,49 g (70%).

1H NMR (200 MHz, CDCl3): 7,43-7,20 (m, 3H), 7,10 (DD, 1H), 3,98 (Shir. s, 2H), 3,55-3,40 (Shir. d, 2H), 3,35-3,10 (m, 2H), 2,99 (s, 3H), of 2.15 (t, 2H), 2,00 (t, 2H).

Stage b: N-[1(R)-[(1,2-Dihydro-1-methanesulfonamide[3H-indole-3,4'-piperidine]-1'-yl) carbonyl]-2-(phenylmethoxy)ethyl]-2-[(1,1-dime is[2-(phenylmethoxy)ethyl]-1-propanoic acid in 13 ml of dichloromethane added 1,2-dihydro-1-methanesulfonamide[3H-indole-3,4'-piperidine] hydrochloride (0,325 g, 1.07 mmol), of 0.18 ml (1,63 mmol) N-methylmorpholine, (strength of 0.159 g, 1.18 mmol) of N-hydroxybenzotriazole (HOBT) and stirred for 15 minutes. EDC (0.31 g, of 1.62 mol) is added and stirring is continued for 1 hour. Add an additional 60 μl of N-methylmorpholine and stirred for 45 minutes. The reaction mixture was poured into 5 ml of water, and the organic layer isolated. The organic layer was washed with 5 ml of 0.5 N. aqueous hydrochloric acid and 5 ml of saturated aqueous sodium bicarbonate solution. The combined organic layers dried over anhydrous magnesium sulfate and concentrated to obtain 0,627 g of the product as a yellow foam, which is used without further purification.

To 0,627 g (1.07 mmol) previously specified product in 5 ml of dichloromethane add 1.0 ml triperoxonane acid, and stirred at room temperature for 75 minutes. Add a 1.00 ml triperoxonane acid and stirred for further 10 minutes, the reaction mixture was concentrated, diluted with 5.0 ml of dichloromethane and carefully alkalinized, pouring in 10 ml of 10% aqueous solution of sodium carbonate. The organic layer is allocated, and the aqueous layer was further extracted (2 x 15 ml) of dichloromethane. The combined organic layers washed with 5 ml of water, dried over potassium carbonate, filtered the Oh cleanup.

To 0,486 g (1.01 mmol) of amine and 10 ml dichloromethane added 0.26 g (1.28 mmol) of 2-[1,1-dimethylmethoxy)carbonyl]amino - 2-methylpropanoic acid, 0,173 g (1.28 mmol) of 1-hydroxybenzotriazole (HOBT), EDS (0,245 g, 1.28 mol), and stirred at room temperature overnight. The reaction mixture is poured into 5.0 ml of water, and the organic layer isolated. The aqueous layer was again extracted with 5 ml dichloromethane. The combined organic layers washed with 5.0 ml of 0.5 N. aqueous hydrochloric acid, 5 ml of saturated aqueous sodium bicarbonate solution and dried over anhydrous magnesium sulfate, concentrated to obtain 0,751 g of the crude product as a yellow foam. A solution of this product in dichloromethane process chromatography on 25 g of silica gel, elwira first mixture hexane/acetone/dichloromethane (70/25/5), and then the mixture hexane/acetone/dichloromethane (65/30/5). The result 0,63 g specified in the title compound as a white solid.

1H NMR (400 MHz, CDCl3), the compound exists as a mixture of 3:2 rotamers: 7.40-7.10 (m, 6H), 7.06 (d, 1/3H), 7.02 (t, 1/3H), 6.90 (t, 1/3H), 6.55 (d, 1/3H), 5.15 (m, 1H), 4.95 (Shir.s, 1H), 4.63 (Shir.d, 1/3H), 4.57-4.40 (m, 2 2/3H), 4.10 (Shir.d, 1/3H), 4.00 (Shir.d, 1/3H), 3.82 (t, 1H), 3.78-3.62 (m, 2H), 3.60-3.50 (m, 1H), 3.04 (q, 1H), 2.87 (s, 1H), 2.86 (s, 2H), 2.80-2.60 (m, 1H), 1.90 (Shir.s, 1H), 2.85-2.75 (m,H - indole-3,4'-piperidine] -1'-yl)carbonyl-2- (phenylmethoxy)ethyl-2-amino-2-methylpropanesulphonic

To 0,637 g (0,101 mmol) of the intermediate stage In 5 ml dichloromethane add 2.5 ml triperoxonane acid and stirred at room temperature for 30 minutes. The reaction mixture was concentrated to oil, placed in 10 ml of ethyl acetate and washed with 8 ml of 10% aqueous solution of sodium carbonate. The aqueous layer was extracted with 5 ml ethyl acetate. The combined organic layers are washed with 10 ml of water, dried over magnesium sulfate, filtered and concentrated to obtain 0,512 g of the free base as a white foam.

To 0,512 g of the free base in 5 ml of ethyl acetate at 0oC add 0.2 ml of saturated hydrochloric acid in ethyl acetate, and stirred for 1.5 hours Resulting white precipitate is filtered off under nitrogen atmosphere, washed with ether, and dried to obtain 0.50 g specified in the title compound as a white solid.

1H NMR (400 MHz, CD3OD), the compound exists as a mixture of 3:2 rotamers: 7.40-7.28 (m, 4H), 7.25-7.17 (m, 2H), 7.08 (t, 1/3H), 7.00 (t, 1/3H), 6.80 (d, 1/3H), 5.16 (DDD, 1H), 4.60-4.42 (m, 3H), 4.05 (t, 1H), 3.90 (Shir. s, 2H), 3.83-3.70 (m, 2H), 3.30-3.15 (m, 1H), 2.97 (s, 1H), 2.95 (s, 2H), 2.90-2.78 (m, 1H), 1.96 (t, 1/3H), 1.85-1.65 (m, 4H), 1.63 (s, 2H), 1.60 (s, 4H).

Example 19 (method 2)

N-[1(R)-[(1,2-Dihydro-1-methanesulfonamide [3H-indole-3,4, immolators)carbonyl]- amino]-2,2-dimethyl-1-oxoethyl]amino-2-(phenylmethoxy)ethyl-1-propanoic acid allyl ester

Is obtained from (2R)-2-[(1,1-dimethylmethoxy)carbonyl]- amino-3-(phenylmethoxy)ethyl-propanoic acid and allyl alcohol, carrying out the reaction in CH3Cl2in the presence of EDC and DMAP.

1H NMR (400 MHz, CDCl3): of 7.25 (s, 5H), and 5.8 (m, 1H), and 5.2 (DD, 2H), 5,0 (Shir. c, 1H), 4,7 (m, 1H), 4,6 (m, 2H), 4,4 (DD, 2H), 3,9 (DD, 1H), 3,6 (DD, 1H), 1,45 (D, 6H), 1.39 in (c, 9H).

Stage b: (R)-[[[-2-(1,1-Dimethylmethoxy)carbonyl]-amino]-2,2 - dimethyl-1-oxyethyl]amino-2- (phenylmethoxy)ethyl-1-propanoic acid

To a stirred solution of the crude intermediate compound obtained in stage A (6.7 g, 15.9 mmol), tetrakis(triphenylphosphine)-palladium (1.8 g, 0.1 EQ.) and triphenylphosphine (1.25 g, 0.3 EQ.) add a solution of potassium-2 - ethylhexanoate (35 ml, 0.5 M solution in EtOAc). The reaction mixture was stirred at room temperature under nitrogen atmosphere for 1 hour and then diluted with ether (100 ml) and poured into a mixture of ice and water. The organic layer is allocated, and the aqueous fraction is acidified with citric acid (20%), then extracted with EtOAc. EtOAc extracts washed with brine, dried over magnesium sulfate, filtered and evaporated to obtain the title compound in the form of a solid substance.

1H NMR (400 MHz, CD3OD): at 7.3 (s, 5H), 4,7 (m, 1H), and 4.5 (s, 2H), 4,0 (m, 1H), 3,6 (m, 1H), 1,4 (d, ylmethylene)ethyl-2-[(1,1-dimethyl-ethoxy)carbonyl]-amino-2-methylpropanamide

To a solution of 1.0 g (3,44 mmol) 1-methanesulfonamido/- indolin-3,4'-piperidine/hydrochloride, 1.44 g (of 3.78 mmol) (2R)-[[-2-(1,1-dimethylmethoxy)carbonyl)amino] -2,2-dimethyl - 1-oxoethyl]amino-2-(phenylmethoxy)ethyl)-1-propanoic acid, N-methylmorpholine (of 0.58 ml, 5,20 mmol) and 1-hydroxybenzotriazole (HOBT) (0,58 g of 3.78 mmol) in 50 ml of dichloromethane added EDC (1,03 g, 5,20 mmol) and stirred at room temperature for 16 hours, the reaction mixture is diluted with an additional 50 ml of dichloromethane and washing with an aqueous solution of sodium bicarbonate (50 ml), dried over anhydrous magnesium sulfate, filtered and concentrated. After processing flash chromatography (50 g silica gel) of the crude oily residue receive 2,148 g (90%) of the target material in the form of a colorless foam.

1H NMR (400 MHz, CDCl3), the compound exists as a mixture of 3:2 rotamers: 7.40-7.10 (m, 6H), 7.06 (d, 1/3H), 7.02 (t, 1/3H), 6.90 (t, 1/3H), 6.55 (d, 1/3H), 5.15 (m, 1H), 4.95 (Shir.s, 1H), 4.63 (Shir.s, 1/3H), 4.57-4.40 (m, 2 2/3H), 4.10 (Shir. d, 1/3H), 4.00 (Shir.d 1/3H), 3.82 (t, 1H), 3.78-3.62 (m, 2H), 3.60-3.50 (m, 1H), 3.04 (q, 1H). 2.87 (s, 1H), 2.86 (s, 2H), 2.80-2.60 (m, 1H), 1.90 (Shir.s, 1H), 2.85-2.75 (m, 1H), 1.82-1.60 (m, 3H), 1.55-1.45 (m, 1H), 1.45 (s, 4H), 1.42 (s, 2H), 1.39 (s, 9H).

Stage D: N-[1(R)-[(1,2-Dihydro-1-methanesulfonamide[3H - indole-3,4'-piperidine] -1'-yl)carbonyl] 2-(phenylmethoxy)ethyl]-2-amino-2 is armeana add 5 ml triperoxonane acid and stirred for one hour. The reaction mixture was concentrated and alkalinized 100 ml of 5% aqueous sodium carbonate solution, and extracted with dichloromethane (3 x 50 ml). The combined organic layers washed with brine (50 ml), dried over anhydrous potassium carbonate, filtered and concentrated to obtain a colorless foam. To a solution of the foam in 25 ml of ethyl acetate at 0oC add 4 ml of 1 M hydrochloric acid solution in ethyl acetate. The precipitate is filtered and washed first with ethyl acetate and then a mixture of ethyl acetate-ether (1:1); dried to obtain 1,79 g (93%) specified in the title compound as a colourless solid.

1H NMR (400 MHz, CD3OD), the compound exists as a mixture of 3:2 rotamers: 7.40-7.28 (m, 4H), 7.25-7.17 (m, 2H), 7.08 (t, 1/3H), 7.00 (t, 1/3H), 6.80 (d, 1/3H), 5.16 (DDD, 1H), 4.60-4.42 (m, 3H), 4.05 (t, 1H), 3.90 (Shir. s, 2H), 3.83-3.70 (m, 2H), 3.30-3.15 (m, 1H), 2.97 (s, 1H), 2.95 (s, 2H), 2.90-2.78 (m, 1H), 1.96 (t, 1/3H), 1.85-1.65 (m, 4H), 1.63 (s, 2H), 1.60 (s, 4H).

Example 20

N-[1(R)-[1,2-Dihydro-1-methanesulfonyl-5-bromospiro[- 3H-indole-3,4'-piperidine] -1'-yl)carbonyl] -2-(phenylmethoxy)- ethyl]-2-amino-2-methylpropanesulfonate

Stage A: N-[1(R)-[(1,2-Dihydro-1-methanesulfonyl-5 - bromospiro[3H-indole-3,4'-piperidine]-1'-yl)- carbonyl-2-(phenylmethyl-hydroxy)ethyl]-2-[(1,1 - dimethylmethoxy)carbonyl]amino-2-methylpropanamide

slots added 0.28 g (of 2.06 mmol) of bromine and stirred at room temperature for 1 hour. The reaction mixture is concentrated to dryness, alkalinized with 10 ml 5% aqueous sodium carbonate solution, and extracted with dichloromethane (3 x 10 ml). The combined organic extracts washed with brine (10 ml), dried over anhydrous potassium carbonate, filtered and concentrated to obtain 0.25 g of the crude product in the form of a yellow oil, which was used further without additional purification.

Stage:

To a solution of above crude product in 10 ml of dichloromethane type of 0.43 g (1.13 mmol) of the intermediate compound of example 19 with stage (0.17 g, 31,13 mmol) HOBT, and 0.34 g (1.70 mmol) of EDC and stirred at room temperature for 16 hours. The reaction mixture was diluted with 15 ml of ether and washed with 10% aqueous citric acid (15 ml), saturated sodium bicarbonate solution (15 ml), dried over anhydrous magnesium sulfate, filtered and concentrated to obtain a crude oily product. The residue is purified using flash chromatography (15 g of SiO2; CH2Cl2-acetone (10:1) as eluent) to obtain 0,184 g (26% in two stages) of the collected material in the form of a colorless foam.

To 0,184 g (0.26 mmol) of the above material in 2 ml of dichloromethane and 2 ml triperoxonane acid and stirred at to the title compound as a white solid. Mass spectrum by fast atom bombardment calculated for C27H34BrN4O5S 608, found 609,5.

Example 21

N-[1(R)-[(1,2-Dihydrospiro[3H-indole-3,4'-piperidine] -1'-yl)carbonyl] - 2-(indol-3-yl)ethyl]-2-amino-2-methylpropanesulphonic

Stage A: Spiro/3H-indole-3,4'-piperidine/

To a solution of 1.0 g (5.0 mmol) 1'-methylspiro/3H-indole - 3,4'-piperidine (obtained by the method of H. Ong. et al., J. Med. Chem., 1983, 23, 981-986) and 1.0 g of powdered potassium carbonate in 30 ml of dry dichloromethane at room temperature, add 0.5 g of cyanogenmod, and stirred for 1 hour. The reaction mixture was filtered through a layer of celite and washed with a mixture of chloroform-methanol (95:5). The obtained filtrate is concentrated and the residue passed through a layer of silica gel, washing with a mixture of chloroform-methanol (95:5) as eluent. The result is approximately 1.2 g of yellow oil which is used without further purification.

To a suspension of the above compound in 30 ml of dry DMF at 0oC add 0,30 g sociallyengaged, and warmed to room temperature and then refluxed for 1 hour. The reaction mixture was cooled to 0oC and quenched to 0.30 ml of water, 0,30 ml of 15% aqueous sodium hydroxide solution and concentration of the filtrate obtain 0.74 g of the compound in the form of a yellow foam. This material is a mixture of 1:1 is specified in the title compound and 1'-methyl-Spiro/3H-indole-3,4'-piperidine).

Stage b: (2R)-//-2-//1,1-dimethylmethoxy)carbonyl/- amino/-2,2-dimethyl-1-oxoethyl/amino/-1H-indole-3 - propanoic acid benzyl ester

To 5.0 g (16.5 mmol) of commercial N-tert-BOC-D - tryptophan in 100 ml of chloroform type of 1.80 ml (16.5 mmol) of benzyl alcohol, 0.20 g (of 1.65 mmol) of 4-N, N - dimethylaminopyridine (DMAP) and 3,20 g of EDC and stirred for 16 hours. The reaction mixture was poured into 100 ml of water, and the organic layer isolated. The aqueous layer was extracted twice with 100 ml of chloroform. The combined organic layers washed with 50 ml of 10% aqueous citric acid, 100 ml of 10% aqueous sodium bicarbonate solution dried over anhydrous magnesium sulfate, filtered and concentrated to obtain a thick oil.

To a solution of this oil in 10 ml of dichloromethane are added 20 ml triperoxonane acid and stirred for 1 hour. The reaction mixture was concentrated, alkalinized carefully saturated aqueous sodium bicarbonate and extracted with chloroform (2 x 100 ml). The combined organic layers washed with brine (100 ml), dried over anhydrous potassium carbonate, filtered and tx2">

To 5,46 g of the above product in 100 ml of chloroform, add 3,40 g (22,2 mmol) HOBT, 4,60 g (22,2 mmol) N-BOC-methylalanine and 5.32 g (28,0 mmol) of EDC and stirred for 16 hours. The reaction mixture was poured into 100 ml of water, and the organic layer isolated. The aqueous layer was initially extracted with chloroform (2 x 100 ml). The combined organic extracts washed with 50 ml of 10% aqueous citric acid, 100 ml of 10% aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered and concentrated to obtain 6,94 g of the product as a thick oil. Processing using flash chromatography (200 g of SiO2; hexane-ethyl acetate as eluent) gives of 4.75 g of the target material in the form of a colorless foam.

1H NMR (200 MHz, CDCl3): 8,48 (Shir.s, 1H), 7,54 (Shir.d, 1H), 7,38-of 7.23 (m, 3H), 7,19 (Shir.d, 2H), 7,15-7,00 (m, 1H), 6.90 to (d, 1H), 6,86 (d, 1H), 5,06 (Shir.s, 2H), 4.95 points (DDD, 1H), 3,30 (2 DD, 2H), 1,40 (s, 15H).

Stage C: (2R)-//-2-/(1,1-Dimethylmethoxy)carbonyl/amino/- 2,2-dimethyl-1-oxoethyl/amino/-1H-indole-3 - propanoic acid

To a solution of 4.75 g of the material from step B in 100 ml of ethanol is added 1.0 g of 10% Pd/C and stirred at room temperature in an atmosphere of H2within 18 hours. The catalyst is filtered through a layer of celite and washed with ethyl acetate. The obtained filtrate choir.with, 1H), 7,55 (d, 1H), 7,26-of 6.90 (m, 3H), 6,88 (Shir.d, 1H), 4,80 (m, 1H), 3,32 (2 DD, 2H), of 1.37 (s, 3H), of 1.35 (s, 12H).

Stage D: N-/1(R)-/(1,2-Dihydro-Spiro/3H-indole-3,4'- piperidine/-1'-yl)carbonyl/-2-(indol-3-yl)- ethyl/-2-/(1,1-dimethylmethoxy)carbonyl/amino - 2-methylpropanamide

To a solution of 0,122 g (0,542 mmol) of 1:1-mixture of the intermediate from step A and 1'-methyl-Spiro/3H-indole - 3,4'-piperidine/ in 5 ml of dry chloroform at room temperature add 0,105 g (0,271 mmol) of the intermediate from step C, 41 mg (0,271 mmol) NOWT, and 80 mg (0.41 mmol) of EDC and stirred at room temperature for 2 hours. The reaction mixture was diluted with 10 ml of chloroform and washed with saturated aqueous sodium bicarbonate (10 ml) and 10 ml of brine, dried over anhydrous potassium carbonate, filtered and concentrated. Processing using flash chromatography (10 g of SiO2, 2% MeOH - CHCl3the remainder give 94 mg of the desired product as a yellow foam.

The compound exists as a mixture of 3:2 rotamers.

1H NMR (400 MHz, CDCl3): 8.37 (d, 1/3H), 8.35 (d, 2/3H), 8.19 (d, 1H), 7.72 (d, 2/3H), 7.60 (d, 1/3H). 7.38 (d, 2/3H), 7.32 (d, 1/3H). 7.22-7.08 (m, 3H). 7.00 (2T, 1H), 6.93 (d, 1/3H), 6.69 (t, 1H). 6.60 (d, 1/3H), 6.56 (d, 2/3H), 6.50 (d, 2/3H), 5.30-5.15 (m, 1H), 5.00 (Shir.s, 1H), 4.34 (m, 1H), 3.62-3.50 (m, 1H), 3.30-3.11 (m, 4H), 2.90 (dt, 1H), 2.40 (dt, 1/3H) 1.70-1.55 (m, 1 2/3H), 1.34 (s, 2H), 1,31 (s, 4H), 1.2 IMT]-2-(indol-3-yl)- ethyl]-2-amino-2-methylpropanamide

To 27,5 mg of the intermediate from step D add 1.0 ml of methanol and 1.0 ml of concentrated hydrochloric acid and stirred at room temperature for one hour. The reaction mixture was concentrated, alkalinized 5 ml of 10% aqueous sodium carbonate and extracted with chloroform (3 x 5 ml). The combined organic layers washed with brine (10 ml), dried over potassium carbonate, filtered and concentrated to obtain a thick oil. Preparative TLC (0.50 mm plate, chloroform-methanol 96:5 + 1% NH4OH) give 12 mg of the desired product as a yellow solid. The compound exists as a mixture of 3:2 rotamers.

1H NMR (400 MHz, CDCl3): 8.37 (d, 1/3H), 8.35 (d, 2/3H), 8.19 (d, 1H), 7.72 (d, 2/3H), 7.60 (d, 1/3H), 7.38 (d, 2/3H), 7.32 (d, 1/3H), 7.22-7.08 (m, 3H). 7.00 (2T, 1H), 6.93 (d, 1/3H), 6.69 (t, 1H), 6.60 (d, 1/3H), 6.56 (d, 2/3H), 6.50 (d, 2/3H), 5.30-5.15 (m, 1H), 4.34 (m, 1H), 3.62-3.50 (m, 1H), 3.30-3.11 (m, 4H), 2.90 (dt, 1H), 2.40 (dt, 1/3H), 1.70-1.55 (m, 1 2/3H), 1.34 (s, 2H), 1.31 (s, 4H), 1.28 (s, 1H), 1.20-1.11 (m, 1H), 0.32 (dt, 1/3H).

Example 22

N-[1(R)-[(1,2-Dihydro-1-methylcarbonate[3H-indole - 3,4'-piperidine-1'-yl)carbonyl]-2-(indol-3-yl)ethyl]-2-amino-2 - methylpropanesulphonic

To 26 mg of the intermediate obtained in example 21 in stage D in 1.0 ml of 1,2-dichloromethane and 55 μl (0.14 mmol) of N-methylmorpholine at 0

To the above material in 1.0 ml dichloromethane add 1.0 ml triperoxonane acid and stirred at room temperature for 1 hour, the reaction mixture was concentrated, alkalinized 5 ml of 10% aqueous sodium carbonate, extracted with chloroform (3 x 5 ml).

The combined organic layers washed with brine (10 ml), dried over potassium carbonate, filtered and concentrated to obtain a thick oil. To a solution of this material in 1.0 ml of methanol, add 1.0 ml of 4 M hydrochloric acid in dioxane and concentrated to dryness to obtain 16 mg specified in the title compound in a solid yellow color. The compound exists as a mixture of 3:2 rotamers.

1H NMR (400 MHz, CD3OD): 8.43 (d, 1H), 8.35 (t, 1H), 7.72 (d, 2/3H), 7.61 (d, 1/3H), 7.40-7.25 (m, 2H), 7.20-7.08 (m, 3H), 7.05-6.95 (m, 22/3H), 6.50 (d, 1/3H), 5.25-5.10 (m, 1H), 5.00-4.84 (Shir.d, 1H), 3.68-3.45 (m, 3H), 3.20 (m, 2H), 2.60-2.48 (m, 1 1/3H), 2.30 (dt, 1/3H), 2.00 (s, 1H), 1.98 (s, 2H), 1.81-1.40 (m, 4H), 1.35 (s, 2H), 1.33 (s, 2H), 1.32 (s, 1H), 1.30 (s, 1H), 1.25-1.15 (m, 1H), 1.10-1.00 is arbonyl]-2-(indol-3-yl)ethyl]- 2-amino-2-methylpropanamide

To 26 mg (0,050 mmol) intermediate compound of example 21 with stage D in 1.0 ml of 1,2-dichloroethane and 5 μl of N-methylmorpholine added at 0oC 7,5 ál benzosulfimide and stirred for 1 hour. The reaction mixture was diluted with 10 ml ether, washed with 5 ml of 10% aqueous citric acid, 5 ml of saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered and concentrated to obtain 29,8 mg of the crude product as a pale yellow foam. To a solution of this material in 2 ml of methanol, add 1.0 ml of concentrated hydrochloric acid and stirred for 1 hour. The solvent is removed under reduced pressure to obtain the title compound in the form of a solid brown color.

The compound exists as a mixture of 3:2 rotamers.

1H NMR (400 MHz, CDCl3): 8.30 (Shir.s, 1/3H), 8.20 (Shir.s, 2/3H), 8.05 (Shir. s, 2/3H), 7.88 (d, 1/3H), 7.72-7.45 (m, 5H), 7.43-7.30 (m, 4H), 7.20-7.05 (m, 2H), 7.00-6.90 (m, 2 2/3H), 6.35 (d, 1/3H), 5.25-5.10 (m, 1H), 4.90 (Shir.s, 1H), 4.30 (dt, 1H), 4.15 (dt, 1H), 3.95 (DD, 1H), of 3.60-3.40 (m, 3H), 3.25-3.20 (m, 2H), 2.90 (dt, 1H), 2.73 (dt, 2 2/3H), 2.35 (m, 1 1/3H), 1.80 (m, 1H), 1.50 (s, 1H), 1.43 (s, 2H), 1.39 (s, 3H), 1.30-1.20 (m, 2H), 1.00 (Shir.d, 1/3H), 0.90-0.70 (m, 2H), 0.55 (Shir.d, 1/3H), 0.48 (DD, 2/3H), -0.90 (dt, 1/3H).

Example 24

N-[1(R)-[(1,2-Dihydro-1-sulfonylamino[3H (0.50 mmol) intermediate compound of example 21 stage D in 10 ml of dry dichloromethane at 0oC type of 0.39 ml (1.00 mmol) of N-methylmorpholine and 45 μl (0,60 mmol) methanesulfonanilide, and stirred for 30 minutes. The reaction mixture was diluted with 10 ml of ether and washed with saturated sodium bicarbonate solution (5 ml), brine (5 ml), dried over anhydrous magnesium sulfate, filtered and concentrated to obtain the product as pale yellow foam, which is used without further purification. To a solution of this material in 3.0 ml of dichloromethane add 1.0 ml triperoxonane acid and stirred at room temperature for 1 hour. The reaction mixture was concentrated, alkalinized 5 ml of 10% aqueous sodium carbonate and extracted with chloroform (3 x 5 ml). The combined organic layers washed with brine (10 ml), dried over potassium carbonate, filtered and concentrated to obtain a thick oil. To a solution of this material in 3.0 ml of methanol, add 200 ál of 4 M hydrochloric acid in dioxane and concentrated to dryness to obtain 93 mg of the target material in the form of a pale yellow solid.

The compound exists as a mixture of 3:2 rotamers.

1H NMR (400 MHz, CD3OD): 8.43 (d, 1H), 8.35 (t, 1H), 7.72 (d, 2/3H), 7.61 (d, 1/3H), 7.40-7.25 (m, 2H), 7.20-7.08 (m, 3H), 7.05-6.95 (m, 22/3H), 6.50 (d, 1/3H), 5.25-5.10 (m, 1H), 5.00-4.84 (W, .25-1.15 (m, 1H), 1.10-1.00 (m, 1H), 0.20 (dt, 1/3H).

Example 25

N-1(R)-[1,2-Dihydro-1-methanesulfonamide[3H-indole-3,4'- piperidine] -1'-yl)carbonyl]-3-phenylpropyl]-2 - amino-2-methylpropanesulphonic

Stage A: N-1(R)-[1,2-dihydro-[methanesulfonyl - Spiro[3H-indole-3,4'-piperidine]-1'-yl)carbonyl]-3-phenylpropyl]-2-[1,1 - dimethylmethoxy)-carbonyl]amino-2-methylpropanamide

Specified in the title compound is obtained from (2R)-2- /(1,1-dimethylmethoxy)carbonyl/-amino-4-phenyl-1-butane acid and 1,2-dihydro-1-methylsulfonylamino/3H-indole-3,4'- piperidine/-hydrochloride using the method of combination of example 18, stage C. the Crude product is purified on silica gel using 5% acetone in CH2Cl2.

1H NMR (400 MHz, CDCl3): to 7.2 (m, 9H), 4,9 (m, 1H), and 4.5 (m, 1H), and 3.8 (m, 2H), 3,2 (m, 2H), 2,9 (s, 3H), and 2.7 (m, 2H), 2,3 (c, 2H), 2.0 (m, 2H), and 2.7 (m, 4H), 1.5 a (c, 6H), 1,4 (c, 9H).

Stage b: N-1(R)-/1,2-Dihydro-1-methanesulfonyl - Spiro/3H-indole-3,4'-piperidine/-1'-yl)carbonyl/-3 - phenylpropyl/-2-amino-2-methylpropanesulphonic

Obtained from intermediate compounds obtained in stage A, using the method of removing the protection described in example 18 on stage C.

1H NMR (400 MHz, CD3OD): to 7.3 (m, 9H), and 4.5 (m, 1H), 3,9 (m, 2H), 3,5 (m, 2H), 3,2 (m, 2H), 2,9 (c, 3H), and 2.7 (m, 4H), 2.0 (m, 4H), 1,6 (c, 6H).

He primal)ethyl/-2-amino-2-methylpropanesulfonate

Stage A: 1,2-Dihydro-1-benzyloxycarbonyl-5-pterospora/3H-indole-3,4'-piperidine/

To of 7.82 g of 60% sodium hydride added hexane and the liquid portion is decanted. To this add a solution 11,10 ml (89 mmol) of 2,5-differentiational in 150 ml of DMSO, and stirred for 30 minutes. Was added dropwise a solution 15,10 g 1-chlorodimethylvinylsilane in 150 ml of DMSO and heated at 75oC for 4 hours. The reaction mixture is poured into 600 g of ice and extracted with ether (5 x 200 ml). The combined organic layers washed with 2 N. hydrochloric acid (3 x 100 ml). The combined aqueous extracts alkalinized to pH 9 with 50% aqueous sodium hydroxide solution and extracted with ether (3 x 200 ml). The combined organic layers washed with brine (100 ml), dried over potassium carbonate and concentrated to obtain 15,54 g of a thick oil.

Was added dropwise 24 ml of ethanol to 9,90 g sociallyengaged in 250 ml of DFID at 0oC, and then heated to boiling under reflux. A solution of the compound in 250 ml of DFID added, and the mixture was refluxed for 72 hours. The reaction mixture was cooled to 0oC and quenched with water (10 ml), 10 ml of 15 NaOH and 30 ml of water. The resulting suspension is dried over K2CO3filter and concentrate to polivaut and washed with hexane. NMR (200 MHz, CDCl3) the solid parts (2.6 g) gives about 75% target serontonin.

To a solution of 1.02 g of this mixture in 50 ml of CH2Cl2at 0oC add 1.0 ml of triethylamine and 0.80 ml CBZ-C1, and the resulting mixture is stirred for 1 hour at room temperature, the reaction mixture is poured into 50 ml of 5% HCl, and the aqueous layer was isolated. The aqueous layer was alkalinized with 50% NaOH to pH = 10 and extracted with CH2Cl2(3 x 25 ml). The combined organic layers washed with brine (50 ml), dried over K2CO3and concentrate to obtain 1.26 g of the compound as a thick oil.

1H NMR (200 MHz, CDCl3): 7,7-of 7.90 (m, 1H), 7,50-to 7.15 (m, 6H), 6,95-6,60 (m, 2H), 5,28 (Shir.s, 2H), 3,90 (Shir.s, 2H), 2,85 (Shir.d, 2H), 2,30 (s, 3H), 2,20-of 1.80 (m, 4H), 1,65 (Shir.d, 2H).

Stage b: N-/1(R)-/(1,2-Dihydro-1-benzyloxycarbonyl - 5-pterospora/3H-indole-3,4'-piperidine/-1'-yl)- carbonyl/-2-(indol-3-yl)ethyl/-//(1,1-dimethylethylene) carbonyl/amino/-2-methylpropanamide

To of 1.62 g (to 4.62 mmol) specified intermediate compound from step A in 10 ml of 1,2-dichloroethane at 0oC add 0,65 ml ACE-Cl and refluxed for one hour. The reaction mixture was concentrated to 1/3 volume and diluted with 10 ml of methanol and heated to boiling under reflux for 1 hour. is avago color. This material is dissolved in a saturated aqueous solution of sodium bicarbonate (25 ml) and extracted with dichloromethane (2 x 25 ml). The combined organic extracts dried over K2CO3and concentrate to obtain 0,384 g of free base.

To 0,384 g of this material in 15 ml of CH2Cl2add 0,483 g of the acid intermediate from step C of example 21, 0,189 g HOBT and 0.34 g of EDC and stirred for 18 hours, the reaction mixture is poured into 10 ml of water and extracted with CH2Cl2(2x10 ml). The combined organic layers washed with 20 ml of 10% citric acid, 20 ml of saturated NaHCO3, dried over magnesium sulfate and concentrated. After treatment of the residue by flash chromatography on 25 g of silica gel, elwira a mixture of 1:1 hexane-acetone, get 0,389 g of the target material.

1H NMR (200 MHz, CDCl3): 7,7-of 7.90 (m, 1H), 7,50 - to 7.15 (m, 6H), 6,95-6,60 (m, 2H), 5,28 (Shir.s, 2H), 3,90 (Shir. s, 2H), 2,85 (Shir.d, 2H), 2,30 (s, 3H), 2,20-of 1.80 (m, 4H), 1,65 (Shir.d, 2H).

Stage C: N-/1(R)-/(1,2-Dihydro-5-pterospora/3H-indole-3,4'-piperidine/-1'-yl) carbonyl/-2-(indol-3-yl)ethyl/-//(1,1-dimethylethylene)carbonyl/- amino/-2-methylpropanamide

To a solution of 0,363 g of the intermediate product obtained in stage b In 5 ml of ethanol, add 0.10 g of 20% of the hydroxide PE methanol. The resulting filtrate is concentrated to obtain 0,262 g of the target material.

1H NMR (400 MHz, CDCl3). This material exists in the form of a mixture 2:1 rotamers: 8.85-8.60 (2 Shire.s, 1H), 7.70 (d, 2/3H), 7,55 (d, 1/3H), 7.38 (d, 2/3H), 7,30 (d, 1/3H), 7.28-7.15 (m, 4H), 7.13-7.02 (m, 2H), 6.65 (dt, 2H), 6.50 (DD, 1/3H), 6.45 (DD, 2/3H), 6.14 (DD, 2/3H), 5.30-5.13 (m, 1H), 5.10 (Shir. s, 1H), 4.30 (Shir. d, 2/3H), 4.22 (Shir.d, 1/3H), 3.50-3.30 (m, 1H), 3.30-3.00 (m, 4H), 3.00-2.80 (m, 1H), 2.73 (t, 1H), 2.53-2.40 (m, 1 1/3H), 2.20 (t, 1/3H), 1.49 (s, 3H), 1.45 (s, 3H), 1.41 (s, 9H) 1.20 (dt, 1/3H), 0.95 (Shir.d, 2/3H), 0.90 (dt, 2/3H), -0.05 (dt, 1/3H).

Stage D: N-[1(R)-[(1,2 - Dihydro-1-trifloromethyl-6-pterospora[3H-indole-3,4' -piperidine]-1'-yl)carbonyl)-2-(indol-3-yl)ethyl]-[[(1,1 - dimethylethylene)carbonyl]-amino]-2-methylpropanamide

To a solution of 30 mg of the intermediate obtained from step C in 1 ml of dichloromethane at 0oC add 0,050 ml of triethylamine and 0,020 ml triflic anhydride and stirred for 5 minutes. The catalyst is filtered off and washed with more methanol, the reaction mixture is poured into 5 ml of 5% aqueous sodium carbonate solution and stirred for 5 minutes. The aqueous layer was extracted with CH2Cl2(2 x 5 ml) and the combined organic extracts are dried over magnesium sulfate, filtered and concentrated. As a result of processing using flash-chromatography is one.

1H NMR (400 MHz, CDCl3). This material is a mixture of 2:1 rotamers: 8.40 (Shir.s, 2/3H), 8.25 (Shir.s, 1/3H), 7.70 (d, 2/3H), 7.60 (d, 1/3H), 7.40 (d, 2/3H), 7.35-7.10 (m, 5H), 6.90-6.80 (m, 2H), 6.18 (DD, 1H), 5.30-5.13 (m, 1H), 4.95 (Shir.s, 2/3H), 4.90 (s, 1/3H), 4.45 (Shir.d, 2/3H), 4.35 (Shir.d, 1/3H), 3.85-3.70 (m, 2H), 3.70-3.55 (m, 2H), 3.30-3.10 (m, 2H), 2.70 (t, 1H), 2.45 (t, 1/3H), 2.35 (t, 2/3H), 1.49 (s, 3H), 1.45 (s, 3H), 1.41 (s, 9H), 1.20 (dt, 1/3H), 0.95 (Shir.d, 2/3H), 0.90 (dt, 2/3H), -0.05 (dt, 1/3H).

Stage E: N-[1(R)-[(1,2-Dihydro-1-trifloromethyl-5 - pterospora[3H-indole-3,4'-piperidine] - 1'-yl)carbonyl]-2-(indol-3-yl)ethyl]-2-methylpropanesulfonate

A solution of 21 mg of the intermediate obtained in stage D, incubated in 1 ml of dichloromethane and 1 ml triperoxonane acid at room temperature for 30 minutes. Volatile is evaporated to dryness and triturated with ether to obtain a solid yellow color.

1H NMR (400 MHz, CD3OD). This material exists as a mixture of rotamers (2: 1): 7.65 (d, 2/3H), 7.60 (d, 1/3H), 7.42 (d, 2/3H), 7.35-7.10 (m, 5H), 6.93-6.80 (m, 2H), 6.24 (DD, 1H), 5.30-5.13 (m, 1H), 4.95 (Shir.s, 2/3H), 4.90 (s, 1/3H), 4.45 (Shir.d, 2/3H), 4.35 (Shir.d, 1/3H), 3.85-3.70 (m, 2H), 3.70-3.55 (m, 2H), 3.30-3.10 (m, 2H), 2.70 (t, 1H), 2.45 (t, 1/3H), 2.35 (t, 2/3H), 1.49 (s, 3H), 1.45 (s, 3H), 0.93 (Shir.d, 2/3H), 0.90 (dt, 2/3H), -0.05 (dt, 1/3H).

Example 27

N-[(1(R)-[(1,2-Dihydro-1-[methoxycarbonyl] metalsalt the

Stage A: N-[1(R)-[(1,2-Dichloro-1-[methoxycarbonyl]- methylsulphonyl-5-pterospora[3H-indole-3,4'-piperidine] ]-1'-yl) carbonyl]-2-(indol-3-yl)ethyl]-2-methylpropanesulfonate

To a solution of 77 mg of the intermediate obtained in stage C of example 26, in 1 ml of dichloromethane at 0oC add to 0.30 ml of N-methylmorpholine and 0.024 ml of 2-carbamidomethylated, and stirred for 1 hour. The reaction mixture was poured into 5 ml of 5% aqueous sodium carbonate solution and stirred for 5 minutes. The aqueous layer was extracted with CH2Cl2(2 x 5 ml) and the combined organic extracts washed with brine (5 ml), dried over magnesium sulfate, filtered and concentrated. As a result of processing of the residue using flash chromatography on 5 g of silica gel, elwira a mixture of CH2Cl2/acetone (4:1) to obtain 64 g of product.

1H NMR (400 MHz, CDCl3). This material is a mixture of rotamers of 2: 1: 8.48 (Shir.s, 2/3H), 8.35 (Shir.s, 1/3H), 7.70 (d, 2/3H), 7.60 (d, 1/3H), 7.40 (d, 2/3H), 7.32 (d, 1/3H), 7.25-7.00 (m, 4H), 6.90-6.78 (m, 2H), 6.18 (DD, 1H), 5.30-5.20 (m, 1H), 4.97 (Shir.s, 2/3H), 4.91 (s, 1/3H), 4.50-4.35 (Shir. d, 1H), 4.02 (s, 2/3H), 3.99 (s, 1/3H), 3.76 (q, 2H), 3.58 (s, 1H), 3.56 (s, 2H), 3.08-3.07 (m, 2H), 2.72 (t, 1H), 2.50-2.30 (2T, 1H), 1.65 (t, 1/3H), 1.50 (s, 2H), 1.46 (s, 4H), 1.40 (s, 9H), 1.30 (m, 1/3H), 1.10 (Shir.d, 2/3H). 0.88 (dt, 2/3H), -0.13 (dt, 1/3H).


A solution of 24 mg of the intermediate obtained from step A, incubated in 1 ml of dichloromethane and 1 ml triperoxonane acid at room temperature for 30 minutes. Volatile is evaporated to dryness and triturated with ether to obtain 23 mg of a colorless solid.

1H NMR (400 MHz, CD3OD). This material exists in the form of a mixture 2:1 rotamers: 8,70 (Shir.s, 1/3H), 8.60 (Shir.s, 2/3H), 7.60 (m, 2/3H), 7.50 (d, 2/3H), 7.48 (m, 1/3H), 7.40 (d, 2/3H), 7.31 (d, 1/3H), 7.25-7.00 (m, 4H), 6.95-6.85 (m, 1H), 6.70 (DD, 1/3H), 6.15 (DD, 2/3H), 5.20-5.10 (m, 1H), 4.38 (Shir.d, 1/3H), 4.28 (Shir.d, 2/3H), 4.02 (s, 2/3H), 3.99 (s, 1/3H), 3.76 (q, 2H), 3.58 (s, 1H), 3.56 (s, 2H), 3.08-3.07 (m, 2H), 2.72 (t, 1H), 2.50-2.30 (2T, 1H), 1.65 (t, 1/3H), 1.65 (s, 2H), 1.60 (s, 4H), 1.30 (m, 1/3H), 1.00 (Shir.D. 2/3H), 0.88 (dt, 2/3H), -0.10 (dt, 1/3H).

Example 28

N-[(R)-[(1,2-Dihydro-1-methanesulfonyl-5-pterospora[- 3H-indole-3,4'-piperidine] -1'-yl)carbonyl] -2- (phenylmethoxy)ethyl]-2-amino-2-methylpropanesulphonic

Stage A: N-[1(R)-[(1,2-Dihydro-1-benzyloxycarbonyl-5-pterospora[3H-indole-3,4'-piperidine]- 1'-yl)carbonyl]-2-(phenylmethoxy)ethyl]- [[(1,1-dimethylethylene)carbonyl]amino]-2 - methylpropanamide

To 0.33 g of 1,2-dihydro-1-benzyloxycarbonyl-5-peropero- /3H-indole-3,4'-piperidine/ obtained in stage A of example 26, in 10 ml of 1,2-dichloromethane at room temperature add 0.35 g of N-tre extracted with CH2Cl2(2 x 10 ml). The combined organic layers washed with 20 ml of 10% citric acid, 20 ml saturated sodium bicarbonate, dried over magnesium sulfate and concentrated. To a solution of intermediate compound obtained in stage A, in 5 ml of CH2Cl2add 5 ml triperoxonane acid, and stirred at room temperature for 30 minutes. The reaction mixture was concentrated, diluted with 5.0 ml of dichloromethane and carefully alkalinized with 10 ml of 10% aqueous solution of sodium carbonate. The organic layer is allocated, and the aqueous layer extracted with a further 2 x 15 ml dichloromethane. The combined organic layers washed with 5 ml of water, dried over potassium carbonate, filtered and concentrated to obtain 0.39 g amine as a thick oil.

To 0.39 g of the above intermediate compound in 10 ml of 1,2-dichloromethane at room temperature is added 0.24 g of N-tert-BOC-methylalanine, of € 0.195 g of HOBT and 0.30 g of EDC and stirred for 18 hours. The reaction mixture was poured into 10 ml of water and extracted twice with portions of CH2Cl210 ml the combined organic layers washed with 20 ml of 10% citric acid, 20 ml of saturated NaHCO3, dried over magnesium sulfate and concentrated. As a result of processing using the flash chromatogra.

1H NMR (200 MHz, CDCl3): 7.80 (Shir.s, 1H), 7.50-7.15 (m, 5H), 7.10 (Shir. d, 1H), 6.90-6.70 (m, 1H), 6.27 (Shir.d, 1H), 7.35-7.10 (m, 5H), 5.35-5.10 (m, 3H), 4.99 (s, 1H), 4.70-4.40 (m, 3H), 3.90-3.50 (m, 4H), 3.15-2.90 (m, 2H), 2.80-2.50 (m, 2H), 1.80-1.40 (m, 2H), 1.50 (3H), 1.42 (, 6H).

Stage b: N-[1(R)-[(1,2-Dihydro-5-pterospora[3H - indole-3,4'-piperidine] -1'-yl)carbonyl] -2- (phenylmethoxy)ethyl]-[[(1,1-dimethylethylene) carbonyl] amino]-2-methylpropanamide

To a solution of 0.33 g of the intermediate connection obtained in stage A, in 5 ml of ethanol was added 1 drop of triethylamine, and hydronaut from hydrogen balloon for 3 hours. The catalyst is filtered through a layer of celite and washed with ethyl acetate. Charged with the filtrate concentrated to obtain 0,269 g of the product as a colourless foam.

1H NMR (400 MHz, CDCl3): 7.35-7.20 (m, 4H), 7.17-7.08 (m, 2H), 6.80-6.65 (m, 2/2/3H), 6.27 (dt, 1/3H): 5.20-5.10 (m, 1H), 4.90 (s, 1H), 4.60-4.40 (m, 3H), 4.00 (Shir. t, 1H), 3.75-3.60 (m, 1H), 3.55-3.40 (m, 3H), 3.18-3.30 (m, 2H), 2.90-2.65 (m, 1H), 1.83-1.50 (m, 4H), 1.48 (s, 4H), 1.42 (s, 2H), 1.39 (s, 9H).

Stage C: N-[1(R)-[(1,2-Dihydro-1-methanesulfonyl-5 - pterospora[3H-indole-3,4'-piperidine]-1'-yl)- carbonyl]-2-(phenylmethoxy)ethyl]-[[(1,1-dimethylethylene) carbonyl]-amino]-2-methylpropanamide

To a solution of 0,134 g the intermediate from step b In 5 ml of dichloromethane add 0,080 ml of N-methylmorpholine and of 0.022 ml Maino 5 ml saturated sodium bicarbonate solution, brine (5 ml), dried over magnesium sulfate and concentrated. As a result of processing of the residue using flash chromatography on 20 mg of silica gel receiving 0,101 g of the target product.

1H NMR (400 MHz, CDCl3): 7.40-7.20 (m, 5H), 7.08 (d, 1H), 6.95-6.80 (m, 2/1/3H), 6.23 (DD, 2/3H), 5.20-5.10 (m, 1H), 4.90 (Shir.s, 1H), 4.60 (Shir. d, 2/3H), 4.58-4.40 (m, 3/1/3H), 4.10-4.00 (m, 1H), 3.388-3.70 (m, 21/3H), 3.66-3.60 (m, 1/2H), 3.60-3.50 (m, 1H), 3.10-2.95 (m, 1H), 2.86 (s, 1H), 2.84 (s, 2H), 2.80 (t, 1/3H), 2.65 (t, 2/3H), 2.90-2.50 (m, 4H), 1.45 (s, 4H), 1.44 (s, 2H), 1.42 (s, 3H), 1.40 (s, 6H).

Stage D: N-[1(R)-[(1,2-Dihydro-1-methanesulfonyl-5 - pterospora[3H-indole-3,4'-piperidine]-1'-yl)- carbonyl]-2-(phenylmethoxy)ethyl]-amino - 2-methylpropanesulphonic

To a solution 0,101 g the intermediate from step C in 1 ml dichloromethane add 1.0 ml triperoxonane acid, and incubated at room temperature for 30 minutes. The reaction mixture is evaporated to dryness, alkalinized with 10% aqueous solution of sodium carbonate (10 ml), and extracted with dichloromethane (3 x 5 ml). The combined organic layers washed with brine (5 ml), dried over potassium carbonate and concentrated. This material was dissolved in 2 ml of ethyl acetate and at 0oC add 0.10 ml of 4 M HCl in EtOAc. The precipitate is filtered off under nitrogen atmosphere and washed with EtOAc/ether (1:1) and dried to obtain 62 mg of the product of the), 6.23 (DD, 2/3H), 5.20-5.10 (m, 1H), 4.60 (Shir.d, 2/3H), 4.58-4.40 (m, 3/1/3H), 4.10-4.00 (m, 1H), 3.388-3.70 (m, 21/3H), 3.66-3.60 (m, 1/2H), 3.60-3.50 (m, 1H), 3.10-2.95 (m, 1H), 2.86 (s, 1H), 2.84 (s, 2H), 2.80 (t, 1/3H), 2.65 (t, 2/3H), 2.90-2.50 (m, 4H), 1.45 (s, 4H), 1.44 (s, 2H).

Example 29

Stage A: N-[1(R)-[(1,2-Dihydro-1-benzazolyl - 5-pterospora[3H-indole-3,4'-piperidine]-1'-yl)- carbonyl]-2-phenylmethoxy)ethyl]-2-amino-2 - methylpropanesulfonate

To the solution was 0.026 g of the intermediate from step b of example 27 in 2 ml of dichloromethane add 0,020 ml of N-methylmorpholine and a 0.012 ml benzosulfimide, and stirred at 0oC for 1 hour. The reaction mixture was poured into 10 ml of ether and washed with 5 ml saturated sodium bicarbonate solution, dried over magnesium sulfate and concentrated. As a result of processing of the residue using flash chromatography on 10 g of silica gel, using as eluent CH2Cl2-ether (2:1), receive 0,019 g of the product.

This material is treated with 1 ml dichloromethane and 1 ml triperoxonane acid for 1 hour. The reaction mixture is evaporated to dryness and the residue triturated with ether to obtain 18 mg of the desired product in the form of a solid white color.

1H NMR (400 MHz, CD3OD): 7.80 (d, 2H), 7.70-7.55 (m, 2H), 7.55-7.50 (m, 2H), 7.40-7.20 (m, 42/3H), 7.03-6.92 (m, s, 4H), 1.56 (s, 2H), 1.50 (dt, 1H), 1.38 (dt, 1H), 1.10 (dt, 2H).

Example 30

N-[1(R)-[(1,2-Dihydro-econsultancy-Spiro[3H-indole - 3,4'-piperidine] -1'-yl)carbonyl] -2-(phenylmethoxy)ethyl] -2 - amino-2-methylpropanesulphonic

Stage A: N-[1(R)-[(1,2-Dihydro-1-benzyloxycarbonyl/- Spiro/3H-indole-3,4'-piperidine/-1'-yl)carbonyl/- 2-(phenylmethoxy)ethyl/-//(1,1-dimethylethylene) carbonyl/amino/-2-methylpropanamide

To 5 g of 1,2-dihydro-1-benzyloxycarbonyl-Spiro/3H-indole - 3,4'-piperidine/hydrochloride in 100 ml of dichloromethane at room temperature add to 3.64 g of N-tert-BOC-O - benzyl-D-serine and 1.83 g of HOBT, 2,60 ml of N-methylmorpholine and 3.70 g of EDC and stirred for 18 hours. The reaction mixture was poured into 100 ml of water and extracted with CH2Cl2(2 x 100 ml). The combined organic layers are washed with 100 ml of 10% citric acid, 100 ml saturated NaHCO3, dried over magnesium sulfate and concentrate.

To a solution of intermediate compound obtained in stage A, in 20 ml of CH2Cl2add 20 ml triperoxonane acid and stirred at room temperature for 30 minutes. The reaction mixture was concentrated, diluted with 50 ml dichloromethane and carefully acidified with 100 ml of 10% aqueous solution of sodium carbonate. The organic layer emit, and aq is over potassium carbonate, filter and concentrate to obtain the amine as a thick oil.

To the above intermediate compound in 50 ml of dichloromethane at room temperature add 2.50 g of N-tert-BOC-methylalanine and 1.83 g of HOBT and 3.70 g of EDC and stirred for 18 hours. The reaction mixture was poured into 10 ml of water and extracted with CH2Cl2(2 x 10 ml). The combined organic fractions washed with 20 ml of 10% citric acid, 20 ml of saturated NaHCO3, dried over magnesium sulfate and concentrated. As a result of processing of the residue using flash chromatography on 300 g of silica gel, elwira a mixture of hexane-ethyl acetate (2:1), gain of 8.1 g of the product.

1H NMR (400 MHz, CDCl3): 7.85 (Shir.s, 1H), 7.45-7,20 (m, 10H), 7.20-7.05 (m, 22/3H), 6.95 (t, 1/3H), 6.88 (t, 1/3H), 6.53 (DD, 2/3H), 5.35-5.20 (m, 2H), 5.20-5.10 (m, 1H), 4.92 (Shir.s, 1H), 4.65-4.20 (m, 4H), 4.05 (DD, 2/3H), 4.00-3.80 (m, 1,1/3H), 3.80-3.60 (m, 1H), 3.10 (t, 2/3H), 3.00-2.85 (m, 1/3H), 2.82-2.60 (2m, 1H), 1.90-1.55 (m, 5H), 1.49 (s, 4H), 1.42 (s, 2H), 1.40 (s, 9H).

Stage B: N-/1(R)-/(1,2-Dihydro-Spiro/3H-indole - 3,4'-piperidine/-1'-yl)carbonyl/-2-(phenylmethoxy) ethyl/-//(1,1-dimethylmethoxy)carbonyl/amino/-2-methylpropanamide

To a solution 8,10 g of the intermediate compound obtained in stage A, in 80 ml of ethanol was added 1 g of 20% palladium hydroxide on coal and hydronaut hydrogen from a cylinder in accordance with intronaut to get 4,69 g of the product as a colourless foam.

1H NMR (400 MHz, CDCl3): 7.35-7.20 (m, 5H), 7.18 (d, 1/2H), 7.10 (d, 1/2H), 7.04-6.98 (m, 2H), 6.75-6.60 (m, 2H), 5.20-5.10 (m, 1H), 4.97 (Shir.s, 1H), 4.55-4.40 (m, 3H), 3.95 (DD, 1H), 3.73-3.61 (m, 1H), 3.60-3.50 (m, 1H), 3.50-3.33 (m, 3H), 3.10 (dt, 1H), 2.83 (dt, 1H), 1.85-1.55 (m, 5H), 1.47 (s, 4H), 1.42 (s, 2H), 139 (s, 9H).

Stage C: N-/1(R)-/(1,2-Dihydro-1-econsultancy - Spiro/3H-indole-3,4'-piperidine/-1'-yl)carbonyl/-2- (phenylmethoxy)-ethyl/-2-amino-2-methylpropanamide

To a solution of 0,158 g of the intermediate obtained in stage b In 5 ml of dichloromethane add 0,053 ml of N-methylmorpholine and 0,034 ml acanaloniidae and stirred at 0oC for 30 minutes at room temperature for 1 hour. The reaction mixture is diluted with an additional 5 ml of dichloromethane and washed with 5 ml saturated sodium bicarbonate solution, brine (5 ml), dried over magnesium sulfate and concentrated. As a result of processing of the residue using flash chromatography on 10 g of silica gel, elwira a mixture of CH2Cl2-ether (3:1), receive 0,057 g of the target product.

To a solution of 0,057 g of the above intermediate compound in 1 ml of dichloromethane add 1.0 ml triperoxonane acid and incubated at room temperature for 30 minutes. The reaction mixture is concentrated to dryness and triturated with ether to 0-7.25 (m, 5H), 7.25-7.13 (m, 21/2H), 7.03 (t, 1/2H), 6.95 (t, 1/2H), 6.80 (d, 1/2H), 5.18 (dt, 1H), 4.60-4.42 (m, 3H), 4.08 (t, 1H), 3.96 (s, 2H), 3.83-3.70 (m, 2H), 3.29-3.15 (m, 3H), 2.84 (dt, 1H), 1.90 (dt, 1H), 1.74-1.62 (m, 4H), 1.62 (s, 2H), 1.60 (s, 4H), 1.33 (dt, 3H).

Example 31

Stage A: N-/1(R)-/(1,2-Dihydro-1-/2-methyl-2 - propanesulfonic/3H-indole-3,4'-piperidine/-1'- yl)carbonyl/-2-(phenylmethoxy)ethyl/-//(1,1 - dimethoxy)carbonyl/amino-2-methylpropanamide

To a solution of 0,212 g the intermediate from step B of example 29 in 2 ml of 1,2-dichloromethane add 0,083 ml of triethylamine and 0,054 ml isopropylacetanilide and stirred at 0oC for 30 minutes and at room temperature for 3 hours. The reaction mixture was diluted with 5 ml of dichloromethane and washed with 5 ml of saturated solution

sodium bicarbonate, brine (5 ml), dried over magnesium sulfate and concentrated. As a result of processing of the residue using flash chromatography on 10 g of silica gel, elwira a mixture of CH2Cl2-ether (3:1) get the target product.

To a solution 0,101 g of the above intermediate compound in 1 ml of dichloromethane add 1.0 ml triperoxonane acid and incubated at room temperature for 30 minutes. The reaction mixture is evaporated to dryness, alkalinized with 10% aqueous solution of sodium carbonate (10 ml) and what rebonato potassium and concentrate. This material was dissolved in 2 ml of ethyl acetate, and 0.10 ml of 4 M HCl in EtOAc was added when 0oC. the Precipitate is filtered off under nitrogen atmosphere and washed with mixture of EtOAc/ether (1:1) and dried, resulting in a gain of 88 mg of the product as a white solid.

1H NMR (400 MHz, CD3OD): 7.40-7.20 (m, 5H), 7.08 (d, 1H), 6.95-6.80 (m, 2/1/3H), 6.23 (DD, 2/3H), 5.20-5.10 (m, 1H), 4.60 (Shir.d, 2/3H), 4.58-4.40 (m, 3/1/3H), 4.10-4.00 (m, 1H), 3.388-3.70 (m, 21/3H), 3.66-3.60 (m, 1/2H), 3.60-3.50 (m, 1H), 3.10-2.95 (m, 1H), 2.86 (s, 1H), 2.84 (s, 2H), 2.80 (t, 1/3H), 2.65 (t, 2/3H), 2.90-2.50 (m, 4H), 1.45 (s, 4H), 1.44 (s, 2H).

Example 32

Stage A: N-/1(R)-/(1,2-Dihydro-1-/2-carbomethoxybiphenyl-Spiro/3H-indole-3,4'- piperidine//-1'-yl)carbonyl/-2-(phenylmethoxy)- ethyl/-//(1,1-dimethylethylene)-carbonyl/- amino/-2-methylpropanesulphonic

To a solution of 0.50 g of the intermediate product from step b of example 29 in 10 ml of dichloromethane type of 0.21 ml of N-methylmorpholine and 0.10 ml of 2-carbomethoxybiphenyl and stirred at 0oC for 30 minutes. The reaction mixture was diluted with 10 ml dichloromethane and washed with 5 ml saturated aqueous sodium bicarbonate solution, brine (5 ml), dried over magnesium sulfate and concentrated. As a result of processing of the residue using flash chromatography on 20 g of silica gel, elwira a mixture of CH2Cl2-EPE is, H), 6.92 (t, 1/2H), 6.55 (d, 1/2H), 5.20-5.10 (m, 1H), 4.94 (Shir.s, 1H), 4.60 (Shir. d, 1H), 4.53-4.40 (m, 2H), 4.10 (Shir.s, 2H), 4.05-3.90 (m, 2H), 3.70 (dt, 1H), 3.63 (s, 11/2H), 3.61 (s, 11/2H), 3.59-3.50 (m, 1H), 3.05 (dt, 1H), 2.70 (dt, 1H), 1.90-1.50 (m, 4H), 1.49 (s, 4H), 1.44 (s, 2H), 1.39 (s, 9H).

Stage b: N-/1(R)-/(1,2-Dihydro-1-/2 - carbomethoxybiphenyl/3H-indole-3,4'-piperidine//- -1'-yl)carbonyl/-2-(phenylmethoxy)ethyl/-2 - amino-2-methylpropanesulphonic

To a solution of 0,113 g of the above intermediate compound in 1 ml of dichloromethane add 1.0 ml triperoxonane acid and incubated at room temperature for 30 minutes. The reaction mixture is evaporated to dryness, alkalinized with 10% aqueous solution of sodium carbonate (10 ml), extracted with dichloromethane (3 x 5 ml). The combined organic fractions washed with brine (10 ml), dried over potassium carbonate and concentrated. This material was dissolved in 2 ml of ethyl acetate, and 0.20 ml of 4 M HCl in EtOAc was added when 0oC. Add the ether, and the precipitate is filtered off under nitrogen atmosphere and washed with ether and dried, resulting in a gain to 0.108 g of the product as a white solid.

1H NMR (400 MHz, CD3OD): 7.40-7.20 (m, 5H), 7.08 (d, 1H), 6.95-6.80 (m, 2/1/3H), 6.23 (DD, 2H), 5.20-5.10 (m, 1H), 4.60 (Shir.d, 2/3H), 4.58-4.40 (m, 3/1/3H), 4.10-4.00 (m, 1H), 3.388-3.70 (m, 21/3H), 3.66-3.60 (m, 1/2H), 3.6-3.50 (m, 1H), 3.10-2.95 (m, gidro-1-/2-carboxymethyllysine/3H-indole-3,4'- piperidine//-1'-yl)carbonyl/-2-/phenylmethoxy/ethyl/-//(1,1 - dimethylethylene)carbonyl/amino/-2-methylpropanesulfonate

To a solution of 0.126 g of the intermediate from step A of example 32 in 3 ml methanol and 1 ml of water at 0oC add 2 drops of 5 N. aqueous sodium hydroxide and stirred for 30 minutes. The reaction mixture is acidified to pH = 2 to 0.5 N. aqueous hydrochloric acid, diluted with brine (5 ml) and extracted with CH2Cl2(2 x 5 ml). The combined organic extracts washed with brine (10 ml), dried over magnesium sulfate and concentrated to obtain 0,098 g of white foam.

1H NMR (400 MHz, CDCl3): 9.80 (Shir.s, 1H), 7.45 (d, 1/2H), 7.40-7.13 (m, 7H), 7.02 (t, 1/2H), 6.90 (t, 1/2H), 6.50 (d, 1/2H). 5.22-5.10 (m, 1H), 4.60-4.40 (m, 3H), 4.20-4.00 (m, 3H), 3.92 (d, 1H), 3.70-5.50 (m, 2H), 3.04 (dt, 1H), 2.70 (dt, 1H), 1.93-1.50 (m, 4H), 1.42 (s, 6H), 1.33 (s, 9H).

Stage b: N-/1(R)-/(1,2-Dihydro-1-/2-carboxytetramethyl - Spiro/3H-indole-3,4'-piperidine/-1'- yl)carbonyl/-2-(phenylmethoxy)ethyl/-2-amino-2-methylpropanamide

To a solution 0,098 g the intermediate from step A in 1 ml of dichloromethane was added 1 ml of triperoxonane acid and stirred for 80 minutes. The reaction mixture is evaporated to dryness and triturated with ether to obtain 0,096 g of the product as a white solid.

1H NMR (400 MHz, CD3OD): 7.40-7.28 (m, 6H), 7.24-7.15 (m, 21/2H), 7.00 (dt, 1H), 6.80 (d, 1/2H), 5.17 (dt, 1H), 4.60-4.45 (m, 2H), 4.22 (d Stage A: N-/1(R)-/(1,2-Dihydro-1-/2-hydroxyethanesulfonic-Spiro/ 3H-indole-3,4'-piperidine//-1'- yl)carbonyl/-2-(phenylmethoxy)ethyl/-//(1,1 - dimethylethylene)-carbonyl/-amino/-2-methylpropanesulfonate

To a solution of 0,222 g of the intermediate product from step A of example 32 in 2 ml of anhydrous tetrahydrofuran at room temperature add to 0.48 ml of a 2 M solution of lithium borohydride in tetrahydrofuran, and stirred for 3 hours. The reaction mixture was quenched 0,50 ml of acetone, diluted with 15 ml of water and extracted with CH2Cl2(2 x 15 ml). The combined organic extracts washed with brine (10 ml), dried over magnesium sulfate and concentrated to obtain 0.27 g of a white foam. As a result of processing of the residue using flash chromatography on 10 g of silica gel, elwira a mixture of CH2Cl2-acetone (2:1), receive 0,129 g of the target material in the form of a thick oil.

1H NMR (400 MHz, CDCl3): 7.32-7,20 (m, 6H), 7.20-7.10 (m, 2H), 7.09 (d, 1/2H), 6.98 (t, 1/2H), 6.90 (t, 1/2H), 6.54 (d, 1/2H), 5.17-5.10 (m, 1H), 5.00 (Shir.s, 1H), 4.61-4.39 (m, 3H), 4.10-3.95 (m, 5H), 3.93-3.74 (m, 2H), 3.66 (DDD, 1H), 3.53 (dt, 1H), 3.27 (dt, 2H), 3.00 (dt, 1H), 2.70 (dt, 1H), 1.90-1.50 (m, 4H), 1.43 (s, 4H), 1.41 (s, 2H), 1.36 (s, 9H).

Stage b: N-/1(R)-/(1,2-Dihydro-1-/2-hydroxyethanesulfonic-Spiro/3H-indol-3, 4'-piperidine/-1'-yl)carbonyl/-2-(phenylmethoxy) ethyl/-2-amino-2-methylpropanesulfonate

To a solution of 0,129 g the intermediate from step A in 1 ml of dichloromethane was added 1 ml of triperoxonane acid and stirred for 30 minutes. Verdugo substances.

1H NMR (400 MHz, CD3OD): 7,40-7,25 (m, 6H), 7,35-7,13 (m, 21/2H), 6,98 (dt, 1H), 6,80 (d, 1/2H), 5,20 - 5,10 (m, 1H), 4,60-4,43 (m, 3H), 4,10-8,90 (m, 5H), 3,81-3,70 (m, 2H), 3,40-to 3.33 (dt, 2H), 3,20 (dt, 1H), 3,82 (dt, 1H), 2,00-to 1.63 (m, 4H), 1.61 of (s, 1H), 1,58 (s, 5H).

Example 35

Stage A: N-[1(R)-[(1,2-Dihydro-1-trifloromethyl-Spiro[3H-indole-3,4' -piperidine]-1'-yl)-carbonyl]-2-(phenylmethoxy)ethyl]-[[(1,1-dimethylethylene) carbonyl]-amino]-2-methylpropanesulphonic

To a solution of 0.15 g of the intermediate from step B of example 29 in 5 ml of dichloromethane add 0.10 ml of N-methylmorpholine and 0,057 ml triftormetilfullerenov anhydride, and stirred at 0oC for 15 minutes. The reaction mixture was diluted with 5 ml saturated aqueous sodium bicarbonate solution, and extracted (2 x 5 ml) of dichloromethane. The combined extracts washed with brine (5 ml), dried over magnesium sulfate and concentrated. As a result of processing of the residue using flash chromatography on 10 g of silica gel, elwira a mixture of hexane-acetone (3:1), receive 0,136 g of the target product.

1H NMR (400 MHz, CDCl3): 7.40-7.15 (m, 6H), 7.15-6.93 (m, 21/2H), 6.53 (d, 1/2H), 5.20-5.10 (m, 1H), 4.90 (Shir.s, 1H), 4.70-4.60 (m, 3H), 4.15-3.90 (m, 3H), 3.70 (DDD, 1H), 3.60-3.50 (m, 1H), 3.00 (dt, 1H), 2.70 (dt, 1H), 1.93-1.55 (m, 4H), 1.46 (s, 4H), 1.43 (s, 2H), 1 40 (s, 9H).

Stage b: N-[1(R)-[(1,2-Dihydro-1-trift the hydrochloride

To a solution of 0,136 g of the above intermediate compound in 1 ml of dichloromethane add 1.0 ml triperoxonane acid, and incubated at room temperature for 30 minutes. The reaction mixture is evaporated to dryness, alkalinized with 10% aqueous solution of sodium carbonate (5 ml) and extracted with ethyl acetate (2 x 5 ml). The combined organic extracts washed with brine (5 ml), dried over potassium carbonate and concentrated. This material was dissolved in 2 ml of ethyl acetate and 0.20 ml of 4 M HCl in EtOAc was added when 0oC. Add ether and the precipitate is filtered off under nitrogen atmosphere and washed with ether and dried, resulting in a gain of 0.94 g of the product in the form of a solid white color.

1H NMR (400 MHz, CD3OD): 7.10-7.15 (m, 6H), 7.15-6.93 (m, 21/2H), 6.53 (d, 1/2H), 5.20-5.10 (m, 1H), 4.90 (Shir.s, 1H), 4.70-4.60 (m, 3H), 4.15-3.90 (m, 3H), 3.70 (DDD, 1H), 3.60-3.50 (m, 1H), 3.00 (dt, 1H), 2.70 (dt, 1H), 1.93-1.55 (m, 4H), 1.46 (s, 4H), 1.43 (s, 2H).

Example 36

Stage A: N-[1(R)-[1,2 - Dihydro-1-benzazolyl-Spiro[3H-indole-3,4'-piperidine] -1'- yl)carbonyl] -2-(phenylmethoxy)ethyl]-2-amino-2-methylpropanamide

To a solution of 0,148 g the intermediate from step b of example 29 in 3 ml of dichloromethane added to 0.30 ml of N-methylmorpholine and of 0.022 ml benzosulfimide, and premesis the l of a saturated aqueous solution of sodium bicarbonate, dried over magnesium sulfate and concentrated. As a result of processing of the residue using flash chromatography on 10 g of silica gel, elwira a mixture of hexane-acetone (3:1), receive 0,190 g of the target product.

To a solution of 0,190 g of the above intermediate compound in 3 ml of dichloromethane add 3 ml triperoxonane acid and incubated at room temperature for 30 minutes. The reaction mixture is evaporated to dryness, alkalinized with 10% aqueous solution of sodium carbonate (5 ml) and extracted with ethyl acetate (2 x 5 ml). The combined organic extracts washed with brine (5 ml), dried over potassium carbonate and concentrated. This material was dissolved in 2 ml of ethyl acetate, and 0.40 ml of 4 M HCl in EtOAc was added when 0oC. Add the ether, and the precipitate was filtered under nitrogen atmosphere and washed with ether and dried, yielding 0,136 g of the product as a white solid.

1H NMR (400 MHz, CD3OD): 7.82 (d, 2H), 7.67-7.58 (m, 2H), 7.52 (t, 2H), 7.40-7.20 (m, 6H), 7.10-6.90 (m, 11/2H), 6.68 (d, 1/2H), 5.10 (dt, 1H), 4.53 (ABq, 2H), 4.35 (t, 1H), 4.00-3.80 (m, 3H), 3.75-3.65 (m, 2H), 3.10 (dt, 1H), by 2.73 (dt, 1H), 1.75 (dt, 1/2H), 1.48 (m, 11/2H), 1.20-1.05 (m, 2H).

Example 37

Stage A: N-[1(R)-[(1,2-Dihydro-[1-freedomites - Spiro[3H-indole-3,4'-piperidine] -1'-yl)carbonyl - 2-(phenylmethoxy)ethyl]-2-amino-2-methylpropanamide the ml of methyl isocyanate and stirred at room temperature for 1 hour. The reaction mixture is evaporated to dryness. As a result of processing of the residue using flash chromatography on 15 g of silica gel, elwira a mixture of CH2Cl2-acetone (2:1), receive 0,137 g of the target product.

This material is treated with 3 ml of dichloromethane and 3 ml triperoxonane acid for 30 minutes at room temperature. The reaction mixture is evaporated to dryness and triturated with ether to obtain 0.126 g of pale yellow solid.

1H NMR (400 MHz, CD3OD): 7.82 (DD, 1H), 7.42-7.35 (m, 5H). 7.30 - 7.20 (m, 21/2H), 6.75 (d, 1/2H), 5.19 (dt, 1H), 4.60-4.50 (m, 3H), 4.13 (Shir.d, 1H), 3.90-3.68 (m, 4H), 3.25 (t, 1H), 2.90-2.70 (2s, 4H), 1.98 (dt, 1/2H), 1.85-1.65 (m, 31/2H), 1.62 (s, 2H), 1.59 (s, 4H).

Example 38

N-[1(R)-[(1,2-Dihydro-1-[1-methoxycarbonyl-1 - methylaminomethyl-Spiro[3H-indole-3,4'-piperidine-1'-yl) carbonyl]-2-(indol-3-yl)ethyl]-2-amino-2-methylpropanesulfonate

Stage A: 1,2-Dihydro-1-[1-methoxycarbonyl-1-methylaminomethyl]-Spiro[3H - indole-3,4'-piperidine]

It is 5.06 g of 1,2-dihydro-1-benzyloxycarbonyl-Spiro/3H - indole-3,4'-piperidine/hydrochloride in 50 ml of dichloromethane add 3.0 ml of triethylamine and 3.40 g of di-tert-BUTYLCARBAMATE and stirred at room temperature for 3 hours. The reaction mixture is evaporated to dryness and diluted with 100 ml of ether, and promo product in 50 ml of ethanol was added 1 g of 20% palladium hydroxide on coal and hydronaut H2from the container during the night. To 0,506 g of this compound in 15 ml dichloromethane at 0oC add to 0.74 ml of triethylamine and 0.41 ml of carbamidomethylated and stirred for 1 hour. The reaction mixture is diluted with 25 ml of ether and washed with saturated sodium bicarbonate solution (20 ml), dried over magnesium sulfate and concentrated. As a result of processing of the residue using flash chromatography on 25 g of silica gel, elwira a mixture of hexane-ethyl acetate (4:1) as eluent, get to 1.79 g of the target material in the form of a thick oil.

Sodium hydride (is 0.102 g 60% in mineral oil) is washed with hexane, and then suspended in 5 ml of DMF. The solution 0,158 g of the above intermediate compound in 1 ml of DMF is added and stirred for 30 minutes. Add methyliodide (of 1.85 mmol) and stirred for 3 hours. The reaction mixture is poured into 15 ml of a saturated aqueous solution of ameriglide and extracted with ether (2 x 15 ml). The combined organic extracts washed with water (15 ml), brine (15 ml), dried over magnesium sulfate and concentrated to obtain 0,179 g of the target material.

1H NMR (200 MHz, CDCl3): to 7.32 (d, 1H), 7,20-of 6.90 (m, 3H), 4,13 (Shir.d, 2H), 2,83 (Shir.t, 2H), 1.85 to to 1.70 (m, 4H), 1.69 in (s, 6H), to 1.48 (s, 9H).

One hundred of the Dol-3-yl)ethyl]- [[(1,1-dimethylethylene)carbonyl]amino]-2 - methylpropanamide

To a solution of 0,179 g the intermediate from step A was added 1 ml of dichloroethane and 1 ml triperoxonane acid and stirred for 30 minutes. The reaction mixture is evaporated to dryness, alkalinized with 10 ml of 10% aqueous sodium carbonate solution and extracted (2 x 10 ml) of dichloromethane. The combined organic extracts washed with brine (10 ml), dried over potassium carbonate, filtered and concentrated to 0,120 g of piperidine in the form of a thick oil. To a solution of this compound in 5 ml of dichloromethane add 0,132 g of the acid intermediate compound of example 21 (stage), to 0.055 g of HOBT, is 0.102 g EDC, stirred for 18 hours. The reaction mixture is diluted with 25 ml of ether and washed with 15 ml of 0.05 N. HCl, saturated sodium bicarbonate solution (15 ml), dried over magnesium sulfate and concentrated. As a result of processing of the residue using flash chromatography on 20 g of silica gel, elwira a mixture of CH2Cl2-acetone (5:1) get 0,094 g of the target product.

1H NMR (400 MHz, CDCl3): 8.60 (s, 2/3H), 8.50 (s, 1/3H), 7.70 (d, 2/3H), 7.60 (d, 1/3H), 7.35 (d, 2/3H), 7.30 (d, 1/3H), 7.26-7.00 (m, 5H), 6.90 (t, 11/3H), 6.40 (d, 2/3H), 5.28-5.16 (m, 1H), 5.05 (Shir.s, 1H), 4.41 (Shir.d, 2/3H), 4.32 (Shir.d, 1/3H), 3.78-3.65 (m, 2H), 3.56 (s, 2H). 3.55 (s, 1H), 3.50 (Shir.d, 1H), 3.20 (dt, 1H), 3.15 (DDD, 1H), 2.75 (t, 1H), 2.42 (m, 1H), 1.18 (d, 2H), 1.24 (s, 4H), 1.50 (s, 2H), 1.48 latinsolder] -Spiro[3H-indole-3,4'- piperidine]-1'-yl)carbonyl]-2-(indol-3-yl)- ethyl] -2-amino-2-methylpropanesulfonate

The solution 0,094 g of the intermediate product from step C is treated with 1 ml dichloromethane and 1 ml triperoxonane acid for 30 minutes, evaporated to dryness and triturated with ether to obtain 0,082 g of the target product.

1H NMR (400 MHz, CD3OD): 7.70 (d, 2/3H), 7.60 (d, 1/3H), 7.35 (d, 2/3H), 7.30 (d, 1/3H), 7.26-7.00 (m, 5H), 6.90 (t, 11/3H), 6.40 (d, 2/3H), 5.28-5.16 (m, 1H), 5.05 (Shir.s, 1H), 4.41 (Shir.d, 2/3H), 4.32 (Shir.d, 1/3H), 3.78-3.65 (m, 2H), 3.56 (s, 2H), 3.55 (s, 1H), 3.50 (Shir.d, 1H), 3.20 (dt, 1H), 3.15 (DDD, 1H), 2.75 (t, 1H), 2.42 (m, 1H), 1.18 (d, 2H), 1.24 (s, 4H), 1.50 (s, 2H), 1.48 (s, 4H), 1.30-1.18 (m, 1H), 1.10-0.90 (m, 11/3H), 0.03 (dt, 2/3H).

Example 39

N-[1(R)-[(1,2-Dihydro-1-methanesulfonamide[3H - indole-3,4'-piperidine]-1'-yl)carbonyl]-2-(indol-3-yl)ethyl]- 3-amino-3-methylbutyronitrile

Stage A: N-[1(R)-[(1,2-Dihydro-1-methanesulfonamide [3H-indole-3,4'-piperidine]-1'-yl)carbonyl]-2-(indol-3-yl) ethyl/-3-amino-2-methylbutanoic

To a suspension of 1.14 g of 1,2-dihydro-1-methanesulfonamido- /3H-indole-3,4'-piperidine/hydrochloride /obtained according to the method of stage A of example 18/ 50 ml dichloromethane added to 0.80 ml of N-methylmorpholine, and 1.00 g of N-tert-BOC-D-tryptophan, 0,80 g HOBT and 1.20 g of EDC and stirred at room temperature for 18 hours, the reaction mixture is diluted with 100 ml ether and washed with 50 ml of 0.05 N. HCl, 50 ml of a saturated solution of bicarbonate soda is acetate at 0oC is treated with HCl (gas) for 2 minutes, and then stirred for 1 hour, 50 ml of dry ether is added, and the precipitated precipitated solid part is collected by filtration. The output of 1.44 g

To 0,86 g amidohydrolase in 30 ml of dichloromethane type of 0.24 ml of N-methylmorpholine, 0.36 g HOBT, 0.56 g of EDC and stirred over night. The reaction mixture is diluted with 100 ml ether and washed 0,05 N. HCl (50 ml), 50 ml saturated NaHCO3, dried over magnesium sulfate and concentrated. As a result of processing of the residue using flash chromatography on 20 g of silica gel, elwira a mixture of CH2Cl2-acetone (5:1) obtain 0.74 g of the target product.

Through a solution of 0.74 g of the above intermediate product in 5 ml of ethyl acetate at 0oC bubbled dry HCl gas at 0oC for 3 minutes, and stirred for 30 minutes. Add ether to fully plant product. The hard part is filtered off and washed with ether in a nitrogen atmosphere, and dried gain of 0.57 g of the target product.

1H NMR (400 MHz, CD3OD): 7.69 (d, 2/3H), 7.55 (d, 1/3H), 7.37-6.90 (m, 5H), 6.82 (Shir. t, 11/3H), 6.43 (d, 2/3H), 5.31-5.18 (m, 1H), 4.40 (Shir.d, 2/3H), 4.30 (Shir.d, 1/3H), 3.63-3.38 (m, 4H), 3.22-3.05 (m, 2H), 2.83-2.75 (m, 1H), 2.80 (s, 1H), 2.74 (s, 2H), 2.63 (DD, 1H), 2.55-2.43 (m, 2H), 2.20 (Shir. d, 1H), 1.70-1.53 (m, 1H), 1.38 (2H), 1.36 (s, 2H), 1.35 (IIR[3H-indole - 3,4'-piperidine]-1'-yl)carbonyl] -2-(indol-3-yl)ethyl]-[3-[2(R)- 3-hydroxypropyl]-amino]-3-methylbutyronitrile

Stage A: N-[1(R)-[(1,2-Dihydro-1-methanesulfonamido- [3H-indole-3,4'-piperidine]-1'-yl)carbonyl-2- (indol-3-yl)ethyl]-[3-[2(R)-3-dihydroxypropyl]- amino]-3-methylbutyronitrile

To a solution of 0.30 g of compound obtained in stage b of example 39 in 5 ml of methanol is added 1.5 g of anhydrous sodium acetate, of 0.30 g of (R)-1,2-isopropylideneglycerol (Tetrahedron, 1985, 41, 3117) and stirred for 1 hour. Solution in THF of cyanoborohydride sodium (8,7 ml of 1 M solution) is added and the resulting mixture stirred for 18 hours. The reaction mixture was diluted with 20 ml of water and extracted with dichloromethane (3 x 10 ml). The combined organic extracts washed with saturated sodium bicarbonate solution (10 ml), dried over K2CO3and concentrate. As a result of processing of the residue using flash chromatography on 10 g of silica gel, elwira a mixture of CH2Cl2-methanol (98: 2), receive 0,146 g recovery laminirovannogo connection.

1H NMR (400 MHz, CDCl3): 8.70-8.40 (m, 2H), 7.63 (d, 2/3H), 7.55 (d, 1/3H), 7.37 (t, 1H). 7.32 (d, 1/3H), 7.28 (d, 2/3H), 7.20-6.95 (m, 41/3H), 6.52 (d, 2/3H), 5.20-5.08 (m, 1H), 4.55-4.24 (m, 3H), 4.10 (t, 2/3H), 4.05 (t, 1/3H), 3.80-3.70 (m, 1H), 3.70-3.50 (m, 4H), 3.30-3.10 (m, 2H), 2.84 (s, 1H), 2.80 (s, 2H), 2.80-2.70 (m, 2H), 2.68-2.45 (m, 1H), 2.37 (s, 2H), 1.70 (m, 2/3H), 1.52 (Shir. d, 1/3H), 1.44 (s, 2H), 1.43 (s, 1H), 1.35 (s, 2H), 1.33 (s, 1H), 1.25 (s, 3H), 1.33 (the connection is stirred in 3 ml of methanol and 0.10 ml of concentrated hydrochloric acid for 30 minutes. The reaction mixture is evaporated to dryness, and the solid part was washed with ether and dried, resulting in a gain 0,109 g of the target material.

1H NMR (400 MHz, CD3OD): 7.63 (d, 2/3H), 7.55 (d, 1/3H), 7.41 (d, 2/3H), 7.38 (d, 1/3H), 7.32 (d, 1/3H), 7.26 (d, 2/3H), 7.21-7.10 (m, 4H), 7.08-7.00 (m, 21/3H), 6.63 (d, 2/3H), 5.25 (DD, 2/3H), 5.19 (DD, 1/3H), 4.36 (Shir. d, 2/3H), 4.30 (Shir.d, 1/3H), 3.92-3.83 (m, 1H), 3.80-3.50 (m, 6H), 3.28-3.10 (m, 3H), 3.05-2.95 (m, 2H), 2.90 (s, 1H), 2.86 (s, 2H), 2.78-2.55 (m, 4H), 1.83-1.65 (m, 1H), 1.43 (s, 2H), 1.39 (s, 2H), 1.37 (s, 1H), 1.32 (s, 1H), 1.36-1.20 (m, 1H), 0.04-0.18 (m, 22/3H), -0.08 (dt, 2/3H).

Example 41

N-[1(R)-[(1,2-Dihydro-1-methanesulfonamide[3H-indole-3,4'- piperidine]-1'-yl)carbonyl] -2-(indol-3-yl)ethyl] - [3-[2(R)-hydroxypropyl]amino]-3-methylbutyronitrile

Stage A: N-[1(R)-[(1,2-Dihydro-1-methanesulfonamido- [3H-indole-3,4'-piperidine] -1'-yl)carbonyl] -2-(indol-3-yl)ethyl] -[3-[2- (R)-hydroxypropyl] amino-3-methylbutyronitrile

To 0.26 g of the intermediate from step B of example 39 add 5 ml of dry methanol, 1.5 g of anhydrous sodium acetate, freshly prepared 0.10 g 2(R)-(tetrahydropyranyl)- oxopropanenitrile, and mix all at room temperature for 1 hour. Solution in THF of cyanoborohydride sodium (8,5 ml of 1 M solution) is added, and everything is stirred for 18 hours. The reaction mixture was diluted with 10 ml nasyshenostyu washed with brine (10 ml), dried over K2CO3and concentrate. As a result of processing of the residue using flash chromatography on 10 g of silica gel, elwira a mixture of CH2Cl2-methanol (98:2), receive 0,219 g of the target product.

The above material is stirred in 3 ml of dry methanol with 0.10 ml of concentrated hydrochloric acid, evaporated to dryness and the residue triturated with ether to obtain 0,174 g specified in the title compounds as pale yellow foam.

1H NMR (400 MHz, CD3OD): 7.63 (d, 2/3H), 7.55 (d, 1/3H), 7.41 (d, 2/3H), 7.38 (d, 1/3H), 7.32 (d, 1/3H), 7.26 (d, 2/3H), 7.21-7.10 (m, 4H), 7.08-7.00 (m, 21/3H), 6.63 (d, 2/3H), 5.25 (DD, 2/3H), 5.19 (DD, 1/3H), 4.36 (Shir. d, 2/3H), 4.30 (Shir.d, 1/3H), 3.92-3.83 (m, 1H), 3.80-3.50 (m, 4H), 3.28-3.10 (m, 3H), 3.05-2.95 (m, 2H), 2.90 (s, 1H), 2.86 (s, 2H), 2.78-2.55 (m, 4H), 1.83-1.65 (m, 1H), 1.43 (s, 2H), 1.39 (s, 2H), 1.37 (s, 1H), 1.32 (s, 1H), 1.36-1.20 (m, 1H), 1.28 (d, 3H), 0.04-0.18 (m, 22/3H), -0.08 (dt, 2/3H).

Example 42

N-[1(R)-[[3-ecotopia[isobenzofuran-1(3H), 4'-piperidine] -1' -yl]carbonyl]-2-(phenylmethoxy)ethyl]-2-amino-2 - methylpropanesulfonate

Stage A:

To 0,165 g of the acid intermediate compounds obtained by the method steps In example 19, in 10 ml of CH2Cl2add 0,095 g 3 oxaspiro/isobenzofuran-1(3H),4'-piperidine/, 0,067 g HOBT and 0,110 g EDC and all was stirred at room temperature in technosystem solution of sodium bicarbonate (5 ml), dried over magnesium sulfate and concentrated. As a result of processing of the residue using flash chromatography on 10 g of silica gel, elwira a mixture of hexane-acetone (3:1), receive 0,234 g of the product.

To a solution of 0,024 g of the above intermediate compound in 1 ml of CH2Cl2add 1.0 ml triperoxonane acid and incubated at room temperature for 30 minutes. Volatiles are evaporated and the residue triturated with ether to obtain 21 mg specified in the title compound in the form of a solid substance.

1H NMR (400 MHz, CD3OD): 7.85 (d, 1/2H), 7.80 (d, 1/2H), 7.63 (t, 1/2H), 7.54-7.40 (m, 21/2H), 7.35-7.20 (m, 51/2H), 7.06 (d, 1H), 6.58 (d, 1/2H), 5.25-5.15 (m, 1H), 4.93 (s, 1H), 4.69 (Shir.s, 1H), 4.55-4.40 (m, 2H) 4.14 (Shir. d, 1H), 3.70-3.40 (m, 2H), 3.18-3.10 (m, 1H), 2.13 (dt, 1H), 2.90-2.75 (m, 2H), 2.70-2.50 (m, 2H), 1.47 (s, 1.5 H), 1.46 (s, 1.5 H), 1.44 (s, 1.5 H), 1.43 (s, 1.5 H).

Example 43

N-[1(R)-[1,2-Dihydro-1-methanesulfonamide[3H - indole-3,4'-piperidine] -1'-yl)carbonyl]-4-phenylbutyl]-2 - amino-2-methylpropanesulphonic

Stage A: N-[1(R)-[1,2-Dihydro-1-methanesulfonamide[3H-indole-3,4'- piperidine] -1'-yl)carbonyl] -4 - phenylbutyl]-2-amino-2-methylpropanesulphonic

This compound is obtained from 2(R)-N-tert.-butoxycarbonyl - 5-phenylpentane acid and 1,2-dihydro-1-methanesulfonamido/3H-indole-3,4'-piperidine/g the s atoms, calculated for C28H38N4O4S: MB = 526,2; found: m/e = (M+1) RUR 527.9.

Example 44

N-[1(R)-[1,2-Dihydro-1-methanesulfonamide[3H-indole - 3,4'-piperidine] -1'-yl)carbonyl] -2-feniletilic)ethyl] - 2-amino-2-methylpropanesulfonate

Stage A: N-[1(R)-[1,2-Dihydro-1-methanesulfonamide [3H-indole-3,4'-piperidine] -1'-yl)carbonyl] -2 - feniletilic)ethyl]-2-amino-2-methyl - propanesulfonate

This compound is obtained from commercially available N-tert-BOC-S-benzyl-D-cysteine and 1,2-dihydro-1-methanesulfonamido/3H-indole-3,4' -piperidine/hydrochloride using the method of obtaining the compound of example 18.

Mass spectrum by fast atom bombardment calculated for C27H36N4O4S2: MB = 544,7; found: m/e = (M+1) 548,5.

Example 45

N-[1(R, S)-[1,2-Dihydro-1-methanesulfonamide[3H - indole-3,4'-piperidine] -1'-yl)carbonyl] -2-(2'-peridomicile) ethyl] -2-amino-2-methylpropanesulfonate

Stage A: N-[1(R,S)-[1,2-Dihydro-1-methanesulfonamide [3H-indole-3,4'-piperidine] -1'-yl)carbonyl] -2-hydroxy her carbamino acid 1,1-dimethylethylene ester

To a solution of N-tert-BOC-(D)-serine (56 mg, 274 mmol) in 2.5 ml THF at room temperature add 1,2-dihydro-1-methanesulfonamido/3H-indol-3,, ,33 mmol), and EDC (63 mg, 0.33 mmol). After 3 hours the mixture is diluted with ethyl acetate and then washed successively with water and brine. The organic layer is dried over sodium sulfate, filtered and concentrated. The residue is purified using SCH (silica gel, 100% ethyl acetate) to obtain 112 mg (90%) specified in the title compound.

Stage b: N-[1(R,S)-[1,2-Dihydro-1-methanesulfonamide[3H-indole-3,4' -piperidine] -1'-yl)carbonyl]-2-(2'-peridomicile) ethyl]carbamino acid 1,1-dimethyl ester

To nestorgames oil to sodium hydride (obtained from 60% oil dispersion of sodium hydride by washing with hexane (3 x), 9 mg, 0.21 mmol) in 0.3 ml of THF is added 2-picolylamine (16 mg, 0.1 mmol) in 0.3 ml of DMF. After 5 minutes add the intermediate compound obtained in stage A (45 mg, 0.1 mmol) and the reaction mixture was stirred at room temperature for 2 hours and then diluted with ether. The ether layer is washed with water 5 times, brine and dried over sodium sulfate. After purification (preparative TCX, silica gel, 100% ethyl acetate) was isolated 16 mg specified in the title compounds (29).

1H NMR (400 MHz, CDCl3, mixture of rotamers): 8,53 (m, 1H), to 7.77-6,83 (m, 7H); of 5.75 (m, 1/3H), to 4.98 (m, 2H), 4,67 (m, 2 1/2H), 4,25 (m, 1/2H), 4,10 (m, 1/2H), 3,91-methanesulfonamido[3H-indole-3,4' -piperidine] -1'-yl)carbonyl] - 2-(2'-peridomicile)ethyl]-2-amino-2-methylpropanesulfonate

A solution of the intermediate obtained in stage (16 mg, 0,029 mmol) in 0.5 ml triperoxonane acid is stirred at room temperature for 1/2 hour, and then concentrated. To a solution of this residue in 1 ml of chloroform added tert-butyloxycarbonyl- -methylalanine (6.5 mg, to 0.032 mmol), HOBT (4.3 mg, to 0.032 mmol), triethylamine (10 ml, 0,064 mmol) and EDC (6 mg, to 0.032 mmol). After 12 hours at room temperature the mixture is diluted with methylene chloride and then washed with water and brine. The organic layer is dried over sodium sulfate, filtered and concentrated. The residue is purified using preparative TCX/ silica gel, 100% ethyl acetate. The purified compound concentrate. To the residue add triperoxonane acid at room temperature. After 1 hour the mixture concentrated to obtain the title compound (5.3 mg).

1H NMR (400 MHz, CO3OD, mixture of rotamers): 8.70 (Shir.s, 1H), 8.30 (m, 1H), 7.84 (m, 1H), 7.77 (m, 1H), 7.36 (m, 1H), 7.24 (m, 11/2H), 7.06 (m, 1 1/2H), 5.24 (t, 6 Hz, 1H), 4.86 (m, 2H), 4.56 (d, 13 Hz, 1H), 4.08 (m, 1H), 3.95 (m, 4H), 3.36 (m, 1H), 2.97 (s, 3/2H), 2.96 (s, 3/2H), 2.01-1.78 (m, 4H), 1.63 (s, 3/2H), 1.61 (s, 3/2H), 1.59 (s, 3/2H), 1.58 (s, 3/2H).

Example 46

N-[1(R, S)-[1,2-Dihydro-1-R>
Stage A: N-[1(R,S)-[1,2-Dihydro-1-methanesulfonamide[3H-indole-3,4' -piperine] -1 yl)carbonyl] -2-(2'-peridotite)ethyl] carbamino acid 1,1-dimethylethylene ether

To nestorgames oil to sodium hydride (600 mg, 7.5 mmol) in suspension in 20 ml of DMF is added N-tert - BOC-D-cysteine (1.2 g, 5.4 mmol) in 20 ml of DMF at -10oC. the resulting mixture was heated to room temperature and stirred for further one hour. To the reaction mixture add a solution of 2-bromopyridine (0,514 ml, 5.4 mmol) in 10 ml of DMF. After heating for 20 hours at 80oC to the reaction mixture are added CuI (1,03 g, 5.4 mmol) and stirred at the same temperature for another 20 hours. The resulting mixture was cooled to room temperature and poured into a 0.5 N. hydrochloric acid, extracted with ether. The ether layer is filtered through celite, dried over sodium sulfate and concentrated. The residue is purified using SCH (silica gel, methylene chloride/methanol = 10/1). To a purified compound (170 mg, or 0.57 mmol) in methylene chloride added 1,2-dihydro-1 - methanesulfonamido/3H-indole-3,4'-piperidine/-hydrochloride (obtained in stage A of example 18, 172 mg, or 0.57 mmol), triethylamine (95 ml of 0.68 mmol), HOBT (92 mg, of 0.68 mmol) and EDC (130 mg, of 0.68 mmol) and carry out the reaction according to the method of example 45 stage A to obtain ukazannogo]-1'-yl)-carbonyl]-2-(2'-pyridine)ethyl]-2-amino-2 - methylpropanesulfonate

Receive from the intermediate obtained in stage A (290 mg, of 0.53 mmol) due to the removal of protection with TFA. The result is indicated in the title compound (102 mg).

1H NMR (400 MHz, CD3OD, mixture of rotamers): to 8.45 (DD, 5,1 Hz, 1H), to 7.61 (m, 1H), 7,39-7,05 (m, 6H), 5,27 (m, 1H), to 4.52 (t, 12 Hz, 2H), 4,01 (m, 3H), 3,80 (m, 1H), of 3.45 (m, 1H), 2,89 (c, 3H), 2,90 (m, 1H), 2,10-to 1.79 (m, 4H), 1,63 (c, 3/2H), 1,60 (s, 3/2H), 1,59 (s, 3/2H), 1,58 (s, 3/2H).

Mass spectrum by fast atom bombardment: 532,7 (M+1).

Example 47

N-[1(R, S)-[1,2-Dihydro-1-methanesulfonamide[3H - indole-3,4'-piperidine] -1'-yl)carbonyl] -2-(cyclohexylthio)- ethyl] -2-amino-2-methylpropanesulfonate

Stage A: N-tert-BOC-cyclohexylidene

To a solution of cyclohexylaniline (1 ml, 8,18 mmol) and methyl-2-acetamidoacrylate (1.29 g, 9 mmol) in THF added a catalytic amount of sodium hydride at room temperature. After 7 days the reaction mixture was concentrated. A solution of the residue in 20 ml of 6 N. hydrochloric acid is refluxed for 4 hours to room temperature. The resulting solution was left to stand for 12 hours and filtered. The hard part is dried in vacuum. To a mixture of this salt of hydrochloric acid in 1 N. the solution of sodium hydroxide (15 ml) is added di-tert-bodily acid and extracted with ethyl acetate. The organic layer is washed with water, brine and dried over sodium sulfate. After filtration and concentration specified in the title compound allocate exit 92% (2,23 g).

Stage b: N-[1(R,S)-[1,2-Dihydro-1-methanesulfonamide[3H-indole-3,4'-piperidine] -1'-yl) carbonyl-2-(cyclohexylthio)ethyl] carbamino acid 1,1-dimethylethylene ester

Receive from the intermediate from step A (303 mg, 1.0 mmol) according to the method of example 45 (stage A) to obtain the title compound (420 mg, yield 76%).

Stage C: N-[1(R,S)-[1,2-Dihydro-1-methanesulfonamide [3H-indole-3,4'-piperidine] -1'-yl)carbonyl] - 2-(cyclohexylthio)ethyl]-2-[[1,1-dimethylethylene)carbonyl]amino]- 2-methylpropanamide

A solution of the intermediate obtained in stage (420 mg, from 0.76 mmol) in 5 ml triperoxonane acid is stirred at room temperature for 1/2 hour, and then concentrated and dried. To a solution of this residue in 10 ml of chloroform added tert-butyloxycarbonyl- -methylalanine (170 mg, 0.84 mmol), HOBT (113 mg, 0.84 mmol), triethylamine (116 ml, 0.84 mmol) and EDC (160 mg, 0.84 mmol). After 2 hours at room temperature the mixture is diluted with methylene chloride and washed with water and brine. The organic layer is dried on the = 1:1) to obtain the title compound (430 mg, 89%).

Stage D: N-[1(R,S)-[1,2-Dihydro-1-methanesulfonamide[3H-indole-3,4'-piperidine] -1'-yl) carbonyl]-2-(cyclohexylthio) ethyl]-2-amino-2-methylpropanesulfonate

A solution of the intermediate obtained in stage C (35 mg, by 0.055 mmol) in 0.5 ml triperoxonane acid is stirred at room temperature for half an hour, and then concentrated to obtain the title compound (33 mg).

1H NMR (400 MHz, CD3OD, mixture of rotamers): 7.38 (d, 8 Hz, 1H), 7.25-7.17 (m, 2H), 7.06 (m, 1H), 5.02 (m, 1H), 4.52 (m, 1H), 4.11 (m, 1H), 3.97 (m, 2H), 3.39 (m, 1H), 3.02 (m, 1H), 2.98 (s, 3H), 2.90-2.71 (m, 3H), 2.05-1.74 (m, 9H), 1.62 (s, 3/2H), 1.61 (s, 3/2H), 1.60 (s, 3/2H), 1.57 (s, 3/2H), 1.32 (m, 5H). FAB-MS: 537.9 (M+1).

Example 48

N-[1(R, S)-[1,2-Dihydro-1-methanesulfonamide[3H - indole-3,4'-piperidine] -1'-yl)carbonyl] -2- (cyclohexylmethyl)ethyl]-2-amino-2-methylpropanesulphonic

To a solution of the intermediate obtained in stage C of example 47 (35 mg, by 0.055 mmol) in 1 ml of methanol add periodate sodium in 1 ml of water at room temperature. After a couple of hours, the reaction mixture was diluted with ethyl acetate and washed with aqueous solution of sodium sulfite.

The organic layer is dried over sodium sulfate, filtered and concentrated. Remove protection from the remainder of the by preparative TCX (silica gel, methylene chloride/metaanalytical ammonia = 10/1/0,1). The purified product again acidified with HCl in ether to obtain the title compound (21 mg).

1H NMR (400 MHz, CD3OD, mixture of diastereoisomers and rotamers): 7,38? 7.04 baby mortality (m, 4H), 5,43 (m, 1H), 4,50 (m, 1H), of 4.05 (m, 1H), 3.96 points (m, 2H), 3,38 (m, 1H), 3,13 (m, 1H), 2,98 (s, 3H), 2,90-a 2.71 (m, 3H), 2.05 is-of 1.74 (m, 9H), of 1.62 (m, 6H), 1,51-1,32 (m, 5H).

Mass spectrum by fast atom bombardment: 553,9 (M+1).

Example 49

N-[1(R, S)-[1,2-Dihydro-1-methanesulfonamide[3H - indole-3,4'-piperidine] -1'-yl)carbonyl] -2-(cyclohexylcarbonyl) ethyl]-2-amino-2-methylpropanesulphonic

To a solution of the intermediate obtained in stage C of example 47 (35 mg, by 0.055 mmol) in 1 ml of methanol added OXONE in 1 ml of water at room temperature. After a couple of hours, the reaction mixture was diluted with ethyl acetate and washed with aqueous solution of sodium sulfite. The organic layer is dried over sodium sulfate, filtered and concentrated. To the residue add triperoxonane acid according to the method of stage D of example 47 to obtain the crude product, which was purified using preparative TCX (silica gel, methylene chloride/methanol/ammonium hydroxide = 10/1/0,1). The purified product again acidified with HCl in ether to obtain specified in sagm, 1H), 5.53 (m, 1H), 4.51 (m, 1H), 4.11 (m, 1H), 3.95 (m, 2H), 3.49 (m, 2H), 3.38 (m, 1H), 3.10 (m, 1H), 2.98 (s, 3/2H), 2.97 (s, 3/2H), 2.91 (m, 1H), 2.20-1.74 (m, 9H), 1.62 (s, 3/2H), 1.61 (s, 3/2H), 1.58 (s, 3/2H), 1.57 (s, 3/2H), 1.51-1.32 (m, 5H). FAB-MS: 569.9 (M+1).

Mass spectrum by fast atom bombardment: 569,9 (M+1).

Example 50

N-[(R)-[Spiro[benzo[b] thiophene-3(2H)-4'-piperidine] - 1'-yl]carbonyl-2-indol-3-yl)ethyl-2-amino-2-methylpropanesulphonic

Stage A: 1-/(1,1-Dimethylethoxysilane/-3-hydroxy 4-methylene-1,2,5,6-tetrahydropyridine

To a suspension/solution of methyltriphenylphosphonium (30 g, 74 mmol) in 150 ml of THF is added slowly utility (2,5 N., of 25.5 ml of 63.7 mmol) at 0oC. After stirring for one hour at room temperature to the reaction mixture is added slowly at room temperature

N-tert-BOC-protected 4-piperidone obtained from 4 - piperidinemethanol (according to the method described in Protective Groups in Organic Synthesis, T. W. Greene, John Wiley and Sons, NY, 1981) in 50 ml of THF. This reaction mixture is stirred for 2 hours and filtered. The obtained filtrate is concentrated and purified (SJH, silica gel, hexane/ethyl acetate = 10/1) to obtain the product of the Wittig (7.9 g, yield 82%).

To a suspension of selenium dioxide/silica gel /obtained by the method described in Chem. Lett. 1981, 1703/ in 30 ml of metranil is milenaria. The cloudy solution is stirred with water, brine and dried over sodium sulfate. The organic layer is concentrated and purified using flash chromatography (hexane/ethyl acetate = 4/1) to obtain the title compound with a 52% yield (0,41 g).

Stage b: 1-/(1,1-Dimethylmethoxy)carbonyl/-4-chloromethyl - 1,2,5,6-tetrahydropyridine

The intermediate compound from step A (400 mg, 1.88 mmol) dissolved in 10 ml of benzene and thionyl chloride (165 ml of 2.26 mmol) is added and heated to 60oC for 25 minutes. The resulting mixture was poured into NaHCO3(aq.) and extracted with ether. The ether layer is dried over magnesium sulfate and concentrate to obtain the title compound (333 mg, 77%).

Stage C: 1-/1,1-Dimethylmethoxy)carbonyl/-4-//(2-bromophenyl) thio/methyl-1,2,5,6-tetrahydropyridine

The intermediate compound obtained in stage (330 mg, 1,43 mmol), dissolved in 10 ml of acetone and 2-bromothiophene (172 ml of 1.43 mmol), and potassium carbonate (390 mg, of 2.86 mmol) is added. The reaction mixture is heated to 60oC for one hour, and then filtered through silica gel (100% ether). The organic layer is concentrated and purified using flash chromatography (silica gel, hexane/ethyl acetate = 10/1) to obtain specified in the title link
The intermediate compound obtained in stage C (450 mg, at 1.17 mmol), dissolved in 60 ml of benzene and added AIBN (10 ml) and anti-hydride (644 ml, 2,39 mmol). The resulting mixture was refluxed for 2 hours and concentrated. The residue is dissolved in ether and add bromine to until the reaction solution does not acquire a brownish color. To this brown solution at room temperature add DBU (650 ml) dropwise. The obtained turbid solution is filtered through silica gel and washed with ether. The ethereal solution is concentrated and the residue purified using radial chromatography (silica gel, hexane/ethyl acetate = 10/1) to obtain the title compound (157 mg, yield 43%).

Stage E: N-/1(1R)-/Spiro/benzo[b] thiophene-3(2H) -, y'- piperidine/-1'-yl)carbonyl/-2-(indol-3-yl)- ethyl/-2-amino-2-methylpropanesulphonic

A solution of the intermediate obtained in stage D (50 mg, 0,164 mmol) in 0.5 ml of TFA was stirred at room temperature for half an hour, and then concentrated. The residue is diluted with chloroform and washed with NaHCO3(aq.). The organic layer is dried over sodium sulfate, filter and concentrate to obtain the free amine (32 mg) in 95%. To a solution of svobodnogo,2 mg, 0,0246 mmol), HOBT (4.0 mg, 0,0295 mmol) and EDC (5.6 mg, 0,0295 mmol) at room temperature. After 12 hours the reaction mixture was poured into water and extracted with chloroform. Chloroformate layer is dried over sodium sulfate, filtered and concentrated. The residue is purified using preparative TCX (silica gel, hexane/ethyl acetate = 3/1) to obtain a colorless foam (13 mg, 94%). Specified in the title compound obtained as a colorless foam according to the method of stage C of example 18.

1H NMR (400 MHz, CD3OD, mixture of rotamers): 7.62 (d, 8 Hz, 2/3H), 7.54 (d, 8 Hz, 1/3H), 7,39 (d, 8 Hz, 2/3H), 7.35 (d, 8 Hz, 1/3H), 7.19-7.00 (m, 6 1/3H), 2.62 (m, 1H), 1.72-1.65 (m, 2 1/3H), 1.61 (s, 4H), 1.50 (s, 2H), 0.94 (m, 1H), 0.10 (m, 2/3H).

Mass spectrum by fast atom bombardment 477 (M+1).

Example 51

Stage A: 1',2 Dimethylimino/isoindoline-1-one-3,4'-piperidine/

To a stirred solution of 2-methylisoquinoline-1-it (1.47 g, 10 mmol, available from Aldrich Chem. Co. and mechanicalengineering (2.9 g, 15 mmol) in 50 ml DMF atoC in argon atmosphere slowly add potassium hydride (35% in mineral oil, 4.5 g, 40 mmol). Then the reaction mixture is slowly warmed to room temperature and stirred for further 3 hours. According to TCX (60 ethyl acetate in hexane), the reaction is finished. The resulting mixture was slowly pouring the sodium and evaporated. The residue is purified using flash chromatography elwira gradient solvent of 5-10% methanol in dichloromethane to obtain 1,17 g of the product.

1H NMR (400 MHz, CDCl3): 7.85 (DD, J = 1.5 Hz, 6.5 Hz, 1H), 7.81 (d, J = 7.1 Hz, 1H), 7.50-7.40 (m, 2H), 3.03 (s, 3H), 2.95-2.90 (m, 2H), 2.71 (dt, J = 2.6 Hz, 11.4 Hz, 2H) 2.46 (s, 3H), 2.31 (dt, J = 4.7 Hz, 13 Hz, 2H), 1.44 (DD, J = 1.6 Hz, 13 Hz, 2H).

Mass spectrum by fast atom bombardment calculated for C14H18N2O: 230; found: 231 (M+H).

Stage B: 2-Methylspiro/isoindoline-1-one-3,4'-piperidine/

Procedure demetilirovania carried out by Tidwell and Buchwald, J. Org. Chem. 1992, 57, 6380-6382.

To a stirred solution of the product from step A (1.0 g, 4.35 mmol) in 1,2 dichloromethane (10 ml) at 0oC add 1-chlorethane high (0.56 ml, 5.2 mmol) and the resulting mixture is stirred for 20 minutes. Add 10 ml of methanol, and the resulting mixture is refluxed for one hour. After evaporation and purification using flash chromatography, elwira 10-20% NH4OH-MeOH (1:10) in chloroform, get to 0.63 g of product.

1H NMR (400 MHz, CD3OD): 8.02 (d, J = 8 Hz, 1H), 7.85 (d, J = 8 Hz, 1H), 7.70 (t, J = 8 Hz, 1H), 7.60 (t, J = 8 Hz, 1H), 3.75-3.60 (m, 4H), 3.10 (s, 3H), 2.60-2.51 (m, 2H), 1.72 (Shir.d, J = 14 Hz, 2H).

Mass spectrum E1, calculated for C13/-1'-carboxylic acid 1,1-dimethylethylene ester

To a stirred solution of 2-methylisoquinoline-1-it (100 mg) in 2 ml of DMF is added an excess of KH in mineral oil (oC in argon atmosphere. After 5 minutes add bis/2-bromacil/tert.-BUTYLCARBAMATE (300 mg), and the resulting mixture was stirred at room temperature for 1 hour, and heated at 80oC during the night. The resulting mixture was poured on ice and extracted with ethyl acetate. The organic extracts are dried (Na2SO4) and evaporated. The residue is purified using preparative TCX, elwira 60% ethyl acetate in hexane to obtain 16 mg of product.

1H NMR (400 MHz, CDCl3): 7.89 (DD, J = 1.3 Hz, 5.8 Hz, 1H), 7.75 (d, J = 6.5 Hz, 1H), 7.54-7.40 (m, 2H), 4.35-4.10 (Shir.m, 2H), 3.02 (s, 3H), 2.14 (dt, J = 5.3 Hz, 13 Hz, 2H), 1.49 (s, 9H), 1.46-1.40 (m, 2H).

Mass spectrum by fast atom bombardment calculated for C18H24N3O3316; found 317 (M+H, 100%).

Stage D:; 2 Methylspiro/isoindoline-1-one-3,4'-piperidine/

The intermediate compound from step C (16 mg) is treated with concentrated HCl and MeOH at room temperature for 2 hours and evaporated to obtain the target product. All spectral data correspond to stage Century.

Stage E: N-/1(R)-/(2-Methylspiro/isoindoline-1-one-3,4'- piperidine/-1'what do have in accordance with the standard method combination of peptides from (R)-//2-//(1,1-dimethylmethoxy) carbonyl/-amino/-2,2-dimethyl-1-oxoethyl/amino/-1H - indole-3-propanoic acid (25 mg) and the product from step Century.

1H NMR (400 MHz, CDCl3): 8.58, 8.44 (sir.s, 1H), 7.80-7.15, 6.44 (m, d, J = 7.6 Hz, all 10H), 5.43-5.36, 5.22-5.15, (2m, 1H), 4.98 (Shir.s, 1H), 4.60-4.50 (Shir. m, 1H), 3.64-3.50 (Shir.m, 1H), 3.40-3.05, 2.72-2.64, (2m, 4H), 2.88, 2.51 (2s, 3H), 2.00-1.90 (m, 2H), 1.52, 1.51 (2s, 3H), 1.49 (s, 3H), 1.45, 1.44 (2s, 9H), 1.40-0.40 (several.m, 2H).

Mass spectrum by fast atom bombardment calculated for C33H41N5O5587; found: 588 (M+H), 532, 488.

Stage F: N-/1(R)-/(2-Methylspiro/isoindoline-1-one - 3,4'-piperidine/-1'-yl)carbonyl/-2-(indol-3-yl)- ethyl/-2-amino-2-methylpropanesulphonic

Specified in the title compound gain, using HCl in ethyl acetate, the product from step E.

1H NMR (400 MHz, CD3OD): 7.84-6.89 (m, 9H), 5.30, 5.15 (DD, 1H), 4.50-4.40 (m, 1H), 3.85-3.77 (m, 1H), 3.65-3.50 (m), 3.40-3.15 (m), 2.95, 2.58 (2s, 3H), 2.95-2.85 (m), 2.55-2.47 (m), 2.22-2.15 (m), 2.09-2.00 (m), 1.65, 1.64, 1.60 (3C, 6H), 1.50-1.20 (m), 1.15-1.05 (m), 0.9-0.8 (m), 0.61-0.52 (m).

Mass spectrum by fast atom bombardment calculated for C28H33N5O3471, found 472 (M+H).

Example 52

N-/1(R)-//1-/////6-///4-Azido-2-hydroxy-5-iodophenyl/ carbonyl/amino/hexyl/amino/carbonyl/methyl/sulfanil/- 2,3-dihydrospiro/3H-indole-3,4'-piperidine/-1'-yl/carbonyl/- 2-(phenylmethoxy)ethyl/-2-amino-2-methylpropanesulphonic

To a solution of commercial ostoperosistramadol and 0.10 ml of base Haninge and stirred for 4 hours. The reaction mixture is evaporated to dryness and process chromatography on 15 g of silica gel. In the elution mixture hexane-ethyl acetate (2:1) receive 0,229 acylated product. To 29 mg indicated earlier material add 2 ml THF and 2 ml of 0.01 M aqueous sodium hydroxide, 25 mg of potassium iodide. Add chloramine-T (15 mg) and stirred for 30 minutes. The reaction is quenched with 2 ml saturated solution of sodium thiosulfate, diluted with 5 ml of 0.05 N. HCl and extracted with ethyl acetate (2 x 5 ml). The combined organic extracts washed with brine (5 ml), dried over magnesium sulfate and concentrated. As a result of processing of the residue using flash chromatography (5 g silica gel), elwira a mixture hexameter (3:1) to obtain 26 mg iodized material. Remove protection N-tert-BOC exercise 4 M HCl in ethyl acetate to obtain 21,4 mg hydrochloride.

To a solution of this material in 5 ml of CH2Cl2add 49 mg of the acid intermediate from step A of example 33, 0,016 ml of NMM, and 19.8 mg of HOBT and 29 mg of EDC and stirred for 18 hours. The reaction mixture was treated and purified in the usual way.

Repeated removal of protection N-tert-BOC group is carried out at the expense of 4 M HCl in ethyl acetate. Get listed in the title SUB>3
and extracted with CH2Cl2(2 x 3 ml). The combined organic extracts dried over sodium sulfate and concentrate to obtain the title compound.

1H NMR (400 MHz, CDCl3): 8.40-8.20 (m, 1H), 7.95 (s, 2/3H), 7.90 (s, 1/3H), 7.40 - 6.90 (m, 91/3H), 6.70 (s, 2/3H), 6.55 (m, 1H), 5.20-5.10 (m, 1H), 4.70-4.40 (m, 4H), 4.10-3.80 (m, 5H), 3.80-3.50 (m, 4H), 3.40-3.10 (m, 4H), 3.10-3.00 (m, 1H), 2.70 (dt, 1H), 1.90-1.20 (m, 14H), 1.30 (s, 6H).

Example 53

N/1(S)-/(1,2-Dihydro-1-methylsulfonylamino/3H - indole-3,4'-piperidine/-1'-yl)carbonyl/-2-(phenylmethylsulfonyl) ethyl/-2-amino-2-methylpropanesulphonic

Stage A: N-/1(S)-/(1,2-Dihydro-1-methylsulfonylamino/3H-indole-3,4'- piperidine/-1'-yl)carbonyl/-2- (phenylmethyl)sulfonyl)ethyl/-2-amino-2-methyl-propanamide

Sample N/1(S)-/(1,2-Dihydro-1-methylsulfonylamino/- 3H-indole-3,4'-piperidine/-1'-yl)carbonyl/-2-(feniletilic)- ethyl/-2-//1,1-dimethylethylene)carbonyl/amino/-2-methylpropanamide (example 44, step C), 72 mg, dissolved in 0.5 ml of methanol and cooled in an ice bath. To this is added dropwise with stirring a solution of 101 mg of OXONE (TM) in 0.5 ml of water. Over the course of the reaction for several hours following according to TCX on plates of silica gel CF, showing a mixture of 2:1 EtOAc:hexane; see the rise of two more polar spots over time as resut almost to dryness in a nitrogen atmosphere, and the residue is extracted with chloroform, dried over magnesium sulfate, the extract is treated using a preparative TCX on the CF plate of silica gel (10 x 10 cm x 1,00 μm), showing EtOAc:hexane; there are two bands. The less polar component was dissolved in 0.5 ml of anisole, cooled in an ice bath and treated with 0.5 ml of TFA. The reaction is stopped and the reaction mixture is removed from the bath. After 30 minutes the main part of the TFA is removed under reduced pressure, and the major part of the remaining anisole is evaporated in a stream of nitrogen. The residue is placed in chloroform and shaken with 1 M K2HPO4to which is added sufficient NaOH to create a pH over 9. Then the chloroform was removed and the aqueous phase is extracted several times with chloroform, the combined organic extracts are dried over magnesium sulfate and concentrated under reduced pressure until the resin. As a result of processing using preparative TCX on a plate of silica gel GF of 0.5:5:95 conc. NH4:MEOH:CHCl3get listed in the title compound in the form of a free base, calculated for C27H36N4O6S2: MB 576,7, found: m/e = (M+1) 577,5.

Stage b: N-/1(S)-/(1,2-Dihydro-1-methylsulfonylamino/ 3H-indole-3,4'-piperidine/-1'-yl)carbonyl/- 2-(phenylmethylsulfonyl)AUA previously described standard procedures and get listed in the title compound.

Example 54

Getting two N-/1(S)-/(1,2-dihydro-1-methylsulfonylamino/ 3H-indole-3,4'-piperidine/-1'-yl)carbonyl/-2-(phenylmethylsulfonyl)ethyl/-2 - amino-2-methylpropanesulphonic

Stage A: N-/1(S)-/(1,2-Dihydro-1-methylsulfonylamino/ 3H-indole-3,4'-piperidine/-1'-yl)carbonyl/-2- (phenylmethylsulfonyl)ethyl/-2-amino-2-methylpropanamide

Exposing the more polar band from the stage A of example 53 uninstalling protection TFA /anisole, followed by processing using preparative TCX, there are two bands corresponding to the two expected diastereoisomerism the sulfoxidov. For the less polar diastereoisomer: calculated for C27H36N4O5S2: MB 560,7, found m/e = (M+1) 561,7.

For more polar diastereoisomer calculated for C27H36N4O5S2: MB= 560,7; found m/e = (M+1) 561,7.

Stage b: N-/1(S)-/(1,2-Dihydro-1-methylsulfonylamino/ 3H-indole-3,4'-piperidine/-1'-yl)carbonyl/- 2-(phenylmethylsulfonyl)ethyl/-2-amino-2-methylpropanesulphonic

Specified in the title compound, receive, replacing the compound obtained in stage A of example 53 and on stage In example 53, on any connection that was previously allocated to starrmatica)- ethyl/-2-amino-2-methylpropanamide

This connection receive, treating the free base of stages C of example 18 methanesulfonic acid. Specified in the title compound are due to recrystallization him from a mixture of ethyl acetate-ethanol-water. So melting point 166-168oC.

Example 56

2,3,3 a,4,6,6 a-Hexahydro-2-oxo-1H-thieno[3,4-b]imidazole - 4(S)-pentane acid-6-/////1'-//(29R)-//2-amino - 2-methyl-1-oxopropyl/-amino/-3-(phenylmethoxy)-1-oxopropyl/- 2,3-dihydrospiro/3H-indole-3,4'-piperidine/-1'-yl/ sulfanil/methyl/carbonyl/amino/hexyl ether complex triptorelin

The solution to 0.108 g of the intermediate compound obtained in example 33 in stage A, in 5 ml of CH2Cl2add 20 mg of 6-aminohexanoic, 28 mg of HOBT, and 42 mg of EDC and stirred for 4 hours. The reaction mixture was diluted with 10 ml of CH2Cl2and washed with 0.5 N. HCl (5 ml), saturated aqueous NaHCO3(5 ml), dried over magnesium sulfate and concentrated. The residue is purified using flash chromatography (10 g silica gel), elwira a mixture of CH2Cl2-acetone (1:1).

To 56,2 mg of the above intermediate compound in 2 ml of CH2Cl2and 2 ml of DMF added 23 mg of Biotin, 14 mg of DMAP, 28 mg of EDC and stirred for 18 hours. The reaction mixture is treated in the usual way. In financial p is given 22 mg bioteknologi conjugate. Remove protection N-tert-BOC carried out in CH2Cl2-TFA to obtain 18,9 mg specified in the title compound as a white solid.

1H NMR (CDCl3400 MHz processor, the compound exists as a mixture of 3:2 rotamers): 8.45-8.23 (m, 1H), 7.9 (s, 1H), 7.40-7.28 (m, 4H), 7.25-7.17 (m, 2H). 7.00 (dt, 2/3H), 6.80 (D., 1/3H), 5.21-5.14 (m, 1H), 4.60-4.42 (m, 4H), 4.28 (bt, 1H), 4.15-4.00 (m, 6H), 3.85-3.70 (m, 2H), 3.20-3.10 (m, 3H), 2.90 (DD, 1H), 2.83 (dt, 1H), 2.70 (d, 1H), 2.40-2.25 (m, 2H), 2.00-0.60 (m, 18H), 1.62 (s, 3H), 1.60 (s, 3H).

Data on the biological activity of the claimed compounds.

Analysis methods cell culture the pituitary gland.

Aseptically remove the pituitary gland in male Wistar rats (150-200 g) and prepare culture of pituitary cells by the method described in Cheng, K., Chan, W. W.-S., Barreto, A. , Convey, E. M. and Smith R. G (1988), Endocrinology 124, 2791-2798.

In this method cells treated with various agents that increase the secretion of H and examine H secretory activity.

Also measured the intracellular levels of AMP and determine EC50.

Test data presented in the table.

1. Spirobiindane formula I or II

< / BR>
or

< / BR>
where R1represents aryl(C1-C6-alkyl), C3-C7cycloalkyl(C1-C6-alkyl), aryl(C1-C5-alkyl), where K is O, S(O)mwhere the aryl group is a phenyl, pyridyl and indolyl, and the aryl group may be substituted by 1-2 halogen atoms;

R2represents hydrogen;

R3aand R3bindependently represents hydrogen, halogen, C1-C5-alkyl;

R4and R5independently represent hydrogen, substituted C1-C6-alkyl, where the substituents can be 1-3 hydroxy;

R6represents hydrogen;

And is

< / BR>
where x is 0 or 1;

R7and R7aindependently represent1-C6-alkyl;

B, D, E and F independently represent C(R8)(R10) OH, C=O, S(O)mor NR9so that one or two of b, D, E or F may not necessarily be absent, thus forming a 5-, 6 - or 7-membered ring, and provided that b, D, E or F can represent C(R8)(R10), or C=O only if one of the remaining b, D, E or F of groups is O, S(O)mor NR9;

R8and R10independently represent hydrogen;

R2is R'2, SO2-R'2, SO2(CH2)qaryl, C(O)R'2C(O)OR'2and R'2may not necessarily be Dov>R2or SO2(CH2)qCONH(CH2)w-NHC(O)R11, w is 2 to 6, and R11is aryl, substituted OR OR2, halogen, azido or nitro, R'2and R2are hydrogen or C1-C4the alkyl,

q = 0; 1;

m = 0, 1, or 2;

n = 1;

G, H, I and J represent the carbon atoms or sulfur so that at least one is a heteroatom and one of G, H, I and J may not necessarily be absent, which ensures the formation of 5-membered heterocyclic aromatic ring or 6-membered aromatic ring,

and its pharmaceutically acceptable salts and individual diastereoisomer.

2. Connection on p. 1 of formula III

< / BR>
where R1represents aryl(C1-C4-alkyl), C3-C6-cycloalkyl(C1-C4alkyl), aryl(C0-C5alkyl)-K-(C1-C4-alkyl) or (C3-C7-cycloalkyl (C0-C5alkyl)-K-(C1-C4-alkyl), where K is O, S(O)m,

R3aand R3bindependently represents hydrogen, halogen, C1-C4alkyl;

R4and R5independently represent hydrogen, substituted C1-C6-alkyl, where the substituents may be 1-2 hydroxy;
The4-alkyl,

B, D and F independently represent C(R8)(R10) OH, C=O, S(O)mor NR9so that one of b, D or F may not necessarily be absent, which ensures the formation of 5 - or 6-membered ring, and provided that b, D or F are(R8)(R10), or C=O, if one of the remaining b, D or F groups is O, S(O)mor NR9;

R8and R10independently represent hydrogen;

R9is R'2, SO2R'2C(O)R'2, SO2(CH2)qaryl, where R'2may optionally be substituted OR a"2by 1-2 halogen atoms, 1-2 C1-C4the alkyl, C(O)-OR"2and-N(R2)C(O)NR2R2, SO2(CH2)wCONH(CH2)w-NHC(O)R11w is 1-6 and R11is aryl, substituted OR OR2, halogen, azido, R'2and R2are hydrogen or C1-C4-alkyl;

m is 0, 1 or 2;

q is 1;

aryl represents phenyl, pyridyl, indolyl,

and its pharmaceutically acceptable salts and individual diastereoisomer.

3. Connection on p. 2, where F is missing.

4. Connection on p. 3 formula IV

< / BR>
where R1represents aryl(C1l)-TO-(C1-C2-alkyl) or (C3-C6-cycloalkyl(C0-C2-alkyl)-K-(C1-C2-alkyl), where K is O or S(O)mand aryl may be optionally substituted by 1-2 halogen;

R3aand R3bindependently represents hydrogen, halogen, C1-C4-alkyl;

R4and R5independently represent hydrogen, substituted C1-C4-alkyl, where the substituents may be 1-2 hydroxy;

And is

< / BR>
where x = 0 or 1;

R7and R7aindependently represent1-C3-alkyl;

B and D independently represent C(R8)(R10), FROM=0, OH, S(O)mor NR9provided that one of b and D can be C(R8)(R10or C=0, only if different from b and D represents O, S(O)mor NR9;

R8and R10independently represent hydrogen, '

R9represents C(O)R'2, SO2R'2where R'2may be optionally substituted OR a"2C(O)OR"2and N(R2)C(O)NR2R2by 1-2 halogen atoms, 1-2 s1-C4the alkyl or SO2(CH2)qCONH(CH2)w-NHC(O)R11, q is 2-6; R11may not necessarily represent aryl, substituted OR OR2, halogen, R>
aryl represents phenyl, pyridyl, indolyl,

and its pharmaceutically acceptable salts and individual diastereoisomer.

5. Connection on p. 1 of formula V

< / BR>
where R1choose from:

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
R3arepresents hydrogen or fluorine;

D is O, S, S(O)mN(R2), NSO2(R2), NSO2(CH2)t-aryl, NC(O)(R2), NSO2(CH2)qOH, NSO2(CH2)qCOOR"2,

< / BR>
aryl represents phenyl or pyridyl;

R2represents hydrogen or C1-C4-alkyl;

m = 1 or 2;

t = 1;

q = 1;

w = 2-6,

and its pharmaceutically acceptable salts and individual diastereoisomer.

6. Connection on p. 1, selected from the group which includes:

N-[1(R)-[(1,2-dihydro-1-methanesulfonamide[3H-indole-3,4'-piperidine] -1'-yl)carbonyl]-2-(1H-indol-3-yl)ethyl]-2-amino-2-methylpropanamide,

N-[1(R)-[(1,2-dihydro-1-metacarbonate[3H-indole-3,4'-piperidine] -1-yl)carbonyl]-2-(1H-indol-3-yl)ethyl]-2-amino-2-methylpropanamide,

N-[1(R)-[(1,2-dihydro-1-benzosulfimide[3H-indole-H, 4'-piperidine]-1'-yl)carbonyl]-2-(1H-indol-3-yl)ethyl-2-amino-2-methylpropanamide,

N-[1(R)-[(3,4-dihydro-Spiro[2H-1-benzopyran-2,4'-PIP is in-4,4'-piperidine] -1'-yl)carbonyl]-2-(indol-3-yl)ethyl]-2-amino-2-methylpropanamide,

N-[1(R)-[(1,2-dihydro-1-methanesulfonamide[3H-indole-3,4'-piperidine] -1'-yl)carbonyl]-2-(phenylmethoxy)-ethyl-2-amino-2-methylpropanamide,

N-[1(R)-[(1,2-dihydro-1-methanesulfonamide[3H-indole-3,4'-piperidine] -1'-yl)carbonyl] -2-(phenylmethoxy)-ethyl-2-amino-2-methylpropanamide, salt,

N-[1(R)-[(1,2-dihydro-1-methanesulfonamide[3H-indole-3,4'-piperidine] -1'-yl)carbonyl] -2-(2', 6'-differgenerations)ethyl] -2-amino-2-methylpropanamide,

N-[1(R)-[(1,2-dihydro-1-methanesulfonyl-5-pterospora[3H-indole-3,4'-piperidine]-1'-yl)carbonyl]-2-(phenylmethoxy)ethyl]-2-amino-2-methylpropanamide,

N-[1(S)-[1,2-dihydro-1-methanesulfonamide[3H-indole-3,4'-piperidine] -1'-yl)carbonyl]-2-(feniletilic)ethyl]-2-amino-2-methylpropanamide,

N-[1(R)-[(1,2-dihydro-1-methanesulfonamide[3H-indole-3,4'-piperidine] -1'-yl)carbonyl]-3-phenylpropyl]-2-amino-2-methylpropanamide,

N-[1(R)-[(1,2-dihydro-1-methanesulfonamide[3H-indole-3,4'-piperidine] -1'-yl)carbonyl-3-cyclohexylprop]-2-amino-2-methylpropanamide,

N-[1(R)-[(1,2-dihydro-1-methanesulfonamide[3H-indole-3,4'-piperidine] -1'-yl)carbonyl]-4-phenylbutyl-2-amino-2-methylpropanamide,

and their pharmaceutically acceptable salts.

7. Connection on p. 1 of formula Ia

< / BR>
where R1, R2, R3a, R3b, R4, R5, R6And, the tives such as those that includes the interaction of the compounds of formulas 4 or 4A

< / BR>
or

< / BR>
with the compound of the formula

< / BR>
or

< / BR>
where R1, R2, R3a, R3b, R4, R5, R6A , b, D, E, F, G, H, I, J and n are specified in paragraph 1 values;

L represents a protective group, which is then removed (if present),

and, if desired, receive salt.

9. The method of producing spiroperidol formula I or II wherein involves reacting the compounds of formula 2 and 2A

< / BR>
or

< / BR>
with the compound of the formula

< / BR>
or

< / BR>
where R1, R2, R3a, R3b, R4, R5, R6A , b, D, E, F, G, H, I, J and n are specified in paragraph 1 values;

L represents a protective group, which is then removed (if present),

and, if desired, receive salt.

10. N-[1(R)-[(1,2-dihydro-1-methanesulfonamide[3H-indole-3,4'-piperidine] -1'-yl)carbonyl] -2-(phenylmethoxy)-ethyl]-2-amino-2-methylpropanamide or its pharmaceutically acceptable salt.

11. N-[1(R)-[(1,2-dihydro-1-methanesulfonamide[3H-indole-3,4'-piperidine] -1'-yl)carbonyl] -2-(phenylmethoxy)-ethyl]-2-amino-2-methylpropanamide, salt.

Priority points:

11.12.199

 

Same patents:

The invention relates to products derived from histamine and, in particular, the condensation products of histamine or methylsiloxanes histamine and amino acids, the method of their preparation and use as active principle in areas such as therapy and cosmetology, as well as the factor (agent), improving the stability of compositions used in therapy, cosmetology, agriculture and food industry (region)

The invention relates to biotechnology and can be used for Introduzione nucleic acids into cells

The invention relates to new derivatives of pyrrolidinone possessing biological activity, in particular derivatives of 1H-3-aryl-pyrrolidin-2,4-dione

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

The invention relates to new derivatives of pyrrolidinone possessing biological activity, in particular derivatives of 1H-3-aryl-pyrrolidin-2,4-dione
Up!