FR2781799A1 - Benzofuran and benzothiophene alkyl heterocyclyl derivatives having smooth muscle contractile agonist activity with low arterial contractile activity, useful for treating e.g. urinary incontinence, migraine or gastro-intestinal disorders - Google Patents

Abstract

Benzofuran and benzothiophene alkyl heterocyclyl derivatives (I) are new. Benzofuran and benzothiophene alkyl heterocyclyl derivatives (I) of formula (I) and their addition acid salts are new. X = O or S; A = H, OH, 1-6C hydroxyalkyl, SH, alkyl sulfanyl, NH2, alkylamino, dialkylamino, alkyl hydroxylamine, alkoxy, hydroxylamine, N,O-dialkyl hydroxylamine, azido or halogen; B' = H, alkyl, alkenyl, fluoroalkyl, 1-2C perfluoroalkyl, alkoxy, phenyl or oxo; n = 1 or 2; R1, R2 = H, halogen, CN, CONH2, alkyl, alkenyl, 6C cycloalkyl, alkoxy carbonyl, hydroxyalkyl, alkoxy, 1-6C alkoxyalkyl, fluoroalkyl, 1-2C perfluoroalkyl; or R1 + R2 = 6C cycloalkenyl, 4-6C cycloalkadienyl, or 5-6C aryl; R3 = alkyl, alkenyl, fluoroalkyl, 1-2C perfluoroalkyl, hydroxyalkyl, alkoxy or 1-6C alkoxyalkyl; R4 = H, alkyl, alkenyl, fluoroalkyl, 1-2C perfluoroalkyl, hydroxyalkyl, alkoxy or 1-6C alkoxyalkyl; R5 = H or halogen; alkyl, alkoxy, alkenyl = 1-6C (unless otherwise stated).

Description

The present invention relates to benzofuran derivatives and

  benzothiophene, their preparations and

  pharmaceutical compositions containing them.

  The compounds have the general formula I: R3) n

RI R4

R2 B

  Wherein X represents either an oxygen atom or a sulfur atom; A represents either a hydrogen atom, a hydroxyl, a C16 hydroxyalkyl, a thiol, a C-6 alkylsulfanyl, an amino C16 alkylamino, di (C16 alkyl) amino, C16 alkyl hydroxylamine, C6 alkoxy, hydroxylamine, Cl6 N, O-dialkyl hydroxylamine, azido or halogen such as fluorine, chlorine or bromine, B represents a hydrogen atom, a C1_alkyl, a C26 alkenyl, a C6 fluoroalkyl, a C12 perfluoroalkyl, a Cl6 alkoxy, a phenyl or an oxo; n represents 1 or 2 - R1 and R2 represent, independently the one of the other, a hydrogen atom, a halogen such as fluorine, chlorine or bromine; a cyano, a carboxamide, a C16 alkyl, a C26 alkenyl, a C36 cycloalkyl, a C16 alkoxycarbonyl, a Cl6 hydroxyalkyl, a C1i alkoxy, a C16 alkoxyalkyl, a Cl-fluoroalkyl, a Cl2 perfluoroalkyl or R1 and R2 together form, with the double bond to which they are attached, a cycle C3. cycloalkenyl, a cycloalkenyl C46 ring or a C6- aryl; R3 represents a C1-alkyl, a C26 alkenyl, a C1-6 fluoroalkyl, a C1-2 perfluoroalkyl, a C16 hydroxyalkyl, a C1-alkoxy, C1-6 alkoxyalkyl, - R4 represents a a hydrogen atom, a C1-alkyl, a C26 alkenyl, a C1-fluoroalkyl, a C2 perfluoroalkyl, a C1-hydroxyalkyl, a C1-6 alkoxy or C1-1 alkoxyalkyl; and - Rs represents a hydrogen atom or a halogen, as

fluorine, chlorine or bromine.

  According to a preferred embodiment of the invention, A represents a hydroxyl and B represents a hydrogen atom. Other preferred compounds according to the invention are the compounds for which R3 represents a Cl6 alkyl, preferably a Cl3 alkyl. Of these, the particularly preferred compounds are those for which R3 is

  found on carbon in alpha of the nitrogen of the cycle.

  S15 In the present application an alkyl, alkenyl or alkoxy represents respectively an alkyl, alkenyl or alkoxy

linear or branched.

  The compounds of general formula I can comprise one or more asymmetric carbon atoms. They can therefore

  exist as enantiomers or diastereoisomers.

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

the invention.

  The compounds of general formula I may be in the form of a free base or of addition salts with pharmaceutically acceptable acids, which are also part of

of the invention.

  The compounds derived from benzofuran or benzothiophene of formula I according to the invention may be prepared according to

  different processes. These methods are described below.

  1. The compounds of formula I, in particular those for which A represents a hydroxyl, may be prepared

according to scheme 1.

Diagram (1) R Xi X OH R3 RR3 R4

/ X OH B B

R2-9, / B, R2 B

  OH Protection R5 2) Deprotection OH III According to this process, the substitute B-substituted hydroxyl of the compound of formula III is selectively protected by a protecting group P, in a manner known to those skilled in the art, for example by formation of a silylated ether, so as to obtain the compound of formula II. The hydroxyl borne by the alpha carbon of the heterocyl compound thus obtained may be optionally activated, in a manner known to those skilled in the art, so as to obtain a nucleophuge, such as a mesyl, tosyl or an atom bromine. For example, mesyl or tosyl chloride is added to a solution of the compound of formula II in an organic solvent such as ether, tetrahydrofuran or dichloromethane, in the presence of an organic base such as triethylamine, preferably at a temperature between 0 and -40 C. The compound of formula I according to the invention is then prepared from the compound thus obtained by reacting it with an amine of formula IV. The reaction can be carried out without solvent or in an organic solvent such as dichloromethane, chloroform or acetonitrile, preferably under reflux. This latter reaction is followed by a deprotection reaction according to methods known to those skilled in the art. The meanings of X, R 1, R 2, R 3, R 4, R 5, n and B in each of the compounds of formulas II, III and IV are those indicated for formula I. 2. The compounds of formula I according to the invention, for which A is a hydroxyl, may be further prepared according to the following reaction scheme (2): Scheme (2) R1 X4O 5R3 R1 R4 R4

R2 '<R2 X N

R2 B t B IV OH

R5 V R5

  According to this process, the compound of formula I is prepared by reacting an oxirane derivative of formula V with a cyclic amine of formula IV, according to methods known to those skilled in the art. For example, the reaction is carried out in an organic solvent such as ether, tetrahydrofuran or acetonitrile. This reaction can also be carried out in the presence of an excess of amine of formula IV or in the presence of an organic base such as triethylamine. The meanings of X, R 1, R 2, R 3, R 4, R 5, n and B of the oxirane derivative of formula V and of said amine are those indicated above for formula I. 3. The compounds of formula I, wherein B represents an oxo, can be advantageously prepared according to the following reaction scheme (3): Scheme (3) RI R3XiV R4 RR3_ "R4

R2- ^ A IV, R2A

3O R5

R5 R5

  According to this process, the hydroxyl of the compound of formula VI can be activated, by methods known to those skilled in the art, so as to obtain a nucleophuge, such as a mesyl, tosyl or a bromine atom. It is then made to react with a

  cyclic amine of formula IV as defined above.

  The reaction conditions may be identical to those

described in point 1.

  4. The compounds of formula I according to the invention, for which A is not a hydroxyl, can be prepared from the compound of formula I, where A is a hydroxyl, by activating this group, in a manner known per se. skilled in the art, so as to obtain a nucleophuge W, such as a mesyl, tosyl or a bromine atom. The compound thus obtained is

  reacted with a nucleophile A according to the reaction scheme (4).

  (4) R 1 N R 4 R 1 R 3 R 1 -R 4 R 1 R 34

// 'X' N // 'X' /// X "'N

R2

R2 B A R2 B

  Alternatively, the compounds of formula I according to the invention, for which A is a hydrogen atom, may be further prepared by dehydroxylation of a

  corresponding compound of formula I, where A is hydroxyl.

  The dehydroxylation reaction can be carried out, in a manner known to those skilled in the art, by reaction with

  triethylsilane and trifluroacetic acid.

  The starting compounds of formula IV are commercially available or can be obtained according to methods

known to those skilled in the art.

  The starting compounds II, III, V and VI can be obtained according to methods known to those skilled in the art, for example according to those described in the patent application WO98 / 008834. Similarly, other compounds of formula I may be synthesized according to other methods described in

patent application WO98 / 008834.

  The following examples are intended to illustrate the

present invention.

  Example 1: 2,3-dimethyl-7- (1- [2'-hydrochloride

  ethylpiperidinel -2-hydroxvethyl) -benzofuran (1) 2,3-dimethyl-7- (1- [2-ethylpiperidine] -2- [tert-butyl dimethylsilyloxy] -ethyl) -benzofuran In a 100 ml flask, introduced 3 g (9.82 mmol) of 2,3-dimethyl-7- (1-hydroxy-2- [tert-butyl dimethyl silyloxy] -1-hydroxyethyl) benzofuran (obtained according to the methods described in the patent application WO98 / 008834 ), 50 ml

  ethyl ether and 2.2 ml (15.7 mmol) of triethylamine.

  The mixture is cooled to -30 ° C with a dry ice bath in acetone and 1.24 ml (15.7 mmol) of mesyl chloride are added. The cooling bath is removed and the reaction mixture is allowed to warm to room temperature for 30 minutes. 200 ml of water are added and extraction is carried out with ethyl ether (3 × 150 ml). The organic phases are combined, dried over magnesium sulfate and concentrated. The residue is transferred without further purification into a 100 ml three-necked flask equipped with a refrigerant. 8.7 g (113.2 mmol) of 2-ethylpiperidine, 10 ml of chloroform are added and the mixture is refluxed for 16 hours. The reaction mixture was cooled to room temperature, concentrated in vacuo, 150 ml of water was added and extracted with ethyl ether (3 x 200 ml). The organic phases are combined, dried over magnesium sulphate and concentrated in vacuo. The residue is purified by chromatography on a silica column (elution solvent 10% of methanol in dichloromethane). We obtain 0.75 g

  (Yield 18%) 2,3-dimethyl-7- (1- [2'-ethylpiperidine] -

  2- [butyl-dimethyl silyloxy] ethyl) -benzofuran under

form of an oil.

  (2) 2,3-Dimethyl-7- [1- [2'-ethylpiperidine] -2-hydroxyethyl)

  benzofuran. 0.57 g (1.37 mmol) is introduced into a 50 ml flask.

  2,3-dimethyl-7- [1- [2'-ethylpiperidine] -2- [tert-

  butyldimethylsilyloxy] -ethyl] -benzofuran and 10 ml of tetrahydrofuran. It is cooled to 0 ° C. with an ice bath and a solution of 0.48 g (1.54 mmol) of tert-butylammonium fluoride trihydrate in 5 ml of tetrahydrofuran is added. The reaction mixture is stirred at 0 ° C. for 1 hour and at room temperature for 16 hours. 25 ml of water are added and extraction is carried out with ethyl ether (3 × 20 ml). The organic phases are combined, dried over magnesium sulphate and concentrated in vacuo. The residue is purified by chromatography on a silica column (elution solvent 5% of methanol in dichloromethane). We

  0.322 g (Yield: 78%) of 2,3-dimethyl-7- (1-

  [2'-ethylpiperidine] -2-hydroxyethyl) -benzofuran in the form

of an oil.

  (3) 2,3-Dimethyl-7- (1 - [2'-ethylpiperidine] hydrochloride

2-hydroxyethyl) benzofuran

  In a 100 ml flask, 0.285 mg of

  dimethyl-7- (1- [2'-ethyl-piperidine] -2-hydroxyethyl) -

  benzofuran and 10 ml of a 0.1N solution of hydrochloric acid in isopropanol. The salt is concentrated in vacuo and recrystallized from ethyl acetate. We obtain

  0.280 g of 2,3-dimethyl-7- (1- [2'-

  ethylpiperidine] -2-hydroxyethyl) benzofuran. Mp = 59-60C.

  EXAMPLE 2 Asymmetric Synthesis The chiral compounds of formula I are obtained according to the method described in example 2 of the patent application.

W098 / 008834.

Example 3

  Using essentially the same process as that of Example 1 or 2 of the present invention, using a suitable cyclic amine of formula IV as well as a suitable compound of formula II, other

formula I according to the invention.

Example 4

  Other compounds of formula I may be synthesized according to the methods described in the patent application

W098 / 008834.

BOARD

  R3) n R1 R3l-R4 Rx R2 AB R5 NX R1 R2 R3 R4 R5 n AB Salt F (OC) 1 O CH3 CH3 C2Hs HH 2 OH H - oil 2 O CH3 CH3 C2H5 HH 2 OH H HCl CH3 CH3 CH3 C2H, HH 2 OH H - oil CH3 CH3 CH20H HH 1 OH H - oil O CH3 CH3 CH2OCH3 HH 2 OH H - oil 6 O CH3 CH3 CH3 CH3 H 2 OH H - oil In this table : - ClH represents a hydrochloride, - "-" represents a compound in free form The compounds of the invention have been subjected to tests

  biological tests designed to demonstrate their contractile activity on the urethral and arterial smooth muscles.

  1. The in vitro activity of the compounds of the invention has been

  studied on the urethral and arterial smooth muscles. These tests were carried out on neoplastic female rabbits.

  Zealanders weighing from 3 to 3.5 kg. The animals were killed by vertebral dislocation, then rings of mesenteric artery and ureter tissue were removed. These rings of tissue were immersed in a modified Krebs solution, oxygenated with a mixture of 95% O 2 and 5% CO 2. Each tissue sample was tensioned at 1 g and then phenylephrine was added at cumulative doses and the dose / response curve was established. After rinsing the samples, the test compound was introduced at cumulative doses and the dose / response curve was established. The contractile effect of each compound is evaluated by calculating the pD2 (negative logarithm of the agonist concentration that induces 50% of the maximal contraction) as well as by the maximum effect representing the percentage of the

  maximum contraction obtained with phenylephrine (% Water).

  The results obtained show that the compounds in accordance with the invention exhibit: a pD2 urethra, usually between 4 and 9, a pD2 artery usually less than 3, a% E max urethra greater than 30, usually between 40 and 90 ,

  * a% Ea artery usually equal to zero.

  2. The in vitro activity of the compounds of the invention has been studied on the saphenous veins of micro-pig Yucatan. The fabric is cut into a helix and is mounted in a tank with isolated organs in a modified Krebs solution oxygenated with a mixture of 95% O2 and 5% CO2 maintained at 37 ° C.

  vessel is connected to an isometric sensor at a basal tension of 1 g and is connected to a polygraph allowing the recording of tensional variations.5 The viability of each preparation is tested by pre-

  stimulation with norepinephrine 3pM. After rinsing, the

  compound to be studied is introduced and its concentration-

  response constructed cumulatively until a maximum response is obtained. The contractile effect of each compound is evaluated by calculating the EC50 (concentration

  producing 50% of the maximum response).

  The compounds of the invention have made it possible to obtain a venoconstructive activity with an EC50 value.

  usually between 1 MM and 100 MM.

  The compounds of the invention can be used in the treatment of venous insufficiency and venous ulcer. 3. The in vivo activity of the compounds of the invention on blood pressure and urethral was studied in amyelated rat and rabbit, according to the following protocols: * Rats demedulated Wistar rats are anesthetized and demedulated (according to the described technique) by Gillespie, MacLaren A. and Polock D., A method of stimulating different segments of the autonomic outflow from the spinal column to various organs in the

  pithed cat and rat; Br. J. Pharmacol., 1970, 40: 257-

  267). The catheters are introduced through the aorta and jugular vein. Another catheter is introduced into the urethra by an incision performed in the bladder. The compounds to be tested are administered at increasing doses by

intravenous infusion.

  The results are expressed in doses (Mg / kg) necessary to increase the urethral pressure of 10 cm of water (PU10) or the blood pressure of 10 mmHg (PA, 0) or 50 mmHg (PA0so) 5 The compounds of the invention thus tested, made it possible to obtain: a PU10 with doses of less than 500 mg / kg, usually between 5 and 200 g / kg, of a PA10 with doses greater than 600 mg / kg, usually between 600 and 2000 mg / kg,

- the PA50 could not be reached.

* Awake conscious rabbits

  The experiments are carried out on neoplastic female rabbits.

  Zelander weighing between 3 and 4 kg, anesthetized with pentobarbital. The catheters are introduced for the descending aorta into the femoral artery, into a jugular vein and into the urethra (1.5 cm below the bladder neck). The compounds to be tested are administered 5 to 15 days after the operation, by intravenous (i.v.) administration in 5 minutes.

  minutes, and in a single dose (100 gg / kg).

  Here, the increase in urethral pressure (PU) and arterial pressure (BP) compared to

  basal pressure, respectively urethral and arterial.

  The results obtained are expressed as a percentage of

  premedicamentous values at 5 minutes after dosing.

  Compounds of the invention thus tested, allowed an increase of the PU greater than 70%, usually between 150 and 25%. The increase in PA was

  always less than 10%, usually it was 0%.

  All the above results show that the compounds of the invention have a strong urethral contractile action and a low arterial contractile action. They can be used as a medicament, particularly as a contracting agent for smooth muscle, and even more particularly, in the treatment of stress urinary incontinence. In this indication, the compounds according to the invention have a good efficacy and, usually, lesser side effects than the drugs conventionally used for such treatment, in particular with regard to the side effects affecting the cardiovascular system,

especially the arterial beds.

  The compounds according to the invention can also be used for the treatment of venous insufficiency, migraine, gastrointestinal disorders and as a

  Vaso-constrictor of the nasal mucosa.

  The compounds according to the invention may be presented in different pharmaceutical forms suitable for administration by the digestive or parenteral route, where appropriate by combining with at least one pharmaceutical excipient. Suitable dosage forms are, for example, tablets, capsules, dragees, capsules, oral or injectable solutions,

syrups, suppositories.

  These dosage forms can be assayed for

  allow a daily dose of 0.1 mg / kg to 50 mg / kg.

Claims (9)

CLAIM 1. Compound of formula I R31 (I) R1 R3R4 R2 B   Wherein X represents either an oxygen atom or a sulfur atom; A represents either a hydrogen atom, a hydroxyl, a Cl6 hydroxyalkyl, a thiol, a C16 alkylsulfanyl, a   amino, Cl-alkylamino, di (Cl, alkyl) amino, ClI.   alkyl hydroxylamine, a C16 alkoxy, a hydroxylamine, a Cl.   N, O-dialkyl hydroxylamine, an azido or a halogen such as fluorine, chlorine or bromine, B represents a hydrogen atom, a C-16 alkyl, a C2-6 alkenyl, a C16 fluoroalkyl, an IC2 perfluoroalkyl, a C1-alkoxy, a phenyl or an oxo-n represents 1 or 2, - R1 and R2 represent, independently of one another, a hydrogen atom, a halogen such as fluorine, chlorine or bromine; a cyano, a carboxamide, a C1-6 alkyl, a C26 alkenyl, a C6 cycloalkyl, a C1 6 alkoxycarbonyl, a C1-hydroxyalkyl, a C1-alkoxy, a C16 alkoxyalkyl, a C1 fluoroalkyl, a C12 perfluoroalkyl or R1 and R2 sets form, with the double bond to which they   are attached, a C-6 cycloalkenyl ring, a C4- ring.   cycloalkadienyl or C 6 aryl; R 3 represents a C 1-6 alkyl, a C 2-6 alkenyl, a C 6 fluoroalkyl, a C 1 2 perfluoroalkyl, a C 1. hydroxyalkyl, a C1 1 alkoxy or C1-alkoxyalkyl, - R4 represents a hydrogen atom, a C1. alkyl, C2-6 alkenyl, fluoroalkyl C16, perfluoroalkyl CI, hydroxyalkyl CI6, C1, alkoxy or C16 alkoxyalkyl; and R represents a hydrogen atom or a halogen, such as fluorine, chlorine or bromine, in enantiomeric form, diastereoisomer or mixture of these different forms, including racemic mixture and their salts; addition to pharmaceutically acceptable acids. 2. Compound of formula I according to claim 1, characterized in that A represents a hydroxyl and B represents a hydrogen.   3. A compound of formula I according to any of   Claims 1 or 2, characterized in that R3 represents a C1-6 alkyl.   4. Compound of formula I according to claim 3 characterized in that R3 is on the carbon alpha nitrogen cycle.   5. Process for the preparation of a compound according to any one of claims 1 to 4, wherein A is a hydroxyl, characterized in that one activates the hydroxyl of a compound of formula II R1 / X HO B R2 -P   Wherein R 1, R 2, R 5, X and B are as defined in claim 1 and P is a protecting group, and this compound is reacted with a cyclic amine of formula IV, wherein R 3, R 4 and n are such as defined in claim 1, R4) n IV followed by deprotection, or a compound of formula V R1 R2B v R5 is reacted wherein R1, R2, Rs, X and B are as defined in claim 1 with a cyclic amine of formula IV10 wherein R3, R4 and n are as defined in claim 1.   6. Process for the preparation of a compound according to any one of claims 1 to 4, for which B is an oxo, characterized in that one activates the hydroxyl of a compound of formula VI R1 -X OH vi 1A AT   Wherein R 1, R 2, R 5 and X are as defined in claim 1 and B represents an oxo, and this compound is reacted with an amine of formula IV in which R 3,   R4 and n are as defined in claim 1.   7. Process for the preparation of a compound according to any one of claims 1, 3 or 4, for which A is not a hydroxyl, characterized in that a compound of formula VII is reacted, RI R4 R2 'W B VII   wherein R 1, R 2, R 3, R 4, R 5, X, B and n are as defined in claim 1 and W is a nucleophore, with a nucleophile A as defined in claim 1. 8. Drug characterized in that it consists of a compound according to any one of claims 1 to 4. 9. Pharmaceutical composition characterized in that it comprises a compound according to any one of claims 1 to 4 and one or more excipients appropriate.