Antithrombotic azacycloheptane

 

(57) Abstract:

Antithrombotic peptides of formula 1, where A, R is hydrogen, - alkyl; Z represents-NE-CHF-(CO)r-G; E is hydrogen; F - H, alkyl, hydroxyalkyl, cycloalkyl, cycloalkenyl, aralkyl or substituted aralkyl; G-cycloalkenyl, OR1or NR1R2, R1, R2Is h or alkyl, r = 0 or 1, m = 1-5, n = 0-6, and p = 1-4, or their pharmaceutically acceptable salts, applicable to the prevention and treatment of thrombosis. 4 C. and 9 C.p. f-crystals, 1 table.

This application is a partial continuation in the process of simultaneous consideration of the application of the U.S. N 08/138 820, filed October 15, 1993.

This invention relates to compounds having antithrombotic activity. More specifically, the invention concerns azacyclopentadecan and pseudopeptides that inhibit platelet aggregation and thrombus formation in mammals and which are applicable for the prevention and treatment of thrombosis associated with such pathological conditions such as myocardial infarction, thrombotic stroke, peripheral artery disease and disseminated intravascular coagulation.

Hemostasis, biochemistry of blood coagulation, is chrisv is more of bleeding from damaged blood vessels. Effective hemostasis requires the combined activity of vascular, platelet and plasma factors, as well as an adjustable mechanism to prevent excessive clotting. Defects, lack or excess of any of these components can lead to hemorrhagic or thrombotic consequences.

Adhesion of platelets, growth and aggregation on extracellular matrices are the Central events in the formation of a blood clot. These events are mediated by a family of adhesive glycoproteins, i.e., fibrinogen, fibronectin and von Willebrand's disease. Fibrinogen is a cofactor for platelet aggregation, whereas fibronectin supports the adherence of platelets and reactions of expansion, and the factor a background of Villebranda important for attachment of platelets to the subendothelial matrix and spread on it. The binding sites for fibrinogen, fibronectin and von Willebrand's disease have been found in the protein complex membranes of platelets, known as glycoprotein IIb/IIIa.

Adhesive glycoproteins such as fibrinogen, are not associated with normal resting platelets. However, when activation of the platelet agonist such as thrombin or is novena. Connections in the scope of the present invention inhibit the fibrinogen receptor, inhibiting thus, platelet aggregation, and the introduction in the form of pharmaceutical compositions containing such compounds, applicable to the prevention and treatment thrombopathia diseases such as myocardial infarction, thrombotic stroke, peripheral artery disease and disseminated intravascular coagulation.

It is known that the presence of Arg-Gly-Asp (RGD) is necessary in fibrinogen, fibronectin and factor a background of Villebranda for their interaction with the receptor surface cells (Ruoslahti E., and Pierschbacher, Cell 1986, 44, 517-18). Apparently, the other two amino acid sequences are also involved in the function of the attachment of platelets, fibrinogen, namely, Gly-Pro-Arg and the sequence of dodecapeptide His-His-Leu-Gly-Gly-Ala-Lys-Gln-Ala-Gly-Asp-Val. It is shown that small synthetic peptides containing RGD or dodecapeptide, contact the platelet receptor GPIIb/IIIa and competitively inhibit the binding of fibrinogen, fibronectin and von Willebrand's disease, and inhibit the aggregation of activated platelets (Plow et al., Proc. Natl. Acad. Sci. USA 1985, 82, 8057-61; Ruggeri, et al. , Proc. Natl. Acad. Sci. USA 1986, 5708-12; Ginsberg, et al., J. Biol. Chem. 1985, 260, 3931 shall aydinolcay and guanidinoacetate, are inhibitors of platelet aggregation (Tjoeng, et al., U.S. patent N 5037808 and N 4879313).

U.S. patent N 4992463 (Tjoeng et al.), issued February 12, 1991, describes a number of aryl - and arlbergwanderer.at mimetic compounds which have activity of inhibiting platelet aggregation, and specifically describes a number of mono - and dimethoxyphenylacetic mimetic compounds and biphenylacetic mimetic connection.

U.S. patent N 4857508 (Adams, et al), issued August 15, 1989, describes a number of guanidinoacetate derivatives containing end kalkilya substituents, that are active in the inhibition of platelet aggregation, and specifically describes the range containing O-methyltyrosine, biphenyl and afterprocessing having a terminal amide group.

Haverstick, D. M. , et al., Blood 66(4), 946-952 (1985) describe a number of synthetic peptides comprising Arg-Gly-Asp-Ser and Gly-Arg-Gly-Asp-Ser, is able to inhibit thrombin-induced platelet aggregation.

Plow, E. F. , et ai., Proc. Natl. Acad. Sci. USA 79, 3711-3715 (1982) describe that tetrapeptide glycyl-L-prolyl-L-arginyl-L - Proline inhibits the binding of fibrinogen to platelets person.

Application France N 86/17507 from 15.12.1986, reveals that thrombotic funds.

U.S. patent N 4683291 (Zimmerman, et al.), issued July 28, 1987, reports that the number of peptides consisting of 6-40 amino acids containing the sequence Arg-Gly-Asp, is an inhibitor of the binding of platelets.

EPO N 0319506, published June 7, 1989, discloses a number of Tetra-, Penta - and Hexapeptide derivatives containing the sequence Arg-Gly-Asp, which is a platelet aggregation inhibitors.

In U.S. patent N 5023233 reported that cyclic peptide analogues containing the sequence Gly-Asp, are antagonists of the fibrinogen receptor.

In pending application U.S. NN 07/677006, 07/534385 and 07/460777 filed March 28, 1991, 7 June 1990 and January 4, 1990, respectively, and also in U. S. Patent N 4952562 and International N Application PCT/US90/05448, filed September 25, 1990, describes peptides and pseudopeptides containing amino-, guanidinium, imidazolyl, and/or aminoalkanoic and alkanol are antithrombotic agents.

It is known that peptides and pseudopeptides containing the amino group and the radicals guanidinate and alkenylbenzenes, phenylalkanoic and phenylalkanoic are antithrombotic agents (application USA N 07/475, filed February 5, 1990, N PCT/US91/02471, filed April 11, 1991, published as an Int is the same assignee, and having the same authors as this invention, it is reported that contains alkanoyl and (substituted alkanoyl) azacycloheptane aspartic acid are inhibitors of platelet aggregation.

In U.S. patent N 5064814 filed April 5, 1990 by the same authors and assigned to the same assignee, it is reported that derivatives of N-substituted azacycloheptan (cyclic aminoacyl)aspartic acid are antithrombotic agents. Derivatives azacycloheptane acids are antithrombotic agents according to U.S. patent N 5051406, filed October 10, 1989 and assigned to the same assignee, which is the assignee of the present invention.

EP application 0479 481, published on 8 April 1992, describes azacyclopentadecan as antagonists of the fibrinogen receptor.

EP application N 0478 362, published on April 1, 1992, describes azacyclopentadecan -- alanine as antagonists of the fibrinogen receptor.

This invention concerns azacyclopentadecan and pseudopeptides that inhibit platelet aggregation and tout formula I

< / BR>
in which a represents a-H, amidinopropane or replaced amidinopropane;

B represents alkyl, cycloalkyl, cycloalkenyl, alkylsilanes, alkylcyclohexanes, aryl, aralkyl, alkylaryl or alkylaryl

Z represents:

< / BR>
in which E represents-H or, in combination with F, forms a 4-, 5-, 6 - or 7-membered azacycloheptane ring,

F - carbon side chain of natural amino acids, -H, alkyl, cycloalkyl, cycloalkenyl, alkylsilanes, alkylcyclohexanes, aryl, substituted aryl, aralkyl, substituted aralkyl, heterocyclyl, substituted heterocyclyl, geterotsiklicheskikh, substituted geterotsiklicheskikh or in combination with E, forms a 4-, 5-, 6 - or 7-membered azacycloheptane ring.

G denotes alkyl, cycloalkyl, cycloalkenyl, alkylsilanes, alkylcyclohexanes, aryl, substituted aryl, aralkyl, substituted aralkyl, heterocyclyl, substituted heterocyclyl, geterotsiklicheskikh, substituted geterotsiklicheskikh, OR1or NR1R2where R1and R2independently denote-H, alkyl, cycloalkyl, cycloalkenyl, alkylsilanes, alkylcyclohexanes, aryl, aralkyl, alkylaryl or alkylaryl and

r 0 denotes the AET 1-4;

or are their pharmaceutically acceptable salt.

In addition, this invention relates to pharmaceutical compositions containing such compounds, and methods of preventing or treating thrombosis in a mammal requiring such treatment, providing for the introduction of such compounds and pharmaceutical compositions.

This invention is characterized by marked and prolonged antithrombotic activity of the compounds of formula I, above, the activity observed after oral administration of these compounds.

As in the preceding text, and in this invention the following terms shall have the following meanings (unless otherwise noted);

"Amidino" refers to a group

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"Substituted amidino" means amidinopropane, N-substituted on one or both nitrogen atoms by one or more alkyl, cycloalkyl, cycloalkylation, alkylcyclohexanes, alkylcyclohexanes, aryl or aralkyl.

"Alkyl" denotes a saturated aliphatic hydrocarbon group which may be straight or branched having about 1-20 carbon atoms in the chain. Branched group indicates that the group NMI or branched alkyl groups are groups of "lower alkyl", represents an alkyl group having from 1 to about 10 carbon atoms. The most preferred group of the lower alkyl have from 1 to about 5 carbon atoms.

"Cycloalkyl" denotes a saturated carbocyclic group having one or more rings having approximately 3-10 carbon atoms. Preferred cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and decahydronaphthalene.

"Cycloalkenyl" refers to a group of alkyl, substituted cycloalkyl group. Preferred cycloalkenyl include cyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl, decahedron-1-ylmethyl and decahedron-2-ylmethyl.

"Alkylsilanes" means cycloalkyl, substituted alkyl. Examples of alkylcyclohexanes are 1-, 2-, 3 - or 4-methyl or ethylcyclohexyl.

"Alkylcyclohexanes" refers to alkyl substituted by alkylcyclohexanes. Examples of alkylcyclohexane include 1-, 2-, 3 - or 4-methyl - or ethylcyclohexylamine or 1-, 2-, 3 - or 4-methyl - or ethylcyclohexylamine.

"Azacycloheptan" refers to a saturated aliphatic ring containing the nitrogen atom. Predpochtite the em glycine, alanine, valine, leucine, isoleucine, serine, threonine, phenylalanine, tyrosine, tryptophan, cysteine, methionine, Proline, hydroxyproline, aspartic acid, asparagine, glutamine, glutamic acid, histidine, arginine, ornithine and lysine.

"- carbon side chain of natural amino acids" refers to the portion of the molecule, which replaces - carbon natural amino acids. Examples - carbon side chains of natural amino acids include isopropyl, methyl and carboxymethyl for valine, alanine and aspartic acid, respectively.

"Aryl" means phenyl or naphthyl.

"Substituted aryl" denotes phenyl or naphthyl, substituted by one or more substituents of aryl groups which may be the same or different, where "Deputy aryl group" includes alkyl, alkenyl, quinil, aryl, aralkyl, the hydroxy-group, alkoxygroup, alloctype, urlcategory, hydroxyalkyl, acyl, formyl, carboxylate, alkanoyl, aroyl, halogen, the nitro-group, trihalomethyl, cyano, alkoxycarbonyl, aryloxyalkyl, arelaxation, allmenalp, aroylamino, carbarnoyl, allylcarbamate, dialkylamino, arylcarbamoyl, aralkylamines, alkylsulfonyl is where Raand Rbdenote independently hydrogen, alkyl, aryl or aralkyl.

"Aralkyl" denotes alkyl, substituted radical the aryl. Preferred kalkilya groups include benzyl, naphthas-1-ylmethyl, naphthas-2-ylmethyl and phenethyl.

"Substituted aralkyl" means aralkyl, substituted aryl part by one or more substituents aryl group.

"Heterocyclyl" means 4 to 15-membered monocyclic or polycyclic system, where one or more atoms in the ring represent an element other than carbon, for example nitrogen, oxygen or sulfur. Preferred heterocyclyl groups include pyridyl, pyrimidyl and pyrrolidyl.

"Substituted heterocyclyl" means heterocyclyl substituted by one or more substituents aryl group.

"Heteroseksualci" and "substituted geterotsiklicheskikh" denote alkyl, which is substituted by heterocyclyl and replaced by heterocyclyl respectively.

A preferred class of compounds of the present invention is described by formula 1, in which F denotes-H, alkyl, hydroxymethyl, 1-hydroxyethyl, mercaptomethyl, 2-methylthioethyl, carboxymethyl, 2-carboxyethyl, 4-aminobutyl, 3-guanidino the military aralkyl, heterocyclyl, substituted heterocyclyl, geterotsiklicheskikh, substituted geterotsiklicheskikh or in combination with E, forms a 4-,5-, 6 - or 7 - membered azacycloheptane ring, provided that geterotsiklicheskikh other than indole-3-ylmethyl.

A more preferred class of compounds of this invention are described in the form of preferred class of compounds, in which F denotes-H, alkyl, hydroxymethyl, 1-hydroxyethyl, mercaptomethyl 2-methylthioethyl, carboxymethyl, 2-carboxyethyl, 4-aminobutyl, 3-guanidinopropionic, cycloalkyl, cycloalkenyl, alkylsilanes, alkylcyclohexanes, aryl, substituted aryl, aralkyl, substituted aralkyl or in combination with E, forms a 4-, 5-, 6 - or 7-membered azacycloheptane ring.

Even more preferred class of compounds of this invention are described in more preferred class of compounds, in which F denotes-H, alkyl, hydroxymethyl, 1-hydroxyethyl, mercaptomethyl, 2-methylthioethyl, carboxymethyl, 2-carboxyethyl, 4-aminobutyl, 3-guanidinopropionic, cycloalkyl, cycloalkenyl, alkylsilanes, alkylcyclohexanes or in combination with E, forms a 4-, 5-, 6 - or 7-membered ring azacycloheptane.

The most preferred class of compounds of this ikil, cycloalkenyl, alkylsilanes or alkylcyclohexanes.

A special variant of the present invention is described by formula II:

< / BR>
in which A denotes-H or amidinopropane,

B denotes alkyl, cycloalkyl, cycloalkenyl, alkylsilanes, alkylcyclohexanes, aryl, aralkyl, alkylaryl or alkylaryl,

j represents-H, alkyl, cycloalkyl, cycloalkenyl, alkylsilanes, alkylcyclohexanes, aryl, substituted aryl, aralkyl, substituted aralkyl,

L denotes OR1or NR1R2where R1and R2denote independently-H, alkyl, cycloalkyl, cycloalkenyl, alkylsilanes, alkylcyclohexanes, aryl, aralkyl, alkylaryl or alkylaryl.

m is 1-5,

n denotes 2-6 and

p denotes 1 or 2,

or is a pharmaceutically acceptable salt of this compound.

More preferred is a special variant of the present invention describes compounds of particular variants, in which a denotes-H,

B denotes alkyl, cycloalkyl, cycloalkenyl, alkylsilanes, alkylcyclohexanes,

j represents-H, alkyl, cycloalkyl, cycloalkenyl, alkylsilanes or alkylcyclohexanes,

m is 3 and

the connections preferred special options, in which

And denotes-H,

B denotes alkyl,

j denotes alkyl, cycloalkyl or cycloalkenyl,

R1and R2independently denote-H, alkyl, cycloalkyl, cycloalkenyl, alkylsilanes, alkylcyclohexanes,

m represents 3,

n denotes 3 or 4 and

p denotes 1.

Typical compounds of this invention include:

N-[N-[N-(4-(piperidine-4-yl)butanoyl)-N-ethylglycine]aspartyl]-valine,

N-[N-[N-(4-(piperidine-4-yl)butanoyl)-N-ethylglycine]aspartyl]-D-valine,

N-[N-[N-(3-piperidine-4-yl)propanol)-N-ethylglycine]aspartyl]-valine,

N-[N-[N-(5-(piperidine-4-yl)pentanoyl)-N-ethylglycine]aspartyl]-valine,

N-[N-[N-(4-piperidine-4-yl)butanoyl)-N-ethylglycine] aspartyl] -L-- cyclohexylglycine,

N-[N-[N-(4-piperidine-4-yl)butanoyl)-N-ethylglycine] aspartyl] -- cyclohexylamine,

N-[N-[N-(4-(piperidine-4-yl)butanoyl)-N - ethylglycine]aspartyl]norleucine,

N-[N-[N-(4-(piperidine-4-yl)butanoyl)-N - ethylglycine] aspartyl] -L - (2,2-dimethyl)prop-3-iglitzin,

N-[N-[N-(4-(piperidine-4-yl)butanoyl)-N - ethylglycine] aspartyl]-L - decahydronaphthalene-1-ylalanine,

N-[N-[N-(4-(piperidine-4-yl)butanoyl)-N - ethylglycine]aspartyl]-L - (2-cyclohexylethyl)glycine,

N-[N-[N-(4-(piperidine-4-yl)butanoyl)-N - ethylglycine]ispartially-4-yl)butanoyl)-N - ethylglycine[aspartyl] -L- - the naphthas-2-ylalanine,

N-[N-[N-(4-(piperidine-4-yl)butanoyl)-N-ethylglycine] aspartyl] -L - cyclohexylamine,

Ethyl ester of N-[N-[N-(4-(piperidine)butanoyl)-N - ethylglycine]aspartyl]-L- -- cyclohexylamine,

2-cyclohexyl-N-[N-[N-(4-(piperidine-4-yl)butanoyl)-N - ethylglycine] aspartyl]-ethylamine,

N-[N-[N-(4-(piperidine-4-yl)butanoyl)-N - ethylglycine] aspartyl] -L - CIS-decahedron-2-ylalanine,

3-adamant-1-ylpropyl-N-[N-(4-(piperidine-4-yl)butanoyl)-N - ethylglycine] aspartate,

N-[N-[N-(4-(piperidine-4-yl)butanoyl)-N - ethylglycine] aspartyl] -- aminocyclohexanecarboxylic acid,

N-[N-[N-(4-(piperidine-4-yl)butanoyl)-N - ethylglycine] aspartyl] -- cyclohexyl-D-alanine,

N-[N-[N-(4-piperidine-4-yl)butanoyl)-N - ethylglycine] aspartyl] -- decahedron-1-ylalanine,

N-[N-[N-(4-piperidine-4-yl)butanoyl)-N - ethylglycine] aspartyl] -- cyclohexylaniline,

N-[N-[N-(4-(piperidine-4-yl)butanoyl)-N - ethylglycine] aspartyl] -- cyclooctylamine,

N-[N-[N-(4-piperidine-4-yl)butanoyl)- N-ethylglycine] aspartyl] -- cyclohexyldimethylamine,

N-[N-[N-(4-(piperidine-4-yl)butanoyl)-N - ethylglycine]aspartyl] -- cyclohexylethylamine,

N-[N-[N-(4-(piperidine-4-yl)butanoyl)-N - ethylglycine]aspartyl] -- adamant-1-ylalanine,

N-[N-[N-(4-(piperidine-4-yl)butanoyl)-N - ethylglycine] aspxi)cyclohexylamine,

N-[N-[N-[ (4-(piperidine-4-yl)butanoyl)-N - ethylglycine]aspartyl] -- cycloheptylamine,

N-[N-[N-(4-(piperidine-4-yl)butanoyl)-N - ethylglycine]aspartyl] -- cyclooctylamine,

N-[N-[N-(4-(piperidine-4-yl)butanoyl)-N-ethylglycine] aspartyl] -- cyclohexylpropionic,

N-[N-[N-(4-(piperidine-4-yl)butanoyl)-N-ethylglycine] aspartyl] -- cyclooctatetraene,

N-[N-[N-(4-(piperidine-4-yl)butanoyl)-N - ethylglycine]aspartyl] -- cyclopentylamine and

ethyl ester of N-[N-[N-(4-(piperidine-4-yl)butanoyl)-N - ethylglycine]aspartyl] -- cyclohexylethylamine,

and their pharmaceutically acceptable salts.

The compounds of this invention contain asymmetric centers. These asymmetric centers can be independently in the R-configuration or S-configuration. The invention includes the individual stereoisomers and mixtures thereof.

The compounds of this invention can be used in free base form or acid or in the form of their pharmaceutically acceptable salts. All of these forms are within the scope of this invention.

If the connection of the present invention is substituted by a basic radical, can be formed salts with acids, which are more convenient form for use; and in practice premenopause salts with acids, include preferably those acids which give when combined with the free base of the pharmaceutically acceptable salts, i.e. salts, the anions of which are non-toxic to the animal organism in pharmaceutical doses of the salts so that beneficial antithrombotic properties inherent in the free bases, do not disappear due to the side effects attributed to the anions. Although the preferred pharmaceutically acceptable salts of basic compounds, all of salt with the acid used as sources of the free base form even if the particular salt, per se, is desired only as an intermediate product, for example, in the formation of salt only for purposes of purification or identification, or when it is used as an intermediate product in the preparation of pharmaceutically acceptable salts using ion-exchange procedures. Pharmaceutically acceptable salts within the scope of the present invention are salts derived from the following acids: mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid and sulfamic acid; and organic acids such as acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methansulfonate acid, Hinn acid, etc., the Corresponding salts with acids include: hydrochloride, sulfate, phosphate, sulpham, acetate, citrate, lactate, tartrate, malonate, methanesulfonate, aconsultant, bansilalpet, p-toluensulfonate, cyclohexylsulfamate and hinnat, respectively.

Salts with acids of the compounds of this invention are produced either by dissolving the free base in aqueous or aqueous-alcohol solution or other suitable solvents containing the appropriate acid and the release of salt by evaporating the solution, or by reaction of the free base and acid in an organic solvent, in which case the salt separates directly or it can be obtained by concentration of the solution.

If the connection of the invention is substituted by the acid part of the molecule, the salt with a base can be formed and they are absolutely more convenient form for use; and in practice the use of such salts is equivalent to the application form of the free acid. The base that can be applied to obtain the salts with bases include preferably those bases that react with the free acid form pharmaceutically acceptable salts, i.e. salts, cations to micromotions properties, inherent in the free acid does not disappear due to the side effects attributed to cations. Pharmaceutically acceptable salts within the scope of the present invention are salts derived from the following bases: sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, Ethylenediamine, N-methylglucamine, lysine, arginine, ornithine, procaine, N-benzyldimethylamine, diethylamine, choline, N,N'-benzylpenicillin, piperazine, Tris(hydroxymethyl)aminomethane, hydroxide of Tetramethylammonium etc.

Metal salts of the compounds of this invention can be obtained by contacting the hydroxide, carbonate or similar reactive compound of the chosen metal in an aqueous solvent with the form of the free acid of this connection. Used aqueous solvent may be water or a mixture of water with an organic solvent, preferably an alcohol such as methanol or ethanol, or a ketone, such as acetone, simple aliphatic ether, such as tetrahydrofuran, or a complex ester, such as ethyl acetate. Such reactions are usually carried out at room temperature, but can be, if desired, with nahrawan is storytale with the free acid form of the compounds. Suitable aqueous solvents include water and mixtures of water with alcohols, such as methanol or ethanol, ethers, such as tetrahydrofuran, NITRILES, such as acetonitrile, or ketones, such as acetone. Similarly, you can also get salt with amino acids.

The compounds of this invention can be obtained in accordance with the following sequence of reactions, or they can be obtained by methods known in this field. Raw materials, applicable in obtaining the compounds of this invention, a known or commercially available or they can be prepared by known methods or described here are characteristic diagrams of reactions.

The compounds of this invention can be easily obtained using standard procedures of peptide synthesis in solid phase or in solution phase using the original materials and/or readily available intermediates of supplying chemical companies such as Aldrich or Sigma (N. Paulsen, G. Merz, V. Weichart, "Solid Phase Synthesis of O-Glycopeptide Sequences", Angew. Chem. Int. Ed. Engl. 27 (1988); N. Mergler, R. Tanner, J. Gosteli, and P. Grogg, "Peptide Synthesis by a Combination of Solid-Phase and solution BU on Methods 1: A New Very Acid-Labile Anchor Group for the Solid-Phase Synthesis of Fully Protected Fragments. Tetrahedron letters 29, 4005 (1988); Merrifield, R. B. "Solid Phase is BOM of obtaining compounds of this invention is the liquid-phase method, depicted in scheme 1 (see the end of the description).

in which A, B, E, F, G, R, m, n, p and r are as defined above values;

A', E', F', G' and R' denote A, B, E, F, G, and R, respectively, or are they protected their substituted analogues or precursors of deputies; and

P1P2and P3represent a protective group for the amino acids.

The compounds of this invention usually get the original accession of a suitable amino acid or other suitable groups Z (predecessor), where Z has the above meaning, which contains a free primary and secondary amine, with a free part of a carboxylic acid protected derivative of aspartic acid.

Functional groups of aspartic acid, or any functional group precursor Z group, which should not connect, reserved, if necessary, the blocking groups to prevent cross-reactions during the accession process, as well as derivatives of amino acids and derivatives azacycloheptane acid used in the subsequent stages of the synthesis. These blocking groups include N-tert - butyloxycarbonyl (VOS), benzyloxycarbonyl (CBZ), benzyl, METI is S="ptx2">

Preferred protected derivative of aspartic acid is benzyl ester of BOC-aspartic acid. The interaction is carried out by methods known in this field. The preferred method of carrying out connection is a consolidation of the amine and carboxylic acid in a suitable aprotic organic solvent such as methylene chloride or dimethylformamide (DMF) in the presence of suitable binders. The preferred binding agent is isopropylcarbamate in the presence of N-methylpiperidine. Another preferred binding agent is the hydrochloride of 1-(3-dimethylaminopropyl)-3 - ethylcarbodiimide (EDC) in the presence of 1-hydroxybenzotriazole (NOVT) and triethylamine. Another preferred binding agent is an acid chloride of bis(2-oxo-3-oxazolidinyl)-phosphonic acid (THIEF-C1) in the presence of triethylamine.

Received protected product selectively freed from the protective groups by known methods with the formation of the N-terminal free amine part of aspartic acid. The preferred method for removal of the BOC group is processing triperoxonane acid in an aprotic organic solvent, for example methylthioadenosine glycine or alanine amino acid having a free carboxyl group. Then the obtained product is released from the N-protective groups. Obtained the free amine is then combined with a suitable protected azacycloheptane acid and this product is freed from the protective groups (deprotection) by known methods, obtaining the final product.

In another preferred method, the compounds of this invention can be obtained by solid-phase methods, well known in this area. In this solid-phase method, the C-terminal residue linked through a carboxyl part with an insoluble resin, for example, the residue can be linked in the form of ester polymer of n-alkoxybenzyl alcohol. In a manner similar to the liquid-phase method, a protected amino acid or other residue are added one by one until until the entire sequence is not built on the polymer. Then this connection deprotection and separated from the resin by standard methods, obtaining the target compound

While obtaining compounds of this invention or intermediates in their synthesis, it may be desirable or necessary to prevent cross-reaction between the chemically active substituents, other than those present in parie can then be deleted or saved, if necessary, by known methods to obtain the target products or intermediate products (see , for example. Green, "Protective Groups in Organic Synthesis", Wiley, New York, 1981). Selective protection or deprotection may also be necessary or desirable to make possible the transformation or removal of existing deputies and getting in subsequent reactions the final target product.

Hereinafter the invention is explained in illustrative examples. In the following examples, unless otherwise indicated, the amino acids, which may have a chiral - carbon, are in L-configuration.

Unless otherwise noted, data reported mass spectral analysis was obtained by way Lou Resolution Fast Atom Bombard - ment carried out on a VG 70SE with a "calculated" values (M+N)+. Spectral data of nuclear magnetic resonance receive on a Bruker ACF 300, D2A. Flash chromatography was performed on silica gel. Liquid chromatography high resolution (IHVR, HPLC) performed on a Dynamax 8 micron C-18 column with reversed phase.

Example 1

N-[N-[N-(4-(piperidine-4-yl)butanoyl)-N - ethylglycine] aspartyl] - cyclohexylamine

< / BR>
A. - cyclohexylamine (1.12 g) was dissolved in methanol (50 ml) and skipping the mind and distilled in the form of an azeotrope with toluene from the precipitate, receiving methyl ether - cyclohexyl-L-alanine in the form of hydrochloride salt.

B - benzyl ester of BOC-L-aspartic acid (1.27 g) was dissolved in methylene chloride (20 ml). The solution is cooled to 0oC and add N-methylpiperidin (of 0.48 ml), and then isopropylcarbamate (3,94 ml). This solution was stirred at 0oC for about 2 minutes and add methyl ester hydrochloride - cyclohexyl-L-alanine (0.88 g). The solution is allowed to warm to room temperature and stirred over night. The solution is evaporated in vacuo and the residue distributed between ethyl acetate (200 ml) and 1 N. hydrochloric acid (HCl) (50 ml). The organic layer was washed with 1 N. HCl, saturated sodium bicarbonate solution, brine, dried over magnesium sulfate, filtered and evaporated in vacuum, obtaining the methyl ester of N-/BOC-L-aspartyl] (- benzyl ester)] -- cyclohexyl-L-alanine.

C. Methyl ester N-[BOC-L-aspartyl (- benzyl ester)]- - cyclohexylamine (2,01 g) dissolved in methylene chloride (15 ml). The solution is cooled to 0oC and add triperoxonane acid (5 ml) over a period of approximately 1 min This solution was stirred at 0oC for 2 hours, evaporated in vacuo and the residue absorbed in ethyl acetate, poslano alkaline. This organic solution is washed with saline, dried over magnesium sulfate, filtered and evaporated in vacuum, obtaining the methyl ester of L-aspartyl (- benzyl ester) - cyclohexyl-L-alanine.

D. Using the procedure of example 1B, described above, with the subsequent procedure of removal of the protective groups according to the example, receive the methyl ester of N-ethylglycol-L - aspartyl -(- benzyl ester) -L-cyclohexyl-L-alanine of the methyl ester of L - aspartyl- (- benzyl ester) - cyclohexyl-L-alanine and N-BOC-N - ethylglycine.

E. Mix 4-pyridinylamino acid (10 g) and platinum oxide (1.0 g) in acetic acid (100 ml) and the mixture is pumped under hydrogen at 50 psi (344734,85 PA) for approximately 18 hours. The mixture is filtered and the solution evaporated in vacuo and distilled in the form of an azeotrope with tutuola of balance, getting 2-(piperidine-4-yl) acetic acid.

F. 2-(piperidine-4-yl) acetic acid (11.6 g) was dissolved in 1 N aqueous sodium hydroxide solution (200 ml) and the solution cooled to 0oC. thereto are added dropwise a solution of di-tert - BUTYLCARBAMATE (18.0 g) in tetrahydrofuran (THF) (100 ml) and the mixture allowed to warm to room temperature and stirred for approximately 18 hours. Next, the mixture is evaporated in vacuoles acidified with 1 N HCl. The organic layer is separated and the aqueous layer was extracted with ethyl acetate. The combined organic portions are washed with water, brine, dried over magnesium sulfate, filtered and evaporated in vacuum, obtaining N-BOC-2-(piperidine-4-yl)acetic acid.

G. N-BOC-2-(piperidine-4-yl)acetic acid (15,8 g) dissolved in THF (150 ml) and add drops of 1 M borane/THF (70 ml). The solution was stirred at room temperature for about 20 hours and added dropwise 1 N sodium hydroxide solution (200 ml). THF is evaporated in vacuo and the aqueous residue extracted with ethyl acetate. The solution in ethyl acetate washed with water, dried over sodium sulfate, filtered, evaporated in vacuum, obtaining N-BOC-2-(piperidine-4-yl)ethanol.

N. The solution oxalicacid (11.8 g) in methylene chloride (180 ml) cooled to -70oC and added dropwise dimethyl sulfoxide (DMSO) in (8.9 ml). The solution was stirred at -78oC for about 3 minutes and add a solution of N-BOC-2-(piperidine-4-yl) ethanol (14.3 g) in methylene chloride (250 ml) over a period of approximately 10 minutes. The solution is stirred for approximately 1 hour and add N-methylmorpholine (21,6 g) for approximately 15 minutes. The solution is allowed to warm to room temperatur at room temperature for about 18 hours, is evaporated in vacuum and the residue is absorbed in ethyl acetate. The ethyl acetate solution is washed with water, 5% HCl, 5% sodium hypochlorite solution, water, brine, dried over sodium sulfate, filtered and evaporated in vacuum, obtaining methyl-4-(N-BOC-piperidine-4-yl)TRANS-crotonate.

I. Methyl-4-(N-BOC-piperidine-4-yl)TRANS-crotonate in (11.5 g) dissolved in methanol (200 ml) and add palladium/charcoal (3 g) and this mixture is pumped under hydrogen at 50 psi (344737,85 PA) for 18 hours. The mixture was filtered and added to a solution of fresh catalyst and the hydrogenation is repeated. The mixture is filtered and evaporated in vacuum, obtaining methyl-4-(N-BOC-piperidine-4-yl)butyrate.

J. To a mixture of 1 N aqueous sodium hydroxide (100 ml) and methanol (200 ml) is added methyl-4-(N-BOC-piperidine-4-yl)butyrate (10.1 g) and the mixture is stirred at room temperature for approximately 18 hours. The mixture is evaporated in vacuo, diluted with water and washed with ether. The aqueous portion is acidified with 5% HCl, extracted with ethyl acetate and the organic solution washed with water, brine, dried over sodium sulfate, filtered and evaporated in vacuum, obtaining 4-(N-BOC-piperidine-4-yl)butyric acid.

K. a Solution of 4-(N-BOC-piperidine-4-yl) butyric acid (0,91 g) in methylthio) (0,86 g) and triethylamine (0,47 ml). The solution was stirred at 0oC for about 10 minutes and add methyl ester N-ethylglycol-L-aspartyl (- benzyl ester) -L-cyclohexyl-L - alanine (1.52 g) in a minimum amount of methylene chloride, followed by adding dropwise triethylamine (of 0.47 ml) in methylene chloride for about 15 minutes. The mixture was stirred at 0oC for about 1 hour at room temperature for approximately 18 hours. The mixture is evaporated in vacuum and the residue is absorbed in the ethyl acetate. This organic solution was washed with 1 N HCl, saturated sodium bicarbonate solution, brine, dried over magnesium sulfate, filtered, evaporated in vacuo and the residue purified flash-chromatography with elution with 60% ethyl acetate in hexano, receiving methyl ester N-[N-[N-(4-(N-BOC - piperidine-4-yl)butanoyl)-N-ethylglycine]aspartyl (- benzyl ester)] -- cyclohexylamine.

L. Methyl ester N-[N-[N-(4-(N-BOC-piperidine-4-yl)butanoyl) -N-ethylglycine]aspartyl] (- benzyl ester)] - cyclohexylamine, (1,79 g) dissolved in methanol (40 ml) and add 10% palladium on coal (0.25 g). This mixture is pumped under hydrogen at 50 psi (344737, 85 PA) for approximately 18 hours. The mixture is filtered through zletovo pillow and the filtrate particularin. The ester is dissolved in methanol (20 ml) and add 1 N aqueous sodium hydroxide solution (10 ml). The mixture is stirred at room temperature for approximately 4 hours, diluted with water (25 ml) and acidified with 1 N HCl to pH 2. This mixture is extracted with ethyl acetate (CH ml) and the solution in ethyl acetate is dried over magnesium sulfate, filtered and evaporated in vacuum, obtaining N-[N-[N-(4-(N-BOC-piperidine-4-yl)butanoyl)- N-ethylglycine]aspartyl] -- cyclohexylamine.

M N-[N-[N-(4-(N-BOC-piperidine-4-yl)butanoyl)-N-ethylglycine] aspartyl] -- cyclohexylamine (1.39 g) was dissolved in methylene chloride (15 ml) and the solution cooled to 0oC. Triperoxonane acid (5 ml) is added and the solution stirred at 0oC for about 2.5 hours. The solution is evaporated in vacuum and the residue diluted with water, frozen and lyophilizers. The residue is purified HPLC (IHVR) with reversed phase elution gradient 40-80% methanol in water containing 1.0% of triperoxonane acid. The desired fractions are combined and lyophilizers, receiving N-[N-[N-(4-piperidine-4-yl)-butanoyl)-N-ethylglycine] aspartyl] -- cyclohexylamine in the form of a salt triperoxonane acid. M. S. calculated: 525, Found: 525; NMR, = 4,58-4,48 (m, 1H), 4,35-4,22 (m, 1H), 3,88 (s, 2H), 3,32 (K, 2H), 3,28-3,10 (m, 2H), 2,88-2,60 (m, 4H), of 2.33 (t, 2H), 1.85 to to 1.70 (m, 2H), 1,62-is inane obtained from the corresponding starting materials.

Example 2

N-[N-[N-(4-(piperidine-4-yl)butanoyl)-N - ethylglycine]aspartyl]valine

< / BR>
M. S. Calculated; 471, found: 471; NMR, = 4,15-of 4.05 (m, 2H), 3,90 (s, 2H), 3,30 (K, 2H), 3,30-3,15 (m, 2H), 2,90-2,60 (m, 4H), of 2.33 (t, 2H), 2.05 is (K, 1H), 1.85 to 1,72 (m, 2H), 1.55V is 1.35 (m, 3H), 1.30 and a 1.08 (m, 4H), of 1.02 (t, 3H), 0.70 and (d, 6H).

Example 3

N-[N-[N-(4-piperidine-4-yl)-N-ethylglycine]aspartyl]phenylalanine

< / BR>
M. S. calculated: 519, found: 519; NMR, = 7,20-to 6.95 (m, 5H), 4,55 is 4.35 (m, 2H), of 3.73 (s,2H), 3,30-to 2.40 (m, 10H), of 2.25 (t, 2H), 1,75-to 1.60 (m, 2H), 1,45-1,25 (m, 3H), 1,20 to 0.97 (m, 4H), to 0.92 (t, 3H).

Example 4

N-[N-[N-4-(piperidine-4-yl)butanoyl)-N-ethylglycine] aspartyl]-D-valine

< / BR>
M. S. Calculated: 471, found: 471; NMR, = 4,10-3,98 (m, 2H), 3,85 (s, 2H), 3,28 (K, 2H), 3,23-3,10 (m, 2H), 2,82-of 2.58 (m, 4H), 2,28 (t, 2H), 2,02 (K, 1H), 1,80-of 1.65 (m, 2H), 1.50 is of 1.28 (m, 3H), of 1.25 to 1.00 (m, 4H), of 0.95 (t, 3H), 0,78 is 0.65 (m, 6H).

Example 5

N-[N-[N-(4-(piperidine-4-yl)butanoyl)-N-(ethylglycol] aspartyl] - L - 2,2-dimethyl)prop-3-iglitzin

< / BR>
M. S. Calculated: 499, found: 499; NMR = 4,63-4,55 (m, 1H), 4,30-4,20 (m, 1H), 3,38 (s,2H), 3.33 and (K, 2H), 3,30-3,15 (m, 2H), 2,88-2,60 (m, 4H), to 2.35 (t, 2H), 1.85 to about 1.75 (m, 2H), 1,73-of 1.35 (m, 5H), 1.30 and a 1.08 (m, 4H), of 1.03 (t, 3H), 0,78 (s, 9H).

Example 6

N-[N-[N-(4-piperidine-4-yl)butanoyl)-N-ethylglycine]aspartyl]norleucine

< / BR>
M. S. Calculated: 485, found: 485; NMR, = 4,59-4,50 (m, 1H), 4,20-4,10 (m, 1H), 3,85 (s, 2H), 3,32 (K, 2H), 3.25 to 3,10 (m, 2H), 2,85 is 2.55 (m, 4H), 2,30 (t, 2H), 1,82 of 1.50 (m, 4H), 1,50-party] -L-naphthas-1-ylalanine

< / BR>
M. S. Calculated: 569, found: 569; NMR, = 8,00-to 7.15 (m, 7H), 4,60 is 4.45 (m, 2H), 3,71 (c, 2H), 3,65-to 3.50 (m, 2H), 3,40 are 2.98 (m, 4H), 2,70-to 2.42 (m, 4H), of 2.21 (t, 2H), 1.70 to a 1.45 (m, 2H), 1,40-to 0.96 (m, 7H), to 0.92 (t, 3H).

Example 8

N-[N-[N-(4-(piperidine-4-yl)butanoyl)-N - ethylglycine] aspartyl] -L- -- naphthas-2-ylalanine

< / BR>
M. S. Calculated: 569, found: 569; NMR, = the 7.65 7.03 is (m, 7H), 4,60 is 4.45 (m, 2H), 3,41 (s, 2H), 3,20-a 2.01 (m, 3H), 3.00 and-a 2.71 (m, 3H), 2,68-to 2.40 (m, 4H), to 1.98 (t, 2H), 1,68-of 1.42 (m, 3H), 1, 25-0,85 (m, 6H), of 0.71 (t, 3H).

Example 9

N-[N-[N-(3-(piperidine-4-yl)propanol)-N-ethylglycine]aspartyl]-valine

< / BR>
M. S. Calculated: 547, found: 457; NMR, = to 4.62 (m, 2H), 3,90 (s,2H), 3.33 and (m, 4H), to 2.66 (m, 4H), is 2.37 (t, 2H), 2,16 (m, 1H), 2,03 (m, 1H), 1,78 (m, 2H), 1,44 (m, 2H), 1,20 (m, 2H), and 1.00 (m, 3H), 0,78 (d, 6H).

Example 10

N-[N-[N-(5-(piperidine-4-yl)pentanoyl)-N-ethylglycine]aspartyl]-valine

< / BR>
M. S. Calculated: 485, found: 485; NMR, = 4,20-of 4.05 (m, 2H), 3,92 (s, 2H), 3.33 and (m, 2H), 3,28 is 3.15 (m, 2H), 2,90-2,61 (m, 4H), of 2.34 (t, 2H), 2.06 to (m, 1H), 1.85 to to 1.70 (m, 2H), 1,55-of 1.32 (m, 3H), 1.30 and of 1.12 (m, 6H), 1.06 a (t, 3H), 0,81 (d, 6H).

Example 11

Ethyl ester of N-[N-[N-(4-(piperidine-4-yl)butanoyl)-N - ethylglycine] aspartyl] -L-cyclohexylamine

< / BR>
A. - cyclohexylamine (1.5 g) is dissolved in absolute ethanol (75 ml) and the solution cooled to 0oC. thionyl chloride (1.1 ml) is added dropwise over 10-15 minutes, the solution is allowed to warm to comnat mixture is evaporated in vacuum, distilled in the form of an azeotrope with toluene 2 times and the residue absorbed in ethyl acetate. The solution in ethyl acetate washed with water, 1 N sodium hydroxide, water, brine, dried over sodium sulfate, filtered and evaporated in vacuum, obtaining the ethyl ester of cyclohexylamine.

C. Using the procedure of example 1B-1M (with the exception of the hydrolysis of aqueous sodium hydroxide phase 1L), get target product.

M. S. Calculated: 553, found: 553; NMR = 4,4 (1H, m), 4,1 (2H, d), a 3.2 to 3.5 (5H, m), of 2.7-3.0 (5H, m), 2,4 (2H, t), 1,9 (2H, d), 1,4-1,7 (7H, m) at 0.7-1.4 (18H, m).

Example 12

N-[N-[N-(4-(piperidine-4-yl)butanoyl)-N - ethylglycine] aspartyl] - cyclohexylamine

< / BR>
A. N-BOC-cyclohexylamine (2.0 g) and triethylamine (1,03 ml) are dissolved together in THF (100 ml) and the solution cooled to -20oC. Add isobutylparaben (1,06 ml) and the solution stirred at -20oC for about 30 minutes. Add a saturated solution of ammonia in methanol (20 ml) and the solution is allowed to warm to room temperature and stirred at room temperature for approximately 18 hours. The solution is evaporated in vacuum and the residue is dissolved in ethyl acetate. The solution in ethyl acetate washed with water, 5% HCl, saturated solution of bicarbonate logicielle.

C. N-BOC-cyclohexylaniline (2.0 g) is dissolved in ethyl acetate (100 ml) and gaseous hydrogen chloride HCl propulsive through the solution and stir the solution at room temperature for approximately 18 hours. The solution is evaporated in vacuo and distilled 2 times in the form of an azeotrope with toluene, getting cyclohexylamine as hydrochloride.

C. Using the procedure of example 1B-1M (with the exception of the hydrolysis of aqueous sodium hydroxide of example IL), get target product.

M. S. Calculated: 524 found: 524; NMR, = 8,4 (1H, d) and 8.1 (1H, d) and 4.2 (2H, K), 4,1 (1H, s), 3,9 (4H, K), 3,4 (2H, K), 3,3 (4H, d), of 2.8-3.0 (6H, m), 2,4 (2H, t), 2,2 (1H, m), 1,8 (4H, d), 1,4-1,7 (7H, m), of 0.7 to 1.3 (10H, m).

Example 13

N-[N-[N-(4-(piperidine-4-yl)butanoyl)-N - ethylglycine] aspartyl] -L - cyclohexylglycine

< / BR>
A. a Solution of methyl ester hydrochloride - phenylglycine (1.0 g) in THF (25 ml) cooled to 0oC and add triethylamine (1,38 ml). To this mixture add a solution of di-tert - BUTYLCARBAMATE (1.08 g) in THF (25 ml) and the mixture allowed to warm to room temperature and stirred at room temperature for approximately 18 hours. The solution is evaporated and the residue is dissolved in ethyl acetate (200 ml) and the organic solution washed with 1 N HCl, a saturated solution of methyl ester of N-BOC-phenylglycine.

Century Methyl ester of N-BOC-phenylglycine (1.2 g) dissolved in methanol (50 ml) containing acetic acid (1 ml). Add 5% rhodium on alumina powder (0,60 g) and the mixture is pumped under hydrogen at 50 psi for approximately 18 hours. The mixture is filtered, evaporated in vacuo and the residue is dissolved in ethyl acetate. This organic solution is washed with water, saturated sodium bicarbonate solution, water, brine, dried over magnesium sulfate, filtered, evaporated in vacuum, obtaining the methyl ester of N-BOC- -- -cyclohexylglycine.

C. Using the procedure of example 1B-1M, get the target product.

M. S. Calculated: 511, found: 511; NMR, = 4,62-4,55 (1H, m) 4,06 (2H, m), 3,85 (2H, s), 3,30 (2H, K), 3,23-3,10 (2H, m), 2,85 is 2.55 (4H, m), is 2.30 (2H, t), 1,83 is 1.60 (3H, m), 1,59-of 1.32 (8H, m), 1.30 and 0,75 (12H, m).

Example 14

N-[N-[N-(4-(piperidine-4-yl)butanoyl)-N - ethylglycine]aspartyl]-L -- decahedron-1-ylalanine

< / BR>
A. - (1-naphthyl)alanine (2.0 g) was stirred in a saturated solution of HCl/methanol for about 2 hours at room temperature. The mixture is evaporated in vacuum and double-distilled in the form of an azeotropic mixture with toluene from the rest. The residue is suspended in methylene chloride, add N-methylmorpholine (1,02 ml) and the mixture cooled to 0oC. DOB is mperature and stirred at room temperature for about 2 hours. The mixture was washed with 5% HCl, water, dried over sodium sulfate, filtered and evaporated in vacuum, obtaining the methyl ester of N-BOC -- (1-naphthyl)alanine.

Century Methyl ester of N-BOC -- (1-naphthyl)alanine (2.0 g) and 5% rhodium on alumina (1.0 g) are combined in methanol (50 ml) containing acetic acid (1.0 ml) and the mixture is pumped in the atmosphere of hydrogen at 50 psi for approximately 18 hours. The mixture is filtered, evaporated in vacuo and the residue is dissolved in ethyl acetate. This organic solution is washed with water, 5% sodium bicarbonate solution, water, brine, dried over sodium sulfate, filtered and evaporated in vacuum, obtaining the methyl ester of L-decahedron-1-ylalanine.

C. Using the procedure of example 1B-1M, get the target product.

M. S. Calculated: 579, found: 579; NMR, = 4,1-4,3 (m, 1H), of 3.8-4.1 (m, 2H), 2,6-2,9 (m, 4H), 2,3 (m, 1H), 2.0 (m, 1H), 1.8 m (d, 3H), 0.5 to 1.6 (m, 33H).

Example 15

2-cyclohexyl-N-[N-[N-(4-(piperidine-4-yl)butanoyl)-N - ethylglycine] aspartyl]-ethylamine

< / BR>
A. 2-Phenylethylamine (2.0 g) is dissolved in methylene chloride and the solution cooled to 0oC. Add di-tert-BUTYLCARBAMATE (4.0 g) and DMAP (0.4 g). The solution is allowed to warm to room temperature and stirred at room temperature for PR is in.

C. N-BOC-2-phenylethylamine (3.1 g) and 5% rhodium on aluminum oxide (1.1 g) are combined in methanol (40 ml) containing acetic acid (1.0 ml). The mixture is pumped under hydrogen at 50 psi for about 20 hours. The mixture is filtered, evaporated in vacuo and the residue is dissolved in ethyl acetate. This organic solution is washed with water, 5% sodium bicarbonate solution, water, brine, dried over sodium sulfate, filtered and evaporated in vacuum, obtaining N-BOC-2-cyclohexylethylamine.

C. Using the procedure of example 1B-1M (with the exception of the hydrolysis of aqueous sodium peroxide of example 1L), get target product.

M. S. Calculated: 481, found: 481; NMR, = 3,9 (s, 2H), 3,35 (d, 4H), 3,25 (d, 4H), 2,6-2,9 (m, 8H), to 2.35 (t, 2H), 2,15 (t, 1H), 1,8 (4H, d), 1,4-1,7 (m, 7H), 0,9-1,3 (m, 12H), 0,7 (t, 2H).

Example 16

N-[N-[N-(4-(piperidine-4-yl)butanoyl)-N - ethylglycine]aspartyl]-L - (2-cyclohexylethyl)glycine

< / BR>
A. Using the procedure of example 13A, methyl ester of N-BOC- - (2 - phenylethyl) glycine produced from L-homophenylalanine.

C. using mainly the procedure of example 14C (above) of N-BOC- -- (2-cyclohexylethyl)glycine (methyl ether) is obtained from the methyl ester of N-BOC -- (2-phenylethyl)glycine.

C. using the procedure of Example 1B-1M receive about the target, H) to 2.29 (t, 2H), 1,83-of 1.65 (m, 2H), 1,63-of 1.32 (m, 10H), 1,28-0,81 (m, 13H), 0,79-of 0.56 (m, 2H).

Using procedures presented above are examples of suitable starting materials have the following connections.

Example 17

N-[N-[N-(4-(piperidine-4-yl)butanoyl)-N - ethylglycine] aspartyl] -L- -- CIS-decahedron-2-ylalanine

< / BR>
M. S. Calculated: 579, found: 579; NMR, = 4,7(m, 1H), 4,3 (m, 1H), 4,1 (d, 2H), 3,3-3,7 (m, 5H), 2,6-2,8 (m, 5H), 2,5 (t, 2H), 2,3 (t, 1H), and 1.9 (d, 2H), 1,3-1,8 (m, 14H), 0,9-1,3 (m, 14H), of 0.7-0.8 (m, 3H).

Example 18

3-adamant-1-ylpropyl-N-[N-(4-(piperidine-4-yl)butanoyl)-N - ethylglycine] aspartate

< / BR>
M. S. Calculated: 548 found: 548; NMR (DMSO-d6), = 4,65 ñ 4.50 (m, 1H), 4,05-of 3.85 (m, 4H), 3,35 is 3.15 (m, 4H), 2,90-of 2.50 (m, 4H), 2,30 (t, 2H), 2,18 (t, 1H), 1,94 (d, 2H), 1.85 to about 1.35 (m, 20H), 1,32 by 1.12 (m, 4H), 1,10-of 0.90 (m, 5H).

Example 19

N-[N-[N-(4-(piperidine-4-yl)butanoyl)-N - ethylglycine] aspartyl] -- aminocyclohexanecarboxylic acid

< / BR>
M. S. Calculated: 497, found: 497; NMR, = 4,60-4,55 (m, 1H), 4,05 (s, 1H), 3,90 (s, 1H), 3,30 (K, 2H), 3.25 to of 3.12 (m, 2H), 2,85 is 2.55 (m, 4H), 2,35 (t, 1H), 2,11 (t, 1H), 1,90 is 1.70 (m, 4H), 1,53-of 1.32 (m, 6H), 1.30 and of 1.06 (m, 7H), of 1.05 to 1.85 (m, 3H).

Example 20

N-[N-[N-(4-piperidine-4-yl)butanoyl)- ethylhexyl] aspartyl] -- cyclohexyl-D-alanine

< / BR>
M. S. Calculated: 525, found: 525; NMR, = 4,60-4,55 (m, 1H), 4,32-4,20 (m, 1H), 4,05 (s, 1H), 3,85 (s, 1H), 3,32 (K, 2H), 2,25-of 3.12 (m, 24), 2,85-anol)-N-ethylglycine] aspartyl] -- decahedron-1-ylalanine

< / BR>
M. S. Calculated: 579, found: 579; NMR, = 4,1-4,3 (1H, m), of 3.8-4.1 (2H, m), 3.1 to 3.4 (4H, m), 2,6-2,9 (4H, m), 2,3 (1H, m), 2,0 (1H, m), 1.8 m (3H, d), 0.5 to 1.6 (33H, m).

Example 22

N-[N-[N-(4-(piperidine-4-yl)butanoyl)-N - ethylglycine] aspartyl] -- cyclohexylaniline

< / BR>
M. S. Calculated: 552, found: 552; NMR, = 4,55 is 4.45 (m, 1H), 4,20-4,06 (m, 1H), 4,05-of 3.85 (m, 2H), 3,40-of 3.25 (m, 2H), 3,28 is 3.15 (m, 2H), 3,10-2,90 (m, 2H), 2,88 is 2.55 (m, 4H), 2.40 a was 2.25 (m, 1H), 2,20-2,05 (m, 1H), 1,85 is 1.70 (m, 2H), 1.60-to of 1.32 (m, 9H), 1.30 and of 0.62 (m, 17H).

Example 23

N-[N-[N-(4-(piperidine-4-yl)butanoyl)-N-ethylglycine] aspartyl] -- cyclooctylamine

< / BR>
M. S. Calculated: 553, found: 553; NMR, = 4,1-4,3 (1H, m), of 3.8-4.1 (2H, m), 3.1 to 3.4 (4H, m), 2,6-2,9 (4H, m), 2,3 (1H, m), 2,0 (1H, m), 1,8 (2H, d), 0.5 to 1.6 (31H, m).

Example 24

N-[N-[N-(4-(piperidine-4-yl)butanoyl)-N - ethylglycine] aspartyl] -- cyclohexyldimethylamine

< / BR>
M. S. Calculated: 511, found: 511; NMR, = 4,60 is 4.45 (m, 1H), 4,10-of 3.75 (m, 3H), 3.45 points is 3.15 (m, 6H), 2,90-2,60 (m, 4H), 2,35 (t, 1H), 2.00 in of 2.08 (m, 1H), 1,88 is 1.75 (m, 2H), 1,62-of 1.35 (m, 8H), 1.30 and a 1.08 (m, 7H), 1,10-of 0.60 (m, 8H).

Example 25

N-[N-[N-(4-(piperidine-4-yl)butanoyl)-N - ethylglycine] aspartyl] -- cyclohexylethylamine

< / BR>
M. S. Calculated: 538, found: 538; NMR, = 4,60-4,50 (m, 1H), 4,15-4,00 (m, 1H), 4,00-of 3.80 (m, 2H), 3,35 (K, 2H), 3,30-3,15 (m, 2H), 2,90-2,62 (m, 4H), 2,35 (t, 1H), 2,15 (t, 1H), 1,88 is 1.75 (m, 2H), 1,65-of 1.40 (m, 9H), 1,30-0,88 (m, 14H), 0,85 is 0.65 (m, 2H).

Example 26

Example 27

N-[N-[N-(4-(piperidine-4-yl)butanoyl)-N - ethylglycine] aspartyl] -- (1,2,3,4)-tetrahedronal-5-ylalanine

< / BR>
M. S. Calculated: 573 found; 573; NMR, = 6,9 (d, 4H), 4,7 (m, 1H), 4,3 (m, 1H), 4,1 (d, 2H), 3,3-3,7 (m, 6H), 2,6-3,1 (m, 12H), 2,5 (t, 2H), 2,3 (t, 1H), and 1.9 (d, 2H), 1,2-1,8 (m, 16H), 1,1 (t, 2H), 1,0 (t, 2H).

Example 28

N-[N-[N-(4-(piperidine-4-yl)butanoyl)-N - ethylglycine] aspartyl] -- (4-cyclohexyl)cyclohexylamin

< / BR>
M. S. Calculated: 607, found: 607; NMR, = 4,2-4,3 (1H, m), 3,9-4,1 (2H, m), 3.1 to 3.4 (5H, m), 2,6-2,9 (5H, m), 2,3 (1H, m), 2,0 (1H, m), 1.8 m (3H, d), 0,9-1,6 (32H, m), 0,7-08 (3H, m).

Example 29

N-[N-[N-(4-(piperidine-4-yl)butanoyl)-N - ethylglycine] aspartyl] -- cycloheptylamine

< / BR>
M. S. Calculated: 539, found: 539; NMR, = 4,60-4,55 (m, 1H), 4,35-of 4.25 (m, 1H), 4,08 (s, 1H), 3,35 (K, 2H), 3.33 and-3,20 (m, 2H), 2,90-2,60 (m, 4H), 2,35 (t, 1H), 2,18 (t, 1H), 1,90 is 1.75 (m, 2H), 1.70 to 1,10 (m, 22H), 1,10-of 0.85 (m, 3H).

Example 30

N-[N-[N-(4-(piperidine-4-yl)butanoyl)-N - ethylglycine] aspartyl] -- cyclooctylamine

< / BR>
M. S. Calculated: 551, found: 551; NMR, = 4,46 (DD, 1H, H-12), 4,18 (m, 1H, H-14), the 3.89 (d, 1H, H-11), of 3.69 (d, 1H, H-11), and 3.31 (K, 2H, H-9), 3,18 (dt, 2H, H-1A), is 2.74 (dt, 2H, H-1E), to 2.65 (DD, 2H, H-13 in), 2.25 (t, 2H, H-8), 1,85-1,10 (m, 26H, H-3 - H-7 and H-15 - H-23), of 1.06 (t, 3H, H-10).

Example 31

Example 32

N-[N-[N-(4-(piperidine-4-yl)butanoyl)-N-ethylglycine] aspartyl] - -- cyclooctatetraene

< / BR>
M. S. Calculated: 567, found: 567, NMR, = 4,05-to 4.15 (m, 1H, 14 in), 3.75-4.00 points (m, 2H, 11 and 18), 3,10-3,30 (m, 4H, 19 and 26 EC), 2,50 is 2.80 (m, 4H, 15 and 26 ACU), 2,05 was 2.25 (m, 2H, 21) of 0.75 to 1.75 (m, 31H, 1-10, 20, 22-25).

Example 33

N-[N-[N-(4-(piperidine-4-yl)butanoyl)-N - ethylglycine] aspartyl] -- cyclopentylamine

< / BR>
M. S. Calculated; 511, found: 511, NMR, = 4,7 (m, 1H), 4,3 (m, 1H), 4,1 (d, 2H), 3,3-3,7 (m, 5H), and 2.8 (t, 2H), and 2.7 (m, 3H), 2,5 (t, 2H), 2,3 (t, 1H), and 1.9 (d, 2H), 1,0-1,8 (m, 16H).

Example 34

Ethyl ester of N-[N-[N-(4-(piperidine-4-yl)butanoyl)-N - ethylglycine] aspartyl] -- cyclohexylethylamine

< / BR>
M. S. Calculated: 567, found: 567; NMR, = 4,30-4,10 (m, 1H), 4,10-of 3.80 (m, 3H), 3,35 (K,2H), 3,30-3,15 (m, 2H), 2,90-2,60 (m, 4H), 2.40 a-2,10 (t, 2H), 1,90 is 1.70 (m, 2H), 1,65-of 1.40 (m, 10H), 1,35-of 0.85 (m, 18H), of 0.85 to 0.60 (m, 2H).

Connections in the scope of the present invention inhibit platelet aggregation by inhibiting the binding of fibrinogen to activated platelets and other adhesive glycoproteins involved in platelet aggregation and blood clotting, and applicable in procard, thrombotic stroke, peripheral artery disease and disseminated intravascular coagulation in humans and other mammals.

The compounds of this invention can generally be administered orally or parenterally in the treatment or prevention-related thrombosis pathological conditions.

The compounds of this invention can be prepared in a form for administration by any standard, and the invention includes within its scope pharmaceutical compositions containing at least one compound of the invention, adapted for use in medicine and veterinary medicine. Such compositions can be manufactured by conventional methods using one or more pharmaceutically acceptable carriers or excipients. Suitable carriers include diluents or fillers, sterile aqueous medium and a variety of non-toxic organic solvents. Compositions can be prepared in the form of tablets, capsules, pellets, lozenges, candies, powders, aqueous suspensions or solutions, injectable solutions, elixirs, syrups, etc., and may contain one or more agents selected from the group comprising sweetening agents who/P> Specific media in relation to inhibiting platelet aggregation and thrombus formation connection to the carrier is determined on the basis of solubility and chemical properties of these compounds, based on the specific route of administration and standard pharmaceutical practice. For example, in the manufacture of tablets can be used fillers, such as lactose, sodium citrate, calcium carbonate and acid phosphate of calcium (Ca2HPO4), and various disintegrators such as starch, alginic acid and certain complex silicates, together with wetting agents, such as magnesium stearate, sodium lauryl sulfate and talc. For the capsules are lactose and high molecular weight glycols are the preferred pharmaceutically acceptable carriers. In the manufacture of aqueous suspensions for oral administration, the carrier may be emulsifying or suspenders agent. Diluents such as ethanol, propylene glycol, glycerin and chloroform, and combinations thereof, can be used, and other materials.

For parenteral administration, you can use the solutions or suspensions of these compounds in sesame or peanut oil or aqueous solutions of polypropylenglycol, aola these compounds are particularly suitable for the purposes of intramuscular and subcutaneous injections. Aqueous solutions, including solutions of salts in pure distilled water, are also applicable for intravenous provided that their pH is properly informed, they contain a suitable buffer, made isotonic with the help of sufficient quantities of saline or glucose and sterilized by heating or by microfiltration.

Regimen when performing the method of this invention is that it provides the maximum therapeutic response until improvement will be obtained, and thereafter the minimum effective level which gives a calming effect. In General, the oral dose may be between about 0.1 mg/kg and about 100 mg/kg, preferably between 0.1 mg/kg and 20 mg/kg and most preferably between about 1 mg/kg and 20 mg/kg, and intravenous dose of approximately 0.1 mg/kg to 100 μg/kg, preferably between 0.1 mg/kg and 50 mg/kg, bearing in mind that in selecting the appropriate dosage in any specific case, you should consider the patient's weight, General health, age and other factors, which may influence response to the drug. The drug can be administered orally 1 to 4 times a day, the site is of these compounds of this invention against mediawindow fibrinogen platelet aggregation, binding of fibrinogen stimulated with thrombin in platelets and inhibition of ADP-induced platelet aggregation ex vivo. The results of these tests correlate with inhibitory properties in vivo of the compounds of this invention.

Test of platelet aggregation based on the test described in Blood 66(4), 946-952 (1985). Test binding of fibrinogen is essentially a test Ruggeri, Z. M., et al., Proc. Natl. Acad. Sci. USA 83, 5708-5712 (1986) and Plow, E. F. , et al., Proc. Natl. Acad. Sci. USA 82, 8057-8061 (1985). Test of inhibition of ADP - induced platelet aggregation ex vivo based on the test Zucker, "Platelet Aggregation Measured by the Photoelectric Method", Methods in Enzymology 169, 117-133 (1989).

Test platelet aggregation

Receive fixed-activated platelets

Platelets were isolated from human platelets concentrates using gel-filtration method described Marguerie, G. A., et al., J. Biol. Chem. 254, 5357-5363 (1979) M Ruggeri, Z. M., et al., J. Clin. Invest. 72, 1-12 (1983). Platelets are suspended at a concentration of 2 to 10-8cells/ml in a modified does not contain calcium Tyrode buffer containing 137 mm sodium chloride, 2 mm magnesium chloride, 0,42 mm N2HPO4, 11.9 mm NaHCO3, 2.9 mm KCl, 5.5 mm glucose, 10 mm HEPES, at pH of 7.35 and 0.35% human serum albumin (HSA). These washed trombi is of thrombin inhibitor I-2581 at a final concentration of 40 μm. To the activated platelets add paraformaldehyde to a final concentration of 0.50% and incubated them at room temperature for 30 minutes. Fixed activated platelets are then harvested by centrifugation at 650 xg for 15 minutes. Precipitation platelets washed 4 times above Tyrode buffer with 0,35% HSA and resuspended in the same buffer to a concentration of 2 to 10 cells per ml.

Analysis of platelet aggregation

Fixed activated platelets incubated with the selected dose of the test compounds tested for inhibition of platelet aggregation, 1 minute and aggregation initiated by the addition of fibrinogen person to a final concentration of 250 µg/ml For registration of platelet aggregation used the analyzer platelet aggregation Profiler, Model PAP-4. The degree of inhibition of aggregation was expressed as the percentage of the speed of aggregation observed in the absence of inhibitor. IC50, i.e., the amount of inhibitor required to reduce the rate of aggregation by 50%, was then calculated for each compound (see , for example. Plow, E. F., et al., Proc. Natl. Acad. Sci. USA 82, 8057-8061 (1985).

Analysis of the binding of fibrinogen

The washed platelets to release the component from the al., J. Clin. Invest. 76, 1950-1958 (1985). In each experimental mixture of platelets in a modified Tyrode buffer (Ruggeri,Z. M.,et al.,J. Clin.lnvest,72, 1-12 (1983) stimulate human - thrombin at 22-25oC for 20 minutes (3,125 1011platelets per liter and thrombin at 0.1 NIH units/ml (NIH - national Institute of health, USA). Then add hirudin at 25-fold excess (unit/unit) for 5 minutes before adding the125I-labeled fibrinogen and test connection. After a finite number of platelets in the mixture is 1 to 1011platelets per liter. After incubation for an additional 30 minutes at 22-25oC bound and free ligand is separated by centrifugation, 50 μl of the mixture through 300 μl of 20% sucrose at 12000 xg for 4 minutes. The precipitate platelets are separated from the rest of the mix to determine associated with platelet radioactivity. Nonspecific binding was measured in mixtures containing its ligand. In the analysis of binding curves using the analysis of Scatchard nonspecific binding obtained as fit parameter of the binding isotherms using a computerized program (Munson, P. J., Methods Enzymology, 92, 542-576 (1983)). To determine the concentration of each inhibitor compounds, neo is B>each compound was tested at 6 or more concentrations125I-labeled fibrinogen at a concentration of 0,176 µmol/l (60 ág/ml). IC50obtained by curve remaining binding of fibrinogen depending on the logarithm of the concentration of the compound in the sample.

Inhibition of ADP-induced platelet aggregation ex vivo

Experimental Protocol

Control blood samples get for 5-10 minutes before administration of the test compound half-dogs weighing 10 to 20 kg of the Compound administered intragastrically through a stomach tube or orally, in the form of gelatin capsules. Then get blood samples (5 ml) every 30 minutes for 3 hours and at 6, 12 and 24 hours after dosing. Each sample of blood is obtained by venipuncture head vein and collected directly into a plastic syringe containing one part of 3.8% sodium citrate to nine parts blood.

Platelet aggregation dogs ex vivo

Blood samples are centrifuged at 1000 rpm for 10 minutes to obtain platelet-rich plasma (PRP). After removal of the PRP sample is centrifuged for 10 minutes at 2000 rpm, receiving platelet-poor plasma (PPP). The number of platelets in PRP determined using counters is t PPP to bring the number of platelets up to 300,000 platelets per μl. Then aliquots of PRP (250 μl) is placed in a siliconized glass cuvette (7,h mm, Bio/Data Corp. Horsham, PA). Then add to the PRP epinephrine (final concentration 1 μm) and spend incubation for 1 minute at 37oC. Then add to the PRP stimulator of platelet aggregation ADP at a final concentration of 10 μm. Platelet aggregation observed spectrophotometrically with the use of transmissive light aggregometer (Bio/Data Platelet Aggregation Profiler, Model PAP-4, Bio/Data Corp., Horsham, PA). To test connection speed changes (falls) light transmittance and maximum light transmission (maximum aggregation) are recorded in two replications. Data aggregation of platelets are given as percentage (mean SEM) in the fall or the maximum aggregation compared with the data obtained in the case of control PRP prepared from blood samples taken before administration of the test compounds.

The compounds of this invention find significant activity in the above tests and are considered applicable in the prevention and treatment of thrombosis associated with some pathological conditions. Antithrombotic activity in the test of platelet aggregation dogs ex vivo predicts similar activity Tiravanija compounds of this invention above described methods are presented in the table below. Also shown in the table the results of a comparative test for 4-4(piperidyl)butanilicaine, i.e., compounds described in European Patent Application N 0479481.

The specialist in this area it will be understood that this invention is well adapted to carry out the objectives and obtain the results and advantages mentioned herein as well as other inherent advantages. These compounds, compositions and methods are presented as typical preferred options are or are intended to serve as examples, but not limitations of the scope of this invention. Changes therein and other applications can meet the experts in this field, and these changes can be made without departing from the essence of the invention or defined by the scope of the attached claims.

1. The connection formulas

< / BR>
in which A represents - H;

B denotes alkyl;

Z denotes

< / BR>
where E denotes - H;

F denotes - H, alkyl, hydroxyalkyl, cycloalkyl, cycloalkenyl, aralkyl or substituted aralkyl;

G denotes cycloalkyl, OR1or NR1R2where R1and R2independently denote - H, alkyl, and r represents 0 or 1,

R oboznachenie by p. 1, wherein F represents - H, alkyl, hydroxymethyl, cycloalkyl, cycloalkenyl, aralkyl, or substituted aralkyl.

3. Connection on p. 2, wherein F represents - H, alkyl, hydroxymethyl, cycloalkyl, cycloalkenyl.

4. Connection on p. 1 formula

< / BR>
in which A represents - H;

B denotes alkyl;

J represents - H, alkyl, cycloalkyl, cycloalkenyl, aralkyl, substituted aralkyl;

L denotes OR1or NR1R2where R1and R2independently denote - H, alkyl,

m = 1 to 5;

n = 2 - 6;

p = 1 or 2

or its pharmaceutically acceptable salt.

5. Connection on p. 4, characterized in that A represents - H; represents alkyl, J represents - H, alkyl, cycloalkyl, cycloalkenyl, m = 3 and n = 3 or 4.

6. Connection on p. 5, wherein A denotes-H, B - alkyl, J - alkyl, cycloalkyl or cycloalkenyl, R1and R2independently - H, alkyl, m = 3, n = 3 or 4 and p = 1.

7. The compound, which is N-[N-[N-(4-piperidine-4-yl)butanoyl)-N-ethylglycine]aspartyl]valine,

N-[N-[N-(4-piperidine-4-yl)butanoyl)-N-ethylglycine]aspartyl]-D-valine,

N-[N-[N-(3-(piperidine-4-yl)propanol)-N-ethylglycine]aspartyl]valine,

N-[party] -L--cyclohexylglycine,

N-[N-[N-(4-(piperidine-4-yl)butanoyl)-N-ethylglycine]aspartyl] -L--cyclohexylamine,

N-[N-[N-(piperidine-4-yl)butanoyl)-N-ethylglycine]aspartyl]norleucine,

N-[N-[N-(4-(piperidine-4-yl)butanoyl)-N-ethylglycine]aspartyl]-L-Cys-decahedron-2-ylalanine,

N-[N-[N-(4-(piperidine-4-yl)butanoyl)-N-ethylglycine]aspartyl] --aminocyclohexanecarboxylic acid,

N-[N-[N-(4-(piperidine-4-yl)butanoyl)-N-ethylglycine]aspartyl] --cyclohexyl-D-alanine,

N-[N-[N-(4-(piperidine-4-yl)butanoyl)-N-ethylglycine]aspartyl] --decahedron-1-ylalanine,

N-[N-[N-(4-(piperidine-4-yl)butanoyl)-N-ethylglycine]aspartyl] --cyclooctylamine,

N-[N-[N-(4-(piperidine-4-yl)butanoyl)-N-ethylglycine] aspartyl] --adamant-1-ylalanine,

N-[N-[N-(4-(piperidine-4-yl)butanoyl)-N-ethylglycine] aspartyl]--(4-cyclohexyl)cyclohexylamine,

N-[N-[N-(4-(piperidine-4-yl)butanoyl)-N-ethylglycine]aspartyl] --cycloheptylamine,

N-[N-[N-(4-(piperidine-4-yl)butanoyl)-N-ethylglycine]aspartyl] --cyclohexylpropionic,

N-[N-[N-(4-(piperidine-4-yl)butanoyl)-N-ethylglycine]aspartyl] --cyclooctatetraene,

N-[N-[N-(4-(piperidine-4-yl)butanoyl)-N-ethylglycine]aspartyl] --cyclopentylamine,

N-[N-[N-(4-(piperidine-4-yl)butanoyl)-N-ethylglycine]aspartyl] -L--decahedron-1-ylalanine or

N-[N-[N-(4-(piperidine-4-yl)b is Spartel]-phenylalanine,

N-[N-[N-(4-(piperidine-4-yl)butanoyl)-N-ethylglycine]aspartyl]--cyclohexylamine,

N-[N-[N-(4-(piperidine-4-yl)butanoyl)-N-ethylglycine]aspartyl] --cyclooctylamine,

N-[N-[N-(4-(piperidine-4-yl)butanoyl)-N-ethylglycine]aspartyl] --cyclohexylethylamine, or

N-[N-[N-(4-(piperidine-4-yl)butanoyl)-N-ethylglycine]aspartyl] --cyclohexylaniline,

ethyl ester of N-[N-[N-(4-(piperidine-4-yl)butanoyl)-N-acylglycerol-L--cyclohexyldimethylamine,

or their pharmaceutically acceptable salts.

8. Pharmaceutical composition comprising an antithrombotic effective amount of the compounds on p. 1 and a pharmaceutically acceptable carrier.

9. The composition according to p. 8, containing antithrombotic effective amount of a compound p. 4 and a pharmaceutically acceptable carrier.

10. A method of preventing or treating thrombosis in a mammal in need of such therapy, wherein introducing a therapeutically effective amount of compound p. 1.

11. A method of preventing or treating thrombosis in a mammal in need of such treatment, under item 10, wherein introducing a therapeutically effective amount of the compounds of p. 4.

12. How preventive care is automatic effective amount of the composition p. 8.

13. A method of preventing or treating thrombosis in a mammal in need of such treatment, under item 12, wherein introducing a therapeutically effective amount of the composition p. 9.

 

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