CN101472890A - 3- (1H-indol- 3-ydindan-1-ylamine derivatives for the treatment of depression and anxiety - Google Patents
3- (1H-indol- 3-ydindan-1-ylamine derivatives for the treatment of depression and anxiety Download PDFInfo
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Abstract
The invention provides novel indane compounds which are useful in the treatment of affective disorders, pain disorders, attention deficit hyperactivity disorder (ADHD), cognitive disorders, substance abuse, smoking cessation and stress urinary incontinence. The compounds are inhibitors of serotonin, norepinephrine and dopamine re-uptake.
Description
Invention field
The invention provides the new indane compound that is used for the treatment of depression, anxiety and other CNS illness.
Background of invention
All present obtainable antidepressives can be divided into 3 classes:
1) oxidase inhibitor (MAOI),
2) biogenic amine neurotransmitter [serotonin (5-HT), norepinephrine (NE) and Dopamine HCL (DA)] transporter reuptake blocade and
The blocade of 3) conditioning agent, particularly one or more 5-HT and/or NE acceptor.
Because it is depressed relevant with the relative deficiency of biogenic amine, therefore proved that using 5-HT and/or NE-beta blocker (being 5-HT and/or NE-antagonist) is not very successful in treatment depression and anxiety, preferred and the most effective treatment at present is based on blocking-up 5-HT and/or NE neurotransmission and strengthens its neurotransmission (Slattery from the reuptake of synaptic cleft, D.A. wait the people, " Theevolution of antidepressant mechanisms ", fundamental and Clinicalpharmacology, 2004,18,1-21; Schloss, people such as P., " new insights into themechanism of antidepressant therapy ", and Pharmacology and therapeutics, 2004,102,47-60).
Selectivity serotonin reuptake inhibitor (hereinafter referred to as SSRI) has become treatment depression, the anxiety of some type and the first-selected therapeutical agent of social phobia, because compare with classical tricyclics, they normally effectively, tolerance good and have a favourable safe feature.The medicine that is called as SSRI is for example Fu Saiting (flouxetine), Sertraline and paroxetine.
Yet, the clinical study of depression is shown known SSRI unresponsive quite a lot of, up to 30%.In addition, the factor of often ignoring in anti depressant therapy is for existing the slow fact of SSRI result of treatment usually.Sometimes, symptom even deterioration between the treatment period 1.And sexual dysfunction is a kind of common adverse effect of SSRI normally.Therefore, the expectation exploitation can improve the compound of the treatment of depression and other serotonin relative disease.
A kind of updating strategy is the dual reuptake inhibitor of exploitation, for example at compound such as duloxetine (Wong, " Duloxetine (LY-248686): an inhibitor of serotonin andnoradrenaline uptake and an antidepressant drug candidate ", ExpertOpinion on Investigational Drugs, 1998,7,10,1691-1699) and Venlafaxine (people such as Khan-A, 30 " Venlafaxine in depressed outpatients ", Psychopharmacology Bulletin, 1991,27, studied the 5-HT reuptake in clinical study 141-144) and suppressed and NE (suprarenin, be also referred to as norepinephrine, NA) reuptake suppresses the combined action to depression.Compound with such dual function is also referred to as SNRI " serotonin and norepinephrine reuptake inhibitor " or NSRI " norepinephrine and serotonin reuptake inhibitor ".
Because the treatment with selective N E reuptake inhibitor Reboxetine has shown the release (Svensson that stimulates the interior 5-HT neurone of brain and regulate 5-HT, T. wait the people, J.Neural.Transmission, 2004,111,127), so in treatment depression or anxiety, use SNRI to have collaborative advantage.
Clinical study shows uses SNRI that pain (for example fibromyalgia syndrome, whole body pain, backache, shoulder pain, headache, pain when pain (pain while awake) is movable with every day when waking up) is had useful effect (Berk with relevant with depression especially pain, M.Expert Rev.Neurotherapeutics 2003,3,47-451; Fishbain, D.A., wait the people. " Evidence-baseddata from animal and human experimental studies on pain relief withantidepressants:A structured review " Pain Medicine 20001:310-316).
Clinical study also shows SNR1, and how moving obstacle (ADHD) has useful effect (N.M.Mukaddes to attention deficit; Venlafaxine in attention deficit hyperactivitydisorder, European Neuropsychopharmacology, the 12nd volume, supplementary issue in October, 3,2002, the 421st page).
And, shown SNRI to the treatment stress urinary incontinence effectively (people such as Dmochowski R.R.. " Duloxetine versus placebo for the treatment of North Americanwomen with stress urinary incontinence ", Journal of Urology 2003,170:4,1259-1263.).
Naranjo, C. wait the people, " The role of the brain reward system in depression " Prog.Neuro-Psychopharmacol.Biol.Psychiatry 2001,25,781-823 disclose that extracellular Dopamine HCL in the mesocorticolimbic system lacks and anhedonia between get in touch clinical and clinical before find that anhedonia is one of cardinal symptom of depression.
Some research and propose serotonin and Dopamine HCL neurotransmission dysfunction has caused the physiopathology of some neuropsychopathy diseases, described illness comprises dysthymia disorders, schizophrenia and drug abuse (Fibiger, H.C., Deng the people, " In Depression and Mania:from neurobiologyto treatment " Raven Press, New York 1995, the 1-17 pages or leaves; Roth, B.L. waits the people, J.Pharmacol.Exp.Ther.1992,260, the 1361-1365 pages or leaves; Koob, G.F waits the people, Trends Pharmacol.Sci.1992,13, pp.177-184; Brown, A.S. waits the people, J.Neural.Trans.1993,91, the 75-109 pages or leaves).Esposito, E., medicine (for example SSRI and the 5-HT of 5-HT system are proposed to act on Deng " Serotonin-Dopamine Interaction as focus of Novel Antidepressant Drugs " Curr.Drug Targets 2006,7, the 177-185 page or leaf of people
2cReceptor antagonist) by strengthening mesolimbic system's their antidepressant effect of dopaminergic transmission performance, use this medicine that limbic brain DA transmits in the influence to be used for the treatment of in the depressed new antidepressive very important and useful in research.
And, three joint groups that people such as Axford L. have described exploitation 5-HT, NE and DA reuptake inhibitor share in treatment depressed (2003, Bioorganic ﹠amp; Medical Chemistry Letters, 13,3277-3280: " Bicyclo[2.2.1.] heptanes as novel triple re-uptake inhibitorsfor the treatment of depression ").Have the active Bupropion of DA reuptake (Wellbutrin) in vitro and in vivo and demonstrate the antidepressant effect.Other combination research demonstrate increase at DA picked-up position some avidity can have some clinical benefit (Nelson, J.C.J.Clin.Psychiatry 1998,59,65; Masand, people .Depression Anxiety 1998,7,89 such as P.S.; Bodkin, people .J.Clin.Psychiatry such as J.A 1997,58,137).
The combination that has shown SSRI and norepinephrine and dopamine reuptake inhibitor has effect (people such as Lam R.W. preferably to the SSRI-nonresponder, " Citalopram andBupropion-SR:Combining Versus Switching in Patients WithTreatment-Resistant Depression. " J.Clin.Psychiatry 2004,65,337-340).
Existence shows with independent SSRI treatment to be compared, the combination inductive sexual dysfunction of SSRI and norepinephrine and dopamine reuptake inhibitor clinical evidence (people such as Kennedy S.H. still less, " Combining Bupropion SR With Venlafaxine; Paroxetine; orDuloxetine:A Preliminary Report on Pharmacokinetic; Therapeutic; andSexual Dysfunction Effects " J.Clin.Psychiatry 2002,63,181-186).
For effect and the reduction effect that improves them delays, it is the target (Millan of present many pharmaceutical companies that three joint groups of exploitation serotonin, norepinephrine and dopamine reuptake inhibitor close, M.J., Deng the people, " Multi-target strategies for the improvement ofdepressive states:Conceptual Foundations And Neuronal Substrates, DrugDiscovery And Therapeutic Application. " Pharmacology ﹠amp; Therapeutics.110 (2006), 135-370).
The invention provides new indane compound, it is the inhibitor of thrombotonin, norepinephrine and dopamine reuptake.Therefore, compound of the present invention is used for the treatment of affective disorder, antalgesic, attention deficit how moving obstacle (ADHD), substance abuse, cognitive defect and stress urinary incontinence.
Summary of the invention
An object of the present invention is to provide the compound as the formula I-X that gives a definition, it is the inhibitor of serotonin, norepinephrine and dopamine reuptake.Therefore, compound of the present invention is used for the treatment of affective disorder, antalgesic, attention deficit how moving obstacle (attention deficit how moving obstacle), cognitive disorder, substance abuse, smoking cessation and stress urinary incontinence.
In one embodiment, as the compound of the formula I-X that gives a definition be used for the treatment of affective disorder.In order further to set forth but do not limit the present invention, the described affective disorder that will treat is selected from depressed illness and anxiety illness.
In one embodiment, the described depressed illness that will treat is selected from serious depressibility obstacle, melancholia, postpartum depression, spirit depressing and the depression relevant with bipolar disorder, alzheimer's disease, psychosis or parkinsonism.In order further to set forth but do not limit the present invention, one embodiment of the invention relate to treats the depression relevant with bipolar disorder; Another scheme relates to treats the depression relevant with alzheimer's disease; Another embodiment relates to treats the depression relevant with psychosis; Relate to another embodiment and to treat the depression relevant with parkinsonism.
In another embodiment, the described anxiety illness that will treat is selected from General Anxiety Disorder, social anxiety's illness, posttraumatic stress disorder, obsession, panic disorder, panic attack, specific phobia disease, social phobia and agoraphobia.
In another embodiment, compound of the present invention is used for the treatment of antalgesic.In order further to set forth but do not limit the present invention, the described antalgesic that will treat is selected from fibromyalgia syndrome (FMS), whole body pain, backache, shoulder pain, headache and pain when pain and every day are movable when awake.In order further to set forth but do not limit the present invention, one embodiment of the invention relate to treatment fibromyalgia syndrome (FMS); Another scheme relates to treatment whole body pain; Another embodiment relates to the treatment backache; Another embodiment relates to the treatment shoulder pain; Another embodiment relates to the treatment headache; Pain when pain and every day are movable when relating to treatment and wake up with another embodiment.
In another embodiment, how moving compound of the present invention be used for the treatment of attention deficit obstacle (ADHD) and other cognitive disorder.
In another embodiment, compound of the present invention is used for the treatment of substance abuse and smoking cessation.
In another embodiment, compound of the present invention is used for the treatment of stress urinary incontinence.
Aspect second, the present invention relates to be used for the treatment of the how purposes in the medicine of moving obstacle (ADHD), cognitive disorder, substance abuse, smoking cessation and stress urinary incontinence of affective disorder, antalgesic, attention deficit in preparation as the compound of the formula I-X that gives a definition.
In one embodiment, the present invention relates to be used for the treatment of purposes in the medicine of affective disorder in preparation as the compound of the formula I-X that gives a definition.In order further to set forth but do not limit the present invention, the described affective disorder that will treat is selected from depressed illness and anxiety illness.
In one embodiment, the described depressed illness that will treat is selected from serious depressibility obstacle, melancholia, postpartum depression, spirit depressing and the depression relevant with bipolar disorder, alzheimer's disease, psychosis or parkinsonism.In order further to set forth but do not limit the present invention, one embodiment of the invention relate to treats the depression relevant with bipolar disorder; Another scheme relates to treats the depression relevant with alzheimer's disease; Another embodiment relates to treats the depression relevant with psychosis; Relate to another embodiment and to treat the depression relevant with parkinsonism.
In another embodiment, the described anxiety illness that will treat is selected from General Anxiety Disorder, social anxiety's illness, posttraumatic stress disorder, obsession, panic disorder, panic attack, specific phobia disease, social phobia and agoraphobia.
In another embodiment, the present invention relates to be used for the treatment of purposes in the medicine of antalgesic in preparation as the compound of the formula I-X that gives a definition.In order further to set forth but do not limit the present invention, the described antalgesic that will treat is selected from fibromyalgia syndrome (FMS), whole body pain, backache, shoulder pain, headache and pain when pain and every day are movable when awake.
In another embodiment, the present invention relates to be used for the treatment of the how purposes in the medicine of moving obstacle (ADHD) and other cognitive disorder of attention deficit in preparation as the compound of the formula I-X that gives a definition.
In another embodiment, the present invention relates to be used for the treatment of purposes in the medicine of substance abuse and smoking cessation in preparation as the compound of the formula I-X that gives a definition.
In another embodiment, the present invention relates to be used for the treatment of purposes in the medicine of stress urinary incontinence in preparation as the compound of the formula 1-X that gives a definition.
Aspect the 3rd, the present invention relates to a kind of pharmaceutical composition, it comprises compound and one or more pharmaceutically acceptable carrier or the thinner as the formula I-X that gives a definition of treatment significant quantity.
Aspect the 4th, the present invention relates to treat and wherein relate to the disease that suppresses serotonin and/or norepinephrine and/or dopamine reuptake, it comprises that administration comprises the compound as the formula I-X that gives a definition of human Mammals treatment significant quantity.
Aspect the 5th, the present invention relates to treat the how method of moving obstacle (ADHD), cognitive disorder, substance abuse, smoking cessation and stress urinary incontinence of affective disorder, attention deficit, it comprises that administration comprises the compound as the formula I-X that gives a definition of human Mammals treatment significant quantity.
In one embodiment, the present invention relates to treat the method for affective disorder, it comprises that administration comprises the compound as the formula I-X that gives a definition of human Mammals treatment significant quantity.In order further to set forth but do not limit the present invention, the described affective disorder that will treat is selected from depressed illness and anxiety illness.
In one embodiment, the described depressed illness that will treat is selected from serious depressibility obstacle, melancholia, postpartum depression, spirit depressing and the depression relevant with bipolar disorder, alzheimer's disease, psychosis or parkinsonism.In order further to set forth but do not limit the present invention, one embodiment of the invention relate to treats the depression relevant with bipolar disorder; Another scheme relates to treats the depression relevant with alzheimer's disease; Another embodiment relates to treats the depression relevant with psychosis; Relate to another embodiment and to treat the depression relevant with parkinsonism.
In another embodiment, the anxiety illness that treat is selected from General Anxiety Disorder, social anxiety's illness, posttraumatic stress disorder, obsession, panic disorder, panic attack, specific phobia disease, social phobia and agoraphobia.
In further embodiment, the described depressed illness that will treat is selected from serious depressibility obstacle, melancholia, postpartum depression, spirit depressing and the depression relevant with bipolar disorder, alzheimer's disease, psychosis or parkinsonism.In order further to set forth but do not limit the present invention, one embodiment of the invention relate to treats the depression relevant with bipolar disorder; Another scheme relates to treats the depression relevant with alzheimer's disease; Another embodiment relates to treats the depression relevant with psychosis; Relate to another embodiment and to treat the depression relevant with parkinsonism.
In embodiment further, the present invention relates to treat the method for anxiety illness, it comprises that administration comprises the compound as the formula I-X that gives a definition of human Mammals treatment significant quantity.
In further embodiment, the described anxiety illness that will treat is selected from General Anxiety Disorder, social anxiety's illness, posttraumatic stress disorder, obsession, panic disorder, panic attack, specific phobia disease, social phobia and agoraphobia.
In another embodiment, the present invention relates to treat the method for antalgesic, it comprises that administration comprises the compound as the formula I-X that gives a definition of human Mammals treatment significant quantity.In order further to set forth but do not limit the present invention, the described antalgesic that will treat is selected from fibromyalgia syndrome (FMS), whole body pain, backache, shoulder pain, headache and pain when pain and every day are movable when awake.
In another embodiment, the present invention relates to treat the how method of moving obstacle (ADHD) and other cognitive disorder of attention deficit, it comprises that administration comprises that human Mammals treats the compound as the formula I-X that gives a definition of significant quantity.
In another embodiment, the present invention relates to the method for therapeutant abuse and smoking cessation, it comprises that administration comprises the compound as the formula I-X that gives a definition of human Mammals treatment significant quantity.
In another embodiment, the present invention relates to treat the method for stress urinary incontinence, it comprises that administration comprises the compound as the formula I-X that gives a definition of human Mammals treatment significant quantity.
Detailed Description Of The Invention
The invention provides the compound or pharmaceutically acceptable salt thereof that following formula is represented:
R wherein
1And R
2Be hydrogen, C independently of one another
1-C
8-straight or branched alkyl or C
3-C
8-cycloalkyl; Perhaps R wherein
1And R
2Be connected big nitrogen with them and form azetidine, piperidines, tetramethyleneimine, azepan (azapane) or morpholine;
R wherein
3Be hydrogen, C independently of one another
1-C
8-straight or branched alkyl, C
1-C
5-alkoxyl group, C
1-C
8-straight or branched Polyfluoroalkyl, halogen, cyano group, hydroxyl, tetrazolium-randomly replaced by methyl or amino; Perhaps two R on adjacent carbons wherein
3Group is combined together to form methylene-dioxy and connects base;
R wherein
4Be hydrogen, C
1-C
8-straight or branched alkyl or C
3-C
8-cycloalkyl;
R wherein
5Hydrogen, halogen C respectively do for oneself
1-C
5-alkoxyl group, C
1-C
8-straight or branched alkyl, C
1-C
8-straight or branched Polyfluoroalkyl, cyano group or hydroxyl;
Wherein m is 1 to 4 integer, comprises end value;
Wherein n is 1 to 4 integer, comprises end value; With
R wherein
6Be hydrogen, C
1-C
8-straight or branched alkyl or phenyl.
In one embodiment, the compound represented of formula I is pure enantiomer, diastereomer and composition thereof.
In another embodiment, the compound represented of formula I is the cis-isomeride of formula II and III; In another embodiment, the compound represented of formula I is the trans-isomer(ide) of formula IV and V.
In another embodiment, the present invention relates to the compound of formula II-V
R wherein
1, R
2, R
3, R
4, R
5, R
6, m and n be for as defined above.
In one embodiment, R
1Be hydrogen.In one embodiment, R
2Be methyl.In one embodiment, R
4Be hydrogen.In one embodiment, R
3Be selected from hydrogen, halogen and methoxyl group.In one embodiment, R
3Be hydrogen or halogen.In one embodiment, described halogen is a fluorine or chlorine.In one embodiment, R
5And R
6Be hydrogen.
In another embodiment, R
1Be hydrogen, and R
2, R
3, R
4, R
5And R
6For what as above in formula II-V, define.In further embodiment, R
1Be hydrogen, R
2Be methyl, R
3, R
4, R
5And R
6For what as above in formula II-V, define.
In further embodiment, R
1Be hydrogen, R
2Be methyl, R
4Be hydrogen, R
3, R
5And R
6For what as above in formula II-V, define.
In further embodiment, R
1Be hydrogen, R
2Be methyl, R
4Be hydrogen, R
3Be hydrogen, halogen or methoxyl group, described halogen is selected from fluorine or chlorine, R
5And R
6For what as above in formula II-V, define.
In further embodiment, R
1Be hydrogen, R
2Be methyl, R
4Be hydrogen, R
3Be hydrogen, halogen or methoxyl group, described halogen is selected from fluorine or chlorine, R
5And R
6Be hydrogen.
In further embodiment, the present invention relates to the compound or pharmaceutically acceptable salt thereof of formula VI-X
Be to be understood that the compound of formula I-X means the example that comprises all this paper examples as used herein.
In the present invention, term halogen refers to fluorine, chlorine, bromine or iodine.
In the present invention, term " C
1-C
8The straight or branched alkyl " refer to have the stable hydrocarbon of one to eight (comprising end value) carbon atom.Substituent example like this includes, but are not limited to methyl, ethyl, 1-propyl group, 2-propyl group, 1-butyl, 2-butyl, 2-methyl-2-propyl group, 2-methyl isophthalic acid-propyl group, n-pentyl and n-octyl.
And, term " C
3-C
8Cycloalkyl " refer to have the saturated cyclic hydrocarbon of three to eight (comprising end value) carbon atoms.This term comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexyl and ring octyl group.
Term " C
1-C
5-alkoxyl group " refer to have the saturated alkoxyl group that open valency (open valency) arranged on one to five (comprising end value) carbon atom and the oxygen.Substituent example like this includes, but are not limited to methoxyl group, oxyethyl group, n-butoxy, tert.-butoxy and n-pentyloxy.
Term " C
1-C
8The straight or branched Polyfluoroalkyl " refer to the stable hydrocarbon that has one to eight (comprising end value) carbon atom and replaced by one or more fluorine atoms.Substituent example like this includes, but are not limited to trifluoromethyl, pentafluoroethyl group, 1-fluoro ethyl and 1,2-two fluoro ethyls and 2,3-difluoro octyl group.
" the treatment significant quantity " of compound refers to enough healings, alleviates or part suppresses the amount of the clinical manifestation of given disease and/or its complication as used herein.The amount that can reach these herein is defined as " treatment significant quantity ".The significant quantity that is used for every kind of purpose for example will depend on the seriousness of i or I and experimenter's body weight and general situation.Be to be understood that and use normal experiment to determine suitable dosage that it is all within the routine techniques of the doctor through training by the difference that makes up in valuable model and the rating model.
Term " treatment " refers in order to resist purpose management and the care of patients of illness such as disease or obstacle as used herein.This term means the treatment of the complete wide spectrum that comprises the known illness that is just suffering at the patient, such as the described active compound of administration with mitigation symptoms or complication, delay disease, disorder or illness development, alleviate or slow down symptom and complication and/or healing or eliminate a disease, disorder or illness and prevention illness, wherein prevention should be understood to for resist the disease, illness or disorderly purpose management and care of patients, and it comprises the morbidity of the described active compound of administration with prevention symptom or complication.However, the treatment of preventative (prevention) and therapeutic (healing) is two independent aspects of the present invention.The described patient that will treat, the patient who promptly needs it can be a Mammals, comprises the mankind especially.
Salt of the present invention can be acid salt.Acid salt of the present invention can be the pharmacologically acceptable salt that compound of the present invention and non-toxic acid form.Acid salt comprises mineral acid and organic acid salt.Suitable representative examples of mineral pigments comprises hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, phosphoric acid, sulfuric acid, thionamic acid, nitric acid etc.The example of appropriate organic comprises formic acid, acetate, trichoroacetic acid(TCA), trifluoroacetic acid, propionic acid, phenylformic acid, styracin, citric acid, fumaric acid, oxyacetic acid, methylene-succinic acid, lactic acid, methylsulfonic acid, toxilic acid, oxysuccinic acid, propanedioic acid, amygdalic acid, oxalic acid, picric acid, pyruvic acid, Whitfield's ointment, succsinic acid, methylsulfonic acid, ethyl sulfonic acid, tartrate, xitix, pounce on acid, the dimethylene Whitfield's ointment, ethyl sulfonic acid, glyconic acid, citraconic acid, Aspartic Acid, stearic acid, palmitinic acid, EDTA, oxyacetic acid, Para-Aminobenzoic, L-glutamic acid, Phenylsulfonic acid, right-toluenesulphonic acids, theophylline acetate and 8-halogen theophylline be 8-bromine theophylline etc. for example.The further example of pharmaceutically acceptable mineral acid or organic acid addition salt is included in J.Pharm.Sci.1977, and the pharmacologically acceptable salt of listing in 66,2 is introduced into this paper as a reference.
The example of metal-salt comprises lithium salts, sodium salt, sylvite, magnesium salts etc.
The example of ammonium salt and alkylated ammonium comprise ammonium, methyl-, dimethyl-, trimethylammonium-, ethyl-, hydroxyethyl-, diethyl-, normal-butyl-, sec-butyl-, the tertiary butyl-, tetramethyl ammonium salt etc.
Further, compound of the present invention can exist with the non-solvent form or with the solvation form of acceptable solvent such as water, ethanol etc.Usually, think solvation form and non-solvent form to the objective of the invention is the equivalence.
Compound of the present invention can have one or more asymmetric centers, this means any isomer (being enantiomer or diastereomer), comprise racemic mixture and non-enantiomer mixture as independent, pure or partially purified and any its mixture, promptly the mixture of steric isomer all comprises within the scope of the invention.
Can racemic form be split as optically active enantiomorph by known method, for example by its diastereomeric salt of fractional separation and optically active acid with by discharge optically active amine with alkaline purification.Be used for becoming the another kind of method of optically active enantiomorph to be based on the chromatography of optical activity matrix mesotomy.Also can split compound of the present invention by forming non-enantiomer derivative.Can use the other method that is used to split optically active isomer well known by persons skilled in the art.Such method comprises, J.Jaques, A.Collet and S.Wilen be at " Enantiomers, Racemates, and Resolutions ", those that discuss among the John Wiley and Sons, New York (1981).Also can be by stereoselectivity synthetic or enzyme split and prepare optically active compound from optically active starting raw material.
Pharmaceutical composition of the present invention or prepared in accordance with the present invention those can be by any suitable way administration, for example oral administration of forms such as tablet, capsule, powder, syrup, or the parenteral route administration of injection solution form.In order to prepare such composition, can use method well-known in the art and can use any pharmaceutically acceptable carrier, thinner, the normally used additive of vehicle or other this area.Tablet can pass through mixed active composition and common auxiliary agent and/or thinner, then this mixture preparation of compacting in conventional tabletting machine.The example of auxiliary agent or thinner comprises: W-Gum, yam starch, talcum, Magnesium Stearate, gelatin, lactose, natural gum etc.Can use any other auxiliary agent or the additive that is usually used in this purpose, such as tinting material, seasonings, sanitas etc., condition is that they and activeconstituents are compatible.Injection solution can prepare by the following method: activeconstituents and possible additive are dissolved in solvent ratio such as the sterilized water that part is used for injecting, this solution is adjusted to the volume of expectation, make this solution sterilization and fill it in the suitable ampoule or bottle.Can add the normally used any suitable additive in this area, such as tension regulator, sanitas, oxidation inhibitor etc.
Easily, compound formulation of the present invention can be become unit dosage, each dosage comprises about 0.01 to about 1000mg, or about 0.05 to about 5000, or about 0.1 to about 1000mg, yet actual dose can for example change according to particular compound.Term " unit dosage " refers to suitable to the physics discrete units that acts on human and other mammiferous unitary dose, and each unit contains the combination that active substance and one or more pharmaceutically acceptable carrier, thinner, vehicle or this area that calculating can produce the predetermined amount of required result of treatment are used other additive always.
Compound of the present invention is effective in wide dosage range.For example, every day, common dose fell into scope about 0.01 to about 100mg/kg body weight, or about 0.1 to about 75mg/kg body weight.Yet, be to be understood that, the amount of the compound of actual administration will be determined according to correlation circumstance by the doctor, described correlation circumstance comprises the illness that will treat, the route of administration of selection, the pragmatize compound of administration, age, body weight and the response of individual patient and the severity of patient's symptom, therefore, above-mentioned dosage range can not mean by any way and limits the scope of the invention.In some cases, the dosage level that is lower than above-mentioned scope lower limit may be more than q.s, and in other cases, can use still bigger dosage and can not cause any harmful side effect, condition is that bigger dosage is divided into several smaller doses and is used for the whole day administration like this.
At this, the full content of all documents that will quote in whole specification sheets is incorporated herein by reference.
Preparation is used for the general method of the intermediate of synthetic compound of the present invention
According to: Bartoli, Guiseppe; Palmieri, Gianni; Bosco, Marcella; Dalpozzo, Renato; Tetrahedron Lett., 30,16,1989,2129-2132 synthesizes the 7-fluoro indole.
Indoles, 5-chloro-indole and 6-methoxyl group indoles are available from Aldrich.
Method 1:3-(1H-indol-3-yl)-indan-1-one
Can shown in scheme 1, prepare 3-(1H-indol-3-yl)-indan-1-one.
Scheme 1.R
3, R
4, R
5And R
6For as defined above.
With the 3-bromo-indan-1-one of alkali, form the 1-Indanone of general formula X II such as triethylamine processing general formula X I.Lewis acid catalyst such as trifluoromethanesulfonic acid scandium or copper trifluoromethanesulfcomposite in the presence of, handle the 1-Indanone of general formula X II with the indoles of general formula X III, obtain 3-(1H-indol-3-yl)-indan-1-one of general formula X IV.
Method 2: cis-3-(1H-indol-3-yl)-indane-1-alcohol
Cis-3-(the 1H-indol-3-yl)-indane-1-alcohol that can shown in scheme 2, prepare general formula X V
Scheme 2.R
3-R
6For as defined above.
With 3-(1H-the indol-3-yl)-indan-1-one of reductive agent, obtain cis-3-(1H-indol-3-yl)-indane-1-alcohol of general formula X V such as sodium borohydride processing general formula X IV.
The enzyme chiral separation of method 3: cis-3-(1H-indol-3-yl)-indane-1-alcohol
Can be shown in scheme 3 cis-3-(1H-indol-3-yl)-indane-1-alcohol of general formula X V be split into its enantiomer.
Scheme 3.R
3-R
6For as defined above, R
7Be C
1-C
8The straight or branched alkyl group.
By at lipase such as Novozym 435 (from Novozymes A/S; Krogshoejvej36; 2880 Bagsvaerd; Denmark obtains) exist down; handle racemic cis-3-(1H-indol-3-yl)-indane-1-alcohol with irreversible acry radical donor such as the vinyl butyrates, cis-3-(1H-indol-3-yl)-indane-1-alcohol of general formula X V is split into its enantiomer.Then, with the ester of a kind of enantiomer esterification formation general formula X VI, and the another kind of enantiomer of general formula X VII keeps unreacted.By the compound of standard colour chart technical point from general formula X VI and XVII.
Method 4: optically active cis-3-(1H-indoles-4-yl)-indane-1-alcohol
Shown in scheme 4, obtain the optically active cis-3-of general formula X VIII (1H-indol-3-yl)-indane-1-alcohol by the ester of hydrolysis general formula X VI or by the ester of handling general formula X VI such as sodium methylate with transesterify reagent.
Scheme 4.R
3-R
6For as defined above, R
7Be C
1-C
8The straight or branched alkyl group.
Method 5: optically active 3-(1H-indol-3-yl)-indan-1-one
Shown in scheme 5, by optically active cis-3-(the 1H-indol-3-yl)-indane-1-alcohol of oxygenant, obtain optically active 3-(1H-indol-3-yl)-indan-1-one of general formula X IX and XX such as Dess-Martin periodane oxidation general formula X VII and XVlII.
Scheme 5.R
3-R
6For as defined above.
Method 6: trans-3-(3-azido--indane-1-yl)-1H-indoles
Trans-3-(3-azido--indane-1-yl)-1H-indoles of preparation general formula X XI shown in scheme 6.
Scheme 6.R
3-R
6For as defined above.
Use azide (azidating) reagent to handle racemic cis-3-(1H-indol-3-yl)-indane-1-alcohol of general formula X V or optically active cis-3-(1H-indol-3-yl)-indane-1-alcohol of general formula X VII or XVIII such as DBU respectively such as diphenyl phosphoryl azide and alkali, obtain general formula X XI racemic or optically active trans-3-(3-azido--indane-1-yl)-1H-indoles.
Method 7: trans-[3-(3-azido--indane-1-yl) indoles-1-yl] phosphonic acid diphenyl ester
Trans-[3-(3-azido--indane-1-yl)-indoles-1-yl] phosphonic acid diphenyl ester of preparation general formula X XI shown in scheme 7.
Scheme 7.R
3-R
6For as defined above, Pg is that the indoles protecting group is such as the diphenylphosphine carboxyl groups.
Handle R with excessive diphenyl phosphoryl azide and alkali such as DBU respectively
4Racemic cis-3-of the general formula X V of=H (1H-indol-3-yl)-indane-1-alcohol or processing R
4Optically active cis-3-of the general formula X VII of=H or XVIII (1H-indol-3-yl)-indane-1-alcohol, obtain general formula X XII racemic or optically active trans-[3-(3-azido--indane-1-yl)-indoles-1-yl]-phosphonic acid diphenyl ester.
Trans-3 (3-azido--indane-1-the yl)-1H-indoles of method 8:N-protection
Shown in scheme 8, by handling R such as right-toluenesulphonic acids chlorine with suitable protecting group reagent
4Trans-3-of the general formula X XI of=H (3-azido--indane-1-yl)-1H-indoles prepares trans-3-(3-azido--indane-1-the yl)-1H-indoles of the N-protected of general formula X XII.
Scheme 8.R
3-R
6For as defined above, Pg is that the indoles protecting group is such as tosyl group.
The general method for preparing compound of the present invention
Method 9: trans-3-(1H-indol-3-yl)-indane-1-base amine
Shown in scheme 9; respectively by under hydrogen; suitable transition-metal catalyst such as Pd/C in the presence of; at suitable reductive condition such as adding under the sodium borohydride; reduction general formula X XI racemic or optically active trans-trans-3-(3-azido--indane-1-the yl)-1H-indoles of racemic or optically active N-protected of 3-(3-azido--indane-1-yl)-1H-indoles or general formula X XII; the trimethyl-phosphine that perhaps is used in pyridine and the ammonium hydroxide aqueous solution is handled, make general formula X XIII racemic or optically active trans-3-(1H-indol-3-yl) indane-1-base amine.
Scheme 9.R
3-R
6For as defined above, Pg is that the indoles protecting group is such as the diphenylphosphine carboxyl groups.
Method 10: cis-3-(1H-indol-3-yl)-indane-1-base amine
Shown in scheme 10, preparation R
1Racemic or optically active cis-3-(1H-indol-3-yl)-indane of the general formula X XV of=H-1-base amine.
Scheme 10.R
1=H, R
2, R
3-R
6For as defined above.
With amine (NH
2R
2) and dried reagent handle racemic or optically active 3-(1H-indol-3-yl)-indan-1-one of general formula X IV, XIX or XX such as tetraethoxysilane, obtain the imines of formula XXIV, use reductive agent such as sodium borohydride with its reduction or by at transition-metal catalyst such as PtO
2Existence under handle with hydrogen, obtain R
1Racemic or optically active cis-3-(1H-indol-3-yl)-indane of the general formula X XV of=H-1-base amine.
Method 11: cis-3-(1H-indol-3-yl)-indane-1-base amine
Racemic or optically active cis-3-(1H-indol-3-yl)-indane of preparation general formula X XV shown in scheme 11-1-base amine.
Scheme 11.R
1-R
6For as defined above.
In acetate/methanol solution of suitable pH, with amine (NHR
1R
2) and reductive agent handle 3-(1H-indol-3-yl)-indan-1-one of general formula X IV, XIX or XX respectively such as sodium cyanoborohydride, obtain racemic or optically active cis-3-(1H-indol-3-yl)-indane-1-base amine of general formula X XV.
Method 12: cis-3-(1H-indol-3-yl)-indane-1-base amine and trans-3-(1H-indol-3-yl)-indane-1-base amine
Scheme 12.R
1-R
6For as defined above.
Shown in scheme 12, handle racemic cis-3-(1H-indol-3-yl)-indane-1-alcohol of general formula X V or optically active cis-3-(1H-indol-3-yl)-indane-1-alcohol of processing general formula X VlI or XVlIl with pure activating reagent and alkali such as triethylamine, follow and amine (NHR
1R
2) reaction, obtain racemic or optically active cis of general formula X XV-and the mixture of trans-3-(1H-indol-3-yl)-indane-1-base amine, it is separated such as HPLC or flash chromatography by the reference colour spectrometry, obtain racemic or optically active cis-3-(1H-indol-3-yl)-indane of general formula X XV-1-base amine or general formula X XV racemic or optically active trans-3-(1H-indol-3-yl)-indane-1-base amine.
Method 13: trans-3-(1H-indol-3-yl)-indane-1-base amine
Shown in scheme 13, by using (R
1)
2BBr handles trans-3-(3-azido--indane-1-the yl)-1H-indoles of the N-protected of general formula X XII, then removes the indoles protecting group and prepares R
1, R
4Trans-3-of the general formula X XVI of=H (1H-indol-3-yl)-indane-1-base amine.
Scheme 13.R
2, R
3, R
5And R
6For as defined above, Pg is that the indoles protecting group is such as tosyl group or diphenylphosphine carboxyl groups.
Method 14: trans-3-(1H-indol-3-yl)-indane-1-base amine
Shown in scheme 14, by handling R with methyl-chloroformate
4Trans-3-of the general formula X XIII of=H (1H-indol-3-yl)-indane-1-base amine then prepares R with appropriate reductant such as lithium aluminium hydride reduction
1, R
4Trans-3-of the general formula X XVI of=H (1H-indol-3-yl)-indane-1-base amine.
Scheme 14.R
3, R
5And R
6For as defined above.
Method 15: optically active 3-(1H-indol-3-yl)-indane-1-base amine
Such as chirality supercritical fluid chromatography (SFC) and chirality HPLC the racemic cis of general formula X XV and XXVI or trans-3-(1H-indol-3-yl)-indane-1-base amine are separated into by chromatographic technique respectively that its optically active cis-or trans-3-(1H-indol-3-yl)-indane-1-base amine is right.
Method 16: optically active 3-(1H-indyl-3-yl)-indane-1-base amine
By salt, and discharge this optically active amine compound with alkaline purification and come respectively the racemic cis of general formula X XV and XXVI-or trans-3-(1H-indol-3-yl)-indane-1-base amine is separated into, and its optically active cis-or trans-3-(1H-indol-3-yl)-indane-1-base amine is right with optically active sour fractional separation diastereomer.
Test portion
General LC-MS method A and B: solvent systems: A=water/TFA (100:0.05), B=water/acetonitrile/TFA (5:95:0.035) (TFA=trifluoroacetic acid).By integrating UV (254nm) and ELSD trace mensuration purity, retention time (RT) is with minute representing.The MS instrument is from PESciex (API), and it is equipped with the APPI-source and operates in the positively charged ion mode.
Method A:API 150EX and Shimadzu LC8/SLC-10A LC system.Post: 30 * 4.6mm Waters Symmetry C18 has the particle of 3.5 μ M, at room temperature operation.In 4 minutes, the B of the A to 100% with 90% carries out linear gradient elution, flow velocity 2ml/min.
Method B:API 150EX and Shimadzu LC8/SLC-10A LC system.Post: 30 * 4.6mm Waters Symmetry C18, have the particle of 3.5 μ M, 40 ℃ of operations down, in 2.4 minutes, carry out linear gradient, flow velocity 3.3ml/min with 90% A to 100% B.
LC-MS TOF (TOF=flight time) method C:micromass LCT 4-ways MUX is equipped with Waters 2488/Sedex 754 detector systems.Post: 30 * 4.6mm WatersSymmetry C18 post, have the particle diameter of 3.5 μ m, operation at room temperature, in 4 minutes, the B of the A to 100% with 90% carries out linear gradient elution, flow velocity 2ml/min.By integrating UV (254nm) and ELSD trace mensuration purity, retention time (RT) is with minute representing.
Respectively on Bruker DRX 500 with 500.13MHz and 125.67 records
1H NMR and
13C NMR spectrum.Use deuterochloroform (99.8%D) or methyl-sulphoxide (99.9%D) as solvent.Use TMS as the internal reference standard.Chemical shift is with the ppm value representation.The multiplicity of NMR signal is used following abbreviation: s=is unimodal, d=doublet, t=triplet, q=quartet, the qv=quintet, h=septet, the two doublets of dd=, the two triplets of dt=, the two quartets of dq=, the heavy peak of tt=triplet, m=multiplet, b=broad peak.
Embodiment
Synthesizing of 3-bromo-indan-1-one
The N-bromine succinimide (powder of no block) of 390g (2.2mol) and the Benzoyl Peroxide of 0.5g are joined the CCl at 1500mL
4In the 264g indan-1-one in, and mechanical stirring and refluxing 1.5 hours.The color flipflop yellowly of this reaction mixture, all N-bromine succinimides (compare CCl
4Heavily) being transformed into succinimide (compares CCl
4Gently).This reaction mixture is cooled to 20 ℃, filters and concentrate in a vacuum.Thick 3-bromo-indan-1-one is dissolved in the ethyl acetate/heptane (1:2) of 600mL, and cooling is 2 hours in ice bath, is placed on refrigerator overnight then, obtains the crystal (productive rate 62%) of the 3-bromo-indan-1-one of 257g.
Synthetic (method 1) of 3-(7-fluoro-1H-indol-3-yl)-indan-1-one
Under 0 ℃, with triethylamine (4.5mL; 32mmol; 1.2 equivalent) join 3-bromo-indan-1-one (5.6g in 100mlTHF; 27mmol), at room temperature stirred 1 hour.Filter this reaction mixture removing three second ammonium bromides, and under vacuum, concentrate and obtain 1-Indanone.Under 0 ℃, with the 7-fluoro indole (3.3g, 22mmol) and Sc (OTf)
3(550mg, 5mol%) CH that joins at 100ml
2Cl
2In 1-Indanone in.This reaction mixture is heated to ambient temperature overnight.The ethyl acetate that adds 100ml is filtered this mixture and is concentrated under vacuum by silica filler.Behind flash chromatography (heptane/ethyl acetate, silica gel), separate 3-(7-fluoro-1H-indol-3-yl)-indan-1-one of 5.9g.
Synthesize following compound by similar method:
3-(1H-indol-3-yl)-indan-1-one
3-(1-Methyl-1H-indole-3-yl)-indan-1-one
3-(5-fluoro-1H-indol-3-yl)-indan-1-one
3-(6-fluoro-1H-indol-3-yl)-indan-1-one
3-(6-methoxyl group-1H-indol-3-yl)-indan-1-one
3-(5-fluoro-2-Methyl-1H-indole-3-yl)-indan-1-one
3-(4-chloro-1H-indol-3-yl)-indan-1-one
3-(5-chloro-1H-indol-3-yl)-indan-1-one
3-(7-chloro-1H-indol-3-yl)-indan-1-one
5-fluoro-3-(7-Methyl-1H-indole-3-yl)-indan-1-one
3-(6-bromo-1H-indol-3-yl)-5-fluoro-indan-1-one
3-(4-chloro-1H-indol-3-yl)-6-fluoro-indan-1-one
3-(4,6-two fluoro-1H-indol-3-yls)-6-fluoro-indan-1-one
3-(4-chloro-1H-indol-3-yl)-6-methoxyl group-indan-1-one
3-(5,6-two fluoro-1H-indol-3-yls)-6-methoxyl group-indan-1-one
5-chloro-3-(5-fluoro-1H-indol-3-yl)-indan-1-one
3-(6-chloro-3-oxygen-indane-1-yl)-1H-indoles-5-nitrile
6-chloro-3-(5-methoxyl group-1H-indol-3-yl)-indan-1-one
6-chloro-3-(7-methoxyl group-1H-indol-3-yl)-indan-1-one
Synthetic (method 2) of cis-3-(1H-indol-3-yl)-indane-1-alcohol
Under 0 ℃, with NaBH
4(6.2g, 163mmol, 2 equivalents) join 3-(1H-indol-3-yl)-indan-1-one in the THF of the methyl alcohol of 200ml and 100mL (20g, 80.9mmol) in.This reaction mixture is heated to ambient temperature overnight.Obtain racemic cis-3-indoles-indane-1-alcohol (quantitatively) with water treatment (aqueous workup).
Synthesize following compound by similar method:
Cis-3-(6-fluoro-1H-indol-3-yl)-indane-1-alcohol
Cis-3-(6-methoxyl group-1H-indol-3-yl)-indane-1-alcohol
Cis-3-(5-chloro-1H-indol-3-yl)-indane-1-alcohol
Cis-3-(4-chloro-1H-indol-3-yl)-6-fluoro-indane-1-alcohol
Cis--6-chloro-3-(5-methoxyl group-1H-indol-3-yl)-indane-1-alcohol
Butyric acid (1R, 3S)-3-(1H-indol-3-yl)-indane-1-base ester and (1S, 3R)-synthetic (method 3) of 3-(1H-indol-3-yl)-indane-1-alcohol
With Novozym 435 (1g) (from Novozymes A/S, Krogshoejvej 36,2880Bagsvaerd, Denmark obtains) and vinyl butyrate (20.5mL 162mmol) joins in racemic cis-3-indoles-indane-1-alcohol (80.9mmol) in 200ml toluene.This reaction mixture of jolting is 2 days under argon gas, up to
1H-NMR demonstrates and has transformed 50%.Filter and concentrate in a vacuum this reaction mixture.Behind flash chromatography (heptane/ethyl acetate, silica gel), separate 13.49g butyric acid (1R, 3S)-(1S, 3R)-3 (the 1H-indol-3-yl)-indane-1-alcohol of 3-(1H-indoles-3 base)-indane-1-base ester and 9.78g.
Synthesize following compound by similar method:
Butyric acid (1R, 3S)-3-(7-fluoro-1H-indol-3-yl)-indane-1-base ester
(1S, 3R)-3-(7-fluoro-1H-indol-3-yl)-indane-1-alcohol
(1S, 3R)-3-(5-chloro-1H-indol-3-yl)-indane-1-alcohol
(1S, 3R)-3-(6-methoxyl group-1H-indol-3-yl)-indane-1-alcohol
(1R, 3S)-synthetic (method 4) of 3-(1H-indol-3-yl)-indane-1-alcohol
With 30% NaOMe of 3mL in methyl alcohol join 13.49g butyric acid in 100ml methyl alcohol (1R, 3S)-3-(1H-indol-3-yl)-indane-1-base ester in.After 1.5 hours, TLC demonstrates fully and transforms.The solid NH that adds 1.5g
4The water of Cl and 50mL.Remove methyl alcohol in a vacuum and after with water treatment, obtain (1R, 3S)-3-(1H-indol-3-yl)-indane-1-alcohol (37.9mmol).
Synthesize following compound by similar method:
(1R, 3S)-3-(7-fluoro-1H-indol-3-yl)-indane-1-alcohol
(R)-synthetic (method 5) of 3-(1H-indol-3-yl)-indan-1-one
Under 0 ℃, will be at 10mL CH
2Cl
2In Dess-Martin Periodane (1.08g 2.55mmol) joins the CH at 10ml
2Cl
2In (1S, 3R)-3-(1H-indol-3-yl)-indane-1-alcohol in.This reaction mixture is heated to room temperature, stirs 40 minutes-TLC and demonstrate conversion fully.In this reaction mixture, add ethyl acetate and saturated NaHCO
3Separate organic phase,, use MgSO with 2N NaOH and salt water washing
4Dry and concentrated in a vacuum.Behind flash chromatography (heptane/ethyl acetate, silica gel), obtain (R)-3-(1H-the indol-3-yl)-indan-1-one of quantitative yield.
Synthesize following compound by similar method:
(R)-3-(7-fluoro-1H-indol-3-yl)-indan-1-one
(S)-3-(7-fluoro-1H-indol-3-yl)-indan-1-one
3-(synthetic (method 6) of (1S, 3S)-3-azido--indane-1-yl)-1H-indoles
Under 0 ℃; with 1; 8-diazabicylo [5.4.0] 11 carbon-7-alkene (4.8mL; 32.1mmol; 1.45 equivalent) join (1R in the anhydrous THF of 150ml; 3S)-3-(1H-indol-3-yl)-indane-1-alcohol (22.2mmol) and diphenyl phosphoryl azide (6.0ml, 27.8mmol, 1.25 equivalents) in.Under 0 ℃, stir this reaction 0.5 hour, at room temperature stir 2 hours-TLC then and demonstrate conversion fully.In this reaction mixture impouring water, and use ethyl acetate extraction.With the 0.5N HCl of 100mL, saturated NaHCO
3The washing organic phase is used MgSO
4Dry and concentrate in a vacuum, obtain 3-((1R, 3S)-3-azido--indane-1-yl)-1H-indoles.
Synthesize following compound by similar method:
3-((1R, 3R)-3-azido--indane-1-yl)-6-methoxyl group-1H-indoles
Synthetic (method 7) of [3-((1R, 3R)-3-azido--indane-1-yl)-5-chloro-indoles-1-yl]-phosphonic acid diphenyl ester
Under 5 ℃, with diphenyl phosphoryl azide (23g, 85mmol) join in the anhydrous THF of 150ml (1S, 3R)-3-(5-chloro-1H-indol-3-yl)-indane-1-alcohol (10g, 35mmol) in.Added 1 through 0.5 hour, and 8-diazabicylo [5.4.0] 11 carbon-7-alkene (13.7ml, 92mmol).Stir this reaction mixture and spend the night, be heated to room temperature simultaneously.In this reaction mixture impouring salt solution, use Et
2The O extraction.0.1N HCl, 0.1N NaOH with 100ml wash organic phase, use MgSO
4Dry and concentrated in a vacuum.Behind flash chromatography (heptane/ethyl acetate, silica gel), isolate [3-((1R, 3R)-3-azido--indane-1-yl)-5-chloro-indoles-1-yl]-phosphonic acid diphenyl ester of 19.1g.
Synthesize following racemic compound by similar method:
[3-(3-azido--indane-1-yl)-indoles-1-yl]-phosphonic acid diphenyl ester
[3-(3-azido--indane-1-yl)-6-fluoro-indoles-1-yl]-phosphonic acid diphenyl ester
[3-(3-azido--indane-1-yl)-6-methoxyl group-indoles-1-yl]-phosphonic acid diphenyl ester
[3-(3-azido--5-fluoro-indane-1-yl)-4-chloro-indoles-1-yl]-phosphonic acid diphenyl ester
[3-(3-azido--5-chloro-indane-1-yl)-5-methoxyl group-indoles-1-yl]-phosphonic acid diphenyl ester
3-(synthetic (method 8) of (1R, 3R)-3-azido--indane-1-yl)-6-methoxyl group-1-(toluene-4-alkylsulfonyl)-1H-indoles
Under 5 ℃, 1g sodium hydride (in mineral oil 60%) is joined 2g3-in the anhydrous THF of 50mL (in (1R, 3R)-3-azido--indane-1-yl)-6-methoxyl group-1H-indoles, and stirred these reaction mixtures 1 hour down at 5 ℃.Under 5 ℃, add in batches 2g right-the toluenesulphonic acids muriate, continue to stir again 4 hours.Add ice, after 1 hour, add entry and ethyl acetate.Separate organic phase, use the salt water washing, use MgSO
4Dry and concentrated under vacuum.Behind flash chromatography (heptane/ethyl acetate, silica gel), the 3-of separation 2.5g ((1R, 3R)-3-azido--indane-1-yl)-6-methoxyl group-1-(toluene-4-alkylsulfonyl)-1H-indoles.
Synthesize following compound by similar method:
3-(1R, 3R)-3-azido--indane-1-yl)-1-(toluene-4-alkylsulfonyl)-1H-indoles (1R, 3R)-synthetic (method 9) of 3-(5-chloro-1H-indol-3-yl)-indane-1-base amine
At room temperature, through 2 hours, the trimethyl-phosphine of 32g is joined in [3-((1R, 3R)-3-azido--indane-1-yl)-5-chloro-indoles-1-yl]-phosphonic acid diphenyl ester of 19g in 100ml pyridine and 36mL9N ammonium hydroxide.At room temperature stir this reaction mixture and spend the night, and concentrate in a vacuum.Add ethyl acetate and water.With the NaOH aqueous solution this mixture that alkalizes, and filter.Concentrate organic phase in a vacuum, and it is dissolved in the ethyl acetate once more.2N methylsulfonic acid with 2 * 250mL extracts this ethyl acetate solution.With 9N NaOH alkalization water, form throw out, make it carry out flash chromatography (ethyl acetate, methyl alcohol, triethylamine, silica gel), obtain 0.6g (1R, 3R)-3-(5-chloro-1H-indol-3-yl)-indane-1-base amine.Concentrate from the above-mentioned ethyl acetate phase that obtains in a vacuum, and it is dissolved in the 100ml methyl alcohol, add the 30%NaOMe of 10mL in methyl alcohol.At room temperature stirred this reaction mixture 2 hours, and concentrated in a vacuum, and by flash chromatography (ethyl acetate, methyl alcohol, triethylamine, silica gel) purifying, further obtain 0.45g (1R, 3R)-3-(5-chloro-1H-indol-3-yl)-indane-1-base amine.
Embodiment 7:[(1S, 3R)-3-(1H-indol-3-yl)-indane-1-yl]-synthetic (method 10) of methyl-amine
Use Emry Optimizer
TMInstrument under microwave irradiation, under 150 ℃, is stirred in (R)-3-in the 10mL methyl alcohol (1H-indol-3-yl)-indan-1-one, methylamine (5mL, 2M in THF) and 1mL tetraethoxysilane 11 minutes.Add PtO
2(10mg), at room temperature, under 1 air pressure hydrogen, stir this reaction mixture and spend the night, filter and concentrate in a vacuum.Behind flash chromatography (ethyl acetate, methyl alcohol, triethylamine, silica gel), isolate [(1S, 3R)-3-(1H-indol-3-yl)-indane-1-yl]-methyl-amine, productive rate 66%.
Synthesize following compound by similar method:
Embodiment 1:
Racemic cis-[3-(5-fluoro-2-Methyl-1H-indole-3-yl)-indane-1-yl]-methyl-amine
Embodiment 2:
Racemic cis-[3-(7-methoxyl group-1H-indol-3-yl)-indane-1-yl]-methyl-amine
Embodiment 3:
Racemic cis-methyl-[3-(1-Methyl-1H-indole-3-yl)-indane-1-yl]-amine
Embodiment 4:
Racemic cis-[3-(5-fluoro-1H-indol-3-yl)-indane-1-yl]-methyl-amine
Embodiment 5:
Racemic cis-[3-(7-chloro-1H-indol-3-yl) indane-1-yl]-methyl-amine
Embodiment 6:
Racemic cis-[3-(4-chloro-1H-indol-3-yl)-indane-1-yl]-methyl-amine
Embodiment 8:
[(1R, 3S)-3-(7-fluoro-1H-indol-3-yl)-indane-1-yl]-methyl-amine
Preparative scale chirality SFC purifying (method 15): method: post: Chiralcel OJ-H (2 * 25cm), operation at room temperature.35% the methyl alcohol that use contains in CO2 (100bar) as 0.1% (v/v) diethylamine of conditioning agent carries out chromatogram, and flow velocity is 50ml/min.
Analyze chirality SFC: method: post: 250 * 4.6mm Chiralcel AD-H has the particle of 5 μ M, operation at room temperature.40% ethanol that use contains in CO2 (100bar) as 0.1% (v/v) diethylamine of conditioning agent carries out chromatogram, and flow velocity is 3ml/min.Under 220nm, detect.RT
Mainly=2.52min, RT
Minimum=3.29min,〉99.5% ee.
LC/MS: method A:RT=1.85min.UV-purity=99.30%, ELSD purity=96.78%
1H-NMR (hydrobromate; d
6-DMSO): δ 2.23-2.27 (m, 1H), 2.71 (s, 3H), 2.93-2.95 (m, 1H), 4.62 (dd, J=7.8Hz, 10.2Hz, 1H), 4.88 (t, J=8.3Hz, 1H), 6.87-6.96 (m, 3H), 7.12 (d, J=7.7Hz, 1H), 7.30 (t, J=14.8Hz, 1H), and 7.35-7.38 (m, 2H), 7.72 (d, J=7.6Hz, 1H), 11.5 (bs, 1H).
Embodiment 9:
[(1S, 3R)-3-(7-fluoro-1H-indol-3-yl)-indane-1-yl]-methyl-amine
Preparative scale chirality SFC purifying (method 15): method: post: Chiralcel OJ-H (2 * 25cm), operation at room temperature.35% methyl alcohol that use contains in CO2 (100bar) as 0.1% (v/v) diethylamine of conditioning agent carries out chromatogram, and flow velocity is 50ml/min.
Analyze chirality SFC: method: post: 250 * 4.6mm Chiralcel AD-H has the particle of 5 μ M, operation at room temperature.40% ethanol that use contains in CO2 (100bar) as 0.1% (v/v) diethylamine of conditioning agent carries out chromatogram, and flow velocity is 3ml/min.Under 220nm, detect.RT
Mainly=3.36min, RT
Minimum=2.46min,〉99.5% ee.
LC/MS: method B:RT=0.90min.UV-purity 99.80%, ELSD purity=96.08%
1H-NMR(d
6-DMSO)：δ?1.89-1.96(m，1H)，2.15(bs，1H)，2.40(s，3H)，2.75-2.80(m，1H)，4.17(dd，J＝7.3Hz，8.7Hz，1H)，4.44(dd，J＝7.5Hz，10.4Hz，1H)，6.82-6.90(m，3H)，7.07-7.11(m，2H)，7.20(t，J＝7.4Hz，1H)，7.26(d，J＝2.2Hz，1H)，7.42(d，J＝7.5Hz，1H)，11.4(bs，1H)。
13C-NMR(d6-DMSO)：δ?33.7，394，63.3，106.1(J
CF＝16Hz)，115.7，118.5，118.8，124.0，124.1，124.3，124.8，124.9，126.6，127.2，130.8，145.7，146.2，149.7(J
cF＝243Hz)。
Embodiment 11:
Racemic cis-[6-chloro-3-(7-methoxyl group-1H-indol-3-yl)-indane-1-yl]-methyl-amine
Embodiment 12:
Racemic cis-[3-(4-chloro-1H-indol-3-yl)-6-methoxyl group-indane-1-yl]-methyl isophthalic acid-amine
Embodiment 13:
Racemic cis-[3-(5,6-two fluoro-1H-indol-3-yls)-6-methoxyl group-indane-1-yl]-methyl-amine
Embodiment 14:
Racemic cis-3-(6-chloro-3-methylamino--indane-1-yl)-1H-indoles-5-nitrile
Embodiment 15:
Racemic cis-[5-fluoro-3-(7-Methyl-1H-indole-3-yl)-indane-1-yl]-methyl-amine
Embodiment 16:
Racemic cis-[3-(6-bromo-1H-indol-3-yl)-5-fluoro-indane-1-yl]-methyl-amine
Embodiment 23:
Racemic cis-[3-(4,6-two fluoro-1H-indol-3-yls)-6-fluoro-indane-1-yl]-methyl-amine
Embodiment 24:
Racemic cis-[5-chloro-3-(5-fluoro-1H-indol-3-yl)-indane-1-yl]-methyl-amine
Embodiment 19: synthetic (method 11) of cis 3-(3-piperidines-1-base-indane-1-yl)-1H-indoles
With sodium cyanoborohydride (61mg; 0.97mmol) join 3-(the 1H-indol-3-yl)-indan-1-one (200mg in 3mL methyl alcohol and 0.5mL acetate; 0.81mmol) and piperidines (344mg; 4.05mmol) in.Use Emry Optimizer
TMInstrument under microwave irradiation, under 150 ℃, stirred this reaction mixture 30 minutes.In this reaction mixture impouring water, the NaOH aqueous solution alkalization with 27%.With this mixture of ethyl acetate extraction.Use MgSO
4Dry organic phase, and concentrate in a vacuum.Behind flash chromatography (ethyl acetate, heptane, triethylamine, silica gel), obtain cis-3-(3-piperidines-1-base-indane-1-yl)-1H-indoles.
Synthesize following compound by similar method:
Embodiment 20:
Racemic cis-3-(3-tetramethyleneimine-1-base-indane-1-yl)-1H-indoles
Embodiment 21:
Racemic cis-3-(3-morpholine-4-base-indane-1-yl)-1H-indoles
Embodiment 10:[(1R, 3R)-3-(1H-indol-3-yl)-indane-1-yl]-synthetic (method 13) of methyl-amine
Under 0 ℃; under argon gas; with dimethyl bromo borine (1.77ml; 1.05 equivalent) (according to N ǒ th, H., Vahrenkamp; H.Journal of Organometallic Chemistry 11 (1968); 399-405 is synthetic) join at 100ml 1, the 3-in the 2-ethylene dichloride is (in (1R, 3R)-3-azido--indane-1-yl)-1-(toluene-4-alkylsulfonyl)-1H-indoles (17.3mmol).This reaction mixture is heated to room temperature, and stirred 2.5 hours.The ethanol that adds 1mL.With ethyl acetate and this reaction mixture of 0.5N NaOH aqueous solution extraction.With salt water washing organic phase, use MgSO
4Drying concentrates in a vacuum, behind flash chromatography (ethyl acetate, methyl alcohol, triethylamine, silica gel), obtain methyl-(1R, 3R)-3-[1-(toluene-4-alkylsulfonyl)-1H-indol-3-yl]-indane-1-yl-amine.With methyl-(1R, 3R)-3-[1-(toluene-4-alkylsulfonyl)-1H-indol-3-yl]-indane-1-yl-amine is dissolved in the methyl alcohol of the acetone of 8mL and 20mL.The 28%NaOH aqueous solution that adds 8mL uses Emry Optimizer
TMInstrument under microwave irradiation, stirred this reaction mixture 10 minutes in two batches under 120 ℃.In the water with this reaction mixture impouring 250mL, form throw out.Recrystallization obtain 2.15g's [(1R, 3R)-3-(1H-indol-3-yl)-indane-1-yl]-methyl-amine.
Chirality SFC: method: post: 250 * 4.6mm Chiralcel OJ-H has the particle of 5 μ M, at room temperature operation.30% ethanol that use contains as 0.1% (v/v) diethylamine of conditioning agent carries out chromatogram, and pressure is 20MPa, and flow velocity is 3ml/min.Under 230nm, detect.RT
Mainly=2.40min, RT
Minimum=2.93min, 95.9% ee.
LC/MS: method A:RT=1.63min.UV-purity=98.28%, ELSD purity=99.61%.
1H-NMR((d
6-DMSO)：δ?2.35(m，5H)，4.17(dd，J＝3.8Hz，6.6Hz，1H)，4.75(t，J＝7.5Hz，1H)，6.90(W＝7.1Hz，1H)，7.00(m，3H)，7.14(t，J＝7.3Hz，1H)，7.19(t，J＝7.3Hz，1H)，7.26(d，J＝8.0Hz，1H)7.34(d，J＝7.3Hz，1H)，7.38(d，J＝7.3Hz，1H)，10.80(bs，1H)。
13C-NMR(d
6-DMSO)：δ?34.2，39.9，41.3，63.6，111.9，118.0，118.5，119.1，121.3，122.4，124.8，125.0，126.4，126.7，127.6，137.1，145.3，147.2。
Synthesize following compound by similar method:
Embodiment 27:
[(1R, 3R)-3-(6-methoxyl group-1H-indol-3-yl)-indane-1-yl]-methyl-amine
LC/MS: method A:RT=1.60min.UV-purity=98.52%, ELSD purity=99.53%
1H-NMR(CDCl
3)：δ?2.41(ddd，J＝3.8Hz，7.5Hz，12.8Hz，1H)，2.50(t，J＝6.8Hz，1H)，2.53(s，3H)，3.83(s，3H)，4.27(dd，J＝3.8Hz，6.8Hz，1H)，4.79(t，J＝7.5Hz，1H)，6.72(m，2H)，6.85(s，1H)，7.2(m，4H)，7.40(d，J＝7.3Hz，1H)，7.82(bs，1H)。
Embodiment 25: racemic trans-synthetic (method 13) of [6-chloro-3-(5-methoxyl group-1H-indol-3-yl)-indane-1-yl]-methyl-amine
Will be at 0.5mL anhydrous 1,0.15mmol dimethyl bromo borine in the 2-ethylene dichloride is (according to N ǒ th, H., Vahrenkamp, H.Journal of Organometallic Chemistry 11 (1968), 399-405 is synthetic) join at 2mL anhydrous 1, in [3-(3-azido--6-chloro-indane-1-yl)-indoles-1 the base]-phosphonic acid diphenyl ester of the about 0.1mmol in the 2-ethylene dichloride.At room temperature stirred this reaction mixture 3 hours.By the 1N NaOH of adding 1mL and the salt solution termination reaction of 1mL.With this mixture of ethyl acetate extraction.Under vacuum, concentrate organic phase.At room temperature, handled resistates 3 hours with the 1M sodium methylate of 3mL in methyl alcohol.Add 1mL acetate, behind preparation HPLC, isolate [6-chloro-3-(1H-indol-3-yl)-indane-1-yl]-methyl-amine.
Synthesize following compound by similar method:
Embodiment 17:
Racemic trans-[3-(6-fluoro-1H-indol-3-yl)-indane-1-yl]-methyl-amine
Embodiment 18:
Racemic trans-[3-(6-methoxyl group-1H-indol-3-yl)-indane-1-yl]-methyl-amine
Embodiment 22:
Racemic trans-[3-(4-chloro-1H-indol-3-yl)-6-fluoro-indane-1-yl]-methyl-amine
Embodiment 26:[(1R, 3R)-3-(5-chloro-1H-indol-3-yl)-indane-1-yl]-synthetic (method 14) of methyl-amine
With 0.73g (1R, 3R)-3-(5-chloro-1H-indol-3-yl)-indane-1-base amine is suspended in 1 of 200ml, among the 9N NaOH of the water of 2-ethylene dichloride, 100mL and 0.5mL.The Bu that adds 0.25mL methyl-chloroformate (1.2 equivalent) and 50mg
4NBr.At room temperature, stirred this reaction mixture 30 minutes.Use MgSO
4Dry organic phase, and concentrating in a vacuum, obtain 0.6g [(1R, 3R)-3-(5-chloro-1H-indol-3-yl)-indane-1-yl]-Urethylane.After with water treatment, obtain 0.6g [(1R, 3R)-3-(5-chloro-1H-indol-3-yl)-indane-yl]-Urethylane.Will [(1R, 3R)-3-(5-chloro-1H-indol-3-yl)-indane-1-yl]-Urethylane is dissolved among the anhydrous THF of 250mL, adds the LiAlH of 0.6g
4This reaction mixture 2 hours refluxes.Water with 2mL stops this reaction, filters and concentrates in a vacuum, obtains oily matter.This oily matter is dissolved in the ethyl acetate, after standing over night at room temperature, be settled out 350mg [(1R, 3R)-3-(5-chloro-1H-indol-3-yl)-indane-1-yl]-methyl-amine.
Chirality SFC: method: post: 250 * 4.6mm Chiralcel AD-H has the particle of 5 μ M, at room temperature operation.30% ethanol that use contains as 0.1% (v/v) diethylamine of conditioning agent carries out chromatogram, and pressure is 20MPa, and flow velocity is 3ml/min.Under 230nm, detect.RT
Mainly=2.89min, RT
Minimum=3.84min, 88.6% ee.
LC/MS: method C:RT=1.54min.UV-purity=95.21%, ELSD purity=100%
13H-NMR(CDCl
3)：δ?2.38-2.52(m，2H)，2.53(s，3H)，4.27(dd，J＝3.9Hz，6.6Hz)，4.77(t，J＝7.4)，6.82(s，1H)，7.12(dd，J＝2.0hZ，8.5Hz，1H)，7.20-7.27(m，3H)，7.37(d，J＝2.0Hz)，7.42(d，J＝7.4Hz)，8.16(bs，1H)。
The chiral separation (method 15) of racemic cis-3-(7-fluoro-1H-indol-3-yl)-indane-1-base-methyl-amine
Racemic cis-3-(7-fluoro-1H-indol-3-yl)-indane-1-base-methyl-amine (from method 10) by chirality SFC purifying 20g, obtain the [(1S of 9.3g, 3R)-3-(7-fluoro-1H-indol-3-yl)-indane-1-yl]-methyl-amine (〉 99.5% ee) and 9.5g [(1R, 3S)-3-(7-fluoro-1H-indol-3-yl)-indane-1-yl]-methyl-amine (〉 99.5% ee).
Preparative scale chirality SFC purification process: post: Chiralcel OJ-H (2 * 25cm), have the particle of 5 μ M, 35 ℃ of operations down.35% methyl alcohol that use contains in CO2 (100bar) as 0.1% (v/v) diethylamine of conditioning agent carries out chromatogram, and flow velocity is 50ml/min.
The fractional crystallization (method 16) of racemic cis-3-(7-fluoro-1H-indol-3-yl)-indane-1-base-methyl-amine and optically active acid
In the solution of the cis-3-of raceme (7-fluoro-1H-indol-3-yl)-indane-1-base-methyl-amine (409mg/2ml EtOH), add the tartaric solution (leq of two-right-toluoyl-D-; 564mg/2ml acetone).With this mixture heating up to 50 ℃, and stirred 15 minutes.Evaporating solvent grinds with acetone (2ml).Collect white solid (84%ee), and stirred 30 minutes with the EtOH of 10ml heat.Collect remaining white solid, be converted into free alkali, obtain [(1S, 3R)-3-(7-fluoro-1H-indol-3-yl)-indane-1-yl]-methyl-amine (93%ee).
Table A: actual measurement molecular weight (M+H
+), actual measurement HPLC-retention time (room temperature, minute) and UV-and ELSD-purity (%).
| The embodiment numbering | M+H + | R t(minute) | UV purity % | ELSD purity % | Method |
| 1 | 295.2 | 1.82 | 98.6 | 99.9 | A |
| 2 | 293.2 | 1.79 | 96.7 | 99.2 | A |
| 3 | 277.2 | 1.91 | 92.5 | 99.9 | A |
| 4 | 281.1 | 1.78 | 91.5 | 99.6 | A |
| 5 | 297.1 | 1.94 | 89.7 | 99.6 | A |
| 6 | 297.1 | 1.98 | 89.3 | 99.6 | A |
| 7 | 263.1 | 1.66 | 91.1 | 99.6 | A |
| 8 | 281.1 | 1.85 | 99.3 | 96.8 | A |
| 9 | 281.0 | 1.89 | 95.2 | 99.5 | A |
| 10 | 263.1 | 1.64 | 91.9 | 100.0 | A |
| 11 | 327.1 | 1.97 | 92.9 | 99.9 | A |
| 12 | 327.1 | 2.02 | 74.5 | 99.3 | A |
| 13 | 329.1 | 1.94 | 88.0 | 99.7 | A |
| 14 | 322.1 | 1.83 | 89.2 | 99.9 | A |
| 15 | 295.2 | 1.93 | 92.2 | 99.1 | A |
| 16 | 359.0 | 2.07 | 87.7 | 99.4 | A |
| 17 | 281.1 | 1.77 | 96.8 | 99.6 | A |
| 18 | 293.2 | 1.75 | 96.2 | 100.0 | A |
| 19 | 317.1 | 1.85 | 85.1 | 99.0 | A |
| 20 | 303.1 | 1.82 | 98.3 | 98.9 | A |
| 21 | 319.0 | 1.72 | 94.3 | 99.4 | A |
| 22 | 315.1 | 1.88 | 90.2 | 99.8 | A |
| 23 | 317.1 | 1.89 | 87.8 | 99.3 | A |
| 24 | 315.1 | 1.90 | 89.3 | 98.6 | A |
| 25 | 327.1 | 1.89 | 82.7 | 99.3 | A |
| 26 | 297.2 | 0，94 | 94，5 | 99，4 | B |
| 27 | 293.1 | 1.60 | 98.5 | 99.5 | A |
The transporter inhibition analysis
Measure the rat layer synaptosome to [
3H]-picked-up of 5-HT
With glass/tetrafluoroethylene homogenizer in replenishing the 0.40M sucrose of 1mM nialamide homogenizing from the full brain of male Wistar rat (125-225g), except cerebellum.With homogenate 1000 * g and 4 ℃ centrifugal 10 minutes down.Discard spheroidal particle, and with supernatant liquor under 40.000 * g centrifugal 20 minutes.The final spheroidal particle of homogenizing in this analysis buffer (0.5mg original structure/hole).With test compound (or damping fluid) and 10nM[
3H]-5-HT adds 96 orifice plates.The composition of analysis buffer: 123mM NaCl, 4.82mM KCl, 0.973mM CaCl 2,1.12mM MgSO
4, 12.66mM Na
2HPO
4, 2.97mM NaH
2PO
4, 0.162mM EDTA, 2g/l glucose and 0, the 2g/l xitix.O with 95%
2/ 5% CO
2Oxidation buffer liquid 10 minutes.Begin in the final analysis volume that adds 0.2ml to cultivate by organizing.Cultivation is after 15 minutes down at 37 ℃ with radioligand, and directly on Unifilter GF/C glass fibre filter (soaking 30 minutes in 0.1% polymine), filtered sample under vacuum uses 1 * 0 immediately, the washing of 2ml analysis buffer.Use citalopram (10 μ M ultimate density) to measure non-specific uptake.Wrap into the contrast of citalopram as the dose response curve of all experiments.
Measure the rat layer synaptosome to [
3H] picked-up of norepinephrine
With glass/tetrafluoroethylene homogenizer in replenishing the 0.40M sucrose of 1mM nialamide homogenizing from the fresh occipital bone of male Wistar rat (125-225g)-, temporo-the og parietal cortex.With homogenate 1000 * g and 4 ℃ centrifugal 10 minutes down.Discard granular substance, and with supernatant liquor under 40.000 * g centrifugal 20 minutes.In this analysis buffer: 123mM NaCl, 4.82mM KCl, 0.973mM CaCl
2, 1.12mM MgSO
4, 12.66mM Na
2HPO
4, 2.97mM NaH
2PO
4, 0.162mM EDTA, 2g/l glucose and 0, the final granular substance of homogenate in the 2g/l xitix (7,2mg original structure/mL=1mg/140 μ l).O with 95%
2/ 5% CO
2Oxidation buffer liquid 10 minutes.Granular substance is suspended in the analysis buffer of 140 volumes.Mixed structure and test compound are after pre-cultivation in 10 minutes, with 10nM[
3H]-norepinephrine joins 0, in the final volume of 2ml, and cultivates these mixtures 15 minutes down at 37 ℃.After cultivating 15 minutes, directly on Unifilter GF/C glass fibre filter (soaking 30 minutes in 0.1% polymine), filtered sample under vacuum is used the washing of 1 * 0.2mL analysis buffer immediately.Use Talsupram (10 μ M ultimate density) to measure non-specific uptake.Wrap into the contrast of duloxetine as the dose response curve of all experiments.
Measure the rat layer synaptosome to [
3H] picked-up of Dopamine HCL
Tissue preparation: by sacrificed by decapitation male wistar rat (125-250g), dissect out striatum fast, and be placed on ice-cold 0, in the 40M sucrose.This tissue of homogenizing (glass tetrafluoroethylene homogenizer) obtains the P2 fraction by centrifugal (1000g, 10 minutes and 40000g, 20 minutes, 4 ℃) lenitively, it is suspended in the Krebs-Ringer-phosphate buffered saline buffer of 560 volume modifications, among the pH 7.4.
Mixed structure 0,25mg/ hole (140 μ l) (original structure) and analysis suspension.After at room temperature cultivating 5 minutes in advance, add the 3H-Dopamine HCL of 12.5nM, and at room temperature cultivated this mixture 5 minutes.Final volume is 0,2mL.
Stop cultivating by under vacuum, passing Whatman GF/C strainer filtered sample, with 1 * 0, the washing of 2ml damping fluid.Dry this strainer, and add suitable scintillating liquid (OptiphaseSupermix).After storing 2 hours in the dark, measure contamination by liquid scintillation counting(LSC).Non-specific binding and the passive transport measured in the presence of the Benzatropine of 100 μ M by deduction obtain picked-up.In order to measure inhibition, use 60 kinds of (6decades) medicines of containing of ten kinds of concentration to picked-up.
3H-DA=3,4-(ring-2,5,6-
3H) dopamine hydrochloride is from New England Nuclear, specific activity 30-50Ci/mmol.
The full content of following reference is incorporated herein by reference.
Hyttel，Biochem.Pharmacol.1978，
27，1063-1068；
Hyttel，Prog.Neuro-Psychopharmacol.&?bil.Psychiat.1982，
6，277-295；
Hyttel?&?Larsen，Acta?Pharmacol.Tox.1985，
56，suppl.1，146-153。
As shown in table 1, record the activity (IC of the monoamine transporter of compound described in the present invention50) in the scope of 0.1-200nM.
Table 1: the activity of the monoamine transporter of compound
| 5-HTT (IC 50nM) | DAT (IC 50nM) | NAT (IC 50nM) | |
| Formula VI | * | * | * |
| Formula VII | * | * | * |
| Formula VIII | * | * | * |
| Formula IX | * | * | * |
| Formula X | * | * | * |
| Indatraline | * | * | * |
| Sertraline | * | * | * |
*0.1-200nM.
5-HTT serotonin transporter
The DAT DAT
NAT noradrenaline transporter body
Claims (18)
1. the compound or pharmaceutically acceptable salt thereof represented of formula I:
R wherein
1And R
2Be hydrogen, C independently of one another
1-C
8-straight or branched alkyl or C
3-C
8-cycloalkyl; Perhaps R wherein
1And R
2The nitrogen that is connected with them forms azetidine, piperidines, tetramethyleneimine, azepan or morpholine;
R wherein
3Be hydrogen, C independently of one another
1-C
8-straight or branched alkyl, C
1-C
5-alkoxyl group, C
1-C
8-straight or branched Polyfluoroalkyl, halogen, cyano group, hydroxyl, tetrazolium-randomly replaced by methyl or amino; Perhaps two R on adjacent carbons wherein
3Group is combined together to form methylene-dioxy and connects base;
R wherein
4Be hydrogen, C
1-C
8-straight or branched alkyl or C
3-C
8-cycloalkyl;
R wherein
5Hydrogen, halogen C respectively do for oneself
1-C
5-alkoxyl group, C
1-C
8-straight or branched alkyl, C
1-C
8-straight or branched Polyfluoroalkyl, cyano group or hydroxyl;
Wherein m is 1 to 4 integer, comprises end value;
Wherein n is 1 to 4 integer, comprises end value; With
R wherein
6Be hydrogen, C
1-C
8-straight or branched alkyl or phenyl.
2. the compound of claim 1, wherein said compound is a cis-isomeride.
3. the compound of claim 1, wherein said compound is a trans-isomer(ide).
4. according to the compound of the claim 1 of formula II-V, be selected from:
5. according to the compound of formula II, III, IV or the V of claim 4, R wherein
1Be hydrogen.
6. the compound of claim 5, wherein R
2Be methyl.
7. the compound of claim 6, wherein R
4Be hydrogen.
8. the compound of claim 7, wherein R
3Be selected from hydrogen, halogen and methoxyl group.
9. the compound of claim 8, wherein R
3Be hydrogen or halogen.
10. the compound of claim 9, wherein halogen is a fluorine or chlorine.
11. the compound of claim 10, wherein R
5And R
6Be hydrogen.
12. be selected from following compound or pharmaceutically acceptable salt thereof:
13. a pharmaceutical composition, it comprises in the claim 1,2,3,4 and 12 for the treatment of significant quantity each compound and pharmaceutically acceptable carrier.
14. affective disorder among the patient who is used for the treatment of needs, antalgesic, attention deficit be the method for moving obstacle (ADHD), cognitive disorder, substance abuse, smoking cessation and stress urinary incontinence how, it comprises in the claim 1,2,3,4 and 12 of the described patient treatment significant quantity of administration each compound.
15. the method for claim 14, the wherein said affective disorder that will treat is selected from depressed illness and anxiety illness.
16. the method for claim 15, the wherein said depressed illness that will treat are selected from serious depressibility obstacle, melancholia, postpartum depression, spirit depressing, the depression relevant with bipolar disorder, the depression of being correlated with alzheimer's disease, the depression of being correlated with psychosis and the depression relevant with parkinsonism.
17. the method for claim 15, the wherein said anxiety illness that will treat is selected from General Anxiety Disorder, social anxiety's illness, posttraumatic stress disorder, obsession, panic disorder, panic attack, specific phobia disease, social phobia and agoraphobia.
Pain when 18. the method for claim 14, the wherein said antalgesic that will treat are selected from fibromyalgia syndrome (FMS), whole body pain, backache, shoulder pain, headache, pain and every day are movable when waking up.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US84194206P | 2006-08-31 | 2006-08-31 | |
| US60/841,942 | 2006-08-31 | ||
| US60/938,945 | 2007-05-18 |
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| Publication Number | Publication Date |
|---|---|
| CN101472890A true CN101472890A (en) | 2009-07-01 |
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ID=40829511
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2007800224250A Pending CN101472890A (en) | 2006-08-31 | 2007-08-29 | 3- (1H-indol- 3-ydindan-1-ylamine derivatives for the treatment of depression and anxiety |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111302999A (en) * | 2020-03-27 | 2020-06-19 | 江苏师范大学 | 3- (1H-indole-3-yl) -2, 3-dihydro-1H-indene-1-ketone derivative and synthetic method thereof |
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2007
- 2007-08-29 CN CNA2007800224250A patent/CN101472890A/en active Pending
Cited By (2)
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| CN111302999A (en) * | 2020-03-27 | 2020-06-19 | 江苏师范大学 | 3- (1H-indole-3-yl) -2, 3-dihydro-1H-indene-1-ketone derivative and synthetic method thereof |
| CN111302999B (en) * | 2020-03-27 | 2023-01-20 | 江苏师范大学 | 3- (1H-indole-3-yl) -2,3-dihydro-1H-indene-1-ketone derivative and synthetic method thereof |
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