5-Aryl-3H-1,2,4-triazol-3-ones and their use as anticonvulsants

Abstract: This invention relates to 5-aryl-3H-1,2,4-triazol­ -3-ones and to their use as anticonvulsants for treatment of seizure disorders.

Description: This invention relates to the use of 5-aryl-3H-1,2,4-triazol-3-ones for preparing a medicament for treatment of seizure disorders. M.Y. Mhasalkar, et al., (J. Med. Chem. 14, 260-262, 1971) teach that a compound of formula I has hypoglycemic activity. U.S.-A-3,514,466; BE-A-621,842 and DE-A-1,126,882 teach that various compounds of formula I have sedative and hypnotic activity. ZA 65/1537 and NL 6504121 teach that some compounds of formula I have anti-inflammatory, antipyretic and analgetic activity. DD-A-160,447; DD-A-153,953 and BE-A-894,856 teach that some compounds of formula I are herbicides. U.S.-A-4,414,221 teaches that some compounds of formula I are insecticides and acaricides. JP 50-63119 teaches that some compounds of formula I have anticoccidial activity. More specifically this invention relates to the use of a compound of the formula: wherein Ar represents phenyl, naphthyl or an aromatic heterocyclic moiety, selected from 2-, 3- or 4-pyridyl, 2- or 3-furyl, 2- or 3-thienyl, 2- or 3-pyrrolyl, N-(C₁₋₆ alkyl)-pyrrolyl, 6-isoquinolyl, 6-quinolyl and 3-quinolyl, R₁ is hydrogen or C₁₋₆ alkyl, R₂ is C₁₋₆ alkyl, R is C₁₋₆ alkyl, C₁₋₆ alkoxy, hydroxy, halogeno, or trifluoromethyl, and n is zero, 1 or 2, or R n -(Ar) is methylenedioxyphenyl, and m is zero, 1 or 2, and the pharmaceutically acceptable salts of the compounds wherein Ar is a nitrogen-containing heterocyclic moiety for preparing a medicament for treating seizure disorders. For R, preferably halogeno represents chloro or fluoro, and methyl and ethyl represent the preferred C₁-C₆ alkyl moieties, although all the straight, branched and cyclic manifestations thereof such as n-propyl, cyclopentyl, cyclohexyl and cyclopropyl are herein included. C 1- C₆ alkoxy radicals include ethers having alkyl moieties paralleling the C₁₋₆ alkyl group. R₁ and R₂ are preferably methyl or ethyl, although any straight or branched C₁₋₆ alkyl group may be used. When "Ar" is phenyl, preferably n is one, representing a mono-substituted phenyl moiety with the R-substitutent being a group located at any of the ortho, meta or para positions, although the ortho- and para-substituted compounds are preferred. When Ar is disubstituted (i.e., n is 2), the 2,3-; 2,4-; 2,5-; 2,6-; 3,4-; and 3,5- positions are contemplated. The tautomeric forms are included for each of the compounds embraced within formula I. Except when Ar is phenyl,it is preferred that m is zero. When Ar is phenyl it is preferred that m is zero or one. When "Ar" of formula I represents a heterocyclic moiety such heterocyclic moieties as 2-, 3- or 4-pyridyl, 2- or 3-furyl, 2- or 3-thienyl, 2- or 3-pyrrolyl, N-(C₁₋₆ alkyl)-pyrrolyl, 6-isoquinolyl, 6-quinolyl and 3-quinolyl are contemplated. Preferred is 4-pyridyl, with or without an R substituent. State of the art salts formed with the heterocyclic moieties are generally employed, with the hydrochloride being one of convenience and general applicability: such salts being formed by standard techniques well known in the art. When "Ar" represents naphthyl, the preferred isomer is 2-naphthyl with the R moiety being attached thereto at any of the available positions, although positions 5-, 6-, 7- or 8- are preferred for either the mono- or di-R-substituted naphthyl compounds of formula I. Another object of the present invention is represented by a compound of formula I wherein: Ar represents phenyl, naphthyl, or an aromatic heterocyclic moiety selected from 2-, 3- or 4-pyridyl, 2- or 3-furyl, 2- or 3-thienyl, 2- or 3-pyrrolyl, N-(C₁₋₆ alkyl)-pyrrolyl, 6-isoquinolyl, 6-quinolyl and 3-quinolyl, R₁ is hydrogen or C₁₋₆ alkyl, R₂ is C₁₋₆ alkyl, R is C₁₋₆ alkyl, C₁₋₆ alkoxy, hydroxy, halogeno, or trifluoromethyl, and n is 1 or 2, or R n -(Ar) is methylenedioxyphenyl, and m is zero, 1 or 2, with the proviso that when R n -(Ar)-(CH₂) m -represents 4-chlorophenyl and R₂ represents ethyl, R₁ cannot represent hydrogen, and when R n -(Ar)-(CH₂) m -represents phenyl and R₁ represents methyl, R₂ cannot represent methyl or ethyl, and the pharmaceutically acceptable salts of the compounds wherein Ar is a nitrogen-containing heterocyclic moiety for use as a medicament. A further object of the present invention is represented by the compounds of formula I wherein R n -(Ar)-(CH₂) m - represents 4-chlorophenyl, R₁ represents methyl and R₂ represents ethyl or wherein R n -(Ar)-(CH₂) m - represents 2-chlorophenyl, R₁ represents hydrogen and R₂ represents methyl. The compounds of Formula I may readily be prepared using processes and techniques analogously known in the art, for example in the method of S. Kuboda and M. Uda, Chem. Pharm. Bull. 21 , 1342 (1979), as seen by the following reaction scheme: wherein R n -(Ar)-(CH₂) m -, R₁ and R₂ are as defined in formula I, and X is a suitable leaving group. The preparation of the 1-aroylsemicarbazides (IV) is readily effected by reacting an aroyl hydrazide (II) with an R₂-substituted isocyanate (III) by contacting the reactants together in a suitable aprotic solvent, preferably one in which the hydrazide reactant is soluble, e.g., tetranydrofuran (THF),CHCl₃, CH₂Cl₂, benzene, toluene, Et₂O and the like. The reaction is quite rapid and may be carried out at 0°C to about room temperature and, although the reaction proceeds rapidly, the mixture may be left for 24 hours without any significant decrease in yield. The required hydrazides and isocyanates are readily available but may be prepared by known techniques quite obvious to one of ordinary skill in the art. The desired 5-aryl-2,4-dihydro-3H-1,2,4-triazol-3-ones (Ia) may be prepared by reacting the semicarbazides (IV) with a base, preferably an aqueous alkali metal hydroxide (e.g., NaOH, KOH) at about 50-120°C, although reflux temperatures are preferred. Normal reaction time is about 7 hours, although 4-24 hours may be needed depending on the temperature of the mixture. The desired 2,4-disubstituted-2,4-dihydro-3H-1,2,4-triazol-3-ones (Ib) may be prepared by reacting the 4-substituted-2,4-dihydro-3H-1,2,4-triazol-3-ones (Ia) with an appropriate R₁X reactant wherein X is a suitable leaving group, e.g., Cl, Br, OSO₂CF₃ and the like. Preferably the reaction takes place in a solution of an aqueous alkali metal hydroxide, (e.g., KOH, NaOH) although more reactive bases (e.g., NaH, KH, LDA) may be used if the reaction is effected under aprotic dry conditions. The reaction preferably takes place at room temperature over periods of about 18 hours to two weeks. The following specific examples are given to illustrate the preparation of the compounds Preparation of Intermediate 1-Aroyl-4-substituted semicarbazides EXAMPLE 1 1-(4-Chlorobenzoyl)-4-ethylsemicarbazide A stirred suspension of 4-chlorobenzoic acid, hydrazide (17.1 g, 1.00 x 10⁻¹ mole), and THF (425 ml) was warmed until homogeneous, at which time ethyl isocyanate (8.7 ml, 1.1 x 10⁻¹ mole) was added via syringe. A precipitate soon formed. After stirring overnight the reaction was diluted with Et₂O and the precipitate was collected by filtration affording a colorless powder: 23.7 g (98%). Crystallization from ethanol gave a colorless solid: 21.4 g (88%), mp 237-239°. EXAMPLE 2 1-(4-Pyridoyl)-4-methylsemicarbazide When, in the procedure of Example 1, isonicotinic acid is substituted for 4-chlorobenzoic acid, the title compound is obtained. Preparation of 5-Aryl-4-substituted-2,4-dihydro-3H-1,2,4-triazol-3-ones EXAMPLE 3 5-(4-Chlorophenyl)-2,4-dihydro-4-ethyl-3H-1,2,4-triazol-3-one 1-(4-chlorobenzoyl)-4-ethylsemicarbazide (23.7 g, 9.81 x 10⁻² mole) and 1 molar aqueous NaOH (118 ml, 1.18 x 10⁻¹ mole) were stirred and warmed to reflux. After refluxing 23 hours, heating was discontinued and the reaction was acidified by the dropwise addition of 1 molar aqueous hydrochloric acid (130 ml, 1.30 x 10⁻¹ mole). A colorless solid formed as the reaction was acidified and, after cooling in an ice bath, this was collected by filtration. Crystallization from isopropanol gave colorless spars: 18.2 g (83%), mp 188-189°. EXAMPLE 4 2,4-Dihydro-4-methyl-5-(4-pyridinyl)-3H-1,2,4-triazol-3-one When, in the procedure of Example 3, 1-(4-pyridoyl)-4-methylsemicarbazide is substituted for 1-(4-chlorobenzoyl)-4-ethylsemicarbazide, the title compound is obtained. Mp 249-251°C. Preparation of 5-Aryl-2,4-dihydro-2,4-disubstituted-3H-1,2,4-triazol-3-ones EXAMPLE 5 5-(4-Chlorophenyl)-2,4-dihydro-4-ethyl-2-methyl-3H-1,2,4-triazol-3-one To a stirred, room temperature solution of 5-(4-chlorophenyl)-2,4-dihydro-4-ethyl-3H-1,2,4-triazol-3-one (6.00 g, 2.68 x 10⁻² mole) and 1 molar aqueous NaOH (30.0 ml, 3.00 x 10⁻² mole) was added a solution of methyl iodide (2.5 ml, 4.0 x 10⁻² mole) and ethanol (10 ml). After stirring overnight at room temperature, the reaction mixture was transferred to a separatory funnel where it was extracted three times with EtOAc. The EtOAc extracts were combined, washed with saturated aqueous NaCl, and dried over Na₂SO₄. The drying agent was removed by filtration and the filtrate was evaporated at reduced pressure leaving an oil which slowly solidified. Chromatography and crystallization from cyclohexane gave small colorless needles: 3.4 g (53%), mp 73-75°. In a similar manner the following compounds also may be prepared. A r R₁ R₂ mp (°C) C₆H₅ H CH₃ 177-178 C₆H₅ CH₃ CH₃ 140-141 C₆H₅ C₂H₅ CH₃ 87-89 C₆H₅ H C₂H₅ 163-165 C₆H₅ CH₃ C₂H₅ oil 2-ClC₆H₄ H CH₃ 168-170 2-ClC₆H₄ CH₃ CH₃ 61-63 4-ClC₆H₄ H CH₃ 213-215 4-ClC₆H₄ CH₃ CH₃ 126-128 4-ClC₆H₄ C₂H₅ CH₃ 79-81 4-ClC₆H₄ H C₂H₅ 188-189 4-ClC₆H₄ CH₃ C₂H₅ 73-75 4-ClC₆H₄ C₂H₅ C₂H₅ 62-64 4-ClC₆H₄ n-C₃H₇ C₂H₅ oil 2-FC₆H₄ H CH₃ 189-191 2-FC₆H₄ CH₃ CH₃ 69-71 4-FC₆H₄ H CH₃ 216-218 4-FC₆H₄ CH₃ CH₃ 104-106 3,4-Cl₂C₆H₃ H CH₃ 170-172 3,4-Cl₂C₆H₃ CH₃ CH₃ 107-109 4-CH₃C₆H₄ H CH₃ 206-208 4-CH₃C₆H₄ CH₃ CH₃ 92-94 4-CH₃O-3-(n-C₄H₉O)C₆H₃ H CH₃ 96-98 4-CH₃O-3-(n-C₄H₉O)C₆H₃ CH₃ CH₃ 112-114 4-CH₃O-3-(cyclo-C₅H₉O)C₆H₃ H CH₃ 184-186 4-CH₃O-3-(cyclo-C₅H₉O)C₆H₃ CH₃ CH₃ 153-155 The pharmacological profile of these compounds and their relative potencies may readily be demonstrated through standard laboratory tests indicative of compounds known to be useful as anticonvulsants suitable for use in the treatment of seizure disorders, particularly idiopathic epilepsy. For example, in the evaluation and characterization of the anticonvulsant and GABAergic activity and to observe a suitable pharmacological profile of the compounds of this invention, it is convenient to employ such tests as the antagonism of 3-mercaptopropionic acid-induced convulsions, an assay performed on mice wherein wild running fits or generalized seizures are induced by 3-mercaptopropionic acid; the antagonism of strychnine-induced seizures in mice; the antagonism to maximal electroshock, an assay performed in mice wherein seizures are caused by the administration of electroshock; and the antagonism to pentylenetetrazol, an assay to measure the prevention of seizures caused by administration of pentylenetetrazol. Compounds which inhibit pentylenetetrazol-induced seizures in mice are known to possess anticonvulsant and anti-anxiety effects. An appropriate dose of test compound is administered to groups of mice and, at a selected time thereafter, pentylenetetrazol, prepared as a solution in distilled water such that 10 ml/kg delivers a dose of 60 mg/kg, is administered by rapid intravenous injection. Absence of clonic convulsions for 2 minutes after pentylenetetrazol is considered significant protection. Prevention of tonic extensor convulsions is also reported and usually occurs at a dose lower than that required to block clonic convulsions. Inhibition of clonic seizures induced by this dose of pentylenetetrazol is evidence of potential anticonvulsant/anti-anxiety activity. Against seizures caused by pentylenetetrazol, 5-(4-chlorophenyl)-2,4-dihydro-4-ethyl-2-methyl-3H-1,2,4-triazol-3-one has an ED₅₀ of 16.5 mg/kg. Based upon standard laboratory methodology (including comparative tests with known anticonvulsants), the compounds of this invention will exert anticonvulsant activity useful in the treatment of idiopathic epilepsy at oral dosage levels of about 0.25 to 25 mg/kg of body weight per day. Of course the degree of severity of the disease, age of the patient and other factors normally considered by the attending diagnostician will influence the individual regimen for each patient. In general, the parenterally administered doses are about 1/4 to 1/2 that of the orally administered dose. For oral administration the compounds can be formulated into solid or liquid preparations such as capsules, pills, tablets, troches, powders, solutions, suspensions or emulsions. The solid unit dosage forms can be a capsule which can be of the ordinary gelatin type containing, for example, lubricants and inert fillers such as lactose, sucrose or cornstarch. In another embodiment the compounds of general formula I can be tableted with conventional tablet bases such as lactose, sucrose and cornstarch, in combination with binders such as acacia, cornstarch or gelatin, disintegrating agents such as potato starch or alginic acid, and a lubricant such as stearic acid or magnesium stearate. For parenteral administration, the compounds may be administered as injectable dosages of a solution or suspension of the compound in a physiologically acceptable diluent with a pharmaceutical carrier which can be a sterile liquid such as water, alcohol, oils and other acceptable organic solvents, with or without the addition of a surfactant and other pharmaceutically acceptable adjuvants. Illustrative of oils which can be employed in these preparations are those of petroleum, animal, vegetable or synthetic origin, for example, peanut oil, soybean oil and mineral oil. In general, water, saline, aqueous dextrose and related sugar solutions, ethanol, glycols such as propylene glycol or polyethylene glycol, or 2-pyrrolidone are preferred liquid carriers, particularly for injectable solutions. The compounds can be administered in the form of a depot injection or implant preparation which may be formulated in such a manner as to permit a sustained release of the active ingredient. The active ingredient can be compressed into pellets or small cylinders and implanted subcutaneously or intramuscularly as depot injections or implants. Implants may employ inert materials such as biodegradable polymers or synthetic silicones, for example, Silastic®, a silicone rubber manufactured by the Dow-Corning Corporation. As is true for most classes of compounds generally suitable as therapeutic agents, certain subgeneric groups and specific members of that class, in the light of their overall biological profile, are preferred. In this instance those compounds wherein m is zero are preferred, with those wherein m is one being next preferred. The preferred Ar moiety is phenyl. The preferred R substituent is chloro, with the chloro being at the 2- or 4-positions of the aromatic moiety being preferred. It is preferred to have an alkyl substituent at both of the R₁ and R₂ positions with methyl and ethyl being the preferred groups. Particularly preferred compounds are 5-(4-chlorophenyl)-2,4-dihydro-4-ethyl-2-methyl-3H-1,2,4-triazol-3-one 5-(4-chlorophenyl)-2,4-diethyl-2,4-dihydro-3H-1,2,4-triazol-3-one 5-(2-chlorophenyl)-2,4-dihydro-4-methyl-3H-1,2,4-triazol-3-one 5-(2-chlorophenyl)-2,4-dihydro-2,4-dimethyl-3H-1,2,4-triazol-3-one. In the present description and claims the term therapeutic "treatment" includes any kind of treatment such as prophylaxis and cure.

Claims: Claims for the following Contracting States : AT, BE, CH, DE, FR, GB, GR, IT, LI, LU, NL, SE Use of a compound of the formula wherein Ar represents phenyl, naphthyl, or an aromatic heterocyclic moiety selected from 2-, 3- or 4-pyridyl, 2- or 3-furyl, 2- or 3-thienyl, 2- or 3-pyrrolyl, N-(C₁₋₆ alkyl)-pyrrolyl, 6-isoquinolyl, 6-quinolyl and 3-quinolyl, R₁ is hydrogen or C₁₋₆ alkyl, R₂ is C₁₋₆ alkyl, R is C₁₋₆ alkyl, C₁₋₆ alkoxy, hydroxy, halogeno, or trifluoromethyl, and n is zero, 1 or 2, or R n -(Ar) is methylenedioxyphenyl, and m is zero, 1 or 2, and the pharmaceutically acceptable salts of the compounds wherein Ar is a nitrogen-containing heterocyclic moiety, for preparing a medicament for treating seizure disorders. Use of a compound of claim 1 wherein Ar in said compound represents phenyl. Use of a compound of claim 1 or 2 wherein m in said compound represents zero. Use of a compound of claim 1, 2 or 3 wherein R₁ in said compound represents C₁₋₆ alkyl. Use of a compound of claim 1, 2 or 3 wherein R₁ in said compound represents methyl or ethyl. Use of a compound of claim 1 wherein Ar in said compound is phenyl, m is zero and R is halogeno. Use of a compound of claim 6 wherein R in said compound is chloro. Use of a compound of claim 1 wherein R n -(Ar)-(CH₂) m -in said compound represents 4-chlorophenyl, R₁ is methyl and R₂ is ethyl. Use of a compound of claim 1 wherein R n -(Ar)-(CH₂) m -in said compound represents 4-chlorophenyl, R₁ is hydrogen and R₂ is ethyl. Use of a compound of claim 1 wherein R n -(Ar)-(CH₂) m -in said compound represents 2-chlorophenyl, R₁ is hydrogen and R₂ is methyl. A compound of the formula wherein Ar represents phenyl, naphthyl, or an aromatic heterocyclic moiety selected from 2-, 3- or 4-pyridyl, 2- or 3-furyl, 2- or 3-thienyl, 2- or 3-pyrrolyl, N-(C₁₋₆ alkyl)-pyrrolyl, 6-isoquinolyl, 6-quinolyl and 3-quinolyl, R₁ is hydrogen or C₁₋₆ alkyl, R₂ is C₁₋₆ alkyl, R is C₁₋₆ alkyl, C₁₋₆ alkoxy, hydroxy, halogeno, or trifluoromethyl, and n is 1 or 2, or R n -(Ar) is methylenedioxyphenyl, and m is zero, 1 or 2, with the proviso that when R n -(Ar)-(CH₂) m -represents 4-chlorophenyl and R₂ represents ethyl, R₁ cannot represent hydrogen, and when R n -(Ar)-(CH₂) m -represents phenyl and R₁ represents methyl, R₂ cannot represent methyl or ethyl, and the pharmaceutically acceptable salts of the compounds wherein Ar is a nitrogen-containing heterocyclic moiety for use as a medicament. A compound of claim 11 wherein Ar is phenyl. A compound of claim 11 or 12 wherein m is zero. A compound of claim 11, 12, or 13 wherein R₂ is methyl or ethyl. A compound of claim 11 wherein Ar is phenyl, m is zero and R is halogeno. A compound of claim 15 wherein R is chloro. A compound of claim 11 wherein R n -(Ar)-(CH₂) m -represents 2-chlorophenyl, R₁ is hydrogen and R₂ is methyl. A compound of claim 11 wherein R n -(Ar)-(CH₂) m -represents 4-chlorophenyl, R₁ is methyl and R₂ is ethyl. A compound of the formula I wherein R n -(Ar)-(CH₂) m -represents 4-chlorophenyl, R₁ is methyl and R₂ is ethyl. A compound of the formula I wherein R n -(Ar)-(CH₂) m -represents 2-chlorophenyl, R₁ is hydrogen and R₂ is methyl. A pharmaceutical formulation containing a compound of any one of claims 11 to 20 in admixture with a pharmaceutically acceptable carrier. A process for preparing a compound of the formula wherein R n -(Ar)-(CH₂) m - represents 4-chlorophenyl, R₁ represents methyl and R₂ represents ethyl, which comprises reacting a semicarbazide of formula IV R n -(Ar)-(CH₂) m CONHNHCONHR₂ wherein R n -(Ar)-(CH₂) m -is as defined above, with a base at about 50°C-120°C; and transforming the obtained intermediate wherein R₁ represents hydrogen into the compound of formula I by reacting it with a compound of formula R₁X wherein X is a good leaving group and R₁ is methyl. A process for preparing a compound of the formula wherein R n -(Ar)-(CH₂) m - represents 2-chlorophenyl, R₁ represents hydrogen and R₂ represents methyl, which comprises reacting a semicarbazide of formula IV R n -(Ar)-(CH₂) m CONHNHCONHR₂ wherein R n -(Ar)-(CH₂) m -is as defined above, with a base at about 50°C-120°C. Claims for the following Contracting State : ES A process for preparing a compound of the formula wherein R n -(Ar)-(CH₂) m - represents 4-chlorophenyl, R₁ represents methyl and R₂ represents ethyl, which comprises reacting a semicarbazide of formula IV R n -(Ar)-(CH₂) m CONHNHCONHR₂ wherein R n -(Ar)-(CH₂) m -is as defined above, with a base at about 50°C-120°C; and transforming the obtained intermediate wherein R₁ represents hydrogen into the compound of formula I by reacting it with a compound of formula R₁X wherein X is a good leaving group and R₁ is methyl. A process for preparing a compound of the formula wherein R n -(Ar)-(CH₂) m - represents 2-chlorophenyl, R₁ represents hydrogen and R₂ represents methyl, which comprises reacting a semicarbazide of formula IV R n -(Ar)-(CH₂) m CONHNHCONHR₂ wherein R n -(Ar)-(CH₂) m -is as defined above, with a base at about 50°C-120°C.

Inventors: KANE JOHN M, MILLER FRANCIS P, KANE, JOHN M., MILLER, FRANCIS P.
Applicants: MERRELL DOW PHARMA, MERRELL DOW PHARMACEUTICALS INC.
Application year: 1987
Main classification: A61K31
IPC codes: C07D401, C07D249, A61K31, A61P25