SK8394A3 - Fivemembers heterocyclecs method of their production and medicine containing these matters - Google Patents

Abstract

The invention relates to 5-membered heterocycles of the general formula <IMAGE> in which X1 to X5 are as defined in Claim 1, tautomers thereof, stereoisomers thereof including mixtures thereof and salts thereof, in particular physiologically tolerable salts thereof with inorganic or organic acids or bases, which have useful pharmacological properties, preferably aggregation-inhibiting actions, medicaments containing the compounds and processes for their preparation.

Description

The invention relates to the general formula I relates to five-membered heterocycles having all ^X 1 /

^X 2 \

^X 5 (I) ^X 3 ^X 4 of their tautomers, their stereoisomers, including mixtures thereof, and their salts, in particular their physiologically acceptable salts with inorganic or organic acids or bases, which exhibit, inter alia, valuable pharmacological properties, in particular aggregation suppressing drug, drug, containing these compounds and processes for their preparation.

In the above general formula I means

(i) provided that the five-membered heterocyclic ring is not a pyrrolidine, pyrolinone or pyrrolidinone ring and contains at least one carbon atom; and (ii) with the exception of 3- (4-amidinophenyl) -1- [4- (2-aminocarboxyethyl) compounds phenyl] -2H-pyrazol-5-one and 3- (4-amidinophenyl) -

1- [4- (2-amino-2-methoxycarbonyl-ethyl) phenyl] -2H-pyrazol-5-one means one of the radicals to a group of formulas

A - B - C - N <

A-B-C-CH 2 or A-B-C-C 2 in which

A is optionally 1 to 4 alkyl groups, once hydroxy-, alkoxy-, phenylalkoxy-, cyano-, aminocarbonyl-, carboxy-, alkoxycarbonyl- or phenylalkoxycarbonyl-substituted cycloalkyl of 5 to 7 carbon atoms, in which one unsubstituted methylene group is replaced R _and -Nc, wherein

R _&lt; 6 _& gt _; represents a hydrogen atom, an alkyl group, a phenylalkyl group, a total of 2 to 6 carbon atoms, a phenylalkoxycarbonyl group, an alkenyloxycarbonyl group of 4 to 6 carbon atoms, a cycloalkoxycarbonyl group of 6 to 8 carbon atoms or An -O- (1H) -O-CO-group wherein

R ^ is C znamená-C alky alkyl, C až-C cyk cycloalkyl, phenylalkyl, C až-C alko alkoxy, C až-C cyk cycloalkoxy or phenyl; and

R 2 is hydrogen, C 1 -C 4 alkyl, C 5 -C 7 cycloalkyl or phenyl, and in the 6- or 7-membered azacycloalkyl groups so formed, one> CH-unit at the 4-position can be replaced by an atom nitrogen or in the 5- to 7-membered azacycloalkyl groups thus formed, one -CH2-CH <unit may be replaced by a -CH = C <unit and in the piperazinyl or homopiperazinyl rings thus formed the methylene group adjacent to the 4-nitrogen atom may be replaced by carbonyl group,

- a pyridyl or quinuclidinyl group or also when

D represents R ₃ R ₄ N-CO-NR 5 - or R 8 -SO ₂ -NR ₃ -substituted alkylene or alkenylene of up to 8 carbon atoms in each case wherein _{d 1} to R 6, which may be the same or different, each represent a hydrogen atom, an alkyl group or a phenylalkyl group and

R 8 is C 1 -C 5 alkyl, phenylalkyl or phenyl; or

E represents hydroxy-, alkoxy-, alkylsulfenyl-, r ₃ r ₄ n-, r ₃ o-co-, r ₆ co-nr ₃ -, r ₆ o-co-nr ₃ -, r ₆ so ₂ -nr ₃ or R ₃ R ₄ N-CO-NR 8 -substituted by a straight or branched alkylene or alkenylene group of up to 5 carbon atoms each where R ₃ to R 8 are as defined above, a phenyl group which is substituted in the 4-position by RNH-CH ₇ - or R is NH-C (= NH) - or a phenyl group to which it is attached via two adjacent carbon atoms by the R _& NH-group. a substituted n-alkylene bridging group having 3 or 4 carbon atoms, wherein R _{a is} each as defined above,

B represents a bond, an alkylene group, -CH ₂ -, -CH ₂ O-, -SCH ₂ -, -CH ₂ S-, -CONR ₃ -, -R ₃ NCO-, -CH ₂ NR ₃ -, NR ₃ CH _{A 2-} , -SO ₂ NR ₃ - or -NR ₃ SO ₂ - group wherein R ₃ is as defined above and the oxygen or nitrogen atom of residue B is not directly linked to the nitrogen atom of residue A or a five-membered heterocycle,

C represents a phenyl group which may be mono- or disubstituted by a fluorine, chlorine or bromine atom, an alkyl, trifluoromethyl, hydroxyl, alkoxy, alkylsulfenyl, alkylsulfinyl or alkylsulfonyl group, the substituents being the same or different, pyridinylene, pyrimidinylene or pyrazinylene a pyridazinylene group which may in each case be substituted in the carbon residue by a chlorine atom, an alkyl or alkoxy group,

1,4-cyclohexylene-, 1,3-piperidinylene-, 1,4-piperidinylene- or 1,4-piperazinylene, or even if A is not a pyridyl group and at the same time B is an alkylene-, -CONH- or -CF2S- group , wherein at the same time B can only represent a bond when A is an amidinophenyl group, the other of the radicals X 1 to X ₃ represents a group of formulas

R _b 0 -CO-E-D-N <,

R _b 0 -CO-E-D-CH <or

R _b 0 - CO - E - D - C s where

D is -CO-NR -, -NR -CO-, -SO 2 NR 3 or -NR ₃ -SO 2 group, or hydroxy, alkoxy, alkylsulfenyl-, R3R4N-, _R3 O-CO-, R ₆ CO-NR ₃ -, R ₆ O-CO-NR ₃ -, R ₆ SO ₂ -NR ₃ - or

R ₃ R ₄ N-CO-NR 4 -substituted straight or branched alkylene or alkenylene in which the alkylene moiety can each contain 1 to 8 carbon atoms and the alkenylene moiety has 2 to 8 carbon atoms and R ₃ to R 8 are as defined above, phenylene a group which may be mono or disubstituted by a fluorine, chlorine or bromine atom, an alkyl-, trifluoromethyl-, hydroxy-, alkoxy-, alkylsulfenyl-, alkylsulfinyl- or alkylsulfonyl group, pyridinylene-, pyrimidinylene-, pyrazinylene-, pyridazinylene or triazinylene group in each of the carbon radicals, they may be substituted by a chlorine atom, an alkyl or an alkoxy group, in addition one or two -CH = N- groups may be replaced by a -CO-NR3-group, wherein R3 is as defined above and one of the nitrogen atoms it can also be bonded to the radical E instead of the radical R1, provided that it does not represent a bond and is not attached via an oxygen atom; or the sulfur atom to the radical D or may be attached to the ring atom of any one of the radicals to an optionally alkyl, phenylalkyl or phenyl substituted cycloalkylene group having 4 to 5 carbon atoms in which one> CH-unit may be replaced by a nitrogen atom and a methylene group , adjacent to the nitrogen atom may be replaced by a carbonyl group, optionally an alkyl, phenylalkyl or phenyl substituted cycloalkylene group having 6 or 7 carbon atoms, in which one or two> CH-units may be replaced by a nitrogen atom, in addition one or two methylene in each case groups adjacent to a nitrogen atom may be replaced by a carbonyl group or a C 1 -C 5 alkylene group linked via the radical V V £ to a ring atom of any one of the radicals to X,, where V- ^ is NR -, where R ^ ^ is is as defined above, wherein the oxygen or sulfur atom the residue cannot be directly attached to the nitrogen atom of the five-membered ring,

E represents a bond, and at the same time does not represent a C bond and A represents a 1-methyl- or 1-benzyl-4-piperazinyl group or, optionally, hydroxy-, alkoxy-, alkylsulfenyl-, R RR N-N-, R ^O-CO-, RgCO -NR 1 -, R 6 SO 2 -NR 3 - or R 1 R 1, N-CO-NR 3 - substituted or unsubstituted alkylene or alkenylene, in which the alkylene moiety may each contain 1 to 5 carbon atoms and the alkenylene moiety 2 to 5 carbon atoms; R 3 to R 8 are as defined above, or

- 6 through a radical linked ^{to the} group D alkylene group, wherein represents O, S, sulfinyl, sulfonyl, NR ₃ -, - (R ₆ CO) m - (R ₆ SO ₂₎ N, -CONR _3- or -NR ₃ CO, wherein R ₃ and R 8 are as defined above, and when the oxygen or sulfur atom of the radical V ₂ is not directly attached to the nitrogen atom of the radical D and

R ^ represents a hydrogen atom, an alkyl group having from 1 to 5 carbon atoms, an alkenyl group having from 3 to 5 carbon atoms, a phenylalkyl group having from 1 to 3 carbon atoms in the alkyl moiety, a cycloalkyl or cycloalkylalkyl group having from 5 to 7 carbon atoms each or a group R 1 -CO-O- (R ₂ CH) - in which R y and R ₂ are as previously defined, wherein the distance between the furthest nitrogen atom of the group A and the COOR 4 group is at least 11 bonds, the third of residues X y to X 8 represents a sulfur atom, HN,, R gN,, RyC 5 or a (Ry) ₂ C skupinu group or an N-atom, where R g is as previously defined and Ry represents a hydrogen atom, alkyl-, phenylalkyl-, phenyl-, alkoxy-, R ₃ R 4 N-, R ₃ OCO- or R ₃ R 4 N-CO-, wherein R ₃ and R 4 are as previously defined, the fourth of X y to X 8 is oxygen, sulfur or nitrogen or RyC; wherein Ry is as previously defined or also a carbonyl group, unless it is between two and a Toma nitrogen, the fifth residue of the radicals X? and X $ is N, spade ^ or (R y) ₂ C <group, wherein R y is as defined above, or else two adjacent radicals of the radicals X? and X g together are an o-phenylene group, wherein, unless otherwise specified, the above alkyl, alkylene and alkoxy moieties may each contain 1 to 3 carbon atoms.

Thus, for example, furan-, tetrahydrofuran-,

2,3-dihydrofuran-, 2,5-dihydrofuran-, thiophene-, 2,3-dihydro-thiophene-, 2,5-dihydrothiophene-, tetrahydrothiophene-, 1,2-dithiolane-, 1,3-dithiolane-, pyrrole-, indole-, isoindole-, 2,3-dihydroindole-, 2,3-dihydroisoindole-, 2-indolone-, imidazole-, 4,5-dihydroimidazole-, tetrahydroimidazole-, benzimidazoline-, pyrazole-, 2H-pyrazole -5-one-, 4,5-dihydropyrazole-, 2,3-dihydropyrazole-, indazole-, 2,3-dihydroindazole-, oxazole-, isoxazole-, oxazoline-, oxazolidine-, thiazole-, isothiazole-, thiazoline, thiazolidine, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,2,3-triazole,

1,2,4-triazole and tetrazole derivatives.

Preferred are those compounds of formula (I) above wherein one of X 1 to X 8 is a group of formulas

A-B-C-N <

A - B - C - 'CH <or A-B-C-C <where

A is optionally 1 to 4 alkyl groups, hydroxy, alkoxy, cyano, aminocarbonyl, carboxy or alkoxycarbonyl substituted of 5 to 7 carbon atoms in which one unsubstituted methylene group is replaced by R _and -N < wherein hydrogen is alkyl, phenylalkyl, C 2 -C 6 alkoxy, C 6 -C 8 phenylalkoxycarbonyl, or R 1 -CO-O- (R 2 CH) -O- -CO-group wherein

R 6 represents an alkyl group, a C 5 -C 7 cycloalkyl group, a C 1 -C 5 alkoxy group, a C 5 -C 7 cycloalkoxy group or a phenyl group; and

R2 represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, and in addition, in the 6- or 7-membered azacycloalkyl groups thus formed, one> CH-unit at the 4-position can be replaced by a nitrogen atom or 5-7-membered azacycloalkyl groups thus formed. one -CH2-CH <unit may be replaced by a -CH = C <unit, a pyridyl or quinuclidinyl group or also when

D is R 3 R 4 N-CO-NR 5 - or R 8 -SCN-NR 4 -substituted alkylene of 1 to 5 carbon atoms, wherein:

R 1 to R 8, which may be the same or different, each represent a hydrogen atom, an alkyl or phenylalkyl group, and

R 8 is C 1 -C 5 alkyl, phenylalkyl or phenyl; or

E is R3R4N-, R8CO-NR4-, R8SC4NR1-,

R3R4N-CO-NR 5, hydroxy or alkoxy substituted alkylene group having 1 to 5 carbon atoms, wherein R 3 and R are as defined above, phenyl which is substituted in the 4-position R-NH CH _O -, or R "NH -C (= NH) - or a phenyl radical, which is between positions 3 and 4 in place of n-propylene and n-butylene bridge, n-propylene and n-butylene bridge is substituted by R _a NH group and R is each _and the above meaning,

B represents a bond, -CH 2 -CH 2 -, -OCH 2 -, -CH 2 O-, -CONR 4 - or R 4 NCO-, wherein R 4 is as defined above and the oxygen or nitrogen atom of residue B is not directly linked to the nitrogen atom residue A or a five-membered hetero-ring,

C represents a phenyl group which may be mono or disubstituted by a fluorine, chlorine or bromine atom, by an alkyl, trifluoromethyl, hydroxyl or alkoxy group, wherein the substituents may be equal or different, ⁹ pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene, wherein the carbon moiety may in each case be substituted by an alkyl or alkoxy group,

1,4-cyclohexylene-, 1,4-piperidinylene- or 1,4-piperazinylene or, if A is not a pyridyl group and B is not an ethylene- or -CONH- group, at the same time B can only be a bond when A is an amidinophenyl group, the other of the radicals to represents a group of formulas

4 R _b 0 - WHAT - E - D - N <, R _b 0 - WHAT - E - D - CH < or • R _b 0 - WHAT - E - D - C ž, where

D is -CO-NR3- or NR4 -CO-, optionally hydroxy-, alkoxy-, R3R4N-, R3O-CO-, R8CO-NR4-, R6O-CO-NR1-, R6SO2-NR3- or R3R4N- A CO-NR 5 -substituted straight or branched alkylene or alkenylene group, wherein each alkylene moiety may contain 1 to 5 carbon atoms and the alkenylene moiety 2 to 5 carbon atoms and R 3 to R 8 are as defined above, a phenyl group which may be mono or disubstituted by fluorine, chlorine or bromine, alkyl-, trifluoromethyl-, hydroxy- or alkoxy groups,

- a pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene group which in each case may be substituted in the carbon residue by an alkyl or alkoxy group, a cyclohexyl group in which one or two> CH-units may each be replaced by a nitrogen atom, the methylene group adjacent to the carbonyl group can be replaced by a carbonyl group or through a group containing any atom of the residues X ^ and contained in a circle, linked alkylene having 1 to 4 carbon atoms, wherein W represents NR ¹ -group, wherein R is as defined above, a hydrogen an oxygen or sulfur atom, wherein the oxygen or sulfur atom of the residue cannot be directly attached to the nitrogen atom of a five-membered heterocycle,

E represents a bond, at the same time C cannot be a bond and A 1-methyl- or 1-benzyl-4-piperazinyl or optionally hydroxy-, alkoxy-, ^R 3 ^R 4 N-, ^R 8 CO-NR 4 -, ^R 6 ^SO 2 ^-NR 3 ' or R ^R ^ NN-CO-NR ^-substituted or straight-chained or branched alkylene of 1 to 5 carbon atoms, where R až-Rg are as defined above or the alkylene group linked via the radical V V V V represents an oxygen or sulfur atom, (RGSC ^ N group wherein R 3 and R are as to the group D, wherein NR ₃ -, - (R ₆ CO) n, as defined above and wherein the oxygen or sulfur atom V 2 moiety is directly attached to the nitrogen atom of the residue D and

R is H, alkyl having 1 to 5 carbon atoms, phenylalkyl having 1 to 3 carbon atoms in the a'lkylovej parts, cycloalkyl having 5 to 7 carbon atoms, or R-CO-O- (CH ₂ R) - a group in which R 1 and R ₂ are as previously defined, wherein the distance between the furthest nitrogen atom of the A group and the COOR 4 group is at least 11 bonds, the third of X y to X 8 being HN <, RgN <, RyC ^ or R ₇ ) is a C ₂ group or an N-atom where R 8 is as defined above and Ry is a hydrogen atom, an alkyl or phenyl group, the fourth of Xy to X 4 is an oxygen, sulfur or nitrogen atom, or a RyC 6 group where Ry is as defined above, the fifth of the radicals X g and X? = N, spade ^ or (R y) ₂ C <group, wherein R y is as defined above, or else two adjacent radicals of the radicals X g and X ^ together are O- a phenylene group, especially those compounds wherein one of the residues Xy to Xg is s formula

A-B-C-N <or

A-B-C-C =? Where

A is optionally substituted by 1 to 4 methyl, hydroxy, methoxy, cyano or aminocarbonyl substituted 1,3-pyrrolidinyl, 1,3-piperidinyl or 1,4-piperidyl groups, wherein said pyrrolidinyl and piperidinyl groups are in the position 1 substituted with R &lt; a _&gt;

R _a represents a hydrogen atom, a methyl group, an ethyl group, a benzyl group or an alkoxycarbonyl group having a total of 2 to 6 carbon atoms,

1,4-piperazinyl- or 3,4-dehydro-1,4-piperidyl, each of which is substituted in the 1-position by R &lt; a _& gt _; and R _& lt _; 2 _& gt _; , a pyridyl or quinuclidinyl group, or else when

- 12 D represents an R 8 -SC 1 -NR 4 -substituted ethylene group wherein

R ₃ is H, methyl or ethyl and

R 8 is C 1 -C 5 alkyl or phenyl or E is amino, R 8 CO-NR 6 -, R 8 S 5 -NR 6 - or hydroxy substituted ethylene, where R ₃ to R 8 are as defined above, phenyl which is substituted in the 4-position by R _and NH-C (= NH) -,

B represents a bond, -CH 2 -CH 2 -, -OCH 2 -, -CH 2 O-, -CONR 8 - or R 4 NCO-, wherein R 8 is as defined above and the oxygen or nitrogen atom of residue B is not directly linked to the nitrogen atom of residue A or a 5-membered heterocycle,

C represents a phenyl group which may be substituted by a chlorine atom or a methyl group, a pyridinylene, a pyrimidinylene, a pyridazinylene or a 1,4-piperidinylene group, or else, if A is not a pyridyl group and B is not an ethylene or -CONH group, a bond, where at the same time B can only represent a bond when A represents an amidinophenyl group, the other of the radicals X 1 to X 8 represents a group of formulas

R _fe 0 - CO - E - D - N <, or

R _b 0 -CO-EDC <, where

D represents a -CO-NR6- or NR8-CO- group wherein R8 has the above

- a defined meaning or desire or a branched alkylene group having 1 to 5 carbon atoms, a RgSC 1 -NR 3 - substituted ethylene group, a phenyl group which may be substituted by a chlorine atom or a methyl group,

A 1,4-cyclohexylene group or via an -NR 4 -group, where R 4 is as defined above, a C 1 -C 4 alkylene group attached to the ring atom of any of the radicals X 1 to X 1,

E represents a bond, wherein at the same time C is not a bond and A is a 1-methyl- or 1-benzyl-4-piperazinyl group or an optionally R8CO-NR4- or R8SC4NR6-substituted ethylene group, where R8 to R8 have already defined meaning, or

-O-CH 2 - or -NR 1 -C 1 - wherein R 1 is as defined above and

R ^ is hydrogen, C až-C až alkyl or C až-C cyk cycloalkyl, wherein the distance between the furthest nitrogen of the A group and the COOR skupinou group is at least 11 bonds, the third of X ^ to Xg being HN < , RgN <or RyCs group or N-atom, where Rg is as defined above and Ry is hydrogen, methyl or ethyl, the fourth of Xy to Xg is nitrogen, sulfur or oxygen, or RyC6, where Ry has already as defined above, the fifth of the radicals Xy to Xg represents a nitrogen atom, a RyC3 group wherein Ry is as defined above, or also two adjacent radicals of radicals to Xg together represent an o-phenylene group, their tautomers, their stereoisomers including mixtures thereof and salts thereof, in particular their physiologically acceptable salts with inorganic or organic acids or bases.

Particularly preferred compounds of the formula above are those wherein the first of the radicals X 1 to X 8 is a group of the formula

A-B-C-N <or

A-B-C-C 1, wherein

A is in the 1-position by R _{and a} substituted 4-piperidyl group wherein

R _represents hydrogen, benzyl or alkoxycarbonyl group with a total of 2 to 6 carbon atoms,

A 1,4-piperazinyl group which at the 1-position is substituted with the radical R _a , where R _a is as defined above, or also when

D is R-S0 ₂ -NR-substituted ethylene group, wherein

R 8 represents a hydrogen atom and

R 8 represents a C 1 -C 5 alkyl group, a phenyl group which is substituted in the 4-position by a group

NH ₂ -C (= NH) -,

B represents a bond, -CH ₂ -CH ₂ - or -CH ₂ O-group,

C represents a phenylene or 1,4-piperidinylene group or, if B does not simultaneously represent a bond, also a bond, the other of the residues Xy to X ^ represents a group of formulas

R _b 0 - CO - E - D - Ca where

D is -CO-NH-, alkylene of 1 to 5 carbon atoms, phenylene, 1,4-cyclohexylene or R8-SO2 -NR6-substituted ethylene,

E represents a bond wherein simultaneously C cannot be a bond and A is a 1-benzyl-4-piperazinyl or ethylene group; or

R _b represents a hydrogen atom or a C 1 -C 4 alkyl group wherein the distance between the furthest nitrogen atom of the group A and the COOR _b group is at least 11 bonds, the third of the radicals X ^-X $ represents a phenyl-N <or RyC ^ group; N-atom where Ry is hydrogen, methyl or ethyl, the fourth of Xy to X $ is nitrogen, sulfur or oxygen, or the RyCs group where Ry is as previously defined, the fifth of Xy to X $ is nitrogen , their tautomers, their stereoisomers, including mixtures thereof, and their salts, in particular their physiologically acceptable salts with inorganic or organic acids or bases.

The following are particularly preferred compounds:

(i) 2- (trans-4-carboxy-cyclohexyl) -5- [4- (4-piperidyl) phenyl] -1,3,4-thiadiazole; (ii) 2- [trans-4- (methoxycarbonyl) cyclohexyl] - 5- [4- (4-piperidyl) phenyl] -1,3,4-thiadiazole, iii) 1- [6- (4-amidinophenyl) -3-pyridazinyl] -4- [2- (n-butanesulfonylamino)] Iv) 1- [6- (4-amidinophenyl) -3-pyridazinyl] -4- [2- (n-butanesulfonylamino) -2- (methoxycarbonyl-ethyl) imidazole,

v) 2- [trans -4- (isobutylcarbonyl) cyclohexyl] -5- [4- (4-piperidinyl) phenyl] -1,3,4-thiadiazole; and vi) 2- [trans -4- (ethoxycarbonyl)] cyclohexyl] -5- [4- (4-piperidyl) phenyl] -1,3,4-thiadiazole, and salts thereof.

According to the invention, the compounds are obtained, for example, by the following methods:

(a) for the preparation of a compound of formula (I), wherein the second of the radicals to Xg is R _b O-CO-ED-CH? or

R ^ O-CO-E-D-C ^ group:

Reaction of a compound of formula II

Χ _χ / \

X ₂ Xg (II) \ / x ₃ - x ₄ where

X-E to Xg are as defined above, with the restriction that the second residue of X-E to Xg is a HO-CO-CH <or HO-CO-Os group or a reaction-capable derivative thereof, with a compound of formula III

R _b 0 -CO-E-HNR 8 (H 1) where

R g, R _b and E are as defined above.

The reaction is preferably carried out in a solvent or solvent mixture such as methylene chloride, dimethylformamide, dimethylsulfoxide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane, optionally in the presence of water-withdrawing agents, e.g. in the presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, hydrochloric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphorus trichloride, phosphorus pentachloride, N, N'-dicyclohexylcarbodiimide, N, N'-dicyclohexylcarbodiimide / [(1 H) benzotriazol] -1,1,

3,3-tetramethyluronium salts of N, N'-1ionyldiimidazole, N, N'carbonyldiimidazole or triphenylphosphine / carbon tetrachloride, optionally in the presence of dimethylaminopyridine; or

1-hydroxy-benzotriazole and / or bases such as triethylamine, N-ethyl-diisopropylamine or N-methyl-morpholine, preferably at temperatures between -10 to 150 ° C, in particular at temperatures between 0 to 50 ° C.

(b) For the preparation of compounds of the formula I in which R _a represents a hydrogen atom:

The protective residue from the compound of formula IV is cleaved ^X 1 / x ₂ x ₅ (IV) 1 / x ₃ - x ₄ where

Xy to X ^ are as defined above except that R _a is C 2 -C 6 alkoxy, C 2 -C 6 phenylalkoxycarbonyl, C 4 -C 6 alkenyloxycarbonyl, C 6 -C 8 cycloalkoxycarbonyl, or cleavable. an imino protecting group such as acetyl, trifluoroacetyl, benzoyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl by hydrolysis, hydrogenolysis or thermolysis.

The hydrolysis is preferably carried out either in the presence of an acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, acetic acid / hydrochloric acid, trichloroacetic acid or trifluoroacetic acid or in the presence of a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide. in a suitable solvent such as water, methanol, water / methanol, ethanol, water / ethanol, water / isopropanol, water / tetrahydrofuran, ether / dioxane or water / dioxane at temperatures between -10 ° C and 120 ° C, e.g. . at temperatures between room temperature and the boiling point of the reaction mixture.

In acid hydrolysis, other hydrolytically cleavable groups present in the compound of formula IV, such as alkoxycarbonyl or phenylalkoxycarbonyl, can also be hydrolytically cleaved at the same time according to the conditions used.

For example, when R _a is tert-butyloxycarbonyl, the tert-butyl may also be cleaved by an acid such as trifluoroacetic acid, hydrochloric acid, formic acid, p-toluenesulfonic acid, sulfuric acid, phosphoric acid or polyphosphoric acid, in an inert solvent such as methanol, methylene chloride, chloroform, benzene, toluene, tetrahydrofuran, dioxane, ether / dioxane or ether / dioxane / methanol, preferably at temperatures between -10 ° C to 120 ° C, e.g. at temperatures between 0 and 60 ° C or else thermally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane and optionally in the presence of a catalytic amount of an acid such as p-toluenesulfonic acid, sulfuric acid, phosphoric acid or polyphosphoric acid preferably at the boiling point of the solvent used, e.g. at temperatures between 40 ° C and 100 ° C.

For example, when R _a is benzyloxycarbonyl, the benzyl group can also be cleaved hydrogenolytically in the presence of a hydrogenation catalyst such as palladium on carbon in a suitable solvent such as methanol, ethanol, ethanol / water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide, preferably temperatures between 0 and 50 ° C, e.g. at room temperature and at a hydrogen pressure of 1 to 10 bar. In hydrogenolysis, other residues, e.g. an amino group or a benzyloxy group for a hydroxy group and a benzylamino group for an amino group. In addition, C = C double bonds may be hydrogenated simultaneously.

(c) For the preparation of compounds of the formula I in which Rg represents a hydrogen atom:

The protective residue from the general compound is cleaved off

of formula V (IN) ^X 1 7 ^X 2 \ ^X 3 \ / ^X 4 ^X 5 where X- £ to Xg have higher this meaning and thus above said measure that R 6 is alkyl group with 1 to 5 carbon atoms Ika, alkenyl with 3 to 5 carbon

C 1 -C 3 -phenylalkyl, C 5 -C 7 -cycloalkyl or cycloalkylalkyl or a leaving group of a carboxy group such as trimethylsilyl-, methoxybenzyl-, 2,4-dimethoxybenzyl-, 2,4-dimethoxybenzyl or hydrolysis, hydrogenolysis or thermolysis.

The hydrolysis is conveniently carried out either in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, acetic acid / hydrochloric acid, trichloroacetic acid or trifluoroacetic acid or in the presence of a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a suitable solvent such as water, methanol, water / methanol, ethanol, water / ethanol, water / isopropanol, water / tetrahydrofuran, water / dioxane or at temperatures between -10 ° C and 120 ° C, e.g. at temperatures between room temperature and the boiling point of the reaction mixture.

In acid hydrolysis, other hydrolytically cleavable groups such as acetyl, trifluoroacetyl, benzoyl, tert-butyloxycarbonyl or benzyloxycarbonyl groups may also be cleaved at the same time according to the conditions used.

For example, when R _a is tert-butyl, the tert-butyl may also be cleaved by treatment with an acid such as trifluoroacetic acid, hydrochloric acid, formic acid, p-toluenesulfonic acid, sulfuric acid, phosphoric acid or polyphosphoric acid in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane, preferably at temperatures between -10 ° C to 120 ° C, e.g. at temperatures between 0 and 60 ° C or also thermally, for example in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane and optionally in the presence of a catalytic amount of an acid such as p-toluenesulfonic acid, sulfuric acid, phosphoric acid or polyphosphoric acid preferably at the boiling point of the solvent used, e.g. at temperatures between 40 ° C and 100 ° C.

For example, when R &lt; 8 _& gt _; is benzyl, the benzyl group may also be hydrogenolytically cleaved in the presence of a hydrogenation catalyst such as palladium on carbon in a suitable solvent such as methanol, ethanol, ethanol / water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide. temperatures between 0 and 50 ° C, e.g. at room temperature and at a hydrogen pressure of 1 to 10 bar. In hydrogenolysis, other residues, e.g. an amino group or a benzyloxy group for a hydroxy group and a benzylamino or benzyloxycarbonylamino group for an amino group. In addition, a C = C double bond to a single bond can be hydrogenated simultaneously.

(d) For the preparation of 1,3,4-oxadiazole-, 1,2,4-triazole- and 1,3,4-thiazole derivatives of formula I:

The compound of formula (VI), optionally prepared in the reaction mixture, is cyclized

* N - N R (VI) R ' // w / - c c 1 1 1 1 ^Z 1 ^Z 2 where Z- £ and Z2, which can be simultaneously same or different,

halogen, optionally R8 substituted amino, hydroxy, alkoxy, mercapto or alkyl mercapto, one of the radicals

R alebo or R is an A-B-C-group and the other R alebo or R ^ R O O-CO-E-D-group and, if desired, alkylation is then performed.

The reaction is conveniently carried out in a solvent such as tetrahydrofuran, dioxane, 1,2-dichlorobenzene or pyridine at temperatures up to the boiling point of the solvent used, e.g. at temperatures between 20 and 180 ° C.

When in the compound of formula (VI) and Z2 is always a hydroxy group, the reaction is preferably carried out in the presence of a water-withdrawing agent such as thionyl chloride, to produce the 1,3,4-thiadiazole derivative preferably in the presence of a sulfur introducing reagent such as 2,4bis - (4-methoxyphenyl) -1,3-dithia-2,4-diphosphoethane-2,4-disulfide and for the preparation of the 1,3,4-triazole derivative, the reaction is preferably carried out in the presence of a halogen introducing agent such as phosphorus trichloride and presence of aniline.

For the preparation of the other 1,2,4-triazole derivatives, a compound of formula VI wherein one of Z 2 or Z ₂ is hydroxy and the other of Z 2 or Z _{2 is} amino is cyclized and optionally then alkylated if desired.

The subsequent alkylation is conveniently carried out in a solvent such as methylene chloride, tetrahydrofuran, dioxane, dimethylsulfoxide or dimethylformamide, optionally in the presence of a base such as sodium carbonate, potassium carbonate or sodium hydroxide or in the presence of a tertiary organic base such as N-ethyl-diisopropylamine or N- methyl morpholine, which can simultaneously serve as a solvent, at temperatures between -30 to 100 ° C, but preferably at temperatures between -10 to 80 ° C.

e) For the preparation of compounds of formula I, wherein A represents a phenyl group which is substituted at the 4-position with an R _and HN-C (= NH) -group.

Or by treatment of the reaction mixture formed a compound of formula VII, ^X 1 / \ x ₅ x ₂ (VII) \ /

X ₃ - X ₄ where

X 1 to X 6 are as defined above, with the proviso that A is a phenyl group which is substituted at the 4-position with Zg-C (= NH) -group, wherein Zg is alkoxy, aralkoxy such as methoxy, ethoxy, -propoxy-, isopropoxy- or benzyloxy or alkylthio or aralkylthio such as methylthio, ethylthio, n-propylthio- or benzylthio or amino, with an amine of formula VIII

R _a '- NH ₂ (VIII) wherein

R 'represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms.

The reaction is conveniently carried out in a solvent such as methanol, ethanol, n-propanol, water, methanol / water, tetrahydrofuran or dioxane at temperatures between 0 to 150, preferably at temperatures between 20 and 120 ° C, with the corresponding free amine or the corresponding addition an acid salt such as ammonium carbonate or ammonium acetate.

For example, a compound of formula (VII) is obtained by reacting the corresponding nitrile with a corresponding alcohol such as methanol, ethanol, n-propanol, isopropanol or benzyl alcohol in the presence of an acid such as hydrochloric acid or in the presence of the corresponding alcoholate such as sodium ethylate; is triethyloxonium tetrafluoroborate in a solvent such as methylene chloride, tetrahydrofuran or dioxane at temperatures between -10 and 50 ° C, preferably at temperatures between 0 and 20 ° C or the corresponding nitrile with hydrogen sulfide, preferably in a solvent such as pyridine or dimethylformamide and in the presence of bases such as triethylamine followed by alkylation of the formed thioamide with the corresponding alkyl or aralkyl halide.

f) For the preparation of compounds of formula I wherein A is phenyl which is substituted in the 4-position with R _and NH-C (= NH) -group:

Reaction of a compound of formula IX

where

(IX)

X2-X to Xg are as defined above, with the proviso that A represents a phenyl group which is substituted at the 4-position with cyano, with a hydroxyamine and then a reduction of the amidoxime thus obtained.

The reaction with the hydroxyamine is conveniently carried out in a solvent such as methanol, ethanol, n-propanol, water, methanol / water, ethanol / water, tetrahydrofuran or dioxane, optionally with the addition of a base such as sodium carbonate at temperatures between 0 to 100 ° C. , preferably at temperatures between 20 and 80 ° C, with either the free hydroxyamine or the corresponding acid addition salt such as hydrochloride.

The subsequent reduction is preferably carried out in an aqueous solvent such as methanol, methanol / water, methanol / ammonia, methanol / water / ammonia, methanol / hydrochloric acid, ethanol, ether, tetrahydrofuran, dioxane, dimethylformamide or glacial acetic acid in the presence of catalytically treated hydrogen, e.g. hydrogen in the presence of Raney-nickel, platinum or palladium on carbon at temperatures between 0 and 100 ° C, preferably at temperatures between 20 and 80 ° C.

(g) For the preparation of compounds of the formula I in which A represents a phenyl group in which the 4-position is substituted by an R _and NH-C (= NH) -group:

Reaction of a compound of formula IX ^X 1 x ₂ x ₅ ( ₁ x)

X ₃ - X ₄ where

X 1 to X 8 are as defined above, with the proviso that A represents a phenyl group which is substituted at the 4-position with cyano, with the corresponding alkylchloroaluminium amide.

The reaction is conveniently carried out in a suitable solvent, for example benzene, toluene, at temperatures between 0 and 100 ° C, preferably at between 20 and 80 ° C, and the aluminum complex thus obtained is then hydrolytically decomposed, preferably by slurry of silica gel in chloroform. RS Garigipati, Tetrahedron Letters 31, 1969 (1990)).

r

(h) For the preparation of 1,3-thiazoles and imidazoles of the general formula I:

Reaction of a compound of formula X

R 1 -CO-CH ₂ -Z ₄ (X) with a compound of formula XI

R-CU-NH ₂ (XI) wherein one of the radicals R 'or R represents an ABC group and the other of the radicals R' or R represents an R 6 -O-CO-ED group,

Z ₄ represents a nucleophilic leaving group such as a chlorine, bromine or iodine atom;

U represents a sulfur atom or an imino group.

The reaction is conveniently carried out in a solvent such as methanol, ethanol or isopropanol, optionally in the presence of a base such as sodium carbonate at elevated temperatures, e.g. at the boiling point of the solvent used.

i) For a compound of formula I, wherein R _& is hydrogen except as defined above and B is -CH ₂ O-group:

Reaction of a compound of formula XII

A - CH ₂ - S ₅ (XII) wherein

A is as defined above with the proviso that R _& lt _; 6 _& gt _; is hydrogen as defined above and represents a nucleophilic leaving group such as a halogen atom or a sulfonyloxy group, e.g. methanesulfonyloxy, chloro or bromo, with a compound of formula XIII ^X 1 / x ₂ X ₅ (XIII) 1 / x ₃ - x ₄ where

X 1 to X 1 are as defined above, with the proviso that one of the radicals X 1 to X 2 is a HO-C-CH 2 - or HO-C-C 2 group, wherein C is as defined above or a salt thereof with an alkali metal or an alkaline earth metal such as lithium, sodium, potassium, cesium, magnesium or calcium salts.

The reaction is conveniently carried out in a solvent such as tetrahydrofuran, acetone, dioxane, dimethylsulfoxide, sulfolane, dimethylpharmamide or dimethylacetamide in the presence of an inorganic base such as potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride or potassium tert-butylate or tertiary. organic bases such as N-ethyl-diisopropylamine, which may optionally also serve as a solvent and optionally in the presence of a phase transfer catalyst such as polyethylene glycol-750-monoethyl ether to polystyrene or hexadecyl trimethylammonium chloride at temperatures between 0 and 180 ° C, preferably at temperatures between 10-160 ° C.

j) For the preparation of compounds of formula I, wherein one of the radicals to X až represents an A-B-C-N?

Alkylation of a compound of formula XIV ^X 1 / X ₂ X ₅ (XIV) ^X / ^X 3 ^X 4 wherein:

X 1 to X 5 are as defined above, with the proviso that one of X 1 to X 8 is an imino group, a compound of formula XV

V - Z ₆ (XV) where

V represents an A-B-C- or R 10 -O-CO-E-D-group wherein A to B is C-O-CO-E-D;

D have the previously defined meaning a

Zg represents a nucleophilic leaving group, such as a halogen atom or a sulfonyloxy group, e.g. methanesulfonyloxy, chlorine or bromine.

Suitably the alkylation is carried out in a solvent or solvent mixture such as methylene chloride, dimethylformamide, dimethylsulfoxide, benzene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane in the presence of an acid binding agent, e.g. an alcoholate such as potassium tert-butylate, an alkali metal hydroxide such as sodium or potassium hydroxide, an alkali metal carbonate such as potassium carbonate, an alkali metal amide such as sodium hydride, preferably at temperatures between 0 to 150 ° C, especially at temperatures between 0 to 150 ° C 50 C.

k) For the preparation of compounds of the formula I in which R @ 1 is R @ 5 --CO - O-- (R @ ₂ CH) - wherein R @ 1 to R @ ₂ are as previously defined, C1 -C5 alkyl, (C 3 -C 5) alkenyl, (C 1 -C 3) phenylalkyl, (C 5 -C 7) cycloalkyl or cycloalkylalkyl:

Esterification of a compound of formula XVI ^X 1 / \ x ₂ x ₅ (xvi) \ / x ₃ - ₄ x wherein

X- až to X majú are as previously defined with the proviso that R _b is hydrogen, a compound of formula XVII

Z _? - R _b '(XVII) wherein

R _b 'represents a R 1 -CO-O- (R ₂ CH) -group where R 1 to R ₂ are as previously defined, a C 1 -C 5 alkyl group, a C 3 -C 5 alkenyl group, a phenylalkyl a (C 1 -C 3) alkyl group, a (C 5 -C 7) cycloalkyl or cycloalkylalkyl group; and

Γγ represents a hydroxy group or a nucleophilic leaving group such as a halogen atom or a sulfonyloxy group, e.g. a chlorine, bromine or iodine atom, methanesulfonyloxy- or p-toluenesulfonyloxy.

The esterification is conveniently carried out in a suitable solvent, e.g. in a corresponding alcohol such as methanol, ethanol or isopropanol, methylene chloride, tetrahydrofuran, dioxane, pyridine, toluene or dimethylsulfoxide in the presence of an acid activating and / or water-withdrawing agent such as hydrogen chloride, horses, sulfuric acid, thionyl chloride, ethyl chloroformate, or , N'-dicycloyl-lohexylcarbodiimide, or in the presence of accelerators by esterification e.g. carbon dioxide or genide, preferably at low cost and optionally for action such as iodide ° C, preferably at temperatures between about 20 ° C.

isourea esters, reactions such as chloride by the corresponding diesters with a suitable corresponding optionally copper, by an acid-base reaction such as a carbonate of the presence of a potassium-precipitating agent at temperatures between 0 ° C and 100 ° C and boiling point. an alkali metal salt of a compound of formula XVI.

In these reactions described, reactive groups such as hydroxy, carboxy, amino, alkylamino or imino groups may optionally be present during the reaction, protected by conventional reaction groups, which are cleaved again after the reaction.

Examples of suitable hydroxyl protecting groups are trimethylsilyl-, acetyl-, benzoyl-, tert-butyl-, trityl-, benzyl- or tetrahydropyranyl-, as protecting groups for the carboxyl group of trimethylsilyl-, methyl-, ethyl-, tert-butyl-, benzyl. - or a tetrahydropyranyl group and, as a protecting group of an amino, alkylamino or imino group, acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert-butoxycarbonyl, benzoyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl groups and for an amino group additionally a phthalyl group.

The subsequent cleavage of the protecting residue used, for example, is carried out hydrolytically in an aqueous solvent, e.g. in water, isopropanol / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali metal base such as lithium hydroxide, sodium or potassium hydroxide or via ether cleavage, e.g. . in the presence of iodotrimethylsilane, at temperatures between 0 and 100 ° C, preferably at temperatures between 10 and 50 ° C.

The cleavage of the benzyl, methoxybenzyl or benzyloxycarbonyl radical is carried out, for example, by hydrogenolysis, e.g. with hydrogen in the presence of a catalyst such as palladium on carbon in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide / acetone or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 to 50 ° C, preferably at room temperature and at a hydrogen pressure of 0.1 to 0.7 MPa, preferably 0.3 to 0.5 MPa.

Cleavage of the methoxybenzyl group can also be carried out in the presence of an oxidizing agent such as cerium ammonium nitrate in a solvent such as methylene chloride, acetonitrile or acetonitrile / water at temperatures between 0 to 50 ° C, preferably at room temperature. The cleavage of the 2,4-dimethoxybenzyl residue is preferably carried out in trifluoroacetic acid in the presence of anisole.

The cleavage of the tert-butyl or tert-butyloxycarbonyl radical is preferably carried out by treatment with an acid such as trifluoroacetic acid or hydrochloric acid using a solvent such as methylene chloride, dioxane or ether.

The cleavage of the phthalyl residue is preferably carried out in the presence of hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine in a solvent such as methanol, ethanol, isopropanol, toluene / water or dioxane at temperatures between 20 and 50 ° C.

The cleavage of the allyloxycarbonyl residue is carried out by treatment with a catalytic amount of tetrakis (triphenylphosphine) palladium, preferably in a solvent such as tetrahydrofuran and preferably in the presence of an excess of a base such as morpholine or

1,3-dimedone at temperatures between 0 to 100 ° C, preferably at room temperature and under an inert gas or treatment with a catalytic amount of tris- (triphenylphosphine) native chloride in a solvent such as aqueous ethanol and optionally in the presence of a base such as 1,4 -diazabicyclo [2.2.2] octane at temperatures between 20 and 70 ° C.

Furthermore, the compounds of the formula I obtained above can be separated into their enantiomers * and / or diastereomers. Thus, for example, cis / trans mixtures can be resolved into their cis and trans isomers and chiral compounds into their enantiomers.

Thus, it is possible, for example, to separate the cis / trans mixtures obtained by chromatography into their cis and trans isomers.

N. L. and Eliel E. L. in Topics in Stereochemistry, Vol. 6, Viley Interscience, 1971) to their optical antipodes. and compounds of formula I having at least 2 stereogenic centers due to their physicochemical differences by methods known per se, e.g. chromatography and / or fractional crystallization, into their diastereomers, which, when present in racemic form, can be separated into the enantiomers as mentioned above.

•

The separation of enantiomers is preferably carried out by column separation on chiral phases or by recrystallization from an optically active solvent or by reaction with an optically active substance which forms salts or derivatives with a racemic compound such as e.g. an ester or amide, in particular with acids and their activated derivatives or alcohols, and separating the diastereomeric mixtures of salts or derivatives thus obtained, e.g. on the basis of different solubilities, the antipodes are then released from the pure diastereomeric salts or derivatives by treatment with a suitable agent. Particularly useful optically active acids are e.g. D- and L-forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid. Suitable optically active alcohol is, for example, (+) or (-) - menthol and, as optically active acyl residue in amides, for example, (+) - or (-) - mentyloxycarbonyl.

Furthermore, the compounds of the formula I obtained can be converted into their salts, in particular pharmaceutically acceptable salts for pharmaceutical use, with inorganic or organic acids. Suitable acids here are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

In addition, the compounds of the formula I thus obtained, if they contain a carboxyl group, can optionally be converted into their addition salts with inorganic or organic bases, in particular for pharmaceutical use into their physiologically acceptable addition salts. Suitable bases here are sodium hydroxide, potassium hydroxide, ammonia, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.

The compounds used as starting materials are partly known from the literature or can be obtained according to methods known in the literature (see Examples I to XXI).

As mentioned above, the novel 5-membered heterocycles of the formula I and their salts, in particular their physiologically acceptable salts with inorganic acids or bases, exhibit valuable pharmacological properties, in addition to inflammatory-inhibiting and bone-degrading activity, in particular antithrombotic, antiplatelet and tumor-suppressing metastases. efficiency. The compounds of formula I wherein R _a is an oxycarbonyl radical as defined above and / or an ester radical as defined above are an intermediate.

The compounds of formula I have been investigated for their biological activity, for example, as follows:

Ο

1. Competitive binding of H-BIBU 52 / tattooed substance to human platelets:

Plasma suspension of human platelets is mixed with 1 H-BIBU 52 [= (3S, 5S) -5 - [(4'-amidino-4-biphenylyl) oxymethyl] q

3 - [(carboxyl) methyl] -2-pyrrolidinone [3- Η-4-biphenylyl]], from li-9c teratures by known ligands of I-fibrinogen (see German patent application P 42 14 245.8, the same applicant from 30.4. (Internal mark: Time 5/1093-FL) and incubated with various concentrations of test substance. Free and bound ligand is collected by centrifugation and quantitated by scintillation counting. The H-BIBU 52-binding inhibition by the test substance is determined from the measured values.

To this end, blood is drawn from the donor anticubital vein and anticoagulated with sodium citrate (final concentration 13 mM). The blood is centrifuged at 170 xg for 10 minutes and platelet-rich plasma (PRP) supernatant is collected. The remaining blood is rapidly centrifuged once more to obtain plasma. PRP is diluted 1:10 with autologous plasma. Incubate 750 μΐ with 50 μΐ saline. 100 μΐ of test substance solution, 50 μΐ of ¹⁴ C-sucrose (3,700 Bq) and 50 μΐΐH-BIBU 52 (final concentration 5 nM) at room temperature for 20 minutes. 5 μΐ BIBU 52 (final concentration: 30 μπι) is used instead of the test substance to measure non-specific binding. The samples are centrifuged for 20 seconds at 1000 xg and the supernatant is collected. 100 μΐ of the supernatant is used to measure the free ligand. Dissolve the pellet in 500 μΐ 0.2 N NaOH, mix 450 μ 450 with 2 ml scintillator and 25 μΐ 5 N HCl and measure. The pellet still contains residual plasma and this is determined from the ligand-bound content of the 1 H-measurement. After subtraction of the non-specific binding, the activity of the pellet is plotted against the concentration of the test substance and the concentration is determined for 50% suppression.

2. Antithrombotic efficacy

methodics

Platelet aggregation is measured by the Born and Gross method. (J.Physiol: 170, 397 (1964)) in platelet-rich plasma, from healthy subjects. To suppress clotting, blood is mixed with 3.14% sodium citrate in a 1: 10 by volume ratio.

Collagen-induced aggregation «·

It is registered and measured photometrically the course of the decrease in optical density t after addition of the aggregation-inducing substance. The aggregation rate is determined from the angle of inclination of the density curve. The point on the curve at which the greatest light transmission occurs is to calculate the optical density.

The collagen concentration is chosen to be as small as possible but nevertheless such that an irreversibly running reaction curve is obtained. The commercially available Collagen of Hormonchemie, Munich is used. Prior to the addition of collagen, the plasma is incubated with the substance at 37 ° C for 10 minutes.

From the concentration-efficiency curves, EC 50 is calculated, which indicates the concentration at which the change in optical density is suppressed by half the maximum.

The following table shows the results found:

substance (example #) competitive binding BIBU ^ H-BIBU 52 test, substance on human platelets IC ₅₀ (nM) suppression of ^E 50 platelet aggregation ^[nM] 2 24,000.0 3000 2 (3) 550.0 380 3 400.0 880 3 (1) 6,800.0 4400 3 (3) 1.6 40 5 510.0 320 5 (3) 11.0 100

The compounds of the invention are well tolerated, for example, when intravenous administration of 30 mg / kg of each of the 3 mice of the compounds of Examples 5 and 5 (3), none of the animals died.

In addition, for example, with rat plasma obtained after oral administration of 10 mg / kg of the compound of Example 2 (19) ex vivo after 3 hours, 80% suppression of collagen-induced aggregation of human platelets is achieved.

Because of their suppressing effect on cell-cell or cell-matrix interactions, the novel carboxylic acid derivatives of the formula I and their physiologically acceptable acid addition salts are suitable for the treatment and / or treatment. ameliorating diseases in which smaller or larger cellular aggregates arise or play a role in cell-matrix interaction, for example in the treatment or prevention of venous and arterial thromboses, cerebrovascular diseases, pulmonary embolism, cardiac infarction, arteriosclerosis, osteoporosis or tumor metastasis and tumor metastases also obtained cell interaction disorders with one another or with solid structures. Furthermore, they are useful in supportive therapy for thrombolysis of fibrinolytics or vascular interventions such as transluminal angioplasty or also in the treatment of shock conditions, psoriasis, diabetes and inflammation.

Dosages between 0.1 gg and 30 mg / kg body weight, preferably 1 gg to 15 mg / kg body weight, for up to 4 administrations per day are used to treat or prevent said diseases. For this purpose, the compounds of the formula I prepared according to the invention may optionally be treated in combination with other active substances such as thromboxane receptor antagonists and thromboxane synthesis inhibiting agents or combinations thereof, serotonin antagonists, α-receptor antagonists, alkyl nitrates such as glycerin nitrate, phosphodiesterase, prostacyclin and analogs thereof, fibrinolytics such as tPA, prourokinase, urokinase, streptokinase or anticoagulants such as heparin, dermatan sulfate, activated protein C, vitamin K antagonists, hirudin, thrombin inhibitors or other activated clotting factors, together with one or more clotting factors or diluents, e.g. corn starch, milk sugar, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerin, water / sorbitol, water / polyethylene glycol, propylene glycol, propylene glycol, propylene glycol, stearlene glycol fat, such as hardened fat or suitable mixtures thereof, for conventional galenic preparations such as tablets, dragees, capsules, powders, suspensions, solutions, sprays or lace.

The following examples illustrate the invention in more detail.

DETAILED DESCRIPTION OF THE INVENTION

Example I

4- (4-Piperidyl) -benzoic acid hydrochloride

To a solution of 63.0 g of 1-acetyl-4-phenyl-piperidine in 1000 ml of methylene chloride was added dropwise 157.4 g of oxalyl chloride with good stirring at -10 ° C to -20 ° C. 46.7 g of aluminum chloride are then added. Stir 1 hour at -10 ° C and add another 82.7 g of aluminum chloride. After an additional 2 hours, the cooling bath was removed and stirred at room temperature for 24 hours. The reaction solution is carefully mixed into about 4 L of ice / water and the aqueous phase is extracted twice with methylene chloride. The combined organic phases are washed with water, dried over sodium sulphate and the solvent is evaporated under reduced pressure. The residue was dissolved in 2.5 L of sodium hydroxide with brief stirring. To the dark solution was added α-ad and acidified with concentrated hydrochloric acid. The precipitate is filtered off with suction, washed with water and heated under reflux with 2 1 of 6 N hydrochloric acid for 5 hours. The solvent was removed under reduced pressure. The remaining solid is triturated with a small amount of water and suction filtered.

Yield: 40.5 g (54% of theory)

R.f-value: 0.07 (silica gel, methylene chloride / methanol / conc.

/ ammonia = 4: 1: 0.25)

Example II

4- [1- (tert-Butyloxycarbonyl) -4-piperidyl] benzoic acid

To 16.4 g of sodium hydroxide in 300 ml of water was carefully added 47.5 g of 4- (4-piperidyl) benzoic acid hydrochloride.

The suspension is diluted with 500 ml dioxane and 250 ml water. Then 54.6 g of di-tert-butyl pyrocarbonate are added portionwise. Stir for 16 hours at room temperature. The precipitate is filtered off with suction and the filtrate is partially evaporated under reduced pressure. The precipitate and the remaining aqueous filtrate were combined and diluted with 12 L of water. The aqueous phase was adjusted to pH 2 with saturated potassium bicarbonate solution and extracted twice with ethyl ester. The combined ethyl acetate phases are washed with saturated sodium chloride solution, dried over sodium sulphate and the solvent is removed under reduced pressure. The crystalline crude product is triturated with a small amount of ethyl acetate, filtered off with suction and dried.

Yield: 54.0 g (90% of theory)

B

Melting point: 172-174 ° C

Rf value: 0.73 (silica gel, ethyl acetate / cyclohexane = 4: 1);

EXAMPLE III

4- [1- (tert-Butyloxycarbonyl) -4-piperidyl] benzoic acid hydrazide

To a solution of 21.3 g of 4- [1- (tert-butyloxycarbonyl) -

Of 4-piperidyl] benzoic acid in 150 ml of dimethylformamide was added at -10 ° C 9.6 g of 1-hydroxy- (1H) -benzotriazole and 17.4 g of N, N'-dicyclohexylcarbodiimide. Stir 15 minutes at -10 ° C, remove the cooling bath and allow the temperature to reach room temperature. The reaction mixture was then added dropwise to a solution of 50 ml of 80% hydrazine hydrate cooled to -10 ° C. It is stirred for 16 hours at room temperature and the precipitate is suction filtered. The filtrate was evaporated under reduced pressure. Water was added to the residue and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulfate and the solvent is evaporated under reduced pressure. The residual solid was chromatographed with ethyl acetate / hexane (4: 1) over silica gel. It will be obtained

18.5 g of crystalline solid which is triturated with ethyl acetate and then filtered off with suction.

Yield: 12.7 g (57% of theory) Melting point: 151-154 ° C Rf value: 0.26 (silica gel, ethyl acetate / cyclohexane = 4: 1)

Example IV

N- [4- [1- (terc.butyloxykarbony1) -4-piperidyl] benzoyl] -N '- [(methoxycarbonyl) carbonyl] hydrazine

To a solution of 3.2 g of 4- [1- (tert-butyloxycarbonyl) -4-piperidyl] benzoic acid hydrazide and 1.7 g of ethyldiisopropylamine in 50 ml of anhydrous tetrahydrofuran is added dropwise a solution of 1.3 g of monoethyl ether chloride while cooling in an ice bath. oxalic acid in 10 ml of anhydrous tetrahydrofuran. It is stirred for 16 hours at room temperature, the precipitate is filtered off with suction and the filtrate is evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed once with 0.5 N hydrochloric acid. The organic phase is dried and the solvent is evaporated off under reduced pressure. The crude product is chromatographed on silica gel with ethyl acetate / cyclohexane (4: 1).

Yield: 3.5 g (86% of theory) Melting point: 105-108 ° C Rf value: 0.27 (silica gel, ethyl acetate / cyclohexane = 4: 1)

The following compounds are obtained analogously:

1) N- [4- [1- (tert-butyloxycarbonyl) -4-piperidyl] benzoyl] -N'- [[4- (methoxycarbonyl) butyl] carbonyl] hydrazine _f Adipic acid monomethyl chloride chloride is used. Melting point: 150-153 ° C

Rf value: 0.26 (silica gel, ethyl acetate / cyclohexane = 4: 1)

2) N- [4- [4- (tert-butyloxycarbonyl) -4-piperidyl] benzoyl] -N '[[cis-4- (methoxycarbonyl) cyclohexyl] carbonyl] hydrazine

Cis-4- (methoxycarbonyl) cyclohexanoic acid chloride was used.

Rf value: 0.20 (silica gel, methylene chloride / methanol = 20: 1)

3) N- [4- [4- (tert-butyloxycarbonyl) -4-piperidyl] benzoyl] -N '[[trans-4- (methoxycarbonyl) cyclohexyl] carbonyl] hydrazine

A cis / trans mixture of 4- (methoxycarbonyl) cyclohexanecarboxylic acid chloride is used. The trans-product is excluded from the organic phase.

Melting point: 198 - 201 ° C

Rf value: 0.20 (silica gel, methylene chloride / methanol = 20: 1)

4) N- [4- [1- (tert-butyloxycarbonyl) -4-piperidyl] benzoyl] -N '[[trans-4- (ethoxycarbonyl) cyclohexyl] carbonyl] hydrazine

Rf value: 0.53 (silica gel, methylene chloride / methanol = 9: 1)

5) N- [4- (1-benzoyl-4-piperazinyl) benzoyl] -N '- [[trans -4 (ethoxycarbonyl) cyclohexyl] carbonyl] hydrazine

Melting point: 182-184 ° C

Rf value: 0.78 (silica gel, methylene chloride / methanol = 9: 1)

6) N - [[1- [1- (tert-butyloxycarbonyl) -4-piperidyl] -4-piperidyl] carbonyl] -N '- [[trans -4- (ethoxycarbonyl) cyclohexyl] carbonyl] hydrazine

Melting point: 222-224 ° C

Rf value: 0.79 (silica gel, methylene chloride / methanol = 9: 1)

Example V

2- [4- [1- (tert -butyloxycarbonyl) -4-piperidinyl] phenyl] -5-methoxycarbonyl-1,3,4-thiadiazole

A solution of 3.32 g of N- [4- [1- (tert-butyloxycarbonyl) -4-piperidyl] benzoyl] -N - [(methoxycarbonyl) carbonyl] hydrazine and 3.64 g

2,4-Bis- (4-methoxyphenyl) -1,3-dithia-2,4-diphosphoethane-2,4-disulfide (Lawesson's reagent) in 60 mL tetrahydrofuran was boiled under reflux for 30 minutes. The solvent was removed under reduced pressure and the residue was chromatographed on silica gel with ethyl acetate / cyclohexane (2: 1).

Yield: 2.75 g (83% of theory). Melting point: 143 DEG -146 DEG C. Rf value: 0.59 (silica gel, ethyl acetate / cyclohexane = 1: 1).

Example VI

2- [4- [1- (tert -butyloxycarbonyl) -4-piperidinyl] phenyl] -5-carboxy-1,3,4-thiadiazole

A solution of 2.7 g of 2- [4- [1- (tert-butyloxycarbonyl) -4-piperidyl] phenyl] -5-methoxycarbonyl-1,3,4-thiadiazole and 1.1 g of lithium hydroxide hydrate in 50 ml of tetrahydrofuran and 40 ml of water are stirred at room temperature for 30 minutes. The reaction solution was neutralized with 1 N hydrochloric acid (pH 6.3). The solvent was removed under reduced pressure and the residue was triturated with a small amount of water and filtered off with suction.

Yield: 2.25 g (87% of theory) Rf value: 0.42 (silica gel, methylene chloride / methanol / conc.

ammonia = 4: 1: 0.25)

Example VII

4- [2-amino-2- (methoxycarbonyl) ethyl] -1- [6- (4-cyano-phenyl) -3-pyridazinyl] -imidazole dihydrochloride

To a suspension of 1.55 g of a 55% dispersion of sodium hydride in mineral oil in 50 ml of anhydrous dimethylformamide was added dropwise a solution of N-tert-butyloxycarbonyl-L-histidine methyl ester in 100 ml of dry dimethyl-41 formamide under nitrogen. After stirring at 0 ° C for 30 minutes, a solution of 7.6 g of 3-chloro-6- (4-cyano-phenyl) -pyridazine in 400 ml of dried dimethylformamide is added dropwise. Stir 2 hours at 0 ° C and 16 hours at room temperature. The reaction solution is poured onto ice / sodium chloride solution and the aqueous phase is extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulfate and the solvent is evaporated under reduced pressure. The residue is chromatographed on silica gel with methylene chloride / methanol (20: 1). After removal of the solvent, the crude product thus obtained (11.0 g) is dissolved in 500 ml of dioxane. 150 ml of hydrogen chloride-saturated ether are added and the precipitate is filtered off with suction. The solid was dissolved in a mixture of 750 mL of dioxane, 750 mL of methanol and 250 mL of hydrogen chloride saturated ether and stirred at room temperature for 16 hours. The precipitate was filtered off with suction and washed with dioxane (yield 4.4 g). Evaporation of the mother liquor to about 100 ml and suctioning off the precipitate yielded an additional 4.7 g of product.

Yield: 9.1 g (61% of theory)

Melting point: sintered at 220 ° C

Rf value: 0.43 (silica gel, methylene chloride / methanol / conc. Ammonia = 9: 1: 0.1)

Example VIII

4- [2- (n-butanesulfonylamino) -2- (methoxycarbonyl) ethyl] -1- [6- (4-cyanophenyl) -3-pyridazinyl] imidazole

To a solution of 4.2 g of 4- [2-amino-2- (methoxycarbonyl) -ethyl] -1- [6- (4-cyano-phenyl) -3-pyridazinyl] -imidazole dihydrochloride and 4.5 g of ethyldiosopropylamine in 150 ml of methylene chloride was added dropwise at 0 ° C a solution of 2.0 g of n-butanesulfonyl chloride in 20 ml of dimethylformamide. It is stirred for 2 days at room temperature and then the precipitate is filtered off with suction. The filtrate was washed twice with water. The organic phase is dried over sodium sulphate and the solvent is evaporated off under reduced pressure. The residue is triturated in a small amount of methanol and filtered off with suction.

Yield: 0.85 g (18% of theory)

R.f-value: 0.49 (silica gel, methylene chloride / methanol / conc. Ammonia = 9: 1: 0.1)

Example IX

1- (tert -butyloxycarbonyl) -4- (2-cyano-ethyl) piperidine

A suspension of 4.61 g of 1- (tert-butyloxycarbonyl) -4- [2- (methanesulfonyl) ethyl] piperidine, 10.5 g of potassium cyanide dimethylformamide was stirred at room temperature for 16 hours. After addition of a few ml of dimethylformamide, it is heated at 70 ° C for 7 hours. To the cooled mixture was added ice water and 3 mL 2

N sodium hydroxide and the aqueous phase is extracted several times with tert-butyl methyl ether. The combined organic phases were washed with ice water and saturated sodium chloride solution and dried over sodium sulfate. The solvent was removed under reduced pressure.

Yield: 3.1 g (86% of theory) of a yellowish oil

Rf value: 0.63 (silica gel, cyclohexane / ethyl acetate = 1: 1) Example X

1- (tert-butyloxycarbonyl) -4- [2- (aminothiocarbonyl) ethyl] piperidine <· A solution of 3.0 g of 1- (tert-butyloxycarbonyl) -4- (2-cyanoethyl) piperidine in 15 ml of pyridine and 1.15 ml of triethylamine is bubbled at room temperature at -5 to 0 ° C for several minutes with hydrogen sulfide. The reaction solution was stirred at 0 ° C for 16 hours and at room temperature for a further 24 hours. Nitrogen is then introduced into the reaction solution for 3 hours. The solution is poured into 150 ml of ice / water and the aqueous phase is extracted twice with tert-butyl methyl ether. The combined organic phases (the extracts were washed successively twice with water, once with 2 N citric acid solution, once with water and once with saturated sodium chloride solution. The organic phase was dried and the solvent was evaporated under reduced pressure to give a yellow oil which was stirred with a small amount After addition of petroleum ether, it is cooled in an ice / water bath and the precipitated colorless crystals are filtered off with suction.

Yield: 550 mg (16% of theory) Melting point: 148-154 ° C R.f-value: 0.28 (silica gel, cyclohexane / ethyl acetate = 1: 1)

Analogously to Example X, the following compound is obtained:

1) 1-4- (Benzyloxy) benzoic acid-thioamide

The reaction solution was poured into water and the precipitate was filtered off with suction. The solid was dissolved in ethyl acetate and the solution was dried over sodium sulfate. After evaporation of the solution under reduced pressure, the product precipitates.

Melting point: 172-174 ° C.

Example XI

3- [4- (2-Chloroacetyl) phenyl] propionic acid ethyl ester

23.7 g of chloroacetyl chloride were added dropwise at 0 ° C to 56.0 g of aluminum chloride in 150 ml of dichloroethane. 35.6 g of 3-phenyl-propionic acid ethyl ester are then added dropwise, maintaining the temperature between -5 and 5 ° C. Stir 3 hours at room temperature. The reaction suspension is poured into a mixture of ice and 30 ml of concentrated hydrochloric acid, the phases are separated and the aqueous phase is extracted twice with chloroform. The combined organic phases are washed with water and dried over magnesium sulphate. The solvent was removed under reduced pressure, triturated with petroleum ether and filtered off with suction.

Yield: 44.2 g (87% of theory) Rf value: 0.73 (silica gel, cyclohexane / ethyl acetate = 1: 1)

Example XII

2- [4- (benzyloxy) phenyl] -4- [2- (methoxycarbonyl) ethyl] -1,3

A solution of 14.0 g of 4- (benzoyloxy) -benzoic acid thioamide and 12.0 g of 4-bromo-3-oxo-butanecarboxylic acid methyl ester in 1000 ml of methanol is heated under reflux for 24 hours. The solvent was removed under reduced pressure and the residue was partitioned between methylene chloride and dilute sodium carbonate solution. The organic phase is shaken once with dilute sodium carbonate solution and once with water, dried over sodium sulfate and the solvent is removed under reduced pressure. The residue was recrystallized from methanol.

Yield: 15.0 g (74% of theory)

Rf value: 0.25 (silica gel, methylene chloride / ethyl acetate =

19: 1)

Example XIII

4- (2-carboxyethyl) -2- (4-hydroxyphenyl) -1,3-thiazole

A solution of 8.0 g of 2- [4- (benzoyloxy) phenyl] -4- [2- (methoxycarbonyl) ethyl] -1,3-thiazole in 200 ml of glacial acetic acid and 40 ml of methanol saturated with hydrogen chloride in the presence of 4.0 g 10% palladium on carbon is hydrogenated at room temperature

1.5 hours under a hydrogen pressure of 1 bar. The catalyst is filtered off and the filtrate is evaporated under reduced pressure. The residue is heated to boiling with ethyl acetate, cooled and the precipitate is filtered off with suction.

Yield: 5.4 g (96% of theory) Melting point: 224-226 ° C R.f-value: 0.53 (silica gel, toluene / dioxane / ethanol / glacial acetic acid = 9: 1: 1: 0.6)

Example XIV

2- (4-hydroxy-phenyl) -4- [2- (metoxykarbony1) ethyl] -1,3-thiazole

Solution 5.0 g of 4- (2-carboxyethyl) -2- (4-hydroxyphenyl) -

1,3-thiazole in 100 ml of methanol and 10 ml of hydrogen chloride-saturated methanol were stirred at room temperature for 16 hours. The solvent was evaporated under reduced pressure. The residue is heated in about 100 ml of water on a steam bath, then cooled in an ice bath and the precipitate is filtered off with suction.

Yield: 4.2 g (79% of theory) Melting point: 103-105 ° C R.f-value: 0.33 (silica gel, cyclohexane / ethyl acetate = 2: 1)

Example XV

4- [4- [2- (ethoxycarbonyl) ethyl] phenyl] -2-methyl-imidazole

A suspension of 5.1 g of 3- [4- (2-chloroacetyl) phenyl] propionate, 2.3 g of acetamidine hydrochloride and 4.7 g of sodium carbonate in 20 ml of anhydrous ethanol was heated at reflux for 2 hours. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic phase is washed three times with water, dried over magnesium sulphate and the solvent is evaporated off under reduced pressure. The residue is chromatographed on cyclohexane / ethyl acetate (3: 7) on activity II alumina.

Yield: 900 mg (17% of theory)

Rf value: 0.23 (AloxN, ethyl acetate / cyclohexane = 7: 3)

Example XVI [4- (1-benzyl-4-piperazinyl) benzoyl] hydrazine g N- [4- (benzyl-4-piperazinyl) benzoyl] -N '- (tert-butyloxycarbonyl) hydrazine is dissolved in 30 ml of methylene chloride, mixed with 15 ml of trifluoroacetic acid and stirred at room temperature for 4 hours. Evaporate, evaporate twice with acetone and partition the residue between 2 N sodium hydroxide and ethyl acetate. The ethyl acetate phases are evaporated and the residue is purified over silica gel (eluent: methylene chloride / methanol = 40: 1 to 25: Yield: 0.82 g (36% of theory). Melting point: 168-170 ° C Rf value: 0.51 (silica gel, methylene chloride / methanol = 9: 1)

Example XVII

N- [4- (1-benzyl-4-piperazinyl) benzoyl] -N '- (tert-butyloxycarbonyl) hydrazine g of 4- (1-benzyl-4-piperazinyl) benzoic acid is dissolved in 100 ml of dimethylformamide with heating and mixed with 1.05 ml of chlorodiphenylphosphine. It is cooled, 1.5 ml of triethylamine are added, stirred for 1 hour under ice-cooling, mixed with 1.4 g of tert-butyloxycarbonyl-hydrazine, stirred for 5 days at room temperature and evaporated. The residue was mixed with ethyl acetate and shaken with water to filter off the solid formed. The ethyl acetate phase is washed with sodium bicarbonate solution and evaporated. The residue is crystallized by rubbing with ethyl acetate / petroleum ether.

Yield: 0.94 g (23% of theory) Melting point: 162-165 DEG C. Rf value: 0.45 (silica gel, methylene chloride / methanol = 9: 1)

Example XVIII

4- (1-Benzyl-4-piperazinyl) benzoic acid

A mixture of 4- (1-benzyl-4-piperazinyl) benzoic acid nitrile (29.8 g), potassium hydroxide (48 g) and glycol (200 ml) was added.

- Heat at reflux for 47 hours. The glycol is further distilled off under vacuum, the residue is mixed with water and acidified with glacial acetic acid and the precipitated product is filtered off, washed with acetone.

Yield: 31.4 g (99% of theory) Melting point: 225-227 ° C

R.f-value: 0.57 (silica gel, methylene chloride / methanol 9: 1)

Example XIX

4- (1-Benzyl-4-piperazinyl) benzoic acid nitrile g of 4-fluorobenzonitrile, 37.3 ml of N-benzylpiperazine and 36.7 ml of N-ethyl-diisopropylamine were heated together at 140 ° C for 8 hours. Pour into water and extract with methylene chloride. The organic phases are evaporated and the residue is triturated with ether / petroleum ether.

Yield: 29.8 g (50% of theory). Melting point: 106 DEG-108 DEG C. Rf value: 0.89 (silica gel, methylene chloride / methanol 9: 1).

Example XX [[1- [1- (tert-butyloxycarbonyl) -4-piperidyl] -4-piperidyl] carbonyl] hydrazine g 1- [1- (tert-butyloxycarbonyl) -4-piperidyl] -4-ethoxycarbonyl-piperidine and 10 ml of hydrazine hydrate was heated under reflux in 20 ml of methanol for 4 hours. Evaporate and triturate the residue with ether.

Yield: 0.72 g (76% of theory)

Rf value: 0.42 (silica gel, methylene chloride / methanol 4: 1)

Example XXI

1- [1- (tert-Butyloxycarbonyl) -4-piperidyl] -4-ethoxycarbonylpiperidine

24.9 g of 1-tert-butyloxycarbonyl-4-piperidone 19.3 g of piperidine-4-carboxylic acid ethyl ester and 46.5 ml of titanium isopropanol are stirred at room temperature for 1 hour, mixed with 170 ml of ethanol and 5 g of cyanoborohydride. The mixture was stirred at room temperature for 20 hours. 34 ml of water are added, filtered, the filtrate is evaporated, extracted with ethyl acetate and the extract is evaporated. The residue is chromatographed for purification (silica gel, eluent: cyclohexane / ethyl acetate = 2: 3)

Yield: 32.9 g (77% of theory)

Rf value: 0.44 (silica gel, ethyl acetate).

Example 1

2- [4- [1- (tert-butyloxycarbonyl) -4-piperidyl] phenyl] -5 - [[2 (methoxycarbonyl) ethyl] aminocarbonyl] -1,3,4-thiadiazole

Solution 2.0 g of 2- [4- [1- (tert-butyloxycarbonyl) -4-piperidyl] phenyl] -5-carboxy-1,3,4-thiadiazole, 1.77 g of 2 - [(1H) -benzotriazole -1-yl] -1,1,3,3-tetramethyluronium tetrafluoroborate, 0.72 g of b-alanine methyl ester hydrochloride, 0.75 g of 1-hydroxy (1H) -benzotriazole and 1.4 g of N-methylmorpholine in 50 ml of dimethylformamide was stirred at room temperature for 5 hours. The solvent was removed under reduced pressure. Water was added to the residue and the aqueous phase was extracted with ethyl acetate. The organic phase is dried over sodium sulfate and the solvent is removed under reduced pressure. The crude product is chromatographed over silica gel with methylene chloride / methanol (9: 1) and the product obtained after removal of the solvent is triturated with ethyl acetate and filtered off with suction.

Yield: 1.5 g (62% of theory) Melting point: 176 DEG-178 DEG C. Rf value: 0.76 (silica gel, ethyl acetate / cyclohexane = 4: 1).

Example 2

2 - [[2- (methoxycarbonyl) ethyl] aminocarbonyl] -5 [4- (4-piperidyl) phenyl] -1,3,4-thiadiazole hydrochloride

A solution of 1.4 g of 2- [4- [1- (tert-butyloxycarbonyl) -4-piperidyl] phenyl] -5 - [[2- (methoxycarbonyl) ethyl] aminocarbonyl] -1,3,4-thiadiazole in 40 ml of dioxane and 40 ml of ether saturated with hydrogen chloride were stirred at room temperature for 2.5 hours. The precipitated product is filtered off with suction and washed with ether.

Yield: 1.05 g (85% of theory)

Melting point: 250-255 ° C Mass spectrum: M ⁺ = 374

Rf value: 0.16 (silica gel, methylene chloride / methanol / conc. Ammonia = 9: 1: 0.1)

The following compounds are obtained analogously:

1) 2- [4- (Methoxycarbonyl) butyl] -5- [4- (4-piperidyl) phenyl] -1,3,4-thiadiazole hydrochloride Mass Spectrum: (M + H) ⁺ = 360

R.f-value: 0.70 (silica gel, methylene chloride / methanol / conc. Ammonia = 4: 1: 0.25)

2) 2- [cis-4- (methoxycarbonyl) cyclohexyl] -5- [4- (4-piperidyl) phenyl] -1,3,4-thiadiazole hydrochloride

The reaction solution was added and treated with hydrogen chloride saturated with methanol. After stirring at room temperature for one hour, the solvent was evaporated under reduced pressure.

mass spectrum: M ⁺ = 385

Rf value: 0.45 (silica gel, methylene chloride / methanol / conc.

ammonia = 4: 1: 0.25)

3) 2- [trans-4- (methoxycarbonyl) cyclohexyl] -5- [4- (4-piperidyl) phenyl] -1,3,4-thiadiazole hydrochloride

The reaction is carried out in a 1: 1: 1 mixture of dioxane, hydrogen chloride saturated ether and hydrogen chloride saturated methanol. After stirring for three hours, the precipitated product is filtered off with suction and washed with ether.

Mass Spectrum: M ⁺ = 385

Rf value: 0.67 (silica gel, methylene chloride / methanol / conc. Ammonia = 4: 1: 0.25)

4) 2- [trans-4- (methoxycarbonyl) cyclohexyl] -4- [4- (4-piperidyl) phenyl] imidazole dihydrochloride;

5) 2- [trans-4- (methoxycarbonyl) cyclohexyl] -4- [3,4-dihydro-4-piperidyl) phenyl] -1,3-thiazole hydrochloride

6) 2 - [[3- (methoxycarbonyl) propyl] amino-4- [4- (4-piperidyl) phenyl] -1,3-thiazole dihydrochloride

7) 2- [trans-4- (methoxycarbonyl) cyclohexyl] -5- [4- (1-piperazinyl) phenyl] -1,3,4-thiadiazole dihydrochloride

8) 4- [4- [2- (ethoxycarbonyl) ethyl] phenyl] -2- [2- (4-piperidyl) ethyl] -1,3-thiazole

9) 4- [4- [2- (methoxycarbonyl) ethyl] phenyl] -2- [2- (4-piperidyl) ethyl] imidazole dihydrochloride

10) 4- [4- [2- (methoxycarbonyl) ethyl] phenyl] -1-methyl-2- [2- (4-piperidyl) ethyl] imidazole dihydrochloride

11) 4- [4- [2- (ethoxycarbonyl) ethyl] phenyl] -2-methyl-1- [2- (4-piperidyl) ethyl] imidazole dihydrochloride hydrate

The reaction is carried out in ethanol with the addition of ethereal hydrochloric acid.

R.f-value: 0.48 (reverse phase, RP8, methanol / 5% sodium chloride solution = 6: 4)

Elemental analysis: 1.95 HCl.

calculated: 57.82% C, 7.70% H, 9.15% N, 14.95% C1 found 57.62% C, 7.68% H, 9.16% N, 15.07% C1

12) 2- [4- [2- (methoxycarbonyl) ethyl] phenyl] -1-methyl-4 - [(3-pyrrolidinyl) oxymethyl] imidazole dihydrochloride

13) 4- [4- [2- (methoxycarbonyl) ethyl] -2- [N - [(4-piperidyl) carbonyl] -N-methylamino] -1,3-thiazole hydrochloride

14) 2- [4- [2- (methoxycarbonyl) ethyl] phenyl] -4 - [(4-piperidyl) aminocarbonyl] -1,3-thiazole hydrochloride

15) 2- [2- (methoxycarbonyl) ethyl] -4- [4- [N - [(4-piperidyl) carbonyl] -N-methyl-amino] phenyl] -1,3-thiazole hydrochloride

16) 2- [2- (methoxycarbonyl) ethyl] -5- [2- [2- (4-piperidyl) ethyl] -5-pyrimidyl] -1,3,4-thiadiazole hydrochloride

17) 4- [2- (methoxycarbonyl) ethyl] -2- [4 - [(4-piperidyl) methoxy] phenyl] -1,3-thiazole dihydrochloride dihydrate

The reaction is carried out in hydrogen chloride-saturated methanol.

The precipitate is filtered off with suction and washed with tert-butyl methyl ether.

Melting point: 95-98 ° C

R.f-value: 0.28 (reverse phase, RP8, methanol / 5% sodium chloride solution = 6: 4)

18) 4- [4 - [(methoxycarbonyl) methyloxy] phenyl] -2- [2- (4-piperidyl) ethyl] -1,3-thiazole hydrochloride

19) 2- [trans-4- (ethoxycarbonyl) cyclohexyl] -5- [4- (4-piperidyl) phenyl] -1,3,4-thiadiazole hydrochloride

The reaction is carried out in a 2: 1 mixture of methylene chloride and trifluoroacetic acid. The product is treated with a mixture of ethanol and ethereal hydrochloric acid.

Melting point: 274-280 ° C

Ry-value: 0.41 (silica gel, methylene chloride / methanol 9: 1)

20) 2- [trans-4- (ethoxycarbonyl) cyclohexyl] -5- [1- (4-piperidyl) -4-piperidyl] -1,3,4-thiadiazole hydrochloride * The procedure is analogous to Example 19.

Melting point:> 320 ° C

Ry-value: 0.67 (reverse phase, RP18 plate, methanol / 5% sodium chloride solution = 6: 4)

Example 3

2 - [(2-carboxyethyl) aminocarbonyl] -5- [4- (4-piperidyl) phenyl] -1,3,4-thiadiazole hydrochloride

A suspension of 2 - [[2- (methoxycarbonyl) ethyl] aminocarbonyl] -5- [4- (4-piperidyl) phenyl] -1,3,4-thiadiazole hydrochloride (550 mg) in 100 ml of 6 N hydrochloric acid was added for 3 hours Stir at room temperature. After an additional 500 ml of 6 N hydrochloric acid was added, it was stirred for an additional hour. The solvent was removed under reduced pressure and the crude product was triturated with a small amount of water and filtered off with suction.

Yield: 480 mg (91% of theory)

Mass spectrum: M ⁺ = 360 Ry-value: 0.06 (silica gel, methylene chloride / methanol / conc.

ammonia = 4: 1: 0.25)

The following compounds are obtained analogously:

1) 2- (4-carboxybutyl) -5- [4- (4-piperidyl) phenyl] -1,3,4-oxadiazole

The crude product is purified by chromatography.

Mass Spectrum: M ⁺ = 329

- 53 R f value: 0.35 (silica gel, methylene chloride / methanol / conc. Ammonia = 2: 1: 0.25)

2) 2- (cis-4-carboxycyclohexyl) -5- [4- (4-piperidyl) phenyl] -1,3,4-oxadiazole hydrochloride

Melting point:> 310 ° C Mass spectrum: M ⁺ = 371

R.f-value: 0.17 (silica gel, methylene chloride / methanol / conc. Ammonia = 4: 1: 0.25)

3) 1- [6- (4-amidinophenyl) -3-pyridazyl] -4- [2- (n-butanesulfonylamino) -2-carboxyethyl] imidazole hydrochloride Mass Spectrum: (M + H) ⁺ = 472

Rf value: 0.20 (silica gel, methylene chloride / methanol / conc. Ammonia = 2: 1: 0.25)

4) 4- [4- (2-carboxyethyl) phenyl] -2- [2- (4-piperidyl) ethyl] -1,3-thiazole

The product of Example 9 was heated with 3 N hydrochloric acid on a steam bath for one hour.

Melting point: decomposition at 168 ° C

Rf value: 0.38 (reverse phase RP8, methanol / 5% sodium chloride solution = 6: 4)

5) 2- (trans-4-carboxycyclohexyl) -4- [4- (4-piperidyl) phenyl] -imidazole dihydrochloride

6) 2- (trans-4-carboxycyclohexyl) -1-methyl-

4- [4- (l-methyl-4-piperidinyl) phenyl] imidazole

7) 2- (trans-4-carboxycyclohexyl) -1-methyl-

4- [4- (4-piperidinyl) phenyl] imidazole

8) 2- (trans-4-carboxycyclohexyl) -4- [4- (3,4-dehydro-4-piperidyl) phenyl] -1,3-thiazole hydrochloride

9) 2 - [(3-carboxypropyl) amino] -4- [4- (4-piperidyl) phenyl] -1,3-thiazole dihydrochloride

10) 2- (trans-4-carboxycyclohexyl) -5- [4- (1-piperazinyl) phenyl] -1,3,4-thiadiazole dihydrochloride

11) 4- [4- (2-carboxyethyl) phenyl] -2- [2- (4-piperidyl) ethyl] imidazole dihydrochloride

12) 4- [4- (2-carboxyethyl) phenyl] -1-methyl-2- [2- (4-piperidyl) ethyl] imidazole dihydrochloride

13) 4- [4- (2-carboxyethyl) phenyl] -2-methyl-1- [2- (4-piperidyl) ethyl] imidazole dihydrochloride hydrate

Rf value: 0.64 (reverse phase, RP8, methanol / 5% sodium chloride solution = 6: 4)

Elemental analysis: 1.95 HCl. 0.6 H ₂ 0 calculated 56.77% C, 7.37% H, 9.84% N, 16.40% Found C 1 56.77% C, 7.13% H, 9.93% N, 16 , 34% C1

14) 2- [4- (2-carboxyethyl) phenyl] -1-methyl-4 - [(3-pyrrolidinyl) oxymethyl] -imidazole dihydrochloride

15) 4- [4- (2-carboxyethyl) phenyl] -2- [N - [(4-piperidyl) carbonyl] -N-methylamino] -1,3-thiazole hydrochloride

16) 2- [4- (2-carboxyethyl) phenyl] -4 - [(4-piperidyl) aminocarbonyl] -1,3-thiazole hydrochloride

17) 2- (2-carboxyethyl) -4- [4- [N - [(4-piperidyl) carbonyl] -N-methylamino] phenyl] -1,3-thiazole hydrochloride

18) 2- (2-carboxyethyl) -5- [2- [2- (4-piperidyl) ethyl] -5-pyrimidinyl] -1,3,4-thiadiazole hydrochloride

19) 1- [3- (4-amidinophenyl) -6-pyridazinyl] -3- [2-carboxy-2- (phenylsulfonylamino) ethyl] indole hydrochloride

20) 2- (4-amidinophenyl) -4- [4- [2- (acetylamino) -2-carboxyethyl] phenyl] -5-methyl-1,3-thiazole hydrochloride

21) 4- (4-amidinophenyl) -2- [4- [2- (methanesulfonylamino) -2-carboxyethyl] phenyl] -1-methyl-imidazole hydrochloride

22) 4- (2-Carboxyethyl) -2- [4 - [(4-piperidyl) methoxy] phenyl] -1,3-thiazole dihydrochloride hydrate

Melting point: decomposition at 225 C ^q

Rf value: 0.36 (reverse phase, RP8, methanol / 5% sodium chloride solution = 6: 4)

23) 4- [4- (carboxymethyloxy) phenyl] -2- [2- (4-piperidyl) ethyl] -1,3-thiazole hydrochloride

24) 4- [4- (2-carboxyethyl) phenyl] -2- [2- (4-piperidyl) ethyl] -1,3-thiazole hydrochloride

25) 4- [4- (2-carboxyethyl) cyclohexyl] -1- [2- (4-quinuclidinyl) ethyl] -2-methyl-imidazole dihydrochloride

26) 2- [4- (1-benzyl-4-piperazinyl) phenyl] -5- (trans-4-carboxycyclohexyl) -1,3,4-thiadiazole mass spectrum: M ⁺ = 462

Rf value: 0.15 (reverse phase plate RP8, methanol / 5% sodium chloride solution = 6: 4)

27) 2- (trans -4-carboxycyclohexyl) -5- [1- (4-piperidyl) -4-piperidyl] -1,3,4-thiazole

Melting point: 320 ° C

Rf value: 0.67 (reverse phase, RP8 plate, methanol / 5% sodium chloride solution = 6: 4)

Example 4

2- [4- [1- (tert-butyloxycarbonyl) -4-piperidyl] phenyl] -5- [4 (methoxycarbonyl) butyl] -1,3,4-thiadiazole

A solution of 2.4 g of N- [4- [1- (tert-butyloxycarbonyl) -4-piperidyl) benzoyl] -N '- [[4- (methoxycarbonyl) butyl] carbonyl] hydrazine and 2.1 g of 2,4- bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's reagent) in 40 ml tetrahydrofuran was heated under reflux for 30 minutes. The solvent was then evaporated under reduced pressure and the residue was chromatographed over silica gel.

Yield: 2.4 g (quantitative) Melting point: 111-113 ° C Mass spectrum: M ⁺ = 459

Rf value: 0.38 (silica gel, ethyl acetate / cyclohexane = 1: 1)

The following compounds are obtained analogously:

1) 2- [4- [1- (tert-butyloxycarbonyl) -4-piperidyl] phenyl] -5 [cis-4- (methoxycarbonyl) cyclohexyl] -1,3,4-thiadiazole

M.p .: 130-132 ° C mass spectrum: M ⁺ = 485

Rf value: 0.49 (silica gel, ethyl acetate / cyclohexane = 1: 1)

2) 2- [4- [1- (tert-butyloxycarbonyl) -4-piperidyl] phenyl] -5 [trans -4- (methoxycarbonyl) cyclohexyl] -1,3,4-thiadiazole

Melting point: 180-182 ° C

Rf value: 0.57 (silica gel, cyclohexane / ethyl acetate = 1: 1)

3) 2- [4- [4- (tert-butyloxycarbonyl) -1-piperazinyl] phenyl] -5 [trans -4- (methoxycarbonyl) cyclohexyl] -1,3,4-thiadiazole

4) 2- [4- [1- (tert-butyloxycarbonyl) -1-piperidyl] phenyl] -5 [trans -4- (ethoxycarbonyl) cyclohexyl] -1,3,4-thiadiazole

Melting point: 164-166 ° C

Rf value: 0.78 (silica gel, methylene chloride / methanol = 9: 1)

5) 2- [trans -4- (ethoxycarbonyl) cyclohexyl] -5- [4- (1-benzyl-4-piperazinyl) phenyl] -1,3,4-thiadiazole

Melting point: 166-170 ° C

Rf value: 0.63 (silica gel, methylene chloride / methanol = 9: 1)

6) 2- [1- [1- (tert-butyloxycarbonyl) -4-piperidyl] -4-piperidyl] -5- [trans-4- (ethoxycarbonyl) cyclohexyl] -1,3,4-thiadiazole

Rf value: 0.49 (silica gel, methylene chloride / methanol = 9: 1)

Example 5

2- (4-Carboxybutyl) -5- [4- (4-piperidyl) phenyl] * 1,3,4-thiadiazole hydrochloride

Solution 1.0 g of 2- [4- (methoxycarbonyl) butyl] - hydrochloride

Of 5- [4- (4-piperidyl) phenyl] -1,3,4-thiadiazole and 0.22 g of lithium hydroxide hydrate in 30 ml of tetrahydrofuran and 24 ml of water were stirred at room temperature for 60 minutes. The reaction solution was acidified with 1 N hydrochloric acid. Excess tetrahydrofuran was evaporated under reduced pressure and the precipitate was filtered off with suction and washed with a little water.

Yield: 0.80 g (83% of theory) Mass Spectrum: M ^{@ +} = 345 R @ 20 -value: 0.18 (silica gel, methylene chloride / methanol / conc.

ammonia = 4: 1: 0.25)

The following compounds are obtained analogously:

1) 3- (4-carboxy-cyclohexyl) -4-phenyl-5- [4- (4-piperidyl) phenyl] -1,2,4-triazole

After acidification, the solvent mixture is evaporated under reduced pressure and the crude product is chromatographed over silica gel. Mass Spectrum: M ⁺ = 430

Rf value: 0.12 (silica gel, methylene chloride / methanol / conc. Ammonia = 4: 1: 0.25)

2) 3- (4-Carboxybutyl) -4-phenyl-5- [4- (4-piperidyl) phenyl] -

1,2,4-triazole

After acidification, the solvent mixture is evaporated under reduced pressure and the crude product is chromatographed over silica gel. Mass Spectrum: M ⁺ = 404

Rf value: 0.24 (silica gel, methylene chloride / methanol / conc. Ammonia = 2: 1: 0.25)

3) 2- (trans-4-carboxycyclohexyl) -5- [4- (4-piperidyl) phenyl] -1,3,4-thiadiazole hydrochloride Mass Spectrum: M ⁺ = 371

R.f-value: 0.09 (silica gel, methylene chloride / methanol / conc. Ammonia = 4: 1: 0.25)

4) 2- (4-carboxycyclohexyl) -5- [4- (4-piperidyl) phenyl] -1,3,4-oxadiazole

After acidification, the solvent mixture is evaporated under reduced pressure and the crude product is chromatographed over silica gel. mass spectrum: M ⁺ = 355

Rf value: 0.09 (silica gel, methylene chloride / methanol / conc. Ammonia = 4: 1: 0.25)

5) 2- (trans-4-carboxycyclohexyl) -5- [4- (2,2,6,6-tetramethyl-4-piperidyl) phenyl] -1,3,4-thiazole hydrochloride

6) 2- (trans-4-carboxycyclohexyl) -4- [4- (4-cyano-4-piperidyl) phenyl] -1-methyl-imidazole dihydrochloride

Example 6

2- [4- (methoxycarbonyl) butyl] -5- [4- (4-piperidyl) phenyl] -1,3,4-oxadiazole

A solution of 2.0 g of N- [4- [1- (tert-butyloxycarbonyl) -4-piperidyl) benzoyl] -N '- [[4- (methoxycarbonyl) butyl] carbonyl] hydrazine and 0.3 ml of pyridine in 18 ml The thionyl chloride was stirred at room temperature for 3 hours. It is then heated to reflux for 45 minutes. The excess thionyl chloride was evaporated under reduced pressure, the residue was treated with toluene and the solvent was evaporated under reduced pressure. The residue is chromatographed over silica gel. Yield: 0.24 g (15% of theory) Mass spectrum: M ^{@ +} = 343

Rf value: 0.16 (silica gel, methylene chloride / methanol / conc. Ammonia = 8: 1: 0.1)

The following compound is obtained analogously:

1) 2- [4- (methoxycarbonyl) cyclohexyl] -5- [4- (4-piperidyl) phenyl] -1,3,4-oxadiazole mass spectrum: M ⁺ = 369

Rf value: 0.24 (silica gel, methylene chloride / methanol / conc. Ammonia = 9: 1)

Example 7

3- [4- (methoxycarbonyl) -cyclohexyl] -4-phenyl-5- [4- (4-piperidyl) -phenyl] -1,2,4-triazole

To a solution of 785 mg of aniline in 5 ml of 1,2-dichlorobenzene was added 220 mg of phosphorus trichloride and briefly heated to 60 ° C. Then 700 mg of N- [4- [4- (tert-butyloxycarbonyl) -4-piperidyl) -benzoyl] -N '- [[cis -4- (methoxycarbonyl) cyclohexyl] carbonyl] hydrazine is added and heated for 2.5 hours under reflux. The solvent was evaporated under reduced pressure. Water and an equal amount of 1 N sodium hydroxide are added to the residue until the solution is alkaline. The aqueous phase is extracted once with methylene chloride and once with ethyl acetate. The combined organic phases are dried over sodium sulfate and the solvent is evaporated under reduced pressure. The residue is chromatographed over silica gel.

Yield: 550 mg (86% of theory) Mass spectrum: (M + H) ⁺ = 445 Rf -value: 0.36 (silica gel, methylene chloride / methanol / conc.

ammonia = 4: 1: 0.25)

The following compound is obtained analogously:

1) 3- [4- (methoxycarbonyl) butyl] -4-phenyl-5- [4- (4-piperidyl) phenyl] -1,2,4-triazole

R.f-value: 0.34 (silica gel, methylene chloride / methanol / conc. Ammonia = 4: 1: 0.25)

Example

- [6- (4-amidinophenyl) -3-pyridazinyl] -4- [2- (n-butanesulfonyl-4-amino) -2- (methoxycarbonyl) ethyl] imidazole

A solution of 700 mg of 4- [2- (n-butanesulfonylamino) -2- (methoxycarbonyl) ethyl] -1- [6- (4-cyanophenyl) -3-pyridazinyl] imidazole in 250 mL of anhydrous methanol is introduced at 0 ° C. with stirring for one hour hydrogen chloride. After stirring at room temperature for 16 hours, the solvent was evaporated under reduced pressure at a bath temperature of 30 ° C. The residue was dissolved in 50 ml of anhydrous methanol and stirred at room temperature for 4 hours after addition of 3 g of ammonium carbonate. The precipitate was filtered off with suction and then washed with anhydrous methanol. The filtrate was evaporated under reduced pressure and the residue was chromatographed over silica gel. Yield: 250 mg (34% of theory) Melting point: 227-229 [deg.] C. Mass spectrum: (M + H) &lt; ^{+ &gt}; = 486 [.alpha.] D-Value: 0.09 (silica gel, methylene chloride / methanol / conc. Ammonia = 4: 1) 0.25).

The following compounds are obtained analogously:

1) 1- [3- [4-amidinophenyl] -6-pyridazinyl] -3- [2- (methoxycarbonyl) -2- (phenylsulfonylamino) ethyl] indole

2) 4- [4- [2- (acetylamino) -2- (methoxycarbonyl) ethyl] phenyl] -2 (4-amidinophenyl) -5-methyl-1,3-thiazole

3) 4- [4-amidinophenyl] -1-methyl-2- [4- [2- (methanesulfonylamino-

2- (methoxycarbonyl) ethyl] phenyl] imidazole

Example 9

2- [2- [1- (tert -butyloxycarbonyl) -4-piperidinyl] ethyl] -4- [4- [2- (ethoxycarbonyl) ethyl] phenyl] -1,3-thiazole

A solution of 550 mg of 1- (tert-butyloxycarbonyl) -4- (2-thioamidoethyl) piperidine and 530 mg of propionic acid in 30 ml of methanol is heated under reflux for 14 hours. Then 500 mg of ethyldiisopropylamine and a solution of di-tert-butyl pyrocarbonate are added dropwise at room temperature. Stir 10 minutes at room temperature and remove the solvent under reduced pressure. The residue is chromatographed over silica gel.

Yield: 300 mg (32% of theory) R.f-value: 0.26 (silica gel, cyclohexane / ethyl acetate = 8: 2)

Example 10

2- [4 - [[1- (tert -butyloxycarbonyl) -4-piperidylJmetyloxy] phenyl] -

4- [2- (methoxycarbonyl) ethyl] -1,3-thiazole

To a solution of 4.09 g of 2- (4-hydroxyphenyl) -4- [2- (methoxycarbonylethyl) -1,3-thiazole in 1000 ml of anhydrous dimethylformamide is added 1.7 g of potassium tert-butylate and stirred for 15 hours. 4.5 g of 1- (tert-butyloxy) -4- (mesyloxymethyl) piperidine was added and heated at 60 ° C for 24 hours. After the addition of an additional 0.9 g of potassium tert-butylate and 2.2 g. g of 1- (tert-butyloxycarbonyl) -4- (mesyloxymethyl) piperidine was stirred for 2 days at 60 [deg.] C. The solvent was removed under reduced pressure and the residue was chromatographed over silica gel.

Yield: 4.3 g (68% of theory) Melting point: 75-77 ° C Rf value: 0.70 (silica gel, methylene chloride / ethyl acetate =

4: 1)

Example 11

1- [2- [1- (tert -butyloxycarbonyl) -4-piperidinyl] ethyl] -4- [4- [2- (etoxykarbony1) ethyl] phenyl] -2-methyl-imidazole

A suspension of 820 mg of 4- [4- [2- (ethoxycarbonyl) ethyl] phenyl] -2-methylimidazole and 140 mg of 55% sodium hydride in mineral oil in 5 ml of dimethylformamide was stirred at room temperature for 30 minutes. 980 mg of 1- (tert-butyloxycarbonyl) 4- [2- (methanesulfonyloxy) ethyl] piperidine are then added and stirred for 2 hours at room temperature. The solvent was evaporated under reduced pressure and the residue was partitioned between water and ethyl acetate. After neutralization of the aqueous phase with 2 N citric acid, the aqueous phase is extracted several times with ethyl acetate. The combined ethyl acetate phases are washed with water, dried over magnesium sulphate and the solvent is evaporated under reduced pressure. The residue is chromatographed through activity III alumina with cyclohexane / ethyl acetate (1: 1).

Yield: 650 mg (43% of theory) Rf value: 0.29 (aluminum oxide N, cyclohexane / ethyl acetate 1: 1)

Example 12

2- [trans-4- (isobutyloxycarbonyl) -cyclohexyl] 5- [4- (4-piperidyl) phenyl] -1,3,4-thiadiazole hydrochloride

To a stirred suspension of 0.5 g of 2- (trans-4-carboxycyclohexyl) -5- [4- (4-piperidyl) phenyl] -1,3,4-thiadiazole hydrochloride in 25 ml of isobutanol was added hydrogen chloride gas for 1.5 hours. It is stirred for 16 hours at room temperature, evaporated, the residue is triturated with acetone and filtered off with suction.

Yield: 0.54 g (95% of theory) Melting point: 265-267 ° C Rf value: 0.63 (reverse phase, plate RP18, methanol / 5% sodium chloride solution = 6: 4)

The following compound is obtained analogously:

1) 2- [trans-4- (isopropyloxycarbonyl) -cyclohexyl] -5- [4- (4-piperidyl) phenyl] -1,3,4-thiadiazole hydrochloride

Rf value: 0.67 (silica gel, methylene chloride / methanol / conc. Ammonia = 4: 1: 0.25)

Example 13

2- (trans-4- (carboxycyclohexyl) -5- [4- (1-piperazinyl) phenyl] -

1,3,4-thiadiazole

0.08 g of 2- [4- (1-benzyl-4-piperazinyl) phenyl] -5- (trans-4-carboxycyclohexyl) -1,3,4-thiadiazole was treated with hydrogen at room temperature for 7 days in 30 ml of dimethylformamide at room temperature. 0.1 MPa.

R.f-value: 0.29 (reverse phase plate RP18, methanol / 5% sodium chloride solution = 6: 4)

The following compound is obtained analogously:

1) 2- [trans-4- (ethoxycarbonyl) cyclohexyl] -5- [4- (1-piperazinyl) phenyl] -1,3,4-thiadiazole hydrochloride

Rf value: 0.35 (silica gel, methylene chloride / methanol = 9: 1) mass spectrum: M ⁺ = 400

Example 14

Dry ampoule with 2.5 mg active Ingredients: per ml active substance 2.5 mg mannitol 50.9 mg water for injection purposes etc. 1 ml

Preparation:

The active substance and mannitol are dissolved in water. After filling, freeze-dried. Dissolve the solution for use with water for injections.

Example

Dry ampoule with 35 mg active 2 ml Ingredients: active substance 35.0 mg mannitol 100.0 mg water for injection purposes etc. 2.0 ml

Preparation:

The active substance and mannitol are dissolved in water. After filling, freeze-dried. Dissolve into a ready-to-use solution with water for injection.

Example 16

Tablet with 50 mg of the active substance

Ingredients:

1) active substance 50.0 mg 2) milk sugar 98.0 mg 3) maize starch 50.0 mg 4) polyvinylpyrrolidone 15.0 mg 5) magnesium stearate 2.0 mg 215.0 mg

preparation

1), 2) and 3) are mixed and granulated with an aqueous solution

4). 5) is added to the dried granulate. Tablets are compressed from this mixture, biplanar with a double faced facet with a score line on one side. Tablet diameter: 9 mm.

Example 17

Tablet with 350 mg of the active substance

Ingredients:

1) active substance 350.0 mg 2) milk sugar 136.0 mg 3) maize starch 80.0 mg 4) polyvinylpyrrolidone 30.0 mg 5) magnesium stearate 4.0 mg

preparation

1), 2) and 3) are mixed and granulated with an aqueous solution 4). 5) is added to the dried granulate. Tablets are compressed from this mixture, biplanar with a double faced facet and unilaterally provided with a score line. Tablet diameter: 12 mm.

Example 18

Capsules containing 50 mg of the active substance

composition

1) active substance 50.0 mg 2) dried corn starch 58.0 mg 3) powdered milk sugar 50.0 mg 4) magnesium stearate 2.0 mg

160.0 mg

Preparation:

1) is spread with 3).

2) the powder mixture is filled with the gelatin insertion mass and 4) with vigorous stirring. This on a capsule device into hard capsule size

Example <1

Capsules with 350 mg

Ingredients:

of the active substance

1) active substance 350.0 mg 2) dried corn starch 46.0 mg 3) powdered milk sugar 30.0 mg 4) magnesium stearate 4.0 mg

430.0 mg

Preparation:

1) is rubbed with mixing and the mixture is added 2) to a capsule device of size 0 capsules.

3) · and 4).

to this mass under intense This powder mixture is filled on hard gelatin insertion

Claims (10)

1. Five-membered heterocycles of formula I (I) / where (i) provided that the five-membered heterocyclic ring is not a pyrrolidine, pyrrole, pyrolinone or pyrrolidinone ring and contains at least one carbon atom; and (ii) except for the compounds 3- (4-amidino-phenyl) -1- [4- (2-aminocarboxy- ethyl) phenyl] -2H-pyrazol-5-one and 3- (4-amidinophenyl) - 1- [4- (2-amino-2-methoxycarbonyl-ethyl) phenyl] -2H-pyrazol-5-one, one of the radicals Xy to X ^ represents a group of formulas A - B - C - N < A-B-C-CH 2 or A-B-C-Ca in which A is optionally 1 to 4 alkyl groups, hydroxy-, alkoxy-, phenylalkoxy-, cyano-, aminocarbonyl-, carboxy-, alkoxycarbonyl- or phenylalkoxycarbonyl-substituted cycloalkyl of 5 to 7 carbon atoms in which one unsubstituted methylene group is replaced by R _and -N <, where R _a represents a hydrogen atom, an alkyl group, a phenylalkyl group, a total of 2 to 6 carbon atoms, a phenylalkoxycarbonyl group, an alkenyloxycarbonyl group of 4 to 6 carbon atoms, a total cycloalkoxycarbonyl group 6 to 8 carbon atoms, or R-CO-O- (R ₂ CH) -O-CO- group, wherein an alkyl group having 1 to 5 carbon atoms, cycloalkyl having 5 to 7 carbon atoms, phenylalkyl, C C 1 -C 5, C 5 -C 7 cycloalkoxy, or phenyl; and R ₂ represents a hydrogen atom, a C 1 -C 4 alkyl group, a C 5 -C 7 cycloalkyl group or a phenyl group, and furthermore in the 6- or 7-membered azacycloalkyl groups thus formed, one> CH-unit in the 4-position may be replaced by N and in that 5- to 7-membered azacykloalkylskupinách one unit _-CH2 -CH <can be replaced by -CH = C <unit and the thus formed piperazinyl or homopiperazinyl methylene group adjacent to the nitrogen atom at position 4, it may be replaced by a carbonyl group, a pyridyl or quinuclidinyl group or also when RGR D is N, N-CO-R-NRg-, or _{-NR-SO2-substituted} alkylene or alkenylene group having up to 8 carbon atoms, wherein R 8 to R 8, which may be the same or different, each represent a hydrogen atom, an alkyl or phenylalkyl group, and R 8 represents a carbon alkyl group, a phenylalkyl group or a phenyl group having from 1 to 5 atoms, E represents hydroxy-, alkoxy-, alkylsulfenyl-, r ₃ r ₄ n-, r ₃ o-co-, r ₆ co-nr ₃ -, r ₆ o-co-nr ₃ -, r ₆ so ₂ -nr ₃ or R (4) N-CO-NR (4) substituted by a straight or branched alkylene or alkenylene group having up to 5 carbon atoms, where R ( ₃₎ to R8 are as defined above, a phenyl group which is substituted at the 4-position by R _and NH -CH 2 or R _and NH-C (= NH) - or a phenyl group to which is attached via two adjacent carbon atoms R _{and the} NH-substituted n-alkylene bridge group having 3 or 4 carbon atoms, wherein R _a always has a higher this meaning, B is a bond, alkylene, -OC ^ -, -CH ₂ 0-, -SCF ^ -, -CH ₂ S-, -CONR ₃ -, R ₃ NCO, -CH ₂ NR ₃ -, NR ₃ CH _{A 2-} , -SO ₂ NR ₃ - or -NR ₃ SC> 2-group wherein R ₃ is as defined above and the oxygen or nitrogen atom of residue B is not directly linked to the nitrogen atom of residue A or a five-membered heterocycle, C represents a phenyl group which may be mono or disubstituted by a fluorine, chlorine or bromine atom, an alkyl, trifluoromethyl, hydroxyl, alkoxy, alkylsulfenyl, alkylsulfinyl or alkylsulfonyl group, wherein the substituents may be the same or different, pyridinylene, pyrimidinylene, pyrazinylene, pyrazinylene which may in each case be substituted in the carbon residue by a chlorine atom, an alkyl or alkoxy group, A 1,4-cyclohexenylene-, 1,3-piperidinylene-, 1,4-piperidinylene or 1,4-piperazinylene group, or even if A is not a pyridyl group and at the same time B is an alkylene, -CONH- or -CF2S- group, a bond, wherein at the same time B can only represent a bond when A is an amidinophenyl group, the other of the residues Xf to Xg represents a group of formulas R _b ° - R _b 0 - R _b 0 - CO - E - CO - E - CO - E - D - N <, D - CH < D - C á, or In which »· D stands for -co-nr ₃ -, nr ₃ -co-, -SO ₂ -NR ₃ - or -NR ₃ -SO ₂ - groups well, or hydroxy, alkoxy, alkylsulfenyl-, RGR ^ N-, R ₃ O-CO-, R ₆ CO-NR ₃ -, R ₆ O-CO-NR ₃ -, R ₆ SO ₂ -NR ₃ - or a R 8 R 8 N-CO-NR 8 group substituted by a straight or branched alkylene or alkenylene group, in which the alkylene moiety may each contain 1 to 8 carbon atoms and the alkenylene moiety 2 to 8 carbon atoms and R ₃ to R 8 are as defined above, phenylene a group which may be mono or disubstituted by a fluorine, chlorine or bromine atom, an alkyl-, trifluoromethyl-, hydroxy-, alkoxy-, alkylsulfenyl-, alkylsulfinyl- or alkylsulfonyl group, pyridinylene-, pyrimidinylene-, pyrazinylene-, pyridazinylene or triazinylene group each of the carbon residue can be substituted by chlorine, alkyl or alkoxy, wherein additionally one or two -CH-N- groups may be replaced by a -CO-NR ₃ group joining them, wherein R ₃ is as defined above and one of the nitrogen atoms in place of the residue R ₃ it may also be attached to radical E, provided that it is not a bond and is not attached via an oxygen or sulfur atom to radical D, or it may be attached to the ring atom of any one of radicals Xf-Xg, optionally an alkyl, phenylalkyl or phenyl substituted cycloalkylene group 4 to 5 carbon atoms in which one> CH-unit may be replaced by a nitrogen atom and further a methylene group adjacent to the nitrogen atom may be replaced by a carbonyl group or an alkyl, phenylalkyl or phenyl substituted cycloalkylene group having 6 or 7 carbon atoms, wherein one or two> CH-units may be replaced by a nitrogen atom, in addition in each case one or two methylene groups adjacent to the nitrogen atom may be replaced by a carbonyl group or a C 1 -C 5 alkylene group linked via a Vf radical to a ring atom any of the customs Metal and X ^ X f, wherein RF is a radical NR J wherein R ₃ is as defined above, wherein the oxygen or sulfur moiety can not be directly attached to the nitrogen atom a five-membered ring, E represents a bond, while at the same time C is not a bond and A is 1-methyl- or 1-benzyl-4-piperazinyl or optionally hydroxy-, alkoxy-, alkylsulfenyl-, R ₃ R ₄ N-, R ₃ O-CO-, R ₈ CO -NR ₃ -, R ₈ SO ₂ - NR ₃ - or R ₃ R ₄ N-CO-NR ₃ -substituted or branched alkylene or alkenylene in which the alkylene moiety may each contain 1 to 5 carbon atoms and the alkenylene moiety 2 to 5 the carbon atoms and R ₃ to R 8 have the above-mentioned meaning or an alkylene group in which D is an oxygen or sulfur atom, sulfinyl-, sulfonyl-, NR ₃ -, - (R ₆ CO) M-, via a radical V2 connected with the radical D (R ₆ SO ₂ ) N-, -CONR ₃ - or -NR ₃ CO, wherein R ₃ and R 8 are as defined above and wherein the oxygen or sulfur atom of the radical V ₂ is not directly attached to the nitrogen atom of the radical D and ^R b represents a hydrogen atom, a C 1 -C 5 alkyl group, a C 3 -C 5 alkenyl group, a C 1 phenylalkyl group up to 3 carbon atoms in the alkyl moiety, cycloalkyl or cycloalkylalkyl each having 5 to 7 carbon atoms in the cycloalkyl moiety, or Rf-CO-O- (R2CH) - in which Rf and R2 are as previously defined, the distance between the outermost atoms the nitrogen of the group A and the group COOR _b is at least 11 bonds, the third of the residues up to Xg being a sulfur atom, HN <, RgN <, RyO = or (Ry) ₂ C <group or N-atom, where Rg is as defined above; R y represents a hydrogen atom, an alkyl-, phenylalkyl-, phenyl-, alkoxy-, R ₃ R ₄ N-, R 4 OCO- or R 4 R 4 N-CO-group, wherein R ₃ and R ₄ are as defined above, the fourth of Xy to X ^ represents an oxygen, sulfur or nitrogen atom, or a RyC4 group, where Ry is as previously defined or also a carbonyl group, if it is not between two nitrogen atoms, the fifth of X X to X ^ represents an atom nitrogen, RyC = s or a (Ry) ₂ C <group, where Ry is as previously defined, or also d and adjacent residues from residues X 1 to X ₅ together represent an o-phenylene group, wherein, unless otherwise indicated, the above alkyl, alkylene and alkoxy moieties may each contain 1 to 3 carbon atoms, their tautomers, their stereoisomers, including their mixtures and salts thereof. 2. A five-membered heterocycle of formula I wherein the first of Xy to X8 is a group of formulas < 1 ' A - B - C - N < A - B - C - CH <or A-B-C-Ca, where A is optionally 1 to 4 alkyl, hydroxy, alkoxy, cyano, aminocarbonyl, carboxy or alkoxycarbonyl substituted cycloalkyl of 5 to 5 carbon atoms; 7 carbon atoms in which one of the unsubstituted methylene groups is replaced by R &lt; -N &gt; R „represents a hydrogen atom, an alkyl group, a phenylalkyl group, a total of 2 to 6 carbon atoms, a phenylalkoxycarbonyl group, a total of 6 to 8 carbon atoms, a cycloalkoxycarbonyl group, or R --CO-O- (R 2 CH) -O-CO -group where R 1 represents an alkyl group, a C 5 -C 7 cycloalkyl group, a C 1 -C 5 alkoxy group, a C 5 -C 7 cycloalkoxy group or a phenyl group; and R 2 represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, and in addition, in the 6- or 7-membered azacycloalkyl groups thus formed, one> CH-unit at the 4-position can be replaced by a nitrogen atom or 5-7-membered azacycloalkyl one -CH2-CH <group may be replaced by a -CH = C <unit, a pyridyl or quinuclidinyl group or also when D is R3R4N-CO-NR5- or R8-SC1NR-j-substituted alkylene of 1 to 5 carbon atoms, wherein: R ^ to R ^, which may be the same or different, each represent a hydrogen atom, an alkyl or phenylalkyl group, and R 8 represents a C 1 -C 5 alkyl, phenylalkyl or phenyl group; or E represents R ₃ R ₄ N -, R ₈ CO-NR 4 -, R ₈ SO ₂ -NR ₃ -, R ₃ R ₄ N-CO-NR 8 -, hydroxy or alkoxy substituted C 1 -C 5 alkylene, in which R 8 to R 8 are as defined above, a phenyl group which is substituted in the 4-position by R 11 NH-CH ₉ - or R NH-C (= NH) - or a phenyl group on which an n-propylene and n-butylene bridge is introduced between positions 3 and 4, the n-propylene and n-butylene bridge being substituted by the R8 NH group and R _& apos _; the above meaning, B represents a bond, -CH 2 -CH 2 -, -OCH 2 -, -CH 2 O-, -CONR 8 - or R 8 NCO-, wherein R 8 is as defined above and the oxygen or nitrogen atom of residue B is not directly linked to the nitrogen atom of residue A or five-membered heterocyclic, C represents a phenyl group which may be mono- or disubstituted by a fluorine, chlorine or bromine atom, by an alkyl, trifluoromethyl, hydroxyl or alkoxy group, the substituents being the same or different, a pyridinylene-, pyrimidinylene-, pyrazinylene- or pyridazinylene group, each in carbon the radicals may be substituted by an alkyl or alkoxy group, 1,4-cyclohexylene-, 1,4-piperidinylene- or 1,4-piperazinylene or, if A is not a pyridyl group and B is not an ethylene- or -CONH- group, at the same time B can only is a bond when A is an amidinophenyl group, the other of residues Xg to Xg is a group of formulas R _b 0 -CO-E N <, - 74 R _b 0 - CO - E - D - CH <or R _b O - CO - E - D - C, where D is -CO-NR 3, or NR ₃ -CO-radical, optionally hydroxy, alkoxy, R ₄ R N, R ₃ O-CO-, RgCO-NR ₃ -, R ₆ O-CO-NR ₃ -, R ₈ SO ₂ -NR ₃ or R ₃ R _{4 by an} N-CO-NR 8 group substituted straight or branched alkylene or alkenylene group, wherein each alkylene moiety may contain 1 to 5 carbon atoms and the alkenylene moiety 2 to 5 carbon atoms and R ₃ to R8 are as defined above, a phenyl group which may be mono or disubstituted by a fluorine, chlorine or bromine atom, alkyl, trifluoromethyl, hydroxy or alkoxy, pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene groups, which in each case may be substituted in the carbon residue or an alkoxy group, a cyclohexyl group in which one or two CH-units may in each case be replaced by a nitrogen atom, the methylene group adjacent to the nitrogen atom being replaced by a carbonyl group or (C až-C) alkylene group attached via a V £ £ moiety to the ring atom of each of the moieties X- ^ až Xgg where V V represents an NR _3- group wherein R ₃ is as defined above, an oxygen atom or a sulfur atom where the oxygen atom is or the sulfur atom of the residue cannot be directly attached to the nitrogen atom of the five-membered heterocycle, E may be 1-methyl- or 1-benzyl-4-piperazinyl or optionally hydroxy-, alkoxy-, R ₃ R ₄ N-, R ₈ CO-NR ₃ -, R ₈ SO ₂ -NR ₃ or R ₃ R ₄ N-CO -NR 8 -substituted straight or branched (C 1 -C 5) alkylene group wherein R ₃ - 75 to R 8 are as defined above or an alkylene group linked via the residue V ₂ with the radical D, where V ₂ represents an oxygen or sulfur atom, NR g -, - (R g CO) N-, - (R gSO ₂ ) N-group wherein R g and R 8 are as defined above, and wherein the oxygen or sulfur atom of the residue V ₂ is not directly bonded to the nitrogen atom of the residue D, and R @ 1 is hydrogen, C1 -C5 alkyl, C1 -C3 phenylalkyl, C5 -C7 cycloalkyl or R @ 1 --CO - O-- (R @ ₂ CH) -, wherein R and R ₂ are as defined above, wherein the distance between the outermost nitrogen atom of group a and the group COOR ^ is at least 11 bonds, the third of the radicals X g and X g represents HN <RGN <spade ^ or (R y) ₂ C skupinu a group or N-atom where R 8 is as defined above and Ry represents a hydrogen atom, an alkyl or phenyl group, the fourth of the residues X 8 to X 8 represents an oxygen, sulfur or nitrogen atom or a RyC 6 group where Ry is as previously defined; the radicals X g and X g represents a hydrogen atom, spade ^ or (R y) ₂ C <group, wherein R y is as defined above, or else two adjacent radicals of the radicals X g and X g together are an o-phenylene group, the tautomers, the stereoisomers including the mixtures thereof and salts thereof. The five-membered heterocycles of the general formula I according to claim 1, wherein the first of the radicals Xg to Xg represents a group of formulas - 76 A-B-C-N <or A-B-C-Ca, where A is optionally substituted by 1 to 4 methyl, hydroxy, methoxy, cyano or aminocarbonyl substituted 1,3-pyrrolidinyl-, 1,3-piperidinyl or 1,4-piperidinyl groups, wherein said pyrrolidinyl and piperidinyl groups are in the position 1 substituted with R _a and a R _represents hydrogen, methyl, ethyl, benzyl or alkoxycarbonyl group with a total of 2 to 6 carbon atoms, 1,4-piperazinyl or 3,4-dehydro-4-piperidinyl, each of which is substituted in the 1-position _and a radical R _& R is as defined above, pyridyl or quinuclidinyl, or alternatively, where D is R8-SO2-NR6-substituted ethylene, wherein R2 is hydrogen, methyl or ethyl; and R 8 is C 1 -C 5 alkyl or phenyl; E represents amino-, R8CO-NR4-, R8SC4NR6- or a hydroxy-substituted ethylene group wherein R3 to R8 are as defined above, a phenyl group which is substituted at the 4-position by R _and NH-C ( = NH) -, B represents a bond, -CH 2 -CH 2 -, -OCH 2 -, -CH 2 O-, -CONR 4 - or R ₃ NHCO, wherein R ₃ is as defined above and the oxygen or nitrogen atom of residue B is not directly linked to the nitrogen atom of residue A or a 5-membered heterocycle, C represents a phenyl group which may be substituted by a chlorine atom or a methyl group, a pyridinylene, a pyrimidinylene, a pyridazinylene or a 1,4-piperidinylene group, or else, if A is not a pyridyl group and B is not an ethylene or -CONH group, a bond, while at the same time B can only be a bond when A is an amidinophenyl group, the other of the residues up to X $ is a group of formulas R _b 0 - CO - E - D - N <or R _b 0 - CO - E - D - C s where D is -CO-NR4- or NR4 -CO-, wherein the meaning is as defined above, or a straight or branched alkylene group having 1 to 5 carbon atoms, an ethylene group substituted by a R5-SO2-NR6-group, a phenyl group, which may be substituted by a chlorine atom or a methyl group, A 1,4-cyclohexylene group or a (C 1 -C 4) alkylene group linked via an -NR 6 group, where R 3 is as defined above, to a ring atom of any of the radicals X 1 to X 8, E represents a bond, wherein at the same time C can represent a bond and A represents a 1-methyl- or 1-benzyl-4-piperazinyl group or an optionally RgCO-NRj- or RgSC1 -NRj-substituted group An ethylene group, wherein R 8 to R 8 are as defined above, or -0-CH ₂ - or -NR-CH ₂ -group, wherein R g are as defined above, and R _b is hydrogen, C 1 -C 5 alkyl or C 5 or C 6 cycloalkyl, the distance between the furthest nitrogen of the A group and the C00R _b group is at least 11 bonds, the third of the residues up to Xg being HN <, RgN <RTIgt; or </RTI> RyQs group or N-atom, wherein Rg is as defined above and Ry is hydrogen, methyl or ethyl, the fourth of X1 to Xg is nitrogen, sulfur or oxygen, or RyOs group, wherein Ry is as previously defined , the fifth of X 1 to X 8 is a nitrogen atom, a RyC 5 group where Ry is as previously defined, or two adjacent X 1 to X 8 radicals together are an o-phenylene group, their tautomers, their stereoisomers, including mixtures thereof, and their salts. The five-membered heterocycles of the general formula according to claim 1, wherein the first of the residues X 1 to X 8 is a group of formulas A-B-C-N <or A-B-C-Cs, where A at position 1 is R &lt; 4 _& gt _; substituted 4-piperidyl, wherein - R _&lt; 79 _& gt _; represents a hydrogen atom, a benzyl group or an alkoxycarbonyl group having a total of 2 to 6 carbon atoms, 1,4-piperazinyl group which in position 1 is substituted by _a radical R, wherein R _and is as defined above, and also where D is R8-SO2-NR6-substituted ethylene, wherein R 1 represents a hydrogen atom and R 8 represents a C 1 -C 5 alkyl group, a phenyl group which is substituted at the 4-position with NH ₂ -C (= NH) -, B represents a bond, -CH 2 -CH 2 - or -CF 2 O-group, C represents a phenylene or 1,4-piperidinylene group or, if B is not a bond at the same time, also a bond, the other of the radicals X 1 to X 1 represents a group of formulas R _b 0 - CO - E - D - C a where D is -CO-NH-, C 1 -C 5 alkylene, phenylene, 1,4-cyclohexylene or R 8 -SO ₂ -NR ₂ -substituted ethylene, E represents a bond, and at the same time does not represent a C bond and A represents a 1-benzyl-4-piperazinyl or ethylene group; or R _b represents a hydrogen atom or a C 1 -C 4 alkyl group wherein the distance between the furthest nitrogen atom of the group A and the COOR _b group is at least 11 bonds, li. i) ii) the third of the radicals X to X is phenyl-N <or a group or N-atom, wherein Ry represents a hydrogen atom, a methyl or ethyl group, the fourth of the radicals Xf to X6 represents a nitrogen, sulfur or oxygen atom or RyC4; a group wherein Ry is as defined above, the fifth of X 1 to X 8 is a nitrogen atom, their tautomers, their stereoisomers, including mixtures thereof, and their salts; Compounds of formula I according to claim 1: 2- (trans-4-carboxy-cyclohexyl) -5- [4- (4-piperidyl) phenyl] -1,3,4-thiadiazole, 2- [trans -4- (methoxycarbonyl) cyclohexyl] -5- [4- (4-piperidyl) phenyl] -1,3,4-thiadiazole, 1- [6- (4-amidinophenyl) -3-pyridazinyl] -4- [2- (n-butanesulfonylamino) -2-carboxyethyl] imidazole, 1- [6- (4-amidinophenyl) -3-pyridazinyl] -4- [2- (n-butanesulfonylamino) -2- (methoxycarbonyl-ethyl) imidazole, 2- [trans -4- (isobutylcarbonyl) cyclohexyl] -5- [4- (4-piperidinyl) phenyl] -1,3,4-thiadiazole; and 2- [trans -4- (ethoxycarbonyl) cyclohexyl] -5- [4- (4-piperidyl) phenyl] -1,3,4-thiadiazole, and salts thereof. Physiologically acceptable addition salts of the compounds according to at least one of claims 1 to 5 with inorganic or organic acids or bases. iii) iv) (v) (vi) Medicament, characterized in that it contains a compound according to at least one of Claims 1 to 5 or a physiologically acceptable addition salt according to Claim 6 next to optionally one or more inert carriers and / or diluents. Use of a compound according to at least one of claims 1 to 6 for the manufacture of a medicament suitable for the treatment or prevention of diseases in which small or larger cell aggregates act or play a role of cell-matrix interaction. A method for the manufacture of a medicament according to claim 7, characterized in that the compound according to at least one of claims 1 to 6 is incorporated in a non-chemical way into one or more inert carriers and / or diluents. A process for the preparation of a five membered heterocycle according to any one of claims 1 to 7, characterized in that: (a) for the preparation of compounds of the formula I, wherein the second of the radicals X 1 to X 8 represents a R 6 O-CO-E-D-CH 2 or R 6 O-CO-E-D-C 5 group, a compound of the formula II (II) X-Ι to Xg are as defined in claims 1 to 5 with the proviso that the second residue of X X-Xg is an HO-CO-CH CH or HO-CO-C ^ group, or a reaction-capable derivative thereof, is reacted with a compound of formula III 82 R _b 0 -CO-E-HNRg where (III) R g, R _b and E are as defined in claims 1 to 5, or b) for the preparation of a compound of formula I, wherein R _a is a hydrogen atom by hydrolysis, hydrogenolysis or thermolysis removing the protective radical of the compound of general formula ^X 1 / \ x ₂ X ₅ (IV) \ / Xg- x ₄ where X -? - Xg are as defined in claims 1 to 5 with the proviso that R _a is C 2 -C 6 alkoxy, phenylalkoxycarbonyl, C 4 -C 6 alkenyloxycarbonyl, C 6 -C 8 cycloalkoxycarbonyl or a leaving group protecting the imino group; or (c) for the preparation of compounds of the formula I in which R _b represents a hydrogen atom, cleavage by means of hydrolysis, hydrogenolysis or thermolysis, protecting the remainder of the compound of formula V; ^x 5 (V) / / ^X 2 \ ^χ 3- X ₄ where X ₄ to X 8 are as defined in claims 1 to 5 with the proviso that R _b is C 1 -C 5 alkyl, C 3 -C 5 alkenyl, C 1 -C 3 phenylalkyl, a cycloalkyl- or cycloalkylalkyl group having from 5 to 7 carbon atoms in the cycloalkyl moiety or a leaving group carboxy protecting group; or d) optionally producing a compound of the formula VI in the reaction mixture for the preparation of the 1,3,4-oxadiazole, 1,2,4-triazole and 1,3,4-thiazole derivatives N - N R // w / R '- C C (VI) II ^Z 1 where and Z 2, which may at the same time be the same or different, represent a halogen atom or optionally R 8 substituted amino, hydroxy, alkoxy, mercapto or alkyl mercapto groups, one of the radicals R alebo or R is an A-B-C-group and the other R alebo or R ^ O-CO-E-D-group is cyclized and optionally the compound thus obtained is alkylated or e) for the preparation of the compounds of the formula I in which A represents a phenyl group which is substituted in the 4-position by an R _{and a} HN-C (= NH) -group, optionally a compound of the formula VII Χ ₂ Χ ₅ (VII) \ / χ ₃ - χ ₄ where Χ ^ to Χ ^ are as defined in claims 1 to 5 with the proviso that A represents a phenyl group which is substituted at the 4-position with Z ₃ -C (= NH) -group, wherein Z ₃ represents alkoxy, aralkoxy, an alkylthio, aralkylthio or amino group is reacted with an amine of formula VIII R _a '- NH ₂ (VIII) wherein R 'represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms. (f) for the preparation of compounds of formula I wherein A is a phenyl group which is substituted in the 4-position with R _and NH-C (= NH) -group, a compound of formula IX ^X 1 / x ₂ x ₅ (IX) \ / ^X 3 “ ^X 4 where X -? - Xg are as defined in claims 1 to 5 with the proviso that A represents a phenyl group which is substituted at the 4-position with a cyano group, is reacted with a hydroxyamine, and then the amidoxime thus obtained is reduced or (g) for the preparation of compounds of the formula I in which A is a phenyl group in which the 4-position is substituted by R _{and an} NH-C (= NH) -group, a compound of the formula IX