WO1998003540A2

WO1998003540A2 - 1,2-substituted cycloalkane derivatives as thrombine inhibitors, a process for the preparation thereof and the use thereof in pharmaceutical formulations

Info

Publication number: WO1998003540A2
Application number: PCT/EP1997/003774
Authority: WO
Inventors: Cristina Di Bugno; Raffaello Giorgi; Nicholas Harmat
Original assignee: A Menarini Industrie Farmaceutiche Riunite SRL
Current assignee: A Menarini Industrie Farmaceutiche Riunite SRL
Priority date: 1996-07-19
Filing date: 1997-07-15
Publication date: 1998-01-29
Anticipated expiration: 1999-01-19
Also published as: ITMI961512A1; WO1998003540A3; ITMI961512A0; AU3543797A; IT1283467B1

Abstract

Compounds containing a 1,2-disubstituted cycloalkane or cycloalkene ring with inhibitory activity on serinoproteases of general formula (I) wherein A is selected from the (CH2)n group with n = -3, CH=CH and Ar, L, X, Q, Y, W are as defined; processes for the preparation thereof, pharmaceutical compositions containing them and the use thereof as therapeutical agents.

Description

1 . 2-SUBSTITUTED CYCLQΛLKAWE DERIVATIVES &s THROMBI WE

INHIBITORS. A PROCESS FOR THE PREPARATION THEREOF AND THE USE THEREOF IN PHARMACEUTICAL FORMULATIONS

The present invention relates to novel compounds containing a 1 , 2-disubstituted cycloal ane or cyclαalkene ring of general formula (I) and the salts thereof, in enantio- or diastereo erically pure forms or as stereomeric mixtures.

The compounds of the invention have inhibitory activity on some serine-proteases; more particularly they turned out to be active in inhibiting the action of the enzyme thrombin and therefore they can be used, for example, as antithrombotic, antiaggregation and anticoagulant agents. PRIOR RT

The peptide sequence Phe-Pro-Arg occurs in the structure of fibrinogen and it is belevied to be important in the recognition of thrombin active site. A number of examples of thrombin inhibitors are known, which are based on structural changes of the Phe-Pro-Arg sequence: see for instance EP 526877, US 4478745 and the articles by Bajusz et al . , J. Med. Chem. 1990, 33, 1729- 1735 and by Kettner et al., Thro b. Res., 1979, 14, 969- 973.

The novel derivatives are characterized by having a 1,2 disubstituted cycloalkane or cycloalkene ring which is surprisingly capable of acting as a conformational analogue of proline in a peptide sequence of the type Phe-Pro-Arg. Detailed disclosure of the invention

The present invention relates to novel compounds having general formula (I)

(I) in which:

A is a (CH₂)_n group wherein n = 1-3 or CH=CH;

W is CN, CH₂OH, COR_j^, BR_{2 3} wherein ₁ is H, OR₄ ,

C0NHR₄, CH₂C1, CF₃ or C₂F₅; R₂ and R₃ , which are the same or different, are OR₄ or together they form the residue of a diol; R₄ is H, C^ - η alkyl, aryl or C₇-C₁₀ arylalkyl;

Y is selected from aryl, aryl substituted with 1-3 hydroxy, ^-C_j alkoxy or halogen residues; C₇-C₁₀ alkylaryl substituted with 1-3 hydroxy, ^cι~^c3 alkoxy or halogen residues; (CH₂)m-T and CH -CgH₄-T wherein = 1-6, preferably 3-5, and T is H, hydroxy, Cι~ ₃ alkoxy, ammo, amidmo, lmidazole, guamdino or isothioureido, - Q is H or C^ - _η alkyl; is (CH₂)p, OCH₂ or SCH₂ wherein p = 0-3, Ar is an aromatic group preferably selected from the group consisting of phenyl, thienyl, pyridyl, naphthyl, thionaphthyl, indolyl, optionally substituted with 1-3 residues which are the same or different, selected from C._j_-C₇ alkyl, alkoxy groups or halogen, or a group selected from the corresponding saturated analogues of said aromatic groups;

X is selected from the group consisting of H, C^-C-_j alkyl, esyl, tosyl , benzenesulfonyl , butyloxy- carbonyl, benzyloxycarbonyl , acetyl, benzoyl .

The compounds of the invention can form salts with various acids both inorganic and organic, which salts are also object of this invention. Said salts include for example hydrochloπdes , hydrobromides , sulfateε, phosphates, maleateε, fumarates.

The invention also comprises the compounds or the salts in enantio- or diastereomerically pure forms or as stereo eric mixtures. Examples of ^-Cη alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl , lεobutyl, t-butyl.

Examples of aryl groups are phenyl, thienyl, furyl and pyπdyl; preferably phenyl.

Examples of

arylalkyl groups comprise benzyl and phenethyl, preferably benzyl.

Examples of diol residues are ethanediol, propanediol, butanediol, pmane diol and pinacol, preferably pmane diol or pinacol

Preferred compounds of formula (I) are those in which A is (CH₂)_n with n = 1-2

Another group of preferred compounds is the one wherein A is (CH₂)_n with n = 1-2 and W is CN or COH or W is a BR₂R group.

A further group of preferred compounds is the one in which A is a -CH=CH- group.

Particularly preferred compounds of general formula (I) are those in which:

A is a (CH₂)_n group wherein n = 1-2 or CH=CH; W is CN, COR^ B ₂R₃, wherein ^_^ is H, 0R₄; R₂ and R₃, which are the same or different, are OR₄ or together they are a diol residue; R₄ is H or ₁-C₇ alkyl;

Y is selected from the ^c7^_cιo alkylaryl group substituted with one to three hydroxy residues, (CH₂)m-T and Cfi^-Cgϊ^-T wherein is 3 and T is C₁- C₃ alkoxy, amidino or guanid o; Q is H;

L is (CH₂)p or OCH₂ wherein p = 1; Ar is phenyl, naphthyl or cyclohexyl; X is selected from H, ^cι~^c7 alkyl, mesyl, benzyloxycarbonyl or acetyl .

Most preferred compounds are the following: l) N-α-[cιs-2-(2S)-[( ( )-N-methylphenylalanyl )amιno]- cyclohexanecarbonyl]-argιnme-aldehyde hydrochlori- de; n) N-α-[cιs-2-(2R)-[ ( (R)-N-methylphenylalanyl )amιno]- cyclohexanecarbony1 ]-arg ine-aldehyde hydrochlori- de; m) N-α-[trans-2-(2S)-[ ( (R )-N-methylphenylalanyl )a- m o ]eyelohexanecarbony1 ]-argmιne-aldehyde hydro- chloride; lv ) N-α-[trans-2-(2R)-[{ (R )-N-methylphenylalanyl )amι- no]cyclohexanecarbonyl]-argιnιne-aldehyde hydro- chloride; v) N-α-[cιs-2-(2R)-[((R ) -phenylalanyl )amιno jcyclohexa- necarbonyl ]argιnιne-aldehyde hydrochloride; vi) N-α-[cιs-2-(2S)-[(( )-phenylglycyl )ammo]cyclohexa- necarbonyl]argιnιnealdehyde hydrochloride; vii) N-α-[cιs-2-(2S)-[( ( R )-{-.-( 2-naphthyl ) alanyl ) amino]- cyclohexane-carbonyl]-argιnιne-aldehyde hydrochlo- πde ; vm) N-α-[cιs-2-(2S)-[{ (R)-N-methyl-C.-(2-naphthγl)- alanyl ) ammo] eyelohexanecarbony1 ]-argιnme- aldehyde hydrochloride; lx ) N-α-[cιs-2-(2S)-t( (R)-β-( 1-naphthyl ) alanyl )ammo]- cyclohexane-carbonyl]argminealdehyde hydrochlo- ride; x) N-α-[cιs-2-(2S)-[( ( R )-N-methyl-β- ( 1-naphthyl ) alanyl ) ammo] eyelohexanecarbonyl]-argιnιne-aldehyde hydrochloride; xi) pmanediol N-α-[cιs-2- ( 2S )-[ ( ( R )-{.-( 2-naphthyl )- alanyl )ammo]cyclohexanecarbonyl]-( 3-methoxypro- pyl )boroglycinate; xn) N-α-[cιs-2-(2S)-t( ( R )-N-acetyl-β- ( 2-naphthyl ) alanyl ) ammo] eyelohexanecarbonyl]-argιnme-aldehyde hydrochloride; xm) N-α-[cιs-2-(2S)-[ ( ( R )-N-methanesulfonyl-β- ( 2-naph- thyl Jalanyl )amιno]cyclohexanecarbonyl]-arginme- aldehyde hydrochloride; xiv) N-α-[cιs-2-(2S)-[( (R )-N-methyl-β- ( 2-naphthyl ) alanyl )amιno] eyelohexanecarbony1 ] -boroarginine; xv) pmanediol N-α- [cιs-2- ( 2S )-[(( R ) -N-methyl-β- ( cyclohexyl ) alanyl )amιno] eyelohexanecarbony1 ]- ( 3-methoxy- propyl Jboroglycinate; xvi ) pinacol N-α- [cιs-2- ( 2S )- [ ( ( R )-N-benzyloxycarbonyl- C_- ( 2-naphthyl ) alanyl ) ammo] eyelohexane-carbonyl]- ( 3-methoxypropyl )boroglycιnate; xvn) pmanediol N-α- [cιs-2-( 2S )- [ ( ( R )-phenylala- nyl )amιno] eyelohexanecarbony1 ]-( 3-bromopro- pyl Jboroglycinate; xvm) N-α-[cιs-2-(2S)-[((R ) -N-acetyl-β-phenyloxyala- nyl ) ammo] eyelohexanecarbony1 ]-boroargιnme; xix) pmanediol N-α-[cιs-2-( 2S )-[ ( ( R ) -β-cyclohexylala- nyl ) amino] eyelohexanecarbony1 ]- ( 4-amιdιnophenylme- thyl Jboroglycinate; xx) N-α-[cιs-2-(2S)-[( ( R )-N-methyl-β- ( 2-naphthyl ) alanyl ) ammo]cyclopentane-carbonyl]-argmmonιtrlie hydrochloride; xxi) methyl N-α-[cιs-2-( 2S )- [ ( (R )-N-methyl-β-( 2-naph- thyl )alanyl )amino]cyclopentane-carbonyl]-boroargι- ninate; xxil ) N-α-[cιε-2-( 2S )-[ ( (R )-N-methyl-β- ( 2-naphthyl )- alanyl )ammo]cyclohex-4-enecarbonyl ] -argmme; xxiii) pinacol N-α-[cιs-2- ( 2S )- [ ( (R )-N-methyl-β-( 2- naphthyl )alanyl )ammo]cyclohex-4-enecarbonyl]- { 4-amιdιnophenylmethyl Jboroglycinate ; xxiv) ethyl N-α- [cιs-2-( 2S )- [ ( ( R )-N-methyl-β- ( 2- naphthyl ) alanyl ) amino ] cyclo ex-4-enecarbony1 ]-

( 4-hydroxyphenylmethyl )glycmate; in which boroglyc ate and boroargimnate define glyc e and arg me analogues in which the carboxylic group is substituted with the boronic one. According to the invention, the compounds of general formula (I) can be obtained by means of known condensation reactions between ammo acids starting from the following intermediates: ammo acids of general formula

suitably protected at the nitrogen, wherein Ar and X are as defined above

2-amino cycloalkyl or alkenyl carboxylic acids amino derivatives of general formula

wherein Y and , defined above, are optionally protected with suitable groups . Particularly important is the synthesis in which the 2-amino-cycloalkyl-carboxylic acid used is one of the possible isomers of 2-amino-cyclohexanecarboxylic acid. These were prepared starting from the corresponding enantio ers of 2-methoxycarbonyl- cyclohexanecarboxylic acid, according to scheme A:

SCHEME A

The acid 1 (by way of example, the 1S,2R iεomer) is converted to azide with diphenylphosphorylazide (DPPA) and transformed into urethane by thermal treatment in the presence of benzyl alcohol. The methyl ester 2 is saponified with 2M NaOH and MeOH and, after hydrogenolysis with Pd/C, the desired amino acid 4 is obtained (the 1R, 2S isomer in the example in question).

The Arg(Z)lactam residue has been prepared according to the method of literature (S. Bajusz et al.

J. Med. Chem. 1990, 21, 1729).

The synthesis of the tripeptides with the end boronic group (W = BR₂R ) has been carried out according to the methods reported in literature (J. ityak et al.

J. Org. Chem. 1995, £0_, 3717; C. Kettner et al. J. Biol .

Chem. 1990, 2__ώ, 18289).

By way of example, scheme B reports the general synthesis of the tripeptides of formula (I), containing the Arginine-aldehyde residue, starting from the enantiomers of 2-amino-cyclohexanecarboxylic acid 4

SCHEME B

9

The protected amino acid 5 is condensed with 2- amino-cyclohexanecarboxylic acid by means of 2,4,5- trichlorophenyl ester. The resulting dipeptide 7 is reacted with Arg(Z)lactam via mixed anhydride with isobutyl chloroformate and N-methylmorpholine as the base, or using N,N ' -dicyclohexylcarbodiimide (DCC) and

1-hydroxy-benzotrιazole (HOBT) The lactam tripeptide 8 is reduced with LιAlH₄ at -

60^βC and finally deproteeted by hydrogenolysis with

Pd/C.

The compounds described in the present invention act as thrombin inhibitors. In order to characterize and evaluate the efficacy thereof, an n_. vitro test for the inhibition of human thrombin has been selected, using as a synthetic substrate tosyl-glycyl-prolyl-argmιne-4- nitroanilme .

The compounds of the invention proved to be active in the above test, showing IC_5Q values lower than 5 mM; for example the compound vii has shown a 0.022 mM I _5Q. The compounds of the invention can therefore be used as active principles of pharmaceutical compositions with antithrombotic activity. The compositions of the invention can be prepared according to conventional techniques and excipients, and will contain typically 1 to 1000 g of the compounds of general formula ( I ) , and they will be administered 1 to 4 times a day through the oral, parenteral, transder al routes or any other convenient administration route

The following examples further illustrate the invention, without limiting it. Example 1 ( lR,2S)-2-Amιno-cyclohexanecarboxγlιc acid (Compound of formula 4)

A solution of monoester 1 (20 g) in toluene (200 ml) was added under nitrogen with DPPA (24.5 ml, 107.5 mmoles), NEt₃ (15 ml) and benzyl alcohol (11.2 ml). The reaction mixture was refluxed for 4 hours, added with

100 ml of toluene, washed with 5% HC1 , 5% NaHC0₃ and H₂0.

The solvent was evaporated off, the residue was purified by f lash-chro atography through silica gel

(petroleum ether/AcOEt = 90/10) to obtain 15.8 g of the desired compound 2 as a colourless oil; TLC: R.f. 0.4 (petroleum ether/ethyl acetate = 9:1); [α]_D = -29.0° (c = 1, EtOH) .

A solution of ester 2 (11 g) in methanol (104 ml) was added with under stirring with a solution of 2M NaOH (76.3 ml) . The suspension was stirred for 1 hour at room temperature, to obtain a clear solution. Methanol was evaporated under vacuum, the aqueous phase was washed with AcOEt, acidified with 6N HC1 and extracted with CH₂C1₂. The organic phases were washed with H₂0, dried and evaporated. The residue was treated with ether and filtered, to obtain 8.2 g of the desired compound 3 as a white solid; TLC R.f. 0.5 ( CHCl₃/cyclohexane/acetιc acid/ethanol = 45:45:5:5); [α]_D = -15.1° (c = 1, EtOH). A solution of acid 3 (8.1 g) m methanol (100 ml) was hydrogenated in the presence of 10% Pd/C (900 mg ) . The catalyst was filtered off and the solvent was evaporated under vacuum. The residue was taken up into ether and filtered, to obtain 4.1 g of compound 4 as a white solid; TLC: 0.6 ( butanol/acetic acid/water 6:2:2); [α]_D = -16.8° (c = 1, H₂0). The other enantiomers of 2-amιno-cyclohexanecarbo- xylic acid were obtained analogously:

(1S,2R) enantiomer [α]_D = +15.6° (c = 1, H₂0)

(1R,2R) enantiomer [α]_D = -71.9" (c = 1, H₂0) (1S,2S) enantiomer [α]_D = +71.5° (c = 1, H₂0).

Example 2

N-α-[cis-2-(2S)-[{ (R)-N-methylphenylalanyl)- ammo ] eye lohexanecar bony l ] argmme-aldehyde hydrochloride (Compound of formula 10) Preparation o_f Z-(D)-I.-πethγlphenylalanιne-2 A ,5- trichloroohenyl ester

(6; X = CH₃, L = CH₂, Ar = phenyl)

A solution of Z-(D)-MePhe (5 g) 5 in THF (40 ml), cooled at 0^βC, was added with 2 ,4 , 5-trιchlorophenol (HOTCP) (3.15 g) and DCC (3.29 g). The reaction mixture was stirred at 0°C for 1 hour and at room temperature for 2 hours.

The cold dicyclohexylurea formed was filtered off and the solvent was evaporated to obtain 8.3 g of the desired compound 6 as an oily residue (HPLC titre =

86%), which was used without further purifications.

Preparation of cis-2-.2S.-H ( R )-N-methvlphenvlalanvl )- aminolcvclohexanecarboxvlic acid (7; X = CH₃, L = CH₂ ,

Ar = phenyl) A solution of ( 1R , 2S )-2-amιno-cyclohexanecarboxylιc acid (1.5 g) in pyridine (60 ml) was added with NEt₃

(1.46 ml) and Z- (D)-MePhe-OTCP 6 (6 g). The reaction mixture was left under stirring at room temperature for

24 hours and evaporated under vacuum at 35-40°C. The residue was taken up into AcOEt , cold washed with 2N

HC1 , H₂0, dried and evaporated. The crude product was dissolved in ether and extracted with 5% NaHC0₃. The combined aqueous phases were acidified to pH 2 while cold with IN HC1 and extracted with AcOEt . The combined organic phases were dried and evaporated under vacuum at 30°C, to obtain 3.3 g of the desired compound 7 as a white solid.

TLC: R.f. 0.7 ( CHCl₃/cyclohexane/acetic acid/water

45:45:5:5)

Preparation of N-α- _cιs-2-.2S ) - { ( f R )-N-methylphenylala- nvl )ammo .cvclohexanecarbonvl .-Z-arαιn ne lactam (8; X = CH₃, L = CH₂, Ar = phenyl)

A solution of compound 7 (2.6 g) in CHC1 (20 ml), cooled at -10^*C, was added with N-methylmorpholine (0.65 ml) and isobutyl chloroformate (0.78 ml). The reaction mixture, after 5' at -10^*C, was added with a solution of Arg(Z)lactam hydrochloride (2.15 g) and NEt₃ (1.65 ml) in CHC1₃ (40 ml). The reaction mixture was left under stirring at -10^βC for 30' and at room temperature for 3 hours, then diluted with CHC1₃ (60 ml) and washed with IN HC1, H₂0, 5% NaHC0₃ and H₂0 (60 ml). The organic phase was dried and evaporated under vacuum at 30 ^*C. The residue was purified by flaεh-chromatography, to obtain 2.4 g of the desired compound 8 as a white solid; TLC: R.f. 0.5 (ethyl acetate/hexane 8:2). 1H-NMR (CDC1₃): d 1.15-2.45 (m, 12H), 2.55 (m, 1H ) , 2.84-3.05 (2s+m, 4H ) , 3.31 (m, 1H), 3.60 (m, 1H ) , 4.10 (m, 1H), 4.30-4.65 ( , 2H ) , 4.78 (t, 1H ) , 4.97-5.14 (2d, 4H), 6.50-6.98 (2d, 1H), 7.13-7.43 (m, 15H), 9.40 ( bs , 2H), 9.62 (bs, 1H).*** Preparation of N-α- f cιs-2- ( 2S - ϊ ( ( R - ( Z -N-methvlPhenvl- alanyl amιno1cvclohexanecarbonyll-Z-arαιnιne-aldehvde

(9; X = CH₃, L = CH₂, Ar = phenyl)

A solution of compound 8 (1 g) in THF (40 ml) stirred under N₂ and cooled at -60^βC, was added with 1M

LιAlH₄ in THF (1.4 ml). The reaction mixture was left under stirring for 30' at -60^βC, added with 10% H₂S0₄ to pH 2 and diluted with H₂0 (20 ml). The aqueous phase was extracted with CH₂Cl^>. The combined organic phases were washed with H 0, dried and evaporated under vacuum, to obtain 980 mg of the desired compound 9 as a white solid.

1H-NMR (CDC1₃): d 1.05-1.95 (m, 12H), 2.68 (bs, 1H)

2.85-3.00 (m +s, 4H ) , 3.20-3.33 (m, 3H), 4.29 ( bs , 2H ) , 4.87-5.20 (2S+m, 5H ) 6.85-7.33 (m+2d 16H), 7.70 (d, 1H), 8.53 (bs, 2H), 9.15 (bs, 1H ) , 9.49 (s, 1H). Preparation of N-α-T e s-2- ( 2S )-H . R )-N-methvlPhenvla- lanvl )am . no level ohexanecarbonvl.-arαmme-aldehvde hv_ drochloride (10; X = CH₃, L = CH₂ , Ar = phenyl) Compound 9 (500 mg, 0) in THF (15 ml) and H₂0 (5 ml) was hydrogenated in the presence of 10% Pd/C (100 mg) and IN HC1 (0.63 ml) under atmosphere pressure and at room temperature. At the end of the reaction the catalyst was filtered off, IN HC1 (0.77 ml) was added and the solvent was evaporated under vacuum at 30°C.

The residue was taken up into AcOEt and filtered to obtain 280 mg of the desired compound 10 as a white solid: m.p. 190-4'C; TLC R.f 0.4 ( butanol/acetic acid/water 6:2:2).

1H-NMR (D₂0): d 0.60-1.80 (m, 12H), 2.43 (m, 1H ) , 2.56 (s, 3H), 2.85-3.60 (2m, 4H ) , 3.58 ( , 1H), 4.07 (m, 2H ) , 4.83 (d, 1H), 5.10-5.20 (2d, 1H), 7.11-7.27 (m, 5H),

7.84 (t, 2H), 9.27 (ε, 1H ) .

Repeating the procedure described in example 2, the following compounds were obtained: ii) N-α-[cιs-2-( 2R )-[ ( (R)-N-methylphenylalanyl )amino]- cyclohexanecarbonyl]-argmine-aldehyde hydrochloride; lii ) N-α-[trans-2-(2S)-[ ( ( )-N-methylphenylalanyl ) ami- no] eyelohexanecarbony1] -argm e-aldehyde hydro- chloride; lv ) N-α-[trans-2-(2R)-[ ( (R )-N-methylphenylalanyl ) ami- no] eyelohexanecarbonyl]arginine-aldehyde hydrochloride; v ) N-α-[cis-2-( 2R)-[ ( (R ) -phenylalanyl )amino]cyclohexa- necarbonyl]-arginine-aldehyde hydrochloride; vi) N-α-[cis-2-(2S)-[( ( R )-phenylglycyl )amino]eyelohexanecarbonyl]arginine-aldehyde hydrochloride; vii) N-α-[cιs-2-(2S)-[( (R )-β-( 2-naphthyl ) alanyl )amino] cyclohexanecarbony1] -argmme-aldehyde hydroe lo- ride; viii) N-α- [cis-2- ( 2S)-[ ( ( R )-N-methyl-β- ( 2-naphthyl )- alanyl )amino] eyelohexanecarbony1 ]-argιnιne- aldehyde hydrochloride; lx ) N-α-[cis-2-(2S)-[( (R)-β-( 1-naphthyl ) alanyl )ammo]- cyclohexanecarbonyl]-arginme-aldehyde hydrochloride; x) N-α-[cιs-2-(2S)-[( (R)-N-methyl-β-(l-naphthyl)ala- nyl )amino] eyelohexanecarbonyl]-argmme-aldehyde hydrochloride; xi) pinanediol N-α-[cis-2-( 2S )-[ ( (R )-β-( 2-naphthyl )ala- nyl )amino] cyclohexanecarbonyl]-( 3-methoxypropyl )- boroglycinate; xii ) N-α-[cis-2-(2S)-[( (R)-N-acetyl-β-_.2-naphthyl ) alanyl ) amino] eyelohexanecarbony1] -arginine-aldehyde hydrochloride; xiii) N-α-[cis-2-(2S)-[( (R )-N-methanesulfonyl-β-( 2- naphthyl ) alanyl ) amino] eyelohexanecarbonyl ]- arginine-aldehyde hydrochloride; xiv) N-α-[cis-2-(2S)-[( { R )-N-methyl-β-( 2-naphthyl ) alanyl )amino] eyelohexanecarbonyl]boroarginine; xv) pinanediol N-α-[cis-2-(2S )-[ ( (R)-N-methyl-β- (cyclohexyl ) alanyl ) amino] eyelohexanecarbonyl ]-( 3- methoxypropyl )boroglycinate; xvi) pinacol N-α-[cis-2-( 2S)- [ ( ( R )-N-benzyloxycarbonyl- β-( 2-naphthyl )alanyl )amino]cyclohexanecarbonyl ]- ( 3- methoxypropyl )boroglycinate; xvii) pinanediol N-α-[cis-2- ( 2S )- [ ( ( R )-phenylala- nyl )amino]cyclohexanecarbonyl]-( 3-bromopro- pyl ) boroglycinate; xviii) N-α-[cis-2-(2S)-[(( )-N-acetyl-β-phenyloxyala- nyl )amino]cyclohexanecarbonyl ]boroarginine hydrochloride; xix) pinanediol N-α-[cis-2-( 2S )-[ ( ( R )-β-cyclohexyla- lanyl )amino]cyclohexanecarbonyl]-( 4-amidinophenyl methyl )boroglycinate hydrochloride; xx) N-α-[cis-2-(2S)-[( ( )-N-methyl-β- ( 2-naphthyl )ala- nγl ) amino]eyelopentane-carbonyl ]-argininonitrile hydrochloride; xxi) methyl N-α- [ciε-2-( 2S )- [ ( (R )-N-methyl-β-( 2-naph- thyl )alanyl )amino]cyclopentane-carbonyl]-boroargi- ninate hydrochloride; xxii) N-α-[cis-2-(2S)-[( ( R )-N-methyl-β-( 2-naphthyl )- alanyl )amino]cyclohex-4-enecarbony2 ]-arginine; xxiii) pinacol N-α-[cis-2- ( 2S )-[ ( (R )-N-methyl-β-( 2- naphthyl )alanyl )amino]cyclohex-4-enecarbonyl]- ( 4amidinophenylmethyl )boroglycinate hydrochlo- ride; xxiv) ethyl N-α-[cis-2-( 2S )-[ ( ( R )-N-methyl-β-( 2- naphthyl )alanyl )amino]cyclohex-4-enecarbonyl]- ( 4hydroxyphenγlmethyl )glγcinate .

Claims

C ΔIHS

Compounds of general formula (I)

in which:

A is a (CH₂)_n group wherein n = 1-3 or CH=CH;

W is CN, CH₂0H, COR-_j^ , BR₂R₃ wherein R₁ is H, 0R₄ ,

CONHR₄, CH₂C1, CF₃ or C₂F₅; R₂ and R₃, which are the same or different, are OR₄ or together they form the residue of a diol; R₄ is H, -^-C-y alkyl, aryl or C₇-C₁₀ arylalkyl;

Y is selected from aryl, aryl substituted with 1-3 hydroxy, ₁-C alkoxy or halogen residues; ^C-J ~^C±_Q alkylaryl substituted with 1-3 hydroxy, ^Cι^-C3 alkoxy or halogen reεidues; (CH₂)m-T and CH₂-C₈H₄-T wherein m = 1-6, preferably 3-5, and T is H, hydroxy, ^-C₃ alkoxy, amino, amidino, imidazole, guanidino or isothioureido; - Q is H or C^C-_j alkyl;

L is (CH₂)p, OCH₂ or SCH₂ wherein p = 0-3; Ar is an aromatic group preferably selected from the group consisting of phenyl, thienyl, pyridyl, naphthyl, thionaphthyl , indolyl, optionally subεtituted with 1-3 residues which are the same or different, selected from C_*-C₇ alkyl, C.,-C₃ alkoxy groups or halogen, or a group selected from the corresponding saturated analogues of said aromatic groups;

X is selected from the group consisting of H, C^-Cη alkyl, mesyl, toεyl, benzeneεulfonyl , butyloxycar- bonyl, benzyloxycarbonyl , acetyl, benzoyl; their stereomeric forms and the salts thereof with pharmaceutically acceptable acids.

2. Compounds according to claim 1, wherein A is (CH₂)_n with n = 1-2.

3. Compounds according to claim 2, wherein W is CN or C0R₁ in which R.^ is H.

4. Compounds according to claim 3, which are: N-α-[cis-2-(2R)-[( (R)-N-methylphenylalanyl ) amino] eyelo- hexanecarbonyl]arginine-aldehyde hydrochloride;

N-α-[tranε-2-( 2S)-[ ( (R )-N-methylphenylalanyl ) amino ] - eyelohexanecarbonyl]arginine-aldehyde hydrochloride; N-α-[tranε-2-( 2R)-[ ( (R )-N-methylphenylalanyl ) amino] cy- clohexanecarbonyl]-arginine-aldehyde hydrochloride; N-α-[ciε-2-(2R)-[( ( R )-phenylalanyl ) amino] eyelohexanecar- bonyl ] arginine-aldehyde hydrochloride ;

N-α-[ciε-2-(2S)-[( ( R ) -phenylglycyl ) amino] eyelohexanecar- bonyl] arginine-aldehyde hydrochloride; N-α-[cis-2-(2S)-[ ( ( R )-β- ( 2-naphthyl ) alanyl ) amino] eyelo- hexanecarbonyl]argininealdehyde hydrochloride;

N-α-[cis-2-(2S)-[ ( ( R )-N-methyl-β-( 2-naphthyl ) alanyl ) amino] eyelohexanecarbonyl ] arginine-aldehyde hydrochloride; N-α-[cis-2-(2S)-[( (R)-β-(l-naphthyl)alanyl)amino] eyelohexanecarbonyl] -arginine-aldehyde hydrochloride; N-α-[cis-2-(2S)-[( (R )-N-methyl-β- ( 1-naphthyl ) alanyl ) amino] eyelohexanecarbonyl ]-arginine-aldehyde hydrochloride; N-α-[ciε-2-(2S)-[ ( ( R )-N-acetyl-β- ( 2-naphthyl ) alanyl ) amino ]eyelohexanecarbonyl ]-arginine-aldehyde hydrochloride; N-α- £ cis-2- ( 2S )- [ { ( R )-N-methanesulfonγl-β- ( 2-naphthyl ) - alanyl )amino]cyclohexanecarbonyl] -arginine-aldehyde hy- drochloride;

N-α- [cis-2- ( 2S)-[ ( (R )-N-methyl-β-( 2-naphthyl ) alanyl )amino]cyclopentancarbonyl]-argininonitrile hydrochloride;

5. Compounds according to claim 2, wherein is BR₂R₃.

6. Compounds according to claim 5, which are: pinanediol N-α- [cis-2-( 2S )-[ ( ( )-β-( 2-naphthyl )alanyl )- amino]eyelohexanecarbonyl]-boro-3-methoxy propyl- glycinate;

N-α-[cis-2-(2S)-[( ( R )-N-methyl-β-( 2-naphthyl ) alanyl ) amino]eyelohexanecarbonyl]-boroarginine; pinanediol N-α-[cis-2-( 2S )-[ ( (R )-N-methyl-β-

( cyclohexyl )alanyl )amino]cyclohexanecarbonyl]-( 3-methoxy propyl)boroglycinate; pinacol N-α- [cis-2- ( 2S )-[ ( (R )-N-benzyloxycarbonyl-β-( 2- naphthyl) alanyl )amino]eyelohexanecarbonyl]- ( 3-methoxy- propyl )boroglycinate; pinanediol N-α-[cis-2-(2S)-[( ( R )-phenylalanyl ) amino] - eyelohexanecarbonyl]- ( 3-bromopropyl )boroglycinate ; N-α-[cis-2-(2S)-[( ( R )-N-acetyl-β-phenyloxyalanyl ) amino]- cyclohexanecarbonyl]-boroarginine hydrochloride; pinanediol N-α-[cis-2-( 2S )-[ ( (R )-β-cyclohexylalanyl )ami- no]cyclohexanecarbonyl]-( 4-amidinophenyl methyl )borogly- cinate hydrochloride; methyl N-α- [cis-2- ( 2S )-[ ( (R )-N-methyl-β- ( 2-naphthyl ) alanyl )amino]cyclopentanecarbonyl]-boroargininate hydro- chloride.

7. Compounds according to claim 1, wherein A is CH=CH.

8. Compounds according to claim 7, which are:

N-α- [ cis-2- (2S)-[( ( R )-N-methyl-β-( 2-naphthyl ) alanyl ) amino]eyelohex4-enecarbony1 ]-arginine; pinacol N-α- [cis-2- ( 2S )-[ ( ( R )-N-methyl-β- ( 2-naphthy1 )- alanyl ) amino]cyclohex-4-enecarbonyl]- (4-amidinophenyl e- thyl )boroglycinate hydrochloride; ethyl N-α-[cis-2-(2S)-[( ( R )-N-methyl-β-( 2-naphthyl )- alanyl )amino]cyclohex-4-enecarbonyl]-( 4-hydroxyphenylme- thyl )glycinate .

9. A process for the preparation of the compounds of general formula (I) obtainable by condensation of amino acids of general formula

suitably protected at the nitrogen, with 2-amino eycloalkyl or alkenyl carboxylic acids and with amino derivatives of general formula

suitably protected at the Y and W functional groups.

10. A process for the preparation of the compounds of general formula (I), according to claim 9, in which the 2-amino-cycloalkyl-carboxylic acid used is one of the isomers of 2-amino-cyclohexane-carboxylic acid obtained in enantiomerically pure forms, which process comprises: a) the treatment of the suitable enantiomerically pure

1 ,2-cyclohexanedicarboxylic acid monoester with diphenylphosphoryl azide; b) the transformation of the resulting acyl azide into urethane by thermal treatment in the presence of benzyl alcohol; c) the saponification of the methyl ester and the deprotection of the amino group by hydrogenolysis with Pd/C.

11. As an intermediate, the optically active (lR,2S)-2- amino-cyclohexanecarboxylic aci .

12. As an intermediate, the optically active (lS,2R)-2- amino-cyclohexanecarboxylic acid .

13. Compounds of the claims 1-8, as antithro botic , anticoagulant and antiaggregation therapeutical agents.

14. Pharmaceutical compositions containing as the active ingredient an effective amount of a compound of claims 1-8, together with suitable excipients.

15. The use of the compounds of claims 1 - 8 for the preparation of a medicament having antithrombotic, anticoagulant and antiaggregation activities.