SI9210295A - N-acyl-alpha-aminoacides derivatives - Google Patents

Abstract

N-acyl-alpha-amino acid derivatives 0 R "R" ' II \ / L — c — N — c — C —Q l II R 'o I, in which L, R 'to R' 'and Q have the meaning given in the description. They can be used to treat or prophylaxis of adhesive binding disorders proteins to the blood platelets, as well as the aggregation of blood tile and cell-to-cell adhesion. Let's fix them with cleavage of protecting groups into appropriate protective groups compounds or by conversion of the cyano group to amidine group in the corresponding nitriles.

Description

The invention relates to novel derivatives of N-acyl-α-amino acids, to a process for their preparation, to pharmaceutical preparations containing such compounds, and to the use of these compounds in the preparation of pharmaceutical preparations.

The invention relates in particular to derivatives of N-acyl-α-amino acids of formula

R R ·

II \ /

L-C-N-C-C-Q i

I II

R 'o in which

L denotes a group of formula

X = Y

R ° -NH (CH ₂ ) t L ²

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

R ° denotes hydrogen or amidino, t denotes an integer from 2 to 6,

R 'R' and R '' denote hydrogen or N-substituents, respectively. side chains common to α-amino acids, wherein hydroxy or hydroxy are present at R 'R' and R '', respectively. carboxy groups of the ethereal or esterified or amidated, and amino groups C 1-6 alkanoylated or aroylated may be present,

Q denotes a group of formula

or

-N (V ') (CH ₂ ) _to -C (V, V') CH ₂ OCH ₂ COO-T q ⁸ or, to the extent that R 'and R' together with the N atom or C atom with which they are bound form a ring, they can also denote a group of formula

n represents the number 0 or 1, v denotes the integer from 0 to 3,

T and T 'denote hydrogen or lower alkyl or phenyl-lower alkyl which can be cleaved under physiological conditions,

V to V '' denote hydrogen or lower alkyl,

U and U 'denote hydrogen, C 1-6 alkanoyl or aroyl,

Ar denotes aryl, and

R ² to R ⁵ denote hydrogen, lower alkyl, lower alkoxy, halogen or the group -OCH ₂ COO-T, or

R ² and R ³ together with the phenyl group to which they are attached denote the 1-naphthyl group, as well as their hydrates or solvates and physiologically acceptable salts.

In the context of the invention Me denotes methyl, Ac denotes acetyl, tBu denotes tert-butyl, Boc denotes t-butoxycarbonyl, Z denotes benzyloxycarbonyl, and Fmoc denotes 9-fluorenylmethoxycarbonyl; Wave stands for L-valyl, Phe stands for L-phenyl-alanyl, Ser stands for L-seryl, Gly stands for glycyl, Ala stands for L-alanyl, Asp stands for L-aaspartyl, Leu stands for L-leucyl, Tyr stands for L-tyrosyl, sar stands for sarcosyl, Orn stands for L-ornithyl, Lys stands for L-lysyl, Phg stands for La-phenylglycyl, Pro stands for L-prolyl, Glu stands for L-glutamyl, Trp stands for L-tryptophan.

The term lower denotes groups of 1-6, preferably 1-4 C atoms. Examples of lower alkyl groups are methyl, ethyl, propyl, isopropyl, n-, s- or t-butyl and hexyl. Examples of lower alkyl groups that can be cleaved under physiological conditions are primary and secondary lower alkyl groups.

The symbols R ', R' and R '' in the α-aminocarboxylic acid residue (in the α-aminocarboxylic acid residue) -N (R ') C (R', R '') CO- denote hydrogen or N-substituents or side chains common in acyclic (open chain) or cyclic, natural or synthetic α-aminocarboxylic acids. Examples of such N-substituents R 'and the side chains R' and R '' are lower alkyl, which is optionally substituted by OH, COOH, NH2 or an aryl group, especially a phenyl group, hydroxy-phenyl, hydroxy-iodphenyl or hydroxy-diiodenyl group. Two such lower alkyl groups R 'and R', which are optionally substituted in this case, together with the Nosy C-atom to which they are attached, may form a 4- to 6-membered, preferably 5 membered ring. The hydroxy or carboxy groups present in the N-substituents R 'and the side chains R' and R '' may be ethereal or esterified or amidated, and the amino groups present may be C1-8 alkanoylated or aroylated. Examples of such ether, ester or amide groups are -OT °, -COO-T ⁰ or. -CON (V, V ') in which V and V' have the meanings given above and T ° denotes lower alkyl, especially methyl, hexyl and tBu, or aralkyl, especially benzyl.

Examples of open-chain α-aminocarboxylic acids are H-Gly-OH, H-Ala-OH, HOrn-OH and H-Tyr-OH; examples of cyclic α-aminocarboxylic acids, i.e. those in which R'in R ”together with N- or. The C-atoms to which they are attached form a ring are H-Pro-OH, H-Pro (4-OH) -OH and 2-piperidinecarboxylic acid.

Examples of C 1-4 alkanoyl groups U and U 'are formyl, acetyl and propionyl. Aryl denotes phenyl optionally substituted with up to 3 substituents such as alkyl, OH, lower alkoxy, halogen or halogen-lower alkyl, especially CF3. Aroyl indicates the corresponding benzoyl groups.

The compounds of formula I may be solvated, especially hydrated. Hydration may be carried out during the preparation process, but may also be due to the hygroscopic characteristics of the compound of formula I, which was originally anhydrous.

Examples of the physiologically useful salts of the compounds of formula I are salts with physiologically tolerable mineral acids such as hydrochloric acid, sulfuric acid or phosphoric acid; or with 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 formula I with a free carboxyl group may also form salts with physiologically relevant bases. Examples of such salts are alkali metal salts, alkaline earth metal salts, ammonium and alkylammonium salts such as Na-, K-, Ca- or tetramethylammonium salts. The compounds of formula I may be present in the form of dipolar ions (Zwitterion).

Compounds of formula I containing one or more asymmetric C atoms may be present in the form of an enantiomer, diastereomer or mixtures thereof, e.g. in the form of racemates.

In formula I, R is preferably amidino, X is preferably CH, Y is preferably CH or N, and Q is preferably a group Ql, Q ² , q4 q5 or q9

In compounds of formula I in which Q = Q1, n is preferably 1, T is preferably hydrogen or methyl, and -N (R ') C (R', R '') CO- is preferably one of the residues Gly, Ala, D-Ala, Val, Leu, Sar, Orn, Lys, Phg, 2-methyl-Pro, Phe, Tyr, 3 iodine-Tyr, 3,5-diode-Tyr, Ser (Ac), Ser, Asp, Glu , Pro, 4-benzyloxy-Pro, 4-hydroxyPro, 2-piperidylene carbonyl, NHCH (CH2CH2NH2) CO, Trp, Tyr (Me), Tyr (hexyl), Tyr (O-tBu), O, N (Me) ₂ - Tyr and N (MeOCH ₂ CH2) Gly.

Suitable compounds with Q = Q ² , Q ⁴ or are those compounds in which 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.

When Q = Q9, R ² to R 4 are preferably H, or R ^{2 is} carboxymethoxy or methoxycarbonyl-methoxy, T = HaliCH 3, and -N (R ') C (R', R '') CO- = Pro.

Examples of preferred compounds are compounds from the following 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, [[1- [N (p-amidinobenzoyl) -3- (4-hydroxy-3-iodophenyl) -L-alanyl] -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 in particular [[1- [N - (p-Amidinobenzoyl) -L-tyrosyl] -4-piperidinyl] oxy] -acetic acid.

Further preferred compounds of formula I are those compounds in which Q denotes a group (p, especially those where n = O and T denotes hydrogen, or a group Q ² , especially that group in which T denotes hydrogen, as well as those compounds , in which Q denotes a group Q ^, especially one where v = l, T denotes hydrogen or butyl and V 'to V'"denote hydrogen.

Examples of such compounds are:

(S) -1- [2- (5-Amidinopyridin-2-ylcarbonylamino) -3- (4-methoxyphenyl) propionyl] piperidin-4-yloxyacetic acid, (S) -1- [2- (4-amidinobenzamido) ethyl ester ) -3- (4-methoxyphenyl) propionyl] -piperidin4-yloxyacetic acid, (S) -1- [2- (4-amidinobenzamido) -3- (4-methoxyphenyl) propionyl] -piperidine-4yloxyacetic acid, [1- [N- (4-Amidinobenzoyl) -4'-hexyloxy-L-phenylalanyl] -piperidin-4-yloxy] -acetic acid.

The above N-acyl-a-aminocarboxylic acids can be prepared according to the invention by:

a) in a compound of the formula o e e II \ /

L ° —C — N — C —C — G

II in which

L ° denotes a group of formula

X = Y oi or

R ^ol - (CH ₂ ) t _l o 2 in which A is optionally a protected amidino or guanidino group,

R ^o1 denotes a protected amino or guanidine group, as appropriate,

E ', E', E '' and G have the same meaning as R ', R', R '' or. Q in the formula I, wherein when R 1 denotes amino or guanidine, or when A denotes amidino or

"Guanidino, at least one of E ', E", E' "and G contains at least one carboxylic acid ester group and / or ether group and / or protected amino group; a protected amino, amidine or guanidine group, respectively. a carboxylic acid ester group, or

b) in nitrile of formula

translate the cyano group into an amidine group, or

c) an amine of formula

The R'-NHC (R ”, R” ') of CO-Q ^{IV is} converted to an acid of the formula L ^ -COOH or a reactive derivative of this acid, and

d) optionally functionally converting the reactive group contained in the compound of formula I, and

e) optionally, the compound of formula I is converted into a physiologically acceptable salt, or the salt of the compound of formula I is converted to free acid or base.

Examples of the fissionable carboxylic acid ester groups are: benzyl-OCO- and lower alkyl-OCO- than t-Bu-OCO-.

Examples of fissionable protected amino, amidino and guanidino groups are:

-NH-Z, -NH-Boc and -N ₃ ; -C (NH) NH-Z, -C (NH) NH-Boc, -C (N-Boc) N (Boc) _2, and -C (N-Boc) NH-boc; -NHC (NH) NHNO2 and -NHC (N-Boc) NH-Boc.

An example of a fissionable ether group is t-Bu-O.

The ester groups can be hydrolyzed in a manner known per se, e.g. with a base such as an alkali metal hydroxide, e.g. sodium hydroxide, in a solvent such as methanol or water; or with an acid such as hydrochloric acid. Benzyl esters can be cleaved by hydrogenation in the presence of a precious metal catalyst, such as e.g. palladium on activated carbon (Pd / C) in a solvent such as methanol, ethanol, formic acid or acetic acid, at a temperature up to about 40 ° C, preferably at room temperature.

In doing so, we simultaneously cleave an amidine protecting group such as Z, which contains group A.

Ester groups such as t-Bu-OCO-, as well as amino or amino protecting groups. the amidine group and ester groups such as t-Bu-Ο- may be cleaved by an acid such as formic or trifluoroacetic acid, optionally in a solvent such as dichloromethane, respectively. using acetic acid saturated with gas HCl at a temperature up to 40 ° C, preferably at room temperature.

Variant b) can be realized by converting nitrile III by reaction with sulfur (hydrogen sulfide) and triethylamine in pyridine to thioamide, and by methylation with methyliodide in acetone and subsequent ammonolysis with ammonium acetate in methanol to form a compound of formula I .

The coupling of c) amine IV with acid ΐΛ (Ό0Η or its reaction derivative such as acid chloride) is carried out 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.

The functional transformations of the reactive groups according to a variant of process d) include the cleavage of the lower-alkoxy-carbonyl group -COO-T or -COO-T ', or the C 1-8 alkanoyloxy or aroyloxy group OU or O-U' which are in the Q group, or the esterification of the carboxylic group in acid I, and halogenation, especially iodination of the aryl group, which is located in the side chain R "or R".

Thus, butoxycarbonyl or The methoxycarbonyl groups in the Q group are cast with an acid such as aqueous hydrochloric acid or. acetic acid, or under basic conditions, e.g. using an aqueous solution of sodium hydroxide in methanol. Carboxy group esterification is realized e.g. by reaction of an acid with a suitable alcohol in the presence of catalytic amounts of H2SO4.

Iodination of the aryl group, especially the hydroxyphenyl group, located in the side chain R "or R" "can be accomplished by reaction of the compound of formula I with chloramine T, followed by reaction with sodium iodide in a water / dimethylformamide mixture.

An amine of formula I in which L is a group H2N (CH2) t is converted to the corresponding guanidine of formula I in which L is HN = C (NH2) -NH (CH2) t such that the amine is reacted with ethanesulfonate 2- S-isothioureas in the presence; bases, such as Na ₂ CO3 or NaOH at temperatures up to 40 ° C.

The compounds of formulas II and III are novel and as such constitute the object of the present invention. We obtain them in a manner known per se.

A compound of formula II in which L ° denotes an aryl group L ⁰¹ is obtained by reaction of an amine of formula

E'-NHC (E ”, E '”) CO-G' V in which G 'denotes one of the groups Ql to Q9, in which the carboxylic acid ester groups are the -COO-T group and, optionally, the group present - COO-T ', with an acid of formula

COOH

VI or with its reactive derivative, e.g. acid chloride.

This reaction may optionally be carried out in the presence of tetra-n-butylammonium hydrogen sulfate, in a solvent such as e.g. dichloromethane, and in the presence of a base such as e.g. aqueous solutions of sodium hydrogen carbonate.

An amine of the formula HQ ° in which Q ° denotes one of the amino groups Ql to Q8 in which the -COO-T group is present as the ester group of the carboxylic acid and, optionally, the -COO-T 'group can be converted by acid with formula

to the nitrile of formula III.

The reaction can be carried out in the presence of 2- (1H-benzotria7.ol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) and an organic base such as e.g. Nmethylmorpholine, in a solvent such as e.g. DMF.

A compound of formula II in which A denotes an amidine group can be obtained by converting a cyano group to an amidine group in nitrile corresponding to a compound of formula

II. This last nitrile can be obtained by coupling an amine of formula V above with an acid of formula

COOH

VIII or with a functional derivative thereof, e.g. acid chloride.

This coupling can be carried out in the presence of 2-chloro-4,6-dimethoxy-l, 3,5-triazine (CDMT) and a base such as e.g. n-methyl-morpholine, in a solvent such as e.g. dichloromethane.

A compound of formula II in which L ° denotes a group L ⁰² with a protected amino or guanidine group R ⁰¹ is obtained by coupling an amine of formula V with an acid of formula R ^ol - (CH 2) t -COOH, e.g. in the presence of HBTU and N-methylmorpholine.

The nitrile of formula III in which Q denotes the group Q9 can be obtained as follows:

Amin with the formula

R ² R ³

R 'R'

HN

IX in which R 'and R' together with the N atom and the C atom to which they are attached form a cycle and denote a protecting group, react with an acid of formula VIII or a functional derivative thereof, cleave the protecting group and the phenol formed reacts with bromoacetic acid derivative BrCH ₂ COO-T.

The reaction of an amine of formula IX with an acid chloride corresponding to an acid of formula VIII can be carried out in the presence of a base such as triethylamine in dimethylformamide. Cleavage of the protecting group V / l, e.g. benzyl groups can be carried out by hydrogenolysis over Pd / C in ethanol, and the reaction of the above phenol with the bromoacetic acid derivative can be carried out in dimethylformamide in the presence of potassium carbonate.

The amines of formulas IV and V can be obtained e.g. by coupling an N-protected amino acid of formula

W2-N (E ') C (E', E '') COOH X with an amine of the formula H-Q ° and deprotecting e.g. protecting groups Z or Boc in the coupling product.

The acids of formula VII can be obtained by coupling a functional acid derivative of formula VIII, e.g. of acid chloride, with amine

R'-NH-C (R ”, R” ') COO-lower alkyl X' and ester group cleavage at coupling product. Coupling can be accomplished e.g. in dichloromethane in the presence of triethylamine. A lower alkyl group, e.g. methyl group can be removed by using an aqueous solution of LiOH in methanol.

It can also be an amino acid of formula

R'-NHC (R ”, R” ') COOH X ”e.g. glycine, with acid chloride corresponding to formula VIII, in the presence of an aqueous solution of sodium hydrogen carbonate, optionally in the presence of tetramethylammonium sulfate in dichloromethane, is directly converted to an acid of formula VII.

An amine of formula IX can be obtained by Grignard's bromide reagent of formula

is converted with a compound of formula w ^{2 -} N - C - CO - N XII ¹ OCH,

R < ³ > and a protecting group protecting the amino group (W < + >) are removed from the reaction product.

The aforementioned amines of the formula HQ °, in which Q ° denotes one of the amino groups to Q8 in which the -COO-T group is present, and optionally the -COO-T 'group present as the ester group of carboxylic acids can be obtained at manner as described in the following Examples la) b) c), 2a), 46a) b), 47a) and 48a) b).

The compounds of formula I, their solvates and their salts, inhibit both the binding of fibrinogen, fibronectin, and the Willebrand factor to the platelet fibrinogen receptor (glycoprotein Ilb / IIIa), as well as their binding and binding of further adhesion proteins, e.g. vitronectin, collagen and laminin, to the appropriate receptors on the surface of different cell types. These compounds thus affect cell-cell and cell-matrix interactions. These compounds, in particular, prevent the formation of platelets of blood platelets and can be used to eliminate or suppress blood platelets. prevention of diseases such as thrombosis, stroke, heart attack, inflammation and arteriosclerosis. Furthermore, these compounds affect tumor cells by inhibiting the metastasis of these cells. They can therefore be used as an antitumor agent. They can further accelerate wound healing. They also prevent bone breakdown, so they can be used to treat osteoporosis.

Inhibition of fibrinogen-fibrinogen receptor binding, the Ilb / IIIa glycoprotein, can be demonstrated as follows:

The Ilb / IIIa glycoprotein was obtained from Triton Χ-100 extract from human blood platelets and purified by Lectin affinity chromatography (Analytical Biochemistry 151, 1985, 169-177) and using Arg-Gly-Asp-Ser affinity column chromatography (Science 231, 1986, 1559-62). The receptor protein thus obtained binds to microtiter plates. The specific formation of fibrinogen bonds to the immobilized receptor is determined by an ELISA system (enzyme-linked immunosorbent assay). The IC50 values below correspond to the concentration of test substance required to inhibit the binding of fibrinogen to the immobilized receptor by 50%:

Product from examples 1 3 4 5 6 7 8 9 IC50 (μΜ) 0.01 0.0017 0.14 0.001 0.027 0.033 0.008 0.08

Product from examples 10 13 14 15 16 18 21 22 IC ₅₀ (μΜ) 0.017 0.001 0.018 0.053 0.002 0.0017 0.16 0.47

Product from examples 24 27 30 37 39 40 41 IC50 (μΜ) 0.026 0.008 0.015 0.0003 0.0008 0.05 0.0007

Product from examples 42 43 44 IC ₅₀ (μΜ) 0.007 0.0016 0.01

These compounds are slightly toxic since the LD5q of the product of Examples 3 and 14 is at 250 and the product of Example 5 at 500 mg / kg i.v. in mice.

As mentioned at the beginning of the description, medicaments containing a compound of formula I, a solvate of this compound or a salt thereof, are also an object of the present invention, further a process for the preparation of such medicaments, characterized in that one or more of said compounds and optionally translate one or more other therapeutically valuable substances into a galenic dosage form. These drugs may be administered enterally, e.g. orally in the form of tablets, lacquer tablets, dragees, soft and hard gelatin capsules, solutions, emulsions or suspensions, or rectally, e.g. in the form of suppositories, or in the form of sprays. Administration may also be performed parenterally, e.g. as injectable solutions or as infusions.

For the production of tablets, lacquer tablets, dragees and hard gelatin capsules, the active substance may be mixed with pharmaceutically inert, inorganic or organic additives (fillers). As such, the fillers can be used for tablets, dragees and hard gelatin capsules, e.g. lactose, corn starch or derivatives thereof, talc, stearic acid or its salts. For soft gelatin capsules, e.g. vegetable oils, waxes, greases, semi-solids and liquid polyols; depending on the characteristics of the active substances, no fillers are required at all in the soft gelatin capsules. For the preparation of solutions and syrups, they are suitable as additives e.g. water, polyols, sucrose, invert sugar and glucose; for injection solutions are suitable e.g. water, alcohols, polyols, glycerin and vegetable oils; natural or solid oils, waxes, greases and semi-liquid or liquid polyols are suitable for suppositories. In addition, pharmaceutical preparations may also contain preservatives, solubilizers, stabilizing agents, wetting agents, emulsifying agents, sweeteners, colorants, flavors, osmotic pressure salts, buffers, coating agents and antioxidants.

For the treatment or prevention of the diseases mentioned above, the dosage of such substances may vary within wide limits and must be adapted to the individual circumstances in each individual case. Generally, an oral dose of about 0.1 to 20 mg / kg, preferably about 0.5 to 4 mg / kg, per day for an adult should be appropriate, with the upper limit of the individual case also exceeding where appropriate.

Example 1

A solution of 2.43 g of [[1- (p-amidinobenzoyl) -glycyl] -4-piperidinyl] oxyacetic acid tert-butyl ester in 15 ml of dichloromethane / trifluoroacetic acid (1: 1) was allowed to stand at room temperature for 5 hours. After evaporation of the solvent and chromatography [silylated silica gel (LiChroprep Rp-18), methanol / water gradient], 0.46 g of trifluoroacetate [[1- [N- (p-amidinobenzoyl) glycyl] -4-piperidinyl] -oxy-acetic acid was obtained. m.p. 233-236 ° C. MS (FAB): 363 (M + H) < + >.

The starting material was obtained as follows:

a) A solution of 50 g of 4-hydroxypiperidine in 500 ml of dichloromethane was sequentially added at 0 ° C to 69.1 ml of triethylamine and 70.2 ml of hydrochloric acid benzyl ester. The resulting suspension was stirred overnight at room temperature and then filtered. The residue, which appeared after concentrating the filtrate, was introduced into ethyl acetate, washed with water and 1N hydrochloric acid, dried and concentrated.

73.6 g of N-benzyloxycarbonyl-4-hydroxy-piperidine were obtained;

Rf = 0.56 (ethyl acetate / methanol 9: 1 mixture), MS (E): 235 (M ⁺ ).

b) To a solution of 30.1 g of N-benzyloxycarbonyl-4-hydroxypiperidine in 300 ml of toluene was added 28 ml of bromoacetic acid tert-butyl ester and 1.4 g of tetra-n-butylammonium hydrogen sulfate in 10 ml of water. A solution of 125 g of sodium hydroxide in 125 ml of water was then added dropwise. After stirring overnight, the organic extracts were separated, dried and concentrated. After drying, 34.1 g of N-benzyloxycarbonyl-4 - [(tert-butoxycarbonyl) -methoxy] -piperidine were obtained;

R f = 0.76 (ethyl acetate), MS (E): 293 (MC ₄ Hg) +.

c) To a solution of 30 g of the product of b) in 50 ml of ethanol was added 1.5 g of Pd / C (10%). The reaction mixture was hydrogenated at room temperature. Then it was filtered off from the catalyst, washed with ethanol and the resulting filtrate was concentrated. We got

17.4 g of 4-piperidinyloxyacetic acid tert-butyl ester;

Rf = 0.14 (ethyl acetate / methanol 1: 1 mixture), MS (E): 215 (M ⁺ ).

d) Combining 5.8 g of Z-glycine (activated with 5.4 g of CDMT) with 6.0 g of 4-piperidinyloxyacetic acid tert-butyl ester and 6.3 ml of N-methylmorpholine in dichloromethane gave 10 g of benzyl - [[4 - [(tert- butoxycarbonyl) methoxy] piperidinyl] carbonyl] methylcarbamate. MS (SW): 406 (M ⁺ ).

e) Hydrogenolysis of a solution of 10 g of the product of d) in 200 ml of ethanol in the presence

0.7 g of 10% Pd / C and 1.4 ml of acetic acid were isolated by chromatography on silica gel using ethyl acetate / methanol (1: 1), 4.1 g of tert-butyl ester 1 - [(1glycyl-4-piperidinyl) oxy] acetic acids, MS (E): 273 (M + H) ⁺ . IR: 1746 cm' ·

f) Mixtures of 4.1 g of product from e) and 0.03 g of tetra-n-butyl ammonium hydrogen sulfate in 210 ml of a mixture of dichloromethane and saturated aqueous sodium hydrogen carbonate solution (4: 3) were added at room temperature 2.95 g of pamidinobenzoyl chloride hydrochloride (which was obtained from p-amidinobenzoic acid by reaction with thionyl chloride in tetrahydrofuran in the presence of dimethylformamide). After stirring overnight, it was diluted with the addition of dichloromethane and water, and the pH was adjusted to 9-10 by the addition of a 1N sodium hydroxide solution, the organic extracts were settled, dried and then concentrated. After drying, 2.43 g of the desired starting material were obtained, MS (FAB): 419 (M + H) +.

Example 2

A) A solution of 1.5 g of [[1- [N- (p-cyanobenzoyl) -glycyl] -4-piperidinyl] oxy] acetic acid methyl ester in 215 ml of pyridine / triethylamine (40: 3) was saturated with hydrogen sulfide and allowed stand for 24 hours at room temperature. After the solvent was decided, the residue was taken up in ethyl acetate and washed with saturated sodium chloride solution. The organic extracts were dried and concentrated. After chromatography of the residue obtained on silica gel, 1.34 g of [[1- [N- [p (thiocarbamoyl) benzoyl] glycyl] -4-piperidinyl] oxy] was isolated using ethyl acetate as eluent, followed by the use of ethyl acetate / methanol as eluent. acetic acids;

MS (FAB): 394 (M + H) < + >.

B) The reaction of 1.25 g of the compound obtained in the previous step with 7.5 ml of methyl iodide in 150 ml of acetone on boiling gave 1.65 g of methyl ester hydroiodide [[l- [N- [p- [l - (methylthio) formamidoyl] benzoyl] glycyl] -4-piperidinyl] oxy] acetic acid; MS (FAB): 408 (M + H) < + >.

C) By ammonolysis of 1.5 g of the product from B) in the presence of 0.32 g of ammonium acetate in 100 ml of methanol at boiling point 0.76 g of methyl ester of [[1- [N- (p-amidinobenzoyl) glycyl] -4-piperidinyl] oxy was obtained ] acetic acids; m.p. 103-105 ° C, MS (FAB): 377 (M + H) +.

The starting nitrile was obtained as follows:

a) The esterification of 4-piperidinyloxyacetic acid trifluoroacetate (obtained by treating the product of Example lc) with trifluoroacetic acid in dichloromethane) in the presence of thionyl chloride gave the hydrochloride of 4-piperidinyloxyacetic acid methyl ester (MS) 173 (M (E)) (M (173)

b) By coupling 1.35 g of the product from a) with 1.18 g of N- (p-cyanobenzoyl) glycine (obtained by reaction of glycine with p-cyanobenzoyl chloride in saturated aqueous sodium hydrogen carbonate solution) in the presence of HBTU and N-methylmorpholine in dimethylformamide , obtained by chromatography on silica gel (using ethyl acetate / methanol 9: 1 to 1: 1) 1.66 g of the desired starting nitrile,

MS (EI): 359 (M < + >).

Example 3

From 13 g of [[1- [N- (p-amidinobenzoyl) -L-alanyl] -4-piperidinyl] oxy] acetic acid tert-butyl ester] was analogous to Example 1 by treatment with trifluoroacetic acid in dichloromethane after recrystallization from methanol / diethyl ether 8.9 g of [[1- [N- (p-amidinobenzoyl) -L-alanyl] -4-piperidinyl] oxy] -acetic acid trifluoroacetate were obtained, m.p. 120 ° C (decomposition). MS (FAB): 377 (M + H < + >). [α] ²⁰ D = + 24.7 ° (c = 0.7, water).

The starting material was obtained as follows:

a) Coupling 18 g of ZL-alanine with 17.4 g of 4-piperidinyloxyacetic acid tert-butyl ester and hydrogenolysis of the resulting product as described in Example ld) and e) gave 15.8 g of l - [(1L tert-butyl ester) -alanyl-4-piperidinyl) -oxy] acetic acid. Tal. 93-96 ° C. [a] ² % = + 2.0 ° (C = 1.0, methanol).

b) Coupling of 4.7 g of the product from a) with 3.4 g of p-amidinobenzoyl chloride hydrochloride as described in 1f) gave 4.2 g of the desired starting material. MS (ES): 433 (M + H) +.

Example 4

From 0.3 g of [[N1- [N- [p- [N- (tert-butoxycarbonyl) amidinobenzoyl] -Dalanyl] -4-piperidinyl] oxy] -acetic acid tert-butyl ester, 0.1 g was obtained analogously to Example 1 [[1 [N- (p-Amidinobenzoyl) -D-alanyl] -4-piperidinyl] -oxy] -acetic acid in the form of trifluoroacetate. Tal. 115 ° C (decomposition).

[α] ^2θ 0 = −27.5 ° (C = 0.8, water). MS (FAB); 377 (M + 1) +.

The starting material was obtained as follows:

a) Reaction of 3 g of 4-piperidinyloxyacetic acid tert-butyl ester with 2.43 g of Z-Dalanin as described in Example ld) was obtained by chromatography on silica gel using ethyl acetate / hexane (1: 1), 3.1 g of benzyl - [(R) -1 - [[4 - [(tert-butoxycarbonyl) methoxy] piperidinyl] carbonyl] ethyl] carbamate. MS (EI): 420 (M < ^{+ >} ).

b) Hydrogenolysis of 3.1 g of the product from a) as described in Example le) was obtained

2.5 g of 1- [(1-D-alanyl-4-piperidinyl) oxy] -acetic acid acetate tert-butyl ester.

MS (SW): 215 (M-C3H5NO).

c) Reaction of 1 g of the previous step compound with 0.66 g of p-amidinobenzoyl chloride hydrochloride in dimethylformamide in the presence of triethylamine and treatment with diterbutyl dicarbonate gave, after chromatography on silica gel, using a dichloromethane / methanol mixture (20: 1) , 0.3 g of desired starting material. MS (FAB); 533 (M + H < + >).

Example 5

Hydrolysis of 1.6 g of [[1- [N - [(5-amidino-2-pyridyl) carbonyl] -L-alanyl] -4-piperidinyloxy-acetic acid tert-butyl ester in hydrochloric acid-saturated ice was obtained by chromatography on silylated RP-18 silica gel and recrystallization from tetrahydrofuran / ethyl acetate, 0.15 g [[1- [N - [(5-amidino-2-pyridyl) carbonyl] -L-alanyl] 4-piperate and yloxy] -acetic acid. Tal. above 200 ° C (decomposition).

MS (FAB): 378 (M + H) < + >.

The starting material was obtained as follows.

a) By reacting 2.4 g of 1 - [(1 L-alanyl-4-piperidinyl) -oxy] acetic acid tert-butyl ester (Example 3a) with 1.0 g of 5-cyan-2-picolic acid, according to example 1d) , 2.43 g of [[1- [N - [(5-cyan-2-pyridyl) carbonyl] -L-alanyl] -4-piperidinyloxy-acetic acid tert-butyl ester was obtained, MS (FAB): 417 (M + H) +.

b) Subsequent treatment of 2.4 g of the product from the previous step in the manner described in Example 2A) B) C) gave 2g of the desired starting material. Tal. 142-145 ° C.

MS (FAB); 434 (M + H) < + >.

Example 6

[1- [N- (p-amidinobenzoyl) -L-valyl] -4-piperidinyl] oxyacetic acid was obtained from 1 g of acetate tert-butyl ester after analogy to Example 1 after crystallization from ethyl acetate, 0.8 g. [[1- [N- (benzyloxy) carbonyl] -L-avalyl] -4-piperidinyl] -oxy] acetic acid as trifluoroacetate.

Tal. 210-211 ° C: MS (FAB): 405 (M + H) +. [α] ² % = + 32.6 ° (C = 0.8, water).

The starting material can be prepared as follows:

a) Coupling 2.5 g of ZL-valine with 2 g of piperidinyloxyacetic acid tert-butyl ester as described in Example 2b) gave 4 g of [[1- [N [(benzyloxy) carbonyl]] -L- valyl] -4-piperidinyl) -oxy] acetic acid;

MS (ES): 449 (M + H) +.

b) Analogous to Example 1), but without the addition of acetic acid, 1.4 g of l - [(1 L-valyl-4-piperidinyl) oxyacetic acid, MS (E) were obtained from 1.9 g of the product of Example 6a): 315 (M + H) < ⁺ >.

c) Analogous to Example lf) from 3.3 g of the product of Example 6b) and 2.5 g of p-amidinobenzoyl chloride hydrochloride by chromatography (silica gel, dichloromethane / methanol / acetic acid 95: 4: 1) and crystallization from diethyl ether gave 1.1 g of the desired starting material acetate. Tal. Mp 179-182 ° C. MS (FAB): 461 (M + H) < ⁺ >.

Example 7

From 1.5 g of tert-butyl ester [[1- [N- (p-amidinobenzoyl) -L-leucyl] -4-piperidinyl] oxyacetic acid acetate], analogous to Example 1, after crystallization from ethyl acetate / diethyl ether, 1.1 g [[l - [N- (p-Amidinobenzoyl) -L-leucyl] -4-piperidinyl] -oxy] acetic acid in the form of trifluoroacetate. Tal. 216-218 ° C.

MS (FAB); 419 (M + H) < + >. [α] ²⁰ D = + 22.5 ° (C = 0.8, water).

The starting acetate was obtained as follows:

a) Combining 2.6 g of ZL-leucine with 2 g of 4-piperidinyloxyacetic acid tert-butyl ester as described in Example ld) gave 4.1 g of tert-butyl ester [[1- [N [(benzyloxy) carbonyl] - L-leucyl] -4-piperidinyl] oxy] acetic acid.

b) Analogous to Example 6b) and 1f) were obtained from 4.1 g of the product of Example 7a) by chromatography (silica gel; dichloromethane / methanol / acetic acid mixture, 95: 4: 1) and then crystallization from diethyl ether 1.5 g of the desired acetate. Tal. 120-129 ° C (decomposition).

MS (FAB): 475 (M + H) < + >.

MS (FAB); 463 (M + H) < + >.

Example 8

From 1.4 g of tert-butyl ester of [[1 - [(p-amidino-N-methylbenzamido) acetyl] -4-piperidinyloxyacetic acid acetate was obtained, after crystallization from diethyl ether, 0.9 g [[l - [(p-amidino- N-methylbenzamido) acetyl] -4-piperidinyl] oxy] acetic acid in the form of trifluoroacetate. Tal. 134-135 ° C. MS (FAB). 377 (M + H) < ⁺ >.

The starting material was obtained as follows:

a) Coupling 2.0 g of Z-sarcosine-N-hydroxysuccinimidester with 1.3 g of 4-piperidinyloxyacetic acid tert-butyl ester in the presence of triethylamine in tetrahydrofuran gave 2.1 g of benzyl- [4 - [[[(tert-butoxycarbonyl) - methoxy] piperidinoicarbamoyl] methyl] methylcarbamate. MS (FAB): 421 (M + H) < ⁺ >.

b) Analogous to Example 6b) and 1f) from 4 g of the product of Example 8a) after chromatography (silica gel; dichloromethane / methanol / acetic acid 93: 5: 2) and after crystallization from diethyl ether, 1.5 g of the desired acetate was obtained. Tal. 188-189 ° C.

MS (FAB): 432 (M + H) < + >.

Example 9

From 5.4 g of [[1- [N ² - (p-amidinobenzoyl) -N5- (tert-butoxycarbonyl) -Lornyl] -4-piperidinyl] -oxy] acetic acid tert-butyl ester, analogous to Example 1, 4.9 g [[ 1 [N ² - (p-Amidinobenzoyl) -L-ornyl] -4-piperidinyl] -oxy] acetic acid in the form of trifluoroacetate. MS (FAB): 420 (M + H) < ⁺ >. [α] 2 ° _D = + 4.5 ° (C = 0.8, MeOH).

The starting material can be prepared as follows:

a) Reaction of 6 g of 4-piperidinyloxyacetic acid tert-butyl ester with 10.2 g of N, N -ZN ^ Boc-L-ornithine, by analogy to Example ld) after chromatography on silica gel using ethyl acetate / hexane 1: 1, gave 11 g [[1- [N ² 21 (Benzyloxycarbonyl) -N ⁵ - (tert-butoxycarbonyl) -L-ornyl] -4-piperidinyl] oxyacetic acid tert-butyl ester. MS (FAB): 564 (M + H) < ⁺ >.

b) Hydrogenolysis of the ligands of the product of a) as described in Example le) gave 9 g of tert-butyl ester of [[1- [N ⁵ - (tert-butoxycarbonyl) -L-ornyl] -4-piperidinyl] oxy] acetate] acetic acids. MS (FAB): 430 (M + H) < + >.

c) Reaction of 9 g of the product from b) with 4.4 g of p-amidinobenzoyl chloride hydrochloride gave 5.7 g of the desired starting material as described in Example 1f). MS (FAB). 576 (M + H) < + >.

Example 10

0.54 g of tert-butyl ester of [[1- [N ² - [pN- (tert-butoxycarbonyl) amidinobenzoyl] -N ^ (tert-butoxycarbonyl) -L-lysyl] -4-piperidinyl] oxy] acetic acid were obtained analogous to Example 1, 0.35 g of [[1- [N ² - (p-amidinobenzoyl) -L-lysyl] -4-piperidinyl] -oxy] acetic acid trifluoroacetate.

MS (FAB). 434 (M + H) +. [«] ²⁰ D = + 12.4 ° (c = 0.8, water).

The starting material was obtained as follows:

a) By reaction of 2 g of 4-piperidinyloxyacetic acid tert-butyl ester with 2.8 g of N ² -NZ-Boc-L-lysine, as described in Example ld), after chromatography on silica gel using ethyl acetate / hexane 1 : 1, yield 2.6 g of [[1 [N ² - (benzyloxycarbonyl) -N ^ - (tert-butoxycarbonyl) -L-lysyl] -4-piperidinyl] -oxy] acetic acid tert-butyl ester. MS (FAB): 578 (M + H) < + >.

b) Hydrogenolysis of 2.6 g of the obtained product as described in Example le) gave 2 g of acetate of tert-butyl ester [[1- [N ^ - (tert-butoxycarbonyl) -L-lysyl] 4-piperidinyl] ] oxy] acetic acid. MS (FAB): 444 (M + H) < ⁺ >.

c) Reaction of 2 g of the previous step product with 1 g of p-amidinobenzoyl chloride hydrochloride was obtained by chromatography (silica gel; dichloromethane / methanol 20: 1), 1.95 g of desired starting material as described in Example 4c. . MS (FAB): 690 (M + H) < ⁺ >.

Example 11

From 0.4 g of tert - [[1- [N- (p-amidinobenzoyl) -L-phenylglycyl] -4-piperidinyl] -oxyacetic acid acetate], 0.25 g of trifluoroacetate [[1- [N- (pamidinobenzoyl)] were obtained analogously to Example 1. -L-Phenylglycyl] -4-piperidinyl] -oxy] acetic acid. Tal. above 250 ° C (ethyl acetate / diethyl ether 1: 1).

MS (FAB); 439 (M + H) < + >. [α] ² % = + 6.5 ° (c = 0.6, MeOH).

The starting material was obtained as follows:

a) By reaction of 1.85 g of 4-piperidinyloxyacetic acid tert-butyl ester with 3.5 g of Z-Lphenylglycine-N-hydroxysuccinimide ester, as described in Example 8a), after chromatography on silica gel using a 1: 1 petroleum ether / diethyl ether mixture as eluent, 3.8 g of [[1- (N-benzyloxycarbonyl) -L-phenylglycyl) -4-piperidinyl] oxyacetic acid tert-butyl ester are obtained. MS (FAB): 483 (M + H) < ⁺ >.

b) Hydrogenolysis of 4.7 g of the obtained product gave 3.2 g of [[1- (L-phenylglycyl) -4-piperidinyl] oxy] -acetic acid tert-butyl ester as described in Example 6b). MS (FAB); 349 (M + H) < + >.

c) Reacting 3.2 g of the previous step compound with 2.2 g of p-amidinobenzoyl chloride hydrochloride as described in Example 1f) by chromatography (silica gel; dichloromethane / methanol / acetic acid 95: 5: 2) to give 0.4 g of the desired acetate. Tal. 207-220 ° C (ethyl acetate, decomposition). MS (FAB): 495 (M + H) < ⁺ >.

Example 12

From 0.5 g of tert-butyl ester of [[1- [1- (p-amidinobenzoyl) -2-methyl-L-prolyl] -4-piperidinyl] oxyacetic acid acetate gave 0.14 g of trifluoroacetate [[1- [1- (p-Amidinobenzoyl) -2-methyl-L-prolyl] -4-piperidinyl-oxy] acetic acid. Tal. 219-220 ° C (acetonitrile).

MS (FAB); 417 (M + H) < + >. [α] ^2ΰ0 = + 17.1 ° (c = 0.9, MeOH).

The starting material was obtained as follows:

a) Reaction of 2-methyl-L-proline hydrobromide with p-cyanbenzoyl chloride analogous to Example 2b) gave 1- (p-cyanobenzoyl) -2-methyl-L-proline.

MS (SW): 213 (M-COOH) +.

b) Reaction of 1.67 g of 4-piperidinyloxyacetic acid tert-butyl ester with 0.8 g of 1- (p-cyanobenzoyl) -2-methyl-L-proline acid chloride (obtained by treating the previous step product with thionyl chloride) [[1- [1- (p-Cyanobenzoyl) -2-methyl-L-prolyl] -4-piperidinyl] -oxy] acetic acid tert-butyl ester 0.89 g. Tal. 180-182 ° C (ethyl acetate).

c) Following treatment with 0.89 g of the product of b) as described in Example 2A) B) C), 0.59 g of the desired acetate was obtained by chromatography (silica gel silica gel RP-18; water / methanol 9: 1). Tal. 191-192 ° C (ethyl acetate, decomposition).

MS (FAB); 473 (M + H) < + >.

Example 13

From 2.5 g of tert-butyl ester of [[1- [N- (p-amidinobenzoyl) -3-phenyl-L-alanyl] -4-piperidinyl] oxyacetic acid acetate gave 1.9 g of trifluoroacetate [[1- [N- (p-Amidinobenzoyl) -3-phenyl-L-alanyl] -4-piperidinyloxyacetic acid. Tal. 234-235 ° C (ethyl acetate).

W ²⁰ D = + ¹⁷ - ⁹ ° ( ^c = MeOH). MS (ES): 453 (M + H) +.

The starting acetate was obtained as follows:

a) Reaction of 2.15 g of 4-piperidinyloxyacetic acid tert-butyl ester with 3.0 g of Z-Lphenylalanine gave 4.8 g of tert-butyl ester [[1- (N-benzyloxycarbonyl) -3 as described in Example 2B); -phenyl-L-alanyl-4-piperidinyl] oxy] acetic acid.

MS (FAB): 497 (M + H) < + >.

b) Hydrogenolysis of 4.8 g of the obtained product as described in Example 6b) and subsequent conversion with 2.0 g of p-amidinobenzoyl chloride hydrochloride in the manner as described in Example 1f) was carried out by chromatography (silica gel; dichloromethane / methanol mixture). / acetic acid 22: 2: 1) to give 2.5 g of the desired acetate.

Tl. 176-178 ° C (diethyl ether). MS (FAB): 509 (M + H) < + >.

Example 14

From 2.5 g of t-butyl ester of [[1- [N- (p-amidinobenzoyl) -3- (p-tert-butoxyphenyl) -Lanylyl] -4-piperidinyl] -oxy] -acetic acid acetate was obtained analogously to Example 1 , by chromatography (silylated silica gel RP-18), water / methanol gradient, 1.0 g of [[1- [N- (p-amidinobenzoyl) -L-tyrosyl] -4-piperidinyl] -oxy] -acetic acid trifluoroacetate. M.p .: 125-130 ° C (ethyl acetate, decomposition): MS (FAB): 469 (M + 1) ⁺ .

The starting acetate was obtained as follows:

a) By reacting 2.15 g of 4-piperidinyloxyacetic acid tert-butyl ester with 3.71 g of NZ (O-tert-Bu) -L-tyrosine, by chromatography (silica gel, diethyl ether / light petroleum 1: 1), yield 4.8 g of [[1 [N-benzyloxycarbonyl) -3- [p- (tert-butoxyphenyl) -L-alanyl] -4-piperidinyl] oxy] -acetic acid tert-butyl ester. Tal. 96 ° C (diethyl ether).

MS (E): 417 (MC ₇ H ₇ -C ₄ H ₈ ) +, [σ] ²⁰ ο = + 5.4 ° (c = 0.8, CH ₃ OH).

b) Hydrogenolysis of 4.8 g of precursor as described in Example 6b) and the subsequent reaction with 1.5 g of p-amidinobenzoyl chloride hydrochloride as described in Example 1f) were chromatographed (silica gel; dichloromethane / methanol / acetic acid 22: 2) : 1) gave 2.6 g of the desired acetate. Tal. 170-172 ° C (diethyl ether).

MS (FAB): 581 (M + H) < + >.

Example 15

As a by-product of the chromatography described in Example 14, 0.09 g of [[1- [N- (p-amidinobenzoyl) -L-tyrosyl] -4-piperidinyloxyacetic acid] trifluoroacetate methyl ester was isolated. Tal. 189-190 ° C (ethyl acetate).

MS (FAB); 483 (M + H) < + >.

Example 16

By reacting 0.58 g of trifluoroacetate [[1- [N- (p-amidinobenzoyl) -L-tyrosyl] -4-piperidinyloxyacetic acid (Example 14) with chloramine T, followed by reaction with sodium iodide in water / dimethylformamide (8: 1). chromatography (silylated silica gel RP-18, water / acetonitrile gradient) yielded 0.04 g [[1- [N- (p-amidinobenzoyl) -3- (4-hydroxy-3-iodophenyl) -L-alanyl] -4] -piperidinyl] oxy] acetic acid. Tal. 230 ° C (water, decomposition). MS (FAB): 595 (M + H) < ⁺ >.

Example 17

0.09 g of [[1- [N- (p-amidinobenzoyl) -3- (4-hydroxy-3,5-diodophenyl) -L-alanyl] -4-piperidinyl] were further isolated from the reaction mixture described in Example 16. ] oxyacetic acid. Tal. 220-221 ° C (water, decomposition). MS (FAB): 720 (M + H) < ⁺ >.

Example 18

From 1.3 g of [[1- [3-tert-butoxy-N- [p- [N- (tert-butoxycarbonyl) amidino] benzoyl] -L-alanyl] -4-piperidinyl] -4-piperidinyl] acetic acid tert-butyl ester by treating with hydrogen chloride in ice, by chromatography (silylated silica gel RP-18, methanol / water gradient), 0.45 g of [[1- [3-acetoxy-N- (p-amidinobenzoyl) -4-piperidinyl]] hydrochloride was obtained. oxy] acetic acids.

[?] ²⁰ D = + 0-9 ° (c = 1.0, MeOH). MS (FAB): 435 (M + H) < + >.

The starting material was obtained as follows:

a) Coupling 7.5 g of ZL-Ser (tert-Bu) -OH with 7.0 g of 4-piperidinyloxyacetic acid tert-butyl ester and further hydrolyzing the resultant product as described in Example ld) e) gave 10.6 g of tert-acetate acetate; [[1- [3-tert-Butoxy-Lalanyl] -4-piperidinyl] oxy] acetic acid butyl ester.

Tal. 76-78 ° C. MS (FAB): 359 (M + H) < + >.

b) Reaction of 9.9 g of the previous step compound with 5.2 g of p-amidinobenzoyl chloride hydrochloride in dimethylformamide in the presence of triethylamine and further treatment with diethyl tert-butyl dicarbonate, after chromatography on silica gel using dichloromethane / methanol 20: 1, using chichuramethane / methanol 20: 1 followed by the use of ethyl acetate / hexane 3: 1 as eluent to give 4.3 g of tert-butyl ester [[1- [3-tert-butoxy-N [p- [N- (tert-butoxycarbonyl) amidino] benzoyl] -L- alanyl] -4-piperidinyl] oxy] acetic acid. Tal. Mp 162-165 ° C. MS (FAB); 605 (M + H) < + >.

Example 19

From 1.0 g of [[1- [3-tert-butoxy-N- [p- [N- (tert-butoxycarbonyl) amidino] benzoyl] -L-alanyl) -4-piperidinyl] acetic acid tert-butyl ester ( Example 18) Analogous to Example 1, after chromatography (silylated silica gel RP-18, water), 0.58 g of [[1- [N- (p-amidinobenzoyl) -4-piperidinyl] oxy] acetic acid trifluoroacetate was obtained. . [α] ²⁰ D = + 17.6 ° (c = 1.0, water). MS (FAB): 393 (M + H) < + >.

Example 20

From 5 g of LN- (p-amidinobenzoyl) -3 - [[4 - [(tert-butoxycarbonyl) methoxy] piperidinyl] carbonyl- / 3-alanine tert-butyl ester, analogous to Example 1 after crystallization from ethyl acetate / tetrahydrofuran. obtained 2.0 g of LN- (p-amidinobenzoyl) -3 - [[4 - [(carboxymethoxy) piperidino] carbonyl-O-alanine triflucacerate, m.p. 145-150 ° C. MS (FAB); 421 (M + H) < + >.

The starting material was obtained as follows:

a) By coupling 11 g of ZL-Asp (O-tert-Bu) -OH monohydrate with 7.0 g of 4-piperidinyloxyacetic acid tert-butyl ester, 16 g of tert-butyl were obtained in an analogous manner as described in Example 2b). LN- (benzyloxycarbonyl) -3 - [[4 - [(tertbutoxycarbonyl) methoxypiperidino] carbonyl- / 3-alanine ester.

MS (FAB): 521 (M + H) < + >.

b) After hydrogenolysis, 17 g of the compound from the previous step, performed as described in Example 6b), isolated 11 g of L-3 - [[4 - [(tert-butoxycarbonyl) methoxy] piperidino] carbonyl-O- tert-butyl ester. alanine. MS (FAB): 387 (M + H) < ⁺ >.

c) By coupling 11 g of the previous step compound with 6.9 g of pamidinobenzoyl chloride hydrochloride as described in Example 1f), 10.2 g of the desired starting material were isolated by chromatography (silica gel, dichloromethane / methanol 9: 1). MS (FAB): 533 (M + H) < ⁺ >.

Example 21

From 0.5 g of [[1- [N- (p-amidinobenzoyl) -4-tert-butoxy-L-glutamoyl] -4-piperidinyloxyacetic acid] tert-butyl ester, 0.25 g of trifluoroacetate [[l were obtained after crystallization from ethyl acetate] - [N- (p-Amidinobenzoyl) -La-glutamoyl] 4-piperidinyl] oxy] acetic acid. Tal. Mp 105-108 ° C.

[«] ²⁰ D = + 6.9 ° ( ^c = methanol). MS (FAB): 435 (M + H) < + >.

The starting material was obtained as follows:

a) Coupling 11 g of ZL-Glu (O-tert-Bu) -OH with 7.0 g of 4-piperidinyloxyacetic acid tert-butyl ester gave 15.4 g of tert-butyl ester in an analogous manner as described in Example ld) [[ 1- [N- (Benzyloxycarbonyl) -4-tert-butoxy-Lgutamoyl] -4-piperidinyl] oxy] acetic acid. MS (FAB): 535 (M + H) < ⁺ >.

b) Hydrogenolysis of 15.4 g of the compound from the previous step as described in Example 6b) gave 7.5 g of acetate of [[1- (4-tert-butoxy-L-glutamoyl) 4-piperidinyl] oxy] acetic acid acetate acid. MS (FAB): 401 (M + H) < ⁺ >.

c) Coupling 7.5 g of the previous step compound with 3.9 g of pamidinobenzoyl chloride hydrochloride as described in Example 1f) gave 6.9 g of tert-butyl ester [[1- [N- (p-amidinobenzoyl) -4-tert-butoxy] -L-glutamoyl] -4-piperidinyl] oxyacetic acid. MS (FAB): 547 (M + H) < + >.

Example 22

From 2 g of [[(R / S) -1- [N- (p-amidinobenzoyl) -L-alanyl] -3-piperidinylmethoxyacetic acid tert-butyl ester] 0.6 g of trifluoroacetate [[(R / S) were obtained analogously to Example 1 -1- [N- (p-Amidinobenzoyl) -L-alanyl] -3-piperidinyl] methoxy] -acetic acid. Tal. 87-90 ° C (ethyl acetate). MS (FAB): 391 (M + H) < + >.

The starting material was obtained as follows:

a) Rac-3- (hydroxymethyl) piperidine was obtained analogous to Example 1a) to give rac-N-benzyloxycarbonyl-3- (hydroxymethyl) piperidine. MS (ES): 249 (M) ⁺ .

b) Benzyl-rac-3 - [[(tertbutoxycarbonyl) methoxy] methyl] -1-piperidinecarboxylate was obtained from product a) in analogy to Example 1b).

MS (SW): 307 (MC ₄ H ₈ ) +.

c) The product of b) was hydrogenated analogously to Example lc) to rac- (3piperidinylmethoxy) acetic acid tert-butyl ester. MS (SW): 172 (M-C4Hg) ⁺ .

d) By coupling the product of c) with ZL-alanine, as in Example ld), benzyl - [(S) -1 [[(R / S) -3 - [(tert-butoxycarbonyl) methoxy] piperidino] was obtained -carbonyl] ethylcarbamate. MS (SW): 434 (M) ⁺ .

e) Hydrogenation of the product of d) as described in Example le) gave the acetate of [[(R / S) -1-L-alanyl-3-piperidinyl] methoxy] acetic acid tert-butyl ester.

MS (SW): 285 (M-CH ₃ ) +

f) Coupling the product from e) with the p-amidinobenzoyl chloride hydrochloride when: as described in Example 1f) gave the desired starting material after chromatography (silylated silica gel RP-18). MS (FAB): 447 (M + H) < ⁺ >.

Example 23

From 2.7 g of [[1- [N- (p-amidinobenzoyl) -L-alanyl-4- (a, a, α-trifluoromethyl) -4-piperidinyl] oxy] acetic acid tert-butyl ester, are analogous to Example 1 gave 0.7 g of [[1- [N (p-amidinobenzoyl) -L-alanyl] -4- (a, a, α-trifluoro-m-tolyl) -4-piperidinyl] -oxy] acetic acid. Tal. above 280 ° C (water / methanol). MS (FAB): 521 (M + H) < ⁺ >.

The starting material was obtained as follows:

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

MS (SW): 379 (M) ⁺ .

b) From product a), analogous to Example 1b), benzyl-4 - [(tert-butoxycarbonyl) methoxy] -4- (a, o :, a-trinuoro-m-tolyl) -1-piperidinecarboxylate was obtained.

MS (FAB): 494 (M + H) < + >.

c) Hydrogenation of the product from b) analogous to Example le) gave the acetate of [[4- (a, a, a-trifluoro-m-tolyl) -4-piperidinyl] oxy] acetic acid tert-butyl ester.

MS (SW): 227 (MC ₁₆ H ₁₂ O ₃ ) +.

d) By coupling the product of c) with ZL-alanine as in Example 1d), benzyl - [(S) -1 [[4 - [(tert-butoxycarbonyl) methoxy-4- (a, Q 1, o) was obtained: -trifluoro-m-tolyl) -1-piperidinylcarbonyl ethylcarbamate. MS (FAB): 565 (M + H) < ⁺ >.

e) Hydrogenation of the product from d), as in Example le), gave the acetate of the tert-butyl ester of 1- [[L-alanyl-4- (a, a, a-trifluoro-m-tolyl) -4-piperidinyl] oxy] acetic acids. MS (SW): 415 (M-CH ₃ ) +.

f) Coupling the product from e) with p-amidinobenzoyl chloride hydrochloride, as in Example 1f), gave the desired starting material. MS (SW): 577 (M + H) ⁺ .

Example 24

A solution of 150 mg of tert-butyl - [[1- [1- (p-amidinobenzoyl) -L-prolyl] -4-piperidinyl] oxy] -acetate in 10 ml of dichloromethane and 10 ml of trifluoroacetic acid was stirred at room temperature for 2 hours and then evaporated. The residue was suspended in ether and then filtered through a suction flask. 141 mg of [[1- [1- (pamidinobenzoyl) -L-prolyl] -4-piperidinyl] oxy] acetic acid trifluoroacetate were obtained. Tal. 234-236 ° C.

The starting material was obtained as follows:

a) 4.97 g of 4-cyanobenzoic acid chloride, 3.45 g of L-proline and 0.73 g of tetramethylammonium sulfate were stirred in 300 ml of dichloromethane and 150 ml of 5% sodium hydrogen carbonate solution, stirred for 48 hours and then extracted with ethyl acetate. The ethyl acetate phase was washed with saturated aqueous sodium chloride solution, dried and then evaporated. Chromatography of the residue obtained on silica gel in (RP-18), using water as the eluent, gave 3.70 g of 1- (p-cyanobenzoyl) -L-proline. Tal. 8085 ° C.

b) Coupling 250 mg of 1- (p-cyanobenzoyl) -L-proline with 215 mg of 4-piperidinyloxyacetic acid tert-butyl ester gave 300 mg of tert-butyl- [98: 2] by chromatography on silica gel. [1- [1- (p-Cyanobenzoyl) -L-prolyl] 4-piperidinyl] oxy] acetate. MS: 442 (M + H) < ⁺ >.

c) Treatment of 1 g of the precursor as in Example 2A) B) C) is conducted via tert-butyl - [[1- [l- [p- (thiocarbamoyl) -benzoyl] -L-prolyl] -4-piperidinyl] oxy] acetate, m.p. 108-110 ° C and tert-butyl - [[1- [1- [p- (1-methylthio) formimidoyl] benzoyl] -L-prolyl] -4-piperidinyl] oxyacetate, m.p. 132-133 ° C, up to 72 g of desired acetate, m.p. 100 ° C (decomposition).

Example 25

Analogous to Example 24, 150 mg of tert-butyl - [[1 - [(4R) -1- (p amidinobenzoyl) -4-benzyloxy-L-prolyl] -4-piperidinyl] oxy] acetate hydrochloride was obtained by chromatography on silica gel (RP-18, water / THF 95: 5), afforded 72 mg [[1 - [(4R) -1- (p-amidino benzoyl) -4-benzyloxy-L-prolyl] -4-piperidinyl] oxy] acetic acid. Tal. 226-227 ° C.

The starting material was 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 was added 1.46 ml of triethylamine. After stirring, the solution was washed with saturated aqueous sodium chloride solution, dried and then evaporated. Chromatography of the residue on silica gel (using ethyl acetate / hexane 5: 1) gave 810 mg of (4R) -1- (p-cyanobenzoyl) -4-hydroxy-L-proline methyl ester. Tal. 101-102 ° C.

b) A solution of 730 mg of the previous step compound and 600 μ 600 benzyltrichloroacetimidate in 5 ml of cyclohexane and 5 μΐ of dichloromethane was added dropwise to 40 ml of trifluoromethanesulfonic acid. The resulting precipitate was filtered off and the filtrate was washed with 5% aqueous sodium hydrogen carbonate solution, dried and then evaporated. Chromatography of the residue on silica gel (ethyl acetate) gave 940 mg of (4R) 4-benzyloxy-1- (p-cyanobenzoyl) -L-proline methyl ester. MS: 305 (M-59).

c) 880 mg The compounds of the previous step and 1.2 ml of 2N lithium hydroxide solution were mixed in 10 ml of methanol. After methanol was determined, the aqueous residue was acidified with 2.4 ml of 1N hydrochloric acid and extracted with ethyl acetate. Organic phase drying and evaporation gave 470 mg of (4R) -4-benzyloxy-1- (p-cyanobenzoyl) -L-proline. Tal. 58 to 60 ° C.

d) 450 mg The product of c) was combined in the presence of HBTU with 280 mg of 4-piperidinyloxyacetic acid tert-butyl ester. The residue was dissolved in ethyl acetate and the ethyl acetate phase was washed with 5% aqueous sodium hydrogen carbonate solution, 1N aqueous potassium hydrogen sulphate solution and saturated aqueous sodium chloride solution, dried and then evaporated. Chromatography of the residue on silica gel (using dichloromethane / methanol 98: 2) gave 500 mg of tert-butyl - [[1 [(4R) -4-benzyloxy-1- (p-cyanobenzoyl) -L-prolyl] -4 -piperidinyl] oxy] acetate.

MS: 548 (M + H) < + >.

e) Treatment of 400 mg of the compound from the previous step in the manner described in Example 2a) B) C) resulted in 177 mg of the desired acetate.

Tal. hydroiodide 148-150 ° C.

Example 26

A solution of 1.60 g of tert-butyl - [[1 - [(4R) -1- (p-amidinobenzoyl) -4-hydroxy-L-propyl] -4-piperidinyloxyacetate in 20 ml of dichloromethane and 20 ml of trifluoroacetic acid was stirred for 2 hours at room temperature. and then evaporated. The residue was dissolved in ethanol and ether was added. Filtration through suction and drying of the residue gave 1.25 g of [[1 - [(4R) -1- (p-amidinobenzoyl) -4-hydroxy-L-prolyl] -4-piperidinyl] oxyacetic acid trifluoroacetate. Tal. 220 ° C (decomposition).

The starting material was obtained as follows:

a) Coupling of 14.78 g of (4R) -1- (benzyloxycarbonyl) -4-hydroxy-L-proline with 12.0 g of 4-piperidinyloxyacetic acid tert-butyl ester was obtained by chromatography on silica gel (using ethyl acetate / methanol 95: 5 mixture) as eluent) 17.83 g of tert-butyl - [[1 - [(4R) -1- (benzyloxycarbonyl) -4-hydroxy-L-prolyl] -4-piperidinyl] oxy] acetate. MS: 463 (M + H) < + >.

b) Hydrogenation of 17.0 g of the compound from the previous step in the presence of 2.0 g of 10% Pd on charcoal gave, after filtering out the catalyst and concentrating, 11.06 g of tert-butyl - [[l [(4R) -4-hydroxy-L-prolyl] - 4-piperidinyl] oxy] acetate. MS: 329 (M + H) < ⁺ >.

c) Reaction of 2.0 g of the previous step compound with 1.34 g of p-amidinobenzoyl chloride analogous to Example 1f) gave 1.95 g of the desired acetate.

Example 27

A solution of 700 mg of tert-butyl - [[1 - [[1- (p-amidinobenzoyl) -2-piperidinyl] carbonyl] -4-piperidinyloxyacetate in 20 ml of dichloromethane and 20 ml of trifluoroacetic acid was stirred for 3 hours at room temperature and then evaporated. The residue was dissolved in ethanol and ether was added. It was filtered through a pad and dried the resulting precipitate, chromatographed on silica gel (RP-18, water / tetrahydrofuran 9: 1) to give 111 mg [[l - [[1- (p-amidinobenzoyl) -2-piperidinyl] carbonyl] -4 -piperidinyl) oxy] acetic acid. Tal. 233 to 234 ° C.

The starting material was obtained as follows:

a) Coupling with 5.26 g of 1- (benzyloxycarbonyl) -2-piperidine-carboxylic acid with 4.30 g of 4-piperidinyloxyacetic acid tert-butyl ester and chromatography on silica gel (ethyl acetate / hexane 2: 1) gave 7.33 g of benzyl ester 2 - [[4 - [(tertbutoxycarbonyl) methoxy] piperidino] carbonyl] -piperidine carboxylic acid.

MS: 461 (M + H) < + >.

b) Hydrogenation of 4.6 g of the previous step compound in ethanol in the presence of 0.4 g% Pd on charcoal was obtained after filtration of the catalyst and concentration of the solvent

3.2 g of tert-butyl - [[1- (2-piperidinylcarbonyl) -4-piperidinyl] oxy] acetate.

MS: 327 (M + H) < + >.

c) Reacting 3.26 g of the previous step compound with 2.49 g of p-amidinobenzoyl chloride analogous to Example If) 1.56 g of the desired acetate, m.p. 93-95 ° C.

Example 28

A solution of 130 mg of tert-butyl [[(1RS, 2RS, 3RS, 4SR) -4 - [[N- (pamidinobenzoyl) -L-alanyl] amino] -2,3-diacetoxy-cyclohexyl] oxy] acetate hydrochloride in 5 ml of dichloromethane and 5 ml of trifluoroacetic acid were stirred for 2 hours at room temperature and then concentrated. Suspension of the residue in ether and stripping gave 126 mg of trifluoroacetate [[(1RS, 2RS, 3RS, 4SR) -4 - [[N- (p-amidinobenzoyl) -L-alanyl] amino] -2,3-diacetoxycyclohexyl] oxy ] acetic acid.

MS: 507 (M + H) < + >.

The starting material was obtained as follows:

a) A solution of 4.64 g of cis-4-amino-2-cyclohexen-1-ol, 10.2 g of N- (benzyloxycarbonyloxysuccinimide and 5.7 g of triethylamine in dimethylformamide was diluted with ether after stirring, then washed with saturated aqueous sodium chloride, then dried over sodium chloride. Chromatography of the residue on silica gel (ethyl acetate / hexane 2: 1) gave 5.62 g of benzyl- (1RS, 4SR) -4-hydroxy-2-cyclohexene-1-carbamate, MS: 156 (M-91) ⁺ .

b) Under the conditions of phase transfer (30 ml of toluene, 30 ml of 50% sodium hydroxide solution, 100 mg of tetrabutylammonium hydrogen sulfate), 2.1 g of the previous step compound was reacted with 1.76 ml of bromoacetic acid tert-butyl ester. After stirring, the organic phase was decided, washed with saturated aqueous sodium chloride solution, dried and concentrated. Chromatography of the residue on silica gel (hexane / ethyl acetate 3: 1) gave 1.91 g of benzyl- (1RS, 4SR) -4 - [(tert-butoxycarbonyl) methoxy] -2-cyclohexene-1-carbamate. MS: 333 (M-28) < ^{+ &gt};.

c) A solution of 722 mg of the compound from the previous step, 280 mg of N-methylmorpholine-Noxide and 26 mg of osmium tetroxide in 20 ml of acetone and 10 ml of water were stirred and then acetone was removed under reduced pressure and the aqueous phase was extracted with ether.

Washing the organic phase with saturated aqueous sodium chloride, drying and concentrating, was carried out by chromatography on silica gel (ethyl acetate / hexane 2: 1)

476 mg benzyl- (1RS, 2SR, 3SR, 4SR) -4 - [(tert-butoxycarbonyl) methoxy] -2,3 dihydroxy-cyclohexanecarbamate. MS: 396 (M + H) < + >.

d) A solution of 728 mg of the compound from the previous step in 10 ml of ethanol was hydrogenated in the presence of 100 mg of 10% Pd on charcoal. Then the catalyst was filtered off, the filtrate was evaporated and the residue was taken up in 30 ml of tetrahydrofuran in the presence of 697 mg of HBTU and 200 μΐ of triethylamine with 410 mg of N-benzyloxycarbonyl-L-alanine. The reaction solution was diluted with ether, washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride, then dried and concentrated. Chromatography on silica gel (ethyl acetate / methanol 95: 5) afforded 521 mg of benzyl - [(S) -1 - [[(1RS, 2SR, 3SR, 4SR) -4 - [(tert-butoxycarbonyl) methoxy-2,3 -dihydroxycyclohexyl] carbamoyl] ethylcarbamate. MS: 467 (M + H) < ⁺ >.

e) Acetylating 800 mg of the compound from the previous step into 10 ml of acetanhydride and 10 ml of pyridine and concentrating the reaction solution gave, after chromatography on silica gel (ethyl acetate / hexane 2: 1), 670 mg of benzyl - [(S) -1- [ [(1RS, 2SR, 3SR, 4SR) -4 [(tert-butoxycarbonyl) methoxy] -2,3-acetoxycyclohexyl] carbamoyl] ethyl] carbamate. MS: 551 (M + H) < + >.

f) Hydrogenation of 670 mg of the previous step compound into 10 ml of ethanol in the presence of 100 mg of 10% Pd on charcoal, filtering off the catalyst and concentrating the solution was obtained after treatment (analogous to Example 1f) with 329 mg of p-amidinobenzoyl chloride and after chromatography on silica gel ( RP-18, water / methanol 9: 1), 230 mg of starting material desired. MS: 563 (M + H) < ⁺ >.

Example 29

220 mg of the product of Example 28 and 300 mg of potassium carbonate were stirred in 10 ml of methanol at room temperature and then the methanol was evaporated. Chromatography on silica gel (RP-18, water / acetonitrile 95: 5) gave 110 mg [[(1RS, 2RS, 3RS, 4SR) -4 [[N- (p-amidinobenzoyl) -L-alanyl] amino] -2 , 3-Dihydroxycyclohexyl] oxy] acetic acid.

Example 30

Treatment of 1.3 g of rac- [p - [[1- (p-cyanobenzoyl) -2-pyrrolidinyl] carbonyl] -¾ ⁴ phenoxy] -acetic acid methyl ester in the manner described in Example 2A) B) C), after chromatography (silylated silica gel RP-18, water / methanol gradient) and after recrystallization from ethanol, 0.45 g of acetate of rac- [p - [[1- (pamidinobenzoyl) -2-pyrrolidinylcarbonyl] -phenoxy] acetic acid. Tal. 210-211 ° C. MS (FAB): 410 (M + H) < + >.

The starting material was obtained as follows:

a) The Grignard reagent reaction obtained from 8.3 g of p-benzyloxybromobenzene and 0.8 g of magnesium chips, with 9.34 g of ZL-proline-N-methoxymethylamide in tetrahydrofuran was isolated by chromatography (silica gel, diethyl ether / petroleum ether 1: 1). ) 4.3 g of rac-1- (benzyloxycarbonyl) -12- (p-benzyloxybenzoyl) -pyrrolidine. MS (SW): 211 (C ₁₄ H _n O 2) ⁺ , 204 (C ₁₂ H ₁₄ NO 2) +.

b) Hydrogenation of 3.3 g of the compound from the previous step as described in Example 6b) and subsequent reaction with 1.32 g of p-cyanobenzoyl chloride in dimethylformamide in the presence of triethylamine gave 2.8 g of rac-1- (p-cyanobenzoyl) -2 - (p-Hydroxybenzoyl) -pyrrolidine. Tal. 194-196 ° C (ethyl acetate). MS (SW): 320 (M) ⁺ .

c) Reaction of 2.8 g of the previous step compound with 1.53 g of bromoacetic acid methyl ester in dimethylformamide in the presence of potassium carbonate gave, by chromatography (silica gel, dichloromethane / methanol 99: 1), 1.3 g of the desired starting material.

MS (SW): 392 (M) +.

Example 31

Heating 0.30 g of the product of Example 30 in aqueous acetic acid afforded, after chromatography (silylated silica gel RP-18, gradient water / acetonitrile), 0.11 g rac- [p [[1- (p-amidinobenzoyl) -2-pyrrolidinyl] carbonyl] phenoxyacetic acid.

Tal. above 250 ° C. MS (FAB): 396 (M + H) < + >.

Example 32

Treatment of 0.85 g of [[4- [1- (p-cyanobenzoyl) -DL-prolyl] -phenylenedioxyacetic acid dimethyl ester] in the manner as described in Example 2A) B) C) was obtained by chromatography (silylated silica gel RP- i8, gradient of water / methanol) and crystallization from diethyl ether, 0.09 g of acetate of dimethyl ester of [4- [1- (p-amidinobenzoyl) DL-prolyl] -m-phenylene] dioxy] -acetic acid.

Tal. 93-95 ° C. MS (FAB); 498 (M + H) < + >.

The starting material was obtained as follows:

a) Magnesium salt reaction was obtained from 4 g of 3-hydroxy-phenoxyacetic acid methyl ester with 5.8 g of ZL-prolineal and etching the product with 3.8 g of bromoacetic acid methyl ester as described in Example 30c) by chromatography (silica gel, diethyl ether / petroleum ether 4: 1), 7.6 g of [[4 - [(RS) -1 (benzyloxycarbonyl) -DL-pyrrolyl] -hydroxymethyl-m-phenylene] dioxy] -acetic acid dimethyl ester. MS (FAB): 488 (M + H) < + >.

b) From 5.3 g of the previous step compound, oxidation with 7.5 ml of Jones reagent in diethyl ether by chromatography (silica gel, dichloromethane / methanol 99: 1) gave 2.2 g of dimethyl ester [[4- [1- (benzyloxycarbonyl) -DL-]. prolyl] -m-phenylene] dioxy] -acetic acid. MS (SW): 485 (M) +.

c) Hydrogenation of 2.2 g of the compound from the previous step in the manner described in Example 6b) and the subsequent reaction with 1.0 g of p-cyanobenzoyl chloride in chloroform in the presence of triethylamine was obtained by chromatography (silica gel dichloromethane / methanol 99: 1) , 0.85 g of starting material desired. MS (SW): 480 (M) ⁺ .

Example 33

From 0.09 g of the product of Example 32 was obtained by hydrolysis with aqueous sodium hydroxide solution in methanol at 50 ° C, after neutralization with acetic acid and chromatography (silylated silica gel RP-18, gradient water / acetonitrile) and crystallization from ethanol, 0.09 g monosodium salts of [[4- [1- (p-amidinobenzoyl) -DL-prolyl] -phenylenedioxydioacetic acid.

Tal. 241-242 «C. MS (FAB); 492 (M + Na) +, 470 (M + H) +.

Example 34

0.47 g of [[1- [N- (p-amidinobenzoyl) -L-tyrosyl] -4-piperidinyl] oxy] acetic acid (Example 14) were obtained by esterification in ethanol in the presence of catalytic amounts of concentrated sulfuric acid, by chromatography ( LiChroprep RP-18, water / ethanol gradient), 0.3 g [[1- [N- (p-amidinobenzoyl) -L-tyrosyl] -4-piperidinyloxyacetic acid] ethyl ester hemisulfate, m.p. 182-184 ° C (ethanol).

MS (ISO = ion spray); 497 (M + H) < ⁺ >.

Example 35

From 0.48 g of [[1- [N- [5- (1-tertbutoxyformamido) pentanoyl] -3- (pterbutoxyphenyl) -L-alanyl] -4-piperidinyl] oxy] acetic acid tert-butyl ester was treated analogously to Example 1 , upon crystallization from diethyl ether, 0.2 g of [[1- [N- (5-aminopentanoyl) -L-tyrosyl] -4-piperidinyl] oxy] acetic acid trifluoroacetate salt, m.p. 78 to 88 ° C (decomposition). [α] ² % = +11.6 ⁰ (c = 0.7, methanol). MS (FAB): 422 (M + H) < + >.

The starting ester was prepared as follows:

Reaction of 0.7 g of [[1- [3- (p-tert-butoxy-phenyl) -L-alanyl] -4-piperidinyl] oxyacetic acid tert-butyl ester (obtained by hydrogenolysis of the product of Example 14a) with 0.35 g N-Boc-5-aminopentanoic acid in the presence of HBTU and N-methylmorpholine (as in Example 2b)) gave 0.55 g of the starting ester.

[a] ²⁰ D = +1.2 ^O (c = 0.4, methanol). MS (FAB); 634 (M + H) < + >.

Example 36

From 0.6 g of [(S) -3- (p-amidinobenzamido) -3 - [[4 - [(tert-butoxycarbonyl) methoxypiperidino] carbonyl] propyl] tert-butyl carbamate, analogous to Example 1, was chromatographed (LiChroprep RP- 18, water / methanol gradient) and after stirring in tetrahydrofuran, 0.26 g of [[1 - [(S) -2- (p-amidinobenzamido) -4-amino-butanoyl] -4-piperidinyl] oxy] acetic acid were obtained 0.26 g. , tal. above 170 ° C (decomposition). [α] ² θ ₀ = + 5.8 ⁰ (c = 0.5, water). MS (ES): 406 (M + H) +.

The starting material could be prepared as follows:

a) Reaction of 1.0 g of 4-piperidinyloxyacetic acid tert-butyl ester with 2.0 g of N ² -FmocN4-Boc- (S) -2,4-diaminobutyric acid in the presence of HBTU and Hunig's base was obtained as described in Example 2b) , by chromatography (silica gel, EtOAc / hexane 1: 1.5), 2.2 g of 3-tert-butyl-1- (fluoren-9-ylmethyl) - (S) -1 - [[4 - [(tert-butoxycarbonyl) methoxy] piperidino] carbonyl] -trimethylene-dicarbamate,

MS (FAB): 638 (M + H) < + >.

37 '

b) Reaction of 2.3 g of the product (a) with · piperidine (20% solution in dimethylformamide) was obtained by chromatography (silica gel, ethyl acetate / methanol: 1), 0.65 g of tert-butyl - [(S) -3- amino-3 - [[4 - [(tert-butoxycarbonyl) -methoxy] piperidine-carbonylpropylcarbamate, MS (FAB): 416 (M + H) ⁺ .

c) Reaction of 0.65 g of the product of b) with 0.38 g of p-amidinobenzoyl chloride hydrochloride (as in Example 1f) yielded 0.6 g of starting carbamate.

MS (FAB): 562 (M + H) < ⁺ >.

Example 37

From 0.25 g of [[1- [N - [(5-amidino-2-pyridyl) carbonyl] -3- (pert-butoxyphenyl) -L-alanyl] -4-piperidinyl] acetic acid acetate salt tert-butyl ester] , obtained (as in Example 1), after chromatography (LiChoprep RP-18, water / methanol gradient) and stirring in ethyl acetate, 0.12 g [[1- [N - [(5-amidino-2-pyridyl) carbonyl] -L-tyrosyl] -4-piperidinyloxyacetic acid, m.p. 198-200 ° C (decomposition).

MS (FAB): 470 (M + H) < + >.

The starting material was obtained as follows:

a) By reacting 2.5 g of [[1- [3- (p-tert-butoxyphenyl) -L-alanyl-4-piperidinyloxyacetic acid] tert-butyl ester with 0.85 g of 5-cyan-2-picolic acid (as in Example ld), 1.55 g of [[1- [3- (p-tert-butoxyphenyl) -N - [[5-cyan-2-pyridyl] carbonyl] -L-alanyl] -4-piperidinyl] oxy] acetic acid tert-butyl ester, m.p. . 122-123 ° C (diethyl ether / petroleum ether 4: 1). MS (FAB): 565 (M + H) < ⁺ >.

b) Sequential treatment of 1.43 g of the product from the previous step, as described in Example 2A) B) C), yields 0.98 g of the desired starting material.

Tal. 183-186 ° C. MS (ES): 582 (M + H) +.

Example 38

Reaction of 0.7 g of (S) -1- [2- (5-cyanopyridin-2-yl-carbonylamino) -3- (4-methoxyphenyl) propionyl] piperidin-4-yloxy-acetic acid ethyl ester, in an analogous manner as described in Example 2A) B) C), after crystallization from water, 0.1 g of the acetate salt of (S) -1- [2- (5-amidinopyridin-2-ylcarbonylamino) -3- (4-methoxyphenyl) propionyl ethyl ester] piperidin-4-yloxy-acetic acid.

Tal. 180-181 ° C (decomposition). MS (ISP): 512 (M + H) < + >.

The starting nitrile was obtained as follows:

a) Reaction of 7 g of NZL-tyrosine dihydrate with 4.5 g of 4-piperidinyloxyacetic acid ethyl ester (obtained by treating the corresponding tert-butyl ester as described in Example lc) with trifluoroacetic acid followed by ethanol treatment hydrochloric acid solution) as described in Example ld) gave 6.5 g of ethyl [[1- [N- (benzyloxycarbonyl) -L-tyrosyl] -4-piperidinyl] oxy] acetic acid ethyl ester. This product was treated in dimethylformamide in the presence of potassium carbonate with methyl iodide to give 4.2 g of ethyl (S) -1- [benzyloxycarbonylamino-3- (4-methoxyphenyl) propionyl by chromatography (silica gel, methylene chloride / methanol 99: 1). ] piperidin-4-yloxyacetic acid, [a] ²⁰ D = +1.9 ° C (c = 0.8, methanol). MS (ISP); 499 (M + H) < + >.

b) From 4 g of the product from a) by analogous treatment as in Example le), 3.5 g of (S) -1- [2-amino-3- (4-methoxyphenyl) propionyl] piperidin-4-yloxyacetic acid ethyl ester was obtained , MS (SW): 365 (M + H) +.

c) Coupling 1.46 g of the product from b) with 0.74 g of 5-cyan-2-picolinic acid analogous to Example 1d) was obtained by chromatography on silica gel (methylene chloride / methanol 40: 1), 0.72 g of starting nitrile,

MS (ISP): 495.5 (M + H) < + >.

Example 39

Saponification of (S) -1- [2- (5-amidinopyridin-2-ylcarbonylamino) -3- (4methoxyphenyl) propionyl] piperidin-4-yloxyacetic acid ethyl ester (Example 38) at pH = 12 was performed by chromatography (LiChroprep RP -18, water / methanol gradient) and stirring in ethanol gave (S) -1- [2- (5-amidino-pyridin-2-ylcarbonylamino) -3- (4-methoxyphenyl) propionyl] piperidin-4-yloxyacetic acid; m.p. above 250 ° C.

MS (ISP): 484.4 (M + H) < + >.

Example 40

By coupling 1.2 g of (S) -1- [2-amino-3- (4-methoxyphenyl) propionyl] piperidin-4-yloxyacetic acid ethyl ester (Example 38b) with 0.77 g of 4-amidino-benzoic acid hydrochloride in 3-picoline (analogous to Example 1f) was obtained by chromatography (LiChroprep RP-18, water / ethanol gradient) and stirring with ethyl acetate, 0.25 g of ethyl ester (S) -1- [2 · (4-amidinobenzamido) -3- ( 4methoxyphenyl) -propionyl] piperidin-4-yloxyacetic acid; m.p. Mp 105-107 ° C.

MS (ISP); 511.3 (M + H) < + >.

Example 41

Saponification of 0.35 g of (S) -1- [2- (4-amidinobenzamido) -3- (4methoxyphenyl) propionyl] piperidin-4-yloxyacetic acid ethyl ester hydrochloride (Example 40) at pH 12 was obtained by chromatography (LiChroprep RP -18, water / methanol gradient) and after crystallization from ethanol / water, 0.05 g (S) -1- [2- (4-amidinobenzamido) -3- (4methoxyphenyl) propionyl] piperidin-4-yloxyacetic acid, m.p. 191-192 ° C.

MS (ISP); 483.3 (M + H) < + >.

Example 42

From 1.6 g of [1- [N- (4-amidinobenzoyl) -L-tryptophanyl] piperidin-4-yloxyacetic acid tert-butyl ester] was obtained analogously to Example 1 by chromatography (LiChroprep RP-18, water / methanol gradient) and by mixing with tetrahydrofuran and acetonitrile, 0.7 g of [1- [N- (4-amidinobenzoyl) -L-tryptophanyl] piperidin-4-yloxyacetic acid; m.p. 210 ° C (decomposition). MS (ISP): 492.2 (M + H) < ⁺ >.

The starting ester can be obtained as follows:

a) Reaction of 5.1 g of 4-piperidinyloxyacetic acid tert-butyl ester (Example 1c) with 8.0 g of Z-Trp-OH in the presence of HBTU and N-methylmorpholine was obtained as in Example 2b) by chromatography (silica gel, methylene chloride / methanol 20: 1), 11.5 g of [1 (N-benzyloxycarbonyl-L-tryptophanyl) piperidin-4-yloxy] acetic acid tert-butyl ester;

MS (ISP): 536.0 (M + H) < + >.

b) A solution of 6.6 g of the product from a) in methanol was heated in the presence of 10% Pd on charcoal and ammonium formate at boiling point. Filtration and chromatography (silica gel, methylene chloride / methanol 9: 1) gave 4.3 g of tert-butyl ester (1L-tryptophanyl-piperidin-4-yloxy) acetic acid; MS (SW): 384 (M-NH3) ⁺ .

c) Reaction of 1.9 g of the product of b) with 1.15 g of 4-amidinobenzoic acid chloride hydrochloride in pyridine in the manner as described in Example 1f) to give 1.6 g of starting ester after chromatography (silica gel, methylene chloride / methanol 7: 1);

MS (ISP); 548.3 (M + H) < + >.

Example 43

A solution of 3.2 g of [1- [N- (4-amidinobenzoyl-4'-hexyloxy-phenylalanyl] piperidin-4-yloxy] acetic acid tert-butyl ester was allowed to stand overnight at room temperature. After concentration, chromatography ( LiChroprep RP-18, water / methanol gradient) and 0.45 g of [1- [N (4-amidinobenzoyl-4'-hexyloxy-L-phenylalanyl] piperidin-4-yloxy] acetic acid, m.p. 160 ° C, were isolated by stirring with diethyl ether. C (decomposition). [Α] 2θ ₀ = - 3.2 θ (c = 0.5, methanol) MS (ISP): 553.2 (M + H) +

The starting ester was obtained as follows:

a) Analogous to Example 38a), the reaction of 5.6 g of [[1- [N (benzyloxycarbonyl) -L-tyrosyl] -4-piperidinyl] oxy] acetic acid tert-butyl ester) with 1-iodoxane at 80 ° C was obtained by chromatography ( silica gel, hexane / ethyl acetate 2.5: 1), 3.9 g of [1- (N-benzyloxycarbonyl-4'-hexyloxy-L-phenylalanyl) piperidin-4-yloxyacetic acid tert-butyl ester; MS (SW): 445 (MZ-NH ₂ ) ⁺ .

b) Hydrogenation of 3.9 g of the product from a) in methanol (analogous to Example 1c) gave 2.85 g of [1- (4'-hexyloxy-L-phenylalanyl) piperidine-4yloxyacetic acid tert-butyl ester; MS (SW): 462 (M) ⁺ , 445 (M-NH 3) ⁴ -.

c) Reaction of 0.5 g of the Product of b) with 0.3 g of 4-amidinobenzoyl chloride hydrochloride in pyridine (treatment method analogous to Example 1f) gave, after completion of chromatography (silica gel, methylene chloride / methanol 5: 1), 0.7 g of the starting ester;

MS (ISP): 609.4 (M + H) +.

Example 44

A solution of 0.65 g of (R, S) -1- [2- (4-aminoiminomethyl-N-methylbenzoylamino) -3- (4-methoxyphenyl) propionyl] -piperidin-4-yloxy] acetic acid tert-butyl ester in formic acid was obtained. allowed to stand overnight at room temperature. After concentration and chromatography (LiChroprep RP-18, water / acetonitrile gradient), 0.13 g (R, S) -1- [2- (4-aminoiminomethyl-N-methylbenzoyl-amino) -3- (4-methoxyphenyl) was isolated propionyl] -piperidine-4-yloxyacetic acid, m.p. 181-182 ° C.

MS (ISP); 497.1 (M + H) < + >.

The starting ester was obtained as follows:

'' Ί

a) Coupling 1.37 g of ZN-Me-Tyr (Me) -GH (FA.CS, 112, 1990, 7663) with 0.86 g of 4-piperidinyloxyacetic acid tert-butyl ester (Example lc) as described in 2b ), was obtained by chromatography (silica gel, diethyl ether / hexane 5: 1), 1.6 g of (R, S) tert-butyl ester -1- [2- (N-benzyloxycarbonyl-N-methylamino) -3- (4-methoxyphenyl) ) propionyl] piperidin-4-yloxy] acetic acid; MS (ES): 541.0 (M + H) ⁺ .

b) Hydrogenation of 1.5 g of the product from a) in methanol in an analogous manner to that described in Example lc) gave 1.05 g of an oil which was directly converted from 0.58 g of 4-amidinobenzoic acid hydrochloride in pyridine to method as described in (Example lf). Chromatography (silica gel, methylene chloride / methanol 9: 1) afforded 0.7 g of the starting ester, m.p. 109-111 ° C. MS (ISP): 553.2 (M + H) < ⁺ >.

Example 45

By esterifying 0.07 g of (R, S) -1- [2- (4-aminoiminomethyl-N-methylbenzoylamino) -3- (4methoxyphenyl) propionyl] piperidin-4-yloxy] acetic acid in ethanol in an analogous manner as in Example 34 , was obtained by chromatography (LiChroprep RP-18, gradient water / ethanol) and stirring with diethyl ether 0.056 g ethyl ester (R, S) -1- [2- (4 aminoiminomethyl- N-methylbenzoylamino) -3- (4-methoxyphenyl) propionyl] piperidine-4yloxyacetic acid, m.p. 126-128 ° C. MS (ISP): 525.5 (M + H) < ⁺ >.

Example 46

To a solution of (S) -cis-1- [2- (4-amidinobenzoylamino) propionyl] -4-tert-butoxycarbonylmethoxy-pyrrolidin-3-yloxyacetic acid tert-butyl ester in 5 ml of methylene chloride was added 5 ml of trifluoroacetic acid. After stirring at room temperature, the solvents were removed and the residue was chromatographed on a RP-18 silica gel column using a water / tetrahydrofuran (0-50%) mixture as eluent.

73 mg of (S) -cis-1- [2- (4-amidinobenzoylamino) -propionyl] -4-carboxymethoxy-pyrrolidin-3-yloxy-acetic acid was obtained. MS: 437 (M + H) < ⁺ >.

The starting ester was obtained as follows:

a) Under phase transfer conditions, 237 mg of cis-N-benzyloxycarbonylpyrrolidine-3,4-diol, 1 ml of bromoacetic acid tert-butyl ester and 100 mg of tetrabutyl ammonium hydrogen sulfate in 10 ml of touen were mixed with 10 ml of 50% sodium hydroxide solution. The organic phase was washed with water and then concentrated. Chromatography of the residue after evaporation on silica gel using a mixture of ethyl αΊ.

acetate / hexane (1: 3) gave 354 mg of cis-3,4-bis-tert-butoxycarbonylmethoxy-pyrrolidine-1-carboxylic acid benzyl ester. MS: 354 (M-11ll).

b) 320 mg of the compound of the previous step was hydrogenated with 10 ml of EtOH in the presence of 100 mg of 10% Pd on charcoal, the catalyst was filtered off after 2 hours and the residue was stirred in 10 ml of tetrahydrofuran with 224 mg of N-benzyloxycarbonyl-L-alanine-N- ester hydroxysuccinimide in the presence of 100 μΐ triethylamine. The reaction solution was diluted with ether, the organic phase was washed with 1 N KHSO4 solution, dried and then evaporated. Chromatography of the residue on a silica gel column using hexane / ethyl acetate (1: 1) afforded 260 mg of (S) -cis-1- (2-benzyloxycarbonylaminopropionyl) -4-tert-butoxycarbonylmethoxy-pyrrolidine-tert-butyl ester. 3-yl-oxy-acetic acid.

MS: 537 (M + H) < + >.

c) 250 mg of the compound of the previous step was hydrogenated in 10 ml of EtOH in the presence of 100 mg of 10% Pd on charcoal, the catalyst was filtered off after 4 hours and the residue was stirred in 10 ml of pyridine with 102 mg of p-amidinobenzoyl chloride hydrochloride. Evaporation of the solution and chromatography of the residue on silica gel RP-18 using a water / tetrahydrofuran mixture (gradient 5-30%) gave 143 mg of the starting ester.

Tal. 127 ° C (decomposition).

Example 47

A solution of 150 mg of (S) -8- [2- (4-aminoiminomethylbenzoylamino) -3- (4-tert-butoxyphenyl) propionyl] -8-azabicyclo ethyl ester hydrochloride [3.2. l] octane-endo-3yloxyacetic acid was stirred in 5 ml of methylene chloride and 2.5 ml of trifluoroacetic acid at room temperature and then evaporated. The residue was taken up in ether with crystals which were stripped off and dissolved in 5 ml of EtOH. To this solution was added 40 mg of NaOH (which was dissolved in 1 ml of water) and stirred at room temperature. The reaction solution was neutralized with 1N hydrochloric acid and then evaporated. Chromatography of the residue on silica gel RP-18 using a water / tetrahydrofuran mixture afforded 75 mg of (S) -8- [2- (4-aminoiminomethyl-benzoylamino) -3- (4hydroxyphenyl) -propionyl] -8-azabicyclo- [3.2. 1] octane-endo-3-yloxyacetic acid;

MS: 495 (M + H) < + >.

The starting ester was obtained as follows:

a) A solution of 1 g of N-benzyloxycarbonyl-nortropine and 20 mg of rhodium (II) -acetate in 3 ml of toluene was added at 80 ° C to 2 ml of diazoacetic acid ethyl ester in 2 ml of toluene. After ',

For 3.5 hours, the solution was purified by chromatography on silica gel using a hexane / ethyl acetate mixture (gradient 20-50%). 555 mg of endo-3-ethoxycarbonylmethoxy-8-azabicyclo [3.2.1] octane-8-carboxylic acid benzyl ester was obtained; M: 348 (M + H) < + >.

b) A solution of 500 mg of the compound from the previous step was hydrogenated in 20 ml of EtOH in the presence of 100 mg of 10% Pd on charcoal, the catalyst was filtered off after 3 hours and the filtrate was then evaporated. The residue was dissolved in 10 ml of tetrahydrofuran and 828 mg of NZL-Tyr (tert-Bu) -OH solution, 140 μ \ N-methylmorpholine and 569 mg HBTU were added in 10 ml of tetrahydrofuran, which was stirred for 1 hour at 0 ° C. After stirring, the reaction solution was evaporated and the residue was chromatographed with hexane / ethyl acetate (1: 1) on a silica gel column. (S) -8- [2-Benzyloxycarbonylamino-3- (4-tert-butoxyphenyl) propionyl] -8-azabicyclo [3.2.1] octane-endo-3-yloxyacetic acid ethyl ester was obtained 650 mg. MS: 567 (M + H) < ⁺ >.

c) 600 mg of the compound of the previous step was hydrogenated in 20 ml of EtOH in the presence of 100 mg of 10% Pd on charcoal, the catalyst was filtered off after 16 hours and the residue was stirred in 10 ml of pyridine with 262 mg of p-amidinobenzoyl chloride hydrochloride at room temperature. Evaporation of the solution and chromatography of the residue on silica gel RP-18 using a water / tetrahydrofuran mixture (gradient 0-50%) as eluant gave 198 mg of the starting ester. MS: 579 (M + H) < ⁺ >.

Example 48

706 mg of (E) - or (Z) - (S) - [3- [2- [4- (tert-butoxycarbonylimino-di-tert-butoxycarbonylaminomethyl) benzoylamino] propionylamino] propoxyacetic acid butyl ester was stirred in 1.5 ml. of methylene chloride and 1.5 ml of trifluoroacetic acid at 20 ° C. Evaporation of the solvent in vacuo, evaporation with toluene and crystallization from acetonitrile gave 407 mg of (S) - [3- [2- [4- (aminoiminomethyl) benzoylamino] propionylamino] propoxy-acetic acid trifluoroacetate (1: 1); m.p. Mp 163-165 ° C. [α] ² % = + 19 ⁰ (c = 0.5, in methanol).

The starting material was obtained as follows:

a) Acrylonitrile, glycolic acid butyl ester and potassium carbonate were heated at 60 ° C. After treatment with ethyl acetate and water, the 2-cyanethoxyacetic acid butyl ester was distilled. Boiling point 100-120 ° C, 40 Pa (in apparatus with ball tube).

b) The resulting ester was hydrogenated in acetic acid at Pd / C, and the resulting amine was coupled to N-benzyloxycarbonyl-L-alanine to (S) - [3- (2-benzyloxycarbonyl-aminopropionylamino) propoxyacetic acid butyl ester, mp 54-55 ° C. , [a] ²⁰ D ⁼ -11-0 ^O (c = 0.5, in methanol).

c) Hydrogenation of the compound from the previous step in acetic acid to Pd / C gave [3- (2-aminopropionylamino) propoxy] acetic acid butyl ester, which was treated with p- [E / Z] tri (tert-butoxycarbonyl) amidinobenzoic the acid was attached to the starting material.

MS: 707 (27 M + H), [α] ^2ΰ ο ⁼ + 21.4 ° (c = 0.5, in methanol).

Example 49

(S) - [3- [2- [4- (aminoiminomethyl) benzoylamino] propionyl-amino] propoxyacetic acid 416 mg of butyl ester was stirred in 8.3 ml of 25% hydrochloric acid at 20 ° C. The solution was evaporated and the residue was evaporated with water. From tetrahydrofuran, 211 mg of hydrochloride (S) - [3- [2- [4- (aminoiminomethyl) benzoyl] -aminopropionylamino] propoxyacetic acid were obtained in the form of a hydrate (1: 1). Tal. 89-90 ° C.

[α] ² ° D ~ + 23.4 ° (c = 0.5, in methanol).

Example 50 1- (N- [4- (tert-Butoxycarbonylimino-di-tert-butoxycarbonylamino-methyl) -benzoyl-N- (2-methoxyethyl) -glycylpiperidin-4-yloxyacetic acid tert-butyl ester) was stirred in 3.8 ml. methylene chloride and 3.8 ml of trifluoroacetic acid at 20 ° C. The solvent mixture was evaporated, the residue was evaporated with water, dissolved in ethyl alcohol and adjusted to pH 8 with methanolic ammonia solution. Crystallized 1- [N- [4 (aminoiminomethyl) -benzoyl] -N- (2-methoxyethyl) glycyl] piperidine -4-Hydroxyacetic acid as hydrate (2: 1). Tal. above 250 ° C. MS: 421 (100, M + H).

The starting ester was prepared as follows:

a) N- (2-Methoxyethyl) -glycine tert-butyl ester was reacted in ether and saturated aqueous sodium hydrogen carbonate solution with hydrochloric acid benzyl ester to N-benzyl-oxycarbonyl-N- (2-methoxyethyl) glycine tert-butyl ester. ,

MS: 324 (82, M + H).

b) This was cleaved in methylene chloride / trifluoroacetic acid to N-benzyloxycarbonyl-N- (2-methoxyethyl) -glycine, MS: 267 (1, M).

c) Coupling this last compound with piperidin-4-yloxyacetic acid tert-butyl ester gave 1- (N-benzyloxycarbonyl-N- (2-methoxyethyl) glycylpiperidin-4-yl-oxyacetic acid tert-butyl ester, MS: 465 (100, M + H).

d) Catalytic hydrogenation of this compound in ethanol at Pd / C gave 1- [N- (2-methoxyethyl) -glycyl] piperidin-4-yloxyacetic acid tert-butyl ester;

MS: 331 (100, M + H).

e) This last compound was attached to 4- (tert-butoxycarbonylimino-di-tert-butoxycarbonylaminomethyl) benzoic acid to the starting ester, MS: 777 (70, M + H).

The compound of formula I can be used in an inherently known manner as an active ingredient for the production of tablets of the following composition:

Example A per tablet

active substance 200 mg microcrystalline cellulose 155 mg corn starch 25 mg talc (talkum) 25 mg hydroxypropylmethylcellulose 20 mg 425 mg

Example B

The compound of formula I can be prepared in a manner known per se as an active ingredient for capsule production with the following composition:

per capsule active substance 100.0 mg corn starch 20.0 mg milk sugar 95.0 mg talc (talkum) 4.5 mg magnesium stearate 0.5 mg

220,0 mg

For:

F.HOFFMANN - LA ROCHE AG

AVRELHA Gti

Claims (16)

1. N-acyl-α-amino acid derivatives of formula O R R ' II \ / L — C— N— c-c — O I II R 'o in which L denotes a group of formula x ~ γ or R ° -NH (CH ₂ ) t L ² R is amidine or guanidine, one of X and Y is CH and the other is CH or N, R ° denotes hydrogen or amidino, t denotes an integer from 2 to 6, R 'R' and R '' denote hydrogen or N-substituents, respectively. side chains common to the "-amino acids, with hydroxy and / or hydroxy at the R 'R' and R '" carboxy groups of the ethereal or esterified or amidated, and amino groups may be present C1-8 alkanoylated or aroylated, Q denotes a group of formula or -N (V ') (CH ₂ ) _to -C (V, V') CH ₂ OCH ₂ COO-T q ⁸ or, to the extent that R 'and R' together with the N atom or C atom with which they are bound form a ring, they may also denote a group having the formula o coo-T V Q 'n represents the number 0 or 1, v denotes the integer from 0 to 3, T and T 'denote hydrogen or lower alkyl or phenyl-lower alkyl which can be cleaved under physiological conditions, V to V '' denote hydrogen or lower alkyl, U and U 'denote hydrogen, C 1-8 alkanoyl or aroyl, Ar denotes aryl, and R ² to R ⁵ denote hydrogen, lower alkyl, lower alkoxy, halogen or the group -OCH ₂ COO-T, or R ² and R ² , together with the phenyl group to which they are attached, denote the 1-naphthyl group, as well as their hydrates or solvates and physiologically acceptable salts. Compounds according to claim 1, characterized in that L denotes a group L ^, R ', R' and R '"denote hydrogen or N-substituents, respectively. side chains that are common in α-aminocarboxylic acids, with hydroxy or R 'and R' being present. carboxy groups esterified or esterified or amidated, and T in group Q denotes hydrogen or lower alkyl which can be cleaved under physiological conditions. Compounds according to claim 1 or 2, characterized in that L denotes a group iJ, R stands for amidino, X stands for CH, Y stands for CH or N, and Q stands for O ¹ , Q ² , Q ⁴ , Q ⁵ or Q9. Compounds according to claim 1, 2 or 3, characterized in that Q denotes a group Q ^ in which n = 1 and T denotes hydrogen or methyl, N (R ') C (R', R '') CO - Designates one of the residues Gly, Ala, D-Ala, Val, Leu, Sar, Orn, Lys, Phg, 2-methyl-Pro, Phe, Tyr, 3-iodine-Tyr, 3,5-diode-Tyr, Ser (Ac), Ser, Asp, Glu, Pro, 4-benzyloxy-pro, 4-hydroxy-Pro, 2-piperidylene carbonyl, NHCH (CH ₂ CH ₂ NH ₂ ) CO, Trp, Tyr (Me), Tyr (hexyl) and O, N (Me) ₂ -Tyr. Compounds according to claim 1, 2 or 3, characterized in that Q denotes a group Q ² > in which n = 1 is preferred, T denotes hydrogen and -N (R ') C (R ", R'") CO - indicates the remnant of Al. Compounds according to claim 1, 2 or 3, characterized in that Q denotes a group Q4, especially one in which n = 1, T denotes hydrogen, U and U 'denote hydrogen or Ac, and -N (R' ) C (R ”, R” ’) CO- indicates the residue of Ala. Compounds according to claim 1, 2 or 3, characterized in that Q denotes a group Q5, especially one in which n = 1, T denotes hydrogen, Ar denotes α, α, α-trifluoro methyl and -N (R ') C (R ", R"') CO- indicates the residue of Ala. Compounds according to claim 1, 2 or 3, in which Q denotes a group Q9 preferably one in which R ² to R 4 denotes hydrogen, or R ² denotes a group -OCH ² COO (H or methyl), T denotes hydrogen or methyl and - N (R ') C (R ”, R”') CO denotes the residue Pro. Compounds according to claim 1 or 3 from the group of the following compounds: [[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, [[1- [N (p-amidinobenzoyl) -3- (4-hydroxy-3-iodophenyl) -L-alanyl] -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 in particular [[1- [N - (p-Amidinobenzoyl) -L-tyrosyl] -4-piperidinyl] oxy] -acetic acid. Compounds according to claim 1, characterized in that Q denotes a group Q ² , preferably one in which n = 0 and T denotes hydrogen, or a group Q ² , preferably one in which T denotes hydrogen. Compounds according to claim 1, characterized in that Q denotes a group preferably one in which v = 1, T denotes hydrogen or butyl and V 'to V' denote hydrogen, Compounds according to claim 1, characterized in that -N (R ') C (R ”, R”') CO- denotes the residue N (methoxyethyl) Gly. Compounds according to claim 1, from the group of the following compounds: (S) -1- [2- (5-Amidinopyridin-2-ylcarbonylamino) amino] -3- (4-ylt () xiphenyl) propionyl] piperidin-4-yloxyacetic acid, ethyl ester (S) -1 - [2- (4-amidinobenzamido) -3- (4-methoxyphenyl) propionyl] -piperidin4-yloxyacetic acid, (S) -1- [2- (4-amidinobenzamido) -3- (4-methoxyphenyl) propionyl] - Piperidin-4-yloxyacetic acid, [1- [N- (4-amidinobenzoyl) -4'-hexyloxy-L-phenylalanyl] -piperidin-4-yloxy] -acetic acid. 14. Compounds of formula o E E 'o ¹¹ L ° -C-N-C-C-G I II E 'O or II III in which they mark L ° group of formula Χ-Υ and 02 or R ⁰¹ - (CH ₂ ) _t in which A denotes a protected amidino- or guanidine group, as appropriate, R ⁰¹ denotes a protected amino or guanidine group as appropriate, E ', E', E '' and G have the same meaning as R ', R', R '' or. Q in formula I, wherein when R ° 1 denotes amino or guanidine, or when A denotes amidine or guanidine, at least one of E ', E', E '' and G contains at least one carboxylic acid ester group and / or an ether group and / or a protected amino group. A process for the preparation of a compound according to any one of claims 1-13, characterized in that a) in a compound of formula o EE 'o ¹¹ L ° —C — N — C-C-G I II E '0 II in which L ° denotes a group of formula Χ-Ύ K ⁰¹ - (CH ₂ ) _t L ⁰² in which A is optionally a protected amidino or guanidino group, R ⁰¹ denotes a protected amino or guanidine group as appropriate, E ', E', E '' and G have the same meaning as R ', R', R '' or. Q in the formula I, wherein when R ° I is amino or guanidine, or when A is amidine or guanidine, at least one of E ', E', E '' and G contains at least one carboxylic acid ester group and / or an ether group and / or a protected amino group, cleave the ether group, or. protected amines, amidines or guanidine groups, respectively. a carboxylic acid ester group, or b) in the nitrile of the formula, the cyano group is converted to the amidine group, or c) an amine of formula The R'-NHC (R ”, R” ') of CO-Q ^{IV is} converted with an acid of formula Ll-COOH or a reactive derivative of this acid, and d) optionally functionally converting the reactive group contained in the compound of formula I, and e) optionally, the compound of formula I is converted into a physiologically acceptable salt, or the salt of the compound of formula I is converted to free acid or base. Pharmaceutical preparations comprising the compound of any one of claims 1-13 as an active ingredient.