MXPA01008067A - Heterocyclic derivatives as inhibitors of factor xa - Google Patents

Abstract

The invention relates to heterocyclic derivatives, or pharmaceutically-acceptable salts thereof, of formula (I) wherein:A is an optionally substituted 5- or 6-membered monocyclic aromatic ring containing 1, 2 or 3 ring heteroatoms selected from oxygen, nitrogen and sulphur atoms;which possess antithrombotic and anticoagulant properties and are accordingly useful in methods of treatment of humans or animals. The invention also relates to processes for the preparation of the heterocyclic derivatives, to pharmaceutical compositions containing them and to their use in the manufacture of medicaments for use in the production of an antithrombotic or anticoagulant effect.

Description

HETEROCICLIC DERIVATIVES AS INHIBITORS OF THE XA FACTOR. DESCRIPTION OF THE INVENTION The invention relates to heterocyclic derivatives, or pharmaceutically acceptable salts thereof, which possess antithrombotic and anticoagulant properties and are consequently useful methods for the treatment of humans and animals. The invention also relates to processes for the preparation of heterocyclic derivatives, to pharmaceutical compositions containing them and to their use in the manufacture of medicaments for use in the production of an antithrombotic and anticoagulant effect. The antithrombotic and anticoagulant effect produced by the compounds of the invention is believed to be attributable to their strong inhibitory effect against the activated coagulation protease known as Factor Xa. Factor Xa is from a protease cascade involved in the complex process of blood coagulation. The protease known as thrombin is the final protease in the cascade and Factor Xa is the protease which preferably unfolds prothrombin to generate thrombin. Some compounds that possess inhibitory properties of Factor Xa are known and the field has been reviewed by R.B. Wallis, Current Opinion in Therapeutic Patents, 1993, 1173-1179. Thus it is known that two proteins, one known as antistatin and the other known as tick anticoagulant protein (TAP), are specific Factor Xa inhibitors that possess antithrombotic properties in various animal models of the thrombotic disease. It is known that some non-peptidic compounds have inhibitory properties of factor Xa. Of the low molecular weight inhibitors mentioned in the review by R.B. Wallis, all possess a strongly basic group such as an amidinophenyl or amidinonaphthyl group. It has been found that some heterocyclic derivatives have inhibitory activity of Factor Xa. Many of the compounds of the present invention also possess the advantage of being selective Factor Xa inhibitors, which is the Factor Xa enzyme is strongly inhibited at concentrations of the test compound which do not inhibit or inhibit to a lesser extent the thrombin enzyme that It is also a member of the enzymatic cascade of blood coagulation. The compounds of the present invention possess activity in the treatment or prevention of a variety of medical disorders wherein anticoagulant therapy is indicated, for example in the treatment or prevention of thrombotic conditions such as coronary artery disease and cerebrovascular disease. Additional examples of such medical disorders include various cardiovascular and cerebrovascular conditions such as myocardial infarction, the formation of atherosclerotic plaques, venous or arterial thrombosis, coagulation syndromes, vascular injury including reocclusion and restenosis after angioplasty and bypass surgery. the coronary artery, formation of thrombi after the application of operative techniques of the blood vessels or after general surgery such as hip replacement surgery, the introduction of artificial heart valves or in the recirculation of blood, cerebral infarction, cerebral thrombosis, attack, cerebral embolism, pulmonary embolism, ischemia and angina (which includes unstable angina). The compounds of the invention are also useful as inhibitors of blood coagulation in an ex vivo situation such as, for example, the storage of whole blood or other biological samples that are suspected to contain Factor Xa and in which coagulation It is harmful. Accordingly, an aspect of the present invention provides compounds of the formula I wherein: A is an optionally substituted 5 to 6 membered monocyclic aromatic ring containing 1, 2 or 3 ring heteoms selected from the oxygen, nitrogen and sulfur atoms; Bi, B2, B3 and B4 are independently CH or a nitrogen atom, wherein the ring formed of Bi, B2, B3 and B can be optionally substituted; with the proviso that at least one of Bi, B2, B3 and B4 is nitrogen; Ti is CH or N; T2 is CH or N; with the condition of at least one of Tx and T2 be N; Xi is SO, S02, C (R) 2 or CO when Ti is CH or N; or in addition Xi is 0 or S when Ti is CH; and wherein each R4 is independently hydrogen or (Cl-4) alkyl; Li is alkylene of (Cl-4) or alkylenecarbonyl of (Cl-3); R2 is hydrogen or alkyl of (Cl-4); R3 is hydrogen or alkyl of (Cl-4); or R2 and R3 join to form an alkylene of (Cl-4) or a group -CH2CO-; wherein the ring formed by Ti, R2, R3, T2 and Li is optionally substituted; X2 is S (0) and where y is one or two, C (R5) 2 or CO; and each R5 is independently hydrogen or (Cl-4) alkyl; Y is selected from hydrogen, halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, amino, nitro, carboxy, carbamoyl, alkyl of (Cl-4), alkenyl of (C 2-4), alkynyl of (C 2-4), alkoxy of (Cl-4), alkenyloxy (C 2-4), alkynyloxy of (C 2-4), alkylthio of (Cl-4), alkylsulfinyl of (Cl-4), alkylsulfonyl of (Cl-4), alkylamino of (Cl-) 4); dialkylamino of (Cl-4); alkoxycarbonyl of (Cl-4), N-alkylcarba oyl of (Cl-4), N, N-di-alkylcarbamoyl of (Cl-4), alkanoyl of (C2-4), alkanoylamino of (C2-4), hydroxyalkyl of (Cl-4), (Cl-4) alkoxy-alkyl of (Cl-4), carboxyalkyl of (Cl-4), alkoxycarbonyl of (Cl-4) -alkyl of (Cl-4), carbamoylalkyl of ( Cl-4), N-alkylcarbamoyl * of (Cl-4) -alkyl of (Cl-4) and N, N-di-alkylcarbamoyl of (Cl-4) -alkyl of (Cl-4); n is 1 or 2; and B5 and B6 are selected from N or CH; with the proviso that at least one of B5 and B6 is N; and pharmaceutically acceptable salts thereof. In this specification the term "alkyl" includes straight and branched chain alkyl groups but references to individual alkyl groups such as "propyl" are specific to the linear string version only. A similar convention applies to other generic terms. It is to be understood that some heterocyclic derivatives of the present invention may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It should be understood that the invention encompasses all of such solvated forms that possess Factor Xa inhibitory activity. It should further be understood that, with respect to some of the compounds of the formula defined above may exist in optically active or racemic forms by virtue of one or more asymmetric carbon atoms, the invention encompasses any optically active or racemic form possessing inhibitory activity of the Factor Xa. The synthesis of the optically active forms can be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis of optically active starting materials or by resolution of a racemic form. Preferably A is a pyridyl, pyrimidinyl or pyridazinyl ring, for example 4-pyridyl, 2-pyridyl, 4-pyridazinyl, 3-pyrimidinyl, 4-pyrimidinyl or 3-pyridyl. Of these, 4-pyrimidinyl, 4-pyrazinyl and 4-pyridyl are preferred, with 4-pyrimidinyl and 4-pyridyl being the most preferred. In an aspect A is unsubstituted. In another aspect A is substituted by one, two or three atoms or groups selected from halo (for example fluoro, chloro or bromo), trifluoromethyl, cyano, amino, oxo, hydroxy, nitro, alkyl (Cl-4) (for example, methyl or ethyl), (Cl-4) alkoxy (for example methoxy or ethoxy), alkylamino of (Cl-4) (for example methylamino or ethylamino) or dialkylamino of (Cl-4) (for example dimethylamino or diethylamino). To avoid doubt the substituents can also be in any heteroatom. Preferably, the ring formed by Bi, B2, B3 and B4 is a pyridinediyl, wherein Bi or B3 is a nitrogen atom, pyrimidindiyl, wherein Bi and B2 or B3 and B4 are nitrogen atoms, pyridazindiyl, wherein Bi, B3 and B4 or Bi, B2 and B3 are hydrogen atoms. nitrogen. Of these, pyridindiyl and pyrimidindiyl are preferred, and pyrimidindiyl is most preferred. In one aspect the ring containing Bi, B2, B3 and B4 is unsubstituted. In another aspect the ring containing Bi, B2, B3 and B is substituted by one or two substituents selected from the hydroxy, carboxy, alkoxycarbonyl of (Cl-4) or one of the following; - (CH2) n -R, - (CH2) n -NRRi, -CO-R, -CO-NRRx, - (CH2) n -CO-R and (CH2) n -CO-NRR ?; where n is 1 or 2; R and Ri are independently selected from hydrogen, alkyl of (Cl-4), alkenyl of (C 2-4), alkynyl of (C 2-4), hydroxyalkyl of (Cl-4), carboxyalkyl of (Cl-4), and alkoxycarbonyl of (Cl-4) -alkyl of (Cl-4) or where possible R and Ri may together form an optionally substituted 5- or 6-membered heterocyclic ring which may include in addition to the nitrogen atom to which R and R are attached. Ri 1 or 2 additional heteroatoms selected from nitrogen, oxygen and sulfur. In a particular aspect the heterocyclic rings formed by R and Ri are preferably selected from pyrrolidin-1-yl, imidazolin-1-yl, piperidin-1-yl, piperazin-1-yl, 4-morpholino and 4-thiomorpholino. In a particular aspect the heterocyclic ring formed by R and Ri may be unsubstituted. In an alternative aspect the ring formed by R and Rx is substituted by 1 or 2 substituents selected from oxo, hydroxy and carboxy. In a particular aspect, when Ti is CH or N, Xi is CO, S02, or CH2 or, when Ti is CH, Xi is also O or S. Preferably Xi is CO. Ti is CH or N and T2 is CH or N with the proviso that at least one of Tx and T2 is N. To avoid doubt Tx joins directly to the groups Xi and Li and T2 joins directly to the groups Li and X2 Li is alkylene of (Cl-4) for example methylene, ethylene or propylene or is C 1 -3 alkylenecarbonyl for example ethylenecarbonyl (-CH 2 CO-), preferably Li is ethylene. In one aspect R2 is hydrogen or (Cl-4) alkyl for example methyl or ethyl. In one aspect R 3 is hydrogen or C 1 alkyl - for example methyl or ethyl. In a preferred aspect R2 and R3, join to form an alkylene group of (Cl-4), for example a methylene, ethylene or propylene group or a methylenecarbonyl group (-CH 2 CO-), preferably ethylene. In a particular aspect R2 and R3 join to form, together with Ti, T2 and Li, a heterocyclic ring wherein at least one of Ti and T2 is N. Examples of such heterocyclic rings are piperazine (wherein Ti and T2 are N). ), piperidine (where Ti or T2 is N and the other is CH) and pyrrolidine (where Ti or T2 is N and the other is CH). In one aspect the heterocyclic ring formed by Ti, T2 and Li, R2 and R3 are unsubstituted. In another aspect this ring is substituted by one or two substituents selected from hydroxy, oxo, carboxy, alkoxycarbonyl of (Cl-4) or one of the following; - (CH2) n -R, - (CH2) n -NRR ?, -CO-R, -CO-NRRi, - (CH2) n-CO-R and - (CH2) n-CO-NRR ?; where n is 1 or 2; R and Ri are independently selected from hydrogen, alkyl of (Cl-4), alkenyl of (C 2-4), alkynyl of (C 2-4), hydroxyalkyl of (Cl-4), carboxyalkyl of (Cl-4), and alkoxycarbonyl of (Cl-4) -alkyl of (Cl-4) or where possible R and Ri can together form an optionally substituted 5- or 6-membered heterocyclic ring which can include in addition to the nitrogen atom to which R and Ri are attached 1 or 2 additional heteroatoms selected from nitrogen, oxygen and sulfur. In a particular aspect the heterocyclic rings formed by R and Rx are preferably selected from pyrrolidin-1-yl, imidazolin-1-yl, piperidin-1-yl, piperazin-1-yl, 4-morpholino and 4-thiomorpholino. In a particular aspect the heterocyclic ring formed by R and Ri may be unsubstituted. In an alternative aspect the ring formed by R and Rx is substituted by 1 or 2 substituents selected from oxo, hydroxy, carboxy and alkyl of (Cl-4), preferably oxo, hydroxy and carboxy. In a particular aspect X2 is S02, CH2 or CO. Preferably X2 is S02. In a preferred aspect Y is selected from hydrogen, halo (bromo or chloro), trifluoromethyl, trifluoromethoxy, cyano, hydroxy, amino, nitro, carboxy, carbamoyl, alkyl of (Cl-4), alkenyl of (C 2-4), alkynyl of (C2-4), alkoxy (Cl-4), alkenyloxy of (C2-4), alkynyloxy of (C2-4), alkylthio of (Cl-4), alkylsulfinyl of (Cl-4), alkylsulfonyl of (1) -4), alkylamino of (1-4), dialkylamino of (Cl-4) and alkoxycarbonyl of (Cl-4). Suitable values for the Y substituents are: for halo: fluoro, chloro, bromo; for (Cl-4) alkyl: methyl, ethyl, propyl, butyl; for (Cl-4) alkoxy: methoxy; ethoxy; for alkylamino of (Cl-4): methylamino, ethylamino; for dialkylamino of (Cl-4): dimethylamino, diethylamino for alkenyl of (C 2-4): vinyl and allyl; for (C2-4) alkynyl: ethynyl and prop-2-ynyl; for (C 2-4) alkenyloxy: vinyloxy and allyloxy; for (C 2-4) alkynyloxy: ethynyloxy and prop-2-ynyloxy; for alkylthio of (Cl-4): methylthio, ethylthio and propylthio; for alkylsulfinyl of (Cl-4) methylsulfinyl, ethylsulfinyl and propylsulfinyl; for alkylsulfonyl of (Cl-4) methylsulfonyl, ethylsulphonyl and propylsulfonyl; for (C 2-4) alkanoylamino acetamido, propionamido and butyramido; for (Cl-4) alkoxycarbonyl methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and tert-butoxycarbonyl; for N-alkylcarbamoyl of (Cl-4) N-methylcarbamoyl, N-ethylcarbamoyl and N-propylcarbamoyl; for N, N-dialkylcarbamoyl of (Cl-4) N, N-dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl N, N-diethylcarbamoyl; for (C2-4) alkanoyl, acetyl, propionyl and butyryl; for hydroxyalkyl (Cl-4] hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl and 3-hydroxypropyl; for (Cl-4) alkoxy-alkyl (Cl-) 4): methoxymethyl, ethoxymethyl, 1-methoxymethyl, 2-methoxyethyl, 2-ethoxyethyl and 3-methoxypropyl, for carboxyalkyl of (Cl-4) carboxymethyl, 1-carboxyethyl, 2-carboxyethyl and 3-carboxypropyl, for alkoxycarbonyl of (Cl -4) -alkyl (Cl-4) ethoxycarbonylmethyl, ethoxycarbonylmethyl, tert-butoxycarbonylmethyl, 1-methoxycarbonylethyl, 1-ethoxycarbonylethyl, 2-methoxycarbonylethyl, 2-ethoxycarbonylethyl, 3-methoxycarbonylpropyl and 3-ethoxycarbonylpropyl, for carbamoylalkyl (Cl-4) ) Carbamoylmethyl, 1-carbamoylethyl, 2-carbamoylethyl and 3-carbamoylpropyl, for N-alkylcarbamoyl of (Cl-4) -alkyl of (Cl-4): N-methylcarbamoylmethyl, N-ethylcarbamoylmethyl, N-propylcarbamoylmethyl, 1- (N -methylcarbamoyl) ethyl, 1- (N-ethylcarbamoyl) ethyl, 2- (N-methylcarbamoyl) ethyl, 2- (N-ethylcar bamoyl) ethyl and 3- (N-methylcarbamoyl) -propyl; for N, N-di- [(Cl-4) alkyl] -carba-oyl-alkyl (Cl-4): N, N-dimethylcarbamoylmethyl, N-ethyl-N-methylcarbamoylmethyl, N, N- diethylcarbamoylmethyl, 1- (N, N-dimethylcarbamoyl) ethyl, 1- (N, N-diethylcarbamoyl) -ethyl, 2- (N, N-dimethylcarbamoyl) ethyl, 2- (N, N-diethylcarbamoyl) ) ethyl and 3- (N, N-dimethylcarbamoyl) -propyl; A preferred class of compounds of the present invention is that wherein: A is 4-pyridyl, 4-pyrimidinyl or 4-pyridazinyl; Bi to 4 forms a pyridindiyl, pyrimidindiyl or pyridazindiyl; Xi is CO, S02 or CH2, ideally CO; Ti and T2 are N; Li is ethylene or propylene; R2 and R3 are joined to form an ethylene or propylene or methylenecarbonyl group; wherein the heterocyclic ring formed by Ti, T2, Li, R2 and R3 is unsubstituted or substituted; X2 is S02; B5 or B6 is N: n is 1 at position 5; Y is halo, preferably bromine or chlorine; and pharmaceutically acceptable salts thereof. A particular compound of the invention is: 1- (5-chloroindol-2-ylsulfonyl) -4- [6- (4-pyridyl) -nicotinoyl] piperazine; and 1- (5-bromoindol-2-ylsulfonyl-4- [6 [4-pyridyl) nicotinoyl] piperazine. The compounds of formula I, or pharmaceutically acceptable salts thereof, can be prepared by any process known to be applicable to the preparation of related compounds. Such procedures are provided as a further feature of the invention and are illustrated by the following representative processes in which, unless otherwise indicated A, Bx, B2, B3, B4, Xl f Ti, T2, Ll f R2, R3, X2, B5, B6, Y and n have any of the meanings defined above wherein any functional group, eg, amino, alkylamino, carboxy or hydroxy, is optionally protected by a protecting group that can be removed when necessary. The necessary initial materials can be obtained by standard procedures of organic chemistry. According to another aspect, the present invention provides a process for preparing a compound of the formula I or a pharmaceutically acceptable salt thereof, comprising: (a) For the production of compounds of the formula (I) wherein Ti is N and Xi is CO, by the reaction, conveniently in the presence on a suitable base, of an amine with an acid or a reactive derivative of the acid. A suitable reactive derivative of the acid, for example, an acyl halide, an anhydride, an activated amide, an active ester or the product of the reaction of the acid and a carbodiimide such as N, N-dicyclohexylcarbodiimidia or N- (3-dimethylaminopropyl) ) -N'-ethyl carbodiimide. The reaction is conveniently carried out in the presence of a suitable base such as, for example, an alkali or alkaline earth metal carbonate, alkoxide, hydroxide or hydride, for example sodium carbonate, potassium carbonate, sodium ethoxide, butoxide potassium, sodium hydroxide, potassium hydroxide, sodium hydride or potassium hydride, or a lithium dialkylamino, for example lithium di-isopropylamide, or, for example, an organic, basic amine such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine or diazabicyclo [5.4.0] undec-7-ene. The reaction is also preferably carried out in a suitable inert solvent or diluent, for example methylene chloride, chloroform, carbon tetrachloride, tetrahydrofuran, 1,2-dimethoxyethane, N, N-dimethylformamide, N, N-dimethylacetamide, N- methylpyrrolidin-2-one, dimethylsulfoxide or acetone, and at a temperature in the range of, for example -78 ° to 150 ° C, conveniently at or near room temperature. (b) For the production of those compounds of the formula (I) wherein Ti is CH and Xi is 0, by the reaction, conveniently in the presence of a suitable coupling agent; A suitable value for the displaceable group Z is, for example, a halogen or sulphonyloxy group, for example a fluoro, chloro, bromo, mesyloxy or 4-tolylsulfonyloxy group. A suitable reagent for the reaction and coupling when Z is a halogen or sulfonyloxy group, is for example as a suitable base, for example an alkali or alkaline earth metal carbonate, hydroxide or hydride, for example sodium carbonate, hydroxide or hydride, for example Examples are sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride or potassium hydride. The alkylation reaction is preferably carried out in a suitable inert solvent or diluent, for example N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, 1, 2-dimethoxyethane acetone. or tetrahydrofuran, and at a temperature in the range, for example, -10 ° to 150 ° C, conveniently at or near room temperature. An analogous process can be used for the preparation of those compounds of the formula (I) wherein Ti is CH and Xi is a group of the formula S. A suitable reagent for the coupling reaction of the alcohol, wherein Z is a hydroxy group , wherein the hydroxy group is converted in situ to a displaceable group as defined above, is, for example, the reagent obtained when the alcohol is reacted with a dialkyl of (Cl-4) azodicarboxylate in the presence of a triarylphosphine or trialkylphosphine of (Cl-4), for example with diethyl azodicarboxylate in the presence of triphenylphosphine or tributylphosphine. The reaction is preferably carried out in a suitable inert solvent or diluent, for example acetone, 1,2-dimethoxyethane or tetrahydrofuran, and at a temperature in the range, for example, 10 ° to 80 ° C, conveniently at or near the temperature ambient. (c) For the production of those compounds of the formula (I) wherein Ti is N and Xi is CH (R4), the reductive amination of a subsequent keto compound: with an amine as defined in (a) above.

A suitable reducing agent is, for example, a hydride reducing agent, for example an aluminum and alkali metal hydride such as an aluminum-lithium hydride or, preferably, an alkali metal borohydride such as sodium borohydride, sodium cyanoborohydride, triethylborohydride of sodium, sodium trimethoxyborohydride and sodium triacetoxyborohydride. The reaction is conveniently carried out in a suitable inert solvent or diluent, for example tetrahydrofuran and diethyl ether for the stronger reducing agents such as lithium aluminum hydride, and, for example, methylene chloride or a protic solvent such as methanol and ethanol for the less strong reducing agents such as sodium triacetoxyborohydride. The reaction is carried out at a temperature in the range of, for example, 10 ° to 80 ° C, conveniently at or near room temperature. (d) For the reaction of: Z ~? Hxrtíry-LrtíRj-xj- ¿1 -? (N) wherein Z is a displaceable group such as halo, with an activated derivative of heterocyclic ring A. Suitable activated derivatives include metallized derivatives, such as with zinc or tin, and borane derivatives. The activated derivative of the heterocyclic ring A is reacted with the above compound to effect cross-coupling where Z is a halo group, such as iodine, bromine or chlorine and triflate. The reaction is suitably catalyzed by the use of a metal catalyst of the transition state, such as palladium, for example tetrakis (triphenylphosphine) palladium (0). Alternatively it is possible for ring A to contain the displaceable group Z and the ring containing Bx to B4 to be activated, as described above. The reaction not suitable for compounds containing halo substituents on A, B, or L. (e) Forming a ring A on the above compound (d), wherein Z is a functional group capable of cyclization. Suitable reagents and conditions are described in Bredereck H. Chem. Ber .; 96, 1505, (1963); Fuchigami, T., Bull. Chem. Soc. Jpn., 49, p3607, (1976); Huffman, K.R., J. Org. Chem., 28, pl812, (1963); Palusso, G., Gazz. Chim. Ital., 90, pl290, (1960) and Ains orth C.J., Heterocycl. Chem., 3, p470, (1966). Suitable processes for the synthesis of the starting materials in such cyclization reactions are described in Zhang M. Q. et. to the; J. Heterocyclic. Chem ,; 28, 673, (1991) and Kosugi, M. et al., Bull. Chem. Soc. Jpn., 60, 767-768 (1987). (f) For the production of compounds where T2 is N, by the reaction: wherein Z is a displaceable group for example, chlorine, under conditions similar to those of variant (a) of the previous process. (g) For the production of compounds where Ti is N and Xi is SO or S02, by the reaction: where x is one or two and Z is a displaceable group; under appropriate conventional coupling conditions, similar to those of the variant (a) of the previous process. (h) Coupling the heteroaryl group to T2 with methods analogous to those described in variants (a), (c) and (f) of the process for preparing the B-X1-T1- portion can be employed. (i) For the production of compounds of the formula (I) wherein Xi is a group of the formula SO, S02, wherein the ring containing Bi to B4 carries a 1-oxothiomorpholino or 1, 1-dioxothiomorpholino group or a substituent containing an alkylsulfinyl group of (Cl-4) ', alkylsulfonyl of (Cl-4), 1-oxothiomorpholino or 1,1-dioxothiomorpholino, wherein X 2 is a group of the formula SO or S02 wherein Q carries a group alkylsulfinyl of (Cl-4), alkylsulfonyl of (Cl-4), phenylsulfinyl, phenylsulfonyl, heteroarylsulfinyl or heteroarylsulfonyl, the oxidation of the corresponding compound of the formula I wherein Xi, X2, or Xi and X2 is S. A suitable oxidizing agent is, for example, any agent known in the art for the oxidation of thio to sulfinyl and / or sulfonyl, for example, hydrogen peroxide, a peracid (such as 3-chloroperoxybenzoic acid or peroxyacetic acid), an alkali metal peroxysulfate (such as potassium peroxymonosulfate), chromium trioxide or gaseous oxygen in the presence of platinum. Oxidation is generally carried out under as moderate conditions as possible and with the required stoichiometric amount of the oxidizing agent to reduce the risk of over oxidation and damage to other functional groups. In general, the reaction is carried out in a suitable solvent or diluent such as methylene chloride, chloroform, acetone, tetrahydrofuran or methyl-tert-butyl ether and at a temperature of, for example, at or near room temperature, this is in the range from 15 to 35 ° C. Reagents and suitable conditions are described in, for example, Page G. O.; Synth Commun. 23, 1993) 6, 765-769. When a compound carrying a sulfinyl group is required, a moderate oxidizing agent, for example sodium or potassium metaperiodate, may also be conveniently used in a polar solvent such as acetic acid or ethanol. It will be appreciated that when a compound of the formula I which contains a sulfonyl group is required, it can be obtained by oxidation of the corresponding sulfinyl compound as well as the corresponding thio compound. Those compounds of formula I containing oxygen-unstable groups (such as ring A is pyridyl) are probably not suitable intermediates for this step of the process, unless oxidation of such groups is desired. When a pharmaceutically acceptable salt of a compound of formula I is required, it can be obtained, for example, by reacting the compound with a suitable base acid using a conventional procedure. When an optically active form of a compound of formula I is required, it may be obtained, for example, by carrying out one of the above procedures using an optically active starting material or by resolution of a racemic form of the compound using a conventional procedure, by example by the formation of diastereomeric salts, use of chromatographic techniques, conversion using chirally specific enzymatic processes, or by the addition of a temporary extra chiral group to aid in separation. As previously stated, the compounds of the formula I are inhibitors of the Factor Xa enzyme. The effects of this inhibition can be demonstrated using one or more of the standard procedures indicated below: a) Measurement of Factor Xa Inhibition. An in vitro test system is carried out based on the method of Kettner et al, J. Biol. Chem., 1990, 265, 18289-18297, whereby various concentrations of a test compound are dissolved in a regulator of pH 7.5 containing 0.5% of a polyethylene glycol (PEG 6000) and incubated at 37 ° C with a human Factor Xa (0.001 Units / ml, 0.3 ml) for 15 minutes. The chromogenic substrate S-2765 (KabiVitrum AB, 20 μM) is added and the mixture is incubated at 37 ° C for 20 minutes while the absorbance at 405 nm is measured. The maximum reaction rate (V ax) is determined and compared with that of a control sample that does not contain test compound. The potency of the inhibitor is expressed as a value ICso-b) Measurement of Thrombin Inhibition. The procedure and method a) is repeated except that it is employed in the human tombrin (0.005 Units / ml) and the chromogenic substrate S-2238 (KabiVitrum AB, 7 μM). c) Measurement of the Anticoagulant Activity. An in vitro test by means of which rat or rabbit venous blood is collected and added directly to a solution of sodium citrate (3.2 g / 100 ml, 9 parts of blood per one part of citrate solution). Blood plasma is prepared by centrifugation (1000 g, 15 minutes) and stored at 2-4 ° C. Conventional prothrombrine time (PT) tests are carried out in the presence of various concentrations of a test compound and the concentration of the test compound required to double the coagulation time, hereinafter referred to as CT2, is determined. In the PT test, the test compound and blood plasma are incubated at 37 ° C for 10 minutes. Calcium tissue tomboplastin is added (Sigma Limited, Poole, England) and the fibrin formation and the time required to form a clot are determined. d) An Ex vivo test of anticoagulant activity. The test compound is administered intravenously or orally to a group of Alderley Park Wistar rats. On several occasions afterwards the animals were anesthetized, the blood was collected and the coagulation tests PT analogous to those described in the above were conducted. e) An in vivo Measurement of Antithrombotic Activity. Thrombus formation is induced using a method analogous to that described by Vogel et al., Thromb. Research, 1989, 54, 399-410. A group of Alderley Park Wistar rats is anesthetized and surgery is performed to expose the vena cava.

The collateral veins are joined and two loose sutures are located, 0.7 cm apart, around the inferior vena cava. The test compound is administered intravenously or orally. At an appropriate time thereafter, thromboplastin tissue (30 μl / kg) is administered via the jugular vein and, after 10 seconds, the two sutures are tightened to induce stasis within the ligated portion of the vena cava. After 10 minutes the ligated tissue is cut and the thrombi are isolated therein they are isolated they stain and weigh. (f) In vivo Activity Test of Disseminated Intravascular Coagulation in Rat. Alderley Park male fasting rat (300-450g) are pre-dosed by oral forced feeding (5 mls / kg) with compound or vehicle (5% DMSO / PEG200) at various times before being anesthetized with Intraval® (120 mg / kg) ip). The left jugular vein and the right carotid artery are exposed and cannulated. A blood sample of 1 mL of the carotid cannula is taken in 3.2% trisodium citrate. 0.5 mL of the whole blood is then treated with EDTA and used to determine the platelet count while the remainder is centrifuged to (5 minutes, 20000g) and the resulting plasma is frozen for subsequent determinations of the drug level, fibrinogen complex or thrombin antithrombin (TAT). The recombinant human tissue factor (Dade Innovin Cat. B4212-50), reconstituted according to the manufacturer's specification, (2 mL / kg / hr) is infused into the cannular vein for 60 minutes. Immediately after the infusion is stopped a blood sample of 2 mL is taken and the platelet count, drug level, plasma fibrinogen concentration and TAT complex as above are determined. The platelet count is performed using a Coulter T540 blood analyzer. Plasma fibrinogen and TAT levels are determined using a coagulation test (Sigma Cat.880-B) and TAT ELISA (Behring) respectively. The plasma concentration of the bioassay compound using a human Factor Xa and a chromogenic substrate S2765 (Kabi), extrapolated from a standard curve (Fragmin) and is expressed in anti-Factor Xa units. The data is analyzed as follows; the reductions induced by the tissue factor in the platelet count is normalized with respect to the pre-dose platelet count and the activity of the drug is expressed as a percentage of inhibition of thrombocytopenia induced by tissue factor when compared to treated animals with vehicles. The compounds are active if there is statistically significant inhibition (p <0.05) of thrombocytopenia induced by TF. The example had an IC5o (Factor Xa) of 0.007 μM as measured in test a). According to a further feature of the invention, there is provided a pharmaceutical composition comprising a heterocyclic derivative of the formula I, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier. The composition may be in a form suitable for oral use, for example a tablet, capsule, aqueous or oily solution, suspension or emulsion; for local use, for example a cream, ointment, gel or aqueous or oily solution or suspension; for nasal use, for example an inhalant, nasal spray or nasal drops; for vaginal or rectal use, for example a suppository; for administration by inhalation, for example as a finely divided powder such as a dry powder, a microcrystalline form or a liquid aerosol; for sub-lingual or buccal use, for example a tablet or capsule; or for parenteral use (including intravenous, subcutaneous, intramuscular, intravascular or infusion), for example a sterile aqueous or oily solution or suspension. In general, the above compositions can be prepared in a conventional manner using conventional excipients. The amount of active ingredient (which is a heterocyclic derivative of formula I or a pharmaceutically acceptable salt thereof) that is combined with one or more excipients to produce an individual dosage form will necessarily vary depending on the host treated and the particular route of administration. . For example, a formulation intended for oral administration to humans will generally contain, for example, 0.5 mg to 2 g of the active agent compound with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 weight percent of the total composition . The unit dosage forms will generally contain about 1 mg to about 500 mg of an active ingredient. According to a further feature of the invention there is provided the use of a heterocyclic derivative of the formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in a method of treating the human or animal body by therapy. The invention also includes the use of such an active ingredient in the production of a medicament for use in: - (i) producing an inhibitory effect on Factor Xa; (ii) produce an anticoagulant effect; (iii) produce an antithrombotic effect; (iv) treating a disease or medical condition medi by Factor Xa; (v) treating a disease or medical condition medi by thrombosis: (vi) treating coagulation disorders; and / or (vii) treating thrombosis or embolism that involves coagulation medi by Factor Xa.

The invention also includes a method for producing an effect as defined above or treating a disease or disorder as defined above which comprises administering to a warm-blooded animal that requires such treatment an effective amount of an active ingredient as defined above. The size of the dose for therapeutic or prophylactic purposes of a compound of formula I will naturally vary according to the nature and severity of the medical condition, the age and sex of the animal or patient being treated and the route of administration, according to principles well-known in medicine. As mentioned above, the compounds of the formula I are useful in the treatment or prevention of a variety of medical disorders in which anticoagulant therapy is indicated. To use a compound of formula I for such a purpose it will generally be administered so that a daily dose is received in the range, for example, from 0.5 to 500 mg / kg of body weight, given if required in divided doses. In general, lower doses will be administered when a parenteral route is used, for example, a dose for intravenous administration in the range, for example, 0.5 to 50 mg / kg body weight will generally be used. For the preferred and especially preferred compounds of the invention, in general, lower doses will be employed, for example a daily dose in the range, for example, from 0.5 to 10 mg / kg of body weight. Although the compounds of formula I are primarily of value as therapeutic or prophylactic agents for use in warm-blooded animals including man, they are also useful when required to produce an anticoagulant effect, for example during the ex vivo storage of whole blood or in the development of biological tests for compounds that have anticoagulant properties. The compounds of the invention can be administered as a single therapy or can be administered together with other pharmacologically active agents such as a thrombolytic agent, for example plasminogen activator in tissue or derivatives thereof or streptokinase. The compounds of the invention can also be administered with, for example, a known platelet aggregation inhibitor (for example aspirin, a thromboxane antagonist or a thromboxane-tapesa inhibitor), a known hypolipidemic agent or a known anti-hypertensive agent. The invention will now be illustrated in the following examples, unless otherwise indicated: - (i) the evaporations were carried out by rotary vacuum evaporation and the work-up procedures were carried out after the removal of the residual solids by filtration; (ii) the operations were carried out at room temperature, that is in the range of 18-25 ° C and under an atmosphere of an inert gas such as argon; (iii) the final products of formula I have satisfactory microanalyses and their structures were confirmed by nuclear magnetic resonance techniques (NMR) and mass spectrum. The values of chemical change were measured in the delta scale; the following abbreviations have been used: s, simple; d, doublet; t, triplet; q, quartet; m, manifold; (iv) the intermediates were generally not completely characterized and the purity was assessed by thin layer chromatography, infrared (IR) or NMR analysis; and (v) the melting points were determined using a Mettler SP62 automatic melting point apparatus or an oil bath apparatus; the melting points for the final products of the formula I were generally determined after crystallization from a conventional organic solvent such as ethanol, methanol, acetone, ether or hexane, alone or as a mixture. Example 1 1- (5-Chloroindol-2-ylsulfonyl) -4- [6- (4-pyridyl) nicotinoyl] piperazine A stirred suspension of 6- (4-pyridyl) nicotinic acid ((400 mg, 2 mmol) in dimethylformamide DMF (10 ml) was treated with 1- (5-chloroindol-2-ylsulfonyl) piperazine (600 mg, 2 mmoles, 1 mol eq. ) and l- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDAC, 460 mg, 2.4 mmol, 1.2 mol eq.). After stirring overnight the solvent was removed in vacuo and the residue taken to chromatography (cartridge of 20 g of Isolute silica eluting with dichloromethane containing 2.5% -5% v / v methanol) to produce 1- (5-chloroindole -2-ylsulfonyl) -4- [6- (4-pyridyl) -nicotinoyl] piperazine as a colorless foam (680 mg). This was dissolved in a dichloromethane / methanol mixture (40 ml of 1: 1) and treated with a saturated solution of HCl in methanol until acid gave the indicator paper (slight excess). The resulting solution of hydrochloride salt was evaporated to dryness and the residue was boiled in 2-propanol (100 ml, incomplete solution). Filtration and cooling gave 1- (5-chloroindol-2-ylsulfonyl) -4- [6- (4-pyridyl) nicotinoyl] piperazine hydrochloride as a colorless solid, (220 mg ^ H NMR (d6DMSO) 3.0-3.3 (broad d, 4H), 3.6-4.0 (broad d, 4H), 7.05 (s, 1H), 7.35 (dd, 1H), 7.5 (d, 1H), 7.8 (d, 1H), 8.1 (dd, 1H) ), 8.35 (d, 1H), 8.5 (m, 2H), 8.8 (d, 1H), 8.95 (d, 2H), 12.4 (s, 1H), the signals were also present due to 2-propanol (0.5 mol equiv.) MS (M + H) + 481/483; mp 186-190 ° C (not acute) The starting material of requisite 6- (4-pyridyl) nicotinic acid was prepared as follows: A solution of 1- [6- (4-pyridyl) 3-pyridyl] 4- (tert-butyloxycarbonyl) -piperazine (3.7 g, 10 mmol) and potassium carbonate (6.9 g, 50 mmol) in methanol / water (90 ml of a 2: 1 mixture) (30 ml) was heated to reflux for 7 hours. It was then cooled and neutralized with dilute HCl (50 ml of 2M), and some of the solvent was removed in vacuo. More water was added and the resulting suspension allowed to remain for 2 hours. Filtering, washing with water and drying gave the above starting material (870 mg) which was used without further purification, XH NMR (d6-DMSO), 8.1 (d, 2H), 8.25 (d, 1H), 8.45 (dd) , 1H), 8.75 (d, 2H), 9.2 (d, 1H), MS (M + H) + 201, (MH) "199. Prepared from 1- [6- (4-pyridyl) 3-pyridyl] -4- (tert-Butyloxycarbonyl) -piperazine as shown in Example 1 of PCT / GB98 / 02210. 1- (5-Chloroindol-2-ylsulfonyl) piperazine was prepared as shown in Example 3 of GB9809351. 1. Example 2 l- (5-Bromeindol-2-ylsulfonyl) -4- [6- (4-pyridyl) nicotinoyl] piperazine In a method exactly analogous to that of Example 1, starting from 6- (4-) acid pyridyl) nicotinic acid (400 mg, 2 mmol) and 1- (5-bromoindol-2-ylsulfonyl) piperazine, (700 mg, 2 mmol, 1 mol eq.), a free base of 1- (5-bromoindol- 2-ylsulfonyl) -4- [6- (4-pyridyl) nicotinoyl] piperazine as a colorless solid, (540 mg), 1H NMR (d6-DMSO) 3.0-3.3 (broad d, 4H), 3.4-3.9 (d broad, 4H), 7.0 (s, 1H), 7. 45 (s, 2H), 7.95 (s, 1H), 8.0 (d, 1H), 8.1 (dd, 2H), 8.15 (d, 1H), 8.75 (, 3H), 12.4 (s, 1H), were also present signals due to DMF (1 mol equiv.); MS (M + H) + 526/528. The starting material of requirement 1- (5-bromoindol-2-ylsulfonyl) piperazine was prepared in a manner analogous to that for the corresponding 5-chloro compound.

Claims (16)

1. CLAIMS 1. A compound of the formula I characterized in that: A is an optionally substituted 5 to 6 membered monocyclic aromatic ring containing 1, 2 or 3 heteroatoms in the ring selected from oxygen, nitrogen and sulfur atoms; Bi, B2, B3 and B4 are independently CH or a nitrogen atom, wherein the ring formed of Bi, B2, B3 and B4 can be optionally substituted; with the proviso that at least one of Bi, B2, B and B4 is nitrogen; Ti is CH or N; T2 is CH or N; with the condition of at least one of Tx and T2 be N; Xi is SO, S02, C (R4) 2 or CO when Ti is CH or N; or else Xi is O or S when Ti is CH; and wherein each R4 is independently hydrogen or (Cl-4) alkyl; Li is alkylene of (Cl-4) or alkylenecarbonyl of (Cl-3); R2 is hydrogen or. alkyl (Cl-4); R3 is hydrogen or alkyl of (Cl-4); or R2 and R3 join to form an alkylene (Cl-4) or -CH2CO- group; wherein the ring formed by Ti, R2, R3, T2 and Li is optionally substituted; X2 is S (0) and where y is one or two, C (R °) 2 or CO; and each R5 is independently hydrogen or (Cl-4) alkyl; Y is selected from hydrogen, halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, amino, nitro, carboxy, carbamoyl, alkyl of (Cl-4), alkenyl of (C 2-4), alkynyl of (C 2-4), alkoxy of (Cl-4), alkenyloxy of (C2-4), alkynyloxy of (C2-4), alkylthio of (Cl-4), alkylsulfinyl of (Cl-4), alkylsulfonyl of (Cl-4), alkylamino of (Cl -4); dialkylamino of (Cl-4), alkoxycarbonyl of (Cl-4), N-alkylcarbamoyl of (Cl-4), N, N-dialkylcarbamoyl of (Cl-4), alkanoyl of (C2-4), alkanoylamino of (C2) -4), hydroxyalkyl of (Cl-4), alkoxy of (Cl-4) -alkyl of (Cl-4), carboxyalkyl of (Cl-4), alkoxycarbonyl of (Cl-4) -alkyl of (Cl-4) ), carbamoylalkyl of (Cl-4), N-alkylcarbamoyl-de (Cl-4) -alkyl of (Cl-4) and N, N-dialkylcarbamoyl of (Cl-4) -alkyl of (Cl-4); n is 1 or 2; and B5 and B6 are selected from N or CH; with the proviso that at least one of B5 and B6 is N; and pharmaceutically acceptable salts thereof.
2. 2. The compound of the formula I according to claim 1, characterized in that A is a pyridyl, pyrimidinyl or pyridazinyl ring.
3. 3. The compound of formula I according to claim 2, characterized in that A is 4-pyridyl, 2-pyridyl, 4-pyridazinyl, 3-pyrimidinyl, 4-pyrimidinyl or 3-pyridyl.
4. 4. The compound of formula I according to claim 1, characterized in that A is unsubstituted or substituted by one, two or three atoms or groups selected from halo, trifluoroethyl, cyano, amino, oxo, hydroxy, nitro, alkyl of (Cl-4), alkoxy of (Cl-4), alkylamino of (Cl-4) or dialkylamino of (Cl-4).
5. 5. The compound of formula I according to claim 1, 3 or 4, characterized in that the ring formed by Bl r B2, B3 and B4 is a pyridinediyl, wherein Bi or B3 is a nitrogen atom, pyrimidinediyl, wherein Bi and B2 or B3 and B4 are nitrogen or pyridazindiyl atoms, wherein Bi, B3 and B4 or Bi, B2 and B3 are nitrogen atoms.
6. 6. The compound of formula I according to claims 1, 3, 4 or 5 characterized in that the ring containing Bi, B2, B3 and B4 is unsubstituted or the ring containing Bi, B2, B3, and B4 is substituted by one or two substituents selected from hydroxy, carboxy, alkoxycarbonyl of (Cl-4) or one of the following: - (CH2) nR, - (CH ^ n'-NRRi., -CO-R, -CO-NRRi , - (CH2) n-CO-R and (CH2) n-CO-NRR ?; where n is 1 or 2; R and Ri are independently selected from hydrogen, alkyl of (Cl-4), alkenyl of (C 2-4), alkynyl of (C 2-4), hydroxyalkyl of (Cl-4), carboxyalkyl of (Cl-4), and alkoxycarbonyl of (Cl-4) -alkyl of (Cl-4) or where possible R and Ri can together form an optionally substituted 5- or 6-membered heterocyclic ring which can include in addition to the nitrogen atom to which R and Ri are attached 1 or 2 additional heteroatoms selected from nitrogen, oxygen and sulfur.
7. 7. The compound of the formula I according to claim 1, 3, 4, 5 or 6 characterized in that the heterocyclic ring formed by R and Ri are preferably selected from pyrrolidin-1-yl, imidazolin-1-yl, piperidin-lyl, piperazin-1-yl, 4-morpholino and thiomorpholino.
8. The compound of formula I according to claims 1, 3, 4, 5, 6 or 7, characterized in that the heterocyclic ring formed by R and Rx is unsubstituted or the ring formed by R and Ri is substituted by one or two substituents selected from oxo, hydroxy and carboxy.
9. 9. The compound of formula I according to claims 1, 3, 4, 5, 6, 7 or 8, characterized in that when Tx is CH or N then Xi is CO, S02, or CH2 or when Ti is CH then Xi is also 0 or S.
10. 10. The compound of formula I according to claims 1, 3, 4, 5, 6, 7, 8 or 9, characterized in that R2 and R3 are joined to form an alkylene group of C? -4 to form together with Ti, T2 and Li, a heterocyclic ring selected from piperazine, piperidine and pyrrolidine.
11. 11. The compound of formula I according to claims 1 6 3, characterized in that the heterocyclic ring formed by Ti, T2, Li, R2, and R3 is unsubstituted or is substituted by one or two substituents selected from hydroxy, oxo , carboxy, alkoxycarbonyl of (Cl-4) or one of the following: ~ (CH2) nR, - (CH2) n -NRR ?, -CO-R, -CO-NRRi, - (CH2) n-CO-R and (CH2) n-CO-NRR ?; where n is 1 or 2; R and Ri are independently selected from hydrogen, alkyl of (Cl-4), alkenyl of (C 2-4), alkynyl of (C 2-4), hydroxyalkyl of (Cl-4), carboxyalkyl of (Cl-4), and alkoxycarbonyl of (Cl-4) -alkyl of (Cl-4) or where possible R and Ri can together form an optionally substituted 5- or 6-membered heterocyclic ring which can include in addition to the nitrogen atom to which R and Ri are attached 1 or 2 additional heteroatoms selected from nitrogen, oxygen and sulfur.
12. 12. The compound of formula I according to claims 1, 3, 4, 5, 6, 7, 8, 9, 10 or 11, characterized in that X2 is S02, CH2 or CO.
13. The compound of formula I according to claims 1, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, characterized in that Y is selected from hydrogen, halo, trifluoromethyl, trifluoromethoxy, cyano , hydroxy, amino, nitro, carboxy, carbamoyl, alkyl of (Cl-4), alkenyl of (C 2-4), alkynyl of (C 2-4), alkoxy of (Cl-4), alkenyloxy (C 2-4), alkynyloxy of (C 2-4), alkylthio of (Cl-4), alkylsulfinyl of (Cl-4), alkylsulfonyl of (Cl-4), alkylamino of (Cl-4); dialkylamino of (Cl-4); alkoxycarbonyl of (Cl-4).
14. The compound of the formula I according to any of claims 1 or 12, for use in medical therapy.
15. 15. The pharmaceutical composition comprising a compound of formula I, as defined according to any of claims 1 to 12, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier.
16. 16. The use of a compound of formula I, or a pharmaceutically acceptable salt thereof, as defined in any of claims 1 to 12, in the manufacture of a medicament for use to produce an inhibitory effect of human Factor Xa.