FR2699171A1 - New amino-carbonyl-pyrimidinyl-amino-alkyl-pyridimine-carboxamide derivs. - Google Patents

Abstract

Derivs. of 2-amino-N-(((4-(aminocarbonyl) pyrimidin-2-yl) amino)alkyl) pyrimidine-4-carboxamide of formula (I), their optical isomers and their acid addn. salts, are new. n, m are 0 or 1; R1 is CH3 and R2 is phenoxy(1-4C)alky (opt. substd. on phenoxy by 1 or 2 halo or methoxy gps) or R1+R2+N to which they are bonded = 4-phenoxypiperidin-1-yl (opt. substd. on phenoxy as above), 4-phenylpiperazin-1-yl (opt. substd. on phenyl as phenoxy above) or phenoxymethypiperidin-1-yl (opt. substd. on phenoxy by 1 or 2 1-4C alkyl); R3 is H or when n is 1, OH or methoxy. Specifically claimed is N-(2-((4-(aminocarbonyl)pyrimidin-2-yl) amino)ethyl)-2-((3-(4- (5-chloro -2-methoxyphenyl) -piperazin-1-yl) propyl)amino)pyrimidine- 4-carboxamide (cpd.1).

Description

The present invention relates to 2-amino derivatives
N - (((4- (aminocarbonyl) pyrimidin-2-yl) amino] alkyl] pyrimidine-4-carboxamide, their preparation and their therapeutic application.

dans laquelle m représente le nombre 0 ou 1,
R1 représente un groupe méthyle, auquel cas
R2 représente un groupe phénoxy(C1-C4)alkyle (dont le groupe phénoxy porte éventuellement 1 ou 2 substituants choisis parmi les atomes d'halogènes et les groupes méthoxy), ou bien Rl et R2 forment ensemble, et avec l'atome d'azote qui les porte, un groupe 4-phénoxypipéridin-l-yle (dont le groupe phénoxy porte éventuellement 1 ou 2 substituants choisis parmi les atomes d'halogènes et les groupes méthoxy), un groupe phénoxyméthylpipéridin-l-yle (dont le groupe phénoxy porte éventuellement 1 ou 2 groupes alkyles en Cl-C4), ou (lorsque R3 représente un groupe hydroxy ou méthoxy) un groupe 4-phénylpipérazin-l-yle (dont le groupe phényle porte éventuellement 1 ou 2 substituants choisis parmi les atomes d'halogènes et les groupes méthoxy),
R3 représente un atome d'hydrogène, un groupe hydroxy ou un groupe méthoxy,
R4 représente un atome d'hydrogène,
R5 représente un atome d'hydrogène, et R6 représente un atome d'hydrogène.The compounds of the invention correspond to the general formula (I)

in which m represents the number 0 or 1,
R1 represents a methyl group, in which case
R2 represents a phenoxy (C1-C4) alkyl group (of which the phenoxy group optionally carries 1 or 2 substituents chosen from halogen atoms and methoxy groups), or else R1 and R2 form together, and with the atom of nitrogen which carries them, a 4-phenoxypiperidin-1-yl group (of which the phenoxy group bears optionally 1 or 2 substituents chosen from halogen atoms and methoxy groups), a phenoxymethylpiperidin-1-yl group (of which the phenoxy group optionally carries 1 or 2 C 1 -C 4 alkyl groups), or (when R 3 represents a hydroxyl or methoxy group) a 4-phenylpiperazin-1-yl group (of which the phenyl group optionally carries 1 or 2 substituents chosen from halogens and methoxy groups),
R3 represents a hydrogen atom, a hydroxy group or a methoxy group,
R4 represents a hydrogen atom,
R5 represents a hydrogen atom, and R6 represents a hydrogen atom.

The compounds of the invention may exist in the form of bases or addition salts with acids. On the other hand, when its molecule contains an asymmetric carbon atom, a compound can exist in optically pure form or in the form of a mixture of optical isomers.

According to the invention, the compounds of general formula (I) can be prepared by a process illustrated by the following scheme.

An amide of general formula (II) (in which R 1, R 2, R 3 and R 4 are as defined above) is converted into an ester of general formula (III) (in which R 'represents a C 1 -C 4 alkyl group ), by reaction with a C 1 -C 4 aliphatic alcohol, for example methanol, in the presence of an acid, for example gaseous hydrochloric acid, at a temperature of 0 to 100 C.

The ester thus obtained is then converted by reaction with an amine of general formula (IV) (in which R 5 and R 5 are as defined above and R 7 represents either a hydrogen atom or an amine protecting group. , for example a tert-butyloxycarbonyl) amide group of general formula (V), in an aliphatic alcohol as a solvent, for example methanol, at a temperature of 0 to 600C.

Then, if necessary, the amine of general formula (V) is deprotected by a known method, for example by treatment with trifluoroacetic acid in dichloromethane when R7 represents a tert-butyloxycarbonyl group.

Finally, the amine of general formula (V) (in which R7 represents a hydrogen atom) is reacted with 2-chloropyrimidine-4-carboxamide of formula (VI) in an aprotic solvent, for example N, N -dimethylformamide, in the presence of a base, for example potassium carbonate, at a temperature of 20 to 400C, to obtain the compound of general formula (I).

The 2-aminopyrimidine-4-carboxamide derivatives of general formula (II) can be obtained by methods analogous to those described in patent applications FR-2675799,
FR-2678271 and EP-0480794.

Monoprotected diamines of general formula (IV) can be prepared by methods analogous to those described in Synthesis (1984) 1032-1033 and Synthesis (1990) 366-368.

The following examples illustrate in detail the preparation of some compounds according to the invention. The elemental microanalyses and the IR and NMR spectra confirm the structures of the compounds obtained.

The numbers of the compounds, indicated in parentheses in the titles, correspond to those of the table given below.

Example 1 (Compound No. 1)
N- [2 - [[4- (aminocarbonyl) pyrimidin-2-yl] amino] ethyl] -2 - [[3 - [[2- (2-methoxyphenoxy) ethyl] methylamino] propyl] amino] pyrimidine] 4-carboxamide 1.1 2 - [[3 - [[2- (2-methoxyphenoxy) ethyl] methylamino] propyl] a-
methyl] pyrimidine-4-carboxylate.

0.5 g (35.3 mmol) of 2-tt3-tt2- (2-methoxyphenoxy) ethyl] methylamino] propyl] amino] pyrimidine-4-carboxamide and 300 ml are introduced into a 0.5 l flask. of methanol, then a stream of hydrochloric acid gas is passed for a few minutes and heated at the reflux temperature of methanol for 4 hours.

The solvent is evaporated under reduced pressure, the residue is added 100 ml of dichloromethane and cooled to 0OC. The mixture is basified with a saturated aqueous solution of sodium hydrogencarbonate, the mixture is decanted and the organic phase is dried over sodium sulfate, filtered and the solvent is evaporated under reduced pressure.

After purification by column chromatography on silica gel (eluent: dichloromethane / methanol mixture, 96/4 to 88/12), 8.7 g of compound in oily form are isolated and used as such in the next step.

1.2 N- (2-aminoethyl) -2 - [[3 - [[2- (2-methoxyphenoxy) ethyl] methylamino] propyl] amino] pyrimidine-4-carboxamide.

In a three-necked flask of 0.25 l, 3.0 g (8 mmol) of 2 - [[3 - [[2- (2-methoxyphenoxy) ethylmethylamino] propyl] amino] pyrimidine-4-carboxylate are introduced. methyl and 4.8 g (80 mmol) of ethylenediamine in 100 ml of a 1: 1 mixture of methanol / dichloromethane. The reaction medium is stirred for 48 hours at room temperature, and then the solvents are evaporated off under reduced pressure.

The crude residue is taken up in 100 ml of dichloromethane, the organic phase is washed with water (2 × 100 ml), dried over sodium sulphate, filtered and the solvent is evaporated off under reduced pressure to give 3.05 g of compound in oily form, which is used as such in the next step.

1.3 N- [2 - [[4- (aminocarbonyl) pyrimidin-2-yl] amino] ethyl] -2-
[[3 - [[2- (2-methoxyphenoxy) ethyl] methylamino] propyl] amine] pyrimidine-4-carboxamide.

In a three-necked flask of 0.25 l, 3.0 g (7.45 mmol) of N- (2-aminoethyl) -2-E [3-E [2- (2-methoxyphenoxy) ethyl] are introduced. methylamino] propyl] amino] pyrimidine-4-carboxamide, 1.23 g (7.8 mmol) 2-chloropyrimidine-4-carboxamide, 1.55 g (11.2 mmol) potassium carbonate, 0.1 g sodium iodide in 40 ml of N, N-dimethylformamide, and the reaction medium is heated at 600C for 15h.

It is cooled to room temperature, the reaction product is poured into 100 ml of water and extracted with ethyl acetate (3 × 100 ml). The organic phase is washed with water, dried over sodium sulfate, filtered and the solvents evaporated under reduced pressure.

After recrystallization from ethyl acetate, 1.95 g of compound are obtained.

Melting point: 131-1330C.

Example 2 (Compound No. 02)
N- [2- [[4- (aminocarbonyl) pyrimidin-2-yl] amino] ethyl] -2 - [[3- [4- [[5-methyl-2- (1-methylethyl) phenoxy] methyl] piperidine 1-yl] propyl] amino] pyrimidine-4-carboxamide.

2.1 2-E [3- [4- [[5-Methyl-2- (1-methylethyl) phenoxy] methyl] pI
peridin-1-yl] propyl] amino] pyrimidine-4-carboxylate
methyl.

In a flask of 1 liter, 6.3 g (14.8 mmol) of 2- [[3- [4- [[5-methyl-2- (1-methylethyl) phenoxy] methyl] piperidin are added. 1-yl] propyl] amino] pyrimidine-4-carboxamide and 250 ml of methanol, then a stream of hydrochloric acid gas is passed for a few minutes and heated to the temperature of the reflux of methanol for 1:30.

The solvent is evaporated under reduced pressure, the residue is added 150 ml of dichloromethane and cooled to 0OC. The mixture is alkanilized with a saturated aqueous solution of sodium hydrogencarbonate, the mixture is decanted and the organic phase is dried over magnesium sulfate, filtered and the solvent is evaporated off under reduced pressure.

After purification by column chromatography on silica gel (eluent: dichloromethane / methanol mixture, 100/0 to 90/10), 4.3 g of compound in oily form are isolated, which is used as it is in the next step. .

2.2 [2 - [[[2 - [[3- [4 - [[5-Methyl-2- (1-methylethyl) phenoxy] methyl
thyl] piperidin-1-yl] propyl] amino] pyrimidin-4-yl] carboxylic
1,1-dimethylethyl nyl] amino] ethyl] carbamate.

0.1 g (9.76 mmol) of 2 - [[3- [4- [[5-methyl-2- (1-methylethyl) phenoxy) methyl] piperane are introduced into a 0.1 l flask. methyl din-1-yl] propyl] amino] pyrimidine-4-carboxylate and 1.9 g (11.7 mmol) of 1,1-dimethylethyl (2-aminoethyl) carbamate in 15 ml of a mixture of 1 g of propan-2-ol / methanol and the mixture is refluxed for 10 hours.

The solvent is evaporated under reduced pressure and the residue is purified on a column of neutral alumina (eluent: cyclohexane / ethyl acetate, 80/20 to 0/100) to obtain 2.8 g of compound in the form of an oil, we use it as it is in the next step.

2.3 N- (2-aminoethyl) -2-t3-t4-t5-methyl-2- (1-methylethyl) phenoxy] methyl] piperidin-1-yl] propyl] amino] pyrimidine-4-carboxamide.

0.2 g (4.92 mmol) of (2 - [[[2 - [[3- [4 - [[5-methyl-2- (1-methylethyl)) are introduced into a 0.25 l flask. 1,1-dimethylethyl phenoxy] methyl] propan-1-yl] propyl] amino] pyrimidin-4-yl] carbonyl] amino] ethyl] carbamate dissolved in 20 ml of dichloromethane, then 20 ml of trifluoroacetic acid and the mixture is refluxed for 5 hours.

The solvents are evaporated off under reduced pressure and 70 ml of water and then 1N sodium hydroxide are added to the crude residue. It is extracted with dichloromethane (3 × 150 ml) and then the organic phase is washed with water (100 ml), dried over sodium sulphate, filtered and the solvent is evaporated off under reduced pressure.

2.31 g of compound are obtained in the form of an oil, which is used as it is in the next step.

2.4 N- [2 - [[4- (aminocarbonyl) pyrimidin-2-yl] amino] ethyl] -2-
[[3- [4 - [[5-methyl-2- (1-methylethyl) phenoxy] methyl] PIPE
ridin-1-yl] propyl] amino] pyrimidine-4-carboxamide.

0.25 l of N- (2-aminoethyl) -2 - [[3- [4 - [[5-methyl) -l, were added to a 0.25 l flask under an argon atmosphere. 2- (1-Methylethyl) phenoxy] methyl] piperidin-1-yl] propyl] amino] pyrimidine-4-carboxamide, 0.82 g (5.2 mmol) 2chloropyrimidine-4-carboxamide, 0.89 g (6.4 mmol) of potassium carbonate and 75 ml of acetonitrile and refluxed for 30 h.

The solvent is evaporated, then 100 ml of water are added to the crude residue and the mixture is extracted with dichloromethane (3 × 100 ml). The organic phase is washed with water (100 ml), dried over sodium sulfate, filtered and the solvent evaporated under reduced pressure. The product is purified by column chromatography on silica gel (dichloromethane / methanol eluent, 100/0 to 90/10) and recrystallized from acetonitrile. Finally, 1.75 g of compound are finally isolated.

Melting point: 164-1670C.

Example 3 (Compound No. 4) (+) -N- [2- [[4- (aminocarbonyl) pyrimidin-2-yl] amino] ethyl] -2-t [3-t4- (5-chloro) -2- methoxyphenyl) piperazin-1-yl] -2-hydropropyl] amino] pyrimidine-4-carboxamide.

3.1 () -2 - [[3- [4- (5-Chloro-2-methoxyphenyl) piperazin-1-yl]
2-hydroxypropyl] amino] pyrimidine-4-carboxylate
Thyle.

1.7 g (11.16 mmol) of (+) - 2-t3-t4- (5-chloro-2-methoxyphenyl) piperazin-1-yl] -2-hydroxypropyl are introduced into a 1 l flask. amino] pyrimidine-4-carboxamide and 450 ml of methanol, then a stream of gaseous hydrochloric acid is passed for a few minutes and heated at the reflux temperature of methanol for 2 hours.

The solvent is evaporated off under reduced pressure, 300 ml of dichloromethane are added to the residue and the mixture is cooled to 0 ° C.

The mixture is basified with saturated aqueous sodium hydrogencarbonate solution, decanted and extracted again with dichloromethane. The organic phase is dried over sodium sulfate, filtered and the solvent evaporated under reduced pressure. The product is purified by chromatography on a column of silica gel (eluent: dichloromethane / methanol mixture, 100/0 to 90/10) and is recrystallized from cyclohexane. 3.07 g of ester are obtained.

Melting point: 119-1220C.

3.2 (+) - [2- [t2- [t3-t4- (5-Chloro-2-methoxyphenyl) piperazin-1-yl] -2-hydroxypropyl] amino] pyrimidin-4-yl] carbonyl]
amino, ethyl] carbamate of 1,1-dimethylethyl.

0.21 g (5.07 mmol) of (+) - 2-t-3- [4- (5-chloro-2-methoxyphenyl) piperazin-1-yl] -2 are introduced into a 0.25 l flask. -
methyl hydroxypropyl] amino] pyrimidine-4-carboxylate and 2.6 g (16.2 mmol) of 1,1-dimethylethyl (2-aminoethyl) carbamate in 25 ml of propan-2-ol, and heating the reaction mixture for 16h.

The solvent is evaporated under reduced pressure and the crude product is purified by column chromatography on silica gel (eluent: dichloromethane / methanol, 100/0 to 90/10). 2.8 g of pasty compound are obtained, which is used as such in the next step.

3.3 (+) - N- (2-aminoethyl) -2-t3-t4- (5-chloro-2-methoxyphenyl) piperazin-1-yl] -2-hydroxypropyl] amino] pyrimidine-4-
carboxamide.

In a 0.5 liter flask, 2.8 g (4.96 mmol) of (+) - [2 - [[[2 - [[3- (4- (5-chloro-2-methoxyphenyl)) are introduced. 1, 1-dimethylethyl piperazin-1-yl] -2-hydroxypropyl] amino] pyrimidin-4-yl] carbonyl] amino] ethyl] carbamate dissolved in a few ml of methanol, followed by dropwise addition of 7 ml of Concentrated hydrochloric acid After stirring for 15 minutes, the mixture is cooled to 0 ° C. with an ice / salt / water mixture, then 1N sodium hydroxide is added in small portions until the pH is basic.

It is extracted with dichloromethane, the organic phase is dried over sodium sulphate, filtered and the solvents are evaporated off under reduced pressure. 2.3 g of oil are obtained which is used as it is in the next step.

3.4 (+) - N- [2- [4- (aminocarbonyl) pyrimidin-2-yl] amino] -
ethyl] -2 - [[3- [4- (5-chloro-2-methoxyphenyl) piperazin-1-yl] -2-hydroxypropyl] amino] pyrimidine-4-carboxamide.

0.52 g (4.96 mmol) of () -N- (2-aminoethyl) -2 - [[3- [4- chloro-2-methoxyphenyl) piperazin-1-yl] -2-hydroxypropyl] aminopyrimidine-4-carboxamide, 0.8 g (5.1 mmol) of 2-chloropyrimidine-4-carboxamide, 1 g (7 g. 2 mmol) of potassium carbonate in 150 ml of acetonitrile and heated at reflux for 17h.

The mixture is cooled to room temperature, the insoluble material is collected by filtration and purified by column chromatography on silica gel (eluent: dichloromethane / methanol 100/0 to 85/15). 0.6 g of compound are isolated after recrystallization from acetonitrile.

Melting point: 178-1810C.

Board

<tb> NO <SEP> -NR1R2 <SEP> | <SEP> R3 <SEP> - <SEP> R5 <SEP> R <SEP> m <SEP> F <SEP> (OC)
<tb><SEP> 1 <SEP> XK <SEP> S <SEP> H <SEP> H <SEP> H <SEP> H <SEP> 0 <SEP> 131-133
<tb><SEP> 2 <SEP> ~ tz <<SEP> H <SEP> H <SEP> H <SEP> H <SEP> 0 <SEP> 164-167
<tb><SEP> 3 <SEP> H <SEP> H <SEP> H <SEP> H <SEP> 0 <SEP> 167-168
<tb><SEP> OH <SEP> H <SEP> H <SEP> H <SEP> 0 <SEP> 178-181
<tb><SEP> 5 <SEP> 40 <SEP> OCH3 <SEP> H <SEP> H <SEP> H <SE> O <SEP> 143,5-145
<Tb>
Note: all compounds are in the basic state; Compounds Nos. 4 and 5 are racemates.

The compounds of the invention have been studied for their al-adrenergic receptor antagonist activity in the lower urinary tract.

Their in vitro activity was studied on rabbit isolated urethra.

Adult male rabbit urethra rings are prepared according to the method of Ueda et al., Eur. J. Pharmacol., (1984), 103, 249254, then, after sensitization to norepinephrine, the concentration-response curve to phenylephrine is determined, in the absence and in the presence of the compound to be studied.

The potency of α1-adrenergic antagonism of each compound is evaluated by calculating pA2, antilogarithm of the molar concentration of antagonist in the presence of which the agonist concentration must be doubled to produce the same effect as in its absence.

The pA2 of the compounds are of the order of 7 to 10.

The in vivo activity of the compounds of the invention was investigated for their effect on urethral hypertonia generated by stimulation of the sympathetic fibers of the hypogastric nerve in the anesthetized cat.

Adult male cats were anesthetized with sodium pentobarbital and prepared according to the method of Theobald, J.

Auton. Pharmac., (1983), 3, 235-239, to obtain urethral hypertonia by stimulation of the sympathetic fibers of the hypogastric nerve. The contractile responses of the urethra to electrical stimulation of the hypogastric nerve are noted before and after intravenous administration of the compounds to be studied at cumulative doses of 1 to 1000 μg / kg.

The potency of α1-adrenergic antagonism of each compound is evaluated by calculating DIso, a dose which inhibits urethral hypertonia by 50%.

The Dl50 of the compounds of the invention are of the order of 0.01 to 1 mg / kg.

The results of the tests show that the compounds of the invention show, in vitro, an α1-adrenergic receptor activity of the smooth muscles of the lower urinary tract (urethra) stimulated by an α1-adrenergic agonist (phenylephrine). In vivo, they inhibit urethral hypertonia caused by sympathetic nerve stimulation.

The compounds of the invention can therefore be used for the symptomatic treatment of diseases and conditions involving hyperactivity of the α-adrenergic system at the level of the lower urinary tract, and in particular for the treatment of micturition disorders of benign prostatic hypertrophy, such as dysuria and pollakiuria.

For this purpose they may be presented in any form suitable for enteral or parenteral administration, combined with pharmaceutical excipients, for example in the form of tablets, dragees, capsules, solutions or suspensions drinkable or injectable, suppositories, being dosed for allow a daily dose of 0.1 to 500 mg of active substance.

Claims (4)

claims Compound, optionally in the form of a pure optical isomer or a mixture of such isomers, corresponding to the general formula (I)

 in which m represents the number 0 or 1, R1 represents a methyl group, in which case R2 represents a phenoxy (C1-C4) alkyl group (of which the phenoxy group optionally carries 1 or 2 substituents chosen from halogen atoms and methoxy groups), or else R1 and R2 form together, and with the atom of nitrogen which carries them, a 4-phenoxypiperidin-1-yl group (of which the phenoxy group bears optionally 1 or 2 substituents chosen from halogen atoms and methoxy groups), a phenoxymethylpiperidin-1-yl group (of which the phenoxy group optionally carries 1 or 2 C 1 -C 4 alkyl groups), or (when R 3 represents a hydroxy or methoxy group) a 4-phenylpiperazin-1-yl group (of which the phenyl group optionally carries 1 or 2 substituents chosen from the atoms of halogens and methoxy groups), R3 represents a hydrogen atom, a hydroxyl group or a methoxy group, R4 represents a hydrogen atom, R5 represents a hydrogen atom, and R6 represents a hydrogen atom, in the form of a base or salt addition to an acid. 2. Process for the preparation of a compound according to claim 1, characterized in that an amide of general formula (II) is converted into

 (wherein R1, R2, R3 and R4 are as defined in claim 1) to an ester of the general formula (III)

 (in which R 'represents a C1-C4 alkyl group), by reaction with a C1-C41 aliphatic alcohol in the presence of an acid, at a temperature of 0 to 1000C, and then the ester thus obtained is converted, by reaction with an amine of general formula (IV)

 (wherein R5 and R6 are as defined in claim 1 and R7 represents either a hydrogen atom or an amine protecting group) to an amide of the general formula

 in an aliphatic alcohol as a solvent, at a temperature of 0 to 600C, then, if necessary, deprotecting the amine of general formula (V) by a known method, and finally reacting the amine of general formula (V) (wherein R7 represents a hydrogen atom) with 2-chloropyrimidine4-carboxamide in an aprotic solvent, in the presence of a base, at a temperature of 20 to 400C. 3. Medicinal product characterized in that it consists of a compound according to claim 1. 4. Pharmaceutical composition characterized in that it contains a compound according to claim 1, combined with a pharmaceutical excipient.