CN1223115A - Pharmaceutical composition containing quinoline and quinazoline derivatives and novel compounds therefor - Google Patents
Pharmaceutical composition containing quinoline and quinazoline derivatives and novel compounds therefor Download PDFInfo
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- CN1223115A CN1223115A CN 98109507 CN98109507A CN1223115A CN 1223115 A CN1223115 A CN 1223115A CN 98109507 CN98109507 CN 98109507 CN 98109507 A CN98109507 A CN 98109507A CN 1223115 A CN1223115 A CN 1223115A
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Abstract
An anti-inflammatory agent comprising a compound of the formula (I) is disclosed. The quinoline compounds included in the compound (I) are novel and there is also disclosed processes for producing them.
Description
The present invention relates to contain the medicament of the antiinflammatory of quinoline or quinazoline derivant, particularly treatment of arthritis; Relate to novel uqinoline derivatives or its salt as antiinflammatory.
Arthritis is the inflammatory diseases in joint, and its main example has rheumatoid arthritis and the similar disease thereof of observing inflammation in the joint.
Wherein, rheumatoid arthritis also claims chronic rheumatism, is the polyarthritis chronic disease, and its main damage is that the inflammatory of joint capsule internal layer synovial membrane changes.Arthritis and rheumatoid arthritis are progressive, and cause joint disease such as joint deformity, tetanic etc.As effectively not treating, sb.'s illness took a turn for the worse, often causes the serious dyskinesia.
Up to now, in above-mentioned arthritic treatment, adopt following medicine to carry out chemotherapy always: steroid, as adrenocortical hormone (as cortisone etc.) etc.; Non-steroidal anti-inflammatory agent is as aspirin, piroxicam, indometacin etc.; Gold preparation and as the mercaptosuccinic acid. gold etc.; Rheumatism is as chloroquine preparation, Beracilline etc.; Antigout drug is as colchicine etc.; Immunosuppressant is as cyclophosphamide, azathioprine, methotrexate, nemicide etc.; Or the like.
Yet, be used for chemotherapeutical medicine and have some problems, for example serious adverse (these side effect make them be difficult to life-time service), poor effect, invalid the arthritis of existing symptom.
Therefore in arthritic clinical treatment, need low toxicity always, prevent and treat arthritis drug efficiently.
One of purpose of the present invention provides the new antiinflammatory that contains quinoline or quinazoline derivant.
Two of purpose of the present invention provides new quinoline or the quinazoline derivant as antiinflammatory.
Three of the object of the invention provides the method for above-mentioned quinoline of preparation or quinazoline derivant.
Above-mentioned purpose of the present invention and other purpose and advantage are conspicuous to the professional from the following description.
The inventor finds: the quinoline or the quinazoline derivant that are connected with sulphur atom, oxygen atom or the alkylidene of any oxidation in its 2-position by methylene have arthritis activity, anti-inflammatory activity, antipyretic activity and analgesic activity, anti-IL-1 activity, antigen reactivity T cell growth inhibiting activity or the like, so useful as anti-inflammatory agents.So finished the present invention.
That is to say, the invention provides:
(1) contains the antiinflammatory of formula I compound or its salt
Y is nitrogen-atoms or C-G (wherein G be can esterified carboxyl) in the formula; X be any oxidation sulphur atom, oxygen atom or-(CH
2)
q-(wherein q is an integer 1 to 5); R is the alkyl of replacement arbitrarily or the heterocyclic group of any replacement that ring carbon atom is connected with X; A ring and B ring all can at random have at least one substituent group; K is 0 or 1;
(2) formula (I ') compound or its salt
Y is C-G (wherein G be can esterified carboxyl) in the formula; X be any oxidation sulphur atom or-(CH
2)
q-(wherein q is an integer 1 to 5); R is the alkyl of replacement arbitrarily or the heterocyclic group of any replacement that ring carbon atom is connected with X; A ring and B ring all can at random have at least one substituent group; K is 0 or 1;
(3) method of preparation formula (I-1) compound or its salt
Y is C-G (wherein G be can esterified carboxyl) in the formula; Z is the sulphur atom of any oxidation; R is the alkyl of replacement arbitrarily or the heterocyclic group of any replacement that ring carbon atom is connected with Z; A ring and B ring all can at random have at least one substituent group; K is 0 or 1; This method comprises that with formula II compound or its salt and the reaction of formula III chemical compound in case of necessity product is carried out oxidation, formula II is
Q ' is a leaving group in the formula, and Y is C-G (wherein G be can esterified carboxyl), and A ring and B encircle and all can at random have at least one substituent group, and k is 0 or 1; Formula III is
R is the alkyl of replacement arbitrarily or the heterocyclic radical of any replacement that ring carbon atom is connected with sulphur atom in R-SH (III) formula;
(4) method of preparation formula (I-2) compound or its salt
Y is C-G (wherein G be can esterified carboxyl) in the formula; R be the alkyl that replaces arbitrarily or ring carbon atom and-(CH
2)
qThe heterocyclic radical of-any replacement that (wherein q is an integer 1 to 5) is connected; A ring and B ring all can at random have at least one substituent group; K is 0 or 1; This method comprises reacts formula IV chemical compound and formula (V) chemical compound, and product is reduced, and formula IV is
Y is C-G (wherein G be can esterified carboxyl) in the formula; Q
2It is halogen atom; A ring and B ring all can at random have at least one substituent group; K is 0 or 1; Formula (V) is R
1-(CH
2)
qIn-1-CHO (V) formula R be the alkyl that replaces arbitrarily or ring carbon atom and-(CH
2)
qThe heterocyclic radical of-any replacement that (wherein q is an integer 1 to 5) is connected.
The alkyl example of R representative is aliphatic chain alkyl, aliphatic cyclic hydrocarbon group, aryl etc. in formula I, (I '), (I-1), (I-2), (III) and (V).
Aliphatic chain alkyl comprises the straight or branched aliphatic alkyl, as alkyl, and preferred C
1-10Alkyl; Thiazolinyl, preferred C
2-10Thiazolinyl; C
2-10Alkynyl etc.
The preferred embodiment of alkyl comprises: methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, the tert-butyl group, amyl group, isopentyl, neopentyl, tertiary pentyl, 1-ethyl propyl, hexyl, isohesyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethyl-butyl, heptyl, octyl group, nonyl, decyl etc.
The preferred embodiment of thiazolinyl comprises vinyl pi-allyl, isopropenyl, 1-acrylic, 2-methyl isophthalic acid-acrylic, 1-butylene base, crotyl, 3-cyclobutenyl, 2-ethyl-1-butylene base 3-methyl-2-butene base, 1-pentenyl, pentenyl 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl etc.
The preferred embodiment of alkynyl comprises: acetenyl, 1-propinyl, 2-propynyl, ethyl acetylene base, 2-butyne base, 3-butynyl, 1-pentynyl, valerylene base, 3-pentynyl, 4-pentynyl, 1-hexin base, 2-hexin base, 3-hexin base, 4-hexin base, 5-hexin base etc.
The aliphatic cyclic hydrocarbon group comprises saturated or the unsaturated lipid cyclic hydrocarbon radical, as cycloalkyl, cycloalkenyl group, cycloalkadienyl etc.
The preferred embodiment of cycloalkyl comprises: cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, ring octyl group dicyclo [2.2.1] heptyl, dicyclo [2.2.2] octyl group, dicyclo [3.2.1] octyl group, dicyclo [3.2.2] nonyl, dicyclo [3.3.1] nonyl, dicyclo [4.2.1] nonyl, dicyclo [4.3.1] decyl etc.
The preferred embodiment of cycloalkenyl group comprises 2-cyclopentenes-1-base, 3-cyclopentenes-1-base, 2-cyclohexene-1-base, 3-cyclohexene-1-base etc.
The preferred embodiment of cycloalkadienyl comprises 2,4-cyclopentadiene-1-base, 2,4-cyclohexadiene-1-base 2,5-cyclohexadiene-1-base etc.
Aryl comprises monocycle or thick polycyclic aromatic hydrocarbon base.Its preferred embodiment comprises C
6-14Aryl, for example phenyl, naphthyl, anthryl, phenanthryl, acenaphthenyl etc.Wherein preferred phenyl, 1-naphthyl, 2-naphthyl etc.
The heterocyclic radical of R representative refers to aromatic heterocyclic in formula I, (I '), (I-1), (I-2), (III) and (V), saturated or undersaturated non-aromatic heterocyclic (aliphatic heterocyclic radical), described heterocyclic radical all have at least one hetero atom that is selected from oxygen, sulfur and nitrogen as the atom (becoming annular atoms) that constitutes ring system.Described heterocyclic radical becomes ring carbon atom to link to each other with the group that the front is defined as X by it.
Aromatic heterocyclic comprises fragrant single heterocyclic radical, fragrant condensed hetero ring base etc.
The single heterocyclic preferred embodiment of virtue comprises furyl, thienyl, pyrrole radicals, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazole radicals, pyrazolyl, 1,2,3-oxadiazole base, 1,2,4-oxadiazole base, 1,3,4-oxadiazole base, furazan base, 1,2,3-thiadiazolyl group, 1,2,4-thiadiazolyl group, 1,3,4-thiadiazolyl group, 1,2,3-triazoles base, 1,2,4-triazolyl, tetrazole radical, pyridine radicals, pyridazinyl, pyrimidine radicals, pyrazinyl, triazine radical etc.
The preferred embodiment of virtue condensed hetero ring base comprises: benzofuranyl, isobenzofuran-base, benzo [b] thienyl, indyl, isoindolyl, the 1H-indazolyl, benzimidazolyl benzoxazolyl, 1,2-benzoisoxazole base, benzothiazolyl, 1,2-benzisothiazole base, 1H-benzotriazole base, quinolyl, isoquinolyl, cinnolinyl, quinazolyl, quinoxalinyl, 2, the 3-phthalazinyl, 1, the 5-phthalazinyl, purine radicals, pteridyl, carbazyl, α-carbolinyl, the B-carboline base, the gamma-carbolines base, acridinyl phenoxazine group, phenothiazinyl, phenazinyl, the phenoxathiin base, thianaphthenyl, phenanthridinyl, the phenanthroline base, the indolizine base, pyrrolo-[1,2-b] pyridazinyl, pyrazolo [1,5-a] pyridine radicals, imidazo [1,2-a] pyridine radicals, imidazo [1,5-a] pyridine radicals, imidazo [1,2-b] pyridazinyl, imidazo [1,2-a] phonetic basic 1,2,4-triazol [4,3-a] pyridine radicals, 1,2,4-triazol [4,3-b] pyridazinyl, or the like.
The preferred embodiment of nonaromatic heterocycles group comprises Oxyranyle, azetidinyl, oxetanyl, Thietane base, pyrrolidinyl, tetrahydrofuran base, thiophene alkyl, piperidyl, THP trtrahydropyranyl, morpholinyl, thio-morpholinyl, piperazinyl etc.
Above-mentioned aliphatic chain alkyl, alicyclic hydrocarbon base aromatic hydrocarbyl and heterocyclic radical etc. all can have at least one, preferred 1 to 3 suitable substituent group.
Described substituent example comprises C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, cycloalkyl, aryl, aromatic heterocyclic, non-aromatic heterocyclic, aralkyl, amino, the mono-substituted amino of N-, N; the dibasic amino of N-, amidino groups, acyl group, carbamyl, the mono-substituted carbamyl of N-, N; the dibasic carbamyl of N-, sulfamoyl; the mono-substituted sulfamoyl of N-, N, have C at the dibasic sulfamoyl of N-, carboxyl
1-6The lower alkoxycarbonyl of alkoxyl, hydroxyl, C
1-6Alkoxyl, C
1-6Alkene oxygen base, cycloalkyloxy, aralkoxy, aryloxy group, sulfydryl, C
1-6Alkylthio group, alkylthio-aryl, arylthio, sulfo group, cyano group, azido, nitro, nitroso-group, halogen etc.
When the chemical compound of formula I, (I '), (I-1), (I-2), (II) or (IV) is a quinoline, when promptly Y represents C-G, comprise alkoxy carbonyl group and aralkoxycarbonyl by the example of the esterifying carboxyl group of G representative.
The example of the alkyl in the alkoxy carbonyl group comprises C
1-6Alkyl is as methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, the tert-butyl group etc.
Aralkyl in the aromatic alkoxy carbonyl refers to has aryl as substituent alkyl (aralkyl).The example of this aryl comprises phenyl, naphthyl etc.Aryl can have the identical substituent group of substituent group on the aryl of representing with R, as alkyl, and C
1-6Alkyl is preferred.The preferred embodiment of aralkyl comprises: benzyl, phenethyl, 3-phenyl propyl, (1-naphthyl) methyl, (2-naphthyl) methyl etc.Wherein more preferably benzyl, phenethyl etc.
Sulphur atom by any oxidation of X and Z representative comprises sulfenyl, sulfinyl and sulfonyl.
Example by the leaving group of Q ' representative in the formula II comprises halogen, preferred chlorine, bromine or iodine; The activatory hydroxyl by esterification is as organic sulfonic acid moieties (for example tolysulfonyl oxygen base, mesyloxy etc.) and organic phosphoric acid residue (for example diphenylphosphine acyloxy, dibenzyl phosphorus acyloxy, solutions of dimethyl phosphoryl oxygen base etc.); Or the like.
In the formula IV by Q
2The example of the halogen atom of representative comprises chlorine, bromine and iodine.
Ring A in formula I, (I '), (I-1), (I-2), (II) and (IV) and ring B can have-individual or a plurality of substituent groups.Described substituent example comprises the carboxyl of halogen, nitro, the alkyl that replaces arbitrarily, the hydroxyl that replaces arbitrarily, any thiol that replaces, the amino that replaces arbitrarily, any esterification of acyl group of replacement arbitrarily and the aromatic ring yl that replaces arbitrarily.
Example as substituent halogen comprises fluorine, chlorine, bromine and iodine.Preferred especially fluorine and chlorine.
The alkyl that replaces can be any straight chain, side chain or cyclic C arbitrarily
1-10Alkyl, for example methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, the tert-butyl group, amyl group, isopentyl neopentyl, hexyl, heptyl, octyl group, nonyl, decyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl etc.
Arbitrarily the example of the hydroxyl that replaces has hydroxyl, has suitable substituent group the hydroxyl of (especially as the group of hydroxyl protecting group, for example alkoxyl, alkene oxygen base, aralkoxy, acyloxy, aryloxy group etc.).
The example of alkoxyl comprises C
1-10Alkoxyl, for example methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, amoxy, isoamoxy, neopentyl oxygen, hexyloxy, heptan oxygen base, the ninth of the ten Heavenly Stems oxygen base, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc.
The example of alkene oxygen base comprises C
1-10Alkene oxygen base, for example allyloxy, butenyloxy, 2-amylene oxygen base, 3-hexene oxygen base, 2-cyclopentenyl methoxyl group, 2-cyclohexenyl group methoxyl group etc.
The example of aralkoxy comprises phenyl C
1-4Alkoxyl is as benzyloxy, benzene ethyoxyl etc.
The preferred embodiment of acyloxy comprises C
2-4Alkanoyloxy is as acetoxyl group, propionyloxy, positive butyryl acyloxy, isobutyl acyloxy etc.The example of aryloxy group comprises phenoxy group, 4-chlorophenoxy etc.
Arbitrarily the example of the thiol that replaces has: thiol, have suitable substituent thiol (especially as the group of thiol protecting group, for example alkylthio group, aromatic alkylthio, acyl sulfur benzene etc.).
The preferred embodiment of alkylthio group comprises C
1-10Alkylthio group, for example methyl mercapto, ethylmercapto group, rosickyite base, iprotiazem base, butylthio, isobutyl sulfenyl, secondary butylthio, uncle's butylthio, penta sulfenyl, isoamyl sulfenyl, new penta sulfenyl, own sulfenyl, heptan sulfenyl, the ninth of the ten Heavenly Stems sulfenyl, ring butylthio, ring penta sulfenyl, hexamethylene sulfenyl etc.
The example of aromatic alkylthio comprises phenyl C
1-4Alkylthio group, for example benzylthio, benzene ethylmercapto group etc.
The example of acyl sulfenyl comprises 2-4 alkane acyl sulfenyl, as thioacetyl, propionyl sulfenyl, positive butyryl sulfenyl, isobutyryl sulfenyl etc.
The example of the amino that replaces has arbitrarily: have 1 or 2 and be selected from C
1-10Alkyl, C
1-10The substituent amino of thiazolinyl and aryl, for example methylamino, dimethylamino, ethylamino, lignocaine, dibutylamino, diallyl amino, cyclohexyl amino, phenylamino, N-methyl-N-phenyl amino etc.
The example of the acyl group that replaces has arbitrarily: formoxyl; With C
1-10Alkyl, C
1-10The carbonyl that thiazolinyl or aryl link to each other is as acetyl group, propiono, bytyry, isobutyryl, valeryl, isovaleryl, valeryl, caproyl, heptanoyl group, caprylyl, ring bytyry, ring valeryl, hexamethylene acyl group, ring heptanoyl group, crotonyl, 2-cyclohexene carbonyl, benzoyl, nicotinoyl etc.
The example of the carboxyl of esterification has arbitrarily: carboxyl, alkoxy carbonyl group, aralkoxycarbonyl etc.The example of alkyl comprises C in the alkoxy carbonyl group
1-10Alkyl, for example methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, the tert-butyl group etc.
Aralkyl in the aralkoxycarbonyl refers to the alkyl (aryl alkyl) with substituent group aryl.The example of aryl comprises phenyl, naphthyl etc.These groups can have with by the identical substituent group of substituent group on the above-mentioned aromatic ring yl of R representative.As alkyl, preferred C
1-6Alkyl.The preferred embodiment of aralkyl comprises benzyl, phenethyl, 3-phenyl propyl, (1-naphthyl methyl) methyl, (2-naphthyl) methyl etc.Wherein preferred benzyl and phenethyl.
The example of the aromatic ring yl that replaces has arbitrarily: C
6-14Aryl is as phenyl, naphthyl, anthryl etc.; Aromatic heterocyclic is as pyridine radicals, furyl, thienyl, imidazole radicals, thiazolyl etc.
The substituent group that A ring and B encircle can be on any position of each ring, and can be identical or different.Substituent number is 1 to 4.When the substituent group of A ring or B ring was adjacent one another are, these two substituent groups can be joined together to form the ring of a following formula:
-(CH
2)
mOr-O-(CH
2)
n-O-
M is an integer 3 to 5 in the formula, and n is an integer 1 to 3.The ring that forms comprises 5 to 7 yuan of rings that form with carbon atoms on a benzene ring.
In the formula I chemical compound, formula (I ') chemical compound is a noval chemical compound.
The preferred embodiment of formula (I ') chemical compound comprises:
6,7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl)-2-[(1-Methylimidazole .-2-yl) the sulfenyl methyl] quinoline-3-Ethyl formate (embodiment 2);
6,7-dimethoxy-4 '-(4-aminomethyl phenyl)-2-[(1-Methylimidazole .-2-yl) the sulfenyl methyl] quinoline-3-Ethyl formate (embodiment 33);
6,7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl)-2-[(4-methyl isophthalic acid, 2,4-triazole-3-yl) the sulfenyl methyl] quinoline-3-Ethyl formate (embodiment 35);
6,7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl)-2-[(1-Methylimidazole .-2-yl) the sulfenyl methyl] quinoline-3-Ethyl formate (embodiment 36);
6,7-dimethoxy-4 '-(3,4-methylenedioxyphenyl base)-2-[(1-Methylimidazole .-2-yl) the sulfenyl methyl] quinoline-3-Ethyl formate (embodiment 69);
6,7-diethoxy-4-(3, the 4-Dimethoxyphenyl)-2-[(1-Methylimidazole .-2-yl) the sulfenyl methyl] quinoline-3-Ethyl formate (embodiment 72);
6,7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl)-2-[(1-Methylimidazole .-2-yl) ethyl] quinoline-3-Ethyl formate (embodiment 87);
The 2-[(2-benzimidazolyl) sulfenyl methyl]-6,7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl) quinoline-3-Ethyl formate (embodiment 3);
6,7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl)-2-[(5-fluorobenzene and imidazoles-2-yl) the sulfenyl methyl] quinoline-3-Ethyl formate (embodiment 54);
6,7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl)-2-[(benzothiazole-2-yl) the sulfenyl methyl] quinoline-3-Ethyl formate (embodiment 60);
6,7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl)-2-[(3,4-dihydro-4-oxo quinazoline-2-yl) the sulfenyl methyl] quinoline-3-Ethyl formate (embodiment 64);
6, the sulfenyl methyl of 7-dimethoxy-4 '-(4-methoxyphenyl)-2-[(benzimidazolyl-2 radicals-yl)] quinoline-3-Ethyl formate (embodiment 27);
6,7-dimethoxy-4 '-(4-methoxyphenyl)-2-[(1-Methylimidazole .-2-yl) the sulfenyl methyl] quinoline-3-Ethyl formate (embodiment 28);
6,7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl)-2-[(4-chlorphenyl) the sulfenyl methyl] quinoline-3-Ethyl formate (embodiment 42);
6,7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl)-2-[(pyrido [1,2-a] [1,3,4] triazole-5-yl) the sulfenyl methyl] quinoline-3-Ethyl formate (embodiment 66);
6,7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl)-2-[(4-chlorphenyl) methylthiomethyl] quinoline-3-Ethyl formate (embodiment 41);
6, the sulfenyl methyl of 7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl)-2-[(benzimidazolyl-2 radicals-yl)] quinoline-3-Ethyl formate (embodiment 53);
6,7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl)-2-[(6-(1 H)-pyrimidine-2-base) the sulfenyl methyl] quinoline-3-Ethyl formate (embodiment 45);
6,7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl)-2-[(3-pyridone-2-yl) the sulfenyl methyl] quinoline-3-Ethyl formate (embodiment 64);
6,7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl)-2-[2-thiazoline-2-yl) the sulfenyl methyl] quinoline-3-Ethyl formate (embodiment 47);
Embodiment in the bracket number with hereinafter disclosed identical.
The most preferably example of chemical compound (I ') is 6,7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl)-2-[(1-Methylimidazole .-2-yl) ethyl] quinoline-3-Ethyl formate.
The salt of target compound of the present invention is pharmaceutically acceptable salt preferably, for example the salt that forms with inorganic base, the salt that forms with organic base, the salt that forms with mineral acid, the salt that forms with organic acid, the salt that forms with alkalescence or acidic amino acid etc.
The preferred embodiment of the salt that forms with inorganic base comprises: alkali metal salt, as sodium salt, potassium salt etc.; Alkali salt is as calcium salt, magnesium salt etc.; Aluminum salt; Ammonium salt etc.
The preferred embodiment of the salt that forms with organic base comprises: front three amine salt, triethylamine salt, pyridiniujm, picoline salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, dicyclohexyl amine salt, N, N '-dibenzyl ethylenediamine salt etc.
The preferred embodiment of the salt that forms with mineral acid comprises: the salt that forms with hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid, phosphoric acid etc.
The preferred embodiment of the salt that forms with organic acid comprises: the salt that forms with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-methyl benzenesulfonic acid etc.
The preferred embodiment of the salt that forms with basic amino acid comprises the salt that forms with arginine, lysine, ornithine etc.The preferred embodiment of the salt that forms with acidic amino acid comprises the salt that forms with aspartic acid, glutamic acid etc.
Above-mentioned chemical compound (I) can prepare as follows.
Y ' is nitrogen-atoms or C-G ' (wherein G ' is the carboxyl of esterification) in the formula, and the definition of other symbol is the same.
In the method, in the presence of a kind of alkali, chemical compound (II) and (III) are reacted in suitable solvent, make chemical compound (I-3).
The example of solvent comprises: aromatic hydrocarbons (as benzene,toluene,xylene etc.), ethers (as dioxanes, oxolane, dimethoxy-ethane base), alcohols (as methanol, ethanol, propanol etc.), ethyl acetate, acetonitrile, pyridine, N, dinethylformamide, dimethyl sulfoxide, chloroform, dichloromethane, 1,2-dichloroethanes, 1,1,2,2-sym-tetrachloroethane, acetone, 2-butanone, and their mixed solvent.
The example of alkali comprises: alkali metal hydroxide such as sodium hydroxide, potassium hydroxide; Alkali metal salt such as potassium carbonate, sodium carbonate, sodium bicarbonate etc.; Disilver carbonate (Ag
2CO
3); Amine is as pyridine, triethylamine, N, accelerine etc.The consumption of alkali is every mole compound (II) with about 1 to 5 mol alkali.
This reaction is carried out under-20 ℃ to 150 ℃ usually, preferred-10 ℃ to 100 ℃.
Quinoline that obtains or quinazoline derivant (I-3) can be by known purification and separation methods, for example concentrate, concentrating under reduced pressure, solvent Herba Marsileae Quadrifoliae are got, crystallization, recrystallization, reallocation, chromatography etc. separate and purification.Method B
In the method, with chemical compound (I-4), promptly wherein X ' is formula (I-3) compound oxidation of sulphur atom, makes chemical compound (I-4):
P is 1 or 2 in the formula, and other symbol definition is the same.
According to a conventional method, use a kind of oxidant, for example metachloroperbenzoic acid, hydrogen peroxide, perester, sodium metaperiodate etc. can carry out this oxidation reaction.
Press chemical compound (I-4) and calculate,, preferentially generate P and be 1 formula (I-5) chemical compound when when waiting mole or oxidant still less; When the oxidant used greater than equimolar amounts, be that to produce P be 2 formula (I-5) chemical compound for 1 formula (I-5) chemical compound by oxidation P.
It is to carry out in the inert solvent that this oxidation reaction is preferably under the reaction condition, for example halogenated hydrocarbon (as dichloromethane, chloroform, dichloroethanes etc.), aromatic hydrocarbons (as benzene, toluene etc.) and alcohols (as methanol, ethanol, propanol etc.).
This is reflected under room temperature or the lower temperature, preferably carries out under-50 ℃ to 20 ℃ approximately, reacts usually 0.5 to 10 hour.
By separation known and purification process, for example concentrate, concentrating under reduced pressure, solvent extraction, crystallization, recrystallization, reallocation, chromatography etc. separable and purification quinoline or quinazoline derivant (I-5).
Method C
Wherein the definition of each symbol is the same.
In the method, (V) then with its reduction, gets chemical compound (I-2) Yu phosphonium salt (IV) condensation gets chemical compound (VI) with aldehyde derivatives.
The condensation reaction of chemical compound (IV) and (V) carries out in The suitable solvent in the presence of a kind of alkali.
The example of solvent comprises: alcohols (as methanol, ethanol, propanol etc.), ethers (as ether, dioxanes, oxolane, dimethoxy-ethane etc.), aromatic hydrocarbons (as benzene,toluene,xylene etc.), dichloromethane, 1,2-dichloroethanes, N, dinethylformamide, dimethylbenzene sulfoxide and their mixed solvent.
The example of alkali comprises: alkali metal hydride (as sodium hydride, hydrofining etc.), alkoxide (as Sodium ethylate, Feldalat NM, potassium tert-butoxide etc.), organo-lithium compound (as lithium methide, butyl lithium, phenyl lithium etc.), oxygen base sodium etc.The consumption of alkali is preferably every mole compound (IV) with about 1 to 1.5 mol alkali.
This reaction is usually at-50 ℃ to 100 ℃, carries out under preferred-20 ℃ to 50 ℃.Response time is 0.5 to 20 hour.
The chemical compound that obtains (VI) is (E) and (Z) mixture of type irregular part with regard to two keys of new formation, separates the back or does not separate, will (E) and (Z) type isomer reduction, get chemical compound (I-2).
This reduction reaction and is carried out in a kind of solvent under nitrogen atmosphere according to a conventional method in the presence of a kind of catalyst.The example of described catalyst comprises: for example palladium catalyst (as palladium charcoal, palladium black etc.), platinum catalyst (as platinum dioxide etc.), Buddhist nun's Ruan nickel etc.The example of solvent comprises: alcohols (as methanol, ethanol, propanol etc.), ethers (as ether, dioxanes, oxolane, dimethoxy-ethane etc.), aromatic hydrocarbons (as benzene,toluene,xylene etc.), dichloromethane, 1,2-dichloroethanes, ethyl acetate, acetonitrile, acetone, 2-butanone, N, dinethylformamide, dimethyl sulfoxide, and mixed solvent.The pressure of hydrogen is 1 to 150 atmospheric pressure, preferred 1 to 20 atmospheric pressure.
By known purification and separation method, for example concentrate, concentrating under reduced pressure, solvent extraction, crystallization, recrystallization, reallocation, chromatography etc. quinoline or quinazoline derivant (I-2) that separable and purification obtains.
Can prepare initiation material (II) and (IV) among the present invention as follows.Method D
The definition of each symbol is the same in the formula.
In the method, in the presence of a kind of acid, 2-ADP ketone derivatives (VI) and chemical compound (VIII) are reacted in The suitable solvent, make chemical compound (II-1).
The example of solvent comprises: aromatic hydrocarbons (as benzene,toluene,xylene etc.), ethers (such as diox oxolane, dimethoxy-ethane etc.), N, dinethylformamide, dimethyl sulfoxide, chloroform, dichloromethane, 1,2-dichloroethanes, 1,1,2,2-sym-tetrachloroethane, acetic acid etc.
The example of acid comprises lewis acid (as aluminum chloride, zinc chloride etc.), p-methyl benzenesulfonic acid, sulphuric acid, trifluoroacetic acid etc.The consumption of acid is preferably every mole compound (VII) with about 0.05 to 0.5 equimolar acid.
This reaction is usually at 20 ℃ to 200 ℃, carries out under preferred about 30 ℃ to 150 ℃, and the response time is 0.5 to 20 hour, preferred 1 to 10 hour.
By separation known and purification process, for example concentrate, concentrating under reduced pressure, solvent extraction, crystallization, recrystallization, reallocation, chromatography etc. the chemical compound (II-1) that separable and purification obtains.Method E
The definition of each symbol is the same in the formula.
In this method, in the presence of a kind of acid,, get chemical compound (X) with 2-ADP ketone derivatives (VII) and acetoacetate derivatives (IX) reaction.Brominated compound (X) gets 2-bromomethyl quinoline derivant (II-2) then.
Reaction between chemical compound (VII) and (IX) is undertaken by the same procedure among the method D.
According to a conventional method, in the presence of radical initiator, in The suitable solvent, carry out the bromination of chemical compound (X).The example of solvent comprises: halogenated hydrocarbons, and as carbon tetrachloride, chloroform, dichloromethane, 1,2-dichloroethanes, sym.-tetrachloroethane etc.The example of radical initiator comprises: benzoyl peroxide, 2,2-azo two (isopropyl cyanide) etc.The consumption of radical initiator is preferably each mole compound (X) with about 0.001 to 0.01 mole.This reaction is usually at 20 ℃ to 150 ℃, carries out under preferred about 30 ℃ to 100 ℃.Response time is 0.5-20 hour, preferred 1-10 hour.
By separation known and purification process, for example concentrate, concentrating under reduced pressure, solvent extraction, crystallization, recrystallization, reallocation, chromatography etc. the chemical compound (II-2) of separable and purification gained.Method F
The definition of each symbol is the same in the formula.
In the method,, make 2-halomethyl quinazoline derivant (II-3) with 2-ADP ketone derivatives (VII) and halogen acetonitrile derivative (XI) reaction.In the presence of a kind of acid, as solvent, carry out the reaction between chemical compound (VII) and (XI) with excessive chemical compound (XI).As described acid, can adopt those acid described in the method D.Acid consumption be per 1 mole compound (VII) with about 1 to 5 mole, preferred 1 to 2 equimolar acid.Normally 0.5-30 hour response time, preferred 1-10 hour.Reaction temperature is generally 20 ℃ to 200 ℃, preferred about 30 ℃ to 150 ℃.
By separation known and purification process, for example concentrate, concentrating under reduced pressure, solvent extraction, crystallization, recrystallization, reallocation, chromatography etc. the separable and resulting quinazoline derivant of purification (II-3).Method G
The definition of each symbol is the same in the formula.
In the method,, get 2-methyl quinazoline derivant (XII) with 2-ADP ketone derivatives (VII) and acetonitrile reaction.Chemical compound (XII) makes 2-bromomethyl quinazoline derivant (II-4) then through bromination reaction.Carry out the reaction of chemical compound (VII) and acetonitrile by the same procedure of method F.Carry out the bromination of chemical compound (XII) by the bromination process of chemical compound (X) among the method E.
By separation known and purification process, for example concentrate, concentrating under reduced pressure, solvent extraction, crystallization, recrystallization, reallocation, chromatography etc., can separate and purification quinazoline derivant (II-4).Method H
The definition of each symbol is the same in the formula.
In the method, the chemical compound that selective oxidation obtains by method D, E, F and G (II-1), (II-2), (II-3) and (II-4) get chemical compound (II-5).
Use a kind of oxidant, for example metachloroperbenzoic acid, hydrogen peroxide, perester, sodium metaperiodate etc. carry out this oxidation reaction by identical method.The consumption of oxidant is each mole compound (II-1), (II-2), (II-3) or (II-4), with 1 to 5 mole, preferred 1 to 3 mole.
Be preferably under the reaction condition and carry out oxidation reaction in the inert solvent.The example of described solvent is: halogenated hydrocarbons (as dichloromethane, chloroform, dichloroethanes etc.), aromatic hydrocarbons (as benzene, toluene etc.) and alcohols (as methanol, ethanol, propanol etc.).
This reaction is carried out under preferred 0 ℃ to 100 ℃ generally at-10 ℃ to 150 ℃, and the response time is generally 0.5-10 hour.
By separation known and purification process, for example concentrate, concentrating under reduced pressure, solvent extraction, crystallization, recrystallization, reallocation, chromatography etc., can separate and the quinoline 1-oxide derivative or the quinazoline 1-oxide derivative (II-5) of purification gained.The method I
The definition of each symbol is the same in the formula.
In the method,, get the salt derivative of formula IV chemical compound with the triphenylphosphine reaction of formula (II-6) chemical compound and respective amount.
In a solvent, for example in aromatic hydrocarbons (as benzene,toluene,xylene etc.), ethers (as oxolane, diox, dimethoxy-ethane etc.), acetonitrile and their mixed solvent, carry out above-mentioned reaction.This is reflected at 10 ℃ to 200 ℃, carries out 0.5 to 50 hour under preferred 30 ℃ to 150 ℃.
Method J
The definition of each symbol is the same in the formula.
In the method,, obtain chemical compound (I-7) with formula (I-6) hydrolysis.
Reaction according to a conventional method is hydrolyzed in water or aqueous solvent.
The aqueous solvent that is suitable for is water and alcohol (as methanol or ethanol), ether (as oxolane Huo diox), N, dinethylformamide, dimethyl sulfoxide, acetonitrile or acetone, mixture.
This is reflected under a kind of alkali (as potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide or Lithium hydrate) or a kind of acid (example hydrochloric acid, sulphuric acid, acetic acid or the hydrobromic acid) existence and carries out.The consumption of acid or alkali is preferably excessive, and (I ' a) is calculated, and alkali is 1.2 to 6 equivalents, and acid is 2 to 50 equivalents to press chemical compound.Reaction is carried out under-20 ℃ to 150 ℃ approximately, preferred about-10 ℃ to 100 ℃ usually.
Chemical compound provided by the invention and salt thereof have anti-inflammatory activity and bring down a fever and analgesic activity.In addition, in the mammal experimental model that can produce the adjuvant arthritis that is similar to the rheumatic arthritis symptom, also observed good arthritis activity.Also observe the active and antigen reactivity T cell growth inhibiting activity of anti-IL-1 in addition, these activity have been pointed out the mechanism of action of the anti-inflammatory activity of The compounds of this invention.
The compounds of this invention is hypotoxic, for example, gives mice with the chemical compound of preparation in embodiment 36,45,47,54 and 64 with the oral dose of 300mg/kg, and not seeing has death.Therefore, The compounds of this invention can be used as people and other mammiferous antiinflammatory, especially produces the arthritis drug of inflammatory symptoms as treatment.
The compounds of this invention (I) acceptable carrier preparation on pharmacology, and with solid preparation (as tablet, capsule, granule, powder) or liquid preparation form, oral administration or parenterai administrations such as (as syrup, injections).
As acceptable carrier on the pharmacology, can adopt as the habitual various organic or inorganic carrier mass of pharmacy material.Described carrier mass is used as excipient, lubricant, binding agent or disintegrating agent in the preparation solid preparation; And in liquid preparation, be used as lytic agent, solution aid, suspending agent, tonicity agents, slow in agent or tranquilizer.In case of necessity, also can use the pharmacy additive, for example antiseptic, antioxidant, coloring agent, sweeting agent etc.
The preferred embodiment of excipient comprises: lactose, sucrose, D-mannitol, starch, crystalline cellulose, light silicon anhydride etc.
The preferred embodiment of lubricant comprises: magnesium stearate, calcium stearate, Pulvis Talci, silica sol etc.
The preferred embodiment of binding agent comprises: crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, polyvinylpyrrolidone etc.
The preferred embodiment of disintegrating agent comprises: starch, carboxymethyl cellulose, carboxymethylcellulose calcium, cross-linked carboxymethyl cellulose sodium (sodium croscalmerose), carboxymethyl starch sodium etc.
The preferred embodiment of lytic agent comprises in the liquid preparation: water for injection, alcohols, propylene glycol, Polyethylene Glycol, Oleum sesami, corn wet goods.
The preferred embodiment of solution aid comprises: Polyethylene Glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, Trisaminomethane, cholesterol, ethanolamine, sodium carbonate, sodium citrate etc.
The preferred embodiment of suspending agent comprises: surfactant, for example stearyl triethanolamine, sodium lauryl sulfate, laurylamino-propionic acid, incubate phospholipid, geramine, phemerol chloride ,-tristerin etc.; Hydrophilic macromolecular compound is as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose, methylcellulose, hydroxy methocel, hydroxyethyl-cellulose, hydroxypropyl cellulose etc.
The preferred embodiment of tonicity agents comprises: sodium chloride, glycerol, D-mannitol etc.
The preferred embodiment of buffer agent comprises phosphate, acetate, carbonate, citrate etc.
The preferred embodiment of tranquilizer comprises benzylalcohol etc.
The preferred embodiment of antiseptic comprises p-Hydroxybenzoate, methaform, phenethanol, dehydroactic acid, sorbic acid etc.
The preferred embodiment of antioxidant comprises sulphite, ascorbic acid etc.
The dosage of The compounds of this invention (I) alters a great deal, and depends on the concrete patient's that concrete route of administration, desire are treated situation etc.Adult patient's daily dose is selected from following ranges usually: oral administration is 5-1000mg, and parenterai administration is 1 to 100mg.The daily dose of above-claimed cpd (I) can divide 1 to 4 administration.
Estimate the pharmacologically active of The compounds of this invention (I) or its salt by following experimental example.Experimental technique and result are expressed as follows.Experimental example 1
Effect to rat assist agent arthritis
With Freund's complete adjuvant (0.5% suspension of the tubercule bacillus of deactivation in liquid paraffin) (0.05ml) the right rear leg foot claw of subcutaneous injection Lewis rat (male, 7 ages in week, Charles RiverJapan Inc.) make its sensitization.Trial drug (50mg/kg) is suspended in 5% arabic gum, was administered once in one day, and totally 14 days, (0 day) beginning administration before the sensitization.Before sensitization (0 day) and measured the volume and the body weight of left back lower limb on the 14th day, and calculate inhibitory rate of intumesce (%) and weight increase rate (%) with respect to administration rat batch total not.
Compare and evaluation gained result by the Dunnett method of inspection.Risk is be evaluated as less than 5% has significance.As shown in table 1, it is all symptoms that index observing arrives that The compounds of this invention can effectively improve with sufficient claw edema inhibition and weight increase.Table 1
*P＜0.01,
*P＜0.05 experimental example 2
| Chemical compound (embodiment number) | Inhibitory rate of intumesce (%) | Weight increase rate (%) |
| ????2 ????33 ????36 ????69 ????72 ????35 ????87 ????88 | ????73 **????67 **????48 **????63 **????50 **????64 **????75 **????62 ** | ????39 **????12 ????30 **????17 ????27 **????11 ????27 **????24 ** |
Rat carrageenan foot pawl edema suppresses active
Measure the volume at the position, right rear leg vola of Jcl:SD rat (male, 6 ages in week), 5% suspension of orally give trial drug (50mg/kg) in 5% arabic gum gives water more then, and making the total amount of liquid that gives is every rat 5ml.After 1 hour, the normal saline suspension (0.05ml) that will contain 10% carrageenin is subcutaneously injected into the right vola of rat portion and brings out swelling [Winter, C.A.et al; Proc.Soc.Exp.Biol.Med., 111,544 (1962)].The injection carrageenin is measured the volume of right rear leg once more after 3 hours, calculate inhibitory rate of intumesce by the volume differences before and after the injection.
The results are shown in the table 2, The compounds of this invention demonstrates chondrus ocellatus Holmes amine foot pawl edema is suppressed active table 2
Experimental example 3
| Chemical compound (embodiment number) | Inhibitory rate of intumesce (%) |
| ????3 ????54 ????60 ????64 | ????23 ????21 ????31 ????36 |
The intravital analgesic activity of mice
With medicine (50mg/kg) the orally give Slc:ICR mice (male, 4 ages in week) that is suspended in 5% arabic gum.Be dissolved in 0.02% phenyl benzoquinone solution (0.1ml/10kg body weight) in 5% ethanol in 30 minutes in the posterior peritoneum.Calculate after every injected in mice 20 minutes roll and stretch reaction, with analgesic activity [Siegmun d, the E.et al. of evaluation test medicine; Proc.Soc.Exp.Biol.Med., 95,729 (1957)].
The results are shown in the table 3, The compounds of this invention demonstrates significant analgesic activity in mice phenyl benzoquinone rolling model.Table 3
Experimental example 4
| Chemical compound (embodiment number) | Suppression ratio (%) |
| ????27 ????28 ????36 ????42 ????66 ????64 | ????39 ????43 ????59 ????47 ????58 ????27 |
Anti-IL-1 activity
Press known method [fujio Suzuki et al., Sin Seikagaku JikkenKohza, 18, P.871-875 (1990)] preparation rat cartilage cell, and be incubated in the Dulbecco culture medium that contains 10% hyclone.The test compound and the IL-1 β (0.2ng/ml) that add various concentration after 8 days, and cultured cell 3 days again measure the amount of the extracellular matrix that produces.
The results are shown in the table 4.Though the extracellular matrix of IL-1 β inhibition chondrocyte is synthetic, adds medicine and can suppress the IL-1 activity, the synthetic quantity of extracellular matrix is restored.Table 4
Experimental example 5
| Compound I L-1 suppresses active (%) (embodiment number) 1 μ M 10 μ M |
| ????28????????34??????44 ????36????????22??????48 ????41????????17??????50 ????53????????39??????71 ????64????????23??????50 |
Antigen reactivity T cell growth inhibiting activity
By the method for experimental example 1, in Lewis rat (male, 7 ages in week), bring out adjuvant arthritis.After 14 days, cut out the inguinal lymph joint,, in a nylon fiber post, cultivated 1 hour then at 37 ℃ with the unicellular suspension of RPMI-1640 medium preparation that contains 5% hyclone.Go out cell with identical culture medium eluting from post.Xi Fu cell fraction is not as the T cell.
On the other hand, from unsensitized Lewis rat (male, 8 to 9 week ages), take out splenocyte, with soft X-ray (20,000R) irradiation.To described splenocyte (1 * 10
5Individual cell/well) adds above-mentioned T cell (5 * 10 in
5Individual cell/well), PPD (protein derivatives of purification, ultimate density are 2 μ g/ml) and 2%Lewis rat blood serum (handling 30 minutes) at 56 ℃.In 5% CO2 gas incubator, mixture was cultivated 72 hours at 37 ℃.In addition, add
3H-Tdr (0.5 μ Ci/ well), and then cultivated 24 hours.Reclaim cell, measure the radioactivity that is incorporated into the 3H-Tdr in the cell.Just before adding PPD, trial drug is added in the cell suspension, and observe in its pair cell
3The influence of H-Tdr binding capacity.
The results are shown in the table 5, The compounds of this invention has the activity of inhibition to the T cell growth that PPD stimulates.Table 5
| Chemical compound (embodiment number) | The long suppression ratio of antigen reactivity T cell master (%) 1 μ M 10 μ M |
| ????36 ????45 ????46 ????47 ????53 ????60 ????64 | ????33????79 ????36????70 ????39????92 ????61????93 ????51????91 ????59????91 ????53????78 |
Following is further explained in detail the present invention with reference to embodiment and embodiment, but its scope is not construed as limiting.With reference to embodiment 1
With concentrated vitriol (0.3ml) add 2-amino-3 ', 4 '-dimethoxy-4 ', in the mixture of 5-ethylidene dioxy base benzophenone (6.5g), 4-chloroacetyl acetacetic ester (3.7g) and acetic acid (60ml), the gained mixture was in 100 ℃ of stirrings 3 hours.The concentrating under reduced pressure reactant mixture, residue injects water, transfers to alkalescence with 2N NaOH, uses chloroform extraction.Washing chloroform layer and dry (MgSO
4), pressure reducing and steaming solvent, residue be through silica gel chromatography, from chloroform/ethyl acetate (7: 3, V/V) in the fraction that eluting goes out, obtain 2-chloromethyl-4-(3, the 4-dimethoxy phenyl)-6,7-ethylenedioxy quinoline-3-Ethyl formate (5.5g, 60%).Recrystallization in acetone gets the crystallization of colourless rib shape, m.p.197-198 ℃.Elementary analysis: value of calculation:
C
23H
22NO
6Cl:
C, 62.24; H, 5.00; N, 3.16 measured values: C, 61.95; H, 5.15; N, 3.01. is with reference to embodiment 2 to 25
Make table 6 chemical compound in 8 by the same procedure of reference embodiment 1.
Table 6
Annotate: 1) NMR (δ ppm) in CDCl
3: 0.92 (3H, t, J=7.2Hz), 4.06 (2H, q, J=7.2Hz), 5.03 (2H, s), 7.33-7.37 (2H, m), 7.50-7.55 (3H, m), 7.90-7.98 (2H, m), 8.26 (1H, d, J=9.4Hz).
Table 7
Table 8
With reference to embodiment 26
Concentrated sulphuric acid is added 2-amino-4,5,3 ', 4 '-mixture of tetramethoxy benzophenone, ethyl acetoacetate and acetic acid in, the mixture that obtains is handled by the same procedure of reference embodiment 1, get 6,7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl)-2-methylquinoline-3-Ethyl formate (83%), recrystallization in ethanol, the crystallization of colourless rib shape, p.147-148 ℃ m.With reference to embodiment 27
Concentrated sulphuric acid is added 2-amino-4,5,3 ', 4 '-mixture of tetramethoxy benzophenone, propyl acetoacetate and acetic acid in, the mixture that obtains is handled by the same procedure of reference embodiment 1, get 6,7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl)-2-methylquinoline-3-propyl formate (79%), recrystallization in ethyl acetate/diisopropyl ether, get the crystallization of colourless rib shape, m.p.153-155 ℃.
With reference to embodiment 28
Concentrated sulphuric acid is added 2-amino-4,5,3 ', 4 '-mixture of tetramethoxy benzophenone, butyl-acetoacetate and acetic acid in, the mixture that obtains is handled by the same procedure of reference embodiment 1, get 6,7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl)-2-methylquinoline-3-butyl formate (53%), recrystallization in ethyl acetate/hexane, get the crystallization of colourless rib shape, m.p.119-120 ℃.With reference to embodiment 29
With 6,7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl)-2-methylquinoline-3-Ethyl formate (411mg), the white acid imide of N-bromine amber (NBS) (214mg), 2,2 '-azo two (isopropyl cyanide) is (10mg) and the mixture stirring and refluxing of carbon tetrachloride (10ml) 5 hours, the washed reaction mixture, dry (MgSO
4), the pressure reducing and steaming solvent, residue is through silica gel chromatography, by with chloroform/ethyl acetate (10: 1, V/V) fraction that goes out of eluting obtains 2-bromomethyl-6,7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl) quinoline-3-Ethyl formate (285mg, 58%), recrystallization in ethyl acetate/hexane, get the crystallization of colourless rib shape, m.p.135-136 ℃.Elementary analysis: value of calculation: C
23H
24NO
6Br:
C,56.34；H,4.93；N,2.86
Measured value: C, 55.98; H, 5.23; N, 2.62. is with reference to embodiment 30
Same procedure by with reference to embodiment 29 has made 2-bromomethyl-6,7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl)-quinoline-3-propyl formate (48%), and recrystallization in ethyl acetate/diisopropyl ether gets the crystallization of colourless rib shape, m.p.160-161 ℃.Elementary analysis: value of calculation: C
24H
26NO
6Br:
C, 57.15; H, 5.20; N, 2.78 measured values: C, 56.75; H, 5.30; N, 2.68. is with reference to embodiment 31
Same procedure by with reference to embodiment 29 has made 2-bromomethyl-6,7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl)-quinoline-3-butyl formate (56%), and recrystallization in ethylacetate/ether gets the crystallization of colourless rib shape, m.p.160-161 ℃.Elementary analysis: value of calculation: C
25H
28NO
6Br:
C, 57.92; H, 5.44; N, 2.70 measured values: C, 57.96; H, 5.53; N, 2.50. is with reference to embodiment 32
With 2-chloromethyl-6,7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl) quinoline-3-Ethyl formate (3.0g), metachloroperbenzoic acid (85%, 2.3g) and the mixture of methanol (40ml) reflux and stirred 2 hours down, solvent in the pressure reducing and steaming reactant mixture, residue is poured in the chloroform, washing chloroform layer, dry (MgSO
4), the pressure reducing and steaming solvent, remaining through silica gel chromatography, by with chloroform/ethyl acetate (6: 4, V/V) fraction that goes out of eluting obtains 2-chloromethyl-6,7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl) quinoline-3-Ethyl formate 1-oxide (2.0g, 65%), recrystallization in acetone/diisopropyl ether, get the crystallization of colourless rib shape, m.p.193-194 ℃.Elementary analysis: value of calculation: C
23H
24NO
7Cl:
C, 59.81; H, 5.24; N, 3.03 measured values: C, 59.69; H, 5.32; N, 3.05. is with reference to embodiment 33
Aluminum chloride powder (6.7g) is added 2-amino-4,5,3 ', 4 '-mixture of tetramethoxy benzophenone (8.0g) and chloroacetonitrile (25ml) in, the gained mixture stirs in 100 ℃ and fell back in 2 hours, uses chloroform extraction, the washing chloroform layer, dry (MgSO
4), the pressure reducing and steaming solvent, residue is through silica gel chromatography, by with chloroform/ethyl acetate (10: 1, V/V) fraction that goes out of eluting obtains 2-chloromethyl-6,7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl) quinazoline-3-Ethyl formate (4.9g, 52%), recrystallization in acetone, get the crystallization of colourless rib shape, m.p.183-184 ℃.With reference to embodiment 34
With 2-chloromethyl-6,7-diethoxy-4-(3, the 4-Dimethoxyphenyl) mixture of quinoline-3-Ethyl formate (7.1g), triphenylphosphine (3.9g) and toluene (70ml) refluxes and stirred 2 hours down, after the cooling, filter to isolate precipitated solid, get chlorination [6,7-diethoxy-4-(3, the 4-Dimethoxyphenyl)-and 3-carbethoxyl group quinoline-2-yl] methyl-triphenyl phosphonium (9.6g, 87%), m.p.172-174 ℃ (decomposition).
With reference to embodiment 35
By same procedure, made chlorination [6,7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl)-3-carbethoxyl group quinoline-2-yl] Jia base triphenyl phosphonium, m.p.200-202 ℃ (decomposition) with reference to embodiment 34.With reference to embodiment 36
Same procedure by with reference to embodiment 34 has made chlorination [6,7-dimethoxy-4 '-(4-methoxyphenyl)-3-carbethoxyl group quinoline-2-yl] methyl triphenyl, m.p.178-180 ℃ (decomposition).With reference to embodiment 37
Same procedure by with reference to embodiment 34 has made chlorination [6,7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl) quinazoline-2-yl] methyl triphenyl, m.p.208-210 ℃ (decomposition).With reference to embodiment 38
Same procedure by reference embodiment 1 has made 2-chloromethyl-4-(3, the 4-Dimethoxyphenyl)-6-methylquinoline-3-Ethyl formate, and recrystallization in ethanol gets the crystallization of colourless rib shape, m.p.125-126 ℃.With reference to embodiment 39
With the mixture of sodium iodide (1.68g) and methyl ethyl ketone (15ml) in 80 ℃ stir 1 hour after, add 2-chloro-6,7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl) quinoline-3-Ethyl formate (2.0g), the gained mixture stirred 12 hours with relaxing the bowels with purgatives of warm nature, the filtering insoluble matter, concentrating under reduced pressure filtrate, residue are poured in the water, use ethyl acetate extraction, the washing ethyl acetate layer, dry (MgSO
4), boil off solvent, remaining grease is through silica gel chromatography, by with chloroform/ethyl acetate (1: 1, V/V) fraction that goes out of eluting obtains 6,7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl)-and 2-iodomethyl quinoline-3-Ethyl formate (1.4g, 58%), recrystallization in ethyl acetate/hexane, get the crystallization of colourless rib shape, m.p.170-171 ℃.Elementary analysis: value of calculation: C
23H
24NO
6I:
C, 51.41; H, 4.50; N, 261 measured values: C, 51.25; H, 4.53; N, 2.58 embodiment 1
With 2-chloromethyl-6,7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl) quinoline-3-Ethyl formate (3.0g), 1-ethyl-2-mercaptoimidazole (1.0g), potassium carbonate (1.1g) and N, during stirring was fallen back in 3 hours under the mixture room temperature of dinethylformamide (30ml), use ethyl acetate extraction, the washing ethyl acetate layer, dry (MgSO
4), the pressure reducing and steaming solvent, residue is through silica gel chromatography, by with chloroform/ethyl acetate (3: 2, V/V) fraction that goes out of eluting obtains 2-[(1-ethyl imidazol(e)-2-yl) sulfenyl methyl]-6,7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl) quinoline-3-Ethyl formate (2.8g, 78%), recrystallization in ethyl acetate/hexane, get the crystallization of colourless rib shape, m.p.157-158 ℃.Elementary analysis: value of calculation: C
28H
31N
3O
6S:
C, 62.55; H, 5.81; N, 7.82 measured values: C, 62.55; H, 5.84; N, 7.79. embodiment 2
Under ice-cooled, with metachloroperbenzoic acid (85%, 830mg) add 6 bit by bit, 7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl)-and 2-[(1-Methylimidazole .-2-yl) the sulfenyl methyl] in dichloromethane (75ml) solution of quinoline-3-Ethyl formate (3.0g), stir after 2.5 hours under the room temperature, use 5%NaHSO in succession
3Aqueous solution, saturated NaHCO
3Aqueous solution and washing, dry (MgSO
4); the pressure reducing and steaming solvent; residue is through silica gel chromatography, by with ethyl acetate/methanol (10: 1, V/V) fraction that goes out of eluting obtains 6; 7-dimethoxy-4 '-(3; the 4-Dimethoxyphenyl)-and 2-[(1-Methylimidazole .-2-yl) the sulfinyl methyl] quinoline-3-Ethyl formate (1.8g, 58%), recrystallization in acetone; get the crystallization of colourless rib shape, m.p.193-194 ℃.Elementary analysis: value of calculation: C
27H
29N
3O
7S:
C, 60.10; H, 5.42; N, 7.79 measured values: C, 59.80; H, 5.60; N, 7.51 embodiment 3
Same procedure by embodiment 2 makes the 2-[(2-benzimidazolyl) the sulfinyl methyl]-6,7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl) quinoline-3-Ethyl formate, recrystallization in acetone gets the crystallization of colourless rib shape, m.p.160-161 ℃.Elementary analysis: value of calculation: C
30H
29N
3O
7S:
C, 62.6O; H, 5.08; N, 7.30 measured values: C, 62.21; H, 5.10; N, 7.09. embodiment 4
Under ice-cooled, with metachloroperbenzoic acid (85%, 2.5g) add 6 bit by bit, 7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl)-and 2-[(1-Methylimidazole .-2-yl) the sulfenyl methyl] in dichloromethane (60ml) solution of quinoline-3-Ethyl formate (2.5g), stir after 4 hours under the room temperature, use 5%NaHSO in succession
3Aqueous solution, saturated NaHCO
3Aqueous solution and washing, dry (MgSO
4); the pressure reducing and steaming solvent; residue is through silica gel chromatography, by with ethyl acetate/methanol (10: 1, V/V) fraction that goes out of eluting obtains 6; 7-dimethoxy-4 '-(3; the 4-Dimethoxyphenyl)-and 2-[(1-Methylimidazole .-2-yl) the sulfonyl methyl] quinoline-3-Ethyl formate (1.5g, 58%), recrystallization in acetone; get the crystallization of colourless rib shape, m.p.183-184 ℃.Elementary analysis: value of calculation: C
27H
29N
3O
8S:
C, 58.37; H, 5.26; N, 7.56 measured values: C, 58.46; H, 5.24; N, 7.20. embodiment 5
Same procedure by embodiment 4 makes the 2-[(2-benzimidazolyl) the sulfonyl methyl]-6,7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl) quinoline-3-Ethyl formate, recrystallization in acetone/diisopropyl ether gets the crystallization of colourless rib shape, m.p.181-182 ℃.Elementary analysis: value of calculation: C
30E
29N
3O
8S:
C, 60.90; H, 4.94; N, 7.10 measured values: C, 60.76; H, 4.86; N, 7.09 embodiment 6
Under the room temperature with alcoholic solution (27%, 1.3g) splash into 6,7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl)-2-[(1-Methylimidazole .-2-yl) the sulfenyl methyl of hydrogen chloride] in ethanol (100ml) solution of quinoline-3-Ethyl formate (4.99).Add ether behind about 2/3 solution of pressure reducing and steaming, filter to isolate sedimentary crystallization, with its recrystallization in isopropyl alcohol, get 6,7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl)-2-[(1-Methylimidazole .-2-yl) sulfenyl methyl] quinoline-3-Ethyl formate hydrochloride monohydrate (3.0g, 55%), the crystallization of colourless rib shape, m.p.133-134 ℃.Elementary analysis: value of calculation: C
27H
29N
3O
6SHClH
2O
C, 56.10; H, 5.58; N, 7.27 measured values: C, 55.84; H, 5.72; N, 7.16. embodiment 7
With 2-chloromethyl-6,7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl) quinoline-3-propyl formate (3.3g), 2-sulfydryl-1-Methylimidazole. (821mg), potassium carbonate (1.08g) and N, during stirring was fallen back in 3 hours under the mixture room temperature of dinethylformamide (60ml), use ethyl acetate extraction, the washing ethyl acetate layer, dry (MgSO
4), the pressure reducing and steaming solvent, residue is through silica gel chromatography, by with chloroform/ethyl acetate (7: 3, V/V) fraction that goes out of eluting obtains 6,7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl)-and 2-[(1-ethyl imidazol(e)-2-yl) the sulfenyl methyl] quinoline-3-propyl formate (1.77g, 51%), recrystallization in acetone/diisopropyl ether, get the crystallization of colourless rib shape, m.p.131-132 ℃.Elementary analysis: value of calculation: C
28H
31N
3O
6S:
C, 62.55; H, 5.81; N, 7.82 measured values: C, 62.18; H, 5.72; N, 7.73. embodiment 8
Press the same procedure of embodiment 7, made 6,7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl)-and 2-[(1-Methylimidazole .-2-yl) the sulfenyl methyl] quinoline-3-butyl formate (60%), recrystallization in ethyl acetate/hexane gets the crystallization of colourless rib shape, m.p.131-132 ℃.Elementary analysis: value of calculation: C
29H
33N
3O
6S:
C, 63.14; H, 6.03; N, 7.62 measured values: C, 62.87; H, 6.00; N, 7.39. embodiment 9
Press the same procedure of embodiment 1, made 6,7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl)-and 2-[(1-Methylimidazole .-2-yl) the sulfenyl methyl] quinoline-3-methyl formate (69%), recrystallization in acetone gets the crystallization of colourless rib shape, m.p.159-160 ℃.Elementary analysis: value of calculation: C
26H
27N
3O
6S:
C, 61.28; H, 5.34; N, 8.25 measured values: C, 61.05; H, 5.59; N, 8.13. embodiment 10
Press the same procedure of embodiment 1, made 6,7-dimethoxy-4 '-(2-methoxyphenyl)-2-[(1-Methylimidazole .-2-yl) the sulfenyl methyl] quinoline-3-Ethyl formate (89%), grease.
NMR (δ ppm) in CDCl
3: 0.90 (3H, t, J=7Hz), 3.34 (3H, s), 3.70 (3H, s), 3.74 (3H, s), 3.98 (2H, q, J=7Hz), 4.03 (3H, s), 4.64 (2H, s), 6.66 (1H, s), 6.86 (1H, s), 7.01-7.16 (4H, m), 7.34 (1H, s), 7.45 (1H, two t, J=8 and 2Hz).
Above-mentioned grease is dissolved in the ethanol (15ml), the alcoholic solution (23% that adds hydrogen chloride, 1.2g), the pressure reducing and steaming solvent, get 6,7-dimethoxy-4 '-(2-methoxyphenyl)-2-[(1-Methylimidazole .-2-yl) the sulfenyl methyl] quinoline-3-Ethyl formate hydrochlorate (2.0g), recrystallization in ethanol/ether, get the crystallization of faint yellow rib shape, m.p.180-181 ℃.
Elementary analysis: value of calculation:
C
26H
27N
3O
5S·HCl·1/2H
2O
C, 57.93; H, 5.42; N, 7.80 measured values: C, 58.05; H, 5.32; N, 7.72. embodiment 11
Press the same procedure of embodiment 1, made 6,7-dimethyl-4-(3, the 4-3,5-dimethylphenyl)-2-[(1-Methylimidazole .-2-yl) the sulfenyl methyl] quinoline-3-Ethyl formate (97%), grease.
NMR(δppm)in?CDCl
3:0.93(3H,t,J=7Hz),2.31(3H,s),2.32(3H,s),2.35(3H,s),2.44(3H,s),3.42(3H,s),4.03(2H,q,J=7Hz),4.61(2H,s),6.88(1H,d,J=1Hz),7.03-7.10(3H,m),7.23(1H,d,J=8Hz),7.35(1H,s),7.7?8(1H,s).
Above-mentioned grease is dissolved in the ethanol (10ml), the alcoholic solution (23% that adds hydrogen chloride, 0.584g), the pressure reducing and steaming solvent gets 6,7-dimethyl-4-(3, the 4-3,5-dimethylphenyl)-and 2-[(1-Methylimidazole .-2-yl) the sulfenyl methyl] quinoline-3-Ethyl formate hydrochlorate (1.1g), recrystallization in ethanol/ether gets the crystallization of faint yellow rib shape, m.p.133-134 ℃.
Elementary analysis: value of calculation: C
27H
29N
3O
2SHCl3/2H
2O
C, 62.00; H, 6.36; N, 8.03 measured values: C, 62.31; H, 6.01; N, 7.98. embodiment 12
Press the same procedure of embodiment 1, made 6,7-dimethoxy-4 '-(3, the 4-3,5-dimethylphenyl)-and 2-[(1-Methylimidazole .-2-yl) the sulfenyl methyl] quinoline-3-Ethyl formate 1-oxide (69%), recrystallization in ethyl acetate/hexane gets the crystallization of colourless rib shape, m.p.171-172 ℃.Elementary analysis: value of calculation: C
27H
29N
3O
7S:
C, 60.10; H, 5.42; N, 7.79 measured values: C, 60.29; H, 5.53; N, the same procedure that 7.49. embodiment 13-72 presses embodiment 1 has made table 9 chemical compound in 17.
Table 9
Table 10
Table 11
Table 12
Table 13
Table 14
Table 15
Table 16
Table 17
Embodiment 73-75
Press the same procedure of embodiment 1, made chemical compound in the table 18.Table 18
Embodiment 76
With 2-chloromethyl-6,7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl) quinazoline (4.5g), 2 mercapto ethanol (1.13g), potassium carbonate (2.8g) and N, during stirring was fallen back in 2 hours under the mixture room temperature of dinethylformamide (50ml), use ethyl acetate extraction, the washing ethyl acetate layer, dry (MgSO
4), steaming desolventizes, and gets-6,7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl)-2-[(2-hydroxyl ethylmercapto group) methyl] quinazoline (4.1g, 82%), recrystallization gets the crystallization of colourless rib shape, m.p.154-155 ℃ in ethanol.Embodiment 77-83
Same procedure by embodiment 76 has prepared chemical compound in the table 19.
Table 19
Embodiment 84-86
Same procedure by embodiment 2 has prepared chemical compound in the table 20.Table 20
Embodiment 87
With chlorination [6; 7-dimethoxy-4 '-(3; the 4-Dimethoxyphenyl)-and 3-carbethoxyl group quinoline-2-yl] Jia base triphenyl phosphonium (17.4g) adds under room temperature in the alcoholic solution (by 0.62g Na and 150ml ethanol preparation) of Sodium ethylate, splashes into ethanol (20ml) solution of 2-formoxyl-1-Methylimidazole. (3.7g) then.Mixture in the routine entry, is used ethyl acetate extraction in stirring at room 3 hours, washing ethyl acetate layer, dry (MgSO
4), boil off solvent, residue is through silica gel chromatography, by with chloroform/methanol (100: 1, V/V) fraction that goes out of eluting obtains (E)-6,7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl)-and 2-[2-(1-Methylimidazole .-2-yl) vinyl] quinoline-3-Ethyl formate (8.3g, 67%), recrystallization gets the crystallization of colourless rib shape, m.p.206-208 ℃ in ethanol.
From the fraction that eluting goes out subsequently, get (Z)-6,7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl)-2-[2-(1-Methylimidazole .-2-yl) vinyl] quinoline-3-Ethyl formate (2.6g, 21%), grease.NMR(δppm?CDCl
3):0.96(3H,t,J=7H2),3.35(3H,s),3.78(3H,s),3.87(3H,s),3.96(3H,s),3.97(3H,s),3.98(2H,q,J=7H2),6.69(1H,d,J=12Hz),6.8-7.1(7H,m),7.13(1H,s).
In the presence of 5% palladium/charcoal in ethanol/oxolane (1: 1, V/V) in, with (E)-and (Z)-6,7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl)-and 2-[(2-(1-Methylimidazole .-2-yl) vinyl] hydrogenation under an atmospheric Hydrogen Vapor Pressure respectively of quinoline-3-Ethyl formate, obtain-6,7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl)-and 2-[(2-(1-Methylimidazole .-2-yl) ethyl] quinoline-3-Ethyl formate, recrystallization gets the crystallization of colourless rib shape, m.p.147-148 ℃ in ethanol.Embodiment 88
With chlorination [6; 7-dimethoxy-4 '-(3; the 4-Dimethoxyphenyl) quinazoline-2-yl] Jia base triphenyl phosphonium (9.1g) adds under room temperature in the alcoholic solution (by 0.394g Na and 100ml ethanol preparation) of Sodium ethylate, splashes into ethanol (10ml) solution of 2-formoxyl-1-Methylimidazole. (1.7g) then.Mixture is poured in the water in stirring at room 3 hours, uses chloroform extraction, washing ethyl acetate layer, dry (MgSO
4), boil off solvent, residue is through silica gel chromatography, by with chloroform/methanol (20: 1, V/V) fraction that goes out of eluting obtains (E)-6,7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl)-and 2-[2-(1-Methylimidazole .-2-yl) vinyl] quinazoline (5.1g, 82%), recrystallization gets the crystallization of first color rib shape, m.p.254-255 ℃ in ethanol/chloroform.Elementary analysis: value of calculation: C
24H
24N
4O
43/2H
2O:
C, 62.73; H, 5.92; N, 12.19 measured values: C, 62.62; H, 5.85; N, 11.90.
From the fraction that eluting goes out subsequently, get (Z)-6,7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl)-2-[2-(1-Methylimidazole .-2-yl) vinyl] quinazoline (0.61g, 10%), recrystallization in ethanol/chloroform gets colourless flaky crystal, m.p.180-181 ℃.Elementary analysis: value of calculation: C
24H
24N
4O
41/2H
2O:
C, 65.29; H, 5.71; N, 12.69 measured values: C, 65.28; H, 5.66; N, 12.42.
In the presence of 5% palladium/charcoal in chloroform/ethyl acetate (1: 1, V/V) in, with (E)-and (Z)-6,7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl)-2-[(2-(1-Methylimidazole .-2-yl) vinyl] quinazoline hydrogenation under-individual atmospheric Hydrogen Vapor Pressure respectively, obtain 6,7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl)-and 2-[(2-(1-Methylimidazole .-2-yl) ethyl] quinazoline, recrystallization gets the crystallization of colourless rib shape, m.p.170-171 ℃ in ethyl acetate.Embodiment 89-94
Same procedure by embodiment 87 has made chemical compound in the table 21.
Table 21
Annotate 1) 1/2 hydrate embodiment 95
With 6,7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl)-and 2-[2-(1-Methylimidazole .-2-yl) ethyl] quinoline-3-Ethyl formate (9.0g) is suspended in the ethanol (40ml), add ethanol solution of hydrogen chloride (22%, 10g), stirred 5 minutes under the room temperature, add ether (150ml), filter out sedimentary crystallization, and in ethanol/ether recrystallization, 6,7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl)-and 2-[2-(1-Methylimidazole .-2-yl) ethyl] quinoline-3-Ethyl formate dihydrochloride (9.1g), the crystallization of faint yellow rib shape, m.p.154-160 ℃.Elementary analysis: value of calculation: C
28H
31N
3O
62HCl1/3C
2H
5OH1/2H
2O:
C, 57.11; H, 6.02; N, 6.97 measured values: C, 57.03; H, 6.15; N, 7.00.
Embodiment 96
With chlorination [6,7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl)-and 3-carbethoxyl group quinoline-2-yl] Jia base triphenyl phosphonium (3.0g) adds under room temperature in the alcoholic solution (by 0.13g Na and 45ml ethanol preparation) of Sodium ethylate, adds 3-(1-Methylimidazole .-2-yl) propionic aldehyde solution (0.787g) then.Mixture is poured in the water in stirring at room 3 hours, uses ethyl acetate extraction, washing ethyl acetate layer, dry (MgSO
4), boil off solvent, residue is through silica gel chromatography, by using ethyl acetate/methanol (30: 1, V/V) fraction that goes out of eluting obtains (E)-6,7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl)-2-[2-[2-(1-Methylimidazole .-2-yl) ethyl] vinyl] quinoline-3-Ethyl formate (0.36g, 15%) grease.
NMR(δppm?CDCl
3):1.03(3H,t,J=7Hz),2.7-3.0(4H,m),3.60(3H,s),3.79(3H,s),3.87(3H,s),3.97(3H,s),????4.05(3H,s),4.09(2H,q,J=7Hz),6.7-7.2(8H,m),7.43(1H,s).
From the fraction that eluting goes out subsequently, get (Z)-6,7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl)-2-[2-[2-(1-Methylimidazole .-2-yl) ethyl] vinyl] quinoline-3-Ethyl formate (0.2g, 8%), grease.
NMR(δppm?CDCl
3):1.02(3H,t,J=7Hz),2.8-3.2(4H,m),3.58(3H,s),3.80(3H,s),3.88(3H,s),3.96(3H,s),4.05(3H,s),4.07(2H,q,J=7Hz),6.08(1H,dt,J=7.481.4Hz),6.6-7.0(7H,m),7.42(1H,s).
In the presence of 5% palladium/charcoal in ethanol/oxolane (1: 4, V/V) in, with (E)-and (Z)-6,7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl)-and 2-[2-[2-(1-Methylimidazole .-2-yl) ethyl] vinyl] mixture hydrogenation under an atmospheric Hydrogen Vapor Pressure of quinoline-3-Ethyl formate, handle with ethanol solution of hydrogen chloride then, obtain 6,7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl)-and 2-[4-(1-Methylimidazole .-2-yl) butyl] quinoline-3-Ethyl formate, recrystallization in chloroform/ethyl acetate gets the crystallization of faint yellow rib shape, m.p.180-183 ℃.Elementary analysis: value of calculation:
C
30H
35N
3O
6·2HCl·H
2O:
C, 57.69; H, 6.29; N, 6.73 measured values: C, 57.48; H, 6.09; N, 6.60. embodiment 97
With 2-chloromethyl-6,7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl) quinoline-3-Ethyl formate (1.5g), 2-hydroxyl-6-picoline (0.4g), carbon ester potassium (0.511g) and N, the mixture of dinethylformamide (20ml) is in 120 ℃ of stirrings were fallen back in 2 hours, use ethyl acetate extraction, the washing ethyl acetate layer, dry (MgSO
4), boil off solvent, remaining grease is through silica gel chromatography, get 6,7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl)-2-[(2-methyl-6-pyridine radicals by the level that goes out with eluent ethyl acetate) the oxygen ylmethyl] quinoline-3-Ethyl formate (0.79g, 46%), recrystallization in chloroform/hexane gets the crystallization of yellow rib shape, m.p.173-174 ℃.Elementary analysis: value of calculation: C
29H
30N
2O
7:
C, 67.17; H, 5.83; N, 5.40 measured values: C, 66.97; H, 6.02; N, 5.16. embodiment 98
With 2-iodomethyl-6,7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl) quinoline-3-Ethyl formate (9.0g), 2-hydroxyl-1-Methylimidazole. (1.8g), Disilver carbonate (I) (Ag
2CO
3, 5.1g) and the mixture of benzene (100ml) stirred filtering insoluble matter, washing filtrate, dry (MgSO 18 hours in 50 ℃
4), boil off solvent, remaining grease is through silica gel chromatography, from chloroform/ethyl acetate (5: 1, V/V) in the fraction that goes out of eluting 6,7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl)-and 2-[(1-methyl-2-imidazole radicals) the oxygen methyl] quinoline-3-Ethyl formate (0.8g, 9%), recrystallization in ethyl acetate/hexane, get the crystallization of colourless rib shape, m.p.151-152 ℃.Elementary analysis: value of calculation: C
27H
29N
3O
7:
C, 63.90; H, 5.87; N, 8.28 measured values: C, 63.74; H, 5.87; N, 7.99. embodiment 99
With 6,7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl)-and 2-[(1-Methylimidazole .-2-yl) the sulfenyl methyl] mixture of quinoline azoles-3-Ethyl formate (0.6g), 2N NaOH (1.7ml) and ethanol (12ml) refluxed 6 hours, the reactant mixture vacuum concentration, residue diluted with water, wash with ethyl acetate, with 2N HCl acidify and use ethyl acetate extraction.The washing extracting solution is used MgSO
4Drying, vacuum concentration gets crystallization, gets 6 behind the recrystallization in ethanol/ether, 7-dimethoxy-4 '-(3, the 4-Dimethoxyphenyl)-2-[(1-Methylimidazole .-2-yl) sulfenyl methyl] quinoline azoles-3-formic acid (0.3g, 53%), the crystallization of colourless rib shape, m.p.213-214 ℃.Elementary analysis: value of calculation: C
25H
25N
3O
6S1/2H
2O:
C, 59.51; H, 5.19; N, 8.32. measured value: C, 59.38; H, 5.40; N, 7.93.
Claims (6)
- One kind the prevention or the treatment inflammatory diseases pharmaceutical composition, said composition contains the formula I compound or its salt:Y is the N atom in the formula; X be any oxidation sulphur atom or-(CH 2) q-, wherein q is an integer 1 to 5; R is the alkyl that replaces arbitrarily, the aliphatic unsaturated cyclic alkyl that described alkyl is selected from the sturated aliphatic hydrocarbon base with 1-10 carbon atom, the unsaturated aliphatic hydrocarbon base with 2-10 carbon atom, the aliphatic saturated cyclic alkyl with 3-10 carbon atom and has 5-6 carbon atom; Perhaps R is aromatics or the non-aromatic heterocyclic group that replaces arbitrarily, and described heterocyclic group has an one-tenth ring carbon atom that is connected with X and has at least one hetero atom that is selected from oxygen, sulfur and nitrogen as becoming annular atoms; A ring and B ring all can at random have at least one substituent group; K is 0 or 1.
- 2. by the compositions of power requirement 1, wherein X is-(CH 2) q-.
- 3. by the compositions of power requirement 1, wherein R is aromatics or the non-aromatic heterocyclic group that replaces arbitrarily, and described heterocyclic group has an one-tenth ring carbon atom that is connected with X and has at least one hetero atom that is selected from oxygen, sulfur and nitrogen as becoming annular atoms.
- 4. by the compositions of power requirement 1; wherein A ring and B ring can be replaced by 1 to 4 identical or different substituent group independently of one another; described substituent group is selected from halogen atom, nitro, the alkyl that replaces arbitrarily, is substituted with the carboxyl of hydroxyl, the thiol that replaces arbitrarily, the amino that replaces arbitrarily, the acyl group that replaces arbitrarily, esterification arbitrarily and the aromatic ring yl that replaces arbitrarily arbitrarily, and two adjacent substituent groups can be joined together to form the following formula group and makeup ring:-(CH 2) m-or-O-(CH 2) n-O-wherein m is an integer 3 to 5, and n is that integer 1 is to 3m
- 5. power requires 1 compositions, and it is the medicament that suppresses joint damage.
- 6. power requires 1 compositions, and it is the rheumatism medicament.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 98109507 CN1223115A (en) | 1992-04-24 | 1998-05-29 | Pharmaceutical composition containing quinoline and quinazoline derivatives and novel compounds therefor |
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP106424/92 | 1992-04-24 | ||
| JP121887/92 | 1992-05-14 | ||
| JP285865/92 | 1992-10-23 | ||
| JP37952/93 | 1993-02-26 | ||
| CN 98109507 CN1223115A (en) | 1992-04-24 | 1998-05-29 | Pharmaceutical composition containing quinoline and quinazoline derivatives and novel compounds therefor |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN93104980A Division CN1079222A (en) | 1992-04-24 | 1993-04-24 | The medicinal compositions and the new compound thereof that contain quinoline and quinazoline derivant |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105814022A (en) * | 2013-12-09 | 2016-07-27 | Ucb生物制药私人有限公司 | Fused bicyclic heteroaromatic derivatives as modulators of tnf activity |
| CN115368300A (en) * | 2022-10-27 | 2022-11-22 | 北京拓领博泰生物科技有限公司 | Compound for TLR8 inhibitor and preparation method and application thereof |
-
1998
- 1998-05-29 CN CN 98109507 patent/CN1223115A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105814022A (en) * | 2013-12-09 | 2016-07-27 | Ucb生物制药私人有限公司 | Fused bicyclic heteroaromatic derivatives as modulators of tnf activity |
| CN105814022B (en) * | 2013-12-09 | 2018-09-28 | Ucb生物制药私人有限公司 | Condensed bicyclic heteroaromatic derivative as TNF active regulators |
| CN115368300A (en) * | 2022-10-27 | 2022-11-22 | 北京拓领博泰生物科技有限公司 | Compound for TLR8 inhibitor and preparation method and application thereof |
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