SK899A3 - Thrombin inhibitors - Google Patents

Abstract

Compounds having formula (I) wherein A, B, E and D have the m eanings indicated in the description, are described, in addition to the production thereof. The substances can be used to combat illnesses.

Description

The present invention relates to novel five-membered heterocyclic amidines, their preparation and their use as competitive inhibitors of trypsin-like serine proteases, in particular thrombin and kininogenases, such as kallikrein. The invention also relates to pharmaceutical compositions containing these compounds as active ingredients, and to the use of these compounds as thrombin inhibitors, anticoagulants and anti-inflammatory agents.

BACKGROUND OF THE INVENTION

Thrombin belongs to the serine protease family and plays a central role in the blood coagulation cascade as a terminal enzyme. Both internal and external coagulation cascade leads to thrombin production from prothrombin through several amplification stages. Thrombin-catalyzed cleavage of fibrinogen to fibrin then initiates blood clotting and platelet aggregation, which in turn accelerate thrombin formation due to the binding of blood platelet factor 3 and coagulation factor XIII and a large number of highly active mediators.

Thrombin formation and action are central events in the development of white arterial and red - venous thrombi and are therefore potentially effective attack points for drugs. Unlike heparin, thrombin inhibitors are able to completely inhibit the simultaneous effects of thrombin and platelet-bound effects independently of cofactors. They are able to prevent in the acute phase thromboembolic events after percutaneous transluminal coronary angioplasty (PTCA) and lysis, and act as anticoagulants in the extracorporeal circulation (cardiovascular device, hemodialysis). They can also be used in general for the prophylaxis of thrombosis, for example after surgical operations.

Synthetic arginine derivatives are known to affect the enzymatic activity of thrombin by interacting with the active serine residue of protease thrombin. Phe-Pro-Arg-based peptides in which the N-terminal amino acid is in the D form have been shown to be particularly beneficial. D-Phe-Pro-Arg isopropyl ester is described as a competitive thrombin inhibitor (C. Mattson et al., Foil Haematol, 109 (1983) 4351).

Derivatization of arginine at the C terminus to the aldehyde leads to an accelerated inhibitory effect. Therefore, many arginals capable of binding the hydroxyl group of the "active" serine to the semiacetal have been described (EP 185390, 479489, 526877, 542525; WO 93/15756, 93/18060).

The thrombin-inhibitory activity of peptide ketones, fluorinated alkyl ketones and ketoesters, boric acid derivatives, phosphoric esters and α-ketocarboxamides can similarly be explained by this serine interaction (EP 118280, 195212, 362002, 364344, 410411, 471651, 5897403 293881 530167; WO 92/07869, 94/08941).

The peptide 4-amidinophenylglycine phosphonate diphenyl esters described by J. Oleksyszyn et al. in J. Med. Chem. 37 (1994) 226-231, are irreversible thrombin inhibitors with inadequate selectivity with respect to other serine proteases.

DE 3 108 810, WO 93/11152 and EP 601 459 disclose agmatine and therefore arginine derivatives which are not capable of interacting with active serine in serine proteases.

WO 94/29336, EP 0 601 459 and WO 95/23609 represent a further development step in which agmatine is replaced by an arylamidine residue.

Kininogenases are serine proteases that release vasoactive peptides called kinins (bradykinin, calidine and Met-Lys-bradykinin) from kininogens.

Kininogens are multifunctional proteins that occur in coagulation and inflammatory cascade reactions. As inhibitors, they protect cells from damage by cysteine proteases (Muller Esteri, FEBS Lett. 182 (1985) 310-314). Important kininogenases are plasma kallikrein, tissue kallikrein and heparinocyte tryptase.

Kinins such as bradykinin and calidine are vasoactive peptides that affect a large number of biological processes. They play an important role in inflammatory processes. Increasing vascular permeability leads to hypotension and edema. In addition, they are very potent pain-inducing antacoids [sic] and are of great importance as cell mediators in the pathophysiology of asthma, allergic rhinitis and arthritis (CD Bhoola, CD Figueroa, K. Worthy, Pharmacological Revies [sic] 44 (1) (1992) 1- 80).

Regardless of the mechanisms underlying inflammatory processes, fluid containing all protein systems in the circulating blood leaks from the blood vessels. This means that the leakage of plasma fluid from blood vessels occurs in diseases such as asthma, rhinitis and inflammatory internal diseases. In addition, heparinocyte tryptase is mainly released in allergic processes (Salomonsson et al., Am. Rev. Respir. Dis. 146 (1992) 1535-1542).

The arginine chloromethyl ketones H- (D) -Pro-Phe-Arg-CH ₂ Cl and H- (D) -Phe-PheArg-CH ₂ -CI have been described by Kettner and Shaw as inhibitors of plasma kallikrein (Biochem. 17 (1978) 4778-4784 and Meth Enzyme 80 (1981) 826-842).

Various synthetic derivatives of benzamidines and benzylamines have been shown to be inhibitors of plasma kallikrein, with benzamidines having a significantly more potent inhibitory effect (F. Markward, S. Drawert, P. Walsmann, Biochemical Pharmacology 23 (1974) 2247-2256).

PKSI-527, N- (trans-4-aminomethylcyclohexylcarbonyl) -L-phenylalanine 4-carboxymethylanilide hydrochloride, is also a potent inhibitor of this kininogenase (Wanaka, Ohamoto et al., Thromb. Res., 57 (6) (1990) 889-895) .

SUMMARY OF THE INVENTION

The invention relates to compounds of formula I

where

And it is

R ²

R ¹ - (CH ₂ ) _m -C (CH ₂ ) _n -R ³ where m is 0, 1 or 2, n is 0, 1 or 2,

R ¹ is HOOC-, C 1-4 -alkyl-OOC-, aryl-OOC or -OH,

R ² is H, C 1-6 -alkyl or R ¹ - (CH ₂ ) _m -,

R ³ is H or C 1-6 -alkyl,

B is

R ⁶

R ⁴ (R ⁷ -C-R ') _p - N --- C --- CO-

I

R ⁵ where

R ⁴ is H, -4 1-4 alkyl or R ¹ - (CH 2) _m - (wherein R ¹ and _m are as defined above), p is 0 or 1,

R ⁵ is H or C 1-6 -alkyl,

R ⁶ is H, alkyl, phenyl which may carry up to three identical or different radicals from the group of G _{w-alkyl, CF3,} C ^ alkoxy, F or Cl, or C-cycloalkyl, which may carry the four identical or different C 1-4 alkyl radicals, or wherein one or two single CC bonds in the ring may be replaced by a C = C double bond or a fused phenyl ring, C ₇ -C ₁₂ -bicycloalkyl or C _10- tricycloalkyl or

R ⁴ and R ⁶ together are an ethylene or propylene group,

R ⁷ is H, C 1-6 -alkyl, phenyl which may carry up to three identical or different radicals from the group C 1-6 -alkyl, CF ₃ , C 1-6 -alkoxy, F or Cl, or C 1-6 -cycloalkyl which may bear up to four identical or different C1-6-alkyl radicals,

R ⁸ is H or C 1-6 -alkyl,

E is

q is 0 or 1

D is

where

R ⁹ is H or _t _ ₃ alkyl,

R ¹⁰ is H or C 1-6 -alkyl,

R ¹¹ is H or C 1-6 -alkyl,

X is O, S, -NR ¹² (R ¹² = H, C _1-6 -alkyl),

Y is -N = or -CR ¹³ = (R ¹³ = H, C 1-4 -alkyl, Cl, CF ₃ ),

Z is -N = or -CR ¹³ =, and salts thereof with physiologically tolerated acids.

The amino acid derivatives represented by B preferably have the (D) configuration; 3,4-dehydroproline and 4,5-dehydropipecolic acid have the (L) configuration.

Preferred compounds of formula I are those wherein A to E have the following meanings:

And it is

HOOC- (CH ₂ ) _t - (t = 1, 2 or 3), (HOOC-CH ₂ ) ₂ -CH- (HO-CH ₂ ) ₂ CHHOOC-CH ₂ -CH (COOH) -, HOOC-CH ( CH ₂ CH ₂ OH) -, HOOC-CH (C _w-alkyl) -, HOOC-C (C _{w-alkyl) 2} -, C _w-alkyl-OOC- (CH _{2) r,}

B is

R ⁶

I

R ⁴ (R ⁷ -CR ⁸ ) _p

I I - N - C - CO -

I

R '

P is 0.1,

R ⁴ is H, C 1-6 -alkyl or HOOC- (CH ₂ ) _m - (m = 1, 2 or 3),

R ⁵ is H, methyl

R ⁶ is H, Ο, _ ₈ alkyl, phenyl which may carry up to three identical or different radicals from the group of CH _3, CF _3, CH ₃ O, F or Cl, or a C ₃ _ ₈ cycloalkyl, which may carry up to four methyl radicals, 1,4-cyclohexadienyl, bicyclo [2.2.2] octyl, bicyclo [2.2.1] heptyl, norbornyl, adamantyl, indanyl, decalinyl,

R ⁷ is H, C, _ _s alkyl, phenyl which may carry up to three identical or different radicals from the group of CH _3, CF _3, CH ₃ O, F or Cl, or a C ₃ _ ₈ cycloalkyl, which may carry up to four methyl radicals,

R ⁸ is H, C 1-4 -alkyl, (B preferably has the D configuration),

E is

q is 0,1 (E preferably has L configuration),

D is

H

Y ^- Z

while X = S. 0, NH, NCH _3, NC ₂ H _s, Y = CH, c-ch ₃ , c-ci, c-cf _; z = CH, c-ch ₃ , C-Cl, c-cf _: or X = S, 0, NH, _N-CH3 or X = S, 0, NH, _N-CH3 or X = S, 0, NH, _N-CH3

Y = N a

Z = CH, C-CH ₃ , C-CF ₃

Y = CH, C-CH ₃ , C-CF ₃ Z = N

Y = N

while

X = S, O, NH, NCH _3, NC ₂ H _s,

Y = CH, C-CH ₃ , C-CF ₃ and

Z = CH, C-CH ₃ , C-CF, C-Cl or X = O, NH, NCH _; Y = NZ = CH, C-CH ₃ , C-CF ₃ or X = O, S, NH, NCH, Y = CH, C-CH ₃ , C-CF ₃ Z = N or X = O, S, NH , _NCH3 Y = Z = N

while X = S, 0, NH, NCH _3, NC ₂ H _5, Y = CH, C-CH ₃ , C-CF ₃ and z = CH, c-ch ₃ , c-c ₃ , c-ci or X = 0, NH, _NCH3 Y = N Z = CH, C-CH c-cf ₃ , c-ci or X = O, S, NH, NCH _3; Y = CH, C-CH ₃ , C-CF ₃ Z = N or X = O, NH, NCH ₃ Y = Z = N.

Particularly preferred compounds of formula I are those wherein A, B, D and E have the following meanings

A is _HOOC-CH2 HOOC-CH ₂ CH ₂ HOOC-CH _(CH3), HOOC-CH (C ₂ H _s)

B is

R ⁶

R ⁴ (R ⁷ -CR ⁸ ) _p - N - C - c

R

P is 0.1,

R ⁴ is H, CH ₃

R ⁵ is H, CH ₃ ,

R ⁶ is 0, -8 alkyl, C ₅ _ ₈ -cycloalkyl which may carry up to four methyl radicals, bicyclo [2.2.2] octyl, bicyclo [2.2.1 heptyl [sic], norbornyl, adamantyl, indanyl, decalinyl, with cyclopentyl, cyclohexyl and cycloheptyl being particularly preferred, R ⁷ is H, CH ₃ ,

R ⁸ is H, CH ₃₎

E is

q is 0, 1 D is

H

H

H

H

H

· R ''

Η

Η

Ν

Η

N-Ν

Η

while R ¹⁴ : H, CH ₃ , Cl, CF ₃₎ preferably H R ¹⁵ : H, Cl, CF ₃ , preferably H R ¹⁶ : H, CH ₃ , C ₂ H ₅ , preferably CH ₃ R ¹⁷ : H, CH ₃ , CF ₃ , preferably H, CH ₃ The following compounds are particularly preferred:

_tBuOOC-CH2 - (D) _{Chg-Pyr-NH-CH2-5-} (2-am) -thioph

HOOC-CH ₂ - (D) Chg-Pyr-NH-CH ₂ -5- (2-am) -thiophobuOOC-CH ₂ - (D) Chg-Dep-NH-CH ₂ -5- (2-am) -thioph HOOC-CH ₂ - (D) Chg-Dep-NH-CH ₂ -5- (2-am) -thioph

HOOC-CH ₂ - (D, L) Cpg-Pyr-NH-CH ₂ -5- (2-am) -thioph

_HOOC-CH2 - (D, L) _{Cheg-Pyr-NH-CH2-5-} (2-am) -thioph

HOOC-CH ₂ - (D, L) Cog-Pyr-NH-CH ₂ -5- (2-am) -thioph

_HOOC-CH2 - (D, L) _{Nog-Pyr-NH-CH2-5-} (2-am) -thioph

HOOC-CH ₂ - (D, L) Adaala-Pyr-NH-CH ₂ -5- (2-am) -thioph

HOOC-CH ₂ - (D, L) 4-MeCha-Pyr-NH-CH ₂ -5- (2-am) -thioph

_HOOC-CH2 - (D, L) of the _{bellows-yl-Pyr-NH-CH2-5-} (2-am) -thioph

HOOC-CH ₂ - (D, L) 4-MeChg-Pyr-NH-CH ₂ -5- (2-am) -thioph

HOOC-CH ₂ - (D, L) 3,3-Me ₂ Chg-Pyr-NH-CH ₂ -5- (2-am) -thioph

HOOC-CH ₂ - (D, L) 3,3-Me ₂ Cha-Pyr-NH-CH ₂ -5- (2-am) -thioph

HOOC-CH ₂ - (D, L) 4-iPr-Chg-Pyr-NH-CH ₂ -5- (2-am) -thioph

HOOC-CH ₂ - (D, L) 3,4,5 (MeO) ₃ Phe-Pyr-NH-CH ₂ -5- (2-am) -thioph

CHOC-CH ₂ - (D, L) Chea-Pyr-NH-CH ₂ -5- (2-am) -thioph

HOOC-CH ₂ - (D) Diphe-Pyr-NH-CH ₂ -5- (2-am) -thioph

HOOC-CH ₂ - (D, L) pp-Me ₂ Cha-Pyr-NH-CH ₂ -5- (2-am) -thioph

HOOC-CH ₂ - (D, L) -Adagly-Pyr-NH-CH ₂ -5- (2-am) -thioph

HOOC-CH ₂ - (D, L) -1-Tic-Pyr-NH-CH ₂ -5- (2-am) -thioph

HOOC-CH ₂ - (D, L) D-Pyr-NH-CH ₂ -5- (2-am) -thioph HOOC-CH ₂ - (D, L) 4-iPrCha-Pyr-NH-CH ₂ -5 - (2-am) -thioph

HOOC-CH ₂ - (D) α-MeCha-Pyr-NH-CH ₂ -5- (2-am) -thioph

HOOC-CH ₂ - (D) α-MeCha-Dep-NH-CH ₂ -5- (2-am) -thioph

HOOC-CH ₂ - (N-Me) (D) _{Cha-Pyr-NH-CH2-5-} (2-am) -thioph

_HOOC-CH2 - (D) _{Cha-Pyr-NH-CH2-5-} (2-am) -thioph

_HOOC-CH2 - (D) _{Cha-Dep-NH-CH2-5-} (2-am) -thioph

_HOOC-CH2 - (D) Cha-Pyr-NH-CH ₂ -4- (2-am) -thioph

_HOOC-CH2 - (D) Cha-Dep-NH-CH ₂ -4- (2-am) -thioph

HOOC-CH ₂ - (D) Cha-Pyr-NH-CH ₂ -5- (3-am) -thioph

_HOOC-CH2 - (D) _{Cha-Dep-NH-CH2-5-} (3-am) -thioph

_HOOC-CH2 - (D) _{Chg-Pyr-NH-CH2-5-} (3-am) -thioph

_HOOC-CH2 - (D) Chg-Pyr-NH-CH ₂ -4- (2-am) -thioph

HOOC-CH ₂ - (D) Cha-Pyr-NH-CH ₂ -5- (2-am) -fur

HOOC-CH ₂ - (D) Cha-Dep-NH-CH ₂ -5- (2-am) -fur

HOOC-CH ₂ - (D) Cha-Pyr-NH-CH ₂ -4- (2-am) -fur

_HOOC-CH2 - (D) Cha-Dep-NH-CH ₂ -4- (2-am) furo

_HOOC-CH2 - (D) _{Cha-Pyr-NH-CH2-5-} (3-am) furo

HOOC-CH ₂ - (D) Cha-Dep-NH-CH ₂ -5- (3-am) -fur

_HOOC-CH2 - (D) _{Chg-Pyr-NH-CH2-5-} (2-am) furo

_HOOC-CH2 - (D) _{Chg-Pyr-NH-CH2-5-} (3-am) furo

HOOC-CH ₂ - (D) Cha-Pyr-NH-CH ₂ -5- (1-Me-2-am) -pyrr

HOOC-CH ₂ - (D) Chg-Pyr-NH-CH ₂ -5- (1-Me-2-am) -pyrr

HOOC-CH ₂ - (D) Cha-Dep-NH-CH ₂ -5- (1-Me-2-am) -pyrr

HOOC-CH ₂ - (D) Cha-Pyr-NH-CH ₂ -4- (1-Me-2-am) -pyrr

HOOC-CH ₂ - (D) Cha-Dep-NH-CH ₂ - (1-Me-2-am) -pyrr

HOOC-CH ₂ - (D) Cha-Pyr-NH-CH ₂ -5- (1-Me-3-am) -pyrr

_HOOC-CH2 - (D) _{Cha-Dep-NH-CH2-5-} (1-Me-3-am) pyrrole _HOOC-CH2 - (D) _{Cha-Pyr-NH-CH2-5-} ( 2-amino-3,4-Me ₂₎ -thioph

_HOOC-CH2 - (D) _{Cha-Pyr-NH-CH2-5-} (2-amino-3-Me) -thioph

HOOC-CH ₂ - (D) Cha-Pyr-NH-CH ₂ -5- (2-am 1 -Me) -thioph

HOOC-CH ₂ - (D) Cha-Pyr-NH-CH ₂ -5- (2-am-3-Me) -fur

HOOC-CH ₂ - (D) Cha-Pyr-NH-CH ₂ -5- (2-am-4-Me) -fur

HOOC-CH ₂ - (D) Cha-Pyr-NH-CH ₂ -5- (3-am-2-Me) -fur

HOOC-CH ₂ - (D) Cha-Pyr-NH-CH ₂ -2- (5-am) -thiaz

HOOC-CH ₂ - (D) Cha-Pyr-NH-CH ₂ -2- (4-am) -thiaz

_HOOC-CH2 - (D) Cha-Pyr -NH-CH ₂ -4- (2-am) -thiaz

_HOOC-CH2 - (D) _{Cha-Pyr-NH-CH2-5-} (2-am) -thiaz

_HOOC-CH2 - (D) _{Chg-Pyr-NH-CH2} -2- (5-am) -thiaz

_HOOC-CH2 - (D) _{Chg-Pyr-NH-CH2} -2- (4-am) -thiaz

_HOOC-CH2 - (D) Chg-Pyr-NH-CH ₂ -4- (2-am) -thiaz

_HOOC-CH2 - (D) _{Chg-Pyr-NH-CH2-5-} (2-am) -thiaz

HOOC-CH ₂ - (D) Cha-Dep-NH-CH ₂ -2- (5-am) -thiaz

HOOC-CH ₂ - (D) Cha-Pyr-NH-CH ₂ -2- (4-am) -oxaz

HOOC-CH ₂ - (D) Chg-Pyr-NH-CH ₂ -2- (4-am -) - oxaz

HOOC-CH ₂ - (D) Cha-Pyr-NH-CH ₂ -5- (3-amino-1-Me) -pyraz

HOOC-CH ₂ - (D) Cha-Pyr-NH-CH ₂ -3- (5-am) -1,2,4-oxadiaz

HOOC-CH ₂ - (D) Cha-Pyr-NH-CH ₂ -5- (3-am) -1,2,4-oxadiaz

HOOC-CH ₂ - (D) Chg-Pyr-NH-CH ₂ -5 ~ (3-am) -1,2,4-oxadiazine HOOC-CH ₂ - (D) Cha-Pyr-NH-CH ₂ -5 - (3-am-1-Me) -1,2,4-triazine HOOC-CH ₂ -CH ₂ - (D) Cha-Pyr-NH-CH ₂ -5- (2-am) -thioph HOOC-CH _2- CH ₂ - (D) Cha-Pyr-NH-CH ₂ -5- (2-am) -fur HOOC-CH ₂ -CH ₂ - (D) Cha-Pyr-NH-CH ₂ -5- (1 -Me-2-am) -pyrr (HOOC-CH ₂ ) ₂ - (D) Cha-Pyr-NH-CH ₂ -5- (2-am) -thioph (HOOC-CH ₂ ) ₂ CH- (D) _{Cha-Pyr-NH-CH2-5-} (2-am) -thioph _HOOC-CH2 - (D) _{Chg-Pyr-NH-CH2-5-} (2-am) -1,3,4-thiadaz HOOC-CH ₂ - (D) Cha-Pyr-NH-CH ₂ -5- (2-am) -1,3,4-thiadaz HOOC-CH ₂ - (D) Chg-Pyr-NH-CH ₂ -5 - (2-am) -1,3,4-oxadiazol _HOOC-CH2 - (D) _{Cha-Pyr-NH-CH2-5-} (2-am) -1,3,4-oxadiazole

List of abbreviations:

Adaala: Adamantylalan

Adagly: adamantylglycine AIBN: azobisisobutyronitrile ac: acetyl Ala: alanine am: amidino asp: Aspartic acid Aze Azetidinecarboxylic acid bn: benzyl Boe: t-butyloxycarbonyl Bu: butyl cbz: benzyloxycarbonyl Cha: cyclohexylalanine Chea: cycloheptyalanine Cheg: Cykloheptylglycín chg: cyclohexylglycine Cog: cyclooctylglycine CPA: Cyklopentylalanín CPG: cyclopentylglycine DCC: dicyclohexylcarbodiimide DCH: Dicyklohexylalanín DCHA: dicyclohexylamine DCM: dichloromethane dep: 4,5-Dehydropipecolic acid DMF: dimethylformamide DIPEA: diisopropylethylamine dpa: Dpa Diphu: 2,5-Dihydrofenylalanín et: ethyl ECU: equivalents fur: furan Gly: glycine ham: ethoxycarbonylethyl

HOSucc: hydroxysuccinimide HPLC: High performance liquid chromatography Hyp: hydroxyproline imi: imidazole 2-Ind: 2-Dihydroindolecarboxylic acid Pr: isopropyl Leu leucine Me: methyl and the bellows-: a-methylcyclohexylalanine pp-Me ₂ Cha: 2-Amino-3-cyclohexyl-3-methylbutanoic acid or pp-dimethylcyclohexylalanine 4 bellow: (4-methyl-1-cyclohexyl) alanine The bellows-γ: (1-methyl-1-cyclohexyl) alanine 3.3-Me ₂ Cha: (3,3-dimethyl-1-cyclohexyl) alanine 4-MeChg: (4-Methyl-1-cyclohexyl) glycine [sic] 3,3-Me ₂ Chg: (3,3-dimethyl-1-cyclohexyl) glycine MPLC: Medium pressure liquid chromatography MTBE: Methyl tert-butyl ether NBS: N-Bromosuccinimide Nog: norbornylglycine oxadiazole: 1,2,4-oxadiazole oxazole: oxazole ph: phenyl Phe phenylalanine 2Phi: 2-Perhydroindolecarboxylic acid Pic: rpr'rv Pipecolic acid pjLf r> | \ / | r PIM: piperidinylmethyl PPA: Propylphosphonic anhydride to: FiOÍin

Py: pyridine Pyr: 3,4-dehydro-proline pyrazole pyrazole pyrrolidone: pyrrole RT: Room temperature RP-18: t: Reversed Phase C-18 (Reverse Phase C-18) tertiary Bu: Tertiary butyl tert: tertiary TBAB: Tetrabutylammonium bromide TEA: Triethylamine [sic] TFA: Trifluoroacetic acid TFFA: Trifluoroacetic anhydride TLC: Thin layer chromatography thiaz: thiazole Thioph: thiophene 1 1Tic: 1-Tetrahydroisoquinolinecarboxylic acid 3Tic; 3-Tetrahydroisoquinolinecarboxylic acid TOTU 0- (Cyanoethoxycarbonylmethylene) amino] -N, N, N ', N'Tetramethyluronium [sic] tetrafluoroborate triazine: 1,3,4-triazole FROM: benzyloxycarbonyl

The invention further relates to compounds which contain a structural element

NH NH ² , where E and D are as defined above, and at the nitrogen atom E is a hydrogen atom, a protecting group, an unsubstituted or substituted natural or synthetic amino acid, an unsubstituted or substituted carboxylic acid or sulfonic acid or an unsubstituted or substituted alkyl radical. This structural fragment is of value as a component of serine protease inhibitors and in particular of thrombin and kallikrein inhibitors.

The invention further relates to intermediates of formula IIIa and IIb

A B E - D - CN Ha

A B-E-D-CSNH; 11b, wherein A, B, E and D are as defined in claim 1.

These novel intermediates are used to prepare compounds I and are valuable building blocks for the synthesis of serine protease inhibitors.

The compounds of formula I may exist as such or in the form of their salts with physiologically tolerated acids. Examples of such acids are: hydrochloric acid, citric acid, tartaric acid, lactic acid, phosphoric acid, methanesulfonic acid, acetic acid, formic acid, maleic acid, fumaric acid, succinic acid, hydroxysuccinic acid, sulfuric acid, glutaric acid, aspartic acid, pyruvic acid, benzoic acid, glucuronic acid, oxalic acid, ascorbic acid and acetylglycine.

The novel compounds of formula I can be used for the following indications:

• diseases whose pathogenetic mechanism is derived directly or indirectly from the proteolytic effect of thrombin, • diseases whose pathogenetic mechanism is derived from thrombin-dependent receptor activation and signal transduction, • diseases associated with stimulation [e.g. by PAI-1, PDGF (platelet-derived growth factor), P-selectin, ICAM-1, tissue factor] or by inhibition (e.g., NO synthesis in smooth muscle cells) of gene secretion in body cells, diseases based on mitogenic effect thrombin • diseases based on thrombin-dependent change in contractility and permeability of epithelial cells (eg vascular endothelial cells) intravascular coagulation (DIC), • reocclusion and to reduce reperfusion time when comedicating with thrombolytics such as streptokinase, urokinase, prourokinase, t-PA, APSAC, plasminogen activators from the salivary glands of animals, and these, recombinant and mutated forms, the occurrence of early reocclusion and late re PTCA stenosis; thrombin-dependent proliferation of smooth muscle cells; accumulation of active thrombin in the CNS (e.g. in Alzheimer's disease), tumor growth and to prevent tumor cell adhesion and metastasis.

In particular, the novel compounds can be used for the therapy and prophylaxis of thrombin-dependent thromboembolic events such as deep-vein thromboses, pulmonary embolisms, cardiac or cerebral infarction and unstable angina, as well as for the treatment of disseminated intravascular coagulation (DIC). They are further suitable for combination therapy with thrombolytics, such as streptokinase, urokinase, prourokinase, tPA, APSAC, and other plasminogen activators to reduce reperfusion time and increase reocclusion time.

Other preferred fields of application are the prevention of thrombin-dependent reocclusion and late restenosis after percutaneous transluminal coronary angioplasty, the prevention of thrombin-induced smooth muscle cell proliferation, the prevention of active thrombin accumulation in the CNS (e.g., Alzheimer's disease), tumor control and tumor control. that lead to tumor cell adhesion and metastasis.

These novel compounds can also be used to coat artificial surfaces, such as hemodialysis membranes and associated tubing systems, and oxidants in extravascular circulation, stents and heart valves.

Moreover, these novel compounds can be used in diseases in which the pathogenetic mechanism is directly or indirectly derived from the proteolytic action of kininogenases, in particular kallikrein, e.g. in inflammatory diseases such as asthma, pancreatitis, rhinitis, arthritis, urticaria and other internal inflammatory diseases.

The compounds of the invention may be administered in a conventional manner orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally, rectally). Administration can also be by vapor or spray through the nasopharynx space.

The dosage depends on the age, condition and weight of the patient and on the mode of administration. As a rule, the daily dose of the active ingredient per person is about 10 - 2000 mg for oral administration and about 1 - 200 mg for parenteral administration. This dose can be administered in 2-4 individual doses or once daily as a storage form.

These novel compounds can be used in conventional solid or liquid pharmaceutical forms, e.g. as uncoated or coated tablets, capsules, powders, granules, supositories, solutions, ointments, creams or sprays. These are produced in a conventional manner. For this purpose, the active substances can be mixed with conventional pharmaceutical auxiliaries such as tablet binders, swelling agents, preservatives, tablet disintegrators, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, release retardants, antioxidants and / or Discharge gases (cf. H. Sucker et al., Pharmazeutische Technológie, Thieme-Verlag, Stuttgart, 1978).

The dosage forms thus obtained normally contain from 0.1 to 99% by weight of active ingredient.

DETAILED DESCRIPTION OF THE INVENTION

Experimental part

Compounds of formula I may be prepared as outlined in Schemes I-III.

Components A, B, E and D are preferably assembled separately in advance and used in a suitably protected form (see Scheme I-III).

Scheme I

A B e d

(P = protecting group, (P) = protecting group or H)

Scheme I describes the linear assembly of molecule I by coupling the amine HD-CN with the N-protected amino acid PE-OH to give PED-CN, removing the N-terminus protecting group to give HED-CN, coupling with the N-protected amino acid PB- OH to give PBED-CN by deprotection of P to give HBED-CN, followed by alkylation with an unprotected or protected (P) -AU (U-leaving group) or reductive alkylation with (P) -A'-U (U = aldehyde, ketone) or Michael addition with a suitable derivative of (P) -A "-C = C- to give (P) -ABED-CN. Conversion of the nitrile group to the amidine proceeds either by classical Pinner synthesis (R. Boder, DG Neilson, Chem. Rev. 61 (1962) 179) or by modified Pinner synthesis via the iminothioester salts as intermediates (H. Vieweg et al., Pharmazie 39 (1984) 226) or directly by the method of A. Eschenmoser, Helv. Chimica Acta 69 (1986) 1224. Subsequently, the protecting groups still present in the molecule are removed, preferably by acid hydrolysis.

When component D is involved in the synthesis as HD-CONH ₂ , dehydration of the amide to nitrile or conversion to thioamide functions takes place on one of the protected intermediates. As an alternative, component D can be used in the synthesis as HD-CSNH ₂ .

Scheme II (P) (P) (P) (P) (P) (P) (P) (P)

H (H) H

P

P

OH H

P

Scheme II describes the linear assembly of molecule I by alkylation, reductive amination [sic] or Michael addition of H-B-P to suitably protected components

A to give (P) -AB-OH, coupling with [sic] HEP to form (P) -ABEP, removing the C terminal protecting group to form (P) -ABE-OH, coupling with HD-CN to form ( P) -AECD-CN and reacting this intermediate to give the final product of Scheme I.

When compounds (P) -A-B-P still have a free NH function on B, they must be provided with a suitable protecting group before the end C protecting group is removed. The protecting groups used in each case must be orthogonal to each other.

As an alternative to the HD-CN component, it is also possible to use HD-CONH ₂ , HD-CSNH ₂ , HDC (NH) NH _2, HDC (NP) NH ₂ , HDC (NP) NHP, the combined intermediate (P) -ABED-CONH ₂ in the first case is dehydrated to (P) -ABED-CN or directly converted to (P) -ABED-CSNH ₂ .

Scheme III

Scheme III describes a very efficient method for preparing compounds I by convergent synthesis. The suitably protected components (P) -A-B-OH and H-E-D-CN are coupled together and the resulting intermediate (P) -A-B-E-D-CN is reacted to give the final product according to Scheme I.

As an alternative to HED-CN, HED-CONH ₂ or HED-CSNH ₂ may also be used, and in the first case the combined (P) -ABED-CONH ₂ intermediate is dehydrated to (P) -ABED-CN or converted to (P) -ABED-CSNH ₂ .

The N-terminal protecting groups used are Boe, Cbz or Fmoc, preferably Boe, and the C-terminal protecting groups are methyl, terebutyl and benzyl. If several protecting groups are present in the molecule, they must be orthogonal to each other if they are not to be removed simultaneously. If the intermediates contain component E, Cbz and benzyl are unsuitable as protecting groups.

The desired coupling and deprotection reactions are performed under standard peptide chemistry conditions (see M. Bodanszky, A. Bodanszky, "The Practice of Peptide Synthesis", 2nd edition, Springer Verlag Heidelberg, 1994).

The Boe protecting groups are removed with dioxane / HCl or TFA / DCM and the Cbz protecting groups are removed with hydrogenolysis or HF.

The ester groups are hydrolyzed with LiOH in an alcoholic solvent or dioxane / water. TFA or dioxane / HU [sic] is used to cleave t-butyl esters.

Reactions were checked by TLC routinely using the following mobile phases: A. DCM / MeOH 95: 5 B. DCM / MeOH 9: 1 C. DCM / MeOH 8: 2 D. DCM / MeOH / 50% HOAc 40: 10: 5 E. DCM / MeOH / 50% HOAc 35: 15: 5 Where are the separations mentioned column chromatography

separation on silica gel using the above mobile phases.

Reverse phase HPLC separations were performed with acetonitrile / water and HOAc buffer.

The starting compounds can be prepared by the following methods:

Examples of building components A used for alkylation are tert-butyl abromoacetate, tert-butyl β-bromopropionate, tert-butyl α-bromopropionate, tert-butyl bromobutyrate, tert-butyl alpha-bromobutyrate, THP-protected bromoethanol, TH-protected bromo-β-protected γ. the reductive amination is dihydroxyacetone, di-tert-butyl acetone dicarboxylate, and for the Michael addition are t-butyl acrylate, t-butyl methacrylate, di-tert-butyl fumarate. Those of these tert-butyl esters which are not commercially available are prepared by methods similar to G. Uray, W. Lindner, Tetrahedron, 44 1988 4357-4362.

Components B:

A wide variety of possibilities for general and specific amino acid synthesis are available in the literature. For an overview, see, inter alia, Houben-Weyl, Volume E16d / Part 1, pages 406 et seq.

The precursors that were frequently used were ethyl benzophenone imino acetic acid [sic], diethyl acetamidomalonate and ethyl isonitrilacetate [sic].

Various glycine and alanine derivatives have been prepared, for example, starting from ethyl isonitrile acetate [sic] and the appropriate ketone or aldehyde (see H.-J. Prätorius, J. Flossdorf, M.-R. Kula Chem. Ber. 108 (1975) 3079).

The syntheses of cyclooctylglycine, 2-norbornylglycine, adamantylalanine, γ-methylcyclohexylalanine, 4-isopropyl-1-cyclohexylalanine, 4-methyl-1-cyclohexylalanine and 4-methyl-1-cyclohexylglycine were carried out via the corresponding ethyl 2-formyl acrylates; Meyer, Liebigs Ann. Chem. 1977, 1174) starting from ethyl isocyanatoacetate with the relevant carbonyl compounds - cyclooctanone, 2norboronone, 1-formyladamantane, 1-formyl-1-methylcyclohexane, 1-formyl-4-isopropylcyclohexane, 1-formyl-4-methylcyclohexane and 4-methyl-cyclohexanone by the following general methods:

General method for the synthesis of ethyl 2-formylaminoacrylates

A solution of 100 mmol of ethyl isocyanoacetate in 50 mL of THF was added dropwise to 100 mmol of potassium tert-butoxide in 150 mL of THF at 0 to -10 ° C. After 15 minutes at the same temperature, 100 mmol of the appropriate carbonyl compound in 50 mL of THF was added, the reaction mixture was allowed to warm slowly to room temperature and the solvent was removed by rotary evaporation. The residue was mixed with 50 mL of water, 100 mL of acetic acid and 100 mL of DCM, and the product was extracted into DCM. The DCM phase was dried over Na ₂ SO ₄ and the solvent was removed by rotary evaporation. The products were obtained almost pure but could be further purified if necessary by column chromatography on silica gel (mobile phases: ether / petroleum ether mixtures).

General method for amino acid hydrochlorides starting from ethyl 2-formylaminoacrylates

100 mmol of ethyl 2-formylaminoacrylate was hydrogenated with Pd / C (10%) and hydrogen in 200 mL glacial acetic acid until reaction was complete. The catalyst was then filtered off, the acetic acid was evaporated as much as possible using a rotary evaporator and the residue was refluxed in 200 ml of 50% concentrated hydrochloric acid for 5 hours. The hydrochloric acid was evaporated in a rotary evaporator and the product was dried at 50 ° C under reduced pressure and then washed several times with ether. The hydrochlorides were obtained as light colored crystals.

25.0 g of cyclooctylglycine hydrochloride were obtained starting from 18.9 g (150 mmol) of cyclooctanone. 26.6 g of 2-norbornylglycine hydrochloride was obtained starting from 16.5 g (150 mmol) of 2-norbornanone. 26.0 g of adamantylalanine hydrochloride were obtained starting from 19.7 g (120 mmol) of 1-formyladamantane. 16.6 g of γ-methylcyclohexylalanine hydrochloride was obtained starting from 12.6 g (100 mmol) of 1-formyl-1-methyl-cyclohexane. 25.9 g of 4-methylcyclohexylglycine hydrochloride was obtained from 16.8 g (150 mmol) of 4-methylcyclohexanone. 18 g of trans-4-methyl-1-cyclohexylalanine hydrochloride were obtained starting from 15 g of trans-1-formyl-4-methylcyclohexane. 10 g of 3,3-dimethyl-1-cyclohexylalanine hydrochloride was obtained starting from 9 g of 3,3-dimethyl-1-formylcyclohexane.

The aldehyde-1-formyl-3,3-dimethylcyclohexane - required for the synthesis was prepared by a method based on the methods of Moskal and Lensen (Rec. Grass. Chim. Pavs-Bas 106 (1987) 137-141).

A solution of n-butyllithium in n-hexane (72 mL, 115 mmol) was added dropwise over 10 minutes to a stirred solution of diethyl isocyanomethylphosphonate (17 mL, 105 mmol) in 280 mL of anhydrous diethyl ether at -60 ° C. The resulting suspension was then stirred at -60 ° C for 15 minutes, and a solution of 3,3-dimethylcyclohexanone (13 g, 105 mmol) in 100 mL of anhydrous diethyl ether was added over 10 minutes while maintaining the temperature below -45 ° C. The temperature of the reaction mixture was allowed to rise to 0 ° C, and after stirring at this temperature for 90 minutes, 150-200 ml of 38% aqueous hydrochloric acid was carefully added. The mixture was stirred vigorously at room temperature for 15 hours to complete the hydrolysis. The organic phase was separated and washed with 200 ml of water, saturated sodium bicarbonate solution and saturated sodium chloride solution. It was dried over magnesium sulfate, filtered and concentrated in a rotary evaporator. The residue obtained was used without further purification as the starting material for amino acid synthesis.

Boc- (D) -a-methylcyclohexylalanine

3.4 g (12.2 mmol) of Boc- (D) -α-methyl-Phe-OH was hydrogenated in 100 mL of MeOH in the presence of 250 mg of 5% Rh on Al ₂ O ₃ under 10 bar of hydrogen at 50 ° C for 24 hours. Filtration and evaporation of the solvent gave 2.8 g of Boc- (D) -oc-methyl-ChaOH.

¹ H-NMR (DMSO-d ⁶ , δ in ppm): 12 (very broad signal, COOH); 1.7-0.8 (25H; 1.35 (s, Boe), 1.30 (s, Me))

Boc- (3-Ph) -Pro-OH was synthesized by a method similar to J.Y.L. Chung et al. (J.Y. L. Chung et al. J. Org. Chem. 55 (1990) 270).

Preparation of Boc-1-tetralinylglycine

Boc-1-Tetralinylglycine was prepared starting from 1,2-dihydronaphthalene.

1,2-dihydronaphthalene was first converted to 1-tetralyl bromide with HBr (similar to J. Med. Chem. 37 (1994) 1586). The bromide was subsequently reacted with diethyl acetamidomalonate and after hydrolytic cleavage, the obtained α-amino acid was converted to the Boc-protected form under standard conditions. Another possible preparation has been described by E. Reimann and D. Voss (E. Reimann, D. Voss, Ar. Pharm. 310 (1977) 102).

Preparation of Boc-1- (D, L) Tic-OH

Boc-1- (D, L) Tic-OH was prepared by the method of R. T. Shuman et al. (R.T. Shuman et al. J. Med. Chem. 36 (1993) 314).

Preparation of Boc- (D, L) Dch-OH

Boc- (D, L) -Dpa-OH (1 mmol) was hydrogenated in 12 mL of MeOH along with catalytic amounts of 5% Rh / Al ₂ O ₃ at 5 bar. Filtration and removal of the solvent under reduced pressure gave the product in quantitative yield.

Preparation of cycloheptylglycine, cyclopentylglycine, 4-isopropylcyclohexylglycine and 3,3-dimethylcyclohexylglycine

These amino acids were prepared by reacting cycloheptanone, cyclopentanone, 4-isopropylcyclohexanone and 3,3-dimethylcyclohexanone with ethyl isonitrilacetate [sic] by H.J. Pratorius (H. J. Pratorius, J. Flossdorf, M. Kula, Chem. Ber. 108 (1985) 3079).

Preparation of H-D, L-Chea-OH

4.0 g of cycloheptylmethyl methanesulfonate (19.39 mmol), prepared from cycloheptylmethanol and methanesulfonyl chloride, were refluxed together with 4.9 g of benzophenoneimine glycine ethyl ester (sic) (18.47 mmol), 8.9 g of dry, finely powdered potassium carbonate (64.65 mmol) and 1 g of tetrabutylammonium bromide (3 mmol) in 50 ml of dry acetonitrile under an inert gas atmosphere for 10 hours. The potassium carbonate was then filtered off, the filtrate was evaporated to dryness and the crude product was directly hydrolyzed with 20 ml of 2 N hydrochloric acid in 40 ml of ethanol with stirring at room temperature for 1.5 hours. The reaction solution was diluted and the benzophenone was then extracted with ethyl acetate under acidic conditions and then extracted with H-D, LChea-OEt dichloromethane in an alkaline medium (pH = 9) and the solution was dried over magnesium sulfate and concentrated on a rotary evaporator. Yield 3.7 95% of theoretical.

Boc- (D, L) - (3,4,5- (MeO) ₃ ) Phe-OH was prepared by alkylation of benzophenoneimine glycine ethyl ester [sic] trimethoxybenzyl chloride, followed by introduction of a Boe protecting group and ester hydrolysis.

D- (1,4-Cyclohexadien-1-yl) ala-OH [sic] was prepared according to the method of G. Zivilichovsky, V. Gurvich J. Chem. Soc., Perkin Trans 19 (1995) 2509-15.

H- (D, L) -pp-Me ₂ Cha-OH was prepared according to the method of U. Schollkopf, R. Meyer, L. Ann. Chem. (1977) 1174-82.

Said amino acids were converted using di-tert-butyl dicarbonate in water / dioxane by conventional methods to the Boc-protected form in each case and then recrystallized from ethyl acetate / hexane or purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether).

Boc-protected amino acids were used as building components B according to Scheme I.

Said amino acids as building components B were also in some cases converted to the corresponding benzyl esters and attached to suitably protected building components A. In the case of compounds with NH function which was still free, this was then protected with Boe, the benzyl ester group was removed by hydrogenation and The AB-OH component was purified by crystallization, salt precipitation or column chromatography. This route is described by way of example for _tBuOOC-CH2 - (Boc) (D) Cha-OH.

Synthesis of D-cyclohexylalanine benzyl ester

A suspension of 100 g (481 mmol) of D-cyclohexylalanine hydrochloride, 104 g (962 mmol) of benzyl alcohol and 109.7 g (577 mmol) of p-toluenesulfonic acid monohydrate in 2200 ml of toluene was slowly heated to reflux with a water separator. Hydrogen evolution and dissolution of the suspension to form a clear solution were observed in the temperature range of 80-90 ° C. When no more water was removed (after about 4 hours), 500 ml of toluene were distilled off, the reaction mixture was allowed to cool overnight, and the residue was filtered and washed twice with 1000 ml of hexane each.

; I

The residue (195 g) was then suspended in 2000 ml of dichloromethane and, after the addition of 1000 ml of water, its pH was adjusted to 9-9.5 by successively adding 50% sodium hydroxide solution with stirring. The organic phase was separated, washed twice with 500 ml of water, dried over sodium sulfate and filtered to remove the desiccant, and the filtrate was concentrated to give 115 g (94%) of the title product as a light oil.

N- (tert-butyloxycarbonylmethylene) -D-cyclohexylalanine benzyl ester [sic]

115 g (440 mmol) of D-cyclohexylalanine benzyl ester were dissolved in 2000 ml of acetonitrile and 607.5 g (4.40 mol) of potassium carbonate and 94.3 g (484 mmol) of tert-butyl bromoacetate were added at room temperature and the mixture was stirred at at this temperature for 3 days. The carbonate was filtered off, washed with acetonitrile, the solution was concentrated (30 ° C, 20 mbar), the residue was dissolved in 1000 ml of methyl tert-butyl ether and the organic phase was extracted with 5% citric acid and saturated sodium bicarbonate solution. The organic phase was dried over sodium sulfate, filtered to remove the desiccant, concentrated, and the obtained oil (168 g) was used directly in the next reaction.

N-Boc-N- (tert-butyloxycarbonylmethylene) -D-cyclohexylalanine benzyl ester [sic]

The oil (168 g, 447 mmol) obtained in the previous synthesis was dissolved in 1400 mL of acetonitrile and after addition of 618 g (4.47 mmol) of powdered potassium carbonate and 107.3 g (492 mmol) of di-tert-butyl dicarbonate were stirred at room temperature. days. The potassium carbonate was aspirated, washed with about 1000 mL of acetonitrile, and the filtrate was concentrated. 230 g of the expected product are obtained.

. Cyclohexylammonium salt of N-Boc-N- (tert-butyloxycarbonylmethylene) -Dcyclohexylalanine [sic]

115 g of N-Boc-N- (tert-butyloxycarbonylmethylene) -D-cyclohexylalanine benzyl ester [sic] was dissolved in 1000 ml of pure ethanol and hydrogenated in the presence of 9 g of 10% Pd on activated carbon with hydrogen at atmospheric pressure at 25-30 ° C for 2 hours. Filtration and removal of the solvent in a rotary evaporator gave 100 g (260 mmol) of a yellow oil which was dissolved in 1600 ml of acetone and heated to reflux. The heating bath was removed, and a solution of 27 g (273 mmol) of cyclohexylamine in acetone was quickly added via an addition funnel. The desired salt crystallized upon cooling the reaction mixture to room temperature. The solid was filtered off, washed with 200 ml of acetone and, for final purification, recrystallized again from acetone. Drying the residue in a vacuum oven at about 30 ° C afforded 70.2 g of the desired salt as a white powder.

The cyclohexylammonium salt of N-Boc-N- (tert-butyloxycarbonylmethylene) -Dycyclohexylglycine [sic] was prepared in a similar manner from cyclohexylglycine as a precursor.

Cyclohexylammonium salt of N-Boc-N- (tert-butyloxycarbonylethylene) O-cyclohexylalanine »

[sic]

(a) tert-butyl 3-bromopropionate

16.64 g (109 mmol) of bromopropionic acid, 150 ml of condensed 2-methylpropene and 2 ml of concentrated sulfuric acid were placed at -30 ° C under a countercurrent of nitrogen in a glass vessel suitable as an autoclave, sealed and stirred at room temperature for 72 hours. Upon processing, the reaction vessel was recooled to -30 ° C and the solution was carefully poured into 200 mL of ice cold saturated sodium bicarbonate solution. Excess 2-methylpropene was allowed to evaporate with stirring, the residue was extracted three times with 50 ml dichloromethane, the combined organic phases were dried over sodium sulfate, the desiccant was filtered off and the solution was concentrated under a water pump vacuum. The oily residue was purified by column chromatography (mobile phase n-hexane, then n-hexane / diethyl ether 9: 1). 18.86 g of the title compound were obtained.

(b) N- (tert-butyloxycarbonylethylene) -D-cyclohexylalanine benzyl ester [sic]

49.4 g (189 mmol) of D-cyclohexylalanine benzyl ester were dissolved in 250 mL of acetonitrile and refluxed for 5 days after addition of 31.6 g (151 mmol) of tert-butyl bromopropionate at room temperature. The precipitate obtained was filtered off and washed several times with acetonitrile, the filtrate was concentrated under water pump vacuum, the residue was dissolved in 350 ml of dichloromethane and the organic phase was extracted with 5% citric acid and saturated sodium bicarbonate solution. The organic phase was dried over sodium sulfate, the desiccant was removed by filtration and the solution was concentrated. The oily residue was purified by column chromatography (eluent dichloromethane, then dichloromethane / methanol 95: 5). A slightly contaminated oil was obtained and used directly in the next reaction.

(c) N-Boc-N- (tert-butyloxycarbonylethylene) -D-cyclohexylalanine benzyl ester [sic]

The oil obtained in the previous synthesis (30 g, max. 70 mmol) was dissolved in 150 ml of acetonitrile and after addition of 28 ml (160 mmol) of diisopropylethylamine and 19.2 g (88 mmol) of di-tert-butyl dicarbonate were stirred at room temperature for 3 days. The reaction mixture was concentrated in a rotary evaporator under water pump vacuum, the residue was dissolved in n-hexane and washed five times with 3 ml of 5% citric acid each, the combined organic phases were dried over sodium sulfate, the desiccant was filtered off and the residue was concentrated by column chromatography. (mobile phase hexane / ethyl acetate 95: 5). 32.66 g (64 mmol) of the desired product are obtained.

d) N-Boc-N- (tert-butyloxycarbonylethylene) -cyclohexylammonium cyclohexylammonium salt [sic]

32.66 g (64 mmol) of N-Boc-N- (tert-butyloxycarbonylethylene) -Decyclohexylalanine benzyl ester [sic] was dissolved in 325 ml of pure ethanol and hydrogenated under hydrogen at atmospheric pressure at 25-30 ° C in the presence of 3 g of 10% Pd on activated carbon for 14 hours. Filtration of the solution through Celite®, washing with ethanol and removal of solvent on a rotary evaporator gave 26.7 g of a yellow oil which was dissolved in acetone and heated to reflux. The heating bath was removed, and a solution of 7 g (70 mmol) of cyclohexylamine in acetone was quickly added via an addition funnel. The desired salt crystallized upon cooling the reaction mixture to room temperature. The solid was filtered off, washed with 25 ml of acetone and, for final purification, recrystallized again from acetone. Drying the residue in a vacuum oven at 30 ° C gave 26.6 g (54 mmol) of the desired salt as a white powder.

N-Boc-N- (tert-butyloxycarbonylmethylene) - (D) -cyclohexylalanyl-3,4-dehydroproline [sic]

a) N-Boc-Pyr-OH (5 g, 23.45 mmol) was dissolved in MeOH (50 mL) and HCl in dioxane (4 N, 30 mL) was added. After refluxing for 12 h, the solvent was removed on a rotary evaporator to give the product H-Pyr-OMe hydrochloride. Yield: 3.84 g (100%). J

b) N- (t-BuO ₂ C-CH ₂ ) -N-Boc- (D) -Cha-OH (8 g, 20.75 mmol) was dissolved in dichloromethane (75 mL) and at -10 ° C was added ethyl diisopropylamine (15.5 ml,

89.24 mmol). After stirring at this temperature for 5 minutes, a solution of H-Pyr-OMe hydrochloride (3.4 g, 20.75 mmol) in dichloromethane (25 mL) was added dropwise. Then a solution of propanephosphonic anhydride in ethyl acetate (50%, 20 mL, 26.96 mmol) was added dropwise and the mixture was stirred at -10 to 0 ° C for 2 hours. The mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate solution (2 x 80 mL), 5% citric acid solution (2 x 15 mL) and saturated sodium chloride solution (1 x 20 mL). The organic phase was dried over sodium sulfate and the solvent was removed by rotary evaporation. The crude product was purified by flash chromatography (silica gel, dichloromethane / methanol = 95/5). Yield = 6.2 g (60%).

c) N- (t-BuO ₂ C-CH ₂ ) -N-Boc- (D) -Cha-Pyr-OMe (5.5 g, 11.12 mmol) was dissolved in dioxane (40 mL) and after addition sodium hydroxide solution (1 N, 22.2 ml,

22.24 mmol) was stirred at room temperature for 2 hours. The dioxane was removed by rotary evaporation and the aqueous phase was washed with ethyl acetate and acidified to pH 1-2 with potassium hydrogen sulphate solution (20%). The aqueous phase was extracted with dichloromethane and the combined organic phases were dried over sodium sulfate. Yield: 5 g (94%) of a colorless foam. Recrystallization from water-saturated n-hexane gave colorless crystals (m.p. = 158-160 ° C).

N-Boc-N- (tert-butyloxycarbonylmethylene) - (D) -cyclohexylglycyl-3,4-dehydroproline [sic]

This compound was obtained in a similar manner from N-Boc-N (tert-butyloxycarbonylmethylene) - (D) -cyclohexylglycine [sic] and 3,4-dehydroproline methyl ester.

(L) 3,4-Dehydroproline used as building component E can be purchased and (D, L) -4,5-dehydropipecolic acid can be prepared by the method of A. Burgstahler, CE Aiman, J. Org. Chem. 25 (1960) 489 or by C. Herdeis, W. Engel Arch. Pharm. 326 (1993) 297 and then converted with (Boc) ₂ O to Boc- (D, L) -Dep-OH.

Building components D were synthesized as follows:

5-Aminomethyl-2-cyanothiophene

The preparation of this building component was carried out as described in WO 95/23609.

4-Aminomethyl-2-cyanothiophene

a) 2-Bromo-4-formylthiophene;

g (320 mmol) of 3-formylthiophene was dissolved in 600 ml of dichloromethane and cooled to 5 ° C, 100 g (750 mmol) of aluminum chloride were added portionwise and the reaction mixture was then refluxed. A solution of 59 g (19 mL, 360 mmol) of bromine in 40 mL of dichloromethane was added dropwise over 45 minutes and the reaction was allowed to continue under reflux for 4 hours. After cooling, the reaction solution was poured into 600 g of ice water and extracted with dichloromethane, and the organic phase was washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and concentrated on a rotary evaporator. 64.5 g of crude product was obtained, which was purified by column chromatography (silica gel, dichloromethane / petroleum ether) to give a total of 56.5 g of slightly impure product.

b) 2-Cyano-4-formylthiophene

Copper cyanide (7.6 g, 85 mmol) was added to a solution of 2-bromo-4-formylthiophene (13.53 g, 70.82 mmol) in DMF (25 mL) and the reaction mixture was refluxed

3.5 hours during which the initially light green suspension turned into a black solution. After addition of water, the reaction mixture was extracted several times with ethyl acetate, the organic phases were combined, washed with saturated NaCl solution, dried over sodium sulfate and concentrated in a rotary evaporator under a slight vacuum. Addition of ether to the residue (7 g) gave 1.6 g of pure product. The crystallization solution was purified along with the crude products from other batches by chromatography (silica gel, dichloromethane / petroleum ether 1: 1). A total of 56.5 g of 2-bromo-4-formylthiophene was used for the reactions and 12.6 g of pure 2-cyano-4-formylthiophene was obtained (31% yield).

c) 2-Cyano-3-hydroxymethylthiophene

3.47 g (91.8 mmol) of sodium borohydride was added portionwise to the suspension

12.6 g (91.8 mmol) of 2-cyano-4-formylthiophene in 200 ml of ethanol and the reaction mixture was stirred at room temperature for 2 hours, during which time it gradually formed a clear solution. After concentrating under reduced pressure, the residue was dissolved in ethyl acetate and washed successively with saturated NaCl solution, 5% citric acid and saturated NaCl solution, and the organic phase was dried over sodium sulfate and concentrated under reduced pressure to give 11.7 g of almost pure product (yield). 91.5%).

I '.

d) 3-Bromomethyl-2-cyanothiophene

11.7 g (84.07 mmol) of 2-cyano-3-hydroxymethylthiophene were dissolved together with 24.1 g (91.87 mmol) of triphenylphosphine in 100 ml of THF at room temperature and quenched in an ice bath in portions. , 47 g (91.87 mmol) of tetrabromomethane. Stirring at room temperature for 3 hours was followed by concentration under reduced pressure and purification by silica gel chromatography (dichloromethane / petroleum ether) to give 18.8 g of a light yellow crystalline product containing petroleum ether.

e) 4-N, N-Bis (tert-butoxycarbonyl) aminomethyl-2-cyanothiophene

18.81 g of 3-bromomethyl-2-cyanothiophene (crude product, maximum 84.07 mmol) was dissolved in 160 ml THF and cooled to 5 ° C and 3.07 g (102.4 mmol) 80% added in portions sodium hydride suspension. Then added dropwise

22.25 g (102.4 mmol) of di-tert-butyliminodicarboxylate dissolved in 160 mL of THF at ° C was then stirred at room temperature overnight. Since the conversion was incomplete by TLC, the mixture was heated to 30-35 ° C for 4.5 hours. After cooling to 0-5 ° C, 33 ml of saturated ammonium chloride solution was slowly added dropwise, THF was distilled off under reduced pressure, the residue was extracted several times with ethyl acetate and the ethyl acetate phases were washed with saturated NaCl solution, dried over sodium sulfate and concentrated by rotary evaporation. . A viscous red residue (34.61 g) was used as a crude product in the next reaction.

f) 4-Aminomethyl-2-cyanothiophene hydrochloride

34.61 g of 4-N, N-bis (tert-butoxycarbonyl) aminomethyl-2-cyanothiophene (crude product, maximum 84.07 mmol) was dissolved in 600 ml of ethyl acetate, cooled to 0 ° C, saturated with gaseous HCl and heated to room temperature. After 3 hours, the resulting suspension was concentrated in a rotary evaporator and distilled several times together with dichloromethane, and the residue was extracted by stirring with ether and dried under reduced pressure. 13.85 g of product were obtained as a pale powder. Two-stage yield 94.3%.

2-Aminomethyl-4-cyanothiophene

a) 4-Cyanothiophene-2-carbaldehyde

49.3 g (258.05 mmol) of 4-bromothiophene-2-carbaldehyde and 27.8 g (310.41 mmol) of copper (I) cyanide were suspended in 130 ml of absolute DMF and refluxed for 8 hours. The solvent was removed on a rotary evaporator at 40 ° C and the residue was suspended in ethyl acetate and transferred to a Soxhlet [sic] apparatus. This residue was extracted overnight, the yellow solution was dried over sodium sulfate, concentrated on a rotary evaporator, and the yellow solid obtained was recrystallized from ether to give 25.3 g of product (80% of theory).

b) 4-Cyanothiophene-2-carbaldehyde oxime

11.6 g (84.6 mmol) of 4-cyanothiophene-2-carbaldehyde were dissolved in 140 ml of methanol and 12.3 g (116.1 mmol) of sodium carbonate were added. Then 6.5 [lacuna] (93.5 mmol) hydroxylamine hydrochloride was added portionwise with cooling to 15 ° C and the mixture was stirred at 10 ° C for 2 hours. After addition of 80 ml of water, the reaction mixture was extracted five times with 50 ml of diethyl ether each time, the organic phase was dried over sodium sulfate and the solvent was removed under reduced pressure to give

12.5 g of the desired product as a yellow crystalline powder (96% of theory).

c) 2-Aminomethyl-4-cyanothiophene hydrochloride

11.22 g (171.64 mmol) of fine zinc dust were carefully added in small portions to a solution of 4.65 g (30.60 mmol) of 4-cyanothiophene-2-carbaldehyde oxime in 50 mL of trifluoroacetic acid cooled to 0-5 ° C. in such a way that the temperature does not exceed 15 ° C. After stirring at room temperature for 3 hours and decanting from excess zinc, the trifluoroacetic acid was mostly removed under reduced pressure (oil pump), the remaining oil was cooled to 0 ° C and a mixture of 150 mL of 3 N sodium hydroxide solution and 2 I dichloromethane was added in portions. , which was cooled to 0 ° C. The insolubles were removed by filtration and then the organic phase was separated, the aqueous phase was extracted eight times with 20 ml of dichloromethane, the combined organic phases were dried over sodium sulfate and then 20 ml of 6M methanolic hydrochloric acid were added under ice-cooling. The product precipitated as the hydrochloride as a white solid and crystallization was completed by cooling the suspension to 4 ° C overnight. 2.2 g of product were obtained as colorless needles (50% of theory).

5-Aminomethyl-3,4-dimethylthiophene-2-carboxamide hydrochloride g (105.42 mmol) of 5-cyano-3,4-dimethylthiophene-2-carboxamide was suspended in 760 ml of methanol and 110 ml of 2 N hydrochloric acid and uploads

9.5 g of Pd on carbon (10%) was hydrogenated at room temperature. After use

4.7 L of hydrogen (4 hours) methanol was distilled off under reduced pressure and the aqueous phase was extracted three times with ethyl acetate and then freeze-dried. 16.3 g of the expected product are obtained as a white solid (70.4% of theory).

5-Aminomethylisoxazole-3-carboxamide

a) Ethyl 5-chloromethylisoxazole-3-carboxylate

21.2 g (210 mmol) of triethylamine was added dropwise to a stirred mixture of 30 g (198 mmol) of ethyl 2-chloro-2-hydroxyiminoacetate and 150 ml of propargyl chloride cooled to 10-15 ° C and after stirring at room temperature for 1 hour water, the mixture was extracted with ether and the organic phase was dried over magnesium sulfate and concentrated on a rotary evaporator. The residue was distilled under 0.5 torr, distilling the product at 116-122 ° C.

b) 5-Chloromethylisoxazole-3-carboxylic acid

47.3 g (250 mmol) of ethyl 5-chloromethylisoxazole-3-carboxylate in 150 ml of ethanol were mixed with 14 g (250 mmol) of potassium hydroxide and stirred at 60 70 ° C for 6 hours. After cooling and concentrating under reduced pressure, the residue was dissolved in water and extracted with ether, the aqueous phase acidified with hydrochloric acid and then extracted several times with ether. The ether phase was dried over sodium sulfate and concentrated under reduced pressure (oil pump, 50 ° C). 31 g of the desired product are obtained (77% of theory).

. I

c) 5-Chloromethylisoxazole-3-carbonyl chloride

120 g (743 mmol) of 5-chloromethylisoxazole-3-carboxylic acid were refluxed together with 500 ml of thionyl chloride and 2 drops of pyridine for 10 hours, the mixture was concentrated under reduced pressure and then distilled under 20 torr. The product was distilled at 125-133 ^° C to give 78 g (58% of theory).

d) 5-Chloromethylisoxazole-3-carboxamide

Ammonia was introduced into a solution of 10 g (55.56 mmol) of 5-chloromethylisoxazole-3-carbonyl chloride in 100 ml of dichloromethane at 10-15 ° C for 1 hour, and the mixture was then stirred at room temperature for 1 hour. After cooling the solution to 0 ° C, the precipitate was filtered off with suction and washed with a little cold dichloromethane, and the residue was extracted by stirring with water twice to remove ammonium salts. Drying under reduced pressure gave 6.58 g of pure product as a pale powder (74% of theory).

e) 5-Aminomethylisoxazole-3-carboxamide hydrochloride

2.44 g (15.2 mmol) of 5-chloromethylisoxazole-3-carboxamide was added to a mixture of 100 ml of concentrated ammonia solution and 72 ml of methanol, the solution was heated to 40 ° C and during this time was continuously saturated with ammonia gas. The precursor reacted after 6 hours. The methanol was removed under reduced pressure, the aqueous phase was extracted twice with dichloromethane and then the aqueous phase was carefully evaporated to dryness under reduced pressure. The white solid residue was used as a crude product in the Boc-dehydroproline coupling reaction.

2-Aminomethylthiazole-4-thiocarboxamide was prepared as described by G. Videnov, D. Kaier, C. Kempter, and G. Jung, Angew. Chemie 108, (1996) 1604, by removing the protecting group from the N-Boc-protected compound described therein with ethereal hydrochloric acid in dichloromethane.

4-Aminomethylthiazole-2-thiocarboxamide

The precursor - ethyl 4-aminomethylthiazole-2-carboxylate - was prepared as described in U.S. Pat. No. 4,826,816. After the introduction of the Boe protecting group on the amine function, the ester group was hydrolyzed, the obtained acid group was converted into carboxamide using mixed anhydride (isobutyl carbonate). using Lawesson's reagent to thioamide. Removal of the protecting group affords the above-mentioned nitrates and compounds.

5-Aminomethyl-2-cyanofuran

(a) 5-Cyanofuran-2-carbaldehyde:

165 ml (264 mmol) of a 1.6 molar solution of n-butyllithium in n-hexane was added over 20 minutes to a solution of 26.7 g (264 mmol) of diisopropylamine in 600 ml of tetrahydrofuran cooled to -78 ° C. The solution was allowed to warm to -20 ° C, re-cooled to -75 ° C, and a solution of 22.3 g (240 mmol) of 2-cyanofuran in 100 mL of tetrahydrofuran was slowly added dropwise at this temperature. After stirring for 30 minutes, 93 ml of dimethylformamide was slowly added dropwise and the mixture was stirred for another 30 minutes. For work-up, a solution of 40 g of citric acid in 200 ml of water was added at -70 ° C. After concentration in a rotary evaporator, 600 ml of saturated sodium chloride solution were added and the mixture was extracted three times with 200 ml of diethyl ether each time. The combined organic extracts were dried over magnesium sulfate. The desiccant was filtered off and the solvent was then distilled off under water pump vacuum and the residue was purified by column chromatography (dichloromethane eluent). The eluate was concentrated and the residue was distilled with steam (azeotrope boiling range with water: 60-65 ° C at p = 0.1 mm Hg). Extraction of the distillate with diethyl ether, drying of the organic phase and concentration of the solution gave 10.6 g (88 mmol, 36%) of the title compound. 1 H-NMR (270 MHz, d ₆ -DMSO): δ = 7.7 (d, 1H), 7.8 (d, 1H), 9.75 (s, 1H).

(b) 5-hydroxymethyl-2-cyanofuran:

2.34 g (62 mmol) of sodium borohydride was added portionwise to a solution of 30 g (0.25 mol) of 5-cyanofuran-2-carbaldehyde in 500 ml of absolute ethanol at -30 ° C. The solution was stirred at -30 ° C for 2 hours and the pH adjusted to 7 with 5% citric acid in water while cooling. The reaction mixture was concentrated under a water pump vacuum, saturated sodium chloride solution was added to the residue, the mixture was extracted several times with 150 ml diethyl ether, the combined organic phases were dried over magnesium sulfate, the desiccant was filtered off and the solvent was distilled under water pump vacuum at room temperature. . This afforded 27 g (22 mmol, 88%) of the title compound as a dark red oil, which was used without further purification in subsequent reactions. ¹ H-NMR (250 MHz, d ₆ -DMSO): δ = 4.4 (m, 2H), 5.6 (bs, 1H), 6.6 (d, 1H), 7.5 (d , 1H).

(c) 5-Bromomethyl-2-cyanofuran:

g (145 mmol) of triphenylphosphine was added to a solution of 15 g (121 mol [sic]) of 5-hydroxymethyl-2-cyanofuran in 250 ml of tetrahydrofuran. The mixture was cooled to -10 ° C and a solution of 48 g (145 mmol) of tetrabromomethane in 100 mL of tetrahydrofuran was added. The mixture was allowed to warm to room temperature and stirred at this temperature for 3 hours. The mixture was concentrated on a rotary evaporator under water pump vacuum and the residue was purified by column chromatography (eluent petroleum ether: dichloromethane 1: 1, Rf = 0.5). 11.5 g of the title compound were obtained. ¹ HNMR (250 MHz, d ₆ -DMSO): δ = 4.8 (m, 2H), 6.7 (d, 1H), 7.7 (d, 1H).

(d) 5-N, N-Bis (tert-butoxycarbonyl) aminomethyl-2-cyanofuran:

4.0 g (135 mmol) of sodium hydride (80% suspension in mineral oil) was added portionwise to a solution of 22.9 g (123 mmol) of 5-bromomethyl-2-cyanofuran in 400 ml of tetrahydrofuran cooled to 0 ° C. Then a solution of 29.4 g (135 mmol) of di-tert-butyl iminodicarboxylate in 200 mL of tetrahydrofuran was added dropwise while the temperature did not exceed 5 ° C. The mixture was allowed to warm to room temperature and stirred overnight. Since the conversion was incomplete by TLC, total was added

1.2 g of sodium hydride in three portions over 9 hours. To complete the reaction, the mixture was then heated to 35 ° C for three hours and, after cooling to room temperature, 600 mL of saturated ammonium chloride solution was slowly added. The solvent was distilled off under water pump vacuum, the residue was extracted several times with ethyl acetate, the combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated on a rotary evaporator. 37.3 g of an oily residue were obtained which still contained di-tert-butyl iminodicarboxylate and was used as a crude product in the next reaction. ¹ H-NMR (250 MHz, d ₆ -DMSO): δ = 1.40, 1.45 (s, 18H), 4.75 (s, 2H), 6.55 (d, 1H), 7.55 (d, 1 H).

(e) 5-Aminomethyl-2-cyanofuran hydrochloride:

37.3 g of 5-N, N-bis (tert-butoxycarbonyl) aminomethyl-2-cyanofuran (crude product from zd), maximum 123 mmol) were dissolved in 600 ml of ethyl acetate and cooled to 0 ° C. The solution was saturated with hydrogen chloride gas. After 30 minutes a white precipitate precipitated. The mixture was allowed to reach room temperature and stirred overnight and then the resulting suspension was concentrated in a rotary evaporator, the residue was extracted by stirring with diethyl ether, the solvent was removed by filtration, and the solid residue was dried at room temperature under reduced pressure. 15.1 g of the title compound (77% yield over two steps) were obtained as a pale blue powder. ¹ H-NMR (250 MHz, d ₆ -DMSO): δ = 4.15 (bs, 2H), 6.85 (d, 1H), 7.65 (d, 1H), 8.8-9, O (bs, 3H).

5-Aminomethyl-3-cyanofuran

(a) Ethyl 4-oxopentanoate

100 g (0.86 mol) of 4-oxopentanoic acid, 150 g of ethanol and 1 ml of sulfuric acid in 200 ml of benzene were refluxed until the water had separated in the DeanStark trap. The cooled reaction mixture was washed with water, sodium carbonate solution and again with water and then dried under reflux under a DeanStark trap. When the separation of water was complete, the solvent was removed by distillation and the residue was distilled under reduced pressure. Boiling point 85 87 ° C / 16 mm Hg, yield 105.5 g (85%).

b) Ethyl 4,4-diethoxypentanoate

A mixture of 171.3 g (1.19 mol) of ethyl 4-oxopentanoate, 207 ml (184.2 g, 1.24 mol) of triethyl orthoformate, 26 ml of absolute ethanol and 1 g of p-toluenesulfonic acid was refluxed for 8 hours with vigorous stirring and then distilled under reduced pressure. 187.9 g (72.5%) of ethyl 4,4-diethoxypentanoate were obtained, b.p. 104-106 ° C / 14 mm Hg.

c) Ethyl 2-formyllevulinate

A mixture of 106.3 g (0.489 mol) of ethyl 4,4-diethoxypentanoate and 80 ml (73.6 g, 0.99 mol) of ethyl formate was added dropwise to the vigorously stirred suspension.

12.7 g (0.55 gram) of sodium (shavings) in 300 ml of anhydrous benzene at 10 15 ° C for 3 h. Stirring was continued for an additional 3 hours and the reaction mixture was allowed to stand overnight. Under vigorous stirring, 250 ml of water was added and stirring was continued for a further 15 minutes. The aqueous layer was separated and the benzene layer was extracted with 70 mL of water. The combined aqueous extracts were acidified to pH 2 and extracted with ethyl acetate (5 x 50 mL), and the organic extracts were dried over calcium chloride.

The ethyl acetate solution was distilled under reduced pressure and the fraction boiling at 102-110 ° C / 1 mm Hg was collected. This fraction is a mixture of ethyl 2-formyllevulinate and its diethyl ketal. The ratio in the mixture depends on the mixing intensity and the duration of phase separation when isolating the molding products.

The benzene layer was similarly dried over calcium chloride, the solvent was removed and the residue distilled under reduced pressure, after which the obtained mixture of ethyllevulinate and ketal was treated as described in b) instead of pure ethyllevulinate. Steps (2) and (3a) were repeated until the desired amount of ethyl 2-formyllevulinate was obtained.

d) Ethyl 5-methylfuran-3-carboxylate

The above mixture of ethyl 2-formyllevulinate and its diethyl ketal was dissolved in benzene, catalyst was added and the resulting solution was refluxed under a Dean-Stark trap for 3 - 3.5 hours until the water was completely removed. The reaction mixture was then distilled under reduced pressure to obtain 15 g (97 mmol) of ethyl 5-methylfuran-3-carboxylate having a boiling point of 97 ° C / 15 mm Hg.

e) 5-Methylfuran-3-carboxylic acid

A mixture of 31.7 g (206 mmol) of ethyl 5-methylfuran-3-carboxylate, 40 mL of 45% potassium hydroxide and 100 mL of water was refluxed for 4 hours, then cooled to 0 ° C and acidified to pH 1 with 15% hydrochloric acid. The resulting mixture was left at this temperature for 2 hours and the precipitate was filtered off and dried to constant weight at 45-50 ° C to give 23.7 g (188 mmol, 91%) of 5-methyl-furan-3-carboxylic acid.

f) 5-Methylfuran-3-carbonyl chloride

39.2 g (188 mmol) of phosphorus pentachloride was added in small portions to a stirred suspension of 23.7 g (188 mmol) of 5-methylfuran-3-carboxylic acid in 100 ml of benzene. Considerable heat and hydrogen chloride evolution was observed. The resulting mixture was refluxed for 4 hours and then distilled under reduced pressure to give 24.7 g (171 mmol, 91%) of the acid chloride boiling point 79 ° C / 12 mm Hg.

g) 5-Methylfuran-3-carboxamide

24.7 g (171 mmol) of 5-methylfuran-3-carbonyl chloride were added dropwise to a stirred mixture of 80 ml of 25% ammonium hydroxide solution and 80 ml of benzene at 25-40 ° C. The resulting mixture was stirred for 3 hours and allowed to stand overnight. The next day, the white amide crystals were filtered off, washed with cold water and dried to constant weight at 40-45 ° C. Yield 19.7 g (158 mmol, 92%), mp 158 ° C.

h) 5-Methyl-3-cyanofuran

32.9 g of phosphorus pentachloride was added in small portions to the suspension

19.7 g (158 mmol) of 5-methylfuran-3-carboxamide in 100 ml of benzene at 30-40 ° C. The resulting mixture was refluxed until clear (3.5-4 h) and then distilled under reduced pressure. The boiling fraction was collected at 79-140 ° C / 15 mm Hg. A second distillation yielded 12.7 g (119 mmol, 75%) of the title compound, bp 79-80 ° C / 15 mm Hg.

i) 5-Bromomethyl-3-furancarbonitrile

12.7 g (119 mmol) of 5-methyl-3-cyanofuran was dissolved in 100 ml of carbon tetrachloride and 22 g (122 mmol) of NBS and 12 g (73 mmol) of AIBN were added.

The resulting mixture was heated to 70 ° C with vigorous stirring at which time an exothermic reaction started. When heat evolution ceased, the reaction mixture was stirred at 80 ° C for 3 hours and then cooled to room temperature and the obtained succinimide was filtered and washed on the filter with carbon tetrachloride (2 x 15 mL).

The solvent was removed under reduced pressure and distillation of the residue under reduced pressure gave 12.7 g (86 mmol, 57%) of 5-bromomethyl-3-furancarbonitrile, b.p. 105 ° C / 1mm Hg. ^{The 1} H-NMR spectrum shows that the substance contains impurities that give signals at δ 1.3 and 2.2 ppm. Their proportion was satisfactorily lower after the second distillation, but about 15% of the product was lost. 5-Bromomethyl-3-furancarbonitrile is a white crystalline solid with a melting point of 40-45 ° C. ¹ H-NMR (CDCl 3, ppm): 4.41 (2H, CH 2), 6.58 (1H, H 4), 7.92 1H, H 2); ¹³ C-NMR (CDCl 3, ppm): 20.86 (CH ₂ ), 99.03 (CN or less likely C3), 109.97 (C4), 112.27 (C3 (or CN)), 149, 84 (C2), 152.32 (C5).

The reaction product is very irritating and must be handled with extreme caution. _|

5-N, N-Bis (tert-butoxycarbonyl) aminomethyl-3-cyanofuran was synthesized in a similar manner to 5-N, N-bis (tert-butoxycarbonyl) aminomethyl-2-cyanofuran. Subsequent removal of the tert-butoxycarbonyl groups was carried out in a saturated solution of hydrogen chloride in chloroform.

2-Amidino-5- (N-Boc-aminomethyl) -1-methylpyrrole acetate

a). 5-cyano-1-methylpyrrole-2-carbaldehyde

1-Methylpyrrole can be converted to 2-cyano-1-methylpyrrole by reaction with chlorosulfonyl isocyanate and dimethylformamide in acetonitrile (see, for example, C. E. Loader et al. Can. J. Chem. 59, (1981) 2673-6). Diisopropylamine (17.5 mL, 124.38 mmol) was introduced into THF (100 mL) under nitrogen. A solution of n-butyllithium in hexane (15%, 75.9 mL, 124.38 mmol) was added dropwise at -78 ° C. The mixture was then stirred at -20 ° C for 45 minutes and then re-cooled to -78 ° C at which temperature a solution of N-methylpyrrole-2-carbonitrile (12 g,

113.07 mmol) in THF (50 mL). After stirring at -78 ° C for 45 minutes, DMF (43.9 mL, 546.46 mmol) was added dropwise and stirring was continued at this temperature for 2 hours. Addition of citric acid monohydrate (20.56 g) was followed by warming to room temperature and addition of water (112 mL). THF was removed by rotary evaporation and the aqueous phase was saturated with sodium chloride and extracted with diethyl ether (3 x 200 mL). The combined organic phases were washed with saturated sodium chloride solution and dried over sodium sulfate. The solvent was removed by rotary evaporation and the crude product was purified by flash chromatography (silica gel, dichloromethane). Yield: 8.25 g (54%). ¹ H-NMR (CDCl ₃ ) δ = 4.1 (s, 3H), 6.8 (d, 1H), 6.9 (d, 1H), 9.7 (s, 1H).

b) 5-Hydroxymethyl-1-methylpyrrole-2-carbonitrile

The product (8.2 g, 61.1 mmol) obtained in a) was dissolved in ethanol (200 mL) and sodium borohydride (2.31 g, 61.13 mmol) was added at 10 ° C. After stirring at 0-5 ° C for 1.5 hours, the solvent was removed by rotary evaporation and ice water and 20% sodium bisulfate solution were added to the residue. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium bicarbonate solution after neutral reaction and dried over sodium sulfate. The solvent was removed by rotary evaporation and the crude product was purified by flash chromatography (silica gel, dichloromethane / methanol = 97.5 / 2.5). Yield: 7.6 g (91%).

¹ H-NMR (CDCl ₃ ) δ = 1.9 (t, 1H), 3.75 (s, 3H), 4.6 (d, 2H), 6.1 (d, 1H), 6.7 ( d, 1H).

c) 5-Azidomethyl-1-methylpyrrole-2-carbonitrile

The product (7.5 g, 55.08 mmol) obtained in b) was dissolved in DMF (220 mL) and triphenylphosphine (43.34 g, 165.25 mmol) was added at 0 ° C. After stirring at this temperature for 5 minutes, tetrabromomethane (54.8 g, 165.25 mmol) was added. The mixture was then stirred at 0 ° C for 30 minutes and at room temperature for 1.5 hours. After cooling to 0 ° C, sodium azide (4.37 g, 67.21 mmol) was added and the mixture was stirred at room temperature for 4.5 hours. Saturated sodium chloride solution was added dropwise at

0 ° C and diluted with ethyl acetate. The organic phase was separated and the aqueous phase was extracted with diethyl ether. The combined organic phases were washed with water and dried over sodium sulfate. The solvent was removed by rotary evaporation and the crude product was purified by flash chromatography (silica gel, ethyl acetate / hexane = 1/20). Yield: 5.6 g (63%).

^1H-NMR _(CDCl3) δ = 3.75 (s, 3H), 4.35 (s, 2H), 6.2 (d, 1H), 6.7 (d, 1H).

d) 5-Aminomethyl-1-methylpyrrole-2-carbonitrile

The product (4.71 g, 29.25 mmol) obtained in c) was dissolved in methanol (100 mL) and palladium on carbon (10%, 1 g) was added. The mixture was then hydrogenated with hydrogen under 1 atmosphere of pressure for 4 hours. The catalyst was filtered through Celite® and the filtrate was concentrated on a rotary evaporator. The residue was extracted by stirring with dichloromethane / diethyl ether = 1/1. The product was aspirated and dried in a vacuum oven at 35 ° C. Yield: 2.7 g (68%).

^{@ 1} H-NMR (CDCl3) .delta. = 3.75 (s, 3H), 3.85 (s, 2H), 6.05 (d, 1H), 6.7 (d, 1H).

e) 5- (N-Boc-Aminomethyl) -1-methylpyrrole-2-carbonitrile

The product (2.7 g, 19.97 mmol) obtained in d) was dissolved in dichloromethane (50 mL) and triethylamine (2.8 mL, 19.97 mmol) was added. A solution of di-tert-butyl dicarbonate (4.36 g, 19.97 mmol) in dichloromethane (30 mL) was then added dropwise. After stirring at room temperature for 2 hours, water was added and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated! on a rotary evaporator. The crude product was used in the next reaction without further purification. Yield: 4.4 g (94%).

'Γ - And fzrz. _SA i.,. n · nn -8 f.

t, Μ-sj dl ^ cuuy S, υσίΛυιιι u _f <

2H), 4.7 (sbr, 1H), 6.05 (d, 1H), 6.7 (d, 1H).

f) 5- (N-Boc-Aminomethyl) -1-methylpyrrole-2-hydroxyamidine [sic]

The product (4.3 g, 18.27 mmol) obtained in e) was dissolved in methanol / dichloromethane (100 mL, 1/1) and hydroxylamine hydrochloride (3.17 g,

45.61 mmol). Then, ethyldiisopropylamine (19.1 mL, 109.65 mmol) was added dropwise at room temperature. After stirring at 40 ° C for 12 h and removing the solvent on a rotary evaporator, water was added to the residue and the mixture was acidified to pH 5 with acetic acid and extracted with dichloromethane and ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated on a rotary evaporator. The crude product was purified by flash chromatography (silica gel, dichloromethane / methanol = 95/5). Yield: 3.4 g (69%).

^1H-NMR _(CDCl3) delta = 1.4 (s, 9H), 3.7 (s, 3H), 4.3 (d, 2H), 4.7-4.9 (m, 3H), 6.05 (d, 1H), 6.3 (d, 1H), 7.3 (sbr, 1H).

g) 2-Amidino-5- (N-Boc-aminomethyl) -1-methylpyrrole acetate

The product (3.4 g, 12.67 mmol) obtained in f) was dissolved in methanol (150 mL) and acetic acid (1.45 mL, 25.31 mmol) and Raney nickel (421 mg) were added. It was then hydrogenated under 1 atmosphere of hydrogen at 50 ° C for 5 hours. After cooling to room temperature, the catalyst was filtered off through Celite® and the filtrate was concentrated. The resulting product was used in the next reaction without further purification. Yield: 3.7 g (94%).

FAB-MS (M + H &lt; ^{+ &gt;} ): 253.

2-Amidino-4- (N-Boc-aminomethyl) -1-methylpyrrole acetate

a) 5-Cyano-1-methylpyrrole-3-carbaldehyde

Aluminum chloride (24.24 g, 180.86 mmol) was dissolved in nitromethane / dichloromethane (1/1, 320 mL) and, after cooling to -20 ° C, 1-methylpyrrole-2-carbonitrile (8 g, 75.36) was added. mmol). Then, α, α-dichlorodimethyl ether (10.4 g, 90.43 mmol) dissolved in dichloromethane (42 mL) was added dropwise. After stirring at 0 ^° C for hours, the mixture was poured onto ice (200 g). The aqueous phase was extracted with diethyl ether. The combined organic phases were washed with saturated sodium bicarbonate solution, water and saturated sodium chloride solution until neutral. After drying over sodium sulfate, the solvent was removed by rotary evaporation. The crude product was used in the following reactions without further purification. Yield: 9.2 g (91%).

Δ-NMR (CDCl 3) δ = 3.8 (s, 3H); 7.2 (s, 1H); 7.4 (s, 1 H); 9.85 (s, 1H).

b) 4-Aminomethyl-1-methylpyrrole-2-carbonitrile was prepared starting from 5-cyano-1-methylpyrrole-3-carbaldehyde similar to the synthesis of 5-aminomethyl-1-methylpyrrole-2-carbonitrile. However, 4-azidomethyl-1-methylpyrrole-2-carbonitrile was preferably reduced by the Staudinger reaction (see, for example, S. Nagarajan et al., J. Org. Chem. 52 (1987) 5044-6).

c) 2-Amidino-4- (N-Boc-aminomethyl) -1-methylpyrrole acetate was prepared starting from 4-aminomethyl-1-methylpyrrole-2-carbonitrile similar to the synthesis of 2-amidino-5- (N-Boc- aminomethyl) -1-methylpyrrole acetate.

FAB-MS (M &lt; + &gt; IT): 253.

4-Amidino-2- (N-Boc-aminomethyl) -1-methylpyrrole acetate

a) 4-Cyano-1-methylpyrrole-2-carbaldehyde

1-Methylpyrrole-2-carbaldehyde (10 g, 91.6 mmol) was dissolved in acetonitrile (100 mL) and cooled to -45 ° C. Chlorosulfonyl isocyanate (38.9 g, 274.9 mmol) in acetonitrile (40 mL) was added dropwise over 40 minutes. The mixture was then stirred at room temperature for 12 hours. After dropwise addition of dimethylformamide (35 mL), the mixture was heated at 50 ° C for 1 hour. After cooling to room temperature, the reaction mixture was poured into ice (20 µm) and a 2 N solution of early hyaroxia (286 mi), and the resulting precipitate was filtered off with suction. The filtrate was [sic] extracted with diethyl ether. The combined ether phases were washed with dilute sodium bicarbonate solution and water until neutral and dried over sodium sulfate. The solvent was distilled off under water pump vacuum and the residue was combined with the precipitate obtained above. Recrystallization from petroleum ether gave 4-cyano-1-methylpyrrole-2-carbaldehyde (4.3 g) (see, for example, C. E. Loader et al. Can. J. Chem. 59 (1981) 2673-6).

^1H-NMR _(CDCl3) delta = 4.0 (s, 3H); 7.2 (s, 1H); 7.3 (s, 1 H); 9.6 (s, 1 H).

¹³ C-NMR (CDCl 3) δ = 37.4; 94.1; 114.7; 125.8; 132.2; 135.8; 179.7.

b) 5-Aminomethyl-1-methylpyrrole-3-carbonitrile was prepared starting from

4-cyano-1-methylpyrrole-2-carbaldehyde similar to the synthesis of 5-aminomethyl-1-methylpyrrole-2-carbonitrile.

Δ-NMR (DMSO-d ₆ ) δ = 3.6 (s, 3H), 3.8 (s, 2H), 4.2 (sbr, 2H), 6.4 (s, 1H), 7.6 (s, 1 H).

c) 3-Amidino-5- (N-Boc-aminomethyl) -1-methylpyrrole acetate was prepared starting from 5 aminomethyl-1-methylpyrrole-3-carbonitrile similar to the synthesis of 2-amidino-5- (N-Boc-aminomethyl) -1-methylpyrrole hydroacetate.

FAB-MS (M + H &lt; ^{+ &gt;} ): 253.

5-Aminomethyl-3-cyano-1,2,4-oxadiazole hydrochloride

a) N-Boc-5-Aminomethyl-3-cyano-1,2,4-oxadiazole

Ethyl N-Boc-5-aminomethyl-1,2,4-oxadiazole-2-carboxylate (S. Borg et al. J. Org. Chem. 60 (1995) 3112-20) was dissolved in methanol (50 mL). Ammonia from -10 ° C to room temperature was introduced into this solution until the conversion was complete. The solvent was removed on a rotary evaporator. The obtained crude product was dissolved in dichloromethane (70 mL) and diisopropylethylamine (2.9 mL, 16.55 mmol) was added at -5 ° C. Trifluoroacetic anhydride (1.06 ml,

7.61 mmol) dissolved in dichloromethane (10 mL). After stirring at 0 ° C for 1.5 hours, the mixture was diluted with dichloromethane, washed with 2 x saturated sodium bicarbonate solution, 2 x 5% citric acid solution and 1 x saturated sodium chloride solution and then dried over sodium sulfate. The solvent was removed by rotary evaporation and the crude product was purified by chromatography (silica gel, dichloromethane: methanol = 97.5: 2.5). Yield: 1.2 g (80%).

b) 5-Aminomethyl-3-cyano-1,2,4-oxadiazole hydrochloride i

The product (0.9 g, 4.0 mmol) obtained in a) was dissolved in dichloromethane (45 ml) and 4 M hydrochloric acid in dioxane (3.9 ml,

15.61 mmol). After stirring at room temperature for 16 hours, the solvent was removed by rotary evaporation. Yield: 645 mg (100%).

¹ H-NMR (DMSO-d ₆ ) δ = 4.6 (s, 2H), 9.2 (s, 3H).

N-Methyl-5-aminomethylpyrazole-3-carboxamide

(a) Methyl N-methyl-5-amidopyrazole-3-carboxylate [sic]

N-Methyl-3-methoxycarbonylpyrazole-5-carbonyl chloride (prepared from 3.7 g, 20.09 mmol of N-methyl-3-methoxycarbonyl-3-carboxylic acid [sic], J. Org. Chem. 54 (1989) 428 ) was dissolved in toluene and cooled to -10 ° C. Ammonia was then introduced at temperatures from -10 ° C to 0 ° C until the conversion was complete. The solvent was removed on a rotary evaporator. The residue was dissolved in ethanol and after stirring for 15 minutes the ethanol was removed on a rotary evaporator and the residue was dissolved in warm water and precipitated by cooling to 0 ° C. The precipitate was suction filtered, washed with acetone and dried at 45 ° C under reduced pressure. Yield: 1.5 g (41%).

b) Methyl N-methyl-5-cyanopyrazole-3-carboxylate

The product (1.5 g, 8.19 mmol) obtained in a) was dissolved in dichloromethane (20 mL). Diisopropylethylamine (3.85 mL, 22.11 mmol) was added at -10 ° C and a solution of trifluoroacetic anhydride (1.3 mL, 9.44 mmol) in dichloromethane (5 mL) was added dropwise at this temperature over the course of 45 minutes. The mixture was then stirred at 0 ° C for 1 hour and then diluted with dichloromethane and washed with 2 x saturated sodium bicarbonate solution, 2 x 5% citric acid solution and 1 x saturated sodium chloride solution. After drying over sodium sulfate, the solvent was removed by rotary evaporation. Yield: 1.35 g (100%).

EI-MS (M &lt; + &gt;): 165.

c) N-Methyl-5-cyanopyrazole-3-carboxamide

The product (1.35 g, 8.19 mmol) obtained in b) was dissolved in methanol (50 mL) and the mixture was cooled to -10 ° C. Ammonia was then introduced over 8 hours. After stirring at room temperature for 12 hours, the precursor was completely reacted. The precipitated product was filtered off with suction, washed with cold methanol and dried under reduced pressure. Yield: 1.22 g (100%).

^{@ 1} H-NMR (DMSO-d6) _.delta . = 4.0 (s, 3H), 7.4 (s, 1H), 7.5 (s, 1H), 7.8 (s, 1H).

d) N-Methyl-5-aminomethylpyrazole-3-carboxamide

The product (0.4 g, 2.66 mmol) obtained in c) was dissolved in acetic acid (30 mL) and 10% palladium on carbon (78 mg) was added. The mixture was then hydrogenated at atmospheric pressure at room temperature until complete conversion. The catalyst was filtered off through Celite® and the solvent was removed by rotary evaporation. Yield: 0.4 g (100%).

EI-MS (M &lt; + &gt;): 154.

Example 1

N- (Hydroxycarbonylmethylene) - (D) -cyclohexylalanyl-3,4-dehydroprolyl 5- (2amidino) -thienylmethylamide [sic] hydroacetate:

(a) 3,4-Dehydroprolyl 5- (2-cyano) -thienylmethylamide [sic]:

Boc-3,4-dehydroproline (5 g, 23.4 mmol) and 5-aminomethyl-2-cyanothiophene hydrochloride (4.5 g, 25.8 mmol) were dissolved in dichloromethane (25 mL) and at 0 ° C. Ethyl diisopropylamine (28 mL, 163.8 mmol) was added with a [sic] 50% solution of propanephosphonic anhydride in ethyl acetate (24.8 mL, 117 mmol). After stirring at 0 ° C for 1 hour, the mixture was warmed to room temperature and then stirred for 12 h. The reaction mixture was diluted with dichloromethane and washed with sodium hydrogensulfate solution (4x), sodium bicarbonate solution (3x) and saturated sodium chloride solution (1x). After drying over sodium sulfate and removing the desiccant by filtration, the solvent was distilled off under water pump vacuum. To remove the Boe group, the residue was stirred [lacuna] in dichloromethane (95 mL) at room temperature, evaporated to dryness, distilled twice with dichloromethane, concentrated again and purified by column chromatography. 6.6 g of the expected product were obtained containing a small amount of solvent.

(b) N- (tert-butoxycarbonylmethylene) - (N-Boc) - (D) -cyclohexylalanyl-3,4-dehydroprolyl 5- (2-cyano) -thienylmethylamide [sic]:

t-BuO ₂ C-CH ₂ -Boc- (D) -Cha-OH (7.3 g, 18.98 mmol) and H-Pyr-NH-CH ₂ -5 (2-CN) -thioph hydrochloride (5 , 12 g, 18.98 mmol) was dissolved in dichloromethane (100 mL), and ethyldiisopropylamine (12.26 g, 94.9 mmol) was added. The reaction mixture was cooled to 0 ° C and a 50% solution of propanephosphonic anhydride in ethyl acetate (20 mL) was added dropwise. Stirring at 0-10 ° C for 3 hours was followed by dilution with dichloromethane (100 mL) and washing with dilute sodium hydrogensulfate solution (3x), saturated sodium bicarbonate solution (2x) and water (1x). After drying over sodium sulfate and removing the desiccant, the solvent was distilled off under a water pump vacuum. 12.47 g of a light brown oil were obtained.

(c) N- (tert-butoxycarbonylmethylene) - (N-Boc) - (D) -cyclohexyl-alanyl-3,4-dehydroprolyl 5- (2-amidothiocarbonyl) -thienylmethylamide [sic]:

The product obtained in b) was dissolved in pyriaine (70 ml) and triethylamine (12 ml). The reaction mixture was cooled to 0 ° C saturated with hydrogen sulfide (the solution turned green): It was then stirred at room temperature for 48 hours. Excess hydrogen sulfide was discharged with nitrogen and the solvent was distilled off under water pump vacuum. The residue was dissolved in diethyl ether (200 mL) and washed with dilute sodium hydrogensulfate solution (2 x), saturated sodium bicarbonate solution (2 x) and water (1 x). After drying over sodium sulfate, the solvent was distilled off under a water pump vacuum. The crude product (12.6 g) was purified by flash chromatography (silica gel, gradient from dichloromethane to dichloromethane: methanol = 40: 1). 12.1 g of the desired product were obtained, which still contained a small amount of solvent.

(d) N- (tert-butoxycarbonylmethylene) - (N-Boc) - (D) -cyclohexylalanyl-3,4-dehydroprolyl 5- (2-S-methylimidocarbonyl) thienylmethylamide [sic] hydroiodide:

The product obtained in c) was dissolved in dichloromethane (120 mL) and methyl iodide (16.24 g, 114.38 mmol) was added. After stirring at room temperature for 12 h, the solvent was distilled off under water pump vacuum. 14.6 g of a yellowish oil were obtained.

(e) N- (tert-butoxycarbonylmethylene) - (N-Boc) - (D) -cyclohexylalanyl-3,4-dehydroprolyl 5- (2-amidino) thienylmethylamide [sic] hydroacetate:

The crude product obtained in d) was dissolved in acetonitrile (90 mL) and ammonium acetate (2.94 g, 38.12 mmol) was added. After stirring at room temperature for 2 hours and at 40 ° C for 1.5 hours, a 10% solution of ammonium acetate in methanol (14.65 g, 19.05 mmol) was added. The mixture was then stirred at 50 ° C for 4.5 hours and the solvent was distilled off under water pump vacuum. The residue was mixed with dichloromethane, the salts were filtered off with suction and the filtrate was concentrated. The residue was converted to the acetate salt on an ion exchanger (Fluka, order number 00402) to give 11.15 g of a yellowish oil.

f) N- (Hydroxycarbonylmethylene) - (D) -cyclohexylalanyl-3,4-dehydroprolyl 5- (2amidino) thienylmethylamide [sic] hydroacetate

The product obtained in e) was dissolved in dichloromethane (175 ml) and ethereal hydrochloric acid (38.3 ml) was added dropwise. After stirring at room temperature for 2 hours, the solvent was distilled off under water pump vacuum.

The residue was mixed with dichloromethane, and the solvent was distilled off under water pump vacuum (2 x). The crude product (9.35 g) was purified on an ion exchanger (Fluka, Order No. 00402) and then flash chromatography (silica gel, gradient from dichloromethane: methanol: [sic] 4: 1 over dichloromethane: methanol: 50% acetic acid: [sic] 40: 10: 2 to dichloromethane: methanol: 50% acetic acid = 35: 15: 5). The product thus obtained was dissolved in water. Insoluble matter was removed by filtration and the filtrate was lyophilized to give 5.55 g as an amorphous white solid.

FAB-MS (m + H &lt; + &gt;) [sic]: 462

The following compounds were prepared as in Example 1:

Example 2

N- (Hydroxycarbonylethylene) - (D) -cyclohexylalanyl-3,4-dehydroprolyl 5- (2-amino) thienylmethylamide [sic] hydroacetate, ‘

FAB-MS (M + H &lt; ^{+ &gt;} ): 476

Prepared in several steps as in Example 1 starting from N (tert-butoxycarbonylethylene) - (N-Boc) - (D) -cyclohexylalanine [sic] and 3,4-dehydroprolyl 5- (2-cyano) -thienylmethylamide [sic].

Example 3

N- (Hydroxycarbonylmethylene) - (D) -cyclohexylglycyl-3,4-dehydroprolyl 5- (2amidino) -thienylmethylamide [sic] hydroacetate:

FAB-MS (M + H +): 448

Prepared in several steps as in Example 1 starting from N- (tert-butoxycarbonylmethylene) - (N-Boc) - (D) -cyclohexylglycine [sic] and 3,4-dehydroprolyl 5- (2-cyano) -thienylmethylamide [sic].

Example 4

N- (Hydroxycarbonylmethylene) - (D) -cyclohexylalanyl-3,4-dehydroprolyl 5- (2-amidino-3,4-dimethyl) -thienylmethylamide [sic] hydroacetate:

FAB-MS (M + H &lt; ^{+ &gt;} ): 490

Prepared starting from 5-aminomethyl-3,4-dimethylthiophene-2-carboxamide by coupling with Boc-3,4-dehydroproline to give Boc-3,4-dehydroprolyl 5- (2-carbamoyl-3,4-dimethyl) -thienylmethylamide [sic] as in Example 1. After removal of the Boe protecting group, this building component was coupled with N- (tert-butoxycarbonylmethylene) - (N-Boc) - (D) -cyclohexylalanine [sic] as in Example 1. Dehydration of the amide to nitrile was performed as follows:

4.8 g (7.42 mmol) of N- (tert-butoxycarbonylmethylene) - (N-Boc) - (D) -cyclohexylalanyl-3,4-dehydroprolyl 5- (2-carbamoyl-3,4-dimethyl) -thienylmethylamide [sic] ] was dissolved in 60 ml of dichloromethane and, after addition of 3.83 g (29.64 mmol) of diisopropylethylamine, the mixture was cooled to 0 ° C. 2.8 g of trifluoroacetic anhydride in 3 ml of dichloromethane were slowly added dropwise and the mixture was stirred at 0 ° C for two hours. The mixture was then diluted with 60 mL of dichloromethane and then washed three times with 20 mL of 20% citric acid, twice with 20 mL of saturated sodium bicarbonate solution and twice with saturated sodium chloride solution, and the dichloromethane phase was dried over sodium sulfate and concentrated on a rotary evaporator. 5.35 g of N- (tert-butoxycarbonylmethylene) - (N-Boc) - (D) cyclohexylalanyl-3,4-dehydroprolyl 5- (2-cyano-3,4-dimethyl) -thienylmethylamide [sic], which still contained the solvent was used directly in the next step.

The conversion of the nitrile function to the amidine group and subsequent deprotection was carried out as in Example 1.

Example 5

N- (Hydroxycarbonylmethylene) - (D) -cyclohexylalanyl-3,4-dehydroprolyl 5- (3-amidino) thienylmethylamide [sic] hydroacetate:

FAB-MS (M + H &lt; ^{+ &gt;)} : 462

Prepared as in Example 1 using 5-aminomethyl-3-cyanothiophene hydrochloride instead of 5-aminomethyl-2-cyanothiophene hydrochloride.

Example 6

N- (Hydroxycarbonylmethylene) - (D) -cyclohexylalanyl-3,4-dehydroprolyl 4- (2-amidino) thienylmethylamide [sic] hydroacetate:

FAB-MS (M + H &lt; ^{+ &gt;} ): 462

Prepared as in Example 1 using 4-aminomethyl-2-cyanothiophene hydrochloride instead of 5-aminomethyl-2-cyanothiophene hydrochloride.

Example 7a

N- (Hydroxycarbonylmethylene) - (D) -cyclohexylalanyl- (D) -4,5-dehydropipecolyl 5- (2amidino) -thienylmethylamide [sic] hydroacetate:

FAB-MS (M + H &lt; ^{+ &gt;} ): 476

Example 7b

N- (Hydroxycarbonylmethylene) - (D) -cyclohexylalanyl-4,5-dehydropipecolyl 5- (2amidino) -thienylmethylamide [sic] hydroacetate:

FAB-MS (M + H &lt; ^{+ &gt;} ): 476

Prepared as in Example 1 using racemic Boc (D, L) -4,5-dehydropipecolic acid instead of Boc-3,4-dehydroproline. At stage N (tert-butoxycarbonylmethylene) - (N-Boc) - (D) -cyclohexylalanyl- (D, L) -4,5-dehydropipecolyl 5- (2-cyano) -thienylmethylamide [sic] it was possible to separate two diastereomeric compounds by chromatography ( silica gel, cyclohexane / ethyl acetate 7: 3). The two diastereoisomers were subsequently converted to the end products as in Example 1.

Example 8

N- (Hydroxycarbonylmethylene) - (D) -cyclohexylglycyl-3,4-dehydroprolyl 5- (3-amidino) thienylmethylamide [sic] hydroacetate:

FAB-MS (M + H &lt; ^{+ &gt;} ): 448

Prepared as in Example 1 starting from 5-aminomethyl-3-cyanothiophene and N- (tert-butoxycarbonylmethylene) -N-Boc- (D) -cyclohexylglycyl-3,4-dehydroproline [sic].

Example 9

N- (Hydroxycarbonylmethylene) - (D) -cyclohexylglycyl-3,4-dehydroprolyl 4- (2-amidino) thienylmethylamide [sic] hydroacetate:

FAB-MS (M + H &lt; ^{+ &gt;} ): 448

Prepared as in Example 1 starting from 4-aminomethyl-2-cyanothiophene and N- (tert-butoxycarbonylmethylene) -N-Boc- (D) -cyclohexylglycyl-3,4-dehydroproline [sic].

Example 10

N- (Hydroxycarbonylmethylene) - (D) -cyclohexylalanyl-3,4-dehydroprolyl 5- (2-amidino) furanylmethylamide [sic] hydroacetate:

FAB-MS (M + H &lt; ^{+ &gt;} ): 446

Prepared as in Example 1 using 5-aminomethyl-2-cyanofuran hydrochloride instead of 5-aminomethyl-2-cyanothiophene hydrochloride.

Example 11

N- (Hydroxycarbonylethylene) - (D) -cyclohexylalanyl-3,4-dehydroprolyl 5- (2-amidino) furanylmethylamide [sic] hydroacetate:

FAB-MS (M + H &lt; ^{+ &gt;} ): 460

Prepared as in Example 1 using 5-aminomethyl-2-cyanofuran hydrochloride instead of 5-aminomethyl-2-cyanothiophene hydrochloride.

Example 12

N- (Hydroxycarbonylmethylene) - (D) -cyclohexylglycyl-3,4-dehydroprolyl 5- (2-amidino) furanylmethylamide [sic] hydroacetate:

FAB-MS (M + H +): 432

Example 13

N- (Hydroxycarbonylmethylene) - (D) -cyclohexylalanyl-3,4-dehydroprolyl 5- (3-amidinofuranylmethylamide [sic] hydroacetate:

FAB-MS (M + H &lt; ^{+ &gt;} ): 446

Example 14

N- (Hydroxycarbonylmethylene) - (D) -cyclohexylalanyl-3,4-dehydroprolyl 5- (2-amidino-1-methyl) -pyrrolomethylamide [sic] hydrochloride:

a) 5- (N-Boc-Aminomethyl) -1-methylpyrrole-2-amidine [sic] hydroacetate (1.5 g, 4.4 mmol) was dissolved in isopropanol (70 ml) and after addition of hydrochloric acid in isopropanol ( 5.5 M, 4.5 mL, 24.0 mmol) was heated at 50 ° C for 2 hours. After cooling to room temperature, the solvent was removed by rotary evaporation and the residue was added to a solution of t-BuO ₂ C-CH ₂ - (Boc) - (D) -Cha-Pyr-OH in DMF (50 mL). The solution was cooled to 0 ° C and N-methylmorpholine (1.92 mL, 17.44 mmol) was added. TOTU (1.18 g, 3.58 mmol) was then added portionwise. After stirring at 0 ° C for 45 minutes, the solvent was removed by rotary evaporation and the crude product was purified by MPLC (RP-18, acetonitrile / water). Yield: 980 mg (45%).

FAB-MS (M + H &lt; ^{+ &gt;} ): 615

b) The product (550 mg, 0.845 mmol) obtained as in a) was dissolved in dichloromethane (50 mL) and the solution was saturated at 0-5 ° C with HCl gas. It was then stirred at 0 ° C for 1.5 h. The solvent was removed by rotary evaporation and the crude product was lyophilized. Yield: 450 mg (100%).

FAB-MS (M + H &lt; ^{+ &gt;} ): 459

Example 15

N- (Hydroxycarbonylmethylene) - (D) -cyclohexylalanyl-3,4-dehydroprolyl 2- (4-amidino-1-methyl) -pyrrolomethylamide [sic] hydrochloride was prepared as in Example 14.

FAB-MS (M + H &lt; ^{+ &gt;} ): 459.

Example 16

N- (Hydroxycarbonylmethylene) - (D) -cyclohexylalanyl-3,4-dehydroprolyl 4- (2-amidino-1-methyl) pyrrolomethylamide [sic] hydrochloride was prepared as in Example 14.

FAB-MS (M + H) 459;

Example 17

N- (tert-butoxycarbonylmethylene) - (N-Boc) - (D) -cyclohexylalanyl-3,4-dehydroprolyl 2- (4-aminothiocarbonyl) oxazolemethylamide [sic] hydrochloride:

a) t-BuO ₂ C-CH ₂ - (Boc) - (D) -Cha-Pyr-OH (2.36 g, 4.92 mmol) was dissolved in dichloromethane (60 mL). Diisopropylethylamine (4.3 mL, 24.59 mmol) was added dropwise at -10 ° C. After stirring at this temperature for 5 minutes, 2-aminomethyloxazole-4-thiocarbamide [sic] hydrochloride (1 g, 5.16 mmol, G. Videnov et al. Angew. Chem. 108 (1996) 1604-9, Boe Group) was added. in the N-Boc-2-aminomethyloxazole-4-thiocarbamide [sic] described in this reference was cleaved with ethereal hydrochloric acid and the corresponding hydrochloride was obtained by concentration) and then a 50% solution of propanephosphonic anhydride in ethyl acetate (5.06 ml, 6) was added dropwise. (39 mmol) diluted with dichloromethane (10 mL) over 20 min. Stirring at 0 ° C for 1 hour was followed by warming to room temperature for 3 hours. The mixture was diluted with dichloromethane, washed with 2 x saturated sodium bicarbonate solution, 2 x 5% citric acid solution and 1 x saturated sodium chloride solution, and dried over sodium sulfate. The solvent was removed by rotary evaporation and the crude product was purified by chromatography (silica gel, dichloromethane: methanol = 95: 5) (Yield: 2.5 g (82%)).

^{@ 1} H-NMR (DMSO-d6) .delta. = 0.5-2.0 (m, 31H), 3.1-5.5 (m, 8H), 5.8-6.2 (m, 2H), 8.5-9.3 (m, 3H), 9.8 (sbr, 1H).

(b) N- (tert-butoxycarbonylmethylene) - (N-Boc) - (D) -cyclohexylalanyl-3,4-dehydroprolyl 2- (4-amidino) oxazolemethylamide [sic] hydroacetate:

The product obtained in a) was dissolved in acetone (50 mL) and refluxed for 2 hours after addition of methyl iodide (1.97 mL, 31.29 mmol). The solvent and excess methyl iodide were removed by rotary evaporation. Then, the obtained crude product was dissolved in tetrahydrofuran (50 mL) and after addition of ammonium acetate (466 mg, 6.05 mmol) was heated to 60 ° C for 1.5 hours. The solvent was removed on a rotary evaporator and the crude product was converted to acetate using an ion exchanger (polymer supported acetate, Fluka 00402), followed by purification by chromatography (silica gel, dichloromethane: methanol: acetic acid = 75: 20: 5). Yield: 2.0 g (75%).

FAB-MS (M + H &lt; ^{+ &gt;} ): 603.

(c) N- (Hydroxycarbonylmethylene) - (D) -cyclohexylalanyl-3,4-dehydroprolyl 2- (4amidino) oxazolomethylamide [sic] hydrochloride:

The product (1.95 g, 2.94 mmol) obtained in b) was dissolved in dichloromethane (50 mL) and 4 M hydrochloric acid in dioxane (3.7 mL, 14.71 mmol) was added. After stirring at room temperature for 20 hours, the solvent was removed by rotary evaporation and the crude product was dissolved in water and lyophilized. Yield: 1.5 g (100%).

@ 13 H-NMR .delta. (DMSO-d6) _.delta . = 168.6, 167.8, 166.2, 162.2, 156.4, 144.7, 129.6, 127.7, 125, 5, 67.9, 55.0, 53.5, 45.3, 36.4, 35.7, 33.0, 32.5, 32.0, 25.7, 25.4, 25.2.

Example 18

N- (Hydroxycarbonylmethylene) - (D) -cyclohexylalanyl-3,4-dehydro-prolyl 5- (3amidino) -1,2,4-oxadiazolomethylamide [sic] hydrochloride:

(a) N- (tert-butoxycarbonylmethylene) - (N-Boc) - (D) -cyclohexylalanyl-3,4-dehydroprolyl 5- (3-cyano) -1,2,4-oxadiazolomethylamide [sic]

N- (t-BuO ₂ C-CH ₂ ) -N-Boc- (D) -Cha-Pyr-OH (1.93 g, 4.0 mmol) was dissolved in dichloromethane (65 mL) at -10 ° C was added diisopropylethylamine (3.1 mL, 17.67 mmol). 5-Aminomethyl-3-cyano-1,2,4-oxadiazole hydrochloride (645 mg, 4.0 mmol) dissolved in dichloromethane (30 mL) was then added. After stirring for 5 minutes, a 50% solution of propanephosphonic anhydride in ethyl acetate (3.9 mL, 4.93 mmol) diluted with dichloromethane (15 mL) was added dropwise over 30 minutes. After 1 h at 0 ° C, the mixture was diluted with dichloromethane and washed with 2 x saturated sodium bicarbonate solution, 2 x 5% citric acid solution and 1 x saturated sodium chloride solution. After drying over sodium sulfate, the solvent was removed by rotary evaporation and the crude product was purified by chromatography (silica gel, dichloromethane: methanol = 95: 5). Yield: 1.55 g (71%).

FAB-MS (M + IT) 587;

b) N- (tert-butoxycarbonylmethylene) - (N-Boc) - (D) -cyclohexylalanyl-3,4-dehydroprolyl 5- (3-amidino) -1,2,4-oxadiazolomethylamide hydroacetate

The product (1.5 g, 2.56 mmol) obtained in a) was dissolved in methanol (5 mL) and acetylcysteine (450 mg, 2.76 mmol) was added. Then ammonia was introduced into the mixture at 35 ° C until the conversion was complete. The solvent was removed on a rotary evaporator and the crude product was converted to acetate using an ion exchanger (polymer-supported acetate, Fluka 00402). The crude product obtained was purified by chromatography (RP-18, acetonitrile, water). Yield: 300 mg (18%).

FAB-MS (M + H &lt; ^{+ &gt;} ) 604.

c) N- (Hydroxycarbonylmethylene) - (D) -cyclohexylalanyl-3,4-dehydroprolyl 5- (3amidino) -1,2,4-oxadiazolomethylamide [sic] hydrochloride

The product (300 mg, 0.45 mmol) obtained in b) was dissolved in dichloromethane (20 mL) and a 4 M solution of hydrochloric acid in dioxane (0.6 mL, 2.48 mmol) was added at room temperature. After stirring at room temperature for 20 hours, the solvent was removed by rotary evaporation. and the product was dissolved in water and lyophilized. Yield: 230 mg (98%).

FAB-MS (M + H &lt; ^{+ &gt;} ): 448.

Example 19

N- (Hydroxycarbonylmethylene) - (D) -cyclohexylalanyl-3,4-dehydroprolyl 5- (3-amidino-N-methylpyrazolmethylamide [sic] hydrochloride:

(a) N- (tert-butoxycarbonylmethylene) - (N-Boc) - (D) -cyclohexylalanyl-3,4-dehydroprolyl 5- (3-amido-N-methyl) -pyrazolomethylamide [sic]

N- (t-BuO ₂ C-CH ₂ ) -N-Boc- (D) -Cha-Pyr-OH (1.25 g, 2.59 mmol) was dissolved in dichloromethane (30 mL). Diisopropylethylamine (1.95 mL, 11.16 mmol) was added dropwise at -10 ° C. A solution of N-methyl-5-aminomethylpyrazole-3-carboxamide (0.4 g, 2.59 mmol) in tetrahydrofuran (20 mL) was then added. After stirring for 5 minutes, a 50% solution of propanephosphonic anhydride in ethyl acetate (2.36 mL, 3.11 mmol) and dichloromethane (5 mL) was added dropwise over 5 minutes. Stirring at 0 ° C for 45 minutes was followed by warming to room temperature for 12 hours. The solvent was removed on a rotary evaporator and the residue was dissolved in dichloromethane and washed with 2 x saturated sodium bicarbonate solution, 2 x 5% citric acid solution and 1 x saturated sodium chloride solution. After drying over sodium sulfate, the solvent was removed by rotary evaporation and the crude product was purified by chromatography (RP-18, acetonitrile, water). Yield: 220 mg (14%).

FAB-MS (M + H +): 617.

b) N- (tert-butoxycarbonylmethylene) - (N-Boc) - (D) -cyclohexylalanyl-3,4-dehydroprolyl 5- (3-cyano-N-methyl) pyrazolomethylamide [sic]

The product (220 mg, 0.36 mmol) obtained in a) was dissolved in dichloromethane (15 mL) and diisopropylethylamine (0.17 mL, 0.96 mmol) was added at -10 ° C. After stirring for 5 minutes, a solution of trifluoroacetic acid hydride (0.057 mL, 0.41 mmol) in dichloromethane (1 mL) was added dropwise. After 1 hour at 0 ° C, the mixture was diluted with dichloromethane and washed with 2 x saturated sodium bicarbonate solution, 2 x 5% citric acid solution and 1 x saturated sodium chloride solution. After drying over sodium sulfate, the solvent was removed by rotary evaporation. Yield: 180 mg (84%).

c) N- (tert-butoxycarbonylmethylene) - (N-Boc) - (D) -cyclohexylalanyl-3,4-dehydroprolyl 5- (3-amidino-N-methyl) pyrazolomethylamide [sic] hydroacetate

The product (180 mg, 0.3 mmol) obtained in b) was dissolved in methanol (1 mL), and acetylcysteine (52.8 mg, 0.32 mmol) was added. Then ammonia was introduced into the mixture at 35 ° C until the conversion was complete. The solvent was removed on a rotary evaporator and the crude product was converted to acetate using an ion exchanger (polymer-supported acetate, Fluka 00402). The crude product was purified by chromatography (RP18, acetonitrile, water). Yield: 50 mg (16%).

FAB-MS (M + H &lt; ^{+ &gt;} ): 616.

d) N- (Hydroxycarbonylmethylene) - (D) -cyclohexylalanyl-3,4-dehydroprolyl 5- (3-amidino-N-methyl) pyrazolomethylamide [sic] hydrochloride

The product (50 mg, 0.081 mmol) obtained in c) was dissolved in dichloromethane (5 mL) and 5 M hydrochloric acid in diethyl ether (0.147 mL) was added. After stirring at room temperature for 12 hours, the solvent was removed by rotary evaporation and the product was taken up in water and lyophilized. Yield: 40 mg (92%).

FAB-MS ([+] -): 460.

Example 20

N- (Hydroxycarbonylmethylene) - (D) -cyclohexylalanyl-3,4-dehydroprolyl 5- (3amidino) isoxazole methyl amide [sic] hydrochloride:

Prepared starting from 5-aminomethylisoxazolyl-3-carboxamide and BOC3,4-dehydroproline. After coupling and elimination of the BOC protecting group, the obtained building component was attached to N- (tert-butoxycarbonylmethylene) - (N-Boc) - (D) cyclohexylalanine [sic] to give N- (tert-butoxycarbonylmethylene) - (N-Boc) - (D-Boc) - (D-Boc) ) cyclohexylalanyl-3,4-dehydroprolyl 5- (3-carbamoyl) isoxazole methyl amide [sic]. Dehydration of the primary amide to the nitrile as in Example 4 gave the amidine as shown below.

N- (tert-butoxycarbonylmethylene) - (N-Boc) - (D) -cyclohexylalanyl-3,4-dehydroprolyl 5- (3amidino) isoxazole methyl amide [sic] hydroacetate:

1.75 g (3.0 mmol) of N- (tert-butoxycarbonylmethylene) - (N-Boc) - (D) -cyclohexylalanyl-3,4-dehydroprolyl 5- (3-cyano) -isoxazole-methylamide [sic] was dissolved in 10 ml methanol and after addition of 0.54 g (3.28 mmol) of N-acetylcysteine, the mixture was refluxed with the introduction of ammonia gas for 4 hours. Removal of N-acetylcysteine, purification of the product, and conversion to acetate were performed by MPL chromatography (RP-18, acetonitrile / water / 0.1 M acetic acid). Freeze-drying gave 1.39 g of a white powder (70% of theory).

Deprotection of the purified product with ethereal hydrochloric acid in dichloromethane gave the title compound [sic].

FAB-MS (M + H &lt; + &gt;): 448.

Example 21

N- (Hydroxycarbonylmethylene) - (D) -cyclohexylalanyl-3,4-dehydroprolyl 2- (4-amidino) thiazolomethylamide [sic] hydroacetate

FAB-MS (M + H &lt; ^{+ &gt;} ): 463.

Prepared as in Example 1 starting from 2-aminomethylthiazol-4-yl thiocarboxamide and N-Boc-N- (tert-butyloxycarbonylmethylene) - (D) -cyclohexylalanyl-3,4-dehydroproline [sic].

Example 22

N- (Hydroxycarbonylmethylene) - (D) -cyclohexylglycyl-3,4-dehydroproline 2- (4amidino) thiazolomethylamide [sic] hydrochloride

FAB-MS (M + H &lt; ^{+ &gt;} ): 449.

Example 23 »N- (Hydroxycarbonylmethylene) - (D) -cyclohexylalanyl-3,4-dehydroprolyl 4- (2amidino) thiazolomethylamide [sic] hydroacetate

íí

FAB-MS (M + H &lt; ^{+ &gt;} ): 463.

Prepared as in Example 1 starting from 4-aminomethylthiazole-2-thiocarboxamide and N- (tert-butoxycarbonylmethylene) -N-Boc- (D) -cyclohexylalanyl-3,4-dehydroproline [sic].

Example 24

N- (Hydroxycarbonylmethylene) - (D) -cyclohexylglycyl-3,4-dehydroprolyl 4- (2amidino) thiazolomethylamide [sic] hydroacetate

FAB-MS (M + H &lt; ^{+ &gt;} ): 449.

Prepared as in Example 1 starting from 4-aminomethylthiazole-2-thiocarboxamide and N- (tert-butoxycarbonylmethylene) -N-Boc- (D) -cyclohexylglycyl-3,4-dehydroproline [sic].

Example 25

N- (Hydroxycarbonylmethylene) - (D) -cyclohexylalanyl-3,4-dehydroprolyl 2- (5amidino) thiazolomethylamide [sic] hydroacetate

FAB-MS (M + H &lt; ^{+ &gt;} ): 463.

Prepared as in Example 21.

Example 26 i

N- (Hydroxycarbonylmethylene- (D) -cyclohexylglycyl-3,4-dehydroprolyl 2- (5amidino) thiazolomethylamide [sic] hydroacetate

FAB-MS (M + H &lt; ^{+ &gt;} ): 449.

! '

Prepared as in Example 22.

Example 27

N- (Hydroxycarbonylmethylene) - (D) -cyclohexylalanyl-3,4-dehydroprolyl 5- (2amidino) thiazolomethylamide [sic] hydroacetate

FAB-MS (M + H &lt; ^{+ &gt;} ): 463.

Prepared as in Example 23.

Example 28

N- (Hydroxycarbonylmethylene) - (D) -cyclohexylglycyl-3,4-dehydroprolyl 5- (2amidino) thiazolomethylamide [sic] hydroacetate ₃ FAB-MS (M + H ⁺ ): 449.

j Prepared as in example 24.

τ ι / <- - <<-

Claims (7)

PATENT CLAIMS A compound of formula I NH NH ₂ where And it is R ² R ¹ - (CH ₂ ) _m -C (CH ₂ ) _n -R ³ where m is 0, 1 or 2, n is 0, 1 or 2, R ¹ is HOOC-, C 1-4 -alkyl-OOC-, aryl-CC ₄ -alkyl-OOC or -OH, R ² is H, C 1-4 -alkyl or R ¹ - (CH 2) _m -, R ³ is H or C _1-6 -alkyl, B is R ⁶ I R * (R'-C-r'Ij I c --- I R ⁵ CO - where R ⁴ is H, C 1-4 -alkyl or R ¹ - (CH 2) _m - (wherein R ¹ and _m are as defined above), p is 0 or 1, R ⁵ is H or C _1-4 -alkyl, R ⁶ is H, C 1-6 -alkyl, phenyl which may carry up to three identical or different radicals from the group C 1-6 -alkyl, CF ₃ , C 1-6 -alkoxy, F or Cl, or C 1-6 -cycloalkyl which may bear up to four identical or different C 1-4 alkyl radicals, or wherein one or two single CC bonds in the ring may be replaced by a C = C double bond, or a phenyl ring, a C ₇ -C ₁₂ bicycloalkyl or a C ₁₀ -tricycloalkyl may be fused thereto; R ⁴ and R ⁶ together are an ethylene or propylene group, R ⁷ is H, C 1-8 -alkyl, phenyl which may carry up to three identical or different radicals from the group C 1-4 -alkyl, CF ₃ , C 1-4 -alkoxy, F or Cl, or C 1-4 -cycloalkyl which may carry up to four identical or different C 1-4 -alkyl radicals, R ⁸ is H or C 1-6 -alkyl, Eje kde R ⁹ is H or C 1-6 -alkyl, R ¹⁰ is H or C 1-6 -alkyl, R ¹¹ is H or C 1-6 -alkyl, X is O, S, -NR ¹² (R ¹² = H, C 1-4 -alkyl), Y is -N = or -CR ¹³ = (R ¹³ = H, C 1-4 -alkyl), Cl, CF ₃ , Z is -N = or -CR ₁₃ =, * and salts thereof with physiologically tolerated acids. A compound of formula I according to claim 1 for use in disease control. Use of a compound of formula I according to claim 1 for the manufacture of a medicament for: • diseases whose pathogenetic mechanism is directly or indirectly related to the proteolytic effect of thrombin, • diseases whose pathogenetic mechanism is based on thrombin-dependent receptor activation and signal transduction, diseases associated with stimulation or inhibition of gene expression in body cells, diseases based on mitogenic effect of thrombin, a disease based on thrombin-dependent change in contractility and epithelial cell permeability, • thrombin-dependent thromboembolic events, • disseminated intravascular coagulation, reocclusion, and a reduction in reperfusion time for comedication with relapse, and thrombosis after comedication with thrombosis; • thrombin - dependent proliferation of smooth muscle cells, • accumulation of active thrombin in the CNS,. • tumor growth and to prevent tumor cell adhesion and metastasis. Use of a compound of formula I according to claim 1 for the manufacture of a medicament for: diseases whose pathogenetic mechanism is directly or indirectly related to the proteolytic effect of kininogenases, in particular kallikrein, inflammatory diseases such as asthma, pancreatitis, rhinitis, arthritis, urticaria and other internal diseases in which kallikrein is involved. A compound of formula I according to claim 1 for surface treatment. 6. A compound comprising a structural fragment of the formula NH NH ₂ wherein E and D are as defined in claim 1. A compound of formula IIa and IIb A-B-E-D-CN ha, A - B - E - D - CSNH ₂ IIb, wherein A, B, E and D are as defined in claim 1.