FR2792635A1 - 2-Amino-cyclobutene-3,4-dione cyclohexane carboxamide derivatives are phosphodiesterase inhibitors useful for treating e.g. incontinence, dysmenorrhea, premature labor, sexual dysfunction, angina and asthma - Google Patents

Abstract

2-Substituted amino cyclobutene-3,4-dione derivatives (I) are new. 2-Substituted amino cyclobutene-3,4-dione derivatives of formula (I) are new. R1, R2 = H, 1-6C alkyl, 2-6C alkenyl, or -(CH2)n-3-6C cycloalkyl; R3 = H or 1-6C alkyl; W = NR4R5; R4 = phenyl; and R5 = H, 1-6C alkyl, or 2-6C alkenyl; or NR4R5 = indole, indoline or quinoline; and n = 0-2. An Independent claim is included for the preparation of (I).

Description

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CYCLOBUTENE-3,4-DIONE DERIVATIVES
The present invention relates to cyclobutene-3,4-dione derivatives, their preparation and their therapeutic application.

dans laquelle : R1 et R2 représentent, indépendamment l'un de l'autre, un atome d'hydrogène, un groupe CI-6 alkyle, un groupe C2-6 alkényle, un groupe -(CH2)n-C3-6 cycloalkyle, R3 représente un atome d'hydrogène, un groupe CI-6 alkyle, W représente un groupe NR4R5, dans lequel R4 représente un groupe phényle lorsque R5 représente un atome d'hydrogène, un groupe C1-6 alkyle ou un groupe C2-6 alkényle, ou R4 et R5 forment ensemble avec l'azote les portant un hétérocycle azoté tel qu'un indole, une indoline ou une quinoléine, et n représente 0,1 ou 2. The compounds correspond to the general formula (I)

in which: R 1 and R 2 represent, independently of one another, a hydrogen atom, a C 1-6 alkyl group, a C 2-6 alkenyl group, a - (CH 2) n-C 3-6 cycloalkyl group, R3 is hydrogen, CI-6alkyl, W is NR4R5, wherein R4 is phenyl when R5 is hydrogen, C1-6alkyl or C2-6alkenyl or R4 and R5 together with the nitrogen carrying them a nitrogen heterocycle such as indole, indoline or quinoline, and n is 0,1 or 2.

The preferred compounds according to the invention are the compounds for which: R1 and R2 represent, independently of one another, a hydrogen atom, a C1-4 alkyl group, preferably methyl or ethyl, or a group - (CH2) n-C3-6 cycloalkyl, preferably -CH2-cyclopropyl and / or

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 R3 represents a hydrogen atom, a C1-4 alkyl group, preferably a methyl, and W represents a NR4R5 group, wherein R4 represents a phenyl group when R5 represents a hydrogen atom, a C1-6 alkyl group or a C2-6 alkenyl group, or R4 and R5 together form an indoline.

In the context of the present invention, the term C1-6alkyl (preferably C1-4alkyl) is understood to mean a saturated, linear or branched aliphatic group comprising from 1 to 6 (preferably 1 to 4) carbon atoms. , such as, for example, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl group, etc.

The term C2-6 alkenyl denotes a linear or branched aliphatic group comprising from 2 to 6 carbon atoms and 1 or 2 ethylenic unsaturations.

The term C3-6 cycloalkyl refers to a cyclic saturated aliphatic system having from 3 to 6 carbon atoms.

The compounds of general formula (I) may comprise one or more asymmetric carbon atoms. They can therefore exist as enantiomers or diastereoisomers.

These enantiomers, diastereoisomers, as well as their mixtures, including the racemic mixtures are part of the invention.

The compounds of formula (I) can be prepared according to the method described in the scheme.

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According to this process, a bis-ester derivative of squaric acid (3,4-dihydroxy-3-cyclobutene-1,2-dione) of formula V, in which R represents a C1-4 alkyl group, is reacted with an NHR4R5 amine of formula VI to give a squarate derivative of formula IV. The reaction can be carried out in an organic solvent such as tetrahydrofuran, usually at room temperature, the reactants being in a stoichiometric amount. Then similarly, the squarate derivative of formula IV reacts with an acid ester

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 tranexamic acid (trans-4- (aminomethyl) -cyclohexanecarboxylic acid) of formula III, in which R 'represents a Cl-4 alkyl group, to provide, after saponification according to standard methods known to those skilled in the art, the bisamide of squaric acid of formula II. The meanings of R 3, R 4 and R 5 in each of the compounds of formulas II, III, IV, VI and VII are those indicated for formula (I).

Alternatively, and when R 3 does not represent hydrogen, the compound of formula VII may be prepared by coupling between a bis-ester derivative of squaric acid of formula V and the ester of tranexamic acid of formula III in a first step according to the method described above, followed by coupling with the amine NHR4R5 of formula VI in excess. This latter coupling can be carried out in the absence of a solvent, usually by heating to 100 C.

The compound of formula (I) according to the invention is then prepared from the bis-amide of squaric acid of formula II, after saponification according to standard methods known to those skilled in the art, by reacting the latter with an amine NHR1R2 and a coupling agent such as BOP (benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate) according to methods known to those skilled in the art. The meanings of R 1, R 2, R 4 and R 5 in each of the compounds of formulas II, IV, VII and amines NHR 1 R 2 and NHR 4 R 5 are those indicated for formula (I).

The compound of formula V as defined above can be prepared according to methods known to those skilled in the art and in particular according to the method described by Liebeskind et al J.

Org. Chem. 1988,53, 2482-2488.

The following examples illustrate the processes and techniques

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 suitable for the preparation of this invention without, however, limiting the scope of the claim. Microanalyses and mass spectra, NMR and IR confirm the structures of the compounds.

-3,4-dioxocyclobut-1-én-1-yllméthylaminolméthyllcyclohexane- carboxamide (1) . Acide trans-4-(N-carbobenzyloxy-aminométhyl)- cyclohexane-carboxylique On dissout 15 g (95 mmoles) d'acide trans-4-(aminométhyl)cyclohexane-carboxylique dans 39 mL d'une solution aqueuse à 10% de NaOH. A cette solution, refroidie au bain de glace, sont additionnés 19,5 g de chloroformiate de benzyle (115 mmoles) et 48 mL de solution aqueuse à 10% de NaOH par ampoule de coulée. L'agitation se poursuit pendant 1 h. Le milieu est ensuite acidifié au bain de glace avec HCl à 35%. Example 1: 4 - [[[2- (2,3-Dihydro-1H-indol-1-yl)

-3,4-dioxocyclobut-1-en-1-ylmethylaminolmethylcyclohexanecarboxamide (1). Trans-4- (N-carbobenzyloxyaminomethyl) cyclohexanecarboxylic acid 15 g (95 mmol) of trans-4- (aminomethyl) cyclohexanecarboxylic acid are dissolved in 39 ml of a 10% aqueous solution of NaOH. . To this solution, cooled in an ice bath, are added 19.5 g of benzyl chloroformate (115 mmol) and 48 ml of aqueous 10% NaOH solution per dropping funnel. Stirring is continued for 1 hour. The medium is then acidified in an ice bath with 35% HCl.

The product obtained is filtered, washed with water, drained and dried over P2O5 before being taken up in CH2Cl2, dried over Na2SO4, filtered and evaporated to give 32.5 g (111.5 mmol) of 4- (N-carbobenzyloxy-aminomethyl) -cyclohexanecarboxylic acid, as a white solid.

Quantitative yield.

Melting point: 100 - 110 C.

(2) Trans-4- (N-carbobenzyloxy-methylaminomethyl) -cyclohexane carboxylate methyl.

In a three-necked 500 mL equipped with a thermometer and an addition funnel, 2.12 g (88.34 mmol) of sodium hydride (95%) are placed in 60 mL of DMF (anhydrous dimethylformamide). ). In the ampoule, a solution of 11 g (37.75 mmol) of trans-4- (N-carbobenzyloxy-aminomethyl) cyclohexane carboxylic acid in 82 ml of DMF is added and added.

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 drip. The mixture is heated at 80 ° C. for 20 minutes and then cooled to 0 ° C. with an ice bath and 5.9 ml of methyl iodide are added by addition funnel and dropwise. The mixture is heated at 50 ° C. for 30 minutes. Then hydrolyzed by adding 400 mL of water. Extraction is carried out with ether, the organic phases are combined, washed with water, dried over MgSO 4, concentrated and purified on a silica column (eluent: dichloromethane) to give 12 g of trans-4- (N methylcarbobenzyloxymethylaminomethyl) -cyclohexane carboxylate in the form of a white solid.

Yield = 76%.

(3) Trans-4- (N-carbobenzyloxy-methylaminomethyl) -cyclohexane carboxylic acid.

16.8 g (52.6 mmol) of methyl trans-4- (N-carbobenzyloxy-methylaminomethyl) -cyclohexane carboxylate, 200 ml of dioxane and 200 ml of a molar sodium hydroxide solution are placed in a flask. The reaction medium is allowed to stir at room temperature for 1 h and then the solvent is evaporated.

200 ml of water and hydrochloric acid are added to the residue until a pH of close to 1 is obtained. The medium is then extracted with ether and the organic phases are combined, washed with water. water, dried over MgSO 4 and concentrated to provide 12.6 g of trans-4- (N-carbobenzyloxymethylaminomethyl) -cyclohexane carboxylic acid as a white solid.

Yield = 79%.

(4) Trans-4- (N-carbobenzyloxy-methylaminomethyl) -cyclohexanecarboxamide To a solution of 3.05 g (7.0 mmol) of trans-4- (Ncarbobenzyloxy-methylaminomethyl) -cyclohexane carboxylic acid

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 Acid in 85 mL of tetrahydrofuran (THF) is added 2.5 mL of triethylamine. The mixture is cooled to 0 ° C. with an ice bath and 1.42 ml of isobutyl chloroformate is added. After stirring for 15 minutes, anhydrous ammonia is bubbled into the solution for 40 minutes. The reaction mixture is concentrated in vacuo, water and ethyl acetate are added and extraction is carried out. The organic phases are combined, washed with water, dried over MgSO 4 and concentrated to give 2.5 g trans-4- (N-carbobenzyloxy-methylaminomethyl) -cyclohexanecarboxamide in the form of a white solid.

Yield = 82%.

Melting point: 98 C (5). Trans-4-methylaminomethyl-cyclohexanecarboxamide hydrochloride.

In a Parr flask, 2.5 g (8.2 mmol) of trans-4- (N-carbobenzyloxy-methylaminomethyl) -cyclohexanecarboxamide, 50 ml of methanol (MeOH) and 1.8 ml of HCl are placed in a flask of Parr. %. Then the 10% Pd-C catalyst (50% wet) is added. The reaction medium is allowed to stir at room temperature for 30 min at 35 psi. After the reaction is complete, the catalyst is filtered and rinsed with ethanol. The reaction medium is evaporated to dryness to give a syrup which crystallizes and is taken up in 20 ml of MeOH. 30 ml of acetone are added and the appearance of a crystalline precipitate is observed which is washed with acetone and then drained and dried under vacuum in an oven on P2O5, to 70 C. Finally, 1.1 g of trans-4-methylaminomethyl-cyclohexane-carboxamide hydrochloride as a white solid.

Yield = 79%.

Melting point: 143-144 ° C

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(6). 1-(méthoxy)-2-[trans-4'-(méthylaminométhyl)-cyclohexane- carboxamidel-cyclobutène-3,4-dione.

(6). 1- (methoxy) -2- [trans-4 '- (methylaminomethyl) -cyclohexanecarboxamido-cyclobutene-3,4-dione.

 A solution of 2.13 g of 1,2-di- (methoxy) -cyclobutene-3,4-dione and 2.55 g of trans-4-methylaminomethyl-cyclohexanecarboxamide in 15 mL of THF is stirred at room temperature for 96 hours. . The solvent is evaporated and the residue purified on a silica column (eluent: dichloromethane: methanol 95: 5) to give 1.60 g of 1- (methoxy) -2- [trans-4 '- (methylaminomethyl) -cyclohexanecarboxamide ] -cyclobutene-3,4-dione as a white solid.

Yield: 55% Melting point: 225 C (7) .4 - [[[2- (2,3-dihydro-1-H-indol-1-yl) -3,4-dioxocyclobut-1-en-1 -yl] methylamino] methyl] cyclohexanecarboxamide To a solution of 0.56 g of 1- (methoxy) -2- [trans-4'- (methylaminomethyl) -cyclohexanecarboxamide] -cyclobutene-3,4-dione in 30 mL of 8.5 ml of indoline are added to the methanol. The reaction medium is refluxed for 48 hours before being filtered. 0.6 g of 4 - [[[2- (2,3-dihydro-1-H-indol-1-yl-3,4-dioxocyclobut-1-en-1-yl] methylamino] methyl are thus obtained. cyclohexanecarboxamide Yield = 81%.

Melting Point: 248 ° C. EXAMPLE 2 Using essentially the same process as in Example 1, using an amine suitable in step (4) or (7), other compounds of formula (I) comply with to the invention can be prepared. Some of these compounds are shown in the table below.

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<Tb>
<tb> W <SEP> = <SEP> NR4R5
<Tb>

N Rl R2 R3 R R5~~~~

N R1 R2 R3 R5 ~~~~

<Tb>
<tb> 1 <SEP> And <SEP> H <SEP> H <SEP> Indoline <SEP> 381
<tb> 2 <SEP> Me <SEP> H <SEP> H <SEP> Indoline <SEP> 367
<tb> 3 <SEP> i-Pr <SEP> H <SEP> H <SEP> Indoline <SEP> 395
<tb> 4 <SEP> CH2-c-Pr <SEP> H <SEP> H <SEP> Indoline <SEP> 407
<tb> 5 <SEP> c-Pr <SEP> H <SE> H <SE>> Indoline <SEP> 393
<tb> 6 <SEP> And <SEP> And <SEP> H <SEP> Indoline <SEP> 409
<tb> 7 <SEP> H <SEP> H <SEP> H <SEP> Indoline <SEP> 353
<tb> 8 <SEP> H <SEP> H <SEP> Me <SEP> Indoline <SEP> 367
<tb>'9<SEP> H <SEP> H <SEP> Me <SEP> Ph <SEP> And <SEP> 369
<Tb>
In this Table: - n-Pr represents a linear propyl group, - c-Pr represents a cyclopropyl group, i-Pr represents an iso-propyl group, - and represents an ethyl group,
Me represents a methyl group.

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The compounds according to the invention have been subjected to biological tests intended to demonstrate their inhibitory activity of phosphodiesterase 5.

Assays are performed with a partially purified phosphodiesterase 5 (PDE 5) preparation from human platelets. Purification of the enzyme is based on methods described in the literature (Grant, P.G., and Colman, R. W. Biochemistry 1984, 23: 1801-1807, Simpson, A.W.M., Reeves, M.L., and Timothy, J.R. Biochem.

Pharmacol. 1988, 37: 2315-2320; Ito, M., Nishikawa, M., Fujioka, M., Miyahara, M., Isaka, N., Shiku, H., and Nakano, T. Cellular Signaling 1996, 8: 575-581). The enzymatic preparation obtained after purification does not contain the other phosphodiesterase activities found in the platelets (ie PDE 2 and PDE 3). The enzyme preparation is also free of 5'-nucleotidase and / or phosphatase activities. The PDE 5 test used is based on the separation of cyclic GMP (cGMP, PDE 5 substrate) from 5'-GMP (product of the enzymatic reaction) by thin layer chromatography on polyethyleneimine (PEI) cellulose. The reaction medium contains 40 mM Tris-HCl (pH 7.5), 15 mM MgCl2, 1 mM EGTA, 0.5 mg / ml bovine albumin, 0.25 Ci of [3H] -cGMP , 3 M cGMP, the inhibitor to be tested (concentration: 0 to 10 M) and the enzyme in a total volume of 100 l. The reaction is started by addition of enzyme and is carried out at room temperature. The reaction is stopped after 30 min (conversion rate 10-15%) by introducing the clogged test tube (Eppendorf polypropylene cone) in a boiling water bath for 3 minutes. After homogenization, an aliquot of the sample (10 l) is deposited at the bottom of a PEI plastic cellulose (Merck) plate on which cGMP and 5'-GMP (10 g of each trainer) have been deposited. beforehand. The plate is developed with 450 mM LiCl solution. The 5'-GMP (Rf =

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 0.20) and cGMP (Rf = 0.48) are visualized under ultraviolet light. The PEI cellulose band containing the 5'-GMP is cut out and the nucleotide is quantitatively extracted with 2 ml of a 16 M solution of formic acid and 2 M of ammonium formate in a counting vial. After addition of 10 ml of Aquasol-2 scintillation mixture (Packard), the radioactivity of the sample is measured with a scintillation counter. Each experiment includes two trials without inhibitor (controls) and two trials stopped immediately after enzyme addition (blanks). The radioactivity associated with the 5'-GMP formed in the enzymatic reaction (specific radioactivity) is obtained by subtracting the average value of the whites from the average value of the controls. The IC50 value (concentration of inhibitor that produces a 50% inhibition of specific radioactivity) is determined using a graph on which the specific radioactivity measured at different concentrations of inhibitor is plotted against the logarithm of Inhibitor concentrations tested. The products to be tested are dissolved in dimethylsulfoxide (10 mM stock solutions). These solutions are diluted extemporaneously in the DMSO and then in the test buffer. The final concentration of DMSO in the test is 1%. Activity measurement experiments with or without DMSO have shown that it does not cause significant inhibition of activity at this concentration. PDE inhibitors zaprinast and sildenafil (IC50 values found = 180 and 0.5 nM, respectively) are used as reference inhibitors.

The compounds of the invention make it possible to obtain an IC 50 value which is usually less than 50 nM.

The results of the biological tests show that the compounds of the invention are inhibitors of phosphodiesterase 5.

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Thus, these compounds can be used in the treatment of erectile dysfunction or sexual dysfunction in humans, but also in the treatment of sexual dysfunction in women, such as orgasmic dysfunction.

On the other hand, these compounds can also be used in the treatment of angina pectoris, pulmonary hypertension, diabetes, hyperlipidemia and prostate diseases.

The compounds of the invention, in combination with suitable pharmaceutically acceptable excipients, may be presented in any form suitable for oral or parenteral administration (sublingual or oral), such as tablets, dragees, capsules, capsules, suspensions or oral solutions. or injectable, and dosed to allow administration of 0.1 to 100 mg / kg per day.

Claims (4)

 wherein: R1 and R2 are, independently of one another, a hydrogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a - (CH2) n-C3-6 cycloalkyl group, R3 is hydrogen, C1-6alkyl, W is NR4R5, wherein R4 is phenyl when R5 is hydrogen, C1-6alkyl or C2-6alkenyl or R4 and R5 together form an indole, an indoline or a quinoline, and n represents 0,1 or 2, and optionally as an enantiomer, a diastereoisomer, or a mixture of these different forms.

1. Compound of general formula (I) <Desc / Clms Page number 14> 2. Process for the preparation of a compound of formula (I) according to claim 1, characterized in that a compound of formula II, in which W represents a group -NR4R5, is reacted,

 with an amine NHR1R2 and a coupling agent to give a compound of formula I, wherein R1, R2, R3, R4 and R5 are as defined in claim 1. 3. Medicinal product characterized in that it consists of a compound according to claim 1. 4. Pharmaceutical composition characterized in that it comprises a compound according to claim 1 and one or more suitable excipients.