CN1348452A - Derivatives of pyrimido [6,1-a] isoquinolin -4-one - Google Patents

Derivatives of pyrimido [6,1-a] isoquinolin -4-one Download PDF

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CN1348452A
CN1348452A CN00806771A CN00806771A CN1348452A CN 1348452 A CN1348452 A CN 1348452A CN 00806771 A CN00806771 A CN 00806771A CN 00806771 A CN00806771 A CN 00806771A CN 1348452 A CN1348452 A CN 1348452A
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A·W·牛津
D·杰克
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Abstract

Compounds of general formula (I) wherein each of R<1> and R<2> independently represents a C1-6 alkyl or C2-7 acyl group; X represents OCH2 or a group CR<3>R<4>, wherein each of R<3> or R<4> independently represents a hydrogen atom or a C1-3 alkyl group; R<5> represents a hydrogen atom or a C1-3 alkyl, C2-3 alkenyl or C2-3 alkynyl group; R<6> represents a hydrogen atom or a C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, amino, C1-6 alkylamino, di(C1-6) alkylamino or C2-7 acylamino group; each of R<7> and R<8> independently represents a hydrogen or halogen atom or a hydroxy, trifluoromethyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C2-7 acyl, C1-6 alkylthio, C1-6 alkoxy, C3-6 cycloalkyl; R<9> represents a hydrogen or halogen atom or a hydroxy, trifluoromethyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C2-7 acyl, C1-6 alkylthio, C1-6 alkoxy or C3-6 cycloalkyl group, or salts thereof are useful for treatment of respiratory disorders such as asthma. Compounds of the invention have a longer duration of action than the known compound trequinsin (9,10-dimethoxy-3-methyl-2-mesitylimino-2,3,6,7-tetrahydro-4H-pyrimido[6,1-a]isoquinolin-4-one) and do not have trequinsin's very bitter taste.

Description

The derivative of Mi Dingbing [6,1-a] isoquinoline 99.9-4-ketone
Technical field
The present invention relates to the derivative of Mi Dingbing [6,1-a] isoquinoline 99.9-4-ketone and they purposes as phosphodiesterase (PDE) isozyme inhibitor.More particularly, the present invention relates to the 2-derivatives containing phenoxy group of Mi Dingbing [6,1-a] isoquinoline 99.9-4-ketone and their purposes in medical science for example as bronchodilator with anti-inflammatory performance.
Background technology
In all cells that ring APM (cAMP) exists as secondary courier, the intracellular concentration of cAMP is by being regulated with its formation and two the relevant processes of degrading.The stimulation of the membrane-bound receptor on the cell outer surface (for example by the receptor, agonist) causes adenylate cyclase activating and produces cAMP from ATP.The phosphodiesterase that exists in the cell can be by being hydrolyzed to it concentration that adenylic acid (AMP) reduces cAMP.
In disease, dwindle the inhibitory control that the main cell relevant with inflammatory process is subjected to cAMP with the segmental bronchus of following resemble asthma.The intracellular concentration of the inhibitor rising cAMP of III type phosphodiesterase causes bronchial smooth muscle lax, and the inhibitor of IV type phosphodiesterase suppresses destructive medium and discharges from short inflammatory cell.Therefore, in principle, the receptor, agonist that combined PD E III/IV inhibitor should have an expectation adds the effect of the anti-inflammatory steroids of suction, and this two classes medicine is the pillar medicine in the serious asthma of treatment at present.In addition, combined PD E III/IV inhibitor should reach with beta-2-agonists by inhalation and add beneficial effect like the steroid of suction, and should be to asthma and other respiratory diseases, do not have undesirable glucocorticosteroid effect of steroid such as effective therapeutic modality osteoporosis and dysplasia, uncommon.
The possible detrimental action of PDE III/IV inhibitor (for example: nausea and vomiting, gastric acid secretion, the increase of all after one's own heart convergent forces of cardiovascular effect, vasorelaxation and potential cause the arrhythmia activity) should be avoided by utilizing suction that compound is directly released into lung.We expect that this material is that effect is lasting, not having pungency and have can the offensive taste that produces any disadvantageous effect to the compliance to patient.
Have PDE III/IV and suppress active and known Mi Dingbing [6 with antihypertensive vasodilator activity, 1-a] example of isoquinoline 99.9-4-ketone derivatives is trequinsin (9,10-dimethoxy-3-methyl-2-base imino--2,3,6,7-tetrahydrochysene-4H-Mi Dingbing [6,1-a] isoquinoline 99.9-4-ketone), it by De Souza etc. in medical chemistry magazine 27 1470-1480 (1984) and in GB-A-1597717, put down in writing.
As the description among De Souza etc. and the GB-A-1597717, trequinsin has valuable pharmacology performance, and can be to suffering from for example people curee's administration of respiratory disease.But, since its bitter taste and vitro data show its not really ideal effect persistence make it be not suitable for passing through inhalation.
Summary of the invention
Have now found that and to design the Mi Dingbing that certain is the PDE inhibitor [6,1-a] isoquinoline 99.9-4-ketone derivatives that it has the longer continuous action time of relative trequinsin and the taste of other useful performances such as improvement.
According to first aspect of the present invention, provide compound of Formula I:
Figure A0080677100161
Wherein:
R 1And R 2Represent C independently of one another 1-6Alkyl or C 2-7Acyl group;
X represents OCH 2Or group CR 3R 4, R wherein 3And R 4Represent hydrogen atom or C independently of one another 1-3Alkyl;
R 5Expression hydrogen atom or C 1-3Alkyl, C 2-3Alkenyl or C 2-3Alkynyl;
R 6Expression hydrogen atom or C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, amino, C 1-6Alkylamino, two (C 1-6) alkylamino or C 2-7Amido;
R 7And R 8Represent hydrogen or halogen atom or hydroxyl, trifluoromethyl, C independently of one another 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 2-7Acyl group, C 1-6Alkylthio, C 1-6Alkoxyl group or C 3-6Cycloalkyl;
R 9Expression hydrogen or halogen atom or hydroxyl, trifluoromethyl, C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 2-7Acyl group, C 1-6Alkylthio, C 1-6Alkoxyl group or C 3-6Cycloalkyl;
Or its salt;
But do not comprise compound 6,7-dihydro-2-phenoxy group-9,10-dimethoxy-4 ' H-Mi Dingbing [6,1a] isoquinoline 99.9-4-ketone.
The compound of getting rid of in the scope of first aspect of the present invention 6,7-dihydro-2-phenoxy group-9,10-dimethoxy-4 ' H-Mi Dingbing [6,1a] isoquinoline 99.9-4-ketone are the compounds of putting down in writing in the article of De Souza of above mentioning etc. " 8f ".De Souza etc. only puts down in writing 6,7-dihydro-2-phenoxy group-9, and 10-dimethoxy-4 ' H-Mi Dingbing [6,1a] isoquinoline 99.9-4-ketone is bad ypotension agent, does not have bronchiectasis activity and put down in writing it.
Term used herein " halogen " or its are write a Chinese character in simplified form " halogen " and are meant fluorine, chlorine, bromine or iodine.
Term " C used herein 1-6Alkyl " refer to straight or branched alkyl with 1 to 6 carbon atom.The illustration of this class alkyl is methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, neo-pentyl and hexyl.C 1-4Alkyl is preferred.
Term " C used herein 2-3Alkenyl " refer to and have 2 to 3 carbon atoms and have a suitable E in addition or the straight or branched alkyl of stereochemical pair of key of Z.This term comprises for example vinyl and 1-propenyl.
Term " C used herein 2-3Alkynyl " refer to and have 2 to 3 carbon atoms and have a triple-linked straight-chain alkyl in addition.This term comprises for example ethynyl and 1-proyl.
Term " C used herein 2-6Alkenyl " refer to and have 2 to 6 carbon atoms and have a suitable E in addition or the straight or branched alkyl of stereochemical pair of key of Z.This term comprises for example vinyl, 1-propenyl, 1-and crotyl and 2-methyl-2-propenyl.C 2-3Alkenyl is preferred.
Term " C used herein 2-6Alkynyl " refer to and have 2 to 6 carbon atoms and have a triple-linked straight or branched alkyl in addition.This term comprises for example ethynyl, 1-proyl, 1-and 2-butyne base, 2-methyl-2-propynyl, valerylene base, 3-pentynyl, 4-pentynyl, 2-hexin base, 3-hexin base, 4-hexin base and 5-hexin base.C 2-3Alkynyl is preferred.
Term " C used herein 1-6Alkoxyl group " refer to straight or branched alkoxyl group with 1 to 6 carbon atom.The illustration of this class alkoxyl group is methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert.-butoxy, pentyloxy, neopentyl oxygen and hexyloxy.C 1-4Alkoxyl group is preferred.
Term " C used herein 2-7Acyl group " refer to straight or branched acyl group with 2 to 7 carbon atoms.The illustration of this class acyl group is ethanoyl, propionyl (or propiono or propanoyl), different propionyl (or isopropiono or isopropanoyl), butyryl radicals (or butanoyl), isobutyryl (or isobutanoyl), pentanoyl (or valeryl), caproyl (or capronyl) and oenanthyl.
Term " C used herein 2-7Acyloxy " refer to straight or branched acyloxy with 2 to 7 carbon atoms.The illustration of this class acyloxy be acetoxyl group, propionyl (or propiono or propanoyl) oxygen base, different propionyl (or isopropiono or isopropanoyl) oxygen base, butyryl (or butanoyl) oxygen base, isobutyryl (or isobutanoyl) oxygen base, valeryl (or valeryl) oxygen base, hexanoyl (or capronyl) oxygen base and heptan acyloxy.C 2-4Acyloxy is preferred.
Term " C used herein 3-6Cycloalkyl " refer to alicyclic radical with 3 to 6 carbon atoms.The illustration of this class cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.Cyclopentyl and cyclohexyl are preferred.
Term " C used herein 1-6Alkylthio " refer to straight or branched alkylthio with 1 to 6 carbon atom.The illustration of this class alkylthio is methylthio group, ethylmercapto group, rosickyite base, iprotiazem base, butylthio, isobutyl sulfenyl, secondary butylthio, uncle's butylthio, penta sulfenyl, new penta sulfenyl and own sulfenyl.C 1-4Alkylthio is preferred.
Term " C used herein 1-6Alkylamino " refer to straight or branched alkylamino with 1 to 6 carbon atom.The illustration of this class alkylamino is methylamino-, ethylamino, third amino, isopropylamino, fourth amino, isobutyl amino, Zhong Ding amino, uncle's fourth amino, penta amino, new penta amino and own amino.C 1-4Alkylamino is preferred.
Term used herein " two (C 1-6) alkylamino " refer to the straight or branched two-alkylamino that in each alkyl, has 1 to 6 carbon atom.The illustration of this class dialkyl amido is two-methylamino-, two-ethylamino, two-the third amino, two-isopropylamino, two-Ding amino, two-isobutyl amino, two-Zhong Ding amino, two-uncle fourth amino, two-penta amino, two-Xin, penta amino and two-own amino.Two (C 1-4) alkylamino is preferred.
Term " C used herein 2-7Amido " refer to straight or branched amido with 2 to 7 carbon atoms.The illustration of this class amido is kharophen, propionyl (or propiono or propanoyl) amino, different propionyl (or isopropiono or isopropanoyl) amino, butyryl (or butanoyl) amino, isobutyryl (or isobutanoyl) amino, valeryl (or valeryl) amino, hexanoyl (or capronyl) amino and heptanamido.C 2-4Amido is preferred.
When making compound be the substituting group of alkalescence, for example work as R 6When being amino, alkylamino or dialkyl amido, adding acid and can cause salify.Acid can any suitable acid, and can be organic or inorganic.
Preferred compound of formula I comprises that each group wherein meets those of following condition, and these conditions are independently or any compatible combination:
R 1And R 2Represent C separately 1-6Alkyl, preferred C 1-4Alkyl;
R 1And R 2Be mutually the same;
R 3And R 4Represent hydrogen atom separately;
R 5The expression hydrogen atom;
R 6The expression hydrogen atom;
R 7And R 8Represent C separately 1-6Alkyl, preferable methyl, ethyl or sec.-propyl;
R 7And R 8Be mutually the same;
R 9Expression halogen atom or methyl or ethanoyl.
Exemplary compound comprises:
1,6,7-dihydro-2-(2, the 6-dimethyl phenoxy)-9,10-dimethoxy-4 ' H-Mi Dingbing-[6,1-a] isoquinoline 99.9-4-ketone;
2,2-(2,6-diethyl phenoxy group)-6,7-dihydro-9,10-dimethoxy-4 ' H-Mi Dingbing-[6,1-a] isoquinoline 99.9-4-ketone;
3,6,7-dihydro-2-(2,6-di-isopropyl phenoxy group)-9,10-dimethoxy-4 ' H-Mi Dingbing-[6,1-a] isoquinoline 99.9-4-ketone;
4,6,7-dihydro-9,10-dimethoxy-2-(2,4,6-trimethylammonium phenoxy group)-4H-Mi Dingbing-[6,1-a] isoquinoline 99.9-4-ketone;
5,2-(4-chloro-2,6-dimethyl phenoxy)-6,7-dihydro-9,10-dimethoxy-4 ' H-Mi Dingbing-[6,1-a] isoquinoline 99.9-4-ketone;
6,2-(4-bromo-2,6-dimethyl phenoxy)-6,7-dihydro-9,10-dimethoxy-4 ' H-Mi Dingbing-[6,1-a] isoquinoline 99.9-4-ketone;
7,6,7-dihydro-9,10-dimethoxy-2-(4-ethanoyl-2,6-dimethyl phenoxy)-4H-Mi Dingbing-[6,1-a] isoquinoline 99.9-4-ketone;
8,2-(2, the 6-dichlorophenoxy)-6,7-dihydro-9,10-dimethoxy-4 ' H-Mi Dingbing-[6,1-a] isoquinoline 99.9-4-ketone;
9,9,10-dimethoxy-2-(2-methylphenoxy)-6,7-dihydro-4H-Mi Dingbing [6,1-a] isoquinoline 99.9-4-ketone;
10,9,10-dimethoxy-2-(2-isobutyl-phenoxy group)-6,7-dihydro-4H-Mi Dingbing [6,1-a] isoquinoline 99.9-4-ketone;
11,2-(2-tertiary butyl phenoxy group)-9,10-dimethoxy-6,7-dihydro-4H-Mi Dingbing [6,1-a] isoquinoline 99.9-4-ketone;
12,9,10-dimethoxy-2-(2-ethyl phenoxy group)-6,7-dihydro-4H-Mi Dingbing [6,1-a] isoquinoline 99.9-4-ketone;
13,2-(2-cyclopentyl phenoxy group)-9,10-dimethoxy-6,7-dihydro-4H-Mi Dingbing [6,1-a] isoquinoline 99.9-4-ketone.
Compound 2-(2,6-diethyl phenoxy group)-6,7-dihydro-9,10-dimethoxy-4 ' H-Mi Dingbing-[6,1-a] isoquinoline 99.9-4-ketone and 6,7-dihydro-2-(2,6-di-isopropyl phenoxy group)-9,10-dimethoxy-4 ' H-Mi Dingbing-[6,1-a] isoquinoline 99.9-4-ketone is particularly preferred.
Compound of Formula I can be utilized in this area any suitable currently known methods and/or utilize following method to be prepared, and itself also constitutes a part of the present invention following method.
According to second aspect of the present invention, compound of Formula I is provided as defined above but does not comprise compound 6,7-dihydro-2-phenoxy group-9, the preparation method of 10-dimethoxy-4 ' H-Mi Dingbing [6,1a] isoquinoline 99.9-4-ketone, this method comprises:
(a) general formula I I compound: R wherein 1, R 2, R 5, R 6With X in the mutual-through type I definition, and LG represents leavings group,
React with compound of formula III: R wherein 7, R 8And R 9I defines as mutual-through type; Perhaps
(b) X represents group CR in general formula I 3R 4, R wherein 3Expression hydrogen atom, R 4Expression hydrogen atom or C 1-3Alkyl and R 5Expression hydrogen atom or C 1-3During alkyl, with general formula I X hydrogenation of compounds:
Figure A0080677100213
R wherein 1, R 2, R 6, R 7, R 8And R 9I defines as mutual-through type; With
(c) compound of Formula I that will so form alternatively is converted into another compound of Formula I.
In general formula I I compound, leavings group LG can be a chlorine, alkylthio (thioalkyl), preferred sulphomethyl, or alkyl sulphonyl, preferable methyl alkylsulfonyl.Chlorine preferably.
Normally such as helping this reaction, this reaction is a nucleophilic displacement reaction to the reaction conditions of step (a), preferably carry out in the presence of alkali such as salt of wormwood in suitable solvent such as dimethyl formamide or Virahol.Proper reaction conditions can be seen GB-A-1597717 and EP-A-0124893, and they disclose the preparation of related compound.
Step (a) reaction is applicable to usually produces such compound of Formula I: R wherein 6Expression hydrogen atom or C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, amino, C 1-6Alkylamino or C 2-7Amido, and R 1To R 5And R 7To R 9And X has the implication that above provides.
Wherein LG represents that the general formula I I compound of chlorine atom can react by general formula I V compound or general formula V compound and phosphoryl chloride and prepares, and perhaps prepares by general formula I V compound is heated with phosphorus pentachloride:
Figure A0080677100221
R wherein 1, R 2, R 5, R 6Define with X such as mutual-through type I.Wherein LG represents that the general formula I I compound of alkylthio can be by following process from general formula I V compound: general formula I V compound heats solvent such as diox or pyridine with thiophosphoric anhydride, obtain intermediate at first: the thio derivative of formula IV compound, it with for example methyl-iodide processing of alkylating agent such as alkyl iodide, obtains the alkylthio compound in suitable solvent such as tetrahydrofuran (THF) or ethyl acetate.This alkylthio compound solvent such as methylene dichloride in for example 3-chlorine peroxybenzoic acid oxidation, obtain Alkylsulfone derivative.
Compound of formula III is as known in the art and can perhaps can easily utilizes method preparation known per se from the fortified phenol of commercial source acquisition, for example passes through the aniline compound preparation of the hydrolysis of diazonium salt from corresponding replacement.
General formula I V compound can utilize general formula V compound (R wherein 1, R 2, R 5And R 6I defines as mutual-through type) under the more weak condition of condition required than will obtain LG wherein and represent the general formula I I compound of chlorine atom time the, lower temperature, react such as phosphoryl chloride and prepare with the cyclodehydration agent.NL-A-6 has also put down in writing another kind of method among 401,827 (the Hoffmann-La Roche), and this method relates to carbamyl methylene-tetrahydroisoquinoline and the diethyl carbonate that the formula VIII of making represents and reacts in the alcoholic acid sodium ethylate:
Figure A0080677100231
General formula V compound can utilize general formula VI compound: R wherein 1, R 2, R 5Define with X such as mutual-through type I, with R 6CH (CO 2Et) 2(R wherein 6I defines as mutual-through type) and highly basic such as sodium ethylate in hot ethanol solution, react and prepare.On the other hand, in the presence of the sodium methylate of the methyl alcohol of heat, can use corresponding dimethyl ester.
General formula VI compound can utilize general formula VII compound
Figure A0080677100241
R wherein 1, R 2, R 5Define with X such as mutual-through type I, descend heating to react with urea at 160 ℃ and prepare.On the other hand, general formula VII compound can react in such as ethanol at suitable solvent in the presence of the acetic acid with potassium cyanate.
General formula VII compound is as known in the art or can easily utilizes method preparation known per se.For example, B.Lal etc. have described the preparation of 1-(3,4-dimethoxy styroyl) malonylurea in medical chemistry magazine 271470-1480 (1984).
Present step (b), the reaction conditions of step (b) normally help hydrogenation, and this reaction is for example at room temperature carried out with noble metal catalyst such as palladium, platinum, rhodium or nickel in the ethanol at suitable solvent such as alcohol usually.Catalyzer can be supported with for example charcoal or alumina.
General formula I X compound can be from the general formula X compound:
Figure A0080677100242
R wherein 1, R 2And R 6I defines as mutual-through type, and R 4And R 5Represent hydrogen atom or C independently 1-3Alkyl.Compound of Formula I is described carries out like that about general formula I V compound is converted into via general formula I I compound in this reaction as mentioned, the preferred also corresponding unanimity of reaction conditions.
The general formula X compound can (wherein X represents group CR from general formula I V compound 3R 4, R wherein 3The expression hydrogen atom, R 4Expression hydrogen atom or C 1-3Alkyl; And R 5Expression hydrogen atom or C 1-3Alkyl) prepares by under 300 to 350 ℃ temperature, heating with noble metal catalyst such as palladium, platinum, rhodium or nickel.Catalyzer can be supported on charcoal or the alumina, and is reflected at inert solvent such as aromatic hydrocarbon and for example carries out in the Paracymene.
In optional step (c), compound of Formula I can be converted into another compound of Formula I.For example, R wherein 6Expression NH 2Compound of Formula I can be converted into wherein R by standard chemical 6Expression C 1-6The compound of Formula I of alkylamino is such as by being protected the alkylation of derivative such as acyl group or tolysulfonyl radical derivative, then such as removing protecting group by acid hydrolysis.R wherein 6Expression two (C 1-6) compound of Formula I of alkylamino can be by the direct alkylation preparation of alkyl amino derivatives.R wherein 5, R 6, R 7, R 8And/or R 9Expression C 2-3Alkenyl, C 2-6Alkenyl, C 2-3Alkynyl or C 2-6The compound of Formula I of alkynyl can hydrogenation obtain having the respective compound of saturated bond.The hydrogenant reaction conditions as mentioned in to the description of step (b).
According to the 3rd aspect, the invention provides and comprise compound of Formula I, comprise the compound (6 that is excluded, 7-dihydro-2-phenoxy group-9,10-dimethoxy-4 ' H-Mi Dingbing [6,1a] isoquinoline 99.9-4-ketone) and the composition of animal doctor or pharmaceutically acceptable carrier or thinner.Preferred said composition is the pharmaceutical composition that is used for physianthropy.
The compounds of this invention is the PDE inhibitor, therefore has valuable pharmacology performance, stimulate the bronchodilator activity of the inhibition proof of shrinking and the anti-inflammatory activity of in research, illustrating such as the field that utilizes cavy to separate tracheae to the person monocytic cell that stimulates by PHA (phytoh(a)emagglutinin).This compound of data presentation has long action time in the external and body, as when directly being drawn into lung as dry powder by they to the histamine inductive bronchospasm of cavy lasting provide protection proved.Therefore the present invention also relates to and comprises the particularly patient's of asthma, allergic asthma, spring fever, allergic rhinitis, bronchitis, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS) and vesical fibrosis acute, chronic or prophylactic treatment to suffering from respiratory disease.They also can be used for dermatosis in the part, such as atopic dermatitis and psoriasis, or are used for that the inflammation of eyes or any other disease comprise the brain local hemorrhage or the cAMP intracellular concentration that wherein increases progressively is considered to useful autoimmune disease.
One or more compounds of listing in aspect first of the present invention can with one or more nontoxic pharmaceutically and/or veterinarily acceptable carrier and/or thinner and/or adjuvant and/or propelling agent and, if desired, other activeconstituentss are in conjunction with existence.Suitable carriers or thinner are (for example pharmaceutical excipient handbook (1994) second edition, A.Wade/PJ Weller edits, The Pharmaceutical Press, American Pharmaceutical Association) as known in the art.
Compound of the present invention and composition be preferably by inhalation, for example by can powder type or with the aerosol or the sprays of solution or form of suspension dispersion medicine activeconstituents.Pharmaceutical composition with powder dispersing property except activeconstituents, also contain usually the subambient liquid propellant of boiling point and, if desired, additives such as liquid or solid nonionic or anion surfactant and/or wetting agent are to form stable dispersion.Wherein the pharmaceutical composition of active constituents of medicine in solution also contains suitable propelling agent except activeconstituents, and in addition, if desired, additional solvent and/or stablizer.Also can use pressurized air to replace propelling agent, for this reason might be as required by proper compression and bloating plant.Pharmaceutical composition can also discharge by breathing the activated inhalation device.For preferred dry powder composite by inhalation.
According to the 4th aspect, the invention provides the compound of Formula I that is used for medical science or contain compound of Formula I, comprise the composition of the compound (6,7-dihydro-2-phenoxy group-9,10-dimethoxy-4 ' H-Mi Dingbing [6,1a] isoquinoline 99.9-4-ketone) that is excluded.
The compounds of this invention can be used as the inhibitor of phosphodiester enzyme isoenzyme.Compound of the present invention or composition can be used to prevent or treat wherein compound or composition is useful any disease, but particularly wherein wish the disease of the intracellular concentration of rising cAMP.The example of the disease that compound can effectively resist comprises respiratory disease, particularly comprises asthma, bronchitis, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS), allergic asthma, spring fever, allergic rhinitis and vesical fibrosis.They also can be used for dermatosis such as atopic dermatitis or psoriasis in the part, the inflammation of eyes, or any other disease comprises cerebral ischemia or the cAMP intracellular concentration that wherein increases progressively is considered to useful autoimmune disease.
This aspect of the present invention is special relevant with people's treatment, but also is applicable to common animal doctor's industry, particularly domestic animal such as dog and cat and farm-animals such as horse, pig, ox, sheep etc.
In above-mentioned treatment of diseases, take every day be no more than 3 times, the dosage level of order is useful from about 0.02mg to about 200mg.More particularly, take every day be no more than 3 times, about 0.2mg is effective to the dosage range of about 20mg.But, particular dosage regimen is determined by the attending doctor the most at last and will consider the seriousness that resembles the seriousness of used medicine, age, body weight, symptom and/or using the treatment that maybe will use, more such factors such as medication, side reaction and/or other contraindications of medicine.
Medication according to this aspect of the present invention can give patient with other active agents, and these active agents can be different compounds for example of the present invention, or other compounds.Example comprises beta-2-adrenoreceptor agonists, glucocorticosteroid steroid, xanthine derivative, antihistamine compounds, leukotriene antagonist, leukotriene synthetic inhibitor and/or its binding substances.
According to the 5th aspect, the invention provides compound of Formula I, comprise the compound (6 that is excluded, 7-dihydro-2-phenoxy group-9,10-dimethoxy-4 ' H-Mi Dingbing [6,1a] isoquinoline 99.9-4-ketone) purposes in preparation III/IV type phosphodiester enzyme isoenzyme inhibitor.The present invention includes compound of Formula I, comprise the compound (6 that is excluded, 7-dihydro-2-phenoxy group-9,10-dimethoxy-4 ' H-Mi Dingbing [6,1a] isoquinoline 99.9-4-ketone) preparing bronchodilator and/or antiasthmatic drug and/or be used for prevention or the purposes of the medicine of treatment chronic obstructive pulmonary disease (COPD).
The invention still further relates to mammiferous wherein phosphodiester enzyme isoenzyme inhibitor and/or bronchodilator expection is useful treatment of diseases or prevention method, this method comprises the compound of Formula I to an amount of effective, the nontoxic amount of described Mammals administration, comprise the compound (6 that is excluded, 7-dihydro-2-phenoxy group-9,10-dimethoxy-4 ' H-Mi Dingbing [6,1a] isoquinoline 99.9-4-ketone).The method that the present invention includes treatment or prevent mammiferous asthma and/or chronic obstructive pulmonary disease (COPD).
The preferred feature of each aspect of the present invention is applicable to each side of the present invention each other, makes necessary modifications on the details.
Following non-restrictive example is set forth the present invention with reference to following accompanying drawing:
Fig. 1 mentions in the embodiment A (i) hereinafter, has shown the influence (experiment number (n) be 10) of DMSO (0.05%) to the cholinergic contractile response of the guinea pig trachea of outflow (superfused);
Fig. 2 mentions in the embodiment A (i) hereinafter, has shown the influence to electrical field stimulation in time contraction (experiment number (n) be 3) of 10 μ M embodiment, 3 compounds to guinea pig trachea, and wherein arrow is represented the beginning of flush period;
Fig. 3 mentions in the embodiment A (i) hereinafter, has shown the influence (experiment number (n) be 3) of 10 μ M embodiment, 11 compounds to the cholinergic contractile response of effusive guinea pig trachea, and wherein arrow is represented the beginning of flush period;
Fig. 4 mentions in the embodiment A (i) hereinafter, has shown the influence (experiment number (n) be 3) of 10 μ M embodiment, 12 compounds to the cholinergic contractile response of effusive guinea pig trachea, and wherein arrow is represented the beginning of flush period;
Fig. 5 mentions in the embodiment A (i) hereinafter, has shown the influence (experiment number (n) be 3) of 10 μ M embodiment, 13 compounds to the cholinergic contractile response of effusive guinea pig trachea, and wherein arrow is represented the beginning of flush period;
Fig. 6, embodiment A is mentioned in (ii) hereinafter, has shown the influence to electrical field stimulation in time contraction (n=1) of 10 μ M embodiment, 1 compound to guinea pig trachea, and wherein arrow is represented the beginning of flush period;
Fig. 7, embodiment A is mentioned in (ii) hereinafter, has shown the influence to electrical field stimulation in time contraction (n=1) of 10 μ M embodiment, 8 compounds to guinea pig trachea, and wherein arrow is represented the beginning of flush period;
Fig. 8, embodiment A is mentioned in (ii) hereinafter, has shown the influence to electrical field stimulation in time contraction (n=1) of 10 μ M embodiment, 2 compounds to guinea pig trachea, and wherein arrow is represented the beginning of flush period;
Fig. 9 mentions in the embodiment A (i) hereinafter, has shown the influence to the contraction of electrical field stimulation to guinea pig trachea of 10 μ M embodiment 10 compounds;
Figure 10 mentions in the Embodiment B hereinafter, has shown the effect of all cpds of the present invention antagonism person monocytic cell's the propagation that is stimulated by PHA, and wherein each some represent the mean value of testing for 6 times, and vertical line is represented the standard error of mean value.
Preparation 1:2-chloro-6,7-dihydro-9,10-dimethoxy-4 ' H-Mi Dingbing-[6,1-a] isoquinoline 99.9-4-ketone synthetic.
Figure A0080677100281
Will according to 1-(3, the 4-Dimethoxyphenyl) malonylurea of the method preparation of record in medical chemistry magazine 27 1470-1480 (1984) such as B.Lal (70g, 0.24mol) and phosphoryl chloride (300ml, mixture backflow 3.22mol) 2.5 hours.Excessive phosphoryl chloride is removed by the distillation (20mmHg) of heating.After the cooling, resistates Yong diox (100ml) furnishing pulpous state also joins in the ice/aqueous solution (1 liter) that firmly stirs carefully.Add chloroform (1 liter), the gained mixture alkalizes with 30% sodium hydroxide solution.Organic layer is separated, and water is further used chloroform (2 * 750ml) extractions.Organic extract water after the merging (1.5 liters) washing with dried over mgso and vacuum concentration, obtains resinoid (90g).It stirs in methyl alcohol somewhat and plants, and filters and (2 * 200ml) wash, and 40 ℃ of following vacuum-dryings, obtain title compound, are yellow/orange solid with methyl alcohol (200ml), diethyl ether.47g，62％(300MHz，CDCl 3)δ2.96(2H，t，C (7)H 2)；3.96(6H，s，2xOCH 3；4.20(2H，t，C (6)H 2)；6.61(1H，s，C (1)H)；6.76(1H，s，Ar-H)；7.10(1H，s，Ar-H).
Preparation 2:2, the 6-diethyl phenol
To 2, (14.9g drips the vitriol oil (90ml) to the 6-Diethyl Aniline while stirring in glacial acetic acid solution 0.10mol) (200ml), cooling simultaneously makes temperature remain on 10-20 ℃.This solution stirs down at 0 ℃ then, and (speed of dropping will make temperature keep below 5 ℃ for 9.0g, aqueous solution 0.13mol) (50ml) to drip Sodium Nitrite simultaneously.This mixture was 0 ℃ of following restir 20 minutes, and the ice cold water solution (300ml) that slowly adds urea (3.0g) then is to produce amber solution.The mixture of the vitriol oil (150ml) and water (600ml) is stirred and is heated to gentle reflux, simultaneously at the ice-cold solution that keeps dripping under the gentle reflux diazonium salt.Importantly diazonium salt solution is directly dripped in the sulphuric acid soln and do not touch the sidewall of flask.This mixture restir 10 minutes under refluxing at room temperature stirred 18 hours then after adding.Dark red brown product is by filter taking out, and washes with water and is dissolved in methylene dichloride.This solution obtains solid with dried over mgso and evaporation, and it uses column chromatography purifying (silica gel; 2: 1 sherwood oil 40-60 ℃: methylene dichloride), obtain title compound, be colourless crystallization.9.6g，64％
mpt.：38-39℃
(60MHz，CDCl 3)δ1.23(6H，t，CH 3)；2.63(4H，q，CH 2)；4.67(1H，s，OH)；6.90-7.20(3H，m，Ar-H)。
Embodiment 1:6,7-dihydro-2-(2, the 6-dimethyl phenoxy)-9,10-dimethoxy-4 ' H-Mi Dingbing-[6,1-a] isoquinoline 99.9-4-ketone synthetic
Will be according to the preparation 1 2-chloro-6 that makes, 7-dihydro-9,10-dimethoxy-4 ' H-Mi Dingbing-[6,1-a] and isoquinoline 99.9-4-ketone (20g, 68.4mmol) with 2,6-xylenol (buying) (25.1g from Aldrich, 167mmol) be dissolved in anhydrous N, dinethylformamide (160ml).(28.3g, 205mmol) also this mixture is heated to 90 ℃ under nitrogen reach 3 hours to add salt of wormwood.With this mixture cooling, join in the water (600ml) then also with ethyl acetate (3 * 300ml) extractions.Organic extract after the merging with sodium bicarbonate (300ml), water (2 * 500ml) and salt solution (300ml) wash, obtain the gumminess resistates with dried over mgso and vacuum concentration.Its with ether (250ml) development, by filtering separation and from methyl alcohol (300ml) recrystallization, obtain title compound, be faint yellow solid.20g，67％
mpt.：216-218℃。(300MHz，d 6DMSO)δ2.05(6H，s，2x?CH 3)；2.95(2H，t，C (7)H 2)；3.85(3H，s，OCH 3)；3.90(3H，s，OCH 3)；4.05(2H，t，C (6)H 2)；6.95-7.15(5H，m，Ar-H)；7.55(1H，s，Ar-H).
Embodiment 2:6,7-dihydro-2-(2,6-di-isopropyl phenoxy group)-9,10-dimethoxy-4 ' H-Mi Dingbing-[6,1-a] isoquinoline 99.9-4-ketone synthetic
Figure A0080677100311
Will be according to the preparation 1 2-chloro-6 that makes, 7-dihydro-9, (23.1g, 79mmol) with 2, (42.2g 237mmol) is dissolved in anhydrous N to the 6-diisopropyl phenol to 10-dimethoxy-4 ' H-Mi Dingbing-[6,1-a] isoquinoline 99.9-4-ketone, dinethylformamide (160ml).(32.3g, 234mmol) also this mixture is heated to 90 ℃ under nitrogen reach 4.5 hours to add salt of wormwood.With this mixture cooling, join in the water (800ml) then also with ethyl acetate (3 * 300ml) extractions.Organic extract after the merging with sodium bicarbonate (300ml), water (2 * 500ml) and salt solution (300ml) wash, with dried over mgso and vacuum concentration.Resistates utilizes column chromatography purifying (silica gel; Methylene dichloride is 2% methyl alcohol that is present in the methylene dichloride then).Separated product is recrystallization from ethyl acetate (250ml), is faint yellow solid.The residual acetic acid ethyl ester obtains title compound by compound being dissolved in the methylene dichloride and vacuum concentration is removed, and is faint yellow solid.20.5g，52％
mpt.：123-126℃。(300MHz，CDCl 3)δ1.15(12H，d，4x?CH-Me)；3.0(4H，m)；4.00(6H，s，2xOCH 3)；4.25(2H，t，C (6)H 2)；6.40(1H，s，C (1)H)；6.65(1H，s，Ar-H)；7.20(4H，m).
Embodiment 3:2-(2,6-diethyl phenoxy group)-6,7-dihydro-9,10-dimethoxy-4 ' H-Mi Dingbing-[6,1-a] isoquinoline 99.9-4-ketone synthetic
Figure A0080677100321
Will be according to the preparation 1 2-chloro-6 that makes, 7-dihydro-9, (1.0g, 3.41mmol) with 2, (1.53g 10.2mmol) is dissolved in propan-2-ol (125ml) to the 6-diethyl phenol to 10-dimethoxy-4 ' H-Mi Dingbing-[6,1-a] isoquinoline 99.9-4-ketone.(1.41g 10.2mmol) and with this mixture is heated to backflow 24 hours under nitrogen to add salt of wormwood.Then with this mixture cooling and solids removed by filtration.With filtrate vacuum-evaporation, resistates column chromatography purifying (silica gel; 2: 1 ethyl acetate: methylene dichloride), obtain title compound, be faint yellow solid.1.21g，88％
mpt.：180-181℃。
HPLC: area (%) 100.00
Post ODS (150 * 4.6mm)
MP??????pH＝4?KH 2PO 4/MeOH(50/50)
FR 0.8ml/ minute
RT??????11.634
Detect 250nm (300MHz, CDCl 3) δ 1.21 (6H, t, CH 3); 2.54 (4H, q, CH 2); 2.99 (2H, t, J=6.5Hz, C (7)H 2); 3.98 (3H, s, OCH 3); 4.00 (3H, s, OCH 3); 4.22 (2H, t, J=6.5Hz, C (6)H 2); 6.42 (1H, s, C (1)H); 6.79 (1H, s, Ar-H); 7.10-7.19 (3H, m, Ar-H); 7.22 (1H, s, Ar-H).
Embodiment 4:6,7-dihydro-9,10-dimethoxy-2-(2,4,6-trimethylammonium phenoxy group)-4H-Mi Dingbing-[6,1-a] isoquinoline 99.9-4-ketone synthetic
Figure A0080677100331
Will be according to the preparation 1 2-chloro-6 that makes, 7-dihydro-9,10-dimethoxy-4 ' H-Mi Dingbing-[6,1-a] (1.2g is 4.10mmol) with 2,4 for isoquinoline 99.9-4-ketone, (1.68g 12.34mmol) is dissolved in propan-2-ol (145ml) to 6-pseudocuminol (buying from Aldrich).(1.70g 12.30mmol) also heats this mixture 16 hours under nitrogen to add salt of wormwood.After being cooled to room temperature, this mixture is filtered the precipitation washing with acetone.With the filtrate vacuum-evaporation after merging.Resistates is dissolved in methylene dichloride (200ml) and (40ml) washs with 10% sodium hydroxide (aqueous solution), water (40ml) washing then.Organic layer obtains brown oil with dried over mgso, filtration and vacuum-evaporation.Through column chromatography (silica gel; 4: 1 ethyl acetate: sherwood oil 40-60 ° then is 4: 1 ethyl acetate: methylene dichloride) obtain yellow solid.This material washs with diethyl ether, collects and vacuum-drying by filtering, and obtains title compound, is faint yellow solid.0.56g，35％.
mpt.：????230-231℃
M/z:C 23H 24N 2O 4Require M=392 actual measurement (M+1)=393
HPLC: area (%) 99.65
Post ODS (150 * 4.6mm)
MP??????????????0.2M?NH 4Ac/MeOH(30/70)
FR (ml/ minute) 0.7
RT (minute) 13.006
Detect 250nm (300MHz, CDCl 3) δ 2.15 (6H, s, 2xCH 3); 2.28 (3H, s, CH 3); 3.0 (2H, t, C (7)H 2); 3.98 (6H, s, 2xOCH 3); 4.23 (2H, t, C (6)H 2); 6.42 (1H, s, C (1)H); 6.78 (1H, s, Ar-H); (6.86 2H, s, 2x Ar-H); 7.20 (1H, s, Ar-H).
Embodiment 5:2-(4-chloro-2,6-dimethyl phenoxy)-6,7-dihydro-9,10-dimethoxy-4 ' H-Mi Dingbing-[6,1-a] isoquinoline 99.9-4-ketone synthetic
Figure A0080677100341
Will be according to the preparation 1 2-chloro-6 that makes, 7-dihydro-9,10-dimethoxy-4 ' H-Mi Dingbing-[6,1-a] isoquinoline 99.9-4-ketone (1.5g, 5.13mmol) and 4-chloro-2, (2.41g 15.39mmol) is dissolved in propan-2-ol (180ml) to 6-xylenol (buying from Lancaster Chemicals).(2.13g 15.41mmol) also heats this mixture 16 hours under nitrogen to add salt of wormwood.After being cooled to room temperature, this mixture is filtered the precipitation washing with acetone.With the filtrate vacuum-evaporation after merging.Resistates is dissolved in methylene dichloride (200ml) and (45ml) washs with 10% sodium hydroxide (aqueous solution), water (45ml) washing then.Organic layer obtains orange oil with dried over mgso, filtration and vacuum-evaporation.Through column chromatography (silica gel; 4: 1 ethyl acetate: methylene dichloride) obtain yellow solid.This material washs with diethyl ether, collects and vacuum-drying by filtering, and obtains title compound, is pale yellow powder.1.78g，84％.
mpt.：????201-203℃。
M/z:C 22H 21 35ClN 2O 4Require M=412 actual measurement (M+1)=413
C 22H 21 37CIN 2O 4Require M=414 actual measurement (M+1)=415
HPLC: area (%) 97.91
Post ODS (250 * 4.6mm)
MP???????????????????0.1M?NH 4Ac/MeCN(40/60)
FR (ml/ minute) 0.7
RT (minute) 12.466
Detect 250nm (300MHz, CDCl 3) δ 2.13 (6H, s, 2xCH 3); 2.99 (2H, t, C (7)H 2); 3.98 (3H, s, OCH 3); 4.02 (3H, s, OCH 3); 4.23 (2H, t, C (6)H 2); 6.43 (1H, s, C (1)H); 6.78 (1H, s, Ar-H); (7.04 2H, s, 2x Ar-H); 7.21 (1H, s, Ar-H).
Embodiment 6:2-(4-bromo-2,6-dimethyl phenoxy)-6,7-dihydro-9,10-dimethoxy-4 ' H-Mi Dingbing-[6,1-a] isoquinoline 99.9-4-ketone synthetic
Will be according to the preparation 1 2-chloro-6 that makes, 7-dihydro-9,10-dimethoxy-4 ' H-Mi Dingbing-[6,1-a] isoquinoline 99.9-4-ketone (1.5g, 5.13mmol) and 4-bromo-2, (3.1g 15.43mmol) is dissolved in propan-2-ol (180ml) to 6-xylenol (buying from Lancaster Chemicals).(2.13g 15.41mmol) also heats this mixture 16 hours under nitrogen to add salt of wormwood.After being cooled to room temperature, this mixture is filtered the precipitation washing with acetone.With the filtrate vacuum-evaporation after merging.Resistates is dissolved in methylene dichloride (200ml) and (45ml) washs with 10% sodium hydroxide (aqueous solution), water (45ml) washing then.Organic layer obtains orange oil with dried over mgso, filtration and vacuum-evaporation.Through column chromatography (silica gel; 4: 1 ethyl acetate: methylene dichloride) obtain yellow solid.This material washs with diethyl ether, collects and vacuum-drying by filtering, and obtains title compound, is pale yellow powder.1.90g，81％.
mpt.：???232-234℃。
M/z:C 22H 21 79BrN 2O 4Require M=456 actual measurement (M+1)=457
C 22H 21 81BrN 2O 4Require M=458 actual measurement (M+1)=459
HPLC: area (%) 99.77
Post ODS (150 * 4.6mm)
MP???????????????0.1M?NH 4Ac/MeCN(57/43)
FR (ml/ minute) 1.0
RT (minute) 11.565
Detect 250nm (300MHz, CDCl 3) δ 2.14 (6H, s, 2xCH 3); 2.98 (2H, t, C (7)H 2); 3.97 (3H, s, OCH 3); 3.99 (3H, s, OCH 3); 4.22 (2H, t, C (6)H 2); 6.43 (1H, s, C (1)H); 6.78 (1H, s, Ar-H); (7.19 2H, s, 2x Ar-H); 7.21 (1H, s, Ar-H).
Embodiment 7:6,7-dihydro-9,10-dimethoxy-2-(4-ethanoyl-2,6-dimethyl phenoxy)-4H-Mi Dingbing-[6,1-a] isoquinoline 99.9-4-ketone synthetic
Will be according to the preparation 1 2-chloro-6 that makes, 7-dihydro-9,10-dimethoxy-4 ' H-Mi Dingbing-[6,1-a] isoquinoline 99.9-4-ketone (1.5g, 5.13mmol) and 2, (2.53g 15.41mmol) is dissolved in propan-2-ol (180ml) to 6-dimethyl-4-hydroxy acetophenone (buying from Maybridge Chemicals).(2.13g 15.41mmol) also heats this mixture 23 hours under nitrogen to add salt of wormwood.After being cooled to room temperature, this mixture is filtered the precipitation washing with acetone.With the filtrate vacuum-evaporation after merging.Resistates is dissolved in methylene dichloride (200ml) and water (2 * 45ml) washings.Organic layer obtains orange oil with dried over mgso, filtration and vacuum-evaporation.Through column chromatography (silica gel; 4: 1 ethyl acetate: methylene dichloride) obtain yellow solid.This material washs with diethyl ether, collects and vacuum-drying by filtering, and obtains title compound, is pale yellow powder.1.81g，84％.
mpt.：??228-230℃。
M/z:C 24H 24N 2O 5Require M=420 actual measurement (M+1)=421
HPLC: area (%) 99.32
Post ODS
MP???????????????0.1M?NH 4Ac/MeCN(65/35)
FR (ml/ minute) 1.0
RT (minute) 13.840
Detect 250nm (300MHz, CDCl 3) δ 2.25 (6H, s, 2xCH 3); 2.60 (3H, s, CH 3CO); 3.02 (2H, t, C (7)H 2); 3.99 (3H, s, OCH 3); 4.01 (3H, s, OCH 3); 4.23 (2H, t, C (6)H 2); 6.47 (1H, s, C (1)H); 6.78 (1H, s, Ar-H); 7.21 (1H, s, Ar-H); 7.68 (2H, s, 2xAr-H).
Embodiment 8:2-(2, the 6-dichlorophenoxy)-6,7-dihydro-9,10-dimethoxy-4 ' H-Mi Dingbing-[6,1-a] isoquinoline 99.9-4-ketone synthetic
Figure A0080677100371
Will be according to the preparation 1 2-chloro-6 that makes, 7-dihydro-9, (25g, 85mmol) with 2, (25.1g 153mmol) is dissolved in anhydrous N to the 6-chlorophenesic acid to 10-dimethoxy-4 ' H-Mi Dingbing-[6,1-a] isoquinoline 99.9-4-ketone, dinethylformamide (150ml).(30g, 217mmol) also this mixture is heated to 90 ℃ under nitrogen reach 2 hours to add salt of wormwood.With this mixture cooling, between water (1 liter) and ethyl acetate (500ml), distribute then.With the gained sedimentation and filtration,, be dissolved in methylene dichloride (500ml) once more and use salt solution (200ml) washing, with dried over mgso and vacuum concentration with ethyl acetate (100ml) and water (100ml) washing.Resistates is recrystallization from acetonitrile (600ml), obtains title compound, is faint yellow solid.22g，53％
mpt.：240-242℃。(300MHz，d 6DMSO)δ2.05(2H，t，C (7)H 2)；3.85(3H，s，OCH 3)；3.90(3H，s，OCH 3)；4.05(2H，t，C (6)H 2)；7.00(1H，s，C (1)H)；7.15(1H，s，Ar-H)；7.35(1H，t，Ar-H)；7.65(1H，s，Ar-H).
Embodiment 9:9,10-dimethoxy-2-(2-methylphenoxy)-6,7-dihydro-4H-Mi Dingbing [6,1-a] isoquinoline 99.9-4-ketone synthetic
Figure A0080677100381
With 2-chloro-9,10-dimethoxy-6,7-dihydro-4H-Mi Dingbing [6,1-a] isoquinoline 99.9-4-ketone (1) (1.5g, 5.13mmol) and ortho-cresol (1.66g 15.4mmol) is dissolved in Virahol (180ml).(2.13g is 15.4mmol) and with this mixture reflux 18 hours under nitrogen to add salt of wormwood.After being cooled to room temperature, this mixture is filtered the precipitation washing with acetone.With the filtrate vacuum-evaporation after merging, resistates is dissolved in methylene dichloride (220ml), and with 10%NaOH (40ml) washing, water (40ml) washs and dry (MgSO then 4).Vacuum-evaporation obtains brown oil, and it uses silica gel column chromatography purifying (EtOAc/ sherwood oil 80: 20).Obtain title compound, be faint yellow solid, 0.56g, 35%.
M.p.：???201-203℃。
M/z:C 21H 20N 2O 4Require M=364 actual measurement (M+1)=365
HPLC: area (%) 99.01
Post ODS (150 * 4.6mm)
MP?????????????0.2M?NH 4OAc/MeOH(40/60)
FR (ml/ minute) 0.8
RT (minute) 14.976
Detect 235nm 1H NMR (300MHz, CDCl 3): δ 2.22 (3H, s, ArCH 3), 2.97 (2H, t, CH 2), 3.98 (6H, s, 2xOCH 3), 4.21 (2H, t, CH 2), 6.40 (1H, s, C=CH), 6.78 (1H, s, ArH), 7.04-7.25 (5H, m, 5xArH).
Embodiment 10:9,10-dimethoxy-2-(2-isobutyl-phenoxy group)-6,7-dihydro-4H-Mi Dingbing [6.1-a] isoquinoline 99.9-4-ketone synthetic
2-isobutyl-phenol
With potassium tert.-butoxide (44.8g, 400mmol) be suspended in through the degassing heptane (1300ml) and add butyllithium (258ml, 400mmol).This reaction mixture was at room temperature stirred 20 minutes, and (10.8g, 100mmol), then reflux is 3 hours to add ortho-cresol then.This mixture is cooled to room temperature then and makes the precipitation sedimentation.Excessive solvent is decanted, and resistates washs with pentane.Repeat once this process again and the gained precipitation is suspended in THF (1500ml).This suspension is transferred to the 2-N-PROPYLE BROMIDE by sleeve pipe, and (10.33ml, in the THF solution (500ml) 110mmol), this reaction mixture at room temperature stirs and spends the night.This mixture makes quenching and uses HCl (5M) acidifying by adding entry (50ml).(3 * 100ml) extract with aqueous phase separation and with chloroform.With organic phase merging, dry (MgSO 4), filter and concentrate and obtain reddish-brown liquid.This thick matter utilization flash column chromatography purifying (90: 10 gasoline: EtOAc) obtain title compound, be yellow oil (7.63g, 51%).
9,10-dimethoxy-2-(2-isobutyl-phenoxy group)-6,7-dihydro-4H-Mi Dingbing [6,1-a] isoquinoline 99.9-4-ketone
(1.24g 8.16mmol) is dissolved in THF (40ml) and be cooled to-78 ℃ with 2-isobutyl-phenol.(5.12ml, 8.16mmol), this reaction mixture stirred 1 hour down at-78 ℃, slowly was heated to ambient temperature overnight then to add butyllithium then.Reaction is by adding NH 4Cl (40ml) stops, and (3 * 50ml) extract this mixture with EtOAc.Organic phase NH after the merging 4Cl (50ml) washing.The water that obtains after this water and the previous washing is merged, extract with EtOAc (50ml).Now all organic phases are merged, use the salt water washing, dry (MgSO 4), filter and the concentrated yellow oily solid that obtains.In resistates, add ether, leach the gained solid also with ice-cold ether washing.Resistates utilizes the flash column chromatography purifying, obtains title compound with eluent ethyl acetate, is white solid (0.5g, 18%).
Embodiment 11:2-(2-tertiary butyl phenoxy group)-9,10-dimethoxy-6,7-dihydro-4H-Mi Dingbing [6,1-a] isoquinoline 99.9-4-ketone synthetic
Figure A0080677100402
With 2-chloro-9,10-dimethoxy-6, (1.47g, 5.0mmol) (2.25g 15.0mmol) is dissolved in 2-propyl alcohol (180ml) to 7-dihydro-4H-Mi Dingbing [6,1-a] isoquinoline 99.9-4-ketone with the 2-tert.-butyl phenol.(2.07g, 15.0mmol), this mixture stirs and reflux 6 hours under nitrogen to add salt of wormwood.After being cooled to room temperature, this mixture is filtered filtrate vacuum-evaporation.Resistates obtains above-claimed cpd (1.35g, 66%) with silica gel column chromatography purifying [ethyl acetate/dichloromethane (3: 2)], is pale solid.
M.p.：??226-228℃
M/z:C 24H 26N 2O 4Require M=406, actual measurement m/z[ES+]=407
HPLC: area (%) 99.68
Post S5 C8 (250 * 4.6mm)
MP???????????????pH4?0.02M?KH 2PO 4/CH 3CN(35/65)
RT (minute) 9.175
FR (ml/ minute) 0.7
Detect 254nm 1H NMR (300MHz, CDCl 3): δ 1.39 (9H, s, CH (CH) 3), 2.97 (2H, t, CH 2), 3.97 (3H, s, OCH 3), 3.98 (3H, s, OCH 3), 4.23 (2H, t, CH 2), 6.38 (1H, s, C=CH), 6.78 (1H, s, ArH), 7.05-7.27 (4H, m, 4xArH), 7.40 (1H, m, ArH).
Embodiment 12:9,10-dimethoxy-2-(2-ethyl phenoxy group)-6,7-dihydro-4H-Mi Dingbing [6,1-a] isoquinoline 99.9-4-ketone synthetic
Figure A0080677100411
With 2-chloro-9,10-dimethoxy-6, (1.47g, 5.0mmol) (1.22g 10.0mmol) is dissolved in 2-propyl alcohol (180ml) to 7-dihydro-4H-Mi Dingbing [6,1-a] isoquinoline 99.9-4-ketone with the 2-ethylphenol.(1.38g, 10.0mmol), this mixture stirs and reflux 6 hours under nitrogen to add salt of wormwood.After being cooled to room temperature, this mixture is filtered filtrate vacuum-evaporation.Resistates obtains above-claimed cpd (1.27g, 67%) with silica gel column chromatography purifying [ethyl acetate/dichloromethane (3: 2)], is faint yellow solid.
M.p.：167-169℃
M/z:C 22H 22N 2O 4Require M=378, actual measurement m/z[ES+]=379
HPLC: area (%) 99.46
Post S5 C8 (250 * 4.6mm)
MP??????????pH4?0.02M?KH 2PO 4/CH 3CN(35/65)
RT (minute) 7.725
FR (ml/ minute) 0.7
Detect 254nm 1H NMR (300MHz, CDCl 3): δ 1.21 (3H, t, CH 2CH 3), 2.59 (2H, q, CH 2CH 3), 2.97 (2H, t, CH 2), 3.97 (6H, s, 2xOCH 3), 4.21 (2H, t, CH 2), 6.41 (1H, s, C=CH), 6.78 (1H, s, ArH), 7.05-7.28 (5H, m, 5xArH).
Embodiment 13:2-(2-cyclopentyl phenoxy group)-9,10-dimethoxy-6,7-dihydro-4H-Mi Dingbing [6,1-a] isoquinoline 99.9-4-ketone synthetic
Figure A0080677100421
With 2-chloro-9,10-dimethoxy-6, (1.20g, 4.11mmol) (1.0g 6.17mmol) is dissolved in 2-propyl alcohol (150ml) to 7-dihydro-4H-Mi Dingbing [6,1-a] isoquinoline 99.9-4-ketone with 2-cyclopentyl phenol.(1.14g, 8.23mmol), this mixture stirs under nitrogen and is heated to and refluxed 18 hours to add salt of wormwood.After being cooled to room temperature, this mixture is filtered filtrate vacuum-evaporation.Resistates obtains above-claimed cpd (0.51g, 30%) with silica gel column chromatography purifying [ethyl acetate/dichloromethane (3: 2)], is faint yellow solid.
M.p.：122-125℃
M/z:C 25H 26N 2O 4Require M=418, actual measurement m/z[ES+]=419
HPLC: area (%) 99.43
Post S5 C8 (250 * 4.6mm)
MP???????????????pH4?0.02M?KH 2PO 4/CH 3CN(35/65)
RT (minute) 10.191
FR (ml/ minute) 0.7
Detect 254nm 1H NMR (300MHz, CDCl 3): δ 1.57-2.05 (8H, m, cyclopentyl 4xCH 2), 2.97 (2H, t, CH 2), 3.13 (1H, m, ArCH), 3.97 (6H, s, 2xOCH 3), 4.21 (2H, t, CH 2), 6.38 (1H, s, C=CH), 6.78 (1H, s, ArH), 7.07 (1H, m, ArH), 7.18 (3H, m, 3xArH), 7.32 (1H, m, ArH).
The pharmacology function of The compounds of this invention has obtained proof in using the research that the synthetic compound carries out described in previous as the above-mentioned embodiment.Following result is used for setting forth the general application of The compounds of this invention.
Embodiment A: the electricity of The compounds of this invention antagonism cavy separation tracheae is induced the effect of contraction
The electricity of test The compounds of this invention antagonism cavy separation tracheae is induced the effect of contraction.The result proves that the compound of embodiment 2,3,10,11,12 and 13 has suppressed contractile response, and the long continuous action time is arranged.
Embodiment A (i)-outflow experiment
Method
The outflow of guinea pig trachea ring is carried out (Coleman etc., lung pharmacology 9107-117 (1996)) according to previously disclosed method.In brief, the guinea pig trachea sample is cut into ring, then by in the face of the unstriated muscle cut ring and with its incision and be suspended between two platinum electrodes under the 1g tension force.This is organized in 37 ℃ and flows out and feeding gas 95%O with the speed from 1 to 3.25ml/ minute with the Krebs-Henseleit solution that contains cyclooxygenase inhibitors INDOMETHACIN (5 μ M) down 2And 5%CO 2Make tracheae sample balance 40 minutes, utilize the physiology rectangular pulse stimulator to begin electricity irritation then, discharge the square-wave pulse of the 3Hz in a string 10 seconds, continue 0.1ms and produced 20V (about 400mAmps) in per 100 seconds.The compounds of this invention flows out with 0.2 to 0.3ml/ minute speed, uses the MacLab software records on macintosh computer to the contractile response of electrical field stimulation.Medicine is with DMSO preparation and use the Krebs-Henseleit solution dilution, and making final outflow concentration is 0.05 to 0.1%DMSO.
The result
Measure continuous action time and the time opening of being expressed as (OT 50) and time of recovery (RT 50).Mensuration reaches 50% maximum the inhibition (time opening: OT) time of being spent to contractile response, similarly, reach (the time of recovery: RT50) time that 50% reverse that the maximum to contractile response suppresses is spent after measuring tissue and contacting of compound stopping.These numerical value are presented in the table 1.
As shown in table 1, all test compounds have caused that all the time-dependent manner to the contractile response of the electrical field stimulation generation of cavy separation tracheae suppresses.The recovery of the contractile response of electrical field stimulation is slow, and inhibited reaction is stopping administration still not reverse after 4 hours.Carrier DMSO does not have obviously to suppress the contractile response (Fig. 1) of electrical field stimulation.
Table 1.OT 50And RT 50Value
Compound OT50 (minute) RT50 (minute) Figure
2-(2,6-diethyl phenoxy group)-6,7-dihydro-9,10-dimethoxy-4 ' H-Mi Dingbing [6,1-a] isoquinoline 99.9-4-ketone (embodiment 3) ????17±1 ????＞240 Fig. 2
2-(2-tertiary butyl phenoxy group)-9,10-dimethoxy-6,7-dihydro-4H-Mi Dingbing [6,1-a] isoquinoline 99.9-4-ketone (embodiment 11) ??14.7±1.33 ????＞300 Fig. 3
9,10-dimethoxy-2-(2-ethyl phenoxy group)-6,7-dihydro-4H-Mi Dingbing [6,1-a] isoquinoline 99.9-4-ketone (embodiment 12) ???9.7±0.6 ??????263 Fig. 4
2-(2-cyclopentyl phenoxy group)-9,10-dimethoxy-6,7-dihydro-4H-Mi Dingbing [6,1-a] isoquinoline 99.9-4-ketone (embodiment 13) ??18.6±1.5 ????＞300 Fig. 5
9,10-dimethoxy-2-(2-isobutyl-phenoxy group)-6,7-dihydro-4H-Mi Dingbing [6,1-a] isoquinoline 99.9-4-ketone (embodiment 10) ??17.5±1.25 ????＞300 Fig. 9
6,7-dihydro-2-(2,6-di-isopropyl phenoxy group)-9,10-dimethoxy-4 ' H-Mi Dingbing [6,1-a] isoquinoline 99.9-4-ketone (embodiment 2) ??24.9±5.0 ????＞240 Fig. 8
Trequinsin (9,10-dimethoxy-3-methoxyl group-2-base imino--2,3,6,7-tetrahydrochysene-4H-Mi Dingbing [6,1-a] isoquinoline 99.9-4-ketone) ????14 ??????146
(unless the explanation to " n " is arranged in addition, otherwise each numerical value all being the average and the standard error average of 3 observed values)
Embodiment A (ii)-organ bath experiments
Method
Be suspended on the guinea pig trachea ring in the organ bath between two electrodes under the 1g tension force and accept the electrical field stimulation (3Hz, 0.1ms time length and 20V (about 400mAmps)) that utilizes the physiology rectangular pulse stimulator to produce in per 100 seconds.Embodiment 1,2 and 8 compounds are dissolved among the DMSO that contains tween 80 (10%) and distilled water (0.01M), and it being joined make final concentration in the organ bath then is 10 μ M.
The result
The results are shown in Fig. 6 (about embodiment 1 compound), Fig. 7 (about embodiment 8 compounds) and Fig. 8 (relevant embodiment 2 compounds).All compounds all cause the inhibition fully of the contractile response of electrical field stimulation and effect were kept more than 2-4 hour.
Embodiment B: the effect of The compounds of this invention antagonism person monocytic cell's the propagation that stimulates by PHA
Also studied the effect of The compounds of this invention to person monocytic cell's the propagation that stimulates by PHA.Propagation is subjected to the remarkable inhibition of these compounds, shows that they have anti-inflammatory activity.Following result is used for setting forth the general application of novel The compounds of this invention.
Method
Normal healthy volunteer is implemented bloodletting and gathers 25ml blood.Method (Banner etc., Britain pharmacology magazine 116 3169-3174 (1995)) according to Banner etc. is separated and the purifying monocyte.Human peripheral mononuclear cell (100,000/ hole) under 37 ℃ at 95% air, 5%CO 2Under the condition that has or do not exist embodiment 1,2 and 8 compounds (0.001-100 μ M), stimulated 24 hours in the atmosphere with phytoh(a)emagglutinin (PHA, 2 μ g/ml).After 24 hours, in each hole, add [ 3H]-thymidine (0.1 μ Ci), cell was cultivated 24 hours again.(ICN Flow Buckinghamshire) counts cell harvesting to glass fibre filter and in scintillometer to use cell harvester then.
The result
All test-compounds all cause the concentration dependent of the person monocytic cell's propagation that is stimulated by PHA is suppressed (n=6; Fig. 9).The IC that has shown these compounds in the table 2 50Value and 95% fiducial limit.The result also is shown among Figure 10.Table 2: the IC that the person monocytic cell that all cpds antagonism is stimulated by PHA breeds 50Value (n=6)
Compound IC 50
6,7-dihydro-2-(2, the 6-dimethyl phenoxy)-9,10-dimethoxy-4 ' H-Mi Dingbing [6,1-a] isoquinoline 99.9-4-ketone (embodiment 1) ?5.13μM (2.88-9.14)
6,7-dihydro-2-(2,6-di-isopropyl phenoxy group)-9,10-dimethoxy-4 ' H-Mi Dingbing [6,1-a] isoquinoline 99.9-4-ketone (embodiment 2) ?2.90μM (1.56-5.41)
2-(2, the 6-dichlorophenoxy)-6,7-dihydro-9,10-dimethoxy-4 ' H-Mi Dingbing [6,1-a] isoquinoline 99.9-4-ketone (embodiment 8) ??8.22μM (4.23-16.0)
Embodiment C
6,7-dihydro-2-(2,6-di-isopropyl phenoxy group)-9,10-dimethoxy-4 ' H-Mi Dingbing [6,1-a] isoquinoline 99.9-4-ketone (embodiment 2 compounds) has shown it is the potent inhibitor of phosphodiesterase (PDE) 3 and 4 type isozymes.The IC50 value is as follows.
PDE3(nM)????????PDE4(nM)
(human blood platelets) (human neutrophils)
Embodiment 2 107 1195
Rolipram ND 6412
Cilostamide 89 ND
Rolipram is known PDE4 inhibitor, and Cilostamide is known PDE3 inhibitor.
ND-does not determine
Embodiment D
Test 6,7-dihydro-2-(2,6-di-isopropyl phenoxy group)-9,10-dimethoxy-4 ' H-Mi Dingbing [6,1-a] isoquinoline 99.9-4-ketone (embodiment 2 compounds) is to the effect of LPS inductive TNF-α from person monocytic cell's release.The result is as follows.
IC 50(nM)
Compound 250 n=6
CDP 840 (PDE4 inhibitor) 92 n=6
Siguazodan (PDE3 inhibitor)＞100 μ M
Embodiment E: about 6,7-dihydro-2-(2,6-di-isopropyl phenoxy group)-9, the in vivo test of 10-dimethoxy-4 ' H-Mi Dingbing [6,1-a] isoquinoline 99.9-4-ketone (embodiment 2 compounds)
1, above-claimed cpd is tested with histamine inductive bronchospasm model.Make clear-headed cavy accept compound dry powder (micronized).Medicine is mixed with lactose, and making final concentration is 0.25,2.5 and 25%.Different time after accepting medicine also stimulates Animal Anesthesia with the histamine of various dose.Record air flue total-resistance and mean arterial blood pressure.Accepting dry powder (25%) has produced the remarkable protection of antihistamine inductive bronchospasm and has not changed mean arterial blood pressure.
2, embodiment 2 compounds (0.1 to 300 μ g/kg) make mean arterial blood pressure produce the dose-dependently reduction to the cavy intravenously administrable of urethane anesthesia.Compound is dissolved in DMSO, then with salt solution dilution (evidence suggests that compound comes out from solution).
3, in the eosinophilia model of the antigen induction of ovalbumin sensitization cavy, embodiment 2 compounds (10mg/kg) of preceding 1 hour oral administration of antigenic stimulation significantly suppressed in the sensitized guinea pig body eosinocyte in antigenic stimulation (aerosol) back the recruitment to lung.
Embodiment F: the taste of compound
For the medical compounds of oral administration, how the taste of compound is the important factors of guaranteeing patient's compliance.Unexpectedly, The compounds of this invention is tasteless basically.Therefore they are particularly suitable for oral administration, for example as inhalant dry powder doses.
Method
All compounds, trequinsin (9 with the foregoing description 1 to 13,10-dimethoxy-3-methyl-2-base imino--2,3,6,7-tetrahydrochysene-4H-Mi Dingbing [6,1-a] isoquinoline 99.9-4-ketone) and the demethyl trequinsin (9,10-dimethoxy-2-base imino--2,3,6,7-tetrahydrochysene-4H-Mi Dingbing [6,1-a] isoquinoline 99.9-4-ketone) each places on a small quantity on the tip of the tongue of the healthy male volunteers of being apprised of truth, and evaluates the taste of every kind of compound.
The result
All compounds of embodiment 1 to 13 are not bitter, so they are compared taste with very bitter trequinsin or demethyl trequinsin significant improvement is arranged.

Claims (43)

1, compound of Formula I:
Figure A0080677100021
Wherein:
R 1And R 2Represent C independently of one another 1-6Alkyl or C 2-7Acyl group;
X represents OCH 2Or group CR 3R 4, R wherein 3And R 4Represent hydrogen atom or C independently of one another 1-3Alkyl;
R 5Expression hydrogen atom or C 1-3Alkyl, C 2-3Alkenyl or C 2-3Alkynyl;
R 6Expression hydrogen atom or C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, amino, C 1-6Alkylamino, two (C 1-6) alkylamino or C 2-7Amido;
R 7And R 8Represent hydrogen or halogen atom or hydroxyl, trifluoromethyl, C independently of one another 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 2-7Acyl group, C 1-6Alkylthio, C 1-6Alkoxyl group or C 3-6Cycloalkyl;
R 9Expression hydrogen or halogen atom or hydroxyl, trifluoromethyl, C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 2-7Acyl group, C 1-6Alkylthio, C 1-6Alkoxyl group or C 3-6Cycloalkyl;
Or its salt;
But get rid of compound 6,7-dihydro-2-phenoxy group-9,10-dimethoxy-4 ' H-Mi Dingbing [6,1a] isoquinoline 99.9-4-ketone.
2, compound according to claim 1, wherein independently or with any in combination compatible:
R 1And R 2Represent C separately 1-6Alkyl, preferred C 1-4Alkyl;
R 1And R 2Be mutually the same;
R 3And R 4Represent hydrogen atom separately;
R 5The expression hydrogen atom;
R 6The expression hydrogen atom;
R 7And R 8Represent C separately 1-6Alkyl, preferable methyl, ethyl or sec.-propyl;
R 7And R 8Be mutually the same;
R 9Expression halogen atom or methyl or ethanoyl.
3,6,7-dihydro-2-(2, the 6-dimethyl phenoxy)-9,10-dimethoxy-4 ' H-Mi Dingbing-[6,1-a] isoquinoline 99.9-4-ketone.
4,2-(2,6-diethyl phenoxy group)-6,7-dihydro-9,10-dimethoxy-4 ' H-Mi Dingbing-[6,1-a] isoquinoline 99.9-4-ketone.
5,6,7-dihydro-2-(2,6-di-isopropyl phenoxy group)-9,10-dimethoxy-4 ' H-Mi Dingbing-[6,1-a] isoquinoline 99.9-4-ketone.
6,6,7-dihydro-9,10-dimethoxy-2-(2,4,6-trimethylammonium phenoxy group)-4H-Mi Dingbing-[6,1-a] isoquinoline 99.9-4-ketone.
7,2-(4-chloro-2,6-dimethyl phenoxy)-6,7-dihydro-9,10-dimethoxy-4 ' H-Mi Dingbing-[6,1-a] isoquinoline 99.9-4-ketone.
8,2-(4-bromo-2,6-dimethyl phenoxy)-6,7-dihydro-9,10-dimethoxy-4 ' H-Mi Dingbing-[6,1-a] isoquinoline 99.9-4-ketone.
9,6,7-dihydro-9,10-dimethoxy-2-(4-ethanoyl-2,6-dimethyl phenoxy)-4H-Mi Dingbing-[6,1-a] isoquinoline 99.9-4-ketone.
10,2-(2, the 6-dichlorophenoxy)-6,7-dihydro-9,10-dimethoxy-4 ' H-Mi Dingbing-[6,1-a] isoquinoline 99.9-4-ketone.
11,9,10-dimethoxy-2-(2-methylphenoxy)-6,7-dihydro-4H-Mi Dingbing [6,1-a] isoquinoline 99.9-4-ketone.
12,9,10-dimethoxy-2-(2-isobutyl-phenoxy group)-6,7-dihydro-4H-Mi Dingbing [6,1-a] isoquinoline 99.9-4-ketone.
13,2-(2-tertiary butyl phenoxy group)-9,10-dimethoxy-6,7-dihydro-4H-Mi Dingbing [6,1-a] isoquinoline 99.9-4-ketone.
14,9,10-dimethoxy-2-(2-ethyl phenoxy group)-6,7-dihydro-4H-Mi Dingbing [6,1-a] isoquinoline 99.9-4-ketone.
15,2-(2-cyclopentyl phenoxy group)-9,10-dimethoxy-6,7-dihydro-4H-Mi Dingbing [6,1-a] isoquinoline 99.9-4-ketone.
16, compound of Formula I as defined in claim 1 but do not comprise compound 6,7-dihydro-2-phenoxy group-9, the preparation method of 10-dimethoxy-4 ' H-Mi Dingbing [6,1a] isoquinoline 99.9-4-ketone, this method comprises:
(a) general formula I I compound: R wherein 1, R 2, R 5, R 6Define with X such as mutual-through type I, and LG represents leavings group,
React with compound of formula III:
Figure A0080677100042
R wherein 7, R 8And R 9I defines as mutual-through type; Perhaps
(b) X represents group CR in general formula I 3R 4, R wherein 3Expression hydrogen atom, R 4Expression hydrogen atom or C 1-3Alkyl and R 5Expression hydrogen atom or C 1-3During alkyl, with general formula I X hydrogenation of compounds:
Figure A0080677100043
R wherein 1, R 2, R 6, R 7, R 8And R 9I defines as mutual-through type; With
(c) compound of Formula I that will so form alternatively is converted into another compound of Formula I.
17, method as claimed in claim 16, wherein the LG among the general formula I I represents the chlorine atom.
18, as claim 16 or 17 described methods, wherein step (a) is carried out in the presence of alkali such as salt of wormwood in suitable solvent such as dimethyl formamide or Virahol.
19, as claim 16,17 or 18 described methods, wherein each defines in compound of Formula I such as the claim 1 to 15.
20, a kind of composition, it comprises compound of Formula I:
Figure A0080677100051
Wherein:
R 1And R 2Represent C independently of one another 1-6Alkyl or C 2-7Acyl group;
X represents OCH 2Or group CR 3R 4, R wherein 3And R 4Represent hydrogen atom or C independently of one another 1-3Alkyl;
R 5Expression hydrogen atom or C 1-3Alkyl, C 2-3Alkenyl or C 2-3Alkynyl;
R 6Expression hydrogen atom or C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, amino, C 1-6Alkylamino, two (C 1-6) alkylamino or C 2-7Amido;
R 7And R 8Represent hydrogen or halogen atom or hydroxyl, trifluoromethyl, C independently of one another 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 2-7Acyl group, C 1-6Alkylthio, C 1-6Alkoxyl group or C 3-6Cycloalkyl;
R 9Expression hydrogen or halogen atom or hydroxyl, trifluoromethyl, C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 2-7Acyl group, C 1-6Alkylthio, C 1-6Alkoxyl group or C 3-6Cycloalkyl;
Or its salt;
With animal doctor or pharmaceutically acceptable carrier or thinner.
21, composition as claimed in claim 20, it further comprises active agents such as β 2-adrenoceptor agonists or glucocorticosteroid steroid.
22, as claim 20 or 21 described compositions, wherein said composition is the pharmaceutical composition that is used for physianthropy.
23, as claim 20,21 or 22 described compositions, it is suitable for passing through aerosol drug delivery.
24, as each described composition of claim 20-23, wherein each defines in compound such as the claim 1 to 15.
25, the compound of Formula I that is used for medicine:
Figure A0080677100061
Wherein:
R 1And R 2Represent C independently of one another 1-6Alkyl or C 2-7Acyl group;
X represents OCH 2Or group CR 3R 4, R wherein 3And R 4Represent hydrogen atom or C independently of one another 1-3Alkyl;
R 5Expression hydrogen atom or C 1-3Alkyl, C 2-3Alkenyl or C 2-3Alkynyl;
R 6Expression hydrogen atom or C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, amino, C 1-6Alkylamino, two (C 1-6) alkylamino or C 2-7Amido;
R 7And R 8Represent hydrogen or halogen atom or hydroxyl, trifluoromethyl, C independently of one another 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 2-7Acyl group, C 1-6Alkylthio, C 1-6Alkoxyl group or C 3-6Cycloalkyl;
R 9Expression hydrogen or halogen atom or hydroxyl, trifluoromethyl, C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 2-7Acyl group, C 1-6Alkylthio, C 1-6Alkoxyl group or C 3-6Cycloalkyl;
Or its salt.
26, be used as the compound of Formula I of phosphodiester enzyme isoenzyme inhibitor:
Figure A0080677100071
Wherein:
R 1And R 2Represent C independently of one another 1-6Alkyl or C 2-7Acyl group;
X represents OCH 2Or group CR 3R 4, R wherein 3And R 4Represent hydrogen atom or C independently of one another 1-3Alkyl;
R 5Expression hydrogen atom or C 1-3Alkyl, C 2-3Alkenyl or C 2-3Alkynyl;
R 6Expression hydrogen atom or C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, amino, C 1-6Alkylamino, two (C 1-6) alkylamino or C 2-7Amido;
R 7And R 8Represent hydrogen or halogen atom or hydroxyl, trifluoromethyl, C independently of one another 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 2-7Acyl group, C 1-6Alkylthio, C 1-6Alkoxyl group or C 3-6Cycloalkyl;
R 9Expression hydrogen or halogen atom or hydroxyl, trifluoromethyl, C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 2-7Acyl group, C 1-6Alkylthio, C 1-6Alkoxyl group or C 3-6Cycloalkyl;
Or its salt.
27, be used to prevent or treat the compound of Formula I of the disease of the intracellular concentration of wherein wishing rising cAMP:
Wherein:
R 1And R 2Represent C independently of one another 1-6Alkyl or C 2-7Acyl group;
X represents OCH 2Or group CR 3R 4, R wherein 3And R 4Represent hydrogen atom or C independently of one another 1-3Alkyl;
R 5Expression hydrogen atom or C 1-3Alkyl, C 2-3Alkenyl or C 2-3Alkynyl;
R 6Expression hydrogen atom or C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, amino, C 1-6Alkylamino, two (C 1-6) alkylamino or C 2-7Amido;
R 7And R 8Represent hydrogen or halogen atom or hydroxyl, trifluoromethyl, C independently of one another 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 2-7Acyl group, C 1-6Alkylthio, C 1-6Alkoxyl group or C 3-6Cycloalkyl;
R 9Expression hydrogen or halogen atom or hydroxyl, trifluoromethyl, C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 2-7Acyl group, C 1-6Alkylthio, C 1-6Alkoxyl group or C 3-6Cycloalkyl;
Or its salt.
28, be used to prevent or treat the compound of Formula I of asthma:
Figure A0080677100081
Wherein:
R 1And R 2Represent C independently of one another 1-6Alkyl or C 2-7Acyl group;
X represents OCH 2Or group CR 3R 4, R wherein 3And R 4Represent hydrogen atom or C independently of one another 1-3Alkyl;
R 5Expression hydrogen atom or C 1-3Alkyl, C 2-3Alkenyl or C 2-3Alkynyl;
R 6Expression hydrogen atom or C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, amino, C 1-6Alkylamino, two (C 1-6) alkylamino or C 2-7Amido;
R 7And R 8Represent hydrogen or halogen atom or hydroxyl, trifluoromethyl, C independently of one another 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 2-7Acyl group, C 1-6Alkylthio, C 1-6Alkoxyl group or C 3-6Cycloalkyl;
R 9Expression hydrogen or halogen atom or hydroxyl, trifluoromethyl, C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 2-7Acyl group, C 1-6Alkylthio, C 1-6Alkoxyl group or C 3-6Cycloalkyl;
Or its salt.
29, the compound of Formula I that is used for prevention or treatment chronic obstructive pulmonary disease (COPD):
Figure A0080677100091
Wherein:
R 1And R 2Represent C independently of one another 1-6Alkyl or C 2-7Acyl group;
X represents OCH 2Or group CR 3R 4, R wherein 3And R 4Represent hydrogen atom or C independently of one another 1-3Alkyl;
R 5Expression hydrogen atom or C 1-3Alkyl, C 2-3Alkenyl or C 2-3Alkynyl;
R 6Expression hydrogen atom or C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, amino, C 1-6Alkylamino, two (C 1-6) alkylamino or C 2-7Amido;
R 7And R 8Represent hydrogen or halogen atom or hydroxyl, trifluoromethyl, C independently of one another 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 2-7Acyl group, C 1-6Alkylthio, C 1-6Alkoxyl group or C 3-6Cycloalkyl;
R 9Expression hydrogen or halogen atom or hydroxyl, trifluoromethyl, C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 2-7Acyl group, C 1-6Alkylthio, C 1-6Alkoxyl group or C 3-6Cycloalkyl;
Or its salt.
30, as each described compound of claim 25-29, wherein each defines in this compound such as the claim 1 to 15.
31, the purposes of compound of Formula I in preparation III/IV type phosphodiester enzyme isoenzyme inhibitor:
Wherein:
R 1And R 2Represent C independently of one another 1-6Alkyl or C 2-7Acyl group;
X represents OCH 2Or group CR 3R 4, R wherein 3And R 4Represent hydrogen atom or C independently of one another 1-3Alkyl;
R 5Expression hydrogen atom or C 1-3Alkyl, C 2-3Alkenyl or C 2-3Alkynyl;
R 6Expression hydrogen atom or C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, amino, C 1-6Alkylamino, two (C 1-6) alkylamino or C 2-7Amido;
R 7And R 8Represent hydrogen or halogen atom or hydroxyl, trifluoromethyl, C independently of one another 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 2-7Acyl group, C 1-6Alkylthio, C 1-6Alkoxyl group or C 3-6Cycloalkyl;
R 9Expression hydrogen or halogen atom or hydroxyl, trifluoromethyl, C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 2-7Acyl group, C 1-6Alkylthio, C 1-6Alkoxyl group or C 3-6Cycloalkyl;
Or its salt.
32, the purposes of compound of Formula I in the preparation bronchodilator:
Wherein:
R 1And R 2Represent C independently of one another 1-6Alkyl or C 2-7Acyl group;
X represents OCH 2Or group CR 3R 4, R wherein 3And R 4Represent hydrogen atom or C independently of one another 1-3Alkyl;
R 5Expression hydrogen atom or C 1-3Alkyl, C 2-3Alkenyl or C 2-3Alkynyl;
R 6Expression hydrogen atom or C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, amino, C 1-6Alkylamino, two (C 1-6) alkylamino or C 2-7Amido;
R 7And R 8Represent hydrogen or halogen atom or hydroxyl, trifluoromethyl, C independently of one another 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 2-7Acyl group, C 1-6Alkylthio, C 1-6Alkoxyl group or C 3-6Cycloalkyl;
R 9Expression hydrogen or halogen atom or hydroxyl, trifluoromethyl, C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 2-7Acyl group, C 1-6Alkylthio, C 1-6Alkoxyl group or C 3-6Cycloalkyl;
Or its salt.
33, the purposes of compound of Formula I in the preparation antiasthmatic drug:
Wherein:
R 1And R 2Represent C independently of one another 1-6Alkyl or C 2-7Acyl group;
X represents OCH 2Or group CR 3R 4, R wherein 3And R 4Represent hydrogen atom or C independently of one another 1-3Alkyl;
R 5Expression hydrogen atom or C 1-3Alkyl, C 2-3Alkenyl or C 2-3Alkynyl;
R 6Expression hydrogen atom or C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, amino, C 1-6Alkylamino, two (C 1-6) alkylamino or C 2-7Amido;
R 7And R 8Represent hydrogen or halogen atom or hydroxyl, trifluoromethyl, C independently of one another 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 2-7Acyl group, C 1-6Alkylthio, C 1-6Alkoxyl group or C 3-6Cycloalkyl;
R 9Expression hydrogen or halogen atom or hydroxyl, trifluoromethyl, C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 2-7Acyl group, C 1-6Alkylthio, C 1-6Alkoxyl group or C 3-6Cycloalkyl;
Or its salt.
34, compound of Formula I is used for the purposes of the medicine of prevention or treatment chronic obstructive pulmonary disease (COPD) in preparation:
Figure A0080677100112
Wherein:
R 1And R 2Represent C independently of one another 1-6Alkyl or C 2-7Acyl group;
X represents OCH 2Or group CR 3R 4, R wherein 3And R 4Represent hydrogen atom or C independently of one another 1-3Alkyl;
R 5Expression hydrogen atom or C 1-3Alkyl, C 2-3Alkenyl or C 2-3Alkynyl;
R 6Expression hydrogen atom or C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, amino, C 1-6Alkylamino, two (C 1-6) alkylamino or C 2-7Amido;
R 7And R 8Represent hydrogen or halogen atom or hydroxyl, trifluoromethyl, C independently of one another 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 2-7Acyl group, C 1-6Alkylthio, C 1-6Alkoxyl group or C 3-6Cycloalkyl;
R 9Expression hydrogen or halogen atom or hydroxyl, trifluoromethyl, C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 2-7Acyl group, C 1-6Alkylthio, C 1-6Alkoxyl group or C 3-6Cycloalkyl;
Or its salt.
35, as each described purposes of claim 31-34, wherein each defines in compound such as the claim 1 to 15.
36, be useful treatment of diseases or prevention method to mammiferous wherein phosphodiester enzyme isoenzyme inhibitor and/or bronchodilator expection, compound of Formula I effective to described Mammals administration, nontoxic amount that this method comprises:
Wherein:
R 1And R 2Represent C independently of one another 1-6Alkyl or C 2-7Acyl group;
X represents OCH 2Or group CR 3R 4, R wherein 3And R 4Represent hydrogen atom or C independently of one another 1-3Alkyl;
R 5Expression hydrogen atom or C 1-3Alkyl, C 2-3Alkenyl or C 2-3Alkynyl;
R 6Expression hydrogen atom or C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, amino, C 1-6Alkylamino, two (C 1-6) alkylamino or C 2-7Amido;
R 7And R 8Represent hydrogen or halogen atom or hydroxyl, trifluoromethyl, C independently of one another 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 2-7Acyl group, C 1-6Alkylthio, C 1-6Alkoxyl group or C 3-6Cycloalkyl;
R 9Expression hydrogen or halogen atom or hydroxyl, trifluoromethyl, C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 2-7Acyl group, C 1-6Alkylthio, C 1-6Alkoxyl group or C 3-6Cycloalkyl;
Or its salt.
37, the method for treatment or prevention Mammals asthma, compound of Formula I effective to described Mammals administration, nontoxic amount that this method comprises:
Wherein:
R 1And R 2Represent C independently of one another 1-6Alkyl or C 2-7Acyl group;
X represents OCH 2Or group CR 3R 4, R wherein 3And R 4Represent hydrogen atom or C independently of one another 1-3Alkyl;
R 5Expression hydrogen atom or C 1-3Alkyl, C 2-3Alkenyl or C 2-3Alkynyl;
R 6Expression hydrogen atom or C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, amino, C 1-6Alkylamino, two (C 1-6) alkylamino or C 2-7Amido;
R 7And R 8Represent hydrogen or halogen atom or hydroxyl, trifluoromethyl, C independently of one another 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 2-7Acyl group, C 1-6Alkylthio, C 1-6Alkoxyl group or C 3-6Cycloalkyl;
R 9Expression hydrogen or halogen atom or hydroxyl, trifluoromethyl, C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 2-7Acyl group, C 1-6Alkylthio, C 1-6Alkoxyl group or C 3-6Cycloalkyl;
Or its salt.
38, treat or prevent the method for mammiferous chronic obstructive pulmonary disease (COPD), compound of Formula I effective to described Mammals administration, nontoxic amount that this method comprises:
Figure A0080677100141
Wherein:
R 1And R 2Represent C independently of one another 1-6Alkyl or C 2-7Acyl group;
X represents OCH 2Or group CR 3R 4, R wherein 3And R 4Represent hydrogen atom or C independently of one another 1-3Alkyl;
R 5Expression hydrogen atom or C 1-3Alkyl, C 2-3Alkenyl or C 2-3Alkynyl;
R 6Expression hydrogen atom or C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, amino, C 1-6Alkylamino, two (C 1-6) alkylamino or C 2-7Amido;
R 7And R 8Represent hydrogen or halogen atom or hydroxyl, trifluoromethyl, C independently of one another 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 2-7Acyl group, C 1-6Alkylthio, C 1-6Alkoxyl group or C 3-6Cycloalkyl;
R 9Expression hydrogen or halogen atom or hydroxyl, trifluoromethyl, C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 2-7Acyl group, C 1-6Alkylthio, C 1-6Alkoxyl group or C 3-6Cycloalkyl;
Or its salt.
39, as claim 36,37 or 38 described methods, wherein each defines in compound such as the claim 1 to 15.
40, as each described method of claim 36-39, wherein compound passes through aerosol drug delivery.
41, as each described method of claim 36-40, wherein animal is the people.
42, basically as mentioned in the compound described in any one embodiment.
43, basically as mentioned in the method described in any one embodiment.
CN00806771A 1999-03-31 2000-03-29 Derivatives of pyrimido [6,1-a] isoquinolin -4-one Pending CN1348452A (en)

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