CN1072220C - 1-benzoyl-2-(indolyl-3-alkyl)-piperazine derivs. as neurokinin receptor antagonists - Google Patents

Abstract

This invention relates to compounds of generic formula (I), to a process for preparation thereof, to a pharmaceutical composition comprising the same, and to a use of the same 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 -CH2- or (a), and -R<4> is (b), (c) or (d) in which 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, or its pharmaceutically acceptable salt.

Description

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

technical field

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

More specifically, the present invention relates to novel piperazine derivatives having pharmacological activities such as tachykinin antagonism, especially substance P antagonism, neurokinin A antagonism, neurokinin B antagonism, etc., and pharmaceutically acceptable salts of , relating to preparation methods thereof, pharmaceutical compositions containing such compounds, and uses of such compounds as medicaments.

Accordingly, it is an object of the present invention to provide new and useful piperazine derivatives having pharmacological activities such as tachykinin antagonism, especially substance P antagonism, neurokinin A antagonism, neurokinin B antagonism, etc. and Its pharmaceutically acceptable salts.

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

Still another object of the present invention is to provide a pharmaceutical composition containing said piperazine derivative and a pharmaceutically acceptable salt thereof as an active ingredient.

Yet another object of the present invention is to provide the use of said piperazine derivatives or pharmaceutically acceptable salts thereof as tachykinin antagonists, especially substance P antagonists, neurokinin A antagonists or neurokinin B antagonists , for the treatment or prevention of diseases mediated by tachykinins in humans or mammals, for example, respiratory diseases such as asthma, bronchitis, rhinitis, cough, expectoration, etc.; eye diseases such as conjunctivitis, vernal (catarrhal) conjunctiva inflammation, etc.; skin diseases such as contact dermatitis, atopic dermatitis, urticaria and other eczema-like dermatitis, etc.; inflammatory diseases such as rheumatoid arthritis, osteoarthritis, etc.; pain or pain (such as migraine, headache, toothache, cancer pain, back pain, etc.); etc.

invention disclosure

即(2R)-1-〔3，5-二(三氟甲基)苯甲酰基〕-2-(1H-吲哚-3-基甲基)-4-〔N-(4-甲基-1-哌嗪基)氨基甲酰基甲基〕-哌嗪，或其富马酸盐，即(2R)-1-〔3,5-二(三氟甲基)苯甲酰基〕-2-(1H-吲哚-3-基甲基)-4-〔N-(4-甲基-1-哌嗪基)氨基甲酰基甲基〕-哌嗪富马酸盐〔以下简称为(If)〕。The object compound of the present invention is the compound of following formula (I):

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

其中R¹是三卤(低级)烷基，R²是三卤(低级)烷基，R³是吲哚基(低级)烷基，-A-是-CH₂-或

，以及-R⁴是

或

Other object compounds of the present invention can be represented by compounds represented by the following general formula (Ig) 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

, and -R ⁴ is

or

in

R ⁵ is hydrogen or lower alkoxycarbonyl,

R ⁶ is hydrogen or lower alkanoyl,

^R is hydrogen, lower alkyl, lower alkanoyl, lower alkoxycarbonyl, lower alkoxy (lower

(lower) alkanoyl, cyclo(lower)alkylcarbonyl, aroyl or lower alkylsulfonyl.

方法2 方法3

方法4 According to the present invention, said object compounds can be prepared by the methods illustrated in the following schemes. method 1

Method 2 Method 3

Method 4

Wherein R ¹ , R ² , R ³ and R ⁴ are as defined above;

-A ₁ -is -CH ₂ -; and

W is a leaving group.

Applicable salts and pharmaceutically acceptable salts of starting compounds and target compounds are generally non-toxic salts, including acid addition salts, such as salts of organic acids (such as acetate, trifluoroacetate, fumarate salt, maleate, tartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, etc.), or with amino acids (such as arginine, aspartic acid, glutamic acid, etc. ), or metal salts, such as alkali metal salts (such as sodium salt, potassium salt, etc.) and alkaline earth metal salts (such as calcium salt, magnesium salt, etc.), ammonium salts, organic alkali salts (such as trimethylamine salt, triethylamine amine salt, pyridinium salt, picoline salt, dicyclohexylamine salt, N,N'-benzylethylenediamine salt, etc.), or similar salts.

In the foregoing and subsequent descriptions of this specification, applicable examples and specific descriptions of each definition included within the scope of the present invention are explained in detail as follows.

The term "lower" means 1-6, preferably 1-4 carbon atoms, unless otherwise indicated.

"Lower alkyl" and "lower alkyl moieties" as used in the terms "indolyl(lower)alkyl" and "lower alkylsulfonyl" are straight chain or branched groups containing 1 to 6 carbon atoms Groups may include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, and the like.

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

"Lower alkoxy" and "lower alkoxy moieties" as used in the terms "lower alkoxycarbonyl" and "lower alkoxy(lower)alkanoyl" may include methoxy, ethoxy, isopropoxy base, butoxy, etc.

"Lower alkanoyl" and "lower alkanoyl moieties" as used in the term "lower alkoxy(lower)alkanoyl" may include formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl Acyl, pivaloyl, etc.

The "cyclo(lower)alkyl moiety" used in the term "cyclo(lower)alkylcarbonyl" may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

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

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

Applicable "reactive groups derived from hydroxyl groups" may include acid residues and the like.

Suitable "acid residues" may include halogens (such as fluorine, chlorine, bromine, iodine), acyloxy groups (such as acetoxy, tosyloxy, etc.), and the like.

Methods 1-4 for preparing the object compound of the present invention are explained in detail below.

method 1

The target compound (I) or its salt can be prepared by reacting compound (II) or its carboxyl reactive derivative or its salt with compound (III) or its amino reactive derivative or its salt.

Suitable reactive derivatives on the carboxyl group in compound (II) may include acid chlorides, acid anhydrides, activated amides, activated esters, and the like.

Examples of suitable reactive derivatives may be acid chlorides; acid azides; Phosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acid [such as methanesulfonic acid, etc.], aliphatic carboxylic acid [such as acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, valeric acid, isopentyl acid acid, 2-ethylbutyric acid, trichloroacetic acid, etc.] or mixed anhydrides formed from aromatic carboxylic acids [such as benzoic acid, etc.]; symmetrical anhydrides; imidazole, 4-substituted imidazole, dimethylpyrazole, Triazole or tetrazole-activated amides; or activated esters [such as cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl [(CH ₃ ) ₂ N ⁺ =CH-] ester, ethylene phenyl esters, propargyl esters, p-nitrophenyl esters, 2,4-dinitrophenyl esters, trichlorophenyl esters, pentachlorophenyl esters, methanesulfonyl phenyl esters, phenylazobenzene phenyl thioester, p-nitrophenyl thioester, p-toluene thioester, carboxymethyl thioester, pyryl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, etc.], or With N-hydroxy compounds [such as N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridine ester, N-hydroxysuccinimide, N-hydroxyphthalimide, 1 -Hydroxy-1H-benzotriazole, etc.] formed esters, etc. Active derivatives may optionally be selected from the above-mentioned ones according to the kind of compound (II) used.

Applicable active derivatives on the amino group of compound (Ⅲ) may include Schiff base-type imino groups or tautomeric enamine-type isomers generated by the reaction of compound (Ⅲ) with carbonyl compounds such as aldehydes, ketones or similar compounds body; from compound (Ⅲ) and silyl compounds such as bis (trimethylsilyl) acetamide, mono (trimethylsilyl) acetamide, bis (trimethylsilyl) urea or similar Silyl derivatives produced by the reaction of compounds; derivatives produced by the reaction of compound (Ⅲ) with phosphorus trichloride or phosgene and the like.

The reaction is usually carried out in a common solvent, such as water, alcohol [such as methanol, ethanol, etc.], acetone, 2-butanone, dioxane, acetonitrile, chloroform, dichloromethane, dichloroethane, tetrahydrofuran, ethyl acetate ester, N,N-dimethylformamide, pyridine, or any other organic solvent or mixture thereof that does not adversely affect the reaction.

In this reaction, when the compound (II) is used in the form of a free acid or its salt, the reaction is preferably carried out in the presence of a commonly used condensing agent, such as N,N'-dicyclohexylcarbodiimide, N -Cyclohexyl-N'-morpholinoethylcarbodiimide, N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide, N,N'-diethylcarbodiimide Imine, N,N′-diisopropylcarbodiimide, N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide, pentamethyleneketene-N-ring Hexylimine, diphenylketene-N-cyclohexylimine, ethoxyacetylene, 1-alkoxy-1-chloroethylene, trialkylphosphite, ethyl polyphosphate, isopropyl poly Phosphate, phosphorus oxychloride (phosphoryl chloride), phosphorus trichloride, diphenylphosphoryl azide, thionyl chloride, oxalyl chloride, lower alkyl haloformate [such as ethyl chloroformate, isopropyl chloroformate etc.], triphenylphosphine, 2-ethyl-7-hydroxybenzisoxazolium salt, 2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide internal 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 itself or in combination with 1-hydroxybenzotriazole, from N,N-dimethylformamide and thionyl chloride , Phosgene, trichloromethyl chloroformate, phosphorus oxychloride and other so-called Vilsmeier reagents, or similar condensing agents, or mixtures thereof.

The reaction can also be carried out in the presence of inorganic bases or organic bases such as alkali metal bicarbonate, tri(lower) alkylamine, pyridine, N-(lower) alkylmorpholine, N,N-di(lower)alkylbenzylamine , or in the presence of a similar base.

The reaction temperature is not critical, and the reaction is usually carried out under cooling or warming.

Method 2

The objective compound (If) can be produced by reacting compound (I) or a salt thereof (excluding fumarate) with fumaric acid.

The reaction is usually carried out in a common solvent, such as water, alcohol [such as methanol, ethanol, etc.], acetone, 2-butanone, dioxane, acetonitrile, chloroform, dichloromethane, dichloroethane, tetrahydrofuran, ethyl acetate ester, N,N-dimethylformamide, pyridine, or any other organic solvent or mixture thereof that does not adversely affect the reaction.

The reaction temperature is not critical, and the reaction is usually carried out under cooling or warming.

Method 3

The objective compound (Ig') or a salt thereof can be produced by reacting a compound (IV) or a reactive derivative thereof at the imine group or a salt thereof with a compound (V) or a salt thereof.

Applicable active derivatives on the imine group of compound (IV) may include imino groups of Schiff base type or tautomeric enamine types generated by the reaction of compound (IV) with carbonyl compounds such as aldehydes, ketones or similar compounds. Isomers; from compound (IV) and silyl compounds such as bis(trimethylsilyl)acetamide, mono(trimethylsilyl)acetamide, bis(trimethylsilyl)urea or Silyl derivatives generated by the reaction of similar compounds; derivatives generated by the reaction of compound (IV) with phosphorus trichloride or phosgene and the like.

The reaction is usually carried out in a solvent, such as alcohol [such as methanol, ethanol, etc.], dichloromethane, benzene, N,N-dimethylformamide, tetrahydrofuran, diethyl ether or any other solvent that does not adversely affect the reaction. in a solvent.

The reaction can be carried out in the presence of an inorganic base or an organic base, for example, in alkali metal hydroxides (such as sodium hydroxide, potassium hydroxide, etc.), alkali metal carbonates (such as sodium carbonate, potassium carbonate, etc.), alkali Metal bicarbonate (such as sodium bicarbonate, potassium bicarbonate, etc.), alkali metal hydride (such as sodium hydride, potassium hydride, etc.), tri (lower) alkylamine (such as trimethylamine, triethylamine, diisopropyl ethylamine, etc.], pyridine or its derivatives [such as picoline, lutidine, 4-dimethylaminopyridine, etc.], or similar bases. In case the base used is a liquid, the base can also be used as a solvent.

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

Method 4

Compound (Ig") or a salt thereof can be produced by reacting compound (IV) or a reactive derivative at the imine group or a salt thereof with compound (VI) or a carboxyl reactive derivative or a salt thereof.

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

The compounds of interest of the present invention have pharmacological activity, such as tachykinin antagonism, in particular substance P antagonism, neurokinin A antagonism or neurokinin B antagonism, and thus can be used for the treatment or prevention of tachykinin-mediated Diseases, especially those mediated by substance P, for example, respiratory diseases such as asthma, bronchitis (such as chronic bronchitis, acute bronchitis and diffuse panbronchitis, etc.), rhinitis, cough, expectoration, etc.; eye diseases such as conjunctivitis, Spring (catarrhal) conjunctivitis, etc.; skin diseases such as contact dermatitis, atopic dermatitis, urticaria and other eczema-like dermatitis, etc.; inflammatory diseases such as rheumatoid arthritis, osteoarthritis, etc.; pain or pain (such as migraine, headache, cluster headache, toothache, cancer pain, back pain, neuralgia, etc.); etc.

Furthermore, it is expected that the object compound of the present invention can also be used for the treatment or prevention of eye diseases, such as glaucoma, uveitis, etc.; gastrointestinal diseases, such as ulcers, ulcerative colitis, irritable bowel syndrome, food allergies, etc.; Diseases, such as nephritis, etc.; circulatory diseases, such as hypertension, angina pectoris, heart failure, thrombosis, Raynaud's disease, etc.; epilepsy; spastic paralysis; frequent urination; cystitis; bladder detrusor hyperreflexia; urinary incontinence; Parkinson's disease ; dementia; AIDS-related dementia; Alzheimer's disease; Down syndrome; Huntington's disease; carcinoid syndrome; Disorders caused by blue-negative bacteria; sunburn; angiogenesis or diseases caused by angiogenesis; etc.

It is further expected that the object compound of the present invention can also be used for the treatment or prevention of chronic obstructive pulmonary disease, especially chronic emphysema, iritis; proliferative vitreoretinopathy; psoriasis; inflammatory bowel disease, especially Crohn's disease; hepatitis, Superficial pain from frostbite, burns, herpes zoster, or diabetic neuropathy; tendon pain associated with hyperlipidemia; neuroma after surgery, especially mastectomy; vaginal vestibulitis; prurigo associated with hemodialysis; lichen planus ;Laryngopharyngitis; Bronchiectasis; Dust sickness; Pertussis; Tuberculosis; Bladder fibrosis; Vomiting; Psychiatric disorders, especially anxiety, depression, depressive disorders, and schizophrenia; Demyelinating disorders, such as multiple sclerosis and muscular atrophy Lateral sclerosis; reduced morphine withdrawal; edema, e.g. from heat injury; small cell carcinoma, especially small cell lung cancer (SCLC); hypersensitivity disorders, e.g. poison ivy; fibrosis and Collagen disorders such as scleroderma and fascioliasis eosinophilia; reflex sympathetic dystrophies such as shoulder/hand syndrome; addiction disorders such as alcoholism; somatic disorders related to stress responses; rheumatic diseases such as Fibrosis; etc.

For therapeutic purposes, the object compound of the present invention can be used in the form of a pharmaceutical preparation, which contains one of the compounds as an active ingredient, and blends a pharmaceutically acceptable carrier, for example, suitable for oral administration, parenteral Administration, Topical (including Topical), Enteral, Intravenous, Intramuscular, Inhalation, Nasal, Intra-articular, Intraspinal Organic or inorganic solid or liquid excipients for drug, tracheal or ophthalmic administration. Pharmaceutical preparations may be solid, semi-solid, or liquid, for example, capsules, tablets, pills, dragees, powders, granules, suppositories, ointments, creams, lotions, inhalants, injections, poultices , gels, tapes, eye drops, solutions, syrups, aerosols, suspensions, emulsions, etc. These formulations may, if desired, also contain auxiliary substances, solubilizers, wetting or emulsifying agents, buffers and other customary additives.

Although dosages of these compounds of interest will vary depending on the age and condition of the patient, average single doses of about 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg, and 1000 mg of these compounds of interest are effective in the treatment of tachycardia. Peptide-mediated diseases, such as asthma, etc. Generally, the dosage per day can be between 0.1 mg/body to about 1000 mg/body.

In order to illustrate the usefulness of these target compounds, the pharmacological test data of representative compounds of the present invention are described below.

The following test compounds showed that at a concentration of 0.1 μg/ml, the inhibition rate of ¹²⁵ I-BH-substance P binding to the h-NK ₁ receptor was over 90%.

Test compound: the object 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) Crude CHO cell membrane preparation

Harvest CHO cells permanently expressing h-NK ₁ receptors in a buffer (0.25M sucrose, 25mM Tris-HCl pH 7.4, 10mM MgCl ₂ , 1mM EDTA, 5μg/ml p-APMSF) at 4°C Homogenize with a Dounce homogenizer. The homogenate was centrifuged (500xg, 10 minutes), the pellet was resuspended in the same buffer, homogenized and centrifuged. The two supernatants were combined and centrifuged (100,000xg, 1 hour). Crude cell membranes thus isolated were resuspended 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 formulation membrane

Cell membranes (6 μg/ml) together with ¹²⁵ I-BH-substance P (0.1 nM), with or without test compound, in 0.25 ml medium 2 (50 mM Tris-HCl pH 7.4, 5 mM MnCl ₂ , 20 μg/ml chymotrypsin 40 μg/ml bacitracin, 4 μg/ml leupeptin, 5 μg/ml p-APMSF, 200 μg/ml BSA), and cultivated at 22°C for 90 minutes. At the end of the incubation period, the contents were rapidly filtered under aspiration using a Wahtman GF/C glass filter (pretreated with 0.1% polyethyleneimine for 3 hours before use). Then, each filter was washed 4 times with 5 ml of buffer (50 mM Tris-HCl pH 7.4, 5 mM MnCl ₂ ). Radioactivity counts were performed with an automatic gamma counter (Packerd RIASTAR 5420A). The data expressed are all defined as that specific binding which can be displaced by 3 μM of unlabeled substance P.

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

EXAMPLES The following Preparations and Examples are given to illustrate the invention in more detail. preparation 1

In a nitrogen atmosphere, N ² -(tert-butoxycarbonyl)-N'-formyl-D-tryptophan (3.99g) and N-benzyl p-hydroxyphenylglycine benzyl ester hydrochloride (3.50g) in To the mixture in dichloromethane (70ml) was added triethylamine (5.85ml). To the mixture was added 2-chloro-1-methylpyridinium iodide (3.67 g) at room temperature, and the resulting mixture was stirred for 2 hours. After the reaction was complete, dichloromethane (30ml) and water (30ml) were added. The organic layer was separated, washed successively with 0.5N hydrochloric acid (10ml), water (10ml), aqueous sodium bicarbonate (10ml) and brine (20ml), and dried over magnesium sulfate. After solvent evaporation, the residue was purified on a silica gel column (140 g) eluting 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).

IR(CHCl ₃ ): 3300, 2970, 1740, 1700, 1644, 1604cm ^-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(15H,m);

7.98 and 8.22(1H,2 br s); 9.22 and 9.61(1H,2 br

s)

MASS: 570 (M+1) Preparation 2

To an ice-cooled solution of the title compound of Preparation 1 (6.39 g) in dichloromethane (50 ml) was added 4N hydrogen chloride in dioxane (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 (50ml) and aqueous sodium bicarbonate (30ml). The organic layer was separated, dried over magnesium sulfate, and filtered. To the filtrate was added triethylamine (1.67 ml) at room temperature, and the mixture was stirred for 1.5 hours. After evaporation, the residue was triturated with diisopropyl ether, collected by filtration and dried to give (3R)-1-benzyl-3-(N-formyl-1H-indol-3-ylmethyl)piperazine-2 , 5-diketone (3.93 g).

mp:176-178℃

IR (liquid paraffin): 3250, 1709, 1648, ^{1630cm -1}

NMR(DMSO-d ₆ ,δ):2.95-3.30 and 3.3S-3.70(4H,2m);

4.22(1H,d,J=14.6Hz); 4.30-4.40(1H,m); 4.54

(1H,d,J=14.9Hz); 6.80-7.75(9H,m); 7.95-8.50

(2H,m); 9.20 and 9.65(1H,2 br s)

preparation 3

To an ice-cooled solution of the objective compound of Preparation 2 (3.89 g) in a mixture of methanol (175 ml) and tetrahydrofuran (50 ml) was added 0.1N aqueous 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, 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℃

IR (liquid paraffin): 3402, 1650cm ^-1

NMR(DMSO-d ₆ ,δ):2.68(1H,d,J=17.2Hz); 3.04(1H,

dd,J=14.4 and 4.4Hz); 3.20-3.40(2H,m); 4.24(1H,

s); 4.10-4.40(2H,m); 6.75-7.60(10H,m); 8.35

(1H,s); 10.94(1H,s)

MASS:334(M+1)

preparation 4

To a suspension of lithium aluminum hydride (0.77 g) in tetrahydrofuran (40 ml) was added dropwise a solution of the object compound of Preparation 3 (3.40 g) in tetrahydrofuran (40 ml) at 0°C in a nitrogen atmosphere. The mixture was stirred at room temperature for 50 minutes and at reflux temperature for 1 hour. The resulting mixture was diluted with tetrahydrofuran (60ml) and cooled to 0°C. Water (3.0ml) and 15% aqueous sodium hydroxide solution (0.8ml) were added slowly. The resulting insoluble inorganic matter 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 (3.68g) as an oil.

IR(CHC1 ₃ ):3240,3040,2900cm ^-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(1H,s)

MASS:306(M+1)

Preparation 5

3,5-bis(trifluoromethyl)benzoic acid (1.15 g) and (3R)-1-benzyl-3-(1H-indol-3-ylmethyl) To a mixture of piperazine (1.61g) in dichloromethane (80ml) was added triethylamine (1.55ml). Then 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 (20ml). The organic layer was washed successively with 0.5N hydrochloric acid, water, aqueous sodium bicarbonate solution and brine, and dried over magnesium sulfate. After evaporation under reduced pressure the residue was chromatographed on a silica gel column using toluene/ethyl acetate (4:1) as eluent to give (2R)-4-benzyl-1-[3,5-di( Trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)piperazine (0.87g). In the form of a paste.

IR(CHCl ₃ ):3430,3300,3000,2910,2800,

1630-1610cm ^-1

NMR(DMSO-d ₆ ,δ):1.90-2.40(2H,m); 2.70-3.90(8H,

m); 4.25-4.40 and 4.75-4.90(1H,m); 6.50-7.45

(10H,m); 7.50-8.25(3H,m); 10.77(1H,s)

MASS:546(M+1)

Preparation 6

(2R)-4-Benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)piperazine (5.20g), formic acid A mixture of ammonium (1.50 g) and 10% Pd/charcoal (0.52 g) in ethanol (50 ml) was refluxed under nitrogen for 7.5 hours. The reaction mixture was allowed to cool to room temperature, then filtered through a pad of celite. The filtrate was concentrated under reduced pressure, and the residue was purified by a silica gel column, eluting with a mixture of dichloromethane and methanol (20:1) to give (2R)-1-[3,5-bis(trifluoromethyl)benzene Formyl]-2-(1H-indol-3-ylmethyl)piperazine (2.67g) syrup.

IR(CHCl ₃ ):3280,2900,1622cm ^-1

NMR(DMSO-d ₆ ,δ):2.50-3.50(9H,m); 3.6-4.8(1H,m);

6.55-7.40(5H,m); 7.50-8.22(3H,m); 10.84(1H,s)

MASS:456(M+1)

Preparation 7

(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)piperazine (1.5g), benzyl 2-bromoacetate (0.79g), triethylamine (0.55ml) and tetrahydrofuran (15ml) were stirred overnight at room temperature. The formed insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was chromatographed on a silica gel column eluting with a mixture of dichloromethane and methanol (30:1) to give (2R)-4-(benzyloxycarbonylmethyl)-1-[3,5-bis(tri Fluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)piperazine (1.92 g).

[α] _D ²¹ :-11.6°(C=1.0,MeOH)

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

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

m); 10.85(1H,br s)

MASS:604(M+1),454

Preparation 8

(2R)-4-(benzyloxycarbonylmethyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)piperazine ( A mixture of 1.869), 10% Pd/charcoal (0.1869) and tetrahydrofuran (93 ml) was stirred under hydrogen atmosphere (1 atm) for 17 hours. The catalyst was removed by filtration, and the filtrate was concentrated. The residue was triturated with ether to give (2R)-4-(carboxymethyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl base) piperazine (0.83g) white powder.

[α] _D ¹⁹ :-3.0°(C=0.5,DMF)

mp:152-156℃

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

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

m); 10.85(1H,s)

MASS:514(M+1)

Preparation 9

To (2R)-2-benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]piperazine (0.3g) and triethylamine (0.39ml) in dimethylformamide (8ml ) was added 3-(chloromethyl)pyridine hydrochloride (0.12 g). The reaction mixture was stirred at the same temperature for 30 minutes and then at room temperature for 2 hours. Additional triethylamine (0.39ml) and 3-(chloromethyl)pyridine hydrochloride (0.12g) were added and the resulting mixture was stirred overnight. The reaction mixture was filtered, and the filtrate was concentrated and purified by silica gel column chromatography, eluting with a mixture of toluene and ethyl acetate (5:1). The eluate was treated with 4N hydrogen chloride in ethyl acetate to give (2R)-2-benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(pyridin-3-yl Methyl)piperazine dihydrochloride.

mp:164-168℃

[α] _D ²⁵ :+9.1°(C=1.0,MeOH)

IR (liquid paraffin): 3700-3100, 2700-2000, 1630, 1270, 1120,

900cm ^-1

NMR(DMSO-d ₆ ,δ):2.80-5.40(11H,m); 6.85-6.90-(1H,…

m); 7.10-7.40(4H,m); 7.46(1H,s); 7.75(1H,s);

7.90-8.00(1H,m); 8.19-8.23(1H,m); 8.66-8.70

(1H,m); 8.88-8.91(1H,m); 9.09(1H,s)

MASS:508(M+1)(free)

Prepare 10

To (2R)-2-benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]piperazine (0.3 g) and 2-(1H-indole- To a stirred mixture of 3-yl)acetic acid (0.13g) in dichloromethane (8ml) containing triethylamine (0.25ml) was added 2-chloro-1-methylpyridinium iodide (0.22g). After stirring for 5 hours, the reaction mixture was diluted with dichloromethane, washed with 0.1N hydrochloric acid, saturated aqueous sodium bicarbonate and brine, then dried over magnesium sulfate. After removing the solvent, the residue was chromatographed on a silica gel column, eluting with chloroform/methanol (50:1) to give (2R)-2-benzyl-1-[3,5-bis(trifluoromethyl) Benzoyl]-4-[2-(1H-indol-3-yl)acetyl]piperazine (0.34 g) white powder.

mp:201-210℃

[α] _D ²⁷ :+27.6°(C=1.0,MeOH)

IR (liquid paraffin): 3270, 1630, 1276, 1115, 900, ^{737cm -1}

NMR(DMSO-d ₆ ,δ):2.60-5.00(11H,m); 6.70-7.70(12H,

m); 8.10-8.20(1H,m); 10.85-11.10(1H,m)

MASS:574(M+1),417

Preparation 11

To (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)piperazine (0.1g) dichloro To the methane (10ml) solution was added 4N hydrogen chloride in dioxane (0.05ml). The resulting mixture was stirred at the same temperature for 50 minutes, then concentrated under reduced pressure. The resulting powder was collected by filtration and washed with ether to obtain (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)piperazine salt salt (0.1 g).

IR (liquid paraffin): 3340, 1648cm ^-1

NMR(DMSO-d ₆ ,δ):2.9-3.9(8H,m); 3.9-5.2(1H,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 12

(2R)-4-(2-aminoethyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethyl To a mixture of benzyl)piperazine dihydrochloride (110mg), triethylamine (0.2ml) in dichloromethane was added methanesulfonyl chloride (0.1ml). After stirring for 1 hour, the reaction mixture was poured into ice water, followed by extraction with ethyl acetate. The extract was washed successively with saturated aqueous sodium bicarbonate solution and brine, and dried. After evaporation of the solvent in vacuo, the residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (40:1), and then treated with 4N hydrogen chloride in ethyl acetate to give (2R)-1-[3 ,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[2-(methylsulfonylamino)ethyl]piperazine hydrochloride (50mg ).

mp:＞220℃

[α] _D ²² :+0.2°(C=0.5,DMF)

IR (liquid paraffin): 3350, 2700-2400, 1645, 1500, 1450,

1380cm ^-1

NMR(DMSO-d 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(1H,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-ylmethanol) under stirring at room temperature To a solution of piperazine (1 g) in dry dimethylformamide (10 ml) was added 1-hydroxybenzotriazole (0.29 g) and 1-(3-dimethylaminopropyl)-3- Ethylcarbodiimide hydrochloride (0.41 g). After stirring at room temperature for 15 minutes, 1-amino-4-methylpiperazine (320 mg) was added and stirred at the same temperature for an additional 5 hours. The reaction mixture was poured into a solution of sodium bicarbonate (1.8g) in water (100ml) and extracted three times with 20ml of ethyl acetate. The organic layers were combined and washed with brine (30ml). The organic layer was dried over magnesium sulfate, filtered, and the solvent was removed on a rotary evaporator. The crude product was purified by chromatography (silica gel, dichloromethane:methanol=5:1) to obtain (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2 as light red powder -(1H-indol-3-ylmethyl)-4-[N-(4-methyl-1-piperazinyl)carbamoylmethyl]piperazine (0.94 g).

IR (liquid paraffin): 3180, 1680, 1630, 1276, 1170, 1130, 1005 ^{, 897cm -1}

NMR(DMSO-d ₆ ,δ):2.16(3H,s); 2.0-5.0(19H,m);

6.6-8.2(8H,m); 8.47,8.77(1H,2s);

10.85(1H,s)

Example 2

(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-[N-(4-methyl- 1-Piperazinyl)carbamoylmethyl]piperazine (10.89g) and fumaric acid (2.07g) were dissolved in 70°C ethanol (50ml). After cooling, the resulting solution was concentrated under reduced pressure to obtain a powder (13.18 g). The powder (9.68g) was dissolved in 2-butanone (194ml) at reflux temperature, and the solution was stirred at room temperature to obtain crystals, which were collected by filtration and dried to obtain (2R)-1-[3 ,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-[N-(4-methyl-1-piperazinyl)carbamoyl Methyl]piperazine fumarate (7.94 g).

mp:169.5-171℃

IR (liquid paraffin): 3220, 1700, 1653, 1630, 1275, 1217, 1168, 1122,

979,894,730cm ^-1

NMR(DMSO-d ₆ ,δ):2.23,2.26(3H,2s); 2.10-4.93

(19H,m); 6.60(2H,s); 6.54-8.23(8H,m); 8.50,

8.85(1H,2s); 10.85(1H,s)

Example 3

Compound (If), namely (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-[N-( 4-methyl-1-piperazinyl) carbamoyl methyl] piperazine fumarate can also be prepared according to the following scheme:

Example 4

(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)piperazine (120mg), 4-chloromethyl- A mixture of 2-(2-methoxyethylcarbonylamino)triazole (70 mg) and powdered sodium bicarbonate (27 mg) in dry dimethylformamide was stirred for 5 hours and at 60°C for 20 minutes. The reaction mixture was poured into water, and the formed precipitate was collected by filtration. The crude product was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (30:1). The effluent was evaporated under reduced pressure and then treated with 17.6% ethanolic hydrogen chloride (0.12ml) to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H- Indol-3-ylmethyl)-4-[[2-(3-methoxypropionylamino)thiazol-4-yl]methyl]piperazine hydrochloride (140 mg).

[α] _D ²² :-34.0°(C=0.5,MeOH)

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

NMR(DMSO-d ₆ ,δ):2.60-5.20(18H,m); 6.60-8.21(9H,

m); 10.90-11.00(1H,m); 11.20=12.00(1H,m); 12.19

(1H,s)

MASS:654(M+1)(free)

Example 5

表1(续)

表1(续)

The following piperazine derivatives (Table 1) were prepared in a manner analogous to the respective Example No. or Preparation No. indicated in the "Method" column. The physical properties of each target compound are listed after the table. Table 1

Table 1 (continued)

Table 1 (continued)

The physical property of example 5 compound: example 5-1)

mp:185-189℃

[α] _D ²⁴ :30.2°(c=0.5,MeOH)

IR (liquid paraffin): 3660-3100, 2800-2000, 1635, 1545, 1276,

1183,1130,900cm ^-1

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

11.00(1H,m); 12.15(1H,s)

MASS: 610 (M+1) (free), 456 instance 5-2)

[α] _D ²² :-33.4°(c=0.5,MeOH)

IR (liquid paraffin): 3650-3100, 2800-2000, 1715, 1635, 1555, 1274,

1130,900cm ^-1

NMR(DMSO-d ₆ ,δ):1.25(3H,t,J=7.1Hz); 2.73-5.10(13H,m),6.60

-8.30(9H,m); 10.90-11.00(1H,m); 11.81(1H,brs)

MASS: 640 (M+1) (free), 456 instance 5-3)

[α] _D ²² :-42.0°(c=0.5,MeOH)

IR (liquid paraffin): 3600-3100, 2750-2000, 1635, 1540, 1277,

1175,1130cm ^-1

NMR(DMSO-d ₆ ,δ):2.73-5.20(11H,m); 6.59-8.21(14H,

m); 10.90-11.00(1H,m); 12.69(1H,s)

MASS: 672 (M+1) (free), 456 instance 5-4)

[α] _D ²² :-24.2°(C=0.5,MeOH)

IR (liquid paraffin): 3650-3100, 2750-2000, 1635, 1540, 1276,

1170,1129,900cm ^-1

NMR(DMSO-d ₆ ,δ):1.23(9H,s); 2.73-5.10(11H,m);

6.50-8.20(9H,m); 10.80-11.00(1H,m); 11.84(1H,

s)

MASS: 652 (M+1) (free), 456 instance 5-5)

[α] _D ²² :-35.8°(C=0.5,MeOH)

IR (liquid paraffin): 3650-3100, 2750-2000, 1635, 1540, 1276,

1170, 1130, 900cm ^-1

NMR(DMSO-d ₆ ,δ):0.80-1.00(4H,m); 1.90-2.00(1H,

-m); 2.73-5.15(11H,m); 6.60-8.21(9H,m); 10.90-

11.00(1H,m); 12.43(1H,m)

MASS: 636 (M+1) (free), 456 instance 5-6)

[α] _D ²² :-30.4°(C=0.5,MeOH)

IR (liquid paraffin): 3650-3100, 2750-2000, 1635, 1542, 1275,

1170,1131,900cm ^-1

NMR(DMSO-d ₆ ,δ):0.89(3H,t,J=7.4Hz); 1.56-1.67

(2H,m); 2.40-2.50(2H,m); 2.73-5.15(11H,m);

6.56-8.21(9H,m); 10.90-10.94(1H,m); 12.12(1H,

s)

MASS: 638 (M+1) (Free) Examples 5-7)

[α] _D ²² :-34.0°(C=0.5,MeOH)

IR (liquid paraffin): 3650-3100, 2750-2000, 1635, 1543, 1277,

1170, 1130, 900cm ^-1

NMR(DMSO-d ₆ ,δ):1.08(3H,t,J=7.4Hz); 2.43-2.50

(2H,m); 2.73-5.15(11H,m); 6.55-8.21(9H,m);

10.90-10.94(1H,m); 12.11(1H,s)

MASS: 624 (M+1) (Free) Examples 5-8)

[α] _D ²² :-15.2°(C=0.5,MeOH)

IR (liquid paraffin): 3 600-3100, 2750-2000, 1635, 1278, 1172,

1130,900cm ^-1

NMR(DMSO-d ₆ ,δ):2.73-5.20(11H,m); 6.60-8.52(11H,

m); 10.94(1H,s)

MASS: 596 (M+1) (free), 456 examples 5-9)

[α] _D ²² :-20.6°(C=0.5,MeOH)

IR (liquid paraffin): 3650-3100, 2750-2000, 1635, 1276, 1170,

1129,900cm ^-1

NMR(DMSO-d ₆ ,δ):2.09(3H1,s); 2.73-5.20(11H,m);

6.60-8.20(11H,m); 10.46(1H,s); 10.91(1H,s)

MASS: 604 (M+1) (Free) Examples 5-10)

[α] _D ²² :-13.0°(C=0.5,MeOH)

IR (liquid paraffin): 3650-3050, 2750-2000, 1685, 1636, 1524,

1275,1130,900cm ^-1

NMR(DMSO-d ₆ ,δ):1.31(3H,t,J=6.5Hz); 2.24(3H,

s); 2.73-5.20(13H,m); 6.66-8.25(8H,m); 10.94

(1H,s),12.71(1H,s)

MASS: 682 (M+1) (Free) Examples 5-11)

[α] _D ¹⁸ :-20.8°(C=0.5,MeOH)

IR (neat phase): 3700-3000, 1615, 1515, 1272, 1125,

900cm ^-1

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

m); 10.80(1H,s)

MASS: 568 (M+1), 456 instances 5-12)

[α] _D ²² :-10.4°(C=0.5,MeOH)

IR (liquid paraffin): 3650-3100, 2750-2000, 1635, 1277,

1130cm ^-1

NMR(DMSO-d ₆ ,δ):3.00-5.20(11H,m); 6.60-8.30(11H,

m); 10.95(1H,s)

MASS: 568 (M+1) (free), 456 instance 5-13)

[α] _D ²² :-31.8°(C=0.5,MeOH)

IR (liquid paraffin): 3270, 2750-2000, 1637, 1531, 1279, 1124,

964cm ^-1

NMR(DMSO-d ₆ ,δ):2.73-5.15(14H,m); 6.60-8.2S

(10H,m); 10.89(1H,s)

MASS: 64 6 (M+1) (free), 568, 456 instances 5-14)

[α] _D ²³ :11.8°(C=0.5,MeOH)

IR (liquid paraffin): 3 650-3100, 1625, 1543, 1275, 1130cm ^-1

NMR(DMSO-d ₆ ,δ):2.09-2.11(3H,m); 2.52-5.00(11H,

m),6.63-8.20(9H,m); 10.85(1H,s); 12.07(1H,s)

MASS: 638 (M+1), 456 instances 5-15)

[α] _D ¹⁸ :-51.6°(C=0.5,MeOH)

IR (liquid paraffin): 3650-3100, 2750-2000, 1634, 1540, 1274,

1170,1127,900cm ^-1

NMR(DMSO-d ₆ ,δ):2.31(3H,s); 2.73-5.35(11H,m);

6.63-8.25(8H,m); 10.94-11.00(1H,m); 13.20(1H,

s)

MASS: 611 (M+1) (Free) Examples 5-16)

[α] _D ²² :-23.4°(C=0.5,MeOH)

IR (liquid paraffin): 3650-3000, 2750-2000, 1620, 1274, 1175,

1128,900cm ^-1

NMR(DMSO-d ₆ ,δ):1.10(3H,t,J=7.2Hz),2.60-5.10

(16H,m); 6.50-8.21(9H,m); 10.91(1H,s); 11.50-

11.90(1H,br s)

MASS:638(M+1)(free)

Claims (3)

1. Compounds represented by the formula:

2. The preparation method of the compound of claim 1, The method comprises: making the compound shown in the following formula or its salt except its fumarate: Reaction with fumaric acid gives the compound represented by the following formula:

3. A pharmaceutical composition comprising the compound of claim 1 as an active ingredient in combination with a pharmaceutically acceptable, substantially non-toxic carrier or excipient.