CN1361783A - Thiazoloderivatives and pharmaceutical compositions containing them - Google Patents

Abstract

Compounds of formula (I); processes to prepare such compounds; compositions containing such compounds and their use in the treatment of depression, anxiety, psychoses (for examples schizophrenia), tardive dyskinesia, obesity, drug addiction, drug abuse, cognitive disorders, Alzheimer's disease, cerebral ischaemia, obsessive-compulsive behaviour, panic attacks, social phobias, eating disorders such as bulimia, anorexia, snacking and binge eating, non-insulin dependent diabetes mellitus, hyperglycaemia, hyperlipidaemia, stress, and their use in the treatment and/or prophylaxis of seizures, neurological disorders such as epilepsy and/or conditions in which there is neurological damage such as stroke, brain trauma, cerebral ischaemia, head injuries and haemorrhage and as an aid to smoking cessation; are described.

Description

Thiazole and derivative and the pharmaceutical composition that contains them

The glyoxalidine that the present invention relates to some new replacements is [2,1-b] thiazole and dihydro-5H-thiazole [3,2-a] pyrimidine compound also also, and described compound is to 5-HT _1AAcceptor has avidity, and inhibition neuron re-uptake serotonin and/or norepinephrine, the invention still further relates to the preparation of described compound, the pharmaceutical composition that contains them, and their application in the following disease of treatment: dysthymia disorders, anxiety, psychosis (for example schizophrenia), tardive dyskinesia, fat, drug habit, drug abuse, cognitive disorder, Alzheimer, obsessional idea and behavior, panic attack, social phobia, eating disorder is Bulimia nerovsa for example, apocleisis, snacking and eating without restraint, non insulin dependent diabetes, hyperglycemia, hyperlipemia, nervous.Help smoking cessation, and treat and/or prevent epileptic seizures, neuropathy for example epilepsy and/or illness that nerve injury takes place for example apoplexy, cerebral trauma, cerebral ischemia, head injury and hemorrhage in application.

WO 98/41528 discloses the formula A compound that is independent enantiomorph, racemic modification or other mixture of enantiomers form

Comprise its pharmacologically acceptable salt, wherein

Ar is phenyl, naphthyl or benzo [b] thienyl, described group can be chosen wantonly respectively by one or more and be selected from following substituting group and replace: a) halogen, b) the optional alkyl that contains 1-3 carbon atom that is replaced by one or more halogens, c) the optional alkoxyl group that contains 1-3 carbon atom that is replaced by one or more halogens, d) the optional alkylthio that contains 1-3 carbon atom that is replaced by one or more halogens, e) the optional phenyl that is replaced by the one or more halogens optional phenoxy group that is replaced by one or more halogens, or f);

R ₁And R ₂Can be identical or different, and be a) H independently, b) contain the alkyl of 1-6 carbon atom, c) contain the alkenyl of 3-6 carbon atom, d) contain the cycloalkyl of 3-7 carbon atom, e) in ring, contain the methyl cycloalkyl of 3-7 carbon atom, f) optional by one or more aryl or heteroaryls that are selected from following substituting group replacement: i) halogen, the ii) optional alkyl that contains 1-3 carbon atom that is replaced by one or more halogens, the iii) optional alkoxyl group that contains 1-3 carbon atom that is replaced by one or more halogens, the iv) optional alkylthio that contains 1-3 carbon atom that is replaced by one or more halogens, g) arylalkyl or heteroarylalkyl, wherein alkyl chain contains 1-3 carbon atom, and aryl or heteroaryl can be chosen wantonly by one or more and be selected from following substituting group and replace: i) halogen, the ii) optional alkyl that contains 1-3 carbon atom that is replaced by one or more halogens, the iii) optional alkoxyl group that contains 1-3 carbon atom that is replaced by one or more halogens, the iv) optional alkylthio that contains 1-3 carbon atom that is replaced by one or more halogens; Perhaps R ₁With R ₂Formation can be chosen the alkylidene chain that is replaced by one or more alkyl that contain 1-3 carbon atom respectively wantonly, and they form 5 yuan or 6 yuan of rings with the atom that it connected like this,

R ₃Be a) H, b) optional by one or more aryl or heteroaryls that are selected from following substituting group replacement: i) halogen, the ii) optional alkyl that contains 1-3 carbon atom that is replaced by one or more halogens, the iii) optional alkoxyl group that contains 1-3 carbon atom that is replaced by one or more halogens, the iv) optional alkylthio that contains 1-3 carbon atom that is replaced by one or more halogens, c) arylmethyl, wherein aryl is optional is selected from following substituting group and replaces by one or more: i) halogen, the ii) optional alkyl that contains 1-3 carbon atom that is replaced by one or more halogens, the iii) optional alkoxyl group that contains 1-3 carbon atom that is replaced by one or more halogens, the iv) optional alkylthio that contains 1-3 carbon atom that is replaced by one or more halogens; Or d) contains the alkoxyalkyl of 3-6 carbon atom; And

R ₄And R ₅Can be identical or different, and independently for containing the alkyl of 1-3 carbon atom, perhaps R ₄And R ₅Form the cycloalkyl ring that comprises 3-6 carbon atom with the atom that they connected;

Described compound can be used for treating for example epilepsy of dysthymia disorders, anxiety, Parkinson's disease, obesity, cognitive disorder, epileptic seizures, neuropathy, and is used as for example neuroprotective of apoplexy of preventing disease.The not open or proposition The compounds of this invention of this document.

Sharpe C.J and Shadbolt R.S. (Journal of MedicinalChemistry, 1971, Vol 14 No.10 p977-982) disclose also [2,1-b] thiazolium compounds of some glyoxalidine with antidepressant activity.Yet this document also points out, generally speaking, the specific activity of these compounds also in this document disclosed tetrahydroglyoxaline low, and toxicity is than tetrahydroglyoxaline height.The not open or proposition The compounds of this invention of this document.WO 97/02269 discloses formula B compound

Comprise its pharmacologically acceptable salt, wherein

A is S (O) _pOr O;

P is 0,1 or 2;

G is 0,1,2,3 or 4;

N is 2 or 3;

R ₁It is a) halogen, b) the optional alkyl that contains 1-3 carbon atom that is replaced by one or more halogens, c) the optional alkoxyl group that contains 1-3 carbon atom that is replaced by one or more halogens, d) the optional respectively alkylthio that contains 1-3 carbon atom that is replaced by one or more halogens, alkyl sulfinyl or alkyl sulphonyl, e) hydroxyl, f) contain the acyloxy of 1-3 carbon atom, g) contain the hydroxyalkyl of 1-3 carbon atom, h) cyano group, i) contain the alkanoyl of 1-6 carbon atom, j) contain the alkoxy carbonyl of 2-6 carbon atom, k) optional respectively by 1 or 2 formamyl or carbamyl ylmethyl that contains the alkyl N-replacement of 1-3 carbon atom respectively, l) optional respectively by 1 or 2 sulfamyl or sulfamyl methyl that contains the alkyl N-replacement of 1-3 carbon atom respectively, or m) optional by 1 or 2 amino that contains the alkyl replacement of 1-3 carbon atom respectively; When g is 2,3 or 4, R ₁Identical or different;

R ₂, R ₃And R ₄Be H or the optional alkyl that contains 1-3 carbon atom that is replaced by one or more halogens independently; And

R ₅It is a) halogen, b) the optional alkyl that contains 1-3 carbon atom that is replaced by one or more halogens, c) the optional alkoxyl group that contains 1-3 carbon atom that is replaced by one or more halogens, d) the optional alkylthio that contains 1-3 carbon atom that is replaced by one or more halogens, alkyl sulfinyl or alkyl sulphonyl, e) hydroxyl, f) contain the acyloxy of 1-3 carbon atom, g) contain the hydroxyalkyl of 1-3 carbon atom, h) cyano group, i) contain the alkanoyl of 1-6 carbon atom, j) contain the alkoxy carbonyl of 2-6 carbon atom, k) optional respectively by 1 or 2 formamyl or carbamyl ylmethyl that contains the alkyl N-replacement of 1-3 carbon atom respectively, l) optional respectively by 1 or 2 sulfamyl or sulfamyl methyl that contains the alkyl N-replacement of 1-3 carbon atom respectively, m) optional by 1 or 2 amino that contains the alkyl replacement of 1-3 carbon atom respectively, or n) H;

Described compound is to 5-HT _1AAcceptor has avidity, and suppresses neuron re-uptake serotonin and/or norepinephrine.This document points out that these compounds can be used for treating the CNS disease.Yet, these compounds show as the active of oxidase inhibitor and/or to other acceptor for example muscarinic receptor have avidity, therefore may cause unwanted side effect.Surprisingly, the invention provides and have the unexpected more selectivity and the compound of effectiveness.The not open or proposition The compounds of this invention of WO 97/02269.

US 4,160, and 768 disclose the 3-(2-benzofuryl)-5 as anti-inflammatory agent, and the 6-glyoxalidine is [2,1-b] thiazole also.The not open or proposition The compounds of this invention of this document.

The invention provides formula I compound

Comprise its pharmacologically acceptable salt, wherein

A is S or O;

G is 0,1,2,3 or 4;

N is 2 or 3;

R ₁It is a) halogen, b) the optional alkyl that contains 1-3 carbon atom that is replaced by one or more halogens, c) the optional alkoxyl group that contains 1-3 carbon atom that is replaced by one or more halogens, d) the optional alkylthio that contains 1-3 carbon atom that is replaced by one or more halogens, alkyl sulfinyl or alkyl sulphonyl, e) hydroxyl, f) contain the acyloxy of 1-3 carbon atom, g) contain the hydroxyalkyl of 1-3 carbon atom, h) cyano group, i) contain the alkanoyl of 1-6 carbon atom, j) contain the alkoxy carbonyl of 2-6 carbon atom, k) optional respectively by 1 or 2 formamyl or carbamyl ylmethyl that contains the alkyl N-replacement of 1-3 carbon atom respectively, l) optional respectively by 1 or 2 sulfamyl or sulfamyl methyl that contains the alkyl N-replacement of 1-3 carbon atom respectively, or m) optional by 1 or 2 amino that contains the alkyl replacement of 1-3 carbon atom respectively; When g is 2,3 or 4, R ₁Identical or different;

R ₂And R ₃Be respectively H;

R ₄Representative contains the hydroxyalkyl of 1-6 carbon atom, Alpha-hydroxy (2-C _1-3Alkoxyl phenyl) methyl, contain the hydroxyl alkenyl on the carbon atom that 3-6 carbon atom and hydroxyl directly be not connected in two keys, contain 3-6 carbon atom and hydroxyl and directly be not connected in hydroxyl alkynyl on the triple-linked carbon atom, the hydroxyl cycloalkyl that contains 3-6 carbon atom, the alkenyl that contains 2-8 carbon atom, the aromatic yl alkenyl that contains 8-10 carbon atom contains the cycloalkyl of 3-6 carbon atom, C _3-7Alkynyl alkoxy C _1-3Alkyl, C _4-7Cycloalkyl alkoxy C _1-3Alkyl, C _1-3Alkoxy C _1-3Alkyl, C _1-3Alkylthio C _1-3Alkyl, C _1-3Alkoxyl group, C _1-3Alkylthio, arylthio, C _1-6Alkanoyl, C _3-6Alkoxy carbonyl alkyl, cyano group, halogen, C _1-4The alkyl imino methyl, C _1-4Alkylamino alkyl or oxyimino methyl;

R ₅Be H or halogen.

One preferred aspect, the invention provides formula I compound

Comprise its pharmacologically acceptable salt, wherein

A is S or O;

G is 0,1,2,3 or 4;

N is 2 or 3;

R ₁It is a) halogen, b) the optional alkyl that contains 1-3 carbon atom that is replaced by one or more halogens, c) the optional alkoxyl group that contains 1-3 carbon atom that is replaced by one or more halogens, d) the optional alkylthio that contains 1-3 carbon atom that is replaced by one or more halogens, alkyl sulfinyl or alkyl sulphonyl, e) hydroxyl, f) contain the acyloxy of 1-3 carbon atom, g) contain the hydroxyalkyl of 1-3 carbon atom, h) cyano group, i) contain the alkanoyl of 1-6 carbon atom, j) contain the alkoxy carbonyl of 2-6 carbon atom, k) optional respectively by 1 or 2 formamyl or carbamyl ylmethyl that contains the alkyl N-replacement of 1-3 carbon atom respectively, l) optional respectively by 1 or 2 sulfamyl or sulfamyl methyl that contains the alkyl N-replacement of 1-3 carbon atom respectively, or m) optional by 1 or 2 amino that contains the alkyl replacement of 1-3 carbon atom respectively; When g is 2,3 or 4, R ₁Identical or different;

R ₂And R ₃Be respectively H;

R ₄Representative contains the hydroxyalkyl of 1-6 carbon atom, contain the hydroxyl alkenyl on the carbon atom that 3-6 carbon atom and hydroxyl directly be not connected in two keys, contain 3-6 carbon atom and hydroxyl and directly be not connected in hydroxyl alkynyl on the triple-linked carbon atom, the hydroxyl cycloalkyl that contains 3-6 carbon atom, the alkenyl that contains 2-8 carbon atom, the cycloalkyl that contains 3-6 carbon atom, C _1-3Alkoxy C _1-3Alkyl, C _1-3Alkylthio C _1-3Alkyl, C _1-3Alkoxyl group, C _1-3Alkylthio, C _1-6Alkanoyl, halogen, C _1-4Alkyl imino methyl, or oxyimino methyl; And

R ₅Be H or halogen.

Should be appreciated that when using in this article, term halogen comprises fluorine, chlorine, bromine and iodine.Should be appreciated that in the alkyl that contains 2 above carbon atoms, alkenyl, alkynyl, alkylthio and alkoxyl group, alkyl can be straight or branched.Aryl is meant the optional phenyl that is replaced by one or more following radicals: C _1-3Alkyl, C _1-3Alkoxy or halogen.

In first group of preferred The compounds of this invention, A is S.

In second group of preferred The compounds of this invention, A is O.

Preferably, g is 0 or 1, and R ₁Be a) halogen, b) the optional alkyl that contains 1-3 carbon atom that is replaced by one or more halogens c) is chosen the alkoxyl group that contains 1-3 carbon atom that is replaced by one or more halogens wantonly.R ₁Be preferably placed at the 5-position of benzo [b] thiphene ring.More preferably, g is 0 or 1, and R ₁Be halogen or the alkoxyl group that contains 1-3 carbon atom.Most preferably, g is 0 or 1, and R ₁Be chlorine or methoxyl group.

N is preferably 2.

R ₂And R ₃Preferably be respectively H.

R ₄Preferred representative contains the hydroxyalkyl of 1-6 carbon atom, contain the hydroxyl alkenyl on the carbon that 3-6 carbon atom and hydroxyl directly be not connected in two keys, contain 3-6 carbon atom and hydroxyl and directly be not connected in hydroxyl alkynyl on the triple-linked carbon, optional by one or more C _1-2The alkenyl that contains 2 carbon atoms that alkyl replaces, C _1-4Alkyl imino methyl or oxyimino methyl.R ₄More preferably representative contains the hydroxyalkyl of 1-5 carbon atom, contain the hydroxyl alkenyl on the carbon that 3-5 carbon atom and hydroxyl directly be not connected in two keys, contain 3-4 carbon atom and hydroxyl and directly be not connected in hydroxyl alkynyl on the triple-linked carbon, or optional by one or more methyl substituted alkenyls that contain 2 carbon atoms.R ₄Most preferably representation hydroxy methyl or vinyl.R ₄Especially be preferably hydroxymethyl.

R ₄Be preferably hydroxymethyl, 1-hydroxyethyl, 1-hydroxyl-1-methylethyl; The 1-hydroxypropyl; 1-hydroxy-2-methyl propyl group; the 1-hydroxybutyl; 1-hydroxy-3-methyl butyl; 1-hydroxyl amyl group; 1-hydroxyl propenyl; 1-hydroxyl fourth-3-thiazolinyl; 1-hydroxy-2-methyl propenyl; 1-hydroxy-2-methyl fourth-3-thiazolinyl; 1-hydroxyl penta-4-thiazolinyl; 1-hydroxypropyn base; 1-hydroxyl fourth-2-alkynyl; methoxymethyl; ethoxyl methyl; methylthio group; bromine; chlorine; vinyl; allyl group; the 1-methyl ethylene; formyl radical; ethanoyl; N-(1-methylethyl) iminomethyl; with the oxyimino methyl.R ₄More preferably hydroxymethyl, 1-hydroxyethyl, 1-hydroxyl-1-methylethyl; 1-hydroxypropyl, 1-hydroxy-2-methyl propyl group, 1-hydroxybutyl, 1-hydroxy-3-methyl butyl, 1-hydroxyl amyl group, 1-hydroxyl propenyl, 1-hydroxyl fourth-3-thiazolinyl, 1-hydroxy-2-methyl propenyl, 1-hydroxy-2-methyl fourth-3-thiazolinyl, 1-hydroxyl penta-4-thiazolinyl, 1-hydroxypropyn base, 1-hydroxyl fourth-2-alkynyl, vinyl, 1-methyl ethylene, ethanoyl, N-(1-methylethyl) iminomethyl and oxyimino methyl.R ₄Most preferably be hydroxymethyl or vinyl.Hydroxymethyl is especially preferred.

R ₅Be preferably H.

N is preferably 2.

In one group of preferred formula I compound, A is S, and g is 0 or 1; N is 2; R ₁Be halogen or the alkoxyl group that contains 1-3 carbon atom; R ₂And R ₃Be respectively H; R ₄Representative contains the hydroxyalkyl of 1-5 carbon atom, contain the hydroxyl alkenyl on the carbon that 3-5 carbon atom and hydroxyl directly be not connected in two keys, contain 3-4 carbon atom and hydroxyl and directly be not connected in hydroxyl alkynyl on the triple-linked carbon, or optional by one or more methyl substituted alkenyls that contain 2 carbon atoms; And R ₅Be H.

In one group of preferred formula I compound, preferably, g is 0 or 1; And R ₁Be chlorine or methoxyl group.More preferably, R ₁5-position in benzo [b] thiphene ring.

Another preferred aspect, the invention provides formula Ia compound

Comprise its pharmacologically acceptable salt, wherein

A is S or O;

G is 0,1,2,3 or 4;

N is 2 or 3;

R ₁It is a) halogen, b) the optional alkyl that contains 1-3 carbon atom that is replaced by one or more halogens, c) the optional alkoxyl group that contains 1-3 carbon atom that is replaced by one or more halogens, d) the optional respectively alkylthio that contains 1-3 carbon atom that is replaced by one or more halogens, alkyl sulfinyl or alkyl sulphonyl, e) hydroxyl, f) contain the acyloxy of 1-3 carbon atom, g) contain the hydroxyalkyl of 1-3 carbon atom, h) cyano group, i) contain the alkanoyl of 1-6 carbon atom, j) contain the alkoxy carbonyl of 2-6 carbon atom, k) optional respectively by 1 or 2 formamyl or carbamyl ylmethyl that contains the alkyl N-replacement of 1-3 carbon atom respectively, l) optional respectively by 1 or 2 sulfamyl or sulfamyl methyl that contains the alkyl N-replacement of 1-3 carbon atom respectively, or m) optional by 1 or 2 amino that contains the alkyl replacement of 1-3 carbon atom respectively; When g is 2,3 or 4, R ₁Identical or different;

R ₄Representative contains the hydroxyalkyl of 1-6 carbon atom, Alpha-hydroxy (2-C _1-3Alkoxyl phenyl) methyl, contain the hydroxyl alkenyl on the carbon atom that 3-6 carbon atom and hydroxyl directly be not connected in two keys, contain 3-6 carbon atom and hydroxyl and directly be not connected in hydroxyl alkynyl on the triple-linked carbon atom, the alkenyl that contains 2-8 carbon atom, the aryl alkenyl that contains 8-10 carbon atom, the cycloalkyl that contains 3-6 carbon atom, C _3-7Alkynyl alkoxy C _1-3Alkyl, C _4-7Cycloalkyl alkoxy C _1-3Alkyl, C _1-3Alkoxy C _1-3Alkyl, C _1-3Alkylthio C _1-3Alkyl, C _1-3Alkoxyl group, C _1-3Alkylthio, arylthio, C _1-6Alkanoyl, C _3-6Alkoxy carbonyl alkyl, cyano group, halogen, C _1-4The alkyl imino methyl, C _1-4Alkylamino methyl or oxyimino methyl.

In first group of preferred The compounds of this invention, A is S.In this group compound, n is preferably 2.In this group compound, g is preferably 0 or 1.R ₁Be preferably halogen, contain the alkoxyl group of 1-3 carbon atom or contain the alkylthio of 1-3 carbon atom.

In second group of preferred The compounds of this invention, A is 0.In this group compound, n is preferably 2.In this group compound, g is preferably 0 or 1.R ₁Be preferably halogen, contain the alkoxyl group of 1-3 carbon atom or contain the alkylthio of 1-3 carbon atom.

In formula I and formula Ia compound, R ₁Be preferably methyl; ethyl; propyl group; sec.-propyl; cyclopropyl; methoxyl group; oxyethyl group; isopropoxy; bromine; chlorine; fluorine; iodine; trifluoromethyl; trifluoromethoxy; methylthio group; methyl sulfinyl; methyl sulphonyl; hydroxyl; methanoyl; acetoxyl group; hydroxymethyl; the 1-hydroxyethyl; 1-hydroxyl-1-methylethyl; the 1-hydroxypropyl; cyano group; formyl radical; ethanoyl; methoxycarbonyl; ethoxy carbonyl; formamyl; the carbamyl ylmethyl; sulfamyl; the sulfamyl methyl; amino; methylamino; dimethylamino; ethylamino or diethylamino.R ₁More preferably methoxyl group, chlorine or methylthio group.

In formula I and formula Ia compound, R ₄Be preferably cyclopropyl, methoxyl group, oxyethyl group, bromine, chlorine, fluorine, iodine, trifluoromethyl, trifluoromethoxy, hydroxymethyl, 1-hydroxyethyl, 1-hydroxyl-1-methylethyl; The 1-hydroxypropyl; 1-hydroxy-2-methyl propyl group; the 1-hydroxybutyl; 1-hydroxy-3-methyl butyl; 1-hydroxyl amyl group; 1-hydroxyl propenyl; 1-hydroxyl fourth-3-thiazolinyl; 1-hydroxy-2-methyl propenyl; 1-hydroxy-2-methyl fourth-3-thiazolinyl; 1-hydroxyl penta-4-thiazolinyl; 3-hydroxyl but-1-ene base; 1-hydroxypropyn base; 1-hydroxyl fourth-2-alkynyl; alpha-hydroxy-2-methoxy-benzyl; methoxymethyl; ethoxyl methyl; the isopropoxy methyl; the cyclo propyl methoxy methyl; cyclobutyl methoxy ylmethyl; Propargyl oxygen ylmethyl; methylthio group; thiophenyl; vinyl; allyl group; third-1-thiazolinyl; 2-methyl-prop-2-thiazolinyl; the 1-methyl ethylene; styryl; formyl radical; ethanoyl; cyano group; the ethoxy carbonyl methyl; N-(1-methylethyl) iminomethyl; N-methylamino methyl and oxyimino methyl.R ₄More preferably hydroxymethyl, 1-hydroxyethyl or vinyl.R ₄Most preferably be hydroxymethyl or vinyl.

In especially preferred formula Ia compound, A is S or O; G is 0 or 1, and n is 2; R ₁Represent halogen, contain the alkoxyl group of 1-3 carbon atom or contain the alkylthio of 1-3 carbon atom; And R ₄Representative contains the hydroxyalkyl of 1-4 carbon atom, Alpha-hydroxy (2-C _1-3Alkoxyl phenyl) methyl, contain the hydroxyl alkenyl on the carbon atom that 3-4 carbon atom and hydroxyl directly be not connected in two keys, contain 3-4 carbon atom and hydroxyl and directly be not connected in hydroxyl alkynyl on the triple-linked carbon atom, contain the alkenyl of 2-3 carbon atom, C _1-3Alkylthio, C _1-2Alkanoyl or oxyimino methyl.

In the rest part of this specification sheets, term " formula I compound " is meant formula I compound or formula Ia compound.Equally, " a kind of formula I compound " is meant a kind of formula I compound or a kind of formula Ia compound.

Formula I compound can be used as the salt existence with pharmaceutically acceptable acid.The present invention includes all these salt, the example of such salt comprise hydrochloride, hydrobromate, vitriol, mesylate, nitrate, maleate, formate, acetate, Citrate trianion, fumarate, tartrate [for example (+)-tartrate, (-)-tartrate or comprise its mixture of racemic mixture], succinate, oxalate, benzoate and with the amino acid salt that forms of L-glutamic acid for example.Such salt is by making as the method known to those skilled in the art of describing in an embodiment.

Some formula I compounds can exist with different tautomeric forms or as different geometrical isomers, and the present invention includes each tautomer of formula I compound and/or geometrical isomer and composition thereof.

Some formula I compounds can exist with different separable stable conformation forms.For example, if there is huge group, because steric hindrance, one or more single bonded rotations may be restricted.Because asymmetric single bonded rotation is restricted, for example because reversing asymmetric making and to isolate different conformers due to steric hindrance or the ring torsion.The present invention includes each conformer of formula I compound and composition thereof.

Some formula I compounds and salt thereof can exist with more than one crystalline form, and the present invention includes each crystalline form and composition thereof.Some formula I compounds and salt thereof can with solvate for example the form of hydrate exist, and the present invention includes each solvate and composition thereof.

Some formula I compounds contain one or more chiral centres, and exist with different optically-active forms.When formula I compound contained a chiral centre, compound existed with two kinds of enantiomerism forms, and the present invention includes the mixture of these two kinds of enantiomers and enantiomer.Can split enantiomer by method known to those skilled in the art, for example forming can be by for example diastereo-isomerism salt of Crystallization Separation; Formation can be passed through for example crystallization, solution-air phase or isolating diastereo-isomerism derivative of liquid chromatography or mixture; Solution-air phase or liquid chromatography in chiral environment for example exist the therapeutic method to keep the adverse qi flowing downward-liquid phase or liquid chromatography with chiral support as having in conjunction with the silica gel of chiral ligand or at chiral solvent.Should be appreciated that when required enantiomer being changed into another chemical entities, need further step to discharge required enantiomerism form by a kind of above-mentioned separation method.Perhaps, can use optical activity reagent, reactant, catalyzer or solvent to synthesize given enantiomer, perhaps a kind of enantiomer be changed into another kind of enantiomer by asymmetric conversion by asymmetric synthesis.

When formula I compound contained more than one chiral centre, it can exist with the diastereo-isomerism form.Can for example chromatography or crystallization process and can separate each internal independent enantiomer as mentioned above with paired diastereomeric separation by method known to those skilled in the art.The present invention includes each diastereomer of formula I compound and composition thereof.

Specific formula I compound is:

3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazole-2-formaldehyde also;

[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] methyl alcohol;

3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazole-2-formoxime also;

1-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] ethanol;

3-(benzo [b] thiene-3-yl-)-2-bromo-5, the 6-glyoxalidine is [2,1-b] thiazole also;

3-(benzo [b] thiene-3-yl-)-2-bromo-6,7-dihydro-5H-thiazole is [3,2-a] pyrimidine also;

1-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also]-the 1-methyl ethanol;

1-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] third-1-alcohol;

2-bromo-3-(5-methoxyl group benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazole also;

2-bromo-3-(the 5-chlorobenzene is [b] thiene-3-yl-also)-5, the 6-glyoxalidine is [2,1-b] thiazole also;

3-(benzo [b] thiene-3-yl-)-2-ethoxyl methyl-5, the 6-glyoxalidine is [2,1-b] thiazole also;

1-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] third-2-alkene-1-alcohol;

1-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] fourth-2-alkynes-1-alcohol;

3-(benzo [b] thiene-3-yl-)-2-vinyl-5, the 6-glyoxalidine is [2,1-b] thiazole also;

2-allyl group-3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazole also;

[3-(benzo [b] furans-3-yl)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] methyl alcohol;

N-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl methylene radical also]-1-methylethyl amine;

3-(benzo [b] thiene-3-yl-)-2-chloro-5, the 6-glyoxalidine is [2,1-b] thiazole also;

2-ethanoyl-3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazole also;

3-(benzo [b] thiene-3-yl-)-2-(methoxymethyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also;

3-(benzo [b] thiene-3-yl-)-2-(methylthio group)-5, the 6-glyoxalidine is [2,1-b] thiazole also;

3-(benzo [b] thiene-3-yl-)-2-(1-methyl ethylene)-5, the 6-glyoxalidine is [2,1-b] thiazole also;

1-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also]-2-methyl-prop-1-alcohol;

1-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] fourth-1-alcohol;

1-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also]-2-methyl fourth-3-alkene-1-alcohol;

1-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also]-3-methyl fourth-1-alcohol;

1-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] penta-1-alcohol;

1-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] third-2-alkynes-1-alcohol;

1-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] fourth-3-alkene-1-alcohol;

1-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also]-2-methyl-prop-2-alkene-1-alcohol;

1-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] penta-4-alkene-1-alcohol;

[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] (2-p-methoxy-phenyl) methyl alcohol;

3-(benzo [b] thiene-3-yl-)-2-third-1-thiazolinyl-5, the 6-glyoxalidine is [2,1-b] thiazole also;

[3-(benzo [b] thiene-3-yl-)-6,7-dihydro-5H-thiazole is [3,2-a] pyrimidine-2-base also] methyl alcohol;

3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazole-2-nitrile also;

3-(benzo [b] thiene-3-yl-)-2-styryl-5, the 6-glyoxalidine is [2,1-b] thiazole also;

3-(the 5-chlorobenzene is [b] thiene-3-yl-also)-5, the 6-glyoxalidine is [2,1-b] thiazole-2-formaldehyde also;

[3-(the 5-chlorobenzene is [b] thiene-3-yl-also)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] methyl alcohol;

3-(benzo [b] thiene-3-yl-)-2 (thiophenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also;

[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also]-N-propylhexedrine;

3-(thionaphthene [b]-3-yl)-2-cyclopropyl-5, the 6-glyoxalidine is [2,1-b] thiazole also;

3-(benzo [b] thiene-3-yl-)-2-iodo-5, the 6-glyoxalidine is [2,1-b] thiazole also;

4-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] fourth-3-alkene-2-alcohol;

3-(benzo [b] thiene-3-yl-)-2-(2-methyl-prop-2-thiazolinyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also;

[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] ethyl acetate;

2-bromo-3-[5-(methylthio group) benzo [b] thiene-3-yl-]-5, the 6-glyoxalidine is [2,1-b] thiazole also;

3-[5-(methylthio group) benzo [b] thiene-3-yl-]-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also } methyl alcohol;

3-(benzo [b] thiene-3-yl-)-2-cyclo propyl methoxy methyl-5, the 6-glyoxalidine is [2,1-b] thiazole also;

3-(benzo [b] thiene-3-yl-)-2-Propargyl oxygen ylmethyl-5, the 6-glyoxalidine is [2,1-b] thiazole also;

2-bromo-3-(7-methoxyl group benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazole also;

3-(benzo [b] thiene-3-yl-)-2-isopropoxy methyl-5, the 6-glyoxalidine is [2,1-b] thiazole also; With

3-(benzo [b] thiene-3-yl-)-2-cyclobutyl methoxy ylmethyl-5, the 6-glyoxalidine is [2,1-b] thiazole also

Comprise its pharmacologically acceptable salt and independent enantiomer, racemic modification or other enantiomeric mixture.

The present invention also comprises pharmaceutical composition, wherein comprises formula I compound or its salt and the pharmaceutically acceptable diluent or the carrier for the treatment of significant quantity.

The term of Shi Yonging " active compound " is meant formula I compound or its salt hereinafter.In treatment was used, active compound can be oral, rectum, parenteral route or topical application, and preferred oral is used.Therefore, therapeutic composition of the present invention can be the form of any known drug composition that is used for oral, rectum, parenteral route or topical.Be applicable to that the pharmaceutically acceptable carrier in such composition is that pharmaceutical field is well-known.The present composition can contain the active compound of 0.1-99% weight.The present composition is made unit dosage usually.The unitary dose of active ingredient is preferably 1-500mg.The vehicle that uses in these preparation of compositions is the known vehicle of pharmaceutical field.

Being used for liquid preparations for oral administration is preferred compositions of the present invention, and they are known oral Pharmaceutical dosage forms, for example tablet, capsule, syrup and water or oil-suspending agent.The vehicle that uses in these preparation of compositions is the known vehicle of pharmaceutical field.Tablet can make like this: at disintegrating agent for example W-Gum and lubricant for example in the presence of the Magnesium Stearate, with active compound and inert diluent for example calcium phosphate mix, and by currently known methods with the mixture film-making.These tablets can be prepared to reach the lasting release of The compounds of this invention by the known mode of those of ordinary skills.If necessary, can be by currently known methods for example by using Cellacefate enteric coating to be provided for such tablet.Similarly, can prepare for example hard or soft gelatin capsule of capsule that contains active compound, adding or do not add vehicle by ordinary method, and if necessary, provide enteric liquid to it by currently known methods.For the purpose of convenient, tablet and capsule contain the 1-500mg active compound respectively.Other composition that is used for oral administration comprises the aqeous suspension that for example contains active compound in the presence of nontoxic suspension agent such as Xylo-Mucine at water medium, or for example contains the oil suspension of The compounds of this invention in the peanut oil at suitable vegetables oil.

The present composition is preferably with known oral Pharmaceutical dosage forms oral administration.The formulation that is applicable to oral administration can comprise tablet, pill, and capsule, many granules comprise: granula, bead, pilule and little granula of sealing; Pulvis, elixir, syrup, suspension and solution.

Solid oral dosage form for example tablet can make by the following component of pharmaceutical composition of the present invention and one or more or its mixture are mixed: inert diluent, for example lime carbonate, calcium sulfate, sompressible sugar, sugar,confectioner's, dextran, dextrin, glucose, dicalcium phosphate dihydrate, the palmitinic acid stearin, hydrogenated vegetable oil, kaolin, lactose, magnesiumcarbonate, magnesium oxide, Star Dri 5, mannitol, Microcrystalline Cellulose, the polyisobutene acid esters, Repone K, Solka-floc, starch,pregelatinized, sodium-chlor, sorbyl alcohol, starch, sucrose, the sugar ball, talcum powder, with three alkali calcium phosphates;

Disintegrating agent, for example alginic acid, calcium carboxymethylcellulose, Xylo-Mucine, colloidal silica, croscarmellose sodium, polyvidone, guar gum, neusilin, methylcellulose gum, Microcrystalline Cellulose, polacrilin potassium, Solka-floc, starch,pregelatinized, sodiun alginate, sodium starch glycolate, starch comprise W-Gum and agar;

Lubricant, for example calcium stearate, glyceryl monostearate, palmitinic acid stearin, hydrogenated castor oil, hydrogenated vegetable oil, light mineral oil, Magnesium Stearate, mineral oil, polyoxyethylene glycol, Sodium Benzoate, sodium lauryl sulphate, stearyl fumarate, stearic acid, talcum powder and Zinic stearas;

Tackiness agent, for example gum arabic, alginic acid, carbomer, Xylo-Mucine, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, Natvosol, hydroxypropylcellulose, Vltra tears, Liquid Glucose, neusilin, Star Dri 5, methylcellulose gum, the polyisobutene acid esters, polyvidone, starch,pregelatinized, sodiun alginate, starch comprises W-Gum, zein, sugar (sucrose for example, molasses and lactose), with natural and synthetical glue (carrageen extract for example, polyoxyethylene glycol, wax, Microcrystalline Cellulose and polyvinylpyrrolidone);

Tinting material, for example Chang Yong acceptable dyes;

Sweetener and correctives;

Sanitas;

When being added in the water, solid dosage can produce bubble to promote one or more pharmaceutically acceptable paired materials (material that for example comprises acid plus carbonate or supercarbonate) of dissolved; With

Can make can by currently known methods for example film-making prepare other optional components known in the art of oral dosage form.

Can prepare solid oral dosage form to continue release of active compounds by mode well known by persons skilled in the art.According to the character of active compound, the film coated solid oral dosage form that comprises the present composition may be favourable.Can use for example shellac and/or sugared of various materials, perhaps change the physical form of oral dosage form as dressing.For example, if necessary, can for example use Cellacefate and/or Hydroxypropyl Methylcellulose Phathalate enteric coating to be provided for tablet or pill by currently known methods.

Can comprise the capsule and/or the nut type preparation (for example hard or soft gelatin capsule) of active compound (adding or do not add for example fatty oil of vehicle) by the ordinary method preparation, and if necessary, can provide enteric coating to it by currently known methods.The content of available currently known methods preparation capsule and/or nut type preparation is to continue release of active compounds.

The liquid oral dosage form that comprises the present composition can be elixir, suspension and/or syrup (for example at the aqeous suspension that contains active compound in the presence of the nontoxic suspension agent [for example Xylo-Mucine] in water medium and/or contain the oil suspension of active compound in suitable vegetables oil [for example peanut oil and/or wunflower seed oil]).Liquid dosage form can also contain one or more sweeteners, correctives, sanitas and/or its mixture.

Active compound can be mixed with the granula that contains or do not contain other vehicle.Granula can directly be swallowed picked-up by the patient, perhaps it can be added in the suitable liquid vehicle (for example water), and then swallow picked-up.Granula can contain disintegrating agent (for example pharmaceutically acceptable effervesce doublet that forms with acid plus carbonate or supercarbonate) to promote the dispersion in liquid medium.

Each above-mentioned oral dosage form preferably contains the about 1000mg of the 1mg-that has an appointment, the about 500mg of 5mg-(for example 10mg, 50mg, 100mg, 200mg or 400mg) active compound more preferably from about.

The present composition that is suitable for rectal administration is known rectal administration formulation, for example has the suppository of stearic fat, semi-synthetic glyceryl ester, Oleum Cocois and/or polyoxyethylene glycol matrix.

Pharmaceutical composition can also parenteral administration (for example subcutaneous with pharmaceutical dosage form (for example sterile suspensions in water and/or oily medium and/or the isoosmotic sterile solution in appropriate solvent of the blood preferred and patient) with known parenteral administration, intramuscular, intradermal and/or intravenous administration [for example by injecting and/or infusion]).Can be with the sterilization of parenteral administration formulation (for example sterilizing) by micro-filtration and/or use suitable sterile agent [for example ethylene oxide].

Can choose wantonly one or more are applicable to that the following pharmaceutically acceptable auxiliaries of parenteral administration is added in the parenteral administration formulation: local anesthetic, sanitas, buffer reagent and/or its mixture.The parenteral administration formulation can be stored in the suitable sterile seal container (for example ampoule and/or bottle) until use.In order to improve stability at lay up period, can be with parenteral administration formulation postlyophilization in being filled into container, and liquid (for example water) is removed in decompression.

Pharmaceutical composition can also be with known medicine feeding through nose pharmaceutical dosage form (for example sprays, aerosol, atomized soln and/or pulvis) nose administration.Can use metering drug delivery system well known by persons skilled in the art (for example aerosolizer and/or sucker).

Pharmaceutical composition can also be administered to (for example sublingual administration) in the cheek cavity with known cheek administrable pharmaceutical dosage form (for example slow molten, Chewing gum, lozenge, dragee, pastille, gelifying agent, paste, mouth wash shua, lotion and/or pulvis).

Topical comprises matrix with composition, and pharmaceutical activity composition wherein of the present invention is dispersed in the matrix, like this compound just with skin contact with can the transdermal administration compound.Suitable transdermal administration composition can by with pharmaceutical active compounds and topical with carrier for example mineral oil, Vaseline and/or wax for example paraffin or beeswax and possible transdermal enhancer for example methyl-sulphoxide or mixed with propylene glycol make.Perhaps, active compound can be dispersed in pharmaceutically acceptable creme or the paste substrate.The content of active compound should be such in the local administration preparation, local administration preparation be placed on the skin during this period of time in the compound of transmissibility treatment significant quantity.

The compounds of this invention also can come administration by continuous infusion, and continuous infusion can be from external source infusion intravenous infusion for example, perhaps from placing intravital compound source infusion.The drug disposition source comprises the drug storehouse storage of implantation, and this drug storehouse storage contains the compound of wanting infusion, and described compound can discharge continuously, for example discharges continuously by osmosis; With such implant: (a) can be liquid, suspension or the solution of infusion compound (for example being the derivative compound of bay salt form for example that is insoluble in very much water) in acceptable oil for example, or the implantation carrier that (b) is the infusion compound solid of synthetic resins or wax-like materials carrier format for example.Carrier can be the single carrier that contains all compounds, perhaps contains a series of carriers that part is sent compound respectively.The amount of active compound should be such in the interior medicine source of body, can be at the compound of long-time delivery treatments significant quantity.

In some preparations, it is favourable using the The compounds of this invention of the particle form that the very little particle of particle diameter for example obtains by fluid energy mill.

In the present composition, can mix by the medicine activity component that active compound and other is compatible if necessary.

The present invention also comprises the formula I compound as medicine.

The pharmaceutical composition that contains treatment significant quantity formula I compound be used in Mammals, particularly philtrum treatment dysthymia disorders, anxiety, psychosis (for example schizophrenia), tardive dyskinesia, obesity, drug habit, drug abuse, cognitive disorder, Alzheimer, obsessional idea and behavior, panic attack, social phobia, eating disorder for example Bulimia nerovsa, apocleisis, snacking and eat without restraint, non insulin dependent diabetes, hyperglycemia, hyperlipemia, anxiety, and help the people to give up smoking.In addition, such composition also can be used for treating and/or preventing for example for example apoplexy, cerebral trauma, cerebral ischemia, head injury and hemorrhage of epilepsy and/or illness that nerve injury takes place of epileptic seizures, neuropathy.In such treatment, though the definite dosage of active compound depends on multiple factor for example patient age, disease serious degree and medical history in the past, and always determine by the attending doctor, but the day dosage of active compound is 1-1000mg, be preferably 5-500mg, and applied once, perhaps one or many divides agent to use in one day.

On the other hand, the invention provides formula I compound and have application in the medicine of following effects: the treatment dysthymia disorders in preparation, anxiety, psychosis (for example schizophrenia), tardive dyskinesia, fat, drug habit, drug abuse, cognitive disorder, Alzheimer, obsessional idea and behavior, panic attack, social phobia, eating disorder is Bulimia nerovsa for example, apocleisis, snacking and eating without restraint, non insulin dependent diabetes, hyperglycemia, hyperlipemia, nervous, help smoking cessation, and treat and/or prevent epileptic seizures, neuropathy is epilepsy and/or illness that nerve injury takes place apoplexy for example for example, cerebral trauma, cerebral ischemia, head injury and hemorrhage.

The present invention also provides the method for the treatment of following disease: dysthymia disorders, anxiety, psychosis (for example schizophrenia), tardive dyskinesia, fat, drug habit, drug abuse, cognitive disorder, Alzheimer, obsessional idea and behavior, panic attack, social phobia, eating disorder is Bulimia nerovsa for example, apocleisis, snacking and eating without restraint, non insulin dependent diabetes, hyperglycemia, hyperlipemia, anxiety and epileptic seizures, neuropathy is epilepsy and/or illness that nerve injury takes place apoplexy for example for example, cerebral trauma, cerebral ischemia, head injury and hemorrhage, this method comprise the formula I compound to patient's administering therapeutic significant quantity of needs treatment.

The present invention also provides the method that alleviates people's craving for tobacco, and this method comprises the formula I compound to patient's administering therapeutic significant quantity that this needs are arranged.The present invention also provide alleviate the people give up smoking the back weight increase method, this method comprises the formula I compound to patient's administering therapeutic significant quantity that this needs are arranged.

In addition, The compounds of this invention can be used for treating or preventing metabolic trouble and by its illness that causes, syndrome, the urinary incontinence, superfunction disease, HH and reflux oesophagitis, pain before living heat of for example non-motor activity and accretion rate increase, sexual dysfunction, insomnia, the menstruation, especially neuropathic pain, weight increase, chronic fatigue syndrome, osteoarthritis and the gout relevant, cancer, menstruation dysfunction, gallbladdergallstonecholetithiasis, postural hypotension and the pulmonary hypertension relevant with weight increase with pharmacological agent.

The compounds of this invention can be used for treating cardiovascular disorder and alleviates platelet adhesion, and losing weight and help after the help pregnancy loses weight after the smoking cessation.

The compounds of this invention is specially adapted to treat obesity and relevant complication for example diabetes, hyperglycemia and hyperlipemia.Becoming known for treating fat monoamine reuptake inhibitor can bring cardiovascular side effects for example to increase heart rate usually and increase blood pressure.The compounds of this invention has reduced cardiovascular side effects, and estimates that using monoamine reuptake inhibitor, particularly NRI may bring this cardiovascular side effects.Though be not wishing to be bound by theory, in The compounds of this invention, 5-HT _1AThe combination of agonism has alleviated the cardiovascular side effects that possibility produces owing to its monoamine reuptake inhibition, particularly its norepinephrine reuptake restraining effect.

On the other hand, the invention provides the method for the cardiovascular side effects that alleviates the anti-obesity medicine, comprise mixing to have 5-HT _1AThe compound of agonism.

On the other hand, the invention provides is 5-HT _1AAgonist and also be the compound of monoamine reuptake inhibitor, particularly NRI at treatment obesity and related complication, do not cause the application of cardiovascular side effects simultaneously again.

The beneficial property rat remote measurement of continuous recording heart rate, blood pressure, body temperature and motor activity therein that particularly preferred The compounds of this invention alleviates cardiovascular side effects confirms in testing.Suitable method is described in: Brockway, BP, Mills, PA ﹠amp; Azar, SH (1991) slowly measures rat blood pressure, heart rate and active novel method continuously by radiotelemetry.Clinical and experiment hypertension-theory and practice (Clinical and ExperimeutalHypertension-Theory and Practice) A13 (5), 885-895 and Guiol, C, Ledoussal, C ﹠amp; Surg é, J-M (1992) slowly measure the radio telemetry system of blood pressure and heart rate in the free rat.The approval of method.Journal?of?Pharmacologicaland?Toxicological?Methods?28，99-105。

The 5-HT of particularly preferred The compounds of this invention _1AAgonism can be measured by electric physiology mode with method known to those skilled in the art.

The method of preparation I compound is described below.Described method can be carried out on individual primary, perhaps by being called carrying out a plurality of parallel synthesizing of high speed similar (High Speed Analoguing).These methods are preferably carried out under normal pressure.

Formula I compound can be by the method preparation of describing in WO 97/02269.In addition, can be by following method preparation I compound.

Formula I compound can be by choosing wantonly in acid for example in the presence of acetate or the sulfuric acid, under 0-200 ℃, preferred 20-150 ℃ of temperature with the dehydration of formula II compound and make:

Wherein A, R ₁, R ₂, R ₃, R ₄, R ₅, g and n as defined above.

Formula II compound can make like this: with the formula III compound

R wherein ₂, R ₃With n as defined above,

React with formula IV compound

Wherein Z is for example halogen such as a bromine of leavings group, and A, R ₁, R ₄, R ₅With g as defined above,

Wherein said reaction is at solvent for example in the presence of the ethanol and choose wantonly in acid and for example carry out in 0-200 ℃ in the presence of the acetate; Preferably carry out this reaction by heating under the boiling temperature of 20 ℃-solvent for use.

Formula I compound can also as described belowly directly make: choose wantonly in acid for example in the presence of the acetate, and choose wantonly at solvent for example in the presence of the ethanol, formula III compound and formula IV compound are reacted under 0-200 ℃ of temperature and without separate type II intermediate; Preferably carry out this reaction by heating under 20-150 ℃ of temperature.

R wherein ₄Represent the formula I compound of halogen to make like this: to choose wantonly at solvent for example in the presence of methylene dichloride, tetrahydrofuran (THF) or the acetone, with formula V compound

Wherein A, R ₁, R ₂, R ₃, R ₅, n and g as defined above,

For example bromine, tribromide phenyltrimethyammonium, iodine monochloride or benzyltrimethylammon.um tetrachloro iodate react under-50-200 ℃ temperature with halogenating agent.

R wherein ₄Represent Shi-CH (OH) R _xShown in group, and R _xBe C _1-5Alkyl, the alkenyl that contains 2-5 carbon atom, the alkynyl that contains 2-5 carbon atom or (2-C _1-3Alkoxyl phenyl) formula I compound can make like this: at solvent for example in the presence of tetrahydrofuran (THF) or the ether, with formula VI compound

Wherein A, R ₁, R ₂, R ₃, R ₅, n and g as defined above, and R _yBe H,

With organometallic reagent formula R for example _xMgX or R _xThe Li compound reacts under the boiling temperature of-50 ℃-solvent for use, wherein R _xAs defined above, and X be for example bromine of halogen.

R wherein ₄Represent Shi-CH (OH) R _yShown in group, and R _yBe C _1-5Alkyl, the alkenyl that contains 2-5 carbon atom, the alkynyl that contains 2-5 carbon atom or (2-C _1-3Alkoxyl phenyl) formula I compound can make like this: at solvent for example in the presence of the ethanol, and wherein A, R ₁, R ₂, R ₃, R ₅, g and n as defined above, and R _yBe C _1-5Alkyl, the alkenyl that contains 2-5 carbon atom, the alkynyl that contains 2-5 carbon atom or (2-C _1-3Alkoxyl phenyl) formula VI compound and reductive agent for example sodium borohydride react under the boiling temperature of 0 ℃-solvent for use.

R wherein ₄The formula I compound that is hydroxymethyl can make like this: at solvent for example in the methyl alcohol, and wherein A, R ₁, R ₂, R ₃, R ₄, R ₅, g and n as defined above, and R _yBe the formula VI compound of H and reductive agent for example sodium borohydride under the boiling temperature of-50 ℃-solvent for use, react.

R wherein ₄The formula I compound that is the oxyimino methyl can make like this: choose wantonly solvent for example alcohol as in the presence of the ethanol, general wherein A, R ₁, R ₂, R ₃, R ₅, g and n as defined above, and R _yBe that the formula VI compound of H and azanol or its salt react under 0-250 ℃ of temperature.

R wherein ₄The formula I compound that is cyano group can make like this: in the presence of formic acid, incite somebody to action wherein A, R ₁, R ₂, R ₃, R ₅, g and n as defined above, and R _yBe that the formula VI compound of H and azanol or its salt react under 0-250 ℃ of temperature.

R wherein ₄Represent C _1-4The formula I compound of alkyl imino methylene radical can make like this: choose wantonly at solvent for example in the presence of the ethanol, and choose wantonly at acid catalyst for example in the presence of the acetate, wherein A, R ₁, R ₂, R ₃, R ₅, g and n as defined above, and R _yRepresent the formula VI compound of H and R wherein _aRepresent C _1-4The formula R of alkyl _aNH ₂Amine under 0-250 ℃ of temperature, react.

R wherein ₄Represent C _1-4The formula I compound of alkylamino methylene radical can make like this: for example pure at solvent as in the presence of the ethanol, incite somebody to action wherein R ₄Represent C _1-4Alkyl imino methylene radical, and A, R ₁, R ₂, R ₃, R ₄, R ₅, g and n as defined above formula I compound and reductive agent for example sodium borohydride under the boiling temperature of 0 ℃-solvent for use, react.

R wherein ₄Represent C _1-4The formula I compound of alkylamino methylene radical can as described belowly directly make: at solvent for example in the presence of the tetrahydrofuran (THF), and wherein A, R ₁, R ₂, R ₃, R ₅, g and n as defined above, and R _yRepresent the formula VI compound of hydrogen and R wherein _aRepresent C _1-4The formula R of alkyl _aNH ₂Amine and reductive agent for example sodium borohydride under the boiling temperature of 0 ℃-solvent for use, react.

R wherein ₄Represent Shi-C (OH) R _xR _yShown in group, and R _xAnd R _yBe C independently respectively _1-5The formula I compound of alkyl can make like this: at solvent for example in the presence of tetrahydrofuran (THF) or the ether, and R wherein _yBe C _1-5Alkyl, and A, R ₁, R ₂, R ₃, R ₅, n and g formula VI compound and organometallic reagent formula R for example as defined above _xMgX or R _xThe Li compound reacts under the boiling temperature of-50 ℃-solvent for use, wherein R _xAs defined above, and X be for example bromine of halogen.

R wherein ₄Represent Shi-C (OH) R _xR _yShown in group, and R _xAnd R _yBe identical C _1-2The formula I compound of alkyl can make like this: at solvent for example in the presence of tetrahydrofuran (THF) or the ether, and will be except R _yBe OR _z, and R _zBe C _1-6The VI compound of formula as defined above of alkyl and organometallic reagent be formula R for example _xMgX or R _xThe Li compound reacts under the boiling temperature of-50 ℃-solvent for use, wherein R _xAs defined above, and X be for example bromine of halogen.

R wherein ₄Represent C _2-6Two keys in alkenyl and the described alkenyl are connected on the alpha-carbon of thiazole ring or represent the formula I compound of styryl to make like this: at alkali for example in the presence of the n-Butyl Lithium, and at solvent for example in ether such as the tetrahydrofuran (THF), R wherein _yRepresent hydrogen or C _1-4Alkyl, and A, R ₁, R ₂, R ₃, R ₅, n and g formula VI compound and formula R as defined above _zPh ₃P ⁺Br ^-Phosphonium salt reacts under the boiling temperature of-78 ℃-solvent for use, wherein R _zRepresent C _1-5Alkyl or benzyl.

R wherein ₄Represent C _2-6The formula I compound of alkanoyl can make like this: at solvent for example in the presence of ether such as ether or the tetrahydrofuran (THF), and R wherein ₄Represent halogen for example bromine or chlorine, and A, R ₁, R ₂, R ₃, R ₅, n and g formula I compound as defined above, or formula V compound and formula R _bMgX or R _bThe Li compound reacts under the boiling temperature of-78 ℃-solvent for use, wherein R _bBe C _1-6Alkyl, and X is for example bromine or a chlorine of halogen; Then at solvent for example in ether such as the tetrahydrofuran (THF), with products therefrom and acylating agent formula R for example _cCON (CH ₃) OCH ₃Compound reacts under the boiling temperature of 0 ℃-solvent for use, wherein R _cRepresent C _1-5Alkyl.Can pass through similar approach preparation formula VI compound.

R wherein ₄Represent C _1-3Alkoxy C _1-3The formula I compound of alkyl can make like this: at alkali for example in the presence of the sodium hydride, and at solvent N for example, in the dinethylformamide, R wherein ₄Representation hydroxy C _1-3Alkyl, and A, R ₁, R ₂, R ₃, R ₅, n and g formula I compound and C as defined above _1-3Alkylating agent is C for example _1-3Alkylogen such as C _1-3Alkyl iodide reacts under-50-150 ℃ temperature.

R wherein ₄Represent C _4-7Cycloalkyl alkoxy C _1-3The formula I compound of alkyl can make like this: at alkali for example in the presence of the sodium hydride, and at solvent N for example, in the dinethylformamide, R wherein ₄Representation hydroxy C _1-3Alkyl, and A, R ₁, R ₂, R ₃, R ₅, n and g formula I compound and C as defined above _4-7The cycloalkyl alkylating agent is C for example _4-7Cycloalkylalkyl halogen such as C _4-7Cycloalkylalkyl iodine reacts under-50-150 ℃ temperature.

R wherein ₄Represent C _3-7Alkynyl alkoxy C _1-3The formula I compound of alkyl can make like this: at alkali for example in the presence of the sodium hydride, and at solvent N for example, in the dinethylformamide, R wherein ₄Representation hydroxy C _1-3Alkyl, and A, R ₁, R ₂, R ₃, R ₅, n and g formula I compound and C as defined above _3-7The alkynyl alkylating agent is C for example _3-7Alkynyl alkylogen such as C _3-7The alkynyl alkyl iodide reacts under-50-150 ℃ temperature.

R wherein ₄Represent C _1-3Alkylthio C _1-3The formula I compound of alkyl can make like this: at alkali for example in the presence of sodium hydride or the sodium hydroxide, and at solvent N for example, in the dinethylformamide, R wherein ₄Represent sulfydryl C _1-3Alkyl, and A, R ₁, R ₂, R ₃, R ₅, n and g formula I compound and C as defined above _1-3Alkylating agent is C for example _1-3Alkylogen such as C _1-3Alkyl iodide reacts under-50-150 ℃ temperature.

R wherein ₄Represent C _1-3Alkylthio or arylthio, and A, R ₁, R ₂, R ₃, R ₅, n and g as defined above formula I compound can make like this: at solvent for example in ether or ether mixture such as tetrahydrofuran (THF) or the ether, R wherein ₄Represent the formula I compound of halogen or formula V compound and metalating agent for example formula RMgX or RLi compound under the boiling temperature of-100 ℃-solvent for use, react, wherein R is C _1-6Alkyl, and X is for example chlorine, bromine or iodine of halogen, to generate the intermediate mixture, with this intermediate and formula R _dS-SR _dDisulphide reacts under the boiling temperature of-100 ℃-solvent for use, wherein R _dBe C _1-3Alkyl or aryl.

R wherein ₄Represent C _1-3Alkoxyl group, and A, R ₁, R ₂, R ₃, R ₅, n and g as defined above formula I compound can make like this: choose wantonly at solvent C for example _1-3Alcohol or dimethyl formamide exist down, choose wantonly at catalyzer for example in the presence of copper (I) salt, and the general is R wherein ₄Represent halogen for example the formula I compound and the C of bromine or iodine _1-3Sodium salt that alkoxide is for example pure or sylvite are 0-350 ℃ of reaction.

R wherein ₄Represent C _3-6Alkenyl, and the formula I compound that two keys of this thiazolinyl are not connected on the alpha-carbon of thiazole ring can make like this: at solvent for example in the presence of ether such as ether or the tetrahydrofuran (THF), R wherein ₄Represent halogen for example bromine or chlorine, and A, R ₁, R ₂, R ₃, R ₅, n and g formula I compound as defined above, or formula V compound and formula R _bMgX or R _bThe Li compound reacts under the boiling temperature of-78 ℃-solvent for use, wherein R _bBe C _1-6Alkyl, and X is for example bromine or a chlorine of halogen; Then at solvent for example in ether such as the tetrahydrofuran (THF), with products therefrom and alkylene agent C for example _3-6Alkenyl methyl halide such as C _3-6The alkenyl methyl-iodide reacts under the boiling temperature of 0 ℃-solvent for use.

R wherein ₄Be C _3-6The formula I compound of alkoxy carbonyl alkyl can make like this: at alkali for example in the presence of the sodium hydride, solvent for example ether as 1, in the 4-dioxane, R wherein _yRepresent hydrogen, and A, R ₁, R ₂, R ₃, R ₅, n and g formula VI compound and R wherein as defined above _zRepresent C _1-4The formula Me of alkyl ₂NCH[PO (OR _z) ₂] ₂Phosphonic acid ester reacts under the boiling temperature of-78 ℃-solvent for use, for example in the presence of the hydrochloric acid gained intermediate is carried out partial hydrolysis in acid then.

R wherein ₄Represent C _4-6Hydroxyl alkenyl, and the formula I compound that two keys of thiazolinyl are connected on the alpha-carbon of thiazole ring can make like this: at alkali for example in the presence of the sodium hydride, at solvent for example in ether such as the tetrahydrofuran (THF), R wherein _yRepresent hydrogen, and A, R ₁, R ₂, R ₃, R ₅, n and g formula VI compound and R wherein as defined above _zRepresent C _1-2Alkyl and R _cRepresent C _1-3Formula (the R of alkyl _zO) ₂POCH ₂COR _cCompound reacts under the boiling temperature of-78 ℃-solvent for use, then solvent for example in the ethanol with gained intermediate product and reductive agent for example sodium borohydride under the boiling temperature of-20 ℃-solvent for use, react.

The commercially available acquisition of formula III compound perhaps can make by method known to those skilled in the art.Formula IV compound can be by making as specifically described method known to those skilled in the art in each embodiment of this paper.

Confirmed the ability of formula I compound (embodiment 1-56 product) and serotonin (5-HT) acceptor interaction by following test, following measurements determination compound at the vitro inhibition tritium for part and 5-HT acceptor, particularly 5-HT _1AThe binding ability of acceptor.

To derive from male Sprague-Dawley rat (Charles River; Body weight is 150-250g) brain hippocampal tissue ice-cold 50mM Tris-HCl damping fluid (when being pH7.7 25 ℃ of mensuration, 1: homogenizing 40w/v), and 4 ℃ with 40, centrifugal 10 minutes of 000g.With centrifugal settling group homogenizing again in identical damping fluid, kept 10 minutes at 37 ℃, and 4 ℃ with 40, centrifugal 10 minutes of 000g.Final centrifugal settling group is resuspended to contains 4mM CaCl ₂, 0.1%L-xitix and 10 μ M pargyline hydrochlorides 50mMTris-HCl damping fluid (pH7.7) in (be equivalent to the tissue of 6.25mg weight in wet base/ml), and be used for immediately in conjunction with measuring.

With film (400 μ l; Tissue/the pipe that is equivalent to 2.5mg Wen Chong) with 50 μ l[of the single concentration of 1nM ³H] 8-hydroxyl-2-(dipropyl amino) naphthane ([ ³H] 8-OH-DPAT) and 50 μ l distilled water (total binding) or 50 μ l test compounds (10 ^-6The single concentration of M or between 10 ^-11-10 ^-310 concentration between the M) or 50 μ l 5-HT (10 μ M, non-specific binding) cultivated 30 minutes at 25 ℃.Use Skatron Cell Harvester to end to cultivate by under vacuum, filtering rapidly via Skatron 11734 filters.With ice-cold 50mMTris-HCl damping fluid, pH7.7 washing nozzle (at 25 ℃, washing is provided with 9,9,0).The filter paper perforation of band groove is outputed in the bottle, add scintillating liquid, and measure radioactivity by liquid scintillation counting(LSC).

Confirmed formula I compound (embodiment 1-56 product) and the interactional ability of serotonin (5-HT) reuptake sites by following test, following measurements determination compound external from the 5-HT reuptake sites replace the standard part [ ³H] ability of citalopram.

With derive from body weight be the preceding cortical tissue of brain of male Charles River rat of 150-250g at the ice-cold 50mMTris-HCl that contains 120mM sodium-chlor and 5mM Repone K, pH7.4 (25 ℃ of mensuration) (Tris damping fluid; 1: homogenizing 30w/v), and with 40, centrifugal 10 minutes of 000g.Abandoning supernatant, and with centrifugal settling group at the Tris damping fluid, 1: homogenizing again among the 60w/v, and with 40, centrifugal 10 minutes of 000g.This step repeats once again.Final centrifugal settling group is resuspended to the 50mM Tris-HCl that contains 120mM sodium-chlor and 5mM Repone K, (is equivalent to the tissue of 3.125mg weight in wet base/ml), and is used for immediately among the pH7.4 in conjunction with measuring.All are centrifugal all carries out at 4 ℃.

With film (400 μ l; Tissue/the pipe that is equivalent to the 1.25mg weight in wet base) with 50 μ l[of the single concentration of 1.3nM ³H] citalopram and 50 μ l distilled water (total binding) or 50 μ l test compounds (10 ^-6The single concentration of M or between 10 ^-11-10 ^-310 concentration between the M) or 50 μ l Paroxetines (0.5 μ M, non-specific binding) cultivated 1 hour at 27 ℃.Use Skatron Cell Harvester by filtering collection membrane bonded radioactivity under the vacuum that is dipped in the Skatron11734 filter among the 0.5%PEI in advance.Use ice-cold 50mMTris-HCl damping fluid then, pH7.4 (at 25 ℃, washing is provided with 9,9,0) washing nozzle.The filter paper perforation of band groove is outputed in the bottle, add scintillating liquid, and measure radioactivity by liquid scintillation counting(LSC).

Confirmed formula I compound (product of embodiment 1-33) and the interactional ability of norepinephrine (NA) reuptake sites by following test, following measurements determination compound external replace from the norepinephrine reuptake site standard part [ ³H] ability of nisoxetine.

(speed is set to 6 to use Kinematic polytron, 10 seconds) will derive from body weight be the preceding cortical tissue of brain of male Charles River rat of 150-250g at the ice-cold 50mM Tris-HCl that contains 120mM sodium-chlor and 5mM Repone K, pH7.4 (25 ℃ of mensuration) (Tris damping fluid; 1: homogenizing 60w/v), and with 40, centrifugal 10 minutes of 000g.Abandoning supernatant, and with centrifugal settling group at the Tris damping fluid, 1: homogenizing again among the 60w/v, and with 40, centrifugal 10 minutes of 000g.This step repeats twice, like this cerebral tissue homogenizing and centrifugal 4 times altogether.Final centrifugal settling group is resuspended to the 50mM Tris-HCl that contains 300mM sodium-chlor and 5mM Repone K, (is equivalent to the tissue of 18.75mg weight in wet base/ml), and is used for immediately among the pH7.4 in conjunction with measuring.All are centrifugal all carries out at 4 ℃.

With film (400 μ l; Tissue/the pipe that is equivalent to the 7.5mg weight in wet base) with 50 μ l[of the single concentration of 0.6nM ³H] nisoxetine and 50 μ l distilled water (total binding) or 50 μ l test compounds (10 ^-6The single concentration of M or between 10 ^-11-10 ^-310 concentration between the M) or 50 μ l SaH-42548s (1 μ M, non-specific binding) cultivated 4 hours at 4 ℃.Use SkatronCell Harvester to come collection membrane bonded radioactivity by under vacuum, filtering via Skatron 11734 filters.Then with the ice-cold 50mM Tris-HCl damping fluid that contains 120mM sodium-chlor and 5mM Repone K, the rapid washing nozzle of pH7.4 (washing is provided with 9,9,0).The filter paper perforation of band groove is outputed in the bottle, add scintillating liquid, and measure radioactivity by liquid scintillation counting(LSC).

Confirmed formula I compound (embodiment 1-56 product) and the interactional ability of muscarinic receptor by following test, following measurements determination compound external from muscarinic receptor replace the standard part [ ³H] ability of N-epoxytropine tropate.

(speed is set to 21700rpm to use Polytron PT3100,3 * 5 seconds) will to derive from body weight be that the preceding cortical tissue of brain of male Charles River rat of 150-250g is at the ice-cold 20mM HEPES damping fluid that contains 100mM sodium-chlor and 10mM magnesium chloride, pH7.5 (25 ℃ of mensuration) (1: homogenizing 10w/v), and 4 ℃ with 49, centrifugal 30 minutes of 500g.Abandoning supernatant, and centrifugal settling group contained the 20mM HEPES damping fluid of 100mM sodium-chlor and 10mM magnesium chloride, among the pH7.5 again homogenizing (be equivalent to the tissue of 12.5mg weight in wet base/ml).With film-80 ℃ of storages until needs.

Film is melted, use aforesaid Polytron PT3100 with 1: 10 ratio containing the 20mM HEPES damping fluid of 100mM sodium-chlor and 10mM magnesium chloride, dilute among the pH7.5.Film (200 μ l with dilution; Tissue/the pipe that is equivalent to the 0.25mg weight in wet base) contains the 20mM HEPES damping fluid of 100mM sodium-chlor and 10mM magnesium chloride, 50 μ l[of pH7.5 and the single concentration of 0.15nM with 200ml ³H] N-epoxytropine tropate and 50 μ l distilled water (total binding) or 50 μ l test compounds (10 ^-6The single concentration of M or between 10 ^-11-10 ^-310 concentration between the M) or 50 μ l Tropintrans (1 μ M, non-specific binding) cultivated 30 minutes at 30 ℃.Use Skatron Cell Harvester to come collection membrane bonded radioactivity by under vacuum, filtering via the Skatron11734 filter.Use ice-cold 20mMHEPES damping fluid then, the rapid washing nozzle of pH7.5 (in that 5,5 washings 1,2 are set).The filter paper perforation of band groove is outputed in the bottle, add scintillating liquid, and measure radioactivity by liquid scintillation counting(LSC).

For each measure formula I compound external from 5-HT _1AAcceptor and serotonin (5-HT) and norepinephrine (NA) reuptake sites and muscarinic receptor are replaced these tests of the ability of standard part, calculate 10 by following method ^-6The M test compounds with tritium for the specificity of part in conjunction with the per-cent of replacing.

At first, measure and not have (A) and tritium under the situation that (B) test compounds exists to be arranged for the specificity combination of part: do not have compound to exist to descend:

A (dpm)=total binding (dpm)-non-specific binding (dpm) is in the presence of compound (10 ^-6M):

B (dpm)=10 ^-6The combination of M (dpm)-non-specific binding (dpm)

Then, will be in the presence of compound the tritium of (B) account for the tritium that do not have (A) in the presence of the compound specificity bonded per-cent for the specificity of part in conjunction with changing into for part:

10 ^-6The % specificity combination=B (dpm) of M/A (dpm) * 100

Acquisition test compounds (10 as described below then ^-6M) with tritium for the specificity of part in conjunction with the per-cent of replacing: will not have compound to exist specificity down to deduct the specificity bonded per-cent in the presence of compound in conjunction with per-cent (its as maximum combined, so equal 100%):

10 ^-6% replacement=the 100-of M is 10 ^-6The % specificity combination of M

In some cases, use the compound of finite concentration scope, make about 10 ^-6M replaced 〉=and 50% tritium is for the replacement curve of ligand specificity's bonded compound.Carry out entirely (robust) non-linear regression by the data that will derive from 3 parallel experiments then and come the following simultaneous equations of match (deriving from the Feldman equation), thereby calculate K _i: F ₁=[L] _Tw-B ${K_i}^{\′}=K_i(1+\frac{F_1}{K_d})$ $\mathrm{ab}=\frac{C_k{r}_1-L+{K_i}^{\′}}{2}$ $F_2=-\mathrm{ab}+\sqrt{{\mathrm{ab}}^2+{K_i}^{\′}L}$

Wherein B is the concentration of bonded ligand-receptor mixture.For each observation, B calculates like this:

B=DPM/ (specific activity * volume of culture)

L is a compound concentrations

[L] _TotBe the concentration of used tritium for part, it is to calculate like this:

[L] _Tot=(total DPM adds the average DPM * extent of dilution of sample)/(specific activity * volume of culture)

K _dIt is the dissociation equilibrium constant of part.

F ₁And F ₂Be respectively the concentration of free ligand and free cpds.

r ₁It is the total concn of acceptor in first experiment.For experiment subsequently, it must multiply by C _k(C ₁=1).

N _kIt is non-specific binding constant.

In above-mentioned test, use that embodiment 1-56 end product obtained about 5-HT _1AIn conjunction with the results are shown in the following table 1 with 5-HT and NA re-uptake and muscarine bonded.K _iThe unit of s is nM, and is 3 independent mean values of measuring.The % data be about each measure separately 10 ^-6The % of M replaces.

Table 1

Embodiment number	???5-HT 1A	The 5-HT re-uptake	The NA re-uptake	Muscarine
					????1	????51％	????1％	????58％	????0％
????2	????13	????398	????3.7	????19％
					????3	????201	????200	????12	????28％
????4	????26	????72％	????6.2	????0％
					????5	????11	????162	????3.1	????16％
????6	????7.7	????378	????3.5	????9％
					????7	????18	????492	????8.9	????338
????8	????79％	????48％	????85％	????87％
					????9	????114	????119	????17	????17％
????10	????73％	????19％	????94％	????16％
					????11	????97％	????8％	????61％	????39％
????12	????93％	????18％	????87％	????54％
					????13	????101	????89	????2.0	????15
????14	????82％	????39％	????3.1％	????16％
					????15	????60	????269	????8.1	????4％
????16	????27	????510	????3.8	????418
					????17	????16	????162	????2.7	????10.4
????18	????2.0	????14％	????46	????11％
					????19	????59％	????8％	????57％	????19％
????20	????5.0	????623	????9.3	????420
					????21	????62％	????13％	????93％	????22％
????22	????93	????283	????2.2	????49
					????23	????27	????71	????1.1	????63

Embodiment number	???5-HT 1A	The 5-HT re-uptake	The NA re-uptake	Muscarine
					????24	????98	????245	????5.6	????353
????25	????74％	????34％	????99％	????51％
					????26	????61％	????57％	????99％	????33％
????27	????64％	????43％	????99％	????49％
					????28	????73％	????48％	????97％	????48％
????29	????55％	????42％	????99％	????35％
					????30	????58％	????42％	????99％	????-5％
????31	????53％	????62％	???101％	????28％
					????32	????69％	????54％	????100％	????36％
????33	????55％	????48％	????101％	????28％
					????34	????76	????234	????61	????23％
????35	????36.5	????347	????2.2	????245
					????36	????62％	????68％	????104％	????95％
????37	????189	????30％	????146	????20％
					????38	????50％	????5％	????84％	????16％
????39	????73％	????64％	????64％	????64％
					????40	????75％	????62％	????44％	????16％
????41	????2.9	????110	????7.5	????28％
					????42	????100％	????65％	????101％	????31％
????43	????57％	????60％	????102％	????99％
					????44	????53％	????4％	????86％	????32％
????45	????8.8	????28	????1.6	????7.9
					????46	????94％	????92％	????100％	????88％
????47	????53％	????65％	????97％	????39％
					????48	????23	????24.3	????4.1	????3.9

Embodiment number	???5-HT 1A	The 5-HT re-uptake	The NA re-uptake	Muscarine
					????49	????77％	????61％	????102％	????73％
????50	????98％	????46％	????82％	????81％
					????51	????2.1	????251	????17	????39％
????52	????66％	????86％	????103％	????97％
					????53	????64％	????71％	????101％	????100％
????54	????54％	????97％	????101％	????2％
					????55	????60％	????85％	????101％	????NT
????56	????61％	????81％	????101％	????96％

K _iValue is n=1, the mean value of n=2 or the mean value of n=3.NT=does not test.

Suppress the active ability of monoamine oxidase A by following measurements determination The compounds of this invention.

Use the following general method of the wherein tissue-derived people's of being placenta to measure:

Enzyme	Substrate	Cultivate	Reaction product	Detection method
					??MAO-A(h)	Kynuramine (0.15mM)	30 minutes/30 ℃	The 4-OH quinoline	Spectrophotometry

Compound 1 and 10 micromoles to carry out in duplicate.

Reference: Weyler, W. and Salach, J.I. (1985) is purifying plastosome monoamine oxidase A type and feature thereof from people's placenta.J.Biol.Chem.，260：13199-13207。

Monoamine oxidase combination active and that the 5-HT re-uptake suppresses can cause serotonin syndrome (Sternbach, H. serotonin syndrome.Am.J.Psychiatry 148,705-713,1991), this is highly unfavorable.Acute feeding laboratory animal and environment

Experimentize with the male Sprague-Dawley rat that derives from Charles River (Margate) (body weight is 300-450g when experiment begins).Animal is raised separately under 22 ± 1 ℃ and 55% temperature in having the polypropylene cage of metal grid floor.Placement polypropylene tray below each cage.Animal is remained in anti-phase illumination-dark cycle.From 09: 30-17: 30 close black out, shine the room by red light during this.Allow animal can freely obtain powdery rat feed and tap water always.Feed is placed on the glass raising jar with aluminium cover, and (diameter is 10cm; Dark 8cm) in.Each aluminium cover has the hole of cutting (diameter is 3cm) to allow rat can obtain food.Before experiment, allow rat adapt at least 2 weeks of these conditions.Testing method

Test the day before yesterday beginning, animal is assigned randomly in every group of treatment group that comprises 6-8 rat, weigh, measure their food intakes at 6 hours.These datum readings of record are to guarantee that not body weight and the ingestion of food of rat do not have significant difference on the same group before pharmacological agent.On the same day of test, use in the middle of carrier or 3 the dosage testing drugs one to rat.All medicines all are Orally administered when dark period begins, because the food of most of rat its maximum of picked-up in during this period.When administration and the administration feed of weighing after 1,2,4,6 and 24 hours irritate (approximate) to 0.1g.For each reading, all be determined at the food that overflows on the plate below the cage, then it is put back to during feed irritates.Yet, irritate the food debris that overflows from feed and ignore usually.

All drug doses are all by free alkali.Use ultra sonic bath with medicine dissolution at deionized water or be suspended in 0.4% Mierocrystalline cellulose (cellosize).Data analysis

Body weight change is with g/kg rat body weight (treatment cell mean ± s.e. mean value) expression.Use computer dependent program to calculate ED from the logarithm sigmoid curve ₅₀Value (food intake being reduced to 50% required drug dose of control value).The statistics that user's difference analysis and Dunnett ' s check (two tail) average between the group compares.

Compare with the embodiment of WO 97/02269, particularly preferred formula Ia compound has the wonderful lower avidity to muscarinic receptor, and/or compares with the compound of WO 97/02269 illustrated, has significantly reduced MAO _ASuppress active.For example, the muscarinic receptor of the embodiment 1 of WO97/02269 is in conjunction with K _iBe 130nM.The muscarine affinity can cause unwanted side effect, and for example dry, the dimness of vision, perspiration, palpitaition, constipation and angle closure glaucoma increase the weight of (Blackwell, the side effect of B. antidepressant drug.Part 1: monoamine oxidase inhibitor and tricyclic antidepressants medicine.Drugs?21，202-219，1981)。Clearly, muscarinic receptor being had the compound of minimum avidity is ideal.

In the experiment of acute feeding, and to compare at the compound of WO 97/02269 illustrated, the particularly preferred compound of the present invention has better activity.

Illustrate the present invention by following embodiment, providing these embodiment only is to illustrate for example.Characterize by the end product of one or more following methods: high performance liquid chromatography each embodiment; Ultimate analysis; Nuclear magnetic resonance spectrometry, mass spectroscopy and infrared spectroscopy.

EXAMPLE Example 1

＜10 ℃, stir under, triethylamine (75ml) is added drop-wise to 3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazole hydrobromide salt (50g also; The method described among the WO97/02269 makes according to being similar to) methylene dichloride (400ml) suspension in, then with this mixture stirring at room 1 hour.Add entry (300ml), isolate organic phase then, water and (2 * 100ml) and saturated sodium-chloride water solution (100ml) washing, drying (Na ₂SO ₄), under vacuum, remove and desolvate, obtained 3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazole also, for light yellow solid (34g), need not be further purified direct use.

Under-70 ℃, nitrogen atmosphere, stirring, with n-Butyl Lithium (2.5M hexane solution; 17.5ml) being added drop-wise to 3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine also in tetrahydrofuran (THF) (260ml) solution of [2,1-b] thiazoles (10.14g), stirs this mixture 20 minutes at-70 ℃, is warmed to 0 ℃, and stirs 30 minutes at 0 ℃.Add dimethyl formamide (2.86ml), and with this mixture stirring at room 20 minutes.Add saturated sodium-chloride water solution (200ml) and ether (400ml), isolate organic phase then, water (100ml) and saturated sodium-chloride water solution (100ml) washing, dry (Na ₂SO ₄), and under vacuum, remove and desolvate.By dodging formula silica gel chromatography purifying resistates, use 10: 1 methylene dichloride and carbinol mixture as eluent.Merge suitable fraction, and under vacuum, remove and desolvate.With resistates and propan-2-ol (100ml) reflux 5 minutes,, and be cooled to room temperature then with this mixture filtered while hot.Collect the gained solid by filtering, and 60 ℃ of dryings under vacuum, obtained 3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazole-2-formaldehyde also, and it is yellow solid (1.4g), m.p.206 ℃.Embodiment 2

With 3-(benzo [b] thiene-3-yl-)-5,6-glyoxalidine also [2,1-b] mixture of thiazole-2-formaldehyde (0.198g), sodium borohydride (0.026g) and methyl alcohol (20ml) stirred 1 hour under nitrogen atmosphere in room temperature, adds entry (2ml) then, and concentrate to remove methyl alcohol under vacuum.Resistates is distributed between water (30ml) and ethyl acetate (50ml), isolate organic phase then, with saturated sodium-chloride water solution (20ml) washing, dry (Na ₂SO ₄), and under vacuum, remove and desolvate, obtained [3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] methyl alcohol, be yellow solid (0.077g), m.p.168-170 ℃.Embodiment 3

With 3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine also mixture heating up of [2,1-b] thiazole-2-formaldehyde (0.44g), hydroxylamine hydrochloride (0.118g) and ethanol (30ml) refluxed 2.75 hours, was cooled to room temperature then.Collect the gained solid by filtering, and be suspended in the methylene dichloride (50ml).Add triethylamine (3ml), then with gained solution with water (20ml) and saturated sodium-chloride water solution (20ml) washing, dry (MgSO ₄), and under vacuum, remove and desolvate, having obtained 3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazole-2-formoxime also, is white solid (0.07g), m.p.226-228 ℃.Embodiment 4

Under 0 ℃, nitrogen atmosphere, stirring, with methylmagnesium-bromide (3M diethyl ether solution; 1.2ml) be added drop-wise to 3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is also in tetrahydrofuran (THF) (30ml) solution of [2,1-b] thiazole-2-formaldehyde (0.286g), then with this mixture stirring at room 15 minutes.Add entry (5ml) and ethyl acetate (70ml), isolate organic phase then, water (20ml) and saturated sodium-chloride water solution (20ml) washing, dry (Na ₂SO ₄), and under vacuum, remove and desolvate.Resistates with ether (30ml) development, is collected the gained solid by filtering, and dry under vacuum at 100 ℃, obtained 1-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] ethanol, be beige solid (0.213g), m.p.174-176 ℃.Embodiment 5

Ethanol (25ml) the suspension reflux of [3-(benzo [b] thiene-3-yl-)-5,6-glyoxalidine be [2,1-b] thiazol-2-yl also] methyl alcohol (0.5g) is all dissolved until all solids.Add ether solution of hydrogen chloride (1M; 2ml), then this mixture heating up was refluxed 3 minutes, and be cooled to room temperature.Collect the gained solid by filtering, with ether (20ml) washing, and dry under vacuum at 60 ℃, obtained 3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazole-2-methylate hydrochlorate also, be white solid (0.32g) m.p.240-250 ℃ (decomposition).With ether solution of hydrogen chloride (1M; 2ml) be added to and separate in the filtrate that above-mentioned solid obtained, and with this mixture stirring at room 18 hours.Collect the gained solid by filtering, with ether (20ml) washing, and dry under vacuum at 60 ℃, obtained another batch [3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] methylate hydrochlorate, be white solid (0.1g) m.p.240-250 ℃ (decomposition).Embodiment 6

With 3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazole hydrobromide salt (200g also; According to being similar among the WO 97/02269 the method preparation described), the mixture of saturated sodium bicarbonate aqueous solution (1000ml) and methylene dichloride (2000ml) vigorous stirring 1.5 hours at room temperature, isolate organic layer then, water (500ml) washing, dry (MgSO ₄), and under vacuum, remove and desolvate.Repeat this operation with identical scale; Two batches of products are merged, obtained 3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazole also, for light yellow solid (264.3g), need not be further purified direct use.

0-5 ℃, stir under, with 1.75 hours bromine (55.5ml) is added drop-wise to 3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is also in the dichloromethane solution of [2,1-b] thiazoles (264.3g), then this mixture was stirred 30 minutes at 0 ℃, and stirring at room 1 hour.Collect the gained solid by filtering, with methylene dichloride (300ml) washing, and dry under vacuum at 70 ℃, obtained 3-(benzo [b] thiene-3-yl-)-2-bromo-5, the 6-glyoxalidine is [2,1-b] thiazole hydrobromide salt also, for light yellow solid (431g), need not be further purified direct use.

Under 0-8 ℃, nitrogen atmosphere, stirring, with 1 hour with 3-(thionaphthene-3-yl)-2-bromo-5,6-glyoxalidine also [2,1-b] thiazole hydrobromide salt (170g) is added in tetrahydrofuran (THF) (1700ml) solution of ethyl-magnesium-chloride [2.0M diethyl ether solution (620ml)] in batches, then this mixture stirred 1.5 hours at 3 ℃.3-8 ℃ with adding dimethyl formamide (136ml) in 30 minutes, then with this mixture stirring at room 2 hours, be cooled to 8 ℃, and by adding saturated aqueous ammonium chloride (600ml) carefully and water (350ml) comes stopped reaction.Add ethyl acetate (1500ml), and with this mixture stirring at room 18 hours, collect gained solid (first part's solid) by filtering.Isolate the organic layer of filtrate, with saturated sodium-chloride water solution (500ml) washing, dry (MgSO ₄), and under vacuum, remove and desolvate.Resistates is dissolved in the propan-2-ol (1000ml) of heat, with the solution filtered while hot, placed 20 hours in room temperature then, collect the gained solid, with propan-2-ol (100ml) washing by filtering, and it is dry under vacuum at 70 ℃, obtained 3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazole-2-formaldehyde also, be yellow solid (19.4g), m.p.206 ℃.The mixture of first part's solid, methylene dichloride (2100ml), 2M hydrochloric acid (250ml) and water (1000ml) stirring at room 15 minutes, is added triethylamine (80ml) then.Isolate dichloromethane layer, from water layer, isolate all the other products by being extracted in the methylene dichloride (500ml).With the dichloromethane solution drying (MgSO that merges ₄), under vacuum, remove and desolvate, obtained another part 3-(benzo [b] thiophene 3-yl)-5, the 6-glyoxalidine is [2,1-b] thiazole-2-formaldehyde also, is yellow solid (63.0g), m.p.208 ℃.

Under agitation, with 10 minutes sodium borohydride (12.5g) is added to 3-(benzo [b] thiene-3-yl-)-5 in batches, 6-glyoxalidine also [2,1-b] in the ice-cooled suspension of thiazole-2-formaldehyde (63 g) in methyl alcohol (1200ml), then this mixture was stirred 30 minutes at 5 ℃, stirring at room 4 hours, and under reflux temperature, stirred 20 minutes.With 1 hour this mixture is cooled to room temperature, adds entry (200ml) then, and continue to stir 1 hour in room temperature.Collect the gained solid by filtering, water (200ml), ethanol (200ml) and ether (200ml) washing, dry under vacuum at 60 ℃ then, obtained [3-(benzo [b] thiene-3-yl-)-5,6-glyoxalidine also [2,1-b] thiazol-2-yl] methyl alcohol, for beige solid (52.1g), need not be further purified direct use.

Under agitation, with methyl alcohol (2200ml) the suspension reflux of [3-(benzo [b] thiene-3-yl-)-5,6-glyoxalidine be [2,1-b] thiazol-2-yl also] methyl alcohol (52.1g), all dissolve until all solids.Remove heating source, with the solution of 1 minute adding fumaric acid (21g) in methyl alcohol (250ml).This mixture was stirred 10 minutes, placed 1 hour, in ice, cooled off 3 hours then in room temperature.By filter collecting the gained solid, with ice-cold methyl alcohol (200ml) washing, and 60 ℃ under vacuum dry 3 hours, 80 ℃ of dryings 2 hours under vacuum, obtained white solid, NMR spectrum shows that it is by 1 normal methanol solvateization.With this solid and according to another part product (5.2g that is similar to above-mentioned method preparation; Also by methanol solvateization) merge, with pestle and mortar the product that merges is ground, under the vacuum of 90 ℃ and 133Pa dry 15 hours then, obtained [3-(benzo [b] thiene-3-yl-)-5,6-glyoxalidine also [2,1-b] thiazol-2-yl) methyl alcohol fumarate (by 0.05 normal methanol solvateization), be white solid (53.4g) m.p.258-262 ℃ (decomposition).Embodiment 7

Under 0 ℃, nitrogen atmosphere, stirring, tribromide phenyltrimethyammonium (3.0g) is added to 3-(benzo [b] thiene-3-yl-)-5 in batches, 6-glyoxalidine also [2,1-b] in the suspension of thiazole (2.0g) in tetrahydrofuran (THF) (50ml), then this mixture was stirred 1 hour at 0 ℃, and stirring at room 18 hours.Add entry (50ml) and triethylamine (50ml), isolate organic phase then, with saturated sodium-chloride water solution (50ml) washing, dry (MgSO ₄), and under vacuum, remove and desolvate.By dodging formula silica gel chromatography purifying resistates, use 9: 1 ethyl acetate and methanol mixture as eluent.Merge suitable fraction, remove under vacuum and desolvate, obtained 3-(benzo [b] thiene-3-yl-)-2-bromo-5, the 6-glyoxalidine is [2,1-b] thiazole also, is yellow solid (1.0g), m.p.196-200 ℃.Embodiment 8

Under 0 ℃, nitrogen atmosphere, stirring, tribromide phenyltrimethyammonium (0.75g) is added to 3-(benzo [b] thiene-3-yl-)-6 in batches, 7-dihydro-5H-thiazole is [3,2-a] pyrimidine (0.5g also; The method described makes according to being similar among the WO 97/02269) in the solution tetrahydrofuran (THF) (15ml) in, then with this mixture 0 ℃ of stirring 4 hours, be warmed to room temperature then.Add entry (50ml) and triethylamine (50ml), isolate organic phase then, with saturated sodium-chloride water solution (50ml) washing, dry (MgSO ₄), and under vacuum, remove and desolvate.By dodging formula silica gel chromatography purifying resistates, use 9: 1 ethyl acetate and methanol mixture as eluent.Merge suitable fraction, remove under vacuum and desolvate, obtained 3-(benzo [b] thiene-3-yl-)-2-bromo-6,7-dihydro-5H-thiazole is [3,2-a] pyrimidine also, is light yellow solid (0.2g), m.p.200-202 ℃.Embodiment 9

Under room temperature, nitrogen atmosphere, stirring, with sodium hydride (60% mineral oil dispersion; 1.35g) be added in the solution of 3-ethanoyl benzo [b] thiophene (2.9g) in diethyl carbonate (50ml), then this mixture was stirred 1.5 hours at 80 ℃, and pour in the mixture of water (300ml) and acetate (5ml). in batchesProduct is extracted in the ether (3 * 150ml), then with the extraction liquid water that merges (2 * 50ml) and saturated sodium-chloride water solution (50ml) washing, drying (MgSO ₄), and under vacuum, remove and desolvate.At Biotage Flash 40i ^By sudden strain of a muscle formula silica gel chromatography purifying resistates, the mixture that uses 9: 1 hexanes and ethyl acetate is as eluent in the device.Merge suitable fraction, under vacuum, remove and desolvate, obtained 3-(benzo [b] thiene-3-yl-)-3-oxo ethyl propionate,, need not be further purified direct use for brown oil (1.5g).

Under 0 ℃, nitrogen atmosphere, stirring, tribromide phenyltrimethyammonium (2.15g) is added in 3-(benzo [b] the thiene-3-yl-)-solution of 3-oxo ethyl propionate (1.5g) in tetrahydrofuran (THF) (30ml) in batches, then this mixture was stirred 30 minutes at 0 ℃, stirring at room 1.5 hours.Collect the gained solid by filtering, and wash with tetrahydrofuran (THF) (30ml).Merging filtrate and washings, and under vacuum, remove and desolvate.At Biotage Flash 40i ^By sudden strain of a muscle formula silica gel chromatography purifying resistates, the mixture that uses 9: 1 sherwood oils (b.p.60-80 ℃) and ethyl acetate is as eluent in the device.Merge suitable fraction, under vacuum, remove and desolvate, obtained 3-(benzo [b]-thiene-3-yl-)-2-bromo-3-oxo ethyl propionate, be brown solid (1.7g), m.p.81-83 ℃.

The mixture heating up of 3-(benzo [b] thiene-3-yl-)-2-bromo-3-oxo ethyl propionate (1.7g), 2-imidazolidine thioketones (0.53g) and ethanol (30ml) was refluxed 10 minutes, add acetate (15ml) then, and this mixture heating up was refluxed 18 hours.Under vacuum, remove and desolvate, resistates is developed with ethanol (20ml).Collect the gained solid by filtering, with ethanol (10ml) and ether (20ml) washing, dry under vacuum at 60 ℃ then, obtained 3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazole-2-ethyl formate also, be beige solid (1.15g), m.p.209-211 ℃.

With 3-(benzo [b] thiene-3-yl-)-5,6-glyoxalidine also [2,1-b] mixture of thiazole-2-ethyl formate (0.4g), triethylamine (2ml) and methylene dichloride (15ml) is stirring at room 20 minutes, then it is diluted with methylene dichloride (40ml), water (2 * 20ml) and saturated sodium-chloride water solution (20ml) washing, dry (Na ₂SO ₄), and under vacuum, remove and desolvate.Resistates (0.22g) is dissolved in the tetrahydrofuran (THF) (7ml), and under nitrogen atmosphere, adds methylmagnesium-bromide (3M diethyl ether solution; 0.66ml).This mixture stirring at room 2 hours, and then is added methylmagnesium-bromide (3M diethyl ether solution; 0.66ml) and toluene (5ml).This mixture stirring at room 5 minutes, was stirred 5 hours at 90-95 ℃, be cooled to room temperature then, and water (30ml) dilution.This product is extracted into ethyl acetate (in 2 * 30ml), with extraction liquid water (30ml) and saturated sodium-chloride water solution (30ml) washing that merges, dry (MgSO ₄), and under vacuum, remove and desolvate.The mixture heating up of resistates, fumaric acid (0.037g) and ethanol (5ml) was refluxed 5 minutes, and this hot solution is inclined leaving with a small amount of undissolved solids constituent then, and is cooled to room temperature.Collect the gained solid by filtering, wash with ether (10ml), and it is dry under vacuum at 60 ℃, obtained 1-[3-(benzo [b] plug fen-3-yl)-5,6-glyoxalidine also [2,1-b] thiazole also-the 2-yl]-1-methyl ethanol fumarate, be beige solid (0.057g) that fusing point is 180-182 ℃.Embodiment 10

In room temperature, stir under with ethyl-magnesium-chloride (2M diethyl ether solution; 1.4ml) being added drop-wise to 3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine also in [2, the 1-b] thiazole-solution of 2-formaldehyde (0.52g) in tetrahydrofuran (THF) (30ml), at room temperature stirred this mixture 30 minutes then.Add ethyl-magnesium-chloride (2M diethyl ether solution again; 0.5ml), with this mixture stirring at room 1 hour, then by adding entry (30ml) stopped reaction.Product is extracted in the ether (50ml), and (2 * 50ml) extractions are with extraction liquid saturated sodium-chloride water solution (2 * 30ml) washings, the dry (Na that merges to use ethyl acetate then ₂SO ₄), and under vacuum, remove and desolvate.At Biotage Flash 40i ^By sudden strain of a muscle formula silica gel chromatography purifying resistates, use 99: 1 methylene dichloride and carbinol mixture in the device as eluent.Merge suitable fraction, and remove under vacuum and desolvate, obtained 1-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] third-1-alcohol, be orange solids (0.24g), m.p.92-94 ℃.Embodiment 11

Under room temperature, stirring, triethylamine (50ml) is added drop-wise to 3-(5-methoxyl group benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazole hydrobromide salt (1g also; The method described makes according to being similar among the WO 97/02269) in the suspension in methylene dichloride (25ml), then with this mixture stirring at room 10 minutes.Add entry (25ml), isolate organic phase then, water (25ml) washing, dry (Na ₂SO ₄), under vacuum, remove and desolvate, obtained 3-(5-methoxyl group benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazole also, for brown solid (0.65g), need not be further purified direct use.

Under 0 ℃, nitrogen atmosphere, stirring, tribromide phenyltrimethyammonium (1.5g) is added to 3-(5-methoxyl group benzo [b] thiene-3-yl-)-5,6-glyoxalidine also [2,1-b] in the solution of thiazole (0.65 g) in tetrahydrofuran (THF) (25ml), this mixture was stirred 16 hours at 0 ℃, be warmed to room temperature then.Add triethylamine (50ml) and water (50ml), isolate organic phase then, dry (Na ₂SO ₄), and under vacuum, remove and desolvate.By dodging formula silica gel chromatography purifying resistates, the mixture that uses 99: 1: 0.1 ethyl acetate, methyl alcohol and triethylamines is as eluent.Merge suitable fraction, and under vacuum, remove and desolvate.With residue crystallized, collect the gained solid with methyl alcohol by filtering, and dry under vacuum in room temperature, obtained also [2,1-b] thiazole of 2-bromo-3-(5-methoxyl group benzo [b] thiene-3-yl-)-5,6 glyoxalidine, be beige solid (0.05g) m.p.210 ℃ (decomposition).Embodiment 12

Under 0-5 ℃, nitrogen atmosphere, stirring, with 15 minutes tribromide phenyltrimethyammonium (1.0g) is added to 3-(the 5-chlorobenzene is [b] thiene-3-yl-also)-5 in batches, the 6-glyoxalidine is [2,1-b] thiazole (0.8g also; The method described makes according to being similar among the WO 97/02269) in the solution in tetrahydrofuran (THF) (20ml), and with this mixture stirring at room 18 hours.Add entry (30ml) and triethylamine (5ml), then product is extracted into methylene dichloride (in 2 * 20ml), extraction liquid water (4 * 20ml) washings, the dry (MgSO that merges ₄), under vacuum, remove and desolvate, obtained 2-bromo-3-(the 5-chlorobenzene is [b] thiene-3-yl-also)-5, the 6-glyoxalidine is [2,1-b] thiazole also, is yellow solid (0.72g) m.p.205-208 ℃ (decomposition).Embodiment 13

The mixture heating up of 3-ethanoyl benzo [b] thiophene (25g), dimethyl amine hydrochloride (15.05g), paraformaldehyde (5.7g), concentrated hydrochloric acid (1ml) and ethanol (75ml) was refluxed 18 hours, be cooled to room temperature then.Collect the gained solid by filtering, and dry under vacuum in room temperature, obtained 1-(benzo [b] thiene-3-yl-)-3-(dimethylamino) third-1-keto hydrochloride, be pink solid (15.7g), m.p.169-171 ℃.Solvent vacuum from filtrate is removed, and develop resistates with ether (100ml).Collect the gained solid by filtering, and dry under vacuum in room temperature, obtained another batch 1-(benzo [b] thiene-3-yl-)-3-(dimethylamino)-third-1-keto hydrochloride, be pink solid (13.8g).

Alkalize to pH9.0 by the mixture of adding saturated aqueous sodium carbonate 1-(benzo [b] thiene-3-yl-)-3-(dimethylamino) third-1-keto hydrochloride (29.4g) and water (600ml), this mixture stirring at room 1 hour, is extracted into ether (in 3 * 100ml) with this free alkali then.With the extraction liquid drying (MgSO that merges ₄), and under vacuum, remove and desolvate.Resistates is dissolved in the methyl alcohol (50ml), then this solution is cooled off in ice, and drip methyl iodide (15.7ml).This mixture stirring at room 1 hour, is collected the gained solid by filtering then, use the ether thorough washing, and it is dry under vacuum in room temperature, obtain iodate [3-(benzo [b] thiene-3-yl-)-3-oxopropyl] trimethyl ammonium, be pink solid (28.7g), m.p.165-167 ℃.

The mixture of iodate [3-(benzo [b] thiene-3-yl-)-3-oxopropyl] trimethyl ammonium (5.0g), sodium bicarbonate (5.0g), ether (150ml) and water (130ml) stirring at room 4 hours, is extracted into ether (in 3 * 150ml) with this product then.With the extraction liquid drying (MgSO that merges ₄), and under vacuum, remove and desolvate, obtained 1-(benzo [b] thiene-3-yl-) acrylketone, for pink solid (2.1g), need not be further purified direct use.

1-(benzo [b] thiene-3-yl-) acrylketone (0.75g) and the solution of benzylalcohol (0.41ml) in methylene dichloride (2ml) are cooled to 0 ℃, and add the vitriol oil (2).This mixture was stirred 3 hours at 0 ℃, placed 18 hours at 4 ℃ then.Add benzyl alcohol (0.82ml) again, this mixture stirred 7 hours at 0 ℃, use methylene dichloride (20ml) dilution then, with saturated sodium bicarbonate aqueous solution (2 * 10ml) and water (10ml) washing, drying (MgSO ₄).Under vacuum, remove and desolvate,, use methylene dichloride as eluent by carrying out preparative thin layer chromatography purifying resistates on the sheet glass of silica gel being covered with.Take off suitable silicon gel part from expansion plate, and by coming extraction product with methylene dichloride (30ml) development.Extraction liquid is filtered, under vacuum, remove and desolvate, obtained 1-(benzo [b] thiene-3-yl-)-3-benzyloxy third-1-ketone,, need not be further purified direct use for orange (0.49g).

Under nitrogen atmosphere, stirring, tribromide phenyltrimethyammonium (0.4g) is added in 1-(benzo [b] the thiene-3-yl-)-solution of 3-benzyloxy third-1-ketone (0.43g) in tetrahydrofuran (THF) (5ml) in batches, with this mixture stirring at room 18 hours, filter then, under vacuum, remove and desolvate, obtained 1-(benzo [b] thiene-3-yl-)-3-benzyloxy-2-bromine third-1-ketone,, need not be further purified direct use for yellow oil (0.56g).

With the mixture of 1-(benzo [b] thiene-3-yl-)-3-benzyloxy-2-bromine third-1-ketone (0.54g), 2-imidazolidine thioketones (0.15g), ethanol (3ml) and acetate (1ml) reflux 18 hours under nitrogen atmosphere, under vacuum, remove then and desolvate.Resistates is developed with ice-cold ethanol (5ml), collect the gained solid by filtering, wash with ethanol (5ml), and it is dry under vacuum in 60 ℃, obtained 3-(benzo [b] thiene-3-yl-)-2-ethoxyl methyl-5, the 6-glyoxalidine is [2,1-b] thiazole hydrobromide salt also, be lacteous solid (0.19g) m.p.＞250 ℃.Embodiment 14

Under 0 ℃, nitrogen atmosphere, stirring, with ethylene chloride base magnesium (1M tetrahydrofuran solution; 6.7ml) being added drop-wise to 3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine also in [2, the 1-b] thiazole-suspension of 2-formaldehyde (0.64g) in tetrahydrofuran (THF) (30ml), stirred this mixture 10 minutes at 0 ℃ then, stirring at room 30 minutes.Add entry (50ml), this mixture is concentrated to remove tetrahydrofuran (THF) under vacuum, then product is extracted into ethyl acetate (in 3 * 30ml).With extraction liquid saturated sodium-chloride water solution (2 * 25ml) washings, the dry (MgSO that merges ₄), and under vacuum, remove and desolvate.At Biotage Flash 40i ^By sudden strain of a muscle formula silica gel chromatography purifying resistates, use the mixture of 1-5% methyl alcohol in methylene dichloride in the device as eluent.Merge suitable fraction, remove under vacuum and desolvate, obtained 1-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] third-2-alkene-1-alcohol, be light yellow foam (0.12g), m.p.60-65 ℃.Embodiment 15

Under 0 ℃, nitrogen atmosphere, stirring, with bromination 1-proyl magnesium (0.5M diethyl ether solution; 10.5ml) being added drop-wise to 3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine also in [2, the 1-b] thiazole-solution of 2-formaldehyde (0.5g) in tetrahydrofuran (THF) (30ml), stirs this mixture 10 minutes at 0 ℃ then, and stirring at room 30 minutes.Add entry (60ml) and ethyl acetate (100ml), isolate organic phase then, with saturated sodium-chloride water solution (2 * 25ml) washings, dry (MgSO ₄), and under vacuum, remove and desolvate.At Biotage Flash 40i ^By sudden strain of a muscle formula silica gel chromatography purifying resistates, use the mixture of 1-5% methyl alcohol in methylene dichloride in the device as eluent.Merge suitable fraction, remove under vacuum and desolvate, obtained 1-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] fourth-2-alkynes-1-alcohol, be white solid (0.11g) m.p.190-200 ℃ (decomposition).Embodiment 16

Under 0 ℃, nitrogen atmosphere, stirring, with n-Butyl Lithium (2.5M hexane solution; 4.7ml) be added drop-wise in the solution of Diethylaminoethyl triphenyl phosphonium (4.2g) in tetrahydrofuran (THF) (30ml), then this mixture was stirred 5 minutes at 0 ℃, stirring at room 30 minutes.Add 3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazole-2-formaldehyde (3.05g) also in batches, then this mixture heating up was refluxed 3 hours, and be cooled to room temperature.Add ethyl acetate (75ml) and water (50ml), isolate organic phase then, with saturated sodium-chloride water solution (50ml) washing, dry (MgSO ₄), and under vacuum, remove and desolvate.With 2.5M hydrochloric acid (75ml) dilution, stirring at room 3 hours, filter to remove gluey semi-solid then this mixture resistates.Filtrate with ethyl acetate (25ml) jolting, is isolated organic phase then, dry (MgSO ₄), and under vacuum, remove and desolvate, having obtained impure a little 3-(benzo [b] thiophene 3-yl)-2-vinyl-5, the 6-glyoxalidine is [2,1-b] thiazole hydrochloride also, is white solid (0.85g).By (other product is isolated in 2 * 50ml) extractions, dry (MgSO with methylene dichloride ₄), and under vacuum, remove and desolvate, having obtained 3-(benzo [b] thiene-3-yl-)-2-vinyl-5, the 6-glyoxalidine is [2,1-b] thiazole hydrochloride also, is white solid (0.49g), m.p.221-223 ℃.Embodiment 17

Under 0-5 ℃, nitrogen atmosphere, stirring, with 10 minutes with 3-(benzo [b] thiene-3-yl-)-2-bromo-5,6-glyoxalidine also [2,1-b] thiazole hydrobromide salt (2g) is added to ethyl-magnesium-chloride (2M diethyl ether solution in batches; 7.2ml) in the solution in tetrahydrofuran (THF) (20ml), then this mixture was stirred 30 minutes at 0-5 ℃.Drip allyl bromide 98 (0.87ml), with this mixture stirring at room 18 hours, then by adding saturated aqueous ammonium chloride (15ml) successively and water (10ml) comes stopped reaction.Product is extracted in the ethyl acetate (50ml), then with extraction liquid water (25ml) and saturated sodium-chloride water solution (25ml) washing, dry (MgSO ₄), and under vacuum, remove and desolvate.By dodging formula silica gel chromatography purifying resistates, use the mixture of 5-7% methyl alcohol in methylene dichloride as eluent.Merge suitable fraction, under vacuum, remove and desolvate, obtained brown jelly (0.36g).This jelly is dissolved in the ethanol (2mL), adds the solution of fumaric acid (0.13g) in ethanol (2ml).Collect the gained solid by filtering, with ethanol (10ml) washing, and dry under vacuum in 75 ℃, obtained 2-allyl group-3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazole fumarate also, be beige solid (0.22g), m.p.163-164 ℃.Embodiment 18

Under-70 ℃, nitrogen atmosphere, stirring, with 10 minutes with n-Butyl Lithium (2.5M hexane solution; 1ml) be added drop-wise to 3-(benzo [b] furans-3-yl)-5, the 6-glyoxalidine is [2,1-b] thiazole (0.5g also; The method described makes according to being similar among the WO 97/02269) in the solution tetrahydrofuran (THF) (6ml) in, then with this mixture-70 ℃ of stirrings 30 minutes.Add dimethyl formamide (0.2ml), this mixture was stirred 5 minutes at-70 ℃, be warmed to room temperature then.Add saturated aqueous ammonium chloride (30ml), and product is extracted into methylene dichloride (in 3 * 30ml).With extraction liquid water (30ml) washing that merges, dry (Na ₂SO ₄), and under vacuum, remove and desolvate.By dodging formula silica gel chromatography purifying resistates, use 9: 1 methylene dichloride and carbinol mixture as eluent.Merge suitable fraction, remove under vacuum and desolvate, obtained 3-(benzo [b] furans-3-yl)-5, the 6-glyoxalidine is [2,1-b] thiazole-2-formaldehyde also, is brown solid (0.24g), m.p.192-195 ℃.

Warm 6-glyoxalidine also [2,1-b] thiazole-2-formaldehyde (0.17g) is dissolved in the methyl alcohol (6ml), adds sodium borohydride (0.035g) then with 3-(benzo [b] furans-3-yl)-5 by slight, with this mixture stirring at room 30 minutes.Add entry (50ml), with this mixture stirring at room 1 hour, collect the gained solid by filtering then, water (10ml) washing, and, obtained [3-(benzo [b] furans-3-yl)-5 in 60 ℃ of dryings under vacuum, 6-glyoxalidine also [2,1-b] thiazol-2-yl] methyl alcohol, be white solid (0.08g), m.p.184-187 ℃.Embodiment 19

With 3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine also mixture heating up of [2,1-b] thiazole-2-formaldehyde (0.5g), isopropylamine (1ml), ethanol (50ml) and acetate (1) refluxed 4 hours, removed under vacuum then and desolvated.Resistates is developed with ether (30ml), collect the gained solid by filtering, wash with ether (10ml), and it is dry under vacuum in room temperature, obtained N-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl methylene radical also]-1-methylethyl amine, be light brown solid (0.38g), m.p.180-182 ℃.Embodiment 20

In room temperature, stir under, zephiran chloride trimethyl ammonium (8g) is added in the solution of iodine trichloride (10g) in methylene dichloride (120ml) in batches, then with this mixture stirring at room 2.5 hours.Collect the gained solid by filtering, washing, and dry under vacuum in room temperature, obtained benzyltrimethylammon.um tetrachloro iodate, for yellow solid (16.2g), need not be further purified direct use.

0 ℃, stir under, with 10 minutes benzyltrimethylammon.um tetrachloro iodate (5g) is added to 3-(benzo [b] thiene-3-yl-)-5 in batches, the 6-glyoxalidine also in the solution of [2,1-b] thiazoles (3g) in acetone (125ml), stirs this mixture 1 hour at 0 ℃ then.Collect the gained solid by filtering,, and, obtained beige solid (0.74g) with ethanol (150ml) crystallization with propan-2-ol (150ml) development of heat.Mother liquor is concentrated into 75ml, has obtained another batch solid (0.41g).These two batches of solids are merged, ethanol (40ml) development with heat, and by filtering collection gained solid, with ethanol (10ml) washing, and, obtained 3-(benzo [b] thiene-3-yl-)-2-chloro-5 in 60 ℃ of dryings under vacuum, 6-glyoxalidine also [2,1-b] thiazole hydrochloride 0.5 hydrate, be beige solid (0.91g), m.p.255-257 ℃.Embodiment 21

Under 0-5 ℃, nitrogen atmosphere, stirring, with 10 minutes with 3-(benzo [b] thiene-3-yl-)-2-bromo-5,6-glyoxalidine also [2,1-b] thiazole hydrobromide salt (6g) is added to ethyl-magnesium-chloride (2M diethyl ether solution in batches; 21.6ml) in the solution in tetrahydrofuran (THF) (100ml), then this mixture was stirred 1 hour at 0-5 ℃.50-70 ℃, stir under, with 10 minutes this mixture is added in the N-methoxyl group-solution of N-methylacetamide (5g) tetrahydrofuran (THF) (50ml) in, then 70 ℃ of continuation stirrings 2.5 hours.This mixture is cooled off in ice, add saturated aqueous ammonium chloride (100ml), water (100ml) and ethyl acetate (150ml) then.Isolate organic layer, with the mixture washing of saturated sodium-chloride water solution (100ml) and water (100ml), dry (MgSO ₄), and under vacuum, remove and desolvate.(3 * 50ml) develop, and by filtering collection gained solid, wash with ether (30ml), and dry under vacuum, have obtained yellow solid (1.84g) with ether with resistates.With this solid sample of a part (0.25g) crystallization from ethanol (3.5ml); and by filtering collection gained solid; wash with ethanol (5ml); and it is dry under vacuum in 75 ℃; obtained 2-ethanoyl-3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazole also; be yellow solid (0.043g), m.p.203-205 ℃.Embodiment 22

In room temperature, stir under, with 10 minutes with sodium hydride (60% mineral oil dispersion; 0.15g) be added in [3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] methyl alcohol (1g) suspension in dimethyl formamide (20ml) in batches, then with this mixture stirring at room 45 minutes.Add methyl iodide (240 μ l), and continue to stir 2 hours in room temperature.Add entry (25ml) and ethyl acetate (50ml), isolate organic phase then, and water (4 * 25ml) and saturated sodium-chloride water solution (25ml) washing, dry (MgSO ₄), and under vacuum, remove and desolvate.By dodging formula silica gel chromatography purifying resistates, use the mixture of 5-8% methyl alcohol in methylene dichloride as eluent.Merge suitable fraction, and under vacuum, remove and desolvate.Resistates is dissolved in the warm ethanol (3ml), adds the solution of fumaric acid (0.085g) in warm ethanol (2ml), and this mixture is cooled to room temperature.Collect the gained solid by filtering, with ethanol (3ml) washing, and dry under vacuum in 75 ℃, obtained 3-(benzo [b] thiene-3-yl-)-2-(methoxymethyl)-5, the 6-glyoxalidine is [2,1-b] thiazole fumarate also, be white solid (0.23g), m.p.175-176 ℃.Embodiment 23

Under 0-5 ℃, nitrogen atmosphere, stirring, with 30 minutes with 3-(benzo [b] thiene-3-yl-)-2-bromo-5,6-glyoxalidine also [2,1-b] thiazole hydrobromide salt (5g) is added in the solution of ethyl-magnesium-chloride [2.0M diethyl ether solution (15ml)] in tetrahydrofuran (THF) (75ml) in batches, then with this mixture stirring at room 1 hour.This mixture is cooled to 0 ℃, adds dimethyl disulphide (1.8ml), come stopped reaction then in this mixture of stirring at room 24 hours, and by adding saturated aqueous ammonium chloride (50ml) carefully.Product is extracted in the ethyl acetate (150ml), then with extraction liquid water (50ml) and saturated sodium-chloride water solution (50ml) washing, dry (Na ₂SO ₄), and under vacuum, remove and desolvate.At Biotage Flash40i ^By sudden strain of a muscle formula silica gel chromatography purifying resistates, use 19: 1 ethyl acetate and methanol mixture in the device as eluent.Merge suitable fraction, and under vacuum, remove and desolvate.Resistates is developed with ether (20ml), and collected the gained solid by filtering, dry under vacuum, obtained 3-(benzo [b] thiene-3-yl-)-2-(methylthio group)-5, the 6-glyoxalidine is [2,1-b] thiazoles (1.9g) also, be beige solid, m.p.129-131 ℃.Embodiment 24

Under nitrogen atmosphere, stirring, with n-Butyl Lithium (2.5M hexane solution; 1.7ml) be added in the ice-cooled solution of Diethylaminoethyl triphenyl phosphonium (1.5g) in tetrahydrofuran (THF) (25ml), then with this mixture stirring at room 30 minutes.Add 2-ethanoyl-3-(benzo [b] thiene-3-yl-)-5; the 6-glyoxalidine is the solution of [2,1-b] thiazoles (1.6g) in tetrahydrofuran (THF) (15ml) also, then this mixture heating up refluxed 4 hours; placed 18 hours in room temperature, come stopped reaction by adding entry (50ml) then.Product is extracted in the ethyl acetate (50ml), then extraction liquid is washed with saturated sodium-chloride water solution (50ml), dry (MgSO ₄), and under vacuum, remove and desolvate.By dodging formula silica gel chromatography purifying resistates, use the mixture of 5-6% methyl alcohol in methylene dichloride as eluent.Merge suitable fraction, remove under vacuum and desolvate, obtained 3-(benzo [b] thiene-3-yl-)-2-(1-methyl ethylene)-5, the 6-glyoxalidine is [2,1-b] thiazoles (0.14g) also, are brown solid, m.p.76 ℃.Embodiment 25-33

Embodiment 25-33 makes with the part of following general method as high speed analogue storehouse:

Suitable commercially available Grignard reagent (3 molar equivalent) is added to 3-(benzo [b] thiene-3-yl-)-5,6-glyoxalidine also [2,1-b] in the solution of thiazole-2-formaldehyde (about 50mg) in tetrahydrofuran (THF) (4ml), with this mixture stirring at room 1 hour, add entry (1ml), then this mixture is exposed 18 hours under air with solvent evaporation.Add methylene dichloride (4ml), and this solution suction is moved on to ChemElute, and (CE 1103; PH9) in the tube, placed 15 minutes, (3 * 4ml) come out product wash-out from this tube to use methylene dichloride then.Under vacuum, remove and desolvate, obtained required product, usefulness Hypersil BDS C18 post (100 * 4.6mm) by the high-efficient liquid phase chromatogram technique analysis products therefrom, uses the mixture of acetonitrile and 0.1M ammonium acetate buffer to carry out gradient elution according to following proposal:

Time (minute)	Acetonitrile (%)	Ammonium acetate (%)
			????0	????10	????90
????8-9	????100	????0
			????11	????10	????90

The product of following embodiment all has gratifying mass spectrum: all provided HPLC retention time and % purity for each embodiment.Embodiment 25

1-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also]-2-methyl-prop-1-alcohol (retention time: 3.28 minutes-purity: 80%).Embodiment 26

1-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] fourth-1-alcohol (retention time: 3.29 minutes-purity: 100%).Embodiment 27

1-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also]-2-methyl fourth-3-alkene-1-alcohol (retention time: 3.42 minutes-purity: 100%).Embodiment 28

1-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also]-3-methyl fourth-1-alcohol (retention time: 3.61 minutes-purity: 90%).Embodiment 29

1-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] penta-1-alcohol (retention time: 3.68 minutes-purity: 100%).Embodiment 30

1-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] third-2-alkynes-1-alcohol (retention time: 2.71 minutes-purity: 100%).Embodiment 31

1-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] fourth-3-alkene-1-alcohol (retention time: 3.12 minutes-purity: 96%).Embodiment 32

1-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also]-2-methyl-prop-2-alkene-1-alcohol (retention time: 3.13 minutes-purity: 97%).Embodiment 33

1-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] penta-4-alkene-1-alcohol (retention time: 3.44 minutes-purity: 85%).Embodiment 34

According to being similar to the method for describing among the embodiment 4, with 3-(benzo [b] thiene-3-yl-)-5,6-glyoxalidine also [2,1-b] thiazole-2-formaldehyde (making) and bromination 2-p-methoxy-phenyl reactive magnesium by the method for in embodiment 6, describing, and with the mixture of methyl alcohol and propan-2-ol with the product recrystallization, obtained [3-(benzo [b] thiene-3-yl-)-5,6-glyoxalidine also [2,1-b] thiazol-2-yl] (2-p-methoxy-phenyl) methyl alcohol, be white solid, m.p.195-197 ℃.Embodiment 35

Under 0-4 ℃, nitrogen atmosphere, stirring, with 45 minutes with n-Butyl Lithium (2.5M hexane solution; 73.8ml) be added drop-wise in the mixture of Diethylaminoethyl triphenyl phosphonium (65.7g) and tetrahydrofuran (THF) (680ml), then this mixture was stirred 10 minutes at 4 ℃, stirring at room 30 minutes.Add 3-(benzo [b] thiene-3-yl-)-5 in room temperature, the 6-glyoxalidine is [2,1-b] thiazole-2-formaldehyde (48g also in batches; Make according to the method that is similar to description among the embodiment 6), then this mixture heating up was refluxed 3 hours, be cooled to room temperature, and be added in the water (500ml).Product is extracted into ethyl acetate (in 3 * 400ml), then with extraction liquid water (400ml) washing that merges, dry (MgSO ₄), and under vacuum, remove and desolvate.Resistates is developed with ethyl acetate (300ml), and collected the gained solid, use re-crystallizing in ethyl acetate, obtained beige solid by filtering.To develop and the mother liquid obtained merging of recrystallization, concentrate, obtain another part solid.Repeat this operation, until not isolating any solid.All each batch products are merged, with ethyl acetate recrystallization repeatedly, until purity＞99% (HPLC), obtained 3-(benzo [b] thiene-3-yl-)-2-vinyl-5, the 6-glyoxalidine is [2,1-b] thiazole also, is beige solid (43.5g).Most of solid (41g) is dissolved in the warm methyl alcohol (500ml), and is added in the saturated solution of fumaric acid (16.7g) in methyl alcohol, under vacuum, remove then and desolvate.Resistates was stirred 3 hours with ether (500ml), collect the gained solid by filtering, washing, and in room temperature under vacuum dry 24 hours, obtained 3-(benzo [b] thiene-3-yl-)-2-vinyl-5, the 6-glyoxalidine is [2,1-b] thiazole fumarates (56.8g) also, be white solid, m.p.161-162 ℃.Embodiment 36

According to being similar to the method for in embodiment 35, describing, with 3-(benzo [b] thiene-3-yl-)-5,6-glyoxalidine also [2,1-b] thiazole-2-formaldehyde and bromination Yi base triphenyl phosphonium and n-Butyl Lithium reaction, obtained crude product, by dodging formula silica gel chromatography purifying, use 19: 1 methylene dichloride and carbinol mixture as eluent.Merge suitable fraction, and remove under vacuum and desolvate, obtained 3.7: 1 E-and Z-3-(benzo [b] thiene-3-yl-)-2-third-1-thiazolinyl-5, the 6-glyoxalidine is the mixture of [2,1-b] thiazole also, is yellow solid, m.p.62-68 ℃.Embodiment 37

According to being similar to the method for in embodiment 6, describing, with 3-(benzo [b] thiene-3-yl-)-6,7-dihydro-5H-thiazole also [3,2-a] pyrimidine (making) bromination according to the method that is similar to description among the WO 97/02269, react with ethyl-magnesium-chloride and dimethyl formamide successively then, obtained 3-(benzo [b] thiene-3-yl-)-6,7-dihydro-5H-thiazole is [3,2-a] pyrimidine-2-formaldehyde also.It is reduced with sodium borohydride according to being similar to the method for in embodiment 2, describing, obtained [3-(benzo [b] thiene-3-yl-)-6,7-dihydro-5H-thiazole is [3,2-a] pyrimidine-2-base also] methyl alcohol, be beige solid, m.p.174-176 ℃.Embodiment 38

With 3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazole-2-formaldehyde (0.5g also; The method described makes according to being similar in embodiment 6), the mixture of hydroxylamine hydrochloride (0.16g) and formic acid (1.3ml) is 90-95 ℃ of heating 25 hours, uses ether (50ml) to dilute then.By filter collecting the gained solid, with ether (30ml) washing, by dodging formula silica gel chromatography purifying, used successively 95: 5 and 85: 15 methylene dichloride and methanol mixture as eluent.Merge suitable fraction, remove under vacuum and desolvate, obtained 3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazole-2-nitrile 0.3 fumarate (0.12g) also, is white solid, m.p.195-196 ℃.Embodiment 39

Under room temperature, nitrogen atmosphere, stirring, the drips of solution of benzylphosphonic acid diethyl ester (1.5ml) in tetrahydrofuran (THF) (10ml) is added to sodium hydride (60% mineral oil suspensoid; 0.26g) in the suspension in tetrahydrofuran (THF) (15ml), then with this mixture stirring at room 20 minutes.Disposable adding 3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazole-2-formaldehyde (0.83g also; The method described makes according to being similar in embodiment 6), this mixture stirring at room 72 hours, is come stopped reaction by adding entry (30ml) then.Product is extracted into methylene dichloride (in 3 * 30ml), with the extraction liquid drying (MgSO that merges ₄), and under vacuum, remove and desolvate.Resistates is developed with ether (20ml), and collected the gained solid by filtering.The ether mother liquor is concentrated under vacuum,, obtained another batch solid with ether (10ml) development resistates.The solid that merges is dry under vacuum, obtained 3-(benzo [b] thiene-3-yl-)-2-styryl-5, the 6-glyoxalidine is [2,1-b] thiazoles (0.49g) also, are yellow solid, m.p.153-155 ℃.Embodiment 40

According to being similar to the method for in embodiment 6, describing, with 3-(the 5-chlorobenzene is [b] thiene-3-yl-also)-5,6-glyoxalidine also [2,1-b] thiazole (by what will make) bromination according to the hydrobromate alkalization that is similar to the method acquisition of describing among the WO97/02269, react with ethyl-magnesium-chloride and dimethyl formamide successively then, obtained 3-(the 5-chlorobenzene is [b] thiene-3-yl-also)-5,6-dihydro-imidazol-also [2,1-b] thiazole-2-formaldehyde, be yellow solid, m.p.258-260 ℃.Embodiment 41

Under agitation, sodium borohydride (0.06g) is added to 3-(the 5-chlorobenzene is [b] thiene-3-yl-also)-5, and the 6-glyoxalidine is also in [2, the 1-b] thiazole-suspension of 2-formaldehyde (0.31g) in ethanol (15ml), this mixture stirring at room 4 hours, is added entry (15ml) then.Collect the gained solid by filtering, with ether (15ml) washing, and dry under vacuum in 60 ℃, obtained [3-(the 5-chlorobenzene is [b] thiene-3-yl-also)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] methyl alcohol (0.14g), be white solid, m.p.204-206 ℃.Embodiment 42

Made [3-(the 5-chlorobenzene is [b] thiene-3-yl-also)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] methyl alcohol (0.6g) according to being similar to the method for in embodiment 40 and 41, describing.Yet product is impure in this case.By preparation HPLC purifying, the mixture that uses acetonitrile and triethylammonium formate damping fluid is as eluent then.Merge suitable fraction, and under vacuum, remove and desolvate.With (2 * 3ml) developments of resistates water, and by filtering collection gained solid, washing, and it is dry under vacuum in 60 ℃, obtained [3-(the 5-chlorobenzene is [b] thiene-3-yl-also)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also]-methyl alcohol formate (0.19g), be beige solid, m.p.171-173 ℃.Embodiment 43

According to being similar to the method for in embodiment 23, describing, with 3-(benzo [b] thiene-3-yl-)-2-bromo-5,6-glyoxalidine also [2,1-b] thiazole hydrobromide salt (5g) and tonsilon reactive magnesium, with the reaction of phenylbenzene disulphide, obtained 3-(benzo [b] thiene-3-yl-)-2-(thiophenyl)-5 then, 6-glyoxalidine also [2,1-b] thiazole (0.6g), be yellow solid, m.p.123-125 ℃.Embodiment 44

Under nitrogen atmosphere, stirring, with methylamine (2M tetrahydrofuran solution; 8.7ml) and sodium triacetoxy borohydride (0.56g) be added to 3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazole-2-formaldehyde (0.5g also; The method described makes according to being similar in embodiment 6) in the solution in tetrahydrofuran (THF) (20ml), then with this mixture stirring at room 72 hours.Add methylamine solution (4.3ml) again, this mixture stirring at room 48 hours, is come stopped reaction by adding saturated sodium bicarbonate aqueous solution (50ml) then.Product is extracted into ethyl acetate, and (in 3 * 30ml), extraction liquid water (30ml) and saturated sodium-chloride water solution (30ml) washing with merging are dried (MgSO then ₄), and under vacuum, remove and desolvate.By dodging formula silica gel chromatography purifying resistates, use 9: 1 methylene dichloride and carbinol mixture as eluent.Merge suitable fraction, and under vacuum, remove and desolvate, obtained [3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also]-N-methyl methylamine (0.19g), be waxy solid, m.p.102-104 ℃.Embodiment 45

Under-10-0 ℃, nitrogen atmosphere, stirring, the drips of solution of oxalyl chloride (13ml) in methylene dichloride (20ml) is added in cyclopropyl acetate (5g) and the solution of dimethyl formamide (2) in methylene dichloride (20ml), then with this mixture stirring at room 24 hours, and under vacuum, remove and desolvate, obtained the cyclopropyl Acetyl Chloride 98Min., be brown oil, need not be further purified direct use.

0-5 ℃, stir under, with 10 minutes salt of wormwood (9.2g) is added to N in batches, in the solution of O-dimethyl hydroxylamine hydrochloride (5.1g) in minimum desired body ponding, add methylene dichloride (30ml) then.Above-mentioned cyclopropyl Acetyl Chloride 98Min. is dissolved in the methylene dichloride (20ml), is added drop-wise in this dimethyl hydroxylamine solution at-5-0 ℃.This mixture was stirred 30 minutes at 0 ℃,, then product is extracted into methylene dichloride (in 3 * 50ml) stirring at room 2 hours.With the extraction liquid drying (Na that merges ₂SO ₄), under vacuum, remove and desolvate, obtained cyclopropyl-N-methoxyl group-N-methylacetamide (6.2g), for light brown oily thing, need not be further purified direct use.

Under nitrogen atmosphere, with several 3-bromobenzenes also the solution of [b] thiophene (8.7g) in tetrahydrofuran (THF) (35ml) be added in the mixture of magnesium chips (1.05g), 2 iodine crystal and tetrahydrofuran (THF) (5ml), this mixture is slight warm to start reaction.The remainder that adds this solution then with the speed that is enough to keep gentle reflux.After adding fully, this mixture was stirred 1.5 hours under reflux temperature, be cooled to room temperature then.Add the cyclopropyl-N-methoxyl group-solution of N-methylacetamide (6g) in tetrahydrofuran (THF) (35ml) in room temperature, this mixture was stirred 5 hours under reflux temperature, and room temperature placement 18 hours, then by adding 2M hydrochloric acid (50ml) and coming stopped reaction in 1 hour in stirring at room.With product be extracted into ethyl acetate (in 2 * 100ml), with the extraction liquid water that merges (2 * 30ml) and saturated sodium-chloride water solution (2 * 30ml) wash, and are dried (MgSO then ₄), and under vacuum, remove and desolvate.By dodging formula silica gel chromatography purifying resistates, the mixture that uses 1: 3 methylene dichloride and sherwood oil (b.p.60-80 ℃) is as eluent.Merge suitable fraction, and under vacuum, remove and desolvate, obtained 1-(benzo [b] thiene-3-yl-)-2-cyclopropyl second-1-ketone (4.15g), be orange, need not be further purified direct use.

Under nitrogen atmosphere, stirring, tribromide phenyltrimethyammonium (1.74g) is added in 1-(benzo [b] the thiene-3-yl-)-2-cyclopropyl second-solution of 1-ketone (1g) in tetrahydrofuran (THF) (15ml), this mixture stirring at room 18 hours, then with its filtration, and is removed under vacuum and desolvates.Resistates is dissolved in the ethanol (12ml), adds 2-imidazolidine thioketones (0.47g) and acetate (4ml), with this mixture reflux 18 hours under nitrogen atmosphere, then under vacuum except that desolvating.By dodging formula silica gel chromatography purifying resistates, the mixture that uses 1: 3 methylene dichloride and ether is as eluent.Merge suitable fraction, remove under vacuum and desolvate, obtained 3-(benzo [b] thiene-3-yl-)-2-cyclopropyl-5, the 6-glyoxalidine is [2,1-b] thiazole hydrobromide salt (0.72g) also, are beige solid, m.p.181-183 ℃.Embodiment 46

Under room temperature, stirring, the drips of solution of iodine monochloride (1.83g) in methylene dichloride (5ml) is added to 3-(benzo [b] thiophene 3-yl)-5, the 6-glyoxalidine is [2,1-b] thiazole (3.8g also; The method described makes according to being similar in embodiment 6) in the solution in methylene dichloride (200ml), with this mixture stirring at room 15 minutes.Collect the gained solid by filtering, with methylene dichloride (50ml) washing, at air drying, obtained 3-(benzo [b] thiene-3-yl-)-2-iodo-5, the 6-glyoxalidine is [2,1-b] thiazole hydrochlorides (1.3g) also, be light yellow solid, m.p.194.7-195.2 ℃.Embodiment 47

Under nitrogen atmosphere, stirring, the drips of solution of 2-oxopropyl dimethyl phosphonate (1.28g) in tetrahydrofuran (THF) (10ml) is added to sodium hydride (60% mineral oil dispersion; 0.46g) in the suspension in tetrahydrofuran (THF) (15ml), then with this mixture stirring at room 20 minutes.Add 3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazole-2-formaldehyde (2g also in batches; The method described makes according to being similar in embodiment 6), this mixture stirring at room 18 hours, and was stirred 7 hours under reflux temperature, then it was placed 18 hours in room temperature.Under vacuum, remove and desolvate, resistates water (200ml) is diluted, and product is extracted in the methylene dichloride (200ml).With extraction liquid drying (Na ₂SO ₄), under vacuum, remove and desolvate, then by sudden strain of a muscle formula silica gel chromatography purifying resistates, use 19: 1 methylene dichloride and methanol mixture as eluent.Merge suitable fraction, remove under vacuum and desolvate, obtained 4-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] fourth-3-alkene-2-ketone (1.15g), be yellow solid, m.p.164-166 ℃.

Under agitation, sodium borohydride (36mg) is added to 4-[3-(benzo [b] thiene-3-yl-)-5, and the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] in the fourth-3-alkene-solution of 2-ketone (0.28g) in ethanol (10ml), this mixture stirring at room 3 hours, is removed under vacuum then and desolvates.With resistates water (100ml) dilution, product is extracted in the methylene dichloride (100ml), then with extraction liquid drying (Na ₂SO ₄), and under vacuum, remove and desolvate.Resistates is developed with ether (20ml), and collected the gained solid by filtering, dry under vacuum, obtained 4-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] fourth-3-alkene-2-alcohol (0.16g), be white-yellowish solid, m.p.161-162 ℃.Embodiment 48

According to being similar to the method for in embodiment 17, describing, with 3-(benzo [b] thiene-3-yl-)-2-bromo-5,6-glyoxalidine also [2,1-b] thiazole hydrobromide salt and tonsilon reactive magnesium, with 3-bromo-2-methacrylic and fumaric acid reaction, obtained 3-(benzo [b] thiene-3-yl-)-2-(2-methyl-prop-2-thiazolinyl)-5 then, 6-glyoxalidine also [2,1-b] the thiazole fumarate, be beige solid, m.p.54-64 ℃.Embodiment 49

Under room temperature, nitrogen atmosphere, stirring, 1, the drips of solution in the 4-dioxane (5ml) is added to sodium hydride (60% mineral oil dispersion with (dimethylamino) Tetraethyl diphosphonomethane (2.32g); 0.28g) in the suspension in 1,4 dioxane (5ml), this mixture is discharged until no longer including hydrogen in stirring at room.Add 3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazole-2-formaldehyde (2g also; The method described makes according to being similar in embodiment 6), this mixture was stirred 1.3 hours at 60 ℃, stirring at room 18 hours, be poured into then in the water (50ml).Product is extracted into ethyl acetate (in 3 * 30ml), with the extraction liquid drying (MgSO that merges ₄), and under vacuum, remove and desolvate.By dodging formula silica gel chromatography purifying resistates, use 93: 7 methylene dichloride and carbinol mixture as eluent.Merge suitable fraction, and under vacuum, remove and desolvate, obtained 2-[3-(benzo [b] thiene-3-yl-)-5,6-glyoxalidine also [2,1-b] thiazol-2-yl]-1-(dimethylamino) vinyl phosphonic diethyl phthalate (1.78g), be red oil, need not be further purified direct use.

With 2-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also]-mixture heating up of 1-(dimethylamino) vinyl phosphonic diethyl phthalate (1.7g) and concentrated hydrochloric acid (12ml) refluxed 1 hour, and cooled off in ice then.Product is extracted into methylene dichloride (in 3 * 30ml), with the extraction liquid drying (MgSO that merges ₄), and under vacuum, remove and desolvate.In resistates water-soluble (30ml), by adding excessive saturated sodium bicarbonate aqueous solution this solution is neutralized, and product is extracted into methylene dichloride (in 3 * 30ml).With the extraction liquid drying (MgSO that merges ₄), and under vacuum, remove and desolvate.Resistates is dissolved in the ethanol (2ml), adds oxalic acid (15mg), and under vacuum, remove and desolvate.Resistates with ether (10ml) development, is collected the gained solid by filtering, dry under vacuum, obtained [3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] ethyl acetate oxalate (40mg), be beige solid, m.p.102-104 ℃.Embodiment 50

Under-70 ℃, nitrogen atmosphere, stirring, with the s-butyl lithium (solution of 1.25M in the mixture of 92: 8 hexanaphthenes and hexane; 100ml) be added drop-wise in the solution of 4-fluorophenyl methyl sulfide (22.0g) in tetrahydrofuran (THF), then this mixture stirred 65 minutes at-70 ℃.At-68 ℃--70 ℃ drip dimethyl formamide (13.2ml), with 20 hours this mixture are warmed to room temperature lentamente, then it are added in the solution of acetate (10ml) in water (500ml).Product is extracted into ether (in 3 * 150ml), then the extraction liquid that merges is washed dry (Na with 2M hydrochloric acid (200ml) and saturated sodium-chloride water solution (200ml) ₂SO ₄), and under vacuum, remove and desolvate.The resistates (25g) that need not be further purified direct use is estimated mainly to be made up of 2: 3 4-fluorophenyl methyl sulfide and 2-fluoro-5-(methylthio group) phenyl aldehyde (being confirmed by NMR (Nuclear Magnetic Resonance) spectrum respectively) mixture.

With Thiovanic acid (8.9ml), 2-fluoro-5-(methylthio group) phenyl aldehyde crude product (25g), N,N-DIMETHYLACETAMIDE (250ml) and N, the mixture of N-diisopropyl ethyl amine (42ml) removes under vacuum then and desolvates 140-150 ℃ of stirring heating 3.5 hours under nitrogen atmosphere.(650ml) is added in the resistates with water, then product is extracted into methylene dichloride (in 3 * 150ml).With extraction liquid water (3 * 150ml) washings, the dry (Na that merges ₂SO ₄), and under vacuum, remove and desolvate.By coming the purifying resistates, collect the gained solid by filtering, with ether (2 * 50ml) washings with ether (250ml) development, and it is dry under vacuum, obtained 5-(methylthio group) benzo [b] thiophene-2-carboxylic acid methyl esters (13.3g), be light yellow solid, m.p.89.7-90.4 ℃.

In sodium hydroxide (8g) water-soluble (100ml), under agitation this solution is added to 5-(methylthio group) benzo [b] thiophene-2-carboxylic acid methyl esters (23.8g then; Above-mentioned method makes according to being similar to) in the solution in methyl alcohol (300ml).This mixture heating up was refluxed 10 minutes, placed 3 days in room temperature then.By the heating this suspension is concentrated into about 250ml, add entry (100ml) then, with this mixture filtered while hot to remove insolubles.The solution of concentrated hydrochloric acid (40ml) in water (20ml) is added in the filtrate, collects the gained solid by filtering, and wash with water, dry under vacuum in 80 ℃ then, obtained 5-(methylthio group) benzo [b] thiophene-2-carboxylic acid (21g), be light yellow solid, m.p.186-186.5 ℃.

Mixture reflux under nitrogen atmosphere of copper powder (5.3g), 5-(methylthio group) benzo [b] thiophene-2-carboxylic acid (20g) and quinoline (100ml) was stirred 30 minutes, then filtered while hot.This filtrate is added in the mixture of concentrated hydrochloric acid (100ml), ice (500g) and ether (200ml), and collects the gained solid, with ether (200ml) washing by filtering.Isolate water layer, and other product is extracted into ether (in 2 * 150ml) from water layer.The diethyl ether solution that merges is washed dry (Na with 2M hydrochloric acid (200ml) and water (200ml) ₂SO ₄), and under vacuum, remove and desolvate, obtained 5-(methylthio group) benzo [b] thiophene (14.7g), be the light brown solid, it need not be further purified direct use.

Less than 0 ℃, stir under, the solution of 5-(methylthio group) benzo [b] thiophene (14.7g) in methylene dichloride (180ml) is added in the mixture of aluminum bromide (26.2g), bromoacetyl bromide (7.12ml) and methylene dichloride (120ml), gained reddish dark brown solution was being stirred 30 minutes below 0 ℃, and, then it is added in the mixture of ice (600g) and concentrated hydrochloric acid (50ml) stirring at room 20 hours.Add methylene dichloride (300ml), and by filtering (Celite ^) remove insolubles.Isolate water, and other product wherein is extracted in the methylene dichloride (300ml), then with the dichloromethane solution drying (MgSO that merges ₄), and under vacuum, remove and desolvate.Resistates is dissolved in the mixture of acetate (200ml) and methylene dichloride (200ml), adds the solution of 2-imidazolidine thioketones (5.29g) in acetate (200ml), remove methylene dichloride by distillation then.With remaining mixture reflux 2 hours, by heating under vacuum cumulative volume is reduced to about 200ml then.By dumping the solution and the insolubles of heat are separated, then cooling.Be settled out other solid, and removed as mentioned above, then solvent has been removed under vacuum in 50 ℃.Resistates is mixed with water (300ml) and 5M aqueous sodium hydroxide solution (300ml), product is extracted in the methylene dichloride (300ml) then.With extraction liquid drying (Na ₂SO ₄), and under vacuum, remove and desolvate.By dodging formula silica gel chromatography partial purification resistates, the mixture that uses ethyl acetate and 8: 1: 1 ethyl acetate, methyl alcohol and triethylamines successively is as eluent.Merge suitable fraction, and under vacuum, remove and desolvate, obtained 3-[5-(methylthio group) benzo [b] thiene-3-yl-]-5, the 6-glyoxalidine is [2,1-b] thiazole also, for yellowish brown jelly (3.6g), need not be further purified direct use.

15-20 ℃, stir under, the drips of solution of bromine (1.87g) in methylene dichloride (10ml) is added to 3-[5-(methylthio group) benzo [b] thiene-3-yl-]-5,6-glyoxalidine also [2,1-b] in the solution of thiazole (3.55g) in methylene dichloride (80ml), with this mixture stirring at room 10 minutes, by dumping dichloromethane solution and insolubles are separated then, and under vacuum, concentrated.Resistates with methylene dichloride (10ml) development, is collected the gained solid by filtering, and dry under vacuum, obtained 2-bromo-3-[5-(methylthio group) benzo [b] thiene-3-yl-]-5, the 6-glyoxalidine is [2,1-b] thiazole hydrobromide salt (2.97g) also, be the yellowish brown solid, m.p.260-265 ℃.Embodiment 51

Under-10 ℃, nitrogen atmosphere, stirring, with ethyl-magnesium-chloride (2.8M tetrahydrofuran solution; 8.76ml) be added to 2-bromo-3-[5-(methylthio group) benzo [b] thiene-3-yl-]-5,6-glyoxalidine also [2,1-b] in the suspension of thiazole hydrobromide salt (2.9g) in tetrahydrofuran (THF) (40ml), then with this mixture stirring at room 90 minutes, and be cooled to-5 ℃.Add dimethyl formamide (5ml), gained suspension stirring at room 2 hours, is added ethyl acetate (200ml) and saturated aqueous ammonium chloride (200ml) then, isolate ethyl acetate layer, drying (Na ₂SO ₄), and under vacuum, remove and desolvate, obtained 3-[5-(methylthio group) benzo [b] thiene-3-yl-]-5, the 6-glyoxalidine is [2,1-b] thiazole-2-formaldehyde (1.4g) also, is solid, m.p.157-158.5 ℃, need not be further purified direct use.

Under agitation sodium borohydride (0.114g) is added to 3-[5-(methylthio group) benzo [b] thiene-3-yl-]-5,6-glyoxalidine also [2,1-b] in the thiazole-solution of 2-formaldehyde (0.664g) in ethanol (40ml), then with this mixture stirring at room 24 hours, and come stopped reaction by adding 5M hydrochloric acid (10ml).By adding the 1M aqueous sodium hydroxide solution this mixture is alkalized, and under vacuum, concentrate, then product is extracted into methylene dichloride (in 3 * 30ml) to remove ethanol.With the extraction liquid drying (MgSO that merges ₄), under vacuum, remove and desolvate, by silicon-dioxide Biotage purified by flash chromatography resistates, the mixture that uses 34: 3: 3 ethyl acetate, industrial methylated spirit and triethylamines is as eluent.Merge suitable fraction, under vacuum, remove and desolvate, then resistates is developed with ether (10ml).Collect the gained solid by filtering, at air drying, obtained 3-[5-(methylthio group) benzo [b] thiene-3-yl-]-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also } methyl alcohol (0.13g), be beige solid, m.p.164-167 ℃.Embodiment 52

According to being similar to the method for in embodiment 22, describing,, react with fumaric acid then [3-(benzo [b] thiene-3-yl-)-5,6-glyoxalidine be [2,1-b] thiazol-2-yl also] methyl alcohol (0.5g) and sodium hydride and the reaction of brooethyl cyclopropane.In this preparation, salify carries out in methanol solution, and is not settled out any solid product.Under vacuum, remove then and desolvate, and develop resistates with ether (10ml).Collect the gained solid by filtering, and dry under vacuum, having obtained 3-(benzo [b] thiene-3-yl-)-2-cyclo propyl methoxy methyl-5, the 6-glyoxalidine is [2,1-b] thiazole fumarates (40mg) also, are the light brown solid, m.p.82-98 ℃.Embodiment 53

In room temperature, stir under, with 10 minutes with sodium hydride (60% mineral oil dispersion; 0.153g) be added in [3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] methyl alcohol (1g) suspension in dimethyl formamide (50ml) in batches, then with this mixture stirring at room 2 hours.Add 1-chlorine third-2-alkynes (276 μ l), and continue to stir 2 hours in room temperature.Add 1-chlorine third-2-alkynes (27 μ l) again, with this mixture stirring at room 18 hours.Add entry (50ml), with product be extracted into ethyl acetate (in 3 * 50ml), then with the extraction liquid water that merges (4 * 25ml) and saturated sodium-chloride water solution (25ml) washing, drying (MgSO ₄), and under vacuum, remove and desolvate.By dodging formula silica gel chromatography purifying resistates, use the mixture of 5-8% methyl alcohol in methylene dichloride as eluent.Merge suitable fraction, and under vacuum, remove and desolvate.Resistates is dissolved in the methyl alcohol (15ml), adds fumaric acid (0.185g), this mixture is stirring at room 5 hours, warm with lysate with it then, filter to remove a small amount of insolubles.Remove under vacuum and desolvate, obtained 3-(benzo [b] thiene-3-yl-)-2-Propargyl oxygen ylmethyl-5, the 6-glyoxalidine is [2,1-b] thiazole fumarates (0.67g) also, are brown solid, m.p.120 ℃ (80-90 ℃ of deliquescing).Embodiment 54

Under room temperature, nitrogen atmosphere, stirring, be added in the solution of 2-methoxybenzenethiol (10.6ml) in the mixture of ethanol (125ml) and water (7.5ml) the solution of sodium hydroxide (4.87g) in the mixture of ethanol (140ml) and water (35ml) is disposable, then with this mixture stirring at room 3.5 hours.With dripping the 1-chloro-4-phenoxy group fourth-solution of 2-alkynes (15.7g) in the mixture of ethanol (125ml) and water (7.5ml) in 1.5 hours, then with this mixture stirring at room 18 hours, and under vacuum except that desolvating.With resistates water (75ml) dilution, product is extracted into ethyl acetate (in 2 * 115ml), then with the extraction liquid water (50ml) and saturated sodium-chloride water solution (50ml) washing that merge, dry (MgSO ₄), and under vacuum, remove and desolvate, obtained 1-(2-anisole sulfenyl)-4-phenoxy group fourth-2-alkynes (24.7g), be yellow oil, need not be further purified direct use.

0-5 ℃, stir under, with 1.5 hours with 3-chlorine peroxybenzoic acid (70% purity; 9.1g) drips of solution in chloroform (210ml) is added in 1-(2-anisole the sulfenyl)-4-phenoxy group fourth-solution of 2-alkynes (10.5g) in chloroform (95ml), with this mixture stirring at room 18 hours, then with it with 5% aqueous sodium carbonate (3 * 120ml) and water (3 * 80ml) washings, and dry (MgSO ₄).This chloroformic solution reflux was stirred 7 hours, placed 18 hours, use 5M aqueous sodium hydroxide solution (115ml), water (4 * 110ml) and saturated sodium-chloride water solution (100ml) washing, and drying (MgSO then in room temperature ₄).Under vacuum, remove and desolvate, obtained 1-(7-methoxyl group-2,3-dihydrobenzo [b] thiene-3-yl-)-2-phenoxy group second-1-ketone (10.7g), be brown jelly, need not be further purified direct use.

The mixture of 1-(7-methoxyl group-2,3-dihydrobenzo [b] thiene-3-yl-)-2-phenoxy group second-1-ketone (10.7g), acetate (100ml) and the vitriol oil (12) was heated 3 hours at 90-95 ℃, be cooled to room temperature then, and pour in the water (800ml).With product be extracted into methylene dichloride (in 2 * 250ml), with the extraction liquid that merges with the 2M aqueous sodium hydroxide solution (2 * 200ml) and water (3 * 200ml) wash, and are dried (MgSO then ₄), and under vacuum, remove and desolvate.By dodging formula silica gel chromatography purifying resistates, the mixture that uses 1: 1 methylene dichloride and sherwood oil (b.p.60-80 ℃) is as eluent.Merge suitable fraction, and under vacuum, remove and desolvate, obtained 1-(7-methoxyl group benzo [b] thiene-3-yl-) second-1-ketone (2g), be brown oil, need not be further purified direct use.

Under room temperature, nitrogen atmosphere, stirring, with 20 minutes tribromide phenyltrimethyammonium (2.55g) is added in 1-(7-methoxyl group benzo [b] thiene-3-yl-) second-solution of 1-ketone (1.4g) in tetrahydrofuran (THF) (40ml) in batches, with this mixture stirring at room 1 hour, then with its filtration, and under vacuum, remove and desolvate.Resistates is dissolved in the ethanol (30ml), adds 2-imidazolidine thioketones (0.69g) and acetate (20ml), this mixture heating up was refluxed 18 hours, then it is cooled to room temperature.Collect the gained solid by filtering, with ether (20ml) washing, and dry under vacuum in 60 ℃, obtained 3-(7-methoxyl group benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazole hydrobromide salt (1.48g) also, be gray solid, m.p.277-279 ℃.

By adding 2M aqueous sodium hydroxide solution (110ml) with 3-(7-methoxyl group benzo [b] thiene-3-yl-)-5,6-glyoxalidine also [2,1-b] thiazole hydrobromide salt (1.48g) alkalization, then free alkali is extracted in the methylene dichloride (150ml), with extraction liquid water (2 * 70ml) washings, dry (MgSO ₄), and under vacuum, remove and desolvate.Resistates is dissolved in the methylene dichloride (23ml), is cooled to 0-5 ℃ then, with the solution of 45 minutes dripping bromine (0.68g) in methylene dichloride (4.7ml).This mixture was stirred 30 minutes at 0-5 ℃, and room temperature placement 18 hours, collect the gained solid by filtering then, with methylene dichloride (20ml) washing, dry under vacuum, obtained 2-bromo-3-(7-methoxyl group benzo [b] thiene-3-yl-)-5,6-glyoxalidine also [2,1-b] thiazole hydrobromide salt (1.22g), be white solid, m.p.240-242 ℃.Embodiment 55

In room temperature, stir under, with 10 minutes with sodium hydride (60% mineral oil dispersion; 0.38g) be added in [3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] methyl alcohol (2.5g) suspension in dimethyl formamide (50ml) in batches, then with this mixture stirring at room 2 hours.Add 2-N-PROPYLE BROMIDE (0.9ml), and continue to stir 2 hours in room temperature.Add 2-N-PROPYLE BROMIDE (0.4ml) again, and with this mixture stirring at room 72 hours.Add sodium hydride (60% mineral oil dispersion; 0.07g), this mixture was stirred 10 minutes, add 2-N-PROPYLE BROMIDE (0.16ml) then, and with this mixture stirring at room 18 hours.Add entry (100ml), with product be extracted into ethyl acetate (among the 100+2 * 75ml), with the extraction liquid water that merges (3 * 100ml) and saturated sodium-chloride water solution (100ml) washing, drying (MgSO ₄), and under vacuum, remove and desolvate.By dodging formula silica gel chromatography purifying resistates, the mixture that uses 1: 19 methyl alcohol and methylene dichloride is as eluent.Merge suitable fraction, and under vacuum, remove and desolvate.By dodging formula silica gel chromatography purifying resistates, use 9: 1 ethyl acetate and methanol mixture as eluent.Merge suitable fraction, and remove under vacuum and desolvate, obtained 3-(benzo [b] thiene-3-yl-)-2-isopropoxy methyl-5, the 6-glyoxalidine is [2,1-b] thiazoles (0.12g) also, are yellow solid, m.p.64-66 ℃.Embodiment 56

In room temperature, stir under, with 10 minutes with sodium hydride (60% mineral oil dispersion; 0.46 g) be added in [3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] methyl alcohol (3g) suspension in dimethyl formamide (80ml) in batches, then with this mixture stirring at room 2 hours.Dripping bromine methyl cyclobutane (1.7g), and with this mixture stirring at room 2.5 hours.Dripping bromine methyl cyclobutane (0.16g) again, and with this mixture stirring at room 1 hour.Dripping bromine methyl cyclobutane (0.16g) again, and with this mixture stirring at room 18 hours.TLC shows and still has raw material, therefore adds brooethyl tetramethylene (0.32g), and with this mixture stirring at room 2 hours, stirred 1 hour at 55 ℃.Add sodium hydride (0.042g) and brooethyl tetramethylene (0.8g) again, this mixture was stirred 1 hour at 55 ℃, stirring at room 18 hours.Add entry (100ml), with product be extracted into ethyl acetate (100+3 * 75ml), then with the extraction liquid water that merges (4 * 75ml) and saturated sodium-chloride water solution (75ml) washing, drying (MgSO ₄), and under vacuum, remove and desolvate.By dodging formula silica gel chromatography purifying resistates, the mixture that uses 1: 19 methyl alcohol and methylene dichloride is as eluent.Merge suitable fraction, and under vacuum, remove and desolvate.By dodging formula silica gel chromatography purifying resistates, use the mixture of 3: 1 sherwood oils (b.p.60-80 ℃) and ethyl acetate and 19: 1 methylene dichloride and carbinol mixture as eluent successively, merge suitable fraction, and under vacuum except that desolvating.Use the anti-guard post of C8 symmetry to be further purified resistates sample (taking out 30mg from 70mg) by preparation HPLC, the mixture that uses 2: 3 acetonitriles and triethylammonium formate damping fluid is as eluent.Merge suitable fraction, and remove under vacuum and desolvate, obtained 3-(benzo [b] thiene-3-yl-)-2-cyclobutyl methoxy ylmethyl-5, the 6-glyoxalidine is [2,1-b] thiazoles (12mg) also, are brown jelly, ¹H-NMR (DMSO-d ₆): δ _H1.61-1.84 (6H, m, 3 * tetramethylene CH ₂), 2.36-2.41 (1H, m, tetramethylene CH), 3.22 (2H, d, CH ₂O), 3.49-3.61 (2H, m, CH ₂N), 3.98-4.05 (2H, m, CH ₂O), 4.11-4.15 (2H, m, CH ₂N), 7.45-7.49 (2H, m, 2 * ArH), 7.77-7.81 (1H, m, ArH), 8.01 (1H, s, ArH), 8.08-8.11 (1H, m, ArH).Embodiment A

Illustrate the application of The compounds of this invention in pharmaceutical compositions by following description.In the explanation, term " active compound " is meant any The compounds of this invention in this section, but particularly as any compound of the end product of one of them previous embodiment.A) capsule

In capsular preparation, with the lactose depolymerization (de-aggregated) of the active compound of 10 weight parts and 240 weight parts and mix.This mixture is filled in the hard gelatin capsule, and every capsules contains unitary dose or part unit dose of active compound.B) tablet

Prepare tablet with following component.

Parts by weight

Active compound 10

Lactose 190

W-Gum 22

Polyvinylpyrrolidone 10

Magnesium Stearate 3

With active compound, lactose and a part of starch depolymerization, mix, and with the solution of polyvinylpyrrolidone in ethanol with the gained granulating mixture.Dried particles is mixed with Magnesium Stearate and all the other starch.In pelleter that this mixture compacting is in blocks then, every contains unitary dose or part unit dose of active compound.C) enteric coated tablet

As above (b) described preparation tablet.Use 20% Cellacefate and 3% diethyl phthalate at ethanol: the solution in the methylene dichloride (1: 1) carries out enteric coating by ordinary method with the gained tablet.D) suppository

In the preparation of suppository, the active compound of 100 weight parts is incorporated in the triglyceride level suppository base of 1300 weight parts, and this mixture is made suppository, every suppository contains the active compound for the treatment of significant quantity.

Claims (33)

1. formula I compound

Comprise its pharmacologically acceptable salt, wherein

A is S or O;

G is 0,1,2,3 or 4;

N is 2 or 3;

R ₁It is a) halogen, b) the optional alkyl that contains 1-3 carbon atom that is replaced by one or more halogens, c) the optional alkoxyl group that contains 1-3 carbon atom that is replaced by one or more halogens, d) the optional respectively alkylthio that contains 1-3 carbon atom that is replaced by one or more halogens, alkyl sulfinyl or alkyl sulphonyl, e) hydroxyl, f) contain the acyloxy of 1-3 carbon atom, g) contain the hydroxyalkyl of 1-3 carbon atom, h) cyano group, i) contain the alkanoyl of 1-6 carbon atom, j) contain the alkoxy carbonyl of 2-6 carbon atom, k) optional respectively by 1 or 2 formamyl or carbamyl ylmethyl that contains the alkyl N-replacement of 1-3 carbon atom respectively, 1) optional respectively by 1 or 2 sulfamyl or sulfamyl methyl that contains the alkyl N-replacement of 1-3 carbon atom respectively, or m) optional by 1 or 2 amino that contains the alkyl replacement of 1-3 carbon atom respectively; When g is 2,3 or 4, R ₁Identical or different;

R ₂And R ₃Be respectively H;

R ₄Representative contains the hydroxyalkyl of 1-6 carbon atom, Alpha-hydroxy (2-C _1-3Alkoxyl phenyl) methyl, contain the hydroxyl alkenyl on the carbon atom that 3-6 carbon atom and hydroxyl directly be not connected in two keys, contain 3-6 carbon atom and hydroxyl and directly be not connected in hydroxyl alkynyl on the triple-linked carbon atom, the hydroxyl cycloalkyl that contains 3-6 carbon atom, the alkenyl that contains 2-8 carbon atom, the aryl alkenyl that contains 8-10 carbon atom contains the cycloalkyl of 3-6 carbon atom, C _3-7Alkynyl alkoxy C _1-3Alkyl, C _4-7Cycloalkyl alkoxy C _1-3Alkyl, C _1-3Alkoxy C _1-3Alkyl, C _1-3Alkylthio C _1-3Alkyl, C _1-3Alkoxyl group, C _1-3Alkylthio, arylthio, C _1-6Alkanoyl, C _3-6Alkoxy carbonyl alkyl, cyano group, halogen, C _1-4The alkyl imino methyl, C _1-4Alkylamino alkyl or oxyimino methyl;

R ₅Be H or halogen.

2. the formula I compound of claim 1 comprises its pharmacologically acceptable salt, wherein

A is S or O;

G is 0,1,2,3 or 4;

N is 2 or 3;

R ₁It is a) halogen, b) the optional alkyl that contains 1-3 carbon atom that is replaced by one or more halogens, c) the optional alkoxyl group that contains 1-3 carbon atom that is replaced by one or more halogens, d) the optional respectively alkylthio that contains 1-3 carbon atom that is replaced by one or more halogens, the alkyl sulfinyl, alkyl sulphonyl, e) hydroxyl, f) contain the acyloxy of 1-3 carbon atom, g) contain the hydroxyalkyl of 1-3 carbon atom, h) cyano group, i) contain the alkanoyl of 1-6 carbon atom, j) contain the alkoxy carbonyl of 2-6 carbon atom, k) optional respectively by 1 or 2 formamyl or carbamyl ylmethyl that contains the alkyl N-replacement of 1-3 carbon atom respectively, 1) optional respectively by 1 or 2 sulfamyl or sulfamyl methyl that contains the alkyl N-replacement of 1-3 carbon atom respectively, or m) optional by 1 or 2 amino that contains the alkyl replacement of 1-3 carbon atom respectively; When g is 2,3 or 4, R ₁Identical or different;

R ₂And R ₃Be respectively H;

R ₄Representative contains the hydroxyalkyl of 1-6 carbon atom, contain the hydroxyl alkenyl on the carbon atom that 3-6 carbon atom and hydroxyl directly be not connected in two keys, contain 3-6 carbon atom and hydroxyl and directly be not connected in hydroxyl alkynyl on the triple-linked carbon atom, the hydroxyl cycloalkyl that contains 3-6 carbon atom, the alkenyl that contains 2-8 carbon atom, the cycloalkyl that contains 3-6 carbon atom, C _1-3Alkoxy C _1-3Alkyl, C _1-3Alkylthio C _1-3Alkyl, C _1-3Alkoxyl group, C _1-3Alkylthio, C _1-6Alkanoyl, halogen, C _1-4Alkyl imino methyl, or oxyimino methyl; And

R ₅Be H or halogen.

3. claim 1 or 2 compound, wherein A is S.

4. claim 1 or 2 compound, wherein A is O.

5. each compound of aforementioned claim, wherein R ₄Representative contains the hydroxyalkyl of 1-6 carbon atom, contains the hydroxyl alkenyl on the carbon that 3-6 carbon atom and hydroxyl directly be not connected in pair keys, contains 3-6 carbon atom and hydroxyl and directly is not connected in hydroxyl alkynyl on the triple-linked carbon, chooses wantonly by one or more C _1-2The alkenyl that contains 2 carbon atoms that alkyl replaces, C _1-4Alkyl imino methyl or oxyimino methyl.

6. each compound of aforementioned claim, wherein R ₄Representative contains the hydroxyalkyl of 1-5 carbon atom, contain the hydroxyl alkenyl on the carbon that 3-5 carbon atom and hydroxyl directly be not connected in two keys, contain 3-4 carbon atom and hydroxyl and directly be not connected in hydroxyl alkynyl on the triple-linked carbon, or optional by one or more methyl substituted alkenyls that contain 2 carbon atoms.

7. each compound of aforementioned claim, wherein R ₄Representation hydroxy methyl or vinyl.

8. each compound of aforementioned claim, wherein n is 2.

9. each compound of aforementioned claim, wherein g is 0 or 1, and R ₁Be a) halogen, b) the optional alkyl that contains 1-3 carbon atom that is replaced by one or more halogens, or c) chooses the alkoxyl group that contains 1-3 carbon atom that is replaced by one or more halogens wantonly.

10. each compound of aforementioned claim, wherein R ₅Be H.

11. the formula Ia compound of claim 1 Comprise its pharmacologically acceptable salt, wherein

A is S or O;

G is 0,1,2,3 or 4;

N is 2 or 3;

R ₁It is a) halogen, b) the optional alkyl that contains 1-3 carbon atom that is replaced by one or more halogens, c) the optional alkoxyl group that contains 1-3 carbon atom that is replaced by one or more halogens, d) the optional respectively alkylthio that contains 1-3 carbon atom that is replaced by one or more halogens, alkyl sulfinyl or alkyl sulphonyl, e) hydroxyl, f) contain the acyloxy of 1-3 carbon atom, g) contain the hydroxyalkyl of 1-3 carbon atom, h) cyano group, i) contain the alkanoyl of 1-6 carbon atom, j) contain the alkoxy carbonyl of 2-6 carbon atom, k) optional respectively by 1 or 2 formamyl or carbamyl ylmethyl that contains the alkyl N-replacement of 1-3 carbon atom respectively, 1) optional respectively by 1 or 2 sulfamyl or sulfamyl methyl that contains the alkyl N-replacement of 1-3 carbon atom respectively, or m) optional by 1 or 2 amino that contains the alkyl replacement of 1-3 carbon atom respectively; When g is 2,3 or 4, R ₁Identical or different;

R ₄Representative contains the hydroxyalkyl of 1-6 carbon atom, Alpha-hydroxy (2-C _1-3Alkoxyl phenyl) methyl, contain the hydroxyl alkenyl on the carbon atom that 3-6 carbon atom and hydroxyl directly be not connected in two keys, contain 3-6 carbon atom and hydroxyl and directly be not connected in hydroxyl alkynyl on the triple-linked carbon atom, the alkenyl that contains 2-8 carbon atom, the aryl alkenyl that contains 8-10 carbon atom, the cycloalkyl that contains 3-6 carbon atom, C _3-7Alkynyl alkoxy C _1-3Alkyl, C _4-7Cycloalkyl alkoxy C _1-3Alkyl, C _1-3Alkoxy C _1-3Alkyl, C _1-3Alkylthio C _1-3Alkyl, C _1-3Alkoxyl group, C _1-3Alkylthio, arylthio, C _1-6Alkanoyl, C _3-6Alkoxy carbonyl alkyl, cyano group, halogen, C _1-4The alkyl imino methyl, C _1-4Alkylamino methyl or oxyimino methyl.

12. the compound of claim 11, wherein A is S.

13. the compound of claim 11 or 12, wherein n is 2.

14. each compound of claim 11-13, wherein g is 0 or 1.

15. each compound of claim 11-14, wherein R ₁Be halogen, contain the alkoxyl group of 1-3 carbon atom or contain the alkylthio of 1-3 carbon atom.

16. each compound of claim 11-15, wherein A is O.

17. each compound of claim 11-16, wherein R ₄Representative contains the hydroxyalkyl of 1-4 carbon atom, Alpha-hydroxy (2-C _1-3Alkoxyl phenyl) methyl, contain the hydroxyl alkenyl on the carbon atom that 3-4 carbon atom and hydroxyl directly be not connected in two keys, contain 3-4 carbon atom and hydroxyl and directly be not connected in hydroxyl alkynyl on the triple-linked carbon atom, contain the alkenyl of 2-3 carbon atom, C _1-3Alkylthio, C _1-3Alkanoyl or oxyimino methyl.

18. be selected from following compound:

3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazole-2-formaldehyde also;

[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] methyl alcohol;

3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazole-2-formoxime also;

1-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] ethanol;

3-(benzo [b] thiene-3-yl-)-2-bromo-5, the 6-glyoxalidine is [2,1-b] thiazole also;

3-(benzo [b] thiene-3-yl-)-2-bromo-6,7-dihydro-5H-thiazole is [3,2-a] pyrimidine also;

1-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also]-the 1-methyl ethanol;

1-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] third-1-alcohol;

2-bromo-3-(5-methoxyl group benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazole also;

2-bromo-3-(the 5-chlorobenzene is [b] thiene-3-yl-also)-5, the 6-glyoxalidine is [2,1-b] thiazole also;

3-(benzo [b] thiene-3-yl-)-2-ethoxyl methyl-5, the 6-glyoxalidine is [2,1-b] thiazole also;

1-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] third-2-alkene-1-alcohol;

1-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] fourth-2-alkynes-1-alcohol;

3-(benzo [b] thiene-3-yl-)-2-vinyl-5, the 6-glyoxalidine is [2,1-b] thiazole also;

2-allyl group-3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazole also;

[3-(benzo [b] furans-3-yl)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] methyl alcohol;

N-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl methylene radical also]-1-methylethyl amine;

3-(benzo [b] thiene-3-yl-)-2-chloro-5, the 6-glyoxalidine is [2,1-b] thiazole also;

2-ethanoyl-3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazole also;

3-(benzo [b] thiene-3-yl-)-2-(methoxymethyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also;

3-(benzo [b] thiene-3-yl-)-2-(methylthio group)-5, the 6-glyoxalidine is [2,1-b] thiazole also;

3-(benzo [b] thiene-3-yl-)-2-(1-methyl ethylene)-5, the 6-glyoxalidine is [2,1-b] thiazole also;

1-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also]-2-methyl-prop-1-alcohol;

1-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] fourth-1-alcohol;

1-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also]-2-methyl fourth-3-alkene-1-alcohol;

1-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also]-3-methyl fourth-1-alcohol;

1-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] penta-1-alcohol;

1-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] third-2-alkynes-1-alcohol;

1-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] fourth-3-alkene-1-alcohol;

1-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also]-2-methyl-prop-2-alkene-1-alcohol;

1-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] penta-4-alkene-1-alcohol;

[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] (2-p-methoxy-phenyl) methyl alcohol;

3-(benzo [b] thiene-3-yl-)-2-third-1-thiazolinyl-5, the 6-glyoxalidine is [2,1-b] thiazole also;

[3-(benzo [b] thiene-3-yl-)-6,7-dihydro-5H-thiazole is [3,2-a] pyrimidine-2-base also] methyl alcohol;

3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazole-2-nitrile also;

3-(benzo [b] thiene-3-yl-)-2-styryl-5, the 6-glyoxalidine is [2,1-b] thiazole also;

3-(the 5-chlorobenzene is [b] thiene-3-yl-also)-5, the 6-glyoxalidine is [2,1-b] thiazole-2-formaldehyde also;

[3-(the 5-chlorobenzene is [b] thiene-3-yl-also)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] methyl alcohol;

3-(benzo [b] thiene-3-yl-)-2 (thiophenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also;

[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also]-N-methyl methylamine;

3-(benzo [b] thiene-3-yl-)-2-cyclopropyl-5, the 6-glyoxalidine is [2,1-b] thiazole also;

3-(benzo [b] thiene-3-yl-)-2-iodo-5, the 6-glyoxalidine is [2,1-b] thiazole also;

4-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] fourth-3-alkene-2-alcohol;

3-(benzo [b] thiene-3-yl-)-2-(2-methyl-prop-2-thiazolinyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also;

[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] ethyl acetate;

2-bromo-3-[5-(methylthio group) benzo [b] thiene-3-yl-]-5, the 6-glyoxalidine is [2,1-b] thiazole also;

3-[5-(methylthio group) benzo [b] thiene-3-yl-]-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also } methyl alcohol;

3-(benzo [b] thiene-3-yl-)-2-cyclo propyl methoxy methyl-5, the 6-glyoxalidine is [2,1-b] thiazole also;

3-(benzo [b] thiene-3-yl-)-2-Propargyl oxygen ylmethyl-5, the 6-glyoxalidine is [2,1-b] thiazole also;

2-bromo-3-(7-methoxyl group benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazole also;

3-(benzo [b] thiene-3-yl-)-2-isopropoxy methyl-5, the 6-glyoxalidine is [2,1-b] thiazole also; With

3-(benzo [b] thiene-3-yl-)-2-cyclobutyl methoxy ylmethyl-5, the 6-glyoxalidine is [2,1-b] thiazole also

Comprise its pharmacologically acceptable salt and independent enantiomer, racemic modification or other enantiomeric mixture.

19. be selected from following compound:

3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazole-2-formaldehyde also;

[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] methyl alcohol;

3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazole-2-formoxime also;

1-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] ethanol;

3-(benzo [b] thiene-3-yl-)-2-bromo-5, the 6-glyoxalidine is [2,1-b] thiazole also;

3-(benzo [b] thiene-3-yl-)-2-bromo-6,7-dihydro-5H-thiazole is [3,2-a] pyrimidine also;

1-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also]-the 1-methyl ethanol;

1-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] third-1-alcohol;

2-bromo-3-(5-methoxyl group benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazole also;

2-bromo-3-(the 5-chlorobenzene is [b] thiene-3-yl-also)-5, the 6-glyoxalidine is [2,1-b] thiazole also;

3-(benzo [b] thiene-3-yl-)-2-ethoxyl methyl-5, the 6-glyoxalidine is [2,1-b] thiazole also;

1-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] third-2-alkene-1-alcohol;

1-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] fourth-2-alkynes-1-alcohol;

3-(benzo [b] thiene-3-yl-)-2-vinyl-5, the 6-glyoxalidine is [2,1-b] thiazole also;

2-allyl group-3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazole also;

[3-(benzo [b] furans-3-yl)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] methyl alcohol;

N-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl methylene radical also]-1-methylethyl amine;

3-(benzo [b] thiene-3-yl-)-2-chloro-5, the 6-glyoxalidine is [2,1-b] thiazole also;

2-ethanoyl-3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazole also;

3-(benzo [b] thiene-3-yl-)-2-(methoxymethyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also;

3-(benzo [b] thiene-3-yl-)-2-(methylthio group)-5, the 6-glyoxalidine is [2,1-b] thiazole also;

3-(benzo [b] thiene-3-yl-)-2-(1-methyl ethylene)-5, the 6-glyoxalidine is [2,1-b] thiazole also;

1-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also]-2-methyl-prop-1-alcohol;

1-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] fourth-1-alcohol;

1-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also]-2-methyl fourth-3-alkene-1-alcohol;

1-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also]-3-methyl fourth-1-alcohol;

1-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] penta-1-alcohol;

1-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] third-2-alkynes-1-alcohol;

1-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] fourth-3-alkene-1-alcohol;

1-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also]-2-methyl-prop-2-alkene-1-alcohol; With

1-[3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] penta-4-alkene-1-alcohol;

And their pharmacologically acceptable salt.

20. a pharmaceutical composition, it contains each formula I compound and the pharmaceutically acceptable diluent or the carrier of aforementioned claim for the treatment of significant quantity.

21. as each formula I compound of the aforementioned claim of medicine.

22. be used for the treatment of each the formula I compound of aforementioned claim of following disease: dysthymia disorders, anxiety, psychosis, schizophrenia, tardive dyskinesia, obesity, drug habit, drug abuse, cognitive disorder, Alzheimer, cerebral ischemia, obsessional idea and behavior, panic attack, social phobia, eating disorder for example Bulimia nerovsa, apocleisis, snacking and eat without restraint, non insulin dependent diabetes, hyperglycemia, hyperlipemia, anxiety, and help smoking cessation.

23. be used for the treatment of and/or prevent each the formula I compound of aforementioned claim of following disease: epileptic seizures, neuropathy be for example apoplexy, cerebral trauma, cerebral ischemia, head injury and hemorrhage of epilepsy and/or illness that nerve injury takes place for example.

24. each formula I compound of claim 1-19 is used for the treatment of application in the medicine of following disease in preparation: treatment dysthymia disorders, anxiety, psychosis, schizophrenia, tardive dyskinesia, obesity, drug habit, drug abuse, cognitive disorder, Alzheimer, cerebral ischemia, obsessional idea and behavior, panic attack, social phobia, eating disorder for example Bulimia nerovsa, apocleisis, snacking and eat without restraint, non insulin dependent diabetes, hyperglycemia, hyperlipemia and anxiety, help is given up smoking; And be used for the treatment of and/or prevent application in the medicine of following disease in preparation: epileptic seizures, neuropathy be for example apoplexy, cerebral trauma, cerebral ischemia, head injury and hemorrhage of epilepsy and/or illness that nerve injury takes place for example.

25. the method for the following disease of treatment comprises each the formula I compound to the claim 1-19 of patient's administering therapeutic significant quantity of needs treatments: dysthymia disorders, anxiety, psychosis, schizophrenia, tardive dyskinesia, fat, drug habit, drug abuse, cognitive disorder, Alzheimer, cerebral ischemia, obsessional idea and behavior, panic attack, social phobia, eating disorder is Bulimia nerovsa for example, apocleisis, snacking and eating without restraint, non insulin dependent diabetes, hyperglycemia, hyperlipemia, anxiety and epileptic seizures, neuropathy is epilepsy and/or illness that nerve injury takes place apoplexy for example for example, cerebral trauma, cerebral ischemia, head injury and hemorrhage.

26. a method that alleviates people's craving for tobacco comprises each the formula I compound to the claim 1-19 of patient's administering therapeutic significant quantity that this needs are arranged.

27. one kind alleviates the give up smoking method of back weight increase of people, comprises each the formula I compound to the claim 1-19 of patient's administering therapeutic significant quantity that this needs are arranged.

28. be used for the treatment of or prevent each the formula I compound of claim 1-19 of following disease: metabolic trouble and by its illness that causes is that non-motor activity is given birth to heat and accretion rate increase especially, sexual dysfunction, insomnia, syndrome before the menstruation, the urinary incontinence, the superfunction disease, HH and reflux oesophagitis, pain, especially neuropathy pain, the weight increase relevant with pharmacological agent, chronic fatigue syndrome, osteoarthritis and gout, the cancer relevant with weight increase, the menstruation dysfunction, gallbladdergallstonecholetithiasis, postural hypotension and pulmonary hypertension.

29. be used for preventing cardiovascular disease, alleviate platelet adhesion, each formula I compound of the claim 1-19 that loses weight after helping to lose weight and to help to give up smoking after the pregnancy.

30. be 5-HT _1AAgonist and also be the compound of monoamine reuptake inhibitor, particularly NRI at treatment obesity and related complication, do not cause the application in the cardiovascular side effects simultaneously again.

31. the method that treatment is fat, the while does not cause cardiovascular side effects again comprises that using to the patient that this needs are arranged is 5-HT _1AAgonist and also be the compound of monoamine reuptake inhibitor, particularly NRI.

32. be used for the treatment of each the formula I compound of claim 1-19 of obesity and related complication.

33. the method for preparation I compound comprises:

A) choose wantonly in the presence of acid, under 0-200 ℃ of temperature, formula II compound dewatered:

Wherein A, R ₁, R ₂, R ₃, R ₄, R ₅, g and n as defined above; Or

B) with the formula III compound

R wherein ₂, R ₃With n as defined above,

React with formula IV compound Wherein Z is a leavings group, and A, R ₁, R ₄, R ₅With g as defined above,

Wherein said reaction is in the presence of solvent and choose wantonly in the presence of acid in 0-200 ℃ and carry out, and does not isolate formula II intermediate; Or

C) choose wantonly in the presence of solvent, formula V compound Wherein A, R ₁, R ₂, R ₃, R ₅, n and g as defined above,

React under-50-200 ℃ temperature with halogenating agent, to generate wherein R ₄Represent the formula I compound of halogen; Or

D) in the presence of solvent, with formula VI compound Wherein A, R ₁, R ₂, R ₃, R ₅, n and g as defined above, and R _yBe H,

With formula R _xMgX or R _xThe Li organometallic reagent reacts under the boiling temperature of-50 ℃-solvent for use, wherein R _xBe C _1-5Alkyl, the alkenyl that contains 2-5 carbon atom, the alkynyl that contains 2-5 carbon atom or (2-C _1-3Alkoxyl phenyl), and X is halogen, to generate wherein R ₄Represent Shi-CH (OH) R _xShown in group, and R _xFormula I compound as defined above; Or

E) in the presence of solvent, incite somebody to action wherein A, R ₁, R ₂, R ₃, R ₅, g and n as defined above, and R _yBe C _1-5Alkyl, the alkenyl that contains 2-5 carbon atom, the alkynyl that contains 2-5 carbon atom or (2-C _1-3Alkoxyl phenyl) formula VI compound and reductive agent react under the boiling temperature of 0 ℃-solvent for use, to generate wherein R ₄Represent Shi-CH (OH) R _yShown in group, and R _yBe C _1-5Alkyl, the alkenyl that contains 2-5 carbon atom, the alkynyl that contains 2-5 carbon atom or (2-C _1-3Alkoxyl phenyl) formula I compound; Or

F) in solvent, incite somebody to action wherein A, R ₁, R ₂, R ₃, R ₅, g and n as defined above, and R _yThe formula VI compound and the reductive agent that are H react under the boiling temperature of-50 ℃-solvent for use, to generate wherein R ₄It is the formula I compound of hydroxymethyl; Or

G) choose wantonly in the presence of solvent, wherein A, R ₁, R ₂, R ₃, R ₅, g and n as defined above, and R _yBe that the formula VI compound of H and azanol or its salt react under 0-250 ℃ of temperature, to generate wherein R ₄It is the formula I compound of oxyimino methyl; Or

H) in the presence of formic acid, incite somebody to action wherein A, R ₁, R ₂, R ₃, R ₅, g and n as defined above, and R _yBe that the formula VI compound of H and azanol or its salt react under 0-250 ℃ of temperature, to generate wherein R ₄It is the formula I compound of cyano group; Or

I) choose wantonly in the presence of solvent, and choose wantonly in the presence of acid catalyst, wherein A, R ₁, R ₂, R ₃, R ₅, g and n as defined above, and R _yRepresent the formula VI compound of H and R wherein _aRepresent C _1-4The formula R of alkyl _aNH ₂Amine under 0-250 ℃ of temperature, react, to generate wherein R ₄Represent C _1-4The formula I compound of alkyl imino methylene radical; Or

J) in the presence of solvent, incite somebody to action wherein R ₄Represent C _1-4Alkyl imino methylene radical, and A, R ₁, R ₂, R ₃, R ₄, R ₅, g and n as defined above formula I compound and reductive agent under the boiling temperature of 0 ℃-solvent for use, react, to generate wherein R ₄Represent C _1-4The formula I compound of alkylamino methylene radical; Or

K) in the presence of solvent, incite somebody to action wherein A, R ₁, R ₂, R ₃, R ₅, g and n as defined above, and R _yRepresent the formula VI compound of hydrogen and R wherein _aRepresent C _1-4The formula R of alkyl _aNH ₂Amine and reductive agent under the boiling temperature of 0 ℃-solvent for use, react, to generate wherein R ₄Represent C _1-4The formula I compound of alkylamino methylene radical; Or

1) in the presence of solvent, incites somebody to action wherein R _yBe C _1-5Alkyl, and A, R ₁, R ₂, R ₃, R ₅, n and g formula VI compound and formula R as defined above _xMgX or R _xThe L organometallic reagent reacts under the boiling temperature of-50 ℃-solvent for use, wherein R _xBe C _1-5Alkyl, and X is halogen, to generate wherein R ₄Represent Shi-C (OH) R _xR _yShown in group, and R _xAnd R _yBe C independently respectively _1-5The formula I compound of alkyl; Or

M) in the presence of solvent, will be except R _yBe OR _z, and R _zBe C _1-6Alkyl is formula VI compound and formula R as defined above outward _xMgX or R _xThe Li organometallic reagent reacts under the boiling temperature of-50 ℃-solvent for use, wherein R _xBe C _1-2Alkyl, and X is halogen, to generate wherein R ₄Represent Shi-C (OH) R _xR _yShown in group, and R _xAnd R _yBe identical C _1-2The formula I compound of alkyl; Or

N) in the presence of alkali, in solvent, incite somebody to action wherein R _yRepresent hydrogen or C _1-4Alkyl, and A, R ₁, R ₂, R ₃, R ₅, n and g formula VI compound and formula R as defined above _zPh ₃P ⁺Br ^-Phosphonium salt reacts under the boiling temperature of-78 ℃-solvent for use, wherein R _zRepresent C _1-5Alkyl or benzyl are to generate wherein R ₄Represent C _2-6Two keys in alkenyl and the described alkenyl are connected on the alpha-carbon of thiazole ring or the formula I compound of styryl; Or

O) in the presence of solvent, incite somebody to action wherein R ₄Represent halogen, and A, R ₁, R ₂, R ₃, R ₅, n and g formula I compound as defined above, or formula V compound and formula R _bMgX or R _bThe Li compound reacts under the boiling temperature of-78 ℃-solvent for use, wherein R _bBe C _1-6Alkyl, and X is a halogen; Then in solvent, with products therefrom and formula R _cCON (CH ₃) OCH ₃Acylating agent reacts under the boiling temperature of 0 ℃-solvent for use, wherein R _cRepresent C _1-5Alkyl is to generate wherein R ₄Represent C _2-6The formula I compound of alkanoyl; Or

P) in the presence of alkali, in solvent, incite somebody to action wherein R ₄Representation hydroxy C _1-3Alkyl, and A, R ₁, R ₂, R ₃, R ₅, n and g formula I compound and C as defined above _1-3Alkylating agent reacts under-50-150 ℃ temperature, to generate wherein R ₄Represent C _1-3Alkoxy C _1-3The formula I compound of alkyl; Or

Q) in the presence of alkali, in solvent, incite somebody to action wherein R ₄Representation hydroxy C _1-3Alkyl, and A, R ₁, R ₂, R ₃, R ₅, n and g formula I compound and C as defined above _4-7The cycloalkyl alkylating agent reacts under-50-150 ℃ temperature, to generate wherein R ₄Represent C _4-7Cycloalkyl alkoxy C _1-3The formula I compound of alkyl; Or

R) in the presence of alkali, in solvent, incite somebody to action wherein R ₄Representation hydroxy C _1-3Alkyl, and A, R ₁, R ₂, R ₃, R ₅, n and g formula I compound and C as defined above _3-7The alkynyl alkylating agent reacts under-50-150 ℃ temperature, to generate wherein R ₄Represent C _3-7Alkynyl alkoxy C _1-3The formula I compound of alkyl; Or

S) in the presence of alkali, in solvent, incite somebody to action wherein R ₄Represent sulfydryl C _1-3Alkyl, and A, R ₁, R ₂, R ₃, R ₅, n and g formula I compound and C as defined above _1-3Alkylating agent reacts under-50-150 ℃ temperature, to generate wherein R ₄Represent C _1-3Alkylthio C _1-3The formula I compound of alkyl; Or

T) in solvent, incite somebody to action wherein R ₄Represent the formula I compound of halogen or formula V compound and formula RMgX or RLi metalating agent to react under the boiling temperature of-100 ℃-solvent for use, wherein R is C _1-6Alkyl, and X is halogen, to generate the intermediate mixture, with this intermediate and formula R _dS-SR _dDisulphide under the boiling temperature of-100 ℃-solvent for use, react R wherein _dBe C _1-3Alkyl or aryl is to generate wherein R ₄Represent C _1-3Alkylthio or arylthio, and A, R ₁, R ₂, R ₃, R ₅, n and g formula I compound as defined above; Or

U) choose wantonly in the presence of solvent, choose wantonly in the presence of catalyzer, wherein R ₄Represent the formula I compound and the C of halogen _1-3Alkoxide is 0-350 ℃ of reaction, to generate wherein R ₄Represent C _1-3Alkoxyl group, and A, R ₁, R ₂, R ₃, R ₅, n and g formula I compound as defined above; Or

V) in the presence of solvent, incite somebody to action wherein R ₄Represent halogen, and A, R ₁, R ₂, R ₃, R ₅, n and g formula I compound as defined above, or formula V compound and formula R _bMgX or R _bThe Li compound reacts under the boiling temperature of-78 ℃-solvent for use, wherein R _bBe C _1-6Alkyl, and X is for example bromine or a chlorine of halogen; Then in solvent, with products therefrom and alkylene agent for example C3-6 alkenyl methyl halide under the boiling temperature of 0 ℃-solvent for use, react, to generate wherein R ₄Represent C _3-6Alkenyl, and two keys of this thiazolinyl are not connected the formula I compound on the alpha-carbon of thiazole ring; Or

W) in the presence of alkali, in solvent, incite somebody to action wherein R _yRepresent hydrogen, and A, R ₁, R ₂, R ₃, R ₅, n and g formula VI compound and R wherein as defined above _zRepresent C _1-4The formula Me of alkyl ₂NCH[PO (OR _z) ₂] ₂Phosphonic acid ester under the boiling temperature of-78 ℃-solvent for use, react, in the presence of acid, the gained intermediate is carried out partial hydrolysis then, to generate wherein R ₄Be C _3-6The formula I compound of alkoxy carbonyl alkyl; Or

X) in the presence of alkali, in solvent, incite somebody to action wherein R _yRepresent hydrogen, and A, R ₁, R ₂, R ₃, R ₅, n and g formula VI compound and R wherein as defined above _zRepresent C _1-2Alkyl and R _cRepresent C _1-3Formula (the R of alkyl _zO) ₂POCH ₂COR _cCompound reacts under the boiling temperature of-78 ℃-solvent for use, in solvent gained intermediate product and reductive agent is reacted under the boiling temperature of-20 ℃-solvent for use then, to generate wherein R ₄Represent C _4-6The hydroxyl alkenyl, and two keys of thiazolinyl are connected the formula I compound on the alpha-carbon of thiazole ring.