ZA200209153B - Serine protease inhibitors. - Google Patents

Description

a

SERINE PROTEASE INHIBITORS

, This invention relates to compounds which are inhibitors - ~ of serine proteases and to pharmaceutical compositions thereof " 5 and their use in the treatment of the human or animal body.

The serine proteases are a group of proteolytic enzymes which have a common catalytic mechanism characterized by a particularly reactive Ser residue. Examples of serine proteases include trypsin, tryptase, chymotrypsin, elastase, thrombin, plasmin, kallikrein, Complement Cl, acrosomal protease, lysosomal protease, cocoonase, o-lytic protease, protease A, protease B, serine carboxypeptidase II, : subtilisin, urokinase, Factor VIIa, Factor IXa, and Factor Xa.

The serine proteases have been investigated extensively over a period of several decades and the therapeutic value of inhibitors of serine proteases is well understood.

Serine protease inhibitors play a central role in the regulation of a wide variety of physiological process including coagulation, fibrinolysis, fertilization, development, malignancy, neuromuscular patterning and inflammation. It is well known that these compounds inhibit a variety of circulating proteases as well as proteases that are activated or released in tissue. It is also becoming clear that serine protease inhibitors inhibit critical cellular processes, such as adhesion, migration, free radical . production and apoptosis. In addition, animal experiments indicate that intravenously administered serine protease inhibitors, variants or cells expressing serine protease inhibitors, provide a protective effect against tissue damage. ¢ 30 Serine protease inhibitors have also been predicted to have potential beneficial uses in the treatment of disease in a wide variety of clinical areas such as oncology, neurology, haematology, pulmonary medicine, immunology, inflammation and infectious disease.

In particular serine protease inhibitors may be beneficial in the treatment of thrombotic diseases, asthma, ] emphysema, cirrhosis, arthritis, carcinoma, melanoma, restenosis, atheroma, trauma, shock and reperfusion injury. / 4 5 Thus for example an inhibitor of Factor Xa has value as a therapeutic agent as an anticoagulant, e.g. in the treatment and prevention of thrombotic disorders. The use of a Factor Xa inhibitor as an anticoagulant is desirable in view of the selectivity of its effect. Many clinically approved anticoagulants have been associated with adverse events owing to the non-specific nature of their effects on the coagulation cascade.

Also, there are well-known associations of al protease inhibitor deficiency with emphysema and cirrhosis and C1 esterase inhibitor deficiency with angioedema.

It has now been found that certain aromatic compounds carrying bulky lipophilic side chains are particularly effective as inhibitors of serine proteases, especially proteases with negatively charged Pl specificity pockets, and most especially the serine proteases thrombin, and most importantly Factor Xa. The Factor Xa inhibitors of this invention are potentially useful for the prophylaxis or treatment of thrombotic disorders such as amongst others venous thrombosis, pulmonary embolism, arterial thrombosis, myocardial ischaemia, myocardial infarction, and cerebral thrombosis. They potentially have benefit in the treatment of acute vessel closure associated with thrombolytic therapy and , restenosis, e.g. after transluminal coronary angioplasty or bypass grafting of the coronary or peripheral arteries and in ” 30 the maintenance of vascular access patency in long term hemodialysis patients.

Factor Xa inhibitors of this invention may, with benefit, form part of a combination therapy with an anticoagulant with a different mode of action or with a thrombolytic agent.

It has been reported in W099/11658 and W099/11657 that certain benzamidine and aminoisoquinoline derivatives carrying i a bulky lipophilic side chain are excellent inhibitors of serine proteases. Unfortunately, it has since been found that ’ ‘ 5 benzamidine compounds of WO 99/11658 in general demonstrate poor oral bicavailability.

Surprisingly, it has now been found that certain other aromatic compounds also show inhibitory activity against serine proteases, in particular Factor Xa, despite the lack of the amidino or l-aminoisoquinoline functionality previously believed to be crucial for activity as a factor Xa inhibitor.

Many of these compounds also possess other structural features that further distinguish them from the compounds of W099/11658 and WO099/11657.

Where compounds of the invention have been tested, they have generally demonstrated superior oral bioavailability in comparison with benzamidines disclosed in WO 99/11658. Also, it has been found that the compounds of the invention perform excellently in the prothrombin time assay (PT) when compared to aminoisoquinolines of similar factor Xa activity and structure. The PT assay is a coagulation assay and it is widely accepted that direct acting Factor Xa inhibitors which perform well in the PT assay are more likely to be good antithrombotics.

In WO99/09053 certain 2-aminobenzamide compounds are disclosed as potential motilin receptor antagonists and in US 3268513 similar 2-aminobenzamide compounds are suggested as potential antibacterial agents. However, the novel compounds ‘ of the present invention have not before been suggested as y 30 potential serine protease inhibitors.

Thus viewed from one aspect the invention provides a serine protease inhibitor compound of formula (I)

Ti » » (I) wherein:

Ry is a 5 or 6 membered aromatic carbon ring optionally interrupted by a nitrogen, oxygen or sulphur ring atom, optionally being substituted in the 3 and/or 4 position (in relation to the point of attachment of X-X) by halo, nitro, thiol, haloalkoxy, hydrazido, alkylhydrazido, amino, cyano, haloalkyl, alkylthio, alkenyl, alkynyl, acylamino, tri or difluoromethoxy, carboxy, acyloxy, MeSO;- or Rp, or the substituents at the 3 and 4 positions taken together form a fused ring which is a 5 or 6 membered carbocyclic or heterocyclic ring optionally substituted by halo, haloalkoxy, haloalkyl, cyano, nitro, amino, hydrazido, alkylthio, alkenyl, alkynyl or R14, and optionally substituted in the position alpha to the X-X group (i.e. 6 position for a six membered aromatic ring etc) by amino, hydroxy, halo, alkyl, carboxy, alkoxycarbonyl, cyano, amido, aminoalkyl, alkoxy or alkylthio with the proviso that Ry cannot be aminoisoquinolyl; each X independently is a C, N, O or S atom or a CO,

CR1a: C(R1a)z or NR group, at least one X being C, CO, CRjz or C(Rya)ai each Rj independently represents hydrogen or hydroxyl, alkoxy, alkyl, aminoalkyl, hydroxyalkyl alkoxyalkyl, alkoxycarbonyl, alkylaminocarbonyl, alkoxycarbonylamino, ) acyloxymethoxycarbonyl or alkylamino optionally substituted by : hydroxy, alkylamino, alkoxy, oxo, aryl or cycloalkyl;

Ri is as defined for Rj, provided that R; is not unsubstituted aminoalkyl;

Y (the a-atom) is a nitrogen atom or a CRip group;

Cy is a saturated or unsaturated, mono or poly cyclic,

homo or heterocyclic group, preferably containing 5 to 10 ring atoms and optionally substituted by groups R3z or R3iXj: each R35 independently is Rj, amino, halo, cyano, nitro, thiol, alkylthio, alkylsulphonyl, alkylsulphenyl, triazolyl, . 5 imidazolyl, tetrazolyl, hydrazido, alkylimidazolyl, thiazolyl, alkylthiazolyl, alkyloxazolyl, oxazolyl, alkylsulphonamido, alkylaminosulphonyl, aminosulphonyl, haloalkoxy, haloalkyl, a group of the formula -C(X3)N(R11)R12 (wherein X3 is 0 or S; and R11 and R12 are independently selected from hydrogen, methyl or ethyl or together with the nitrogen atom to which they are attached form a pyrrolidin-1-yl, piperidin-1-yl or morpholino group), or -OCH,O0- which is bonded to two adjacent ring atoms in Cy;

Xj is a bond, O, NH or CHy;

R3i is phenyl, pyridyl or pyrimidinyl optionally substituted by R35;

Rib, Ric and R34 are as defined for Rj; and -L-Lp(D)p is of the formula:

VAR hy N-—R. __/ in which Ry is -(CHp)o-Re, -CHReRf, -CHy-CHReRg, -CHp-CHp-CHRgRf, Or Rg in which c¢ is 1 or 2; Rc is thienyl, thiazolyl (which may bear an amino substituent), isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, pyridyl (which may bear an alkylsulphonyl, aminosulphonyl, alkylaminosulphonyl, alkylaminocarbonyl, amino, amido, (1-

B 4C) alkoxycarbonyl, carboxy, acetylamino, chloro, fluoro, cyano, (1-3C)alkyl, trifluoromethyl, methoxy, ethoxy, nitro, ’ hydroxy, alkylsulphonylamino, triazolyl or tetrazolyl substituent), pyrimidinyl, pyridazinyl, pyrazinyl or phenyl (which may bear a methyl, methylamino, dimethylamino, carboxy, dialkylaminosulphonyl, alkylsulphonyl, aminosulphonyl,

alkylaminosulphonyl, alkylaminocarbonyl, amino, amido, alkoxycarbonyl, acetylamino, chloro, fluoro, cyano, methoxy, } ethoxy, nitro, hydroxy, alkylsulphonylamino, triazolyl or ’ tetrazolyl substituent); each of Re and Rf independently is o 5 hydrogen or Cj_zalkyl; or CHRgRf is cyclopentyl (which may bear a hydroxy, amino, (1-3C)alkoxy, (1-3C) hydroxyalkyl, (1- 3C)alkyl, carboxy, methoxycarbonyl or ethoxycarbonyl substituent at the 3- or 4-position), cyclohexyl (which may bear a hydroxy, amino, (1-3C)alkoxy, (1-3C)hydroxyalkyl, (1- : 10 3C)alkyl, carboxy, methoxycarbonyl or ethoxycarbonyl substituent at the 3- or 4-position), tetrahydropyran-4-yl, tetrahydrothiopyran-4-yl, pyrrolidin-3-yl (which may bear a hydroxy, amino, (1-3C)alkoxy, (1-3C)hydroxyalkyl, (1-3C)alkyl, carboxy, methoxycarbonyl or ethoxycarbonyl substituent at the 1-position), piperidin-4-yl (which may bear a hydroxy, amino, (1-3C)alkoxy, (1-3C)hydroxyalkyl, (1-3C)alkyl, carboxy, methoxycarbonyl or ethoxycarbonyl substituent at the 1- position), or indan-2-yl; and Rg is 2-methylsulphonylphenyl which may bear a 4-fluoro substituent or Ry is A6-1,1- dioxobenzo [b]thiophen-7-y1; or a physiologically-tolerable salt thereof (e.g. a halide, phosphate or sulfate salt or a salt with ammonium or an organic amine such as ethylamine or meglumine); provided that Lp(D)n is not of the formula (K): —S80, ~~ e __/ (K) wherein X5 is fluoro or hydrogen.

In another aspect the invention relates to a serine protease inhibitor compound of formula (I)

IU re NO (1) . wherein:

Ry; is a 5 or 6 membered aromatic carbon ring optionally interrupted by a nitrogen, oxygen or sulphur ring atom, optionally being substituted in the 3 and/or 4 position (in relation to the point of attachment of X-X) by halo, nitro, thiol, haloalkoxy, hydrazido, alkylhydrazido, amino, cyano, haloalkyl, alkylthio, alkenyl, alkynyl, acylamino, tri or difluoromethoxy, carboxy, acyloxy, MeSO;- or Rj, or the substituents at the 3 and 4 positions taken together form a fused ring which is a 5 or 6 membered carbocyclic or heterocyclic ring optionally substituted by halo, haloalkoxy, haloalkyl, cyano, nitro, amino, hydrazido, alkylthio, alkenyl, alkynyl or R14, and optionally substituted in the position alpha to the X-X group (i.e. 6 position for a six membered aromatic ring etc) by amino, hydroxy, halo, alkyl, carboxy, alkoxycarbonyl, cyano, amido, aminoalkyl, alkoxy or alkylthio with the proviso that Rp, cannot be aminoisoquinolyl; each X independently is a C, N, O or S atom or a CO,

CRia, C(R1a)2 or NRj, group, at least one X being C, CO, CRqg or C(Ryag) 2; each Rj; independently represents hydrogen or hydroxyl, alkoxy, alkyl, aminoalkyl, hydroxyalkyl alkoxyalkyl, alkoxycarbonyl, alkylaminocarbonyl, alkoxycarbonylamino, acyloxymethoxycarbonyl or alkylamino optionally substituted by ’ hydroxy, alkylamino, alkoxy, oxo, aryl or cycloalkyl;

Ry is as defined for Rj, provided that Rj; is not unsubstituted aminoalkyl;

Y (the a-atom) is a nitrogen atom or a CRqp group;

Cy is a saturated or unsaturated, mono or poly cyclic, homo or heterocyclic group, preferably containing 5 to 10 ring atoms and optionally substituted by groups Riz; or phenyl optionally substituted by Riza; : ) each R35 independently is Rj, amino, halo, cyano, nitro, thiol, alkylthio, alkylsulphonyl, alkylsulphenyl, triazolyl, imidazolyl, tetrazolyl, hydrazido, alkyl imidazolyl, thiazolyl, alkyl thiazolyl, alkyl oxazolyl, oxazolyl, alkylsulphonamido, alkylaminosulphonyl, aminosulphonyl, haloalkoxy and haloalkyl;

Rip, Ric and Rp are as defined for Ria; and -L-Lp(D)p is of the formula: 0 /\

Ay N—R. _/ in which Ry is -(CHp)c-Rg, -CHRgRf, -CHp-CHRgRf, Or Rg in which ¢ is 1 or 2; Rc is pyridyl or phenyl (which phenyl may bear a fluoro, chloro, methyl, CONH,, SO,NH5, methylaminosulphonyl, dimethylaminosulphonyl, methoxy or methylsulfonyl substituent); each of Rg and Rf independently is hydrogen or Cj_3alkyl; or CHRgRf is cyclopentyl (which may bear a methyl, ethyl or hydroxymethyl substituent at the 3- or 4-position), cyclohexyl (which may bear a methyl, ethyl or hydroxymethyl substituent at the 3- or 4-position), tetrahydropyran-4-yl, tetrahydrothiopyran-4-yl, pyrrolidin-3- yl (which may bear a 1-methyl substituent), piperidin-4-yl (which may bear a l-methyl substituent), or indan-2-yl; and Rg is 2-methylsulphonylphenyl which may bear a 4-fluoro substituent or Rg is A6-1,1-dioxobenzo [b] thiophen-7-yl; ¢ or a physiologically-tolerable salt thereof; provided that Lp(D)n is not of the formula (K): —S0,

(K) wherein X, is fluoro or hydrogen.

In the compounds of the invention, where the alpha atom ) is carbon it preferably has the conformation that would result » 5 from construction from a D-a-aminoacid NH;-CRjpp (Cy) -COOH where the NH, represents part of X-X. Likewise the fourth substituent Rjp at an alpha carbon is preferably a methyl or hydroxymethyl group or hydrogen. It will be appreciated that the compounds of formula (I) may exist in racemic or chiral form, and that the preferred D-isomer may be administered in a racemic mixture with the L-isomer, or alone.

In the compounds of the invention, unless otherwise indicated, aryl groups preferably contain 5 to 10 ring atoms optionally including 1, 2 or 3 heteroatoms selected from O, N and S; alkyl, alkenyl or alkynyl groups or alkylene moieties preferably contain up to 6 carbons, e.g. Ci.g or Ci.3; cyclic groups preferably have ring sizes of 3 to 8 atoms; and fused multicyclic groups preferably contain 8 to 16 ring atoms.

Examples of particular values for Rj are: hydrogen, methyl or ethyl. Ry is preferably a hydrogen atom.

The linker group (X-X) from the Ry group to the alpha atom is preferably selected from -CH=CH-, -CONH-, -CONRq 5-, -NH-CO-, -NH-CHy-, -CHy-NH-, -CHy0-, -OCHz-, -COO-, -OC=0- and -CH;CHp-. Preferably, the X moiety nearest to the alpha atom is an NH or O atom, most preferably a NH group. The X moiety alpha to the aromatic ring is preferably a carbon based group such as CHp or CO, preferably CO. Thus a particularly preferred linker X-X is -CONH-. In an alternative embodiment ) the linker is a -OCHy- group.

Examples of particular values for Rip are: hydrogen, (1-4C)alkyl, such as methyl or hydroxy (1-4C)alkyl, such as hydroxymethyl. Rjp is preferably a hydrogen atom.

The alpha atom (Y) is preferably a CH or C(CH3) group.

Especially the alpha atom (Y) is CH.

Claims (26)

® PCT/GB01/02553 Claims

1. A serine protease inhibitor compound of formula (I) 7 re” x SPO (1) wherein: Ro, represents: (i) phenyl optionally being substituted in the 3 and/or 4 position by halo, nitro, thiol, haloalkoxy, hydrazido, alkylhydrazido, amino, cyano, haloalkyl, alkylthio, alkenyl, alkynyl, acylamino, tri or difluoromethoxy, carboxy, acyloxy, MeSO5- or Rj, and optionally substituted at the 6 position by amino, hydroxy, halo, alkyl, carboxy, alkoxycarbonyl, cyano, amido, aminoalkyl, alkoxy or alkylthio; (ii) naphth-2-yl optionally substituted at the 6 or 7 position by halo, haloalkoxy, haloalkyl, cyano, nitro, amino, hydrazido, alkylthio, alkenyl, alkynyl or Rij and optionally substituted at the 3 position by amino, hydroxy, halo, alkyl, carboxy, cyano, amido, aminoalkyl, alkoxy or alkylthio; (iii) isoquinolin-7-yl, indol-5-y1, indol-6-yl, indazol- 5-yl, indazol-6-yl, benzothiazol-6-yl or benzisoxazol-5-yl ’ optionally substituted at the 3 position by halo, haloalkoxy, : haloalkyl, cyano, nitro, amino, hydrazido, alkylthio, alkenyl, alkynyl or Ris; (iv) benzimidazol-5-yl or benzothiazol-6-yl optionally substituted at the 2 position by amino; (v) thien-2-yl or thien-3-yl optionally substituted at the 4 or 5 position by halo, haloalkoxy, haloalkyl, cyano, nitro, amino, hydrazido, alkylthio, alkenyl, alkynyl or Ri; (vi) 3, 4-methylenedioxyphenyl, 2,3-dihydroindol-6-vyl, 3,3-dichloro-2-oxo-indol-6-yl or 1-methyl-3-aminoindazol-5-yl; (vii) benzothiazol-2-yl, {imidazol[l,2-alpyrimidin-2-yl or tetrahydroimidazo[1,2-alpyrimidin-2-yl; AMENDED SHEET

® PCT/GB01/02553

(viii) pyrazol-2-yl optionally substituted at the 5 position by halo, haloalkoxy. haloalkyl, cyano, nitro, amino, hydrazido, alkylthio, alkenyl, alkynyl or Ri;

(ix) pyrid-2-yl optionally substituted at the 5 position by halo, haloalkoxy, haloalkyl, cyano, nitro, amino, hydrazido, alkylthio, alkenyl, alkynyl or Ri; :

(x) pyrid-3-yl optionally substituted at the 6 position by halo, haloalkoxy, haloalkyl, cyano, nitro, amino, hydrazido, alkylthio, alkenyl, alkynyl or Ri;

(xi) benzofur-2-yl optionally substituted at the 3 position by amino, hydroxy, halo, alkyl, carboxy, cyano, amido, aminoalkyl, alkoxy or alkylthio and at the 5 or 6 position by halo, haloalkoxy, haloalkyl, cyano, nitro, amino, hydrazido, alkylthio, alkenyl, alkynyl or Rigi

(xii) indol-2-yl optionally substituted on the indole nitrogen atom by alkyl and optionally substituted at the 5 or 6 position by halo, haloalkoxy, haloalkyl, cyano, nitro, amino, hydrazido, alkylthio, alkenyl, alkynyl or Rij;

(xiii) indol-6-yl substituted at the 5 position by amino,

hydroxy, halo, alkyl, carboxy, alkoxycarbonyl, cyano, amido, aminoalkyl, alkoxy or alkylthio and optionally substituted at the 3 position by halo, haloalkoxy, haloalkyl, cyano, nitro,

amino, hydrazido, alkylthio, alkenyl, alkynyl or Rij; OF : (xiv) benzo [b] thiophen-2-yl optionally substituted at the

3 position by amino, hydroxy, halo, alkyl, carboxy, cyano, amido, aminoalkyl, alkoxy or alkylthio and at the 5 or 6 position by halo, haloalkoxy, haloalkyl, cyano, nitro, amino, hydrazido, alkylthio, alkenyl, alkynyl or Rij; with the proviso that Ry cannot pe aminoisoguinolyl;

Rp represents hydrogen, hydroxy, alkoxy, alkyl, alkylaminoalkyl, alkanoyl, hydroxyalkyl, alkoxyalkyl, alkoxycarbonyl, alkylaminocarbonyl, alkylamino, carboxyl, carboxymethyl, amido or amidomethyl;

Ri represents hydrogen, hydroxy, alkoxy, alkyl,

alkanoyl, hydroxyalkyl, alkoxyalkyl, alkoxycarbonyl, alkylamino, carboxyl, carboxymethyl, amido or amidomethyl;

-X-X- is -CONH-;

Y (the a-atom) is CH; : AMENDED SHEET

C PCT/GB01/02553

Cy represents an optionally Ria substituted: phenyl, pyridyl, thienyl, thiazolyl, naphthyl, piperidinyl, furanyl, pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxazolyl, imidazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,

pyrimidinyl, pyridazinyl, quinolyl, isoquinolyl, benzofuryl, benzothienyl or cycloalkyl group, or a phenyl group : substituted by R3jXji in which Xj is a bond, O, NH or CHp and R3i is phenyl, pyridyl or pyrimidyl group optionally substituted by R3ai each Rag independently represents hydrogen; hydroxyl; alkoxy; aralkyloxy; alkyl; alkylaminoalkyl; hydroxymethyl; carboxy; alkoxyalkyl; alkoxycarbonyl; alkylaminocarbonyl;

aminomethyl; CONHp; CHCONHZ; (1-6C)alkanoylamino; alkoxycarbonylamino; ‘amino; halo; cyano; nitro; thiol;

alkylthio; alkylsulphonyl; alkylsulphenyl; alkylsulphonamido; alkylaminosulphonyl; aminosulphonyl; haloalkoxy; haloalkyl; a group of the formula _c(x3)N(RY1)R12 (wherein X3 is O or S and R11 and R12 are independently selected from hydrogen, methyl, ethyl, or together with the nitrogen atom to which they are attached form a pyrrolidin-1-yl, piperidin-1-yl or morpholino group; Or -OCH0- which is bonded to two adjacent ring atoms in Cy; and

-L-Lp(D)p is of the formula:

I / \ piu N—R, \ /

in which Ry is - (CHp) ¢-Re, -CHReRf, -CHz-CHReRf, -CH,-CHy-CHReRf, Or Rg in which c is 1 or 2; Rc is thienyl, thiazolyl (which may bear an amino substituent), isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, pyridyl (which may bear an alkylsulphonyl, aminosulphonyl,

alkylaminosulphonyl, alkylaminocarbonyl, amino, amido, (1- 4C) alkoxycarbonyl, carboxy, acetylamino, chloro, fluoro, cyano, (1-3C)alkyl, trifluoromethyl, methoxy, ethoxy. nitro, hydroxy, alkylsulphonylamino, triazolyl or tetrazolyl substituent), pyrimidinyl, pyridazinyl, pyrazinyl or phenyl

(which may bear a methyl, methylamino, dimethylamino, carboxy,

AMENDED SHEET

) PCT/GB01/02553 dialkylaminosulphonyl, alkylsulphonyl, aminosulphonyl, alkylaminosulphonyl, alkylaminocarbonyl, amino, amido, alkoxycarbonyl, acetylamino, chloro, fluoro, cyano, methoxy, ethoxy, nitro, hydroxy, alkylsulphonylamino, triazolyl or tetrazolyl substituent); each of Re and Rf independently is hydrogen or Cj.3alkyl; or CHReRf is cyclopentyl (which may bear a hydroxy, amino, (1-3C) alkoxy, (1-3C) hydroxyalkyl, (1- : 3C)alkyl, carboxy, methoxycarbonyl or ethoxycarbonyl substituent at the 3- or 4-position), cyclohexyl (which may bear a hydroxy, amino, (1-3C) alkoxy, (1-3C) hydroxyalkyl, (1- ~ 3C)alkyl, carboxy, methoxycarbonyl or ethoxycarbonyl substituent at the 3- or 4-position), tetrahydropyran-4-yl, tetrahydrothiopyran-4-yl, pyrrolidin-3-yl (which may bear a hydroxy, amino, (1-3C) alkoxy. (1-3C) hydroxyalkyl, (1-3C)alkyl, carboxy, methoxycarbonyl or ethoxycarbonyl substituent at the 1-position), piperidin-4-yl (which may bear a hydroxy, amino, (1-3C) alkoxy, (1-3C) hydroxyalkyl, (1-3C)alkyl, carboxy, methoxycarbonyl or ethoxycarbonyl substituent at the 1- position), or indan-2-yl; and Rg is 2-methylsulphonylphenyl which may bear a 4-fluoro substituent or Rg is A6-1,1- dioxobenzo [b] thiophen-7-yl; oo or a physiologically-tolerable salt thereof; provided that Lp(D)n is not of the formula (K): —S80, a —%, (K) wherein X; is fluoro or hydrogen.

2. A compound according to Claim 1, wherein: Cy is an optionally R3a substituted: phenyl, pyridyl, thienyl, thiazolyl, naphthyl, piperidinyl or cycloalkyl group; each R35 is independently selected from hydrogen, hydroxyl, methoxy, ethoxy, methyl, ethyl, methylaminomethyl, dimethylaminomethyl, hydroxymethyl, carboxy, methoxymethyl, AMENDED SHEET

PCT/GB01/02553 methoxycarbonyl, ethoxycarbonyl, methylaminocarbonyl, dimethylamino-carbonyl, aminomethyl, CONHy, CHoCONHp, acetylamino, methoxycarbonylamino, ethoxycarbonylamino, t- butoxycarbonylamino, amino, fluoro, chloro, cyano, nitro, thiol, methylthio, methylsulphonyl, ethylsulphonyl, methylsulphenyl, methylsulphonylamido, ethylsulphonylamido, methylaminosulphonyl, ethylaminosulphonyl, aminosulphonyl, trifluoromethoxy and trifluoromethyl; and -L-Lp(D)p is of the formula: EVER Jp" N—R, ’ __/ in which Ry is -(CH2)-—Re, —CHRgRf, -CH2-CHRgRf, or Rg in which ¢ is 1 or 2; Rc is pyridyl or phenyl (which phenyl may bear a fluoro, chloro, methyl, CONHz, SO2NH>, methylaminosulphonyl, dimethylaminosulphonyl, methoxy or methylsulphonyl substituent); each of Re and Rf independently is hydrogen or Cj_3alkyl; or CHRgRf is cyclopentyl (which may bear a methyl, ethyl or hydroxymethyl substituent at the 3- or 4-position), cyclohexyl (which may bear a methyl, ethyl or hydroxymethyl substituent at the 3- or 4-position), tetrahydropyran-4-yl, tetrahydrothiopyran-4-yl, pyrrolidin-3- yl (which may bear a l1-methyl substituent), piperidin-4-yl (which may bear a l-methyl substituent) or indan-2-yl; and Rg is 2-methylsulphonylphenyl which may bear a 4-fluoro substituent or Rg is A6-1,1-dioxobenzo[b]thiophen-7-yl.

3. A compound according to Claim 1 or claim 2, wherein Rj represents: (i) phenyl optionally being substituted in the 3 and/or 4 position by fluoro, chloro, bromo, iodo, nitro, difluoromethoxy, trifluoromethoxy, amino, cyano, trifluoromethyl, methylthio, vinyl, carboxy, acetoxy, MeSOs-, hydroxy, methoxy, ethoxy, methyl, methoxycarbonyl, methylamino, ethylamino or amido, and optionally substituted AMENDED SHEET

PCT/GB01/02553 at the 6 position by amino, hydroxy, fluoro, methoxycarbonyl, cyano or aminomethyl (preferably phenyl substituted in the 4 position by chloreo, amino, vinyl, methylamino, methyl or methoxy, optionally at the 3 position with amino or hydroxy, and optionally at the 6 position with amino or hydroxy) ; (ii) naphth-2-yl optionally substituted at the 6, position by hydroxy and optionally substituted at the 3 position by amino or hydroxy; : (iii) isoguinolin-7-yl, indol-5-yl, indol-6-yl, indazol- S5-yl, indazol-6-yl, benzothiazol-6-yl or benzisoxazol-5-yl optionally substituted at the 3 position by chloro, bromo, amino, methyl or methoxy (preferably indol-6-yl optionally BE substituted at the 3 position by chloro, bromo, methyl or methoxy) ; (iv) benzimidazol-5-yl or benzothiazol-6-yl optionally substituted at the 2 position by amino; (v) thien-2-yl or thien-3-yl optionally substituted at the 4 or 5 position by methylthio, methyl or acetyl; (vi) 3,4-methylenedioxyphenyl, 2, 3-dihydroindol-6-yl1, } 3,3-dichloro-2-oxo-indol-6-yl or 1-methyl-3-aminoindazol-5-yl1; (vii) benzothiazol-2-yl, imidazol[l,2-alpyrimidin-2-yl or tetrahydroimidazo[l,2-alpyrimidin-2-yl; (viii) pyrazol-2-yl substituted at the 5 position by methyl; Se : (ix) S-chloropyrid-2-yl; (x) pyrid-3-yl or 6-chloropyrid-3-yl; (xi) benzofur-2-yl, S—chlorobenzofur-2-yl, 3- methylbenzofur-2-yl, S-methylbenzofur-2-yl or 6-methoxybenzofur- 2-yl; (xii) indol-2-yl optionally substituted on the indole nitrogen atom by methyl and optionally substituted at the 5 or 6 position by fluoro, chloro, bromo, methyl or methoxy; (xiii) indol-6-yl substituted at the 5 position by chloro, fluoro or hydroxy and optionally substituted at the 3 position by chloro or methyl; or AMENDED SHEET

) PCT/GB01/02553 (xiv) benzo [blthiophen-2-yl optionally substituted at the 3 position by fluoro, chloro or methyl, and optionally substituted at the 5 or 6 position by fluoro, chloro, methyl, hydroxy, or methoxy.

4. A compound according to Claim 3, wherein Ry is: (1) phenyl, 2-aminophenyl, 3-aminophenyl, 2-amino-4- fluorophenyl, 2-amino-4-chlorophenyl, 2-amino-4-nitrophenyl, 2- amino-4-methylphenyl, 3,4-diaminophenyl, 3-amino-4-fluorophenyl, 3-amino-4-chlorophenyl, 3-amino-4-bromophenyl, 3-amino-4- hydroxyphenyl, 3-amino-4-carboxymethylphenyl, 3-amino-4- methylphenyl, 3-amino-4-methoxyphenyl, 2-fluorophenyl, 4-fluoro- - 3-cyanophenyl, 3-chlorophenyl, 3-chloro-4-hydroxphenyl, 4- chlorophenyl, 4-chloro-2-hydroxyphenyl, 4-chloro-3- 12 hydroxyphenyl, 4-chloro-3-methylphenyl, 4-chloro-3- methoxyphenyl, 4-bromophenyl, 4-bromo-3-methylphenyl, 4- iodophenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2- hydroxyphenyl, 2-hydroxy-4-methoxyphenyl, 3-hydroxyphenyl, 3- hydroxy-4-methylphenyl, 2,4-dihydroxyphenyl, 3,4- ~ dihydroxyphenyl, 3-hydroxy-4-methoxyphenyl, 4- difluoromethoxyphenyl, 4-trifluoromethoxphenyl, 4- trifluoromethylphenyl, 4-methylthiophenyl, 4- : methoxycarbonylphenyl, 4-acetoxyphenyl, 4- methanesulfonylphenyl, 3-methylphenyl, : 4-methylphenyl, 4-vinylphenyl, 4-methoxyphenyl, 4- ethoxyphenyl, 4-methoxy-3-chlorophenyl, 4-methoxy-3- methylphenyl, 3-methylaminophenyl, 4-methylaminophenyl, 4- ethylaminophenyl or 2-aminomethylphenyl; (ii) naphth-2-yl, 3-aminonaphth-2-yl, 3-hydroxynaphth-2- yl or 6-hydroxynaphth-2-yl; (iii) isoquinolin-7-yl, indol-5-yl, indol-6-yl, 3- chloroindol-6-yl, 3-bromoindol-6-yl, 3-methylindol-6-yl, 3- methoxyindol-6-y1, indazol-5-yl, 3-aminoindazol-5-yl, indazol- 6-yl, benzothiazol-6-yl, 3-aminobenzisoxazol-5-y1; AMENDED SHEET

[ PCT/GB01/02553 (iv) benzimidazol-5-yl, 2-aminobenzimidazol-5-y1, or benzothiazol-6-yl; (v) thien-2-yl, 5-methylthien-2-yl, 5-methylthio-thien-2- vl, S-acetylthien-2-yl or thien-3-yl; (vi) 3,4-methylenedioxyphenyl, 2,3-dihydroindol-6-yl, 3,3-dichloro-2-oxo-indol-6-yl or 1-methyl-3-aminoindazol-5-y1; (vii) benzothiazol-2-yl, imidazo[1l,2-alpyrimidin-2-yl or tetrahydroimidazo[1,2-alpyrimidin-2-yl; (viii) S5-methylpyrazol-2-yl; (ix) S5-chloropyrid-2-yl; (x) pyrid-3-yl, 6-chloropyrid-3-yl; (xi) benzofur-2-yl, 5-chlorobenzofur-2-yl, 3- methylbenzofur-2-yl, 5-methylbenzofur-2-yl, 6 -met hoxybenzofur- 2-yl; (xii) indol-2-yl, 5-fluoroindol-2-yl, 5-chloroindol-2-yl, 5-methylindol-2-yl, 5-methoxindol-2-y1, 6-methoxyindol-2-yl and 1-methyl-indol-2-yl; (xiii) 5-fluoroindol-6-yl; ox (xiv) benzo [b] thiophen-2-y1, 5-chloro- benzo [b]thiophen- 2-yl or 6-chlorobenzo [b] thiophen-2-yl.

5. A compound according to Claim 2 or Claim 3, wherein Rp is selected from one of the formula (A') to (H"): AMENDED SHEET

’ PCT/GB01/02553 Ris S aa IL Rye N Ris (A) (8) ©) Ri 74 N Ris Coy Ris Ss CI) (G) wherein Rj; is selected from hydrogen, fluoro [except for (C')], chloro or methyl and Rijs is selected from hydrogen, methyl, ethyl, fluoro, chloro, and methoxy and Ris is selected from hydrogen, methyl, fluoro, chloro and amino.

6. A compound according to claim 5, wherein Rp; is 4- chlorophenyl, 4-methoxyphenyl, 3-amino-4-chlorophenyl, indol-2- yl, 5-chloroindol-2-yl, indol-6-yl, 3-chloroindol-6-yl or 3- methylindol-6-yl.

7. A compound according to any one of claims 1 to 6, wherein Cy is selected from: AMENDED SHEET

C PCT/GB01/02553

R, R,, R., Rn X' — R, Va R, NX H Ro : : Roy Ss xX -~ xX / \ N Y' [a SS) Sr x? “Rg RE Ry,” YN we US ~~ Rm = id “N \ // \/ ZN N—N H R N R Z »Z ZN : R : R H E ° g ° or g wherein:

X' is selected from O, S and NMe;

X'' is selected from O and S;

X'" is selected from O, S, NH and NMe;

y' is selected from hydrogen, amino and methyl;

Ro is selected from hydrogen, methyl, fluoro, chloro, trifluoromethyl, methoxy, methylthio, methylsulphinyl and methylsulphonyl;

Ry is selected from hydrogen, methyl, fluoro, chloro, trifluoromethyl, methoxy, methylthio, methylsulphinyl, methylsulphonyl, carboxy, methoxycarbonyl and a group of the formula —c(x3)N(R11)R1Z2 (wherein x3 is 0 or S and R11 and R12 are independently selected from hydrogen, methyl or ethyl or

AMENDED SHEET

[ PCT/GB01/02553 together with the nitrogen atom to which they are attached form a pyrrolidin-1-yl, piperidin-1-yl or morpholino group)’ Rp is selected from hydrogen and fluoro; or Ro and Rp or Rp and Rp form an -OCH20- group; Or Ro, and Ry together with the ring to which they are attached form a 5 or 6 membered aryl or heteroaryl ring (wherein the heteroary ring contains 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur); one of Ro] and Rp is hydrogen and the other is Rg.

8. - A compound according to any. one of claims 1 to 7 wherein Cy is selected from phenyl, 2-chlorophenyl, 2-methoxyphenyl, 4-carbamoylphenyl, pyrid-2-yl, pyrid-4-yl, thien-2-yl, thien- 3-yl, furan-2-yl, furan-3-yl, imidazol-2-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl and guinolin-4-yl.

9S. A compound as claimed in any one of Claims 1 to 8, wherein Ry is a -CHReREf, -CH-CHRgRf OT -CH,-CHy -CHReRf group.

10. A compound as claimed in claim 9, wherein -CHReRf is 2- propyl, 3-pentyl, cyclopentyl, cyclohexyl, 4-methylcyclohexyl, tetrahydrothio-pyran-4-yl, pyrrolidin-3-yl, 1- methylpyrrolidin-3-yl, 1- (2-propyl)pyrrolidin-3-yl, piperidin- 4-yl, 1-methylpiperidin-4-yl, 1- (2-propyl)piperidin-4-yl or indan-2-yl.

11. A compound as claimed in claim 10, wherein Rr is 1- methylpiperidin-4-yl.

12. A compound as claimed in any one of Claims 1 to 11, in which the alpha atom in Y is carbon and has the conformation that would result from construction from a D-a-aminoacid NHo~-CH (Cy) ~COOH where the NHp represents part of X-X.

13. A compound as claimed in Claim 1, which is selected from: (Indole-6-carbonyl-D-phenylglycinyl) -4- [2- (4-pyridinyl)- ethyllpiperazine; AMENDED SHEET

® 181 PCT/GB01/02553 1- (3-Chloroindole-6-carbonyl-D-phenylglycinyl) - 4-[2- (4-pyridinyl)ethyllpiperazine; 1- (4-Methoxybenzoyl-D-phenylglycinyl) -4- (1-methylpiperidin-4- yvl)piperazine; 1- (Indole-6-carbonyl-D-phenylglycinyl) -4- (1-methylpiperidin-4- yl) piperazine; 1- (4-Methoxybenzoyl-D- (2-chlorophenyl)glycinyl)-4- (1-methyl- piperidin-4-yl) piperazine; 1- (Indole-6-carbonyl-D- (2-chlorophenyl) glycinyl)-4- (1-methyl- piperidin-4-yl) piperazine; and 1- (4-Methoxybenzoyl-D- (2-trifluoromethylphenyl)glycinyl)-4-(1- methylpiperidin-4-yl)piperazine; and physiologically-tolerable salts thereof.

14. A compound as claimed in Claim 13, which is 1-(indole-6- carbonyl-D-phenylglycinyl) -4- (1-methylpiperidin-4-yl) piperazine; or a physiologically tolerable salt thereof.

15. A pharmaceutical composition, which comprises a compound as claimed in any one of Claims 1 to 14 together with at least one pharmaceutically acceptable carrier or excipient.

16. A compound as claimed in any one of Claims 1 to 14, for use in therapy.

17. Use of a compound as claimed in any one of Claims 1 to 14 for the manufacture of a medicament for the treatment of a thrombotic disorder.

18. A substance or composition for use in a method of treatment of a human or non-human animal body to combat a thrombotic disorder, said substance or composition comprising a compound as claimed in claim 1, and said method comprising administering to said body an effective amount of said substance or composition.

19. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 14 for use to combat a thrombotic disorder. AMENDED SHEET

® PCT/GB01/02553

20. A compound of formula I as claimed in claim 1 and named in : any of the Examples herein, or a physiologically-tolerable salt thereof.

21. A compound of the formula Cy N v—( on. _/ NH 2 or a salt thereof, in which Cy is as defined in- Claim 1.

22. A compound as claimed in any one of claims 1 to 14 or 21, substantially as herein described and illustrated.

23. A composition as claimed in claim 15, or claim 19 substantially as herein described and illustrated.

24. Use as claimed in claim 17, substantially as herein described and illustrated.

25. A substance or composition for use in a method of treatment according to claim 18, substantially as herein described and illustrated.

26. A new compound, a new composition, a new use of a compound as claimed in any one of claims 1 to 14, or a substance or composition for a new use in a method of treatment, substantially as herein described. AMENDED SHEET