Derivatives dolastatin 15

 

(57) Abstract:

The invention relates to the derivatives of dolastatin 15 General formula (I) a-b-D-E-F(G)r-(K)s-L, where a, b, D, E, F, G and K are residues of amino acids and s and r are each independently 0 or 1. L is a monovalent radical, such as, for example, amino group, N-substituted amino group, -gidroksilaminopurina, Gerasimova, alkoxygroup, Tolkacheva, aminochrome or oxymora; in addition, the invention also includes a method of treating cancer in a mammal, such as man, which consists in the introduction to the mammal an effective amount of the compounds of formula I. 4 C. and 35 C.p. f-crystals, 3 tables.

A series of short peptides with significant activity as inhibitors of cell growth was isolated from living in the Indian ocean sea hare Dolabella auricularia (Bai et al. , Biochem. Pharmacology, 40: 1859-1864 (1990); Beckwith et al., J. Natl. Cancer Inst., 85: 483-488 (1993) and cited there). These compounds include dolastatin 1-10 (U.S. patent 4816444 issued by Pettit and others) and dolastatin-15 (application for European patent 398558). Dolastatin 15, for example, markedly inhibits the growth of cell line lymphocytic leukemia (PS system) R National cancer Institute, which is an important zwyczajna small number of different dolastatin peptides present in Dolabella auricularia (due to difficulties in purification sufficient for evaluation and use amounts of efforts have been made in relation to the synthesis of these compounds (Roux et al. Tetrahedron 50: 5345-5360 (1994); Shioiri et al. Tetrahedron 49: 1913-24 (1993); Patino et al., Tetrahedron 48: 4115-4122 (1992) and cited there). Synthetic dolastatin 15, however, also has disadvantages, which include poor solubility in aqueous systems and the need to use expensive raw materials for its synthesis. This, in turn, has led to the synthesis and evaluation of structurally modified derivatives of dolastatin 15 [cf.: Bioorg. Med. Chem. Lett. 4: 1947-50 (1994); international patent application 93 03054; patent application Japan 06234790; international patent application 93 23424].

However, there is a need for synthetic compounds with biological activity dolastatin 15, which have the desired solubility in water and can be produced efficiently and economically.

BRIEF DESCRIPTION OF THE INVENTION

Compounds of the present invention include inhibitors of cell growth, which are peptides of formula I:

A-B-D-E-F-(G)r-(TO)s-L (I)

and their salts with acids, where a, b, D, E, F, G and K are residues of amino acids, and the indices s and r are each independently 0 or 1. L is a monovalent radical, such as, for example, amino group, N-substituted amino group, -gidroksilaminopurina, Gerasimova, alkoxygroup, dialkoxy iticheskie composition, containing the compounds of formula I and a pharmaceutically acceptable carrier.

An additional embodiment of the present invention is a method of treating cancer in a mammal, such as man, involving the administration to a mammal an effective amount of the compounds of formula I in a pharmaceutically acceptable composition.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to peptides with antitumor activity. It also includes pharmaceutical compositions containing such compounds, and methods of treating cancer in mammals, including humans, through the introduction of these compounds to the mammal.

Dolastatin 15, peptide, isolated from the sea hare Dolabella auncularia, is an active inhibitor of cell growth. The specified connection, however, is present in trace quantities in the sea hare and therefore it is difficult to distinguish. Synthesis of dolastatin 15 roads, and lack of dolastatin 15 is its poor solubility in water. As here shown, however, dolastatin 15 can serve as the starting material for producing compounds devoid of these shortcomings, but at the same time preserving the antitumor activity which structural modifications dolastatin 15 lead to compounds with strikingly improved therapeutic option for the treatment of tumors compared with dolastatin 10 and dolastatin 15. In addition, the compounds of the present invention can be conveniently synthesized as described in detail below.

For the purposes of the present invention, the term "monovalent radical" means electrically neutral molecular fragment that can form one covalent bond with a second neutral molecular fragment. Monovalent radicals include hydrogen atom, alkyl groups such as methyl, ethyl and various groups, halogen atoms such as fluorine atoms, chlorine and bromine, aryl groups such as phenyl and naftalina group, and alkoxygroup, such as methoxy and ethoxypropan. Two monovalent radicals on adjacent connected link atoms may together form a bond between adjacent atoms. The two monovalent radical may also be connected together, for example, using polymethene link with the formation of cyclic structures. For example, the slice-N(R)R' in which R and R' are each a monovalent radical, may together with the nitrogen atom to form a heterocyclic ring. In addition, two monovalent radical attached to the same atom, may together form a divalent radical, such as an oxygen atom is min "normal alkyl" refers to alkyl group with non-branched or straight carbon chain, for example, normal propyl (n-propyl, -CH2CH2CH3).

Compounds of the present invention can be represented by formula I:

A-B-D-E-F-(G)r-(TO)s-L (I)

where a, b, D, E, F, G and mean residues of amino acids, the indices s and r denote each independently 0 or 1 and L is a monovalent radical such as amino, N-substituted amino group, -gidroksilaminopurina, Gerasimova, alkoxygroup, Tolkacheva, aminochrome or oxymora.

The peptides of formula I are usually composed of L-amino acids, but they may contain one or more D-amino acids. In the following discussion, reference to a single amino acid includes both enantiomers, if you don't specify a specific enantiomer. Presents compounds may also be present as salts with physiologically compatible acids, including hydrochloric acid, citric acid, tartaric acid, lactic acid, phosphoric acid, methanesulfonate acid, acetic acid, formic acid, maleic acid, fumaric acid, malic acid, succinic acid, malonic acid, sulfuric acid, L-glutamic acid, L-aspartic acid, pyruvic acid, mucus acid, Bdale follows the description of the present invention, including a detailed description of the individual components and methods of use of the claimed compounds.

Compounds of the present invention

Identity AND

In one embodiment of the invention And is a derivative of Proline of the formula IIa:

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where nandmeans integer, preferably 0, 1, 2 or 3. Rameans a monovalent radical such as a hydrogen atom or an unsubstituted or substituted by fluorine, an alkyl group, for example, C1-C3is an alkyl group with straight or branched chain, or cyclic, which is optionally substituted by 1-3 fluorine atoms; suitable examples include methyl, ethyl, isopropyl, 2-foretel, 2,2,2-triptorelin, 1-methyl-2-foretel, 1-vermeil-2-foradil or cyclopropyl; preferred methyl, ethyl or isopropyl.

In this embodiment of the invention Ra1is a monovalent radical such as a hydrogen atom, an alkyl group such as methyl, ethyl or through a group, or phenyl group. The phenyl group may be substituted; suitable substituents include one or more halogen atoms, preferably fluorine atoms, chlorine and bromine, C1-C4-alkyl groups, methoxy, the bridge.

Ra2, Ra3, Ra4and Ra5are each independently monovalent radical such as a hydrogen atom or alkyl, preferably methyl, group.

In another embodiment of the invention And is substituted derivatives of glycine of the formula IIIa:

< / BR>
where Rahas set for Rain formula IIA is and Ra1is a monovalent radical, for example, an atom of hydrogen or C1-C6is an alkyl group, preferably methyl, ethyl or through the group.

In this embodiment of the invention Ra6means a monovalent radical, such as alkyl, substituted alkyl, Alchemilla, phenyl or substituted phenyl group. Suitable examples include methoxymethyl, 1-ethoxyethyl, 1,1-dimethylhydroxylamine, 1-trifloromethyl, 1-trifluoromethyl-2,2,2-triptorelin, vinyl and 1-methylvinyl. The phenyl substituents may include one or more halogen atoms, preferably fluorine atoms, chlorine or bromine, and alkyl, methoxy, ethoxy, triptorelin and nitro.

When Ra1means alkyl group, Ra6can also be adamie substituents of the benzyl include one or more halogen atoms, such as fluorine atoms, chlorine or bromine, C1-C4is an alkyl group and methoxy, ethoxy, triptorelin and nitro.

Ra7means a monovalent radical, preferably a methyl, ethyl or isopropyl group.

In another embodiment of the invention And is derived from a-amino acid of formula IVa:

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where mais an integer, preferably 1 or 2, and Raand Ra7have the values set for these substituents in formula IIIa.

In another embodiment of the invention And is derived from a-amino acids of formula Va:

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where Raand Ra7have the values set for Raand Ra7in formula IIIa.

In another embodiment of the invention And is substituted derivatives of Proline of the formula VIa:

< / BR>
where Raand Ra1ahave the values set for Raand Ra1ain formula IIa, Xandis a monovalent radical, preferably hydroxy, alkoxy, for example methoxy or ethoxy, group, or fluorine atom.

In another embodiment of the invention And is ciprolisina of proizvodia5have the values set for the respective substituents in formula IIa.

In another embodiment of the invention And is a derivative of 1,3-dihydroindol formula VIIIa:

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where Rahas a value of Rafor formula IIa.

In another embodiment of the invention And is a derivative of 2-azabicyclo[2.2.1]heptane-3-carboxylic acid of the formula IXa:

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where Zandmeans simple or double bond and Rahas an established formula IIavalue. 3-Carbonyl Deputy may have Exo - or andorientation.

In another embodiment of the invention And is derived from a-amino acids of formula Xa:

< / BR>
where nandhas the value of nafor formula IIa, and Ra7and Rahave the values set for Ra7and Rafor formula IIIa.

Identity

In the mean valelly, isolately, alliteratively, normally, 2-tert-butylpyridinium or 2-acylglycerides balance. In may also be a residue of amino acid of formula IIb:

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in which Rb1and Rb2are each monovalent R is Inoi, alkoxyalkyl or alkenylphenol group. In preferred embodiments of the invention Rb2is cyclopropylidene group, butilkoi group with a straight or branched chain, preferably tert-butilkoi group, methoxymethyl group, 1-ethoxyethylene group or 1-methylvinyl group. In addition, Rb1and Rb2together can represent isopropylidene group.

Identity D

D is an N-alkylvinyl, N-alkyl-2-ethylpyridinium, N-alkyl-2-tert-butylpyridinium, N-alkylolamides, N-alkylsalicylate, N-alkyl-ALLO-isolationism or N-alkilirovanny the balance, where the N-alkyl group is preferably a methyl or ethyl group.

In another embodiment of the invention D is a residue of amino acid of formula IId:

< / BR>
where Rdhas a value of Randin formula IIIa, Rd1is a monovalent radical, preferably a hydrogen atom, and Rd2is a monovalent radical, for example alkyl, alkoxyalkyl or alkenylphenol group. In preferred embodiments of the invention Rd2mean group methoxymethyl group, 1-methoxyaniline group or 1-methylvinyl group. In addition, Rd1and Rd2together can form isopropylidene group.

Alternative D can be derived Proline of the formula IIId:

< / BR>
where ndis an integer, for example 1 or 2, and Rd3has set for Ra1in formula IIIa is. Xdis a monovalent radical, preferably a hydrogen atom, and when ndis 1, can also be hydroxy or alkoxy, for example methoxy - or ethoxypropane, or fluorine atom.

The identity E

E. means prolly, thiazolidine-4-carbonyl, homopolymeric or hydroxyproline residue or a residue of a cyclic-aminocarbonyl acid of formula IIE:

< / BR>
where nemeans integer, preferably 0, 1 or 2. Re1has set for Ra1in formula IIIa is. Re2and Re3are each a monovalent radical, and can be independently a hydrogen atom or alkyl, preferably methyl, group. Re4means a monovalent radical, preferably a hydrogen atom, gaudichon, preferably a hydrogen atom or a fluorine atom. In the case where nemeans 1, Re3and Re4may together form a double bond, or Re4and Re5may together represent a radical in the form attached double bond of the oxygen atom. In the case when nemeans 1 or 2, Re1and Re2may together form a double bond.

In another embodiment of the invention E is the residue of 2 - or 3-aminocyclopentane acid of formula IIIe:

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where Reis an alkyl group such as methyl or ethyl, and Re1has set for Ra1in formula IIIa is.

The identity F

F is prollenium, thiazolidine-4-carbonyl, homopolymer or hydroxyproline balance. F can also be the residue of a cyclic-amino acids of formula IIf:

< / BR>
where nfis an integer, preferably 0, 1 or 2. Rf1has set for Ra1in formula IIIa is. Rf2and Rf3are each a monovalent radical, and can be independently a hydrogen atom or alkyl, predpoklada, hydroxy, alkoxy, for example methoxy - or ethoxypropane, or fluorine atom. Rf5is a monovalent radical, preferably a hydrogen atom or a fluorine atom. In the case where nfmeans 1, Rf3and Rf4may together form a double bond, or Rf4and Rf5may together represent a radical in the form attached double bond of the oxygen atom. In the case where nfmeans 1 or 2, Rf1and Rf2may together form a double bond.

In another embodiment of the invention F is a remnant of the 2 - or 3-aminocyclopentane acid of formula IIIf:

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where Rfis a monovalent radical, such as methyl or ethyl group, and Rf1has set for Ra1in formula IIIa is.

In another embodiment of the invention F is N-alkylpyridinium or N-acylalanines balance, and the alkyl group is preferably methyl group or ethyl group.

The identity G

G is a residue of amino acid of formula IIg:

< / BR>
where Rg1is a hydrogen atom or alkyl grusnoj, arylalkyl, heteroarylboronic or aryl group. Preferably Rg2is ethyl, ISO-propyl, tert-butilkoi, isobutylene, 2-methylpropyloxy, cyclohexylmethyl, benzyl, thiazolyl-2-methyl, pyridyl-2-methyl, n-butilkoi, 2,2-dimethylpropylene, naphthylmethyl or n-sawn group, or substituted or unsubstituted phenyl group. Suitable phenyl substituents include one or more halogen atoms, preferably fluorine, chlorine or bromine, C1-C4-alkyl groups, methoxy, ethoxy, nitro or triptorelin group or dioxomolybdenum group. Alternative Rg1and Rg2may together with the carbon atom to form a cyclopentane or cyclohexane ring or benzododecinium cyclopentane ring, such as, for example, indayla group.

Identity

It is the remnant of a-amino acids of formula IIk:

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where Rk1is identical to Rg1in the formula IIg and Rk2is identical to Rg2in the formula IIg.

Identity L

In one embodiment of the invention L is amino or substituted aminogroup, saturated or unsaturated C1-C18-alkoxygroup straight or branched chain, substituted or unsubstituted, alloctype, substituted or unsubstituted aryl-C1-C6-alkoxygroup, or substituted or unsubstituted, aryloxy-C1-C6-alkoxy or heteroaryl-C1-C6-alkoxygroup. Aryl group is preferably phenyl or naftilos group. Heteroaryl group is a 5 - or 6-membered ring system, preferably containing nitrogen, oxygen or sulfur, such as, for example, a heteroaryl group, a derivative of imidazole, isoxazol, isothiazole, thiazole, oxazole, pyrazole, thiophene, furan, pyrrole, 1,2,4 - or 1,2,3-triazole, pyrazine, indole, benzofuran, benzothiophene, isoindole, indazole, quinoline, pyridazine, pyrimidine, benzimidazole, benzopyran, benzothiazole, oxadiazole, thiadiazole or pyridine. Suitable substituents of aryl include one or more halogen atoms, preferably fluorine, bromine or chlorine, C1-C4-alkyl groups, methoxy, ethoxy or triptorelin group, dioxymethylene group or nitro group.

Rl2means a monovalent radical such as a hydrogen atom, feast upon the B>-cycloalkyl group, substituted or unsubstituted aryl group, or substituted or unsubstituted heteroaryl group. Aryl group is preferably phenyl or naftilos group. Heteroaryl group is a 5 - or 6-membered ring system, preferably containing nitrogen, oxygen or sulfur, such as, for example, a heteroaryl group, a derivative of imidazole, isoxazol, isothiazole, thiazole, oxazole, pyrazole, thiophene, furan, pyrrole, 1,2,4 - or 1,2,3-triazole, pyrazine, indole, benzofuran, benzothiophene, isoindole, indazole, quinoline, pyridazine, pyrimidine, benzimidazole, benzopyran, benzothiazole, oxadiazole, thiadiazole or pyridine. Suitable substituents of aryl include one or more halogen atoms, preferably fluorine, bromine or chlorine, WITH1-C4-alkyl groups, methoxy, ethoxy or triptorelin group, dioxymethylene group or nitro group.

Alternative Rl2can have the formula IIr:

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where alis an integer such as 0, 1, 2, 3, 4 or 5. Rl3means a monovalent radical, preferably a lower alkyl group such as methyl, ethyl, sawn or isopropylidene unsaturated carbocyclic system, comprising from about 3 to about 10 carbon atoms, substituted or unsubstituted aryl or heteroaryl group, where the aryl and heteroaryl and preferred substituents have the values set for Rl2in the formula IIl.

Rl2can also be the Deputy of formula IIIr:

-(CH2)2-Wl-Rl5(IIIr),

where Wlmeans an oxygen atom or sulfur or N-Rl6-group. Rl5is a monovalent radical such as a hydrogen atom, a 1-C4is an alkyl group or3-C7-cycloalkyl group, or a substituted or unsubstituted aryl or arylmethylidene group, where the aryl and its preferred substituents have the values set for Rl2from the formula IIl. Rl6is a monovalent radical, preferably a hydrogen atom, a C1-C4is an alkyl group or3-C7-cycloalkyl group, C1-C18-alkanoyloxy group, bentilee group or a substituted or unsubstituted aryl or arylmethylidene group, where the aryl and its preferred substituents have the values set for Rl2in the formula IIl.

Rl2can also be the Deputy of the formula Vr:

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in which blhas the aforementioned significance. Rl7can be a monovalent radical, such as polyglycolide group of the formula- (CH2-CH2-O)d1-CH3where dlis an integer, preferably in the range from about 2 to about 4 or from about 40 to about 90.

Rl2may be, in addition, the hydrocarbon of the formula VIr:

< / BR>
where Rl8is a monovalent radical such as a hydrogen atom, a1-C4-alcoolica or an alkyl group, benzoline group or benzyl group.

L can also be gidroksilaminopurina formula IIIl:

< / BR>
where Rl9means a monovalent radical such as a hydrogen atom, a C1-C6is an alkyl group or a substituted or unsubstituted aryl group, where the aryl and its preferred substituents have the meaning of the volume of hydrogen, alkyl, for example methyl or phenyl group.

When r and/or s mean 1, L can also be an amino group of formula IVl:

< / BR>
where Rl2and Rl4are each a monovalent radical. Rl2and Rl4can also be connected to the carbon-carbon bond.

Another subclass of compounds of this invention includes peptides of formula I, in which L is an hydrazinopropionic formula Vl:

< / BR>
and Rl11means a monovalent radical, preferably a hydrogen atom. Rl12can be a monovalent radical such as hydrogen, C1-C8is an alkyl group with straight or branched chain, WITH3-C8-cycloalkyl group3-C8-cycloalkyl-C1-C4is an alkyl group or a substituted or unsubstituted aryl, heteroaryl, aryl-C1-C4is an alkyl or heteroaryl-C1-C4is an alkyl group, and where the aryl, heteroaryl and their preferred substituents may be selected from the options listed for Rl2.

When r and/or s mean 1, Rl11can also be selected from predstavleniyami propylene or butylene bridge.

Another subclass of compounds of this invention includes peptides of formula I, in which L is a monovalent radical of the formula-O-Rl13or of the formula-S-Rl13where Rl13is a monovalent radical, such as3-C10-cycloalkyl group, C2-C16-alkenylamine group with a straight or branched chain or C1-C16is an alkyl group which may be substituted from 1 to about 5 atoms of halogen, preferably fluorine.

Rl13can also represent a radical (CH2)e-Rl14where e is an integer, preferably 1, 2 or 3. Rl14means a monovalent radical, preferably a saturated or partially unsaturated WITH3-C10-carbocycle.

Rl13in addition, there may be a monovalent radical-(CH2-CH=C(CH3)-CH2]f-H, where f is an integer, preferably 1, 2, 3, or 4.

Rl13can also be a radical [CH2-CH2-O]g-CH3where g denotes an integer, preferably in the range from 1 to about 5.

Rl13can also be a radical -(CH2)h-aryl or -(With substituents can be selected from the group compiled for Rl2. The index h is an integer, preferably 0, 1, 2, or 3.

Rl13can also be the radical (CH2)b-W1-Rl5. Each of b, W1and Rl5can be selected from the options described for formula IVl.

Another subclass of compounds of this invention includes peptides of formula I, in which L is an aminochrome formula-0-N(Rl15) (Rl16), where Rl15and Rl16are each a monovalent moiety which can independently be a hydrogen atom, a C1-C8is an alkyl group with straight or branched chain which may be substituted by halogen atoms, preferably fluorine,3-C8-cycloalkyl group3-C8-cycloalkyl-C1-C4is an alkyl group,

substituted or unsubstituted aryl or heteroaryl group or a substituted or unsubstituted aryl-C1-C4is an alkyl group. Aryl and heteroaryl groups and their preferred substituents may be selected from the options listed for Rl2. Rl16can be selected from the options, when 7-membered heterocycle. Compounds of the present invention include, in addition, salts of the above compounds with physiologically tolerated acids.

Another subclass of compounds of this invention includes peptides of formula I, in which L is an oximetry formula-0-N=C(Rl15) (Rl16), Rl15and Rl16can be selected from the above options and, in addition, may together form a cyclic system containing preferably from about 3 to about 7 ring atoms. This cyclic system may further be condensed with one or more aromatic rings. Particularly preferred cyclic system is shown below.

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In one embodiment, the invention provides compounds of formula I, where a is a derivative of the amino acids selected from N-alkyl-D-prolyl, N-alkyl-L-prolyl, N-alkyl-D-piperidine-2-carbonyl, N-alkyl-L-piperidine-2-carbonyl, N, N-dialkyl-D-2-ethyl-2-phenylglycine and N,N-dialkyl-L-2-ethyl-2-phenylglycyl, where the alkyl means methyl, ethyl or isopropyl; and means valelly, isolately or 2-tert-butyl-L-glilly the rest.

Preferred compounds according to the selected from

D-N-methylpiperidin-2-carbonyl,

L-N-methylpiperidin-2-carbonyl, N,N-dimethylamino-isobutyryl, N-methyl-L-prolyl,

N-methyl-L-thiazolidine-4-carbonyl, N,N-dimethylglycine,

L-prolyl, L-piperidine-2-carbonyl,

N-propyl-D-piperidine-2-carbonyl,

D-piperidine-2-carbonyl, N-ethyl-D-piperidine-2-carbonyl,

N-methyl-[of 2.2.5.5-tetramethyl]-L-thiazolidine-2-carbonyl,

N-isopropyl-D-piperidine-2-carbonyl, N,N-dimethyl-2 - cyclopropylethyl, N,N-dimethyl-L-2-ethyl-2-phenylglycyl,

N,N-dimethyl-D-2-ethyl-2-phenylglycyl, D-prolyl,

N-methyl-D-prolyl, N,N-dimethyl-2-(2-forfinal)gizela,

1-Aza-[3,3,0]bicycloalkyl-5-carbonyl,

N,N-dimethyl-2-[4-fluoro]phenylglycine,

N-methyl-[of 2.2.5.5-tetramethyl]thiazolidin-2-carbonyl,

2-(R,S)-ethyl-2-phenylglycyl, D,L-1-aminoindan-1-carbonyl,

N, N-dimethyl-2-(R,S)-methyl-2-phenylglycine, 2-[N,N-dimethylamino]indan-2-carbonyl,

5-[N, N-dimethylamino] -5,6,7,8-tetrahydronaphthalen-5-carbonyl, N-isopropyl-2-(R,S)-ethyl-2-phenylglycyl, 1-[N,N-dimethylamino]indan-2-carbonyl,

N,N-dimethyl-2-propyl-2-phenylglycyl,

N,N-dimethyl-2-[4-methoxy]phenylglycine,

N-methyl-3-hydroxy-D, L-poured, N, N-dimethyl-D,L-2-isopropyl - 2-phenylglycyl, N-methylpiperidin-2-carbonyl,

N-methyl-L-prolyl, N-methyl-1,2,3,4-tetrahed who was serila,

N,N-dimethyl-[O-methyl]threonine,

N-methyl-1,2,3,4-tetrahydroisoquinoline-3-carbonyl,

1-[N,N-dimethylamino]cyclohexyl-1-carbonyl,

1-[N,N-dimethylamino]cyclopentyl-1-carbonyl and

1,2,3,4-tetrahydroisoquinoline-3-carbonyl. In is poured, isoleucyl or 2-tert-butylglycol. D represents N-methylallyl, N-methyl-2-tert-butylglycol or N-methylisoleucine. E and F each independently represents shed, tiapamil, gemopolis, hydroxypropyl, 3,4-didehydroretinal, 4-FERROLI and 3-methylpropyl. L is alkoxygroup or amino group of the formula Rl1-N-Rl2where Rl1and Rl2independently selected from the group consisting of hydrogen, alkoxy, hydroxy, alkyl and alkylaryl.

In a particularly preferred set of compounds of the invention r and s mean each 0. And is derived amino acids, selected from

D, N-methylpiperidin-2-carbonyl, N-ethyl-D-piperidine-2-carbonyl, N-isopropyl-D-piperidine-2-carbonyl,

N,N-dimethyl-2-cyclopropylmethyl, N-methyl-D-prolyl,

1-Aza-[3,3,0]bicycloalkyl-5-carbonyl,

N-methyl-[of 2.2.5.5-tetramethyl]thiazolidin-2-carbonyl,

2-(R,S)-ethyl-2-phenylglycyl, D,L-1-aminoindan-1-carbonyl,

N,N-dimethyl-2-(R,S)-methyl-2-phenylglycyl N, N-dimethyl-2-propyl-2-phenylglycyl, N, N-dimethyl-L-2-ethyl-2-phenylglycyl, N,N-dimethyl-D-2-ethyl-2-phenylglycyl, N-methyl-3-hydroxy-D,L-poured,

N,N-dimethyl-D,L-2-isopropyl-2-phenylglycyl,

N-methylpiperidin-2-carbonyl, N-methyl-D,L-prolyl,

N-methyl-1,2,3,4-tetrahydroisoquinoline-1-carbonyl,

N-methylaziridine-2-carbonyl,

N-isopropylpyridine-2-carbonyl,

N,N-dimethyl-[O-methyl]serila,

1-[N,N-dimethylamino]cyclohexyl-1-carbonyl and

1-[N, N-dimethylamino] cyclopentyl-1-carbonyl. In is poured; D is N-methylallyl; and E and F each represents shed. L represents C1-C6-alkoxygroup or the amino group of the formula Rl1-N-Rl2where Rl1and Rl2each independently selected from the group consisting of hydrogen, a1-C6-alkoxy, hydroxy, C1-C12-alkyl straight or branched chain or cyclic, and phenylalkyl.

Synthetic methods

Compounds of the present invention can be obtained by known methods of peptide synthesis. Thus, the peptides can be composed sequentially of individual amino acids or by linking suitable small peptide fragments. In the case of a sequential combination of fragments of fragments of different lengths can be connected, and fragments, in turn, can be obtained by the sequential joining of amino acids or a combination of fragments shorter peptides.

As with the serial connection, and when combined fragments it is necessary to connect the individual elements through the formation of amide linkages, which can be accomplished through a series of enzymatic and chemical methods. Chemical methods of amide bond formation are described in detail in the standard recommendations for peptide chemistry, including Methods der organischen Chemie Vol. XV/2, 1-364, Thieme Verlag, Stuttgart, (1974); Stewart and Young, Solid Phase Peptide Synthesis, 31-34 and 71-82, Pierce Chemical Company, Rockford, IL (1984); Bodanszky et al., Peptide Synthesis, 85-128, John Wiley & Sons, New York, (1976). Preferred methods include the azide method, the method of symmetric and mixed anhydrides, using in situ generated or pre-formed active esters, the use of protected urethane N-carboxyanhydrides amino acids and amide bond formation using reagent combinations, such as activators of carboxylic acids, especially dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-etoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), pivaloyloxy, the hydrochloride of 1-ethyl-3-(3-dimethy foreshore (THIEF-C1), hexaphosphate bromo-Tris(pyrrolidino)phosphonium (PyBrop), diphenylphosphoryl (DPPA), reagent Castro (THIEF, Rumor), O-benzotriazolyl-N, N, N', N'-tetramethyluronium salt (HBTU), O-isobenzofuranyl-N,N,N',N'-tetramethyluronium salt (HATU), diethylphosphoramidite (DEPCN), dioxide, 2,5-diphenyl-2,3-dihydro-3-oxo-4-hydroxythiophene (reagent of Steglich; HOTDO) and 1,1'-carbonyldiimidazole (CDI). Reagents for combination can be used by themselves or in combination with additives, such as N,N-dimethyl-4-aminopyridine (DMAP), N-hydroxybenzotriazole (HOBt), N-gidroksibenzotriazola (HOAt), N-hydroxy-benzotriazine (HOOBt), N-hydroxysuccinimide (HOSu) or 2-hydroxypyridine.

Although the use of protective groups is not usually necessary in enzymatic peptide synthesis, can be easily removed to protect reactive groups not involved in the formation of amide linkages necessary for both reagents in chemical synthesis. Three common methods of using protective groups are preferred for chemical peptide synthesis techniques using benzyloxycarbonyl (Z), tert-butoxycarbonyl (BOC) and 9-fluorenylmethoxycarbonyl (Fmoc) protection. Defining in each case is a protective group of the amino group extending C, Thieme Verlag, Stuttgart (1974). The fragments used for the Assembly of the peptide chain can react in solution, in suspension or in the manner similar to that described Merrifield, J. Am. Chem. Soc. 85: (1963) 2149.

Solvents suitable for peptide synthesis include any inert under the reaction conditions, the solvent, in particular water, N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), acetonitrile, dichloromethane (DHM), 1,4-dioxane, tetrahydrofuran (THF), N-methyl-2-pyrrolidone (NMP) and mixtures of these solvents.

Peptide synthesis on polymeric carrier can be carried out in a suitable inert organic solvent, in which a soluble source of the substance to obtain derivatives of amino acids. However, the preferred solvents additionally possess properties that contribute to swelling of the polymer, such as, for example, DMF, DHM, NMP, acetonitrile and DMSO and mixtures of these solvents. After synthesis, the peptide is removed from the polymer carrier. The conditions under which this splitting for different types of polymers are described in the literature. Most often used in the cleavage reaction kataliziruetsa acids and palladium, in the first case, the reaction is carried out, for example, in liquid anhydrous

the fluoride, bezvezaa acetic acid/dichloromethane/triptorelin. The second option can be carried out in THF or mixtures of THF-DHM in the presence of a weak base, such as morpholine. Some protective group also hatshepsuts in these conditions.

The partial withdrawal of protection from the peptide may also be necessary before specific derivatization reactions. For example, dialkylamines N-end of the peptides can be obtained by attaching a suitable N,N-dialkylaminoalkyl to the peptide in solution or on the polymer carrier is the reductive alkylation associated with polymer-peptide in a mixture of DMF/1% acetic acid using NaN3and the corresponding aldehyde or hydrogenation of the peptide in solution in the presence of an appropriate aldehyde or ketone and Pd/coal.

Various naturally occurring amino acids, as well as various diaminotoluene residues described herein may be obtained from commercial sources or can be synthesized from commercially available materials using methods known in this field. For example, amino acid structural elements to build with groups of R1and R2can be obtained according to the method described Dr. Thomas wŁnsch and Weyl, Methods der Organische Chemie, vol. XV, Springer Ver In another embodiment, the invention presents the invention includes a method of partial or complete inhibition of the formation or otherwise of treatment (for example, revertive or inhibiting further development of solid tumors (e.g., tumors of lung, breast, colon, prostate, bladder, rectal or uterine tumors or hematologic malignancies (such as leukemias, lymphomas) in mammals, for example humans, by introducing to a mammal a therapeutically effective amount of a compound or combination of compounds of formula I. the Compound(I) can be entered separately or in pharmaceutical compositions comprising compound(I) and an acceptable carrier or solvent. The introduction can be performed by any of the methods conventional for the pharmaceutical, preferably cancer, means, including oral and parenteral methods, as, for example, subcutaneously, intravenously, intramuscularly and intraperitoneally, nasal or rectal. Compounds can be entered separately or in the form of a pharmaceutical composition containing the compound or compounds of formula I together with a pharmaceutically acceptable carrier suitable for the desired route of administration. Such pharmaceutical composition can be a combination of substances, i.e., they can also contain other terapeutica therapeutically effective amount of the compounds described herein. Used herein, the expression "therapeutically effective amount" means an amount sufficient for inhibition (partial or full) education tumors or hematological malignant disease or to prevent or reduce its further development. For a particular condition or treatment dose is determined empirically using known methods and depends on factors such as the biological activity of the individual connections in use, routes of administration, the age, condition and body weight of the recipient, the nature and extent of symptoms, frequency of treatment, the use of other treatment options and the desired effect. The usual daily dose is from about 0.05 to about 50 mg per 1 kg of body weight when administered orally or from about 0.01 to about 20 mg per 1 kg of body weight at parenteral administration.

Compounds according to the present invention can be introduced in the form of a conventional solid or liquid pharmaceutical forms for administration, for example, in the form of uncoated tablets or film-coated tablets, capsules, powders, granules, suppositories or solutions. These forms are prepared in a common manner. Active substances for this purpose you can amrabat the population tablets fillers, preservatives, disintegrant, the fluidity regulators, plasticizers, wetting means, dispersing funds, emulsifiers, solvents, compositions for maintaining release, antioxidants and/or propellant in the form of gases (cf. N. et al. : Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, (1978). Thus obtained forms for administration generally contain from about 1 to about 90% by weight of the active substance.

The presented invention will be illustrated in the following examples, which are not restrictive.

EXAMPLES

Names forming proteins amino acids are reduced in the examples using a known three-letter code. Other abbreviations used are: TFU = triperoxonane acid. AC = acetic acid, DHM = dichloromethane, DMSO = dimethylsulfoxide, BU = butyl, Et = ethyl, Me = methyl, Bzl = benzyl. In these connections, all forming proteins amino acids are L-amino acids unless otherwise specified. Other abbreviations: IU2Vl = N,N-dimethylamine, MeVal = N-methylvaline, PG = benzyl, Me2Aib = [2-N,N-dimethylamino]somalina acid.

General methods

The peptides according to the invention synthesize or classical synthesis in solid phase synthesis, using the technique with the use of Vos and Fmo-protective groups.

In the case of solid-phase synthesis of acid N,N-dialkylphenol or hexapeptides otscheplaut from solid medium and then combined with the corresponding C-terminal amines in solution. THIEF-C1 and PyBrop were used as reagents for the combination of the amino acid following the N-methyliminodiacetic. The reaction time is correspondingly increased. For reductive alkylation of N-end removed the protection from the peptide-polymer with N-end and then subjected to reaction with 3-fold molar excess of aldehyde or ketone in a mixture of DMF/1% acetic acid with addition of 3 equivalents of NaCNBH3. After completion of the reaction (negative test Kaiser) polymer was repeatedly washed with water, isopropanol, DMF and dichloromethane.

In the case of synthesis in solution using either BOC-protected amino acid NCAs (N-tert-butyloxycarbonyl-amino-N-carboxyanhydride), Z-protected amino acid NCAs (N-benzyloxycarbonyl-amino-N-carboxyanhydride), or the use of pualeilani as a condensing agent, respectively, is the most favorable combination of amino acid following the N-methyliminodiacetic. Vosstanovitelem is authorized at N-end protection with the appropriate aldehydes or ketones using NaCNBH3or hydrogen in the presence of Pd on charcoal grill.

Hydrochloride poured-N-methylallyl-shed-propylbenzamide was obtained, for example, according to the methods described in the patent application Germany 19527575 A1.

Purification and characterization of peptides

Purification of peptides was performed by gel-chromatography (Sephadex G-10, G-15/10% HOAc, Sephadex LH2O/MeOH), by medium pressure chromatography (stationary phase: HD-SIL C-18, 20-45 micron, 100 Angstrom; mobile phase: gradient with A= 0.1% OF TFU/Meon, IN= 0,1% TFU/water), preparative HPLC (stationary phase: Waters Delta-Pak C-18, 15 micron, 100 Angstrom; mobile phase: gradient with A=0.1% OF TFU/Meon, IN=0,1% TFU/water) or by crystallization.

The purity of the obtained products was determined by analytical HPLC (stationary phase: 100 2.1 mm VYDAC C-18, 5 micron, 300 A; mobile phase: a gradient of acetonitrile-water, buffered with 0.1% TFU, 40oWith; or 3.9 mm VYDAC C-18, 30oC). Characterization was carried out by mass spectroscopy with fast atom bombardment and NMR spectroscopy.

Example 1. Synthesis of [N-methyl-L-piperidine-2-carbonyl]-Val-MeVal-Pro-Pro-NHBn (compound 1) and [N-methyl-D-piperidine-2-carbonyl] -Vl-Vl-Pro-Pro-NHBn (compound 2)

Obtaining N-methylpiperidin-2-carboxylic acid

Ethyl ester of N-methylpiperidin-2-ka is shivali at room temperature over night. Then the solution was neutralized with hydrochloric acid, evaporated to dryness and four times was evaporated with toluene. The obtained powdery precipitate directly used in the next stage.

Getting [N-methylpiperidin-2-carbonyl]-Val-MeVal-Pro-Pro-NHBn

The precipitate (of 5.05 g), obtained as described above, and H-Val-MeVal-Pro-Pro-NHBn x HC1 (4,88 g) was dissolved in 50 ml of dry DMF. After cooling the solution in an ice bath was added 1.52 g DEPCN and 2.66 ml of triethylamine. The reaction mixture was stirred 2 hours at 0oC and then overnight at room temperature. DMF was removed by evaporation under reduced pressure. The residue was diluted with dichloromethane and the organic phase is washed with aqueous hydrochloric acid (pH 2) and water, dried over sodium sulfate and evaporated to dryness. Diastereomer mixture was then divided by flash chromatography with a gradient, using heptane/ethyl acetate and dichloro-methane/methanol. The HPLC conditions described in the previous section (reversed phase C-18), isomer 1 has a retention time of 14.9 minutes and isomer 2 has a retention time of 15.8 minutes. Both isomers were characterized by mass spectrometry with fast atom bombardment ([M+H]+= 639).

Example 2. Getting Me2Aib-Val-MeVal-Pro-Pro-NHBn (compound 3)
methanol. After adding 25 ml of aqueous formaldehyde and 1 g of 10% Pd/C, the reaction mixture was first made over night at room temperature. The catalyst was filtered and the filtrate was evaporated to dryness. The residue was led from isopropanol, receiving 4.8 g of the desired product.

Getting Me2Aib-Val-MeVal-Pro-Pro-NHBn x HC1

2-[N, N-Dimethylamino] somaclonal acid (1.3 g, 10 mmol) and 5.5 g (10 mmol) of H-Val-MeVal-Pro-Pro-NHBn HC1 was dissolved in 50 ml of dry DMF. After cooling to 0oTo the reaction mixture was added 1.6 g DEPCN (10 mmol) and 2.9 ml of triethylamine. The resulting mixture was stirred 2 hours at 0oC and at room temperature over night. Then added ice water (50 ml) and the resulting mixture was twice extracted with diethyl ether. The ether extracts washed with 1 N NaOH (lx) and aqueous NaCl (3x), then dried over sodium sulfate and evaporated to dryness under reduced pressure. The product was led from 100 ml of diethyl ether with a mixture of HCl/ether and recrystallized from acetone, obtaining 1.2 g of the desired product which was characterized by mass spectrometry with fast atom bombardment ([M+H]+=627).

Example 3. Getting [N,N-dimethyl-2-ethyl-2-phenylglycyl]-Val-MeVal-Pro-Pro-NHBn x HCl (compound 4)

Getting [N,5 g (10 mmol) of H-Val-MeVal-Pro-Pro-NHBn x HCl in 100 ml of dry DMF. After cooling to 0oWith added 1.6 g DEPCN (10 mmol) and 2.9 ml of triethylamine. The reaction mixture was stirred 2 hours at 0oC and overnight at room temperature, then treated as described above. The crude product was led from diethyl ether with a mixture of HCl/ether, receiving 4 g of the desired product which was characterized by mass spectrometry with fast atom bombardment ([M+H]+=703).

Example 4. Getting [N-methyl-D-Pro]-Val-MeVal-Pro-Pro-NHBn (compound 5)

Obtaining Z-D-Pro-Val-MeVal-Pro-Pro-NHBn

Dissolved 3,74 g of Z-D-Pro-OH (15 mmol, VANEM) and of 8.25 g of H-Val-MeVal-Pro-Pro-NHBn x HCl (15 mmol) in 80 ml of dry DMF. After cooling to 0oWith added 2.4 g DEPCN (2.25 ml, 15 mmol) and 4.2 ml of triethylamine (30 mmol). The reaction mixture was stirred for several hours at 0oC and at room temperature overnight, then DMF is evaporated under reduced pressure. The residue was diluted with ethyl acetate and thoroughly washed with dilute aqueous HC1 (pH 2), water, dilute aqueous NaOH (pH 9-10) and water. The organic phase was dried over sodium sulfate and was evaporated to dryness, obtaining of 9.2 g of the desired protected Pentapeptide.

Getting D-Pro-Val-MeVal-Pro-Pro-NHBn x HC1

Dissolved 8,2 g (11 mmol) of Z-D-Pro-Val-MeVal-Pro-Pro-NHBn in 70 ml of m is Aravali. After filtration and evaporation of the solvent was obtained a residue, which was dissolved in water, brought the pH to 2 and was extracted twice with ethyl acetate. Brought the pH of the aqueous phase to 9-10 and was twice extracted with dichloromethane. The organic extracts were evaporated and the residue was again dissolved in diethyl ether and was led by adding a mixture of HCl/ether in the form of cleaners containing hydrochloride salt, receiving 6.5 g of the desired product.

Getting [N-methyl-D-RHS]-Vl-Vl-RHS-RHS-Nn x Hcl

Dissolved 1,94 g (3 mmol) of D-Pro-Val-MeVal-Pro-Pro-NHBn x Hcl in 30 ml of methanol. To this solution was then added 0.3 g of 10% Pd/C and 1.5 ml of an aqueous solution of formaldehyde and the reaction mixture was first made. After filtration and evaporation of the solvent, the obtained residue was dissolved in water, brought the pH to 2 and was twice extracted with diethyl ether, and optionally several times with dichloromethane. Brought the pH of the aqueous phase to 9-10 and was twice extracted with dichloromethane. The organic extracts were dried over sodium sulfate and evaporated to dryness. The residue is crystallised in the form of cleaners containing hydrochloride salt with obtaining 0.5 g of the desired product which was characterized by mass spectrometry with fast atom bombardment ([M+H]+=625).

Connections shown wheelie "isomer 2", isomer 1 means the diastereoisomer with a shorter retention time in the system in the analysis of HPLC with reversed phase. The results of mass spectrometry with fast atom bombardment for a number of selected compounds are shown in table 2.

Example 5. Evaluation of biological activity

In vitro methods

Cytotoxicity was measured using a standard methodology for fused cell lines, for example, tetrazolium analysis for micro cultures (MTT). The details of this analysis have been published (Alley, M. C. et al. Cancer Research 48: 589-601, (1988)). To prepare cultures for titration tablets used exponentially growing cell culture HT-29 colon cancer. Cells were seeded on 5000-20000 in the cell 96-well tablet (150 ml medium) and grown overnight at 37oC. was Added the compounds in 10-fold dilutions varied from 10-4M to 10-10M. the cells are Then incubated for 48 hours. To determine the number of viable cells in each well was added the dye MTT (50 ml of a solution of bromide 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium in saline solution with a concentration of 3 mg/ml). This mixture was incubated 5 hours at 37oC and then added to each lounge at 550 nm, using the device for counting used in the ELISA test. The mean standard deviations of the data from duplicate wells was calculated using the formula % Of (% of viable cells treated/control). The concentration of the tested compound, which gives About/To 50% inhibition of growth was identified as IR50.

Table 3 presents the values MK50defined in the test with HT-29 for a number of compounds according to the invention.

In vivo technique

The compounds of this invention can be further investigated in in vivo activity in any of the various pre-clinical trials that suggest clinical applicability. Such experiments are performed with hairless mice that had been transplanted ("xenotransplantation") tumor tissue, preferably from a person that is well known in this field. The compounds are evaluated with regard to their antitumor efficacy after administration to mice with xenograft.

More specifically, tumors of the people who grew up in hairless mice with congenital absence of the thymus gland, can be transplanted into a new recipient animals when using fragments of the view of the studied compounds, which is injected in the form of intravenous or intraperitoneal injection to groups of 5-10 mice for each dose. The compound is administered daily for 5 days, 10 days or 15 days at doses of 10-100 mg/kg of body weight. Twice a week, measure the diameter of the tumor and body weight. Mass tumors calculated using the diameters measured by Vernier compass, according to the formula:

(length x width2)/2 = mg tumor mass

The average weight of the tumors then calculated for each treated group, and the value Of K is determined for each group relative to the untreated control tumors.

Compounds presented here as examples, correspond to sequences: th. 1: connection 1-4, 7, 9, 10, 12-19, 22-44, 46, 47, 49, 50, 54-59, 61-65, 67-108, 119-142, 144, 145, 147, 148, 150, 151, 153, 154, 156, 157, 159, 160, 162, 163, 165, 166, 168, 169, 171, 172, 174, 175; PEFC. 2: connection 5, 6, 8, 20, 45, 48, 51-53, 60, 66, 109-118, 143, 146, 149, 152, 155, 158, 161, 167, 170, 173; PEFC. 3: compound 11; th. 4: connection 21.

EQUIVALENT SUBSTITUTES

Specialists in this field will recognize, or be able to verify that for certain embodiments of the invention described here is sufficient to use no more than the equivalent methods of experimentation than in practice is that ek is s claims.

1. The connection formulas

A-B-D-E-F(G)r-(K)s-L

where And denotes the derivative of Proline of the formula IIa< / BR>
< / BR>
where nais a number from 0 to 3;

Rameans hydrogen or unsubstituted or substituted by fluorine1-C3-alkyl straight or branched chain, or cyclic;

Ra1means hydrogen, C1-C3-alkyl, phenyl or substituted phenyl; or Raand Ra1together form a propylene bridge;

Ra2, Ra3, Ra4and Ra5denote each independently hydrogen or alkyl;

or derivative-amino acids of formula IIIa< / BR>
< / BR>
where Rameans hydrogen or unsubstituted or substituted by fluorine1-C3-alkyl;

Ra1means1-C4-alkyl;

Ra6means alkyl, substituted alkyl, alkenyl, phenyl or substituted phenyl;

or Ra1is an alkyl group and Ra6is1-C6-alkyl, cycloalkylation, benzyl or substituted benzyl;

Ra7is hydrogen or alkyl,

or derivative of the amino acid of formula IVa< / BR>
< / BR>
where ma
or derivative-amino acids of formula Vand< / BR>
< / BR>
where Ra7is hydrogen or alkyl;

Rais hydrogen or unsubstituted or substituted fluorine-alkyl;

or derivative-amino acids of formula VIa< / BR>
< / BR>
where Rais hydrogen or unsubstituted or substituted fluorine-alkyl;

Ra1is hydrogen, alkyl, phenyl or substituted phenyl;

or Raand Ra1together form a propylene bridge;

Xandis hydroxy, alkoxy or fluorine,

or derivative-amino acids of formula VIIa< / BR>
< / BR>
where Rais hydrogen or unsubstituted or substituted fluorine-alkyl;

Ra1is hydrogen, alkyl, phenyl or substituted phenyl;

or Raand Ra1together form a propylene bridge;

Ra2, Ra3, Ra4and Ra5are each independently hydrogen or alkyl,

or a residue of amino acid of formula VIIIa< / BR>
< / BR>
where Rais hydrogen or unsubstituted or substituted by fluorine, the alkyl,

or derived 2-azabicyclo[2.2.1] heptane-3-carboxylic acid will Fouchet simple bond or double bond;

Rais hydrogen or unsubstituted or substituted by fluorine, the alkyl,

or a residue of amino acid of the formula Xand< / BR>
< / BR>
where nameans 1, 2 or 3;

Ra7means hydrogen or alkyl;

Rais hydrogen, unsubstituted alkyl or substituted fluorine-alkyl;

In the mean valelly, isolately, ALLO-isolately, normally, 2-tert-butylpyridinium or 2-acylglycerides the rest,

or a residue of amino acid of formula IIb< / BR>
< / BR>
where Rb1is hydrogen;

Rb2is alkyl or alkenyl;

or Rb1and Rb2together form isopropylidene group;

D means N-alkylvinyl, N-alkyl-2-ethylglycine, N-alkyl-2-tert-butylpyridinium, N-alternately, N-alkylsalicylate, N-alkyl-ALLO-isolately or N-alternatvely the rest,

or a residue of amino acid of formula IId< / BR>
< / BR>
where Rdis hydrogen or unsubstituted or substituted fluorine-alkyl;

Rd1is hydrogen;

Rd2is alkyl, substituted alkyl or alkenyl;

or Rd1and Rd2together they form from the Lee 2;

Rd3is hydrogen, alkyl or substituted fluorine-alkyl;

Xdis hydrogen;

or ndmeans 1 and Xdmeans fluorine, hydroxy, methoxy or ethoxy;

E. means prolly, thiazolidine-4-carbonyl, homopolymeric or hydroxyproline the rest,

or the residue of a cyclic-aminocarbonyl acid of the formula IIe< / BR>
< / BR>
where nemeans 0, 1 or 2;

Re1means hydrogen or unsubstituted or substituted by fluorine alkyl;

Re2and Re3denote each independently hydrogen or alkyl;

Re4means hydrogen, hydroxy or alkoxy;

Re5means hydrogen or fluorine;

or nemeans 1 and Re3and Re4together form a double bond; or nemeans 1 and Re4and Re5together form a bivalent radical in a linked double bond of the oxygen atom; or nemeans 1 or 2 and Re1and Re2together form a double bond,

or the rest aminocyclopentane acid of the formula IIIe< / BR>
< / BR>
where Reis alkyl and Re1is hydrogen israely or hydroxyproline the rest,

or a residue of amino acid of formula IIf< / BR>
< / BR>
where nfmeans 0, 1 or 2;

Rf1is hydrogen or unsubstituted or substituted fluorine-alkyl;

Rf2and Rf3are each independently hydrogen or stands;

Rf4is hydrogen, hydroxy, alkoxy, or fluorine;

Rf5is hydrogen or fluorine;

or nfmeans 1 and Rf3and Rf4together form a double bond; or nfmeans 1 and Rf4and Rf5together form a bivalent radical in a linked double bond of the oxygen atom; or nfmeans 1 or 2 and Rf1and Rf2together form a double bond,

or the remainder of the 2 - or 3-aminocyclopentane acid of the formula IIIf< / BR>
< / BR>
where Rfis alkyl and Rf1is hydrogen or unsubstituted or substituted fluorine-alkyl; or N-alkylpyridinium or N-acylalanines balance;

G means the residue of amino acid of formula IIg< / BR>
< / BR>
where Rg1is hydrogen or alkyl and Rg2is hydrogen, alkyl, arylalkyl, heteroallyl, Fe is 5-C6ring or benzododecinium5ring;

It is a-amino acid of formula IIk< / BR>
< / BR>
where Rk1is hydrogen or alkyl;

Rk2is hydrogen, alkyl, arylalkyl, heteroallyl, phenyl or substituted phenyl; or Rk1and Rk2together with the carbon atom, form a cyclopentane ring or benzododecinium cyclopentane ring;

L is a substituted or unsubstituted amino, hydrazido, aminoxy or oximetry;

r and s denote independently 0 or 1.

2. Connection on p. 1, where a is a derivative of Proline of the formula IIa; Rameans hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, 2-foretel, 2,2,2-triptorelin, 1-methyl-2-foradil or 1-vermeil-2-foretel; Ra1means hydrogen, methyl, ethyl, propyl, phenyl or substituted phenyl, where the phenyl substituents include one or more alkyl, alkoxy, triptorelin or nitro groups; or Raand Ra1together form a propylene bridge and Ra2, Ra3, Ra4and Ra5denote each independently hydrogen or methyl.

3. The connection of dps, isopropyl, cyclopropyl, 2-foretel, 2,2,2-triptorelin, 1-methyl-2-foradil or 1-vermeil-2-foretel; Ra1means1-C3is an alkyl group; Ra6means methoxymethyl,

1-methoxyethyl, vinyl, 1-methylvinyl, 1-triptoreline, 1-trifloromethyl, 1-trifluoromethyl-2,2,2-triptorelin, 1,1-dimethylhydroxylamine, phenyl or substituted phenyl, where the phenyl substituents include one or more halogen atoms or one or more1-C4-alkyl, methoxy, triptorelin or nitro group, or Ra1means1-C3-alkyl and Ra6means1-C6-alkyl, cycloalkenyl, benzyl or substituted benzyl, where the substituents of the benzyl include one or more halogen atoms, or one or more1-C4-alkyl, methoxy, ethoxy, triptorelin or nitro group; and Ra7means methyl, ethyl or isopropyl.

4. Connection on p. 1, where a is a residue of amino acid of formula IVawhere Ra7means methyl, ethyl or isopropyl and Rameans hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, 2-foretel, 2.2.2-triptorelin, 1-methyl-2-foradil or 1-vermeil-2-feratel.

ethyl, ethyl or isopropyl and Rameans hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, 2-foretel, 2,2,2-triptorelin, 1-methyl-2-foradil or 1-vermeil-2-feratel.

6. Connection on p. 1, where a is a residue of amino acid of formula VIawhere Rameans hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, 2-foretel, 2,2,2-triptorelin, 1-methyl-2-foradil or 1-vermeil-2-foretel; Ra1means hydrogen, methyl, ethyl, propyl, phenyl or substituted phenyl, where the phenyl substituents include one or more alkyl, alkoxy, triptorelin or nitro groups; or Raand Ra1together form a propylene bridge; and Xandmeans hydroxy, methoxy or ethoxypropan, or a fluorine atom.

7. Connection on p. 1, where a is a residue of amino acid of formula VIIawhere Rameans hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, 2-foretel, 2,2,2-triptorelin, 1-methyl-2-foradil or 1-vermeil-2-foretel; Ra1means hydrogen, methyl, ethyl, propyl, phenyl or substituted phenyl, where the phenyl substituents include one or more alkyl, alkoxy, triptorelin or nitro groups; or Raand Ra1together form impregnated is IMO hydrogen or methyl.

8. Connection on p. 1, where a is a residue of amino acid of formula VIIIandwhere Rameans hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, 2-foretel, 2,2,2-triptorelin, 1-methyl-2-foradil or 1-vermeil-2-feratel.

9. Connection on p. 1, where a is a residue of amino acid of formula IXawhere Rameans hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, 2-foretel, 2,2,2-triptorelin, 1-methyl-2-foradil or 1-vermeil-2-feratel.

10. Connection on p. 1, where a is a residue of amino acid of the formula Xandwhere Ra7means methyl, ethyl or isopropyl and Rameans hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, 2-foretel, 2,2,2-triptorelin, 1-methyl-2-foradil or 1-vermeil-2-feratel.

11. Connection on p. 1, where b means the remainder of the compounds of formula IIbwhere Rb1means hydrogen and Rb2means cyclopropyl, n-butyl, isobutyl, tert-butyl, methoxymethyl, 1-methoxyethyl or 1-methylvinyl.

12. Connection on p. 1, where D denotes the N-alkylvinyl residue, N-alkyl-2-acylglycerides residue, N-alkyl-2-tert-butylpyridinium residue, N-alternately residue, N-alkylsalicylate residue, N-alkyl-aleila or ethyl.

13. Connection on p. 1, where D denotes the residue of amino acid of formula IId, Rd1is hydrogen and Rd2means cyclopropyl, methoxymethyl, 1-methoxyethyl or 1-methylvinyl.

14. Connection on p. 1, where D denotes the residue of amino acid of formula IIIdwhere Rd3means hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, 2-foretel, 2,2,2-triptorelin, 1-methyl-2-foradil or 1-vermeil-2-foretel; and Xdmeans a hydrogen atom; or ndmeans 1 and Xdmeans a fluorine atom, or a hydroxy, methoxy or ethoxypropan.

15. Connection on p. 1, where E denotes the residue of amino acid of formula IIeand Re1means hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, 2-foretel, 2,2,2-triptorelin, 1-methyl-2-foradil or 1-vermeil-2-foretel; Re2and Re3are each independently hydrogen or stands; Re4means a hydrogen atom or a hydroxy, methoxy or ethoxypropan and Re5means hydrogen or fluorine; or nemeans 1 and Re3and Re4together form a double bond; or nemeans 1 and Re4and Re5together represent dvuhvalenten thee2together form a double bond.

16. Connection on p. 1, where E is the remainder aminocyclopentane acid of the formula IIIewhere Remeans a methyl or ethyl group, and Re1means hydrogen or methyl, ethyl, n-propyl, isopropyl, cyclopropyl, 2-foretel, 2,2,2-triptorelin, 1-methyl-2-foradil or 1-vermeil-2-feratel.

17. Connection on p. 1, where F is a residue of amino acid of formula IIfwhere Rf1means a hydrogen atom or a methyl, ethyl, n-propyl, isopropyl, cyclopropyl, 2-foretel, 2,2,2-triptorelin, 1-methyl-2-foradil or 1-vermeil-2-foretel, Rf2means a hydrogen atom or methyl group; Rf3is a hydrogen atom or methyl group; Rf4means a hydrogen atom, hydroxy, methoxy, ethoxy or a fluorine atom; Rf5means a hydrogen atom or a fluorine atom; or nfmeans 1 and Rf3and Rf4together form a double bond; or nfmeans 1 and Rf4and Rf5together form a radical in a linked double bond of the oxygen atom; or nfmeans 1 or 2 or Rf1and Rf2together form a double bond.

where Rfmeans methyl or ethyl and Rf1means hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, 2-foretel, 2,2,2-triptorelin, 1-methyl-2-foradil or 1-vermeil-2-feratel.

19. Connection on p. 1, where F denotes the N-alkylpyridinium residue or N-acylalanines the residue and the N-alkyl group is stands or ethyl.

20. Connection on p. 1, where G is a residue of amino acid of formula IIgwhere Rg1means hydrogen, methyl, ethyl or n-propyl and Rg2means hydrogen, ethyl, isopropyl, tert-butyl, isobutyl, 2-methylpropyl, cyclohexylmethyl, benzyl, thiazolyl-2-methyl, pyridyl-2-methyl, n-butyl, 2,2-dimethylpropyl, netilmicin, n-propyl, phenyl or substituted phenyl, where the phenyl substituents are one or more halogen atoms, one or more1-C4-alkyl, methoxy, ethoxy, nitro or triptorelin groups or dioxopentanoate group.

21. Connection on p. 1, where K is a-amino acid of formula IIkwhere Rk1means hydrogen, methyl, ethyl or n-propyl and Rk2means hydrogen, ethyl, isopropyl, tert-butyl, isobutyl, 2-methylpropyl, cyclohexylmethyl, benzyl, thiazolyl-2-methyl, pyridyl-2 is ucaut one or more halogen atoms, or one or more1-C4-alkyl, methoxy, ethoxy, nitro or triptorelin groups or dioxomolybdenum group; or Rk1and Rk2together with the carbon atom, form a cyclopentane ring or benzododecinium cyclopentane ring.

22. Connection on p. 1, where L is an amino group of formula II1< / BR>
< / BR>
where R11means a hydrogen atom, saturated or unsaturated WITH1-C18-alkoxygroup straight or branched chain, substituted or unsubstituted alloctype, substituted or unsubstituted aryl-C1-C6-alkoxygroup, substituted or unsubstituted, aryloxy-C1-C6-alkoxygroup, where the substituents of the aryl include one or more halogen atoms or one or more1-C4-alkyl, methoxy, ethoxy, triptorelin, dioxomolybdenum or nitro groups; or heteroaryl-C1-C6-alkoxygroup;

R12means a hydrogen atom, a C1-C18is an alkyl group with straight or branched chain, WITH1-C18-alkenylphenol group with a straight or branched chain, WITH3-C10-cycloalkyl group, aryl group or zameshano the1-C4-alkyl, methoxy, ethoxy, triptorelin, cyano or nitro groups, WITH1-C7-alkoxycarbonyl group, dioxymethylene group1-C7-alkylsulfonyl group, amino group or1-C6-dialkylamino; heteroaryl group or a substituted heteroaryl group, which is a derivative of imidazole, isoxazol, isothiazole, thiazole, oxazole, pyrazole, thiophene, furan, pyrrole, 1,2,4 - or 1,2,3-triazole, persona, indole, benzofuran, benzothiophene, isoindole, indazole, quinoline, pyridazine, pyrimidine, benzimidazole, benzopyran, benzothiazole, oxadiazole, thiadiazole or pyridine, where the substituents of heteroaryl include one or more1-C6-alkyl, hydroxyl or phenyl groups.

23. Connection on p. 22, where R12corresponds to the formula IIr< / BR>
< / BR>
where a1means 0, 1, 2, 3, 4 or 5;

R13means methyl, ethyl, n-propyl or isopropyl;

R14is a saturated or partially unsaturated carbocyclic system comprising from about 3 to about 10 carbon atoms, aryl group or substituted aryl group, where the substituents of the aryl include one or NESCO is iano or nitro group, WITH1-C7-alkoxycarbonyl group, dioxymethylene group1-C7-alkylsulfonyl group, amino group or1-C6-dialkylamino; heteroaryl group or a substituted heteroaryl group derived from imidazole, isoxazol, isothiazole, thiazole, oxazole, pyrazole, thiophene, furan, pyrrole, 1,2,4 - or 1,2,3-triazole, pyrazine, indole, benzofuran, benzothiophene, isoindole, indazole, quinoline, pyridazine, pyrimidine, benzimidazole, benzopyran, benzothiazole, oxadiazole, thiadiazole or pyridine, where the substituents of heteroaryl include one or more1-C6-alkyl, hydroxyl or phenyl groups.

24. Connection on p. 22, where R12corresponds to the formula IIIr< / BR>
-(CH2)2-W1-R15(IIIr)

where W1means N(R16)-group, an oxygen atom or a sulfur atom;

R15and R16denote each independently a hydrogen atom or a C1-C4-alkyl, C3-C7-cycloalkyl, aryl, arylmethyl, substituted aryl or substituted arylmethyl group, where the aryl substituents comprise one or more halogen atoms and the SCP, WITH1-C7-alkoxycarbonyl group, dioxymethylene group1-C7-alkylsulfonyl group, amino group or1-C6-dialkylamino; or R16means1-C18-alkanoyloxy group or benzoyloxy group.

25. Connection on p. 22, where R12is a monovalent radical of the formula IVr< / BR>
-(CH2)b1-Z1(IVr)

where b1means 2, 3 or 4;

Z1means formyl, aminocarbonyl, hydrazinecarboxamide, cyclic acetaldol, cyclic thioacetals, acyclic acatalog or acyclic thioacetal group.

26. Connection on p. 22, where R12has the formula Vr< / BR>
< / BR>
where b1means 2, 3 or 4;

R17means polyglycolide group of the formula:

-O-(CH2CH2O)d1-CH3,

where d1is between about 2 and about 4, or between about 40 and about 90.

27. Connection on p. 22, where R12has the formula VIr< / BR>
< / BR>
where R18means a hydrogen atom or a C1-C4-alkanoyloxy,1-C4-alkyl, benzoyloxy or benzyl group.

29. Connection on p. 1, where at least one of the indices r and s is 1, and L is an amino group of formula IV1< / BR>
< / BR>
where R12and R14denote each independently hydrogen or C1-C10-alkyl, or R12, R14and-carbon atom form together WITH5-C6-carbocycle.

30. Connection on p. 1, where L is hydrazinopropionic formula V1< / BR>
< / BR>
where R112means a hydrogen atom, a C1-C8is an alkyl group with straight or branched chain, WITH3-C8-cycloalkyl group3-C8-cycloalkyl-C1-C1-C4-alkyl group, where the aryl substituents comprise one or more halogen atoms or one or more methoxy, ethoxy, triptorelin, dioxymethylene, nitro, cyano,1-C7-alkoxycarbonyl,1-C7-alkylsulfonyl, amino or1-C7-dialkylamino; or heteroaryl-C1-C4-alkyl group, where the heteroaryl group is a derivative of imidazole, pyrrole, thiophene, furan, thiazole, oxazole, pyrazole, 1,2,4 - or 1,2,3-triazole, oxadiazole, thiadiazole, isoxazol, isothiazole, pyrazine, pyridazine, pyrimidine, pyridine, benzofuran, benzothiophene, benzimidazole, benzothiazole, benzopyrane, indole, isoindole, indazole or quinoline and the Deputy heteroaryl include one or more1-C6-alkyl, hydroxyl or phenyl groups;

R111means a hydrogen atom; or r is 1, s is 1 or both r and s mean 1 and R111is1-C8is an alkyl group with straight or branched chain, WITH3-C8-cycloalkenes group3-C8-cycloalkyl-C1-C4is an alkyl group, aryl-C1-C4is an alkyl group, aryl group or samewe the halogen atoms or one or more1-C4-alkyl groups, methoxy, ethoxy, triptorelin, cyano or nitro groups, WITH1-C7-alkoxycarbonyl group, dioxymethylene group1-C7-alkylsulfonyl group, amino group or1-C6-dialkylamino; heteroaryl group, heteroaryl-C1-C4is an alkyl group or substituted heteroaryl or heteroaryl-C1-C4is an alkyl group derived from imidazole, isoxazol, isothiazole, thiazole, oxazole, pyrazole, thiophene, furan, pyrrole, 1,2,4 - or 1,2,3-triazole, pyrazine, indole, benzofuran, benzothiophene, isoindole, indazole, quinoline, pyridazine, pyrimidine, benzimidazole, benzopyran, benzothiazole, oxadiazole, thiadiazole or pyridine, where the substituents of heteroaryl include one or more1-C6-alkyl, hydroxyl or phenyl groups; or R111and R112together form a propylene bridge or butylene bridge.

31. Connection on p. 1, where L is a monovalent radical of the formula

-W-R113,

where W is oxygen or sulfur;

R113means3-C10-cycloalkyl,2-C16-alkenylacyl with the straight line and the y or R113is a monovalent radical of formula -(CH2)e-R114where e denotes 1, 2 or 3 and R114is a saturated or partially unsaturated WITH3-C10-carbocyclic group; or R113is a monovalent radical of the formula

-[(CH2-CH= C(CH3)-CH2]f-H, where f means 1, 2, 3 or 4; or R113is a monovalent radical of the formula -[CH2-CH2-OH]g-CH3and g is 1, 2, 3, 4, or 5; or R113is a monovalent radical of formula -(CH2)h-X, where h stands for 0, 1, 2 or 3, X is aryl group or substituted aryl group in which the aryl substituents comprise one or more halogen atoms or one or more1-C4-alkyl groups, methoxy, ethoxy, triptorelin, cyano or nitro groups, WITH1-C7-alkoxycarbonyl group, dioxymethylene group1-C7-alkylsulfonyl group, amino group or1-C6-dialkylamino; or X is a heteroaryl group or a substituted heteroaryl group derived from imidazole, isoxazol, isothiazole, thiazole, oxazole, pyrazole, thiophene, fornicating, pyrimidine, benzimidazole, benzopyran, benzothiazole, oxadiazole, thiadiazole or pyridine, where the substituents of heteroaryl include one or more1-C6-alkyl, hydroxyl or phenyl groups, aryl-C1-C4is an alkyl group or heteroaryl-C1-C4is an alkyl group; or R113means a monovalent radical of the formula -(CH2)b-W1-R15where b stands for an integer W1is an oxygen atom, a sulfur atom or NR16group, b represents 2, 3 or 4; R15is a saturated or partially unsaturated carbocyclic system containing from about 3 to about 10 carbon atoms, aryl or substituted aryl group, where the aryl substituents comprise one or more halogen atoms or one or more1-C4-alkyl groups, methoxy, ethoxy, triptorelin, cyano or nitro groups, WITH1-C7-alkoxycarbonyl group, dioxymethylene group1-C7-alkylsulfonyl group, amino group or1-C6-dialkylamino; heteroaryl group or a substituted heteroaryl group derived from imidazole, isoxazol, isothiazole, is Atofina, isoindole, indazole, quinoline, pyridazine, pyrimidine, benzimidazole, benzopyran, benzothiazole, oxadiazole, thiadiazole or pyridine, where the substituents of heteroaryl include one or more1-C6-alkyl, hydroxyl or phenyl groups; R16means a hydrogen atom or a C1-C4-alkyl, C3-C7-cycloalkyl,1-C18-alkanoyloxy, benzoyloxy, aryl or arylmethyl group or substituted aryl or arylmethyl group, where the aryl substituents comprise one or more halogen atoms or one or more1-C4-alkyl groups, methoxy, ethoxy, triptorelin, cyano or nitro groups, WITH1-C7-alkoxycarbonyl group, dioxymethylene group1-C7-alkylsulfonyl group, amino group or1-C6-dialkylamino.

32. Connection on p. 1, where L is aminochrome formula-O-N(R115)(R116), where R115and R116denote each independently a hydrogen atom, a C1-C8is an alkyl group with straight or branched chain, substituted with halogen WITH1-C8is an alkyl group with straight or razvetvlenno the group, aryl group, the aryl-C1-C4is an alkyl group or substituted aryl or aryl-C1-C4-alkyl group, where the aryl substituents comprise one or more halogen atoms or one or more1-C4-alkyl groups, methoxy, ethoxy, triptorelin, cyano or nitro groups, WITH1-C7-alkoxycarbonyl group, dioxymethylene group1-C7-alkylsulfonyl group, amino group or1-C6-dialkylamino; heteroaryl group, heteroaryl-C1-C4is an alkyl group or substituted heteroaryl or heteroaryl-C1-C4-alkyl group, which are derived from imidazole, etoxazole, isothiazole, thiazole, oxazole, pyrazole, thiophene, furan, pyrrole, 1,2,4 - or 1,2,3-triazole, pyrazine, indole, benzofuran, benzothiophene, isoindole, indazole, quinoline, pyridazine, pyrimidine, benzimidazole, benzopyran, benzothiazole, oxadiazole, thiadiazole or pyridine, where the substituents of heteroaryl include one or more1-C6-alkyl, hydroxyl or phenyl groups; or R115and R116together with the nitrogen atom form a heterocyclic structure which comprises 5, 6 Il the/SUB>16), where R115and R116denote each independently a hydrogen atom, a C1-C8is an alkyl group with straight or branched chain, substituted with halogen WITH1-C8is an alkyl group with straight or branched chain, WITH3-C8-cycloalkyl group3-C8-cycloalkyl-C1-C4is an alkyl group, aryl group, aryl-C1-C4is an alkyl group or substituted aryl or aryl-C1-C4-alkyl group, where the aryl substituents comprise one or more halogen atoms or one or more1-C4-alkyl groups, methoxy, ethoxy, triptorelin, cyano or nitro groups, WITH1-C7-alkoxycarbonyl group, dioxymethylene group1-C7-alkylsulfonyl group, amino group or1-C6-dialkylamino; heteroaryl group or a substituted heteroaryl group, a derivative of imidazole, isoxazol, isothiazole, thiazole, oxazole, pyrazole, thiophene, furan, pyrrole, 1,2,4 - or 1,2,3-triazole, pyrazine, indole, benzofuran, benzothiophene, isoindole, indazole, quinoline, pyridazine, pyrimidine, benzimidazole, benzopyran, benzothiazole, oxadiazole, thiadiazole, ilnik or phenyl groups; or R115and R116together with the carbon atom form a cyclic system or a cyclic system, a condensed aromatic ring.

34. Connection on p. 33, where the cyclic system selected from the group consisting of

< / BR>
< / BR>
< / BR>
< / BR>
35. Connection on p. 1, where a denotes the derived amino acid selected from the group consisting of N-alkyl-D-prolyl, N-alkyl-L-prolyl, N-alkyl-D-piperidine-2-carbonyl, N-alkyl-L-piperidine-2-carbonyl, N, N-dialkyl-D-2-ethyl-2-phenylglycine and N, N-dialkyl-L-2-ethyl-phenylglycyl, where the alkyl means methyl, ethyl or isopropyl; and means felled, isoleucyl or 2-tert-butyl-L-glycyl.

36. The connection formulas

A-B-D-E-F-L

where a is derived from an amino acid selected from the group comprising D-N-methylpiperidin-2-carbonyl, L-N-methylpiperidin-2-carbonyl, N, N-dimethylamino-isobutyryl, N-methyl-L-prolyl, N-methyl-L-thiazolidine-4-carbonyl, N, N-dimethylglycine, L-prolyl, L-piperidine-2-carbonyl, N-propyl-D-piperidine-2-carbonyl, D-piperidine-2-carbonyl, N-ethyl-D-piperidine-2-carbonyl, N-methyl-[of 2.2.5.5-tetramethyl] -L-thiazolidine-2-carbonyl, N-isopropyl-D-piperidine-2-carbonyl, N, N-dimethyl-2-cyclopropylethyl, N, N-dimethyl-D-2-ethyl-2-phenylglycyl, N, N-dimethyl-L-2-ethyl-2-fil-2-[4-fluoro] phenylglycyl, N-methyl-[of 2.2.5.5-tetramethyl] thiazolidin-2-carbonyl, 2-(R, S)-ethyl-2-phenylglycyl, D, L-1-aminoindan-1-carbonyl, N, N-dimethyl-2-(R, S)-methyl-2-phenylglycyl, 2-[N, N-dimethylamino] indan-2-carbonyl, 5-[N, N-dimethylamino] -5,6,7,8-tetrahydronaphthalen-5-carbonyl, N-isopropyl-2-(R, S)-ethyl-2-phenylglycyl, 1-[N, N-dimethylamino] indan-2-carbonyl, N, N-dimethyl-2-propyl-2-phenylglycyl, N, N-dimethyl-2-[4-methoxy] phenylglycyl, N-methyl-3-hydroxy-D, L-poured, N, N-dimethyl-D, L-2-isopropyl-2-phenylglycyl, N-methylpiperidin-2-carbonyl, N-methyl-L-prolyl, N-methyl-1,2,3,4-tetrahydroisoquinoline-1-carbonyl, N-methylaziridine-2-carbonyl, N-isopropylpyridine-2-carbonyl, N, N-dimethyl-[O-methyl] seryl, N, N-dimethyl-[O-methyl] threonyl, N-methyl-1,2,3,4-tetrahydroisoquinoline-3-carbonyl, 1-[N, N-dimethylamino] cyclohexyl-1-carbonyl, 1-[N, N-dimethylamino] cyclopentyl-1-carbonyl and 1,2,3,4-tetrahydroisoquinoline-3-carbonyl;

In an amino acid residue selected from the group consisting of poured, isoleucyl and 2-tert-butylglycol;

D is a residue of an amino acid selected from the group comprising N-methylallyl, N-methylisoleucine and N-methyl-L-2-tert-butylglycol;

E and F denote each independently an amino acid residue selected from the group that includes shed, tiapamil, gemopolis, hydroxypropyl, 3,4-dedeh is 1-N-R12where R11and R12independently selected from the group consisting of hydrogen, alkoxy, hydroxy, alkyl and alkylaryl.

37. The connection formulas

A-B-D-E-F-L

where a is derived from an amino acid selected from the group comprising D-N-methylpiperidin-2-carbonyl, N-ethyl-D-piperidine-2-carbonyl, N-isopropyl-D-piperidine-2-carbonyl, N, N-dimethyl-2-cyclopropylmethyl, N-methyl-D-propyl, 1-Aza-[3,3,0] -bicycloalkyl-5-carbonyl, N-methyl-[of 2.2.5.5-tetramethyl] thiazolidin-2-carbonyl, 2-(R, S)-ethyl-2-phenylglycyl, D, L-1-aminoindan-1-carbonyl, N, N-dimethyl-2-(R, S)-methyl-2-phenylglycyl, 5-[N, N-dimethylamino] -5,6,7,8-tetrahydronaphthalen-5-carbonyl, 1-[N, N-dimethylamino] -indan-2-carbonyl, N, N-dimethyl-2-propyl-2-phenylglycyl, N-methyl-3-hydroxy-D, L-poured, N, N-dimethyl-D, L-2-isopropyl-2-phenylglycyl, N-methylpiperidin-2-carbonyl, N-methyl-D, L-prolyl, N-methyl-1,2,3,4-tetrahydroisoquinoline-1-carbonyl, N-utilisation-2-carbonyl, N-isopropylpyridine-2-carbonyl, N, N-dimethyl-[O-methyl] seril, 1-[N, N-dimethylamino] cyclohexyl-1-carbonyl, N, N-dimethyl-D-2-ethyl-2-phenylglycyl, N, N-dimethyl-L-2-ethyl-2-phenylglycyl and 1-[N, N-dimethylamino] cyclopentyl-1-carbonyl;

In the mean felled;

D means N-methylallyl;

E and F indicate each shed;

L is1and R12selected independently from the group consisting of hydrogen, C1-C6-alkoxy, hydroxy, C1-C10-alkyl straight or branched chain, or cyclic and phenylalkyl.

38. A method of treating cancer in a mammal, involving the administration to a mammal a therapeutically effective amount of the compounds under item 1.

39. The method according to p. 38, where the mammal is man.

 

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< / BR>
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< / BR>
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< / BR>
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