KR19990021857A - 1-benzoyl-2- (indolyl-3-alkyl) -piperazine derivatives as neurokinin receptor antagonists - Google Patents

Abstract

The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, a preparation method thereof, a pharmaceutical composition containing the same, and their use as a medicament.

In formula (I), R ¹ is trihalo (lower) alkyl,

R ² is trihalo (lower) alkyl,

R ³ is indolyl (lower) alkyl,

-A- is -CH ₂ -or ,

-R ⁴ is , or ego

Wherein R ⁵ is hydrogen or lower alkoxycarbonyl, R ⁶ is hydrogen or lower alkanoyl, R ⁷ is hydrogen, lower alkyl, lower alkanoyl, lower alkoxycarbonyl, lower alkoxy (lower) alkanoyl, cyclo (lower) Alkylcarbonyl, aroyl or lower alkylsulfonyl.

Description

1-benzoyl-2- (indolyl-3-alkyl) -piperazine derivatives as neurokinin receptor antagonists

The present invention relates to novel piperazine derivatives and pharmaceutically acceptable salts thereof.

More specifically, the present invention relates to novel piperazine derivatives and medicaments having pharmacological activity such as tachykinin antagonism, in particular, substance P antagonism, neurokinin A antagonism, and the like. Scientifically acceptable salts thereof, methods for their preparation, pharmaceutical compositions containing them, and their use as medicaments.

Accordingly, it is an object of the present invention to provide novel useful piperazine derivatives and pharmaceutical agents with pharmacological activity such as tachykinin antagonism, in particular substance P antagonism, neurokinin A antagonism, neurokinin B antagonism, and the like. It is to provide a salt thereof that is acceptable.

Another object of the present invention is to provide a method for preparing this piperazine derivative and salts thereof.

A further object of the present invention is to provide a pharmaceutical composition containing, as an active ingredient, this piperazine derivative and a pharmaceutically acceptable salt thereof.

It is a further object of the present invention to provide a human or animal tachykinin-associated disease, such as respiratory diseases such as asthma, bronchitis, rhinitis, cold, sputum, and the like; Eye diseases such as conjunctivitis, spring conjunctivitis and the like; Skin diseases such as contact dermatitis, atopic dermatitis, urticaria, and other eczema dermatitis; Inflammatory diseases such as rheumatoid arthritis, osteoarthritis, and the like; Takkinin antagonists, especially substance P antagonists, neurokinin A antagonists or neurokies, useful for treating or preventing pain or pain (eg, migraine, headache, toothache, cancer pain, back pain, etc.) It is to provide the use of this piperazine derivative or a pharmaceutically acceptable salt thereof as a nin B antagonist.

A target compound of the present invention is a compound of formula (I)

Namely (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- (1H-indol-3-ylmethyl) -4- [N-(4-methyl-1-piperazinyl ) Carbamoylmethyl] -piperazine, or fumarate thereof, ie (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- (1H-indol-3-ylmethyl)- 4- [N- (4-methyl-1-piperazinyl) carbamoylmethyl] piperazin fumarate (hereinafter referred to simply as compound (If)).

Other desired compounds of the invention may be represented by the following formula (Ig) or a pharmaceutically acceptable salt thereof:

Wherein R ¹ is trihalo (lower) alkyl,

R ² is trihalo (lower) alkyl,

R ³ is indolyl (lower) alkyl,

-A- is -CH ₂ -or ,

-R ⁴ is , or ego

Wherein R ⁵ is hydrogen or lower alkoxycarbonyl, R ⁶ is hydrogen or lower alkanoyl, R ⁷ is hydrogen, lower alkyl, lower alkanoyl, lower alkoxycarbonyl, lower alkoxy (lower) alkanoyl, cyclo (lower) Alkylcarbonyl, aroyl or lower alkylsulfonyl.

According to the invention, the desired compound can be prepared by the process illustrated in the following scheme.

Process 1

Process 2

Process 3

Process 4

Wherein R ¹ , R ² , R ³ and R ⁴ are each as defined above; -A ₁ -is -CH _2- ; W is a leaving group.

Suitable salts and pharmaceutically acceptable salts of the starting compound and the desired compound are conventional non-toxic salts and are organic acid salts (e.g. acetate, trifluoroacetate, fumarate, maleate, tartrate, methanesulfonate, benzenesulfonate) , Formate, toluenesulfonate, etc.), inorganic acid salts (e.g. hydrochloride, hydrobromide, hydroiodide, sulphate, nitrate, phosphate, etc.), or amino acids (e.g. arginine, aspartic acid, gurutamic acid Acid addition salts such as salts with salts such as salts, and metal salts such as alkali metal salts (e.g. sodium salts, potassium salts, etc.) and alkaline earth metal salts (e.g. calcium salts, magnesium salts, etc.), ammonium salts, organic base salts ( Such as trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, etc.), and the like.

In the above description and the following description of the present specification, preferred examples and examples of various definitions included in the scope of the present invention will be described in detail as follows.

Lower means, unless otherwise indicated, 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms.

Suitable lower alkyl and lower alkyl moieties in indolyl (lower) alkyl and lower alkylsulfonyl are straight or branched chains having 1 to 6 carbon atoms and are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, etc. It may include.

Suitable trihalo (lower) alkyl may include trichloromethyl, tribromomethyl, trifluoromethyl and the like.

Suitable lower alkoxy and lower alkoxy moieties in lower alkoxycarbonyl and lower alkoxy (lower) alkane oils may include methoxy, ethoxy, isopropyloxy, butoxy and the like.

Suitable lower alkane and lower alkane oil moieties in lower alkoxy (lower) alkane oils may include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, hexane oil, pival oil, and the like.

Suitable cyclo (lower) alkyl moieties in cyclo (lower) alkylcarbonyl may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

Suitable aroyl may include benzoyl, toluoyl, naphthoyl and the like.

Suitable leaving groups may include hydroxy, reactive groups derived from hydroxy, and the like.

Reactive groups derived from suitable hydroxys may include acid residues and the like.

Suitable acid residues may include halogens (eg, fluoro, chloro, bromo, urethra), acyloxy (eg, acetoxy, tosyloxy, mesyloxy, etc.) and the like.

Hereinafter, the processes 1 to 4 for preparing the target compound of the present invention will be described in detail.

Process 1

The desired compound (I) or a salt thereof can be prepared by reacting a compound (II) or a derivative thereof whose carboxyl group is reactive or a salt thereof with a compound (III) or a derivative thereof whose amino group is reactive or a salt thereof.

Suitable reactive derivatives in which the carboxyl group of compound (II) is reactive may include acid halides, acid anhydrides, activated amides, activated esters, and the like.

Suitable examples of reactive derivatives include acid chlorides; Acid azide; Substituted phosphoric acids [eg dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid, etc.], dialkyl phosphorous acid, sulfurous acid, thiosulfic acid, sulfuric acid, sulfonic acid [eg, methanesulfonic acid, etc.], aliphatic carboxyl Mixed with acids such as acids [e.g. asteric acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, pentanic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.] or aromatic carboxylic acids [e.g. benzoic acid, etc.] Acid anhydrides; Symmetric acid anhydride 'imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or terazole and activated amide; Or activated esters [eg cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl [(CH ₃ ) ₂ N ⁺ = CH-] ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2, 4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyran Monoesters, pyridyl esters, piperidyl esters, 8-quinolyl thioesters, and the like], or N-hydroxy compounds [eg N, N-dimethylhydroxyamine, 1-hydroxy-2- (1H)- Pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-1H-benzotriazole, and the like. These reactive derivatives may be arbitrarily selected from the above depending on the kind of the compound (II) to be used.

Suitable reactive derivatives in the amino group of compound (III) include Schiff base type imino formed by reaction of compound (III) with a carbonyl compound such as aldehyde, ketone or the like; Silyl derivatives formed by the reaction of a compound (III) with a silyl compound such as bis (trimethylsilyl) acetamide, mono (trimethylsilyl) acetamide, bis (trimethylsilyl) urea and the like; Phosphorus trichloride or derivatives formed by the reaction of phosgene with compound (III) and the like.

Typically the reaction is water, alcohol (eg methanol, ethanol, etc.), acetone, 2-butanone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylform It is carried out in conventional solvents such as amides, pyridine or other organic solvents that do not adversely affect the reaction, or mixtures thereof.

In this reaction, when compound (II) is used in free acid form or in salt form thereof, the reaction is preferably a conventional condensing agent such as N, N'-dicyclohexylcarbodiimide; N-cyclohexyl-N'-morpholinoethylcarbodiimide; N-cyclohexyl-N '-(4-diethylaminocyclohexyl) carbodiimide; N, N'-diethylcarbodiimide; N, N'-diisopropylcarbodiimide; N-ethyl-N '-(3-dimethylaminopropyl) carbodiimide; Pentamethyleneketene-N-cyclohexylimine; Diphenylketene-N-cyclohexylimine; Ethoxyacetylene; 1-alkoxy-1-chloroethylene; Trialkyl phosphites; Ethyl polyphosphate; Isopropyl polyphosphate; Phosphorus oxychloride (phosphoryl chloride); Phosphorus trichloride; Diphenyl phosphoryl azide; Thionyl chloride; Oxalyl chloride; Lower alkyl haloformates (eg ethyl chloroformate, isopropyl chloroformate, and the like); Triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5- (m-sulfophenyl) isoxazolium hydroxide intramolecular salt; 1- (p-chlorobenzenesulfonyloxy) -6-chloro-1H-benzotriazole; 1-hydroxybenzotriazole; So-called Mukaiyama reagents such as 2-chloro-1-methylpyridinium iodide; 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride alone or in combination with 1-hydroxybenzotriazole; So-called Vilsmeier reagents prepared by the reaction of thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus oxychloride, and the like with N, N-dimethylformamide; And the like, or mixtures thereof.

The reaction can also be carried out in the presence of inorganic or organic bases such as alkali metal bicarbonates, tri (lower) alkylamines, pyridine, N- (lower) alkylmorpholines, N, N-di (lower) alkylbenzylamines, and the like. have.

The reaction temperature is not limited and the reaction is usually carried out in a cooled to heated state.

Process 2

The desired compound (If) may be prepared by reacting a salt other than compound (I) or a fumarate thereof with fumaric acid.

The reaction is usually carried out with water, alcohols (eg methanol, ethanol, etc.), acetone, 2-butanone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylform It is carried out in conventional solvents such as amides, pyridine or other organic solvents that do not adversely affect the reaction, or mixtures thereof.

The reaction temperature is not limited and the reaction is usually carried out under cooling to heating.

Process 3

The desired compound (Ig ') or a salt thereof can be prepared by reacting compound (IV) or a derivative thereof or a salt thereof with which an imino group is reactive with compound (V) or a salt thereof.

Suitable reactive derivatives in which the imino group of compound (IV) is reactive include Schiff-based imino or a tautomer enamine type isomer thereof formed by the reaction of compound (IV) with a carbonyl compound such as aldehyde, ketone, or the like; Silyl derivatives formed by the reaction of a compound (IV) with a silyl compound such as bis (trimethylsilyl) acetamide, mono (trimethylsilyl) acetamide, bis (trimethylsilyl) urea and the like; Phosphorus trichloride or derivatives formed by the reaction of phosgene with compound (IV) and the like.

This reaction is usually carried out in solvents such as alcohols (eg methanol, ethanol, etc.), dichloromethane, benzene, N, N-dimethylformamide, tetrahydrofuran, diethyl ether or other solvents which have no adverse effect on the reaction.

The reactions include alkali metal hydroxides [eg sodium hydroxide, potassium hydroxide, etc.], alkali metal carbonates [eg sodium carbonate, potassium carbonate, etc.], alkali metal bicarbonates [eg sodium bicarbonate, potassium bicarbonate, Etc.], alkali metal hydrides [eg sodium hydride, potassium hydride, etc.], tri (lower) alkylamines [eg trimethylamine, triethylamine, diisopropylethylamine, etc.], pyridine or derivatives thereof Picoline, lutidine, 4-dimethylaminopyridine, and the like], and the like. If the base is used in liquid phase, it can also be used as a solvent.

The reaction temperature is not limited and the reaction can be carried out under cooling, at room temperature or under warming or heating.

Process 4

Compound (Ig) or a salt thereof may be prepared by reacting compound (IV) or a derivative thereof whose imino group is reactive or a salt thereof with a compound (VI) or a derivative thereof whose salt or carboxyl group is reactive.

The reaction can be carried out in the manner described in Preparation 10 or in a manner similar thereto.

The compound of interest of the present invention has pharmacological activity such as tachykinin antagonism, in particular substance P antagonism, neurokinin A antagonism or neurokinin B antagonism, and thus Takikinin-mediated disease, in particular sub Stance P-intervening diseases such as asthma, bronchitis (eg chronic bronchitis, acute bronchitis and widespread bronchiolitis, etc.), rhinitis, colds, sputum, and the like; Eye diseases such as conjunctivitis, spring conjunctivitis, and the like; Skin diseases such as contact dermatitis, atopic dermatitis, urticaria, and other eczema dermatitis, and the like; Inflammatory diseases such as rheumatoid arthritis, osteoarthritis, and the like; Pain or pain (eg migraine, headache, cluster headache, toothache, cancer pain, back pain, neuralgia, etc.); It is useful for treating or preventing the back.

In addition, the target compounds of the present invention include eye diseases such as glaucoma, uveitis, and the like; Gastrointestinal diseases such as ulcers, ulcerative colitis, irritable bowel syndrome, food allergies, and the like; Inflammatory diseases such as nephritis, etc .; Circulatory diseases such as hypertension, angina pectoris, heart failure, thrombosis, Raynaud's disease, and the like; epilepsy; Convulsive paralysis; Frequent uremia; cystitis; Bladder pressure reflex hyperactivity; Urinary incontinence; Parkinson's disease; dementia; AIDS-related dementia; Alzheimer's disease; Down syndrome; Huntington chorea; Carcinoid syndrome; Disorders associated with increased or suppressed immunity; Disorders caused by Helicobacter pyrroli or other spiral urease-positive Gram-negative bacteria; burn; Diseases caused by angiogenesis or angiogenesis; It is assumed to be useful for treating or preventing the back.

In addition, the target compounds of the present invention include chronic obstructive pulmonary disease, especially chronic emphysema; Iris salt; Proliferative vitreoretinopathy; psoriasis; Inflammatory bowel disease, especially Crohn's disease; hepatitis; Superficial pain for frostbite, burns, shingles or diabetic neurosis; Tenderness associated with hyperlipidemia; For postoperative neuroma, especially mastectomy; Vulvar spermitis; Hemodialysis-related itching; Lichen planus; Pharyngitis; Bronchiectasis; Pneumoconiosis; whooping cough; tuberculosis; Cystic fibrosis; throw up; Mental disorders, especially anxiety, depression, mood modulation disorders and schizophrenia; Dehydration diseases such as multiple sclerosis and amyotrophic lateral sclerosis; Morphine withdrawal; Edema, such as edema caused by laceration; Small cell cancer, in particular small cell lung cancer (SCLC); Hypersensitivity diseases such as ivy; Fibrotic and collagen diseases such as scleroderma and eosinophilic epilepsy; Reflex sympathetic dystrophy, such as shoulder / hand syndrome; Addictive diseases such as alcoholism; Stress related physical diseases; Rheumatic diseases such as fibritis; It is expected to be useful for treating or preventing the back.

For therapeutic purposes, the compound of interest of the present invention may be used as an active ingredient, orally, parenterally, externally, including topical, intestinal, intravenous, intramuscular, inhaled, nasal, intraarticular, intravertebral, canal or ophthalmic. It may be used in the form of a pharmaceutical formulation which is mixed with a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient suitable for administration. Pharmaceutical preparations are solids such as capsules, tablets, pellets, dragees, powders, granules, suppositories, ointments, creams, lotions, inhalants, injections, cataplasms, gels, tapes, eye drops, solutions, syrups, aerosols, suspensions, emulsions, etc. , Semisolid or solution. If necessary, these preparations may contain auxiliary substances, stabilizers, wetting or emulsifying agents, buffers and other commonly used additives.

Dosages of the target compound will vary depending on the age and symptoms of the patient, but mean single doses of about 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg of the target compound may be used, such as asthma. It can be effective in treating kininine-mediated diseases. Generally, an amount of 0.1 mg / body to about 1,000 mg / body may be administered daily.

In order to illustrate the usefulness of the target compound, pharmacological test data for the representative compound of the present invention is presented below.

The following test compound showed a greater than 90% inhibition rate for ¹²⁵ I-BH-substances P bound to the h-NK ₁ receptor at a concentration of 0.1 μg / ml.

Test compound: target compound of Example 2

¹²⁵ I-BH-Substance P bound to h-NK ₁ receptor

Test Method: ¹²⁵ I-BH-Substance P Binding to h-NK ₁ Receptor

(a) original CHO cell membrane specimen

CHO cells permanently expressing the h-NK ₁ receptor were harvested and buffered as a Downs homogenizer (0.25 M sucrose, 25 mM Tris-HCl pH 7.4, 10 mM MgCl ₂ , 1 mM EDTA, 5 μg). / Ml p-APMSF) at 4 ° C. The homogenate was centrifuged (500 X g, 10 minutes), the pellet was redispersed in the same buffer, homogenized and centrifuged. Two supernatants were combined and centrifuged (100,000 X g, 1 hour). The original cell membrane thus separated was redispersed in buffer (25 mM Tris-HCl pH 7.4, 10 mM MgCl ₂ , 1 mM EDTA, 5 μg / ml p-APMSF) and stored at −80 ° C. until use.

(b) ¹²⁵ I-BH-Substance P bound to the sample membrane

Cell membrane (6 μg / ml) was added to Medium 2 (50 mM Tris-HCl pH 7.4, 5 mM MnCl ₂ , 20 μg / ml Chimostatin, 40 μg / ml Bacitracin, 4 μg / ml Lupetin, 5 μg / ml ) p-APMSF, 200 μg / ml BSA) was incubated with ¹²⁵ I-BH-substance P (0.1 nM) for 90 min at 22 ° C. with or without test compound. At the end of the incubation period, the contents were filtered rapidly under intake in a Whatman GF / C glass filter (pretreated for 3 hours as 0.1% polyethylene amine before use). Each filter was then washed four times with 5 ml of buffer (50 mM Tris-HCl pH 7.4, 5 mM MnCl ₂ ). Radioactivity was measured using an Auto Gamma counter (Packerd RIASTAR 5420A). All data presented are specific binding defined as replaceable by 3 μΜ unlabeled substance P.

In addition, the compound of the present invention, in particular, the compound (If) is excellent in stability and the like.

The following preparations and examples are given in more detail for the purpose of illustrating the invention.

Preparation Example 1

To a mixture of N2- (tert-butoxycarbonyl) -N1-formyl-D-tryptophan (3.99 g) and N-benzyl glycine benzyl ester hydrochloride (3.50 g) in dichloromethane (70 mL) under a nitrogen atmosphere Ethylamine (5.85 mL) was added. 2-chloro-1-methylpyridinium iodide (3.67 g) was added to the mixture at room temperature, and the obtained mixture was stirred for 2 hours. After the reaction was completed, dichloromethane (30 mL) and water (30 mL) were added. The organic layer was separated, washed successively with 0.5 N hydrochloric acid (10 mL), water (10 mL), aqueous sodium bicarbonate solution (10 mL) and brine (20 mL) and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified on a silica gel column (140 g) eluted with a mixture of toluene and ethyl acetate (4: 1) to give (2R) -N-benzyl-N-benzyloxycarbonylmethyl- as an oil. 2- (tert-butoxycarbonylamino) -3- (N-formyl-1H-indol-3-yl) propanamide (6.41 g) was provided.

IR (CHCl ₃ ): 3300, 2970, 1740, 1700, 1644, 1604 cm ^-1

NMR (DMSO-d ₆ , δ): 0.89, 1.22 and 1.29 (9H, 3s); 2.80-3.10 (2H, m); 3.95-4.25 (2H, m); 4.40-4.90 (3H, m); 4.95-5.20 (2H, m); 7.05-7.75 (15 H, m); 7.98 and 8.22 (1 H, 2 br s); 9.22 and 9.61 (1 H, 2 br s)

MASS: 570 (M + 1)

Preparation Example 2

To an ice-cold solution of the target compound (6.39 g) of Preparation Example 1 in dichloromethane (50 mL) was added 4N hydrogen chloride in dioxane solution (50 mL). The mixture was stirred at the same temperature for 30 minutes and at room temperature for 1 hour. After evaporation of the solvent, the residue was partitioned between dichloromethane (50 mL) and aqueous sodium bicarbonate solution (30 mL). The organic layer was separated, dried over magnesium sulphate and filtered. Triethylamine (1.67 mL) was added to the filtrate at room temperature, and the mixture was stirred for 1.5 hours. After evaporation, the residue is triturated with diisopropyl ether, collected by filtration and dried to (3R) -1-benzyl-3- (N-formyl-1H-indol-3-ylmethyl) piperazin- 2,5-dione (3.93 g) was provided.

mp: 176-178 ° C

IR (Nujol): 3250, 1709, 1648, 1630 cm ^-1

NMR (DMSO-d ₆ , δ): 2.95-3.30 and 3.35-3.70 (4H, 2 m); 4.22 (1H, doublet, J = 14.6 Hz); 4.30-4.40 (1 H, m); 4.54 (1H, doublet, J = 14.9 Hz); 6.80-7.75 (9H, m); 7.95-8.50 (2H, m); 9.20 and 9.65 (1 H, 2 br s)

Preparation Example 3

To an ice-cold solution of the target compound (3.89 g) of Preparation Example 2 in a mixture of methanol (175 mL) and tetrahydrofuran (50 mL) was added an aqueous 0.1 N sodium hydroxide solution (108 mL). The mixture was stirred at the same temperature for 30 minutes and at room temperature for 1.5 hours. After evaporation of the solvent, the residue was extracted with dichloromethane. The organic layer was washed with water and aqueous sodium chloride solution and dried over magnesium sulfate. Evaporation of the solvent gave (3R) -1-benzyl-3- (1H-indol-3-ylmethyl) piperazine-2,5-dione (3.68 g).

mp: 207-208 ° C

IR (Nujol): 3402, 1650 cm ^-1

NMR (DMSOd ₆ , δ): 2.68 (1H, d, J = 17.2 Hz,); 3.04 (1H, doublet of doublets, J = 14.4 and 4.4 Hz); 3.20-3.40 (2H, m); 4.24 (1 H, s); 4.10-4.40 (2H, m); 6.75-7. 60 (10H, m); 8.35 (1 H, s); 10.94 (1 H, s)

MASS: 334 (M + 1)

Preparation Example 4

To a suspension of lithium aluminum hydride (0.77 g) in tetrahydrofuran (40 mL) was added dropwise a solution of the target compound (3.40 g) of Preparation Example 3 in tetrahydrofuran (40 mL) at 0 ° C. under nitrogen atmosphere. The mixture was stirred at room temperature for 50 minutes and at reflux for 1 hour. The resulting mixture was diluted with tetrahydrofuran (60 mL) and cooled to 0 ° C. Water (3.0 mL) and 15% aqueous sodium hydroxide solution (0.8 mL) were added slowly. The insoluble inorganic material obtained was removed by filtration and washed with tetrahydrofuran. The filtrate and washings were combined and evaporated under reduced pressure to give (3R) -1-benzyl-3- (1H-indol-3-ylmethyl) piperazine (3.68 g) as an oil.

IR (CHCl ₃ ): 3240, 3040, 2900 cm ^-1

NMR (DMSO-d ₆ , δ): 1.70-2.00 and 2.30-2.45 (2H, 2 m); 2.50-3.00 (7H, m); 3.25-3.60 (3H, m); 6.80-7. 60 (10H, m); 10.80 (1 H, s)

MASS: 306 (M + 1)

Preparation Example 5

A mixture of 3.5-bis (trifluoromethyl) benzoic acid (1.15 g) and (3R) -1 -benzyl-3- (1H-indol-3-ylmethyl) piperazine (1.61 g) in dichloromethane (80 mL) To this was added triethylamine (1.55 mL) at room temperature under a nitrogen atmosphere. 2-chloro-1-methylpyridinium iodide (1.37 g) was added and the mixture was stirred at room temperature for 2.5 hours. The resulting mixture was poured into water (20 mL). The organic layer was washed successively with 0.5 N hydrochloric acid, water, aqueous sodium bicarbonate solution and brine, and dried over magnesium sulfate. After evaporation under reduced pressure, the residue was chromatographed on silica gel with toluene-ethyl acetate (4: 1) as eluent to give (2R) -4-benzyl-1- [3,5-bis (trifluoromethyl) as a syrup. Benzoyl] -2- (1H-indol-3-ylmethyl) piperazine (0.87 g) was provided.

IR (CHCl ₃ ): 3430, 3300, 3000, 2910, 2800, 1630-1610 cm ^-1

NMR (DMSOd ₆ , δ): 1.90-2.40 (2H, m); 2.70-3.90 (8H, m); 4.25-4.40 and 4.75-4.90 (1 H, m)); 6.50-7.45 (10H, m); 7.50-8.25 (3H, m); 10.77 (1H, s)

MASS: 546 (M + 1)

Preparation Example 6

(2R) -4-benzyl-1- [3,5-bis (trifluoromethyl) -benzoyl] -2- (1H-indol-3-ylmethyl) piperazine (5.20 g) in ethanol (50 mL) A mixture of, ammonium formate (1.50 g) and 10% Pd charcoal (0.52 g) was refluxed for 7.5 hours under nitrogen atmosphere. The reaction mixture was cooled to room temperature and filtered through a pad of celite. The filtrate was concentrated under reduced pressure and the residue was purified on a silica gel column eluted with a mixture of dichloromethane and methanol (20: 1) to give (2R) -1- [3,5-bis (trifluoromethyl) as a syrup. -Benzoyl] -2- (1H-indol-3-ylmethyl) piperazine (2.67 g) was provided.

IR (CHCl ₃ ): 3280, 2900, 1622 cm ^-1

NMR (DMSOd ₆ , δ): 2.50-3.50 (9H, m); 3.6-4.8 (1 H, m); 6.55-7.40 (5H, m); 7.50-8.22 (3H, m); 10.84 (1H, s)

MASS: 456 (M + 1)

Preparation Example 7

(2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- (1H-indol-3-ylmethyl) piperazine (1.5 g), benzyl 2-bromoacetate (0.79 g) , A mixture of triethylamine (0.55 mL) and tetrahydrofuran (15 mL) was stirred overnight at room temperature. The obtained insoluble matter was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluted with a mixture of dichloromethane and methanol (30: 1) to give (2R) -4- (benzyloxycarbonylmethyl) -1- [3,5-bis ( Trifluoromethyl) benzoyl] -2- (1H-indol-3-ylmethyl) -piperazine (1.92 g) was provided.

[α] _D ²¹ : -11.6。 (C = 1.0, MeOH)

IR (Neat): 3600-3100, 1735, 1626, 1275, 1129, 900 cm ^-1

NMR (DMSO-d ₆ , δ): 2.20-5.20 (13H, m); 6.60-8.20 (13 H, m); 10.85 (1H, broad singlet)

MASS: 604 (M + 1), 454

Preparation Example 8

(2R) -4- (benzyloxycarbonylmethyl) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- (1H-indol-3-ylmethyl) piperazine (1.86 g), A mixture of 10% Pd charcoal (0.186 g) and tetrahydrofuran (93 mL) was stirred for 17 hours under hydrogen gas atmosphere (1 atm). The catalyst was removed by filtration and the filtrate was concentrated. The residue was triturated with ethyl ether to give (2R) -4- (carboxymethyl) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- (1H-indol-3-ylmethyl as white powder. ) Benzoyl] piperazine (0.83 g) was provided.

[α] _D ¹⁹ : -3.0。 (C = 0.5, DMF)

mp: 152-156 ° C.

IR (Nujol): 3600-3100, 1654, 1630, 1277, 1196, 1130 cm ^-1

NMR (DMSO-d ₆ , δ): 2.20-5.20 (11H, m); 6.60-8.20 (8H, m); 10.85 (1 H, s)

MASS: 514 (M + 1)

Preparation Example 9

To an ice cold mixture of (2R) -2-benzyl-1- [3,5-bis (trifluoromethyl) benzoyl] piperazine (0.3 g) and triethylamine (0.39 mL) in dimethylformamide (8 mL). 3- (chloromethyl) pyridine hydrochloride (0.12 g) was added. The reaction mixture was stirred at the same temperature for 30 minutes and then at room temperature for 2 hours. Additional triethylamine (0.39 mL) and 3- (chloromethyl) pyridine hydrochloride (0.12 g) were added and the resulting mixture was stirred overnight. The reaction mixture was filtered and the filtrate was concentrated and chromatographed on silica gel eluted with a mixture of toluene and ethyl acetate (5: 1). The eluate was treated with 4N hydrogen chloride in ethyl acetate solution to give (2R) -2-benzyl-1- [3,5-bis (trifluoromethyl) benzoyl] -4- (pyridin-3-ylmethyl) piperazine dihydro. Chloride was provided.

mp: 164-168 ° C.

[α] _D ²⁵ : +9.1。 (C = 1.0, MeOH)

IR (Nujol): 3700-3100, 2700-2000, 1630, 1270, 1120, 900 cm ^-1

NMR (DMSO-d ₆ , δ): 2.80-5.40 (11H, m); 6.85-6.90 (1 H, m); 7.10-7.40 (4H, m); 7.46 (1 H, s); 7.75 (1 H, s); 7.90-8.00 (1 H, m); 8.19-8.23 (1 H, m); 8.66-8.70 (1 H, m); 8.88-8.91 (1 H, m); 9.09 (1 H, s)

MASS: 508 (M + 1) (free)

Preparation Example 10

(2R) -2-benzyl-1- [3,5-bis (trifluoromethyl) benzoyl] piperazine (0.3 g) and 2- in dichloromethane (8 mL) containing triethylamine (0.25 mL) To a stirred mixture of (1H-indol-3-yl) acetic acid (0.13 g) was added 2-chloro-1-methylpyridinium iodide (0.22 g) at ambient temperature under a nitrogen atmosphere. After stirring for 5 hours, the reaction mixture was diluted with dichloromethane and washed with 0.1N hydrochloric acid, saturated aqueous sodium bicarbonate and brine and dried over magnesium sulfate. After removal of the solvent, the residue was purified by column chromatography on silica gel using chloroform-methanol (50: 1) as eluent to afford (2R) -2-benzyl-1- [3,5-bis () as a white powder. Trifluoromethyl) benzoyl] -4- [2- (1H-indol-3-yl) acetyl] piperazine (0.34 g) was provided.

mp: 201-210 ° C.

[α] D 27: +27.6. (C = 1.0, MeOH)

IR (Nujol): 3270, 1630, 1276, 1115, 900, 737 cm-1

NMR (DMSOd6, δ): 2.60-5.00 (11H, m); 6.70-7.70 (12H, m); 8.10-8.20 (1 H, m); 10.85-11.10 (1H, m)

MASS: 574 (M + 1), 417

Preparation Example 11

To a solution of (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- (1H-indol-3-ylmethyl) piperazine (0.1 g) in dichloromethane (10 mL) 4N hydrogen chloride in oxane solution (0.05 mL) was added at 0 ° C. The resulting mixture was stirred at the same temperature for 50 minutes and then concentrated under reduced pressure. The powder obtained was collected by filtration and washed with ethyl ether to give (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- (1H-indol-3-ylmethyl) piperazine hydrochloride (0.1 g) was provided.

IR (Nujol): 3340, 1648 cm-1

NMR (DMSOd6, δ): 2.9-3.9 (8H, m); 3.9-5.2 (1 H, m); 6.57-7.50 (5H, m); 7.50-8.30 (3H, m); 9.40-10.00 (2H, m); 10.96 (1H, s)

MASS: 456 (M + 1) (free)

Preparation Example 12

(2R) -4- (2-aminoethyl) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) piperazine di in dichloromethane (10 mL) To a stirred mixture of hydrochloride (110 mg) and triethylamine (0.2 mL) was added methanesulfonyl chloride (0.1 mL) at 0 ° C. After stirring for 1 hour, the reaction mixture was poured into iced water and extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium bicarbonate and brine and dried. After evaporation of the solvent under vacuum, the residue was purified by column chromatography on silica gel eluted with a mixture of dichloromethane and methanol (40: 1) and treated with 4N hydrogen chloride in ethyl acetate solution to give (2R) -1- [ 3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- [2- (mesylamino) ethyl] piperazine hydrochloride (50 mg) was provided.

mp: 220 ° C.

[α] _D ²² : +0.2。 (C = 0.5, DMF)

IR (Nujol): 3350, 2700-2400, 1645, 1500, 1450, 1380 cm ^-1

NMR (DMSOd ₆ , δ): 2.10 and 2.18 (6H, 2s); 2.7-5.2 (17H, m); 6.6-7.7 (5H, m); 8.1-8.2 (1 H, m); 11.05-11.4 (1H, m)

MASS: 566 (M + 1) (free)

Example 1

(2R) -4- (carboxymethyl) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- (1H-indol-3-ylmethyl) pipet in dry dimethylformamide (10 mL) To a stirred solution of lazine (1 g) was added 1-hydroxybenzotriazole (0.29 g) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.41 g) at room temperature. After 15 minutes of stirring at room temperature, 1-amino-4-methylpiperazine (320 mg) was added, followed by stirring at the same temperature for 5 hours. The reaction mixture was poured into a solution of sodium hydrogencarbonate (1.8 g) in water (100 mL) and extracted three times with 20 mL portions of ethyl acetate. The organic layers were combined and washed with brine (30 mL). The organic layer was dried over magnesium sulphate, filtered and the solvent removed by rotary evaporator. The crude product was purified by chromatography (silica gel, dichloromethane: methanol, 5: 1) to give (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- (1H as a yellow powder. -Indol-3-ylmethyl) -4- [N- (4-methyl-1-piperazinyl) carbamoylmethyl] piperazin (0.94 g) was obtained.

IR (Nujol): 3180, 1680, 1630, 1276, 1170, 1130, 1005, 897 cm-1

NMR (DMSOd6, δ): 2.16 (3H, s); 2.0-5.0 (19 H, m); 6.6-8.2 (8H, m); 8.47, 8.77 (1 H, 2s); 10.85 (1 H, s)

Example 2

(2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- (1H-indol-3-ylmethyl) -4- [N- (4-methyl-1-piperazinyl) Carbamoylmethyl] piperazine (10.89 g) and fumaric acid (2.07 g) were dissolved in ethanol (50 mL) at 70 ° C. After cooling, the resulting solution was concentrated under reduced pressure to give a powder (13.18 g). The powder (9.86 g) was dissolved in 2-butanone (194 mL) at reflux temperature and the solution was stirred at room temperature to obtain crystals, which were filtered out and dried by (2R) -1- [3,5-bis (Trifluoromethyl) benzoyl] -2- (1H-indol-3-ylmethyl) -4- [N- (4-methyl-1-piperazine) carbamoylmethyl] piperazin fumarate (7.94 g) Provided.

mp: 169.5-171 ° C.

IR (Nujol): 3220, 1700, 1653, 1630, 1275, 1217, 1168, 1122, 979, 894, 730 cm-1

NMR (DMSOd6, δ): 2.23, 2.26 (3H, 2s); 2.10-4.93 (19 H, m); 6.60 (2H, s); 6.54-8.23 (8H, m); 8.50, 8.85 (1 H, 2s); 10.85 (1 H, s)

Example 3

Compound (If), i.e. (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- (1H-indol-3-ylmethyl) -4- [N- (4-methyl- 1-piperazinyl) carbamoylmethyl] piperazin fumarate was obtained according to the following scheme.

Example 4

(2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- (1H-indol-3-ylmethyl) piperazine (120 mg), 4-chloromethyl- in dry dimethylformamide A mixture of 2- (2-methoxyethylcarbonylamino) triazole (70 mg) and bovine sodium hydrogencarbonate (27 mg) was stirred at 60 ° C. for 5 hours 20 minutes. The reaction mixture was poured into water and the precipitate obtained was collected by filtration. The crude product was purified by column chromatography on silica gel eluted as a mixture of dichloromethane and methanol (30: 1). Eluate was evaporated under reduced pressure and treated with 17.6% hydrogen chloride in ethanol (0.12 mL) to give (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- (1H-indol-3-yl Methyl) -4-[[2- (3-methoxypropanoylamino) triazol-4-yl] methyl] piperazin hydrochloride (140 mg) was provided.

[α] D22: -34/0。 (C = 0.5, MeOH)

IR (Nujol): 3650-3100, 2750-2000, 1635, 1275, 1130, 900 cm-1

NMR (DMSOd6, δ): 2.60-5.20 (18H, m); 6.60-8.21 (9H, m); 10.90-11.00 (1 H, m); 11.20-12.00 (1 H, m); 12.19 (1 H, s)

MASS: 654 (M + 1) (free)

Example 5

The following piperazine derivatives (Table 1) were prepared in a manner similar to that of each example number or preparation number defined in the process column. The physical properties of the target compound are shown after the table.

Physical Properties for the Compound of Example 5:

Example 5-1)

mp: 185-189 ° C.

[α] _D ²⁴ : 30.2 ° (C = 0.5, MeOH)

IR (Nujol): 3660-3100, 2800-2000, 1635, 1545, 1276, 1183, 1130, 900 cm ^-1

NMR (DMSO-d ₆ , δ): 1.36-5.10 (14H, m); 6.59-8.22 (10 H, m); 10.90-11.00 (1 H, m); 12.15 (1 H, s)

MASS: 610 (M + 1) (free), 456

Example 5-2

mp: 185-189 ° C.

[α] _D ²² : -33.4 ° (C = 0.5, MeOH)

IR (Nujol): 3650-3100, 2800-2000, 1715, 1635, 1555, 1274, 1130, 900 cm ^-1

NMR (DMSOd ₆ , δ): 1.25 (3H, t, J = 7.1 Hz,); 2.73-5.10 (13 H, m); 6.60-8.30 (9H, m); 10.90-11.00 (1 H, m); 11.81 (1H, broad singlet)

MASS: 640 (M + 1) (free), 456

Example 5-3)

[α] _D ²² : -42.0 ° (C = 0.5, MeOH)

IR (Nujol): 3600-3100, 2750-2000, 1635, 1540, 1277, 1175, 1130 cm ^-1

NMR (DMSOd ₆ , δ): 2.73-5.20 (11H, m); 6.59-8.21 (14H, m); 10.90-11.00 (1 H, m); 12.69 (1 H, s)

MASS: 672 (M + 1) (free), 456

Example 5-4)

[α] _D ²² : -24.2 ° (C = 0.5, MeOH)

IR (Nujol): 3650-3100, 2750-2000, 1635, 1540, 1276, 1170, 900 cm ^-1

NMR (DMSOd ₆ , δ): 1.23 (9H, s); 2.73-5.10 (11 H, m); 6.50-8.20 (9H, m); 10.80-11.00 (1H, m); 11.84 (1 H, s)

MASS: 652 (M + 1) (free), 456

Example 5-5)

[α] _D ²² : -35.8 ° (C = 0.5, MeOH)

IR (Nujol): 3650-3100, 2750-2000, 1635, 1540, 1276, 1170, 1130, 900 cm ^-1

NMR (DMSO-d ₆ , δ): 0.80-1.00 (4H, m); 1.90-2.00 (1 H, m); 2.73-5.15 (11 H, m); 6.60-8.21 (9H, m); 10.90-11.00 (1 H, m); 12.43 (1 H, m)

MASS: 636 (M + 1) (Free), 456

Example 5-6)

[α] _D ²² : -30.4 ° (C = 0.5, MeOH)

IR (Nujol): 3650-3100, 2750-2000, 1635, 1542, 1275, 1170, 1131, 900 cm ^-1

NMR (DMSOd ₆ , δ): 0.89 (3H, t, J = 7.4 Hz); 1.56-1.67 (2H, m); 2.40-2.50 (2H, m); 2.73-5.15 (11 H, m); 6.56-8.21 (9H, m); 10.90-10.94 (1 H, m); 12.12 (1H, s)

MASS: 638 (M + 1) (free)

Example 5-7)

[α] _D ²² : -34.0 ° (C = 0.5, MeOH)

IR (Nujol): 3650-3100, 2750-2000, 1635, 1543, 1277, 1170, 1130, 900 cm ^-1

NMR (DMSOd ₆ , δ): 1.08 (3H, t, J = 7.4 Hz); 2.43-2.50 (2H, m); 2.73-5.15 (11 H, m); 6.55-8.21 (9H, m); 10.90-10.94 (1 H, m); 12.11 (1 H, s)

MASS: 624 (M + 1) (free)

Example 5-8)

[α] _D ²² : -15.2 ° (C = 0.5, MeOH)

IR (Nujol): 3600-3100, 2750-2000, 1635, 1278, 1172, 1130, 900 cm ^-1

NMR (DMSOd ₆ , δ): 2.73-5.20 (11H, m); 6.60-8.52 (11 H, m); 10.94 (1 H, s)

MASS: 596 (M + 1) (free), 456

Example 5-9)

[α] _D ²² : -20.6 ° (C = 0.5, MeOH)

IR (Nujol): 3650-3100, 2750-2000, 1635, 1`276, 1170, 1129, 900 cm ^-1

NMR (DMSOd ₆ , δ): 2.09 (3H, s); 2.73-5.20 (11 H, m); 6.60-8.20 (11 H, m); 10.46 (1 H, s); 10.91 (1 H, s)

MASS: 604 (M + 1) (free)

Example 5-10)

[α] _D ²² : -13.0 ° (C = 0.5, MeOH)

IR (Nujol): 3650-3050, 2750-2000, 1685, 1636, 1524, 1275, 1130, 900 cm ^-1

NMR (DMSOd ₆ , δ): 1.31 (3H, t, J = 6.5 Hz); 2.24 (3H, s); 2.73-5.20 (13 H, m); 6.66-8.25 (8H, m); 10.94 (1 H, s); 12.71 (1 H, s)

MASS: 682 (M + 1) (free)

Example 5-11)

[α] _D ¹⁸ : -20.8 ° (C = 0.5, MeOH)

IR (Neat): 3700-3000, 1615, 1515, 1272, 1125, 900 cm ^-1

NMR (DMSO-d ₆ , δ): 2.00-5.00 (13H, m); 6.38-8.20 (9 H, m); 10.80 (1 H, s)

MASS: 568 (M + 1), 456

Example 5-12)

[α] _D ²² : -10.4 ° (C = 0.5, MeOH)

IR (Nujol): 3650-3100, 2750-2000, 1635, 1277, 1130 cm ^-1

NMR (DMSOd ₆ , δ): 3.00-5.20 (11H, m); 6.60-8.30 (11 H, m); 10.95 (1H, s)

MASS: 568 (M + 1) (free), 456

Example 5-13)

[α] _D ²² : -31.8 ° (C = 0.5, MeOH)

IR (Nujol): 3270, 2750-2000, 1637, 1531, 1279, 1124, 964 cm ^-1

NMR (DMSOd ₆ , δ): 2.73-5.15 (14H, m); 6.60-8.25 (10 H, m); 10.89 (1H, s)

MASS: 646 (M + 1) (free), 568, 456

Example 5-14)

[α] _D ²³ : 11.8 ° (C = 0.5, MeOH)

IR (Nujol): 3650-3100, 1625, 1543, 1275, 1130 cm ^-1

NMR (DMSOd ₆ , δ): 2.09-2.11 (3H, m); 2.52-5.00 (11 H, m), 6.63-8.20 (9 H, m); 10.85 (1 H, s); 12.07 (1 H, s)

MASS: 638 (M + 1), 456

Example 5-15)

[α] _D ¹⁸ : -51.6 ° (C = 0.5, MeOH)

IR (Nujol): 3650-3100, 2750-2000, 1634, 1540, 1274, 1170, 1127, 900 cm ^-1

NMR (DMSOd ₆ , δ): 2.31 (3H, s); 2.73-5.35 (11 H, m); 6.63-8.25 (8H, m); 10.94-11.00 (1 H, m); 13.20 (1 H, s)

MASS: 611 (M + 1) (free)

Example 5-16)

[α] _D ²² : -23.4 ° (C = 0.5, MeOH)

IR (Nujol): 3650-3000, 2750-2000, 1620, 1274, 1175, 1128, 900 cm ^-1

NMR (DMSOd ₆ , δ): 1.10 (3H, t, J = 7.2 Hz), 2.60-5.10 (16H, m); 6.50-8.21 (9H, m); 10.91 (1 H, s); 11.50-11.90 (1H, broad singlet)

MASS: 638 (M + 1) (free)

Claims (8)

Compounds of the formula or fumarates thereof: A compound according to claim 1 which is a compound of the formula: A process for preparing a compound of the formula: (1) A compound of the formula By reacting a compound of formula To obtain a compound of formula (2) by reacting a compound of the following formula or a salt other than fumarate with fumaric acid Obtaining a compound of the formula: A pharmaceutical composition comprising the compound of claim 1 as an active ingredient in combination with a pharmaceutically acceptable and in fact non-toxic carrier or excipient. A method of treating or preventing tachykinin-mediated disease comprising administering to a human or animal an effective amount of the compound of claim 1. The compound of claim 1 for use as a medicament. Use of the compound of claim 1 for the manufacture of a medicament for treating or preventing tachykinin-intervening disease. Compounds of the formula or pharmaceutically acceptable salts thereof Wherein R ¹ is trihalo (lower) alkyl, R ² is trihalo (lower) alkyl, R ³ is indolyl (lower) alkyl, -A- is -CH ₂ -or , -R ⁴ is , or ego Wherein R ⁵ is hydrogen or lower alkoxycarbonyl, R ⁶ is hydrogen or lower alkanoyl, R ⁷ is hydrogen, lower alkyl, lower alkanoyl, lower alkoxycarbonyl, lower alkoxy (lower) alkanoyl, cyclo (lower) Alkylcarbonyl, aroyl or lower alkylsulfonyl.