FR2781800A1 - 7-(2-heterocyclylethyl) benzofuran and benzothiophene derivatives having smooth muscle contractile agonist activity with low arterial contractile activity, useful for treating e.g. urinary incontinence or gastro-intestinal disorders - Google Patents

Abstract

7-(2-heterocyclylethyl)benzofuran and 7-(2-heterocyclylethyl)benzothiophene derivatives (I) are new. 7-(2-heterocyclylethyl)benzofuran and 7-(2-heterocyclylethyl)benzothiophene derivatives of formula (I) and their acid addition salts are new. X = O or S; A = H or OH; B' = H, 1-8C alkyl, 2-8C alkenyl, 1-8C fluoroalkyl, 1 or 2C perfluoroalkyl; n = 1 or 2; R1, R2 and R5 = H, halogen, 1-8C alkyl, 2-8C alkenyl, 3-8C cycloalkyl or cycloalkenyl, 6, 10, or 14C aryl, 1-6C alkoxy carbonyl, 1-6C alkoxyalkyl, 1-8C fluoroalkyl, 1 or 2C perfluoroalkyl; or R1 + R2 = 3-8C cycloalkyl, or 6, 10 or 14C aryl, with the carbon atoms to which they are attached; R3 = 1-6C alkyl, 2-6C alkenyl, 1-6C fluoroalkyl, 1-2 C perfluoroalkyl, 1-6C hydroxyalkyl,1-6C alkoxy,or 1-6C alkoxyalkyl; R4 = H, 1-6 C alkyl, 2-6C alkenyl, 1-6C fluoroalkyl, 1-2 C perfluoroalkyl, 1-6C hydroxyalkyl, 1-6C alkoxy or 1-6C alkoxyalkyl. An Independent claim is also included for the preparation of (I).

Description

The present invention relates to derivatives of 2-aminoethyl-

  benzofuran and 2-aminoethyl-benzothiophene,

  their preparations and their therapeutic applications.

  These compounds according to the invention correspond to the following general formula I: R1 / bx A

R2 B

R3 R

  R5 in which: - X represents either an oxygen atom or a sulfur atom, - A represents either a hydrogen atom or a hydroxyl group, - B represents either a hydrogen atom or a C1 group,

  alkyl, C1-8 alkenyl, Cl-8 fluoroalkyle or Cl2 perfluoro-

  alkyl, - n represents 1 or 2, - RI, R2, Rs, identical or different, each represent a hydrogen atom, a halogen such as chlorine, bromine or fluorine, a Cl- alkyl group, Cl- a alkenyl, C38 cycloalkyle, C38 cycloalkényle, aryl in C6, C1o or Ci4, C16 alkoxycarbonyle, C16 hydroxyalkyle, C16 alkoxyalkyle, Cl_ alkoxy, Cl8 fluoroalkyle or Cl_2 perfluoroalkyle,

  or R1 and R2 together form a C3- ring. cycloalkyl, C3.

  cycloalkenyl, or a C6, C10 or C14 aryl, -R3 represents a linear or branched Cl6 alkyl group, a C26 alkenyl group, a C1.6 fluoroalkyl group, a Cl.2 perfluoroalkyl group, a C1_6 hydroxyalkyl group, a C1i6 group alkoxy or C1l-alkoxyalkyl; and - R4 represents a hydrogen atom, a Cl.6 linear or branched alkyl group, a C2.6 alkenyl group, a Cl_ fluoroalkyl group, a C1.2 perfluoroalkyl group, a Cl6 group

  hydroxyalkyl, a Cl.6 alkoxy or Cl-6 alkoxyalkyl group.

  The preferred compounds according to the invention are those for

  which X represents an oxygen atom.

  Other preferred compounds are those comprising radicals having the following meanings: * R1 and R2 each represent a C1.4 alkyl group, more preferably methyl, ethyl or i-propyl, or a group CF3_ * R3 and R4 independently represent the one of the other a C1.4 alkyl group, more preferably a methyl or ethyl group, a C16 hydroxyalkyl group, more preferably a hydroxymethyl or a C.6 alkoxyalkyl group, more preferably a methyloxymethyl, * Rs represents a hydrogen atom , * A represents a hydroxyl group and

  * B represents a hydrogen atom.

  Among these, the particularly preferred compounds are those for which R3 is found on the alpha carbon of

cycle nitrogen.

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

linear or branched.

  The compounds of general formula I have one or more asymmetric carbon atoms. They can therefore exist in the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as their mixtures, including

  including racemic mixtures, are part of the invention.

  The pharmaceutically acceptable salts of the compounds of formula I according to the invention can be either salts of mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid, or salts of organic acids such as acetic acid, citric acid, tartaric acid, maleic acid, succinic acid, methanesulfonic acid or fumaric acid.

  The hydrochloric acid salts are preferred.

  The compounds of formula I according to the invention can be prepared according to different methods. These processes are described below. 1. The compounds of formula I, in particular those for which A represents a hydroxyl group, can be

prepared according to diagram 1.

Diagram 1

R3

X R4 N Sn (C4H9) 3 R1

RCHO B A

R2- CHOIII R2 B

  R5 C4H9Li, THF R4 II According to this process, an aldehyde of formula II is reacted with an aminoalkyl stannate derivative of formula III. The meanings of R1, R2, R3, R4, R5, X, n and B of the compounds of formula II and III are those indicated in formula I. This reaction can be carried out in an organic solvent

  such as tetrahydrofuran, in the presence of n-butyl lithium.

  0.2 to 1.5 moles of the compound are generally reacted

  formula II for one mole of the compound of formula III.

  The compounds of formula III can be prepared by a person skilled in the art according to the method described by Katrizky, A.R .; Chang,

H-X .; Wu, J. Synthesis, 1994, 907.

  2. The compounds of formula I according to the invention, for which A is a hydroxyl group, can also be prepared according to the following reaction scheme (2): Scheme 2 R4

R1 HN R3 RO

R / X HO W R O

2 B V R2 '.B

B N

R R -) R4

R5 IV 5 3

  According to this process, a compound of formula IV is reacted, in which W represents a nucleofuge group, such as a tosyl group, a mesyl group or a bromine atom with an amine of formula V. Usually 0.01 is reacted to 2 moles of the compound of formula IV for one mole of said amine of formula V. The reaction can be carried out, for example, by adding to a solution of the compound of formula IV, mesyl or tosyl chloride in an organic solvent such than 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 of the compound thus obtained by reacting it with an amine of formula V. The reaction can be carried out without solvent or in an organic solvent such as

  dichloromethane or chloroform, preferably under reflux.

  The meanings of RI, R2, R3, R4, R5, X, n and B in each of the compounds of formulas IV and V are those indicated in formula I. 3. The compounds of formula I according to the invention, for which A is a hydroxyl group, can also be prepared according to the following reaction scheme (3): Scheme 3 R4

R. HN) R

X / 0 --X OH

R, R / X

R2 B V R2 B

R5 VI R5 3 R4

  According to this process, the compound of formula I is prepared by reacting an oxirane derivative of formula VI with an amine of formula V. For example, the reaction is carried out in an organic solvent such as ether, tetrahydrofuran, or acetonitrile. This reaction can 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 R1, R2, R3. R4, R5, X, n and B of the oxirane derivative of formula V and of said amine are those indicated above in formula I. 4. The compounds of formula I according to the invention, for which A and R5 each represent a hydrogen atom, can advantageously be prepared according to the following reaction scheme (4): Scheme 4

1) CH3SO2CI

2) R4 R

Ri HNIJR

R OH

R2 R3V R

  According to this process, the compound of formula VII is activated, for example by means of mesyl chloride (MsCl), and reacted with an amine of formula V, as defined above. Usually, 0.01 to 1 mole of compound of formula VII is used for one mole of said amine of formula V. The reaction conditions may be identical

to those indicated in point 1.

  5. The compounds of formula I according to the invention, for which A is a hydrogen atom, can also be prepared by dehydroxylation of a corresponding compound of formula I, o

A is a hydroxyl group.

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

  triethylsilane and trifluroacetic acid.

  The starting compounds of formula V are commercially available or can be synthesized according to methods

known to those skilled in the art.

  The starting compounds of formula II, IV, VI and VII can be synthesized according to methods known to those skilled in the art, for example according to the methods described in

Patent application W097 / 32870.

  The following examples are intended to illustrate the present invention.

  Example 1 :: 2,3-dimethyl-7- (2- [r2.6-dimethylpiperidinel-1-

  hydroxyethyl) -benzofuran In a 50 ml flask fitted with an agitator and a

  0.5 g (2.65 mmol) of 2,3-dimethyl-

  7- (oxirane) -benzofuran (synthesized according to the example of patent application WO97 / 32870), 13 ml of chloroform and 7.20 ml (52.9 mmol) of 2,6-dimethylpiperidine. The solution is stirred at reflux for 24 h and the solution is concentrated. The residue is purified by a chromatographic column (elution solvent dichloromethane: methanol 98: 2) and dried in a desiccator under

vacuum on phosphoric anhydride.

  0.5 g of 2,3-dimethyl-7- (2- [2,6-dimethylpiperidine] -

  1-hydroxyethyl) -benzofuran. F: 122 C.

Example 2:

  Using essentially the same process as that of Example 1, using a suitable amine as well as a suitable compound of formula II, other compounds are prepared

  of formula I according to the invention.

BOARD

R1 X A

R2 B

R5 R3R

  N X R1 R2 R3 R4 Rs n A B Sel F (OC)

  1 O CH3 CH3 2-CH3 6-CH3 H 2 OH H 122

  2 O CH3 CH3 2 - CH3 6 - CH3 H 2 OH H HC 1> 2 50

  3 O CH3 CH3 2 - C2H5 HH 2 OH H - oil 4t O CH3 CH3 2-CH3 5-CH3 H 1 OH H - oil 5t O CH3 CH3 2-CH3 5-CH3 H 1 OH H HCl1 202 6c O CH3 CH3 2 -CH3 5-CH3 H 1 OH H - oil

  7c O CH3 CH3 2-CH3 5-CH3 H 1 OH H HCl1 155-

  9 O CH3 CH3 2 - CH2OH H H 2 OH H - oil O CH3 CH3 3 2-CH2OCH3 H H 1 OH H - oil In this Table: - HC1 represents a hydrochloride,

  - "-" represents a compound in free form.

  - "t" indicates that the substituents R3 and R4 are in the trans position relative to each other - "c" indicates that the substituents R3 and R4 are in position

cis in relation to each other.

  The hydrochloric salts described in the table were prepared, as follows: An excess of a saturated ethanol solution in anhydrous hydrochloric acid is added to the compound according to the invention. Then the salt obtained is concentrated under vacuum, recrystallized from ethyl acetate and then dried with

  vacuum desiccator on phosphoric anhydride.

  The compounds of the invention have been subjected to biological tests intended to demonstrate their activity

  selective smooth muscle contracting.

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

  studied on smooth urethral and arterial muscles.

  These tests were carried out on neo-female rabbits

  Zealanders weighing 3 to 3.5 kg. The animals were killed by vertebral dislocation, and then rings of tissue from the mesenteric arteries and urethra were removed. These tissue rings were immersed in a modified Krebs solution, oxygenated by a mixture of 95% O 2 and 5% CO2. Each tissue sample was subjected to a tension of 1 g and then phenylephrine was introduced at cumulative doses and the dose / response curve was established. After rinsing the samples, the compound to be studied was introduced at cumulative doses and the dose / response curve established. The contractile effect of each compound is evaluated by calculating pD2 (negative logarithm of the agonist concentration which induces 50% of the maximum contraction) as well as by the Maximum effect representing the percentage of the maximum contraction obtained

with phenylephrine (% Ea).

  The results obtained show that the compounds in accordance with the invention have: * a pD2 urethra greater than 2.5, usually between 4 and 8, more generally between 5 and 8, * a pD2 artery less than 3, * a % E urethra greater than 30, usually between 40 and 90,

* a% E = artery equal to zero.

  2. The in vivo Activity of the Compounds of the Invention on the Blood and Urethral Pressure Was Studied in the Rat

  amyele and rabbit, according to the following protocols :.

  * Demedulated rats Wistar rats are anesthetized and demedulated (according to the technique described 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 a jugular vein. Another catheter is introduced into the urethra through an incision made in the bladder. The compounds to be tested

  are administered in increasing doses by intravenous infusion

  venous. The results are expressed in doses (gg / kg) necessary to increase the urethral pressure by 10 cm of water (PU10) or the blood pressure by 10 mm Hg (PA, 0) or 50 mm Hg (PAso0). compounds of the invention thus tested, made it possible to obtain: - a PU10 with doses less than 100 Mg / kg, usually between 20 and 50 pg / kg, - a PAlo0 with doses greater than 110 Mg / kg,

  usually between 130 and 250 Mg / kg.

- PAso could not be reached.

* Conscious rabbits

  The experiments are carried out on neo-female rabbits

  Zealanders weighing between 3 and 4 kg, anesthetized with pentobarbital. 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 test compounds are administered 5 to 15 days after the operation, by intravenous (i.v.) or per ilZ administration.

bone (p.o.).

  The compounds are administered i.v. over 5 minutes,

a single dose (100 pg / kg).

  The compounds are administered orally by gavage to the

dose of 3 mg / kg.

  We measured here the increase in urethral pressure (PU) and blood pressure (PA), compared to the pressure

  basal, respectively urethral and arterial.

  The results obtained are expressed as a percentage of values

  premedicated 5 minutes after dosing.

  The compounds of the invention thus tested, allowed an increase in the PU greater than 70%, usually between 90 and 25%. The increase in BP was

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

  All of the above results show that the compounds of the invention have a strong urethral action and a weak

arterial action.

  They can be used as a medicament, in particular as a contracting agent for smooth muscles, and more particularly still, in the treatment of urinary incontinence, in particular stress urinary incontinence. In this indication, the compounds according to the invention exhibit good efficacy and, usually, less side effects than the drugs conventionally used for such treatment, in particular as regards

  concerns side effects affecting the arteries.

  The compounds of the invention were subjected to biological tests intended to demonstrate their venoconstrictor activity. 1. The in vitro activity of the compounds of the invention was studied on the saphenous veins of Yucatan micro-pigs. The tissue is cut in a helix and mounted in a tank with organs isolated in a modified Krebs solution oxygenated by a mixture of 95% 02 and 5% CO2 maintained at 37 C. The vessel is connected to an isometric sensor under a basal voltage of 1 g and connected to a polygraph allowing the recording of blood pressure variations. The viability of each preparation

  is tested by pre-stimulation with noradrenaline 3MM.

  After rinsing, the compound to be studied is introduced and its concentration-response curve constructed cumulatively until a maximum response is obtained. The contractile effect of each compound is evaluated by calculation of the EC50

  (concentration producing 50% of the maximum response).

  The compounds of the invention made it possible to obtain a venoconstrictor activity with a value of CEs0

  usually between 1 MM and 100, M.

  The compounds of the invention can be used in the

  treatment of venous insufficiency and venous ulcer.

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

nasal mucosa.

  The compounds according to the invention can be presented in different pharmaceutical forms suitable for oral administration and for topical application, if necessary in combination with at least one pharmaceutical excipient. Suitable pharmaceutical forms are for example tablets, capsules, dragees, capsules, oral or injectable solutions, syrups, suppositories. These pharmaceutical forms can be dosed to allow a daily dose of 0.1 gg / kg to 50

mg / kg.

Claims (8)

1. Compound of formula I R1 52_ A A R2 B   R5 in which: - X represents either an oxygen atom or a sulfur atom, - A represents either a hydrogen atom or a hydroxyl group, - B represents either a hydrogen atom or a CI group - 8   alkyl, C1-a alkenyl, C18- fluoroalkyle or C12 perfluoro-   alkyl, - n represents 1 or 2 - R1, R2, Rs, identical or different, each represent a hydrogen atom, a halogen such as chlorine, bromine or fluorine, a C1-a alkyl group, C18- alkenyl, C3-a cycloalkyle, C38 cycloalkényle, aryl in C6, C10 or C14, C16 alkoxycarbonyle, Cl-6 hydroxyalkyle, Cl6 alkoxyalkyle, C16 alkoxy, C18-fluoroalkyle or C12 perfluoroalkyle, or R1 and R2 together, form a cycle C3_ cycloalkyle , C38 cycloalkenyl, or a C6, C10 or C14 aryl, -R3 represents a linear or branched C16 alkyl group, a C26 alkenyl group, a C16 fluoroalkyl group, a C112 perfluoroalkyl group, a C1 group. hydroxyalkyl, a C16 alkoxy or C1 group. alkoxyalkyl; and - R4 represents a hydrogen atom, a linear or branched C16 alkyl group, a C26 alkenyl group, a C16 fluoroalkyl group, a C12 perfluoroalkyl group, a C16 hydroxyalkyl group, a C16 alkoxy or C16 alkoxyalkyl group, in the form of enantiomer, diastereoisomer, or mixture of these different forms, including racemic mixture and their addition salts with acids pharmaceutically acceptable.   2. Compound of formula I according to claim 1,   characterized in that X represents an oxygen atom.   3. Compound of formula I according to any one of   claims 1 or 2, characterized in that R1 and R2   each represents a Cl4 alkyl group, - R3 and R4 independently of one another represent a C1-4 alkyl group, - Rs represents a hydrogen atom, - A represents a hydroxyl group and   - B represents a hydrogen atom.   4. Compound of formula I according to claim 3 characterized in that R3 is on the carbon in alpha of the ring nitrogen. 5. Process for the preparation of a compound of formula I, according to   any one of claims 1 to 4, in which A   is a hydroxyl, characterized in that a compound of formula II R1 \ X is reacted R2 CHO   CHO R5 in which R1, R2, R5 and X are as defined in claim 1 with a cyclic amine of formula III, in which R3, R4, B and n are as defined in claim 1, R3 R4 NY "Sn (C4H9) 3 III n B or else a compound of formula IV R1 / x HO W is reacted R2 B X IV   R 5 in which R1, R2, Rs, X and B are as defined in claim 1, and W represents a nucleophuge group, with a cyclic amine of formula V, R4) n -A3 R3 V   i5f in which R3, R4 and n are as defined in claim 1, or else a compound of formula VI is reacted R SX O   R5 in which R1, R2, R5, B and X are as defined in claim 1, with the amine of formula V in which R3,   R4 and n are as defined in claim 1.   6. Process for the preparation of a compound of formula I, according to   any of claims 1, 3 or 4, wherein   A and R5 each represent a hydrogen atom, characterized in that a compound of formula VII, R1 is activated R2 OH VII S BI B   in which R, R2, X and B are as defined in claim 1 and then reacted with an amine of formula V R4) n --R3 in which R3, R4 and n are as defined in claim 1 7. Medicine characterized in that it consists of a compound according to claim 1.   8. Pharmaceutical composition characterized in that it comprises a compound according to claim and one or more suitable excipients.