CN1309654A - Biphenyl derivs. - Google Patents
Biphenyl derivs. Download PDFInfo
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- CN1309654A CN1309654A CN99808739A CN99808739A CN1309654A CN 1309654 A CN1309654 A CN 1309654A CN 99808739 A CN99808739 A CN 99808739A CN 99808739 A CN99808739 A CN 99808739A CN 1309654 A CN1309654 A CN 1309654A
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Abstract
Biphenyl derivatives of formula (I) wherein R, X, Y, A<1>, A<2>, A<3>, Q and n are as defined in Claim 1, and their salts, are active on the central nervous system showing serotonin antagonistic properties.
Description
The present invention relates to the new biphenyl derivative of formula I
Wherein R be-C (=NH)-NH
2, C (=NH)-NHA
3,-C (=NH)-NHAc ,-C (=NH)-NHSO
2CH
3, R
2,-CO-NH-Z-R
3Or-CO-R
1, X is-CONH-,-SO
2NH-,-NHCO-or-NHSO
2-, Y is CH or N, A
1Be H, wherein have 1-7 the H atom can be by alkyl, the SO of the displaced 1-6 of containing of a F carbon atom
2CH
3Or SO
2CF
3, A
2Be H or the alkyl that contains 1-6 carbon atom, A
3, A
5Be the alkyl that contains 1-6 carbon atom independently of one another, A
6, A
7Be H or (CH independently of one another
2)
pCH
3, Q is H or OA
1, R
1Be 4-A
5-piperazine-1-base, 4-A
5-Gao piperazinyl, by R
4Or-Z-R
4Replace once 1-pyrrolidyl, by R
4Or-Z-R
4Replace once piperidino (piperidinyl), N-A
5-pyrrolidyl-amino, N-A
5-piperidyl-amino, N-A
5-pyrrolidyl-Z-amino or N-A
5-piperidyl-Z-amino ,-N (A
6) (ZR
3) or NA
6A
7, R
2Be the 5-methyl isophthalic acid, 3,4-oxadiazole-2-base or 5-methyl isophthalic acid, 2,4-oxadiazole-3-base, R
3, R
4Be NHA independently of one another
5, N (A
5)
2, 4-morpholinyl, 1-pyrrolidyl or piperidino, Z is the alkylidene group that contains 1-6 carbon atom, n is 0 or 1, p is 0,1 or 2,
Condition is, if Y is N, and X=-CONH-and n=1, then R ≠ R
2Perhaps R ≠-CONA
6A
7, comprise their racemic modification and enantiomorph and physiologically acceptable salt and solvate.
The biphenyl amide derivative for example is disclosed in WO 96/31508 or is recorded in P.J.Pauwels, Gen.Pharmac.29 volume, No.3,293-303 (1997).
The N-Benzanilide derivatives is disclosed in EP 0533267, EP 0533268 or WO 94/15920.
The objective of the invention is to find the new compound with valuable performance, particularly those can be used for preparing the compound of medicine.
Have found that the compound of formula I and its salt have very valuable drug character, and have good tolerance.
Therefore, particularly, they can act on central nervous system, particularly as the antagonist of serotonin (serotonine).
Serotonin is distributed in central nervous system (CNS), thrombocyte and the gi tract.There is polytype 5-hydroxytryptamine receptor, as 5-HT
1A, 5-HT
1B, 5-HT
1COr 5-HT
1D
5-HT
1CAcceptor has been renamed recently is 5-HT
2CThe variation of transmitting serotonin in CNS for example can relax mental state, psychomotor activity, appetite, memory and blood pressure.Can mediate vasospasm by the serotonin that thrombocyte discharges, and the change of free serotonin level also can relax secretion (sectretion) and motility in the gi tract.
Pharmaceutical research shows, 5-HT
1BThe activation of acceptor may cause the increase of anxiety and action, and can cause ingestion of food, property vigor and Aggression to reduce.And then, selective exclusion maincenter 5-HT
1B/DShould there be the 5-HT of promotion to transmit from receptor body, thereby new anti depressant therapy method (P.J.Pauwels, Gen.Pharmac.Vol.29, No.3,293-303 (1997)) can be provided.Studies show that of other, supersensitivity 5-HT
1B/DAcceptor in the physiopathology of obsessive compulsivedisorder (OCD), play an important role (O.T.Dolberg etc., Eur.Neuropsychopharmac.5,161-162 (1995)).Another kind of research provides 5-HT
1B/DThe application possibility of receptor antagonist in the growth of 5-HT dependent tumors cell.
The compound of formula I can be used for treating with serotonergic system in the interference diseases associated.These compound exhibits go out powerful 5-HT
1BAnd/or 5-HT
1DThe antagonism performance.
Has 5-HT
1DThe compound of antagonism performance can be by just discerning in conjunction with avidity level in testing in external human body cortex and guinea pig striatum radioligand, described experiment is stated in following document: Hoyer etc., Neuroscience Letters, 1988,85,357-362.Compound is to 5-HT
1AThe avidity of acceptor adopts the described in vitro tests of following document to record: Gozlan etc., Nature, 1983,305,140-142.
Compound is to 5-HT in the oxtail film
1DAcceptor (main composition homologous ox 5-HT
1BAcceptor) avidity and from being pre-loaded into the K of rat occipitalia cortex section
+-stimulation release [
3H]-5-HT among the 5-HT
1BAntagonism can be measured by the described method of following document similarly: S.Berg etc., J.Med.Chem.1998,41,1934-1942.Compound can adopt 5-HTP accumulation technology (S.Berg etc.) to measure to the effect of 5-HT conversion in the body in the rat brain.
Thereby the compound of formula I is applicable to veterinary drug and human body medicine as treatment central nervous system functional disease and/or cardiovascular disorder.They can be used for treatment or prevent various CNS diseases, as: the mental state disease, comprise dysthymia disorders and depression (dysthymia), anxiety disorder comprises general anxiety disease (generalized anxiety), panic disease, agoraphobe, social phobia, obsessive compulsivedisorder and post-traumatic stress disorder memory disease comprise dementia, amnesia and the memory impairment relevant with the age.They can be used for treating the dementia that Parkinson's disease, Parkinson's disease cause, Parkinson's disease and the tardive dyskinesia that Antipsychotic drug causes.And then they can be used for treating the growth of 5-HT-dependent tumors cell, and the dietary behavior disease comprises anorexia nervosa and Bulimia nerovsa.In addition, they also can be used for treatment with periphery 5-HT
1B/DThe bad relevant cardiovascular disorder of receptor function controlling, treatment or prevention endocrinopathy, vasospasm, hypertension relates to gastrointestinal tract disease and sexual disorder that motility and secretion change.
Yet, they are specially adapted to be used as anxiolytic, thymoleptic, antipsychotic drug and/or treat following disease energetically as pharmaceutically active compound: obsessive compulsivedisorder, the sleep dysfunction, tardive dyskinesia, the learning machine dysfunction, depend on the memory disease at age, eating disorder such as Bulimia nerovsa and/or sexual disorder.
Thereby, the compound of formula I and the acceptable salt of its physiology can be used as pharmaceutical active compounds as anxiolytic, thymoleptic, antipsychotic drug, Antipsychotic drug and/or antihypertensive drug, with be used for treating energetically obsessive compulsivedisorder, eating disorder such as Bulimia nerovsa, tardive dyskinesia, learning machine dysfunction and the memory disease that depends on the age.
The compound of formula I can be used as the pharmaceutical active compounds of people and veterinary drug.They can be further as the intermediate for preparing the other medicines active compound.
Therefore, the present invention relates to compound and its salt and the solvate of formula I, relate to the preparation method of formula I compound and its salt and solvate, it is characterized in that:
A) make the compound of formula II
Wherein
L is Cl, Br, I or is modified the OH base that forms reactive group, particularly a kind of suitable leavings group, R and A by functional group
3As preceding definition,
Boric acid derivatives reaction with the formula III
Wherein
X, Y, A
1, A
2, Q and n such as preceding definition,
Perhaps
B) make the compound of formula IV
Wherein
R and A
3As preceding definition, X ' is CO or SO
2With
L is Cl, Br, I or is modified the OH base that forms reactive group by functional group, particularly a kind of suitable leavings group,
Compound reaction with the formula V
Wherein
Y, A
1, A
2, Q and n such as preceding definition,
Perhaps
C) be the compound of preparation formula I,
Wherein
R is-CO-NH-Z-R
3Or-CO-R
1
Compound with the formula VI
Wherein
L is the OH base that Cl, Br, I or free or active functional group are modified, X, Y, A
1, A
2, A
3, Q and n such as preceding definition,
Compound reaction with the formula VII
H-R′ Ⅶ
Wherein
R ' is NH-Z-R
3Or R
1
And, Z, R
3And R
1As preceding definition,
And/or it is characterized in that, in the following manner, with one or more radicals R, Q, the A in the compound of formula I
1And/or A
2Change into one or more other radicals R, Q, A
1And/or A
2,
ⅰ) with radicals R
2Change into amidino groups,
ⅱ) ether group is hydrolyzed into hydroxyl,
ⅲ) hydroxyl is changed into sulfonyloxy,
And/or with the basic cpd of formula I by change into its salt with acid treatment.
If specially be not additionally instructed, radicals R, X, Y, X ', R ', A below reaching above
1, A
2, A
3, A
5, Q, L have the definition identical with formula I, II, III, IV, V, VI and VII with n.
The invention still further relates to and have serotonin (5-HT
1BAnd/or 5-HT
1D) the formula I compound of antagonistic action and the medicine of its physiologically acceptable salt and solvate.
The present invention relates to compound and its salt and solvate according to the formula I of claim 1.
Solvate is meant according to the compound of the formula I of claim 1 and the addition compound between inert solvent.Described solvate for example is list or dihydrate or alcohol adduct, for example with methyl alcohol or alcoholic acid solvate.
A
1Be preferably H, methyl, ethyl, CH
2CH
2F, CF
3, SO
2CH
3Or SO
2CF
3
A
2Be preferably H, methyl or ethyl.
A
3And A
5The alkyl that preferably has 1-6 carbon atom each other independently of one another.
A
3Be preferably methyl, ethyl or propyl group.
A
5Be preferably methyl, ethyl or propyl group.
Q is preferably H, further preferred methoxy or ethoxy.
X is preferably-CONH-or-SO
2NH-.
Z preferably is meant methylene radical, ethylidene or propylidene.
N-A
5-pyrrolidyl-amino is meant
N-A
5-piperidyl-amino is meant
N-A
5-pyrrolidyl-Z-amino is meant
N-A
5-piperidyl-Z-amino is meant
-N (A
6) (ZR
3) preferably be meant-NH (CH
2NHCH
3) ,-NH (CH
2CH
2NHCH
3) ,-NH (CH
2CH
2NMe
2) ,-NMe (CH
2CH
2NMe
2) ,-NH (CH
2CH
2CH
2NMe
2) ,-NMe (CH
2CH
2CH
2NMe
2).NA
6A
7Preferably be meant NH
2, NHCH
3, NHC
2H
5, N (CH
3)
2Or N (C
2H
5)
2
R
1Preferably be meant 4-methyl-piperazine-1-base, morpholine-4-base, 4-methyl-Gao piperazinyl, 2-dimethylaminomethyl-tetramethyleneimine-1-base, 2-dimethylaminomethyl-piperidines-1-base, N-methyl-tetramethyleneimine-2-base-amino, N-methyl-piperidines-3-or-4-base-amino, N-methyl-tetramethyleneimine-2-base-methylamino or N-methyl piperidine base-methyl-amino.
Ac is an acyl group, preferably is meant ethanoyl, propionyl or benzoyl.
Me or Me are methyl, and et or Et are ethyls.
In following formula, alkyl has 1,2,3,4,5 or 6 carbon atom, preferably has 1,2,3,4 or 5 carbon atom, and preferable methyl, ethyl or propyl group, more preferably sec.-propyl, butyl, isobutyl-, sec-butyl or the tertiary butyl, but also can be n-pentyl, neo-pentyl or isopentyl.
NHA
5Being preferably methylamino, also is ethylamino, n-propyl amino, sec.-propyl amino, normal-butyl amino, isobutylamino, sec-butyl amino or tertiary butyl amino.N (A
5)
2Be preferably dimethylamino, also can be diethylamino, di amino, diisopropylaminoethyl or di-n-butyl amino.
Alkylidene group preferably is meant straight chain methylene radical, ethylidene, propylidene, butylidene, pentylidene or hexylidene.And then alkylidene group also refers to the branched alkylidene residue.
Thereby the present invention is specifically related to following formula I compound, and wherein, one of above-mentioned at least group has as above one of preferred definition.Some preferred compound can represent to I h by inferior formula I a, and it is corresponding to the formula I, and the wherein not definition of group with formula I in greater detail, but wherein: in formula I a R be-C (=NH)-NH
2Or R
2, X is SO in formula I b
2NH, in formula I c R be-C (=NH)-NH
2Or R
2,
A
3Be alkyl with 1-6 carbon atom, in formula I d R be-C (=NH)-NH
2, R
2Or 4-methyl-piperazinyl, in formula I e R be-C (=NH)-NH
2, R
2Or-CO-R
1,
A
3Be alkyl with 1-6 carbon atom, in formula I f R be-C (=NH)-NH
2, R
2Or-CO-R
1,
A
3Be alkyl with 1-6 carbon atom,
A
1Be H or alkyl with 1-6 carbon atom,
A
2Be alkyl with 1-6 carbon atom,
A
5Be alkyl with 1-6 carbon atom, in formula I g R be-C (=NH)-NH
2, R
2Or-CO-R
1,
A
3Be alkyl with 1-6 carbon atom,
A
1Be H or alkyl with 1-6 carbon atom,
A
2Be alkyl with 1-6 carbon atom,
A
5Be alkyl with 1-6 carbon atom,
X is SO
2NH, in formula I h R be-C (=NH)-NH
2, R
2Or-CO-R
1,
A
3Be alkyl with 1-6 carbon atom,
A
1Be H or alkyl with 1-6 carbon atom,
A
2Be alkyl with 1-6 carbon atom,
A
5Be alkyl with 1-6 carbon atom,
X is SO
2NH,
Y is CH, in formula I i R be-C (=NH)-NH
2, R
2Or-CO-R
1,
A
3Be alkyl with 1-6 carbon atom,
A
1Be H or alkyl with 1-6 carbon atom,
A
2Be alkyl with 1-6 carbon atom,
A
5Be alkyl with 1-6 carbon atom,
X is CONH,
Y is CH.
In addition, the raw material that the compound of formula I and being used to prepares them all can adopt the known method preparation, they also are disclosed in the following document: for example, in the standard publication, as Hoube n-Weyl, the method in the Methoden der organischen Chemie[organic chemistry], Georg-Thieme-Verlag, Stuttgart), the reaction conditions of described reaction also is known, and is applicable to above-mentioned reaction.Equally, also can use known variant, in the present invention not to its more detailed description.
In the derivative of formula II, IV and VI, L is preferably Cl or Br, but also can be I or modify to be formed the OH base of reactive group by functional group.If L is active esterified OH group, its aryl-sulfonyl oxygen (preferred phenyl-or p-methylphenyl-sulfonyloxy also can be 2-naphthalene sulfonyl oxygen base) that preferably has the alkylsulfonyloxy (preferable methyl sulfonyloxy or trifluoromethyl sulfonyloxy) of 1-6 carbon atom or have 6-10 carbon atom then.
If necessary, raw material also can on-the-spotly form, thereby they need not separate from reaction mixture and can react immediately to obtain the compound of formula I again.
On the other hand, can the proceed step by step reaction.
The compound of the preferred through type II of the compound of formula I and the reaction of the compound of formula III obtain.The raw material of formula II and formula III is said so known to a certain extent.If unknown, they can be by known method preparation own.
The compound of formula III for example can obtain like this: for example use B (OPr)
3Or B (OMe)
3Under approximately-80 to 30 ℃, handle corresponding halo derivatives with n-Butyl Lithium.
In more detail, the inert solvent that is reflected at of compound ii and III exists or does not exist down and carries out, and, for example there is Pd (PPh in-20 to about 180 ℃ of temperature of reaction pacts by preferred 40 to 130 ℃ in the reaction process
3)
4(Suzuki-reaction).Can advantageously can add acid binding agent, for example: alkali metal hydroxide, alkaline carbonate, alkali metal hydrocarbonate, alkaline earth metal hydroxides, alkaline earth metal carbonate or alkali metal bicarbonates, the another kind of salt of faintly acid that perhaps adds basic metal or alkaline-earth metal, preferred potassium, sodium or calcium salt, perhaps add a kind of organic bases, as triethylamine, dimethylamine or pyridine or quinoline or excessive amine component.The example of suitable inert solvent is a hydrocarbon, as hexane, sherwood oil, benzene, toluene or dimethylbenzene; Hydrochloric ether, as trieline, 1,2-ethylene dichloride, tetracol phenixin, chloroform or methylene dichloride; Alcohol is as methyl alcohol, ethanol, Virahol, n-propyl alcohol, propyl carbinol or the trimethyl carbinol; Ether such as ether, Di Iso Propyl Ether, tetrahydrofuran (THF) (THF) Huo diox; Glycol ethers is as ethylene glycol monomethyl ether, ethylene glycol monoethyl ether (methyl glycol or ethyl glycol) or glycol dimethyl ether (diglyme); Ketone is as acetone or butanone; Acid amides is as ethanamide, N,N-DIMETHYLACETAMIDE or dimethyl formamide (DMF); Nitrile is as acetonitrile; Sulfoxide is as dimethyl sulfoxide (DMSO) (DMSO); Nitro-compound is as Nitromethane 99Min. or oil of mirbane; Ester such as ethyl acetate, or the mixture of above-mentioned solvent and water.
The compound of the compound that equally, can be by making the formula IV and the compound reaction acquisition formula I of formula V.The compound of some formula IV and V, particularly the compound of formula V is known; Unknown compound is easy to adopt and the similar method preparation of known compound.Therefore, formula IV compound can be by making corresponding carboxylic acid or sulfonic acid and SOCl
2Reaction prepares.
The reaction of formula IV and formula V compound can be carried out according to known method in the document that forms acid amides or sulphonamide.Component directly can be melted with another kind of, need not solvent and exist, under normal pressure or elevated pressure, carry out, can add rare gas element such as nitrogen with pressure boost.But, compound is carried out in the presence of inert solvent.The suitable solvent is previously mentioned those solvents.In reaction mixture, add acid binding agent and also have useful effect.Identical alkali suits, as previously mentioned.
According to selected reaction conditions, the best reaction times is several minutes to 14 day, and temperature of reaction is about 0 ℃ to 150 ℃, is generally 20 ℃ to 130 ℃.
And then compound by making the formula VI and the reaction of the compound of formula VII can obtain the compound of formula I, and wherein, R is-CO-NH-Z-R
3Or-CO-R
1
The reaction of formula VI and formula VII compound can be carried out according to known method in the document that forms acid amides.The embodiment that is used for the formula VII compound of the suitable derivative of N-acylations formula VI compound is a carboxylic acid halides; preferred acyl chlorides, trinitride (azide), acid anhydrides, tetrahydroglyoxaline (imidazolides) (it can for example make from carbonization diimidazole (carbodiimidazole)), Acibenzolar or O-acylurea; it can be by suitable carbonization imines (carboximide); as the dialkyl group carbodiimide, for example cyclohexyl-carbodiimide makes.Before carrying out this reaction, possibility must be by introducing suitable protecting group so that other amino that is contained in the formula VII participate in acylation reaction.
Reaction is usually in inert solvent, at acid binding agent, the oxyhydroxide of preferred as alkali or alkaline-earth metal, basic metal or alkaline earth metal carbonate or supercarbonate perhaps add the another kind of salt of faintly acid of basic metal or alkaline-earth metal, carry out under preferred potassium, sodium, calcium salt or cesium salt exist.Adding a kind of organic bases, also is useful as the compound of triethylamine, xylidine or pyridine or quinoline or excessive formula VII or the alkyl derivative of formula VI.According to the condition that is adopted, the reaction times is several minutes to 14 day, and temperature of reaction is about 0 ℃ to 150 ℃, is generally 20 ℃ to 130 ℃.The suitable solvent as previously described.
Term " amino protecting group " is normally known, relates to being applicable to that protection (being used for sealing) amino makes its group that does not carry out chemical reaction, and this group should be easy to remove after the required chemical reaction that carries out on another position in molecule is finished.Particularly, this type of examples of groups is that the acyl group that do not replace or replace, aryl are (as dinitrophenyl (DNP), aralkoxy methyl (as benzyloxymethyl (BOM)) or aralkyl (as benzyl, 4-nitrobenzyl, trityl group).Because amino protecting group after required reaction (or in reaction process) is removed, their character and size are unimportant; But preferably those have the group of 1-20 carbon atom, a particularly 1-8 carbon atom.Term herein " acyl group " may be interpreted as the broadest implication.It comprises: by aliphatic series, araliphatic, aromatics or heterocycle family carboxylic acid or sulfonic acid deutero-carboxyl groups, particularly carbalkoxy, aryloxycarbonyl, particularly aromatic alkoxy carbonyl.The example of this type of acyl group is an alkanoyl, as: ethanoyl, propionyl, butyryl radicals; Aralkanoyl such as phenylacetyl; Aroyl such as benzoyl or tolyl; Virtue oxygen alkyloyl such as phenoxy group ethanoyl; Carbalkoxy, as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloro-ethoxycarbonyl, the different third oxygen carbonyl, tertbutyloxycarbonyl (BOC), 2-iodo-ethoxycarbonyl; Aromatic alkoxy carbonyl is as carbobenzoxy-(Cbz) (CBZ), 4-methoxy-benzyl-oxygen carbonyl and 9-fluorenylmethyloxycarbonyl (FMOC).
Preferred amino protecting group is BOC, DNP and BOM, and CBZ, benzyl and ethanoyl.Can the deciding factor when selecting the protecting group that is adopted for selectivity to remove this group behind real reaction.
(wherein, R is-CO-NH-Z-R the acid amides of preferred formula I
3Or-CO-R
1) for example by adopting P-EDC (the 1-ethyl-3-of conjugated polymer (3-dimethylaminopropyl)-carbodiimide) to make amine and carboxylic acid carry out the coupling preparation, method is according to following document: M.Desai etc., Tetrahedron Letters 1993,34 (48), 7685-7688), be reflected in the inert solvent and carry out, temperature of reaction is-20 to about 100 ℃ approximately, preferred-10 ℃ to about 60 ℃.The suitable solvent as previously mentioned.
And then, preferably carry out the compound that the reductive amination reaction obtains another kind of formula I by the compound that makes the formula I.Raw material is known in some cases, if unknown, they can be by self known method preparation.
Reductive amination process can be at reductive agent such as NaBH
3CN, NaBH
4And NaBH (OAc)
3Carry out under existing.Solvent that this reaction is carried out and temperature of reaction are as previously mentioned.
Can also pass through one or more R, Q, A
1And/or A
2Change into another or a plurality of other radicals R, A
1, and/or A
2, for example by in inert solvent such as methyl alcohol or ethanol, carrying out hydrogenation on Raney nickel or the Pd/C with radicals R
2Change into amidino groups and/or ether group is hydrolyzed into hydroxyl, and a kind of formula I compound is changed into the compound of another kind of formula I.
Free amine group can further adopt acyl chlorides or acid anhydrides to carry out acidylate in a conventional manner; perhaps adopt the alkylogen that does not replace or replace to carry out alkylation, this reaction can be carried out under-60 to 30 ℃ in inert solvent such as methylene dichloride or THF and/or in the presence of alkali such as triethylamine or pyridine expediently.
If necessary, amino that the functional group in the formula I compound is modified and/or hydroxyl can discharge by solvolysis or hydrogenolysis according to ordinary method.For example, the compound that comprises the formula I of NHCOO alkyl can change into to replace accordingly and comprise NH
2The formula I compound of group.
The alkali usable acid of formula I changes into corresponding acid salt, for example, reacts in inert solvent such as acetone by the alkali and the acid that make equivalent, evaporates then and finishes conversion.The acid that is specially adapted to this reaction is for providing those acid of acceptable salt on the physiology.Therefore, can use mineral acid, sulfuric acid for example, nitric acid, haloid acid example hydrochloric acid or Hydrogen bromide, phosphoric acid such as ortho-phosphoric acid, thionamic acid, can also adopt organic acid, particularly aliphatic, alicyclic, araliphatic, the monobasic of aromatics or heterocycle family or polycarboxylic acid, sulfonic acid or sulfuric acid are as formic acid, acetate, propionic acid, PIVALIC ACID CRUDE (25), diethylacetic acid, propanedioic acid, succsinic acid, pimelic acid, fumaric acid, toxilic acid, lactic acid, tartrate, oxysuccinic acid, citric acid, glyconic acid, xitix, nicotinic acid, Yi Yansuan, first-or ethyl sulfonic acid, ethane disulfonic acid, 2-hydroxyl ethane-sulfonic acid, Phenylsulfonic acid, tosic acid, naphthene sulfonic acid and naphthalene disulfonic acid, lauryl sulfate.Those with have physiology on the salt that forms of unacceptable acid such as picrate can be used for separating and/or the compound of purifying formula I.
On the other hand, if necessary, the free alkali of formula I can adopt alkali (as sodium hydroxide, yellow soda ash, potassium hydroxide or salt of wormwood) to discharge from its salt.
The invention still further relates to formula I compound and/or its physiologically acceptable salt or solvate at the preparation medicament production, particularly by the purposes in the flow preparation medicament production non-chemically.One or more other activeconstituentss of recombinant formed the appropriate drug form when they can and need with at least a solid, liquid and/or semiliquid vehicle or auxiliary agent.
And then, the present invention relates to medicament production, wherein comprise compound and/or its physiologically acceptable salt of at least a formula I.
These products can be used as the patent medicine of people's medicine or veterinary drug.Suitable vehicle is for being applicable to enteral administration (for example oral), parenteral administration or topical and the organic or inorganic material that can not react with new compound, for example, water, vegetables oil, phenylcarbinol, alkylene glycol, polyoxyethylene glycol, vanay, gelatin, sugar, Magnesium Stearate, talcum, mineral jelly such as lactose or starch.The formulation that is used for oral administration is specially tablet, pill, sugar coated tablet, capsule, pulvis, granule, syrup, liquid or drops, the formulation that is used for rectal administration is specially suppository, the formulation that is used for parenteral administration is specially solvent, the preferred oil or the aqueous solution, and suspension agent, emulsion or implant, the formulation that is used for topical is ointment, creme or pulvis.But the also lyophilize of new compound, and the lyophilized products that forms for example is used to prepare injectable product.The said products can be sterile form and/or comprises auxiliary agent such as slip(ping)agent (glidant), sanitas, stablizer and/or wetting agent, emulsifying agent, the salt that is used to improve osmotic pressure, buffer substance, tinting material, correctives and/or other activeconstituents such as one or more VITAMIN.
The present invention also relates to the compound of formula I of claim 1 and its physiologically acceptable salt and solvate as serotonin (5-HT
1B/D) antagonist.
The present invention relates to the compound of the formula I of claim 1 and its physiologically acceptable salt and solvate be used for the treatment of or prevent following disease: the mental state disease, comprise dysthymia disorders and depression, anxiety disorder, comprise general anxiety disease, panic disease, agoraphobe, social phobia, obsessive compulsivedisorder and post-traumatic stress disorder, the memory disease comprises dementia, amnesia and the memory impairment relevant, Parkinson's disease with the age, the growth of 5-HT-dependent tumors cell, the dietary behavior disease, comprise anorexia nervosa and Bulimia nerovsa, with periphery 5-HT
1B/DReceptor function controlling is bad to be the cardiovascular disorder of feature, endocrinopathy, and vasospasm, hypertension relates to gastrointestinal tract disease and sexual disorder that motility and secretion change.
First-selection of the present invention is used for the treatment of the compound of the formula I of claim 1 and its physiologically acceptable salt and solvate or prevents following disease: dysthymia disorders, general anxiety disease, obsessive compulsivedisorder and Bulimia nerovsa.
In this case, material of the present invention preferably with other known be used for alleged indication be purchased similarly mode administration of preparation (for example imipramine, fluoxetine, chlorimipramine), preferred dose be per unit dosage about 0.1 to 500mg, particularly 5 to 300mg.The dosage of every day is preferably about 0.01 to 10mg/kg body weight.But, concrete dosage for individual patient will depend on various factors, the activity of the particular compound that is adopted for example, patient's age, body weight and healthy state, sex, diet, administration time and mode, excretion speed, the severity of the disease specific that the medicine of Combined Preparation and quilt are treated.The preferred oral administration that adopts.
The invention still further relates to the formula I compound of claim 1 and/or its physiologically acceptable salt or solvate is used for the treatment of or prevents purposes in dysthymia disorders, general anxiety disease, obsessive compulsivedisorder and the bulimiac medicine in preparation.
The invention still further relates to formula I compound and/or its physiologically acceptable salt or the purposes of solvate in treatment or prevention dysthymia disorders, general anxiety disease, obsessive compulsivedisorder and Bulimia nerovsa of claim 1.
The compound of formula I of the present invention can be a chipal compounds according to its molecular structure, thereby may occur with two kinds of enantiomeric forms.Thereby they can racemic modification or the existence of optically-active form.
Because the racemic modification of The compounds of this invention or the pharmaceutical activity of steric isomer may be different, therefore, may wish to use enantiomorph.Under these situations, final product or even intermediate all can disassemble into enantiomeric compounds by well known to a person skilled in the art chemistry or physical means, perhaps in building-up process, self adopt the correlation method preparation.
Under the situation of racemic amine,, form diastereomer from mixture by reacting with optically active resolving agent.The suitable agent of disassembling for example is optically-active acid; as R and S type tartrate, diacetyl tartrate, dibenzoyl tartaric acid, amygdalic acid, oxysuccinic acid, lactic acid, amino acid of N-protected (as N-benzoyl-proline(Pro) or N-benzenesulfonyl proline(Pro)) or various optically-active camphorsulfonic acid aptly.Chromatography is disassembled enantiomorph also advantageously, adopts optically active resolving agent (as the methacrylate polymers of other derivative of dinitrobenzoyl phenylglycocoll, cellulosic triacetate or sugar or the chirality derivatize that links to each other with silica gel).The suitable eluent that is used for this purpose is moisture or contains alcohol solvent mixture that as hexane/isopropyl alcohol/acetonitrile, for example its ratio is 82: 15: 3.
But, under special conditions of contract, also can in building-up process, adopt the intermediate of suitable enantiomer-pure, this intermediate is by the preparation of one of aforesaid method.In this case, further can keep chirality in the building-up process.
In this article, all temperature all refers to ℃.In the following embodiments, " conventional processing " is meant, if necessary, add entry, if necessary, the pH value of regulating mixture according to the composition of final product with ethyl acetate or dichloromethane extraction, is separated organic phase to 2-10, use dried over sodium sulfate, evaporation and carry out purifying with silica gel chromatography and/or crystallization.On silica gel, carry out Rf; Elutriant: ethyl acetate/methanol 9: 1.
Mass spectrum (MS): EI (electron impact ionization) M
+
FAB (fast atom bombardment) (M+H)
+
Embodiment 1
At room temperature, add the 2ml triethylamine in the mixture in 10ml THF to 511mg 4-bromo-phenyl SULPHURYL CHLORIDE (" A ") and 588mg 4-methoxyl group-3-(N methyl piperazine subbase) aniline dihydrochloride (4-methoxy-3-(N-methylpiperazino) aniline dihydrochloride).Mixture was stirred 15 hours.After the filtration, carry out conventional processing, obtain N-[4-methoxyl group-3-(4-methyl-piperazine-1-yl)-phenyl]-4-bromo-benzene sulfinyl amine, 850mg, m.p.180-182 ℃; IR (KBr) 3005,29462830,1594,1574,1510,1334,1153,998cm
-1EI m/z 439
Similarly, by 4-methoxyl group-3-(N-methyl-tetramethyleneimine-3-yl) aniline and " A ", obtain following compound
N-[4-methoxyl group-3-(N-methyl-tetramethyleneimine-3-yl)-phenyl]-4-bromobenzene and sulphonamide.
Similarly, by 4-methoxyl group-3-(N methyl piperazine subbase) aniline, 4-methoxyl group-3-(N-methyl-tetramethyleneimine-3-yl) aniline and 4-bromo-Benzoyl chloride obtain following compound:
N-[4-methoxyl group-3-(4-methyl-piperazine-1-yl)-phenyl]-4-bromo-benzamide,
N-[4-methoxyl group-3-(N-methyl-tetramethyleneimine-3-yl)-phenyl]-4-bromo-benzamide.
Embodiment 2
2.1ml three-isopropoxy boron is added to N-[4-methoxyl group-3-(4-methyl-piperazine-1-the yl)-phenyl that is cooled to the 329mg under-80 ℃ under nitrogen atmosphere]-solution of 4-bromo-benzene sulfinyl amine in the anhydrous THF of 15ml in.In solution, drip 3.8ml n-Butyl Lithium (2.5M, hexane solution).Mixture was stirred 3 hours under this temperature, at room temperature stirred subsequently 15 hours.After adding 5ml water, restir 1 hour removes and desolvates.The resistates preadsorption to the silica gel of 10ml, is carried out purifying [SiO by flash chromatography
2, CH
2Cl
2: EtOH: 25%NH
4The OH aqueous solution (90: 10: 1 to 70: 30: 3) is as eluent]; obtain 4-{N-[4-methoxyl group-3-(4-methyl-piperazine-1-yl)-phenyl of 220mg]-amino-sulfonyl } phenylo boric acid (" B "); be a kind of white foam thing, m.p.＞217 ℃, Rf0.20 (CH
2Cl
2/ EtOH/25%NH
4The OH aqueous solution 60: 40: 3).
Similarly, obtain following compound
4-{N-[4-methoxyl group-3-(N-methyl-tetramethyleneimine-3-yl)-phenyl]-amino-sulfonyl } phenylo boric acid
4-{N-[4-methoxyl group-3-(4-methyl-piperazine-1-yl)-phenyl]-aminocarboxyl } phenylo boric acid
4-{N-[4-methoxyl group-3-(N-methyl-tetramethyleneimine-3-yl)-phenyl]-aminocarboxyl } phenylo boric acid
Embodiment 3
Under nitrogen atmosphere, 18mg four (triphenyl phosphine) palladium (O) is added to 180mg " B ", 189mg2-(4-bromo-3-methyl-phenyl)-5-methyl isophthalic acid, 3,4-oxadiazole (＂ C ＂) and 230mgNa
2CO
310H
2O is in the mixture of 10ml DME (glycol dimethyl ether).Mixture was refluxed 15 hours, remove and desolvate.With the resistates preadsorption to 5g SiO
2On, by purification by flash chromatography (SiO
2, THF; 90: 10: 1 70: 30: 3 CH then
2Cl
2: EtOH: 25%NH
4The OH aqueous solution), obtain N-[4-methoxyl group-3-(4-methyl-piperazine-1-yl)-phenyl]-2 '-methyl-4 '-(5-methyl isophthalic acid, 3,4-oxadiazole-2-yl)-xenyl-4-sulphonamide, it is carried out recrystallization: 200mg, m.p.242-244 ℃ in ethyl acetate; IR (KBr) 2984,2824,1584,1503,1339,1236,1166cm
-1EI m/z 533:
Similarly, by making " B " and 3-(4-bromo-3-methyl-phenyl)-5-methyl isophthalic acid, 2,4-oxadiazole (＂ D ＂) reaction, obtain N-[4-methoxyl group-3-(4-methyl-piperazine-1-yl)-phenyl]-2 '-methyl-4 '-(5-methyl isophthalic acid, 2,4-oxadiazole-3-yl)-xenyl 4-sulphonamide.
Similarly, by making following compound
4-{N-[4-methoxyl group-3-(N-methyl-tetramethyleneimine-3-yl)-phenyl]-amino-alkylsulfonyl }-phenylo boric acid,
4-{N-[4-methoxyl group-3-(4-methyl-piperazine-1-yl)-phenyl]-amino-carbonyl }-phenylo boric acid,
4-{N-[4-methoxyl group-3-(N-methyl-tetramethyleneimine-3-yl)-phenyl]-amino-carbonyl }-phenylo boric acid,
With " C " reaction, obtain following compound:
N-[4-methoxyl group-3-(N-methyl-tetramethyleneimine-3-yl)-phenyl]-2 '-methyl-4 '-(5-methyl isophthalic acid, 3,4-oxadiazole-2-yl)-xenyl-4-sulphonamide,
N-[4-methoxyl group-3-(4-methyl-piperazine-1-yl)-phenyl]-2 '-methyl-4 '-(5-methyl isophthalic acid, 3,4-oxadiazole-2-yl)-xenyl-4-methane amide,
N-[4-methoxyl group-3-(N-methyl-tetramethyleneimine-3-yl)-phenyl]-2 '-methyl-4 '-(5-methyl isophthalic acid, 3,4-oxadiazole-2-yl)-xenyl-methane amide.
Similarly, by making following compound
4-{N-[4-methoxyl group-3-(N-methyl-tetramethyleneimine-3-yl)-phenyl]-amino-alkylsulfonyl }-phenylo boric acid,
4-{N-[4-methoxyl group-3-(4-methyl-piperazine-1-yl)-phenyl]-amino-carbonyl }-phenylo boric acid,
4-{N-[4-methoxyl group-3-(N-methyl-tetramethyleneimine-3-yl)-phenyl]-amino-carbonyl }-phenylo boric acid,
With " D " reaction, obtain following compound:
N-[4-methoxyl group-3-(N-methyl-tetramethyleneimine-3-yl)-phenyl]-2 '-methyl-4 '-(5-methyl isophthalic acid, 2,4-oxadiazole-3-yl)-xenyl-4-sulphonamide,
N-[4-methoxyl group-3-(4-methyl-piperazine-1-yl)-phenyl]-2 '-methyl-4 '-(5-methyl isophthalic acid, 2,4-oxadiazole-3-yl)-xenyl-4-methane amide,
N-[4-methoxyl group-3-(N-methyl-tetramethyleneimine-3-yl)-phenyl]-2 '-methyl-4 '-(5-methyl isophthalic acid, 2,4-oxadiazole-3-yl)-xenyl-methane amide, m.p.97-99 ℃.
Embodiment 4
N-[4-methoxyl group-3-(4-methyl-piperazine-1-yl)-phenyl with 200mg]-2 '-methyl-4 '-(5-methyl isophthalic acid, 2,4-oxadiazole-3-yl)-xenyl-4-methane amide is dissolved in the mixture of 50ml methyl alcohol and 10ml acetate, adds the slurries of Raney nickel in water again.With mixture hydrogenation 12 hours.Filter,, filtrate is evaporated, obtain a kind of oily resistates with the acetate washing.Handle through routine, obtain N-[4-methoxyl group-3-(4-methyl-piperazine-1-yl)-phenyl]-2 '-methyl-4 '-amidino groups-xenyl-4-methane amide: 140mg, m.p.159-162 ℃; IR (KBr) 3300,2935,2801,1645,1607,1508cm
-1FAB m/z 458:
Similarly.By the following compound of hydrogenation
N-[4-methoxyl group-3-(4-methyl-piperazine-1-yl)-phenyl]-2 '-methyl-4 '-(5-methyl isophthalic acid, 2,4-oxadiazole-3-yl)-xenyl-4-sulphonamide,
N-[4-methoxyl group-3-(N-methyl-tetramethyleneimine-3-yl)-phenyl]-2 '-methyl-4 '-(5-methyl isophthalic acid, 2,4-oxadiazole-3-yl)-xenyl-4-sulphonamide,
N-[4-methoxyl group-3-(N-methyl-tetramethyleneimine-3-yl)-phenyl]-2 '-methyl-4 '-(5-methyl isophthalic acid, 2,4-oxadiazole-3-yl)-xenyl-methane amide,
Obtain following compound:
N-(4-methoxyl group-3-(4-methyl-piperazine-1-yl)-phenyl]-2 '-methyl-4 '-amidino groups-xenyl-4-sulphonamide,
N-[4-methoxyl group-3-(N-methyl-tetramethyleneimine-3-yl)-phenyl]-2 '-methyl-4 '-amidino groups-xenyl-4-sulphonamide,
N-[4-methoxyl group-3-(N-methyl-tetramethyleneimine-3-yl)-phenyl]-2 '-methyl-4 '-amidino groups-xenyl-4-methane amide.
Embodiment 5
SOCl with 3ml
2Add to 2 ' of 338mg-methyl-4 '-(4-methyl-piperazine-1-carbonyl)-xenyl-4-formic acid [can under the Suzuki condition, react acquisition] and 1ml triethylamine at 15ml CH by making 4-carboxyl-phenyl-boron dihydroxide and (4-bromo-3-methyl-phenyl)-(4-methyl-piperazine-1-yl)-ketone
2Cl
2In.Solution was refluxed 30 minutes.Remove and desolvate, add the CH of 10ml
2Cl
2Solution is cooled to 0 ℃, adds the 2ml triethylamine again, add 4-methoxyl group-3-(N methyl piperazine subbase) aniline of 265mg again.After stirring 15 hours, carry out conventional processing, obtain N-[4-methoxyl group-3-(4-methyl-piperazine-1-yl)-phenyl of 210mg]-2 '-methyl-4 '-(4-methyl-piperazine-1-carbonyl)-xenyl-4-methane amide, m.p.195-197 ℃; MS (APCI) 524[M+1]; IR:3430,1663 cm
-1 
Similarly, by making 2 '-methyl-4 '-(4-methyl-piperazine-1-carbonyl)-xenyl-4-formic acid and 2,4-dimethoxy-3-(N methyl piperazine subbase)-aniline reaction, obtain compound N-[2,4-dimethoxy-3-(4-methyl-piperazine-1-yl)-phenyl]-2 '-methyl-4 '-(4-methyl-piperazine-1-carbonyl)-xenyl-4-methane amide, EI 571; FAB 572; Rf0.14 (CH
2Cl
2/ EtOH4: 1).
Embodiment 5 '
Similar to Example 5, by making 2 '-methyl-4 '-(4-methyl-piperazine-1-base-carbonyl)-xenyl-4-formic acid and 4-methoxyl group-3-(N-methylpyrrolidin-3-yl)-aniline reaction, obtain compound N-[4-methoxyl group-3-(N '-methyl-tetramethyleneimine-3-yl)-phenyl]-2 '-methyl-4 '-(4-methyl-piperazine-1-base-carbonyl)-xenyl-methane amide; Rf0.25 (CH
2Cl
2/ EtOH/25%NH
4The OH aqueous solution 80: 20: 1).
Embodiment 6
1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) of 7.9g was stirred 24 hours down in 100 ℃ in the DMF of 400ml with 50g chloromethylated polystyrene-Vinylstyrene 2% resin.Filter, washing, drying obtains the P-EDC of 53g.
With 0.3mmol methylpiperazine, 0.45mmol N-[4-methoxyl group-3-(4-methyl-piperazine-1-yl)-phenyl]-2 '-methyl-4 '-carboxyl-xenyl-4-methane amide (＂ E ＂) [can under the Suzuki condition 4-carboxyl-2-methyl-phenyl-boron dihydroxide and N-[4-methoxyl group-3-(4-methyl-piperazine-1-yl)-4-bromo-phenyl-formamide be obtained] and 1.0g P-EDC be at 8ml CHCl
3Suspension among the/THF (7: 1) at room temperature stirred 48 hours.After the filtration, with polymkeric substance CHCl
3Washing.Except that after desolvating, obtain N-[4-methoxyl group-3-(4-methyl-piperazine-1-yl)-phenyl]-2 '-methyl-4 '-(4-methyl-piperazine-1-carbonyl)-xenyl-4-methane amide, m.p.195-197 ℃.
Similarly, react by making ＂ E ＂ and following compound,
N
1, N
1-dimethyl-ethane-1, the 2-diamines,
N
1, N
1-dimethyl-propane-1, the 3-diamines,
4-amino-N-methyl-piperidines,
3-amino-N-methyl-tetramethyleneimine,
4-dimethylamino-piperidines,
3-dimethylamino-piperidines,
Morpholine
Obtain following compound:
N-[4-methoxyl group-3-(4-methyl-piperazine-1-yl)-phenyl]-2 '-methyl-4 '-[(2-dimethylamino-ethyl)-aminocarboxyl]-xenyl-4-methane amide,
N-[4-methoxyl group-3-(4-methyl-piperazine-1-yl)-phenyl]-2 '-methyl-4 '-[(3-dimethylamino-propyl group)-aminocarboxyl]-xenyl-4-methane amide,
N-[4-methoxyl group-3-(4-methyl-piperazine-1-yl)-phenyl]-2 '-methyl-4 '-[(N-methyl-piperidin-4-yl)-aminocarboxyl]-xenyl-4-methane amide,
N-[4-methoxyl group-3-(4-methyl-piperazine-1-yl)-phenyl]-2 '-methyl-4 '-[(N-methyl-tetramethyleneimine-3-yl)-aminocarboxyl]-xenyl-4-methane amide,
N-[4-methoxyl group-3-(4-methyl-piperazine-1-yl)-phenyl]-2 '-methyl-4 '-[(4-dimethylamino-piperidines-1-yl)-aminocarboxyl]-xenyl-4-methane amide,
N-[4-methoxyl group-3-(4-methyl-piperazine-1-yl)-phenyl]-2 '-methyl-4 '-[(3-dimethylamino-piperidines-1-yl)-aminocarboxyl]-xenyl-4-methane amide,
N-[4-methoxyl group-3-(4-methyl-piperazine-1-yl)-phenyl]-2 '-methyl-4 '-(morpholine-4-base carbonyl)-xenyl-4-methane amide.
Similarly, by making N-[4-methoxyl group-3-(N-methyl-tetramethyleneimine-3-yl)-phenyl]-2 '-methyl-4 '-carboxyl-xenyl-4-methane amide and the reaction of following compound
N
1, N
1-dimethyl-ethane-1, the 2-diamines,
N
1, N
1-dimethyl-propane-1 3-diamines,
4-amino-N-methyl-piperidines,
3-amino-N-methyl-tetramethyleneimine,
4-dimethylamino-piperidines,
3-dimethylamino-piperidines,
Morpholine
Obtain following compound:
N-[4-methoxyl group-3-(N-methyl-tetramethyleneimine-3-yl)-phenyl]-2 '-methyl-4 '-[(2-dimethylamino-ethyl)-aminocarboxyl]-xenyl-4-methane amide,
N-[4-methoxyl group-3-(N-methyl-tetramethyleneimine-3-yl)-phenyl]-2 '-methyl-4 '-[(3-dimethylamino-propyl group)-aminocarboxyl]-xenyl-4-methane amide,
N-[4-methoxyl group-3-(N-methyl-tetramethyleneimine-3-yl)-phenyl]-2 '-methyl-4 '-[(N-methyl-piperidin-4-yl)-aminocarboxyl]-xenyl-4-methane amide,
N-[4-methoxyl group-3-(N-methyl-tetramethyleneimine-3-yl)-phenyl]-2 '-methyl-4 '-[(N-methyl-tetramethyleneimine-3-yl)-aminocarboxyl]-xenyl-4-methane amide,
N-[4-methoxyl group-3-(N-methyl-tetramethyleneimine-3-yl)-phenyl]-2 '-methyl-4 '-[(4-dimethylamino-piperidines-1-yl)-aminocarboxyl]-xenyl-4-methane amide,
N-[4-methoxyl group-3-(N-methyl-tetramethyleneimine-3-yl)-phenyl]-2 '-methyl-4 '-[(3-dimethylamino-piperidines-1-yl)-aminocarboxyl]-xenyl-4-methane amide,
N-[4-methoxyl group-3-(N-methyl-tetramethyleneimine-3-yl)-phenyl]-2 '-methyl-4 '-(morpholine-4-base carbonyl)-xenyl-4-methane amide.
Embodiment 7
Similar to Example 6, by making N-[4-methoxyl group-3-(4-methyl-piperazine-1-yl)-phenyl]-2 '-methyl-4 '-carboxyl-xenyl-4-sulphonamide [can under the Suzuki condition, 4-carboxyl-2-methyl-phenyl-boron dihydroxide and N-[4-methoxyl group-3-(4-methyl-piperazine-1-yl)-4-bromo-phenyl-sulfuryl amine reaction be obtained] and following compound reaction
N
1, N
1-dimethyl-ethane-1, the 2-diamines,
N
1, N
1-dimethyl-propane-1 3-diamines,
4-amino-N-methyl-piperidines,
3-amino-N-methyl-tetramethyleneimine,
4-dimethylamino-piperidines,
3-dimethylamino-piperidines,
Morpholine
1-methyl-piperazine
Obtain following compound:
N-[4-methoxyl group-3-(4-methyl-piperazine-1-yl)-phenyl]-2 '-methyl-4 '-[(2-dimethylamino-ethyl)-aminocarboxyl]-xenyl-4-sulphonamide, m.p.117-120 ℃,
N-[4-methoxyl group-3-(4-methyl-piperazine-1-yl)-phenyl]-2 '-methyl-4 '-[(3-dimethylamino-propyl group)-aminocarboxyl]-xenyl-4-sulphonamide,
N-[4-methoxyl group-3-(4-methyl-piperazine-1-yl)-phenyl]-2 '-methyl-4 '-[(N-methyl-piperidin-4-yl)-aminocarboxyl]-xenyl-4-sulphonamide,
N-[4-methoxyl group-3-(4-methyl-piperazine-1-yl)-phenyl]-2 '-methyl-4 '-[(N-methyl-tetramethyleneimine-3-yl)-aminocarboxyl]-xenyl-4-sulphonamide,
N-[4-methoxyl group-3-(4-methyl-piperazine-1-yl)-phenyl]-2 '-methyl-4 '-[(4-dimethylamino-piperidines-1-yl)-aminocarboxyl]-xenyl-4-sulphonamide,
N-[4-methoxyl group-3-(4-methyl-piperazine-1-yl)-phenyl]-2 '-methyl-4 '-[(3-dimethylamino-piperidines-1-yl)-aminocarboxyl]-xenyl-4-sulphonamide,
N-[4-methoxyl group-3-(4-methyl-piperazine-1-yl)-phenyl]-2 '-methyl-4 '-(morpholine-4-base carbonyl)-xenyl-4-sulphonamide,
N-[4-methoxyl group-3-(4-methyl-piperazine-1-yl)-phenyl]-2 '-methyl-4 '-(1-methyl-piperazine-4-base carbonyl)-xenyl-4-sulphonamide, EI 577.
Similarly, by making N-[4-methoxyl group-3-(N-methyl-tetramethyleneimine-3-yl)-phenyl]-2 '-methyl-4 '-carboxyl-xenyl-4-sulphonamide and the reaction of following compound
N
1, N
1-dimethyl-ethane-1, the 2-diamines,
N
1, N
1-dimethyl-propane-13-diamines,
4-amino-N-methyl-piperidines,
3-amino-N-methyl-tetramethyleneimine,
4-dimethylamino-piperidines,
3-dimethylamino-piperidines,
Morpholine
Obtain following compound:
N-[4-methoxyl group-3-(N-methyl-tetramethyleneimine-3-yl)-phenyl]-2 '-methyl-4 '-[(2-dimethylamino-ethyl)-aminocarboxyl]-xenyl-4-sulphonamide,
N-[4-methoxyl group-3-(N-methyl-tetramethyleneimine-3-yl)-phenyl]-2 '-methyl-4 '-[(3-dimethylamino-propyl group)-aminocarboxyl]-xenyl-4-sulphonamide,
N-[4-methoxyl group-3-(N-methyl-tetramethyleneimine-3-yl)-phenyl]-2 '-methyl-4 '-[(N-methyl-piperidin-4-yl)-aminocarboxyl]-xenyl-4-sulphonamide,
N-[4-methoxyl group-3-(N-methyl-tetramethyleneimine-3-yl)-phenyl]-2 '-methyl-4 '-[(N-methyl-tetramethyleneimine-3-yl)-aminocarboxyl]-xenyl-4-sulphonamide,
N-[4-methoxyl group-3-(N-methyl-tetramethyleneimine-3-yl)-phenyl]-2 '-methyl-4 '-[(4-dimethylamino-piperidines-1-yl)-aminocarboxyl]-xenyl-4-sulphonamide,
N-[4-methoxyl group-3-(N-methyl-tetramethyleneimine-3-yl)-phenyl]-2 '-methyl-4 '-[(3-dimethylamino-piperidines-1-yl)-aminocarboxyl]-xenyl-4-sulphonamide,
N-[4-methoxyl group-3-(N-methyl-tetramethyleneimine-3-yl)-phenyl]-2 '-methyl-4 '-(morpholine-4-base carbonyl)-xenyl-4-sulphonamide.
Embodiment 8
Similar to Example 6, by making " E " and following compound reaction
The high piperazine of 1-methyl,
2-(N, N-dimethylaminomethyl)-tetramethyleneimine,
C-(N-methyl-tetramethyleneimine-2-yl)-methylamine,
2-(tetramethyleneimine-1-ylmethyl)-tetramethyleneimine,
2-(N, N-diethylamino methyl)-piperidines,
2-(morpholine-4-yl)-ethylamine
Obtain following compound:
N-[4-methoxyl group-3-(4-methyl-piperazine-1-yl)-phenyl]-2 '-methyl-4 '-[(1-methyl-Gao piperazine-4-yl)-carbonyl]-xenyl-4-methane amide,
N-[4-methoxyl group-3-(4-methyl-piperazine-1-yl)-phenyl]-2 '-methyl-4 '-[(2-(N, N-dimethylaminomethyl)-tetramethyleneimine-1-yl)-carbonyl]-xenyl-4-methane amide,
N-(4-methoxyl group-3-(4-methyl-piperazine-1-yl)-phenyl)-2 '-methyl-4 '-(N-methyl-tetramethyleneimine-2-yl)-methylamino carbonyl)-xenyl-4-methane amide,
N-[4-methoxyl group-3-(4-methyl-piperazine-1-yl)-phenyl]-2 '-methyl-4 '-[(2-(tetramethyleneimine-1-ylmethyl)-tetramethyleneimine-1-yl)-carbonyl]-xenyl-4-methane amide,
N-[4-methoxyl group-3-(4-methyl-piperazine-1-yl)-phenyl]-2 '-methyl-4 '-[(2-(N, N-diethylamino methyl)-piperidines-1-yl)-carbonyl]-xenyl-4-methane amide,
N-[4-methoxyl group-3-(4-methyl-piperazine-1-yl)-phenyl]-2 '-methyl-4 '-[(2-(morpholine-4-yl)-ethylamino)-carbonyl]-xenyl-4-methane amide.
Embodiment 9
With 200mg N-[4-methoxyl group-3-(4-methyl-piperazine-1-yl)-phenyl]-2 '-methyl-4 '-(5-methyl isophthalic acid, 2,4-oxadiazole-3-yl)-xenyl-4-methane amide is at 3.0ml EtSH and 2ml CH
2Cl
2In solution be cooled to 0 ℃, add the AlCl of 1.0g
3, mixture was at room temperature stirred 15 hours, add 20ml ice-water, use NaHCO
3(powder) neutralization is about 8 until the pH of solution, uses CH
2Cl
2(4 * 30ml) extractions.Organic layer MgSO after the merging
4Dry, suction filtration, evaporation, obtain 200mg N-[4-hydroxyl-3-(4-methyl-piperazine-1-yl)-phenyl]-2 '-methyl-4 '-(5-methyl isophthalic acid, 2,4-oxadiazole-3-yl)-xenyl-4-methane amide, it is passed through purification by flash chromatography, with 1: 2 ethyl acetate/hexane recrystallization, obtain 140mg:m.p.140-142 ℃; IR (KBr) 3296 (brs), 1504 (s), 1425 (s), 1261 (s) cm
-1EI 483
Similarly, obtain N-(4-hydroxyl-3-(4-methyl-piperazine-1-yl)-phenyl)-2 '-methyl-4 '-(5-methyl isophthalic acid, 3,4-oxadiazole-2-yl)-xenyl-4-methane amide: m.p.149-152 ℃; IR (KBr) 3504,3350,3294,1646,1505,1262,1241cm
-1
Embodiment 10
Similar to Example 3, make " B " of 180mg and the N-[2-(N of 143 mg, the N-dimethylamino)-ethyl]-4-bromo-3-methyl-benzamide is [by 4-bromo-3-methyl-phenylformic acid and N ', N '-dimethyl-ethane-1, the 2-diamine reactant makes], obtain compound N-[4-methoxyl group-3-(4-methyl-piperazine-1-yl)-phenyl]-2 '-methyl-4 '-[(2-dimethylamino-ethyl)-aminocarboxyl]-xenyl-4-sulphonamide: 120mg; M.p.117-120 ℃; Rf:0.22 (CH
2Cl
2/ EtOH/25%NH
4The OH aqueous solution 90: 10: 1); IR (KBr) 1642cm
-1 
Similarly, by making " B " and following compound reaction
N-methyl-N-(2-dimethylamino-ethyl)-4-bromo-3-methyl-benzamide,
N-(3-dimethylamino-propyl group)-4-bromo-3-methyl-benzene-methane amide,
N-methyl-N-(3-dimethylamino-propyl group)-4-bromo-3-methyl-benzene-methane amide,
Obtain following compound:
N-[4-methoxyl group-3-(4-methyl-piperazine-1-yl)-phenyl]-2 '-methyl-4 '-[N '-methyl-N '-(2-dimethylamino-ethyl)-aminocarboxyl]-xenyl-4-sulphonamide,
N-(4-methoxyl group-3-(4-methyl-piperazine-1-yl)-phenyl]-2 '-methyl-4 '-[N '-(3-dimethylamino-propyl group)-aminocarboxyl]-xenyl-4-sulphonamide,
N-[4-methoxyl group-3-(4-methyl-piperazine-1-yl)-phenyl]-2 '-methyl-4 '-[N '-methyl-N '-(3-dimethylamino-propyl group)-aminocarboxyl]-xenyl-4-sulphonamide.
Embodiment 11
Similar to Example 3, by " B " and 4-methyl isophthalic acid-(4 '-bromo-3 '-methyl-phenyl-1 '-the carbonyl)-piperazine reaction of 230mg that makes 350mg, obtain compound N-[4-methoxyl group-3-(4-methyl-piperazine-1-yl)-phenyl]-2 '-methyl-4 '-(4-methyl-piperazine-1-carbonyl)-xenyl-4-sulphonamide: 300mg, m.p.106-108 ℃
Similarly, by making " B " and following compound reaction
1-(4 '-N, N-dimethylamino-piperidines-1 '-carbonyl) 4-bromo-3-methyl-benzene,
N-(N-methyl-piperidin-4-yl)-4-bromo-3-methyl-benzene-methane amide,
Obtain following compound:
N-[4-methoxyl group-3-(4-methyl-piperazine-1-yl)-phenyl]-2 '-methyl-4 '-(4-dimethylamino-piperidines-1-base-carbonyl)-xenyl-4-sulphonamide,
N-[4-methoxyl group-3-(4-methyl-piperazine-1-yl)-phenyl]-2 '-methyl-4 '-(1-methyl-piperidin-4-yl-aminocarboxyl)-xenyl-4-sulphonamide.
Embodiment 12
Similar to Example 6, by making 2 '-methyl-4 '-(4-methyl-piperazine-1-base-carbonyl)-xenyl-4-formic acid and 2,4-dimethoxy-3-(4-methyl-piperazine-1-yl)-aniline reaction, obtain compound N-[2,4-dimethoxy-3-(4-methyl-piperazine-1-yl)-phenyl]-2 '-methyl-4 '-(4-methyl-piperazine-1-base-carbonyl)-xenyl-4-methane amide, Rf0.14 (CH
2Cl
2/ EtOH 4: 1); FAB 572.
Embodiment 13
With 40mg N-[4-hydroxyl-3-(4-methyl-piperazine-1-yl)-phenyl]-2 '-methyl-4 '-(5-methyl isophthalic acid, 3,4-oxadiazole-2-yl)-xenyl-4-methane amide and 0.1ml triethylamine be at 3ml CH
2Cl
2In solution be cooled to 0 ℃, handled 1 hour with 0.06ml methyl sulphonyl chlorine.In mixture, add 0.1ml 2N NaOH and 2g SiO
2After evaporation, resistates is passed through purification by flash chromatography, carry out recrystallization with ethyl acetate/hexane, obtain N-[4-mesyloxy-3-(4-methyl-piperazine-1-yl)-phenyl of 40mg]-2 '-methyl-4 '-(5-methyl isophthalic acid, 3,4-oxadiazole-2-yl)-and xenyl-4-methane amide, m.p.194-197 ℃; IR (KBr) 3420 (brm), 2977 (s), 2941 (s), 2603 (vs), 2496 (vs), 1655 (s), 1397 (s), 1186 (s), 1037 (s) cm
-1EI 561.
Similarly, obtain N-[4-trifluoro-methanesulfonyl oxy-3-(4-methyl-piperazine-1-yl)-phenyl]-2 '-methyl-4 '-(5-methyl isophthalic acid, 2,4-oxadiazole-3-yl)-xenyl-4-methane amide, m.p.140 ℃; IR (KBr) 3416 (brm), 1676 (m), 1595 (s), 1422 (s), 1212 (brs), 1139 (s) cm
-1
Embodiment 14
With 120mg N-[4-hydroxyl-3-(4-methyl-piperazine-1-yl)-phenyl]-2 '-methyl-4 '-(5-methyl isophthalic acid, 2,4-oxadiazole-3-yl)-xenyl-4-methane amide, 52mg BrCH
2CH
2F and 600mg CsCO
3Solution in the 15ml acetonitrile refluxed 3 hours.Remove acetonitrile, after conventional processing, obtain N-[4-(2-fluoro ethyl)-3-(4-methyl-piperazine-1-yl)-phenyl of 94mg]-2 '-methyl-4 '-(5-methyl isophthalic acid, 2,4-oxadiazole-3-yl)-and xenyl-4-methane amide, m.p.128-130 ℃, IR (KBr) 3417 (brm), 1654 (m), 1643 (m), 1607 (m), 1507 (m), 1257 (s), 1230 (s) cm
-1EI 529.
Following examples relate to medicament production:
Embodiment A: bottle
Make the pH value of the solution of Sodium phosphate dibasic in twice distillatory water of 3L of the activeconstituents of 100g formula I and 5g become 6.5 with the hydrochloric acid of 2N, filtration sterilization is filled in the bottle, carries out lyophilize under aseptic condition, seals with sterile manner.Each bottle comprises the activeconstituents of 5mg.
Embodiment B: suppository
The activeconstituents of 20g formula I is melted in the soybean lecithin and 1400g theobroma oil of 100g, pour into mixture in the mould and make its cooling.Each suppository comprises the activeconstituents of 20mg.
Embodiment C: solution
Solution is by the formula I activeconstituents of 1g, the NaH of 9.38g
2PO
42H
2The Na of O, 28.48g
2HPO
412H
2The benzalkonium chloride of O and 0.1g is made in twice deionized water of 940ml.Making the pH value of solution is 6.8, and solution is supplemented to 1L, carries out sterilization by irradiation.This solution can the dripping eyedrop form use.
Embodiment D: ointment
Under aseptic condition, the formula I activeconstituents of 500mg is mixed with the mineral jelly of 99.5g.
Embodiment E: tablet
The mixture of the Magnesium Stearate of the talcum of the yam starch of the lactose of the activeconstituents of 1kg formula I, 4kg, 1.2kg, 0.2kg and 0.1kg is made tablet in a usual manner, and each sheet comprises the activeconstituents of 10mg.
Embodiment F: sugar coated tablet
With embodiment E is similar mixture is made tablet, again tablet is carried out conventional dressing with the coating material of sucrose, yam starch, talcum, tragacanth gum and tinting material in a usual manner.
Embodiment G: capsule
The formula I activeconstituents of 2kg is filled in the hard gelatin capsule in a usual manner, and each capsules comprises the activeconstituents of 20mg.
Embodiment H: ampoule
The solution of 1kg formula I activeconstituents in twice distilled water of 60L is carried out sterile filtration, be filled in the ampoule, under aseptic condition, carry out freeze-drying, in sealed under aseptic conditions.Each ampoule comprises the activeconstituents of 10mg.
Embodiment I: suck and use sprays
The activeconstituents of 14g formula I is dissolved in the isotonic sodium chlorrde solution of 10L, this solution is packed in the pump operated automiser spray that is purchased.Solution can spray in admission port or the nose.Starting (about 0.1ml) each time is about 0.14mg corresponding to dosage.
Claims (9)
1, the biphenyl derivative of formula I
Wherein R be-C (=NH)-NH
2,-C (=NH)-NHA
3,-C (=NH)-NHAc ,-C (=NH)-NHSO
2CH
3, R
2,-CO-NH-Z-R
3Or-CO-R
1, X is-CONH-,-SO
2NH-,-NHCO-or-NHSO
2-, Y is CH or N, A
1Be H, wherein have 1-7 the H atom can be by alkyl, the SO of the displaced 1-6 of containing of a F carbon atom
2CH
3Or SO
2CF
3, A
2Be H or the alkyl that contains 1-6 carbon atom, A
3, A
5Be the alkyl that contains 1-6 carbon atom independently of one another, A
6, A
7Be H or (CH independently of one another
2)
pCH
3, Q is H or OA
1, R
1Be 4-A
5-piperazine-1-base, 4-A
5-Gao piperazinyl, by R
4Or-Z-R
4Replace once 1-pyrrolidyl, by R
4Or-Z-R
4Replace once piperidino, N-A
5-pyrrolidyl-amino, N-A
5-piperidyl-amino, N-A
5-pyrrolidyl-Z-amino or N-A
5-piperidyl-Z-amino ,-N (A
6) (ZR
3) or NA
6A
7, R
2Be the 5-methyl isophthalic acid, 3,4-oxadiazole-2-base or 5-methyl isophthalic acid, 2,4-oxadiazole-3-base, R
3, R
4Be NHA independently of one another
5, N (A
5)
2, 4-morpholinyl, 1-pyrrolidyl or piperidino, Z is the alkylidene group that contains 1-6 carbon atom, n is 0 or 1, p is 0,1 or 2,
Condition is, if Y is N, and X=-CONH-and n=1, then R ≠ R
2Perhaps R ≠-CONA
6A
7, comprise racemic modification and enantiomorph, and physiologically acceptable salt and solvate.
2, according to the formula I compound of claim 1,
A) N-[4-methoxyl group-3-(4-methyl-piperazine-1-yl)-phenyl]-2 '-methyl-4 '-amidino groups-xenyl-4-methane amide;
B) N-[4-methoxyl group-3-(4-methyl-piperazine-1-yl)-phenyl]-2 '-methyl-4 '-(5-methyl isophthalic acid, 2,4-oxadiazole-3-yl)-xenyl-4-sulphonamide;
C) N-[4-methoxyl group-3-(N-methyl-tetramethyleneimine-3-yl)-phenyl]-2 '-methyl-4 '-(5-methyl isophthalic acid, 2,4-oxadiazole-3-yl)-xenyl-4-methane amide;
D) N-[4-methoxyl group-3-(N-methyl-tetramethyleneimine-3-yl)-phenyl]-2 '-methyl-4 '-(5-methyl isophthalic acid, 2,4-oxadiazole-3-yl)-xenyl-4-sulphonamide;
E) N-[4-methoxyl group-3-(4-methyl-piperazine-1-yl)-phenyl]-2 '-methyl-4 '-[4-methyl-piperazine-1-carbonyl)-xenyl-4-methane amide;
And physiologically acceptable salt and solvate.
3. the preparation method of the described formula I of claim 1 compound and its salt and solvate is characterized in that,
A) make the compound of formula II
Wherein
L is Cl, Br, I or is modified the OH base that forms reactive group, particularly a kind of suitable leavings group, R and A by functional group
3As preceding definition,
Boric acid derivatives reaction with the formula III
Wherein
X, Y, A
1, A
2, Q and n such as preceding definition such as preceding definition,
Perhaps
B) make the compound of formula IV
Wherein
R and A
3As preceding definition, X ' is CO or SO
2With
L is Cl, Br, I or is modified the OH base that forms reactive group by functional group, particularly a kind of suitable leavings group,
Compound reaction with the formula V
Wherein
Y, A
1, A
2, Q and n such as preceding definition,
Perhaps
C) be the compound of preparation formula I,
Wherein
R is-CO-NH-Z-R
3Or-CO-R
1,
Compound with the formula VI
Wherein
L is the OH base that Cl, Br, I or free or active functional group are modified, X, Y, A
1, A
2, A
3, Q and n such as preceding definition,
Compound reaction with the formula VII
H-R′ Ⅶ
Wherein
R ' is NH-Z-R
3Or R
1
And, Z, R
3And R
1As preceding definition,
And/or it is characterized in that, in the following manner, with one or more radicals R, Q, the A in the compound of formula I
1And/or A
2Change into one or more other radicals R, Q, A
1And/or A
2,
ⅰ) with radicals R
2Change into amidino groups,
ⅱ) ether group is hydrolyzed into hydroxyl,
ⅲ) hydroxyl is changed into sulfonyloxy,
And/or with the basic cpd of formula I by change into its salt with acid treatment.
4, a kind of method for preparing medicament production is characterized in that, the compound of the formula I of claim 1 and/or its physiologically acceptable salt or solvate are formed the appropriate drug form with at least a solid, liquid or semiliquid vehicle or auxiliary agent.
5, a kind of pharmaceutical preparation is characterized in that, it comprises formula I compound and/or its physiologically acceptable salt or the solvate of at least a claim 1.
6, the formula I compound of claim 1 and/or its physiologically acceptable salt and solvate are as serotonin (5-HT
1B/D) antagonist.
7, the formula I compound of claim 1 and its physiologically acceptable salt and solvate are used for the treatment of or prevent following disease: the mental state disease, comprise dysthymia disorders and depression, anxiety disorder, comprise general anxiety disease, panic disease, agoraphobe, social phobia, obsessive compulsivedisorder and post-traumatic stress disorder, the memory disease comprises dementia, amnesia and the memory impairment relevant with the age, Parkinson's disease, the growth of 5-HT-dependent tumors cell, the dietary behavior disease comprises anorexia nervosa and Bulimia nerovsa, with periphery 5-HT
1B/DReceptor function controlling is bad to be the cardiovascular disorder of feature, endocrinopathy, and vasospasm, hypertension relates to gastrointestinal tract disease and sexual disorder that motility and secretion change.
8, the formula I compound of claim 1 and/or its physiologically acceptable salt or solvate are used for the treatment of or prevent purposes in dysthymia disorders, general anxiety disease, obsessive compulsivedisorder and the bulimiac medicine with serotonin antagonist properties in preparation.
9, the formula I compound of claim 1 and/or its physiologically acceptable salt or the solvate purposes in treatment or prevention dysthymia disorders, general anxiety disease, obsessive compulsivedisorder and Bulimia nerovsa.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP98113488 | 1998-07-20 | ||
| EP98113488.5 | 1998-07-20 |
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| Publication Number | Publication Date |
|---|---|
| CN1309654A true CN1309654A (en) | 2001-08-22 |
Family
ID=8232308
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN99808739A Pending CN1309654A (en) | 1998-07-20 | 1999-07-08 | Biphenyl derivs. |
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| Country | Link |
|---|---|
| EP (1) | EP1098892A1 (en) |
| JP (1) | JP2002521377A (en) |
| KR (1) | KR20010070997A (en) |
| CN (1) | CN1309654A (en) |
| AR (1) | AR019415A1 (en) |
| AU (1) | AU5033899A (en) |
| BR (1) | BR9912299A (en) |
| CA (1) | CA2338209A1 (en) |
| HU (1) | HUP0102622A3 (en) |
| ID (1) | ID27846A (en) |
| NO (1) | NO20010333L (en) |
| PL (1) | PL345283A1 (en) |
| SK (1) | SK492001A3 (en) |
| WO (1) | WO2000005225A1 (en) |
| ZA (1) | ZA200101379B (en) |
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| CN101039904B (en) * | 2004-10-14 | 2014-09-24 | Abbvie德国有限责任两合公司 | Heterocyclic compounds suitable for treating disorders that respond to modulation of the dopamine d3 receptor |
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| HUP0302751A3 (en) * | 2000-11-14 | 2007-06-28 | Merck Patent Gmbh | Novel uses of combined 5-ht1a agonists and serotonin reuptake inhibitors |
| WO2002060378A2 (en) | 2000-12-21 | 2002-08-08 | Nitromed, Inc. | Substituted aryl compounds as cyclooxygenase-2 selective inhibitors, compositions and methods of use |
| US7718650B2 (en) | 2001-05-11 | 2010-05-18 | Biovitrum Ab | Aryl sulfonamide compounds for treating obesity |
| PL366619A1 (en) | 2001-05-11 | 2005-02-07 | Biovitrum Ab | Novel, arylsusfonamide compounds for the treatment of obesity, type ii diabetes and cns-disorders |
| AU2002327627B2 (en) | 2001-09-14 | 2006-09-14 | Methylgene Inc. | Inhibitors of histone deacetylase |
| SE0103644D0 (en) * | 2001-11-01 | 2001-11-01 | Astrazeneca Ab | Therapeutic isoquinoline compounds |
| PE20060574A1 (en) | 2004-07-28 | 2006-06-24 | Glaxo Group Ltd | ARILPIPERAZINE SULFONAMIDE DERIVATIVES AS AGONISTS OF GROWTH HORMONE SECRETAGOG RECEPTORS (GHS) |
| WO2007077457A2 (en) * | 2006-01-06 | 2007-07-12 | The Royal Veterinary College | Treatment of equine laminitis with 5-ht1b/ 1d antagonists |
| US7713978B2 (en) | 2006-03-31 | 2010-05-11 | Nigel Paul King | Compounds |
| US8642642B2 (en) * | 2006-04-19 | 2014-02-04 | Abbott Laboratories | Heterocyclic arylsulphones suitable for treating disorders that respond to modulation of the serotonin 5HT6 receptor |
| CA2648892A1 (en) | 2006-04-19 | 2007-10-25 | Abbott Gmbh & Co. Kg | Heterocyclic compounds suitable for treating disorders that respond to modulation of the serotonin 5ht6 receptor |
| WO2007136668A2 (en) | 2006-05-19 | 2007-11-29 | Wyeth | N-benzoyl-and n-benzylpyrrolidin-3-ylamines as histamine-3 antagonists |
| US8507469B2 (en) | 2007-03-23 | 2013-08-13 | Abbott Gmbh & Co. Kg | Azetidin compounds suitable for treating disorders that respond to modulation of the serotonin 5-HT6 receptor |
| KR20100038295A (en) | 2007-06-05 | 2010-04-14 | 엔에스아베 필리알 아프 뉴로서치 스웨덴 아베 스베리게 | Disubstituted phenylpyrrolidines as modulators of cortical catecholaminergic neurotransmission |
| JO2972B1 (en) | 2007-06-08 | 2016-03-15 | جانسين فارماسوتيكا ان. في | Piperidine/Piperazine derivatives |
| CA2687912C (en) | 2007-06-08 | 2015-11-03 | Janssen Pharmaceutica N.V. | Piperidine/piperazine derivatives |
| JP5464709B2 (en) | 2007-06-08 | 2014-04-09 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | Piperidine / piperazine derivatives |
| AU2008258487B2 (en) | 2007-06-08 | 2012-11-15 | Janssen Pharmaceutica N.V. | Piperidine/piperazine derivatives |
| AU2009253892B2 (en) | 2008-06-05 | 2015-07-30 | Janssen Pharmaceutica Nv | Drug combinations comprising a DGAT inhibitor and a PPAR-agonist |
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| GB9119920D0 (en) * | 1991-09-18 | 1991-10-30 | Glaxo Group Ltd | Chemical compounds |
| ES2162792T3 (en) * | 1991-09-18 | 2002-01-16 | Glaxo Group Ltd | BENZANILIDE DERIVATIVES AS 5-HT1D ANTAGONISTS. |
| GB2273930A (en) * | 1992-12-30 | 1994-07-06 | Glaxo Group Ltd | Benzanilide derivatives |
| GB9507203D0 (en) * | 1995-04-07 | 1995-05-31 | Smithkline Beecham Plc | Novel compounds |
-
1999
- 1999-07-08 SK SK49-2001A patent/SK492001A3/en unknown
- 1999-07-08 WO PCT/EP1999/004803 patent/WO2000005225A1/en not_active Application Discontinuation
- 1999-07-08 CN CN99808739A patent/CN1309654A/en active Pending
- 1999-07-08 AU AU50338/99A patent/AU5033899A/en not_active Abandoned
- 1999-07-08 BR BR9912299-5A patent/BR9912299A/en not_active Application Discontinuation
- 1999-07-08 PL PL99345283A patent/PL345283A1/en unknown
- 1999-07-08 JP JP2000561181A patent/JP2002521377A/en active Pending
- 1999-07-08 HU HU0102622A patent/HUP0102622A3/en unknown
- 1999-07-08 ID IDW20010307A patent/ID27846A/en unknown
- 1999-07-08 EP EP99934632A patent/EP1098892A1/en not_active Withdrawn
- 1999-07-08 CA CA002338209A patent/CA2338209A1/en not_active Abandoned
- 1999-07-08 KR KR1020017000849A patent/KR20010070997A/en not_active Application Discontinuation
- 1999-07-16 AR ARP990103510A patent/AR019415A1/en not_active Application Discontinuation
-
2001
- 2001-01-19 NO NO20010333A patent/NO20010333L/en unknown
- 2001-02-19 ZA ZA200101379A patent/ZA200101379B/en unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101039904B (en) * | 2004-10-14 | 2014-09-24 | Abbvie德国有限责任两合公司 | Heterocyclic compounds suitable for treating disorders that respond to modulation of the dopamine d3 receptor |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA200101379B (en) | 2002-05-20 |
| CA2338209A1 (en) | 2000-02-03 |
| BR9912299A (en) | 2001-11-20 |
| NO20010333D0 (en) | 2001-01-19 |
| SK492001A3 (en) | 2001-08-06 |
| AR019415A1 (en) | 2002-02-20 |
| ID27846A (en) | 2001-04-26 |
| EP1098892A1 (en) | 2001-05-16 |
| HUP0102622A2 (en) | 2001-12-28 |
| WO2000005225A1 (en) | 2000-02-03 |
| PL345283A1 (en) | 2001-12-03 |
| KR20010070997A (en) | 2001-07-28 |
| JP2002521377A (en) | 2002-07-16 |
| AU5033899A (en) | 2000-02-14 |
| HUP0102622A3 (en) | 2002-12-28 |
| NO20010333L (en) | 2001-01-19 |
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