WO1991016323A1

WO1991016323A1 - Serotonin antagonist naphtosultam derivatives, their preparation and drugs containing same

Info

Publication number: WO1991016323A1
Application number: PCT/FR1991/000326
Authority: WO
Inventors: Claude Gueremy; Jean-Luc Malleron; Serge Mignani
Original assignee: Rhone-Poulenc Rorer S.A.
Priority date: 1990-04-23
Filing date: 1991-04-19
Publication date: 1991-10-31
Also published as: AU7855591A; FR2661177A1; IE911337A1; NZ237885A; PT97457A; IL97918A0; ZA912975B

Abstract

Compounds of formula (I) in which n is 2 or 3 and R1? represents a cycle of formulae (a) or (b) in which R2? represents a hydrogen or halogen atom. The invention also concerns their salts with mineral or organic acids, the preparation of said derivatives and drugs containing same.

Description

DERIVATIVES OF NAPHTOSULTAM ANTAGONISTS OF SEROTONIN, THEIR PREPARATION AND THE MEDICINAL PRODUCTS CONTAINING THEM

The present invention relates to compounds of formula

their salts, their preparation process and the drugs containing them.

In formula (I), n is equal to 2 or 3 and represents a heterocycle chosen from the following formulas:

in which R ₂ represents a hydrogen or halogen atom.

The invention also relates to the salts of the compounds of formula (I) with mineral or organic acids.

The halogen atoms are preferably fluorine atoms. The compounds of formula (I) can be prepared by the action of a halogen derivative of formula:

(II)

in which Hal represents a halogen atom and has the same meanings as in formula (I), on an amine of formula:

HR _X (III)

in which i has the same meanings as in formula (I).

This reaction is generally carried out in the presence of a base such as an alkali metal hydrogen carbonate (sodium, potassium preferably) or a trialkylamine, optionally in the presence of sodium iodide, in an inert solvent such as dimethylformamide, benzene, toluene, tetrahydrofuran or acetone, at a temperature between 20 ^β C and the boiling point of the solvent.

The halogen derivatives of formula (II) can be obtained by application or adaptation of the method described by M.T. COMTE et al. in patent EP 350403.

The amines of formula (III) can be obtained by application or adaptation of the methods described by J.J. PLATTNER, US patent 4,001,263 and Z. PELCHO ICZ et al., J. Chem. Soc, 847 (1959). The reaction mixtures obtained by the various processes described above are treated according to conventional physical (evaporation, extraction, distillation, crystallization, chromatography, etc.) or chemical (salt formation, etc.) methods.

The compounds of formula (I), in the form of the free base, can optionally be converted into addition salts with a mineral or organic acid by the action of such an acid within an organic solvent such as an alcohol, a ketone, ether or chlorinated solvent.

The compounds of formula (I) and their salts have interesting properties. These compounds have antagonistic properties of serotonin (5 HT2 receptors) and are therefore useful for the treatment of conditions in which serotonin is involved, in particular affections of the central nervous system, of the system cardiovascular and gastrointestinal disorders.

These compounds are, in particular, useful for the treatment of anxiety, sleep disorders, depression, psychoses and in particular schizophrenia, migraine, asthma, hypertension and hives, as pain relievers and as inhibitors of platelet aggregation.

The affinity of the compounds of formula (I) for the central serotonin receptor sites (type S2) was determined according to a technique inspired by that of J.E. LEYSEN et al., Mol. Pharmacol., 21, 301 (1982) which consists in measuring the affinity of the products for the binding sites of tritiated ketanserin. In this test, the IC50 of the compounds of formula (I) is generally less than 25 nM.

The compounds of formula (I) have a low toxicity. They are generally non-toxic at 300 mg / kg orally in mice given once.

The following compounds are particularly interesting:

- {(tetrahydro-1,2,3,4 5H-pyrido [4,3-b] indolyl-2) -2 ethyl] -2 naphtho [1,8-cd] isothiazole dioxide-1,1 - {(fluoro -8 tetrahydro-1,2,3,4 5H-pyrido [, 3-b] indolyl-2)

-2 ethyl) -2 naphtho [1,8-cd] isothiazole dioxide-1,1

- ((fluoro-8 tetrahydro-1,2,3,4 5H-pyrido [4,3-b] indolyl-2) -3 propyl} -2 naphtho [1,8-cd] isothiazole dioxide-1,1

- {(tetrahydro-1,2,3,4 9H-pyrido [3,4-b] indolyl-2) -2 ethyl) -2 naphtho [1,8-cd] isothiazole dioxide-1,1

- ((tetrahydro-1,2,3,4 9H-pyrido [3,4-b] indolyl-2) -3 propyl) -2 naphtho [1,8-cd] isothiazole dioxide 1,1

For therapeutic use, use may be made of the compounds of formula (I) as such or in the form of pharmaceutically acceptable salts.

As pharmaceutically acceptable salts, there may be mentioned in particular the addition salts with mineral acids such as hydrochlorides, sulfates, nitrates, phosphates or organic compounds such as acetates, propionates, succinates, oxalates, benzoates, fumarates, maleates, methanesulfonates, isethionates, theophillins - acetates, salicylates, phenolphthalinates, methylene-bis-β-oxy-naphthoates or substitution derivatives of these derivatives.

The following examples, given without limitation, show how the invention can be put into practice.

EXAMPLE 1

A mixture of 2.08 g of tetrahydro-1, 2,3,4 5H-pyrido [, 3-b] indole monohydrochloride, 2.67 g of (2-chloroethyl) -2 naphtho is brought to reflux for 48 hours. 1, 8-cd] isothiazole dioxide-1,1, 1,68 g of sodium hydrogencarbonate and 1,5 g of sodium iodide in 25 cm ^ of dimethylformamide. After evaporation to dryness at 80 ° C. under reduced pressure (20 mm of mercury; 2.7 Pa), the residue is taken up in 50 cm3 of water and extracted twice with 50 cm3 of dichloromethane. The combined organic phases are dried over magnesium sulfate and brought to dryness at 80 ° C under reduced pressure (20 mm of mercury; 2.7 kPa). The residue is purified by flash chromatography on a silica column, under nitrogen pressure, at medium pressure (0.5-1.5 bar) with a dichloroethane-methanol mixture (99-1 by volume) as eluent. 3.1 g of a yellow oil are obtained which is crystallized from 30 c 3 of boiling acetone. Is thus isolated 1.62 g of {(tetrahydro-1,2,3,4 5H-pyrido [4,3-b] indolyl-2) -2 ethyl} -2 naphtho [1, 8-cd] isothiazole dioxide- 1.1, melting at 104 ° C.

Tetrahydro-1,2,3,4 5H-pyrido [, 3-b] indole monochlorhydrate can be prepared according to the method described by JJ PLATTNER, American patent 4,001,263. (2-Chloroethyl) -2 naphtho [1,8-cd] isothiazole dioxide-1,1 can be prepared according to the method described by M.. COMTE et al., European patent 350,403.

EXAMPLE 2

A mixture of 1.9 g of fluoro-8 tetrahydro-1,2,3,4 5H-pyrido [4,3-b] indole, 2.67 g of (chloro-2) is brought to reflux for 60 hours. ethyl) -2 naphtho [1,8-cd] isothiazole dioxide-1,1, 0.84 g of sodium hydrogencarbonate and 1.5 g of sodium iodide in 30 cm3 of dimethylformamide. After evaporation to dryness at 80 ° C under reduced pressure (20 mm of mercury; 2.7 kPa), the residue is taken up in 50 c 3 of water and extracted twice with 50 cm 3 of dichloromethane. The combined organic phases are dried over magnesium sulfate and brought to dryness at 80 ° C under reduced pressure (20 mm of mercury; 2.7 kPa). The residue is purified by flash chromatography on a silica column, under nitrogen pressure, at medium pressure (0.5-1.5 bar) with a dichloromethane-methanol mixture (97-3 by volume) as eluent. 1.9 g of a brown oil are obtained which is crystallized from 50 cm ³ of boiling ethanol. 1.2 g of {(fluoro-8 tetrahydro-1,2,3,4 5H-pyrido [4,3-b] indolyl-2) -2 ethyl} -2 naphtho [1, 8-cd] are thus isolated. isothiazole-1,1 dioxide melting at 169 ° C. Fluoro-8 tetrahydro-1, 2,3,4 5H-pyrido [4,3-b] indole can be prepared according to the method described by JJ PLATTNER in American patent 4,001,263.

EXAMPLE 3

The mixture is refluxed for 24 hours with 1.9 g of fluoro-8 tetrahydro-1,2,3,5H-pyrido [4,3-b] indole, 3,1 g of (3-chloro-propyl) -2 naphtho [1, 8-cd] isothiazole dioxide-1,1 and 0.84 g of sodium hydrogen carbonate in 30 cm ³ of dimethylformamide. After dry evaporation at 80 ° C under reduced pressure (20 mm of mercury;

2.7 kPa), the residue is taken up in 50 cm ³ of water and extracted twice with 50 cm ³ of dichloromethane. The combined organic phases are dried over magnesium sulfate and brought to dryness at 80 ° C under reduced pressure (20 mm of mercury; 2.7 kPa). The residue is purified by flash chromatography on a silica column, under nitrogen pressure, at medium pressure (0.5-1.5 bar) with a dichloromethane-methanol mixture (97-3 by volume) as eluent. We obtain

2.8 g of a brown oil which dissolved in 35 cm ³ of acetone and after addition of 0.41 g of oxalic acid gives 1.9 g of {(fluoro-8 tetrahydro-1,2,3,4 5H-pyrido [4,3-b] indolyl-2) -3 propyl} -2 naphtho [1,8-cd] isothiazole dioxide-1,1 in the form of oxalate, fondant at 250 ° C.

(3-Chloro-propyl) -2 naphtho [1,8-cd] isothiazole dioxide-1,1 can be prepared according to the method described by M. COUNT in European patent 350 403.

EXAMPLE 4

A mixture of 1.7 g of tetrahydro-1,2,3,4 9H-pyrido [3,4-b] indole, 2.67 g of (2-chloroethyl) -2 naphthoM is brought to reflux for 48 hours. 8-cd] isothiazole dioxide-1,1, 1.7 g of sodium hydrogencarbonate and 1.5 g of sodium iodide in 25 cm ³ of dimethylformamide. After evaporation to dryness at 80 ° C. under reduced pressure (20 mm of mercury; 2.7 kPa), the residue is taken up in 50 cm ³ of water and extracted three times with 25 cm ³ of dichloromethane. The combined organic phases are dried over magnesium sulfate and brought to dryness at 80 ° C under reduced pressure (20 mm of mercury; 2.7 kPa). The residue is purified by flash chromatography on a silica column, under nitrogen pressure, at medium pressure (0.5-1.5 bar) with a dichloromethane-ethyl acetate mixture (99.5-0.5 volumes) as eluent. 2.6 g of a brown solid are obtained, which is recrystallized from 80 cm ³ of boiling acetonitrile. 2.2 g of {(tetrahydro-1,2,3,4 9H-pyrido [3,4-b] indolyl-2) -2 ethyl} -2 naphtho [1, 8-cd] isothiazole dioxide are thus isolated. 1.1 melting at 180 ° C.

EXAMPLE 5

A mixture of 1.7 g of tetrahydro-1,2,3,4 9H-pyrido [3,4-b] indole, 3.4 g of (3-chloro-propyl) -2 naphtho is brought to reflux for 16 hours. 1, 8-cd] isothiazole dioxide-1,1, 1.7 g of sodium hydrogencarbonate and 1.5 g of sodium iodide in 40 cm ³ of dimethylformamide. After dry evaporation at 80 ° C under reduced pressure (20 mm of mercury; 2.7 kPa), the residue is taken up in 50 cm ³ of water and extracted three times with 50 cm ³ of dichloromethane. The combined organic phases are dried over magnesium sulfate and brought to dryness at 80 ° C under reduced pressure (20 mm of mercury; 2.7 kPa). The residue is purified by flash chromatography on a silica column, under nitrogen pressure, at medium pressure (0.5-1.5 bar) with a dichloromethane-methanol mixture (99-1 by volume) as eluent. 2.6 g of a beige solid are obtained which is recrystallized from a mixture of 200 cm ³ of ethanol and 50 cm ³ of boiling acetone. 2 g of {(tetrahydro-1,2,3,4 9H-pyrido [3,4-b] indolyl-2) -3 propyl} -2 naphtho [1,8-cd] isothiazole dioxide-1 are thus isolated, 1 melting at 189 ° C.

The medicaments according to the invention consist of a compound of formula (I) in free form or in the form of an addition salt with a pharmaceutically acceptable acid, in the pure state or in the form of a composition in which it is associated with any other pharmaceutically compatible product, which may be inert or physiologically active. The medicaments according to the invention can be used orally, parenterally, rectally or topically. As solid compositions for oral administration, tablets, pills, powders (gelatin capsules, cachets) or granules can be used. In these compositions, the active principle according to the invention is mixed with one or more inert diluents, such as starch, cellulose, sucrose, lactose or silica, under a stream of argon. These compositions can also comprise substances other than diluents, for example one or more lubricants such as magnesium stearate or talc, a dye, a coating (dragees) or a varnish. As liquid compositions for oral administration, there can be used pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, oils vegetable or paraffin oil. These compositions can include substances other than diluents, for example wetting, sweetening, thickening, flavoring or stabilizing products. The sterile compositions for parenteral administration can preferably be aqueous or non-aqueous solutions, suspensions or emulsions. As solvent or vehicle, it is possible to use water, propylene glycol, a polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate or other suitable organic solvents. These compositions can also contain adjuvants, in particular wetting agents, isotonizers, emulsifiers, dispersants and stabilizers. Sterilization can be done in several ways, for example by aseptic filtration, by incorporating sterilizing agents into the composition, by irradiation or by heating. They can also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in sterile water or any other sterile injectable medium. The compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active product, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.

The compositions for topical administration can be, for example, creams, ointments, lotions, eye drops, mouthwashes, nasal drops or aerosols.

In human therapy, the compounds according to the invention are particularly useful for the treatment of conditions in which serotonin is involved and in particular affections of the central nervous system, of the cardiovascular system and intestinal disorders. They are, in particular, useful for the treatment of anxiety, sleep disorders, depression, psychoses and in particular schizophrenia, migraine, asthma, hypertension and hives , as pain relievers and as platelet aggregation inhibitors.

The doses depend on the desired effect, on the duration of the treatment and on the route of administration used; they are generally between 10 and 300 mg per day orally for an adult with unit doses ranging from 5 to 150 mg of active substance.

In general, the doctor will determine the appropriate dosage based on age, weight and all other factors specific to the subject to be treated. The following examples illustrate compositions according to the invention:

EXAMPLE A

Using the usual technique, capsules containing 50 mg of active product having the following composition are prepared:

- {(tetrahydro-1,2,3,4 5H-pyrido [4,3-b] indolyl-

2) -2 ethyl} -2 naphtho [1, 8-cd] isothiazole di-oxide-1, 1 50 mg

- Cellulose 18 mg

- Lactose 55 mg - Colloidal silica 1 mg

- Carboxymethyl starch sodium 10 mg

- Talc 10 mg

- Magnesium stearate 1 mg

EXAMPLE B

Tablets containing 50 mg of active product having the usual composition are prepared according to the usual technique: - {(fluoro-8 tetrahydro-1,2,3,5H-pyrido [4,3-b] indolyl-2) -3 propyl} -2 naphtho [1, 8-cd] isothi¬ azole dioxide-1,1 50 mg

- Lactose 104 mg

- Cellulose 40 mg - Polyvidone 10 mg

- Carboxymethyl starch sodium 22 mg

- Talc 10 mg

- Magnesium stearate 2 mg

- Colloidal silica 2 mg - Mixture of hydroxymethylcellulose, glycerin, titanium oxide (71-3, 5-24, 5) q.s.p. 1 film-coated tablet finished at 245 mg

EXAMPLE C

A solution for injection containing 10 mg of active product having the following composition is prepared:

- {(tetrahydro-1,2,3,4 9H-pyrido [3, -b] indolyl -2) -2 ethyl} -2 naphtho! 1,8-cd] isothiazole di-oxide-1,1 10 mg

- Benzoic acid 80 mg - Benzyl alcohol 0.06 cm ³

- Sodium benzoate 80 mg

- 95% ethanol 0.4 cm ³

- Sodium hydroxide 24 mg

- Propylene glycol 1.6 cm ³ - Water q.ε.p. 4 cm ³

Claims

1 - Compounds of formula

in which n is 2 or 3 and Ri represents a cycle chosen from the formulas:

in which ~ 2 represents a hydrogen or halogen atom and their salts with mineral or organic acids.

2 - Compounds of formula (I) according to claim 1 for which 2 represents a fluorine atom as well as their salts with mineral or organic acids.

Process for preparing the compounds of formula (I) according to claim 1 characterized in that 1'on reacting a alo ^g ene derivative of formula:

in which Hal represents a halogen atom and n is 2 or 3, with an amine of formula:

HRi (III)

in which Ri has the same meanings as in claim 1.

Medicaments characterized in that they contain as active principle at least one compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt of such a compound.

Medicines according to claim 5 for the treatment of diseases in which serotonin is involved.