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  New amidino derivatives and their use as thrombin inhibitorsUSPTO Application #: 20070249578Title: New amidino derivatives and their use as thrombin inhibitors Abstract: wherein R1, Rx, Y, Ry, n and B have meanings given in the description which are useful as competitive inhibitors of trypsin-like proteases, such as thrombin, and in particular in the treatment of conditions where inhibition of thrombin is required (e.g. thrombosis) or as anticoagulants. There is provided compounds of formula I (end of abstract) Agent: Nixon & Vanderhye, PC - Arlington, VA, US Inventors: Tord Inghardt, Olle Karlsson, Marcel Linschoten, Jan-Erik Nystrom USPTO Applicaton #: 20070249578 - Class: 514210180 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai, Hetero Ring Is Four-membered And Includes At Least One Ring Nitrogen, Having -c(=x)-, Wherein X Is Chalcogen, Bonded Directly To The Four-membered Hetero Ring, Additional Hetero Ring Attached Directly Or Indirectly To The Four-membered Hetero Ring By Nonionic Bonding The Patent Description & Claims data below is from USPTO Patent Application 20070249578. Brief Patent Description - Full Patent Description - Patent Application Claims
FIELD OF THE INVENTION [0001] This invention relates to novel pharmaceutically useful compounds, in particular compounds that are, or are prodrugs of, competitive inhibitors of trypsin-like serine proteases, especially thrombin, their use as medicamnents, pharmaceutical compositions containing them and synthetic routes to their production. BACKGROUND [0002] Blood coagulation is the key process involved in both hemostasis (i.e. the prevention of blood loss from a damaged vessel) and thrombosis (i.e. the formation of a blood clot in a blood vessel, sometimes leading to vessel obstruction). [0003] Coagulation is the result of a complex series of enzymatic reactions. One of the ultimate steps in this series of reactions is the conversion of the proenzyme prothrombin to the active enzyme thrombin. [0004] Thrombin is known to play a central role in coagulation. It activates platelets, leading to platelet aggregation, converts fibrinogen into fibrin monomers, which polymerise spontaneously into fibrin polymers, and activates factor XIII, which in turn crosslinks the polymers to form insoluble fibrin. Furthermore, thrombin activates factor V and factor VIII leading to a "positive feedback" generation of thrombin from prothrombin. [0005] By inhibiting the aggregation of platelets and the formation and crosslinking of fibrin, effective inhibitors of thrombin would be expected to exhibit antithrombotic activity. In addition, antithrombotic activity would be expected to be enhanced by effective inhibition of the positive feedback mechanism. [0006] Further, it is known that administration of prodrugs of thrombin inhibitors may give rise to improvements in: [0007] (a) certain pharmacokinetic properties after administration of; and [0008] (b) the prevalence of certain side effects associated with, those inhibitors. PRIOR ART [0009] The early development of low molecular weight inhibitors of thrombin has been described by Claesson in Blood Coagul. Fibrinol. (1994) 5, 411. [0010] Blomback et al (in J. Clin. Lab. Invest. 24, suppl. 107, 59, (1969)) reported thrombin inhibitors based on the amino acid sequence situated around the cleavage site for the fibrinogen A.alpha. chain. Of the amino acid sequences discussed, these authors suggested the tripeptide sequence Phe-Val-Arg (P9-P2-P1, hereinafter referred to as the P3-P2-P1 sequence) would be the most effective inhibitor. [0011] Thrombin inhibitors based on dipeptidyl derivatives with an .alpha.,.omega.-aminoalkyl guanidine in the PI-position are known from U.S. Pat. No. 4,346,078 and International Patent Application WO 93/11152. Similar, structurally related, dipeptidyl derivatives have also been reported. For example International Patent Application WO 94/29336 discloses compounds with, for example, aminomethyl benzamidines, cyclic aminoalkyl amidines and cyclic aminoalkyl guanidines in the P1-position (International Patent Application WO 97/23499 discloses prodrugs of certain of these compounds); European Patent Application 0 649 780, discloses compounds with, for example, cyclic aminoalkyl guanidines in the P1-position. [0012] Thrombin inhibitors based on peptidyl derivatives, also having cyclic aminoalkyl guanidines (e.g. either 3- or 4-aminomethyl-1-amidinopiperidine) in the P1-position are known from European Patent Applications 0 468 231, 0 559 046 and 0 641 779. [0013] Thrombin inhibitors based on tripeptidyl derivatives with arginine aldehyde in the P1-position were first disclosed in European Patent Application 0 185 390. [0014] More recently, arginine aldehyde-based peptidyl derivatives, modified in the P3-position, have been reported. For example, International Patent Application WO 93/18060 discloses hydroxy acids, European Patent Application 0 526 877 des-amino acids, and European Patent Application 0 542 525 0-methyl mandelic acids in the P3-position. [0015] Inhibitors of serine proteases (e.g. thrombin) based on electrophilic ketones in the P1-position are also known. For example, European Patent Application 0 195 212 discloses peptidyl .alpha.-keto esters and amides, European Patent Application 0 362 002 fluoroalkylamide ketones, European Patent Application 0 364 344 .alpha.,.beta.,.delta.-triketocompounds, and European Patent Application 0 530 167 .alpha.-alkoxy ketone derivatives of arginine in the P1-position. [0016] Other, structurally different, inhibitors of trypsin-like serine proteases based on C-terminal boronic acid derivatives of arginine and isothiouronium analogues thereof are known from European Patent Application 0 293 881. [0017] More recently, thrombin inhibitors based on peptidyl derivatives have been disclosed in European Patent Application 0 669 317 and International Patent Applications WO 95/35309, WO 95/23609, WO 96/03374, WO 96/25426, WO 96/31504, WO 97/02284, WO 97/46577, WO 96/32110, WO 98/06740, WO 97/49404 and WO 98/57932. [0018] However, there remains a need for effective inhibitors of trypsin-like serine proteases, such as thrombin. There is a particular need for compounds which are both orally bioavailable and selective in inhibiting thrombin over other serine proteases. Compounds which exhibit competitive inhibitory activity towards thrombin would be expected to be especially useful as anticoagulants and therefore in the therapeutic treatment of thrombosis and related disorders. DISCLOSURE OF THE INVENTION [0019] According to the invention there is provided a compound of formula I, wherein R.sup.1 represents H, C.sub.1-4 alkyl (optionally substituted by one or more substituents selected from cyano, halo, OH, C(O)OR.sup.1a or C(O)N(R.sup.1b)R.sup.1c) or OR.sup.1d; R.sup.1d represents H, C(O)R.sup.11, SiR.sup.12R.sup.13R.sup.14 or C.sub.1-6 alkyl, which latter group is optionally substituted or terminated by one or more substituent selected from OR.sup.15 or (CH.sub.2).sub.qR.sup.16; R.sup.12, R.sup.13 and R.sup.14 independently represent H, phenyl or C.sub.1-6 alkyl; R.sup.16 represents C.sub.1-4 alkyl, phenyl, OH, C(O)OR.sup.17 or C(O)N(H)R.sup.18; R.sup.18 represents H, C.sub.1-4 alkyl or CH.sub.2C(O)OR.sup.19; R.sup.15 and R.sup.17 independently represent H, C.sub.1-6 alkyl or C.sub.1-3 alkylphenyl; R.sup.1a, R.sup.1b, R.sup.1c, R.sup.11 and R.sup.19 independently represent H or C.sub.1-4 alkyl; and q represents 0, 1 or 2; [0020] R.sub.x represents a structural fragment of formula IIa, IIb or IIc, wherein the dotted lines independently represent optional bonds; A and E independently represent O or S, CH or CH.sub.2 (as appropriate), or N or N(R.sup.21) (as appropriate); D represents --CH.sub.2--, O, S, N(R.sup.22), --(CH.sub.2).sub.2--, --CH.dbd.CH--, --CH.sub.2N(R.sup.22)--, --N(R.sup.22)CH.sub.2--, --CH.dbd.N--, --N.dbd.CH--, --CH.sub.2O--, --OCH.sub.2--, --CH.sub.2S-- or --SCH.sub.2--; X.sub.1 represents C.sub.2-4 alkylene; C.sub.2-3 alkylene interrupted by Z; --C(O)-Z-A.sup.1-; -Z-C(O)-A.sup.1-; --CH.sub.2--C(O)-A.sup.1-; -Z-C(O)-Z-A.sup.2-; --CH.sub.2-Z-C(O)-A.sup.2-; -Z-CH.sub.2--C(O)-A.sup.2-; -Z-CH.sub.2--S(O).sub.m-A.sup.2-; --C(O)-A.sup.3; -Z-A.sup.3-; or -A.sup.3-Z-; X.sub.2 represents C.sub.2-3 alkylene, --C(O)-A.sup.4- or -A.sup.4-C(O)--; X.sub.3 represents CH or N; X.sub.4 represents a single bond, O, S, C(O), N(R.sup.23), --CH(R.sup.23)--, --CH(R.sup.23)--CH(R.sup.24)-- or --C(R.sup.23).dbd.C(24); A.sup.1 represents a single bond or C.sub.1-2 alkylene; A.sup.2 represents a single bond or --CH.sub.2--; A.sup.3 represents C.sub.1-3 alkylene; A.sup.4 represents C(O) or C.sub.1-2 alkylene; Z represents, at each occurrence, O, S(O).sub.m or N(R.sup.25); R.sup.2 and R.sup.4 independently represent one or more optional substituents selected from C.sub.1-4 alkyl, C.sub.1-4 alkoxy (which latter two groups are optionally substituted by one or more halo substituent), methylenedioxy, halo, hydroxy, cyano, nitro, S(O).sub.2NH.sub.2, C(O)OR.sup.26, SR.sup.26, S(O)R.sup.26a, S(O).sub.2R.sup.26a or N(R.sup.27)R.sup.2s; R.sup.3 represents one or more optional substituents selected from OH, C.sub.1-4 alkoxy, C.sub.1-6 alkyl (optionally substituted by one or more halo group), or N(R.sup.29a)R.sup.29b; R.sup.25, R.sup.29a and R.sup.29b independently represent H, C.sub.1 alkyl or C(O)R.sup.30; R.sup.26 represents H or C.sub.1-4 alkyl; R.sup.26a represents C.sub.1-4 alkyl; R.sup.27 and R.sup.28 independently represent H, C.sub.1-4 alkyl or C(O)R.sup.30, or together represent C.sub.3-6 alkylene, thus forming a 4- to 7-membered ring, which ring is optionally substituted, on a carbon atom .alpha. to the nitrogen atom, with an .dbd.O group; R.sup.21, R.sup.22, R.sup.23, R.sup.24 and R.sup.30 independently represent, at each occurrence, H or C.sub.1-4 alkyl; Y represents CH.sub.2, (CH.sub.2).sub.2, CH.dbd.CH (which latter group is optionally substituted by C.sub.1-4 alkyl), (CH).sub.3, CH.sub.2CH.dbd.CH or CH.dbd.CHCH.sub.2 (which latter three groups are optionally substituted by C.sub.1-4 alkyl, methylene, .dbd.O or hydroxy); R.sup.y represents H or C.sub.1-4 alkyl; n represents 0, 1, 2, 3 or 4; and B represents a structural fragment of formula IIIa, IIIb or IIIc wherein X.sup.5, X.sup.6, X.sup.7 and X.sup.8 independently represent CH, N or N--O; X.sup.9 and X.sup.10 independently represent a single bond or CH.sub.2; R.sup.31 represents an optional substituent selected from halo, C.sub.1-4 alkyl (which group is optionally substituted by one or more halo group), N(R.sup.32)R.sup.33, OR.sup.34 or SR.sup.35; R.sup.32 and R.sup.33 independently represent H, C.sub.1-4 alkyl or C(O)R.sup.36; R.sup.34, R.sup.35 and R.sup.36 independently represent H or C.sub.1-4 alkyl; and one of D.sup.1 and D.sup.2 represents H, and the other represents H, OR.sup.a, NHR.sup.a, C(.dbd.X.sup.11)X.sup.12R.sup.b, or D.sup.1 and D.sup.2 together represent a structural fragment of formula IVa:-- R.sup.a represents H or -A.sup.5[X.sup.14].sub.n[C(O)].sub.rR.sup.e; R.sup.b represents -A.sup.5[X.sup.14].sub.n[C(O)].sub.rR.sup.e; A.sup.5 represents, at each occurrence, a single bond or C.sub.1-12 alkylene (which alkylene group is optionally interrupted by one or more O, S(O).sub.m and/or N(R.sup.f) group, and is optionally substituted by one or more of halo. OH, N(H)C(O)R.sup.g, C(O)N(R.sup.g)R.sup.h, C.sub.3-7-cycloalkyl (which cycloalkyl group is optionally interrupted by one or more O, S(O).sub.m and/or N(R.sup.f) group and/or is optionally substituted by one or more substituents selected from C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halo, .dbd.O or .dbd.S), Het and C.sub.6-10 aryl (which aryl and Het groups are themselves optionally substituted by one or more substituents selected from C.sub.1-6 alkyl (optionally substituted by one or more halo substituent), C.sub.1-6 alkoxy, halo, cyano, C(O)OR.sup.g, C(O)N(R.sup.g)R.sup.h and N(R.sup.f)R.sup.g)); R.sup.c and R.sup.d both represent H; or one of R.sup.c and R.sup.d represents H or C.sub.1-7 alkoxy and the other represents C.sub.1-7 alkyl (which alkyl group is optionally interrupted by one or more O atoms); or R.sup.c and R.sup.d together represent C.sub.3-8 cycloalkyl, which cycloalkyl group is interrupted by one or more O, S(O).sub.m and/or N(R.sup.f) group; R.sup.e represents, at each occurrence, H, C.sub.1-12 alkyl (which alkyl group is optionally interrupted by one or more O, S(O).sub.m and/or N(R.sup.f) group, and/or is optionally substituted by one or more substituents selected from halo, OH, N(H)C(O)R.sup.g and C(O)N(R.sup.g)R.sup.h), A.sup.7-C.sub.3-7-cycloalkyl (which cycloalkyl group is optionally interrupted by one or more O, S(O).sub.m and/or N(R.sup.f) group and/or is substituted by one or more substituents selected from C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halo, .dbd.O and .dbd.S), A.sup.7-C.sub.6-10 aryl or A.sup.7-Het (which aryl and Het groups are optionally substituted by one or more substituents selected from C.sub.1-- alkyl (optionally substituted by one or more halo substituent), C.sub.1-6 alkoxy, halo, cyano, C(O)OR.sup.g, C(O)N(R.sup.g)R.sup.h and N(R.sup.f)R.sup.g); A.sup.7 represents a single bond or C.sub.1-7 alkylene (which alkylene group is optionally interrupted by one or more O, S(O).sub.m and/or N(R.sup.f) group, and/or are optionally substituted by one or more of halo, OH, N(H)COR.sup.g and CON(R.sup.g)R.sup.h); Het represents, at each occurrence, a five- to ten-membered heteroaryl group, which may be aromatic in character, containing one or more nitrogen, oxygen or sulphur atoms in the ring system; n and r independently represent 0 or 1; X.sup.11, X.sup.12 and X.sup.14 independently represent O or S; X.sup.13 represents O or N(R.sup.f); R.sup.f represents, at each occurrence, H, C.sub.1-4 alkyl or C(O)R.sup.g; [0021] R.sup.g and R.sup.h independently represent, at each occurrence, H or C.sub.1-4 alkyl; and m represents, at each occurrence, 0, 1 or 2; Continue reading... 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