CN104926797B - Furanone derivatives, Preparation method and use - Google Patents
Furanone derivatives, Preparation method and use Download PDFInfo
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- CN104926797B CN104926797B CN201510230627.0A CN201510230627A CN104926797B CN 104926797 B CN104926797 B CN 104926797B CN 201510230627 A CN201510230627 A CN 201510230627A CN 104926797 B CN104926797 B CN 104926797B
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
The present invention relates to a new class of COX-2 selective inhibitor compound, Preparation method and use belongs to chemical medicine field.Compound as described in formula (I) is able to suppress Cycloxygenase, bioconversion of the arachidonic acid to prostaglandin in interfering bodies, therefore, the compound and its pharmaceutical composition can treat the related disease of Cycloxygenase mediation, the various diseases that such as can be used for treating and alleviating the inflammation of animal and people and caused by inflammation, such as arthritis, neurodegenerative disorders, depression, psychotic disorder disease and cancer (including non-small cell lung cancer, liver cancer, cancer of pancreas, colon cancer, breast cancer, oophoroma, prostate cancer, cervical carcinoma, cutaneum carcinoma, head and neck cancer).
Description
Technical field
The present invention relates to a new class of furanone derivatives and its pharmaceutical composition in Cycloxygenase treating correlative diseases
Application.Compound in the present invention is able to suppress Cycloxygenase, and arachidonic acid turns to the biology of prostaglandin in interfering bodies
Change, therefore, the various diseases that can be used for treating and alleviating the inflammation of animal and people and caused by inflammation, as cancer is (including non-
Small Cell Lung Cancer, liver cancer, cancer of pancreas, colon cancer, breast cancer, oophoroma, prostate cancer, cervical carcinoma, cutaneum carcinoma, head and neck cancer etc.),
Arthritis, neurodegenerative disorders, depression, psychotic disorder disease, Postoperative analgesia.
Background technique
Arachidonic metabolite takes part in many Acute and chronic inflammation pathogenic processes.And this major class fatty
Arachidonic acid metabolite is obtained under the action of a series of enzymes.Consider in the sense that treatment, most important one
One enzyme is exactly prostaglandin G/H sythase, i.e. Cycloxygenase (COX).It, which is catalyzed, generates many angiotensins and inflammation object
Matter, such as prostaglandin (PGE2、PGD2、PGF2), prostacyclin (PGI2) and thromboxane (TXA2) etc..
Because of the remarkable activity in terms of anti-inflammatory and antalgic, non-steroidal anti-inflammatory drugs (NSAIDs) has been widely used in treating pain
And arthritis.NSAIDs, which mainly passes through, inhibits Cycloxygenase (COX), that is, prostaglandin G/H sythase (PGHs), thus
Arachidonic acid metabolic is inhibited to form prostaglandins and work.Prostaglandin, especially Prostaglandin PGE2, be
The main eicosanoids that are detected when inflammation occurs are lead to pain, fever and other inflammation-related conditions main
Mediators.The biosynthesis of prostaglandin is inhibited to have proven to the important target spot of anti-inflammatory drug effect.However the non-steroid of tradition
Body anti-inflammatory agent makes its application in the treatment by very big because of side effects such as the ulcer and the Toxicity of Kidney that will lead to threat to life
Limitation.Though corticosteroids can be used as the substitution of NSAIDs, long-time service can also generate serious adverse reaction.
The beginning of the nineties the study found that Cycloxygenase there are two kinds of enzymes, i.e. COX-1 and COX-2.COX-1 be present in stomach, kidney and
In many normal tissues such as blood platelet.The toxic side effect of stomach and intestine caused by NSAIDs and kidney is exactly to be led by the inhibition of COX-1
It causes.And COX-2 is derivable enzyme, and in many tissues, in macrophage, osteocyte, fibroblast and endothelial cell,
Induction and great expression through a series of inflammatory factors or cell factor.
The discovery of COX-2 makes it possible the synthesis of Selective COX-2 inhibitor.Highly selective cox 2 inhibitor
The inhibiting effect of COX-1 is substantially reduced, so that the toxicity in terms of reducing ulcer, improves the gastrointestinal tolerant power of this kind of medicine.
The present invention elaborates a new class of Selective COX-2 inhibitor.
Summary of the invention
The present invention relates to such as formula (I) compounds represented:
Here:
Work as X=N, Y=C；Or Y=N, X=C atom；
Substituent R1Representative-SOR7、-SO2R7Or-SR7Base；
Substituent R2-R6It is each independently selected from hydrogen, halogen, C1-8Alkyl, R8OC0-8Alkyl, R8SC0-8Alkyl ,-SOR9、-
SO2R9、C1-8Halogenated alkyl, cyano, nitro, amino；
Substituent R7Representative-NH2、C1-8Alkyl, C1-8Halogenated alkyl；
Substituent R8Represent hydrogen, C1-8Alkyl, C1-8Halogenated alkyl；
Substituent R9Represent C1-8Alkyl, C1-8Halogenated alkyl.
One embodiment of the present invention includes one group of compound with formula (I) structure, the structure of the compound
It is characterized in that:
Substituent R1Representative-SO2R7、-SR7Base；
Substituent R2-R6It is each independently selected from hydrogen, halogen, C1-5Alkyl, R8OC0-4Alkyl, R8SC0-4Alkyl ,-SOR9、-
SO2R9、C1-5Halogenated alkyl, amino；
Substituent R7Representative-NH2、C1-5Alkyl, C1-5Halogenated alkyl；
Substituent R8Represent hydrogen, C1-5Alkyl, C1-5Halogenated alkyl；
Substituent R9Represent C1-5Alkyl, C1-5Halogenated alkyl.
The quantity of carbon atom is by a carbon atoms minimum number and maximum number in hydrocarbon moiety mentioned here
Prefix is named, for example, prefix is Ca-bAlkyl indicate the alkyl of a carbon atom containing a to b.Therefore, C1-8Alkyl just refers to
Alkyl containing 1-8 carbon atom.
" alkoxy " refers to the carbocyclic aliphatic chain with the straight chain of an oxygen atoms bond or branched, monovalent saturation, including
But it is not limited to such as methoxyl group, ethyoxyl, propoxyl group, butoxy, isobutoxy, tert-butoxy and other similar groups.
" alkyl " refers to straight chain or branched, monovalent, saturated carbon aliphatic chain, including but not limited to as methyl, ethyl,
Propyl, isopropyl, butyl, isobutyl group, tert-butyl, amyl, isopentyl, hexyl and other similar groups.
" aryl " refers to a kind of cricoid aromatic hydrocarbon, including but not limited to such as phenyl, naphthalene, anthryl, phenanthryl and other
Similar group.
" halogen " refers to chlorine, bromine, fluorine and iodine atom or group.
" heteroaryl " refers to the monocycle or polycyclic that wherein one or more carbon atoms are replaced Bei such as nitrogen, oxygen or sulphur hetero atom
Aromatic hydrocarbon.If heteroaryl contains more than one hetero atom, these hetero atoms replaced can be the same or different.Heteroaryl
Base includes but is not limited to such as benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzopyrene
It mutters base, furyl, imidazole radicals, indazolyl, indolizine base, indyl, isobenzofuran-base, isoindolyl, isoquinolyl, isothiazole
Base, isoxazolyl, naphthyridines base, oxadiazoles base, oxazines base, oxazolyl, phthalazinyl, pteridyl, purine radicals, pyranose, pyrazinyl,
Pyrazolyl, pyridazinyl, pyridine [3,4-b] indyl, pyridyl group, pyrimidine radicals, pyrrole radicals, quinazinyl, quinolyl, quinoxalinyl,
Thiadiazolyl group, thiatriazole base, thiazolyl, thienyl, triazine radical, triazolyl, xanthyl and other similar groups；
" substitution " refers to that the hydrogen atom in molecule is substituted by other different atoms or molecule.Replace the atom of hydrogen atom
Or molecule is referred to as " substituent group ".
Another embodiment of the invention includes one group of compound with formula (I) structure, the knot of the compound
Structure is characterized in that:
Substituent R1Representative-SO2R7、-SR7Base；
Substituent R2-R6It is each independently selected from hydrogen, halogen, C1-5Alkyl, R8OC0-4Alkyl, R8SC0-4Alkyl ,-SOR9、-
SO2R9、C1-5Halogenated alkyl, amino；
Substituent R7Representative-NH2、C1-5Alkyl；
Substituent R8Represent hydrogen, C1-5Alkyl, C1-5Halogenated alkyl；
Substituent R9Represent C1-5Alkyl, C1-5Halogenated alkyl.
Another embodiment of the invention includes one group of compound with formula (I) structure, the knot of the compound
Structure is characterized in that:
Substituent R1Representative-SO2R7、-SR7Base；
Substituent R2-R6It is each independently selected from hydrogen, halogen, C1-3Alkyl, R8OC0-3Alkyl, R8SC0-3Alkyl ,-SOR9、-
SO2R9、C1-5Halogenated alkyl, amino；
Substituent R7Representative-NH2、C1-3Alkyl；
Substituent R8Represent hydrogen, C1-3Alkyl, C1-3Halogenated alkyl；
Substituent R9Represent C1-3Alkyl, C1-3Halogenated alkyl.
Another embodiment of the invention includes one group of compound with formula (I) structure, the knot of the compound
Structure is characterized in that:
Substituent R1Representative-SO2R7、-SR7Base；
Substituent R2-R6It is each independently selected from hydrogen, chlorine atom, fluorine atom, C1-3Alkyl, R8OC0-3Alkyl, R8SC0-3Alkane
Base ,-SOR9、-SO2R9、C1-5Halogenated alkyl, amino；
Substituent R7Representative-NH2, methyl；
Substituent R8Represent hydrogen, C1-3Alkyl, C1-3Halogenated alkyl；
Substituent R9Represent C1-3Alkyl, C1-3Halogenated alkyl.
In a preferred embodiment of the present invention, the compound of formula (I) is selected from:
2,2- dimethyl -5- [5- (mesyl) -2- pyridine] -4- phenyl -3 (2H)-furanone,
4- (4- benzyloxy) -2,2- dimethyl -5- [5- (mesyl) -2- pyridine] -3 (2H)-furanones,
2,2- dimethyl -5- [5- (mesyl) -2- pyridine] -4- p-methylphenyl -3 (2H)-furanone,
4- (4- fluorophenyl) -2,2- dimethyl -5- [5- (mesyl) -2- pyridine] -3 (2H)-furanones,
4- (4- chlorphenyl) -2,2- dimethyl -5- (5- (mesyl) -2- pyridine) -3 (2H)-furanones,
4- (3- fluorophenyl) -2,2- dimethyl -5- [5- (mesyl) -2- pyridine] -3 (2H)-furanones,
4- (2- fluorophenyl) -2,2- dimethyl -5- [5- (mesyl) -2- pyridine] -3 (2H)-furanones,
4- (3- chlorphenyl) -2,2- dimethyl -5- [5- (mesyl) -2- pyridine] -3 (2H)-furanones,
4- (the fluoro- 4- aminomethyl phenyl of 3-) -2,2- dimethyl -5- [5- (mesyl) -2- pyridine] -3 (2H)-furanones,
4- (the fluoro- 3- benzyloxy of 4-) -2,2- dimethyl -5- [5- (mesyl) -2- pyridine] -3 (2H)-furanones,
4- (4- chlorphenyl) -2,2- dimethyl -5- [5- (mesyl) -2- pyridine] -3 (2H)-furanones,
4- (2,5- difluorophenyl) -2,2- dimethyl -5- [5- (mesyl) -2- pyridine] -3 (2H)-furanones,
4- (3,5- dichlorophenyl) -2,2- dimethyl -5- [5- (mesyl) -2- pyridine] -3 (2H)-furanones,
4- (the fluoro- 4- benzyloxy of 3-) -2,2- dimethyl -5- [5- (mesyl) -2- pyridine] -3 (2H)-furanones,
2,2- dimethyl -5- [5- (mesyl) -2- pyridine] -4- (4- (trifluoromethyl) phenyl) -3 (2H)-furanones,
2,2- dimethyl -4- [4- (methylsulfinyl) phenyl] -5- [5- (mesyl) -2- pyridine] -3 (2H)-furans
It mutters ketone,
4- [4- (ethylsulfinyl) phenyl] -2,2- dimethyl -5- [5- (mesyl) -2- pyridine] -3 (2H)-furans
It mutters ketone,
4- (3- methoxyl group -5- aminomethyl phenyl) -2,2- dimethyl -5- [5- (mesyl) -2- pyridine] -3 (2H)-furans
Ketone,
2,2- dimethyl -4- [3- methyl -4- (trifluoromethoxy) phenyl] -5- [5- (mesyl) -2- pyridine] -3
(2H)-furanone,
4- (4- ethoxyphenyl) -2,2- dimethyl -5- [5- (mesyl) -2- pyridine] -3 (2H)-furanones,
4- (chloro- 3 benzyloxy of 4-) -2,2- dimethyl -5- [5- (mesyl) -2- pyridine] -3 (2H)-furanones,
4- (3,5- diethoxy phenyl) -2,2- dimethyl -5- [5- (mesyl) -2- pyridine] -3 (2H)-furanones,
4- (3,5- dichlorophenyl) -2,2- dimethyl -5- [5- (mesyl) -2- pyridine] -3 (2H)-furanones,
2,2- dimethyl -5- [(5- mesyl) -2- pyridine] -4- propoxyphenyl -3 (2H)-furanone,
2,2- dimethyl -5- [(5- mesyl) -2- pyridine] -4- nitrobenzophenone -3 (2H)-furanone,
2,2- dimethyl -5- [(5- mesyl) -2- pyridine] -4- aminophenyl -3 (2H)-furanone,
- 3 (2H)-furanone of 2,2- dimethyl -5- [(5- mesyl) -2- pyridine] -4- (2,4- dichlorophenyl),
2,2- dimethyl -5- [(5- mesyl) -2- pyridine] -4- (the chloro- 4- aminomethyl phenyl of 2-) -3 (2H)-furanones,
2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -4- phenyl -3 (2H)-furanone,
4- (4- benzyloxy) -2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -3 (2H)-furanones,
2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -4- p-methylphenyl -3 (2H)-furanone,
4- (4- fluorophenyl) -2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -3 (2H)-furanones,
4- (4 chlorphenyl) -2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -3 (2H)-furanones,
4- (3- fluorophenyl) -2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -3 (2H)-furanones,
4- (2- fluorophenyl) -2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -3 (2H)-furanones,
4- (3- chlorphenyl) -2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -3 (2H)-furanones,
4- (the fluoro- 4- tolyl of 3-) -2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -3 (2H)-furanones,
4- (the fluoro- 3- benzyloxy of 4-) -2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -3 (2H)-furanones,
4- (4- chlorphenyl) -2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -3 (2H)-furanones,
4- (2,5- difluorophenyl) -2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -3 (2H)-furanones,
4- (3,5- dichlorophenyl) -2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -3 (2H)-furanones,
4- (the fluoro- 4- benzyloxy of 3-) -2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -3 (2H)-furanones,
2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -4- [4- (trifluoromethyl) phenyl] -3 (2H)-furanones,
2,2- dimethyl -4- [4- (methylsulfinyl) phenyl] -5- [6- (mesyl) -3- pyridine] -3 (2H)-furans
It mutters ketone,
4- [4- (ethylsulfinyl) phenyl] -2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -3 (2H)-furans
It mutters ketone,
4- (3- methoxyl group -5- aminomethyl phenyl) -2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -3 (2H)-furans
Ketone,
2,2- dimethyl -4- [3- methyl -4- (trifluoromethoxy) phenyl] -5- [6- (mesyl) -3- pyridine] -3
(2H)-furanone,
4- (4- ethoxyphenyl) -2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -3 (2H)-furanones,
4- (chloro- 3 benzyloxy of 4-) -2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -3 (2H)-furanones,
4- (3,5- diethoxy phenyl) -2,2- dimethyl -5- (6- (mesyl) -3- pyridine) -3 (2H)-furanones,
4- (3,5- dichlorophenyl) -2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -3 (2H)-furanones,
- 3 (2H)-furanone of 2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -4- (4- propoxyphenyl),
- 3 (2H)-furanone of 2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -4- (4- nitrobenzophenone),
4- (4- aminophenyl) -2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -3 (2H)-furanones,
4- (2,4- dichlorophenyl) -2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -3 (2H)-furanones,
4- (chloro- 4 aminomethyl phenyl of 2-) -2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -3 (2H)-furanones.
In the more preferable embodiment of of the invention one, the compound of formula (I) is selected from:
2,2- dimethyl -5- [5- (mesyl) -2- pyridine] -4- phenyl -3 (2H)-furanone,
4- (4- benzyloxy) -2,2- dimethyl -5- [5- (mesyl) -2- pyridine] -3 (2H)-furanones,
2,2- dimethyl -5- [5- (mesyl) -2- pyridine] -4- p-methylphenyl -3 (2H)-furanone,
4- (4- fluorophenyl) -2,2- dimethyl -5- [5- (mesyl) -2- pyridine] -3 (2H)-furanones,
4- (2,5- difluorophenyl) -2,2- dimethyl -5- [5- (mesyl) -2- pyridine] -3 (2H)-furanones,
4- (3,5- dichlorophenyl) -2,2- dimethyl -5- [5- (mesyl) -2- pyridine] -3 (2H)-furanones,
4- (the fluoro- 4- benzyloxy of 3-) -2,2- dimethyl -5- [5- (mesyl) -2- pyridine] -3 (2H)-furanones,
2,2- dimethyl -5- [5- (mesyl) -2- pyridine] -4- (4- (trifluoromethyl) phenyl) -3 (2H)-furanones,
- 3 (2H)-furanone of 2,2- dimethyl -5- [(5- mesyl) -2- pyridine] -4- (2,4- dichlorophenyl),
2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -4- phenyl -3 (2H)-furanone,
4- (4- benzyloxy) -2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -3 (2H)-furanones,
2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -4- p-methylphenyl -3 (2H)-furanone,
4- (4- fluorophenyl) -2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -3 (2H)-furanones,
4- (2,5- difluorophenyl) -2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -3 (2H)-furanones,
4- (3,5- dichlorophenyl) -2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -3 (2H)-furanones,
4- (the fluoro- 4- benzyloxy of 3-) -2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -3 (2H)-furanones,
2,2- dimethyl -5- (6- (mesyl) -3- pyridine) -4- [4- (trifluoromethyl) phenyl] -3 (2H)-furanones,
4- (2,4 dichloro benzene base) -2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -3 (2H)-furanones.
The invention further relates to the salt of foregoing invention compound, solvate, isomers and pro-drugs.So-called pro-drug
Any precursor for referring to compound representated by above-mentioned formula (I) can decompose in vivo and discharge compound representated by formula (I).
There may be chiral centres for some compounds representated by formula (I), therefore can generate various stereoisomers.
The present invention also includes each stereoisomer and its mixture among these.Moreover, some compounds in the present invention may be deposited
In cis-trans-isomer.The present invention includes each geometric isomer and its mixture therein.
The invention also includes Pharmaceutical composition, by formula (I) compound of effective dose or its pharmaceutically acceptable salt, molten
Agent is closed object, isomers or pro-drug and is formed plus one or more pharmaceutic adjuvants.
The invention also includes formula (I) compound or its pharmaceutically acceptable salt, solvate, isomers or precursor medicines
Object preparation for prevent or treat animal and people by Cycloxygenase, especially cyclooxygenase 2 (COX-2), the disease of mediation
Drug in application.
The invention also includes formula (I) compound or its pharmaceutically acceptable salt, solvate, isomers or precursor medicines
Application of the object in the drug for preparing the cancer for treating animal and people, inflammation, pain, fever, including cancer (including it is non-small
Cell lung cancer, liver cancer, cancer of pancreas, colon cancer, breast cancer, oophoroma, prostate cancer, cervical carcinoma, cutaneum carcinoma, head and neck cancer etc.),
Osteoarthritis, rheumatoid arthritis, Acute Pain, perioperative pain, postoperative pain, pain in the loins, the periarthritis of shoulderjoint, neck shoulder
Wrist syndrome, tenosynovitis, dysmenorrhea, toothache etc..
The invention also includes formula (I) compound or its pharmaceutically acceptable salt, solvate, isomers or precursor medicines
Object preparation for prevent or treating cancer, including colon cancer, breast cancer drug in application.
The invention also includes formula (I) compound or its pharmaceutically acceptable salt, solvate, isomers or precursor medicines
Application of the object in the drug for preparing the depression for preventing or treating animal and people.
The invention also includes formula (I) compound or its pharmaceutically acceptable salt, solvate, isomers or precursor medicines
Object is preparing the application in the schizoid drug for preventing or treating animal and people.
The invention also includes formula (I) compound or its pharmaceutically acceptable salt, solvate, isomers or precursor medicines
Object preparation for prevent or treat animal and people cerebral infarction, epilepsy, neurodegenerative disease (such as alzheimer's disease and
Senile dementia), the application in the adenomatous polyps especially drug of familial rectal polyp.
Animal recited above includes Canidae, equine, cat family, Cervidae etc., such as dog, wolf, cat, panda, horse, deer.
" pharmaceutically acceptable " refers to certain carrier, load, diluent, auxiliary material, and/or is formed by salt and is usually changing
On or physically with constitute the other compatible at split-phase of certain pharmaceutical dosage form, and be physiologically mutually compatible with.
" salt " and " pharmaceutical salt " refers to the organic of formula (I) compound represented or its stereoisomer or its prodrug
Salt and inorganic salts.These salt, which can be, to be directly obtained in being finally separating and purify of compound, or by using conjunction
Suitable organic or inorganic acid or alkali is reacted with compound shown in formula (I) or its stereoisomer or its prodrug respectively, is then divided
From acquisition salt.Common salt include as hydrobromate, hydrochloride, sulfate, disulfate, nitrate, acetate, oxalates,
Benzene sulfonate, palmitate, stearate, laruate, borate, benzoate, lactate, phosphate, toluene fulfonate,
Citrate, maleate, fumarate, succinate, tartrate, naphthoate, mesylate, gluconate, cream
Sugar lime, dodecane sulfonate and other similar salt.These salt may also include the cation in alkali or alkaline-earth metal, such as
Sodium, lithium, potassium, calcium, magnesium and other analogs and nontoxic ammonium, quaternary ammonium and ammonium cation, including but not limited to ammonium, tetramethyl
Base ammonium, etamon, methylamine, dimethylamine salt, trismethylamine salt, triethylamine salt, ethamine and other analogs.Other examples are detailed in
Bibliography Berge, the et al., J.Pharm.Sci., 66 of this patent, 1-19 (1977).
The salt of compound shown in formula (I) can by by the solution of compound shown in formula (I) and it is required acid or alkali suitably into
Row is obtained by mixing.These salt may form precipitating in the solution, can be collected by filtering, or recycle after the solvent evaporates
And it obtains.
The compound of formula (I) can be with nonsolvated forms or such as water, the solvation of the acceptable solvent of ethyl alcohol etc.
Form exists, and expectedly the present invention includes all solvations and non-solvated form.
" prodrug " refers to that a kind of compound as prodrug, the compound can pass through in vivo after main body is administered
One chemistry or physiology course (for example, by being placed in physiological ph or passing through enzyme effect) discharge active medicine.About prodrug
The discussion for synthesizing and using, referring to the article of T.Higuchi and W.Stella: " Prodrugs as Novel Delivery
Systems, " vol.14 of the ACS Symposium Series, and in Bioreversible Carriers in
Drug Design, ed.Edward B.Roche, American Pharmaceutical Association and
Pergamon Press, 1987.The content of this two articles, which is cited, to be incorporated herein." prodrug " may also comprise of the present inventionization
The metabolic precursor thereof of object is closed, such prodrug may not have activity when main body is administered, but can be converted into vivo of the invention
Compound.Prodrug is also possible to naturally occurring or chemically synthesized compound.
Formula (I) compound represented may include asymmetric or chiral centre, thus with different stereoisomer forms
In the presence of.It is contemplated that the stereoisomer and its mixture of all formula (I) compounds represented, including racemic mixture
It is all a part of the invention.In addition, also including all geometric isomer and position isomer.Such as: if shown in formula (I)
Compound contain double bond, then its is cis- with trans- two kinds of forms and its mixture is also included within the scope of the present invention.
Non-enantiomer mixture can by method well known within the skill of those ordinarily skilled (such as chromatography and/or
Steppecd crystallization) their each diastereoisomer is separated into based on their physical chemical differences.Enantiomter
Enantiomeric mixture can be converted to diastereoisomer and mixed by separation by reacting with compound with optical activation
Then object separates diastereoisomer, then by individual diastereoisomer conversion (as hydrolyzed) at corresponding pure enantiomerism
Body.In addition, certain formula (I) compounds represented can be in atropisomer (e.g., substituted biaryl) and the present invention
A part.
The compound of formula (I), which is also used as the tautomer in balance, to be existed, and all these forms all wrap
It includes within the scope of the invention.
In one embodiment of the present invention, present invention comprises the formula of isotope labelling (I) compound, the isotopes
Labeled compound refers to identical as listed compound herein, but one or more of atoms are taken by another atom
Generation, the atomic mass or mass number of the atom are different from atomic mass or mass number common in nature.It can be with introduction-type
(I) including hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, i.e., the isotope in compound includes2H、3H、13C、14C、15N、17O、 18O、31P
、32P、35S、18F and36Cl.The compound and its alloisomerism of formula (I) containing above-mentioned isotope and/or other atom isotopes
The pharmaceutical salt of body and prodrug and the compound, stereoisomer or prodrug should be included within the scope of the invention.
Formula (I) compound of certain isotope labellings, such as those are by such as3H and14The change of the labelled with radioisotope such as C
Object is closed, is used as in the tissue distribution assays of compound and/or substrate.Tritium is (i.e.3H) and carbon 14 (i.e.14C) isotope is because of its phase
To it is easy preparation and be easy to detect and it is particularly preferred.In addition, some isotopes, such as it is deuterated (i.e.2H), due to there is better metabolism
Stability (as improved Half-life in vivo or reducing dosage), therefore, can be certain to provide certain treatment advantages
In the case of preferably.Formula (I) compound of the isotope labelling usually can be used method known to persons of ordinary skill in the art all
Such as isotope-labeled reagent is substituted with the reagent of isotope labelling to prepare.
The present invention includes all compounds mentioned above, especially formula (I) compound represented, solely including those
Vertical existing or any compatible combination.
As described above, the compound in the present invention is mainly by inhibiting cyclooxygenase 2 (COX-2 enzyme) to play a role.Cause
This, they are used as inflammation caused by treating or preventing various diseases or pathogen, pain and/or fever, these diseases
Include: rheumatic fever, influenza or other viral infection symptoms, flu, waist neck pain, dysmenorrhea, headache, have a toothache, courbature, nerve
Bitterly, synovitis, synovia capsulitis, arthritis include rheumatoid arthritis and juvenile arthritis, degenerative joint disease include
Osteoarthritis, ankylosing spondylitis, lupus erythematosus, myotenositis, strain pull and other damage (such as those are in sports
The damage of generation), the pain after surgery or dental operation, cancer pain.They can also be used in the treatment of scytitis, such as ox-hide
Tinea, eczema, burn and dermatitis.
The compound of the present invention can be also used for treating the infectious disease of the other pathogens mediated by COX-2 enzyme.For example,
Formula (I) compound is able to suppress cell Proliferation, so as to the treatment or prevention for cancer, especially generation prostaglandin or
Express the cancer of Cycloxygenase.The compound of the present invention can be used for treating, for example, non-small cell lung cancer, liver cancer, bladder cancer, pancreas
Gland cancer, oophoroma, prostate cancer, cervical carcinoma, lung cancer, colon cancer, breast cancer, cutaneum carcinoma, head and neck cancer, especially non-small cell lung
Cancer, liver cancer and cancer in digestive system, such as colon cancer.
The compound of the present invention can be used for treating or preventing cerebral infarction, epilepsy, depression, schizophrenia and neurological
Property disease, such as alzheimer's disease and dementia.
According to Product Activity described herein, the invention also includes by the present invention compound and excipient or its
The composition of his necessary auxiliary material composition.Compound in the present invention can be taken with any pharmaceutical dosage form, and as everybody institute
Know, is mainly determined by administration route and pathology with which kind of dosage form.
Content according to the present invention, Orally-administered solid composition include tablet, suspension, granule and capsule.In tablets, living
Property ingredient at least with a kind of inert diluent (such as lactose, starch, mannitol, microcrystalline cellulose or calcium phosphate), adhesive (as form sediment
Powder, gel, microcrystalline cellulose or polyvinylpyrrolidone) and lubricant (such as magnesium stearate, stearic acid, talcum powder) mixing.
Tablet can be coated to delay its disintegration and absorption in the gastrointestinal tract by known technology, and then reaches the mesh of sustained-release and controlled release
's.The preparations such as stomach and intestine clothing sugar, mannitol, microcrystalline cellulose, acrylic resin.Sustained-release tablet may be by using production
What the excipient of raw osmotic pressure was realized, such as galacturonic acid polymer.Oral preparation is also possible to using absorbable hard capsule, such as
Gel, the pastes that wherein reactive compound and inert solid diluent and lubricant or such as ethyoxyl are saturated glyceride,
Also the effect of controlled release can be generated.Soft gel capsule may also be applied, wherein reactive compound is mixed with water or oil medium,
Such as coconut oil, levant cotton oil, atoleine or olive oil.
By be added water prepare suspension powder and particle can by by reactive compound and dispersing agent or wetting agent,
Suspension and one or more preservatives are mixed to get, and wherein suspension may be sodium carboxymethylcellulose, methylcellulose, hydroxyl
Propyl methocel, mosanom, polyvinylpyrrolidine, bassora gum, xanthan gum, gum arabic, preservative may be for hydroxyls
Yl benzoic acid methyl esters or propyl ester.It is also possible to add such as sweetener, flavoring agent and colorant.
Oral liquid includes emulsion, suspension, syrup and elixir, usually can wherein add inert diluent, is such as steamed
Distilled water, ethyl alcohol, sorbierite, glycerol or propylene glycol.So-called composition also contains total adjuvant, as wetting agent, suspension, sweetener,
Flavoring agent, preservative or buffer.
According to the present invention, injection ejection preparation is molten by sterile aqueous or water-insoluble solution, suspension or lotion
It is formed in suitable innoxious solvent or dilution.Water-soluble solvent or suspension medium can be distilled water for injection, Green
Solution and sodium chloride isotonic solution.And water-insoluble solvent or suspension medium can be propylene glycol, polyethylene glycol, vegetable oil (such as
Olive oil) or alcohol (such as ethyl alcohol).These components can also be used in combination with wetting agent, preservative, emulsifier and dispersing agent.It
Can be sterilized by any of method, or be prepared into sterile solid composition, and can using it is preceding in water
Or it is dissolved in the medium of any other sterile injection.It may also be directly made of sterile raw material, and entirely produced
Guarantee in the process sterile.
Dosage and administration number of times depend primarily on animal and the type of people, and the property of treated disease and serious
Property, the age of patient and weight and administration route.Usually, the daily dosage of adults or adult are arrived in 1mg
Between 1000mg, single administration or multiple dosing can be.But for special case, it is also possible to need beyond above range.
Professional and technical personnel will determine suitable dosage according to the concrete condition of each case.
It is a further object to provide the preparation processes of compound representated by formula (I).Compound representated by formula (I)
It can be prepared according to following reaction equation and discussion.Unless stated otherwise, below reaction equation and discuss in, R1It represents
H and C1-3Alkyl.R2, R3、R4、R5、R6, X, Y be group defined above.For those skilled in the art it is readily apparent that
Really cutting Preparation Method can be slightly different compound according to chemical structure.Moreover, the most preparations illustrated below
In the process, unstable or reactive group is protected to be necessary using conventional blocking group.The property of above-mentioned blocking group,
And they are introduced or the preparation method of removal is all disclosed technology.(example is shown in the Greene T.W. " guarantor in organic synthesis
Protect group ", John Wiley&Sons, New York, 1981)
Scheme 1 illustrates a kind of method of compound representated by synthesis formula (I).According to above scheme 1, Formula (M3)
It is obtained from being reacted under suitable solvent and reaction condition as Formula (M1) and Formula (M2).In the reaction
The solvent being applicable in includes ether (such as 1,2- dimethoxy-ethane, 1,2- diethoxyethane, THF, DMF) or above-mentioned ether
Mixture.The reaction is pre-mixed M1 and Grignard Reagent such as i-PrMgCl first in aprotic solvent, and aprotic solvent is such as
Then M2 is added at -30 DEG C to 0 DEG C in THF, temperature, -15 DEG C of reaction temperature~5 DEG C, and the reaction time 1~5 hour.Formula
It (M4) is to react to obtain under suitable solvent and reaction condition by Formula (M3), the solvent suitable for the reaction
Have alcohol (such as methanol, ethyl alcohol, propyl alcohol), ether (such as 1,2- dimethoxy-ethane, 1,2- diethoxyethane, THF) and other non-matter
The mixture of sub- solvent (such as DMF) or above-mentioned solvent.The reaction can be deposited in the palladium catalyst of chemical equivalent or catalytic amount
In lower progress, such as Pd (OAc)2Dppp, and it is passed through CO in the reaction system, which usually carries out at 50 DEG C to 100 DEG C, most
It is 10~30 hours of reaction well.
Scheme 1
Formula (M5) can react to obtain by Formula (M4) under suitable solvent and reaction condition.It is first
The ester group being first used in hydrolyzed under basic conditions M4 is allowed to be converted into carboxylic acid, such as with LiOH and with methanol as solvent, then separates
Obtained carboxylic acid.Then the carboxylic acid is converted into M5 with well known method, such as use ClCOCOCl at the DMF of catalytic amount with two first
Chloromethanes is that solvent and the acid react, and is then converted into M5 with Me (OMe) NH reaction again.Formula (M6) can pass through chemical combination
Object formula (M5) is reacted under suitable solvent and reaction condition to be obtained.As under alkaline condition with 2- methyl -3- crotonylene -
Alcohol reaction.Formula (M7) can be applicable in by obtaining under Formula (M6) alkaline condition in suitable solvent reaction
Have alcohol (such as methanol, ethyl alcohol, propyl alcohol) in the solvent of the reaction, ether (such as 1,2- dimethoxy-ethane, 1,2- diethoxyethane,
THF) and the mixture of other aprotic solvent (e.g., DMF) or above-mentioned solvent, the alkali suitable for the reaction have amine, and such as three
Ethylamine, diethylamide etc..Formula (M8) can be obtained in acid condition by Formula (M7) and bromine reaction.Change
Closing object formula (M10) is to react to obtain under suitable solvent and reaction condition by Formula (M8) and Formula (M9)
, well known method has Suzuki coupling reaction.
Scheme 2 illustrates the method for compound representated by another synthesis formula (I).According to above scheme 2, Formula
(N2) be by Formula (M1) under suitable solvent and reaction condition and NaSR7What reaction obtained.It is fitted in the reaction
Solvent include alcohol (such as methanol, ethyl alcohol, propyl alcohol) and ether (such as 1,2- dimethoxy-ethane, 1,2- diethoxyethane,
) and the mixture of other polar solvents such as DMF or above-mentioned solvent THF.Temperature is 50-150 DEG C, reaction 10-30 small
When.
Scheme 2
Formula (N3) is reacted in the presence of butyl lithium with DMF by Formula (N2).Suitable for this
Solvent in reaction includes non-protonic solvent, such as 1,2- dimethoxy-ethane, 1,2- diethoxyethane, THF, DMF), or
Person is the mixture of above-mentioned solvent.
Formula (N4) can be by Formula (N3) in the presence of butyl lithium and 2- methyl -3- butyne-2-alcohol is anti-
It should obtain.Optimum solvent used in the reaction is THF.Optimal reaction temperature is -70 DEG C to -50 DEG C.
Formula (N5) can be obtained by oxidized compound formula (N4).Many well known all achievable above institutes of method
The conversion stated.Such as use MnO2It and with methylene chloride is that solvent is stirred at room temperature 10 to 30 hours.
Formula (N6) can reaction obtains in a suitable solvent under alkaline condition by Formula (N5).It is suitable
Solvent for the reaction has alcohol (such as methanol, ethyl alcohol, propyl alcohol), ether (such as 1,2- dimethoxy-ethane, 1,2- diethoxy second
Alkane, THF) and other aprotic solvent (e.g., DMF) or above-mentioned solvent mixture.Alkali suitable for the reaction has amine,
Such as triethylamine, diethylamide etc..Formula (N7) can be obtained by Formula (N6) and bromine reaction.Formula
It (N9) is obtained from being reacted under suitable solvent and reaction condition as Formula (N7) and Formula (N8).It is known
Method have Suzuki coupling reaction.Formula (N10) can be obtained by oxidized compound formula (N9).Many well known sides
The all achievable above-described conversion of method.Such as use Na2WO4, H2O2(AcOH) is that solvent and N9 are stirred with THF in acid condition
10 to 30 hours.Temperature is between 0 DEG C to 80 DEG C.
The following example in detail preparation method of formula (I) compound.These detailed methods also belong to model of the invention
Within enclosing, and the method for the above-mentioned general synthesis path of illustration is also a part of the invention.These hairs described in detail
Cloth is only used for illustration, and for the scope of the present invention, there is no limit.
Embodiment 1:2,2- dimethyl -5- [5- (mesyl) -2- pyridyl group] -4- benzo -3 (2H)-furanone system
Standby (compound A-001).
The preparation of step 1:2- bromo- 5- (mesyl) pyridine (compound 2)
2,5- dibromo pyridine (50g, 211mmol) is dissolved in 175mL THF, ice bath is cooled to 0 DEG C.Isopropylmagnesium chloride
(2M THF solution, 274mmol) is added slowly in above-mentioned solution, and control temperature is no more than 8 DEG C.Reaction mixture is stirred at 0 DEG C
45 minutes, it is subsequently cooled to subzero 15 DEG C.THF (40mL) solution of mesyl chloride is added slowly in above-mentioned reaction solution, is controlled
Temperature is no more than 5 DEG C, and drop stirs 30 minutes after finishing, and adds water stratification.Water phase is extracted twice with methyl tertiary butyl ether(MTBE).Merge organic
Phase, washing.It is concentrated under reduced pressure, crude product re crystallization from toluene obtains compound 2 (20g, 40%).LC-MS:237(M++1)
The preparation of step 2:5- methanesulfonylpyridine methyl formate (compound 3)
By methanol, DMF and Et3N mixing.It is passed through CO (5 minutes), removes air.Sequentially add compound 2 (25.5g,
108mmol), Pd (OAc)2(1.5g, 10.8mmol) and DPPP (3g, 10.8mmol).It is heated to 90 DEG C under CO atmosphere, keeps
24 hours.System is diluted with EtOAc, is saturated NH4Cl is washed.After removing solvent, crude product purifies to obtain compound 3 with column chromatography
(18.6g, 80.5%).1H-NMR(300MHz,CDCl3): δ 3.16 (s, 3H), 4.08 (s, 3H), 8.33 (dd, J=8.1Hz,
0.6Hz, 1H), 8.41 (dd, J=8.1Hz, 2.1Hz, 1H), 9.26 (dd, J=2.1Hz, 0.9Hz, 1H)
LC-MS:216(M++1)
The preparation of step 3:N- methoxy-. N-methyl -5- methanesulfonylpyridine formamide (compound 4)
In methanol/water (60mL/20mL), compound 3 (8.6g, 20mmol) and LiOH (3.3g, 80mmol) is added.Instead
Mixture is answered to be stirred at room temperature 2 hours.Sediment is precipitated in acidified reaction mixture to PH=6, filtering.The sediment filtered out is molten
In methylene chloride (100mL), the DMF of catalytic amount is added, then slowly instills oxalyl chloride (6.8g, 54mmol) in 0 DEG C.It will be warm
Degree is warmed to room temperature and is kept for 2 hours.Then solvent is removed, mixture is dissolved in CH2Cl2In (100mL), and Et is added3N
(13.8mL,108mmol).N, O- dimethyl hydroxylamine hydrochloride (5.3g, 54mmol) is added in stirring 5 minutes.React on room temperature after
Continuous stirring 30 minutes.Water (40mL) is added in the reactive mixture and successively uses water, saturated common salt water washing.Organic phase is collected,
With anhydrous MgSO4It is dry.Product 4 (7.3g, 82%) is obtained after removing solvent1H-NMR(300MHz,CDCl3):δ3.13(s,
3H), 3.40 (s, 1H), 3.73 (s, 1H), 7.80 (m, 1H), 8.32 (dd, J=8.1Hz, 2.1Hz, 1H), 9.14 (d, J=
2.1Hz,1H).LC-MS:245(M++1)
The preparation of step 4:4- hydroxy-4-methyl -1- (5- mesyl -2- pyridine) pentyne -2- ketone -1 (compound 5)
2- methyl -3- butyne-2-alcohol (193mL, 1.8mmol) and HMPA (1.15mL, 6.6mmol) are dissolved in 190mL THF
In.BuLi (hexane solution of 2.5M) (1.5mL, 3.75mmol) is added in above-mentioned solution in -78 DEG C, then stirs 20 points
Clock.Then reaction mixture is warming up to 0 DEG C and stirs 1 hour.Then reaction mixture is cooled to -40 DEG C and compound 4 is added
The THF solution (5mL) of (360mg, 1.5mmol).Then reaction mixture is warming up to room temperature and stirs 2 hours.It is mixed in reaction
Ice and 1N hydrochloric acid are added in object, is extracted with ethyl acetate.Remove solvent, crude product column chromatography (n-hexane: ethyl acetate
=1:1) purify to obtain compound 5 (60mg, 17%).1H-NMR(300MHz,CDCl3):δ1.68(s,6H),3.15(s,3H),
8.27 (d, J=Hz, 1H), 8.38 (d, J=8.4Hz, 1H), 9.29 (s, 1H) .LC-MS:268 (M++1)。
The preparation of step 5:2,2- dimethyl -5- (5- mesyl -2- pyridine) -3 (2H)-furanones (compound 6)
Compound 5 (88mg, 0.33mmol) is dissolved in 16mL methanol.By diethylamine (0.08mL), water (0.05mL) in
Room temperature is added in above-mentioned solution.Reaction mixture is heated to 40 DEG C and stays overnight.After solvent is removed in vacuum, crude product column chromatography
(n-hexane: ethyl acetate=1.5:1) purifies to obtain compound 6 (50mg, 57%).1H NMR(300MHz,CDCl3):δ1.53(s,
6H), 3.16 (s, 3H), 6.50 (s, 1H), 8.08 (dd, J=8.4Hz, 0.9Hz, 1H), 8.39 (dd, J=8.1Hz, 2.4Hz,
1H), 9.24 (dd, J=2.4Hz, 0.6Hz, 1H), LC-MS:268 (M++1)。
The system of the bromo- 2,2- dimethyl -5- of step 6:4- (5- mesyl -2- pyridine) -3 (2H)-furanones (compound 7)
It is standby
Compound 6 (50mg, 0.19mmol) is dissolved in 20mL carbon tetrachloride.0.2mL acetic acid is added in above-mentioned solution
With 0.05mL bromine.Reaction mixture is stirred at room temperature 18 hours.Then 20mL saturated sodium thiosulfate is added to be quenched.Decompression removes
Carbon tetrachloride is removed, methylene chloride extracts (50mLx3).(50mL) is washed with water in organic phase.It is dry, concentration, crude product column chromatography
(n-hexane: ethyl acetate=1:2) purifies to obtain compound 7 (40mg, 57%).LC-MS:346(M++1)
Step 7:2,2- dimethyl -5- [5- (mesyl) -2- pyridine] -4- phenyl -3 (2H)-furanone (compound A-
001) preparation
Compound 7 (40mg, 0.12mmol) is dissolved in 15mL toluene.Tetra- (triphenyl of 10mg is added in above-mentioned solution
Phosphine) palladium (0), 2mL aqueous sodium carbonate (2M), 2mL ethyl alcohol and 80mg phenyl boric acid.Reaction mixture flows back 12 hours.Decompression removes
After removing solvent, water is added in residue, methylene chloride extracts (30mL × 3).Merge organic phase, is concentrated under reduced pressure.Crude product column
Chromatography (n-hexane: ethyl acetate=1:1) purifies to obtain compound A-001 (20mg, 50%).1H NMR(300MHz,CDCl3):δ
1.63 (s, 6H), 3.15 (s, 3H), 7.39 (m, 5H), 7.84 (d, J=8.4Hz, 1H), 8.24 (d, J=8.4Hz, 1H), 9.21
(s,1H).LC-MS:344(M++ 1) .HPLC purity (214nm, 254nm): 95%.
Embodiment 2 to 28 can refer to the method for embodiment 1 and be prepared, it is also possible to which method for distinguishing preparation should not be managed
Solution is limitation of the present invention.For corresponding compound as shown in table 1-1 and 1-2, the structural identification data of compound is shown in Table 1-3.
The chemical structural formula of table 1-1 embodiment 1-28
The chemical name of table 1-2 A-001~A-028
The structural identification data of table 1-3 embodiment 2-28 part of compounds
Embodiment 29:2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -4- benzo -3 (2H)-furanone preparation
(compound B-001)
The bromo- 2- methylsulfanyl pyridine (compound S1) of 5-
2,5- dibromo pyridine (35g, 0.15mol) is dissolved in 50mL DMF.In above-mentioned solution, 150mL is added
NaSCH3Aqueous solution (20%, 0.43mol).Reaction mixture is heated to 85 DEG C and is kept for 24 hours.After cooling, mixture is used
CH2Cl2Extraction.Organic phase saturated common salt water washing.Remove solvent after, Purified on column chromatography purify compound S1 (15g,
50%, white solid).1H-NMR(300MHz,CDCl3):δ8.49(s,1H),7.597(d,1H),7.280(d,1H),2.530
(s,3H)；LCMS[M+H]+:204；Purity (LCMS) > 95%.
6- methyl mercapto -3- aldehyde radical pyridine (compound S2)
Compound S1 is dissolved in 20mL THF, and is cooled to -78 DEG C.N-BuLi is slowly added in above-mentioned solution
(2mL, 10.3mmol, 2.5M) is stirred 2 hours.It is then slowly added into DMF (0.9g, 13.4mmol) and stirs 3 hours.It is added
It is saturated NH4Cl aqueous solution is quenched.Reaction mixture is extracted with ether.Extract liquor saturated common salt water washing.It is obtained after removing solvent
Crude product.Purified on column chromatography purifies to obtain compound S2 (0.5g, 60%, white solid)1H-NMR(300MHz,CDCl3):δ
10.039(s,1H),8.830(s,1H),7.968(d,1H),7.367(d,1H),2.662(s,3H)；LCMS[M+H]+:154；
Purity (LCMS) > 95%.
4- methyl-1-(6- methyl mercapto-3- pyridine)-valerylene-1,4- glycol (compound S3)
2- methyl -3- butyne-2-alcohol (6.3g, 75mmol) is dissolved in the dried THF of 100mL, simultaneously with nitrogen protection
It is cooled to -70 DEG C.It is slowly added to n-BuLi (18mL, 45mmol, 2.5M) in above-mentioned solution, adds within 30 minutes.By compound 2
(4.6g, 30mmol) slowly instills in above-mentioned reaction solution (1 hour).Then reaction system is slowly raised to room temperature, and it is small to stir 4
When.Saturation NH is added4Cl aqueous solution is quenched.Reaction mixture CH2Cl2Extraction.Extract liquor saturated common salt water washing.It removes
Crude product is obtained after solvent.Purified on column chromatography purifies to obtain compound S3 (5.6g, 80%, white solid).1H-NMR
(300MHz,CDCl3):δ8.528(s,1H),7.583(d,1H),7.056(d,1H),5.390(s,1H),3.673(s,1H),
2.474(s,3H),1.465(s,6H)；LCMS[M+H]+:238；Purity (LCMS) > 95%.
4- hydroxy-4-methyl -1- [6- (methyl mercapto) -3- pyridine] amyl -2- alkynes -1- ketone (compound S4)
Compound S3 (2.0g, 8.4mmol) is dissolved in DCM (100mL), is added manganese dioxide (4.3g, 50mmol).Mixing
Object is stirred overnight at room temperature.Solid is precipitated in system, and filtering is washed, crude product is through column chromatography column purification (ethyl acetate: petroleum ether repeatedly
=0:1~1:1), it is concentrated under reduced pressure, obtains yellow solid compound S4 (1.39,70%, yellow solid).1H-NMR(300MHz,
CDCl3):δ9.121(s,1H),8.093(d,1H),7.261(d,1H),2.622(s,3H),1.663(s,6H)；LC-MS[M+
H]+:235；Purity (LC-MS) > 95%.
2,2- dimethyl -5- [6- (methyl mercapto) -3- pyridine] -3 (2H)-furanones (compound S5)
S4 (2.7g, 11.5mmol) is added in ethyl alcohol (100mL), diethylamine is slowly added dropwise to dissolving in stirring
(1.8mL), reaction solution is stirred overnight.Vacuum concentration, residue are extracted with dichloromethane.Organic phase saturated common salt water washing.
Crude product column chromatography (ethyl acetate: petroleum ether=0:1~1:5) purifying, be concentrated under reduced pressure to give compound S5 (2.3g, 90%, it is white
Color solid).1H-NMR(300MHz,CDCl3):δ8.859(s,1H),8.847(d,1H),7.291(d,1H),5.944(s,1H),
2.616(s,3H),1.484(s,6H)；LC-MS[M+H]+:235；Purity (LC-MS) > 91%.
Tetrabromobisphenol, 2 dimethyl -5- [6- (methyl mercapto) -3- pyridine] -3 (2H)-furanones (compound s 6)
S5 (1.0g, 4.3mmol) is dissolved in carbon tetrachloride (100mL), is added bromine (1.36g, 8.6mmol), mixture stirs
It mixes 5 hours, is saturated Na2S2O3Solution is quenched, and is extracted with dichloromethane.Organic phase saturated common salt water washing.It is obtained after removing solvent
Crude product.Purified on column chromatography purifying, obtains compound s 6 (0.8g, 60%, white solid).1H-NMR(300MHz,
CDCl3):δ9.296(s,1H),8.262(d,1H),7.294(d,1H),2.616(s,3H),1.473(s,6H)；LC-MS[M+
H]+:314；Purity (LC-MS) > 97%.
2,2- dimethyl -5- [6- (methyl mercapto) -3- pyridine] -4- benzo -3 (2H)-furanone (compound S7)
S6 (160mg, 0.5mmol) is dissolved in 30mL toluene and 10mL ethyl alcohol, Pd (PPh is added to dissolving in stirring3)4
(25mg), saturated sodium carbonate solution (10mL), phenyl boric acid (100mg).Reaction solution stirs 12 hours at 90 DEG C, vacuum concentration, and two
Chloromethanes extraction, organic phase saturated common salt water washing.It is concentrated under reduced pressure, Purified on column chromatography (ethyl acetate: petroleum ether=0:
1~1:5) purifying, it is concentrated under reduced pressure to give compound S7 (105mg, 68%, white solid).1H-NMR(300MHz,CDCl3):δ
8.704(s,1H),7.675(d,1H),7.287-7.420(t,5H),7.152(d,1H),2.572(s,3H),1.577(s,
6H)；LC-MS[M+H]+:311；Purity (LC-MS) > 95%.
2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -4- benzo -3 (2H)-furanone (compound B-001)
Sodium tungstate (67mg) and acetic acid (1.6mL) are dissolved in water/tetrahydrofuran mixed solution and stirred 20 minutes, is added
Compound S7 (0.6g, 2mmol), instills hydrogen peroxide in batches, and mixture is stirred overnight at room temperature.Extracted after having reacted with ethyl acetate
It takes, organic phase is washed with water.Crude product is obtained after removing solvent.Purified on column chromatography purify to obtain compound B-001 (0.33g,
50%, white solid).1H-NMR(300MHz,CDCl3):δ8.924(s,1H),8.236(d,1H),8.088(d,1H),
7.266-7.426(t,5H),3.245(s,3H),1.581(s,6H)；LC-MS[M+H]+:343；Purity (HPLC) > 95%.
The compound that embodiment 30-56 is obtained is B-002~B-028 respectively, as shown in table 2-1, can refer to embodiment
29 method and be prepared, but should not be construed as limiting the invention, it is also possible to which other synthetic methods are prepared.Portion
The structural identification data of compound is divided to be shown in Table 2-2.
The chemical name of table 2-1 B-001~B-028
The structural formula and mass spectrometric data of the part of compounds of table 2-2 B-001~B-028
Experimental example 1: the in vitro test (people's whole blood test) to COX-1 and COX-2 inhibitory activity
To Cycloxygenase -1 (COX-1 enzyme) and Transitional cell carcinomas (COX-2 enzyme) active inhibition in people's blood.Take blood previous
The healthy volunteer that Zhou Wei took non-steroidal anti-inflammatory drugs and do not drank in 24 hours takes its whole blood, and blood sample is divided into
Two parts: for portion for detecting the activity of COX-1 enzyme, another is used to measure the activity of COX-2 enzyme.Compound is dissolved in DMSO
In, and be ready in advance equipped with 2 μ L and concentration 500,50,5,0.5,0.05,0.005,0.0005 μ g/mL solution.Containing
Have and the whole blood that 200 μ L are free of heparin is added in the test tube of drug, is then incubated for 1 hour at 37 DEG C, by using EIA kit
Detect the thromboxane B of blood platelet synthesis2(TXB2) amount measure the activity of COX-1 enzyme.The sample of non-dosing is as negative right
According to.For COX-2, the 200 μ L whole blood for containing heparin is added in the test tube equipped with drug and 10 μ g/mL LPS.LPS pairs
Produced PGE is respectively used to according to the blank control with only solvent2The measurement of maximum value and background value.Sample is incubated at 37 DEG C
It 24 hours, is then centrifuged for, collects serum/plasma, be stored at -80 DEG C and detected with EIA kit.Explanation according to producer
Book detects TXB using the EIA kit of Cayman company respectively2And PGE2Amount, to measure COX-1 and COX-2 respectively
Activity.It the results are shown in Table 3.
3 active determination in vitro of table
Claims (14)
1. formula (I) compound represented or its pharmaceutically acceptable salt, in which:
Work as X=N, Y=C；Or Y=N, X=C atom；
Substituent R1Representative-SOR7、-SO2R7Or-SR7Base；
Substituent R2-R6It is each independently selected from hydrogen, halogen, C1-8Alkyl, R8OC0-8Alkyl, R8SC0-8Alkyl ,-SOR9、-SO2R9、
C1-8Halogenated alkyl, cyano, nitro, amino；
Substituent R7Representative-NH2、C1-8Alkyl, C1-8Halogenated alkyl；
Substituent R8Represent hydrogen, C1-8Alkyl, C1-8Halogenated alkyl；
Substituent R9Represent C1-8Alkyl, C1-8Halogenated alkyl.
2. compound described in claim 1 or its pharmaceutically acceptable salt, it is characterised in that:
Substituent R1Representative-SO2R7、-SR7Base；
Substituent R2-R6It is each independently selected from hydrogen, halogen, C1-5Alkyl, R8OC0-4Alkyl, R8SC0-4Alkyl ,-SOR9、-SO2R9、
C1-5Halogenated alkyl, amino；
Substituent R7Representative-NH2、C1-5Alkyl, C1-5Halogenated alkyl；
Substituent R8Represent hydrogen, C1-5Alkyl, C1-5Halogenated alkyl；
Substituent R9Represent C1-5Alkyl, C1-5Halogenated alkyl.
3. compound as claimed in claim 2 or its pharmaceutically acceptable salt, it is characterised in that:
Substituent R7Representative-NH2、C1-5Alkyl.
4. compound as claimed in claim 3 or its pharmaceutically acceptable salt, it is characterised in that:
Substituent R2-R6It is each independently selected from hydrogen, halogen, C1-3Alkyl, R8OC0-3Alkyl, R8SC0-3Alkyl ,-SOR9、-SO2R9、
C1-5Halogenated alkyl, amino；
Substituent R7Representative-NH2、C1-3Alkyl；
Substituent R8Represent hydrogen, C1-3Alkyl, C1-3Halogenated alkyl；
Substituent R9Represent C1-3Alkyl, C1-3Halogenated alkyl.
5. compound as claimed in claim 4 or its pharmaceutically acceptable salt, it is characterised in that:
Substituent R2-R6It is each independently selected from hydrogen, chlorine atom, fluorine atom, C1-3Alkyl, R8OC0-3Alkyl, R8SC0-3Alkyl ,-
SOR9、-SO2R9、C1-5Halogenated alkyl, amino；
Substituent R7Representative-NH2, methyl.
6. compound described in claim 5 or its pharmaceutically acceptable salt, compound therein are selected from:
2,2- dimethyl -5- [5- (mesyl) -2- pyridine] -4- benzo -3 (2H)-furanone,
4- (4- benzyloxy) -2,2- dimethyl -5- [5- (mesyl) -2- pyridine] -- 3 (2H)-furanones,
2,2- dimethyl -5- [5- (mesyl) -2- pyridine] -4- to methyl benzo -3 (2H)-furanone,
4- (4- fluorophenyl) -2,2- dimethyl -5- [5- (mesyl) -2- pyridine] -3 (2H)-furanones,
4- (4- chlorphenyl) -2,2- dimethyl -5- (5- (mesyl) -2- pyridine) -3 (2H)-furanones,
4- (3- fluorophenyl) -2,2- dimethyl -5- [5- (mesyl) -2- pyridine] -3 (2H)-furanones,
4- (2- fluorophenyl) -2,2- dimethyl -5- [5- (mesyl) -2- pyridine] -3 (2H)-furanones,
4- (3- chlorphenyl) -2,2- dimethyl -5- [5- (mesyl) -2- pyridine] -3 (2H)-furanones,
4- (the fluoro- 4- aminomethyl phenyl of 3-) -2,2- dimethyl -5- [5- (mesyl) -2- pyridine] -3 (2H)-furanones,
4- (the fluoro- 3- benzyloxy of 4-) -2,2- dimethyl -5- [5- (mesyl) -2- pyridine] -3 (2H)-furanones,
4- (4- chlorphenyl) -2,2- dimethyl -5- [5- (mesyl) -2- pyridine] -3 (2H)-furanones,
4- (2,5- difluorophenyl) -2,2- dimethyl -5- [5- (mesyl) -2- pyridine] -3 (2H)-furanones,
4- (3,5- dichlorophenyl) -2,2- dimethyl -5- [5- (mesyl) -2- pyridine] -3 (2H)-furanones,
4- (the fluoro- 4- benzyloxy of 3-) -2,2- dimethyl -5- [5- (mesyl) -2- pyridine] -3 (2H)-furanones,
2,2- dimethyl -5- [5- (mesyl) -2- pyridine] -4- (4- (trifluoromethyl) phenyl) -3 (2H)-furanones,
2,2- dimethyl -4- [4- (methylsulfinyl) phenyl] -5- [5- (mesyl) -2- pyridine] -3 (2H)-furanones,
4- [4- (ethylsulfinyl) phenyl] -2,2- dimethyl -5- [5- (mesyl) -2- pyridine] -3 (2H)-furanones,
4- (3- methoxyl group -5- aminomethyl phenyl) -2,2- dimethyl -5- [5- (mesyl) -2- pyridine] -3 (2H)-furanones,
2,2- dimethyl -4- [3- methyl -4- (trifluoromethoxy) phenyl] -5- [5- (mesyl) -2- pyridine] -3 (2H)-furans
It mutters ketone,
4- (4- ethoxyphenyl) -2,2- dimethyl -5- [5- (mesyl) -2- pyridine] -3 (2H)-furanones,
4- (chloro- 3 benzyloxy of 4-) -2,2- dimethyl -5- [5- (mesyl) -2- pyridine] -3 (2H)-furanones,
4- (3,5- diethoxy phenyl) -2,2- dimethyl -5- [5- (mesyl) -2- pyridine] -3 (2H)-furanones,
4- (3,5- dichlorophenyl) -2,2- dimethyl -5- [5- (mesyl) -2- pyridine] -3 (2H)-furanones,
2,2- dimethyl -5- [(5- mesyl) -2- pyridine] -4- propoxyphenyl -3 (2H)-furanone,
2,2- dimethyl -5- [(5- mesyl) -2- pyridine] -4- nitrobenzophenone -3 (2H)-furanone,
2,2- dimethyl -5- [(5- mesyl) -2- pyridine] -4- aminophenyl -3 (2H)-furanone,
- 3 (2H)-furanone of 2,2- dimethyl -5- [(5- mesyl) -2- pyridine] -4- (2,4- dichlorophenyl),
2,2- dimethyl -5- [(5- mesyl) -2- pyridine] -4- (the chloro- 4- aminomethyl phenyl of 2-) -3 (2H)-furanones,
2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -4- benzo -3 (2H)-furanone,
4- (4- benzyloxy) -2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -3 (2H)-furanones,
2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -4- p-methylphenyl -3 (2H)-furanone,
4- (4- fluorophenyl) -2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -3 (2H)-furanones,
4- (4 chlorphenyl) -2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -3 (2H)-furanones,
4- (3- fluorophenyl) -2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -3 (2H)-furanones,
4- (2- fluorophenyl) -2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -3 (2H)-furanones,
4- (3- chlorphenyl) -2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -3 (2H)-furanones,
4- (the fluoro- 4- tolyl of 3-) -2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -3 (2H)-furanones,
4- (the fluoro- 3- benzyloxy of 4-) -2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -3 (2H)-furanones,
4- (4- chlorphenyl) -2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -3 (2H)-furanones,
4- (2,5- difluorophenyl) -2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -3 (2H)-furanones,
4- (3,5- dichlorophenyl) -2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -3 (2H)-furanones,
4- (the fluoro- 4- benzyloxy of 3-) -2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -3 (2H)-furanones,
2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -4- [4- (trifluoromethyl) phenyl] -3 (2H)-furanones,
2,2- dimethyl -4- [4- (methylsulfinyl) phenyl] -5- [6- (mesyl) -3- pyridine] -3 (2H)-furanones,
4- [4- (ethylsulfinyl) phenyl] -2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -3 (2H)-furanones,
4- (3- methoxyl group -5- aminomethyl phenyl) -2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -3 (2H)-furanones,
2,2- dimethyl -4- [3- methyl -4- (trifluoromethoxy) phenyl] -5- [6- (mesyl) -3- pyridine] -3 (2H)-furans
It mutters ketone,
4- (4- ethoxyphenyl) -2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -3 (2H)-furanones,
4- (chloro- 3 benzyloxy of 4-) -2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -3 (2H)-furanones,
4- (3,5- diethoxy phenyl) -2,2- dimethyl -5- (6- (mesyl) -3- pyridine) -3 (2H)-furanones,
4- (3,5- dichlorophenyl) -2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -3 (2H)-furanones,
- 3 (2H)-furanone of 2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -4- (4- propoxyphenyl),
- 3 (2H)-furanone of 2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -4- (4- nitrobenzophenone),
4- (4- aminophenyl) -2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -3 (2H)-furanones,
4- (2,4- dichlorophenyl) -2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -3 (2H)-furanones,
4- (chloro- 4 aminomethyl phenyl of 2-) -2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -3 (2H)-furanones.
7. compound as claimed in claim 6 or its pharmaceutically acceptable salt, compound therein are selected from:
2,2- dimethyl -5- [5- (mesyl) -2- pyridine] -4- benzo -3 (2H)-furanone,
4- (4- benzyloxy) -2,2- dimethyl -5- [5- (mesyl) -2- pyridine] -- 3 (2H)-furanones,
2,2- dimethyl -5- [5- (mesyl) -2- pyridine] -4- to methyl benzo -3 (2H)-furanone,
4- (4- fluorophenyl) -2,2- dimethyl -5- [5- (mesyl) -2- pyridine] -3 (2H)-furanones,
4- (2,5- difluorophenyl) -2,2- dimethyl -5- [5- (mesyl) -2- pyridine] -3 (2H)-furanones,
4- (3,5- dichlorophenyl) -2,2- dimethyl -5- [5- (mesyl) -2- pyridine] -3 (2H)-furanones,
4- (the fluoro- 4- benzyloxy of 3-) -2,2- dimethyl -5- [5- (mesyl) -2- pyridine] -3 (2H)-furanones,
2,2- dimethyl -5- [5- (mesyl) -2- pyridine] -4- (4- (trifluoromethyl) phenyl) -3 (2H)-furanones,
- 3 (2H)-furanone of 2,2- dimethyl -5- [(5- mesyl) -2- pyridine] -4- (2,4- dichlorophenyl),
2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -4- benzo -3 (2H)-furanone,
4- (4- benzyloxy) -2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -3 (2H)-furanones,
2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -4- p-methylphenyl -3 (2H)-furanone,
4- (4- fluorophenyl) -2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -3 (2H)-furanones,
4- (2,5- difluorophenyl) -2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -3 (2H)-furanones,
4- (3,5- dichlorophenyl) -2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -3 (2H)-furanones,
4- (the fluoro- 4- benzyloxy of 3-) -2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -3 (2H)-furanones,
2,2- dimethyl -5- (6- (mesyl) -3- pyridine) -4- [4- (trifluoromethyl) phenyl] -3 (2H)-furanones,
4- (2,4 dichloro benzene base) -2,2- dimethyl -5- [6- (mesyl) -3- pyridine] -3 (2H)-furanones.
8. any compound of claim 1~7 or its pharmaceutically acceptable salt are in preparation for treating or preventing epoxy
Change the application in the disease mediated drug of enzyme.
9. application according to any one of claims 8, wherein the Cycloxygenase is Transitional cell carcinomas.
10. any compound of claim 1~7 or its pharmaceutically acceptable salt are dynamic for treating or preventing in preparation
Application in the drug of the inflammation of object or people, pain and/or fever.
11. application described in any one of claim 10, wherein the application be osteoarthritis, it is rheumatoid arthritis, scapulohumeral periarthritis, acute
Pain, perioperative pain, postoperative pain, pain in the loins, neck shoulder wrist syndrome, tenosynovitis, dysmenorrhea.
12. any compound of claim 1~7 or its pharmaceutically acceptable salt are dynamic for treating or preventing in preparation
The depression of object or people, schizophrenia, cancer, cerebral infarction, epilepsy, neurodegenerative disease, adenomatous polyps drug in
Using.
13. application described in claim 12, wherein the cancer be non-small cell lung cancer, liver cancer, cancer of pancreas, colon cancer,
Breast cancer, oophoroma, prostate cancer, cervical carcinoma, cutaneum carcinoma, head and neck cancer；The neurodegenerative disease is Alzheimer
Family name's disease, senile dementia；The adenomatous polyps are familial rectal polyp.
14. a kind of pharmaceutical composition, any compound of the claim 1~7 containing effective dose and one or more
Pharmaceutically acceptable auxiliaries.
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