CA2114178A1 - 5-membered heterocycles, processes for preparing them and pharmaceutical compositions containing these compounds - Google Patents

Abstract

Abstract Five-membered heterocycles The invention relates to five-membered heterocycles of the formula I:

(I)

Description

21141 1~

60675.573 Five-membered heterocvcles This invention relates to novel five-membered heterocycles, their preparation, pharmaceutical compositions containing them and their use.

It has been found that certain novel five-membered heterocycles have valuable pharmacological properties, particularly aggregation-inhibiting effects.

Thus viewed from one aspect the present invention provides a compound of formula I

Xl X2' X5 (1) (wherein:
(i) with the proviso that the five-membered heterocyclic ring is not a pyrrolidine, pyrroline, pyrrolinone or pyrrolidinone ring and contains at least one carbon atom and (ii) with the exception of the compounds 3-(4-amidino-phenyl)-l-[4-(2-amino-2-carboxyethyl)-phenyl]-2H-pyrazol-5-one and 3-(4-amidinophenyl)-l-[4-(2-amino-2-methoxycarbonyl-ethyl)-phenyl]-2H-pyrazol-5-one, a first of the groups X~, X2, X3, X4 and X5 is a group of formula A - B - C' - N< , A - B - C' - CH< or A - B - C' - C~

- 2 - 21~178 (wherein A denotes a pyridyl or quinuclidinyl group, or a C57-cycloalkyl group optionally substituted by 1 to 4 a].kyl groups, by a hydroxy, alkoxy, phenylalkoxy, cyano, aminocarbonyl, carboxy, alkoxycarbonyl or phenylalkoxycarbonyl group, in which an unsubstituted ring methylene group is replaced by an Ra-N~ group, .
and, additionally, in a 6- or 7-membered azacycloalkyl group thus formed a >CH- unit in the 4-position is .
optionally replaced by a nitrogen atom, or in a 5- to 7-membered azacycloalkyl group thus formed a -CH2-CH< unit ~ :
is optionally replaced by a -CH=C< unit, and in a piperazinyl or homopiperazinyl ring thus formed a methylene group, which is adjacent to the nitrogen atom :
in the 4-position, is optionally replaced by a carbonyl group, or, if D denotes a C18-alkylene or C18-alkenylene group substituted by a R3R4N-C0-NR5- or R6-S02-NR3- group (wherein R3, R4 and R5 independently denote hydrogen atoms, or alkyl or phenylalkyl groups and R6 denotes a :
Cl5-alkyl, phenylalkyl or phenyl group), or, if E denotes a straight-chain or branched Cl 5-alkylene or C15-alkenylene group substituted by a hydroxy, alkoxy, alkylsulphenyl, R3R4N-, R30-C0-, R6C0-NR3-, R6o-co-NR3-~ R6S02-NR3- or R3R4N C0 NR5 gr p (wherein R3, R4, Rs and R6 are as hereinbefore defined~, then A may also denote a phenyl group substituted in the 4-position by a RaNH-CH2- or RaNH-C(=NH)- group, or a phenyl group to which a C34-n-alkylene bridge substituted by a RaNH group is attached via two adjacent carbon atoms;

- 3 ~ 2 ~ 8 Ra denotes a hydrogen atom or an alkyl, phenylalkyl, (C
5-alkoxy)carbonyl, phenylalkoxycarbonyl, (C35-alkenyl)oxycarbonyl, (C57-cycloalkyl)oxycarbonyl, or R1-CO-O-(R2CH)-O-CO-group;

R1 denotes a C15-alkyl, C57-cycloalkyl, phenylalkyl, C15-alkoxy, C57-cycloalkyloxy or phenyl group;

R2 denotes a hydrogen atom or a C14-alkyl, C57-cycloalkyl or phenyl group;

B denotes a bond or an alkylene, -OCH2-, -CH20-, -SCH2-, -CH2S-, -CONR~-, -R3NCO-, -CH2NR3-, -NR3CH2-, -SO2NR3- or -NF~SO2- group, wherein F~ is as hereinbefore defined and an oxygen or nitrogen atom of group B is not directly bonded to a nitrogen atom of group A or to a ring nitrogen of the five-membered heterocyclic ring;

C' denotes a phenylene group optionally mono- or - disubstituted by fluorine, chlorine or bromine atoms or by alkyl, trifluoromethyl, hydroxy, alkoxy, alkylsulphenyl, alkylsulphinyl, or alkylsulphonyl groups, wherein the substituents may be identical or different, or C' denotes a pyridenylene, pyrimidinylene, pyrazinylene or pyridazinylene group, optionally substituted in the carbon skeleton by a chlorine atom or by an alkyl or alkoxy group, or C' denotes a 1,4-cyclohexylene, 1,3-piperidinylene, 1,4-piperidinylene or 1,4-piperazinylene group, or, if A is not a pyridyl group and B is an alkylene, -CONH- or -CH2S- group, then C may also denote a bond, and if A is an amidinophenyl group and B is a bond then C may also denote a bond);

'.''`t ' 2~i~178 a second of the groups X1, X2, X3, X4 and X5 is a group of formula .'- ':-RbO-CO - E - D - N< , ~ :
RbO-CO - E - D - CH< or RbO-CO - E - D - C<

(wherein D denotes a -C0-NR3-, -NF~-CO-, -S02-NR3 or -NR3-S02-group, a straight-chain or branched C18-alkylene or C28-alkenylene group optionally substituted by a hydroxy, alkoxy, alkylsulphenyl, R3R4N-, R30-C0-, R6C0- :.
NR3-, R~0-C0-NR3-, R6S02-NR3- or R3R4N-C0-NR5- group, ~ :
wherein R3, R4, R5 and R6 are as hereinbefore defined, or D denotes a phenylene group optionally mono- or disubstituted by fluorine, chlorine, or bromine atoms or by alkyl, trifluoromethyl, hydroxy, alkoxy, alkylsulphenyl, alkylsulphinyl or alkylsulphonyl groups, .
or D denotes a pyridenylene, pyrimidinylene, pyrazinylene, pyridazinylene or triazinylene group ~.
optionally substituted in the carbon skeleton by a chlorine atom or by an alkyl or alkoxy group, and in which additionally one or two -CH=N- groups may each be replaced by a -C0-NR3- group, wherein R3 is as hereinbefore defined, and one of the nitrogen atoms, instead of being bonded to the group R3, may also be bonded to the group E (if this group is itself not a::
bond and is not bonded to the group D via an oxygen or sulphur atom) or to the ring atom of the said second of the groups X1, X2, X3, X4 and X5, . :
.....
or D denotes a C4s-cycloalkylene group optionally substituted by an alkyl, phenylalkyl or phenyl group, wherein a >CH-unit may be replaced by a nitrogen atom and, additionally a methylene group adjacent to this :, 2~4178 nitrogen atom may be replaced by a carbonyl group, or D denotes a C67-cycloalkylene group optionally substituted by an alkyl, phenylalkyl or phenyl group, wherein one or two >CH-units may each be replaced by a nitrogen atom, and, additionally, one or two methylene groups adjacent to such a nitrogen atom may each be replaced by a carbonyl group, or D denotes a C15-alkylene group bonded via a group W1 to the ring atom of the said second of the groups X1, X2, X3, X4 and Xs~ wherein W~ denotes a NR3-group (in which R3 is as hereinbefore defined) or an oxygen or sulphur atom, whilst an oxygen or sulphur atom W1 cannot be directly bound to a ring nitrogen atom of the five-membered heterocyclic ring;

E, unless at the same time C' denotes a bond and A
denotes a l-methyl- or l-benzyl-4-piperazinyl group, may ~-denote a bond, or E denotes a straight-chain or branched C1s-alkylene or C25-alkenylene group optionally substituted by a hydroxy, alkoxy, alkylsulphenyl, R3R4N-, R30-CO-, R6C-NR3-~ R60-C-NR3-, R6S02-NR3- or R3R4N CO NRs gr p wherein R3, R4, Rs and R6 are as hereinbefore defined, or E denotes an alkylene group bonded to group D via a group W2, wherein W2 denotes an oxygen or sulphur atom or a sulphinyl, sulphonyl, -NR3-, -(R6CO)N-, -(R6SO~)N-, ~
-CONR3- or NR3CO- group, wherein R3 and R6 are as ~.
hereinbefore defined and wherein an oxygen or sulphur atom W2 is not directly bound to a nitrogen atom of group D; and Rb denotes a hydrogen atom, a C15-alkyl group, a C3 5-alkenyl group, a phenyl(C13-alkyl) group, a Cs 7---` 21~178 cycloalkyl group, a (Cs7-cycloalkyl)alkyl group or a R1-C0-0-(R2CH)-group, wherein R1 and R2 are as hereinbefore :~
defined, the separation between the furthest nitrogen atom of group A and the COORb group being at least ll bonds);

a third of the groups X1, X2, X3, X4 and Xs denotes a sulphur atom, a HN<,R6N<, R7C< or (R7)2C< group or a nitrogen atom, wherein R6 is as hereinbefore defined and R7 denotes a hydrogen atom or an alkyl, phenylalkyl, phenyl, alkoxy, R3R4N-, R30-C0- or R3R4N-C0- group, wherein R3 and R4 are as hereinbefore defined;

a fourth of the groups X1, X2, X3, X4 and X5 denotes an oxygen, sulphur or nitrogen atom or a R7CS group, wherein R7 is as hereinbefore defined, or a carbonyl group if it is not positioned between two ring nitrogen atoms; and the fifth of the groups X1, X2, X3, X4 and X5 denotes a nitrogen atom or a R7C< or (R7)2C< group, wherein R7 is as hereinbefore defined;

or two adjacent X1, X2, X3, X4 and X5 groups may together denote an o-phenylene group; and wherein, unless otherwise specified, each alkyl, alkylene or alkoxy moiety contains l to 3 carbon atoms) or an isomer (eg. tautomer, stereoisomer or mixture thereof) or a salt thereof.

Thus formula I includes for example substituted furan, tetrahydrofuran, 2,3-dihydro-furan, 2,5-dihydro-furan, -~
thiophene, 2,3-dihydro-thiophene, 2,5-dihydro-thiophene, tetrahydrothiophene, l,2-dithiolane, l,3-dithiolane, pyrrole, indole, isoindole, 2,3-dihydro-indole, 2,3-dihydro-isoindole, 2-indolone, imidazole, 4,5-dihydro- :;.

-~ ~

~ . .

21~4~7~

imidazole, tetrahydroimidazole, benzimidazoline, pyrazole, 2H-pyrazol-5-one, 4,5-dihydro-pyrazole, 2,3-dihydro-pyrazole, indazole, 2,3-dihydro-indazole, oxazole, isoxazole, oxazoline, oxazolidine, thiazole, isothiazole, thiazoline, thiazolidine, 1,3,4-oxadiazole, l,3,4-thiadiazole, l,2,3-triazole, l,2,4-triazole and tetrazole derivatives.

Preferred compounds according to the invention include those of formula I wherein:

a first of the groups X~, X2, X3, X4 and Xs represents a group of formula A - B - C' - N< , :
A - B - C' - CH< or A - B - C' - C<

(wherain A denotes a pyridyl or quinuclidinyl group, or a C57-cycloalkyl group optionally substituted by l to 4 alkyl groups or by a hydroxy, alkoxy, cyano, .
aminocarbonyl, carboxy or alkoxycarbonyl group, wherein an unsubstituted ring methylene group is replaced by an Ra-N< group, and, additionally, in a 6- or 7-membered azacycloalkyl group thus formed a >CH-unit in the 4-position is optionally replaced by a nitrogen atom, or in a 5- to 7-membered azacycloalkyl group thus formed a -CH2-CH<-unit is optionally replaced by a -CH=C<-unit, ::

or if D is a C1s-alkylene group substituted by a R3R4N- :~
CO-NR5- or R6-S02-NR3- group (wherein R3, R4 and R5 independently denote hydrogen atoms or alkyl or phenylalkyl groups and R6 denotes a Cl5-alkyl, - 8 _ 211417~
phenylalkyl or phenyl group), or if ~ is a straight-chain or branched C15-alkylene group substituted by a R3R4N-, R6-CO-NR3-, R6-SO2-NR3, -R3R4N-CO-NR5-, hydroxy or alkoxy group (wherein R3, R4, R5 and R6 are as hereinbefore defined), then A may also denote a phenyl group substituted in the 4-position by a RaNH-CH2- or RaNH-C(=NH)- group, or a phenyl group to which a n-propylene or n-butylene bridge is attached via the positions 3 and 4, wherein the n-propylene and n-butylene bridge is substituted by a RaNH-group; :

Ra denotes a hydrogen atom or an alkyl, phenylalkyl, (C5-alkoxy)carbonyl, phenylalkoxycarbonyl, ( Cs 7-cycloalkyl)oxycarbonyl or R1-CO-O-(R2CH)-O-CO- group;

R1 denotes an alkyl, Cs7-cycloalkyl, C15-alkoxy, . .
C57-cycloalkoxy or phenyl group; ~

R2 denotes a hydrogen atom or a C14-alkyl group: ;:

B denotes a bond or a -CH2-CH2-, -OCH2-, -CH20-, -CONR3-, :
or -R3NCO- group, wherein R3 is as hereinbefore defined and an oxygen and nitrogen atom of group B is not directly bonded to a nitrogen atom of group A or to a ring nitrogen of the five-membered heterocyclic ring;

C' denotes a phenylene group optionally mono- or :~
disubstituted by fluorine, chlorine, or bromine atoms or by alkyl, trifluoromethyl, hydroxy or alkoxy groups, wherein the substituents may be identical or different, or C' denotes a pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene group optionally substituted in the carbon skeleton by an alkyl or alkoxy - 9 - 21~4~78 group, or C' denotes a 1,4-cyclohexylene, 1,4-piperidinylene or 1,4-piperazinylene group, or, if A does not denote a pyridyl group and B denotes an ethylene or CONH- group, C' may also denote a bond, or, if A is an amidinophenyl group and B denotes a bond C' may also denote a bond);

a second of the groups X~, X2, X3, X4 and Xs is a group of formula RbO--CO - E -- D - N<, RbO-CO - E - D - CH< or RbO-CO - E -- D -- C<

(wherein D denotes a -CO-NR3- or -NR3-CO- group or a straight-chain or branched C15-alkylene or C25alkenylene group optionally substituted by a hydroxy, alkoxy, R~R4N-, R6CO-NR3~, R6o-CO-NR3-~ R6S02-NR3~ or R3R4N-C-NR~-group, wherein R3, R4, R5 and R6 are as hereinbefore .
defined, or D denotes a phenylene group optionally mono- or disubstituted by fluorine, chlorine or bromine or by alkyl, trifluoromethyl, hydroxy or alkoxy groups, or D denotes a pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene group optionally substituted in the carbon skeleton by an alkyl or alkoxy group, or D denotes a cyclohexylene group, wherein one or two >CH-units are optionally replaced by a nitrogen atom and additionally a methylene group adjacent to such a nitrogen atom is optionally replaced by a carbonyl .

-group, 211~178 or D denotes a C14-alkylene group linked via a group W1 to the ring atom of said second of the groups X1~ X2~ X3, X4 and Xs~ wherein W1 denotes an NR3-group (wherein R3 is as hereinbefore defined) or an oxygen or sulphur atom, -whilst an oxygen or sulphur atom W1 cannot be directly linked to a ring nitrogen atom of the five-membered heterocyclic ring;

E, unless C' denotes a bond and A denotes a 1-methyl or l-benzyl-4-piperazinyl group, may denote a bond, or E denotes a straight-chain or branched C15 alkylene group optionally substituted by a hydroxy, alkoxy, : :.
R R N R co-NR -, R60-CO-NR3-~ R6SO2-NR3 or R3R4 5 group, wherein R3, R4, R5 and R6 are as hereinbefore -defined, or E denotes an alkylene group linked via a group W2 to the group D, wherein W2 is an oxygen or sulphur atom or a -~R3-, -(R6CO)N- or -(R6SO2)N- group (wherein R3 and R6 are as hereinbefore defined) wherein an oxygen or sulphur -atom W2 may not be directly linked to a nitrogen atom of group D; and Rb denotes a hydrogen atom or a C15-alkyl, phenyl-(C13-alkyl), C57-cycloalkyl or R1-CO-O-(R2CH)-group, wherein R
and R2 are as hereinbefore defined, the separation between the furthest nitrogen atom of group A and the COORb-group being at least 11 bonds);

a third of the groups X1, X2, X3, X4 and X5 denotes a HN<, ~:
R6N<, R7CS or (R7)2C< group or an nitrogen atom, wherein R6 is defined as above and R7 denotes a hydrogen atom or an alkyl or phenyl group;

11- 2~1417~
a fourth of the groups X1~ X2, X3, X4 and X5 denotes an oxygen, sulphur or nitrogen atom or a R7C< group, wherein R7 is as hereinbefore defined; and the fifth of the groups X1, X2, X3, X4 and Xs denotes a nitrogen atom or a R7C< or (R7)2C< group, wherein R7 is as hereinbefore defined;

or two adjacent Xl, X2, X3, X4 and Xs groups may together denote an o-phenylene group) or an isomer (eg. tautomer, stereoisomer, or mixture thereof) or salt thereof.

More particularly preferred compounds according to the invention include those of formula I wherein~

a first of the groups Xl, X2, X3, X4 and Xs is a group of formula A - B - C' - N< or A - B - C' - CS

(wherein A denotes a 1,3-pyrrolidinyl, 1,3-piperidyl or 1,4-piperidyl group optionally substituted in the carbon skeleton by l to 4 methyl groups or by a hydroxy, methoxy, cyano or aminocarbonyl group, and wherein the above-mentioned pyrrolidinyl and piperidyl groups are substituted in the l-position by a group Ra (wherein Ra denotes a hydrogen atom or a methyl, ethyl, benzyl, or (C15-alkoxy)carbonyl group), or A ~enotes a pyridyl or quinuclidinyl group, a 1,4-piperazinyl or 3,4-dehydro-1,4-piperidyl group substituted in the l-position by a group Ra (wherein Ra is as hereinbefore defined), ;, ~, , , ~' . ~, - 12 - 21~4178 or, if D denotes an ethylene group substituted by a R6-SO2-NR3-group (wherein R3 denotes a hydrogen atom or a methyl or ethyl group and R6 denotes a C15-alkyl group or a phenyl group), .:

or, if E denotes an ethylene group substituted by an amino, R6CO-NR3-, R6SO2-NR3- or hydroxy group (wherein R3 and R6 are as hereinbefore defined), then A may also denote a phenyl group substituted in the 4-position by a RaNH-C (=NH) -group;

B denotes a bond or a -CH2-CH2-, -OCH2-, -CH20-, -CONCR3--R3NCO-group, wherein R3 is as hereinbefore defined and an oxygen or nitrogen atom of group B is not directly linked to a nitrogen atom of group A or of the five-membered heterocyclic ring;

C' denotes a phenylene group optionally substituted by a chlorine atom or by a methyl group, or C' denotes a pyridinylene, pyrimidinylene, pyridazinylene or 1,4-piperidinylene group, ::

or, if A is not a pyridyl group and B is an ethylene or -~
CONH-group, C' may also denote a bond, or, if A is an amidinophenyl group and B is a bond C' may also denote a bond);

a second of the groups X1, X2, X3, X4 and X5 denotes a group of formula RbO-CO ~ E ~ D ~ N< or RbO-CO ~ E ~ D ~ C<

(wherein - 13 - 21 t 417 8 D denotes a -CO-NR3- or -NR3-CO-group (wherein R3 is as hereinbefore defined), or a straight-chain or branched C15-alkylene group, .

or D denotes an ethylene group substituted by a R6SO2-NR3- group, or D denotes a phenylene group optionally substituted by a chlorine atom or a methyl group, or D denotes a 1,4-cyclohexylene group, or D denotes a C14-alkylene group linked to the ring atom of said second of the groups X1, X2, X3, X~, and X5 via a -NR3-group (wherein R3 is as hereinbefore defined);

E, unless C' denotes a bond and A denotes a 1-methyl or 1-benzyl-4-piperazinyl group, may denote a bond, or E denotes an ethylene group optionally substituted by a R6CO-NR3- or R6SO2-NR3- group (wherein R3 and R6 are as hereinbefore defined);

or E denotes a -O-CH2- or -NR3-CH2- group (wherein R3 is as hereinbefore defined); and Rb denotes a hydrogen-atom or a C15-alkyl, or C56- :
cycloalkyl group, the separation between the furthest nitrogen atom of group A and the COORb-group being at least 11 bonds); ~

a third of the groups X1, X2, X3, X4 and X5 denotes a HN<, ~:
R6N< or R7C< group or a nitrogen atom (wherein R6 is as hereinbefore defined and R7 is a hydrogen atom or a methyl or ethyl group);

a fourth of the groups X1, X2, X3, X4 and X5 denotes an .. . ::
': '~ ' .

21~ ~178 oxygen, sulphur or nitrogen atom or a R7C< group (wherein R7 is as hereinbefore defined); and the fifth of the groups X1, X2, X3, X4 and Xs denotes a nitrogen atom or a R7CS group (wherein R7 is as hereinbefore defined);

or two adjacent X1, X2, X3, X4 and Xs groups together denote an o-phenylene group;

and the isomers (eg. tautomers, stereoisomers, including mixtures thereof) and the salts thereof.

More particularly preferred compounds according to the invention include those of formula I wherein: ~ .

a first of the groups X1, X2, X3, X4 and X5 denotes a group of formula A - B - C' - N< or ~.
A - B - C' - CS

(wherein A denotes a 4-piperidyl group substituted in the 1-position by a group Ra (wherein Ra denotes a hydrogen atom or a benzyl or C15-alkoxycarbonyl group), .

or A denotes a 1,4-piperazinyl group substituted in the 1-position by a group Ra (wherein Ra is as hereinbefore defined), or, if D is an ethylene group substituted by a R6-SO2-NR3-group (wherein R3 is a hydrogen atom and R~ is an Cls-alkyl group), A may also denote a phenyl group substituted in the 4-position by a NH2-C(=NH)- group;

B denotes a bond or a -CH2-CH2- or -CH20- group;
i 21~4178 c' denotes a phenylene or a 1,4-piperidinylene group or, if B is not also a bond, C' may also denote a bond);

a second of the groups X1 ~ X2, X3, X4 and Xs denotes a group of formula :
RbO--CO-E--D-C<

(wherein D denotes a -CO-NH-, C15-alkylene, phenylene or 1,4-cyclohexylene group or an ethylene group substituted by a R6-SO2-NR3-group (wherein R6 is as hereinbefore defined);

E, unless C' denotes a bond and A denotes a 1-benzyl-4-piperazinyl group, may denote a bond, or E denotes an ethylene group, and Rb denotes a hydrogen atom or a C14-alkyl group, the separation between the furthest nitrogen atom and the : :
COORb-group being at least 11 bonds);

a third of the groups X1, X2, X3, X4 and X5 denotes a phenyl-N< or R7C< group or a nitrogen atom (wherein R7 is a hydrogen atom or a methyl or ethyl group); ;~

a fourth of the groups X1, X2, X3, X4 and X5 denotes an oxygen, sulphur or nitrogen atom or a R7C< group (wherein R7 is as hereinbefore defined); and the fifth of the groups X1, X2, X3, X4 and X5 denotes a - --nitrogen atom; ~-~

and the isomers (eg. tautomers, stereoisomers including mixtures thereof) and salts thereof.

2 ~ 8 Particularly preferred compounds according to the: :
invention include:

(i) 2-(trans-4-carboxycyclohexyl)-5-[4-(4-piperidyl)- ~`
phenyl]-l,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-butanesulphonylamino)-2-carboxy-ethyl]-imidazole, : :

(iv) 1-[6-(4-amidinophenyl)-3-pyridazinyl]-4-[2-(n-butanesulphonylamino)-2-(methoxycarbonyl)-ethyl~- :
imidazole, :
(v) 2-[trans-4-(isobutyloxycarbonyl)-cyclohexyl]-5-[4-(4-piperidinyl)-phenyl]-1,3,4-thiadiazole and (vi) 2-[trans-4-(ethyloxycarbonyl)-cyclohexyl]-5-[4-(4-piperidinyl)-phenyl]-1,3,4-thiadiazole and the salts thereof.

Viewed from a different aspect the invention provides a process for preparing a compound of formula I or salt thereof, said process comprising at least one of the following steps:

a) (to prepare a compound of formula I, wherein the second of the groups X1~ X2 ~ X3 ~ X4 and X5 is a RbO-CO-E-D-CH< or RbO-CO-E-D-C< group) reacting a compound of formula II

17 2~4~8 - .: .

X1 ~ ~:
X ' `X (Il) ~
X3-X4 . ~.

(wherein X1, X2, X3, X4 and X5 are as hereinbefore defined with the proviso that a second of the groups X1, Xz, X3, X4 and Xs denotes an HO-CO-CH< or HO-CO-C< group) or a reactive derivative thereof with a compound of formula III
..: '~` :' , ' RbO - CO - E - HNR3 (III) -~-~

(wherein R3, Rb and E are as hereinbefore defined); ~ ;

b) (to prepare compounds of formula I, wherein Ra denotes a hydrogen atom) :, ~:' .
cleaving a protecting group from a compound of formula IV ~-X .~.
`X5 ( (wherein X1, Xz, X3, X4 and X5 are as hereinbefore defined :
with the proviso that Ra denotes a (C15-alkoxy)carbonyl, phenylalkoxycarbonyl, (C35-alkenyloxy)carbonyl, (C57~
cycloalkyl)oxycarbonyl group or a cleavable imino group protecting group such as an acetyl, trifluroacetyl, benzoyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl - 18 - 2 ~ ~17 group) : ' by hydrolysis, hydrogenolysis or thermolysis;

c) (to prepare compounds of formula I, in which Rb denotes a hydrogen atom) cleaving a protecting group from a compound of formula V

X2' `Xs x3-x4 (wherein Xl, X2, X3, X4 and X5 are as hereinbefore defined with the proviso that Rb denotes a C15-alkyl, C3 5-alkenyl, phenyl(Cl3-alkyl), C57-cycloalkyl or (C5 7-cycloalkyl)alkyl group or a cleavable carboxy group protecting group such as a trimethylsilyl, methoxybenzyl, or 2,4-dimethoxybenzyl or tetrahydropyranyl group) by hydrolysis, hydrogenolysis or thermolysis;

d) (to prepare 1,3,4-oxadiazole, 1,2,4-triazole and 1,3,4-thiadiazole compounds of formula I) cyclising a compound of formula VI

N--N
R' C C--R"
Z~ Z2 2 ~ r~

(wherein Z1 and Z2 independently denote halogen atoms, amino groups optionally substituted by a group R6, or hydroxy, alkoxy, mercapto or alkylmercapto groups, and one of the groups R' or R~ denotes an A-B-C'- group and the other denotes a RbO-CO-E-D- group) which may optionally be formed in the reaction mixture and if necessary subsequently alkylating the product formed;

, e) (to prepare compounds of general formula I, in which A denotes a phenyl group substituted in the 4-position by a RaNH-C (=NH) - group) ~ -. . .
reacting a compound of formula VII

X2- X5 ~ll) X3-X4 ~ ~
~ .
(wherein X1, X2~ X3, X4 and X5 are as hereinbefore defined -with the proviso that A denotes a phenyl group ~-substituted in the 4-position by a Z3-C (=NH)- group (wherein Z3 denotes an alkoxy or aralkoxy group such as a methoxy, ethoxy, n-propoxy, isopropoxy or benzyloxy group, or an alkylthio or aralkylthio group such as methylthio, ethylthio, n-propylthio or benzylthio group, or an amino group)), which may optionally be formed in ~:~
the reaction mixture, with an amine of formula VIII

Ra~ - NH2 (VIII) .
:~ ' 21~417~

(wherein Ra' denotes a hydrogen atom or a C13-alkyl group~;

f) (to prepare compounds of general formula I, wherein A denotes a phenyl group substituted in the 4-position by a R~NH-C(=NH)-group) reacting a compound of formula IX

X / `X (IX) x3-x4 (wherein X1, X2, X3, X4 and X5 are as hereinbefore defined with the proviso that A denotes a phenyl group substituted in the 4-position by a cyano group) with hydroxylamine and subsequently reducing the resultant amidoxime;

g) (to prepare compounds of formula I, wherein A is a phenyl group substituted in the 4-position by a RaNH-C(=NH)- group) reacting a compound of formula IX

X2' `X (IX) (wherein X1, X2, X3, X4 and Xs are as hereinbefore defined with the proviso that A denotes a phenyl group :
substituted in the 4-position by a cyano group) ~ .

~. ~ . . : I

~1~4178 with an alkylchloroaluminiumamide; - .

h) (to prepare 1,3-thiazolenes and imidazolenes of .
formula I) reacting a compound of formula X

R~ - CO - CH2 - Z4 (X) with a compound of formula XI

R" - CU - NH2 (XI) (wherein one of the groups R ~ and R" denotes an A-B-C' : ~ :
group and the other denotes a RbO-CO-E-D- group, Z4 denotes a nucleophilic leaving group, such as a ~ :
chlorine, bromine, or iodine atom, .
and U denotes a sulphur atom or an imino group) i) (to prepare compounds of formula I, wherein Ra is as hereinbefore defined with the exception of the hydrogen atom, and B denotes a -CH20- group) reacting a compound of formula XII

A - CH2 - Z5 (XII) ~, (wherein A is as hereinbefore defined with the proviso .
that Ra is as hereinbefore defined with the exception of the hydrogen atom, and Zs denotes a nucleophilic leaving .
group such as a halogen atom or a sulphonyloxy group, ~ :
for example a methanesulphonyloxy group or a chlorine or :
bromine atom) -with a compound of formula XIII

21~78 x1\
x2~ x5 (X1113 x3-x4 (wherein Xll X2~ X3~ X4 and X5 are as hereinbefore defined with the proviso that one of X1 ~ X2, X3, X4 and X5 denotes a HO-C'-CH< or HO-C'-C< group, wherein C' is as hereinbefore defined) or an alkali or alkaline earth metal salt such as a lithium, sodium, potassium, cesium, magnesium, or calcium salt thereof;

j) (to prepare compounds of formula I, wherein one of the groups X1~ X2, X3, X4 and X5 denotes an A-B-C ' -N< or RbO-CO-E-D-N< group) alkylating a compound of formula XIV

X / 1`X (Xl\/) (wherein X1, X2, X3, X4 and Xs are as hereinbefore defined -~
with the proviso that one of X1, X2, X3, X4 and X5 denotes an imino group) with a compound of formula XV
.
W - Z6 (XV) (wherein W denotes an A-B-C ' - or RbO-CO-E-D- group, wherein A, B, C' and D are as defined above, and Z6 denotes a nucleophilic leaving group, e.g. a halogen atom or a sulphonyloxy group such as a .~,. . . ~ ~ ..

21~417~

methanesulphonyloxy group or a chlorine or bromine atom);

k) (to prepare compounds of formula I, wherein Rb denotes a R1-CO-O-(R2CH)-group (in which R1 and R2 are as hereinbefore defined), a C15-alkyl groupl a C3s-alkenyl group, a phenyl-(C13-alkyl) group, a C57-cycloalkyl group or a (C57-cycloalkyl)alkyl group) esterifying a compound of formula XVI

X2' X5 ~ 1) ~.

(wherein Xl, X2, X3, X4 and Xs are defined as above with the proviso that Rb denotes a hydrogen atom) with a compound of formula XVII

z7 _ Rb~ (XVII) (wherein Rb' denotes a R1-CO-O-(R2CH)- group (in which R1 and R2 are as hereinbefore defined), a C1s-alkyl group, a C35-alkenyl group, a phenyl(C13-alkyl) group, a C5 7-cycloalkyl group or a (Cs7-cycloalkyl)alkyl group, and 27 denotes a hydroxy group or a nucleophilic leaving group such as a halogen atom or a sulphonyloxy group, e.g. a chlorine, bromine or iodine atom or a : :
methanesulphonyloxy or p-toluenesulphonyloxy group);

l) performing any one of steps (a) to (k) using a protected reagent and subsequently removing the protecting groups from the product;

- 24 - 2114~78 m) converting a compound of formula I into a salt thereof; and n) resolving a compound of formula I into its isomers.

The reaction of step (a) is expediently carried out in a solvent or solvent mixture such as methylene chloride, dimethylformamide, dimethylsulphoxide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane, optionally in the presence of a dehydrating agent, for example in the presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, hydrochloric acid, sulphuric acid, methanesulphonic acid, p-toluenesulphonic acid, phosphorus trichloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide, N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide, 2-t(lH)-benzotriazolyl]-1,1,3,3-tetramethyl-uronium-salts, N'N'-thionyldiimidazole, N,N'-carbonydiimidazole or triphenylphosphine/carbon tetrachloride, optionally in the presence of dimethylaminopyridine or 1-hydroxy-benzotriazole and/or a base such as triethylamine, N-ethyl-diisopropylamine or N-methyl-morpholine, suitably at temperatures between -10 and 150C, preferably at temperature between 0 and 50C.

The hydrolysis of step (b) is appropriately carried out either in the presence of an acid such as hydrochloric acid, hydrobromic acid, sulphuric 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 -lO~C and 120C, e.g. at temperatures between ambient temperature and the boiling temperature of the reaction - 25 - 21~178 mixture.

In the acid hydrolysis, depending on the conditions used, other hydrolytically cleavable groups such as alkoxycarbonyl or phenylalkoxycarbonyl groups optionally present in a compound of formula IV, may also be cleaved simultaneously.

When Ra denotes, for example, a tert.butyloxycarbonyl group, the tert.butyl group may also be cleaved by treating with an acid such as trifluoroacetic acid, hydrochloric acid, formic acid, p-toluenesulphonic acid, sulphuric acid, phosphoric acid or polyphosphoric acid, optionally in an inert solvent such as methanol, methylene chloride, chloroform, benzene, toluene, tetrahyrofuran, dioxane, ether/dioxane, or -~ ~-ether/dioxane/methanol preferably at temperatures between -10C and 120C, e.g. at temperatures between 0 and 60C, or optionally 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-toluenesulphonic acid, sulphuric acid, phosphoric acid, or polyphosphoric acid, preferably at the boiling temperature of the solvent used, e.g. at temperatures between 40C and 100C.
, When Ra represents, for example, a benzyloxycarbonyl group, the benzyl group may also be hydrogenolytically cleaved in the presence of a hydrogenation catalyst such as palladium/charcoal, in a suitable solvent such as methanol, ethanol, ethanol/water, glacial acetic acid, -ethyl acetate, dioxane or dimethylformamide, preferably at temperatures between 0 and 50 D C, e.g. at ambient temperature, under a hydrogen pressure of 1 to 10 bar.
During the hydrogenolysis, other groups may simultaneously be reduced, e.g. a nitro group may to a :

21~4178 amino group or a benzyloxy group to a hydroxy group, or a benzylamino group to an amino group. Furthermore, any C=C double bonds may simultaneously be hydrogenated to single bonds.

The hydrolysis of step (c) is appropriately carried out either in the presence of an acid such as hydrochloric, sulphuric acid, phosphoric acid, acetic acid, acetic/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 or water/dioxane, at temperatures between -10C and 120C
e.g. at temperatures between ambient temperature and the boiling temperature of the reaction mixture.

In the acid hydrolysis, depending on the conditions used, other hydrolytically cleavable groups such as acetyl, trifluoroacetyl, benzoyl, tert.butyloxycarbonyl or benzyloxycarbonyl group optionally present in a compound of formula V may simultaneously be cleaved.
:
When Rb denotes, for example, a tert.butyl group, this ~ ~
may also be cleaved by treating with an acid such as -trifluoroacetic acid, hydrochloric acid, formic acid, p-toluenesulphonic acid, sulphuric acid, phosphoric acid or polyphosphoric acid, optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane, preferably at temperatures between -10C and 120C, e.g. at temperatures between 0 and 60~C, or thermally, optionally 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-toluenesulphonic acid, .
.~ .

21~178 sulphuric acid, phosphoric acid, or polyphosphoric acid, preferably at the boiling temperature of the solvent used, e.g. at temperatures between 400C and 100C.

When Rb represents, for example, a benzyl group, the benzyl group may also be hydrogenolytically cleaved in the presence of a hydrogenation catalyst such as palladium/charcoal, in a suitable solvent such as methanol, ethanol, ethanol/water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide, preferably at temperatures between 0 and 50C, e.g. at ambient temperature, under a hydrogen pressure of 1 to 10 bar.
During the hydrogenolysis, other groups may simultaneously be reduced, e.g. a nitro group to an amino group or a benzyloxy group to a hydroxy group, and a benzylamino or benzyloxycarbonylamino group to an amino group. At the same time, C=C-double bonds may, moreover, be hydrogenated to single bonds.

The reaction of step (d) is expediently carried out in solvent such as tetrahydrofuran, dioxane, 1,2-dichlorobenzene or pyridine, at temperatures up to the boiling temperature of the solvent used e.g. at temperatures at between 20 and 180C.

When, in a compound of general formula VI, Z1 and Zz each represent a hydroxy group, to prepare a 1,3,4-oxadiazole derivative the reaction is preferably carried out in the presence of a desiccating substance such as thionyl chloride, and to prepare a 1,3,4-thiadiazole derivative the reaction is preferably carried out in the presence of a sulphur-introducing reagent such as 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulphide and .
to prepare a 1,3,4-triazole derivative the reaction is - 28 - 2~178 preferably carried out in the presence of a halogen-introducing reagent such as phosphorus trichloride and in the presence of aniline.

In order to prepare the other l,2,4-triazole derivatives, a compound of general formula VI, in which -one of the groups Z1 and Z2 is a hydroxy group and the --other of the groups Z1 and Z2 is an amino group, is cyclised and then alkylated if necessary.

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

The reaction of step (e) is appropriately carried out in `~
a solvent such as methanol, ethanol, n-propanol, water, methanol/water, tetrahydrofuran or dioxane at temperatures between 0 and 150C, preferably at temperatures between 20 and 120C with a correspondingly free amine or with a corresponding acid addition salt -such as e.g. ammonia carbonate or ammonia acetate.

A compound of general formula VII is obtained, for example, by reacting a corresponding nitrile with a corresponding alcohol such as methanol, ethanol, propanol, isopropanol or benzylalcohol, in the presence of an acid such as hydrochloric acid or in the presence of a corresponding alcoholate such as sodium methoxide, or sodium ethoxide, or by reacting a corresponding amide with a trialkyloxonium salt such as triethyloxonium-~ ~, Z

- 29 - 211~78 tetrafluoroborate, in a solvent such as methylene chloride, tetrahydrofuran or dioxane, at temperatures between -10 and 50C but preferably at temperatures between 0 and 20OC, or by reacting a corresponding nitrile with hydrogen sulphide, suitably in a solvent such as pyridine or dimethylformamide and in the presence of a base such as triethylamine, and subsequent alkylation of the resultant thioamide with a corresponding alkyl or aralkyl halide.

The reaction of step (f) with hydroxylamine is appropriately 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 e.g. sodium carbonate, at temperatures between 0 and 100C, bùt preferably at temperatures between 20 and 80C, either with free hydroxylamine or with a corresponding acid addition salt such as the hydrochloride.

The subsequent reduction is preferably carried out in a suitable solvent such as methanol, methanol/water, ~ -methanol/ammonia, methan~l/water/ammonia, methanol/hydrochloric acid, ethanol, ether, tetrahydrofuran, dioxane, dimethylformamide or glacial -~
acetic acid, in the presence of catalytically activated hydrogen e.g. hydrogen in the presence of Raney-nickel, -~
platinum or palladium/charcoal at temperatures of between 0 and 100C, preferably at temperatures between 20 and 80C.

The reaction of step (g), using an appropriate corresponding alkylchloroaluminiumamide is preferably carried out in a suitable solvent, such as benzene or toluene, at temperatures of between 0 and 100C, but preferably at a temperature between 20 and 80C, and the resultant aluminium complex is then decomposed by 211L~7 8 hydrolysis, preferably using a suspension of silica gel in chloroform (see R.S. Garigipati, Tetrahedron Letters 31, 1969 (1990)).

The reaction of step (h) is suitably 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 temperature of the solvent used.

The reaction of step (i) is suitably carried out in a solvent such as tetrahydrofuran, acetone, dioxane, dimethylsulphoxide, sulpholane, dimethylformamide or dimethylacetamide, in the presence of an inorganic base such as potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride or potassium tert.butoxide, or in the presence of tertiary organic bases such as N-ethyl-diisopropylamine, which may optionally, also serve as solvent, and optionally in the presence of a phase transfer catalyst such as polyethyleneglycol-750-monomethylether on polystyrene or hexadecyl-trimethylammonium chloride, at temperatures between 0 and 180C, but preferably at temperatures between 10 and 160C.
:
The alkylation of step (j) is appropriately carried out in a solvent or mixture of solvents such as methylenechloride, dimethylformamide, dimethylsulphoxide, benzene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane, in the presence of an acid-binding agent, e.g. an alcoholate such as potassium-tert.butoxide, or an alkali/metal hydroxide such as sodium or potassium -~
hydroxide, or an alkali metal carbonate such as potassium carbonate, or an alkali metal amide such as sodium amide, or an alkali metal hydride such as sodium hydride, suitably at temperatures between 0 and 150C, 211~17~

preferably at temperatures between 0 and 50C.

The esterification of step (k) is appropriately carried out in a suitable solvent, for example in a corresponding alcohol such as methanol, ethanol or isopropanol, methylene chloride, tetrahydrofuran, dioxane, pyridine, toluene or dimethylsulphoxide, in the presence of an acid activating and/or dehydrating agent such as hydrogen chloride, concentrated sulphuric acid, thionyl chloride, ethyl chloroformate, carbonyldiimadazole or N,N'-dicyclohexyl-carbodiimide or the isourea esters thereof, optionally in the presence of a reaction accelerator such as copper chloride, by esterification, for example, with a corresponding diester, or by reaction with a corresponding halogenide, .
- preferably in the presence of a base such as potassium :
carbonate, and optionally in the presence a reaction accelerator such as potassium iodide, at temperatures --:
between 0 and 100C, but preferably at temperatures ::
between 20C and the boiling temperature of the solvent.

When Z7 denotes a nucleophilic leaving group, the reaction is preferably carried out with an alkali metal salt of a compound of formula XVI.

In the above reactions, the active groups optionally .
present such as hydroxy, carboxy, amino, alkylamino or imino groups may be protected during the reaction by ~:
conventional protecting groups which may be cleaved after the reaction.

For example, the hydroxy group protecting group may be a trimethylsilyl, acetyl, benzoyl, tert.butyl, trityl, benzyl or tetrahydropyranyl group, the carboxyl group, protecting group may be a trimethylsilyl, methyl, ethyl, tert.butyl, benzyl or tetrahydropyranyl group, and the amino, alkylamino or imino group protecting group may be an acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and for the amino group a phthalyl group may also be considered.

The optionally subsequent cleaving of a protecting group may, for example, be 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 sulphuric acid or in the presence of an alkali metal base such as lithium hydroxide, sodium hydroxide or potassium hydroxide, or by ether cleaving, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 100C, preferably at temperatures between 10 and 50C.

However, a benzyl, methoxybenzyl or benzyloxycarbonyl group may for example be cleaved hydrogenolytically, eg.
using hydrogen in the presence of a catalyst such as -palladium/charcoal, 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 and 50C, but preferably at ambient temperature, under a hydrogen pressure of 1 to 7 bar, preferably 3 to 5 bar.

A methoxybenzyl group may also be cleaved in the presence of an oxidising agent such as cerium(IV)-ammonium nitrate, in a solvent such as methylene chloride, acetonitrile or acetonitrile/water at ;
temperatures between 0 and 50C, but preferably at `
ambient temperature.

A 2,4-dimethoxybenzyl group, however, is preferably -cleaved in trifluoroacetic acid in the presence of 21~417~

anisole.

A tert.butyl or tert.butyloxycarbonyl group is preferably cleaved by treating with an acid such as trifluoroacetic acid or hydrochloric acid, optionally using a solvent such as methylene chloride, dioxane or ether.

The cleaving of a phthalyl group 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 50c.

An allyloxycarbonyl group is cleaved by treating with a catalytic amount of tetrakis-(triphenylphosphine)-palladium(0), 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 and 100C, preferably at ambient temperature and under inert gas, or by treating with a catalytic amount of tris-(triphenylphosphine)-rhodium(I)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 70C.
.

Furthermore, the compounds of formula I obtained may be resolved into their enantiomers and/or diastereomers as mentioned hereinbefore. Thus, for example, cis/trans mixtures may be resolved into their cis and trans isomers, and chiral compounds may be resolved into their enantiomers.

Thus, for example, the cis/trans mixtures obtained may be resolved by chromatography into the cis and trans isomers thereof and the compounds of formula I which 21~4~8 occur in racemate fo~m may be separated by methods known ~er se (see Allinger N. L. and Eliel E. L. in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) into their optical antipodes and compounds of formula I
having at least 2 stereogPnic centres may be separated on the basis of their physical-chemical differences using known methods, e.g. by chromatography and/or fractional crystallisation, into the diastereomers thereof which, if they occur in racemic form, may subsequently be separated into the enantiomers as mentioned above.

~he separation of enantiomers is preferably effected by column separation on chiral phases or by recrystallisation from an optically active solvent or by reacting with an optically active substance (especially an acid or an activated derivative thereof or an alcohol) which forms salts or derivatives such as esters -~
or amides with the racemic compound, and separating the diastereomeric salt mixtures or derivative thus obtained, e.g. on the basis of their different solubilities, whilst the free antipodes may be released from the pure diastereomeric salts or derivatives by the action of suitable agents. Particularly common, optically active acids include, for example, the D- and L-forms of tartaric acid and dibenzoyltartaric acid, di-o-tolyl tartaric acid, malic acid, mandelic acid, camphorsulphonic acid, glutamic acid, aspartic acid or quinic acid. Examples of optically active alcohols include for example (+)- or (-)-menthol and examples of optically active acyl groups in amides include for example (+)- or (-)-menthyloxycarbonyl.

Moreover, the compounds of formula I obtained may be converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts thereof with inorganic or organic acids. Examples -- 35 - 21~7~
of suitable acids include hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

In addition, the new compounds of formula I thus obtained, if they contain a carboxyl group, may subsequently, if desired, be converted into the addition salts thereof with inorganic or organic bases, more particularly, for pharmaceutical use, into the physiologically acceptable addition salts thereof.
Examples of suitable bases include sodium hydroxide, potassium hydroxide, ammonia, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.

The compounds used as starting materials are known from the literature in some cases or may be obtained by methods known from the literature ~see Examples I to XXI
below).

As already mentioned, the new five-membered heterocycles of formula I and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, have valuable pharmacological properties, and in addition to having an inhibitory effect on inflammation and bone degradation, they have in particular antithrombotic, antiaggregatory and tumour- or metastasis-inhibiting effects.

The compounds of formula I, wherein Ra is one of the above-mentioned oxycarbonyl groups and/or Rb is one of the above-mentioned ester groups, represent valuable prodrugs.

Viewed from a further aspect the invention thus provides a pharmaceutical composition comprising a compound of formula I or a physiologically acceptable salt thereof, , . . ... . ~ .. ,., ~ .. - - .

- 36 - 2 ~ 8 together with at least one physiologically acceptable carrier or excipient.

Viewed from a still further aspect the invention also provides the use of a compound of formula I or a physiologically acceptable salt thereof for the manufacture of a medicament for use in combatting inflammation, bone degradation, tumours, metastases, and aggregation-related conditions.

Viewed from a yet still further aspect the invention provides a method of treatment of the human or non-human, preferably mammalian, body to combat inflammation, bone degradation, tumours, metastases, and aggregation-related conditions, said method comprising -administering to said body a compound of formula I or a -physiologically acceptable salt thereof. -~

By way of example, compounds of formula I were investigated for their biological effects as follows: `

2 1 ~ 8 1. Competitive binding of 3H-BIBU 52/test substance to human thrombocytes:

A suspension of human thrombocytes in plasma is incubated with 3H-BIBU 52 [(3S,5S)-5-[(4'-amidino-4-biphenylyl)oxymethyl]-3-[(carboxyl)methyl]-2-pyrrolidinone[3-3H-4-biphenylyl] - see DE-A-4214245], which replaces the conventionally used 125I fibrinogen ligand, and various concentrations of the substance to be tested. The free and bound ligand are separated by centrifuging and quantitatively determined by scintillation counting. The inhibition of 3H-BIBU 52 binding by the test-substance is determined from the measurements obtained.

In order to do this, donor blood is taken from an anticubital vein and anticoagulated with trisodium citrate (final concentration 13 mM~. The blood is centrifuged for 10 minutes at 170 x g and the supernatant platelet-rich plasma (PRP) is removed. The remaining blood is vigorously centrifuged once more in order to obtain plasma. The PRP is diluted 1:10 with autologous plasma. 750 ~1 are incubated with 50 ~1 of physiological saline solution, 100 ~1 of test substance solution, 50 ~1 of 14C-sucrose (3700 Bq) and 50 ~1 of 3H-BIBU 52 (final concentration: 5 nM) at ambient temperature for 20 minutes. In order to measure the non-specific binding, 5 ~1 of BIBU 52 (final concentration: 30 ~M) are used instead of the test substance. The samples are centrifuged for 20 seconds at 10000 x g and the supernatant is poured off. 100 ~1 thereof are measured in order to determine the free ligand. The pellet is dissolved in 500 ~1 of 0.2N NaOH, 450 ~1 are mixed with 2 ml of scintillator and 25 ~1 of 5N HCl and measured. The residual plasma remaining in the pellet is determined from the 14C-content and the bound ligand is determined from the 3H-measurement.

- 38 - 2 1 ~ 4 1 ~
After the non-specific binding has been deducted, the pellet activity is plotted against the concentration of the test substance and the concentration for a 50%
inhibition of binding is determined.

2. Antithrombotic activitY -Method The thrombocyte aggregation is measured using the method of Born and Cross (J. Physiol. 170: 397 (1964)) in platelet-rich plasma taken from healthy volunteers. To inhibit coagulation the blood is mixed with 3.14% sodium citrate in a volume ratio of 1:10.

Collaqen-induced aaareaation The pattern of the decrease in optical density of the platelet suspension is photometrically measured and recorded after the addition of the aggregation-triggering substance. The rate of aggr~gation is determined from the angle of inclination of the density curve. The point on the curve where there is maximum light transmittance is used to calculate the optical density.

The concentration of collagen used is as small as -possible but sufficient to produce an irreversible reaction curve. Standard commercial collagen produced by Hormonchemie of Munich is used.

Before the addition of the collagen the plasma is incubated for 10 minutes with the substance at 37~C.

From the concentration/activity curve an EC50 is determined, which describes the concentration giving a 50% change in the optical density in terms of the 2~17~

inhibition of aggregation.

The following table shows the results which were obtained:

Substance Competitive binding Inhibition of (Example No.) of 3H-BIBU 52/test platelet substance to humanaggregation thrombocytes EC50 [nM]
ICso [nM]
224000.0 3000 2(3)550.0 380 3 400.0 880 3(1)6800.0 4400 3(3) 1.6 40 510.0 320 5(3)11.0 100 The compounds according to the invention are well tolerated because on intravenous administration of 30 mg/kg of the compounds of Examples 5 and 5(3) to three mice in each case, no animals died.

Furthermore, for example, an 80% inhibition of collagen induced human thrombocyte aggregation is achieved ex vivo with the rat plasma obtained 3 hours after peroral administration of lO mg/kg of the compound of Example 2(19).
~ ' In the light of their inhibitory effect on cell-cell or cell-matrix interactions, compounds of formula I and the physiologically acceptable addition salts thereof are suitable for treating or preventing diseases in which smaller or greater cell aggregates occur or in which cell-matrix interactions play a part, e.g. in treating or preventing venous and arterial thrombosis, - ~;. - ,: -: . -.. ; ~. .

- 40 - 211417~ -cerebrovascular diseases, lung embolism, cardiac infarction, arteriosclerosis, osteoporosis and the metastasis of tumours and the treatment of genetically caused or acquired disorders of cell interactions with one another or with solid structures. They are also suitable for parallel therapy in thrombolysis with fibrinolytics or vascular interventions such as transluminal angioplasty or in the treatment of shock, psoriasis, diabetes and inflammation.

For treating or preventing the diseases mentioned above the dosage is between 0.1 ~g and 30 mg/kg of body weight, preferably 1 ~g to 15 mg/kg of body weight, given in up to 4 doses per day. For this purpose the compounds according to the invention, optionally in conjunction with other active substances such as -thromboxane-receptor-antagonists and thromboxane synthesis inhibitors or combinations thereof, serotonin antagonists, ~-receptor antagonists, alkylnitrates such as glycerol trinitrate, phospho-diesterase inhibitors, prostacyclin and the analogues thereof, fibrinolytics such as tPA, prourokinase, urokinase, streptokinase, or anticoagulants such as heparin, dermatane sulphate, activated protein C, vitamin K antagonists, hirudine, ~ -inhibitors of thrombin or other activated clotting factors, may be incorporated together with one or more inert conventional carriers and/or diluents, e.g. corn starch, lactose, sucrose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethyleneglycol, propyleneglycol, stearylalcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof, into conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions, solutions, sprays or suppositories.

21~17~

The Examples which follow are provided to illustrate the invention in a non-limiting fashion.

All ratios and percentages are by weight unless otherwise specified except for eluant ratios which are by volume.

2 1 ~

Exam~le 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, 157.4 g of oxalyl chloride are added dropwise at -10 to -20C, whilst stirring thoroughly. Then 46.7 g of aluminium chloride are added. The mixture is stirred for 1 hour at -10C and a further 82.7 g of aluminium chloride are added. After another 2 hours the cooling bath is removed and the mixture is stirred for 24 hours at ambient temperature. The reaction solution is carefully stirred into about 4 litres of ice/water and the aqueous phase is extracted twice with methylene chloride. The combined organic phases are washed with water, dried with sodium sulphate and the solvent is removed under reduced pressure. The remaining residue is dissolved in 2.5 litres of 2N sodium hydroxide solution whilst -~
stirring vigorously. To the dark aqueous solution, ice is added and the solution is acidified with concentrated hydrochloric acid. The precipitate is suction filtered off, washed with water and refluxed for 5 hours in 2 litres of 6N hydrochloric acid. The solvent is removed under reduced pressure. The remaining solid matter is triturated with a little water and suction filtered.
Yield: 40.5 g (54 % of theory), Melting point: > 300C
Rf 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, 47.5 g of 4-(4-piperidyl)-benzoic acid hydrochloride is added.

- 43 - 2~178 The suspension is diluted with 500 ml of dioxane and 250 ml of water. Then 54.6 g of di-tert.butyl pyrocarbonate are added in batches. The mixture is stirred for 16 hours at ambient temperature. The precipitate is suctioned filtered and the filtrate is partly concentrated by evaporation under reduced pressure. The precipitate and the remaining aqueous filtrate are combined and diluted with 1 litre of water. The aqueous phase is set to pH 2 with saturated potassium hydrogen sulphate solution and extracted twice with ethyl acetate. 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 little ethyl acetate, suction filtered and dried.
Yield: 54.0 g (90% of theory), 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)-4-piperidyl]-benzoic acid in 150 ml dimethylformamide, 9.6 g of l-hydroxy-(lH)-benzotriazole and 17.4 g of N,N'-dicyclohexylcarbodiimide are added at -10C. The mixture is stirred for 15 minutes at -10C, the cooling bath is remo~ed and the temperature is allowed to increase to ambient temperature. This reaction solution is then added dropwise to a solution of 50 ml of 80%
hydrazine-hydrate in 150 ml dimethylformamide, cooled to -10C. The mixture is stirred for 16 hours at ambient temperature and the precipitate is suction filtered.

~, ~, ................... - . . . - - - . ~ . . . -. : . : , . . . . . .

_ 44 _ 21i417 8 The filtrate is concentrated under reduced pressure.
Water is added to the residue and the aqueous phase is extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulphate and the solvent is concentrated by evaporation under reduced pressure. The remaining solid material is chromatographed over silica gel using ethyl acetate/cyclohexane (4:1). 18.5 g of a crystalline solid material is obtained which is triturated with -ethyl acetate and then suction filtered.
Yield: 12.7 g (57% of theory) Melting point: 151-154C
Rf value: 0.26 (silica gel; ethyl acetate/cyclohexane a 4:1) -.: ', ' ' Example IV

N-[4-[1-(tert.Butyloxycarbonyl)-4-piperidyl]-benzoyl]-N'-[(methoxycarbonyl)-carbonyl]-hydrazine To a solution of 3.2 g of 4-[1-(tert.butyloxycarbonyl)-4-piperidyl]-benzoic hydrazide and 1.7 g of ethyldiisopropylamine in 50 ml of anhydrous tetrahydro~uran, a solution of 1.3 g of oxalic acid-monomethylester-chloride in 10 ml of anhydrous tetrahydrofuran is added dropwise whilst cooling in an ice bath. The mixture is stirred for 16 hours at ambient temperature, the precipitate is suction filtered and the filtrate is concentrated under reduced pressure. The residue is dissolved in ethyl acetate and washed once , using 0.5 N hydrochloric acid. The organic phase is I dried and the solvent is evaporated under reduced pressure. The crude product is chromatographed over silica gel using ethyl acetate/cyclohexane (4:1).
Yield: 3.5 g (86% of theory) Melting point: 105-108C
j Rf value: 0.27 (silica gel; ethyl acetate/cyclohexane - 45 - 2~ 7~
= 4:1) The following compounds are obtained in an analogous manner:

(1) N-[4-[1-(tert.butyloxycarbonyl)-4-piperidyl]-benzoyl]-N'-[[4-(methoxycarbonyl)-butyl]-carbonyl]-hydrazine Adipic acid-monomethylester-chloride is used.
Melting point: 150-153C -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)-cyclohexanecarboxylic acid chloride is 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)-cyclo-hexanecarboxylic acid chloride is used. The trans-product precipitates from the organic phase.
Melting point: 198-201DC
Rf value: 0.20 (silica gel; methylene chloride/
methanol = 20:1) .
(4) N-[4-[1-(tert.butyloxycarbonyl)-4-piperidyl~-benzoyl]-N'-t[trans-4-(ethoxycarbonyl)-cyclohexyl]-carbonyl~-hydrazine Rf value: 0.53 (silica gel; methylene chloride/methanol = 9:1) (5) N-[4-(1-benzyl-4-piperazinyl)-benzoyl]-N'-[[trans-4-(ethoxycarbonyl)-cyclohexyl]-carbonyl]-hydrazine - 46 - 21~ 8 : ~-Melting point: 182-184C
Rf value: 0.78 (silica gel; methylene chloride/methanol = 9:1) (6) N-[[1-[1-(tert.butyloxycarbonyl)-4-pipe.ridyl]-4-piperidyl]carbonyl]-N'-[[trans-4-(ethoxycarbonyl)-cyclohexyl]-carbonyl]-hydrazine -Melting point: 222-224C (decomp.) Rf value: 0.79 (silica gel; methylene chloride/methanol = 9:1) Example V

2-[4-[1-(tert.Butyloxycarbonyl)-4-piperidyl]-phenyl]-5-methoxycarbonyl-1,3,4-thiadiazole A solution of 3.32g of N-[4-[1-(tert.butyloxycarbonyl)-4-piperidyl]-benzoyl]-N-[(methoxycarbonyl)-carbonyl]-hydrazine and 3.64g of 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulphide (Lawesson's Reagent) in 60 ml tetrahydrofuran is heated to reflux for 30 minutes. The solvent is removed under reduced pressure `
and the residue is chromatographed over silica gel using ethyl acetate/cyclohexane (2~
Yield: 2.75 g (83% of theory), Melting point: 143-146~C
Rf value: 0.59 (silica gel; ethyl acetate/cyclohexane = 1: 1) ExamDle VI

2-~4-[1-(tert.Butyloxycarbonyl)-4-piperidyl]-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 is stirred for 30 `` 21141~

minutes at ambient temperature. The reaction solution is neutralised with lN hydrochloric acid (pH 6.63). The solvent is evaporated under reduced pressure and the residue triturated with a little water and suction filtered.
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-t2-Amino-2-(methoxycarbonyl)-ethyl]-1-[6-(4-cyanophenyl) -3-pyridazinyl~-imidazole-dihydrochloride To a suspension of 1.55 g of 55% dispersion of sodium hydride in mineral oil in 50 ml of anhydrous dimethylformamide, a solution of 9.6 g of N-~-tert.butyloxycarbonyl-L-histidine-methylester in 100 ml of dry dimethylformamide is added dropwise under nitrogen atmosphere at 0C. The mixture is stirred for 30 minutes at 0C and then a solution of 7.6 g of 3-chloro-6-(4-cyanophenyl)-pyridazine in 400 ml of dry dimethylformamide ~
is added dropwise. The mixture is stirred for 2 hours at 0C and 16 hours at ambient temperature. The reaction solution is poured on to an ice/sodium chloride solution and the aqueous phase is extracted three times using ethyl acetate. The combined organic phases are dried over sodium sulphate and the solvent is evaporated under reduced pressure. The residue is chromatographed over silica gel using methylene chloride/methanol (20:1).
After the removal of the solvent, the resultant crude product (11.0 g) is dissolved in 500 ml of dioxane. 150 ml of ether saturated with hydrogen chloride is added and the precipitate is suction filtered. The solid substance is dissolved in a mixture of 750 ml of dioxane, 750 ml of methanol and 250 ml of ether saturated with hydrogen chloride and stirred for 16 hours at ambient temperature.
Then, the precipitate is suction filtered and washed with - : ~ 211~17~ ~

dioxane (yield 4.4 g). By concentrating the mother liquor to about lO0 ml and suction-filtering the precipitate, a further 4.7 g of the product are obtained.
Total yield: 9.1 g (61% of theory), Melting point: Sintering from 220C
Rf value: 0.43 (silica gel; methylene chloride/methanol/
conc. ammonia = 9:1:0.1) Exam~le VIII

4-[2-(n-Butanesulphonylamino)-2-(methoxycarbonyl)-ethyl]-l-[6-(4-cyanophenyl)-3-pyridazinyl]-imidazole To a solution of 4.2 g of 4-[2-amino-2-(methoxycarbonyl)-ethyl]-1-[6-(4-cyanophenyl)-3-pyridazinyl]-imidazole-dihydrochloride and 4.5 g ethyldiisopropylamine in 150 ml of methylene chloride, a solution of 2.0 g of n-butanesulphonylchloride in 20 ml of dimethylformamide is ~ -added dropwise at 0C. The mixture is stirred for 2 days at ambient temperature and the precipitate is suction filtered. The filtrate is washed twice with water. The organic phase is dried over sodium sulphate and the solvent is evaporated under reduced pressure. The residue is triturated with a little methanol and suction filtered.
Yield: 0.85 g (18% of theory), Rf value: 0.49 (silica gel; methylene chloride/methanol/
conc. ammonia = 9:1:0.1) Exam~le IX

1-(tert.Butyloxycarbonyl)-4-(2-cyanoethyl)-piperidine A suspension of 4.61 g of 1-(tert.butyloxycarbonyl)-4-[2-(methanesulphonyl)-ethyl]-piperidine, 10.5 g of potassion cyanide and a spatula tip of sodium iodide in 10 ml of anhydrous dimethylformamide are stirred for 16 hours at ambient temperature. After adding a few ml of dimethylformamide the mixture is heated for 7 hours to -` 211~178 70C. To the cooled suspension, ice water and 3 ml of 2N
sodium hydroxide solution are added, the aqueous phase is ~ -~
extracted several times using tert.butyl-methylether. The combined organic phases are washed with ice water and saturated with sodium hydroxide solution and dried over sodium sulphate. The solvent is evaporated under reduced pressure.
Yield: 3.1 g (86% of theory), yellowish oil Rf value: 0.63 (silica gel; cyclohexane/ethyl acetate = 1:1) Example X

1-(tert.Butyloxycarbonyl)-4-[2-(aminothiocarbonyl)-ethyl]-piperidine Hydrogen sulphide is passed for a few minutes at a temperature of -5 to 0C through-a solution of 3.0 g -of 1-(tert.butyloxycarbonyl)-4-(2-cyanoethyl)-piperidine in 15 ml of pyridine and 1.15 ml of tri-ethylamine. The reaction solution is stirred for 16 hours -at 0C and a further 24 hours at ambient temperature.
Then, nitrogen is passed through the reaction solution for 3 hours, the solution is poured into 150 ml of ice/water -mixture and the aqueous phase is extracted twice using tert.butyl-methyl-ether. The combined organic extracts are successively washed twice with water, once with 2N
citric acid solution, once with water and once with saturated sodium chloride solution. The organic phase is dried and the solvent is evaporated under reduced pressure. A yellow oil is obtained which is mixed with a little cyclohexane. After adding petroleum ether the mixture is cooled in the ice/water bath and the colourless crystalline precipitate is suction filtered.
Yield: 550 mg (16~ of theory), Melting point: 148-154C
Rf value: 0.28 (silica gel; cyclohexane/ethyl acetate = 1:1) f'~
- 50 - 211417~
The following compound is obtained analogously to that of Example X:

(1) 4-(benzyloxy)-benzoic acid thioamide The reaction solution is poured into water and the precipitate is suction filtered. The solid substance is dissolved in ethyl acetate and the solution is dried over sodium sulphate. After concentrating the solution under reduced pressure, the product is precipitated.
Melting point: 172-174C
Rf value: 0.57 (silica gel; methylene chloride/ethyl acetate = 9:1) -~

Exam~le XI

Ethyl-3-t4-(2-chloroacetyl)-phenyl]-propionate To 56.0 g of aluminium trichloride in 150 ml of dichlorethane, 23.7 g of chloroacetylchloride is added dropwise at 0C. Then, 35.6 g of ethyl 3-phenyl-propionate are added dropwise whilst the temperature is maintained between -5 and 5C. The mixture is stirred for `
3 hours at ambient 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 is evaporated under reduced pressure, stirred with petroleum ether and suction filtered.
Yield: 44.2 g ~87% of theory), Rf value: 0.73 (silica gel; cyclohexane/ethyl acetate = 1:1) 211~7~

Example XII

2-[4-(Benzyloxy)-phenylJ-4-[2-(methoxycarbonyl)-ethyl]-1,3-thiazole A solution of 14.0 g of 4-(benzyloxy)-benzoic acid-thioamide and 12.0 g of methyl 4-bromo- -3-oxo-butanoate in 1000 ml methanol is heated for 24 hours until refluxing. The solvent is evaporated under reduced pressure and the residue is distributed between methylene chloride and dilute sodium carbonate solution. The -organic phase is extracted once with dilute sodium -carbonate solution and once with water, dried over sodium sulphate and the solvent is evaporated under reduced pressure. The residue is recrystallised from methanol.
Yield: 15.0 g (74% of theory), Melting point: 80C
Rf value: 0.25 (silica gel; methylene chloride/ethyl ;~
acetate = 19:1) Exam~le XIII

4-(2-Carboxyethyl)-2-(4-hydroxyphenyl)-1,3-thiazole . .
A solution 8.0 g of 2-[4-(benzyloxy)-phenyl]-4-[2-(methoxycarbonyl)-ethyl]-1,3-thiazole in 200 ml of glacial acetic acid and 40 ml of methanol (saturated with hydrogen -chloride) is hydrogenated in the presence of 4.0 g of 10~
palladium on charcoal for 1.5 hours at ambient temperature and a hydrogen pressure of 5 bar. The catalyst is filtered off and the filtrate is concentrated under reduced pressure. The residue is heated with ethyl acetate until boiling, cooled and the precipitate is suction filtered.
Yield: 5.4 g (96% of theory), Melting point: 224-226C
Rf value: 0.53 (silica gel; toluene/dioxane/ethanol/glacial acetic acid = 9:1:1:0.6) -~

- 52 - 211~178 Example XIV

2-(4-Hydroxyphenyl)-4-[2-(methoxycarbonyl)-ethyl]-1,3-thiazole A solution of 5.0 g 4-(2-(carboxyethyl)-2-(4-hydroxy-phenyl)-1,3-thiazole in 100 ml methanol and 10 ml of methanol (saturated with hydrogen chloride) is stirred for 16 hours at ambient temperature. The solvent is concentrated under reduced pressure. The residue is heated in about 100 ml of water over a steam bath, then cooled in an ice bath and the precipitate is suction filtered. ~-Yield: 4.2 g (79% of theory), Melting point: 103-105C
Rf value: 0.33 (silica gel; cyclohexane/ethyl acetate = 2:1) Example XV

4-t4-[2-(Ethoxycarbonyl)-ethyl]-phenyl]-2-methyl-imidazole A suspension of 5.1 g of ethyl 3-[4-(2-chloro-acetyl)-phenyl]-propionate, 2.3 g of acetamidine-hydrochloride and 4.7 g of sodium carbonate in 20 ml of anhydrous ethanol are heated to reflux for 2 hours. The solvent is evaporated under reduced pressure and the residue is distributed between ethyl acetate and water. The organic phase is washed three times with water, dried over magnesium sulphate and the solvent is evaporated under reduced pressure. The residue is chromatographed over a uminium oxide (activity stage II) using cyclohexane/ethyl acetate (3:7).
Yield: 900 mg (17% of theory), Rf value: 0.23 (AloxN; ethyl acetate/cyclohexane = 7:3) - 53 ~ 2 1 14~7 8 Example XVI

[4-(1-Benzyl-4-piperazinyl)-benzoyl]-hydrazine 3 g of N-[4-(1-benzyl-4-piperazinyl)-benzoyl]-N'- ~`
(tert.butyloxycarbonyl)-hydrazine are dissolved in 30 ml of methylene chloride, mixed with 15 ml of trifluoro ~-acetic acid and stirred for 4 hours at ambient `
temperature. The mixture is concentrated, evaporated twice with acetone and the residue is distributed between 2N sodium hydroxide solution and ethyl acetate. The ethyl i~
acetate phases are concentrated and the residue is purified over silica gel (eluant: methylene chloride/methanol = 40:1 to 25:1).
Yield: 0.82 g (36% of theory), Melting point: 168-170C
Rf value: 0.51 (silica gel; methylene chloride/methanol = 9: 1) ' Exam~le XVII

N-t4-(1-Benzyl-4-piperazinyl)-benzoyl]-N'-(tert.butyloxy-carbonyl)-hydrazine ~`

3 g of 4-(1-benzyl-4-piperazinyl)-benzoic-acid are dissolved with warming in 100 ml of dimethylformamide and mixed with 1.05 ml of chlorodiphenylphosphine. The mixture is then cooled, 1.5 ml of triethylamine is added, ~`
and the mixture is stirred for 1 hour under ice cooling. -It is mixed with 1.4 g of tert.butyloxycarbonyl-hydrazine, stirred for 5 days at ambient temperature and concentrated. The residue is mixed with ethyl acetate and extracted with water, whilst the resultant solid product is filtered off. The ethyl acetate phases are washed with sodium bicarbonate solution and concentrated. The residue is crystallised from ethyl acetate/petroleum ether.
Yield: 0.94 g (23% of theory), _ 54 _ 2~4~7 8 Melting point: 162-165C
Rf value: 0.45 (silica gel; methylene chloride/methanol = 9:1) Exam~le XVIII

4-(1-Benzyl-4-piperazinyl)-benzoic acid A mixture of 29.8 g of 4-(1-benzyl-4-piperazinyl)-benzoic acid nitrile, 48 g of potassium hydroxide and 200 ml of glycol are heated to reflux for 8 hours. The glycol is largely distilled off in vacuo. The residue is mixed with water, acidified with glacial acetic acid and the preciptated product is filtered off and washed with acetone.
Yield: 31.4 g (99~ of theory), Melting point : 225-227C
Rf value: 0.57 (silica gel; methylene chloride/methanol = 9:1) Example XIX

4-(1-Benzyl-4-piperazinyl)-benzoic acid-nitrile 26 g of 4-fluoro-benzonitrile, 37.3 ml of N-benzylpiperazine and 36.7 ml N-ethyl-diisopropylamine are heated together for 8 hours at 140C. The mixture is then poured onto water and extracted using methylene chloride.
The organic phase is concentrated and the residue is crystallised from ether/petroleum ether.
Yield: 29.8 g (50% of theory), Melting point : 106-108C
Rf value: 0.89 (silica gel; methylene chloride/methanol = 9:1) - 55 - 2~17~ ~ ~
Example XX

[[1-[1-(tert.Butyloxycarbonyl)-4-piperidyl]-4-piperidyl]-carbonyl]-hydrazine 1 g of 1-[l(tert.butyloxycarbonyl)-4-piperidyl]-4-ethoxycarbonyl-piperidine and lO ml hydrazine hydrate are heated to reflux in 20 ml of methanol for 4 hours.
The mixture is concentrated and the residue triturated using 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-ethoxy-carbonyl-piperidine -A mixture of 24.9 g of 1-tert.butyloxycarbonyl-4-piperidone, 19.3 g of ethyl piperdine-4-carbonate and ;
46.5 ml of` titanium(IV)-isopropoxide are stirred for 1 hour at ambient temperature, mixed with 170 ml of ethanol and 5 g of sodium cyanborohydride and stirred for 20 hours at ambient temperature. 34 ml of water is added, the mixture is filtered, the filtrate is concentrated, extracted with ethyl acetate and concentrated by evaporation. The residue is purified chromatographically (silica gel, eluant, cyclohexane/ethyl acetate = 2:3).
Yield: 32.9 g (77% of theory), Rf value: 0.44 (silica gel; ethyl acetate) .~,.',:,: ' - 56 - 21~17~
Exam~le 1 2-[4-[1-(tert.Butyloxycarbonyl)-4-piperidyl]-phenyl]-5-[[2-(methoxycarbonyl)-ethyl]-aminoca~bonyl]-1,3,4-thiadiazole A solution of 2.0 g of 2-[4-[1-(tert.butyloxycarbonyl)-4-piperidyl]-phenyl]-5-carboxy-1,3,4-thiadiazole, 1.77 g of 2-[(lH)-benzotriazol-1-yl]-1,1,3,3-tetramethyluronium-tetrafluoroborate, 0.72 g of~-alanine-methylester-hydrochloride, 0.75 g 1-hydroxy-(lH-) benzotriazole and 1.4 g of N-methyl-morpholine in 50 ml of dimethylformamide is stirred for 5 hours at ambient temperature. The solvent is removed under reduced pressure. Water is added to the residue and the aqueous phase is extracted using ethyl acetate. The organic phase is dried over sodium sulphate and the solvent is removed under reduced pressure. The crude product is chromatographed over silica gel using methylene chloride/methanol (9:1), and the product obtained after removing the solvent is triturated with ethyl acetate and suction filtered.
Yield: 1.5 g (62% of theory), Melting point: 176-178C, Rf value: 0.76 (silica gel; ethyl acetate/cyclohexane = 4:1) Exam~le 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]-amino-carbonyl]-1,3,4-thiadiazole in 40 ml of dioxane and 40 ml of ether saturated with hydrogen chloride is stirred for 2.5 hours at ambient temperature. The precipitate is --~-~
suction filtered and washed with ether.

~, . , . :

- 57 _ 21~178 Yield: 1.05 g (85% of theory), Melting point: 250-255C, Massspectrum: 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 Rf 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 Methanol saturated with hydrogen chloride is added to the reaction solution. After stirring for 1 hour at ambient temperature, the solvent is 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 consisting of dioxane, ether (saturated with hydrogen chloride) and methanol (saturated with hydrogen chloride). After stirring for 3 hours, the precipitate is suction filtered 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 ~ -21~4178 - 58 ~
(5) 2-[trans-4-tMethoxycarbonyl)-cyclohexyl]-4-[3,4-dehydro-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-hydrochloride (9) 4-[4-[2-(Methoxycarbonyl)-ethyl]-phenyl]-2-[2-(4-piperidyl)-ethyl]-imidazole-dihydrochloride (10) 4-[4-[2-(Methoxycarbonyl)-ethyl]-phenyl]-l-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.
Rf value: 0.48 (Reversed Phase; RP8; methanol/5% saline solution = 6:4) Calc.x 1.95 HCl x H2O: C 57.82 H 7.70 N 9.15 Cl 14.95 Found : 57.62 7.68 9.16 15.07 (12) 2-t4-[2-(Methoxycarbonyl)-ethyl]-phenyl]-l-methyl-4-[(3-pyrrolidinyl)-oxymethyl]-imidazole-dihydrochloride (13) 4-[4-[2-(Methoxycarbonyl)-ethyl]-2-[N-[(4-piperidyl)-carbonyl]-N-methyl-amino]-1,3-thiazole-hydrochloride (14) 2-[4-[2-(Methoxycarbonyl)-ethyl]-phenyl]-4-[(4-piperidyl)-aminocarbonyl]-1,3-thiazole-hydrochloride ::

. i'~ " s ,,, ' ~ ",' ,,; ~

211417~

(15) 2-[2-(Methoxycarbonyl)-ethyl]-4-[4-[N-[(4-piperidyl) -carbonyl]-N-methyl~amino]-phenyl]-1,3-thiazole-hydro-chloride (16) 2-[2-(Methoxycarbonyl)-ethyl]-5-[2-[2-(4-piperidyl)-ethyl]-5-pyrimidinyl]-1,3,4-thiadiazole-hydrochloride (17) 4-[2-(Methoxycarbonyl)-ethyl]-2-[4-[(4-piperidyl)-methyloxy]-phenyl]-1,3-thiazole-dihydrochloride-dihydrate -The reaction is carried out with methanol saturated with hydrogen chloride. The precipitate is suction filtered and washed with tert.butyl-methyl-ether.
Melting point: 95-98~C
Rf value: 0.28 (Reversed Phase; RP8; methanol/5% saline solution = 6:4) --(18) 4-t4-[(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-thiadiazol-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: 274-280C (decomp.) Rf 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 reaction is carried out analogously to Example 2(19).
Melting point: >320~
Rf value: 0.67 (Reversed Phase Plate RP18; methanol/
5% saline solution = 6:4) 21~417~

Example 3 2-[(2-Carboxyethyl)-aminocarbonyl]-5-[4-(4-piperidyl)-phenyl]-1,3,4-thiadiazole-hydrochloride A suspension of 550 mg of 2-[[2-(methoxycarbonyl)-ethyl]-aminocarbonyl]-5-[4-(4-piperidyl)-phenyl]-1,3,4-thiadiazole-hydrochloride in 100 ml of 6N hydrochloric acid is stirred for 3 hours at ambient temperature.
After adding a further 500 ml of 6N hydrochloric acid, the solution is stirred for another hour. The solvent is removed under reduced pressure and the crude product is triturated with a little water and suction filtered.
Yield: 480 mg (91% of theory), Mass spectrum: M~ = 360 Rf 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 Rf 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-thiadiazole-hydrochloride Melting point: > 310~C
Mass spectrum: M~ = 371 value: 0.17 (silica gel; methylene chloride/methanol/
conc. ammonia = 4:1:0.25) (3) 1-[6-(4-Amidino-phenyl)-3-pyridazinyl]-4-[2-(n-butane -sulphonylamino)-2-carboxy-ethyl]-imidazole-hydrochloride 21~4~78 Mass spectrum: (M+H)+ = 472 Rf value: 0.20 (silica gel; methylene chloride/methanol/
conc. ammonia = 2:1:0.25) (4) 4-[4-(2-Carboxy-ethyl)-phenyl]-2-[2-(4-piperidyl)- :~ ~
ethyl]-1,3-thiazole -The product of Example 9 is heated in 3N hydrochloric acid for 1 hour on a steam bath.
Melting point: Decomposition from 168C
Rf value: 0.38 (Reversed Phase RP8; methanol/5% saline solution = 6:4) -(5) 2-(trans-4-Carboxycyclohexyl)-4-[4-(4-piperidyl)-phenyl]-imidazole-dihydrochloride (6) 2-(trans-4-Carboxycyclohexyl)-l-methyl-4-[4-(1-methyl -4-piperidyl)-phenyl]-imidazole-dihydrochloride (7) 2-(trans-4-Carboxycyclohexyl)-l-methyl-4-[4-(4-piperidyl)-phenyl]-imidazole-dihydrochloride (8) 2-(trans-4-Carboxycyclohexyl)-4-[4-(3,4-dehydro-4- ~i .
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-t4-(2-Carboxy-ethyl)-phenyl~-2-[2-(4-piperidyl)-ethyl~-imidazole-dihydrochloride -~

(12) 4-[4-(2-Carboxy-ethyl)-phenyl~-l-methyl-2-[2-(4-piperidyl)-ethyl]-imidazole-dihydrochloride (13) 4-[4-(2-Carboxy-ethyl)-phenyl]-2-methyl-1-[2-(4-piperidyl)-ethyl]-imidazole-dihydrochlorid-hydrate Rf value: 0.64 (Reversed Phase RP8; methanol/5~ saline solution = 6:4) Calc. x 1.95 HCl x 0.6 H2O:
C 56.77 H 7.37 N 9.84 Cl 16.40 Found: 56.77 7.13 9.93 16.34 (14) 2-[4-(2-Carboxy-ethyl)-phenyl]-1-methyl-4-[(3-pyrrolidinyl)-oxymethyl]-imidazole-dihydrochloride (15) 4-[4-(2-Carboxy-ethyl)-phenyl]-2-[N-[(4-piperidyl)-carbonyl]-N-methyl-amino~-1,3-thiazole-hydrochloride (16) 2-[4-(2-Carboxy-ethyl)-phenyl]-4-[(4-piperidyl)-aminocarbonyl]-1,3-thiazole-hydrochloride :,, ", ~,, , (17) 2-(2-Carboxy-ethyl)-4-[4-[N-[(4-piperidyl)-carbonyl]
-N-methyl-amino]-phenyl]-1,3-thiazole-hydrochloride (18) 2-(2-Carboxy-ethyl)-5-[2-[2-(4-piperidyl)-ethyl]-5-pyrimidinyl]-1,3,4-thiadiazole-hydrochloride ~ .
(19) 1-[3-(4-Amidino-phenyl)-6-pyridazinyl]-3-[2-carboxy-2-(phenylsulfonylamino)-ethyl]-indole-hydro-chloride (20) 2-(4-Amidino-phenyl)-4-[4-[2-(acetylamino)-2-carboxy-ethyl]-phenyl]-5-methyl-1,3-thiazole-hydrochloride (21) 4-(4-Amidino-phenyl)-2-[4-[2-(methanesulfonylamino)-2-carboxy-ethyl]-phenyl]-1-methyl-imidazole-hydrochloride (22) 4-(2-Carboxy-ethyl)-2-[4-[(4-piperidyl)-methyloxy]-phenyl]-1,3-thiazole-dihydrochloride-hydrate Melting point: decomposition from 225C
Rf value: 0,36 (Reversed Phase, RP8; methanol/5% saline - 63 - 21~4178 solution = 6:4) ~ '."

(23) 4-[4-(CarboxymethylQxy)-phenyl]-2-[2-(4-piperidyl)-ethyl]-1,3-thiazole-hydrochloride (24) 4-[4-(2-Carboxy-ethyl)-phenyl]-2-[2-(4-pyridyl)-ethyl]-1,3-thiazole-hydrochloride (25) 4-[4-(2-Carboxy-ethyl)-cyclohexyl]-1-[2-(4-quinuclidinyl)-ethyl]-2-methyl-imidazole-dihydrochloride (26~ 2-t4~ enzyl-4-piperazinyl)-phenyl]-5-(trans-4-carboxycyclohexyl)-1,3,4-thiadiazole Mass spectrum: M~ = 462 Rf value: 0.15 (Reversed Phase Plate RP18; methanol/5%
sodium chloride solution = 6:4) (27) 2-(trans-4-Carboxycyclohexyl)-5-[1-(4-piperidyl)-4-piperidyl]-1,3,4-thiadiazole Melting point: > 320~C
Rf value: 0.67 (Reversed Phase Plate RP18; methanol 5%
sodium chloride solution = 6:4) .
ExamPle 4 2-t4-tl-(tert.13utyloxycarbonyl)-4-piperidyl)-phenyl]-5- ,.
t4-(methoxycarbonyl)-butyl]-1,3,4-thiadiazole A solution of 2.4 g of N-t4-tl-(tert.butyloxycarbonyl)-4-piperidyl]-benzoyl]-N'-tt4-(methoxycarbonyl)-butyl]-carbonyl]-hydrazine and 2.1 g of 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulphide (Lawesson's Reagent) in 40 ml of tetrahydrofuran is heated to reflux for 30 minutes. The solvent is then evaporated off under reduced pressure and the residue is chromatographed over silica gel.
Yield: 2.4 g (quant~tative), ..... . , .. . . . . , . . ... .... . , ., . , ,, , ~, , ,, ~ ,, - 64 - 2~178 Melting point: 111-113C, Mass spectrum: M~ = 459 Rf value: 0.38 (silica gel; ethyl acetate/cyclohexane The following compounds are obtained analogously:
-....,~
(1) 2-[4-[1-(tert.Butyloxycarbonyl)-4-piperidyl]-phenyl]-5-tcis-4-(methoxycarbonyl)-cyclohexyl]-1,3,4-thiadiazole Melting point: 130-132C
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: 180-182C
Rf value: 0.57 (silica gel; cyclohexane/ethyl acetate ..
= 1:1) , (3) 2-[4-[4-(tert.Butyloxycarbonyl)-l-piperazinyl]-phenyl]-5-[trans-4-(methoxycarbonyl)-cyclohexyl]-1,3,4- . :
thiadiazole :~:

(4) 2-[4-[1-(tert.Butyloxycarbonyl)-4-piperidyl]-phenyl]-5-[trans-4-(ethoxycarbonyl)-cyclohexyl]-1,3,4-thiadiazole Melting point: 164-166C :
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: 166-170C : `~
Rf value: 0.63 (silica gel; methylene chloride/methanol = 9 ~

(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-Carboxy-butyl)-5-[4-(4-piperidyl)-phenyl]-1,3,4- -thiadiazole-hydrochloride ~ ;

A solution of 1.0 g of 2-[4-(methoxycarbonyl)-butyl]-5-[4-(4-piperidyl)-phenyl]-1,3,4-thiadiazole-hydrochloride and 0.22 g of lithium hydroxide-hydrate in 30 ml tetrahydrofuran and 24 ml of water is stirred for 60 minutes at ambient temperature. The reaction solution is acidified with lN hydrochloric acid. Excess tetrahydrofuran is evaporated off under reduced pressure and the precipitate is suction filtered and washed with a little water.
Yield: 0~80 g (83% of theory), -~ -Mass spectrum: M~ = 345 Rf 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 off 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-Carboxy-butyl)-4-phenyl-5-[4-(4-piperidyl)-- 66 - 211~17~
phenyl]-1,2,4-triazole After acidification the solvent mixture is evaporated off 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-Carboxy-cyclohexyl)-5-[4-(4-piperidyl)-phenyl]-1,3,4-thiadiazole-hydrochloride Mass spectrum: M~ = 371 Rf value: O.o9 (silica gel; methylene chloride/methanol/
conc. ammonia = 4:1:0.25) -: .
(4) 2-(4-Carboxy-cyclohexyl)-5-[4-(4-piperidyl)-phenyl]-1,3,4-oxadiazole -After acidification the solvent mixture is evaporated off under reduced pressure and the crude product is chromatographed over silica gel.
Mass spectrum: M~ = 355 Rf value: O.o9 (silica gel; methylene chloride/methanol/
conc. ammonia = 4:1:0.25) (5) 2-(trans-4-Carboxy-cyclohexyl)-5-[4-(2,2,6,6-tetramethyl-4-piperidyl)-phenyl]-1,3,4-thiazole-hydrochloride (6) 2-(trans-4-Carboxy-cyclohexyl)-4-[4-(4-cyano-4-piperidyl)-phenyl]-l-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]-~ . .

- 211~

carbonyl]-hydrazine and 0.3 ml of pyridine in 18 ml thionyl chloride is stirred for 3 hours at ambient temperature. Then it is heated to reflux for 45 minutes.
Excess thionyl chloride is evaporated off under reduced pressure, the residue is mixed with toluene and the solvent again evaporated off 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, 220 mg phosphorus trichloride are added and the mixture is heated briefly to 60C. Then 700 mg of N-[4-[4-(tert.-butyl-oxycarbonyl)-4-piperidyl]-benzoyl]-N'-[tcis-4-(methoxycarbonyl)-cyclohexyl]-carbonyl]-hydrazine are added and the mixture is heated to reflux for 2.5 hours. The solvent is evaporated off under reduced pressure. Water and lN sodium hydroxide solution are added to the residue until the solution becomes alkaline. The aqueous phase is extracted once with methylene chloride and once with ethyl acetate. The combined organic phases are dried over sodium sulphate 21~17~ ~

and the solvent is evaporated off 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 Rf value: 0.34 (silica gel; methylene chloride/methanol/
conc. ammonia = 4:1:0.25) Example 8 -. .
l-t6-(4-Amidino-phenyl)-3-pyridazinyl]-4-[2-(n-butanesulphonylamino)-2-(methoxycarbonyl)-ethyl]-imidazole :
To a solution of 700 mg of 4-[2-(n-butanesulphonylamino)-2-(methoxycarbonyl)-ethyl]-1-[6-(4-cyanophenyl)-3-pyridazinyl~-imidazole in 250 ml of anhydrous methanol, is introduced hydrogen chloride at 0C for 1 hour whilst stirring. After stirring for 16 hours at ambient temperature, the solvent is evaporated off under reduced pressure at a bath temperature of 30C. The residue is dissolved in 50 ml of anhydrous methanol and after adding 3 g of ammonium carbonate, stirred for 4 hours at ambient temperature. The precipitate is suction filtered and washed again with anhydrous methanol. The filtrate is concentrated by evaporation under reduced pressure and the residue is chromatographed over silica gel.
Yield: 250 mg (34 % of theory), Melting point: 227-229C
Mass spectrum: (M+H)~ = 486 R~ value: 0.09 (silica gel: methylene chloride/methanol/

9 21~178 -conc. ammonia = 4:1:0.2S) The following compounds are obtained analogously:

(1) 1-[3-[4-Amidino-phenyl]-6-pyridazinyl]-3-[2-(methoxycarbonyl)-2-(phenylsulfonylamino)-ethyl]-indole (2) 4-[4-[2-(Acetylamino)-2-(methoxycarbonyl)-ethyl]-phenyl~-2-(4-amidino-phenyl)-5-methyl-1,3-thiazole (3) 4-[4-Amidino-phenyl]-l-methyl-2-[4-[2-(methane-sulphonylamino)-2-(methoxycarbonyl)-ethyl]-phenyl]-imidazole Example 9 2-[2-[1-(tert.Butyloxycarbonyl)-4-piperidyl]-ethyl]-4-[4-[2-(ethoxycarbonyl)-ethyl]-phenyl]-1,3-thiazole A solution of 550 mg of 1-(tert.butyloxycarbonyl)-4-(2-thio-amido-ethyl)-piperidine and 530 mg of ethyl 3-[4-(2-chloroacetyl)-phenyl]-propionate in 30 ml of methanol are heated to reflux for 14 hours. Then 500 mg of ethyl diisopropylamine and a solution of 500 mg of di-tert.-butyl pyrocarbonate in ether are added dropwise at ambient temperature. The mixture is stirred for 10 minutes at ambient temperature and the solvent is removed at reduced pressure. The residue is chromatographed over silica gel.
Yield: 300 mg (32 % of theory), Rf value: 0.26 (silica gel; cyclohexane/ethyl acetate = 8:2) Exam~le 10 - 211~178 2-[4-[[1-(tert.Butyloxycarbonyl)-4-piperidyl]-methyloxy]-phenyl]-4-[2-(methoxycarbonyl)-ethyl]-1,3-thiazole To a solution of 4.09 g of 2-(4-hydroxy-phenyl)-4-[2-(methoxycarbonyl)-ethyl)-1,3-thiazole in 1000 ml of - -~
anhydrous dimethylformamide, are added 1.7 g of potassium-tert.butoxide and stirred for 15 minutes at ambient temperature. 4.5 g of l-(tert.butyloxy- -carbonyl)-4-(mesyloxymethyl)-piperidine are added and the mixture is heated for 24 hours to 60C. After the addition of a further 0.9 g of potassium-tert.butoxide and 2.2 g of 1-(tert.butyloxy-carbonyl)-4-(mesyloxymethyl)-piperdine, the stirring is continued for -2 days at 60C. The solvent is evaporated off at reduced pressure, and the remaining residue is chromatographed -over silica gel.
Yield: 4.3 g (68 % of theory), Melting point: 75-77C
Rf value: 0.70 (silica gel; methylene chloride/ethyl acetate = 4:1) -Exam~le 11 1-[2-tl-(tert.Butyloxycarbonyl)-4-piperidyl]-ethyl]-4-[4-[2-(ethoxycarbonyl)-ethyl]-phenyl]-2-methyl-imidazole - ~
.: .
A suspension of 820 mg of 4-[4-[2-(ethoxycarbonyl)-ethyl]-phenyl]-2-methyl-imidazole and 140 mg of 55%
sodium hydride in mineral oil in 5 ml of dimethylformamide is stirred for 30 minutes at ambient temperature. 980 mg of 1-(tert.butyloxycarbonyl)-4-[2-~methanesulfonyloxy)-ethyl]-piperidine are added and the mixture is stirred for 2 hours at ambient temperature.
The solvent is evaporated off under reduced pressure and the residue is distributed between water and ethyl - 71 - 211~17~ :
acetate. After neutralising the aqueous phase with 2N
citric acid, the aqueous phase is extracted several times using ethyl acetate. The combined ethyl acetate phases are washed with water, dried over magnesium sulphate, and the solvent is evaporated off under reduced pressure.
The residue is chromatographed over alumunium oxide (activity stage III), using cyclohexane/ethyl acetate ( 1 : 1) .
Yield: 650 mg (43 % of theory), Rf value: 0.29 (Aluminium oxide N; cyclohexane/ethyl acetate = 1:1) Example 12 2-ttrans-4-(Isobutyloxycarbonyl)-cyclohexyl]-5-[4-(4-piperidyl)-phenyl]-1,3,4-thiadiazole-hydrochloride Through 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, hydrogen chloride gas is passed for 1.5 hours. The stirring is continued for 16 hours at ambient temperature. The mixture is concentrated, the residue is triturated with acetone and suction filtered.
Yield: 0.54 g (95 % of theory), Melting point: 265-267C
Rf value: 0.63 (Reversed Phase Plate RP18: methanol/5%
sodium chloride solution = 6:4) The following compound is obtained analogously:

(1) 2-ttrans-4-(Isopropyloxycarbonyl)--cyclohexyl]-5-t4-(4-piperidyl)-phenyl]-l~3~4-thiadiazole-hydrochloride Rf value: 0.67 (silica gel; methylenechloride/methanol/
conc.
ammonia = 4:1:0.25) - 72 - 21~78 Exam~le 13 .

2-(trans-4-Carboxy-cyclohexyl)-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 in 30 ml of dimethylformamide are treated with hydrogen at a pressure of 4 bar in the presence of 0.5 g of palladium hydroxide on charcoal for 7 days at ambient temperature.
Rf value: 0.29 (Reversed Phase Plate RP18; methanol/5%) sodium chloride solution = 6:4) The following compound is obtained analogously: -(1) 2-~trans-4-(Ethoxycarbonyl)-cyclohexyl]-5-[4 (l-piperazinyl)-phenyl]-1,3,4-thiadiazole-hydrochloride Mass spectrum: M~ = 400 ;
Rf value: 0.35 (silica gel; methylene chloride/
methanol = 9:1) ~ -Example 14 ', ~,:..
Dry ampoule containing 2.5 mg of active substance per 1 ml -'.

:
Composition:
:.
Active substance 2.5 mg Mannitol 50.0 mg Water for injections ad 1.0 ml ' Preparation:
The active substance and mannitol are dissolved in water.
After transferring the solution to the ampoule it is freeze dried. At the point of use, the solution is made - 73 - 211~178 up with water for injections.

Example 15 Dry ampoule containing 35 mg of active substance per 2 ml .

Composition:

Active substance35.0 mg Mannitol 100.0 mg ~ater for injections ad 2.0 ml Preparation:
The active substance and mannitol are dissolved in water.
After transferring the solution to the ampoule, it is freeze-dried.

At a point of use, the solution is made up with water for injections Exam~le 16 Tablet containing 50 mg of active substance _ Composition:

(1) Active substance50.0 mg (2) Lactose 98.0 mg (3) Corn starch 50.0 mg (4) Polyvinylpyrrolidone15.0 mg (5) Magnesium stearate2.0 mq 215.0 mg ~ :

Preparation: :
Components (1), (2) and (3) are mixed and granulated with - 74 - ~ 7 8 an aqueous solution of component (4). Component (5) is added to the dried granules. From this mixture, tablets are compressed, biplanar, facetted on both sides and notched on one side. Diameter of tablets: 9 mm.

Exam~le 17 Tablet with 350 mg of active substance Composition:

(1) Active substance350.0 mg (2) Lactose 136.0 mg -(3) Corn starch80.0 mg (4) Polyvinylpyrrolidone 30.0 mg (5) Magnesium stearate 4.0 ma 600.0 mg Components (1), (2) and (3) are mixed and granulated with an aqueous solution of component (4). Component (5) is added to the dried granules. From this mixture, tablets are compressed, biplanar, facetted on both sides and notched on one side.
Diameter of tablets: 12 mm. ;~

Exam~le 18 -~

Capsules containing 50 mg of active substance ' Composition:

(1) Active substance50.0 mg (2) Dried corn starch58.0 mg (3) Powdered lactose50.0 mg (4) Magnesium stearate 2.0 mg 160.0 mg 2~178 Preparation:
Component (1) is triturated with component (3). This triturate is added to the mixture of components (2) and (4) with thorough mixing.

This powdered mixture is packed into size 3 hard gelatine oblong capsules in a capsule filling machine.

Example 19 Capsules containing 350 mg of active substance Composition:

(1) Active substance 350.0 mg (2) Dried corn starch 46.0 mg (3) Powdered lactose 30.0 mg (4) Magnesium stearate 4.0 ma 430.0 mg Preparation:
Component (1) is triturated with component (3). This triturate is added to the mixture of components (2) and (4), with thorough mixing. This powdered mixture is packed into size O hard gelatine oblong capsules in a capsule filling machine.

Claims (11)

1. Compounds of formula I
(I) (wherein:

(i) with the proviso that the five-membered heterocyclic ring is not a pyrrolidine, pyrroline, pyrrolinone or pyrrolidinone ring and contains at least one carbon atom and (ii) with the exception of the compounds 3-(4-amidino-phenyl)-1-[4-(2-amino-2-carboxy-ethyl)-phenyl]-2H-pyrazol-5-one and 3-(4-amidino-phenyl)-1-[4-(2-amino-2-methoxycarbonyl-ethyl)-phenyl]-2H-pyrazol-5-one, a first of the groups X1, X2, X3, X4 and X5 denotes a group of formula A - B - C' - N< , A - B - C' - CH< or A - B - C' - C?

(wherein A denotes a pyridyl or quinuclidinyl group, or A denotes a C5-7-cycloalkyl group optionally substituted by 1 to 4 alkyl groups or by a hydroxy, alkoxy, phenylalkoxy, cyano, aminocarbonyl, carboxy, alkoxycarbonyl or phenylalkoxycarbonyl group, in which an unsubstituted ring methylene group is replaced by an Ra-N<
group, and, additionally, in a 6- or 7-membered azacycloalkyl group thus formed a >CH- unit in the 4-position is optionally replaced by a nitrogen atom, or in a 5- to 7-membered azacycloalkyl group thus formed a -CH2-CH< unit is optionally replaced by a -CH=C< unit, and in a piperazinyl or homopiperazinyl ring thus formed a methylene group, which is adjacent to the nitrogen atom in the 4-position, is optionally replaced by a carbonyl group, or, if D denotes a C1-8-alkylene or C1-8-alkenylene group substituted by a R3R4N-CO-NR5- or R6-SO2-NR3-group (wherein R3, R4 and R5 independently denote hydrogen atoms or alkyl or phenylalkyl groups and R6 denotes a C1-5-alkyl, phenylalkyl or phenyl group), or if E denotes a straight-chain or branched C1-5-alkylene or C1-5-alkenylene group substituted by a hydroxy, alkoxy, alkylsulphenyl, R3R4N-, R3O-CO-, R6CO-NR3-, R6O-CO-NR3-, R6SO2-NR3- or R3R4N-CO-NR5-group (wherein R3, R4, R5 and R6 are as hereinbefore defined), then A may also denote a phenyl group substituted in the 4-position by a RaNH-CH2- or RaNH-C(=NH) -group, or a phenyl group to which a C3-4-n-alkylene bridge substituted by a RaNH group is attached via two adjacent carbon atoms;

Ra denotes a hydrogen atom or an alkyl, phenylalkyl, (C1-5-alkoxy)carbonyl, phenylalkoxycarbonyl, (C3-5-alkenyl)oxycarbonyl, (C5-7-cycloalkyl)oxycarbonyl, or R1-CO-O-(R2CH)-O-CO-group;

R1 denotes a C1-5-alkyl, C5-7-cycloalkyl, phenylalkyl, C1-5-alkoxy, C5-7-cycloalkyloxy or phenyl group;

R2 denotes a hydrogen atom or a C1-4-alkyl, C5-7-cycloalkyl or phenyl group, B denotes a bond or an alkylene, -OCH2-, -CH2O-, -SCH2-, -CH2S-, -CONR3-, -R3NCO-, -CH2NR3-, -NR3CH2-, -SO2NR3- or -NR3SO2- group, wherein R3 is as hereinbefore defined and an oxygen or nitrogen atom of group B is not directly bonded to a nitrogen atom of group A or of the five-membered heterocyclic ring;

C' denotes a phenylene group optionally mono- or disubstituted by fluorine, chlorine or bromine atoms or by alkyl, trifluoromethyl, hydroxy, alkoxy, alkylsulphenyl, alkylsulphinyl, or alkylsulphonyl groups, wherein the substituents may be identical or different, or C' denotes a pyridenylene, pyrimidinylene, pyrazinylene or pyridazinylene group optionally substituted in the carbon skeleton by a chlorine atom or by an alkyl or alkoxy group, or C' denotes a 1,4-cyclohexylene, 1,3-piperidinylene, 1,4-piperidinylene or 1,4-piperazinylene group, or, if A is not a pyridyl group and B is an alkylene, -CONH- or -CH2S- group, then C' may also denote a bond, and if A is an amidinophenyl group and B is a bond, then C' may also denote a bond);

a second of the groups X1, X2, X3, X4 and X5 denotes a group of formula RbO-CO - E - D - N< , RbO-CO - E - D - CH< or RbO-CO - E - D - C?

(wherein D denotes a -CO-NR3-, -NR3-CO-, -SO2-NR3 or -NR3-SO2- group, a straight-chain or branched C1-8-alkylene or C2-8-alkenylene group optionally substituted by a hydroxy, alkoxy, alkylsulphenyl, R3R4N-, R3O-CO-, R6CO-NR3-, R6O-CO-NR3-, R6SO2-NR3- or R3R4N-CO-NR5- group (wherein R3, R4, R5 and R6 are as hereinbefore defined), or D denotes a phenylene group optionally mono- or disubstituted by fluorine, chlorine, or bromine atoms or by alkyl, trifluoromethyl, hydroxy, alkoxy, alkylsulphenyl, alkylsulphinyl or alkylsulphonyl groups, or D denotes a pyridenylene, pyrimidinylene, pyrazinylene, pyridazinylene or triazinylene group optionally substituted in the carbon skeleton by a chlorine atom or by an alkyl or alkoxy group, and in which additionally one or two -CH=N- groups may each be replaced by a -CO-NR3- group (wherein R3 is as hereinbefore defined) and one of the nitrogen atoms, instead of being bonded to the group R3, may also be bonded to the group E (if this group is not itself a bond and is not bonded to the group D via an oxygen or sulphur atom) or to the ring atom of said second of the groups X1, X2, X3, X4 and X5, or D denotes a C4-5-cycloalkylene group optionally substituted by an alkyl, phenylalkyl or phenyl group, wherein a >CH-unit may be replaced by a nitrogen atom and, additionally a methylene group adjacent to this nitrogen atom may be replaced by a carbonyl group, or D denotes a C6-7-cycloalkylene group optionally substituted by an alkyl, phenylalkyl or phenyl group, wherein one or two >CH-units may each be replaced by a nitrogen atom, and additionally, one or two methylene groups adjacent to such a nitrogen atom may each be replaced by a carbonyl group, or D denotes a C1-5-alkylene group bonded via a group W1 to the ring atom of said second of the groups X1, X2, X3, X4 and X5, wherein W1 denotes a NR3-group (in which R3 is as hereinbefore defined) or an oxygen or sulphur atom, whereby an oxygen or sulphur atom W1 cannot be directly bound to a ring nitrogen atom of the five-membered heterocyclic ring;

E, unless C' denotes a bond and A denotes a l-methyl- or 1-benzyl-4-piperazinyl group, may denote a bond, or E denotes a straight-chain or branched C15-alkylene or C2-5-alkenylene group optionally substituted by a hydroxy, alkoxy, alkylsulphenyl, R3R4N-, R3O-CO-, R6CO-NR3-, R6O-CO-NR3-, R6SO2-NR3- or R3R4N-CO-NR5-group (wherein R3, R4, R5 and R6 are as hereinbefore defined), or E denotes an alkylene group bonded to group D via a group W2, wherein Wz denotes an oxygen or sulphur atom or a sulphinyl, sulphonyl, -NR3-, - (R6CO)N-, - (R6SO2)N-, -CONR3- or NR3CO- group (wherein R3 and R6 are as hereinbefore defined) and wherein an oxygen or sulphur atom W2 is not directly bound to a nitrogen atom of group D; and Rb denotes a hydrogen atom, a C1-5-alkyl group, a C3-5-alkenyl group, a phenylC1-3-alkyl group, a C5-7-cycloalkyl or (C5-7-cycloalkyl)alkyl group or a R1-CO-O-(R2CH)-group, wherein R1 and R2 are as hereinbefore defined, the separation between the furthest nitrogen atom of group A
and the COORb group being at least 11 bonds);

a third of the groups X1, X2, X3, X4 and X5 denotes a sulphur atom, a HN<, R6N<, R7C? or (R7)2C< group or a nitrogen atom, wherein R6 is as hereinbefore defined and R7 denotes a hydrogen atom or an alkyl, phenylalkyl, phenyl, alkoxy, R3R4N-, R3O-CO- or R3R4N-CO-group (wherein R3 and R4 are as hereinbefore defined);

a fourth of the groups X1, X2, X3, X4 and X5 denotes an oxygen, sulphur or nitrogen atom or a R7C< group (wherein R7 is as hereinbefore defined), or a carbonyl group if it is not positioned between two ring nitrogen atoms; and the fifth of the groups X1, X2, X3, X4 amd X5 denotes a nitrogen atom or a R7C? or (R7)2C< group (wherein R7 is as hereinbefore defined);

or two adjacent X1, X2, X3, X4 and X5 groups may together denote an o-phenylene group; and wherein, unless otherwise specified, each alkyl, alkylene or alkoxy moiety contains 1 to 3 carbon atoms) and the isomers and salts thereof.

2. Compounds of formula I as claimed in claim 1 wherein:

a first of the groups X1, X2, X3, X4 and X5 denotes a group of formula A - B - C' - N< , A - B - C' - CH< or A - B - C' - C? , (wherein A denotes a pyridyl or quinuclidinyl group, a C5-7-cycloalkyl group optionally substituted by 1 to 4 alkyl groups or by a hydroxy, alkoxy, cyano, aminocarbonyl, carboxy or alkoxycarbonyl group, wherein an unsubstituted ring methylene group is replaced by an Ra-N< group, and, additionally, in such a 6- or 7-membered azacycloalkyl group a >CH-unit in the 4-position is optionally replaced by a nitrogen atom or in such a 5 to 7-membered azacycloalkyl group a -CH2-CH<- unit is optionally replaced by a -CH=C<- unit, or, if D denotes a C1-5-alkylene group substituted by a R3R4N-CO-NR5- or R6-SO2-NR3- group (wherein R3, R4 and R5 independently denote hydrogen atoms or alkyl or phenylalkyl groups and R6 denotes a C1-5-alkyl, phenylalkyl or phenyl group), or, if E is a straight-chain or branched C1-5-alkylene group substituted by a R3R4N-, R6-CO-NR3-, R6-SO2-NR3, -R3R4N-CO-NR5-, hydroxy or alkoxy group (wherein R3, R4, R5 and R6 are as hereinbefore defined), then A may also denote a phenyl group substituted in the 4-position by a RaNH-CH2- or RaNH-C(=NH) -group, or a phenyl group to which a n-propylene or n-butylene bridge is attached via the positions 3 and 4, wherein the n-propylene and n-butylene bridge is substituted by a RaNH-group;

Ra denotes a hydrogen atom or an alkyl, phenylalkyl, (C1-5-alkoxy)carbonyl, phenylalkoxycarbonyl, (C5-7-cycloalkyl)-oxycarbonyl or R1-CO-O-(R2CH)-O-CO- group;

R1 denotes an alkyl, C5-7-cycloalkyl, C1-5-alkoxy, C5-7-cycloalkyloxy or phenyl group;

R2 denotes a hydrogen atom or a C1-4-alkyl group;

B denotes a bond or a -CH2-CH2-, OCH2-, -CH2O-, -CONR3-, or -R3NCO- group, wherein R3 is as hereinbefore defined and an oxygen and nitrogen atom of group B is not directly bonded to a nitrogen atom of group A or of the five-membered heterocyclic ring;

C' denotes a phenylene group optionally mono- or disubstituted by fluorine, chlorine, or bromine atoms or by alkyl, trifluoromethyl, hydroxy or alkoxy groups, wherein the substituents may be identical or different, or C' denotes a pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene group, optionally substituted in the carbon skeleton by an alkyl or alkoxy group, or C' denotes a 1,4-cyclohexylene, 1,4-piperidinylene or 1,4-piperazinylene group, or, if A does not denote a pyridyl group and B denotes an ethylene or CONH-group, then C' may also denote a bond, or, if A is an amidinophenyl group and B is a bond then C' may also denote a bond);

a second of the groups X1, X2, X3, X4 and X5 denotes a group of formula RbO-CO - E - D - N< , RbO-CO - E - D - CH< or RbO-CO - E - D - C?

(wherein D denotes a -CO-NR3- or -NR3-CO-group or a straight-chain or branched C1-5-alkylene or C2-5-alkenylene group optionally substituted by a hydroxy, alkoxy, R3R4N-, R6CO-NR3-, R6O-CO-NR3-, R6SO2-NR3- or R3R4N-CO-NR5- group, wherein R3, R4, R5 and R6 are as hereinbefore defined, or D denotes a phenylene group optionally mono- or disubstituted by fluorine, chlorine or bromine or by alkyl, trifluoromethyl, hydroxy or alkoxy groups, or D denotes a pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene group optionally substituted in the carbon skeleton by an alkyl or alkoxy group, or D denotes a cyclohexylene group, wherein one or two >CH-units are optionally replaced by a nitrogen atom and wherein additionally a methylene group adjacent to such a nitrogen atom is optionally replaced by a carbonyl group, or D denotes a C1-4-alkylene group linked via a group W1 to the ring atom of said second of groups X1, X2, X3, X4 and X5, wherein W1 is a NR3-group (in which R3 is as hereinbefore defined), or an oxygen or sulphur atom, whereby an oxygen or sulphur atom W1 cannot be directly linked to a ring nitrogen atom of the five-membered heterocyclic ring;

E, unless C' denotes a bond and A denotes a 1-methyl or 1-benzyl-4-piperazinyl group, may denote a bond, or E denotes a straight-chain or branched C1-5-alkylene group optionally substituted by a hydroxy, alkoxy, R3R4N-, R6CO-NR3-, R6O-CO-NR3-, R6SO2-NR3 or R3R4N-CO-NR5- group, wherein R3, R4, R5 and R6 are as hereinbefore defined, or E denotes an alkylene group linked via a group W2 to group D, wherein W2 is an oxygen or sulphur atom or a NR3-, -(R6CO)N- or (R6SO2)N- group (wherein R3 and R6 are as hereinbefore defined) and wherein an oxygen or sulphur atom W2 is not directly linked to a nitrogen atom of group D; and Rb denotes a hydrogen atom, a C1-5-alkyl group, a phenyl C1-3-alkyl group, a C5-7-cycloalkyl group or a R1-CO-O-(R2CH)-group, wherein R1 and R2 are as hereinbefore defined, the separation between the furthest nitrogen atom of group A and the COORb-group being at least 11 bonds);

a third of the groups X1, X2, X3, X4 and X5 denotes a HN<, R6N<, R7C or (R7)2C< group or a nitrogen atom, wherein R6 is as hereinbefore defined and R7 denotes a hydrogen atom or an alkyl or phenyl group;

a fourth of the groups X1, X2, X3, X4 and X5 denotes an oxygen, sulphur or nitrogen atom or a R7C? group (wherein R7 is as hereinbefore defined); and the fifth of the groups X1, X2, X3, X4 and X5 denotes a nitrogen atom or a R7C? or (R7)2C< group (wherein R7 is as hereinbefore defined);

or two adjacent X1, X2, X3, X4 and X5 groups together denote an o-phenylene group) and the isomers and salts thereof.

3. Compounds of formula I as claimed in claim 1 wherein:

a first of the groups X1, X2, X3, X4 and X5 denotes a group of formula A - B - C' - N< or A - B - C' - C?

(wherein A denotes a pyridyl or quinuclidinyl group, or a 1,3-pyrrolidinyl, 1,3-piperidyl or 1,4-piperidyl group optionally substituted in the carbon skeleton by 1 to 4 methyl groups or by a hydroxy, methoxy, cyano or aminocarbonyl group, wherein the above-mentioned pyrrolidinyl and piperidyl groups are substituted in the 1-position by a group Ra (wherein Ra denotes a hydrogen atom or a methyl, ethyl, benzyl, or (C1-5-alkoxy)carbonyl group), or A denotes a 1,4-piperazinyl or 3,4-dehydro-1,4-piperidyl group substituted in the 1-position by a group Ra (where Ra is as hereinbefore defined), or, if D denotes an ethylene group substituted by a R6-SO2-NR3-group (wherein R3 denotes a hydrogen atom or a methyl or ethyl group and R6 is a C1-5-alkyl group or a phenyl group), or, if E denotes an ethylene group substituted by an amino, R6CO-NR3-, R6SO2-NR3- or hydroxy group (wherein R3 and R6 are as hereinbefore defined), then A may also denote a phenyl group substituted in the

4-position by a RaNH-C(=NH)-group;

B denotes a bond or a -CH2-CH2-, -OCH2-, -CH2O-, -CONCR3-, -R3NCO- group, wherein R3 is as hereinbefore defined and an oxygen or nitrogen atom of group B is not directly linked to a nitrogen atom of group A or of the five-membered heterocyclic ring;

C' denotes a phenylene group optionally substituted by a chlorine atom or by a methyl group, or C' denotes a pyridinylene, pyrimidinylene, pyridazinylene or 1,4-piperidinylene group, or, if A is not a pyridyl group and B is an ethylene or CONH-group, then C' may also denote a bond, or if A is an amidinophenyl group and B is a bond, then C' may also denote a bond);

a second of the groups X1, X2, X3, X4 and X5 denotes a group of formula RbO-CO - E - D - N< or RbO-CO - E - D - C?

(wherein D denotes a -CO-NR3- or -NR3-CO- group (wherein R3 is as hereinbefore defined), or a straight-chain or branched C1-5-alkylene group, or D denotes an ethylene group substituted by a R6SO2-NR3-group, or D denotes a phenylene group optionally substituted by a chlorine atom or a methyl group, or D denotes a 1,4-cyclohexylene group, or D denotes a C1-4-alkylene group linked to the ring atom of said second of groups X1, X2, X3, X4 and X5 via a -NR3-group (wherein R3 is as hereinbefore defined);

E, unless C' denotes a bond and A denotes a 1-methyl or 1-benzyl-4-piperazinyl group, may denote a bond, or E denotes an ethylene group optionally substituted by a R6CO-NR3- or R6SO2-NR3- group (wherein, R3 and R6 are as hereinbefore defined), or E denotes a -O-CH2- or -NR3-CH2- group (wherein R3 is as hereinbefore defined); and Rb is a hydrogen atom or a C1-5-alkyl or C5-6-cycloalkyl group, the separation between the furthest nitrogen atom of group A and the COORb-group being at least 11 bonds);

a third of the groups X1, X2, X3, X4 and X5 denotes a HN<, R6N< or R7C? group or a nitrogen atom (wherein R6 is as hereinbefore defined and R7 is a hydrogen atom or a methyl or ethyl group);

a fourth of the groups X1, X2, X3, X4 and X5 denotes an oxygen, sulphur or nitrogen atom or a R7C? group (wherein R7 is as hereinbefore defined); and the fifth of the groups X1, X2, X3, X4 and X5 denotes a nitrogen atom or a R7C? group (wherein R7 is as hereinbefore defined);

or two adjacent X1, X2, X3, X4 and X5 groups together denote an o-phenylene group;

and isomers and salts thereof.

4. Compounds of formula I as claimed in claim 1 wherein:

a first of the groups X1, X2, X3, X4 and X5 denotes a group of formula A - B - C' - N< or A - B - C' - C?

(wherein A denotes a 4-piperidyl group substituted in the 1-position by a group Ra (wherein Ra is a hydrogen atom or a benzyl or a (C1-5-alkoxy)carbonyl group), or A denotes a 1,4-piperazinyl group substituted in the 1-position by a group Ra (wherein Ra is as hereinbefore defined), or, if D denotes an ethylene group substituted by a R6-SO2-NR3-group (wherein R3 is a hydrogen atom and R6 is a C1-5-alkyl group), then A may also denote a phenyl group substituted in the 4-position by a NH2-C(=NH)-group;

B denotes a bond or a -CH2-CH2- or -CH2O- group; and C' denotes a phenylene or 1,4-piperidinylene group or, C' may also denote a bond if B is not also a bond);

a second of the groups X1, X2, X3, X4 and X5 denotes a group of formula RbO-CO-E-D-C?

(wherein D denotes a -CO-NH-group, a C1-5-alkylene group, a phenylene group, a 1,4-cyclohexylene group or an ethylene group substituted by a R6-SO2-NR3-group;

E, unless C' is a bond and A is a 1-benzyl-4-piperazinyl group, may denote a bond, or E denotes an ethylene group;

and Rb denotes a hydrogen atom or a C1-4-alkyl group, the separation between the furthest nitrogen atom and the COORb-group being at least 11 bonds);

a third of the groups X1, X2, X3, X4 and X5 denotes a phenyl-N< or R7C? group or a nitrogen atom (wherein R7 is a hydrogen atom or a methyl or ethyl group);

a fourth of the groups X1, X2, X3, X4 and X5 denotes an oxygen, sulphur or nitrogen atom or a R7C? group (wherein R7 is as hereinbefore defined); and the fifth of the groups X1, X2, X3, X4 and X5 denotes a nitrogen atom;

and isomers and salts thereof.

5. A compound of formula I as claimed in claim 1 being:

(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-amidino-phenyl)-3-pyridazinyl]-4-[2-(n-butanesulphonylamino)-2-carboxy-ethyl]-imidazole;

(iv) 1-[6-(4-amidino-phenyl)-3-pyridazinyl]-4-[2-(n-butanesulphonylamino)-2-(methoxycarbonyl)-ethyl]-imidazole;

(v) 2-[trans-4-(isobutyloxycarbonyl)-cyclohexyl]-5-[4-(4-piperidinyl)-phenyl]-1,3,4-thiadiazole; or (vi) 2-[trans-4-(ethyloxycarbonyl)-cyclohexyl]-5-[4-(4-piperidinyl)-phenyl]-1,3,4-thiadiazole;

or a salt thereof.

6. A compound as claimed in any one of claims 1 to 5 in the form of a physiologically acceptable addition salt with an inorganic or organic acid or base.

7. A pharmaceutical composition comprising a compound of formula I as claimed in any one of claims 1 to 5 or a physiologically acceptable addition salt thereof, together with at least one physiologically acceptable carrier or excipient.

8. A process for preparing compounds as claimed in claim 1, said process comprising at least one of the following steps:

a) (to prepare compounds of formula I, wherein one of the groups X1, X2, X3, X4 and X5 is a RbO-CO-E-D-CH<- or RbO-CO-E-D-C? group) reacting a compound of formula II

(II) (wherein X1, X2, X3, X4 and X5 are defined as in any one of claims 1 to 5 with the proviso that a second of the groups X1, X2, X3, X4 and X5 denotes a HO-CO-CH< or HO-CO-C? group) or a reactive derivative thereof with a compound of formula III

RbO - CO - E - HNR3 (III) (wherein R3, Rb and E are as defined in any one of claims 1 to 5);

b) (to prepare compounds of formula I, wherein Ra denotes a hydrogen atom) cleaving a protecting group from a compound of formula IV

(IV) (wherein X1, X2, X3, X4 and X5 are as defined in any one of claims 1 to 5 with the proviso that Ra denotes a (C1-5-alkoxy)-carbonyl, phenylalkoxycarbonyl, (C3-5-alkenyl)oxycarbonyl or (C3-5-cycloalkyl)oxycarbonyl group or a cleavable imino group protecting group) by hydrolysis, hydrogenolysis or thermolysis;

c) (to prepare compounds of formula I, in which Rb denotes a hydrogen atom), cleaving a protecting group from a compound of formula V

(V) (wherein X1, X2, X3, X4 and X5 are as defined in any one of claims 1 to 5 with the proviso that Rb denotes a C1-5-alkyl, C3-5-alkenyl, phenyl(C1-3-alkyl), C5-7-cycloalkyl or (C5-7-cycloalkyl)alkyl group or a cleavable carboxy group protecting group) by hydrolysis, hydrogenolysis or thermolysis;

d) (to prepare 1,3,4-oxadiazole, 1,2,4-triazole and 1,3,4-thiadiazole compounds of formula I) cyclising a compound of formula VI

(wherein Z1 and Z2 independently denote halogen atoms, amino groups optionally substituted by a group R6, or hydroxy, alkoxy, mercapto or alkylmercapto groups, one of the groups R' and R" denotes an A-B-C'- group and the other denotes a RbO-CO-E-D- group), optionally formed in the reaction mixture is cyclized and, if necessary, alkylating the compound obtained;

e) (to prepare compounds of formula I, in which A
denotes a phenyl group substituted in the 4-position by a RaNH-C(=NH)- group) reacting a compound of formula VII

(VII) (wherein X1, X2, X3, X4 and X5 are defined as in any one of claims 1 to 5 with the proviso that A denotes a phenyl group substituted in the 4-position by a Z3-C(=NH)- group (wherein Z3 is an alkoxy, aralkoxy, alkylthio, aralkylthio or amino group)), optionally formed in the reaction mixture, with an amine of formula VIII

Ra' - NH2 (VIII) (wherein Ra' is a hydrogen atom or a C1-3-alkyl group);

f) (to prepare compounds of formula I, wherein A
denotes a phenyl group substituted in the 4-position by a RaNH-C(=NH)- group) reacting a compound of formula IX

(IX) (wherein X1, X2, X3, X4 and X5 are defined as in any one of claims 1 to 5 with the proviso that A denotes a phenyl group substituted in the 4-position by a cyano group) with hydroxylamine and subsequently reducing the resultant amidoxime;

g) (to prepare compounds of formula I, wherein A
denotes a phenyl group substituted in the 4-position by a RaNH-C(=NH)- group) reacting a compound of formula IX

(IX) (wherein X1, X2, X3, X4 and X5 are defined as in any one of claims 1 to 5 with the proviso that A denotes a phenyl group substituted in the 4-position by a cyano group) with an alkylchloroaluminiumamide;

h) (to prepare 1,3-thiazolene and imidazolenes of formula I) reacting a compound of formula X

R' - CO - CH2 - Z4 (X) with a compound of formula XI

R" - CU - NH2 (XI) (wherein one of the groups R' or R" denotes an A-B-C'- group and the other denotes a RbO-CO-E-D-group, Z4 denotes a nucleophillic leaving group and U denotes a sulphur atom or an imino group);

i) (to prepare compounds of formula I, wherein Ra is as hereinbefore defined, with the exception of the hydrogen atom and B denotes a -CH2O- group) reacting a compound of formula XII

A - CH2 - Z5 (XII) (wherein A is defined as in any one of claims 1 to 5 with the proviso that Ra is as defined above with the exception of a hydrogen atom, and Z5 denotes a nucleophillic leaving group) with a compound of general formula XIII

(XIII) (wherein X1, X2, X3, X4 and X5 are defined as in any one of claims 1 to 5 with the proviso that one of these groups is a HO-C'-CH< or HO-C'-C? group, wherein C' is defined as in any one of claims 1 to 5) or an alkali or alkaline earth metal salt thereof;

j) (to prepare compounds of formula I, wherein one of the groups X1, X2, X3, X4 and X5 denotes an A-B-C'-N< or RbO-CO-E-D-N< group) reacting a compound of formula XIV, (XIV) (wherein X1, X2, X3, X4 and X5 are defined as in any one of claims 1 to 5 with the proviso that one of these groups is an imino group) with a compound of formula XV

W - Z6 (XV) (wherein W denotes an A-B-C'- or RbO-CO-E-D- group, wherein A, B, C' and D are defined as in any one of claims 1 to 5, and Z6 is a nucleophillic leaving group);

k) (to prepare compounds of formula I, wherein Rb denotes a R1-CO-O-(R2CH)-group (wherein R1 and R2 are defined as in any one of claims 1 to 5), a C1-5-alkyl group, a C3-5-alkenyl group, a phenyl(C1-3-alkyl) group, a C5-7-cycloalkyl group or a (C5-7-cycloalkyl)alkyl group) esterifying a compound of formula XVI

(XVI) (wherein X1, X2, X3, X4 and X5 are defined as in any one of claims 1 to 5 with the proviso that Rb denotes a hydrogen atom) with a compound of formula XVII

Z7 - Rb' (XVII) (wherein Rb' denotes a R1-CO-O-(R2CH)-group (wherein R1 and R2 are defined as in any one of claims 1 to 5), a C1-5-alkyl group, a C3-5-alkenyl group, a phenylC1-3-alkyl, a C5-7-cycloalkyl group, or a (C5-7-cycloalkyl)alkyl group and Z7 denotes a hydroxy group or a nucleophilic leaving group);

1) performing any one of steps (a) to (k) using a protected reagent and subsequently removing the protecting groups from the product;

m) converting a compound of formula I into a salt thereof; and n) resolving a compound of formula I into its isomers.

9. Use of a compound of formula I as claimed in any one of claims 1 to 5, or a physiologically acceptable salt thereof for the manufacture of a medicament for use in combatting inflammation, bone degradation, tumours, metastases, and aggregation-related conditions.

10. A method of treatment of the human or non-human body to combat inflammation, bone degradation, tumours, metastases, and aggregation-related conditions, said method comprising adminstering to said body a compound of formula I as claimed in any one of claims 1 to 5 or a physiologically acceptable salt thereof.

11. Each and every novel compound, composition, process, method and use herein disclosed.