WO2006030285A1

WO2006030285A1 - New 1,2,4-triazole-3-carboxamide derivatives

Info

Publication number: WO2006030285A1
Application number: PCT/IB2005/002720
Authority: WO
Inventors: Jorg Holenz; Jordi Frigola Constansa; Mª Rosa CUBERES ALTISEN; Alberto Dordal Zueras; Pilar Goya Laza; Nadine Jagerovic; Laura Hernandez-Folgado; Maria Isabel Martin Fontelles; Angela Alsasua Del Valle
Original assignee: Laboratorios del Dr Esteve SA
Current assignee: Esteve Pharmaceuticals SA
Priority date: 2004-09-14
Filing date: 2005-09-14
Publication date: 2006-03-23
Anticipated expiration: 2007-03-14
Also published as: ES2255834A1; ES2255834B1

Abstract

The invention relates to new 1,2,4-triazole-3-carboxamide derivatives, as well as to their use for the treatment of diseases in which cannabinoid receptors are involved.

Description

NEW 1,2,4-TRIAZOLE~3-CARBOXAMIDE DERIVATIVES

FIEIJD OF THE INVENTION

The present invention refers to new 1,2, 4-triazole-3- carboxamide derivatives and to their use as medical products intended to human and/or veterinary therapy, for the treatment of several diseases in which cannabinoid receptors are involved.

BACKGROUND OF THE INVENTION

Cannabinoid receptors belong to the family of G- protein coupled receptors. Nowadays, there have been identified and cloned two types of cannabinoid receptors CBi and CB₂ (Howlett A. C. et al. , Pharmacol. Rev., 2002, 54, 161-202) . These receptors are involved in the modulation of different functions, such as memory, cognition, appetite, immune responses, pain, etc., and, therefore, the compounds which interact with said receptors will be useful in those therapeutic fields in which they are involved (R.G. Pertwee, Exp. Opin. Invest. Drugs., 2000, 9_ 7-19) .

Cannabinoid ligands with a large variety of structures have been disclosed (P. Goya et al., Exp. Opin. Ther. Pat., 2000, 1Q_ 1529-1538). An aim of great interest during the last years has been the structure-activity relationship studies of said compounds (Reggio H. P. et al., Cur. Pharm. Design, 2003, 9_^ 1607-1633) . In 1994, it was identified the first antagonist of CBi cannabinoid receptor, SR141716A, a pyrazole-3-carboxamide derivative (Rinaldi-Carmona M. et al. , FEBS Lett., 1994, 35J) 240- 244) . Nowadays, SR141716A is the object of clinical assays as appetite suppressor (Drugs R D, 2002, 3_^ 65-66) . Triazole derivatives with cannabinoid properties are disclosed in the literature (WO-03082833) (Dyck B. et al. ,

Bioorg. Med. Chem. Lett., 2004, 14_ 1151-1154) . Dyck B. et al. in Bioorg. Med. Chem. Lett., 2004, L4_ 1151 disclose triazole-3-carboxamide derivatives of formula:

in which R represents 3-azabicyclo [3.3.0] octan-3-yl, 1-homopiperidyl or CH₂CH₂N(S-CF₃C₆H₄)CH₂CH₂. These compounds have affinity for CBj cannabinoid receptors. However, these ligands are less potent in front of CB₁ receptor than the reference pyrazole SR141716A.

DESCRIPTION OF THE INVENTION

The object of the present invention is to provide new 1,2,4-triazole-3-carboxamide derivatives, which have affinity for cannabinoid receptors, and more particularly, for CBi receptors.

Therefore, the present invention refers to a 1,2,4- triazole-3-carboxamide derivative of general formula (I) :

in which R represents a group which is selected from piperidino, morpholino, cyclohexyl and 1-adamantyl.

The process for preparing a 1,2, 4-triazole-3- carboxamide derivative of general formula (I) , according to the first aspect of the invention, can be carried out according to that shown in the Reaction Scheme. The synthetic route described in said Scheme consist, firstly, on the preparation of ethyl l-(2,4- dichlorophenyl) -5- (4-chlorophenyl) -1, 2, 3-triazole-3-carbo- xilate from 2, 4-dichloroaniline and 4-chlorobenzoyl chloride. For that, 2,4-dichloroaniline was submitted to diazotization conditions in presence of tetrafluoroboric acid. The resulting diazonium salt reacts with ethyl acetoacetate, producing the ethyl 2- (2, 4- dichlorophenyl)hidrazono-3-oxobutanoate. This is treated with bromine, and, subsequently, with ammonium hydroxide, obtaining the ethyl 2- [N'- (2, 4-dichlorophenyl) hidrazinyl] -2-iminoacetate. This iminoacetate is cycled by reaction with 4-chlorobenzoyl chloride in presence of piridine, obtaining ethyl 1- (2, 4-dichlorophenyl) -5- (4- chlorophenyl) -1,2, 4-triazole-3-carboxilate. The 1, 2, 4-triazole-3-carboxamide derivatives object of the present invention are obtained from the corresponding ethylcarboxilate in one-pot procedure. In a heterocyclic series, the transformation of the ester in the amide generally involves three steps: hydrolysis of the ester in acid medium followed by the formation of the acid chloride and, finally, the reaction with an amine.

An alternative process for obtaining 1,2, 4-triazole-3- carboxamide derivatives of general formula (I) would be that described by A. Benderly et al. , Tetrahedron Lett., 1988, 2_9 739-740, in which it is disclosed the preparation of hydrazides from esters in mild conditions. Briefly, said process consists on in situ formation of an aluminium complex by reacting trimethylaluminium with the corresponding amines or hydrazines, which reacts, subsequently, with ethyl 1- (2, 4-dichlorophenyl) -5- (4- chlorophenyl) -1,2,3-triazole-3-carboxilate.

Reaction Scheme

(a) i) NaNO₂, HBF₄, 0 °C/ ii) ethyl acetoacetate , NaOAc, EtOH, H₂O,

0 ⁰C; (b) i) Br₂, NaOAc, AcOH; ii) NH L₄₄OOHH,, aacceettoonnee;; (c) 4-clorobenzoyl chloride, piridine, 1,4-dioxane, reflux; (d) piridine, 1,4-dioxane, reflux; (e) 1-aminopiperidine, 4-aminomorpholine, ciclohexylamine or

1-aminoadamantane, Al(Me 3' N 2' UH₂OX₂ , 40

Another aspect of the present invention are the following 1,2,4-triazole-3-carboxamide derivatives:

(e)

(g)

Derivatives (a)-(i) can be obtained following procedures well known for the person skilled in the art, such as those disclosed in the applications WO 04/26301 and WO 03/082833.

The inventors of the present invention have proved that the compounds of general formula (I) , according to the first aspect of the invention have affinity for cannabinoid receptors. In the present invention, the concept of "affinity for cannabinoid receptors" is determined assessing the binding of a derivative of general formula (I) , according to the first aspect of the invention, to the cannabioid receptors, in particular CBi receptors, by displacement of radioligands in vitro. Said assessment is performed following well known protocols for the person skilled in the art.

The characterization of the cannabinoid activity of the new derivatives, described in the present invention, was performed assessing their ability to displace the radioligand [³H]-CP55940 from CBi cannabinoid receptors. The compounds of the present invention showed a significant affinity for the CB₁ cannabinoid receptor. At a concentration of ICT⁶ M, the derivatives of general formula (I) , in which R represents a piperidino, morpholino and cyclohexyl group, displace the radioligand

[³H]-CP55940 at 31.7, 32.1 y 55.9% respectively. When R represents a 1-adamantyl group in the derivative of general formula (I) , it was proved that said compound showed a greater affinity with a displacement of 77.5% (Ki = 498.2 nM) .

Therefore, a second aspect of the present invention refers to a derivative of general formula (I) , according to the first aspect of the invention to use as a medicament, preferably as antagonist of cannabinoid receptors and, more preferably, as antagonist of CBi receptors.

It was observed, furthermore, that the 1,2, 4-triazole- 3-carboxamide derivatives of general formula (I) , act suppressing the appetite, reducing the dyskinesia caused by L-dopa in Parkison patients, permitting the treatment of acute schizophrenia and improving the cognitive and memory dysfunctions associated to the Alzheimer disease.

In a preferred embodiment, the present invention refers to a pharmaceutical composition which comprises at least one compound of general formula (I) , according to the first aspect of the invention, and at least one pharmaceutically acceptable diluent and/or adjuvant to use as a medicament, more preferably to use as antagonist of cannabionid receptors and, even more preferably, to use as antagonist of CBi receptors.

Said pharmaceutical composition can be adapted to its topical, oral or parenteral application, among others. The diluent and/or adjunvant will be selected depending on the desired application of the pharmaceutical composition.

Because of the affinity of the compounds of the present invention for the cannabinoid receptors, said compounds can be used as active principles in medicaments for the treatment of diseases associated with cannabinoid receptors.

In the present invention by "disease associated with the cannabinoid receptors" is meant a pathological state which is started by the lack of modulation in the cannabinoid receptors.

Therefore, a third aspect of the invention refers to the use of at least one 1, 2, 4-triazole-3-carboxamide derivative of general formula (I) , according to the first aspect of the invention, for the manufacture of a medicament for the treatment and/or prevention of diseases in which cannabinoid receptors are involved, preferably CBi receptors and, more preferably, being selected said disease from: glaucoma, bronchial asthma and chronic bronchitis; allergies, such as the contact dermatitis or allergic conjunctivitis; arthritis; pain; diseases associated with organ transplants; motor diseases related to Tourette syndrome; Parkinson disease or Huntington chorea; malignant glioma; multiple sclerosis; emesis related to anti-cancer chemotherapy; appetite.

Now there are included the following illustrative and no limitative examples. EXAMPLES OF EMBODIMENT OF THE INVENTION

In the examples are used the following abbreviations: ac: aqueous AcOEt: ethyl acetate

AcOH: acetic acid

Al(Me)₃: trimethylaluminium

Anal.: Elemental analysis

Br₂: bromine CH₂CI₂: dichloromethane

EtOH: ethanol

Et₂O: ethyl ether g: gram

HBF₄: boron tetrahidrofluoride HCl: hydrochloric acid

H₂O: water int. rel. : relative intensity

K₂CO₃: potassium carbonate min: minutes ml: mililitre μl: microlitre

NaNO₂: sodium nitrite

NaOAc: sodium acetate

NaOH: sodium hydroxide Na₂SO₄: sodium sulphate

NH₄OH: ammonium hydroxide

P.f.: melting point t.a.: room temperature Example 1.- Preparation and obtaining of 5- (4- chlorophenyl) -1- (2, 4-dichlorophenyl) -N- (piperidin-1-yl) - IH-I,2, 4-triazole-3-carboxamide

A) Ethyl 2- (2,4-Dichlorophenyl)hidrazono-3- oxobutanoate

To a solution of HBF₄ (13 ml, 48%) in H₂O(13 ml), 8.00 g. of 2, 4-dichloroaniline are added. It is cooled in an ice bath and a cold solution of 3.41 g. of NaNC>₂ in H₂O (5 ml) is added on it. The mixture is stirred 30 min. at 0⁰C, and it is stirred continuously until t.a. is reached. The resulting diazonium salt is filtered, washed with HBF₄ ac, EtOH and Et₂O, and dried. A solution of the salt in 250 ml of EtOH is added to 6.25 ml of a solution at 0°C of ethyl acetoacetate, EtOH (25 ml), 11.12 g. of NaOAc and H₂O (25 ml) and the mixture is stirred at this temperature for 1 h. The resulting solid is filtered, washed with H₂O, dried and recrystallized with cyclohexane, obtaining 4.89 g. of desired product. P.f. = 118-121 ⁰C. EM (ES⁺) m/z (ReI. Int.): 303 (100 %) [M+H]⁺. Anal. (C₁₂H₁₂Cl₂N₂O₃) % theoretical (% experimental) C: 47.54 (47.80); H: 3.99 (4.21) ; N: 9.24 (9.43) .

B) Ethyl 2- [N'- (2, 4-Dichlorophenyl)hidrazino]-2- iminoacetate

To a solution of 1.44 g of the compound obtained in the previous step A and 3.52 g of NaOAc in AcOH (35 ml), 243 μl of Br₂ are added dropwise.

After stirring the solution 30 min. at t.a., it is poured onto 100 ml. of H₂O, and it is extracted with CH₂Cl₂

(3x50 ml) . The organic phase is dried over Na₂SO₄ anhydrous, the solvent is removed in vacuum, and the obtained residue is dissolved in 50 ml of acetone. On this reaction mixture a solution of 4 ml of 30% NH₄OH in 10 ml of acetone is added dropwise, and the mixture is stirred at t.a. for 1 h. After this time, the solvent is removed, the residue is dissolved in 100 ml of 10% HCl and is washed with toluene (3 x 50 ml) . The aqueous phase is basified with NaOH until pH 8, precipitating a solid. This 5 solid is filtered and suspended in hot EtOH. The solid impurity is filtered. The liquid phase is treated with active carbon for 30 min, it is filtered on celite and the solvent is removed in vacuum, obtaining 1.76 g of the desired product. P.f. = 82-87 °C. EM (ES⁺) m/z (int. lO rel.) : 276 (100 %) [M+H]⁺. Anal. (CiOHIiCl₂N₃O₂) % theoretical (% experimental) C: 43.50 (43.61); H: 4.02 (4.30) ; N: 15.22 (15.25) .

C) Ethyl 5- (4-Chlorophenyl)-l- (2, 4-dichlorophenyl) - IH-I,2, 4-triazole-3-carboxilate

15 A mixture of 0.60 g of the compound obtained in the previous step B, 0.20 ml of pyridine, and 0.32 ml of 4- chlorobenzoyl chloride is dissolved in 50 ml of 1,4- dioxane and it is stirred at reflux for 3 h. Then, the solvent evaporates, the obtained residue is dissolved in

20120 ml of CH₂Cl₂ and it is washed with HCl IM (3 x 50 ml) , H₂O (50 ml) , saturated solution of K₂CO₃ (3 x 50 ml) and H₂O again (50 ml) . The organic phase is dried over anhydrous Na₂SO₄, the solvent is removed, and the obtained residue is purified by medium pressure chromatography,

25 using cyclohexane/AcOEt (8:1) as eluent. 0.31 g. of desired product are isolated. P.f. = 113-118 ⁰C. EM (ES⁺) m/z (rel. Int.): 296 (90 %) [M+H]⁺. Anal.

(Ci₇Hi₂Cl₃N₃O₂.1.25H₂O) % theoretical (% experimental) C:

48.71 (48.74); H: 3.48 (3.37); N: 10.02 (9.98) .

30 D) 5- (4-Chlorophenyl)-l- (2, 4-dichlorophenyl) -W- (piperidin-1-yl) -IH-I,2, 4-triazole-3-carboxamide

To a solution of 0.32 ml of 1-aminopiperidine in dry CH₂Cl₂ (3-5 ml) under N₂ atmosphere, a solution of 1.50 ml of a 2M solution of Al(Me)₃ in heptane is added. The

35 mixture is stirred at t.a. and under N₂ atmosphere for 1 h. Then a solution of 240 mg. of the compound obtained in the previous step C in dry CH₂CI2 (3-6 ml) is added dropwise, and it is stirred continuously at 35-50 °C (external t.) for 21 h. Then, the solution is poured onto HCl IN (20-30 ml) . The formed biphasic solution is stirred at 40⁰C (external t.) for 30 min. Then it is cooled, and it is extracted with CH₂Cl₂ (3 x 20 ml) . The organic phase is dried over Na₂SO₄, the solvent is removed, and the obtained residue is purified by medium pressure chromatography [cyclohexane/AcOEt (25:1)- cyclohexane/AcOEt (3:1)]. 214 mg. of desired product are obtained. P.f.= 115-118 °C. EM (ES⁺) m/z (rel. int.) : 450 (99 %) [M+H]⁺. Anal. (C_2OHi₈Cl₃N₅O) % theoretical (% experimental) C: 53.29 (53.25); H: 4.03 (4.20); N: 15.54 (15.38) .

Example 2.- Preparation and obtaining of 5- (4- chlorophenyl) -1- (2, 4-dichlorophenyl) -JV-morpholino-lH- 1,2, 4-triazole-3-carboxamide A) 5- (4-Chlorophenyl)-l- (2, 4-dichlorophenyl) -N- morpholino-lH-l,2, 4-triazole-3-carboxamide

The desired compound is prepared according to the embodiment described in step D of the Example 1, from 0.18 ml of 4-aminomorpholine, 0.95 ml of an hexane solution of Al(Me)₃ 2M, and 150 mg of the obtained compound in step C of the Example 1 with a reaction time of 2.5 h (instead of 21 h of Example 1) . The raw material is purified by toluene recrystallization. 161 mg of the desired compound are obtained. P.f.= 193-195 ⁰C. EM (ES⁺) m/z (rel. Int.): 452 (100%) [M+H]⁺. Anal. (Ci₉Hi₆Cl₃N₅O₂-O-SC₆H₅CH₃) % theoretical (% experimental) C: 54.18 (53.62); H: 4.04 (4.41) ; N: 14.04 (14.38) . Example 3.- Preparation and obtaining of 5-(4- chlorophenyl) -N-cyclohexyl-l-(2,4-dichlorophenyl)-Ii-T- 1,2,4-triazole-3-carboxamide

A) 5-(4-Chlorophenyl)-N-cyclohexyl-1-(2,4- dichlorophenyl)-IiT-I,2,4-triazole-3-carboxamide

The desired compound is prepared according to the embodiment described in step D in the Example 1, from 0.18 ml cyclohexylamine, 0.76 ml of an hexane solution of Al(Me)₃2M, and 120 mg of the compound obtained in step C of Example 1 with a reaction time of 4.5 h (instead of 21 h of Example 1) . The raw material is purified by toluene recrystallization and flash chromatography [cyclohexane/AcOEt (2:1)]. 83 mg of the desired compound are obtained. P.f.= 181-185 ⁰C. EM (ES⁺) m/z (rel. int.): 449 (100 %) [M+H]⁺. Anal. (C_2IHi₉Cl₃N₄O) % theoretical (% experimental) C: 56.08 (55.96); H: 4.26 (4.35); N: 12.46 (12.18) .

Example 4,- Preparation and obtaining of 5-(4- chlorophenyl)-N-(1-adamantyl)-1- (2,4-dichlorophenyl)-IH- 1,2,4-triazole-3-carboxamide

A) 5-(4-Chlorophenyl)-N- (1-adamantil)-1- (2,4- dichlorophenyl) -IH-I,2,4-triazole-3-carboxamide

The desired compound is prepared according to the embodiment described in step D in the Example 1, from 145 mg 1-adamantanylamine, 0.48 ml of an hexane solution of

Al(Me)₃ 2M and 76 mg of the compound obtained in step C in the Example 1 with a reaction time of 26 h (instead of 21 h. in the Example 1) . The raw material is purified by flash chromatography [cyclohexane/AcOEt (4:1)]. 75 mg. of the desired compound are obtained. P.f.= 185-189 ⁰C. EM

(ES⁺) m/z (rel. int.): 501 (100 %) [M+H]⁺. Anal.

(C₂₅H₂₃Cl₃N₄O) % theoretical (% experimental) C: 59.83

(59.67); H: 4.62 (4.90); N: 11.16 (10.87).

Claims

CIAIMS

1. 1,2, 4~triazole-3-carboxamide derivative of general formula (I) :

wherein R represents a group selected from piperidino, morpholino, cyclohexyl and 1-adamantyl.

2. Derivative according to claim 1 for use as a medicament.

3. Derivative according to claim 2 for use as antagonist of cannabinoid receptors.

4. Derivative according to any of claims 2-3 for use as antagonist of CBi receptors.

5. Pharmaceutical composition comprising at least one derivative according to claim 1, and at least one pharmaceutically acceptable diluent and/or adjuvant for use as a medicament.

6. Pharmaceutical composition according to claim 5 for use as antagonist of cannabinoid receptors.

7. Pharmaceutical composition according to claim 6 for use as antagonist of CBi receptors.

8. Use of a derivative of 1,2, 4-triazole-3-carboxamide of general formula (I) , according to claim 1 for the manufacture of a medicament for the treatment and/or prevention of dysfunctions related with cannabinoid receptors.

9. Use according to claim 8, wherein said dysfunction is one selected from: glaucoma, bronchial asthma and chronic bronchitis, for allergies as contact dermatitis, allergic conjunctivitis, for arthritis, for pain, for diseases or disorders caused by organ transplant, for motor diseases related to Tourette syndrome, Parkinson disease or Huntingdon chorea, for malign gliomas, for multiple sclerosis, for emisis related to anticancer chemotherapy, and for appetite.