CA2073064A1 - (hetero) 4-arylmethoxy phenyl diazole derivatives, method for preparing same and their therapeutical applications - Google Patents
(hetero) 4-arylmethoxy phenyl diazole derivatives, method for preparing same and their therapeutical applicationsInfo
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- CA2073064A1 CA2073064A1 CA002073064A CA2073064A CA2073064A1 CA 2073064 A1 CA2073064 A1 CA 2073064A1 CA 002073064 A CA002073064 A CA 002073064A CA 2073064 A CA2073064 A CA 2073064A CA 2073064 A1 CA2073064 A1 CA 2073064A1
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- C07C243/24—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids
- C07C243/38—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to carbon atoms of six-membered aromatic rings
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- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
- C07D271/113—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
Title: "Derivatives of 4-(hereto)arylmethyloxy phenyl diazole, a method of preparing them and use thereof in therapy"
(Inventors: Jean-Jacques KOENIG, Luc LEBRETON and Maryse MASSON) Applicant : DELALANDE S.A. (soci?t? anonmye) A B S T R A C T
Derivatives having the formula:
(I) in which R1 = C1-C4 alkyl and Ar is an aryl or heteroaryl group chosen from among the following:
(i) where R2 represents a hydrogen atom one or two halogen atoms, a CN, NO2 or CF3 group, one, two or three C1-C4 alkyl or C1-C4 alkoxy groups or an amino group substituted by two C1-C4 alkyl groups, in which case the -W-V- chain represents -N = N- or and n = 2-6;
(ii) pyridyl, in which case the -W-V- chain represents -N=N-and n = 1-6, and acid addition salts of those derivatives (I) which are salt-forming.
These derivatives are of use in therapy as agents for inhibiting type B monoamine oxydase.
(Inventors: Jean-Jacques KOENIG, Luc LEBRETON and Maryse MASSON) Applicant : DELALANDE S.A. (soci?t? anonmye) A B S T R A C T
Derivatives having the formula:
(I) in which R1 = C1-C4 alkyl and Ar is an aryl or heteroaryl group chosen from among the following:
(i) where R2 represents a hydrogen atom one or two halogen atoms, a CN, NO2 or CF3 group, one, two or three C1-C4 alkyl or C1-C4 alkoxy groups or an amino group substituted by two C1-C4 alkyl groups, in which case the -W-V- chain represents -N = N- or and n = 2-6;
(ii) pyridyl, in which case the -W-V- chain represents -N=N-and n = 1-6, and acid addition salts of those derivatives (I) which are salt-forming.
These derivatives are of use in therapy as agents for inhibiting type B monoamine oxydase.
Description
207306~
ves~ of ~-(hetero)aryl~ethvloxy phenyl diazole. a method of preparinq them and use thereof in thera~y The invention relates to new deriva.ives of 4-(hetero) arylmethyloxy phenyl diazole, a method of preparing them and use thereof in therapy.
More precisely, the derivatives according to the invention have the formula:
~.--N / ( CH2)n- ~ ~ l Ar - Cit2 - O ~W /~ (I) in which R1 denotes C1-C4 alkyl and Ar is an aryl or heteroaryl group chosen from among the following:
(i) R2 where R2 represents a hydrogen atom, one or two halogen atoms, a CN, NO2 or CF3 group, one, two or three C1-C4 alkyl or C1-Cb alkoxy groups or an amino group substituted by two C1-C4 alkyl groups, in which case the -W-V- chain represents -N = N- or -O-C-o and n = 2-6;
(ii) pyridyl, in which case the -W-V- chain represents -N=N- and n = 1-6.
Hereinbefore and hereinafter, the expression "C1-C4 alkyl"
denotes straight-chain or branched hydrocarbon groups containing 1 to 4 carbon atoms, i.e. methyl, ethyl,
ves~ of ~-(hetero)aryl~ethvloxy phenyl diazole. a method of preparinq them and use thereof in thera~y The invention relates to new deriva.ives of 4-(hetero) arylmethyloxy phenyl diazole, a method of preparing them and use thereof in therapy.
More precisely, the derivatives according to the invention have the formula:
~.--N / ( CH2)n- ~ ~ l Ar - Cit2 - O ~W /~ (I) in which R1 denotes C1-C4 alkyl and Ar is an aryl or heteroaryl group chosen from among the following:
(i) R2 where R2 represents a hydrogen atom, one or two halogen atoms, a CN, NO2 or CF3 group, one, two or three C1-C4 alkyl or C1-Cb alkoxy groups or an amino group substituted by two C1-C4 alkyl groups, in which case the -W-V- chain represents -N = N- or -O-C-o and n = 2-6;
(ii) pyridyl, in which case the -W-V- chain represents -N=N- and n = 1-6.
Hereinbefore and hereinafter, the expression "C1-C4 alkyl"
denotes straight-chain or branched hydrocarbon groups containing 1 to 4 carbon atoms, i.e. methyl, ethyl,
2~7~0~ ~
n-propyl, i-propyl, n-butyl, i-butyl, sec.-butyl or tert-butyl; the expression "C1-C4 alkoxy" has the formula O-(Cl-C~ alkyl) ; the term halogen denotes fluorine, chlorine bromine or iodine~ and the term pyri~yl denotes 4-pyridyl,
n-propyl, i-propyl, n-butyl, i-butyl, sec.-butyl or tert-butyl; the expression "C1-C4 alkoxy" has the formula O-(Cl-C~ alkyl) ; the term halogen denotes fluorine, chlorine bromine or iodine~ and the term pyri~yl denotes 4-pyridyl,
3-pyridyl or 2-pyridyl.
The invention also relates to addition salts of a mineral acid (e.g. hydrochloric or sulphuric acid) or an organic acid (e.g. acetic, oxalic, maleic or tartric) of those derivatives (I) which are salt-forming.
The invention also covers a method of preparing the derivatives (I), the method comprising:
(a) condensation of compounds having the formula:
X - ( CH2 ) n ~ ORl ( I I ) where n = 2-6, R1 = Cl-C4 alkyl and X denotes a good leaving group such as a halogen atom (chlorine, bromine or iodine) or a mesyloxy or tosyloxy group, on to respective compounds having the formula:
~ CH2- o ~ ~v (III) where -W-V- denotes -N=N- or -O-g- and R2 has the same meaning as in formula (I), in the presence of a base such as a metal hydride, inter alia sodium hydride, in an aprotic anhydrous solvent such as dimethyl formamide;
(b) condensation of compounds having the formula:
2~73~
Ar - CH2 - X (IV) where Ar has the same meaning as in formula (I) and X
has the same meaning as in formula (II), on to respective compounds having the formula:
N N / 2 n ~0 ~ \ (V) where R1 and n have the same meanings as in formula (I) and -W-V- represents either -N=N- or -O-C- when Ar in formula (IV) is a phenyl ring substituted by R2, the latter having the same meaning as in formula (I), or -N=N- when Ar in formula (IV) represents pyridyl,in the presence of a base such as K2C03 or a metal hydride such as sodium hydride, in an anhydrous solvent such as DMF
or acetonitrile;
(c) condensation of compounds having the formula:
2 CH - ~ ~ c-NH-NH-(cH2)n ORl (VI) where n, R1 and R2 have the same meaning as in formula (I), with phosgene in an aprotic solvent such as dioxane, chloroform or toluene, for the purpose of cyclisation of the -I_NH_NH- (CH2)n-OR1 chain 2 o 7 ~ ~ ~ L~
compounds (VI~ into N - N'( 2 n \0 The formula (V) compounds can be obtained by debenzylation in the presence of hydrogen and a catalyst such as palladium on carbon, of the respective formula (I) compounds having the special structure:
~ 2 ~ /(CH2)n-ORl (Ia) where -W-V-, R1 and n have the same meaning as in formula (I), preferably in an alcoholic solvent such as ethanol or methanol.
The formula (III) compounds having the special structure:
Rz 2 ~ NN~\ (IIIa) where R2 has the same meaning as in formula (I), can be obtained by action of sodium azide on compounds having the formula:
~ CH2 - ~ CN (VII) . . . ~
~ ~ ~ o ~
where R2 has the same meaning as in formula (I), preferably by the method of R. M. HERBS~ described in J. Org. Chem.
22, 1142, 1957.
The formula (VII) compounds are obtained by treating the compound having the formula:
H0 ~ - C~ (VIII) with a metal hydride such as sodium hydride in an aprotic solvent such as DMF and by reacting the resulting compound with formula (IV) compounds in which Ar = ~ ~
The formula (III) compounds having the special structure ~ CH2- 0 ~ / ~ (IIIb) where Rz has the same meaning as in formula (I), can be obtained by the method of FREUND and GOLDS~ITH described in Ber. 21, 1240, 1882, by using hydrazides having the formula:
z 2 ~ C - NH - NH2 (IX) where R2 has the same meaning as in formula (I).
The formula (IX) compounds can be obtained by action of hydrazine respectively on the ethyl or methyl ester of acids having the formula:
,, ~
2~73~
2 C!~2-- {~} C - OH (X) where R2 has the same meaning as in formula (I), in an alcoholic medium, preferably ethanol.
The formula (VI) compounds are obtained by action of the methyl or ethyl ester of acids of formula (X) i.n an alcoholic medium such as ethanol or methanol, on the respective compounds having the formula:
NH2 ~ NH - (CH2)n - ORl (XI) where n and R1 have the same meaning as in formula (I), the last-mentioned compounds being obtained preferably by the method described in CA 63 : 9962.
The acid addition salts of the salt-forming derivatives of formula (I) can be obtained in conventional manner by action of an inorganic or organic acid on the salt-forming derivatives of formula (I), the acids and derivatives preferably being used in the form of miscible solutions.
The following preparations are given by way of example in order to illustrate the invention:
Exam~le 1:
5-(4-benzyloxy phenyl) 2-methoxyethyl 2H tetrazole -[(I) ; n = 2, R1 = CH3, -W-V- : - N=N-, Ar = phenyl]
Code No: MD 230300 2~7~
1st ste~: 4-benzyloxy benzonitrile (VII) 5 10-2 mol of NaH was added little by little to a solution of 5 10-2 mol of 4-hydroxy benzonitrile in 100 ml DMF so as to obtain a temperature o~ 25C. The solution was then heated to 50C until no more hydrogen was liberated.
After cooling to 0C, 5.10-2 benzyl chloride was added.
The reaction mixture was heated to 40C for 1 hour, then poured into 300 ml iced water. The resulting solid was separated by filtration.
2nd step: 5-(4-benzyloxy phenyl) tetrazole [(IIIa); R2= H]
6.6 x 10-2 mol of sodium azide and 6.6 x 10-2 mol of acetic acid were added to a solution of 5 x 10-2 mol of 4-benzyloxy benzonitrile (VIII) in 20 ml butanol. The reaction medium was then reflux-heated for 4 hours. 1 g sodium azide, 2 g acetic acid and 10 ml butanol were added and the reaction medium was again reflux-heated for 2 days. After concentration by evaporation of the solvent, the residue was dissolved in 20 ml of 10% aqueous NaOH.
After filtration, the aqueous phase was extracted with ether. The alkaline solution was acidified with 2 N HCl to obtain the expected compound, which was isolated with an 85~ yield (M.P. = 228C).
3rd step: 5-(4-benzyloxy phenyl) 2-methoxyethyl 2H tetrazole (I) 2x102 mol of the compound obtained in the second step was added to a solution of 2x10-2 mol of sodium hydride in 50 ml D~F and the reaction medium was heated to 60 - 80C
until no more gas was evolved. After cooling, 2x10-2 mol of 2-chloro-1-methoxyethane was added little by little.
The reaction medium was heated to 80C for 12 hours, then 2~73~6~
concentrated to two-thirds and poured on to iced water.
After extraction with ether, the expec:ted product was obtained with a 48% yield.
M.P. = 96C
I~ (KBr, ~ cm~1) : 1610, 1450 H NMR (~ ppm, DMSOd6) : 3.2 (3H) ; 3.9 (2H) ; 5-3 (2H) ;
7.2 (2H) ; 7.4 (5H) ; 8 (2H).
The other formula (I) derivatives in which Ar =
can be obtained in the same manner, inter alia the following:
5-[4-(4-chlorobenzyloxy) phenyl] 2-methoxyethyl 2H-tetrazole [(I) ; -W-V- : -N=N-, R1 = CH3, n = 2, Ar = 4-chloro phenyl]
Code No: MD 230305 Yield = 44%
M.P. = 90C
IR (KBr, ~ cm1); 1620, 1420, 1410, 1210 lH NMR (~ ppm, DMSOd6) : 3.2 (3H) ; 3.9 (2H) ; 4.9 (2H);
5.2 (2H) ; 7.2 (2H) ; 7.5 (4H) ; 8 (2H);
5-[4-(3-chlorobenzyloxy) phenyl] 2-methoxyethyl 2H
tetrazole [(I) : -W-V-:-N=N-, R1 = CH3, n = 2, Ar = 3-chloro pheny~
Code No: MD 230324 M.P. = 92C
1H NMR (~ ppm, DMSOd6) : 3.4 (3H) ; 4 ~2H) ; 4.8 (2H);
5.l (2H) ; 7 (2H) ; 7.3 (4H) ; 8 (2H)-207~
Exam~le 2:
5-[4-(4-chlorobenzyloxy)phenyl] 3-methoxyethyl 3H-1,3,4 oxadiazol 2-one [(I) : -W-V-:-o-C-, R1 = CH3, n = 2, Ar = 4-chloro phenyl]
Code No: MD 230306 1st step: 1-[4-(4-chlorobenzyloxy) benzoyl] hydrazine (IX) 2.75 mol of hydrazine hydrate was added to a solution of 0.275 mol of ethyl ester of 4-(4 chloro benzyloxy) benzoic acid (X) in 300 ml ethanol. The reaction medium was reflux-heated for 48 hours. After cooling, the expected product was separated by filtration and recrystallised from ethanol.
. Yield = 63%
. M.P. = 168C
nd step: 5-[4-(4-chlorobenzyloxy) phenyl~ 3H 1,3,4-oxadiazol 2-one (IIIb) A solution of 0.0723 mol of phosgene in 5 ml toluene was added to a solution of 0.0723 mol of the compound obtained in the preceding step in 200 ml toluene. The mixture was agitated at ambient temperature for 18 hours. After filtration, the substance obtained was recrystallised from butanol.
. Yield = 78%
. M.P. = 236C
rd step: 5-[4-(4-chlorobenzyloxy) phenyl] 3-methoxyethyl 3H 1,3,4-oxadiazol-2-one (I) 0.016 mol of NaH was added to a solution of 0.016 mol of 2~3~
the compound obtained in the preceding step in 50 ml DMF, followed by heating to 60 - 80C until no more hydrogen was evolved. After cooling, 0.016 mol of 2-chloro 1-methoxy ethane was added dropwise, and then the reaction medium was heated to 80C for 12 hours, then concentrated to two-thirds and poured on to iced water.
The expected product was obtained by extraction with ether, with a 36% yield.
. M.P. = 140~C
. IR (KBr, ~ ~m~1) : 1780, 1610, 1245, 1115, 1000.
. 1H NMR (DMSOd6) ~ ppm : 3.2 (3H) ; 3.8 (4H) ;
5.2 (2H); 7.2 (2H) ; 7.5 (4H) ; 7.7 (2H).
Example 3:
2-methoxyethyl 5-[4-(4-pyridyl methyloxy)phenyl] 2H
tetrazole hydrochloride [(I); -W-V-:-N=N-, n = 2, R1 =
CH3 , Ar = 4-pyridyl]
Code No: MD 230307 1st step: 5-(4-hydroxyphenyl) 2-methoxyethyl 2H tetrazole [(V) ; -W-V-:-N=N-, n=2, R1 = CH3]
0.04 g of 10% palladium on carbon moistened to 50% was added to a solution of 0.6x103 mol of compound MD 230300 in 20 ml of a mixture of methanol and methylene chloride (50-50) and a stream of hydrogen was supplied at normal pressure for 3 hours. After filtration and concentration, the resulting substance was recystallised from a mixture of ethyl ether and petroleum ether.
. Yield = 75%
. M.P. = 110C
2~3~
nd step: 2-methoxyethyl 5-[4-(4-pyridyl methyloxy) phenyl] 2H tetrazole hydrochloride ~I) 0.0567 mol of K2CO3 and 0.0227 mol of 4-chloromethyl pyridine were added to a solution of 0.0227 mol of the compound obtained in the preceding step in 100 ml acetonitrile. The reaction medium was reflux-heated for 48 hours, then concentrated and dissolved in a 0.1 N
solution of NaOH. After extraction with methylene chloride, the organic phase was dried on sodium sulphate and concentrated. The resulting base was dissolved in ethanol, followed by addition of hydrochloric ethanol.
The expected hydrochloride precipitated and was recrystallised from ethanol.
. Yield = 15%
. M.P. = 190C
. IR (KBr, ~ cm~l) : 2400, 2100, 2000, 1640, 1615, 1470, 1260, 1250, 1120 . 1H NMR (~ ppm, DMSOd6) : 3.2 (3H) ; 3.9 (2H) ; 4.9 (2H) ;
5.6 (2H) ; 7.2 (2H) ; 8 (4H) ; 8.9 (2H) ; 7.7 (lH
exchangeable).
The other derivatives (I) are obtained in the same manner, inter alia 2-(methoxyethyl) 5-[4-(3-pyridyl methyloxy)phenyl] 2H tetrazole [(I) ; -W-V-:-N=N-, n ~ 2, Rl = CH3, Ar = 3-pyridyl]. Code No: MD 230308.
. M.P. = 160C
. IR (KBr, ~ cm~1) : 2550, 2100, 1615, 1550, 1420, 1405, . 1H NMR (~ ppm, DMSOd6) : 3.3 (3H) ; 4 (2H) ; 4.95 (2H) ;
5.5 (2H) ; 7.3 (2H) ; 8 (3H) ; 8.5-8.9 (3H) ; 9.1 (lH
exch).
The formula ~I) derivatives and their pharmaceutically 2 ~ 7.~
acceptable acid addition salts have been s~udied in laboratory animals and have shown pharmacological activity, inter alia selective activity for inhibiting type B monoamine oxidase (MAO-B).
The activity of the compounds in inhibiting monoamine oxidase was shown by measurements of ~AO in vitro.
The MAO activity was determined, using a mitochondrial suspension of rat brain as a source of enzyme. The standard method of determination consists in pre-incubating the enzyme for 20 minutes, first in the absence and then in the presence of the inhibitors. The activities were determined by using serotonin (5 HT) and phenethylamine (PEA) as substrates of MAO-A and MAO-B, the reaction time being 40 minutes with 5 HT and 10 minutes with PEA. The method of operation used was that of P.C.
Baker: Dev. Biol. 14, 267, 1966.
The activities of a number of compounds according to the invention as against MA0-B and MA0-A are given via their inhibition constants Ki(MAo-B) and Ki(MAo-A) and are shown in the following Table.
TABLE
.
Compound testedKi (MAO-B) Ki (MAO-A) Code Number _ MD 2303001.56 x 10-8 M/L inactive MD 2303051.84 x 10-7 M/L inactive MD 2303065 x 10-9 M/L inactive MD 2303243.5 x 10-8 M/L inactive With regard to the toxicity of the formula (I) derivatives and their pharmaceutically acceptable acid addition salts, ~7 ?~
after oral administration to the mouse, no toxicity was observed for 24 hours, up to a dose of 1500 mg/kg.
The formula (I) derivatives and their pharmaceutically acceptable acid addition salts can be used for preparation of drugs for inhibiting type B monoamine oxidase. These drugs are of use in therapy, inter alia for treatment of neurological disturbances connected with pathological ageing, disturbances of memory, mood, schizophrenia, psychasthenia or psychic slowing-down due to ageing, certain forms of depression and Parkinson's disease.
The drugs can be administered to man or any warm-blooded animal in various pharmaceutical forms well known in the art, inter alia in the form of compounds formulated for oral, parenteral or rectal administration.
For oral administration, the compositions can be in the form of pills, dragees or capsules, prepared by conventional methods using known supports and excipients such as binders, fillers, lubricants and disintegrating agents; they may also take the form of solutions, syrup or suspensions.
For parenteral administration, the compositions according to the invention can be in the form of injectable solutions, suspensions or emulsions comprising a parenterally acceptable,oily or agueous liqui~ vehicle.
For rectal administration, the compositions can be in the form of suppositories containing conventional bases for suppositories.
The amount of the active principles, i.e. derivatives (I) and their pharmaceutically acceptable acid addition salts, 2~73a~l~
1~
which can be administered depends inter alia on the way of administration, the body weight of the patient and the therapeutic power of the compounds used. The amount orally administered may generally be up to 50 mg/kg of active principle per day (in one or two doses); the amounts for parenteral administration may be up to 5 mg/kg of active principle per day (in one or more doses);and the amounts for rectal administration may be up to 10 mg/kg of active principle per day (in one or two suppositories).
The invention also relates to addition salts of a mineral acid (e.g. hydrochloric or sulphuric acid) or an organic acid (e.g. acetic, oxalic, maleic or tartric) of those derivatives (I) which are salt-forming.
The invention also covers a method of preparing the derivatives (I), the method comprising:
(a) condensation of compounds having the formula:
X - ( CH2 ) n ~ ORl ( I I ) where n = 2-6, R1 = Cl-C4 alkyl and X denotes a good leaving group such as a halogen atom (chlorine, bromine or iodine) or a mesyloxy or tosyloxy group, on to respective compounds having the formula:
~ CH2- o ~ ~v (III) where -W-V- denotes -N=N- or -O-g- and R2 has the same meaning as in formula (I), in the presence of a base such as a metal hydride, inter alia sodium hydride, in an aprotic anhydrous solvent such as dimethyl formamide;
(b) condensation of compounds having the formula:
2~73~
Ar - CH2 - X (IV) where Ar has the same meaning as in formula (I) and X
has the same meaning as in formula (II), on to respective compounds having the formula:
N N / 2 n ~0 ~ \ (V) where R1 and n have the same meanings as in formula (I) and -W-V- represents either -N=N- or -O-C- when Ar in formula (IV) is a phenyl ring substituted by R2, the latter having the same meaning as in formula (I), or -N=N- when Ar in formula (IV) represents pyridyl,in the presence of a base such as K2C03 or a metal hydride such as sodium hydride, in an anhydrous solvent such as DMF
or acetonitrile;
(c) condensation of compounds having the formula:
2 CH - ~ ~ c-NH-NH-(cH2)n ORl (VI) where n, R1 and R2 have the same meaning as in formula (I), with phosgene in an aprotic solvent such as dioxane, chloroform or toluene, for the purpose of cyclisation of the -I_NH_NH- (CH2)n-OR1 chain 2 o 7 ~ ~ ~ L~
compounds (VI~ into N - N'( 2 n \0 The formula (V) compounds can be obtained by debenzylation in the presence of hydrogen and a catalyst such as palladium on carbon, of the respective formula (I) compounds having the special structure:
~ 2 ~ /(CH2)n-ORl (Ia) where -W-V-, R1 and n have the same meaning as in formula (I), preferably in an alcoholic solvent such as ethanol or methanol.
The formula (III) compounds having the special structure:
Rz 2 ~ NN~\ (IIIa) where R2 has the same meaning as in formula (I), can be obtained by action of sodium azide on compounds having the formula:
~ CH2 - ~ CN (VII) . . . ~
~ ~ ~ o ~
where R2 has the same meaning as in formula (I), preferably by the method of R. M. HERBS~ described in J. Org. Chem.
22, 1142, 1957.
The formula (VII) compounds are obtained by treating the compound having the formula:
H0 ~ - C~ (VIII) with a metal hydride such as sodium hydride in an aprotic solvent such as DMF and by reacting the resulting compound with formula (IV) compounds in which Ar = ~ ~
The formula (III) compounds having the special structure ~ CH2- 0 ~ / ~ (IIIb) where Rz has the same meaning as in formula (I), can be obtained by the method of FREUND and GOLDS~ITH described in Ber. 21, 1240, 1882, by using hydrazides having the formula:
z 2 ~ C - NH - NH2 (IX) where R2 has the same meaning as in formula (I).
The formula (IX) compounds can be obtained by action of hydrazine respectively on the ethyl or methyl ester of acids having the formula:
,, ~
2~73~
2 C!~2-- {~} C - OH (X) where R2 has the same meaning as in formula (I), in an alcoholic medium, preferably ethanol.
The formula (VI) compounds are obtained by action of the methyl or ethyl ester of acids of formula (X) i.n an alcoholic medium such as ethanol or methanol, on the respective compounds having the formula:
NH2 ~ NH - (CH2)n - ORl (XI) where n and R1 have the same meaning as in formula (I), the last-mentioned compounds being obtained preferably by the method described in CA 63 : 9962.
The acid addition salts of the salt-forming derivatives of formula (I) can be obtained in conventional manner by action of an inorganic or organic acid on the salt-forming derivatives of formula (I), the acids and derivatives preferably being used in the form of miscible solutions.
The following preparations are given by way of example in order to illustrate the invention:
Exam~le 1:
5-(4-benzyloxy phenyl) 2-methoxyethyl 2H tetrazole -[(I) ; n = 2, R1 = CH3, -W-V- : - N=N-, Ar = phenyl]
Code No: MD 230300 2~7~
1st ste~: 4-benzyloxy benzonitrile (VII) 5 10-2 mol of NaH was added little by little to a solution of 5 10-2 mol of 4-hydroxy benzonitrile in 100 ml DMF so as to obtain a temperature o~ 25C. The solution was then heated to 50C until no more hydrogen was liberated.
After cooling to 0C, 5.10-2 benzyl chloride was added.
The reaction mixture was heated to 40C for 1 hour, then poured into 300 ml iced water. The resulting solid was separated by filtration.
2nd step: 5-(4-benzyloxy phenyl) tetrazole [(IIIa); R2= H]
6.6 x 10-2 mol of sodium azide and 6.6 x 10-2 mol of acetic acid were added to a solution of 5 x 10-2 mol of 4-benzyloxy benzonitrile (VIII) in 20 ml butanol. The reaction medium was then reflux-heated for 4 hours. 1 g sodium azide, 2 g acetic acid and 10 ml butanol were added and the reaction medium was again reflux-heated for 2 days. After concentration by evaporation of the solvent, the residue was dissolved in 20 ml of 10% aqueous NaOH.
After filtration, the aqueous phase was extracted with ether. The alkaline solution was acidified with 2 N HCl to obtain the expected compound, which was isolated with an 85~ yield (M.P. = 228C).
3rd step: 5-(4-benzyloxy phenyl) 2-methoxyethyl 2H tetrazole (I) 2x102 mol of the compound obtained in the second step was added to a solution of 2x10-2 mol of sodium hydride in 50 ml D~F and the reaction medium was heated to 60 - 80C
until no more gas was evolved. After cooling, 2x10-2 mol of 2-chloro-1-methoxyethane was added little by little.
The reaction medium was heated to 80C for 12 hours, then 2~73~6~
concentrated to two-thirds and poured on to iced water.
After extraction with ether, the expec:ted product was obtained with a 48% yield.
M.P. = 96C
I~ (KBr, ~ cm~1) : 1610, 1450 H NMR (~ ppm, DMSOd6) : 3.2 (3H) ; 3.9 (2H) ; 5-3 (2H) ;
7.2 (2H) ; 7.4 (5H) ; 8 (2H).
The other formula (I) derivatives in which Ar =
can be obtained in the same manner, inter alia the following:
5-[4-(4-chlorobenzyloxy) phenyl] 2-methoxyethyl 2H-tetrazole [(I) ; -W-V- : -N=N-, R1 = CH3, n = 2, Ar = 4-chloro phenyl]
Code No: MD 230305 Yield = 44%
M.P. = 90C
IR (KBr, ~ cm1); 1620, 1420, 1410, 1210 lH NMR (~ ppm, DMSOd6) : 3.2 (3H) ; 3.9 (2H) ; 4.9 (2H);
5.2 (2H) ; 7.2 (2H) ; 7.5 (4H) ; 8 (2H);
5-[4-(3-chlorobenzyloxy) phenyl] 2-methoxyethyl 2H
tetrazole [(I) : -W-V-:-N=N-, R1 = CH3, n = 2, Ar = 3-chloro pheny~
Code No: MD 230324 M.P. = 92C
1H NMR (~ ppm, DMSOd6) : 3.4 (3H) ; 4 ~2H) ; 4.8 (2H);
5.l (2H) ; 7 (2H) ; 7.3 (4H) ; 8 (2H)-207~
Exam~le 2:
5-[4-(4-chlorobenzyloxy)phenyl] 3-methoxyethyl 3H-1,3,4 oxadiazol 2-one [(I) : -W-V-:-o-C-, R1 = CH3, n = 2, Ar = 4-chloro phenyl]
Code No: MD 230306 1st step: 1-[4-(4-chlorobenzyloxy) benzoyl] hydrazine (IX) 2.75 mol of hydrazine hydrate was added to a solution of 0.275 mol of ethyl ester of 4-(4 chloro benzyloxy) benzoic acid (X) in 300 ml ethanol. The reaction medium was reflux-heated for 48 hours. After cooling, the expected product was separated by filtration and recrystallised from ethanol.
. Yield = 63%
. M.P. = 168C
nd step: 5-[4-(4-chlorobenzyloxy) phenyl~ 3H 1,3,4-oxadiazol 2-one (IIIb) A solution of 0.0723 mol of phosgene in 5 ml toluene was added to a solution of 0.0723 mol of the compound obtained in the preceding step in 200 ml toluene. The mixture was agitated at ambient temperature for 18 hours. After filtration, the substance obtained was recrystallised from butanol.
. Yield = 78%
. M.P. = 236C
rd step: 5-[4-(4-chlorobenzyloxy) phenyl] 3-methoxyethyl 3H 1,3,4-oxadiazol-2-one (I) 0.016 mol of NaH was added to a solution of 0.016 mol of 2~3~
the compound obtained in the preceding step in 50 ml DMF, followed by heating to 60 - 80C until no more hydrogen was evolved. After cooling, 0.016 mol of 2-chloro 1-methoxy ethane was added dropwise, and then the reaction medium was heated to 80C for 12 hours, then concentrated to two-thirds and poured on to iced water.
The expected product was obtained by extraction with ether, with a 36% yield.
. M.P. = 140~C
. IR (KBr, ~ ~m~1) : 1780, 1610, 1245, 1115, 1000.
. 1H NMR (DMSOd6) ~ ppm : 3.2 (3H) ; 3.8 (4H) ;
5.2 (2H); 7.2 (2H) ; 7.5 (4H) ; 7.7 (2H).
Example 3:
2-methoxyethyl 5-[4-(4-pyridyl methyloxy)phenyl] 2H
tetrazole hydrochloride [(I); -W-V-:-N=N-, n = 2, R1 =
CH3 , Ar = 4-pyridyl]
Code No: MD 230307 1st step: 5-(4-hydroxyphenyl) 2-methoxyethyl 2H tetrazole [(V) ; -W-V-:-N=N-, n=2, R1 = CH3]
0.04 g of 10% palladium on carbon moistened to 50% was added to a solution of 0.6x103 mol of compound MD 230300 in 20 ml of a mixture of methanol and methylene chloride (50-50) and a stream of hydrogen was supplied at normal pressure for 3 hours. After filtration and concentration, the resulting substance was recystallised from a mixture of ethyl ether and petroleum ether.
. Yield = 75%
. M.P. = 110C
2~3~
nd step: 2-methoxyethyl 5-[4-(4-pyridyl methyloxy) phenyl] 2H tetrazole hydrochloride ~I) 0.0567 mol of K2CO3 and 0.0227 mol of 4-chloromethyl pyridine were added to a solution of 0.0227 mol of the compound obtained in the preceding step in 100 ml acetonitrile. The reaction medium was reflux-heated for 48 hours, then concentrated and dissolved in a 0.1 N
solution of NaOH. After extraction with methylene chloride, the organic phase was dried on sodium sulphate and concentrated. The resulting base was dissolved in ethanol, followed by addition of hydrochloric ethanol.
The expected hydrochloride precipitated and was recrystallised from ethanol.
. Yield = 15%
. M.P. = 190C
. IR (KBr, ~ cm~l) : 2400, 2100, 2000, 1640, 1615, 1470, 1260, 1250, 1120 . 1H NMR (~ ppm, DMSOd6) : 3.2 (3H) ; 3.9 (2H) ; 4.9 (2H) ;
5.6 (2H) ; 7.2 (2H) ; 8 (4H) ; 8.9 (2H) ; 7.7 (lH
exchangeable).
The other derivatives (I) are obtained in the same manner, inter alia 2-(methoxyethyl) 5-[4-(3-pyridyl methyloxy)phenyl] 2H tetrazole [(I) ; -W-V-:-N=N-, n ~ 2, Rl = CH3, Ar = 3-pyridyl]. Code No: MD 230308.
. M.P. = 160C
. IR (KBr, ~ cm~1) : 2550, 2100, 1615, 1550, 1420, 1405, . 1H NMR (~ ppm, DMSOd6) : 3.3 (3H) ; 4 (2H) ; 4.95 (2H) ;
5.5 (2H) ; 7.3 (2H) ; 8 (3H) ; 8.5-8.9 (3H) ; 9.1 (lH
exch).
The formula ~I) derivatives and their pharmaceutically 2 ~ 7.~
acceptable acid addition salts have been s~udied in laboratory animals and have shown pharmacological activity, inter alia selective activity for inhibiting type B monoamine oxidase (MAO-B).
The activity of the compounds in inhibiting monoamine oxidase was shown by measurements of ~AO in vitro.
The MAO activity was determined, using a mitochondrial suspension of rat brain as a source of enzyme. The standard method of determination consists in pre-incubating the enzyme for 20 minutes, first in the absence and then in the presence of the inhibitors. The activities were determined by using serotonin (5 HT) and phenethylamine (PEA) as substrates of MAO-A and MAO-B, the reaction time being 40 minutes with 5 HT and 10 minutes with PEA. The method of operation used was that of P.C.
Baker: Dev. Biol. 14, 267, 1966.
The activities of a number of compounds according to the invention as against MA0-B and MA0-A are given via their inhibition constants Ki(MAo-B) and Ki(MAo-A) and are shown in the following Table.
TABLE
.
Compound testedKi (MAO-B) Ki (MAO-A) Code Number _ MD 2303001.56 x 10-8 M/L inactive MD 2303051.84 x 10-7 M/L inactive MD 2303065 x 10-9 M/L inactive MD 2303243.5 x 10-8 M/L inactive With regard to the toxicity of the formula (I) derivatives and their pharmaceutically acceptable acid addition salts, ~7 ?~
after oral administration to the mouse, no toxicity was observed for 24 hours, up to a dose of 1500 mg/kg.
The formula (I) derivatives and their pharmaceutically acceptable acid addition salts can be used for preparation of drugs for inhibiting type B monoamine oxidase. These drugs are of use in therapy, inter alia for treatment of neurological disturbances connected with pathological ageing, disturbances of memory, mood, schizophrenia, psychasthenia or psychic slowing-down due to ageing, certain forms of depression and Parkinson's disease.
The drugs can be administered to man or any warm-blooded animal in various pharmaceutical forms well known in the art, inter alia in the form of compounds formulated for oral, parenteral or rectal administration.
For oral administration, the compositions can be in the form of pills, dragees or capsules, prepared by conventional methods using known supports and excipients such as binders, fillers, lubricants and disintegrating agents; they may also take the form of solutions, syrup or suspensions.
For parenteral administration, the compositions according to the invention can be in the form of injectable solutions, suspensions or emulsions comprising a parenterally acceptable,oily or agueous liqui~ vehicle.
For rectal administration, the compositions can be in the form of suppositories containing conventional bases for suppositories.
The amount of the active principles, i.e. derivatives (I) and their pharmaceutically acceptable acid addition salts, 2~73a~l~
1~
which can be administered depends inter alia on the way of administration, the body weight of the patient and the therapeutic power of the compounds used. The amount orally administered may generally be up to 50 mg/kg of active principle per day (in one or two doses); the amounts for parenteral administration may be up to 5 mg/kg of active principle per day (in one or more doses);and the amounts for rectal administration may be up to 10 mg/kg of active principle per day (in one or two suppositories).
Claims (13)
1. Derivatives having the formula:
(I) in which R1 denotes C1-C4 alkyl and Ar is an aryl or heteroaryl group chosen from among the following:
(i) where R2 represents a hydrogen atom, one or two halogen atoms, a CN, NO2 or CF3 group, one, two or three C1-C4 alkyl or C1-C4 alkoxy groups or an amino group substituted by two C1-C4 alkyl groups, in which case the -W-V- chain represents -N = N- or and n = 2-6;
(ii) pyridyl, in which case the -W-V- chain represents -N=N-and n = 1-6, and acid addition salts of those derivatives (I) which are salt-forming.
(I) in which R1 denotes C1-C4 alkyl and Ar is an aryl or heteroaryl group chosen from among the following:
(i) where R2 represents a hydrogen atom, one or two halogen atoms, a CN, NO2 or CF3 group, one, two or three C1-C4 alkyl or C1-C4 alkoxy groups or an amino group substituted by two C1-C4 alkyl groups, in which case the -W-V- chain represents -N = N- or and n = 2-6;
(ii) pyridyl, in which case the -W-V- chain represents -N=N-and n = 1-6, and acid addition salts of those derivatives (I) which are salt-forming.
2. A derivative according to claim 1, characterised in that it is chosen from among the following:
- 5-(4-benzyloxy phenyl) 2-methoxyethyl 2H tetrazole, - 5-[4(4-chloro benzyloxy) phenyl] 2-methoxyethyl 2H
tetrazole, - 5[4-(3-chloro benzyloxy)phenyl] 2-methoxyethyl 2H
tetrazole.
- 5-(4-benzyloxy phenyl) 2-methoxyethyl 2H tetrazole, - 5-[4(4-chloro benzyloxy) phenyl] 2-methoxyethyl 2H
tetrazole, - 5[4-(3-chloro benzyloxy)phenyl] 2-methoxyethyl 2H
tetrazole.
3. 5-[4-(4-chloro benzyloxy) phenyl] 3-methoxyethyl 3H
1,3,4-oxadiazol-2-one.
1,3,4-oxadiazol-2-one.
4. A derivative and salt according to claim 1, characterised in that they are chosen from among the following:
- 5-[4-(4-pyridyl methyloxy)phenyl] 2H tetrazole and its acid addition salts, - 5-[4-(3-pyridyl methyloxy)phenyl] 2H tetrazole and its acid addition salts.
- 5-[4-(4-pyridyl methyloxy)phenyl] 2H tetrazole and its acid addition salts, - 5-[4-(3-pyridyl methyloxy)phenyl] 2H tetrazole and its acid addition salts.
5. A pharmaceutical composition characterised in that it comprises a formula (I) derivative according to any of claims 1 to 4 or a pharmaceutically acceptable acid addition salt of a salt-forming derivative of formula (I) and a pharmaceutically acceptable excipient.
6. Use of the derivatives and salts according to any of claims 1 to 4 for manufacturing a drug for inhibiting type B monoamine oxidase.
7. A method of preparing formula (I) derivatives and salts according to any of claims 1 to 4, characterised in that it comprises:
(a) condensation of compounds having the formula:
X - (CH2)n - OR1 (II) where n = 2-6, R1 = C1-C4 alkyl and X represents a good leaving group, on to the respective compounds having the formula (III) where -W-V- represents -N=N- or and R2 have the same meaning as in formula (I), in the presence of a base, (b) condensation of compounds having the formula:
Ar - CH2 - X (IV) where Ar has the same meaning as in formula (I) and X has the same meaning as in formula (II), on to the respective compounds having the formula:
(V) where R1 and n have the same meaning as in formula (I) and -W-V- represents either -N=N- or when Ar in formula (IV) is a phenyl ring substituted by R2, the latter having the same meaning as in formula (I), or -N=N- when Ar in formula (IV) represents pyridyl, in the presence of a base, or (c) condensation of compounds having the formula:
(VI) where n, R1 and R2 have the same meaning as in formula (I), with phosgene.
(a) condensation of compounds having the formula:
X - (CH2)n - OR1 (II) where n = 2-6, R1 = C1-C4 alkyl and X represents a good leaving group, on to the respective compounds having the formula (III) where -W-V- represents -N=N- or and R2 have the same meaning as in formula (I), in the presence of a base, (b) condensation of compounds having the formula:
Ar - CH2 - X (IV) where Ar has the same meaning as in formula (I) and X has the same meaning as in formula (II), on to the respective compounds having the formula:
(V) where R1 and n have the same meaning as in formula (I) and -W-V- represents either -N=N- or when Ar in formula (IV) is a phenyl ring substituted by R2, the latter having the same meaning as in formula (I), or -N=N- when Ar in formula (IV) represents pyridyl, in the presence of a base, or (c) condensation of compounds having the formula:
(VI) where n, R1 and R2 have the same meaning as in formula (I), with phosgene.
8. A method according to claim 7, characterised in that X in formula (II) represents a halogen atom or a mesyloxy or tosyloxy group and the base used in condensation a) is a metal hydride.
9. A method according to claim 7, characterised in that the base used in condensation b) is K2CO3 or a metal hydride.
10. Compounds having the formula:
(III) in which -W-V- represents -N=N- or and R2 represents a hydrogen atom, one or two halogen atoms, a CN, NO2 or CF3 group, one, two or three C1-C4 alkyl groups or C1-C4 alkoxy groups or an amino group substituted by two C1-C4 alkyl groups.
(III) in which -W-V- represents -N=N- or and R2 represents a hydrogen atom, one or two halogen atoms, a CN, NO2 or CF3 group, one, two or three C1-C4 alkyl groups or C1-C4 alkoxy groups or an amino group substituted by two C1-C4 alkyl groups.
11. Compounds having the formula:
(V) where R1 = C1-C4 alkyl and n = 1-6
(V) where R1 = C1-C4 alkyl and n = 1-6
12. Compounds having the formula:
(VI) in which n = 2-6, R1 = C1-C4 alkyl and R2 represents a hydrogen atom, one or two halogen atoms, a CN, NO2 or CF3 group, one, two or three C1-C4 alkyl groups or C1-C4 alkoxy groups or an amino group substituted by two C1-C4 alkyl groups.
(VI) in which n = 2-6, R1 = C1-C4 alkyl and R2 represents a hydrogen atom, one or two halogen atoms, a CN, NO2 or CF3 group, one, two or three C1-C4 alkyl groups or C1-C4 alkoxy groups or an amino group substituted by two C1-C4 alkyl groups.
13. Compounds having the formula:
(IX) in which R2 represents a hydrogen atom, one or two halogen atoms, a CN, NO2 or CF3 group, one, two or three C1-C4 alkyl groups or C1-C4 alkoxy groups, or an amino group substituted by two C1-C4 alkyl groups.
(IX) in which R2 represents a hydrogen atom, one or two halogen atoms, a CN, NO2 or CF3 group, one, two or three C1-C4 alkyl groups or C1-C4 alkoxy groups, or an amino group substituted by two C1-C4 alkyl groups.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8915499A FR2655044B1 (en) | 1989-11-24 | 1989-11-24 | DERIVATIVES OF (HETERO) ARYLMETHYLOXY-4 PHENYL TETRAZOLE AND OXADIAZOLE, THEIR PREPARATION PROCESS AND THEIR THERAPEUTIC APPLICATION. |
| FR89/15499 | 1989-11-24 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2073064A1 true CA2073064A1 (en) | 1991-05-25 |
Family
ID=9387765
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002073064A Abandoned CA2073064A1 (en) | 1989-11-24 | 1990-11-23 | (hetero) 4-arylmethoxy phenyl diazole derivatives, method for preparing same and their therapeutical applications |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0502110B1 (en) |
| JP (1) | JPH05508620A (en) |
| AT (1) | ATE117997T1 (en) |
| CA (1) | CA2073064A1 (en) |
| DE (1) | DE69016672T2 (en) |
| FR (1) | FR2655044B1 (en) |
| WO (1) | WO1991008201A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5744500A (en) | 1990-01-03 | 1998-04-28 | Teva Pharmaceutical Industries, Ltd. | Use of R-enantiomer of N-propargyl-1-aminoindan, salts, and compositions thereof |
| FR2712886B1 (en) * | 1993-11-26 | 1996-01-05 | Synthelabo | 1,3,4-Oxadiazol-2 (3H) -one derivatives, their preparation and their therapeutic use. |
| FR2715155B1 (en) * | 1994-01-19 | 1996-07-26 | Mayoly Spindler | Monoamine oxidase B inhibitors and methods of preparing them. |
| FR2766485B1 (en) * | 1997-07-23 | 2002-05-24 | Synthelabo | 2,4-DIHYDRO-3H-1,2,4-TRIAZOL-3-ONE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR8005M (en) * | 1967-05-24 | 1970-07-27 | ||
| US3597429A (en) * | 1968-02-15 | 1971-08-03 | Miles Lab | Derivatives of tetrazolyl alkanoic acids |
| US3865570A (en) * | 1972-02-28 | 1975-02-11 | Ici Ltd | Plant growth stunting process |
| JPH021482A (en) * | 1988-02-25 | 1990-01-05 | Toshiba Corp | Heterocyclic compound and liquid crystal element using liquid crystal material containing the same compound |
| FR2631827B1 (en) * | 1988-05-27 | 1992-03-27 | Delalande Sa | NOVEL (HETERO) ARYL-5 TETRAZOLE DERIVATIVES, THEIR PREPARATION PROCESS AND THEIR THERAPEUTIC APPLICATION |
-
1989
- 1989-11-24 FR FR8915499A patent/FR2655044B1/en not_active Expired - Fee Related
-
1990
- 1990-11-23 WO PCT/FR1990/000847 patent/WO1991008201A1/en active IP Right Grant
- 1990-11-23 EP EP91900836A patent/EP0502110B1/en not_active Expired - Lifetime
- 1990-11-23 AT AT91900836T patent/ATE117997T1/en active
- 1990-11-23 DE DE69016672T patent/DE69016672T2/en not_active Expired - Fee Related
- 1990-11-23 JP JP91501280A patent/JPH05508620A/en active Pending
- 1990-11-23 CA CA002073064A patent/CA2073064A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| WO1991008201A1 (en) | 1991-06-13 |
| FR2655044A1 (en) | 1991-05-31 |
| JPH05508620A (en) | 1993-12-02 |
| ATE117997T1 (en) | 1995-02-15 |
| FR2655044B1 (en) | 1995-03-03 |
| DE69016672T2 (en) | 1995-09-07 |
| EP0502110B1 (en) | 1995-02-01 |
| EP0502110A1 (en) | 1992-09-09 |
| DE69016672D1 (en) | 1995-03-16 |
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