LT3681B - N-acyl-alpha-amino acid derivatives, method for producting thereof,pharmaceutical compositions and preparing them - Google Patents

Abstract

N-Aroyl-α- amino carbonic acid formula of which is<IMAGE>where α, R'-R''' and Q meanings are indicated in description, derivatives may be used for treatment and prevention of diseases, caused by connection of adhesive proteins with thrombocyte as well as aggregation of thrombocytes and connection of cell-cells. These derivatives are obtained by splitting protective groups of certain compounds or changing a corresponding group of nitrile cyan by an amide group.

Description

The present invention relates to novel N-acyl-α-amino acid derivatives, processes for their preparation, pharmaceutical preparations containing such compounds and their use in the preparation of pharmaceutical preparations.

The present invention is primarily directed to N-acyl-α-amino acid derivatives of the general formula

R '»Κ»' n \ / o <-C-N ~ C-C-Q i u

H '0 where a is a formula

or

R 0 - NH (CH ₂ ) _t a ²

R is amidine or guanidine, one of X and Y being CH and the other being CH or N,

R ° is hydrogen or amidine, t is an integer from 2 to 6,

R ', R' 'and R' '' are hydrogen or conventional a-aminocarboxylic acid substituents or side chains, and the hydroxyl or carboxyl groups of R ', R' 'and R' '' may be etherified, esterified or substituted with an amide group, and the existing amino groups may be C 1 -C 8 alkanoylated or aroylated, a group of the formula

or

-N (V ') (CH ₂ ) _v

C (V '', V '') CH ₂ OCH ₂ COO-T or, if R 'and R''together with the N- and C-atom to which they are attached form a ring, may also be a group of formula

n is an integer equal to 0 or 1,

V is an integer from 0 to 3,

T and T 'are hydrogen or cleavable under physiological conditions lower alkyl or phenyl-lower alkyl, hydrogen or lower alkyl u and u' - hydrogen, C 1-8 alkanoyl or aroyl,

Ar - aryl and

R ² - R ⁵ - hydrogen, lower alkyl, lower alkoxy, halogen or -OCH ₂ COO-T 'or

R - R - together with the phenyl group to which they are attached form a 1-naphthyl group, as well as hydrates or solvates and their physiologically acceptable salts.

The claimed novel derivatives exhibit more potent activity compared to other compounds, for example EP-A-0381033, which can be considered as their structural analogs and are known as inhibitors of platelet binding.

In the present invention, Me is methyl, Ac - acetyl, tBu tert-butyl, Boc - tert-butoxycarbonyl, Z - benzyloxycarbonyl, Fmoc - 9-fluorenylmethoxycarbonyl, Val - α - valyl, Phe - α - phenylalanyl, Ser - a - seryl , Gly - glycyl, Ala-α-alanyl, Asp - α-aspartyl, Leu - α-leucyl, Tyr - α-tyrosyl, Sar sarcosyl, Orn - α-ornithyl, Lys - α-lysyl, Phg - L α-phenylglycyl , Pro - α - prolyl, Glu - α - glutamyl, Trp - α - tryptophan.

The term lower refers to groups having 1-6 conspicuous, preferably 1-4 C-atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, n-, secondary or tert-butyl and hexyl. Examples of lower alkyl groups that are recovered under physiological conditions include primary and secondary lower alkyl groups.

and

I I

Symbols R ', R' 'in residue - (R') C {R

R ' ¹ ' α-aminocarboxylic acid R ''') CO is hydrogen, either in open-chain α-aminocarbonic acids or in cyclic, natural or synthetic - conventional N-substituents or side chains. Examples of such N-substituents R 'and side chains R''andR''' are substituted probably by OH, COOH, NH ₂ or aryl, especially phenyl, hydroxyphenyl, hydroxyiodophenyl or hydroxydiododenyl, lower alkyl. The two thus substituted, if necessary, the lower alkyl groups R 'and R''together with the N- or C-atom to which they are attached may form a 4- to 6-membered ring, especially a 5-membered ring. Common N-substituents R 'and side-chains R &quot; and R''' by a hydroxy or carboxyl group may be esterified or eterifikuojamos or modulated by an amide group and amino group occurring may Ο ₃ _ ₆ alkanoilinamos or aroilinamos. Examples of such groups - ether, ester or amide - are OT °, -COO-T ° or -CON (V, V) where V and V have the meanings given above and T ° is lower alkyl, especially methyl, hexyl and tertiary. . butyl or aralkyl, especially benzyl.

Examples of open-chain α-aminocarbonic acids are: H-Gly-OH, H-Ala-OH, H-Orn-OH, and H-Tyr-OH; of cyclic α-aminocarbonic acids, e.g. examples of such acids wherein R 'and R' 'together with the N or C atom to which they are attached form a ring: H-Pro-OH, H-Pro (4OH) -OH and 2-piperidinecarboxylic acid.

Examples of C _1-6 alkanoyl groups u and u 'are formyl, acetyl and propionyl. Aryl is phenyl optionally substituted with up to 3 substituents such as alkyl, OH, lower alkoxy, halogen or halo-lower alkyl, especially CF ₃ . Aroyl is the corresponding benzoyl group.

The compounds of general formula I may be solvated, in particular hydrated. Hydration can be achieved at the time of preparation or this process is gradual due to the hygroscopic properties of Compound I which was previously anhydrous.

Examples of physiologically acceptable salts of the compounds of general formula I are those of physiologically acceptable mineral acids, such as salts or phosphoric acid; or salts of organic acids such as methanesulfonic acid, acetic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid. Compounds of general formula I having a free carboxy group may also form salts with physiologically acceptable bases. Examples of such salts are alkali metal, alkaline earth metal, ammonium and alkylammonium salts such as Na, K, Ca or tetramethylammonium salts. Compounds of general formula I may also exist in the form of amphoteric ions.

Compounds of general formula I having one or more asymmetric C atoms may exist as enantiomers, as diastereomers, or as mixtures thereof, for example as racemates.

In the formula, and are amidino, X - CH, Y or N and Q - Q ^x, Q ^2, Q ^4, Q ⁵ or Q ⁹ group.

CH

In the compounds, usually -N (R ') C (R' ') having the general formula I, where Q = Q, or methyl, and the residues: Gly,

Area,

Phe,

1, T - hydrogen R '' ') - CO - one of

D-Ala, Val, Leu, Sar, Orn, Lys, Phg-2-methyl-Pro,

Tyr, 3-Iodo-Tyr, 3,5-Diiodo-Tyr, Ser (Ac), Ser, Asp, Glu, Pro, 4-Benzyloxy-Pro, 4-Hydroxy-Pro, 2-Piperidylenecarbonyl, NHCH (CH ₂ CH) ₂ NH ₂ ) CO, Trp, Tyr (Me), Tyr (hexyl), Tyr (o-tBu), ON (Me) ₂ -Tyr and N (MeOCH ₂ CH ₂ ) Gly.

Most preferred compounds wherein Q = Q ² , Q ⁴ or Q ⁵ are compounds having n = 1, T = H; u and u '= H or Ac;

Ar = a, a, a-trifluoro-m-tolyl, and -N (R ') C (R' ', R' '') CO- =

Ala.

If QQ ⁹ , then R ² -R ⁵ are usually H, or R ² is carboxymethoxy or methoxycarbonylmethoxy, T = H or CH ₃ , and -N (R ') C (R'',R''') CO- = Pro .

Examples of preferred compounds are:

// 1- N - (p-amidinobenzoyl) -L-alanyl / -4-piperidinyl / oxy / acetic acid, 1- (N - (5-amidino-2-pyridyl) carbonyl) -L-alanyl 4-piperidinyl-oxy-acetic acid, N-N- (p-amidinobenzoyl) -3- (4-hydroxy-3-iodophenyl) -Lalanyl, -4-piperidinyl / oxy / acetic acid, // 1- [3-Acetoxy-N- (p-amidinobenzoyl) -L-alanyl] -4-piperidinyl] -oxy-acetic acid, p- // 1- (p-amidinobenzoyl) -2-pyrrolidinyl / carbonyl / phenoxy / acetic acid, // 1- / N- (5-amidino-2-pyridyl) carbonyl / -L-tyrosyl / -4-piperidinyl / oxy / acetic acid and especially // l- / n- (p -amidinobenzoyl) -L-tyrosyl / -4-piperidinyl / oxy / acetic acid.

Other suitable compounds of the general formula I are those wherein Q represents a group Q, in particular where n = O and T is hydrogen, or a group Q ⁷ , in particular where T is a wang denyl, and also compounds wherein Q represents Q, especially where V = 1, T is hydrogen or butyl and V'-V '''is hydrogen.

Examples of such compounds are:

(S) -1- / 2- (5-amidinopyridin-2-ylcarbonylamino) -3- (4-methoxyphenylpropionyl / piperidin-4-yloxyacetic acid, (S) -1- / 2- (4-amidinobenzamide) -3- (4-Methoxyphenyl) propionyl] -piperidin-4-yloxyacetic acid ethyl ester, (S) -1- [2- (4-amidinobenzamide) -3- (4-methoxyphenyl) propionyl] -piperidin-4-yloxyacetic acid, / 1- N - (4-amidinobenzoyl) -4'-hexyloxy-α-phenylalanyl / piperidin-4-yloxyacetic acid.

The above N-acyl-α-amino acids according to the present invention can be obtained:

a) In a compound of the general formula "E"

II where a ° is the formula group 'X = Y y'

or oi (CH ₂ ) _t where A is a protected amidine or guanidine group, optionally an amine or guanidine group, E ', E'',E' ¹ 'and G having the same meaning as oi

R ', R' ', R' '' or Q in formula I, in addition, if R is an amine or guanidine, or if A is an amidine or guanidine, at least one of E ', E' ', E' '' and G has at least one carboxylic acid ester group and / or an ether group and / or a protected amino group by cleavage of an ether group or a protected amino, amidine or guanidine group or a carboxylic acid ester, or

(b) nitrile of general formula

l //

R 'o

By replacement of cyano group III with an amidine group, or

(c) an amine of the general formula

R '- NHC (R' ', R' '') CO - Q

IV is treated with an acid of the general formula C 1 -COOH or its reactive derivatives, and

(d) where appropriate, a compound of general formula I replaces a reactive functional group; and

e) where appropriate, converting the compound of the general formula I into a physiologically acceptable salt or the salt of the compound of the general formula I into the free acid or base.

Examples of the cleavage groups of the carboxylic acid ester are benzyl-OCO- and lower alkyl-OCO, such as t-Bu-OCO-. Examples of protected amino, amidine, and guanidine groups are: -NH-Z, -NH-Boc and N ₃ ; -C (NH) NH-Z, -C (NH) H-Boc, C (N-Boc) N (Boc) _2, and -C (N-Boc) NH-Boc; -NHC (NH) NHNO ₂ and -NHC (N-Boc) NH-Boc. An example of a spaced ether group is tBu-O-.

The ester groups may be hydrolyzed in a known manner, for example using bases such as an alkali metal hydroxide such as sodium hydroxide dissolved in a solvent such as methanol or water; or using an acid such as hydrochloric acid. The benzyl ester can be cleaved by hydrogenation in the presence of a noble metal catalyst such as palladium on activated carbon (Pd / C) in a solvent such as methanol, ethanol, formic or acetic acid at about 40 ° C, preferably at room temperature. At the same time, a protecting group such as Z is cleaved in A.

Ester groups such as tBu-OCO, as well as protecting amino ara amidine groups such as Boc, and ester groups such as tBu-galima- may be cleaved using acids such as formic acid or trifluoroacetic acid; it can be in a solvent such as dichloromethane or with saturated HCl acetic acid at temperatures up to 40 ° C, preferably at room temperature.

n

Variant b) may be carried out as follows: Nitrile III is converted to thioamide with hydrogen sulfide and triethylamine dissolved in pyridine, which is then methylated with methyl iodide dissolved in acetone, followed by ammonolysis with ammonium acetate in methanol to give compound I.

The combination c) - that is, with an amino IV a ¹ -COOH acid or a reactive derivative thereof such as anhydrochloric acid - is obtained in the presence of a base such as picoline in a solvent such as dichloromethane at a temperature up to 40 ° C, preferably at room temperature.

As functional modifications of reactive groups according to embodiment d) examples include lower alkoxycarbonyl -COO-T or -COO-T 'groups present in group Q, cleaving or C _x _ ₆ alkanoyloxy or aryloxycarbonyl, aroyloxy or Qu Qu' cleaving or acid I esterification of the carboxy group; and halogenation of the aryl group in the side chain R '' or R ''', in particular iodination.

The butoxycarbonyl or methoxycarbonyl groups in Q may be hydrolyzed with an acid such as aqueous saline or acetic acid, or in an alkaline medium such as aqueous sodium hydroxide solution in methanol; acetoxy groups - potassium carbonate in methanol. Esterification of the carboxy group is effected, for example, by reaction of an acid with the corresponding alcohol in the presence of a catalytic amount of H ₂ SO ₄ .

The iodination of the aryl group, especially the hydroxyphenyl group in the side chain R '' or R '' ', may be carried out by reacting compound I with chloramine T in the presence of sodium iodide dissolved in water / dimethylformamide.

Amine 1, where L is a group H ₂ N (CH ₂ ), is converted to the corresponding guanidine 1, where a is -HN = C (NH ₂ ) NH (CH ₂ ) _t , and the amine is reacted with 2-S-isothiourea ethanesulfonate in the presence of a base such as Na ₂ CO ₃ or NaOH at temperatures up to 40 ° C.

The compounds of the general formulas II and III are novel and are also the object of the present invention.

Compound II wherein a ° is an aryl group a ^o1 obtained by reaction of an amine of formula

E'-NHC (E '', E ''')CO-G' V where G 'is one of the groups ζ ^ -ζ) ⁹ , wherein -COO-T and optionally -COO-T is present. exists as ester groups of a carbonic acid, with an acid of formula

GOOH vi or with its reactive derivatives such as acid chloro anhydride.

This reaction may be carried out, if necessary, by the addition of tetra-n-butylammoniohydrogensulphate in a solvent such as dichloromethane and a base such as an aqueous solution of sodium bicarbonate.

The amine HQ °, where Q ° is one of the amino groups (- (-)) ⁸ , in which the -COO-T group and, if necessary, the available -COO-T 'group exist as carbonic acid ester groups, can react with an acid which formula

N ~ Q

O

R 'R' \ /

K - G - C - OH

II

R '0

VII to Nitrile III.

This reaction can be carried out in the presence of 2- (1H-benzotriazol-1-yl) -1,1,3,3, -tetramethyluronium-hexafluorophosphate (HBTU) and an organic base such as N-methylmorpholine in a solvent such as dimethylformamide.

Compound II, where A is an amidine, can be obtained from the corresponding nitrile of compound II by replacing its cyano group with an amidine group. The nitrile can be obtained by reacting an amine of general formula V with an acid of formula

N = fC

COOK

VIII or its functional derivatives such as acid chloro anhydride.

This reaction may take place in the presence of 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) and a base such as N-methylmorpholine dissolved in a solvent such as dichloromethane.

Compound II, wherein a ° - a a ² with a protected amino or guanidine group R ⁰¹ is obtained by reacting amine V with an acid of formula R ⁰¹ - (CH ₂ ) _t - COOH, for example in the presence of HBTU and N-methylmorpholine.

Nitrile III, where Q is a group Q ⁹ , can be obtained, for example, as follows:

Amine of general formula

wherein R 'and R''together with the N and C atoms form a ring and W ³ is a protecting group, reacts with acid VIII or its functional derivatives, cleaves the protecting group and treats the resulting phenol with bromoacetic acid derivatives BrCH ₂ COO-T.

The reaction of the amine IX with the corresponding acid VIII chloro anhydride can be carried out in the presence of a base such as triethylamine in dimethylformamide. Protecting groups ii ¹ such as benzyl can be cleaved by hydrogenation on Pd / C in ethanol, and the reaction of the above phenol with bromoacetic acid derivatives can be carried out in dimethylformamide in the presence of potassium carbonate.

Amines IV and V can be obtained, for example, by reacting a protected amino acid of formula (E ') C (E'',E''') COOH with an amine HQ ° and removing the protecting group W ^{2 in the} reaction product, e.g. or Boc.

Acid VII can be obtained by reacting a functional derivative of acid VIII, such as acid chloro anhydride, with an amine.

R '- NHC (R' ', R' '') COO-lower alkyl X 'followed by cleavage of the ester group of the reaction product. This reaction may take place, for example, in the presence of triethylamine in dichloromethane. A lower alkyl group such as methyl can be removed by aqueous LiOH in methanol.

So is the amino acid, which has the general formula

For example, R '- NHC (R' ', R' '') COOH X '', for example, glycine may be reacted with the corresponding acid VIII chloro anhydride to acid VII in the presence of aqueous sodium bicarbonate solution, if necessary with tetramethylammonium sulfate in dichloromethane.

Amine IX can be obtained by reacting a Grignard reagent made from bromide of formula

XI with a compound of the formula

w ² - K - C - CO - K

OCH and removing the protecting amino group of the reaction product

The amines used are HQ °, where Q ° is one of the amino groups

8th

Q-Q, where the -COO-T group and optionally the available -COO-T 'group exist as carboxylic acid ester groups can be obtained as described in the following examples: 1 a) b) c), 2a), 46a) b), 47a) and 48a) b).

Compounds of general formula I, their solvates and their salts inhibit not only the binding of fibrinogen, fibrinectin and Villebrand factor to the platelet fibrinogen receptor (glycoprotein Ilb / IIIa), but also to these and other adhesive proteins such as vitronectin, collagen and laminin. with the appropriate receptors on the surface of various cell types. Thus, said compounds affect the cell-to-cell and cell-matrix interactions. In particular, they inhibit platelet formation and can be used to prevent or fight diseases such as thrombosis, cerebral haemorrhage, myocardial infarction, inflammation and arteriosclerosis. In addition, these compounds have an effect on tumor cells, e.g. stops the formation of metastases. In this way, they can also be used as anticancer agents. These compounds accelerate wound healing. They can be used to treat osteoporosis as they inhibit bone tissue resorption.

The inhibition of fibrinogen binding to the fibrinogen receptor glycoprotein Ilb / IIIa can be determined as follows:

Glycoprotein Ilb / IIIa is obtained from Triton-X-100 extracts from human blood plaques and purified by lectin affinity chromatography (Analytical Biochemistry 151, 169-177, 1985) and chromatography on an Arg-Gly-Asp-Ser column (Science 231,

1986, 1559-62). The receptor protein thus obtained is bound to microtiter plates. Specific binding of fibrinogen to the immobilized receptor is determined using the EhISA system (EnzymeLinked immunosorbent assay). The IC ₅₀ values given below correspond to the concentration of test substance required to stop the binding of fibrinogen to the immobilized receptor by 50%:

For example product 1 3 4 5 6th 7th 8th 9th IC ₅₀ (mM) 0, 01 0.0017 0.14 0, 001 0.027 0.033 0.008 0.08 For example product 10th 13th 14th 15th 16th 18th 21st 22nd IC ₅₀ (mM) 0.017 0.001 0.018 0.053 0.002 0.0017 0.16 0.47

For example

product 24th 27th 30th 37 39 40 41 IC ₅₀ (ohms) 0, 026 0.008 0.015 0.0003 0.0008 0.05 0.0007

Sample product

44

IC ₅₀ (μΜ) 0.007 0.0016 0, 01

These compounds exhibit low toxicity, but the product of Examples 3 and 14 has an LD ₅₀ of 250 and the product of Example 5 has 500 mg / kg given intravenously to mice.

As mentioned above, the medicaments comprising the compound I, its solvates or its salts are also the subject of the present invention, as well as a process for the preparation of similar medicaments, characterized in that one or more of the said compounds and where appropriate, one or more other therapeutically valuable materials are processed into galenic form. The medicaments may be administered by the enteric route, for example, in the form of tablets orally, in the form of tablets with a lacquer surface, in the form of dragees, capsules in hard and soft gelatine, solutions, emulsions or suspensions, or rectally, e.g. or using nozzles. However, it can also be used parenterally, for example, as solutions for injection or infusion.

To obtain tablets, lacquer tablets, dragees, and capsules in hard gelatine, the active ingredient may be mixed with pharmaceutically inert, inorganic or organic excipients. Such excipients for tablets, dragees and capsules in solid gelatin may be, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts. Soft gelatine fillers include, for example, vegetable oils, waxes, fats, semi-solid and liquid polyatomic alcohols, but depending on the properties of the active ingredient, soft gelatine fillers are completely unnecessary. Fillers used in the manufacture of solutions and syrups are, for example, water, polyhydric alcohols, sucrose, invert sugar and glucose; solutions for injection use, for example, water, alcohols, polyhydric alcohols, glycerol and vegetable oils, and suppository fillers use natural or hardened oils, waxes, fats and semi-solid or liquid polyhydric alcohols. In addition to these excipients, the pharmaceutical preparations may further comprise preservatives, solubilizers, stabilizers, wolfgangs, emulsifiers, sweeteners, dyes, aromatics, salts for osmotic pressure change, buffers, coatings or antioxidants.

In the fight against the aforementioned diseases, the active substances can change over a wide range and, of course, must be adapted to the individual conditions in each individual case. In the case of oral administration, the dose range should be approximately 0.1 to 20 mg / kg, preferably approximately 0.5 to 4 mg / kg / day in adults, but the upper limit may be exceeded if it is determined that it is expedient to do so.

EXAMPLE

A solution of 2.43 g of N- (N- (p-amidinobenzoyl) glycyl / -4-piperidinyl / oxyacetic acid tert-butyl ester and 15 ml of dichloromethane / trifluoroacetic acid (1: 1) is kept for 5 hours. at room temperature. Evaporation of the solvents and chromatography (Silylated silica gel LiChroprep RP-18, methanol-water gradient) gives 0.46 g of N- (N-p-amidinobenzoyl) glycyl / -4-piperidinyl / oxy / acetic acid trifluoroacetate, m.p. 233-236 ° C. MS (PAB): 363 (M + H) &lt; ^{+ &gt};.

The starting material can be obtained as follows:

(a) To a solution of 50 g of 4-hydroxypiperidine in 500 ml of dichloromethane are added successively, at 0 ° C, 69.1 ml of triethylamine and 70.2 ml of chloroformate benzyl ester. The resulting suspension is stirred overnight at room temperature and then filtered. The residue obtained after concentration of the filtrate is dissolved in ethyl acetate, washed with aqueous and 1N hydrochloric acid, dried and concentrated. Yielding 73.6 g Nbenziloksikarbonil-4-hydroxypiperidine, R _f = 0.56 (ethyl acetate / methanol 9: 1). MS (EI): 235 (M &lt; ^{+ &} gt ^; ).

(b) To a solution of 30.1 g of N-benzyloxycarbonyl-4-hydroxypiperidine in 300 ml of toluene are added 28 ml of bromoacetic acid tert-butyl ester and

1.4 g of tetra-n-butylammoniohydrosulfate dissolved in 10 ml of water. Thereafter, a solution of 125 g of sodium hydroxide solution in 125 ml of water is added dropwise. After stirring overnight, the organic extracts are separated, dried and concentrated. Dried, yielding 34.1 g of N-benzyloxycarbonyl-4 - / (t-butoxycarbonyl) methoxy / piperidino, R _f = 0.76 (ethyl acetate).

MS (EI): 293 (MC ₄ H ₈ ) ⁺ .

c) To a solution of 30 g of product b) in 50 ml of ethanol is added 1.5 g of Pd / C (10%). The reaction mixture is hydrogenated at room temperature. The catalyst is then filtered off, washed with ethanol and the filtrate is concentrated. Yielding 17.4 g of 4-piperidiniloksiacto acid tert-butyl ester R _f = 0.14 (ethyl acetate / methanol 1: 1). MS (EI): 125 (M &lt; ^{+ &} gt ^; ).

d) Reaction of 5.8 g (with 5.4 g of activated CDMT) of Z-glycine with 6.0 g of 4-piperidinyloxyacetic acid tert-butyl ester and 6.3 ml of N-methylmorpholine dissolved in dichloromethane gives 10 g of benzyl- /// 4- (t-Butoxycarbonyl) methoxy / piperidinyl / carbonyl / methyl / carbamate. MS (EI): 406 (M &lt; ^{+ &} gt ^; ).

(e) Hydrogenolysis of 10 g of product d) in 200 ml of ethanol in the presence of 0.7 g of Pd / C (10%) and 1.4 ml of acetic acid yields 4 by chromatography on silica gel (ethyl acetate / methanol 1: 1). 1 g of 1- (1-glycyl-4-piperidinyl) oxy / acetic acid tert-butyl ester. MS (EI): 273 (M + H) &lt; ^{+ &gt};. IR: 1746 cm ^-1 .

(f) To a mixture of 4.1 g of product (e) and 0.03 g of tetra-n-butylammonium hydrosulphate in 210 ml of a dichloromethane / sodium bicarbonate saturated solution (4: 3) are added 2.95 g of p-amidinobenzoyl at room temperature. chloride hydrochloride (obtained from p-amidinobenzoic acid by reaction with thionyl chloride in tetrahydrofuran in the presence of dimethylformamide). Stir overnight, then dilute with dichloromethane and water. By adding

N sodium hydroxide, adjusts the pH to 9-10, separates, dries and concentrates the organic extracts. Upon drying, 2.43 g of the desired starting material are obtained. MS (FAB): 419 (M + H) ^{@ +} .

EXAMPLE

A). A solution of 1.5 g of N- (N- (p-cyanobenzoyl) -glycyl / -4-piperidinyl / oxy / acetic acid methyl ester dissolved in 215 ml of pyridine / triethylamine (40: 3), saturated with sulfuric hydrogen and kept at room temperature for 24 hours. After removal of the solvent, the residue is dissolved in ethyl acetate and washed with saturated sodium chloride solution. The organic extracts are dried and concentrated. The residue is then purified by silica gel chromatography (carrier: ethyl acetate, then ethyl acetate / methanol) to give 1.34 g of N, N-p- (thiocarbamoyl) benzoyl / glycyl / -4-piperidinyl / oxide. / acetic acid methyl ester. MS (FAB): 394 (M + H) &lt; ^{+ &gt};.

B). Reaction with 1.25 g of the product of the previous step with

7.5 ml of methyl iodide in 150 ml of the acetone reaction mixture, after filtration and removal of the solvent, gives 1.65 g of N- (N- / p- / l- (tethylthio) formimidoyl / benzoyl / glycyl / -4-piperidinyl / oxy / acetic acid methyl ester hydroiodide. MS (FAB): 408 (M + H) &lt; ^{+ &gt};.

C). Ammonolization of 1.5 g of product B) with 0.32 g of ammonium acetate gives 100 ml of methanolic reaction mixture at reflux, yielding 0.76 g of N- (p-amidinobenzoyl) glycyl / -4-piperidinyl-oxy. / acetic acid methyl ester hydroiodide. Melting point 103105 ° C. MS (FAB): 377 (M + H) &lt; ^{+ &gt};.

The starting nitrile can be obtained as follows:

a). Esterification of 4-piperidinyloxyacetic acid trifluoroacetate (obtained by treating the product of Example 1c with trifluoroacetic acid in dichloromethane) in methanol in the presence of thionyl chloride affords 4-piperidinyloxyacetic acid methyl ester hydrochloride. MS (EI): 173 (M) &lt; ^{+ &gt};.

b). Reaction of 1.35 g of product (a) with 1.18 g of N- (cyanobenzoyl) glycine (obtained by treatment of glycine with p-cyanobenzoyl chloride-saturated sodium bicarbonate solution) in the presence of HBTU and N-methylmorpholine in dimethylformamide by silica gel chromatography (ethyl acetate / methanol). 9: 1 to 1: 1) yields 1.66 g of the desired starting nitrile. MS (EI): 359 (M) &lt; ^{+ &gt};.

EXAMPLE

From 13 g of N- (N- (p-amidinobenzoyl) -L-alanyl / -4-piperidinyl / oxy / acetic acid tert-butyl ester, it was recrystallized from trifluoroacetic acid in dichloromethane (as described in Example 1). of methanol / diethyl ether gives 8.9 g of N- (N- / p-amidinobenyl) -L-alanyl / -4-piperidinyl / oxy / acetic acid trifluoroacetate. Melting point 120 ° C (decomposes). MS (FAB): 377 (M + H) &lt; ^{+ &gt};. / a / p ²⁰ = + 24.7 ° C (c = 0.7, water).

The starting material can be obtained as follows:

a) Reaction of 18 g of ZL-alanyl with 17.4 g of 4-piperidinyloxyacetic acid tert-butyl ester followed by hydrogenolysis of the product as in Example 1 d) and e) yields 15.8 g of 1 - / (II L-alanyl) -4-piperidinyl) oxyacetic acid tert-butyl ester acetate. Melting point 93-96 ° C. / α / ^ ² θ = + 2.0 ° (c = 1.0, methanol).

b) Reaction of 4.7 g of product a) with 3.4 g of p-amidinobenzoyl chloride hydrochloride as in Example 1 f) yields 4.2 g of the desired starting material. MS (EI): 433 (M + H) &lt; ^{+ &gt};.

EXAMPLE

0.3 g of tert-butyl ester of N- (N- / p- / N- (t-butoxycarbonyl) amidinobenzoyl) -D-alanyl / -4-piperidinyl / oxy / acetic acid are obtained analogously to Example 1. 0.1 g of N- (N- (p-amidinobenzoyl) -D-alanyl / -4-piperidinyl / oxyacetic acid trifluoroacetate. Melting point 115 ° C (dec.). / a / ^ ² ^ = 27.5 ° (c = 0.8, water). MS (FAB): 377 (M + H) &lt; ^{+ &gt};.

The starting material can be obtained as follows:

a) Reaction of 3 g of 4-piperidinyloxyacetic acid tert-butyl ester with 2.43 g of ZD-alanyl as described in Example 1 d) on silica gel chromatography (carrier: ethyl acetate / hexane 1: 1) gives 3.1 g of benzyl. - (R) -1 - [4- (t-butoxycarbonyl) methoxy / piperidinyl / carbonyl / ethyl / carbamate. MS (EI): 420 (M) &lt; ^{+ &gt};.

b) Hydrogenolysis of 3.1 g of product a) as described in Example le) gives 2.5 g of 1- (1D-alanyl-4-piperidinyl) oxy / acetic acid tert-butyl ester acetate. MS (EI): 215 (MC ₃ H ₅ NO).

c) Reaction of 1 g of the product from the preceding step with 0.66 g of amidinobenzoyl chloride hydrochloride dimethylformamide in the presence of triethylamine and subsequent treatment with di-t-butyl dicarbonate on silica gel (carrier: dichloromethane / methanol 20: 1) affords 0.3 g of the desired product. starting materials. MS (FAB): 533 (M + H) &lt; ^{+ &gt};.

EXAMPLE

Hydrolysis on 1.6 g of [1- (N - [(5-amidino-2-pyridyl) carbonyl] -L-alanyl) -4-piperidinyloxyacetic acid tert-butyl ester saturated with hydrogen chloride in glacial acetic acid, chromatography on silica gel containing silica gel RP-18 followed by recrystallization from tetrahydrofuran / ethyl acetate yields 0.15 g of N, N- (5-amidino-2-pyridyl) carbonyl / -L-alanyl / -4-piperidinyl / oxyacetic acid. Melting point: above 200 ° C (dec.)> MS (FAB): 378 (M + H) ⁺ .

The starting material can be obtained as follows:

a) Reaction of 2.4 g of 1- (L-alanyl-4-piperidinyl) oxy / acetic acid tert-butyl ester acetate (Example 3a) with 1.0 g of 5-cyano-2-picolinic acid according to Example 1d) yields 2.43 g of N- (N - [(5-cyano-2-pyridyl) carbonyl] -L-alanyl / -4-piperidinyl) -oxy-acetic acid tert-butyl ester. MS (FAB): 417 (M + H) &lt; ^{+ &gt};.

b) Further treatment of the previous step with 2.4 g of product as described in Examples 2 A) B) C) gives 2 g of the desired starting material. Melting point 142-145 ° C. MS (FAB): 434 (M + H) &lt; ^{+ &gt};.

EXAMPLE

Recrystallization from 1 g of N- (N- (p-amidinobenz-oil) -L-valyl / -4-piperidinyl / oxy / acetic acid tert-butyl ester, analogous to Example 1, affords 0. , 8 g of N- (N- (p-amidinobenzoyl) -L-valyl / 4-piperidinyl / oxy / acetic acid trifluoroacetate. Melting point 210-211 ° C. MS (FAB): 405 (M + H) ^{@ +} . = + 32.6 ° (c = 0.8, water).

The starting material can be obtained as follows:

a) Reaction of 2.5 g of ZL-valine with 2 g of 4-piperidinyloxy-acetic acid tert-butyl ester as described in Example 2b) gives 4 g of 1- (N - [(benzyloxy) carbonyl] -L-). valyl / -4-piperidinyl / -oxy / acetic acid tert-butyl ester. MS (EI): 449 (M + H) &lt; ^{+ &gt};.

b) In analogy to Example le, but without the addition of acetic acid, 1.9 g of the product of Example 6a) is obtained in the form of 1.4 g of l- (L-valyl-4-piperidinyl) oxy / acetic acid tert-butyl. Ester MS (EI): 315 (M + H) &lt; ^{+ &gt};.

c) By analogy to Example 1f), 3.3 g of the product of Example 6b) and 2.5 g of p-amidinobenzoyl chloride hydrochloride (silica gel; dichloromethane / methanol / acetic acid 95: 4: 1) and recrystallization from diethyl ether gives 1.1 g of the desired starting acetate. Melting point 179-182 ° C. MS (FAB): 461 (M + H) ^{@ +} .

EXAMPLE

From 1.5 g of N- (N- (p-amidinobenzoyl) -L-leucyl / -4-piperidinyl / oxy / acetic acid tert-butyl ester acetate, analogous to Example 1, recrystallized from ethyl acetate / diethyl ether. 1.1 g of N- (N- (p-amidinobenzoyl) -L-leucyl / -4-piperidinyl) -oxy-acetic acid trifluoroacetate are obtained. Melting point 216-218 ° C. MS (FAB): 419 (M + H) ^{@ +} . / a / p ²⁰ = + 22.5 ° (c = 0.8, water).

The starting acetate can be obtained as follows:

a) Reaction of 2.6 g of ZL-leucine with 2 g of tert-butyl ester of 4-piperidinyloxyacetic acid as described in Example 1 d) yields 4.1 g of N- (N-benzyloxycarbonyl) -L. -leucyl / -4-piperidinyl / oxy / acetic acid tert-butyl ester. MS (FAB): 463 (M-H) -.

b) By analogy to Examples 6b) and 1f), 4.1 g of product from Example 7a) are chromatographed (silica gel; dichloromethane / methanol / acetic acid 95: 4: 1) and recrystallized from diethyl ether to give 1.5 g. of the desired acetate. Melting point 120-129 ° C (decomposes). MS (FAB): 475 (M + H) &lt; ^{+ &gt};.

EXAMPLE

1.4 g of N- (p-amidino-N-methylbenzamide) acetyl-4-piperidinyl / oxyacetic acid tert-butyl ester acetate are obtained in the same manner as in Example 1, after recrystallization from diethyl ether, to give 0.9 g of the title compound. N - [(p-amidino-N-methylbenzamide) acetyl] -4-piperidinyl] -oxy-acetic acid trifluoroacetate. Melting point 134-135 ° C. MS (FAB): 377 (M + H) &lt; ^{+ &gt};.

The source material can be obtained as follows:

a) Reaction of 2.0 g of Z-sarcosine-N-hydroxysuccinimide ether with 1.3 g of 4-piperidinyloxyacetic acid tert-butyl ester in the presence of triethylamine in tetrahydrofuran yields 2.1 g of benzyl / -4 - /// (t- butoxycarbonyl) methoxy / piperidino / carbamoyl / methyl / methylcarbamate. MS (FAB): 421 (M + H) &lt; ^{+ &gt};.

b) By analogy to Examples 6 b) and 1 f), 4 g of product from Example 8 a) are chromatographed (silica gel; dichloromethane / methanol / acetic acid 93: 5: 2) and recrystallized from diethyl ether to give 1.5 g. g of desired acetate. Melting point 188-189 ° C. MS (FAB): 432 (M + H) &lt; ^{+ &gt};.

EXAMPLE

5

5.4 g of N - (p-amidinobenzoyl) -N - (t-butoxycarbonyl) -L-ornithyl / -4-piperidinyl / oxy / acetic acid tert-butyl ester, analogous to Example 1, 4.9 g of 1- [N - (p-amidinobenzoyl) -L-ornithyl] -4-piperidinyl / oxy / acetic acid trifluoroacetate are obtained. MS (FAB): 420 (M + H) &lt; ^{+ &gt};. / α / _β ²⁰ = + 4.5 ° (c = 0.8, MeOH).

The starting material can be obtained as follows:

(a) Chromatography on silica gel (carrier - ethyl acetate / hexane 1) of 6 g of 4-piperidinyloxyacetic acid tert-butyl ester with 10.2 g of N ² -ZN ⁵ -Boc-L-ornithine as described in Example 1 d): 1) 11 g of N - (N - (benzyloxycarbonyl) -N - (t-butoxycarbonyl) -L-ornithyl / -4-piperidinyl / oxy / acetic acid tert-butyl ester are obtained. MS (FAB): 564 (M + H) &lt; + &gt;.

b) hydrogenolysis of the product on a 11 g) as described in Example 1 e) receive 9 g // 1- / ⁵ N - (t-butoxycarbonyl) L-ornitil / -4-piperidinyl / oxy / acetic acid tert-butyl of ester acetate. MS (FAB): 430 (M + H) &lt; ^{+ &gt};.

c) Reaction of 9 g of product b) with 4.4 g of p-amidinobenzyl chloride hydrochloride as described in Example 1 f) gives 5.7 g of the desired starting material. MS (FAB): 576 (M + H) ^{@ +} .

EXAMPLE

From 0.54 g // L / N ² - / pN- (t-butoxycarbonyl) amidinobenzoil / N ⁶ - (t-butoxycarbonyl) / - L-lysyl / -4-piperidinyl / oxy / acetic acid tret.- of the butyl ester, analogous to Example 1, gives 0.35 g of N - (N - (pamidinobenzoyl) / - L-lysyl / -4-piperidyloxy / acetic acid trifluoroacetate. MS (FAB): 434 (M + H) &lt; ^{+ &gt};. / α / θ2θ = ΐ2.4 ° (c = 0.8, water).

The starting material can be obtained as follows:

a) Reaction of 2 g of 4-piperidinyloxyacetic acid tert-butyl ester with 2.8 g of N ² -ZN ⁶ -Boc-L-lysine as described in Example 1 d) on silica gel (carrier: ethyl acetate / hexane 1: 1). ) gives 2.6 g of N - (N ² - (benzyloxycarbonyl) -N ⁵ - (t-butoxycarbonyl) -Lisilyl-4-piperidinyl / oxy / acetic acid tert-butyl ester. MS (FAB): 578 (M + H) ^{@ +} .

b) Hydrogenolysis on 2.6 g of the product obtained as described in Example 1 e) gives 2 g of N- (N-butyl- ⁶ -t-butoxycarbonyl-L-lysyl) -4-piperidinyl / oxy / acetic acid. butyl ester acetate. MS (FAB): 444 (M + H) &lt; ^{+ &gt};.

c) Reaction of 2 g of the product of the preceding step with 1 g of pamidinobenzoyl chloride hydrochloride as described in Example 4 c) (silica gel; dichloromethane / methanol 20: 1) gives 1.95 g of the desired starting material. MS (FAB): 690 (M + H) &lt; ^{+ &gt};.

EXAMPLE

0.4 g of N- (N- (p-amidinobenzoyl) -2-phenylglycyl / -4-piperidinyl / oxy / acetic acid tert-butyl ester acetate, analogous to Example 1, is obtained in the form of 0.25 g of 1- / N- (p-amidinobenzoyl) -phenylglycyl / -4-piperidinyl / oxy / acetic acid trifluoroacetate. Melting point above 250 ° C (ethyl acetate / diethyl ether 1: 1). MS (FAB): 439 (M + H) &lt; ^{+ &gt};. [α] D ²⁰ = + 6.5 (c = 0.6 in MeOH).

The starting material can be obtained as follows:

a) Chromatography of 1.85 g of 4-piperidinyloxyacetic acid tert-butyl ester with 3.5 g of Za-phenylglycyl-N-hydroxysuccinimide ether as described in Example 8 a) on silica gel (carrier: light petroleum) diethyl ether 1: 1) 3.8 g of N- (N-benzyloxycarbonyl-α-phenylglycyl) -4-piperidinyl / oxy-acetic acid tert-butyl ester are obtained. MS (FAB): 483 (M + H) &lt; ^{+ &gt};.

b) Hydrogenolysis of 4.7 g of the product obtained as described in Example 6 b) gives 3.2 g of N- (1- (α-phenylglycyl) 4-piperidinyl) -oxy / acetic acid tert-butyl ester. MS (FAB): 349 (M + H) &lt; ^{+ &gt};.

c) Reaction of 3.2 g of the product from the preceding step with 2.2 g of p-amidinobenzoyl chloride hydrochloride as described in Example 1f) (silica gel; dichloromethane / methanol / acetic acid 95: 5: 2) gives 0.4 g. of the desired acetate. Melting point 207-220 ° C (ethyl acetate decomposes). MS (FAB): 495 (M + H) ^{@ +} .

EXAMPLE

0.5 g of 1- [1- (1- (p-amidinobenzoyl) -2-methyl-α-prolyl] -4-piperidinyl / oxy / acetic acid tert-butyl ester acetate, analogous to Example 1, gives 0.14 g. // 1- / 1- (p-Amidinobenzoyl) -2-methyl-α-prolyl / -4-piperidinyl / oxy / acetic acid trifluoroacetate. Melting point 219-220 ° C (acetonitrile). MS (FAB): 417 (M + H) &lt; ^{+ &gt};. [α] _D ²⁰ = + 17.1 ° (c = 0.9, MeOH).

The starting material can be obtained as follows:

a) Reaction of 2-methyl-a-proline hydrobromide with p-cyanobenzoyl chloride, analogous to Example 2 b), yields 1- (p-cyanobenzoyl) -2-methyl-a-proline. MS (EI): 213 (M-COOH) ⁺ .

b) Reaction of 1.67 g of tert-butyl ester of 4-piperidinyloxyacetic acid with 0.8 g of 1- (p-cyanobenzoyl) -2-methyl-a-proline acid chloro anhydride (obtained by treating the product of the preceding step with thionyl chloride) gives // 1- / 1- (p-Cyanobenzoyl) -2-methyl-α-prolyl / 4-piperidinyl / oxy / acetic acid tert-butyl ester. Melting point 180-182 ° C (ethyl acetate).

c) Further chromatography (0.89 g of product b) as described in Examples 2 A) B) C) (silica gel RP-18 silica gel; water / methanol 9: 1) gives 0.59 g of the desired acetate. Melting point 191-192 ° C (ethyl acetate decomposes). MS (FAB): 473 (M + H) &lt; ^{+ &gt};.

EXAMPLE

2.5 g of N- (N- (p-amidinobenzoyl) -3-phenyl-α-alanyl / -4-piperidinyl / oxy / acetic acid tert-butyl ester acetate, analogous to Example 1, are obtained in a yield of 1.9 g. // N- (p-amidinobenzoyl) -3-phenyl-α-alanyl / -4-piperidinyl / oxy / acetic acid trifluoroacetate. Melting point 234-235 ° C (ethyl acetate). / α / ρ ² θ = + 17.9 ° (c = 1.0, MeOH). MS (EI): 453 (M + H) &lt; ^{+ &gt};.

The starting material can be obtained as follows:

a) Reaction of 2.15 g of 4-piperidinyloxyacetic acid tert-butyl ester with 3.0 g of α-α-phenylalanine as described in Example 2 b) yields 4.8 g of 1- (N-benzyloxycarbonyl-3-). phenyl-α-alanyl) -4-piperidinyl / oxy / acetic acid tert-butyl ester. MS (FAB): 497 (M + H) &lt; ^{+ &gt};.

b) Hydrogenolysis by chromatography (silica gel; dichloromethane / methanol / acetic acid) on 4.8 g of the product obtained as described in Example 6 b) followed by 2.0 g of p-amidine benzoyl chloride hydrochloride as described in Example 1 f). : 2: 1) obtains 2.5 g of the desired acetate. Melting point 176-178 ° C (diethyl ether). MS (FAB): 509 (M + H) &lt; ^{+ &gt};.

EXAMPLE

From 2.5 g of N- (N- (p-amidinobenzoyl) -3- (p-butoxyphenyl) -α-alanyl / -4-piperidinyl / oxy / acetic acid tert-butyl ester acetate, analogous to Example 1, Chromatography (silica gel RP-18 silica gel, water / methanol gradient) yields 1.0 g of N, N- (p-amidinobenzoyl) -α-tyrosyl / -4-piperidinyl / oxy / acetic acid trifluoroacetate. Melting point 125-130 ° C (ethyl acetate, decomposes). MS (FAB): 469 (M + H) ^{@ +} .

The starting material can be obtained as follows:

a) Chromatography (silica gel; diethyl ether / petroleum ether 1: 1) of 2.15 g of 4-piperidinyloxyacetic acid tert-butyl ester with 3.71 g of NZ- (OtBU) -α-tyrosine as described in Example 2 b). ) yields 4.8 g of N- (N- (benzyloxycarbonyl) -3- (p- (t-butoxyphenyl)) - alanyl) -4-piperidinyl / oxy / acetic acid tert-butyl ester. Melting point 96 ° C (diethyl ether). MS (EI): 417 (MC-C ₇ H _{7 4} H ₈₎ ^+, / α / β ²⁰ = + 5.4 ° (c = 0.8, CH3 OH).

(b) Hydrogenolysis of 4.8 g of the product of the previous step as described in Example 6 (b) followed by

Chromatography (silica gel; silica gel; dichloromethane / methanol / acetic acid 22: 2: 1) of 1.5 g of p-amidinobenzoyl chloride hydrochloride as in Example 1 f) affords 2.6 g of the desired acetate. Melting point 170-172 ° C (diethyl ether). MS (FAB): 581 (M + H) &lt; ^{+ &gt};.

EXAMPLE

As a by-product of the chromatography described in Example 14, 0.09 g of N- (N- (p-amidinobenzoyl) -atyrosyl) -4-piperidinyl / oxy / acetic acid methyl ester trifluoroacetate is isolated. Melting point 189-190 ° C (ethyl acetate). MS (FAB): 483 (M + H) &lt; ^{+ &gt};.

EXAMPLE

By reaction of 0.58 g of N- (N- (p-amidinobenzoyl) -α-tyrosyl / 4-piperidinyl / oxy / acetic acid trifluoroacetate (Example 14) with chloramine T in the presence of sodium iodide dissolved in water / dimethylformamide 8: 1. , chromatography (silica gel RP-18; silica gel gradient RP / 18; water / acetonitrile gradient) gives 0.04 g of 1- [N - (p-amidinobenzoyl) -3- (4-hydroxy-3-iodophenyl) -α-alanyl] -piperidinyl / oxy / acetic acid Melting point 230 ° C (water, decomposes) MS (FAB): 595 (M + H) ⁺ .

EXAMPLE

From the reaction mixture described in Example 16, 0.09 g of N- (N- (p-amidinobenzoyl) -3- (4-hydroxy-3,5-diiodophenyl) -oc-alanyl / -4-piperidinyl / oxy) is further isolated. acetic acid. Melting point 220-221 ° C (water, decomposes). MS (FAB): 720 (M + H) &lt; ^{+ &gt};.

EXAMPLE

From 1.3 g of N- [1- (3-t-butoxy-N '-? - N - (t-butoxycarbonyl) amidino / benzoyl) -α-alanyl] -4-piperidinyl / oxy / acetic acid tert.- chromatography of the butyl ester by treatment with hydrogen chloride in glacial acetic acid (silica gel RP-18; gradient of methanol / water) affords 0.45 g of N- (3-acetoxy-N- (p-amidinobenzoyl) -α-alanyl). -4-piperidinyl / oxy / acetic acid hydrochloride, / α / β ² → = + 0.9 ° (c = 1.0, MeOH).

MS (FAB): 435 (M + H) ^{@ +} .

The starting material can be obtained as follows:

a) Reaction of 7.5 g of ZL-Ser (tBu) -OH with 7.0 g of tert-butyl ester of 4-piperidinyloxyacetic acid followed by hydrogenolysis of the product as described in Examples 1 d) e) yields 10.6 g // 1- (3-t-Butoxy-Lalanyl) -4-piperidinyl / oxy / acetic acid tert-butyl ester acetate. Melting point 76-78 ° C. MS (FAB): 359 (M + H) &lt; ^{+ &gt};.

(b) Chromatography (silica gel; dichloromethane / methanol 20: 1) followed by chromatography of 9.9 g of the product from the preceding step with 5.2 g of p-amidinobenzoyl chloride hydrochloride dimethylformamide in the presence of triethylamine followed by treatment with di-t-butyl dicarbonate. hexane 3: 1) yields 4.3 g of tert-butoxy-N- / p- / N- (t-butoxycarbonyl) amidino / benzoyl / -L-alanyl / -4-piperidinyl / oxy / tert-butyl ester of acetic acid. Melting point 162-165 ° C. MS (FAB): 605 (M + H) &lt; ^{+ &gt};.

EXAMPLE

From 1.0 g of N- [1- (3-t-butoxy-N '-? - N - (t-butoxycarbonyl) amidino / benzoyl) -L-alanyl / -4-piperidinyl / oxy / acetic acid tert.- butyl ester (Example 18), analogous to Example 1, afforded 0.58 g of 1- [N- (p-amidinobenzoyl) -L-seryl] - as silica gel in Example 1 (silica gel RP-18; water). 4-piperidinyl / oxy / acetic acid trifluoroacetate. / α / θ = + 17.6 ° (c = 1.0, water). MS (FAB): 393 (M + H) ^{@ +} .

EXAMPLE

From 5 g of LN- (p-amidinobenzoyl) -3- [4 - [(t-butoxycarbonyl) -methoxy / piperidinyl / carbonyl] -p-alanine tert-butyl ester, analogous to Example 1, recrystallized from ethyl acetate / tetrahydrofuran, yield 2.0 g of LN- (p-amidinobenzoyl) -3- [4- (carboxymethoxy) piperidine / carbonyl] -p-alanine trifluoroacetate, m.p. 145-150 ° C. MS (FAB): 421 (M + H) &lt; ^{+ &gt};.

The starting material can be obtained as follows:

a) Reaction of 11 g of ZL-Asp (O-tBu) -OH with 7.0 g of 4-piperidinyloxyacetic acid tert-butyl ester as described in Example 2 b) gives 16 g of LN- (benzyloxycarbonyl) -3 - H 4 - [(t-Butoxycarbonyl) methoxy / piperidino / carbonyl] -p-alanine tert-butyl ester. MS (FAB): 521 (M + H) &lt; ^{+ &gt};.

b) Hydrogenolysis of 17 g of the product of the previous step as described in Example 6 b) gives 11 g of L-3- [4- (t-butoxycarbonyl) methoxy] piperidine / carbonyl] -p-alanine tert-butyl ester. MS (FAB): 387 (M + H) &lt; ^{+ &gt};.

c) Reaction of 11 g of the product from the preceding step with 6.9 g of p-amidinobenzoyl hydrochloride as described in Example 1, chromatography (silica gel; dichloromethane / methanol 9: 1) gives 10.2 g of the desired starting material. MS (FAB): 533 (M + H) &lt; ^{+ &gt};.

EXAMPLE

After recrystallization from 0.5 g of N- (N- (p-amidinobenzoyl) -4-t-butoxy-L-glutamoyl / -4-piperidinyl / oxy / acetic acid tert-butyl ester, analogous to Example 1, ethyl acetate gives 0.25 g of N- (N- (p-amidinobenzoyl) -La-glutamoyl / -4-piperidinyl) -oxy-acetic acid trifluoroacetate. Melting point 105-108 ° C. [α] _D ²⁰ = + 6.9 ° (c = 0.8, methanol). MS (FAB): 435 (M + H) ^{@ +} .

The starting material can be obtained as follows:

a) Reaction of 11 g of ZL-Glu (Ot-Bu) -OH with 7.0 g of tert-butyl ester of 4-piperidinyloxyacetic acid as described in Example 1 d) gives 15.4 g of N- (N- ( benzyl xycarbonyl) -4-t-butoxy-L-glutamoyl / -4-piperidinyl / oxy / acetic acid tert-butyl ester. MS (FAB): 535 (M + H) ^{@ +} .

b) Hydrogenolysis of 15.4 g of the product of the preceding step as described in Example 6 b) yields 7.5 g of tert-butyl ester of 1- (4-t-butoxy-L-glutamoyl / -4-piperidinyl / oxyacetic acid). acetate MS (FAB): 401 (M + H) ⁺ .

c) Reaction of 7.5 g of the product of the preceding step with 3.9 g of p-amidinobenzoyl chloride hydrochloride as described in Example 1f) gives 6.9 g of N- (p-amidinobenzoyl) 4-t-butoxy. -L-glutamoyl / -4-piperidinyl / oxy / acetic acid tert-butyl ester. MS (FAB): 547 (M + H) &lt; + &gt;.

EXAMPLE

2 g of (R / S) -1- / N- (p-amidinobenzoyl) -L-alanyl / -3-piperidinyl / methoxy / acetic acid tert-butyl ester, analogous to Example 1, gives 0.6. g // (R / S) -1- N - (p-amidinobenzoyl) -L-alanyl / -3-piperidinyl / methoxy / acetic acid trifluoroacetate. Melting point 87-90 ° C (ethyl acetate). MS (FAB): 391 (M + H) &lt; ^{+ &gt};.

The starting material can be obtained as follows:

a) From rac ^X) -3- (hydroxymethyl) piperidine, analogous to Example 1 a), yields rac-N-benzyloxycarbonyl-3 (hydroxymethyl) -piperidine. MS (EI): 249 (M) &lt; ^{+ &gt};.

b) From product a), in analogy to Example 1 b), affords benzyl rac-3 - [(t-butoxycarbonyl) methoxy / methyl] -1-piperidine carboxylate. MS (EI): 307 (MC ₄ H ₈ ) ⁺ .

c) The product b) is hydrogenated to the tert-butyl ester of rac- (3-piperidinylmethoxy) acetic acid in analogy to Example 1 c). MS (E): 172 (MC ₄ H ₈ ) ⁺ .

d) Reaction of product c) with Z-L-alanine as in Example 1 d) affords benzyl- () -1 - [(R / S) -3 - / (t-butoxycarbonyl) -methoxy / piperidine / ethyl / carbamate.

MS (EI): 434 (M) &lt; ^{+ &gt};.

e) Hydrogenation of product d) as in Example 1 e) affords N- (R / S) -1L-alanyl-3-piperidinyl / methoxy / acetic acid tert-butyl ester acetate. MS (EI): 285 (M-CH ₃ ) &lt; ^{+ &gt};.

f) Reaction of the products e) with p-amidinobenzoyl chloride hydrochloride as in Example 1f) gives chromatography (silica gel RP-18 containing the silyl groups) to give the desired starting material. MS (FAB): 447 (M + H) ^{@ +} .

EXAMPLE

From 2.7 g of 1- [N - (p-amidinobenzoyl) -L-alanyl] -4- (α, α, atrifluoro-m-tolyl) -4-piperidinyl / oxy / acetic acid

X) Rac - Racemate (Vertical Note) Tert-butyl ester, in analogy to Example 1, gives 0.7 g of N, N- (p-amidinobenzoyl) -L-alanyl-4 (α, α, α -trifluoro-m-tolyl) -4-piperidinyl / oxy / acetic acid. Melting point above 280 ° C (water / methanol). MS (FAB): 521 (M + H) &lt; ^{+ &gt};.

The starting material can be obtained as follows:

a) From 4- (3-trifluoromethyl) phenyl) piperidin-4-ol, analogous to Example 1a), benzyl-4-hydroxy-4- (a, a, a-trifluoro-m-tolyl) -1-piperidin- carboxylate.

MS (EI): 379 (M) &lt; ^{+ &gt};.

b) From product a) in analogy to example 1 b), benzyl 4 - [(t-butoxycarbonyl) methoxy] -4- (α, α, α-trifluoro- m-tolyl) -1-piperidinecarboxylate is obtained. MS (FAB): 494 (M + H) &lt; ^{+ &gt};.

c) Hydrogenation of product b) as in Example 1 e) affords N- [4- (α, α, α-trifluoro-m-tolyl-4-piperidinyl / oxy / acetic acid tert-butyl ester acetate) MS (EI) : 227 (MC ₆ H ₁₂ O ₃ ) ⁺ .

d) Reaction of products c) with ZL-alanine as in Example 1 a) affords benzyl - ((S) -1 - [4 - [(t-butoxycarbonyl) methoxy) -4- (a, a, α-trifluoride) -m-tolyl) -1-piperidinyl / carbonyl / ethyl / carbamate. MS (FAB): 565 (M + H) ^{@ +} .

e) Hydrogenation of product d) as in Example 1 e) affords 1- N -L-alanyl-4- (α, α, α-trifluoro-m-tolyl) -4-piperidinyl / oxy / acetic acid tert. butyl ester acetate. MS (EI): 415 (M-CH ₃ ) &lt; ^{+ &gt};.

f) Reaction of product e) with p-amidinobenzoyl chloride hydrochloride as in Example 1f) gives the desired starting material. MS (EI): 577 (M + H) &lt; ^{+ &gt};.

EXAMPLE

A solution of 150 mg of tert-butyl - N - [1- (pamidinobenzoyl) -L-prolyl] -4-piperidinyl / oxy / acetate in 10 ml of dichloromethane and 10 ml of trifluoroacetic acid is stirred for 2 hours. at room temperature and evaporated. The residue is suspended in ether and filtered through a suction funnel. 141 mg of 1- [1- / 1- (pamidinobenzoyl) -L-prolyl] -4-piperidinyl / oxy / acetic acid trifluoroacetate are obtained. Melting point 234-236 ° C.

The starting material can be obtained as follows:

(a) A mixture of 4.97 g of cyanobenzoic acid chloro anhydride, 3.45 g of L-proline, 0.73 g of tetramethylammonium sulphate, 300 ml of dichloromethane and 150 ml of 5% sodium bicarbonate solution is stirred for 48 hours. The aqueous phase is acidified with 3 g of sulfuric acid and extracted with ethyl acetate. The ethyl acetate phase is washed with saturated sodium chloride solution, dried and evaporated. Chromatography on silica gel (RP-18) using water as a carrier gives 3.70 g of 1- (p-cyanobenzoyl) -L-proline. Melting point 80-85 ° C.

b) Reaction of 250 mg of 1- (p-cyanobenzoyl) -L-proline with 215 mg of 4-piperidinyloxyacetic acid tert-butyl ester gives 300 mg of t-butyl on silica gel (ethyl acetate / methanol 98: 2). 1- / 1- (p-cyanobenzoyl) -L-prolyl / -4-piperidinyl / oxy / acetate. MS: 442 (M + H) &lt; ^{+ &gt};.

c) Reaction with 1 g of the product of the preceding step as in Example 2 A) B) C) initially gives t-butyl - N - [l - (p - (thiocarbamoyl) benzoyl) - L - prolyl / -4 - piperidinyl]. oxy / acetate having a melting point of 108-110 [deg.] C., followed by t-butyl - N - [l - [l- [p-] l-methylthio / formimidoyl / benzoyl / -L-prolyl / -4-piperidinyl / oxy acetate containing m.p. 132-133 ° C and finally 72 mg of the desired acetate, melting point 100 ° C (decomposition).

EXAMPLE

In analogy to Example 24, from 150 mg of t-butyl - N - (4R) -1- (p-amidinobenzoyl) -4-benzyloxy-L-prolyl / -4-piperidinyl / oxy-acetate hydrochloride was chromatographed on silica gel (RP-18; carrier-water / tetrahydrofuran 95: 5) affords 72 mg of N- (1R) - ((4R) -1- (p-amidinobenzoyl) -4-benzyloxy-L-prolyl / -4-piperidinyl / oxy). -acetic acid. Melting point 226-227 ° C.

The starting material can be obtained as follows:

(a) To a solution of 905 mg of (4R) -hydroxy-L-proline methyl ester and 828 mg of 4-cyanobenzoyl chloride in 50 ml of dichloromethane are added 1.46 ml of triethylamine. After mixing, the solutions are washed with saturated sodium chloride solution, dried and evaporated. The residue is purified by chromatography on silica gel (ethyl acetate / hexane 5: 1) to give 810 mg of (4R) -1- (p-cyanobenzoyl) -4-hydroxy-L-proline. Melting point 101-102 ° C.

(b) To a solution of 730 mg of the product from the preceding step in 600 l of benzyl trichloroacetimidate in 5 ml of cyclohexane and 5 ml of dichloromethane are added 40 l of trifluoromethanesulfonic acid. The precipitate formed is filtered through a suction funnel, the filtrate washed with 5% sodium bicarbonate solution, dried and evaporated. The residue was purified by silica gel chromatography (ethyl acetate) to give 940 mg of (4R) -4-benzyloxy-1- (p-cyanobenzoyl) -L-proline methyl ester. MS: 305 (M-59).

(c) A mixture of 880 mg of the product of the preceding step and 1.2 ml of 2N lithium hydroxide solution in 10 ml of methanol. After removing methanol from PaLT 3681 B, the aqueous residue was acidified with 2.4 ml of 1N hydrochloric acid and extracted with ethyl acetate. The organic phase is dried and evaporated to give 470 mg of (4R) -4-benzyloxy-i- (p-cyanobenzoyl) -L-proline. Melting point 58-60 ° C.

d) 450 mg of product c) is reacted in the presence of HBTU with 280 mg of 4-piperidinyloxyacetic acid tert-butyl ester. The residue is dissolved in ethyl acetate and the ethyl acetate phase is washed with 5% sodium bicarbonate, 1N potassium bisulphate and saturated sodium chloride solutions, dried and evaporated. The residue is purified by chromatography on silica gel (dichloromethane / methanol 98: 2) to give 500 mg of t-butyl - N - ((4R) -4-benzyloxy-1- (p-cyanobenzoyl) -L-propyl) -4-piperidinyl / oxy. / acetate. MS: 548 (M-H) -.

e) By working 400 mg of the product of the previous step as in Example 2 A) B) C), 177 mg of the desired acetate is obtained. Melting point of hydroiodide 148-150 ° C.

EXAMPLE

A solution of 1.60 g of t-butyl - N - [(4R) -1- (pamidinobenzoyl) -4-hydroxy-L-prolyl / -4-piperidinyl / oxy / acetate in 20 ml of dichloromethane and 20 ml of trifluoroacetic acid, stirred at room temperature for 2 hours and evaporated. The residue is dissolved in ethanol and mixed with ether. Filtration through a suction funnel, drying of the precipitate. 1.25 g of 1 H - (4R) -1- (p-amidinobenzoyl) 4-hydroxy-L-prolyl / -4-piperidinyl / oxy / acetic acid trifluoroacetate are obtained. Melting point 220 ° C (decomposes).

The starting material can be obtained as follows:

(a) Chromatography on 14.78 g of (4R) -1- (benzyloxycarbonyl) -4-hydroxy-L-proline with 12.0 g of 4-piperidinyloxyacetic acid tert-butyl ester on SiO2 3681 B castor gel (ethyl acetate / methanol 95): 5) 17.83 g of t-butyl - N - (4R) -1- (benzyloxycarbonyl) -4-hydroxy-Lprolyl / -4-piperidinyl / oxy / acetate are obtained. MS: 463 (M-H) -.

b) Hydrogenation of 17.0 g of the product from the preceding step in 2.0 g of Pd / C (10%) gives 11.06 g of t-butyl - (1R) - (4R) -4-hydroxy by filtration and concentration of the catalyst. L-prolyl / -4-piperidinyl / oxy / acetate. MS: 329 (M + H) &lt; ^{+ &gt};.

c) Reaction of 2.0 g of the product of the preceding step with 1.34 g of p-amidinobenzoyl chloride, analogous to Example 1 f), gives 1.95 g of the desired acetate.

EXAMPLE

A solution of 700 mg of t-butyl - N - [1- (p-amidinobenzoyl) -2-piperidinyl / carbonyl / -4-piperidinyl / oxy / acetate in 20 ml of dichloromethane and 20 ml of trifluoroacetic acid is stirred for 3 hours. hours at room temperature and then evaporated. The residue is dissolved in ethanol and mixed with ether. Filtration through a suction funnel, drying and purification of the residue by chromatography on silica gel (RP-18, water / tetrahydrofuran 9: 1) gives 111 mg of // 1 - // 1- (p-amidinobenzoyl) 2-piperidinyl / carbonyl / -4 -piperidinyl / oxy / acetic acid. Melting point 233-234 ° C.

The source material is obtained as follows:

a) Reaction of 5.26 g of 1- (benzyloxycarbonyl) -2-piperidinecarboxylic acid with 4,30 4-piperidinyloxyacetic acid tert-butyl ester gives 7.33 g of 2- (4-piperidinyloxyacetic acid tert-butyl ester) chromatography on silica gel (ethyl acetate / hexane). // Benzyl ester of 4 - ((- butoxycarbonyl) methoxy) -piperidine / carbonyl / 1-piperidinecarboxylic acid. MS: 461 (M + H) &lt; ^{+ &gt};.

b) Hydrogenation of 4.6 g of the product from the previous step in ethanol at 0.4 g Pd / C (10%) gives 3.2 g of t-butyl - N - (2-piperidinylcarbonyl) -4 by filtration of the catalyst and concentration of the solvent. -piperidinyl / oxy / acetate. MS: 327 (M + H) &lt; ^{+ &gt};.

(c) By reaction with 3.26 g of the product of the previous step with

2.49 g of p-amidinobenzoyl chloride, as in Example 1 f), yields 1.56 g of the desired acetate, melting point 93-95 ° C.

EXAMPLE

A solution of 130 mg of t-butyl - N - (IRS, 2RS, 3RS, 4RS) -4 - N - (p-amidinobenzoyl) -L-alanyl / amino / -2,3-diacetoxycyclohexyl / oxy / acetate hydrochloride, 5 ml dichloromethane and 5 ml trifluoroacetic acid, stirred at room temperature for 2 hours and concentrated. The residue is suspended in ether and filtered through a suction funnel. 126 mg of // (IRS, 2RS, 3RS, 4RS) -4H-N- (amidinobenzoyl) -L-alanyl / amino / -2,3-diacetoxycyclohexyl / oxy / acetic acid trifluoroacetate are obtained. MS: 507 (M + H) &lt; ^{+ &gt};.

The source material is obtained as follows:

(a) A solution of 4.64 g of cis -4-amino-2-cyclohexen-1-ol, 10.2 g of N- (benzyloxycarbonyloxy / succinimide) and 5.7 ml of triethylamine in dimethylformamide is stirred and diluted with ether, washed with saturated sodium chloride solution, dried and concentrated to give 5.62 g of benzyl- (IRS, 4SP) -4-hydroxy-2-cyclohexene-1-carbamate on silica gel (ethyl acetate / hexane 2: 1) M: 156 (M-91). ⁺ .

b) Under phase conversion (30 mL of toluene, 30 mL of 50% sodium hydroxide solution, 100 mg of tetrabutylammonium LT 3681 B hydrosulfate), 2.1 g of the product from the previous step are reacted with 1.76 mL of tert-butyl ester of bromoacetic acid. After stirring, the organic phase is separated off, washed with saturated sodium chloride solution, dried and concentrated. The residue was purified by chromatography (silica gel; hexane / ethyl acetate 3: 1) to give 1.91 g of benzyl (IRS, 4SP) -4 - [(t-butoxycarbonyl) methoxy] -2-cyclohexene-1-carbamate. MS: 333 (M-28) ^&lt; ^{+ &gt};.

house acetone, The organic phase in solution, dried by physical purification

c) A solution of 722 mg of the product of the preceding step, 280 mg of N-methylmorpholine-N-oxide and 26 mg of osmium tetraoxide, 20 ml of acetone and 10 ml of water is stirred and then the aqueous phase is extracted with ether under reduced pressure, washed with saturated sodium chloride and concentrated. Chromatography on silica gel (ethyl acetate / hexane 2: 1) gives 476 mg of benzyl- (IRS, 2SP, 3SP, 4SP) -4 - [(t-butoxycarbonyl) methoxy-2,3-dihydroxycyclohexanecarbamate. MS: 396 (M + H) &lt; ^{+ &gt};.

d) A solution of 728 mg of the product of the preceding step in 10 ml of ethanol is hydrogenated at 100 mg of 20% Pd / C. The catalyst is then filtered off, and the filtrate is evaporated and the residue dissolved in 30 ml of tetrahydrofuran is reacted with 410 mg of N-benzyloxycarbonyl L-alanine in the presence of 697 mg of HBTU and 200 μΐ of triethylamine. The reaction mixture was diluted with ether, washed with saturated sodium bicarbonate followed by saturated sodium chloride solution and concentrated. Chromatography on silica gel (ethyl acetate / methanol 95: 5) yields 521 mg of benzyl - ((S) -1 - // (IRS, 2SP, 3SP, 4SP) -4 - [(t-butoxycarbonyl) methoxy] -2. 3-dihydroxycyclohexyl / carbamoyl / ethyl / carbamate. MS: 467 (M + H) &lt; ^{+ &gt};.

e) 800 mg of the reaction product of the preceding step is acetylated with 10 ml of acetic anhydride and 10 ml of pyridine, followed by concentration and purification on silica gel (ethyl acetate / hexane 2: 1) to give 670 mg of benzyl - (S) - 1 - // (IRS, 2SP, 3SP, 4SP) -4 - ((t-butoxycarbonyl) methoxy) -2,3-acetoxycyclohexyl / carbamoyl / ethyl / carbamate. MS: 551 (M + H) &lt; + &gt;.

f) Hydrogenate 670 mg of the reaction product from the previous step in 10 ml of ethanol at 100 mg of 10% Pd / C. The catalyst is then filtered off and the solution is evaporated. Acting as in Example 1f, 329 mg of p-amidinobenzoyl chloride and purification by chromatography on silica gel (RP-18, water / methanol 9: 1) affords 230 mg of the desired starting material. MS: 563 (M + H) &lt; + &gt;.

EXAMPLE

220 mg of the product of Example 28, 300 mg of potassium carbonate and 10 ml of methanol are mixed at room temperature and then methanol is evaporated. Chromatography on silica gel (RP-18, water / acetonitrile 95: 5) gives 110 mg // (1 RS, 2 RS, 3 RS, 4 SR) -4 - // N- (p-amidinobenzoyl) -Lalanyl / amino / -2,3-dihydroxycyclohexyl / oxy / -acetic acid.

EXAMPLE

Reaction (1.3 g) of rac-p - [1- (p-cyanobenzoyl) -2-pyrrolidinyl] -carbonyl / phenoxy / acetic acid methyl ester as described in Example 2 A) B) C) chromatography (silica gel containing silyl groups) RP-18, water / methanol gradient) and recrystallized from ethanol to give 0.45 g of rac- / p - [1- (p-amidinobenzoyl) -2-pyrrolidinyl / carbonyl / phenoxy / acetic acid methyl ester acetate. Melting point 210-211 ° C. MS (FAB): 410 (M + H) ^{@ +} .

The source material can be obtained as follows:

(a) Grignard reagent from 8.3 g of p-benzyloxybromobenzene and 0.8 g of magnesium turnings is reacted with 9.34 g of ZL-proline-N-methoxymethylamide in tetrahydrofuran. Chromatography (silica gel; diethyl ether / petroleum ether 1: 1) yields 4.3 rac-1- (benzyloxycarbonyl) -2- (p-benzyloxybenzoyl) pyrrolidine. MS (EI): 211 (C ₁₄ H ₁₁ O ₂ ) ⁺ , 204 (C ₁₂ H ₁₄ NO ₂ ) ⁺ .

b) Hydrogenation of 3.3 g of the product of the preceding step as in Example 6b) followed by treatment with 1.32 g of p-cyanobenzoyl chloride in dimethylformamide gives triethylamine.

2.8 g of rac-1- (p-cyanobenzoyl) -2- (p-hydroxybenzoyl) pyrrolidine. Melting point 194-196 ° C (ethyl acetate). MS (EI): 320 (M) &lt; ^{+ &gt};.

c) Reaction of 2.8 g of the product of the preceding step with 1.53 g of methyl ester of bromoacetic acid in dimethylformamide in the presence of potassium carbonate gives silica gel; 99: 1 dichloromethane / methanol as the desired starting material. MS (EI): 392 (M) &lt; ^{+ &gt};.

EXAMPLE

Heated 0.30 g of the product of Example 30 in aqueous acetic acid solution, chromatography (silica gel RP-18, gradient water / acetonitrile) gives 0.11 g of rac - / - p - [l - (p-amidinobenzoyl) -2-pyrrolidinyl]. carbonyl / phenoxyacetic acid. Melting point above 250 ° C. MS (FAB): 396 (M + H) ^{@ +} .

EXAMPLE

Reaction (0.85 g) of 4- [1- (p-cyanobenzoyl) -DL-prolyl] -phenylene / dioxy / diacetic acid dimethyl ester as described in Example 2 A) B) C) chromatography (silica gel RP) -18, water / methanol gradient) and recrystallized from diethyl ether

0.09 g of // 4- [1- (p-amidinobenzoyl) -DL-prolyl] -m-phenylene / dioxy / diacetic acid dimethyl ester acetate. Melting point 93-95 ° C. MS (FAB): 498 (M + H) &lt; + &gt;.

The starting material can be obtained as follows:

a) Chromatography (silica gel; diethyl ether / petroleum ether) of 4 g of magnesium salt of 3-hydroxy-phenoxyacetic acid methyl ester with 5.8 g of ZL-proline and 3.8 g of bromoacetic acid methyl ester as described in Example 30 c). ether 4: 1) receives

7.6 g of N- (4 - [(RS) -1-benzyloxycarbonyl) -DL-pyrrolyl] hydroxymethyl] -m-phenylene / dioxy / diacetic acid dimethyl ester. MS (FAB): 488 (M + H) &lt; ^{+ &gt};.

b) Oxidation of 5.3 g of the product from the preceding step in 7.5 ml of Jones reagent in diethyl ether gives 2.2 g of [4- / 1-benzyloxycarbonyl] -DL-prolyl-m in the chromatography (silica gel; 99: 1 dichloromethane / methanol). -dimethyl ester of phenylene / dioxy / diacetic acid. MS (EI): 485 (M) &lt; ^{+ &gt};.

c) Chromatography (silica gel: 99: 1 silica gel: dichloromethane / methanol) of 2.2 g of the product of the preceding step as described in Example 6 b) followed by treatment with 1.0 g of cyanobenzoyl chloride in chloroform in the presence of triethylamine gives 0.85 g of the desired product. starting materials. MS (EI): 480 (M) &lt; ^{+ &gt};.

EXAMPLE

0.09 g of Example 32 is obtained by hydrolysis with aqueous sodium hydroxide in methanol at 50 ° C followed by neutralization with acetic acid, chromatography (silica gel RP-18, gradient water / acetonitrile) and crystallization from ethanol. 0.09 g of mono-sodium salt of 4- [1- (p-amidinobenzoyl) -DL-propyl] -m-phenylene / dioxy / diacetic acid. Melting point 241-242 ° C. MS (FAB): 492 (M + Na) ⁺ , 470 (M + H) ⁺ .

EXAMPLE

Esterification on 0.47 g of N-1- (N- (p-amidinobenzoyl) -L-tyrosyl / -4-piperidinyl / oxy / acetic acid in ethanol (Example 14) with catalytic concentration of concentrated sulfuric acid (Lichroprep RP- 18, water / ethanol gradient) yields 0.3 g of semi-sulfate of 1- (N- (pamidinobenzoyl) -L-tyrosyl / -4-piperidinyl / oxy / acetic acid ethyl ester, m.p. 182-184 ° C. ethanol). MS (ISO = ion-scattering): 497 (M + H) ⁺ .

EXAMPLE

From 0.48 g of 1- [N- [5- (tert-butoxyformamide) pentanoyl] -3- (p-1-butoxyphenyl) -L-alanyl] -4-piperidinyl / oxy / acetic acid tert-butyl ester , analogous to that described in Example 1, recrystallization from diethyl ether gives 0.2 g of the N-1- (N- (5-aminopentanoyl) -L-tyrosyl / -4-piperidinyl / oxy / acetic acid trifluoroacetate salt, m.p. 78-88 ° C (dec.). [α] _D ²⁰ = + 11.6 ° (c = 0.7, methanol). MS (FAB): 422 (M + H) &lt; ^{+ &gt};.

The starting material can be obtained as follows:

By reaction of 0.7 g of the product N-1- (3- (p-butoxyphenyl) -L-alanyl / -4-piperidinyl / oxy / acetic acid tert-butyl ester (obtained by hydrogenolysis on Example 14 a)) with 0.35 g of N -Boc-5-aminopentanoic acid in the presence of HBTU and Nmethylmorpholine (as described in Example 2 b) yields 0.55 g of the starting ester. [Α] _D ⁼ + 1.2 ° (c = 0.4, methanol). MS (FAB): 634 (M + H) &lt; ^{+ &gt};.

EXAMPLE

Chromatography of 0.6 g of (S) -3- (p-amidinobenzamide) -3- [4 - [(t-butoxycarbonyl) methoxy / piperidine / carbonyl / propyl] -butylcarbamate analogous to that described in Example 1. (Lichroper RP-18, water / methanol gradient) and stirring in tetrahydrofuran gives 0.26 g of 1 - [(S) -2- (p-amidinobenzamide) -4-aminobutanoyl] - 4-piperidinyl / oxy / acetic acid. trifluoroacetate salts.

q D

Melting point above 170 ° C (decomposes). / cc / _D ⁼ +5.8 (c = 0.5, water). MS (EI): 406 (M + H) &lt; ^{+ &gt};.

The starting material can be obtained as follows:

a) By reacting 1.0 g of 4-piperidinyloxyacetic acid tert-butyl ester with 2.0 g of N ² -Fmoc-N ⁴ -Boc (S) -2,4-diaminobutyric acid in the presence of HBTU and Chununig base as described in Example 2 b. ), chromatography (silica gel, EtOAc / hexane 1: 1.5) yields 2.2 g of 3-t-butyl-l (fluoren-9-ylmethyl) - (S) -1- / 4 - / (t- butoxycarbonyl) methoxy / piperidino / carbonyl / trimethylenedicarbamate. MS (FAB): 638 (M + H) &lt; ^{+ &gt};.

b) Reaction with 2,3-dimethylformamide) gives acetate / methanol g of product a) with piperidine (20% chromatography (silica gel; ethyl 4: 1)) to give 0.65 g of t-butyl - ((S) -3-amino-3 - H). 4 - [(t-butoxycarbonyl) methoxy / piperidino / carbonyl] propyl / carbamate MS: 416 (M + H) ⁺ .

c) Reaction of 0.65 g of product b) with 0.38 dinobenzoyl chloride hydrochloride (as in Example 1f) gives 0.6 g of the starting carbamate g of p-amia as described by MS (FAB):

562 (M + H) @ +.

EXAMPLE

From 0.25 g of N- (N - [(5-amidino-2-pyridyl) carbonyl) -3- (pt-butoxyphenyl) -L-alanyl] -4-piperidinyl / oxy / acetic acid tert-butyl Chromatography of the ester acetate salt (as described in Example 1) (Lichroprep RP-18, water, methanol gradient) and mixing with ethyl acetate gives 0.12 g of N- (N-butyl) (5-amidino-2-pyridyl) carbonyl. L-tyrosyl / -4-piperidinyl / oxy / acetic acid, m.p. 198-200 ° C (decomposed). MS (FAB): 470 (M + H) &lt; ^{+ &gt};.

The starting material can be obtained as follows:

a) Reaction of 2.5 g of N-1- (3- (pt-butoxyphenyl) -L-alanyl / -4-piperidinyl / oxy / acetic acid tert-butyl ester with 0.85 g of 5-cyano-2-picoline of the acid (as described in Example 1d) gives 1.55 g of N- [1- (3- (p-t-butoxyphenyl) -N- [5-cyano-2-pyridyl] carbonyl] -L-alanyl] -4-piperidinyl). / oxy / acetic acid tert-butyl ester. Melting point 122-123 ° C (diethyl ether / petroleum ether 4: 1). MS (FAB): 565 (M + H) ^{@ +} .

b) Further treatment with 1.43 g of the reaction product of the previous step as described in Example 2 A) B) C) gives 0.98 g of the desired starting material. Melting point 183-186 ° C. MS (EI): 582 (M + H) &lt; ^{+ &gt};.

EXAMPLE

By reaction of 0.7 g of (S) -1- / 2- (5-cyanopyridin-2-ylcarbonylamino) -3- (4-methoxyphenyl) propionyl / piperidin-4-yloxyacetic acid ethyl ester as described in Example 2 A) B). C) and then crystallizes from water to give 0.1 g of (S) -1- / 2- (5-amidinopyridin-2-ylcarbonylamino) -3- (4-methoxyphenyl) propionyl / piperidin-4-yloxyacetic acid ethyl ester. acetate salts. Melting point 180-181 ° C (decomposes). MS (ISP): 512 (M + H) &lt; ^{+ &gt};.

The starting nitrile can be obtained as follows:

a) By reaction of Ί g of N-Z-L-tyrosine dihydrate with 4.5 g of ethyl 4-piperidinyloxyacetic acid ester (obtained by reaction with the corresponding tert-butyl ester, Example 1)

c) with trifluoroacetic acid in the presence of an ethanolic hydrochloric acid solution as in Example 1 d)) gives 6.5 g of N- (N- (benzyloxycarbonyl) -L-tyrosyl-4-piperidinyl / oxy / acetic acid ethyl ester). This product is treated with methyl iodide in dimethylformamide in the presence of potassium carbonate. Chromatography (silica gel; methylene chloride.methanol 99: 1) yields 4.2 g of (S) -1- / 2- (benzyloxycarbonylamino-3- (4-methoxyphenyl) -propionyl / piperidin-4-yloxyacetic acid ethyl ester, / α / θ = 1.9 ° (c = 0.8, methanol) MS (ISP): 499 (M + H) ⁺ .

b) From 4 g of product a), 3.5 g of (S) -2- (2-amino-3- (4-methoxyphenyl) propionyl) -piperidin-4-yloxyacetic acid ethyl are obtained in analogy to Example 1 e). of an ester. MS (EI): 365 (M + H) &lt; ^{+ &gt};.

c) Reaction of 1.46 g of product b) with 0.74 g of 5-cyano-2-picolinic acid according to Example 1 d) on silica gel (methylene chloride / methanol 40: 1) gives 0.72 g of the starting nitrile. MS (ISP): 495.5 (M + H) &lt; + &gt;.

EXAMPLE

Hydrolysis of (S) -1- / 2- (5-amidinopyridin-2-ylcarbonylamino) -3- (4-methoxyphenyl) propionyl / piperidin-4-yloxyacetic acid ethyl ester (Example 39) at pH = 12 Lichroprep RP-18; water / methanol gradient) and (S) -1- / 2- (5-amidinopyridin-2-ylcarbonylamino) -3- (4-methoxyphenyl) propionyl / piperidin-4-yloxyacetic acid, mixed with ethanol. Melting point above 250 ° C. MS (ISP): 484.4 (M + H) &lt; + &gt;.

EXAMPLE

1.2 g of (S) -1- (2-amino-3- (4-methoxyphenyl) propionyl) -piperidin-4-yloxyacetic acid ethyl ester (Example 38 b)) are reacted with 0.77 g of 4-amidinobenzoic acid chloro anhydride. hydrochloride 3-picoline (analogous to that described in Example 1f)), chromatography (Lichroprep RP-18; water / ethanol gradient) and stirring with ethyl acetate gives 0.25 g of (S) -1- / 2- (4-amidinobenzamide). -3- (4-methoxyphenyl) propionyl / piperidin-4-yloxyacetic acid ethyl ester hydrochloride, m.p. 105-107 ° C. M (ISP): 511.3 (M + H) ⁺ .

EXAMPLE

Hydrolysis by chromatography on 0.35 g of (S) -1- / 2- (4-amidinobenzamide) -3 (4-methoxyphenyl) propionyl / piperidin-4-yloxyacetic acid ethyl ester hydrochloride (Example 40) at pH = 12 ( Lichroprep RP-18; water / methanol gradient) and crystallization from ethanol / water yields 0.05 g of (S) -1- / 2- (4-amidinobenzamide) -3- (4-methoxyphenyl) propionyl / piperidin-4-yloxyacetate acid, melting point 191-192 ° C. MS (ISP): 483.3 (M + H) &lt; + &gt;.

EXAMPLE

Chromatography of 1.6 g of 1- [N- (4-amidinobenzoyl) -L-tryptophanyl / piperidin-4-yloxy / acetic acid tert-butyl ester analogous to that described in Example 1 (Lichroprep RP-18; water / methanol gradient) and, when mixed with tetrahydrofuran and acetonitrile, gives 0.7 g of 1-N / N- (4-amidinobenzoyl) -L-tryptophanyl / piperidin-4-yloxyacetic acid, m.p. 210 ° C (dec.). MS (ISP): 492.2 (M + H) &lt; + &gt;.

The source material is obtained as follows:

(a) Chromatography (silica gel; 5.1 g of 4-piperidinyloxyacetic acid tert-butyl ester (Example 1c) with 8.0 g of Z-Tzp-OH in the presence of HBTU and N-methylmorpholine as described in Example 2 (b)); methylene chloride / methanol 20: 1) yields 11.5 g of tert-butyl ester of 1- (N-benzyloxycarbonyl-L-tryptophanyl) piperidin-4-yloxy / acetic acid. MS (ISP): 536.0 (M + H) &lt; + &gt;.

(b) A solution of 6.6 g of product a) dissolved in methanol is heated at 10% Pd-C and ammonium formate to boiling. After filtration and purification by chromatography (silica gel; methylene chloride / methanol 9: 1), 4.3 g of (lL-tryptophanyl-piperidin-4-yloxy) -acetic acid tert-butyl ester are obtained. MS (EI): 384 (M-NH) &lt; ^{+ &gt};.

c) Reaction of 1.9 g of product b) with 1.15 g of benzoic acid chloro-anhydride hydrochloride pyridine as described in Example 1 f) gives 1.6 g of the starting ester by chromatography (silica gel; methylene chloride / methanol 7: 1). MS (ISP): 548.3 (M + H) &lt; + &gt;.

EXAMPLE

A solution of 3.2 g of N- (N- (4-amidinobenzoyl) 4'-hexyloxy-L-phenylalanyl / piperidin-4-yloxy / acetic acid in tert-butyl ester in formic acid is left overnight at room temperature. After concentration, chromatography (Lichroprep RP-18, water / methanol gradient) and stirring with diethyl ether gives 0.45 g of 1- [N- (4-amidinobenzoyl) -4'-hexyloxy-L-phenylalanyl / piperidin-4-yloxy] / acetic acid, m.p. 160 ° C (decomposes). / α / θ ² ^ = -3.2 ° (c = 0.5, methanol). MS (ISP): 553.2 (M + H) &lt; + &gt;.

The starting ester is obtained in the following manner:

a) In a manner analogous to that described in Example 38a), 5,6 g of N- (N- (benzyloxycarbonyl) -L-tyrosyl / -4-piperidinyl / oxy / acetic acid tert-butyl ester with 1-iodohexane were obtained. At ° C, chromatography (silica gel; hexane / ethyl acetate 2.5: 1) gives 3.9 / 1 (N-benzyloxycarbonyl-4'-hexyloxy-L-phenylalanyl) piperidin-4-yloxy / acetic acid tert-butyl. of an ester. MS (EI): 445 (M-NH ₂ ) ⁺ .

b) Hydrogenation of 3.9 g of product a) in methanol (analogous to that described in Example -1c) gives 2.85 g / l- (4'-hexyloxy-L-phenylalanyl) piperidin-4-yloxy / acetic acid tert. -butyl ester. MS (EI): 462 (M) ^+, 445 (M-NH ₃₎ ^+.

c) Reaction of 0.5 g of product b) with 0.3 g of 4-amidinobenzoic acid chloro-anhydride hydrochloride pyridine (analogous to that described in Example 1f) gives 0.7 g of the starting ester by chromatography (silica gel; methylene chloride / methanol 5: 1). . MS (ISP): 609.4 (M + H) &lt; + &gt;.

EXAMPLE

A solution of 0.65 g of (R, S) -1- / 2- (4-aminoiminomethyl-N-methylbenzoylamino) -3- (4-methoxyphenyl) propionyl / piperidin-4-yloxyacetic acid, tert-butyl ester formic acid acid, left overnight at room temperature. After concentration, chromatography (Lichroprep RP-18; water / acetonitrile gradient) gives 0.13 g of (R, S) -1- / 2- (4-aminoiminomethyl-N-methylbenzoylamino) -3- (4-methoxyphenyl) propionyl / piperidine. -4yloxy / acetic acid, mp 181-182 ° C. MS (ISP): 497.1 (M + H) &lt; + &gt;.

The starting ester is obtained in the following manner:

a) Reaction 1.37 g of Z-N-Me-Tyr (Me) -OH (J.A.C.S., 112,

1990, 7663) with 0.86 g of 4-piperidinyloxyacetic acid (Example 1c) as described in (silica gel; diethyl

1.6 g of (R, S) -1- / 2- (N-tert-butyl ester in Example 2b), chromatography ester / hexane 5: 1) gives benzyloxycarbonyl-N-methylamino) -3- (4-methoxyphenyl) propionyl. piperidin-4-yloxy / acetic acid tert-butyl ester. MS (EI): 541.0 (M + H) &lt; + &gt;.

b) Hydrogenation of 1.5 g of product a) in methanol as described in Example le) gives 1.05 g of an oil which is further reacted with 0.58 g of 4-amidinobenzoic acid chloro-anhydride hydrochloride pyridine as described in Example 1f). Chromatography (silica gel; methylene chloride / methanol 9: 1) yields 0.7 g of the starting ester, m.p. 109-111 ° C. MS (ISP): 553.2 (M + H) &lt; + &gt;.

EXAMPLE

0.07 g of (R, S) -1- / 2- (4-aminoiminomethyl-N-methylbenzoylamino) -3- (4-methoxyphenyl) propionyl / piperidin-4-yloxyacetic acid is esterified in ethanol as described in Example 34. Chromatography (Lichroprep RP-18; water / ethanol gradient) and stirring with diethyl ether gives 0.056 g of (R, S) -1- / 2- (4-aminoiminomethyl-N-methylbenzoylamino) -3- (4-methoxyphenyl) propionyl. of piperidin-4-yl-oxyacetic acid ethyl ester, mp 126-128 ° C. MS (ISP): 525.5 (M + H) &lt; + &gt;.

EXAMPLE

To 100 mg of (S) -cis-1- (2- (4-amidinobenzoylamino) propionyl) -4-t-butoxycarbonylmethoxypyrrolidin-3-yloxyacetic acid tert-butyl ester dissolved in 5 ml methylene chloride are added 5 ml trifluoroacetic acid. After stirring at room temperature, the solvent was evaporated and the residue was purified by chromatography on silica gel RP-18 (carrier: water / tetrahydrofuran (0-50%)) to give (S) -cis-1- [2- (4-amidinobenzoylamino) propionyl] -4-carboxymethoxypyrrolidin-3-yloxyacetic acid MS: 437 (M + H) ⁺ .

The starting ester is obtained as follows:

(a) Under phase transition, stir 237 mg of cis-N-benzyloxycarbonylpyrrolidine-3,4-diol, 1 ml of tert-butyl ester of bromoacetic acid and 100 ml of tetrabutylammonium hydrosulphate in 10 ml of 50% sodium hydroxide. The organic phase is washed with water and evaporated. The residue was purified by silica gel chromatography (carrier: ethyl acetate / hexane 1: 3) to give 354 mg of cis-3,4-bis-butoxycarbonylmethoxy-pyrrolidine-1-carboxylic acid benzyl ester. MS: 354 (M-III).

b) Hydrogenate 320 mg of the product of the previous step in 10 ml

After 2 hours in EtOH at 100 mg 10% Pd / C, the catalyst was filtered off and the residue dissolved in 10 mL tetrahydrofuran was mixed with 224 mg N-benzyloxycarbonyl-L-alanine-N-hydroxysuccinimide ether in 100 μ 100 triethylamine. The reaction mixture was diluted with ether, the organic phase was washed with 1 M KHSO ₄ solution, dried and evaporated. The residue is purified by chromatography on silica gel (hexane / ethyl acetate 1: 1 carrier) to give 260 mg of (S) -cis-1- (2-benzyloxycarbonylaminopropionyl) -4-t-butoxycarbonylmethoxypyrrolidin-3-yloxyacetic acid tert-butyl ester. MS: 537 (M + H) &lt; + &gt;.

c) Hydrogenate 250 mg of the reaction product from the previous step in 10 ml of ethanol at 100 mg of 10% Pd / C, after 4 hours, filter the catalyst and stir the residue dissolved in 10 ml of pyridine with 102 mg of p-amidinobenzoyl chloride hydrochloride. The solution is evaporated and the residue is purified by chromatography on silica gel 3681 B RP-18 (carrier: water / tetrahydrofuran 5-30%) to give 143 mg of the starting ester, m.p. 127 ° C (d).

EXAMPLE

A solution of 150 mg of (S) -8- / 2- (4-aminoiminomethylbenzoylamino) -3- (4-t-butoxyphenyl) propionyl · 8-azabicyclo [3.2.1] octan-endo-3-yloxyacetic acid of ethyl ester hydrochloride, 5 mL of CH ₂ Cl ₂ and 2.5 mL of trifluoroacetic acid are stirred at room temperature and then the solvent is evaporated. After addition of ether with the residue, crystals precipitate out which are filtered off with suction and dissolved in 5 ml of EtOH. solution f is added 40 mg of NaOH dissolved in 1 mL of water and stirred at room temperature. The reaction mixture is neutralized with 1N hydrochloric acid and evaporated. The residue was purified by silica gel chromatography RP-18 to give 75 mg of (S) -8- [2- (4-aminoiminomethyl-benzoylamino) -3- (4-hydroxyphenyl) propionyl] -8-azabicyclo [3.2.1] octane-endo. -3-yloxyacetic acid. MS: 495 (M + H) &lt; ^{+ &gt};.

The source material is obtained as follows:

(a) 1 ml of a solution of 1 g of N-benzyloxycarbonylnorthropin and 20 mg of rhodium (II) acetate in 3 ml of toluene is added at 80 ° C with 2 ml of ethyl diazoacetic acid dissolved in 2 ml of toluene. After 3.5 hours, the solvent is evaporated and the residue is purified by silica gel chromatography (carrier: hexane / ethyl acetate 20-50%) to give 555 mg of endo-3-ethoxycarbonylmethoxy-8-azabicyclo / 3.2.1 / octane-8-carbonic acid. benzyl ester.M: 348 (M + H) ⁺ .

b) A solution of 500 mg of the reaction product of the preceding step in 20 ml of ethanol is hydrogenated at 100 mg of 10% Pd / C. After 3 hours, the catalyst was filtered off and the filtrate was evaporated. The residue was dissolved in 10 ml of tetrahydrofuran and added to a solution of 828 mg of NZL-Tyr (tBu) -OH, 140 μΐ of N-methylmorpholine and 569 mg of HBTU in 10 ml of tetrahydrofuran, which was stirred for 1 hour at 0 ° C. After stirring, the reaction mixture was evaporated and the residue was purified by silica gel chromatography (carrier: hexane: ethyl acetate = 1: 1). 650 mg of (S) -8- (2-benzyloxycarbonylamino-3- (4-t-butoxyphenyl) propionyl) -8-azabicyclo [3.2.1] octane-endo-3-yloxyacetic acid ethyl ester are obtained. MS: 567 (M + H) &lt; ^{+ &gt};.

c) Hydrogenate 600 mg of the reaction product from the previous step in 20 ml of ethanol at 100 mg of 10% Pd / C. After 1 hour, the catalyst is filtered off and the residue is dissolved in 10 ml of pyridine, mixed with 262 mg of p-amidinobenzoyl chloride hydrochloride at room temperature. The solvent is evaporated and the residue is purified by chromatography on silica gel RP-18 (carrier water / tetrahydrofuran 0-50%) to give 198 mg of the starting ester. MS: 579 (M + H) &lt; ^{+ &gt};.

EXAMPLE

706 mg of a mixture of (E) - or (Z) - (S) - / 3- / 2- / 4- (t-butoxycarbonyliminodi-t-butoxycarbonylaminomethyl) benzoylamino / propionylamino / propoxy / acetic acid butyl ester in 1.5 ml of methylene chloride and 1.5 mL of trifluoroacetic acid at 20 ° C. After evaporation of the solvent in vacuo, boiling with toluene and crystallization from acetonitrile gives 407 mg of (S) - [3- / 4- (aminoiminomethyl) benzoylamino / propionylamino / propoxy / acetic acid butyl ester trifluoroacetate (1: 1), mp 163-165 °. C. / α / θ ^ Ο = + 19 ° (c = 0.5 in methanol).

The starting material is obtained as follows:

(a) The mixture of acrylonitrile, butyl ester of glycolic acid and potassium carbonate is heated to 60 ° C. After treatment with ethyl acetate and water, the butyl ester of 2-cyanoethoxyacetic acid is distilled off. Boiling point 100-120 ° C / 0.3 mm mercury column (ball-point expansion tube).

b) The latter product of the reaction is hydrogenated in Pd / C in acetic acid and the resulting amine is treated with N-benzyloxycarbonyl-L-alanine. The butyl ester of (S) - [3- (2-benzyloxycarbonylamino-propionylamino) propoxy / acetic acid is formed, m.p. 54-55 [deg.] C., [alpha] / [lambda] = - ii, o (c = 0.5 in methanol). .

c) Hydrogenation on Pd / C in acetic acid yields the butyl ester of [3- (2-aminopropionylamino) propoxy / acetic acid which is treated with p- / E / Z / -tri (t-butoxycarbonyl) amidinobenzoic acid. The starting material is formed. MS: 707 (27 M + H), [α] _D ²⁰ = + 21.4 ° (c = 0.5 in methanol).

EXAMPLE

416 mg of (S) - / 3- / 2- / 4- (aminoiminomethyl) benzoylamino / propionylamino / propoxy / acetic acid butyl ester at 20 ° C are stirred with 8.3 ml of 25% hydrochloric acid. The solution is evaporated and the residue is boiled with water. From tetrahydrofuran 211 mg of (S) / 3- / 2- / 4- (aminoiminomethyl) benzoylamino / propionylamino / propoxy / acetic acid are obtained.

acid hydrochloride hydrate (1: 1), melting point- 89-90 ° C. / α / θ ² * ¹ = + 23.4 ° (c = 0.5 in methanol). EXAMPLE 50 Mixture prepared from i g 1- / N- / 4 - (t-butoxycarbo-

nilimino-di-t-butoxycarbonylamino-methyl) benzoyl-N- (2-methoxyethyl) glycyl] -piperidin-4-yloxyacetic acid tert-butyl ester, 3.8 mL of methylene chloride and 3.8 mL of trifluoroacetic acid. ° C. The solvent mixture is evaporated and the residue is boiled with water, dissolved in ethanol and adjusted to pH 8 with methanolic ammonia solution, followed by crystallization of 1- / N- / 4- (aminoiminomotyl) benzoyl / -N- (2-methoxyethyl) glycyl / piperidine- 4-yloxyacetic acid hydrate (2: 1). Melting point above 250 ° C. MS: 421 (100, M + H) @ +.

The starting material can be obtained as follows:

a) The tert-butyl ester of N- (2-methoxyethyl) glycine in ether and saturated aqueous sodium bicarbonate solution reacts with the benzyl ester of chloroformic acid to the tert-butyl ester of N-benzyloxycarbonyl-N- (2-methoxyethyl) glycine. MS: 324 (82, M + H) @ +.

b) The latter reaction product is decomposed to N-benzyloxycarbonyl-N- (2-methoxyethyl) glycine in methylene chloride / trifluoroacetic acid. MS: 267 (1, M).

c) Reaction of the latter reaction product with piperidin-4-yloxyacetic acid tert-butyl ester gives 1- (N-benzyloxycarbonyl-N- (2-methoxyethyl) glycyl / piperidin-4-yloxyacetic acid tert-butyl ester. MS: 465 (100, M + H) <^+> .

d) Catalytic hydrogenation on Pd / C in ethanol yields 1- tert -butyl ester of 1- N - (2-methoxyethyl) glycyl / piperidin-4-yloxyacetic acid. MS: 331 (100, M + H) @ +.

e) The latter product reacts with 4- (t-butoxycarbonylimino-di-t-butoxycarbonylaminomethyl) benzoic acid to the initial ester. MS: 777 (70, M + H) @ +.

EXAMPLE A

Compound I can be used in a known manner as an active ingredient in the manufacture of tablets containing:

For one tablet

active substance 200 mg microcrystalline cellulose 155 mg corn starch 25th mg talc 25th mg hydroxypropylmethylcellulose 20th mg

5 mg

EXAMPLE B

Compound I can be used in a known manner as an active ingredient in the manufacture of capsules containing:

per capsule

active substance 100.0 mg corn starch 20.0 mg milk sugar 95.0 mg talc 4.5 mg magnesium stearate 0.5 mg

220.0 mg

Claims (16)

DEFINITION OF INVENTION Claims 1. N-acyl-α-amino acid derivatives of the general formula Group 20, or R 0 - NH (CH ₂ ) _t a ² R is amidine or guanidine, one of X and Y being CH and the other being CH or N, 30 R ° for hydrogen or amidine, t for an integer from 2 to 6, R ', R' ', and R' '' 'are hydrogen or a-amino35 carboxylic acid substituents or side chains, in addition to IR ', R''andR' ¹ 'incoming Hydroxyl or carboxyl groups may be etherified, esterified or substituted with an amide group, and the existing amino groups may be C 1 -C 8 alkanoylated or aroylated group of formula Q is a group of formula (0H ₂ ) ₅ COO-T or - N (V) (CH ₂ ) _v - C (V ', V'') CH ₂ OCH ₂ COO-T or if R' and R '' together with the N and C atom to which they are attached, to form a ring, there may also be a group of formulas R ² E ^{5 in} fuel \\ // R ¹ · COO-T n is an integer equal to 0 or 1, V is an integer from 0 to 3, T and T 'are hydrogen or, under physiological conditions, lower alkyl or phenyl-lower alkyl, V - V '' is hydrogen or lower alkyl, U and U 'are hydrogen, C _1-6 alkanoyl or aroyl, Ar - aryl and 2 5 R - R - hydrogen, lower alkyl, lower alkoxy, halogen or -OCH ₂ COO-T ', or 2 3 R and R together with the phenyl group to which they are attached form a 1-naphthyl group, as well as hydrates or solvates and their physiologically acceptable salts. Compounds according to claim 1, characterized in that a is a group a ¹ ; R ', R''andR''' are hydrogen or conventional substituents or side chains of α-aminocarboxylic acids, and the hydroxyl or carboxyl groups of R ', R''andR' ¹ 'may be etherified, esterified or substituted with an amide group, and T represents hydrogen in Q or is cleaved under lower physiological conditions. Compounds according to claim 1 or 2, characterized in that a is a group a ¹ ; R is amidine, X is CH, V is CH or N and Q is a group of q \ Q ² , Q ^{3 4} , Q ⁵ or Q ⁹ . Compounds according to claim 1, 2 or 3, characterized in that Q is a group ζ) ¹ , especially when n = 1 and T is hydrogen or methyl, and -N (R ') C (R'',R'').') CO is one of the following residues: Gly, Ala, D-Ala, Vai, Leu, Sar, Orn, Lys, Phy, 2-methyl-Pro, Phe, Tyr, 3-iodine-Tyr, 3,5-diiodo-Tyr, Ser (Ac), Ser, Asp, Glu, Pro, 4-benzyloxyPro, 4-hydroxy-Pro, 2-piperidylenecarbonyl, NHCH (CH ₂ CH ₂ NH ₂ ) CO, Trp, Tyr (Me), Tyr (hexyl) and ON (Me) ₂ Tyr. Compounds according to claim 1, 2 or 3, characterized in that Q is a group Q ² , especially when n = 1, T is hydrogen and -N (R ') C (R'',R''') CO - Ala remains. Compounds according to claim 1, 2 or 3, characterized in that Q is a group Q ⁴ , in particular those compounds wherein n = 1, T is hydrogen; U and U 'are hydrogen or Ac and -N (R') C (R '', R ''') CO are a residue of Ala. Compounds according to claim 1, 2 or 3, characterized in that Q is a group Q ⁵ , especially when n = 1, T is hydrogen, Ar - a, a, a-trifluoro- m-tolyl and -N (R '). ) C (R '', R ''') CO is a residue of Ala. 8. Compounds according to claim 1, 2 or 3 wherein Q is Q ⁹ , especially when R ² -R ⁵ is hydrogen or R ² is -OCH ₂ COO (H or methyl), T - hydrogen or methyl and -N (R ') C (R'',R''') CO is a Pro residue. Compounds according to claim 1 or 3, characterized in that they are selected from the group: // 1- N - (p-amidinobenzoyl) -L-alanyl / -4-piperidinyl / oxy / acetic acid, 1- (N - (5-amidino-2-pyridyl) carbonyl) -L-alanyl / -4-piperidinyl / oxy / acetic acid, N-N- (p-amidinobenzoyl) -3- (4-hydroxy-3-3-iodophenyl) -L-alanyl / -4-piperidinyl / oxy / acetic acid acid, N- (3-acetoxy-N- (p-amidinobenzoyl) -L-alanyl / -4-piperidinyl / oxy / acetic acid, N, N- (p-amidinobenzoyl) -2-pyrrolidinyl / carbonyl / phenoxy / acetic acid, // 1- / N - ((5-amidino-2-pyridyl) carbonyl / -L-tyrosyl / -4-piperidinyl / oxy / acetic acid and especially // 1- / N - (p-amidinobenzoyl) -L-tyrosyl / -4-piperidinyl / oxy / acetic acid. Compounds according to claim 1, characterized in that Q is a group Q, especially when n = 0 and T is hydrogen, or a group Q ⁷ , especially when T is hydrogen. Compounds according to claim 1, characterized by θ wherein Q is a group Q, especially when V = 1, T is hydrogen or butyl and V'-V '' 'is hydrogen. Compounds according to claim 1, characterized in that -N (R ') C (R' ', R' '') CO is a N (methoxyethyl) Gly residue. 13. Compounds according to claim 1, characterized in that they belong to the group: (S) -1- / 2- (5-amidinopyridin-2-ylcarbonylamino) -3- (4-methoxyphenyl) -propionyl / piperidin-4-yloxyacetic acid, (S) -1- / 2- (4-amidinobenzamide) -3- (4-Methoxyphenyl) propionyl] -piperidin-4-yloxyacetic acid ethyl ester, (S) -1- [2- (4-Amidinobenzamide) -3- (4-methoxyphenyl) propionyl] -piperidin-4-yloxyacetate acid, 1 - N - (4-amidinobenzoyl) -4'-hexyloxy-L-phenylalanyl / piperidin-4-yloxyacetic acid. 14. Compounds of general formula E * 'Έ' '\ / N - C - C - G t H E '0 II or III wherein oi group of formula or R ⁰¹ - (CH ₂ ) _t a ⁰² wherein A-protected, if appropriate, amidine or guanidine group, R ⁰¹ - protected, if necessary, amino or guanidine group, E ', E' ¹ , E ' ¹ ' and G - having the same meaning as in formula R ', R'',R''' or QI, in addition, when R ⁰¹ is an amine or guanidine, or if A is an amidine or guanidine, at least one of E ', E'', E ' ¹ ' and G have at least one carboxylic acid ester group and / or ether group and / or protected amino group. Pharmaceutical preparations characterized in that they contain, as an active ingredient, a compound according to any one of claims 1 to 13, particularly suitable for the treatment of diseases caused by adhesion of platelet adhesive proteins, as well as platelet aggregation and cell-cell fusion. and prophylaxis. Use of a compound according to one of claims 1 to 13 for the manufacture of a medicament for the treatment of diseases caused by adhesion of proteins to platelets, as well as platelet aggregation and cell-cell fusion, in particular thrombosis, thrombus formation, haemorrhage in the brain, myocardium. for the treatment and prophylaxis of infarction, inflammation, arteriosclerosis or osteoporosis, as an antitumor agent or as a wound healing agent.