MXPA97001841A - Amino heterocyclic derivatives as antitrombotic agents or anticoagulant - Google Patents

Abstract

The invention relates to compounds of the formula (I), in which each of G1, G2 and G3 is CH or Ni, m is 1 or 2, R1 includes hydrogen, halogen and C1-4 alkyl, M1 is a group of the formula: NR2-L1-T1ru, in which R2 and R3 together form an alkylene group of C1-4 and T1 is CH or N; A may be a direct bond; M2 is a group of the formula: (T2R4) r -L2-T3R5 in which R is 0 or 1, each of T2 and Túes CH or N, each of R4 and r5 is hydrogen or C1-4alkyl or R4 and R5 together form an alkylene group of C1-4 and L2 includes C4 alkylene, M can be a direct bond with X, X includes sulfonyl, and Q includes naphthyl and a heterocyclic portion, or its pharmaceutically acceptable salt, process for its preparation, pharmaceutical compositions containing them and their use as agents antithrombotics and anticoagulant

Description

AMINOHETEROCICLIC DERIVATIVES AS ANTITROMBOTIC OR ANTICOAGULANT AGENTS DESCRIPTION OF THE INVENTION The invention relates to a group of aminoheterocyclic derivatives or their pharmaceutically acceptable salts, which possess antithrombotic and anticoagulant properties and are therefore useful in methods of treatment of the human or animal body. The invention also relates to processes for the preparation of aminoheterocyclic 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. 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 one of a cascade of proteases 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 preceding protease, which unfolds prothrombin to generate thrombin.

Certain compounds that possess Factor Xa inhibitory properties 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 thickening anticoagulant protein (TAP) are specific Factor Xa inhibitors, which have antithrombotic properties in several animal models of thrombotic disease. It is also known that certain non-peptidic compounds possess inhibitory properties of Factor Xa. Of the low molecular weight inhibitors mentioned in the review by R.B. Wallis, all have a strongly basic group such as a group of idinophenyl or amidinonaphthyl. It is the object of the present invention to provide a new class of agents, which lacks the amidino group that was previously believed to be an essential characteristic for a Factor Xa inhibitor. It has now been found that certain aminosubstituted heterocyclic derivatives have Factor Xa inhibitory activity. Many of the compounds of the present invention also have the advantage of being selective Factor Xa inhibitors, ie the above Factor Xa is strongly inhibited at concentrations of the test compound which do not inhibit or inhibit to a lesser extent the Thrombin enzyme, which 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, where anticoagulant therapy is indicated, for example in the treatment or prevention of thrombotic conditions such as coronary artery disease and cerebrovascular disease. Other examples of such medical disorders include various cardiovascular and cerebrovascular states such as myocardial infarction, formation of atherosclerotic plaques, venous or arterial thrombosis, coagulation syndromes, vascular injury including reocclusion and restenosis after angioplasty and coronary artery bypass surgery, thrombus formation after the application of operative techniques in blood vessels, the introduction of artificial heart valves or in the recirculation of blood, cerebral infarction, cerebral thrombosis, stroke, cerebral embolism, pulmonary embolism, ischemia and angina (including unstable angina) . The compounds of the invention are also useful as inhibitors of blood coagulation in an ex vivo situation such as, for example, storage of whole blood or other biological samples suspected of containing Factor Xa and in the coagulation of which is harmful.

According to one aspect of the invention, there is provided an aminoheterocyclic derivative of the formula I (set forth in the following) wherein G1 is CH or N; G2 is CH or N; G3 is CH or N; m is 1 or 2; R1 is hydrogen, amino, halogen, cyano, alkyl Cl-4 ° alco? I of ci-4 'M1 is a group of the formula NR2_L1_T1R3 wherein R2 and R3 together form an alkylene group of C ^ C ^, L1 is C1-C4 alkylene, and T1 is CH or N, and wherein 1 or 2 methylene groups within L1 and the ring are formed when R2 and R3 are attached, optionally bears a C1-4 alkyl substituent; A is a direct bond for the carbonyl group, or A is C 1-4 alkylene; M2 is a group of the formula (T2R4) r-L2-T R5 in which r is O or 1, T2 is CH or N, T3 is CH or N, R4 is hydrogen or C1-4 alkyl, R5 is hydrogen or C1-4 alkyl or R4 and R4 together form a C1-4 alkylene group, methylenecarbonyl or carbonylmethylene or R4 is an alkylene group of 2_3, which is attached to a methylene group within L2 that form a 5- or 6-membered ring that involves or implies R4 and T2, or R5 is an alkylene group of c2-3 's which are attached to a methylene group within L2 which forms a 5- or 6-membered ring involving R ^ and T3, L2 is C1-4 alkylene , cycloalkane of C3_g-1, 2-diyl, alkylene of C-L_3-carbonyl or phenylene and, when r is 1, L2 can also be carbonyl-alkylene of and in which 1 or 2 methylene groups within L2 and the rings formed, when R 4 and R 5, R 4 and L 2 or R 5 and L 2 are optionally formed, they carry a substituent selected from the group consisting of oxo, carboxy, alkoxycarbonyl of c 1-4, carbamoyl, N-alkylcarbamoyl of C 1-4, N, N-di-alkyl arbamoyl of C-, 4-pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, morpholino-carbonyl, piperazin-1-ylcarbonyl, 4-alkyl-4-piperazin-1-ylcarbonyl, N-phenylcarbamoyl, N-C1-4 alkyl- N-Phenylcarbamoyl, N- [phenyl-C 1-3 alkyl] carbamoyl, N-C 1-4 alkyl-N- [phenyl-C 1-3 -alkyl] carbamoyl, N- [hydroxy-C 2-31 carbamoyl] alkyl, N-C 1 alkyl- L_4-N- [hydroxy-C2_3 alkyl] carbamoyl, N- [C1-4 alkoxy-C2_3 alkyl] -carbamoyl, N-C1_4 alkyl-N- [C1_4 alkoxy-C2_3 alkyl] carbamoyl, N- [carboxyC1_3alkyl] carbamoyl, N-C1_4alkyl-N- [carboxyC1-3alkyl] carbamoyl, N- [carboxyC1-3alkyl] -N- [C2_3 hydroxyalkyl] -carbamoyl, N- [carboxy-C 1-3 alkyl] -N- [C 1-4 alkoxy-C 2-31 alkyl carbamoyl, N- [C 1-4 alkoxycarbonyl] -3-carbamoyl alkyl, N-C 1-4 alkyl-N- [alkoxycarbonyl] C1_4-C1-3alkyl] carbamoyl, N- [C1_4alkoxycarbonyl] -N- [hydroxyC2_3alkyl] carbamoyl, N- [alkoxy] C 1-4 oxycarbonyl-C 1-3 alkyl] -N- [C-L-4 alkoxy-C 2 -C 3 alkyl] carbamoyl, C 1-4 alkyl, carboxy C 1-4 alkyl, C 1-4 alkoxycarbonyl C 1-4 alkyl , carbamoyl-C1_4alkyl, C1_4-N-alkylcarbamoyl-C1_4alkyl, N, N-di-alkylcarbamoyl of C1_4-alkyl of c-> > pyrrolidin-1-ylcarbonyl-C1-4alkyl, piperidinocarbonyl-C1-4alkyl, orfolinocarbonyl-C1,4'-piperazin-1-ylcarbonyl-C1-4 alkyl, 4-C1-4-piperazin-1-ylcarbonyl alkyl - C1_4 alkyl, N-phenylcarbamoyl-C1_4alkyl, N- [phenyl-C1-3alkyl] carbamoyl-C1_4alkyl, C1-4 hydroxyalkyl, C1_4alkoxy-C4_4alkyl and C1_ phenylalkyl / l, and wherein any heterocyclic group in the substituent optionally, carries 1 or 2 substituents selected from the group consisting of C 1 -4 alkyl, C 1-4 alkoxy, carboxy, C 1-4 alkoxycarbonyl, carbamoyl, N-alkylcarbamoyl C1_4 and N, N-di-alkylcarbamoyl of Cj ^, and in which any phenyl or phenylene group in M2 optionally carries 1 or 2 substituents selected from the group consisting of halogen, trifluoromethyl, Cl-4 alkyl and C1_4 alkoxy; M3 is a direct link for X, or M3 is a group of the formula L3- (NR6) wherein s is 0 or 1, R6 is hydrogen or C1-4alkyl, or R5 and R6 together form an alkylene group of c-> > methylenecarbonyl or carbonylmethylene, or R6 is an alkylene group of C2_3, which is bonded to a methylene group within L3 which forms a 5- or 6-membered ring involving NR6, L3 is C1-4 alkylene, C3_g-1 cycloalkane , 2-diyl, carbonyl-alkylene of 3-phenylene and, when s is 1, L3 can also be 1-g-carbonyl alkylene, and wherein 1 or 2 methylene groups within L3 and the rings formed when R5 and R6 or R6 and L3 are optionally attached, they carry a substituent selected from the group consisting of oxo, carboxy, C? _4 alkoxycarbonyl, carbamoyl, C? _4 N-alkylcarbamoyl, N, N, N-di-alkylcarbamoyl of C 1 -4 pyrrolidin-1-ylcarbonyl , piperidinocarbonyl, morpholinocarbonyl, piprazrazin-1-ylcarbonyl, 4-alkyl-C1_4-piperazin-1-ylcarbonyl, N-phenylcarbamoyl, N-alkyl of C-L_4-N-phenylcarbamoyl, N- [phenyl-C1_3] alkylcarbamoyl, N-C 1-4 alkyl-N- [phenyl-C 1-3 -alkyl] carbamoyl, C 1-4 -alkyl, C 1-4 -carboxy-alkyl, C 1-4 -alkoxycarbonyl- C 1-4 -carbamoyl-alkyl-, 1-4'-alkylcarbamoyl of C 1-4-alkyl of C 4 -4 N, N-di-alkylcarbamoyl of C 1-4-4-C 1-4 -alkyl, pyrrolidin-1-ylcarbonyl-C 1-4 -alkyl, piperidinocarbonyl-C-L_4 alkyl, morpholinocarb onyl-cyclo-4-alkyl piperazin-1-ylcarbonyl-C1-4alkyl, 4-C1-4alkyl -piperazin-1-ylcarbonyl-C1-4alkyl, N-phenylcarbamoyl-C1-4alkyl, N- [phenyl-C 1-3 alkyl] carbamoyl-C 1-4 alkyl, hydroxy C 1-4 alkyl, C 1-4 alkoxy C 1-4 alkyl and phenyl-C 1-4 alkyl, and wherein any heterocyclic group in the substituent optionally it carries 1 or 2 substituents selected from the group consisting of C-, 4-alkyl, C 1 -koxy, carboxy, C 1 -4 alkoxycarbonyl, carbamoyl, C 1 -C 4 -alkylcarbamoyl, and N, N-di-alkylcarbamoyl of C 1 and that any phenylene group in M3 optionally bears 1 or 2 substituents selected from the group consisting of halogen, trifluoromethyl, C? _4 alkyl, and C-j? 4 alkoxy; X is oxy, thio, sulfinyl, sulfonyl, carbonyl, carbonyloxy, carbonylamino, N-alkylcarbonylamino of 1-4, sulfonylamino, methylene, alkylmethylene of c1_4 or di-alkylmethylene of C1-4 or, when T3 is CH and M3 is a bond direct for X, X may also be aminosulfonyl or oxycarbonyl; and Q is phenyl, naphthyl, phenyl-allyl of 1-4, phenyl-alkenyl of C2_4, phenyl-alkynyl of C2_4, cycloalkyl of Ce7 or a heterocyclic portion containing up to 4 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and Q optionally bears 1, 2 or 3 substituents selected from the group consisting of hydroxy, amino, halogen, cyano, trifluoromethyl, nitro, carboxy, carbamoyl, formyl, formimidoyl, formmo-hydroxymethyl, C1-4 alkoxycarbonyl, alkyl of 1-4, ci-4 * N-alkylcarbamoyl alkoxy of c4-4 N, N-di-alkylcarbamoyl of C 1-4, alkylamino of C 1-4, di-alkylamino of c4-4 alkanoylamino of c 2-4, alkanoyl of C2-4 'C2_4 alkanoimidoyl, C2_4 -alkanohydroxy, phenyl, heteroaryl, phenoxy, phenylthio, phenylsulfinyl, phenylsulfonyl, heteroaryloxy, heteroarylthio, heteroarylsulfinyl, heteroarylsulphonyl, benzyl and benzoyl, and in which the heteroaryl substituent or the heteroaryl group in a substituent containing heteroaryl comprises a 5 or 6 membered monocyclic heteroaryl ring containing up to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and wherein the substituent phenyl, heteroaryl, phenoxy, phenylthio, phenylsulfinyl, phenylsulfonyl, heteroaryloxy, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, benzyl or benzoyl optionally bears 1, 2, 3 or 4 substituents selected from the group consisting of halogen, trifluoromethyl, cyano, trifluoromethoxy, nitro, C 1-4 alkyl, alkoxy 1-4, hydroxy, amino, carboxy, carbamoyl , C 1-4 alkoxycarbonyl, N-alkylcarbamoyl of C-L_4, N, N-di-alkylcarbamoyl of C 1-4, alkylamino of C 1-4, di-C 1-4 alkylamino, C 2-4 alkanoylamino and tetrazolyl; or its pharmaceutically acceptable salt. The "chemical formulas mentioned herein by Roman numerals, are established for convenience on a separate sheet in the following.In this specification, the term" alkyl "includes both straight-chain and branched-chain alkyl groups, but references to individual alkyl groups, such as "propyl" are specific for the straight chain version only An analogous convention applies to other generic terms It should be understood that certain aminoheterocyclic derivatives of the present invention may exist in a solvate as well as in unsolvated forms such as, for example, hydrated forms It should be understood that the invention encompasses all such solvated forms, which possess Factor Xa inhibitory activity It should be further understood that to what extent certain of the compounds of the formula defined above, can exist in optically active or racemic forms by virtue of one or more carbon atoms or asymmetric, the invention encompasses any of such optically active or racemic form, which possesses Factor Xa inhibitory activity. 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 from optically active starting materials or by resolution of a racemic form. According to a further aspect of the invention, there is provided an aminoheterocyclic derivative of the formula la, wherein G1 is CH or N; G2 is CH or N; is 1 or 2; R1 is hydrogen, amino, halogen, cyano, alkyl Cl-4 ° C 1-4 alkoxy; M1 is a group of the formula NR2-L1-T1R3 in which R2 and R3 together form an alkylene group of 1-4, L1 is C1-4alkylene, and T1 is CH or N, and wherein 1 or 2 methylene groups within L1 and the rings formed when R2 and R3 are optionally attached, bears a C1-4 alkyl substituent; A is a direct bond to the carbonyl group or A is C1-4 alkylene; M2 is a group of the formula (T2R4) r-L2-T3R5 wherein r is 0 or 1, T2 is CH or N, T3 is CH or N, R4 is hydrogen or C1-4 alkyl, R5 is hydrogen or C1-4 alkyl, or R4 and R5 together form an alkylene group of C1_4, methylenecarbonyl or carbonylmethylene or R4 is an alkylene group of C2_3, which is attached to a methylene group within L2 which forms a 5- or 6-membered ring, which involves R4 and T2, or R5 is an alkylene group of C2_3 , which is attached to a methylene group within L2 which forms a 5 or 6 membered ring involving R5 and T3, L2 is C1_4 alkylene, C3_g-1,2-diyl cycloalkane, C- ^ alkylene. j -carbonyl or phenylene and, when r is 1, L2 can also be carbonyl-alkylene of C- ^ _ 3, and in which or 2 methylene groups within L2 and the rings formed when R4 and R5, R4 and L2 or R5 and L2 are optionally attached, carries a substituent selected from the group consisting of carboxy, c4-4 carbamoyl alkoxycarbonyl, N- (C1-4 alkylcarbamoyl, N, N-di-C1-C4 alkylcarbamoyl, pyrroli din-1-ylcarbonyl, piperidinocarbonyl, morpholino-carbonyl, piperazin-1-ylcarbonyl, 4-alkyl of cyclo-4-piperazin-1-ylcarbonyl, N-phenylcarbamoyl, N-C4-N-phenylcarbamoyl-alkyl, N- [ phenyl-C- ^ - j] carbamoyl alkyl, N-alkyl of C-L_4-N- [phenyl-C1-3 alkyl] carbamoyl, N- [hydroxy-C2_3 alkyl] carbamoyl, N-alkyl of C-, 4-N- [hydroxy-C2_3 alkyl] carbamoyl, N- [(C 1-4 alkoxy-C 2 -3 alkyl) -carbamoyl, N-C 1-4 alkyl-N- [C 1-4 alkoxy-C 2-3 alkyl] carbamoyl, N- [carboxy-C- ^ 3 alkyl] carbamoyl, N-C 1-4 alkyl-N- [carboxy-C-, 3-carbamoyl] alkyl, N- [carboxy-C-L-3 alkyl] -N- [hydroxy-C 2-3 alkyl] -carbamoyl, N- [ carboxy-C 1-3 alkyl] -N- [C 1-4 alkoxy-C 2-31 alkyl carbamoyl, N- [C 1-4 alkoxycarbonyl] -3 ^ carbamoyl alkyl, N-4 alkyl "alkyl" [alkoxycarbonyl] of C1_4-C1_3alkyl] carbamoyl, N- [C1_4alkoxycarbonyl] -N- [hydroxy-C2_3alkyl] carbamoyl, N- [C1_alkyl] alkoxycarbonyl] -N- [C1_4alkoxy-C2_3alkyl] carbamoyl, C1_4alkyl, C1_4carboxy_alkyl, C-L4_alkoxycarbarylcarbamoyl-C1_4alkyl_alkyl_ ??? ~ alkylocarbamoyl of C1_4-alqu C 1 -4 N, N-di-alkylcarba, C 1-4 alkylolkyl, C 1-4 alkyl, pyrrolidin-1-ylcarbonyl-cycloalkyl 4-piperidinocarbonyl-alkyl, morpholinocarbonyl-C 1-4 alkyl 4-piperazin-1-ylcarbonyl-C1-4alkyl, 4-C1-4-piperazin-1-ylcarbonyl-C1_4alkyl, N-phenylcarbamoyl-C1-4alkyl, N- [phenyl-C1-3alkyl] carbamoyl -C1_4alkyl, C1_4 hydroxyalkyl, C1_4alkoxy-C1-4alkyl, and phenyl-C1_4alkyl, and wherein any heterocyclic group in the substituent optionally carries 1 or 2 substituents selected from the group consisting of C1_4, C1_4 alkoxy, carboxy, C1_2alkoxycarbonyl, carbamoyl, N-alkylcarbamoyl of C-L_4 and N, N-di-alkylcarbamoyl of -j *, and in which any phenyl or phenylene group in M2 optionally carries 1 or 2 substituents selected from the group consisting of halogen, trifluoromethyl, Cl-4 alkyl and C 1-4 alkoxy; M3 is a direct link for X, or M3 is a group of the formula L3- (NR6) wherein s is 0 or 1, R6 is hydrogen or C1-4 alkyl, or R5 and R6 together form an alkylene group of ^^, methylenecarbonyl or carbonylmethylene, or R6 is an alkylene group of C2_3, which is attached to a methylene group within L3 that forms a 5- or 6-membered ring that involves NR6, L3 is alkylene, C3_g-l, 2-diyl cycloalkane, C1_3 carbonyl-alkylene or phenylene and, when s is 1, L3 is also it can be alkylene of C-L_3 -carbonyl, and wherein 1 or 2 methylene groups within L3 and the rings formed when R5 and R6 or R6 and L3 are attached, optionally bears a substituent selected from the group consisting of carboxy, alkoxycarbonyl of C1-4, carbamoyl, N-alkylcarbamoyl of C-L_4, N, N-di-alkylcarbamoyl of cyclo-4-pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, morpholinocarbonyl, piperazin-1-ylcarbonyl, 4-C1-4-piperazin-1-ylcarbonyl alkyl, N-phenylcarbamoyl, N-C1-4-N-phenylcarbamoyl-alkyl, N- [phenyl-C1-3alkyl] carbamoyl, N- C 1-4 alkyl- N- [phenyl- C 1-3 alkyl carbamoyl, alkyl 1-4, carboxy-C 1-4 alkyl, C 1-4 alkoxycarbonyl-4'-carbamoyl-cyclo-4'-alkylcarbamoyl] of C 1-4-C 1-4 alkyl, N-di-C 1-4 alkylcarbamoyl-C 1-4 alkyl, pyrrolidin-1-ylcarbonyl-C 1-4 alkyl, piperidinocarbonyl-C-L-4 alkyl, morpholinocarbonyl-C 1-4 alkyl 4 >; piperazin-1-ylcarbonyl-C de4-4alkyl, 4-C1-4-piperazin-1-ylcarbonyl-C1_4alkyl, N-phenylcarbamoyl-C1-4alkyl, N- [tenyl-C-] alkylcarbamoyl -C1_4alkyl, C1_4 hydroxyalkyl, C1_4alkoxy-C1_4alkyl and phenylalkyl of 1-4, and wherein any heterocyclic group in the substituent optionally carries 1 or 2 substituents selected from the group consisting of C1_alkyl -4, C-, 4-alkoxy, carboxy, C 1-4 alkoxycarbonyl, carbamoyl, N-alkylcarbamoyl of C- ^ _ ^ and N, N-di-alkylcarbamoyl of C 1-4 and in which any phenyl or phenylene group in M3 optionally it carries 1 or 2 substituents selected from the group consisting of halogen, trifluoromethyl, Cl-4 alkyl and C 1-4 alkoxy; X is oxy, thio, sulfinyl, sulfonyl, carbonyl, carbonyloxy, carbonylamino, N-alkylcarbonylamino of 4, sulfonylamino, methylene, alkylmethylene of c4-4 di-C1-4 alkyl or, when T3 is CH and M3 is a direct bond for X, X can also be aminosulfonyl or oxycarbonyl; and Q is phenyl, naphthyl, phenyl-C1-4 alkyl, phenyl-C2_4 alkenyl, C2_4 phenyl-alkynyl, C5_7 cycloalkyl or a heterocyclic portion containing up to 4 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and Q optionally carries 1, 2 or 3 substituents selected from the group consisting of hydroxy, amino, halogen, cyano, trifluoromethyl, nitro, carboxy, carbamoyl, formyl, formyloyl, formmo-hydroxymethyl, C1-4 alkoxycarbonyl, C1-4 alkyl, N-alkylcarbamoyl alkoxy of C 4 -4 N, N-di-alkylcarbamoyl of C 1-4, C 1-4 alkylamino, di-C 1-4 alkylamino. C2-4 alkanoylamino 'C2-4 alkanoyloxy C2_4 alkanoimidoyl, C2_4 alkanoyloxy, phenyl, heteroaryl, phenoxy, phenylthio, phenylsulfinyl, phenylsulfonyl, heteroaryloxy, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, benzyl and benzoyl, and in which the heteroaryl substituent or the heteroaryl group in a heteroaryl-containing substituent comprises a 5- or 6-membered monocyclic heteroaryl ring containing up to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and wherein the substituent is phenyl, heteroaryl, phenoxy, phenylthio, phenylsulfinyl, phenylsulfonyl, heteroaryloxy, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, benzyl or benzoyl optionally carries 1 or 2 substituents selected from the group consisting of halogen, trifluoromethyl, C1-4 alkyl, C-, 4 alkoxy, hydroxy, amino, carboxy, carbamoyl, C-, 4-alkoxycarbonyl, N-alkylcarbamoyl of C 1-4, N, N-di-alkylcarbamoyl of C-, 4, alkylamino not of C- ^^, di-alkylamino of C-j *, alkanoylamino of C2-4 and tetrazolyl; or its pharmaceutically acceptable salt.

The appropriate values for the generic terms referred to in the above include those established in the following. When m is 2, each R 1 is independently selected from hydrogen, amino, halogen, cyano, C 1-4 alkyl and C 1-4 alkoxy. A suitable value for R1 when it is a halogen group, for a halogen substituent on M2 or M3 or for a halogen substituent on Q is, for example, fluoro, chloro, bromo or iodo. Suitable values for R1 when it is an alkyl group of 1_4, for an alkyl substituent of C-L_4 in M1, M2 or M3 or for a C1-4 alkyl substituent in Q is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl. A suitable value for R1 when it is a C1_4 alkoxy group, for a C1_4 alkoxy substituent on M2 or M3 or for a C4_4 alkoxy substituent on Q is, for example, methoxy, ethoxy, propoxy, isopropoxy or butoxy. A suitable value for R, R5 or R6 when it is C1-4 alkyl, is, for example, methyl, ethyl, propyl, isopropyl, butyl or sec-butyl. A suitable value for an alkylene group of C1_4 formed by R2 and R3 together, by R4 and R5 together or by R5 and R6 together is, for example, methylene, ethylene, trimethylene or tetramethylene. A suitable value for an alkylene group of C2_3 by which R4 can be attached to a methylene group within L, R5 can be attached to a methylene group within L2 or R6 can be attached to a methylene group within L3 is, by example, ethylene or trimethylene. A suitable value for L1, L2 or L3 when it is C1-4alkylene is, for example, methylene, ethylene, trimethylene or tetramethylene; a suitable value for L2 or L3 when it is C3_g-diyl cycloalkane is, for example, cyclopropan-1, 2-diyl, cyclobutan-1,2-diyl, cyclopentan-1,2-diyl or cyclohexane-1,2-diyl; when it is alkylene of C-, 3-carbonyl is, for example, methylenecarbonyl, ethylenecarbonyl or trimethylenecarbonyl; and when it's phenylene is, for example, 1,3- or 1, 4-phenylene. A suitable value for L2 and L3 when it is carbonyl-alkylene of C1 -3 is, for example, carbonylmethylene, carbonylethylene or carbonyltrimethylene. Suitable values for the substituents which are present within M1, M2 or M3 include, for example: - for 1-4-methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and tert-butoxycarbonyl alkoxycarbonyl; for N-alkylcarbamoyl: N-methylcarbamoyl, N-ethylcarbamoyl and N-propylcarbamoyl; for N, N-di- [C 1-4 alkylcarbamoyl: N, N-dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl and N, N-diethylcarbamoyl; for 4-alkyl of C-L-4-piperazin-1-ylcarbonyl: 4-methylpiperazin-1-ylcarbonyl and 4-ethylpiperazin-1-ylcarbonyl; for N-C1-4-N-phenylcarbamoyl-alkyl: N-methyl-N-phenylcarbamoyl and N-ethyl-N-phenylcarbamoyl, - for N- [phenyl-C ^ _3] alkylcarbamoyl: N-benzylcarbamoyl and N- phenethylcarbamoyl; for N-C 1-4 alkyl-N- [phenyl-C-j] -carbamoyl-alkyl: N-benzyl-N-methylcarbamoyl and N-methyl-N-phenethyl-carbamoyl; for N- [hydroxy-C2.3 alkyl] -carbamoyl: N- (2-hydroxyethyl) carbamoyl and N- (3-hydroxypropyl) carbamoyl; for N-C 1-4 alkyl-N- [hydroxy-C 2 -C 3 alkyl] -carbamoyl: N- (2-hydroxyethyl) -N-methylcarbamoyl and N- (2-hydroxyethyl) -N-ethylcarbamoyl; for N- [C 1-4 alkoxy] C 2-31 alkylcarbamoyl: N- (2-methoxyethyl) carbamoyl and N- (2-ethoxyethyl) carbamoyl; for N-C 1-4 alkyl-N- [C 1-4 alkoxy-C 2-3 alkyl] carbamoyl: N- (2-methoxyethyl) -N-methylcarbamoyl and N- (2-ethoxyethyl) -N-ethylcarbamoyl; for N- [carboxy-C 1-3 alkyl] -carbamoyl: N- (carboxymethyl) carbamoyl, N- (1-carboxyethyl) carbamoyl and N- (2-carboxyethyl) carbamoyl; for N-C 1-4 alkyl-N- [carboxy-C-, 3] -carbamoyl-alkyl: N- (carboxymethyl) -N-methylcarbamoyl, N- (1-carboxyethyl) -N-methylcarbamoyl and N- (2 carboxyethyl) -N-methylcarbamoyl; for N- [carboxy-alkyl of C - ^ - j] -N- [hydroxy-C2_3 alkyl] carbamoyl: N- (carboxymethyl) -N- (2-hydroxyethyl) -carbamoyl; for N- [carboxy-alkyl of C- ^ g] -N- [C1-4 alkoxy-C2_3 alkyl] -carbamoyl: N- (carboxymethyl) -N- (2-methoxyethyl) -carbamoyl; for N- [C 1-4 alkoxycarbonyl- C-, 3] -carbamoyl-N- (methoxycarbonylmethyl) carbamoyl, N- (ethoxycarbonylmethyl) carbamoyl, N- (1-methoxycarbonylethyl) carbamoyl and N- (2-methoxycarbonylethyl) carbamoyl; for N-C 1-4 alkyl-N- [1-4-alkoxycarbonyl of c? -3 ^ carbamoyl: N- (methoxycarbonylmethyl) -N-methylcarbamoyl; for N- [1-4C-alkoxycarbonyl-C-, 3-alkyl] -N- [hydroxy-C2_3] alkylcarbamoyl: N- (2-hydroxyethyl) -N- (methoxycarbonyl ethyl) carbamoyl; for N- [1-4C-alkoxycarbonyl-C1_3alkyl] -N- [C1_4alkoxy-C2_3alkyl] carbamoyl ester: N- (methoxycarbonylmethyl) -N- (2-methoxyethyl) carbamoyl; for alkyl of 1-4: methyl, ethyl, propyl, isopropyl and butyl; for carboxy-alkyl of 4-carboxymethyl, 1-carboxyethyl, 2-carboxyethyl and 3-carboxypropyl; for 1-4C-alkoxycarbonyl-1-4-alkyl: methoxycarbonylmethyl, ethoxycarbonylmethyl, tert-butoxycarbonylmethyl, 1-methoxycarbonylethyl, 1-ethoxycarbonylethyl, 2-methoxycarbonylethyl, 2-ethoxycarbonylethyl, 3-methoxycarbonylpropyl and 3-ethoxycarbonylpropyl; for carbamoyl-C 1-4 alkyl: carbamoylmethyl, 1-carbamoylethyl, 2-carbamoylethyl and 3-carbamoylpropyl; for C 1-4 N-alkylcarbamoyl-C 1-4 alkyl: timethylcarbamoylmethyl, N-ethylcarbamoylmethyl, N-propylcarbamoylmethyl, 1- (N-methylcarbamoyl) ethyl, 1- (N-ethylcarbamoyl) ethyl, 2- (N-methylcarbamoyl) ethyl, 2- (N-ethylcarbamoyl) ethyl and 3- (N-methylcarbamoyl) propyl; for N, N-di- [C 1-4 alkyl] -carbamoyl-1-4 alkyl: N, N-dimethylcarbamoylmethyl, N-ethyl-N-methylcarbamoyl-methyl, 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; for pyrrolidin-1-yl-carbonyl-alkyl of c: 1_4: pyrrolidin-1-ylcarbonylmethyl, 1- (pyrrolidin-1-ylcarbonyl) -ethyl and 2- (pyrrolidin-1-ylcarbonyl) ethyl; for piperidinocarbonyl-alkyl of < -'i-4: piperidinocarbonylmethyl, 1- (piperidinocarbonyl) ethyl and 2- (piperidinocarbonyl) ethyl; for morpholinocarbonyl-1-4 alkyl: morpholinocarbonylmethyl, 1- (morpholinocarbonyl) ethyl and 2- (morpholinocarbonyl) ethyl; for piperazin-1-yl-carbonyl-C1-4 alkyl: piperazin-ylcarbonylmethyl, 1- (piperazin-1-ylcarbonyl) ethyl and 2- (piperazin-1-ylcarbonyl) ethyl; for 4-C1-4-piperazin-1-ylcarbonyl-C1-4 alkyl: 4-methylpiperazin-1-ylcarbonylmethyl, 4-ethylpiperazin-1-ylcarbonylmethyl, 2- (4-methylpiperazin-1-ylcarbonyl) ethyl and 2- (4-ethylpiperazin-1-ylcarbonyl) ethyl; for N-phenylcarbamoyl-cyclo-4-yl-phenylcarbamoylmethyl and 2- (N-phenylcarbamoyl) ethyl; for N- [phenyl-C1_3 alkyl] -carbamoyl-C1_4 alkyl: N-benzylcarbamoylmethyl, N-phenethylcarbamoylmethyl and 2- (N-benzylcarbamoyl) ethyl; for hydroxyC 1-4 alkyl: hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl and 3-hydroxypropyl; for C 1-4 alkoxy-C 1-4 alkyl: methoxymethyl, ethoxymethyl, 1-methoxymethyl, 2-methoxyethyl, 2-ethoxyethyl and 3-methoxypropyl; and for phenyl-C 1-4 alkyl: benzyl, phenethyl and 3-phenylpropyl. Suitable values for substituents which are present in a heterocyclic group within a substituent which is present within M2 or M3 include, for example: - for C1-4 alkyl: methyl, ethyl, propyl and isopropyl, - for C -] __ 4 alkoxy: methoxy, ethoxy and propoxy; for C 4 _4 alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and tert-butoxycarbonyl; for C 1-4 N-alkylcarbamoyl: N-methylcarbamoyl and N-ethylcarbamoyl; and for N, N-di-C 1-4 alkyl-carbamoyl: N, N-dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl and N, N-diethylcarbamoyl. A suitable value for A when it is alkylene of 1-4 is, for example, methylene, ethylene, trimethylene and tetramethylene. It should be understood that when M1 is a group of the formula NR2-L1-T1R3 The order of presentation of this group is important in terms of the group's orientation of union. In this way, it is the group NR2, which is linked to the heterocyclic group, for example, when G1 and G2 are each CH, the pyridyl group which bears the substituent R1. It should also be understood that within the group NR2 is the atom N, which binds to L1. Likewise, the group R2 is linked to the N atom and not to the L1 group. Similarly in the group T1R3 it is the group T1 which is linked to the group A of the formula I (or the group CO within the formula I when A is a direct link) and the group R3 is linked to the group T1 and not to group A of formula I. A similar convention applies to the union of groups M2 and M3 and to the union of groups T2, T3 and NR6 within M2 or M3. It should further be understood that when R4 is an alkylene group of C2_ such as ethylene and trimethylene which are attached to a methylene group which L2 which forms a 5- or 6-membered ring involves T2 and R4, a suitable ring formed when T2 is N is, for example, pyrrolidin-1,3-diyl, piperidin-1,3-diyl and piperidin-1,4-diyl and a suitable ring formed when T2 is CH is, for example, cyclopentan-1,3-diyl, cyclohexane-1,3-diyl and cyclohexane-1,4-diyl. Such ring systems are also suitable when, for example, R 5 is attached to the methylene group within L 2. Ring systems such as pyrrolidin-1,3-diyl, pipéridin-1,3-diyl and piperidin-1,4-diyl are also suitable when R6 is attached to a methylene within L3. To avoid doubt it is established that a suitable heterocyclic group in a substituent, which may be present within M2 and M3 includes, for example, pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl and 4-alkyl Cj ^ -piperazin-1-yl either directly attached or linked via a linking group, for example, as in pyrrolidin-1-ylcarbonyl-C 1-4 alkyl such as 2- (pyrrolidin-1-ylcarbonyl) ethyl . A suitable value for X when it is an N-alkylcarbonylamino group of C ^ _4 is, for example, N-methylcarbonyl-amino or N-ethylcarbonylamino; when it is alkylmethylene of C-, 4 is, for example, ethane-1,1-diyl or propane-1,1-diyl; and when it is di-C1-4 alkyl ethylene is, for example, propan-2,2-diyl. It should also be understood that when X is a carbonyloxy, carbonylamino or N-alkylcarbonylamino group of C-, 4, it is the carbonyl group within which it is attached to M3, Also, when X is a sulfonylamino group is the sulfonyl group within which is bound to M3 while, when X is an aminosulfonyl group, the sulfonyl group within is linked to Q. A suitable value for Q when it is naphthyl is, for example, 1-naphthyl or 2-naphthyl; when it is phenyl-C 4 alkyl is, for example, benzyl, phenethyl and 3-phenylpropyl, when it is phenyl-C 2-4 alkenyl is, for example, styryl, cinnamyl or 3-phenylprop-2-enyl; when it is phenyl-alkynyl of c2-4 is By eJemPl 2-phenylethynyl, 3-phenylprop-2-ynyl and 3-phenylprop-1-ynyl; and when it is C5_7 cycloalkyl it is, for example, cyclopentyl, cyclohexyl and cycloheptyl. A suitable value for Q when it is a heterocyclic portion containing up to 4 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur is, for example, a 5- or 6-membered heterocyclic moiety which is a single ring or is fused to one or two benzo rings such as furyl, benzofuranyl, tetrahydrofuryl, chromanyl, thienyl, benzothienyl, pyridyl, piperidinyl, quinolyl, 1, 2, 3, 4-tetrahydroquinolinyl, isoquinolyl, 1, 2, 3,4-tetrahydroisoquinolinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, quinoxalinyl, quinazolinyl, cinolinyl, pyrrolyl, pyrrolidinyl, indolyl, indolinyl, imidazolyl, benzimidazolyl, pyrazolyl, indazolyl, oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, isothiazolyl, morpholinyl, 4H-1,4-benzoxazinyl, 4H- 1, 4-benzothiazinyl, 1,2,3-triazolyl, 1,4-triazolyl, oxadiazolyl, furazanyl, thiadiazolyl, tetrazolyl, dibenzofuranyl and dibenzothienyl, which may be linked through any available position that includes, by an appropriate group X such as, for example, carbonyl and methylene, through any available nitrogen and which can be carried up to three substituents including a substituent on any available nitrogen atom. Suitable values for the substituents which may be present within Q include, for example: for C 1-4 alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl and tert-butoxycarbonyl; for C 1-4 alkyl: methyl, ethyl, propyl and isopropyl; for C ^ _4 alkoxy: methoxy, ethoxy, propoxy and isopropoxy, - for N-alkylcarbamoyl of C1- ^: -methylcarbamoyl and N-ethylcarbamoyl; for N, N-di-alkylcarbamsyl of C 1-4: N, N-dimethyl-carbamoyl and N, N-diethylcarbamoyl; for C1-4 alkylamino: methylamino, ethylamino and propylamino; for di-alkylamino of C -] __ 4: dimethylamino, N-ethyl-N-methylamino and diethylamino; for C2_4 alkanoylamino: acetamido, propionamido and butyramido; for C2_4 alkanoyl: acetyl, propionyl and butyryl; for c2-4 alkanoimidoyl: acetimidoyl and propionimidoyl; and for alkanehydroxyperoxy: acetohydroximoyl and propionohydroximoyl. A suitable value for the heteroaryl substituent or the heteroaryl group in a heteroaryl-containing substituent, which comprises a 5- or 6-membered monocyclic heteroaryl ring containing up to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur is, for example , furyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, furazanyl and thiadiazolyl, which can be be united through any available position that includes through any available nitrogen atom. A suitable pharmaceutically acceptable salt of an aminoheterocyclic derivative of the invention is, for example, an acid addition salt of an aminoheterocyclic derivative of the invention, which is sufficiently basic, for example, an acid addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, citric or maleic acid. In addition, a suitable pharmaceutically acceptable salt of an aminoheterocyclic derivative of the invention, which is sufficiently acidic is an alkali metal salt, for example, a sodium or potassium salt, an alkaline earth metal salt, for example calcium salt or magnesium, an ammonium salt or a salt with an organic base which provides a physiologically acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris- (2-hydroxyethyl) amine. Particular compounds of the invention include, for example, aminoheterocyclic derivatives of formula I or formula la, or pharmaceutically acceptable salts thereof, wherein unless otherwise stated, each of G1, G2, G3 , m, R1, M1, A, M2, M3, X and Q have any of the meanings defined hereinbefore or in this section with respect to the particular compounds of the invention: - (a) each of G1, G2 and G3 is CH; (b) each of G1 and G2 is CH and G3 is N, or G1 is N and each of G2 and G3 is CH; (c) m is 1 and R1 is hydrogen; (d) A is a direct link to the carbonyl group; (e) A is C1-4 alkylene; (f) M2 is a group of the formula (T2R4) r-L2-T3R5 in which r is 1, T2 is CH or N, T3 is CH or N, R4 is hydrogen or C1-4 alkyl, R ^ is hydrogen or C? _4 alkyl, or R4 and R5 together form an alkylene group of C1_4, or R4 is an alkylene group of C2_3, which is attached to a methylene group within L2 which forms a 5- or 6-membered ring involving R4 and T2, and L2 is ^ alkylene of C1-4, and in which 1 or 2 methylene group within L2 and the rings formed when R4 and R5 or R4 and L2 are "optionally added, carries a substituent selected from the group consisting of carboxy, cycloalkoxycarbonyl, 4 »carbamoyl, N-alkylcarbamoyl of C 1-4, N, N-di-alkylcarbamoyl of C 1-4, pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, morpholino-carbonyl, piperazin-l-ylcarbonyl-4-alkyl of c? -4 piperazin-1-ylcarbonyl, N-phenylcarbambil, C 1-4 alkyl and phenyl-C 1-4 alkyl; and wherein any heterocyclic group in the substituent, optionally bears 1 or 2 alkyl substituents of - ^ _ ^, and in which any phenyl group in M2 optionally bears 1 or 2 substituents selected from the group consisting of halogen, alkyl of 1-4 and C1-4 alkoxy; (g) M3 is a direct link to X; (h) M3 is a group of the formula L3- (NR6) in which s is 1, R6 is hydrogen or C1-4alkyl, L3 is C1-4alkylene or C1_3carbonyl-alkylene, and wherein 1 or 2 methylene groups within L3 optionally carries a substituent selected from the group consisting of C 1 -C 4 alkyl, C 1-4 hydroxy alkyl, and phenyl C 1 alkyl, and wherein any phenyl group in M 3 optionally bears 1 or 2 substituents selected from the group consisting of of halogen, C 1-4 alkyl and C 1-4 alkoxy; (i) X is thio, sulfinyl or sulfonyl; (j) X is sulfonyl; (k) X is carbonyl, carbonyloxy, carbonylamino or N-alkylcarbonylamino of C1_4; (1) X is sulfonylamino or, when T3 is CH and M3 is a direct bond with X, X may also be aminosulfonyl; (m) X is methylene, C1-4 alkylmethylene or C1-4 alkylmethylene; (n) Q is phenyl, naphthyl or phenyl-C1-4 alkyl, which optionally carries 1, 2 or 3 substituents selected from the group consisting of hydroxy, halogen, cyano, trifluoromethyl, alkyl of 1-4, alkoxy of C-, 4, phenyl, phenoxy, phenylthio, phenylsulfinyl, phenylsulfonyl, benzyl and benzoyl and wherein the phenyl substituent or the phenyl group on a phenyl substituent optionally carries 1 or 2 substituents selected from the group consisting of halogen, C1-6alkyl 4 and alkoxy Cl-4; (o) Q is phenyl which bears a phenyl substituent and optionally carries 1 or 2 substituents selected from the group consisting of hydroxy, halogen, c, trifluoromethyl, C1_4alkyl and C1_4alkoxy and in which the phenyl substituent optionally carries up to 4 substituents selected from the group consisting of halogen, trifluoromethyl, c, trifluoromethoxy, alkyl of 1-4 and alkoxy of C1_4; (p) Q is phenyl-C 1-4 alkyl, phenyl-C 2-4 alkenyl phenyl "C 2-4 alkynyl", which optionally bears 1, 2 or 3 substituents selected from the group consisting of halogen, c, trifluoromethyl, C1-4 alkyl and alkoxy q, Q is C2-4 phenyl-alkenyl which optionally bears 1, 2 or 3 substituents selected from the group consisting of halogen, c, trifluoromethyl, C1-4alkyl and C1-4alkoxy; (R) Q is phenyl or phenyl-alkyl C -, _ 4 which bears 1 substituent selected from the group consisting of heteroaryl, heteroaryloxy, heteroarylthio, heteroaryl sulphinyl and heteroarylsulphonyl, wherein the heteroaryl substituent or the heteroaryl group in a substituent containing heteroaryl comprising a monocyclic heteroaryl ring of 5 or 6 members containing up to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and wherein the heteroaryl or heteroaryl-containing substituent optionally bears 1 or 2 substituents selected of the group consisting of halogen, C 1-4 alkyl and C 1-4 alkoxy; (S) Q is phenyl which bears 1 substituent selected from the group consisting of heteroaryl, heteroaryloxy, heteroarylthio and heteroarylsulphonyl, wherein the heteroaryl substituent or the heteroaryl group in heteroaryl-containing substituent is selected from the group consisting of thienyl , pyridyl, pyrimidinyl, pyrazolyl, oxazolyl, thiazolyl, 1,2,3-triazolyl and 1,2,4-triazolyl, and wherein the heteroaryl or heteroaryl-containing substituent optionally carries 1 or 2 substituents selected from the group consisting of of halogen and alkyl of Cl-4; (t) Q is naphthyl, which optionally carries 1 or 2 substituents selected from the group consisting of hydroxy, halogen, c, trifluoromethyl, C-, 4- alkyl and alkoxy Cl-4; (U) Q is a heterocyclic moiety containing up to 2 heteroatoms selected from the group consisting of benzofuranyl, quinolyl, tetrahydroquinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, cinnolinyl, indolyl, benzimidazolyl, indazolyl, benzoxazolyl and benzothiazolyl, and Q optionally bears 1 or 2 substituents selected from the group consisting of halogen, c, trifluoromethyl, C-j__4 alkyl and C1_ ^ alkoxy; (V) Q is a heterocyclic moiety containing up to 2 heteroatoms selected from the group consisting of benzofuranyl, quinolyl, tetrahydroquinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, cinnolinyl, indolyl, benzimidazolyl, indazolyl, benzoxazolyl, benzothiazolyl, dibenzofuranyl and dibenzothienyl, and Q optionally it has 1 or 2 substituents selected from the group consisting of halogen, c, trifluoromethyl, C 1-4 alkyl and alkoxy Cl-4; () Q is a heterocyclic moiety containing up to 4 heteroatoms selected from the group consisting of furyl, thienyl, pyridyl, pyrimidinyl, pyrrolyl, pyrrolidinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1, 2, 3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl and tetrazolyl and Q optionally carries 1 or 2 substituents selected from the group consisting of halogen, c, carboxy, carbamoyl, C 1-4 alkoxycarbonyl, C 1-4 alkyl, C-alkoxy ? 4, N-alkylcarbamoyl of C 1-4 and N, N-di-alkylcarbamoyl of C 1-; (x) Q is a heterocyclic portion containing up to 2 heteroatoms selected from the group consisting of thienyl, pyridyl, pyrimidinyl, imidazolyl, pyrazolyl, oxazolyl and thiazolyl and Q optionally bears 1 or 2 substituents selected from the group consisting of halogen, alkyl of Cj._4, C 4 'alkoxy phenyl, heteroaryl, phenoxy, phenylthio, phenylsulfinyl, phenylsulfonyl, heteroaryloxy, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, benzyl and benzoyl, wherein the heteroaryl substituent or the heteroaryl group in a substituent containing heteroaryl is selected from the group consisting of thienyl, pyridyl, pyrimidinyl, pyrazolyl, oxazolyl and thiazolyl, and wherein the phenyl, the phenyl-containing heteroaryl or heteroaryl-containing substituent optionally carries 1 or 2 substituents selected from the group consisting of of halogen, alkyl of C-, _4 and alkoxy of Cj ^; or (and, Q is a heterocyclic moiety that comprises up to 2 heteroatoms selected from the group consisting of thienyl, pyridyl, oxazolyl and thiazolyl, and Q bears a substituent selected from the group consisting of phenyl, thienyl, pyridyl, pyrimidinyl , oxazolyl and thiazolyl, which substituent optionally carries 1 or 2 substituents selected from the group consisting of halogen, C 1-4 alkoxy alkyl of C 1 YQ optionally bears an additional substituent selected from the group consisting of halogen and C 1-4 alkyl; or its pharmaceutically acceptable salt A preferred compound of the invention is an aminoheterocyclic derivative of the formula I wherein each of G1, G2 and G3 is CH, or each of G1 and G2 is CH and G3 is N, or G1 is N and each of G2 and G3 is CH; m is 1 or 2 and each R ^ - is independently selected from hydrogen, amino, fluoro, chloro, bromo, cyano, methyl, ethyl and methoxy; M1 is a group of the formula NR2_L1_T1R3 wherein R2 and R3 together form an ethylene group.

L - * - is methylene or ethylene and T1 is CH or N, and wherein le *, methylene groups within L1 and the ring formed when R2 and R3 are optionally attached bears a substituent selected from the group consisting of methyl and ethyl; A is a direct bond to the carbonyl group or A is methylene; M2 is a group of the formula (T2R) r-L2-T3R5 in which r is O or 1, T2 is CH or N, T3 is N, R4 is hydrogen, methyl or ethyl, R ^ is hydrogen, methyl or ethyl or R4 and R5 together form a methyl, ethylene, trimethylene or methylenecarbonyl group, or R4 is an ethylene group which is attached to a methylene group within L2 which forms a 5- or 6-membered ring involving R4 and T2, and L2 is methylene, ethylene, trimethylene, methylenecarbonyl or phenylene, and wherein 1 or 2 methylene groups within L2 and the ring formed when R4 and R ^ are together optionally bears a substituent selected from the group consisting of oxo, carboxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl, N-methylcarbamoyl , N, N-dimethylcarbamoyl, pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, morpholinocarbonyl, piperazin-1-ylcarbonyl, 4-methylpiperazin-1-ylcarbonyl, methyl, ethyl, carboxymethyl, ethoxycarbonylmethyl, ethoxycarbonylmethyl, hydroxymethyl, methoxymethyl and benzyl, and that the pyrrolidin-1-ylcarbonyl substituent, piperidinocarbo nyl, morpholinocarbonyl, piperazin-1-ylcarbonyl or 4-methylpiperazin-1-ylcarbonyl optionally bears a methyl or ethyl substituent; M3 is a direct link to X, or M3 is a group of the formula L3- (NR6) in which s is 1, R6 is hydrogen and L3 is carbonylmethylene or carbonylethylene; X is thio, sulfinyl, sulfonyl, carbonyl, carbonyloxy or methylene; and Q is phenyl, naphthyl, benzyl, phenethyl, styryl, 2-phenylethynyl, dibenzofuranyl, biphenylyl, pyridylphenyl or pyridylthienyl, and Q optionally bears 1, 2 or 3 substituents selected from the group consisting of hydroxy, amino, fluoro, chlorine, bromine , iodo, cyano, trifluoromethyl, nitro, carboxy, carbamoyl, methoxycarbonyl, ethoxycarbonyl, methyl, ethyl, methoxy and ethoxy; or its pharmaceutically acceptable salt. A further preferred compound of the invention is an aminoheterocyclic derivative of the formula I, wherein each of G1, G2 and G3 is CH, or each .'_ ac - and G2 is CH and G3 is N, or G1 is N and each of G2 and G3 is CH; m is 1 or 2 and each R1 is independently selected from hydrogen, amino, chloro, methyl and ethyl; M1 is a group of the formula NR2-L1-T1R3 wherein R2 and R3 together form an ethylene group, L1 is ethylene, and T1 is CH or N; A is a direct bond with the carbonyl group or A is methylene; M2 is a group of the formula (T2R4) r-L2-T3R5 wherein r is 0 or 1, T2 is N, T3 is N, R4 is hydrogen, R5 is hydrogen, or R4 and R5 together form an ethylene group or R4 is an ethylene group which is attached to a methylene group within L2 forming a 5 or 6 membered ring involving R4 and T2, and L2 is methylene, ethylene or phenylene, and wherein 1 or 2 methylene groups within L2 and the ring formed when R4 and R5 are optionally attached, carries a substituent selected from the group consisting of carboxy, methoxycarbonyl, ethoxycarbonyl, pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, morpholinocarbonyl, piperazin-1-ylcarbonyl, 4-methylpiperazin-1-ylcarbonyl, methyl, ethyl and benzyl and wherein the substituent pyrrolidin -1-ylcarbonyl, piperidinocarbonyl, morpholinocarbonyl, piperazin-1-ylcarbonyl or 4-methylpiperazin-1-ylcarbonyl optionally bears a methyl or ethyl substituent; M3 is a direct link to X, or M3 is a group of the formula L3- (NR6) S wherein s is 1, R6 is hydrogen and L3 is carbonylmethylene; X is sulfonyl; and Q is phenyl, naphthyl, benzyl, phenethyl, styryl, 2-phenylethynyl, dibenzofuranyl, biphenylyl, pyridylphenyl or pyridylthienyl and Q optionally bears 1 or 2 substituents selected from the group consisting of fluoro, chloro, bromo, iodo, methyl, ethyl, methoxy and ethoxy; or its pharmaceutically acceptable salt. A further preferred compound of the invention is an aminoheterocyclic derivative of the formula la, wherein each of G1 and G2 is CH; m is 1 and R1 is hydrogen; M1 is a group of the formula N 2_L1_T1R3 wherein R 2 and R 3 together form an ethylene group, L 1 is methylene or ethylene, and T 1 is CH or N, and wherein 1 or 2 methylene groups within L 1 and the ring formed when R 2 and R 3 are optionally attached, carries a substituent selected from the group consisting of methyl and ethyl; A is a direct bond with the carbonyl group or A is methylene; M2 is a group of the formula (T2R) r-L2-T3R5 wherein r is 1, T2 is CH or N, T3 is N, R4 is hydrogen, methyl or ethyl, R5 is hydrogen, methyl or ethyl or R4 and R5 together form an ethylene group or R "ee" n ethylene group, which is attached to a methylene group within L2 which forms a 5- or 6-membered ring involving R4 and T2, and L2 is tethylene, ethylene or trimethylene, and ... - q_ ~ 1 t 2 methylene groups within L2 and the ring formed when R4 and R5 are optionally attached, carries a substituent selected from the group consisting of carboxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl, N-methylcarbamoyl, N, N-dimethylcarbamoyl, pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, methyl, ethyl and benzyl and wherein the substituent pyrrolidin-1-ylcarbonyl or piperidinocarbonyl optionally bears a methyl or ethyl substituent; M3 is a direct link to X, or M3 is a group of the formula L3- (NR6) S wherein s is 1, R6 is hydrogen and L3 is carbonylmethylene or carbonylethylene; X is sulfonyl; and Q is phenyl, 2-naphthyl or benzyl which optionally bears 1 or 2 substituents selected from the group consisting of fluoro, chloro, bromo and trifluoromethyl; or its pharmaceutically acceptable salt. A further preferred compound of the invention is an aminoheterocyclic derivative of the formula I, wherein G3 is CH or N and each of G1 and G2 is CH; m is 1 and R1 is hydrogen; 1 is a group of the formula NR2_L1_T1R3 wherein R2 and R3 together form an ethylene group, L1 is methylene or ethylene, and T1 is CH or N, and wherein 1 or 2 methylene groups within L1 and the ring formed when R2 and R3 are optionally attached, bears a substituent selected from the group consisting of methyl and ethyl; A is a direct bond with the carbonyl group or A is methylene; M2 is a group of the formula (T2R) r-L2-T3R5 wherein r is 1, T2 is CH or N, T3 is N, R4 is hydrogen, methyl or ethyl, R5 is hydrogen, methyl or ethyl or R4 and R5 together form a methylene, ethylene or trimethylene group, or R4 is a ethylene group, which is attached to ur. methylene group within L2 which forms a 5 or 6 membered ring involving R4 and T2, and L2 is methylene, ethylene or trimethylene, and in which 1 or 2 methylene groups within L2 and c. ar.-ll: r-.áác c ar.do R4 and R ^ are joined opcicr.al-er. *. a substituent selected from the group consisting of oxo, carboxy, methoxycarbonyl, ethoxycarbomoryl, carbamoyl, N-methylcarbamoyl, N, N-dimethylcarbamoyl, pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, morpholinocarbonyl, methyl, ethyl and benzyl and in which the substituent pyrrolidin-1-icarbony or piperidinocarbonyl optionally bears one or doe methyl or ethyl substituents; M- is a direct link to X, or M3 is a group of the formula L3- (NR6) wherein s is 1, R6 is hydrogen and L3 is carbonylmethylene or carbonylethylene; X is sulfonyl; and 0 is 3- or 4-biphenylyl, which optionally bears, on the X-linked ring, 1 or 2 substituents selected from the group consisting of hydroxy, fluoro, chloro, bromo, cyano, trifluoromethyl, methyl, ethyl, methoxy and ethoxy and which optionally bears in the terminal phenyl group up to 4 substituents selected from the group consisting of fluoro, chloro, bromo, trifluoromethyl, cyano, trifluoromethoxy, methyl, ethyl, methoxy and ethoxy; or its pharmaceutically acceptable salt. tt_ additional preferred compound of the invention. It's ur. arrinoheterocyclic derivative of the formula I, er. that G3 is CH or N and each of G1 and G2 is CH; is 1 and R1 is hydrogen; M1 is a group of the formula NR2-L1-T1R3 er. wherein R2 and R3 together form an ethylene group, L1 is methylene or ethylene, and T1 is CH or N, and wherein 1 or 2 methylene groups within L1 and the ring formed when R2 and R3 are optionally attached, carries a substituent selected from the group consisting of methyl and ethyl; A is a direct bond with the carbonyl group or A is methylene; M2 is a group of the formula (T2R4).-L2-T3R5 wherein r is 1, T2 is CH or N, T3 is N, R4 is hydrogen, methyl or ethyl, R ^ is hydrogen, methyl or ethyl or R4 and R5 together form a methylene, ethylene or trimethylene group, or R4 is an ethylene group, which is bonded to a "useful" ring within L2 that forms a ring of 5 or 6 members that go to R4 and T, and L2 is methylene, ethylene or trimethylene, and in wherein 1 or 2 methylene groups within L2 and the ring formed when R4 and R ^ are optionally attached, carries a substituent selected from the group consisting of oxo, carboxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl, N-methylcarbamoyl, N, N- dimethylcarbamoyl, pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, morpholinocarbonyl, methyl, ethyl and benzyl and wherein the substituent pyrrolidin-1-ylcarbonyl or piperidinocarbonyl optionally bears one or two methyl or ethyl substituents; M3 is a direct link to X, or M3 is a group of the formula L3- (NR6) S wherein s is 1, R6 is hydrogen and L3 is carbonylmethylene or carbonylethylene; X is sulfonyl; and Q is benzyl, phenethyl, styryl or 2-phenylethynyl which optionally bears 1, 2 or 3 substituents selected from the group consisting of fluoro, chloro, bromo, cyano, trifluoromethyl, methyl, ethyl, methoxy and ethoxy; or its pharmaceutically acceptable salt. A further preferred compound of the invention is an aminoheterocyclic derivative of the formula la, wherein each of G ^ - and G2 is CH; m is 1 and R1 is hydrogen; M1 is a group of the formula NR2-L1-T1R3 wherein R 2 and R 3 together form an ethylene group, L 1 is methylene or ethylene, and T 1 is CH or N, and wherein 1 or 2 methylene groups within L 1 and the ring formed when R 2 and R 3 are optionally attached, carries a substituent selected from the group consisting of methyl and ethyl; A is a direct bond with the carbonyl group or A is methylene; M2 is a group of the formula (T2R4) r-L2-T3R5 wherein r is 1, T2 is CH or N, T3 is N, R4 is hydrogen, methyl or ethyl, R ^ is hydrogen, methyl or ethyl or R4 and R5 together form an ethylene group or R4 is an ethylene group, which is attached to a methylene group within L2 which forms a 5 or 6 membered ring which involves R4 and T2, and L2 is methylene, ei or tethylene, and in which 1 or 2 methylene groups within L2 and the ring formed when R4 and R5 are optionally attached, bears a substituent selected from the group consisting of carboxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl, N-methylcarbamoyl, N, N-dimethylcarbamoyl, pyrrolidin-1-ylcarbonyl, piperidmocarbonyl, methyl, ethyl and benzyl and wherein the substituent pyrrolidin-1-ylcarbonyl or piperidinocarbonyl optionally bears a methyl or ethyl substituent; M3 is a direct link to X, or M3 is a group of the formula L3- (NR6) S wherein s is 1, R6 is hydrogen and L3 is carbonylmethylene or carbonylethylene; X is sulfonyl; and Q is 2-thienyl which bears a substituent selected from the group consisting of phenyl, thienyl, pyridyl and pyrimidinyl and wherein the substituents optionally carry 1 or 2 substituents selected from the group consisting of fluoro, chloro, bromo and methyl; or its pharmaceutically acceptable salt. A further preferred compound of the invention is a moheterocyclic derivative of the formula I, wherein G3 is CH or N and each of G1 and G2 is CH; m is 1 and R1 is hydrogen; M1 is a group of the formula NR2_ 1_T1R3 wherein R 2 and R 3 together form an ethylene group, L 1 is methylene or ethylene, and T 1 is CH or N, and wherein 1 or 2 methylene groups within L 1 and the ring formed when R 2 and R 3 are optionally attached, carries a substituent selected from the group consisting of methyl and ethyl; A is a direct bond with the carbonyl group or A is methylene; M2 is a group of the formula (T2R) r-L2 -T3R5 wherein r is 1, T2 is CH or N, T3 is N, R4 is hydrogen, methyl or ethyl, R5 is hydrogen, methyl or ethyl or R4 and R5 together form an ethylene group, or R4 is an ethylene group, which is attached to a methylene group within L2 that forms a 5 or 6 membered ring that involves R4 and T2, and L2 is methylene, ethylene c.rrt; .e:.;, and in which 1 or 2 methylene groups within? and the ring formed when R4 and R5 are optionally attached, bears a substituent selected from the group consisting of carboxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl, N-methylcarbamoyl, N, N-dimethylcarbamoyl, pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, morfoiinocarbonyl, methyl, ethyl and benzyl and wherein the substituent pyrrolidin-1-ylcarbonyl or piperidinocarbonyl optionally bears a methyl or ethyl substituent; M3 pfi? N direct link to X, or M3 is a group of the formula L3- (NR6) S wherein s is 1, R6 is hydrogen and L3 is carbonylmethylene or carbonylethylene; X is his Jfonilo; and Q is 3- or 4-biphenylyl, which optionally bears in the terminal phenyl group up to 4 substituents selected from the group consisting of fluoro, chloro, bromo, trifluoromethyl, trifluoromethoxy, methyl and methoxy; or its pharmaceutically acceptable salt. A further preferred compound of the invention is an aminoheterocyclic derivative of the formula I, wherein G3 is CH or N and each of G1 and G2 is CH; m is 1 and R1 is hydrogen; 1 is a group of the formula NR2-L1-T1R3 wherein R 2 and R 3 together form an ethylene group, L 1 is methylene or ethylene, and T 1 is CH or N, and wherein 1 or 2 methylene groups within L 1 and the ring formed when R 2 and R 3 are optionally attached, carries a substituent selected from the group consisting of methyl and ethyl; A is a direct bond with the carbonyl group or A is methylene, - M2 ñ. a group of the formula. '.. • (T2R4) r-L2-T3R5 wherein r is 1, T2 is CH or N, T3 is N, R4 is hydrogen, methyl or ethyl, R ^ is hydrogen, methyl or ethyl or 4 and 5 together form an ethylene group, or R4 is an ethylene group, which is attached to a methylene group within L2 which forms a 5- or 6-membered ring involving R4 and T2, and L2 is methylene, ethylene or trimethylene, and in which 1 or 2 methylene groups within L2 and the ring formed when R4 and R5 are optionally attached, bears a substituent selected from the group consisting of carboxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl, N-methylcarbamoyl, N, -dimethylcarbamoyl, pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, morpholinocarbonyl, methyl, ethyl and benzyl and wherein the pyrrolidin-1-ylcarbonyl or piperidinocarbonyl substituent optionally bears a methyl or ethyl substituent; M3 is a direct link to X, or M3 is a group of the formula L3- (NR6) S wherein s is 1, R6 is hydrogen and L3 is carbonylmethylene or carbonylethylene; X is sulfonyl; and Q is phenethyl, styryl or 2-phenylethynyl which optionally bears 1, 2 or 3 substituents selected from the group consisting of fluoro, chloro, bromo, trifluoromethyl, methyl and methoxy; or its pharmaceutically acceptable salt. A further preferred compound of the invention is an aminoheterocyclic derivative of the formula la, wherein each of G1 and G2 is CH; m is 1 and R1 is hydrogen; 1 is a group of the formula NR2-L1-T1R3 in the group R2 and R3 together form an ethylene group, IJ1 ep ethylene, and T1 e. < ! CU or N, A is a direct bond with the carbonyl group; M2 e;; a group of the formula; T2R4) ^ - L2-T3R5 wherein r is 1, T2 is N, T3 is N, R4 is hydrogen, R5 is hydrogen, or R4 and R5 together form an ethylene group, and L2 is ethylene and wherein 1 methylene group within L2 optionally bears an substituent selected from carboxy, ethoxycarbonyl, N-methylcarbamoyl, piperidinocarbonyl and benzyl; M is a direct link to X, or M3 is a group of the formula L3- (NR6: wherein s is 1, R6 is hydrogen and L3 is carbonylmethylene; and Q is 2-naphthyl; or its pharmaceutically acceptable acid addition salt. A further preferred compound of the invention is an aminoheterocyclic derivative of the formula la, wherein each of G1 and G2 is CH, G1 is N and G2 is CH or G1 is CH and G2 is N; m is 1 and R1 is hydrogen; M1 is a group of the formula NR2-L1-T1R3 in which R2 and R3 together form an ethylene group, L1 is ethylene, and T1 is CH or N; A is a direct bond with the carbonyl group; M2 is a group of the formula (T2R4) r-L2-T3R5 wherein r is 1, T2 is N, T3 is N, R4 is hydrogen, R5 is hydrogen, or R4 and R5 together form an ethylene group, and L2 is ethylene and wherein 1 methylene group within L2 optionally bears an substituent selected from carboxy, ethoxycarbonyl, N-methylcarbamoyl, piperidinocarbonyl, methyl and benzyl; M3 is a direct link with X, - or M3 is a group of the formula L3- (NR6) wherein s is 1, R6 is hydrogen and L3 is carbonylmethylene; X is sulfonyl; and Q is 2-naphthyl, which optionally carries 1 or 2 substituents selected from the group consisting of fluoro, chloro, bromo, trifluoromethyl, methyl, methoxy and ethoxy; or its pharmaceutically acceptable acid addition salt A further preferred compound of the invention is an aminoheterocyclic derivative of the formula I, wherein each of G1, G2 and G3 is CH, is 1 and R1 is hydrogen; a group of the formula- NR2_L1_T1R3 wherein R2 and R3 together form an ethylene group, L1 is ethylene, and J T1 is CH or N; A is a direct bond with the carbonyl group; M2 is a group of the formula, (T2R4) r-L2 T3R5 wherein r is 1, T2 is N, T3 is N, R4 is hydrogen, R5 is hydrogen, or R4 and R5 together form an ethylene group, and L2 is ethylene and wherein 1 methylene group within L2 optionally bears an substituent selected from carboxy, ethoxycarbonyl, N-methylcarbamoyl, piperidinocarbonyl and benzyl; M3 is a direct link to X, or M3 is a group of the formula L3- (NR6) S wherein s is 1, R6 is hydrogen and L3 is carbonylmethylene; X is sulfonyl; and Q is 4-biphenylyl, which bears in the terminal phenyl group 1 or 2 substituents selected from fluoro, chloro, bromo, trifluoromethyl and methyl; or its pharmaceutically acceptable acid addition salt. A further preferred compound of the invention is an aminoheterocyclic derivative of the formula I, wherein each of G1, G2 and G3 is CH, G1 is N and each of G2 and G3 is CH or G3 is N and each of G1 and G2 is CH; m is 1 and R1 is hydrogen; M1 is a group of the formula NR2_L1_T1R3 wherein R2 and R3 together form an ethylene group, L1 is ethylene, and T1 is CH or N; A is a direct bond with the carbonyl group; M2 is a group of the formula (T2R4) V - L2-T3R5 wherein r is 1, T2 is N, T3 is N, R4 is hydrogen, R5 is hydrogen, or R4 and R5 together form an ethylene group, and L2 is ethylene and wherein 1 methylene group within L2 optionally bears an substituent selected from carboxy, ethoxycarbonyl, N-methylcarbamoyl, piperidinocarbonyl, methyl and benzyl; M3 is a direct link to X, or M3 is a group of the formula L3- (NR6) s wherein s is 1, R6 is hydrogen and L3 is carbonylmethylene; X is sulfonyl; and Q is 4-biphenylyl, which bears in the terminal phenyl group 1 or 2 substituents selected from fluoro, chloro, bromo, trifluoromethyl and methyl; or its pharmaceutically acceptable acid addition salt. A further preferred compound of the invention is an aminoheterocyclic derivative of the formula I, wherein each of G1, G2 and G3 is CH; m is 1 and R1 is hydrogen; M1 is a group of the formula NR2-L1-T1R3 wherein R2 and R3 together form an ethylene group, L1 is ethylene, and T1 is CH or N; A is a direct bond with the carbonyl group; M2 is a group of the formula (T2R4) r-L2-T3R5 wherein r is 1, T2 is N, T3 is N, R4 is hydrogen, R5 is hydrogen, or R4 and R5 together form an ethylene group, and L2 is ethylene and wherein 1 methylene group within L2 optionally bears an substituent selected from carboxy, ethoxycarbonyl, N-methylcarbamoyl, piperidinocarbonyl and benzyl; M3 is a direct link to X, or M3 is a group of the formula (NR6) in which s is 1, Rb is hydrogen and L3 is carbonyl ethylene; X is sulfonyl; and Q is styryl which optionally carries 1 or 2 substituents selected from the group consisting of fluoro, chloro, bromo, trifluoromethyl and methyl; or its pharmaceutically acceptable acid addition salt. A further preferred compound of the invention is an aminoheterocyclic derivative of the formula I, wherein each of G1, G2 and G3 is CH, G1 is N and each of G2 and G3 is CH or G3 is N and each of G1 and G2 is CH; m is 1 and R1 is hydrogen; M1 is a group of the formula NR2-L1-T1R3 wherein R2 and R3 together form an ethylene group, L1 is ethylene, and T1 is CH or N; A is a direct bond with the carbonyl group, - M2 is a group of the formula (T2R4) ^ - L2-T3R5 in which r is 1, T2 is N, T3 is N, R4 is hydrogen, R5 is hydrogen, or R4 and R5 together form an ethylene group, and L2 is ethylene and wherein methylene group within L2 optionally bears a substituent selected from carboxy, ethoxycarbonyl, N-methylcarbamoyl, piperidinocarbonyl, methyl and benzyl; M3 is a direct link to X, or M3 is a group of the formula L3- (NR6) wherein s is 1, R6 is hydrogen and L3 is carbonylmethylene; X is sulfonyl; and Q is styryl which optionally carries 1 or 2 substituents selected from the group consisting of fluoro, chloro, bromo, trifluoromethyl and methyl; or its pharmaceutically acceptable acid addition salt. A specific preferred compound of the invention is the following aminoheterocyclic derivative of the formula I: 2- (2-naphthalenesulfonamido) -N-. { 1-piperidinocarbonyl-2- [1- (4-pyridyl) -piperidin-4-ylcarbonylamino] ethyl} acetamide, 1- (2-naphthylsulfonyl) -4- [1- (4-pyridyl) piperidin-4-ylcarbonyl] -piperazine, 2- (2-naphthalenesulfonamido) -N- (1-piperidinocarbonyl-2-. {2- [2- 1- (4-pyridyl) piperidin-4-yl] acetamido.} Ethyl) acetamide, 2- (2-naphthalenesulfonamido) -N- (1-piperidinocarbonyl-2- { 2- [4- (4-pyridyl ) piperazin-l-yl] acetamido.} ethyl) acetamide, ethyl 2- (2-naphthalenesulfonamido) -3- [1- (4-pyridyl) -piperidin-4-ylcarbonylamino] propionate, 1- [1- ( 2-naphthylsulfonyl) piperidin-4-ylcarbonyl] -4- (4-pyridyl) -piperazine or 2- (2-naphthalenesulfonamido) -N-. { l-Phenyl-3- [1- (4-pyridyl) piperidin-4-ylcarbonylamino] prop-2-yl} ethyl) acetamide; or its pharmaceutically acceptable acid addition salt. A further specific preferred compound of the invention is the following aminoheterocyclic derivative of the formula I: 4- [1- (4-pyridyl) piperidin-4-ylcarbonyl] -1- [(E) -styrylsulfonyl] -piperazine, 1- [(E) -4-chlorostyrylsulfonyl] -4- [1- (4-pyridyl) -piperidin-4-ylcarbonyl] piperazine, 1- [(E) -4-methylstyrylsulfonyl] -4- [1- (4-pyridyl ) -piperidin-4-ylcarbonyl] piperazine, 4- [(E) -4-chlorostyrylsulfonyl] -2-methyl-1- [1- (4-pyridyl) piperidin-4-ylcarbonyl] piperazine, 1- (4-biphenylsulfonyl) ) -4- [1- (4-pyridyl) piperidin-4-ylcarbonyl] -piperazine, 1- (4'-chloro-4-biphenylylsulfonyl) -4- [1- (4-pyridyl) -pipéridin-4-ylcarbonyl ] piperazine or 1- [(E) -4-chlorostyrylsulfonyl] -4- [1- (4-pyrimidyl) -piperidin-4-ylcarbonyl] piperazine; or its pharmaceutically acceptable acid addition salt. A further specific preferred compound of the invention is the following aminoheterocyclic derivative of the formula I: 1- (7-chloronaphth-2-ylsulfonyl) -4- [1- (4-pyridyl) -piperidin-4-ylcarbonyl] piperazine , 2-ethoxycarbonyl-4- (2-naphthylsulfonyl) -1- [1- (4-pyridyl) piperidin-4-ylcarbonyl] piperazine or 1- (2-naphthylsulfonyl) -4- [1- (4-pyrimidinyl) piperidin -4-carbonyl) -piperazine; or its pharmaceutically acceptable acid addition salt. A further specific preferred compound of the invention is the following aminoheterocyclic derivative of the formula I: - 1- [(E) -4-fluoro-styrylsulfonyl] -4- [1- (4-pyridyl) -piperidin-4-ylcarbonyl] piperazine , 1- [(E) -4-bromo-styrylsulfonyl] -4- [1- (4-pyridyl) -piperidin-4-ylcarbonyl] piperazine, or 1- (4'-bromo-4-biphenylylsulfonyl) -4- [1 - (4-pyridyl) -piperidin-4-ylcarbonyl] piperazine; or its pharmaceutically acceptable acid addition salt. A further specific preferred compound of the invention is the following aminoheterocyclic derivative of the formula I: 1- (6-chloronaphth-2-ylsulfonyl) -4- [1- (4-pyridyl) -piperidin-4-ylcarbonyl] piperazine , 1- (6-bromonaphth-2-ylsulfonyl) -4- [1- (4-pyridyl) -piperidin-4-ylcarbonyl] piperazine, 1- (6-chloronaphth-2-ylsulfonyl) -4- [4- ( 4-pyridyl) -piperidin-1-ylcarbonyl] piperazine, 4- (2-naphthylsulfonyl) -2-piperidinocarbonyl-l- [1- (4-pyridyl) -piperidin-4-ylcarbonyl] piperazine, 4- (6-chloronaft -2-ylsulfonyl) -2-ethoxycarbonyl-1- [1- (4-pyridyl) -piperidin-4-ylcarbonyl] piperazine, 2-carboxy-4- (6-chloronaphth-2-ylsulfonyl) -1- [1- (4-pyridyl) piperidin-4-ylcarbonyl] piperazine, 1- (6-chloronaphth-2-ylsulfonyl) -4- [1- (4-pyrimidinyl) -piperidin-4-ylcarbonyl] piperazine, 4- [1- ( 2-aminopyrimidin-4-yl) piperidin-4-ylcarbonyl] -1- (6-chloronaphth-2-ylsulfonyl) piperazine, or 1- (6-chloronaphth-2-ylsulfonyl) -4- [1- (4-pyridazinyl ) -piperidin-4-ylcarbonyl] piperazine; or its pharmaceutically acceptable acid addition salt. A further specific preferred compound of the invention is the following aminoheterocyclic derivative of the formula I: 4- (6-bromonaphth-2-ylsulfonyl) -2-ethoxycarbonyl-1- [1- (4-pyridyl) -piperidin-4 -ylcarbonyl] piperazine, 4- (6-bromonaphth-2-ylsulfonyl) -2-carboxy-l- [1- (4-pyridyl) piperidin-4-ylcarbonyl] piperazine, 4- (6-bromonaphth-2-ylsulfonyl) -2-morpholinocarbonyl-l- [1- (4-pyridyl) piperidin-4-ylcarbonyl] piperazine, 4- (6-chloronaphth-2-ylsulfonyl) -2-methoxycarbonyl-1- [1- (4-pyridyl) - piperidin-4-ylcarbonyl] piperazine or 2-carboxy-4- (6-chloronaphth-2-ylsulfonyl) -1- [1- (4-pyridyl) piperidin-4-ylcarbonyl] piperazine; or its pharmaceutically acceptable salt. An aminoheterocyclic derivative of formula I or formula la, or its pharmaceutically acceptable salt, can be prepared by any known process that is applicable to the preparation of structurally related compounds. Such procedures are provided as another feature of the invention and are illustrated by the following representative processes in which, unless otherwise stated, G1, G2, G3, m, R1, M1, A, M2, M3, X and Q (and any of the groups defined therein) have any of the meanings defined in the foregoing, with the proviso that when there is an amino, alkylamino, hydroxy or carboxy group in R1, M1, M2, M3 or Q then either of such group is protected by a conventional protective group, which can be eliminated when desired by conventional means. The necessary initial materials can be obtained by standard procedures of organic chemistry. The preparation of such starting materials is illustrated within the appended Examples; Alternatively analogous procedures, to those illustrated, can be employed by applying no more than the ordinary skill of an organic chemist. (a) For the production of those compounds of the formula I, wherein M2 is a group of the formula (T2R4) _- L2-T3R5 wherein T2 is N and r is 1, the reaction, conveniently in the presence of a suitable base, of an acid of the formula II, or a reactive derivative thereof, with an amine of the formula HNR4-L2-T3R5-M3-XQ A suitable reactive derivative of an acid of the formula II is, for example, an acyl halide, for example an acyl chloride formed by the reaction of the acid and an inorganic acid chloride, for example thionyl chloride; a mixed anhydride, for example an anhydride formed by the reaction of the acid and a chloroformate such as isobutyl chloroformate; an active ester, for example an ester formed by the reaction of the acid and a phenol such as pentafluorophenol, an ester such as pentafluorophenyl trifluoroacetate or an alcohol such as N-hydroxybenzotriazole or N-hydroxysuccinimide; an acyl azide, for example an azide formed by the reaction of the acid and an azide such as diphenylphosphoryl azide; an acyl cyanide, for example a cyanide formed by the reaction of an acid and a cyanide such as diethylphosphoryl cyanide; or the product of the reaction of the acid and a carbodiimide such as N, N'-dicyclohexylcarbodiimide or N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide. The reaction is conveniently carried out in the presence of a suitable base such as, for example, an alkali metal or alkaline earth metal carbonate, alkoxide, hydroxide or hydride, for example sodium carbonate, potassium carbonate, sodium ethoxide, potassium butoxide , sodium hydroxide, potassium hydroxide, sodium hydride or potassium hydride, or an organometallic base such as an alkyl lithium, for example n-butyllithium or a dialkylamino lithium, for example lithium di-isopropylamide or, for example, an organic amine base 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, dimethyl sulfoxide or acetone and a temperature in the range , for example -78 ° to 150 ° C, conveniently at or near room temperature. A suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl group, ethoxycarbonyl or tert-butoxycarbonyl, an arylmethoxycarbonyl group, for example benzyloxycarbonyl or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of the protecting group. In this way, for example an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group can be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a tert-butoxycarbonyl group can be removed, for example, by treatment with a suitable acid such as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group can be removed, for example, by hydrogenation on a catalyst such as carbon in palladium or by treatment with a Lewis acid for example boron tris (trifluoroacetate). An alternative protecting group suitable for a primary amino group is, for example, a phthaloyl group which can be removed by treatment with an alkylamine, for example dimethylaminopropylamine or with hydrazine. A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of the protecting group. In this way, for example, an acyl group such as an alkanoyl group or an aroyl group can be removed, for example by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively, an arylmethyl group such as a benzyl group can be removed, for example, by hydrogenation over a catalyst such as palladium carbon. A suitable protecting group for a carboxy group is, for example, an esterified group, for example a methyl group or an ethyl group, which can be removed, for example, by hydrolysis with a base such as sodium hydroxide or for example a tert-butyl group which can be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid or for example a benzyl group which can be removed, for example, by hydrogenation on a catalyst such as Palladium coal. (b) For the production of those compounds of the formula I, wherein M2 is a group of the formula (T2R) r-L2-T3R5 wherein T3 is N, and wherein M3 is a direct bond with X, the reaction, conveniently in the presence of a suitable base as defined above, of an amine of formula III with a compound of the formula ZXQ , in which Z is a replaceable group.

A suitable value for the replaceable group Z is, for example, a halogen or sulphonyloxy group, for example a fluoro, chloro, bromo, mesyloxy or 4-tolylsulphonyloxy group. The reaction is conveniently carried out in a suitable inert solvent or diluent as defined above and at a temperature in the range, for example, 0 ° C to 150 °, conveniently at or near room temperature. (c) For the production of those compounds of the formula I, wherein M1 is a group of the formula NR2_ 1_T1R3 wherein T1 is N, and wherein A is a direct bond to the carbonyl group, the reaction, conveniently in the presence of a suitable base as defined above, of an amine of formula IV with an acid of the formula H02C-M2-M3-X-Q or its reactive derivative as defined in the foregoing. The reaction is conveniently carried out in a suitable inert solvent or diluent as defined above and at a temperature in the range, for example, 0 ° to 150 ° C, conveniently at or near room temperature. (d) For the production of those compounds of the formula I, wherein M2 is a group of the formula (T2R4) r-L2-T3R5 in which T3 is N, and in which M3 is a group of the formula L3- (NR6) S wherein L3 is carbonylmethylene, the reaction, conveniently in the presence of a suitable base as defined above, of an amine of formula III with an acid of the formula H02C-CH2- (NR6) S-X-Q or its reactive derivative as defined in the foregoing. The reaction is conveniently carried out in an inert solvent or diluent, suitable as defined above and at a temperature in the range, for example, 0 ° to 150 ° C, conveniently at or near room temperature. (e) For the production of those compounds of the formula I, wherein M2 is a group of the formula (T2R) r-L2-T R5 wherein T3 is N, and wherein M3 is a direct bond with X and X is carbonylamino, the reaction of an amine of formula III with an isocyanate of the formula OCN-X-Q The reaction is conveniently carried out in an inert solvent or diluent, suitable as defined above and at a temperature in the range, for example, 0 to 60 ° C, conveniently at or near room temperature. (f) The reaction, conveniently in the presence of a base as defined above, of a compound of formula V, wherein Z is a replaceable group as defined above, with an amine of the formula HNR2-L1-T1R3-A-CO-M2-M3-X-Q The reaction is conveniently carried out in an inert solvent or diluent, suitable as defined above and at a temperature in the range, for example, 0 ° to 150 ° C, conveniently in the range of 15 ° to 100 ° C. (g) For the production of those compounds of the formula I, wherein M2, M3 or Q bears a carboxy or carboxy-containing group, the hydrolysis of a compound of the formula I, in which M2, M3 or Q carries a C 1-4 alkoxycarbonyl group. The hydrolysis reaction can conveniently be carried out in a conventional manner which is used, for example in acidic or basic catalysts. An acid suitable for the acid hydrolysis of an ester group is, for example, an inorganic acid such as hydrochloric or sulfuric acid. A suitable base for the basic hydrolysis of an ester group is, for example, an alkali metal or alkaline earth metal hydroxide such as sodium hydroxide or potassium hydroxide. The reaction is conveniently carried out in a suitable solvent or diluent such as an alcohol, for example methanol or ethanol and at a temperature in the range, for example, 0 ° to 120 ° C, conveniently in the range of 15 ° to 60 ° C. (h) For the production of those compounds of the formula I, wherein M2, M3 or Q bears a carbamoyl, N-alkylcarbamoyl or N, N-dialkylcarbamoyl group, the reaction of a compound of formula I, wherein M2, M3 or Q bears a carboxy group or its reactive derivative as defined above, with ammonia or an appropriate alkylamine or dialkylamine. The reaction is conveniently carried out in an inert solvent or diluent, suitable as defined above and at a temperature in the range, for example, 0 ° to 120 ° C, conveniently in the range of 15 ° to 60 ° C. (i) For the production of those compounds of the formula I, in which Q carries a hydroxy group, the dealkylation of a compound of the formula I, wherein Q bears a C1-4 alkoxy group. A suitable dealkylating reagent is, for example, any of the many reagents known to effect such transformation. The reaction can be carried out, for example by using a C 1-4 alkylsulfide of metal aralir.such as sodium ethanethiolate or, for example, using an alkali metal diarylphosphide such as lithium diphenylphosphide. Alternatively, the reaction can be conveniently carried out using a boron or aluminum trihalide such as boron tribromide. The dealkylation reaction is conveniently carried out in an inert solvent or diluent, suitable as defined above and at a temperature in the range, for example, from -80 ° to 100 ° C, conveniently in the range of 0 ° to 50 °. C.

When a pharmaceutically acceptable salt of a compound of the formula I is required, it can be obtained, for example, by reacting the compound with a suitable acid or base using a conventional procedure. When an optically active form of a compound of formula I is required, it can be obtained, for example, by carrying out one of the above-mentioned processes using an optically active starting material or by resolution of a racemic form of the compound using a conventional procedure. As previously stated, the compounds of formula I and formula la are inhibitors of the factor Xa enzyme. The effects of this inhibition can be demonstrated using one or more of the standard procedures established in the above: a; Measurement of Factor Xa Inhibition An in vitro testing system was carried out based on the method of Kettner et al. , J. Biol. Chem., 1990, 265, 18289-18297, whereby several concentrations of a test compound are dissolved in a buffer at pH 7.5, containing 0.5% polyethylene glycol and incubated at 37 ° C with Human Factor Xa (0.001 Units / ml, 0.3 ml) for 15 minutes. The chrogenic substrate S-2765 (KabiVitum AB, 20 μM) was added and the mixture is incubated at 37 ° C for 20 minutes while the absorbance at 405 nm is measured. The maximum reaction rate (Vmax) is determined and compared with that of the control sample that does not contain the test compound. The inhibitory potency is expressed as a CI ^ Q value. b) Measurement of Thrombin Inhibition The procedure of method a) was repeated except that human thrombin (0.005 Units / ml) and chromogenic substrate S-2238 (KabiVitum AB) were used. c) Measurement of the Anticoagulant Activity An in vi tro test whereby human venous blood is collected and added directly to a solution of sodium citrate (3.2 g / 100 ml, 9 parts of blood to 1 part of citrate solution) . The blood plasma is prepared by centrifugation (1000 g, 15 minutes) and stored at 2-4 ° C. The activated partial thromboplastin time (APTT) and prothrombin time (PT) tests are carried out in the presence of several Concentrations of a test compound and the concentration of the test compound required to double the clotting time, hereinafter referred to as CT2, is determined. In the APTT test, the test compound, blood plasma and APTT reagent are incubated at 37 ° C for 3 minutes. Calcium chloride (0.02M) is added and the formation of fibrin and the time required to form a clot are determined. In the PT test, an analogous procedure was followed except that tissue thromboplastin was used in place of the APTT reagent. d) An Ex vivo Assay of the Anticoagulant Activity The test compound is administered intravenously or orally to a group of Alderley Park Wistar rats. At several times thereafter, the animals are anesthetized, the blood is collected and the APTT and PT coagulation assays analogous to those described in the above are carried out. e) 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 are anesthetized and surgery is performed to expose the vena cava. Two loose sutures, 0.7 cm apart, are located around the inferior vena cava. The test compound is administered intravenously or orally. An appropriate time later, tissue thromboplastin (1 ml / kg) is administered into the jugular vein and 10 seconds later, the two sutures are tightened to induce ecstasy within the ligated portion of the vena cava. After 10 minutes, the ligated tissue is cut and the thrombus in it is isolated, dried and weighed. Although the pharmacological potencies of the compounds of the formula I and the vary with the structural changes as expected, in general the compounds of the formulas I and I possess activity at the following concentrations or doses in at least one of the above tests a) ac): test a): CI5Q (Factor Xa) in the range, for example 0.001-25 μM; test b): IC 50 (thrombin), for example greater than 50 μM; c) test: CT2 (PT) in the range, for example 1-50 μM; CT2 (APTT) in the range, for example 10-100 μM. By way of example, the compound of Example 1 as described in the following has yna CI5Q of 0.3 μM against Factor Xa in test a), a Cf: 50 greater than 100 μM against thromb in test b) and a CT2 (PT) of 14 μM and CT2 (APTT) of 62 μM in test c) and shows an increased coagulation time after intravenous administration of a dose of 10 mg / kg in the dr test. and a reduced thrombus weight after intravenous administration of a dose of 5 mg / kg in test e). By way of another example, the compound of Example 39, Compound No. 2, as described in the following has an IC 50 of 0.012 μM against Factor Xa in test a), an IC 50 of greater than 100 μM against thrombin in test b), a CT2 (PT) of 1 μM and CT2 (APTT) of 1.8 μM in test c) and shows an increased coagulation time after intravenous administration of a dose of 5 mg / kg in test d) and a reduced thrombus weight after administration intravenous dose of 5 mg / kg in test d). By way of another example, the compound of Example 41, Compound No. 3, as described in the following, has a CICQ of 0.01 μM against Factor Xa in test a) and an ICJ-Q of 83 μM against thrombin in the test b). By way of another example, the compound of Example 40, Compound No. 5, as described in the following has an IC 50 of 0.003 μM against Factor Xa in test a), an IC 50 of 34 μM against thrombin in test b ), a CT2 (PT) of 0.5 μM and CT2 (APTT) of 1.2 μM in test c), and show an increased coagulation time after intravenous administration of a dose of 5 mg / kg in test d). By way of another example, the compound of Example 62 as described in the following, has an IC 50 of 0.002 μM against Factor Xa in test a), an IC 50 of > 10 μM against thrombin in test b), a CT2 (PT) of 0.7 μM in test c) and shows an increased coagulation time after intravenous administration of a dose of 5 mg / kg in test d).

By way of another example, the compound of Example 63 as described in the following has an CI5Q of 0.008 μM against Factor Xa in test a), an IC5Q of > 10 μM against thrombin in test b), a CT2 (PT) of 4.6 μM in test c), and shows an increased coagulation time after intravenous administration of a dose of 5 mg / kg in test d) and a reduced thrombus weight after intravenous administration of a dose of 5 mg / kg in test e). According to another feature of the invention, there is provided a pharmaceutical composition which comprises an aminoheterocyclic derivative of the formula I or the pharmaceutically acceptable formula, in association with a pharmaceutically acceptable diluent or carrier. The composition may be in a form suitable for oral use, for example a board, capsule, an aqueous or oily solution, a suspension or emulsion; for topical use for example a cream, ointment, gel or an aqueous or oily solution or suspension; for nasal use for example a vacuum cleaner, 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 sublingual or buccal use, for example a board 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 the active ingredient (which is an aminoheterocyclic derivative of the formulas I or the, or its pharmaceutically acceptable salt) that is combined with one or more excipients to produce a single dose form, will necessarily vary depending on the host treated and the route of particular 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 forming a compound with an appropriate and convenient amount of excipients, which may vary from about 5 to about 98. percent by weight of the total composition. Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient. According to another feature of the invention, there is provided an aminoheterocyclic derivative of formula I or formula la, or its pharmaceutically acceptable salt for use in a method of treatment of 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 of Factor Xa; (ii) produce an anticoagulant effect; (iii) produce an antithrombotic effect; (iv) treating a medical condition or disease mediated by Factor Xa; (v) treating a medical condition or disease mediated by thrombosis; (vi) treat coagulation disorders; and / or (vii) treating thrombosis or embolism involving coagulation mediated by Factor Xa. The invention also includes a method for producing an effect as defined above or treating a disease or disorder as defined in the foregoing, which comprises administering to a warm-blooded animal requiring such treatment, an effective amount of an active ingredient as defined in the above. The size of the dose for therapeutic or prophylactic purposes of a compound of formula I or of course will 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 well-known medicine principles. As mentioned in the above, the compounds of the formulas I or I are useful in the treatment or prevention of a variety of medical disorders, where anticoagulant therapy is indicated. In the use of a compound of formula I for such a purpose, it will generally be administered in such a way that a daily dose in the range, for example 0.5 to 500 mg / kg of body weight is received, given if required in divided doses. . In general, lower doses will be administered when the parenteral route is used, for example a dose for intravenous administration in the range, for example 0.5 to 50 mg / kg of body weight will generally be used. For preferred compounds and especially preferred compounds of the invention, lower doses, for example a daily dose in the range, for example 0.5 to 10 mg / kg body weight, will generally be used. Although the compounds of the formulas I and A are primarily of value as therapeutic or prophylactic agents for use in warm-blooded animals including man, they are also useful whenever required to produce an anticoagulant effect, for example during the ex vivo storage of blood. complete 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 tissue plasminogen activator or its derivatives or streptokinase. The compounds of the invention can also be administered for example with a known platelet aggregation inhibitor (for example aspirin, a thromboxane antagonist or a thromboxane synthetase inhibitor), a known hypolipidemic agent or a known antihypertensive agent. The invention will now be illustrated in the following Examples, in which unless stated otherwise: (i) evaporations are carried out by rotary evaporation in vacuo and the work-up procedures are carried out after the elimination of residual solids by filtration; (ii) the operations are 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) column chromatography (by flash evaporation) and medium pressure liquid chromatography (MPLC) are performed on silica Kieselgel from Merck (Art. 9385) or RP-18 Lichroprep of Merck (Art. 9303) reverse phase silica obtained from E. Merck, Darmstadt, Germany; (iv) the returns are given for illustration only and are not necessarily the maximum that can be achieved; (v) the final products of formula I have satisfactory microanalyses and their structures are confirmed by nuclear magnetic resonance (NMR) and mass spectrum techniques; unless otherwise stated, the CDC13 solutions of the final products of Formula I were used for the determination of the NMR spectral data, the chemical shift values were measured on the delta scale; the following abbreviations have been used: s, singlet; d, doublet; t, triplet; m, multiplet; (vi) intermediaries were not generally fully characterized and purity was evaluated by chromatographic analysis < thin layer, infrared analysis DMF N, -dimethylformamide; THF tetrahydrofuran; DMSO dimethyl sulfoxide; DMPU 1, 3-dimethyl-3,4,5,6-tetrahydro-2 (1H) pyrimidinone.

Example 1 The hydrochloride salt of N- [2-amino-1- (piperidino-carbonyl) ethyl] -2- (2-naphthalenesulfonamido) acetamide (2.6 g) and triethylamine (3.18 g) are in turn added in a stirred solution of 1- (4-pyridyl) piperidine-4-carbonyl chloride (1.54 g) in methylene chloride (20 ml) and the mixture is stirred at room temperature for 16 hours. The mixture is partitioned between ethyl acetate and water. The organic phase is washed with water, dried (MgSO 4) and evaporated. The residue is purified by column chromatography using a mixture of ethyl acetate, methanol and ammonia as eluent 89: 10: 1. The material thus obtained is triturated under diethyl ether to give 2- (2-naphthalenesulfonamido) -N-. { 1-piperidino-carbonyl-2- [1- (4-pyridyl) -piperidin-4-ylcarbonyl-amino] ethyl} -acetamide as a foam (1.9 g, 55%); NMR spectrum (CD3SOCD3) 1.37-1.76 (m, 10H), 3.15-3.5 (m, 10H), 3.6 (s, 2H), 4.1-4.2 (d, 2H), 4.9 (t, ÍH), 7.1 (d) , 2H), 7.6-8.2 (m, 10H), 8.4 (s, ÍH); Elemental Analysis Found C, 60.7; H, 6.5; N, 13.2; 31H38N605S 0.5H20 required C, 60.5; H, 6.3; N, 13-6%. The N- [2-amino-1- (piperidinocarbonyl) ethyl] -2- (2-naphthalenesulfonamido) acetamide, used as an initial material is obtained as follows: N-hydroxybenzotriazole (10.16 g) and N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide (14.17 g) are in turn added in a stirred solution of N2-benzyloxycarbonyl-DL-asparagine (20 g) in DMF (200 ml) which has been cooled in an ice bath. The mixture is stirred at 0 ° to 5 ° C for 1 hour. Piperidine (7.4 ml) is added and the mixture is stirred for 16 hours and allowed to warm to room temperature. The mixture is concentrated by evaporation. Water (500 ml) is added and the precipitate is isolated and dried. In this way, the N2-benzyloxycarbonyl-DL-asparagine piperidide (12 g), m.p. 159-162 ° C. After repeating the reaction, the thus obtained piperidide (17 g) is added to a stirring solution of bis (trifluoroacetoxy) iodobenzene (33 g) in a mixture of DMF (100 ml) and water (100 ml). The mixture is stirred at room temperature for 20 minutes. Triethylamine (14.2 ml) is added and the mixture is stirred for 16 hours. The mixture is acidified by the addition of 2N aqueous hydrochloric acid and extracted with ethyl acetate. The aqueous phase is basified to pH 8 by the addition of the 2N aqueous sodium hydroxide solution and extracted with ethyl acetate (3 x 60 ml).

The 'extracts are combined, washed with water, dried (MgS4) and evaporate. In this way 1- [3-amino-2- (benzyloxycarbonylamino) propionyl] piperidine was obtained as an oil (8.12 g). Di-tert-butyl dicarbonate (8.75 g) and triethylamine (7.1 ml) are in turn added in a stirring solution of the piperidine thus obtained in methylene chloride (150 ml) and the mixture is stirred at room temperature for 16 hours. hours. The mixture is divided between methylene chloride and a solution of citric acid, aqueous IN. The organic phase is washed with water, dried (MgSO 4) and evaporated. The residue is purified by column chromatography using a mixture of hexane and ethyl acetate as eluent 1: 1. In this way 1- [2- (benzyloxycarbonylamino) -3- (tert-butoxycarbonylamino) propionyl] piperidine was obtained as an oil (7.98 g). A mixture of a portion (4.2 g) of the material thus obtained, 10% of the carbon catalyst in palladium (0.3 g) and ethanol (100 ml) is stirred under a hydrogen atmosphere for 8 hours. The mixture is filtered and the filtrate is evaporated. The residue is triturated under diethyl ether to give 1- [2-amino-3- (tert-butoxycarbonylamino) -propionyl] piperidine (2.3 g), m.p. 87-90 ° C.

A solution of N- (2-naphthylsulfonyl) glycine (2.93 g) in DMF (20 ml) is added to a stirred mixture of N-hydroxybenzotriazole (1.5 g), N- (3-dimethylaminopropyl) -N-ethylcarbodiimide (2.16). g) and DMF (80 ml) which has been cooled in an ice bath. The mixture is stirred for 1 hour. A solution of 1- [2-amino-3- (tert-butoxycarbonyl-amino) -propionyl] piperidine (2.98 g) in DMF (10 ml) is added and the mixture is allowed to warm to room temperature and is stirred for 16 hours . The mixture is divided between methylene chloride and water. The organic phase is washed with water, it is dried (MgSO4) and evaporated. The residue is purified by column chromatography using ethyl acetate as eluent. In this way N- [2- (tert-butoxycarbonyl-amino) -1- (piperidinocarbonyl) ethyl] -2- (2-naphthalenesulfonamido) -acetamide (3.2 g), m.p. 95-98 ° C. A portion (0.5 g) of the material thus obtained is suspended in ethyl acetate (25 ml) and the mixture is cooled in an ice bath. Hydrogen chloride is formed followed by the deposition of a precipitate. The solid is isolated and dried. In this way the hydrochloride salt of N- [2-amino-1- (piperidinocarbonyl) ethyl] -2- (2-naphthalenesulfonamido) -acetamide (0.34 g) was obtained; NMR spectrum (CD3S0CD3 + CD3C02D) 1.2-1.6 (m, 6H), 2.7-3.1 (m, 2H), 3.1-3.25 (t, 2H), 3.3-3.5 (m, 2H), 3.6 (s, 2H) , 4.8-5.0 (t, ÍH), 6.5-8.1 (m, 7H), 8.4 (s, ÍH); Elemental Analysis Found C, 50.9; H, 6.3; N, 11. B; C20H26N4O4S H20 H20 required C, 50.7; H, 6.1; N, 11.8%. The 1- (4-pyridyl) piperidin-4-carbonyl chloride used as starting material is obtained as follows: Oxalyl chloride (0.14 ml) and DMF (2 drops) are in turn added in a stirred solution of acid 1 - (4-pyridyl) piperidine-4-carboxylic acid [Tetrahedron, 1988, 44, 7095; 0.21 g] in methylene chloride (20 ml). The mixture is stirred at room temperature for 4 hours. The mixture evaporates and in this way the required initial material was obtained, which is used without further purification.

Example 2 A solution of 2-naphthylsulfonyl chloride (0.55 g) in methylene chloride (10 ml) is added to a stirring mixture of the l- [1- (4-pyridyl) piperidin-4-ylcarbonyl] piperazine trichlorohydrate salt ( 0.85 g), triethylamine (3.1 ml) and methylene chloride (80 ml) and the resulting mixture is stirred at room temperature for 18 hours. The mixture is divided between methylene chloride and water. The organic phase is washed with water, dried (MgSO 4) and evaporated. The residue is purified by chromatography using polar mixtures in an increase in methylene chloride and methanol (100: 6 to 100: 10) as eluent. In this way 1- (2-naphthylsulfonyl) -4- [1- (4-pyridyl) piperidin-4-ylcarbonyl] -piperazine was obtained as a solid (0.727 g); NMR spectrum (CD3S0CD3) 1.4-1.65 (m, 4H), 2.75-3.05 (m, 7H), 3.5-3.7 (m, 4H), 3.8-3.95 (m, 2H), 6.8 (d, 2H), 7.65 -7.8 (, 3H), 8.05-8.25 (, 5H), 8.45 (d, ÍH); Elemental Analysis Found C, 63.4; H, 6.1; N, 11. 5; C25H28N403S 0.5H20 required C, 63.4; H, 6.1; N, 11.8%. The 1- [1- (4-pyridyl) piperidin-4-ylcarbonyl] -piperazine used as an initial material is obtained as follows: Thionyl chloride (1.6 ml) is added dropwise to a stirring suspension of acid 1- ( 4-pyridyl) piperidine-4-carboxylic acid (2.17 g) in methylene chloride (30 ml) and the mixture is stirred .j & room temperature for 1 hour. The mixture is evaporated to give 1- (4-pyridyl) piperidin-4-carbonyl chloride, which is used without further purification. The material thus obtained is suspended in methylene chloride (30 ml) and triethylamine (7.8 ml) and a solution of 1-tert-butoxycarbonylpiperazine (2.08 g) in methylene chloride (10 ml) are added in turn. The mixture is stirred at room temperature for 4 hours. The mixture is divided between methylene chloride and water. The organic phase is washed with water, dried (MgSO 4) and evaporated. The residue is purified by column chromatography using polar mixtures in an increase in methylene chloride and methanol as eluent (100: 5 to 100: 13). In this way, 1- (tert-butoxycarbonyl) -4- [1- (4-pyridyl) piperidin-4-ylcarbonyl] -piperazine (2.38 g) was obtained. A saturated solution of hydrogen chloride in diethyl ether (25 ml) is added to a stirring solution of the 1-tert-butoxycarbonylpiperazine thus obtained in methylene chloride (120 ml) and the mixture is stirred at room temperature for 18 hours. The mixture is evaporated and the residue is triturated under diethyl ether. In this way, the trichlorohydrate salt of 1- [1- (4-pyridyl) piperidin-4-ylcarbonyl] -piperazine (2.85 g) was obtained; NMR spectrum (CD3SOCD3) 1.5-1.9 (m, 4H), 3.0-3.2 (m, 7H), 3.6-3.85 (m, 4H), 4.15-4.3 (m, 2H), 7.2 (d, 2H), 8.2 (d, 2H).

Example 3 The 1,1 '-carbonyldiimidazole (0.089 g) and triethylamine (0.08 ml) are in turn added in a solution of the hydrochloride salt of N- [2-amino-1- (piperidinocarbonyl) ethyl] -2- (2- naphthalenesulfonamido) acetamido (0.25 g) in DMF (15 ml) which has been cooled in an ice bath. The mixture is stirred for 30 minutes. 1- (4-pyridyl) piperazine is added (0.089 g) and the mixture is stirred at room temperature for 16 hours. The mixture is partitioned between ethyl acetate and water.

The organic phase is washed with water, dried (MgSO 4) and evaporated. The residue is purified by column chromatography using ethyl acetate as eluent. In this way, 2- (2-naphthalenesulfonamido) -N- was obtained. { 1-piperidinocarbonyl-2- [4- (4-pyridyl) piperazin-1-ylcarbonylamino] -ethyl} Acetamide as a foam (0.118 g); NMR spectrum (CD3SOCD3 + CD3C02D) 1.3-1.6 (m, 6H), 3.0-3.15 (m, ÍH), 3.2-3.6 (m, 15H), 4.8-4.9 (m, ÍH), 7.0 (d, 2H) , 7.5-7.7 (m, 2H), 7.75-7.83 (m, ÍH), 7.9-8.1 (m, 3H), 8.1-8.2 (d, 2H), 8.4 (s, ÍH); Elemental Analysis Found C, 58.9; H, 6.4; N, 15.3; C30H37N7O5S 2.5EtAc required C, 59.1; H, 6.2; N, 15.6%.

Example 4 Using a procedure analogous to that described in Example 1, except that the hydrochloride salt of 2- [1- (4-pyridyl) piperidin-4-yl] acetyl chloride is used in place of 1- (4-pyridyl) chloride ) Piperidin-4-carbonyl and the product is purified by high pressure liquid chromatography using a mixture of acetonitrile, water and trifluoroacetic acid 50:50:01 as eluent. In this way 2- (2-naphthalenesulfonamido) -N- (1-piperidinocarbonyl-2- {2- [1- (4-pyridyl) piperidin-4-yl] acetamido} ethyl) acetamide was obtained as a foam in 18% yield; NMR spectrum (CD3SOCD3 + CD3C02D) 1.0-1.7 (m, 6H), 1.7-1.21 (m, 8H), 3.0-3.4 (m, 9H), 3.5-3.6 (s, 2H), 4.1-4.2 (d, 2H), 4.8-4.9 (m, ÍH), 7.05-7.2 (d, 2H), 7.6-8.2 (m, 8H), 8.4-8.5 (s, ÍH); Elemental Analysis Found C, 52.8; H, 5.4; N, 11.4; C32H40NgO5S CF3C02H H20 required C, 53.0; H, 5.8; N, 10.9%. The salt 2- [1- (4-pyridyl) -piperidin-4-yl] acetyl chloride hydrochloride used as an initial material is obtained as follows: Triethyl phosphonoacetate (19.8 ml) is added dropwise into a suspension under stirring of sodium hydride (50% dispersion in mineral oil, 4.8 g) in dimethoxyethane (300 ml) which has been cooled in an ice bath and the mixture is stirred at 0 ° to 5 ° C for 1 hour. The l-benzyl-4-piperidone (17.85 ml) is added dropwise and the mixture is stirred at room temperature for 16 hours. The mixture is divided between diethyl ether and water. The organic phase is washed with water and brine, dried (MgSO 4) and evaporated. The residue is purified by column chromatography using a mixture of hexane and ethyl acetate 3: 2. In this way, l-benzyl-4- (ethoxycarbonylmethylene) piperidine (5.52 g) was obtained.

A mixture of the material thus obtained, carbon catalyst in 10% palladium (1 g) and ethanol (250 ml) are stirred under a hydrogen atmosphere for 6 hours. The mixture is filtered to give the ethyl 2- (piperidin-4-yl) acetate as an oil (3.31 g) which is used without further purification; NMR spectrum (CDCl3) 1.0-1.2 (m, 2H), 1.25 (t, 3H), 1.7 (s, 2H), 1.9 (m, ÍH), 2.2 (d, 2H), 2.6 (, 2H), 3.05 (m, 2H), 4.0 (m, 2H). A mixture of a portion (3.25 g) of the material thus obtained is stirred with 4-chloropyridine hydrochloride (2.85 g), triethylamine (5.28 ml) and xylene (100 ml) and heated at reflux for 16 hours. The mixture is cooled to room temperature and filtered. The filtrate is evaporated and the residue is divided between methylene chloride and water. The organic phase is washed with water, dried (MgSO 4) and evaporated. The residue is purified by column chromatography using a 10: 1 mixture of methylene chloride and methanol as eluent. In this way ethyl 2- [1- (4-pyridyl) piperidin-4-yl] acetate was obtained as an oil (2.15 g). A mixture of the material thus obtained, the IN aqueous hydrochloric acid (35.5 ml) and dioxane (100 ml) are stirred and heated at 95 ° for 3 hours. The mixture is evaporated and the residue is lyophilized to give the salt 2- [1- (4-pyridyl) piperidin-4-yl] acetic acid hydrochloride (2.3 g), m.p. 105-108 ° C.

Using an analogous procedure to that described in the portion of Example 1, which is related to the preparation of the starting materials, the acetic acid is reacted with oxalyl chloride to give the hydrochloride salt of 2- [1- ( 4-pyridyl) piperidin-4-yl] acetyl in a quantitative yield.

Example 5 Using an analogous procedure to that described in Example 1, except that 2- [4- (4-pyridyl) piperazin-1-yl] acetyl chloride is used in place of the 1- (4-pyridyl) piperidine- chloride. 4-carbonyl. In this way, 2- (2-naphthalenesulfonamido) -N- (1-piperidino-carbonyl-2-. {2- [4- (4-pyridyl) piperazin-1-yl] acetamidojetyl) -acetamide was obtained as a foam in yield of 6%; NMR spectrum (CD3SOCD3) 1.3-1.6 (m, 6H), 2.9-3.05 (s, 2H), 3.1-3.7 (m, 14H), 4.8-5.0 (t, ÍH), 7.0-7.2 (d, 2H) , 7.6-8.2 (m, 9H), 8.4 (s, ÍH); Elemental Analysis Found C, 57.4; H, 6.2; N, 14. 5; C31H39N705S 1.5H20 required C, 57.4; H, 6.5; N, 15.1%. The 2- [4- (4-pyridyl) piperazin-1-yl] acetyl chloride used as an initial material is obtained as follows: Sodium hydride (50% dispersion in mineral oil, 1.9 g) is added portionwise in a stirring mixture of 1- (4-pyridyl) piperazine (3 g) and DMF (20 ml) and the mixture is stirred at room temperature. environment for 1 hour. Tert-butyl bromoacetate (6.5 ml) is added dropwise and the mixture is stirred for 18 hours. The mixture is partitioned between ethyl acetate and water. The organic phase is washed with water, dried (MgSO 4) and evaporated. The residue is purified by column chromatography using a mixture of methylene chloride and methanol 17: 3 as eluent. In this way, tert-butyl 2- [4- (4-pyridyl) piperazin-1-yl] acetate was obtained as a solid (2.85 g). A mixture of the material thus obtained and trifluoroacetic acid (7 ml) is stirred at room temperature for 18 hours. The mixture is evaporated to give 2- [4- (4-pyridyl) piperazin-1-yl] acetic acid in quantitative yield; NMR spectrum (CD3SOCD3) 3.35-3.5 (m, 4H), 3.9-4.05 (m, 4H), 4-1 (s, 2H), 7.25 (d, 2H), 8.35 (d, 2H). A mixture of the material thus obtained (2.27 g), oxalyl chloride (1.5 ml), DMF (3 drops) and methylene chloride (20 ml) is stirred at room temperature for 4 hours. The mixture is evaporated to give 2- [4- (4-pyridyl) piperazin-1-yl] acetyl chloride which is used without further purification.

Example 6 Triethylamine (0.77 ml) is added to a stirred mixture of the ethyl 2-amino-3- [1- (4-pyridyl) piperidin-4-ylcarbonylamino] propionate dihydrochloride salt. (1 g), 2- (2-naphthalenesulfonamido) -succinimidoacetate (0.92 g) and methylene chloride (50 ml) which has been cooled in an ice bath. The mixture is allowed to warm to room temperature and is stirred for 4 hours. The mixture is divided between methylene chloride and water. The organic phase is washed with water, dried (MgSO 4) and evaporated. The residue is purified by column chromatography using a mixture of ethyl acetate and methanol 4: 1 as eluent. In this way the N- was obtained. { l-ethoxycarbonyl-2- [1- (4-pyridyl) -piperidin-4-ylcarbonylamino] ethyl} -2- (2-naphthalenesulfonamido) -acetamide as a foam (0.203 g); NMR spectrum (CD3S0CD3) 1.1-1.2 (t, 3H), 1.4-1.8 (m, 4H), 2.2-2.4 (m, ÍH), 2.7-3.0 (t, 2H), 3.5 (s, 2H), 3.8 -4.1 (m, 4H), 4.2-4.4 (t, ÍH), 6.7-6.8 (d, 2H), 7.6-8.3 (m, 11H), 8.4 (s, ÍH); Elemental Analysis Found C, 55.7; H, 6.0; N, 11.1; C2gH33N50gS 2H20 required C, 55.5; H, 6.1; N, 11.6%.

The dihydrochloride of ethyl 2-amino-3- [1- (4-pyridyl) piperidin-4-ylcarbonylamino] propionate used as an initial material is obtained as follows: N2-benzyloxycarbonyl-DL-asparagine (25 g) is added to a stirred solution of bis (trifluoroacetoxy) -iodobenzene (60.6 g) in a mixture of DMF (350 ml) and water (350 ml). The mixture is stirred at room temperature for minutes. Pyridine (15 ml) is added and the mixture is stirred for 16 hours. The mixture is evaporated and the residue is partitioned between water and diethyl ether. The aqueous layer is evaporated to give a mixture of oil with a solid. The solid is isolated, washed with diethyl ether and dried. In this way, 3-amino-2- (benzyloxycarbonylamino) propionic acid was obtained (6.3 g). A portion (3 g) of the thus obtained material is added to a stirring mixture of thionyl chloride (1.01 ml) and ethanol (100 ml) which has been cooled to -10 ° C. The mixture is allowed to warm to room temperature and is stirred for 16 hours. The mixture is evaporated and the residue is triturated under diethyl ether. In this way the hydrochloride salt of ethyl 3-amino-2- (benzyloxycarbonylamino) propionate (3.45 g) was obtained; NMR spectrum (CD3SOCD3) 1.1-1.25 (t, 3H), 3.0-3.2 (m, 2H), 4.05-4.2 (q, 2H), 4.3-4.5 (m, ÍH), 5.1 (s, 2H), 7.3 (m, 5H), 7.8-7.9 (d, ÍH), 8.3 (s, 2H).

Triethylamine (0.7 ml) is added to a stirring mixture of the hydrochloride salt of ethyl 3-amino-2- (benzyloxycarbonylamino) propionate (0.5 g), l- (4-pyridyl) piperidine-4-carbonyl chloride (0.45 g) and methylene chloride (20 ml) and the resulting mixture is stirred at room temperature for 16 hours. The mixture is divided between methylene chloride and water. The organic phase is washed with brine, dried (MgSO 4) and evaporated. The residue is purified by column chromatography using polar mixtures in an increase of ethyl acetate and methanol as eluent. In this way ethyl 2- (benzyloxycarbonylamino) -3- [1- (4-pyridyl) -piperidin-4-ylcarbonylamino] propionate (0.5 g) was obtained. After the repetition of the previous step, a mixture of the material thus obtained (2 g), 10% palladium carbon catalyst (0.2 g), INN aqueous hydrochloric acid (8.8 ml) and ethanol (50 ml) are stirred under a hydrogen atmosphere for 6 hours. The mixture is filtered and the filtrate is evaporated. In this way, the dihydrochloride of ethyl 2-amino-3- [1- (4-pyridyl) piperidin-4-ylcarbonylamino] -propionate (2.48 g) was obtained; NMR spectrum (CD3SOCD3) 1.2-1.3 (t, 3H), 1.5-1.7 (m, 2H), 1.8-2.0 (m, 2H), 2.6-2.7 (m, ÍH), 3.2-3.4 (t, 2H) , 4.0-4.3 (m, 6H), 7.15-7.82 (d, 2H), 8.1-8.2 (d, 2H), 8.5-8.65 (t, ÍH).

The 2- (2-naphthalenesulfonamido) succinimido acetate used as the starting material is obtained as follows: A solution of N, N '-dicyclohexylcarbodiimide (4.12 g) in ethyl acetate (50 ml) is cooled to 0 ° C and add to a stirring mixture of N- (2-naphthylsulfonyl) -glycine (5.3 g), N-hydroxysuccinimide (2.3 g) and ethyl acetate which has been cooled to 0 ° C. The mixture is stirred at 0 ° C for 1 hour, allowed to warm to room temperature and stirred for 16 hours. The mixture is re-cooled at 0 ° C for 1 hour and filtered. The filtrate is evaporated and the residue is recrystallized from a mixture of hexane and ethyl acetate. In this way the required initial material (6.2 g) was obtained; NMR spectrum (CD3SOCD3) 2.8 (, 4H), 4.25 (d, 2H), 7.6-7.75 - (m, 2H), 7.8-7.9 (m, ÍH), 8.0-8.2 (m, 3H), 8.45 (S , ÍH), 8.6 (t, ÍH).

Example 7 Using a procedure analogous to that described in Example 2, 2-naphthylsulfonyl chloride is reacted with ethyl 2-amino-3- [1- (4-pyridyl) piperidin-4-yl-carbonylamino] propionate dihydrochloride give ethyl 2- (2-naphthalenesulfonamido) -3- [1- (4-pyridyl) piperidin-4-ylcarbonylamino] propionate, as a foam in 37% yield; NMR spectrum (CD3SOCD3) 1.1-1.2 (t, 3H), 1.3-1.7 (m, 4H), 2.1-2.3 (m, ÍH), 2.7-2.9 (m, 2H), 3.1-3.9 (m, 6H) , 3.9-4.1 (t, ÍH), 6.7-6.8 (d, 2H), 7.6-8.2 (m, 11H), 8.35 (s, ÍH); Elemental Analysis Found C, 59.8; H, 6.4; N, 10.3; C 26 H 30 N 4 O 5 S 0.75H 2 O required C, 59.6; H, 6.0; N, 10.7%.

Example 8 A mixture of N-. { l-ethoxycarbonyl-2- [1- (4-pyridyl) -piperidin-4-ylcarbonylamino] ethyl} -2- (2-naphthalenesulfonamido) -acetamide (0.1 g), methylamine (33% of a solution in ethanol, 0.2 ml) and ethanol (5 ml) is stirred at room temperature for 2 hours. The precipitate is isolated and purified by column chromatography using polar mixtures in increase of ethyl acetate and methanol as eluent. In this way, N-methyl-2- [2- (2-naphthalenesulfonamido) -acetamido] -3- [1- (4-pyridyl) piperidin-4-ylcarbonylamino] -propionamide (0.01 g) was obtained; Elemental Analysis Found C, 57.6; H, 6.1; N, 13.9; 27H32N6C5 0.5H20 0.5EtOH required C, 57.5; H, 6.1; N, 14.3%.

Example 9 A mixture of N-. { l-ethoxycarbonyl-2- [1- (4-pyridyl) -piperidin-4-ylcarbonylamino] ethyl} -2- (2-naphthalenesulfonamido) -acetamide (0.15 g), a solution of aqueous sodium hydroxide IN (5.3 ml) and methanol (3 ml) is stirred at room temperature for 2 hours. The basic solution is neutralized by the addition of a 0. IN aqueous hydrochloric acid (5.3 ml) and evaporated. The residue is triturated under diethyl ether. In this way, 2- [2- (2-naphthalenesulfonamido) -acetamido] -3- [1- (4-pyridyl) piperidin-4-ylcarbonylamino] -propionic acid (0.123 g) was obtained; NMR spectrum (CD3SOCD3) 1.4-1.65 (m, 2H), 1.6-1.75 (m, 2H), - 2.3-2.5 (m, ÍH), 2.8-3.0 (t, 2H), 3.25-3.4 (m, 2H) ), 3.85-3.95 (d, 2H), 4.0-4.15 (m, ÍH), 6.7-6.9 (s, 2H), 7.6-8.4 (m, 10H), 8.4 (s, ÍH); Elemental Analysis Found C, 46.7; H, 4.5; N, 10.3; C26H29N50gS 2NaCl H20 required C, 46.3; H, 4.6; N, 10.4%.

Example 10 Using an analogous procedure to that described in Example 1, 1- (4-pyridyl) piperidine-4-carbonyl chloride is reacted with an l- [3-amino-2- (2-naphthalenesulfonamido) propionyl] piperidine hydrochloride salt to give N- [2- (2-naphthalenesulfonamido) -2- (piperidinocarbonyl) ethyl] -1- (4-pyridyl) -piperidin-4-carboxamide in 17% yield. Elemental Analysis Found C, 61.4; H, 6.8; N, 12.1; C29H35N504S H20 required C, 61.3; H, 6.5; N, 12.3%. The hydrochloride salt of 1- [3-amino-2- (2-naphthalenesulfonamido) propionyl] piperidine as an initial material is obtained as follows: Triethylamine (3.1 ml) is added to a stirring mixture of 2-naphthylsulfonyl chloride (1.67). g), 1- [2-amino-3- (terbutoxycarbonylamino) propionyl] piperidine (2 g) and DMF (25 ml) and the mixture is stirred at room temperature for 16 hours. The mixture is partitioned between ethyl acetate and water. The organic phase is washed with brine, it is dried (HgS04) and evaporated. The residue is purified by column chromatography using polar mixtures in an increase of hexane and ethyl acetate as eluent. In this way 1- [3-tert-butoxycarbonylamino) -2- (2-naphthalene-sulfonamido) propionyl] -piperidine was obtained as a solid (2.6 g). The compound thus obtained is suspended in ethyl acetate and the mixture is cooled in an ice bath. The hydrogen chloride gas is carried into the mixture for 1 hour. A clear solution is formed followed by the deposition of a precipitate which is isolated. In this way, the hydrochloride salt of 1- [3-amino-2- (2-naphthalenesulfonamido) -propionyl] piperidine was obtained as a foam (2 g), which is used without further purification.

Example 11 Using an analogous procedure to that described in Example 1, 1- (4-pyridyl) piperidine-4-carbonyl chloride is reacted with N- [2-amino-2- (piperidinocarbonyl) ethyl] -2- (2- naphthalenesulfonamido) acetamide to give 2- (2-naphthalenesulfonamido) -N-. { 2-piperidino-carbonyl-2- [1- (4-pyridyl) piperidin-4-ylcarbonylamino] ethyl] -acetamide in 41% yield, m.p. 200-202 ° C; NMR spectrum (CD3SOCD3 + CD3C02D) 1.1-1.8 (m, 9H), 3.0-3.6 (m, 12H), 4.0-4.2 (m, 2H), 4.8-5.0 (t, ÍH), 7.0-7.2 (s, 2H), 7.6-7.8 (m, _2H), 7.8-7.9 (m, ÍH), 8.0-8.3 (m, SH), 8.4-8.5 (s, ÍH); Elemental Analysis Found C, 61.1; H, 6.4; N, 13.7; C31H38Ng05S required C, 61.4; H, 6.3; N, 13.9%. The N- [2-amino-2- (piperidinocarbonyl) ethyl] -2- (2-naphthalenesulfonamido) acetamido used as an initial material is obtained as follows: - A mixture of 1- [3-amino-2- (benzyloxycarbonylamino) propionyl] piperidine (2 g), 2- (2-naphthalenesulfonamido) -succinimidoacetate (2.4 g) and ethyl acetate (25 ml) is stirred at room temperature for 12 hours. The mixture is partitioned between ethyl acetate and water. The organic phase is washed with water, dried (MgSO 4) and evaporated. The residue is purified by column chromatography using ethyl acetate as eluent. In this way N- [2- (benzyloxycarbonylamino) -2- (piperidinocarbonyl) ethyl] -2- (2-naphthalene-sulfonamido) acetamide was obtained as a foam (1.83 g). A mixture of the material thus obtained, charcoal catalyst in 10% palladium (0.3 g) and ethanol (40 ml) is stirred under a hydrogen atmosphere for 8 hours. The mixture is filtered and the filtrate is evaporated. The residue is purified by column chromatography using a mixture of hexane and ethyl acetate 1: 1 as eluent. In this way N- [2-amino-2- (piperidinocarbonyl) ethyl] -2- (2-naphthalenesulfonamido) acetamide (0.52 g) was obtained which is used without further purification.

Example 12 The procedure described in Example 2 is repeated, except that the 1-naphthylsulfonyl chloride is used in place of the 2-naphthylsulfonyl chloride. In this way, 1- (1-naphthylsulfonyl) -4- [1- (4-pyridyl) -piperidin-4-ylcarbonyl] piperazine was obtained in a yield of 52%; NMR spectrum (CD3S0CD3) 1.4-1.7 (m, 4H), 2.75-2.95 (m, 3H), 3.0-3.2 (m, 4H), 3.45-3.65 (m, 4H), 3.8-3.95 (m, 2H) , 6.75 (d, 2H), 7.6-7.8 (m, 3H), 8.0-8.2 (m, 4H), 8.35 (d, ÍH), 8.7 (d, ÍH); Elemental Analysis Found C, 62.2; H, 6.1; N, 11.3; C25H28 403S H20 required 62.2; H, 6.2; N, 11.6%.

Example 13 N-methylmorpholine (0.095 g) and isobutyl chloroformate (0.13 g) are in turn added to a stirred suspension of 1- (2-naphthylsulfonyl) piperidine-4-carboxylic acid (0.3 g) in THF (6 ml). which has been cooled to -10 ° C. The mixture is stirred at -10 ° C for 30 minutes. A solution of 1- (4-pyridyl) piperazine (0.155 g) in DMF (3 ml) is added and the mixture is stirred at room temperature for 18 hours. The mixture is evaporated and the residue is purified by column chromatography using a mixture of methylene chloride and methanol 22: 3 as eluent. In this way 1- [1- (2-naphthylsulfonyl) piperidin-4-ylcarbonyl] -4- (4-pyridyl) -piperazine was obtained as a solid (0.07 g); NMR spectrum (CD3SOCD3) 1.5-1.75 (m, 4H), 2. 3-2.45 (m, 2H), 2.5-2.65 (, ÍH), 3.5-3.75 (m, 10H), 7.05 (d, 2H), 7.6-7.75 (m, 3H), 8.0-8.2 (m, 5H) , 8.35 (d, ÍH). The 1- (2-naphthylsulfonyl) piperidine-4-carboxylic acid used as an initial material is obtained as follows: A solution of ethyl piperidin-4-carboxylate (1.02 ml) in methylene chloride (5 ml) is added to a stirred mixture of 2-naphthylsulfonyl chloride (1.5 g), triethylamine (4 ml) and methylene chloride ( 10 ml) which has been cooled to 5 ° C. The mixture is stirred at room temperature for 18 hours. The mixture is evaporated and the residue is partitioned between ethyl acetate and water. The organic phase is washed with 2N aqueous hydrochloric acid and water, dried (MgSO 4) and evaporated. In this way, ethyl 1- (2-naphthylsulfonyl) -piperidin-4-carboxylate (1.95 g) was obtained. A mixture of the material thus obtained, potassium hydroxide (0.62 g) and ethanol (18 ml) is stirred and heated to reflux for 4 hours. The mixture is evaporated and the residue is divided between methylene chloride and water. The organic phase is dried (MgSO 4) and evaporated. In this way, 1- (2- (naphthylsulfonyl) piperidine-4-carboxylic acid (1.35 g) was obtained; NMR spectrum (CD3SOCD3) 1.5-1.7 (m, 2H), 1.8-1.95 (m, 2H), 2.2-2.3 (m, ÍH), 2.45-2.55 (m, 2H), 3.5-3.6 (m, 2H) , 7.65-7.8 (m, 3H), 8.05-8.25 (m, 3H), 8.45 (d, ÍH).

Example 14 N, N'-dicyclohexylcarbodiimide (0.5 g) is added to a stirred mixture of N- (2-amino-3-phenylpropyl) -1- (4-pyridyl) piperidin-4-carboxamide (1.08 g), N- ( 2-naphthylsulfonyl) glycine (0.85 g), N-hydroxybenzotriazole (0.34 g), N-methylmorpholine (0.71 ml) and DMF (20 ml) which has been cooled to 5 ° C. The mixture is stirred at room temperature for 18 hours. The mixture is evaporated and the residue is purified by column chromatography using polar mixtures in an increase in methylene chloride and methanol (20: 1 to 20: 3) as eluent. In this way, 2- (2-naphthalene-sulfonamido) -N- was obtained. { l-Phenyl-3- [1- (4-pyridyl) piperidin-4-ylcarbonylamino] pro-2-yl} acetamide as a solid (0.52 g); NMR spectrum (CD3SOCD3) 1.5-1.7 (m, 2H), 1. 75-1.9 (m, 2H), 2.4-2.65 (m, 4H), 2.9-3.4 (m, 6H), 3.85-4.0 (m, ÍH), 4.0-4.15 (m, 2H), 7.0-7.2 (, 6H), 7.55-7.65 (, 3H), 7.75 (m, ÍH), 7.9-8.1 (m, 5H), 8.35 (d, ÍH). The N- (2-amino-3-phenylpropyl) -1- (4-pyridyl) -piperidin-4-carboxamide used as an initial material is obtained as follows: Using a procedure analogous to that described in J. Chem. Res. (S), 1992, 391, N2-tert-butoxycarbonyl-DL-phenylalanine is converted into four stages in l-amino-2- (tert-butoxycarbonylamino) -3-phenylpropane. Using a procedure analogous to that described in the second paragraph of the portion of Example 2, which is related to the preparation of starting materials, 1- (4-pyridyl) piperidin-4-carbonyl chloride is reacted with l-amino -2- (tert-butoxycarbonylamino) -3-phenylpropane to give N- [2- (tert-butoxycarbonylamino) -3-phenylpropyl] -1- (4-pyridyl) piperidine-4-carboxamide in a yield of 39%. A mixture of the material thus obtained (0.95 g) and trifluoroacetic acid (2 ml) is stirred at room temperature for 18 hours. The mixture is evaporated and the residue is triturated under diethyl ether. In this way, N- (2-amino-3-phenylpropyl) -1- (4-pyridyl) piperidin-4-carboxamide (0.9 g) was obtained, which is used without further purification. NMR spectrum (CD3SOCD3) 1.5-1.7 (m, 2H), 1. 85-2.0 (m, 2H), 2.75-3.0 (m, 2H), 3.1-3.5 (m, 6H), 4.15-4.3 (m, 2H), 7.15-7.4 (m, 7H), 8.2-8.3 (m , 2H).

Example 15 Using a procedure analogous to that described in Example 2, except that DMF is used in place of methylene chloride as the reaction solvent, l-. { 2- [4- (4-pyridyl) piperazin-1-yl] acetyl} Piperazine is reacted with 2-naphthylsulfonyl chloride to give 1- (2-naphthylsulfonyl) 4-. { 2- [4- (4-pyridyl) piperazin-1-yl] acetyl} -piperazine in a yield of 22%. NMR spectrum (CD3SOCD3 + CD3C02D) 2.4-2.5 (m, 4H), 2.9-3.05 (m, 4H), 3.15 (s, 2H), 3.3-3.45 (m, 4H), 3.45-3.65 (m, 4H) , 6.95 (d, 2H), 7.5-7.75 (m, 3H), 7.95-8.2 (m, '5H), 8.4 (s, ÍH); Elemental Analysis Found C, 62.1; H, 6.1; N, 14.4; 25H29 503S required C, 62.6; H, 6.1; N, 14.6%. The 1-. { 2- [4- (4-pyridyl) piperazin-1-yl] acetyl} -piperazine used as an initial material is obtained as follows: N, N'-dicyclohexylcarbodiimide (0.84 g) is added to a stirring mixture of 2- [4- (4-pyridyl) piperazin-1-yl] acetic acid (1 g), 1- (tert-butoxycarbonyl) piperazine (0.67 g), N-hydroxybenzotriazole (0.382 g), N-methylmorpholine (0.79 ml) and DMF (30 ml) which has been cooled to 5 ° C. The mixture is stirred at room temperature for 18 hours. The mixture is evaporated and the residue is purified by column chromatography using a mixture of methylene chloride and methanol 17: 3 as eluent. In this way, 1- (tert-butoxycarbonyl) -4- was obtained. { 2- [4- (4-pyridyl) piperazin-1-yl] acetyl} -piperazine as a foam (0.87 g). A mixture of a portion (0.75 g) of the material thus obtained, trifluoroacetic acid (2 ml) and methylene chloride (5 ml) is stirred at room temperature for 4 hours. The mixture is evaporated to give 1-. { 2- [4- (4-pyridyl) piperazin-1-yl] acetyl} piperazine in a quantitative yield.

NMR spectrum (CD3S0CD3) 3.05-3.25 (m, 4H), 3.55-3.7 (m, 2H), 3.7-3.8 (, 2H), 3.9-4.1 (m, 4H), 4.3 (s, 2H), 7.3 (d, 2H), 8.4 (d, 2H), 9.35 (s, 2H).

Example 16 Using a procedure analogous to that described in Example 1, the 1- (4-pyridyl) piperidine-4-carbonyl chloride is reacted with the hydrochloride salt of N- [3-amino-1- (piperidinocarbonyl) propyl] - 2- (2-naphthalenesulfonamido) -acetamide to give 2- (2-naphthalenesulfonamido) -N-. { 1-piperidinocarbonyl-3- [1- (4-pyridyl) piperidin-4-ylcarbonylamino] propyl} acetamide in a yield of 17%; NMR spectrum (CD3SOCD3) 1.3-1.8 (m, ^ 12H), 2. 3-2.5 (m, ÍH), 2.7-3.1 (m, 4H), 3.2-3.45 (m, 4H), 3.5-3.6 (m, 2H), 3.8-4.0 (m, 2H), 4.6-4.7 (m , ÍH), 6.7-6.85 (m, 2H), 7.6-7.8 (m, 3H), 7.8-7.9 (m, HH), 8.0-8.35 (m, 7H), 8.4 (s, HH); Elemental Analysis Found C, 59.6; H, 6.6; N, 13. 0; C32H40N6O5S 1.25H20 required C, 59.8; H, 6.6; N, 13.1%. The hydrochloride salt of N- [3-amino-1- (piperidinocarbonyl) propyl] -2- (2-naphthalenesulfonamido) acetamide used as an initial material is obtained as follows: 1, 1'-Carbonyldiimidazole (3.95 g) is added to a stirred solution of N2-benzyloxycarbonyl-DL-glutamine (8.47 g) in DMF (60 ml) and the mixture is stirred at room temperature for 15 minutes. The mixture is cooled to 5 ° C and piperidine (4.82 ml) is added in drops. The mixture is allowed to warm to room temperature for 1 hour. The mixture is partitioned between ethyl acetate and 2N aqueous hydrochloric acid. The organic phase is washed with water and with brine, dried (MgSO 4) and evaporated. The residue is purified by column chromatography using a mixture of ethyl acetate and methanol 9: 1 as eluent. In this way, the N2-benzyloxycarbonyl-DL-glutamine piperidide (4.78 g), m.p. 136-138 ° C. Using a procedure analogous to those described in the second, third and fourth paragraphs of the portion of Example 1, which is related to the preparation of the starting materials, the piperidide DL-glutamine is converted to the 1- [2-amino- 4- (tert-butoxycarbonylamino) -butyryl] piperidine in a yield of 14%. The 1,1'-carbonyldiimidazole (0.31 g) is added to a stirred solution of N- (2-naphthylsulfinyl) glycine (0.446 g) in DMF (5 ml) and the mixture is stirred at room temperature for 30 minutes. The mixture is cooled to 5 ° C and 1- [2-amino-4- (tert-butoxycarbonylamino) butyryl] -piperidine (0.546 g) is added. The mixture is stirred at room temperature for 6 hours. The mixture is divided between ethyl acetate and a 1M aqueous citric acid solution. The organic phase is washed with water and with brine, dried (MgSO 4) and evaporated. The residue is purified by column chromatography using a mixture of methylene chloride and ethyl acetate 1: 1 as eluent. In this way N- [3- (tert-butoxycarbonylamino) -1- (piperidinocarbonyl) propyl] -2- (2-naphthalenesulfonamido) acetamide was obtained as a solid (0.607 g). The material thus obtained is suspended in ethyl acetate (50 ml) and the mixture is cooled in an ice bath. The hydrogen chloride gas is carried into the mixture for 5 minutes. A clear solution is obtained followed by the deposition of a precipitate. The mixture is evaporated to give the N- [3-amino-1- (piperidinocarbonyl) -propyl] -2- (2-naphthalenesulfonamido) acetamide hydrochloride salt (0.528 g), which is used without further purification.

Example 17 The N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride salt (0.575 g) is added to a stirred mixture of (3S) -3- (2-naphthalenesulfonamido) -3- (piperidinocarbonyl) propionic acid (1.17 g) , N-hydroxybenzotriazole (0.405 g), triethylamine (0.417 ml) and DMF (10 ml) and the mixture is stirred at room temperature for 30 minutes. 1- (4-pyridyl) piperazine (0.489 g) is added and the mixture is stirred at room temperature for 16 hours. The mixture is partitioned between ethyl acetate and water. The organic phase is washed with water and with brine, dried (MgSO 4) and evaporated. The residue is purified by column chromatography using polar mixtures in an increase in methylene chloride and methanol as eluent. In this way, 1- [(3S) -3- (2-naphthalenesulfonamido) -3- (piperidinocarbonyl) -propionyl] -4- (4-pyridyl) piperazine was obtained as a solid (0.407 g); NMR spectrum (CDCl3) 0.8-1.1 (m, 2H), 1.2-1.5 (m, 4H), 2.5-2.8 (m, 2H), 3.0-3.2 (m, ÍH), 3.2-3.45 (, 7H), 3. 5-3.7 (m, 3H), 3.75-3.9 (m, ÍH), 4.6-4.7 (m, ÍH), 6.2-6.4 (m, HH), 6.6-6.65 (m, 2H), 7.5-8.0 (m, 6H), 8.3-8.4 (m, 2H), 8.43 (m, HH); Elemental Analysis Found C, 60.0; H, 6.0; N, 12.3; C28H33N504S 0.3CH2Cl2 required C, 60.4; H, 6.0; N, 12.4%. The (3S) -3- (2-naphthalenesulfonamido) -3- (piperidinocarbonyl) propionic acid used as an initial material is obtained as follows: The 0 -benzyl ester of N2- (tert-butoxycarbonyl) -L-aspartic acid (16.2 g ) is added in portions to a stirring mixture of 1,1 '-carbonyldiimidazole (8.1 g) in DMF (100 ml). The resulting mixture is stirred at room temperature for 30 minutes. The mixture is cooled in an ice bath and piperidine (6 ml) is added in drops. The mixture is stirred and allowed to warm to room temperature for 3 hours. The mixture is partitioned between ethyl acetate and 2N aqueous hydrochloric acid. The organic phase is washed with water, dried (MgSO 4) and evaporated. The residue is purified by column chromatography using ethyl acetate as eluent. In this way, 04-benzyl ester of N2- (tert-butoxycarbonyl) -L-aspartic acid 1-piperidide (17.9 g) was obtained. One portion (4.5 g) of the material thus obtained is dissolved in ethyl acetate (75 ml) and the solution is cooled in an ice bath. The hydrogen chloride gas is carried into the solution for 20 minutes. The mixture is evaporated to give the hydrochloride salt of the 04-benzyl ester of the L-aspartic 1-piperidide (3.6 g); NMR spectrum (CDCl3) 1.3-1.8 (, 6H), 3.05-3.3 (m, 2H), 3.4-3.6 (m, 4H), 4.9-5.0 (m, ÍH), 5.15 (s, 2H), 7.3- 7.4 (m, 5H), 8.5-8.8 (m, 3H). A portion (2.63 g) of the material thus obtained is reacted with 2-naphthylsulfonyl chloride (2 g) using an analogous procedure to that described in Example 2. In this way (3S) -3- (2- naphthalene sulfonamido) -3- (piperidinocarbonyl) benzyl propionate as an oil (2.96 g, 82%).

A mixture of the material thus obtained, charcoal catalyst in 10% palladium (0.2 g) and ethanol (25 ml) is stirred under a hydrogen atmosphere for 6 hours. The mixture is filtered and the filtrate is evaporated. In this way (3S) -3- (2-naphthalenesulfonamido) -3- (piperidinocarbonyl) -propionic acid was obtained as a foam (2.2 g, 86%). NMR spectrum (CDCl3) 0.8-1.1 (m, ÍH), 1.1-1.5 (m, 5H), 2.4-2.7 (m, 2H), 3.0-3.4 (m, 4H), 4.7 (t, ÍH), 5.3 -5.7 (m, 2H), 7.5-7.7 (m, 2H), 7.75-8.0 (m, 4H), 8.45 (s, ÍH).

Example 18 1, 1'-Carbonyldiimidazole (0.307 g) is added to a solution of (3S) -3- [2- (2-naphthalenesulfonamido) -acetamido] -3- (piperidinocarbonyl) propionic acid (0.85 g) in DMF (10 ml) and the mixture is stirred at room temperature for minutes. 1- (4-pyridyl) piperazine (0.309 g) is added and the mixture is stirred at room temperature for 16 hours. The mixture is partitioned between ethyl acetate and water. The organic phase is washed with water and with brine, dried (HgSO4) and evaporated. The residue is purified by column chromatography using polar mixtures in an increase in methylene chloride and methanol as eluent. The material thus obtained is recrystallized from acetonitrile. In this way, 2- (2-naphthalenesulfonamido) -N- is obtained. { (SS) -1- (piperidinocarbonyl) -2- [4- (4-pyridyl) piperazin-1-ylcarbonyl] -ethyl} acetamide (0.201 g, 17%), m.p. 201-203 ° C; NMR spectrum (CDC13 + CD3C02D) 1.2-1.6 (m, 6H), 2.1-2.3 (m, ÍH), 2.7-2.9 (, ÍH), 3.1-4.8 (m, 14H), 4.9-5.0 (m, ÍH) ), 7.0 (d, 2H), 7.6-7.75 (, 2H), 7.8-7.85 (m, ÍH), 7.9-8.15 (m, 3H), 8.2-8.3 (m, 2H), 8.4 (s, ÍH); Elemental Analysis Found C, 59.9; H, 6.2; N, 14.1; C30H36N6O5S 0.5H20 required C, 59.9; H, 6.2; N, 14.0%. The (3S) -3- [2- (2-naphthalenesulfonamido) -acetamido] -3- (piperidinocarbonyl) propionic acid used as an initial material is obtained as follows: 1, 1'-carbonyldiimidazole (0.81 g) is added to a stirring mixture of N- (2-naphthylsulfonyl) glycine (1.33 g) and DMF (10 ml) and the mixture is stirred at room temperature for 30 minutes. The hydrochloride salt of the 04-benzyl ester of the 1-piperidide of L-aspartic acid (1.63 g) and triethylamine (0.87 ml) are in turn added and the mixture is stirred at room temperature for 16 hours. The mixture is partitioned between ethyl acetate and water. The organic phase is washed with water and brine, it is dried (MgSO4) and evaporated. The residue is purified by column chromatography using a mixture of methylene chloride and ethyl acetate 3: 2 as eluent. In this way (3S) -3- [2- (2-naphthalenesulfonamido) -acetamido] -3- (piperidinocarbonyl) -propionate benzyl was obtained as a foam (1.59 g). A mixture of a portion (1.44 g) of the material thus obtained, charcoal catalyst in 10% palladium (0.2 g) and ethanol (30 ml) is stirred under a hydrogen atmosphere for 6 hours. The mixture is filtered and the filtrate is evaporated. The residue is purified by column chromatography using ethyl acetate as eluent. In this way (3S) -3- [2- (2-naphthalenesulfonamido) acetamido] -3- (piperidinocarbonyl) propionic acid was obtained as an oil (0.858 g); NMR spectrum (CDC13) 1.4-1.7 (m, 6H), 2.4-2.8 (m, 2H), 3.4-3.6 (m, 4H), 3.6-3.8 (m, 2H), 5.1-5.35 (m, ÍH) , 6.5-6.6 (m, 2H), 7.5-7.7 (m, 2H), 7.8-8.0 (m, 5H), 8.4 (s, ÍH).

Example 19 Using an analogous procedure to that described in Example 1, 1- (4-pyridyl) piperidine-4-carbonyl chloride is reacted with 1- [3-amino-2- (benzyloxycarbonylamino) propionyl] piperidine to give the N- [2- (benzyloxycarbonylamino) -2- (piperidinocarbonyl) ethyl] -1- (4-pyridyl) piperidine-4-carboxamide in 44% yield; NMR spectrum 1.5-2.0 (m, 10H), 2.2-2.4 (m, ÍH), 2.8-3.0 (m, 2H), 3.2-3.35 (m, ÍH), 3.4-3.7 (m, 5H), 3.8- 3.95 (m, 2H), 4.7-4.8 (m, ÍH), 5.2 (s, 2H), 6.0-6.2 (m, ÍH), 6.2-6.4 (, ÍH), 6.6-6.7 (m, 2H), 7.3 -7.4 (, 5H), 8.2-8.3 (m, 2H); Elemental Analysis Found C, 63.1; H, 7.4; N, 13.3; C27H34N504 H20 required C, 63.4; H, 7.2; N, 13.7%.

Example 20 A mixture of 3- (2-naphthalenesulfonamido) -propionic acid [is prepared by the reaction of 2-naphthylsulfonyl chloride and 3-aminopropionic acid; 0.163 g], N-hydroxysuccinimide (0.067 g), N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide (0.112 g) and DMF (10 ml) is stirred at room temperature for 30 minutes. A solution of N- [2-amino-2- (piperidinocarbonyl) ethyl] -1- (4-pyridyl) piperidin-4-carboxamide (0.21 g) in DMF (2 ml) is added and the mixture is stirred at room temperature for 16 hours. The mixture is evaporated and the residue is divided between methylene chloride and water. The organic phase is washed with a 2N aqueous sodium hydroxide solution and with water, dried (MgSO 4) and evaporated. The residue is purified by column chromatography using polar mixtures in an increase of ethyl acetate and methanol as eluent. In this way, 3- (2-naphthalenesulfonamido) -N- is obtained. { 1- (piperidinocarbonyl) -2- [1- (4-pyridyl) piperidin-4-ylcarbonylamino] ethyl} propionamide (0.14 g), m.p. 201-203 ° C; NMR spectrum (CD3SOCD3) 1.2-1.6 (m, 10H), 2. 1-2.3 (m, 3H), 2.6-2.8 (, 2H), 2.9 (t, 2H), 3.0-3.1 (m, ÍH), 3.3-3.5 (m, 3H), 3.7-3.9 (m, 2H) , 4.7-4.8 (, ÍH), 6. 6-6.7 (m, 2H), 7.5-7.7 (m, 3H), 7.7-7.8 (m, 2H), 7.9-8.2 (m, 6H), 8.35 (m, ÍH); Elemental Analysis Found C, 61.2; H, 6.4; N, 12.8; C32H4QNg05S 0.5EtAc required C, 61.4; H, 6.6; N, 12.7%. The N- [2-amino-2- (piperidinocarbonyl) ethyl] -1- (4-pyridyl) -piperidin-4-carboxamide used as an initial material is obtained as follows: A mixture of N- [2- (benzyloxycarbonylamino) -2- (piperidinocarbonyl) ethyl] -1- (4-pyridyl) piperidine-4-carboxamide (1.37 g), 10% palladium carbon catalyst (0.2 g) and ethanol are stirred under a hydrogen atmosphere for 1 hour . The mixture is filtered and the filtrate is evaporated. In this way the required initial material was obtained in a 91% yield.

Example 21 Using an analogous procedure to that described in Example 2, the N- [2-amino-2- (piperidinocarbonyl) ethyl] -1- (4-pyridyl) piperidine-4-carboxamide chloride is reacted with naphthalene chloride. 2-carbonyl to give the N-. { 1- (Piperidinocarbonyl) -2- [1- (4-pyridyl) piperidin-4-ylcarbonylamino] -ethyl} inaphthalene-2-carboxamide in an 85% yield; NMR spectrum (CDC13) 1.5-2.1 (m, 10H), 2.3-2.4 (m, ÍH), 2.8-3.0 (m, 2H), 3.4-4.0 (m, 8H), 5.15-5.25 (m, ÍH) , 6.6 (m, ÍH), 6.85 (, ÍH), 7.5-7.7 (, 2H), 7.8-8.0 (m, 5H), 8.2 (d, 2H), 8.35 (s, ÍH); Elemental Analysis Found C, 67.6; H, 7.0; N, 13. 0; C30H35N5O3 H2 ° required C, 67.8; H, 7.0; N, 13.1%.

Example 22 A solution of 4-tolyl isocyanate (0.133 g) in methylene chloride (5 ml) is added dropwise to a stirred solution of N- [2-amino-2- (piperidinocarbonyl) ethyl] -1- (4-pyridyl ) piperidin-4-carboxamide (0.359 g) in methylene chloride (10 ml). The mixture is stirred at room temperature for 2 hours. The precipitate is isolated and purified by column chromatography using a mixture of methylene chloride and methanol 9: 1 as eluent. In this way the N- was obtained. { 2-piperidinocarbonyl-2- [3- (4-tolylureido] ethyl] -1- (4-pyridyl) -piperidine-4-carboxamide (0.13 g), m.p. 252-253 ° C; NMR spectrum (CD3SOCD3) 1.4-1.8 (m, 10H), 2.2 (s, ~ 3H), 2.25 (m, ÍH), 2.7-2.9 (m, 2H), 3.05-3.25 (m, 2H), 3. 35-3.5 (m, 2H), 3.5-3.6 (m, 2H), 3.75-4.0 (m, 2H), 4.8-5.0 (m, ÍH), 6.3 (d, ÍH), 6.7 (m, 2H), 7.0 (d, 2H), 7.25 (d, 2H), 7.95 (m, ÍH), 8.05-8.15 (m, ÍH), 8.7 (s, ÍH); Elemental Analysis Found C, 65.8; H, 7.4; N, 16.9; C27H3gN603 required C, 65.8; H, 7.4; N, 17.1%.

Example 23 Using a procedure analogous to that described in Example 2, the hydrochloride salt of 2-amino-N- (1-piperidinocarbonyl-2- [1- (4-pyridyl) piperidin-4-ylcarbonylaminolethyl} acetamide is reacted with 4-toluenesulfonyl chloride to give the N-. {1-piperidinocarbonyl-2- [1- (4-pyridyl) piperidin-4-ylcarbonyl-amino] ethyl} -2- (4-toluenesulfonamido) acetamide in a 50% yield as a foam; NMR spectrum (CD3SOCD-,) 1.3-1.8 (m, 10H), 2.2-2.4 (m, 4H), 2.7-2.9 (m, 2H), 3.0-3.2 (m, 1H) ), 3.3-3.6 (m, 12H), 3.8-4.0 (m, 2H), 4.8-4.95 (m, ÍH), 6.7-6.8 (m, 2H), 7.35 (d, 2H), 7.6-7.7 (m , 2H), 8.05-8.2 (m, 2H), 8.25 (d, 2H) The hydrochloride salt of 2-amino-N-. {1-piperidinocarbonyl-2- [1- (4-pyridyl) -piperidine- 4-ylcarbonyl-amino] ethyl.} Acetamide used as an initial material is obtained as follows: The N-hydroxysuccinimide ester of 2- (tert-butoxycarbonylamino) acetic acid [is obtained by the reaction of the acid and N-hydroxysuccin imidate in the presence of 0.272 g dicyclohexyl-carbodiimide] are added to a stirred solution of N- [2-amino-2- (piperidinocarbonyl) ethyl] -1- (4-pyridyl) piperidine-4-carboxamide (0.359 g) in methylene chloride (5 ml). The mixture is stirred at room temperature for 16 hours. The mixture is partitioned between methylene chloride and a 2N aqueous sodium hydroxide solution. The organic phase is washed with water, dried (MgSO 4) and evaporated.

The material thus obtained is suspended in methylene chloride (25 ml) and the hydrogen chloride gas is carried into the solution for 5 minutes. A clear solution is obtained followed by the deposition of a precipitate. The mixture is evaporated to give the required starting material.

Example 24 1, 1'-Carbonyldiimidazole (0.11 g) is added to a stirred solution of 2- (2-naphthalenesulfonamido) -acetic acid (0.182 g) in DMF (2 ml), which has been cooled to ° C. The mixture is stirred at 5 ° C for 30 minutes. A solution of 1- [4-amino-4- (piperidinocarbonyl) butyryl] -4- (4-pyridyl) piperazine (0.247 g) in DMF (3 ml) is added and the mixture is stirred at room temperature for 16 hours. The mixture is partitioned between ethyl acetate and water. The organic phase is washed with water, dried (MgSO 4) and evaporated. The residue is purified by column chromatography using a mixture of ethyl acetate, methanol and aqueous ammonium hydroxide 95: 5: 0.5 as eluent. In this way, 2- (2-naphthalenesulfonamido) -N- was obtained. { 1-piperidinocarbonyl) -3- [4- (4-pyridyl) piperazin-1-ylcarbonyl] propyl} acetamide (0.14 g); NMR spectrum (CD3SOCD3) 1.4-1.7 (m, 7H), 1.8- 1.95 (m, ÍH), 2.1-2.4 (m, 2H), 3.2-3.6 (, 14H), 4.65-5.75 (, ÍH), 6.8 (d, 2H), 7.6-7.75 (m, 2H), 7.8-7.9 (m, ÍH), 7.9-8.2 (m, 7H), 8.45 (s, ÍH). The 1- [4-amino-4- (piperidinocarbonyl) butyryl] -4- (4-pyridyl) -piperazine used as an initial material is obtained as follows: A solution of piperidine (0.85 g) in methylene chloride (5 ml. ) is added dropwise to a solution of N2-benzyloxycarbonyl-DL-glutamic anhydride [J. Chem. Soc .. 1950, 1954; 2.63 g] in methylene chloride (20 ml), which has been cooled to 0 ° C. The mixture is stirred at 0 ° C for 1 hour. The mixture is extracted with ethyl acetate. The extract is acidified by the addition of concentrated hydrochloric acid, washed with water, dried (MgSO 4) and evaporated. The residue is purified by column chromatography using polar mixtures in an increase of ethyl acetate, acetic acid and methanol as eluent (99: 1: 0 to 99: 1: 5). In this way, the C1-piperidide N2-benzyloxycarbonyl-DL-glutamic acid (0.78 g), m.p. 92-93 ° C. A portion (0.7 g) of the material thus obtained is dissolved in DMF (10 ml) and cooled in an ice bath. It adds 1, 1 'carbonyldiimidazole (0.325 g) and the mixture is stirred at 5 ° C for 30 minutes. A solution of 1- (4-pyridyl) piperazine (0.327 g) in DMF (2 ml) is added and the mixture is stirred at room temperature for 3 hours. The mixture is partitioned between ethyl acetate and water. The organic phase is washed with water, dried (MgSO 4) and evaporated. In this way, 1- [4- (benzyloxycarbonylamino) -4- (piperidinocarbonyl) -butyryl] -4- (4-pyridyl) piperazine (0.55 g) was obtained. A portion (0.4 g) of the material thus obtained, charcoal catalyst in 10% palladium (0.1 g) and ethanol (20 ml) are stirred under a hydrogen atmosphere for 6 hours. The mixture is filtered and the filtrate is evaporated. In this way 1- [4-amino-4- (piperidinocarbonyl) butyryl] -4- (4-pyridyl) piperazine (0.26 g) was obtained; NMR spectrum (CDC13 + CD3SOCD3) 1.4-1.7 (m, 6H), 1.9-2.1 (m, ÍH), 2.3-2.6 (m, 2H), 2.7-2.8 (m, ÍH), 3.2-3.8 (m, 12H), 6.65 (d, 2H), 8.3 (d, 2H).

Example 25 Using an analogous procedure to that described in Example 1, 2- [4- (4-pyridyl) piperazin-1-yl] acetyl chloride is reacted with N- (3-aminopropyl) naphthalene-2-sulfonamide to give N- [3- (2-naphthalenesulfonamido) propyl] -2- [4- (4-pyridyl) piperazin-1-yl] acetamide in 34% yield; NMR spectrum (CD3SOCD3) 1.5-1.7 (, 2H), 2.75-2.9 (t, 2H), 2.9-3.0 (s, 2H), 3.1-3.25 (t, 2H), 3.4-3.6 (m, 8H), 7.6-7.9 (m, 6H), 8.0-8.2 (m, 4H), 8.4 (s, ÍH), 8.7-8.8 (d, 2H); Elemental Analysis Found C, 61.6; H, 6.25; N, 15.0; C24H29N503S required C, 61.2; H, 6.2; N, 14.8%. The N- (3-aminopropyl) naphthalene-2-sulfonamide used as a starting material is obtained by the reaction of 2-naphthylsulfonyl chloride (2 g) and 1,3-diaminopropane (2.95 ml) in a methylene chloride solution. (25 ml) at room temperature for 16 hours.

Example 26 Using an analogous procedure to that described in Example 1, the 1- (4-pyridyl) piperidin-4-carbonyl chloride is reacted with the hydrochloride salt of N- (piperidin-4-yl) naphthalene-2-sulfonamide to give '4- (2-naphthalenesulfonamido) -1- [1- (4-pyridyl) piperidin-4-ylcarbonyl] -piperidine in 28% yield; NMR spectrum (CD3SOCD3) 1.1-1.4 (m, 2H), 1.5-1.8 (m, 6H), 2.6-2.8 (m, ÍH), 2.85-3.3 (m, 6H), 3.7-3.9 (m, ÍH) , 4.0-4.2 (, 4H), 6.9-7.1 (d, 2H), 7.5-7.7 (m, 2H), 7.8-8.1 (m, 6H), 8.4 (s, ÍH); Elemental Analysis Found C, 62.7; H, 6.5; N, 11.0; C26H30N4O3S 0.5H20 required C, 64.1; H, 6.3; N, 11.4%. The hydrochloride salt of N- (piperidin-4-yl) naphthalene-2-sulfonamide used as an initial material is obtained as follows: A mixture of 4-amino-1-benzylpiperidine (1.8 ml), 2-naphthylsulfonyl chloride ( 2 g), triethylamine (3.7 ml) and methylene chloride (25 ml), is stirred at room temperature for 16 hours. The mixture is partitioned between ethyl acetate and water. The organic phase is washed with water, dried (MgSO 4) and evaporated. The residue is purified by column chromatography using polar mixtures in an increase of ethyl acetate and methanol as eluent. In this way, N- (1-benzylpiperidin-4-yl) naphthalene-2-sulfonamide (2.98 g) was obtained. A mixture of a portion (0.5 g) of the material thus obtained and methylene chloride (20 ml) is added and cooled in an ice bath and 1-chloroethyl chloroformate (0.2 ml). The mixture is stirred overnight at room temperature.

The mixture evaporates. The residue is dissolved in methanol (5 ml) and the solution is refluxed for 3 hours. The mixture is evaporated and the residue is purified by column chromatography using polar mixtures in an increase of ethyl acetate and methanol as eluent. In this way, the N- (piperidin-4-yl) naphthalene-2-sulfonamide hydrochloride salt (0.2 g) was obtained; NMR spectrum (CD3SOCD3) 1.5-1.8 (m, 4H), 2.75-2.9 (, 2H), 3.05-3.2 (m, 2H), 3.25-3.4 (m, ÍH), 7.6-7.7 (m, 2H), 7.8-7.9 (m, ÍH), 7.9-8.15 (m, 3H), 8.4 (s, ÍH).

Example 27 Using a procedure analogous to that described in Example 2, the hydrochloride salt of 3-amino-1- [1- (4-pyridyl) piperidin-4-ylcarbonyl] pyrrolidine is reacted with 2-naphthylsulfonyl chloride to give 3- (2-naphthalenesulfonamido) -1- [1- (4-pyridyl) piperidin-4-ylcarbonyl] -pyrrolidine in 37% yield; NMR spectrum (CD3SOCD3 + CD3C02D) 1.5-2.0 (m, 6H), 2.75-2.9 (m, ÍH), 3.1-4.0 (m, 7H), 4.0-4.3 (m, 2H), 7.0-7.1 (m, 2H), 7.6-7.7 (m, 2H), 7.9- 8.0 (m, ÍH), 8.0-8.2 (m, 5H), 8.5 (d, ÍH); Elemental Analysis Found C, 56.8; H, 5.5; N, 10.3; C25H28N4S03 2H20 0.5CH2Cl2 required C, 56.4; H, 6.1; N, 10.3%. The hydrochloride salt of 3-amino-1- [1- (4-pyridyl) -piperidin-4-ylcarbonyl] -pyrrolidine used as a starting material is obtained as follows: Using a procedure analogous to that described in Example 1, the l- (4-pyridyl) piperidine-4-carbonyl chloride is reacted with the 3- (tert-butoxycarbonylamino) irrolidine to give 3- (tert-butoxycarbonylamino) -1- [1- (4-pyridyl) piperidine- 4-ylcarbonyl] -pyrrolidine in 41% yield. The material thus obtained is treated with hydrogen chloride gas using a procedure analogous to that described in the last paragraph of the portion of Example 1, which relates to the preparation of the starting materials. In this way, the hydrochloride salt 3-amino-1- [1- (4-pyridyl) piperidin-4-ylcarbonyl] pyrrolidine was obtained in a quantitative yield; NMR spectrum (CD3SOCD3) 1.5-1.8 (m, 2H), 1.75-2.4 (m, 4H), 2.8-3.0 (, ÍH), 3.25-4.0 (m, 7H), 4.2-4.4 (d, 2H), 7.7 (d, 2H), 8.1-8.3 (d, 2H), 8.5-8.7 (m, 2H). 28 The procedure described in Example 2 is repeated except that the 8-chloronaphth-2-ylsulfonyl chloride is used in place of the 2-naphthisulfonyl chloride. In this way, 1- (8-chloronaphth-2-ylsulfonyl) -4- [1- (4-pyridyl) piperidin-4-ylcarbonyl] piperazine was obtained in a yield of 74%; NMR spectrum (CD3SOCD3 + CD3C02D) 1.35-1.7 (m, 4H), 2-85-3.15 (m, 7H), 3.5-3.7 (m, 4H), 3.95-4.1 (m, 2H), 7.0 (d, 2H), 7.75 (t, ÍH), 7.85-7.95 (m, 2H), 8.1-8.2 (m, 3H), 8.3 (d, ÍH), 8.55 (s, ÍH); Elemental Analysis Found C, 59.4; H, 5.5; N, 10.9; C25H27C1N403S 0.5H20 required C, 59.1; H, 5.5; N, 11.0%.

Example 29 Using a procedure analogous to that described in Example 2, 2-naphthylsulfonyl chloride is reacted with 3-ethoxycarbonyl-1- (1- (4-pyridyl) piperidin-4-ylcarbonyl] piperazine to give 2-ethoxycarbonyl -1- (2-naphthylsulfonyl) -4- [1- (4-pyridyl) piperidin-4-ylcarbonyl] piperazine in a yield of 31%; NMR spectrum (CD3SOCD3, 100 ° C) 1.05 (t, 3H), 1.5-1.8 (m, 4H), 2.9-3.25 (, 5H), 3.35-3.5 (m, 2H), 3.7-4.15 (m, 7H) ), 5.5-5.7 (m, 2H), 6.75-6.95 (m, 2H), 7.6-7.85 (m, 3H), 8.0-8.15 (m, 5H), 8.45 (d, ÍH); Elemental Analysis Found C, 60.4; H, 6.1; N, . 1; C28H32N405S H20 required C, 60.6; H, 6.1; N, 10.1%. The 3-ethoxycarbonyl-l- [1- (4-pyridyl) piperidin-4-ylcarbonyl] -piperazine used as an initial material is obtained as follows: Using a procedure analogous to that described in Example 1, the 1- (4-pyridyl) piperidine-4-carbonyl is reacted with ethyl 1-benzylpiperazine-2-carboxylate (Helv. Chim. Acta, 1962, 45, 2383) to give l-benzyl-2-ethoxycarbonyl-4- [ 1- (4-pyridyl) piperidin-4-ylcarbonyl] -piperazine in a 67% yield. A mixture of the material thus obtained (0.667 g), trifluoroacetic acid (2 ml), 10% palladium carbon catalyst (0.15 g) and methanol (2 ml) is stirred for 7 atmospheric pressures of hydrogen for 48 hours. The mixture is filtered and evaporated. The residue is divided between methylene chloride and a saturated aqueous sodium bicarbonate solution. The organic phase is washed with water, dried (MgSO 4) and evaporated. The residue is triturated under diethyl ether to give the required starting material in a quantitative yield. NMR spectrum (CD3SOCD3) 1.2-1.4 (m, 3H), 1.8-2.0 (m, 4H), 2.7-3.55 (m, 8H), 3.6-3.85 (m, 2H), 3.9-4.05 (m, 2H) , 4.15-4.3 (m, 2H), 6.75 (d, 2H), 8.3 (d, 2H).

Example 30 Using an analogous procedure to that described in Example 1, the hydrochloride salt of the 1- (4-pyridyl) piperidine-4-carbonyl chloride is reacted with the hydrochloride salt of N- (2-aminoethyl) -2- (2 -naphthalenesulfonamido) -acetamide to give 2- (2-naphthalenesulfonamido) -N-. { 2- [1- (4-pyridyl) piperidin-4-ylcarbonylamino] ethyl} acetamide in a yield of 49% p.f. 107-109 ° C; NMR spectrum (CD3SOCD3) 1.4-1.6 (m, 4H), 2.2-2.4 (m, ÍH), 2.7-2.9 (m, 2H), 2.9-3.1 (m, 4H), 3.2-3.4 (m, 2H) , 3.6-4.0 (m, 2H), 6.7-6.8 (d, 2H), 7.6-8.2 (m, 11H), 8.4 (s, ÍH); Elemental Analysis Found C, 59.7; H, 5.9; N, 14. 1; C25H29 504S 0.4H20 required C, 59.7; H, 5-9; N, 13-9% The hydrochloride salt of N- (2-aminoethyl) -2- (2-naphthalenesulfonamido) acetamide used as an initial material is obtained as follows: 1, 1'-Carbonyldiimidazole (1.62 g) is added to a stirred solution of N- (2-naphthylsulfonyl) glycine (2.65 g) in DMF (20 ml) and the mixture is stirred at room temperature for 20 minutes. The mixture is cooled to 5 ° C and a solution of 2- (N-tert-butoxycarbonylamino) ethylamine (1.6 g) in DMF (5 ml) is added. The mixture is stirred at room temperature for 2 hours. The mixture is evaporated and the residue is partitioned between ethyl acetate and a 1M aqueous citric acid solution. The organic phase is washed with water, dried (MgSO 4) and evaporated. The residue is purified by column chromatography using polar mixtures in an increase of methylene chloride and ethyl acetate as eluent. In this way N- [2- (tert-butoxycarbonylamino) ethyl] -2- (2-naphthalene-sulfonamido) acetamide (2.3 g) was obtained, p.f. 150-152 ° C. A portion (2 g) of the initial material thus obtained is suspended in ethyl acetate and the mixture is cooled to 5 ° C. The hydrogen chloride gas is carried into the mixture for 10 minutes to give a clear solution followed by the deposition of a precipitate. The solid is isolated, washed with diethyl ether and dried. In this way the required initial material (1.37 g) was obtained; NMR spectrum (CD35OCD3) 2.7-2.9 (m, 2H), 3.15-3.3 (m, 2H), 3.4-3.5 (d, 2H), 7.6-7.9 (m, 3H), 7.9-8.3 (m, 8H) , 8.45 (d, ÍH).

Example 31 Using a procedure analogous to that described in Example 3, the hydrochloride salt of N- (2-aminoethyl) -2- (2-naphthalenesulfonamido) acetamide, 1,1'-carbonyldiimidazole and 1- (4-pyridyl) piperazine they react to give 2- (2-naphthalenesulfonamido) -N-. { 2- [4- (4-pyridyl) piperazin-1-ylcarbonylamino] ethyl} acetamide in a yield of 10%; NMR spectrum (CD3SOCD3 + CD3C02D) 3.1-3.2 (m, 4H), 3.4-3.6 (m, 6H), 3.6-3.7 (m, 4H), 7.1 (d, 2H), 7.6-7.75 (m, 2H), 7.8-7.9 (m, ÍH), 8.0-8.05 (m, ÍH), 8.1-8.2 (m, 4H), 8. 4 (s, ÍH); Elemental Analysis Found C, 56.4; H, 5.9; N, 15.5; C24H28Ng04S 0.5H20 0.5EtAc required C, 56.8; H, 6.0; N, 15.3%.

Example 32 Triethylamine (0.686 ml) is added to a stirring solution of 4-chloropyrimidine hydrochloride (0.151 g), 2- (2-naphthalenesulfonamido) -N- [2- (piperidin-4-ylcarbonylamino) ethyl] acetamide hydrochloride salt (0.453) g) and ethanol (10 ml) and the mixture is stirred at room temperature for 4 days. The mixture is partitioned between ethyl acetate and water. The org phase is washed with water, dried (MgSO 4) and evaporated. The residue is recrystallized from acetonitrile. In this way, 2 - (2-naphthalenesulfonamido) -N- was obtained. { 2- [1- (4-pyrimidinyl) piperidin-4-ylcarbonylamino] ethyl} acetamide (0.08 g), m.p. 178-179 ° C; NMR spectrum (CD3SOCD3) 1.3-1.6 (m, 2H), 1.65-1.85 (m, 2H), 2.3-2.45 (m, ÍH), 2.8-3.05 (m, 6H), 3.4 (d, 2H), 4.3 -4.5 (m, 2H), 6.8 (d, ÍH), 7.3-7.8 (m, 3H), 7.8-7.95 (m, 2H), 8.0 (m, 2H), 8.1-8.2 (m, 3H), 8.4 -8.5 (, 2H); Elemental Analysis Found C, 57.6; H, 5.7; N, 16.6; C24H28Ng04S required C, 58.0; H, 5.7; N, 16.9%. The 2- (2-naphthalenesulfonamido) -N- [2- (piperidin-4-ylcarbonylamino) ethyl] acetamide used as an initial material is obtained as follows: N-hydroxybenzotriazole (0.135 g) and N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide (0.191 g) are in turn added to a stirring solution of 1- (tert-butoxycarbonyl) piperidin-4-carboxylic acid (0.229 g) in DMF (10 ml), which has been cooled to 0 ° C. The mixture is stirred at 0 ° C for 30 minutes. A solution of the hydrochloride salt of N- (2-aminoethyl) -2- (2-naphthalenesulfonamido) acetamide (0.343 g) is added in DMF (5 ml), followed by triethylamine (0.101 g). The resulting mixture is allowed to warm to room temperature and is stirred for 3 hours. The mixture is partitioned between ethyl acetate and water. The org phase is washed in turn with 2N aqueous hydrochloric acid, a saturated aqueous sodium bicarbonate solution and brine, dried (MgSO 4) and evaporated. In this way the N- was obtained. { 2- [1- (tert-butoxycarbonyl) -piperidin-4-ylcarbonylamino] ethyl} -2- (2-naphthalenesulfonamido) -acetamide (0.192 g), m.p. 176-178 ° C. The tert-butoxycarbonyl group is removed using a procedure analogous to that described in the last paragraph of the portion of Example 30, which relates to the preparation of the starting materials. In this way, the hydrochloride salt of 2- (2-naphthalenesulfonamido) -N- [2- (piperidin-4-ylcarbonylamino) ethyl] acetamide was obtained in a 96% yield.

Example 33 The procedure described in Example 32 is repeated, except that the hydrochloride salt 2-amino-4-chloropyrimidine is used in place of the hydrochloride salt 4-chloropyrimidine. In this way the N- was obtained. { 2- [1- (2-aminopyrimidin-4-yl) piperidin-4-ylcarbonylamino] ethyl} -2- (2-naphthalene-sulfonamido) acetamide in a yield of 53%. p.f. 197-199 ° C; NMR spectrum (CD3SOCD3) 1.3-1.55 (m, 2H), 1.6-1.8 (m, 2H), 2.2-2.4 (m, ÍH), 2.7-2.9 (m, 2H), 2.9-3.1 (m, 4H) , 3.4 (s, 2H), 4.2-4.4 (m, 2H), 5.9 (s, 2H), 6.0 (d, ÍH), 7.6-7.8 (m, 4H), 7.8-7.95 (, 2H), 7.95- 8.2 (m, 4H), 8.45 (s, ÍH); Elemental Analysis Found C, 55.9; H, 5.6; N, 19.1; C24H29N704S required C, 56.3; H, 5.7; N, 19.2%.

Example 34 The procedure described in Example 32 is repeated, except that 2-amino-4-chloro-6-methylpyrimidine hydrochloride is used in place of 4-chloropyrimidine hydrochloride and that the reaction mixture is heated at 80 ° C for 16 hours . In this way the N- was obtained. { 2- [1- (2-amino-6-methylpyrimidin-4-yl) piperidin-4-ylcarbonylamino] -ethyl} -2- (2-naphthalenesulfonamido) acetamide in a 38% yield. p.f. 225-226 ° C; NMR spectrum 1.3-1.5 (m, 2H), 1.6-1.8 (m, 2H), 2. 05 (s, 3H), 2.2-2.4 (m, ÍH), 2.7-2.9 (, 2H), 2.95-3.1 (m, 4H), 3.45 (s, 2H), 4.2-4.4 (m, 2H), 5.8 (s, 2H), 5.9 (s, ÍH), 7.6-7.75 (m, 3H), 7.8-8.0 (, 2H), 8.0-8.2 (, 4H), 8.45 (s, ÍH); Elemental Analysis Found C, 57.1; H, 6.0; N, 18.4; C25H31N704S required C, 56.9; H, 5.9; N, 18.4%.

Example 35 Using an analogous procedure to that described in Example 18, 4- [2- (2-naphthalenesulfonamido) acetamido] butyric acid is reacted with 1- (4-pyridyl) piperazine to give the 2- (2-naphthalene-sulfonamido) ) -N-. { 3- [4- (4-pyridyl) piperazin-1-ylcarbonyl] -propyl} acetamide in a 21% yield as a foam; NMR spectrum (CD3SOCD3) 1.45-1.65 (m, 2H), 2.3 (t, 2H), 2.9-3.1 (m, 2H), 3.2-3.4 (m, 4H), 3.5-3.65 (m, 4H), 6. 8 (m, 2H), 7.6-7.75 (m, 4H), 8.0-8.3 (m, 6H), 8.45 (s, ÍH); Elemental Analysis Found C, 57.7; H, 6.1; N, 12.7; C25H29N504S H20 0.5EtAc required C, 58.2; H, 6.3; N, 12.6%. The 4- [2- (2-naphthalenesulfonamido) acetamido] -butyric acid used as an initial material is obtained as follows: Using a procedure analogous to that described in the first paragraph of the portion of Example 30, which is related to the Preparation of the starting materials, N- (2-naphthylsulfonyl) glycine is reacted with methyl 4-aminobutyrate to give methyl 4- [2- (2-naphthalenesulfonamido) acetamido] butyrate in 56% yield.

The material thus obtained is hydrolyzed using a procedure analogous to that described in Example 9. In this way the required starting material was obtained in a yield of 79%, m.p. 187-189 ° C; NMR spectrum (CD3SOCD3 + CD3C02D) 1.5-1.7 (m, 2H), 2.15 (t, 2H), 3.0 (t, 2H), 3.5 (s, 2H), 7.6-7.8 (m, 2H), 7.8-7.9 (m, ÍH), 7.95-8.2 (, 3H) ), 8.5 (s, ÍH).

Example 36 N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide (0.21 g) is added to a stirring mixture of N- (2-naphthylsulfonyl) glycine (0.265 g), 1- (4-pyridyl) piperazine (0.169 g) and DMF (10 ml), which has been cooled to 5 ° C. The mixture is stirred at room temperature for 3 hours. The mixture is partitioned between ethyl acetate and water. The organic phase is washed with water, dried (MgSO 4) and evaporated. The residue is purified by column chromatography using a mixture of methylene chloride and methanol 19: 1 as eluent. In this way N- [4- (4-? Iridyl) piperazin-1-ylcarbonylmethyl] naphthalene-2-naphthalene-2-sulfonamide (0.126 g), m.p. 182-184 ° C; NMR spectrum (CD3SOCD3) 3.1-3.6 (m, 8H), 3.8-3.9 (m, 2H), 6.7-6.8 (m, 2H), 7.6-7.75 (m, 2H), 7.75-7.9 (m, 2H) , 8.0-8.2 (m, 5H), 8.45 (s, ÍH); Elemental Analysis Found C, 61.0; H, 5.3; N, 13.5; C21H22N403S required C, 61.4; H, 5.4; N, 13.5%.

Example 37 Using an analogous procedure to that described in Example 36, 4- (2-naphthalenesulfonamido) butyric acid is reacted with 1- (4-pyridyl) piperazine to give the N- (3- [4- (4-pyridyl ) piperazin-1-ylcarbonyl] propyl.} naphthalene-2-sulfonamide in a 15% yield as a foam; NMR spectrum (CD3SOCD3) 1.7-1.9 (m, 2H), 2.3-2.4 (t, 2H), 2.95-3.05 (m, 2H), 3.2-3.3 (m, 4H), 3.4-3.5 (m, 2H), 3.6-3.75 (m, 2H), 5.4-5.6 (d, ÍH), 6.5-6.6 (m , 2H), 7.5-7.65 (m, 2H), 7.75-8.0 (m, 4H), 8.2-8.3 (m, 2H), 8.35 (s, ÍH). The 4- (2-naphthalenesulfonamido) butyric acid used as an initial material is obtained as follows: Using a procedure analogous to that described in Example 2, the 2-naphthylsulfonyl chloride is reacted with methyl 4-aminobutyrate to give methyl 4- (2-naphthalenesulfonamido) butyrate in a 94% yield The material thus obtained is hydrolyzed using a procedure analogous to that described in E Example 9. In this way the required initial material was obtained in a yield of 88%, p.f. 123-125 ° C; NMR spectrum (CDCI3) 1.7-1.9 (m, 2H), 2.35 (t, 2H), 2.9-3.1 (m, 2H), 6.3-6.5 (m, ÍH), 7.5-7.7 (m, 2H), 7.8 -8.1 (, 4H), 8.4 (s, ÍH).

Example 38 A solution of 5- (2-pyridyl) thien-2-ylsulfonyl chloride fChem. Abs., 1983, 98., 215349; 0.162 g] in methylene chloride (5 ml) is added to a stirred mixture of 1- [1- (4-pyridyl) piperidin-4-ylcarbonyl] -piperazine (0.314 g), triethylamine (0.9 ml) and chloride of methylene (15 ml). The resulting mixture is stirred at room temperature for 18 hours. The mixture is divided between methylene chloride and water. The organic phase is washed with water, dried (MgSO 4) and evaporated. The residue is purified by column chromatography using polar mixtures in an increase in methylene chloride and methanol as eluent. In this way 1- [1- (4-pyridyl) piperidin-4-ylcarbonyl] -4- [5- (2-pyridyl) thien-2-ylsulfonyl] piperazine was obtained (0.231 g, 74%); NMR spectrum (CD3SOCD3) 1.4-1.7 (m, 4H), 2.8-3.1 (m, 7H), 3.55-3.75 (m, 4H), 3.85-3.95 (m, 2H), 6.8 (d, 2H), 7.35 -7.45 (m, ÍH), 7.65 (d, ÍH), 7.9-8.0 (m, 2H), 8.05-8.15 (m, '3H), 8.55-8.6 (m, ÍH); Elemental Analysis Found C, 57.2; H, 5.5; N, 13.9; C24H27N5 ° 3S2 ° -25H2 ° required C, 57.4; H, 5.5; N, 14.0%.

Example 39 Using an analogous procedure to that described in Example 2, 1- [1- (4-pyridyl) piperidin-4-ylcarbonyl] piperazine is reacted with the appropriate (E) -styrene sulfonyl chloride. In this way, the (E) -resorts described in Table I were obtained, the structures of which are confirmed by NMR spectroscopy. Unless otherwise stated, the appropriate (E) -styrene sulfonyl chlorides are obtained from the corresponding styrenes using a procedure analogous to that described in Note b, Table I below.

Table I Notes to. The product gives the following NMR signals (CD3SOCD3) 1.45-1.8 (m, 4H), 2.95-3.25 (m, 7H), 3.5-3.75 (m, 4H), 4.12 (m, 2H), 7.05 (d, 2H ), 7.38 (m, 5H), 7.75 (m, 2H), 8.2 '(d, 2H). b. The product gives the following NMR signals (CD3SOCD3) 1.4-1.65 (m, 4H), 2.8-3.0 (m, 3H), 3.12 (m, 4H), 3.65 (m, 4H), 3.92 (m, 2H), 6.8 (d, 2H), 7 4 (d, 2H), 7.5 (d, 2H), 7.8 (d, 2H), 8.15 (d, 2H). The 4-chlorostyrene sulfonyl chloride used as an initial material is obtained as follows: Sulfuryl chloride (1.37 ml) is added dropwise to DMF (1.55 ml), which is stirred and cooled to a temperature in the range of 0 at 25 ° C. The mixture is stirred at room temperature for 30 minutes. 4-Chlorostyrene (1.2 ml) is added and the mixture is stirred and heated to 90 ° C for 3.5 hours. The mixture is cooled to room temperature and emptied into a mixture (-25 ml) of ice and water. The precipitate thus formed is isolated, washed with water and dried. In this way, 4-chloro-β-styrenesulfonyl chloride (1.8 g) was obtained; NMR spectrum (CD3SOCD3) 6.95 (s, 2H), 7.4 (d, 2H), 7.55 (d, 2H). c. The product gives the following NMR signals (CD3SOCD3) 1.4-1.85 (, 4H), 2.3 (s, 3H), 2.95-3.3 (m, 7H), 3.6 (m, 4H), 4.07 (m, 2H), 7.0 (m, 3H), 7.25 (m, 3H), 7.5 (d, 2H), 8.05 (d, 2H). d. The product gives the following NMR signals (CD3SOCD3) 1.45-1.75 (m, 4H), 2.4 (s, 3H), 2.85-3.25 (m, 7H), .55-3.75 (m, 4H), 3.92 (m, 2H), 6.8 (d, 2H), 7.1-7.4 (m, H), 7.68 (m, 2H), 8.15 (d, 2H). e. The product gives the following NMR signals (CD3SOCD3) 1.45-1.75 (, 4H), 2.85-3.0 (m, 3H), 3.05-3.2 (m, 4H), 3.5-3.75 (m, 4H), 3.92 (m, 2H), 6.85 (d, 2H) ), 7.2-7.5 (m, 4H), 7.85 (m, 2H), 8.15 (d, 2H). F. The product gives the following NMR signals (CD3SOCD3) 1.45-1.75 (m, 4H), 2.85-2.95 (m, 3H), 3.05-3.25 (m, 4H), 3.55-3.75 (m, 4H), 3.92 (m, 2H), 6.8 (d, 2H), 7.4-7.7 (m, 5H), 8.0 (m, ÍH), 8.1 (d, 2H) ). g. The product gives the following NMR signals (CD3SOCD3) 1.45-1.75 (m, 4H), 2.85-3.0 (, 3H), 3.0-3.2 (, 4H), 3.55-3Í75 (m, 4H), 3.92 (m, 2H) ), 6.8 (d, 2H), 7.4t7.5 (m, 4H), 7.72 (m, ÍH), 7.93 (m, ÍH), 8.15 (d, 2H). h. The product gives the following NMR signals (CD3SOCD3 + CD3C02D) 1.5-1.9 (m, 4H), 3.0-3.3 (m, 7H), 3.55-3.75 (m, 4H), 4.15 (, 2H), 7.1 (d, 2H), 7.4 (d, 2H), 7.7 (m, 2H), 8.1 (s, ÍH), 8.15 (d, 2H). i. The product gives the following NMR signals (CD3SOCD3 + CD3C02D) 1.55-1.85 (m, 4H), 3.0-3.35 (m, 7H), 3.6-3.75 (m, 4H), 4.17 (m, 2H), 7.1 (d) , 2H), 7.15-7.5 (m, 2H), 7.65 (m, 4H), 8.15 (d, 2H). j. The product gives the following NMR signals (CD3SOCD3 + CD3C02D) 1.5-1.85 (m, 4H), 3.0-3.3 (m, 7H), 3.55-3.75 (m, 4H), 4.15 (m, 2H), 7.1 (d) , 2H), 7.5 (m, 2H), 7.8 (d, 2H), 7.95 (d, 2H), 8.15 (d, 2H).

Example 40 Using an analogous procedure to that described in Example 2, 1- [1- (4-pyridyl) piperidin-4-ylcarbonyl] piperazine is reacted with the appropriate 2-naphthalenesulfonyl chloride. In this way, the compounds described in Table II were obtained, the structures of which are confirmed by NMR spectroscopy. Unless otherwise stated, the appropriate naphthylsulfonyl chlorides are obtained from the corresponding naphthalenes, using a procedure analogous to that described in Note c. Table III below in Example 41.

Table II Notes to. The product gives the following NMR signals (CD3SOCD3) 1.35-1.65 (m, 4H), 2.75-2.9 (m, 3H), 3.0-3.15 (m, 4H), 3.6 (m, 4H), 3.85 (m, 2H ), 6.75 (d, 2H), 7.9 (m, 3H), 8.1 (d, 2H), 8.35 (t, 2H), 8.5 (s, ÍH). b. The product gives the following NMR signals (CD3SOCD3) 1.35-1.65 (m, 4H), 2.8-3.05 (m, 7H), 3.5-3.7 (m, 4H), 3.8-3.9 (m, 2H), 6.75 (d , 2H), 7.78 (m, 2H), 8.15 (m, 4H), 8.45 (d, ÍH). c. The product gives the following NMR signals (CD3SOCD3) 1.35-1.7 (tn, 4H), 1.45 (t, 3H), 2.8-3.05 (m, 7H), .3 (m, 2H), 3.5-3.7 (m, 4H), 3.83 (m, 2H), 4.2 (m, 2H), 6.85 (d, 2H), 7.35 (m, ÍH), 7.58 (m, 2H), 7.95-8.15 (m, 4H), 8.3 (d , ÍH). d. The product gives the following NMR signals (CD3SOCD3) 1.35-1.65 (m, 4H), 2.75-3.0 (m, 7H), 3.5-3.7 (m, 4H), 3.85 (m, 2H), 3.95 (s, 6H) ), 6.75 (d, 2H), 7.5 (s, ÍH), 7.6 (m, 2H), 7.95 (d, ÍH), 8.1 (m, 2H), 8.25 (s, ÍH). and. The product gives the following NMR signals (CD3SOCD3 + CD3C02D) 1.45-1.8 (m, 4H), 2.9-3.1 (m, 5H), 3.22 (m, 2H), 3.55-3.75 (m, 4H), 4.1 (m, 2H), 7.05 (d, 2H), 7.65-7.85 (m, 2H), 8.1-8.25 (m, 5H), 8.45 (s, ÍH); and the following analytical data: Found C, 58.9; H, 5.3; N, 10.9; C25H27C1N403S 0.2CH2Cl-2 required C, 58-7; H, 5-3; N, 10.9%. The 6-chloro-2-naphthylsulfonyl chloride used as an initial material is obtained as follows: A solution of sodium nitrite (2.7 g) in water (5 ml) is added for 2 hours to an agitated mixture of 6-acid. amino-2-naphthalenesulfonic acid (8.8 g), dilute aqueous hydrochloric acid (2.8% w / v, 20 ml) and water (15 ml), which has been cooled to 0 ° C. The mixture is stirred at 0 ° C for 30 minutes and then emptied into a stirred suspension of cuprous chloride (3.96 g) in dilute aqueous hydrochloric acid (2.8%, 20 ml). The mixture is stored at room temperature for 18 hours. The mixture is evaporated to give 6-chloro-2-naphthalenesulfonic acid, which is used without further purification. The material is suspended in DMF (40 ml) and cooled to 5 ° C. Thionyl chloride (8.6 ml) is added dropwise and the mixture is stirred at 5 ° C for 3 hours. The mixture is emptied on ice and extracted with methylene chloride. The organic solution is dried (MgSO4) and evaporated. The residue is purified by column chromatography using a mixture of hexane and ethyl acetate 20: 1 as an eluent. In this way, 6-chloro-2-naphthylsulfonyl chloride (2.49 g) was obtained; NMR spectrum (CD3SOCD3) 7.45 (m, ÍH), 7.8 (m, ÍH), 7.85 (d, ÍH), 8.05 (m, 2H), 8.2 (s, ÍH). f. The product gives the following NMR signals (CD3SOCD3) 1.35-1.65 (m, 4H), 2.75-3.05 (m, 7H), 3.5-3.7 (m, 4H), 3.87 (m, 2H), 6.8 (d, 2H), 7.85 (m, 2H) , 8.05-8.25 (m, 4H), 8.4 (d, ÍH), 8.5 (d, ÍH). The 6-bromo-2-naphthylsulfonyl chloride used as an initial material is obtained in a 22% yield from 6-amino-2-naphthalenesulfonic acid using a procedure analogous to that described in Note e above, except that the Hydrobromic acid and cuprous bromide are used instead of hydrochloric acid and cuprous chloride, respectively. The material gives the following NMR signals (CD3SOCD3) 7.65 (m, ÍH), 7.75-8.0 (m, 3H), 8.15-8.2 (m, 2H). g. The product gives the following NMR signals (CD3SOCD3, 100 ° C) 1.48-1.73 (m, 4H), 2.75-3.02 (m, 3H), 3.06-3.11 (t, 4H), 3.56 (t, 4H), 3.76 (t, ÍH), 3.81 ( t, ÍH), 3.95 (s, 3H), 6.7 (d, 2H), 7.32 (m, ÍH), 7.44 (m, ÍH), 7.71 (, ÍH), 8.03 (m, 2H), 8.12 (d, 2H), 8.31 (d, ÍH). The 6-methoxy-2-naphthylsulfonyl chloride used as an initial material is obtained as follows: A mixture of sodium 6-hydroxy-2-naphthylsulfonate (5 g) and DMSO (100 ml) is added to a stirring suspension of sodium hydride (60% dispersion in mineral oil, 1 g) in DMSO (20 ml) and the mixture is stirred at room temperature for 30 minutes. . The mixture is cooled to 10 ° C and methyl iodide (22 ml) is added in drops. The mixture is allowed to warm to room temperature and is stirred for 2 hours. The mixture is drained in acetone and the precipitate is isolated and washed in turn with acetone and diethyl ether. In this way sodium 6-methoxy-2-naphthylsulfonate (3.3 g) was obtained. Thionyl chloride (0.82 ml) is added to a stirring solution of a portion (0.96 g) of the material thus obtained in DMF (10 ml). The mixture is stirred at room temperature for 2 hours. The mixture is emptied in ice. The precipitate is isolated and dried. In this way, 6-methoxy-2-naphthylsulfonyl chloride (0.7 g) was obtained, which is used without further purification. h. The product gives the following NMR signals (CD3SOCD3) 1.4-1.65 (m, 4H), 2.75-3.0 (m, 7H), 3.5-3.7 (m, 4H), 3.88 (m, 2H), 6.75 (d, 2H ), 7.35-7.65 (m, 3H), 7.95-8.1 (m, 4H), 8.35 (s, ÍH). The 7-methoxy-2-naphthylsulfonyl chloride used as an initial material is obtained from sodium 7-hydroxy-2-naphthylsulfonate using procedures analogous to those described in Note g above. i. The product gives the following NMR signals (CD3SOCD3 + CD3C02D) 1.45-1.8 (m, 4H), 2.9-3.1 (m, 5H), 3.22 (m, 2H), 3.55-3.75 (m, 4H), 4.12 (m, 2H), 7.1 (d, 2H), 7.57 (m, ÍH), 7.75-7.9 (m, 2H), 8.15 (m, 2H), 8.3 (m, ÍH), 8.5 (d, ÍH). The 6-fluoro-2-naphthylsulfonyl chloride used as an initial material is obtained as follows: The 6-amino-2-naphthalenesulfonic acid (5.41 g) is added in portions over 10 minutes to a stirred suspension of nitrosonium tetrafluoroborate ( 3.12 g) in methylene chloride (100 ml), which has been cooled to 5 ° C. The mixture is stirred at 5 ° C for 2 hours and at room temperature for 18 hours. The mixture is evaporated and 1,2-dichlorobenzene (100 ml) is added to the residue. The mixture is stirred and heated at 150 ° C for 2 hours. The mixture is cooled to 5 ° C and thionyl chloride (3.6 ml) and DMF (10 ml) are added. The mixture is stirred at room temperature for 18 hours. The mixture is divided between methylene chloride and water. The organic phase is dried (MgSO 4) and evaporated. The residue is purified by column chromatography using a mixture of hexane and ethyl acetate 9: 1 as eluent. In this way, 6-fluoro-2-naphthylsulfonyl chloride (1.53 g) was obtained; NMR spectrum (CD3SOCD3) 7.4 (m, ÍH), 7.65-7.9 (, 3H), 8.05 (m, 2H), 8.2 (d, ÍH).

Example 41 Using an analogous procedure to that described in Example 2, 1- [1- (4-pyridyl) piperidin-4-ylcarbonyl] piperazine is reacted with the appropriate benzenesulfonyl chloride. In this way, the compounds described in Table II were obtained, the structures of which are confirmed by NMR spectroscopy.

Table III Notes to. The product gives the following NMR signals (CD3SOCD3) 1.4-1.7 (m, 4H), 2.8-3.0 (m, 7H), 3.5-3.7 (m, 4H), .8-3.95 (m, 2H), 6.75 ( d, 2H), 7.65 (d, 2H), 7.85 (d, 2H), .12 (broad s, 2H). b. The product gives the following NMR signals (CD3SOCD3) 1.35-1.37 (m, 4H), 2.8-3.0 (m, 7H), 3.5-3.7 (m, 4H), 3.88 (m, 2H), 6.8 (d, 2H) ), 7.5 (m, 3H), 7.78 (m, 4H), 7.95 (d, 2H), 8.1 (d, 2H). c. The product gives the following NMR signals (CD3SOCD3 + CD3C02D) 1.55-1.8 (m, 4H), 2.8-3.05 (m, 3H), 3.15 (t, 4H), 3.6 (t, 4H), 3.85 (m, 2H ), 6.75 (d, 2H), 7.55 (d, 2H), 7.75 (d, 2H), 7.9 (d, 2H), 8.15 (d, 2H). The 4'-chloro-4-biphenylsulfonyl chloride used as an initial material is obtained as follows: The chlorosulfonic acid (9 ml) is added dropwise to a stirring solution of 4-chlorobiphenyl (21 g) in chloroform (200 ml). ) and the mixture is stirred at room temperature for 30 minutes. The precipitate is isolated and washed with chloroform (50 ml). In this way, 4'-chloro-4-biphenylsulfonic acid (26.8 g) was obtained. Thionyl chloride (0.85 ml) is added in drops to a stirring solution of 4'-chloro-4-biphenylsulfonic acid (1.7 g) in DMF (120 ml), which has been cooled to 5 ° C. The mixture is stirred at room temperature for 3 hours. The mixture is poured into water and the resulting precipitate is isolated, dissolved in diethyl ether, dried (MgSO4) and reabsorbed by evaporation of the solvent. In this way, 4'-chloro-4-biphenylsulfonyl chloride (0.7 g) was obtained, which is used without further purification.

Example 42 Using an analogous procedure to that described in Example 2, 1- [1- (4-pyridyl) piperidin-4-ylcarbonyl] piperazine is reacted with dibenzofuran-3-sulfonyl chloride to give the 1- (dibenzofuran- 3-ylsulfonyl) -4- [1- (4-pyridyl) piperidin-4-ylcarbonyl] piperazine as a crystalline solid in 75% yield. NMR spectrum (CD3SOCD3) 1.35-1.75 (m, 4H), 2.8-3.1 (m, 7H), 3.6-3.8 (m, 4H), 3.9-4.0 (m, 2H), 6.8 (d, 2H), 7.67 (m, 2H), 7.85-8.2 (m, 5H), 8.5 (d, ÍH), 8.75 (d, ÍH); Elemental Analysis Found C, 62.8; H, 5.5; N, 10.8; C27H28N404S 0.5H20 required C, 63.1; H, 5.7; N, 10.9%.

Example 43 A mixture of 2-ethoxycarbonyl-1- (2-naphthylsulfonyl) -4- [1- (4-pyridyl) piperidin-4-ylcarbonyl] piperazine, a solution of 2N aqueous sodium hydroxide (0.37 ml) and methanol (4 ml) ) is stirred at room temperature for 3 hours. The mixture evaporates. The residue is dissolved in water (4 ml) and acidified by the addition of glacial acetic acid. The resulting precipitate is washed with water, dried and triturated under diethyl ether. In this way, 1- (2-naphthylsulfonyl) -4- [1- (4-pyridyl) piperidin-4-ylcarbonyl] -piperazine-2-carboxylic acid (0.082 g), m.p. 188-193 ° C; NMR spectrum (CD3SOCD3 + CT> 3C02D) 1.45-1.8 (m, 4H), 2.9-3.4 (m, 5H), 3.78 (m, ÍH), 4.1 (m, 2H), 4.5 (m, 2H), 7.1 (d, 2H), 7.6-7.9 (m, 3H), 8.0-8.2 (m, 5H), 8.45 (d, ÍH); Elemental Analysis Found C, 59.6; H, 5.7; N, 10.3; C26H28N405S 0.75H2O required C, 59.8; H, 5.7; N, 10.7%.

Example 44 Using an analogous procedure to that described in Example 1, the 1- (4-pyridyl) -piperidine-4-carbonyl chloride is reacted with ethyl 1- (2-naphthylsulfonyl) piperazine-3-carboxylate to give the 2-ethoxycarbonyl-4- (2-naphthylsulfonyl) -1- [1- (4-pyridyl) -piperidin-4-ylcarbonyl] piperazine as a crystalline solid in a yield of 9%; NMR spectrum (CD3SOCD3) 1.3 (t, 3H), 1.65-2.1 (m, 4H), 2-5 (m, 2H), 2.78 (m, ÍH), 3.05 (m, 2H), 3.6-3.95 (m, 5H), 4.2 (m, 2H), 4.4 (, ÍH), 5.07 (m, ÍH), 5.3 (m, ÍH), 6. 65 (d, 2H), 7.7 (m, 3H), 7.98 (m, 3H), 8.2 (d, 2H), 8.35 (d, ÍH); Elemental Analysis Found C, 62.3; H, 6.5; N, 10.8; C28H32N405S required C, 62.7; H, 6.1; N, 10.4%.

The ethyl 1- (2-naphthylsulfonyl) piperazine-3-carboxylate is used as an initial material is prepared as follows: Using an analogous procedure to that described in Example 2, the ethyl l-benzylpiperazine-2-carboxylate is made react with 2-naphthylsulfonyl chloride to give ethyl l-benzyl-4- (2-naphthylsulfonyl) piperazine-2-carboxylate in 93% yield. The chloroformate of 1-chloroethyl (1.5 ml) is added to a solution of ethyl l-benzyl-4- (2-naphthylsulfonyl) piperazine-2-carboxylate (2.44 g) in 1,2-dichloroethane (50 ml) and the The mixture is stirred and refluxed for 48 hours. The mixture is evaporated and the residue is triturated under hexane. Methanol (50 ml) is added to the resulting gum and the mixture is heated at reflux for 2 hours. The mixture is evaporated and the residue is divided between methylene chloride and water. The organic phase is dried (MgSO 4) and evaporated. The residue is purified by column chromatography using polar mixtures in an increase in methylene chloride and methanol as eluent. In this way ethyl 1- (2-naphthylsulfonyl) piperazine-3-carboxylate was obtained as a gum (1.55 g); NMR spectrum (CDC13) 1.3 (t, 3H), 2.65-3.0 (m, 3H), 3.5 (m, 2H), 3.75 (m, ÍH), 4.2 (q, 2H), 7.7 (m, 3H), 7.98 (m, 3H), 8.35 (d, ÍH).

Example 45 Using an analogous procedure to that described in Example 14, 1- (4-pyridyl) piperazine is reacted with 1- (2-naphthylsulfonyl) -piperidine-3-carboxylic acid to give 1- [1- (2 -naphthylsulfonyl) -piperidin-3-ylcarbonyl] -4- (4-pyridyl) piperazine as a foam in 25% yield; NMR spectrum (CD3SOCD3) 0.95-1.75 (m, 6H), 2.3-2.45 (m, 2H), 2.6 (m, ÍH), 3.5-3.75 (m, 8H), 7.05 (d, 2H), 7.6-7.75 (, 3H), 8.1 (m, 5H), 8.4 (s, ÍH). The 1- (2-naphthylsulfonyl) piperidine-3-carboxylic acid used as an initial material is obtained as follows: Using a procedure analogous to that described in Example 2, ethyl piperidin-3-carboxylate is reacted with sodium chloride. 2-naphthylsulfonyl to give the ethyl 1- (2- (naphthylsulfonyl) piperidin-3-carboxylate in 62% yield A mixture of the material thus obtained (1.33 g), potassium hydroxide (0.43 g) and ethanol (17 ml) is stirred and heated at 80 ° C. for 4 hours, the mixture is evaporated, the residue is dissolved in water (5 ml) and the solution is acidified by the addition of 2N aqueous hydrochloric acid. it is washed with water and dried.

In this way, 1- (2-naphthylsulfonyl) -pipéridine-3-carboxylic acid (0.81 g) was obtained; NMR spectrum (CD3SOCD3) 1.45-1.64 (m, 2H), 1.8-1.95 (m, 2H), 2.25 (m, ÍH), 2.5 (m, 2H), 3.58 (m, 2H), 7.72 (, 3H) , 8.15 (m, 3H), 8.45 (d, ÍH).

Example 46 Using an analogous procedure to that described in Example 1, except that DMF is used in place of methylene chloride as the reaction solvent, 1- (4-pyridyl) piperidine-4-carbonyl chloride is reacted with the trifluoroacetate salt of 1- (2-naphthylmethyl) -2-oxopiperazine to give 1- (2-naphthylmethyl) -2-oxo-4- [1- (4-pyridyl) -piperidin-4-ylcarbonyl] -piperazine in a yield of 18%; NMR spectrum (CD3SOCD3) 1.45-1.75 (m, 4H), 2.85- 3-05 (m, 3H), 3.3 (m, 2H), 3.65-4.4 (m, 6H), 4.75 (s, 2H), 6. 8 (d, 2H), 7.5 (m, 3H), 7.8 (s, ÍH), 7.9 (d, 2H), 8.1 (d, 2H); Elemental Analysis Found C, 70.6; H, 6.7; N, 12. 5; C26H28N402 0.8H20 required C, 70.5; H, 6.7; N, 12.6%. The trifluoroacetate salt of 1- (2-naphthylmethyl) -2-oxopiperazine used as an initial material is obtained as follows: The di-tert-butyl pyrocarbonate (7.75 g) is added in portions to a stirring mixture of 2-oxopiperazine (3.23 g), potassium carbonate (4.46 g), tert-butanol (15 ml) and water (15 ml). The mixture is stirred at room temperature for 2 hours. The mixture is extracted with ethyl acetate. The organic phase is dried and evaporated. The residue is recrystallized from ethyl acetate. In this way, 4-tert-butoxycarbonyl-2-oxopiperazine (5.31 g), m.p. 157-159 ° C. Sodium hydride (60% dispersion in mineral oil, 0.145 g) is added in drops to a stirring mixture of 4-tert-butoxycarbonyl-2-oxopiperazine (0.5 g) and DMF (15 ml), which has been cooled to 5 ° C. The mixture is stirred at temperature for 1.5 hours. A solution of 2-bromoethylnaphthalene (0.552 g) in DMF (3 ml) is added dropwise. The mixture is allowed to warm to room temperature and is stirred for 18 hours. The mixture is divided between methylene chloride and water. The organic phase is dried (MgSO 4) and evaporated. The residue is purified by column chromatography using a mixture of hexane and ethyl acetate 3: 2 as eluent. In this way, 4-tert-butoxycarbonyl-1- (2-naphthylmethyl) -2-oxopiperazine was obtained as a gum (0.41 g). A mixture of the material thus obtained, trifluoroacetic acid (1.5 ml) and methylene chloride (10 ml) is stirred at room temperature for 18 hours. Water (0.5 ml) is added and the mixture evaporates. In this way the salt was obtained: 1- (2-naphthylmethyl) -2-oxopiperazine trifluoroacetate (0.4 g), which is used without further purification; NMR spectrum (CD3SOCD3) 3.4-3.5 (m, 4H), 3.9 (s, 2H), 4-8 (s, 2H), 7.4-7.6 (m, 3H), 7.8-8.0 (m, 4H).

Example 47 Using an analogous procedure to that described in Example 20, 2- [2- (2-naphthalenesulfonamido) acetamido] -3- [1- (4-pyridyl) piperidin-4-ylcarbonylamino] propionic acid is reacted with 4- methylpiperidine to give the N-. { l- (4-methylpiperidin-1-ylcarbonyl) -2- [1- (4-pyridyl) piperidin-4-ylcarbonylamino] -ethyl} -2- (2-naphthalenesulfonamido) acetamide in a yield of 22%.

Example 48 Using an analogous procedure to that described in Example 20, 2- [2- (2-naphthalene-sulfonamido) acetamido] -3- [1- (4-pyridyl) piperidin-4-ylcarbonylamino] propionic acid is reacted with morpholine to give the N-. { 1- (Morpholinocarbonyl-2- [1- (4-pyridyl) -piperidin-4-ylcarbonylamino] ethyl] -2- (2-naphthalenesulfonamido) -acetamide in 36% yield.

Example 49 Using an analogous procedure to that described in Example 1, the 1- (4-pyridyl) piperidin-4-carbonyl chloride is reacted with 1- (2-naphthylsulfonyl) -1,4-diazepam to give 1- (2-naphthylsulfonyl) -4- [1- (4-pyridyl) piperidin-4-ylcarbonyl] -1,4-diazepam in a yield of 42%, m.p. 178-180 ° C; NMR spectrum (CD3SOCD3 + CD3C02D) 1.5-2.0 (m, 6H), 3-15 (m, ÍH), 3.3-3.6 (m, 5H), 3.65 (m, 2H), 3.75 (m, 2H), 3.85 (m, HH), 4.28 (m, 2H), 7.25 (m, HH), 7.75-8.0 (m, 3H), 8.15-8.4 (m, 5H), 8.6 (d, HH); Elemental Analysis Found C, 64.5; H, 6.2; N, 11.8; C26H3QN403S 0.25H2O required C, 64.6; H, 6.3; N, 11-6%. The 1- (2-naphthylsulfonyl) -1,4-diazepam used as an initial material is obtained as follows: A solution of 2-naphthylsulfonyl chloride (2.26 g) in methylene chloride (5 ml) is added to a stirring solution of 1,4-diazepam (in another form known as homopiperazine, 5 g) in methylene chloride (50 ml), which has been cooled at 5 ° C. The mixture is stirred at room temperature for 2 hours. The mixture is partitioned between ethyl acetate and 2N aqueous hydrochloric acid. The aqueous layer is basified to pH 13 by the addition of an aqueous sodium hydroxide solution ION and extracted with ethyl acetate. The organic phase is washed with water, dried (MgSO 4) and evaporated to give the required starting material in 96% yield; NMR spectrum (CD3SOCD3) 1.6-1.75 (m, 2H), 2.6-2.8 (m, 4H), 3.2-3.4 (m, 4H), 7.6-7.9 (m, 3H), 8.0-8.3 (m, 3H) , 8.5 (s, ÍH).

Example 50 A mixture of 1- (4-pyridyl) piperazine (0.136 g), 4- (2-naphthylsulfonyl) piperazine-1-carboxylic acid 1,4,5-trichlorophenyl (0.2 g) and DMF (2 ml) is stirred and stirred. heat at 80 ° C for 24 hours. The mixture is cooled to room temperature and partitioned between ethyl acetate and water. The organic phase is washed with brine, dried (MgSO 4) and evaporated. The residue is purified by column chromatography using a mixture of methylene chloride and methanol 19: 1 as eluent. The oil thus obtained is triturated under diethyl ether. In this way, 1- (2-naphthylsulfonyl) -4- [4- (4-pyridyl) -piperazin-1-ylcarbonyl] piperazine (0.139 g, 73%), p.f. 210-212 ° C; NMR spectrum (CD3SOCD3) 2.9-3.05 (m, 4H), 3.1-3.4 '(m, 12H), 6.7 (d, 2H), 7.7 (m, 3H), 8.1-8.3 (mt' 5H), 8.45 ( YES H); Elemental Analysis Found C, 61.4; H, 6.0; N, 14.7; C24H27N503S required C, 61.9; H, 5.9; N, 15.0%. The 2,4,5-trichlorophenyl 4- (2-naphthylsulfonyl) piperazine-1-carboxylate used as starting material is obtained as follows: 2,4,5-trichlorophenyl chloroformate < (0.26 g) is added in drops to a stirring mixture of the hydrochloride salt of 1- (2-naphthylsulfinyl) piperazine (0.63 g), triethylamine (0.41 g) and methylene chloride (10 ml). The mixture is stirred at room temperature for 18 hours. The mixture is partitioned between ethyl acetate and 2N aqueous hydrochloric acid. The organic phase is washed with water and with brine, dried (MgSO 4) and evaporated. The residue is purified by column chromatography using a mixture of hexane and methylene chloride 1: 1 as eluent. In this way, the required initial material (0.32 g) was obtained; 1 NMR spectrum (CD3SOCD3) 3.0-3.2 (m, 4H), 3.5-3.8 (, 4H), 7.65-7.8 (m, 4H), 7.9 (s, ÍH), 8.05 (m, ÍH), 8.2 (m, 2H), 8.45 (s, ÍH). The hydrochloride salt of 1, (2-naphthylsulfonyl) -piperazine used as an initial material is obtained as follows: A solution of 2-naphthylsulfonyl chloride (6.12 g) in methylene chloride (20 ml) is added dropwise to a stirring mixture of 1-tert-butoxycarbonylpiperazine (5 g), triethylamine (5.63 ml) and methylene chloride (50 ml), which has been cooled in an ice bath. The mixture is stirred at 5 ° to 10 ° C for 4 hours. The mixture is partitioned between ethyl acetate and a 1M aqueous citric acid solution.

The organic phase is washed with water and with brine, dried (MgSO4) and evaporated. In this way, 1- (tert-butoxycarbonyl) -4- (2-naphthylsulfonyl) piperazine was obtained as a solid (4.84 g), m.p. 174-176 ° C. A portion (0.25 g) of the material thus obtained is suspended in ethyl acetate (20 ml) and the mixture is cooled in an ice bath. The hydrogen chloride gas is carried into the mixture for 20 minutes. The mixture evaporates. In this way, the hydrochloride salt of 1- (2-naphthylsulfonyl) piperazine (0.21 g) was obtained; NMR spectrum (CD3SOCD3) 3.1-3.3 (m, 8H), 7.7-7.85 (m, 3H), 8.1 (d, ÍH), 8.15-8.2 (m, 2H), 8.5 (s, ÍH), 9.2-9.4 (Yes H) .

Example 51 Using a procedure analogous to that described in Example 1, the 1- (4-pyridyl) piperidine-4-carbonyl chloride is reacted with the (2RS, 5SR) -2,5-Dimethyl-1- (2-naphthylsulfonyl) piperazine to give (2RS, 5SR) -2,5-dimethyl-l-82-naphthylsulfonyl) -4- [1- (4- pyridyl) -piperidin-4-ylcarbonyl] piperazine in a yield of 13%; NMR spectrum (CDCl3) 0.85-1.03 (m, 3H), 1.1-1.4 (m, 2H), 1.65-2.1 (m, 4H), 2.65 (, ÍH), 2.90 (m, 2H), 3.18 (m, ÍH), 3.58 (m, 2H), 3.89 (m, 2H), 4.25 (m, 2H), 6.62 (d, 2H), 7.7 (m, 3H), 7.95 (m, 3H), 8.25 (d, 2H) ), 8.39 (s, ÍH); Elemental Analysis Found C, 58.7; H, 6.2; N, 9. 5; C27H32N403S 0.9CH2Cl2 required C, 58.5; H, 6.0; N, 9.8%. The (2RS, 5SR) -2,5-dimethyl-1- (2-naphthylsulfonyl) -piperazine used as an initial material is obtained in a yield of 50% by the reaction of (2RS, 5SR) -2, 5- dimethylpiperazine and 2-naphthylsulfonyl chloride using a procedure analogous to that described in Example 2.

Example 52 Using an analogous procedure to that described in Example 1, the 1- (4-pyridyl) -piperidin-4-carbonyl chloride is reacted with 3-methyl-1- (2-naphthylsulfonyl) piperazine to give the 3-methyl -l- (2-naphthyl-sulfonyl) -4- [1- (4-pyridyl) piperidin-4-ylcarbonyl] piperazine in 32% yield; NMR spectrum (CD3SOCD3, 100 ° C) 1.5-1.75 (m, 4H), 2. 45-2.7 (m, 3H), 3.19 (m, HH), 3.57 (m, HH), 3.75 (m, 3H), 4.06 (d, HH), 4.52 (m, HH), 6.65 (d, 2H) , 7.6-7.79 (m, 3H), 8. 0-8.15 (m, 5H), 8.38 (s, ÍH); Elemental Analysis Found C, 64.1; H, 6.4; N, 11. 3; C26H30N4O3S 0.25EtOAc 0.15H2O required C, 64.4; H, 6. 47; N, 11.1%. The 3-methyl-1- (2-naphthylsulfonyl) piperazine used as an initial material is obtained in a quantitative yield by the reaction of 2-methylpiperazine and 2-naphthylsulfonyl chloride using a procedure analogous to that described in Example 2.

Example 53 Using an analogous procedure to that described in Example 2, 3-methyl-1- [1- (4-pyridyl) -piperidin-4-ylcarbonyl] piperazine is reacted with 2-naphthylsulfonyl chloride. The reaction mixture is evaporated and the residue is partitioned between ethyl acetate and 2N aqueous hydrochloric acid. The aqueous layer is basified to pH 14 by the addition of an aqueous sodium hydroxide solution ION and extracted with ethyl acetate. The organic phase is dried (MgSO 4) and evaporated. In this way 2-methyl-1- (2-hafthylsulfonyl) -4- [1- (4-pyridyl) piperidin-4-ylcarbonyl] -piperazine was obtained in 96% yield; NMR spectrum (CD3SOCD3, 100 ° C) 1.5-1.75 (m, 4H), 2.75-3.3 (m, 6H), 3.6-4.2 (m, 6H), 6.7 (d, 2H), 7.61-7.84 (m, 3H), 8.0-8.16 (m, 5H), 8.45 (s, ÍH); Elemental Analysis Found C, 63.2; H, 6.5; N, 11.1; C26H30N4O3S 0.8H20 required C, 63.2; H, 6.5; N, 11.3%. The 3-methyl-l- [1- (4-pyridyl) piperidin-4-ylcarbonyl] -piperazine used as an initial material is obtained in a yield of 39% by the reaction of the 1- (4-pyridyl) piperidine- 4-carbonyl and 2-methylpiperazine using a procedure analogous to that described in Example 1, Example 54 Using an analogous procedure to that described in Example 1, l- (4-pyridyl) piperidine-4-carbonyl chloride is reacted with 1- [(E) -4-chlorostyrylsulfonyl] -3-methylpiperazine. The reaction is evaporated and the residue is partitioned between ethyl acetate and 2N aqueous hydrochloric acid. The aqueous layer is basified to pH 14 by the addition of an aqueous sodium hydroxide solution ION and extracted with ethyl acetate. The organic phase is dried (MgSO 4) and evaporated. The residue is purified by column chromatography using polar mixtures in an increase of ethyl acetate and methanol as eluent. In this way, 4- [(E) -4-chlorostyrylsulfonyl] -2-methyl-1- [1- (4-pyridyl) piperidin-4-ylcarbonyl] piperazine was obtained in a yield of 24%; NMR spectrum (CD3SOCD3, 100 ° C) 1.24 (d, 3H), 1. 6-1.8 (m, 4H), 2.7 to 3.05 (m, 5H), 3.22 (m, ÍH), 3.45 (, ÍH), 3.62 (m, ÍH), 3.84 (m, 2H), 4.12 (m, ÍH), 4.6 (m, ÍH), 6. 71 (d, 2H), 7.14 (d, ÍH), 7.42 (d, ÍH), 7.4-7.7 (m, 4H), 8.15 (d, 2H); Elemental Analysis Found C, 57.6; H, 6.2; N, 10.5; C24H29C1N403 0.5EtOAc 0.5H20 required C, 57.6; H, 6.3; N, 10.30%. 1- [(E) -4-Chlorostyrylsulfonyl] -3-methylpiperazine used as an initial material is obtained in a yield of 35% by the reaction of 2-methylpiperazine and (E) -4-chlorostyrylsulfonyl chloride using a procedure analogous to that described in Example 2.

Example 55 A mixture of 4-chloropyrimidine hydrochloride (0.151 g), 1- (2-naphthylsulfonyl) -4- (4-piperidinylcarbonyl) -piperazine (0.387 g), triethylamine (0.202 g) and ethanol (5 ml) is stirred and heated at reflux for 1 hour. The mixture is evaporated and the residue is purified by column chromatography using a mixture of methylene chloride and methanol 19: 1 as eluent. The solid thus obtained is recrystallized from acetonitrile. In this way, l- (2-naphthylsulfonyl) -4- [1- (4-pyrimidinyl) piperidin-4-ylcarbonyl] -piperazine (0.135 g, 29%), m.p. 203-205 ° C; NMR spectrum (CD3SOCD3) 1.38 (m, 2H), 1.63 (m, 2H), 2.8-3.1 (m, 7H), 3.5-3.8 (m, 4H), 4.3 (m, 2H), 6.75 (d, IH) ), 7.7-7.85 (m, 3H), 8.05-8.3 (m, 4H), 8.45 (m, 2H); Elemental Analysis Found C, 61.4; H, 5.9; N, . 1; C24H27N503S 0.2H20 required C, 61.5; H, 5.85; N, 14.9%. The 1- (2-naphthylsulfonyl) -4- (4-piperidinylcarbonyl) -piperazine used as an initial material is obtained as follows: A solution of di-tert-butyl dicarbonate (10.9 g) in methylene chloride (50 ml) is added dropwise to a stirred mixture of ethyl piperidin-4-carboxylate. (7.85 g), triethylamine (10.1 g) and methylene chloride (100 ml), which is cooled in an ice bath at a temperature in the range of 5 to 10 ° C. The mixture is stirred at 5 ° C for 1 hour. The mixture is evaporated and the residue is partitioned between diethyl ether and a 1M aqueous citric acid solution. The organic phase is washed with water and with brine, dried (MgSO 4) and evaporated. In this way ethyl 1-tert-butoxycarbonylpiperidin-4-carboxylate was obtained as an oil. A mixture of the material thus obtained, a solution of 2N aqueous sodium hydroxide (50 ml) and methanol (125 ml) is stirred at room temperature for 1 hour. The mixture is concentrated by evaporation of the methanol volume and the residue is partitioned between diethyl ether and a 1M aqueous citric acid solution. The organic phase is washed with water and with brine, dried (MgSO 4) and evaporated. In this way, 1-tert-butoxycarbonylpiperidine-4-carboxylic acid (10.6 g, 92%) was obtained. The N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide (2.5 g) is added to a stirring mixture of l- (2-naphthylsulfonyl) piperazine [3.61 g; obtained by dividing the corresponding piperazine hydrochloride salt between diethyl ether and a solution of aqueous sodium hydroxide ION and drying (MgSO4) and evaporating the organic phase], 1-tert-butoxycarbonylpiperidine-4-carboxylic acid (3 g) and DMF (40 ml), which has been cooled in an ice bath. The mixture is stirred at room temperature for 18 hours. The mixture is partitioned between ethyl acetate and water. The organic phase is washed with water and with brine, dried (MgSO 4) and evaporated. The residue is purified by column chromatography using ethyl acetate as eluent. In this way, 1- (2-naphthylsulfonyl) -4- (1-tert-butoxycarbonyl-piperidin-4-ylcarbonyl] piperazine (3.79 g, 59%), mp 195-1976 C. A mixture of one portion (1 g) of the material thus obtained and trifluoroacetic acid (5 ml) is stirred at room temperature for 2 hours.The mixture is divided between methylene chloride and a 2N aqueous sodium hydroxide solution.The organic phase is washed with water, dried (MgSO4) and evaporated. In this way, l- (2-naphthylsulfonyl) -4- (4-piperidinylcarbonyl) piperazine (0.61 g, 77%) was obtained; NMR spectrum (CD3SOCD3) 1.2-1.5 (m, 4H), 2.4-2.7 (m, 3H), 2.8-3.1 (m, 6H), 3.5-3.7 (m, 4H), 7.6-7.8 (m, 3H) , 8.0-8.3 (m, 3H), 8.4 (s, ÍH).

Example 56 A mixture of 2-amino-4-chloro-6-methylpyrimidine (0.143 g), 1- (2-naphthylsulfonyl) -4- (4-piperidinylcarbonyl) -piperazine (0.387 g), triethylamine (0.101 g) and ethanol (5 ml) is stirred and heated at reflux for 18 hours. The mixture is cooled to room temperature and partitioned between ethyl acetate and water. The organic phase is washed with water, dried (MgSO4) and evaporated. The residue is triturated under diethyl ether. In this way, 4- [1- (2-amino-6-methylpyrimidin-4-yl-yl) piperidin-4-ylcarbonyl] -1- (2-naphthylsulfonyl) piperazine (0.29 g, 58%; NMR spectrum (CD3SOCD3) 1.2-1.45 (m, 2H), 1.55 (m, 2H), 2.05 (s, 3H), 2.8 (m, 3H), 2.9-3.2 (m, 4H), 3.5-3.7 (m , 4H), 4.23 (m, 2H), 5.95 (d, 3H), 7.7-7.85 (m, 3H), 8.2 (m, 3H), 8.45 (s, ÍH), Elemental Analysis Found C, 60.1; H, 6.4; N, 16.6; C25H30NgO3S 0.3H20 required C, 60.1; H, 6.1; N, 16.82.

Example 57 A mixture of succinimido-1- (4-pyrimidinyl) piperidin-4-carboxylate (0.326 g), 1- [(E) -4-chlorostyrylsulfonyl] piperazine (0.4 g) and DMF (5 ml) is stirred at room temperature environment for 16 hours. The mixture is partitioned between ethyl acetate and water. The organic phase is washed with water, dried (MgSO 4) and evaporated. The residue is purified by column chromatography using a mixture of methylene chloride and methanol 49: 1 as eluent. The material thus obtained is recrystallized from acetonitrile. In this way, 1- [(E) -4-chlorostyrylsulfonyl] -4- [1- (4-pyrimidinyl) piperidin-4-ylcarbonyl] piperazine (0.133 g, 22%), m.p. 209-210 ° C; NMR spectrum (CT> 3SOCD3) 1.3-1.6 (m, 2H), 1.7 (m, 2H); 2.9-3.2 (m, 7H), 3.5-3.8 (m, 4H), 4.4 (m, 2H), 6.8 (d, ÍH), 7.4 (m, 4H), 7.8 (d, 2H), 8.15 (d, ÍH), 8.45 (s, ÍH); Elemental Analysis Found C, 55.2; H, 5.5; N, 14.7; C22H26C1N503S required C, 55.5; H, 5.5; N, 14.7%. The 1- (4-pyrimidinyl) piperidin-4-succinimidocarboxylate used as an initial material is obtained as follows: Using an analogous procedure to that described in Example 32, the 4-chloropyrimidine hydrochloride is reacted with piperidin-4. ethylcarboxylate to give ethyl 1- (4-pyrimidinyl) piperidin-4-carboxylate in a 46% yield. A mixture of the material thus obtained (0.5 g), 2N aqueous hydrochloric acid (5 ml) and THF (15 ml) is stirred and heated to reflux for 18 hours. The mixture is evaporated and the residue is washed with ethyl acetate. In this way, the hydrochloride salt of 1- (4-pyrimidinyl) -piperidin-4-carboxylic acid (0.49 g, 95%) was obtained. NMR spectrum (CD3SOCD3) 1.6 (m, 2H), 2.0 (m, 2H), 2.7 (m, ÍH), 3.4 (m, 2H), 4.5 (s broad, 2H), 7.2 (d, ÍH), 8.3 (d, ÍH), 8.8 (s, ÍH). A mixture of the acid thus obtained, N-hydroxysuccinimide (0.29 g), triethylamine (0.61 g), N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide (0.48 g) and DMSO (10 ml) is stirred at room temperature for 5 hours. hours. The mixture is partitioned between ethyl acetate and water. The organic phase is washed with water, dried (MgSO 4) and evaporated. In this way, 1- (pyrimidinyl) piperidine-4-carboxylate succinimido was obtained, which is used without further purification. The 1- [(E) -4-chlorostyrylsulfonyl] piperazine used as an initial material is obtained in a yield of 42 by the reaction of piperazine and (E) -4-chlorostyrylsulfinyl chloride using an analogous procedure to that described in the Example 2.

Example 58 Using a procedure analogous to that described in Example 1, the l- (4-pyridyl) piperidine-4-carbonyl chloride is reacted with l- (4'-methylbiphenyl-4-ylsulfonyl) piperazine to give the 1- ( 4'-methylbiphenyl-4-ylsulfonyl) -4- [1- (4-pyridyl) piperidin-4-ylcarbonyl] piperazine in a 67% yield, mp 213-217 ° C; NMR spectrum (CD3SOCD3 + CT> 3C02D) 1.6-1.85 (m, 4H), 2-35 (s, 3H), 2.98 (m, ÍH), 3.05-3.3 (m, 6H), 3.55-3.65 (m , 4H), 3.95 (m, 2H), 6.95 (d, 2H), 7.3 (d, 2H), 7.55 (d, 2H), 7.8 (m, 4H), 8.05 (d, 2H); Elemental Analysis Found C, 65.0; H, 6.3; N, 10.8; C28H32N403S 0.66H2O required C, 65.1; H, 6.5; N, 10.8%. The 1- (4'-methyl-biphenyl-4-ylsulfonyl) piperazine used as an initial material is prepared as follows: A solution of 4-iodophenylsulfonyl chloride (5 g) in methylene chloride (150 ml) is added dropwise to a stirred solution of piperazine (7.1 g) in methylene chloride (50 ml), which has been cooled in an ice bath. The mixture is stirred at room temperature for 14 hours. The mixture is extracted with 2N aqueous hydrochloric acid.

The aqueous solution is washed with ethyl acetate, basified by the addition of an aqueous sodium hydroxide solution. 2N and extracted with ethyl acetate. The organic extract is washed with water, dried (MgSO4) and evaporated. In this way, 1- (4-iodophenylsulfonyl) piperazine (4.6 g) was obtained, which is used without further purification. A mixture of the material thus obtained (0.5 g), 4-tolylboronic acid (0.19 g), 2M aqueous sodium carbonate solution (7.8 ml), tetrakis (triphenylphosphine) palladium (0) (0.1 g), ethanol (15 ml) and toluene (21 ml) are stirred and dried. heat at reflux for 5 hours. The mixture is cooled to room temperature and partitioned between ethyl acetate and water. The organic phase is washed with water, dried (MgSO 4) and evaporated. In this way, 1- (4 '-methylbiphenyl-4-ylsilphonyl) piperazine (0.43 g) was obtained; NMR spectrum (CD3SOCD3) 2.35 (s, 3H), 2.7-2.9 (, 8H), 7-35 (d, 2H), 7.65 (d, 2H), 7.8 (d, 2H), 7.95 (d, 2H) .

Example 59 Using a procedure analogous to that described in Example 1, the 1- (4-pyridyl) -piperidine-4-carbonyl chloride is reacted with the appropriate 1- (phenylsulfonyl) piperazine. In this way, the compound described in Table IV was obtained, the structures of which are confirmed by NMR spectroscopy. Unless otherwise indicated, the appropriate 1- (phenylsulfonyl) piperazine is obtained from 1- (4-phenylsulfonyl) -piperazine using an analogous procedure to that described in the last paragraph of the portion of Example 58 , which is related to the preparation of the initial materials.

Table IV Notes to. The product gives the following NMR signals (CD3SOCD3 + CD3C02D) 1.6-1.85 (m, 4H), 2.98 (m, ÍH), 3.05-3.3 (m, 6H), 3.55-3.65 (m, 4H), 3.93 (m , 2H), 6.9 (d, 2H), 7.55- .65 (m, 4H), 7.8-7.9 (m, 4H), 8.1 (d, 2H).

The 1- (4'-bromobiphenyl-4-ylsulfonyl) piperazine used as an initial material is obtained from 4-bromobiphenyl. That compound is converted to 4'-bromo-4-biphenylylsulfonyl chloride using a procedure analogous to those described in Note c to Table III below in Example 41. The material thus obtained is reacted with piperazine using a procedure analogous to that described in Example 2. The required initial material gives the following NMR signals (CD3SOCD3) 2.7-2.8 (, 4H), 2.8-2.9 (m, 4H), 7.75 (d, 4H), 7.8 (d, 2H) 7.95 (d, 2H). b. The product gives the following NMR signals (CD3SOCD3) 1.5-1.75 (ra, 4H), 2.8-3.15 (m, 7H), 3.55-3.65 (m, 4H), 3.8 (m, 2H), 6.7 (d, 2H ), 7.55 (t, ÍH), 7.7 (d, 2H), 7.8-7.95 (m, 4H), 8.1 (d, 2H). The starting material of 1- (3 ', 5'-dichlorobiphenyl-4-ylsulfonyl) piperazine gives the following NMR signals (CD3SOCD3) 2.7-2.8 (m, 4H), 2.8-2.9 (m, 4H), 7.65 ( t, ÍH), 7.75-7.85 (m, 4H), 8.0 (d, 2H). c. The product gives the following NMR signals (CD3SOCD3) 1.55-1.75 (m, 4H), 2.7-3.05 (m, 3H), 3.05-3.15 (m, 4H), 3.55-3.6 (m, 4H), 3.6-3.75 (m, 2H), 6.7 ( d, 2H), 7.5 (d, 2H), 7.65-7.8 (m, 4H), 7.92 (m, 2H), 8.1 (d, 2H). The initial material 1- (4'-chlorobiphenyl-3-ylsulfonyl) -piperazine is obtained by the reaction of 1- (3-bromophenylsulfonyl) piperazine (obtained by the reaction of pipérazine and 3-bromo-phenylsulfonyl chloride) and 4-chlorophenylboronic acid using a procedure analogous to that described in the last paragraph of the portion of Example 58, which relates to the preparation of the starting materials. The required initial material gives the following NMR signals (CD3SOCD3) 2.7-2.8 (m, 4H), 2.8-2.9 (m, 4H), 7.6 (d, 2H), 7.7-7.8 (m, 5H), 8.05 (m , ÍH). d. The product gives the following NMR signals (CD3SOCD3) 1.6-1.8 (m, 4H), 2.98 (m, ÍH), 3.1-3.3 (m, 6H), 3. 55-3.65 (m, 4H), 3.95 (m, 2H), 6.95 (d, 2H), 7.4-7.55 (m, 3H), 3.65-3.8 (m, 4H), 7.92 (m, 2H), 8.1 ( d, 2H). and. The product gives the following NMR signals (CD3SOCD3) 1.41-1.64 (m, 4H), 2.82-2.91 (m, 7H), 3.54-3.62 (m, 4H), 3.89 (d, 2H), 6.78 (d, 2H ), 7.49 (d, 2H), 8.02 (d, 2H), 8.10 (d, 2H). f. The product gives the following NMR signals (CD3SOCD3) 1.28-1.68 (m, 7H), 2.76-3.07 (m, 7H), 3.49-3.75 (m, 4H), 3.8-4.07 (d, 2H), 4.42-4.43 (m, 2H), 6.76 (d, 2H), 7.8-8.2 (m, 10H). The starting material 1- (4'-ethoxycarbonylbiphenyl-4-ylsulfonyl) piperazine is obtained as follows: A mixture of 1- (4-iodophenylsulfonyl) piperazine (5 g), bis (tributyltin) (11 ml), tetrakis (triphenylphosphine) -palladium (0) (0.16 g) and toluene (200 ml) are stirred and heated at 120 ° C for 36 hours. The mixture is cooled to room temperature and filtered. The filtrate is evaporated and the residue is purified by column chromatography using polar mixtures in an increase of methylene chloride and methanol as eluent. The material thus obtained is dissolved in a mixture of methylene chloride (20 ml), methanol (5 ml) and water (0.2 ml). Potassium fluoride (3 g) is added and the mixture is stirred at room temperature for 1 hour. The mixture is divided between methylene chloride and water. The organic phase is washed with water, dried (MgSO 4) and evaporated. In this way, [4- (piperazin-1-ylsulfonyl) phenyl] tributyltin was obtained (1.5 g). A mixture of the initial material thus obtained, ethyl 4-iodobenzoate (1.6 g), tetrakis (triphenylphosphine) -palladium (0) - (0.034 g) and toluene (50 ml) is stirred and heated at reffor 72 hours. The mixture is evaporated and the solid residue is washed with a mixture of methylene chloride and methanol 97: 3. In this way, 1- (4'-ethoxycarbonyl-biphenyl-4-ylsulfonyl) piperazine (0.76 g) was obtained; NMR spectrum (CD3SOCD3) 1.3-1.43 (t, 3H), 3.07-3.37 (db 8H), 4.27-4.44 (m, 2H), 7.65-7.97 (m, 4H), 7.97-8.15 (m, 4H). g. The product gives the following NMR signals (CD3SOCD3, 100 ° C) 1.57-1.78 (m, 4H), 2.79-3.08 (m, 3H), 3.08-3.18 (t, 4H), 3.55-3.68 (t, 4H) , 3.75-3.82 (t, ÍH), 3.85 (t, ÍH) ', 6.74 (d, 2H), 7.85-8.02 (m, 8H), 8.14 (m, 2H). The 1- (4'-cyclobiphenyl-4-ylsulfonyl) piperazine used as an initial material is obtained by the reaction of [4- (piperazin-1-ylsulfonyl) phenyl] tributyltin and 4-iodobenzonitrile using an analogous procedure to that described in Note f immediately preceding. h. The product gives the following NMR signals (CD3SOCD3, 100 ° C) 1.53-1.8 (m, 4H), 2.65-3.08 (m, 3H), 3.08-3.20 (t, 4H), 3.54-3.65 (t, 4H), 3.84 (t, ÍH), 3.90 (t, ÍH), 6. 75-6.85 (d, 2H), 7.58 (t, ÍH), 7.7-7.9 (m, 4H), 7.95-8.08 (m, 2H), 8.08-8.18 (m, 2H). The 1- (3 ', 5'-dichlorobiphenyl-3-ylsulfonyl) piperazine used as an initial material is obtained as follows: Using a procedure analogous to that described in the portion of Example 58, which is related to the preparation of materials Initially, piperazine is reacted with 3-bromophenylsulfonyl chloride to give 1- (3-bromo-phenylsulfonyl) piperazine which, in turn, is reacted with 3,5-dichlorophenylboronic acid to give 1- (3 ', 5'-dichlorobiphenyl-3-ylsulfonyl) piperazine in a yield of 29%; NMR spectrum (CD3SOCD3, 100 ° C) 2.7-2.85 (m, 4H), 2. 95-3.05 (m, 4H), 7.58 (t, ÍH), 7.68-7.85 (m, 4H), 7.91-8.05 (m, 2H). i. The product gives the following signals = NMR (CD3SOCD3; 100 ° C) 1.5-1.75 (ra, 4H), 2.75-3.04 (m, 5H), 3.05- 3.17 (t, 4H), 3.53-3.65 (t, 4H), 3.75 (t, ÍH), 3.81 (t, ÍH), 6. 69 (d, 2H), 7.88 (d, 2H), 7.93-8.04 (d, 4H), 8.1 (d, 2H), 8.3 (d, 2H). The 1- (4'-nitrobiphenyl-4-ylsulfonyl'-) piperazine used as an initial material is obtained by the reaction of [4- (piperazin-1-ylsulfonyl) phenyl] tributyltin and 1-iodo-4-nitrobenzene using a procedure analogous to that described in Note f immediately preceding. The product gives the following NMR signals (CD3SOCD3, 100 ° C) 1.53-1.77 (m, 4H), 2.61-3.06 (m, 3H), 3.11 (t, 4H), 3.58 (t, 4H) , 3.75 (t, ÍH), 3.86 (t, ÍH), 6.73 (d, 2H), 7.58 (d, 3H), 7.82 (m, 4H), 8.12 (d, 2H). Chloro-2'-nitrobiphenyl-4-ylsulphonyl) -piperazine used as an initial material is obtained by the reaction of [4- (piperazin-1-ylsulfonyl) phenyl] -tributyltin and 2-bromo-5-chloro-l -nitrobenzene using a procedure analogous to that described in Note f immediately above.

Example 60 Using a procedure analogous to that described in Example 1, the 1- (4-pyridyl) -piperidin-4-carbonyl chloride is reacted with l- [4- (2-pyridyl) phenylsulfonyl] piperazine to give the - [4- (2-pyridyl) phenylsulfonyl] -4- [1- (4-pyridyl) piperidin-4-ylcarbonyl] piperazine in a yield of 54%, mp 224-226 ° C; NMR spectrum (CD3SOCD3) 1.35-1.65 (m, 4H), 2.75-3.05 (m, 7H), 3.5-3.7 (m, 4H), 3.88 (m, 2H), 6.75 (d, 2H), 7.45 (m , HH), 7.8-8.0 (m, 3H), 8.05-8.15 (m, 3H), 8.35 (d, 2H), 8.72 (m, HH); Elemental Analysis Found C, 62.7; H, 5.9; N, 14. 0; C26H29N503S 0.5H20 required C, 62.4; H, 6.0; N, 14.0%. The 1- [4- (2-pyridyl) phenylsulfonyl] piperazine used as an initial material is obtained as follows: A mixture of 1- (4-iodophenylsulfonyl) piperazine (0.48 g), (2-pyridyl) tributyltin (1.18 g) , tetrakis (triphenylphosphine) palladium (O) (0.1 g) and toluene (15 ml) is stirred and heated at reffor 18 hours. The mixture is evaporated and the residue is purified by column chromatography using polar mixtures in an increase in methylene chloride and methanol as eluent. In this way 1- [4- (2-pyridyl) phenylsulfonyl] piperazine (0.439 g) was obtained; NMR spectrum (CD3SOCD3) 2.65-2.8 (m, 4H), 2.8-2.9 (m, 4H), 7.45 (m, ÍH), 7.8-8.1 (m, 3H), 8.35 (d, 2H), 8.73 (m , ÍH).

Example 61 A mixture of l-ethoxycarbonyl-4- (2-naphthylsulfonyl) -1- [1- (4-pyridyl) piperidin-4-ylcarbonyl] piperazine (0.67 g), 2N aqueous sodium hydroxide solution (2.5 ml) and methanol (10 ml) is stirred at room temperature for 3 hours. The mixture is evaporated and the residue is dissolved in water (10 ml).

The solution is acidified by the addition of acetic acid. The precipitate is isolated and dried. In this way, 2-carboxy-4- (2-naphthylsulfonyl) -1- [1- (4-pyridyl) piperidin-4-ylcarbonyl] piperazine (0.47 g), m.p. 225-228 ° C (decomposition); NMR spectrum (CD3SOCD3 + CD3C02D, 100 ° C) 1.55-1.9 (m, 4H), 2.45-2.55 (m, ÍH), 2.65-2.75 (m, ÍH), 2.9-3.05 (m, ÍH), 3.1- 3.4 (m, 3H), 3.7 (m, ÍH), .3.92 (m, 2H), 4.07 (m, ÍH), 4.25 (m, ÍH), 4.98 (m, ÍH), 6.9 (d, 2H), 7.6-7.8 (m, 3H), 7.95-8.2 (m, 5H), 8.4 (d, ÍH). Elemental Analysis Found C, 58.4; H, 5.8; N, 10.3; C26H28N405S 1.5H20 required C, 58.3; H, 5.8; N, 10.45%.

Example 62 Using an analogous procedure to that described in Example 1, the 1- (4-pyridyl) -piperidin-4-carbonyl chloride is reacted with ethyl 1- (6-chloronaphth-2-ylsulfonyl) piperazine-3-carboxylate to give 4- (6-chloronaphth-2-ylsulfonyl) -2-ethoxycarbonyl-1- [1- (4-pyridyl) -piperidin-4-ylcarbonyl] piperazine in 37% yield; NMR spectrum (CD3SOCD3, 100 ° C) 1.2 (t, 3H), 1.5- 1.8 (m, 4H), 2.6 (m, ÍH), 2.8 (m, ÍH), 2.85-3.05 (m, 4H), 3.65 -3.85 (m, 3H), 4.05-4.25 (m, 4H), 5.1 (m, ÍH), 6.7 (d, 2H), 7.65 (m, ÍH), 7.8 (m, ÍH), 8.1-8.25 (m , 5H), 8.45 (d, ÍH); Elemental Analysis Found C, 58.5; H, 5.6; N, 9. 6; C28H31C1N405S required C, 58.9; H, 5.5; N, 9.8%. The ethyl 1- (6-chloronaphth-2-ylsulfonyl) piperazine-3-carboxylate used as a starting material is obtained in a yield of 78% from ethyl 1-benzylpiperazine-2-carboxylate - and 6-chloride. chloronaphth-2-ylsulfonyl using a procedure analogous to those described in the portion of Example 44, which relates to the preparation of the starting materials.

Example 63 Using a procedure analogous to that described in Example 61, 4- (6-chloronaphth-2-ylsulfonyl) -2-ethoxycarbonyl-1- [1- (4-pyridyl) -piperidin-4-ylcarbonyl] -piperazine is hydrolyzed to give 2-carboxy-4- (6-chloronaphth-2-ylsulfonyl) -1- [1- (4-pyridyl) piperidin-4-ylcarbonyl] -piperazine in a yield of 90%, m.p. 215-220 ° C (decomposition); NMR spectrum (CD3SOCD3, 100 ° C) 1.5-1.8 (m, 4H), 2.7-3.05 (m, 5H), 3.6-3.85 (m, 4H), 4.1 (m, ÍH), 4.25 (m, ÍH) , 4.95 (m, HH), 6.7 (d, 2H), 7.65 (m, HH), 7.8 (m, HH), 8.05-8.25 (m, 5H), 8.45 (d, HH); Elemental Analysis Found C, 56.7; H, 5.0; N, 9.9; C26H27C1N405S 0.5H20 required C, 56.6; H, 5.1; N, 10.15%.

Example 64 A mixture of 2-carboxy-4- (2-naphthylsulfonyl) -1- [1- (4-pyridyl) piperidin-4-ylcarbonyl] piperazine (0.11 g), piperidine (0.064 ml), N-hydroxybenzotriazole (0.029 g) , N, N-dicyclohexylcarbodiimide (0.054 g), DMF (2 ml) and DMSO (2 ml) is stirred at room temperature for 18 hours. The mixture is divided between methylene chloride and water. The organic phase is dried (MgSO 4) and evaporated. The residue is purified by column chromatography using polar mixtures in an increase in methylene chloride and methanol as eluent. In this way 4- (2-naphthylsulfonyl) -2-piperidine-carbonyl-1- [1- (4-pyridyl) piperidin-4-ylcarbonyl] piperazine was obtained as a glass (0.63 g); NMR spectrum (CD3S0CD3 + CD3C02D, 100 ° C) 1.2-1.8 (m, 'lOH), 2.7-3.05 (m, 3H), 3.12 (m, 2H), 3.25-3.4 (m, 5H), 3.65 (m , ÍH), 3.75-4.0 (m, 4H), 5.2 (m, ÍH), 6.85 (d, 2H), 7.6-7.75 (m, 3H), 7.95-8.1 (m, 5H), 8.35 (d, ÍH ); Elemental Analysis Found C, 63.6; H, 7.0; N, 12. 0; C31H37N504S 0.5H20 required C, 63.7; H, 6.5; N, 12.0%. 65 A mixture of 1- (2-naphthylsulfonyl) -4- [1- (4-pyridyl) -piperidin-4-ylcarbonyl] piperazine-2-carboxylic acid (0.121 g) and thionyl chloride (0.2 ml) is stirred at room temperature for 1 hour. The mixture is evaporated and methylene chloride (8 ml) and piperidine (0.23 ml) are added to the residue. The mixture is stirred at room temperature for 2 hours. The mixture is divided between methylene chloride and water. The organic phase is dried (MgSO 4) and evaporated. The residue is purified by column chromatography using polar mixtures in an increase in methylene chloride and methanol as eluent. In this way 1- (2-naphthylsulfonyl) -2-piperidinocarbonyl -4- [1- (4-pyridyl) -piperidin-4-ylcarbonyl] piperazine was obtained as a glass (0.061 g); NMR spectrum (CD3SOCD3 + CD3C02D) 1.2-1.8 (m, 10H), 2.9-3.3 (m, 6H), 3.45-3.7S (m, 4H), 3.9-4.2 (m, 4H), 4.47 (m, HI) ), 5.0 (m, ÍH), 6.8 (d, 2H), 7.68 (m, 3H),: 8.0-8.2 Elemental Analysis Found C, 62.5; H, '6.4; N, 11.7; C31H37N504S H20 required C, 62.7; H, 6.6; N, 11.8%.

Example 66 Using a procedure analogous to that described in Example 1, the 1- (4-pyridyl) -piperidin-4-carbonyl chloride is reacted with 2-benzyl-1- (2-naphthylsulfonyl) piperazine to give 2-benzyl -l- (2-naphthylsulfonyl) -4- [1- (4-pyridyl) piperidin-4-ylcarbonyl] -piperazine in 70% yield; p.f. 186- 188 ° C; ' NMR spectrum (CD3SOCD3) 1.6 (m, 4H), 2.7 (m, 3H), 3.0 (m, 4H), 3.9 (m, 4H), 4.2 (d, 2H), 6.6 (d, 3H), 7.2 ( d, 5H), 7.7 (m, 3H), 8.1 (m, 5H), 8.5 (s, ÍH). Elemental Analysis Found C, 67.9; H, 6.3; N, 9.8; C32H34N403S 0.6H20 required C, 68.0; H, 6.3; N, 9.9%. The 2-benzyl-1- (2-naphthylsulfonyl) piperazine used as an initial material is obtained as follows: N-methylmorpholine (3.12 ml) is added to a stirred mixture of N-tert-butoxycarbonyl-DL-phenylalanine (3 g). ), N-benzylglycine ethyl ester (2.18 g), N-hydroxybenzotriazole (1.26 g) and DMF (50 ml), which is cooled to 0 ° C. The mixture is stirred at 0 ° C for 30 minutes and at room temperature for 16 hours. The mixture is filtered and the filtrate is evaporated. The residue is partitioned between ethyl acetate and water. The organic phase is washed with water, dried (MgSO 4) and evaporated. The residue is purified by column chromatography using a mixture of hexane and ethyl acetate 5: 1 as eluent to give a solid (3.7 g). A mixture of the material thus obtained and a solution of 4M hydrogen chloride in diethyl ether is stirred at room temperature for 16 hours. The mixture is evaporated to give the phenylalanyl-N-benzylglycine ethyl ester (2.65 g); NMR spectrum (CD3SOCD3) 1.2 (m, 2H), 3.1 (t, 2H), 3.6 (m, 4H), 4.1 (m, 2H), 4.6 (m, 2H), 7.2 (m, 10H), 8.4 ( s, 2H). A mixture of a portion (0.5 g) of the material thus obtained, N-methylmorpholino (0.15 g) and a solution of 0.1M acetic acid in sec-butanol (25 ml) is stirred and heated at reflux for 3 hours. The mixture is evaporated and the residue is divided between methylene chloride and water. The organic phase is washed with water, dried (MgSO 4) and evaporated. The residue is purified by column chromatography using polar mixtures in an increase in methylene chloride and methanol as eluent. In this way, 1,3-dibenzyl-2,5-dioxopiperazine (0.29 g), m.p. 173-174 ° C.

After the repetition of the previous reaction, a mixture of 1,3-dibenzyl-2,5-dioxopiperazine (1.6 g), diethyl ether complex of boron trifluoride (0.1 g) and THF (5 ml) is stirred and stirred. heat at reflux for 15 minutes. The mixture is cooled to room temperature and the borane dimethylsulfide complex (0.04 ml) is added in drops. The mixture is stirred at room temperature for 30 minutes. The mixture is evaporated and the residue is heated at 100 ° C for 5 minutes. A solution of 6N aqueous hydrochloric acid (1 ml) is added and the mixture is heated at reflux for 1 hour. The mixture is cooled to 0 ° C and a solution of 6N aqueous sodium hydroxide (1.5 ml) is added. The mixture is divided between methylene chloride and a saturated, aqueous potassium carbonate solution. The organic phase is washed with water, dried (MgSO 4) and evaporated. The residue is purified by column chromatography using polar mixtures in an increase in methylene chloride and methanol as eluent. In this way, 1,3-dibenzylpiperazine (0.29 g) was obtained. A solution of the material thus obtained in methylene chloride (3 ml) is added dropwise to a stirring mixture of 2-naphthylsulfonyl chloride (0.257 g), triethylamine (0.7 ml) and methylene chloride (5 ml), which It has cooled to 0 ° C. The mixture is stirred at room temperature for 16 hours. The mixture is evaporated and the residue is divided between methylene chloride and water. The organic phase is washed with water, dried (MgSO 4) and evaporated. The residue is purified by column chromatography using polar mixtures in an increase in methylene chloride and methanol as eluent. In this way, 2,4-dibenzyl-1- (2-naphthylsulfonyl) piperazine (0.37 g) was obtained; NMR spectrum (CD3SOCD3) 1.8 (m, 2H), 2.6 (m, 3H), 3.1 (m, 2H), 3.45 (d, ÍH), 3.75 (d, ÍH), 4.1 (s, ÍH), 6.95 ( m, 2H), 7.1 (m, 3H), 7.25 (s, 5H), 7.75 (m, 3H), 8.1 (m, 3H), 8.5 (s, ÍH). A mixture of the material thus obtained, charcoal catalyst in palladium 10% (0.23 g) and methylene chde (50 ml) is stirred under a hydrogen atmosphere for 24 hours. The mixture is filtered and the filtrate is evaporated. The residue is purified by column chromatography using a mixture of methylene chde and methanol 99: 1 as eluent. In this way, 2-benzyl-1- (2-naphthylsulfonyl) piperazine (0.08 g) was obtained. NMR spectrum (CD3SOCD3) 2.4-2.8 (m, 4H), 3.1-3.4 (m, 3H), 3.6 (d, ÍH), 4.0 (t, ÍH), 7.2 (m, 5H), 7.7 (m, 3H) ), 8.1 (m, 3H), 8.4 (s, ÍH).

Example 67 Using a procedure analogous to that described in Example 2, the hydrochloride salt of 2-amino-N-. { l-piperidinocarbonyl-2- [1- (4-pyridyl) piperidin-4-ylcarbonyl-amiho] ethyl} acetamide is reacted with (E) -4-chlorostyrylsulfonyl chloride to give 2- [(E) -4-chlorostyrylsulfonamido] -N-ethyl. { 1-piperidinocarbonyl-2- [1- (4-pyridyl) -piperidin-4-ylcarbonylamino] -ethyl-acetaramide as a gum (0.1 g, 16%); NMR (CDCl 3) 1.4-2.1 (m, 10H), 2.45 (m, ÍH), 2.6-3.1 (m, 2H), 3.4-4.0 (m, 10H), 5.1 (m, ÍH), 6.7 (d , 2H), 6.85 (d, HH), 6.95 (m, HH), 7.2-7.55 (m, 6H), 7.65 (d, HH), 8.22 (m, 2H).

Example 68 Using a procedure analogous to that described in Example 2, the hydrochloride salt of l-amino-N-. { 1-piperidinocarbonyl-2- [1- (4-pyridyl) piperidin-4-ylcarbonyl-amino] ethyl} acetamide is reacted with 3,4-dichlorophenylsulfonyl chloride to give 2- (3,4-dichlorophenyl-sulfonamido) -N-. { 1-piperidinocarbonyl-2- [1- (4-pyridyl) -piperidin-4-ylcarbonylamino] ethyl} Acetamide as a gum (0.17 g, 27%); NMR spectrum (CD3SOCD3) 1.4-1.8 (m, 10H), 2.35 (m, ÍH), 2.88 (m, 2H), 3.02 (m, ÍH), 3.15-3.5 (m, 8H), 3.55 (d, ÍH) ), 3.9 (m, 2H), 4.85 (m, ÍH), 6.8 (d, 2H), 7.7-7.9 (m, 3H), 8.0 (d, ÍH), 8.05 (d, ÍH), 8.15 (m, 3H); Elemental Analysis Found C, 49.9; H, 5.4; N, 12.5; C27H34C12N605S 0.4CH2Cl2 required C, 49.9; H, 5.2; N, 12.7%.

Example 69 Using a procedure to that described in Example 56, 4-chloropyrimidine is reacted with 1- (6-chloronaphth-2-ylsulfonyl) -4- (4-piperidinylcarbonyl) -piperazine. The precipitate which is deposited when the reaction mixture is cooled to room temperature is isolated and recrystallized from acetonitrile. In this way 1- (6-chloronaphth-2-ylsulfonyl) -4- [1- (4-pyrimidinyl) -piperidin-4-ylcarbonyl] piperazine was obtained in a yield of 60%, m.p. 218-219 ° C; NMR spectrum (CD3SOCD3) 1.25-1.5 (m, 2H), 1.62 (m, 2H), 2.8-3.1 (m, 7H), 3.5-3.75 (m, 4H), 4.32 (m, 2H), 6.75 (m , ÍH), 7.7 (m, ÍH), 7.85 (m, ÍH), 8.15 (d, ÍH), 8.2 (d, ÍH), 8.28 (m, 3H), 8.45 (s, ÍH), 8.5 (s, ÍH); Elemental Analysis Found C, 57.6; H, 5.3; N, 13. 9; C24H26C1N503S required C, 57.7; H, 5.2; N, 14.0%. The 1- (6-chloronaphth-2-ylsulfonyl) -4- (4-piperidinyl-carbonyl) piperazine used as an initial material is obtained as follows: Using a procedure analogous to those described in two of the paragraphs of the portion of Example 50, which is related to the preparation of the starting materials, 1-tert-butoxycarbonylpiperazine is reacted with 6-chloronaphth-2-ylsulfonyl chloride to give the hydrochloride salt of 1- (6-chloronaphth-2-ylsulfonyl) -piperazine in 58% yield. The material thus obtained is reacted with l-tert-butoxycarbonylpiperidin-4-carboxylic acid using a procedure analogous to those described in the third and fourth paragraphs of the portion of Example 55, which relates to the preparation of the starting materials. In this way, 1- (6-chloronaphth-2-ylsulfonyl) -4- (4-piperidinylcarbonyl) piperazine was obtained in 63% yield; NMR spectrum (CDC13) 1.5-1.75 (m, 4H), 2.4-2.7 (m, 3H), 3.0-3.2 (m, 6H), 3.5-3.75 (m, 4H), 7.55 (m, ÍH), 7.75 (m, ÍH), 7.95 (m, 3H), 8.3 (s, ÍH) ).

Example 70 Using an analogous procedure to that described in Example 56, 2-amino-4-chloropyrimidine is reacted with 1- (6-chloronaphth-2-ylsulfonyl) -4- (4-piperidinylcarbonyl) piperazine. The precipitate which is deposited on cooling, the reaction mixture is isolated, washed with cold ethanol and dried. In this way, 4- [i- (2-aminopyrimidin-4-yl) piperidin-4-ylcarbonyl] -1- (6-chloronaphth-2-ylsulfonyl) piperazine was obtained in a yield of 73%, m.p. 265-267 ° C; NMR spectrum (CD3SOCD3) 1.0-1.4 (m, 4H), 2.5-2.7 (m, 3H), 2.7-2.9 (m, 4H), 3.3-3.5 (m, 4H), 4.08 (m, 2H), 5.7 (s, 2H), 5.8 (d, ÍH), 7.5-7.7 (m , 3H), 7.75 (d, ÍH), 8.05 (s, ÍH), 8.1 (d, ÍH), 8.3 (s, ÍH); Elemental Analysis Found C, 55.9; H, 5.4; N, 15.9; C24H27C1N603S required C, 56.0; H, 5.3; N, 16.3%.

Example 71 Using an analogous procedure to that described in Example 32, 3, 4, 5-trichloropyridazine is reacted with 1- (6-chloronaphth-2-ylsulfonyl) -4- (4-piperidinylcarbonyl) piperazine. The product of the reaction without purification is purified by column chromatography using polar mixtures in an increase of methylene chloride and ethyl acetate as eluent. In this way 1- (6-chloronaphth-2-ylsulfonyl) -4- [1- (3,4-dichloropyridazin-5-yl) piperidin-4-ylcarbonyl] piperazine was obtained in a yield of 35%; NMR spectrum (CD3SOCD3) 1.5-1.7 (m, 4H), 2.7-2.9 (m, ÍH), 2.95-3.1 (m, 6H), 3.5-3.85 (m, 6H), 7.7 (m, ÍH), 7.85 (m, ÍH), 8.15 (d, ÍH), 8.22 (s, ÍH), 8.25 (d, ÍH), 8.5 (s,% 1H), 8.9 (s, ÍH).

Example 72 A mixture of 1- (6-chloronaphth-2-ylsulfonyl) -4- [1- (3,4-dichloropyridazin-5-yl) piperidin-4-ylcarbonyl] piperazine (0.2 g), palladium carbon catalyst 10% (0.05 g) and ethanol (10 ml) is stirred under an atmosphere of hydrogen gas for 48 hours. The mixture is filtered and the filtrate is evaporated. The residue is purified by column chromatography using polar mixtures in an increase in methylene chloride and methanol as eluent. In this way, 1- (6-chloronaphth-2-ylsulfonyl) -4- [1- (4-pyridazinyl) piperidin-4-ylcarbonyl] piperazine (0.045 g, 25%) was obtained; NMR spectrum (CD3SOCD3) 1.4-1.7 (m, 4H), 2.6-3.1 (m, 7H), 3.5-3.7 (m, 4H), 3.9-4.0 (m, 2H), 6.85 (m, ÍH), 7.7 (m, ÍH), 7.82 (m, ÍH), 8.15 (d, ÍH), 8.27 (m, 2H), 8.5 (s, ÍH), 8.55 (d, ÍH), 8.9 (d, ÍH).

Example 73 A mixture of 1- (6-chloronaphth-2-ylsulfonyl) -4 - (4-piperidinylcarbonyl) piperazine (0.96 g), triethylamine (0.35 ml) and methylene chloride (10 ml) is added dropwise to a stirring solution. of 2,4,6-trichloro-1,3,5-triazine (0.42 g) in methylene chloride (20 ml), which has been cooled to 0 ° C. The mixture is stirred at 5 ° C for 1 hour. The mixture is evaporated and the residue is partitioned between ethyl acetate and water. The organic phase is washed with water, dried (MgSO 4) and evaporated. The residue is purified by column chromatography using polar mixtures in an increase of methylene chloride and ethyl acetate as eluent. In this way, 1- (6-chloronaphth-2-ylsulfonyl) -4- [1- (4,6-dichloro-1,3,5-triazin-2-yl) piperidin-4-ylcarbonyl] piperazine (0.96) was obtained. g, 74%), pf 230-233 ° C; NMR spectrum (CDC13) 1.7-1.9 (m, 4H), 2.7 (m, ÍH), 3.0-3.2 (m, 6H), 3.55-3.85 (m, 4H), 4.73 (m, 2H), 7.6 (m , ÍH), 7.75 (m, ÍH), 7.95 (m, 3H), 8.3 (s, ÍH); Elemental Analysis Er? Contrado C, 46.9; H, 3.9; N, 14. 4; C23H23C13N603S 0.25CH2Cl2 required C, 47.3; H, 4.0; N, 14-2%.

Example 74 A mixture of 1- (4-pyridyl) piperazine (0.163 g), 4- (6-chloronaphth-2-ylsulfonyl) piperazine-1-carboxylic acid 4-nitrophenyl ester (0.475 g) in DMF (5 ml) is stirred and stirred. warm up 100 ° C for 16 hours. The mixture is evaporated and the residue is partitioned between ethyl acetate and 2N aqueous hydrochloric acid.

The aqueous layer is basified by the addition of the dilute aqueous sodium hydroxide solution and the mixture is extracted with ethyl acetate. The organic phase is dried (MgSO 4) and evaporated. The solid thus obtained is recrystallized from a mixture of isohexane and ethyl acetate. In this way 1- (6-chloronaphth-2-ylsulfonyl) -4- [4- (4-pyridyl) -piperazin-1-ylcarbonyl] piperazine (0.34 g) was obtained; NMR spectrum (CD3SOCD3) 2.95-3.05 (m, 4H), 3.15-3.3 (m, 12H), 6-75 (m, 2H), 7.75 (m, ÍH), 7.8 (m, ÍH), 8.1-8.3 (m, 5H), 8.5 (s, ÍH); Elemental Analysis Found C, 57.5; H, 5.3; N, 13.9; C24H26C1N503S required C, 57.7; H, 5.2; N, 14.0%. The 4- (6-chloronaphth-2-ylsulfonyl) piperazine-1-carboxylate of 4-nitrophenyl used as the starting material is obtained as follows: A solution of 4-nitrophenyl chloroformate (0.4 g) in methylene chloride (15 ml. ) is added to a stirring mixture of the hydrochloride salt 1- (6-chloronaphth-2-ylsulfonyl) piperazine (0.69 g), triethylamine (0.56 ml) and methylene chloride (30 ml), which has been cooled to 0 ° C. The mixture is stirred at room temperature for 16 hours. The mixture is evaporated and the residue is partitioned between ethyl acetate and concentrated aqueous sodium bicarbonate solution. The organic solution is washed with a solution of hydrochloric acid, aqueous IN and water, dried (MgSO 4) and evaporated. The solid thus obtained is recrystallized from a mixture of isohexane and ethyl acetate. In this way, 4-nitrophenyl 4- (6-chloronaphth-2-ylsulfonyl) piperazine-l-carboxylate (0.73 g) was obtained; NMR spectrum (CD3SOCD3) 3.1 (m, 4H), 3.5-3.75 (m, 4H), 7.25 (m, ÍH), 7.38 (d, 2H), 7.85 (m, ÍH), 8.15-8.3 (m, SH), 8.5 (s, ÍH).

Example 75 Using an analogous procedure to that described in Example 1, l- (4-pyridyl) piperidin-4-carbonyl chloride is reacted with 4- (2-naphthylsulfonyl) piperidine to give 4- (2-naphthylsulfonyl) - 1- [1-4-pyridyl) piperidin-4-ylcarbonyl] piperidine in a yield of 33 #; NMR spectrum (CD3SOCD3) 1.42-1.82 (m, 6H), 1.85-2.21 (m, 2H), 2.82-3.04 (m, 4H), 3.73-3.98 (m, 5H), 4.43 (m, ÍH), 6.78 (d, 2H), 7.64-7.89 (m, 3H), 8.04-8.27 (m, 5H), 8.37 (s, ÍH). The 4- (2-naphthylsulfonyl) piperidine used as an initial material is obtained as follows: Triethylamine (8.8 ml) is added to a stirring mixture of tert-butyl 4-hydroxypiperidine-1-carboxylate (European Patent Application No. 0 495 750, Chem. Abstracts, Vol. 117, Abstract 191869g, 6.38 g), methanesulfonyl chloride (3.7 ml) and methylene chloride (70 ml) which has been cooled to 0 ° C. The mixture is stirred at 0 ° C for 2 hours and then evaporated. The residue is partitioned between ethyl acetate and a concentrated aqueous citric acid solution. The organic phase is washed with water, dried (MgSO 4) and evaporated. The residue is purified by column chromatography using ethyl acetate as eluent to give tert-butyl 4-mesyloxypiperidine-1-carboxylate (7.82 g). A mixture of a portion (0.99 g) of the material thus obtained, sodium 2-naphthalenesulfinate (14.3) and DMF (70 ml) is stirred and heated at 120 ° C for 5 hours. The mixture is evaporated and the residue is partitioned between ethyl acetate and a 2N aqueous sodium hydroxide solution. The organic phase is dried (MgSO 4) and evaporated to give 4- (2-naphthylsulfonyl) -piperidine-1-carboxylic acid tert -butyl ester (0.64 g), which is used without further purification. A mixture of a portion (0.56 g) of the material thus obtained and the trifluoroacetic acid (5 ml) is stirred at room temperature for 1 hour. The mixture is diluted with ethyl acetate and washed with 2N aqueous sodium hydroxide. The organic layer is dried (MgSO 4) and evaporated to give 4- (2- (naphthylsulfoniDpiperidine (0.18 g); NMR spectrum (CD3SOD3) 1.36-2.08 (m, 4H), 2.8-3.05 (m, 4H), 4.12-4.55 (m, ÍH), 7.6-8.25 (m, 6H), 8.34 (s, ÍH). The sodium 2-naphthalenesulfinate used in the above is obtained as follows: The 2-naphthalenesulfonyl chloride (15.9 g) is added in portions over 2 hours to a stirring mixture of sodium sulfite (33 g), sodium bicarbonate ( 11.6 g) and water (66 ml), which has been heated to 70 ° C. The resulting mixture is stirred at 75 ° C for 1 hour and stored at room temperature for 16 hours. The precipitate is isolated. In this way, sodium 2-naphthalenesulfinate (31 g) was obtained.

Example 76 Using an analogous procedure to that described in Example 1, l- (4-pyridyl) piperidin-4-carbonyl chloride is reacted with 4- (2-naphthylthio) piperidine to give 4- (2-naphthylthio) -1 - [1- (4-pyridyl) piperidin-4-ylcarbonyl] piperidine in 62% yield. NMR spectrum (CD3SOCD3, 100 ° C) 1.25-1.75 (m, 6H), 1.87-2.1 (s broad, 2H), 2.78-3.0 (m, 4H), 3.20 (d, ÍH), 3.64 (m, ÍH), 3.6-4.04 (m, 3H), 4.2 (d, ÍH) ), 6.78 (d, 2H), 7.44-7.58 (m, 3H), 7.63-7.74 (m, 3H), 7.75 (d, ÍH), 8.12 (s, 2H) '; Elemental Analysis Found C, 72.2; H, 6.7; N, 9.7; C26H29N3QS required C, 72.4; H, 6.8; N, 9.7%. The A - (2-naphthylthio) piperidine used as an initial material is obtained as follows: A solution of 2-naphthalethiol (2.34 g) in DMF (10 ml) is added dropwise to a stirring mixture of sodium hydride (60 ml). % dispersion in mineral oil, 0.65 g) and DMF (20 ml), which has been cooled to 10 ° C. The resulting mixture is stirred at 0 ° C for 30 minutes. A solution of tert-butyl 4-mesyloxypiperidine-l-carboxylate (3.9 g) in DMF (40 ml) is added in drops. The mixture is allowed to warm to room temperature. The mixture is partitioned between ethyl acetate and water. The organic phase is washed with water, it is dried (MgSO4) and evaporated. The residue is purified by column chromatography using methylene chloride as eluent. In this way, 4- (2-naphthylthio) piperidine-1-carboxylate of tert-butyl (0.65 g) was obtained. A mixture of the material thus obtained and trifluoroacetic acid is stirred at room temperature for 30 minutes. The mixture is diluted with ethyl acetate and washed with a 2N aqueous sodium hydroxide solution. The organic solution is dried (MgSO 4) and evaporated. In this way, 4 - (2-naphthylthio) piperidine (0.32 g) was obtained; NMR spectrum (CD3SOCD3) 1.42 (m, 2H), 1.88 (m, 2H), '2.58 (m, 2H), 2.94 (m, 2H), 3.43 (m, ÍH), 7.5 (m, 3H), 7.89 (m, 4H).

Example 77 Using an analogous procedure to that described in Example 1, l- (4-pyridyl) piperidin-4-carbonyl chloride is reacted with 2-hydroxymethyl-4- (2-naphthylsulfonyl) piperazine to give 2-hydroxymethyl -4- (2-naphthylsulfonyl) -1- [1- (4-pyridyl) piperidin-4-ylcarbonyl] piperazine in a yield of 42%; NMR spectrum (CD3SOCD3, 100 ° C) 1.55-1.72 (m, 2H), 1.83-1.95 (m, 2H), 2.35-3.05 (m, 8H), 3.49 (m, 2H), 3.7 (m, 2H) , 4.01 (m, 2H), 6.72 (d, 2H), 7.63-7.79 (m, 3H), 8.0-8.2 (m, 5H), 8.39 (s, ÍH); Elemental Analysis Found C, 61.2; H, 6.2; N, 10.4; C26H30N4O4S 0.25EtAC 0.75H20 required C, 61.2; H, 6.4; N, 10.6%. The 2-hydroxymethyl-4- (2-naphthylsulfonyl) piperazine used as an initial material is obtained in a yield of 49% by the reaction of 2-hydroxymethylpiperazine (J. Med. Chem. 1990, 3_3, 142) and the 2-naphthylsulfonyl chloride using a procedure analogous to that described in Example 2; NMR spectrum (CD3SOCD3) 1.93 (t, ÍH), 2.24 (m, 2H) ', 2.68 (m, 2H), 2.93 (m, ÍH), 3.6 (m, 2H), 4.67 (t, ÍH), 7.76 (m, 3H), 8.07-8.28 (m, 3H), 8.44 (s, ÍH).

Example 78 1, 1'-carbonyldiimidazole (0.208) is added to a stirred solution of N- (6-chloronaphth-2-ylsulfonyl) glycine (0.39 g) in DMF (10 ml) and the mixture is stirred at room temperature for 30 minutes. 1- (4-pyridyl) -piperazine (0.21 g) is added and the mixture is stirred at room temperature for 18 hours. The mixture is partitioned between ethyl acetate and water. The organic phase is washed with brine, dried (MgSO 4) and evaporated. The residue is recrystallized from a mixture of hexane, ethyl acetate and methanol.

In this way, 1- [2- (6-chloronaphthalenesulfonamido) -acetyl] -4- (4-pyridyl) -piperazine (0.179 g, 20%), m.p. 192- 193 ° C; NMR spectrum (CD3S0CD3) 3.15 (m, 2H), 3.3-3.6 (m, 6H), 3.85 (m, 2H), 6.7-7.0 (m, 2H), 7.6 (m, ÍH), 7.8-8.0 (m , 2H), 8.1-8.3 (m, 4H), 8.5 (s, ÍH); Elemental Analysis Found C, 56.5; H, 4.8; N, 12.4; C21H21C1N403S required C, 56.7; H, 4.8; N, 12.6%. The N- (6-chloronaphth-2-ylsulfonyl) glycine used as an initial material is obtained as follows: Triethylamine (0.278 ml) is added to a stirring mixture of 6-chloronaf-2-ylsulfonyl chloride (0.522 g), glycine methyl ester hydrochloride (0.251 g) and methylene chloride (10 ml) and the mixture is stirred at room temperature. environment for 1 hour. The mixture is partitioned between ethyl acetate and water. The organic phase is washed with brine, dried (MgSO) and evaporated. The residue is recrystallized from methanol to give the methyl N- (6-chloronaphth-2-ylsulfonyl) glycine (0.46 g). A mixture of the material thus obtained and a 2N aqueous sodium hydroxide solution (3 ml) is stirred at room temperature for 30 minutes. The mixture is divided between diethyl ether and water. The aqueous phase is acidified by the addition of 2N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase is washed with water and with brine, dried (MgSO 4) and evaporated. In this way the required initial material (0.39 g) was obtained, which is used without further purification.

Example 79 A mixture of 1- (4'-ethoxycarbonylbiphenyl-4-ylsulfonyl) -4- [1- (4-pyridyl) piperidin-4-ylcarbonyl] piperazine (0.08 g), a solution of 2N aqueous sodium hydroxide (0.28 ml), water (2 ml) and methanol (10 ml) is stirred and heated at reflux for 3 hours. The mixture is poured into water and extracted with methylene chloride. The aqueous suspension is filtered. The solid thus obtained is resuspended in water. The mixture is acidified by the addition of glacial acetic acid and stirred for 2 hours. The solid is isolated, washed with water and with diethyl ether and dried. In this way, 1- (4'-carboxyphenyl-4-ylsulfonyl) -4- [1- (4-pyridyl) piperidin-4-ylcarbonyl] piperazine (0.035 g) was obtained; NMR spectrum (CD3SOCD3, 100 ° C) 1.6-1.86 (m, 4H), 3.0 (m, ÍH), 3.15 (t, 4H), 3.32 (m, 2H), 3.63 (t, 4H), 3.97 (t , HH), 4.03 (t, HH), 7.01 (d, 2H), 7.24-7.96 (m, 6H), 8.09 (d, 4H).

Example 80 Ethantiol (0.15 ml) is added in drops to a stirring suspension of sodium hydride (60% dispersion in mineral oil, 0.083 g) in DMPU (3 ml), which has been cooled to 3 ° C and the mixture stir and allow to warm to room temperature for 30 minutes. A solution of 1- (6-methoxynaphth-2-ylsulfonyl) -4- [1- (4-pyridyl) piperidin-4-ylcarbonyl] piperazine (0.1 g) in DMPU (2 ml) is added and the mixture is stirred and heated at 110 ° C for 90 minutes. The mixture is cooled to room temperature and divided between methylene chloride and water. The organic phase is stirred with light excess of 2M aqueous sodium hydroxide. The resulting precipitate is isolated and dried. In this way, the sodium salt of l- (6-hydroxynaphth-2-ylsulfonyl) -4- [1- (4-pyridyl) piperidin-4-ylcarbonyl] piperazine (0.052 g) was obtained; NMR spectrum (CD3SOCD3, 100 ° C) 1.5-1.73 (m, 4H), 2.72-3.23 (m, 7H), 3.55 (t, 4H), 3.68-3.88 (m, 2H), 6.72 (m, 2H) , 6.8 (m, HH), 6.96 (m, HH), 7.45 (m, 2H), 7.69 (m, HH), 7.99 (m, HH), 8.11 (m, 2H); Elemental Analysis Found C 53.8; H, 5.6; N, . 0; C 25 H 27 N 404 S 3 H 20 Na required C, 53.9; H, 5.9; N, 10.1%.

Example 81 Using a procedure analogous to that described in Example 1, the 1- (4-pyridyl) -piperidin-4-carbonyl chloride is reacted with 2- [1- (2-naphthylsulfonyl) piperazin-2-yl] acetate of methyl to give 2-methoxycarbonylmethyl-1- (2-naphthylsulfonyl) -4- [1- (4-pyridyl) -piperidin-4-ylcarbonyl] piperazine in a 90% yield as a glass, - NMR spectrum (CD3S0CD3 + CD3C02D, 100 ° C) 1.6-1.85 (m, 4H), 2.4-2.65 (m, 2H), 2.85-3.35 (m, 6H), 3.55 (s, 3H), 3.78 (m, ÍH), 3.9- 4.1 (m, 4H), 4.45 (m, ÍH), 6.95 (d, 2H), 7.68 (m, 2H), 7.8 (m, ÍH), 7.95-8.15 (m, 5H), 8.45 (d, ÍH); Elemental Analysis Found C, 61.7; H, 6.3; N, 10.3; C2gH32N405S 0.5H20 required C, 61.65; H, 6.05; N, 10.3%. The methyl 2- [1- (2-naphthylsulfonyl) piperazin-2-yl] acetate used as an initial material is obtained as follows: Using a procedure analogous to that described in Example 2, the 2- (l) is reacted methyl-benzylpiperazin-3-yl) acetate (J. Chera. Soc. Perkin 1, 1992, 1035) with 2-naphthylsulfonyl chloride to give the 2- [4-benzyl-l- (2-naphthylsulfonyl) piperazin-2-yl] methyl acetate in a 90% yield. The material thus obtained is reacted with 1-chloroethyl chloroformate using a procedure analogous to that described in the second paragraph of the portion of Example 44, which relates to the preparation of the starting materials. In this way methyl 2- [l- (2-naphthylsulfonyl) piperazin-2-yl] acetate was obtained in a yield of 87%; NMR spectrum (CD3SOCD3) 2.55-2.7 (m, 2H), 2.9 (m, ÍH), 3.05-3.45 (m, 4H), 3.55 (s, 3H), 3.9 (m, ÍH), 4.6 (m, ÍH) ), 7.65-7.9 (m, 3H), 8.12 (m, 3H), 8.55 (d, ÍH), 9.3 (t, 2H).

Example 82 Using an analogous procedure to that described in Example 1, the 1- (4-pyridyl) -piperidine-4-carbonyl chloride is reacted with the l- (6-bromonaphth-2-ylsulfonyl) piperazine-3-carboxylate of ethyl to give 4- (6-bromonaphth-2-ylsulfonyl) -2-ethoxycarbonyl-1- (1- (4-pyridyl) -piperidin-4-ylcarbonyl] piperazine in 42% yield, mp 117-121 ° C; NMR spectrum (CD3SOCD3, 100 ° C) 1.2 (t, 3H), 1.5- 1.8 (m, 4H), 2.55 (m, ÍH), 2.7-3.05 (m, 5H), 3.65-3.85 (m, 3H) , 4.05-4.25 (m, 4H), 5.08 (m, ÍH), 6.7 (d, 2H), 7.77 (m, 2H), 8.1 (m, 4H), 8.3 (d, ÍH), 8.45 (d, ÍH) ). Elemental Analysis Found C, 54.2; H, 5.2; N, 9.0; C28H31BrN405S required C, 54.6; H, 5.1; N, 9.1%. Ethyl 1- (6-bromonaphth-2-ylsulfonyl) piperazine-3-carboxylate used as a starting material is obtained in a 71% yield from ethyl 1-benzylpiperazine-2-carboxylate and 6-bromonaft chloride -2-ylsulfonyl using a procedure analogous to those described in the portion of Example 44, which relates to the preparation of the starting materials.

Example 83 Using an analogous procedure to that described in Example 61, 4- (6-bromonaphth-2-ylsulfonyl) -2-ethoxycarbonyl-1- [1- (4-pyridyl) piperidin-4-ylcarbonyl] -piperazine is hydrolysed to give 4- (6-Bromonaphth-2-ylsulfonyl) -2-carboxy-l- [1- (4-pyridyl) piperidin-4-ylcarbonyl] piperazine in a yield of 92%, m.p. 216-222 ° C (decomposition); NMR spectrum (CD3SOCD3, 100 ° C) 1.5-1.8 (m, 4H), 2. 52 (m, ÍH), 2.7 (m, ÍH), 2.8-3.05 (m, 3H), 3.25 (m, ÍH), 3.6-4.3 (m, 5H), 4.95 (m, ÍH), 6.75 (d, 2H), 7.75 (m, 2H), 8.0-8.15 (m, 4H), 8.3 (d, ÍH), 8.4 (d, ÍH). Elemental Analysis Found C, 52.4; H, 4.8; N, 9.3; C26H27BrN405S 0.5H20 required -C, 52.35; H, 4.7; N, 9.4%.

Example 84 Using an analogous procedure to that described in Example 20, 4- (6-bromonaphth-2-ylsulfonyl) -2-carboxy-1- [1- (4-pyridyl) piperidin-4-ylcarbonyl] piperazine is reacted with morpholine to give 4- (6-bromonaphth-2-ylsulfonyl) -2-morpholinocarbonyl-l- [1- (4-pyridyl) piperidin-4-ylcarbonyl] piperazine in a yield of 60%, mp 235-237 ° C; NMR spectrum (CD3SOCT > 3, 100 ° C) 1.5-1.8 (ra, 4H), 2.7-3.05 (m, 5H), 3.4 (m, 4H), 3.5-3.6 (m, 4H), 3.67 (m , ÍH), 3.75-3.9 (m, 4H), 3.98 (m, HH), 5.2 (m, HH), 6.65-6.8 (m, 2H), 7.75 (m, 2H), 8.1 (m, 4H), 8.3 (d, ÍH), 8.45 (d, ÍH); Elemental Analysis Found C, 53.7; H, 5.2; N, 10.2; C30H34BrN5O5S H20 required C, 53.5; H, 5.35; N, 10.4%.

Example 85 A mixture of 1- (6-chloronaphth-2-ylsulfonyl) -4- [1- (4,6-dichloro-1,3,5-triazin-2-yl) piperidin-4-ylcarbonyl] -piperazine (0.891 g ), magnesium oxide (0.5 g), 10% palladium carbon catalyst (0.2 g) and DMF (15 ml) is stirred under an atmosphere of hydrogen gas until the incorporation of hydrogen is complete. The mixture is filtered and the filtrate is partitioned between ethyl acetate and water. The organic phase is dried (MgSO 4) and evaporated. In this way l- (2-naphthylsulfonyl) -4- [1- (1, 3, 5-triazin-2-yl) piperidin-4-ylcarbonyl] piperazine (0.36 g) was obtained; NMR spectrum (CD3SOCD3) 1.3-1.7 (m, 4H), 2.8-3.1 (m, 7H), 3.5-3.7 (m, 4H), 4.5-4.7 (m, 2H), 7.6-7.8 (m, 3H) , 8.1-8.3 (m, 3H), 8.45 (s, ÍH), 8.55 (s, 2H).

Example 86 Using an analogous procedure to that described in Example 56, 2-amino-4-chloro-6-methylpyrimidine is reacted with 1- (6-chloronaphth-2-ylsulfonyl) -4- (4-piperidinylcarbonyl) piperazine. The reaction mixture is concentrated by evaporation to one half of its original volume and cooled to room temperature. The precipitate that forms is isolated, washed with diethyl ether and dried. In this way, 4- [1- (2-amino-6-methylpyrimidin-4-yl) piperidin-4-ylcarbonyl] -1- (6-chloronaphth-2-ylsulfonyl) piperazine was obtained in a yield of 39%, pf 210-212 ° C; NMR spectrum (CD3SOCD3) 1.2-1.6 (m, 4H), 2.0 (s, 3H), 2.8 (m, 3H, 2.9-3.1 (m, 4H), 3.5-3.7 (m, 4H), 4.2 (m, 2H), 5.82 (s, 2H), 5.86 (s, ÍH), 7.7 (m, ÍH), 7.8 (m, ÍH), 8.2 (d, ÍH), 8.25 (s, ÍH), 8.3 (d, ÍH) ), 8.5 (s, ÍH), Elemental Analysis Found C, 56.3, H, 5.5, N, 15.3, C25H29C1N603S 0.4H2O required C, 55.9, H, 5.6, N, 15.7%.

Example 87 Using an analogous procedure to that described in Example 56, the 4-chloropyrimidine is reacted with methyl 4- (6-chloronaphth-2-ylsulfonyl) -1- (4-piperidinyl-carbonyl) piperazine-2-carboxylate and the The reaction product is purified by column chromatography using polar mixtures in an increase in methylene chloride and methanol to give 4- (6-chloronaphth-2-ylsulfonyl) -2-methoxy-carbonyl-1- [1- (4- pyridyl) piperidin-4-ylcarbonyl] piperazine in a 77% yield; NMR spectrum 1.6-2.0 (m, 4H), 2.5 (m, 2H), 2.8 (m, ÍH), 3.0 (m, ÍH), 3.6-3.9 (m, 6H), 4.25-4.45 (m, 3H), 5.35 (m, ÍH), 6.5 (d, ÍH), 7.6 (ra, ÍH) ), 7.75 (m, ÍH), 7.95 (m, 3H), 8.2 (d, ÍH), 8.35 (s, ÍH), 8.6 (s, ÍH); Elemental Analysis Found C, 54.5; H, 5.2; N, 11. 8; C26H28C1N505S 0.2CH2C12 required C, 54.7; H, 4.9; N, 12. 2%. The methyl 4- (6-chloronaphth-2-ylsulfonyl) -1- (4-piperidinyl-carbonyl) piperazin-2-carboxylate used as starting material is obtained as follows: The benzyl chloroformate (8.5 g) is added in drops to a stirred mixture of ethyl piperidin-4-carboxylate (7.85 g), triethylamine (6.95 ml) and methylene chloride (50 ml), which has been cooled to 5 ° C. The mixture is stirred at room temperature for 18 hours. The mixture is partitioned between ethyl acetate and 2N aqueous hydrochloric acid. The organic phase is washed with water and brine, dried (MgSO 4) and evaporated. The residue is dissolved in methanol (100 ml) and 2N aqueous sodium hydroxide (125 ml) is added. The mixture is stirred at room temperature for 1 hour. The mixture is concentrated by evaporation and the residue is partitioned between diethyl ether and water. The aqueous phase is acidified to pH 3 by the addition of concentrated hydrochloric acid and the mixture is extracted with ethyl acetate. The organic extract is washed with water, dried (MgSO 4) and evaporated to give 1-benzyloxycarbonylpiperidine-4-carboxylic acid (10.1 g). Oxalyl chloride (0.429 ml) and DMF (1 drop) are added to a stirred solution of 1-benzyloxycarbonylpiperidine-4-carboxylic acid (0.622 g) in methylene chloride (20 ml). The mixture is stirred at room temperature for 2 hours and then evaporated. The residue is dissolved in methylene chloride (10 ml) and added dropwise to a stirred mixture of methyl 4- (6-chloronaphth-2-ylsulfonyl) -piperazine-3-carboxylate (0.93 g), triethylamine (0.7 ml) and methylene chloride (10 ml), which has been cooled to 0 ° C. The mixture is stirred at room temperature for 2 hours. The mixture is partitioned between ethyl acetate and 2N aqueous hydrochloric acid. The organic phase is washed with a solution of saturated aqueous sodium bicarbonate, with water and with brine, dried (MgSO 4) and evaporated. The residue is purified by column chromatography using polar mixtures in an increase of hexane and ethyl acetate as eluent. In this way methyl 1- (4-benzyloxycarbonyl-piperidin-4-ylcarbonyl) -4- (6-chlornaphth-2-ylsulfonyl) piperazine-2-carboxylate (1.21 g); NMR spectrum 1.4-1.9 (m, 4H), 2.3-2.7 (m, 3H), 2.85 (m, 2H), 3.5-3.9 (m, 6H), 4.15 (m, 2H), 4.35 (m, ÍH) , 5.1 (s, 2H), 5.3 (m, ÍH), 7.2-7.4 (m, 5H), 7.6 (m, ÍH), 7.75 (m, ÍH), 7.75-8.0 (m, 3H), 8.3 (s) , ÍH). A mixture of a portion (0.512 g) of the initial material thus obtained and a saturated solution of hydrogen bromide gas in glacial acetic acid (5 ml) is stirred at room temperature for 20 minutes. Diethyl ether (100 ml) is added and the mixture is stirred vigorously. The precipitate is isolated, washed with diethyl ether and dried. In this way methyl 4- (6-chloronaphth-2-ylsulfonyl) -1- (4-piperidinylcarbonyl) piperazin-2-carboxylate which is used without further purification was obtained. The methyl 4- (6-chloronaphth-2-ylsulfonyl) piperazine-3-carboxylate used in the foregoing as an intermediate is obtained by the reaction of methyl 1-benzylpiperazin-2-carboxylate (prepared analogously to the corresponding ethyl ester , which is described in Helv. Chira, Acta, 1962, 45, 2383) and 6-chloronaphth-2-ylsulfonyl chloride using procedures analogous to those described in the portion of Example 44, which is related to the preparation of the initial materials.

Example 88 A mixture of 4- (6-chloronaphth-2-ylsulfonyl) -2-methoxycarbonyl-1- [1- (4-pyridyl) piperidin-4-ylcarbonyl] -piperazine (0.362 g), aqueous sodium hydroxide solution IN ( 1.3 ml) and methanol (5 ml) is stirred and refluxed for 30 minutes. The mixture is acidified by the addition of 2N aqueous hydrochloric acid (2 ml) and evaporated, the residue is dried to give 2-carboxy-4- (6-chloronaphth-2-ylsulfonyl) -1- [1- (4 -pyridyl) piperidin-4-ylcarbonyl] piperazine (0.41 g); NMR spectrum (CD3S0CD3) 1.4-1.9 (m, 4H), 2.1-2.5 (m, ÍH), 3.0-3.75 (m, 8H), 4.0-4.3 (m, 2H), 5.12 (m, ÍH), 7.2 (m, ÍH), 7.7 (m, ÍH), 7.85 (m, ÍH), 8.1-8.3 (m, 4H), 8.55 (s, ÍH), 8.75 (s, ÍH); Elemental Analysis Found C, 41.0; H, 4.2; N, 9. 4; C25H26C1N505S 2NaCl 2 H20 HCl required C, 40.9; H, 4.3; N, 9.6%.

Example 89 A solution of (E) -4-chlorostyril-sulfonyl chloride (0.12 g) in methylene chloride (2 ml) is added to a stirred suspension of 4- [4- (4-pyridyl) piperazin-1-ylcarbonyl] aniline (0.141 g) in methylene chloride (10 ml). The mixture is stirred at room temperature for 64 hours.

The resulting solid is isolated and washed with methylene chloride. The residue is purified by column chromatography using a 10: 1 mixture of methylene chloride and methanol as eluent. In this way the N- was obtained. { 4- [4- (4-pyridyl) piperazin-1-ylcarbonyl] phenyl} - (E) -4-chlorostyrene-sulfonamide (0.089 g), m.p. 207-209 ° C; NMR spectrum (CD3SOCD3, 100 ° C) 3.43 (m, 4H), 3.6 (m, 4H), 6.8 (d, 2H), 7.15 (d, ÍH), 7.27 (d, 2H), 7.3-7.5 (m , 5H), 7.63 (d, 2H), 8.16 (d, 2H); Elemental Analysis Found C, 59.0; H, 4.9; N, 11. 3; C24H23C1N403S 0.25H2O required C, 59.1; H, '4.9; N, 11.5%. The 4- [4- (4-pyridyl) piperazin-1-ylcarbonyl] aniline used as an initial material is obtained as follows: N-Nitrobenzoyl chloride (4.64 g) is added to a stirring suspension of 1- (4- pyridyl) piperazine (4.08 g), triethylamine (3.48 ml) and DMF (50 ml), which has been cooled to 4 ° C. The mixture is stirred at 4 ° C for 1 hour and at room temperature for 16 hours. The mixture is divided between methylene chloride and water. The organic phase is washed with brine, dried (MgSO 4) and evaporated. The residue is purified by column chromatography using a 10: 1 mixture of methylene chloride and methanol as eluent. In this way, 4- [4- (4-pyridyl) piperazin-1-ylcarbonyl] -nitrobenzene (5.09 g), m.p. 158-160 ° C.

A mixture of a portion (3.74 g) of the material thus obtained, 10% palladium carbon catalyst (0.3 g), IN aqueous hydrochloric acid (24 ml) and methanol (75 ml) is stirred under a hydrogen gas atmosphere until that the incorporation of hydrogen has ended. The mixture is filtered and the filtrate is evaporated. The residue dissolves in water (25 ml) and the solution is basified to pH 10 by the addition of an aqueous sodium hydroxide solution. The resulting precipitate is isolated, washed with water and dried. In this way, 4- [4- (4-pyridyl) piperazin-1-ylcarbonyl] -aniline (2.91 g), m.p. 254-256 ° C.

Example 90 Using an analogous procedure to that described in Example 89, 4- [4- (4-pyridyl) piperazin-1-ylcarbonyl] aniline is reacted with 4'-bromo-4-biphenylsulfonyl chloride to give the hydrochloride salt of the N-. { 4- [4- (4-pyridyl) -piperazin-1-ylcarbonyl] phenyl} -4'-bromo-4-biphenylylsulfonamide in a yield of 90%, m.p. 201-205 ° C; NMR spectrum (CD3S0CD3) 3.6 (m, 4H), 3.73 (m, 4H), 7.18 (m, 4H), 7.39 (m, 2H), 7.69 (s, 4H), 7.9 (s, 4H), 8.27 ( d, 2H); Elemental Analysis Found C, 54.0; H, 4.4; N, 9.0; C28H25BrN403S HCl 0.5H20 required C, 54.0; H, 4.4; N, 9.0%.

Example 91 Using an analogous procedure to that described in Example 20, 4- (6-bromonaphth-2-ylsulfonyl) -2-carboxy-1- [1- (4-pyridyl) piperidin-4-ylcarbonyl] piperazine is reacted with glycine methyl ester to give 4- (6-bromonaphth-2-ylsulfonyl) -2- [N- (methoxycarbonylmethyl) carbamoyl] -1- [1- (4-pyridyl) piperidin-4-ylcarbonyl] piperazine in a yield of 76% as a glass; NMR spectrum (CD3SOCD3, 100 ° C) 1.55-1.8 (m, 4H), 2.55-3.1 (m, 6H), 3.4 (m, ÍH), 3.65 (s, 3H), 3.7-3.95 (m, 4H) , 4.15 (m, 2H), 4.95 (m, ÍH), 6.75 (d, 2H), 7.7-7.9 (m, 3H), 8.05-8.15 (m, 4H), 8.3 (m, ÍH), 8.4 (d) , ÍH); Elemental Analysis Found C, 51.9; H, 5.0; N, 10.2; C29H32BrN506S 0.75H2O required C, 51.9; H, 5.0; N, 10.4%.

Example 92 Using a procedure analogous to that described in Example 2, 1- (4-piperidinylcarbonyl) -4- (4-pyridyl) piperazine is reacted with 6-bromonaphth-2-ylsulfonyl chloride to give 1- [1- (6-bromonaphth-2-ylsulfonyl) piperidin-4-ylcarbonyl] -4- (4-pyridyl) piperazine in a yield of 20 °, mp 229-230 ° C; NMR spectrum (CD3SOCD3) 1.6 (m, 4H), 2.3-2.7 (m, 3H), 3.5-3.8 (m, 10H), 6.8 (d, 2H), 7.8 (d, 2H), 8.2 (t, 4H), 8.4 (d, ÍH), 8.5 (d, ÍH). The 1- (4-piperidinylcarbonyl) -4- (4-pyridyl) -piperazine used as an initial material is obtained as follows: Di-tert-butyl dicarbonate (5.09 g) is added to a stirred mixture of piperidinic acid. 4-carboxylic (3 g), sodium carbonate (2.48 g), 1,4-dioxane (20 ml) and water (20 ml), which has been cooled to 0 ° C. The mixture is stirred at room temperature for 18 hours. The mixture is concentrated by evaporation of an original third volume and a saturated sodium bisulfate solution is added to bring the solution to pH 2 to 3. The mixture is extracted with ethyl acetate. The organic phase is washed with water and with brine, dried (MgSO 4) and evaporated to give 1-tert-butoxycarbonylpiperidin-4-carboxylic acid (4.36 g), which is used without further purification. Using a procedure analogous to that described in Example 14, a portion (1.41) of the material thus obtained is reacted with 1- (4-pyridyl) piperazine to give 1- (l-tert-butoxycarbonylpiperidin-4-ylcarbonyl) -4 - (4-pyridyl) piperazine in a yield of 20%. NMR spectrum (CD3SOCD3) 1.4 (s, 9H), 1.6 (m, 2H), 2.9 (m, 6H), 3.4 (s, 2H), 3.6 (d, 3H), 4.0 (m, 4H), 7.0- 8.0 (m, 4H). A mixture of the material thus obtained (0.45 g), 4N aqueous hydrochloric acid (2 ml) and diethyl ether (15 ml) is stirred at room temperature for 18 hours. The mixture is evaporated to give 1- (4-pipridinylcarbonyl) -4- (4-pyridyl) piperazine (0.31 g), which is used without further purification.

Example 93 The following illustrates representative pharmaceutical dosage forms, which contain the compound of the formula I, or a pharmaceutically acceptable salt thereof (hereinafter compound X), for therapeutic or prophylactic use in humans: (a) Tablet I mq / tablet Compound X 100 Lactose Ph.Eur 182.75 Croscarmellose sodium 12.0 Corn starch paste (paste 5% w / v) .... 2.25 Magnesium stearate 3.0 (b) Tablet II mq / tablet Compound X 50 Lactose Ph.Eur 223.75 Croscarmellose sodium 6.0 Corn starch 15.0 Polyvinylpyrrolidone (paste at 5% w / v) 2.25 Magnesium Stearate 3.0 (c) Tablet III mq / tablet Compound X 1.0 Lactose Ph.Eur 93.25 Croscarmellose sodium 4.0 Corn starch paste (5% w / v paste) .... 0.75 Magnesium stearate 1.0 (d) Capsule mg / capsule Compound X 10 Lactose Ph.Eur 488.5 Magnesium stearate 1.5 (e) Invention I (50 ra / ml) Compound X 5.0% w / v 1M sodium hydroxide solution 15.0% v / v 0.1M hydrochloric acid (to adjust the pH to 7.6) Polyethylene glycol 400 4.5% w / v Water for injection for 100% (f) Injection II (10 mq / ml) Compound X 1.0% p / v Sodium Phosphate BP 3.6% w / v Sodium hydroxide solution of 0.1M 15.0% v / v Water for injection for 100% (g) Injection III (1 mq / ml, buffered to pH6) Compound X 0.1% p / v Sodium phosphate BP 2.26% w / v Citric acid 0.38% w / v Polyethylene glycol 400 3.5% w / v Water for injection for 100% Note The above formulations can be obtained by conventional procedures well known in the pharmaceutical art. The tablets (a) - (c) can be enteric coated by conventional means, for example to provide a phthalate-cellulose acetate coating.

CHEMICAL FORMULAS (R1) m G1 = QZ N. VM '- A - CO - (T2? 4) G - L2 - NHRS MJ

Claims (10)

1. An aminoheterocyclic derivative of the formula I • characterized in that G1 is CH or N; G2 is CH or N; G3 is CH or N; m is 1 or 2; R1 is hydrogen, amino, halogen, cyano, C1-4 alkyl or C1-4 alkoxy; M1 is a group of the formula NR2_ 1_T1R3 wherein R 2 and R 3 together form a C 1 -C 4 alkylene group, L 1 is C 1 -C 4 alkylene, and T 1 is CH or N, and wherein 1 or 2 methylene groups within L 1 and the ring is formed when R 2 and R3 are attached, optionally bears an alkyl substituent of C-, _4; A is a direct bond for the carbonyl group, or A is C 1-4 alkylene; M2 is a group of the formula (T2R) r-L2-T3R5 wherein r is 0 or 1, T2 is CH or N, T3 is CH or N, R4 is hydrogen or C1-4 alkyl, R5 is hydrogen or C1-4 alkyl or R4 and R5 together form an alkylene group of C1-4, methylenecarbonyl or carbonylmethylene or R4 is an alkylene group of C2_3, which is attached to a methylene group within L2 forming a 5 or 6 membered ring that involves or implies R4 and T, or R5 is an alkylene group of C2_3, which are attached to a methylene group within L2 that forms a 5 or 6 membered ring involving R5 and T3, L2 is C1_4 alkylene, C3_g-1, 2-diyl cycloalkane, C1-3 alkylene - carbonyl or phenylene and, when r is 1, L2 can also be carbonyl-alkylene of C1-3 and in which 1 or 2 methylene groups within L2 and the rings formed, when R4 and R5, R4 and L2 or R ^ and L2 are optionally formed, they carry a substituent selected from the group consisting of oxo, carboxy, alkoxycarbonyl of 1-4, carbamoyl, N-alkylcarbamoyl of C1_4, N, N-di-alkylcarbamoyl of Cj ^, Pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, morpholinocarbonyl, piperazin-1-ylcarbonyl, 4-alkyl Ci-4 ~ piperazin-1-ylcarbonyl, N-phenylcarbamoyl, N-alkyl of C -, _ 4-N-phenylcarbamoyl, N - [phenyl-C 1-3 -alkyl] carbamoyl, N-C 1-4 -alkyl- N- [phenyl-C 1-3 -alkyl] carbamoyl, N- [hydroxy-C 2- carbamoyl] carbamoyl, N-C 1-4 -alkyl- N- [hydroxy-C2_3 alkyl] carbamoyl, N- [. { C-, 4-C2_3alkyl] -carbamoyl, N-C4_4-N- alkyl- [C1_4alkoxy-C2_3alkyl] carbamoyl, N- [carboxy- C-,] -carbamoyl-, N-alkyl- C1_4-N- [carboxy-Cn_] alkylcarbamoyl, N- [carboxy-C 1-3 alkyl] -N- [hydroxyalkyl of 2_3] -carbamoyl, N- [carboxy-alkyl of C-, _3] -N- [C 1-4 alkoxy-C2_3 alkyl] carbamoyl, N- [C 1-4 alkoxycarbonyl-C 1-3 alkyl] carbamoyl, N-C 1-4 alkyl-N- [C 1-4 alkoxycarbonyl-C 1-3 alkyl] carbamoyl, N- [alkoxycarbonyl C1_4- alkyl C - ^, -,] -N- [hydroxy-C2_3 alkyl] carbamoyl, N- [alkoxycarbonyl C 1-4 alkyl-N [C-L_4 alkoxy-C2_3 alkyl] carbamoyl, C 1-4 alkyl , carboxy-alkyl C 1-4, alkoxycarbonyl C 1-4 alkyl of C-L_4, carbamoyl-alkyl C-L_4, N-alkylcarbamoyl of C 1-4-alkyl C 1-4, N, N-di-alkylcarbamoyl of C 1-4-C1-4alkyl , pyrrolidin-1-ylcarbonyl-C1-4 alkyl, piperidinocarbonyl-C1-4 alkyl, morpholinocarbonyl-C1-4 alkyl, piperazi n-1-ylcarbonyl-C1-4 alkyloxy, 4-C1-4-piperazin-1-ylcarbonyl-C1-4alkyl, N-phenylcarbamoyl-C1-4alkyl, N- [phenyl-C1- ^ alkyl] ] carbamoyl-C1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy-1-4C and C 1-4 phenylalkyl, and wherein any heterocyclic group in the substituent optionally bears 1 or 2 substituents selected from the group consisting of 1-4C alkyl, C 1-4 alkoxy, carboxy, C 1-4 alkoxycarbonyl, carbamoyl, N-alkylcarbamoyl of 1-4 and N, N-di-C 1-4 alkylcarbamoyl of, and wherein any phenyl or phenylene group in M2 optionally bears 1 or 2 substituents selected from the group consisting of halogen, trifluoromethyl, Cl-4 and C1-4 alco-i; M3 is a direct link for X, or M3 is a group of the formula L3- (NR6) S wherein s is 0 or 1, R6 is hydrogen or C-j ^ alkyl, or R5 and R6 together form an alkylene group of C1-4, methylenecarbonyl or carbonylmethylene, or R6 is an alkylene group of C2_3, which is bonded to a methylene group within L3 which forms a 5- or 6-membered ring involving NR6, L3 is alkylene of C-L_4, cycloalkane of C3_g-1, 2- diyl, carbonyl-alkylene of 1-3 or phenylene and, when s is 1, L3 can also be alkylene of C - ^ - ^ - carbonyl, and in which 1 or 2 methylene groups within L3 and the rings formed when R5 and R6 or R6 and L3 are optionally attached, carries a substituent selected from the group consisting of oxo, carboxy, 1-4 alkoxycarbonyl, carbamoyl, N-alkylcarbamoyl of Cl-4 'N, N-di-alkylcarbamoyl of C1_4, pyrrolidine -1-ylcarbonyl, piperidinocarbonyl, holinocarbonyl, piperazin-1-ylcarbonyl, 4-alkyl-C1-4-piperazin-1-ylcarbonyl, N-phenylcarbamoyl, N-C1-4alkyl-N-phenylcarbamoyl, N- [phenyl-alkyl] C1-3] carbamoyl, N-C 1-4 alkyl-N- [phenyl-C 1-3 alkyl] carbamoyl, alkyl of 1-4, carboxy-C 1-4 alkyl, alkoxycarbonyl of 1-4-alkyl of c? -4 ' carbamoyl-alkyl d e ci-4 »? -C1-4alkylcarbamoyl-cyclo-4'N alkyl, N-di-alkylcarbamoyl C1-4 alkyl-pyrrolidin-1-ylcarbonyl-C1-4alkyl, piperidinocarbonyl-alkyl cl-4 'holinocarbonyl-C1-4-piperazin-1-ylcarbonyl-C1-4 alkyl, 4-alkyl of C-L4-piperazin-1-ylcarbonyl-C1-4alkyl, N-phenylcarbamoyl-alkyl C-, _ 4, N- [phenyl-C- ^ .- j-alkyl] carbaraoyl-alkyl of 1_4, hydroxyalkyl of C 1-4, alkoxy of C 1-4-C 1-4 alkyl and phenylalkyl of C 1-4, and in which any heterocyclic group in the substituent optionally carries 1 or 2 substituents selected from the group consisting of C-, 4-alkyl, C 1-carboxy-alkoxy, C 1-4 -alkoxycarbonyl, carbamoyl, C 1-4 -N-alkylcarbamoyl and N, N- di-alkylcarbamoyl of C4 and wherein any phenylene group in M3 optionally carries 1 or 2 substituents selected from the group consisting of halogen, trifluoromethyl, alkyl of 1-4 and C1-4 alkoxy; X is oxy, thio, sulfinyl, sulfonyl, carbonyl, carbonyloxy, carbonylamino, N-alkylcarbonylamino of 1-4, sulfonylamino, methylene, alkylmethylene of c4-4 di-alkyl-ethylene of C1-4 or, when T3 is CH and M3 is a direct bond for X, X can also be aminosulfonyl or oxycarbonyl; and Q is phenyl, naphthyl, phenyl-C1-4 alkyl, C2_4 phenyl-alkenyl, C2_4 phenyl-alkynyl, C5_7 cycloalkyl or a heterocyclic portion containing up to 4 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and Q optionally bears 1, 2 or 3 substituents selected from the group consisting of hydroxy, amino, halogen, cyano, trifluoromethyl, nitro, carboxy, carbamoyl, formyl, formimidoyl, formmo-hydroxymethyl, alkoxycarbonyl 1-4, C- alkyl, 4, c-4-N-alkylcarbamoyl alkoxy of 1,4-N, N-di-alkylcarbamoyl of 1_ ^, alkylamino of C 1-4, di-alkylamino of C 4 -4 alkanoylamino of C 2-4 < C2-4 alkanoyl »C2_4 alkanoimidoyl, C2_4 alkanoyl-hydroxy, phenyl, heteroaryl, phenoxy, phenylthio, phenylsulfinyl, phenylsulfonyl, heteroaryloxy, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, benzyl and benzoyl, and wherein the heteroaryl substituent or the group heteroaryl in a heteroaryl-containing substituent comprises a 5 or 6 membered monocyclic heteroaryl ring containing up to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and wherein the substituent phenyl, heteroaryl, phenoxy, phenylthio, phenylsulfinyl, phenylsulfonyl, heteroaryloxy, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, benzyl or benzoyl optionally carries 1, 2, 3 or 4 substituents selected from the group consisting of halogen, trifluoromethyl, cyano, trifluoromethoxy, nitro, C1_4alkyl, C1_4alkoxy, hydroxy, amino , carboxy, carbamoyl, C-, 4-alkoxycarbonyl, C1-4-N-alkylcarbamoyl, N, N-di-alkylcarbamoyl C-, 4, C 1-4 alkylamino, C 1-4 alkylamino, C 2-4 alkanoylamino, and tetrazolyl; or its pharmaceutically acceptable salt.

2. The aminoheterocyclic derivative of the formula I according to claim 1, characterized in that each of G1, G2 and G3 is CH, or each of G1 and G2 is CH and G3 is N, or G1 is N and each of G2 is and G3 is CH; m is 1 or 2 and each R1 is independently selected from hydrogen, amino, fluoro, chloro, bromo, cyano, methyl, ethyl and methoxy; M1 is a group of the formula NR2-L1-T1R3 wherein R 2 and R 3 together form an ethylene group, L 1 is methylene or ethylene and T 1 is CH or N, and wherein 1 or 2 methylene groups within L 1 and the ring formed when R 2 and R 3 are optionally attached bears a substituent selected from the group consisting of methyl and ethyl; A is a direct bond to the carbonyl group or A is methylene; M2 is a group of the formula (T2R) r-L2-T3R5 where r is 0 or 1, T2 is CH or N, T3 is N, R4 is hydrogen, methyl or ethyl, R ^ is hydrogen, methyl or ethyl or R4 and R5 together form a methyl, ethylene, trimethylene or methylenecarbonyl group or R4 is an ethylene group which is attached to a methylene group within L2 which forms a 5- or 6-membered ring involving R4 and T2, 'and L2 is methylene, ethylene, trimethylene, methylenecarbonyl or phenylene, and in the that 1 or 2 methylene groups within L2 and the ring formed when R4 and R5 are together optionally carries a substituent selected from the group consisting of oxo, carboxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl, N-methylcarbamoyl, N, N-dimethylcarbamoyl, pyrrolidine -1-ylcarbonyl, piperidinocarbonyl, morpholinocarbonyl, piperazin-1-ylcarbonyl, 4-methylpiperazin-1-ylcarbonyl, methyl, ethyl, carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, hydroxymethyl, methoxymethyl and benzyl, and wherein the substituent pyrrolidin-1-ylcarbonyl , piperidinocarbonyl, morpholinoca rbonyl, piperazin-1-ylcarbonyl or 4-methylpiperazin-1-ylcarbonyl optionally bears a methyl or ethyl substituent; M3 is a direct link to X, or M3 is a group of the formula L3- (NR6) wherein s is 1, R6 is hydrogen and L3 is carbonylmethylene or carbonylethylene; X is thio, sulfinyl, sulfonyl, carbonyl, carbonyloxy or methylene; and Q is phenyl, naphthyl, benzyl, phenethyl, styryl, 2-phenylethynyl, dibenzofuranyl, biphenylyl, pyridylphenyl or pyridylthienyl, and Q optionally bears 1, 2 or 3 substituents selected from the group consisting of hydroxy, amino, fluoro, chlorine, bromine , iodo, cyano, trifluoromethyl, nitro, carboxy, carbamoyl, methoxycarbonyl, ethoxycarbonyl, methyl, ethyl, methoxy and ethoxy; or its pharmaceutically acceptable salt.

3. The aminoheterocyclic derivative of the formula I according to claim 1, characterized in that each of G1, G2 and G3 is CH, or each of G1 and G2 is CH and G3 is N, or G1 is N and each of G2 is and G3 is CH; m is 1 or 2 and each R1 is independently selected from hydrogen, amino, chloro, methyl and ethyl; M1 is a group of the formula NR2_L1_T1R3 wherein R2 and R3 together form an ethylene group, L1 is ethylene, and T1 is CH or N; A is a direct bond with the carbonyl group or A is methylene; M2 is a group of the formula (T2R) T.-L2-T3R5 wherein r is O or 1, T2 is N, T3 is N, R4 is hydrogen, R5 is hydrogen, or R4 and R5 together form an ethylene group or R4 is an ethylene group which is attached to a methylene group within L2 forming a 5 or 6 membered ring involving R4 and T2, and L2 is methylene, ethylene or phenylene, and wherein 1 or 2 methylene groups within L2 and the ring formed when R4 and R5 are optionally attached, carries a substituent selected from the group consisting of carboxy, methoxycarbonyl, ethoxycarbonyl, pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, morpholinocarbonyl, piperazin-1-ylcarbonyl, 4-methylpiperazin-1-ylcarbonyl, methyl, ethyl and benzyl and wherein the substituent pyrrolidin -1-ylcarbonyl, piperidinocarbonyl, morpholinocarbonyl, piperazin-1-ylcarbonyl or 4-methylpiperazin-1-ylcarbonyl optionally bears a methyl or ethyl substituent; M3 is a direct link to X, or M3 is a group of the formulaL3- (NR6) wherein s is 1, R6 is hydrogen and L3 is carbonylmethylene; X is sulfonyl; and Q is phenyl, naphthyl, benzyl, phenethyl, styryl, 2-phenylethynyl, dibenzofuranyl, biphenylyl, pyridylphenyl or pyridylthienyl and Q optionally bears 1 or 2 substituents selected from the group consisting of fluoro, chloro, bromo, iodo, methyl, ethyl, methoxy and ethoxy; or its pharmaceutically acceptable salt.

4. The aminoheterocyclic derivative of the formula I according to claim 1, characterized in that G3 is CH or N and each of G1 and G2 is CH; m is 1 and R1 is hydrogen; M1 is a group of the formula NR2-L1-T1R3 wherein R2 and R3 together form an ethylene group, L1 is methylene or ethylene, and T1 is CH or N, and wherein 1 or 2 methylene groups within L1 and the ring formed when R2 and R3 are optionally attached, bears a substituent selected from the group consisting of methyl and ethyl; A is a direct bond with the carbonyl group or A is methylene; M2 is a group of the formula (T2R4) -L2-T3R5 wherein r is 1, T2 is CH or N, T3 is N, R4 is hydrogen, methyl or ethyl, R ^ is hydrogen, methyl or ethyl or R4 and R5 together form a methylene, ethylene or trimethylene group, or R4 is an ethylene group, which is attached to a methylene group within L2 which forms a 5- or 6-membered ring involving R4 and T2, and L2 is methylene, ethylene or trimethylene, and in which 1 or 2 methylene groups within L2 and the ring formed when R4 and R5 are optionally attached, carries a substituent selected from the group consisting of oxo, carboxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl, N-methylcarbamoyl, N, N-dimethylcarbamoyl, pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, morpholinocarbonyl, methyl, ethyl and benzyl and wherein the substituent pyrrolidin-1-ylcarbonyl or piperidinocarbonyl optionally bears one or two methyl or ethyl substituents; M3 is a direct link to X, or M3 is a group of the formula (NR6) wherein s is 1, R6 is hydrogen and L3 is carbonylmethylene or carbonylethylene; X is sulfonyl; and Q is 3- or 4-biphenylyl, which optionally bears, in the X-linked ring, 1 or 2 substituents selected from the group consisting of hydroxy, fluoro, chloro, bromo, cyano, trifluoromethyl, methyl, ethyl, methoxy and ethoxy and which optionally bears in the terminal phenyl group up to 4 substituents selected from the group consisting of fluoro, chloro, bromo, trifluoromethyl, cyano, trifluoromethoxy, methyl, ethyl, methoxy and ethoxy; or its pharmaceutically acceptable salt.

5. The aminoheterocyclic derivative of the formula I according to claim 1, characterized in that G3 is CH or N and each of G1 and G2 is CH; m is 1 and R1 is hydrogen; M1 is a group of the formula NR2-L1-T1R3 wherein R 2 and R 3 together form an ethylene group, L 1 is methylene or ethylene, and T 1 is CH or N, and wherein 1 or 2 methylene groups within L 1 and the ring formed when R 2 and R 3 are optionally attached, carries a substituent selected from the group consisting of methyl and ethyl; A is a direct bond with the carbonyl group or A is methylene; M2 is a group of the formula (T2R4) r-L2-T3R5 wherein r is 1, T2 is CH or N, T3 is N, R4 is hydrogen, methyl or ethyl, R5 is hydrogen, methyl or ethyl or R4 and R5 together form a methylene, ethylene or trimethylene group, or R4 is a ethylene group, which is attached to a methylene group within L2 which forms a 5 or 6 membered ring which involves R4 and T2, and L2 is methylene, ethylene or trimethylene, and in which 1 or 2 methylene groups within L2 and the ring formed when R4 and R ^ are optionally attached, bears a substituent selected from the group consisting of oxo, carboxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl, N-methylcarbamoyl, N, N-dimethylcarbamoyl, pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, morpholinocarbonyl, methyl, ethyl and benzyl and wherein the substituent pyrrolidin-1-ylcarbonyl or piperidinocarbonyl optionally bears one or two methyl or ethyl substituents; M3 is a direct link to X, or M3 is a group of the formula L3- (NR6) a wherein s is 1, R6 is hydrogen and L3 is carbonylmethylene or carbonylethylene; X is sulfonyl; and Q is benzyl, phenethyl, styryl or 2-phenylethynyl which optionally bears 1, 2 or 3 substituents selected from the group consisting of fluoro, chloro, bromo, cyano, trifluoromethyl, methyl, ethyl, methoxy and ethoxy; or its pharmaceutically acceptable salt.

6. An aminoheterocyclic derivative of the formula characterized in that each of G1 and G2 is CH, G1 is N and G2 is CH or G1 is CH and G2 is N; m is 1 and R1 is hydrogen; M1 is a group of the formula NR2-L1-T1R3 wherein R2 and R3 together form an ethylene group, L1 is ethylene, and T1 is CH or N; A is a direct bond with the carbonyl group; M2 is a group of the formula (T2R4) r-L2-T3R5 wherein r is 1, T2 is N, T3 is N, R4 is hydrogen, R5 is hydrogen, or R4 and R5 together form an ethylene group, and L2 is ethylene and wherein 1 methylene group within L2 optionally bears an substituent selected from carboxy, ethoxycarbonyl, N-methylcarbamoyl, piperidinocarbonyl, methyl and benzyl; M3 is a direct link to X, or M3 is a group of the formula L3- (NR6) in which s is 1, R6 is hydrogen and L3 is full carbonylmet; X his I I oni I; and Q is 2-naphlyl, which optionally carries 1 or 2 substituents 1 believed to be of the group consisting of fluoro, chloro, bromo, t-i, loromethyl, methyl, methoxy and ethoxy; or its addition salt to be rmachefically acceptable. .

7. The aminoheterocyclic derivative of the formula I according to claim 1, characterized in that it is selected from 2- (2-naphthalenesulfonamido) -N-. { 1-piperidinocarbonyl-2- [l- (4-pyridyl) piperi din-4-ylcarbonylamino] ethyl} acetamide, 1 - (. '- ni I Li] sulphyl) -4- [i- (4-pyridyl) piperidin-4-ylcarbonyl] - i pe i azine, 2- (2-naEtalenesulfonamido) -N- (1 -piperidinocarbonyl-2- {2- [l- (4-pyridyl) piperidin-4-yl] acetamido Jetyl) acetamide, 2- [2 n ti! alensulfonamido) -N-. { 1-piperidinocarbonyl-? ' -. { 2 - [4 - (4 iii (ii I) i peraxin- J - i 1 I ncetamido.} Ethyl) acetamide, 2 ('n-or I to Lensulfonamido) -3 - [1- (4-pyridyl) - plperidin-4 jlai emi lamino] ethyl propionate, 1- [1 - (A-naphthylsulfonyl) piperidi-4-ylcarbonyl] -4- (4-pyridyl) -piperazine, 2- (2-naphthansulfonamido) -N- . { 1-pheny1-3- [1- (4-pyridyl) p Lipoi idin 4-j 1 caiboni lamino] prop ~ 2-il} ethyl) acetamide, 4- [1- (pyridyl) piperidin-4-ylcarbonyl] -1- [(E) -styrylsulfonyl] -piperazine, 1- [(E) 4-chlorostyrylsulfonyl] -4- [1- (4 -pyridyl) -piperidin-4-i 1-r-atonyl] piperazd-na, l (K) 4-methylsyrylsulphonyl] -4- [1- (4-pyridyl) -piperidin-4-ylcayl] piperazine, 4- [(E) -4-chlorostyrylsulfonyl] -2-methyl-l- [1- (4-pyridyl) piperidin-4-ylcarbonyl] piperazine, 1- (4-phenylsulfonyl) -4- [1- (4-pyridyl) piperidin-4-ylcarbonyl] -piperazine, 1- (4 '-rubo-4-biphenylylsulfonyl) -4- [1- (4-pyridyl) -piperidin-4- iJ c boni]] piperazine, 1- [(E) -4-chlorostyrylsulfonyl] -4- [1- (4-pyrimidyl) -piperidin-4-ylcarbonyl] piperazine, 1- (7-rhloronaphth-2-ylsulfonyl) -4- [1- (4-pyridyl) -piperidine- 4-i-1-carbonyl] -piperazine, 2-et'oxi-rrbonyl-4- (2-naphthylsulfonyl) -1- [1- (4-pyridyl) piper idin -carbonyl] pi-erazin, 1- (2-naphthylsulfonyl) -4 - [1- (4-pyrimidinyl) piperidin-4-ylcarbonyl] -pipej zine; 1 L (E) 4 fluorostyl ilsulfonyl] -4- [1- (4-pyridyl) -piperidin-4-ylcarbonyl] piperazine, 1- [(E) -4-bromoestiryl sulphonyl] -4- [1- (4 - pyridyl) -p -peridin-4-ylcarbonyl] iperazine, 1- (4'-bromo-4-biphenylylsulfonyl) -4- [1- (4-pyridyl) piperidin-4-ylcarbonyl] iperazine, 1- (6- chloronaphth-2-ylsulfonyl) -4- [1- (4-pyridyl) -piperidin-4-ylcarbonyl] piperazine, 1- (G-bromonaphth-2-ylsulfonyl) -4- [1- (4-pyridyl) -piperidine -4-carbonyl] piperazine, 1- (u-1-oronaphth-2-ylsulfonyl) -4- [4- (4-pyridyl) -piperidin-1-ylcarbonyl] piperazine, 4-. { 2-na ii 1sulfonyl) -2-piperidinocarbonyl -1- [1- (4-pyridyl) -pipe in 4-ylcarbonyl] piperazine, 4- (b-chloronaphth-2-ylsulfonyl) -2-ethoxycarbonyl-1- [1- (4-pyridyl) -pi pei i din -4 -ylcarbonyl] piperazine, 2-carboxy-4- (6-chloronaphth-2-ylsulfonyl) -1- [1- (4-pyridyl) piperidin-4- ilcarbonyl] piperazine, 1- [G -c loronaft-2-ylsulfonyl) -4- [1- (4-pyrimidinyl) -piperidin-4-yl carbonyl] piperazine, 4- [1 - (-aminopyrimidin-4-yl) piperidin-4-ylcarbonyl] -1- (-c 1 -oneone-2-ylsulfonyl) iperazine, or 1- (f.-cloi? paf [- 2-ylsul-fonyl] -4- [1- (4-pyridazinyl) -piperidin-4 - i 1 caibonyl] piperazine; 4- ((, -ht oinon l t. -2 -ylsulfonyl) -2-ethoxycarbonyl-1- [1- (4-pyridyl) -piperLdin-4-ylcarbonyl] piperazine, 4- ((-> -bromonaft- 2-ylsulfonyl) -2-carboxy- [1- (4-pyridyl) piperi din-4-ylcarbonyl] piperazine, 4- (r. -bromonaphth-2-ylsulfonyl) -2-morpholinocarbonyl-1-- (4-pyridyl) piperidin-4-ylcarbonyl] piperazine, 4- (6-chloronaphth-2-ylsulfonyl) -2-methoxycarbonyl-1- (1- (4-pyridyl) -J pe iiin 4-ylcarbonyl] piperazine, and 2-RaLboxL 4 - (b-chloronaphth-2-ylsulfonyl) -1- [1- (4-pyridyl) pipe i din -ylcarbonyl] piperazine; or its pharmaceutically acceptable salt.

8. A step for the preparation of an aminoheterocyclic derivative of formula I or formula la, or its pharmaceutically acceptable salt according to any of claims 1 to 5, characterized in that they comprise: (a) for the production of those compounds of the formula I or formula la, wherein M2 is a group of the formula (T2R4) r-L2-T3R5 in which T2 is? < and r is 1, the reaction of an acid of the formula I I, or its reactive reaction cell, with an amine of the formula HNR4-L2-T3R5-M3-X-Q (b) for the production of those compounds of the formula I or formula la, wherein M2 is a group of the formula [T2R4 --L2-T3R5 wherein T3 is N, and where M ^ is a direct bond with X, the reaction of an amine of formula II E with a compound cié the formula Z-X-Q, in which Z is a replaceable group; (c) for the production of those compounds of the formula I or the formula la, wherein M1 is a group of the formula NR2_ 1_T1R3 in which T1 is N, and in which? is a direct link to the carbonyl group, the reaction of an amine of formula IV L NHR3 IV with an acid of the formula H02C-M2-M3-X-Q or its reactive derivative; (d) for the production of those compounds of the formula I or the formula la, wherein M2 is a group of the formula (T2R4) r-L2T3R5 in which T ^, j N, and in which M ^ is a group of the formula L3- (NR6) ^ in which L3 is carbonylmethylene, the reaction of an amine of formula III with an acid of the formula H02C-CH2- (NR6; X-Q or its reactive derivative; (e) pa to the production of those compounds of the formula T or the formula la, in which M2 is a group of the formula (T2R4) r-L2-T3R5 wherein T3 is N, and where M ^ is a direct bond with X and X is carbonylamino, the reaction of an amine of formula III with an isocyanate of the formula OCN-X-0 (f) the i e ction of U composed of the formula V wherein Z is a replaceable group, with an amine of the formula HNR2-L1-T1R3-A-CO-M2M3-X-Q (g) for the production of those compounds of formula I or formula la, wherein M 2, M 3 or Q bears a carboxy or carboxy-containing group, the hydrolysis of a compound of formula I, wherein M, M3 or Q carries an alkoxycarbonyl group of C-1_4; (h) for the production of those compounds of formula 1 or formula Ta, wherein M, M3 or Q bears a carbamoyl, N-alkylcarbamoyl, or N, N-dialkylcarbamoyl group, the reaction of a compound of the Formula I, wherein M2, M3 or Q carries a carboxy group, or its reactive derivative, with ammonia or an appropriate dialkylamine or alkylamine; or (i) pa to the production of those compounds of the formula 1 or the formula la, wherein Q carries a hydroxy group, the desu I < a compound of the formula I, wherein a C1_4 alkoxy group is; and when a pharmaceutically acceptable salt of a compound of the formula I is required, it can be obtained by the reaction of the compound with a suitable base or acid using a conventional procedure; 2 4 and when an optically active form of a compound of the form I is required, it can be obtained by carrying out one of the procedures. previous using an initial optically active mife i or by resolution of a racemic form of the compound using a conventional procedure.

9. A pharmaceutical composition which is characterized by either an aminoheterocyclic derivative of the formula I or the formula la, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 7 in association with a pharmaceutical diluent or carrier Quite acceptable.

10. The use of an aminoheterocyclic derivative of formula 1 or formula la, or its pharmaceutically acceptable salt according to any one of claims 1 to 7, in the production of a medicament for use in producing an anticoagulant or antithrombotic effect.