CN1191533A - 1-benzoyl-2-(indolyl-3-alkyl)-piperazine derivs. as neurokinin receptor antagonists - Google Patents

1-benzoyl-2-(indolyl-3-alkyl)-piperazine derivs. as neurokinin receptor antagonists Download PDF

Info

Publication number
CN1191533A
CN1191533A CN96195744A CN96195744A CN1191533A CN 1191533 A CN1191533 A CN 1191533A CN 96195744 A CN96195744 A CN 96195744A CN 96195744 A CN96195744 A CN 96195744A CN 1191533 A CN1191533 A CN 1191533A
Authority
CN
China
Prior art keywords
compound
salt
alkyl
following formula
compound shown
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN96195744A
Other languages
Chinese (zh)
Other versions
CN1072220C (en
Inventor
松尾昌昭
萩原大二郎
真锅孝司
小西信清
重永信次
村埜贤司
松田博
三宅宏
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Fujisawa Pharmaceutical Co Ltd
Original Assignee
Fujisawa Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Fujisawa Pharmaceutical Co Ltd filed Critical Fujisawa Pharmaceutical Co Ltd
Publication of CN1191533A publication Critical patent/CN1191533A/en
Application granted granted Critical
Publication of CN1072220C publication Critical patent/CN1072220C/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/14—Decongestants or antiallergics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

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 (Ig), 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-(indyl-3-alkyl)-bridged piperazine derivatives as neurokinin receptor antagonists
Technical field
The present invention relates to new bridged piperazine derivatives and pharmaceutically acceptable salt thereof.
More specifically say, the present invention relates to have pharmacologically active such as tachykinin antagonist effect, especially the new bridged piperazine derivatives and the pharmaceutically acceptable salt thereof of Substance P antagonistic action, neurokinin A antagonistic action, neurokinin B antagonistic action etc., relate to its preparation method, contain the pharmaceutical composition of this compounds, and this compounds is as the purposes of medicament.
Therefore, an object of the present invention is to provide and have pharmacologically active such as tachykinin antagonist effect, especially new and the useful bridged piperazine derivatives and the pharmaceutically acceptable salt thereof of Substance P antagonistic action, neurokinin A antagonistic action, neurokinin B antagonistic action etc.
Another object of the present invention provides a kind of method for preparing described bridged piperazine derivatives and salt thereof.
A further object of the present invention provides a kind of containing as the described bridged piperazine derivatives of activeconstituents and the pharmaceutical composition of pharmaceutically acceptable salt thereof.
Another purpose of the present invention provides described bridged piperazine derivatives or its pharmaceutically acceptable salt as tachykinin antagenists, especially the purposes of substance P antagonist, neurokinin A antagonist or neurokinin B antagonist, the disease that is used for the treatment of or prevents to mediate by tachykinin in the mankind or the Mammals, for example, respiratory disease such as asthma, bronchitis, rhinitis, cough, expectoration etc.; Illness in eye such as conjunctivitis, spring (Catarrhal) conjunctivitis etc.; Tetter such as contact dermatitis, atopic dermatitis, urticaria and other eczema-like dermatitis etc.; Inflammatory diseases such as rheumatoid arthritis, osteoarthritis etc.; Ache or pain (as migraine, headache, toothache, pain caused by cancer, backache etc.); Or the like.
Disclosure of the Invention
Purpose compound of the present invention is the compound of following formula (I): I.e. (2R)-1-(3; 5-two (trifluoromethyl) benzoyl)-2-(1H-indol-3-yl methyl)-4-(N-(4-methyl isophthalic acid-piperazinyl) carbamyl ylmethyl)-piperazine; or its fumarate; i.e. (2R)-1-(3,5-two (trifluoromethyl) benzoyl)-2-(1H-indol-3-yl methyl)-4-(N-(4-methyl isophthalic acid-piperazinyl) carbamyl ylmethyl)-piperazine fumarate (being designated hereinafter simply as (If)).
Other purpose compounds of the present invention can be represented with the compound shown in the following general formula (Ig) or its pharmaceutically acceptable salt: R wherein 1Be three halogen (rudimentary) alkyl, R 2Be three halogen (rudimentary) alkyl, R 3Be indyl (rudimentary) alkyl ,-A-is-CH 2-or
Figure A9619574400072
, and-R 4Be
Figure A9619574400073
Wherein
R 5Be hydrogen or lower alkoxycarbonyl,
R 6Be hydrogen or low-grade alkane acidyl,
R 7Be that hydrogen, low alkyl group, low-grade alkane acidyl, lower alkoxycarbonyl, lower alkoxy are (low
Level) alkyloyl, ring (rudimentary) alkyl-carbonyl, aroyl or low alkyl group alkylsulfonyl.
According to the present invention, described purpose compound can prepare by the illustrated method of following scheme.Method 1
Figure A9619574400081
Method 2 Or its salt, but not its fumarate
Figure A9619574400091
Method 3 Method 4
R wherein 1, R 2, R 3And R 4Definition the same;
-A 1-be-CH 2-; And
W is a leavings group.
The salt and the pharmaceutically acceptable salt that are suitable for of initial compounds and purpose compound are general avirulent salt, comprise acid salt, for example organic acid salt is (as acetate, trifluoroacetate, fumarate, maleate, tartrate, mesylate, benzene sulfonate, formate, tosylate etc.), or with amino acid (as arginine, aspartic acid, L-glutamic acid etc.) salt of Xing Chenging, or metal-salt, for example an alkali metal salt is (as sodium salt, sylvite etc.) and alkaline earth salt (as calcium salt, magnesium salts etc.), ammonium salt, organic alkali salt is (as the front three amine salt, triethylamine salt, pyridinium salt, picoline salt, dicyclohexyl amine salt, N, N '-benzyl ethylene amine salt etc.), or similar salt.
Address on this specification sheets in the narration subsequently, the suitable example of each definition that is included in the scope of the present invention is explained as follows with specifying in detail.
" rudimentary " this term is meant 1-6, preferred 1-4 carbon atom, unless otherwise.
" low alkyl group " and " low alkyl group part " that be suitable in term " indyl (rudimentary) alkyl " and " low alkyl group alkylsulfonyl " is straight chain or the branching group that contains 1-6 carbon atom, can comprise methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, amyl group, hexyl etc.
" three halogen (rudimentary) alkyl " that be suitable for can comprise trichloromethyl, trisbromomethyl, trifluoromethyl etc.
" lower alkoxy " and " lower alkoxy part " that be suitable in term " lower alkoxycarbonyl " and " lower alkoxy (rudimentary) alkyloyl " can comprise methoxyl group, oxyethyl group, isopropoxy, butoxy etc.
" low-grade alkane acidyl " and " low-grade alkane acidyl part " that be suitable in term " lower alkoxy (rudimentary) alkyloyl " can comprise formyl radical, ethanoyl, propionyl, butyryl radicals, isobutyryl, pentanoyl, caproyl, valeryl etc.
" ring (rudimentary) moieties " of being suitable in term " ring (rudimentary) alkyl-carbonyl " can comprise cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.
" aroyl " that be suitable for can comprise benzoyl, toluyl, naphthoyl etc.
" leavings group " that is suitable for can comprise hydroxyl, by hydroxyl deutero-active group etc.
" by the hydroxyl deutero-active group " that be suitable for can comprise sour residue etc.
" the sour residue " that is suitable for can comprise halogen (as fluorine, chlorine, bromine, iodine), acyloxy (as acetoxyl group, tosyloxy etc.) etc.
Below explain in detail the method 1-4 for preparing the object of the invention compound.
Method 1
Purpose compound (I) or its salt can be by making reactive derivative or reactive derivative on its salt and compound (III) or its amino or the preparation of its reactant salt on compound (II) or its carboxyl.
The reactive derivative that is suitable in the compound (II) on the carboxyl can comprise acyl chlorides, acid anhydrides, activating terephthalamide amine, Acibenzolar, etc.
The example of the reactive derivative that is suitable for can be a chloride of acid; Acid azide; The phosphoric acid (as dialkyl group phosphoric acid, phosphenylic acid, diphenylphosphoric acid, dibenzyl phosphoric acid, halophosphoric acid etc.) that for example replaces with acid, dialkyl group phosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acid (as methylsulfonic acid etc.), aliphatic carboxylic acid are (as acetate, propionic acid, butyric acid, isopropylformic acid, PIVALIC ACID CRUDE (25), valeric acid, isovaleric acid, 2 Ethylbutanoic acid, trichoroacetic acid(TCA), Deng) or the mixed acid anhydride that forms of aromatic carboxylic acid's (as phenylformic acid, etc.); Symmetric anhydride; Imidazoles, dimethyl pyrazole, triazole or tetrazolium activatory acid amides with imidazoles, 4-replacement; Or the activatory ester is (as cyanomethyl ester, methoxymethyl ester, dimethyl imido grpup methyl ((CH 3) 2N +=CH-) ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2; 4-dinitrophenyl ester, trichlorophenyl ester, five chlorophenyl ester, methylsulfonyl phenylester, phenylazo-phenylester, benzene thioesters, p-nitrophenyl thioesters, to toluene thioesters, carboxymethyl thioesters, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioesters etc.); or the ester that forms with N-oxy-compound (as N, N-dimethyl hydroxyl amine, 1-hydroxyl-2-(1H)-pyridine ester, N-hydroxy-succinamide, N-hydroxyphthalimide, 1-hydroxyl-1H-benzotriazole etc.) etc.Kind according to employed compound (II) can be randomly from above-mentioned selection reactive derivative.
The reactive derivative that is suitable on the amino of compound (III) can comprise the imino-of the Schiff's base type that is generated by compound (III) and carbonyl compound such as aldehyde, ketone or similar compounds reaction or the isomer of its change enamine type; By the silyl derivative of compound (III) with silyl compound such as two (trimethyl silyl) ethanamide, list (trimethyl silyl) ethanamide, two (trimethyl silyl) urea or similar compounds reaction generation; By the derivative of compound (III) with phosphorus trichloride or phosgene and analogue reaction generation.
This reaction is carried out in common solvent usually, for example at water, alcohol (as methyl alcohol, ethanol etc.), acetone, 2-butanone, diox, acetonitrile, chloroform, methylene dichloride, ethylene dichloride, tetrahydrofuran (THF), ethyl acetate, N, carry out in dinethylformamide, pyridine or any organic solvent that other does not have a negative impact to this reaction or its mixture.
In this reaction, when compound (II) uses with free acid form or its salt form, this reaction is preferably carried out in the presence of condensing agent commonly used, for example at N, N '-dicyclohexyl carbodiimide, N-cyclohexyl-N '-morpholino ethyl carbodiimide, N-cyclohexyl-N '-(4-diethylamino cyclohexyl) carbodiimide, N, N '-diethyl carbodiimide, N, N '-di-isopropyl carbodiimide, N-ethyl-N '-(3-dimethylaminopropyl) carbodiimide, pentamethylene ketenes-N-cyclohexyl imines, phenylbenzene ketenes-N-cyclohexyl imines, oxyethyl group acetylene, 1-alkoxyl group-1-vinylchlorid, trialkyl phosphite, the ethyl polyphosphate, the sec.-propyl polyphosphate, Phosphorus Oxychloride (phosphoryl chloride), phosphorus trichloride, the diphenylphosphine acylazide, thionyl chloride, oxalyl chloride, the haloformic acid lower alkyl esters is (as Vinyl chloroformate, isopropyl chlorocarbonate etc.), triphenyl phosphine, 2-ethyl-7-hydroxy benzo isoxazolium salt, hydroxide 2-ethyl-5-(-sulfo group phenyl) isoxazole molecule inner salt, 1-(right-the chlorobenzene sulfonyloxy)-6-chloro-1H-benzotriazole, I-hydroxybenzotriazole, so-called Mukaiyama reagent such as iodate 2-chloro-1-picoline, 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride itself or with the composition of I-hydroxybenzotriazole, by N, dinethylformamide and thionyl chloride, phosgene, superpalite, the so-called Vilsmeier reagent of prepared in reaction such as Phosphorus Oxychloride, or similar condensing agent, or carry out in its mixture.
This reaction also can be at mineral alkali or organic bases such as alkali metal hydrocarbonate, three (rudimentary) alkylamine, pyridine, N-(rudimentary) alkyl morpholine, N, N-two (rudimentary) alkyl benzyl amine, or similarly alkali carries out under existing.
Temperature of reaction is not strict, and reaction is usually carried out under cooling or warm condition.
Method 2
Purpose compound (If) can prepare by compound (I) or its salt (except the fumarate) and fumaric acid are reacted.
This reaction is carried out in common solvent usually, for example at water, alcohol (as methyl alcohol, ethanol etc.), acetone, 2-butanone, diox, acetonitrile, chloroform, methylene dichloride, ethylene dichloride, tetrahydrofuran (THF), ethyl acetate, N, carry out in dinethylformamide, pyridine or any organic solvent that other does not have a negative impact to this reaction or its mixture.
Temperature of reaction is not strict, and reaction is usually carried out under cooling or warm condition.
Method 3
Purpose compound (Ig ') or its salt can prepare with compound (V) or its reactant salt by making reactive derivative or its salt on compound (IV) or its imido grpup.
Suitable reactive derivative on the imido grpup of compound (IV) can comprise the imino-of the Schiff's base type that is generated by compound (IV) and carbonyl compound such as aldehyde, ketone or similar compounds reaction or the isomer of its change enamine type; By the silyl derivative of compound (IV) with silyl compound such as two (trimethyl silyl) ethanamide, list (trimethyl silyl) ethanamide, two (trimethyl silyl) urea or similar compounds reaction generation; By the derivative of compound (IV) with phosphorus trichloride or phosgene and analogue reaction generation.
This reaction is carried out in solvent usually, for example at alcohol (as methyl alcohol, ethanol etc.), methylene dichloride, benzene, N, carries out in dinethylformamide, tetrahydrofuran (THF), diethyl ether or any solvent that other does not have a negative impact to this reaction.
This reaction can be carried out in the presence of mineral alkali or organic bases, for example can be at alkali metal hydroxide (as sodium hydroxide, potassium hydroxide etc.), alkaline carbonate (as yellow soda ash, salt of wormwood etc.), alkali metal hydrocarbonate (as sodium bicarbonate, saleratus etc.), alkalimetal hydride (as sodium hydride, potassium hydride KH etc.), three (rudimentary) alkylamine (as Trimethylamine 99, triethylamine, diisopropyl ethyl amine etc.), pyridine or derivatives thereof (as picoline, lutidine, 4-dimethylaminopyridine etc.), or similarly carry out in the alkali.At employed alkali is under the situation of liquid, and this alkali also can be used as solvent.
Temperature of reaction is not strict, reaction can the cooling under, at room temperature or warm or the heating condition under carry out.
Method 4
(Ig ") or its salt can lead to the reactive derivative that makes on compound (IV) or its imido grpup or reactive derivative or its reactant salt on its salt and compound (VI) or its carboxyl prepares for compound.
This reaction can be undertaken by mode or its similar mode narrated in the preparation 10.
Purpose compound of the present invention has pharmacological activity, for example tachykinin antagonist effect, particularly Substance P antagonistic action, neurokinin A antagonistic action or neurokinin B antagonistic action, thereby can be used for treating or prevent the disease of tachykinin mediation, the disease of Substance P mediation especially, for example, respiratory disease such as asthma, bronchitis (as chronic bronchitis, acute bronchitis and the full bronchitis of diffustivity etc.), rhinitis, cough, expectoration etc.; Illness in eye such as conjunctivitis, spring (Catarrhal) conjunctivitis etc.; Tetter such as contact dermatitis, atopic dermatitis, urticaria and other eczema-like dermatitis etc.; Inflammatory diseases such as rheumatoid arthritis, osteoarthritis etc.; Ache or pain (as migraine, headache, bunch shape headache, toothache, pain caused by cancer, backache, neurodynia etc.); Or the like.
And then, expect that purpose compound of the present invention also can be used for treatment or prevention illness in eye, as glaucoma, uveitis etc.; Gastrointestinal illness is as ulcer, ulcerative colitis, pungency bowel syndrome, food anaphylaxis reaction etc.; Inflammatory diseases is as ephritis etc.; Circulation disease is as hypertension, stenocardia, heart failure, thrombosis, raynaud's disease etc.; Epilepsy; Spastic paralysis; Pollakiuria; Urocystitis; Bladder forces muscular reflex hyperfunction; The urinary incontinence; Parkinson's disease; Dull-witted; The dementia relevant with acquired immune deficiency syndrome (AIDS); Alzheimer's disease; Mongolism; Huntington Chorea; Carcinoid syndrome; With immunostimulant or suppress relevant imbalance; The microbial imbalance of the positive Grain-negative of helicobacter pylori or another kind of spiral urase; Sunburn; Vasculogenesis or the disease that causes by vasculogenesis; Or the like.
Further contemplate that purpose compound of the present invention also can be used for treatment or prevention chronic obstructive pulmonary disease, especially chronic emphysema, iritis; Proliferative vitreous body retinopathy; Psoriasis; Inflammatory bowel disease, Crohn disease especially; The surperficial pain of hepatitis, frostbite, burn, zoster or diabetic neuropathy; The tenontodynia that hyperlipoidemia is followed; Operation, especially postmastectomy neuroma; The vestibule of vagina inflammation; The itch that interrelates with hemodialysis; Lichen planus; Laryngopharyngitis; Bronchiectasis; Coniosis; Whooping cough; Pulmonary tuberculosis; Vesical fibrosis; Vomiting; Psychotic disorder, especially anxiety, depression, spirit depressing sexual maladjustment and schizophrenia; Demyelination, for example multiple sclerosis and amyotrophic lateral sclerosis (spinal cord) lateral sclerosis; Morphine de-addiction reduction; Edema, for example edema that causes of thermal burn; Small cell carcinoma, especially small cell lung cancer (SCLC); The allergy imbalance, for example malicious ivy (poisonivy); Fibrosis and collagen diseases, for example scleroderma and have a liking for the eosin fascioliasis; Reflection sympathetic dystrophy, for example shoulder/hand syndrome; Addiction sexual maladjustment, for example alcoholism; The somatic disorder relevant with stress reaction; Rheumatism, for example fibrosis; Or the like.
For therapeutic purpose, purpose compound of the present invention can use with pharmaceutical preparation form, wherein contain one of described compound as effective constituent, and the pharmaceutically acceptable carrier of fusion, for example, be suitable for oral administration, non-through enteral administration, outside administration (comprising topical), through enteral administration, through intravenous administration, through intramuscular administration, inhalation-type drug administration, nose administration, through intra-articular administration, administration in backbone, through the organic or inorganic solid or the liquid excipient of tracheae administration or administration through eye.Pharmaceutical preparation can be solid, semisolid or liquid, for example, capsule, tablet, pill, dragee, powder, granule, suppository, ointment, creme, lotion, inhalation, injection, paste, gelifying agent, band agent, eye drops, solution, syrup, aerosol, suspension liquor, emulsion agent etc.If wish, can also comprise complementary material, solubilizing agent, wetting agent or emulsifying agent, buffer reagent and other typical additives in these preparations.
Though the dosage of these purpose compounds will be different because of patient's age and the state of an illness, but the average single dose of the about 0.1mg of these purpose compounds, 1mg, 10mg, 50mg, 100mg, 250mg, 500mg and 1000mg just can be used for the treatment of the disease of tachykinin mediation effectively, for example asthma etc.In general, the dosage of every day can be between 0.1mg/ body-Yue 1000mg/ body.
For the availability of these purpose compounds is described, the pharmacology test data of representative compounds of the present invention are described below.
Following test compound shows, with the concentration of 0.1 μ g/ml, to h-NK 1Receptors bind 125The inhibiting rate of I-BH-Substance P reaches more than 90%.
Test compound: the purpose compound of example 2
With h-NK 1Receptors bind 125The I-BH-Substance P
Test method: with h-NK 1Receptors bind 125The I-BH-Substance P
(a) thick Chinese hamster ovary celI film preparation
Collect permanent expression h-NK 1The Chinese hamster ovary celI of acceptor is at a kind of buffer reagent (0.25M sucrose, 25mM Tris-HCl pH7.4,10mM MgCl 2, 1mM EDTA, 5 μ g/ml p-APMSF) at 4 ℃ with the homogenize of a Dounce homogenizer.Homogenize thing centrifugation (500xg, 10 minutes), pellet is suspended in the identical buffer reagent again, homogenize and centrifugation.Twice supernatant liquor merges centrifugation (100,000xg, 1 hour).Isolating like this thickness after birth is suspended in buffer reagent (25mM Tris-HCl pH7.4,10mM MgCl again 2, 1mM EDTA, 5 μ g/ml p-APMSF) in ,-80 ℃ of storages until use.
(b) membrane-bound with preparation 125The I-BH-Substance P
Cytolemma (6 μ g/ml) with 125I-BH-Substance P (0.1nM) has or does not have test compound together, at 0.25ml substratum 2 (50mM Tris-HCl pH7.4,5mM MnCl 2, 20 μ g/ml chymostatins, 40 μ g/ml bacitracins, 4 μ g/ml leupeptin, 5 μ g/mlp-APMSF, 200 μ g/ml BSA) in, cultivated 90 minutes at 22 ℃.When incubation period finished, content filtered rapidly down air-breathing with a Wahtman GF/C glass filter (using preceding with 0.1% polymine pre-treatment 3 hours).Then, each strainer is all used 5ml buffer reagent (50mM Tris-HCl pH7.4,5mM MnCl 2) wash 4 times.(Packerd RIASTAR 5420A) carries out radiocounting with automatic gamma counter.The data of statement all are to be defined as the sort of particular combination of the unmarked Substance P metathetical of available 3 μ M.
In addition, purpose compound of the present invention, especially compound (If) also is excellent at aspects such as stability.
Example provides following preparation and example, is in order to illustrate in greater detail the present invention.Preparation 1
Past N in nitrogen atmosphere 2Add triethylamine (5.85ml) in-(tertbutyloxycarbonyl)-N '-formyl radical-D-tryptophane (3.99g) and the mixture of N-benzyl glycin benzyl ester hydrochloride (3.50g) in methylene dichloride (70ml).At room temperature in this mixture, add iodate 2-chloro-1-picoline (3.67g), then formed mixture was stirred 2 hours.After reaction finishes, add methylene dichloride (30ml) and water (30ml).Isolate organic layer, use 0.5N hydrochloric acid (10ml), water (10ml), sodium bicarbonate aqueous solution (10ml) and salt solution (20ml) washing successively, use dried over mgso again.After solvent evaporation; residue is purified with silicagel column (140g); with the mixture wash-out of toluene and ethyl acetate (4: 1), obtain buttery (2R)-N-benzyl-N-carbobenzoxy-(Cbz) methyl-2-(tertiary butyloxycarbonyl amino)-3-(N-formyl radical-1H-indol-3-yl) propionic acid amide (6.41g).
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
In the ice-cooled solution of purpose compound (6.39g) in methylene dichloride (50ml) of preparation 1, add 4N hydrogenchloride De dioxane solution (50ml).This mixture stirred 30 minutes under same temperature, at room temperature stirred 1 hour.After solvent evaporation, allow residue between methylene dichloride (50ml) and sodium bicarbonate aqueous solution (30ml), distribute.Isolate organic layer, use dried over mgso, and filter.At room temperature in filtrate, add triethylamine (1.67ml), mixture was stirred 1.5 hours.After the evaporation, residue is developed with diisopropyl ether, obtains (3R)-1-benzyl-3-(N-formyl radical-1H-indol-3-yl methyl) piperazine-2,5-diketone (3.93g) after filtration collection and the drying.
mp：176-178℃
IR (whiteruss): 3250,1709,1648,1630cm -1
NMR(DMSO-d 6，δ)：2.95-3.30?and?3.35-3.70(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, 2br s)
Preparation 3
In the ice-cooled solution of purpose compound (3.89g) in the mixture of methyl alcohol (175ml) and tetrahydrofuran (THF) (50ml) of preparation 2, add 0.1N aqueous sodium hydroxide solution (108ml).This mixture stirred 30 minutes under same temperature, at room temperature stirred 1.5 hours.After solvent evaporation, the residue dichloromethane extraction.Dried over mgso is used in organic layer water and sodium chloride aqueous solution washing.Obtain (3R)-1-benzyl-3-(1H-indol-3-yl methyl) piperazine-2 after the solvent evaporation, 5-diketone (3.68g).
mp：207-208℃
IR (whiteruss): 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
Figure A9619574400181
At 0 ℃ of tetrahydrofuran (THF) (40ml) solution that in nitrogen atmosphere, drips the purpose compound (3.40g) of preparation 3 in the suspension of lithium aluminium hydride (0.77g) in tetrahydrofuran (THF) (40ml).This mixture at room temperature stirred 50 minutes, stirred 1 hour under reflux temperature.The gained mixture dilutes with tetrahydrofuran (THF) (60ml), and is cooled to 0 ℃.Slowly add entry (3.0ml) and 15% aqueous sodium hydroxide solution (0.8ml).Filter and take out the insoluble inorganic substance that generated, and wash with tetrahydrofuran (THF).Filtrate and washings are merged, and vapourisation under reduced pressure obtains buttery (3R)-1-benzyl-3-(1H-indol-3-yl methyl) piperazine (3.68g).IR (CHCl 3): 3240,3040,2900cm -1NMR (DMSO-d 6, δ): 1.70-2.00 and 2.30-2.45 (2H, 2m);
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
Figure A9619574400191
At room temperature, in nitrogen atmosphere, toward 3, add triethylamine (1.55ml) in 5-two (trifluoromethyl) phenylformic acid (1.15g) and (the 3R)-mixture of 1-benzyl-3-(1H-indol-3-yl methyl) piperazine (1.61g) in methylene dichloride (80ml).Add iodate 2-chloro-1-picoline (1.37g) then, at room temperature this mixture was stirred 2.5 hours.The gained mixture is poured in the water (20ml).Organic layer is used 0.5N hydrochloric acid, water, sodium bicarbonate aqueous solution and salt water washing successively, uses dried over mgso.Residue carries out the chromatogram purification with silicagel column after the vapourisation under reduced pressure, makes eluent with toluene/ethyl acetate (4: 1), obtains (2R)-4-benzyl-1-(3,5-two (trifluoromethyl) benzoyl)-2-(1H-indol-3-yl methyl) piperazine (0.87g).Be slurry form.
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-two (trifluoromethyl) benzoyl)-2-(1H-indol-3-yl methyl) piperazine (5.20g), ammonium formiate (1.50g) and the mixture of 10%Pd/ charcoal (0.52g) in ethanol (50ml) refluxed in nitrogen atmosphere 7.5 hours.Allow reaction mixture be cooled to room temperature, filter by diatomite layer then.Filtrate under reduced pressure concentrates, and residue is purified with silicagel column, and the mixture wash-out with methylene dichloride and methyl alcohol (20: 1) obtains (2R)-1-(3,5-two (trifluoromethyl) benzoyl)-2-(1H-indol-3-yl methyl) piperazine (2.67g) soup compound.
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-two (trifluoromethyl) benzoyl)-2-(1H-indol-3-yl methyl) piperazine (1.5g), 2-benzyl acetate bromide (0.79g), triethylamine (0.55ml) and tetrahydrofuran (THF) (15ml) at room temperature stir and spend the night.Formed insoluble substance is shifted out in filtration, and filtrate under reduced pressure concentrates.Residue carries out chromatogram with silicagel column purifies, and the mixture wash-out with methylene dichloride and methyl alcohol (30: 1) obtains (2R)-4-(carbobenzoxy-(Cbz) methyl)-1-(3,5-two (trifluoromethyl) benzoyl)-2-(1H-indol-3-yl methyl) piperazine (1.92g).
[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)-mixture of 4-(carbobenzoxy-(Cbz) methyl)-1-(3,5-two (trifluoromethyl) benzoyl)-2-(1H-indol-3-yl methyl) piperazine (1.86g), 10%Pd/ charcoal (0.186g) and tetrahydrofuran (THF) (93ml) stirred 17 hours in atmosphere of hydrogen (1 normal atmosphere).Remove by filter catalyzer, filtrate concentrates.Residue is developed with ether, obtains (2R)-4-(carboxymethyl)-1-(3,5-two (trifluoromethyl) benzoyl)-2-(1H-indol-3-yl methyl) piperazine (0.83g) white powder.
[α] D 19：-3.0°(C＝0.5，DMF)
mp：152-156℃
IR (whiteruss): 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
In (2R)-2-benzyl-1-(3,5-two (trifluoromethyl) benzoyl) piperazine (0.3g) and the ice-cooled mixture of triethylamine (0.39ml) in dimethyl formamide (8ml), add 3-(chloromethyl) pyridine hydrochloride (0.12g).Under same temperature, reaction mixture was stirred 30 minutes, at room temperature stirred then 2 hours.Add extra triethylamine (0.39ml) and 3-(chloromethyl) pyridine hydrochloride (0.12g) again, the gained mixture is stirred spend the night.Reaction mixture is filtered, carry out silica gel column chromatography after filtrate concentrates and purify, with the mixture wash-out of toluene and ethyl acetate (5: 1).Elutant is handled with the ethyl acetate solution of 4N hydrogenchloride, obtains (2R)-2-benzyl-1-(3,5-two (trifluoromethyl) benzoyl)-4-(pyridin-3-yl methyl) piperazine dihydrochloride.
mp：164-168℃
[α] D 25：+9.1°(C＝1.0，MeOH)
IR (whiteruss): 3700-3100,2700-2000,1630,1270,1120,
900cm -1NMR(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) (dissociating) preparation 10
Figure A9619574400221
At room temperature in nitrogen atmosphere, in (2R)-2-benzyl-1-(3,5-two (trifluoromethyl) benzoyl) piperazine (0.3g) and the mixture that stirring of 2-(1H-indol-3-yl) acetate (0.13g) in the methylene dichloride that contains triethylamine (0.25ml) (8ml), add iodate 2-chloro-1-picoline (0.22g).Stir after 5 hours, reaction mixture dilutes with methylene dichloride, with 0.1N hydrochloric acid, saturated sodium bicarbonate aqueous solution and salt water washing, uses dried over mgso then.After removing solvent; residue carries out chromatogram with silicagel column and purifies; with chloroform/methanol (50: 1) wash-out, obtain (2R)-2-benzyl-1-(3,5-two (trifluoromethyl) benzoyl)-4-(2-(1H-indol-3-yl) ethanoyl) piperazine (0.34g) white powder.
mp：201-210℃
[α] D 27：+27.6°(C＝1.0，MeOH)
IR (whiteruss): 3270,1630,1276,1115,900,737cm -1
NMR(DMSO-d 6，δ)：2.60-5.00(11H，m)；?6.7?0-7.70(12H，
m)；8.10-8.20(1H，m)；10.85-11.10(1H，m)
MASS：574(M+1)，417
Preparation 11
In methylene dichloride (10ml) solution of (2R)-1-(3,5-two (trifluoromethyl) benzoyl)-2-(1H-indol-3-yl methyl) piperazine (0.1g), add 4N hydrogenchloride De dioxane solution (0.05ml) at 0 ℃.The gained mixture stirred 50 minutes under same temperature, under reduced pressure concentrated then.Filter and collect the gained powder,, obtain (2R)-1-(3,5-two (trifluoromethyl) benzoyl)-2-(1H-indol-3-yl methyl) piperazine hydrochloride (0.1g) with the ether washing.
IR (whiteruss): 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) (dissociating)
Preparation 12
At 0 ℃ of under agitation past (2R)-4-(2-amino-ethyl)-1-(3; 5-two (trifluoromethyl) benzoyl)-add methylsulfonyl chloride (0.1ml) in 2-(3, the 4-dimethyl benzyl) piperazine dihydrochloride (110mg), the mixture of triethylamine (0.2ml) in methylene dichloride.Stir and after 1 hour reaction mixture is poured in the frozen water, use ethyl acetate extraction then.Extract is used saturated sodium bicarbonate aqueous solution and salt water washing successively, and carries out drying.After the solvent vacuum-evaporation; residue is purified with silica gel column chromatography; mixture wash-out with methylene dichloride and methyl alcohol (40: 1); handle with the ethyl acetate solution of 4N hydrogenchloride then; obtain (2R)-1-(3; 5-two (trifluoromethyl) benzoyl)-2-(3, the 4-dimethyl benzyl)-4-(2-(methylsulfonyl amino) ethyl) piperazine hydrochloride (50mg).
mp：＞220℃
[α] D 22：+0.2°(C＝0.5，DMF)
IR (whiteruss): 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) (dissociating)
Example 1
At room temperature under agitation in (2R)-4-(carboxymethyl)-1-(3,5-two (trifluoromethyl) the benzoyl)-solution of 2-(1H-indol-3-yl methyl) piperazine (1g) in anhydrous dimethyl formamide (10ml), add I-hydroxybenzotriazole (0.29g) and 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (0.41g).At room temperature stir after 15 minutes and to add 1-amino-4-methylpiperazine (320mg), and under same temperature restir 5 hours.Reaction mixture is poured in water (100ml) solution of sodium bicarbonate (1.8g), used ethyl acetate extraction three times, use 20ml at every turn.Organic layer is merged, with salt solution (30ml) washing.The organic layer dried over mgso is filtered, and removes solvent with rotatory evaporator.Crude product chromatography (silica gel; methylene dichloride: methyl alcohol=5: 1) purify; obtain pulverous (the 2R)-1-of light red (3,5-two (trifluoromethyl) benzoyl)-2-(1H-indol-3-yl methyl)-4-(N-(4-methyl isophthalic acid-piperazinyl) carbamyl ylmethyl) piperazine (0.94g).
IR (whiteruss): 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-two (trifluoromethyl) benzoyl)-2-(1H-indol-3-yl methyl)-4-(N-(4-methyl isophthalic acid-piperazinyl) carbamyl ylmethyl) piperazine (10.89g) and fumaric acid (2.07g) are dissolved in 70 ℃ of ethanol (50ml).After the cooling gained solution is under reduced pressure concentrated, obtain powder (13.18g).This powder (9.68g) is dissolved in the 2-butanone (194ml) under the reflux temperature; at room temperature this solution is stirred; obtain xln; filter and collect this xln; obtain (2R)-1-(3,5-two (trifluoromethyl) benzoyl)-2-(1H-indol-3-yl methyl)-4-(N-(4-methyl isophthalic acid-piperazinyl) carbamyl ylmethyl) piperazine fumarate (7.94g) after the drying.
mp：169.5-171℃
IR (whiteruss): 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), promptly (2R)-1-(3,5-two (trifluoromethyl) benzoyl)-2-(1H-indol-3-yl methyl)-4-(N-(4-methyl isophthalic acid-piperazinyl) carbamyl ylmethyl) piperazine fumarate also can make according to following scheme:
Example 4
With (2R)-1-(3; 5-two (trifluoromethyl) benzoyl)-2-(1H-indol-3-yl methyl) piperazine (120mg), 4-chloromethyl-2-(2-methoxy ethyl carbonylamino) triazole (70mg) and the mixture of powdery sodium bicarbonate (27mg) in dry dimethyl formamide stirred 5 hours, and stirred 20 minutes at 60 ℃.Reaction mixture is poured in the water, filtered and collect the throw out that forms.Thick product is purified with silica gel column chromatography, with the mixture wash-out of methylene dichloride and methyl alcohol (30: 1).The effluent vapourisation under reduced pressure; use 17.6% ethanol solution of hydrogen chloride (0.12ml) to handle then; obtain (2R)-1-(3,5-two (trifluoromethyl) benzoyl)-2-(1H-indol-3-yl methyl)-4-[[2-(3-methoxy propyl acyl amino) thiazole-4-yl] methyl] piperazine hydrochloride (140mg).
[α] D 22：-34.0°(C＝0.5，MeOH)
IR (whiteruss): 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) (dissociating)
Example 5
Prepared following bridged piperazine derivatives (table 1) with the mode that is similar to each instance number pointed out in " method " hurdle or preparation number.After the physical properties of each purpose compound is listed in table.
Figure A9619574400291
Table 1
Figure A9619574400292
Table 1 (continuing)
Figure A9619574400301
Table 1 (continuing)
Figure A9619574400311
The physical properties of example 5 compounds: example 5-1)
mp：185-189℃
[α] D 24：30.2°(c＝0.5，Me0H)
IR (whiteruss): 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) (dissociating), 456 example 5-2)
[α] D 22：-33.4°(c＝0.5，MeOH)
IR (whiteruss): 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，br?s)
MASS:640 (M+1) (dissociating), 456 example 5-3)
[α] D 22：-42.0°(c＝0.5，MeOH)
IR (whiteruss): 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) (dissociating), 456 example 5-4)
[α] D 22：-24.2°(C＝0.5，MeOH)
IR (whiteruss): 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) (dissociating), 456 example 5-5)
[α] D 22：-35.8°(C＝0.5，MeOH)
IR (whiteruss): 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) (dissociating), 456 example 5-6)
[α] D 22：-30.4°(C＝0.5，MeOH)
IR (whiteruss): 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) (dissociating) example 5-7)
[α] D 22：-34.0°(C＝0.5，MeOH)
IR (whiteruss): 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) (dissociating) example 5-8)
[α] D 22：-15.2°(C＝0.5，MeOH)
IR (whiteruss): 3600-3100,2750-2000,1635,1278,1172,
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) (dissociating), 456 example 5-9)
[α] D 22：-20.6°(C＝0.5，MeOH)
IR (whiteruss): 3650-3100,2750-2000,1635,1276,1170,
1129，900cm -1
NMR(DMSO-d 6，δ)：2.09(3H，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) (dissociating) example 5-10)
[α] D 22：-13.0°(C＝0.5，MeOH)
IR (whiteruss): 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) (dissociating) example 5-11)
[α] D 18：-20.8°(C＝0.5，MeOH)
IR (net 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 example 5-12)
[α] D 22：-10.4°(C＝0.5，MeOH)
IR (whiteruss): 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) (dissociating), 456 example 5-13)
[α] D 22：-31.8°(C＝0.5，MeOH)
IR (whiteruss): 3270,2750-2000,1637,1531,1279,1124,
964cm -1
NMR(DMSO-d 6，δ)：2.73-5.15(14H，m)；6.60-8.25
(10H，m)；10.89(1H，s)
MASS:646 (M+1) (dissociating), 568,456 example 5-14)
[α] D 23：11.8°(C＝0.5，MeOH)
IR (whiteruss): 3650-3100,1625,1543,1275,1130cm -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 example 5-15)
[α] D 18：-51.6°(C＝0.5，MeOH)
IR (whiteruss): 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) (dissociating) example 5-16)
[α] D 22：-23.4°(C＝0.5，MeOH)
IR (whiteruss): 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) (dissociating)

Claims (8)

1. the compound shown in the following formula or its fumarate:
Figure A9619574400021
2. the described compound of claim 1, this compound is the compound shown in the following formula:
Figure A9619574400022
3. compound shown in the preparation following formula:
Figure A9619574400023
Or the method for its fumarate, this method comprises:
(1) make the compound shown in the following formula:
Figure A9619574400031
Or the compound shown in the reactive derivative on its carboxyl or its salt and the following formula: Or the reactive derivative on its amino or its reactant salt, obtain the compound shown in the following formula:
Figure A9619574400033
Or its fumarate, or
(2) make the compound shown in the following formula: Or its salt (except its fumarate) and fumaric acid reaction, obtain the compound shown in the following formula:
4. a pharmaceutical composition wherein comprises the compound as the claim 1 of activeconstituents, and is combined with pharmaceutically acceptable, nontoxic carrier or vehicle basically.
5. treatment or prevention are by the method for the various diseases of tachykinin mediation, and this method comprises the compound to the claim 1 of the mankind or administration significant quantity.
6. be used as the compound of the claim 1 of medicine.
7. the compound of claim 1 is used to make the purposes of the medicine of the various diseases for the treatment of or preventing to be mediated by tachykinin.
8. the compound shown in the following general formula or its pharmaceutically acceptable salt:
Figure A9619574400042
Wherein
R 1Be three halogen (rudimentary) alkyl,
R 2Be three halogen (rudimentary) alkyl,
R 3Be indyl (rudimentary) alkyl,
-A-is-CH 2-or,
Figure A9619574400043
And
-R 4Be
Figure A9619574400051
R wherein 5Be hydrogen or lower alkoxycarbonyl, R 6Be hydrogen or low-grade alkane acidyl, R 7Be hydrogen, low alkyl group, low-grade alkane acidyl, lower alkoxycarbonyl, lower alkoxy (rudimentary) alkyloyl, ring (rudimentary) alkyl-carbonyl, aroyl or low alkyl group alkylsulfonyl.
CN96195744A 1995-05-25 1996-05-21 1-benzoyl-2-(indolyl-3-alkyl)-piperazine derivs. as neurokinin receptor antagonists Expired - Fee Related CN1072220C (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US45017695A 1995-05-25 1995-05-25
US08/450,176 1995-05-25

Publications (2)

Publication Number Publication Date
CN1191533A true CN1191533A (en) 1998-08-26
CN1072220C CN1072220C (en) 2001-10-03

Family

ID=23787083

Family Applications (1)

Application Number Title Priority Date Filing Date
CN96195744A Expired - Fee Related CN1072220C (en) 1995-05-25 1996-05-21 1-benzoyl-2-(indolyl-3-alkyl)-piperazine derivs. as neurokinin receptor antagonists

Country Status (14)

Country Link
EP (1) EP0846116A1 (en)
JP (1) JP3071829B2 (en)
KR (1) KR19990021857A (en)
CN (1) CN1072220C (en)
AU (1) AU706021B2 (en)
CA (1) CA2222041A1 (en)
EA (1) EA000669B1 (en)
HU (1) HUP9900822A3 (en)
IL (1) IL118369A (en)
NZ (1) NZ307625A (en)
TR (1) TR199600438A2 (en)
TW (1) TW391960B (en)
WO (1) WO1996037489A1 (en)
ZA (1) ZA964101B (en)

Families Citing this family (47)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2189501A1 (en) * 1995-11-06 1997-05-07 Harry R. Howard Nk-1 receptor antagonists for the treatment of cancer
HUP9901037A3 (en) * 1995-12-18 2001-11-28 Fujisawa Pharmaceutical Co Piperazine derivatives,preparation and use thereof, pharmaceutical compositions containing these compounds
AUPO735997A0 (en) * 1997-06-17 1997-07-10 Fujisawa Pharmaceutical Co., Ltd. Piperazine derivatives
EP0899270B1 (en) * 1997-08-27 2008-05-21 Solvay Pharmaceuticals GmbH Indolylmethyl-N,N'-bisacylpiperazines as neurokinine receptor antagonists
DE19824865A1 (en) * 1997-08-27 1999-03-04 Solvay Pharm Gmbh New urea derivatives
US6833373B1 (en) 1998-12-23 2004-12-21 G.D. Searle & Co. Method of using an integrin antagonist and one or more antineoplastic agents as a combination therapy in the treatment of neoplasia
DE10036818A1 (en) * 2000-07-28 2002-02-07 Solvay Pharm Gmbh New N-Triazolylmethyl-Piperazine Derivatives as Neurokinin Receptor Antagonists
UA75425C2 (en) 2001-07-09 2006-04-17 Piperazine oxime derivatives with antagonistic activity to nk-1 receptor, use thereof, a pharmaceutical composition based thereon, a method for producing and a method for producing intermediary compounds
UA77515C2 (en) 2002-04-04 2006-12-15 Diazabicyclo alkane derivatives possessing neuroldnin-nk1 receptor antagonistic activity
KR101412339B1 (en) 2004-07-15 2014-06-25 알바니 몰레큘라 리써치, 인크. Aryl- and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
US8362075B2 (en) 2005-05-17 2013-01-29 Merck Sharp & Dohme Corp. Cyclohexyl sulphones for treatment of cancer
US7956050B2 (en) 2005-07-15 2011-06-07 Albany Molecular Research, Inc. Aryl- and heteroaryl-substituted tetrahydrobenzazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
EP1940842B1 (en) 2005-09-29 2012-05-30 Merck Sharp & Dohme Corp. Acylated spiropiperidine derivatives as melanocortin-4 receptor modulators
GB0603041D0 (en) 2006-02-15 2006-03-29 Angeletti P Ist Richerche Bio Therapeutic compounds
WO2008039327A2 (en) 2006-09-22 2008-04-03 Merck & Co., Inc. Method of treatment using fatty acid synthesis inhibitors
US20110218176A1 (en) 2006-11-01 2011-09-08 Barbara Brooke Jennings-Spring Compounds, methods, and treatments for abnormal signaling pathways for prenatal and postnatal development
PL2336120T3 (en) 2007-01-10 2014-12-31 Msd Italia Srl Combinations containing amide substituted indazoles as poly(adp-ribose)polymerase (parp) inhibitors
CA2676357A1 (en) 2007-01-24 2008-07-31 Glaxo Group Limited Pharmaceutical compositions comprising 3, 5-diamin0-6- (2, 3-dichl0phenyl) -l, 2, 4-triazine or r (-) -2, 4-diamino-5- (2, 3-dichlorophenyl) -6-fluoromethyl pyrimidine and an nk1
US8106086B2 (en) 2007-04-02 2012-01-31 Msd K.K. Indoledione derivative
WO2008147864A2 (en) * 2007-05-22 2008-12-04 Xenon Pharmaceuticals Inc. Methods of using piperazine compounds in treating sodium channel-mediated diseases or conditions
CA2690191C (en) 2007-06-27 2015-07-28 Merck Sharp & Dohme Corp. 4-carboxybenzylamino derivatives as histone deacetylase inhibitors
WO2009111354A2 (en) 2008-03-03 2009-09-11 Tiger Pharmatech Tyrosine kinase inhibitors
US9156812B2 (en) 2008-06-04 2015-10-13 Bristol-Myers Squibb Company Crystalline form of 6-[(4S)-2-methyl-4-(2-naphthyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyridazin-3-amine
WO2010114780A1 (en) 2009-04-01 2010-10-07 Merck Sharp & Dohme Corp. Inhibitors of akt activity
KR101830447B1 (en) 2009-05-12 2018-02-20 알바니 몰레큘라 리써치, 인크. 7-([1,2,4]TRIAZOLO[1,5-α]PYRIDIN-6-YL)-4-(3,4-DICHLOROPHENYL)-1,2,3,4-TETRAHYDROISOQUINOLINE AND USE THEREOF
WO2010132487A1 (en) 2009-05-12 2010-11-18 Bristol-Myers Squibb Company CRYSTALLINE FORMS OF (S)-7-([1,2,4]TRIAZOLO[1,5-a]PYRIDIN-6-YL)-4-(3,4-DICHLOROHPHENYL)-1,2,3,4-TETRAHYDROISOQUINOLINE AND USE THEREOF
US9034899B2 (en) 2009-05-12 2015-05-19 Albany Molecular Research, Inc. Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof
PE20121172A1 (en) 2009-10-14 2012-09-05 Merck Sharp & Dohme PIPERIDINS SUBSTITUTED WITH ACTIVITY IN HDM2
US8999957B2 (en) 2010-06-24 2015-04-07 Merck Sharp & Dohme Corp. Heterocyclic compounds as ERK inhibitors
CA2805265A1 (en) 2010-08-02 2012-02-09 Merck Sharp & Dohme Corp. Rna interference mediated inhibition of catenin (cadherin-associated protein), beta 1 (ctnnb1) gene expression using short interfering nucleic acid (sina)
CA2807307C (en) 2010-08-17 2021-02-09 Merck Sharp & Dohme Corp. Rna interference mediated inhibition of hepatitis b virus (hbv) gene expression using short interfering nucleic acid (sina)
EP2608669B1 (en) 2010-08-23 2016-06-22 Merck Sharp & Dohme Corp. NOVEL PYRAZOLO[1,5-a]PYRIMIDINE DERIVATIVES AS mTOR INHIBITORS
US8946216B2 (en) 2010-09-01 2015-02-03 Merck Sharp & Dohme Corp. Indazole derivatives useful as ERK inhibitors
US9242981B2 (en) 2010-09-16 2016-01-26 Merck Sharp & Dohme Corp. Fused pyrazole derivatives as novel ERK inhibitors
EP2632472B1 (en) 2010-10-29 2017-12-13 Sirna Therapeutics, Inc. Rna interference mediated inhibition of gene expression using short interfering nucleic acids (sina)
US9351965B2 (en) 2010-12-21 2016-05-31 Merck Sharp & Dohme Corp. Indazole derivatives useful as ERK inhibitors
IN2013MN02170A (en) 2011-04-21 2015-06-12 Piramal Entpr Ltd
WO2013063214A1 (en) 2011-10-27 2013-05-02 Merck Sharp & Dohme Corp. Novel compounds that are erk inhibitors
EP2844261B1 (en) 2012-05-02 2018-10-17 Sirna Therapeutics, Inc. SHORT INTERFERING NUCLEIC ACID (siNA) COMPOSITIONS
WO2014052563A2 (en) 2012-09-28 2014-04-03 Merck Sharp & Dohme Corp. Novel compounds that are erk inhibitors
MX363243B (en) 2012-11-28 2019-03-14 Merck Sharp & Dohme Compositions and methods for treating cancer.
BR112015013611A2 (en) 2012-12-20 2017-11-14 Merck Sharp & Dohme compound and pharmaceutical composition
EP2951180B1 (en) 2013-01-30 2018-05-02 Merck Sharp & Dohme Corp. 2,6,7,8 substituted purines as hdm2 inhibitors
EP3041938A1 (en) 2013-09-03 2016-07-13 Moderna Therapeutics, Inc. Circular polynucleotides
WO2019094311A1 (en) 2017-11-08 2019-05-16 Merck Sharp & Dohme Corp. Prmt5 inhibitors
WO2020033284A1 (en) 2018-08-07 2020-02-13 Merck Sharp & Dohme Corp. Prmt5 inhibitors
US20210277009A1 (en) 2018-08-07 2021-09-09 Merck Sharp & Dohme Corp. Prmt5 inhibitors

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE69029231T2 (en) * 1989-02-10 1997-03-20 Otsuka Pharma Co Ltd INDOLDER DERIVATIVES, THEIR PRODUCTION AND THE MEDICINE CONTAINING THEM TO PREVENT AND TREAT NEPHRITIS
IL111730A (en) * 1993-11-29 1998-12-06 Fujisawa Pharmaceutical Co Piperazine derivatives processes for the preparation thereof and pharmaceutical compositions containing the same

Also Published As

Publication number Publication date
IL118369A0 (en) 1996-09-12
JPH11505830A (en) 1999-05-25
NZ307625A (en) 1999-02-25
HUP9900822A2 (en) 1999-06-28
AU5703196A (en) 1996-12-11
HUP9900822A3 (en) 1999-11-29
IL118369A (en) 2000-06-01
ZA964101B (en) 1996-07-29
TW391960B (en) 2000-06-01
AU706021B2 (en) 1999-06-03
WO1996037489A1 (en) 1996-11-28
EA199700425A1 (en) 1998-12-24
TR199600438A2 (en) 1996-12-21
CN1072220C (en) 2001-10-03
EP0846116A1 (en) 1998-06-10
CA2222041A1 (en) 1996-11-28
KR19990021857A (en) 1999-03-25
EA000669B1 (en) 2000-02-28
JP3071829B2 (en) 2000-07-31

Similar Documents

Publication Publication Date Title
CN1072220C (en) 1-benzoyl-2-(indolyl-3-alkyl)-piperazine derivs. as neurokinin receptor antagonists
CN1041923C (en) Piperazine derivatives
CN1260225C (en) Tetrahydropyridino or piperidino hetlrocyclic derivatives
CN1038939C (en) Peptide compounds, processes for preparation thereof and pharmaceutical composition comprising same
CN1209125A (en) Piperazine derivatives as tachykinin antagonists
CN1289500C (en) Azabicyclic compounds, preparation thereof and use as medicines, in particular as antibacterial agents
CN1052231C (en) Adhesion receptor antagonists
CN1064682C (en) Pyrrolidine derivatives having phospholipase A2 inhibitor activity
CN1179960C (en) Indole derivatives and their use for treatment of osteoporosis amongst other applications
CN1434827A (en) Novel piperidine and piperazine derivatives
CN1137886C (en) 2,3-dioxo-1,2,3,4-tetrahydro-quinoyxalinyl derivatives
CN1064080A (en) Peptides, its preparation method and contain the pharmaceutical composition of this compounds
CN1255401C (en) Aroyl-piperazine derivatives, their preparation and their use as tachykinin antagonists
CN1085212A (en) Indole derivatives
CN1207730A (en) Quinoline derivs.
CN1374953A (en) Aromatic nitrogenous six-membered ring compounds
CN87103504A (en) Heterocyclic carboxamide
CN1083074A (en) Peptide compounds
CN1227544A (en) Tetrahydroquinoline derivatives as EAA antagonists
CN1720246A (en) (Purin-6-yl) amino acid and production method thereof
CN100347173C (en) Pyrazoloquinolines with immunomodulating activity
CN1662519A (en) Heterocyclic compounds as glycine transport inhibitors
CN1311785A (en) Tetrahydroquinoline derivatives as glycine antagonists
CN1058015A (en) Benzoic acid derivative
CN1044906C (en) Pyridazinone derivatives with pharmaceutical activity

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
C19 Lapse of patent right due to non-payment of the annual fee
CF01 Termination of patent right due to non-payment of annual fee