CN101239945A - Aminoquinoline derivatives and their use as adenosine a3 ligands - Google Patents

Aminoquinoline derivatives and their use as adenosine a3 ligands Download PDF

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CN101239945A
CN101239945A CNA2008100096757A CN200810009675A CN101239945A CN 101239945 A CN101239945 A CN 101239945A CN A2008100096757 A CNA2008100096757 A CN A2008100096757A CN 200810009675 A CN200810009675 A CN 200810009675A CN 101239945 A CN101239945 A CN 101239945A
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CN101239945B (en
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P·奥劳尼
S·巴托里
G·蒂马里
K·博埃尔
Z·卡布依
E·米库什
K·乌尔班-绍宝
K·格贝尔
J·瓦尔格内塞赖迪
M·菲内
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Sanofi Aventis France
Sanofi Aventis SpA
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Abstract

Compounds of the general formula (I), and their salts, solvates, isomers (tautomers, desmotrops, optically active isomers) as well as the salts and solvates; are strong adenosine A3 receptor ligands preferably antagonists.

Description

Amino quinoline derivatives and they are as adenosine A 3The purposes of part
The application be submitted on July 23rd, 2004, denomination of invention is for " amino quinoline derivatives and they are as adenosine A 3The purposes of part " the dividing an application of PCT application PCT/HU2004/000080, it is on January 25th, 2006 that described PCT application enters the date in China national stage, application number is 200480021520.5.
Technical field
The present invention relates to be adenosine A 3Receptors ligand, be preferably the compound of general formula (I) of antagonist and their salt, solvate and isomer (tautomer, desmotropic form, optically active isomer), the invention still further relates to the medicinal compositions that comprises them, general formula (I) compound and their salt, the purposes of solvate and isomer, general formula (I) compound and their salt, the preparation method of solvate and isomer, in addition, the invention still further relates to the new general formula of part (II "); (III "), (IV "); (V "), (VI "); (VII "), the intermediate of (VIII ") and (XIII ") and their preparation method.
Background technology
As everyone knows, adenosine is multiple endogenous molecule (ATP, NAD +, nucleic acid) integral part.It has played crucial effects in many physiological processs.The effect of adenosine in heart function addressed in 1929 (Drury and Szentgy  rgyi, Physiol.68:213,1929) to some extent.Use by the checking of the increase of the number of a large amount of physiological functions of adenosine mediation and the treatment that is found to be specific ligand that new adenosine is subjected to hypotype that provide may (Poulse, S.A.and Quinn, R.J.Bioorganicand Medicinal Chemistry 6:619,1998).
Up to now, people are divided into three kinds of main type: A with Adenosine Receptors 1, A 2And A 3A 1Hypotype by with G iThe membranin coupling partly is responsible for suppressing adenylate cyclase, and other second messenger systems are produced some effects.A 2Receptor subtype can be further divided into two kinds of hypotypes, i.e. A 2aAnd A 2b, these two kinds of hypotypes can stimulate the activity of adenylate cyclase.Adenosine A 3The sequence of acceptor is identified in rat TESTIS cDNA library first.Subsequently, verified this receptor is a kind of new, functional Adenosine Receptors.A 3The activation of acceptor is also relevant with several second messenger systems: suppress adenylate cyclase, stimulate Phospholipase C and D.
People have found in several organs that Adenosine Receptors and these acceptors have regulating effect to the function of organ.A 1And A 2aAcceptor plays an important role in central nervous system is unified cardiovascular systems.In CNS, adenosine has suppressed the release of synaptic transmitter, and this effect is by A 1Receptor-mediated.In heart, A 1Acceptor has also mediated negative inotropic, negative chronotropic and the negativity dromotropic action of adenosine.Adenosine A 2aThe content of acceptor in striatum is higher relatively, plays interaction with Dopamine Receptors in regulating the cynapse transmission.A in endothelium and the smooth muscle cell 2aAdenosine Receptors is responsible for the vasorelaxation of adenosine inductive.
Qualification result based on to RNA it is found that A 2bAdenosine Receptors is distributed widely in different tissues.Find that also they almost are present in each cell type, but in intestines and bladder, express the highest.This class hypotype also may have important effect in regulating vascular tone, and has also played vital role in the function of mastocyte.
With the A that on protein level, detects its tissue distribution 1And A 2aAcceptor is opposite, A 2bAnd A 3The existence of acceptor is detected on the mRNA level.Compare A with other hypotype 3The expression level of Adenosine Receptors is low-down, and they have very high kind dependency.A 3As if Adenosine Receptors is mainly expressed in central nervous system, testis and immunity system, and also participated in promptly sending out the adjusting that allergy (immediate hypersensitivity reaction) medium discharges from mastocyte.
When treating, must guarantee molecule not with or only with the Adenosine Receptors A of high concentration 1, A 2aAnd A 2bThe hypotype combination.
Summary of the invention
The present invention relates to general formula (I) compound and their salt, solvate and isomer, these compounds are all to Adenosine Receptors A 3Hypotype has high selectivity.
Up to now, the A that introduces in the document 3Antagonist all belongs to flavonoid, 1,4-dihydrogen pyridine derivative, triazoloquinazolines,, thiazole and naphthyridines and thiazole miazines compound.But major part effectively has optionally antagonist to the adenosine hypotype, all has very strong lipotropy, so their solvabilities in water are very little.These character have hindered the application in vivo of described compound.According to bibliographical information, increasing research is devoted to prepare water miscible adenosine A 3Receptor antagonist (Ch.E.M ü ller etc., J.Med.Chem.45:3440,2002; A.Maconi etc., J.Med.Chem.45:3579,2002).
Patent application WO 02/096879 discloses the 2-amino-3-cyano-quinoline derivatives with novel texture, and this is a kind of effective A 3Antagonist.In the formula described in the patent application WO 02/096879
(1) compound is the A of highly selective 3Antagonist.
In general formula (1),
R 1' represent hydrogen atom or straight or branched C 1-4Alkyl;
R 2' represent hydrogen atom or straight or branched C 1-4Alkyl;
R 3' represent hydrogen atom or straight or branched C 1-4Alkyl, phenyl, thienyl or furyl, optional by one or more straight or branched C 1-4Alkyl, straight or branched C 1-4The alkoxy or halogen atom replaces; Six or five yuan of hetero-aromatic rings, described hetero-aromatic ring comprise one, two or three nitrogen-atoms, or a nitrogen-atoms and a Sauerstoffatom, or a nitrogen-atoms and a sulphur atom, and are optional by one or more straight or branched C 1-4Alkyl, straight or branched C 1-4The alkoxy or halogen atom replaces;
R 9', R 10', R 11' and R 12' independent hydrogen atom, the straight or branched C of representing 1-4Alkyl, straight or branched C 1-4Alkoxyl group, hydroxyl or halogen atom, perhaps R 9' and R 12' represent hydrogen atom and R 10' and R 11' form methylene-dioxy together;
R 6' represent hydrogen atom or cyano group, aminocarboxyl, C 1-4Alkoxy carbonyl or carboxyl;
R 7' represent hydrogen atom or straight or branched C 1-4Alkyl, phenyl, benzyl, thienyl or furyl, optional by methylene-dioxy or one or more straight or branched C 1-4Alkyl, straight or branched C 1-4Alkoxyl group, hydroxyl, trifluoromethyl, cyano group or halogen atom replace; Perhaps comprise one, two or three nitrogen-atoms, or a nitrogen-atoms and a Sauerstoffatom, or hexa-atomic or five yuan of hetero-aromatic rings of a nitrogen-atoms and a sulphur atom, optional by one or more straight or branched C 1-4Alkyl, straight or branched C 1-4The alkoxy or halogen atom replaces;
X ' representative-CH 2-group ,-the NH-group ,-NR 8'-group or sulphur atom, Sauerstoffatom, alkylsulfonyl (sulpho) or sulfonyloxy (sulphoxy), wherein R 8' represent straight or branched C 1-4Alkyl or C 3-6Cycloalkyl;
N ' represents 0,1 or 2;
But these compounds also have shortcoming, they water-soluble also very low, and this shortcoming has hindered their purposes as medicine.
A theme of the present invention is the A that preparation has the quinoline structure 3Part, be preferably the method for antagonist, described part is to A 3Acceptor has very strong antagonistic action and to A 3Acceptor has higher selectivity, can be with than suppressing A as them 1, A 2aAnd A 2bThe concentration that acceptor is significantly lower suppresses A 3Acceptor.Other theme of the present invention is the data that obtain stability, bioavailability, therapeutic index, toxicity and solvability aspect, thereby can be developed as medicine by the compound that these are new, and more help the absorption of intestines when making these new compound oral administration administrations.
The applicant finds general formula (I) compound:
Figure S2008100096757D00041
Wherein
R 1Represent hydrogen atom or straight or branched C 1-4Alkyl;
R 2Represent hydrogen atom or straight or branched C 1-4Alkyl;
R 3Represent hydrogen atom or straight or branched C 1-4Alkyl, C 3-6Cycloalkyl, phenyl, thienyl or furyl, optional by one or more straight or branched C 1-4Alkyl, straight or branched C 1-4The alkoxy or halogen atom replaces; Comprise one, hexa-atomic or five yuan of hetero-aromatic rings of two or three nitrogen-atoms, perhaps comprise five yuan of hetero-aromatic rings of a nitrogen-atoms and Sauerstoffatom or a nitrogen-atoms and a sulphur atom, optional by one or more straight or branched C 1-4Alkyl, straight or branched C 1-4The alkoxy or halogen atom replaces;
R 4And R 5Independent hydrogen atom, the C of representing 3-6Cycloalkyl, straight or branched C 1-4Alkyl, this group is optional to comprise an amino, by one or two straight or branched C 1-4The amino that alkyl replaces, hydroxyl, carboxyl or by straight or branched C 1-4The alkoxyl group that alkyl replaces; Perhaps
R 4Represent hydrogen atom or straight or branched C 1-4Alkyl or benzyl, and
R 5Represent hydrogen atom ,-SO 2OH group or straight or branched C 1-4Acyl group, perhaps
R 4And R 5Form general formula a. with nitrogen-atoms) group, wherein R 7And R 8Independent hydrogen atom, the straight or branched C of representing 1-4Alkyl or C 3-6Cycloalkyl;
R 6Represent hydrogen atom or straight or branched C 1-4Alkyl, phenyl, benzyl, thienyl or furyl optional are replaced by methylene-dioxy, perhaps by one or more straight or branched C 1-4Alkyl, straight or branched C 1-4Alkoxyl group, hydroxyl, trifluoromethyl, cyano group or halogen atom replace; Perhaps hexa-atomic or five yuan of hetero-aromatic rings, described hetero-aromatic ring contains one, two or three nitrogen-atoms, perhaps a nitrogen-atoms and a Sauerstoffatom, perhaps a nitrogen-atoms and a sulphur atom are optional by one or more straight or branched C 1-4Alkyl, straight or branched C 1-4The alkoxy or halogen atom replaces;
X representative-CH 2-group ,-the NH-group ,-NR 9-group or sulphur atom, Sauerstoffatom, alkylsulfonyl or sulfonyloxy, wherein R 9Represent straight or branched C 1-4Alkyl or C 3-6Cycloalkyl;
Z represention oxygen atom, sulphur atom ,-CHR 10-group or-NR 11-group, wherein R 10Represent hydrogen atom, straight or branched C 1-4Alkyl, perhaps C 3-6Cycloalkyl and R 11Represent hydrogen atom, straight or branched C 1-4Alkyl, C 3-6Cycloalkyl ,-SO 2OH group or straight or branched C 1-4Acyl group;
N represents 0,1 or 2;
M represents 1,2 or 3;
O represents 1,2 or 3;
P represents 0 or 1;
R represents 0 or 1,
And their salt, solvate, isomer (tautomer, desmotropic form, optically active isomer) and salt thereof and solvate can reach above-mentioned standard, and their solubility data far surpasses known 2-amino-3-cyano quinolines compound, in addition, they also have high reactivity.
Liquid phase NMR studies show that the solution of general formula (I) compound is a kind of tautomeric forms (IA) and equilibrium mixture (IB).Solid phase research then shows, tautomer (IA) and (IB) can be separated into desmotropic form (IA) and (IB).
According to above-mentioned discovery, the present invention also relates to desmotropic form (IA) and (IB).General formula (IA) and substituent implication (IB) such as general formula (I) definition.
General formula (I) compound is according to for example substituent R 1, R 2And R 3The difference of implication, can have chiral centre.Therefore, the present invention also relates to the racemize and the optical activity form of general formula (I) compound and their salt, tautomer and desmotropic form.
Above-mentioned substituent detailed meanings is as described below:
Straight or branched C 1-4Alkyl means methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl or the tertiary butyl, preferred ethyl or methyl.
Straight or branched C 1-4Alkoxyl group means methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert.-butoxy, preferred oxyethyl group or methoxyl group.
C 3-6Cycloalkyl means cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
Straight or branched C 1-4Acyl group means formyl radical, ethanoyl, propionyl, 2-methyl-propionyl or butyryl radicals.
Contain one, the hetero-aromatic ring of two or three nitrogen-atoms and mean pyrroles, imidazoles, pyrazoles, 1,2,3-triazoles, 1,2,4-triazole, pyridine, pyrimidine, pyridazine, pyrazine or 1,2,4-triazine ring.Described ring is optional by C 1-4Alkyl, C 1-4The alkoxy or halogen atom replaces.
Contain a nitrogen-atoms and oxygen-or the hetero-aromatic ring of a sulphur atom mean  azoles, different  azoles, thiazole or isothiazole ring.Described ring is optional by C 1-4Alkyl, C 1-4The alkoxy or halogen atom replaces.
A.) group is preferably represented tetramethyleneimine-1-base (pyrrolidino), piperidines-1-base (piperidino), piperazine-1-base (piperazino), 4-methylpiperazine-1-base, 4-formyl piperazine-1-base, 4-alkylsulfonyl piperazine-1-base or morpholine-4-base (morpholino).
The salt of general formula (I) compound means the salt that forms with inorganic or organic bronsted lowry acids and bases bronsted lowry.Preferred salt is the salt that forms with pharmaceutically acceptable acid, described sour example hydrochloric acid, sulfuric acid, ethyl sulfonic acid, tartrate, oxysuccinic acid, citric acid, fumaric acid, and the salt that forms with pharmaceutically acceptable alkali, described alkali such as sodium hydroxide, potassium hydroxide and thanomin.For example mesylate or a tetrafluoro borate also are themes of the present invention to be used for purifying or isolating salt.
Solvate means the solvate of all kinds of SOLVENTS, as the solvate that forms with water and ethanol.
Preferred general formula (I) compound is as giving a definition, wherein
R 1Represent hydrogen atom or straight or branched C 1-4Alkyl;
R 2Represent hydrogen atom or straight or branched C 1-4Alkyl;
R 3Represent hydrogen atom or straight or branched C 1-4Alkyl, C 3-6Cycloalkyl, phenyl, thienyl or furyl, optional by one or more straight or branched C 1-4Alkyl, straight or branched C 1-4The alkoxy or halogen atom replaces;
R 4And R 5Independent hydrogen atom, the C of representing 3-6Cycloalkyl, straight or branched C 1-4Alkyl, this group is optional to contain amino, by one or two straight or branched C 1-4The amino that alkyl replaces, hydroxyl, carboxyl or by straight or branched C 1-4The alkoxyl group that alkyl replaces; Perhaps
R 4Represent hydrogen atom or straight or branched C 1-4Alkyl or benzyl, and
R 5Represent hydrogen atom ,-SO 2OH group or straight or branched C 1-4Acyl group, perhaps
R 4And R 5Form general formula a. with nitrogen-atoms) group, wherein R 7And R 8Independent hydrogen atom, the straight or branched C of representing 1-4Alkyl or C 3-6Cycloalkyl;
R 6Represent hydrogen atom or straight or branched C 1-4Alkyl, phenyl, benzyl, thienyl or furyl optional are replaced by methylene-dioxy, or by one or more straight or branched C 1-4Alkyl, straight or branched C 1-4Alkoxyl group, hydroxyl, trifluoromethyl, cyano group or halogen atom replace; Perhaps hexa-atomic or five yuan of hetero-aromatic rings, described hetero-aromatic ring contains one, two or three nitrogen-atoms, or a nitrogen-atoms and a Sauerstoffatom, or a nitrogen-atoms and a sulphur atom, and is optional by one or more straight or branched C 1-4Alkyl, straight or branched C 1-4The alkoxy or halogen atom replaces;
X representative-CH 2-group ,-the NH-group ,-NR 9-group or sulphur atom, Sauerstoffatom, alkylsulfonyl or sulfonyloxy, wherein R 9Represent straight or branched C 1-4Alkyl or C 3-6Cycloalkyl;
Z represention oxygen atom, sulphur atom ,-CHR 10-group or-NR 11-group, wherein R 10Represent hydrogen atom, straight or branched C 1-4Alkyl, or C 3-6Cycloalkyl, and R 11Represent hydrogen atom, straight or branched C 1-4Alkyl, C 3-6Cycloalkyl ,-SO 2OH group or formyl radical;
N represents 0,1 or 2;
M represents 1,2 or 3;
O represents 1,2 or 3;
P represents 0 or 1;
R represents 0 or 1,
And their salt, solvate, isomer (tautomer, desmotropic form, optically active isomer) and their salt and solvate.
One group of particularly preferred general formula (I) compound is as giving a definition, wherein
R 1Represent hydrogen atom or methyl;
R 2Represent hydrogen atom or methyl;
R 3Represent phenyl, thienyl or furyl;
R 4And R 5Independent hydrogen atom, the C of representing 3-6Cycloalkyl, straight or branched C 1-4Alkyl, this group is optional to contain amino, by one or two straight or branched C 1-4The amino that alkyl replaces, hydroxyl, carboxyl or by straight or branched C 1-4The alkoxyl group that alkyl replaces; Perhaps
R 4Represent hydrogen atom or straight or branched C 1-4Alkyl-alkyl or benzyl, and
R 5Represent hydrogen atom ,-SO 2OH group or straight or branched C 1-4Acyl group, perhaps
R 4And R 5Form general formula a. with nitrogen-atoms) group, wherein R 7And R 8Independent hydrogen atom, the straight or branched C of representing 1-4Alkyl or C 3-6Cycloalkyl;
R 6Represent 4-p-methoxy-phenyl, 3-aminomethyl phenyl, 3-p-methoxy-phenyl, 3,4-methylenedioxyphenyl, 4-fluorophenyl, 2-thienyl or 2-furyl;
X representative-NH-group or Sauerstoffatom;
Z represention oxygen atom, sulphur atom ,-CH 2-group ,-the NH-group or-NR 11-group, wherein R 11Represent straight or branched C 1-4Alkyl, C 3-6Cycloalkyl ,-SO 2OH group or formyl radical; And
N represents 1;
M represents 2;
O represents 2;
P represents 0;
R represents 0,
And their salt, solvate, isomer (tautomer, desmotropic form, optically active isomer) and their salt and solvate.
The particularly preferred compound that meets above-mentioned standard is such compound:
4-methoxyl group-N-[6-(morpholine-4-yl)-4-benzylamino-3-cyano quinolines-2-yl]-benzamide;
4-methoxyl group-N-[6-(4-methylpiperazine-1-yl)-4-benzylamino-3-cyano quinolines-2-yl] benzamide;
4-methoxyl group-N-(6-dimethylamino-4-benzylamino-3-cyano quinolines-2-yl) benzamide;
3,4-methylene-dioxy-N-(6-dimethylamino-4-benzylamino-3-cyano quinolines-2-yl) benzamide;
4-fluoro-N-(6-dimethylamino-4-benzylamino-3-cyano quinolines-2-yl) benzamide;
4-methoxyl group-N-(6-(piperazine-1-yl)-4-benzylamino-3-cyano quinolines-2-yl) benzamide;
4-methoxyl group-N-(6-amino-4-benzylamino-3-cyano quinolines-2-yl) benzamide;
N-[4-(benzylamino)-3-cyano group-6-(4-formyl piperazine-1-yl) quinoline-2-yl]-the 4-methoxy benzamide;
4-{4-(benzylamino)-3-cyano group-2-[(4-anisoyl) amino] quinoline-6-yl } piperazine-1-sulfonic acid;
N-{3-cyano group-6-(formyl radical amino)-4-[(2-thienyl methyl) amino] quinoline-2-yl }-the 4-methoxy benzamide;
N-{3-cyano group-6-(formyl radical amino)-4-[(2-thienyl methyl) amino] quinoline-2-yl }-1,3-benzo dioxole-5-methane amide;
N-[4-(benzylamino)-3-cyano group-6-(formyl radical amino) quinoline-2-yl]-1,3-benzo dioxole-5-methane amide;
N-[4-(benzylamino)-3-cyano group-6-(formyl radical amino) quinoline-2-yl]-the 4-methoxy benzamide;
N-{4-(benzylamino)-3-cyano group-6-[formyl radical (methyl) amino] quinoline-2-yl }-the 4-methoxy benzamide;
N-{3-cyano group-6-[formyl radical (methyl) amino]-the 4-[(2-thienyl methyl) amino] quinoline-2-yl }-the 4-methoxy benzamide;
3-cyano group-2-[(4-anisoyl) amino]-the 4-[(2-thienyl methyl) amino] quinoline-6-yl } methylamino sulfonic acid;
4-(benzylamino)-3-cyano group-2-[(4-anisoyl) and amino] quinoline-6-yl } methylamino sulfonic acid;
4-(benzylamino)-3-cyano group-2-[(4-anisoyl) and amino] quinoline-6-yl } thionamic acid;
[2-[(1,3-benzo dioxole-5-base carbonyl) amino]-4-(benzylamino)-3-cyano quinolines-6-yl] thionamic acid;
2-[(1,3-benzo dioxole-5-base carbonyl) amino]-3-cyano group-4-[(2-thienyl methyl) amino] quinoline-6-yl } thionamic acid;
3-cyano group-2-[(4-anisoyl) amino]-the 4-[(2-thienyl methyl) amino] quinoline-6-yl } thionamic acid;
And
Their salt, solvate, isomer (tautomer, desmotropic form) and their salt and solvate.
General formula of the present invention (I) compound and their salt, solvate and isomer (tautomer, desmotropic form, optically active isomer) and their salt, solvate, have suitable water-solublely, so they can be as the activeconstituents of medicinal compositions.
The solubleness of formula among the patent application WO 02/096879 (I) compound in Shui Heshui slowly-releasing solution (pH=6.5 and 7.5) is less than 1mg/L, yet the solubleness of general formula of the present invention (I) compound is between 1-200mg/L.
The present invention also relates to contain general formula (I) compound or their isomer (tautomer, desmotropic form, optically active isomer) and salt thereof or solvate as the activeconstituents medicinal compositions, these compositions are to be suitable for oral composition, but can suction, the medicinal compositions of parenteral and preparation capable of permeating skin form also is theme of the present invention.Above-mentioned medicinal compositions can be solid or liquid, as tablet, piller, capsule, patch, solution, suspension or emulsion.With regard to solids composition, most preferably be tablet and capsule.
Above-mentioned medicinal compositions can be by routine pharmaceutical excipient and adopt the standard method preparation.
General formula (I) compound can be used for the treatment of A 3The disease that acceptor plays an important role in advancing of disease.
The compounds of this invention is to A 3Acceptor has selectivity, can be used for the treatment of and/or prevent the dysfunction of the heart, kidney, respiratory system, central nervous system.They can suppress the provide protection of adenosine in growth of tumour cell, hinder the mastocyte threshing, suppress production of cytokines, reduce intraocular pressure, suppress TNF α discharge, suppress eosinophilic granulocyte, neutrophilic granulocyte and other immunocyte migration, suppress bronchoconstriction and plasmexhidrosis.
Based on these effects, adenosine A of the present invention 3Receptor antagonist is effective aspect following: anti-inflammatory, anti-asthma, anti-ischemia, antidepressant, anti-arrhythmia (antiarrhytmic), kidney protection, antitumor, anti-Parkinson and enhancing cognitive function.They also can be used for the treatment of or prevent cardiac muscle (miocardial) reperfusion injury, chronic obstructive pulmonary disease (COPD) and adult respiratory distress syndrome (ARDS), comprise chronic bronchitis, pulmonary emphysema or expiratory dyspnea, anaphylaxis is (as rhinitis, the reaction of toxicodendron inductive, rubella, scleroderma, sacroiliitis) and other autoimmune diseases, inflammatory bowel disease, Addison's disease, Crohn disease, psoriatic, rheumatosis, hypertension, nervous dysfunction, glaucoma and diabetes (K.N.Klotz, Naunyn-Schmiedberg ' s Arch.Pharmacol.362:382,2000; P.G.Baraldi é s P.A.Borea, TiPS 21:456,2000).
The compounds of this invention is preferred for the medicinal compositions of the following disease of production for treating: asthma, COPD and ARDS, glaucoma, tumour, allergy and inflammatory diseases, local asphyxia, histanoxia, arrhythmia (arrythmia) and ephrosis.
The invention further relates to the purposes of general formula (I) compound in the above-mentioned disease of treatment.The suggestion per daily dose is the 0.1-1000mg activeconstituents, and concrete dosage depends on the character of disease and seriousness and patient's sex, body weight etc.
Other theme of the present invention is the method for preparing general formula (I) compound.
The intermediate of general formula (I "), (II "), (III "), (IV "), (V "), (VI "), (VII "), (VIII "), (IX "), (X "), (XI "), (XII "), (XIII ") and (XIV ") and the substituting group of reagent are defined as follows:
R 1" represent hydrogen atom or straight or branched C 1-4Alkyl;
R 2" represent hydrogen atom or straight or branched C 1-4Alkyl;
R 3" represent hydrogen atom or straight or branched C 1-4Alkyl, C 3-6Cycloalkyl, phenyl, thienyl or furyl, optional by one or more straight or branched C 1-4Alkyl, straight or branched C 1-4The alkoxy or halogen atom replaces; Contain one, hexa-atomic or five yuan of hetero-aromatic rings of two or three nitrogen-atoms, or five yuan of hetero-aromatic rings, described hetero-aromatic ring contains a nitrogen-atoms and a Sauerstoffatom, and perhaps a nitrogen-atoms and a sulphur atom are optional by one or more straight or branched C 1-4Alkyl, straight or branched C 1-4The alkoxy or halogen atom replaces;
R 4" and R 5" independent hydrogen atom, the C of representing 3-6Cycloalkyl, straight or branched C 1-4Alkyl or blocking group, described alkyl is optional to contain amino, by one or two straight or branched C 1-4The amino that alkyl replaces, hydroxyl, carboxyl or by straight or branched C 1-4The alkoxyl group that alkyl replaces; Perhaps
R 4" represent hydrogen atom or straight or branched C 1-4Alkyl or benzyl, and
R 5" represent hydrogen atom ,-SO 2OH group or straight or branched C 1-4Acyl group or blocking group, perhaps
R 4" and R 5" form a nitro or general formula a. with nitrogen-atoms) group, wherein R 7" and R 8" independent hydrogen atom, the straight or branched C of representing 1-4Alkyl or C 3-6Cycloalkyl;
R 6" represent hydrogen atom or straight or branched C 1-4Alkyl, phenyl, benzyl, thienyl or furyl optional are replaced by methylene-dioxy, perhaps by one or more straight or branched C 1-4Alkyl, straight or branched C 1-4Alkoxyl group, hydroxyl, trifluoromethyl, cyano group or halogen atom replace; Perhaps hexa-atomic or five yuan of hetero-aromatic rings, described hetero-aromatic ring contains one, two or three nitrogen-atoms, and perhaps a nitrogen-atoms and a Sauerstoffatom, or a nitrogen-atoms and a sulphur atom are optional by one or more straight or branched C 1-4Alkyl, straight or branched C 1-4The alkoxy or halogen atom replaces;
X " representative-CH 2-group ,-the NH-group ,-NR 9"-group, perhaps sulphur atom, Sauerstoffatom, alkylsulfonyl or sulfonyloxy, wherein R 9" represent straight or branched C 1-4Alkyl or C 3-6Cycloalkyl;
Z " represention oxygen atom, sulphur atom ,-CHR 10"-group or-NR 11"-group, wherein R 10" represent hydrogen atom, straight or branched C 1-4Alkyl, perhaps C 3-6Cycloalkyl, and R 11" represent hydrogen atom, straight or branched C 1-4Alkyl, C 3-6Cycloalkyl ,-SO 2OH group, straight or branched C 1-4Acyl group or blocking group;
R 12" represent straight or branched C 1-3Alkyl;
Y " represent leavings group;
N " represent 0,1 or 2;
M " represent 1,2 or 3;
O " represent 1,2 or 3;
P " represent 0 or 1;
R " represent 0 or 1,
Further target of the present invention is the method for the intermediate of the new general formula of preparation general formula (I) compound and part (I "), (II "), (III "), (IV "), (V "), (VI "), (VII "), (VIII ") and (XIII ").
The method according to this invention
V.) with two-methane amide selective hydrolysis of general formula (II "), and if desired blocking group is removed, perhaps
V/i.) be preparation general formula (I) compound, wherein R 4Represent hydrogen atom, straight or branched C 1-4Alkyl or benzyl, and R 5Represent straight or branched C 1-4Acyl group, perhaps R 4And R 5Form general formula a. with nitrogen-atoms) group, wherein Z representative-NR 11Group, wherein R 11Represent straight or branched C 1-4Acyl group, and R 1, R 2, R 3, R 6, R 7, R 8, R 9, X, n, m, o, p and r define as mentioned,
With general formula (I) compound, wherein R 4Represent hydrogen atom, straight or branched C 1-4Alkyl or benzyl and R 5Represent hydrogen atom, perhaps R 4And R 5Form general formula a. with nitrogen-atoms) group, wherein Z representative-NH group and R 1, R 2, R 3, R 6, R 7, R 8, R 9, X, n, m, o, p and r define as mentioned, uses general formula R 12" COY " compound acylation, wherein R 12" and Y " definition as mentioned, perhaps
V/ii.) be preparation general formula (I) compound, wherein R 4Represent hydrogen atom, straight or branched C 1-4Alkyl or benzyl and R 5Representative-SO 2OH group, perhaps R 4And R 5Form general formula a. with nitrogen-atoms) group, wherein Z representative-NR 11-group, wherein R 11Representative-SO 2OH group, and R 1, R 2, R 3, R 6, R 7, R 8, R 9, X, n, m, o, p and r define as mentioned,
Make general formula (I) compound, wherein R 4Represent hydrogen atom, straight or branched C 1-4Alkyl or benzyl and R 5Represent hydrogen atom, perhaps R 4And R 5Form general formula a. with nitrogen-atoms) group, wherein Z representative-NH-group and R 1, R 2, R 3, R 6, R 7, R 8, R 9, X, n, m, o, p and r define as mentioned,
With pyridine-SO 3Mixture or ClSO 3The H reaction, or
V/iii.) be preparation general formula (I) compound, wherein R 4Represent hydrogen atom, straight or branched C 1-4Alkyl or benzyl and R 5Representative-SO 2OH group, and R 1, R 2, R 3, R 6, R 7, R 8, R 9, X, Z, n, m, o, p and r define as mentioned,
Make general formula (XIII ") compound, wherein R 1, R 2, R 3, R 6, R 9, X and n define as mentioned, with Na 2S 2O 4Or NaHSO 3Reaction,
Perhaps
Reduction and with the general formula that obtains (XIV ") compound, wherein R 4Represent hydrogen atom and R 1", R 2", R 3", R 6", R 9", X " and n " definition as mentioned, with pyridine-SO 3Mixture or ClSO 3The H sulfation,
If desired, above-mentioned being reflected at R 4" hydrogen atom is straight or branched C 1-4Carry out behind alkyl or the benzyl, perhaps
V/iv.) be preparation general formula (I) compound, wherein R 4Represent hydrogen atom, C 3-6Cycloalkyl, benzyl, straight or branched C 1-4Alkyl, this group is optional to contain amino, by one or two straight or branched C 1-4The amino that alkyl replaces, hydroxyl, carboxyl or by straight or branched C 1-4The alkoxyl group that alkyl replaces, and R 5Represent hydrogen atom, or
R 4And R 5Form general formula a. with nitrogen-atoms) group, wherein R 7And R 8The independent hydrogen atom, straight or branched C represented 1-4Alkyl or C 3-6Cycloalkyl and Z representative-NR 11Group, wherein R 11Represent hydrogen atom,
Remove the blocking group of general formula (I ") compound, wherein
R 4" represent hydrogen atom, C 3-6Cycloalkyl, benzyl, straight or branched C 1-4Alkyl, this group is optional to contain amino, by one or two straight or branched C 1-4The amino that alkyl replaces, hydroxyl, carboxyl or by straight or branched C 1-4The alkoxyl group that alkyl replaces, and R 5" represent blocking group, or
R 4" and R 5" form general formula a with nitrogen-atoms " .) group, wherein R 7" and R 8" the independent hydrogen atom, straight or branched C represented 1-4Alkyl or C 3-6Cycloalkyl and Z representative-NR 11" group, wherein R 11" represent blocking group,
And if desired, can transform mutually by the substituting group of known method general formula (I) compound that obtains, and/or the formula that will obtain like this (I) compound is converted into its salt or solvate, from they salt or solvate disengage, and if desired, it is split as their optically active isomer, and if desired, the desmotropic form that obtains can be converted into other mesomerism form.
With regard to the reagent of selective hydrolysis, can adopt alkaline hydrated oxide, preferably be dissolved in potassium hydroxide and/or sodium hydroxide in alcohol, the particular methanol, can certainly adopt other to help the reagent of amide hydrolysis at organic chemistry filed reagent.
Selective hydrolysis can carry out in very big temperature range, and preferred temperature is between 20 ℃-100 ℃.
Reaction v/i.) can adopt the derivative of the ester of suitable acid, under the temperature that raises, or adopt activated acid derivatives (as acid-halogenide), under the temperature of room temperature or rising, adopt suitable alkali (as triethylamine) to carry out.
Reaction v/ii.) can under the temperature of room temperature or rising, adopt pyridine-SO 3Mixture is in appropriate solvent (preferred pyridine in) or adopt ClSO 3H adopts strong organic bases (as DBU) or mineral alkali (as K in appropriate solvent (preferred pyridine or chloroform) 2CO 3) carry out.
Reaction v/iii.) can under the temperature (100 ℃) of room temperature or rising, in the alkaline aqueous solution of suitable nitro-compound, adopt excessive N a 2S 2O 4Or NaHSO 3Carry out as reagent.
According to the reaction v/iii.) alternative, by any method nitro-derivative is reduced, at first under known reduction alkanisation or henzylate condition with the aminoderivative alkylation or the benzylization that obtain, alkylamino that will obtain thus or benzylamino derivatives are as ii. then) as described in carry out sulfation.
Blocking group can be any known blocking group.The example of blocking group and protection and the method that removes various functional groups are as " Protective Groups in Organic Synthesis ", Green etc., 2d Edition*John Wiley ﹠amp; Sons, Inc, New York, 1991 is given.Preferred blocking group is Boc, ethoxy carbonyl, benzyloxycarbonyl etc., most preferably benzyl.
The substituting group of general formula (I) compound can transform (ComprehensiveOrganic Transformation, R.C.Larock, VCH Publisher, New York, 1989) by known method mutually.
Can be by in the alcohol of alkali, preferred alcohol solution, adding 1 normal acid, then with the ether dilution, leach at last and the dry crystal that obtains prepares salt.
General formula (II ') compound, wherein R 1", R 2", " R 3", R 4", R 5", R 6", R 7", R 8", X ", Z ", n ", o ", p ", r " and m " definition as mentioned, can be according to several known methods preparations, one of them method is reaction process 1 a described method, by the known process for acylating acidylate of organic chemistry formula (III ") compound.Preferred acyl chlorides as acid binding agent, can adopt triethylamine and/or pyridine, but also can adopt other known acid binding agent compounds as acylating agent.
General formula (III ") compound, wherein R 1", R 2", R 3", R 4", R 5", R 6", R 7", R 8", X ", Z ", n ", o ", p ", r " and m " definition as mentioned, can be according to known method (Nan Zhang, Bioorg.and Med.Chem.Lett., 10,2825,2000), by formula (IV ") compound.
General formula (IV ") compound, wherein R 4", R 5", R 6", R 7", R 8", X ", Z ", r ", o ", p " and m " definition as mentioned, can be according to currently known methods (D.L.Leysen, J.HeterocyclicChem., 24,1611,1987), by formula (V ") compound.
General formula (V ") compound, wherein R 4", R 5", R 7", R 8", Z ", r ", o ", p " and m " definition as mentioned, can be according to currently known methods (Pfizer (Inc) USP 4,175,193), by formula (VI ") compound.
General formula (VI ") compound, wherein R 4", R 5", R 7", R 8", Z ", r ", o ", p " and m " definition as mentioned, can be according to currently known methods (D.L Leysen, J.Heterocyclic Chem., 24,1611,1987), by formula (VII ") compound.
General formula (VII ") compound, wherein R 4", R 5", R 7", R 8", Z ", r ", o ", p " and m " as mentioned the definition, can be according to currently known methods (D.H.Klaubert and J.H.Sellstedt, J.Med.Chem, 24,742,1981), employing formula (VIII ") compound perhaps can directly be buied from market, as R wherein 4" and R 5" form the compound of a nitro with nitrogen-atoms.
General formula (VIII ") compound, wherein R 4", R 5", R 7", R 8", Z ", r ", o ", p " and m " definition as mentioned, can pass through currently known methods (J.H.Hutchinson and J.J.Cook, J.Med.Chem.39,4583,1996), by formula (IX ") compound.
Description of drawings
Fig. 1-Figure 15 is the structural formula of The compounds of this invention.
Figure 16 is the synthetic schemes of The compounds of this invention.
General formula of the present invention (I), (I '), (II "), (III "), (IV "), (V "), (VI "), (VII "), (VIII "), (XIII ") and (XIV ") compound; and their preparation method and biological activity be as described in the embodiment hereinafter, but scope of the present invention is not limited to embodiment.
Embodiment
Embodiment 1.
4-methoxyl group-N-[6-(morpholine-4-yl)-4-benzylamino-3-cyano quinolines-2-yl] benzamide
In general formula (I), R 1And R 2Represent hydrogen atom, R 3Represent phenyl, group a.) represent morpholine-4-base, R 6Represent the 4-p-methoxy-phenyl.
A.) 2-nitro-5-(morpholine-4-yl) phenylformic acid:
In 120 ℃, the mixture of the morpholine of the 2-nitro-5-chlorinated benzene formic acid of 5g and 15ml was stirred 6 hours.In reaction mixture, add the 150ml ethyl acetate.Filter out the yellow crystals species precipitate, be dissolved in 15ml water.With the pH regulator to 6 of acetate with mixture, sedimentable matter is leached, wash with water and drying, obtain the 4.2g target compound.Mp.：172℃。
1H-NMR(DMSO-d 6)7.85?ppm(m，1H)，7.0-6.9(m，2H)，3.67(m，4H)，2.85(m，4H)。
B.) 2-amino-5-(morpholine-4-yl) phenylformic acid:
Under reflux conditions, with the mixture of 2-nitro-5-(morpholine-4-yl) phenylformic acid, 15ml tetrahydrobenzene and the 3g Pd/C (10%) of 6g reflux 6 hours in 120ml ethanol.With thermal reaction mixture through the kieselguhr filter filtering.Evaporated filtrate obtains the 4.8g target compound.M.p.：242℃。
1H-NMR(DMSO-d 6)7.25?ppm(m，1H)，6.96(m，1H)，6.62(m，1H)，3.69(m，4H)，2.85(m，4H)。
C) 5-(morpholine-4-yl) isatoic anhydride:
Under stirring and the cooling of outside cold water, in the mixture of the benzoic 60ml two  alkane of the 2-of 8.9g amino-5-(morpholine-4-yl), drip the 10ml trichloromethylchloroformate.Under reflux conditions, with mixture heating up 4 hours.In the self cooled reaction mixture, leach solid matter, with the washing of 50ml ether.In the mixture of 50ml methyl alcohol and 5ml triethylamine, stir product 5 minutes, leach and use the 30ml methanol wash then.After the drying, obtain the 7g target product, m.p.:235 ℃. 1H-NMR(DMSO-d 6)7.8ppm(m，1H)，6.78(m，1H)，6.66(m，1H)，3.73(m，4H)，2.92(m，4H)。
D) 2-amino-3-cyano group-4-hydroxyl-6-(morpholine-4-yl) quinoline:
The 4g propane dinitrile is dissolved in the dimethyl formamide of 50mL.In solution, divide several parts of oil dispersions that add 14g 60% sodium hydride.In settled solution, add 8g 5-(morpholine-4-yl) isatoic anhydride and mixture was stirred under room temperature 10 hours.Reaction mixture is with the dilution of the water of 70mL and with the ethyl acetate extraction of 2 * 30mL.Vacuum-evaporation water, solid residue are dissolved in the 20mL water, with acetate the pH value are adjusted to 6.Sedimentable matter is leached, wash with water.Obtain the 6.5g target compound after the drying, m.p.:291 ℃. 1H-NMR(DMSO-d 6)7.27ppm(m，1H)，7.14(m，1H)，7.03(m，1H)，3.74(m，411)，3.12(m，4K)。
E.) 2-amino-3-cyano group-4-chloro-6-(morpholine-4-yl) quinoline:
1.7g 2-amino-3-cyano group-4-hydroxyl-6-(morpholine-4-yl) quinoline and 3.4mL phosphoryl chloride mixture were stirred 4 hours in 120 ℃.With the refrigerative reaction mixture incline to 30g on ice, regulate mixture pH value to 8 with 10% sodium hydroxide solution, and leach sedimentable matter.Obtain target compound 1.5g after the drying, m.p.:206 ℃. 1H-NMR(DMSO-d 6)7.69ppm(m，1H)，7.49(m，1H)，7.08(m，1H)，6.83(s，2H)，3.74(m，4H)，3.08(M，4H)。
F) 2-amino-3-cyano group-4-benzylamino-6-(morpholine-4-yl) quinoline:
In 125 ℃, the benzyl amine of 3g 2-amino-3-cyano group-4-chloro-6-(morpholine-4-yl) quinoline and 6mL was stirred 3 hours.Reaction mixture is inclined to the water of 30mL.Leach sedimentable matter, use the 20ml water washing.Obtain target compound 2.3g after the drying, m.p.:202 ℃. 1H-NMR(DMSO-d 6)8.14ppm(m，1H)，7.5-7.2(m，8H)，5.85(s，2H)，5.04(d，2H)，3.65(m，4H)，3.1(m，4H)。
G.) 1-methoxyl group-N-(4-anisoyl)-N-((6-morpholine-4-yl)-4-benzylamino-3-cyano quinolines-2-yl) benzamide:
In stir and cooling down, in the pyridine solution of the 2mL of 0.4g 2-amino-3-cyano group-4-benzylamino-6-(morpholine-4-yl) quinoline, add the 4-methoxy benzoyl chloride of 0.4mL.In 80 ℃, stirred reaction mixture 8 hours inclines then to ice-water of 5mL.Leach sedimentable matter, twice of the water washing of usefulness 3mL.Obtain target compound 0.53g after the drying, m.p.:157 ℃. 1H-NMR(DMSO-d 6)8.92ppm(t，1H)，8.32(m，4H)，7.61(m，3H)，7.38(m，5H)，7.12(m，4H)，5.1(d，2H)，3.82(m，8H)。
H.) benzamide 4-methoxyl group-N-[(6-(morpholine-4-yl)-N-4-benzylamino-3-cyano quinolines-2-yl)];
The 1N hydrogen from methyl alcohol potassium oxide solution that in the 20mL acetonitrile solution of 2.3g 4-methoxyl group-N-(4-anisoyl)-N-(6-(morpholine-4-yl)-4-benzylamino-3-cyano quinolines-2-yl) benzamide, adds 5mL.Under refluxing, reflux reaction mixture 10 minutes, the glacial acetic acid of adding 1.5mL, the 1M sodium hydrogen carbonate solution with 15mL neutralizes then.Leach precipitation, the yellow crystals material is from dimethyl formamide and the 40mL alcohol mixture recrystallize of 5mL.Obtain target compound 1.3g after the drying, m.p.:260 ℃. 1H-NMR(DMSO-d 6)10.5ppm(s，1H)，8.92(t，1H)，8.4(m，2H)，7.66(m，3H)，7.35(m，5H)，7.05(，2H)，5.1(d，2H)，3.82(m，8H)。
Embodiment 2.
4-methoxyl group-N-[6-(4-methylpiperazine-1-yl)-4-benzylamino-3-cyano quinolines-2-yl] benzamide
In general formula (I), R 1And R 2Represent hydrogen atom, R 3Represent phenyl, group a.) represent 4-methylpiperazine-1-base, R 6Represent the 4-p-methoxy-phenyl.
A.) 2-nitro 5-(4-methylpiperazine-1-yl) phenylformic acid:
In 120 ℃, the mixture of the N methyl piperazine of 10g 2-nitro-5-chlorinated benzene formic acid and 30mL was stirred 6 hours.The ethyl acetate that in reaction mixture, adds 150mL.Leach sedimentary yellow crystals material, be dissolved in 15mL water.With the pH regulator to 6 of acetate with mixture.Leach sedimentable matter, wash with water and drying, obtain the 11.2g target compound.Mp.：212℃。 1H-NMR(DMSO-d 6)7.89ppm(d，1H)，7.03-6.93(m，2H)，3.7-3.45(m，8H)，2.25(s，3H)。
B.) 2-amino-5-(4-methylpiperazine-1-yl) phenylformic acid:
Under reflux conditions, the mixture of 9g 2-nitro-5-(4-methylpiperazine-1-yl) phenylformic acid, 20mL tetrahydrobenzene and 3.5g Pd/C (10%) was heated 6 hours in 120mL ethanol.Through Celite pad filtering thermal reaction mixture.Evaporated filtrate obtains the 3.5g target compound.M.p.：212℃。 1H-NMR(DMSO-d 6)7.19ppm(d，1H)，7.06(m，1H)，6.69(d，1H)，2.9(m，4H)，2.43(m，4H)，2.22(s，3H)。
C.) 5-(4-methylpiperazine-1-yl) isatoic anhydride:
Under stirring and the cooling of outside cold water, in the two  alkylating mixtures of the benzoic 30mL of 5.3g 2-amino-5-(4-methylpiperazine-1-yl), be added dropwise to the 6mL trichloromethylchloroformate.In refluxing down heated mixt 4 hours.Leach solid matter in the self cooled reaction mixture, with the washing of 50mL ether.Product was stirred 5 minutes in the mixture of the triethylamine of 50mL methyl alcohol and 5mL, leach, use the 30mL methanol wash.Obtain the 5.4g target product after the drying, m.p.:285 ℃. 1H-NMR(DMSO-d 6)7.81ppm(m，1H)，6.73(m，1H)，6.62(m，1H)，3.73-2.92(m，8H)，2.23(s，3H)。
D.) 2-amino-3-cyano group-4-hydroxyl-6-(4-methylpiperazine-1-yl) quinoline:
The 2g propane dinitrile is dissolved in the dimethyl formamide of 30mL.Mark part adds the oil dispersion of 60% sodium hydride of 1.3g in solution.5-(4-methylpiperazine-1-yl) isatoic anhydride that in settled solution, adds 6.5g, and mixture stirred under room temperature 10 hours.Reaction mixture is with the dilution of 70mL water and with the ethyl acetate extraction of 2 * 30mL.Vacuum-evaporation water, solid residue are dissolved in 20mL water, with acetate the pH value are adjusted to 6.Leach sedimentable matter, wash with water.Obtain target compound 5.2g after the drying, m.p.:156 ℃. 1H-NMR(DMSO-d 6)7.23ppm(m，1H)，7.12(m，1H)，7.03(m，1H)，3.65-2.83(m，8)，2.1(s，3H)。
E.) 2-amino-3-cyano group-4-chloro-6-(4-methylpiperazine-1-yl) quinoline:
In 120 ℃, the mixture of the phosphoryl chloride of 2-amino-3-cyano group-4-hydroxyl-6-(4-methylpiperazine-1-yl) quinoline of 2g and 4mL was stirred 4 hours.With the refrigerative reaction mixture incline to 40g on ice, with 10% sodium hydroxide solution mixture pH value is adjusted to 8, leach sedimentable matter.Obtain target compound 1.5g after the drying, m.p.:189 ℃. 1H-NMR(DMSO-d 6)7.69ppm(m，1H)，7.49(m，1H)，7.08(m，1H)，6.83(s，2H)，3.25-2.57(m，8H)，2.29(s，3H)。
F.) 2-amino-3-cyano group-4-benzylamino-6-(4-methylpiperazine-1-yl) quinoline:
In 125 ℃, the benzyl amine of 3g 2-amino-3-cyano group-4-chloro-6-(4-methylpiperazine-1-yl) quinoline and 6mL was stirred 3 hours.Reaction mixture is inclined to 30mL water.Leach sedimentable matter, use the 20mL water washing.Obtain target compound 2.3g after the drying, m.p.:176 ℃. 1H-NMR(DMSO-d 6)8.5ppm(t，1H)，7.5-7.15(m，8H)，5.85(s，2H)，5.04(d，2H)，3.65-3.12(m，8H)，2.23(s，3H)。
G.) 4-methoxyl group-N-(4-anisoyl)-N-[6-(4-methylpiperazine-1-yl)-4-benzylamino-3-cyano quinolines-2-yl] benzamide:
Stir and cooling under, in the pyridine solution of the 2mL of 0.6g 2-amino-3-cyano group-4-benzylamino-6-(4-methylpiperazine-1-yl) quinoline, add the 4-methoxy benzoyl chloride of 0.6mL.In 80 ℃, stirred reaction mixture 8 hours inclines then to the frozen water of 5mL.Leach sedimentable matter, with 3mL water washing 2 times.Obtain target compound 0.63g after the drying, m.p.:176 ℃. 1H-NMR(DMSO-d 6)8.39ppm(m，1H)，7.95(m，2H)，7.47(m，5H)，7.32(m，5H)，7.14(m，4H)，5.1(m，2H)，3.82(s，3H)，3.52-2.98(m，8H)，2.25(s，3H)。
H.) 4-methoxyl group-N-[6-(4-methylpiperazine-1-yl)-4-benzylamino-3-cyano quinolines-2-yl] benzamide
The 1N hydrogen from methyl alcohol potassium oxide solution that in the acetonitrile solution of 2.3g 4-methoxyl group-N-(4-anisoyl)-N-(6-(4-methylpiperazine-1-yl)-4-benzylamino-3-cyano quinolines-2-yl) benzamide and 15mL, adds 4mL.Under refluxing, reacting by heating mixture 10 minutes, the glacial acetic acid of adding 1mL, the 1M sodium hydrogen carbonate solution with 12mL neutralizes then.Leach precipitation, recrystallize yellow crystals material in the mixture of the methyl alcohol of 15mL and 35mL water.Obtain target compound 1.1g after the drying, m.p.:173 ℃. 1H-NMR(DMSO-d 6)10.53ppm(m，1H)，8.39(m，1H)，7.95(m，2H)，7.57(m，3H)，7.34(m，5H)，7.04(m，2H)，5.1(m，2H)，3.82(s，3H)，3.52-2.98(m，8H)，2.25(s，3H)。
Embodiment 3.
4-methoxyl group-N-(6-dimethylamino-4-benzylamino-3-cyano quinolines-2-yl) benzamide
In general formula (I), R 1And R 2Represent hydrogen atom, R 3Represent phenyl, group a.) represent dimethylamino, R 6Represent the 4-p-methoxy-phenyl.
A.) 2-nitro-5-dimethylaminobenzoic acid:
In 100 ℃, the mixture of the 60% dimethyl amine aqueous solution of 5g 2-nitro-5-chlorinated benzene formic acid and 15mL was stirred 6 hours.Evaporation reaction mixture, residue are dissolved in 15mL water.With acetate with mixture pH regulator to 6.Leach sedimentary yellow crystals material, wash with water and drying, obtain the 3.4g target compound.Mp.：189℃。 1H-NMR(DMSO-d 6)7.78?ppm(d，1H)，6.59(m，1H)，6.48(m，1H)，3.0(s，6H)。
B.) 2-amino-5-dimethylaminobenzoic acid:
In refluxing down, the tetrahydrobenzene of 2.1g 2-nitro-5-dimethylaminobenzoic acid, 7mL and the mixture of 1.5gPd/C (10%) were heated 6 hours in 60mL ethanol.Thermal reaction mixture filters through Celite pad.Evaporated filtrate obtains the 1.1g target compound.M.p.：232℃。 1H-NMR(DMSO-d 6)7.01ppm(m，1H)，6.84(m，1H)，6.78(m，1H)，2.88(s，6H)。
C.) 5-dimethylamino isatoic anhydride:
In stirring and outside cold water cooling time, in the two  alkylating mixtures of the 60mL of 8.9g 2-amino-5-dimethylaminobenzoic acid, be added dropwise to the 10mL trichloromethylchloroformate.In refluxing down heated mixt 4 hours.Leach solid matter in the self cooled reaction mixture, with the washing of 50mL ether.In the triethylamine mixture of the methyl alcohol of 50mL and 5mL, stir product 5 minutes, leach, use the 30mL methanol wash.Obtain the 7g target product after the drying, m.p.:258 ℃. 1H-NMR(DMSO-d 6)7.56ppm(m，1H)，7.42(m，1H)，7.13(m，1H)，2.97(s，6H)。
D.) 2-amino-3-cyano group-4-hydroxyl-6-dimethylamino quinoline:
Portioning adds 60% oil dispersion of 2.4g sodium hydride in the dimethyl formamide solution of the 50mL of 4g propane dinitrile.In settled solution, add 8g 5-dimethylamino isatoic anhydride, and under room temperature, stirred the mixture 10 hours.With mixture with the dilution of 70mL water and with the ethyl acetate extraction of 2 * 30mL.Water vacuum-evaporation, solid residue are dissolved in 20mL water, and the pH value is adjusted to 6 with acetate.Leach sedimentable matter, wash with water.Obtain target compound 6.5g after the drying, m.p.:360 ℃. 1H-NMR(DMSO-d 6)7.43ppm(m，1H)，7.23(m，1H)，7.11(m，1H)，2.95(s，6H)。
E.) 2-amino-3-cyano group-4-chloro-6-dimethylamino quinoline:
In 120 ℃, the phosphoryl chloride mixture of 1.7g 2-amino-3-cyano group-4-hydroxyl-6-dimethylamino quinoline and 3.4mL was stirred 4 hours.With the refrigerative reaction mixture incline to 30g on ice, regulate mixture pH value to 8 with 10% sodium hydroxide solution, and sedimentable matter leached.Obtain target compound 1.5g after the drying, m.p.:285 ℃. 1H-NMR(DMSO-d 6)7.43ppm(mm，1H)，7.21(m，1H)，7.05(m，1H)，6.75(s，2H)，2.99(s，6H)。
F.) 2-amino-3-cyano group-4-benzylamino-6-dimethylamino quinoline:
Stirred 3 hours in 125 ℃ of benzyl amine 3g 2-amino-3-cyano group-4-chloro-6-dimethylamino quinoline and 6mL.Reaction mixture inclines to 30mL water.Leach sedimentable matter, use the 20mL water washing.Obtain target compound 2.3g after the drying, m.p.:265 ℃. 1H-NMR(DMSO-d 6)8.55-8.45ppm(m，2H)，7.8(m，1H)，7.5-7.23(m，7H)，6.25(s，2H)，5.08(d，2H)，2.99(s，6H)。
G.) 4-methoxyl group-N-(4-anisoyl)-N-(6-dimethylamino-4-benzylamino-3-cyano quinolines-2-yl) benzamide:
In stir and cooling down, in the pyridine solution of the 2mL of 0.4g 2-amino-3-cyano group-4-benzylamino-6-dimethylamino quinoline, add the 4-methoxy benzoyl chloride of 0.4mL.In 80 ℃, stirred reaction mixture 8 hours inclines then to ice-water of 5mL.Leach sedimentable matter, with 3mL water washing 2 times.Obtain target compound 0.53g after the drying, m.p.:156 ℃. 1H-NMR(DMSO-d 6)8.35ppm(m，1H)，7.9(m，2H)，7.47(m，5H)，7.3(m，5H)，7.1(m，4H)，5.12(m，2H)，3.82(s，3H)，3.0(s，6H)。
H.) 4-methoxyl group-N-(6-dimethylamino-4-benzylamino-3-cyano quinolines-2-yl) benzamide
The 1N hydrogen from methyl alcohol potassium oxide solution that in the acetonitrile solution of the 20mL of 2.3g 4-methoxyl group-N-(4-anisoyl)-N-(6-dimethylamino-4-benzylamino-3-cyano quinolines-2-yl) benzamide, adds 5mL.The reacting by heating mixture is 10 minutes under refluxing, and adds the glacial acetic acid of 1.5mL, and the 1M sodium hydrogen carbonate solution with 15mL neutralizes then.Leach precipitation, in the alcoholic acid mixture of the dimethyl formamide of 5mL and 40mL with yellow crystals material recrystallize.Obtain the 1.3g target compound after the drying, m.p.:185 ℃. 1H-NMR(DMSO-d 6)10.5ppm(m，1H)，8.35(m，1H)，7.91(m，2H)，7.53(m，3H)，7.3(m，5H)，7.02(m，2H)，5.1(m，2H)，3.85(s，3H)，3.0(s，6H)。
Embodiment 4
4-methoxyl group-N-(6-dimethylamino-4-[2-furyl methyl amino]-3-cyano quinolines-2-yl) benzamide
In general formula (I), R 1And R 2Represent hydrogen atom, R 3Represent 2-furyl amino, group a.) represent dimethylamino, R 6Represent the 4-p-methoxy-phenyl.
A.) 2-amino-3-cyano group-4-[2-furyl methyl amino]-6-dimethylamino quinoline:
In 125 ℃, the furfuryl group amine of 3g 2-amino-3-cyano group-4-chloro-6-dimethylamino quinoline and 6mL was stirred 3 hours.Reaction mixture is inclined to 30mL water.Leach sedimentable matter, use the 20mL water washing.Obtain target compound 2.05g after the drying, m.p.:235 ℃. 1H-NMR(DMSO-d 6)8.7ppm(m，1H)，7.6(m，1H)，7.35-7.23(m，3H)，6.8(s，2H)，6.4(m，2H)，5.06(d，2H)，2.96(s，6H)。
B.) 4-methoxyl group-N-(4-anisoyl)-N-(6-dimethylamino-4-[2-furyl methyl amino]-3-cyano quinolines-2-yl) benzamide:
In stir and cooling down, to 0.4g 2-amino-3-cyano group-4-[2-furyl methyl amino]-add the 4-methoxy benzoyl chloride of 0.4mL in the pyridine solution of the 2mL of 6-dimethylamino quinoline.In 80 ℃ of stirred reaction mixtures 8 hours, incline then to ice-water of 5mL.Leach sedimentable matter, with 3mL water washing 2 times.Obtain target compound 0.5g after the drying, m.p.:143 ℃. 1H-NMR(DMSO-d 6)8.35ppm(m，1H)，7.9-7.1(m，14H)，5.12(m，2H)，3.82(s，6H)，3.0(s，6H)。
C.) 4-methoxyl group-N-(6-dimethylamino-4-[2-furyl methyl amino]-3-cyano quinolines-2-yl) benzamide;
In the 20mL acetonitrile solution of 2.3g 4-methoxyl group-N-(4-anisoyl)-N-(6-dimethylamino-4-[2-furyl methyl amino]-3-cyano quinolines-2-yl) benzamide, add the 1N hydrogen from methyl alcohol potassium oxide solution of 5mL.Under refluxing, reacting by heating mixture 10 minutes, the glacial acetic acid of adding 1.5mL, the 1M sodium hydrogen carbonate solution with 15mL neutralizes then.Leach precipitation, recrystallize yellow crystals material in the alcoholic acid mixture of the dimethyl formamide of 5mL and 40mL.Obtain target compound 1.1g after the drying, m.p.:195 ℃. 1H-NMR(DMSO-d 6)10.5ppm(m，1H)，8.25(t，1H)，7.98(m，2H)，7.63-7.03(m，7H)，6.42(d，1H)，5.04(d，2H)，3.85(s，3H)，3.05(s，6H)。
Embodiment 5
4-methoxyl group-N-(6-dimethylamino-4-[2-thienyl methyl amino]-3-cyano quinolines-2-yl) benzamide
In general formula (I), R 1And R 2Represent hydrogen atom, R 3Represent 2-thienyl methyl amino, group
A.) represent dimethylamino, R 6Represent the 4-p-methoxy-phenyl.
A.) 2-amino-3-cyano group-4-[2-thienyl methyl amino]-6-dimethylamino quinoline:
Under 125 ℃, 3g 2-amino-3-cyano group-4-chloro-6-dimethylamino quinoline and 6mL 2-thienyl methyl amine were stirred 3 hours.Reaction mixture inclines to 30mL water.Leach sedimentable matter, use the 20mL water washing.Obtain the 1.9g target compound after the drying, m.p.:211 ℃. 1H-NMR(DMSO-d 6)8.2ppm(m，1H)，7.46-6.95(m，6H)，6.08(s，2H)，5.18(d，2H)，2.94(s，6H)。
B.) 4-methoxyl group-N-(4-anisoyl)-N-(6-dimethylamino-4-[2-thienyl methyl amino]-3-cyano quinolines-2-yl) benzamide:
In stir and cooling down, to 0.4g 2-amino-3-cyano group-4-[2-thienyl methyl amino]-the 2mL pyridine solution of 6-dimethylamino quinoline in, add the 4-methoxy benzoyl chloride of 0.4mL.In 80 ℃ of stirred reaction mixtures 8 hours, incline then to ice-water of 5mL.Leach sedimentable matter, with 3mL water washing 2 times.Obtain the 0.43g target compound after the drying, m.p.:171 ℃. 1H-NMR(DMSO-d 6)8.35ppm(m，1H)，7.9-7.05(m，14H)，5.12(m，2H)，3.82(s，6H)，3.0(s，6H)。
C.) 4-methoxyl group-N-(6-dimethylamino-4-[2-thienyl methyl amino]-3-cyano quinolines-2-yl) benzamide
In the 20mL acetonitrile solution of 2.3g 4-methoxyl group-N-(4-anisoyl)-N-(6-dimethylamino-4-[2-thienyl methyl amino]-3-cyano quinolines-2-yl) benzamide, add the 1N hydrogen from methyl alcohol potassium oxide solution of 5mL.The reacting by heating mixture is 10 minutes under refluxing, and adds the glacial acetic acid of 1.5mL, and the 1M sodium hydrogen carbonate solution with 15mL neutralizes it then.Leach precipitation, the yellow crystals material is from the dimethyl formamide of 5mL and the alcohol mixture recrystallize of 40mL.Obtain the 1.15g target compound after the drying, m.p.:163 ℃. 1H-NMR(DMSO-d 6)10.5ppm(m，1H)，8.3(t，1H)，7.98(m，2H)，7.63-6.96(m，8H)，5.2(d，2H)，3.85(s，3H)，3.05(s，6H)。
Embodiment 6
4-methoxyl group-N-[6-(piperazine-1-yl)-4-benzylamino-3-cyano quinolines-2-yl] benzamide
In general formula (I), R 1And R 2Represent hydrogen atom, R 3Represent phenyl, group a.) represent piperazine-1-base, R 6Represent the 4-p-methoxy-phenyl.
A.) 2-nitro-5-(4-benzyl diethylenediamine-1-yl) phenylformic acid:
In 120 ℃ 20g 2-nitro-5-chlorinated benzene formic acid and 50mL N-benzyl diethylenediamine mixture were stirred 6 hours.The ethyl acetate that in reaction mixture, adds 250mL.Leach sedimentary yellow crystals material, be dissolved in 200mL water.Mixture pH value is adjusted to 6 with acetate.Leach sedimentable matter, wash with water and drying, obtain 30 g target compounds.Mp.：172℃。 1H-NMR(DMSO-d 6)7.8-6.7ppm(m，8H)，3.5(s，2H)，3.5-2.8(m，8H)。
B.) 2-amino-5-(4-benzyl diethylenediamine-1-yl) phenylformic acid:
In refluxing down, with 6g 2-nitro-5-(4-benzyl diethylenediamine-1-yl) phenylformic acid, the tetrahydrobenzene of 15mL and 3g Pd/C (10%) mixture heated 6 hours in 120mL ethanol.Thermal reaction mixture filters through the diatomite filter bed.Evaporated filtrate obtains the 4.8g target compound.M.p.：242℃。 1H-NMR(DMSO-d 6)7.5-6.8ppm(m，8H)，3.68(s，3H)，3.5-2.95(m，8H)。
C.) 5-(4-benzyl diethylenediamine-1-yl) isatoic anhydride:
Under stirring and the cooling of outside cold water, in the benzoic 90mL two  alkylating mixtures of 15g 2-amino-5-(4-benzyl diethylenediamine-1-yl), drip the 12.7mL trichloromethylchloroformate.In refluxing down with mixture heating up 4 hours.In cold reaction mixture, leach solid matter, with the washing of 120mL ether.In the triethylamine mixture of the methyl alcohol of 100mL and 10mL, product was stirred 5 minutes, leach and use the 50mL methanol wash.Obtain the 17g target product after the drying, m.p.:235 ℃. 1H-NMR(DMSO-d 6)7.68-7.1ppm(m，8H)，3.6(s，2H)，3.5-2.5(m，8H)。
D.) 2-amino-3-cyano group-4-hydroxyl-6-(4-benzyl diethylenediamine-1-yl) quinoline:
The 6.1g propane dinitrile is dissolved in the dimethyl formamide of 100mL.In solution, divide several parts of oil dispersions that add 3.6g 60% sodium hydride.In settled solution, add 18g 5-(4-benzyl diethylenediamine-1-yl) isatoic anhydride and mixture was stirred under room temperature 10 hours.Reaction mixture is with the dilution of 100mL water and with the ethyl acetate extraction of 2 * 50mL.Vacuum-evaporation water, solid residue are dissolved in 50mL water, and the pH value is adjusted to 6 and refluxed 5 hours with acetate.Leach sedimentable matter after the cooling, wash with water.Obtain the 14.3g target compound after the drying, m.p.:291 ℃. 1H-NMR(DMSO-d 6)7.7-6.5ppm(m，10H)，4.2(s，2H)，3.5-2.5(m，8H)。
E.) 2-amino-3-cyano group-4-chloro-6-(4-benzyl diethylenediamine-1-yl) quinoline:
Under 120 ℃, the phosphoryl chloride mixture of 14g 2-amino-3-cyano group-4-hydroxyl-6-(4-benzyl diethylenediamine-1-yl) quinoline and 28mL was stirred 6 hours.The refrigerative reaction mixture incline to 500g on ice, mixture pH value is adjusted to 8 with 10% sodium hydroxide solution, and leaches sedimentable matter.Obtain the 14.5g target compound after the drying, m.p.:206 ℃. 1H-NMR(DMSO-d 6)7.7-7.14ppm(m，8H)，6.9(s，2H)，3.7(s，2H)，3.5-2.5(m，8H)。
F.) 2-amino-3-cyano group-4-benzylamino-6-(4-benzyl diethylenediamine-1-yl) quinoline:
Under 125 ℃, the benzyl amine of 14g 2-amino-3-cyano group-4-chloro-6-(4-benzyl diethylenediamine-1-yl) quinoline and 28mL was stirred 4 hours.Reaction mixture inclines to 100mL water.Leach sedimentable matter, with 2 * 50mL water washing.Obtain the 8g target compound after the drying, m.p.:202 ℃. 1H-NMR(DMSO-d 6)8.1ppm(m，1H)，7.5-7.2(m，13H)，5.8(s，2H)，5.0(d，2H)，3.54(s，2H)，3.5-2.5(m，8H)。
G.) 4-methoxyl group-N-(4-anisoyl)-N-(6-(4-benzyl diethylenediamine-1-yl)-4-benzylamino-3-cyano quinolines-2-yl) benzamide:
In stir and cooling down, in the acetate second solution ester of the triethylamine that contains 0.3mL of the 5mL of 0.9g 2-amino-3-cyano group-4-benzylamino-6-(4-benzyl diethylenediamine-1-yl) quinoline, add the 4-methoxy benzoyl chloride of 0.5mL.In 80 ℃, stirred reaction mixture 8 hours inclines then to ice-water of 10mL.Leach sedimentable matter, with 3mL water washing 2 times.Obtain the 0.53g target compound after the drying, m.p.:157 ℃. 1H-NMR(DMSO-d 6)8.92ppm(t，1H)，8.32(m，4H)，7.61(m，3H)，7.38(m，5H)，7.12(m，4H)，5.1(d，2H)，3.82(s，6H)，3.56(s，2H)，3.5-2.5(m，8H)。
H.) 4-methoxyl group-N-[(6-(4-benzyl diethylenediamine-1-yl)-4-benzylamino-3-cyano quinolines-2-yl] benzamide
The 1N hydrogen from methyl alcohol potassium oxide solution that in the acetonitrile solution of the 20mL of 2.0g 4-methoxyl group-N-(4-anisoyl)-N-(6-(4-benzyl diethylenediamine-1-yl)-4-benzylamino-3-cyano quinolines-2-yl) benzamide, adds 4mL.The reacting by heating mixture is 10 minutes under refluxing, and adds the glacial acetic acid of 1.5mL, and the 1M sodium hydrogen carbonate solution with 15mL neutralizes then.Precipitation leaches, recrystallize yellow crystals material in the alcohol mixture of the dimethyl formamide of 5mL and 40mL.Obtain the 1.3g target compound after the drying, m.p.:260 ℃. 1H-NMR(DMSO-d 6)10.5ppm(s，1H)，8.92(t，1H)，7.97-7.01(m，17H)，5.1(d，2H)，3.82(s，3H)，3.56(s，2H)，3.5-2.5(m，8H)。
I.) benzamide 4-methoxyl group-N-[(6-(piperazine-1-yl)-4-benzylamino-3-cyano quinolines-2-yl)]
With 1g 4-methoxyl group-N-[(6-(4-benzyl diethylenediamine-1-yl)-4-benzylamino-3-cyano quinolines-2-yl] benzamide is dissolved in the dimethyl formamide and water of the acetate that contains 0.5mL, and in 45 ℃, hydrogenation is 4 hours in the presence of 50mgPd/C (10%).After leaching catalyzer and evaporating solvent, through chromatography purification crude product product, obtain the 0.65g target compound, mp:145 ℃. 1H-NMR(DMSO-d 6)10.5ppm(s，1H)，8.48(m，1H)，7.94(m，2H)，7.6-7.35(m，2H)，7.33(s，5H)，7.24(m，1H)，7.02(m，2H)，5.08(d，2H)，3.83(s，3H)，3.22(m，4H)，2.86(m，4H)。
Embodiment 7
N-[6-amino-4-(benzylamino)-3-cyano quinolines-2-yl]-the 4-methoxy benzamide
In general formula (I), R 1And R 2Represent hydrogen atom, R 3Represent phenyl, NR 4R 5Represent NH 2, R 6Represent the 4-p-methoxy-phenyl.
A) 5-nitro isatoic anhydride:
In stirring down, in the 500mL of 37g 2-amino-5-nitrobenzoic acid two  alkylating mixtures, be added dropwise to the 24.5mL trichloromethylchloroformate.In refluxing down, heated mixt was evaporated to dried in 6 hours then.Residue is suspended in the ether of 100mL and leaches, and obtains the 41.4g target product, is hydrochloride, m.p.:256-259 ℃.LC-MS:MH +209; Retention time: 5.00 minutes. 1H-NMR(DMSO-d 6)8.54(d，1H)，8.46(dd，1H)，7.37(d，1H)ppm。
B) 2-amino-3-cyano group-4-hydroxyl-6-nitroquinoline:
In the DMF solution of the 230mL of 47.25g 5-nitro isatoic anhydride, add the triethylamine of 15g propane dinitrile and 63.3mL, in 60 ℃, stirred reaction mixture 2 hours.Solvent evaporated under reduced pressure, residue mixes with the acetonitrile of 570mL and the concentrated hydrochloric acid of 114mL.Stirred solution spends the night under room temperature.Leach precipitation then, water and washing with alcohol obtain the 49.7g product, m.p.:＞360 ℃.LC-MS:MH +231; Retention time: 4.78 minutes. 1H-NMR(DMSO-d 6)8.64(d，1H)，8.36(dd，1H)，7.6(s，2H)，7.55(d，1H)ppm。
C) 2-amino-3-cyano group-4-chloro-6-nitroquinoline:
The 48.5g 2-amino-3-cyano group-4-hydroxyl-6-nitroquinoline of stirring and the phosphoryl chloride mixture of 550mL were refluxed 4 hours.Concentrated reaction mixture is to half of its volume, and with residue incline to 1500g on ice.Leach yellow mercury oxide, wash with water, obtain the 60.5g solid.In under the room temperature this solid of 25g being stirred 6 hours in the 0.5N of 500mL HCl, leach precipitation then, wash with water, obtain the 18.5g product, m.p.:＞360 ℃.LC-MS:MH +249; Retention time: 5.94 minutes. 1H-NMR(DMSO-d 6)8.73(d，1H)，8.48(dd，1H)，7.92(d，1H)ppm。
D) 2-amino-3-cyano group-4-benzylamino-6-nitroquinoline:
In 55 ℃, the benzyl amine mixt of 7g 2-amino-3-cyano group-4-chloro-6-nitroquinoline and 30mL was stirred 1.5 hours.Reaction mixture inclines to 30mL water.Leach sedimentable matter, wash with water, obtain the 7g target compound, m.p.:280-283 ℃.LC-MS:MH +2320; Retention time: 5.19 minutes. 1H-NMR(DMSO-d 6)：9.28(d，1H)，8.90(t，1H)，8.24(dd，1H)，7.3(m，5H)，6.98(s，2H)，5.04(d，2H)ppm。
E) 4-methoxyl group-N-(4-anisoyl)-N-(4-benzylamino-3-cyano group-6-nitroquinoline-2-yl) benzamide:
Anhydrous pyridine suspension and the 5.6g 4-methoxy benzoyl chloride of the 50mL of 3.5g2-amino-3-cyano group-4-benzylamino-6-nitroquinoline were refluxed 3.5 hours.Solvent evaporated under reduced pressure, residue are suspended in the saturated Na of 30mL 2CO 3The aqueous solution.Suspension is with 3 * 25mL CH 2Cl 2Extraction.The organic extract that merges is evaporated to dried, residue is dissolved in ether, and solution goes out to place at refrigerator and spends the night.Leach precipitation,, obtain the 6.25g target compound, m.p.:145-148 ℃ with the ether washing.LC-MS:MH +588; Retention time: 7.00 minutes.
F) N-[(4-benzylamino-3-cyano group-6-nitroquinoline-2-yl)]-4-methoxyl group-benzamide
The acetonitrile suspension of the 75mL of 6.2g N-(4-anisoyl)-N-(4-benzylamino-3-cyano group-6-nitroquinoline-2-yl)-4-methoxy benzamide and the 1N hydrogen from methyl alcohol potassium oxide solution of 25.2mL were refluxed 6 minutes.Glacial acetic acid with 4.4mL drops in the solution while hot, cooling and with 56.3mL 1M NaHCO 3Aqueous solution neutralization.Leach precipitation, wash with water, obtain the 4.1g target compound, m.p.:264-266 ℃. 1H-NMR(DMSO-d 6)10.9(s，1H)，9.55(d，1H)，9.28(t，1H)，8.77(d，1H)，8.48(dd，1H)，8.00(d，2H)，7.90(d，1H)，7.4(m，4H)，7.29(m，1H)，7.05(d，2H)，5.12(d，2H)，3.84(s，3H)ppm。
G) N-[6-amino-4-(benzylamino)-3-cyano quinolines-2-yl]-the 4-methoxy benzamide
The dense HCl mixture of THF, 7.6g iron powder and the 1mL of the ethanol of 320mL, 80mL water, 200mL was refluxed 10 minutes.Add 9g N-[(4-benzylamino-3-cyano group-6-nitroquinoline-2-yl then]-4-methoxyl group-benzamide, reaction mixture was fully refluxed 2 hours, be cooled to 35 ℃ then.Leach precipitation, with 1: 1 CH 2Cl 2Wash with alcohol mixture.The organic solution that merges is through activated carbon filtration and be evaporated to dried.Residue is suspended in the alcohol mixture of 50mL water and 10mL, leaches solid matter, washes with water, obtains the 6.65g target compound, mp:228-230 ℃.LC-MS:MH +424; Retention time: 5.33 minutes. 1H-NMR(DMSO-d 6)10.44(s，1H)，8.0(s+d，3H)，7.50(d，1H)，7.3-7.1(m，7H)，7.03(d，2H)，5.55(s，2H)，5.04(d，2H)，3.83(s，3H)ppm。
Embodiment 8
N-{6-amino-4-[(2-thienyl methyl) amino)]-3-cyano quinolines-2-yl }-the 4-methoxy benzamide
In general formula (I), R 1And R 2Represent hydrogen atom, R 3Represent the 2-thienyl, NR 4R 5Represent NH 2, R 6Represent the 4-p-methoxy-phenyl.
A) 2-amino-3-cyano group-4-(2-thienyl methyl) amino-6-nitroquinoline:
Adopt the method identical, benzyl amine is changed into (2-thienyl methyl) amine, obtain the 7.1g target compound, m.p.:277-280 ℃ with embodiment 7d.LC-MS:MH +326; Retention time: 5.25 minutes.
B) N-(4-anisoyl)-N-[3-cyano group-6-nitro-4-(2-thienyl methyl)-quinolylamine-2-yl]-the 4-methoxy benzamide
With 2-amino-3-cyano group-4-(2-thienyl methyl) amino-6-nitroquinoline (3.6g) is that raw material begins reaction, adopts the described method of embodiment 7e, preparation 6.3g target compound, m.p.:174-177 ℃.LC-MS:MH +595; Retention time: 7.16 minutes.
C) N-[3-cyano group-6-nitro-4-(2-thienyl methyl) quinolylamine-2-yl]-the 4-methoxy benzamide
With N-(4-anisoyl)-N-[3-cyano group-6-nitro-4-(2-thienyl methyl) amino] quinoline-2-yl)-4-methoxy benzamide (6.2g) is that raw material begins reaction; adopt the described method of embodiment 7f; preparation 4.3g target compound, m.p.:217-220 ℃.LC-MS:MH +460; Retention time: 6.57 minutes. 1H-NMR(DMSO-d 6)：11.0(s，1H)，9.50(s，1H)，9.29(s，1H)，8.48(dd，1H)，8.02(d，2H)，7.90(d，1H)，7.48(dd，1H)，7.21(d，1H)，7.0(m，3H)，5.27(s，2H)，3.85(s，3H)ppm。
D) N-{6-amino-4-[(2-thienyl methyl) amino]-3-cyano quinolines-2-yl }-the 4-methoxy benzamide;
N-[4-(2-thienyl methyl) amino-3-cyano group-6-nitroquinoline-2-yl]-4-methoxy benzamide (10g) is for raw material begins reaction, adopts the described method of embodiment 7g, preparation 9.3g target compound, mp:200-203 ℃.LC-MS:MH +430; Retention time: 5.52 minutes. 1H-NMR(DMSO-d 6)10.48(s，1H)，7.98(s+d，3H)，7.50(d，1H)，7.41(dd，1H)，7.21(s，1H)，7.16(dd，1H)，7.11(d，1H)，7.04(d，2H)，6.98(dd，1H)，5.45(s，2H)，5.18(d，2H)，3.84(s，3H)ppm。
Embodiment 9
N-{4-(benzylamino)-3-cyano group-6-(methylamino) quinoline-2-yl }-the 4-methoxy benzamide
In general formula (I), R 1And R 2Represent hydrogen atom, R 3Represent phenyl, R 4Represent Me, R 5Represent H and R 6Represent the 4-p-methoxy-phenyl.
With 1g N-{4-(benzylamino)-3-cyano group-6-quinolylamine-2-yl }-4-methoxy benzamide and 0.65g Paraformaldehyde 96 be at 48mL ethanol and 48mL CH 2Cl 2Suspension in the mixture and the 54%HBF of 0.5mL 4Diethyl ether solution refluxed together 1.5 hours.Add 0.3g NaBH 4After, continue to reflux 1.5 hours, and then add 0.3gNaBH 4And refluxed 2 hours.Repeat to add the 54%HBF of 0.25mL 4Diethyl ether solution and 0.3g NaBH 4After, continue again to reflux 1.5 hours.The filtered while hot reaction mixture, solid was with 1: 1 CH 2Cl 2Wash with alcohol mixture.Concentrate the organic solution that merges, (elutriant is 50: 1 CHCl to residue through silica gel column chromatography 3Mixture with ethyl acetate), obtain the crude product product.Mixture recrystallize from 2: 1 ethanol and DMF obtains the 0.6g target compound, m.p.:237-240 ℃.LC-MS:MH +438; Retention time: 5.76 minutes. 1H-NMR(DMSO-d 6)10.43(s，1H)，8.18(t，1H)，7.94(d，2H)，7.50(d，1H)，7.3-7.0(m，9H)，6.24(m，1H)，5.08(d，2H)，3.83(s，3H)，2.83(d，3H)ppm。
Embodiment 10
N-{3-cyano group-6-(formyl radical amino)-4-[(2-thienyl methyl) amino] quinoline-2-yl]-the 4-methoxy benzamide
In general formula (I), R 1And R 2Represent hydrogen atom, R 3Represent the 2-thienyl, R 4Represent Me, R 5Represent CHO and R 6Represent the 4-p-methoxy-phenyl.
In 100 ℃, with 0.32g N-{6-amino-4-[(2-thienyl methyl) amino]-3-cyano quinolines-2-yl }-suspension of 4-methoxy benzamide places the methyl-formiate of 60mL, and be contained in sealed vessel (interior pressure: 10 crust) 7 hours.Cooling back evaporating solvent, residue is from CH 2Cl 2/ MeOH recrystallize obtains the 0.22g target compound, m.p.:223-226 ℃.LC-MS:MH +458; Retention time: 5.71 minutes.
Embodiment 11
4-(benzylamino)-3-cyano group-2-[(4-anisoyl) and amino] quinoline-6-yl } thionamic acid
In general formula (I), R 1And R 2Represent hydrogen atom, R 3Represent phenyl, R 4Represent H, R 5Represent SO 2OH and R 6Represent the 4-p-methoxy-phenyl.
To 5.2g Na 2S 2O 4(purity: the 1N NaOH aqueous solution that adds 20mL in 160mL water 85%) and the 200mL ethanolic soln.Solution is heated to boiling, adds 2.27g N-[(4-benzylamino-3-cyano group-6-nitroquinoline-2-yl then]-the 4-methoxy benzamide, continue to reflux 2 hours.Under room temperature, place reaction mixture and spend the night, be condensed into half of volume then.Add 1N NaOH solution alkalization residue (pH=8), use CH 2Cl 2Extraction.Add dense HCl solution with acidified aqueous solution to pH=5 and leach precipitation.Solid obtains the 0.5g target compound through silica gel column chromatography (elutriant: earlier with ethyl acetate/methanol/25% ammonia mixture=220/30/2, and then with 200/80/2), is ammonium salt, m.p.:220-222 ℃.LC-MS:MH +504; Retention time: 5.56 minutes. 1H-NMR(DMSO-d 6)10.48(s，1H)，8.21(s，1H)，8.09(t，1H)，7.95(d，2H)，7.70(s，1H)，7.62(d，1H)，7.56(d，1H)，7.3(m，4H)，7.25(m，1H)，7.03(d，2H)，5.05(d，2H)，3.83(s，3H)ppm。
Embodiment 12
4-(benzylamino)-3-cyano group-2-[(4-anisoyl) and amino] quinoline-6-yl } methylamino sulfonic acid
In general formula (I), R 1And R 2Represent hydrogen atom, R 3Represent phenyl, R 4Represent Me, R 5Represent SO 2OH and R 6Represent the 4-p-methoxy-phenyl.
Under room temperature, with 110mg N-{4-(benzylamino)-3-cyano group-6-(methylamino) quinoline-2-yl }-pyridine solution and 0.2mL DBU and the 150mg pyridine -SO of the 10mL of 4-methoxy benzamide 3Mixture stirred 2 hours.Concentrated reaction mixture is to doing, and residue is through silica gel column chromatography (elutriant: mixtures of ethyl acetate/methyl alcohol/25% ammonium=200/80/2), obtain the 10mg target compound, be ammonium salt.LC-MS:MH +518; Retention time: 6.22 minutes.
Embodiment 13
N-{4-(benzylamino)-3-cyano group-6-[formyl radical (methyl) amino] quinoline-2-yl }-the 4-methoxy benzamide
In general formula (I), R 1And R 2Represent hydrogen atom, R 3Represent phenyl, R 4Represent Me, R 5Represent CHO and R 6Represent the 4-p-methoxy-phenyl.
With 110mg N-{4-(benzylamino)-3-cyano group-6-(methylamino) quinoline-2-yl }-suspension of 4-methoxy benzamide refluxed 24 hours in the ethyl formate of 10mL.After the cooling, leach sedimentary crystal,, obtain the 30mg target compound, m.p.:237-240 ℃ with ethyl formate and washing with alcohol.LC-MS:MH +465; Retention time: 6.11 minutes.
Embodiment 14
4-methoxyl group-N-[6-(4-formyl piperazine-1-yl)-4-benzylamino-3-cyano quinolines-2-yl] benzamide
R in general formula (I) 1And R 2Represent hydrogen atom, R 3Represent phenyl, group a.) represent 4-formyl piperazine-1-base, R 6Represent the 4-p-methoxy-phenyl.
With 120mg 4-methoxyl group-N-[6-(piperazine-1-yl)-4-benzylamino-3-cyano quinolines-2-yl] the ethyl formate solution of the 5mL of benzamide refluxed 2 hours.Cooling back evaporating solvent, residue obtains the 65mg target compound from the methyl alcohol recrystallize.mp：243℃。 1H-NMR(DMSO-d 6)10.6ppm(s，1H)，8.48(m，1H)，8.1(s，1H)，7.94(m，2H)，7.6-7.1(m，8H)，7.05(m，2H)，5.1(d，2H)，3.82(s，3H)，3.7-3.2(m，8H)。
Embodiment 15
4-[2-(benzoyl-amido)-4-benzylamino)-and 3-cyano quinolines-6-yl] piperazine-1-sulfonic acid
In general formula (I), R 1And R 2Represent hydrogen atom, R 3Represent phenyl, group a.) represent 4-alkylsulfonyl piperazine-1-base, R 6Represent the 4-p-methoxy-phenyl.
With 50mg 4-methoxyl group-N-[6-(piperazine-1-yl)-4-benzylamino-3-cyano quinolines-2-yl] the 0.5mL pyridine and the pyridine -SO of benzamide 3The solution of mixture refluxed 2 hours and handled (G..F.Smith and D.A.Taylor, Tetrahedron, 29,669,1973) according to the method for describing in the document.
LC-MS:MH +572; Retention time: 5.9 minutes.
R wherein 1And R 2Represent hydrogen atom, X representative-NH-group and n to represent shown in the structure and the following Table I of physical features of 1 other general formula (I) compound:
Figure S2008100096757D00321
Table I
Figure S2008100096757D00322
Figure S2008100096757D00331
Figure S2008100096757D00341
Figure S2008100096757D00351
Embodiment 40
Can prepare tablet according to known method with following component:
Activeconstituents 25mg
Lactose 50mg
Microcrystalline Cellulose 21mg
Hand over poly-polyvidone 3mg
Magnesium Stearate 1mg
Biological assay
Method
With people's adenosine A 3The combination of acceptor
Preparation cytolemma suspension: with the people A of cloning by expression 3Chinese hamster ovary cell (the CHO-hA of acceptor 3) suitably cultivate and keep.The cellular layer that obtains merging, in cell, remove substratum through 37 ℃ of PBS washings, then with cell suspension in ice-cold PBS, centrifugation (1000 * g 10 minutes) (Sigma 3K30) is also adopted special teflon homogenizer (B.Braun Potter S) homogenizing 15 seconds under 1500/ fen rotating speed, and this process is carried out in following damping fluid: 50mM Tris, 10mM MgCl 2, 1mM EDTA, pH 8.0.Centrifugal suspension (43,000g, 10 minutes).Precipitation is suspended in the above-mentioned damping fluid, and protein concentration is 0.1mg/ml (a Bradford method).With the cell membrane preparation portioning be stored in-80 ℃ stand-by.
In conjunction with measuring method: under room temperature, at incubation buffering liquid (50mM Tris, 10mM MgCl 2, 1mM EDTA, the 3U/mL adenosine deaminase, pH 8.0) in, at 0.5nM[ 125I] AB-MECA (p-amino-3-iodo-benzyl-5 '-N-methyl formamido group adenosine) (100,000cpm) with 100 μ MR-PIA (N 6-[L-2-propyloxy phenyl base] adenosine) there is down incubation CHO-hA 3Cell membrane preparation (containing 2 μ g protein) 1 hour, thus the non-specific binding of testing compound in the volume that total amount is 50 μ L measured.On 96 hole Brandel cell harvestors, filter, with 1mL ice-cold 50mM Tris, 10mMMgCl2,1mM EDTA (pH 8.0) washing 4 times through Whatman GF/B glass fibre filter (with 0.5% polymine preimpregnation 3 hours).(1470 Wizard Wallac) measure activity with γ-counter.Inhibiting rate [%]=100-((activity-non-specific activity of in the presence of testing compound, measuring)/(gross activity-non-specific activity)) * 100.
People's adenosine A 1Receptors bind is measured
Preparation cytolemma suspension: with the people A of cloning by expression 1Chinese hamster ovary cell (the CHO-hA of acceptor 1) suitably cultivate and keep.The cellular layer that obtains merging, in cell, remove substratum through 37 ℃ of PBS washings, then with cell suspension in ice-cold PBS, centrifugation (1000 * g 10 minutes) (Sigma 3K30) is also adopted special teflon homogenizer (B.Braun Potter S) homogenizing 15 seconds under 1500/ fen rotating speed, this process is carried out in following damping fluid: 50mM Tris, 10mM HCl, pH 7.4.Centrifugal suspension (43,000g, 10 minutes).Precipitation is suspended in the above-mentioned damping fluid protein concentration 5mg/ml (Bradford method).With the cell membrane preparation portioning be stored in-80 ℃ stand-by.
In conjunction with measuring method: under room temperature, in incubation buffering liquid (pH 7.4 for 50mM Tris, 3U/mL adenosine deaminase), at 10nM[ 3H] CCPA (2-chloro-N 6-cyclopentyl-adenosine) (80,000dpm) with 10 μ M R-PIA (N 6-[L-2-propyloxy phenyl base] adenosine) there is down incubation CHO-hA 1Cell membrane preparation (containing 50 μ g protein components) 3 hours, thus the non-specific binding of testing compound in the volume that total amount is 100 μ L measured.Filter through WhatmanGF/B glass fibre filter (with 0.5% polymine preimpregnation 3 hours) on 96 hole Brandel cell harvestors, the 50mM Tris (pH 7.4) ice-cold with 1mL washs 4 times.In the presence of 200 μ l HiSafe-3 mixed solutions, (1450 Microbeta Wallac) measure activity with beta-counter.Inhibiting rate [%]=100-((activity in the presence of testing compound-non-specific activity)/(gross activity-non-specific activity)) * 100.
People's adenosine A 2aReceptors bind is measured
In conjunction with measuring method: under room temperature, at incubation buffering liquid (50mM Tris-HCl, 10mMMgCl 2, 1mM EDTA, 2U/mL adenosine deaminase, pH 7.4) in, at 20nM[ 3H] and CGS-21680 (2-[p-(2-carbonyl ethyl) phenylethyl amino]-5 '-N-ethyl formamido group adenosine) (200,000dpm) there be down incubation 7 μ g cell membrane preparations (the people A of transfection in the HEK-293 cell with 50 μ M NECA (5 '-N-ethyl formamido group adenosine) 2aAdenosine Receptors is derived from: ReceptorBiology, and Inc.) 90 minutes, thus measure the non-specific binding of testing compound in the volume that total amount is 100 μ L.On 96 hole Brandel cell harvestors,, use ice-cold 50mM Tris, the 10mM MgCl of 1mL through Whatman GF/B glass fibre filter (with 0.5% polymine preimpregnation 3 hours) vacuum filtration 2, 1mM EDTA, 0.9%NaCl (pH 7.4) washing 4 times.In the presence of 200 μ l HiSafe-3 mixed solutions, (1450 Microbeta Wallac) measure activity with beta-counter.Inhibiting rate [%]=100-((activity in the presence of testing compound-non-specific activity)/(gross activity-non-specific activity)) * 100.
People's adenosine A 2bReceptors bind is measured
In conjunction with measuring method: under room temperature, at incubation buffering liquid (50mM Tris-HCl, 10mMMgCl 2, 1mM EDTA, 0.1mM benzenyl amidine, 2U/mL adenosine deaminase, pH 6.5) in, at 32.4nM[ 3H] and DPCPX (8-cyclopentyl-1,3-dipropyl xanthine) (800,000dpm) there be down incubation 20.8 μ g cell membrane preparations (the people A of transfection in the HEK-293 cell with 100 μ MNECA (5 '-N-ethyl formamido group adenosine) 2bAdenosine Receptors is derived from: Receptor Biology, and Inc.) 30 minutes, thus measure the non-specific binding of testing compound in the volume that total amount is 100 μ L.Filter under the 25Hgmm vacuum through Whatman GF/C glass fibre filter (with 0.5% polymine preimpregnation 3 hours) on 96 hole Brandel cell harvestors, the 50mM Tris (pH6.5) ice-cold with 1mL washs 4 times.In the presence of the HiSafe-3 of 200uL mixed solution, (1450Microbeta Wallac) measures activity with beta-counter.Inhibiting rate [%]=100-((activity in the presence of testing compound-non-specific activity)/(gross activity-non-specific activity)) * 100.
The result
If compound suppresses radioligand and people's adenosine A under the test conditions of 1 μ M 3The bonded activity of acceptor can reach 80%, thinks that so then this compound has biologic activity.
[ 125I] AB-MECA is at CHO-hA 3Dissociation constant on the cell membrane preparation (Kd) can be analyzed (G.Scatchard, Ann.N.Y.Acad.Sci.51:660,1949) by means of Scatchard and measure through the saturated research of isotropic substance.With Cheng-Prusoff equation (Y.J.Cheng and W.H.Prusoff, Biochem.Pharmacol.22:3099,1973), with IC 50Through converting affinity costant (K to i).
Many general formulas (I) compound has significant biologic activity.The most activated general formula (I) compound is defined those compounds among the claim 2-4.Special compounds effective is the compound that provides in an embodiment, its K iValue is 0.5nM-900nM, preferred 0.5nM-700nM.The K of compounds effective iValue is 0.5nM-18nM, most preferably 0.5-15nM.
Above-claimed cpd has excellent bioavailability, and with respect to people's adenosine A 1, A 2aAnd A 2bReceptor subtype, their selectivity are at least 3 orders of magnitude.
In addition, above-claimed cpd is when intravenously and orally administering, and acting duration is long, its ED 50Be worth lowlyer, toxicity and side effect are lower.
Above-mentioned data declaration, general formula (I) compound are specially adapted to treatment and use.

Claims (7)

1. general formula (III ") compound:
Figure S2008100096757C00011
In the formula, R 1" represent hydrogen atom or straight or branched C 1-4Alkyl;
R 2" represent hydrogen atom or straight or branched C 1-4Alkyl;
R 3" represent hydrogen atom or straight or branched C 1-4Alkyl, C 3-6Cycloalkyl, phenyl, thienyl or furyl, optional by one or more straight or branched C 1-4Alkyl, straight or branched C 1-4The alkoxy or halogen atom replaces; Contain one, hexa-atomic or five yuan of hetero-aromatic rings of two or three nitrogen-atoms, or contain five yuan of hetero-aromatic rings of a nitrogen-atoms and Sauerstoffatom or a nitrogen-atoms and a sulphur atom, described hetero-aromatic ring is optional by one or more straight or branched C 1-4Alkyl, straight or branched C 1-4The alkoxy or halogen atom replaces;
R 4" and R 5" independent hydrogen atom, the C of representing 3-6Cycloalkyl, straight or branched C 1-4Alkyl or blocking group, described alkyl is optional to contain amino, by one or two straight or branched C 1-4The amino that alkyl replaces, hydroxyl, carboxyl or by straight or branched C 1-4The alkoxyl group that alkyl replaces; Perhaps
R 4" represent hydrogen atom or straight or branched C 1-4Alkyl or benzyl, and
R 5" represent hydrogen atom ,-SO 2OH group or straight or branched C 1-4Acyl group or blocking group, perhaps
R 4" and R 5" form nitro or general formula a with nitrogen-atoms " .) group:
Figure S2008100096757C00012
R wherein 7" and R 8" independent hydrogen atom, the straight or branched C of representing 1-4Alkyl or C 3-6Cycloalkyl;
Z " represention oxygen atom, sulphur atom ,-CHR 10"-group or-NR 11"-group, wherein R 10" represent hydrogen atom, straight or branched C 1-4Alkyl, perhaps C 3-6Cycloalkyl, and R 11" represent hydrogen atom, straight or branched C 1-4Alkyl, C 3-6Cycloalkyl ,-SO 2OH group, straight or branched C 1-4Acyl group;
M " represent 1,2 or 3;
O " represent 1,2 or 3;
P " represent 0 or 1;
R " represent 0 or 1;
X " representative-CH 2-group ,-the NH-group ,-NR 9"-group, perhaps sulphur atom, Sauerstoffatom, alkylsulfonyl or sulfonyloxy, wherein R 9" represent straight or branched C 1-4Alkyl or C 3-6Cycloalkyl;
N " represent 0,1 or 2.
2. general formula (IV ") compound:
Figure S2008100096757C00021
In the formula, R 4" and R 5" define as claim 1.
3. general formula (V ") compound:
Figure S2008100096757C00022
In the formula, R 4" and R 5" define as claim 1.
4. general formula (VI ") compound:
Figure S2008100096757C00031
In the formula, R 4" and R 5" as claim 1 definition, prerequisite is R 4" and R 5" not dimethylamino and amino with nitrogen-atoms.
5. general formula (VII ") compound:
Figure S2008100096757C00032
In the formula, R 4" and R 5" as claim 1 definition, prerequisite is R 4" and R 5" not dimethylamino, diethylamino and amino with nitrogen-atoms.
6. general formula (VIII ") compound:
Figure S2008100096757C00033
In the formula, R 4" and R 5" represent morpholine-4-base, N methyl piperazine-1-base, piperazine-1-base or 4-benzyl diethylenediamine-1-base with nitrogen-atoms.
7. general formula (XIII ") compound:
Figure S2008100096757C00041
Substituent R wherein 1", R 2", R 3", R 6" and n " define as claim 1.
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