EP0699195A1

EP0699195A1 - Thioindole pyperidinyl derivatives used as antalgics

Info

Publication number: EP0699195A1
Application number: EP94913639A
Authority: EP
Inventors: Nicole Françoise BRU-MAGNIEZ; Dominique Louis Potin; Jean-Marie Charles Teulon
Original assignee: UPSA SAS
Current assignee: UPSA SAS
Priority date: 1993-05-18
Filing date: 1994-04-13
Publication date: 1996-03-06
Also published as: HU9503281D0; NZ265304A; FR2705346B1; MD522F1; EE9400296A; CA2161021A1; MD522G2; FI954931A; CN1124026A; JPH09500611A; CZ304195A3; FR2705346A1; AU6571594A; WO1994026736A1; HUT74866A; US5317025A; TW257756B; FI954931A0

Abstract

Derivatives of formula (I), their addition salts and their therapeutic use, namely as drugs with antalgic properties.

Description

PIPERIDINYL THIO INDOLE DERIVATIVES AS ANALGESICS

The present invention relates, as new products, to the piperidinyl thio indole derivatives of general formula (I) below and their addition salts, in particular the pharmaceutically acceptable addition salts.

The compounds in question have a very interesting pharmacological profile insofar as they are endowed with analgesic properties. They will therefore be particularly indicated for the treatment of pain. We can cite, for example, their use in the treatment of muscle, joint or nerve pain, dental pain, zonas and migraines, in the treatment of rheumatic affections, pain of cancerous origin, but also as treatments complementary in infectious and febrile states.

The present invention also relates to the process for the preparation of said products and their applications in therapy.

These piperidinyl thio indole derivatives are characterized in that they correspond to the general formula (I):

Formula (I)

in which :

X-ι and X2 independently represent: - the hydrogen atom;

- a halogen atom;

- a lower alkyl radical of 1 to 6 carbon atoms;

- a trifluoromethyl group;

- a hydroxy group; - an O-lower alkyl radical of 1 to 6 carbon atoms; - a nitrile group

- an acid group

- an amide group

- a hydroxymethyl group - an aminomethyl group

- a sulfonamidomethyl group and can be in position 4, 5, 6 or 7 of the indole ring, R-i represents:

- the hydrogen atom; - a lower alkyl radical of 1 to 6 carbon atoms;

- a methoxy group;

- a group -COR 'in which R' represents the hydrogen atom or a lower alkyl radical of 1 to 6 carbon atoms;

- a group -COOR "; - a group -CSSR" in which R "represents an lower alkyl radical of 1 to 6 carbon atoms, a vinyl radical or a phenyl,

- A group -CSSM in which M represents sodium or potassium;

- a radical - (CH ₂ ) _n - phenyl; - a radical - (CH ₂ ) _n pyrrole; where n is an integer from 0 to 4,

R2 represents:

- the hydrogen atom; - a lower alkyl radical of 1 to 6 carbon atoms;

- a phenyl radical unsubstituted or substituted by a halogen atom,

R ₃ represents:

- the hydrogen atom; - a lower alkyl radical of 1 to 6 carbon atoms;

- a group COOR "in which R" is defined as above;

a radical - (CH ₂ ) _n -phenyl in which the phenyl is unsubstituted or substituted by a halogen atom, n being an integer from 0 to 4, p is an integer from 0 to 2.

In the description and the claims, lower alkyl means a hydrocarbon chain having from 1 to 6 carbon atoms, linear or branched. A lower alkyl radical is for example a methyl, ethyl, propyl, isopropyl, butyl radical. isobutyl, tertiobutyl, pentyl, isopentyl, hexyl, isohexyl.

Halogen means a chlorine, bromine, iodine or fluorine atom.

In the description, the following abbreviations have been used: Ph: phenyl Phenethyl: 2-phenylethyl nBu: butyl tBu: tertiobutyl (1, 1-dimethyl ethyl) iPr: isopropyl (1-methyl ethyl) Me: methyl Et: ethyl

THF: tetrahydrofuran Bn: benzyl Ac: acetyl

Advantageously, in the context of the present invention, a compound of formula (I) will be used in which at least one of the following conditions is achieved:

- X2 represents the hydrogen atom

- X-i represents the chlorine atom in position 5 of the indole cycle - X-ι represents the bromine atom in position 5 of the indole cycle

- X-ι represents the fluorine atom in position 5 of the indole cycle

- R- ^* represents the hydrogen atom

- R-i represents a methyl radical

- R- ^* represents a benzyl group - Ri represents a vinyloxy carbonyl group

- R- ^* represents a methoxy group

- R2 represents the hydrogen atom

- R2 represents a methyl radical

- R ₃ represents the hydrogen atom - R3 represents a methyl radical - p is zero

The particularly preferred compounds of the invention are those which are chosen from the products of formula:

H

According to the invention, the compounds of formula (I) can be synthesized as follows:

By the action of hydrogen sulfide in an alcohol, such as isopropanol, for example, at a temperature less than 15 ^° C, followed by reduction with sodium borohydride or potassium in an alcohol, such as isopropanol, for example, on the 4-piperidinones of formula (II), the 4-piperidinethiols of formula (III) will be obtained, according to the scheme:

Formula (II) Formula (III) in formulas (II) and (III), R represents a lower alkyl radical of 1 to 6 carbon atoms, a benzyl radical, a phenethyl radical, a protective group -COOtBu or a methoxy group .

The piperidinones of formula (II) are commercial with the exception of that where R = -COOtBu which is prepared by the action of ditertiobutyl dicarbonate on 4-piperidinone or its commercial monohydrate according to the method described in the literature with reference: WS SAARl , W. HALCZENKO, JR HUFF, JP GUARE Jr, CA HUNT, WC RANDALL, VJ LOTTI, G.G. YARBROUGH; J. Med. Chem. 1984, 2Z, 1182-5, and that in which R is a methoxy group which has been synthesized according to the method described in the reference: R.T. MAJOR; F. DURSCH; J. Org. Chem. 1961, 2nd, 1867-74.

The derivatives of formula (III) where R represents the hydrogen atom will be prepared from the derivatives of formula (III) where R represents a methyl radical by the action of ethyl chloroformate in acetone, followed by a second treatment with ethyl chloroformate in toluene at reflux then by treatment with hydrochloric acid in acetic acid at reflux, according to the scheme:

This preparation method is described in the literature with reference: J. ENGEL, A. BORK, I. NUBERT, H. SCHÔNENBERGER; Arch. Pharm. (Weinheim) 1988, 321. 821-2.

By reaction of the compounds of formula (III) in which R represents a lower alkyl radical of 1 to 6 carbon atoms, a benzyl radical, a phenethyl radical, a protective group -COOtBu or the hydrogen atom, with a halogen ketone of formula (IV):

X - CH ₂ - CO— R '

Formula (IV)

in which R 'represents a lower alkyl radical of 1 to 6 carbon atoms or a phenyl radical unsubstituted or substituted by a halogen atom, and X represents a halogen atom optimally chlorine or bromine, the derivatives of formula will be obtained (V)

Formula (V)

in which R and R 'are defined as above.

This reaction is carried out in the presence of a sodium, potassium or lithium alcoholate in the corresponding alcohol or in tetrahydrofuran or also by phase transfer in the presence of sodium or potassium carbonate and tetrabutylammonium iodide in toluene at temperatures between 20 and 130 ^* C.

By reaction of the same compounds of formula (III) with a halo aldehyde whose aldehyde function is protected by ketalization of formula (VI):

OR "X-CH ₂ - <

GOLD"

Formula (VI) in which R "represents a lower alkyl of 1 to 6 carbon atoms optimally methyl or ethyl or both, R" together form -CH ₂ -CH ₂ - and X represents a halogen atom optimally chlorine or bromine , we will obtain the derivatives of formula (VII)

Formula (VII)

in which R and R "are defined as above.

This reaction is carried out like that used for halogeno ketones, for example in the presence of sodium methylate in tetrahydrofuran. The derivatives of formula (V) or of formula (VII) will then be reacted with phenyihydrazines of formula (VIII):

Formula (VIII)

in which X--, X ₂ and R ₃ are defined as above.

These phenyhydrazines are commercial or can be prepared according to conventional methods known to those skilled in the art, for example by diazotization of commercial anilines of formula (IX):

Formula (IX)

in which X- * and X ₂ are defined as above, by sodium nitrite in an acid medium then treatment of the diazotized derivative with stannous chloride, to obtain a phenylhydrazine of formula (X):

Formula (X)

wherein X- ^* and X ₂ are defined as above; optionally followed by the reaction of this phenyl hydrazine with halogen derivatives of formula (XI):

R ₃ X

Formula (XI)

in which R ₃ is defined as above and X represents a halogen atom, in liquid ammonia and / or tetrahydrofuran in the presence of sodium amide at a temperature of -40 "C which is allowed to return to ambient temperature.

The reaction of the derivatives of formula (V) or of formula (VII) with the phenyhydrazines of formula (VIII) will be carried out under the conventional conditions of Fischer synthesis for the indolic cycles, optimally in the presence of hydrochloric gas in isopropanol at 0 ^* C to start the reaction which will then be carried out at room temperature. This reaction leads to the derivatives of formula (XII)

Formula (XII)

in which X- *, X ₂ , R ₂ and R ₃ are as defined in formula (I), R representing a lower alkyl radical of 1 to 6 carbon atoms, benzyl, phenethyl or the hydrogen atom.

When the indole formation reaction is carried out with compounds where R represents the group -COOtBu, the compounds of formula (XII) where R represents the hydrogen atom.

The compounds of formula (XII) where R represents the hydrogen atom may react with halides of formula (XIII)

* ι ^X

Formula (XIII)

in which Ri is defined as above and X represents an optimally chlorine, bromine or iodine halogen atom, to lead to the compounds of formula (I) in which p is equal to zero, this reaction being carried out in the presence of a tertiary base such as triethylamine or pyridine or sodium or potassium carbonate in an inert solvent such as toluene or dichloromethane at a temperature between ambient and 130 ^° C, except where Ri is the group CHO , for which the compounds of formula (XII) where R represents the hydrogen atom will be reacted with formic acid in dichloromethane in the presence of dicyclohexylcarbodiimide, and where Ri represents the group CSSR ", for which the compounds of formula (XII) where R represents the hydrogen atom will be reacted with carbon sulfide in basic medium, the salt obtained then reacting with an alkyl halide. mposés of formula (I) where Xi or X ₂ represents a nitrile group, can be obtained from the compounds of formula (I) where Xi or X2 represents a halogen, preferably bromine or iodine, by reflux in N-methyl pyrrolidone with cuprous cyanide.

The compounds of formula (I) where Xi or X ₂ represents an acid group, can be obtained from the compounds of formula (I) where X- or X2 represents a halogen, preferably bromine or iodine, after metallation with nBuLi in tetrahydrofuran at -78 ° C followed by carbonation with carbon dioxide, taking care to protect, if necessary, indole nitrogen with a protective group such as a tosylate, COOtBu, COOBn or t-Butyl dimethyl silane and l piperidine nitrogen by COOtBu or COOBn for example.

The compounds of formula (I) where Xi or X ₂ represents an amide group may be prepared under the same conditions as the previous case but by reacting the compound metalized with nBuLi on trimethyl silane isocyanate in place of carbonation ; they can also be obtained by transformation of the acid previously obtained into acid chloride, for example using thionyl chloride, then reaction of this acid chloride on an amine, for example ammonia.

The compounds of formula (I) where Xi or X ₂ represents an acid group, may be reduced, for example by double aluminum and lithium hydride to obtain the compounds where Xi or X ₂ represents a hydroxymethyl group.

The compounds of formula (I) where Xi or X ₂ represents a nitrile group, may be reduced, for example by double aluminum and lithium hydride to obtain the compounds where Xi or X ₂ represents an amino methyl group, these compounds which can react with a sulfonic acid chloride to lead to the compounds of formula (I) where Xi or X2 represents a sulfonamidomethyl group.

Another access route to these latter compounds can be the reaction of the compounds of formula (I) where Xi or X ₂ represents a hydroxymethyl group with mesyl chloride or tosyl chloride, the mesylate or tosylate thus obtained may react. with a sulfonamide previously metallized to yield these derivatives of formula (I) where Xi or X ₂ represents a sulfonamidomethyl group.

The compounds of formula (I) where X or X2 represents a hydroxy group will be prepared from the derivatives where Xi or X ₂ represents an O-lower alkyl radical by the action of boron tribromide in dichloromethane or chloroform.

The compounds of formula (I) where R ₃ represents the hydrogen atom and p is equal to zero, may be substituted in position 1 of the indole according to methods known to those skilled in the art, for example by presence of a metallizing agent such as sodium amide, a hydride or an alcoholate of sodium, potassium or lithium, in a solvent such as liquid ammonia, tetrahydrofuran or dimethyl formamide at a temperature between -40 "C and 80 "C, or in the presence of sodium hydroxide and a phase transfer agent in toluene, using the derivatives of formula (XI).

The compounds thus obtained of formula (XIV)

Formula (XIV) in which Xi, X2, Ri, R ₂ . R ₃ are as defined in formula (I) can be oxidized using an oxidizing agent such as meta chloroperbenzoic acid in a solvent such as chloroform or methylene chloride or such as potassium peroxy monosulfate (KHSO5) in an alcohol-water mixture, at a temperature between 0 and 30 "C, to yield the compounds of formula (I) where p is equal to 1 or 2. The amount of oxidant will be chosen so as to obtain p = 1 or p = 2.

The compounds of formula (I) as defined above as well as their addition salts, in particular the pharmaceutically acceptable addition salts are endowed with a very good analgesic activity. These properties justify their application in therapy and the invention also relates, as medicaments, to the products as defined by formula (I) above, as well as their addition salts, in particular the salts of pharmaceutically acceptable addition.

The addition salts of the compounds of formula (I) can be obtained by reaction of these compounds with a mineral or organic acid according to a method known per se. Among the acids which can be used for this purpose, hydrochloric, hydrobromic, sulfuric, phosphoric, 4-toluene sulfonic, methane, sulfonic, cyclohexyl sulfamic, oxalic, succinic, formic, fumaric, maleic, citric, aspartic, cinnamic acids are cited. lactic, glutamic, N-acetylaspartic, N-acetylgiutamic, ascorbic, malic, benzoic, nicotinic and acetic.

Thus, the invention also covers a pharmaceutical composition, characterized in that it comprises a pharmaceutically effective amount of at least one compound of formula (I) as defined above or one of its pharmaceutically acceptable addition salts, optionally incorporated in a pharmaceutically acceptable excipient, vehicle or support.

These compositions can be administered by the oral, rectal, parenteral, transdermal, ocular, nasal or auricular route.

These compositions can be solid or liquid and can be presented in the pharmaceutical forms commonly used in human medicine such as, for example, simple or coated tablets, capsules, granules, suppositories, injectables, transdermal systems, eye drops, aerosols and sprays and ear drops. They are prepared according to the usual methods. The active principle, consisting of a pharmaceutically effective amount of at least one compound of formula (I) defined as above or one of its addition salts pharmaceutically acceptable, can be incorporated into excipients usually used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, polyvidone, cellulose derivatives, cocoa butter , semi-synthetic glycerides, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, glycols, various wetting agents, dispersants or emulsifiers, silicone gels, certain polymers or copolymers, preservatives, flavors and dyes.

The invention also covers a pharmaceutical composition with analgesic activity which makes it possible in particular to favorably treat pain, characterized in that it comprises a pharmaceutically effective amount of at least one compound of the abovementioned formula (I) or one of its pharmaceutically added salts. acceptable, optionally incorporated into a pharmaceutically acceptable excipient, vehicle or support.

The invention also covers a process for the preparation of a pharmaceutical composition, characterized in that a pharmaceutically effective amount of at least one compound of formula (I) as defined above, or one of its salts, is incorporated. pharmaceutically acceptable addition to a pharmaceutically acceptable excipient, vehicle or carrier. According to one embodiment, a pharmaceutical composition with analgesic activity is prepared which makes it possible in particular to treat pain favorably.

According to an alternative embodiment, a composition is prepared formulated in the form of capsules or tablets dosed from 1 mg to 1000 mg or in the form of injectable preparations dosed from 0.1 mg to 500 mg. Formulations in the form of suppositories, ointments, creams, gels or aerosol preparations may also be used. The invention also covers a method for the therapeutic treatment of mammals, characterized in that a therapeutically effective amount of at least one compound of formula (I) as defined above, or one of its salts, is administered to this mammal. pharmaceutically acceptable addition. According to an alternative embodiment of this treatment method, the compound of formula (I), either alone or in combination with a pharmaceutically acceptable excipient, is formulated in capsules or tablets dosed from 1 mg to 1000 mg for administration by orally, or in the form of injectable preparations dosed from 0.1 to 500 mg or also in the form of suppositories, ointments, creams, gels or aerosol preparations. In human and animal therapy, the compounds of formula (I) and their salts can be administered alone or in combination with a physiologically excipient. acceptable in any form, in particular orally in the form of capsules or tablets or parenterally in the form of an injectable solution. Other forms of administration such as suppositories, ointments, creams, gels or aerosol preparations can be considered. As will be clear from the pharmacology tests given at the end of the description, the compounds according to the invention can be administered in human therapy in the abovementioned indications orally in the form of tablets or capsules dosed from 1 mg to 1000 mg or parenterally in the form of injections dosed from 0.1 mg to 500 mg in one or more daily doses for an adult of average weight 60 to 70 kg.

In animal therapy, the daily dose that can be used is between 0.01 and 20 mg per kg.

Other characteristics and advantages of the invention will be better understood on reading which will follow from some examples which are in no way limitative, but given by way of illustration.

Using the method described in the literature (H. BARRERA, RE LYLE J. Org. Chem. (1962) 2Z, 641-2), 1-methyl-4-piperidinethiol is prepared (formula III in which R = methyl) as well than the following thiols (examples 1 to 5):

Example 1: l - (phenylmethyl) -4-p.pér.d.nethiol

Formula (III): R = CH ₂ Ph

Oil.

1H NMR (CDCb): 7.15-7.4 (m, 5H); 3.48 (s, CH ₂ benz); 2.65-2.9 (m, 2 CH + SCH) 1.9-2.15 (m, 4 CH); 1.55-1.75 (m, 2 CH); 1, 5 (d, SH, J = 7 Hz).

Example 2: 1- (2-phenylethyl) -4-piperidinethiol

Formula (III): R = CH ₂ CH ₂ Ph

Oil.

^• H NMR (CDCb): 7.15-7.35 (m, 5 H); 2.9-3.05 (m, 2CH); 2.65-2.9 (m, CH ₂ + SCH); 2.5-2.65 (m, CH ₂ ); 1.95-2.25 (m, 4CH); 1.6-1.85 (m, 2CH); 1.54 (d, SH, J = 7.1 Hz).

Example 3: 4-mercap.o - i-piperidinecarboxy.ate of 1,1-dimet yl ethyl

Formula (III): R = C0 ₂ t Bu

Oil.

13C NMR (CDCI ₃ ): 155.0 (Cq); 79.7 (Cq); 43.6 (CHS); 36.5 (CH ₂ ); 36.1 (CH ₂ ); 28.5 (CH ₃ ).

Example 4: l - (l -methylethyl) -4-plpéridinethiol

Formula (III): R = iPr Oil.

1H NMR (CDCb): 2.6-2.9 (m, 4H); 2.1-2.3 (m, 2CH); 1.95-2.1 (m, 2CH); 1.51 (d, SH, J = 7.6 Hz); 1.5-1.75 (m, 2CH); 1.02 (d, 2CH ₃ , J = 6.5 Hz)

Example 5: l-methoxy-4-plpéridinethiol

Formula (III): R = OMe

Synthesized from 1-methoxy-4-piperidinone prepared according to: R.T. MAJOR, F. DURSCH J. Org. Chem. (1961) 2 £, 1867-74.

Oil. 1H NMR (CDCI ₃ ): 3.55 (s, CH ₃ ); 3.4-2.2 (m, 5H); 2.2-1.4 (m, 4H + 5H)

Example 6: 1-methyl-4 - [(2-oxopropyl) thio] -piperidine

Formula (V): R = Me, R '= Me

Sodium methylate (5.9 g) is added in portions to a solution of 1-methyl-4-piperidinethiol (14 g) in anhydrous tetrahydrofuran (100 ml) at room temperature. After 2 hours at this temperature the chloro acetone (8.8 ml) is added dropwise. After 24 hours the precipitate is filtered, the filtrate concentrated and chromatographed on silica gel (eluent: ethyl acetate then ethanol) to give 1-methyl-4 - [(2-oxopropyl) thio] - piperidine (11 , 5 g) in the form of an oil.

ⁱ H NMR (CDCb): 3.28 (s, CH ₂ S); 2.75-2.90 (m, 2H); 2.5-2.7 (m, CHS); 2.30 (s,

CH ₃ N); 2.25 (s, CH ₃ ); 1.85-2.15 (m, 4H); 1.5-1.75 (m, 2H).

Using the same method with the appropriate chloro ketones and 4-piperidinethiols, the following compounds were prepared (Examples 7 and 8):

Example ^p 7: 4 - [(2-oxopropyl) thio] -piperidine

Formula (V): R = H, R '= Me Yellow solid: F = 136 ° C Hydrochloride: F = 118 ° C

1H NMR (CDCb): 3.2 (s, CH ₂ S); 2.95-3.1 (m, 2H); 2.45-2.75 (m, 3H + NH); 2.23 (s, CH ₃ ); 1.75-1.95 (m, 2H); 1.25-1.5 (m, 2H).

Example 8: 4 - [[2- (4-chlorophenyl) -2-oxoethyl] thio] -piperidlne

Formula (V): R = H, R '"4-CI-Ph

Orange solid: F = 202 ° C

1H NMR (CDCb): 7.9 (d, 2CH J = 8.5 Hz); 7.43 (d, 2CH, J = 8.5 Hz); 3.75 (s, SCH ₂ ); 2.95-3.25 (m, 2H + HN); 2.7-2.9 (m, SCH); 2.5-2.7 (m, 2CH); 1.85-2.05 (m, 2CH); 1.35-1.6 (m, 2CH).

Example 9: 4 - [(2-oxopropyl) thio] -1- (phenylmethyl) -piperidlne

Formula (V): R = CH ₂ Ph, R '= Me

A suspension of 1- (phenylmethyl) -4-piperidinethiol (70 g, prepared in Example 1), chloroacetone (26.9 ml), sodium carbonate (71.6 g) and tetrabutylammonium iodide ( 31.2 g) in toluene (350 ml) is stirred at room temperature for 4 hours. The insoluble material is filtered and washed with toluene. After concentration, the filtrate is taken up in dichloromethane, washed with dilute soda and then with water saturated with sodium chloride. After drying over sodium sulfate, the solution is concentrated to give 4- [(2-oxopropyl) thio] -1- (phenylmethyl) -piperidine (82.2 g) in the form of an oil sufficiently pure to be used in the after.

¹ H NMR (CDCb): 7.15-7.35 (m, 5H); 3.5 (s, CH ₂ benz); 3.2 (s, SCH ₂ ); 2.75-2.95 (m,

2H); 2.55-2.75 (m, SCH); 2.28 (s, CH ₃ ); 1.85-2.15 (m, 4H); 1.5-1.75 (m, 2CH).

Using the same synthesis process with the appropriate 4-piperidinethiols, the following compounds were prepared (Examples 10 and 11): Example 10: 4 - [(2-oxopropyl) thio] -1 - (2-phenylethyl) -piperidine

Formula (V): R = CH ₂ CH ₂ Ph, R '= Me

Oil.

1H NMR (CDCb): 7.1-7.35 (m, 5H); 3.27 (s, SCH ₂ ); 2.85-3.05 (m, 2H); 2.75-2.85 (m, 2H); 2.5-2.75 (m, 3H); 2.29 (s, CH ₃ ); 1.9-2.2 (m, 4H); 1.5-1.8 (m, 2H).

Example 11: 4 - [(2-oxopropyl) thid] -1-piperldinecarboxylate of 1, 1-dimethylethyl

Formula (V): R = C0 ₂ tBu, R '= Me

Oil.

¹ H NMR (CDCb): 3.9-4.05 (m, 2CH); 3.26 (s, SCH ₂ ); 2.7-3 (m, 2CH + SCH); 2.32 (s, CH ₃ ); 1.85-2 (m, 2CH); 1.35-1.6 (m, 2CH); 1.45 (s, 3CH ₃ ).

Example 12: 4 - [(2,2-diethoxyethyl) thio] -1 -methyl-piperldlne

Formula (VII): R = Me, R "= And

Sodium methylate (18.1 g) is added in portions to a solution of 1-methyl-4-piperidinethiol (22 g) in anhydrous tetrahydrofuran (200 ml). After one hour, diethyl acetal bromo acetaldehyde (30.3 ml) is added. After 4 hours at room temperature, the solution is heated for 2 hours at 40 "C. The insoluble material is filtered and rinsed with THF. The filtrate is concentrated then distilled under reduced pressure to give 4- [(2,2-diethoxyethyl) thio] -1-methyl-piperidine (36 g; T _Θ b = 104-108 ^* C under 0.05 atm) in the form of an oil.

1H NMR (CDCb): 4.6 (t, 1H, J = 5.6 Hz); 3.45-3.8 (m, 2CH ₂ 0); 2.65-2.9 (m, 3CH); 2.72 (d, SCH ₂ , J = 5.6 Hz); 2.26 (S, NCH ₃ ); 1.9-2.1 (m, 4CH); 1.5-1.75 (m, 2CH); 1.22 (t, 2 CH ₃ , J = 7 Hz). Using the same method, compounds 13 to 16 are also prepared:

Example 13: 4 - [(2,2-diethoxyethyl) thio] -1 - (phenylmethyl) - piperidine

Formula (VII): R = CH PU, R "= And

Oil.

1H NMR (CDCb): 7.2-7.4 (m, 5H); 4.6 (t, 1 HJ = 5.6 Hz); 3.46 (s, CH ₂ benz); 3.5-

3.8 (m, 2CH 0); 2.65-2.95 (m, 4H); 2.75 (d, SCH ₂ , J = 5.6 Hz); 1.85-2.15 (m, 4H); 1.5-1.8 (m, 2H); 1.22 (t, 2 CH ₃ , J = 7 Hz).

Example 14: 4 - [(2,2-dlethoxyethyl) thio] -1 - (1-methylethyl) - piperidine

Formula (VII): R = iPr, R "= And

Oil.

¹ H NMR (CDCb): 4.60 (t, 1H, J = 5.6 Hz); 3.45-3.75 (m, 2CH ₂ O); 2.6-2.9 (m, 4H); 2.73 (d, CH S, J = 5.6 Hz); 2.1-2.25 (m, 2CH); 1.9-2.05 (m, 2CH); 1.5-1.7 (m, 2CH); 1.22 (t, 2 CH ₃ , J = 7 Hz); 1.02 (d, 2CH ₃ , J = 6.6 Hz).

Example 15: 4 - [(2,2-diethoxyethyl) thio] -1-methoxypiperidine

Formula (VII): R = OMe, R "= And Oil.

1H NMR (CDCb): 4.55 (t, 1H, J = 5.6 Hz); 3.8-3.4 (m, 4H, 2 CH ₂ 0); 3.46 (s, 3H, OCH ₃ ); 3.4-2.9 (m, 3H); 2.8-2.6 (m, 3H); 2.5-1.4 (m, 5H); 1, 2 (t, 2CH ₃ , J = 7 Hz)

Example 16: 4 - [(2,2-diethoxyethyl) thio] piperidine

Formula (VII): R = H, R "= And Oil.

1H NMR (CDCb): 4.6 (t, 1H, J = 5.5 Hz); 3.8-3.45 (m, 4H, 2 CH ₂ 0); 3.2-3.05 (m, 2CHN); 2.95-2.8 (m, CHS); 2.75 (d, CH ₂ S, J = 5.5 Hz); 2.7-2.55 (m, 2CHN); 2.05-1.9 (m, 2CH); 1.6-1.35 (m, 2CH); 1.22 (t, 2CH ₃ , J = 6.5 Hz)

Example 17: 2,5-dimethyl-3 - [[1 - (phenylmethyl) -4-piperidinyl] thio] - i H-indole, hydrochloride

Formula (I): Ri = Bn, R ₂ = Me, R ₃ = H, = 5-Me, X ₂ = H, p ≈ 0

Paratolylhydrazine hydrochloride (20 g) is added to a solution of 4 - [(2-oxopropyl) thio] -1- (phenylmethyl) -piperidine (33.2 g, prepared in Example 9) in isopropanol ( 150 ml) under nitrogen. After 30 minutes, the solution was cooled to 0 ^° C and saturated with gaseous hydrochloric acid. After 4 hours at room temperature the precipitate formed is drained, washed with water and then taken up in hot ethanol. After cooling, the white crystals of 2,5-dimethyl-3 - [[1 - (phenylmethyl) -4-piperidinyl] thio] -1 H-indole hydrochloride (28.3 g) are drained.

C22H26N ₂ S, HCI

F = 258 ° C

Using the same synthesis process with the appropriate hydrazines and ketones, the following compounds were prepared (Examples 18 to 35).

Example 18: 5-chloro-2-methyl-3- (4-piperidinylthio) -1 H-indole

Formula (I): R, = H, R ₂ = Me, R ₃ = H, Xi = 5-CI, X ₂ = H, p = 0

Solid off-white. Cι ₄ H ₁₇ CI N2S F = 198-199 ° C.

Example 19: 5-fluoro-2-methyl-3- (4-piperldinylthio) -1 H-indole

Formula (I): R, = H, R ₂ = Me, R ₃ = H, Xi = 5-F, X ₂ = H, p = 0 Solid white. Cι Hι ₇ FN ₂ S

M = 201 ° C (purified by chromatography on silica gel with as eluent: CHCb / MeOH / NH ₄ OH: 80/20/1).

Example 20: 5-methoxy-2-methyl-3- (4-piperidinylthlo) -1 H-indole

Formula (I): Ri = H, R = Me, R ₃ »H, X, - 5-OMe, X ₂ = H, p = 0

Solid pale yellow.

C ₁₅ H2 ₀ N2OS F = 217-218 ° C (recrystallized from xylene)

Example ^p 21: 2-methyl-3- (4-piperidinylthio) -5- (trlfluoromethyl) -1 H- indole, hydrochloride

Formula (I): Ri = H, R ₂ = Me, R ₃ = H, X, = 5-CF ₃ , X ₂ = H, p = 0

Solid white. Cι ₅ Hι ₇ F ₃ N ₂ S, HCI

F = 298-301 ° C (recrystallized from water)

Example 22: 5,7-dichloro-2-methyl-3- (4-piperidinylthio) -1H-indole, hydrochloride

Formula (I): R-, = H, R ₂ = Me, R ₃ = H, Xi = 5-CI, X ₂ = 7-CI, p = 0

Solid beige. Cι ₄ H ₁₆ Cl2N ₂ S, HCI F> 275 ° C

Example ^p 23: 4,6-dichloro-2-methyl-3- (4-piperidinylthio) -1 H-indole, hydrochloride

Formula (I): R ₁ = H, R = Me, R ₃ = H, X ^• = 4-CI, X ₂ = 6-CI, p = 0 Solid beige. C ₁ H ₁₆ CI ₂ N ₂ S, HCI F> 275 ° C

Example 24: 5-chloro-2- (4-chlorophenyl) -3- (4-piperidinylthio) -1 H- indole

Formula (I): R-, = H, R ₂ = 4-CI-Ph, R ₃ = H, Xi = 5-CI, X ₂ = H, p = 0

Solid pale yellow.

C19H18C.2N2S F = 230-231 ^C C (recrystallized from xyiene)

Example 25: 5-chloro-1 - [(4-chlorophenyl) methyl] -2-methyl-3- (4-piperidinylthio) -1 H-indole

Formula (I): Ri = H, R = Me, R ₃ = 4-CI-Bn, Xi = 5-CI, X ₂ = H, p = 0

Solid white.

C2 H22CI N2S F = 122 ° C

Example 26: 5-chloro-2-methyl-3 - [(1-methyl-4-piperidinyl) thio] -1 H- indole

Formula (I): R, = Me, R ₂ = Me, R ₃ = H, Xi = 5-CI, X ₂ = H, p = 0

Solid beige.

C ₁₅ H ₁₉ CI N ₂ SF = 154-157 ° C (recrystallized from cyclohexane). Example 27: 5-fluoro-2-methyl-3 - [(1-methyl-4-piperidinyl) thio] -1 H- indole

Formula (I): Ri = Me, R ₂ = Me, R ₃ = H, X, = 5-F, X ₂ = H, p = 0

Solid pale yellow.

C15H19FN2S

Mp 158-159 ° C (recrystallized from cyciohexane).

Example 28: 5-bromo-2-methyl-3 - [[1- (phenylmethyl) -4-piperidinyl] thio] -1 H-indole, hydrochloride

Formula (I): Ri = Bn, R ^{• *} - * Me, R ₃ = H, X, = 5-Br, X ₂ = H, p = 0

Solid white. F = 266-267 ° C

Example 29: 5-chloro-2,7-dimethyl-3 - [[1- (phenylmethyl) -4- plperidinyl] thio] -1 H-indole, hydrochloride

Formula (I): R, = Bn, R ₂ = Me, R ₃ = H, X, = 5-CI, X ₂ = 7-Me, p = 0

Solid white.

C22H25CI N2S, HCI

M = 245-246 ° C (recrystallized from acetonitrile)

Example 30: 7-chloro-2-methyl-3 - [[1- (phenylmethyl) -4- piperidinyl] thio] -1 H-indole Formula (1): Ri = Bn, R ₂ = Me, R ₃ = H, X, = 7-CI, X ₂ = H, p = 0

Solid white. C21 H23CI N2S

F = 133-134 ° C (recrystallized from ethanol)

Example 31: 4,7-dichloro-2-methyl-3 - [[1- (phenylmethyl) -4- piperidinyl] thio] -1 H-indole, hydrochloride

Formula (I): Ri = Bn, R ₂ = Me, R ₃ = H, X, = 4-CI, X ₂ = 7-CI, p = 0

Solid beige. C ₂ ι H22CI ₂ N ₂ S, HCI

F = 143-144 ° C

Example 32: 5-chloro-1,2,2-dimethyl-3 - [[1- (phenylmethyl) -4- piperidinyl] thio] -1 H-indole, hydrochloride

Formula (I): Ri = Bn, R ₂ = Me, R ₃ = Me, Xi = 5-CI, X ₂ = H, p = 0

Solid white.

F = 231-233 ° C

Example 33: 5-chloro-2-methyl-3 - [[1- (2-phenylethyl) -4- piperidinyl] thio] -1 H-indole

Formula (I): Ri = CH ₂ CH ₂ Ph, R ₂ = Me, R ₃ = H, X, = 5-CI, X ₂ = H, p = 0 Solid pale yellow.

C ₂₂ H ₂₅ CI ₂ S

F ≈ 190-192 ° C

Example 34: 5-bromo-2-methyl-3 - [[1- (2-phenylethyl) -4- piperidinyl] thlo] -1 H-indole

Formula (I): Ri = CH ₂ CH ₂ Ph, R ₂ = Me, R ₃ = H, X, = 5-Br, X ₂ = H, p = 0

Solid white.

C ₂ 2H2 ₅ Br N ₂ S

Mp 188-189 ° C (recrystallized from acetonitrile)

Example 35: 5-chloro-1,2,2-dimethyl-3 - [[1- (2-phenylethyl) -4- piperidinyl] thio] -1 H-indole

Formula (I): Ri = CH ₂ CH ₂ Ph, R ₂ = Me, R ₃ ^• = Me, Xi = 5-CI, X2 = H, p = 0 White solid. C2 ₃ H ₂₇ CI N2S F = 136-137 ° C (recrystallized from acetonitrile)

Example ^p 36: 5-chloro-3 - [[1- (phenylmethyl) -4-piperidinyl] thlo] -1 H- indole, hydrochloride

Formula (I): Ri = Bn, R = H, R ₃ = H, Xi = 5-CI, X ₂ = H, p = 0

4-chlorophenylhydrazine hydrochloride (1 g) and 4 - [(2,2-diethoxyethyl) thio] -1- (phenylmethyl) -piperidine (1.8 g prepared in Example 13) in isopropanol ( 20 ml) are stirred at room temperature under nitrogen until passing into solution. After cooling at O'C, the solution is saturated with gaseous hydrochloric acid. After 4 hours the precipitate is drained, taken up in sodium hydroxide and extracted with ether, then with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated. The residual oil is taken up in hydrochloric ether to give the 5-chloro-3 hydrochloride - [[1 - (phenylmethyl) -4-piperidinyl] thio] -1 H-indole (1, 4 g).

Solid white.

C2θH2i CI N ₂ S, HCI, 0.5 H ₂ 0 F = 158-160 ° C

Using the same synthesis process with the appropriate hydrazines and acetals, the following compounds were prepared (Examples 37 to 52):

Example 37: 5-bromo-3 - [[1- (phenylmethyl) -4-piperidinyl] thio] -1 H- indole

Formula (I): R-- = Bn, R ₂ = H, R ₃ = H, Xi = 5-Br, X ₂ = H, p = 0

Solid white.

C2oH ₂ ι Br ₂ SF = 134-135 ° C (recrystallized from cyclohexane).

Example ^p 38: 3 - [[1 - (phenylmethyl) -4-piperidinyl] thio] -5- (trifluoro methyl) -1 H-indole

Formula (I): Ri = Bn, R ₂ = H, R ₃ = H, Xi = 5-CF ₃ , X ₂ = H, p = 0

Solid white. C ₂ ι H ₂ ι F ₃ N ₂ S

M = 154-155 ° C (recrystallized from cyclohexane).

Example 39: 1-phenyl-3 - [[1- (phenylmethyl) -4-piperidinyl] thio] -1 H- indole, oxaiate

Formula (I): R, = Bn, R = H, R ₃ = Ph, Xi = H, X ₂ = H, p = 0

Solid beige. CasHaeNsS. Cî-H. Mp 193-194 ° C (recrystallized from ether). Example 40: 5-chloro-3 - [(1-methyl-4-plperidinyl) thio] -1 H-

Indole

Formula (I): R, - Me, R ₂ = H, R ₃ = H, X, = 5-CI. X ₂ = H, p = 0

Solid off-white.

Cι Hι ₇ CI N2S

M = 136-137 ° C (recrystallized from cyclohexane).

Example 41: 5-methoxy-3 - [(1-methyl-4-piperidinyl) thio] -1 H- indole

Formula (I): R-, = Me, R ₂ = H, R ₃ ≈ H, Xi = 5-OMe, X ₂ = H, p ≈ 0

Solid beige.

C ₁ 5H20N2OS F ≈ 153 ° C (recrystallized from isopropanol).

Example 42: 3 - [(1-methyl-4-piperidinyl) thio] -1 H-lndole

Formula (I): Ri = Me, R ₂ = H, R ₃ = H, Xι = H, X ₂ = H, p = 0

Solid pale yellow.

Mp 143-144 ° C (recrystallized from cyclohexane).

Example 43: 5- (1-methylethyl) -3 - [(1-methyl-4-piperldinyl) thio] -1 H-

Indole

Formula (I): R, = Me, R ₂ = H, R ₃ = H, X, ≈ 5-iPr, X ₂ = H, p = 0

Solid off-white. F = 110 ° C Example 44: 5-bromo-3 - [(1-methyl-4-piperidinyl) thio] -1 H-lndole

Formula (I): Ri = Me, R ₂ = H, R ₃ = H, X, = 5-Br, X ₂ = H, p = 0

Solid light beige.

M = 135-136 ° C (recrystallized from cyclohexane)

Example 45: 5-methyl-3 [(1-methyl-4-piperidinyl) thio] -1 H-indole

Formula (I): R, = Me, R ₂ = H, R ₃ = H, Xi = 5-Me, X ₂ = H, p = 0

Solid white. C15 H20 N2S

F = 134 ° C (recrystallized from toluene)

Example ^p 46: 5-iodo-3 - [(1-methy.-4-piperidinyl) thlo] -1 H-lndole

Formula (I): Ri = Me, R ₂ = H, R ₃ = H, X, = 5-I, X ₂ = H, p = 0

Solid white.

Cι ₄ H17I N ₂ SF = 136-137 ° C

Example 47: 5-bromo-3 - [[1- (1-methylethyl) -4-piperidinyl] thio] -1 H- indole

Formula (I): Ri = iPr, R ₂ = H, R ₃ = H, X, = 5-Br, X ₂ = H, p = 0

Solid beige.

Cι ₆ H ₂ ι Br N ₂ SF = 116-118 ° C (recrystallized from acetonitrile) Example 48: 5-chloro-3 - [[1- (1-methylethyl) -4-plperidinyl] thlo] -1 H- indole

Formula (I): Ri = iPr, R ₂ = H, R ₃ = H, Xi = 5-CI, X ₂ = H. p = 0

Solid light beige.

C ₁₆ H ₂₁ Cl ₂ S

F = 123 ° C (recrystallized from cyclohexane)

Example 49: 5-bromo-3- (4-piperldinylthio) -1 H-indole

Formula (I): R- ^* = H, R ₂ = H, R ₃ = H, X, = 5-Br, X ₂ = H, p = 0

Solid white. C ₁₃ Hι ₅ BrN ₂ S

F = 180-181 ° C (recrystallized from toluene)

Example 50: 5-chloro-3- (4-piperidinylthio) -1 H-indole, hydrochloride

Formula (I): R-, = H, R ₂ = H, R ₃ ^* = H, Xi = 5-CI, X ₂ = H, p = 0

Solid white. C ₁₃ H ₁₅ Cl N ₂ S, HCI

F = 251-252 ° C (recrystallized from ethaπol)

Example ^p 51: 5-bromo-3 - [(1-methoxy-4-plpéridlnyl) thio] -l H-indole

Formula (I): Ri = OMe, R ₂ = H, R ₃ = H, X, = 5-Br, X ₂ = H, p ≈ 0

Solid beige.

C ₁₄ Hι ₇ Br N ₂ OS

F = 134-135 ° C (recrystallized from cyclohexane) Example 52: 5-chloro-3 - [(1-methoxy-4-piperidinyl) thio] -1 H-indole

Formula (I): Ri = OMe, R = H, R ₃ = H, Xi = 5-CI, X ₂ = H, p = 0

Solid beige.

Cι ₄ Hι ₇ CI N ₂ OS F = 132 ° C

Example 53: 5-bromo-2-methyl-3- (4-piperidinylthio) -1 H-lndole

Formula (I): Ri = H, R ₂ = Me, R ₃ = H, X, = 5-Br, X ₂ = H, p = 0

4-Bromophenylhydrazine hydrochloride (11.5 g) is dissolved in a solution of 1,1-dimethylethyl 4 - [(2-oxopropyl) thio] -1-piperidinecarboxylate (14 g prepared in Example 11) in isopropanol (100 ml) under nitrogen. The solution is cooled to O'C and saturated with gaseous hydrochloric acid. After 4 hours at room temperature the precipitate is drained, taken up in sodium hydroxide and extracted with ether, then with methylene chloride. The organic phases are combined, dried over sodium sulfate and concentrated. The solid obtained is taken up in a minimum of ether and recrystallized from xylene to give 5-bromo-2-methyl-3- (4-piperidinylthio) -1 H-indole (9.5 g).

Solid pale yellow. Cι ₄ H ₁₇ Br N ₂ SF = 207-208 ° C

Example ^p 54: 5-chloro-2-methyl.-3 - [[1- [2- (1 H-pyrrol-1-yl) ethyl] -4- pipér.dinyl] thio] -l H-indole

Formula (I): R, = CH- - CH, -— N, R ₂ = Me, R ₃ = H,

Xι = 5-CI, X ₂ = H, p = 0

A toluene solution (100 ml) of 5-chloro-2-methyl-3- (4-piperidinylthio) -1H- indole (1.09 g, prepared in example 18), sodium carbonate (0.78 g ) and 1- (2- iodoethyl) -1H-pyrτole (0.92 g prepared according to: GALEAZZI, E.; GUZMAN, A.; PINEDO, A.; SALDANA, A. TORRE, D.; MUCHOWSKI, JM Can. J. Chem. (1983) fil, 454-60) is brought to reflux for 15 hours. The reaction mixture is taken up in a water-dichloromethane mixture. The organic phase is dried over magnesium sulfate and concentrated. The residue is chromatographed on silica gel (eluent: CH ₂ CI ₂ / MeOH, 90/10) to give 5-chloro-2-methyl-3 - [[1- [2- (1H-pyrrol-1-yl ) ethyl] -4-piperidinyl] thio] -1H- indole (0.9 g).

Solid off-white.

M = 169-171 ° C

By a similar method, the product of Example 55 is obtained, by reaction of iodoethane with 5-chloro-3- (4-piperidinylthio) -1 H-indole (prepared in Example 50):

Example ^p 55: 5-chloro-3 - [(1-et.yl-4-piperidinyl) thio] -1 H-indole, hydrochloride

Formula (I): R-, = Et, R = H, R ₃ = H, X, = 5-CI, X ₂ = H, p = 0

Solid white.

Cι ₅ H ₁₉ Cl N ₂ S, HCI, 1/2 H ₂ 0

M = 75-77 ° C

Example ^p 56: 3 - [[1 - (phenylmethyl) -4-pIperidinyl] thio] -1, 2,5- trimethyl-1 H-indole

Formula (I): Ri = Bn, R ₂ = Me, R ₃ = Me, Xi = 5-Me, X ₂ = H, p = 0

An aqueous solution (200 ml) of 2,5-dimethyl-3 hydrochloride - [[1- (phenylmethyl) -

4-piperidinyl] thio] -1 H-indole (prepared in Example 17) is basified with sodium hydroxide until pH = 9. After extraction with ether, the organic phase is dried over sodium sulfate and concentrated. After adding heptane, the indole crystallizes (10.4 g).

A solution of this indole (10 g) in anhydrous tetrahydrofuran (50 ml) is added dropwise to a solution of sodium amide (1, 3 g) in ammonia liquid (20 ml) at -40 ^° C. After 10 minutes, methyl iodide (2 ml) in tetrahydrofuran (50 ml) was added.

After 2 hours at room temperature, 10 ml of water are added. After concentration, the mixture is taken up in water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate and concentrated. After recrystallization from ethanol, 3 - [[1 - (phenylmethyl) -4-piperidinyl] thio] -1, 2,5-trimethyl-1 H-indole (8.3 g) is obtained.

Solid white. C23H2-3 2S

F = 134-135 ° C

By a similar method, the compounds 57 to 59 are prepared from Examples 40, 44 and 51:

Example ^p 57: 5-chloro-1-methyl-3 - [(1-méthy.-4-plpéridinyl) thio] -1 H- indole

Formula (I): Ri = Me, R ₂ = H, R ₃ = Me, X _t = 5-CI, X ₂ = H, p = 0

Solid white.

C ₁₅ H19 Cl N ₂ S

Mp 78-79 ° C (recrystallized from heptane)

Example ^p 58: 5-bromo-1-methyl-3 - [(1-methyl-4-piperidinyl) thio] -1 H- indole

Formula (I): Ri = Me, R ₂ = H, R ₃ = Me, X, = 5-Br, X ₂ = H, p = 0

Solid white.

C15 H ₁₉ Br N ₂ SF = 83-84 ° C (recrystallized from heptane) Example 59: 5-bromo-3 - [(1-methoxy-4-plperidinyl) thio] -1-methyl-

1 H-indole

Formula (I): Ri = OMe, R ₂ = H, R ₃ = Me, Xi = 5-Br, X ₂ = H, p = 0

Solid beige. Cι ₅ H ₁₉ Br N ₂ OSF = 84 ° C

Example 60: 5-chloro-2-methyl-3- (4-piperidinylsulfinyl) -1 H-indole

Formula (I): Ri = H, R ₂ = Me, R ₃ = H, X, = 5-CI, X ₂ "H, p = 1

Meta chloroperbenzoic acid (2.79 g) is added in portions to 5-chloro-2-methyl-3- (4-piperidinylthio) -1 H-indole (3g, prepared in Example 18) in solution in dichloromethane (25 ml) at -40 ° C. After 4 hours at room temperature, the insoluble material is filtered. The filtrate is washed with soda and then with water. The aqueous phases are extracted with ether, then with ethyl acetate. The organic phases are combined, dried over magnesium sulfate and concentrated. The oily residue obtained is chromatographed on silica gel (eluent: CH ₂ Cl2tMeOHtNH ₄ OH 90/10/1) to give 5-chloro-2-methyl-3- (4-piperidinylsulfinyl) -1 H-indole in the form of oil which crystallizes by adding ether (0.4 g).

Solid beige. C ₁₄ H ₁₇ CI N ₂ OS, H ₂ 0

F = 140-145'C

By a similar method, Example 61 is prepared from the product of Example

49

Example ^p 61: 5-bromo-3 - [(1-methyl-4-piperidlnyl) su "flnyl] -i H-indole

Formula (I): i = Me, R ₂ " ^** H, R ₃ = H, X ^ = 5-Br, X ₂ = H, p = 1 Solid white. C ₁₄ Hι ₇ Br N ₂ OS F = 215-216 ° C

Example 62: 5- (1-methylethyl) -3 - [(1-methyl-4-piperidinyl) sulfonyl] - i H-indole

Formula (I): Ri = Me, R ₂ = H, R ₃ = H, X, = 5-iPr, X ₂ = H, p = 2

A solution of potassium peroxymonosulfate (KHSO5 at 49.5%, 21.2 g) in water (95 ml) is added dropwise at O'C to a methanolic solution (95 ml) of 5- (1 -methylethyl) -3 - [(1-methyl-4-piperidinyl) thio] -1 H-indole (7.5 g, prepared in Example 43). After 4 hours at room temperature, the white precipitate is filtered and the filtrate is concentrated, basified with sodium carbonate and extracted with ethyl acetate. The organic phase is dried over sodium sulfate and concentrated. After purification on silica gel (eluent: CH ₂ CI ₂ / iPrNH ₂ 95/5) we obtain 5- (1-methylethyl) -3 - [(1-methyl-4-piperidinyl) sulfonyl] -1 H-indole (2.4 g).

Solid beige Cι ₇ H _{24 2} 0 ₂ S

F = 127-129'C

Example ^p 63: 3 - [(1-methyl-4-piperidinyl) thio] -1 H-indole-5-carbonitrile, oxalate

Formula (I): Ri = Me, R ₂ = H, R ₃ = H, X, = 5-CN, X ₂ = H, p = 0

A suspension of copper cyanide (17.7 g) and 5-bromo-3 - [(1-methyl-4-piperidinyl) thio] -1 H-indole (35.5 g, prepared in Example 44) in 1-methyl-2-pyrrolidinone (45 ml) is brought to reflux for 24 hours. After dilution with water, the brown precipitate is separated, then taken up in a mixture of water (110 ml) and ethylenediamine (170 ml). The blue solution is extracted with ethyl acetate. The organic phase is dried over sodium sulfate and concentrated. The residual oil is chromatographed on silica gel (eluent: AcOEt / iPrNH ₂ 95/5) to give 3 - [(1-methyl-4-piperidinyl) thio] -1H- indole-5-carbonitrile (1, 5 g) which is transformed into oxalate in ethanol. Solid white.

C15 Hf7 N ₃ S, C ₂ H 0 ₄

Mp 137-139 ° C.

Example 64: 3 - [(1-methyl-4-piperidlnyl) thio] -1H-lndol-5-ol

Formula (I): Ri = Me, R ₂ = H, R ₃ = H, X, - = 5-OH, X ₂ = H, p = 0

A solution of boron tribromide (6.3 ml) in chloroform (16 ml) is added dropwise to a solution of 5-methoxy-3 - [(1-methyl-4-piperidinyl) thio] -1 H- indole (8 g, prepared in Example 41) in chloroform (105 ml) at 0 ° C. After 3 hours at room temperature, the reaction mixture is poured onto ice and basified with ammonia. The organic phase is dried over sodium sulfate and concentrated. The oily residue is chromatographed on silica gel (eluent CH ₂ CI ₂ / EtOH / 79/20/1) to give 3 - [(1-methyl-4-piperidinyl) thio] -1H-indol-5-ol (0.8 g) which is recrystallized from xylene.

Solid white. C ₁₄ Hι ₈ N ₂ OS

M = 183-184 ° C

Example ^p 65: 4 - [(5-bromo-1 H-lndol-3-yl) thio] -l-piperidyl vinyl carboxylate

Formula (I): R-, = C0 ₂ -CH = CH ₂ , R ₂ = H, R ₃ = H,, = 5-Br, X ₂ = H, p = 0

Vinyl chloroformate (0.75 ml) is added dropwise to a solution of triethylamine (1.2 ml) and 5-bromo-3- (4-piperidinylthio) -1 H-indole (2.5 g, prepared in Example 49) in dichloromethane (25 ml) at 0 ° C. After 2 hours at room temperature the solution is washed with water. The organic phase is dried over magnesium sulfate and concentrated. After chromatography on silica gel (eluent: cyclohexane / AcOEt 70/30), 4 - [(5-bromo-1H-indol-3-yl) thio] -1-piperidinecarboxylate is obtained (1.8 g). Solid white

C ₁₆ Hι ₇ BrN ₂ 0 ₂ S

M = 151-152 ° C

By an analogous method, Examples 66 to 69 are prepared from the products of Examples 49 and 50, by the action of acetyl chloride or ethyl, vinyl or phenyl chloroformates.

Example 66: 3 - [(1-acetyl-4-piperidinyl) thio] -5-bromo-1 H-indole

Formula (I): R, = Ac, R ₂ = H, R ₃ = H, X, = 5-Br, X ₂ = H, p = 0

Solid white Cι ₅ Hι ₇ Br N ₂ OS

M = 155-156 ° C

Example 67: 4 - [(5-bromo-1 H-indol-3-yl) thio] -1-piperidine ethyl carboxylate

Formula (I): Ri = C0 ₂ Et, R ₂ = H, R ₃ = H, Xi = 5-Br, X ₂ = H, p = 0

White solid C ₁₆ Hι ₉ Br N ₂ 0 ₂ SF = 147-149'C (recrystallized from acetonitrile)

Example 68: 4 - [(5-chloro-1 H-indol-3-yl) thio] -1-vinyl piperidine carboxylate

Formula (I): R ₁ = C0 ₂ -CH = CH ₂ , R ₂ = H, R ₃ = H, X, = 5-CI,

X ₂ = H, p = 0

Off-white solid Cι ₆ Hι ₇ CI N ₂ θ2S F = 157 ° C Example 69: 4 - [(5-chloro-1 H-lndol-3-yl) thlo] -1-phenylpiperldine carboxylate

Formula (I): Ri = CC ^ Ph, R = H, R ₃ = H, Xi = 5-CI, X ₂ = H, p = 0

Solid white. C _a H ₁₉ Cl N 0 ₂ SF = 162-163 ° C

Example 70: 3 - [(1-methoxy-4-piperidlnyl) thio] -1-methyl-1 H-indole-5-carboxylic acid

Formula (I): Ri = OMe, R ₂ = H, R ₃ = Me, Xi = 5-C0 ₂ H, X ₂ = H, p = 0

A solution of butyllithium (7.1 ml; 2.5 M in hexane) is added dropwise to 5-bromo-3 - [(1-methoxy-4-piperidinyl) thio] -1-methyl-1 H -indole (4.5 g; prepared in Example 59) in tetrahydrofuran (45 ml) at -78 ° C. After 1 hour at this temperature, a stream of C0 ₂ is passed through the solution. After returning to 0 ° C. an ammonium chloride solution is added. The reaction mixture is concentrated, taken up in ether and washed with water. The organic phase is dried over sodium sulfate and concentrated. The 3 - [(1-methoxy-4-piperidinyl) thio] -1-methyl-1H-indole-5-carboxylic acid obtained (1.4 g) is crystallized from a small volume of isopropyl ether.

Solid white.

Ci6 H2o ₂ 0 ₃ SF = 170-172 ° C

Example 71: 4 - [(5-bromo-1 H-indo! -3-yl) thlo] -l -piperidine carboxaidehyde

Formula (I): R = CHO, R ₂ = H, R ₃ ≈ H, Xi = 5-Br, X ₂ = H, p = 0

A solution of 1,3-dicyclohexylcarbodiimide (1.7 g) in dichloromethane (4 ml) is added dropwise to a solution of 5-bromo-3- (4-piperidinylthio) -1 H-indole (2.4 g; prepared in Example 49) and formic acid (0.3 ml) in dichloromethane (25 ml) at 0 ° C. The dicyclohexylurea formed is separated and the filtrate is washed with water. The organic phase is dried over magnesium sulfate and concentrated. The 4 - [(5-bromo-1 H-indol-3-yl) thio] -1-piperidinecarboxaldehyde obtained is recrystallized from xylene.

Solid white.

Cι H _1s Br N ₂ OS

M = 204-207 ° C

Example 72: ethyl 5-bromo-3 - [(1-carbethoxy-4-piperidinyl) thlo] -1 H-indole-1-carboxylate

Formula (I): R, = C0 ₂ Et, R ₂ = H, R ₃ = CC ^ Et, Xi = 5-Br, X ₂ = H, p = 0

Ethyl chloroformate (4.4 ml) is added dropwise to a toluene solution (50 ml) at 90 ° C of 5-bromo-3 - [(1-methyl-4-piperidinyl) thio] -1 H -indole (5g, prepared in Example 44). After four hours of reflux, the insoluble material is filtered and the reaction mixture is concentrated. The orange oil obtained is taken up in ether and washed with a dilute solution of hydrochloric acid. The organic phase is dried over sodium sulfate and concentrated. After chromatography on silica gel (eluent: CH ₂ CI ₂ / EtOH, 95/5), 5-bromo-3 - [(1-carbethoxy-4-piperidinyl) thio] -1H-indole-1 -carboxylate ethyl (2.5 g) is obtained in the form of an oil which crystallizes by adding isopropyl ether.

Solid white.

CιgH ₂₃ Br 2θ ₄ SF = 95 ° C

Example ^p 73: 3 - [(1-methoxy-4-piperidinyl) thio] -1-methyl-1 H-indole-5-carboxamide

Formula (I): Ri = OMe, R ₂ = H, R ₃ = Me, Xi = CO H ₂ , X = H, p = 0 A solution of 3 - [(1-methoxy-4-piperidinyl) thio] -1-methyl-1 H-indole-5-carboxylic acid (4 g prepared in Example 70) in a mixture of thionyl chloride ( 3.6 ml) and chloroform (40 ml) is brought to reflux for three hours. After concentration, the beige solid is dissolved in dichloromethane (30 ml) and is added dropwise at 0 ° C to a methanolic ammonia solution (50 ml). After 1 hour the reaction medium is concentrated, taken up in ethyl acetate and washed with water. The organic phase is dried over sodium sulfate and then concentrated. The residual oil is chromatographed on silica gel (eluent: AcOEt) to give 3 - [(1-methoxy-4-piperidinyl) thio] -1-methyl-1 H-indole 5-carboxamide (2.2 g) .

White solid Cι ₆ H2o ₃ 0 ₂ SF = 146 ° C

Example 74: 4 - [(5-bromo-1 H-indol-3-yl) thio] -l -piperidlne sodium carbodithioate

Formula (I): Ri = CS ₂ Na, R ₂ = H, R ₃ = H, Xi = 5-Br, X ₂ = H, p = 0

A solution of sodium hydroxide (1.4 g) and carbon sulphide (2.15 ml) in water (3 ml) is added dropwise to a solution of 5-bromo-3- (4-piperidinylthio) -1 H-indole (10 g, prepared in Example 49) in ethanol (30 ml) maintained between 0 and 5 ^* C. After 8 hours at room temperature the mixture is concentrated to dryness, taken up in ethyl acetate and washed with water. The organic phase is concentrated and taken up in ether to give 4 - [(5-bromo-

1H-indol-3-yl) thio] -l -piperidinecarbodithioate sodium (6.1 g).

White solid F = 230 ° C

Example 75: 4 - [(5-bromo-1 H-indol-3-yl) thio] -1-methyl piperidine carbodithioate

Formula (I): R,: CS ₂ Me, R ₂ = H, R ₃ = H, Xi = 5-Br, X ₂ = H, p = 0 A solution of 4 - [(5-bromo-1H-indol-3-yl) thio] -1-piperidinecarbodithioate (3 g, prepared in the previous example) and methyl iodide (0.5 ml) in 95% ethanol (15 ml) is brought to reflux for one hour. The orange reaction mixture is concentrated, taken up in ether and washed with water. The organic phase is dried over sodium sulfate and concentrated. After chromatography on silica gel (eluent: cyclohexane / AcOEt 70/30), 4 - [(5-bromo-1H-indol-3-yl) thio] -1-piperidine methyl carbodithioate (13 g) is obtained in the form of oil which is taken up in pentene to give a white solid.

C ₅ H ₁₇ BrN ₂ S ₃

F ≈ 108-109 ^β C

Example 76: 3 - [(1-methoxy-4-plpérldinyl) thlo] -1-methyl-1 H-lndole-

5-methane

Formula (I): Ri = OMe, R ₂ = H, R ₃ = Me, X, = 5-CH ₂ NH ₂ , X ₂ . H, p ≈ 0

A solution of 3 - [(1-methoxy-4-piperidinyl) thio] -1-methyl-1H-indole-5-carboxamide (3.2 g, prepared in Example 73) in dry THF (40 ml) is added dropwise at 0 ° C to a suspension of double lithium aluminum hydride (LiAlH ₄ ; 1.2 g) in anhydrous THF (200 ml). After 10 hours at room temperature, the reaction mixture is hydrolyzed at 0 ° C by adding a saturated solution of sodium sulfate. After filtration on celite, the solution is concentrated, taken up in ether and extracted with a dilute solution of hydrochloric acid. The aqueous phase is basified with sodium hydroxide and extracted with methylene chloride. The organic phase is dried over sodium sulfate and concentrated. After chromatography on silica gel (eluent: AcOEt), the 3 - [(1-methoxy-4-piperidinyl) thio] -1-methyl-1H-indole-5-methanamine (1.8 g) is obtained in the form of a yellowish solid. VS-. ₆ H2 ₃ .N3OS

F = 96 ° C Example 77: N - [[3 - [(1-methoxy-4-piperidinyl) thio] -1-methyl-1 H-lndol-5-yl] methyl] -methanesulfonamide

Formula (I): Ri = OMe, R ₂ = H, R ₃ = Me, X = 5-CH NHS0 ₂ Me, X ₂ = H, p = 0

Mesyl chloride (0.23 ml) is added dropwise to a 0 ° C solution of 3- [(1-methoxy-4-piperidinyl) thio] -1-methyl-1H-indole-5-methanamine ( 0.8 g, prepared in the previous example) and triethylamine (0.4 ml) in chloroform (10 ml). After two hours at room temperature, the solution is washed with water. The organic phase is dried over sodium sulfate and concentrated.

After chromatography on silica gel (eluent: CH ₂ CI ₂ / acetone, 90/10) [[3 - [(1-methoxy-4-piperidinyl) thio] -1-methyl-1 H-indol-5-yl ] methyl] -methanesulfonamide (0.4 g) is obtained.

Solid white

C. Hs N ₃ 0 ₃ S ₂

M = 115-116 ° C

Example ^p 78: 1-methyl-3 - [(1-methyl-4-piperldinyl) thio] -1 H-indole-5-methanol

Formula (I): R-, = Me, R ₂ = H, R ₃ ≈ Me, X-, = 5-CH ₂ OH, X ₂ = H, p = 0

A solution of 5-bromo-1-methyl-3 - [(1-methyl-4-piperidinyl) thio] -1 H-indole (19 g, prepared in Example 58) in THF (100 ml) is treated at -78 ° C with a solution of butyllithium (31.5 ml, 2.5 M in hexane). After 1 hour at this temperature, carbon dioxide gas is passed into the solution until saturation. After one hour, the reaction mixture is allowed to return to ambient temperature. The solvent is evaporated off and the residue is taken up in ether to give 1-methyl-3 - [(1-methyl-4-piperidinyl) thio] -1H-indole-5-carboxylic acid (22.8 g ) in the form of a yellow solid which is used subsequently without purification.

The acid thus obtained (11 g) is added in portions to a suspension of double lithium aluminum hydride (LiAIH ₄ , 1, 6 g) in anhydrous tetrahydrofuran (60 ml) at 0 ° C. After 4 hours at room temperature, the reaction mixture is cooled to 0 ° C and hydrolyzed with a saturated solution of sodium sulfate. The suspension is filtered through celite and then concentrated. After purification on silica gel (eluent: CH ₂ CI ₂ / ethanol, 80/20) 1-methyl-3 - [(1-methyl-4-piperidinyl) thio] -1H-indole-5-methanol (7, 5 g) is obtained in the form of an oil.

¹ H NMR (CDCb): 7.70 (s, 1H); 7.28 (m, 2H); 7.16 (s, 1H); 4.76 (s, 2H, CH ₂ 0); 3.77 (S, 3H, NMe); 3.37 (broad S, 1H, OH); 2.85-2.75 (m, 2H, 2CHN); 2.8-2.65 (m, 1H, CHS); 2.19 (s, 3H, NMe); 2.05-1.8 (m, 4H, 2CHN + 2 CH); 1.75-1.5 (m, 2H, 2CH).

Example 79: 5-bromo-1-butyl-3 - [(1-methyl-4-piperidinyl) thio] -1 H- indole

Formula (I): Ri = Me, R ₂ = H, R ₃ = nBu, X ^ = 5-Br, X ₂ = H, p = 0

Prepared as in Example 56 by reaction of 5-bromo-3 - [(1-methyl-4-piperidinyl) thio] -1 H-indole (prepared in Example 44) with iodobutane.

White solid Cι ₈ H ₂₅ Br N ₂ S

F = 65-66 ° C

Exam ^p 80: 3 - [(1-methyl-4-piperidinyl) thio] -1H-indole-5-carboxylate

Formula (I): R-, = Me, R ₂ = H, R ₃ = H, X, = 5-C0 ₂ Et, X ₂ = H, p = 0

Prepared as in Example 36 by reaction of 4 - [(2,2-diethoxyethyl) thio] -1-methyl-piperidine (prepared in Example 12) with ethyl 4-hydrazino-benzoate hydrochloride.

White solid C ₁ H2 ₂ N ₂ 0 ₂ SF = 179-180 ^* C PHARMACOLOGY

The analgesic activity of the examples was evaluated according to the method of stretching caused by phenylbenzoquinone in mice, described by Siegmund et al. (1957).

Method

The intraperitoneal injection of phenylbenzoquinone causes torsional and stretching movements in mice. Pain relievers prevent or decrease this syndrome, which can be thought of as the exteriorization of diffuse abdominal pain.

The 0.02% phenylbenzoquinone solution in water is administered in a volume of 1 ml / 100 g.

The products of the examples are administered orally one hour before the injection of phenylbenzoquinone.

Stretching and twisting are counted for each mouse during an observation period of 5 minutes.

Expression of results

The results are expressed in the form of ID50, a dose which makes it possible to obtain a reduction of 50% in the number of painful reactions compared to the control animals.

Results

The results are presented in the table below.

Produces examples Inhibitory dose 50 mg / kg orally

Example 18 0.8

Example 19 5.9

Example 21 19.4

Example 27 35.6

Example 36 9.7

Example 40

Example 41 24.9

Example 46 54.2

Example 51 0.8

Example 53 0.7

Example 57 3.9

Example 58 5.4

Example 59 0.7 TOXICOLOGY

The first toxicology studies carried out show that the products of the examples do not induce any deleterious effect after oral absoφtion in rats of doses which can vary from 30 to 300 mg / kg.

Claims

1. Piperidinyl thio indole derivatives characterized in that they correspond to the general formula (I):

Formula (I) in which:

XT and X ₂ independently represent:

- the hydrogen atom;

- a halogen atom; - a lower alkyl radical of 1 to 6 carbon atoms;

- a trif luoromethyl group;

- a hydroxy group;

- an O-lower alkyl radical of 1 to 6 carbon atoms;

- a nitrile group - an acid group

- an amide group

- a hydroxymethyl group

- an aminomethyl group

- the hydrogen atom;

- a lower alkyl radical of 1 to 6 carbon atoms;

- a methoxy group; - a group -COR 'in which R' represents the hydrogen atom or a radical lower alkyl of 1 to 6 carbon atoms;

- a group -COOR ";

a group -CSSR "in which R" represents an lower alkyl radical of 1 to 6 carbon atoms, a vinyl radical or a phenyl,

- A group -CSSM in which M represents sodium or potassium;

- a radical - (CH ₂ ) _n - phenyl;

- a radical - (CH ₂ ) _n pyrrole; where n is an integer from 0 to 4,

R ₂ represents:

- the hydrogen atom;

- a lower alkyl radical of 1 to 6 carbon atoms;

- a phenyl radical unsubstituted or substituted by a halogen atom,

R ₃ represents:

- the hydrogen atom;

- a lower alkyl radical of 1 to 6 carbon atoms;

- a group COOR "in which R" is defined as above; - a radical - (CH ₂ ) _n -phenyl in which the phenyl is unsubstituted or substituted by a halogen atom, n being an integer from 0 to 4, p is an integer from 0 to 2. as well as their addition salts, in particular pharmaceutically acceptable addition salts.

2. Derivatives according to claim 1, characterized in that X ₂ represents the hydrogen atom and X-- represents a halogen atom: chlorine, bromine, or fluorine and is in position 5 of the indole.

3. Derivatives according to claim 1 or 2, characterized in that R-i represents the hydrogen atom, a methyl radical, a benzyl group, a carbonyl vinyloxy group or a methoxy group.

4. Derivatives according to any one of claims 1 to 3 characterized in that R ₂ represents the hydrogen atom or a methyl radical.

5. Derivatives according to any one of claims 1 to 4 characterized in that R ₃ represents the hydrogen atom or a methyl radical

6. Derivatives according to any one of claims 1 to 5 characterized in that p is equal to zero.

7. Derivatives according to claim 1, characterized in that they are chosen from the derivatives of formula:

H

8. Processes for preparing the compounds of formula (I) according to any one of claims 1 to 7, characterized in that a phenylhydrazine of formula VIII is reacted i

Formula (Wine)

in which, X-ι, X ₂ and R ₃ are defined as in formula (I) with: either a ketone of formula (V)

Formula (V)

in which R represents a lower alkyl radical of 1 to 6 carbon atoms, a benzyl radical, a phenetyl radical, a protective group -COOtBu or the hydrogen atom and R 'represents a lower alkyl radical of 1 to 6 atoms of carbon or a phenyl radical unsubstituted or substituted by a halogen atom, ie a protected aldehyde of formula (VII)

Formula (VII)

in which R has the same meaning as in formula (V) and R "represents a lower alkyl of 1 to 6 carbon atoms optimally methyl or ethyl or the two R" thunder together -CH ₂ -CH ₂ - in an alcoholic solvent like ethanol, methanol or optimally isopropanol in the presence of hydrochloric gas at a temperature between 0 and 85 ° C.

9. Pharmaceutical composition, characterized in that it comprises a pharmaceutically effective amount of at least one compound of formula (I) as defined in any one of claims 1 to 7 or one of its addition salts pharmaceutically acceptable, possibly incoφorated in a pharmaceutically acceptable excipient, vehicle or support.

10. Pharmaceutical composition with analgesic activity, characterized in that it contains a pharmaceutically effective amount of a compound of formula (I) as defined in any one of claims 1 to 7, or one of its addition salts pharmaceutically acceptable, optionally incorporated into a pharmaceutically acceptable excipient, vehicle or support.

11. A method of preparing a pharmaceutical composition, characterized in that a pharmaceutical effective amount of at least one compound of formula (I) as defined in any one of claims 1 to 7 or one of its pharmaceutically acceptable addition salts, in a pharmaceutically acceptable excipient, vehicle or carrier.

12. The method of claim 11, characterized in that the pharmaceutical composition is formulated in the form of capsules, tablets dosed at 1 mg to 1000 mg or in the form of injectable preparations dosed from 0.1 to 500 mg.