[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

CN1420883A - N-aryl-(homopiperazinyl) cyclohexyl amines as 5-HT transporters - Google Patents

N-aryl-(homopiperazinyl) cyclohexyl amines as 5-HT transporters Download PDF

Info

Publication number
CN1420883A
CN1420883A CN00818247A CN00818247A CN1420883A CN 1420883 A CN1420883 A CN 1420883A CN 00818247 A CN00818247 A CN 00818247A CN 00818247 A CN00818247 A CN 00818247A CN 1420883 A CN1420883 A CN 1420883A
Authority
CN
China
Prior art keywords
carbon atom
alkyl
compound
diazesuberane
cyclohexyl
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.)
Pending
Application number
CN00818247A
Other languages
Chinese (zh)
Inventor
A·M·吉尔伯特
R·E·穆肖
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.)
Wyeth LLC
Wyeth Inc
Original Assignee
Wyeth LLC
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 Wyeth LLC filed Critical Wyeth LLC
Publication of CN1420883A publication Critical patent/CN1420883A/en
Pending 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • 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
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/24—Antidepressants
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • 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
    • 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
    • C07D403/08—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 alicyclic rings

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Psychiatry (AREA)
  • Addiction (AREA)
  • Anesthesiology (AREA)
  • Pain & Pain Management (AREA)
  • Hospice & Palliative Care (AREA)
  • Gynecology & Obstetrics (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

This invention provides novel compounds and methods and compositions using them in the treatment of central nervous system disorders, including depression and anxiety, the compounds having the formula (I) wherein Ar is an aryl, arylalkyl or a heteroaryl group; R1 and R2 are independently selected from hydrogen, alkyl of 1 to 12 carbon atoms which may be substituted or cycloalkyl of 3 to 10 carbon atoms which may be substituted; R3 is H, alkyl which may be substituted, cyclic alkyl which may be substituted, halogen, alkoxy, haloalkyl, OH, nitro, amino, CN, carboxy, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl and alkylaminocarbonyl; or a pharmaceutically acceptable salt thereof.

Description

N-aryl-(high piperazinyl)-hexahydroaniline as serotonin transporter
The present invention relates to have N-aryl-Gao piperazinyl (the homopiperazinyl)-cyclohexylamine derivant of pharmacological activity, and preparation method thereof and contain the medicinal compositions of described compound and relate to the disease that they influence by serotonin in treatment neurological disorder causes, as the purposes in dysthymia disorders and the anxiety disorder.
Background of invention
Having the medicine of strengthening serotonin energy neurotransmission is of value to the multiple psychosis of treatment, comprises dysthymia disorders and anxiety disorder.The nonselective medmain pathology of first-generation medicine works by a series of physiological function, and these physiological functions also make them have the tendency of some side effects.Than the popular prescription drugs, selectivity serotonin reuptake inhibitor (SSRIs) mainly works by suppressing 5-HT, initiatively shifts out through presynaptic serotonin transport vehicle from synaptic cleft at cynapse 5-HT.
Wustrow etc. are at J.Med.Chem.1997, disclose a series of 3-[[4-aryl-1-piperazinyl as the dopamine D 2 partial agonist in 40,250) alkyl] cyclohexyl]-the 1H-indoles.
Cipollina etc. disclose a series of indyl Cycloalkyl amines as treatment vascular headache or migrainous serotonin energy vasoconstrictor in European patent application EP 666258.
Shiota etc. disclose a series of ring diaryl alkane radical derivatives (comprising the high piperazine of aryl) as chemokine receptor anagonists in pct international patent application WO 9744329.Hidaka etc. disclose a series of aryl rings diamines (comprising the high piperazine of aryl) as anti-ulcerative drug in United States Patent (USP) 5244895 and european patent application 513691.Hidaka etc. are at United States Patent (USP) 5,081, disclose a series of aryl rings diamines (comprising the high piperazine of aryl) as vessel relaxant in 246,5,216,150 and 5,245,034.
Description of the invention
The invention provides N-aryl-Gao piperazinyl-cyclohexylamine derivant with pharmacological activity as the 5-HT translocator, and the disease that causes of the neurological disorder that influenced by serotonin in treatment such as the purposes of dysthymia disorders and anxiety disorder.
According to the present invention, provide one group of compound and all crystallized form or the pharmacy acceptable salts thereof represented by formula I:
Figure A0081824700081
Wherein:
Ar is that aryl or aryl moiety wherein have 5-14 carbon atom and moieties has the arylalkyl of 1-6 carbon atom, or Ar is the heteroaryl of 5-10 annular atoms, and heteroatoms wherein can be identical or different, is selected from oxygen, nitrogen or sulphur; The aryl moiety of aryl, heteroaryl or arylalkyl is optional to be selected from identical or different substituting group replacement by 1-3: the alkyl that can choose 1-12 the carbon atom that is replaced by halogen, hydroxyl, nitro, amino or cyano group wantonly; The alkylthio of the alkoxyl group of 1-12 carbon atom, a 1-6 carbon atom; The perfluoroalkyl of 1-6 carbon atom; Hydroxyl; Nitro; Halogen; Amino or cyano group;
R 1And R 2Be alone hydrogen; Can be by the alkyl of 1-12 carbon atom of halogen, hydroxyl, nitro, amino or cyano group replacement; Or can be by the cycloalkyl of 3-10 carbon atom of the alkyl-carbonyl oxygen base of the alkoxy carbonyl alkyl of the alkyl-carbonyl of the alkoxy carbonyl of the halogenated alkoxy of the haloalkyl of the alkoxyl group of the alkyl of halogen, a 1-6 carbon atom, a 1-6 carbon atom, a 1-6 carbon atom, a 1-6 carbon atom, hydroxyl, nitro, cyano group, amino, carboxyl, a 2-7 carbon atom, a 2-7 carbon atom, a 3-13 carbon atom or 2-7 carbon atom replacement;
R 3Be H;
Can be by the alkyl of halogen, hydroxyl, nitro, cyano group or amino 1-12 the carbon atom that replaces;
Can be by the cycloalkyl of 3-10 carbon atom of the alkyl-carbonyl oxygen base of the alkoxy carbonyl alkyl of the alkyl-carbonyl of the alkoxy carbonyl of the halogenated alkoxy of the haloalkyl of the alkoxyl group of the alkyl of halogen, a 1-6 carbon atom, a 1-6 carbon atom, a 1-6 carbon atom, a 1-6 carbon atom, hydroxyl, nitro, cyano group, amino, carboxyl, a 2-7 carbon atom, a 2-7 carbon atom, a 3-13 carbon atom or 2-7 carbon atom replacement;
Or R 3Alkyl amino-carbonyl for alkyl-carbonyl, aminocarboxyl or the 2-12 carbon atom of the alkoxy carbonyl of the haloalkyl of the alkoxyl group of halogen, a 1-12 carbon atom, a 2-12 carbon atom, hydroxyl, nitro, nitrile, amino, cyano group, carboxyl, a 2-12 carbon atom, a 2-12 carbon atom.The example of Ar has:
Single, double or the three cyclophane bases of 6-14 carbon atom comprise the list or the bicyclic aryl of 6-10 carbon atom, as phenyl, naphthyl, indenyl, indacenyl, antracenyl and phenanthryl;
Arylalkyl, aryl moiety wherein is as described herein and moieties has 1-4 carbon atom, as methyl; With
The list of 5-10 annular atoms or bicyclic heteroaryl, wherein 1-3 atom oxygen, nitrogen and the sulphur of being selected from as described herein.Substituting group example on the Ar has:
The alkyl of an alkyl such as 1-6 carbon atom, as methyl, ethyl, propyl group, sec.-propyl, butyl, amyl group and hexyl, these alkyl can be replaced by halogen, amino, hydroxyl, cyano group and nitro;
The alkoxyl group of an alkoxyl group such as 1-6 carbon atom is as methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, pentyloxy and hexyloxy;
Alkylthio such as SMe, SEt, SPr, S iPr, SBu;
Perfluoroalkyl such as CF 3, C 2F 5, C 3F 7, i-C 3F 7
Halogen such as fluorine, chlorine or bromine;
Nitro; Amino and cyano group.
R 1(and R 2) example be independently: hydrogen; The alkyl of 1-6 carbon atom such as methyl, ethyl, propyl group, sec.-propyl, butyl, these alkyl can be chosen wantonly by halogen, nitro, amino, hydroxyl or cyano group and replace; As the cycloalkyl of 3-8 carbon atom, as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and suberyl, these cycloalkyl can be replaced by the alkyl of 1-4 carbon atom such as methyl or ethyl, halogen, nitro, amino, hydroxyl or cyano group.R 3Example be hydrogen,
The alkyl of 1-6 carbon atom such as methyl, ethyl, propyl group, sec.-propyl, butyl, these alkyl can be replaced by halogen, nitro, amino, hydroxyl or cyano group;
Cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and suberyl, these cycloalkyl can be by the alkyl of 1-4 carbon atom such as methyl or ethyl, halogen, nitro, amino, hydroxyl or cyano group replacement;
Chlorine, fluorine, bromine;
The alkoxyl group of 1-4 carbon atom such as methoxyl group, oxyethyl group, propoxy-, isopropoxy;
The haloalkyl of 1-4 carbon atom such as trifluoromethyl, chloro methyl;
The halogenated alkoxy of 1-4 carbon atom is as trifluoromethoxy;
Hydroxyl; Nitro; Amino; Cyano group; Carboxyl;
Carbalkoxy such as methoxycarbonyl; Ethoxy carbonyl;
Alkyl-carbonyl such as ethanoyl, propionyl;
-CONH 2With
Alkyl amino-carbonyl is as MeNHCO.
Formula I compound and all crystallized form or pharmacy acceptable salts thereof are arranged in preferred compound of the present invention, wherein:
Ar is the aryl of 5 or 6 carbon atoms or the heteroaryl of 5-10 annular atoms; And/or
R 1And R 2Be alone the straight chained alkyl of H, a 1-8 carbon atom or the branched-chain alkyl of 3-8 carbon atom; And/or
R 3Alkyl amino-carbonyl for alkyl-carbonyl, aminocarboxyl and the 2-6 carbon atom of the alkoxy carbonyl of the halogenated alkoxy of the haloalkyl of the alkoxyl group of the cycloalkyl of the branched-chain alkyl of the straight chained alkyl of H, a 1-8 carbon atom, a 3-6 carbon atom, a 3-8 carbon atom, halogen, a 1-6 carbon atom, a 1-6 carbon atom, a 1-6 carbon atom, hydroxyl, nitro, nitrile, amino, cyano group, carboxyl, a 2-6 carbon atom, a 2-6 carbon atom.
The preferred aspect of the present invention provides the compound of formula I and all crystallized form or pharmacy acceptable salts thereof, wherein:
Ar is the aryl of 6 carbon atoms or the heteroaryl of heteroaryl or 5-10 annular atoms; And/or
R 1And R 2Be alone the straight chained alkyl of H, 1-3 carbon atom or the branched-chain alkyl of 3-6 carbon atom; And/or
R 3Be H, halogen, cyano group, CONH 2Or CO 2H.
Except that defining separately, no matter separately use is still as the part of another group, and alkyl all comprises straight chain and the branched-chain alkyl that contains 1-12 carbon atom (as 1-6 carbon atom, as 1-4 carbon atom).For example, the term alkyl comprises methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-and the tertiary butyl.In some embodiments of the present invention, alkyl can refer to replace or unsubstituted alkyl.The number of carbon refers to carbon backbone chain and does not comprise the carbon atom of substituting group such as alkoxy substituent etc.Halogen refers to chlorine, bromine, iodine and fluorine as used herein.
Be used for herein or relevant with arylalkyl aryl, refer to many cyclic groups of monocycle or 5-14 unit,, include but not limited to phenyl, naphthalene, anthracene, phenanthrene, indenes and indacene as the aromatic ring of 6-10 carbon.The moieties of arylalkyl can have 1-4 carbon atom, as benzyl.Preferred aryl groups or arylalkyl are phenyl, benzyl and naphthalene.In some embodiments of the present invention, aromatic yl group or part can be replaced by alkyl, the preferred trifluoromethyl of perfluoroalkyl, alkoxyl group and halogen.
Heteroaryl used herein comprises aromatic monocyclic or many cyclic groups of 5-10 unit, they have 1-3 the identical or different heteroatoms that is selected from S, O or N, include but not limited to furans, thiophene, pyrroles, imidazoles, oxazole, thiazole, isoxazole, pyrazoles, isothiazole, oxadiazole, triazole, thiadiazoles, quinolizine, quinoline, isoquinoline 99.9, cinnolines, 2, quinazoline, quinoxaline, naphthyridines (napthyridine), pteridine, pyridine, pyrazine, pyrimidine, pyridazine, pyrans, triazine, indoles, isoindole, indazole, indolizine and isobenzofuran.Preferred heteroaryl comprises furans, thiophene, pyrroles, imidazoles, oxazole, thiazole, isoxazole, pyrazoles, isoxazole, isothiazole, oxadiazole, triazole, thiadiazoles, quinolizine, quinoline and isoquinoline 99.9.Preferred heteroaryl comprises furans, thiophene, imidazoles, isoxazole, quinoline and pyrazoles.In some embodiments of the present invention, heteroaryl replaces.
Described substituted aryl is preferably replaced by 1-3 group.Described substituted heteroaryl is preferably also more preferably replaced by 1-2 group by 1-3 group.Alkyl and cycloalkyl also can be substituted.Suitable substituents includes but not limited to halogen, alkyl, alkoxyl group, haloalkyl, halogenated alkoxy, hydroxyl, nitro, nitrile, amino, cyano group, carboxyl, alkoxy carbonyl, alkyl-carbonyl, alkoxy carbonyl alkyl and alkyl-carbonyl oxygen base.
Most preferred of the present invention has: 3-{4-[4-(2-methoxyl group-phenyl)-[1,4] Diazesuberane-1-base (diazepan-1-y1)]-cyclohexyl }-the 1H-indoles; 8-{4-[4-(1H-indol-3-yl)-cyclohexyl]-[1,4] Diazesuberane-1-yl }-quinoline; 3-{4-[4-(2-methoxyl group-phenyl)-[1,4] Diazesuberane-1-yl]-cyclohexyl }-5-fluoro-1H-indoles; 3-{4-[4-(2-methoxyl group-phenyl)-[1,4] Diazesuberane-1-yl]-cyclohexyl }-the 5-cyano-1 H-indol-; 3-{4-[4-(2-methoxyl group-phenyl)-[1,4] Diazesuberane-1-yl]-cyclohexyl }-6-fluoro-1H-indoles; 8-{4-[4-(5-fluoro-1H-indol-3-yl)-cyclohexyl]-[1,4] Diazesuberane-1-yl }-quinoline; 8-{4-[4-(5-cyano-1 H-indol--3-yl)-cyclohexyl]-[1,4] Diazesuberane-1-yl }-quinoline; 8-{4-[4-(6-fluoro-1H-indol-3-yl)-cyclohexyl]-[1,4] Diazesuberane-1-yl }-quinoline; 3-{4-[4-(3-trifluoromethyl-phenyl)-[1,4] Diazesuberane-1-yl]-cyclohexyl }-5-fluoro-1H-indoles; 3-{4-[4-(3-trifluoromethyl-phenyl)-[1,4] Diazesuberane-1-yl]-cyclohexyl }-the 5-cyano-1 H-indol-; 3-{4-[4-(3-trifluoromethyl-phenyl)-[1,4] Diazesuberane-1-yl]-cyclohexyl }-6-fluoro-1H-indoles; Or the pharmacy acceptable salt of one of these compounds.
Compounds of the present invention can be used as 1,4 cis or trans-isomer(ide) exists.This class isomer and composition thereof also within the scope of the invention.Work as R 1, R 2Or R 3When containing asymmetric carbon, need understand that the definition of formula I compound comprises having following active all possible steric isomer and composition thereof.Particularly, it comprises and has described active racemic modification and any optical isomer.Can obtain the optics and the steric isomer of pure form with conventional isolation technique.
Pharmacy acceptable salt is and salt mineral acid organic derived from this class, and described acid is just like lactic acid, citric acid, acetate, tartrate, succsinic acid, toxilic acid, propanedioic acid, oxalic acid, fumaric acid, hydrochloric acid, Hydrogen bromide, phosphoric acid, nitric acid, sulfuric acid, methylsulfonic acid and similarly known acceptable acid.Work as R 1, R 2Or R 4When containing carboxyl, the salt available bases of compound of the present invention such as basic metal (Na, K, Li) or alkaline-earth metal (Ca or Mg) generate.
As mentioned above, formula I compound has avidity to 5-HT reuptake translocator and can be used for treating the disease that the neural disorder by serotonin influence causes, as dysthymia disorders and anxiety disorder, somnopathy, sexual dysfunction, alcohol addiction and cocaine habituation, identification enhancing and associated problem.Therefore the present invention also provides medicinal compositions, and it comprises the The compounds of this invention that combines and mix with pharmaceutically acceptable carrier or vehicle.
Preferred per os of described composition or subcutaneous administration.But also can adopt other administering mode.
Use usual excipients, can prepare composition of the present invention as weighting agent, disintegrating agent, tackiness agent, lubricant, correctives etc.Use ordinary method, as composition as described in preparing with the method similar methods that is used for known hypotensive agent, diuretic(s) and beta-blocker.Solid carrier that is suitable for or vehicle can comprise that one or more also can play the material that correctives, lubricant, solubilizing agent, suspension agent, weighting agent, glidant, compression assistant agent, tackiness agent or tablet disintegrant or encapsulated raw material work.In pulvis, carrier is subdivided into and the activeconstituents that segmented blended solid mutually.In tablet, activeconstituents mixes with suitable proportion with the carrier with essential compression performance, is pressed into the shape and the specification that need again.Described pulvis and tablet preferably contain can reach 99% activeconstituents at most.The solid carrier that is suitable for comprises, as calcium phosphate, Magnesium Stearate, talcum, sugar, lactic acid, dextrin, starch, gelatin, Mierocrystalline cellulose, methylcellulose gum, Xylo-Mucine, polyvinylpyrrolidone/, low melt wax and ion exchange resin.
Liquid vehicle is used to prepare solution, suspension, emulsion, syrup and elixir.Activeconstituents of the present invention can be dissolved in or be suspended in pharmaceutically acceptable liquid vehicle such as water, organic solvent, both mixture or pharmaceutically acceptable oil or fat.Liquid vehicle can contain other suitable medicinal additive such as solubilizing agent, emulsifying agent, buffer reagent, sanitas, sweetener, correctives, suspension agent, thickening material, pigment, viscosity modifier, stablizer or osmotic pressure regulator.The suitable example that is used for the liquid vehicle of oral and parenteral admin comprises that water (particularly contains aforesaid additive, as derivatived cellulose, the preferably carboxymethyl cellulose sodium solution), alcohol (comprising monohydroxy-alcohol and polyvalent alcohol such as dibasic alcohol) and derivative thereof, and oil (as classification cocounut oil and peanut oil).To parenteral admin, carrier also can be grease such as ethyl oleate and tetradecanoic acid isopropyl esters.Sterile liquid carrier is used for the sterile liquid form composition without enteral administration.
Can be by be adopted as the liquid pharmaceutical composition of sterile solution or suspension as intramuscular, intraperitoneal or subcutaneous injection.But sterile solution is intravenous administration also.The peroral administration liquid that both can be also can be the solids composition form.
Preferred medicinal compositions is a unit dosage, as tablet or capsule.The composition of this form is subdivided into the unitary dose that contains an amount of activeconstituents; Unit dosage can be packaged composition, as pulvis, bottle, ampoule, syringe of packing that is pre-charged with or the sachet that contains liquid.The monomer formulation can be, for example, and capsule or tablet itself, or can be any this based composition of the suitable quantity of packaged form.
For reaching the consistence of administration, preferred composition of the present invention is a unit dosage form.The suitable monomers formulation comprises the pulvis in tablet, capsule and sachet or the bottle.This class unit dosage can contain 0.1-100mg, the The compounds of this invention of preferred 2-50mg.Preferred unit dosage contains the The compounds of this invention of 5-25mg.The compounds of this invention can be with about 0.01-100mg/kg dosage range or preferred 0.1-10mg/kg dosage range oral administration administration.Such composition can administration in a day 1-6 time, and more common is 1-4 time.
The present invention also provides the method for preparation I compound, and this method comprises: make formula II compound Wherein the Ar definition is as above reacted with the formula III compound R wherein 1, R 2And R 3Define as above, and isolate its pharmacy acceptable salt if desired.
Usually, formula I compound can synthesize easily as following:
According to the present invention, formula I compound can be by following scheme I preparation.
Scheme I
Therefore, according to Abdel-Magid, Carson, Harris, Maryanoff and Shah at J.Org.Chem.1996, the method described in 61,3849, formula II compound and formula III compound, be dissolved in acetate in the ethylene dichloride, obtain formula I compound in 23 ℃ of reactions.
According to the present invention, formula II compound can be by following scheme II preparation.
Scheme II
Figure A0081824700171
At J.Med.Chem.1997, described in 40,250, under 65 ℃, make formula IV compound and 1 as Wustrow etc., 4-cyclohexanedione list condensed ethandiol (monoethylene ketal), potassium hydroxide react in methyl alcohol, obtain formula V compound.By at appropriate solvent such as alcohol, but be not limited to use H among the EtOH 2Hydrogenation with 5%Pd/C processing realization formula VI compound.Can carry out the hydrolysis of formula III compound with the 1N HCl in 1: 1 the mixture that is dissolved in THF and water.
According to the present invention, formula II compound can be by following scheme III preparation.
Scheme III
Figure A0081824700181
Therefore, with (Boc) that be dissolved in suitable solvent such as chloroform, THF or the alcohol (but being not limited to MeOH) 2O handles formula VII compound to obtain formula VII compound.According to Buchwald etc. at Anew.Chem.Int. Ed.Engl.1995, the method in 34,1348, in 80 ℃ with the aryl bromide that is dissolved in toluene, catalyst P d 2Dba 3, catalyst B INAP, NaOt-Bu handle, and can realize the conversion of compounds to formula IX.In 23 ℃ with being dissolved in CH 2Cl 2In TFA handle, can realize protection and obtain formula II compound.
The present invention further provides The compounds of this invention as the active treatment material.Formula (I) compound has special purposes aspect the treatment of diseases that is caused by the serotonin disorder.
The present invention further provides the treatment Mammals and comprise people's the dysthymia disorders and the method for anxiety disorder, it comprises The compounds of this invention or the medicinal compositions that gives ill Mammals significant quantity.
Proposing the following example is explanation rather than restriction the present invention.
Embodiment
According to the pharmaceutically acceptable test method of standard, with the 5-HT translocator avidity of the following confirmation The compounds of this invention of representational compound: rat brain 3The H-paroxetine is in conjunction with testing (RB 5HT translocator):
Following test is used to determine the 5-HT translocator avidity of compound.
Employing is similar to (Neuropharmac0l.1993,32,737) used schemes such as Cheetham.In brief, in 25 ℃, will from the volume cortex film of male S.D rat preparation with 3H-paroxetine (0.1nM) was hatched 60 minutes.All test tubes all contain the fluoxetine (10 μ M) of vehicle, test compounds (1-8 kind concentration) or saturation concentration to determine the specificity combination.Stop total overall reaction by adding ice-cooled tris buffer, filter fast with from free with Tom Tech filtration unit again 3Isolate binding substances (bound) in the H-paroxetine.With Wallac 1205 Beta Plate Counter is quantitative to the bonded radioactivity.Adopt the method (Biochem.Pharmacol.1973,22,3099) of Cheng and Prusoff, determine to be converted to K with nonlinear regression analysis iThe IC of value 50Value; Has the cell of human body 5-HT translocator (HC5-HT translocator) 3The H-5-HT reuptake inhibition:
Before the test, the human cancer cell system (Jar cell) that will have the flat 5-HT-translocator of low interior unboiled water is inoculated in 96 well culture plates, handles at least 18 hours with Staurosporine again.[Staurosporine greatly increases the expression of 5-HT-translocator].In testing the same day, vehicle, excessive fluoxetine or test compounds are added in each hole of culture plate.Allow porose reception again 3H-5-HT also cultivated 5 minutes in 37 ℃.Also the suction removal is free to wash these holes with 50 ice-cooled mM Tutofusin tris HCl (pH7.4) damping fluids 3H-5-HT.Before with Packard TopCount unit count, in each hole, add 25 μ l0.25M NaOH then, add 75 μ l liquid scintillation cocktail (Microscint again with dissolved cell TM20).Vectorial test tube is housed represents all possible reuptakes, the radioactivity of calculating in the test tube of fluoxetine is housed is represented non-specific binding/reuptake and is deducted from total possible reuptake to obtain total possible specificity reuptake.From the hole gained counting that contains various test compounds (or testing drug of different concns), deduct this non-specific binding (often quantity is few) then, the specificity reuptake when obtaining medicine.% with control value represents the specificity reuptake again, and with non-linear regression analysis (Prizm) it is analyzed to determine IC 50Value.Compound has activity to suppressing the 5-HT reuptake as described, and its counting will be near using the resulting counting of fluoxetine.
Derive under the results are shown in of these two tests in the Table I.
Table I
Compound n RB 5-HT translocator HC 5-HT translocator
K i(nM) IC 50(nM)
Embodiment 11 42.0 578
Embodiment 21 9.0 399
Embodiment 31 12.0 1144
Embodiment 41 27.0-
Embodiment 51 4.9 272
Embodiment 61 9.0 602
Embodiment 71 11.0-
Embodiment 81 2.7 317
Embodiment 91 86.0 4470
Embodiment 10 1 207 3765
Embodiment 11 1 27.0 1284
Therefore, compound of the present invention has significant avidity to the 5-HT translocator, and, be used for the treatment of the caused disease of neural disorder, as dysthymia disorders and anxiety disorder by the serotonin influence by to needs its patient's oral administration, parenteral or inhalation.
The following example explanation the present invention:
Embodiment 13-{4-[4-(2-methoxyl group-phenyl)-[1,4] Diazesuberane-1-yl]-cyclohexyl }-the 1H-indoles
Step 1
3-(1,4-two oxa-s-spiral shell [4,5] last of the ten Heavenly stems-7-alkene-8-yl)-1H-indoles
With indoles (22.6g, 190mmol), 1,4-cyclohexanedione list condensed ethandiol (22.8g, 145mmol) and KOH (4.6g 80mmol) is heated in 50ml MeOH and refluxed 6 hours.Reaction mixture is cooled to 23 ℃, is settled out solid and vacuum filtration and collects.With 3 * 30mlH 2O washs this solid, and the solid target compound is white in color to obtain 33.3g (130.5mmol, 90% yield).MS (ES) m/z (relative abundance): 256 (M ++ H, 100).
Step 2
3-(1,4-two oxa-s-spiral shell [4,5] last of the ten Heavenly stems-8-yl)-1H-indoles
With 3-(1,4-two oxa-s-spiral shell [4,5] last of the ten Heavenly stems-7-alkene-8-yl)-1H-indoles (10.0g, 39.2mmol) and the mixture of 10%Pd/C (1.0g) in 100ml EtOH place the H of 40psi 2In, and under 23 ℃, shook 3 hours.Remove by filter Pd/C, and evaporating solvent.Flash chromatography (CH 2Cl 2/ the solid target compound is white in color MeOH) to obtain 8.66g (33.7mmol, 86% yield).MS (ES) m/z (relative abundance): 258 (M ++ H, 100).
Step 3
4-(1H-indol-3-yl)-pimelinketone
8.66g (33.7mmol) 3-(1,4-two oxa-s-spiral shell [4,5] last of the ten Heavenly stems-8-yl)-1H-that 200ml1N HCl is added to 23 ℃ draws in the solution of diindyl and 200ml THF.Stir after 12 hours evaporation organism, the soup compound of using 2 * 150ml EtOAc extraction to generate again.With the organism that 2 * 100ml1NNaOH washing merges, use MgSO 4Linen solid is filtered and be evaporated to drying.Through flash chromatography on silica gel, with hexane/EtOAc (1/1) wash-out, the solid target compound is white in color to obtain 5.89g (27.6mmol, 82% yield).Fusing point is 123-125 ℃; MS (ES) m/z (relative abundance): 214 (M ++ H, 100).
Step 4
[1,4] Diazesuberane (diazepane)-1-carboxylic acid tert-butyl ester
Under 0 ℃, with 1 hour, (Boc) with 11.93g (54.7mmol) 2The solution of O and 100ml MeOH dropwise adds in the high piperazine of 5.0g (50mmol) that is dissolved in 200ml MeOH.With mixture heating up to 23 ℃, reheat to 50 ℃ 3 hours.After being cooled to 23 ℃, the reaction mixture of generation filters through diatomite (Celite), again with solvent evaporation to the 100ml volume.Extract this solution with 3 * 100ml1N citric acid,, use solid Na again with the water that 1 * 100ml EtOAc washing merges 2CO 3Alkalize this aqueous solution to pH=11.With the soup compound that 3 * 100ml EtOAc extraction generates, use Na 2SO 4The dry organism that merges filters and evaporation, obtains the target compound that 3.2g (15.9mmol, 32% yield) is light yellow oil. 1H NMR (300MHz, CDCl 3): δ 1.46 (s, 9H), 1.70-1.85 (m, 2H), 2.81-2.96 (m, 4H), 3.37-3.53 (m, 4H); IR (KBr, cm -1): 3348w, 1690s; MS (ES) m/z (relative abundance): 201 (M ++ H, 100).
Step 5
4-(2-methoxyl group-phenyl)-[1,4] Diazesuberane-1-carboxylic acid tert-butyl ester
With 1.09ml (1.64g, 8.79mmol) 2-bromobenzene methyl ether, 37mg (0.04mmol) Pd 2Dba 3, 75mg (0.12mmol) (±)-BINAP, 1.08g (11.19mmol) NaOt-Bu, 20ml toluene add in 1.6g (7.99mmol) [1,4] Diazesuberane-1-carboxylic acid tert-butyl ester, the soup compound that generates is heated to 80 ℃ reaches 20 hours.After being cooled to 23 ℃, by the diatomite filtration reaction mixture, revaporization obtains dark-brown oil.Through flash chromatography on silica gel, use CH 2Cl 2/ EtOAc (1/0-40/1-20/1) wash-out obtains the target compound that 2.17g (7.08mmol, yield 89%) is light yellow oil. 1H NMR (300MHz, CDCl 3): δ 1.45 and 1.47 (unimodal, 9H-rotational isomer), 1.91-2.07 (m, 2H), 3.16-3.31 (m, 4H), 3.47-3.65 (m, 4H), 3.85 (s, 3H), 6.72-6.96 (m, 4H); IR (KBr, cm -1): 1691s; MS (ES) m/z (relative abundance): 307 (M ++ H, 100).To C 17H 26N 2O 3The computational analysis value: C, 66.64; H, 8.55; N, 9.14.Measured value: C, 66.18; H, 8.54; N, 8.80.
Step 6
1-(2-methoxyl group-phenyl)-[1,4] Diazesuberane
In 23 ℃, the adding of 5ml trifluoroacetic acid is dissolved in 30ml CH 2Cl 22.03g (6.62mmol) 4-(2-methoxyl group-phenyl)-[1,4]-Diazesuberane-1-carboxylic acid tert-butyl ester in.After 30 minutes, other adds the 4ml trifluoroacetic acid in 23 ℃ of stirrings.Altogether after 1 hour, with the saturated NaHCO of reaction soln impouring 200ml 3In the aqueous solution, and extract with 3 * 100ml EtOAc.With 1 * 200ml H 2The organism that O, the water washing of 1 * 200ml salt merge is used Na 2SO 4Drying is filtered and evaporation, obtains the target compound that 1.01g (4.90mmol, 74% yield) is yellow oil. 1H NMR (300MHz, CDCl 3): δ 1.99 (quintet, J=4.5Hz, 2H), 2.82 (brs, 1H), 3.06 (t, J=4.4Hz, 2H), 3.08-3.13 (m, 2H), 3.29-3.36 (m, 4H), 3.84 (s, 3H), 6.83-6.96 (m, 4H); IR (KBr, cm -1): 3335w; MS (ES) m/z (relative abundance): 207 (M ++ H, 100).
Step 73-{4-[4-(2-methoxyl group-phenyl)-[1,4] Diazesuberane-1-yl]-cyclohexyl }-the 1H-indoles
With 7ml 1,2-ethylene dichloride, 0.06ml (66mg, 1.091mmol) HOAc, 231mg (1.091mmol) NaBH (OAc) 3Add in 150mg (0.727mmol) 1-(2-methoxyl group-phenyl)-[1,4] Diazesuberane and 155mg (0.727mmol) 4-(1H-the indol-3-yl)-pimelinketone, stirred the mixture that generates 19 hours in 23 ℃.Add this reaction mixture of 2ml 1N NaOH quencher, be poured into NaHCO again 3In the saturated aqueous solution.With 2 * 50ml CH 2Cl 2Na is used in extraction 2SO 4The dry organism that merges filters and evaporation, obtains yellow oil.Through flash chromatography on silica gel, use EtOAc/MeOH: dense NH 4(10/1: 0%-10/1: wash-out 0.5%) obtains the target compound of 227mg (0.56mmol, 77% yield) the foam thing that is white in color to OH.Target compound is dissolved among the 10ml EtOAc also with 0.6ml (0.6mmol) 1M HCl/Et 2O Processing of Preparation hydrochloride.Collect the white solid precipitation that occurs in the solution.Mp 148-160 ℃; IR (KBr, cm -1): 3407w, 2529m; MS (ES) m/z (relative abundance): 404 (M ++ H, 100).To C 26H 33N 3O 3HClC 4H 8O 22H 2The computational analysis value of O: C, 63.87; H, 8.22; N, 7.45.Measured value: C, 63.87; H, 7.85; N, 8.43.
Embodiment 2
8-{4-[4-(1H-indol-3-yl)-cyclohexyl]-[1,4] Diazesuberane-1-yl }-quinoline
Step 1
4-quinoline-8-base-[1,4] Diazesuberane-1-carboxylic acid tert-butyl ester
Except replacing with 8-bromo quinoline the 2-bromobenzene methyl ether, prepare target compound, yield according to the method for the step 5 of embodiment 1: 68%; 1H NMR (300MHz, CDCl 3): δ 1.41 and 1.47 (s, 9H-rotational isomer), 2.05-2.19 (m, 4H), 3.52-3.87 (complicated multimodal, 6H), 7.13 (dd, J=1.4,7.4Hz, 1H), 7.27-7.41 (m, 3H), 8.07 (d, J=7.4Hz, lH), 8.83 (d, J=1.4Hz, 1H); IR (KBr, cm -1): 1689s; MS (ES) m/z (relative abundance): 328 (M ++ H, 100).To C 19H 25N 3O 2The computational analysis value: C, 69.70; H, 7.70; N, 12.83.Measured value: C, 70.2l; H, 7.63; N, 12.17.
Step 2
8-[1,4] Diazesuberane-1-yl-quinoline
Except replacing outside 4-(2-methoxyl group-phenyl)-[1,4] Diazesuberane-1-carboxylic acid tert-butyl ester, prepare target compound according to the method for the step 6 of embodiment 1 with 4-quinoline-8-base-[1,4] Diazesuberane-1-carboxylic acid tert-butyl ester.Yield: 100%; 1H NMR (300MHz, CDCl 3): δ 2.05 (quintet, J=6.2Hz, 2H), 3.11 (t, J=5.7Hz, 2H), 3.31 (t, J=5.6Hz, 2H), 3.68 (t, J=6.0Hz, 2H), 3.75 (t, J=6.0Hz, 2H), 4.47 (brs, 1H), 7.09 (dd, J=1.4,7.4Hz, 1H), and 7.28-.39 (m, 3H), 8.02 (dd, J=1.5,7.5Hz, 1H), 8.78 (d, J=1.4Hz, 1H); IR (KBr, cm -1): 3309w; MS (ES) m/z (relative abundance): 228 (M ++ H, 60).
Step 3
8-{4-[4-(1H-indol-3-yl)-cyclohexyl]-[1,4] Diazesuberane-1-yl }-quinoline
Except using 8-[1,4] Diazesuberane-1-yl-quinoline replaces outside 1-(2-methoxyl group-phenyl)-[1, the 4] Diazesuberane, prepares target compound according to the method for the step 7 of embodiment 1.Yield: 65%.Method according to the step 7 of embodiment 1 generates hydrochloride.Fusing point 152-165 ℃; IR (KBr, cm -1): 3406w, 3245w, 2671; MS (ES) m/z (relative abundance): 425 (M ++ H, 100).To C 28H 32N 4HClC 4H 8O 21.5H 2The computational analysis value of O: C, 66.71; H, 7.70; N, 9.72.Measured value: C, 66.54; H, 7.39; N, 11.19.
Embodiment 33-{4-[4-(2-methoxyl group-phenyl)-[1,4] Diazesuberane-1-yl]-cyclohexyl }-5-fluoro-1H-Yin
Diindyl
Step 1
4-(5-fluoro-1H-3-indyl)-hexamethylene-3-alkene condensed ethandiol
Except that replacing the indoles, prepare target compound according to the method for the step 1 of embodiment 1 with 5-fluoro indoles.Yield: 86%.Fusing point 153-155 ℃.
Step 2
4-(5-fluoro-1H-3-indyl)-pimelinketone condensed ethandiol
Remove with 4-(5-fluoro-1H-3-indyl)-hexamethylene-3-alkene condensed ethandiol and replace outside 3-(1,4-two oxa-s-spiral shell [4,5] last of the ten Heavenly stems-7-alkene-8-yl)-1H-indoles, prepare target compound according to the method for the step 2 of embodiment 1.Yield: 82%.Fusing point 183-185 ℃.
Step 3
4-(5-fluoro-1H-3-indyl)-pimelinketone
Remove with 4-(5-fluoro-1H-3-indyl)-pimelinketone condensed ethandiol and replace outside 3-(1,4-two oxa-s-spiral shell [4,5] last of the ten Heavenly stems-8-yl)-1H-indoles, prepare target compound according to the method for the step 3 of embodiment 1.Yield: 91%.Fusing point 112-114 ℃.
Step 43-{4-[4-(2-methoxyl group-phenyl)-[1,4] Diazesuberane-1-yl]-cyclohexyl }-5-fluoro-1H-Yin
Diindyl
In 23 ℃ in 20ml liquid scintillation pipe with 1-(2-methoxyl group-phenyl)-[1,4] Diazesuberane (103mg, 0.5mmol), 4-(5-fluoro-1H-3-indyl)-pimelinketone (116mg, 0.5mmol), 5ml 1,2-ethylene dichloride and 159mg (0.75mmol) NaBH (OAc) 3Stirred 21 hours.With 2ml 1N NaOH quencher reaction, cover scintillation vial, jolting is taken out organic layer (bottom) with aupette.With organism pack into Speed Vac and the decompression spend the night, obtaining 169mg (0.4mmol, yield 80%) is the target compound of pale solid.MS (ES) m/z (relative abundance): 422 (M ++ H, 100).
Embodiment 43-{4-[4-(2-methoxyl group-phenyl)-[1,4] Diazesuberane-1-yl]-cyclohexyl }-5-cyano group-1H-
Indoles
Step 1
4-(5-cyano group-1H-3-indyl)-hexamethylene-3-alkene condensed ethandiol
Remove with the 5-cyanoindole and replace indoles, prepare target compound according to the method for the step 1 of embodiment 1.Yield: 50%; Fusing point 158-160 ℃.
Step 2
4-(5-cyano group-1H-3-indyl)-pimelinketone condensed ethandiol
Remove with 4-(5-cyano group-1H-3-indyl)-hexamethylene-3-alkene condensed ethandiol and replace outside 3-(1,4-two oxa-s-spiral shell [4,5] last of the ten Heavenly stems-7-alkene-8-yl)-1H-indoles, prepare target compound according to the method for the step 2 of embodiment 1.Yield: 95%; Fusing point 153-155 ℃.
Step 3
3-(4-oxo-cyclohexyl)-1H-indoles-5-nitrile
Remove with 4-(5-cyano group-1H-3-indyl)-pimelinketone condensed ethandiol and replace outside 3-(1,4-two oxa-s-spiral shell [4,5] last of the ten Heavenly stems-8-yl)-1H-indoles, prepare target compound according to the method for the step 3 of embodiment 1.Yield: 81%; Fusing point 162-164 ℃.
Step 43-{4-[4-(2-methoxyl group-phenyl)-[1,4] Diazesuberane-1-yl]-cyclohexyl }-5-cyano group-1H-
Indoles
Except that replacing 4-(5-fluoro-1H-3-indyl)-pimelinketone, prepare target compound according to the method for the step 4 of embodiment 3 with 3-(4-oxo-cyclohexyl)-1H-indoles-5-nitrile.Yield: 60%; MS (ES) m/z (relative abundance): 429 (M ++ H, 100).
Embodiment 53-{4-[4-(2-methoxyl group-phenyl)-[1,4] Diazesuberane-1-yl]-cyclohexyl }-6-fluoro-1H-Yin
Diindyl
Step 1
3-(1,4-two oxa-s-spiral shell [4,5] last of the ten Heavenly stems-7-alkene-8-yl)-6-fluoro-1H-indoles
Except that replacing the indoles, prepare target compound according to the method for the step 1 of embodiment 1 with 6-fluoro indoles.Yield: 96%; Fusing point 196-197 ℃.
Step 2
3-(1,4-two oxa-s-spiral shell [4,5] last of the ten Heavenly stems-8-yl)-6-fluoro-1H-indoles
Remove with 3-(1,4-two oxa-s-spiral shell [4,5] last of the ten Heavenly stems-7-alkene-8-yl)-6-fluoro-1H-indoles and replace outside 3-(1,4-two oxa-s-spiral shell [4,5] last of the ten Heavenly stems-7-alkene-8-yl)-1H-indoles, prepare target compound according to the method for the step 2 of embodiment 1.Yield: 60%; Fusing point 183-185 ℃.
Step 3
4-(6-fluoro-1H-indol-3-yl)-pimelinketone
Remove with 3-(1,4-two oxa-s-spiral shell [4,5] last of the ten Heavenly stems-8-yl)-6-fluoro-1H-indoles and replace outside 3-(1,4-two oxa-s-spiral shell [4,5] last of the ten Heavenly stems-8-yl)-1H-indoles, prepare target compound according to the method for the step 3 of embodiment 1.Yield: 60%; MS (ES) m/z (relative abundance): 429 (M ++ H, 100).
Step 43-{4-[4-(2-methoxyl group-phenyl)-[1,4] Diazesuberane-1-yl]-cyclohexyl }-6-fluoro-1H-Yin
Diindyl
Except that replacing 4-(5-fluoro-1H-3-indyl)-pimelinketone, prepare target compound according to the method for the step 4 of embodiment 3 with 4-(6-fluoro-1H-3-indyl)-pimelinketone condensed ethandiol.Yield: 38%; MS (ES) m/z (relative abundance): 422 (M ++ H, 100).
Embodiment 68-{4-[4-(5-fluoro-1H-indol-3-yl)-cyclohexyl]-[1,4] Diazesuberane-1-yl }-quinoline
Remove and use 8-[1,4] outside Diazesuberane-1-yl-quinoline replacement 1-(2-methoxyl group-phenyl)-[1,4] Diazesuberane, prepare target compound according to the method for the step 4 of embodiment 3.Yield: 43%; MS (ES) m/z (relative abundance): 443 (M ++ H, 100).
Embodiment 78-{4-[4-(5-cyano-1 H-indol--3-yl)-cyclohexyl]-[1,4] Diazesuberane-1-yl }-quinoline
Remove and use 8-[1,4] Diazesuberane-1-yl-quinoline replaces 1-(2-methoxyl group-phenyl [1,4] Diazesuberane and substitute outside 4-(5-fluoro-1H-3-indyl)-pimelinketone with 3-(4-oxo-cyclohexyl)-1H-indoles-5-nitrile prepares target compound according to the method for the step 4 of embodiment 3.Yield: 92%; MS (ES) m/z (relative abundance): 450 (M ++ H, 100).
Embodiment 88-{4-[4-(6-fluoro-1H-indol-3-yl)-cyclohexyl]-[1,4] Diazesuberane-1-yl }-quinoline
Remove and use 8-[1,4] Diazesuberane-1-yl-quinoline replaces 1-(2-methoxyl group-phenyl)-[1,4] Diazesuberane and replace outside 4-(5-fluoro-1H-3-indyl)-pimelinketone with 4-(6-fluoro-1H-indol-3-yl)-pimelinketone prepares target compound according to the method for the step 4 of embodiment 3.Yield: 89%; MS (ES) m/z (relative abundance): 443 (M ++ H, 100).
Embodiment 93-{4-[4-(3-trifluoromethyl-phenyl)-[1,4] Diazesuberane-1-yl]-cyclohexyl }-5-fluoro-1H-
Indoles
Step 1
4-(3-trifluoromethyl-phenyl)-[1,4] Diazesuberane-1-carboxylic acid tert-butyl ester
Except that replacing the 2-bromobenzene methyl ether, prepare target compound according to the method for the step 5 of embodiment 1 with 1-bromo-3-trifluoromethylbenzene.Yield: 73%; 1H MR (300MHz, CDCl 3): δ 1.33 and 1.43 (s, 9H-rotational isomer), 1.95-2.03 (m, 4H), 3.22 (t, J=4.2Hz, 2H), 3.34 (t, J=4.2Hz, 2H), 3.53-3.64 (m, 4H), 6.79-6.91 (m, 2H), 7.25-7.33 (m, 2H); IR (KBr, cm -1): 1693s; MS (ES) m/z (relative abundance): 345 (M ++ H, 100).To C 17H 23F 3N 2O 2The computational analysis value: C, 59.29; H, 6.73; N, 8.13.Measured value: C, 59.24; H, 6.68; N, 8.11.
Step 2
1-(3-trifluoromethyl-phenyl)-[1,4] Diazesuberane
Remove with 4-(3-trifluoromethyl-phenyl)-[1,4] Diazesuberane-1-carboxylic acid tert-butyl ester and replace outside 4-(2-methoxyl group-phenyl)-[1,4] Diazesuberane-1-carboxylic acid tert-butyl ester, prepare target compound according to the method for the step 6 of embodiment 1.Yield: 91%; 1H NMR (300MHz, CDCl 3): δ 1.77 (brs, 1H), 1.92 (quintet, J=5.9Hz, 2H), 2.84 (t, J=5.8Hz, 2H), 3.04 (t, J=5.4Hz, 2H), 3.56-3.62 (m, 4H), 6.77-6.88 (m, 3H), 7.29 (d, J=7.7Hz, 1H); IR (KBr, cm -1): 3286w; MS (ES) m/z (relative abundance): 245 (M ++ H, 60).To C 12H 15F 3N 2The computational analysis value: C, 59.01; H, 6.19; N, 11.47.Measured value: C, 58.56; H, 6.03; N, 10.98.
Step 33-{4-[4-(3-trifluoromethyl-phenyl)-[1,4] Diazesuberane-1-yl]-cyclohexyl }-5-fluoro-1H-
Indoles
Remove with 1-(3-trifluoromethyl-phenyl)-[1,4] Diazesuberane and replace outside 1-(2-methoxyl group-phenyl)-[1, the 4] Diazesuberane, prepare target compound according to the method for the step 4 of embodiment 3.Yield: 86%; MS (ES) m/z (relative abundance): 460 (M ++ H, 100).
Embodiment 103-{4-[4-(3-trifluoromethyl-phenyl)-[1,4] Diazesuberane-1-yl]-cyclohexyl }-5-cyano group-
The 1H-indoles
Remove with 1-(3-trifluoromethyl-phenyl)-[1,4] Diazesuberane replaces 1-(2-methoxyl group-phenyl)-[1,4] Diazesuberane and replace outside 4-(5-fluoro-1H-3-indyl)-pimelinketone with 3-(4-oxo-cyclohexyl)-1H-indoles-5-nitrile prepares target compound according to the method for the step 4 of embodiment 3.Yield: 80%; MS (ES) m/z (relative abundance): 467 (M ++ H, 100).
Embodiment 113-{4-[4-(3-trifluoromethyl-phenyl)-[1,4] Diazesuberane-1-yl]-cyclohexyl }-6-fluoro-1H-
Indoles
Remove with 1-(3-trifluoromethyl-phenyl)-[1,4] Diazesuberane replaces 1-(2-methoxyl group-phenyl)-[1,4] Diazesuberane and replace outside 4-(5-fluoro-1H-3-indyl)-pimelinketone with 4-(6-fluoro-1H-indol-3-yl)-pimelinketone prepares target compound according to the method for the step 4 of embodiment 3.Yield: 64%; MS (ES) m/z (relative abundance): 460 (M ++ H, 100).

Claims (14)

1. the compound of a following formula or its pharmacy acceptable salt,
Figure A0081824700021
Wherein: Ar is
The aryl of 5-14 carbon atom;
Wherein aryl moiety has 5-14 carbon atom and moieties has the arylalkyl of 1-6 carbon atom; Or
The heteroaryl of 5-10 annular atoms, wherein heteroatoms is identical or different, is selected from one or more oxygen, nitrogen or sulphur;
Wherein said aryl or heteroaryl moieties are optional to be replaced by 1-3 the identical or different following substituting group that is selected from:
Can be by the alkyl of 1-12 the carbon atom that halogen, hydroxyl, nitro, amino or cyano group replaced,
The alkoxyl group of 1-12 carbon atom,
The alkylthio of 1-6 carbon atom,
The perfluoroalkyl of 1-6 carbon atom,
Hydroxyl,
Nitro,
Halogen,
Amino and
Cyano group; R 1And R 2Independently be selected from
Hydrogen;
Can be by the alkyl of 1-12 carbon atom of halogen, hydroxyl, nitro, amino or cyano group replacement; Or
Can be by the cycloalkyl of 3-10 carbon atom of the alkyl-carbonyl oxygen base of the alkoxy carbonyl alkyl of the alkyl-carbonyl of the alkoxy carbonyl of the halogenated alkoxy of the haloalkyl of the alkoxyl group of the alkyl of halogen, a 1-6 carbon atom, a 1-6 carbon atom, a 1-6 carbon atom, a 1-6 carbon atom, hydroxyl, nitro, amino, cyano group, carboxyl, a 2-7 carbon atom, a 2-7 carbon atom, a 3-13 carbon atom or 2-7 carbon atom replacement; R 3Be hydrogen;
Can be by the alkyl of 1-12 carbon atom of halogen, hydroxyl, nitro, amino or cyano group replacement;
Can be by the cycloalkyl of 3-10 carbon atom of the alkyl-carbonyl oxygen base of the alkoxy carbonyl alkyl of the alkyl-carbonyl of the alkoxy carbonyl of the halogenated alkoxy of the haloalkyl of the alkoxyl group of the alkyl of halogen, a 1-6 carbon atom, a 1-6 carbon atom, a 1-6 carbon atom, a 1-6 carbon atom, hydroxyl, nitro, amino, cyano group, carboxyl, a 2-7 carbon atom, a 2-7 carbon atom, a 3-13 carbon atom or 2-7 carbon atom replacement;
Halogen;
The alkoxyl group of 1-12 carbon atom;
The haloalkyl of 1-12 carbon atom;
Hydroxyl;
Nitro;
Nitrile;
Amino;
Cyano group;
Carboxyl;
The alkoxy carbonyl of 2-12 carbon atom;
The alkyl-carbonyl of 2-12 carbon atom;
Aminocarboxyl or
The alkyl amino-carbonyl of 2-12 carbon atom.
2. the formula of claim 1 (I) compound, wherein Ar be single-, two-or three-cyclophane base-or aryl-alkyl, wherein aryl has 6-14 carbon atom and optional according to claim 1 being substituted, and alkyl has 1-4 carbon atom or Ar to be the list of optional replacement according to claim 1-or two-ring heteroaryl.
3. claim 1 or 2 compound, wherein Ar is selected from furyl, thiophene, pyrroles, imidazoles, oxazole, thiazole, isoxazole, pyrazoles, isoxazole, isothiazole, oxadiazole, triazole, thiadiazoles, quinolizine, quinoline and isoquinoline 99.9, each optional by 1-3 alkyl that is selected from 1-12 carbon atom ,-CF 3, the alkoxyl group of a 1-12 carbon atom and the group of halogen replace.
4. claim 1 or 2 compound, wherein Ar is selected from phenyl, benzyl, naphthalene, anthracene, phenanthrene, indenes and indacene, each optional by the alkyl that is selected from 1-12 carbon atom by 1-3 ,-CF 3, the alkoxyl group of a 1-12 carbon atom and the group of halogen replace.
5. each formula (I) compound among the claim 1-4, wherein Ar is optional is replaced by one or more following groups: the alkoxyl group of 1-4 carbon atom or perfluoro-methyl.
6. each formula (I) compound, wherein R among the claim 1-5 1And R 2Be selected from the alkyl of hydrogen, a 1-6 carbon atom or the cycloalkyl of 3-8 carbon atom independently of one another.
7. each formula (I) compound, wherein R among the claim 1-6 3Be hydrogen, halogen, cyano group, CONH 2Or COOH.
8. the formula I compound of claim 1 or its pharmacy acceptable salt, wherein:
Ar is the aryl of optional 5 or 6 carbon atoms that replace or the heteroaryl of optional 5-10 the carbon atom that replaces;
R 1And R 2Be alone the straight chained alkyl of H, a 1-8 carbon atom or the branched-chain alkyl of 3-8 carbon atom;
R 3Alkyl amino-carbonyl for alkyl-carbonyl, aminocarboxyl and the 2-6 carbon atom of the alkoxy carbonyl of the halogenated alkoxy of the haloalkyl of the alkoxyl group of the cycloalkyl of the branched-chain alkyl of the straight chained alkyl of H, a 1-8 carbon atom, a 3-6 carbon atom, a 3-8 carbon atom, halogen, a 1-6 carbon atom, a 1-6 carbon atom, a 1-6 carbon atom, hydroxyl, nitro, nitrile, amino, cyano group, carboxyl, a 2-6 carbon atom, a 2-6 carbon atom.
9. the formula I compound of claim 1 or its pharmacy acceptable salt, wherein:
Ar is the aryl of 6 carbon atoms or the heteroaryl of heteroaryl or 5-10 carbon atom;
R 1And R 2Be alone the straight chained alkyl of H, a 1-3 carbon atom or the branched-chain alkyl of 3-6 carbon atom;
R 3Be H, halogen, cyano group, CONH 2Or CO 2H.
10. the compound of claim 1, it is one of following compounds: 3-{4-[4-(2-methoxyl group-phenyl)-[1,4] Diazesuberane-1-yl]-cyclohexyl }-the 1H-indoles; 8-{4-[4-(1H-indol-3-yl)-cyclohexyl]-[1,4] Diazesuberane-1-yl }-quinoline; 3-{4-[4-(2-methoxyl group-phenyl)-[1,4] Diazesuberane-1-yl]-cyclohexyl }-5-fluoro-1H-indoles; 3-{4-[4-(2-methoxyl group-phenyl)-[1,4] Diazesuberane-1-yl]-cyclohexyl }-the 5-cyano-1 H-indol-; 3-{4-[4-(2-methoxyl group-phenyl)-[1,4] Diazesuberane-1-yl]-cyclohexyl }-6-fluoro-1H-indoles; 8-{4-[4-(5-fluoro-1H-indol-3-yl)-cyclohexyl]-[1,4] Diazesuberane-1-yl }-quinoline; 8-{4-[4-(5-cyano-1 H-indol--3-yl)-cyclohexyl]-[1,4] Diazesuberane-1-yl }-quinoline; 8-{4-[4-(6-fluoro-1H-indol-3-yl)-cyclohexyl]-[1,4] Diazesuberane-1-yl }-quinoline; 3-{4-[4-(3-trifluoromethyl-phenyl)-[1,4] Diazesuberane-1-yl]-cyclohexyl }-5-fluoro-1H-indoles; 3-{4-[4-(3-trifluoromethyl-phenyl)-[1,4] Diazesuberane-1-yl]-cyclohexyl }-5-cyano-1 H-indol-or 3-{4-[4-(3-trifluoromethyl-phenyl)-[1,4] Diazesuberane-1-yl]-cyclohexyl }-6-fluoro-1H-indoles; Or its pharmacy acceptable salt.
11. a medicinal compositions, it contains the compound just like each defined claim 1 among the claim 1-10, or its pharmacy acceptable salt and pharmaceutically acceptable carrier or vehicle.
12. a method for the treatment of the Mammals dysthymia disorders, described method comprise Mammals pharmaceutically each compound or its pharmacy acceptable salt among the claim 1-10 of significant quantity that needs are arranged.
13. a method for the treatment of the Mammals anxiety disorder, described method comprise Mammals pharmaceutically each compound or its pharmacy acceptable salt among the claim 1-10 of significant quantity that needs are arranged.
14. the preparation method of the formula I compound of claim 1 definition, it comprises makes formula II compound
Figure A0081824700061
Wherein Ar such as claim 1 definition, react with the formula III compound R wherein 1, R 2And R 3Such as claim 1 definition, and if desired, isolate its pharmacy acceptable salt.
CN00818247A 1999-11-08 2000-05-19 N-aryl-(homopiperazinyl) cyclohexyl amines as 5-HT transporters Pending CN1420883A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US43612999A 1999-11-08 1999-11-08
US09/436,129 1999-11-08

Publications (1)

Publication Number Publication Date
CN1420883A true CN1420883A (en) 2003-05-28

Family

ID=23731225

Family Applications (1)

Application Number Title Priority Date Filing Date
CN00818247A Pending CN1420883A (en) 1999-11-08 2000-05-19 N-aryl-(homopiperazinyl) cyclohexyl amines as 5-HT transporters

Country Status (8)

Country Link
EP (1) EP1228064A1 (en)
JP (1) JP2003513969A (en)
CN (1) CN1420883A (en)
AU (1) AU5152300A (en)
BR (1) BR0015425A (en)
CA (1) CA2390530A1 (en)
MX (1) MXPA02004554A (en)
WO (1) WO2001034597A1 (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE0103648D0 (en) * 2001-11-01 2001-11-01 Astrazeneca Ab Therapeutic quinolone compounds
SE0103649D0 (en) * 2001-11-01 2001-11-01 Astrazeneca Ab Therapeutic quinoline compounds
JP2007106746A (en) * 2005-09-13 2007-04-26 Tosoh Corp New aryl homopiperazine compounds, or their salt and production method

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4954502A (en) * 1988-06-10 1990-09-04 Bristol-Myers Squibb Company 1-indolyalkyl-4-(substituted-pyridinyl)piperazines
WO1998028290A1 (en) * 1996-12-20 1998-07-02 H. Lundbeck A/S Indane or dihydroindole derivatives

Also Published As

Publication number Publication date
JP2003513969A (en) 2003-04-15
MXPA02004554A (en) 2004-09-10
CA2390530A1 (en) 2001-05-17
BR0015425A (en) 2002-07-16
AU5152300A (en) 2001-06-06
EP1228064A1 (en) 2002-08-07
WO2001034597A1 (en) 2001-05-17

Similar Documents

Publication Publication Date Title
CN1187325C (en) Pharmaceutical compositions containing 3-amino-azetidine derivatives, novel derivatives and preparation thereof
CN1065536C (en) Process and crystal form of 2-methyl -thieno -benzodiazepine
CN1099413C (en) Certain fused pyrrolecarboxanilides, new class of gaba brain receptor ligands
CN1165537C (en) Pyrroloindoles, pyridoindoles and aza * -indoles as 5-HT 2C agonists
CN1052723C (en) Bicyclic aromatic compounds as therapeutic agents
CN1293072C (en) Heterocyclyloxy-thioxy-and-aminobenzazole derivatives as 5-hydroxytryptamine-6 ligands
CN1124960A (en) Indole derivatives as 5-HT1A and/or 5-HT2 ligands
CN1297438A (en) Substd. indolinones having inhibiting effect on kinases and cycline/CDK complexes
CN1109471A (en) Derivative of imidazol-4yl-piperidine, preparation of same and application of same in treatment
CN1662534A (en) 1,2,3,4,7,8-hexahydro-6h-[1,4]diazepino[6,7,1-1j]quinoline derivatives as antipsychotic and antiobesity agents
CN1114651A (en) 3-indolylpiperidine
CN1293073C (en) Teterocyclyloxy-thioxy-and-aminobenzazole derivatives as 5-Hydroxytryptamine-6-ligands
CN1437596A (en) Phenylpiperazinyl derivatives
CN1265660A (en) 2-(4-aryl or heteroaryl-piperazin-1-ylmethyl)-1H-indole derivatives
CN1842529A (en) Compounds and compositions as protein kinase inhibitors
CN1095712A (en) Compounds
CN1023602C (en) Antipsychotic 3-piperazinylbenzazole derivs.
CN1414962A (en) [(Indol-3-yl)-cycloalkyl]-3-substituted azetidines for treatment of central nervous system disorders
CN1105360A (en) 1-[2H-1-benzopyran-2-one-8yl]-piperazin derivative
CN1150172C (en) 1,5 benzodiazepine derivatives
CN1122601A (en) [1,2,4]triazolo[4,3-a] quinoxaline derivatives, their preparation and use
CN1069491A (en) 2-(piperidines-1-yl) alcohol derivative, its method for making and treatment thereof are used
CN1125052C (en) Substituted isoquinoline derivatives and their use as anticonvulsants
CN1134149A (en) Phenylindole compounds
CN1420883A (en) N-aryl-(homopiperazinyl) cyclohexyl amines as 5-HT transporters

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C02 Deemed withdrawal of patent application after publication (patent law 2001)
WD01 Invention patent application deemed withdrawn after publication