Stimulators of growth hormone secretion

 

(57) Abstract:

Describes new compounds of formula I, racemizes-diastereomeric mixtures and optical isomers of these compounds and their pharmaceutically acceptable salts and prodrugs, where e is 0 or 1; n and w is 1; Y represents oxygen; R1denotes hydrogen, -(CH2)t-AND1where t is 0, 1 or 2; AND1denotes phenyl or fully unsaturated 4 - to 8-membered ring, optionally having 1 to 2 heteroatoms, independently selected from the group including sulfur and nitrogen, a bicyclic ring system consisting of a fully unsaturated 5 - or 6-membered ring, optionally having 1 or 2 heteroatom, represented by nitrogen; AND1in each case, independently, optionally substituted in one or optionally both rings if AND1is a bicyclic ring system, and has up to 2 substituents, each Deputy is independently selected from the group including F, Cl, Br, OCF3, (C1-C6)alkyl, phenyl; R2denotes hydrogen, (C1-C8)alkyl, where the alkyl group is optionally substituted CF3; R3means (C1-C5)alkyl-X1-(C0-C5)alkyl-AND1where X1the seat is dstanley the rest of the formula II, where a and b are 0; X5and X5aeach independently represents unsubstituted (C1-C6)alkyl; Z1denotes a bond; R7and R8each denotes hydrogen. The compounds of formula I are stimulators of growth hormone and can be used for the treatment and prevention of osteoporosis. 7 C. and 87 C.p. f-crystals.

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The invention relates to dipeptide compounds, which are stimulators of growth hormone and can be used for the treatment and prevention of osteoporosis.

Background of the invention

Growth hormone (GH), which is secreted by the pituitary gland, stimulates the growth of all capable of growing tissues of the body. In addition, it is known that growth hormone has the following main effects on the metabolic process in the body:

1. Increases the rate of protein synthesis is essentially all cells of the body.

2. Reduces the rate of use of carbohydrates in the cells of the body.

3. Increases the mobilization of free fatty acids and the use of fatty acids as an energy source.

The growth hormone deficiency leads to various pathological disorders. In children it causes dwarfism (the si body and a concomitant increase in total body fat, in particular, in the trunk of the body. Reduced mass of skeletal and cardiac muscle and muscle strength lead to a significant reduction in the ability of physical exertion. Bone density also decreases. It was shown that introduction of exogenous growth hormone reverses many of these metabolic changes. Additional benefits of this therapy include reduction of LDL-cholesterol and improved psychological state.

In cases where it is desired elevated levels of growth hormone, this problem is usually solved by using exogenous growth hormone or the introduction of a tool to stimulate the formation and/or release of growth hormone. In any case piptadenia nature of such connection is required, so that it was administered by injection. Initially, the growth hormone was obtained by extraction of the hypophysis corpses. This has resulted in costly product and encompasses the risk that the disease associated with the source of the pituitary gland, could be transferred to the recipient growth hormone (for example, disease of Creutzfeldt-Jakob disease). Recently became available recombinant growth hormone, which, though not has any danger of transmission of disease, is still very teas failure of GR due to defects in the release of GR, and not a primary defect in the synthesis of GR in the pituitary gland. Therefore, an alternative strategy to normalize levels of GR in serum stimulates its release from somatotrophs. Increased secretion of GR can be achieved by stimulation or inhibition of different neurotransmitter systems in the brain and hypothalamus. As a result, when the development of synthetic releasing growth hormone agents for the stimulation of GH is secreted by pituitary gland and could be achieved some advantages relatively expensive and inconvenient GR-substitution therapy. Acting on physiological regulatory pathways, the most desirable agents could stimulate the pulsating secretion of G, and excessive levels of GR associated with undesirable side effects of the introduction of exogenous GR, could be excluded due to the intact loops negative feedback.

Physiological and pharmacological stimulators of GH is secreted include arginine, L-3,4-dihydroxyphenylalanine (L-DOPA), glucagon, vasopressin, and induced by insulin hypoglycemia, as well as such activities as sleep and exercise, indirectly cause the release of growth hormone from the pituitary, vozdeystviyna secretion known factor, releasing the human growth hormone (growth hormone releasing factor (GHRF), or unknown endogenous hormone that stimulates growth hormone, or all of these ways.

Were developed by other compounds that stimulate the release of endogenous growth hormone, such as similar peptidyl connection related FGR, or peptides US Patent 4411890. These peptides, although much smaller in size than the growth hormones are still susceptible to various proteases. As in the case of most peptides and their potential oral availability is low. In WO 94/13696 described some spirobiindane and homologues, which increase the release of growth hormone. Preferred compounds have the General structure shown below.

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In WO 94/11012 describes some of the dipeptides, which increase the release of growth hormone. These dipeptides have the General structure

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where L is a

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In WO 94/11012 and WO 94/13696 reported compounds applicable in the treatment of osteoporosis in combination with parathyroid hormone or bisphosphonates.

The invention

This invention relates to compounds of the formula

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racemizes-diastereomeric mixtures and optical from the and w, each independently 0, 1 or 2, provided that w and n cannot be both equal to 0;

Y denotes oxygen or sulfur;

R1denotes hydrogen, -CN, -(CH2)qN(X6)C(O)X6, - (CH2)qN(X6)C(O) (CH2)t-A1, -(CH2)qN(X6)SO2(CH2)t-A1-(CH2)qN(X6)SO2X6- (CH2)qN(X6)C(O)N(X6) (CH2)t-A1, -(CH2)qN(X6)C(O)N(X6) (X6)

-(CH2)qC(O)N(X6) (X6), -(CH2)qC(O)N(X6) (CH2)t-A1-(CH2)qC(O)OX6,

-(CH2)qC(O)O(CH2)t-A1, - (CH2)qOX6, -(CH2)qOC(O)X6, -(CH2)qOC(O)(CH2)t-A1, - (CH2)qOC(O)N(X6)(CH2)t-A1, -(CH2)qOC(O)N(X6)(X6), (CH2)qC(O)X6,

-(CH2)qC(O)(CH2)t-A1, -(CH2)qN(X6)C(O)OX6, -(CH2)qN(X6)SO2N(X6) (X6), -(CH2)qS(O)mX6, -(CH2)qS(O)m(CH2)t-A1-(C1-C10)alkyl, -(CH2)t
-(CH2)q-Y1-(CH2)t-A1or -(CH2)q-Y1-(CH2)t- (C3-C7)cycloalkyl; where the alkyl groups and cycloalkyl in the definition of R1optionally substituted (C1-C4) alkyl, hydroxyl, (C1-C4)alkoxy, carboxyla, -CONH2, -S(O)m(C1-C6) alkyl, CO2(C1- C4)-alkylbis ester, 1H-tetrazol-5-yl or 1, 2, or 3 fluorine atoms;

Y1denotes O, S(O)m, -C(O)NX6-, -CH= CH-, -CC-, - N(X6)C(O)-,-C(O)NX6-,-C(O)O-, -OC(O)N(X6)- or-OC(O)-; q is 0, 1, 2, 3 or 4;

t is 0, 1, 2 or 3;

these groups (CH2)qand (CH2)teach may be optionally substituted by hydroxyl, (C1-C4) alkoxy, carboxyla, -CONH2, -S(O)m(C1-C6)alkyl, -CO2(C1-C4)-alkylbis ester, 1H-tetrazol-5-yl or 1, 2, or 3 fluorine atoms or 1 or 2 (C1-C4)alkilani;

R2means (C1-C8)alkyl, -(C0-C3)alkyl-(C3-C8)cycloalkyl, -(C1-C4)alkyl-A1or AND1;

where the alkyl groups and cycloalkyl group in the definition of2optionally substituted with hydroxyl, - C(O)OH<), CF3, CN or 1, 2, or three halogen atoms;

R3identifies AND1, (C1-C10)alkyl, -(C1-C6)alkyl-A1, -(C1-C6)alkyl- (C3-C7)cycloalkyl,-(C1-C5)alkyl-X1-(C1-C5)alkyl,(C1-C5)alkyl-X1-(C0-C5)alkyl-A1or -(C1-C5)-X1-(C1-C5)alkyl- (C3-C7)cycloalkyl;

where the alkyl groups in the definition of R3optionally substituted

-S(O)m(C1-C6)alkyl, -C(O)OH3, 1, 2, 3, 4 or 5 halogen atoms or 1, 2 or 3 OH3;

X1denotes O, S(O)m, -N(X2)C(O)- , -C(O)N(X2)-, -OC(O)-, -C(O)O-, -CX2=CX2-, -N(X2)C(O)O-, - OC(O)N(X2) or CC-;

R4denotes hydrogen, (C1-C6)alkyl or (C3-C7)cycloalkyl or R4taken together with R3and the carbon atom to which they are connected, form a (C5-C7) cycloalkyl, (C5-C7)cycloalkenyl, partially saturated or fully saturated 4-to 8-membered ring having 1-4 heteroatoms independently selected from the group comprising oxygen, sulfur and nitrogen, or denotes a bicyclic ring system consisting of a partially nassen asystem or fully saturated 5 - or 6-membered ring, optionally having 1-4 heteroatoms independently selected from the group comprising nitrogen, sulfur and oxygen;

X4denotes hydrogen or (C1-C6)-alkyl, or X4taken together with R4and the nitrogen atom to which X4connected, and the carbon atom to which R4connected, forms a 5-7-membered ring;

R6means a connection or is a

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where a and b are independently 0, 1, 2 or 3;

X5and X5aeach independently selected from the group comprising hydrogen, trifluoromethyl, AND1and optionally substituted (C1-C6) alkyl;

optionally substituted C1-C6) alkyl in the definition of X5and X5aoptionally substituted by a Deputy selected from the group including BUT1OH2, - S(O)m(C1-C6) alkyl, -C(O)OH2, (C3-C7)cycloalkyl, -N(X2)(X2and-C(O)N(X2)(X2);

or the carbon bearing X5or X5aforms one or two alkilinity bridge with the nitrogen atom bearing an R7and R8and each alkilinity the bridge contains 1 to 5 carbon atoms, provided that, when there is one Allenby bridge, X5or X5abut not both, may be on the atom ug who are two alkilinity bridge X5and X5acannot be on the carbon atom and R7and R8cannot be on the nitrogen atom;

or X5taken together with X5aand the carbon atom to which they are connected, form a partially saturated or fully saturated 3 to 7 membered ring or a partially saturated or fully saturated 4-to 8-membered ring having 1-4 heteroatoms independently selected from the group comprising oxygen, sulfur and nitrogen;

or X5taken together with X5aand the carbon atom to which they are connected, form a bicyclic ring system consisting of a partially saturated or fully saturated 5 - or 6-membered ring, optionally having 1 or 2 heteroatoms, independently selected from the group comprising nitrogen, sulfur and oxygen, fused to a partially saturated, fully saturated or fully unsaturated 5-or 6-membered ring, optionally having 1-4 heteroatoms independently selected from the group comprising nitrogen, sulfur and oxygen;

Z1denotes a bond, O or N-X2provided that when a and b both represent O, Z1is not N-X2or;

R7and R8independently represent hydrogen or optionally substituted (C1-C6)alkio independently substituted AND1-C(O)O-(C1-C6)alkyl, - S(O)m(C1-C6)alkyl, 1-5-halogen atoms, 1-3 hydroxy, 1-3-O-C(O)(C1-C10)alkyl or 1-3 (C1- C6)alkoxy; or

R7and R8taken together may form - (CH2)r-L-(CH2)r;

where L denotes(X2)(X2), S(O)mor N(X2);

AND1in each case independently denotes (C5-C7)cycloalkenyl, phenyl or a partially saturated or fully saturated or fully unsaturated 4-to 8-membered ring having 1-4 heteroatoms independently selected from the group comprising oxygen, sulfur and nitrogen, a bicyclic ring system consisting of a partially saturated, fully unsaturated or fully saturated 5 - or 6-membered ring, optionally having 1-4 heteroatoms selected from the group comprising nitrogen, sulfur and oxygen, fused to a partially saturated, fully saturated or fully unsaturated 5 - or 6-membered ring, optionally having 1-4 heteroatoms independently selected from the group including nitrogen, sulfur and oxygen;

AND1in each case independently optionally substituted at one or optionally both rings if AND1I the group, including F, Cl, Br, I, OCF3, OCF2H, CF3CH3, OCH3, - OH6, -C(O)N(X6)(X6), -C(O)OH6, oxo, (C1-C6)alkyl, nitro, cyano, benzyl, -S(O)m(C1-C6)alkyl, 1H-tetrazol-5-yl, phenyl, phenoxy, phenylalkylamine, halogenfree, methylendioxy, N(X6)(X6), - N(X6)C(O)(X6), -SO2N(X6)(X6), -N(X6)SO2-phenyl, -N(X6)SO2X6, -CONX11X12, -SO2NX11X12, -NX6SO2X12, -NX6CONX11X12, -NX6SO2NX11X12, -NX6C(O)X12imidazolyl, thiazolyl or tetrazolyl, provided that, if a1optionally substituted, methylendioxy, it can be replaced by only one methylenedioxy;

where X11denotes hydrogen or optionally substituted (C1-C6)alkyl;

optionally substituted (C1-C6)alkyl defined for X12, optionally substituted phenyl, phenoxy, (C1-C6)alkoxycarbonyl, -S(O)m(C1-C6)alkyl, 1-5-halogen atoms, 1-3 hydroxy, 1-3 (C1-C10)alkanoyloxy or 1-3 (C1-C6) alkoxy;

X12denotes hydrogen, (C1-C6)alkyl, phenyl, who consequently substituted by one to three substituents, independently selected from the group comprising Cl, F, CH3, OCH3, OCF3and CF3;

or X11and X12taken together form - (CH2)r-L-(CH2)r;

L1means WITH(X2)(X2), O, S(O)mor N(X2);

r in each case independently is 1, 2 or 3;

X2for each case independently denotes hydrogen, optionally substituted (C1-C6)alkyl or optionally substituted (C3-C7) cycloalkyl, and optionally substituted (C1-C6)alkyl and optionally substituted (C3-C7) cycloalkyl in the definition of X2optionally independently substituted S(O)m(C1-C6)alkyl, -C(O)OH3from 1-5 halogen atoms, or 1-3 OH3;

X3for each case independently denotes hydrogen or (C1-C6)alkyl;

X6means independently hydrogen, optionally substituted (C1-C6)alkyl, (C2-C6) halogenated alkyl, optionally substituted (C3-C7) cycloalkyl, (C3-C7)-halogenated cycloalkyl, and optionally substituted (C1-C6)alkyl and optionally substituted (C3-C7) CEC(C1-C4) alkoxy, carboxyla, CONH2, -S(O)m(C1-C6) alkyl, carboxylate-(C1-C4)alkylbis ester or 1H-tetrazol-5 - yl; or when one atom there are two groups of X6and both X6are independently (C1-C6)-alkyl, the two (C1-C6)-alkyl groups may be optionally joined, together with the atom to which the two groups X6connected with the formation of a 4-9-membered ring optionally having oxygen, sulfur or NX7;

X7denotes hydrogen or (C1-C6)-alkyl, optionally substituted with hydroxyl; and m for each case independently is 0, 1 or 2;

provided that

X6and X12cannot be hydrogen when they are connected with C(O) or SO2in the form C(O)X6, S(O)X12, SO2X6or SO2X12; and when R6denotes a bond, L denotes N(X2) and each r in the definition - (CH2)r-L-(CH2)ris, independently, 2 or 3.

A preferred group of compounds, designated as "group a", contains compounds of the formula I, shown above, in which X4denotes hydrogen; R4denotes hydrogen or methyl; R7means bodony one or two hydroxyl groups;

R6does

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where Z1means a connection and a is 0 or 1;

X5and X5a, each independently, represent hydrogen, trifluoromethyl, phenyl, optionally substituted (C1-C6)-alkyl;

where the optionally substituted (C1-C6)-alkyl optionally substituted by OH2, imidazolyl, phenyl, indolium, p-hydroxyphenyl, (C5-C7) cycloalkyl, -S(O)m(C1-C6)-alkyl, -N(X2)(X2or - C(O)N(X2)(X2);

or X5and R5taken together form a (C1-C5) Allenby bridge, and the other substituents are not defined for connections "Group" have the meanings defined for formula (I) above.

A group of compounds which is preferred among the "Group" of compounds, designated as "Group", contains compounds "Group a", having the formula I above in which b is 0; and X5and X5adenote, each independently, hydrogen, (C1-C3)alkyl or hydroxy(C1-C3)alkyl;

R3selected from the group comprising 1-indolyl-CH2-, 2-indolyl-CH2-, 3-indolyl-CH2-, 1-naphthyl-CH2- 2-naphthyl-CH2-, 1-benzimidazolyl-CH2- 2 - benzimidazolyl-, 4-pyridyl-(C1-C4)-alkyl-, phenyl-CH2-S-CH2- thienyl-(C1-C4)- alkyl-, phenyl-(C0-C3)-alkyl-O-CH2-, phenyl-CH2-O-phenyl-CH2- and 3-benzothiazol-CH2-;

where the aryl part (s) of the groups defined for R3, optionally substituted with one to three substituents, each Deputy is independently selected from the group consisting of methylenedioxy, F, Cl, CH3, OCH3, OCF3, OCF2H and CF3.

A group of compounds which is preferred among the "Group" of compounds, designated as "Group", contains compounds "Group", having the formula I above in which R4denotes hydrogen; and a is 0; n is 1 or 2; w is 0 or 1; X5and X5a, each independently, represent hydrogen, methyl or hydroxymethyl, provided that, when X5denotes hydrogen, X5ais not hydrogen;

R7and R8each represent hydrogen; and

R3denotes phenyl-CH2-O-CH2-, phenyl-CH2-S-CH2-, 1-naphthyl-CH2- 2-naphthyl-CH2-, phenyl-(CH2)3- or 3-indolyl-CH2-;

where the aryl portion of the groups defined for R3optionally substituted with one to three will replace 2
H, OCF3and CF3.

A group of compounds which is preferred among the "Group" of compounds, designated as "Group D", contains compounds "Group", having the formula I above in which R1represents -(CH2)t-A1, -(CH2)q-(C3- C7)cycloalkyl or (C1-C10)-alkyl;

where a1in the definition of R1optionally substituted with one to three substituents, each Deputy is independently selected from the group comprising fluorine, chlorine, methyl, OCH3, OCF2H, OCF3and CF3;

cycloalkyl and alkyl groups in the definition of R1optionally substituted C1-C4)alkyl, hydroxyl, (C1-C4)-alkoxy, carboxyla, CONH2, -S(O)m(C1-C4)alkyl, CO2(C1-C4)alkylbis ester, 1H-tetrazol-5-yl or 1 to 3 fluorine atoms;

Y represents O; R2denotes hydrogen, -(C0-C3)-alkyl-(C3-C8)cycloalkyl, phenyl or (C1-C8) alkyl, where (C1-C8)alkyl optionally substituted by hydroxyl, -CF3or 1-3 halogen atoms.

A group of compounds which is preferred among the "D Group" of compounds, designated as "F is respectful among the "Group D" connections, designated as a "Group E", contains compounds of Group D, having the formula I shown above in which e is 0; n and w are each equal to 1;

R1means (CH2)t-A1;

AND1in the definition of R1denotes phenyl, thienyl, thiazolyl, pyridyl or pyrimidyl, which is optionally substituted with one to three substituents, each Deputy is independently selected from the group comprising F, Cl, Me, OMe, CF3, OCF3and OCF2H;

t is 0, 1 or 2;

and R3denotes phenyl-CH2-O-CH2, phenyl- (CH2)3- or 3-indolyl-CH2- where the aryl part is optionally substituted by one to three substituents, each Deputy is independently selected from the group comprising F, Cl, Me, OMe, CF3, OCF3and OCF2H.

A group of compounds which is preferred among the "F Group" of compounds, designated as "G", contains compounds "Group F", having the formula I above in which X5and X5aeach represent methyl; R1denotes-CH2-phenyl, -CH2-4-forfinal, -CH2-pyridyl or-CH2-thiazolyl and R2denotes hydrogen, methyl, ethyl, tert-butyl or-CH2CF3.

A group of compounds that PR is the following formula

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racemizes-diastereomeric mixtures and optical isomers of these compounds, in which

R1denotes-CH2-phenyl, R2denotes methyl and R3represents -(CH2)3is phenyl;

R1denotes-CH2-phenyl, R2denotes methyl and R3signifies 3-indolyl-CH2-;

R1denotes-CH2-phenyl, R2denotes ethyl and R3signifies 3-indolyl-CH2-;

R1denotes - CH2-4-forfinal, R2denotes methyl and R3signifies 3-indolyl - CH2-;

R1denotes-CH2-phenyl, R2denotes methyl and R3denotes-CH2-O-CH2is phenyl;

R1denotes-CH2-phenyl, R2denotes ethyl and R3denotes-CH2-O-CH2is phenyl;

R1denotes-CH2-phenyl, R2denotes-CH2-CF3and R3denotes-CH2-O-CH2is phenyl;

R1denotes-CH2-4-forfinal, R2denotes methyl and R3denotes-CH2-O-CH2is phenyl;

R1denotes-CH2-phenyl, R2represents tert-butyl and R3denotes-CH2-O-CH2is phenyl; or

R1denotes-CH2Eremina a mixture of 2-amino-N-[2-(3A- (R,S)-benzyl-2-methyl-3-oxo-2, 3, 3A, 4, 6, 7-hexahydropyrazino [4, 3-C]pyridine-5-yl)-1-(R)-(3,4-differentiatedly)-2 - oxoethyl] -2-methylpropionamide preferred among a Group, G1compounds and the separated isomers 3a-(R) and 3a-(S) diastereomeric mixture are preferred.

A group of compounds which is preferred among the "G" of compounds, designated as "Group H", contains compounds "G", having the formula I above in which R1denotes-CH2is phenyl and R3denotes a phenyl-(CH2)3-.

Diastereomer a mixture of 2-amino-N-[1-(3A- (R,S)-benzyl-2-methyl-3-oxo-2,3,3 a, 4,6,7 there is hexahydropyrazino [4,3-C]pyridine-5-carbonyl)-4-phenyl-(R)-butyl] -isobutyramide preferred among the "Group H" of compounds and the separated isomers 3A-(R) and 3a-(S) diastereomeric mixture are preferred.

A group of compounds which is preferred among the "G" of compounds, designated as "Group I", contains compounds "G", in which R1denotes-CH2-phenyl or-CH2-4-forfinal and R3signifies 3-indolyl-CH2-.

Diastereomer a mixture of 2-amino-N-[2-(3A-(R, S)-benzyl-2-methyl-3-oxo-2,3,3 a,4,6,7-hexahydropyrazino [4, 3-C]pyridine-5-yl)-1-(R)- (1H-indol-3-ylmethyl)-2-oxoethyl] -isoutside preferred.

Diastereomer a mixture of 2-amino-N-[2-(3A-(R, S)-benzyl-2-ethyl-3-oxo-2,3,3 a, 4,6,7 there is hexahydropyrazino [4,3-C]pyridine-5-yl)-1-(R)-(1H-indol-3-ylmethyl) -2-oxoethyl] -isobutyramide preferred among the "Group I" of compounds and the separated isomers 3A-(R) and 3a-(S) diastereomeric mixture are preferred.

Diastereomer a mixture of 2-amino-N-[2-(3A-(R,S)-(4-terbisil-2-methyl-3-oxo - 2,3,3 a, 4,6,7 there is hexahydropyrazino[4,3-c] pyridine-5-yl)-1-(R)-(1H - indol-3-ylmethyl)-2-oxoethyl] -isobutyramide preferred among the "Group I" of compounds and the separated isomers 3a-(R) and 3A-(S) diastereomeric mixture are preferred.

A group of compounds which is preferred among the "G" of compounds, designated as "J", includes connection, "G", in which R1denotes-CH2-phenyl or-CH2-4-forfinal and R3denotes phenyl-CH2-O-CH2-. Diastereomer a mixture of 2-amino-N-[2-(3A-(R,S)-benzyl-2-methyl - 3-oxo-2,3,3 a, 4,6,7 there is hexahydropyrazino[4,3-C] pyridine - 5-yl)-1-(R)-benzoyloxymethyl-2-oxoethyl] -isobutyramide preferred among the "J" of compounds and the separated isomer 3a-(R) are preferred in comparison with isomer 3a-(S) and salt L-tartaric acid 3A-(R)isomer is the preferred salt.

Diastereomer-2-oxoethyl] -isobutyramide also preferred among the "J" of compounds and the separated isomers 3a-(R) and 3a-(S) diastereomeric mixture are preferred.

Diastereomer a mixture of 2-amino-N-[2-(3A-(R,S)- benzyl-3-oxo-2- (2,2,2-triptorelin)-2,3,3 a, 4,6,7 there is hexahydropyrazino [4,3-c] pyridine-5-yl)-1-(R)-benzoyloxymethyl-2-oxoethyl] -isobutyramide also preferred among the "J" of compounds and the separated isomers 3a-(R) and 3a-(S) diastereomeric mixtures are preferred and isomer 3a-(R) preferable in comparison with isomer 3a-(S).

Diastereomer a mixture of 2-amino-N-{ 1-(3A-(R)-benzoyloxymethyl - 2-[3A-(R, S)-(4-terbisil) -2-methyl-3-oxo-2,3,3 a,4,6,7-hexahydropyrazino [4,3-c]pyridine-5-yl)-2-oxoethyl} - isobutyramide also preferred among the "J" of compounds and the separated isomers 3a-(R) and 3a-(S) diastereomeric mixture are preferred.

Diastereomer a mixture of 2-amino-N-[2-(3A-(R, S)- benzyl-2-tert-butyl-3-oxo - 2,3,3 a, 4,6,7 there is hexahydropyrazino [4,3-C]pyridine-5-yl)-1-(R)-benzoyloxymethyl-2-oxoethyl] - isobutyramide also preferred among the "J" of compounds and the separated isomers 3a-(R) and 3a-(S) diastereomeric mixture are preferred.

A group of compounds which is preferred among the "D Group" of compounds, designated as "Group K", contains compounds "Group D" in which e is 1; n is 1; w is 1; R1means (CH2)t-AND1;

where And what but substituted one to three substituents, each Deputy is selected from the group comprising F, Cl, Me, OMe, CF3, OCF3and OCF2H;

t is 0, 1 or 2;

and R3denotes phenyl-CH2-O-CH2-, phenyl-(CH2)3- or 3-indolyl-CH2- where the aryl part is optionally substituted by one to three substituents, and Deputy independently selected from the group comprising F, Cl, Me, Ome, CF3, OCF3or OCF2H.

A group of compounds which is preferred among the "Group By" compounds, designated as "Group L", contains compounds "Group, in which X5and X5aeach represent methyl; R1denotes-CH2-phenyl, -CH2-4-forfinal, -CH2-pyridyl or-CH2- thiazolyl and R2denotes hydrogen, methyl, ethyl, tert-butyl or - CH2CF3.

A group of compounds which is preferred among the "Group L", designated as "L1contains connections "Group L", in which R1denotes-CH2is phenyl; R2denotes hydrogen or methyl and R3denotes-CH2-O-CH2is phenyl.

Diastereomer a mixture of 2 - amino-N-[2-(3A-(R, S)-benzyl-3-oxo -2,3,3 a, 4,6,7 there is hexahydropyrazino [4,3-C]pyridine-5-yl)-1-(R)-benzoyloxymethyl-2 - oxoethyl] -isobutyramide also practicality and isomer 3A-(R) are preferred in comparison with isomer 3a-(S).

Another group of compounds which is preferred among the "Group" of compounds, designated as "Group M", contains compounds "Group K", having the formula I, shown above, where b denotes 0; X5and X5aeach independently represents hydrogen, (C1-C3)alkyl or hydroxy(C1-C3)alkyl; R3selected from the group comprising 1-indolyl-CH2-, 2-indolyl-CH2-, 3-indolyl-CH2-, 1-naphthyl-CH2- 2-naphthyl-CH2-, 1-benzimidazolyl-CH2-, 2-benzimidazolyl-CH2-, phenyl-(C1-C4)-alkyl-, 2-pyridyl-(C1-C4)-alkyl-, 3-pyridyl-(C1-C4)-alkyl-,

4-pyridyl-(C1-C4)-alkyl-, phenyl-CH2-S-CH2-thienyl-(C1-C4)-alkyl-, phenyl-(C0-C3)alkyl-O-CH2-, phenyl-CH2-O-phenyl-CH2-, 3-benzothiazol-CH2- thienyl-CH2-O-CH2-, thiazolyl-CH2-O-CH2-, pyridyl-CH2-O-CH2-, pyrimidyl-CH2-O-CH2- and phenyl-CH2-O-CH2-; where the aryl portion (part) of the groups defined for R3, optionally substituted with one to three substituents, each Deputy is independently selected from the group consisting of methylenedioxy, F, Cl, CH3, OCH3, OCF3, OCF2H and CF3.

4denotes hydrogen; and a is 0; n is 1; w is 1; e is 0; X5and X5a, each independently, represent hydrogen, methyl or hydroxymethyl, provided that, when X5denotes hydrogen, X5ais not hydrogen; R7and R8each represent hydrogen; Y represents oxygen; R2denotes hydrogen, methyl, ethyl, propyl, isopropyl, tert-butyl, -CH2CF3, CF3or-CH2- cyclopropyl; R1denotes CH2-AND1; where a1in the definition of R1represents phenyl, thienyl, thiazolyl, pyridyl or pyrimidyl, which is optionally substituted with one to three substituents, each Deputy is independently selected from the group comprising F, Cl, Me, OMe, CF3, OCF3and OCF2H; and R3denotes phenyl-CH2-O-CH2-, phenyl-(CH2)3-, 3-indolyl-CH2- thienyl - CH2O-CH2-, thiazolyl-CH2-O-CH2-, pyridyl-CH2-O-CH2-, pyrimidyl-CH2-O-CH2- or phenyl-CH2-O-CH2- where the aryl part is optionally substituted by one to three substituents, each Deputy is independently selected from the group comprising F, Cl, Me, OMe, CF3, OCF3and OCF2H.

A group of compounds"having the formula I, shown above, where X5and X5aeach represent methyl; R2denotes methyl, ethyl or-CH2CF3;1denotes phenyl, optionally substituted with one to three substituents, each Deputy is independently selected from the group comprising F, Cl, Me, OMe, CF3, OCF3and OCF2H; and R3denotes phenyl-CH2-O-CH2-, phenyl-(CH2)3or thienyl-CH2O-CH2- where the aryl part is optionally substituted by one to three substituents, each Deputy is independently selected from the group comprising F, Cl, Me, OMe, CF3, OCF3and OCF2H.

Another group of compounds which is preferred among the "Group M1"marked "Group N", contains compounds "Group 1"having the formula I, shown above, where X5and X5aeach represent methyl; R2denotes methyl, ethyl or-CH2CF3;1represents 2-pyridyl or 3-pyridyl, optionally substituted with one to three substituents, each Deputy is independently selected from the group comprising F, Cl, Me, OMe, CF3, OCF3and OCF2H; R3denotes phenyl-CH2-O-CH2-, phenyl-(CH2)3or thienyl-CH3, OCF3and OCF2H.

Another group of compounds which is preferred among the "Group M1"marked by "P", contains compounds "Group1"having the formula I, shown above, where X5and X5aeach represent methyl; R2denotes methyl, ethyl or-CH2CF3;1denotes phenyl, optionally substituted with one to three substituents, each Deputy is independently selected from the group comprising F, Cl, Me, OMe, CF3, OCF3and OCF2H; R3represents 2-pyridyl-CH2-O-CH2-or 3-pyridyl-CH2-O-CH2- where the aryl part is optionally substituted by one to three substituents, each Deputy is independently selected from the group comprising F, Cl, Me, OMe, CF3, OCF3and OCF2H.

A group of compounds which is preferred among a Group Of compounds, designated as "Group Q contains compounds "Group", having the formula

< / BR>
racemizes-diastereomeric mixtures and optical isomers of these compounds, where

R2denotes methyl; AND1represents 2-pyridyl and R3denotes-CH2-O-CH2is phenyl;

R2denotes CH22CF3; A1represents 2-pyridyl and R3denotes-CH2-O-CH2-4-chlorophenyl;

R2denotes CH2CF3; A1represents 2-pyridyl and R3denotes-CH2- O-CH2is 2,4-dichlorophenyl;

R2denotes CH2CF3; A1represents 2-pyridyl and R3denotes-CH2-O-CH2-3-chlorothiophene; or

R2denotes CH2CF3; A1represents 2-pyridyl and R3denotes-CH2- O-CH2-2,4-differenl.

Diastereomer a mixture of 2-amino-N-[1-(R)-benzoyloxymethyl-2-(2-methyl-3-oxo-(3a-(R, S) -pyridine-2-ylmethyl - 2,3,3 a,4,6,7-hexahydropyrazino[4,3-c] pyridine-5-yl)-2-oxoethyl] -2-methylpropionamide preferred among the "Group Q" of compounds and the separated isomers 3a-(R) and 3A-(S) diastereomeric mixture are preferred.

Diastereomer a mixture of 2-amino-N-{ 1-(R)-(3-chlorobenzoyloxy) -2-oxo-2-[3-oxo-(3A-(R, S)-pyridine-2-ylmethyl-2-(2,2,2-triptorelin)- 2,3,3 a, 4,6,7 there is hexahydropyrazino [4,3-c] pyridine-5-yl] ethyl} -2 - methylpropionamide preferred among the "Group Q" of compounds and the separated isomers 3a-(R) and 3A-(S) diastereomeric mixture are preferred.

Diastereomer a mixture of 2-amino-N-{1-(R)-(4 - chlorobenzoyloxy) - methylpropionamide preferred among the "Group Q" of compounds and the separated isomers 3a-(R) and 3a-(S) diastereomeric mixture are preferred.

Diastereomer a mixture of 2-amino-N-{1- (R)-(2,4-dichlorosalicylic)-2-oxo-2-[3-oxo-3a-(R, S) -pyridine-2-ylmethyl-2-(2,2,2-triptorelin)-2,3,3 a, 4,6,7 there is hexahydropyrazino [4,3-c] pyridine-5-yl]-ethyl}-2 - methylpropionamide preferred among the "Group Q" of compounds and the separated isomers 3a-(R) and 3a-(S) diastereomeric mixture are preferred.

Diastereomer a mixture of 2-amino-N-{ 1-(R)-(4-chlorothiophene-2-ileocecal)-2-oxo-2- [3-oxo-3a-(R,S)-pyridine-2-ylmethyl-2-(2,2,2-triptorelin)-2,3, 3A,4,6,7-hexahydropyrazino[4,3-c]pyridine-5-yl]-2-ethyl}-2 - methylpropionamide preferred among the "Group Q" of compounds and the separated isomers 3a-(R) and 3a-(S) diastereomeric mixture are preferred.

Diastereomer a mixture of 2-amino-N-{1- (R)-(2,4-differentiatedly)-2-oxo-2-[3-oxo-3a-(R, S) -pyridine-2-ylmethyl-2-(2,2,2 - triptorelin)-2,3,3 a, 4,6,7 there is hexahydropyrazino[4,3-C] pyridine-5-yl] -ethyl} -2 - methylpropionamide preferred among the "Group Q" of compounds and the separated isomers 3a-(R) and 3a-(S) diastereomeric mixture are preferred.

A group of compounds containing intermediate products are applicable in the synthesis of compounds of formula (I) has the formula

< / BR>
racemizes-diastereomeric mixtures and optical isomers of these compounds and their farm is able to be both equal to 0;

R1denotes hydrogen, -CN, -(CH2)qN(X6)C(O)X6, -(CH2)qN(X6)C(O) (CH2)t-A1, - (CH2)qN(X6)SO2(CH2)t-A1, -(CH2)qN(X6)SO2X6,

-(CH2)qN(X6)C(O)N(X6) (CH2)t-A1, -(CH2)qN(X6)C(O)N(X6) (X6)

-(CH2)qC(O)N(X6) (X6), -(CH2)qC(O)N(X6)(CH2)t-A1, -(CH2)qC(O)OX6,

-(CH2)qC(O)O(CH2)t-A1, -(CH2)qOX6, -(CH2)qOC(O)X6, -(CH2)qOC(O)(CH2)t-A1, - (CH2)qOC(O)N(X6)(CH2)t-A1, -(CH2)qOC(O)N(X6)(X6), -(CH2)qC(O)X6,

-(CH2)qC(O)(CH2)t-A1, -(CH2)qN(X6)C(O)OX6, - (CH2)qN(X6)SO2N(X6) (X6), -(CH2)qS(O)mX6, -(CH2)qS(O)m(CH2)t-A1-(C1-C10)alkyl, -(CH2)t-A1, -(CH2)q-(C3-C7)cycloalkyl, (CH2)q-Y1-(C1-C6)alkyl,

-(CH27) cycloalkyl; where the alkyl groups and cycloalkyl in the definition of R1optionally substituted C1-C4) alkyl, hydroxyl, (C1-C4)alkoxy, carboxyla, -CONH2, - S(O)m(C1-C6)alkyl, CO2(C1-C4)-alkyl, 1H-tetrazol-5-yl or 1, 2, or 3 fluorine atoms;

Y1denotes O, S(O)m, -C(O)NX6-, -CH=CH-, -CC-, - N(X6)C(O)-, -OC(O)NX6-, -C(O)O-, -OC(O)N(X6)- or-OC(O)-; q is 0, 1, 2, 3 or 4;

t is 0, 1, 2 or 3;

group -(CH2)qand (CH2)teach may be optionally substituted by 1-3 fluorine atoms, 1 or 2 (C1-C4)-alkyl, hydroxyl, (C1-C4) alkoxy, carboxyla, -CONH2, -S(O)m(C1-C6)alkyl, -CO2(C1-C4)-alkylbis ester or 1H-tetrazol-5-yl;

R2means (C1-C8)alkyl, -(C0-C3)alkyl-(C3-C8)cycloalkyl, -(C1-C4)alkyl-A1or AND1;

where the alkyl groups and cycloalkyl group in the definition of2optionally substituted with hydroxyl, -C(O)OH6C(O)N(X6)(X6), -N(X6)(X6), -S(O)m(C1-C6)alkyl, -C(O)AND1- C(O)(X6), CF3ON or 1-3 halogen atoms is asimenia or fully saturated or fully unsaturated 4-to 8-membered ring, having 1-4 heteroatoms independently selected from the group comprising oxygen, sulfur and nitrogen, or a bicyclic ring system consisting of a partially saturated, fully unsaturated or fully saturated 5 - or 6-membered ring, optionally having 1-4 heteroatoms independently selected from the group comprising nitrogen, sulfur and oxygen, fused to a partially saturated, fully saturated or fully unsaturated 5 - or 6-membered ring, optionally having 1-4 heteroatoms independently selected from the group comprising nitrogen, sulfur and oxygen;

AND1in each case independently optionally substituted at one or optionally both rings if AND1is a bicyclic ring system, and has up to 3 substituents, each Deputy is independently selected from the group comprising F, Cl, Br, I, OCF3, OCF2H, CF3CH3, OCH3, -OH6, -C(O)N(X6)(X6), -C(O)OH6, oxo, (C1-C6)alkyl, nitro, cyano, benzyl, -S(O)m(C1-C6)alkyl, 1H-tetrazol-5-yl, phenyl, phenoxy, phenylalkylamine, halogenfree, methylendioxy, N(X6)(X6), -N(X6)C(O)(X6), -SO2N(X6)(X6), N(X6)SO2-phenyl, -N(X6)SO<1X12, -NX6SO2NX11X12, -NX6C(O)X12imidazolyl, thiazolyl or tetrazolyl, provided that, if a1optionally substituted, methylendioxy, it can be replaced by only one methylenedioxy;

where X11denotes hydrogen or optionally substituted C1-C6) alkyl;

optionally substituted (C1-C6)alkyl defined for X12, optionally substituted phenyl, phenoxy, (C1-C6) alkoxycarbonyl, -S(O)m(C1-C6)alkyl, 1-5-halogen atoms, 1-3 hydroxy, 1-3 (C1-C10)alkanoyloxy or 1-3 (C1-C6)alkoxy;

X12denotes hydrogen, (C1-C6)alkyl, phenyl, thiazolyl, imidazolyl, furyl or thienyl provided that, when X12is not hydrogen, X12optionally substituted with one to three substituents, independently selected from the group comprising Cl, F, CH3, OCH3, OCF3and CF3;

or X11and X12taken together form -(CH2)r-L-(CH2)r;

L1means WITH(X2) (X2), O, S(O)mor N(X2);

r in each case independently is 1, 2 or 3;

X2for each case oboznachaet>-C7) cycloalkyl, and optionally substituted (C1-C6)alkyl and optionally substituted (C3-C7) cycloalkyl in the definition of X2optionally independently substituted S(O)m(C1-C6)alkyl, -C(O)OH3from 1-5 halogen atoms, or 1-3 OH3;

X3for each case independently denotes hydrogen or (C1-C6)alkyl;

X6for each case independently denotes hydrogen, optionally substituted (C1-C6)alkyl, (C2-C6)halogenated alkyl, optionally substituted (C3-C7) cycloalkyl, (C3-C7)-halogenated cycloalkyl, and optionally substituted C1-C6) alkyl and optionally substituted (C3-C7) cycloalkyl in the definition of X6optionally independently substituted with hydroxyl, (C1-C4)alkoxy, carboxyla, CONH2, -S (O)m(C1-C6) alkyl, CO2-(C1-C4) alkyl, 1H-tetrazol-5-yl or 1-2 (C1-C4) alkilani; or

when one atom there are two groups of X6and both X6are independently (C1-C6)-alkyl, the two (C1-C6)-alkyl groups can be optional with the, obazatelno having oxygen, sulfur or NX7;

X7denotes hydrogen or (C1-C6)-alkyl, optionally substituted by hydroxyl; and

m in each case independently is 0, 1 or 2;

provided that

X6and X12cannot be hydrogen when they are connected with C(O) or SO2in the form C(O)X6, S(O)X12, SO2X6or SO2X12; and when R6is hydrogen, R1is-CC - phenyl.

The intermediate group of compounds preferred among the preceding group of the formula (II), designated as "AA Group", contains compounds in which w is 0 or 1; n is 1; R1denotes hydrogen, -(CH2)q-(C3-C7)cycloalkyl, (CH2)t-A1or (C1-C10)alkyl, where (C1-C10)and alkyl (C3-C7) cycloalkyl group substituted by 1-3 fluorine atoms and a1in the definition of R1optionally substituted with one to three substituents, independently selected from the group comprising F, Cl, Me, methoxy, CF3, OCF3and OCF2H; R2denotes hydrogen, (C1-C8)alkyl, (C0-C3)alkyl-(C3-C7)cycloalkyl, phenyl or (C1-C3)alkalmi from the group including F, CF3HE and methoxy.

A group of compounds which is preferred among the "the AA Group" of compounds, designated as Group "BB", contains compounds of Group AA, in which w is 1; e is 0; R1denotes-CH2-pyridyl, -CH2-thiazolyl or-CH2is phenyl, optionally substituted with one to three substituents, independently selected from the group consisting of fluorine and chlorine; and R2denotes hydrogen, (C1-C4) alkyl or phenyl, where (C1-C4)alkyl or phenyl groups in the definition of R2optionally substituted with one to three substituents, independently selected from the group comprising fluorine, hydroxy or methoxy.

Compounds which is preferred among the "Group BB compounds, are diastereomers a mixture of compounds in which R1denotes-CH2is phenyl and R2denotes methyl or hydrogen; and preferred are separated isomers 3a-(R) and 3a-(S) diastereomeric mixture.

Another group of intermediate compounds applicable in the synthesis of compounds of formula (I) has the formula

< / BR>
and also contains racemizes-diastereomeric mixtures and optical isomers of these compounds, where Z100means metamemory methoxy, dimethoxy or nitro; e is 0 or 1; n and w are each equal to independently 0, 1 or 2, provided that w and n are both cannot be 0;

R1denotes hydrogen, -CN, -(CH2)qN(X6)C(O)X6, -(CH2)qN(X6)C(O)(CH2)t-A1, -(CH2)qN(X6)SO2(CH2)t-A1, -(CH2)qN(X6)SO2X6, -(CH2)qN(X6)C(O)N(X6(CH2)t-A1, -(CH2)qN(X6)C(O)N(X6)(X6), -(CH2)qC(O)N(X6)(X6), -(CH2)qC(O)N(X6)(CH2)t-A1, -(CH2)qC(O)OX6, -(CH2)qC(O)O(CH2)t-A1, -(CH2)qOX6-(CH2)qOC(O)X6,

-(CH2)qOC(O)(CH2)t-A1, -(CH2)qOC(O)N(X6)(CH2)t-A1, -(CH2)qOC(O)N(X6)(X6)

-(CH2)qC(O)X6, -(CH2)qC(O)(CH2)t-A1, -(CH2)qN(X6)C(O)OX6, -(CH2)qN(X6)SO2N(X6)(X6), -(CH2)qS(O)mX6, -(CH2)qS(O)m(CH2)t-A1,

-(C1-C10)alkyl, -(CH2)t-A2)q-Y1-(CH2)t-A1or -(CH2)q-Y1-(CH2)t(C3-C7) cycloalkyl;

where the alkyl groups and cycloalkyl in the definition of R1optionally substituted C1-C4) alkyl, hydroxyl, (C1-C4)alkoxy, carboxyla, -CONH2, - S(O)m(C1-C6)alkyl, CO2(C1-C4)-alkyl, 1H-tetrazol-5-yl or 1 to 3 fluorine atoms;

Y1denotes O, S(O)m, -C(O)NX6-, -CH= CH-, -CC-, -N(X6)C(O)-, -C(O)NX6, -C(O)O-, -OC(O)N(X6)- or-OC(O)-;

q is 0, 1, 2, 3 or 4;

t is 0, 1, 2 or 3;

group -(CH2)qand (CH2)teach may be optionally substituted by hydroxyl, (C1-C4)alkoxy, carboxyla, -CONH2, -S(O)m(C1-C6)alkyl, - CO2(C1-C4)-alkyl, 1H-tetrazol-5-yl, 1-3 fluorine atoms or 1 or 2 (C1-C4) alkilani;

R2denotes hydrogen, (C1-C8)alkyl, - (C0-C3)alkyl-(C3- C8)cycloalkyl,

-(C1-C4)alkyl-A1or AND1;

where the alkyl groups and cycloalkyl group in the definition of2optionally substituted with hydroxyl, -C(O)OX6C(O)N(X6)(X6), -N(X
AND1in each case independently denotes (C5- C7) cycloalkenyl, phenyl or a partially saturated or fully saturated or fully unsaturated 4-to 8-membered ring having 1-4 heteroatoms independently selected from the group comprising oxygen, sulfur and nitrogen, or a bicyclic ring system consisting of a partially saturated, fully unsaturated or fully saturated 5 - or 6-membered ring, optionally having 1-4 heteroatoms independently selected from the group comprising nitrogen, sulfur and oxygen, fused to a partially saturated, fully saturated or fully unsaturated 5 - or 6-membered ring, optionally having 1-4 heteroatoms, independently selected from the group comprising nitrogen, sulfur and oxygen;

AND1in each case independently optionally substituted at one or optionally both rings if AND1is a bicyclic ring system, and has up to 3 substituents, each Deputy is independently selected from the group comprising F, Cl, Br, I, OCF3, OCF2H, CF3CH3, OCH3, -OX6, -C(O)N(X6)(X6), -C(O)OX6, oxo, (C1-C6)alkyl, nitro, cyano, benzyl, -S(O)m(C1-C6)alkyl, 1H-those who 6
), -SO2N(X6)(X6), -N(X6)SO2-phenyl, -N(X6)SO2X6, -CONX11X12, -SO2NX11X12, -NX6SO2X12, -NX6CONX11X12, -NX6SO2NX11X12, -NX6C(O)X12imidazolyl, thiazolyl or tetrazolyl provided that, if a1optionally substituted, methylendioxy, it can be replaced by only one methylenedioxy;

where X11denotes hydrogen or optionally substituted C1-C6)alkyl;

optionally substituted C1-C6)alkyl defined for X12, optionally substituted phenyl, phenoxy, (C1-C6)alkoxycarbonyl, -S(O)m(C1-C6)alkyl, 1-5-halogen atoms, 1-3 hydroxy, 1-3 (C1-C10)alkanoyloxy or 1-3 (C1-C6) alkoxy;

X12denotes hydrogen, (C1-C6)alkyl, phenyl, thiazolyl, imidazolyl, furyl or thienyl provided that, when X12is not hydrogen, X12optionally substituted with one to three substituents, independently selected from the group comprising Cl, F, CH3, OCH3, OCF3and CF3;

or X11and X12taken together form -(CH2)r-L1-(CH2
X2for each case independently denotes hydrogen, optionally substituted (C1-C6)alkyl or optionally substituted (C3-C7)cycloalkyl, and optionally substituted C1-C6)alkyl and optionally substituted (C3-C7)cycloalkyl in the definition of X2optionally independently substituted S(O)m(C1-C6)alkyl, -C(O)OH3from 1-5 halogen atoms, or 1-3 OX3;

X3for each case independently denotes hydrogen or (C1-C6)alkyl;

X6for each case independently denotes hydrogen, optionally substituted (C1-C6)alkyl, (C2-C6)halogenated alkyl, optionally substituted (C3-C7)cycloalkyl, (C3-C7)-halogenated cycloalkyl, and optionally substituted C1-C6) alkyl and optionally substituted (C3-C7) cycloalkyl in the definition of X6optionally independently substituted with hydroxyl, (C1-C4)alkoxy, carboxyla, CONH2, -S(O)m(C1-C6)alkyl, CO2-(C1-C4)alkyl, 1H-tetrazol-5-yl or 1-2 (C1-C4) alkilani; or, when one atom has two gr is the group may be optionally connected, together with the atom to which the two groups X6connected with the formation of a 4-9-membered ring optionally having oxygen, sulfur or NX7;

X7denotes hydrogen or (C1-C6)-alkyl, optionally substituted by hydroxyl; and

m in each case independently is 0, 1 or 2;

provided that

X6and X12cannot be hydrogen when they are connected with C(O) or SO2in the form C(O)X6C(O)X12, SO2X6or SO2X12; and when R6is hydrogen, R1is-CC - phenyl;

when R2is H and R1is-CH2-CH=CH-Ph, Z100is not BOC;

when R2is H and R1is H, Z100is not BOC;

when R2is H and R1is-CH2- (CH3)=CH2, Z100is not BOC; and

when R2is phenyl and R1is-CH3, Z100is CH3C(O)-.

The group of compounds preferred among the preceding group of compounds of the formula (III), designated as "SS Group contains compounds in which w is 0 or 1; n is 1;

Z100represents BOC, methyl, benzyl or CBZ;

R1denotes hydrogen, -(CH1-C10)and alkyl (C3-C7)- cycloalkyl group optionally substituted by 1 to 3 fluorine atoms and a1in the definition of R1optionally substituted with one to three substituents, independently selected from the group comprising F, Cl, Me, OMe, CF3, OCF3and OCF3;

R2denotes hydrogen, (C1-C8)alkyl, - (C0-C3)alkyl-(C3-C8) cycloalkyl, phenyl or -(C1-C3)alkylphenyl, where the alkyl and phenyl groups optionally substituted with one to three substituents, independently selected from the group comprising F, CF3HE and OMe.

A group of compounds which is preferred among the "SS Group" of compounds, designated as "DD Group contains compounds in which Z100represents BOC, w equals 1; e is 0; R1denotes-CH2-pyridyl, -CH2-thiazolyl or-CH2is phenyl, optionally substituted with one to three substituents, independently selected from the group comprising fluorine and chlorine; and2denotes hydrogen, (C1-C4)alkyl or phenyl, where (C1-C4)alkyl or phenyl groups in the definition of R2optionally substituted with one to three substituents, independently selected from the group comprising fluorine, hydro is RNA, the mixture of compounds in which R1represents-CH2is phenyl and R2represents methyl or hydrogen; and preferred are separated isomers 3a-(R) and 3a-(S) diastereomeric mixture.

Another group of compounds applicable in the synthesis of compounds of formula (I) includes the compounds of formula IV

< / BR>
racemizes-diastereomeric mixtures and optical isomers of these compounds in which Z200denotes a tert-BOC, CBZ, CF3C(O)-, FMOC, TROC, trityl, tosyl or optionally substituted benzyl, optionally substituted methoxy, dimethoxy or nitro;

e is 0 or 1;

n and w, each equal, independently, 0, 1, or 2, provided that w and n cannot be both equal to 0;

Y denotes oxygen or sulfur;

R1denotes hydrogen, -CN, - (CH2)qN(X6)C(O)X6, -(CH2)qN(X6)C(O) (CH2)t-A1, -(CH2)qN(X6)SO2(CH2)t-A1-(CH2)qN(X6)SO2X6,

-(CH2)qN(X6)C(O)N(X6) (CH2)t-A1, -(CH2)qN(X6)C(O)N(X6)(X6)

-(CH2)qC(O)N(X6)(X6), -(CH2)qC(O)N(X6)(CH2)t-A1, -(CH2)
OC(O)X6, -(CH2)qOC(O)(CH2)t-A1,

-(CH2)qOC(O)N(X6)(CH2)t-A1, -(CH2)qOC(O)N(X6)(X6), -(CH2)qC(O)X6,

-(CH2)qC(O)(CH2)t-A1, -(CH2)qN(X6)C(O)OX6, -(CH2)qN(X6)SO2N(X6)(X6)

-(CH2)qS(O)mX6, -(CH2)qS(O)m(CH2)t-A1-(C1-C10)alkyl, -(CH2)t-A1, -(CH2)q-(C3-C7)cycloalkyl, -(CH2)q-Y1-(C1-C6)alkyl, -(CH2)q-Y1-(CH2)t-A1or -(CH2)q-Y1-(CH2)t-(C3-C7) cycloalkyl;

where the alkyl groups and cycloalkyl in the definition of R1optionally substituted C1-C4) alkyl, hydroxyl, (C1-C4)alkoxy, carboxyla, -CONH2, - S(O)m(C1-C6)alkyl, CO2(C1-C4)-alkylbis ester, 1H-tetrazol-5 - yl or 1 to 3 fluorine atoms;

Y1denotes O, S(O)m, -C(O)NX6-, -CH= CH-, -CC-, -N(X6)C(O)-, -C(O)NX6-C(O)O-, -OC(O)N(X6)- or-OC(O)-;

q is 0, 1, 2, 3 or 4;

t is 0, 1, 2 or 3;

SUB>4) alkoxy, carboxyla, -CONH2, - S(O)m(C1-C6)alkyl, -CO2(C1-C4)-alkyl, 1H-tetrazol-5-yl, 1-3 fluorine atoms or 1 or 2 (C1-C4)alkilani;

R2denotes hydrogen, (C1-C8)alkyl, -(C0-C3)alkyl-(C3-C8)cycloalkyl, -(C1-C4)alkyl-A1or A1;

where the alkyl groups and cycloalkyl group in the definition of2optionally substituted with hydroxyl, -C(O)OH6C(O)N(X6)(X6), -N(X6)(X6), -S(O)m(C1-C6)alkyl, -C(O)A1, -C(O)(X6), CF3, CN or 1 to 3 halogen atoms;

R3represents A1, (C1-C10)alkyl, -(C1-C6)alkyl-A1, -(C1-C6)alkyl-(C3-C7)cycloalkyl, -(C1-C5)alkyl-X1-(C1-C5)alkyl, -(C1-C5)alkyl-X1-(C0-C5)alkyl-A1or -(C1-C5)-X1-(C1-C5) alkyl- (C3-C7)cycloalkyl;

where the alkyl groups in the definition of R3optionally substituted-S(O)m(C1-C6)alkyl, -C(O)OH3, 1, 2, 3, 4 or 5 halogen atoms or 1, 2 or 3 OH3;

X1denotes O, S(O)m, -N(X2the genus, (C1-C6) alkyl or (C3-C7) cycloalkyl or R4taken together with R3and the carbon atom to which they are connected, form a (C5-C7)cycloalkyl, (C5-C7)cycloalkenyl, partially saturated or fully saturated 4-to 8-membered ring having 1-4 heteroatoms independently selected from the group comprising oxygen, sulfur and nitrogen, or denotes a bicyclic ring system consisting of a partially saturated or fully saturated 5 - or 6-membered ring condensed with a partially saturated, fully unsaturated or fully saturated 5 - or 6-membered ring, optionally having 1-4 heteroatoms independently selected from the group comprising nitrogen, sulfur and oxygen;

X4denotes hydrogen or (C1-C6)-alkyl, or X4taken together with R4and the nitrogen atom to which X4connected, and the carbon atom to which R4connected, forms a 5-7-membered ring;

R6means a connection or is a

< / BR>
where a and b are independently 0, 1, 2 or 3;

X5and X5aeach independently selected from the group comprising hydrogen, trifluoromethyl, AND1and optionally substituted (C1-C6) alkyl;
Yong Deputy selected from the group including BUT1, OX2, -S(O)m(C1-C6) alkyl, -C(O)OX2, (C3-C7) cycloalkyl, -N(X2)(X2and-C(O)N(X2)(X2); or the carbon bearing X5or X5aforms one or two alkilinity bridge with the nitrogen atom bearing Z200and R8and each alkilinity the bridge contains 1 to 5 carbon atoms, provided that, when there is one Allenby bridge, X5or X5abut not both, may be on the carbon atom and Z200or R8but not both, may be on the nitrogen atom;

or X5taken together with X5aand the carbon atom to which they are connected, form a partially saturated or fully saturated 3 to 7 membered ring or a partially saturated or fully saturated 4-to 8-membered ring having 1-4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen;

or X5taken together with X5aand the carbon atom to which they are connected, form a bicyclic ring system consisting of a partially saturated or fully saturated 5 - or 6-membered ring, optionally having 1 or 2 heteroatoms, independently selected from the group comprising nitrogen, sulfur and oxygen, condens is definitely having 1-4 heteroatoms, independently selected from the group comprising nitrogen, sulfur and oxygen;

Z1denotes a bond, O or N-X2provided that when a and b both equal to 0, Z1is not N-X2or;

R8denotes hydrogen or optionally substituted C1-C6) alkyl;

where the optionally substituted (C1-C6)alkyl in the definition of R8optionally independently substituted AND1, -C(O)O-(C1-C6)alkyl, -S(O)m(C1-C6)alkyl, 1-5-halogen atoms, 1-3 hydroxy, 1-3-O-C(O)(C1-C10)alkyl or 1-3 (C1-C6)alkoxy;

AND1in each case independently denotes (C5-C7)cycloalkenyl, phenyl or a partially saturated, fully saturated or fully unsaturated 4-to 8-membered ring having 1-4 heteroatoms independently selected from the group comprising oxygen, sulfur and nitrogen, or a bicyclic ring system consisting of a partially saturated, fully unsaturated or fully saturated 5 - or 6-membered ring, optionally having 1-4 heteroatoms independently selected from the group comprising nitrogen, sulfur and oxygen, fused to a partially saturated, fully saturated or fully unsaturated 5 - or 6-member is oxygen;

AND1in each case independently optionally substituted at one or optionally both rings if AND1is a bicyclic ring system, and has up to 3 substituents, each Deputy is independently selected from the group comprising F, Cl, Br, I, OCF3, OCF2H, CF3CH3, OCH3, -OH6, -C(O)N(X6)(X6), - C(O)OH6, oxo, (C1-C6)alkyl, nitro, cyano, benzyl, -S(O)m(C1-C6)alkyl, 1H-tetrazol-5-yl, phenyl, phenoxy, phenylalkylamine, halogenfree, methylendioxy, N(X6)(X6), -N(X6)C(O)(X6), - SO2N(X6)(X6), N(X6)SO2-phenyl, -N(X6)SO2X6, -CONX11X12, - SO2NX11X12, -NX6SO2X12, -NX6CONX11X12, -NX6SO2NX11X12, - NX6C(O)X12imidazolyl, thiazolyl or tetrazolyl, provided that, if a1optionally substituted, methylendioxy, it can be replaced by only one methylenedioxy;

where X11denotes hydrogen or optionally substituted C1-C6)alkyl;

optionally substituted (C1-C6)alkyl defined for X12, optionally substituted phenyl, phenoxy, (C1-C10)alkanoyloxy or 1-3 (C1-C6) alkoxy;

X12denotes hydrogen, (C1-C6)alkyl, phenyl, thiazolyl, imidazolyl, furyl or thienyl provided that, when X12is not hydrogen, X12optionally substituted with one to three substituents, independently selected from the group comprising Cl, F, CH3, OCH3, OCF3and CF3;

or X11and X12taken together form - (CH2)r-L1-(CH2)r;

L1denotes C(X2)(X2), O, S(O)mor N(X2);

r in each case independently denotes 1, 2 or 3;

X2for each case independently denotes hydrogen, optionally substituted (C1-C6)alkyl or optionally substituted (C3-C7)cycloalkyl, and optionally substituted C1-C6)alkyl and optionally substituted (C3-C7) cycloalkyl in the definition of X2optionally independently substituted S(O)m(C1-C6)alkyl, -C(O)OH3from 1-5 halogen atoms, or 1-3 OH3;

X3for each case independently denotes hydrogen or (C1-C6)alkyl;

X6for each case independently denotes hydrogen, neomenia (C3-C7)cycloalkyl, (C3-C7)-halogenated cycloalkyl, and optionally substituted C1-C6)alkyl and optionally substituted (C3-C7) cycloalkyl in the definition of X6optionally independently substituted with hydroxyl, (C1-C4) alkoxy, carboxyla, CONH2, -S(O)m(C1-C6)alkyl, CO2-(C1-C4)alkyl, 1H-tetrazol-5-yl or 1-2 (C1-C4) alkilani; or when one atom there are two groups of X6and both X6are independently (C1- C6)-alkyl, the two (C1-C6)-alkyl groups may be optionally joined, together with the atom to which the two groups X6connected with the formation of a 4-9-membered ring optionally having oxygen, sulfur or NX7;

X7denotes hydrogen or (C1-C6)-alkyl, optionally substituted by hydroxyl; and

m in each case independently is 0, 1 or 2;

provided that

X6and X12cannot be hydrogen when they are connected with C(O) or SO2in the form C(O)X6C(O)X12, SO2X6or SO2X12; and when R6is a bond, L is N(X2) and each r in the definition of

-(CH1represents-CH2is phenyl; R2represents methyl or hydrogen; n is 1; w is 1; R3represents-CH2-O-CH2is phenyl; R4represents hydrogen; X4represents hydrogen; R6represents - C(CH3)2-; Z200represents BOC and R8represents hydrogen.

This invention also provides:

a method of increasing levels of endogenous growth hormone in humans or other animal, which includes the introduction of such human or animal an effective amount of the compounds of formula I;

pharmaceutical composition suitable for amplification of the endogenous formation or release of growth hormone in humans or other animal containing an inert carrier and an effective amount of the compounds of formula I;

pharmaceutical composition suitable for amplification of the endogenous formation or release of growth hormone in humans or other animal containing an inert carrier, an effective amount of the compounds of formula I and another stimulator of growth hormone secretion, such as GHRP-actici osteoporosis, which includes the introduction of a human or other animal in need of such treatment or prevention, the number of the compounds of formula I effective in treating or preventing osteoporosis;

method for the treatment or prevention of osteoporosis which comprises the administration to a human or other animal suffering from osteoporosis, a combination biphosphonates compounds such as alendronate, and particularly preferably biphosphonates connection ibandronate, and the compounds of formula I;

method for the treatment or prevention of osteoporosis which comprises the administration to a human or other animal with osteoporosis a combination of estrogen or Premarinand the compounds of formula I and, optionally, progesterone;

the way to increase the levels of IGF-1 in humans or other animal with deficiency of IGF-1, which includes the introduction of man or other animals with deficiency of IGF-1 compounds of formula I;

a method of treating osteoporosis which comprises the administration to a human or other animal with osteoporosis a combination of an agonist or antagonist of estrogen such as tamoxifen, droloxifene, raloxifene and idoxifene, and the compounds of formula I;

especially preferred method of treatment of osteoporosis VNA, such as CIS-6-(4 - forfinal)-5-[4-(2-piperidine-1-ylethoxy)-phenyl] -5,6,7,8 - tetrahydronaphthalen-2-ol;

(-)-CIS-6-phenyl-5-[4-(2-pyrrolidin - 1 ylethoxy)-phenyl] -5,6,7,8-tetrahydronaphthalen-2-ol;

CIS-6-phenyl-5-[4-(2-pyrrolidin-1 ylethoxy] -5,6,7,8-tetrahydronaphthalen - 2-ol,

CIS-1-[6'-pyrrolidinone-3'-pyridyl] -2-phenyl-6-hydroxy-1,2,3,4-tetrahydronaphthalen;

1-(4-pyrrolidinecarbonyl)-2-(4"-forfinal) -6-hydroxy-1,2,3,4-tetrahydroisoquinoline;

CIS-6-(4-hydroxyphenyl)-5-[4-(2-piperidine-1-ylethoxy)-phenyl] -5,6, 7,8-tetrahydronaphthalen-2-ol; or

1-(4-pyrrolidinecarbonyl)-2-phenyl-6-hydroxy-1,2,3,4 - tetrahydroisoquinoline, and the compounds of formula I;

a method of treating osteoporosis which comprises the administration to a human or other animal with osteoporosis a combination of calcitonin and the compounds of formula I;

the way to increase muscle mass, which includes the introduction of a human or other animal in need of such treatment, the amount of compounds of formula I which is effective in increasing the release of endogenous growth hormone; and

method of strengthening growth in children with growth hormone deficiency, which includes the introduction of a child with growth hormone deficiency amount of the compounds of formula I effective in increasing vysvobojdenie diseases or conditions, which can be treated or prevented by growth hormone, which comprises the administration to a human or other animal in need of such treatment or prevention, the number of the compounds of formula I which is effective in increasing the release of endogenous growth hormone.

In another aspect, the invention provides methods of treatment or prevention of congestive heart failure, frailty associated with aging, and obesity, introducing a person or other animal in need of such treatment or prevention, the number of the compounds of formula I which is effective in increasing the release of endogenous growth hormone; in the case of this method, preferably, the disease or condition under treatment or prevention were congestive heart failure or weakness associated with aging.

In another aspect, the invention provides methods of promoting the healing of bone fractures, attenuation of protein catabolic response after major surgery, reducing cachexia and protein loss caused by chronic disease, such as AIDS and cancer, accelerate wound healing and escortsalabama introduction to human or other animal, in need of such treatment, the amount of compounds of formula I effective in increasing the release of endogenous growth hormone; in the case of this preferred method is to use it to accelerate healing of bone fractures or for accelerating the recovery of patients after extensive surgery.

In another aspect, the invention provides methods of improving muscle strength, mobility, maintenance of skin thickness, metabolic homeostasis and renal homeostasis, which includes the introduction of a human or other animal in need of such treatment, the number of connections p. 1 claims, which is effective in increasing the release of endogenous growth hormone.

The described connections accelerate the release of growth hormone, which is stable under various physiological conditions and can be parenteral, nasal or oral.

Detailed description of the invention

The person skilled in the art it will be clear that some of the substituents listed in this invention can have reduced chemical stability in combination with each other or with heteroatoms in these compounds. Such connection is rmula I can be obtained by means which include methods known in the fields of chemistry, providing for the formation of compounds. Some processes for producing compounds of formula I are provided here as additional characteristics of this invention and are illustrated by the following further schemes reactions.

In the above structural formulas and throughout this application the following terms have these meanings, unless otherwise indicated.

Alkyl groups include alkyl groups specified length straight or branched configuration, which may optionally contain a double or triple bond. Examples of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, allyl, ethinyl, propinyl, butadienyl, hexenyl etc.

When the definition has a0is alkyl, it means ordinary covalent bond.

Alkoxygroup mentioned above, include alkoxygroup specified length straight or branched configuration, which may optionally contain a double or triple bond. Examples of such alkoxygroup are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentek>/P>The term "halogen" or "halo" includes halogen atoms, fluorine, chlorine, bromine and iodine.

The term "halogenated alkyl" includes an alkyl group as defined above, substituted by one or more halogen atoms as defined above.

The term "halogenated cycloalkyl includes cycloalkyl group, substituted by one or more halogen atoms as defined above.

The term "aryl" includes phenyl and naphthyl and aromatic 5-6-membered rings with 1-4 heteroatoms, or a condensed 5 - or 6-membered bicyclic rings with 1-4 heteroatoms of nitrogen, sulfur or oxygen. Examples of such heterocyclic aromatic rings are pyridine, thiophene (also known as Teenel), furan, benzothiophene, tetrazole, indole, N-methylindole, dihydroindol, indazole, N-formylindole, benzimidazole, thiazole, pyrimidine, and thiadiazole.

The chemist of ordinary skill will understand that some combinations containing heteroatom substituents listed in this invention, identify the connections that will be less stable under physiological conditions (for example, compounds containing acetylene or analnye communication). Therefore, these compounds are less predoc medicines, after the introduction of free drug in vivo via some chemical or physiological process (e.g., a prodrug when released into the environment with physiological pH is converted to the desired form of the drug). Given as examples of prodrugs release the corresponding free acid, and such hydrolyzable forming the ester residues of the compounds of this invention include (but are not limited to) the Vice-derived carboxylic acids (for example, R1means (CH2)qC(O)2X6where X6denotes hydrogen, or R2or AND1contain carboxylic acid), in which free hydrogen is replaced by (C1-C4)alkyl, (C2-C12) alkanoyloxy, (C4-C9)-1-(alkanoyloxy) ethyl, 1-methyl-1-(alkanoyloxy)-ethyl having 5-10 carbon atoms, alkoxycarbonylmethyl having 3-6 carbon atoms, 1-(alkoxycarbonyl) ethyl having 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyl)-ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having 3-9 carbon atoms, 1-(N-(alkoxycarbonyl)amino) ethyl having 4 to 10 carbon atoms, 3-phthalidyl, 4 - crotononitrile, gamma-butyrolactone-4-dimethylaminoethyl), carbarnoyl-(C1-C2) alkyl, N, N-di (C1-C2-allylcarbamate-(C1-C2) alkyl and piperidino-, pyrrolidino or morpholino (C2-C3)alkyl.

Other cited as examples of prodrugs release an alcohol of formula I, in which free hydrogen of the hydroxyl substituent (e.g., R1contains hydroxyl) is replaced by (C1-C6) alkanoyloxy, 1-((C1-C6)alkanoyloxy)ethyl, 1-methyl-1-((C1-C6) alkanoyloxy) ethyl, (C1-C6) alkoxycarbonylmethyl, N-(C1-C6) alkoxycarbonylmethyl, succinoyl, (C1-C6)alkanoyl, -amino (C1-C4)alkanoyl, allocation-aminoacyl or aminoacyl-aminoacyl, where these aminoaniline parts are any of prirodnoisredy L-amino acids found in proteins, P(O)(OH)2-P(O)(O)(C1-C6)alkyl)2or glikozidom (the radical resulting from the separation of the hydroxyl polyacetale carbohydrate).

Prodrugs of this invention where a carboxyl group in a carboxylic acid of the formula (I) is replaced by ether can be obtained by combining the carboxylic acid with a suitable at a temperature of ~0oC - 100oC for ~1 - ~24 hours. Alternatively, the acid combine with the appropriate alcohol as solvent in the presence of catalytic amount of acid such as concentrated sulfuric acid, at a temperature of ~20oC - 120oC, preferably at reflux, for ~ 1 - ~ 24 hours. Another method is the reaction of this acid in an inert solvent, such as THF, with simultaneous removal of water, performed physical (e.g., trap Dean-Stark) or chemical (e.g., molecular sieves) means.

Prodrugs of the present invention, in which the alcohol group was used for the formation of a derivative in the form of a simple ester, can be obtained by combining the alcohol with the appropriate alkylbromides or iodide in the presence of a base such as potassium carbonate, in an inert solvent, such as DMF, at a temperature of ~ 0 - 100oC for ~ 1 - ~ 24 hours. Alkanolamines ethers can be obtained by the reaction of alcohol with bis-(alkanolamine) methane in the presence of catalytic amount of acid in an inert solvent, such as THF, according to the method described in US 4997984. Alternatively, these compounds may b the Minov can occur more than once in the above formula and in such cases each term shall be defined independently of the others.

Throughout the description and the attached claims are used the following abbreviations with the following values:

BOC - tert-butyloxycarbonyl

THIEF-Benzotriazol-1-yloxytris(dimethylamino)-phosphonium-hexaphosphate

CBZ - benzyloxycarbonyl,

CDI - N,N'-carbonyldiimidazole,

CH2Cl2- methylene chloride,

CHCl2- chloroform,

DCC - dicyclohexylcarbodiimide,

DMF - dimethylformamide,

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

EtOAc is ethyl acetate;

FMOC - 9-fluorenylmethoxycarbonyl,

h - hours,

Hex - hexane,

HOAT is 1-hydroxy-7-asobancaria,

HOBT - hydrate hydroxybenzotriazole,

HPLC - liquid chromatography high-pressure,

MHz - megahertz,

MS is mass spectrum,

NMR - nuclear magnetic resonance,

PTH - parathyroid hormone,

TFA - triperoxonane acid,

THF is tetrahydrofuran,

TLC - thin layer chromatography,

TRH - thyrotropin releasing hormone

TROC - 2,2,2-trichlorocyanuric.

All the compounds of this invention have at least one asymmetric centre, marked with an asterisk in the structural formula I, above. Additional asymmetric centers could the unbalanced center will produce two optical isomers, and we mean that all such optical isomers are separated, pure or partially purified optical isomers, racemic mixture, or diastereomer mixture, included in the scope of this invention. In the case of the asymmetric center represented by the asterisk, it was found that the absolute stereochemistry more active and thus more preferred isomer is shown in formula IA. This preferred absolute configuration is also applicable to formula I.

< / BR>
With hydrogen as the substituent R4the spatial configuration of the asymmetric center corresponds to the configuration in the D-amino acid. In most cases it is also referred to as R-configuration, although it will vary in accordance with the values of R3and R4used in obtaining the R - or S-stereochemical structures.

These compounds are usually isolated in the form of their pharmaceutically acceptable acid additive salts, such as salts derived from inorganic and organic acids. Examples of such acids are hydrochloric, nitric, sulfuric, phosphoric, formic, acetic, triperoxonane, progynova, maleic, succinic, D-tartaric, L-tartaric, malonic, MEA, can be allocated in the form of their inorganic salts, in which the counterion may be selected from sodium, potassium, lithium, calcium, magnesium, etc. and organic bases.

Pharmaceutically acceptable salts are obtained by taking ~1 equivalent of the compound of formula I and contacting it with about 1 equivalent of a suitable acid salt, which is desirable. Processing and isolation of the salts is well known to specialists of ordinary skill in this field.

Releasing hormone compounds of formula I are applicable in vitro as unique tools for understanding how regulated the secretion of growth hormone at the level of the pituitary. Clarifying this includes use in the assessment of many factors in respect of which it is assumed or known that they affect the secretion of growth hormone, such as age, gender, nutrition, glucose, amino acids, fatty acids, and of abstinence from food or non-restraint. In addition, the compounds of this invention can be used in the evaluation of how other hormones modify releasing the growth hormone activity. For example, it was found that somatostatin inhibits the release of growth hormone.

Connection applicable for the treatment of symptoms related deficits GR; to promote growth or improve feed utilization in animals intended for meat production, to improve carcass quality; to increase milk yield in dairy cattle; to improve the healing of bones or wounds and improve the function of vital organs. The compounds of this invention by inducing the secretion of endogenous GR will alter body composition and modify other dependent GR metabolic, immunological processes, or processes related to development. For example, the compounds of this invention can be given to chickens, turkeys, livestock (such as sheep, pigs, horses, cattle etc), domestic animals (e.g. dogs) or they can be used in agriculture to accelerate growth and improve relations protein/fat. In addition, these compounds can be administered to humans in vivo as a diagnostic tool to directly determine whether the pituitary to release growth hormone. For example, the compounds of formula I can be administered in vivo to children. Serum samples taken before and after such introduction, can be estimated from the growth hormone. Comparison of quantities of growth hormone in each of these samples would have means of direct apreda includes within its scope pharmaceutical compositions containing as active ingredient at least one of the compounds of the formula I together with a pharmaceutically acceptable carrier. Optionally, the pharmaceutical composition may further comprise an anabolic agent in addition to at least one of the compounds of formula I, or another compound which exhibits a different activity, such as antibiotic growth factor, or agent for the treatment of osteoporosis, or other pharmaceutically active materials, when such combination enhances efficacy and reduces side effects.

Stimulating growth and anabolic agents include, but are not limited to, TRH, PTH, diethylstilbesterol, estrogen agonists, theophylline, anabolic steroids, enkephalins, prostaglandins of series E, the compounds described in US Patent N 3239345, the description of which is incorporated herein by reference, for example, including but; compounds described in US Patent N 4411890, the description of which is incorporated herein by reference.

Stimulators of secretion of growth hormone of the present invention in combination with other stimulants secretion of growth hormone, such as releasing growth hormone peptides GHRP-6 and GHRP-1, described in US Patent N 4411890, the description of which is included here is th at WO/93/04081, or releasing hormone growth hormone (GHRH, also designated as FGR) and its analogs or growth hormone and its analogs or somatomedins, including IGF-1 and IGF-2 or a-adrenergic agonists, such as clonidine or serotonin agonists 5HTID, such as sumitriptan or agents which inhibit somatostatin or its release such as physostigmine and pyridostigmine, are applicable to increase endogenous levels of GR in mammals. The combination of stimulants secretion GR of the present invention with FGR leads to synergistic increases in the levels of endogenous growth hormone.

As is also well known to experts in this field, known and potential use of growth hormone are varied and numerous [Cm. "Human Growth Hormone", Strobel and Thomas, Pharmacological Reviews, 46, p. 1-34 (1994); T. Rosen et al., Horm Res, 1995; 43: pp. 93-99; M. Degerblad et al. European Journal of Endocrinology, 1995, 133 pp. 180-188; J. O. Jorgenson, European Journal of Endocrinology, 1994, 130 pp. 224-228; K. C. Copeland et al. Journal of Clinical Endocrinology and Metabolism, Vol. 78, No. 5, pp. 1040-1047; J. A. Aloi

et al. Journal of Clinical Endocrinology and Metabolism, Vol. 79, No. 4, pp. 943-949; F. Corido et al., Metab. Clin. Exp., (1995), 44(6), pp. 745-748; K. M. Fairhall et al., J. Endocrinol., (1995), 145(3), pp. 417-426; RM. Frieboes et al., Neuroendocrinology, (1995), 61(5), pp. 584-589; and M. Llovera et al. Int. J. Cancer, (1995), 61(1), pp. 138-141]. Thus, the introduction of the compounds of this, and the use as the introduction of the hormone. These diverse applications of growth hormone may be summarized as follows: stimulating the release of growth hormone in older people; the treatment of adults with growth hormone deficiency; prevention of catabolic side effects of glucocorticoids, treatment of osteoporosis, stimulation of the immune system, acceleration of wound healing, accelerating the repair of bone fractures, treatment of slow growth, treatment of congestive heart failure, described in PCT publications WO 95/281173 and WO 95/281174 (an example of a method of analysis stimulators of secretion of growth hormone to be effective in the treatment of congestive heart failure is described in R. Yang et al. Circulation, Vol. 92, No. 2, p. 262, 1995), treatment of acute or chronic renal failure or decompensation, the physiological treatment of low growth, including children with growth hormone deficiency, treatment of low growth associated with chronic illness, treatment of obesity, treatment of the slowdown associated with Prader-Willi syndrome and Turner syndrome; accelerating the recovery and reducing hospitalization of burn patients or following extensive surgery such as gastrointestinal surgery; treatment of the Mona growth under stress patients; treatment of osteochondrodysplasia, Noonan syndrome, sleep disorders, Alzheimer's disease, delayed wound healing and psychosocial deprivation; treatment of dysfunction of the lungs and, depending on the ventilator; attenuation of protein catabolic response after a major surgery; treatment of syndromes poor absorption, reducing cachexia and protein loss caused by chronic disease, such as cancer or AIDS; accelerating weight gain and protein accumulation in patients on total parenteral nutrition (TPN); treatment of hyperinsulinemia including hyperplasia of pancreatic islets; additional treatment for induction of ovulation and for the prevention and treatment of gastric ulcers and duodenal ulcers; stimulation of development of the thymus and the prevention of aging related decline in the function of the thymus; additional therapy for patients with chronic hemodialysis; treatment of patients with a weakened immune system and increased formation of antibodies after vaccination; improving muscle strength, increase muscle mass, mobility, maintenance of skin thickness, metabolic homeostasis, renal homeostasis in the weak old people; stimulation osteoblastoma medicines neuropathy, the Guillain-Barre syndrome, amyotrophic lateral sclerosis, multiple sclerosis, stroke and dimilikinya diseases; stimulation of the immune system in animals and treatment of aging-related disorders in domestic animals; the acceleration of growth in cattle and stimulation of wool growth in sheep.

Professionals in this field know that there are numerous compounds currently used in attempts to treat diseases or therapeutic indications described above. Combinations of these therapeutic agents, some of which are mentioned above, with a growth stimulant are anabolic and desirable properties of these various therapeutic agents. In these combinations of therapeutic agents and stimulants secretion of growth hormone of the present invention can be introduced independently and successively or entered together in the dose ranges from 1/100 to 1 dose of those levels, which are effective for the separate use of these compounds and stimulators of secretion. Combination therapy for the inhibition of bone resorption, osteoporosis prevention, healing of skeletal fracture, accelerate healing of bone fractures, stimulation of bone formation and the s secretion of growth hormone of the present invention, see PCT publication WO 95/11029 for discussion of combination therapy with the use of bisphosphonates and stimulators of GH is secreted. An overview of the use of bisphosphonates for these applications are presented, for example, Hambdy, N. A. T., Role of Bisphosphonates in Metabolic Bone Disease, Trends in Endocrinol. Metab. , 1993, 4, pp. 19-25. Used bisphosphonates include, but are not limited to, alendronate, tiludronate, dimethyl-APD, risedronate, etidronate, YM-175, clodronate, pamidronate and VM-210995 (ibandronate). In accordance with their activity, oral levels of doses of bisphosphonates 0.1 mg to 5 g, and the levels of doses of stimulants secretion of growth hormone 0.01 mg/kg to 20 mg/kg body weight of the patient is injected patients to achieve effective treatment of osteoporosis.

The compounds of this invention can be combined with agonist/antagonist of the estrogen mammal. Any agonist/antagonist of estrogen can be used as the second compound of this invention. The term agonist/antagonist of the estrogen refers to compounds that bind to the estrogen receptor, inhibit the update of the bone and prevent bone loss. In particular, agonists of estrogen is defined here as the chemical compounds that are able to communicate with all possible is how many tissues. Antagonists of estrogen is defined here as chemical compounds which are able to bind to receptor sites of estrogen in tissue of a mammal and to block the actions of estrogen in one or more tissues. Such activity can be easily determined by experts in the field of standard methods, including methods of binding with the estrogen receptor, standard histomorphometric and densitometric methods for the bones (see Eriksen E. F. et al. Bone Histomorphometry, Raven Press, New York, 1994, pp. 1-74; Grier S. J. et al. The Use of Dual-Energy X - Ray Absorptiometry in Animals, Inv. Radiol., 1996, 31(l):50-62; Wahner, H. W. and Fogelman I. , The Evalution of Osteoporosis: Dual Energy X-Ray Absorptiometry in Clinical Practice., Martin Dunitz Ltd., London 1994, pp. 1-296). The diversity of these compounds are described and references are given below, but experts in this field can be known and other agonists/antagonists of estrogen. The preferred agonist/antagonist of estrogen is droloxifene (phenol, 3-[4-[2-dimethylamino)ethoxy] -phenyl] - 2-phenyl-1-butenyl]-, (E)-) and related compounds, which are described in US patent 5047431 (the description of which is incorporated herein by reference).

Other preferred agonist/antagonist of estrogen is tamoxifen (ethanamine, 2-[4-(1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethyl, (Z)-2-, 2 - Giano here as a reference). Another related compound is 4-hydroxytamoxifen, which is described in US patent 4623660 (the description of which is incorporated herein by reference).

Other preferred agonist/antagonist of estrogen is raloxifene (metadon, [6-hydroxy-2-(4-hydroxyphenyl) benzo[b]Tien-3-yl]-[4-[2-(1-piperidinyl)ethoxy] phenyl] -, hydrochloride) and related compounds described in US patent 4418068 (the description of which is incorporated herein by reference).

Other preferred agonist/antagonist of estrogen is idoxifene (pyrrolidone, 1-[4-[[1-(4-itfinal)-2-phenyl - 1-butenyl] phenoxy] ethyl] and related compounds described in US patent 4839155 (the description of which is incorporated herein by reference).

Other preferred agonists/antagonists of estrogen include compounds described in US patent N 5552412, the description of which is incorporated herein by reference. Particularly preferred compounds that are described in it, is given below:

CIS-6-(4-forfinal)-5-[4-(2 -piperidine-1-ylethoxy)-phenyl] -5,6,7,8-tetrahydronaphthalen-2-ol;

(-)-CIS-6-phenyl-5-[4-(2-pyrrolidin-1 ylethoxy)-phenyl] - 5,6,7,8-tetrahydronaphthalen-2-ol;

CIS-6-phenyl-5-[4-(2-pyrrolidin-1 ylethoxy] -5,6,7,8-tetrahydronaphthalen-2-ol;

CIS-1-[6'-pyrrolidine what - hydroxy-1,2,3,4-tetrahydroisoquinoline;

CIS-6-(4-hydroxyphenyl)-5-[4-(2 -piperidine-1-ylethoxy)-phenyl] -5,6,7, 8-tetrahydronaphthalen-2-ol; and

1-(4'-pyrrolidinecarbonyl)-2 - phenyl-6-hydroxy-1,2,3,4 - tetrahydroisoquinoline.

Other agonists/antagonists of estrogen described in US patent 4133814 (the description of which is incorporated herein by reference). In US patent 4133814 described derivatives of 2-phenyl-3-aeroelasticity and 2-phenyl-3-koivistoinen-1-oxide.

The following paragraphs give the preferred dose ranges for various antiresorption agents.

The number antiresorptive agent that should be used is determined by its activity as an inhibitor of rarefication (osteoporosis) bone. This activity is determined by determining the pharmacokinetics of individual compounds and its minimum and maximum effective dose in the inhibition of rarefication bones using the Protocol mentioned above.

Typically, an effective dosage for the activities of this invention, for example, for the treatment of osteoporosis, for agonists/antagonists of estrogen (when used with a compound of formula I of this invention) is in the range of 0.01 - 200 mg/kg/day, preferably 0.5 to 100 mg/kg/day.

In particular,S="ptx2">

In particular, an effective dosage for raloxifene is in the range of 0.1 - 100 mg/kg/day, preferably 0.1 to 10 mg/kg/day.

In particular, an effective dosage for tamoxifen is in the range of 0.1 - 100 mg/kg/day, preferably 0.1 to 5 mg/kg/day.

In particular, the effective dose for connections:

CIS-6-(4-forfinal)-5-[4-(2- piperidine-1-ylethoxy)-phenyl] -5,6, 7,8-tetrahydronaphthalen-2-ol;

(-)-CIS-6-phenyl-5-[4-(2 - pyrrolidin-1 ylethoxy)-phenyl] -5,6,7,8 - tetrahydronaphthalen-2-ol;

CIS-6-phenyl-5-[4- (2-pyrrolidin-1 ylethoxy] -5,6,7,8-tetrahydronaphthalen-2-ol;

CIS-1-[6'-pyrrolidinone-3' -pyridyl] -2-phenyl-6-hydroxy-1,2,3,4 - tetrahydronaphthalen;

1-(4'-pyrrolidinecarbonyl) -2-(4"-forfinal) -6-hydroxy-1,2,3,4-tetrahydroisoquinoline;

CIS-6-(4-hydroxyphenyl)-5-[4-(2-piperidine-1-ylethoxy)-phenyl] - 5,6,7,8-tetrahydronaphthalen-2-ol; or

1-(4'-pyrrolidinecarbonyl) -2-phenyl-6-hydroxy-1,2,3, 4-tetrahydroisoquinoline is in the range of 0.0001 - 100 mg/kg/day, preferably 0.001 to 10 mg/kg/day.

In particular, the effective dose for 4-hydroxytamoxifen is in the range of 0.0001 - 100 mg/kg/day, preferably 0.001 to 10 mg/kg/day.

Compounds with the ability to stimulate the secretion of GR stump is Vania with standards to determine the dose levels. Cells are separated from the hypophysis 6-week-old male Wistar rats. After decapitate anterior pituitary is removed in a cold, sterile balanced salt Hanks solution without calcium or magnesium (HBSS). Fabric finely pulverized, and then subjected to two cycles of mechanical dispersion with the enzyme using 10 u/ml of bacterial protease (EC 3.4.24.4, Sigma P-6141) in HBSS. Mixture of fabric is enzyme mix in a rotating flask at 30 rpm in an atmosphere of 5% CO2at ~37oC for approximately 30 minutes, with hand rubbing after ~15 minutes using the pipette 10 ml of This mixture is centrifuged at 200 x g for approximately 5 minutes. To the supernatant add horse serum to neutralize excess protease. The precipitate is re-suspended in fresh protease, stirred for another 30 minutes under the same conditions and manually grind very finely through a needle 23 G. Again add horse serum, and then cells from both digestion products unite, centrifuged (200 x g for ~ 15 minutes), washed, resuspended in culture medium and believe. Cells were seeded at 6.0 to 6.5 104cells / cm248-hole tablets Costar and cultured for 3-4 days in a metal calf serum, 1% non-essential amino acids, 100 u/ml nystatin and 50 mg/ml gentamicin sulfate, prior to determination of secretion GR.

Directly before the test culture wells washed twice, then balance within ~ 30 minutes in the environment for releases (D-MEM, buffered 25 mm HEPES, pH 7.4 and containing 0.5% bovine serum albumin at 37oC). Test compounds dissolved in DMSO, then diluted in pre-warmed medium to release. Tests performed in four replicates. The test is initiated by addition of 0.5 ml of medium for release (with the carrier or with the test compound) in each culture well. Incubation is carried out at ~37oC for 15 minutes, then stopped by removing the culture medium, which is centrifuged at 2000 x g for ~15 minutes to remove cellular material. The concentration of rat growth hormone in supernatant determined according to standard Protocol radioimmunoassay using a reference preparation of rat growth hormone (NIDDK-rGH-RP-2) and antisera against rat growth hormone obtained in monkeys (NIDDK-anti-rGH-S-5) obtained from Dr. A. Parlow (Harbor-UCLA Medical Center, Torrence, CA). Additional rat growth hormone (1,5 E/mg, N G2414, Scripps Labs, S as an indicator. Immune complexes are obtained by adding goat antisera against IgG monkeys (Organon Teknika, Durham, NC) plus polyethylene glycol, MM 10000-20000 to a final concentration of 4.3%; extraction performed by centrifugation. This test has an operating range of 0.08-2.5 µg of rat growth hormone on the tube above the background levels. Active compounds usually stimulate the release of growth hormone more than 1.4 times. Reference: Cheng, K., Chan, W.-S., Barreto, Jr., A., Convey, E. M., Smith, R. G. 1989.

The test to determine whether exogenous stimulated release of growth hormone in rats after intravenous administration of test compounds

The female rats of Sprague-Dawley at the age of 21 days (Charles River Laboratory, Wilmington, MA) and allowed to acclimate to the local vivarium conditions (24oC, a cycle of 12 h light, 12 h dark) for approximately 1 week before testing compounds. All rats given access to water and commercial granular food (Agway County Food, Syracuse NY) ad libitum. Experiments carried out in accordance with the leadership of the NIH Guide for the Care and Use of Laboratory Animals.

On the day of the experiment, the test compound is dissolved in a medium containing 1% ethanol, 1 mm acetic acid and 0.1% bovine serum albumin in saline solution. Each connection is tested with n=3. Rats weighed injection of anesthetic solution take the blood sample rupture tip of the tail, giving blood to drip into microcentrifuge tube (von blood sample, approximately 100 μl). 15 minutes after injection of anesthetic solution of the test compound is administered by intravenous injection into the tail vein, with a total injection volume of 1 ml/kg body weight. Additional blood samples taken from the tail at 5, 10 and 15 minutes after administration of the compound. Blood samples are kept on ice to separate the serum by centrifugation (1430 x q for 10 minutes at 10oC). Serum stored at -80oC before determination of serum growth hormone by radioimmunoassay, as described above and below.

Evaluation of exogenous stimulated release of growth hormone in dogs after oral administration

On the day of the experiment, the test compound is weighed to obtain the appropriate dose and dissolve in water. Dose injected in a volume of 0.5 ml/kg feeding through a stomach tube 4 dogs for each dosing regimen. Blood samples (2 ml) collected from jugular vein by direct puncture of the vein before administration of the dose when 0,08, 0,17, 0,25, 0,5, 0,75, 1, 2, 4, 6 and 8 hours after administration of doses with the use of tanks (vacutainer) in 2 ml containing lithium heparin. The resulting plasma was stored at -20oC until analysis.

Measurement of growth hormone in dogs

the Finance growth hormone dogs (antigen to itinerary and reference drug AFP-1983B) and antisera against growth hormone dogs, formed in monkeys (AFP-21452578) obtained from Dr. A. Parlow (Harbor-UCLA Medical Center, Torrence, CA). The indicator is obtained by itinerantium the way with chloramine T growth hormone dogs to a specific activity of 20-40 µci/µg. Immune complexes are obtained by adding goat antisera against IgG monkeys (Organon Teknika, Durham, NC) plus polyethylene glycol, MM 10000-20000 to a final concentration of 4.3%; extraction performed by centrifugation. This test has an operating range of 0.08-2.5 ág dog GRAMS per tube.

The compounds of this invention can be administered orally, parenteral (e.g. intramuscular, intraperitoneal, intravenous or subcutaneous injection, or implant), nasal, vaginal, rectal, sublingual, or local application and they can be prepared with pharmaceutically acceptable carriers to provide dosage forms appropriate for each route of administration.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage form of the active compound is mixed with at least one pharmaceutically acceptable carrier such as sucrose, lactose or starch. Such metered formerty thinners, for example wetting agents, such as magnesium stearate. In the case of capsules, tablets and pills dosage forms may also contain bufferedio agents. Tablets and pills can be also prepared with intersolubility coverings.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs containing inert diluents commonly used in this field, such as water. Besides such inert diluents, compositions can also include adjuvants, such as specialsee agents, emulsifying and suspendresume agents, and sweetening, improving the taste and smell and flavoring agents.

Preparations according to this invention for parenteral administration include sterile aqueous or nonaqueous solutions, suspensions or emulsions. Examples of nonaqueous solvents or media are propylene glycol, polyethylene glycol, vegetable oils such as olive oil and corn oil, gelatin, and injectable organic esters, such as etiloleat. Such dosage forms may also contain adjuvants such as preserving, specialsee, emulsifying and dispersionen incorporating sterilizing agents into the composition, 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 suitable sterile injectable medium immediately before use.

Compositions for rectal or vaginal injection are preferably suppositories which may contain, besides the active substance, excipients such as cocoa butter or wax for suppositories.

Compositions for nasal and sublingual injection is prepared with standard fillers are well known in this field.

The dose of the active ingredient in the compositions of this invention may vary; however, it is necessary that the amount of active ingredient was such that there was obtained a suitable dosage form. The selected dosage depends upon the desired therapeutic effect, the route of administration and duration of treatment. Typically, the dose levels of 0.0001 and 100 mg/kg of body weight per day is administered to humans and other animals, for example mammals, to obtain effective release of growth hormone.

The preferred dose range sostav the multiple doses.

Obtaining compounds of formula I of this invention can be sequential or convergent synthetic routes. Syntheses, detailing the receipt of the compounds of formula I in a consistent manner presented in the schemes of reactions presented below.

Commercially available are many protected derivatives of amino acids, in which the protective group Prt, Z100and Z200are, for example, the groups BOC, CBZ, benzyl, ethoxycarbonyl groups, CF3C(O)-, FMOC, TROC, Triticum or Totila. Other protected derivatives of amino acids can be obtained by the literature methods. Some 3-oxo-2-carboxyterfenadine and 4-oxo-3-carboxypeptidase are commercially available and many other related pyrrolidine and 4-substituted piperidine known in the literature.

Many schemes (schemes 1 - 27 comments given at the end of the description) describe compounds that contain a protective group Prt, Z100or Z200. Benzyloxycarbonyl group can be removed by several methods, including catalytic hydrogenation with hydrogen in the presence of palladium or platinum catalyst in proton solvent such as metroolitan hydrogen pressure of 1-1000 psi (6894,757-6894757 PA); the preferred pressure 10-70 psi (68947,57-482632,99 PA).

The removal of the BOC protective groups can be performed using a strong acid, such as triperoxonane acid or hydrochloric acid in the presence (or absence) of the co-solvent, such as dichloromethane, ethyl acetate, ether or methanol, at a temperature of ~30 - 70oC, preferably ~5 - ~35oC.

Benzyl esters amines can be removed by several methods including hydrogenation with hydrogen in the presence of palladium catalyst in proton solvent such as methanol. Can be used hydrogen pressure of 1-1000 psi (6894,757-6894757 PA); the preferred pressure 10-70 psi (68947,57-482632,99 PA). Attaching and removing these and other protective groups are discussed in T. Greene in Protective Groups in Organic Synthesis, John Wiley and Sons, New York, 1981.

The following examples are given only for the purpose of further illustration and not intended to be limitations of the described invention.

The basic experimental procedure

Silicon dioxide Amicon 30 μm, the pore size of 60 angstroms, used for column chromatography. The melting point was determined on the device Buchi 510 and they are unadjusted. Spectra of proton and carbon NMR Registrar the field from trimethylsilane. Mass spectra of particle beams received by the spectrometer Hewlett-Packard A using ammonia as a source of chemical ionization. For the initial dissolution of the sample used chloroform or methanol. Mass spectra LSIMS (liquid secondary ion) received on the high-resolution spectrometer

Kratos Concept 1S using a cesium ion bombardment on the sample, dissolved in a mixture of 1:5 dithioerythritol and dithiothreitol, or tagliarino matrix. For the initial dissolution of the sample used chloroform or methanol. Data reported are the sums 3-20 scans, calibrated against cesium iodide. The TLC analyses were performed with the use of plates with silicon dioxide E. Merck Kieselgel 60 F254, with visualization (after elution the specified solvent (solvents)) staining of 15% phosphomolybdic acid in ethanol and heated on a hot plate. The basic procedure A (peptide binding using EDC): 0.2-0.5 M solution of the primary amine (1.0 equivalent) in dichloromethane (or hydrochloride primary amine and 1.0-1.3 equivalents of triethylamine) is treated sequentially with 1.0 to 1.2 equivalents of carboxylic acid as a binding partner, 1.5 and 1.8 equivalents of hydroxybenzotriazole hydrate (HOBT or HOAT and 1.0 to 1.2 equivalent of ethylcarbodiimide (EDC) and the mixture is stirred overnight at a bath with ice bath with ice and allowed to warm, therefore, the reaction mixture is typically incubated at a temperature of approximately 0-20oC for about 4-6 hours and at approximately 20-25oC during the remaining period). The mixture is diluted with ethyl acetate or other solvent, as indicated, and the resulting mixture was washed twice 1 N. NaOH, twice 1 N. HCl (if the product is not the main), once with brine, dried over Na2SO4and concentrate to obtain the crude product, which was purified as specified. Component of the carboxylic acid may be used in the form of salts dicyclohexylamine in binding, primary amine or its hydrochloride; in this case, use the triethylamine.

Example 1

2-Amino-N-{ 1(R)- benzoyloxymethyl-2-[3A-(R) - (4-terbisil)-2-methyl-3-oxo - 2,3,3 a,4,6,7-hexahydropyrazino [4,3-c]pyridine-5-yl]- 2-oxoethyl}-isobutyramide, cleaners containing hydrochloride salt and

2-Amino-N-{ 1(R)-benzoyloxymethyl-2-[3a-(S)-(4-terbisil) -2-methyl-3-oxo-2,3,3 a, 4,6,7 there is hexahydropyrazino [4,3-C] pyridine-5-yl]-2-oxoethyl}-isobutyramide, cleaners containing hydrochloride salt

A. 4-Oxo piperidine-1,3-dicarboxylic acid, 1 - tributyl ether, 3-ethyl ester

A mixture of 8.00 g (a 38.5 mmol) of the hydrochloride of the ethyl ester of 4-oxopiperidin-3-carboxylic acid, 9,23 g (42,4 MB for about 72 hours. The mixture was concentrated and the residue was dissolved in ethyl acetate and washed three times (each solution) 10% aqueous HCl, saturated aqueous sodium bicarbonate and brine, dried over MgSO4m was concentrated to obtain 10.0 g 1A as a white solid. MS (Cl, NH3) 272 (MH+).

Century 3-(R, S)-(4-Terbisil)-4-oxopiperidin-1, 3 - dicarboxylic acid 1-tert-butyl ether, 3-ethyl ester

To a solution of 2.00 g (7.4 mmol) in 10 ml DMF was added 282 mg (7.4 mmol) of sodium hydride (60% oil dispersion) and the mixture was stirred at room temperature for ~15 minutes. To the stirred solution was added a solution of 1.39 g (7.4 mmol) of 4 - ftorangidridy in 7 ml of DMF and the mixture was stirred for about 72 hours at room temperature. The mixture was diluted with ethyl acetate and washed once with water and four times with saline, dried over MgSO4and concentrated to obtain 2.8 g 1B. MS (Cl, NH3) 380 (MH+).

C. 3a-(R, S)-(4-Terbisil)-2-methyl-3-oxo-2, 3,3 a,4,6,7-hexahydropyrazino [4,3-c] pyridine-5-carboxylic acid, tert-butyl methyl ether

A mixture of 2.54 g (6.7 mmol) of 1B and 309 mg (6.7 mmol) of methylhydrazine in 100 ml of ethanol was heated under reflux for ~ 8 hours. The mixture was concentrational and the residue was purified by chromatography on silica gel with elution with a gradient (18:82 (V/V) ethyl acetate: hexane) - (75: 25 (V/V) ethyl acetate:hexane) to give 1.0 g 1C in the form of a colorless transparent oil. MS (Cl, NH3) 362 (MH+).

D. 3a-(R, S)-(4-Terbisil)-2-methyl-2,3 a, 4,5,6,7-hexahydropyrazino [4,3-c]pyridine-3-one, triptorelin

To 1.00 g (2.8 mmol) of 1C was added 10 ml triperoxonane acid at ~ 0oC and the mixture was stirred for ~ 1 hour. Added ethyl acetate and the mixture was concentrated to obtain 1.0 g 1D. MS (Cl, NH3) 263 (MH+).

E. (R)-3-Benzyloxy-2-(2-tert-butoxycarbonylamino-2-methylpropionamide) -propionic acid

To 1,83 g (6.2 mmol) of N-tert-BOC-O-benzyl-D-serine in 35 ml of DMF was added 1,02 g (7.4 mmol) of potassium carbonate and then 0,92 g (6.5 mmol) of iodomethane. The mixture was stirred over night at ~24oC in nitrogen atmosphere. The reaction mixture was diluted with 200 ml of water and was extracted with ethyl acetate three times. The combined organic extracts were washed five times with water and once with brine, dried over MgSO4and concentrated. The crude methyl ester (R)-3-benzyloxy-2-tert-butoxycarbonylamino acid was dissolved in 15 ml of cold triperoxonane acid at ~0oC and the mixture was stirred for ~1 hour. The mixture was concentrated and the residue was diluted 1 N. NaOH and was extracted three is B>4to obtain 0.84 g (4.02 mmol) of the methyl ester of (R)-2-amino-3-benzyloxypropionic acid, which is linked from 0.81 g (4.02 mmol) of N-tBOC-methylamine with the receipt of 1.80 g of methyl ester of (R)-3-benzyloxy-2-(2-tertbutoxycarbonyl - 2-methylpropionamide)-propionic acid. The crude product was dissolved in 20 ml of a mixture of 4:1 THF: water and to the solution was added a solution of 335 mg (7,98 mmol) hydrate of lithium hydroxide in 1 ml of water and the mixture was stirred over night at room temperature. The mixture was concentrated and the residue was diluted with ethyl acetate and acidified with an aqueous solution of HCl and was extracted with ethyl acetate three times. The organic extracts were combined and washed once with saline, dried over Na2SO4and concentrated to obtain 1.60 g 1E in the form of oil, which was aterials when standing.

1H NMR (CDCl3300 MHz): 7.30 (m, 5H), 7.10 (d, 1H), 5.07 (bs, 1H), 4.68 (m, 1H), 4.53 (q, 2H) 4.09 (m, 1H), 3.68 (m, 1H), 1.3-1.5 (m, 15H).

F. (1-{1(R,S)-Benzoyloxymethyl-2-[3A-(R,S)-(4-terbisil) -2-methyl-3-oxo -2,3,3 a, 4,6,7 there is hexahydropyrazino [4,3-c]pyridine - 5-yl]-2-oxoethylidene} -1-methylethyl) - karamanova acid, tert-butyl methyl ether

According to the method described in the Basic procedure And, 193 mg (0.51 mmol) of 1D and 196 mg (0.51 mmol) of 1E were connected with obtaining exan) - 100% ethyl acetate to obtain 60 mg of the less polar 1F isomer 1 and 100 mg of the more polar 1F isomer 2. MS (Cl, NH3) 624 (MH+for both isomers.

G. 2-Amino-N-{1(R)-benzoyloxymethyl-2-[3A-(R) - (4-terbisil)-2-methyl-3-oxo -2,3,3 a, 4,6,7 there is hexahydropyrazino [4, 3-c]pyridine-5-yl]-2-oxoethyl}- isobutyramide, hydrochloride

To 60 mg (0.10 mmol) 1F isomer 1 in 10 ml of ethanol was added 4 ml of concentrated HCl and the mixture was stirred at room temperature for about 2 hours. The mixture was concentrated and the residue was besieged from a mixture of ethanol/hexane to obtain 50 mg 1G isomer 1 as a white powder. MS (Cl, NH3) 524 (MH+).

1H NMR (CD3OD): (partial) 7.32 (m, 5H), 7.12 (m, 2H), 6.91 (m, 2H), 5.15 (m, 1H), 4.54 (s, 2H), 3.78 (m, 2H), 3.02 (m, 7H), 2.66 (m, 2H), 1.57 (s, 6H).

H. 2-Amino-N-{1(R)-benzoyloxymethyl-2-[3A-(R)-(4 - terbisil)-2-methyl-3 - oxo-2,3,3 a, 4,6,7 there is hexahydropyrazino [4,3-c] pyridine-5-yl] -2-oxoethyl}-isobutyramide, hydrochloride

To 100 mg (0.16 mmol) of 1F isomer 2 in 10 ml of ethanol was added 4 ml of concentrated HCl and the mixture was stirred at room temperature for ~ 2 hours. The mixture was concentrated and the residue was besieged from a mixture of ethanol/hexane to obtain the 1H isomer 2 as a white powder. MS (Cl, NH3) 524 (MH+).

1H NMR (CD3OD): (partia,S)-(4-terbisil)-2-methyl-3-oxo-2,3,3 a,4,6,7-hexahydropyrazino [4,3-c]pyridine - 5-yl]-1(R)-(1H-indol-3-ylmethyl)-2-oxoethyl]-isobutyramide, hydrochloride

A.(R)-2-Amino-3-[(1H-indol-3-yl)-propionic acid, methyl ester

To to 4.92 g (16.2 mmol) of N-tert-BOC-D-tryptophan in 100 ml of DMF was added to 2.46 g (17.8 mmol) of potassium carbonate and then to 2.41 g in (17.0 mmol) of iodomethane and the mixture was stirred over night at the 24oC in nitrogen atmosphere. The reaction mixture was diluted with water and was extracted three times with ethyl acetate. The combined organic extracts were washed five times with 500 ml of water and once with brine, dried over MgSO4and concentrated with the receipt of 4.67 g of a white solid. To the crude methyl ether (R)-2-tert-butoxycarbonylamino-3-(1H-indol-3-yl)-propionic acid was added 15 ml of cold triperoxonane acid at ~0oC and the mixture was stirred for ~2 hours. The mixture was concentrated and the residue was diluted 1 N. NaOH and was extracted with ethyl acetate three times. The combined organic extracts were washed with saline and dried over Na2SO4obtaining methyl ester (R)-2-amino-3-(1H-indol-3-yl)-propionic acid as an orange oil in quantitative yield.

C. (R)-2-(2-tert-Butoxycarbonylamino-2-methylpropionamide)-3- (1H-indol-3-yl)-propionic acid, methyl ester

The crude product 2A of 1.55 g (7,Ali chromatography on silica gel with elution with a gradient of 10%, 20%, 30%, 40% and 50% ethyl acetate in hexane. Took 1,32 g of methyl ester of (R)-2-(2-tert - butoxycarbonylamino-2-methylpropionamide)-3-(1H-indol-3-yl) - propionic acid.

C. (R)-2-(2-tert-Butoxycarbonylamino-2-methylpropionamide)-3- (1H-indol-3-yl)-propionic acid

To a solution of 1.03 g (of 2.64 mmol) of 2B in 10 ml of THF was added 381 g (9.1 mmol) of hydrate of lithium hydroxide in 2 ml water and the mixture was stirred over night at room temperature. Excess THF was removed by evaporation and the alkaline aqueous mixture was extracted with ethyl acetate three times, and then acidified to pH 4 with diluted acetic or hydrochloric acid. The product was extracted with ethyl acetate and the combined organic extracts were washed with saline, dried over MgSO4and evaporated obtaining of 1.03 g 2C in the form of an orange foam. MS (Cl, NH3) 390 (MH+).

1H NMR (CDCl3300 MHz): 7.61 (d, 1H), 7.48 (d, 1H), 7.27 (t, 1H), 7.10 (t, 1H), 4.81 (bs, 1H), 3.35 (m.1H), 1.49 (s, 6H), 1.32 (s, 9H).

D. {1-[2-[3a-(R,S)-(4-Terbisil) -2-methyl-3-oxo-2,3,3 a,4,6,7 - hexahydropyrazino [4,3-C] pyridine-5-yl] -1-(R)-(1H-indol-3-ylmethyl) -2-oxoethylidene]-1-methylethyl}-karamanova acid, tert-butyl methyl ether

According to the method described in the basic procedure And, 193 mg (0.51 mmol) of 1D and 200 mg (0.51 mmol) 2C connected at to obtain 230 mg of 2D. MS (Cl, NH2) 633 (MH+).

E. 2-Amino-N-2-[3A-(R,S)-(4-terbisil)-2-methyl-3-oxo-2, 3, 3A,4,6,7-hexahydropyrazino[4,3-c] pyridine-5-yl] -1(R)-(1H-indol-3-ylmethyl)-2-oxoethyl]-isobutyramide, hydrochloride

To 230 mg (0.36 mmol) 2D in 10 ml of ethanol was added 4 ml of concentrated HCl and the mixture was stirred at room temperature for ~2 hours. The mixture was concentrated and the residue was besieged from a mixture of ethanol/hexane to obtain 130 mg of 2E as a white powder. MS (Cl, NH3) 533 (MH+).

1H NMR (CD3OD): (partial) 7.79 (d, 1H), 7.48 (m, 1H), 7.33 (m, 2H), 7.19 - 6.77 (m, 7H), 6.54 (m, 1H), 5.17 (m, 1H), 4.02 (m, 1H), 3.11 - 2.68 (m, 6H), 2.47 (m, 2H), 2.03 (m, 2H), 1.59 (m, 6H).

Example 3

2-Amino-N-2-[3a-(R, S) -benzyl-2-methyl-3-oxo - 2,3,3 a,4,6,7-hexahydropyrazino [4,3-c]pyridine-5-yl]-1(R) - (1H-indol-3-ylmethyl)-2-oxoethyl]-isobutyramide

A. 4-Oxopiperidine-1,3-dicarboxylic acid 1-tert-butyl ether, 3-methyl ester

To a mixture of 7.00 g (36,2 mmol) of methyl ester 4-oxopiperidin-3-carboxylic acid and 8,82 g (72,3 mmol) of 4,4-dimethylaminopyridine in 200 ml of methylene chloride at ~0oC solution was added 7,88 g (36,2 mmol) di-tert - BUTYLCARBAMATE in 150 ml of methylene chloride for ~30 minutes. The mixture was heated at room temperature and then was stirred for ~17 hours. The mixture kontsentrirovaniem, dried over MgSO4and concentrated to obtain 9,18 g of clear yellow oil.

Century 3-(R, S)-Benzyl-4-oxopiperidine-1,3-dicarboxylic acid 1-tert-budilova ether, 3-methyl ester

To a solution of 5.00 g (to 19.4 mmol) of 3A in 10 ml of DMF was added 745 mg (7.4 mmol) of sodium hydride (60% oil dispersion) and the mixture was stirred at room temperature for ~15 minutes. A solution of 3.32 g (to 19.4 mmol) benzylamine in 15 ml of DMF was added to the stirred solution via cannula and the mixture was stirred for ~42 hours at room temperature. The mixture was diluted with ethyl acetate and washed once with water and 4 times with saline, dried over MgSO4and concentrated to obtain 6.0 g 3B as a yellow oil. MS (Cl, NH3) 348 (MH+).

C. 3a-(R, S)-Benzyl-2-methyl-3-oxo-2, 3,3 a, 4,6,7 there is hexahydropyrazino [4,3-c]-pyridine-5 - carboxylic acid, tert-butyl methyl ether

A mixture of 4.00 g (11.5 mmol) of 3B and 530 mg (11.5 mmol) of methylhydrazine in 100 ml of ethanol was heated under reflux for about 8 hours. The mixture was concentrated and the residue was dissolved in 100 ml of toluene and heated under reflux for about 17 hours.

The mixture was concentrated and the residue was purified by chromatography on silica gel with Aloha colorless oil. MS (Cl, NH3) 344 (MH+).

D. 3A-(R,S)-Benzyl-2-methyl-2,3, 3A,4,5,6, 7-hexapetala[4,3-c]pyridine-3-one

To 2,60 g (7.6 mmol) was added 20 ml triperoxonane acid at ~ 0oC and the mixture was stirred for ~ 2.5 hours. Added ethyl acetate and the solution was washed 6 N. NaOH, dried over MgCO4and concentrated to obtain 1.8 g 3D. MS (Cl, NH3) 244 (MH+).

That is, {1-[2-[3a-(R,S)-Benzyl-2-methyl-3-oxo-2, 3,3 a,4,6,7-hexahydropyrazino[4,3-c] pyridine-5-yl]-1-(R)-(1 H-indol-3-ylmethyl)-2-oxoethylidene]-1-methylethyl}-karamanova acid, tert-butyl methyl ether

According to the method described in the basic procedure And, 125 mg (4.6 mmol) of 3C and 1.75 g (0.51 mmol) of 2C were combined and the residue was purified by chromatography on silica gel with elution with a gradient (6:4 V/V ethyl acetate:hexane) to 7% methanol in ethyl acetate to obtain 150 mg of 3E.

F. 2-Amino-N-2 [3a-(R,S)-benzyl-2-methyl-3-oxo-2,3,3 a,4,6,7 - hexahydropyrazino[4,3-c]pyridine-5-yl] -1(R)-(1H-indol-3-ylmethyl)-2-oxoethyl]-isobutyramide, hydrochloride

To 150 mg (0.24 mmol) 3E in 15 ml of ethanol was added to ~5 ml of concentrated HCl and stirred at room temperature for about 3 hours. The mixture was concentrated and the residue was led from a mixture of ethanol/hexane to obtain 100 mg 3F. MS (Cl, NH3) 515 (MH+

Example 4

2-Amino-N-2-[3A-(R)-benzyl-2-methyl-3-oxo-2,3, 3A, 4,6,7 there is hexahydropyrazino [4,3-c]pyridine-5-yl]-1(R)- benzoyloxymethyl-2-oxoethyl]-isobutyramide, hydrochloride and 2-Amino - N-2-[3A-(S)-benzyl-2-methyl-3-oxo-2,3,3 a, 4,6,7 there is hexahydropyrazino[4,3-c] pyridine-5-yl] -1(R)-benzoyloxymethyl - 2-oxoethyl]-isobutyramide, hydrochloride

A. {1-[2-[3a-(R,S)-Benzyl-2-methyl-3-oxo-2,3,3 a,4,6,7 - hexahydropyrazino[4,3-c] pyridine-5-yl] -1-(R) -benzoyloxymethyl-2-oxoethylidene]-1-methylethyl}-karamanova acid, tert-butyl methyl ether

According to the method described in the Basic procedure And 1.12 g (4.6 mmol) of 3C and 1.75 g (0.51 mmol) of 1E were connected with obtaining a mixture of diastereoisomers. The residue was purified by chromatography on silica gel with elution with a gradient (1:1 V/V ethyl acetate: hexane to 100% ethyl acetate to obtain 350 mg of the less polar 4A isomer 1 and 250 mg of the more polar 4A isomer 2. MS (Cl, NH3) 606 (MH+for both isomers.

C. 2-Amino-N-[2-(3A-(R)-benzyl-2-methyl-3-oxo-2,3,3 a,4,6,7 - hexahydropyrazino [4,3-c]pyridine-5-yl)-1-(R)- benzoyloxymethyl-2-oxoethyl]-isobutyramide, hydrochloride

To 250 mg (0.41 mmol) 4A isomer 1 in 15 ml of ethanol was added 5 ml of concentrated HCl and the mixture was stirred at room temperature for ~ 5 hours. The mixture was concentrated and the residue was besieged from smashin NMR (CD3OD): 7.33 (m, 5H), 7.14 (m, 5H), 5.22 (m, 1H), 4.57 (m, 3H), 3.80 (m, 2H) 3.14 (m. 1H), 3.04 (s, 3H), 2.96 (m, 2H), 2.61 (m, 2H), 1.63 (m, 7H).

C. 2-Amino-N-[2-(3A-(S)-benzyl-2-methyl-3-oxo-2,3,3 a,4, 6,7-hexahydropyrazino[4,3-C] pyridine-5-yl)-1-(R)- benzoyloxymethyl-2-oxoethyl]-isobutyramide, hydrochloride

To 250 mg (0.41 mmol) 4A isomer 2 in 15 ml of ethanol was added 5 ml of concentrated HCl and the mixture was stirred at room temperature for ~ 5 hours. The mixture was concentrated and the residue was besieged from a mixture of ethanol/hexane and dried in vacuum to obtain 120 mg of isomer 4C 1. MS (Cl, NH3) 506 (MH+).

1H NMR (CD3OD): 7.31 (m, 5H), 7.13 (m, 5H), 6.78 (m, 1H), 5.28 (m, 1H), 4.62 (m, 3H), 3.81 (m, 2H), 3.14 (m. 1H), 2.62 (m, 3H), 1.58 (m, 7H).

D. 2-Amino-N-[2-(3A-(R) -benzyl-2-methyl-3-oxo - 2,3,3 a,4,6,7-hexahydropyrazino [4,3-C]pyridine-5-yl)-1-(R)- benzoyloxymethyl-2-oxoethyl]-isobutyramide, methanesulfonate

Saturated aqueous sodium bicarbonate solution was added to of 3.60 g (6.6 mmol) of 4B isomer 1 and the mixture was extracted with ethyl acetate. The organic layer was dried over MgSO4and concentrated. The residue was dissolved in ethyl acetate, cooled to ~ 0oC and added of 0.43 ml (6.6 mmol) methanesulfonic acid and the mixture was stirred for about 0.5 hours. To the solution was added hexane (200 ml) and the mixture was stirred for ~1 hour and filter the RA ethyl acetate to obtain 2.55 g 4D isomer 1 as a white crystalline solid. MS (Cl, NH3) 506 (MH+).

Example 5

2-Amino-N-[1-(3A-(R)-benzyl-2-methyl-3-oxo-2,3,3 a,4,6,7 - hexahydropyrazino[4,3-c]pyridine-5-carbonyl)-4-phenyl-(R)-butyl]- isobutyramide, hydrochloride and

2-Amino-N-[1-(3A-(S)-benzyl-2-methyl-3-oxo-2, 3,3 a,4,6,7-hexahydropyrazino[4,3-c] pyridine-5-carbonyl)-4-phenyl- (R)-butyl]-isobutyramide, hydrochloride

A. 2-Oxo-5,6-diphenyl-3-(3-phenylalkyl)-morpholine-4-carboxylic acid, tert-butyl methyl ether

To a cooled to approximately -78oC to a solution of 13.8 g (70,0 mmol) innamibia and 4.94 g (14.0 mmol) of tert-butyl(2S,3R)-(+)-6-oxo-2,3-diphenyl-4-morpholinylcarbonyl in 350 ml of anhydrous THF was added 28 ml (28 mmol) of 1 M of bestremembered sodium in THF. The mixture was stirred at ~ -78oC for ~ 1.5 hours and then poured into 750 ml of ethyl acetate. The mixture was washed twice with saline, dried over MgSO4and concentrated to a yellow oil. The oil was stirred in 150 ml of hexane during the night and the precipitated solid substance was collected by filtration to obtain 3.2 g of 5A as a white solid.

Century 5(S),6(R)-Diphenyl-3(R)-(3 - phenylalkyl)-morpholine-2-he

To 2,97 g (6,33 mmol) of 5A was added 20 ml triperoxonane acid at ~ 0oC and the mixture was stirred for ~2 hours and then concentrated. OST what lacerata and the combined organic extracts were washed with saline, dried over MgSO4and concentrated to obtain an orange oil, which was purified by chromatography on silica gel (10: 90 V/V ethyl acetate:hexane) to give 880 mg of 5B as a white solid.

C. 2-(R)-Amino-5-phenylpentane acid

A mixture of 440 mg (1,19 mmol) of 5B and 120 mg of palladium chloride in 20 ml of ethanol and 10 ml of THF was first made at 45 psi (310264,06 PA) for approximately 16 hours. The mixture was filtered through diatomaceous earth and concentrated and the residue triturated with ether to obtain 240 mg of 5C as a white solid.

D. 2-tert-Butoxycarbonylamino-2-methylpropionate acid, 2,5-dioxopiperidin-1 silt ether

To a suspension of 5.0 g (24.6 mmol) of N-tert-BOC-methylalanine 13.5 ml of methylene chloride was added 3,40 g (29.6 mmol) of N-hydroxysuccinimide and the 5.65 g (29.6 mmol) of EDC. The suspension was stirred for about 17 hours at room temperature. The mixture was diluted with ethyl acetate and washed twice with water, saturated aqueous sodium bicarbonate and brine (each of them). Dried over MgSO4and concentrated. The product was purified by chromatography on silica gel (1: 1 V/V ethyl acetate:hexane) to obtain 5.2 g of the compound of the title of this part D in the form of a white solid.

4and concentrated. The residue was purified by chromatography on silica gel with elution of 80% chloroform in hexane and then 100% chloroform and 10% methanol in chloroform to obtain 127 mg 5E.

F. { 1-[2-[3a-(R, S)-Benzyl-2-methyl-3-oxo -2,3,3 a,4,6,7 - hexahydropyrazino[4,3-c] pyridine-5-carbonyl]-4-phenyl-(R) -butylcarbamoyl]-1-methylethyl} -karamanova acid, tert-butyl methyl ether

According to the method described in the basic procedure And, 130 mg (0,53 mmol) 3C and 200 mg (of 0.53 mmol) 5E connected with obtaining a mixture of diastereoisomers. The residue was purified by chromatography on silica gel with elution with a gradient (1:1 V/V ethyl acetate: hexane to 100% ethyl acetate to obtain 40 mg of the less polar 5F isomer 1 and 40 mg of the more polar 5F isomer 2. MS (Cl, NH3) 604 (MH+for both isomers.

G. 2-Amino-N-[1-(3A-(R)-benzyl-2-methyl-3-oxo-2,3,3 a,4,6,7 - hexahydropyrazino[4,3-c] pyridine-5-carbonyl)-4-phenyl-(R) -butyl]-isobutyramide, hydrochloride

To 40 mg (0,07 more for about 4 hours. The mixture was concentrated and the residue was besieged from a mixture of methylene chloride/hexane and dried under vacuum to obtain 30 mg 5G isomer 1. MS (Cl, NH3) 504 (MH+).

1H NMR (CD3OD): (partial) 7.19 (m, 10H), 4.37 (m, 1H), 3.02 (m, 6H), 2.67 (m, 4H), 1.83 (m, 4H), 1.62 (s, 6H), 1.28 (m, 1H).

H. 2-Amino-N-[1-(3A-(S) -benzyl-2-methyl-3-oxo-2, 3, 3A,4,6,7 - hexahydropyrazino [4,3-c]pyridine-5-carbonyl)-4-phenyl- (R)-butyl]-isobutyramide, hydrochloride

To 40 mg (0.07 mmol) 5F isomer 2 in 10 ml of ethanol was added 4 ml of concentrated HCl and the mixture was stirred at room temperature for approximately 4 hours. The mixture was concentrated and the residue was besieged from a mixture of methylene chloride/hexane and dried under vacuum to obtain 30 mg 5H isomer 1. MS (Cl, NH3) 504 (MH+).

1H NMR (CD3OD): (partial) 7.25 (m, 9H), 6.88 (m, 1H), 3.04 (s, 3H), 2,71 (m, 4H), 2.48 (m, 2H), 1.75 (m, 4H), 1.62 (m, 6H), 1.28 (m, 1H).

Example 6

2-Amino-N-2-[3a-(R, S)-benzyl-2-methyl-3-oxo-2,3,3 a, 4,6,7 there is hexahydropyrazino[4,3-c]pyridine-5-yl]-1(R)- benzoyloxymethyl-2-oxoethyl]-isobutyramide, hydrochloride

A. { 1-[2-[3a-(R, S)-Benzyl-2-methyl-3-oxo-2,3,3 a,4,6,7 - hexahydropyrazino[4,3-C] pyridine-5-yl]-1-(R)- benzoyloxymethyl-2-oxoethylidene] -1-methylethyl}-karamanova acid, tert-butyl methyl ether

According to the method described in the main proctography on silica gel with elution with a gradient (1:1 V/V ethyl acetate:hexane) - 10% methanol in ethyl acetate to obtain 170 mg of 6A.

C. 2-Amino-N-2-[3a-(R,S) -benzyl-2-methyl-3-oxo-2,3,3 a,4,6, 7-hexahydropyrazino [4,3-c]pyridine-5-yl]-1(R)-benzoyloxymethyl - 2-oxoethyl]-isobutyramide, hydrochloride

To 170 mg (0.28 mmol) of 6A in 20 ml of ethanol was added 5 ml of concentrated HCl and the mixture was stirred at room temperature for ~2.5 hours. The mixture was concentrated and the residue was besieged from a mixture of ethanol/hexane to obtain 70 mg of 6B. MS (Cl, NH3) 506 (MH+).

1H NMR (CD3OD): 7.32 (m, 5H), 7.16 (m, 5H), 5.22 (m, 1H), 4.67 (m, 1H), 4.55 (m, 2H), 3.79 (m, 2H), 3.12 (m, 2H), 3.00 (m, 6H), 2.71 (m, 3H), 1.56 (m, 8H).

Example 7

2-Amino-N-[2-(3a-benzyl - 2-ethyl-3-oxo-2,3,3 a, 4,6,7 there is hexahydropyrazino [4,3-c] pyridine-5-yl) -1-(1H-indol-3 - ylmethyl)-2-oxoethyl] -isobutyramide, hydrochloride

A. 3A-(R, S)-Benzyl-2-ethyl-3-oxo -2,3,3 a, 4,6,7 there is hexahydropyrazino [4,3-c]pyridine-5-carboxylic acid, tert-butyl methyl ether

To 555 mg (1,60 mmol) 3B in 27 ml of ethanol was added 240 mg (1,60 mmol) acylhydrazines and the mixture was heated under reflux for ~4 hours. The mixture was concentrated and the residue was purified by chromatography on silica gel with elution with a gradient (10: 1 V/V hexane:ethyl acetate) to (3:7 V/V hexane: ethyl acetate) to give 357 mg 7A. MS (Cl, NH3) 358 (MH+).

Century 3a-(R, S 1.5 ml of concentrated HCl and the mixture was stirred at room temperature for ~ 2 hours. The mixture was concentrated to obtain 257 mg 7B. MS (Cl, NH3) 258 (MH+).

C. { 1-[2-[3a-(R,S)-Benzyl-2-ethyl-3-oxo-2, 3,3 a,4,6,7-hexahydropyrazino[4,3-C] pyridine-5-yl]-1-(R) - (1H-indol-3-ylmethyl)-2-oxoethylidene] -1-methylethyl}-karamanova acid, tert-butyl methyl ether

According to the method described in the basic procedure And 82 mg (0.28 mmol) of 7B and 100 mg (0.26 mmol) of 2C were combined and the residue was purified by chromatography on silica gel with elution with a gradient 100% methylene chloride to 2% methanol in methylene chloride to obtain 110 mg 7C. MS (Cl, NH3) 629 (MH+).

D. 2-Amino-N-[2-(3a-benzyl-2-ethyl-3-oxo-2,3,3 a,4,6,7-hexahydropyrazino [4,3-c]pyridine-5-yl)-1-(1H-indol-3-ylmethyl) -2-oxoethyl]-isobutyramide, hydrochloride

To 100 mg (0.15 mmol) 7C in 2 ml of ethanol was added 1 ml of concentrated HCl and the mixture was stirred at room temperature for ~2 hours. The mixture was concentrated to obtain 72 mg 7D in the form of a colorless foam. MS (Cl, NH3) 529 (MH+).

Example 8

2-Amino-N-[2-(3A-(R)-benzyl-2-ethyl-3-oxo-2,3,3 a,4,6,7 - hexahydropyrazino[4,3-c] pyridine-5-yl)-1-(R)- benzoyloxymethyl-2-oxoethyl]isobutyramide, hydrochloride and 2-Amino-N- [2-(3a-(S)-benzyl-2-ethyl-3-oxo-2,3,3 a,4,6,7-hexahydropyrazino[4, 3-c]pyridine-5-yl)-1-(R)-benzoyloxymethyl-2-oxoethyl] isobutyramide, hydrochlor etilcarbitol]-1-methylethyl}- karamanova acid, tert-butyl methyl ether

According to the method described in the basic procedure And 85 mg (0.29 mmol) of 7B and 100 mg (0.26 mmol) of 1E were connected with obtaining a mixture of diastereoisomers. The residue was purified by chromatography on silica gel with elution with a gradient 100% methylene chloride to 2% methanol in methylene chloride to obtain 6 mg of the less polar 8A isomer 1 and 11 mg of the more polar 8A isomer 2. MS (Cl, NH3) 620 (MH+for both isomers.

C. 2-Amino-N-[2-(3A-(R)-benzyl-2-ethyl-3-oxo-2,3,3 a, 4,6, 7-hexahydropyrazino[4,3-c]pyridine-5-yl)-1-(R) -benzoyloxymethyl-2-oxoethyl] isobutyramide, hydrochloride

To 5.7 mg (0,009 mmol) 8A isomer 1 in 1 ml of ethanol was added 0.4 ml of concentrated HCl and the mixture was stirred at room temperature for about 3 hours. The mixture was concentrated to obtain 4,7 mg 8B isomer 1. MS (Cl, NH3) 520 (MH+).

1H NMR (CD3OD): (partial) 7.41 - 7.05 (m, 10H), 5.20 (m, 1H), 4.61 (m, 1H), 4.52 (s, 2H), 3.71 (m, 1H), 3.60 (m, 1H), 2.61 (m, 3H), 1.39 (m, 9H).

C. 2-Amino-N-[2-(3A-(S)-benzyl-2-ethyl-3-oxo-2,3,3 a, 4,6, 7-hexahydropyrazino [4,3-c]pyridine-5-yl)-1-(R) - benzoyloxymethyl-2-oxoethyl] isobutyramide, hydrochloride

To 10 mg (0,016 mmol) 8A isomer 2 in 1 ml of ethanol was added 0.4 ml of concentrated HCl and the mixture was stirred at room temperature for AP is 1
H NMR (CD3OD): (partial) 7.43 - 7.00 (m, 10H), 6.81 (m, 1H), 5.32 (m, 1H), 4.63 (m, 2H), 4.53 (m, 1H), 3.72 (m, 1H), 1.37 (m, 9H).

Example 9

2-Amino-N-[2-(2-benzyl-3 - oxo-2,3,3 a,4,6,7 - hexahydropyrazino [4,3-c] pyridine-5-yl)-1-(R)- benzoyloxymethyl-2-oxoethyl]-isobutyramide, hydrochloride

A. 2-Benzyl-3-hydroxy-2,4,6,7-tetrahydropyrazolo[4,3-C]pyridine-5 - carboxylic acid, tert-butyl methyl ether

A mixture of 800 mg (3.11 mmol) of 3B and 495 mg (3.11 mmol) of the dihydrochloride of benzylpiperazine and 423 mg (3.11 mmol) of three-hydrate of sodium acetate in 15 ml of ethanol was heated under reflux for ~ 17 hours. The mixture was concentrated and the residue was dissolved in 100 ml of toluene and heated under reflux for about 48 hours. The mixture was diluted with ethyl acetate and washed with saline, dried over MgSO4and concentrated and the residue was purified by chromatography on silica gel with elution with 100% ethyl acetate and then 5% methanol in methylene chloride to obtain 530 mg of 9A in the form of a light brown solid. MS (Cl, NH3) 330 (MH+).

Century 2-Benzyl-4,5,6,7-tetrahydro - 2H-pyrazolo[4,3-C]pyridine-3-ol

To 411 mg (1,24 mmol) 3E in 30 ml of ethanol was added 10 ml of concentrated HCl and the mixture was stirred at room temperature for about 30 minutes. The mixture concentration is ASS="ptx2">

C. {1-[2-[2-Benzyl-3-hydroxy-2,4,6,7 - tetrahydropyrazolo[4,3-c]pyridine-5-yl] -1-R - benzoyloxymethyl-2-oxoethylidene]-1-methylethyl}-karamanova acid, tert-butyl methyl ether

According to the method described in the basic procedure A, 100 mg (0.38 mmol) of 9B and 145 mg (0.38 mmol) of 1E were combined and the residue was purified by chromatography on silica gel (95: 5 V/V methanol:methylene chloride) to give 42 mg 9C as a white solid. MS (Cl, NH3) 592 (MH+).

D. 2-Amino-N-[2-(2-benzyl-3-oxo -2,3,3 a, 4,6,7 there is hexahydropyrazino [4,3-c] pyridine-5-yl)-1-(R)-benzoyloxymethyl-2-oxoethyl] -isobutyramide, hydrochloride

To 42 mg (0.07 mmol) 9D in 20 ml of ethanol was added 6 ml of concentrated HCl and the mixture was stirred at room temperature for about 30 minutes. The mixture was diluted with ethanol, concentrated and the residue was besieged from methanol/ethyl acetate to obtain 35 mg 9D as a white solid. MS (Cl, NH3) 492 (MH+).

1H NMR (CD3OD): (partial) 7.41 - 7.16 (m, 10H), 5.19 (m, 3H), 4.48 (m, 4H), 3.88 (m, 1H), 3.74 (m, 2H), 2.68 (m, 2H), 1.58 (m, 6H).

Example 10

2-Amino-N-{ 2-[3A-(R)-benzyl-3-oxo-2-(2,2,2-triptorelin)- 2,3,3 a,4,6, 7-hexahydropyrazino [4,3-c]pyridine-5-yl]-1-(R) -benzoyloxymethyl-2-oxoethyl} -isobutyramide, hydrochloride and 2-Amino-N- {2-[3A-(S)-benzyl-3-ox, hydrochloride

A. 3A-(R, S)-Benzyl-3-oxo-2-(2,2,2 - triptorelin)-2,3, 3A,4,6,7-hexahydropyrazino [4,3-c]pyridine-5-carboxylic acid, tert-butyl methyl ether

A mixture of 840 mg (2,42 mmol) of 3B and 276 mg (2,42 mmol) 2,2,2-cryptgetuserkey (70% in water) in 20 ml of ethanol was heated under reflux for ~5 hours and then concentrated. The residue was dissolved in 40 ml of toluene and heated under reflux for ~17 hours. The mixture was concentrated and the residue was purified by chromatography on silica gel (9:1 V/V hexane:ethyl acetate) to give 703 mg of 10A as a yellow oil. MS (Cl, NH3) 412 (MH+).

Century 3A-(R,S)-Benzyl-3-(2,2,2 - triptorelin)-2,3,3 a,4,6,7 - hexahydropyrazino [4,3-c] pyridine-3-one

To 600 mg (1,46 mmol) 10A at ~0oC was added 3 ml of cold triperoxonane acid and the mixture was stirred for ~ 3 hours, giving a solution to reach room temperature. The mixture was concentrated and the residue was dissolved in water and the solution was podslushivaet to pH 11 5 N. NaOH and then saturated with potassium carbonate. The solution was extracted 3 times with ethyl acetate and the combined organic extracts were washed with saline, dried over MgSO4and concentrated to obtain 345 mg of 10B in the form of an opaque oil. MS (Cl, NH3) 312 (MH+).

Il - 2-oxoethylidene}-1-methylethyl)-karamanova acid, tert-butyl methyl ether

According to the method described in the basic procedure And, 137 mg (0.44 mmol) 10B and 167 mg (0.44 mmol) of 1E were connected with obtaining a mixture of diastereoisomers. The residue was purified by chromatography on silica gel with elution with a gradient 100% methylene chloride to 5% methanol in methylene chloride to obtain 128 mg of the less polar 10C isomer 1 and 63 mg of the more polar 10C isomer 2. MS (Cl, NH3) 674 (MH+for both isomers.

D. 2-Amino-N-{ 2-[3a-(R)-benzyl - 3-oxo-2-(2,2,2 - triptorelin)-2,3,3 a, 4,6,7 there is hexahydropyrazino[4,3-C] pyridine-5-yl]-1-(R)-benzoyloxymethyl-2-oxoethyl}-isobutyramide, hydrochloride

To 120 mg (0.18 mmol) of 10C isomer 1 in 3.5 ml of ethanol was added 1.5 ml of concentrated HCl and the mixture was stirred at room temperature for ~2 hours. The mixture was concentrated to obtain 94 mg 10D isomer 1 in powder form non-standard white color. MS (Cl, NH3) 574 (MH+).

1H NMR (CD3OD): (partial) 7.31 (m, 5H), 7.18 (m, 5H), 5.21 (m, 1H). 4.57 (m, 3H), 4.26 (m, 1H), 4.08 (m, 1H), 3.79 (m, 2H), 3.09 (m, 4H), 2.65 (m, 2H), 1.63 (m, 6H).

E. 2-Amino-N-{ 2-[3A-(S)- benzyl-3-oxo-2-(2,2,2-triptorelin)-2,3,3 a, 4,6,7 there is hexahydropyrazino[4,3-C]pyridine-5-yl]-1-(R)-benzoyloxymethyl-2-oxoethyl}- isobutyramide, hydrochloride

To 53 mg (0,079 mmol) 10C isomer 2 in 3.5 ml of ethanol was added 1.5 ml koncentrirovannyh 10E isomer 2 as a pale yellow solid. MS (Cl, NH3) 574 (MH+).

1H NMR (CD3OD): (partial) 7.33 (m, 5H), 7.15 (m, 4H), 6.81 (m, 1H), 5.30 (m, 1H), 4.67 (m, 4H), 4.15 (m, 2H), 3.77 (m, 2H), 3.09 (m, 3H), 2.64 (m, 3H), 1.58 (m, 6H).

Example 11

2-Amino-N-[2-(3A-(R)-benzyl-2-tert-butyl-3 - oxo-2,2,3 and, 4,6,7 there is hexahydropyrazino[4,3-C] pyridine-5-yl)-1-(R)-benzoyloxymethyl-2-oxoethyl]-isobutyrate, methanesulfonate and 2-Amino-N-[2-(3A-(S)-benzyl-2-tert-butyl-3 - oxo-2,3,3 a, 4,6,7 there is hexahydropyrazino [4,3-c] pyridine-5-yl) -1-(R)-benzoyloxymethyl-2-oxoethyl]-isobutyrate, methanesulfonate

A. 3a-(R,S)-Benzyl-2-tert-butyl-3-oxo-2,3,3 a,4,6,7 - hexahydropyrazino [4,3-c]pyridine-5-carboxylic acid, tert-butyl methyl ether

To 2,07 g (5,95 mmol) 14B in 40 ml of ethanol was added 0.97 g (7.7 mmol) of the hydrochloride tert-butylhydrazine and 0.63 g (7.7 mmol) of sodium acetate and the mixture was heated at ~70oC for ~17 hours. The mixture was cooled and the solution decantation with sediment and concentrated. The residue was dissolved in 80 ml of toluene and heated under reflux for ~ 6 hours. The mixture was concentrated and the residue was purified by chromatography on silica gel (9:1 V/V hexane:ethyl acetate) to obtain 1.7 g, 11A. MS (Cl, NH3) 386 (MH+).

Century 3a-(R,S)-Benzyl-2-tertbutyl -2,3,3 a,4,6,7-hexahydropyrazino [4,3-c] pyridine-3-one

To 535 mg (1,39 mmol) 11A in 20 ml of methylene chloride to relax was diluted with ethyl acetate and washed twice 1 N. NaOH and 1 times with saline, dried over Na2SO4and concentrated to obtain 246 mg 11B. MS (Cl, NH3) 286 (MH+).

C. {1-[2-[3a-(R,S)-Benzyl-2-tert-butyl-3-oxo-2,3,3 a,4,6,7 - hexahydropyrazino [4,3-c]pyridine-5-yl]-1-(R)-benzoyloxymethyl-2 - oxoethylidene]-1-methylethyl}-karamanova acid, tert-butyl methyl ether

According to the method described in the basic procedure And, 246 mg (0.86 mmol) 11B and 328 mg 14F connected with obtaining a mixture of diastereoisomers. The residue was purified by chromatography on silica gel (6:4 V/V hexane/ethyl acetate) to obtain 250 mg of the less polar 11C isomer 1 and 90 mg of the more polar 11C isomer 2. MS (Cl, NH3) 648 (MH+for both isomers.

D. 2-Amino-N-[2-(3A-(R)-benzyl-2-tert-butyl-3-oxo-2,3,3 a,4,6, 7-hexahydropyrazino [4,3-C] pyridine-5-yl)-1-(R)-benzoyloxymethyl-2-oxoethyl] -isobutyrate, methanesulfonate

To 210 mg (0.32 mmol) 11C isomer 1 in 15 ml of methylene chloride at ~ 0oC was added 28 μl (0.44 mmol) methanesulfonic acid. Bath ice was removed and the mixture was stirred for ~ 3 hours, diluted with 15 ml of diethyl ether and the precipitated solid substance was collected by filtration to obtain 100 mg 11D isomer 1. MS (Cl, NH3) 548 (MH+).

1H NMR (CD3OD): (partial) 7.33 (m, 5 H), 7.27 - 7.07 (m, 5H), 5.21 (m, 1H), 4 kageromaru [4,3-C] pyridine-5-yl)-1-(R)- benzoyloxymethyl-2-oxoethyl]-isobutyrate, methanesulfonate

To 85 mg (0.13 mmol) 11C isomer 2B 10 ml of methylene chloride at ~ 0oC was added 21 μl (0.32 mmol) methanesulfonic acid. Bath ice was removed and the mixture was stirred for ~ 3 hours, diluted with 20 ml diethyl ether and the precipitated solid substance was collected by filtration to obtain 46 mg 11E isomer 2. MS (Cl, NH3) 548 (MH+).

1H NMR (CD3OD): (partial) 8.28 (br d, 1H), 7.32 (m, 5H), 7.18 (m, 4H), 6.84 (m, 1H), 5.31 (m, 1H), 4.60 (m, 3H), 3.70 (m, 3H), 3.18 - 2.92 (m, 3H), 2.68 (s, 3H), 1.57 (m, 6H), 1.13 (s, 9H).

Example 12

2-Amino-N-[1-(R)-(1H-indol-3-ylmethyl)-2-(2 - methyl-3-oxo-3a-(R,S)-pyridine-2-ylmethyl -2,3,3 a, 4,6,7 there is hexahydropyrazino [4,3-c]pyridine-5-yl)-2-oxoethyl]- isobutyramide, dihydrochloride

A. 4-Oxo-3-(R,S)-pyridine-2-iletilerini-1,3-dicarboxylic acid 1-tert-butyl ether, 3-methyl ester

To a solution of 2.00 g (7.8 mmol) of 3A in 32 ml of THF was added 468 mg (11.7 mmol) of sodium hydride (60% oil dispersion) at ~0oC and the mixture was stirred for ~ 30 minutes. To the stirred solution was added a solution of 762 mg (6.0 mmol) of 2-picolylamine in 5 ml of THF for ~ 5 minutes, followed by addition of 432 mg (2.6 mmol) of potassium iodide. Bath ice was removed and the mixture was heated for about 17 hours under reflux. A mixture of rabbalshede chromatography on silica gel with elution with a mixture of 6: 4 V/V ether:hexane and then with a mixture of 6:4 V/V ethyl acetate: hexane to obtain 1.2 g 12A. MS (Cl, NH3) 349 (MH+).

Century 2-Methyl-3-oxo-3A-(R, S)- pyridine-2-ylmethyl-2,3,3 a,4,6,7 - hexahydropyrazino [4,3-C]pyridine-5-carboxylic acid, tert-butyl methyl ether

A mixture of 1.20 g (of 3.45 mmol) 12A and 159 mg (of 3.45 mmol) methylhydrazine in 20 ml of ethanol was heated under reflux for about 6.5 hours. The mixture was concentrated and the residue was dissolved in 25 ml of toluene and heated under reflux for about 17 hours. The mixture was concentrated and the residue was purified by chromatography on silica gel (65:35 V/V ethyl acetate:hexane) to obtain 450 mg of 12B. MS (Cl, NH3) 345 (MH+).

C. 2-Methyl-3a-(R,S)-pyridine-2-ylmethyl-2,3,3 a,4,6,7 - hexahydropyrazino [4,3-c]pyridine-3-one, dihydrochloride

A mixture of 450 mg (1,30 mmol) 12B in 2 ml of a mixture of 4 M HCl/dioxane was stirred at room temperature for about 4.5 hours. The mixture was concentrated to obtain 450 mg 12C. MS (Cl, NH3) 245 (MH+).

D.{ 1-[1-(1-(R)-H-indole-3 - ylmethyl-2-(2-methyl-3-oxo-3A- (R,S)-pyridine-2-ylmethyl - 2,3,3 a, 4,6,7 there is hexahydropyrazino [4,3-c]pyridine-5-yl)-2 - oxoethylidene]-1-methylethyl)- karamanova acid, tert-butyl methyl ether

According to the basic procedure And, 108 mg (0.31 mmol) 12C and 122 mg (0.31 mmol) of 2C were combined and the residue was purified by chromatography is but-N-[1-(R)-(1H-indol-3-ylmethyl)-2-(2-methyl-3-oxo-3A-(R, S)- pyridine-2-ylmethyl - 2,3,3 a, 4,6,7 there is hexahydropyrazino [4,3-C]pyridine-5-yl) -2-oxoethyl]-isobutyramide, dihydrochloride

A mixture of 110 mg (0.18 mmol) 12D in 1 ml of a mixture of 4 M HCl/dioxane was stirred at room temperature for 17 hours. The mixture was concentrated to obtain 51 mg 12E. MS (Cl, NH3) 516 (MH+).

1H NMR (CD3OD): (partial) 8.91-8.52 (m, 2H), 8.04 (m, 2H), 7.76-7.50 (m, 3H), 6.82 (m, 1H), 4.62 (m, 1H), 3.36 (s, 3H), 1.63 (s, 6 H).

Example 13

2-Amino-N-[1-(R)-benzoyloxymethyl-2-(2-methyl-3 - oxo-3A-(R, S)-pyridine-2-ylmethyl-2,3,3 a,4,6,7 - hexahydropyrazino[4,3-c]pyridine-5-yl)-2-oxoethyl] - isobutyramide, dihydrochloride

A. { 1-[1-(R)-Benzoyloxymethyl-2-(2 - methyl-3-oxo-3A-(R,S)- pyridine-2-ylmethyl-2,3,3 a, 4,6,7 there is hexahydropyrazino[4,3 - C]pyridine-5-yl)-2 - oxoethylidene]-1-methylethyl}- karamanova acid, tert-butyl methyl ether

According to the basic procedure And 86 mg (0.27 mmol) 12C and 103 mg (0.27 mmol) of 1E were combined and the residue was purified by chromatography on silica gel (95:5 V/V ethyl acetate:hexane) to obtain 82 mg 13A.

C. 2-Amino-N-[1-(R)-benzoyloxymethyl-2-(2-methyl-3-oxo-3a-(R,S)- pyridine-2-ylmethyl-2,3,3 a, 4,6,7 there is hexahydropyrazino [4,3-C] pyridine-5-yl)-2-oxoethyl]-isobutyramide, dihydrochloride

A mixture of 75 mg (0.12 mmol) of 13A in 1 ml of a mixture of 4 M HCl/dioxane was stirred at room temperature D3OD): (partial) 8.78 (m, 1H), 8.46 (m, 1H), 8.13-7.82 (m, 2H), 7.32 (m, 5H), 4.57 (m, 3H), 3.96 (m, 1H), 3.82 (m, 2H), 1.63 (m, 6H).

Example 14

2-Amino-N-[2-(3A-(R)- benzyl-2-methyl-3-oxo-2, 3,3 a,4,6,7-hexahydropyrazino[4,3-c] pyridine-5-yl)-1-(R)-(1H - indol-3-ylmethyl)-2-oxoethyl]isobutyramide

A. 4-Oxopiperidine-1,3-dicarboxylic acid 1-tert-butyl ether, 3-methyl ester

To a mixture of 100.0 g (516,4 mmol) of methyl ester 4-oxopiperidin-3-carboxylic acid and 63 g (516,4 mmol)

4,4-dimethylaminopyridine in 1 l of methylene chloride at ~0oC solution was added level 113.0 g (516,4 mmol) di-tertbutylbenzene in 100 ml of methylene chloride for approximately 90 minutes. The mixture was slowly heated to room temperature and then was stirred for about 19 hours. The mixture was washed three times with 10% aqueous HCl solution, saturated aqueous sodium bicarbonate and brine (each), dried over MgSO4and concentrated to obtain 130,5 g 14A in the form of an amorphous solid.

1H NMR (CDCl3): 4.03 (br, 2H), 3.74 (s, 3H), 3.56 (t, 2H), 2.36 (t, 2H), 1.42 (s, 9H).

Century 3-(R)-Benzyl-4-oxopiperidine-1,3-dicarboxylic acid 1-tert-butyl ether, 3-methyl ester

To a stirred suspension of 11.7 g (293 mmol) of sodium hydride (60% oil suspension, washed dagiene approximately 45 minutes. Bath ice was removed and the mixture was stirred at room temperature for approximately 45 minutes. The mixture was re-cooled to 0oC and stir the solution was added dropwise 35.2 oz (296 mmol) of benzylbromide in 200 ml of DMF and the mixture was stirred for about 23 hours at room temperature. To the solution was carefully added to 550 ml of water and the mixture was stirred for approximately 30 minutes. The mixture was extracted 3 times with ethyl acetate and the combined organic extracts were washed five times with water, once with brine, dried over MgSO4and concentrated to obtain 98 g of a yellow oil. The oil was led from hexane to obtain 71 g 14B in the form of a white solid. MS (Cl, NH3) 348 (MH+).

1H NMR (CDCl3): (partial) 7.23 (m, 3H), 7.13 (m, 2H), 4.58 (br m, 1H), 4.18 (br, 1H), 3.63 (s, 3H), 3.28 - 2.96 (m, 4H), 2.72 (m, 1H), 2.43 (m, 1H), 1.44 (s, 9H).

C. 3A-(R)-Benzyl-2-methyl-3-oxo-2,3,3 a,4,6,7 - hexahydropyrazino [4,3-c] pyridine-5-carboxylic acid, tert-butyl methyl ether

A mixture of 47.0 g (135 mmol) 14B, of 38.9 g (270 mmol) of methylhydrogensilicone and 44.3 g (540 mmol) of sodium acetate in 900 ml of ethanol was heated under reflux for about 17 hours in a nitrogen atmosphere. The mixture was concentrated and the residue rationale obtaining 41,17 g of 14C in the form of a white solid. MS (Cl, NH3) 344 (MH+).

1H NMR (CDCl3): (partial) 7.19 (m, 3H), 7.05 (m, 2H), 4.61 (br m, 2H), 3.24 (m, 1H), 3.09 (s, 3H), 3.01 (m, 1H), 2.62 (m, 4H), 1.52 (s, 9H).

D. 3a-(R, S)-Benzyl-2-methyl-2, 3,3 a, 4,6,7 there is hexahydropyrazino [4,3-c] pyridine-3-one, hydrochloride

Anhydrous hydrogen chloride was barbotirovany through the solution RUB 24.55 g (71,5 mmol) of 14C in 800 ml of diethyl ether at about 0oC for about 12 minutes. The mixture was stirred for about 3 hours and during this period he formed a white precipitate. The precipitated solid was collected by filtration to obtain 19.2 g 14D. MS (Cl, NH3) 244 (MH+).

1H NMR (CD3OD): (partial) 7.25 (m, 3H), 7.05 (m, 2H), 3.77 (m, 2H), 3.51 (d, 1H), 3.25 (m, 1H), 3.17 (m, 3H), 3.03 (s, 3H), 2.81 (m, 1H).

E. 2-tert-Butoxycarbonylamino-2-methyl propionic acid, 2,5-dioxopiperidin-1 silt ether

To a stirred solution of 100.0 g (492 mmol) of Boc--methylalanine and 94,0 g (492 mmol) of EDC in 1 l of methylene chloride at ~0oC was added 56,63 g (492 mmol) of N-hydroxysuccinimide in portions and then the reaction was allowed to warm to room temperature. The mixture was stirred for approximately 24 hours and washed twice with saturated aqueous sodium bicarbonate solution and brine, dried over sulfate is B>): 4.96 (br, 1H), 2.82 (s, 4H), 1.66 (s, 6H), 1.48 (s, 9H).

F. 3-(R)-Benzyloxy-2-(2-tert - butoxycarbonylamino-2 - methylpropionamide)-propionic acid

A mixture of 50.5 g (168 mmol) of 14E, and 33.5 g (168 mmol) of N-tert-BOC-O-benzyl-D-serine and 51,05 g (505 mmol) of triethylamine in 400 ml of dioxane and 100 ml of water was heated at approximately 45oC for approximately 16 hours. The mixture was diluted with ethyl acetate and acidified to pH 2 with acetic acid. The layers were separated and the organic phase is washed with saline, dried over sodium sulfate and concentrated to obtain 650 g 14F in the form of a white solid.

1H NMR (CD3OD): (partial) 7.55 (d, 1H), 7.29 (m, 5H), 4.52 (m, 1H), 4.48 (s, 2H), 3.84 (d of d, 1H), 3.69 (d of d, 1H), 1.42 (s, 6H), 1.38 (s, 9H).

G. L-tartrate 3A-(R)-Benzyl-2-methyl-2, 3,3 a, 4,6,7 there is hexahydropyrazino[4,3-c]pyridine-3-it

To a mixture of 5.00 g (to 20.6 mmol) of free base 14D and to 3.09 g (to 20.6 mmol) of L-tartaric acid in 80 ml of acetone and 3.2 ml of water was heated in nitrogen atmosphere at approximately 70oC for about 70 hours, and during this period, the reaction mixture became a thick suspension was added 20 ml of acetone. The reaction mixture was slowly cooled to room temperature and then filtered. Then the solid was collected by filtering the 3A-(R)-Benzyl-2-methyl -2,3,3 a,4,6,7-hexahydropyrazino[4,3-c] pyridine-3-one

To a suspension of 5.00 g (12.7 mmol) 14G in 80 ml of methylene chloride at about 0oC was added 1,72 ml (25,4 mmol) of ammonium hydroxide and the mixture was stirred for approximately 15 minutes. The cold solution was filtered and used immediately in the next stage.

I. { 1-[2-(3a-(R)-Benzyl-2-methyl-3-oxo-2, 3,3 a,4,6,7-hexahydropyrazino[4,3-C] pyridine-5-yl)-1- (R)-(1H-indol-3-ylmethyl-2-oxoethylidene]-1-methylethyl}- karamanova acid, tert-butyl methyl ether

A mixture of 4.83 g (12.7 mmol) 14F, solution from 14H, 2,60 g (of 19.1 mmol) of HOAT and 2.45 g (12.8 mmol) EDC was stirred at approximately 0oC in nitrogen atmosphere for about 1 hour and then heated to room temperature and was stirred for approximately 16 hours. The mixture was filtered and the filtrate washed with saturated aqueous sodium bicarbonate and water, dried over MgSO4and concentrated to obtain 7,35 g 14I in the form of a white solid.

J. 2-Amino-N-[2-(3A-(R)-benzyl-2-methyl-3-oxo - 2,3,3 a,4,6,7-hexahydropyrazino [4,3-C] pyridine-5-yl)-1-(R)- (1H-indol-3-ylmethyl-2-oxoethyl]-isobutyramide

To 755 mg (1.25 mmol) 14I in 7 ml of methylene chloride at about 0oC was added 3.5 ml of cold triperoxonane acid and the mixture was stirred for approximately Uchenie approximately 2 hours. The mixture was concentrated and evaporated twice with toluene. The residue was dissolved in chloroform and washed twice with saturated aqueous sodium bicarbonate solution and once with water and brine. The mixture was dried over MgSO4and concentrated with getting 594 mg 14J in the form of butter.

Example 15

2-Amino-N-[1-(R)-benzoyloxymethyl-2-(2-methyl-3-oxo-2,3, 3A,4,6,7-hexahydropyrazino [4,3-C]pyridine-5-yl) -2-oxoethyl]-isobutyramide, hydrochloride

A. 2-Methyl-3-oxo-2,3,3 a, 4,6,7 there is hexahydropyrazino[4,3-C]pyridine - 5-carboxylic acid, tert-butyl methyl ether

A mixture of 3.00 g (11,66 mmol) 3A and 537 mg (11,66 mmol) methylhydrazine in 100 ml of ethanol was heated under reflux for about 17 hours. The mixture was concentrated and the residue was dissolved in 100 ml of toluene and washed twice with saline, dried over MgSO4and concentrated. The residue was purified by chromatography on silica gel with elution with a gradient of 100% ethyl acetate to 5% methanol in methylene chloride to obtain 2.28 g 15A as a white solid.

1H NMR (CD3OD): 4.20 (s, 2H), 3.67 (t, 2H), 3.43 (s, 3H), 2.58 (t, 2H), 1.48 (s, 9H).

C. the Hydrochloride of 2-methyl - 2,3,3 a,4,6,7-hexahydropyrazino [4,3-C]pyridine - 3-it

To 510 mg (for 2.01 mmol) 15A in 30 ml of ethanol was added 10 ml kontsentrirovannoe was led from methanol/ethyl acetate to obtain 425 mg 15B in the form of a yellow solid.

1H NMR (CD3OD): 4.27 (s, 2H), 3.71 (s, 3H), 3.56 (t, 2H), 3.05 (t, 2H).

C. {1-[1-(R)-Benzoyloxymethyl-2-(2-methyl-3-oxo-2,3, 3A,4,6,7-hexahydropyrazino [4,3-c]pyridine-5-yl)-2 - oxoethylidene]-1 - methylethyl}-karamanova acid, tert-butyl methyl ether

According to the method described in the Basic procedure A, 100 mg (of 0.53 mmol) 15B and 202 mg (of 0.53 mmol) of 1E were combined and the residue was purified by chromatography on silica gel (95:5 V/V methylene chloride:methanol) to obtain 54 mg 15C as a white solid. MS (Cl, NH3) 516 (MH+).

D. 2-Amino-N-[1-(R) -benzoyloxymethyl-2- (2-methyl-3-oxo-2,3,3 a,4,6,7 - hexahydropyrazino[4,3-c] pyridine-5-yl)-2-oxoethyl]-isobutyramide, hydrochloride

To 54 mg (0.10 mmol) 15C in 30 ml of ethanol was added 10 ml of concentrated HCl and the mixture was stirred at room temperature for about 40 minutes. The mixture was concentrated and the residue was besieged from methanol/ethyl acetate to obtain 50 mg 15D. MS (Cl, NH3) 416 (MH+).

1H NMR(CD3OD): (partial) 7.28 (m, 5H), 5.18 (m, 1H), 4.69-4.38 (m, 4H), 3.88 (m, 1H), 3.73 (m, 2H), 3.68 (s, 2H), 3.61 (m, 1H), 2.67 (m, 1H), 1.57 (s, 6H).

Example 16

2-Amino-N-[2-(2-benzyl-3-oxo -2,3,3 a, 4,6,7 there is hexahydropyrazino[4,3-c] pyridine-5-yl)-1(R)-(1H-indol-3 - ylmethyl)-2-oxoethyl] -isobutyramide, hydrochloride

A. 2-Benzyl-3-oxo-2,3,3 is 495 mg (3.11 mmol) of benzylideneaniline in 15 ml of ethanol was heated under reflux for about 17 hours. The mixture was concentrated and the residue was dissolved in 100 ml of toluene and heated under reflux for about 48 hours. The mixture was diluted with ethyl acetate and washed twice with saline, dried over Na2SO4and concentrated. The residue was purified by chromatography on silica gel with elution with a gradient of 100% ethyl acetate to 5% methanol in methylene chloride to obtain 530 mg 16A in the form of a reddish-brown solid. MS (Cl, NH3) 330 (MH+).

C. the Hydrochloride of 2-benzyl - 2,3,3 a,4,6,7-hexahydropyrazino[4,3-c] pyridine-3-it

To 411 mg (1,24 mmol) 16A in 30 ml of ethanol was added 10 ml of concentrated HCl and the mixture was stirred at room temperature for about 30 minutes. The mixture was concentrated and the residue was led from methanol/ethyl acetate to obtain 353 mg 16B in the form of a yellow solid. MS (Cl, NH3) 230 (MH+).

1H NMR (CD3OD): 7.26-7.40 (m, 5H), 5.22 (s, 2H), 4.12 (s, 2H), 3.53 (t, 2H), 3.00 (t, 2H).

C. (R)-2-(2-tert-Butoxycarbonylamino-2 - methylpropionamide)-3-(1H-indol-3-yl)-propionic acid

To a stirred solution of 30.6 g (0.15 mol) of D-tryptophan, 30,4 g (0.30 mol) of N-methylmorpholine 450 ml (4:1) dioxane:water was added 45,0 g (0.15 mol) 14E and the mixture was stirred for ptel the pH of the solution was brought to 3 with concentrated HCl and the layers were separated. The organic layer was washed with water and brine, dried over MgSO4and concentrated. The residue was led from a mixture of ethyl acetate/hexane to obtain 37,0 g solids non-standard white color.

D. {1-[2- (2-Benzyl-3-oxo-2, 3,3 a,4,6,7-hexahydropyrazino [4,3-c] pyridine-5-yl) -1-(R)-(1 H-indol-3-ylmethyl)-2-oxoethylidene] -1-methylethyl} -karamanova acid, tert-butyl methyl ether

According to the method described in the basic procedure A, 100 mg (0.38 mmol) 16B and 202 mg (0,53 mmol) 16C connected and the residue was purified by chromatography on silica gel (95:5 V/V methylene chloride:methanol) to obtain 45 mg 16D in the form of a white solid. MS (Cl, NH3) 601 (MH+).

E. 2-Amino-N-[2-(2-benzyl-3-oxo-2, 3,3 a,4,6,7-hexahydropyrazino[4,3-C] pyridine-5-yl)-1(R)-(1H-indol-3-ylmethyl) -2-oxoethyl]-isobutyramide, hydrochloride

To 45 mg (0.07 mmol) 16D in 60 ml of ethanol was added 20 ml of concentrated HCl and the mixture was stirred at room temperature for 35 minutes. The mixture was concentrated and the residue: besieged from methanol/ethyl acetate to obtain 30 mg 16E.

1H NMR (CD3OD): (partial) 7.40 (m, 4H), 7.25 (m, 3H), 7.11 (m, 2H), 6.96 (m, 2 H), 6.81 (m, 1H), 5.38 - 4.93 (m, 3H), 4.46 (m, 1H), 4.22 (m, 1H), 3.96 (m, 1H), 3.69 (m, 1H), 3.18 (m, 1H), 2.28 (m, 1H), 1.57 (m, 6H), 1.38 (m, 1H).

Example ]-isobutyramide, hydrochloride

A. 3-Methyl-4-oxopiperidine-1,3-dicarboxylic acid 1-tert-butyl ether, 3-(R,S)-methyl ester

To a solution of 2.00 g (to 7.77 mmol) of 3A in 30 ml of DMF was added 308 mg (to 7.77 mmol) of sodium hydride (60% oil dispersion) and the mixture was stirred at room temperature for about 25 minutes. To the stirred solution was added to 0.50 ml (to 7.77 mmol) methyliodide and the mixture was stirred for about 17 hours at room temperature. The mixture was diluted with ethyl acetate and washed once with water and 4 times with saline, dried over MgSO4and concentrated. The residue was purified by chromatography on silica gel (7: 3 V/V hexane: ethyl acetate) to obtain 1.75 g 17A in the form of a clear oil. MS (Cl, NH3) 272 (MH+).

Century 2, 3a-(R, S) -Dimethyl-3-oxo-2, 3,3 a,4,6,7-hexahydropyrazino [4,3-c] pyridine-5 - carboxylic acid, tert-butyl methyl ether

A mixture of 1.62 g (9.50 mmol) 17A and 435 mg (9.50 mmol) of methylhydrazine in 30 ml of ethanol was heated under reflux for approximately 4 hours. The mixture was concentrated and the residue was dissolved in 50 ml of toluene and heated under reflux for about 14 hours. The mixture was diluted with ethyl acetate and washed twice with saline, dried over Na2is the group of 1.00 g of 17B as a white solid. MS (Cl, NH3) 268 (MH+).

C. the Hydrochloride 2, 3a-(R,S)-dimethyl-3-2,3,3 a,4,6,7 - hexahydropyrazino [4,3-c] pyridine-3-it

To 1.00 g (3,74 mmol) 17B in 40 ml of ethanol was added 8 ml of concentrated HCl and the mixture was stirred at room temperature for about 35 minutes. The mixture was concentrated and the residue was led from methanol/ethyl acetate to obtain 850 mg 17C in the form of a white solid. MS (Cl, NH3) 168 (MH+).

D. {1-[1-(R)-Benzoyloxymethyl-2-(2,3 a-(R,S) -dimethyl-3-oxo-2,3,3 a,4,6,7-hexahydropyrazino[4,3-c] pyridine-5-yl)-2-oxoethylidene] -1-methylethyl} -karamanova acid, tert-butyl methyl ether

According to the method described in the basic procedure And, 150 mg (0,74 mmol) 17C and 514 mg (1.35 mmol) of 1E were combined and the residue was purified column chromatography (85:15 V/V hexane:ethyl acetate) to give 185 mg 17D in the form of a white solid.

E. 2-Amino-N-[1-benzoyloxymethyl-2-(2,3-dimethyl-3-oxo-2, 3,3 a,4,6,7-hexahydropyrazino [4,3-c] pyridine-5-yl)-2 - oxoethyl]-isobutyramide, hydrochloride

To 173 mg (0.33 mmol) 17B in 40 ml of ethanol was added 15 ml of concentrated HCl and the mixture was concentrated at room temperature for about 1 hour. The mixture was concentrated and the residue was diluted with chloroform and the residue was purified by chromatography on silica gel with elution with a gradient of 100% ethyl acetate - 10% diethylamine in ethyl acetate. The residue was dissolved in ethanol and acidified aqueous HCl. The mixture was concentrated and the residue was led from methanol/ethyl acetate to obtain 65 mg E in the form of a white solid. MS (Cl, NH3) 502 (MN+).

1H NMR (CD3OD): (partial) 7.32(m, 5H), 5.14 (m, 1H), 4.53 (m, 3H), 3.71 (m, 3H), 2.97 (m, 1H), 2.83 (m, 1H), 2.57 (m, 1H), 1.98 (m, 2H), 1.61 (m, 6H), 1.38 (s, 3H).

Example 18

2-Amino-N-[2-(3A-(R)-benzyl-3-oxo-2,3,3 a, 4,6,7 there is hexahydropyrazino[4,3-c] pyridine-5-yl)-1-(R)- benzoyloxymethyl-2-oxoethyl]-isobutyramide, hydrochloride and 2-Amino - N-[2-(3a-(S)-benzyl-3-oxo-2,3,3 a,4,6,7-hexahydropyrazino [4,3-C]pyridine-5-yl)-1-(R)-benzoyloxymethyl-2-oxoethyl] - isobutyramide, hydrochloride

A. 3-Benzyl-4-oxopiperidine-3-carboxylic acid, methyl ester

To 200 mg (of 0.58 mmol) 3B with ~0oC was added 5 ml of cold triperoxonane acid and the mixture was stirred for approximately 1 hour. The mixture was concentrated and the residue together evaporated with ethyl acetate and hexane. To the residue was added 2 N. NaOH for alkalizing and the mixture was extracted with chloroform. The combined organic extracts were dried over MgSO4and concentrated to obtain 18A with a quantitative yield.

Century 3-(R, S)-Benzyl-1-[3-benzyloxy-2-(R)-(2-tert - butoxide is under way, described in the basic procedure And 1.77 g (7,16 mmol) 18A and 3.04 g (8.0 mmol) 14F connected with obtaining a mixture of diastereoisomers. The residue was purified by chromatography on silica gel (7:3 V/V hexane:ethyl acetate) to give 820 mg of the less polar isomer 18B 1 and 1.14 g of the more polar isomer 18B 2. MS (Cl, NH3) 611 (MH+for both isomers.

S. {-[2-(3a-(R,S)-Benzyl-3-oxo-2, 3,3 a,4,6,7-hexahydropyrazino [4,3-c] pyridine-5-yl)-1-(R)- benzoyloxymethyl-2-oxoethylidene] -1-methylethyl}-karamanova acid, tert-butyl methyl ether

To a solution of 820 mg (1,32 mmol) 18B isomer 1 in 13 ml of ethanol was added 342 mg (2,63 mmol) hydroinsulation and 431 mg (5,26 mmol) of sodium acetate and the mixture was heated under reflux for about 17 hours. The mixture was concentrated and the residue was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and brine, dried over MgSO4and concentrated. The residue was purified by chromatography on silica gel with elution with a gradient of 75% ethyl acetate in hexane to 100% ethyl acetate to obtain 550 mg 18C isomer 1.

To a solution of 1.14 g (of 1.86 mmol) 18B isomer 2 in 20 ml of ethanol was added 485 mg (3.73 mmol) of hydroinsulation and 613 mg (of 7.48 mmol) of sodium acetate and the mixture was heated under reflux unnim aqueous solution of sodium bicarbonate and brine, dried over MgSO4and concentrated. The residue was purified by chromatography on silica gel (75:25 V/V ethyl acetate:hexane) to give 710 mg 18C isomer 2.

D. 2-Amino-N-[2-(3A-(R)-benzyl-3-oxo-2,3,3 a,4,6,7 - hexahydropyrazino [4,3-C]pyridine-5-yl)-1-(R) - benzoyloxymethyl-2-oxoethyl] isobutyramide, hydrochloride

To 200 mg (0.34 mmol) 18C-isomer 1 in 12 ml of ethanol was added 6 ml of concentrated HCl and the mixture was stirred at room temperature for approximately 2.5 hours. The mixture was concentrated and co evaporated three times with ethanol to obtain 20 mg 18D isomer 1. MS (Cl, NH3) 492 (MH+).

1H NMR (CD3OD): (partial) 8.42 (br d, 1H), 7.35 (m, 5H), 7.18 (m, 5H), 5.23 (m, 2H), 4.91 (m, 1H), 4.54 (m, 4H), 3.80 (m, 2H), 3.63 (m, 1H), 3.12 (m, 1H), 3.07 (m, 3H), 2.61 (m, 3H), 1.62 (m, 6H), 1.39 (m, 1H).

E. 2-Amino-N-[2-(3a-(S)-benzyl-3-oxo-2,3,3 a,4,6,7 - hexahydropyrazino[4,3-C] pyridine-5-yl)-1-(R)-benzoyloxymethyl - 2-oxoethyl] -isobutyramide, hydrochloride

To 200 mg (0.34 mmol) 18C-isomer 2 in 20 ml of ethanol was added 1 ml of concentrated HCl and the mixture was stirred at room temperature for approximately 2.5 hours. The mixture was concentrated and co evaporated three times with ethanol to obtain 30 mg 18E isomer 2. MS (Cl, NH3) 492 (MH+).

1H NMR (CD3OD): (partial) 8.29 (br >/P>Example 19

2-Amino-N-[1-(R)-benzoyloxymethyl-2-(2-methyl-3 - oxo-3A-(R,S)-thiazole-4-ylmethyl-2,3,3 a,4,6,7 - hexahydropyrazino [4,3-c]pyridine-5-yl)-2-oxoethyl] - isobutyramide, dihydrochloride

A. 4-Oxo-3-(R, S)-thiazole-4 - iletilerini-1,3-dicarboxylic acid 1-tert-butyl ether, 3-ethyl ester

To a solution of 300 mg (1.10 mmol) of 1A in 5 ml of THF at ~0oC was added 67 mg (from 1.66 mmol) of sodium hydride (60% oil dispersion) and the mixture was stirred for 30 minutes. To the cold solution was added a solution of 204 mg (1,21 mmol) of 4-chloromethylthiazole (Hsiao, C. N.; Synth. Comm. 20, R. 3507 (1990)) in 5 ml of THF and then 87 mg (of 0.53 mmol) of potassium iodide and the mixture was heated under reflux for about 17 hours. The mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated and the residue was purified by chromatography on silica gel (7: 3 V/V hexane:ethyl acetate) to obtain 90 mg of the compound of the title. MS (Cl, NH3) 648 (MH+).

Century 2-Methyl-3-oxo-3A-(R, S)-thiazole-4-ylmethyl-2,3,3 a,4,6, 7-hexahydropyrazino [4,3-C] pyridine-5-carboxylic acid, tert-butyl methyl ether

To 90 mg (0.24 mmol) 19A in 2 ml of ethanol was added to 11.2 mg (0.24 mmol) of methylhydrazine and the mixture was heated under reflux in those what rinicom for about 7 hours. The mixture was concentrated and the residue was dissolved in 3 ml of toluene and heated under reflux for about 17 hours. The mixture was concentrated and the residue was purified by chromatography on silica gel (6:4 V/V hexane:ethyl acetate) to give 44 mg 19B. MS (Cl, NH3) 648 (MH+).

C. the Dihydrochloride of 2-methyl-3-3A- (R,S)-thiazole-4 - ylmethyl-2,3,3 a,4,6,7-hexahydropyrazino [4,3-c]pyridine-3-it

A mixture of 44 mg (0.10 mmol) 19B in 1 ml of 4 M HCl in dioxane was stirred at room temperature for approximately 4 hours. The mixture was concentrated and co evaporated with methylene chloride to obtain 40 mg 19C. MS (Cl, NH3) 251 (MH+).

D. { 1-[1-(R)-Benzoyloxymethyl-2- (2-methyl-3-oxo-3A- (R,S)-thiazole-4-ylmethyl - 2,3,3 a,4,6,7-hexahydropyrazino[4, 3-C]pyridine-5-yl)- 2-oxoethylidene]-1-methylethyl]-karamanova acid, tert-butyl methyl ether

According to the method described in the basic procedure A, 40 mg (0.12 mmol) 19C and 39 mg (0.12 mmol) 14F connected and the residue was purified by chromatography on silica gel (9: 1 V/V ethyl acetate:hexane) to give 40 mg 19D. MS (Cl, NH3) 613 (MH+).

E. 2-Amino-N-[1-(R)-benzoyloxymethyl-2-(2-methyl-3-oxo-3a-(R,S) -thiazole-4-ylmethyl-2,3,3 a, 4,6,7 there is hexahydropyrazino[4,3-c] pyridine-5-yl)-2-oxoethyl] -isobutyramide, dehydrocorydaline 5 hours. The mixture was concentrated and evaporated with methylene chloride to obtain 40 mg 19E. MS (Cl, NH3) 513 (MH+).

Example 20

2-Amino-N-[2-(3A-(R)-benzyl-2-methyl-3-oxo -2,3,3 a, 4,6,7 there is hexahydropyrazino[4,3-C] pyridine-5-yl)-1- (R)-(1H-indol-3-ylmethyl-2-oxoethyl]-isobutyramide, salt L-tartaric acid

To 4.6 g of the compound of the title of example 14 in 20 ml of methanol was added a solution of 1.36 g of L-tartaric acid in 20 ml of methanol at ~0oC. the Mixture was heated to room temperature, was stirred for approximately 40 minutes and concentrated in vacuum. The residue was diluted with 220 ml of ethyl acetate, was heated under reflux for about 1.5 hours, then stirred at approximately 72oC for approximately 18 hours. The mixture was cooled to room temperature and filtered to obtain 5,78 g connection header in the form of a colorless crystalline solid.

Example 21

3-Benzyl-3-methoxycarbonylmethyl-4-oxopiperidin-1-carboxylic acid tert-butyl ether

A. 3-Benzyl-4-oxopiperidin-1-carboxylic acid tert-butyl ether

Mix-keeeper (4480 mg, 12.9 mmol) and LiCl (1100 mg, from 25.8 mmol) was heated in DMF (2.0 ml) at approximately 120oC for about 17 cinnie organic extracts were dried and concentrated in vacuum. The crude product on SiO2by elution with a mixture of 20% ethyl acetate/hexane to obtain 1320 mg of the desired product as a yellow oil.

1H NMR (250 MHz, CDCl3): d: 7.4 (m, 5H), 4.2 (m, 1H), 3.4 (m, 1H), 3.3 (dd, 1H), 3.05 (dd, 1H), 2.7 (m. 1H), 2.55 (m, 4H), 1.5 (s, 9H); MS (APCl): 190 (M+1-BOC).

Century 3-Benzyl-3-methoxycarbonylmethyl-4-oxopiperidin-1 - carboxylic acid, tert-butyl-ether

A solution of the product of Stage a of Example 21 above (1320 mg, 4,56 mmol), pyrrolidine (972 mg, 13 mmol) and p-toluensulfonate acid (33 mg) in benzene (30 ml) was heated under reflux with molecular sieves for about 17 hours. The reaction mixture was cooled to room temperature and concentrated in vacuum. The residue was dissolved in benzene (10 ml) and cooled to ~0oC. was added dropwise methylbromide (1530 mg, 10 mmol). The reaction mixture gave to slowly warm to room temperature and then it was heated under reflux for about 17 hours and then was added H2O (5 ml). After heating under reflux for ~ 2 hours, the reaction mixture was cooled to room temperature and was extracted with ethyl acetate (3 x 100 ml). The combined organic extracts were dried and concentrated in vacuum. N is mg of product.

1H NMR (250 MHz, CDCl3): d 7.35 (m, 5H), 4.5 (m, 1H), 3.8 (s, 3H), 3.4 (dd, 1H), 3.1 (m, 1H), 2.85 (m, 4H), 2.6 (m, 1H), 2.4 (m, 1H), 1.5 (s, 9H); MS (APCl): 362 (M+1).

Example 22

6-Oxo-1-phenylcyclohexane-1,3-dicarboxylic acid, 3-tert-butyl ether, 1-methyl ester

A solution of diphenyl-mercury (890 mg, 2.5 mmole) CHCl3(4 ml) is heated to approximately 40oC in a stream of nitrogen.

The leads to compounds, which lead (1110 mg, 2.5 mmole) is added in small portions received greenish-yellow solution is stirred at a temperature of approximately 40oC for about 0.5 hour. Add-ketoester (520 mg, 2.0 mmole), and then pyridine (0.2 ml, 2.5 mmole). After 5 hours at 40oC, the reaction mixture was concentrated in vacuo, the residue is dissolved in ether (100 ml) and filtered. The filtrate is washed three times 3 N. H2SO4, dried and evaporated to obtain 616 mg of yellow solid. Flash chromatography on silica gel using 25% ethyl acetate/hexane as additionally separated by give 368 mg of the target product.

1H NMR (400 MHz, CDCl3): d 7.15 (m, 5H), 4.4 (s, 2H), 3.7 (s, 5H), 2.6 (s, 2H), 1.5 (s, 9H); MS (APCl): 334 (M+1).

Example 23

(D)-2-Amino-3-(2,4 - dichloraniline)-propionic acid hydrochloride

A. (D)-2-tert-Butoxycarbonylamino-3-(2,4 - dichloraniline)-propionic acid

To lane) over a 10 minute period. The reaction mixture was stirred for approximately 1.75 hours at approximately 0oC, then approximately 0.25 hours at room temperature. After cooling to approximately 0oC was added dropwise a solution of 2,4-Dichlorotoluene (5,56 ml, 40 mmol) in DMF (5 ml). The reaction mixture was allowed to warm to approximately 23oC and was stirred for about 17 hours, and then distributed among diisopropyl ether and 10% HCl. The aqueous solution was extracted with diisopropyl ether (2 x). The combined organic extracts were washed with saturated aqueous saline solution, dried and concentrated to obtain 14,75 g of the crude product, which was used without further purification.

1H NMR (400 MHz, CDCl3): d 7.6-7.2 (m, 3H), 5.4 (d, 1H), 4.6 (s, 2H), 4.0 (d, 1H), 3.8 (dd, 2H), 1.1 (s, 9H); MS (APCl): 264,266 (M+1, M+2).

C. (D)-2-Amino-3-(2,4 - dichloraniline)-propionic acid, hydrochloride

The product of stage a of Example 23 above (14,7 g, 40 mmol) was stirred in a mixture of 4 M HCl/dioxane (100 ml) for about 17 hours. The reaction mixture was concentrated in vacuum to obtain 12 g of a pale yellow solid (100%). MS (APCl) 265 (M+1).

Example 24

Example 24 having the formula shown below

*specifies another center stereoisomer at carbon C-3 shown above structure). Mass spectrum (M+1)=520. The way MS is the bombardment of particles.

Examples 25 and 26

Examples 25 and 26 have the formula shown below,

< / BR>
for both examples 25 and 26 R1denotes phenyl and R2denotes methyl, and example 25 is an R,R - isomer, and example 26 represents S, R-isomer. Examples 25 and 26 were synthesized analogously to the procedures described in Examples 3C-3F using the connection header of Example 22 as starting material, followed by chromatographic separation of the two individual isomers. The mass spectrum of each of the example (M+1)=493. The way MS is the bombardment of particles.

Examples 27 - 183 provided at the end of the description.

1. The compound of the formula I

< / BR>
racemizes-diastereomeric mixtures, optical isomers of these compounds and their pharmaceutically acceptable salts and prodrugs,

where e is 0 or 1;

n and w are equal to 1;

Y denotes oxygen;

R1denotes hydrogen, -(CH2)t-ANDthe sory having 1 - 2 heteroatoms, independently selected from the group including sulfur and nitrogen, a bicyclic ring system consisting of a fully unsaturated 5 - or 6-membered ring, optionally having 1 or 2 heteroatom, represented by nitrogen;

AND1in each case, independently, optionally substituted in one or optionally both rings if AND1is a bicyclic ring system, and has up to 2 substituents, each Deputy is independently selected from the group comprising F, CL, Br, F3, (C1-C6)alkyl, phenyl;

R2denotes hydrogen, (C1-C8)alkyl, where the alkyl group is optionally substituted CF3;

R3means (C1-C5)alkyl-X1-(C0-C5)alkyl-A1where X1represents-O-; AND1specified above;

R4denotes hydrogen;

X4denotes hydrogen;

R6is

< / BR>
where a and b equal to 0;

X5and X5aeach independently represents unsubstituted (C1-C6)alkyl;

Z1indicates the connection;

R7and R8each denotes hydrogen.

2. Connection on p. 1, where X5and X5adenote each independently (3
, optionally substituted by one or two substituents selected from the group comprising F, CL, F3, methyl.

3. Connection on p. 2, where X5and X5aeach represent methyl; R3denotes phenyl-CH2-O-CH2where phenyl defined for R3, optionally substituted by one or two substituents, selected from the group comprising fluorine, chlorine, methyl, F3.

4. Connection on p. 3, where R1represents -(CH2)t-AND1where AND1in the definition of R1optionally substituted by one or two substituents, selected from the group comprising fluorine, chlorine, methyl and F3.

5. Connection on p. 4, where e is 0; R1represents -(CH2)t-AND1where AND1in the definition of R1denotes phenyl, thienyl, thiazolyl, pyridyl or pyrimidyl, which is optionally substituted by one or two substituents, each Deputy is independently selected from the group comprising F, Cl, Me, and F3; t is 0, 1 or 2 and R3denotes phenyl-CH2-O-CH2- where the phenyl portion is optional substituted with one or two substituents, each Deputy is independently selected from the group comprising F, Cl, Me, and F3.

6. Connection on p. 5 the, -CH2-pyridyl or-CH2-thiazolyl and R2denotes hydrogen, methyl, ethyl, tert-butyl or-CH2CF3.

7. Connection on p. 6, where R1denotes-CH2-phenyl or-CH2-4-forfinal and R3denotes phenyl-CH2-O-CH2-.

8. Connection on p. 7, which is diastereomers a mixture of 2-amino-N-[2-(3A-(R, S)-benzyl-2-methyl-3-oxo-2,3,3 a, 4,6,7 there is hexahydropyrazino[4,3-C]pyridine-5-yl)-1-(R) -benzoyloxymethyl-2-oxoethyl]isobutyramide.

9. Connection on p. 8, wherein the compound is 2-amino-N-[2-(3A-(R)-benzyl-2-methyl-3-oxo-2,3,3 a, 4,6,7 there is hexahydropyrazino[4,3-C] -pyridine-5-yl)-1-(R)-benzoyloxymethyl-2-oxoethyl]isobutyramide

10. Connection on p. 9, where the compound is a salt of L-tartaric acid 2-amino-N-[2-(3A-(R)-benzyl-2-methyl-3-oxo-2,3,3 a,4,6,7-hexahydropyrazino[4,3-C]pyridine-5-yl)-1-(R)-benzoyloxymethyl-2-oxoethyl]isobutyramide.

11. Connection on p. 8, wherein the compound is 2-amino-N-[2-(3A-(S)-benzyl-2-methyl-3-oxo-2,3,3 a, 4,6,7 there is hexahydropyrazino-[4,3-C] pyridine-5-yl)-1-(R)-benzoyloxymethyl-2-oxoethyl]isobutyramide.

12. Connection on p. 7, which is diastereomers a mixture of 2-amino-N-[2-(3A-(R, S)-benzyl-2-ethyl-3-oxo-2,3,3 a, 4,6,7 there-hexahydro the Association represents 2-amino-[2-(3A-(R)-benzyl-2-ethyl-3-oxo-2,3,3 a, 4,6,7 there is hexahydropyrazino[4,3-C] -pyridine-5-yl)-1-(R)-benzoyloxymethyl-2-oxoethyl]isobutyramide

14. Connection on p. 12, where the compound is 2-amino-N-[2-(3A-(S)-benzyl-2-ethyl-3-oxo-2,3,3 a,4,6,7-hexahydropyrazino[4,3-C]pyridine-5-yl)-1-(R)-benzyloxy-methyl-2-oxoethyl]isobutyramide.

15. Connection on p. 7, which is diastereomers a mixture of 2-amino-N-[2-(3A-(R,S)-benzyl-3-oxo-2-(2,2,2-triptorelin)-2,3,3 a,4,6,7-hexahydropyrazino[4,3-C]pyridine-5-yl)-1-(R)-benzoyloxymethyl-2-oxoethyl]isobutyramide.

16. Connection on p. 15, where the compound is 2-amino-N-[2-(3A-(R)-benzyl-3-oxo-2-(2,2,2-triptorelin)-2,3,3 a, 4,6,7 there is hexahydropyrazino[4,3-C]pyridine-5-yl)-1-(R)-benzoyloxymethyl-2-oxoethyl]-isobutyramide.

17. Connection on p. 15, where the compound is 2-amino-N-[2-(3A-(S)-benzyl-3-oxo-2-(2,2,2-triptorelin)-2,3,3 a, 4,6,7 there is hexahydropyrazino[4,3-C]pyridine-5-yl)-1-(R)-benzoyloxymethyl-2-oxoethyl]-isobutyramide.

18. Connection on p. 7, which is diastereomers a mixture of 2-amino-N-{ 1-(R)-benzoyloxymethyl-2-[3A-(R, S)-(4-terbisil)-2 - methyl-3-oxo-2,3,3 a, 4,6,7 there is hexahydropyrazino[4,3-C] pyridine-5-yl] -2-oxoethyl}isobutyramide.

19. Connection on p. 18, where the compound is 2-amino-T-{ 1-(R)-SS="ptx2">

20. Connection on p. 18, where the compound is 2-amino-N-{ 1-(R)-benzoyloxymethyl-2-[3A-(S)-(4-terbisil)-2-methyl-3-oxo-2,3,3 a, 4,6,7 there is hexahydropyrazino[4,3-C]pyridine-5-yl]-2-oxoethyl}-isobutyramide.

21. Connection on p. 7, which is diastereomers a mixture of 2-amino-N-[2-(3A-(R, S)-benzyl-2-tert-butyl-3-oxo-2,3,3 a, 4,6,7 there is hexahydropyrazino[4,3-C]pyridine-5-yl)-1-(R)-benzoyloxymethyl-2-oxoethyl]-isobutyramide.

22. Connection on p. 21 where the compound is 2-amino-N-[2-(3A-(R)-benzyl-2-tert-butyl-3-oxo-2,3,3 a, 4,6,7 there is hexahydropyrazino-[4,3-C]pyridine-5-yl)-1-(R)-benzoyloxymethyl-2-oxoethyl]isobutyramide.

23. Connection on p. 21 where the compound is 2-amino-N-[2-(3A-(3)-benzyl-2-tert-butyl-3-oxo-2,3,3 a,4,6,7-hexahydropyrazino[4,3-C] pyridine-5-yl)-1-(R)-benzoyloxymethyl-2-oxoethyl]-isobutyramide

24. Connection on p. 4, where e is 1; R1represents -(CH2)t-A1where AND1in the definition of R1denotes phenyl, thienyl, thiazolyl, pyridyl or pyrimidyl, which is optional substituted with one or two substituents, each Deputy is selected from the group comprising F, CL, Me, and F3; t is 0, 1 or 2 and R3denotes phenyl-CH2-O-CH2- where the phenyl part niobate and F3.

25. Connection on p. 24, where X3and X5aeach represent methyl; R1denotes-CH2-phenyl, -CH2-4-forfinal, -CH2-pyridyl or CH2-thiazolyl and R2denotes hydrogen, methyl, ethyl, tert-butyl or-CH2CF3.

26. Connection on p. 7, which is diastereomers a mixture of 2-amino-N-[2-(3A-(R,S)-benzyl-3-oxo-2,3,3 a,4,6,7-hexahydropyrazino[4,3-C]pyridine-5-yl)-1-(R)-benzoyloxymethyl-2-oxyethyl]isobutyramide.

27. Connection on p. 26, where the compound is 2-amino-N-[2-(3A-(R)-benzyl-3-oxo-2,3,3 a, 4,6,7 there is hexahydropyrazino[4,3-C] pyridine-5-yl)-1-(R)-benzoyloxymethyl-2-oxyethyl]isobutyramide.

28. Connection on p. 26, where the compound is 2-amino-N-[2-(3A-(8)-benzyl-3-oxo-2,3,3 a, 4,6,7 there is hexahydropyrazino[4,3-C] pyridine-5-yl)-1-(R)-benzoyloxymethyl-2-oxyethyl]isobutyramide.

29. Connection on p. 1, where X5and X5aeach independently represents (C1-C3)alkyl; R3selected from the group comprising phenyl (C0-C3)alkyl-O-CH2-, 3-benzothiazol-CH2- thienyl-CH2-O-CH2-, thiazolyl-CH2-O-CH2-, pyridyl-CH2-O-CH2-, pyrimidyl-CH2-O-CH2- and phenyl-CH2-O-CH3and F3.

30. Connection on p. 29, where X5and X5aeach independently represent methyl; R2denotes hydrogen, methyl, ethyl, propyl, isopropyl, tert-butyl or-CH2F3, R1denotes-CH2-AND1where AND1in the definition of R1denotes phenyl, thienyl, thiazolyl, pyridyl or pyrimidyl, which optionally is substituted by 1-2 substituents, each Deputy is independently selected from the group comprising F, Cl, Me, and F3; R3denotes phenyl-O-CH2thienyl-CH2-O-CH2-, thiazolyl-CH2-O-CH2-, pyridyl-CH2-O-CH2-, pyrimidyl-CH2-O-CH2- or phenyl-CH2-O-CH2- where the aryl part is optionally substituted by one or two substituents, each Deputy is independently selected from the group comprising F, Cl, Me, and OCF3.

31. Connection on p. 29, where R2denotes methyl, ethyl or-CH2CF3; A1denotes phenyl, optionally substituted with 1-2 substituents, each Deputy is independently selected from the group comprising F, Cl, Me, and OCF3; R3denotes phenyl-CH2-O-CH2or tiani is independently selected from the group including F, Cl, Me, and OCF3.

32. Connection on p. 30, where R2denotes methyl, ethyl or-CH2CF3; A1represents 2-pyridyl or 3-pyridyl, optionally substituted with 1-2 substituents, each Deputy is independently selected from the group comprising F, Cl, Me, and OCF3; R3denotes phenyl-CH2-O-CH2or thienyl-CH2-O-CH2- where the aryl part is optionally substituted by 1-2 substituents, each Deputy is independently selected from the group comprising F, Cl, Me, and OCF3.

33. Connection on p. 30, where X5and X5aeach represent methyl; R2denotes methyl, ethyl or-CH2CF3; A1denotes phenyl, optionally substituted with 1-2 substituents, each Deputy is independently selected from the group comprising F, Cl, Me, and OCF3; R3represents 2-pyridyl-CH2O-CH2- or 3-pyridyl-CH2-O-CH2- where the aryl part is optionally substituted by 1-2 substituents, each Deputy is independently selected from the group comprising F, Cl, Me, and OCF3.

34. Connection on p. 32 having the formula

< / BR>
racemizes-diastereomeric mixtures and optical isomers of these compounds,

where R2means Mechet CH2CF3; A1represents 2-pyridyl and R3denotes-CH2-O-CH2-3-chlorophenyl;

R2denotes CH2CF3; A1represents 2-pyridyl and R3denotes-CH2-O-CH2-4-chlorophenyl;

R2denotes CH2CF3; A1represents 2-pyridyl and R3denotes-CH2-O-CH2is 2,4-dichlorophenyl;

R2oboznachen2CF3;A1oboznachaet-R3denotes-CH2-O-CH2-2,4-differenl.

35. Connection on p. 34, representing diastereomer a mixture of 2-amino-N-[1-(R)-benzoyloxymethyl-2-(2-methyl-3-oxo-3A-(R, S)-pyridine-2-ylmethyl-2,3,3 a, 4,6,7 there is hexahydropyrazino[4,3-c] pyridine-5-yl)-2-oxoethyl] -2-methylpropionamide.

36. Connection on p. 35, where the compound is 2-amino-N-[1-(R)-benzoyloxymethyl-2-(2-methyl-3-oxo-3A-(R)-pyridine-2-ylmethyl-2,3,3 a, 4,6,7 there is hexahydropyrazino[4,3-c] pyridine-5-yl)-2-oxoethyl] -2-methylpropionamide.

37. Connection on p. 35, where the compound is 2-amino-N-[1-(R)-benzoyloxymethyl-2-(2-methyl-3-oxo-3A-(S)-pyridine-2-ylmethyl-2,3,3 a, 4,6,7 there is hexahydropyrazino[4,3-c] pyridine-5-yl)-2-oxoethyl] -2-methylpropionamide.

38. Connection on p. 34, representing diastereomer a mixture of 2-amino-N - {1(R) - c] pyridyl-5-yl] ethyl}-2-methylpropionamide.

39. Connection on p. 38, where the compound is 2-amino-N - {1-(R)-(3-chlorobenzoyloxy)-2-oxo-2-[3-oxo-3A-(R)-pyridine-2-ylmethyl-2-(2,2,2-triptorelin)-2,3,3 a,4,6,7-hexahydropyrazino[4,3-C]pyridine-5-yl]ethyl} -2-methylpropionamide.

40. Connection on p. 38, where the compound is 2-amino-N - {1-(R)-(3-chlorobenzoyloxy)-2-oxo-2-[3-oxo-3A-(S)-pyridine-2-ylmethyl-2-(2,2,2-triptorelin)-2,3,3 a,4,6,7-hexahydropyrazino[4,3-C]pyridine-5-yl]ethyl} -2-methylpropionamide.

41. Connection on p. 34, representing diastereomer a mixture of 2-amino-N - {1-(R)-(4-chlorobenzoyloxy)-2-oxo-2-[3-oxo-3A-(R,S)-pyridine-2-ylmethyl-2-(2,2,2-triptorelin)-2,3,3 a, 4,6,7 there is hexahydropyrazino[4,3-C] pyridine-5-yl]ethyl}-2-methylpropionamide.

42. Connection on p. 41, where the compound is 2-amino-N - {1-(R)-(4-chlorobenzoyloxy)-2-oxo-2-[3-oxo-3A-(R)-pyridine-2-ylmethyl-2-(2,2,2-triptorelin)-2,3,3 a,4,6,7-hexahydropyrazino[4,3-C]pyridine-5-yl]ethyl} -2-methylpropionamide.

43. Connection on p. 41, where the compound is 2-amino-N - {1-(R)-(4-chlorobenzoyloxy)-2-oxo-2-[3-oxo-3A-(S)-pyridine-2-ylmethyl-2-(2,2,2-triptorelin)-2,3,3 a,4,6,7-hexahydropyrazino[4,3-C]pyridine-5-yl]ethyl} -2-methylpropionamide.

44. Connection on p. 34, representing diastereomers mageroyal[4,3-c]pyridine-5-yl]ethyl}-2-methylpropionamide.

45. Connection on p. 44, where the compound is 2-amino-N-{ 1-(R)-(2,4-dichlorosalicylic)-2-oxo-2-[3-oxo-3A-(R)-pyridine-2-ylmethyl-2-(2,2,2-triptorelin)-2,3,3 a, 4,6,7 there is hexahydropyrazino[4,3-c]pyridine-5-yl]ethyl}-2-methylpropionamide.

46. Connection on p. 44, where the compound is 2-amino-N-{ 1-(R)-(2,4-dichlorosalicylic)-2-oxo-2-[3-oxo-3A-(S)-pyridine-2-ylmethyl-2-(2,2,2-triptorelin)-2,3,3 a, 4,6,7 there is hexahydropyrazino[4,3-c]pyridine-5-yl]ethyl}-2-methylpropionamide.

47. Connection on p. 34, representing diastereomer a mixture of 2-amino-N-{ 1-(R)-(4-chlorothiophene-2-ileocecal)-2-oxo-2-[3-oxo-3A-(R, S)-pyridine-2-ylmethyl-2-(2,2,2-triptorelin)-2,3,3 a, 4,6,7 there)-hexahydropyrazino[4,3-C]pyridine-5-yl]ethyl}-2-methylpropionamide.

48. Connection on p. 47, where the compound is 2-amino-N-{ 1-(R)-(4-chlorothiophene-2-ileocecal)-2-oxo-2-[3-oxo-3A-(R)-pyridine-2-ylmethyl-2-(2,2,2-triptorelin)-2,3,3 a, 4,6,7 there is hexahydropyrazino[4,3-c] pyridine-5-yl]ethyl}-2-methylpropionamide.

49. Connection on p. 47, where the compound is 2-amino-N-{ 1-(R)-(4-chlorothiophene-2-ileocecal)-2-oxo-2-[3-oxo-3A-(S)-pyridine-2-ylmethyl-2-(2,2,2-triptorelin)-2,3,3 a, 4,6,7 there is hexahydropyrazino-[4,3-C] pyridine-5-yl]ethyl}-2-methylpropionamide.

50. Connection on p. 34, preimeter-2-(2,2,2-triptorelin)-2,3,3 a, 4,6,7 there is hexahydropyrazino[4,3-c] pyridine-5-yl]ethyl}-2-methylpropionamide.

51. Connection on p. 50, where the compound is 2-amino-N-{ 1-(R)-(2,4-differentiatedly)-2-oxo-2-[3-oxo-3A-(R)-pyridine-2-ylmethyl-2-(2,2,2-triptorelin)-2,3,3 a, 4,6,7 there is hexahydropyrazino[4,3-c]pyridine-5-yl]ethyl}-2-methylpropionamide.

52. Connection on p. 50, where the compound is 2-amino-N-{ 1-(R)-(2,4-differentiatedly)-2-oxo-2-[3-oxo-3A-(S)-pyridine-2-ylmethyl-2-(2,2,2-triptorelin)-2,3,3 a, 4,6,7 there is hexahydropyrazino[4,3-c]pyridine-5-yl]ethyl}-2-methylpropionamide.

53. Connection on p. 6, having the formula

< / BR>
racemizes-diastereomeric mixtures and optical isomers of these compounds,

where R1denotes-CH2-phenyl, R2denotes methyl and R3denotes-CH2-O-CH2is phenyl;

R1denotes-CH2-phenyl, R2denotes ethyl and R3denotes-CH2-O-CH2is phenyl;

R1denotes-CH2-phenyl, R2denotes-CH2-CF3and R3denotes-CH2-O-CH2is phenyl;

R1denotes-CH2-4-forfinal, R2denotes methyl and R3denotes-CH2-O-CH2is phenyl;

R1denotes-CH2the means-CH2-phenyl, R2denotes methyl and R3denotes-CH2-O-CH23,4-differenl.

54. Connection on p. 53, representing diastereomer a mixture of 2-amino-N-[2-3a-(R, S)-benzyl-2-methyl-3-oxo-2,3,3 a, 4,6,7 there is hexahydropyrazino[4,3-c]pyridine-5-yl)-1-(R)-(3,4-differentiatedly)-2-oxoethyl]-2-methylpropionamide.

55. Connection on p. 54, where the compound is 2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3 a, 4,6,7 there is hexahydropyrazino[4,3-c] pyridine-5-yl)-1-(R)-(3,4-differentiatedly)-2-oxoethyl] -2-methylpropionamide.

56. Connection on p. 54, where the compound is 2-amino-N-[2-(3A-(S)-benzyl-2-methyl-3-oxo-2,3,3 a, 4,6,7 there is hexahydropyrazino[4,3-C]-pyridine-5-yl)-1-(R)-(3,4-differentiatedly)-2-oxoethyl] -2-methyl-propionamide.

57. Connection on p. 25, where R1represents-CH2is phenyl; R2represents hydrogen or methyl and R3represents-CH2-O-CH2is phenyl.

58. The pharmaceutical composition used for amplification of the endogenous formation or release of growth hormone in humans or animal containing an inert carrier and an effective amount of the compounds under item 1.

59. The way to increase levels of endogenous g the number of connections on p. 1.

60. The method according to p. 59, where the growth hormone is IGF-1.

61. Method for the treatment or prevention of diseases or conditions associated with growth hormone deficiency, including the introduction of a human or animal in need of such treatment or prevention, the compound under item 1 in an effective amount, in free form or in combination with additives.

62. The method according to p. 61, where the disease is osteoporosis.

63. The method according to p. 61, where the disease or condition is a chronic heart failure, weakness associated with aging or obesity.

64. The method according to p. 61, where the disease or condition are protein catabolic response after major surgery, cachexia and protein loss caused by chronic disease, wounds and burns patients or patients that underwent extensive surgery.

65. The method according to p. 61, where the disease or condition is a weakening of muscle strength, mobility, change of skin thickness, metabolic homeostasis or renal homeostasis.

66. The method according to p. 62, where a connection on p. 1 is administered in combination with bisphosphonates connection.

67. The method according to p. 66, where bi is Yat in combination with estrogen or Premarinand, optionally, progesterone.

69. A method of treating osteoporosis by p. 62, where a connection on p. 1 is administered in combination with calcitonin.

70. A method of treating osteoporosis by p. 62, where a connection on p. 1 is administered in combination with an agonist or antagonist of estrogen.

71. The method according to p. 70, where the agonist or antagonist of estrogen represents tamoxifen, droloxifene, raloxifene or idoxifene.

72. The method according to p. 63, where the disease or condition is a chronic heart failure.

73. The method according to p. 63, where the disease or condition is a weakness associated with aging.

74. The method according to p. 64, where the disease or condition that requires speed up the recovery of patients undergoing extensive surgery.

75. The method according to p. 64, where the disease or condition that requires acceleration of healing of bone fractures.

76. The method according to p. 64, where the disease or condition requires an increase in muscle mass.

77. A method of treating osteoporosis by p. 66, where bisphosphonate connection represents ibandronate.

78. The method according to p. 70, where the agonist or antagonist of estrogen is Wal-pyrrolidin-1 ylethoxy)phenyl] -5,6,7,8-tetrahydronaphthalen-2-ol;

CIS-6-phenyl-5-[4-(2-pyrrolidin-1 ylethoxy)phenyl] -5,6,7,8-tetrahydronaphthalen-2-ol;

CIS-1-[6-pyrrolidinone-3-pyridyl] -2-phenyl-6-hydroxy-1,2,3,4-tetrahydronaphthalen;

1-(4-pyrrolidinecarbonyl)-2-(4-forfinal)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline;

CIS-6-(4-hydroxyphenyl)-5-[4-(2-piperidine-1-ylethoxy)phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol or

1-(4-pyrrolidinecarbonyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline.

79. The method according to p. 61, where the disease or condition is a slow growth in children with growth hormone deficiency.

80. The method according to p. 61, where the disease or condition is insomnia.

81. The connection formulas

< / BR>
racemizes-diastereomeric mixtures, optical isomers of these compounds and their pharmaceutically acceptable salts,

where e is 0 or 1;

n and w are each equal to 1;

R1denotes hydrogen, (CH2)t-AND1where t is 0, 1 or 2;

R2denotes hydrogen, (C1-C8)alkyl, where the alkyl group in the definition of R2optionally substituted CF3;

AND1in each case denotes phenyl or fully unsaturated 4 - to 8-membered ring, optionally having 1 to 2 heteroatoms, independently in asenovo 5 - or 6-membered ring, optionally having 1 or 2 heteroatom, represented by nitrogen;

A1in each case, independently, optionally substituted in one or optionally both rings if AND1is a bicyclic ring system and has up to two substituents, each Deputy is independently selected from the group comprising F, CL, Br, F3, (C1-C6)alkyl, phenyl.

82. Connection on p. 81, where R1denotes hydrogen, (CH2)tAND1and1in the definition of R1optionally substituted by 1 to 2 substituents, independently selected from the group comprising F, Cl, Me, and F3.

83. Connection on p. 82, where e is 0; R1denotes-CH2-pyridyl, -CH2-thiazolyl or-CH2is phenyl, optionally substituted by 1 to 2 substituents, independently selected from the group comprising fluorine and chlorine; and2denotes hydrogen, (C1-C4)alkyl, where (C1-C4)alkyl optionally substituted CF3.

84. Connection on p. 83, where R1represents-CH2is phenyl and R2represents methyl or hydrogen.

85. Connection on p. 84, where the connection is a 3A-(R)enantiomer.

86. Connection on p. 84, where Conn is remenyi mixtures and optical isomers of these compounds

where Z100denotes methyl, BOC, CBZ, CF3C(O)-, FMOC, TROC, trityl, tosyl, CH3C(O)- or optionally substituted benzyl, optionally substituted methoxy, dimethoxy or nitro;

e is 0 or 1;

n and w are equal to 1;

R1denotes hydrogen, (CH3)t-AND1, t is 0, 1 or 2;

R2denotes hydrogen, (C1-C8)alkyl, where the alkyl part is optionally substituted CF3;

AND1in each case independently denotes phenyl or fully unsaturated 4 - to 8-membered ring, optionally having 1 to 2 heteroatoms, independently selected from the group including sulfur and nitrogen, or a bicyclic ring system consisting of a fully unsaturated 5 - or 6-membered ring, optionally having 1 or 2 heteroatom, represented by nitrogen,

AND1in each case independently optionally substituted at one or optionally both rings if AND1is a bicyclic ring system and has up to two substituents, each Deputy is independently selected from the group comprising F, CL, Br, F3, (C1-C6)alkyl, phenyl, provided that when R2is H and R1is H, then Z100is not the SUN.

)t-AND1in the definition of R1optionally substituted by 1 to 2 substituents, independently selected from the group including F, CL and F3; R2denotes hydrogen, (C1-C4)alkyl, where the alkyl part is optionally substituted CF3.

89. Connection on p. 88, where Z100means VOS; w is 1; e is 0; R1denotes-CH2-pyridyl, -CH2-thiazolyl or-CH2is phenyl, optionally substituted by 1 to 2 substituents, independently selected from the group comprising fluorine and chlorine; and2denotes hydrogen, (C1-C4)alkyl, where (C1-C4)alkyl in the definition of R2optionally substituted CF3.

90. Connection on p. 89, where R1represents-CH2-phenyl, and R2represents methyl or hydrogen.

91. Connection on p. 90, where the connection is 3A-(R)enantiomer.

92. Connection on p. 90, where the connection is 3A-(S)enantiomer.

93. The compound of formula IV

< / BR>
racemizes-diastereomeric mixtures and optical isomers of these compounds,

where Z200denotes a tert-BOC, CBZ, CF3C(O)-, FMOC, TROC, trityl, tosyl or optionally substituted benzyl, optionally substituted will Metzmacher hydrogen, (CH2)t-A1, t is 0, 1 or 2; AND1in each case denotes phenyl or fully unsaturated 4 - to 8-membered ring, optionally having 1 to 2 heteroatoms, independently selected from the group including sulfur and nitrogen, or a bicyclic ring system consisting of a fully unsaturated 5 - or 6-Cilento ring, optionally having 1 or 2 heteroatom, represented by nitrogen;

AND1in each case, independently, optionally substituted in one or optionally both rings if AND1is a bicyclic ring system, has up to 2 substituents, each Deputy is independently selected from the group comprising F, CL, Br, F3, (C1-C6)alkyl, phenyl;

R2denotes hydrogen, (C1-C8)alkyl, where the alkyl groups in the definition of R2optionally substituted CF3,

R3denotes -(C1-C5)alkyl-X1-(C0-C5)alkyl-AND1where X1means Of the values AND1above,

R4denotes hydrogen;

X4denotes hydrogen;

R6is

< / BR>
where a and b equal to 0;

X5and X5aevery means independently unsubstituted (C1-C4)alkyl;
where s is 0; R1represents-CH2is phenyl; R2represents methyl or hydrogen; R3represents-CH2-O-CH2is phenyl; R6represents- (CH3)2-; Z200represents the SUN.

 

Same patents:

form with antitumor activity and method thereof" target="_blank">

The invention relates to crystalline trihydrochloride doxicillinform:

< / BR>
having the following parameters of x-ray diraction processes in the powdered state:

15,77; 10,91; 4,88; 4,67;

I/II0,32; 0,42; 0,38; 0,53;

4,14; 3,66; 3,31; 3,21;

I/II0,70; 1,00; 0,52; 0,52,

with antitumor activity and method thereof, which consists in the fact that the powder or syrup-like aqueous suspension of trihydrochloride doxicillin crystallized from aqueous ethanol at a concentration of water of not more than 15 vol.%, 2 S. p.

The invention relates to biotinyl compounds of General formula

< / BR>
where Q is absent or represents-NH-(CH2)5-CO-,

R1denotes X-Arg-Gly-Asp-y,

X - Tripeptide: Gly-Gly-Gly-,

y - dipeptide: -Ser-PrO

or R1denotes A-Cys(R2)-B-U,

R2denotes H, Trt;

And represents Asp or peptide fragment selected from the group consisting of:

Ala-Asp, Thr-Ala-Asp, Lys-Thr-Ala-Asp, Lys-Ala-Ala-Asp,

Arg-Thr-Ala-Asp, Ser-Ala-Asp, Gln-Ser-Ala-Asp,

Gly-Lys-Thr-Ala-Asp, Ile-Ser-Ala-Gly, Arg-Ser-Ala-Gly

Gly-Lys-Thr-Cys (Trt)-Asp

In tstststs or represents Pro or N-methylated derivative of Ala,

moreover, if R1denotes A-Cys(R2)-B-U, only one of the residues a or b may not appear,

U indicates HE or NH2,

or R1means cyclo (Arg-Gly-Asp-Z), Z in the side chain is linked to Q, or if Q is absent, with Biotin,

Z denotes a di - or tripeptides the rest,

moreover, amino acids, independently of one another, are selected from the group consisting of Ala, Val, Tight, Trp, Phe, Cys, Lys, M, these amino acids can be derivatization, and amino acid residues are linked to each other peptidome through N-amino - and = R6- R4< / BR>
where R4= HE

R6= alkylether with 7-14 C atoms,

R8= H, alkyl with 1-6 C-atoms,

moreover, if we are talking about the balance of optically active amino acids and amino acid derivatives, are included as D-, L-forms;

and their salts

-(3-n-methylpyridin s)-alanine as-(l)- rarn-Сhg-Рal iu(3)-nh2" target="_blank">

The invention relates to a new method of obtaining N-acetyl-(L)-4-cyanopyrrolidine separation of the racemate ethyl ester of N-acetyl-(D,L)-4-cyanopyrrolidine and to a new method of obtaining stereoisomer Ac-(L)-pAph-Chg-Me Pal(3)-NH2using as an intermediate compound N-acetyl-(L)-4-cyanopyrrolidine

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 heterobicyclic derivatives and their pharmaceutically acceptable salts, useful as a drug

--carboline" target="_blank">

The invention relates to bellrowan-carbolines, formula I, where R3denotes-CO-R1or group (a); R1- C1-C6alkoxy; R2- N2C1-C4alkyl, C1-C4alkoxy - C1-C2alkyl; And -- 5-6-membered unsaturated cycle, in which 1-2 carbon atoms may be replaced by N, O and/or S, which may be substituted with one R5or R6; R5and R6identical or different, denote H, C1-C6alkyl, NR7R8C1-C6alkyl which may be substituted by hydroxyl or C1-C4alkoxyl, phenyl, 5-6-membered heteroaryl residue, which contains one or two atoms of N, O or S, and phenyl and heteroaryl residue may be substituted C1-C4the alkyl, C1-C4alkoxyl, halogen, or R5and R6together,- CH2)nwhere n = 4; R7and R8- H, C1-C4alkyl, acyl, as well as their isomers, tautomers and salts

The invention relates to compounds, pharmaceutical compositions and methods of using compounds of formula (II) in the treatment or prevention of certain diseases or conditions

The invention relates to new compounds of formula (1), where R1, R2, R3, R4, R5, R6X, Y, Z, W have the values

- aminohydroxylation and carboxylic acid" target="_blank">

The invention relates to new compounds of General formula I, where Q, A, R1n, m are listed in the value formula

The invention relates to new pharmacologically active 2,3-substituted derivatives of octahydro-1H-pyrido[1,2-a] pyrazine, their acid additive salts and some of their predecessors

The invention relates to a new derived chinainternational acids with antibacterial activity, in particular the hydrochloride monohydrate 1-cyclopropyl-7-([S, S]-2,8-diazabicyclo[4.3.0]non-8-yl)- 6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinoline-carboxylic acid formula

< / BR>
in13C-NMR spectrum of which has a characteristic peak at 168,1 M. D.

The invention relates to Amida phosphinic acids f-crystals (I), where R1is hydrogen, alkyl, phenylalkyl, pyridinyl, pyridinylmethyl, alkoxyalkyl, generalkonsulat; R2is hydrogen, alkyl, phenylalkyl, indolyl, generalkonsulat, alkylthiomethyl, acylaminoalkyl; R3- alkyl or phenyl; R4- alkyl, phenyl or substituted phenyl, pyridyl, thienyl or furyl, to their optical isomers, diastereomers, enantiomers, pharmaceutically acceptable salts or biohydrology esters that can be used as inhibitors of matrix metalloprotease in the treatment of conditions characterized by excessive activity of these enzymes
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