HUP0302400A2 - New triazole derivatives and pharmaceutical compositions comprising them - Google Patents

Abstract

3-[2-[[[1-(2-Cyclohexylethyl)-5-(2,5-dimethoxy-4-methylphenyl)-1H-1,2,4-triazol-3-yl]amino]carbonyl]-6-methoxy-4,5-1H-indol-1-yl]propionic acid (I) and its solvates, hydrates, polymorphs or salts are new. Independent claims are included for included for the following: (1) salts of (I) obtained with ethanolamine (a), diethanolamine (b), diethylamine (c) or adamantanamine (d); (2) preparation of (I) by hydrolyzing a compound of formula (II); and if desired further converting into its solvates, hydrates, polymorphs and salts; and (3) use of (I) in the preparation of a medicament. ACTIVITY : Anorectic; Antiinflammatory; Neuroleptic; Antiparkinsonian; Nootropic; Anti-HIV; Tranquilizer; Neuroprotective; and Gastrointestinal-Gen. MECHANISM OF ACTION : Cholecystokin in (cck 1) receptor agonist. The agonist activity of 3-[2-[[[1-(2-cyclohexylethyl)-5-(2,5-dimethoxy-4-methylphenyl)-1H-1,2,4-triazol-3-yl]amino]carbonyl]-6-methoxy-4,5-1H-indol-1-yl]propionic acid) (I) towards cck 1 receptors was evaluated in vitro in 3T3 cells expressing the human cck 1 receptor, by measuring the mobilization of intracellular calcium (Ca 2> +>), according to technique derived from Lignon MF et al.,Ear.J.pharmacolo., 1993, 245, 241 - 245.. The calcium concentration was evaluated by Fura-2 by the double excitation wavelength method. (I) had an EC 50 of 1nM.

Description

PCT/EPO1/12984

The present invention relates to novel triazole derivatives, a process for preparing the compounds and pharmaceutical compositions containing the compounds. These compounds are potent and selective agonists of the cholecystokinin (CCK) CCKi (also known as CCK-A) receptors.

CCK is a peptide that is secreted peripherally in response to food intake and is involved in many digestive processes (Crawley J. N. et al., Peptides, 1994, 15(4), 731735).

CCK has been identified in the brain and may be the most abundant neuropeptide, acting as a neuromodulator of brain function by stimulating CCK-type ₂ (also known as CCK-B) receptors (Crawley JN et al., Peptides, 1994, 15(4), 731-735). In the central nervous system, CCK interacts with dopamine-mediated neuronal transmission (Crawley JN 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 produces physiological changes: palpebral ptosis, hypothermia, hyperglycemia, catalepsy; and causes behavioral changes: reduced movement, decreased exploratory behavior, analgesia, changes in learning ability and sexual behavior, and induces a feeling of satiety.

The biological effects of CCK are mediated by at least two receptor types, the CCKi receptors, which are mainly located peripherally,

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PCT/EP01/12984 and is expressed through CCK2 receptors, which are mainly present in the cerebral cortex. Peripheral-type CCK1 receptors are also found in certain regions of the central nervous system, including the area postrema, 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).

In the periphery, CCK delays gastric emptying, modifies intestinal motility, stimulates gallbladder 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).

International Publication No. WO 98/51686 discloses a series of triazole derivatives which have CCK1 receptor agonist activity.

The present invention provides a 3-aminotriazole derivative of formula (I)

OCH2 and its solvates, hydrates, polymorphs and pharmaceutically acceptable salts are provided.

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PCT/EP01/12984 • · · · · »4«· *· ♦* ··

A specific subject of the invention is the compound of general formula (I) and its salts with organic or mineral bases, for example alkali metal or alkaline earth metal salts, such as sodium, potassium or calcium, or with an amine, for example tromethanol, arginine or lysine. Another specific subject of the invention is the polymorphic and solvated (pseudopolymorphic) forms of the 3-aminotriazole derivative of formula (I), the salts of the 3-aminotriazole derivative of formula (I) and its polymorphs and solvates with ethanolamine, diethanolamine, diethylamine or adamantanamine.

The 3-aminotriazole derivative of formula (I) belongs to the group of 3-aminotriazole derivatives of the general formula described in International Publication No. WO 98/51686, but the compound itself is not disclosed therein.

The compound of formula (I), solvates, polymorphs and salts thereof are much more potent CCK1 agonists than the compounds described in the prior art.

The compounds of the invention were tested to characterize their following properties:

- the efficacy of the compounds in displacing [ ¹²⁵ I]-CCK from binding sites present in rat pancreatic membranes (CCKi receptor) or on 3T3 cells expressing recombinant human CCKi receptor;

- selectivity of the compounds towards the CCK2 receptor;

- the CCKi receptor agonist properties of the compounds, which are determined by intracellular binding in 3T3 cells expressing the human CCKi receptor

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PCT/EPO1/12984 • « «· ·· ··«« • a · · · c - « « ·« was determined by examining their ability to induce calcium mobilization in vitro;

- agonistic effect of the compounds on gastric emptying after oral administration in mice.

These studies have shown that, in contrast to the compounds of the prior art, the compounds of the present invention surprisingly simultaneously satisfy various conditions: they not only have a high affinity for CCKi receptors, but also show good selectivity for CCKi receptors (compared to CCK ₂ receptors) and have a potent CCKi receptor agonist effect, as demonstrated by intracellular calcium mobilization and gastric emptying tests. Due to these properties, the compounds of the invention are of great therapeutic importance for the preparation of drugs for the treatment of diseases whose treatment requires stimulation of CCKi receptors.

The compounds of the invention can be prepared by the methods described in International Publication No. WO 98/51686, using the reaction sequence shown in Scheme 1, where Alk is an alkyl group having 1-4 carbon atoms.

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PCT/EP01/12984

Reaction scheme 1

SOCI ₂ '' pyridine

OCHL

Alk = (C^CAlkyl

Another object of the invention is a process for the preparation of a compound of formula (I), solvates, hydrates, polymorphs and pharmaceutically acceptable salts thereof. This process is characterized in that a compound of formula (II) is prepared.

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PCI7EP01/12984

(II)

we bridge;

if desired, the acid of formula (I) thus obtained is converted into its solvates, hydrates, polymorphs or pharmaceutically acceptable salts.

According to the process, the corresponding ester of general formula (II) is hydrolyzed with a strong alkali and the acid of formula (I) is liberated from the formed salt with a strong mineral acid.

Surprisingly, depending on the conditions of precipitation of the acid of general formula (I), the precipitation temperature, the rate of addition of the acid, the cooling gradient, the rotation speed of the mixer, different polymorphs and solvates can be obtained. The different polymorphs and solvates can be transformed into each other by crystallization. By using the appropriate solvents and applying the appropriate physical parameters (reaction conditions), the most stable forms at room temperature can be obtained.

The synthesis of the intermediate of general formula (IV) is illustrated in Scheme 2.

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PCT/EP01/12984 • « ·· ·« ···«·

1) _PhCH2Br /DBU/DMF

2) Triton B, CH ₂ =CH-CN

(ARC)

The preparation of the intermediate of formula (III) is shown in Scheme 3.

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PCTZEP01/12984

Reaction scheme 3

COOH (XII)

OCH„ _NH

CO-(NH)^—

1) CICOCOCO

2) H ₂ NNHC(NH)NH ₂

_H3C

(XI) nh ₂ and ₃ and ₃

_Ph2O

(HI)

In the reaction schemes, the abbreviation Ph stands for phenyl, DMF stands for dimethylformamide, and DBU stands for 1,8-diazabicyclo[5.4.0]undec-7-ene.

The polymorphs and solvates of the compound of formula (I), their

SSY-70 io PCT/EPO1/12984 • ··· ··· * ···· · ··· e· physical characteristics and the conditions of their preparation are described in Table 1.

summarized in a table.

Table 1

Polymorphs of the acid of formula (I)

Polymorphic code is good Conditions of production M.P. °C (IA) A sample of the acid of formula (I) is dissolved in 32 times its weight of 96% ethanol at boiling temperature, then the solution is cooled to 10 °C at a rate of 15 °C/min, kept at 10 °C for 20 hours, the precipitate is filtered off and dried in a vacuum oven at 50 °C for 3 hours. 230-231 (IC) method a) a sample of the polymorph of the acid (IA) is heated for 6 hours at 160 °C. b) a sample of the polymorph of the acid (IA) is stirred in a silicone oil suspension at 180 °C for 6 hours at 200 rpm, then cooled to room temperature, stirred four times with (tert-butyl)methyl ether, then filtered, dried in a vacuum oven at 50 °C for 1 hour. c) a sample of the polymorph of the acid (I) is heated for 6 hours at 200 °C. d) method: a sample of the polymorph (IC) of the acid of formula (I) is stirred in a silicone oil suspension at 200 °C for 6 hours at a speed of 200 rpm, then cooled to room temperature, mixed four times with 1.2 times the mass of (tert-butyl) methyl ether, then filtered, dried in a vacuum drying cabinet at 50 °C for 1 hour. 230-231

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(IC) method a) : a sample of the acid of formula (I) is dissolved in 30 times its mass in 2-propanol at the boiling point, then the solution is cooled to 25 °C at a rate of 0.5 °C/min, kept at 25 °C for 20 hours, the precipitate is filtered off, and dried in a vacuum drying oven at 50 °C for 3 hours. method b) : a similar result is obtained when the hot solution is cooled to 10 °C at a rate of 15 °C/min, kept at 10 °C for 20 hours, the precipitate is filtered off, and dried. c) method: a sample of the polymorph (IA) of the acid of formula (I) is stirred in 20 times the mass of 96% ethanol at 25-50 °C at 200 rpm for 3 days, then filtered, dried in a vacuum oven at 50 °C for 2 hours. d) method: a sample of the polymorph (IA) of the acid of formula (I) is stirred in 25 times the mass of n-heptane at 25-90 °C at 200 rpm for 3-7 days, then filtered, dried in a vacuum oven at 50 °C for 2 hours. e) method: similar to method c), but starting from polymorph (IE). f) method: similar to method d), but starting from polymorph (IE). g) method: similar to c) method, but starting from polymorph (IF). h) method: a sample of the polymorph (IG) of the acid of formula (I) is stirred in 30 times its weight in 96% ethanol at 25 °C at 200 rpm for 1 hour, filtered, and dried in a vacuum oven at 50 °C for 2 hours. i) method: a sample of the polymorph (IG) of the acid of formula (I) is stirred in 25 times its weight in n-heptane at 200 rpm for 16 days, filtered, and dried in a vacuum oven at 50 °C for 2 hours. 211-213; (melting and crystallization) (229-231)*

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PCT/EPO1/12984 • · ·· · · ····

(ID) (IDa+IDb) A sample of the acid of formula (I) is dissolved in 40 times its weight of 96% ethanol at boiling temperature, then the solution is cooled to 25 °C at a rate of 0.5 °C/min, seeded with crystals of (ID), kept at 25 °C for 20 hours, the precipitate is filtered off, and dried in a vacuum oven at 50 °C for 3 hours. 222-226 (IDb) method a) a sample of the polymorph of the acid (ID) is stirred in a silicone oil suspension at 200 rpm at 205 °C for 8 hours, cooled to room temperature, mixed with 1.5 times the weight of (tert-butyl) methyl ether four times, then filtered, dried at 50 °C for 1 hour in a vacuum drying oven. method b) a sample of the polymorph of the acid (I) is stirred with 15 times the weight of 96% ethanol at 200 rpm at 50 °C for 30 days, then filtered, dried at 50 °C for 2 hours in a vacuum drying oven. Method c) A sample of the polymorphic form (IC) of the acid of formula (I) is stirred in 15 times its mass in 96% ethanol at 200 rpm at 70 °C for 12 hours, then cooled to room temperature, filtered, and dried in a vacuum oven at 50 °C for 2 hours. Method d) is similar to Method c), but starting from polymorphic form (ID). 224-226

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PCI7EP01/12984 • ·· · · · * · ·

(IE) method a) : the pseudopolymorph chloroform solvate of the acid of formula (I) (IG) is dried in a vacuum oven at 80 °C for 3 hours. method b) : the sample of the acid of formula (I) is dissolved in a 20-fold mass mixture of chloroform:ethanol = 3.75:1 mass ratio, seeded with crystals of (IE), kept at 25 °C for 6 hours, the precipitate is filtered off, kept at 50 °C for 3 hours in a vacuum oven. 137-140; 168-180 (crystallization); (229-231) * (IF) method a) : a sample of the acid of formula (I) is dissolved in 60 times its weight in acetone at the boiling point, then the solution is cooled to 25 °C at a rate of 0.5 °C/min, kept at 25 °C for 20 hours, filtered, dried at 50 °C for 2 hours in a vacuum drying oven. method b) : a sample of the polymorph (IA) of the acid of formula (I) is stirred with 30 times its weight in acetone at 200 rpm at 25 °C for 8 days, then filtered, dried at 50 °C for 2 hours in a vacuum drying oven. method c) : similar to method b) , but starting from polymorph (IC) . method d) : similar to method b) , but starting from polymorph (ID) . 154-158; 170-180 (crystallization) (229-231)* (I.G.) Pseudopolymorph of acid (I) with chloroform, in a 1:1 molar ratio. A sample of acid (I) is dissolved in 15 times its weight of chloroform, the solution is kept at 25 °C for 1 hour, the precipitate is filtered off and dried at room temperature. 135-140; 170-180 (crystallization) ; (229-231)*

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PCT7EP01/12984 • · ·« ·· ····

*The (IC), (IE), (IF), (IG) polymorphs are to temperatures above their melting point they transform into polymorph (IB) when heated.

Melting points were determined on a Boetius PHMK 05 apparatus. Heating rate: 10 °C/min.

The invention provides new, novel and effective forms of the acid of formula (I) and its polymorphs and solvates.

with ethanolamine of the formula HO-( _CH2 )2-NH2 (A) or

It also applies to its salts with diethanolamine of the formula HO- (CH ₂ ) 2 -NH- (CH ₂ ) ₂ -OH (B) or with diethylamine of the formula (CH ₃ CH ₂ ) ₂ NH (C) or with adamantanamine of the formula mh ₂ (d).

The new salts of the present invention have constant stoichiometry, are non-hygroscopic, stable and have favorable technological characteristics for the preparation of a pharmaceutical product. In contrast to the acid of formula (I), the new salts of the present invention do not show polymorphism and their solubility in aqueous media is one order of magnitude higher than that of the free acid.

Among the new salts of the present invention, the most advantageous properties are shown by the ethanolamine salt of 3-[2-({[1-(2-cyclohexylethyl)-5-(2,5-diethoxy-4-methylphenyl)-1H-1,2,4-triazol-3-yl]amino}carbonyl)-6-methoxy-4,5 dimethyl-1H-indol-1-yl]propionic acid.

The present invention further relates to novel salts of the acid of formula (I) or polymorphs or solvates of the acid with ethanolamine, diethanolamine, ethylamine or adamantanamine.

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PCT/EP01/12984 *« · · · · Μ Μ relates to a process for the preparation of Μ, which comprises reacting an acid of formula (I) or a polymorph or solvate thereof with ethanolamine of formula (A) or diethanolamine of formula (B) or diethylamine of formula (C) or adamantanamine of formula (D).

The compounds of formula (A), (B), (C) and (D) are preferably reacted in a 1.0, 2 molar excess. The reactions are preferably carried out in a protic solvent, preferably at room temperature. Ethanol, acetone or ethyl acetate are preferably used as protic solvents.

The compounds of formula (I) were tested for their in vitro binding to CCKi and CCK ₂ receptors using the method described in Europ. J. Pharmacol., 1993, 232, 13-19. The compound of Example 1 binds to the human CCKi receptor with high affinity (IC ₅₀ = 0.4 nM) (IC50: Inhibiting Concentration ₅₀ , inhibitory concentration ₅ o) and to the human CCK ₂ receptor with low affinity (IC ₅₀ = 234 nM), which leads to a high level of selectivity (affinity for the CCKi receptor is more than 500 times that for the CCK ₂ receptor). The agonistic activity of the compounds towards the CCKi receptor was evaluated in vitro in 3T3 cells expressing the human CCKi receptor by measuring the mobilization of intracellular calcium ([Ca ⁺⁺ ]i) as described by Lignon MF et al. in Eur. J. Pharmacol., 1993, 245, 241-245 using a technique derived from the method described in the literature. [Ca ⁺⁺ ] i calcium concentration was determined using Fura-2SSY-70

PCT/EPO1/12984

4 4 · 4 ·· 4 · · * ·· ·« vei, was evaluated by the dual excitation wavelength method. The ratio of the fluorescence emitted at the two wavelengths gives the [Ca ⁺⁺ ]j concentration after calibration (Grynkiewiec et al., J. Bioi. Chem., 1985, 260, 3440-3450).

The compounds of the invention, like CCK, stimulate [Ca ⁺⁺ ]i release with an efficiency comparable to CCK8S: in the case of the compound of Example 1, the EC ₅₀ (Efficiency Concentration ₅₀ , effective concentration ₅₀ ) is around 1 nM; and they behave similarly as CCKi receptor agonists.

The agonistic effect of the compounds on gastric emptying was tested in vivo as follows. Female Swiss albino CDI mice weighing 20-25 g were fasted for 18 hours. On the day of the experiment, the products were administered orally 60 minutes before an activated charcoal meal (0.3 ml of a suspension/mouse containing 10% activated charcoal powder, 5% gum arabic and 1% carboxymethylcellulose in water). The mice were killed by decapitation 5 minutes later and gastric emptying was determined based on the presence of activated charcoal in the intestine behind the pyloric sphincter (Europ. J. Pharmacol., 1993, 232, 13-19).

Compounds of formula (I) block gastric emptying in a similar manner to CCK and therefore act as CCK receptor agonists: for example, the compound of Example 3 inhibits gastric emptying at very low doses; ED ₅₀ (Efficient Dose ₅₀ , effective dose ₅₀ ) = 27 Mg/kg po

The compounds of the invention are much more potent CCK1 agonists than the compounds described in International Publication No. WO 98/51686. In fact, surprisingly.

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PCT/EP01/12984 ·« · · ·«· ·« simultaneously fulfill the following different conditions: not only do they have high affinity for CCKj. receptors, but they also have good selectivity for CCKi receptors (compared to CCK ₂ receptors) and have potent agonistic effects on CCKi receptors, as shown by intracellular calcium mobilization and gastric emptying tests.

The compounds of formula (I) are therefore used as CCKi receptor agonists for the preparation of medicaments for the treatment of diseases whose treatment requires stimulation of cholecystokinin CCKi receptors. In particular, the compounds of formula (I) are used for the preparation of medicaments for the treatment of certain disorders of the gastrointestinal tract (prevention of gallstone formation, irritable bowel syndrome, etc.), eating disorders, obesity and associated pathologies such as diabetes and hypertension. The compounds of formula (I) induce a feeling of satiety and are therefore used for the regulation of appetite and food intake, the treatment of obesity and weight loss. The compounds of formula (I) are useful in the treatment of disorders of the central nervous system, in particular memory loss disorders, sexual disorders and emotional and behavioral disorders, psychosis, and more particularly schizophrenia, Parkinson's disease, dyskinesia, such as tardive dyskinesia or facial dyskinesia following treatment with neuroleptics or other agents, such as dopamine agonists, which are used in the treatment of Parkinson's disease, and various disorders of the gastrointestinal tract.

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PCT/EPO1/12984 • · · · · ·* · · · * »· In the treatment of disorders of the Μ. The compounds can be used to control pathological craving disorders, i.e. craving for consumption, in particular for sugars, fat, alcohol or drugs, and more generally for appetitive components. The compounds of formula (I) can be used for the treatment and/or prevention of all diseases involving the degeneration of NGF-sensitive neurons, such as cholinergic neurons and sympathetic or sensory neurons, and in particular for the treatment of the following pathologies: memory disorders, vascular dementia, post-encephalitis disorders, post-stroke disorders, post-traumatic syndromes resulting from head injury, disorders resulting from cerebral anoxia, Alzheimer's disease, senile dementia, AIDS-induced dementia, neuropathies resulting from morbidity or damage to sympathetic or sensory nerves, brain diseases such as cerebral edema and spinal cord degeneration, and diabetic neuropathies.

The present invention therefore also provides pharmaceutical compositions comprising a compound of the invention together with suitable excipients.

The excipients are selected depending on the dosage form and the desired route of administration, whether oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal, rectal or intraocular. These formulations are prepared by techniques well known to those skilled in the art.

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PCT/EP01/12984 • *· * · * ** • · 9 · · » *· · · · * «I

Each unit dose may contain 0.1-1000 mg, preferably 0.1-500 mg, of the active ingredient in combination with a pharmaceutical excipient.

This unit dose may be administered 1-5 times daily to achieve a daily dose of 0.05-5000 mg, preferably 0.1-2500 mg.

The pharmaceutical compositions of the invention can be used to treat or prevent various conditions in which CCK plays a therapeutic role.

The invention also relates to a method of treatment comprising administering effective doses of a compound of the invention to combat diseases whose treatment requires stimulation of cholecystokinin CCK1 receptors.

The following examples illustrate the invention.

1. production

2,5-Dimethoxy-4-methylbenzoic acid [compound of formula (XII)]

a) 2,5-Dimethoxy-4-methylbenzaldehyde

A mixture of 280 ml of phosphoryl chloride and 212 ml of N-methylformanilide is kept at room temperature for 4 hours, then 110 g of 2,5-dimethoxytoluene are added, and the resulting mixture is heated at 70 °C for 2 hours. It is then added dropwise onto ice. The precipitate formed is filtered off, taken up in dichloromethane, and then decanted. The organic phase is dried over anhydrous sodium sulfate and evaporated under reduced pressure. Thus, 116 g of yellow crystalline material are obtained; mp. = 83 °C.

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PCT/EP01/12984 • · « V 4 • · » * · ♦ 1 ·» ·« · · ·* «Λ

b) 2,5-Dimethoxy-4-methylbenzoic acid

A solution of 23.86 g of 2,5-dimethoxy-4-methylbenzaldehyde in 500 ml of water is heated to 75 °C and a solution of 29.3 g of potassium permanganate in 500 ml of water is added. The reaction mixture is kept at 75 °C for 2 hours, then its pH is adjusted to 10 with 10% sodium hydroxide solution, and the insoluble material is filtered off while still hot and washed three times with 80 ml of hot water. The filtrate is cooled and the precipitate formed is filtered off and then dried in vacuo at 40 °C. This gives white crystals; mp. = 120 °C; yield = 71 %.

h1-NMR: 2.15 (s, 3H); 3.73 (s, 6H); 6.94 (s, 1H); 7.17 (s, 1H); 12.40 (s, 1H).

2nd production

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

To a suspension of 43.46 g of 2,5-dimethoxy-4-methylbenzoic acid in 300 ml of toluene, 1 ml of dimethylformamide and 23.3 ml of oxalyl chloride are added dropwise. The reaction mixture is heated at 80 °C for 2 hours and then concentrated 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 cooled to 0 °C and the reaction mixture is left to stand at ambient temperature for 18 hours. It is then concentrated under reduced pressure, the residue is taken up in 180 ml of water and, after adding 141 ml of 2M sodium hydroxide solution, stirred at ambient temperature for 18 hours. The precipitate formed is filtered off

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PCT/EP01/12984 <**·«** «*· ** »* · » ♦ ♦ ♦

*.♦« «'W * and dried under reduced pressure to give a beige solid; mp = 193 °C; yield = 93 %.

3. production

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

A mixture of 29.98 g of 2,5-dimethoxy-4-methylbenzamidoguanidine and 400 ml of diphenyl ether was heated at 170 °C for 5 minutes. It was then cooled to 80 °C, the precipitate was filtered off, washed with diisopropyl ether and then dried under reduced pressure to give a crystalline material; mp. = 248 °C; yield = 80%.

4. production

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

A suspension of 22.4 g of 3-(2,5-dimethoxy-4-methylphenyl)-1H-1,2,4-triazol-5-amine in 50 ml of xylene and 42 ml of benzophenone imine was heated at 140 °C under argon for 48 hours. The reaction mixture was then cooled to 80 °C and poured into 100 ml of diisopropyl ether. The precipitate formed was filtered off, washed with diisopropyl ether and dried under reduced pressure to give a yellow solid; mp = 228 °C; yield = 79%.

5. production

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

a) N-alkylation of triazole

To a solution of 8.8 g of 3-(2,5-dimethoxy-4-methylphenyl)-N-diphenylmethylene)-1H1,2,4-triazol-5-amine in 100 ml of dimethylformamide were added successively 4.5 g of potassium carbonate and 8 ml of l-bromo-2SSY-70.

PCT/EP01/12984 ·**·»* · ·* ** * • · · » · « ··»♦ »fl *· wfc cyclohexylethane is added and the reaction mixture is heated at 70 °C for 18 hours. It is then diluted with 300 ml of ethyl acetate, washed twice with water, the organic phase is dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue is chromatographed on a silica gel column, eluting with a 95:5 mixture of toluene and ethyl acetate, to obtain a colorless oil.

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).

b) Hydrolysis of the diphenylimino group

To a solution of 4.7 g of the oil obtained in the previous step in 100 ml of methanol was added 35 ml of 2M hydrochloric acid. The reaction mixture was left to stand at ambient temperature for 18 hours and then concentrated in vacuo. The oily residue was solidified with diethyl ether, and the precipitate formed was filtered off and dried under reduced pressure to give white crystals; mp = 166 °C (HCl); yield = 90 %.

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).

6. production

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

- Step 1: Preparation of the azide 2.8 g of sodium is added in portions to 100 ml of ethanol. This solution is then added dropwise to 10 g of 2,3-dimethyl-4-methoxybenzaldehyde and 15.5 g of ethyl azidoacetate in 30 ml of ethanol and cooled to -20 °C.

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PCTZEP01/12984 *'? *’?

· * * .<**--* ^Λ *' mixture. The reaction mixture is kept at -15 °C for 4 hours and then poured into 400 ml of 1M hydrochloric acid. The precipitate formed is filtered off and dried under reduced pressure for 18 hours to give yellow crystals; mp = 80 °C; yield = 65 %.

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).

- Step 2: cyclization of the azide

A solution of 7.9 g of the compound obtained in step 1 in 60 ml of xylene was added dropwise to 100 ml of xylene heated to 140 °C. After the addition was complete, the reaction mixture was kept at 140 °C for 5 minutes and then cooled to ambient temperature. The precipitate formed was filtered off and dried to give white crystals; mp = 185 °C; yield = 85 %.

h1-NMR: 1.3 (t, 3H); 2.1 (s, 3H); 2.35 (s, 3H); 3.76 (s, 3H); 4.27 (q, 2H); 6.69 (s, 1H); 7.08 (s, 1H); 11.5 (s, 1H).

7. production

4,5-Dimethyl-6-methoxy-1H-indole-2-carboxylic acid [compound of formula (VI)]

To a mixture of 100 ml of methanol and 150 ml of 1,4-dioxane were added 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 was left to stand at ambient temperature for 48 hours. It was then concentrated under reduced pressure and the residue was taken up in 6N hydrochloric acid. The precipitate formed was 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; mp. = 208 °C; yield = 92%.

SSY-70

PC17EP01/12984 ***tr 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). Preparation 8 Benzyl-[4,5-dimethyl-6-methoxy-1-(2-cyanoethyl)-1H-indole-1carboxylate] [Compound of formula (V)]

Step 1: benzyl-(4,5-dimethyl-6-methoxy-1H-indole-2-carboxylate) ml dimethylformamide were successively added with 5.17 g of 4,5-dimethyl-6-methoxy-1H-indole-2-carboxylic acid and 3.5 ml of 1,8diazabicyclo[5.4.0]undec-7-ene. The reaction mixture was kept at 0 °C for 40 minutes, then 3.9 ml of benzyl bromide were added dropwise. After that, it was left to stand at ambient temperature for 18 hours, then poured into 300 ml of water. The precipitate formed was filtered off, washed with water and dried at 50 °C under reduced pressure for 18 hours, thus obtaining yellow crystals; mp. = 161 °C; yield = 90%.

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).

Step 2

To a solution of 4.24 g of benzyl-(4,5-dimethyl-6-methoxy-1H-indole-2-carboxylate) in 36 ml of 1,4-dioxane, 0.22 ml of 40% aqueous benzyltrimethylammonium hydroxide solution and 2.18 ml of acrylonitrile were added successively, and the reaction mixture was refluxed for 4 hours. It was then concentrated under reduced pressure, the residue was taken up in dichloromethane and washed with water. After decantation, the organic phase was dried over anhydrous sodium sulfate and

SSY-70

PCWW12984;:

The residue was solidified by addition of diethyl ether and dried to give a beige solid; mp = 140 °C; yield = 95%.

^X 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).

9. production

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

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

100 ml of methanol are saturated with hydrogen chloride gas at 0 °C. This solution is added to a solution of 4 g of benzyl-[4,5-dimethyl-6-methoxy-1-(2cyanoethyl)-1H-indole-2-carboxylate] in 100 ml of dichloromethane at -20 °C, and the resulting mixture is kept at 0 °C for 18 hours. The solvents are then evaporated under reduced pressure, the residue is taken up in a mixture of 60 ml of methanol, 60 ml of dichloromethane and 10 g of ice and kept 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 sulfate. A beige solid is thus obtained; m.p. = 198 °C; yield = 92%.

b) 5.69 g of the compound prepared in the previous step are added to a suspension of 3 g of 10% palladium on carbon in 500 ml of ethanol. After adding 40 ml of cyclohexene, the reaction mixture is refluxed for 4 hours, then filtered at 20 °C, and the

SSY-70

PCTZEPO.1/13984·:

··«· ·♦ ·· ·* The filtrate was evaporated to give a beige solid; mp = 198 °C; yield = 90 %.

Example 1

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-1Hindol-1-yl]propionic acid potassium salt

a) Methyl-[3-[2-({[1-(2-cyclohexylethyl)-5-(2,5-dimethoxy-4-methylphenyl)-1H-1,2,4-triazol-3-yl]amino}carbonyl)-6-methoxy-4,5dimethyl-1H-indol-1-yl]propanoate] [Compound of formula (II)]

To a solution of 0.706 g of 4,5-dimethyl-6-methoxy-1-(3-methoxy-3-oxopropyl)-1H-indole-2-carboxylic acid [compound (IV)] in 5 ml of dichloromethane at 0 °C, 1.08 ml of pyridine and 0.195 ml of thionyl chloride were added successively. The mixture was kept at this temperature for 1 hour, then 0.929 g of 1-(2-cyclohexylethyl)-5-(2,5-dimethoxy-4-methylphenyl)-1H-1,2,4-triazol-3-amine [compound (III)] was added, and the reaction mixture was left to stand at 20 °C for 18 hours. It was then diluted with dichloromethane and washed with water, the organic phase was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by chromatography on a silica gel column, eluting with dichloromethane, to give 1.1 g of white crystals; mp = 175 °C; yield = 83%.

^X 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); 4.73 (t, 2H); 6.89 (s, 1H); 6.91 (s, 1H); 7.06 (s, 1H); 7.52 (s, 1H); 11.54 (s, 1H).

b) To a solution of 1.59 g of the compound prepared in the previous step in 5 ml of methanol and 10 ml of 1,4-dioxane, 3 ml of 1 molar

SSY-70

PCWW12?84;:

potassium hydroxide solution is added and the reaction mixture is left to stand for 72 hours at 20 °C. It is then evaporated under reduced pressure and the residue is taken up in diethyl ether, filtered and then dried, giving 1.56 g of beige crystalline material; mp. = 236 °C; yield = 97%.

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

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-1Hindol-1-yl]propionic acid

To a solution of 29.08 g of potassium hydroxide in 22.3 ml of water and 710 ml of ethanol at 50°C was added 95.0 g of the ester obtained in step A) of Example 1.

The mixture was stirred for 30 minutes, then filtered and acidified with a solution of 38 ml of concentrated hydrochloric acid in 340 ml of water. The precipitate formed was filtered off, washed with water to free chloride ions and dried to give 90.1 g of acid; mp = 222-228 °C; yield: 96.6%.

Example 3

3-[2-({[1-(2-Cyclohexylethyl)-5-(2,5-dimethoxy-4-methylphenyl)-1H-1,2,4-1-riazol-3-yl]amino}carbon!1)-6-methoxy-4,5-dimethyl-1-1-Hyridol-1-yl]propionic acid ethanolamine salt

6.17 g of the acid of formula (I) are suspended in a 10-fold amount of ethanol, and 0.66 g of ethanolamine is added to the suspension.

SSY-70

PCT/E P.O1/1,2984

A clear solution is obtained, which is allowed to crystallize. The precipitated salt is filtered off, washed with ethanol and then dried. Thus 6.2 g of the title salt are obtained; mp. = 199-200 °C.

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, ³ JCh 2 , ch 2 = 7.5 Hz); 2.79 (t, 2H, ³ Jch2,ch2 = 5.2Hz); 3.55 (t, 2H, ³ JCh 2 , ch 2 = 5.2 Hz); 3.77 (s, 3H); 3.78 (s, 3H); 3.83 (s, 3H); 3.92 (t, 2H, ³ Jch2ch2 = 7.5 Hz); 4.67 (t, 2H, ³ JCH 2 , ch 2 = 6.9 Hz); 6.90 (s, 1H); 6.94 (s, 1H); 7.08 (s, 1H); 7.48 (s, 1H).

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

3-[2-({[1-(2-Cyclohexylethyl)-5-(2,5-dimethoxy-4-methylphenyl)1H-1,2,4-triazol-3-yl]amino}carbonyl)-6-m.ethoxy-4,5-dimethyl-1Hindol-1-x1]propoxyacid dxethanolamine salt

To a solution of 0.7 g of diethanolamine in 15 ml of ethanol was added 3.7 g of the acid of formula (I). The mixture was left to stand at room temperature, the crystals formed were filtered off and washed with ethanol, thus obtaining 3.75 g of the title diethanolamine salt; mp. = 171-172 °C

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, ³ JCH 2 , ch 2 = 7.5 Hz); 2.83 (t, 4H, ³ Jch2,ch2 = 5.5Hz); 3.56 (t, 4H, ³ JCH 2 , ch 2 = 5.5 Hz); 3.74 (s, 3H); 3.76 (s, 3H); 3.84 (s, 3H); 3.91 (t, 2H, ³ Jch2ch2 = 7.5 Hz); 4.63 (t, 2H, ^3J _CH 2 , ch 2 = 7.5 Hz); 6.90 (s, 1H); 6.93 (s, 1H); 7.07 (s, 1H); 7.41 (s, 1H).

SSY-70

PCT/jiPQl/12984 ···· · · *· ·

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

Example 5

- [2- ( { [1-(2-Cyclohexylethyl)-5-(2,5-dimethoxy-4-methylphenyl) 1H-1,2,4-triazol-3-yl]amino}carbonyl) -6-methoxy-4,5-dimethyl-1Hindol-1-yl]propionic acid adamantanamine salt ,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 to the suspension. The resulting clear solution is evaporated. The residue solidifies under hexane, thus giving the title adamantanamine salt; mp. = 119 °C.

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, ³ Jch2,ch2 = 7.2Hz); 3.76 (s, 3H); 3.77 (s, 3H); 3.85 (s, 3H); 3.91 (t, 2H, ³ Jch 2 , ch 2 = 7.2 Hz); 4.65 (t, 2H, ³ J _C h ₂ , ch 2 = 7.2 Hz); 6.89 (s, 1H); 6.92 (s, 1H); 7.08 (s, 1H); 7.44 (s, 1H); ~ 10.8 (b, 1H).

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

Example 6

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~1Hindol-1-yl]propionic acid diethylamino salt

To a suspension of 3.07 g of the acid of formula (I) in acetone was added a solution of 0.45 g of diethylamine in 11 ml of acetone. The clear solution was evaporated, diethyl ether was added to the residue, and the crystals formed were filtered off, yielding 3.2 g of the title diethylamine salt; mp. = 143 °C (decomposition).

SSY-70

PCT/EPQJ/1298.4

- ··· ·· · > · · · < · *· · · »· ♦· ·

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, ³ JC _h2 ch2 = 7.1 Hz); 4.67 (t, 2H, ³ Jch2,ch2 ⁼ 7.1 Hz); 6.91 (s, 1H); 6.93 (s, 1H); 7.09 (s, 1H); 7.48 (s, 1H); -10.8 (bs, 1H).

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

Example 7

3-[2-({[1-(2-Cyclohexylethyl)-5-(2,5-dimethoxy-4-methylphenyl)1H-1,2,4-triazol-3-yl]amino}carboxylic)-6-methoxy-4,5-doxymethyl-1Hindol-1-yl]propionic acid [Compound of formula (1)]

6.3 g of 3-[2-({[1-(2-cyclohexylethyl)-5-(2,5-dimethoxy-4methylphenyl)-1H-1,2,4-triazol-3-yl]amino]carbonyl)-6-methoxy-4,5dimethyl-1H-indol-1-yl]propionic acid methyl ester are dissolved in 50 ml of 96% ethanol containing 2 g of potassium hydroxide. The solution is kept at 45-50 °C for 40 minutes. It is then clarified with activated carbon, then filtered, and the pH of the filtrate is adjusted to 3 with aqueous hydrogen chloride solution. The precipitated crystals are filtered off and washed thoroughly with water, thus obtaining 5.9 g of the acid of formula (I). Its purity, determined by HPLC, is 98.9%; mp. = 234 °C.

Example 8

3- [2- ({ [1- (2-Cyclohexylethyl)-5- (2,5-dxmethox-4-methxl£enxl)1H-1, 2,4-1riazol-3-i1]amino}carbonyl)-6-methoxy-4,5-dimethyl-1Hindol-1-xl]propoxyacid

6.3 g 3-[2-[[[1-(2-cyclohexylethyl)-5-(2,5-dimethoxy-4methylphenyl)-1H-1,2,4-triazol-3-yl]amino]carbonyl]-6-methoxy-4,5dimethyl-1H-indol-1-yl]propionic acid methyl ester 1.2 g potassium SSY-70 ³¹ PCT/EP01/12984..

ρ· · · · · · · *· hydroxide is dissolved in 60 ml of 96 % ethanol. The solution is stirred for 1 hour at 50 °C. Then it is clarified with activated carbon, filtered, and the warm filtrate is acidified and then allowed to cool. Thus, 6.03 g of the acid of formula (I) is obtained. Its purity is determined by HPLC to be 99 %; mp. = 213 °C (shrinks) - 231 °C (melts).

Example 9

The following solid forms of the acid of formula (I) were identified by the test methods presented below: Polymorphs:

(IA) polymorph (IB ) polymorph (IC) polymorph (IDb) polymorph (IE) polymorph (IF) polymorph Solvates:

solvate (pseudopolymorph) (IG), which is the solvate of polymorph (IE) with chloroform.

Mixed form: (ID) polymorph, which is most likely a mixture of (Idb) polymorph with another polymorph that has not yet been isolated in a pure state.

SSY-70

PCT/EP01/12984 •· ·· · · ···· ·

Test methods

X-ray powder diffraction Conditions Device Philips powder diffractometer PW3710 Radiation CuKa (λ= 1.5418 A) Lambda sub (A) 1.54060 Lambda α2 (A) 1.54439 al:a2 ratio 2:1 20 provinces 3-30° Step distance (20°) 0.02 Measurement speed (sec) 1 see Table 3 and Figure 1-6

IR spectroscopy

Conditions Device Bruker IFS-28 Province 4000-400 cm' ¹ Sample making 1-2 mg sample compressed into a tablet with 0.2 g KBr See Table 2 and Figure 16-23

DSC

Conditions Device Mettler Toledo DSC821e Temperature range 25-250°C Heating speed 10 °C/min Sample holder 40 μΐ aluminum crucible with perforated lid Gas electricity Air, 0 ml/min See Table 5, Figure 7-14

TG-DSC

Conditions Device Setaram TG-DSC111 simultaneous TG-DSC measurements Temperature range 25-250°C Heating speed 5 °C/min Sample holder Platinum crucible Gas electricity n ₂ See Tables 5 and 15

Solid-phase NMR

Conditions Device Bruker DRX-500 Measurement ¹³ C( ¹ H)CP/MAS Rotation speed 15 KHz See Table 4 and Figures 24-28

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PCT/EP01/12984 « · · · · · · <

Table 2

IR spectroscopic characteristics

(IA) Polymorph (IB)) Polymorph (IC)) Polymorph (ID)) Polymorph wavenumber (cm' ¹ ) relative intensity (l/lo) wavenumber (cm' ¹ ) relative intensity (l/lo) wavenumber (cm' ¹ ) relative intensity (l/lo) wavenumber (cm' ¹ ) relative intensity (l/lo) 3281.3 0.221 3309.7 0.279 3337.6 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

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PCT/EP01/12984

Table 2 (continued)

IR spectroscopic characteristics

(IDb) Polymorph (IE) Polymorph (IF) Polymorph (IG) solvate pseudopolymorph wavenumber (cm' ¹ ] relative intensity (l/lo) wavenumber (cm' ¹ ) relath intensity (l/lo wavenumber (cm' ¹ ] relative intensity (l/lo] wavenumber (cm' ¹ ] relative intensity (l/lo) 3296.9 0.270 3276.5 0.15C 3316.4 0.218 3282.7 0.216 3116.5 0.034 3133.5 0.035 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

SSY-70

PCI7EP01/12984 • · · · ·« · ♦ ·♦

Table 3

X-ray powder diffraction data

(IA) po imorphic (IB) polymorph (IC) polymorph (ID) polymorph (IDb) polymorph (IE) polymorph 2Θ (°) l/lo* 2Θ (°) l/lo 2Θ (°) l/lo 2Θ (°) l/lo 2Θ (°) l/lo 2Θ(°) l/lo 4.C 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/Iq is the relative intensity, lo is the signal with the highest intensity

SSY-70

PCT/EP01/12984

Table 4

Solid-phase NMR data

Chemical shift (ppm) (IA) polymorph (IB) polymorph (IC) polymorph (ID) polymorph (IDb) polymorph 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

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PCT/EP01/12984

Table 5

Thermoanalytical characteristics

Differential Colorimetry (DSC) Thermogravimetry (TG) Polymorph, solvate DSC peak Temperature of appearance (°C) Enthalpy J/g Temperature range Weight loss (%) (IA) Sharp endothermic 229.6 -93.1 (IC) Sharp endothermic 229.3 -95.0 (IC) Endothermicexothermic Sharp endotherm 212.3 230.2 - (ID) Sharp endothermic Sharp endothermic 213.5 222.5 - (Idb) Sharp endothermic 224, 6 -88.5 (IE) Broad endothermic Broad exothermic Sharp endothermic 129.1 180.8 229.4 -25.6 71.2 -94.1 (IF) Endothermicexothermic Sharp endotherm 167.4 230.4 -94.1 (I.G.) Broad endotherm Broad exotherm Sharp endotherm 80-140 179.3 229.7 52.5 25-140 25.8

SSY-70

Claims (14)

PCT/EP01/12984 Patent claims: 1. A compound of formula (I), solvates, hydrates, polymorphic forms and pharmaceutically acceptable salts of the compound. 2. The compound of claim 1 in the form of the potassium salt. 3. The 3-aminotriazole derivative of formula (I) and the polymorphic and solvated (pseudopolymorphic) forms of the compound (A) with HO-(CH ₂ ) ₂ -NH ₂ ethanolamine or (B) with HO-(CH ₂ ) ₂ -NH-(CH ₂ ) ₂ -OH diethanolamine or (C) with (CH3CH ₂ ) ₂ NH diethylamine or Salts of MH ₂ (D) with adamantanamine. 4. 3-[2-({[1-(2-Cyclohexylethyl)-5-(2,5-dimethoxy-4-methylphenyl)-1H-1,2,4-triazol-3-yl]amino]carbonyl)-6-methoxy-4,5dimethyl-1H-indol-1-yl]propionic acid ethanolamine salt. 5. A process for the preparation of a compound according to any one of claims 1-4, characterized in that a compound of general formula (II) is prepared. SSY-70 PCTZEP01/12984 where Aik represents an alkyl group having 1-4 carbon atoms, is hydrolyzed; if desired, the acid of formula (I) thus prepared is converted into its solvates, hydrates, polymorphic forms or pharmaceutically acceptable salts. 6. A process according to claim 5 for the preparation of salts of the acid of formula (I) and its polymorphic and solvated (pseudopolymorphic) forms with ethanolamine, diethanolamine, ethylamine or adamantanamine, characterized in that the acid of formula (I) or its polymorphic or solvated (pseudopolymorphic) forms are reacted with ethanolamine of formula (A) or diethanolamine of formula (B) or diethylamine of formula (C) or adamantanamine of formula (D). 7. The process according to claim 6, characterized in that the compounds of formula (A), (B), (C) or (D) are used in excess, preferably in a 1.0-1.2 molar excess. 8. The process according to claim 6 or 7, characterized in that the reaction is carried out in a polar solvent, preferably ethanol, acetone or ethyl acetate. 9. A medicament, characterized in that it contains a compound according to any one of claims 1-4. SSY-70 PCT/EP01/12984 10. Pharmaceutical compositions comprising as active ingredient a compound according to any one of claims 1-4. 11. Pharmaceutical composition according to claim 10, characterized in that it contains 3-[2-({[1-(2-cyclohexylethyl)-5(2,5-dimethoxy-4-methylphenyl)-1H-1,2,4-triazol-3yl]amino}carbonyl)-6-methoxy-4,5-dimethyl-1H-indolyl]propionic acid potassium salt as active ingredient. 12. Pharmaceutical composition according to claim 10, characterized in that it contains 3-[2-({[1-(2-cyclohexylethyl)-5(2,5-dimethoxy-4-methylphenyl)-1H-1,2,4-triazol-3yl]amino}carbonyl)-6-methoxy-4,5-dimethyl-1H-indolyl]propionic acid ethanolamine salt as active ingredient. 13. Use of a compound according to any one of claims 1-4 for the preparation of a medicament for combating diseases whose treatment requires stimulation of cholecystokinin CCK1 receptors. 14. Use of a compound according to any one of claims 1-4 for the preparation of a medicament for the treatment of obesity. Instead of the notifier, the Authorized SSY-70