TRIAZOLE DERIVATIVES AS CYCLOOXYGENASE (COX) INHIBITORS

Description

Technical Field

[0001] This invention relates to triazole compounds having pharmacological activity, to a process for their production and to a pharmaceutical composition containing the same.

Background Art

[0002] The presence of two cyclooxygenase isoenzymes, cyclooxygenase-I (COX-I) and cyclooxygenase-II (COX-II) is known (Proc. Nat. Acad. Sci. USA 88, 2692-2696 (1991)).

[0003] Traditional non steroidal anti-inflammatory compounds (NSAIDs) have inhibiting activities of both COX-I and COX-II (J. Biol. Chem., 268, 6610-6614 (1993), etc). The therapeutic use thereof involves undesired effects on the gastrointestinal tract, such as bleeding , erosions, gastric and intestinal ulcers, etc.

[0004] It was reported that selective inhibition of COX-II shows anti-inflammatory and analgesic activities comparable with conventional NSAIDs but with a lower incidence of some gastrointestinal undesired effects (Pro. Nat. Acad. Sci. USA, 91, 3228-3232(1994)). Accordingly, various selective COX-II inhibitors have been prepared. However, it was reported that those "selective COX-II inhibitor" show some side-effects on kidney and/or insufficient efficacy on acute pains.

[0005] Further, some compounds such as SC-560, mofezolac, etc, which have certain selective inhibiting activity against COX-I. WO98/57910 shows some compounds having such activity. However, their selectivity of inhibiting COX -I does not seem to be enough to use them as a clinically acceptable and satisfactory analgesic agent due to their gastrointestinal disorders.

[0006] WO02/055502 shows some pyridine derivatives having cyclooxygenase inhibiting activity, particularly cyclooxygenase-I inhibiting activity. And WO99/51580 shows some triazole derivatives having an inhibiting activity of cytokine production.

[0007] The 5-aryl-1H-1,2,4-triazole compounds which are described in EP -A- 1 099 695 display a strong inhibition of COX-II with a much weaker effect on COX-I.

[0008] The triazole derivatives described in EP -A- 0 155 486 contain a thioalkyl substituent in the 3-position.

[0009] The triazole derivatives described in EP -A- 0 162 217 contain a substituent in the 3-position which is connected through a carbon atom.

[0010] The triazole derivatives described in EP -A- 0 157 259 contain a substituent in the 3-position which is connected to the heterocycle through a sulphur bridge.

[0011] 1H-1,2,4-Triazole derivatives with a trifluoromethyl group in the 3-position are described by Czollner et al. (Monatshefte für Chemie 1988; 119: 349-353).

[0012] The triazole derivatives which are described in WO 00/10563 do not display a substituent in the 3-posuition which is connection through an oxygen bridge.

[0013] The triazole derivatives of EP -A- 0 051 084 have an optional methyl substitution in the 3-position.

Disclosure of Invention

[0014] This invention relates to triazole compounds, which have pharmaceutical activity such as cyclooxygenase (hereinafter described as COX) inhibiting activity, to a process for their production, to a pharmaceutical composition containing the same and to a use thereof.

[0015] Accordingly, one object of this invention is to provide the triazole compounds, which have a COX inhibiting activity.

[0016] Another object of this invention is to provide a process for production of the triazole compounds.

[0017] A further object of this invention is to provide a pharmaceutical composition containing, as active ingredients, the triazole compounds.

[0018] Still further object of this invention is to provide a use of the triazole compounds for manufacturing a medicament for treating or preventing various diseases.

[0019] The new triazole compounds of this invention can be represented by the following general formula (I):

wherein R¹ is lower alkyl which is optionally substituted with halogen,

R² is lower alkoxy;

R³ is lower alkoxy;

X is O;

Y and Z are each CH; and

m is 1;

or salts thereof.

[0020] The object compound (I) of the present invention can be prepared by the following processes.

[0021] In the above processes, R¹, R², R³, X, Y, Z and m are each as defined above, and

X¹ is O, and

L¹ and L³ are each a leaving group.

[0022] The compounds of formula (I), or (Ib) may contain one or more asymmetric centers and thus they can exist as enantiomers or diastereoisomers. This invention includes both mixtures and separate individual isomers.

[0023] The compounds of the formula (I) or (Ib) may also exist in tautomeric forms and the invention includes both mixtures and separate individual tautomers.

[0024] The compounds of the formula (I) or (Ib) and its salts can be in a form of a solvate, which is included within the scope of the present invention. The solvate preferably includes a hydrate and an ethanolate.

[0025] Also included in the scope of invention are radiolabelled derivatives of compounds of formula (I) or (Ib) which are suitable for biological studies.

[0026] In the above and subsequent description of the present specification, suitable examples of the various definitions to be included within the scope of the invention are explained in detail in the following.

[0027] The term "lower" is intended to mean a group having 1 to 6 carbon atom(s), unless otherwise provided.

[0028] Suitable "lower alkyl", and lower alkyl moiety in the term "lower alkoxy" may be a straight or branched one, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl or the like, in which preferable one is methyl or dimethyl.

[0029] Suitable lower alkoxy is methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, hexoxy, or the like, in which preferable one is methoxy.

[0030] Suitable "halogen" may be fluoro, chloro, bromo or iodo or the like, which preferable one is fluoro.

[0031] Suitable "lower alkyl substituted with halogen" may be lower alkyl substituted with one or more halogen atoms(s), such as fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, bromomethyl, dibromomethyl, tribromomethyl, fluoroethyl, chloroethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 2,2,3,3,3-pentafluoroethyl, fluoropropyl, fluorobutyl, fluorohexyl, or the like. And its preferable one is halogen-substituted C1-C2 alkyl. More preferable one is fluorine-substituted methyl, and most preferable one is trifluoromethyl or 2,2,2-trifluoroethyl.

[0032] Suitable leaving group may be a halogen, such as chloride, etc.

[0033] Preferable (I) may be the following (I').

wherein

R¹ is lower alkyl or lower alkyl substituted with halogen;

R² is lower alkoxy; R³ is lower alkoxy;

X is O; Y and Z are each CH; and m is 1.

[0034] Suitable salts of the compounds (I) are pharmaceutically acceptable conventional non-toxic salts and include a metal salt such as an alkali metal salt (e.g., sodium salt, potassium salt, etc.) and an alkaline earth metal salt (e.g., calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt (e.g., trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, etc.), an organic acid salt (e.g., acetate, maleate, tartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, trifluoroacetate, etc.), an inorganic acid salt (e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc.), asaltwithanaminoacid (e.g., arginine, aspartic acid, glutamic acid, etc.), or the like.

[0035] The processes for preparing the object compounds are explained in detail in the following.

Process (1)

[0036] The compound (V) or a salt thereof can be prepared by converting the compound (IV) or a salt thereof under basic condition.

[0037] The reaction is usually carried out in a conventional solvent such as water, alcohols (e.g., methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane, chloroform, methylene chloride, dimethyl acetamide, N, N-dimethylformamide or any other organic solvent which does not adversely influence the reaction. Among these solvents, hydrophilic solvents may be used in a mixture with water.

[0038] This reaction is preferably carried out in the presence of an inorganic or an organic base such as an alkali metal hydroxide, an alkalimetalhydrogencarbonate, alkali metal carbonate, alkali metal acetate, tri(lower)alkylamine, pyridine (e.g. pyridine, lutidine, picoline, dimethylaminopyridine, etc.), N-(lower)alkylmorpholine, N-,N-di(lower)alkylbenzylamine, N-,N-di(lower)alkylaniline or the like. When the base, the acid and/or the starting compound are in liquid, they can be used also as a solvent.

[0039] The reaction temperature is not critical and the reaction is usually carried out under cooling to heating.

[0040] Subsequently, the obtained compound (V) is condensed with R¹-L² under basic condition to give a compound (Ib).

[0041] The reaction is usually carried out in a conventional solvent such tetrahydrofuran, dioxane, chloroform, methylene chloride, dimethyl acetamide, N,N-dimethylformamide or any other organic solvent which does not adversely influence the reaction.

[0042] Among these solvents, hydrophilic solvents may be used in a mixture with water.

[0043] The suitable base may include a tertiary amine [e.g. triethylamine, pyridine, N,N-dimethylaniline, etc.], an alkali metal hydroxide [e.g. sodium hydroxide, potassium hydroxide, etc.], an alkali metal carbonate [e.g. sodium carbonate, potassium carbonate, etc.], alkali metal bicarbonate (e.g. sodium bicarbonate, etc.), a salt of an organic acid [e.g. sodium acetate, etc.] and the like. In case that the base is liquid, the base can be used as a solvent.

[0044] The reaction temperature is not critical and the reaction is usually carried out under cooling to warming.

Process (2)

[0045] Compound (VIII) or a its salt can be prepared by the reaction of compound (VI) or a its salt with compound (VII) or a its salt under basic condition.

[0046] The reaction is usually carried out in a suitable solvent such asacetates,tetrahydrofuran,dioxane,chloroform,methylene chloride, dimethyl acetamide, N,N-dimethylformamide or any other organic solvent which does not affect the reaction.

[0047] This reaction is preferably carried out in the presence of an inorganic or an organic base such as an alkali metal hydrogencarbonate, alkali metal carbonate, alkali metal acetate, trialkylamine, pyridine (e.g. pyridine, lutidine, picoline, dimethylaminopyridine, etc.), N-alkylmorpholine, N-,N-dialkylbenzylamine, N-,N-dialkylaniline and so on. In case base, acid and/or starting compound are liquid, they can play a role of solvent.

[0048] The reaction temperature is not critical to the reaction in the yield or purity and the reaction is allowed to be carried out independent of temperature.

[0049] Subsequently, compound (VIII) or a its salt is reacted with compound (IX) or a its salt under acidic condition to give a compound (I) or its salt. When a salt of compound (IX) is used in this reaction, a suitable base may be added to neutralize the system.

[0050] The reaction is usually carried out in a suitable solvent such as water, acetic acid, methanol, tetrahydrofuran, dioxane, chloroform, methylene chloride, dimethyl acetamide, N,N-dimethylformamide or any other organic solvent which does not affect the reaction. In addition, a mixed solvent is allowed to be used.

[0051] The suitable acid may include an organic carboxylic acid [e.g. formic acid, acetic acid, propionic acid, etc.), an organic sulfonic acid [e.g.methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.], a mineral acid [e. g. hydrochloric acid, sulfuric acid, etc.]. In case where the acid is liquid, it can play a role of solvent.

[0052] The reaction temperature is not critical to the reaction in the yield or purity and the reaction is allowed to be carried out independent of temperature.

[0053] In order to illustrate the usefulness of the object compounds (I), the pharmacological test data of the compounds (I) are shown in the following.

[A] ANALGESIC ACTIVITY:

[0054] Effect on adjuvant arthritis in rats:

(i) Test Method:

[0055] Arthritis was induced by injection of 0.5 mg of Mycobacterium tuberculosis (Difco Laboratories, Detroit, Mich.) in 50 µl of liquid paraffin into the right hind footpad of Lewis rats aged 7 weeks. Analgesic activity of a single dose of agents in arthritic rats was studied. Arthritic rats were randomized and grouped (n=10) for drug treatment based on pain threshold of left hind paws and body weight on day 22. Drugs (Test compounds) were administered and the pain threshold was measured 2hr after drug administration. The intensity of hyperalgesia was assessed by the method of Randall - Selitto. The mechanical pain threshold of the left hind paw (uninjected hind paw) was determined by compressing the ankle joint with a balance pressure apparatus (Ugo Basile Co. Ltd. , Varese, Italy). The threshold pressure of rats squeaking or struggling was expressed in grams. The threshold pressure of rats treated with drugs was compared with that of non-treated rats. A dose showing the ratio of 1.5 is considered to be the effective dose.

(ii) Test Results:

[0056] 

Test compound	Dose	The coefficient of analgesic
(Example No.)	(mg/kg)
1(4)	3.2	>= 1.5

[B] Inhibiting activity against COX-I and COX-II

(Whole Blood Assay):

(i) Test Method:

Whole blood assay for COX-I

[0057] Fresh blood was collected by syringe without anticoagulants from volunteers with consent. The subjects had no apparent inflammatory conditions and had not taken any medication for at least 7 days prior to blood collection. 500 µl aliquots of human whole blood were immediately incubated with 2 µl of either DMSO vehicle or a test compound at final concentrations for 1hr at 37°C to allow the blood to clot. Appropriate treatments (no incubation) were used as blanks. At the end of the incubation, 5µl of 250mM Indomethacin was added to stop the reaction. The blood was centrifuged at 6000 x g for 5min at 4°C to obtain serum. A 100µl aliquot of serum was mixed with 400 µl methanol for protein precipitation. The supernatant was obtained by centrifuging at 6000 x g for 5min at 4°C and was assayed for TXB2 using an enzyme immunoassay kit according to the manufacturer's procedure. For a test compound, the results were expressed as percent inhibition of TXB2 production relative to control incubations containing DMSO vehicle. The data were analyzed by that a test compound at the indicated concentrations was changed log value and was applied simple linear regression. IC50 value was calculated by least squares method.

Whole blood assay for COX-II

[0058] Fresh blood was collected in heparinized tubes by syringe from volunteers with consent. The subjects had no apparent inflammatory conditions and had not taken any medication for at least 7 days prior to blood collection. 500µl aliquots of human whole blood were incubated with either 2µl DMSO vehicle or 2 µl of a test compound at final concentrations for 15min at 37°C. This was followed by incubation of the blood with 10µl of 5mg/ml lipopolysaccharide for 24hr at 37°C for induction of COX-2. Appropriate PBS treatments (no LPS) were used as blanks. At the end of the incubation, the blood was centrifuged at 6000 x g for 5min at 4°C to obtain plasma. A 100µl aliquot of plasma was mixed with 400µl methanol for protein precipitation. The supernatant was obtained by centrifuging at 6000 x g for 5min at 4°C and was assayed for PGE2 using a radioimmunoassay kit after conversion of PGE2 to its methyl oximate derivative according to the manufacturer's procedure. For a test compound, the results were expressed as percent inhibition of PGE2 production relative to control incubations containing DMSO vehicle. The data were analyzed by that a test compound at the indicated concentrations was changed log value and was applied simple linear regression. IC50 value was calculated by least squares method.

(ii) Test Results:

[0059] 

Test Compound	COX-I	COX-II
(Example No.)	IC50 (µM)	IC50 (µM)
1(4)	< 0.01	> 0.1
3	< 0.01	> 0.1
4	< 0.01	> 0.1
5	< 0.01	> 0.1

[0060] It appeared, from the above-mentioned Test Results, that the compound (I) or pharmaceutically acceptable salts thereof of the present invention have an inhibiting activity against COX, particularly a selective inhibiting activity against COX-I.

[C] Inhibiting activity on aggregation of platelet

(i) Methods

Preparation of platelet-rich plasma

[0061] Blood from healthy human volunteers was collected into plastic vessels containing 3.8% sodium citrate (1/10 volume). The subject had not taken any compounds for at least seven days prior to blood collection. Platelet-rich plasma was obtained from the supernatant fraction of blood after centrifugation at 1200 r.p.m. for 10 min. Platelet-poor plasma was obtained by centrifugation of the remaining blood at 3000 r.p.m. for 10 min.

Measurement of platelet aggregation

[0062] Platelet aggregation was measured according to the turbidimetric method with an aggregometer (Hema Tracer). In the cuvette, platelet-rich plasma was pre-incubated for 2 min at 37°C after the addition of compounds or vehicle. In order to quantify the inhibitory effects of each compound, the maximum increase in light transmission was determined from the aggregation curve for 7 min after the addition of agonist. We used collagen as agonist of platelet aggregation in this study. The final concentration of collagen was 0.5µg/mL. The effect of each compound was expressed as percentage inhibition agonist- induced platelet aggregation compared with vehicle treatment. Data are presented as the mean ± S.E.M. for six experiments. The IC₅₀ value was obtained by linear regression, and is expressed as the compound concentration required to produce 50% inhibition of agonist-induced platelet aggregation in comparison to vehicle treatment.

(ii) Test Result

[0063] 

Compound
(Example No.)	IC50 (µM)
1-(4)	< 0.02

[0064] It appeared, from the above-mentioned Test Result, that the compound (I) or pharmaceutically acceptable salts thereof of the present invention have an inhibiting activity against platelet aggregation. Therefore, the compound (I) or pharmaceutically acceptable salts thereof are useful for preventing or treating disorders induced by platelet aggregation, such as thrombosis.

[0065] Additionally, it was further confirmed that the compounds (I) of the present invention lack undesired side-effects of non-selective NSAIDs, such as gastrointestinal disorders, bleeding, renal toxicity, cardiovascular affection, etc.

[0066] The object compound (I) or pharmaceutically acceptable salts thereof of this invention possesses COX inhibiting activity and possesses strong anti-inflammatory, antipyretic, analgesic, antithrombotic, anti-cancer activities.

[0067] The object compound (I) and pharmaceutically acceptable salt thereof, therefore, are useful for treating and/or preventing COX mediated diseases, inflammatory conditions, various pains, collagen diseases, autoimmune diseases, various immunological diseases, thrombosis, cancer and neurodegenerative diseases in human beings or animals by using administered systemically or topically.

[0068] More particularly, the object compound (I) and pharmaceutically acceptable salts thereof are useful for treating and/or preventing inflammation and acute or chronic pain in joint and muscle [e.g. rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis, juvenile arthritis, scapulohumeral periarthritis, cervical syndrome, etc.]; lumbago; inflammatory skin condition [e.g. sunburn, burns, eczema, dermatitis, etc.]; inflammatory eye condition [e.g. conjunctivitis, etc.]; lung disorder in which inflammation is involved [e.g. asthma, bronchitis, pigeon fancier's disease, farmer's lung, etc.]; condition of the gastrointestinal tract associated with inflammation [e.g. aphthous ulcer, Chrohn's disease, atopic gastritis, gastritis varialoforme, ulcerative colitis, coeliac disease, regional ileitis, irritable bowel syndrome, etc.]; gingivitis; menorrhalgia; inflammation, pain and tumescence after operation or injury [pain after odontectomy, etc ] ; pyrexia, pain and other conditions associated with inflammation, particularly those in which lipoxygenase and cyclooxygenase products are a factor, systemic lupus erythematosus, scleroderma, polymyositis, tendinitis, bursitis, periarteritis nodose, rheumatic fever, Sjogren's syndrome, Behcet disease, thyroiditis, type I diabetes, nephrotic syndrome, aplastic anemia, myasthenia gravis, uveitis contact dermatitis, psoriasis, Kawasaki disease, sarcoidosis, Hodgkin's disease, Alzheimers disease.

[0069] Additionally, the object compound (I) or a salt thereof is expected to be useful as therapeutical and/or preventive agents for cardiovascular or cerebrovascular diseases, the diseases caused by hyperglycemia and hyperlipemia.

[0070] The object compound (I) and a salt thereof can be used for prophylactic and therapeutic treatment of arterial thrombosis, arterial sclerosis, ischemic heart diseases [e.g. angina pectoris (e.g. stable angina pectoris, unstable angina pectoris including imminent infarction, etc.), myocardial infarction (e.g. acute myocardial infarction, etc.), coronary thrombosis, etc.], ischemic brain diseases [e.g. cerebral infarction (e.g. acute cerebral thrombosis, etc.), cerebral thrombosis (e.g. cerebral embolism, etc.), transient cerebral ischemia (e.g. transient ischemic attack, etc.), cerebrovascular spasm after cerebral hemorrhage(e.g. cerebrovascular spasm after subarachnoid hemorrhage, etc.), etc.], pulmonary vascular diseases (e.g. pulmonary thrombosis, pulmonary embolism etc.), peripheral circulatory disorder [e.g. arteriosclerosis obliterans, thromboangiitisobliterans (i.e. Buerger's disease), Raynaud's disease, complication of diabetes mellitus (e.g. diabetic angiopathy, diabetic neuropathy, etc.), phiebothrombosis (e.g. deep vein thrombosis, etc.), etc.], complication of tumors (e.g. compression thrombosis), abortion [e.g. placental thrombosis, etc.], restenosis and reocclusion [e.g. restenosis and/or reocclusion after percutaneous transluminal coronary angioplasty (PTCA), restenosis and reocclusion after the administration of thrombolytic drug (e.g. tissue plasminogen activator (TPA), etc.)], thrombus formation in case of vascular surgery, valve replacement, extracorporeal circulation [e.g. surgery (e.g. open heart surgery, pump-oxygenator, etc.) hemodialysis, etc.] or transplantation, disseminated intravascular coagulation (DIC), thrombotic thrombocytopenia, essential thrombocytosis, inflammation (e.g. nephritis, etc.), immune diseases, atrophic thrombosis, creeping thrombosis, dilation thrombosis, jumping thrombosis, mural thrombosis, etc.

[0071] The object compound (I) and a salt thereof can be used for the adjuvant therapy with thrombolytic drug (e.g. TPA, etc.) or anticoagulant (e.g. heparin, etc.).

[0072] And, the compound (I) is also useful for inhibition of thrombosis during extra corporeal circulation such as dialysis.

[0073] Particularly, the following diseases are exemplified: pains caused by or associated with rheumatoid arthritis, osteoarthritis, lumbar rheumatism, rheumatoid spondylitis, gouty arthritis, juvenile arthritis, etc; lumbago; cervico-omo-brachial syndrome;'scapulohumeral periarthritis; pain and tumescence after operation or injury; etc.

[0074] For therapeutic purpose, the compound (I) and a pharmaceutically acceptable salt thereof of the present invention can be used in a form of pharmaceutical preparation containing one of said compounds as an active ingredient, in admixture with a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient suitable for oral, parenteral or external administration. The pharmaceutical preparations may be capsules, tablets, dragees, granules, inhalant, suppositories, solution, lotion, suspension, emulsion, ointment, gel, or the like. If desired, there may be included in these preparations, auxiliary substances, stabilizing agents, wetting, or emulsifying agents, buffers and other commonly used additives.

[0075] While the dosage of therapeutically effective amount of the compound (I) will vary depending upon the age and condition of each individual patient, an average single dose of about 0.01 mg, 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg of the compound (I) may be effective for treating the above-mentioned diseases. In general, amounts between 0.01 mg/body and about 1,000 mg/body may be administered per day.

[0076] For therapeutic purpose, the analgesic agent of the present invention can be used in a form of pharmaceutical preparation suitable for oral, parenteral or external administration. The pharmaceutical preparations may be capsules, tablets, dragees, granules, inhalant, suppositories, solution, lotion, suspension, emulsion, ointment, gel, or the like.

[0077] Particularly, the analgesic agent of this invention is useful for treating or preventing acute or chronic pains associated with acute or chronic inflammations in human beings or animals by using administered systemically or topically.

[0078] The following Examples are given for the purpose of illustrating the present invention in detail.

Example 1

[0079] 

(1) Under ice-bath cooling, potassium cyanate (1.71g, 21.1mmol) was added to a suspension of 4-methoxyphenylhydrazine hydrochloride (3.35 g, 19.2 mmol)in water (40 mL). The mixture was stirred for 1 hour at the same temperature. And then the mixture was warmed to room temperature and stirred for 12 hours. An insoluble material was isolated by filtration, washed with water, and dried in vacuo to give 2-(4-methoxyphenyl)hydrazine-carboxamide (2.45 g, 70.5% yield).
1H NMR (DMSO-d6, ppm) δ 7.64(s, 1H), 7.26(s, 1H), 6.78(d, J = 8.8 Hz, 2H), 6.67(d, J = 8.8 Hz, 2H), 5.90(s, 2H), 3.66(s, 3H)
MS (ESI, m/e) 223(M+1+MeCN)

(2) To a suspension of 2-(4-methoxyphenyl)hydrazinecarboxamide (1.81 g, 9.99 mmol) in 20 mL of toluene, pyridine (1.01 mL, 12. 5 mmol) and then a solution of 4-methoxybenzoyl chloride (2.13 g, 12. 5 mmol) in 10 mL of toluene were added. The mixture was refluxed with stirring for 1 hour. After cooling, 500 mL of ethyl acetate - tetrahydrofuran (9:1) and 100 mL of water were added to the mixture. After vigorous shaking, an insoluble material was isolated by filtration and dired in vacuo to give 2-(4-methoxybenzoyl)-2-(4-methoxyphenyl)hydrazinecarboxamide (1.95 g, 61.9% yield).
1H NMR (DMSO-d6, ppm) δ 8.86(br s, 1H), 7.49(br d, J = 7.4 Hz, 2H), 7.28(br s, 2H), 6.89(m, 4H), 3.77(s, 3H), 3.73(s, 3H)
MS (ESI, m/e) 316(M+1)

(3) A mixture of 2-(4-methoxybenzoyl)-2-(4-methoxyphenyl)-hydrazinecarboxamide (1.9 g, 6.03 mmol) in 10% potassiumhydroxide solution (16 mL) - ethanol (8 mL) was heated at 60 °C for 1.5 hours. After cooling, the solvent was removed under reduced pressure. Water was added to the residue and the mixture was adjusted pH to ca. 2. A generated precipitate was isolated by filtration, washed with water, and dried in vacuo to give 1,5-bis(4-methoxyphenyl)-1H-1,2,4-triazol-3-ol (1.51 g, 84.3% yield).
1H NMR (DMSO-d6, ppm) δ 7.32(d, J = 8.9 Hz, 2H), 7.28(d, J = 8.9 Hz, 2H), 7.01(d, J=8.9Hz, 2H), 6.93(d, J=8.9Hz, 2H), 3.80(s, 3H), 3.77(s, 3H)
MS (ESI, m/e) 298(M+1)

(4) A mixture of 1,5-bis(4-methoxyphenyl)-1H-1,2,4-triazol-3-ol (1. 5 g, 5.05mmol), potassium carbonate (2.09 g, 15.1 mmol), and iodomethane (3.14 mL, 50.5 mmol) in dimethylformamide (15 mL) was stirred overnight. 100 mL of water and 300 mL of ethyl acetate - tetrahydrofuran (9:1) were poured into the mixture and the organic layer was separated, washed with brine-water (1:1) and brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography (hexane - ethyl acetate 4:1-2:3). 3-Methoxy-1,5-bis(4-methoxyphenyl)-1H-1,2,4-triazole was recrystallized from ethyl acetate - hexane. (658 mg, 41.9% yield)
1H NMR (DMSO-d6, ppm) δ 7.34(d, J = 8.9 Hz, 2H), 7.32(d, J=8.9 Hz, 2H), 7.03(d, J = 8.9 Hz, 2H), 6.94(d, J = 8.9 Hz, 2H), 3.93(s, 3H), 3.80(s, 3H), 3.76(s, 3H)
MS (ESI, m/e) 312(M+1)
mp 125.6-126.0 °C

Example 2

[0080] A mixture of 1,5-bis(4-methoxyphenyl)-1H-1,2,4-triazol-3-ol (0.3 g, 1.01 mmol), potassium carbonate (418 mg, 3.01 mmol), and iodoethane (0.406 mL, 5.05 mmol) in dimethylformamide (3 mL) was stirred for 3 days. Water and ethyl acetate - tetrahydrofuran (9:1) were poured into the mixture and the organic layer was separated, washed with brine-water (1:1) and brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography to give 3-ethoxy-1,5-bis(4-methoxyphenyl)-1H-1,2,4-triazole (143 mg, 43.6% yield).
1H NMR (DMSO-d6, ppm) δ 7.35(d, J = 8.9 Hz, 2H), 7.28 (d, 8.9 Hz, 2H), 7.02(d, J = 8.9 Hz, 2H), 6.93(d, J = 8.9 Hz, 2H), 4.29(q, J= 7.0 Hz, 2H), 3.80(s, 3H), 3.76 (s, 3H), 1.35(t, J = 7.0 Hz, 3H)
MS (ESI, m/e) 326(M+1)

Example 3

[0081] Potassium carbonate (697 mg, 5.05 mmol) was added to a solution of 1,5-bis(4-methoxyphenyl)-1H-1,2,4-triazol-3-ol (0.3 g, 1.01 mmol) in dimethylformamide (3 mL). After 10 minute stirring, 2,2,2-trifluoroethyl iodide (0.497 mL, 5.05 mmol) was added to the mixture and the mixture was heated at 100 °C for 3 hours. After cooling, 100 mL of ethyl acetate and 20 mL of water were poured into the mixture. The organic layer was separated, washed with water and brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane - ethyl acetate 10:1 - 5:1). The desired product was triturated with hexane, isolated by filtartion, and dried in vacuo to give 1,5-bis(4-methoxyphenyl)-3-(2,2,2-trifluoroethoxy)-1H-1,2,4-triazole(205mg, 53.6%).
1H NMR (DMSO-d6, ppm) δ 7.36(d, J=8.8 Hz, 2H), 7.33(d, J = 8.8 Hz, 2H), 7.04(d, J = 8.8 Hz, 2H), 6.95(d, J=8.8 Hz, 2H), 4. 99 (q, J = 8.8 Hz, 2H), 3.81(s, 3H), 3.76(s, 3H)
MS (ESI, m/e) 380(M+1)

Example 4

[0082] 1,5-bis(4-methoxyphenyl)-3-(2-propoxy)-1H-1,2,4-triazole was prepared from 1,5-bis(4-methoxyphenyl)-1H-1,2,4-triazol-3-ol by the similar manner as that described for Example 3.
1H NMR (DMSO-d6, ppm) δ 7.33(d, J=8.9 Hz, 2H), 7.30(d, J = 8.9 Hz, 2H), 7. 02 (d, J=8.9Hz, 2H), 6. 93 (d, J=8.9Hz, 2H), 4.9(sept, J = 6.1 Hz, 1H), 3.80(s, 3H), 3.76(s, 3H), 1.35(d, J = 6.1 Hz, 6H)
MS (ESI, m/e) 340 (M+1)

Example 5

[0083] A mixture of 1,5-bis(4-methoxyphenyl)-1H-1,2,4-triazol-3-ol (0.3 g, 1.01 mmol) and potassium carbonate (418 mg, 3.03 mmol) in bromofluoromethane (1 mL) - dimethylformamide (3 mL) was heated at 100 °C with stirring for 3.5 hours. After cooling, ethyl acetate and water were poured into the mixture. The organic layer was separated, washed with water and brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane - ethyl acetate). The desired product was triturated with hexane, isolated by filtration, and dried in vacuo to give 1,5-bis(4-methoxyphenyl)-3-(fluoromethoxy)-1H-1,2,4-triazole.
1H NMR (DMSO-d6, ppm) δ 7.3-7.4(m, 4H), 7.05(d, J=9.0 Hz, 2H), 6.95(d, J = 8.9 Hz, 2H), 6.02(d, J = 52.4 Hz, 2H), 3.81(s, 3H), 3.76(s, 3H)
MS (ESI, m/e) 330 (M+1)

Example 6

[0084] 

(1) To a solution of dimethylcyanamide (10.0g, 142.7mmol) in methanol (50mL) was added dropwise sulfuric acid (14.0 g, 142.7mmol) over 2 hours at 20-30°C. The mixture was stirred at 20-30°C for 4 hours and then concentrated in vacuo. To the residue was added acetone (50mL) and stirred at 20-30°C. After crystallization, the mixture was stirred at 20-30°C for 30 minutes, then at 0-10°C for 1 hour and filtered. The crystals were washed with acetone (20mL) and dried in vacuo to give N,N,O-trimethylisourea sulfate (22.86g, 80.0% yield) as white granulated solids.
1H NMR (DMSO d6, ppm) δ 2.98(3H, br), 3.01(3H, br), 4.01(3H, s), 8.66(2H, br)

(2) To a cooled (0-15°C) solution of N,N,O-trimethylisourea sulfate (20.0g, 99.9mmol) in a mixture of methanol (100mL) and water (1. 8mL) was added dropwise 28% sodium methoxide in methanol (38.55g, 199.8mmol) over 2 hours at 20-30°C and stirred at the ambient temperature for 1 hour. The resulting precipitate was filtered off and washed with methanol (40mL). The filtrate was concentrated in vacuo and ethyl acetate (180mL) and triethylamine (10.11g, 99.9mmol) were added to the residue. To the mixture was added dropwise a solution of 4-methoxybenzoylchloride (16.15g, 94.9mmol) in ethyl acetate (20mL) over 2 hour, at 20-30°C and then stirred at the same temperature for 2 hours. To the reaction mixture was added water (40mL) and the aqueous layer was extracted with ethyl acetate (100mL). The combined organic layers were concentrated in vacuo and 4-methoxyphenylhydradine hydrochloride (17.44g, 99.9mmol), methanol (120mL) and acetic acid (10mL) were added to the residue. To the mixture was added dropwise triethylamine (10.11g, 99.9mmol) and stirred at 20-30°C for 3 hours then at 40-50°C for additional 3 hours. The reaction mixture was cooled to 20-30°C and stirred for 30 minutes. To the mixture was added dropwise water (120mL) and stirred for 1 hour. The crystals were filtered, washed with 50% aqueous methanol (40mL) and dried in vacuo to give crude 3-methoxy-1,5-bis (4-methoxyphenyl) -1H-1,2,4-triazole (20. 36g, 65.5% yield) as pale brownish yellow needles.

(3) To the stirred purified water (100mL) was added dropwise a solution of 3-methoxy-1,5-bis(4-methoxyphenyl)-1H-1,2,4-triazole (20.0g, 64.2mmol) obtained above in acetone (300mL) and stirred at 20-30°C for 30 minutes. The mixture was concentrated to -200mL in vacuo, stirred at 35-45°C for 1 hour then at 20-30°C for 1 hour and filtered. The crystals were washed with 50% aqueous acetone (40mL) and dried in vacuo to give pure 3-methoxy-1,5-bis(4-methoxyphenyl)-1H-1,2,4-triazole (18.36g, 91.8% yield) as colorless needles.
Representative X-ray powder diffraction Peaks (26): 9.1° ,15.4° ,19.7°
mp 125°C

List of the Compounds Produced by the Examples

[0085] 

Example No.	(X)m	R1	R2	R3	Y	Z
1-(4)	O	-CH3	-OCH3	-OCH3	-CH-	-CH-
2	O	-C2H5	-OCH3	-OCH3	-CH-	-CH-
3	O	-CH2-CF3	-OCH3	-OCH3	-CH-	-CH-
4	O	-CH(CH3)2	-OCH3	-OCH3	-CH-	-CH-
5	O	-CH2-F	-OCH3	-OCH3	-CH-	-CH-
6-(3)	O	-CH3	-OCH3	-OCH3	-CH-	-CH-

Claims

1. A compound of the formula (I):

wherein R¹ is (C₁-C₆) alkyl or (C₁-C₆) alkyl substituted with halogen;

R² is (C₁-C₆) alkoxy; and

R³ is (C₁-C₆) alkoxy.

2. A compound of the formula (I'):

wherein

R¹, R², and R³ are as defined in claim 1.

3. The compound of Claim 1, which is 3-methoxy-1,5-bis(4-methoxyphenyl)-1H-1,2,4-triazole.

4. A process for preparing a compound (I) of Claim 1,

wherein R¹, R² and R³ are as defined in claim 1 ;
or salts thereof, which comprises

(1) converting a compound (IV) of the following formula

wherein R² and R³ are each as defined above, and

X¹ is O,

or a salt thereof to a compound (V) of the following formula:

wherein R² and R³ are each as defined above, and

X¹_, is O,

or a salt thereof, and further condensing the compound (V) with R¹-L¹ , wherein R¹ is the same as defined above and L¹ is a leaving group, under basic condition to give a compound (Ib) of a following formula:

wherein R¹, R², R³ and X¹ are each as defined above,
or a salt thereof, or

(2) reacting a compound (VI) of the following formula

wherein R¹ is as defined above,
or a salt thereof, with a compound (VII) of the following formula:

wherein R² is as defined above,
and L³ is a leaving group,
or a salt thereof to give a compound (VIII) of a following formula

wherein R¹ and R² are each as defined above,
or a salt thereof, and further reacting with a compound of (IX) of the following formula:

wherein R³ is as defined above,
or a salt thereof to give a compound (I) or a salt thereof.

5. A pharmaceutical composition comprising the compound (I) or its salts of any of Claims 1 to 3, as an active ingredient, in association with a pharmaceutically non-toxic carrier or excipient.

6. A compound of any of Claims 1 to 3 for use as a medicament

7. Use of the compound of any of Claims 1 to 3 for the manufacture of a medicament for treatment and/or prevention of inflammatory conditions, various pains, collagen diseases, autoimmune diseases, various immunity diseases, analgesic, thrombosis, cancer or neurodegenerative diseases in human beings or animals.

8. The analgesic agent comprising the compound of any of Claims 1 to 3, which is usable for treating and/or preventing pains caused by or associated with acute or chronic inflammations without causing gastrointestinal disorders.

9. The analgesic agent of Claim 8, which is usable for treating or preventing pains caused by or associated with rheumatoid arthritis, osteoarthritis, lumbar rheumatism, rheumatoid spondylitis, gouty arthritis, or juvenile arthritis; lumbago; cervico-omo-brachial syndrome; scapulohumeral periarthritis; pain and tumescence after operation or injury without causing gastrointestinal disorders.

10. A commercial package comprising the pharmaceutical composition containing the compound (I) identified in any of Claims 1 to 3 and a written matter associated therewith, wherein the written matter states that the compound (I) can or should be used for preventing or treating inflammatory conditions, various pains, collagen diseases, autoimmune diseases, various immunity diseases, analgesic, thrombosis, cancer or neurodegenerative diseases.

Ansprüche

1. Verbindung der Formel (I):

wobei R¹ (C₁-C₆) Alkyl oder mit Halogen substituiertes (C₁ - C₆) Alkyl ist;

R² (C₁ - C₆) Alkoxy ist; und

R³ (C₁ - C₆) Alkoxy ist.

2. Verbindung der Formel (I'):

wobei R¹, R² und R³ wie in Anspruch 1 definiert sind.

3. Verbindung nach Anspruch 1, die 3-Methoxy-1,5-bis(4-methoxyphenyl)-1 H-1,2,4-triazol ist.

4. Verfahren zur Herstellung einer Verbindung (I) nach Anspruch 1,

wobei R¹, R² und R³ wie in Anspruch 1 definiert sind;
oder von Salzen davon, welches umfasst

(1) Umwandlung einer Verbindung (IV) der folgenden Formel

wobei R² und R³ wie oben definiert sind, und

X¹ O ist,

oder eines Salzes davon zu einer Verbindung (V) der folgenden Formel:

wobei R² und R³ jeweils wie oben definiert sind, und

X¹ O ist,

oder eines Salzes davon, und weiter Kondensation der Verbindung (V) mit R¹-L¹, wobei R¹ wie oben definiert ist und L¹ eine Abgangsgruppe ist, unter basischen Bedingungen zur Herstellung einer Verbindung (Ib) der folgenden Formel:

wobei R¹, R² , R³ und X¹ jeweils wie oben definiert sind,
oder eines Salzes davon, oder

(2) Umsetzung einer Verbindung (VI) der folgenden Formel:

wobei R¹ wie oben definiert ist,
oder eines Salzes davon mit einer Verbindung (VII) der folgenden Formel:

wobei R² wie oben definiert ist,
und L³ eine Abgangsgruppe ist,
oder einem Salz davon zur Herstellung einer Verbindung (VIII) der folgenden Formel:

wobei R¹ und R² jeweils wie oben definiert sind,
oder eines Salzes davon, und weitere Umsetzung mit einer Verbindung (IX) der folgenden Formel:

wobei R³ wie oben definiert ist,
oder einem Salz davon zur Herstellung einer Verbindung (I) oder eines Salzes davon.

5. Pharmazeutische Zusammensetzung, umfassend die Verbindung (I) oder ihre Salze nach einem der Ansprüche 1 bis 3 als aktiven Wirkstoff in Verbindung mit einem pharmazeutisch nicht-toxischen Träger oder Exzipienten.

6. Verbindung nach einem der Ansprüche 1 bis 3 zur Verwendung als Medikament.

7. Verwendung der Verbindung nach einem der Ansprüche 1 bis 3 zur Herstellung eines Medikaments zur Behandlung und/oder Vorbeugung von entzündlichen Zuständen, verschiedenen Schmerzen, Kollagenerkrankungen, Autoimmunerkrankungen, verschiedenen Immunerkrankungen, Analgetikum, Thrombose, Krebs oder neurodegenerativen Erkrankungen in Menschen oder Tieren.

8. Analgetisches Mittel, umfassend die Verbindung nach einem der Ansprüche 1 bis 3, welche zur Behandlung und/oder Vorbeugung von Schmerzen geeignet ist, die mit akuten oder chronischen Entzündungen verursacht werden oder damit zusammenhängen, ohne dass gastrointestinale Störungen verursacht werden.

9. Analgetisches Mittel nach Anspruch 8, welches zur Behandlung oder Vorbeugung von Schmerzen verwendbar ist, die mit rheumatoider Arthritis, Osteoarthritis, Lumbarrheumatismus, rheumatoider Spondylitis, Gichtarthritis oder juveniler Arthritis; Lumbago; Cervico-Omo-Brachial-Syndrom; scapulohumeraler Periarthritis; Schmerzen und Schwellung nach Operation oder Verletzung zusammenhängenden oder verursachten Schmerzen verwendbar ist, ohne dass gastrointestinale Störungen verursacht werden.

10. Kommerzielle Verpackung, umfassend die pharmazeutische Zusammensetzung, die die in einem der Ansprüche 1 bis 3 identifizierte Verbindung (I) und ein damit verbundenes Schriftstück enthält, wobei das Schriftstück festhält, dass die Verbindung (I) zur Vorbeugung oder Behandlung von entzündlichen Zuständen, verschiedenen Schmerzen, Kollagenerkrankungen, Autoimmunerkrankungen, verschiedenen Immunerkrankungen, Analgetikum, Thrombose, Krebs oder neurodegenerativen Erkrankungen verwendet werden kann oder sollte.

Revendications

1. Composé répondant à la formule (I) :

dans laquelle R¹ représente un groupe alkyle en C₁-C₆ ou un groupe alkyle en C₁-C₆ substitué avec un atome d'halogène ;

R² représente un groupe alcoxy en C₁-C₆ ; et

R³ représente un groupe alcoxy en C₁-C₆.

2. Composé répondant à la formule (I') :

dans laquelle

R¹, R² et R³ sont tels que définis à la revendication 1.

3. Composé selon la revendication 1, à savoir le 3-méthoxy-1,5-bis(4-méthoxyphényl)-1H-1,2,4-triazole.

4. Procédé pour préparer un composé répondant à la formule (I) selon la revendication 1 :

dans laquelle

R¹, R² et R³ sont tels que définis à la revendication 1 ;

ou ses sels, qui comprend le fait de

(1) transformer un composé (IV) répondant à la formule suivante :

dans laquelle R² et R³ sont chacun tels que définis ci-dessus, et

X¹ représente un atome d'oxygène ;

ou un de ses sels, pour obtenir un composé (V) répondant à la formule suivants :

dans laquelle R² et R³ sont chacun tels que définis ci-dessus, et

X¹ représente un atome d'oxygène ;

ou un de ses sels, et condenser ultérieurement le composé (V) avec un groupe R¹-L¹, R¹ étant tel que défini ci-dessus et L¹ représentant un groupe partant, dans des conditions basiques pour obtenir un composé (Ib) répondant à la formule suivante :

dans laquelle R¹, R², R³ et X¹ sont chacun tels que définis ci-dessus,

ou un de ses sels, ou bien

(2) faire réagir un composé (VI) répondant à la formule suivante :

dans laquelle R¹ est tel que défini ci-dessus,

ou un de ses sels, avec un composé (VII) répondant à la formule suivante :

dans laquelle R² est tel que défini ci-dessus,

et L³ représente un groupe partant,

ou un de ses sels, pour obtenir un composé (VIII) répondant à la formule suivants :

dans laquelle R¹ et R² sont chacun tels que définis ci-dessus,

ou un de ses sels, et en faisant réagir ultérieurement avec un composé (IX) répondant à la formule suivants :

dans laquelle R³ est tel que défini ci-dessus,

ou un de ses sels, pour obtenir un composé (I) ou un de ses sels.

5. Composition pharmaceutique comprenant le composé (I) ou ses sels, selon l'une quelconque des revendications 1 à 3, à titre d'ingrédient actif, en association avec un excipient ou un support pharmaceutiquement non toxique.

6. Composé selon l'une quelconque des revendications 1 à 3, à utiliser comme médicament.

7. Utilisation du composé selon l'une quelconque des revendications 1 à 3, pour la préparation d'un médicament destiné au traitement et/ou à la prévention d'affections inflammatoires, de douleurs diverses, de maladies liées au collagène, de diverses maladies auto-immunes, de diverses maladies du système immunitaire, d'analgésies, de thromboses, de cancers ou de maladies neurodégénératives chez les êtres humains ou les animaux.

8. Agent analgésique comprenant le composé selon l'une quelconque des revendications 1 à 3, qui est utile pour le traitement et/ou la prévention de douleurs provoquées par ou associées à des inflammations aiguës ou chroniques, sans donner lieu à des troubles gastro-intestinaux.

9. Agent analgésique selon la revendication 8, qui est utile pour le traitement ou la prévention de douleurs provoquées par ou associées à la polyarthrite rhumatoïde, l'ostéoarthrite, le rhumatisme lombaire, la spondylite rhumatoïde, l'arthrite goutteuse ou l'arthrite juvénile ; le lumbago ; le syndrome cervico-omo-brachial ; la périarthrite scapulo-humérale ; des douleurs et des tuméfactions survenant après une opération ou une lésion, sans donner lieu à des troubles gastro-intestinaux.

10. Conditionnement commercial comprenant la composition pharmaceutique contenant le composé (I) identifié dans l'une quelconque des revendications 1 à 3, et une notice qui lui est associée, la notice spécifiant que le composé (I) peut ou doit être utilisé pour la prévention ou le traitement d'affections inflammatoires, de douleurs diverses, de maladies liées au collagène, de diverses maladies auto-immunes, de diverses maladies du système immunitaire, d'analgésies, de thromboses, de cancers ou de maladies neurodégénératives.