DE4306873A1 - New 4-aminopyridine processes for their preparation and medicaments containing these compounds - Google Patents

Description

The invention relates to new 4-aminopyridines of the general Formula I.

in the
R _{1 is} an aryl, a heteroaryl or a cycloalkyl group, which can be substituted if desired,
AS an amino acid,
n the numbers 0 or 1,
R ₂ and R _{3 are the} same or different and form hydrogen atoms, alkyl, carboxyalkyl, or alkoxycarbonylalkyl groups or R ₂ and R ₃ together with the nitrogen atom to which they are attached form a heterocyclyl ring, which if desired also contains a second heteroatom contain and can be substituted by alkyl, carboxy or alkoxycarbonyl groups,
R ₄ and R _{5 are} identical or different and are hydrogen atoms or alkyl groups,
m the numbers 0, 1 or 2,
R ₆ , R ₇ , R ₈ and R _{9 are the} same or different and hydrogen atoms or halogen atoms
mean,
and hydrates, solvates and physiologically acceptable salts thereof. The invention also relates to the optically active forms, the racemates and the diastereome mixtures of these compounds.

The invention also relates to processes for producing the above compounds, drugs containing such compounds included, as well as the use of these compounds in the Manufacture of drugs.

The aminopyridines of the general formula I, their solvates and their salts both inhibit the thrombin-induced gerin of fibrinogen in the blood as well as that caused by thrombin induced platelet aggregation. You prevent thus the formation of thrombi and platelets rich thrombi and can help fight and prevent treatment of diseases such as thrombosis, apoplexy, heart attack, Inflammation and arteriosclerosis can be used. Further these compounds have an effect on tumor cells and prevent the formation of metastases. So you can as Antitumor agents are used.  

Thrombin, the last enzyme in the coagulation cascade, cleaves Fibrinogen to fibrin that crosslinks through factor XIIIa and becomes an insoluble gel that the matrix for one Thrombus forms. Thrombin is activated by proteolysis of its Platelet aggregation and also contributes to thrombus formation in this way. At These processes are necessary when a blood vessel is damaged dig to stop bleeding. Under normal circumstances are no measurable thrombin concentrations in the blood plasma available. Increasing the thrombin concentration can lead to Formation of thrombi and thus thromboembolic Lead diseases, especially in the industrialized countries occur very frequently.

Thrombin is prepared in the form of prothrombin in plasma held and released by the factor Xa. Thrombin activates factors V and VIII, which then activate the Convert factor X to Xa. Thrombin thereby catalyzes its own release, which is why it increases very rapidly Thrombin concentrations can come.

Thrombin inhibitors can therefore release the Thrombins, the platelet-induced and the plasmatic Inhibit blood clotting.

In addition to thrombin, there is a whole range of serine proteases, the peptide substrates in addition to a basic amino acid columns. To keep side effects low the thrombin inhibitors are selective, i.e. H. they should inhibit other serine proteases only slightly or not at all. Especially The trypsin as the most unspecific serine protease can be of the various inhibitors are easily inhibited. Inhibition of trypsin can cause pancreatic stimulation and pancreatic hypertrophy (J.D. Geratz, Am. J. Physiol. 216, (1969) p. 812).

Plasma contains the protein plasminogen, which is activated by activators is converted into plasmin. Plasmin is a proteolytic  Enzyme whose activity is similar to that of trypsin. It is used for Disintegration of the thrombi by breaking down fibrin. Inhibition of So plasmins would have exactly the opposite effect with the inhibition of thrombin.

Synthetic thrombin inhibitors have long been known. Starting from the fibrinogen, the throm's natural substrate bins, substances of the (D) -Phe-Pro-Arg type were synthesized tized. Such tripeptides mimic the amino acid sequence the cleavage site on the fibrinogen. To good inhibitors too obtained, the carboxylate group of arginine was so changed that the hydroxyl group of Serin-195 the active site of the thrombin can react with it. This is at possible, for example, that the carboxylate group replaced by the aldehyde function. Corresponding (D) -Phe-Pro Arginals are described in patent application EP-A-185390.

For a second type of thrombin inhibitor, this was called Trypsin inhibitor known benzamidine taken as a basis. The inhibitors thus obtained differ from the (D) - Phe-Pro-Arg types not only in chemical structure, but also also in the type of inhibition: the serine-195 of thrombin does not bind to these inhibitors. This comes from x-rays structure investigations clearly emerge (W. Bode, D. Turk, J. Crash beaker, Eur. J. Biochem. 193: 175-182 (1990)). To this belongs to this second class of thrombin inhibitors Nα- (2-naphthylsulfonylglycyl) -4-amidino- (R, S) -phenylalanine piperidide ("NAPAP", DD 2 35 866).

A disadvantage of the inhibitors of the (D) -Phe-Pro-Arg class is the lack of selectivity towards other serine proteases (J.C. Powers, C.-M. Kam, in Thrombin, Structure and Function (L.J. Berliner, editor), Plenum, New York 1992, 5,117). Selectivity is slightly better with NAPAP. The inhibition constants of the NAPAP are as follows (J. Sturzbecher et al., Pharmazie 34 (1988), p. 782): thrombin 6 nM, trypsin 0.69 µM, plasmin 30 µM. The selectivity of this inhibitor  between thrombin and trypsin, expressed as the quotient of the Inhibition constants is about 1: 100. The main disadvantage These inhibitors are now to be found in the fact that they look for oral administration not or insufficiently at their The place of action, the blood stream. Mainly responsible for this deficiency is due to the strong basicity of the inhibitors. There Thrombin selectively recognizes the amino acid arginine, it is not surprising that the inhibitors are also groups with similarity to that of the guanidino group of Arginins included. The pKa of the side chain of arginine is 12.5 (D. Voet, J.G. Voet, Biochemie, VCH-Verlag Weinheim 1992, 5.60), the pKa value of the benzamidine is 11.8 (Albert, J. Chem. Soc. 1948, 2240).

Efforts have not been lacking, thrombin inhibitors with less basic groups to develop the oral Improve availability. For example, there were falls becher et al (loc.cit.) establish a connection that differs from NAPAP only by replacing the benzamidino group with one Benzylamino group differs. Benzylamine has one significantly reduced basicity compared to benzamidine: pKa = 9.35 (Robinson, Trans. Faraday Soc. 52 (1956), 327). However, this change in NAPAP reduced the inhibitor Compared to thrombin by several orders of magnitude on Ki - 19 µM and the selectivity thrombin / trypsin was only 1: 4, i.e. H. it almost completely disappeared.

We have now surprisingly found that 4-aminopyridines of all general formula I strong and selective thrombin inhibitors although 4-aminopyridine with pKa = 9.29 (J.M. Essen, K.Schofield, J. Chem. Soc. 1961, 3939) a similarly small one Has basicity like benzylamine. It will not only be oral Availability, but also tolerance is improved and the drop in blood pressure seen with the NAPAP derivatives care is reduced.  

In the general formula I, R1 is understood to mean the phenyl, naphthyl and anthryl group which, if desired, has 1-5 identical or different substituents such as halogen, nitro, nitrile, phenyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, trifluoromethyl, , Trifluoromethoxy, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkenyl, C ₁ -C ₈ alkynyl, hydroxy, C ₁ -C ₈ alkyloxy, C ₁ -C ₈ alkenyloxy -, C ₁ -C ₈ -alkynyloxy-, amino-, C ₁ -C ₈ -alkylamino-, C ₁ -C ₈ -alkenylamino-, C ₁ -C ₈ -alkynylamino-, di- (C ₁ -C ₈ - alkyl) amino, benzylamino, dibenzylamino, carboxyl, C ₁ -C ₈ alkyloxycarbonyl, aminocarbonyl, C ₁ -C ₈ alkylaminocarbonyl, di (C ₁ -C ₈ alkyl) aminocarbonyl, C ₁ -C ₈ alkylthio, C ₁ -C ₈ - alkylsulphinyl, C ₁ -C ₈ alkylsulfonyl, or C ₁ -C ₈ alkyl may be substituted sulfonylamino. The phenyl groups can be condensed with a cycloalkyl or heterocyclyl group, the tetrahydronaphthyl, indanyl, chroma nyl, methylenedioxyphenyl, ethylenedioxyphenyl and tetrahydroquinolinyl groups being particularly preferred.

Heteroaryl for R _{1 means} five- and six-membered aromatics with 1-4 heteroatoms such as nitrogen, oxygen or sulfur, which can be condensed with one or two phenyl groups and whose carbon atoms, if desired, substituents such as halogen, nitro, nitrile, phenyl-, trifluoromethyl -, C ₁ -C ₈ -alkyl-, C ₁ -C ₈ -alkenyl-, C ₁ -C ₈ -alkynyl-, hydroxy-, C ₁ -C ₈ -alkyloxy-, C ₁ -C ₈ -alkenyloxy- , C ₁ -C ₈ alkynyloxy, amino, C ₁ -C ₈ alkylamino, C ₁ -C ₈ alkenylamino, C ₁ -C ₈ alkynylamino, di (C ₁ -C ₈ alkyl ) amino, benzylamino, carboxyl, C ₁ -C ₈ alkyloxycarbonyl, aminocarbonyl, C ₁ -C ₈ alkylaminocarbonyl, di (C ₁ -C ₈ alkyl) aminocarbonyl, C ₁ -C ₈ - Alkylthio, C ₁ -C ₈ alkylsulfinyl, C ₁ -C ₈ alkylsulfonyl, or C ₁ -C ₈ alkylsulfonylamino- can wear. Preferred aromatics are furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, triazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, triazine, tetrazine, benzothiophene, dibenzothiophene, benzimidazole or carbazole.

The C ₁ -C ₈ components mentioned can be chain-like or branched. These are preferably to be understood as the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, vinyl, allyl and propargyl radicals. Cycloalkyl groups for R ₁ are rings with 3-8 C atoms, preferably the cyclopentyl, cyclohexyl and cycloheptyl group.

In the general formula I one understands AS glycine, Azaglyzine and the amino acids alanine, valine, leucine, isoleu cin, methionine, proline, phenylalanine, tryptophan, serine, Threonine, asparagine, aspartic acid, glutamine, glutamic acid, Tyrosine, cysteine, lysine, arginine and histidine, which in the D- or L-form or as a mixture of both forms nen.

If R ₂ and R ₃ together with the nitrogen atom to which they are attached form a heterocyclyl ring, this is preferably understood to mean pyrrolidine, piperidine, homopiperidine, pipara tin, morpholine and thiomorpholine. These rings can carry one or two C ₁ -C ₈ alkyl, carboxyl or C ₁ -C ₈ alkyloxycarbo nyl groups.

Compounds of the general formula I in which
R ₁ phenyl, 4-methylphenyl, 4-chlorophenyl, 4-methoxyphenyl, 1-naphthyl, 2-naphthyl, 5,6,7,8-tetrahydro-2-naphthyl, 3-pyridinyl, 2-thienyl, cyclohexyl, 2, 2,5,7,8-pentamethyl chroman-6-yl or 4-methoxy-2,3,6-trimethyl phenyl,
AS means glycine, azaglycine or alanine, glutamine, glutamate, asparagine or aspartate,
n can be 0 or 1,
R ₂ and R _{3 are the} same or different and denote ethyl, ethoxycarbonylmethyl or carboxymethyl or together with the N atom to which they are attached form a pyrrolidine, piperidine, homopiperidine, morpholine, thiomorpholine or piperazine ring, optionally one or two methyl, ethyl, propyl, butyl, carboxyl, methoxycarbonyl, ethoxycarbonyl or tert. Can carry butyloxycarbonyl groups,
R ₄ and R _{5 are} identical or different and denote hydrogen atoms or methyl groups,
R ₆ , R ₇ , R ₈ , R _{9 are the} same or different and are hydrogen, fluorine or chlorine atoms.

Among the physiologically acceptable salts of the compounds the general formula I means formates, acetates, Caproates, oleates, lactates, or salts of carboxylic acids with up to 16 carbon atoms, hydrochloride, hydrobromide, hydroiodide, Alakane sulfonates with up to 10 carbon atoms, salts of dicarbon acids and tricarboxylic acids such as citrates, malonates and tar kicked.

The compounds of general formula I, in which R ₁ -R ₅ , AS, n and m have the meanings given above and R ₆ -R _{9 are} halogen, are shown in which a compound of the general formula II,

in which R ₁ -R ₅ , AS, n and m have the meanings given above with a compound of the general formula III,

in which R ₆ -R _{9 represent} halogen, brings about the reaction.

The compounds of the general formula I in which R ₁ -R ₅ , AS, n and m have the abovementioned meanings and R ₆ -R _{9 are} hydrogen are prepared by using a compound of the general formula I in which R ₁ - R ₅ , AS, n and in the meanings given and R ₆ -R _{9 are} halogen, subject to a dehalogenation reaction.

The compounds of the general formula II, in which R ₁ -R ₅ , AS, n and m have the meanings given above, are prepared by preparing a compound of the general formula IV,

in which R ₁ -R ₅ , AS, n and in the abovementioned meanings, and Sch represents a protective group such as the benzyloxycarbonyl, t-butoxycarbonyl or the phthalimido group, which brings about a reaction with a reagent which cleaves off the protective groups.

The compounds of general formula IV can be represented in which a compound of the general formula V,

in which m, n and Sch have the meanings given, with an amine of the general formula VI,

in which R ₂ and R _{3 have} the meanings given, brings to reaction and the resulting compounds of the general formula VII,

in which R ₂ , R ₃ , Sch and zen in the meanings given, with a compound of general formula VIII

in which R _{1 has} the meaning given and X represents either a halogen atom or a radical of the general formula IX,

in the Y a halogen atom or one in peptide chemistry usual activated radical and A is a nitrogen atom or a Atomic group of the general formula X

mean, wherein R _{10 is} one of the usual amino acid side chain.

The compounds of general formula V are after Literature known methods presented.

The compounds of general formula I can also can be represented by connecting the general Formula XI,

in which R ₂ -R ₉ and have the meanings given, with a compound of the general formula VIII to react.

The connections of the general Formal XI are herge by preparing a compound of the general formula XII,

in R ₂ -R _{9 have} the meanings given and Sch means a protective group which is customary in peptide chemistry, such as the benzyl oxycarbonyl, t-butoxycarbonyl or phthalimide residue, is reacted with a reagent which cleaves the protective groups and is customary in peptide chemistry.

The compounds of general formula XII are obtained in which a compound of the general formula XIII,

in which R ₂ -R ₅ , m and Sch have the meanings given, with a compound of the general formula III to react.

The compounds of general formula XIII are Darge by connecting the amide group to the general formula XIV,

in the R ₂ -R ₅ , Sch and in the meanings given, subject to a Hofmann degradation.

The compounds of general formula XIV are represented made by using a compound of general formula XV,

in which R ₄ , R ₅ , Sch and m have the meanings given, with a compound of the general formula VI.

The compounds of general formula XV are shown represents compounds of the general formula XVI,

in which R ₄ and R _{5 have} the meanings given, by reaction with a protective group reagent customary in peptide chemistry.

The compounds of general formula XVI are literature known.

The reactions of a compound of general formula II with a compound of general formula III to a Compounds of general formula I are carried out in an inert solvent, such as. B. dimethylformamide, Dioxane, dimethyl sulfoxide or toluene at temperatures between 0 degrees Celsius and boiling point of the solvent, preferably at room temperature in the presence of an auxiliary base such as B. triethylamine, N-methylmorpholine, pyridine or N- Ethyl diisopropylamine.

The compounds of general formula I in which R ₆ -R _{9 are} hydrogen, from the compounds of general formula I in which R ₆ -R _{9 are} halogen, are obtained from these by catalytic hydrogenation in an inert solvent such as. B. methanol or ethanol in the presence of an acid-binding agent such. B. sodium methylate or sodium ethylate preferably at room temperature and normal pressure with platinum or palladium as a catalyst.

The preparation of the compounds of general formula II by splitting off a protective group from the compounds of general formula IV follows that in peptide chemistry usual methods by acidic reagents such. B. bromine water substance in glacial acetic acid, trifluoroacetic acid or hydrogenolytic or by cleavage with hydrazine.

The representation of the compounds of general formula V takes place according to methods known from the literature z. B. from a Amino acid precursor with phosgene in an inert solvent such as B. Dioxane.

The conversion of compounds of general formula V to Compounds of the general formula IV also take place methods known from the literature in an inert solution  medium such as B. dimethylformamide at temperatures between - 50 and +50 degrees Celsius.

The reaction of compounds of general formula XI with Compounds of general formula VIII to compounds of general formula I is carried out in an inert solvent such as B. dimethylformamide, methylene chloride or dioxane Temperatures between 0 and 50 degrees Celsius, preferably at Room temperature in the presence of an auxiliary base such. B. Triet hylamine, N-methyl-morpholine or N-ethyl-diisopropylamine.

The amino protective group is split off from a compound of general formula XII to a compound of general Formula XI is hydrolytically z. B. with a solution of Hydrogen bromide in glacial acetic acid, trifluoroacetic acid, hydrogenoly table or by reaction with hydrazine according to the usual in the Peptide chemistry known methods.

The reaction of a compound of general formula XIII with a compound of general formula III to a Compound of the general formula XII takes place in an inert ten solvents such as. B. dimethylformamide, dioxane, dime thylsulfoxide or toluene at temperatures between 0 degrees Celsius and boiling point of the solvent, preferably at room temperature in the presence of an auxiliary base such. B. Triethylamine, N-methyl-morpholine, pyridine or N-ethyl-diiso propylamine.

The conversion of compounds of the general formula XIV into Compounds of the general formula XIII are made by Hofmann degradation preferably with bis (trifluoroacetoxy) - iodo) benzene in a mixture of an inert solvent Water, preferably in an acetonitrile / water mixture, preferably at room temperature.

The preparation of the compounds of general formula XIV from compounds of the general formula XV according to in the usual peptide chemistry processes.  

The representation of the compounds of general formula XV from the compounds of general formula XVI likewise according to methods customary in peptide chemistry.

The compounds of general formula XVI are literature known.

Examples of physiologically usable salts of the verbin Solutions of formula I are salts with physiologically compatible Chen mineral acids, such as hydrochloric acid, sulfuric acid, sulphurous Acid or phosphoric acid; or with organic acids, such as Methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoro acetic acid, citric acid, fumaric acid, maleic acid, tartaric acid re, succinic acid or salicylic acid. The connections of the Formula I with a free carboxy group can also be salts with form physiologically acceptable bases. Examples of such Salts are alkali metal, alkaline earth metal, ammonium and Alkylammonium salts, such as Na, K, Ca or tetramethylam monium salt.

The compounds of formula I can be solvated, in particular be hydrated. The hydration can in the course of Manufacturing processes take place or gradually as a result hygroscopic properties of an initially anhydrous Compound of formula I occur.

Pure enantiomers of the compounds of the formula I come either by racemate splitting (via salt formation with optically active bases), or by depending on the synthesis because it uses optically active raw materials.

The substances of the general formula I with suitable pharmaceutical carriers substances, flavors, flavors and colors mixed and for example shaped as tablets or coated tablets or with the addition of appropriate auxiliary substances in water or oil, e.g. B. suspended or dissolved in olive oil.  

The substances of general formula I and their salts can in liquid or solid form enterally or parenterally be applied. The preferred injection medium Water for use, which is the same for injection solutions usual additives such as stabilizers, solubilizers or contains buffer. Such additives are e.g. B. tartrate and Citrate buffer, complexing agent (such as ethylenediaminetetraacetic acid and their non-toxic salts) and high molecular weight polymers such as liquid polyethylene oxide for viscosity regulation. Celebrations Carriers are e.g. B. starch, lactose, mannitol, methyl cellulose, talc, highly disperse silicas, high molecular weight Fatty acids (such as stearic acid), animal and vegetable fats and solid high molecular polymers (such as polyethylene glycols). Preparations suitable for oral administration can if desired contain flavorings and sweeteners.

The compounds are usually used in amounts of 10-1500 mg applied per day based on 75 kg body weight. Prefers is to take 1-2 tablets with an active ingredient 2-3 times a day content of 5-500 mg to be administered. The tablets can too be delayed, which means that you only need 1-2 tablets once a day must be given with 20-700 mg of active ingredient. The active substance can also be by injection 1-8 times a day or by duration infusion given, 50-2000 mg per day more normal wise enough.

In the sense of the invention, preference is given to those in FIGS Examples of compounds include the following:

• (R) -N-α- (2-naphthylsulfonylglycyl) -N-γ- (4-pyridinyl) -α, γ-di aminobutyric acid homopiperidide
• (R) -N-α- (2-naphthylsulfonylglycyl) -N-γ- (4-pyridinyl) -α, γ-di aminobutyric acid morpholide  
• (R) -N-α- (2-naphthylsulfonylglycyl) -N-γ- (4-pyridinyl) -α, γ-di aminobutyric acid 4-methylpiperazide
• (R) -N-α- (2-naphthylsulfonylglycyl) -N-γ- (4-pyridinyl) -α, γ-di aminobutyric acid thiomorpholide
• (R) -N-α- (2-naphthylsulfonylglycyl) -N-γ- (4-pyridinyl) -α, γ-di aminobutyric acid (N-ethyl-N-ethoxycarbonylmethyl) amide
• (R) -N-α- (2-naphthylsulfonylglycyl) -N-γ- (4-pyridinyl) -α, γ-di aminobutyric acid (N-ethyl-N-carboxymethyl) amide
• (R) -N-α- (2-naphthylsulfonyl azaglycycl) -N-γ- (4-pyridinyl) - α, γ-diaminobutyric acid piperidide
• (R) -N-α- (2-naphthylsulfonylazaglycycl) -N-γ- (4-pyridinyl) - α, γ-diaminobutyric acid homopiperidide
• (R) -N-α- (4-methoxy-2,3,6-trimethylphenylsulfonylglycyl) - N-γ- (4-pyridinyl) -α, γ-diaminobutyric acid piperidide
• (R) -N-α- (4-methoxy-2,3,6-trimethylphenylsulfonylglycyl) - N-γ- (4-pyridinyl) -α, γ-diaminobutyric acid homopiperidide
• (R) -N-α- (4-methoxy-2,3,6-trimethylphenylsulfonylazaglycy l) - N-γ- (4-pyridinyl) -α, γ-diaminobutyric acid piperidide
• (R) -N-α- (2,2,5,7,8-pentamethyl-6-chromanylsulfonylglycyl) - N-γ- (4-pyridinyl) -α, γ-diaminobutyric acid piperidide
• (R) -N-α- (2,2,5,7,8-pentamethyl-6-chromanylsulfonylglycyl) - N-γ- (4-pyridinyl) -α, γ-diaminobutyric acid homopiperidide
• (R) -N-α- (2,2,5,7,8-pentamethyl-6-chromanylsulfonylazaglycyl) -  N-γ- (4-pyridinyl) -α, γ-diaminobutyric acid piperidide
• (R) -N-α- (5,6,7,8-tetrahydronaphthylsulfonylglycyl) - N-γ- (4-pyridinyl) -α, γ-diaminobutyric acid homopiperidide
• (R) -N-α- (5,6,7,8-tetrahydronaphthylsulfonylazaglycyl) - N-γ- (4-pyridinyl) -α, γ-diaminobutyric acid piperidide
• (R) -N-α- (2-naphthylsulfonyl- (S) -asparagyl) -N-γ- (4-pyridinyl) - α, γ-diaminobutyric acid piperidide
• (R) -N-α- (2-naphthylsulfonyl- (S) -asparagyl) -N-γ- (4-pyridinyl) - α, γ-diamino butyric acid homopiperidide
• (R) -N-α- (5,6,7,8-tetrahydronaphthylsulfonyl- (S) -asparagyl) - N-γ- (4-pyridinyl) -α, γ-diaminobutyric acid piperidide
• (R) -N-α- (2,2,5,7,8-pentamethyl-6-chromanylsulfonyl- (S) - asparagyl) -N-γ- (4-pyridinyl) -α, γ-diaminobutyric acid- piperidide
• (R) -N-α- (4-methoxy-2,3,6-trimethylphenylsulfonyl- (S) - asparagyl) -N-γ- (4-pyridinyl) -α, γ-diaminobutyric acid- piperidide
• (R) -N-α- (5,6,7,8-tetrahydronaphthylsulfonyl- (S) -asparagyl) - N-γ- (4-pyridinyl) -α, γ-diaminobutyric acid homopiperidide
• (R) -N-α- (2,2,5,7,8-pentamethyl-6-chromanylsulfonyl- (S) - asparagyl) -N-γ- (4-pyridinyl) -α, γ-diaminobutyric acid- homopiperidide
• (R) -N-α- (4-methoxy-2,3,6-trimethylphenylsulfonyl- (S) - asparagyl) -N-γ- (4-pyridinyl) -α, γ-diaminobutyric acid homopiperidide  
• (R) -N-α- (2-naphthylsulfonyl- (S) -glutamyl) -N-γ- (4-pyridinyl) - α, γ-diaminobutyric acid piperidide
• (R) -N-α- (2-naphthylsulfonyl- (S) -glutamyl) -N-γ- (4-pyridinyl) - α, γ-diaminobutyric acid homopiperidide
• (R) -N-α- (5,6,7,8-tetrahydronaphthylsulfonyl- (S) -glutamyl) - N-γ- (4-pyridinyl) -α, γ-diaminobutyric acid piperidide
• (R) -N-α- (2,2,5,7,8-pentamethyl-6-chromanylsulfonyl- (S) - glutamyl) -N-γ- (4-pyridinyl) -α, γ-diaminobutyric acid - piperidide
• (R) -N-α- (4-methoxy-2,3,6-trimethylphenylsulfonyl- (S) - glutamyl) -N-γ- (4-pyridinyl) -α, γ-diaminobutyric acid - piperidide
• (R) -N-α- (5,6,7,8-tetrahydronaphthylsulfonyl- (S) -glutamyl) - N-γ- (4-pyridinyl) -α, γ-diaminobutyric acid homopiperidide
• (R) -N -α- (2,2,5,7,8-pentamethyl-6-chromanylsulfonyl- (S) - glutamyl) -N-γ- (4-pyridinyl) -α, γ-diaminobutyric acid - homopiperidide
• (R) -N-α- (4-methoxy-2,3,6-trimethylphenylsulfonyl- (S) - glutamyl) -N-γ- (4-pyridinyl) -α, γ-diaminobutyric acid - homopiperidide
• (R, S) -N-α- (2-naphthylsulfonylglycyl) -N-β- (4-pyridinyl) -α, β-di aminopropionic acid homopiperidide
• (R, S) -N-α- (2-naphthylsulfonylglycyl) -N-β- (4-pyridinyl) -α, β-di aminopropionic acid 4-methylpiperidide  
• (R, S) -N-α- (2-naphthylsulfonylglycyl) -N-β- (4-pyridinyl) -α, β-di aminopropionic acid 2-carboxypiperidide
• (R, S) -N-α- (2-naphthylsulfonylglycyl) -N-β- (4-pyridinyl) -α, β-di aminopropionic acid 3-carboxypiperidide
• (R, S) -N-α- (2-Na phthylsulfonylglycyl) -N-β- (4-pyridinyl) -α, β-di aminopropionic acid 4-carboxypiperidide
• (R, S) -N-α- (2-naphthylsulfonylglycyl) N-β- (4-pyridinyl) -α, β-di aminopropionic acid 2-carboxypyrrolidide
• (R, S) -N-α- (5,6,7,8-tetrahydronaphthylsulfonylglycyl) -N-β- (4-pyridinyl) -α, β-diaminopropionic acid piperidide
• (R, S) -N-α- (5,6,7,8-tetrahydronaphthylsulfonylglycyl) -N-β- (4-pyridinyl) -α, β-diaminopropionic acid-4-methylpiperidide
• (R, S) -N-α- (5,6,7,8-tetrahydronaphthylsulfonylglycyl) -N-β- (4-pyridinyl) -α, β-diaminopropionic acid-2-carboxypiperidide
• (R) -N-α- (5,6,7,8-tetrahydronaphthylsulfonylglycyl) -N-β- (4-pyridinyl) -α, β-diaminopropionic acid-2-carboxypyrrolidide
• (R, S) -N-α- (2,2,5,7,8-P entamethyl-6-chromanylsulfonylglycyl) - N-β- (4-pyridinyl) -α, β-diaminopropionic acid piperidide
• (R, S) -N-α- (2,2,5,7,8-pentamethyl-6-chromanylsulfonylglycyl) - N-β- (4-pyridinyl) -α, β-diaminopropionic acid-4-methylpiperidide
• (R, S) -Nα- (2,2,5,7,8-pentamethyl-6-chromanylsulfonylglycyl) - N-β- (4-pyridinyl) -α, β-diaminopropionic acid-2-carboxypiperidide
• (R, S) -N-α- (2,2,5,7,8-pentamethyl-6-chromanylsulfonylglycyl) - N-β- (4-pyridinyl) -α, β-diaminopropionic acid-2-car boxypyrrolidide  
• (R, S) -N-α- (4-methoxy-2,3,6-trimethylphenylsulfonylglycyl) - N-β- (4-pyridinyl) -α, β-diaminopropionic acid piperidide
• (R, S) -N-α- (4-methoxy-2,3,6-trimethylphenylsulfonylglycyl) - N-β- (4-pyridinyl) -α, β-diaminopropionic acid-4-methylpiperidide
• (R, S) -N-α- (4-methoxy-2,3,6-trimethylphenylsulfonylglycyl) - N-β- (4-pyridinyl) -α, β-diaminopropionic acid-2-carboxypiperidide
• (R, S) -N-α- (4-methoxy-2,3,6-trimethylphenylsulfonylglycyl) - N-β- (4-pyridinyl) -α, β-diamine opropionic acid-2-carboxypyrrolidide

example 1 (R, S) -N-α- (2-naphthylsulfonylglycyl) -N-γ- (2,3,5,6-tetra chlorpyridin-4-yl) -α, γ-diaminobutyric acid piperidide 1. (R, S) -N-α- (2-naphthylsulfonylglycyl) -γ-phthalimido α-aminobutyric acid piperidide

A solution of 4.6 g (R, S) -4-β-phthalimidoethyloxazolidine 2,5-dione in 22 ml absolute. Dimethylformamide gets to -50 degrees Celsius cooled down. To do this, drop in the course with stirring 15 min a solution of 1.7 ml of piperidine and 2 ml of N-methyl morpholine in 22 ml absolute. Dimethylformamide. You stir 30 more min and then warms the reaction mixture for 30 min 60 degrees Celsius. The mixture is cooled to room temperature and dripped with further stirring, a solution of 4.5 g of 2-naphthyl sulfonylglycyl chloride in 20 ml absolute. Methylene chloride too. Man Stir for a further 2 hours at room temperature and then evaporate i.Vac. a. The residue is dissolved in methylene chloride and the solution washed with water. The methylene chloride phase is Dried over sodium sulfate and evaporated. The residue  is chromatographed on a silica gel column for purification (Eluent: acetone / toluene 1: 1). After evaporating the ent speaking column fractions, 4.5 g of the title are obtained compound as an amorphous substance.

2. (R, S) -N-α- (2-naphthylsulfonylglycyl) -α, γ-diamino butter acid piperidide

4.5 g (R, S) -N-α- (2-naphthylsulfonylglycyl) -γ-phthalimido-α- aminobutyric acid piperidide are dissolved in 30% ethanol. Man add 4 ml of 2M ethanolic hydrazine hydrate solution and stir the mixture overnight at room temperature. The reaction The mixture is acidified with 10 ml of 2N hydrochloric acid, warmed up briefly and the precipitate is filtered off. The filtrate is evaporated and the residue dissolved in water. The aqueous solution becomes mixed with a dilute soda solution and with methylene chloride extracted. The methylene chloride solution is over Dried sodium sulfate and evaporated. 2.5 g of are obtained Title compound as a yellowish, amorphous residue.

3. (R, S) -N-α- (2-naphthylsulfonylglycyl) -N-γ- (2,3,5,6-tetra chlorpyridin-4-yl) -α, γ-diaminobutyric acid piperidide

2 g (R, S) -N-α- (2-naphthylsulfonylglycyl) -α, γ-diamino butter acid piperidide are absolute in 20 ml. Dioxane dissolved. For this a solution of 1.4 is added while cooling with ice and with stirring g 4-nitro-2,3,5,6-tetrachloropyridine and 0.6 ml triethylamine in 10 ml absolute. Dioxane. The room is stirred for a further 3 hours temperature continues and then evaporates the reaction mixture i.Vak. a. The residue is purified on a silica gel column chromatographed. (Eluent: isohexane / ethyl acetate 1: 2). To Evaporation of the column fractions gives 1.1 g of crystals of Mp. 205 degrees Celsius. FAB-MS: M + H 648.  

Example 2 (R, S) -N-α- (2-naphthylsulfonylglycyl) -N-γ- (pvridin-4-yl) - α, γ-diaminobutyric acid piperidide

1 g (R, S) -N-α- (2-naphthylsulfonylglycyl) -N-γ- (2,3,5,6-tetra chlorpyridin-4-yl) -α, γ-diaminobutyric acid piperide are in 20 ml of methanol dissolved and after adding 5 ml of 1M sodium methylate solution in the presence of 100 mg pd / C (10%) catalyst hydrated. After taking the calculated amount of hydrogen is filtered off from the catalyst and evaporated. The back stand is chromatographed on a silica gel column. (Run medium: methylene chloride / methanol 8: 2). The column fractions are evaporated and the residue is triturated with ether. Man receives 350 mg of the title compound. Mp: 135 degrees Celsius. FAB-MS: M + H 510.

Example 3 (R, S) -N-α- (4-toluenesulfonylglycyl) -N-γ- (pyridin-4-yl) - α, γ-diaminobutyric acid piperidide

The illustration was carried out analogously to Examples 1 and 2, except that in Step 1 instead of 2-naphthylsulfonylglycyl chloride p-toluene sulfonyl-glycyl chloride was used. Mp the title connection: 160 degrees Celsius (dec.). FAB-MS: M + H 474.

Example 4 (R, S) -N-α- (2-naphthylsulfonyl) -N-γ- (pvridin-4-yl) -α, γ- diaminobutyric acid piperidide

The illustration was carried out analogously to Examples 1 and 2, except that in Step 1 instead of 2-naphthylsulfonylglycyl chloride 2-naphthylsulfonyl chloride was used. You got the Title compound as an amorphous substance. FAB-MS: M + H 453.

Example 5 (R, S) -N-α- (2-naphthylsulfonylglycyl) -N-δ- (2,3,5,6- tetrachloropyridin-4-yl) -α, δ-diaminovaleric acid piperidide 1. (R, S) -α-amino-δ-phthalimido-valeric acid

29.6 g of phthalic anhydride together with 23.4 g of 5-amino valeric acid heated to 190 degrees Celsius for 30 min. The after γ-phthalimido-valerian residue obtained after cooling acid is recrystallized from aqueous ethanol. Mp: 117 Centigrade. 47.3 g of this compound are mixed with 2 g of red Mixed phosphorus. This mixture is allowed to stir slowly add 20.7 g of bromine. After adding bromine heated to 100 degrees Celsius for 2 hours and then let down cool. The residue is mixed with 200 ml of ice water and the mixture was stirred for an hour. The mixture comes with Methylene chloride added, the water phase separated and ver throw. The methylene chloride phase is ge over sodium sulfate dries and evaporated. The crude α-bromo-γ-phthal obtained imido-valeric acid (53 g) is converted into 300 without further purification ml of dimethylformamide dissolved. 20.8 g are added to this solution Sodium azide and stir the mixture for 24 hours at room temperature temperature. Then the solution i.Vak. evaporated, the back was dissolved in ethyl acetate, the solution washed with water, Dried over sodium sulfate and evaporated. The received α-Azido-δ-phthalimido-valerian acid is made up in a mixture 240 ml glacial acetic acid and 30 ml conc. Hydrochloric acid dissolved and after Zu administration of 2 g of platinum oxide as a catalyst. After finishing  The uptake of hydrogen is suctioned off the catalyst and the filtrate evaporated. The residue is dissolved in 50 ml of water dissolved and the solution mixed with 12 ml of pyridine. The low blow is suctioned off, washed with water and dried. Man receives 25 g (R, S) -α-amino-δ-phthalimido-valerian acid. Mp: 230 degrees Celsius.

2. (R, S) -4- (γ-phthalimidopropyl) oxazolidine-2,5-dione

12 g of (R, 5) -α-amino-δ-phthalimido-valeric acid are in 100 mlabsol. Dioxane suspended. One leads into this suspension with stirring at 70 degrees Celsius until phosgene is reached clear solution has emerged. Allow to cool and suck the precipitation formed. Yield: 9.5g. Mp: 235 degrees Celsius (dec.)

3. (R, S) -N-α- (2-naphthylsulfonylglycyl) -N-δ-phthalimido α-aminovaleric acid piperidide

The presentation was analogous to step 1 in Example 1, except that instead of (R, S) -4- (β-phthalimidoethyl) oxazolidine-2,5-dione (R, S) -4- (γ-phthalimidopropyl) oxazolidine-2,5-dione used has been. The title compound was obtained as a white, amorphous Solid.

4. (R, S) -N-α- (2-naphthylsulfonylglycyl) -α, δ-diaminovalerian acid piperidide

The presentation was carried out analogously to stage 2 in Example 1 under Use of (R, S) -N-α- (2-naphthylsulfonylglycyl) -6-phthal imido-α-aminovaleric acid piperidide as the starting material. The title compound was obtained as an amorphous solid.

5. (R, S) -N-α- (2-naphthylsulfonylglycyl) -N-δ- (2,3,5,6- tetrachloropyridin-4-yl) -α, δ-diaminoyaleric acid piperidide

The presentation was carried out analogously to stage 3 in example 1 under Use of R, S-N-α- (2-naphthylsulfonylglycyl) -α, δ-di aminovaleric acid piperidide as starting material. Mp Title compound: 187 degrees Celsius (from methanol). FAB-MS: M + H 662.

Example 6 (R, S) -N-α- (2-naphthylsulfonylglycyl) -N-δ-pyridin-4-yl) - α, δ-diaminovaleric acid piperidide

The representation was carried out analogously to Example 2 using (R, S) -N-α- (2-naphthylsulfonylglycyl) -N-δ- (2,3,5,6-tetrachloropyridin-4-yl) -α, δ-diaminovaleric acid as Source material. The title compound was obtained as a white, amorphous solid. FAB-MS: M + H 524.

Example 7 (R, S) -N-α- (2-naphthylsulfonylglycyl) -N-β- (2,3,5,6-tetra chloro-pyridin-4-yl) -α, β-diaminopropionic acid piperidide 1. (R, S) -N-α, N-β-dibenzyloxycarbonyl-α, β-diaminopropionic acid

17.5 g (R, S) -α, β-diaminopropionic acid are in 170 ml of water suspended. By adding dilute sodium hydroxide solution pH adjusted to 9, the substance going into solution. A solution of 53.5 ml of chlorine is then added dropwise with stirring benzyl formate in 300 ml of toluene. By soon early addition of dilute sodium hydroxide solution will bring the pH up 9 held. After the addition of the chloroformic acid benzyl esters are stirred for a further 4 hours at room temperature and  The solution is then acidified to pH 1 with dilute hydrochloric acid. The precipitate is filtered off, washed with water and dried. Yield: 38.3 g mp: 122 degrees Celsius.

2. (R, S) -4- (benzyloxycarbonylaminomethyl) oxazolidine-2,5-dione

25 g (R, S) -N-α, N-β-dibenzyloxycarbonyl-α, β-diaminopropionic acid are absolute in 250 ml. Chloroform dissolved. To do this, give 20 ml of thionyl chloride and the mixture is heated to 50 for 1 hour Centigrade. Then it is evaporated to dryness, the back was taken up in 100 ml of ethyl acetate and 1 hour at the back river warmed. Half evaporate, give 250 ml of absolute. Hexane and allows to crystallize. The crystals are removed sucks, with absolute. Washed and dried hexane. Yield: 17.5 g. Mp: 128 degrees Celsius.

3. (R, S) -N-α- (2-naphthylsulfonylglycyl) -N-β-benzyloxy carbonyl-α, β-diaminopropionic acid piperidide

1.2 g (R, S) -4-benzyloxycarbonylaminomethyloxazolidine-2,5-dione are absolute in 10 ml. Dimethylformamide dissolved and at -50 degrees Celsius cooled down. One is added to this solution with stirring Solution of 0.45 ml piperidine and 0.5 ml N-methylpiperidine in 10 ml absolute. Methylene chloride. It is allowed to come to room temperature men, stir for another 30 min. further and then warms the reaction mix 30 minutes at 60 degrees Celsius. You cool down on the room temperature and drops while stirring a solution of 1.31 g 2-Naphthylsulfonyl-glycyl chloride in 10 ml methylene chloride. The mixture is stirred for a further 4 hours at room temperature, the is diluted Solution with 100 ml of methylene chloride and washes with water. The Methylene chloride phase is dried over sodium sulfate and evaporated. The residue is cleaned on a pebble gel column chromatographed. (Eluent: ethyl acetate / isohexane 1.5: 1). After evaporating the corresponding column fractions 1.45 g of a white solid are obtained. Mp: 148 degrees  Celsius.

4. (R, S) -N-α- (2-naphthylsulfonylglycyl) -α, β-diaminopropione acid piperidide hydrobromide

1.1 g (R, S) -N-α- (2-naphthylsulfonylglycyl) -N-β-benzyloxy carbonyl-α, β-diaminopropionic acid are in 4 ml of a 33% Solution of bromine water dissolved in glacial acetic acid. You stir another one Hour and then steams i.Vak. a. The backlog will triturated with ether, suction filtered and dried. 0.9 is obtained g of the title compound as a white, amorphous solid.

5. (R, S) -N-α- (2-naphthylsulfonylglycyl) -N-β- (2,3,5,6-tetra chloro-pyridin-4-yl) -α, β-diaminopropionic acid piperidide

0.6 g (R, S) -N-α- (2-naphthylsulfonyl) glycyl-α, β-diamino propionic acid piperidide hydrobromide are absolute in 5 ml. Dioxane dissolved. 0.4 g of 4-nitro-2,3,5,6-tetra are added chlorpyridine and 0.2 ml triethylamine and stir the mixture overnight at room temperature. Then it is evaporated and the Chromatograph the residue on a silica gel column. (Eluent: methylene chloride / methanol 97.5: 2.5). The one after Evaporation of the column fractions obtained from residue Recrystallized methanol. Yield: 350 mg, mp: 189 degrees Celsius. FAB-MS: M + H 634.

Example 8 (R, S) -N-α- (2-naphthylsulfonylglycyl) -N-β- (pyridin-4-yl) - α, β-diaminopropionic acid piperidide

300 mg (R, S) -N-α- (2-naphthylsulfonylglycyl) -N-β- (2,3,5, 6- chlor-pyridin-4-yl are dissolved in 15 ml of methanol and after Add 7 ml of 1 M sodium methylate solution and 200 mg Pd / C  (10%) - catalyst hydrogenated. After recording the calculated The amount of hydrogen is filtered off from the catalyst and that The filtrate was evaporated. The residue is on a silica gel column chromatographed. (Mobile solvent: methylene chloride / methanol 8: 2). The column fractions are evaporated and the back stood triturated with ether. 200 mg of the title ver binding as colorless crystals. Mp .: 95 degrees Celsius. FAB-MS: M + H 496.

Example 9 (R) -N-α- (2-naphthylsulfonylglycyl) -N-γ- (2,3,5,6-tetrachlor pyridin-4-yl) -α, γ-diaminobutyric acid piperidide 1. (R) -Z-glutamine piperidide

6 g (R) -Z-glutamine are dissolved in 60 ml absolute dioxane. 2.5 g of N-hydroxysuccinimide and 5 g of dicyclo are added hexyldicarbodiimide and then stirring the mixture 20 Hours at room temperature. The resulting precipitate is filtered off and discarded. The filtrate is mixed with 2.1 ml of piper idin and the mixture 24 hours at room temperature continued stirring. One sucks from a possibly created one Turbidity and the filtrate is concentrated. The arrears with Ethyl acetate triturated and the crystals suctioned off. You get 3.7 g (R) -Z-glutamine piperidide. Mp .: 95 degrees Celsius.

2. (R) -N-α-benzyloxycarbonyl-α, γ-diaminobutyric acid - piperidide

3.4 g of (R) -Z-glutamine piperidide are mixed in a mixture of 30 ml of acetonitrile and 30 ml of water dissolved. Add 6.5 g [Bis (trifluoroacetoxy) iodo] benzene and stir the mixture Night at room temperature. It is diluted with 200 ml of water,  acidifies to pH 1 with dilute hydrochloric acid and shakes with Ether off. The aqueous phase is cooled with 10 N Sodium hydroxide solution made alkaline and extracted with ethyl acetate. The ethyl acetate phase is dried over sodium sulfate and evaporated. 2.1 g of the title compound are obtained as amorphous Substance.

3. (R) -N-α-benzyloxycarbonyl-N-γ- (2,3,5,6-tetrachloro-pvridine 4-yl) -α, γ-diaminobutyric acid piperidide

1.9 g (R) -N-α-benzyloxycarbonyl-α, γ-diaminobutyric acid - piperidide are absolute in 20 ml. Dioxane dissolved. For this one gives 1.7g 4-nitro-2,3,5,6-tetrachloropyridine and stir the mixture 3 hours at room temperature. Then you dilute the Reaction mixture with 300 ml of water and extracted with Ethyl acetate. The ethyl acetate phase is over sodium sulfate dried and evaporated. The residue is for cleaning chromatographed on a silica gel column. (Solvent: Ethyl acetate / isohexane 3: 1). After evaporating the column fractions 1.9 g of the title compound are obtained as an oily substance.

4. (R) -N-γ- (2,3,5,6-tetrachloropyridin-4-yl) -α, γ-diamino butyric acid piperidide hydrobromide

950 mg (R) -N-α-benzyloxycarbonyl-N-γ- (2,3,5,6-tetrachlor pyridin-4-yl) -α, γ-diaminobutyric acid piperidide in 2 ml a 33% solution of hydrogen bromide in glacial acetic acid. The mixture is stirred overnight at room temperature and then i.Vak. evaporated. The residue is triturated with ether ben. 630 mg of the title compound with mp 180 are obtained Centigrade.

5. (R) -N-α- (2-naphthylsulfonylglycyl) -N-γ- (2,3,5,6-tetrachlor ridin-4-yl) -α, γ-diaminobutyric acid piperidide

325 mg (R) -N-γ- (2,3,5,6-tetrachloropyridin-4-yl) -α, γ-diamino butyric acid piperidide hydrobromide are absolute in 4 ml. Dissolved methylene chloride. To do this, add 0.2 ml of N-methyl morpholine and 200 mg of 2-naphthylsulfonylglycyl chloride. The Mixture is stirred for 2 hours at room temperature and then evaporated. The residue is on a silica gel column chromatographed. (Eluent: ethyl acetate / isohexane 2: 1). To Evaporation of the column fractions gives 220 mg of the title connection with the melting point 130 degrees Celsius. FAB-MS: M + H 648.

Example 10 (R) -N-α- (2-naphthylsulfonylglycyl) -N-γ- (pyridin-4-yl) -α, γ- diaminobutyric acid piperidide

140 mg (R) -N-α- (2-naphthylsulfonylglycyl) -N-γ- (2,3,5,6-tetrachloropyridin-4-yl) -α, γ-diaminobutyric acid piperidide are added in 5 ml Dissolved methanol and hydrogenated after adding 2 ml of 1M sodium methylate solution and 100 mg Pd / C (10%) - catalyst. After the calculated amount of hydrogen has been taken up, the catalyst is filtered off and evaporated. The residue is chromatographed on a silica gel column. (Eluent: methylene chloride / methanol 8: 2). The residue obtained after evaporating the column fractions is triturated with ether and suction filtered. 50 mg of the title compound are obtained with the slurry. 148 degrees Celsius. FAB-MS: M + H 510. [α] ^D = + 2.4 ° [ethanol].

Example 11 (S) -N-α- (2-naphthylsulfonylglycyl) -N-γ- (pyridin-4-yl) -α, γ- diaminobutyric acid piperidide

The title compound was prepared analogously to the reaction sequence described in Examples 9 and 10, except that (L) -Z-glutamine was used instead of (R) -Z-glutamine. Mp: 148 degrees Celsius. FAB-MS: M + H 510. [α] ^D = 2.4 ° [ethanol].

Example 12 (R) -N-α- (phenylsulfonylglycyl) -N-γ- (pyridin-4-yl) -α, γ-diamino butyric acid piperidide

The title compound was represented analogously to that in the Examples 9 and 10 described reaction sequence, only that in Level 5 instead of 2-naphthylsulfonylglycyl chloride phenyl sulfonylglycyl chloride was used. Mp: 130 degrees Celsius. FAB-MS: M + H 460.

Example 13 (R) -N-α- (4-methoxyphenylsulfonylglycyl) -N-γ- (pyridin-4-yl) - α, γ-diaminobutyric acid piperidide

The title compound was represented analogously to that in the Examples 9 and 10 described reaction sequence, only that in Step 5 instead of 2-naphthylsulfonylglycyl chloride 4- Methoxyphenylsulfonylglycylchlorid was used. Mp: 140 degrees Celsius. FAB-MS: M + H 490.

Example 14 (R) -N-α- (4-trifluoromethyl-phenylsulfonylglycyl) -N-γ- (pyridine- 4-yl-α, γ-diaminobutyric acid piperidide

The title compound was prepared analogously to the reaction sequence described in Examples 9 and 10, except that in step 5 4-trifluoromethylphenylsulfonylglycyl chloride was used instead of 2-naphthylsulfonylglycyl chloride. Mp: 180 degrees Celsius. FAB-MS: M + H 528. [α] ^D = + 10.7 °.

Example 15 (R) -N-α- (5,6,7,8-tetrahydronaphthalene-2-sulfonylglycyl) -N-γ- (pyridin-4-yl) -α, γ-diaminobutyric acid piperidide

The title compound was represented analogously to that in the Examples 9 and 10 described reaction sequence, only that in Step 5 instead of 2-naphthylsulfonylglycyl chloride 5, 6,7,8- Tetrahydronaphthalene-2-sulfonylglycyl chloride was used. Mp: 120 degrees Celsius. FAB-MS: M + H 514.

Example 16 (R) -N-α- (2-N-naphthylsulfonyl- (R) -alanvl) -N-γ- (pyridin-4-yl) - α, γ-diaminobutyric acid piperidide

The title compound was prepared analogously to the reaction sequence described in Examples 9 and 19, except that in step 5 2-naphthylsulfonyl- (R) -alanyl chloride was used instead of 2-naphthylsulfonylglycyl chloride. Mp: 195 degrees Celsius. FAB-MS: M + H 524. [α] ^D = + 77.6 °.

Example 17 (R) -N-α- (2-naphthylsulfonyl) - (S) -alanyl-N-γ- (pyridin-4-yl-  α, γ-diaminobutyric acid piperidide

The title compound was prepared analogously to the reaction sequence described in Examples 9 and 10, except that in step 5, 2-naphthylsulfonyl- (S) -alanyl chloride was used instead of 2-naphthylsulfonylglycyl chloride. Mp: amorphous substance. [α] ^D = -44.5 ° [ethanol. FAB-MS: M + H 524.

Example 18 (R) -N-α- (4-nitro-phenylsulfonyl) glycyl-N-γ- (pyridin-4-yl) - α, γ-diaminobutyric acid piperidide 1. (R) -N-γ- (pyridin-4-yl) -α, γ-diaminobutyric acid piperidide

960 mg (R) -N-γ- (2,3,5,6-tetrachloropyridin-4-yl) -α, γ-diamino Butyric acid piperidide hydrobromide in 30 ml of methanol dissolved and after adding 25 ml of 1 M sodium methylate solution and hydrogenated 200 mg Pd / C (10%). After recording the calculated The amount of hydrogen is filtered off from the catalyst and that The filtrate was evaporated. The residue is dissolved in water Solution by adding dilute sodium hydroxide solution to pH 10 put and extracted with methylene chloride. The methylene chloride phase is dried over sodium sulfate and turned on steams. 480 mg of the title compound are obtained as amorphous Residue.

2. (R) -N-α- (4-nitrophenylsulfonylglycyl) -N-γ- (pyridin-4-yl) - α, γ-diaminobutyric acid piperidide

220 mg N-γ- (pyridin-4-yl) -α, γ-diaminobutyric acid piperid who the absolute in 5 ml. Dimethylformamide dissolved. For this one gives 0.25 ml of N-methyl morpholine and 250 mg of 4-nitro-phenylsulfonyl glycyl chloride. The mixture is stirred for 2 hours at room temperature  temperature and then steams i.Vak. a. The residue becomes Purification chromatographed on a silica gel column. (Run medium: methylene chloride / methanol 8: 2). To. Evaporate the Column fractions are obtained as 180 mg of the title compound amorphous substance. FAB-MS: M + H 505.

Example 19 (R) -N-α- (3-nitrophenylsulfonylglycyl) -N-γ- (pyridin-4-yl) - α, γ-diaminobutyric acid piperidide

The title compound was presented analogously to stage 2 in Example 18, except that instead of 4-nitro-phenylsulfonyl glycyl chloride 3-nitro-phenylsulfonyl-glycyl chloride inserted was set. Amorphous substance. FAB-MS: 505.

Example 20 (R) -N-α- (4-chlorophenylsulfonylglycyl) -N-γ- (pyridin-4-yl) - α, γ-diaminobutyric acid piperidide

The title compound was presented analogously to stage 2 in Example 18, except that instead of 4-nitro-phenylsulfonyl Glycyl chloride 4-chloro-phenylsulfonyl-glycyl chloride used has been. Amorphous substance. FAB-MS: M + H 495.

Example 21 (R) -N-α- (cyclohexylsulfonylglycyl) -N-γ- (pyridin-4-yl) -α, γ- diaminobutyric acid piperidide

The title compound was represented analogously to that in the  reaction sequence described in Examples 9 and 10, only that in step 5 instead of 2-naphthylsulfonyl-glycyl chloride Cyclohexylsulfonyl chloride was used. Mp: 110 degrees Celcius. FAB-MS: M + H 466.

Example 22 (R) -N-α- (2-naphthylsulfonylglycyl) -N-γ- (pyridin-4-yl) - α, γ-diaminobutyric acid homopiperidide

The title compound was represented analogously to that in the Examples 9 and 10 described reaction sequence, only that homopiperidine was used instead of piperidine. Mp: 150 degrees Celsius. FAB-MS: M + H 524.

Example 23 (R) -N-α- (2-naphthylsulfonylglycyl) -N-γ- (pyridin-4-yl) - α, γ-diaminobutyric acid-4-methylpiperidide

The title compound was represented analogously to that in the Examples 9 and 10 described reaction sequence, only that 4-methylpiperidine was used instead of piperidine. Mp: 170 degrees Celsius. FAB-MS: M + H 524.

Example 24 (R) -N-α- (2-naphthylsulfonylglycyl) -N-γ- (pyridin-4-yl) - α, γ-diaminobutyric acid morpholide

The title compound was represented analogously to that in the Examples 9 and 10 described reaction sequence, only that morpholine was used instead of piperidine. Mp: 135 Centigrade. FAB-MS: M + H 512.  

Example 25 (R) -N-α- (2-naphthylsulfonylglycyl) -N-γ- (pyridin-4-yl) - α, γ-diaminobutyric acid- (S) -2-carbomethoxypyrrolidide

The title compound was represented analogously to that in the Examples 9 and 10 described reaction sequence, only that was used instead of piperidine (S) -proline methyl ester. Mp .: 92 degrees Celsius. FAB-MS: M + H 554.

Example 26 (R) -N-α- (2,2,5,7,8-pentamethyl-chroman-6-sulfonyl) -N-γ- (pyridin-4-yl) - α, γ-diaminobutyric acid piperidide

The title compound was represented analogously to that in the Examples 9 and 10 described reaction sequence, only that instead of 2-naphthylsulfonylglycyl chloride 2,2,5,7,8-Pcntamethyl-chroman-6-sulfonychloride was used. Mp: amorphous. FAB-MS: M + H 586.

Example 27 (R) -N-α- (4-methoxy-2,3,6-trimethylbenzenesulfonylglycyl) -N-γ- (pyridin-4-yl) - α, γ-diaminobutyric acid piperidide

The title compound was represented analogously to that in the Examples 9 and 10 described reaction sequence, only that instead of 2-naphthylsulfonylglycyl chloride 4-methoxy- 2,3,6-trimethylbenzenesulfonyl glycyl chloride was used. Mp: amorphous. FAB-MS: M + H 532.

Claims (6)

1. Compounds of formula I. in the
R _{1 is} an aryl, a heteroaryl or a cycloalkyl group, which can be substituted if desired,
AS an amino acid,
n the numbers 0 or 1,
R ₂ and R _{3 are the} same or different and form hydrogen atoms, alkyl, carboxyalkyl, or alkoxycarbonylalkyl groups or R ₂ and R ₃ together with the nitrogen atom to which they are attached form a heterocyclyl ring, which if desired also contains a second heteroatom contain and can be substituted by alkyl, carboxy or alkoxycarbonyl groups,
R ₄ and R _{5 are} identical or different and are hydrogen atoms or alkyl groups,
m the numbers 0, 1 or 2,
R ₆ , R ₇ , R ₈ and R _{9 are the} same or different and hydrogen atoms or halogen atoms
mean,
and their physiologically tolerable salts, hydrates, solvates and optical isomers. 2. Compounds of formula I according to claim 1,
in the
R ₁ phenyl, 4-methylphenyl, 4-chlorophenyl, 4-methoxyphenyl, 1-naphthyl, 2-naphthyl, 5,6,7,8-tetrahydro-2-naphthyl, 3-pyridinyl, 2-thienyl, cyclohexyl, 2, 2,5,7,8-pentamethyl chroman-6-yl or 4-methoxy-2,3,6-trimethyl phenyl,
AS means glycine, azaglycine or alanine, glutamine, glutamate, asparagine or aspartate,
n can be 0 or 1,
R ₂ and R _{3 are the} same or different and denote ethyl, ethoxycarbonylmethyl or carboxymethyl or together with the N atom to which they are attached form a pyrrolidine, piperidine, homopiperidine, morpholine, thiomorpholine or piperazine ring, optionally one or two methyl, ethyl, propyl, butyl, carboxyl, methoxycarbonyl, ethoxycarbonyl or tert. Can carry butyloxycarbonyl groups,
R ₄ and R _{5 are} identical or different and denote hydrogen atoms or methyl groups,
R ₆ , R ₇ , R ₈ , R _{9 are the} same or different and are hydrogen, fluorine or chlorine atoms. 3. Process for the preparation of compounds of formula I. in the
R _{1 is} an aryl, a heteroaryl or a cycloalkyl group, which can be substituted if desired,
AS an amino acid,
n the numbers 0 or 1,
R ₂ and R _{3 are the} same or different and form hydrogen atoms, alkyl, carboxyalkyl, or alkoxycarbonylalkyl groups or R ₂ and R ₃ together with the nitrogen atom to which they are attached form a heterocyclyl ring, which if desired also contains a second heteroatom contain and can be substituted by alkyl, carboxy or alkoxycarbonyl groups,
R ₄ and R _{5 are} identical or different and are hydrogen atoms or alkyl groups,
m the numbers 0, 1 or 2,
R ₆ , R ₇ , R ₈ and R _{9 are the} same or different and hydrogen atoms or halogen atoms
mean,
as well as their physiologically compatible salts, hydrates, solvates and optical isomers,
characterized in that in a manner known per se

• a) a compound of formula II in which R ₁ -R ₅ , AS, n and m have the meanings given above, with a compound of the general formula III, in which R ₆ -R _{9 are} halogen, causes reaction;
  or
• b) a compound of formula XI in the R ₂ -R ₉ and in the meanings given, with a compound of the general formula VIII implemented in which R _{1 has} the meaning given and X represents either a halogen atom or a radical of the general formula IX, in which Y is a halogen atom or an activated radical customary in peptide chemistry and A is a nitrogen atom or an atomic group of the general formula X mean, wherein R _{10 is} one of the usual amino acid side chain.

and then desired the compounds obtained if necessary in solvates, hydrates or physiologically ver inert salts and racemates converted into enantiomers splits. 4. Medicament containing a compound according to claim 1 or 2 in addition to the usual carriers and auxiliaries. 5. Use of compounds of formula I according to claim 1 or 2 for the manufacture of medicinal products for treatment of thromboembolic diseases.