CA2327784C - Triazolones with a neuroprotective action - Google Patents

Abstract

The invention relates to the use of triazolones as pharmaceutical compositions, particularly as pharmaceutical compositions with a neuroprotective activity, and new triazolones and processes for preparing them.

Description

CA 02327784 2000-10-06 PCT/EP9q/02498 Triazolones with a neuroprotective action The invention relates to the use of triazolones as pharmaceutical compositions, particularly pharmaceutical compositions with a neuroprotective activity, as well as new triazolones and processes for preparing them.
Triazolones are known from the prior art and are disclosed for example by published German applications DE 19521162 and DE 3631511 and also by European Patent applications EP
270 061 and EP 208 321. The compounds disclosed therein are effective pesticides and may be used in particular as insecticides and acaricides.

The present invention, by contrast, discloses triazolones which can be used as pharmaceuticals, particularly pharmaceutical compositions with a neuroprotective activity. Surprisingly, it has been found that the compounds according to the invention have an affinity for or an effect on various types of receptors and exhibit a neuroprotective activity.
Tests in vitro and in vivo have shown that the cell damage and loss of function occurring in the brain as a result of hypoglycaemia, hypoxia, anoxia, global and focal ischaemia, cranial brain trauma, brain oedema and intercranial pressure are due in some measure to an increased synaptic activity and hence increased release of transmitters. Apart from glutamate, histamine and serotonin are of particular importance as neurotransmitters. Moreover, the concentrations of calcium and sodium ions in particular are changed.

5.nK.T.2000 13:40 BI A PATENTE 6132 774377 NR.022 S.2i2 N(."lYJiY99/U249$

It is known that after systemic adminiszratiozl of gli4tatnate neuron,ea are deptxoyed. ~zj mouae brains (S,M.
Roth.tnan and T.W. Olney, Trends in Neurosciences 10 (1987) 299). Thia finding lcadp ono to conclude, Inter a2ia, that glutamate plays a part in neurodegenerative diseases (R,SchwarcQ and H. Meldr4fi, The Irancet 11 (1985) 140).
Moreover, substances such as for example quisqual~c ac+lci, caizijc acid, ibotcnie acid, glutamic ac$ d, N-rnethyl-D-aspartic acid (ivMWA) and a-amino-3-hydroxy-5-methyl-4-, ~.0 isooxazol-propionic acid (AMPA) arc ]cnown 4q oxogenouc or endogenous neurocoxins. Hrain lesions which may be induced by Aueh cubatanees are eompaxable with those which occur in conaunction with epilepsy and other neurodegenerative da.sorders - such as, for example, Huntington's diseas9 and Alzheimer' a ciise4qe. Suk~si-e~tace~s and iolzs wliicli iiiYiibit the activity of the glutamate recqptpr and the ion channel cQllnected to thip recepto:;- - sueri ds e, y. ccautYeLl Li've aizd non-competitive art,ts,gon~atp of excitatory amino acida -pxor-ect brain cells from hypcaxic: cx- .Lac;llaGCttlia damage.
These findinga show that the glut.amate TacePr.nrs pl.ay an :4i{1pu~VL4i1L p4rt =.i.rL medizating ischaem~.c da,m~ge.

Tt has been found that, surprisiTigly, the triagolonep 4ecording to the invPn.tt..l.n.n h.avR an a.ntagonist3e effect on tliG AMPA receptor. Moreover, theme compou,nda e;sh:~bit a high affinity for the follow:Ln.g type r3f re%naptnr ! "Na *
cliannel pite 211 binding site. Zra, view of theae ftndxngs the compounclo acen.r.cli.ng tn 1-h.R inventien may be used t:o t:reat: neurodegera.erative d:.sordexp 4nd cerebral ischccmi4 ot various origins.

'Ih9 invention rPlatas i-n i-hA iaAA nt triazolonee of general formula (z) a.e pharmaceutical compos;.tionp, p4rttcularly as pharmaceutical eomposi.tinnR w1tr a n,euxoprotective act.ivity, I
t ~
Received Oct-05-00 07:36am From-+48 6132 774377 To-Smart i BiQgar Page 002 ! 0 R_~N '\ WIRI

,-=-N
R

~I) wherein R1 denotes C6-10-aryl, preferably phenyl, which may optionally be substituted directly or via a C1-4-alkylene bridge by one or more of the groups halogen, nitro, -CF3, -CN, -OR4, -COOR4, -OCOR4, -SRS, -S02R5, -OS02R5, -NR6R7, C1-C4-alkyl, C2-C4-alkenyl or C2-C4-alkynyl;
R1 denotes a C1-C6-alkyl, C2-C6-alkenyl or C2-C6-alkynyl group, which may optionally be substituted by phenyl, -NR6R7, halogen, nitro, CF3, CN or -OR4;
R2 denotes a C6-C10-aryl, preferably phenyl, which may optionally be substituted directly or via a C1-4-alkylene bridge by one or more of the groups halogen, nitro, -CF3, -CN, -OR4, -COOR4, -OCOR4, -SRS, -S02R5, -OS02R5, -NR6R7, C1-C4-alkyl, C2-C4-alkenyl or C2-4-alkynyl;

R2 denotes a C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl group, which may optionally be substituted by phenyl, -NR6R7, halogen, nitro, CF3, CN or -OR4;
R2 denotes a C-linked 5- or 6-membered saturated or unsaturated heterocycle, which may contain as heteroatoms 1, 2, 3 or 4 atoms selected from the group comprising oxygen, nitrogen or sulphur and which may optionally be substituted by C1-C6-alkyl or benzyl;
R3 denotes hydrogen or a C1-C6-alkyl, C2-C6-alkenyl or C2-C6-alkynyl group, which may optionally be substituted by -NR6R7, halogen, nitro, CF3, CN or -OR4;
R4 denotes hydrogen, C1-4-alkyl optionally substituted by halogen or -NR6R7 or a phenyl or benzyl group, which may optionally carry one or more methoxy groups;
R5 denotes hydrogen, C1-4-alkyl, phenyl or benzyl, wherein the phenyl or benzyl group may optionally be mono- or polysubstituted by methoxy;
R6 denotes hydrogen, C3-6-cycloalkyl, C1-6-alkyl, C2-6-alkenyl or C2-C6-alkynyl, each of which may be mono- or polysubstituted by phenyl, benzyl or -OR4;
R6 denotes C6-10-aryl, preferably phenyl, or benzyl, which may optionally be substituted by halogen, OR4, C1-C4-alkyl, preferably -CH3, -SO3H, or -COOR4;

R7 denotes hydrogen, C3-6-cycloalkyl, C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl, each of which may be mono- or polysubstituted by phenyl, benzyl or -OR4;

R7 denotes C6-10-aryl, preferably phenyl, or benzyl, which may optionally be substituted by halogen, OR4, C1-C4-alkyl, preferably -CH3, -S03H, or -COOR4;

5 or R6 and R7 together with the nitrogen atom form a saturated or unsaturated 5- or 6-membered ring which may contain nitrogen, oxygen or sulphur as further heteroatoms, whilst the heterocycle may be substituted by branched or unbranched alkyl group having 1 to 4 carbon atoms, may be substituted by phenyl or benzyl.

It is preferable to use compounds of general formula (I) as pharmaceutical compositions, particularly as pharmaceutical compositions with a neuroprotective activity, wherein -R1 denotes phenyl, which may optionally be substituted directly or via a C1-4-alkvlene bridge by one or more of the groups fluorine, chlorine, bromine, nitro, -CF3, -CN, -OR4, -COOR4, -OCOR4, -NR6R7, C1-4-alkyl, C2-4-alkenyl or C2-4-alkynyl;
R1 denotes C1-4-alkyl, which may optionally be substituted by phenyl;

R2 denotes phenyl, which may optionally be substituted directly or via a C1-4-alkylene bridge by one or more of the groups fluorine, chlorine, bromine, nitro, -CF3, -CN, -OR4, -COOR4, -OCOR4, -NR6R7, C1-4-alkyl, C2-4-alkynyl or C2-4-alkynyl;

R2 denotes C1-C4-alkyl, which may optionally be substituted by phenyl;

R2 denotes a C-linked 5- or 6-membered saturated or unsaturated heterocycle, which may contain as heteroatoms 1, 2, 3 or 4 atoms selected from the group comprising oxygen or nitrogen and which may optionally be substituted by C1-C4-alkyl or benzyl;
R3 denotes hydrogen or a C1-4-alkyl group, which may optionally be substituted by -NR6R7, fluorine, chlorine, bromine, nitro, CF3, CN or -OR4;
R4 denotes hydrogen, C1-C4-alkyl optionally substituted by halogen or -NR6R7 or a phenyl or benfyl group, which may optionally carry one or more methoxy groups;
R6 denotes hydrogen, C1-4-alkyl, C2-4-alkenyl or C2-4-alkynyl, each of which may be mono- or polysubstituted by phenyl, benzyl or -OR4, R6 denotes phenyl or benzyl, which may optionally be substituted by halogen, OR4, C1-4-alkyl, preferably -CH3, -S03H, or -COOR4;

R7 denotes hydrogen, C1-4-alkyl, C2-4-alkenyl or C2-4-alkynyl, each of which may be mono- or polysubstituted by phenyl, benzyl or -OR4, R7 denotes phenyl or benzyl, which may optionally be substituted by halogen, OR4, C1-4-alkyl, preferably -CH3, -S03H, or -COOR4;
or R6 and R7 together with the nitrogen atom form a saturated or unsaturated 5- or 6-membered ring, which may contain nitrogen or oxygen as further heteroatoms, whilst the heterocycle may be substituted by a branched or unbranched alkyl group having 1 to 4 carbon atoms, or by phenyl or benzyl.

It is particularly preferred to use compounds of general formula (I) as pharmaceutical compositions, particularly as pharmaceutical compositions with a neuroprotective activity, wherein Rl denotes phenyl which may optionally be substituted by one or more of the groups fluorine, chlorine, bromine, -OR4 or C1-4-alkyl; -R1 denotes Cl-4-alkyl, which may optionally be substituted by phenyl;

R2 denotes C1-4-alkyl or phenyl which may optionally be substituted by one or more of the groups fluorine, chlorine, bromine, -OR4 or Cl-4-alkyl;

R2 denotes a C-linked 5- or 6-membered heterocycle selected from the group comprising furan, pyran, pyrrole, pyrazole, imidazole, triazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, oxazole or isoxazole;

R3 denotes hydrogen or a Cl-C4-alkyl group, which may optionally be substituted by -NR6R7, chlorine, bromine or -OH;

R4 denotes hydrogen, C1-4-alkyl optionally substituted by chlorine, bromine or -NR6R7 or a phenyl or benzyl group;

R6 denotes hydrogen, C1-4-alkyl, phenyl or benzyl;
R7 denotes hydrogen, C1-4-alkyl, phenyl or benzyl;
or R6 and R7 together with the nitrogen atom form a saturated or unsaturated 5- or 6-membered ring optionally substituted by C1-4-alkyl or benzyl, selected from the group comprising piperidine, piperazine, morpholine, pyrrole or pyrrolidine.
It is particularly preferable to use compounds of general formula (I) as pharmaceutical compositions, particularly as pharmaceutical compositions with a neuroprotective activity, wherein Rl denotes methyl, ethyl, propyl, butyl, benzyl or phenyl, which may optionally be substituted by one or more of the groups fluorine, chlorine, bromine, methyl, ethyl, propyl or -OR4;

R2 denotes methyl, ethyl, propyl, butyl or phenyl, which may optionally be substituted by one or more of the groups fluorine, chlorine, bromine, methyl, ethyl, propyl or -OR4;

R2 denotes a C-linked heterocycle selected from pyrrole, pyrazole, imidazole, triazole, pyridine, pyridazine, pyrimidine, pyrazine or triazine;

R3 denotes hydrogen, methyl, ethyl or propyl which may optionally be substituted by -NR6R7, chlorine, bromine or -OH;

R4 denotes hydrogen, methyl, ethyl or propyl, which may optionally be substituted by -NR6R7, chlorine, bromine or -OH;

R6 denotes hydrogen, methyl ethyl, propyl or benzyl;

R7 denotes hydrogen, methyl ethyl, propyl or benzyl;
or R6 and R7 together with the nitrogen atom form a ring optionally substituted by methyl, ethyl, propyl or benz-yl, selected from the group comprising piperidine, piperazine, morpholine, pyrrole or pyrrolidine.

Of particular interest according to the invention is the use of compounds of general formula (I) as pharmaceutical compositions, particularly as pharmaceutical compositions with a neuroprotective activity, wherein Rl denotes methyl, ethyl, propyl, butyl, benzyl or phenyl, which may optionally be substituted by one or more of the groups fluorine, chlorine, bromine, methyl, ethyl, propyl or -OR4;

R2 denotes methyl, ethyl, propyl, butyl or phenyl, which may optionally be substituted by one or more of the groups fluorine, chlorine, bromine, methyl, ethyl, propyl or -OR4;

R2 denotes pyrrole, pyrazole, imidazole, pyridine, pyridazine, pyrimidine or pyrazine;

R3 denotes hydrogen, methyl, ethyl or propyl, 5 which may optionally be substituted by -NR6R7;
R4 denotes methyl, ethyl, propyl, -CH2CH2-NR6R7 or -CH2CH2CH2-NR6R7;
R6 denotes hydrogen, methyl, ethyl, propyl or benzyl;

R7 denotes hydrogen, methyl, ethyl, propyl or benzyl.

It is also particularly valuable to use compounds of general formula (I) as pharmaceutical compositions, particularly as pharmaceutical compositions with a neuroprotective activity, wherein R1 denotes methyl, butyl, benzyl or phenyl, which may optionally be substituted by one or more of the groups fluorine, chlorine, bromine, methyl, ethyl or -OR4;

R2 denotes methyl, phenyl, which may optionally be substituted by one or more of the groups chlorine, methyl or -OR4;

R3 denotes hydrogen, methyl, -CH2CH2-NR6R7 or -CH2CH2CH2-NR6R7 ;

R4 denotes methyl or -CH2CH2-NR6R7 ;

R6 denotes methyl;

R7 denotes methyl.

The invention also relates to pharmaceutical compositions, particularly pharmaceutical compositions with a neuroprotective activity containing as active substance one or more compounds of general formula (I), wherein the groups R1, R2 and R3 are as hereinbefore defined.

The use of the compounds of general formula (I) includes the use of any enantiomers or diastereomers in optically pure form or in the form of mixtures which may be present.
Furthermore the compounds of general formula (I) may be converted into their salts, particularly for pharmaceutical use into the physiologically acceptable salts with an inor-ganic or organic acid. Suitable acids include, for example, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, acetic acid, fumaric acid, succinic acid, lactic acid, methanesulphonic acid, citric acid, tartaric acid or maleic acid. Mixtures of the abovementioned acids may also be used.

The activity of the compounds of general formula (I) at the AMPA receptor was demonstrated by electrophysiology on neuronal cells using methods known from the literature (patch-clamp method) (M. L. Mayer, L. Vyklicky and G. L.
Westbrook, J. Physiol. 415 (1989) 329-350). The affinity of the triazolones of general formula (I) to the "Na+
channel site 211 binding site was demonstrated as described by G.B. Brown (J. Neurosci. 6(1986) 2064).

Apart from the use of the compounds of general formula (I) described above as pharmaceutical compositions, particularly as pharmaceutical compositions with a neuroprotective activity, the present invention is also directed to the new triazolones of general formula (I) O
- R~ ~R' N N

R2}N
(I) wherein R1 denotes methyl, butyl, benzyl or phenyl, which may optionally be substituted by one or more of the groups fluorine, chlorine, bromine, methyl, ethyl or -OR4;

R2 denotes methyl, phenyl, which may optionally be substituted by one or more of the groups chlorine, methyl or -OR4;

R3 denotes hydrogen, methyl, -CH2CH2-NR6R7 or -CH2CH2CH2-NR6R7 ;

R4 denotes methyl or -CH2CH2-NR6R7;
R6 denotes methyl;

R7 denotes methyl, with the proviso that R2 cannot be 2-chlorophenyl and with the proviso that if a) R1 denotes phenyl and R3 denotes hydrogen, R2 cannot denote phenyl, 4-chlorophenyl, 4-methylphenyl or 4-methoxyphenyl;
b) R2 denotes phenyl and R3 denotes hydrogen, R1 cannot denote phenyl, 4-chlorophenyl, 4-bromophenyl, 2,4-dibromophenyl, 4-methylphenyl or 4-methoxyphenyl;
c) R3 denotes methyl, R1 and R2 cannot simultaneously be phenyl, optionally in the form of their racemates, their enantiomers, in the form of their diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.

According to the invention, the preferred compounds are the compounds of general formula (I) wherein Rl denotes phenyl, which may optionally be substituted by one or more of the groups fluorirre, chlorine, bromine, methyl, ethyl or methoxy;
R2 denotes phenyl, which may optionally be substituted by methoxy;

R3 denotes hydrogen, methyl or -CH2CH2-NMe2;
with the proviso that if a) R1 denotes phenyl and R3 denotes hydrogen, R2 cannot denote phenyl or 4-methoxyphenyl;
b) R2 denotes phenyl and R3 denotes hydrogen, R1 cannot denote phenyl, 4-chlorophenyl, 4-bromophenyl, 2,4-dibromophenyl, 4-methylphenyl or 4-methoxyphenyl;
c) R3 denotes methyl, R1 and R2 cannot simultaneously be phenyl, optionally in the form of their racemates, their enantiomers, in the form of their diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.

The following compounds are particularly preferred according to the invention:

2-(2-methylphenyl)-5-phenyl-3H-1,2,4-triazol-3-one;
2-(3-methoxyphenyl)-4-methyl-5-phenyl-3H-1,2,4-triazol-3-one;
2-(2-bromophenyl)-4-methyl-5-phenyl-3H-1,2,4-triazol-3-one;
5-(4-methoxyphenyl)-4-methyl-2-phenyl-3H-1,2,4-triazol-3-one;
5-(2-methoxyphenyl)-4-methyl-2-phenyl-3H-1,2,4-triazol-3-one;
4-(2-N,N-dimethylaminoethyl)-2-(2-methyiphenyl)-5-phenyl-3H-1,2,4-triazol-3-one;
2-(2-methoxyphenyl)-5-phenyl-3H-1,2,4-triazol-3-one;
2-(2-chlorophenyl)-5-phenyl-3H-1,2,4-triazol-3-one;
2-(3-chlorophenyl)-4-(2-N,N-dimethylaminoethyl)-5-phenyl-3H-1,2,4-triazol-3-one;
2-(2-fluorophenyl)-5-phenyl-3H-1,2,4-triazol-3-one;
2-(3-fluorophenyl)-4-methyl-5-phenyl-3H-1,2,4-triazol-3-one;
2-(2-fluorophenyl)-4-methyl-5-phenyl-3H-1,2,4-triazol-3-one;
2-(3-methylphenyl)-5-phenyl-3H-1,2,4-triazol-3-one;
2-(2-ethylphenyl)-5-phenyl-3H-1,2,4-triazol-3-one;
2-(3-fluorophenyl)-4-(2-N,N-dimethylaminoethyl)-5-phenyl-3H-1,2,4-triazol-3-one;
4-methyl-2-(3-methylphenyl)-5-phenyl-3H-1,2,4-triazol-3-one;

- --------- -------4-(2-N,N-dimethylaminoethyl)-2-(3-methyiphenyl)-5-phenyl-3H-1,2,4-triazol-3-one;
2-(2-chlorophenyl)-4-methyl-5-phenyl-3H-1,2,4-triazol-3-one;
5 2-(2-bromophenyl)95-phenyl-3H-1,2,4-triazol-3-one.

The compounds of general formula (I) optionally obtained in the form of their racemates, enantiomers, diastereomers and mixtures thereof may be converted into the salts 10 thereof, particularly for pharmaceutical use, into the physiologically acceptable salts thereof with an inorganic or organic acid. Acids suitable for this purpose include, for example, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, 15 acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid. Mixtures of the abovementioned acids may also be used.

The term alkyl groups (including those which are components of other groups, e.g. alkylene bridges), unless otherwise stated, denotes branched and unbranched alkyl groups having 1 to 6 carbon atoms, preferably 1 - 4 carbon atoms. Examples include: methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec.butyl, tert.butyl, pentyl, isopentyl, hexyl, heptyl and octyl. The groups methyl, ethyl, butyl or tert.butyl are also referred to by the abbreviations Me, Et, Bu or tBu.

Unless otherwise specified, substituted alkyl groups (including those which are components of other groups) may carry one or more of the following substituents, for example: halogen, hydroxy, mercapto, C1-6-alkyloxy, amino, alkylamino, dialkylamino, cyano, nitro, =0, -CHO, -COOH, -COO-C1-6-alkyl, -S-C1-6-alkyl.

Examples of alkenyl groups (including those which are part of other groups) include branched and unbranched alkenyl groups having 2 to 6 carbon atoms, preferably 2 to 3 carbon atoms, if they have at least one double bond, e.g.
the alkyl groups xlentioned above if they have at least one double bond, such as vinyl (provided that no unstable enamines or enol-ethers are formed), propenyl, iso-propenyl, butenyl, pentenyl and hexenyl.

Unless otherwise specified, substituted alkenyl groups (including those which are part of other groups) may for example carry one or more of the following substituents:
halogen, hydroxy, mercapto, C1-6-alkyloxy, amino, alkylamino, dialkylamino, cyano, nitro, =0, -CHO, -COOH, -C00-C1-6-alkyl, -S-C1-6-alkyl.
Examples of alkyny-1 groups (including those which are part of other groups) are alkynyl groups having 2 to 10 carbon atoms provided that they have at least one triple bond, such as ethynyl, propargyl, butynyl, pentynyl and hexynyl.
Unless otherwise specified, substituted alkynyl groups (including those which are part of other groups) may, for example, carry one or more of the following substituents:
halogen, hydroxy, mercapto, C1-6-alkyloxy, amino, alkylamino, dialkylamino, cyano, nitro, =0, -CHO, -COOH, -C00-C1-6-alkyl, -S-C1-6-alkyl.

Examples of cycloalkyl groups having 3 - 6 carbon atoms include cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, which may also be substituted by branched or unbranched C1-4-alkyl, hydroxy and/or halogen or may be substituted as hereinbefore. The term halogen generally refers to fluorine, chlorine, bromine or iodine.

The term aryl denotes an aromatic ring system having 6 to carbon atoms which, unless otherwise specified, may for example carry one or more of the following substituents:
C1-6-alkyl, C1-6-alkyloxy, halogen, hydroxy, mercapto, 5 amino, alkylamino, dialkylamino, CF3, cyano, nitro, -CHO, -COOH, -COO-C1-6-alkyl, -S-C1-6-alkyl. The preferred aryl group is phenyl.

Examples of N-linked cyclic groups of general formula 10 NR5R6 include: pyrrole, pyrroline, pyrrolidine, 2-methylpyrrolidine, 3-methylpyrrolidine, piperidine, piperazine, N-methylpiperazine, N-ethylpiperazine, N-(n-propyl)-piperazine, N-benzylpiperazine, morpholine, thiomorpholine, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, preferably morpholine, N-benzylpiperazine, piperazine and piperidine, whilst the above-mentioned heterocycles may 17e substituted by C1-4-alkyl, preferably methyl.
Examples of C-linked 5- or 6-membered heterocyclic rings which may contain nitrogen, oxygen or sulphur as heteroatoms, include furan, tetrahydrofuran, 2-methyltetrahydrofuran, 2-hydroxymethylfuran, tetrahydrofuranone, y-butyrolactone, a-pyran, y-pyran, dioxolane, tetrahydropyran, dioxane, thiophene, dihydrothiophene, thiolane, dithiolane, pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline, imidazole, imidazoline, imidazolidine, triazole, tetrazole, pyridine, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, tetrazine, morpholine, thiomorpholine, oxazole, isoxazole, oxazine, thiazole, isothiazole, thiadiazole, oxadiazole, pyrazolidine, whilst the heterocycle may be substituted as specified in the definitions.

11=0" denotes an oxygen atom linked via a double bond.

The compounds according to the invention may, for example, be synthesised by the method illustrated in Diagram 1.
O O O O
R2,1~ OH + H NNH R2~N

(~) H (2) R'-H-NH2 (3) O O
R3 --N)\ N R~ H, N ~ N' R~
N
R z/N
Z/R
(I) (I) R3=H
Diagram 1:

For this, the carboxylic acid derivatives (1) are converted with urea into the N-acylureas (2). From these the triazolones of general formula (I) wherein R3=hydrogen may be obtained by reacting with correspondingly substituted hydrazine derivatives (3), and these can be converted into the compounds of general formula (I) by alkylation under basic conditions. Suitable alkylating agents include chlorides, bromides, iodides, methanesulphonates, trifluoromethanesuiphonates or p-toluenesulphonates.

The present invention will now be explained more fully with reference to the following general synthesis instructions, without restricting it to their contents.

a) General instructions for preparing the N-acylureas (2)=
0.1 mol of carboxylic acid derivative (1) are dissolved together with 0.1 mol of urea, 0.1 mol of triphenylphosphite and 0.1 mol of pyridine in 100 ml DMF
and stirred at 100 C until the reaction has ended (5- 24 hours). The DMF is evaporated in vacuo, the residue is added to water and recrystallised from ethanol.
Yield: 15 -50%.
b) General method for preparing the triazolones (I, with R3=H :
0.01 mol of N-acylurea compound (2) are stirred with 0.01 mol of hydrazine derivative (3) in 30 ml of decaline at 170 C for 1 - 6 hours. The mixture is left to cool and the crystals formed are filtered off, washed with diethylether and recrystallised from ethyl acetate. Yield: 20 - 70%.

c) General method for preparing the triazolones (I, with R3=methyl):
1.2 mmol of triazolone compound (I, with R3=H) are stirred with 2.4 mmol of methyliodide and 2.4 mmol of potassium carbonate in 20 ml of acetone for 3 hours at 60 C. The acetone is evaporated in vacuo, the residue is taken up in water and ethyl acetate and the aqueous phase is extracted twice with ethyl acetate. The combined ethyl acetate phases are dried over sodium sulphate and evaporated in vacuo. The product is purified by chromatography on silica gel with methylene chloride or toluene/methanol with subsequent recrystallisation from isopropanol/petrol or ethanol. Yield: 45 - 70%.

d) General method for preparing the triazolones (I, with R=2-dimethylaminoethyl):

1. 1.6 mmol of triazolone compound (I, with R3= H) are dissolved in DMF, stirred with 1.6 mmol of a 60% sodium hydride suspension in oil at 80 C for 0.5 hours and 5 then combined with 4.8 mmol of dibromoethane. The mixture is stirred for 4 hours at 120 C. The DMF is evaporated in vacuo, the residue is taken up in water and ethyl acetate and the aqueous phase is extracted once more with ethyl acetate. The combined ethyl 10 acetate phases are dried over sodium sulphate and evaporated in vacuo. The product is purified by chromatography on silica gel with toluene/ethyl acetate mixtures.
2. The quantity of bromoethane derivative thus obtained is 15 reacted for 2 hours at 1.8 bar with an excess of dimethylamine at 100 C in dioxane. The dioxane is evaporated in vacuo, the residue is taken up in dilute aqueous hydrochloric acid solution and ethyl acetate.
The organic phase is extracted twice more with dilute 20 aqueous hydrochloric acid solution and the combined extracts are made alkaline with ammonia solution. The ammoniacal solution is extracted 3 times with ethyl acetate and the combined organic phases are dried over sodium sulphate and evaporated in vacuo. The residue is taken up in ethanol, combined with ethereal HC1 and the hydrochloride is precipitated with anhydrous ether.
Yield: 35 - 50%.

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The activity at the AMPA receptor was demonstrated by electrophysiology on neuronal cells (patch-clamp method) (M. L. Mayer, L. Vyklicky and G. L. Westbrook, J. Physiol.
415 (1989) 329-350).
The testingwas carried out at a test concentration of 100 M.
Table 2: Inhibition of the cainate-induced signal at the AMPA receptor AMPA AMPA
Example Inh. [%] Example Inh. [ s]

The affinity to the "Na+ channel site 2" binding site was demonstrated as described by G.B. Brown (J. Neurosci. 6 (1986) 2064). The testing was typically carried out at a test concentration of lO M.

Table 3:
Ki Example [ m]
27 5,41 35 2.08 49 6.58 53 5.78 The results described above show that the triazolone derivatives of general formula (I) can be used in the treatment of neurodegenerative diseases and cerebral ischaemia of various origins. These include, for example:
Status epilepticus, hypoglycaemia, hypoxia, anoxia, brain trauma, brain oedema, amyotropic lateral sclerosis, Huntington's disease, Alzheimer's disease, hypotonia, cardiac infarction, brain pressure (elevated intracranial pressure), ischaemic and haemorrhagic stroke, global cerebral ischaemia with heart stoppage, diabetic polyneuropathy, tinnitus, perinatal asphyxia, psychosis, schizophrenia, depression and Parkinson's disease.

The compounds of general formula (I) may be used on their own or in conjunction with other active substances according to the invention, optionally also in conjunction with other pharmacologically active substances. Suitable preparations include for example tablets, capsules, suppositories, solutions, particularly solutions for injection (s.c., i.v., i.m.) and infusion, elixirs, emulsions or dispersible powders. The content of the pharmaceutically active compound(s) should be in the range from 0.1 to 90 wt.-%, preferably 0.5 to 50 wt.-% of the composition as a whole, i.e. in amounts which are sufficient to achieve the dosage range specified below.
Suitable tablets may be obtained, for example, by mixing the active substance(s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and/or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets may also comprise several layers.

Coated tablets may be prepared accordingly by coating cores produced analogously to the tablets with substances normally used for tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar.
To achieve delayed release or prevent incompatibilities the core may also consist of a number of layers. Similarly the tablet coating may consist of a number or layers to achieve delayed release, possibly using the excipients mentioned above for the tablets.

Syrups or elixirs containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g.
a flavouring such as vanilline or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates-:

Solutions for injection and infusion are prepared in the usual way, e.g. with the addition of isotonic agents, preservatives such as p-hydroxybenzoates, or stabilisers such as alkali metal salts of ethylenediamine tetraacetic acid, optionally using emulsifiers and/or dispersants, whilst if water is used as the diluent, for example, optionally organic solvents may optionally be used as solvating agents or dissolving aids, and transferred into injection vials or ampoules or infusion bottles.

Capsules containing one or more active substances or combinations of active substances may for example be prepared by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gelatine capsules.

Suitable suppositories may be made for example by mixing with carriers provided for this purpose, such as neutral fats or polyethyleneglycol or the derivatives thereof.
Excipients which may be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g.
groundnut or sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carriers such as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk), synthetic mineral powders (e.g. highly dispersed silicic acid and silicates), sugars (e.g. cane sugar, lactose and glucose) emulsifiers (e.g. lignin, spent sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulphate).

The preparations are administered by the usual methods, preferably by parenteral route, particularly by intravenous infusion. For oral administration the tablets may, of course contain, apart from the abovementioned carriers, additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gelatine and the like. Moreover, lubricants such as magnesium stearate, sodium lauryl sulphate and talc may be used at the same time for the tabletting process. In the case of aqueous suspensions the active substances may be combined with various flavour enhancers or colourings in addition to the excipients mentioned above.
For parenteral use, solutions of the active substances with suitable liquid carriers may be used.
The dosage for intravenous use is from 1 - 1000 mg per hour, preferably between 5 and 500 mg per hour.

However, it may sometimes be necessary to depart from the amounts specified, depending on the body weight, the route of administration, the individual response to the drug, the nature of its formulation and the time or interval over which the drug is administered. Thus, in some cases it may be sufficient to use less than the minimum dose given above, whereas in other cases the upper limit may have to be exceeded. When administering large amounts it may be advisable to divide them up into a number of smaller doses spread over the day.

Moreover, the compounds of general formula I or the acid addition salts thereof may also be combined with other types of active substance.

The Examples which follow illustrate the present invention without restricting its scope:

Examples of pharmaceutical formulations A) Tablets per tablet active substance 100 mg lactose 140 mg corn starch 240 mg polyvinylpyrrolidone 15 mg magnesium stearate 5 mg 500 mg The finely ground active substance, lactose and some of the corn starch are mixed together. The mixture is screened, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet-granulated and dried. The granules, the remaining corn starch and the magnesium stearate are screened and mixed together. The mixture is compressed to produce tablets of suitable shape and size.

B) Tablets per tablet active substance 80 mg lactose 55 mg corn starch- 190 mg microcrystalline cellulose 35 mg polyvinylpyrrolidone 15 mg sodium-carboxymethyl starch 23 mg magnesium stearate 2 mg 400 mg The finely ground active substance, some of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is screened and worked with the remaining corn starch and water to form a granulate which is dried and screened. The sodiumcarboxymethyl starch and the magnesium stearate are added and mixed in and the mixture is compressed to form tablets of a suitable size.

C) Ampoule solution active substance 50 mg sodium chloride 50 mg water for inj. 5 ml The active substance is dissolved in water at its own pH
or optionally at pH 5.5 to 6.5 and sodium chloride is added to make it isotonic. The solution obtained is filtered free from pyrogens and the filtrate is transferred under aseptic conditions into ampoules which are then sterilised and sealed by fusion. The ampoules contain 5 mg, 25 mg and 50 mg of active substance.

Claims (24)

CLAIMS:

1. A pharmaceutical composition comprising a compound selected from the group consisting of:

(a) 2-(2-methylphenyl)-5-phenyl-3H-1,2,4-triazol-3-one;

(b) 2-(3-methoxyphenyl)-4-methyl-5-phenyl-3H-1,2,4-triazol-3-one;

(c) 2-(2-bromophenyl)-4-methyl-5-phenyl-3H-1,2,4-triazol-3-one;

(d) 5-(4-methoxyphenyl)-4-methyl-2-phenyl-3H-1,2,4-triazol-3-one;

(e) 5-(2-methoxyphenyl)-4-methyl-2-phenyl-3H-1,2,4-triazol-3-one;

(f) 4-(2-N,N-dimethylaminoethyl)-2-(2-methylphenyl)-5-phenyl-3H-1,2,4-triazol- 3-one;

(g) 2-(2-methoxyphenyl)-5-phenyl-3H-1,2,4-triazol-3-one;

(h) 2-(2-chlorophenyl)-5-phenyl-3H-1,2,4-triazol-3-one;

(i) 2-(3-chlorophenyl)-4-(2-N,N-dimethylaminoethyl)-5-phenyl-3H-1,2,4-triazol-3-one;
(j) 2-(2-fluorophenyl)-5-phenyl-3H-1,2,4-triazol-3-one;

(k) 2-(3-fluorophenyl)-4-methyl-5-phenyl-3H-1,2,4-triazol-3-one;

(l) 2-(2-fluorophenyl)-4-methyl-5-phenyl-3H-1,2,4-triazol-3-one;

(m) 2-(3-methylphenyl)-5-phenyl-3H-1,2,4-triazol-3-one;

(n) 2-(2-ethylphenyl)-5-phenyl-3H-1,2,4-triazol-3-one;

(o) 2-(3-fluorophenyl)-4-(2-N,N-dimethylaminoethyl)-5-phenyl-3H-1,2,4-triazol-3-one;
(p) 4-methyl-2-(3-methylphenyl)-5-phenyl-3H-1,2,4-triazol-3-one;

(q) 4-(2-N,N-dimethylaminoethyl)-2-(3-methylphenyl)-5-phenyl-3H-1,2,4-triazol-3-one;
(r) 2-(2-chlorophenyl)-4-methyl-5-phenyl-3H-1,2,4-triazol-3-one;

(s) 2-(2-bromophenyl)-5-phenyl-3H-1,2,4-triazol-3-one; and pharmaceutically acceptable salts thereof; and a pharmaceutically acceptable carrier or diluent.

2. A pharmaceutical composition according to claim 1, wherein the compound is compound (a) or the pharmaceutically acceptable salt thereof.

3. A pharmaceutical composition according to claim 1, wherein the compound is compound (b) or the pharmaceutically acceptable salt thereof.

4. A pharmaceutical composition according to claim 1, wherein the compound is compound (c) or the pharmaceutically acceptable salt thereof.

5. A pharmaceutical composition according to claim 1, wherein the compound is compound (d) or the pharmaceutically acceptable salt thereof.

6. A pharmaceutical composition according to claim 1, wherein the compound is compound (e) or the pharmaceutically acceptable salt thereof.

7. A pharmaceutical composition according to claim 1, wherein the compound is compound (f) or the pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition according to claim 1, wherein the compound is compound (g) or the pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition according to claim 1, wherein the compound is compound (h) or the pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition according to claim 1, wherein the compound is compound (i) or the pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition according to claim 1, wherein the compound is compound (j) or the pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition according to claim 1, wherein the compound is compound (k) or the pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition according to claim 1, wherein the compound is compound (1) or the pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition according to claim 1, wherein the compound is compound (m) or the pharmaceutically acceptable salt thereof.

15. A pharmaceutical composition according to claim 1, wherein the compound is compound (n) or the pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition according to claim 1, wherein the compound is compound (o) or the pharmaceutically acceptable salt thereof.

17. A pharmaceutical composition according to claim 1, wherein the compound is compound (p) or the pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition according to claim 1, wherein the compound is compound (q) or the pharmaceutically acceptable salt thereof.

19. A pharmaceutical composition according to claim 1, wherein the compound is compound (r) or the pharmaceutically acceptable salt thereof.

20. A pharmaceutical composition according to claim 1, wherein the compound is compound (s) or the pharmaceutically acceptable salt thereof.

21. A pharmaceutical composition according to any one of claims 1 to 20 for treating a neurodegenerative disease or cerebral ischemia arising from a condition selected from the group consisting of Status epilepticus, hypoglycaemia, hypoxia, anoxia, brain trauma, brain oedema, amyotrophic lateral sclerosis, Huntington's disease, Alzheimer's disease, hypotonia, cardiac infarction, brain pressure (elevated intracranial pressure), ischaemic and haemorrhagic stroke, global cerebral ischaemia with heart stoppage, diabetic polyneuropathy, tinnitus, perinatal asphyxia, psychosis, schizophrenia, depression, and Parkinson's disease in a host in need of such treating.

22. A use of a compound or pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 20 in preparation of a pharmaceutical composition for treating a neurodegenerative disease or cerebral ischemia arising from a condition selected from the group consisting of Status epilepticus, hypoglycaemia, hypoxia, anoxia, brain trauma, brain oedema, amyotrophic lateral sclerosis, Huntington's disease, Alzheimer's disease, hypotonia, cardiac infarction, brain pressure (elevated intracranial pressure), ischaemic and haemorrhagic stroke, global cerebral ischaemia with heart stoppage, diabetic polyneuropathy, tinnitus, perinatal asphyxia, psychosis, schizophrenia, depression, and Parkinson's disease in a host in need of such treating.

23. A use of a compound or pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 20 for treating a neurodegenerative disease or cerebral ischemia arising from a condition selected from the group consisting of Status epilepticus, hypoglycaemia, hypoxia, anoxia, brain trauma, brain oedema, amyotrophic lateral sclerosis, Huntington's disease, Alzheimer's disease, hypotonia, cardiac infarction, brain pressure (elevated intracranial pressure), ischaemic and haemorrhagic stroke, global cerebral ischaemia with heart stoppage, diabetic polyneuropathy, tinnitus, perinatal asphyxia, psychosis, schizophrenia, depression, and Parkinson's disease in a host in need of such treating.

24. A compound or pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 20 for treating a neurodegenerative disease or cerebral ischemia arising from a condition selected from the group consisting of Status epilepticus, hypoglycaemia, hypoxia, anoxia, brain trauma, brain oedema, amyotrophic lateral sclerosis, Huntington's disease, Alzheimer's disease, hypotonia, cardiac infarction, brain pressure (elevated intracranial pressure), ischaemic and haemorrhagic stroke, global cerebral ischaemia with heart stoppage, diabetic polyneuropathy, tinnitus, perinatal asphyxia, psychosis, schizophrenia, depression, and Parkinson's disease in a host in need of such treating.