KR100611262B1 - (1-Phenacy-3-phenyl-3-piperidylethyl)piperidine Derivatives, Method for the Production Thereof and Pharmaceutical Compositions Containing the Same - Google Patents

Abstract

The present invention relates to salts of the compounds of formula (1) with their inorganic or organic acids, solvates and / or hydrates thereof, which exhibit high affinity and high selectivity for the human NK ₁ receptor of substance P. The invention also relates to a process for its preparation, an intermediate compound of formula (7) useful for its preparation, a pharmaceutical composition containing said compound and its use for the manufacture of a medicament for the treatment of all diseases associated with substance P and human NK ₁ receptor.

<Formula 1>

Piperidine Derivatives, Takkinin Receptors

Description

(1-Phenac-3-phenyl-3-piperidylethyl) piperidine derivatives, preparation method thereof and pharmaceutical composition containing same {(1-Phenacy-3-phenyl-3-piperidylethyl) piperidine Derivatives, Method for the Production Thereof and Pharmaceutical Compositions Containing the Same}

The present invention relates to novel piperidine derivatives, methods for their preparation and pharmaceutical compositions containing them as active ingredients.

More specifically, the present invention relates to pathological symptoms including the tachykinin system, such as: pain (L. Urban et al., TINS, 1994, 17 , 432-438, L. Segin (L). Seguin et al. (Pain, 1995, 61 , 325-343), SH Buck et al., 1994, The Tachykinin Receptors, Humana Press, Totowa, NJ), Allergy and Inflammation (1994, The Tachykinin Receptors, Humana Press, Totowa, NJ), gastrointestinal disorders (P. Holzer and U. Holzer-Petsche) Pharmacol. Ther., 1997, 73 , 173-217 and 219-263), respiratory disorders (J. Mizrahi et al., Pharmacology, 1982, 25 , 39-50), C. C. Advenier et al., Eur. Respir. J., 1997, 10 , 1892-1906, C. Advenier and X. Emonds-Alt, Pulmonary. Phamacol., 1996, 9 , 329-333), urinary disorders (S. H. Buck's). 1994, The Tachykinin Receptors, Humana Press, Totowa, NJ, CA Maggi, Progess in Neurobiology, 1995, 45 , 1-98), Neurological Disorders and Neuropsychiatric Physiological disorders (C. A. Maggie et al., J. Autonomic Pharmacol., 1993, 13 , 23-93), M. Otsuka and K. Yoshioka, Physiol. Rev. 1993, 73 , 229-308), relates to novel piperidine derivatives for use in a non-limiting manner.

Recently, much research has been conducted on tachykinin and its receptors. Takkinin is distributed in both the central and peripheral nervous systems. Takkinin receptors are recognized and classified into three types NK ₁ , NK ₂ and NK ₃ . Substance P (SP) is an endogenous ligand of the NK ₁ receptor, neurokinin A (NK _A ) is an endogenous ligand of the NK ₂ receptor, and neurokinin B (NK _B ) is an endogenous ligand of the NK ₃ receptor.

NK ₁ , NK ₂ and NK ₃ receptors have proven to be of several types.

Seed. a. Review by Maggie et al. (J. Autonomic Pharmacol., 1993, 13 , 23-93) and d. A review by D. Regoli et al. (Pharmacol. Rev., 1994, 46 , 551-599) reviews tachykinin receptors and their antagonists and describes their pharmacological studies and their application to human therapy. .

Many patents and patent applications describe compounds that are active on tachykinin receptors. Therefore, European Patent Application No. 0 512 901 relates to compounds of the formula A

<Formula A>

In the above formula, in particular

Q 'represents an oxygen atom or two hydrogen atoms,

-T '= -C (O)-or -CH _2- ,

Y, Ar ', Z', m ', n', p 'and q have different values.

Patent application EP 0 714 891 relates to compounds of formula (B)

<Formula B>

Where

p "is 1, 2 or 3,

m "and n" are independently 0-6,

W, R _a , R _b , R _c , R _d and R _e have different groups.

Novel compounds have now been found which have a strong affinity and strong selectivity for substance P of human NK ₁ receptors and are antagonists of such receptors.

In addition, the compounds according to the invention have good bioavailability of the drugs when they are administered orally.

These compounds are useful in the treatment of any diseases involving substance P and NK ₁ receptors, especially in the respiratory, gastrointestinal, urinary, immune, cardiovascular and central nervous system and the treatment of pain, migraine, inflammation, nausea and vomiting and skin diseases. It can be used to prepare a medicament.

Therefore, according to one aspect, the present invention relates to possible salts of the compound of formula 1 with its inorganic or organic acid, and solvates and / or hydrates thereof.

The present invention relates to possible salts of the compounds of formula (1) with their inorganic or organic acids, and their solvates and / or hydrates.

Where

Ar represents phenyl, (C ₁ -C ₃ ) alkyl mono- or di-substituted with halogen atoms,

, 기

를 나타내고,-X is

, Flag

Indicates,

R ₁ represents a chlorine atom, bromine atom, (C ₁ -C ₃ ) alkyl or trifluoromethyl,

-R ₂ represents a group -CR ₃ R ₄ CONR ₅ R ₆ ,

R ₃ and R ₄ represent the same radicals selected from methyl, ethyl, n-propyl or n-butyl, or alternatively R ₃ and R ₄ together with the carbon atom to which they are attached (C ₃ -C ₆ ) cyclo Form alkyl,

R ₅ and R ₆ each independently represent hydrogen, (C ₁ -C ₃ ) alkyl, or alternatively R ₅ and R ₆ together with the nitrogen atom to which they are attached 1-azetidinyl, 1-pyrrolidinyl And heterocyclic radicals selected from 1-piperidyl, 4-morpholinyl, 4-thiomorpholinyl or perhydro-1-azinyl.

Compounds of formula (1) according to the invention comprise both optically pure isomers and mixtures thereof in any proportion.

Salts of the compounds of formula 1 may be formed. These salts form salts with inorganic or organic acids, such as picric acid or oxalic acid, or salts with optically active acids, such as mandelic acid or camphorsulfonic acid, which are capable of appropriate separation or crystallization of Formula 1, and pharmaceutically acceptable salts. Salts such as hydrochloride, hydrobromide, sulfate, hydrogen sulfate, dihydrogen phosphate, methanesulfonate, methyl sulfate, oxalate, malate, fumarate, succinate, 2-naphthalenesulfonate, glucose Nate, citrate, benzenesulfonate or para-toluenesulfonate.

The term "halogen" means a chlorine, bromine, fluorine or iodine atom.

In the present specification, the alkyl group is straight or branched chain.

According to the present invention, preferred compounds are the compounds of formula 1a and salts thereof with inorganic or organic acids, solvates and / or hydrates thereof.

Wherein X and R ₁ are as defined for the compound of Formula 1.

According to the invention, preferred compounds of formula 1 are those in which Ar represents 3,4-dichlorophenyl or 3,4-dimethylphenyl.

According to the invention, preferred compounds of formula 1 are those in which the substituent R ₁ represents a chlorine atom, methyl, ethyl or trifluoromethyl.

(여기에서 R₂는 기 -CR₃R₄CONR₅R₆임)를 나타내는 것들이다.According to the invention, preferred compounds of formula (1) are those in which X is a group

Wherein R ₂ is a group —CR ₃ R ₄ CONR ₅ R ₆ .

In particular, preferred compounds are those in which R ₃ and R ₄ each represent methyl or alternatively form cyclohexyl with the carbon atom to which they are attached. In particular, further preferred compounds are those in which R ₅ and R ₆ each represent hydrogen or methyl.

(여기에서 R₂는 기 -CR₃R₄CONR₅R₆임)를 나타내는 것들이다.According to the invention, preferred compounds of formula (1) are those in which X is a group

Wherein R ₂ is a group —CR ₃ R ₄ CONR ₅ R ₆ .

In particular, preferred compounds are those in which R ₃ and R ₄ each represent methyl or alternatively form cyclopropyl or cyclohexyl with the carbon atom to which they are attached. In particular, further preferred compounds are those in which R ₅ and R ₆ each represent hydrogen or methyl.

According to the present invention, preferred compounds are salts of compounds of formula 1 'with inorganic or organic acids thereof, and solvates and / or hydrates thereof.

<Formula 1 '>

Where

R ' ₁ represents a chlorine atom, methyl, ethyl or trifluoromethyl,

R ' ₃ and R' ₄ each represent methyl or alternatively form cyclohexyl with the carbon atom to which they are attached,

R ' ₅ and R' ₆ each represent hydrogen or methyl.

According to the present invention, preferred compounds are salts of compounds of formula 1 "with inorganic or organic acids thereof, and solvates and / or hydrates thereof.

<Formula 1 ">

Where

R ' ₁ represents a chlorine atom, methyl, ethyl or trifluoromethyl,

R ' ₃ and R' ₄ each represent methyl or alternatively form cyclohexyl or cyclopropyl with the carbon atoms to which they are attached,

R ' ₅ and R' ₆ each represent hydrogen or methyl.

According to the invention, preferred compounds are those of the formulas 1, I 'and I "in optically pure form.

The following compounds and their salts, solvates and / or hydrates thereof are more particularly preferred.

3- [2-4- (1-carbamoyl-1-methylethyl) -1-piperidyl] ethyl] -3- (3,4-dichlorophenyl) -1- [2- (3,5 -Dimethylphenyl) acetyl] piperidine, (-) isomer,

3- [2-4- (1-carbamoyl-1-methylethyl) -1-piperazinyl] ethyl] -3- (3,4-dichlorophenyl) -1- [2- (3,5 -Dimethylphenyl) acetyl] piperidine, (-) isomer,

3- [2-4- (1-N, N-dimethylcarbamoyl-1-methylethyl) -1-piperazinyl] ethyl] -3- (3,4-dichlorophenyl) -1- [2 -(3,5-dimethylphenyl) acetyl] piperidine, (-) isomer,

3- [2-4- (1-carbamoyl-1-methylethyl) -1-piperidyl] ethyl] -3- (3,4-dichlorophenyl) -1- [2- (3,5 -Dichlorophenyl) acetyl] piperidine, the (-) isomer,

3- [2-4- (1-carbamoyl-1-methylethyl) -1-piperidyl] ethyl] -3- (3,4-dichlorophenyl) -1- [2- (3,5 -Bis (trifluoromethyl) phenyl] acetyl] piperidine, (+) isomer,

3- [2-4- (1-carbamoylcyclohexyl) -1-piperidyl] ethyl] -3- (3,4-dichlorophenyl) -1- [2- (3,5-dimethylphenyl ) Acetyl] piperidine, (-) isomer,

3- [2-4- (1-carbamoylcyclohexyl) -1-piperazinyl] ethyl] -3- (3,4-dichlorophenyl) -1- [2- (3,5-dimethylphenyl ) Acetyl] piperidine, (-) isomer,

3- [2-4- (1-carbamoylcyclohexyl) piperidin-1-yl] ethyl] -3- (3,4-dichlorophenyl) -1- [2- (3,5-dichloro Phenyl) acetyl] piperidine, the (-) isomer,

3- [2-4- (1-carbamoyl-1-methylethyl) piperazin-1-yl] ethyl] -3- (3,4-dichlorophenyl) -1- [2- (3,5 -Dichlorophenyl) acetyl] piperidine, (+) isomer,

3- [2-4- (1-N, N-dimethylcarbamoyl-1-methylethyl) -1-piperazinyl] ethyl] -3- (3,4-dichlorophenyl) -1- [2 -(3,5-dichlorophenyl) acetyl] piperidine, (+) isomer,

3- [2-4- (1-carbamoylcyclohexyl) -1-piperazinyl] ethyl] -3- (3,4-dichlorophenyl) -1- [2- (3,5-dichlorophenyl ) Acetyl] piperidine, (+) isomer,

3- [2-4- (1-carbamoylcyclohexyl) -1-piperidyl] ethyl] -3- (3,4-dichlorophenyl) -1- [2- [3,5-bis ( Trifluoromethyl) phenyl] acetyl] piperidine, (+) isomer,

-3- [2- [4- (1-carbamoylcyclohexyl) -1-piperazinyl] ethyl] -3- (3,4-dichlorophenyl) -1- [2- [3,5-bis (Trifluoromethyl) phenyl] acetyl] piperidine, (+) isomer,

3- [2-4- (1-N, N-dimethylcarbamoyl-1-methylethyl) -1-piperidyl] ethyl] -3- (3,4-dichlorophenyl) -1- [2 -(3,5-dimethylphenyl) acetyl] piperidine, (-) isomer,

3- [2-4- (1-carbamoyl-1-methylethyl) -1-piperidyl] ethyl] -3- (3,4-dichlorophenyl) -1- [2- (3,5 Diethylphenyl) acetyl] piperidine, the (-) isomer,

3- [2-4- (1-carbamoylcyclopropyl) -1-piperidyl] ethyl] -3- (3,4-dichlorophenyl) -1- [2- (3,5-dimethyl Phenyl) acetyl] piperidine, the (-) isomer,

3- [2-4- (1-carbamoylcyclopropyl) -1-piperidyl] ethyl] -3- (3,4-dichlorophenyl) -1- [2- [3,5-bis ( Trifluoromethyl) phenyl] acetyl] piperidine, (+) isomer,

3- [2-4- (1-carbamoylcyclopropyl) -1-piperidyl] ethyl] -3- (3,4-dichlorophenyl) -1- [2- (3,5-dichlorophenyl ) Acetyl] piperidine, (+) isomer,

3- [2-4- (1-carbamoyl-1-methylethyl) -1-piperazinyl] ethyl] -3- (3,4-dichlorophenyl) -1- [2- (3,5 Diethylphenyl) acetyl] piperidine, the (-) isomer,

-3- [2-4- (1-carbamoyl-1-methylethyl) -1-piperidyl] ethyl] -3- (3,4-dimethylphenyl) -1- [2- (3,5 -Dichlorophenyl) acetyl] piperidine,

3- [2-4- (1-carbamoyl-1-methylethyl) -1-piperazinyl] ethyl] -3- (3,4-dimethylphenyl) -1- [2- (3,5 -Dichlorophenyl) acetyl] piperidine.

According to another aspect, the present invention

1a) treating a compound of Formula 2 with a functional group derivative of an acid of Formula 3 to obtain a compound of Formula 4,

2a) optionally, when E represents a protecting group, it is removed by the action of an acid or a base to give an alcohol of formula 4a (E = H),

3a) treating the alcohol of formula 4a (E = H) obtained in step 1a) or 2a) with a compound of formula 5 to give a compound of formula

4a) reacting a compound of Formula 6 with a compound of Formula 7,

5a) optionally, a process for the preparation of a compound of formula (I), salts thereof and solvates and / or hydrates thereof, characterized in that it is converted into one of its salts with inorganic or organic acids.

Y-SO ₂ -Cl

Where

Ar, R ₁ and X are as defined for the compound of formula I,

E represents hydrogen or an O-protecting group,

Y represents a methyl, phenyl, tolyl or trifluoromethyl group.

When E represents an O-protecting group, this group is selected from conventional O-protecting groups known to those skilled in the art, such as 2-tetrahydropyranyl, benzoyl or (C ₁ -C ₄ ) alkylcarbonyl.

In step 1a), the functional derivative of acid III used is one of the functional derivatives which react with the amine itself or alternatively, for example anhydrides, mixed anhydrides, acid chlorides or activated esters such as para-nitrophenyl esters.

When the acid of formula (3) is used, this method is a coupling agent used in peptide chemistry such as 1,3-dicyclohexylcarbodiimide or benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluor In an inert solvent such as dichloromethane or N, N-dimethylformamide in the presence of a base such as triethylamine or N, N-diisopropylethylamine in the presence of rophosphate, at a temperature of from 0 ° C. to room temperature do.

When acid chlorides are used, the reaction is carried out in an inert solvent such as dichloromethane or benzene at temperatures from -60 ° C. to room temperature in the presence of a base such as triethylamine or N-methylmorpholine.

The compound of formula 4 thus obtained is optionally deprotected in step 2a) according to methods known to those skilled in the art. For example, when E represents a 2-tetrahydropyranyl group, deprotection may be achieved by using hydrochloric acid in a solvent such as ether, methanol or a mixture of these solvents, or by using pyridinium p-toluenesulfonate in a solvent such as methanol. Or, alternatively, by acidic hydrolysis using Amberlyst® in a solvent such as methanol. The reaction is carried out at a temperature from room temperature to the reflux temperature of the solvent. When E represents a benzoyl group or a (C ₁ -C ₄ ) alkylcarbonyl group, the deprotection is carried out in water, methanol, ethanol, for example in alkaline media using alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide. In an inert solvent such as dioxane or a mixture of these solvents, by hydrolysis at a temperature between 0 ° C. and the reflux temperature of the solvent.

In step 3a), the reaction of an alcohol of formula 4a (E = H) with a sulfonyl chloride of formula 5 is carried out in the presence of a base such as triethylamine, pyridine, N, N-diisopropylethylamine or N-methylmorpholine. Under an inert solvent such as dichloromethane, benzene or toluene, it is carried out at a temperature of -20 ° C to the reflux temperature of the solvent.

The compound of formula 6 thus obtained is reacted with the compound of formula 7 in step 4a). This reaction is carried out in the presence or absence of a base in an inert solvent such as N, N-dimethylformamide, acetonitrile, methylene chloride, toluene or isopropanol. If a base is used, it is selected from organic bases such as triethylamine, N, N-diisopropylethylamine or N-methylmorpholine and from alkali metal carbonates or bicarbonates such as potassium carbonate, sodium carbonate or sodium bicarbonate. In the absence of a base, the reaction is carried out in the presence of an alkali metal iodide such as potassium iodide or sodium iodide using an excess of the compound of formula 7. This reaction is carried out at a temperature from room temperature to 100 ° C.

According to the modified method,

1b) this is carried out as in step 1a) and optionally step 2a),

2b) oxidizing the compound of formula 4a (E = H) thus obtained to prepare a compound of formula

3b) after reacting the compound of formula 8 with the compound of formula 7 in the presence of an acid, the intermediate iminium salt formed is reduced with a reducing agent,

4b) optionally, the compound thus obtained is converted into one of its salts with inorganic or organic acids.

According to a variant method, in step 2b), the alcohol of formula 4a (E = H) is oxidized to obtain an aldehyde of formula (8). The oxidation reaction is carried out at a temperature of -78 ° C to room temperature in a solvent such as dichloromethane, for example using oxalyl chloride, dimethyl sulfoxide and triethylamine.

In step 3b), the compound of formula 7 is then reacted with an aldehyde of formula 8 in an inert solvent such as methanol or dichloromethane in the presence of an acid such as acetic acid, for example sodium cyanoborohydride or sodium triacetoxyboro Intermediate imines are formed in situ that are chemically reduced using hydride or catalytically reduced using palladium on carbon or Raney® nickel catalysts.

Finally, a compound of formula I according to the invention is obtained.

The compounds of formula (I) thus obtained are separated in accordance with conventional techniques, either in free base form or in salt form.

When the compound of formula (I) is obtained in free base form, chloride is obtained by treatment with an acid selected from an organic solvent. For example, a free base dissolved in an ether such as diethyl ether or in an alcohol such as 2-propanol or in acetone or dichloromethane, or in ethyl acetate is treated with a solution of the selected acid in one of the above solvents. Corresponding salts are obtained which are separated accordingly.

Thus, for example, hydrochloride, hydrobromide, sulfate, hydrogen sulfate, dihydrogen phosphate, methanesulfonate, methyl sulfate, oxalate, malate, succinate, fumarate, 2-naphthalenesulfonate , Benzenesulfonate, para-toluenesulfonate or gluconate is prepared.

At the end of the reaction, the compound of formula (I) can be separated in the form of one of its salts, for example in the form of hydrochloride or oxalate, in which case, if necessary, the free base can be used as the inorganic or organic base. For example by neutralizing with sodium hydroxide or triethylamine or with alkali metal carbonates or bicarbonates such as sodium or potassium carbonates or bicarbonates.

The compound of formula 2 is prepared by known methods, in particular by the methods described in patent applications EP-A-0 512 901, EP-A-0 591 040 or EP-A-O 714 891.

Compounds of formula 3 are commercially available or prepared according to known methods.

Therefore, for example, the compound of formula 3 is prepared according to the following scheme 1.

Steps a1 and b1 of Scheme 1 are described in J. Am. Chem. Soc., 1941, 63 , 3280-3282.

In step c1 , esters of formula XII are prepared according to methods known to those skilled in the art from acids of formula XI.

The ester XII thus obtained is reduced to the alcohol of formula XIII in step d1 according to methods known to those skilled in the art.

Steps e1 and f1 are described in J. Med. Chem., 1973, 16 , 684-687.

The phenylacetonitrile derivatives of the formula (XV) thus obtained are described by the compounds of formula (3) in step g1 . Org. Chem., 1968, 33 , 4288 or EP-A-0 714 891.

Bromo derivatives of formula (IX) are known or described in J. Org. Chem., 1971, 36 (1), 193-196] or [J. Am. Chem. Soc., 1941, 63 , 3280-3282, according to known methods.

(여기에서 R₂는 기 -CR₃R₄CONR₅R₆임)를 나타내는 화학식 7의 화합물이 하기 반응식 2에 따라서 제조된다.X Go

A compound of formula 7 wherein R ₂ is the group —CR ₃ R ₄ CONR ₅ R ₆ is prepared according to Scheme 2 below.

In step a2 of Scheme 2, compound 1 is prepared in the presence of 2-hydroxyisobutyronitrile, with a ketone of formula XVI and Eur. J. Med. Chem., 1990, 25 , 609-615.

The nitrile derivative of formula (XVII) thus obtained is hydrolyzed according to methods known to the person skilled in the art in step b2 to give an acid derivative of formula (XVIII).

Acid XVIII is reacted in accordance with conventional methods of peptide coupling with the amine of formula XIX in step c2 to afford derivative XXI.

Alternatively, in step d2, the nitrile derivative of formula (XVII) is hydrolyzed according to known methods, the carboxamide derivatives of formula (XX) is obtained, which is in the optionally e2, de-protected according to the conventional method, R ₅ Compound VII is obtained, wherein R ₆ = H.

In step f2, in the presence a strong base a compound of formula XX, respectively, (C ₁ -C ₃₎ alkyl halide, or successively with two (C ₁ -C ₃₎ alkyl halide or formula Hal-R ₅ -R ₆ -Hal By reacting with a dihalide of according to conventional alkylation methods, each R ₅ represents (C ₁ -C ₃ ) alkyl halide and R ₆ = H, or R ₅ and R ₆ are each independently (C ₁ -C ₃₎ ) indicate that the alkyl or or R ₅ and R ₆ to produce a compound of formula XXI to form a heterocycle together with the nitrogen atom to which they are attached.

Compound XXI thus obtained is deprotected in step g2 according to known methods to give the desired compound VII.

(여기에서 R₂는 기 -CR₃R₄CONR₅R₆임)를 나타내는 화학식 7의 화합물은 하기 반응식 3에 따라서 제조된다.X Go

A compound of formula 7 wherein R ₂ is the group -CR ₃ R ₄ CONR ₅ R ₆ is prepared according to Scheme 3 below.

In step a3 of Scheme 3, each in linear form with Compound 2 at a temperature between 0 ° C. and room temperature in an inert solvent such as N, N-dimethylformamide or dichloromethane in the presence of a strong base such as sodium hydride or sodium amide _1- C ₄ ) alkyl halide, or a reaction according to the conventional alkylation process with a dihalide of the formula Hal (CH ₂ ) _m -Hal wherein m = 2 to 5 and Hal represents a halogen atom, R ₃ and R, respectively ₄ is each a linear (C ₁ -C ₄₎ compounds of the formula XXII to form a cycloalkyl (C ₃ -C ₆₎ alkyl or together represent, with the carbon atoms are bonded together is obtained.

The nitrile derivative XXII thus obtained is hydrolyzed in step b3 according to a method known to those skilled in the art to obtain a carboxamide derivative XXIII. Optionally, in step c3 , the pyridine ring is hydrogenated in the presence of a catalyst such as platinum oxide, according to known methods to give a compound of formula 7 wherein R ₅ and R ₆ = H.

In step d5 , after the alkylation reaction of the compound of formula XXIII according to the conventional method described above, R ₅ and / or R ₆ are not hydrogen by reduction by conventional catalytic hydrogenation of the compound XXIV thus obtained. Compounds of are obtained.

을 나타내는 화학식 7의 화합물이 하기 반응식 4에 따라서 또한 수득될 수 있다.X Go

Compounds of formula (7) can be obtained according to Scheme 4 below.

In step a4 of Scheme 4, EP-A-0 625 509 with a suitable organolithium or organomagnesium derivative of compound 3 such as methyllithium, ethylmagnesium chloride, propylmagnesium chloride or pentane-1,5-di (magnesium chloride) The reaction according to the described process affords an alcohol of formula XXV.

The alcohol XXV thus obtained is oxidized to the acid of formula XXVI according to the method described in Helvetica Chimica Acta, 1972, 55 , (7), 2439 in step b4 .

Acid XXVI is reacted in accordance with conventional methods of peptide coupling with the amine of formula XIX in step c4 to afford compound XXVII.

Compound XXVII is deprotected in step d4 according to known methods to give the desired compound VII.

Compound 3 is prepared by reacting ethyl isonipekotate with benzyl bromide in the presence of a base, according to conventional alkylation methods.

The compound of formula 7 is novel and forms part of the present invention.

Therefore, according to another aspect, the present invention relates to a compound of formula (7) and salts with inorganic or organic acids thereof.

<Formula 7>

Where

, 기

를 나타내고,-X is

, Flag

Indicates,

-R ₂ represents a group -CR ₃ R ₄ CONR ₅ R ₆ ,

R ₃ and R ₄ represent the same radicals selected from methyl, ethyl, n-propyl or n-butyl, or R ₃ and R ₄ together with the carbon atom to which they are attached form (C ₃ -C ₆ ) cycloalkyl Forming,

R ₅ and R ₆ independently represent hydrogen, (C ₁ -C ₃ ) alkyl, or alternatively R ₅ and R ₆ together with the nitrogen atom to which they are attached 1-azetidinyl, 1-P It forms a heterocyclic radical selected from rollidinyl, 1-piperidinyl, 4-morpholinyl, 4-thiomorpholinyl or perhydro-1-azinyl.

Dividing the racemic mixture of the compound of formula (I) can separate the enantiomers of formula (I ^*) and possible salts thereof with inorganic or organic acids, and solvates and / or hydrates thereof.

<Formula I ^* >

Where

"*" Means that the carbon atoms so labeled have the (S) or (R) absolute configuration determined,

X, Ar and R ₁ are as defined for compounds of formula (I).

However, as described in patent applications EP-A 0 512 901, EP-A-0 612 716 and EP-A-0 591 040, intermediates of formula 2 ^* (E = H) useful for preparing compounds of formula I From the compound, preference is given to performing the partitioning of the racemic mixture.

According to another aspect,

1d) treating the (S) isomer of the compound of formula 2 ^* (E = H) with a functional group derivative of the acid of formula 3 to obtain a compound of formula 4 ^* (E = H),

2d) oxidizing a compound of formula 4 ^* to give a compound of formula 8 ^*

3d) after reacting the compound of formula 8 ^{* with} the compound of formula 7 in the presence of an acid, the intermediate iminium salt formed is reduced with a reducing agent,

4d) optionally, preparing a compound of formula (I), a salt thereof and a solvate and / or hydrate thereof having the (S) configuration, characterized in that it is converted to one of its salts with inorganic or organic acids. It relates to a stereospecific method for.

<Formula 2 ^* >

<Formula 3>

<Formula 4 ^* >

<Formula 8 ^* >

<Formula 7>

Wherein Ar, R ₁ and X are as defined for compounds of formula (I).

The compounds of formula (I) also include those in which one or more hydrogen or carbon atoms have been replaced by their radioisotopes, such as titanium, or carbon-14. Such labeling compounds are useful as receptor ligands in biological tests in the study of metabolic or pharmacokinetics.

The compounds according to the invention have been subjected to biochemical tests.

The affinity of the compound for the tachykinin receptor was assessed in vitro by several biochemical tests using radioligands.

1) [ ¹²⁵ I] BH-SP (Substance P labeled with iodine-125 using Bolton-Hunter reagent) binding to human NK ₁ receptor of human lymphocytes (D. G. Fayan DG Payan et al., J. Immunol., 1984, 133 , 3260-3265.

2) Binding of [ ¹²⁵ I] His-NK ₄ to human NK ₂ cloned receptor expressed by CHO cells (Y. Takeda et al., J. Neurochem., 1992, 59 , 740-745].

3) Binding of the [ ¹²⁵ I] His [MePhe ⁷ ] NK _B to the NK ₃ receptor of the rat cerebral cortex, guinea pig cerebral cortex and gerbils cerebral cortex, and human NK ₃ cloned receptor expressed by CHO cells (Buell et al., FEBS Letters, 1992, 299 , 90-95).

Exam X. Emonds-Alt et al., Eur. J. Pharmacol., 1993, 250 , 403-413, Life Sci., 1995, 56 , PL 27-32.

The compound according to the invention strongly inhibits the binding of substance P to the NK ₁ receptor of human IM9 lymphocytes. The inhibitory constant Ki for human lymphocyte cell receptor is on the order of 10 ⁻¹¹ M.

The inhibition constant Ki for human NK ₂ cloned receptor is on the order of 10 ⁻⁸ and the inhibition constant Ki for human NK ₃ cloned receptor is greater than 10 ⁻⁷ M.

Compounds of formula (I) are strongly selective antagonists of substance P to human NK ₁ receptor.

Therefore, compounds of formula I have also been evaluated in vivo in animal models.

Topical application of an agent specific to the NK ₁ receptor, such as [Sar ⁹ , Met (O ₂ ) ¹¹ ] substance P, to guinea pig striatum enhances the secretion of acetylcholine. Such secretion is inhibited by oral or intraperitoneal administration of the compounds according to the invention. This test is al. By R. Steinberg et al. Neurochemistry, 1995, 65 , 2543-2548.

These results show that the compounds of formula (I) are orally active, which can cross the blood transfusion gateway and block the action specific for the NK ₁ receptor in the central nervous system.

The compound of formula (I) is x. It was evaluated in the bronchial stenosis test of guinea pigs according to the method described by Emonz-Alt et al. In the European Journal of Pharmacology, 1993, 250 , 403-413. Intravenously administered compounds of formula (I) strongly antagonize bronchial stenosis induced by intravenous administration of septide to guinea pigs under these experimental conditions.

In vivo pharmacological activity of the compounds of formula (I) is X. Emons-Alt et al., Eur. J. Pharmacol., 1993, 250 , 403-413, according to the method described in the hypotensive model of dogs. Intravenously administered compounds of formula (I) strongly inhibit hypotension induced by intravenous administration of [Sar ⁹ , Met (O ₂ ) ¹¹ ] substance P to anesthetized dogs under these experimental conditions.

These results show that compounds of formula I block the action specific for the NK ₁ receptor in the peripheral nervous system.

The compounds of the invention are, in particular, the active ingredients of pharmaceutical compositions whose toxicity is compatible with their use as a medicament.

The compound of formula I may be used in an amount of 0.01 to 100 mg, preferably 0.1 to 50 mg / kg, per kg of body weight of the mammal to be treated per day. In humans, the dosage may preferably range from 0.1 to 4000 mg, more particularly 0.5 to 1000 mg per day, depending on the age or type of treatment of the individual being treated: prophylaxis or treatment.

For their use as medicaments, the compounds of formula (I) are generally administered in dosage units. The dosage unit is preferably formulated in the form of a pharmaceutical composition in which the active ingredient is mixed with one or more pharmaceutical excipients.

Therefore, according to another aspect, the present invention relates to a pharmaceutical composition containing as an active ingredient a compound of formula (I) or a pharmaceutically acceptable salt, solvate and / or hydrate thereof.

In the pharmaceutical compositions of the present invention for oral, sublingual, inhalation, subcutaneous, intramuscular, intravenous, transdermal, topical or rectal administration, the active ingredient is administered to the animal or human in the form of a unit of administration mixed with a conventional pharmaceutical support. May be administered. Suitable unit forms of administration are oral-path forms such as tablets, gel capsules, powders, granules and oral solutions or suspensions, sublingual and oral dosage forms, aerosols, topical dosage forms, implants, subcutaneous, intramuscular, intravenous, intranasal Or intraocular and rectal dosage forms.

When solid preparations are prepared in the form of tablets or gel capsules, diluents such as lactose, microcrystalline cellulose, starch, dicalcium phosphate, binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose, disintegrants such as crosslinks Pharmaceuticals that may consist of polyvinylpyrrolidone, crosslinked carboxymethyl-cellulose, flow agents such as silica or talc, and lubricants such as magnesium stearate, stearic acid, glyceryl tribehenate or sodium stearyl fumarate A mixture of excipients is added to the micronized or non-micronized active ingredient.

Wetting agents or surfactants such as sodium lauryl sulfate, polysorbate 80 or poloxamer 188 may be added to the formulation.

Tablets can be prepared by a variety of techniques, direct tableting, dry granulation, wet granulation, heat-melting.

Tablets may be uncoated, sugar-coated (eg with sugar) or coated with various polymers or other suitable materials.

Tablets can be rapidly released, delayed release or sustained release by preparing a polymer matrix or using certain filmed polymers.

Gel capsules may be soft or hard and may be coated with a film or the like to have rapid, sustained release or delayed activity (eg, by enteric skin form).

They are not only solid formulated as described above for tablets, but can also be liquid or semi-solid formulations.

Formulations in syrup or elixir form may contain, together with the active ingredient, a sweetening agent, preferably a calorie-free sweetener, methyl parabens and propyl parabens and flavoring agents as preservatives and suitable colorants.

Water-dispersible powders or granules may contain the active ingredient as a mixture of a dispersing, wetting or suspending agent such as polyvinylpyrrolidone with a sweetening or flavoring enhancer.

For rectal administration, suppositories prepared with binders which melt at rectal temperature, for example cocoa butter or polyethylene glycol, are used.

Pharmacologically compatible dispersing and / or dissolving agents such as aqueous suspensions, isotonic saline solutions or sterile, injectable solutions containing propylene glycol are used for nasal, intranasal or intraocular administration.

Therefore, to prepare aqueous solutions that can be injected intravenously, cosolvents such as alcohols such as ethanol or glycols such as polyethylene glycol or propylene glycol, and hydrophilic surfactants such as polysorbate 80 or poloxamer 188 are used. Can be. To prepare an injectable oily solution for intramuscular administration, the active ingredient may be dissolved in triglycerides or glycerol esters.

Creams, ointments, gels, eye drops and sprays may be used for topical administration.

Patches and sprays in the form of multilayers or reservoirs in which the active ingredient may be present in the alcohol solution may be used for transdermal administration.

For example, administration by inhalation of an aerosol containing sorbitan trioleate or oleic acid with trichlorofluoromethane, dichlorofluoromethane, dichlorotetrafluoroethane, freon substitutes or any other biologically compatible propellant gas Powder form systems may also be used, containing only the active ingredient or together with excipients.

The active ingredient can also be used in the form of a complex with a cyclodextrin, for example α-, β- or γ-cyclodextrin or 2-hydroxypropyl-β-cyclodextrin.

The active ingredient may also be formulated in the form of microcapsules or microspheres, optionally with one or more supports or additives.

Among the sustained release forms useful in the case of chronic treatment, implants can be used. They can be prepared in the form of oily suspensions or in the form of microsphere suspensions in an isotonic medium.

In each dosage unit, the active ingredient of formula I is present in an amount suitable for the expected daily dosage. In general, each dosage unit has a dosage unit of 0.1 to 1000 mg, preferably depending on the expected dosage and the dosage form, for example, of a small pouch, ampule, syrup, or the like, such as tablets, gel capsules, or drops. Is suitably adjusted to contain 0.5 to 250 mg of active ingredient, which should be administered 1 to 4 times a day.

These dosages are examples of average situations, and there may be special cases where lower or higher dosages are appropriate, which dosages also form part of the present invention. According to conventional practice, the dosage appropriate for each patient is determined by the physician depending on the mode of administration, the age, weight and response of the patient.

According to another aspect, the invention provides a medicament for the treatment of any disease involving substance P and human NK ₁ receptor, either of a compound of formula (I), or a pharmaceutically acceptable salt, solvate and / or hydrate thereof. It relates to a use for manufacturing.

According to another aspect, the invention relates to a disease of the respiratory, gastrointestinal, urinary, immune or cardiovascular and central nervous system of a compound of formula (I), or a pharmaceutically acceptable salt, solvate and / or hydrate thereof. And for use in the manufacture of a medicament for the treatment of pain, migraine, inflammation, nausea and vomiting, and skin disease.

By way of example and not by way of limitation, the compounds of formula (I) are useful below.

Especially traumatic pains such as postoperative pain, neuralgia of the brachial plexus, chronic pain such as arthritis pain caused by osteoarthritis, rheumatoid arthritis or psoriatic arthritis, neuropathic pain such as post-herpetic neuralgia, trigeminal neuralgia, segmental or intercostal neuralgia , Fibroids, burning pain, peripheral neuropathy, diabetic neuropathy, chemotherapy-induced neuropathy, AIDS-related neuropathy, laryngeal neuralgia, facial neuralgia or Yeti neuralgia, mesmerizing pain in amputated patients, various forms of headache, such as chronic or acute Migraine, Temporomandibular pain, Maxillary sinus pain, Facial neuralgia or toothache, Pain in cancer patients, Pain from internal organs, Gastrointestinal pain, Pain caused by nerve compression, Pain caused by strong sports activity, Dysmenorrhea, Menstrual pain Pain caused by meningitis or meningitis, musculoskeletal pain, spinal stenosis, prolapsed disc or left As an analgesic in the treatment of lower back pain caused by bone pain, anguish or pain suffered by ankylosing spondylitis, pain caused by ankylosing spondylitis, pain associated with gout, pain associated with burns, scars or benign skin disease, and thalamic pain ,

-Especially in asthma, influenza, chronic bronchitis (especially obstructive chronic bronchitis and COPD (chronic obstructive pulmonary artery disease)), cough, allergy, bronchial spasms and inflammation of the rheumatoid arthritis, inflammatory diseases of the stomach, for example Crohn's disease, ulcerative Colitis, pancreatitis, gastritis, enteritis, inflammatory and secretory consequences caused by disorders caused by non-steroidal anti-inflammatory agents, such as bacterial infections with Clostridium difficile , inflammatory skin diseases, For example as anti-inflammatory agents for the treatment of herpes and eczema, inflammatory bladder diseases such as cystitis and urinary incontinence, eye inflammation such as conjunctivitis and vitreoretinopathy, tooth inflammation such as gingivitis and fasciitis

Especially in the treatment of allergic diseases of the skin, such as damp, contact dermatitis, atopic dermatitis and respiratory diseases such as rhinitis,

Diseases of the central nervous system, in particular psychosis such as schizophrenia, manic and dementia, cognitive disorders such as Alzheimer's disease, anxiety, AIDS-related dementia, diabetic neuropathy, depression, Parkinson's disease, drug dependence, substance abuse, conscious disorder, sleep Disorders, 24-hour rhythm disorders, mood disorders and epilepsy, Down syndrome, Huntington's chorea, stress-related physical disorders, neuropathic diseases such as Peak disease or Creutzfeldt-Jakob syndrome, panic, phobia or stress related disorders ,

In the treatment of inflammatory and autoimmune processes of the central nervous system, for example permeable modifications of blood transfusion gateways during AIDS-related infections,

-Muscle relaxants and antispasmodics,

Radiation therapy during irradiation of the rib cage or abdomen in the treatment of cancer or carcinoidosis, with acute or delayed anticipated nausea and vomiting, eg, drugs used in chemotherapy in the case of cancer During vestibular disorders, such as travel sickness, dizziness or Ménière's disease, during pregnancy, by poisons caused by ingestion of poisons, caused by metabolic or infection disorders such as gastritis, or produced during bacterial or viral gastrointestinal infections With morphine, during migraine, at high severity, during visceral pain caused by myocardial infarction or peritonitis, by gastrointestinal obstruction, by gastrointestinal obstruction, induced by dialysis or prostaglandins, during postoperative disease. Gastric acidity or bitterness, reflux, and gastric acid during gastric-esophageal reflux, or when overeating food or drink, by ingestion of the same opiate analgesic Acids, for example, transient or in the treatment of nausea and vomiting during the night acid reflux or meal and dyspepsia induced by the reverse flow of gastric acid,

In the treatment of gastrointestinal diseases, such as irritable bowel syndrome, gastric ulcer and duodenal ulcer, esophageal ulcer, diarrhea, hypersecretion, lymphoma, gastritis, gastro-esophageal reflux, loss of money, hirsprung disease and food allergy,

In the treatment of skin diseases such as psoriasis, pruritus and burns, in particular sunlight burns,

In the treatment of cardiovascular diseases such as hypertension, vascular appearance of migraine, edema, thrombosis, angina pectoris, vasospasm, circulatory disease caused by vasodilation, Raynaud's disease, fibrosis, collagen disease and atherosclerosis,

-For the treatment of small cell lung cancer, brain tumors and adenocarcinoma of the genital tract,

In the treatment of demyelinating diseases such as multiple sclerosis or amyotrophic lateral sclerosis,

In the treatment of immune system diseases associated with suppression or stimulation of immune cells, for example rheumatoid arthritis, psoriasis, Crohn's disease, diabetes, lupus and post-transplant rejection

-In the treatment of urination disorders, especially urinary bins,

-For example in the treatment of histiocytosis of lymphoid tissue,

As anorexia triggers,

-For the treatment of emphysema, lighter disease, hemorrhoids,

In the treatment of eye diseases such as glaucoma, ocular hypertension, motility and excessive tear secretion,

For the treatment or prevention of cerebral ischemic lesions caused by interstitial seizures, cranial damage, spinal cord injury, vascular attacks or occlusion,

Especially in the treatment of heart rate and heart rate disorders caused by pain or stress,

-For the treatment of sensitive skin and for the prevention or fight against irritation, dandruff, erythema or pruritus of the skin or mucous membranes,

In the treatment of neurological skin disorders such as lichens of the neurological cause, amnesia, positive poisoning and severe pruritus,

For the treatment of all diseases caused by ulcers and Helicobacter pylori or urease-positive Gram-negative bacteria,

In the treatment of diseases caused by angiogenesis or symptomatic of angiogenesis,

In the treatment of eye and / or eyelid pain and / or eye or eyelid sensitisation,

As an antiperspirant.

The invention also includes a method of treating said condition at a dosage as described above.

The pharmaceutical compositions according to the invention may also contain other active products useful for treating diseases or disorders as described above, such as bronchodilators, antitussives, antihistamines, anti-inflammatory agents, anti-emollients and chemotherapeutic agents, and the like. have.

The following abbreviations are used in the Preparations and Examples.

DMF: Dimethylformamide

DMSO: Dimethyl Sulfoxide

DCM: Dichloromethane

THF: tetrahydrofuran

Ether: diethyl ether

Hydrochloric ether: saturated solution of hydrochloric acid in diethyl ether

BOP: Benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate

m.p .: melting point

b.p .: boiling point

RT: room temperature

Silica H: 60H silica gel sold by Merck, Darmstadt.

Quantum nuclear magnetic resonance ( ¹ H NMR) spectra are recorded at 200 MHz in DMSO-d ₆ using the DMSO-d ₆ peak as a standard. Chemical shifts δ are reported in parts per million (ppm). The observation signal is expressed as follows; s: single, bs: wide single, t: triple, q: quadruple, m: multiple.

<Example>

Preparation Example 1.1

3- (3,4-dichlorophenyl) -3- (2-hydroxyethyl) piperidine, the (-) isomer,

Chemical formula

The preparation of this compound is described in patent application EP-A 0 591 040.

Preparation Example 1.2

3- (3,4-dimethylphenyl) -3- [2- (2-tetrahydropyranyloxy) ethyl] piperidine

Chemical formula

A) 2- (3,4-dimethylphenyl) -4- (2-tetrahydropyranyloxy) butanenitrile

6.6 g of 60% sodium hydride in oil was added in portions to a solution of 20 g of 3,4-dimethylphenylacetonitrile in 100 ml of dry THF at RT and the mixture was left stirring at RT for 2 h. 29 g of 1-bromo-2- (2-tetrahydropyranyloxy) ethane was added dropwise and the mixture was left stirring at RT for 2 days. The reaction mixture was poured onto ice and extracted with EtOAc, the organic phase was washed with water and with saturated NaCl solution, dried over Na ₂ SO ₄ and the solvent was evaporated in vacuo. The residue was subjected to silica gel chromatography eluting with toluene followed by a gradient of toluene / EtOAc mixtures from (99/1, v / v) to (90/10, v / v).

17 g of the desired product were obtained.

B) Methyl 4-cyano-4- (3,4-dimethylphenyl) -6- (2-tetrahydropyranyloxy) hexanoate

0.3 ml of a 40% solution of benzyltrimethylammonium hydroxide (Triton B) in MeOH is added to a mixture of 17 g of compound obtained in the above step and 11 ml of methyl acrylate in 30 ml of dioxane and the mixture Was left stirring at RT for 48 h. The reaction mixture was concentrated in vacuo, the residue was dissolved in 0.5N HCl aqueous solution and extracted with ether, the organic phase was washed with 10% Na ₂ CO ₃ aqueous solution, dried over Na ₂ SO ₄ and the solvent was evaporated in vacuo. . 23 g of the desired product were obtained.

C) 5- (3,4-dimethylphenyl) -5- [2- (2-tetrahydropyranyloxy) ethyl] -2-piperidone

40 ml of 20% aqueous ammonia solution was added to a solution of 23 g of compound obtained in the above step in 250 ml of 95% EtOH, followed by Raney® nickel. This mixture was then hydrogenated at 40 ° C. and 16 bar pressure for 24 hours. The catalyst was filtered through Celite (R) and the filtrate was concentrated in vacuo. 22 g of the desired product were obtained.

D) 3- (3,4-dimethylphenyl) -3- [2- (2-tetrahydropyranyloxy) ethyl] piperidine

22 g of the compound obtained in the above step was added to a suspension of 10 g of lithium aluminum hydride in 200 ml of THF and then refluxed for 2 hours. After cooling to RT, 10 ml of water and 80 ml of THF were added, followed by 10 ml of 4N NaOH and 30 ml of water. The inorganic salt was filtered through Celite (R) and the filtrate was concentrated in vacuo. 15 g of the desired product were obtained.

Preparation Example 2.1

3,5-dichlorophenylacetic acid.

Formula 3: R ₁ = Cl.

A) 3,5-dichlorobenzyl chloride.

A solution of 12.5 g of thionyl chloride in 20 ml of chloroform was added dropwise to a solution of 14.5 g of 3,5-dichlorobenzyl alcohol in 150 ml of chloroform, then heated at 40-50 ° C. for 8 hours and then RT Stir overnight at. The mixture was concentrated in vacuo to afford 16 g of the desired product which was used without further processing.

B) 3,5-dichlorophenylacetonitrile

A solution of 6.5 g potassium cyanide in 50 ml of water was added to a solution of 16 g of compound obtained in the above step in 50 ml of EtOH and the mixture was refluxed for 4 hours. The resulting mixture was concentrated in vacuo, the residue was dissolved in water and extracted with ether, the organic phase was washed with water and dried over Na ₂ SO ₄ and the solvent was evaporated in vacuo. The residue was chromatographed on silica H, eluting with a heptane / toluene mixture (50/50) and then with toluene. 7 g of the desired product were obtained and used without further processing.

C) 3,5-dichlorophenylacetic acid

A solution of 8.4 g KOH in 10 ml of water was added to a solution of 7 g of compound obtained in the above step in 50 ml of EtOH, followed by reflux for 5 hours. The mixture was concentrated in vacuo, the residue dissolved in water and the aqueous phase washed with ether and acidified to pH = 1 by addition of concentrated HCl and left to stir overnight at RT. The crystalline product formed was spin-dried, washed with water and vacuum dried at 60 ° C. 7 g of the desired product were obtained, m. P. = 112-114.5 ° C.

Preparation Example 2.2

3,5-diethylphenylacetic acid

Formula 3: R ₁ = Et.

A) 3,5-diethylbromobenzene.

A mixture of 20 g of 4-bromo-2,6-diethylaniline, 160 ml of acetic acid, 100 ml of concentrated HCl solution, 30 ml of water and 100 ml of EtOH was cooled to -5 ° C and 6.6 g of sodium in 25 ml of water A solution of nitrate was added dropwise and the mixture was left stirring at RT for 30 minutes. The reaction mixture was poured into 170 ml of 50% H ₃ PO ₂ cooled to 0 ° C. and left to stir at 0 ° C. for 2 hours and then at RT for 48 hours. The reaction mixture was extracted with ether, the organic phase was washed with water, 1N NaOH solution, with water and dried over Na ₂ SO ₄ and the solvent was evaporated in vacuo. The residue was subjected to silica gel chromatography eluting with cyclohexane to afford 18 g of the desired product.

B) 3,5-diethylbenzonitrile

A mixture of 24.7 g of compound and 12 g of copper cyanide obtained in the above step in 70 ml of DMF was refluxed for 15 hours. After cooling to RT, the reaction mixture was poured into 50 ml of water and left to stir until a gum formed at RT. The mixture was cooled in an ice bath and 150 ml of ethylenediamine were added and the mixture was left stirring at RT for 2 hours. The mixture was extracted with EtOAc, the organic phase was washed with water, dried over Na ₂ SO ₄ and the solvent was evaporated in vacuo. The residue was subjected to silica gel chromatography eluting with a cyclohexane / EtOAc mixture (95/5, v / v). 12 g of the desired product were obtained.

C) 3,5-diethylbenzoic acid.

A solution of 22 g of KOH in 15 ml of water was added to a solution of 12 g of compound obtained in the above step in 60 ml of EtOH and then refluxed for 24 hours. The reaction mixture was concentrated in vacuo, the residue was extracted with water, the aqueous phase washed with ether and acidified to pH = 2 by addition of concentrated HCl, and the formed precipitate was spin-dried, washed with water and vacuum dried. 13 g of the desired product were obtained.

D) methyl 3,5-diethylbenzoate.

The mixture of 13 g obtained in the above step in 90 ml of MeOH and 10 drops of H ₂ SO ₄ was refluxed for 48 hours. The reaction mixture is concentrated in vacuo, the residue is dissolved in water, neutralized by addition of 10% NaHCO ₃ solution and extracted with ether, the organic phase is washed with water, 10% NaHCO ₃ solution, dried over Na ₂ SO ₄ The solvent was evaporated in vacuo. 12 g of the desired product were obtained.

E) 3,5-diethylbenzyl alcohol.

A suspension of 2.5 g lithium aluminum hydride in 50 ml of THF was cooled to 0 ° C., a solution of 12 g of compound obtained in the above step in 50 ml of THF was added dropwise and the mixture was left stirring with 30 minutes. The reaction mixture was hydrolyzed by addition of 2.5 ml water, 2.5 ml 4N NaOH and 7.5 ml water. The inorganic salts were filtered off and the filtrate was concentrated in vacuo. 10.9 g of the desired product were obtained, which was used without further processing.

 F) 3,5-diethylbenzyl methanesulfonate.

A solution of 8.4 g methanesulfonyl chloride in 50 ml of DCM was added dropwise to a solution of 10.9 g of compound and 7.4 g of triethylamine obtained in the above step in 100 ml of DCM at RT and the mixture was left to stir for 30 minutes. . The reaction mixture was concentrated in vacuo, the residue was dissolved in water and extracted with ether, the organic phase was washed with water and dried over Na ₂ SO ₄ and the solvent was evaporated in vacuo. 16 g of the desired product were obtained and used without further processing.

G) 3,5-diethylphenylacetonitrile.

A solution of 5.15 g potassium cyanide in 20 ml of water was added to a solution of 16 g of compound obtained in the above step in 100 ml of DMF and the mixture was heated at 80 ° C. for 1 hour. The reaction mixture was concentrated in vacuo, the residue was dissolved in water and extracted with ether, the organic phase was washed with water and dried over Na ₂ S0 ₄ and the solvent was evaporated in vacuo. The residue was subjected to silica H gel chromatography eluting with DCM. 3 g of the desired product were obtained.

H) 3,5-diethylphenylacetic acid.

A solution of 7.8 g KOH in 10 ml of water was added to a solution of 3 g of compound obtained in the above step in 50 ml of EtOH and then refluxed for 5 hours. The mixture was concentrated in vacuo, the residue dissolved in water and the aqueous phase washed with ether, acidified to pH = 1 by addition of concentrated HCl and left to stir overnight at RT. The crystalline product formed was spin-dried, washed with water and vacuum dried. 2.5 g of the desired product were obtained.

¹ H NMR: δ (ppm): 1.1: t: 6H, 2.4: q: 4H, 3.4: s: 2H, 6.8: m: 3H, 12.2: bs: 1H.

Preparation Example 3.1

2- (4-piperidyl) isobutyramide hydrochloride.

Formula 7, HCl:

A) 2-methyl-2- (4-pyridyl) propionitrile.

The mixture of 3 g 4-pyridylacetonitrile hydrochloride in 50 ml of DMF was cooled to 0 ° C., 2.6 g of 60% sodium hydride in oil was added in portions and the mixture was left stirring at RT for 2 h. The reaction mixture was cooled in an ice bath, 6 g of methyl iodide was added dropwise and the mixture was left stirring at RT overnight. The reaction mixture was poured onto a water / ice mixture and extracted with ether, the organic phase was washed with saturated NaCl solution, dried over MgSO ₄ , filtered and the solvent was evaporated in vacuo. The residue was eluted with DCM and then silica H gel chromatography eluting with a DCM / MeOH mixture (98/2, v / v). 2.39 g of the desired product were obtained in the form of an oily phase which crystallized.

B) 2- (4-pyridyl) isobutyramide hydrochloride.

A mixture of 2.39 g of compound and 10 ml of concentrated H ₂ SO ₄ solution obtained in the above step was heated at 100 ° C. for 15 minutes. The reaction mixture is cooled to RT, 50 g of ice is added and the mixture is basified to pH = 14 by addition of concentrated NaOH solution, the inorganic salts are filtered off, the filtrate is extracted with EtOAc and extracted with DCM, combined The organic phase was dried over MgSO ₄ , filtered and the solvent was evaporated in vacuo (mp = 134 ° C., base). The obtained product was dissolved in acetone and acidified to pH = 1 by addition of hydrochloric ether, and the precipitate formed was spin-dried. 2.9 g of the desired product were obtained.

C) 2- (4-piperidyl) isobutyramide hydrochloride.

The mixture of 2.9 g of compound, 1 g of PtO ₂ and 50 ml of MeOH obtained in the above step was hydrogenated at 60 ° C. under a pressure of 60 bar for 3 days. The catalyst was filtered through Celite (R), washed with MeOH and the filtrate was concentrated in vacuo. The quench was dissolved in acetonitrile and the precipitate formed was spin-dried, washed with acetonitrile and then with ether. 2.5 g of the desired product were obtained, mp> 260 ° C.

Preparation Example 3.2

2- (1-piperazinyl) isobutyramide dihydrochloride.

Formula 7, 2HCl:

A) 2- (4-benzyl-1-piperazinyl) -2-methylpropionitrile.

4.5 ml of acetone, 20 g of anhydrous MgSO ₄ , 10 g of N, N-dimethylacetamide, 10 g of 1-benzylpiperazine and 9.5 ml of 2-hydroxyisobutyronitrile are mixed together and for 48 hours at 45 ° C. Heated with vigorous stirring. The reaction mixture was poured onto ice and left to stir for 30 minutes. The mixture was extracted with ether, the organic phase was washed several times with water and dried over Na ₂ SO ₄ and the solvent was evaporated in vacuo. 13 g of the desired product were obtained.

B) 2- (4-benzyl-1-piperazinyl) isobutyramide dihydrochloride.

The mixture of 13 g of compound and 130 ml of 90% H ₂ SO ₄ solution obtained in this step was heated rapidly at 110 ° C. for 30 minutes. After cooling to RT, the reaction mixture was poured onto ice and basified to pH = 10 by addition of concentrated NH ₄ OH solution and the crystalline product formed was spin-dried. This product was dissolved in DCM, the organic phase was dried over MgSO ₄ and the solvent was evaporated in vacuo. The product was dissolved in hydrochloric ether and the precipitate formed was spin-dried. 9.5 g of the desired product were obtained.

C) 2- (1-piperazinyl) isobutyramide dihydrochloride.

A mixture of 1.3 g of compound and 0.18 g of 10% palladium on carbon obtained in the above step in 30 ml of 95% EtOH was hydrogenated overnight at RT and atmospheric pressure. The catalyst was filtered through Celite® and the filtrate was concentrated in vacuo. 0.6 g of the desired product were obtained.

Preparation Example 3.3

1- (1-piperazinyl) cyclohexanecarboxamide dihydrochloride

Formula (VII), 2HCl: X =

A) 1- (4-benzyl-1-piperazinyl) cyclohexanecarbonitrile.

5.7 g cyclohexanone, 20 g anhydrous MgSO ₄ , 10 g N, N-dimethylacetamide, 10 g 1-benzylpiperazine and 9.5 ml 2-hydroxyisobutyronitrile were mixed together and 48 at 45 ° C. Heated with vigorous stirring for hours. The reaction mixture was poured onto ice and left to stir for 30 minutes. The mixture was extracted with ether, the organic phase was washed several times with water and dried over Na ₂ SO ₄ , and the solvent was evaporated in vacuo. 15 g of the desired product were obtained.

B) 1- (4-benzyl-1-piperazinyl) cyclohexanecarboxamide dihydrochloride.

This compound was obtained starting from 15 g of the compound obtained in the above step and 50 ml of 90% H ₂ SO ₄ solution according to the method described in Step B of Preparation Example 3.2. 5.5 g of the desired product were obtained.

C) 1- (1-piperazinyl) cyclohexanecarboxamide dihydrochloride.

This compound was obtained starting from 2.3 g of the compound obtained in the above step in 30 ml of 95% EtOH and 0.3 g of 10% palladium on carbon according to the method described in step C of Preparation Example 3.2. 1.6 g of the desired product were obtained.

Preparation Example 3.4

N, N-dimethyl-2- (1-piperazinyl) isobutyramide diformate.

Formula 7, 2HCO ₂ H:

A) N, N-dimethyl-2- (4-benzyl-1-piperazinyl) isobutyramide.

1.44 g of 60% sodium hydride in oil was added in portions to a mixture of 2.6 g of compound (free base) obtained in step B of Preparation Example 3.2 in 50 ml of dry THF. 1.3 ml of methyl iodide was added dropwise and the mixture was left stirring at RT for 4 h. The reaction mixture was poured into water and extracted with ether, the organic phase was dried over MgSO ₄ and the solvent was evaporated in vacuo. 1.8 g of the desired product were obtained.

B) N, N-dimethyl-2- (1-piperazinyl) isobutyramide diformate.

2 g of ammonium formate and 0.5 g of 5% palladium on carbon were added to a solution of 1.8 g of compound obtained in the above step in 30 ml of MeOH and the mixture was left stirring at RT for 4 h. The catalyst was filtered through Celite (R) and the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc and the precipitate formed was spin-dried, washed with EtOAc and dried. 1.2 g of the desired product were obtained.

Preparation Example 3.5

1- (4-piperidyl) cyclohexanecarboxamide hydrochloride.

Formula 7, HCl: X =

A) 1- (4-pyridyl) cyclohexanecarbonitrile.

The mixture of 3 g 4-pyridylacetonitrile hydrochloride in 50 ml of DMF was cooled to 0 ° C., 2.6 g of 60% sodium hydride in oil was added in portions and the mixture was left stirring at RT for 1 h 30 min. The reaction mixture was cooled on an ice bath, 2.7 ml of 1,5-dibromopentane was added dropwise and the mixture was left stirring at RT for 48 hours. The reaction mixture was poured into saturated NH ₄ Cl solution and extracted with ether, the organic phase was washed three times with water, dried over MgSO ₄ and the solvent was evaporated in vacuo. The residue was subjected to silica H gel chromatography eluting with DCM and then with DCM / MeOH mixture (98/2, v / v). 2.5 g of the desired product were obtained, mp = 79 ° C.

B) 1- (4-pyridyl) cyclohexanecarboxamide hydrochloride.

The mixture of 2.5 g of compound and 15 ml of concentrated H ₂ SO ₄ solution obtained in the above step was heated at 100 ° C. for 15 minutes. The reaction mixture was cooled to RT, poured onto ice and basified to pH = 14 by addition of concentrated NaOH solution, the precipitate formed was spin-dried, washed with water and dried. The obtained product was dissolved in acetone and acidified to pH = 1 by addition of hydrochloric ether, left to stir at RT for 30 minutes, and the precipitate formed was spin-dried. 3 g of the desired product were obtained, mp = 224 ° C. (decomposition).

C) 1- (4-piperidyl) cyclohexanecarboxamide hydrochloride.

A mixture of 2.9 g of compound, 0.5 g of PtO ₂ and 50 ml of MeOH obtained in this step was hydrogenated at 60 ° C. and 80 bar at 3 days. The catalyst was filtered through Celite (R) and the filtrate was concentrated in vacuo. The residue was dissolved in acetonitrile and left to stir for 1 hour at RT and the precipitate formed was spin-dried. 2.7 g of the desired product were obtained, mp = 235 ° C.

Preparation Example 3.6

N, N-dimethyl-2- (4-piperidyl) isobutyramide hydrochloride.

Formula 7, HCl:

A) ethyl 1-benzyl-4-piperidinecarboxylate.

30 g of benzyl bromide was added dropwise to a mixture of 25 g of ethyl isonipetate and 25 g of K ₂ CO ₃ in 125 ml of DMF, maintaining the temperature of the reaction mixture at 25 to 30 ° C., and the resulting mixture was stirred at RT for 1 hour. Was stirred. The reaction mixture was poured into 1 liter of ice cold water and extracted twice with ether, the organic phase was washed with water and dried over MgSO ₄ and the solvent was evaporated in vacuo. The resulting oil was distilled off under reduced pressure. 29.2 g of the desired product were obtained, bp = 120-122 ° C. (at 2.7 Pa).

B) 2- (1-benzyl-4-piperidyl) -2-propanol.

A solution of 24.73 g of the compound obtained in the above step in 100 ml of benzene was added dropwise under an argon atmosphere to 200 ml of a 1.5 M solution of methyllithium as a complex with lithium bromide in ether while maintaining the temperature of the medium at 25 to 30 ° C. Then, refluxed for 48 hours. The reaction mixture was cooled to RT and then poured into 400 ml of saturated NH ₄ Cl solution in water, previously cooled on an ice bath. The mixture was washed three times with ether, the combined organic phases were dried over MgSO ₄ and the solvent was concentrated in vacuo. The residue was dissolved in 100 ml of acetone, cooled to 10 ° C., acidified to pH = 1 by addition of hydrochloric ether, spin-dried the formed precipitate and washed with acetone / ether mixture (50/50, v / v) did. 24.5 g of the desired product were obtained in the form of hydrochloride, mp = 204 ° C. To liberate the base, hydrochloride was dissolved in concentrated NaOH solution, extracted with ether, dried over MgSO ₄ and the solvent was evaporated in vacuo. 21 g of the desired product were obtained, mp = 66 ° C.

C) 2- (1-benzyl-4-piperidyl) -2-methylpropionic acid.

A mixture of 4.42 g of fuming sulfuric acid containing 5.98 g of 95% sulfuric acid and 30% SO ₃ was cooled to 3 ° C. and a solution of 2 g of compound wool obtained in the above step in 1.55 g of 100% formic acid was heated to temperature. It was added dropwise keeping at 10 ° C. or lower. The mixture was left to stir at 3-5 ° C. for 2 hours, then returned to RT and left at RT overnight. The reaction mixture was poured onto ice, the pH was adjusted to 6.5 and extracted three times with DCM by addition of concentrated NaOH solution and concentrated NH ₄ OH solution, the combined organic phases were dried over MgSO ₄ and the solvent was evaporated in vacuo. . The residue was dissolved in acetone and the precipitate was spin-dried and dried. 1.22 g of the desired product were obtained, mp = 195 ° C.

D) N, N-dimethyl-2- (1-benzyl-4-piperidyl) isobutyramide hydrochloride.

A mixture of 1.2 g of the compound obtained in the above step in 20 ml of DCM, 0.8 ml of triethylamine, 2.8 ml of a 2M solution of diethylamine in THF and 2.5 g of BOP was stirred at RT for 1 h. The reaction mixture was concentrated in vacuo, the residue was dissolved in ether, the organic phase was washed with water, 1N NaOH solution, saturated NaCl solution, dried over MgSO ₄ and the solvent was concentrated in vacuo. The residue was subjected to silica H gel chromatography eluting with DCM followed by a gradient of the DCM / MeOH mixture of (99/1, v / v) to (95/5, v / v). The resulting product was dissolved in acetone and acidified to pH = 1 by addition of hydrochloric ether, and the precipitate formed was spin-dried and dried. 0.8 g of the desired product were obtained, mp = 229 ° C.

E) N, N-dimethyl-2- (4-piperidyl) isobutyramide hydrochloride.

 0.8 g of the compound obtained in the above step in 20 ml of MeOH and 0.2 g of 10% palladium on carbon were hydrogenated overnight at atmospheric pressure and RT. The catalyst was filtered through Celite (R) and the filtrate was concentrated in vacuo. The residue was dissolved in acetonitrile, ether was added and the precipitate formed was spin-dried and dried. 0.51 g of the desired product were obtained, m.p. = 258 ° C.

Preparation Example 3.7

1- (4-piperidyl) cyclopropanecarboxamide hydrochloride.

Formula 7, HCl: X =

A) 1- (4-pyridyl) cyclopropanecarbonitrile.

3.5 g of 4-pyridylacetonitrile was added to a mixture of 2.5 g sodium amide in 80 ml of DCM, followed by 2.6 ml of 1,2-dibromoethane and the mixture was stirred at RT overnight. The reaction mixture was poured into water and extracted with EtOAc, the organic phase was washed with water, dried over Na ₂ SO ₄ and the solvent was evaporated in vacuo. The residue was subjected to silica gel chromatography, eluting with DCM and then with a DCM / MeOH mixture of (99/1, v / v) to (95/5, v / v). 2.5 g of the desired product were obtained.

B) 1- (4-pyridyl) cyclopropanecarboxamide hydrochloride.

The mixture of 2.5 g of compound and 20 ml of 96% H ₂ SO ₄ solution obtained in the above step was rapidly heated to 100 ° C. and left stirring at 100 ° C. for 1 hour. After cooling to RT, the reaction mixture was poured into ice and neutralized to pH = 7 by addition of 20% NH ₄ OH solution and the precipitate formed was spin-dried, washed with water and dried. The precipitate was dissolved in DCM, acidified to pH = 1 by addition of hydrochloric ether and the precipitate formed was spin-dried. 1.8 g of the desired product were obtained.

C) 1- (4-piperidyl) cyclopropanecarboxamide hydrochloride.

The mixture of 1.8 g of compound obtained in the above step and 0.6 g of PtO ₂ in 50 ml of MeOH was hydrogenated at 80 ° C. and a pressure of 100 bar for 15 hours. The catalyst was filtered through Celite® and the filtrate was concentrated in vacuo to a volume of 5 ml and acetonitrile was added until crystallization occurred. 1.7 g of the desired product were obtained after spin-drying and subsequent drying.

Preparation Example 3.8

2-methyl-1- (4-morpholinyl) -2- (4-piperidyl) -1-propanone hydrochloride.

Formula 7, HCl: X =

A) 2- (1-benzyl-4-piperidyl) -2-methyl-1- (4-morpholinyl) -1-propanone hydrochloride.

A mixture of 1 g of compound obtained in step C of Preparation Example 3.6 and 1.2 ml of thionyl chloride in 20 ml of 1,2-dichloroethane was heated at 80 ° C. for 3 hours. The reaction mixture was concentrated in vacuo and the acid chloride thus obtained was dissolved in 20 ml of DCM, and this solution was added to a mixture of 0.7 g of morpholine and 1.6 ml of triethylamine in 20 ml of DCM, precooled to 0 ° C. The resulting mixture was stirred at rt for 24 h. The reaction mixture was concentrated in vacuo, the residue was extracted with ether, the organic phase was washed with 1N NaOH solution, with water, dried over MgSO ₄ and the solvent was evaporated in vacuo. The resulting product was dissolved in acetone and acidified to pH = 1 by addition of hydrochloric ether, and the precipitate formed was spin-dried and dried. 0.7 g of the desired product were obtained.

B) 2-methyl-1- (4-morpholinyl) -2- (4-piperidyl) -1-propanone hydrochloride.

A mixture of 0.7 g compound, 0.7 g ammonium formate and 0.2 g 10% palladium on carbon in 10 ml of MeOH was stirred at RT for 4 h. The catalyst was filtered through Celite (R) and the filtrate was concentrated in vacuo. The residue was dissolved in acetonitrile, ether was added and the precipitate formed was spin-dried and dried. 0.46 g of the desired product was obtained, m.p. = 225 ° C.

Example 1

3- [2- (4- (1-carbamoyl-1-methylethyl) -1-piperidyl] ethyl] -3- (3,4-dichlorophenyl) -1- [2- (3,5 -Dimethylphenyl) acetyl] piperidine hydrochloride monohydrate, the (-) isomer.

Formula I, HCl:

A) 3- (3,4-dichlorophenyl) -3- (2-hydroxyethyl) -1- [2- (3,5-dimethylphenyl) acetyl] piperidine, single isomer.

2.3 ml of triethylamine were added to a mixture of 2.0 g of 3,5-dimethylphenylacetic acid in 100 ml of DCM at RT, followed by the addition of 3 g of compound obtained in Preparation Example 1 and 5.3 g of BOP and the mixture Stir at RT for 1 h. The reaction mixture was concentrated in vacuo, the residue was extracted with ether, the organic phase was washed with water, with 2N HCl solution, with water, with 10% NaON aqueous solution, dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated in vacuo. . The residue was subjected to silica H gel chromatography eluting with DCM followed by a DCM / MeOH mixture (98/2, v / v). 3.9 g of the desired product were obtained and used in the next step without further processing.

B) 3- (3,4-dichlorophenyl) -3- (formylmethyl) -1- [2- (3,5-dimethylphenyl) acetyl] piperidine, single isomer.

A solution of 0.25 ml of oxalyl chloride in 3 ml of DCM was cooled to −70 ° C. and under nitrogen atmosphere, a solution of 0.35 ml of DMSO in 3 ml of DCM was added dropwise, followed by 0.5 g of 5 g of DCM obtained in the above step. A solution of the compound of was added and the mixture was stirred at -50 ° C for 15 minutes. 0.9 ml of triethylamine was added and the mixture was left to stir with recovery to RT. The reaction mixture was washed with water, 1N HCl solution, 10% NaHCO ₃ solution, the organic phase was dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated in vacuo. 0.5 g of the desired product were obtained and used without further processing in the next step.

C) 3- [2- [4- (1-carbamoyl-1-methylethyl) -1-piperidyl] ethyl-3- (3,4-dichlorophenyl) -1- [2- (3, 5-dimethylphenyl) acetyl] piperidine hydrochloride monohydrate, the (-) isomer.

A solution of 0.5 g of the compound obtained in the above step in 5 ml of MeOH after addition of 0.08 ml of acetic acid to a solution of 0.24 g of compound (free base) obtained in Preparation Example 3.1 in 3 ml of MeOH under RT and nitrogen atmosphere. Was added. After 5 minutes, 0.08 g sodium cyanoborohydride was added and the mixture was left stirring at RT overnight. The reaction mixture was poured into 10% aqueous NaHCO ₃ solution and extracted with ether, the organic phase was washed with water, dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated in vacuo. The residue was subjected to silica H gel chromatography eluting with DCM followed by a gradient of the DCM / MeOH mixture of (99/1, v / v) to (90/10, v / v). The resulting product was dissolved in DCM, acidified to pH = 1 by addition of hydrochloric ether and concentrated in vacuo. 0.5 g of the desired product was obtained after trituration, spin-drying and vacuum drying from ether.

=-27.7° (c=1, MeOH)

= -27.7 ° (c = 1, MeOH)

¹ H NMR: δ (ppm): 0.7 to 1.2: bs: 6H; 1.2 to 2.4: m: 16H; 2.5 to 4.8: m: 12H; 6.5 to 8.0: m: 8H; 10.2: bs: 1 H.

Example 2

3- [2- [4- (1-carbamoyl-1-methylethyl) -1-piperazinyl] ethyl-3- (3,4-dichlorophenyl) -1- [2- (3,5- Dimethylphenyl) acetyl] piperidine dihydrochloride.2.7H ₂ O, (-) isomer.

Formula I, 2HCl:

0.23 g of the compound (free base) obtained in Preparation Example 3.2 was added to a solution of 0.5 g of the compound obtained in Step B of Example 1 in 20 ml of DCM under RT and a nitrogen atmosphere, followed by 0.1 ml of acetic acid. Was added and the mixture was stirred at RT for 30 min. 0.55 g sodium triacetoxyborohydride was added and the mixture was left stirring at RT overnight. 10% Na ₂ CO ₃ aqueous solution was added and the reaction mixture was stirred at RT for 15 minutes. The reaction mixture was extracted with DCM and the organic phase was washed with 10% Na ₂ CO ₃ aqueous solution, dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated in vacuo. The residue was subjected to silica gel chromatography eluting with DCM followed by a gradient of a DCM / MeOH mixture of (99/1, v / v) to (95/5, v / v). The resulting product was dissolved in DCM, acidified to pH = 1 by addition of hydrochloric ether, and the precipitate formed was spin-dried, washed with ether and dried in vacuo. 0.4 g of the desired product was obtained.

=-37° (c=1, MeOH)

= -37 ° (c = 1, MeOH)

¹ H NMR: δ (ppm): 0.6 to 2.3: m: 18H; 2.3 to 4.7: m: 16H; 6.4 to 8.0: m: 8H.

Example 3

3- [2- [4- (1-N, N-dimethylcarbamoyl-1-methylethyl) -1-piperazinyl] ethyl] -3- (3,4-dichlorophenyl) -1- [2 -(3,5-dimethylphenyl) acetyl] piperidine dihydrochloride. 1.25H ₂ O, (-) isomer.

Formula I, 2HCl: X =

0.6 g of the compound obtained in step B of Example 1, 0.3 g of the compound obtained in Preparation Example 3.4, 0.1 ml of acetic acid and then 0.12 g of sodium cyanoborohydride were added to 20 ml of MeOH at RT. Was added and the mixture was stirred at RT overnight. A 10% Na ₂ CO ₃ aqueous solution was added to the reaction mixture and the mixture was left to stir for 15 minutes. The reaction mixture was extracted with EtOAc and the organic phase was washed with aqueous Na ₂ CO ₃ solution, with water, saturated NaCl solution, dried over Na ₂ SO ₄ and the solvent was evaporated in vacuo. The residue was subjected to silica gel chromatography eluting with DCM followed by a gradient of a DCM / MeOH mixture of (99/1, v / v) to (95/5, v / v). The resulting product was dissolved in DCM, acidified to pH = 1 by addition of hydrochloric ether, and the precipitate formed was spin-dried, washed with ether and dried in vacuo. 0.4 g of the desired product was obtained.

=-28.4° (c=1, MeOH)

= -28.4 ° (c = 1, MeOH)

¹ H NMR: δ (ppm): 0.7 to 2.3: m: 18H; 2.35 to 4.7: m: 22 H; 6.5 to 7.8: m: 6H; 10.3: s: 1H.

Example 4

3- [2- [4- (1-carbamoyl-1-methylethyl) -1-piperidyl] ethyl] -3- (3,4-dichlorophenyl) -1- [2- (3,5 -Dichlorophenyl) acetyl] piperidine hydrochloride sesquihydrate, the (-) isomer.

Formula I, HCl:

A) 3- (3,4-dichlorophenyl) -3- (2-hydroxyethyl) -1- [2,-(3,5-dichlorophenyl) acetyl] piperidine, single isomer.

4.75 g of compound obtained in Preparation Example 1, 3.55 g of Compound obtained in Preparation Example 2.1, 3.6 ml of triethylamine and then 8.4 g of BOP were added to RT, 150 ml of DCM and the mixture was stirred at RT. It was left to stir for 2 hours. The reaction mixture is concentrated in vacuo, the residue is extracted with EtOAc, the organic phase is washed with 1N HCl solution, with water, with 1N NaOH solution, with water, with saturated NaCl solution, dried over Na ₂ SO ₄ , and the solvent is vacuumed. Evaporated. 8 g of the desired product were obtained and used without further processing.

B) 3- (3,4-dichlorophenyl) -3- (formylmethyl) -1- [2- (3,5-dichlorophenyl) acetyl] piperidine, single isomer.

Step B of Example 1 starting from 0.25 g of oxalyl chloride in 6 ml of DCM, 0.38 ml of DMSO in 3 ml of DCM, 1 g of the compound obtained in the above step in 6 ml of DCM and then 1.5 ml of triethylamine This compound was prepared according to the method described in. 1.0 g of the desired product were obtained, which was used without further processing.

C) 3- [2- [4- (1-carbamoyl-1-methylethyl) -1-piperidyl] ethyl] -3- (3,4-dichlorophenyl) -1- [2- (3 , 5-dichlorophenyl) acetyl] piperidine hydrocide sesquihydrate, (-) isomer.

Starting from 0.25 g of the compound obtained in Preparation Example 3.1 (free base) in 3 ml of MeOH, 0.08 ml of acetic acid, 0.5 g of the compound obtained in the above step in 5 ml of MeOH and then 0.08 g of sodium cyanoborohydride. This compound was prepared according to the method described in Step C of Example 1. 0.52 g of the desired product were obtained.

= -0.6° (c=1, MeOH).

= -0.6 ° (c = 1, MeOH).

Example 5

3- [2- [4- (1-carbamoyl-1-methylethyl) -1-piperidyl] ethyl] -3- (3,4-dichlorophenyl) -1- [2- [3,5 Bis (trifluoromethyl) phenyl] acetyl] piperidine hydrochloride monohydrate, (+) isomer.

Formula I, HCl:

A) 3- (3,4-dichlorophenyl) -3- (2-hydroxyethyl) -1- [2- [3,5-bis (trifluoromethyl) phenyl] acetyl] piperidine, single isomer .

1.2 g of the compound obtained in Preparation Example 1, 1.2 g of 3,5-bis (trifluoromethyl) phenylacetic acid, 1.7 ml of triethylamine and then 2.16 g of BOP were added to 50 ml of DCM at RT The mixture was stirred for 15 minutes. The reaction mixture is concentrated in vacuo, the residue is dissolved in 1N HCl solution and extracted with ether, the organic phase is washed with 1N HCl solution, with water, with 1N NaOH solution, with water and dried over Na ₂ SO ₄ , and the solvent is vacuumed. Evaporated. 2.1 g of the desired product were obtained, which was used without further processing.

B) 3- (3,4-dichlorophenyl) -3- (formylmethyl) -1- [2- [3,5-bis (trifluoromethyl) phenyl] acetyl] piperidine, single isomer.

20 ml of DCM was cooled to -78 ° C, 1.5 g of the compound obtained in the above step, 0.45 ml of DMSO and then 0.3 ml of oxalyl chloride were added under nitrogen atmosphere, and the mixture was stirred at -78 ° C for 30 minutes. I left it. 2 ml of triethylamine were added and the mixture was stirred while recovering to RT. 1N HCl solution is added to the reaction mixture, the resulting mixture is extracted with DCM, and the organic phase is washed with 1N HCl solution, with water, with 10% Na ₂ CO ₃ aqueous solution and dried over Na ₂ SO ₄ , and the solvent is evaporated in vacuo. I was. 1.5 g of the desired product were obtained and used without further processing.

C) 3- [2- [4- (1-carbamoyl-1-methylethyl) -1-piperidyl] ethyl] -3- (3,4-dichlorophenyl) -1- [2- [3 , 5-bis (trifluoromethyl) phenyl] acetyl] piperidine, hydrochloride monohydrate, (+) isomer.

A mixture of 0.35 g of the compound obtained in Preparation Example 3.1 and 0.4 g of K ₂ CO ₃ in 10 ml of acetonitrile was refluxed for 3 hours. Insoluble matter was filtered off and the filtrate was concentrated in vacuo. The product of Preparation 3.1 in the form of the free base thus obtained was dissolved in 3 ml of MeOH, 0.08 ml of acetic acid was added, and then a solution of 0.5 g of the compound obtained in the above step in 5 ml of MeOH was added and this mixture was added. Was left to stir at RT for 5 minutes. 0.08 g sodium cyanobonohydride was added and the mixture was left stirring at RT overnight. The reaction mixture was poured into 10% aqueous NaHCO ₃ solution, extracted with ether, the organic phase was washed with water and dried over Na ₂ SO ₄ and the solvent was evaporated in vacuo. The residue was subjected to silica H gel chromatography eluting with DCM and then with a gradient of the DCM / MeOH mixture of (99/1, v / v) to (90/10, v / v). The resulting product was dissolved in DCM and acidified to pH = 1 by addition of hydrochloric ether and the precipitate formed was spin-dried. This gave 0.54 g of product after vacuum drying.

= +28.2°(c=1, MeOH).

= + 28.2 ° (c = 1, MeOH).

¹ H NMR: δ (ppm): 0.6 to 2.2: m: 16H; 2.3 to 4.2: m: 12H; 6.6 to 8.0: m: 8H; 10.3: s: 1H.

Example 6

3- [2- [4- (1-N, N-dimethylcarbamoyl-1-methylethyl) -1-piperidyl] ethyl] -3- (3,4-dichlorophenyl) -1- [2 -(3,5-dimethylphenyl) acetyl] piperidine hydrochloride hemihydrate, the (-) isomer.

Formula I, HCl:

A mixture of 0.35 g of the compound obtained in Preparation Example 3.6 and 0.4 g of K ₂ CO ₃ in 10 ml of acetonitrile was refluxed for 3 hours. Insoluble matter was filtered off and the filtrate was concentrated in vacuo. The product of Preparation 3.6 thus obtained in free base form was dissolved in 3 ml of MeOH and 0.1 ml of acetic acid was added, followed by addition of a solution of 0.6 g of the compound obtained in step B of Example 1 in 5 ml of MeOH. The mixture was left to stir at RT for 5 minutes. 0.1 g sodium cyanoborohydride was added and the mixture was left stirring at RT overnight. The reaction mixture was poured into 10% aqueous NaHCO ₃ solution, extracted with ether, the organic phase was washed with water and dried over MgSO ₄ and the solvent was evaporated in vacuo. The residue was subjected to silica H gel chromatography eluting with DCM and then with a gradient of the DCM / MeOH mixture of (99/1, v / v) to (90/10, v / v). The product thus obtained was dissolved in DCM and acidified to pH = 1 by addition of hydrochloric ether and the solvent was evaporated in vacuo. 0.68 g of the desired product was obtained after grinding, spin-drying and drying from ether, mp = 202 ° C.

= -27.1°(c=1, MeOH).

= -27.1 ° (c = 1, MeOH).

¹ H NMR: δ (ppm): 0.6 to 2.5: m: 23H; 2.5 to 4.6: m: 18 H; 6.4 to 7.8: m: 6H; 10.1: s: 1H.

Example 7

3- [2- [4- (1-carbamoyl-1-methylethyl) -1-piperidyl] ethyl] -3- (3,4-dichlorophenyl) -1- [2- (3,5 -Diethylphenyl) acetyl] piperidine hydrochloride hemihydrate, the (-) isomer.

Formula I, HCl: X =

A) 3- (3,4-dichlorophenyl) -3- (2-hydroxyethyl) -1- [2- (3,5-diethylphenyl) acetyl] piperidine, single isomer.

1.15 g of 3,5-diphenylphenylacetic acid is added to a mixture of 1.64 g of the compound obtained in Preparation Example 1 in 30 ml of DCM at RT, followed by 3 ml of triethylamine and 3.2 g of BOP and the mixture Was stirred at RT for 2 h. The reaction mixture is concentrated in vacuo, the residue is dissolved in 1N HCl solution, extracted with ether, the organic phase is washed with 1N HCl solution, with water, with 1N NaOH solution, with water, saturated NaCl solution, Na ₂ SO ₄ And the solvent was evaporated in vacuo. The residue was subjected to silica gel chromatography eluting with a gradient of the DCM / MeOH mixture of (99/1, v / v) to (95/5, v / v). 1.1 g of the desired product were obtained, which was used without further processing.

B) 3- (3,4-dichlorophenyl) -3- (formylmethyl) -1- [2- (3,5-diethylphenyl) acetyl] piperidine, single isomer.

The solution of 0.5 g of compound obtained in the above step in 10 ml of DCM is cooled to -78 ° C, under nitrogen atmosphere, 0.23 ml of DMSO is added, then 0.16 ml of oxalyl chloride is added and the mixture is -78 It stirred at 30 degreeC. 0.95 ml of triethylamine was then added and the mixture was left to stir with recovery to RT. 1N HCl solution is added to the reaction mixture, the resulting mixture is extracted with DCM, the organic phase is washed with 1N HCl solution, with water, with 10% Na ₂ CO ₃ solution, dried over Na ₂ SO ₄ , and the solution is vacuumed. Evaporated. 0.5 g of the desired product were obtained and used without further processing.

C) 3- [2- (4-1-carbamoyl-1-methylethyl) -1-piperidyl] ethyl] -3- (3,4-dichlorophenyl) -1- [2- (3, 5-diethylphenyl) acetyl] piperidine hydrochloride hemihydrate, the (-) isomer.

0.08 ml of acetic acid was added to a solution of 0.23 g of the compound (free base) obtained in Preparation Example 3.1 in 3 ml of MeOH under RT and nitrogen atmosphere, followed by 0.5 g of the compound obtained in the above step in 5 ml of MeOH. Solution was added. After 5 minutes, 0.08 g sodium cyanoborohydride was added and the mixture was left overnight with stirring at RT. The reaction mixture was poured into 10% aqueous NaHCO ₃ solution, extracted with ether, the organic phase washed with water, dried over MgSO ₄ and the solvent was evaporated in vacuo. The residue was subjected to silica H gel chromatography eluting with DCM and then with a gradient of the DCM / MeOH mixture of (99/1, v / v) to (93/7, v / v). The product thus obtained was dissolved in DCM and acidified to pH = 1 by addition of hydrochloric ether and the solvent was evaporated in vacuo. 0.51 g of the desired product was obtained after grinding, spin-drying and drying from ether.

= -30.5°(c=1, MeOH).

= -30.5 ° (c = 1, MeOH).

¹ H NMR: δ (ppm): 0.5 to 2.2: m: 23H; 2.2 to 4.65: m: 16H; 6.4 to 7.8: m: 8H; 9.85: s: 1 H.

Performing according to the method described in the above examples, the compounds according to the invention described in Table I were prepared.

TABLE I

This compound is prepared according to the method described in step C of Example 1, starting from the compound obtained in Step B of Example 1 and the compound in free base form obtained in Preparation Example 3.5.

This compound is prepared according to the method described in Example 3, starting from the compound obtained in Step B of Example 1 and the compound in free base form obtained in Preparation Example 3.3.

This compound is prepared according to the method described in step C of Example 4, starting from the compound obtained in Step B of Example 4 and the compound in free base form obtained in Preparation Example 3.5.

This compound is prepared according to the method described in Example 3 starting from the compound obtained in Step B of Example 4 and the compound in free base form obtained in Preparation Example 3.2.

This compound is prepared according to the method described in Example 3, starting from the compound obtained in Step B of Example 4 and the compound obtained in Preparation Example 3.4.

This compound is prepared according to the method described in Example 3, starting from the compound obtained in Step B of Example 4 and the compound in free base form obtained in Preparation Example 3.3.

This compound is prepared according to the method described in Step C of Example 5 starting from the compound obtained in Step B of Example 5 and the compound obtained in Preparation Example 3.5.

This compound is prepared according to the method described in Example 3 starting from the compound obtained in Step B of Example 5 and the compound in free base form obtained in Preparation Example 3.3.

This compound is prepared according to the method described in Example 2, starting from the compound obtained in Step B of Example 1 and the compound in free base form obtained in Preparation Example 3.7.

This compound is prepared according to the method described in step C of Example 5, starting from the compound obtained in Step B of Example 5 and the compound obtained in Preparation Example 3.7.

This compound is prepared according to the method described in step C of example 4, starting from the compound obtained in step B of example 4 and the compound in free base form obtained in preparation example 3.7.

This compound is prepared according to the method described in step C of Example 7, starting from the compound obtained in Step B of Example 7 and the compound in free base form obtained in Preparation Example 3.2.

This compound is prepared according to the method described in step C of Example 1, starting from the compound obtained in Step B of Example 1 and the compound in free base form obtained in Preparation Example 3.8.

Example 8 : ¹ H NMR: δ (ppm): 0.7 to 2.2: m: 27H; 2.3 to 4.6: m: 14 H; 6.4 to 7.7: m: 8H; 10.1: s: 1H.

Example 9 : ¹ H NMR: δ (ppm): 0.6 to 2.35: m: 22H; 2.4 to 4.6: m: 14 H; 6.4 to 8.2: m: 8H.

Example 10 : ¹ H NMR: δ (ppm): 0.7 to 2.25: m: 21H; 2.3 to 4.4: m: 12H; 6.7 to 7.8: m: 8H; 10.1: s: 1H.

Example 11 ¹ H NMR: δ (ppm): 0.6-2.2: m: 12H; 2.3 to 4.4: m: 16H; 6.8 to 8.0: m: 8H.

Example 12 : ¹ H NMR: δ (ppm): 0.8 to 2.3: m: 12H; 2.35 to 4.4: m: 22 H; 7.0-7.9: m: 6H; 10.6: s: 1H.

Example 13 : ¹ H NMR: δ (ppm): 0.9 to 2.3: m: 16H; 2.35 to 4.5: m: 16H; 7.0 to 7.9: m: 8H.

Example 14 ¹ H NMR: δ (ppm): 0.9 to 2.3: m: 21H; 2.4 to 4.3: m: 12H; 6.8 to 8.1: m: 8H; 10.0: s: 1H.

Example 15 : ¹ H NMR: δ (ppm): 1.0 to 2.4: m: 16H; 2.5 to 4.5: m: 16H; 6.9 to 8.1: m: 8H; 11.0: bs: 1 H.

Example 16 : ¹ H NMR: δ (ppm): 0.4-2.3: m: 20H; 2.4 to 4.6: m: 13 H; 6.5 to 7.7: m: 8H; 9.6: s: 1 H.

Example 17 : ¹ H NMR: δ (ppm): 0.4 to 2.2: m: 14H; 2.3 to 4.4: m: 13 H; 6.5 to 7.8: m: 8H; 9.9: s: 1 H.

Example 18 ¹ H NMR: δ (ppm): 0.4-2.2: m: 14H; 2.3 to 4.4: m: 13 H; 6.6 to 7.8: m: 8H; 9.9: s: 1 H.

Example 19 : ¹ H NMR: δ (ppm): 0.6 to 2.6: m: 22H; 2.6 to 4.8: m: 16H; 6.5 to 8.0: m: 10H.

Example 20 : ¹ H NMR: δ (ppm): 0.7 to 2.25: m: 22H; 2.3 to 4.6: m: 21 H; 6.4 to 7.7: m: 6H; 10.4: s: 1H.

Example 21

3- [2- [4- (1-carbamoyl-1-methylethyl) -1-piperidyl] ethyl-3- (3,4-dimethylphenyl) -1- [2- (3,5- Dichlorophenyl) acetyl] piperidine hydrochloride.

Formula I, HCl:

A) 1- [2- (3,5-dichlorophenyl) acetyl] -3- (3,4-dimethylphenyl) -3- [2- (2-tetrahydropyranyloxy) ethyl] piperidine.

A mixture of 3 g compound obtained in Preparation Example 1.2, 1.3 g compound obtained in Preparation Example 2.1, 3.2 ml triethylamine and 4.8 g BOP in 100 ml DCM was stirred at RT for 2 hours. The reaction mixture is concentrated in vacuo, the residue is dissolved in 1N HCl solution, extracted with EtOAc, the organic phase is washed with water, 1N NaOH solution, saturated NaCl solution and dried over Na ₂ so ₄ and the solvent is evaporated in vacuo. I was. 4.5 g of the desired product were obtained.

B) 1- [2- (3,5-dichlorophenyl) acetyl] -3- (3,4-dimethylphenyl) -3- (2-hydroxyethyl) piperidine.

A mixture of 4.5 g of compound and 2 ml of concentrated HCl solution obtained in the above step in 10 ml of MeOH was stirred at RT for 2 h. The reaction mixture was concentrated in vacuo, the residue was dissolved in MeOH and the solvent was evaporated in vacuo. The residue was subjected to silica gel chromatography eluting with DCM and then with a gradient of the DCM / MeOH mixture of (99/1, v / v) to (95/5, v / v). 3 g of the desired product were obtained.

C) 1- [2- (3,5-dichlorophenyl) acetyl] -3- (formylmethyl) -3- (3,4-dimethylphenyl) piperidine.

10 ml of DCM was cooled to -78 ° C, 0.5 g of the compound obtained in the above step and 0.18 ml of DMSO were added under nitrogen atmosphere, then 0.13 ml of oxalyl chloride was added and the mixture was added at -78 ° C 30 It was left to stir for minutes. 0.75 ml of triethylamine was then added and the mixture was left stirring with rising to RT. 1N HCl solution was added to the reaction mixture and the resulting mixture was left stirring with rising to RT. 1N HCl solution was added to the reaction mixture, the resulting mixture was extracted with DCM, the organic phase was washed with water, 10% Na ₂ CO ₃ solution, dried over Na ₂ SO ₄ and the solvent was evaporated in vacuo. 0.5 g of the desired product was obtained.

D) 3- [2- [4- (1-carbamoyl-1-methylethyl) -1-piperidyl] ethyl] -3- (3,4-dimethylphenyl) -1- [2- (3 , 5-dichlorophenyl) acetyl] piperidine hydrochloride.

A mixture of 0.5 g of the compound obtained in the above step in 30 ml of MeOH, 0.35 g of the compound obtained in Preparation Example 3.1 (free base), 0.1 ml of acetic acid and 0.15 g of sodium cyanoborohydride was stirred at RT overnight. I left it. 10% Na ₂ CO ₃ solution is added to the reaction mixture, the resulting mixture is left stirring for 15 minutes, extracted with EtOAc, the organic phase is washed with water, saturated NaCl solution, dried over Na ₂ SO ₄ , solvent Was evaporated in vacuo. The residue was subjected to silica gel chromatography eluting with DCM and then with a gradient of the DCM / MeOH mixture of (99/1, v / v) to (95/5, v / v). The resulting product was dissolved in DCM, acidified to pH = 1 by addition of hydrochloric ether, and the precipitate formed was spin-dried. 0.35 g of the desired product was obtained.

¹ H NMR: δ (ppm): 0.8 to 2.3: m: 22H; 2.3 to 4.0: m: 13H; 6.5 to 7.6: m: 8H; 9.5: s: 1H.

Example 22

3- [2- [4- (1-carbamoyl-1-methylethyl) -1-piperazinyl] ethyl] -3- (3,4-dimethylphenyl) -1- [2- (3,5 -Dichlorophenyl) acetyl] piperidine dihydrochloride, 1 H ₂ O.

Formula I, 2HCl:

This compound was prepared according to the method described in step D of Example 21, starting from the compound obtained in Step C of Example 21 and the compound (free base) obtained in Preparation Example 3.2.

¹ H NMR: δ (ppm): 1.4: 1s: 6H; 2.2: 2s: 6H; 1.3 to 4.0: m: 26H; 7.0 to 8.0: m: 6H.

In the present invention, a salt of a compound of formula (I) with an inorganic or organic acid thereof, solvate and / or hydrate thereof is obtained, which exhibits high affinity and high selectivity for the human NK ₁ receptor of substance P. It was also possible to prepare methods for their preparation, intermediate compounds of formula (7) useful for their preparation, pharmaceutical compositions containing these compounds, and pharmaceuticals for treating all diseases associated with substance P and human NK ₁ receptor.

Claims (1)

The compounds of formula VII and salts with inorganic or organic acids thereof. <Formula 7>

Where -X is

, Or

Indicates, -R ₂ represents a group -CR ₃ R ₄ CONR ₅ R ₆ , R ₃ and R ₄ represent the same radicals selected from methyl, ethyl, n-propyl or n-butyl, or R ₃ and R ₄ together with the carbon atom to which they are attached form (C ₃ -C ₆ ) cycloalkyl, R ₅ and R ₆ each independently represent hydrogen or (C ₁ -C ₃ ) alkyl, or R ₅ and R ₆ together with the nitrogen atom to which they are attached are 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, 4-morpholinyl, 4-thiomorpholinyl or perhydro-1-a Form selected heterocyclic radicals from zefinyl.