Triazole derivatives and pharmaceutical compositions comprising them

[0001] The present invention relates to novel triazole derivatives, to a process for preparing them and to pharmaceutical compositions comprising them.

[0002] These novel compounds are powerful and selective agonists of the CCK1 (also called CCK-A) receptors of cholecystokinin (CCK).

[0003] CCK is a peptide which, in response to an ingestion of food, is secreted peripherally and participates in regulating many digestive processes (Crawley J. N. et al., Peptides, 1994, 15 (4), 731-735).

[0004] CCK has since been identified in the brain, and might be the most abundant neuropeptide acting as a neuromodulator of cerebral functions by stimulating CCK2-type (also called CCK-B) receptors (Crawley J. N. et al., Peptides, 1994, 15 (4), 731-735). Within the central nervous system, CCK interacts with dopamine-mediated neuronal transmission (Crawley J. N. et al., ISIS Atlas of Sci., Pharmac, 1988, 84-90). It also plays a role in mechanisms involving acetylcholine, gaba (4-aminobutyric acid), serotonin, opioids, somatostatin and substance P and in ion channels. Its administration brings about physiological changes: palpebral ptosis, hypothermia, hyperglycaemia, catalepsis; and behavioural changes: hypolocomotion, reduction in exploration behaviour, analgesia, a change in learning faculty, and a change in sexual behaviour and satiety.

[0005] CCK exerts its biological activity via at least two types of receptor: CCK1 receptors, located mainly peripherally, and CCK2 receptors, essentially present in the cerebral cortex. The peripheral-type CCK1 receptors are also present in certain regions of the central nervous system, including the postrema area, the solitary tract nucleus and the interpeduncular nucleus (Moran T. H. et al., Brain Research, 1986, 362, 175-179; Hill D. R. et al., J. Neurosci, 1990, 10, 1070-1081).

[0006] At the periphery, via CCK1 receptors (Moran T. H. et al., Brain Research, 1986, 362, 175-179), CCK delays gastric drainage, modifies intestinal motility, stimulates vesicle contraction, increases bile secretion and controls pancreatic secretion (McHugh P. R. et al., Fed. Proc., 1986, 45, 1384-1390; Pendleton R. G. et al., J. Pharmacol. Exp. Ther., 1987, 241, 110-116).

[0007] The patent application WO 98/51686 describes a series of triazole derivatives possessing CCK1 receptor agonist activity.

[0008] The present invention provides a 3-aminotriazole derivative of formula:

[0009] and its solvates, hydrates, polymorphs and pharmaceutically acceptable salts.

[0010] One specific aspect of the invention is constituted by compounds of formula (I) and the pharmaceutically acceptable salts thereof formed with organic or mineral bases, for example alkali metal or alkaline earth metal, such as sodium, potassium or calcium salts, or salts formed with an amine, such as trometanol, arginine or lysine. Another specific aspect of the invention is constituted by the polymorphic and solvate (pseudopolymorphic) forms of the 3-aminotriazole derivative of the formula (I), to the salts of the 3-aminotriazole derivative of the formula (I) and of its polymorphs and solvates, given with ethanolamine, diethanolamine, diethylamine or adamantanamine.

[0011] The 3-aminotriazole derivative of formula (I) falls under the general formula of the 3-aminotriazole derivatives described in patent application WO 98/51686, although, individually it has not been described.

[0012] The compound of formula (I), their solvates, polymorphs and salts are much more powerful CCK1 agonists than those described in the prior art.

[0013] The compounds of the invention have indeed been the subject of studies for the purpose of characterizing:

[0014] their potentiality for displacing [125I]-CCK from its binding sites present in rat pancreatic membranes (CCK1 receptor) or 3T3 cells expressing recombinant human CCK1 receptor;

[0015] their selectivity for the CCK2 receptor;

[0016] their CCK1 receptor agonist property, by way of their capacity to induce mobilization of intracellular calcium in vitro in 3T3 cells expressing the human CCK1 receptor;

[0017] their agonist effect by the oral route on gastric drainage in the mouse.

[0018] These studies have shown that, in contrast to the compounds of the prior art, the compounds of the present invention surprisingly meet the various criteria below simultaneously: they possess not only a high affinity for CCK1 receptors but also good selectivity for CCK1 receptors (relative to CCK2 receptors) and a powerful CCK1 receptor agonist activity, demonstrated by the intracellular calcium mobilization and gastric drainage tests. These multiple properties make the compounds of the invention of major therapeutic interest as medicaments intended for the treatment of diseases which necessitate stimulation of CCK1 receptors.

[0019] The compounds of the invention may be prepared in accordance with the methods described in the patent application WO 98/51686. Scheme 1 below illustrates their preparation method.

[0020] An other object of the present invention is the preparation process of compound of formula (I), its solvates, hydrates, polymorphs and pharmaceutically acceptable salts. This process is characterized in that:

[0021] a compound of formula:

[0022] is hydrolysed;

[0023] If desired, the acid of formula (I) thus obtained is converted into its solvates, hydrates, polymorphs or pharmaceutical acceptable salts.

[0024] According to the preparation method the appropriate ester (II) is hydrolysed with a strong alkali and the acid of the formula (I) is liberated from the resulting salt, by using a strong mineral acid.

[0025] Surprisingly, depending on the conditions of the precipitation of the acid of the formula (I), on the temperature of the precipitation, on the addition rate of the acid, on the gradient of the cooling, on the rotation rate of the stirrer, different polymorphs and solvates can be obtained. The different polymorphs and solvates can be transformed into one-another by crystallization. By using appropriate solvents and applying appropriate physical parameters (reaction conditions) the forms most stable at room temperature, can be obtained.

[0026] The synthesis of intermediate (IV) is illustrated by Scheme 2 below:

[0027] Scheme 3 illustrates the preparation of intermediates (III):

[0028] In the above Schemes, the abbreviations Ph for phenyl, DMF for dimethylformamide and DBU for 4,5-dimethyl-6-methoxy-2-indolecarboxylic acid are used.

[0029] Polymorphs and solvates of the compounds of the formula (I), their physical characteristics, and conditions of their preparations are presented in Table 1.

1TABLE 1Polymorphs of the acid of the formula (I):Code ofthepoly-morphPreparation conditionsm.p. ° C.(IA)The sample of the acid of formula (I) is dissolved230-231in 32-fold (by mass) 96% ethanol at refluxtemperature, then cooled to 10° C. by a coolingrate of 15° C./min., kept at 10° C. for 20 hours,filtered off, dried in vacuum oven at 50° C. for 3hours.(IB)method a): the sample of polymorph (IA) of the230-231acid is heated at 160° C. for 6 hours.method b): the sample of polymorph (IA) of theacid is stirred at a speed of 200 rpm, in siliconeoil suspension at 180° C. for 6 hours, then cooledto room temperature, filtered off after mixing 4times with tert.butyl methyl ether, dried invacuum oven at 50° C. for 1 hour.method c): the sample of polymorph (IC) of theacid (I) is heated at 200° C. for 6 hours.method d): the sample of polymorph (IC) of theacid (I) is stirred at a speed of 200 rpm in siliconeoil suspension, at 200° C. for 6 hours, then cooledto room temperature, filtered off after mixing 4times with 1.2-fold (by mass) tert.butyl methylether, dried in vacuum oven at 50° C. for 1 hour.(IC)method a): the sample of the acid of the formula 211-213;(I) is dissolved in 30-fold (by mass) 2-propanol at(melting andreflux temperature, then cooled to 25° C. at acrystallizing)cooling rate of 0.5° C./min., kept at 25° C. for 20 (229-231)*hours, filtered off, dried in vacuum oven at 50° C.for 3 hours.method b): similar result is obtained when the hotsolution is cooled to 10° C. at a cooling rate of15° C./min., kept at 25° C. for 20 hours, filteredoff, dried.method c): the sample of polymorph (IA) of theacid of formula (I) is stirred at a speed of 200 rpmin 20-fold (by mass) 96% ethanol at 25-50° C.for 3 days, filtered off, dried in vacuum oven at50° C. for 2 hours.method d): the sample of polymorph (IA) of theacid of formula (I) is stirred at a speed of 200 rpmin 25-fold (by mass) n-heptane at 25-90° C. for3-7 days, filtered off, dried in vacuum oven at50° C. for 2 hours.method e): similar to method c) but starting frompolymorph (IE).method f): similar to method d) but starting frompolymorph (IE).method g): similar to method c) but starting frompolymorph (IF).method h): the sample of polymorph (IG) of theacid of formula (I) is stirred at a speed of 200 rpmin 30-fold (by mass) 96% ethanol at 25° C. for 1hour, filtered off, dried in vacuum oven at 50° C.for 2 hours.method i): the sample of polymorph (IG) of theacid of formula (I) is stirred at a speed of 200 rpmin 25-fold (by mass) n-heptane at 25° C. for 16days, filtered off, dried in vacuum oven at 50° C.for 2 hours.(ID)The sample of the acid of formula (I) is dissolved222-226(IDa +in 40-fold (by mass) 96% ethanol at refluxIDb)temperature, then cooled to 25° C. at a coolingrate of 0.5° C./min., seeded with the crystals of(ID), kept at 25° C. for 20 hours, filtered off,dried in vacuum oven at 50° C. for 3 hours.(IDb)method a): the sample of polymorph (ID) of theacid is stirred at 200 rpm speed in silicone oilsuspension at 205° C. for 8 hours, then cooled toroom temperature, filtered off after mixing 4times with 1.5-fold (by mass) tert.butyl methylether, dried in vacuum oven at 50° C. for 1 hour.method b): the sample of polymorph (IC) of theacid of formula (I) is stirred at 200 rpm speed in15-fold (by mass) 96% ethanol at 50° C. for 30days, filtered off, dried in vacuum oven at 50° C.for 2 hours.method C): the sample of polymorph (IC) of theacid of formula (I) is stirred at a speed of 200 rpmin 15-fold (by mass) 96% ethanol at 70° C. for 12hours, cooled to r.t., filtered off, dried in vacuumoven at 50° C. for 2 hours.method d): Similar to method c) but starting frompolymorph (ID).(IE)method a): chloroform-solvate pseudopolymorph 137-140;(IG) of the acid (I) is dried in vacuum oven at168-18080° C. for 3 hours.(crystal-method b): The sample of the acid of formula (I)lization);is dissolved in 20-fold (by mass) chloroform- (229-231)*ethanol 3,75:1 (by mass) mixture, seeded with thecrystals of (IE), kept at 25° C. for 6 hours,filtered off, dried in vacuum oven at 50° C. for3 hours.(IF)method a): The sample of the acid of formula (I) 154-158;is dissolved in 60-fold (by mass) acetone at reflux170-180temperature, then cooled to 25° C. at a cooling(crystal-rate of 0.5° C./min., kept at 25° C. for 20 hours,lization);filtered off, dried in vacuum oven at 50° C. for (229-231)*2 hours.method b): the sample of polymorph (IA) of theacid of formula (I) is stirred at a speed of 200 rpmin 30-fold (by mass) acetone at 25° C. for 8 days,filtered off, dried in vacuum oven at 50° C. for 2hours.method c): similar to method b) but starting frompolymorph (IC).method d): similar to method b) but starting frompolymorph (ID).(IG)Pseudopolymorph of the acid of the formula (I) 135-140;with chloroform, in molar ratio 1:1170-180The sample of the acid of formula (I) is dissolved(crystal-in 15-fold (by mass) chloroform, kept at 25° C.lization);for 1 hour, the precipitate is filtered off and dried (229-231)*at room temperature.*Polymorphs (IC), (IE), (IF), (IG) transform into polymorph (IB) by heating above their melting points.

[0030] Melting points were determined on a Boetius PHMK 05 type apparatus. Heating rate: 10° C./minute.

[0031] The invention also relates to the new salts of the acid of formula (I) and of its polymorphs and solvates, given with

[0032] ethanolamine of the formula (A): HO—(CH2)2—NH2, or

[0033] diethanolamine of the formula (B): HO—(CH2)2—NH—(CH2)2—OH, or

[0034] diethylamine of the formula (C): (CH3CH2)2NH, or

[0035] adamantanamine of the formula (D):

[0036] The new salts of the present invention have constant stoichiometry, they are non-hygroscopic, stable, and have favourable technological characteristics for drug product manufacturing. In contrast to the acid of the formula (I), the new salts of the present invention do not show polymorphism, and their solubility in aqueous medium is higher by one order than that of the free acid.

[0037] Most favourable properties of the new salts of the present invention are shown by the 3-[2-[[[1-(2-cyclohexylethyl)-5-(2,5-dimethoxy-4-methylphenyl)-1H-1,2,4-triazol-3-yl]amino]carbonyl]-6-methoxy-4,5-dimethyl-1H-indol-1-yl]propionic acid ethanolamine salt.

[0038] The present invention relates further to the process of preparation of the new salts formed between the acid of formula (I), or its polymorphs or solvates, and ethanolamine, diethanolamine, ethylamine, or with adamantanamine, which comprises reacting the acid of formula (I) or a polymorph or solvate of it with

[0039] ethanolamine of the formula (A), or

[0040] diethanolamine of the formula (B), or

[0041] diethylamine of the formula (C), or

[0042] adamantanamine of the formula (D).

[0043] The compounds of formulae (A), (B), (C) and (D) are preferably applied in a molar excess of 1.0-1.2. Reactions are preferably carried out in a protic solvent, preferably at room temperature. As a protic solvent preferably ethanol, acetone, or ethyl acetate are used.

[0044] The compounds of formula (I) underwent studies of in vitro binding to CCK1 and CCK2 receptors, using the method described in Europ. J. Pharmacol., 1993, 232, 13-19. Compound of Example 1 binds with a very high affinity (IC50=0.4 nM) (IC50: Inhibiting Concentration50) to the human CCK1 receptor and with a low affinity to the human CCK2 receptor (IC50=234 nM), leading to a high level of selectivity (affinity CCK1 receptor versus affinity of CCK2 receptor>500-fold). The agonist activity of the compounds towards CCK1 receptors was evaluated in vitro in 3T3 cells expressing the human CCK1 receptor, by measuring the mobilization of the intracellular calcium ([Ca++]i), according to a technique derived from that of Lignon M F et al., Eur. J. Pharmacol., 1993, 245, 241-245. The calcium concentration [Ca++]i is evaluated with Fura-2 by the double excitation wavelength method. The ratio of the fluorescence emitted at two wavelengths gives the concentration of [Ca++]i, after calibration (Grynkiewiez G. et al., J. Biol. Chem., 1985, 260, 3440-3450).

[0045] The compounds of the invention, like CCK1 stimulate [Ca++]i release with an efficiency comparable to that of CCK-8S: for compound of Example 1: EC50 (Efficiency Concentration50), around 1 nM and so behave as CCK1 receptor agonists.

[0046] An in vivo study of the agonist effect of the compounds on gastric emptying was carried out as follows. Female Swiss albino CD1 mice (20-25 g) are placed on a solid fast for 18 hours. On the day of the experiment, the products are administered orally 60 minutes before the administration of a charcoal meal (0.3 ml per mouse of a suspension in water of 10% charcoal powder, 5% gum arabic and 1% carboxymethylcellulose). The mice are sacrificed 5 minutes later by cervical dislocation, and the gastric emptying is defined as the presence of charcoal in the intestine beyond the pyloric sphincter (Europ. J. Pharmacol., 1993, 232, 13-19).

[0047] The compounds of formula (I) block gastric emptying, like CCK itself, and therefore behave as CCK receptor agonists: compound of Example 3 inhibits gastric emptying at very low doses with an ED50 (Efficient Dose50) of 27 μg/kg p.o.

[0048] The compounds of the invention are much more powerful CCK1 agonists than the molecules described in patent application WO 98/51686. Indeed, surprisingly, they simultaneously meet the following different criteria: they possess not only a high affinity for CCK1 receptors but also good selectivity for CCK1 receptors (relative to CCK2 receptors) and a powerful agonist activity for CCK1 receptors, demonstrated by the intracellular calcium mobilization and gastric drainage tests.

[0049] Consequently, the compounds of formula (I) are used as CCK1 receptor agonists for preparing medicaments intended for combating diseases whose treatment necessitates stimulation of cholecystokinin CCK1 receptors. More particularly, the compounds of formula (I) are used for the manufacture of medicaments intended for the treatment of certain disorders of the gastrointestinal field (prevention of bile stones, irritable bowel syndrome, etc), eating disorders, obesity and associated pathologies such as diabetes and hypertension. The compounds (I) induce a state of satiety and are therefore used to regulate appetite and to reduce food intake, to treat obesity and to bring about weight loss. The compounds (I) are also useful in central nervous system disorders, especially disorders of memory loss, sexual disorders and emotional behaviour disorders, psychoses and, in particular, schizophrenia, Parkinson's disease, dyskinesia, such as tardive dyskinesia or facial dyskinesia induced following treatment by neuroleptics or other agents such as dopamine agonists which are used in the treatment of Parkinson's disease, and various disorders of the gastrointestinal field. They may also be used to treat craving disorders, i.e. to regulate the desire to consume—in particular, to consume sugars, fat, alcohol or drugs and, more generally, appetite-inducing ingredients. The compounds (I) are also useful for the treatment and/or prophylaxis of all diseases involving degeneration of NGF-sensitive neurons, such as, for example, cholinergic neurons and sympathic or sensorial neurons, more particularly for the treatment of the following pathologies: memory disorders, vascular dementia, post-encephalitic disorders, post-apoplectic disorders, post-traumatic syndromes due to cranial trauma, disorders deriving from cerebral anoxias, Alzheimer's disease, senile dementia, AIDS-induced dementia, neuropathies as a result of morbidity or damage to sympathic or sensorial nerves, cerebral diseases such as cerebral oedema and spinocerebellar degeneration, and diabetic neuropathies.

[0050] The present invention therefore also provides pharmaceutical compositions comprising a compound of the invention together with appropriate excipients.

[0051] The said excipients are selected depending on the pharmaceutical form and the desired method of administration: oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal, rectal or intraocular. These compositions are prepared in accordance with techniques which are well known to the person skilled in the art.

[0052] Each unit dose may contain from 0.1 to 1 000 mg, preferably from 0.1 to 500 mg, of active ingredient in combination with a pharmaceutical excipient.

[0053] This unit dose may be administered from 1 to 5 times a day such as to administer a daily dose of from 0.05 to 5 000 mg, preferably from 0.1 to 2 500 mg.

[0054] The pharmaceutical compositions of the invention may be used in the treatment or prevention of various conditions in which CCK is of therapeutic interest.

[0055] The invention also relates to a method of treatment which comprises using effective doses of a compound of the invention for combating diseases whose treatment necessitates stimulation of cholerystokinin CCK1 receptors.

[0056] The examples below illustrate the invention.

[0057] Preparation 1

[0058] 2,5-Dimethoxy-4-methylbenzoic acid (Compound XII)

[0059] a) 2,5-Dimethoxy-4-methylbenzaldehyde

[0060] 280 ml of phosphorus oxide trichloride are admixed with 212 ml of N-methylformanilide. After 4 hours at room temperature, 110 g of 2,5-dimethoxytoluene are added and the reaction mixture is brought to 70° C. for 2 hours. The reaction mixture is poured dropwise onto ice. The precipitate obtained is filtered, taken up in dichloromethane and decanted. The organic phase is dried over anhydrous sodium sulphate and the solvents are evaporated under reduced pressure. This gives 116 g of yellow crystals; m.p.=83° C.

[0061] b) 2,5-Dimethoxy-4-methylbenzoic acid

[0062] 23.86 g of 2,5-dimethoxy-4-methylbenzaldehyde in solution in 500 ml of water are heated to 75° C. and 29.3 g of potassium permanganate in solution in 500 ml of water are introduced. The reaction mixture is left at 75° C. for 2 hours, after which the pH is adjusted to 10 with 10% sodium hydroxide solution and the insoluble matter is filtered off hot and washed three times with 80 ml of hot water. The filtrate is cooled and the precipitate formed is filtered off and dried under vacuum at 40° C. to give white crystals; m.p.=120° C.; yield=71%

[0063]

1
H NMR: 2.15 (s, 3H); 3.73 (s, 6H); 6.94 (s, 1H); 7.17 (s, 1H); 12.40 (s, 1H).

[0064] Preparation 2

[0065] 2,5-Dimethoxy-4-methylbenzamidoguanidine (Compound XI)

[0066] 43.46 g of 2,5-dimethoxy-4-methylbenzoic acid in suspension in 300 ml of toluene are admixed with 1 ml of dimethylformamide and then dropwise with 23.3 ml of oxalyl chloride. The reaction mixture is heated at 80° C. for two hours and then the solvents are evaporated under reduced pressure. The crystalline residue is added in portions to a suspension of 36.2 g of aminoguanidine hydrogen carbonate in 350 ml of pyridine at 0° C. and the reaction mixture is left at ambient temperature for 18 hours. The solvents are evaporated under reduced pressure and then the residue is taken up in 180 ml of water and 141 ml of 2M sodium hydroxide solution. Following 18 hours stirring at ambient temperature, the precipitate is filtered off and dried under reduced pressure to give a beige solid; m.p.=193° C.; yield=93%.

[0067] Preparation 3

[0068] 3-(2,5-Dimethoxy-4-methylphenyl)-1H-1,2,4-triazol-5-amine (Compound X)

[0069] 29.98 g of 2,5-dimethoxy-4-methylbenzamidoguanidine are admixed with 400 ml of diphenyl ether and then the reaction mixture is heated at 170° C. for 5 minutes. The temperature is taken down to 80° C. and then the precipitate is filtered off, washed with diisopropyl ether and dried under reduced pressure to give crystals; m.p.=248° C.; yield=80%.

[0070] Preparation 4

[0071] 3-(2,5-Dimethoxy-4-methylphenyl)-N-(diphenylmethylene)-1H-1,2,4-triazol-5-amine (Compound IX)

[0072] 22.4 g of 3-(2,5-dimethoxy-4-methylphenyl)-1H-1,2,4-triazol-5-amine in suspension in 50 ml of xylene and 42 ml of benzophenoneimine are heated at 140° C. for 48 hours under a stream of argon. The temperature is taken down to 80° C. and then the reaction mixture is poured into 100 ml of diisopropyl ether, and the precipitate formed is filtered off, washed with diisopropyl ether and dried under reduced pressure to give a yellow solid; m.p.=228° C.; yield=79%.

[0073] Preparation 5

[0074] 1-(2-Cyclohexylethyl)-5-(2,5-dimethoxy-4-methylphenyl)-1H-1,2,4-triazol-3-amine (Compound III)

[0075] a) N-Alkylation of the Triazole

[0076] 8.8 g of 3-(2,5-dimethoxy-4-methylphenyl)-N-(diphenylmethylene)-1H-1,2,4-triazol-5-amine in solution in 100 ml of dimethylformamide are admixed in successively with 4.5 g of potassium carbonate and 8 ml of 1-bromo-2-cyclohexylethane and the reaction mixture is heated at 70° C. for 18 hours. 300 ml of ethyl acetate are added, the mixture is washed twice with water, the organic phase is dried over anhydrous sodium sulphate and the solvents are evaporated under reduced pressure. The residue is chromatographed on a silica gel column, eluting with a 95/5 (v/v) toluene/ethyl acetate mixture, to give a colourless oil.

[0077]

1
H NMR: 0.66-1.52 (m, 13H); 2.12 (s, 3H); 3.67 (s, 6H); 3.74 (t, 2H); 6.46 (s, 1H); 6.98 (s, 1H); 7.13-7.71 (m, 10H).

[0078] b) Hydrolysis of the Diphenylimine Function

[0079] 4.7 g of the oil obtained above, in solution in 100 ml of methanol, are admixed with 35 ml of 2M hydrochloric acid. The reaction mixture is left at ambient temperature for 18 hours and then the solvents are evaporated under reduced pressure. The oily residue is concreted in diethyl ether and the precipitate obtained is filtered off and dried under reduced pressure to give white crystals; m.p.=166° C. (HCl); yield=90%.

[0080]

1
H NMR: 0.82 (m, 2H); 1.05 (m, 4H); 1.3-1.7 (m, 7H); 2.23 (s, 3H); 3.75 (s, 3H); 3.78 (s, 3H); 3.86 (t, 2H); 7.14 (s, 2H); 7.2-7.5 (m, 2H).

[0081] Preparation 6

[0082] Ethyl 4,5-dimethyl-6-methoxy-1H-indole-2-carboxylate (Compound VII)

[0083] Step 1: Preparation of the Azide

[0084] 2.8 g of sodium are added in portions to 75 ml of ethanol. This solution is admixed dropwise at −20° C. with a mixture of 10 g of 2,3-dimethyl-4-methoxybenzaldehyde and 15.5 g of ethyl azidoacetate in 30 ml of ethanol. After 4 hours at −15° C., the reaction mixture is poured into 400 ml of 1M hydrochloric acid and the precipitate formed is filtered off. It is dried under reduced pressure for 18 hours to give yellow crystals; m.p.=80° C.; yield=65%.

[0085]

1
H NMR: 1.31 (t, 3H); 2.05 (s, 3H); 2.16 (s, 3H); 3.77 (s, 3H); 4.3 (q, 2H); 6.83 (d, 1H); 7.08 (s, 1H); 7.72 (d, 1H).

[0086] Step 2: Cyclization of the Azide

[0087] 7.9 g of the compound obtained in step 1, in solution in 60 ml of xylene, are added dropwise to 100 ml of xylene heated at 140° C. When the addition is complete, the reaction mixture is left at 140° C. for 5 minutes and returned to ambient temperature. The precipitate obtained is filtered off and dried to give white crystals; m.p.=185° C.; yield=85%.

[0088]

1
H NMR: 1.3 (t, 3H); 2.1 (s, 3H); 2.35 (s, 3H); 3.76 (s, 3H); 4.27 (q, 2H); 6.69 (s, 1 H); 7.08 (s, 1H); 11.5 (s, 1H).

[0089] Preparation 7

[0090] 4,5-Dimethyl-6-methoxy-1H-indole-2-carboxylic acid (Compound VI)

[0091] A mixture of 100 ml of methanol and 150 ml of 1,4-dioxane is admixed with 7 g of ethyl 4,5-dimethyl-6-methoxy-1H-indole-2-carboxylate and then 28 ml of 2M sodium hydroxide solution. The reaction mixture is left at ambient temperature for 48 hours. Following evaporation of the solvents under reduced pressure, the residue is taken up in 6N hydrochloric acid and the precipitate formed is filtered off and dried under reduced pressure to give 4,5-dimethyl-6-methoxy-1H-indole-2-carboxylic acid in the form of white crystals; m.p.=208° C.; yield=92%.

[0092]

1
H NMR: 2.1 (s, 3H); 2.35 (s, 3H); 3.76 (s, 1H); 6.69 (s, 1H); 7.03 (s, 1H); 11.38 (s, 1H); 12.5 (m, 1H).

[0093] Preparation 8

[0094] Benzyl 4,5-dimethyl-6-methoxy-1-(2-cyanoethyl)-1H-indole-2-carboxylate (Compound V)

[0095] Step 1: Benzyl 4,5-dimethyl-6-methoxy-1H-indole-2-carboxylate

[0096] 20 ml of dimethylformamide are admixed successively with 5.17 g of 4,5-dimethyl-6-methoxy-1H-indole-2-carboxylic acid and 3.5 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene. The reaction mixture is left at 0° C. for 40 minutes and then 3.9 ml of benzyl bromide are introduced dropwise. After 18 hours of reaction at ambient temperature, the reaction mixture is poured into 300 ml of water and the precipitate formed is filtered off, washed with water and then dried at 50° C. under reduced pressure for 18 hours to give yellow crystals; m.p.=161° C.; yield=90%.

[0097]

1
H NMR: 2.1 (s, 3H); 2.35 (s, 3H); 3.76 (s, 3H); 5.32 (s, 2H); 6.70 (s, 1H); 7.14 (s, 1H); 7.3-7.55 (m, 5H); 11.57 (s, 1H).

[0098] Step 2:

[0099]

4
.24 g of benzyl 4,5-dimethyl-6-methoxy-1H-indole-2-carboxylate in solution in 36 ml of 1,4-dioxane are admixed successively with 0.22 ml of 40% aqueous benzyltrimethylammonium hydroxide solution and 2.18 ml of acrylonitrile and the reaction mixture is heaten to reflux for 4 hours. Following evaporation of the solvents under reduced pressure, the residue is taken up in dichloromethane and washed with water. After decanting, the organic phase is dried over anhydrous sodium sulphate. The residue obtained following evaporation of the organic phase is concreted using diethyl ether and dried to give a beige solid; m.p.=140° C.; yield=95%.

[0100]

1
H NMR: 2.1 (s, 3H); 2.35 (s, 3H); 2.93 (t, 2H); 3.87 (s, 3H); 4.80 (t, 2H); 5.31 (s, 2H); 7.05 (s, 1H); 7.29-7.50 (m, 6H).

[0101] Preparation 9

[0102] 4,5-Dimethyl-6-methoxy-1-(3-methoxy-3-oxopropyl)-1H-indole-2-carboxylic acid (Compound IV.1)

[0103] a) Benzyl 4,5-dimethyl-6-methoxy-1-(3-methoxy-3-oxopropyl)-1H-indole-2-carboxylate

[0104] 100 ml of methanol are saturated at 0° C. with hydrogen chloride gas. This solution is admixed at −20° C. with 4 g of benzyl 4,5-dimethyl-6-methoxy-1-(2-cyanoethyl)-1H-indole-2-carboxylate in solution in 100 ml of dichloromethane and is left at 0° C. for 18 hours. Following evaporation of the solvents under reduced pressure, the residue is taken up in 60 ml of methanol, 60 ml of dichloromethane and 10 g of ice and is left at 20° C. for 3 hours. The solvents are evaporated and the residue is taken up in ethyl acetate, washed with water and dried over anhydrous sodium sulphate to give a beige solid; m.p.=198° C.; yield=92%.

[0105] b) 5.69 g of the compound obtained above are added to 3 g of 10% palladium on carbon in suspension in 500 ml of ethanol. 40 ml of cyclohexene are introduced and the reaction mixture is heaten to reflux for 4 hours. It is filtered at 20° C. and the filtrate is concentrated to give a beige solid; m.p.=198° C.; yield=90%.

EXAMPLE 1

[0106] 3-[2-[[[1-(2-cyclohexylethyl)-5-(2,5-dimethoxy-4-methylphenyl)-1H-1,2,4-triazol-3-yl]amino]carbonyl]-6-methoxy-4,5-dimethyl-1H-indol-1-yl]propionic acid, Potassium Salt

[0107] a) Methyl 3-[2-[[[1-(2-cyclohexylethyl)-5-(2,5-dimethoxy-4-methylphenyl)-1H-1,2,4-triazol-3-yl]amino]carbonyl]-6-methoxy-4,5-dimethyl-1H-indol-1-yl]propanoate, compound II.

[0108] 0.706 g of 4,5-dimethyl-6-methoxy-1-(3-methoxy-3-oxopropyl)-1H-indole-2-carboxylic acid (compound IV) in solution in 5 ml of dichloromethane is admixed successively at 0° C. with 1.08 ml of pyridine and 0.195 ml of thionyl chloride. After 1 hour at this temperature, 0.929 g of 1-(2-cyclohexylethyl)-5-(2,5-dimethoxy-4-methylphenyl)-1H-1,2,4-triazol-3-amine (compound III) is introduced and the reaction mixture is left at 20° C. for 18 hours. Following dilution with dichloromethane and washing with water, the organic phase is dried over anhydrous sodium sulphate and the solvents are evaporated under reduced pressure. The residue is purified by chromatography on a silica gel column, eluting with dichloromethane, to give 1.1 g of white crystals; m.p.=175° C.; yield=83%.

[0109]

1
H NMR: 0.8 (m, 2H); 1.1 (m, 4H); 1.4-1.7 (m, 7H); 2.12 (s, 3H); 2.23 (s, 3H); 2.37 (s, 3H); 3.55 (s, 3H); 3.74 (s, 6H); 3.84 (s, 3H); 3.9 (t, 2H); 4.37 (t, 2H); 6.89 (s, 1H); 6.91 (s, 1H); 7.06 (s, 1H); 7.52 (s, 1H); 11.54 (s, 1H).

[0110] b) 1.59 g of the compound obtained above, in solution in a mixture of 5 ml of methanol and 10 ml of 1,4-dioxane, are admixed with 3 ml of 1 M potassium hydroxide solution and the reaction mixture is left at 20° C. for 72 hours. The solvents are evaporated under reduced pressure and the residue is taken up in diethyl ether, filtered and dried to give 1.56 g of beige crystals; m.p.=236° C.; yield=97%.

[0111]

1
H NMR: 0.8 (m, 2H); 1.1 (m, 4H); 1.35-1.65 (m, 7H); 2.11 (s, 3H); 2.23 (s, 3H); 2.37 (s, 3H); 2.39 (t, 2H); 3.74 (s, 6H); 3.84 (s, 3H); 3.89 (t, 2H); 4.55 (t, 2H); 6.83 (s, 1H); 6.91 (s, 1H); 7.05 (s, 1H); 7.27 (s 1H); 10.50 (s, 1H).

EXAMPLE 2

[0112] 3-[2-[[[1-(2-cyclohexylethyl)-5-(2,5-dimethoxy-4-methylphenyl)-1H-1,2,4-triazol-3-yl]amino]carbonyl]-6-methoxy-4,5-dimethyl-1H-indol-1-yl]propionic acid

[0113] To a solution of 29.08 g potassium hydroxide in 22.3 ml water and 710 ml ethanol, 95.0 g of the ester of Example 1, step A, is added at 50° C.

[0114] After 30 minutes stirring, the mixture is filtered and acidified with 38 ml concentrated HCl in 340 ml water. The precipitate is filtered off, washed with water (to be chloride ion free) and dried to give 90.1 g of the acid; m.p.=222-228° C.; yield: 96.6%.

EXAMPLE 3

[0115] 6.17 g of the acid of formula (I) are suspended in 10-fold amount of ethanol and 0.66 g of ethanolamine are added. Clear solution is obtained, allowed to crystallize. The precipitated salt is filtered off, washed with ethanol and dried. 6.2 g of 3-[2-[[[1-(2-cyclohexylethyl)-5-(2,5-dimethoxy-4-methylphenyl)-1H-1,2,4-triazol-3-yl]amino]carbonyl]-6-methoxy-4,5-dimethyl-1H-indol-1-yl]propionic acid ethanolamine salt are obtained; m.p.=199-200° C.

[0116] NMR: 0.79 (m, 2H), 1.06 (m, 4H); 1.4-1.7 (m, 7H); 2.14 (s, 3H); 2.25 (s, 3H); 2.39 (s, 3H); 2.46 (t, 2H, 3JCH2,CH2=7.5 Hz); 2.79 (t, 2H, 3JCH2,CH2=5.2 Hz); 3.55 (t, 2H, 3JCH2,CH2=5.2 Hz); 3.77 (s, 3H); 3.78 (s, 3H); 3.83 (s, 3H); 3.92 (t, 2H, 3JCH2,CH2=7.5 Hz); 4.67 (t, 2H, 3JCH2,CH2=6.9 Hz); 6.90 (s, 1H); 6.94 (s, 1H); 7.08 (s, 1H), 7.48 (s, 1H).

[0117] IR: KBr, (cm−1): 3215, 2928, 2846, 2651-2412, 1680, 1622, 1561, 1524, 1485, 1442, 1406, 1262, 1216, 1186, 1144, 1108, 1039, 863, 795, 746.

EXAMPLE 4

[0118] To the solution made of 0.7 g of diethanolamine in 15 ml of ethanol, 3.7 g of the acid (I) are added. The mixture is allowed to stand at room temperature, the resulting crystals are filtered off, washed with ethanol. 3.75 g of 3-[2-[[[1-(2-cyclohexylethyl)-5-(2,5-dimethoxy-4-methylphenyl)-1H-1,2,4-triazol-3-yl]amino]carbonyl]-6-methoxy-4,5-dimethyl-1H-indol-1-yl]propionic acid diethanolamine salt are obtained; m.p.=171-172° C.

[0119] NMR: 0.78 (m,2H); 1.03-1.07 (m, 4H); 1.4-1.7 (m, 7H); 2.13 (s, 3H); 2.23 (s, 3H); 2.38 (s, 3H); 2.46 (t, 2H, 3JCH2,CH2=7.5 Hz); 2.83 (t, 4H, 3JCH2,CH2=5.5 Hz); 3.56 (t, 4H, 3JCH2,CH2=5.5 Hz); 3.74 (s, 3H); 3.76 (s, 3H); 3.84 (s, 3H); 3.91 (t, 2H, 3JCH2,CH2=7.5 Hz); 4.63 (t, 2H, 3JCH2,CH2=7.5 Hz); 6.90 (s, 1H); 6.93 (s, 1H); 7.07 (s, 1H); 7.41 (s, 1H).

[0120] IR: KBr, (cm−1): 3439, 2920, 1667, 1620, 1559, 1527, 1478, 1278, 1230, 1146, 1112, 1042, 862, 802, 756, 720.

EXAMPLE 5

[0121] 6.2 g of the acid of formula (I) are suspended in 15 ml of ethyl acetate, and 1.5 g of 1-aminoadamantane are added. The resulting clear solution is evaporated. The residue solidifies under hexane to give the 3-[2-[[[1-(2-cyclohexylethyl)-5-(2,5-dimethoxy-4-methylphenyl)-1H-1,2,4-triazol-3-yl]amino]carbonyl]-6-methoxy-4,5-dimethyl-1H-indol-1-yl]propionic acid adamantanamine salt; m.p.=119° C.

[0122] NMR: 0.80 (m, 2H); 1.04-1.08 (m, 4H); 1.4-1.8 (m, 25H); 2.00 (s, 3H); 2.14 (s, 3H); 2.25 (s, 3H); 2.38 (s, 3H); 2.46 (t, 2H, 3JCH2,CH2=7.2 Hz); 3.76 (s, 3H); 3.77 (s, 3H); 3.85 (s, 3H); 3.91 (t, 2H, 3JCH2,CH2=7.2 Hz); 4.65 (t, 2H, 3JCH2,CH2=7.2 Hz); 6.89 (s, 1H); 6.92 (s, 1H); 7.08 (s, 1H); 7.44 (s, 1H); ˜10.8 (b, 1H).

[0123] IR: KBr, (cm−1): 3425, 2921, 2851, 1677, 1619, 1560, 1489, 1391, 1217, 1144, 1123, 1042, 863, 801, 757.

EXAMPLE 6

[0124] To the suspension of 3.07 g of the acid of formula (I) in acetone, 0.45 g of diethylamine in 11 ml acetonic of solution are added. The clear solution is concentrated, diethyl ether is added, the resulting crystals are filtered off to obtain:

[0125] 3.2 g of 3-[2-[[[1-(2-cyclohexylethyl)-5-(2,5-dimethoxy-4-methylphenyl)-1H-1,2,4-triazol-3-yl]amino]carbonyl]-6-methoxy-4,5-dimethyl-1H-indol-1-yl]propionic acid diethylamine salt; m.p.=143° C. (decomposition).

[0126] NMR: 0.79 (m, 2H); 1.03-1.2 (m, 10H); 1.4-1.7 (m, 7H); 2.15 (s, 3H); 2.52 (s, 3H); 2.39 (s, 3H); 2.49 (m, 2H); 2.75 (q, 4H); 3.76 (s, 3H); 3.78 (s, 3H); 3.85 (s, 3H); 3.92 (t, 2H, 3JCH2,CH2=7.1 Hz); 4.67 (t, 2H, 3JCH2,CH2=7.1 Hz); 6.91 (s, 1H); 6.93 (s, 1H); 7.09 (s, 1H); 7.48 (s, 1H); ˜10.8 (b, 1H).

[0127] IR: KBr, (cm−1): 3419, 2924, 2850, 1675, 1620, 1555, 1519, 1487, 1390, 1217, 1144, 1112, 1043, 867, 803, 757.

EXAMPLE7

[0128] 6.3 g of the methyl ester of the acid of formula (I) are dissolved in 50 ml of 96% ethanol which contains 2 g of potassium hydroxide. The solution is kept at 45-50° C. for 40 minutes. After clarifying with charcoal and filtration, the pH is adjusted to 3 with aqueous hydrochloric acid. The resulting crystals are filtered off, washed thoroughly with water. 5.9 g of the acid of formula (I) are obtained. Purity by HPLC: 98.9%; m.p.=234° C.

EXAMPLE 8

[0129] 6.03 g of the methyl ester of the acid of formula (I) are dissolved in 60 ml of 96% ethanol which contains 1.2 g of sodium hydroxide. The solution is stirred at 50° C. for 1 hour, clarified with charcoal, filtered, the warm solution is made acidic, allowed to cool down. 6.03 g of the acid of formula (I) are obtained. Purity by HPLC: 99%. m.p.=213° C. (shrinking) −231° C. (melting).

EXAMPLE 9

[0130] The following solid forms of the compound of formula (I) have been identified, by using the methods of investigation shown below:

[0131] Polymorphs:

[0132] polymorph (IA)

[0133] polymorph (IB)

[0134] polymorph (IC)

[0135] polymorph (IDb)

[0136] polymorph (IE)

[0137] polymorph (IF)

[0138] Solvates:

[0139] Solvate (pseudopolymorphs) (IG), which is the solvate of polymorph (IE) with CHCl3.

[0140] Mixture form: polymorph (ID), which is most likely the mixture of polymorph (IDb) with another polymorph which has not been obtained in pure state, as yet.

2Methods of investigationConditionsX-RAY POWDER DIFFRACTIONInstrumentPhilips powder diffractometerPW3710RadiationCuKα (λ = 1.5418 ÅLambda α1 (Å)1.54060Lambda α2 (Å)1.54439α1:α2 ratio2:12Θ Range3-30°Scanning speed (2Θ°)0.02Scanning interval (mp)1seeTable 3 and FIGS. 1-6IR SPECTROSCOPYInstrumentBruker IFS-28Range4000-400 cm−1Sample preparation1-2 mg of sample 0.2 g of KBrcompressed in pellettSeeTable 2 and FIGS. 16-23DSCInstrumentMettier Toledo DSC821eTemperature range25-250° C.Heating rate10° C./minuteSample holder40 μl alumina crucible, coverwith holeGas flowAir, 0 ml/percSeeTable 5 and FIGS. 7-14TG-DSCInstrumentSetaram TG-DSC111simultanous TG-DSCmeasurementsTemperature range25-250° C.Heating rate5° C./minutesSample holderPlatinum crucibleGas flowN2SeeTables 5 and 15.SOLID PHASE NMRInstrumentBruker DRX-500Measurement13C (1H) CP/MASSpinning rate15 KHzSeeTable 4 and FIGS. 24-28

[0141]

3

TABLE 2

IR spectroscopic characteristics

Polymorph (IA)
Polymorph (IB)
Polymorph (IC)
Polymorph (ID)

Rel.

Rel.

Rel.

Rel.

Wave
Inten-
Wave
Inten-
Wave
Inten-
Wave
Inten-

number
sity
number
sity
number
sity
number
sity

(cm−1)
(I/Io)
(cm−1)
(I/Io)
(cm−1)
(I/Io)
(cm−1)
(I/Io)

3281.3
0.221
3309.7
0.279
3337.8
0.186
3299.1
0.232

3118.8
0.032
3121.6
0.030
2926.0
0.540
3116.5
0.024

2925.1
0.605
2921.0
0.760
2851.8
0.108
2920.9
0.647

2847.7
0.121
2848.7
0.223
2516.5
0.082
2849.0
0.164

2523.8
0.084
2524.1
0.126
1935.6
0.132
2525.3
0.082

1905.6
0.056
1897.4
0.054
1681.9
0.612
1921.6
0.061

1684.9
0.577
1683.7
0.611
1620.8
0.297
1683.4
0.671

1619.4
0.288
1620.1
0.378
1560.0
0.126
1618.5
0.343

1559.0
0.127
1564.6
0.170
1522.2
0.472
1559.6
0.200

1520.3
0.123
1545.5
0.037
1493.6
0.052
1522.9
0.609

1490.1
0.425
1525.9
0.513
1406.6
0.036
1493.5
0.160

1386.5
0.060
1490.3
0.217
1391.4
0.067
1476.1
0.058

1336.0
0.133
1453.2
0.042
1375.8
0.102
1390.8
0.059

1308.1
0.070
1375.1
0.216
1363.1
0.079
1371.5
0.178

1282.7
0.072
1329.4
0.044
1335.7
0.152
1305.0
0.070

1215.9
0.838
1287.8
0.258
1303.5
0.154
1286.9
0.220

1143.4
0.266
1217.3
0.960
1286.2
0.112
1218.2
0.892

1111.2
0.260
1145.2
0.449
1218.5
0.855
1142.4
0.369

1033.6
0.480
1113.8
0.420
1143.8
0.220
1109.6
0.340

934.3
0.117
1038.3
0.658
1113.8
0.221
1036.9
0.539

908.0
0.046
963.9
0.043
1036.4
0.448
1004.8
0.037

869.4
0.299
942.3
0.093
963.7
0.043
964.6
0.053

801.4
0.347
930.0
0.055
929.7
0.226
938.2
0.059

754.6
0.369
904.8
0.079
899.6
0.045
904.9
0.076

720.6
0.156
863.7
0.456
862.8
0.380
866.7
0.374

676.5
0.071
838.2
0.059
832.0
0.026
813.5
0.107

637.1
0.152
813.9
0.089
807.4
0.201
797.3
0.380

588.4
0.071
805.3
0.133
794.8
0.429
755.8
0.363

521.7
0.078
793.5
0.416
753.8
0.460
729.6
0.165

499.2
0.047
756.3
0.475
726.7
0.281
687.7
0.057

456.5
0.236
725.9
0.281
688.8
0.078
632.2
0.143

708.6
0.045
672.3
0.166
588.2
0.115

675.0
0.079
641.3
0.216
520.0
0.156

632.8
0.217
602.3
0.036
494.4
0.046

590.5
0.106
589.0
0.123
453.8
0.294

520.9
0.146
523.9
0.196

497.5
0.039
500.8
0.145

480.4
0.033
454.1
0.431

453.1
0.355

Solvate

(Pseudo-

Polymorph (IDb)
Polymorph (IE)
Polymorph (IF)
polymorph) (IG)

Rel.

Rel.

Rel.

Rel.

Wave
inten-
Wave
inten-
Wave
inten-
Wave
inten-

number
sity
number
sity
number
sity
number
sity

(cm−1)
(I/Io)
(cm−1)
(I/Io)
(cm−1)
(I/Io)
(cm−1)
(I/Io)

3296.9
0.270
3276.5
0.150
3316.4
0.218
3282.7
0.216

3116.5
0.034
3133.5
0.038
3116.5
0.036
3125.9
0.048

2995.0
0.056
2923.0
0.592
2921.6
0.588
2923.2
0.774

2920.6
0.695
2849.0
0.115
2850.7
0.135
2849.0
0.171

2851.4
0.178
2593.6
0.051
2484.4
0.126
2596.5
0.077

2524.2
0.129
1889.8
0.048
1924.6
0.113
1891.4
0.031

1922.0
0.096
1678.8
0.394
1683.8
0.512
1678.1
0.431

1683.7
0.593
1619.1
0.255
1619.9
0.267
1619.4
0.307

1618.0
0.369
1568.5
0.072
1560.1
0.155
1569.6
0.200

1561.8
0.223
1523.7
0.149
1522.6
0.417
1523.8
0.205

1524.4
0.523
1479.6
0.402
1493.8
0.090
1480.7
0.419

1494.1
0.124
1387.8
0.121
1392.2
0.118
1390.7
0.132

1476.3
0.053
1336.2
0.057
1371.7
0.089
1374.5
0.044

1451.7
0.064
1283.4
0.127
1331.9
0.055
1283.1
0.136

1391.6
0.084
1216.5
0.855
1304.5
0.149
1216.4
0.886

1369.4
0.191
1145.4
0.245
1286.5
0.060
1146.8
0.281

1305.0
0.250
1110.7
0.245
1217.2
0.860
1110.9
0.308

1287.6
0.087
1040.7
0.445
1142.3
0.275
1040.9
0.485

1260.4
0.039
964.2
0.043
1111.5
0.250
1005.6
0.029

1227.9
0.912
935.5
0.110
1034.5
0.479
964.7
0.044

1141.9
0.409
898.8
0.021
1006.5
0.035
936.7
0.103

1109.6
0.364
870.0
0.242
964.5
0.044
870.3
0.233

1037.2
0.521
833.4
0.066
939.0
0.082
801.1
0.309

964.4
0.057
799.8
0.384
905.0
0.114
756.7
0.428

939.7
0.093
757.0
0.431
870.0
0.345
731.0
0.091

904.6
0.116
731.5
0.065
815.1
0.145
665.4
0.082

866.9
0.433
720.8
0.185
794.6
0.393
640.0
0.139

813.5
0.113
667.8
0.101
755.9
0.316
588.9
0.069

797.8
0.498
640.8
0.201
721.2
0.219
520.5
0.135

756.5
0.394
590.3
0.061
692.2
0.061
496.3
0.077

728.9
0.214
521.6
0.104
636.1
0.162
473.1
0.048

689.8
0.071
496.8
0.207
589.5
0.196

633.6
0.269
471.8
0.046
543.7
0.051

588.3
0.133

517.8
0.226

538.0
0.022

493.8
0.073

520.2
0.201

452.2
0.396

494.9
0.052

478.7
0.046

452.2
0.392

[0142]

4

TABLE 3

X-Ray powder diffractometry Data

Polymorph (IA)
Polymorph (IB)
Polymorph (IC)
Polymorph (ID)
Polymorph (IDb)
Polymorph (IE)

2Θ (°)
I/Io*
2Θ (°)
I/Io
2Θ (°)
I/Io
2Θ (°)
I/Io*
2Θ (°)
I/Io
2Θ (°)
I/Io

4.0
58
4.725
63
8.2
92
4.4
2
5.2
8
3.7
1

4.2
60
6.87
15
9.1
29
5.1
7
7.2
32
5.2
35

4.4
21
9.035
28
9.6
100
7.0
21
8.2
7
5.5
100

8.4
12
9.435
22
10.3
56
8.8
45
8.8
48
7.8
1

9.7
8
10.13
32
10.4
59
9.4
16
9.6
14
8.6
2

10.3
17
10.66
100
10.9
47
9.7
23
10.7
95
9.2
2

10.7
25
11.31
9
11.1
20
10.0
26
10.9
41
10.0
4

11.4
16
11.71
17
12.0
9
10.6
45
11.4
12
10.4
8

11.8
24
11.835
12
12.5
9
11.9
21
12.5
14
11.0
2

12.2
10
12.525
21
14.3
20
12.0
23
13.2
18
12.1
3

13.1
9
13.02
28
14.4
17
12.4
13
13.6
21
14.1
4

14.0
8
13.55
15
16.1
21
13.2
14
14.1
40
14.9
4

14.9
69
14.61
28
16.2
18
13.7
44
14.4
31
15.6
6

16.1
21
14.92
15
17.1
31
13.9
42
14.8
20
16.6
5

17.1
23
15.445
30
18.7
15
14.1
28
15.6
31
17.5
5

17.6
45
16.63
14
19.1
14
15.4
36
15.7
31
17.9
4

18.2
28
16.97
23
20.5
13
15.8
28
16.0
21
18.5
4

21.3
100
17.335
29
21.0
45
16.2
33
16.7
31
19.5
4

22.2
59
17.895
8
21.9
43
16.5
45
17.2
27
20.8
5

22.9
16
18.56
14
23.1
5
17.0
41
17.8
35
22.2
7

24.3
21
19.2
34
23.4
5
17.1
36
18.5
29
22.7
7

25.6
17
20.07
38
24.3
43
17.9
30
18.8
35
23.8
3

26.9
11
20.57
18
24.8
42
18.3
39
19.3
14
24.3
3

29.2
2
21.45
37
25.8
5
19.9
52
19.7
20
26.2
3

22.13
14
26.2
3
20.4
27
20.0
28
26.6
3

22.505
11
27.2
4
21.3
100
20.3
39
27.1
2

24.04
69
27.6
4
22.6
14
20.8
26
27.9
2

24.835
24
28.7
7
23.0
9
21.6
100

25.22
13
29.7
5
24.5
38
22.0
15

26.39
13

25.5
28
22.5
12

27.385
13

25.6
25
22.9
12

28.165
1

26.7
12
23.6
14

28.4
9
24.6
24

25.0
64

25.6
17

26.1
28

26.5
24

27.1
7

29.0
12

*I/Io relative intensity, Io the most intensive signal

[0143]

5

TABLE 4

Solid phase NMR data

Chemical shift (ppm)

Polymorph
Polymorph
Polymorph
Polymorph
Polymorph

(IA)
(IB)
(IC)
(ID)
(IDb)

175.0
175.4
176.6
176.1
174.8

156.3
155.6
157.0
157.5
156.8

151.4
151.7
153.8
150.0
153.4

148.6
149.4
150.9
138.7
151.9

135.9
135.9
149.3
137.4
150.2

129.6
129.4
136.9
131.7
148.4

124.4
125.0
135.5
130.0
137.8

119.4
119.3
127.7
123.3
131.4

111.7
112.1
126.5
121.2
129.3

103.3
103.3
1215
120.1
125.2

86.1
85.9
119.1
118.3
120.4

55.6
56.6
112.8
112.9
119.0

51.5
52.5
111.0
111.4
117.1

36.2
36.5
104.1
106.3
112.2

32.5
32.5
87.9
104.0
110.2

25.3
26.0
56.1
87.1
105.8

14.3
16.8
53.4
57.0
102.6

9.1
13.9
44.0
53.2
85.6

11.5
40.4
52.0
55.3

7.9
40.4
46.7
52.9

36.0
40.8
50.3

32.4
36.1
45.3

25.6
31.9
40.1

14.8
25.7
36.0

11.4
17.4
31.5

16.0
24.7

13.6
15.1

11.1
13.8

11.7

10.6

9.3

[0144]

6

TABLE 5

Thermoanalytical characteristics

Differential Scanning
Thermo-

Calorimetry (DSC)
gravimetry

Tem-

(TG)

Poly-

perature of

Tem-
Loss of

morph,

appearance
Enthalpy
perature
weight

Solvate
DSC peak
(° C.)
J/g
range
(%)

(IA)
Sharp Endoterm
229.6
−93.1

(IB)
Sharp endoterm
229.3
−95.0

(IC)
Endoterm-
212.3
—

exoterm

Sharp endoterm
230.2
—

(ID)
Sharp endoterm
213.5
—

Sharp endoterm
222.5
—

(IDb)
Sharp endoterm
224.6
−88.5

(IE)
Broad endoterm
129.1
−25.6

Broad exoterm
180.8
71.2

Sharp endoterm
229.4
−94.1

(IF)
Endoterm-
167.4
—

exoterm

Sharp endoterm
230.4
−94.1

(IG)
Broad endoterm
80-140
—
25-140
25.8%

Broad exoterm
179.3
52.5

Sharp endoterm
229.7
—

Number	Date	Country	Kind
00/13728	Oct 2000	FR
P 0004153	Oct 2000	HU

Triazole derivatives and pharmaceutical compositions comprising them

Information

Publication Number

Date Filed

Date Published

Inventors

CPC

US Classifications

International Classifications

Abstract

Description

Claims

Priority Claims (2)

PCT Information