MXPA00004201A - Orally-active nipecotamide glycolamide esters for the treatment of thrombosis disorders - Google Patents

Abstract

Orally-active nipecotamide glycolamide ester derivatives of formula (I) are disclosed as useful in treating platelet-mediated thrombotic disorders.

Description

ORIGINALLY ACTIVE NIPECOTAMIDOGLYCOLOLIDE ESTERS FOR THE TREATMENT OF TROMBOSIS TRANSTORNES CROSS REFERENCE WITH RELATED APPLICATION This application claims priority of the document with serial number of E.U.A. 60/063366, filed October 29, 1997, the content of which is incorporated herein by reference.

BACKGROUND OF THE INVENTION Platelet aggregation constitutes an initial haemostatic response to suppress hemorrhage induced by vascular injury. However, the pathological extension of this normal hemostatic procedure can lead to the formation of thrombi. The final path, common in platelet aggregation, is the binding of fibrinogen to activated platelet glycoprotein IIb / Illa (GPIIb / Illa). Therefore, agents that interrupt the binding of the fibrinogen to GPIIb / Illa inhibit platelet aggregation. Thus, these agents are useful in the treatment of platelet-mediated thrombotic disorders, such as arterial and venous thrombosis, acute myocardial infarction, unstable angina, reocclusion after thrombolytic therapy and angioplasty, inflammation and a variety of vascular disorders. occlusive The fibrinogen receptor (GPIIb / Illa) is activated by stimuli such as ADP, collagen and thrombin, exposing binding domains to two different regions of fibrinogen peptides: Arg-Gly-Asp (RGD) alpha chain and His-His-Leu Gly-Gly-Ala-Lys-Gln-Ala-Gly-Asp-Val (HHLGGAKQAGDV,? 400-411) gamma chain. Since these peptide fragments themselves have been shown to inhibit the binding of fibrinogen to GPIIb / Illa, a mimetic of these fragments will also serve as an antagonist. In fact, prior to this invention, potent RGD-based antagonists had revealed that they inhibited both fibrinogen binding to GPIIb / Illa and platelet aggregation, for example Ro-438857 (L. Alig, J. Med. Chem. 1992, 35, 4393) has an IC 50 of 0.094 μM compared to platelet aggregation induced by thrombin in vitro. Some of these agents have also demonstrated efficacy in vivo as antithrombotic agents and, in some cases, have been used in conjunction with fibrinolytic therapy, for example, t-PA or streptokinase (JA Zablocki, Current Pharmaceutical Design 1995, 1, 533) . The glycolamide ester compounds of the present invention are orally active GPIIb / Illa antagonists that exhibit improved oral absorption and in vivo activity, as compared to their carboxylic acid congeners. As demonstrated by the results of the pharmacological studies described hereinafter, the compounds demonstrate the ability to block the binding of isolated GPIIb / llla to fibrinogen (IC50 of about 0.0005-0.01 μM), inhibit platelet aggregation in vitro in the presence of a variety of platelet stimuli (IC50 of approximately 0.1-1.0 μM compared to thrombin), and in addition, they exhibit an ex vivo platelet aggregation in animal models. Additionally, these agents exhibit efficacy in animal models of thrombosis as demonstrated by their progenitors ("Nipecotic Acid Derivatives As Antithrombotic Compounds", application serial number 08-213772, filed on March 16, 1994 and "Carboxamide Derivatives of Pyrrolidine, Piperidine, and Hexahydroazepine for the Treatment of Thrombosis Disorders ", application serial number 60-016675, filed May 1, 19996). The compounds of the present invention are esters of carboxylic acid glycolamide which show efficacy as antithrombotic agents by virtue of their ability to prevent platelet aggregation. Additionally, because the compounds of the present invention inhibit adhesion from cell to cell or cell to integrin mediated matrix, they can be useful for inflammation, bone resorption, tumor cell metastasis, etc. (D. Cox, Drug News &Perspectives 1995, 8, 197).

BRIEF DESCRIPTION OF THE INVENTION The present invention is directed to compounds represented by the following general formula (I): where A, X, M, R5, R-io, and n are as defined below. The glycolamide ester compounds of the present invention are orally active GPIIb / Illa antagonists which exhibit improved oral absorption and in vivo activity as compared to other carboxylic acid congeners. These platelet aggregation inhibitors are useful for the treatment of platelet-mediated thrombotic disorders, such as arterial and venous thrombosis, acute myocardial infarction, reocclusion after thrombolytic therapy and angioplasty, inflammation, unstable angina, and a variety of vascular disorders. occlusive These compounds are also useful as antithrombotics used in conjunction with fibrinolytic therapy (for example t-PA or streptokinase). Pharmaceutical compositions containing such compounds are also part of the present invention.

DETAILED DESCRIPTION OF THE INVENTION In particular, the present invention is directed to compounds having the following formula (I): (where M is (CH2) m, CH = CH or C = C; A is chosen from either piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, NHR2 or where R9 is chosen from any of H, alkyl, CH (NH), CMe (NH) or acyl, preferably Rg is hydrogen; R10 is H or C (O) N (R1) YZ, where R1 is chosen from H or cycloalkyl; R2 is chosen from any of H, alkyl or acyl, preferably R2 is hydrogen; R5 is H or C (0) NHQ (CHW) rC02R8; where Q is chosen from CH2, CH-aryl, CH-heteroaryl, heteroaryl substituted with CH or CH-alkyl; preferably Q is CH2, heteroaryl substituted with CH or CH-heteroaryl, W is chosen from H or N (R6) T-R7, preferably W is H when Q is CH, and N (R6) -T-R7 when Q is CH2; where Rβ is selected from any of H, alkyl or acyl, preferably Rβ is hydrogen, T is chosen from C (O), C (N-CN) or SO2, preferably T is C (O); R7 is selected from any of alkyl, aryl, aralkyl, alkoxy or aminoalkyl; and Rs is H or CH2C (0) NRnRi2, preferably R8 is CH2C (0) NRnRi2, most preferably R8 is CH2C (0) NEt2; Rn and R12 are chosen from H, alkyl or cycloalkyl, preferably R-n and R12 are alkyl; m is the integer 1, 2 or 3, preferably m is 1 or 2, X is chosen from any of C (O), C (0) 0, C (0) NH, CH2 > or S02; n is the integer 1, 2 or 3; r is 0 or 1; And it is chosen from any of (CH2) P, CH (R3) (CH2) q, (CH2) qCH (R3), (CH (C02R4) CH2) q, (CH2) qCHOH or piperidin-3-carboxylic acid; with the proviso that when Y is (CH2 and p is 2, X is different from C (O), or when X is C (O), then R1 is different from H or R2 is different from H, and with the proviso that when Y is (CH (C? 2R4) CH2) q X is different from C (O) or CH2; p is 2 or 3, q is 1, 2 or 3, preferably q is 1; R3 is alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, aralkyl or heteroaryl; R is H or alkyl or cycloalkyl, preferably R is hydrogen; Z is C02CH2C (0) NR? 1R 2; provided that at least one of R5 and R-io is hydrogen and R5 and R-io are not hydrogen at the same time; provided that R5 is C (0) NHQ (CHW) rC02 R8, and Q is CH-heteroaryl or heteroaryl substituted with CH, and R8 is H, then M is CH = CH; or the enantiomer or pharmaceutically acceptable salt thereof. Preferably, the group C (0) N (R1) YZ is attached to the carbon of the ring of the central azaciclo in the 3 or 4 position (position 4 when the ring has more than 5 elements), and most preferably in the 3 position.

As used herein, unless otherwise indicated, alkyl and alkoxy, whether used alone or as part of a substituent group, include straight and branched chains having from 1 to 8 carbon atoms. For example, alkyl radicals include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, isobutyl, n-pentyl, 3- (2-methyl) butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl and 2-methylpentyl. Alkoxy radicals are ethers of oxygens from the straight or branched chain alkyl groups described above. The cycloalkyl groups contain from 5 to 8 carbon atoms per ring and preferably from 6 to 7. The term "aryl", "heteroaryl" or "substituted heteroaryl" as used herein, alone or in combination with other terms, denotes aromatic or heteroaromatic groups, such as phenyl, naphthyl, pyridyl, thienyl, furanyl or quinolinyl, where the substituent is an alkyl group . The term "aralkyl" means an alkyl group substituted with an aryl group. The term "acyl" as used herein means an organic radical having from 2 to 6 carbon atoms derived from an organic acid by removal of the hydroxyl group. The compounds of the present invention may also be present in the form of a pharmaceutically acceptable salt. The pharmaceutically acceptable salt generally has a form in which the nitrogen in the substituent 1 -piperidine (pyrrolidine, piperazine) is protonated with inorganic or organic acid. Representative organic or inorganic acids include hydrochloric, hydrobromic, hydroiodic, perchloric, sulfuric, nitric, phosphonic, acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, hydroxyethane sulfonic acid , benzensulfonic, oxalic, pamico, 2-naphthalenesulfonic, p-toluenesulfonic, cyclohexansulfamic, salicylic, saccharinic or trifluoroacetic. The compounds that are particularly preferred in the present invention include those compounds shown in Table I. Where indicated, the letter "R" indicates the absolute configuration (Cahn-Ingold-Prelod rules).

TABLE I 3 5-bromo-3-pyridyl Et H 4 H Et NHC02CH2Ph 5 * H Et NHC02CH2Ph 6 * H (CH2) 5 NHC02CH2Ph * The compound contains 4-piperidin-3-propenoyl N-terminus (compounds # 1 to 4 contain 4) -piperidine-3-propanoyl N-terminus). The compounds of the invention where R-io is H, R5 is C (0) NHQ (CHW) rC02R8, and A is piperidin-4-yl, can be prepared as shown in the AA and AB schemes. The ethyl ester of enantiomerically enriched R - (-) - nipecotic acid was isolated by chiral resolution of racemic material as its corresponding D-tartaric acid salt (AM Akkerman, Rec. Trav. Chim. Pays-Bas 1951, 70, 899) , and subsequently it is converted into Boc-R-nipecotic acid using standard conditions (aqueous sodium hydroxide, di-t-butyldicarbonate). In intermediary AA1 was prepared as detailed in the provisional patent application E.U.A. 60-016675 (May 1, 1996) and as published (J. Rico, J. Org. Chem. 1993, 58, 7948). Under conditions of standard amide bond coupling using AA1, HBTU, HOBT, and Boc-R-nipecotic acid, followed by removal of Boc with HCl gave AA2. Compound AA2 was subsequently acylated with activated Boc-4-piperidinpropanoic acid with HBTU and the resulting methyl ester was saponified with lithium hydroxide to give the acid AA3. The AA3 carboxylate was subsequently alkylated with 2-chloro- / V, N-diethylacetamide / triethylamine in EtOAc, and the Boc group was removed with HCl to give the final product # 1 as its dichlorhydric salt. Compounds # 2 and # 3 were prepared as shown for # 1; the starting materials of ß-amino ester in solution (see experiment AA1) were prepared as shown for AA1.

SCHEME AA Compound # 4 was prepared in a similar manner. Boc-R-nipecotic acid was coupled with methyl Na-CBZ-L-diaminopropionate (prepared by Fischer esterification of MeOH / HCI of the commercially available Na-CBZ-L-diaminopropionic acid) and subsequently the Boc group was removed HCl to give AB2. In this synthetic sequence, the AB3 acid was alkylated using 2-chloro-α /, A / -diethylacetamide / cesium carbonate in DMF, and subsequently converted to # 4 with HCl.

AB SCHEME 2-chloro -? /, A -diethylacetamide was purchased from Aldrich Chemical Company The chloroacetamides can be prepared in a step of 2-chloroacetyl chloride and the appropriate amine (Scheme AC, K. Krakowiak, J. Heterocyclic Chem. 1989, 26, 661). In this procedure, 2-chloroacetyl chloride and aqueous sodium hydroxide were added dropwise to a solution of amine / DCM at room temperature and allowed to react for a period of 1-2 hours.

AC SCHEMA AD SCHEME AD1 AD2 AD3 The intermediate acid? / - Boc-4-piperidinepropenoic acid AD3 can be prepared as shown in the AD scheme. Alcohol AD1 was oxidized to the corresponding aldehyde AD2 using standard Swem conditions (oxalyl chloride / DMSO). AD2 was converted to the olefinic ester using the Witting reagent in dichloromethane. Subsequently this ester was saponified to the acid in sodium hydroxide to give AD3. To prepare compound # 5, AD3 was coupled with AB2 as described for compound # 4 (HBTU / HOBT) and designed to give a final product as shown in scheme AB. To prepare the compounds wherein A is pyrrolidin-2-yl or pyrrolidin-3-yl, the intermediate AA2 was acylated with 3- (N-Boc-pyrrolidinyl) propionic acid to produce the asylated derivative using the HBTU acylation process. 3- (N-Boc-pyrrolidinyl) propionic acid was synthesized using the methods described in US Patent 4,002,643. Using these procedures, 3- (N-Boc-pyrrolcarboxaldehyde (substitution in two or three) was treated with sodium hydride / diethylcyanomethyl-phosphonate in DME to give, 3- (N-Boc-pyrrole) acrylonitrile), which was reduced using standard hydrogenolysis conditions (H2, platinum oxide) to give 3- (N-Boc-pyrrolidinyl) propionitrile. Subsequently, the nitrile was hydrolyzed with aqueous sodium hydroxide to give the 3- (N-Boc-pyrrolidinyl) propionic acid (substitution in two or three). To prepare the compounds wherein A is piperazin-1-yl, the intermediate AA2 was acylated with acryloyl chloride / NMM as published (S.G. Gilbreath, J. Am. Chem. Soc. 1988, 110, 6172), and the corresponding acrylamide was treated with the appropriate piperazine (e.g., N-methylpiperazine) in refluxing ethanol to give the piperazine product. To prepare the compounds wherein A is N-alkyl-piperidine (Rg = alkyl), for example, compound # 1 was treated with sodium aldehyde / cyanoborohydride in ethanol to give N-alkylpiperidine. Formamidinopiperidines were prepared by treatment of compound # 1, for example, with ethyl formimidiate * HCl in ethanol; The corresponding acetamidinopiperidines were prepared using S-2-naphthylmethylthioacetimidate »HCl in ethanol (B. Shearer, Tetrahedron Lett, 1997, 38, 179). To prepare the compounds wherein A is NHR2, the intermediate AA2 was acylated with N-Boc-R2-aminohexanoic acid, for example, using standard HBTU coupling conditions cited for example 1. The compounds wherein M is ethynyl were prepared by displacement of N-Boc-4-methanesulfonyloxypiperidine with potassium ethyl propionate (potassium carbonate / ethylpropionate) to give methyl N-Boc-4-picperidinprop-3-ioneate (T.Jeffery, Tetrahedron Lett 1989, 30, 2225) ). This ester was subsequently saponified to the corresponding carboxylic acid and coupled with the intermediate AA2 using HBTU. The compounds where Rio is C (0) NR (1) YZ and R5 is H were prepared according to the method described in scheme AA using a boc-R-nipecotic acid suitably substituted as starting material. To prepare the pharmaceutical compositions of the present invention, one or more compounds of the formula (I) or salt thereof of the present invention as an active ingredient, are intimately mixed with a pharmaceutical carrier in accordance with conventional pharmaceutical compounding techniques, said vehicle can have a wide variety of forms depending on the form of preparation desired for administration, for example, oral or parenteral such as intramuscular. In the preparation of the compositions of the oral dosage form, any of the usual pharmaceutical media can be employed. Thus for liquid oral preparations, such as, for example, suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, sweetening agents, preservatives, coloring agents and the like; for solid oral preparations such as, for example, powders, capsules, tablets, gel capsules and caplets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of ease of administration, tablets and capsules represent the most useful oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, the tablets may be coated with sugar or an enteric layer by standard techniques. For parenteral administration, the vehicle will usually comprise sterile water, among other ingredients, for example, for purposes of assisting in solubility or for preservation, may be included. Injectable suspensions may also be prepared, in which case suitable liquid carriers, suspending agents and the like may be employed. The pharmaceutical compositions herein will contain per unit dosage, e.g., tablet, capsule, powder, injection, teaspoonful and the like, an amount of the active ingredient necessary to provide an effective dose as described above. The pharmaceutical compositions herein will contain per dosage unit, e.g., tablet, capsule, powder, injection, suppository, teaspoonful and the like, from about 0.03 mg to 100 mg / kg (0.1-30 mg / kg is preferred) and they can be administered in a dosage of about 0.1-300mg / kg / day (1-50 mg / kg / day is preferred). However, dosages may vary depending on the requirement of the patients, the severity of the condition to be treated and the compound used. The use of any daily administration or post-periodic dosing can be used.

Biology The glycolamide ester compounds of the present invention are orally active GPIIb / ILA antagonists which show improved oral absorption and in vivo activity on their carboxylic acid congeners.

For example, compound # 4 exhibited a duration > 240 in vivo (see Table III) while its carboxylic acid congener exhibited a duration of 180 minutes in the same oral dosage. The compounds interrupt the binding of fibrinogen to platelet glycoprotein llb / llla (GPIIb / Illa) and thus inhibit platelet aggregation. Therefore, such compounds are useful in the treatment of platelet-mediated thrombotic disorders such as arterial and venous thrombosis, acute myocardial infarction, reocclusion after thrombolytic therapy and angioplasty, and a variety of vaso-occlusive disorders. Because the common final pathway in platelet aggregation is the binding of fibrinogen to GPIIb / Illa, activated exposed, the inhibition of this binding represents a plausible antithrombotic reach. The receptor is activated by stimuli such as ADP, collagen and thrombin, exposing the domains of the binding to two different regions of fibrinogen peptides: Arg-Gly-Asp (RGD) chain a and chain 400-411 ?. As demonstrated by the results of the pharmacological studies described hereinafter, the compounds of the present invention show the ability to block the binding of fibrinogen to isolated GPIIb / llla (IC50 0.0006-0.005 μM), inhibits platelet aggregation in vitro in the presence of various platelet stimuli (IC5o 0.14-1.1 μM compared to thrombin), and also inhibit ex vivo platelet aggregation in animal models.

In vitro binding assay of purified glycoprotein IIB / IIIA in solid phase A 96-well microtiter-lmmulon-2 plate (Dynatech-Immulon) is coated with 50μl / well with GPIIb / llla purified by affinity with RGD (effective scale 0.5- 1 Oμg / ml) in 10 mM HEPES, 150 mM NaCl, 1 mM with pH 7.4. The plate is covered and incubated overnight at 4 ° C. The GPIIb / lla solution is discarded and 150μl of 5% BSA is added and incubated at room temperature for 1 to 3 hours. The plate is washed well with a modified Tyrodes pH regulator. Biotinylated fibrinogen (25 μl / well) is added at a final concentration of 2x to the wells containing the test compounds (25 μl / well). The plate is covered and incubated at room temperature for 2 to 4 hours. Twenty minutes before finishing the incubation, one drop of reagent A (ABC Vecta Stain peroxidase equipment, Vector Laboratories, Inc.) and one drop of reagent B are added by mixing to 5 ml of a pH regulator mixture of Modified Tyrodes and let it rest. The ligand solution is discarded and the plate washed (5x200 μl / well) with modified Tyrodes pH regulator. The Vecta Stain HRP-Biotin-Avidin reagent (50 μl / well, as prepared above) is added and incubated at room temperature for 15 minutes. The Vecta Stain solution is discarded and the wells are washed (5x200 μl / well) with modified Tyrodes pH regulator. The pH regulator of development (10 ml of 50 mM pH regulator citrate / phosphate @ pH 5.3, 6 mg or phenylalanadiamine, 6 μl 30% H202, 50 μl / well) is added and incubated at room temperature for 3 a 5 minutes, and then 2 / V H2SO4 (50 μl / well) is added. Absorbance is read at 490 nM. The results are shown in tables II.

In vitro analysis of inhibition of thrombin-induced gel-filtered plague aggregation The percentage of platelet aggregation is calculated as an increase in light transmission of a compound-treated platelet concentrate compared to a control-treated platelet concentrate. Human blood is obtained from normal donors who are not taking drugs in test tubes containing 0.13 M sodium citrate. Platelet rich plasma (PRP) is collected by centrifugation of whole blood at 200 xg for 10 minutes at 25 ° C. The PRP (5 ml) is gel filtered through sepharose 2B (bed volume 50 ml), and the platelet count is adjusted to 2x107 platelets per sample. The following constituents were added to a siliconized tube: the concentrated platelet filtrate and the Tyrodes pH regulator (0.14 M NaCl, 0.0027 M KCl, 0.012 M NaHCO3, 0.76 mM Na2HP04, 0.0055 M glucose, 2 mg / ml BSA and 5.0 mM HEPES @ pH 7.4) in an amount equal to 350μl, 50μl of 20mM calcium and 50μl of test compound. The aggregation is monitored in a BIODATA aggregometer for 3 minutes after the addition of the agonist (50 μl of 1 unit / ml thrombin). The results are as shown in table II.

TABLE II In vitro results Fibrinogen binding Platelet aggregation * compound #% Inh. (50 μM) IC 50 (μM)% Inh. (50 μM) IC50 (μM) 1 100% 0.0007 100% 0.14 2 100% 0.005 100% 1.1 3 100% 0.0009 100% 0.19 4 100% 0.0020 100% 0.29 5 100% 0.0097 100% 0.27 6 100% 0.0025 100% 0.51 * Thrombin-induced aggregation of gel-filtered platelets. NT = not tested.

Ex vivo study in dogs Adult mestizo dogs (8 to 13 kg) were anesthetized with sodium pentobarbital (35 mg / kg, i.v.) and given artificial respiration. Blood pressure and heart rate were measured using a Millar catheter tip pressure transducer inserted into a femoral artery. Another Millar transducer was placed in the left ventricle (LV) via a carotid artery to measure the final diastolic pressure of LV and the myocardial contractility indexes. A lead II electrocardiogram was recorded with electrodes placed on the extremities. Catheters were placed in a femoral artery and vein to take blood samples and infuse drugs, respectively. The responses were continuously monitored using a data acquisition system from Modular Systems. Arterial blood samples (5-9 ml) were collected in tubes containing 3.8% sodium citrate to prepare a platelet-rich plasma (PRP) and to determine the effects on the coagulation parameters: prothrombin time (PT) and time of activated partial thromboplastin (APTT). Separate blood samples (1.5 ml) were extracted in EDTA to determine hematocrit and cell counts (platelets, RBC and white blood cells). Bleeding times on plaque were obtained from the buccal surface using a symplate incision device and a Whatman filter paper. The aggregation of PRP was developed using a BioData aggregometer. For the aggregation of the whole blood an impedance aggregometer Chronolog was used. PT and APTT were determined in a BioData or ACL 3000+ coagulation analyzer. The cells were counted with a Sysmex K-1000. The compounds were solubilized in a low volume of dimethylformamide (DMF) and diluted with saline to a final concentration of 10% DMF. The compounds were administered intravenously with a Harvard infusion pump. Doses were administered over a 15 minute interval at a constant rate of 0.33 ml / min. Data were obtained after each dosing at 30 minute intervals after the administration of the drug was completed. The oral doses were administered as an aqueous solution with a syringe. The compounds caused a marked inhibition of platelet aggregation responses ex vivo. Thus, in whole blood, the compounds inhibited aggregation stimulated by collagen (or ADP) in doses of 0.1-10 mg / kg with marked inhibition of ATP release from platelets stimulated by collagen. In PRP, the compounds also inhibited platelet aggregation stimulated by collagen with marked activity at 0.1-10 mg / kg. The compounds did not present hemodynamic effects that could be measured in doses greater than 1 mg / kg, v. The drugs produce an increase in the base time of bleeding at 0.1-1 mg / kg with a rapid recovery after treatment. No coagulation effects were observed (PT or APTT) during the treatment and platelet, the white blood cell count and RBC did not change in any dose of the compounds. The results indicate that the compounds are very effective inhibitors of platelet aggregation ex vivo (antagonizing the trajectories of collagen and ADP) after administration of doses ranging from 0.3 to 1.0 mg / kg or 3 mg / kg orally. The effects of antiaggregation are accompanied by the increase in bleeding time at higher doses. No other hemodynamic or haematological effects were observed. The results are shown in table III.

TABLE III Ex vivo study results in dogs * Indicates duration of > 50% inhibition of ex vivo platelet aggregation induced by collagen. NT = not tested.

EXAMPLES Protected amino acids were purchased from Aldrich Chemical or Bachem Bioscience Inc. N-a-CBZ-L-diaminopriopionic acid was purchased from Fluka. Nicpecic acid enriched enantiomerically ethyl ester was isolated by a chiral resolution of racemic material as published (A.M. Akkerman, Rec.Tray.Chim.Pays-Bas 1951, 70, 899). All other chemicals were purchased from Aldrich Chemical Company, Inc. High field spectra of 1 H NMR were recorded on a Bruker AC-360 spectrometer at 360 MHz, and coupling constants are given at Herz. The melting points were determined in a Mel-Temp II melting point apparatus and are without correction. Microanalyses were performed at Robertson Microlit Laboratories, Inc., Madison, New Jersey and are expressed in percentages by weight of each element by the total molecular weight of each element. In those cases where the products are obtained as a salt, the free base is obtained by methods known to those skilled in the art, for example by basic ion exchange purification. The nuclear magnetic resonance (NMR) spectrum for the hydrogen atoms was measured in the indicated solvent with tetramethylsilane (TMS) as the internal standard in a Bruker spectrometer AM-360 (360 MHz), AM-400 (400 MHz), or AT-300 (300 MHz). The values are expressed in parts per million of the low field of TMS. The mass spectra (MS) were determined on a Finnigan 3300 (methane) spectrometer, using chemical desorption ionization techniques. Unless indicated otherwise, the materials used in the examples were obtained from commercially available suppliers or were synthesized by standard methods known in the chemical synthesis art. Substituent groups, which vary from one example to another, are hydrogen unless otherwise indicated. In the examples and throughout this application, the following abbreviations have the meanings cited below. Bn or Bzl = Benzyl Boc = t-Butoxycarbonyl BOC-ON = 2- (1-Butoxycarbonyloxyimino) -2-phenylacetonitrile BOP-CI = Bis (2-oxo-3-oxazolidinyl) phosphinic chloride CBZ = Benzyloxycarbonyl CP = compound DCE = 1 , 2-Dichloroethane DCM = Dichloromethane DIC = Diisopropylcarbodiimide DIEA = Diisopropylethylamine DMAP = 4-Dimethylaminopyridine DMF = N, N-Dimethylformamide EDC = Etyldimethylaminopropylcarbodiimide EDTA = Ethylenediaminetetraacetic acid Et20 = Diethyl ether HBTU = 2- (1 H-Benzotriazole-1-yl ) -1, 1, 3,3-tetramethyluroniumhexafluorophosphate HOBT = Hydroxybenzotriazole / -Pr = Isopropyl MPK = milligrams per kilogram NMM = N-Methylmorpholino Nip = Nipecotil (racemic in position 3, unless otherwise indicated) NT = not tested PPT = precipitate PTSA = p-toluenesulfonic acid RT = room temperature TFA = trifluoroacetic acid Z = benzyloxycarbonyl The following examples describe the invention in greater detail and are intended to illustrate the invention , not limit it.

.S.-3-amino-3- (3-pyridyl) methyl propionate • 2HCl (AA1) A mixture of 3-pyridinecarboxaldehyde (0.47 moles), EtOH (100 ml), NH4OAc (0.47 moles), and malonic acid (0.70 mol) was heated to reflux for 6 hours, cooled and filtered. The white solid was washed with EtOH and MeOH and dried (E. Profft, J. Prakt, Chem. 1965, 30, 18). This solid was dissolved in 2: 1 acetone / water (360 ml), treated with triethylamine (0.72 mol) and phenylacetyl chloride (0.36 mol), and stirred for 22 hours. The mixture was evaporated and the residue was dissolved in water (500 ml) and adjusted to a pH of 12 (1 N NaOH). The aqueous layer was adjusted to a pH of 2 (concentrated HCl), extracted with Et20, and evaporated to a white foam. The foam was purified by chromatography on silica gel (10% MeOH / DCM) to give the racemic 3-phenylacetamido-3- (3-pyridyl) propionic acid. A solution of this compound (0.22 mol) in water (600 ml) at room temperature was adjusted to a pH of 7.5 using KOH (3.0 N) and treated with penicillin amidase (91520 units)., Sigma). This mixture was stirred for 47 hours, acidified to pH 1 with HCl (conc), and the resulting ppt was filtered through celite. The filtrate was extracted with Et20 (3x300 mL), concentrated in vacuo and treated with MeOH / conc. NH 4 OH (9: 1). This solution containing the product was purified by chromatography on silica gel (eluent DCM / MeOH / NH4OH, 78: 18: 4) to give the ammonium salt of (S) -3-phenylacetamido-3- (3-pyridyl) ) propionic (19.5 g, 58%). This product was treated with HCl (6.0 N, 292 mL), heated to reflux for 5 hours, cooled to room temperature, and extracted with Et20 (3x200 mL). The aqueous layer was adjusted to pH 12, concentrated in vacuo, and the resulting solid was triturated with MeOH (2x300 mL). This solution was evaporated to give approximately 14 g of sodium salt. This material was treated with MeOH (500 ml), 2,2-dimethoxypropane (44 ml), and HCl (4 N in dioxane, 84 ml), and stirred for 90 hours at room temperature. This mixture was filtered and the filtrate was concentrated in vacuo. The resulting off-white solid was triturated with Et20 (2x150 ml) and dried to give compound AA1 (16.7 g, 96% ee) as an amorphous white solid.

EXAMPLE 1 2- (N-3- (4-Piperidinpropionyl) -R- _-) - n -pecotyl-S-3-amino-3- (3-pyridyl) Ester 2- (Diethylamino) -2-oxoethyl acid .lpropionic • 2HCI (1) To a mixture of AA1 • 2HCl (2.0 g, 8.0 mmol), MeCN (120 mL), Boc-R-nipecotic acid (1.8 g), and HOBT (1.1 g) at 5 ° C was added NMM (2.6 mL) and HBTU (3.5 g). The mixture was stirred for 20 hours, diluted with saturated ammonium chloride (25 ml), and the MeCN was evaporated. The mixture was diluted with EtOAc (120 mL) and the layers separated. The organic layer was dried (sodium sulfate) and evaporated to give a tan foam. The foam was dissolved in dioxane (35 ml) and anisole (100 ml), treated with HCl (25 ml, 4 N in dioxane) and stirred at room temperature for 2.5 hours. The resulting mixture was evaporated and the white foam was triturated with Et20 (50 mL) to give 2.8 g of AA2. A mixture of compound AA2, MeCN (120 ml), HOBT (1 g), and HBTU (3.3 g) at 5 ° C was treated with NMM (2.5 ml) and N-Boc-4-piperidinpropionic acid (1.9 g) and it was stirred for 4.5 hours. The reaction was diluted with saturated ammonium chloride (30 mL), and MeCN was evaporated. This mixture was diluted with EtOAc (120 mL) and the layers separated. The organic layer was dried (sodium sulfate) and evaporated to give a foam. The foam was purified by silica gel chromatography (0.5% NH 4 OH / 7% EtOH / DCM) to give a white foam (2.1 g) this foam was dissolved in THF (25 ml), cooled to 5 ° C, and treated with aqueous lithium hydroxide (0.25 g in 35 ml of water). The reaction was stirred for 2 hours, acidified with citric acid (0.6 g), and extracted with CHCl3 (3x50 mL). The combined organic layers were dried (sodium sulfate) and evaporated to give AA3 as a white foam (1.9 g). Compound AA3 (1.0 g, 1.9 mmol) was dissolved in EtOAc (50 mL) and triethylamine (0.3 mL) and treated with sodium iodide (0.09 g) subsequently 2-chloro -? /,? / - diethylacetamide (0.60 ml). ). This mixture was stirred for 22 h, diluted with saturated ammonium chloride (30 mL) and EtOAc (100 mL), and the layers were separated. The organic layer was dried (sodium sulfate) and evaporated to give a foam. The foam was purified by silica gel chromatography (0.5% NH 4 OH / 8% EtOH / DCM) to give a glass (0.56 g). The glass was dissolved in dioxane (25 ml) and anisole (0.5 ml), treated with HCl (15 ml, 4 N in dioxane), and stirred at room temperature for 4 hours. The resulting mixture was evaporated and the white foam was triturated with Et20 (50 mL) to give 1 as an amorphous solid (0.23 g): mp 93-100 ° C. 1 H NMR (DMSO-d 6) d 8.9 (m, 3 H), 8.6 (m, 2 H), 8.5 (t, 1 H), 8.0 (t, 1 H), 5.4 (m, 1 H), 4.7 ( s, 2 H), 4.2 (m, 1 H), 3.7 (m, 2 H), 3.2 (q, 2 H), 3.1 (q, 2 H), 2.8 (m, 4 H), 2.6 (m, 2 H), 2.3 (m, 3 H), 1.2-2.0 (m, 13 H), 1.1 (t, 3 H), 0.9 (t, 3 H); MS m / e 530 (MH +). Analysis calculated for C 28 H 43 N 5 5 5 • 2.3 HCl • 1.3 Dioxane (729.68): C, 52.67; H, 7.69; N 9.59; Cl, 11.18. Found: C, 52.83; H, 7.99; N, 9.02; Cl, 11.53.

EXAMPLE 2 N-3- (4-Piperidinpropionyl) -R - (-) - nipecotyl-rS) -3-amino-3- (3,4-methylenedioxyphenyl) propionate 2- (diethylamino) -2-oxoethyl ester • HCl (2) Compound 2 was prepared as described in example 1 starting with methyl (S) -3-amino-3- (3,4-methylenedioxyphenyl) propionate • HCl (2.2 g), and was isolated as a white powder (0.70 g). ): H NMR (CDCl 3) d 9.2 (m, 1 H), 8.8 (m, 1 H), 8.4 (d, 1 H), 6.8 (m, 3 H), 5.91 (s, 2 H), 5.4 ( m, 1 H), 4.8 (m, 2 H), 4.3 (m, 1 H), 3.7 (m, 1 H), 3.1-3.5 (m, 5 H), 2.6-3.0 (m, 4 H), 2.4 (m, 3 H), 1.6-2.0 (m, 7 H), 1.2-1.5 (m, 7 H), 1.1 (q, 3 H), 0.9 (t, 3 H); MS m / e 573 (MH +). Analysis calculated for C30H44N4O7 • 1.7 TFA • 0.5 H20 (775.55): C, 51.73; H, 6.07; N, 7.22; F, 12.49; KF, 1.16. Found: C, 51.75; H, 6.23; N, 7.13; F, 12.35; KF, 1.12.

EXAMPLE 3 N-3- (4-Piperidinepropionyl) -R- (-.- nipecotyl- .. S-3-amino-3-, 5-bromo-3-2- (diethylamino) -2-oxoethyl ester Propionic pyridyl.l «2HCl (3) Compound 3 was prepared as described in Example 1 starting with methyl (S) -3-amino-3- (5-bromo-3-pyridyl) propionate • 2HCl (2.9 g), and isolated as a white foam ( 0.40 g): mp 63-69 ° C. 1 H NMR (DMSO-d 6) d 8.8 (m, 3 H), 8.55 (s, 1 H), 8.48 (s, 1 H), 8.4 (m, 1 H), 8.0 (m, 1 H), 5.2 ( m, 1 H), 4.72 (s, 2 H), 3.9 (m, 1 H), 3.2 (m, 6 H), 2.9 (m, 2 H), 2.7 (m, 2 H), 2.2 (m, 2 H), 1.9 (m, 3 H), 1.2-1.8 (m, 12 H), 1.1 (t, 3 H), 10 (t, 3 H); MS m / e 608 and 610 (MH +). Analysis calculated for C28H42BrN5? 5 • 2.1 HCl • 1.0 H20 • 0.5 Dioxane (747.23): C, 48.22; H, 6.76; N, 9.37; Cl, 9.96. It was found: C, 48.01; H, 6.97; N, 9.13; Cl, 10.28 EXAMPLE 4 N-3 (4-Piperidinprop8onyl) -R- (-) nipecotyl-f (s) -2-benzyloxycarbonylamino-3-amino-1-propionic acid ester 2- HCl (4) Ester 2- (Diethylamino) oxoethyl acid To a mixture of AB1, • 2HCl (12.2 g, 42 mmol), MeCN (300 mL), Boc-R-nicopecotic acid (9.7 g), and HOBT (5.8 g) at 5 ° C NMM was added. (9.3 mi) and HBTU (15.9 g). The mixture was stirred for 24 hours at 5 ° C, diluted with saturated ammonium chloride (50 ml) and the MeCN was evaporated. This mixture was diluted with EtOAc (300 mL) and the layers separated. The organic layer was washed with saturated sodium bicarbonate (50 ml), dried (magnesium sulfate), evaporated and purified by silica gel chromatography (1.5% MeOH / DCM) to give a white foam (14.8 g). The foam was dissolved in dioxane (30 mL), treated with HCl (30 mL, 4 N in dioxane), and stirred at room temperature for 2 hours. The resulting mixture was evaporated and the white foam was triturated with Et20 (50 mL) to give AB2 (13 g). The mixture of compound AB2 (6.3 g), MeCN (200 ml), HOBT (2.1 g), and HBTU (5.9 g) at 5 ° C was treated with NMM (5.2 ml) and N-Boc-4-piperidinpropionic acid ( 4.0 g) and stirred for 22 hours. The reaction was diluted with ammonium chloride (40 ml), and the MeCN was evaporated. This mixture was diluted with EtOAc (120 mL) and the layers separated. The organic layer was washed with saturated sodium bicarbonate (30 ml), dried (magnesium sulfate), evaporated and purified by chromatography on silica gel (2.5% MeOH / DCM) to give a foam (7.7 g), 2.5 g of this foam was dissolved in THF (15 mL), cooled to 5 ° C and treated with aqueous lithium hydroxide (0.17 g in 30 mL of water). The reaction was stirred for 2.5 h, acidified with acetic acid (1 mL), and extracted with CHCl3 (3x50 mL). The combined organic layers were dried (magnesium sulfate) and evaporated to give AB3 as a white foam (2.1g). Compound AB3 (1.0 g 1.9 mmol) was dissolved in DMF (20 mL), water (5 mL), and cesium carbonate (1.0 g) and treated with 2-chloro-α /, / / -diethyl acetamide (2.1 ML). ). This mixture was heated at 75 ° C for 22 hours, cooled to room temperature, concentrated in vacuo, and diluted with DCM (60 ml). This mixture was washed with water (25 ml), dried (magnesium sulfate), and evaporated to give a foam. The foam was purified by silica gel chromatography (4% MeOH / DCM) to give a glass (1.6 g). The glass was treated with HCl (10 mL, 4 N in dioxane), and stirred at room temperature for 1.5 h to give a ppt. The HCl was decanted and the ppt triturated with Et 0 (50 ml), and dried to give 4 as an amorphous solid (0.95 g): mp 57-61 ° C 1 H NMR (DMSO-d 6) d 8.9 (m, 1 H), 8.6 (m, 1 H), 8.1 (m, 1 H), 7.7 (t, 1 H), 7.3 (m, 5h), 5.05 (s, 2H), 4.8 (m, 2H), 4.2 ( m, 1 H), 3.8 (m, 1 H), 3.1-3.4 (m, 6H), 2.7 (m, 3H), 2.3 (m, 2H), 1.2-1.9 (m, 16 H), 1.1 (t , 3H), 1.0 (t, 3H); MS m / e 602 (MH +). Analysis calculated for C3? H47N507 «1.2 HCl • 1.7 H20 (676.12): C, 55.07, H, 7.69; N, 10.36; Cl, 6.29. Found: C, 54.86, H, 7.72; N, 10.39; Cl, 6.11.

Nt-Butoxycarbonyl-4-piperidin-3-propenoic acid (AD3) To a solution of oxalyl chloride (24.8 ml, 50 mmol) in DCM (200 ml) at -78 ° C was added DMSO (7.0 ml). ) drop by drop. The mixture was stirred for 30 minutes, treated with AD1 (8.2 g, 38 mmol), and stirred for 2 hours. Triethylamine (31.7 ml) was added dropwise, the mixture was warmed to room temperature, and the mixture was diluted with water (30 ml). The layers separated; the organic layer was washed with saturated ammonium chloride (30 ml), and saturated sodium chloride (30 ml), dried (magnesium sulfate), evaporated and purified by silica gel chromatography (20% EtOAc / hexane) give AD2 (7.3 g, 34 mmol) as a white solid. A solution of ethyl 2- (triphenylphosphoranylidene) acetate (13.1 g, 38 mmol) and DCM (40 mL) at 5 ° C was treated with AD2 (7.3 g), warmed to room temperature, stirred at 2.5 h, and evaporated to dryness. This solid was treated with pentane (50 ml), and triphenylphosphine oxide removed by filtration. The pentane solution was concentrated and the solid was purified by silica gel chromatography (10% EtOAc / hexane) to give a glass (8.5 g). The glass was dissolved in EtOH (60 mL) and this solution was treated with water (60 mL) and sodium hydroxide (59 mL)., 1.0 N) at room temperature. The mixture was stirred for 4 h, acidified with citric acid (8 g), and extracted with DCM (3x100 mL). The combined organic layers were dried (magnesium sulfate) and evaporated to give AD3 (7.5 g) as a white solid. MS m / e 256 (MH +).

EXAMPLE 5 N-3- (4-Piperidinpropenoyl) -R- (-) nipecotyl - (S) -2-benzloxycarbonylamino-3-amino-1-propionic acid ester • HCl (5) 2- Ester 2- diethylamino) -2-oxoethyl The intermediate AD3 (8.5 mmoles) and the intermediate AB2 (8.5 mmoles) were coupled using HBTU / HOBT and the product was developed to give 5 as described in example 4. Example 5 was isolated as a white powder (1.6 g); mp 42-45 ° C. MS m / e 600 (MH +). Analysis calculated for C3? H45N507 • 1.0 HCl • 2.0 H20 (672.22): C, 55.39; H, 7.50; N, 10.42; Cl 5.27. C, 55.62; H, 7.37; N, 10.44; Cl, 5.27 EXAMPLE 6 2- (Piperidino) -2-oxoetyl ester of N-3- (4-Piperidinepropenoyl) -R- (-.nipecotyl-.. S) -2-benzmoxycarbonylamino-3-amino-1-propionic acid • HCl (6) The intermediate AD3 (6.2 mmoles) and the piperidine derivative of the intermediate AB2 (6.2 mmoles) were coupled using HBTU / HOBT and the product was developed to give 6 as described in example 4. Compound 6 was isolated as a white powder (0.94 g): mp 52-56 ° C. MS m / e 612 (MH +). Analysis calculated for C32H 5N507 • 1.0 HCl • 2.6 H20 (695.04): C, 55.30; H, 7.42; N, 10.08; Cl 5.10. Found C, 55.05; H, 7.39; N, 9.86; Cl, 5.05.

Claims (20)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound represented by the general formula (I):

(

where M is (CH2) m, CH = CH or C = C; A is chosen from either piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl,

NHR2 or where Rg is chosen from any of H, alkyl,

CH (NH), Cme (NH) or acyl; R10 is H or C (0) N (R1) YZ, where R1 is chosen from H or cycloalkyl; R2 is chosen from any of H, alkyl or acyl; R5 is H or C (0) NHQ (CHW) rC02R8; where Q is chosen from CH2, CH-aryl, CH-heteroaryl, heteroaryl substituted with CH or CH-alkyl; W is chosen from H or N (R6) T-R7; where Re is chosen from any of H, alkyl or acyl; T is chosen from C (O), C (N-CN) or S02; R7 is selected from any of alkyl, aryl, aralkyl, alkoxy or aminoalkyl; and R8 is CH2C (0) NRnR-i2, wherein R-n and R12 are chosen from H, alkyl or cycloalkyl; m is the integer 1, 2 or 3; X is chosen from either C (O), C (0) 0, C (0) NH, CH2, or S02; n is the integer 1, 2, or 3; r is 0 or 1; Y is selected from any of (CH2) P, CH (R3) (CH2) q, (CH2) qCH (R3), (CH (C02R4) CH2) q, (CH2) qCHOH or piperidin-3-carboxylic acid; as long as Y is (CH2) P and p is 2, X is different from C (O) or when X is C (O), then R1 is different from H or R2 is different from H, and with the exception that when And let (CH (C02R4) CH2) q X be different from C (O) or CH2; p is 2 or 3; q is 1, 2 or 3; R3 is alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, aralkyl or heteroaryl; R 4 is H or alkyl or cycloalkyl; Z is C02CH2C (0) NRnRi2; provided that at least one of R5 and R10 is hydrogen and R5 and R- are not hydrogen at the same time; or the enantiomer or pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, further characterized in that the group C (0) N (R?) YZ is attached in the 3 or 4 position of the central azaciclo.

3. The compound according to claim 1, further characterized in that the group C (0) N (R?) YZ is attached at the 3-position of the central azaciclo.

4. The compound according to claim 1, further characterized in that R5 is C (0) NHQ (CHW) rC02R8.

5. The compound according to claim 1 of the formula: (I) wherein M is (CH2) m, CH = CH or C = C; A is chosen from either piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, NHR2 or

where Rg is chosen from any of H, alkyl,

CH (NH), Cme (NH) or acyl; R10 is H or C (0) N (R1) YZ, where R1 is chosen from H or cycloalkyl; R2 is H; R5 is H or C (0) NHQ (CHW) rC02R8; further characterized in that Q is selected from CH 2, CH-heteroaryl or heteroaryl substituted with CH; W is chosen from H or N (R6) T-R7; where R6 is H; T is C (O); R7 is selected from any of alkyl, aryl, aralkyl, alkoxy or aminoalkoxy; and R8 is CH2C (0) NRnR12, where Rn and R-? 2 are alkyl; m is the integer 1 or 2; X is chosen from either C (O), C (0) 0, C (0) NH, CH2, or S02; n is the integer of 1, 2 or 3; r is 0 or 1; Y is selected from any of (CH2) P, CH (R3) (CH2) q, (CH2) qCH (R3), (CH (C02R4) CH2) q, (CH2) qCHOH or piperidin-3-carboxylic acid; with the proviso that Y is (CH2) P and p is 2, X is different from C (O) and when X is C (O) then R1 is different from H or R2 is different from H, and with the exception that when Y is (CH (C02R4) CH2) q X is different from C (O) or CH2; p is 2 or 3; q is 1; R3 is alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, aralkyl or heteroaryl; R4 is H; Z is C02CH2C (0) NRnR? 2; as long as at least one of R5 and R-io is hydrogen; or the enantiomer or pharmaceutically acceptable salt thereof.

6. The compound according to claim 5, further characterized in that the group C (0) N (R1) YZ is attached to the 3 or 4 position of the central azaciclo.

7. The compound according to claim 5, further characterized in that the group C (0) N (R1) YZ is attached at the 3-position of the central azaciclo.

8. The compound according to claim 5, further characterized in that R5 is C (0) NHQ (CHW) rC02R8.

9. The compound according to claim 1, further characterized in that: R5 is H or C (0) NHQ (CHW) rC02R8; where Q is chosen from CH2, CH-heteroaryl or heteroaryl substituted with CH; W is chosen from H or N (R6) T-R7; where R6 is H; T is C (O); R7 is selected from any of alkyl, aryl, aralkyl, alkoxy or aminoalkoxy; and R8 is CH2C (0) NRnR? 2; where Rn and R-I2 are alkyl.

10. The compound according to claim 1 of the formula:

where Rn and R-? 2 are alkyl or together are (CH2J5; R13 is chosen from H, 3-pyridyl, 3,4-OCH2Ph and 3-bromo-3-pyridyl, and R14 is chosen from H and NHC02H2Ph. - A compound chosen from either 2- (diethylamino) -2-oxoethyl ester of N-3- (4-piperidinpropionyl) -R - (-) - n -pecotyl - [(S) -3-amino-3- (3-pyridyl)] propionic • 2HCl, 2- (diethylamino) -2-oxoethyl ester of N-3- (4-piperidinpropionyl) -R - (-) - nipecotyl - [(S) -3-amino) -3- (3,4-methylenedioxyphenyl)] propionic • 2HCl, 2- (diethylamino) -2-oxoethyl ester of N-3- (4-p -peridinpropionyl) -R - (-) - nipecotyl - [(S ) -3-amino-3- (5-bromo-3-pyridyl)] propionic • 2HCl, 2- (diethylamino) -2-oxoethyl ester of N-3- (4-piperidinpropionyl) -R - (-) nipecotil - [(S) -2-benzyloxycarbonylamino-3-aminojpropionic • 2HCl, N-α-butoxycarbonyl-4-piperidin-3-propenoic acid, 2- (diethylamino) -2-oxoethyl ester of N-3- acid ( 4-piperidinepropenoyl) -R - (-) nipecotyl - [(S) -2-benzyloxycarbonylamino-3-amino] propionic • 2HCl and 2- (piperidin) -2-oxoethyl ester of N-3- (4-piperidinepropenoyl) -R - (-) nipecotyl - [(S) -2-benzyloxycarbonylamino-3-amino] propionic acid • 2HCl.

12. The compound according to claim 1 which is: 2- (diethylamino) -2-oxoethyl ester of N-3- (4-piperidinpropionyl) -R - (-) - nipecotyl - [(S) -3-amino) -3- (3-pyridyl)] propionic.

13. A composition for treating platelet-mediated thrombotic disorders comprising the compound of claim 1 in an amount effective to treat such disorders in combination with a pharmaceutically acceptable carrier.

14. A method for making the composition according to claim 13, comprising mixing an effective amount of the compound with a pharmaceutically acceptable carrier.

15. The use of a compound according to claim 1 for the preparation of a medicament for the treatment of thrombotic disorders mediated with platelets in a patient.

16. The use according to claim 15, further characterized in that said medicament comprising the compound of claim 1, provides 0.1 to 300 mg / kg of said compound to the patient per day.

17. The use of the composition according to claim 13 for the manufacture of a medicament for treating thrombotic disorders mediated with platelets in a patient.

18. The use of the compound according to claim 1 for the preparation of a medicament for inhibiting platelet aggregation in a patient.

19. - The use according to claim 18, further characterized in that said medicament comprising the compound according to claim 1 provides 0.1 to 300 mg / kg of said compound to the patient per day.

20. A compound represented by the general formula (I):

(I) where M is CH = CH or C = C; A is chosen from either piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, NHR2 or

where Rg is chosen from any of H, alkyl,

CH (NH), Cme (NH) or acyl; R10 is H or C (0) N (R1) YZ, where R1 is chosen from H or cycloalkyl; R2 is chosen from any of H, alkyl or acyl; R5 is H or C (0) NHQ (CHW) rC02R8; wherein Q is selected from CH-heteroaryl, or heteroaryl substituted with CH, wherein the heteroaryl is selected from pyridyl, thienyl, furanyl or quinolinyl; W is chosen from H or N (R6) T-R7; wherein Rβ is selected from any of H, alkyl or acyl; T is chosen from C (O), C (N-CN) or S0; R7 is selected from any of alkyl, aryl, aralkyl, alkoxy or aminoalkyl; and R8 is H or CH2C (0) NR? - | R? 2, where R-n and R-? 2 are chosen from H, alkyl or cycloalkyl; m is the integer 1, 2 or 3; X is chosen from either C (O), C (0) 0, C (0) NH, CH2 or S02; n is the integer 1, 2 or 3; r is 0 or 1; Y is selected from any of (CH2) p, CH (R3) (CH2) q, (CH2) qCH (R3), (CH (C02R4) CH2) q, (CH2) qCHOH or piperidin-3-carboxylic acid; with the proviso that when Y is (CH2) P and p is 2, X is different from C (O) or when X is C (O) then R1 is different from H or R2 is different from H and with the exception that when Y is (CH (C02R4) CH2) q X is different from C (O) or CH2; p is 2 or 3; q is 1, 2 or 3; R3 is alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, aralkyl or heteroaryl; R 4 is H or alkyl or cycloalkyl; Z is C02CH2C (0) NRnRi2; as long as at least one of R5 and Rio is hydrogen and R5 and R10 are not hydrogen at the same time; as long as R5 is C (0) NHQ (CHW) rC02R8 and Q is CH-heteroaryl or heteroaryl substituted with CH and R8 is H, then M is CH = CH; or the enantiomer or pharmaceutically acceptable salt thereof.