CN1154105A - 4-aryl-1-(indanmethyl, dihydrobenzofuranmethyl or dihydrobenzothiophenemethyl) piperidines, tetrahydropyridines or piperazines - Google Patents

Abstract

4-Aryl-1-(indanmethyl, dihydrobenzofuramethyl or dihydrobenzothiophenemethyl) piperidine, -tetrahydropyridine or -piperazine compounds of general formula (I)wherein one of X and Y is CH2, and the other one is CH2, O or S; Z is N, C, CH or COH; Ar is an optionally substituted aryl group; R1 is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, acyl, thioacyl, alkylsulfonyl, trifluoromethylsulfonyl, arylsulfonyl, a group R9VCO- where V is O or S and R9 is alkyl or aryl, or a group R10R11NCO- or R10R11NCS- wherein R10 and R11 are hydrogen, alkyl or aryl, or R10 and R11 are linked to form a ring; R2 is hydrogen, alkyl, cycloalkyl or cycloalkylalkyl; or R1 and R2 are linked to form a ring; R3-R5 are hydrogen, halogen, alkyl, alkylcarbonyl, phenylcarbonyl, alkoxy, alkylthio, hydroxy, alkylsulfonyl, cyano, trifluoromethyl, cycloalkyl, cycloalkylalkyl or nitro; R6 and R7 are hydrogen or alkyl or they are linked to constitute a 3-7-membered ring; R8 is hydrogen or alkyl; have effects at central serotonergic receptors and are therefore useful in the treatment of certain psychic and neurologic disorders.

Description

4-aryl-1-(indane methyl, Dihydrobenzofuranes methyl or dihydrobenzo thenyl) piperidines ,-tetrahydropyridine or piperazine compounds

Invention field

The present invention relates to a class new, act on 4-aryl-1-(indane methyl, Dihydrobenzofuranes methyl or dihydrobenzo thenyl) piperidines that the maincenter serotonin can (serotonergic) acceptor ,-tetrahydropyridine or piperazine compounds.Therefore these methylamine compounds can be used for treating some spirit and sacred disease.

Background of invention

From prior art, known some amino methyl indane ,-Dihydrobenzofuranes and-the dihydrobenzo thiophene compound.

EP patent 0281261 discloses the 1-amino methyl 2 that has oh group or substituted hydroxy group on 6-position (indane) or 5-position (cumarone, thionaphthene), 3-indane, 3-amino methyl cumarone and 3-amino methyl benzothiophene derivative.These compound exhibits central dopamine agonist activities, the special demonstration acts on presynaptic DA receptor.

The US patent No. 4,500,543 discloseder 1-amino methyl phtalane compound exhibits adrenergic effect and hypertension and heart rate fade performances.Described patent generally comprises at 5-, has substituent compound on 6-and/or the 7-position.

EP0325963A1 also discloses a class 1-amino methyl 2 except disclosing other compounds, 3-indane compound, and in this compounds, the amino methyl group can constitute the 1-pyrroles's methyl group that is replaced by thienyl or phenyl.The compound of claim is α 2 antagonists, is used for the treatment of depression, metabolic disturbance, glaucoma, migraine and hypertension.

In addition, disclosed class 4-benzofuryl of EP0490772A1 or 4-benzodioxan base-2,3-indane-1-methylpiperazine compound is 5-HT _1APart.

EP0428437 relates generally to very widely that a class comprises some 3-[1-[(2,3-indane-1-yl) methyl]-1,1 of 2-benzoisoxazole, 2-benzisoxazole compounds.Yet, this examples for compounds is only arranged, and does not have any data in this example.Described compound exhibits Dopamine HCL and thrombotonin antagonistic activity.

The US patent No. 3886168 relates to the 1-[(2 with antihypertensive active, 3-indane-1-yl) methyl] piperidine compounds.

The various effects of known ligand compound about different serotonin receptor hypotypes.About 5-HT _2AAcceptor is called 5-HT to it at first ₂Acceptor, reported following effect:

5-HT _2AAntagonist ritanserin (Meert, T.F.; Janssen, P.A.J.Drug.Dev.Res.1989,18,119.) shown that by improving sleep quality be effective by inference on treatment anxiety and dysthymia disorders.In addition, shown that the active 5-HT2A antagonist of selection maincenter is effective for the mental patient with the extrapyramidal side effect that the neuroplegic treatment causes for negative symptoms of schizophrenia and minimizing.(Gelders，Y.G.，BritishJ.Psychiatry，1989，155(suppl.5)，33)。At last, select 5-HT _2AAntagonist should be effectively to migrainous prevention and treatment because, known 5-HT is relevant with migraine.Be to have some to get in touch between 5-HT and the migraine, and they have proposed mechanism (the Scrip Report of some relevant 5-HT; " Migraine-Current trends inresearch and treatment "; PJB Publication Ltd.; May1991).

Serotonin 5-HT _2AAntagonist, MDL100,907 (Sorensen, S.M. wait the people, J.Pharmacol.Exp.Ther.1993,266,684-691) and some compounds in 1-Phenylindole (WO93/12790) and 3-Phenylindole derivative (WO93/14758) series be presented at antipsychotic activity in the animal model, and show the unfavourable condition of the pyramidal tract side effect (EPS) outward that does not cause.

The 5-HT that clinical study is known _1APartial agonist such as buspirone, 8-[4-[4-(2-pyrimidyl)-1-piperazinyl] butyl]-8-azaspiro [4,5] certain herbaceous plants with big flowers alkane-7, the 9-diketone, gepirone hydrochloride, 4,4-dimethyl-1-[4-[4-(2-pyrimidyl)-1-piperazinyl] butyl]-2, the 6-dioxopiperidine, and ipsapirone, 2-[4-[4-(2-pyrimidyl)-1-piperazinyl] butyl]-1,2-[4-morpholinodithio-3 (2H)-ketone-1, the 1-dioxide has shown 5-HT _1APartial agonist is used for the treatment of anxiety disorder, as extensive anxiety disorder, Phobias and obsessional idea and behavior disease (Glitz, D.A., Pohl, R., Drugs1991,41,11).Preclinical study point out comprehensive agonist treatment in the above-mentioned symptom relevant also be with anxiety useful (Schipper, Human Psychopharmacol., 1991,6, S53).

Also there is clinical and preclinical evidence to confirm 5-HT _1APartial agonist is in treatment dysthymia disorders, impulse control disorder and alcohol abuse (van Hest, Psychopharmacol., 1992,107,474; Schipper waits the people, Human Psychopharmacol., 1991,6, S53; People such as Cervo, Eur.J.Pharm., 1988,158,53; Glitz and Poh, Dougs1991,41,11; People such as Grof, Int.Clin.Psychopharmacol.1993,8,167-172; People such as Ansseau, Human Psychopharmacol.1993,8, the 279-283) beneficial effect of aspect.

5-HT _1AAgonist and partial agonist suppress male mice and separate inductive and attack, point out these compounds be used for the treatment of attack disease (people such as Sanchez, Psychopharmacol.1993,110,53-59).

In addition, reported 5-HT _1APart shows antipsychotic effect (Wadenberg and Ahlenius, J.Neural.Transm., 1991,83,43 to animal model; Ahlenius, Pharmacol.﹠amp; Toxicol., 1989,64,3; People such as Lowe, J.Med.Chem., 1991,34,1860; People such as New, J.Med.Chem., 1989,32,1147; With people such as Martin, J.Med.Chem., 1989,32,1052).

Nearest research also shows 5-HT _1AIt is important (Hicks, Life Science 1990,47,1609, people Pharmacol.Biochem.﹠amp such as Wadenberg that acceptor can be regulated the cataleptic serotonin of haloperidol inductive; Behav.1994,47,509-513), and 5-HT is proposed _1AAgonist is used for the treatment of the EPS that is caused by conventional antipsychotic drug such as haloperidol.

5-HT _1AAgonist has shown neuroprotective character to rodent focus model and ball cerebral ischaemia, and therefore can be used for treating ischemic disorders (Prehn, Eur.J.Pharm.1991,203,213).

The pharmacological research of by the agency of shows 5-HT _1AAntagonist can be used for treating senile dementia (people such as Bowen, Trends Neur.Sci.1992,15,84).

Animal model and clinical trial have all shown 5-HT _1AAgonist is brought into play antihypertensive function (Saxena and Villalon, Trends Pharm.Sci.1990,11,95 by neuromechanism; People such as Gillis, J.Pharm.Exp.Ther.1989,248,851).Therefore, 5-HT _1APart can be of value to the treatment cardiovascular disorder.

The 5-HT uptake inhibitor is well-known thymoleptic.

Because 5-HT _1AAnd 5-HT _2AReceptors ligand compounds and 5-HT uptake inhibitor are the different animals model of indication anxiety and anti-attack effect (people such as Perregaard, Recent Developments in Anxiolytics.Current Opinion in TherapeuticPatents 1993,1,101-128) and/or in the model of other mental disorder effect of indication has different activity, therefore, the complex state with pharmacological agent anxiety disorder, dysthymia disorders or other mental disorder with bonded serotonin energy effect also can be a high benefit.

Summary of the invention

Have now found that some novel 4-aryl-1-(indane methyl, Dihydrobenzofuranes methyl or dihydrobenzo thenyl) piperidines ,-tetrahydropyridine or piperazine compounds and maincenter serotonin can acceptors, particularly with 5-HT _1AAnd/or 5-HT _2AAcceptor interacts effectively.

The present invention relates to formula I compound and medicinal acid addition salt thereof:

Wherein one of X and Y are CH ₂Be selected from CH with another ₂, O or S;

Represent optional key from the dotted line that Z sends; When it did not represent key, Z represented N, CH or COH; Z represents C when it represents key;

Ar is a phenyl; the 2-thienyl; the 3-thienyl; the 2-furyl; the 3-furyl; the 2-pyrimidyl; the 1-indyl; the 2-indyl; the 3-indyl; 1-indol-2-one base; 3-indol-2-one base; 2-or 3-benzofuryl; 2-or 3-benzothienyl; 1-naphthyl or 2-naphthyl, each group is optional by halogen; low alkyl group; lower alkoxy; lower alkylthio; hydroxyl; the low alkyl group alkylsulfonyl; cyano group; trifluoromethyl; trifluoromethyl sulfonyl oxygen base; cycloalkyl; cycloalkyl low-grade alkyl; nitro; amino; low-grade alkyl amino; two elementary alkyl amido; amido or C _1-2Alkylene dioxo base replaces;

R ¹Be hydrogen, low alkyl group, low-grade alkenyl, low-grade alkynyl, cycloalkanes (alkene) base, the basic lower alkyl of cycloalkanes (alkene) (alkene/alkynes) base, aryl, aromatic yl elementary alkyl, acyl group, sulfo-acyl group, low alkyl group alkylsulfonyl, trifluoromethyl sulfonyl, aryl sulfonyl,

R ¹It is radicals R ⁹VCO-, wherein V is O or S and R ⁹Be low alkyl group, cycloalkyl, cycloalkyl low-grade alkyl or aryl, or

R ¹It is radicals R ¹⁰R ¹¹NCO-or R ¹⁰R ¹¹NCS-, wherein R ¹⁰And R ¹¹Be hydrogen, low alkyl group, cycloalkyl, cycloalkyl low-grade alkyl or aryl or R independently ¹⁰And R ¹¹Form pyrrolidyl, piperidyl or perhydro azatropylidene base with N atom with their bondings;

R ²Be hydrogen, low alkyl group, cycloalkyl or cycloalkyl low-grade alkyl;

Or R ¹And R ²Form group with N atom with their bondings: Wherein Q is C=O, C=S or CH ₂T is NH, S, O or CH ₂With m be 1-4;

R ³-R ⁵Be phenylcarbonyl group, lower alkoxy, lower alkylthio, hydroxyl, low alkyl group alkylsulfonyl, cyano group, trifluoromethyl, cycloalkyl, cycloalkyl low-grade alkyl or the nitro of hydrogen, halogen, low alkyl group, lower alkylcarbonyl, phenylcarbonyl group, halogen replacement independently;

R ⁶And R ⁷Each naturally hydrogen or low alkyl group or they together bonding form 3-7 unit carbocyclic ring;

R ⁸It is hydrogen or alkyl;

Any alkyl, cycloalkyl or the cycloalkylalkyl that exist can be chosen wantonly by one or two oh group and replace, and hydroxyl can be chosen wantonly by aliphatic series or aromatic carboxylic acid's esterification; Can choose wantonly by halogen, low alkyl group, lower alkoxy, lower alkylthio, hydroxyl, low alkyl group alkylsulfonyl, cyano group, trifluoromethyl, trifluoromethyl sulfonyl oxygen base, cycloalkyl, cycloalkyl low-grade alkyl or nitro replacement with any aryl substituent that exists.

Found that The compounds of this invention shows 5-HT _1AAcceptor and/or 5-HT _2AThe strong affinity of acceptor.Except that to these receptor subtype effects, some compound of the present invention also shows 5-HT picked-up restraining effect.

Therefore, The compounds of this invention is used for the treatment of the positive and negative symptoms of schizophrenia, other psychosis, anxiety disorder, side effect, ischemic disease symptom, migraine, senile dementia and the cardiovascular disorder that causes as extensive anxiety disorder, Phobias and obsessional idea and behavior disease, depression, impulse control disorder and alcohol abuse, attack disease, by conventional antipsychotic drug and be used for improvement and sleep.

The present invention provides the pharmaceutical composition that contains at least a I compound of formula as mentioned above for the treatment of significant quantity or its medicinal acid addition salt or its prodrug and one or more pharmaceutical carriers or thinner on the other hand.

The present invention provides formula I compound or acid salt or the purposes of its prodrug aspect the medicament of the above-mentioned disease of preparation treatment as mentioned above on the other hand.

Detailed Description Of The Invention

Compound of Formula I exists with its optical isomer, and this optical isomer is also included among the present invention.

The prodrug of compound of Formula I is also included among the present invention.

The term cycloalkyl represents to have the carbocyclic ring of 3-8 carbon atom, or dicyclo or three ring carbocyclic rings, as adamantyl.

Term lower alkyl refers to have the side chain or the non-branched-chain alkyl group of 1-6 carbon atom, as methyl, ethyl, 1-propyl group, 2-propyl group, 1-butyl, 2-butyl, 2-methyl-2-propyl group and 2-methyl isophthalic acid-propyl group.Term lower alkoxy, lower alkylthio, low alkyl group alkylsulfonyl, low-grade alkyl amino, lower alkylcarbonyl or the like represent that wherein alkyl is the group of low alkyl group as defined above.Equally, low-grade alkenyl and alkynyl represent to have the group of 2-6 carbon atom respectively.Preferred group is to have the group that is no more than four carbon atom.

Term aryl refers to list or bicyclic carbocyclic or heteroaromatic group, as phenyl, indyl, thienyl, pyrimidyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, benzofuryl, benzothienyl, pyridyl, naphthyl and furyl, particularly phenyl, pyrimidyl, indyl and thienyl.

Halogen refers to fluorine, chlorine, bromine or iodine.

Terminology used here acyl group nail acyl group, the basic carbonyl of lower alkyl (alkene/alkynes), aryl carbonyl, the basic carbonyl of aryl lower alkyl (alkene/alkynes), naphthene base carbonyl or the basic carbonyl group of cycloalkyl lower alkyl (alkene/alkynes).

Term sulfo-acyl group is the corresponding carboxyl groups that wherein replaces carbonyl with thiocarbonyl.

Alkane (alkene/alkynes) base refers to it can is the group of alkyl, alkenyl or alkynyl.

In formula I, preferred X is CH ₂Or S is CH with preferred Y ₂More preferably they two all be CH ₂

Preferred R ¹Be acyl group, low alkyl group, lower alkoxy, radicals R ¹⁰R ¹¹NCO-or R ¹⁰R ¹¹NCS-is R wherein ¹⁰Be hydrogen, low alkyl group, cycloalkyl, cycloalkyl low-grade alkyl or aryl and R ¹¹Be hydrogen or low alkyl group or R ¹⁰And R ¹¹Form pyrrolidyl, piperidyl or perhydro azatropylidene group with N atom with their bondings.R most preferably ¹Be formyl radical, ethanoyl, methylamino carbonyl, methylamino thiocarbonyl, dimethylamino carbonyl, dimethylamino thiocarbonyl, methyl sulphonyl, aminocarboxyl, cyclopropyl carbonyl, methyl, pyrrolidyl carbonyl or 4-fluorophenyl aminocarboxyl.Preferred R ²Be hydrogen or low alkyl group, most preferably hydrogen or methyl, or R ¹And R ²Be bonded together and form the 5-7 unsubstituted lactam nucleus of unit or pyrrolidyl, pyridyl or perhydro azatropylidene.

Preferred R ³-R ⁵Be hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl or ethanoyl and preferred R ⁷-R ⁸All be hydrogen.

At last, preferred Ar is a phenyl, 3-indyl, 1-indyl, or pyrimidyl or the phenyl, 3-indyl, 1-indyl or the pyrimidyl that replace with halogen.

Preferably-the group compound is R ¹Be ethanoyl and R ²Be those compounds of hydrogen and particularly wherein Ar be with the halogen particularly indyl that replaces of chlorine, those compounds of phenyl.If Ar is the 3-indyl, if be phenyl preferably, preferably 4 replacements in 6 replacements and it.

The preferred another kind of compound of the present invention is R ¹Be R ¹⁰R ¹¹NCO-or R ¹⁰R ¹¹NCS-, wherein R ¹⁰Be hydrogen, low alkyl group, cycloalkyl, cycloalkyl low-grade alkyl or acyl group and R ¹¹Be hydrogen or low alkyl group and R ²Be those compounds of hydrogen.

Further a preferred compounds is R ¹Be hydrogen, low alkyl group or low alkyl group alkylsulfonyl, particularly methyl or methyl sulphonyl and R ²Be hydrogen or low alkyl group, particularly methyl, or R ¹And R ²Be bonded together and form those compounds of pyrrolidone ring or pyrrolidine ring.

Preferred compound is:

1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl)-4-(4-fluorophenyl) piperidines,

(+)-1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl)-4-(4-fluorophenyl) piperidines,

(-)-1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl)-4-(4-fluorophenyl) piperidines,

1-(6-acetylaminohydroxyphenylarsonic acid 5-fluoro-2,3-indane-1-ylmethyl)-4-(4-fluorophenyl) piperidines,

1-(6-acetylaminohydroxyphenylarsonic acid 4-fluoro-2,3-indane-1-ylmethyl)-4-(4-fluorophenyl) piperidines,

1-(6-acetylaminohydroxyphenylarsonic acid 4-bromo-2,3-indane-1-ylmethyl)-4-(4-fluorophenyl) piperidines,

1-(6-acetylaminohydroxyphenylarsonic acid 4-nitro-2,3-indane-1-ylmethyl)-4-(4-fluorophenyl) piperidines,

1-(6-acetylaminohydroxyphenylarsonic acid 4-cyano group-2,3-indane-1-ylmethyl)-4-(4-fluorophenyl) piperidines,

1-(6-acetylaminohydroxyphenylarsonic acid 5-chloro-2,3-indane-1-ylmethyl)-4-(4-fluorophenyl) piperidines,

1-(6-acetylaminohydroxyphenylarsonic acid 5-bromo-2,3-indane-1-ylmethyl)-4-(4-fluorophenyl) piperidines,

1-(6-acetylaminohydroxyphenylarsonic acid 5-cyano group-2,3-indane-1-ylmethyl)-4-(4-fluorophenyl) piperidines,

1-(6-acetylaminohydroxyphenylarsonic acid 7-chloro-2,3-indane-1-ylmethyl)-4-(4-fluorophenyl) piperidines,

1-(6-acetylaminohydroxyphenylarsonic acid 7-fluoro-2,3-indane-1-ylmethyl)-4-(4-fluorophenyl) piperidines,

1-(5-acetyl-6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl)-4-(4-fluorophenyl) piperidines,

1-(6-acetylaminohydroxyphenylarsonic acid 1-methyl-2,3-indane-1-ylmethyl)-4-(4-fluorophenyl) piperidines,

1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl)-4-(3-fluorophenyl) piperidines,

1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl)-4-(2-fluorophenyl) piperidines,

1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl)-4-(4-aminomethyl phenyl) piperidines,

1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl)-4-(4-dimethylaminophenyl) piperidines,

1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl)-4-(4-aminophenyl) piperidines,

1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl)-4-(3-trifluoromethyl) piperidines,

1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl)-4-(4-fluorophenyl) piperazine,

1-(5-acetylaminohydroxyphenylarsonic acid 2,3-dihydro thionaphthene-3-ylmethyl)-4-(4-fluorophenyl) piperidines,

1-(6-acetylaminohydroxyphenylarsonic acid 1,3-dihydro isobenzofuran-1-ylmethyl)-4-(4-fluorophenyl) piperidines,

1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl)-4-(4-chloro-phenyl-) piperazine,

1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl)-4-(3-chloro-phenyl-) piperazine,

1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl)-4-(2-chloro-phenyl-) piperazine,

1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl)-4-(4-trifluoromethyl sulfonyl oxygen base phenyl) piperazine,

1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl)-4-(3, the 4-dichlorophenyl) piperazine,

1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl)-4-(3, the 4-dichlorophenyl) piperidines,

1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl)-4-(2-p-methoxy-phenyl) piperazine,

1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl)-4-(4-fluorophenyl)-1,2,3, the 6-tetrahydropyridine,

1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl)-4-(4-chloro-phenyl-)-1,2,3, the 6-tetrahydropyridine,

1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl)-4-(2-pyrimidyl) piperidines,

1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl)-4-(2-pyrimidyl) piperazine,

1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl)-4-(2-pyridyl) piperazine,

1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl)-4-(3-thienyl) piperidines,

1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl)-4-(2-thienyl) piperidines,

1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl)-4-(3-thienyl) piperazine,

1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl)-4-(1-naphthyl) piperidines,

1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl)-4-(2-naphthyl) piperidines,

1-(6-butyrylamino-2,3-indane-1-ylmethyl)-4-(4-fluorophenyl) piperidines,

1-(6-formamido group-2,3-indane-1-ylmethyl)-4-(4-fluorophenyl) piperidines,

1-(6-formamido group-2,3-indane-1-ylmethyl)-4-(4-fluorophenyl) piperazine,

4-(4-fluorophenyl)-1-(6-methyl sulphonyl amino-2,3-indane-1-ylmethyl) piperidines,

1-(6-cyclopropyl carbonyl amino-2,3-indane-1-ylmethyl)-4-(4-fluorophenyl) piperidines,

1-(6-cyclopentylcarbonyl amino-2,3-indane-1-ylmethyl)-4-(4-fluorophenyl) piperidines,

4-(4-fluorophenyl)-1-(6-methylamino carbonylamino-2,3-indane-1-ylmethyl) piperidines,

1-[6-(4-fluorophenyl) amino carbonyl amino-2,3-indane-1-ylmethyl)-4-(4-fluorophenyl) piperidines,

4-(4-fluorophenyl)-1-(6-methylamino thio-carbonyl-amino-2,3-indane-1-ylmethyl) piperidines,

1-(6-dimethylamino carbonylamino-2,3-indane-1-ylmethyl)-4-(4-fluorophenyl) piperidines,

1-(6-dimethylamino thio-carbonyl-amino-2,3-indane-1-ylmethyl)-4-(4-fluorophenyl) piperidines,

4-(4-fluorophenyl)-1-[6-(1-pyrrolidyl) carbonylamino-2,3-indane-1-ylmethyl] piperidines,

1-(6-amino carbonyl amino-2,3-indane-1-ylmethyl)-4-(4-fluorophenyl) piperidines,

1-(6-ethoxy carbonyl amino-2,3-indane-1-ylmethyl)-4-(4-fluorophenyl) piperidines,

1-[6-(N, N-dimethylamino)-2,3-indane-1-ylmethyl]-4-(4-fluorophenyl) piperidines,

3-[1-(5-acetylaminohydroxyphenylarsonic acid 2,3-dihydro thionaphthene-3-ylmethyl) piperidin-4-yl]-5-ammonia-1H-indoles,

3-[1-(5-acetylaminohydroxyphenylarsonic acid 2,3-dihydro thionaphthene-3-ylmethyl)-1,2,3,6 tetrahydropyridines-4-yl]-5-chloro-1H-indoles,

3-[1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl) piperidin-4-yl]-5-fluoro-1H-indoles,

3-[1-(6-acetylaminohydroxyphenylarsonic acid 2,3-dihydro thionaphthene-3-ylmethyl)-1,2,3,6-tetrahydropyridine-4-yl]-5-fluoro-1H-indoles,

3-[1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl)-1,2,3,6-tetrahydropyridine-4-yl]-6-chloro-1H-indoles,

3-[1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl) piperidin-4-yl]-6-chloro-1H-indoles,

3-[1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl) piperidin-4-yl]-6-chloro-1-Methyl-1H-indole,

1-[1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl) piperidin-4-yl]-6-chloro-1H-indoles,

1-[1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl) piperidin-4-yl]-5-chloro-1H-indoles,

3-[1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl)-1,2,3,6-tetrahydropyridine-4-yl]-5-chloro-1H-indoles,

4-(4-fluorophenyl)-1-[6-(1-pyrrolidin-2-one base)-2,3-indane-1-ylmethyl] piperidines,

4-(4-fluorophenyl)-1-[6-(1-piperidines-2-ketone group)-2,3-indane-1-ylmethyl] piperidines,

1-[6-(4-fluorophenyl amino)-2,3-indane-1-ylmethyl)-4-(4-fluorophenyl) piperidines,

3-[1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl) piperidin-4-yl]-the 6-chloro thiophene,

3-[1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl)-1,2,3,6-tetrahydropyridine-4-yl]-the 6-chloro thiophene,

3-[1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl) piperidin-4-yl]-the 5-chloro thiophene,

2-[1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl) piperidin-4-yl]-the 6-chloro thiophene,

3-[1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl) piperidin-4-yl]-6-chlorobenzene and furans,

3-[1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl) piperidin-4-yl]-6-chloro-1H-indol-2-one,

3-[1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl) piperidin-4-yl]-6-chloro-1-Methyl-1H-indole-2-ketone,

3-[1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl)-1,2,3,6-tetrahydropyridine-4-yl]-6-chloro-1-Methyl-1H-indole-2-ketone,

2-[1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl) piperidin-4-yl]-6-chloro-1H-indoles,

1-[1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl) piperidin-4-yl]-5-chloro-1H-indol-2-one,

3-[1-(6-methylamino carbonylamino-2,3-indane-1-ylmethyl) piperidin-4-yl]-5-chloro-1H-indolone,

3-[1-(6-methylamino carbonylamino-2,3-indane-1-ylmethyl)-1,2,3,6-tetrahydropyridine-4-yl]-6-chloro-1H-indoles,

1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl)-4-(4-bromophenyl) piperidines,

1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl)-4-hydroxyl-4-(4-chloro-phenyl-) piperidines,

1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl)-4-(3-trifluoromethyl-4-chloro-phenyl-) piperazine,

1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl)-4-(2-chloro-3-thienyl) piperidines,

1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl)-4-(4-chloro-2-thienyl) piperidines,

1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl)-4-(3, the 4-methylenedioxyphenyl) piperidines,

1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl)-4-(3, the 4-methylenedioxyphenyl) piperazine,

1-(6-methylamino carbonylamino-2,3-indane-1-ylmethyl)-4-(3, the 4-methylenedioxyphenyl) piperazine,

1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl)-4-hydroxyl-4-(3-trifluoromethyl-4-chloro-phenyl-) piperidines,

1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl)-4-acetoxyl group-4-(3-trifluoromethyl-4-chloro-phenyl-) piperidines,

5-chloro-1-[1-(6-methylamino carbonylamino-2,3-indane-1-ylmethyl) piperidin-4-yl]-the 1H-indoles.

The pharmaceutical salts of the formula I compound that acid salt right and wrong toxicity acid of the present invention forms.The example of these organic salts is and toxilic acid, fumaric acid, M-nitro benzoic acid, xitix, two hydrogen naphthoic acid, succsinic acid, oxalic acid, dimethylene Whitfield's ointment, methylsulphonic acid, ethylene disulfonic acid, acetic acid, propionic acid, tartrate, Whitfield's ointment, citric acid, glyconic acid, lactic acid, oxysuccinic acid, amygdalic acid, styracin, citraconic acid, aspartic acid, stearic acid, palmitinic acid, methylene-succinic acid, oxyacetic acid, the amino M-nitro benzoic acid of p-, L-glutamic acid, Phenylsulfonic acid and theophylline formic acid, also has 8-halo theophylline, for example the salt of 8-bromine theophylline formation.The example of inorganic salt is the salt that forms with hydrochloric acid, Hydrogen bromide, sulfuric acid, thionamic acid, phosphoric acid and nitric acid.

The present invention or pharmaceutical composition prepared in accordance with the present invention can be by any suitable way administrations, and be for example oral with tablet, capsule, powder, syrup or the like form, or with injection liquid form administered parenterally.Can prepare said composition with method well-known in the art, also can use this area any pharmaceutical carrier, thinner, vehicle or other auxiliary material commonly used.

The compounds of this invention is usually to close the unit dosage form administration of the about 0.01-100mg of described compound.

Whole day dosage is normally at about 0.05-500mg scope, the most preferably from about active compound of the present invention of 0.1-50mg.

In addition, the present invention relates to prepare new formula (I) 4-aryl-1-I amino (indane, Dihydrobenzofuranes or dihydrobenzo thiophene) methyl] piperidines ,-method of tetrahydropyridine or diethylenediamine compound, comprising:

A) R wherein ²-R ⁸, X, Y, Z, the definition of Ar and dotted line Formula Il aminoderivative as above:

With formula R ^{1 '}-hal and R ^{1 '}-OCOR reagent react, hal is a halogen in the formula, R is alkyl, aryl or alkoxyl group and R ^{1 '}Be acyl group, sulfo-acyl group, radicals R ⁹VCO-or radicals R ¹⁰R ¹¹NCO-or R ¹⁰R ¹¹NCS-, wherein R ⁹, V, R ¹⁰And R ¹¹Definition is R as above ¹⁰, R ¹¹All cannot be hydrogen, or with formula R ¹⁰-N=C=O or R ¹⁰Low alkyl group alkylsulfonyl halogenide, trifluoromethyl sulfonyl halogenide or isocyanate or isothiocyanic acid reactant salt, the wherein R of-N=C=S ¹⁰Definition as above;

B) in order to prepare wherein R ^{1 '}Be the formula I compound of rudimentary (alkene/alkynes) alkyl, cycloalkanes (alkene) base, cycloalkanes (alkene) base rudimentary (alkene/alkynes) alkyl or aryl low alkyl group, with alkylating reagent such as alkyl halide R ¹-hal, methanesulfonates R ^{1 "}OSO ₂CH ₃, tosylate R ^{1 "}C ₆H ₄-CH ₃Or have the similar alkylated formula II aminoderivative of suitable leaving group, and wherein, R ¹Be low alkyl group, low-grade alkenyl, low-grade alkynyl, cycloalkanes (alkene) base, cycloalkanes (alkene) base rudimentary (alkene/alkynes) alkyl or aryl low alkyl group;

C) the two keys of tetrahydropyridine in the reduction Formula Il I derivative: R wherein ¹-R ⁸, X, Y and Ar definition as above; Or

D) aryl piperazines, Arylpiperidine or the aryl tetrahydrochysene piperidines of usefulness formula IV alkyl derivative alkylation formula V:

R wherein ¹-R ⁸, X, Y, Ar and dotted line definition as above and W be leaving group, as halogen, methanesulfonates, tosylate; Or

E) in order to form wherein substituent R ¹And R ²Form the formula I compound of ring together, make formula V derivative ring closure:

R wherein ³-R ⁸, X, Y, Z, Ar, m, Q, T and dotted line definition as above and W be leaving group, as halogen, methanesulfonates, tosylate;

F) in order to obtain wherein R ¹Be the formula I compound of rudimentary (alkene/alkynes) alkyl, cycloalkanes (alkene) base, cycloalkanes (alkene) basic lower alkyl (alkene/alkynes) base or aromatic yl elementary alkyl, the carbonyl group of the amide derivative of reduction following formula VII: R wherein ²-R ⁸, X, Y, Z, Ar and dotted line definition as above, and R ¹ Be such group, that is, and R ¹ CH ₂Form as R ¹Rudimentary (alkene/alkynes) alkyl that definition comprises, cycloalkanes (alkene) base, cycloalkanes (alkene) basic lower alkyl (alkene/alkynes) base or aromatic yl elementary alkyl; Or

G) by using the active reaction thing, as halogen, halogenating agent, sulphonating agent, nitrating agent or generation bonium ion (RCO ⁺, R ⁺) promoting agent, wherein R is alkyl alkynyl, cycloalkyl aryl or cycloalkanes (alkene/alkynes) base, makes following formula VIII compound reaction introduce substituent R ³, R ⁴Or R ⁵: R wherein ^{3 '}-R ⁵One of be that hydrogen and other two are R as defined above accordingly ³, R ⁴Or R ⁵And R ¹, R ², R ⁶-R ⁸, X, Y, Z, Ar and dotted line definition as above; Or

H) the two keys in the reduction following formula I X compound:

R wherein ¹-R ⁸, X, Y, Z and Ar definition as above, one of two dotted lines show two keys; Or

I) the acyl aminocarbonyl in the reduction following formula X compound: R wherein ¹-R ⁵, R ⁸, X, Y, Z, Ar and dotted line definition as above.

Subsequently as free alkali or its medicinal acid addition salt separate type I compound.

Method a) in, when with active carboxylic acid muriate, isocyanic ester or different thiocyanide, reaction be (for example, be lower than room temperature) at low temperatures, inert solvent, as carrying out in acetone, methylene dichloride, tetrahydrofuran (THF) or the glycol dimethyl ether.By in formic acid with manthanoate reaction, or by with prepare the reaction of blended formic anhydride on the spot and prepare formylated amine from corresponding amine.Common temperature of reaction is between the boiling point of 0 ℃ and formyl precursor compound.

According to method b) and d), alkylated reaction, in suitable solvent such as acetone, methyl iso-butyl ketone (MIBK), tetrahydrofuran (THF), diox, ethanol or 2-propyl alcohol, is undertaken by backflow under the existence as triethylamine or salt of wormwood normally at alkali.

According to method c) and h), the reduction of its pair key normally low pressure (＜in the Pa Er device, undertaken under 3atm.) by catalytic hydrogenation, or inert solvent as tetrahydrofuran (THF), diox or diethyl ether in by using reductive agent such as diborane to carry out.

According to method f) and i), its reduction normally at room temperature or under the high slightly temperature, in inert solvent such as tetrahydrofuran (THF), diox or diethyl ether by using LiAlH ₄, AlH ₃Or diborane carries out.

According to method g), its halogenating reaction normally catalyzer as Fe ion or mineral acid in the presence of by carrying out with chlorine, bromine or N-chloro-succinimide, N-bromine succinimide or another kind of halogen precursor molecule.

The unsubstituted 4-aryl piperazines of the 1-of formula V (Z=N) or commercially available, or can be according to by people J.Med.Chem.1989 such as Martin, 32, the method that 1052-1056 describes, by in high boiling solvent such as chlorobenzene, N '-two (2-Dichloroethyl) amine is synthetic to be obtained from corresponding aniline and N ' in general backflow 2-3 days.

The 4-Arylpiperidine (Z=CH) of formula V or commercially available, or as USPat.No.2,891,066; People J.Amer.Chem.Soc.1950 such as McElvain, 72,3134; People Chem.Ber.1887 such as Bally, preparation described in 20,2590.The corresponding 4-aryl-1,2,3 of formula V, 6-tetrahydropyridine (Z=C) passes through the 4-piperidone with the addition N-protected of suitable substituted aryl lithium or magnesium halide, and acid catalysis is eliminated the water preparation subsequently.Remove N-protected base (carbamate, benzyl, alkylsulfonyl, ethanoyl) with ordinary method at last.

In embodiments, the synthetic of 3-(4-piperidyl)-1H-indoles and 3-(1,2,3,6-tetrahydrochysene piperidin-4-yl)-1H-indoles described.

According to crucial intermediate such as 1-indane carboxylic acid (the V.Asham and W.H.Linnell of well-known method preparation, J.Chem.Soc.1954,4691-4693, people Helv.Chim.Acta 1982 such as Hansen, 33,325-343) with 5-nitro-3-thionaphthene carboxylic acid (patent application No.88-301073, CA110 (9): 75302y (1988) classifies this paper reference as).

Embodiment

Further specify the present invention by the following example, but the present invention is not limited to this.

In all embodiment, measure fusing point with Buchi SMP-20 instrument, fusing point is modified value not.Bruker AC250 spectrograph record with 250Mhz ¹H NMR spectrum.Deuteriochloroform (99.8%D) or dimethyl sulfoxide (DMSO) (99.9%) are as solvent.TMS is used as interior mark.Express chemical displacement value with the ppm-value.Following abbreviation is used as NMR multiplicity signal: s=is unimodal, d=doublet, t=triplet, q=quartet, qui=quintet, h=septet, the two doublets of dd=, the two triplets of dt=, the two quartets of dq=, the triple triplets of tt=, m=multiplet.

Embodiment 1

6-nitro-2,3-indane-1-carboxylic acid, 1a

Under-10 ℃, in the methylene dichloride (50ml), mix according to people Helv.Chim.Acta 1982 such as Hansen with the vitriol oil (300ml), 33,325-343 method preparation 2, the solution of 3-indane-1-carboxylic acid (30g) is being lower than-10 ℃, under the vigorous stirring, drip the mixture of 100% nitric acid (11.4g) and the vitriol oil (96ml), after stirring one hour under 10 ℃, mixture is poured in the ice.With ethyl acetate (2 * 300ml) extractions, dry (anhydrous MgSO ₄), the final evaporation organic solvent obtains the 42g title compound.MP：126-130℃。

According to EP patent application No.88-301073, CA110 (9): 75302y (1988), J.Amer.Chem.Soc.1948,70,1955, and the method for J.Chem.Soc. (c) 1967,1899, prepare 5-nitro-3-thionaphthene carboxylic acid by corresponding 3-cyano group benzothiophene derivative from 3-bromo-5-oil of mirbane thiophthene.

Embodiment 2 (method i)

1-(6-amino-2,3-indane-1-ylmethyl)-4-(4-fluorophenyl) piperidines, 2a

(DMF 1ml) is added to 6-nitro-2, and 3-indane carboxylic acid is in methylene dichloride (125ml) solution of 1a (13g) and thionyl chloride (18ml) with dimethyl formamide.Heated mixt adds toluene to refluxing 4 hours, and vacuum boils off volatile matter, then, the carboxylic acid chloride that obtains is dissolved in the methylene dichloride (100ml), and under 0-5 ℃, is added drop-wise in methylene dichloride (100ml) solution of 4-(4-fluorophenyl) piperidines (19.5g) and triethylamine (7ml).Under the room temperature, restir mixture 1.5 hours adds entry, separates organic phase, uses the salt water washing, dry (anhydrous MgSO ₄), filter, and the vacuum steaming obtains crude product 6-nitro-2,3-indane-1-carboxamide derivative oily matter (35g) except that methylene dichloride.Obtain the pure methane amide oily matter of 12g by silica gel column chromatography (with 1: 1 ethyl acetate and heptane mixture wash-out) purifying.This all oil is dissolved in 90% ethanol (350ml) of backflow, in 10 minutes Fe powder (10g) and the dense HCl aqueous solution (1ml) short run ground is added continuously, the mixture of generation refluxed 2.5 hours.Filtered while hot inorganic salt, and vacuum-evaporation ethanol add NH ₄The OH dilute aqueous soln is to PH＞9, and (2 * 200ml) also handle organic phase with above-mentioned method, obtain the 6-amino-2 of 8g, 3-indane-1-carboxylic acid amides, Mp:144-145 ℃ with ethyl acetate extraction.All carboxylic acid amides drips of solution among the THF (125ml) are added to LiAlH ₄In anhydrous tetrahydro furan (2.7g) (THF125ml) suspension, the gentle reflux mixture is after 2 hours, is cooled to add entry (10ml) after 10 ℃ carefully and the 15%NaOH aqueous solution destroys excessive LiAlH ₄Filtering inorganic salt also washs up hill and dale with THF, the THF solution that evaporation merges, the title compound 2a oily matter of remaining 6.5g.Crystallization goes out hydrochloride from the 2-propyl alcohol, Mp:198-201 ℃.

¹H?NMR(DMSO-d ₆)：δ1.85-2.40(m，6H)；2.60-2.90(m，3H)；3.00-3.15(m，3H)；3.35(broad?s，3H)；3.45-3.60(m，2H)；3.65-3.75(m，1H)；6.45(d，1H)；6.50(s，1H)；6.95(d，1H)；7.15(t，2H)；7.25-7.35(m，2H).

Prepare following anils with similar method:

1-(6-amino-2,3-indane-1-ylmethyl)-4-(2-p-methoxy-phenyl) piperazine, 2b, oily matter,

1-(6-amino-2,3-indane-1-ylmethyl)-4-(2-chloro-phenyl-) piperazine, 2c, oily matter,

1-(6-amino-2,3-indane-1-ylmethyl)-4-(3-chloro-phenyl-) piperazine, 2d, oily matter,

1-(6-amino-2,3-indane-1-ylmethyl)-4-(4-fluorophenyl) piperazine, 2e, mp:98-109 ℃,

1-(5-amino-2,3-dihydro thionaphthene-3-ylmethyl)-4-(4-fluorophenyl) piperazine, 2f, oily matter,

1-(6-amino-2,3-indane-1-ylmethyl)-4-(4-fluorophenyl)-1,2,3,6-tetrahydrochysene piperidines, 2g, mp:78-84 ℃,

1-(6-amino-2,3-indane-1-ylmethyl)-4-(3, the 4-dichlorophenyl) piperazine, 2h, mp:156-158 ℃, (washing) with diethyl ether.

¹H?NMR(CDCl ₃)：δ1.70-1.90(m，1H)；2.20-2.30(m，1H)；2.45(dd，1H)；2.55-2.75(m，6H)；2.75-2.90(m，2H)；3.20(t，4H)；3.20-3.35(m，1H)；3.55(broad?s，2H)；6.50(dd，1H)；6.70-6.80(m，2H)；6.90-7.00(m，2H)；7.25(d，1H).

1-(6-amino-2,3-indane-1-ylmethyl)-4-(3, the 4-methylenedioxyphenyl) sends piperazine; 2i, oily matter,

1-(6-amino-2,3-indane-1-ylmethyl)-4-hydroxyl-4-(3-three oxygen methyl-4-chloro-phenyl-) sends pyridine; 2j, oily matter,

1-(6-amino-2,3-indane-1-ylmethyl)-4-(4-subunit phenyl) sends piperazine; 2k, oily matter,

1-(6-amino-2,3-indane-1-ylmethyl)-4-(4-chloro-phenyl-)-1,2,3, the 6-tetrahydropyridine, 2l, oily matter,

Embodiment 3 (method i)

1-(6-amino-2,3-indane-1-ylmethyl)-4-(4-fluorophenyl) piperazine, 3a

Make 2,3-indane-1-carboxylic acid (20g), DMF (2ml) and thionyl chloride (53g) refluxed 4 hours in methylene dichloride (250), vacuum is steamed and is removed volatile matter, and remove residual thionyl chloride by vacuum-evaporation with toluene, residual carboxylic acid chloride is dissolved in the methylene dichloride (200ml) and under 0-5 ℃, it is added drop-wise in methylene dichloride (200ml) solution of 1-(4-fluorophenyl) piperazine (58g).After at room temperature stirring 1.5 hours, water and salt water washing organic phase are handled organic phase with aforesaid method at last successively, obtain 66g crude product carboxylic acid amides.Obtain the 36g crystalline product, mp:119-124 ℃ by silica gel column chromatography (with 1: 1 ethyl acetate/heptane wash-out) purifying.Under-10 ℃, all these products are dissolved in dense H ₂SO ₄In (170ml).Under-10 ℃, vigorous stirring, drip 100%HNO ₃(6.9g) with dense H ₂SO ₄(55ml) mixture, under-5 ℃, restir mixture one hour is poured mixture in the ice (500g), and adds 1: 1 methylene dichloride and ethyl acetate (300ml) mixture, separates organic phase and uses rare Na ₂CO ₃Solution (2 * 200ml) and salt solution (200ml) washing.Handle organic phase with aforesaid method, obtain crude product, the oily 6-nitro-2 of 35g, 3-indane-1-carboxamide derivative oily matter.Reflux down, thick product is dissolved in 90% the ethanol, short run ground adds the Fe powder (31.5g) and the dense HCl aqueous solution (3.1ml) successively in 30 minutes, and the mixture of generation refluxed 2.5 hours again.Filtered while hot inorganic salt, and vacuum-evaporation ethanol add NH ₄The OH dilute aqueous soln is to PH＞9, and (2 * 200ml) also handle organic phase with above-mentioned method, obtain 31g crystal 6-amino-2,3-indane-1-carboxamide derivative, Mp:143-149 ℃ with ethyl acetate extraction.All carboxylic acid amides drips of solution among the THF (400ml) are added to LiAlH ₄In anhydrous THF (400ml) suspension (10.4g), make the mixture gentle reflux after 2.5 hours, add entry (40ml) and the 15%NaOH aqueous solution after 15 ℃ carefully and destroy excessive LiAlH being cooled to ₄Filtering inorganic salt also washs up hill and dale with THF, the THF solution that evaporation merges, the title compound 3a oily matter of remaining 23.7g.

(method a) for embodiment 4

1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl)-4-(4-fluorophenyl)-piperidines 4a

Methylene dichloride (50ml) drips of solution of Acetyl Chloride 98Min. (1.7g) is added to 1-(the 6-amino-2 that is cooled to 0 ℃, 3-indane-1-ylmethyl)-4-(4-fluorophenyl)-piperidines, in methylene dichloride (150ml) solution of 2a (6.5g) and triethylamine (3ml), stirred the mixture one hour under the room temperature, add water (500ml), separate organic phase, with salt solution (2 * 50ml) washing organic phases, handle organic phase with aforesaid method at last, the thick title product that is separated to is by silica gel column chromatography (with ethyl acetate/heptane/75: 25: 4 wash-outs of triethylamine mixture) purifying, use the diethyl ether recrystallization, obtain the pure title compound 4a of 7.7g.

Mp：159-162℃. ¹H?NMR(CDCl ₃)：δ1.70-1.90(m，5H)；2.00-2.15(m，1H)；2.15(s，3H)；2.20-2.30(m，1H)；2.35-2.50(m，2H)；2.60(dd，1H)；2.70-2.90(m，2H)；2.95-3.15(m，2H)；3.45(qui，1H)；6.95(t，2H)；7.05-7.25(m，5H)；7.55(s，1H)

Prepare following amido, thio acylamino and sulfonamido derivative with corresponding method:

1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl)-4-(4-fluorophenyl) piperazine 4b, mp:179-187 ℃ (ethanol).

¹H?NMR(DMSO-d ₆)：δ1.70-1.85(m，1H)；2.00(s，3H)；2.10-2.25(m，1H)；2.35(dd，1H)，2.50-2.60(m，5H)；2.65-2.90(m，2H)；3.10(t，4H)；3.35(qui，1H)；6.90-7.10(m，5H)；7.30(d，1H)；7.60(s，1H)；9.75(s，1H)

1-(5-acetylaminohydroxyphenylarsonic acid 2,3-dihydro thionaphthene-3-ylmethyl)-4-(4-fluorophenyl) piperidines 4c, mp:140-142 ℃ (washing) with diethyl ether.

¹H?NMR(DMSO-d ₆)：δ1.55-1.75(m，4H)；1.95(s，3H)；1.90-2.05(m，1H)；2.05-2.20(dt，1H)；2.35(dd，1H)；2.40-2.55(m，3H)；2.95(d，1H)，3.15(d，1H)；3.20-3.35(m，1H)；3.45(t，1H)；3.55-3.70(m，1H)；7.05-7.15(m，3H)；7.25-7.35(m，3H)；7.65(s，1H)；9.85(s，1H)

1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl)-4-(4-chloro-phenyl-) piperazine 4d, mp:191-194 ℃ (acetone).

¹H?NMR(CDCl ₃)：δ1.80-1.95(m，1H)；2.10(s，3H)；2.20-2.35(m，1H)；2.45(dd，1H)；2.60-2.70(m，5H)；2.80-2.95(m，2H)；3.15(t，4H)；3.35(qui，1H)；6.85(d，2H)；7.05-7.25(m，5H)；7.55(s，1H)；

1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl)-4-(3-chloro-phenyl-) piperazine 4e, mp:176-178 ℃ (acetone).

¹H?NMR(CDCl ₃)：δ1.75-1.90(m，1H)，2.15(s，3H)；2.20-2.35(m，1H)；2.45(dd，1H)；2.60-2.75(m，5H)；2.75-2.95(m，2H)；3.20(t，4H)；3.35(qui，1H)；6.80(d，2H)；6.85(s，1H)；7.10-7.30(m，4H)；7.55(s，1H)

1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl)-4-(2-chloro-phenyl-) piperazine, hydrochloride 4f, mp:195-203 ℃ (acetone).

¹H?NMR(DMSO-d ₆)：δ2.00(s，3H)；2.00-2.15(m，1H)；2.30-2.45(m，1H)；2.75-2.95(m，2H)；3.20-3.80(m，11H)；7.05-7.40(m，5H)；7.45(d，1H)；7.65(s，1H)；10.00(s，1H)；10.95(broad?s，1H)

1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl)-4-(2-p-methoxy-phenyl) piperazine, oxalate 4g, mp:210-213 ℃ (acetone 1: 1).

¹H?NMR(DMSO-d ₆)：δ1.85-2.00(m，1H)；2.05(s，3H)；2.25-2.40(m，1H)；2.65-3.05(m，3H)；3.25(broad?s，8H)；3.45-3.60(m，1H)；3.80(s，3H)；6.85-7.05(m，4H)；7.15(d，1H)；7.30(d，1H)；7.60(s，1H)；9.90(s，1H)

1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl)-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine 4h, mp:156-161 ℃ (washing) with diethyl ether.

¹H NMR (CDCl ₃): δ 1.80-1.95 (m, 1H); 2.15 (s, 3H); 2.20-2.35 (m, 1H); 2.45-2.60 (m, 3H); 2.65-3.00 (m, 5H); 3.20 (broad s, 2H); 3.30-3.45 (m, 1H); 6.05 (wide S, 1H); 6.95 (t, 2H); 7.15 (d, 1H); 7.15-7.25 (m, 2H); 7.35 (dd, 2H); 7.50 (s, 1H)

4-(4-fluorophenyl)-1-(6-sulfonyloxy methyl amino-2,3-indane-1-ylmethyl) piperidines 4i, mp:152-155 ℃ (diethyl ether).

¹H NMR (CDCl ₃): δ 1.70-1.90 (m, 5H); 2.00-2.20 (m, 2H); 2.20-2.35 (m, 1H); 2.40-2.70 (m, 3H); 2.75-2.95 (m, 2H); 3.00 (s, 3H); 3.10 (t, 2H); 3.25-3.45 (m, 1H); 6.70 (wide S, 1H); 6.90-7.05 (m, 3H); 7.15-7.25 (m, 3H); 7.35 (s, 1H)

1-(6-cyclopropyl carbonyl amino-2,3-indane-1-ylmethyl)-4-(4-fluorophenyl) piperidines 4j, mp:134-140 ℃ (diethyl ether).

¹H NMR (CDCl ₃): δ 0.75-0.90 (m, 2H); 1.05-1.15 (m, 2H); 1.45-1.60 (m, 1H); 1.75-1.95 (m, 6H); 2.00-2.15 (m, 2H); 2.20-2.35 (m, 1H); 2.35-2.50 (m, 2H); 2.65 (dd, 1H); 2.70-2.95 (m, 2H); 3.00-3.15 (m, 2H); 3.35 (qui, 1H); 6.95 (t, 2H); 7.05-7.25 (m, 4H); 7.40 (wide S, 1H); 7.65 (broad s, 1H)

1-(6-cyclopentadienyl carbonyl amino-2,3-indane-1-ylmethyl)-4-(4-fluorophenyl) piperidines 4k, mp:177-178 ℃ (diethyl ether).

¹H?NMR(CDCl ₃)：δ1.50-1.70(m，2H)；1.70-1.95(m，11H)；2.00-2.15(m，2H)；2.20-2.35(m，1H)；2.35-2.50(m，2H)；2.60-2.75(m，2H)；2.75-2.95(m，2H)；2.95-3.15(m，2H)；3.35(qui，1H)；6.95(t，2H)；7.10-7.25(m，5H)；7.65(s，1H)

1-(6-ethoxycarbonyl amino-2,3-indane-1-ylmethyl)-4-(4-fluorophenyl) piperidines, fumarate 4l, mp:191-193 ℃ (ethanol/acetone 2: 1).

¹H?NMR(DMSO-d ₆)：δ1.15(s，3H)；1.70-1.90(m，5H)；2.10-2.30(m，3H)；2.40-2.90(m，5H)；3.10-3.20(m，2H)；3.25-3.35(m，1H)；4.15(q，1H)；6.60(s，1.5H)；7.00-7.15(m，4H)；7.35(dd，2H)；7.55(s，1H)；9.45(s，1H).

4-(4-chloro-phenyl-)-1-(6-methanesulfonamido-2,3-indane-1-ylmethyl)-1,2,3,6-tetrahydropyridine, oxalate 4m, mp:176-178 ℃ (ethanol). ¹H NMR (DMSO-d ₆): δ 1.90-2.00 (m, 1H); 2.30-2.40 (m, 1H); 2.95 (s, 3H); 2.65-3.10 (m, 5H); 3.20-3.30 (m, 3H); 3.50-3.60 (m, 1H); 3.75 (wide S, 2H); 6.25 (broad s, 1H); 7.05 (dd, 1H); 7.15-7.25 (m, 2H); 7.45 (d, 2H); 7.55 (d, 2H); 9.60 (broad s, 1H).

1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl)-4-(4-aminomethyl phenyl) piperidines 4n, mp:173-175 ℃ (washing) with diethyl ether.

¹H?NMR(CDCl ₃)：δ1.70-1.95(m，5H)；2.10(s，3H)；2.20-2.30(m，1H)；2.30(s，3H)；2.35-2.50(m，2H)；2.65(dd，1H)；2.70-2.90(m，2H)；3.00-3.15(m，2H)；3.35(qui，1H)；7.05-7.25(m，6H)；7.50(s，1H)；7.55(s，1H).

1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl)-4-(3, the 4-dichlorophenyl) piperazine 4o, mp:160-163 ℃ (washing) with diethyl ether.

¹H NMR (CDCl ₃): δ 1.80-1.90 (m, 1H); 2.10 (s, 3H); 2.15-2.30 (m, 1H); 2.45 (dd, 1H); 2.55-2.70 (m, 5H); 2.70-3.00 (m, 2H); 3.20 (t, 4H); 3.35 (qui, 1H); 6.25 (dd, 1H); 6.95 (d, 1H); 7.10 (d, 1H); 7.20 (dd, 1H); 7.25 (d, 1H); 7.40 (wide S, 1H); 7.60 (s, 1H).

1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl)-4-(4-chloro-phenyl-)-1,2,3,6-tetrahydropyridine, oxalate 4p, mp:223-226 ℃ (acetone).

¹H NMR (DMSO-d ₆): δ 1.80-1.95 (m, 1H); 2.05 (s, 3H); 2.20-2.40 (m, 1H); 2.65-3.00 (m, 5H); 3.15-3.30 (m, 3H); 3.50-3.60 (m, 1H); 3.70 (wide S, 2H); 6.25 (wide S, 1H); 7.15 (d, 1H); 7.30 (d, 1H); 7.40 (d, 2H); 7.50 (d, 2H); 7.65 (s, 1H).

1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl)-4-(3, the 4-methylenedioxyphenyl) piperazine 4q, mp:188-189 ℃ (washing) with diethyl ether.

¹H?NMR(CDCl ₃)：δ1.70-1.95(m，1H)；2.15(s，3H)；2.15-2.30(m，1H)；2.45(dd，1H)；2.60-2.70(m，5H)；2.70-2.90(m，2H)；3.10(t，4H)；3.40quin，1H)；5.85(s，2H)；6.45(dd，1H)；6.55(d，1H)；6.70(d，1H)；7.15(d，1H)；7.20-7.35(m，2H)；7.55(s，1H).

1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl)-4-hydroxyl-4-(3-trifluoromethyl-4-chloro-phenyl-) piperidines, half oxalate 4r, mp:163-165 ℃ (acetone).

¹H?NMR(DMSO-d ₆)：δ1.65-1.95(m，3H)；2.05(s，3H)；2.15-2.30(m，3H)；2.65-3.30(m，8H)；3.40-3.50(m，1H)；7.15(d，1H)；7.25(d，1H)；7.70-7.85(m，3H)；8.00(s，1H).

(method a) for embodiment 5

4-(4-fluorophenyl)-1-(6-methylamino carbonyl-2,3-indane-1-ylmethyl) piperidines, 5a

With 1-(6-amino-2,3-indane-1-ylmethyl)-4-(4-fluorophenyl) piperidines, 2a (3g) is dissolved in the methylene dichloride, and adds methyl isocyanate (0.53g).Solution was refluxed 4 hours, steam and remove methylene dichloride, residual crude product title compound is by silica gel column chromatography (being used in 4% triethylamine wash-out in the acetate) purifying, and crystallization goes out pure product title compound 5a from diethyl ether.Productive rate: 0.8g,

Mp:170-173 ℃. ¹H NMR (CDCl ₃): δ 1.70-1.90 (m, 5H); 2.00-2.15 (m, 2H); 2.20-2.35 (m, 1H); 2.35-2.55 (m, 2H); 2.60 (dd, 1H); 2.80 (d, 3H); 2.75-2.95 (m, 2H); 3.05 (wide d, 2H); 3.30 (qui, 1H); 4.95 (q, 1H); 6.55 (s, 1H); 6.90-7.00 (m, 3H); 7.10-7.25 (m, 3H); 7.35 (s, 1H)

Prepare following urea or thiourea derivative with similar methods;

1-[6-(4-fluorophenyl) amino carbonyl amino-2,3-indane-1-ylmethyl]-4-(4-fluorophenyl) piperidines, 5b,

mp：235-238℃(CH ₂Cl ₂). ¹H?NMR(DMSO-d ₆)：δ，1.55-1.80(m，5H)；2.00-2.30(m，3H)；2.35(dd，1H)；2.45-2.60(m，2H)；2.60-2.85(m，2H)；3.05(broad?d，2H)；3.30(qui，1H)；7.05-7.15(m，6H)；7.25-7.35(dd，2H)；7.40-7.50(dd，2H)；7.55(s，1H)；8.50(s，1H)；8.65(s，1H)

4-(4-fluorophenyl)-1-(6-methylamino thio-carbonyl-amino-2,3-indane-1-ylmethyl) piperidines, fumarate, 5c, mp:181-183 ℃ (ethyl ketone/acetone 1: 1).

¹H NMR (DMSO-d ₆): δ 1.70-1.90 (m, 5H); 2.15-2.95 (m, 8H); 2.90d, 3H); 3.20-3.30 (m, 2H); 3.40 (qui, 1H); 6.20 (s, 2H); 7.05-7.20 (m, 4H); 7.30 (dd, 2H); 7.40 (s, 1H); 7.80 (wide S, 1H); 9.60 (wide S, 1H).

1-(6-methylamino carbonylamino-2,3-indane-1-ylmethyl]-4-(3, the 4-methylenedioxyphenyl) piperazine, half oxalate, 5d, mp:132-133 ℃ (acetone).

¹H?NMR(DMSO-d ₆)：δ1.70-1.85(m，1H)；2.15-2.30(m，1H)；2.60(d，3H)；2.70-3.00(m，7H)；3.20(m，4H)；3.35-3.45(m，1H)；5.90(s，2H)；6.00-6.10(m，1H)；6.40(dd，1H)；6.70(d，1H)；6.80(d，1H)；7.05(d，1H)；7.10(d，1H)；7.45(s，1H)；8.40(s，1H).

(method a) for embodiment 6

1-(6-dimethylamino carbonylamino-2,3-indane-1-ylmethyl]-4-(4-fluorophenyl) piperidines, 6a

With 1-(6-amino-2,3-indane-1-ylmethyl]-4-(4-fluorophenyl)-piperidines, 2a (3g) is dissolved among the THF (50ml), and adding triethylamine (2g), under 5 ℃, dropping (15ml) dimethylcarbamyl chloride (1g) in THF behind reinforced the finishing, refluxed mixture 1.5 hours.Steam and remove THF, add entry, with methylene dichloride (2 * 50ml) extractions, handle in conjunction with organic phase with aforesaid method, obtain crude product title product, by silica gel column chromatography (being used in 4% triethylamine wash-out in 1: 1 ethyl acetate and the heptane mixture) purifying, crystallization goes out pure product title compound 6a from diethyl ether.Productive rate:

1.4g，mp：141-144℃. ¹H?NMR(CDCl ₃)：δ1.65-2.55(m，10H)；2.70(dd，1H)；2.70-2.95(m，2H)；2.95-3.05(m，1H)；3.05(s，6H)；3.15(broad?d，1H)；3.35(qui，1H)；6.25(s，1H)；6.95-7.25(m，6H)；7.45(s，1H)

Prepare following urea or thiourea derivative with similar methods:

1-(6-dimethylamino thio-carbonyl-amino-2,3-indane-1-ylmethyl]-4-(4-fluorophenyl) piperidines, 6b, mp:175-180 ℃ (washing) with diethyl ether.

¹H?NMR(CDCl ₃)：δ1.65-1.95(m，5H)；2.00-2.15(m，2H)；2.20-2.35(m，1H)；2.35-2.55(m，2H)；2.60(dd，1H)；2.70-2.90(m，2H)；3.05-3.15(m，2H)；3.85(s，6H)；3.40(qui，1H)；6.95-7.10(m，4H)；7.15-7.30(m，4H)

4-(4-fluorophenyl)-1-[6-(pyrrolidyl) carbonylamino-2,3-indane-1-ylmethyl] piperidines, 6c, mp:190-193 ℃ (washing) with diethyl ether.

¹H?NMR(CDCl ₃)：δ1.65-2.55(m，14H)；2.65(dd，1H)；2.75-2.90(m，2H)；3.00(broad?d，1H)；3.15(broad?d，1H)；3.35(qui，1H)；3.45(t，4H)；6.15(s，1H)；6.95(t，2H)；7.00-7.10(m，2H)；7.20(dd，2H)；7.50(s，1H)

(method a) for embodiment 7

1-(6-amino carbonyl amino-2,3-indane-1-ylmethyl]-4-(4-fluorophenyl) piperidines, hemifumarate, 7a

Isocyanic acid potassium (1.5g) is dissolved in the methylene dichloride (20ml), be cooled to 5 ℃, and methylene dichloride (20ml) solution of dropping trifluoracetic acid (1.9g), with 1-(6-amino-2,3-indane-1-ylmethyl)-and 4-(4-fluorophenyl) piperidines, methylene dichloride (20ml) drips of solution of 2a (3g) is added in this mixture, makes temperature rise to room temperature, after the restir three hours, mixture is poured in the ice into (500g) and added rare NH4OH water to PH＞9.Separate and handle organic phase with aforesaid method.By silica gel column chromatography (being used in 1: 3 4% triethylamine wash-out in ethanol/ethyl acetate) purifying crude product title product, the product (2g) of purifying is dissolved in (20ml) in the acetone, and be added in ethanol (20ml) solution of fumaric acid (0.6g), the hemifumarate of filtering-depositing is also dry, productive rate: 1.6g

mp：172-174℃. ¹H?NMR(DMSO-d ₆)：δ1.65-1.90(m，5H)；2.10-2.35(m，3H)；2.45-2.90(m，5H)；3.10-3.25(m，2H)；3.45(qui，1H)；6.85(s，2H)；6.60(s，1H)；7.00-7.15(m，4H)；7.30(dd，2H)；7.45(s，1H)；8.45(s，1H).

Embodiment 8

5-chloro-3-(1,2,3,6-tetrahydropyridine-4-yl)-1H-indoles, 8a

Make 5-chloro-1H-indoles (25g), piperidin-4-one-, hydrate, ethanol (450ml) mixture of hydrochloride (71g) and potassium hydroxide (38g) refluxed 6 hours, filter the refrigerative inorganic salt, and behind the vacuum-evaporation ethanol, (2 * 200ml) are added in the irreducible oil, separate and handle organic phase with aforesaid method, obtain crude product title product: 45g (hemicrystalline) with salt solution (500ml) and ethyl acetate.

Prepare following 3-(1,2,3,6-tetrahydropyridine-4-yl)-1H-indoles with corresponding method:

6-chloro-3-(1,2,3,6-tetrahydropyridine-4-yl)-1H-indoles, 8b

5-fluoro-3-(1,2,3,6-tetrahydropyridine-4-yl)-1H-indoles, 8c

Embodiment 9

5-chloro-3-(4-piperidyl)-1H-indoles, 9a

With crude product 5-chloro-3-(1,2,3,6-tetrahydropyridine-4-yl)-1H-indoles, 8a (26g) is dissolved in the Glacial acetic acid (330ml), and adds PtO ₂(0.7g).Under the 3atm, hydrogenated mixture 5 hours adds entry in the Pa Er instrument, and adds rare NH ₄OH water is adjusted to PH＞9.(2 * 200ml) extractions are handled in conjunction with organic phase with aforesaid method, and obtaining 19g crude product title compound is viscous oil with ethyl acetate.

Prepare following 3-(4-piperidyl)-1H-indoles with corresponding method:

6-chloro-3-(4-piperidyl)-1H-indoles, 9b

5-fluoro-3-(4-piperidyl)-1H-indoles, 9c

Embodiment 10

3-[1-(5-amino-2,3-dihydrobenzo thiene-3-yl-methyl) piperidin-4-yl]-5-chloro-1H-indoles, 10a

As described in embodiment 2,5-nitro-3-thionaphthene carboxylic acid 1b (20g) is changed into the corresponding carboxylic acid acyl chlorides.At 0-5 ℃, acyl chlorides is dissolved among the THF (200ml), and is added drop-wise to 5-chloro-3-(4-piperidines)-1H-indoles, in THF (200ml) solution of 9a (19g) and triethylamine (10ml), at room temperature, the mixture stirring is spent the night.Steam and remove THF, water is added in the remaining oil, with methylene dichloride (2 * 100ml) extractions, handle organic extract liquid with aforesaid method, obtain crude product 5-nitro-3-thionaphthene carboxylic acid amide, then, obtain 6.6g, mp:243-250 ℃ by silica gel column chromatography (with 1: 1 ethyl acetate and heptane wash-out) purifying.All acid amides are dissolved in 90% ethanol of backflow, in 10 minutes, the Fe powder (5g) and the dense HCl aqueous solution are added continuously in batches, mixture was refluxed 2.5 hours.Filtering inorganic salt, and vacuum-evaporation ethanol are added to water in the remaining oil, add NH ₄The OH dilute aqueous soln is to PH＞9, and (2 * 100ml) then, handles organic phase with above-mentioned method, obtains 5-amino-3-thionaphthene carboxylic acid amide oily matter of 4g with dichloromethane extraction.All oil is dissolved in the methyl alcohol (100ml), adds 0.5gMg turning, be heated 35 ℃, the beginning thermopositive reaction, (3 * 0.5g) short runs add, and maintain the temperature at therebetween below 45 ℃, pour mixture into NH at last with the Mg bits ₄In the Cl aqueous solution, add the dense HCl aqueous solution (1ml), and the usefulness dichloromethane extraction (2 * 50ml), handle organic extract liquid with above-mentioned method, obtain the 5-amino-2 of 2g, 3-dihydrobenzo thiophene-3-carboxylic acid amide oily matter.All carboxylic acid amide drips of solution among the THF (50ml) are added to LiAlH ₄In anhydrous tetrahydro furan (0.6g) (50ml) suspension, gentle reflux mixture 2 hours is cooled to and adds entry (2.4ml) and the 15%NaOH aqueous solution after 10 ℃ carefully and destroy excessive LiAlH ₄After.Filtering inorganic salt also washs up hill and dale with THF, and the THF solution that evaporation merges obtains 1.9g 3-[1-(5-amino-2,3-dihydrobenzo thiene-3-yl-methyl) piperidin-4-yl]-5-chloro-1H-indoles oily matter.

Prepare following anils with similar methods:

3-[1-(5-amino-2,3-dihydrobenzo thiene-3-yl-methyl)-1,2,3,6-tetrahydropyridine-4-yl]-5-chloro-1H-indoles, 10b oily matter

3-[1-(5-amino-2,3-dihydrobenzo thiene-3-yl-methyl)-1,2,3,6-tetrahydropyridine-4-yl]-5-fluoro-1H-indoles, 10c oily matter

From corresponding 2,3-indane-1-carboxylic acid amide prepares corresponding 1-(6-amino-2,3-indane-1-ylmethyl)-4-(3-indyl) piperidines and the 4-(3-indyl)-1 that replace, 2,3,6-tetrahydropyridine, nitrated one by one on 6, the reduction of nitro substituent and the reduction of carboxylic acid amide carbonyl.Prepare following indane derivatives according to reaction sequence as described in embodiment 3:

3-[1-(6-amino-2,3-indane-1-ylmethyl) piperidin-4-yl]-5-fluoro-1H-indoles, 10d oily matter.

3-[1-(6-amino-2,3-indane-1-ylmethyl) piperidin-4-yl]-6-chloro-1H-indoles, 10e oily matter.

3-[1-(6-amino-2,3-indane-1-ylmethyl)-1,2,3,6-tetrahydropyridine-4-yl]-5-chloro-1H-indoles, 10f oily matter.

3-[1-(6-amino-2,3-indane-1-ylmethyl)-1,2,3,6-tetrahydropyridine-4-yl]-6-chloro-1H-indoles, 10g oily matter.

1-[1-(6-amino-2,3-indane-1-ylmethyl) piperidin-4-yl]-5-chloro-1H-indoles, 10h oily matter.

Embodiment 11

3-[1-(5-acetylaminohydroxyphenylarsonic acid 2,3-dihydrobenzo thiene-3-yl-methyl) piperidin-4-yl]-5-chloro-1H-indoles, oxalate, 11a

At 0 ℃, methylene dichloride (10ml) drips of solution of Acetyl Chloride 98Min. (0.4g) is added to 3-[1-(5-amino-2,3-dihydrobenzo thiene-3-yl-methyl) piperidin-4-yl]-5-chloro-1H-indoles, in methylene dichloride (50ml) solution of 10a (1.9g) and triethylamine (2ml), stirred the mixture under the room temperature 2 hours, add entry, handle organic phase with aforesaid method, obtain the crude product title product by silica gel column chromatography (being used in 4% triethylamine wash-out in the ethyl acetate) purifying, productive rate: 0.8g, crystallization goes out the oxalate of title compound from 1: 1 acetone and alcoholic acid mixture.

Mp:168-174 ℃. ¹H NMR (DMSO-d ₆): δ 2.00 (s, 3H); 1.95-2.15 (m, 4H); 2.85-3.25 (m, 5H); 3.40-3.50 (m, 2H); 3.55-3.70 (m, 2H); 3.90-4.00 (m, 1H); 7.00-7.40 (m, 6H); 7.70 (s, 1H); 7.70 (wide s, 2H); 9.95 (wide s, 1H); 11.10 (wide s, 1H).

Prepare following indole derivatives with similarity method:

3-[1-(5-acetylaminohydroxyphenylarsonic acid 2,3-dihydrobenzo thiene-3-yl-methyl)-1,2,3,6-tetrahydropyridine-4-yl]-5-chloro-1H-indoles, oxalate, 11b, mp:214-216 ℃ (ethanol).

¹HNMR (DMSO-d ₆): δ 2.00 (s, 3H); 2.75 (wide s, 2H); 2.95-3.40 (m, 5H); 3.50-3.80 (m, 3H); 3.95 (wide s, 1H); 6.15 (wide s, 1H); 7.15 (t, 2H); 7.25 (d, 1H); 7.45 (d, 1H); 7.60 (s, 1H); 7.65 (s, 1H); 7.85 (s, 1H); 9.95 (s, 1H); 11.50 (s, 1H)

3-[1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl) piperidin-4-yl]-5-fluoro-1H-indoles, oxalate, 11c, mp:145-149 ℃ (acetone).

¹H?NMR(DMSO-d ₆)：δ1.80-2.15(m，6H)；2.00(s，3H)；2.30-2.45(m，1H)；2.70-2.90(m，2H)；2.95-3.20(m，3H)；3.35(d，1H)；3.50-3.80(m，3H)；6.95(dt，1H)；7.15(d，1H)；7.25(s，1H)；7.30(d，1H)；7.40(dd，1H)；7.45(dd，1H)；7.70(s，1H)；9.95(s，1H)；11.05(s，1H)

3-[1-(5-acetylaminohydroxyphenylarsonic acid 2,3-dihydrobenzo thiene-3-yl-methyl)-1,2,3,6-tetrahydropyridine-4-yl]-5-fluoro-1H-indoles, oxalate, 11d, mp:155-165 ℃ (acetone).

¹H NMR (DMSO-d ₆): δ 2.00 (s, 3H); 2.75 (wide s, 2H); 2.95-3.45 (m, 5H); 3.50-3.80 (m, 3H); 3.95 (wide s, 1H); 6.15 (wide s, 1H); 6.95 (t, 1H); 7.20 (d, 1H); 7.30 (d, 1H); 7.45 (m, 1H); 7.55-7.70 (m, 3H); 9.95 (s, 1H); 11.45 (s, 1H)

3-[1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl)-1,2,3,6-tetrahydropyridine-4-yl]-6-chloro-1H-indoles, oxalate semihydrate, 11e, mp:151-164 ℃ (acetone).

¹H NMR (DMSO-d ₆): δ 1.95-2.10 (m, 1H); 2.00 (s, 3H); 2.30-2.45 (m, 1H); 2.70-2.90 (m, 4H); 3.15 (t, 1H); 3.35-3.50 (m, 3H); 3.55-3.70 (m, 1H); 3.95 (wide s, 2H); 6.15 (s, 1H); (7.05 dd 1H); 7.15 (d, 1H); 7.25 (d, 1H); 7.45 (d, 1H); 7.55 (d, 1H); 7.60 (s, 1H); 7.85 (d, 1H); 9.95 (s, 1H); 11.55 (s, 1H)

3-[1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl) piperidin-4-yl]-6-chloro-1H-indoles, 11f, mp:122-130 ℃ (acetone). ¹H?NMR(DMSO-d ₆)：δ1.90-2.15(m，6H)；2.00(s，3H)；2.25-2.40(m，1H)；2.70-3.10(m，6H)；3.35(d，1H)；3.45-3.65(m，2H)；7.00(dd，1H)；7.15-7.25(m，2H)；7.30(d，1H)；7.40(s，1H)；7.60-7.70(m，2H)；9.90(s，1H)；11.05(s，1H)

3-[1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl)-1,2,3,6-tetrahydropyridine-4-yl]-5-chloro-1H-indoles, oxalate 11g, mp:220-223 ℃ (acetone 5: 1).

¹H NMR (DMSO-d ₆): δ 1.95-2.10 (m, 1H); 2.00 (s, 3H); 2.30-2.45 (m, 1H); 2.70-2.95 (m, 4H); 3.10 (t, 1H); 3.30-3.45 (m, 3H); 3.55-3.70 (m, 1H); 3.85 (wide s, 2H); 6.15 (s, 1H); 7.10-7.20 (m, 2H); 7.30 (d, 1H); 7.45 (d, 1H); 7.60-7.70 (m, 2H); 7.85 (s, 1H); 9.90 (s, 1H); 11.50 (s, 1H)

1-[1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl) piperidin-4-yl]-5-chloro-1H-indoles, 11h, mp:189-191 ℃ (ethyl acetate).

¹H NMR (CDCl ₃): δ 1.80-2.00 (m, 1H); 2.05-2.40 (m, 7H); 2.20 (s, 3H); 2.50 (dd, 1H); 2.65 (dd, 1H); 2.80-2.95 (m, 2H); 3.15 (wide t, 2H); 3.35 (quin, 1H); 4.20-4.30 (m, 1H); 6.45 (d, 1H); 7.20-7.35 (m, 4H); 7.30-7.40 (m, 2H); 7.60 (d, 1H); 7.70 (wide s, 1H).

Embodiment 12 (method e)

4-(4-fluorophenyl)-1-(6-(pyrrolidin-2-one base)-2,3-indane-1-ylmethyl) piperidines, fumarate 12a

Under 0 ℃, methylene dichloride (15ml) drips of solution of 4-chlorobutanoylchloride (1.4g) is added to 1-(6-amino-2,3-indane-1-ylmethyl)-4-(4-fluorophenyl) piperidines, in methylene dichloride (50ml) solution of 2a (3g) and triethylamine (2ml), at last, at room temperature, stirred the mixture 5 hours, add ice-cold rare NaOH aqueous solution, then, handle organic phase with aforesaid method, 1-(the 6-(4-neoprene amido)-2 that obtains by silica gel column chromatography (being used in 4% triethylamine wash-out in 1: 3 ethyl acetate and the heptane mixture) purifying, 3-indane-1-ylmethyl)-4-(4-fluorophenyl)-piperidines crude product, obtain crystallized product: 2.4g, mp:129-135 (washing) with diethyl ether, isolating 4-neoprene acyl derivative (1g) and potassium tert.-butoxide (0.4g) solution in anhydrous THF (40ml) was refluxed 2 hours, and vacuum-evaporation THF adds rare NH ₄OH water and methylene dichloride, and handle organic phase with aforesaid method make remaining oil (1g) be dissolved in the acetone (10ml) and are added in ethanol (15ml) solution of hot fumaric acid (0.3g), after refrigerator and cooled is but spent the night, the fumarate of filtering-depositing, and dry, productive rate: 0.7g.

Mp:177-179 ℃. ¹H NMR (DMSO-d ₆): δ 1.70-1.90 (m, 5H); 2.10 (qui, 2H); 2.20-2.40 (m, 3H); 2.45-2.65 (m, 4H); 2.70-2.95 (m, 3H); 3.20 (wide t, 2H); 3.40 (qui, 1H); 3.70-3.90 (m, 2H); 6.60 (s, 2H); 7.15 (t, 2H); 7.20 (d, 1H); 7.30 (dd, 2H); 7.40 (dd, 1H); 7.65 (s, 1H).

Embodiment 13

(+)-6-nitro-2,3-indane-1-carboxylic acid, 13a

In acetone (1.25L), heating 6-nitro-2,3-indane-1-carboxylic acid (1a) (96g) and brucine dihydrate (200g), up to obtaining clear soln.Make solution in refrigerator overnight, the brucine salt of filtering-depositing obtains product: 159.1g.Obtain the pure product of 103g (+)-6-nitro-2 with 2-propyl alcohol recrystallization, 3-indane-1-carboxylic acid brucine salt.Salt is dissolved in the water, adds dilute hydrochloric acid, it is handled, obtain 29.8g13a with the diethyl ether extraction and with aforesaid method, Mp:92-94 ℃, [α] _D=+83.3 ° (c=1, methyl alcohol)

Embodiment 14

(+)-1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl)-4-(4-fluorophenyl) piperidinyl-1 4a

According to the method for embodiment 2 and 4, from (+)-6-nitro-2,3-indane-1-carboxylic acid 13a prepares (+)-corresponding body of compound 4a.

Mp:145-146 ℃, ¹HNMR (CDCl ₃): δ 1.70-1.90 (m, 5H); 2.00-2.15 (m, 1H); 2.15 (s, 3H); 2.20-2.30 (m, 1H); 2.35-2.50 (m, 2H); 2.60 (dd, 1H); 2.70-2.90 (m, 2H); 2.95-3.15 (m, 2H); 3.45 (qui, 1H); 6.95 (t, 2H); 7.05-7.25 (m, 5H); 7.55 (s, 1H) .[α] _D=+24.3 ° (c=1, methyl alcohol).

Embodiment 15

3-(1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl)-1,2,3,6-tetrahydropyridine-4-yl)-6-chloro-1-Methyl-1H-indole 15a

At 10 ℃; 3-(1-(the 6-nitro-2 that will prepare according to the method for embodiment 10; 3-indane-1-base carbonyl)-1; 2; 3; 6-tetrahydropyridine-4-yl)-6-chloro-1H-indoles (23g) is dissolved in the dry DMF (300ml), and adding potassium tert.-butoxide (7.3g), in 30 minutes; drip methyl iodide (23.2g); mixture is placed and at room temperature to be spent the night, and adds entry and diethyl ether, by silica gel column chromatography (with 1: 1 ethyl acetate and heptane mixture wash-out) the purifying crude product N-indoles that methylates; obtain product 2.75g; according to the method for embodiment 10 and 11, be used in Fe reduction nitryl group, reducing amide carbonyl group subsequently in 90% acidic ethanol; at last; be the acetylize of aniline group, obtain title compound 15a, Mp:189-193 ℃ (diethyl ether washing).

¹H NMR (CDCl ₃): δ 1.80 (wide s, 1H); 1.80-1.95 (m, 1H); 2.10 (s, 3H); 2.25-2.40 (m, 1H); 2.50-2.60 (m, 3H); 2.70-2.95 (m, 5H); 3.25 (wide s, 2H); 3.40 (qui, 1H); 3.70 (s, 3H); 6.15 (wide s, 1H); 7.00 (s, 1H); 7.10 (dd, 1H); 7.15 (d, 1H); 7.20-7.30 (m, 3H); 7.50 (s, 1H); 7.80 (d, 1H).

According to embodiment 9 catalytic hydrogenation compound 15a, obtain product:

3-(1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl) piperidin-4-yl)-6-chloro-1-Methyl-1H-indole, oxalate 15b, mp:202-205 ℃ (acetone).

¹H?NMR(DMSO-d ₆)：δ1.90-2.15(m，5H)；2.00(s，3H)；2.30-2.40(m，1H)；2.70-3.15(m，6H)；3.35(d，1H)；3.50-3.70(m，2H)；3.75(s，3H)；7.00(dd，1H)；7.10-7.30(m，3H)；7.55(d，1H)；7.65(s，1H)；7.65(d，1H)；9.90(s，1H).

Embodiment 16 (method f)

4-(4-fluorophenyl)-1-(6-methylamino-2,3-indane-1-ylmethyl) piperidines, 1.5 oxalate 16a

Under 0-5 ℃, methylene dichloride (15ml) drips of solution of chloro ethyl formate (1.5g) is added in the dichloromethane solution of 4-(4-fluorophenyl)-1-(6-methylamino-2,3-indane-1-ylmethyl) piperidines 2a (4g) and triethylamine (3ml).At room temperature, stirred the mixture 2 hours, pour into (500ml) in the saturated brine, separate organic phase, and handle organic phase, obtain the oily matter 4.3g of urethanum with aforesaid method.Under 5 ℃, all the urethanum drips of solution among the THF (25ml) are added to LiAlH ₄In anhydrous diethyl ether (1.2g) (20ml) suspension, under 5 ℃, restir mixture 1 hour at room temperature stirred 5 hours at last, added entry and rare NaOH aqueous solution (6ml) carefully and destroyed excessive LiAlH ₄The inorganic salt of filtering-depositing and vacuum evaporating solvent, by silica gel column chromatography (with 1: 1 ethyl acetate and heptane mixture wash-out) purifying crude product title compound, obtain oily matter 1.5g, crystallization goes out 1.5 oxalate 16a from 1: 1 acetone and alcoholic acid mixture.

Mp：84-86℃. ¹H?NMR(DMSO-d ₆)：δ1.75-2.10(m，5H)；2.20-2.40(m，1H)；2.60(s，3H)；2.60-2.90(m，3H)；3.00-3.15(m，3H)；3.40-3.80(m，4H)；6.40(dd，1H)；6.50(d，1H)；6.95(d，1H)；7.15(t，2H)；7.35(dd，2H)

Embodiment 17

5-chloro-1-(4-piperidyl)-1H-indoles, 17a

With salt of wormwood (82g), CuBr (7.5g) and bronze Cu (3g) are added in N-methyl-2-pyrrolidone (450ml) solution of 5-chloro-1H-indoles (20g), with mixture heating up to 140 ℃, with adding 4-bromopyridine, hydrochloride (22g), under 150 ℃, heated mixt 1 hour further adds the 4-bromopyridine, hydrochloride (15g), repeat twice of this process, at last, under 150 ℃, heated mixt spends the night, the cooled and filtered inorganic salt, add entry (2L), ethyl acetate (500mL) and weak ammonia (200mL) filter undissolved material and abandon, and handle organic phase with aforesaid method, obtain 34g 5-chloro-1-(4-pyridyl)-1H-indoles, mp:153-155 ℃.At 60-70 ℃, all these products that are not further purified are dissolved in glycol dimethyl ether (350mL), add methyl iodide (14mL), reflux mixture 7 hours, cooled and filtered precipitation season pyridinium salt, and wash with glycol dimethyl ether, obtain product 32g, Mp:257-260 ℃, all pyridinium salts are suspended in ethanol (450mL) and the water (50mL), in 1.5 hours, short run adds NaBH ₄(16g), behind the restir 1.5 hours, under the room temperature, the most of ethanol of vacuum-evaporation, add ethyl acetate (300mL) and water (500mL), and handle organic phase with aforesaid method, obtain 5-chloro-1-(1-methyl isophthalic acid, 2,3,6-tetrahydrochysene-4-pyridyl)-the 1H-indoles, 17g oily matter, PtO2 is added in the solution of Glacial acetic acid (150mL) of tetrahydropyridyl derivatives (15g), under Pa Er instrument 3atm, hydrogenated mixture 7 hours, filtering catalyst, the most of acetic acid of vacuum-evaporation extracts crude product 5-chloro-1-(1-methyl-4-pyridyl)-1H-indoles with ethyl acetate at last from alkaline aqueous solution, obtain 13g oily matter, by remove the residual water in this crude product (10g) with toluene evaporates, at last, oily matter is dissolved in 1,1, in the 1-trichloroethane (200mL), under reflux temperature, drip and be dissolved in 1,1, chloroformic acid 2 in the 1-trichloroethane (20mL), 2,2-trifluoro ethyl ester (6.5mL) makes mixture reflux again 2 hours, add yellow soda ash (2g), continue to reflux 0.5 hour, cooling back filtered through silica gel mixture (using the methylene dichloride wash-out) obtains 10g crude product carbamate derivative.At 45 ℃, in 1 hour, with Zn fine powder (12g) short run be added in 90% aqueous acetic acid (110mL) of carbamate (6g), at 50 ℃, heated mixt 1 hour, filter Zn salt, the most of acetic acid of vacuum-evaporation is in irreducible oil water-soluble (200mL) and ethyl acetate (200mL), add weak ammonia and regulate organic phase PH＞9, handle organic phase with aforesaid method, the 3.5g crude product title product 17a oily matter that obtains, it need not be further purified and promptly can be used for preparing compound 10h.

Embodiment 18

1-(6-acetylaminohydroxyphenylarsonic acid 2,3-indane-1-ylmethyl)-4-acetyl oxygen-4-(3-trifluoromethyl-4-chloro-phenyl-) piperidines, 18a

At 5 ℃, the drips of solution of the methylene dichloride (50mL) of chloroacetyl chloride (2.6mL) is added to 1-(6-amino-2,3-indane-1-ylmethyl)-4-hydroxyl-4-(3-trifluoromethyl-4-chloro-phenyl-) piperidines, in methylene dichloride (100mL) solution of 2j (6.7g) and triethylamine (4mL), stir under the room temperature and spend the night, add entry and regulate PH＞9, separate organic phase and handle with aforesaid method, by silica gel column chromatography (being used in 4% triethylamine wash-out in the ethyl acetate) purifying crude product, obtain straight product 18a6.2g oily matter.

Embodiment 19

5-chloro-1-(1-(6-methylamino carbonylamino 2,3-indane-1-ylmethyl) piperidin-4-yl)-1H-indoles, 19a

Methyl isocyanate (0.2mL) is added in methylene dichloride (10ml) solution of 1-(1-(6-amino 2,3-indane-1-ylmethyl) piperidin-4-yl)-5-chloro-1H-indoles 10h (0.9g), under the room temperature, stirred the mixture 16 hours, steam and remove methylene dichloride.When adding ethyl acetate, crystallization goes out title compound 19a.The filtering for crystallizing product, and spend the night 80 ℃ of vacuum-dryings, product obtained: 0.6g.mp：193-195℃. ¹H?NMR(DMSO-d ₆)：δ1.70-1.85(m，1H)；1.90-2.35(m，7H)；2.35-2.85(m，4H)；2.65(d，3H)；3.05-3.15(m，2H)；3.25(quin，1H)；4.35-4.45(m，1H)；5.95(dt，1H)；6.45(d，1H)；7.00-7.20(m，3H)；7.50-7.65(m，4H)；8.35(s，1H).

Pharmacological testing

The compounds of this invention is tested well-known 5-HT with fine distinguishing with reliable method _2AAntagonist MDL100,907 Hes, well-known 5-HT _1AThe antagonist buspirone is included in the interior conduct of this test with reference to compound.Test as followsly, down provide its result in 1 table.

For 3H-8-OH-DPAT in conjunction with rat brain serotonin 5-HT _1AThe vitro inhibition of acceptor

By this method, the external test medicine for ³H-8-OH-DPAT (1nM) is in conjunction with the negative meninx 5-HT of rat brain _1AThe inhibition of acceptor, so this is for 5-HT _1AThe test of receptor affinity is tested as people such as Hyttel, Drug.dev.Res., and 1988,15, the method described in the 389-404 is carried out.

For ³The H-ketanserin is in conjunction with rat cortex 5-HT ₂Vitro inhibition on the acceptor

By this method, the external test medicine for ³H-Ketanserin (0.5nM) is attached to rat film 5-HT _2APharmacology﹠amp is tested as Hyttel in inhibition on the acceptor; Toxicology, 61,126-129, the method described in 1987. is carried out.

Table 1

Binding data (IC ₅₀The value (nM) or with 100nM bonded % restraining effect) compound number ³H 8-OH DPAT (5-HT _1A) ³H Ketanserin (5-HT _2A) 2a 480. 2.5 2h 19%/100. 4.1 4a, 11. 4.0 4b, 21. 2.9 4c, 28. 2.3 4d, 12. 5.0 4e, 38. 5.0 4f, 84. 65. 4g, 31. 280. 4h, 11. 2.8 4i, 500. 2.1 4j, 45. 15. 4k, 240 30. 4l 26%/100 55. 4m, 120. 2.7 4n, 27. 3.9 4o, 11. 51. 4p nt nt 5a, 35 5.1 5b＞100; 000 37. 5c＞1000. 3.9 6a, 1,200 9.1 6b, 1,200 6.7 6c, 8,200 9.9 7a, 13. 2.6 11a, 28. 42. 11b, 21. 44. 11c, 16. 15. 11d, 29. 15. 11e, 27. 130. 11f, 8.0 21. 11g, 26. 180. 12a, 340 3.5 14a, 120. 16. 15a, 91. 25%/100 15b 25%/100 300. 16a, 170. 1.6 buspirones, 41. 1300.MDL100,907 nta 0.51a) nt: there is not test

Except that above-mentioned test, by with people such as Hyttel, J.Neurochem., 1985,44, the method described in 1615 is measured The compounds of this invention for inhibition ³The H-Spiropitan is attached to D ₂Affinity on the acceptor is test The compounds of this invention to dopamine D ₂Affinity, in addition, by with Hyttel and Larsen, Acta Pharmacol.Tox., 1985,56, suppl.1, the method described in the 146-153 is measured The compounds of this invention for suppressing in the external rat brain synaptosome ³The affinity of the picked-up of H-5-hydroxy-tryptamine is test the restraining effect of The compounds of this invention for the 5-HT picked-up.

The The compounds of this invention demonstration had both suppressed deuterate 8-hydroxyl-2-dipropyl Aminotetralin (8-OH-DPAT) forcefully to 5-HT in a word _1AThe external combination of acceptor suppresses again forcefully ³H-Ketanserin is to 5-HT _2AThe external combination of acceptor.Some compounds only are attached to two 5-hydroxytryptamine receptor hypotype 5-HT _1AOr 5-HT _2AOne of on.Except that these effects, proved and absorbed forcefully for 5-HT by chemical compound lot restraining effect has further effect, for example, R wherein ¹Be ethanoyl, R ²Be that hydrogen and Ar are the compounds of the 3-indyl that replaced by halogen 6 or 5, or wherein Ar is compound exhibits IC at 4 phenyl that replaced by Cl ₅₀Value is in being lower than nanomole scope (1-65nM).

Therefore, The compounds of this invention is used for the treatment of the positive and negative symptoms of schizophrenia, other psychosis, anxiety disorder, the side effect, ischemic disease symptom, migraine, senile dementia and the cardiovascular disorder that cause as extensive anxiety disorder, Phobias and obsessional idea and behavior disease, depression, impulse control disorder and alcohol abuse, attack disease, by conventional antipsychotic drug and is used for improvement and sleeps.

Brush agent embodiment

Can prepare pharmaceutical composition of the present invention with this area ordinary method.

For example: tablet can pass through activeconstituents and auxiliary material commonly used and/or mixing diluents, and then compressing mixt prepares in conventional pelleter.The example of auxiliary material or thinner comprises W-Gum, potato starch, talcum powder, Magnesium Stearate, gelatin, lactose, natural gum or the like.Be generally used for that any other auxiliary material of as above toner, spices, sanitas or the like purpose or additive can use as long as them and activeconstituents compatibility.

Injection liquid can be by at the part injection solvent, and lytic activity composition and possible additive in the preferred sterilized water, regulator solution be to volume required, with solution disinfection and install in suitable ampoule or the bottle and prepare.Can add the conventional used any suitable additive in this area, as toning agent, sanitas, antioxidant or the like.Representative formula embodiment for the present composition is as follows:

1) tablet, contain the compound 4a of 5.0mg as free alkali:

Compound 4a 5.0mg

Lactose 60mg

W-Gum 30mg

Hydroxy propyl cellulose 2.4mg

Microcrystalline Cellulose 19.2mg

Croscarmellose sodium, A type 2.4mg

Magnesium Stearate 0.84mg2) tablet, contain the compound 4d of 0.5mg as free alkali:

Compound 4d 0.5mg

Lactose 46.9mg

W-Gum 23.5mg

Polyvinyl pyrrolidone 23.5mg

Microcrystalline Cellulose 14.4mg

Croscarmellose sodium, A type 1.8mg

Magnesium Stearate 0.63mg3) syrup, every milliliter contains:

Compound 11f 25mg

Sorbitol Powder 500mg

Hydroxy propyl cellulose 15mg

Glycerine 50mg

Methyl-metagin 1mg

Propyl-p-hydroxybenzoate ester 0.1mg

Ethanol 0.005ml

Spices 0.05mg

Soluble saccharin 0.5mg

Water adds to 1ml4) injection liquid, every milliliter contains:

Compound 4a 0.5mg

Sorbitol Powder 5.1mg

Acetic acid 0.08mg

Water for injection adds to 1ml

Claims (12)

1. 4-aryl-the 1-of general formula I (indane methyl, Dihydrobenzofuranes methyl or dihydrobenzo thenyl) piperidines ,-tetrahydropyridine or diethylenediamine compound,

   

   Wherein one of X and Y are CH ₂Be selected from CH with another ₂, O and S;

   Choose key wantonly from the dotted line representative that Z sends; When it did not represent key, Z was N, CH or COH; Z is C when it represents key;

   Ar is a phenyl; the 2-thienyl; the 3-thienyl; the 2-furyl; the 3-furyl; the 2-pyrimidyl; the 1-indyl; the 2-indyl; the 3-indyl; 1-indol-2-one base; 3-indol-2-one base; 2-or 3-benzofuryl; 2-or 3-benzothienyl; 1-naphthyl or 2-naphthyl, each group is optional by halogen; low alkyl group; lower alkoxy; lower alkylthio; hydroxyl; the low alkyl group alkylsulfonyl; cyano group; trifluoromethyl; trifluoromethyl sulfonyl oxygen base; cycloalkyl; cycloalkyl low-grade alkyl; nitro; amino; low-grade alkyl amino; two elementary alkyl amido; amido or C _1-2Alkylene dioxo base replaces;

   R ¹Be hydrogen, low alkyl group, low-grade alkenyl, low-grade alkynyl, cycloalkanes (alkene) base, the basic lower alkyl of cycloalkanes (alkene) (alkene/alkynes) base, aryl, aromatic yl elementary alkyl, acyl group, sulfo-acyl group, low alkyl group alkylsulfonyl, trifluoromethyl sulfonyl, aryl sulfonyl,

   R ¹It is radicals R ⁹VCO-, wherein V is O or S and R ⁹Be low alkyl group, cycloalkyl, cycloalkyl low-grade alkyl or aryl, or

   R ¹It is radicals R ¹⁰R ¹¹NCO-or R ¹⁰R ¹¹NCS-, wherein R ¹⁰And R ¹¹Be hydrogen, low alkyl group, cycloalkyl, cycloalkyl low-grade alkyl or aryl independently, or R ¹⁰And R ¹¹Form pyrrolidyl, piperidyl or perhydro azatropylidene base with N atom with their bondings;

   R ²Be hydrogen, low alkyl group, cycloalkyl or cycloalkyl low-grade alkyl;

   Or R ¹And R ²Form group with N atom with their bondings:

   

   Wherein Q is C=O, C=S or CH ₂T is NH, S, O or CH ₂With m be 1-4;

   R ³-R ⁵Be phenylcarbonyl group, lower alkoxy, lower alkylthio, hydroxyl, low alkyl group alkylsulfonyl, cyano group, trifluoromethyl, cycloalkyl, cycloalkyl low-grade alkyl or the nitro of hydrogen, halogen, low alkyl group, lower alkylcarbonyl, phenylcarbonyl group, halogen replacement independently;

   R ⁶And R ⁷Hydrogen or low alkyl group or they are bonded together and form 3-7 unit carbocyclic ring naturally for each;

   R ⁸Be hydrogen or low alkyl group;

   Any alkyl, cycloalkyl or the cycloalkylalkyl that exist can be chosen wantonly by one or two oh group and replace, and this hydroxyl can be chosen wantonly by aliphatic series or aromatic carboxylic acid's esterification; Can choose wantonly by halogen, low alkyl group, lower alkoxy, lower alkylthio, hydroxyl, low alkyl group alkylsulfonyl, cyano group, trifluoromethyl, trifluoromethyl sulfonyl oxygen base, cycloalkyl, cycloalkyl low-grade alkyl or nitro replacement with any aryl substituent that exists

   Or its medicinal acid addition salt.
2. 2. compound according to claim 1 is characterized in that X is CH ₂Or S and Y are CH ₂
3. 3. compound according to claim 1 and 2 is characterized in that R ¹Be acyl group, low alkyl group, lower alkoxy, radicals R ¹⁰R ¹¹NCO-or R ¹⁰R ¹¹NCS-, wherein R ¹⁰Be hydrogen, low alkyl group, cycloalkyl, cycloalkyl low-grade alkyl or aryl and R ¹¹Be hydrogen or low alkyl group, or R ¹⁰And R ¹¹Form pyrrolidyl, piperidyl or perhydro azatropylidene base with N atom with their bondings.
4. 4. compound according to claim 3 is characterized in that R ¹Be formyl radical, ethanoyl, methylamino carbonyl, methylamino thiocarbonyl, dimethylamino carbonyl, dimethylamino thiocarbonyl, methyl sulphonyl, aminocarboxyl, cyclopropyl carbonyl, methyl, pyrrolidyl carbonyl or 4-fluorophenyl aminocarboxyl.
5. 5. according to the described compound of arbitrary claim among the claim 1-4, it is characterized in that R2 is hydrogen or low alkyl group.
6. 6. according to the described compound of arbitrary claim in claim 1 or 2, it is characterized in that R ¹And R ²Be bonded together and form the 5-7 unsubstituted lactam nucleus of unit or pyrrolidyl, piperidyl or perhydro azatropylidene.
7. 7. according to the described compound of arbitrary claim among the claim 1-6, it is characterized in that R ³-R ⁵Be hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl or ethanoyl and R ⁶-R ⁸All be hydrogen.
8. 8. according to the described compound of arbitrary claim among the claim 1-4, it is characterized in that Ar is a phenyl, 3-indyl, 1-indyl or pyrimidyl, or the phenyl, 3-indyl, 1-indyl or the pyrimidyl that are replaced by halogen.
9. 9. according to the described compound of arbitrary claim among claim 1-5 and the 7-8, it is characterized in that R ¹Be ethanoyl, R ²Be indyl or the phenyl that hydrogen and Ar are replaced by halogen.
10. 10. compound according to claim 9 is characterized in that Ar is by chlorine or the 3-indyl of fluorine replacement or the phenyl that is replaced by chlorine on 5-or 6-position on the 4-position.
11. 11. pharmaceutical composition is characterized in that it contains the described at least a compound of arbitrary claim and one or more pharmaceutically acceptable carrier or thinner among the claim 1-10 that treats significant quantity.
12. 12. the described compound of arbitrary claim or its pharmaceutically acceptable acid additive salt or its prodrug can be treated the schizophrenia positive and negative symptoms in preparation among the claim 1-10, other psychosis, anxiety disorder, extensive anxiety disorder, Phobias, obsessional idea and behavior disease, depressed, impulse control disorder and alcohol abuse, attack disease, the side effect that causes by conventional antipsychotic drug, the ischemic disease symptom, migraine, senile dementia and cardiovascular disorder and being used to improved the application of the medicament aspect of sleep.