CN101925590A - Aldh-2 inhibitors in treatment of addiction - Google Patents

Aldh-2 inhibitors in treatment of addiction Download PDF

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CN101925590A
CN101925590A CN200880125439XA CN200880125439A CN101925590A CN 101925590 A CN101925590 A CN 101925590A CN 200880125439X A CN200880125439X A CN 200880125439XA CN 200880125439 A CN200880125439 A CN 200880125439A CN 101925590 A CN101925590 A CN 101925590A
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phenyl
chromene
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ketone
hydroxyphenyl
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雅罗斯拉夫·比洛金
埃尔法蒂赫·埃尔扎因
杰夫·扎布沃茨基
迈克尔·奥根
陶佩里
小林徹也
马修·阿贝尔曼
拉奥·卡拉
范培东
伊万·戴蒙德
罗伯特·江
马里亚·皮亚·阿罗尔福
李小芬
姚丽娜
江湛
姜永明
陶国新
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Gilead Palo Alto Inc
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CV Therapeutics Inc
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    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/34—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 3 only
    • C07D311/36—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 3 only not hydrogenated in the hetero ring, e.g. isoflavones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34—Tobacco-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • 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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    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

Disclosed are novel isoflavone derivatives having the structure of Formula I which are useful as ALDH-2 inhibitors for treating mammals for dependence upon drugs of addiction, for example addiction to dopamine-producing agent such as cocaine, morphine, amphetamines, nicotine, and alcohol.

Description

The ALDH-2 inhibitor of treatment habituation
The application is the U.S. Patent application series of submitting on July 27th, 2007 the 11/829th, No. 836 part continuation application, it requires the U.S. Provisional Patent Application series the 60/834th in submission on July 27th, 2006, No. 083 and the U.S. Provisional Patent Application series the 60/846th submitted on September 21st, 2006, No. 428 right of priority, its full content is incorporated herein with way of reference.
Technical field
The present invention relates to new A LDH-2 inhibitor, and they the treatment Mammals to the application in the dependence of drug habit, for example, Dopamine HCL is produced the habituation of agent such as Cocaine, opium, Amphetamine, Nicotine and alcohol.It is effective that the ALDH-2 inhibitor is further illustrated in the treatment of obesity aspect.The invention still further relates to the method that is used to prepare such compound, and the pharmaceutical composition that comprises them.
Background technology
Today, the dependency of drugs of addiction is worldwide caused main health problem.For example, alcohol abuse and alcohol dependence can cause liver, pancreas and kidney disease, heart trouble, comprise dilated cardiomyopathy, polyneuropathy (polyneuropathy), internal hemorrhage, brain deterioration, alcoholism, many types cancer increase sickness rate, insomnia, depression, anxiety in addition commit suiside.Conceived mother's severe alcohol consumption also can cause fetal alcohol symdrome, and it is the disease that can not cure.In addition, alcohol abuse and alcohol dependence are the factors that mainly works of head injury, motor vehicle accident, violence and attack and other neurosciencies and other medical problems.
National Institute on Drug Abuse estimates the habituation of Nicotine is killed nearly 500,000 Americans every year.On behalf of Americanologist, this sum cross about sixth of all death that any way causes, and it is total to surpass the death that is caused by bonded alcohol, Nicotine, heroine, suicide, motor-vehicle accident, fire and AIDS.Smoking is the modal method of utilizing Nicotine, but has smokeless tobacco product: for example, and snuff, chewing tobacco (chewing tobacco).
Nicotine addiction and morbid state such as leukemia, cataract, pneumonia are relevant, and are about 1/3rd reasons of all cancer mortalities, wherein lung cancer most importantly.Except cancer, smoking also causes lung disease, as bronchitis and pulmonary emphysema, worsens asthma symptom, and the reason of chronic obstructive pulmonary disease normally.Also knowing smoking increases cardiovascular disease risk, comprises apoplexy, heart attack, vascular disease, aneurysma etc.
Another main health problem is caused by cocaine abuse.The physical effects that Cocaine uses comprises the pupil of narrow blood vessel, expansion and body temperature, heart rate and the blood pressure that increases.The user of Cocaine may experience acute cardiovascular or cerebrovascular emergency situation, as heart trouble outbreak or apoplexy, causes sudden death potentially.Use other relevant complication to comprise that upset, pectoralgia and respiratory insufficiency, epileptic seizures and the headache of cardiac rhythm and stomach and intestine complication are as stomachache and nauseating with Cocaine.Because Cocaine has the tendency that reduces appetite, therefore many life-time service persons can become malnutritive.The repeated use of Cocaine can cause the irritability that increases, fidgety and paranoia.This can cause the cycle of full-blown paranoid psychosis, and wherein user forfeiture contacts and experiences phonism with real.
In addition, the co-abuse of knowing Nicotine, Cocaine and alcohol is common.The combination that has been found that Cocaine and alcohol among the mankind is than using the bigger Cardiovascular Toxicity of any medicine performance separately.
In history, processing chemical preparations dependency relates generally to and attempts to persuade the patient to stop using described material (behavior therapy) voluntarily.Yet, the Dopamine HCL of Cocaine, morphine, Amphetamine, Nicotine and alcohol and other types produces the material that agent is the height habituation, and compare the dependency of modal other habituation materials, break and have a significantly bigger destructiveness the dependency of such medicine is more difficult.Especially, alcohol, CH dependency look like the chronic recurrent obstacle usually.
By utilizing nicotine replacement therapy, paste as Nicotine natural gum or Nicotine transdermal, provide effective treatment (processing) aspect to have some medium successes to tobacco addiction.In addition, attempt thymoleptic and antihypertensive drug, had the success of appropriateness.Carried out stopping using tobacco to treat the trial of tobacco addiction (behavior therapy) voluntarily by the persuasion patient, extremely successful but this method does not also prove.Therefore, obviously a kind of processing to tobacco addiction that reduces or prevent the serious hope of Nicotine is found in expectation, and it does not relate to nicotine replacement therapy or uses thymoleptic and antihypertensive drug.
Therefore, existed in scientific circles and attempted to find the very big interest that can be used to improve aspect the dependent material of habituation agent.Previous two kinds of compounds that have been used to handle alcohol addiction are known as abstinence from alcohol sulphur (abstinyl) (Antabuse TM) and cyanamide.In addition, proposed recently abstinence from alcohol sulphur can be used to handle Cocaine rely on (for example, referring to, Bonet et al., Journal of Substance Abuse Treatment, 26 (2004), 225-232)
Recently shown that the compound that is called Daidzein (daidzein) is effective suppressing aspect the alcohol panning.Daidzein is the main active ingredient that obtains from Radix Puerariae extract, and the root of kudzu vine is a kind of traditional Chinese medicine that ethanol is taken in Syria's gold hamster that suppresses.Referring to Keung, W.M.and Vallee, B.L. (1993) Proc.Natl.Acad.Sci.USA 90,10008-10012 and Keung, W.M., Klyosov, A.A., and Vallee, B.L. (1997) Proc.Natl.Acad.Sci.USA 94,1675-1679, and United States Patent (USP) 5,624,910 and 6,121,010.
Shown that daidzin is the isoflavones of following chemical formula:
Figure BPA00001185905000031
The removal of sugar provides the compound that is called Daidzein, and it has been presented at inhibition alcohol panning aspect is effective.
Figure BPA00001185905000041
United States Patent (USP) 5,624,910 and 6,121,010 has disclosed the ether derivant of daidzin, and it is effective demonstrating aspect the processing ethanol dependence.Daidzin with and analogue demonstrate be human mitochondrial aldehyde dehydrogenase (ALDH-2) effectively and selective depressant, described human mitochondrial aldehyde dehydrogenase is and is responsible for the relevant enzyme of main enzymatic pathway of alcohol metabolism in the mankind.Also find, suppress ALDH-2 but the daidzin analogue that also suppresses monoamine oxidase (MAO) approach has minimum effective anti-fatigue active.
Find surprisingly that now the ALDH-2 inhibitor also is used to handle other habituation agent such as Cocaine, heroine and Nicotine, especially, improve the tendency of misuser's recurrence.
Summary of the invention
Therefore, in first aspect, the present invention relates to the compound of Formula I:
Figure BPA00001185905000042
Formula I
Wherein:
R 1Be the heteroaryl of the phenyl of optional replacement, optional replacement or the heterocyclic radical of optional replacement;
R 2Be low alkyl group, cyano group, the heteroaryl of optional replacement, C (O) OR of the lower alkoxy of hydrogen, hydroxyl, halogen, optional replacement, optional replacement 5,-C (O) R 5,-SO 2R 15,-B (OH) 2,-OP (O) (OR 5) 2,-C (NR 20) NHR 22,-NHR 4, or-C (O) NHR 5, wherein,
R 4Be hydrogen ,-C (O) NHR 5, or-SO 2R 15, or-C (O) R 5
R 5It is the low alkyl group of hydrogen, optional replacement;
R 15Be the low alkyl group of optional replacement or the phenyl of optional replacement; Or
R 2Be-O-Q-R 6, wherein Q is covalent linkage or low-grade alkylidene and R 6It is the heteroaryl of optional replacement;
R 3Be amino, low alkyl group, lower alkoxy or the halogen of hydrogen, cyano group, optional replacement;
X, Y and Z are selected from-CR 7-and-N-, wherein R 7Be hydrogen, low alkyl group, lower alkoxy or halogen;
V be oxygen, sulphur or-NH-; And
W is-Q 1-T-Q 2-, wherein
Q 1Be covalent linkage or alternatively by hydroxyl, lower alkoxy, amino, cyano group or=C that O replaces 1-6The straight or branched alkylidene group;
Q 2Be alternatively by hydroxyl, lower alkoxy, amino, cyano group or=C that O replaces 1-6The straight or branched alkylidene group; And
T be covalent linkage ,-O-or-NH-, or
T and Q 1Can form covalent linkage together,
R 20And R 22Be independently selected from by hydrogen, hydroxyl, C 1-15Alkyl, C 2-15Thiazolinyl, C 2-15The group that alkynyl, heterocyclic radical, aryl, benzyl and heteroaryl are formed,
Wherein said alkyl, thiazolinyl, alkynyl, heterocyclic radical, aryl, benzyl and heteroaryl moieties are replaced by 1 to 3 substituting group alternatively, and described substituting group is independently selected from halogen, alkyl, alkyl monosubstituted amino or dialkyl amido, alkyl or aryl or heteroaryl amide, CN, O-C 1-6Alkyl, CF 3, OCF 3, B (OH) 2, Si (CH 3) 3, heterocyclic radical, aryl and heteroaryl,
Wherein said heterocyclic radical, aryl and heteroaryl substituting group are independently selected from halogen, CF alternatively 3, C 1-4Low alkyl group and C 1-31 to 3 substituting group of alkoxyl group replaces.
In a second aspect of the present invention, pharmaceutical dosage form is provided, described pharmaceutical dosage form comprises the ALDH-2 inhibitor and at least a pharmaceutical carrier of the Formula I for the treatment of significant quantity.
In a third aspect of the present invention, utilize the method for the compounds for treating habituation of Formula I.Described method comprises the compound of the Formula I of the Mammals treatment effective dose that needs it.Described habituation can be for medicament as, but be not limited to Cocaine, opium, Amphetamine, Nicotine and alcohol.
A kind of preferred embodiment in, the present invention relates to the compound of one group of Formula I, wherein X, Y and Z all are-CR 6-, R wherein 6Be hydrogen.In this group, preferred compound comprises such class, wherein R 1Be the phenyl of optional replacement, R 2Be the 4-hydroxyl, R 3Be hydrogen, V is an oxygen, and W is a methylene radical.
A preferred subclass in such comprises those compounds, wherein R 1By the phenyl of 1 to 3 substituting group replacement, described substituting group is independently selected from by carboxyl, carboxylicesters, formamido-, cyano group, tetrazyl, halogen or the group formed by the low alkyl group that halogen replaces, especially wherein substituting group is at single substitution compound of 3, and wherein substituting group at 3,5 bisubstituted compound.
In this subclass, also have such compound, wherein R 1Phenyl group is at 3-position quilt-CO 2R 20The single replacement, wherein R 20Be the C that is replaced by 1 to 3 substituting group alternatively 1-3Alkyl, described substituting group are independently selected from halogen, alkyl monosubstituted amino or dialkyl amido and aryl, heteroaryl, cycloalkyl or heterocyclic radical, and described aryl, heteroaryl, cycloalkyl or heterocyclic radical are independently selected from halogen, CF by 1 to 3 alternatively 3, C 1-4Low alkyl group and C 1-3The substituting group of alkoxyl group replaces.In this subclass, R wherein 20Be mono-substituted, the compound of five yuan or single six-membered rings heterocyclic moiety is preferred.
Another preferred class comprises such compound, wherein R 1Be phenyl, the R of optional replacement 2Be 4-NHR 4, R 3Be that hydrogen, V are that oxygen and W are methylene radical.A preferred subclass comprises those compounds, wherein R 1By the phenyl of 1 to 3 substituting group replacement, described substituting group is independently selected from by carboxyl, formamido-, cyano group, tetrazyl, halogen or the group formed by the low alkyl group that halogen replaces, especially wherein substituting group is at single substitution compound of 3, and wherein substituting group at 3,5 bisubstituted compound.More preferably those compounds, wherein R 4Be-SO 2R 5, R wherein more preferably 5It is methyl.
In another is preferably organized, R 1Be the heteroaryl of optional replacement, especially wherein R 1Be five yuan or the six membered heteroaryl ring that comprises Sauerstoffatom and nitrogen-atoms, V is an oxygen, and W is a methylene radical, preferably R wherein 2Be 4-hydroxyl and R 3Be hydrogen.In this group, a preferred subgroup comprises those compounds, wherein R 1Be 1,3-oxazolyl, 1,3-thiazoles base or (1,2,4-oxadiazole-3-yl), it is replaced by phenyl alternatively, and wherein phenyl is by carboxyl, formamido-, cyano group, tetrazyl, halogen, or the low alkyl group that is replaced by halogen, for example trifluoromethyl replaces, especially wherein substituting group is at single substitution compound of 3, and wherein substituting group at 3,5 bisubstituted compound.
At present, being used for compound of the present invention includes, but are not limited to:
3-{[3-(4-hydroxyphenyl)-4-oxo chromene (chromen)-7-base oxygen base] methyl } phenylformic acid;
3-{[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] methyl } cyanobenzene;
3-(4-hydroxyphenyl)-7-[(3-(5H-1,2,3,4-tetrazolium-5-yl) phenyl) methoxyl group] chromene-4-ketone;
3-{[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] methyl } benzamide;
The 3-[(3-{4-[(methylsulfonyl) (methyl sulphonyl) amino] phenyl }-4-oxo chromene-7-base oxygen base) methyl] cyanobenzene;
The 3-[(3-{4-[(methylsulfonyl) amino] phenyl }-4-oxo chromene-7-base oxygen base) methyl] benzamide;
3-(4-hydroxyphenyl)-7-{[3-(trifluoromethyl) phenyl] methoxyl group } chromene-4-ketone;
3-(4-hydroxyphenyl)-7-{[4-methoxyl group-3-(trifluoromethyl) phenyl] methoxyl group } chromene-4-ketone;
7-{[3-fluoro-5-(trifluoromethyl) phenyl] methoxyl group }-3-(4-hydroxyphenyl) chromene-4-ketone;
3-(4-hydroxyphenyl)-7-{[5-(2-p-methoxy-phenyl) (1,2,4-oxadiazole-3-yl)] methoxyl group } chromene-4-ketone;
3-(4-hydroxyphenyl)-7-[(5-phenyl (1,2,4-oxadiazole-3-yl)) methoxyl group] chromene-4-ketone;
3-(4-hydroxyphenyl)-7-(5-[3-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group) chromene-4-ketone;
3-(4-hydroxyphenyl)-7-(5-[4-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group) chromene-4-ketone;
7-(5-[3-fluoro-5-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group)-3-(4-hydroxyphenyl) chromene-4-ketone;
7-(5-[4-fluoro-3-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group)-3-(4-hydroxyphenyl) chromene-4-ketone;
7-(5-[2,5-two (trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group)-3-(4-hydroxyphenyl) chromene-4-ketone;
3-(3-{[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] methyl }-1,2,4-oxadiazole-5-yl) phenylformic acid third-2-alkene ester;
3-{[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] methyl } phenylformic acid third-2-alkene ester;
4-{[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] methyl } methyl benzoate;
3-{[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] methyl } methyl benzoate;
4-{[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] methyl } ethyl benzoate;
3-{[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] methyl } the benzoic acid methyl ethyl ester;
4-{[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] methyl } phenylformic acid;
4-{[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] methyl } benzamide;
3-(4-hydroxyphenyl)-7-{[5-(3-p-methoxy-phenyl) (1,2,4-oxadiazole-3-yl)] methoxyl group } chromene-4-ketone;
3-(3-{[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] methyl }-1,2,4-oxadiazole-5-yl) phenylformic acid;
7-(5-[3,5-two (trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group)-3-(4-hydroxyphenyl) chromene-4-ketone;
3-(3-{[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] methyl }-1,2,4-oxadiazole-5-yl) cyanobenzene;
3-(4-hydroxyphenyl)-7-[(3-phenyl (1,2,4-oxadiazole-5-yl)) methoxyl group] chromene-4-ketone;
3-(4-hydroxyphenyl)-7-(3-[3-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-5-yl) } methoxyl group) chromene-4-ketone;
3-(4-hydroxyphenyl)-7-(the 3-[4-chloro-phenyl-] (1,2,4-oxadiazole-5-yl) } methoxyl group) chromene-4-ketone;
3-(4-hydroxyphenyl)-2-(trifluoromethyl)-7-(5-[3-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group) chromene-4-ketone;
7-(5-[5-fluoro-3-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group)-3-(4-hydroxyphenyl)-2-(trifluoromethyl) chromene-4-ketone;
3-(4-hydroxyphenyl)-7-(5-[4-methoxyl group-3-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group)-2-(trifluoromethyl) chromene-4-ketone;
3-(4-hydroxyphenyl)-7-{[5-(3-(1H-1,2,3,4-tetrazolium-5-yl) phenyl) (1,2,4-oxadiazole-3-yl)] methoxyl group } chromene-4-ketone;
3-(3-{[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] methyl }-1,2,4-oxadiazole-5-yl) phenylformic acid;
The 3-[(3-{4-[(methylsulfonyl) amino] phenyl }-4-oxo chromene-7-base oxygen base) methyl] phenylformic acid;
The 3-{4-[(methylsulfonyl) amino] phenyl }-7-(5-[3-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group) chromene-4-ketone;
7-{[5-(3-fluorophenyl) (1,2,4-oxadiazole-3-yl)] methoxyl group }-3-(4-hydroxyphenyl) chromene-4-ketone;
The 3-{4-[(methylsulfonyl) amino] phenyl }-7-(2-[4-(trifluoromethyl) phenyl] (1,3-thiazoles-5-yl) } methoxyl group) chromene-4-ketone.
4-[7-(5-[3-fluoro-5-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group)-4-oxo chromene-3-yl] cyanobenzene;
4-[7-(4-methyl-2-[4-(trifluoromethyl) phenyl] (1,3-thiazoles-5-yl) } methoxyl group)-4-oxo chromene-3-yl] ethyl benzoate;
7-(3-[5-fluoro-3-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-5-yl) } oxyethyl group)-3-(4-hydroxyphenyl) chromene-4-ketone;
3-[7-(5-[3-fluoro-5-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group)-4-oxo chromene-3-yl] ethyl benzoate;
The 3-{4-[(methylsulfonyl) amino] phenyl }-7-(4-methyl-2-[4-(trifluoromethyl) phenyl] (1,3-thiazoles-5-yl) } methoxyl group) chromene-4-ketone;
4-[7-(4-methyl-2-[4-(trifluoromethyl) phenyl] (1,3-thiazoles-5-yl) } methoxyl group)-4-oxo chromene-3-yl] methyl benzoate;
3-(2H, 3H-benzo [e] 1,4-diox-6-yl)-7-(5-[3-fluoro-5-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group) chromene-4-ketone;
7-(5-[3-fluoro-5-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group)-3-(6-methoxyl group (3-pyridyl)) chromene-4-ketone;
3-(4-hydroxyphenyl)-7-(4-methyl-2-[4-(trifluoromethyl) phenyl] (1,3-thiazoles-5-yl) } methoxyl group) chromene-4-ketone;
7-(5-[3-fluoro-5-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group)-3-(4-{[(4-aminomethyl phenyl) alkylsulfonyl] amino } phenyl) chromene-4-ketone;
3-(4-{[(4-aminomethyl phenyl) alkylsulfonyl] amino } phenyl)-7-(4-methyl-2-[4-(trifluoromethyl) phenyl] (1,3-thiazoles-5-yl) } methoxyl group) chromene-4-ketone;
3-{[3-(6-methoxyl group (3-pyridyl))-4-oxo chromene-7-base oxygen base] methyl } methyl benzoate;
3-(3-[4-(methylol) phenyl]-4-oxo chromene-7-base oxygen base } methyl) methyl benzoate;
7-(5-[3-fluoro-5-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group)-3-[4-(methylol) phenyl] chromene-4-ketone;
4-[7-(5-[3-fluoro-5-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group)-4-oxo chromene-3-yl] phenylformic acid;
7-(5-[3-fluoro-5-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group)-3-(4-morpholine-4-base phenyl) chromene-4-ketone;
7-(5-methyl-2-[4-(trifluoromethyl) phenyl] (1,3-thiazoles-4-yl) } methoxyl group)-3-(4-morpholine-4-base phenyl) chromene-4-ketone;
7-(3-[5-fluoro-3-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-5-yl) } methoxyl group)-the 3-{4-[(methylsulfonyl) amino] phenyl } chromene-4-ketone;
2-fluoro-5-[7-(5-[5-fluoro-3-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group)-4-oxo chromene-3-yl] cyanobenzene;
2-(3-{4-[(ethoxycarbonyl) methoxyl group] phenyl }-4-oxo chromene-7-base oxygen base) ethyl acetate;
7-{[5-(4-fluorophenyl) (1,2,4-oxadiazole-3-yl)] methoxyl group }-3-(4-hydroxyphenyl) chromene-4-ketone;
3-[7-(5-[5-fluoro-3-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group)-4-oxo chromene-3-yl] cyanobenzene;
3-(3-acetylphenyl)-7-(5-[5-fluoro-3-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group) chromene-4-ketone;
7-(5-[5-fluoro-3-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group)-the 3-{4-[(methylsulfonyl) amino] phenyl } chromene-4-ketone;
4-[7-(5-[5-fluoro-3-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group)-4-oxo chromene-3-yl] benzamide;
3-[2,4-two (tert.-butoxy) pyrimidine-5-yl]-7-(5-[5-fluoro-3-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group) chromene-4-ketone;
5-[7-(5-[5-fluoro-3-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group)-4-oxo chromene-3-yl]-1,3-dihydro-pyrimidin-2,4-diketone;
7-(2-[5-fluoro-3-(trifluoromethyl) phenyl]-(1,3-oxazole-4-yl) } methoxyl group)-3-(4-hydroxyphenyl) chromene-4-ketone;
3-(4-hydroxyphenyl)-7-(2-[3-(trifluoromethyl) phenyl] (1,3-oxazole-4-yl) } methoxyl group) chromene-4-ketone;
7-(2-[5-fluoro-3-(trifluoromethyl) phenyl] (1,3-oxazole-4-yl) } methoxyl group)-3-(4-hydroxyphenyl) chromene-4-ketone;
3-(4-hydroxyphenyl)-7-{[2-(3,4, the 5-trifluorophenyl) (1,3-oxazole-4-yl)] methoxyl group } chromene-4-ketone;
7-{[2-(3, the 5-difluorophenyl) (1,3-oxazole-4-yl)] methoxyl group }-3-(4-hydroxyphenyl) chromene-4-ketone;
7-{[2-(3, the 4-difluorophenyl) (1,3-oxazole-4-yl)] methoxyl group }-3-(4-hydroxyphenyl) chromene-4-ketone;
7-{[2-(4-fluorophenyl) (1,3-oxazole-4-yl)] methoxyl group }-3-(4-hydroxyphenyl) chromene-4-ketone;
7-{[2-(4-chloro-phenyl-) (1,3-oxazole-4-yl)] methoxyl group }-3-(4-hydroxyphenyl) chromene-4-ketone;
3-{[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] methyl } methyl benzoate;
3-(4-hydroxyphenyl)-7-(3-[3-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-5-yl) } methoxyl group) chromene-4-ketone;
3-(4-hydroxyphenyl)-2-(trifluoromethyl)-7-(5-[3-(trifluoromethyl) phenyl]-(1,2,4-oxadiazole-3-yl) } methoxyl group) chromene-4-ketone;
3-{[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] methyl } cyanobenzene;
3-(4-hydroxyphenyl)-7-({ 5-[3-(trifluoromethyl) phenyl] isoxazole-3-base } methoxyl group) chromene-4-ketone;
7-{[5-(trifluoromethyl) (3-pyridyl)] methoxyl group }-3-(4-{[6-(trifluoromethyl) (3-pyridyl)] methoxyl group } phenyl) chromene-4-ketone;
3-(4-hydroxyphenyl)-7-[(5-(3-pyridyl) (1,2,4-oxadiazole-3-yl)) methoxyl group] chromene-4-ketone;
3-(4-hydroxyphenyl)-7-[(5-(2-pyridyl) (1,2,4-oxadiazole-3-yl)) methoxyl group] chromene-4-ketone;
2-{[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] methyl }-1,3-oxazole-5-carboxylate methyl ester;
7-{[5-(4-fluorophenyl) (1,2,4-oxadiazole-3-yl)] methoxyl group }-the 3-{4-[(methylsulfonyl) amino]-phenyl } chromene-4-ketone;
2-{[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] methyl }-1,3-oxazole-5-carboxylic acid;
3-(3-[4-((1Z)-1-amino-2-methoxyl group-2-azepine vinyl) phenyl]-4-oxo chromene-7-base oxygen base } methyl) methyl benzoate;
7-{2-[4-(4-chloro-phenyl-) pyrazolyl] oxyethyl group }-3-(4-hydroxyphenyl) chromene-4-ketone;
3-(4-hydroxyphenyl)-7-[(6-pyrazolyl (3-pyridyl)) methoxyl group] chromene-4-ketone;
7-[(2R)-2-hydroxyl-3-({ [3-(trifluoromethyl) phenyl] methyl } amino) propoxy-]-3-(4-hydroxyphenyl) chromene-4-ketone;
3-(4-hydroxyphenyl)-7-[({[3-(trifluoromethyl) phenyl] methyl } amino) methoxyl group] chromene-4-ketone;
7-((2R)-3-{[(3,5-difluorophenyl) methyl] amino }-2-hydroxyl propoxy-)-3-(4-hydroxyphenyl) chromene-4-ketone;
7-(3-{[(1R)-1-(4-fluorophenyl) ethyl] amino }-the 2-oxopropoxy)-3-(4-hydroxyphenyl) chromene-4-ketone;
3-(4-hydroxyphenyl)-7-(3-phenyl propoxy-) chromene-4-ketone;
7-{[5-(3-fluorophenyl) (1,3,4-oxadiazole-2-yl)] methoxyl group }-3-(4-hydroxyphenyl) chromene-4-ketone;
3-(4-hydroxyphenyl)-7-{[3-(trifluoromethyl) phenyl] oxyethyl group } chromene-4-ketone;
3-(4-hydroxyphenyl)-7-(5-[3-(trifluoromethyl) phenyl] (1,3,4-oxadiazole-2-yl) } methoxyl group) chromene-4-ketone;
3-(4-hydroxyphenyl)-7-[(2-phenyl (1,3-oxazole-5-yl)) methoxyl group] chromene-4-ketone;
7-({ 5-[3,5-two (trifluoromethyl) phenyl] isoxazole-3-base } methoxyl group)-3-(4-hydroxyphenyl) chromene-4-ketone;
3-(4-hydroxyphenyl)-7-({ 5-[3-(trifluoromethyl) phenyl] isoxazole-3-base } methoxyl group) chromene-4-ketone;
The 3-{4-[(methylsulfonyl) amino] phenyl }-7-[(2-phenyl (1,3-oxazole-4-yl)) methoxyl group] chromene-4-ketone;
2-[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base]-N-[3-(trifluoromethyl) phenyl]-ethanamide;
7-{[5-(2-chloro-phenyl-) (1,3,4-thiadiazoles-2-yl)] methoxyl group }-3-(4-hydroxyphenyl) chromene-4-ketone;
4-[7-(4-methyl-2-[4-(trifluoromethyl) phenyl] (1,3-thiazoles-5-yl) } methoxyl group)-4-oxo chromene-3-yl] cyanobenzene;
The 3-{4-[(methylsulfonyl) amino] phenyl }-7-(4-methyl-2-[4-(trifluoromethyl) phenyl] (1,3-thiazoles-5-yl) } methoxyl group) chromene-4-ketone;
3-(6-methoxyl group (3-pyridyl))-7-(4-methyl-2-[4-(trifluoromethyl) phenyl] (1,3-thiazoles-5-yl) } methoxyl group) chromene-4-ketone;
4-[7-(5-[5-fluoro-3-(trifluoromethyl) phenyl] (1,3,4-oxadiazole-2-yl) } methoxyl group)-4-oxo chromene-3-yl] cyanobenzene;
4-[4-oxo-7-({ 3-[3-(trifluoromethyl) phenyl] isoxazole-5-base } methoxyl group) chromene-3-yl] cyanobenzene;
7-(5-[3-fluoro-5-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group)-the 3-{4-[(methylsulfonyl) amino] phenyl } chromene-4-ketone;
7-(5-[3-fluoro-5-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group)-3-[4-(methylsulfonyl) phenyl] chromene-4-ketone;
4-[7-(5-[3-fluoro-5-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group)-4-oxo chromene-3-yl] benzamide;
3-(3-acetylphenyl)-7-(5-[3-fluoro-5-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group) chromene-4-ketone;
7-(5-[3-fluoro-5-(trifluoromethyl) phenyl] (1,3,4-oxadiazole-2-yl) } methoxyl group)-3-(4-hydroxyphenyl) chromene-4-ketone;
7-(5-[3-fluoro-5-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group)-3-(5-hydrogen pyrazoles-4-yl) chromene-4-ketone;
3-[7-(3-[3-fluoro-5-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-5-yl) } oxyethyl group)-4-oxo chromene-3-yl] ethyl benzoate;
3-(4-hydroxyphenyl)-7-(2-[4-(trifluoromethyl) phenyl] (1,3-thiazoles-5-yl) } methoxyl group) chromene-4-ketone;
7-[2-(3-fluorophenyl)-2-oxo oxyethyl group]-3-(4-hydroxyphenyl) chromene-4-ketone;
7-(5-[3-fluoro-5-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } oxyethyl group)-3-(4-hydroxyphenyl) chromene-4-ketone;
7-(5-[3-fluoro-5-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group)-3-(4-{[(4-aminomethyl phenyl) alkylsulfonyl] amino } phenyl) chromene-4-ketone;
7-{[5-(2-chloro-phenyl-) (1,3,4-oxadiazole-2-yl)] methoxyl group }-3-(4-hydroxyphenyl) chromene-4-ketone;
7-{[5-(4-fluorophenyl) (1,3,4-oxadiazole-2-yl)] methoxyl group }-3-(4-hydroxyphenyl) chromene-4-ketone;
3-(4-hydroxyphenyl)-7-(4-pyridyl methoxyl group) chromene-4-ketone;
The 3-{4-[(methylsulfonyl) amino] phenyl }-7-(2-[4-(trifluoromethyl) phenyl] (1,3-thiazoles-5-yl) } methoxyl group) chromene-4-ketone;
2-[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base]-N-[2-(trifluoromethyl) phenyl]-ethanamide;
3-(4-hydroxyphenyl)-7-{2-oxo-2-[2-(trifluoromethyl) phenyl] oxyethyl group } chromene-4-ketone;
3-(1H-indazole-5-yl)-7-(5-[5-fluoro-3-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group) chromene-4-ketone;
3-(4-hydroxyphenyl)-7-(2-phenyl ethoxy) chromene-4-ketone;
2-[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] acetonitrile;
7-[2-(4-chlorophenoxy) oxyethyl group]-3-(4-hydroxyphenyl) chromene-4-ketone;
5-{4-[7-(5-[5-fluoro-3-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group)-4-oxo chromene-3-yl] phenyl }-1,3,5,6-tetrahydropyrimidine-2,4-diketone;
N-[(1R)-1-(4-fluorophenyl) ethyl]-2-[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] ethanamide;
3-(4-hydroxyphenyl)-7-(2-pyridyl methoxyl group) chromene-4-ketone;
2-fluoro-5-[7-(5-[5-fluoro-3-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group)-4-oxo chromene-3-yl] cyanobenzene;
7-(2-pyridyl methoxyl group)-3-[4-(2-pyridyl methoxyl group) phenyl] chromene-4-ketone;
3-(4-hydroxyphenyl)-7-[(5-(4-pyridyl) (1,2,4-oxadiazole-3-yl)) oxyethyl group] chromene-4-ketone;
3-(4-hydroxyphenyl)-7-[(5-(3-pyridyl) (1,2,4-oxadiazole-3-yl)) oxyethyl group] chromene-4-ketone;
3-(4-hydroxyphenyl)-7-[(5-(2-pyridyl) (1,2,4-oxadiazole-3-yl)) oxyethyl group] chromene-4-ketone;
3-(4-hydroxyphenyl)-7-{[5-(trifluoromethyl) (3-pyridyl)] methoxyl group } chromene-4-ketone;
7-{[5-(4-chloro-phenyl-) isoxazole-3-base] methoxyl group }-3-(4-hydroxyphenyl) chromene-4-ketone;
7-{[5-(3,4-dichlorophenyl) isoxazole-3-base] methoxyl group }-3-(4-hydroxyphenyl) chromene-4-ketone;
7-{[5-(4-chloro-phenyl-) isoxazole-3-base] methoxyl group }-3-(4-hydroxyphenyl) chromene-4-ketone;
7-[(2R)-2-hydroxyl-3-({ [3-(trifluoromethyl) phenyl] methyl } amino) propoxy-]-3-(4-hydroxyphenyl) chromene-4-ketone;
3-(4-hydroxyphenyl)-7-[2-({ [3-(trifluoromethyl) phenyl] methyl } amino) oxyethyl group] chromene-4-ketone;
7-((2R)-3-{[(3,5-difluorophenyl) methyl] amino }-2-hydroxyl propoxy-)-3-(4-hydroxyphenyl) chromene-4-ketone;
2-{[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] methyl }-1,3-oxazole-4-carboxylate methyl ester;
2-{[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] methyl }-1,3-oxazole-4-carboxylic acid;
N-[(1S)-1-(4-fluorophenyl) ethyl]-2-[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] ethanamide;
7-{[5-(4-fluorophenyl) (1,2,4-oxadiazole-3-yl)] methoxyl group }-3-(4-hydroxyphenyl) chromene-4-ketone;
7-{[5-(4-fluorophenyl) (1,2,4-oxadiazole-3-yl)] methoxyl group }-the 3-{4-[(methylsulfonyl) amino]-phenyl } chromene-4-ketone;
7-{3-[4-(4-chloro-phenyl-) pyrazolyl] propoxy-}-3-(4-hydroxyphenyl) chromene-4-ketone;
3-(4-hydroxyphenyl)-7-(3-phenyl propoxy-) chromene-4-ketone;
3-(4-hydroxyphenyl)-7-[(6-pyrazolyl (3-pyridyl)) methoxyl group] chromene-4-ketone;
7-((2R)-2-hydroxyl-3-phenyl propoxy-)-3-(4-hydroxyphenyl) chromene-4-ketone;
3-(4-hydroxyphenyl)-7-[(5-(3-pyridyl) (1,3,4-oxadiazole-2-yl)) methoxyl group] chromene-4-ketone;
3-[(2-hydroxyl-3-{4-[(methylsulfonyl) amino] phenyl }-4-oxo chromene-7-base oxygen base) methyl] phenylformic acid;
7-{[5-(4-fluorophenyl) (1,3,4-oxadiazole-2-yl)] oxyethyl group }-3-(4-hydroxyphenyl) chromene-4-ketone;
3-(4-hydroxyphenyl)-7-[(5-(3-pyridyl) (1,3,4-oxadiazole-2-yl)) oxyethyl group] chromene-4-ketone;
3-(4-hydroxyphenyl)-7-[(3-(3-pyridyl) (1,2,4-oxadiazole-5-yl)) methoxyl group] chromene-4-ketone;
3-(4-hydroxyphenyl)-7-[(5-(3-pyridyl) (1,3,4-oxadiazole-2-yl)) oxyethyl group] chromene-4-ketone;
3-(4-hydroxyphenyl)-7-[(5-(4-pyridyl) (1,2,4-oxadiazole-3-yl)) oxyethyl group] chromene-4-ketone;
(2-{[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] methyl } (1,3-oxazole-4-yl))-the N-methylformamide;
4-{[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] methyl }-7-methoxyl group benzo pyran-2-one;
7-{[5-(4-fluorophenyl) (1,3,4-oxadiazole-2-yl)] methoxyl group }-the 3-{4-[(methylsulfonyl) amino]-phenyl } chromene-4-ketone;
7-{[5-(3-aminophenyl) (1,3,4-oxadiazole-2-yl)] methoxyl group }-3-(4-hydroxyphenyl) chromene-4-ketone;
1-{2-[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] ethyl } pyrazoles-4-carboxylic acid, ethyl ester;
7-{2-[4-(3-chloro-phenyl-) piperazinyl] oxyethyl group }-3-(4-hydroxyphenyl) chromene-4-ketone;
3-(4-hydroxyphenyl)-7-(2-{4-[3-(trifluoromethyl) phenyl] piperazinyl } oxyethyl group) chromene-4-ketone;
3-(4-hydroxyphenyl)-7-[(5-(2-pyridyl) isoxazole-3-base) methoxyl group] chromene-4-ketone;
7-(3-[3-fluoro-5-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-5-yl) } oxyethyl group)-3-(4-hydroxyphenyl) chromene-4-ketone;
7-[2-(4-fluorophenyl) oxyethyl group]-3-(4-hydroxyphenyl) chromene-4-ketone;
7-((1R)-1-{3-[3-fluoro-5-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-5-yl) } oxyethyl group)-3-(4-hydroxyphenyl) chromene-4-ketone;
7-((1S)-1-{3-[3-fluoro-5-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-5-yl) } oxyethyl group)-3-(4-hydroxyphenyl) chromene-4-ketone;
3-(4-hydroxyphenyl)-7-{2-[3-(trifluoromethyl) pyrazolyl] oxyethyl group } chromene-4-ketone;
7-(1-{3-[3-fluoro-5-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-5-yl) }-isopropoxy)-3-(4-hydroxyphenyl) chromene-4-ketone;
3-(4-hydroxyphenyl)-7-[(3-(1H-1,2,3,4-tetrazolium-5-yl) phenyl) methoxyl group] chromene-4-ketone;
3-{[3-(4-aminophenyl)-4-oxo chromene-7-base oxygen base] methyl } phenylformic acid third-2-alkene ester;
3-(4-aminophenyl)-7-(5-[3-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group) chromene-4-ketone;
3-{[3-(4-aminophenyl)-4-oxo chromene-7-base oxygen base] methyl } methyl benzoate;
7-(5-[5-fluoro-3-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group)-3-(4-aminophenyl) chromene-4-ketone);
3-{[3-(4-aminophenyl)-4-oxo chromene-7-base oxygen base] methyl } cyanobenzene;
3-{[3-(4-aminophenyl)-4-oxo chromene-7-base oxygen base] methyl } benzamide;
The 3-[(3-{4-[(methylsulfonyl) amino] phenyl }-4-oxo chromene-7-base oxygen base) methyl] phenylformic acid third-2-alkene ester;
The 3-[(3-{4-[(methylsulfonyl) amino] phenyl }-4-oxo chromene-7-base oxygen base) methyl] methyl benzoate;
7-(5-[5-fluoro-3-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group)-the 3-{4-[(methylsulfonyl) amino] phenyl } chromene-4-ketone;
The 3-[(3-{4-[(methylsulfonyl) amino] phenyl }-4-oxo chromene-7-base oxygen base) methyl]-cyanobenzene;
3-{[3-(4-methylsulfonyl aminophenyl)-4-oxo chromene-7-base oxygen base] methyl } benzamide;
3-{[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] methyl } phenylformic acid;
3-(3-{[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] methyl }-1,2,4-oxadiazole-5-yl) phenylformic acid;
3-(3-[4-(kharophen) phenyl]-4-oxo chromene-7-base oxygen base } methyl) methyl benzoate;
3-(4-hydroxyphenyl)-7-{2-[4-(4-p-methoxy-phenyl) piperazinyl] oxyethyl group } chromene-4-ketone;
7-{2-[4-(4-fluorophenyl) piperazinyl] oxyethyl group }-3-(4-hydroxyphenyl) chromene-4-ketone;
3-(4-hydroxyphenyl)-7-(2-piperazinyl oxyethyl group) chromene-4-ketone;
N-(3-fluorophenyl) (4-{2-[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] ethyl }-piperazinyl) methane amide;
7-[2-(4-{[(3-fluorophenyl) amino] sulphomethyl } piperazinyl) oxyethyl group]-3-(4-hydroxyphenyl) chromene-4-ketone;
N-(2,4 difluorobenzene base) (4-{2-[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] ethyl } piperazinyl) methane amide;
7-(2-{2-[3-fluoro-5-(trifluoromethyl) phenyl] (1,3-oxazole-5-yl) } oxyethyl group)-3-(4-hydroxyphenyl) chromene-4-ketone;
7-(3-{2[3-fluoro-5-(trifluoromethyl) phenyl] (1,3-oxazole-4-yl) } propoxy-)-3-(4-hydroxyphenyl) chromene-4-ketone;
7-[2-(4-fluorophenyl)-2-oxo oxyethyl group]-3-(4-hydroxyphenyl) chromene-4-ketone;
7-[2-(3-fluorophenyl)-2-oxo oxyethyl group]-3-(4-hydroxyphenyl) chromene-4-ketone;
3-(4-hydroxyphenyl)-7-{2-oxo-2-[2-(trifluoromethyl) phenyl] oxyethyl group } chromene-4-ketone;
3-(4-hydroxyphenyl)-7-{2-oxo-2-[2-(trifluoromethyl) phenyl] oxyethyl group } chromene-4-ketone;
2-[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base]-N-[3-(trifluoromethyl) phenyl]-ethanamide;
N-[(1S)-1-(4-fluorophenyl) ethyl]-2-[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] ethanamide;
2-[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base]-N-[2-(trifluoromethyl)-phenyl] ethanamide;
N-(3-fluorophenyl)-2-[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] ethanamide;
N-[(1R)-1-(4-fluorophenyl) ethyl]-2-[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] ethanamide;
3-(4-hydroxyphenyl)-7-[2-hydroxyl-3-({ [3-(trifluoromethyl) phenyl] methyl } amino)-propoxy-] chromene-4-ketone;
7-(3-{[(3,5-difluorophenyl) methyl] amino }-2-hydroxyl propoxy-)-3-(4-hydroxyphenyl) chromene-4-ketone;
7-(2-{[(4-fluorophenyl) ethyl] amino } oxyethyl group)-3-(4-hydroxyphenyl) chromene-4-ketone;
3-(4-hydroxyphenyl)-7-(2-hydroxyl-3-phenyl propoxy-) chromene-4-ketone;
7-((1R)-1-{3-[5-fluoro-3-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-5-yl) } oxyethyl group)-3-(4-hydroxyphenyl) chromene-4-ketone;
3-((3-(4-(methyl sulfonamido) phenyl)-4-oxo-4H-chromene-7-base oxygen base) methyl) phenylformic acid 2-morpholinyl ethyl ester;
3-((3-(4-(methyl sulfonamido) phenyl)-4-oxo-4H-chromene-7-base oxygen base) methyl) ethyl benzoate;
3-((3-(4-(methyl sulfonamido) phenyl)-4-oxo-4H-chromene-7-base oxygen base) methyl) phenylformic acid 2-(dimethylamino) ethyl ester; And
3-((3-(4-(methyl sulfonamido) phenyl)-4-oxo-4H-chromene-7-base oxygen base) methyl) phenylformic acid 2-(4-methylpiperazine-1-yl) ethyl ester.
Description of drawings
Fig. 1 shows the 3-[(3-{4-[(methylsulfonyl of describing as in the scheme of describing that gives in embodiment 32) amino] phenyl }-4-oxo chromene-7-base oxygen base) methyl] how benzoic increase dosage to reduce the quantity (being plotted as the quantity of injection) of barometric point.
Embodiment
Definition and general parameters
As employed in the present invention, following word and expression is intended to have the following implication of illustrating usually, unless use the context of these word and expressions to indicate in addition.
Term " alkyl " is meant the saturated hydrocarbon chain of the unit price base side chain (branching) with 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19 or 20 carbon atom or the saturated hydrocarbon chain of unbranched (non-branching).This term is illustrated by group such as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-hexyl, positive decyl, tetradecyl etc.
Term " alkyl of replacement " is meant:
1) alkyl group as hereinbefore defined; have 1; 2; 3; 4 or 5 substituting groups; preferred 1 to 3 substituting group, this substituting group is selected from by thiazolinyl; alkynyl; alkoxyl group; cycloalkyl; cycloalkenyl group; acyl group; amido; acyloxy; amino; aminocarbonyl; alkoxycarbonyl amido; azido-; cyano group; halogen; hydroxyl; ketone group; thiocarbonyl (thiocarbonyl group); carboxyl; carboxyalkyl; arylthio; heteroarylthio; the heterocycle sulfenyl; sulfenyl (mercaptan); alkylthio; aryl; aryloxy; heteroaryl; amino-sulfonyl; aminocarbonyl amino; heteroaryloxy; heterocyclic radical; heterocyclic oxy group; hydroxylamino; alkoxy amino; nitro;-SO-alkyl;-SO-aryl;-SO-heteroaryl;-SO 2-alkyl, SO 2-aryl and-SO 2The group that-heteroaryl is formed.Unless in addition by definition, otherwise all substituting groups can be alternatively further by 1,2 or 3 substituting group replacement, this substituting group is selected from alkyl, carboxyl, carboxyalkyl, aminocarbonyl, hydroxyl, alkoxyl group, halogen, CF 3, amino, the amino that replaces, cyano group and-S (O) nR, wherein R is that alkyl, aryl or heteroaryl and n are 0,1 or 2; Or
2) alkyl group as defined above, this group is independently selected from oxygen, sulphur and NR by 1-10 a-atom interrupt R wherein aBe selected from hydrogen, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, aryl, heteroaryl and heterocyclic radical.All substituting groups can be alternatively further by alkyl, alkoxyl group, halogen, CF 3, amino, the amino that replaces, cyano group or-S (O) nR replaces, and wherein R is that alkyl, aryl or heteroaryl and n are 0,1 or 2; Or
3) alkyl group as defined above, this group have as defined above 1,2,3,4 or 5 substituting group and by as above-mentioned defined 1-10 atom interruption.
Term " low alkyl group " is meant unit price base side chain or the unbranched saturated hydrocarbon chain with 1,2,3,4,5 or 6 carbon atom.This term is illustrated by group such as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-hexyl etc.
Term " low alkyl group of replacement " is meant to have 1 to 5 substituting group as defined above, and preferred 1,2 or 3 substituent low alkyl group is as defined at the alkyl that replaces; Or as defined above by as at defined 1,2,3,4 or 5 low-grade alkyl group that atom interrupted of alkyl that replaces; Or low-grade alkyl group as defined above, it has as defined above 1,2,3,4 or 5 substituting group and is interrupted by 1,2,3,4 or 5 atom as defined above.
Term " alkylidene group " is meant the divalent radical of side chain or unbranched saturated hydrocarbon chain, it has 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19 or 20 carbon atom, preferred 1-10 carbon atom, more preferably 1,2,3,4,5 or 6 carbon atom.This term is by group such as methylene radical (CH 2-), ethylidene (CH 2CH 2-), the propylidene isomer (for example ,-CH 2CH 2CH 2-and-CH (CH 3) CH 2-) etc. illustrated.
Term " low-grade alkylidene " is meant the divalent radical of side chain or unbranched saturated hydrocarbon chain, and it preferably has 1,2,3,4,5 or 6 carbon atom.
Term " low-grade alkylidene " is meant the divalent radical of side chain or unbranched saturated hydrocarbon chain, and it preferably has 1,2,3,4,5 or 6 carbon atom.
Term " alkylidene group of replacement " is meant:
(1) has 1 as defined above; 2; 3; 4; or 5 substituent alkylidene groups, wherein said substituting group is selected from by alkyl; thiazolinyl; alkynyl; alkoxyl group; cycloalkyl; cycloalkenyl group; acyl group; amido; acyloxy; amino; aminocarbonyl; alkoxycarbonyl amido; azido-; cyano group; halogen; hydroxyl; ketone group; thiocarbonyl; carboxyl; carboxyalkyl; arylthio; heteroarylthio; the heterocycle sulfenyl; sulfenyl; alkylthio; aryl; aryloxy; heteroaryl; amino-sulfonyl; aminocarbonyl amino; heteroaryloxy; heterocyclic radical; heterocyclic oxy group; hydroxylamino; alkoxy amino; nitro;-SO-alkyl;-SO-aryl;-SO-heteroaryl;-SO 2-alkyl, SO 2-aryl and-SO 2The group that-heteroaryl is formed.Unless in addition by definition, otherwise all substituting groups can further be selected from alkyl, carboxyl, carboxyalkyl, aminocarbonyl, hydroxyl, alkoxyl group, halogen, CF by 1,2 or 3 alternatively 3, amino, the amino that replaces, cyano group and-S (O) nThe substituting group of R replaces, and wherein R is that alkyl, aryl or heteroaryl and n are 0,1 or 2; Or
(2) alkylidene group as defined above, this group is independently selected from oxygen, sulphur and NR by 1-20 a-atom interrupt R wherein aBe selected from alkyl, cycloalkyl, cycloalkenyl group, aryl, heteroaryl and the heterocyclic radical of hydrogen, optional replacement or be selected from the group of carbonyl, carboxylicesters, methane amide and alkylsulfonyl; Or
(3) alkylidene group as defined above, this alkylidene group have 1,2,3,4 or 5 substituting group and interrupted by 1-20 atom as defined above as defined above.The example of the alkylidene group that replaces is chlorine methylene radical (CH (Cl)-), amino ethylidene (CH (NH 2) CH 2-), methylamino-ethylidene (CH (NHMe) CH 2-), 2-carboxyl propylidene isomer (CH 2CH (CO 2H) CH 2-), ethoxyethyl group (CH 2CH 2O-CH 2CH 2-), ethyl methylamino-ethyl (CH 2CH 2N (CH 3) CH 2CH 2-), 1-oxyethyl group-2-(2-oxyethyl group-oxyethyl group) ethane (CH 2CH 2O-CH 2CH 2-OCH 2CH 2-OCH 2CH 2-) etc.
Term " aralkyl " is meant the aromatic yl group that is covalently attached to alkylidene group, and wherein aryl and alkylidene group define in this article." aralkyl of optional replacement " is meant the aromatic yl group of the optional replacement of the alkylidene group that is covalently attached to optional replacement.Such aromatic alkyl group is illustrated by benzyl, styroyl, 3-(4-p-methoxy-phenyl) propyl group etc.
Term " alkoxyl group " is meant radicals R-O-, and wherein R is the alkyl of optional replacement or the cycloalkyl of optional replacement, or R is group-Y-Z, and wherein Y is the alkylidene group of optional replacement and Z is the thiazolinyl of optional replacement, the alkynyl of optional replacement; Or the cycloalkenyl group of optional replacement, wherein alkyl, thiazolinyl, alkynyl, cycloalkyl and cycloalkenyl group are as defined herein.Preferred alkoxy base is the alkyl-O-of optional replacement and comprises for example methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, tert.-butoxy, sec-butoxy, n-pentyloxy, positive hexyloxy, 1,2-dimethyl butoxy, trifluoromethoxy etc.Term " lower alkoxy " is meant radicals R-O-, and wherein R is the low alkyl group of optional replacement as defined above.
Term " alkylthio " is meant radicals R-S-, and wherein R is as defined at alkoxyl group.
Term " thiazolinyl " is meant preferably have 2 to 20 carbon atoms, more preferably 2 to 10 carbon atoms and even more preferably 2 to 6 carbon atoms and have 1-6, the side chain of preferred 1 two key (vinyl) or the unit price base of unbranched unsaturated hydrocarbon group.Preferred alkenyl group comprises ethylidine or vinyl (CH=CH 2), 1-propylidene or allyl group (CH 2CH=CH 2), isopropylidene (C (CH 3)=CH 2), dicyclo [2.2.1] heptene etc.Be connected at thiazolinyl under the situation of nitrogen, two keys can not be the α positions of nitrogen.
Term " low-grade alkenyl " is meant the thiazolinyl that has 2 to 6 carbon atoms as defined above.
Term " thiazolinyl of replacement " is meant to have 1 as defined above; 2; 3; 4 or 5 substituting groups; and preferred 1; 2; or 3 substituent alkenyl groups, wherein said substituting group is selected from by alkyl; thiazolinyl; alkynyl; alkoxyl group; cycloalkyl; cycloalkenyl group; acyl group; amido; acyloxy; amino; aminocarbonyl; alkoxycarbonyl amido; azido-; cyano group; halogen; hydroxyl; ketone group; thiocarbonyl; carboxyl; carboxyalkyl; arylthio; heteroarylthio; the heterocycle sulfenyl; sulfenyl; alkylthio; aryl; aryloxy; heteroaryl; amino-sulfonyl; aminocarbonyl amino; heteroaryloxy; heterocyclic radical; heterocyclic oxy group; hydroxylamino; alkoxy amino; nitro;-SO-alkyl;-SO-aryl;-SO-heteroaryl;-SO 2-alkyl, SO 2-aryl and-SO 2The group that-heteroaryl is formed.Unless in addition by definition, otherwise all substituting groups can further be selected from alkyl, carboxyl, carboxyalkyl, aminocarbonyl, hydroxyl, alkoxyl group, halogen, CF by 1,2 or 3 alternatively 3, amino, the amino that replaces, cyano group and-S (O) nThe substituting group of R replaces, and wherein R is that alkyl, aryl or heteroaryl and n are 0,1 or 2.
Term " alkynyl " is meant the unit price base of unsaturated hydrocarbons, and it preferably has 2 to 20 carbon atoms, more preferably 2 to 10 carbon atoms and even more preferably 2 to 6 carbon atoms and have at least 1 and the preferred unsaturated position of 1-6 acetylene (triple bond).Preferred alkynyl group comprises ethynyl (C ≡ CH), propargyl (or third-1-alkynes-3-base ,-CH 2C ≡ CH) etc.Be connected at alkynyl under the situation of nitrogen, triple bond can not be the α position of nitrogen.
Term " alkynyl of replacement " is meant to have 1 as defined above; 2; 3; 4 or 5 substituting groups; and preferred 1; 2; or 3 substituent alkynyl groups, wherein said substituting group is selected from by alkyl; thiazolinyl; alkynyl; alkoxyl group; cycloalkyl; cycloalkenyl group; acyl group; amido; acyloxy; amino; aminocarbonyl; alkoxycarbonyl amido; azido-; cyano group; halogen; hydroxyl; ketone group; thiocarbonyl; carboxyl; carboxyalkyl; arylthio; heteroarylthio; the heterocycle sulfenyl; sulfenyl; alkylthio; aryl; aryloxy; heteroaryl; amino-sulfonyl; aminocarbonyl amino; heteroaryloxy; heterocyclic radical; heterocyclic oxy group; hydroxylamino; alkoxy amino; nitro;-SO-alkyl;-SO-aryl;-SO-heteroaryl;-SO 2-alkyl, SO 2-aryl and-SO 2The group that-heteroaryl is formed.Unless in addition by definition, otherwise all substituting groups can further be selected from alkyl, carboxyl, carboxyalkyl, aminocarbonyl, hydroxyl, alkoxyl group, halogen, CF by 1,2 or 3 alternatively 3, amino, the amino that replaces, cyano group and-S (O) nThe substituting group of R replaces, and wherein R is that alkyl, aryl or heteroaryl and n are 0,1 or 2.
Term " aminocarbonyl " is meant group-C (O) NRR, and wherein each R is hydrogen, alkyl, aryl, heteroaryl, heterocyclic radical independently, or wherein two R groups link to each other to form heterocyclic group (for example, morpholinyl).Unless in addition by definition, otherwise all substituting groups can further be selected from alkyl, carboxyl, carboxyalkyl, aminocarbonyl, hydroxyl, alkoxyl group, halogen, CF by 1-3 alternatively 3, amino, the amino that replaces, cyano group and-S (O) nThe substituting group of R replaces, and wherein R is that alkyl, aryl or heteroaryl and n are 0,1 or 2.
Term " amido " is meant group-NRC (O) R, and wherein each R is hydrogen, alkyl, aryl, heteroaryl or heterocyclic radical independently.Unless in addition by definition, otherwise all substituting groups can further be selected from alkyl, carboxyl, carboxyalkyl, aminocarbonyl, hydroxyl, alkoxyl group, halogen, CF by 1-3 alternatively 3, amino, the amino that replaces, cyano group and-S (O) nThe substituting group of R replaces, and wherein R is that alkyl, aryl or heteroaryl and n are 0,1 or 2.
Term " acyloxy " be meant group-O (O) C-alkyl ,-O (O) C-cycloalkyl ,-O (O) C-aryl ,-O (O) C-heteroaryl and-O (O) C-heterocyclic radical.Unless in addition by definition, otherwise all substituting groups can be alternatively further by alkyl, carboxyl, carboxyalkyl, aminocarbonyl, hydroxyl, alkoxyl group, halogen, CF 3, amino, the amino that replaces, cyano group or-S (O) nR replaces, and wherein R is that alkyl, aryl or heteroaryl and n are 0,1 or 2.
Term " aryl " is meant the aromatic carbon ring group of 6 to 20 carbon atoms of have monocycle (for example, phenyl) or many rings (for example, xenyl) or a plurality of condensed ring (for example, naphthyl or anthryl).Preferred aryl groups comprises phenyl, naphthyl etc.
Term " arylidene " is meant the divalent radical of aromatic yl group as defined above.This term by group as 1,4-phenylene, 1,3-phenylene, 1,2-phenylene, 1,4 '-biphenylene etc. illustrated.
Unless in addition by limiting at aryl or arylidene substituent definition; otherwise such aryl or arylene group can be alternatively by 1 to 5 substituting groups; preferred 1 to 3 substituting group replaces, and described substituting group is selected from by alkyl; thiazolinyl; alkynyl; alkoxyl group; cycloalkyl; cycloalkenyl group; acyl group; amido; acyloxy; amino; aminocarbonyl; alkoxycarbonyl amido; azido-; cyano group; halogen; hydroxyl; ketone group; thiocarbonyl; carboxyl; carboxyalkyl; arylthio; heteroarylthio; the heterocycle sulfenyl; sulfenyl; alkylthio; aryl; aryloxy; heteroaryl; amino-sulfonyl; aminocarbonyl amino; heteroaryloxy; heterocyclic radical; heterocyclic oxy group; hydroxylamino; alkoxy amino; nitro;-SO-alkyl;-SO-aryl;-SO-heteroaryl;-SO 2-alkyl, SO 2-aryl and-SO 2The group that-heteroaryl is formed.Unless in addition by definition, otherwise all substituting groups can further be selected from alkyl, carboxyl, carboxyalkyl, aminocarbonyl, hydroxyl, alkoxyl group, halogen, CF by 1-3 alternatively 3, amino, the amino that replaces, cyano group and-S (O) nThe substituting group of R replaces, and wherein R is that alkyl, aryl or heteroaryl and n are 0,1 or 2.
Term " aryloxy " is meant group aryl-O-, and wherein aromatic yl group and comprises the aromatic yl group of optional replacement equally as defined above as defined above.Term " arylthio " is meant radicals R-S-, and wherein R is as defined at aryl.
Term " amino " is meant group-NH 2
Term " amino of replacement " is meant group-NRR, wherein each R by hydrogen, alkyl, cycloalkyl, carboxyalkyl (for example is independently selected from, carbobenzoxy-(Cbz)), the group of aryl, heteroaryl and heterocyclic radical composition, condition is that two R groups are not hydrogen, or group-Y-Z, wherein Y is the alkylidene group of optional replacement and Z is thiazolinyl, cycloalkenyl group or alkynyl, unless in addition by definition, otherwise all substituting groups can further be selected from alkyl, carboxyl, carboxyalkyl, aminocarbonyl, hydroxyl, alkoxyl group, halogen, CF by 1-3 alternatively 3, amino, the amino that replaces, cyano group and-S (O) nThe substituting group of R replaces, and wherein R is that alkyl, aryl or heteroaryl and n are 0,1 or 2.
Term " carboxyalkyl " be meant group-C (O) O-alkyl or-C (O) O-cycloalkyl, wherein alkyl and cycloalkyl are as defined herein and can be alternatively further by alkyl, thiazolinyl, alkynyl, alkoxyl group, halogen, CF 3, amino, the amino that replaces, cyano group or-S (O) nR replaces, and wherein R is that alkyl, aryl or heteroaryl and n are 0,1 or 2.
Term " cycloalkyl " is meant the monocycle with 3 to 20 carbon atoms or the carbon ring group of a plurality of condensed ring.Such group of naphthene base for example comprises single ring architecture such as cyclopropyl, cyclobutyl, cyclopentyl, ring octyl group etc., or polynuclear plane such as adamantyl, dicyclo [2.2.1] heptane, 1,3,3-trimethylammonium dicyclo [2.2.1] heptan-2-base, (2,3,3-trimethylammonium dicyclo [2.2.1] heptan-2-yl), or with aromatic yl group condensed carbon ring group, for example indane etc.
Term " cycloalkyl of replacement " is meant to have 1; 2; 3; 4 or 5 substituting groups; and preferred 1; 2; or 3 substituent groups of naphthene base, described substituting group is selected from by alkyl; thiazolinyl; alkynyl; alkoxyl group; cycloalkyl; cycloalkenyl group; acyl group; amido; acyloxy; amino; aminocarbonyl; alkoxycarbonyl amido; azido-; cyano group; halogen; hydroxyl; ketone group; thiocarbonyl; carboxyl; carboxyalkyl; arylthio; heteroarylthio; the heterocycle sulfenyl; sulfenyl; alkylthio; aryl; aryloxy; heteroaryl; amino-sulfonyl; aminocarbonyl amino; heteroaryloxy; heterocyclic radical; heterocyclic oxy group; hydroxylamino; alkoxy amino; nitro;-SO-alkyl;-SO-aryl;-SO-heteroaryl;-SO 2-alkyl, SO 2-aryl and-SO 2The group that-heteroaryl is formed.Unless in addition by definition, otherwise all substituting groups can further be selected from alkyl, carboxyl, carboxyalkyl, aminocarbonyl, hydroxyl, alkoxyl group, halogen, CF by 1,2 or 3 alternatively 3, amino, the amino that replaces, cyano group and-S (O) nThe substituting group of R replaces, and wherein R is that alkyl, aryl or heteroaryl and n are 0,1 or 2.
That term " halogen " or " halogen " are meant is fluorine-based, bromo, chloro and iodo.
Term " acyl group " is meant group-C (O) R, and wherein R is the aryl of the heterocyclic radical of the cycloalkyl of the alkyl of hydrogen, optional replacement, optional replacement, optional replacement, optional replacement and the heteroaryl of optional replacement.
Term " heteroaryl " is meant derived from the aromatics cyclic group (promptly, undersaturated fully) group, this group at least one the ring in have 1,2,3,4,5,6,7,8,9,10,11,12,13,14 or 15 carbon atom and 1,2,3 or 4 heteroatoms that is selected from oxygen, nitrogen and sulphur.Such heteroaryl groups can have monocycle (for example, pyridyl or furyl) or a plurality of condensed ring (for example, indolizine base, benzothiazolyl or benzothienyl).The example of heteroaryl includes but not limited to [1,2,4] oxadiazoles, [1,3,4] oxadiazoles, [1,2,4] thiadiazoles, [1,3,4] thiadiazoles, the pyrroles, imidazoles, pyrazoles, pyridine, pyrazine, pyrimidine, pyridazine, indolizine (indolizine), isoindole, indoles, indazole, purine, quinolizine, isoquinoline 99.9, quinoline, phthalazines, the naphthyl pyridine, quinoxaline, quinazoline, cinnolines, pteridine, carbazole, carboline, phenanthridines, acridine, phenanthroline, thiazole, isothiazole, azophenlyene oxazole isoxazole phenoxazine, thiodiphenylamine, imidazolidine, tetrahydroglyoxaline etc. and the N-oxide compound and the N-alkoxy derivative that contain azaheteroaryl, for example pyridine-N-oxide derivative.
Unless in addition by limiting at heteroaryl or heteroarylidene substituent definition; otherwise such heteroaryl or heteroarylidene group can be alternatively by 1 to 5 substituting groups; preferred 1 to 3 substituting group replaces, and described substituting group is selected from by alkyl; thiazolinyl; alkynyl; alkoxyl group; cycloalkyl; cycloalkenyl group; acyl group; amido; acyloxy; amino; aminocarbonyl; alkoxycarbonyl amido; azido-; cyano group; halogen; hydroxyl; ketone group; thiocarbonyl; carboxyl; carboxyalkyl; arylthio; heteroarylthio; the heterocycle sulfenyl; sulfenyl; alkylthio; aryl; aryloxy; heteroaryl; amino-sulfonyl; aminocarbonyl amino; heteroaryloxy; heterocyclic radical; heterocyclic oxy group; hydroxylamino; alkoxy amino; nitro;-SO-alkyl;-SO-aryl;-SO-heteroaryl;-SO 2-alkyl, SO 2-aryl and-SO 2The group that-heteroaryl is formed.Unless in addition by definition, otherwise all substituting groups can further be selected from alkyl, carboxyl, carboxyalkyl, aminocarbonyl, hydroxyl, alkoxyl group, halogen, CF by 1-3 alternatively 3, amino, the amino that replaces, cyano group and-S (O) nThe substituting group of R replaces, and wherein R is alkyl, aryl or heteroaryl and n is 0,1 or 2.
Term " heteroaralkyl " is meant the heteroaryl groups that is covalently attached to alkylidene group, and wherein heteroaryl and alkylidene group define in this article." heteroaralkyl of optional replacement " is meant the heteroaryl groups of the optional replacement of the alkylidene group that is covalently attached to optional replacement.Such heteroaralkyl group is illustrated by 3-pyridylmethyl, quinoline-8-base ethyl, 4-methoxy thiazole-2-base propyl group etc.
Term " heteroaryloxy " is meant group heteroaryl-O-.
Term " heterocyclic radical " is meant the saturated or part unsaturated group of unit price, this group has monocycle or a plurality of condensed ring, in ring, have 1 to 40 carbon atom and 1 to 10 heteroatoms, preferred 1,2,3 or 4 heteroatoms, this heteroatoms is selected from nitrogen, sulphur, phosphorus and/or oxygen.Heterocyclic group can have monocycle or a plurality of condensed ring, and comprise tetrahydrofuran base, morpholinyl, oxathiane, thio-morpholinyl, tetrahydro-thienyl, THP trtrahydropyranyl, tetrahydro thiapyran base, piperidyl, triazolidine also, piperazinyl, dihydro pyrido, pyrrolidyl, imidazolidine also, hexahydropyrimidine, hexahydro-pyridazine, tetrahydroglyoxaline etc.
Unless limit by definition in addition at heterocyclic substituent; otherwise such heterocyclic group can be alternatively by 1; 2; 3; 4 or 5; and preferred 1; 2 or 3 substituting groups replace, and described substituting group is selected from by alkyl; thiazolinyl; alkynyl; alkoxyl group; cycloalkyl; cycloalkenyl group; acyl group; amido; acyloxy; amino; aminocarbonyl; alkoxycarbonyl amido; azido-; cyano group; halogen; hydroxyl; ketone group; thiocarbonyl; carboxyl; carboxyalkyl; arylthio; heteroarylthio; the heterocycle sulfenyl; sulfenyl; alkylthio; aryl; aryloxy; heteroaryl; amino-sulfonyl; aminocarbonyl amino; heteroaryloxy; heterocyclic radical; heterocyclic oxy group; hydroxylamino; alkoxy amino; nitro;-SO-alkyl;-SO-aryl;-SO-heteroaryl;-SO 2-alkyl, SO 2-aryl and-SO 2The group that-heteroaryl is formed.Unless in addition by definition, otherwise all substituting groups can further be selected from alkyl, carboxyl, carboxyalkyl, aminocarbonyl, hydroxyl, alkoxyl group, halogen, CF by 1-3 alternatively 3, amino, the amino that replaces, cyano group and-S (O) nThe substituting group of R replaces, and wherein R is alkyl, aryl or heteroaryl and n is 0,1 or 2.
Term " sulfenyl " is meant group-SH.
Term " alkylthio of replacement " is meant the alkyl that group-S-replaces.
Term " heteroarylthio " is meant group-S-heteroaryl, and wherein heteroaryl groups is as defined above, comprises the heteroaryl groups of optional replacement equally as defined above.
Term " sulfoxide " is meant group-S (O) R, and wherein R is alkyl, aryl or heteroaryl." sulfoxide of replacement " is meant group-S (O) R, and wherein R is the alkyl that replaces, the aryl of replacement or the heteroaryl that replaces, as defined herein.
Term " sulfone " is meant group-S (O) 2R, wherein R is alkyl, aryl or heteroaryl." sulfone of replacement " is meant group-S (O) 2R, wherein R is the alkyl that replaces, the aryl of replacement or the heteroaryl that replaces, as defined herein
Term " ketone group " be meant group-C (O)-.
Term " thiocarbonyl " be meant group-C (S)-.
Term " carboxyl " is meant group-C (O)-OH.
" optionally " or " alternatively " is meant that subsequently incident or the situation described may take place or may not take place, and described description comprises example that wherein said incident or situation take place and its example of not taking place wherein.
Term " compound of Formula I " is used to contain the compound of the present invention as disclosed, and the pharmaceutical salts of such compound, medicinal ester, prodrug, hydrate and polymorphic form.In addition, compound of the present invention can have one or more asymmetric centers, and can be used as racemic mixture or produce as independent enantiomorph or diastereomer.The number of the steric isomer that exists in the compound of any given Formula I depends on that the number of the asymmetric center of existence (exists 2 nPlant possible steric isomer, wherein n is the number of asymmetric center).Independent steric isomer can be in the racemize or the non--racemic mixture of the intermediate of a certain suitable stage of synthetic by fractionation, and the compound that perhaps splits Formula I by conventional methods obtains.The racemize and the non-racemic mixture of independent steric isomer (comprising independent enantiomorph and diastereomer) and steric isomer comprise within the scope of the invention, indicate unless have clearly in addition, otherwise all these are intended to describe by the structure of this specification sheets.
" isomer " is the different compound with same molecular formula.
" steric isomer " is the different isomer of atoms in space arrangement mode only.
" enantiomorph " is the steric isomer of a pair of non-superimposable mirror image each other.1: 1 mixture of a pair of enantiomorph is " racemize " mixture.In appropriate circumstances, term " (±) " is used for representing racemic mixture.
" diastereomer " is such steric isomer, and it has at least two asymmetric atoms, but it is not mirror image each other
The absolute stereo chemistry is stipulated according to Cahn-Ingold-Prelog R-S system.When compound is pure enantiomorph, can be defined in the stereochemistry at each chiral carbon place with R or S.The compound of the fractionation of its absolute configuration the unknown depends on them and is appointed as (+) or (-) in the planar direction of the wavelength place of sodium D-line rotatory polarization light (dextrorotation-or left-handed).
" parenteral administration " is via injecting the therapeutical agent systemic delivery to the patient.
Term " treatment significant quantity " is meant as following defined, and when needing the Mammals of such treatment, it is enough to the amount of the compound of the Formula I implementing to treat.The treatment significant quantity will be along with the concrete activity of use therapeutical agent, and the existence of patient's age, physical appearance, other morbid state and nutritional status and change.In addition, the other medicines that may just accept of patient will influence the determining of treatment significant quantity of the therapeutical agent that is given.
Term " treatment " or " just treating " are meant any treatment to mammalian diseases, comprising:
(i) preventing disease promptly, does not develop the clinical symptom of disease;
(ii) suppress disease, that is, stop the development of clinical symptom; And/or
(iii) alleviate disease, that is, make clinical symptom disappearance.
In many cases, compound of the present invention can form acid salt and/or subsalt by means of the existence of amino and/or carboxylic group or group similar with it.Term " pharmaceutical salts " is meant such salt, and it keeps the biological effectiveness and the performance of the compound of Formula I, and biologically or in others is not expecting.The medicinal basic additive salt can be prepared by mineral alkali and organic bases.Salt derived from mineral alkali comprises (only illustrating) sodium salt, sylvite, lithium salts, ammonium salt, calcium salt and magnesium salts.Salt derived from organic bases includes but not limited to primary amine, the salt of secondary amine and tertiary amine, as alkylamine, dialkylamine, trialkylamine, the alkylamine that replaces, two (alkyl of replacement) amine, three (alkyl of replacement) amine, alkenyl amine, dialkylene amine, trialkenyl amine, the alkenyl amine that replaces, two (thiazolinyl of replacement) amine, three (thiazolinyl of replacement) amine, Cycloalkyl amine, two (cycloalkyl) amine, three (cycloalkyl) amine, the Cycloalkyl amine that replaces, dibasic Cycloalkyl amine, trisubstituted Cycloalkyl amine, cycloalkenyl group amine, two (cycloalkenyl group) amine, three (cycloalkenyl group) amine, the cycloalkenyl group amine that replaces, dibasic cycloalkenyl group amine, trisubstituted cycloalkenyl group amine, arylamines, diarylamine, triarylamine, heteroaryl amine, two heteroaryl amine, three heteroaryl amine, heterocyclic amine, two heterocyclic amines, three heterocyclic amines, blended diamines and triamine, wherein at least two in the substituting group on amine are different and are selected from by alkyl, the alkyl that replaces, thiazolinyl, the thiazolinyl that replaces, cycloalkyl, the cycloalkyl that replaces, cycloalkenyl group, the cycloalkenyl group that replaces, aryl, heteroaryl, the group that heterocycle etc. are formed.Comprise that also two or three substituting groups wherein form the amine of heterocycle or heteroaryl groups with amino nitrogen.
The specific examples of suitable amine comprises (only explanation by way of example) Isopropylamine, Trimethylamine 99, diethylamine, three (different third) amine, three (positive third) amine, thanomin, 2-dimethylaminoethanol, Trometamol (trometamol), Methionin, arginine, Histidine, caffeine, PROCAINE HCL, PHARMA GRADE, Hai Baming, choline, trimethyl-glycine, quadrol, glycosamine, N-alkylated glucamine, Theobromine, purine, piperazine, piperidines, morpholine, N-ethylpiperidine etc.
Medicinal acid addition salt can be prepared by mineral acid and organic acid.Mineral acid that can salt derivative from it comprises hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid etc.Organic acid that can salt derivative from it comprises acetic acid, propionic acid, oxyacetic acid, pyruvic acid, oxalic acid, oxysuccinic acid, propanedioic acid, Succinic Acid, toxilic acid, fumaric acid, tartrate, citric acid, phenylformic acid, styracin, amygdalic acid, methylsulfonic acid, ethyl sulfonic acid, tosic acid, Whitfield's ointment etc.
As used herein, " pharmaceutical carrier " comprises any and all solvents, dispersion medium, coating, antimicrobial drug and anti-mycotic agent, isotonic agent and absorption delay agent etc.It is well-known in the art that such medium and medicament are used for pharmaceutically active substance.Unless the medium of any routine or medicament and active ingredient are incompatible, otherwise can expect that it is used for the treatment of composition.Auxiliary active ingredient also can join in the composition.
Name
The naming ﹠ numbering of compound of the present invention is that the compound by typical Formula I is illustrated, wherein R 1Be 5-[3-fluoro-5-(trifluoromethyl) phenyl]-(1,2,4-oxadiazole-3-yl) and R 2Be hydroxyl:
Figure BPA00001185905000331
It is named as 7-({ 5-[3-fluoro-5-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group)-3-(4-hydroxyphenyl) chromene-4-ketone.
The building-up reactions parameter
Term " solvent ", " inert organic solvents " or " inert solvent " are meant under the condition of the reaction of therewith describing and [comprise for the inert solvent, for example, benzene, toluene, acetonitrile, tetrahydrofuran (THF) (" THF "), dimethyl formamide (" DMF "), chloroform, methylene dichloride, ether, methyl alcohol, pyridine etc.].Unless opposite regulation is arranged, otherwise employed solvent all is inert organic solvents in reaction of the present invention.
Term " capacity (q.s.) " is meant and adds the amount that is enough to reach the function of being stated, for example makes solution reach the volume (that is, 100%) of expectation.
Synthesizing of the compound of Formula I
Shown in reaction scheme I, can prepare the compound of Formula I, wherein R 2Be that hydroxyl and X, Y and Z all are-CR 6-, R wherein 6Be hydrogen.
Reaction scheme I
Figure BPA00001185905000341
Usually, the compound (Daidzein, commercially available) with chemical formula (1) is dissolved in inert solvent, N for example, in the dinethylformamide, and under the alkali situation that for example salt of wormwood, potassium hydroxide, cesium carbonate etc. exist, with the chemical formula R of about equimolar amount 1The reaction of the compound of WX, wherein W is the low-grade alkylidene of 1-3 carbon atom and X is iodo, bromo or chloro.Can under about 50-100 ℃ temperature, carry out the about 1-10 of this reaction hour or can also at room temperature carry out this reaction 3 to 24 hours.When reaction is finished basically, come the product of separation chemistry formula I by conventional methods, wherein R 2Be hydroxyl, for example by adding entry precipitated product from solution.
Replacedly, the compound dissolution of chemical formula (1) at inert solvent, for example in the acetone, and is added aqueous bases, 2N potassium hydroxide for example, the about 5-30 of supersound process mixture minute then.Then under the situation that the potassiumiodide of about equimolar amount exists, make the chemical formula R of mixture and about equimolar amount 1The reaction of the compound of WX, wherein W is the low-grade alkylidene of 1-3 carbon atom and X is iodo, bromo or chloro, and makes the about 1-5 of mixture reaction days under about reflux temperature.When reaction when finishing basically, (for example pass through chromatography) by conventional methods and come the product of separation chemistry formula I, wherein R 2It is hydroxyl.
A kind of method that is used to prepare the compound of Formula I has been shown, wherein R in reaction scheme II 1By the phenyl that tetrazolium-5-base replaces, W is a methylene radical, and X, Y and Z all are-CR 6-, R wherein 6Be hydrogen.
Reaction scheme II
Figure BPA00001185905000351
The preparation of the compound of step 1-chemical formula (2)
Usually, make the compound (R wherein of Formula I 1Be benzonitrile), the mixture of dibutyl tin oxide and azidotrimethylsilane stands microwave.Under about 150 ℃ temperature, reacted about 10-30 minute.When reaction was finished basically, (for example by chromatography on silica gel) came the product of separation chemistry formula (2) by conventional methods.
The preparation of the compound of step 2-Formula I
The purified product of chemical formula (2) is suspended in water-containing solvent, for example in the acetonitrile/water, and adds the strong acid of catalytic amount, for example trifluoroacetic acid.Remove and desolvate so that the compound of Formula I, wherein R to be provided 1By the phenyl that tetrazolium-the 5-base replaces.
Similarly, incite somebody to action wherein R 1The compound that is replaced the Formula I of [1,2,4]-oxadiazoles-3-base at 5 by benzonitrile changes into wherein R 1Replaced the compound of the Formula I of [1,2,4]-oxadiazoles-3-base by tetrazolium-5-base phenyl.
Shown in reaction scheme III, can prepare the compound of Formula I by intermediate, wherein R with nitryl group precursor 2Be-NHR 5, R wherein 5Be hydrogen.
Reaction scheme III
Figure BPA00001185905000361
The preparation of the compound of step 1-Formula I
Usually, with the nitro-derivative of chemical formula (3) (as the preparation of describing among the reaction scheme I, but utilize commercially available nitro Daidzein derivative as initial substance) be suspended in water-containing solvent, for example in the mixture of tetrahydrofuran (THF) and water, react with V-Brite B then.Under about 50-70 ℃ temperature, react and spend the night.When reaction was finished basically, (for example by chromatography on the silica gel) came the amine of separation chemistry formula I by conventional methods.
Replacedly, the compound of chemical formula (3) can be suspended in the acetate, then slowly adds zinc and reaches 20 to 40 minutes.Because this reaction will be heat release, therefore suspension is cooled off in ice-water bath.In case all zinc are added into, reaction allows to be heated to room temperature under the stirring that continues.After reaction was finished, the amine of separation chemistry formula I for example by filtering with diatomite (celite) to remove by product, with the ETOAc washing, was used Na subsequently by conventional methods 2SO 4Drying, and remove solvent.
Should be noted that if the compound of chemical formula (3) has the R of being present in 1Carboxylic group on the part, then before the reduction of carrying out nitryl group, can be with carboxylic group as allyl group or alkyl, promptly tertiary butyl ester is protected.Should be appreciated that described blocking group can be positioned on the carboxylic group, at the R of Formula I core 1Before the W group, before utilizing-R 1The WX compound is as reactant, perhaps after connection, and for example acidic cpd by making Formula I and 2-methyl propan-2-ol, the MgSO in the methylene dichloride 4, and H 2SO 4Reaction.Such blocking group can the protection carboxylic group in any subsequent reaction, and wherein amine is for example by acidylate, and is removed via the routine hydrolysis condition easily later in acidylate.
The compound of Formula I has been shown in reaction scheme IV, and (wherein W is a methylene radical, and X, Y and Z all are-CR 6-, R wherein 6Be hydrogen, and R 2Be NH 2) change into accordingly wherein R 2Be NHSO 2R 5The compound of Formula I.
Reaction scheme IV
Figure BPA00001185905000371
Formula I Formula I, wherein R 4Be-SO 2R 15
Usually, with the compound of Formula I (R wherein 2Be amino) be suspended in inert solvent, for example in the methylene dichloride, and add tertiary base, for example pyridine.Mixture is cooled to about 0 ℃, adds chemical formula R 15SO 2The compound of Cl, and make the about 1-2 of mixture reaction hour.When reaction was finished basically, (for example by chromatography on silica gel) came the compound of separation chemistry formula I, wherein R by conventional methods 4Be-SO 2R 15
Similarly, the compound of Formula I (R wherein 2Be amino) and chemical formula ClC (O) R 5The reaction of acylating agent the compound of Formula I, wherein R are provided 2Be-NHR 4, R wherein 4Be-C (O) R 5With chemical formula ClC (O) NHR 5Or R 5The reaction of the compound of NCO provides the compound of Formula I, wherein R 4Be-C (O) NHR 5
In reaction scheme V, illustrated before the reduction of carrying out nitryl group at R 1The carboxylic group that exists on the part is as allyl group or alkyl ester when protected, and (wherein W is a methylene radical to the compound of Formula I, and X, Y and Z all are-CR 6-, R wherein 6Be hydrogen, and R 1Be the allyl ester derivative) change into the compound of corresponding Formula I, wherein R 1It is acid derivative.
Reaction scheme V
Usually, work as R 1Part is as allyl ester when protected, and the derivative of Formula I is dissolved in inert solvent, for example in the tetrahydrofuran (THF), and adds alkali, for example morpholine and tetrakis triphenylphosphine palladium (0).Under about room temperature, reacted about 1-12 hour.When reaction was finished basically, (for example by flash chromatography on silica gel) came the compound of separation chemistry formula I, wherein R by conventional methods 1It is benzoic acid derivative.Work as R 1Part is as alkyl, i.e. the tertiary butyl, and when ester was protected, the derivative of Formula I was suspended in HCO 2Heated 1 hour down among the H and at 50 ℃, then be heated to 80 ℃ gradually and carried out about 2 to 3 hours.In case reaction is finished, allow suspension to be cooled to envrionment temperature and to stir other 7 to 10 hours.After the stirring, add entry, and reaction mixture stirred 1 hour under the ice-water bath cooling at least.Collect resulting throw out by filtering, and residue repeats the water flushing.After the drying, collect crude product, and can be by in DMF, coming purifying with recrystallizing methanol.
If expectation, R 1The other modification of carboxylic group can be by making compound and expectation the alcohol of part react and implement, shown in reaction scheme VI.
Reaction scheme VI
Figure BPA00001185905000391
The acidic cpd of Formula I and alkali such as triethylamine and 2,4, the 6-trichloro-benzoyl chloride at first is dissolved among appropriate solvent such as THF or the DMF together.This solution was at room temperature reacted about 1 hour under nitrogen atmosphere.In case this stage of synthetic finishes, add R 20OH reactant and the dimethyl aminopyridine solution in solvent, and other one hour of the mixture that at room temperature stir to merge.After adding entry, the modified compound of Formula I can utilize ordinary method to collect from the organic phase of separating.
Chemical formula R 1The compound of WLG is commercially available, perhaps can be by method preparation well known in the art.For example, for the compound for preparing Formula I (R wherein 1For replaced the De oxazole by the phenyl of optional replacement), (it is chemical formula R to synthetic compound from chemical formula (4) 1The compound of WLG, wherein R 1Be 1 of optional replacement, 3-oxazole, W are methylene radical) beginning, and LG is Cl, it prepares shown in the reaction scheme VII.
Reaction scheme VII
Figure BPA00001185905000392
Wherein R is the phenyl of optional replacement.
Usually, make 1,3-Dichloro acetone (a) reacts with the benzamide derivatives of the suitable replacement of chemical formula (b) (wherein R is the phenyl of optional replacement).Under about 100-140 ℃ temperature, reacted about 1-6 hour.When reaction is finished basically, come the compound of separation chemistry formula (4) by conventional methods, for example by flash chromatography on silica gel or from the inert solvent recrystallize.
Then, as shown in above reaction scheme I, make compound (Daidzein, the commercially available) reaction of the compound and the chemical formula (1) of chemical formula (4), so that the compound of Formula I to be provided.
Similarly, shown in reaction scheme VIII, can prepare chemical formula R 1The compound of WLGl, wherein R 1Be 1,3 of optional replacement, 4-oxadiazole, W are methylene radical, and LG is Cl.
Reaction scheme VIII
Wherein R is the phenyl of optional replacement
Under the organic acid situation that for example acetate exists, the hydrazides of chemical formula (c) commercially available or that prepare by mode well-known in the art is suspended in the 2-chlorine trimethoxy-ethane (d).In microwave oven, under about 140-180 ℃ temperature, mix.When reaction is finished basically, come the compound of separation chemistry formula (4a) by conventional methods.
Similarly, shown in reaction scheme IX, can prepare chemical formula R 1The compound of WLG, wherein R 1Be 1,2 of optional replacement, 4-oxadiazole, W are alkylidene groups, and LG is Cl.
Reaction scheme IX
Figure BPA00001185905000411
Wherein R is the phenyl of optional replacement and R 5Be hydrogen or low alkyl group
Step 1
Usually, for example in the ethanol, make the nitrile (wherein R is the phenyl of optional replacement) and (chemical formula (f) reaction of moisture oxyamine of chemical formula (e) at protonic solvent.Under about 50-100 ℃ temperature, reacted about 2 hours.When reaction is finished basically, come the compound of separation chemistry formula (g) by conventional methods.
Step 2
Make the compound reaction of the compound and the chemical formula (h) of chemical formula (g) then, wherein R 5Be hydrogen or low alkyl group.Under about 50-100 ℃ temperature, reacted about 2 hours.When reaction is finished basically, come the compound of separation chemistry formula (4b) by conventional methods.
Then, shown in above reaction scheme I, make compound (Daidzein, the commercially available) reaction of the compound and the chemical formula (1) of chemical formula (4b), so that the compound of Formula I to be provided.
Replacedly, shown in reaction scheme X, can also prepare chemical formula R 1The compound of WLG, wherein R 1Be 1,2 of optional replacement, 4-oxadiazole, W are alkylidene groups, and LG is Cl.
Reaction scheme X
Wherein R is the phenyl and the R of optional replacement 5Be hydrogen or low alkyl group
Make the compound reaction of the compound and the chemical formula (h ') of chemical formula (g), wherein R 5Be hydrogen or low alkyl group.The compound of chemical formula (h ') is placed suitable solvent such as methylene dichloride and is cooled to about 0 ℃.After 20 to 40 minutes, add the compound of chemical formula (g ') and make linked reaction carry out 1 to 2 hour.Add CBr then 4And Ph 3P also made 4 to 6 hours that dewater other.Remove the solid triphenylphosphine oxide and make remaining solvent evaporation, come the compound of separation chemistry formula (4b) then by conventional methods.
As previously mentioned, shown in above reaction scheme I, make compound (Daidzein, the commercially available) reaction of the compound and the chemical formula (1) of chemical formula (4b) then, so that the compound of Formula I to be provided.
Similarly, shown in reaction scheme XI, can prepare chemical formula R 1The compound of WLG, wherein R 1Shi isoxazole, W are methylene radical, and LG is Cl.
Reaction scheme XI
Figure BPA00001185905000421
Usually, under the alkali situation that for example triethylamine exists, for example in the tetrahydrofuran (THF), make the acetylene-derivative (wherein R is the phenyl of optional replacement) and chloro glyoxylic acid oxime ethyl ester (chemical formula (j)) reaction of chemical formula (i) at inert solvent.Make under the temperature that is reflected at about 0-25 ℃ about 10-24 hour.When reaction is finished basically, come the compound of separation chemistry formula (k) by conventional methods.
Step 2
Usually, for example in the ethanol, make the ester derivative (wherein R is the phenyl of optional replacement) and for example sodium borohydride reaction of reductive agent of chemical formula (k) at protonic solvent.Originally under about 0 ℃ temperature, react, at room temperature reacted then about 1-2 hour.When reaction is finished basically, come the compound of separation chemistry formula (1) by conventional methods.
Step 3
Usually, under the situation that triphenylphosphine exists, make the hydroxymethyl derivative (wherein R is the phenyl of optional replacement) and for example carbon tetrabromide reaction of bromizating agent of chemical formula (1).Make and be reflected under about 0 ℃ temperature about 1-2 hour.When reaction is finished basically, come the compound of separation chemistry formula (4c) by conventional methods.
The interchangeable method of the compound of preparation Formula I is shown among the reaction scheme XII.
Reaction scheme XII
Figure BPA00001185905000431
Chemical formula 1
Step 1
Usually, under the situation that sodium iodide and weak base (for example salt of wormwood) exist, at polar solvent N for example, in the dinethylformamide, make the compound of chemical formula (5), 7-hydroxyl-3-iodobenzene and pyrans-4-ketone is with chemical formula R 1The compound reaction of WLG, wherein LG is leavings group such as halogen or tosylate.Under about 40-80 ℃ temperature, reacted about 1 hour or can at room temperature react the longer time 2 to 24 hours.When reaction is finished basically, come the compound of separation chemistry formula (6) by conventional methods, for example by flash chromatography on silica gel or from the inert solvent recrystallize.
Step 2
Then, make the compound of chemical formula (6) and the acid reaction of chemical formula (7), it is commercially available or prepares by mode well known in the art.Usually, under the situation of tetra-triphenylphosphine palladium and the existence of aqueous carbonic acid sodium, for example react in the Methylal(dimethoxymethane) at inert solvent.Under about 60-100 ℃ temperature, reacted about 1 hour.When reaction is finished basically, come the compound of separation chemistry formula I by conventional methods, for example by flash chromatography on silica gel or from the inert solvent recrystallize.
As those of ordinary skills be will be obvious that, the compound of chemical formula (7) can be at first and the compound reaction of chemical formula (5), with the compound of the chemical formula (5a) that produces expectation as follows:
Figure BPA00001185905000441
Can make itself and aforesaid chemical formula R then 1The compound reaction of WX.
A kind of method for preparing starting raw material 3-iodo-7-methoxyl group benzo pyrans-4-ketone has been shown in reaction scheme XIII.
Reaction scheme XIII
Figure BPA00001185905000442
Step 1
Usually, make compound 1-(2-hydroxyl-4-p-methoxy-phenyl) second-1-ketone and the N of chemical formula (8), the dimethylacetal reaction of dinethylformamide.Under about 50-100 ℃ temperature, reacted about 2 hours.When reaction is finished basically, come the compound of separation chemistry formula (9) by conventional methods, for example by filtering-depositing product 3-(dimethylamino)-1-(2-hydroxyl-4-p-methoxy-phenyl) third-2-alkene-1-ketone.
Step 2
Then, under the situation that silica gel exists, for example in the chloroform, the compound of chemical formula (9) and N-iodosuccinimide are reacted at inert solvent.Under about 0 ℃ temperature, reacted about 1 hour.When reaction is finished basically, come the compound 3-iodo-7-methoxyl group benzo pyrans-4-ketone of separation chemistry formula (5a) by conventional methods, for example, wash solid, and remove and desolvate with chloroform by leaching silica gel.
Step 3
Make the compound and the boron tribromide reaction of chemical formula (5a) then, so that methoxy group is changed into oh group.Usually, the compound dissolution of chemical formula (5a), is cooled to-80 ℃ approximately, and reacted about 1 hour with boron tribromide for example in the chloroform at inert solvent.Then with mixture heating up to about room temperature, and stir about 2-5 days.When reaction is finished basically, come the compound 3-iodo-7-hydroxy benzo pyrans-4-ketone of separation chemistry formula (5) by conventional methods.
Those skilled in the art will understand, before the compound of Formula I final synthetic, and can be with different Q 1And Q 2Linking group joins R 1In the compound of WX reactant or chemical formula (6).Such alkylation techniques is that those of ordinary skills understand and will will be conspicuous.Similarly, after the compound of synthetic chemistry formula I, be used for changing subsequently R 1, R 2, or R 3Substituent method also is that those of ordinary skill is with conspicuous.
For example, a kind of method for preparing compound has been shown, wherein Q in reaction scheme XIX 1Be that methylene radical, T are NH and Q 2Be ethylidene:
Reaction scheme XIX
Figure BPA00001185905000461
Step 1
The compound dissolution of commercially available chemical formula (1) for example in the acetone, is added aqueous bases, for example 2N potassium hydroxide at inert solvent then.Make the chemical formula X of mixture and about equimolar amount then 1Q 2X 2Compound reaction, X wherein 1And X 2Be iodo, bromo or chloro independently.Under about reflux temperature, make the about 1-5 of mixture reaction days.Evaporating solvent and utilize ordinary method such as the column chromatography purification resistates then is to provide the compound of chemical formula (10).
Step 2
In inert solvent such as DMF, make the compound and the chemical formula R of chemical formula (10) 1Q 1-NH 2Compound reaction.Make to be reflected at and carry out 12 to 48 hours under about 50 ℃ to 80 ℃ temperature.When reaction is finished basically, come the compound of separation chemistry formula I by conventional methods, for example by solvent evaporation, then carry out TLC.
To understand as those of ordinary skills, can change such reaction, make according to the Q of the method for describing in the step 2 with change 1Linking group joins suitable halogenated R 1In the derivative, so that chemical formula R to be provided 1-Q 1The compound of-X.
In the another kind of modification of synthetic, the Q of expectation 1And/or Q 2The epoxyethane derivative of linking group can be used for the compound of production Formula I, and one of them or two Q partly are that hydroxyl replaces.For example, a kind of method for preparing compound has been shown, wherein Q in reaction scheme XX 1Be methylene radical, T is NH, and Q 2Be the 2-hydroxy propylidene:
Reaction scheme XX
Figure BPA00001185905000471
In suitable solvent such as DMF, make compound and the Epicholorohydrin and the K of chemical formula (5 ') 2CO 3Reaction.Make and be reflected at 60 ℃ and to the temperature of 90 ℃ of scopes, carried out 1 to 6 hour.When reaction is finished basically, desolvate by evaporating to remove, and by using H 2O handles from the compound of residue collection as sedimentary chemical formula (11).Can come the collecting precipitation thing by conventional methods, for example by flash chromatography method on silica gel or from the inert solvent recrystallize.
Step 2
Make the compound of chemical formula (11) and the R of expectation then 1Q 1The R of segmental aminoderivative as shown in reaction scheme X 1The reaction of methylamino compound.With reactants dissolved in protonic solvent such as ethanol and add the alkali such as the DIPEA (N, N '-diisopropylethylamine) of catalytic amount.Can react by under 70 ℃ to 85 ℃ temperature, stirring yesterday.When reaction when finishing basically, desolvate and by conventional methods as silica gel column chromatography by evaporating to remove, follow from the inert solvent recrystallize and collect compound with the purifying Formula I.
T is under the situation of compound of covalent linkage therein, the compound of chemical formula (11) can with the R of expectation 1Q 1Segmental magnesium bromide derivatives reaction.In such reaction, the magnesium bromide derivative is slowly joined in cooling (60 ℃ to-30 ℃) solution of CuI in THF.In this solution, slowly be added in the compound of the chemical formula (11) among the THF then.-60 ℃ to-30 ℃ following stirred reaction mixtures 1 to 2 hour, use saturated NH then 4The Cl aqueous solution and H 2The O quenching, and extract with EtOAc.Further wash organic layer with salt solution, use Na then 2SO 4Dry also evaporation in a vacuum.Then, by conventional methods as pre--TLC collect compound with the purifying Formula I.
Application, test and administration
The general application
The compound of Formula I handle giving in the illness that the ALDH-2 inhibitor reacts normally effective.Particularly, the compound of Formula I can be used for handling the habituation of the Dopamine HCL-generation agent to habituation, as, for example, Cocaine, opium, Amphetamine, Nicotine and alcohol.
Though do not wish to be bound by theory, think that the ALDH-2 inhibitor is being effectively aspect the processing habituation, this is the ability owing to the dopamine level of their normalizing increase relevant with various Addictive Behaviors.Referring to, N.D.Volkow et al., Dopamine in drug abuse and addiction:results from imaging studies and treatment implications, Mol.Psychiatry 9 (2004), pp.557-569; With B.J.Everitt and M.E.Wolf, Psychomotor stimulant addiction:a neural systems perspective, J.Neurosci.22 (2002), pp.3312-3320.
Consider the mechanism of action of this proposal, believe that the compound of ALDH-2 inhibitor such as Formula I will be used to handle all habituation relevant with the dopamine level that increases and compulsive behavior and neuroscience illness (situation).Such behavior and illness include, but not limited to compulsive gambling, overeating and shopping, persistent compulsive disorder (OCD), schizophrenia, attention deficit hyperactivity disorder etc.
Test
As in the patent quoted in the above and the patent application and described in following examples, and the method by it will be apparent to those skilled in the art, carry out active testing.For example, as at " The Mitrochondrial Monoamine Oxidase-Aldehyde Dehydrogenase Pathway:A Potential Site of Action of Daidzin ", J.Med.Chem.2000,43, described in the 4169-4179.Usually, the compound of analytical chemistry formula I determines that as enzyme source separately they are independently to the influence of MAO and ALDH-2 with the film of the plastosome preparation that uses the density gradient purifying and lysate.The result is with the IC50 value representation.
Pharmaceutical composition
The compound of Formula I gives with the form of pharmaceutical composition usually.Therefore, the invention provides pharmaceutical composition, described pharmaceutical composition comprises as the compound of one or more Formula I of active ingredient or its medicinal salt or ester, and one or more pharmaceutical excipients, carrier (comprising inert solid diluent and filler), thinner (comprising aseptic aqueous solution and various organic solvent), penetration enhancers, solubilizing agent and adjuvant.Can make up the compound that gives Formula I separately or with other therapeutical agent.Such composition is prepared (referring to for example in well-known mode in the pharmacy field, Remington ' s Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, PA 17th Ed. (1985) and " Modern Pharmaceutics ", Marcel Dekker, Inc.3rd Ed. (G.S.Banker﹠amp; C.T.Rhodes, Eds.).
Administration
The compound of Formula I can give with single dose or multiple doses by any acceptable mode of administration with similar effectiveness, for example, as at those with described in way of reference bonded patent and the patent application, comprise in rectum, oral cavity, the nose and through the skin approach,, intramuscular outer, subcutaneous, oral, topical administration by intra-arterial injection, intravenously, intraperitoneal, gi tract, as inhalation, perhaps pass through dipping or apparatus for coating such as support, for example, or the cylindrical polymeric of inserting artery give.
A kind of pattern that is used for administration is outside the intestines, especially by injection.Novel cpd of the present invention can be incorporated into the form that wherein is used for by drug administration by injection and comprise moisture or oil suspension agent or emulsion, adopts sesame oil, Semen Maydis oil, oleum gossypii seminis or peanut oil and elixir, N.F,USP MANNITOL, dextrose or aseptic aqueous solution and similar pharmaceutical carrier.The aqueous solution in salt solution also routine is used for injection, but is less preferred within the scope of the invention.Also can adopt ethanol, glycerine, propylene glycol, liquid macrogol etc. (with and suitable mixture), cyclodextrin derivative and vegetables oil.Can be for example by use coating (as lecithin), under the situation of dispersion system by keeping needed granular size and by using tensio-active agent to keep suitable flowability.Can pass through various antimicrobial drugs and antifungal drug, for example, parabens, chlorobutanol, phenol, Sorbic Acid, Thiomersalate wait to reach and prevent action of microorganisms.
Compound by adding the Formula I of aequum in appropriate solvent (when needs time, have various other components of enumerating as above), then filtration sterilization prepares aseptic injectable solution.Usually, prepare dispersion system in the sterile carrier by various active ingredients through sterilization are joined, wherein sterile carrier comprises basic dispersion medium and needed from above other component of enumerating.Be used to prepare under the situation of sterile injectable solution at sterilized powder, preferred manufacturing procedure is vacuum-drying and Freeze Drying Technique, and it produces activeconstituents and from the powder (powder) of any extra desired constituents of the solution of previous its sterile filtration.
Oral administration is the another kind of approach that is used to give the compound of Formula I.Administration can be by means of capsule or enteric coated tablet etc.When preparation comprised the pharmaceutical composition of compound of at least a Formula I, active ingredient was diluted with vehicle usually and/or is encapsulated in such carrier, and it can be the form of capsule, sachet, paper or other container.When vehicle was used as thinner, it can be solid, semisolid or fluent material (as above-mentioned), and it can be used as vehicle, carrier or the medium that is used for active ingredient.Therefore, composition can have following form: tablet, pill, powder, lozenge, sachet, cachet, elixir, suspensoid, emulsion, solution, syrup, aerosol (as solid or in liquid medium), for example comprise by weight ointment, soft hard capsule, aseptic injectable solution and sterile packed powder up to 10% active compound.
Some examples of suitable vehicle comprise lactose, dextrose, sucrose, sorbyl alcohol, N.F,USP MANNITOL, starch, Sudan Gum-arabic, calcium phosphate, alginate, tragacanth gum, gelatin, Calucium Silicate powder, Microcrystalline Cellulose, polyvinylpyrrolidone, Mierocrystalline cellulose, sterilized water, syrup and methylcellulose gum.Described preparation can comprise in addition: lubricant such as talcum, Magnesium Stearate and mineral oil; Wetting agent; Emulsification and suspension agent; Sanitas such as methyl hydroxybenzoate and Propyl Hydroxybenzoate; Sweeting agent; And sweetener.
By adopting step known in the art, can prepare composition of the present invention, so that giving quick, the lasting or delay release that the patient provides active ingredient later on.The controlled release-drug delivery system that is used for oral administration comprises osmotic pump system and the dissolution system that contains polymer-coated storage capsule or drug-polymer matrix formulation.At United States Patent (USP) the 3rd, 845, No. 770, the 4th, 326, No. 525, the 4th, No. 902514 and the 5th, 616, provided the example of controlled release system in No. 345.The another kind of formulation that is used for method of the present invention has adopted transdermal delivery device (" patch ").Such transdermal patch can be used for providing with controlled quatity the continuous or discontinuous infusion of compound of the present invention.The structure and the application that are used for the transdermal patch of delivering drugs reagent are well-known in the art.Referring to, for example, United States Patent (USP) the 5th, 023, No. 252, the 4th, 992, No. 445 and the 5th, 001, No. 139.Can construct such patch be used for continuously, pulsation or delivering drugs reagent as required.
These compositions preferably are formulated into unit dosage.Term " unit dosage " is meant dispersive unit physically, it is suitable as and is used for people experimenter and other mammiferous unitary dose, each unit comprises the active substance that produces the desired therapeutic effect that calculates of predetermined amount, and suitable drug excipient (for example, tablet, capsule, injection (ampulla)).The compound of Formula I is effectively and usually to give with medicine effective quantity in wide dosage range.Preferably, for oral administration, each dose unit comprises the compound of the Formula I of 10mg to 2g, and more preferably 10 to 700mg, and for the intestines external administration, the compound of preferred 10 to 700mg Formula I, more preferably from about 50-200mg.Yet, be to be understood that, the amount of the compound of the actual Formula I that gives will be determined according to relevant situation by the doctor, comprise the illness that to treat, the route of administration of selecting, the pragmatize compound that gives with and relative reactivity, the age of individual patient, body weight and reaction, the seriousness of patient's symptom etc.
In order to prepare solids composition such as tablet, main active ingredient is mixed the solid preformulation composition that comprises the homogeneous mixture of compound of the present invention with formation with drug excipient.When mentioning that these preformulation composition are equal phase time, it is meant that active ingredient is dispersed in the whole composition, makes composition can easily be subdivided into equal effectively unit dosage such as tablet, pill and capsule.
Tablet of the present invention or pill can be applied or otherwise by compound so that the formulation of the advantage with prolongation effect to be provided, or be protected from the acidic conditions of stomach.For example, tablet or pill can comprise internal dose and outside dose components, and the latter has the form of the tunicle on the former.Can separate this two kinds of compositions by enteric layer, wherein enteric layer is used for stoping disintegration under one's belt and allows internal component to enter duodenum intactly or be delayed release.Various materials can be used for such enteric layer or coating, and such material comprises many polymer acids and polymer acid and the such material such as the mixture of shellac, hexadecanol and cellulose acetate.
The composition that is used for inhalation (inhalation) or insufflation (insufflation) is included in the solution and the suspension of medicinal water solvent or organic solvent or its mixture and powder.The liquid or solid composition can comprise suitable pharmaceutical excipient as indicated above.Preferably, give these compositions to obtain part or systemic effect by oral or nasal respiration approach.Can be by using atomize composition in preferred medicinal solvent of rare gas element.Can directly suck atomized soln, or atomisation unit can be connected in face shield curtain account or intermittent positive pressure breathing machine from atomisation unit.Can be from sending the device of formulation by rights, preferred per os or intranasal give solution, suspensoid or powder composite.
Comprise that following examples are to illustrate preferred implementation of the present invention.It should be understood by those skilled in the art that the technology that discloses represents the technology that is worked well in enforcement of the present invention being used for of finding by the contriver in embodiment subsequently, therefore can be considered to be configured for the optimal way of its enforcement.Yet, according to disclosure content of the present invention, it should be understood by those skilled in the art that under situation without departing from the spirit and scope of the present invention, can carry out many variations and still obtain identical or similar result disclosed embodiment.
Embodiment 1
The preparation of the compound of chemical formula R1WX
A. the preparation of the compound of chemical formula (4), wherein R is a phenyl
Figure BPA00001185905000521
(compound of chemical formula (b), 363.4mg is 3.0mmol) with 1.3-Dichloro acetone (457.1mg, 3.6mmol, 1.2 equivalents) to make the 50mL round-bottomed flask that is equipped with condenser be mounted with benzamide.This mixture of heating is 1 hour under nitrogen atmosphere, under 130 ℃.After being cooled to room temperature, by come the mixture of purifying gained from acetonitrile (6mL) recrystallize.Under the back flow reaction condition, add hot suspension 5 minutes, and be cooled to envrionment temperature then.Filter the solid of gained by glass filter, and with the crystal on acetonitrile (2mL) washing filter.Obtained product, 4-(chloromethyl)-2-phenyl-1,3-oxazole as the expectation of colourless powder.
B. The preparation of other compound of chemical formula (4a), wherein R is a phenyl
Similarly,, but replace benzamide, prepared chemical formula R with other compound of chemical formula (b) according to the step of embodiment 1A 1Other compound of WLG.For example:
4-(chloromethyl)-2-[5-fluoro-3-(trifluoromethyl) phenyl]-1, the 3-oxazole;
2-(3, the 5-difluorophenyl)-4-(chloromethyl)-1, the 3-oxazole;
2-(3, the 4-difluorophenyl)-4-(chloromethyl)-1, the 3-oxazole;
4-(chloromethyl)-2-(4-fluorophenyl)-1, the 3-oxazole;
4-(chloromethyl)-2-(4-chloro-phenyl-)-1, the 3-oxazole;
4-(chloromethyl)-2-[3-(trifluoromethyl) phenyl]-1, the 3-oxazole; And
4-(chloromethyl)-2-(3,4, the 5-trifluorophenyl)-1, the 3-oxazole.
C. The preparation of the compound of chemical formula (4a), wherein R is the 4-fluorophenyl
Figure BPA00001185905000531
(0.3g 2mmol) is suspended in chloro-1,1, in the 1-trimethoxy-ethane (2ml) with 4-fluorobenzene carbohydrazide.Add acetate (1ml) to this suspension, and under 160 ℃ in microwave oven heated solution 30 minutes.Under reduced pressure remove and desolvate, and utilize Biotage, come the purifying residue with 20% ethyl acetate/hexane elution, so that 5-(chloromethyl)-3-(4-fluorophenyl)-1,2 to be provided, 4-oxadiazole, productive rate are 89%.
D. The preparation of the compound of chemical formula (4b), wherein R is a 5-fluoro-3-trifluoromethyl And R 5 It is methyl
Step 1
To 5-fluoro-3-(trifluoromethyl) cyanobenzene (15.0g, 79.3mmol) add in the solution in ethanol (30ml) solution of 50% azanol in water (10ml, 151.5mmol), then at 80 ℃ of mixtures 2 hours of heating gained down.Mixture is cooled to room temperature, under reduced pressure removes and desolvate, add the water of 30ml then.Supersound process suspension, and leach solid, (2 * 20ml) washings, and drying under reduced pressure are to provide [5-fluoro-3-(trifluoromethyl)-phenyl] (oxyimino) methylamine as white solid for water.MS223.1(M+H)。
Step 2
To [5-fluoro-3-(trifluoromethyl) phenyl] (oxyimino)-methylamine (8.884g, 40mmol) at anhydrous methylene chloride/N, add 2-chlorpromazine chloride (6.0ml in the solution in the mixture of dinethylformamide (60/20ml), 58.7mmol) and diisopropylethylamine (14.0ml, 80.3mmol), at room temperature stirred the mixture then two hours.The mixture overnight that refluxes under condition of stirring then is cooled to room temperature, and under reduced pressure removes and desolvate.At ground, vacuum lower section distillation leftover, and be retained in ebullient part under the 95-105 ℃/0.8-1.0mm Hg, so that 5-(chloroethyl)-3-[5-fluoro-3-(trifluoromethyl) phenyl as yellow oil to be provided]-1,2,4-oxadiazole, MS 295.1 (M+H).
Replacedly, can be by flash chromatography on silica gel, come purified product with ethyl acetate/hexane (1/4) elution.
E. The preparation of the compound of chemical formula (4c), wherein R is the 3-trifluoromethyl
Step 1- The preparation of the compound of chemical formula (k)
Chloro glyoxylic acid oxime ethyl ester in ice bath (6.68g, 44.09mmol) slowly add in the stirred solution in tetrahydrofuran (THF) (90mL) 3-(trifluoromethyl) phenylacetylene (5.0g, 29.39mmol), then drip triethylamine (8.19mL, 58.78mmol).At room temperature stir the mixture overnight of gained, it is subsequently by passing through layer of silica gel (top) and anhydrous Na then 2SO 4Filter (bottom), and wash with ethyl acetate.Wash filtrate with water, use the dried over sodium sulfate organic layer, under reduced pressure remove then and desolvate.By silica gel column chromatography (ethyl acetate: hexane=1: 9) come the purifying residue, so that 5-[3-(trifluoromethyl) phenyl] isoxazole-3-carboxylic acid, ethyl ester to be provided.
Similarly, preparation 5-(2-pyridyl) isoxazole-3-carboxylic acid, ethyl ester.
Step 2- The preparation of the compound of chemical formula (1)
5-[3-in ice bath (trifluoromethyl) phenyl] isoxazole-3-carboxylic acid, ethyl ester (2g, 7mmol) portion-wise addition sodium borohydride in the stirred solution in ethanol (70mL) (1.06g, 28mmol).At room temperature stir the mixture 1.5 hours of gained, use the saturated aqueous ammonium chloride quenching then.Under reduced pressure from mixture, remove and desolvate, and be dissolved in residue in the ethyl acetate and wash with water.Use the dried over sodium sulfate organic layer then, and under reduced pressure remove and desolvate.By silica gel column chromatography (ethyl acetate: hexane=2: 3) come the purifying residue so that { 5-[3-(trifluoromethyl) phenyl] isoxazole-3-base } first-1-alcohol to be provided.
Similarly, preparation (5-(2-pyridyl) isoxazole-3-base) first-1-alcohol.
Step 3- The preparation of the compound of chemical formula (4c)
Under 0 ℃ to { 5-[3-(trifluoromethyl) phenyl] isoxazole-3-base } first-1-alcohol (0.28g, 1.15mmol) and carbon tetrabromide (0.5g, 1.5mmol) drip triphenylphosphine (0.41g, 1.58mmol) solution in methylene dichloride (5mL) in the stirred suspension in methylene dichloride (10mL).In 0 ℃ of mixture that stirs down gained 1 hour, then reaction mixture is poured into ethyl acetate and hexane (ethyl acetate: hexane=1: 4,50mL) in.Filter the suspension of gained by thin layer silica gel, and with ethyl acetate and hexane (ethyl acetate: washing hexane=1: 4).Concentrated filtrate under reduced pressure, and by silica gel column chromatography (ethyl acetate: hexane=1: 4) come the purifying residue, so that 3-(brooethyl)-5-[3-(trifluoromethyl) phenyl] isoxazole to be provided.
Similarly, preparation 3-(chloromethyl)-5-(2-pyridyl) isoxazole.
Embodiment 2
The preparation of the compound of chemical formula (5)
Figure BPA00001185905000561
Step 1- The preparation of the compound of chemical formula (9)
90 ℃ stir down 1-(2-hydroxyl-4-p-methoxy-phenyl) second-1-ketone (20g, 120mmol) and N, dinethylformamide dimethylacetal (23g, mixture 181mmol) 2 hours.After being cooled to room temperature, reaction mixture provides yellow mercury oxide, with ethyl acetate (3 * 30ml), (2 * 50ml) wash this throw out to water, drying under reduced pressure then is to produce 3-(dimethylamino)-1-(2-hydroxyl-4-p-methoxy-phenyl) third-2-alkene-1-ketone (9) as trans-isomer(ide); MS 222.1 (M+H).
Step 2- The preparation of the compound of chemical formula (5)
Under 0 ℃ to 3-(dimethylamino)-1-(2-hydroxyl-4-p-methoxy-phenyl) third-2-alkene-1-ketone (20.0g, 90.37mmol) add in the solution in anhydrous chloroform (100ml) N-iodosuccinimide (23.5g, 99.22mmol) and silica gel (40g).0 ℃ of following stirred reaction mixture 60 minutes, leach insoluble substance then.With moisture Sulfothiorine (0.5M, 2 * 50ml), then, use dried over sodium sulfate then with salt solution (100ml) wash filtrate.Under reduced pressure remove and desolvate, so that orange solids to be provided.Add methyl alcohol (30ml) in this solid, and the supersound process mixture, filter, (2 * 5ml) washing solids, drying under reduced pressure solid then is to produce the 3-iodo-7-methoxyl group benzo pyrans-4-ketone as light yellow solid with methyl alcohol.
(9.36g 30.98mmol) is dissolved in the anhydrous chloroform (10ml), and is cooled to-78 ℃ with this product.(90ml, 90mmol) the 1.0M solution in stirred the mixture under-78 ℃ 1 hour then at methylene dichloride to add boron tribromide in this solution.Make mixture heating up to room temperature, and stirred 4 days.Mixture is poured in the water (200ml) then, and is leached brown solid, water (4 * 100ml) and chloroform (3 * 20ml) washing.Concentrated filtrate under reduced pressure, producing yellow gel, to wherein adding methylene dichloride (20ml), and the supersound process mixture.Obtain light yellow solid, and leach, (2 * 5ml) washings, drying under reduced pressure then is to provide 7-hydroxyl-3-iodobenzene and pyrans-4-ketone with methylene dichloride.
Embodiment 3
The preparation of the compound of Formula I
Step 1. The preparation of the compound of chemical formula (6), wherein R 1 Be 4-methyl-2-[4-(three Methyl fluoride) phenyl] (1,3-thiazoles-5-yl), and W is a methylene radical
Figure BPA00001185905000571
Under room temperature and nitrogen, with 7-hydroxyl-3-iodobenzene and pyrans-4-ketone (864mg, 3.0mmol), 5-(chloromethyl)-4-methyl-2-(4-(trifluoromethyl) phenyl) thiazole) (875mg, 3.0mmol), sodium iodide (450mg, 3.0mmol) and salt of wormwood (552mg, 4.0mmol) mixture be dissolved in N, in the dinethylformamide (10ml).60 ℃ of following heated mixt 1 hour, be cooled to room temperature, then water (30ml) is joined in the mixture.(3 * 30ml) extract aqueous mixture, and with the organic layer that salt solution (30ml) washing merges, use dried over sodium sulfate, under reduced pressure remove from filtrate then and desolvate with methylene dichloride.Crude product provides 3-iodo-7-({ 4-methyl-2-[4-(trifluoromethyl) phenyl] (1,3-thiazoles-5-yl) } methoxyl group) chromene-4-ketone, the compound of chemical formula (6) from the crystallization of ethyl acetate (4ml).
Step 2- The preparation of the compound of Formula I, wherein R 1 Be phenyl (1,3-thiazoles-5- Base), R 2 Be 4-sulfonyloxy methyl amine, R 3 Be hydrogen, V is an oxygen, and X, Y and Z be-CH-, And W is a methylene radical
Figure BPA00001185905000581
To 3-iodo-7-(4-methyl-2-[4-(trifluoromethyl) phenyl] (1; 3-thiazole-5-yl) } chromene-4-ketone (55.0mg methoxyl group); 0.10mmol), 4-(dihydroxyl boron)-(methylsulfonyl) aniline (22.5mg; 0.15mmol), two-(triphenylphosphine) palladium chloride (II) (3.5mg; 0.005mmol) mixture in add glycol dimethyl ether (2ml) and aqueous sodium carbonate (2M; 0.1ml, 2 equivalents).Reflux described mixture 1 hour is cooled to envrionment temperature, filters by diatomite (3g), and washs diatomite with ethyl acetate (50ml).With salt solution (30ml) wash filtrate, and use dried over sodium sulfate.Under reduced pressure remove and desolvate; and on silica gel the chromatography residue; with ethyl acetate/hexane 50/1 elution; afterwards from ethyl acetate (3ml) crystallized product; so that the 3-{4-[(methylsulfonyl to be provided) amino] phenyl }-7-(2-[4-(trifluoromethyl) phenyl] (1,3-thiazoles-5-yl) } methoxyl group) chromene-4-ketone.
B.
Similarly, the following compound that has prepared Formula I:
4-[7-(5-[3-fluoro-5-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group)-4-oxo chromene-3-yl] cyanobenzene;
4-[7-(4-methyl-2-[4-(trifluoromethyl) phenyl] (1,3-thiazoles-5-yl) } methoxyl group)-4-oxo chromene-3-yl] ethyl benzoate;
7-(3-[5-fluoro-3-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-5-yl) } oxyethyl group)-3-(4-hydroxyphenyl) chromene-4-ketone;
3-[7-(5-[3-fluoro-5-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group)-4-oxo chromene-3-yl] ethyl benzoate;
The 3-{4-[(methylsulfonyl) amino] phenyl }-7-(4-methyl-2-[4-(trifluoromethyl) phenyl] (1,3-thiazoles-5-yl) } methoxyl group) chromene-4-ketone;
4-[7-(4-methyl-2-[4-(trifluoromethyl) phenyl] (1,3-thiazoles-5-yl) } methoxyl group)-4-oxo chromene-3-yl] methyl benzoate;
3-(2H, 3H-benzo [e] 1,4-diox-6-yl)-7-(5-[3-fluoro-5-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group) chromene-4-ketone;
7-(5-[3-fluoro-5-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group)-3-(6-methoxyl group (3-pyridyl)) chromene-4-ketone;
3-(4-hydroxyphenyl)-7-(4-methyl-2-[4-(trifluoromethyl) phenyl] (1,3-thiazoles-5-yl) } methoxyl group) chromene-4-ketone;
7-(5-[3-fluoro-5-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group)-3-(4-{[(4-aminomethyl phenyl) alkylsulfonyl] amino } phenyl) chromene-4-ketone;
3-(4-{[(4-aminomethyl phenyl) alkylsulfonyl] amino } phenyl)-7-(4-methyl-2-[4-(trifluoromethyl) phenyl] (1,3-thiazoles-5-yl) } methoxyl group) chromene-4-ketone;
3-{[3-(6-methoxyl group (3-pyridyl))-4-oxo chromene-7-base oxygen base] methyl } methyl benzoate;
3-(3-[4-(methylol) phenyl]-4-oxo chromene-7-base oxygen base } methyl) methyl benzoate;
7-(5-[3-fluoro-5-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group)-3-[4-(methylol) phenyl] chromene-4-ketone;
4-[7-(5-[3-fluoro-5-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group)-4-oxo chromene-3-yl] phenylformic acid;
7-(5-[3-fluoro-5-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group)-3-(4-morpholine-4-base phenyl) chromene-4-ketone;
7-(5-methyl-2-[4-(trifluoromethyl) phenyl] (1,3-thiazoles-4-yl) } methoxyl group)-3-(4-morpholine-4-base phenyl) chromene-4-ketone;
7-(3-[5-fluoro-3-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-5-yl) } methoxyl group)-the 3-{4-[(methylsulfonyl) amino] phenyl } chromene-4-ketone;
2-fluoro-5-[7-(5-[5-fluoro-3-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group)-4-oxo chromene-3-yl] cyanobenzene;
2-(3-{4-[(ethoxycarbonyl) methoxyl group] phenyl }-4-oxo chromene-7-base oxygen base) ethyl acetate;
7-{[5-(4-fluorophenyl) (1,2,4-oxadiazole-3-yl)] methoxyl group }-3-(4-hydroxyphenyl) chromene-4-ketone;
3-[7-(5-[5-fluoro-3-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group)-4-oxo chromene-3-yl] cyanobenzene;
3-(3-acetylphenyl)-7-(5-[5-fluoro-3-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group) chromene-4-ketone;
7-(5-[5-fluoro-3-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group)-the 3-{4-[(methylsulfonyl) amino] phenyl } chromene-4-ketone;
4-[7-(5-[5-fluoro-3-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group)-4-oxo chromene-3-yl] benzamide;
3-[2,4-two (tert.-butoxy) pyrimidine-5-yl]-7-(5-[5-fluoro-3-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group) chromene-4-ketone; And
5-[7-(5-[5-fluoro-3-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group)-4-oxo chromene-3-yl]-1,3-dihydro-pyrimidin-2,4-diketone.
Embodiment 4
The preparation of the compound of Formula I
A. The preparation of the compound of Formula I, wherein R 1 Be 2-[5-fluoro-3-(trifluoromethyl) Phenyl]-1,3-oxazole, R 2 Be the 4-hydroxyl, R 3 Be hydrogen, X, Y and Z are-CH-that V is Oxygen, and W is a methylene radical
Figure BPA00001185905000611
With 4 ', 7-dihydroxy isoflavone (101.7mg, 0.40mmol), as 4-(chloromethyl)-2-[5-fluoro-3-(trifluoromethyl) phenyl of the preparation in embodiment 1, described]-1,3-oxazole (111.8mg, 0.40mmol, 1.0 equivalents), sodium iodide (59.6mg, 0.40mmol, 1.0 equivalent) and potassium hydroxide powder (22.4mg, 0.4mmol, 1.0 equivalents) place the 25mL flask that is equipped with condenser.Under room temperature and nitrogen, in described flask, add methyl-sulphoxide (3mL).60 ℃ of following heated solutions 1 hour.In mixture, add entry (30mL), use ethyl acetate (30mL * 3) that integral body is extracted then.Wash the organic layer that merges and use Na with salt solution (30mL) 2SO 4Drying is to provide the crude mixture as water white oil (204.7mg).Come the purifying crude mixture by column chromatography (silica gel=25g is with hexane/ethyl acetate=elution in 7: 1), so that the crude product as clear crystal (149.3mg) to be provided.The recrystallize of this crude product provides 7-as colourless powder ({ 2-[5-fluoro-3-(trifluoromethyl) phenyl]-(1,3-oxazole-4-yl) } methoxyl group)-3-(4-hydroxyphenyl) chromene-4-ketone.
B.
Similarly,, replace 4-(chloromethyl)-2-[5-fluoro-3-(trifluoromethyl) phenyl with other compound of chemical formula (4) according to the step of above embodiment 4A]-1, the 3-oxazole has prepared the following compound of Formula I:
3-(4-hydroxyphenyl)-7-(2-[3-(trifluoromethyl) phenyl] (1,3-oxazole-4-yl) } methoxyl group) chromene-4-ketone;
7-(2-[5-fluoro-3-(trifluoromethyl) phenyl] (1,3-oxazole-4-yl) } methoxyl group)-3-(4-hydroxyphenyl) chromene-4-ketone;
3-(4-hydroxyphenyl)-7-{[2-(3,4, the 5-trifluorophenyl) (1,3-oxazole-4-yl)] methoxyl group } chromene-4-ketone;
7-{[2-(3, the 5-difluorophenyl) (1,3-oxazole-4-yl)] methoxyl group }-3-(4-hydroxyphenyl) chromene-4-ketone;
7-{[2-(3, the 4-difluorophenyl) (1,3-oxazole-4-yl)] methoxyl group }-3-(4-hydroxyphenyl) chromene-4-ketone;
7-{[2-(4-fluorophenyl) (1,3-oxazole-4-yl)] methoxyl group }-3-(4-hydroxyphenyl) chromene-4-ketone; And
7-{[2-(4-chloro-phenyl-) (1,3-oxazole-4-yl)] methoxyl group }-3-(4-hydroxyphenyl) chromene-4-ketone.
Embodiment 5
The preparation of the compound of Formula I
A. The preparation of the compound of Formula I, wherein R 1 It is 3-(trifluoromethyl)-phenyl [1,2,4] oxadiazole bases, R 2 Be the 4-hydroxyl, R 3 Be hydrogen, X, Y and Z are-CH-that V is Oxygen, and W is a methylene radical
Figure BPA00001185905000621
Under 80 ℃, under the argon gas under condition of stirring, heating Daidzein (100mg, 0.4mmol), 3-chloromethyl-5-(3-trifluoromethyl (phenyl [1,2,4] oxadiazole (108mg, 0.41mmol) and salt of wormwood (0.63mg, 0.45mmol) at anhydrous N, the mixture in the dinethylformamide (2ml) 4.5 hours.After being cooled to room temperature,, and stirred 30 minutes with the water chilled mixture of about 12ml.Leach the throw out of formation, wash with water three times, dry under vacuum then, so that crude product (152mg) to be provided.Chromatography crude product on silica gel with 5% to 50% ethyl acetate/hexane elution, provides pure 3-(4-hydroxyphenyl)-7-({ 5-[3-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group) chromene-4-ketone.
1H?NMR(400MHz，DMSO-d6)δ：9.58(s，1H)，8.48-8.39(m，3H)，8.12(d，1H，J＝8.0Hz)，8.08(d，1H，J＝8.8Hz)，7.92(t，1H，J＝8.8Hz)，7.42-7.38(m，3H)，7.23(d，1H，J＝9.2Hz)，6.82(d，2H，J＝8.8Hz)，5.61(s，2H)。LC/MS analyzes: t R=21.98 minutes (linear gradient B5% → 90%), (ESI) m/z 481.5 (M+H) +
B. The replaceable preparation of the compound of Formula I, wherein R 1 Be 3-(trifluoromethyl) Phenyl [1,2,4] oxadiazole bases, R 2 Be the 4-hydroxyl, R 3 Be hydrogen, X, Y and X be-CH-, V is an oxygen, and W is a methylene radical
To Daidzein (2.0g, 7.87mmol) add in the suspension in acetone (80ml) the 2N aqueous potassium hydroxide (3.94ml, 7.87mmol), and supersound process mixture several minutes.In this mixture, add 3-chloromethyl-5-(3-trifluoromethyl)-[1,2,4] oxadiazoles (and 2.17g, 8.26mmol), and reaction mixture refluxed 3 days.Enriched mixture under reduced pressure, and residue is dissolved in the methyl alcohol, mix with silica gel, under reduced pressure remove then and desolvate.By rapid column chromatography, carry out purifying with methylene chloride (95/5 to 90/10) elution, with provide pure 3-(4-hydroxyphenyl)-7-as white solid (5-[3-(trifluoromethyl) phenyl]-(1,2,4-oxadiazole-3-yl) methoxyl group) chromene-4-ketone.
C. The preparation of the compound of Formula I, wherein R 3 Be hydrogen, X, Y and Z be-CH-, And V is an oxygen, changes R 1 And R 2
Similarly, according to the step of above embodiment 5A or 5B, use chemical formula R 1CH 2Other compound of X replaces 3-chloromethyl-5-(3-trifluoromethyl)-[1,2,4] oxadiazole, wherein R 1With X as above-mentioned definition, prepared the following compound of Formula I.
3-{[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] methyl } phenylformic acid; 1HNMR (400MHz, DMSO-d 6) δ: 13.1 (br s, 1H), 9.59 (br s, 1H), 8.38 (s, 1H), 8.08 (s, 1H), 8.05 (d, 1H, J=9.0Hz), 7.94 (d, 1H, J=7.8Hz), 7.75 (d, 1H, J=7.7Hz), 7.56 (dd, 1H, J=7.5Hz, J=7.8Hz), 7.40 (d, 2H, J=8.7Hz), 7.29 (d, 1H, J=1.9Hz), 7.18 (dd, 1H, J=1.9Hz, J=9.0Hz), 6.82 (d, 2H, J=8.7Hz), 5.37 (s, 2H).(ESI)m/z?389(M+H) +。
3-(4-hydroxyphenyl)-7-[(5-phenyl (1,2,4-oxadiazole-3-yl)) methoxyl group] chromene-4-ketone; 1H NMR (300MHz, DMSO-d6) δ: 9.58 (s, 1H), 8.41 (s, 1H), 8.15 (d, 2H, J=7.2Hz), 8.08 (d, 1H, J=9.0Hz), 7.72-7.63 (m, 3H), and 7.42-7.38 (m, 3H), 7.23 (d, 1H, J=9.0Hz), 6.82 (d, 2H, J=8.7Hz), 5.58 (s, 2H).(ESI)m/z413.4(M+H) +。
3-{[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] methyl } cyanobenzene; (ESI) m/z 370 (M+H)+.
3-{[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] methyl } benzamide; 1H NMR (300MHz, DMSO-d 6) δ: 9.56 (s, 1H), 8.41 (s, 1H), 8.35 (d, 2H, J=8.1Hz), 8.09-8.01 (m, 3H), 7.40 (m, 3H), 7.22 (dd, 1H, J=8.8,2.1Hz), 6.82 (d, 2H, J=8.7Hz), 5.61 (s, 2H).(ESI)m/z481.6(M+H) +
3-(4-hydroxyphenyl)-7-{[5-(2-p-methoxy-phenyl) (1,2,4-oxadiazole-3-yl)] methoxyl group } chromene-4-ketone; 1H NMR (400MHz, DMSO-d 6) δ: 9.57 (s, 1H), 8.40 (s, 1H), 8.07 (d, 1H, J=8.8Hz), 8.03 (dd, 1H, J=8.0,1.6Hz), 7.69 (m, 1H), 7.42-7.15 (m, 6H), 6.82 (d, 2H, J=8.4Hz), 5.56 (s, 2H), 3.95 (s, 3H).(ESI)m/z443.3(M+H) +
3-(4-hydroxyphenyl)-7-{[3-(trifluoromethyl) phenyl] methoxyl group } chromene-4-ketone; (K-28-AR-1) 1H NMR (400MHz, DMSO-d 6) δ: 9.55 (s, 1H), 8.39 (s, 1H), 8.06 (d, 1H, J=8.8Hz), 7.89 (s, 1H), 7.84-7.66 (m, 3H), 7.41 (d, 2H, 8.4Hz), 7.29 (s, 1H), 7.20 (d, 1H, J=8.4Hz), 6.82 (d, 2H, J=8.4Hz), 5.40 (s, 2H).(ESI)m/z413(M+H) +。
3-(4-hydroxyphenyl)-7-{[4-methoxyl group-3-(trifluoromethyl) phenyl] methoxyl group } chromene-4-ketone; (DM-K-4-P3); 1H NMR (300MHz, DMSO-d 6) δ: 9.54 (s, 1H), 8.43-8.40 (m, 2H), 8.26 (d, 1H, J=1.8Hz), 8.07 (d, 1H, J=8.9Hz), 7.54 (d, 1H, J=8.9Hz), 7.41 (d, 2H, J=8.7Hz), 7.37 (d, 1H, J=2.4Hz), 7.21 (dd, 1H, J=2.4Hz, J=8.9Hz), 6.82 (d, 2H, J=8.7Hz), 5.56 (s, 2H), 4.03 (s, 3H).(ESI)m/z511(M+H) +
7-{[3-fluoro-5-(trifluoromethyl) phenyl] methoxyl group }-3-(4-hydroxyphenyl) chromene-4-ketone; (DM-K-28-AR-2), (ESI) m/z431 (M+H) +
7-(5-[3-fluoro-5-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group)-3-(4-hydroxyphenyl) chromene-4-ketone; 1H NMR (400MHz, DMSO-d 6) δ: 9.57 (s, 1H), 8.42 (s, 1H), 8.33 (d, 1H, J=8.4Hz), 8.26 (s, 1H), 8.17 (d, 1H, J=8.4Hz), 8.08 (d, 1H, J=8.8Hz), 7.41 (m, 3H), 7.22 (dd, 1H, J=9.2,2.0Hz), 6.82 (d, 2H, J=8.8Hz), 5.62 (s, 2H), (ESI) m/z499 (M+H) +
7-(5-[4-fluoro-3-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group)-3-(4-hydroxyphenyl) chromene-4-ketone; 1H NMR (300MHz, DMSO-d 6) δ: 9.54 (s, 1H), 8.55-8.48 (m, 1H), 8.44-8.40 (m, 2H), 8.07 (d, 1H, J=8.9Hz), 7.83 (dd, 1H, J=9.8Hz, J=9.5Hz), 7.41 (d, 2H, J=8.6Hz), 7.38 (d, 1H, J=2.4Hz), 7.21 (dd, 1H, J=2.4Hz, J=8.9Hz), 6.82 (d, 2H, J=8.6Hz), 5.59 (s, 2H), (ESI) m/z499 (M+H) +
7-(5-[2,5-two (trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group)-3-(4-hydroxyphenyl) chromene-4-ketone; 1H NMR (400MHz, DMSO-d 6) δ: 9.57 (s, 1H), 8.52 (s, 1H), 8.42 (s, 1H), and 8.38-8.31 (m, 2H), 8.08 (d, 1H, J=9.0Hz), 7.41 (d, 2H, 8.7Hz), 7.40 (s, 1H), 7.22 (dd, 1H, J=1.9Hz, J=9.0Hz), 6.82 (d, 2H, J=8.7Hz), 5.66 (s, 2H), (ESI) m/z549 (M+H) +
3-(3-{[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] methyl }-1,2,4-oxadiazole-5-yl) phenylformic acid third-2-alkene ester; (ESI) m/z497 (M+H) +
3-{[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] methyl } phenylformic acid third-2-alkene ester; LC/MS analyzes: t R=23.62 minutes (no gradient (isocratic), 65%B), (ESI) m/z429 (M+H) +
3-{[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] methyl } methyl benzoate; 1H NMR (400MHz, DMSO-d 6) δ: 9.54 (s, 1H), 8.38 (s, 1H), 8.10 (s, 1H), 8.05 (d, 1H, J=8.8Hz), 7.96 (d, 1H, J=7.7Hz), 7.79 (d, 1H, J=7.5Hz), 7.60 (dd, 1H, J=7.5Hz, J=7.7Hz), 7.41 (d, 2H, J=8.5Hz), 7.27 (s, 1H), 7.18 (dd, 1H, J=1.5Hz, J=9.0Hz), 6.82 (d, 2H, J=8.5Hz), 5.38 (s, 2H), 3.88 (s, 3H), (ESI) m/z403 (M+H) +
4-{[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] methyl } ethyl benzoate; (ESI) m/z417 (M+H) +
3-{[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] methyl } the benzoic acid methyl ethyl ester; 1H NMR (400MHz, DMSO-d 6) δ: 9.56 (s, 1H), 8.39 (s, 1H), 8.08 (s, 1H), 8.05 (d, 1H, J=9.0Hz), 7.95 (d, 1H, J=7.8Hz), 7.78 (d, 1H, J=7.7Hz), 7.58 (dd, 1H, J=7.6Hz, J=7.9Hz), 7.41 (d, 2H, J=8.3Hz), 7.28 (d, 1H, J=1.9Hz), 7.18 (dd, 1H, J=1.9Hz, J=9.0Hz), 6.82 (d, 2H, J=8.3Hz), 5.37 (s, 2H), 5.18-5.14 (m, 1H), 1.33 (d, 6H, J=6.3Hz), (ESI) m/z431 (M+H) +
4-{[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] methyl } methyl benzoate.
4-{[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] methyl } phenylformic acid; (ESI) m/z389 (M+H) +
4-{[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] methyl } benzamide; 1H NMR (400MHz, DMSO-d 6) δ: 9.54 (s, 1H), 8.38 (s, 1H), 8.07-8.04 (m, 3H), 7.87 (d, 1H, J=8.0Hz), 7.66 (d, 1H, J=7.6Hz), 7.51 (m, 1H), 7.41 (m, 3H), 7.28 (d, 1H, J=2.0Hz), 7.18 (dd, 1H, J=9.2,2.0Hz), 6.82 (d, 2H, J=8.4Hz), 5.33 (s, 2H), (ESI) m/z388/389.
3-(4-hydroxyphenyl)-7-(5-[4-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group) chromene-4-ketone; 1H NMR (300MHz, DMSO-d 6) δ: 9.56 (s, 1H), 8.41 (s, 1H), 8.35 (d, 2H, J=8.1Hz), 8.09-8.01 (m, 3H), 7.40 (m, 3H), 7.22 (dd, 1H, J=8.8,2.1Hz), 6.82 (d, 2H, J=8.7Hz), 5.61 (s, 2H), (ESI) m/z481.6 (M+H) +
3-(4-hydroxyphenyl)-7-{[5-(3-p-methoxy-phenyl) (1,2,4-oxadiazole-3-yl)] methoxyl group } chromene-4-ketone;
7-(5-[3,5-two (trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group)-3-(4-hydroxyphenyl) chromene-4-ketone; 1H NMR (400MHz, DMSO-d 6) δ: 9.57 (d, 1H, J=1.6Hz), 8.69 (s, 2H), 8.56 (s, 1H), 8.41 (d, 1H, J=2.0Hz), 8.07 (dd, 1H, J=8.8,2.0Hz), 7.40 (m, 3H), 7.22 (d, 1H, J=8.8Hz), 6.82 (d, 2H, J=6.4Hz), 5.63 (s, 2H), (ESI) m/z549.1 (M+H) +
3-(3-{[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] methyl }-1,2,4-oxadiazole-5-yl) cyanobenzene; (ESI) m/z438 (M+H) +
3-(3-{[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] methyl }-1,2,4-oxadiazole-5-yl) phenylformic acid;
7-{[5-(3-fluorophenyl) (1,2,4-oxadiazole-3-yl)] methoxyl group }-3-(4-hydroxyphenyl) chromene-4-ketone. 1H?NMR(300MHz，DMSO-d6)δ:9.55(s，1H)，8.40(s，1H)，8.08(d，1H，J＝8.7Hz)，8.00(d，1H，J＝7.8Hz)，7.94(d，1H，J＝9.0Hz)，7.73-7.60(m，2H)，7.42-7.38(m，3H)，7.21(dd，1H，J＝9.0，2.4Hz)，6.82(d，2H，J＝8.7Hz)，5.59(s，2H)，(ESI)m/z?431(M+H) +。
3-(4-hydroxyphenyl)-7-[(3-phenyl (1,2,4-oxadiazole-5-yl)) methoxyl group] chromene-4-ketone; (ESI) m/z 413.4 (M+H) +
3-(4-hydroxyphenyl)-7-(3-[3-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-5-yl) } methoxyl group) chromene-4-ketone; (ESI) m/z 481.6 (M+H) +
3-(4-hydroxyphenyl)-7-(the 3-[4-chloro-phenyl-] (1,2,4-oxadiazole-5-yl) } methoxyl group) chromene-4-ketone; (ESI) m/z 447.2 (M+H) +
3-(4-hydroxyphenyl)-2-(trifluoromethyl)-7-(5-[3-(trifluoromethyl) phenyl]-(1,2,4-oxadiazole-3-yl) } methoxyl group) chromene-4-ketone; 1H NMR (300MHz, DMSO-d 6) δ: 9.64 (s, 1H), 8.45 (d, 1H, J=7.8Hz), 8.39 (s, 1H), 8.17-7.83 (m, 3H), 7.53 (d, 1H, J=2.4Hz), 7.27 (dd, 1H, J=8.7,2.1Hz), 7.08 (d, 2H, J=8.7Hz), 6.82 (d, 2H, J=8.4Hz), 5.65 (s, 2H), (ESI) m/z 549 (M+H) +
7-(5-[5-fluoro-3-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group)-3-(4-hydroxyphenyl)-2-(trifluoromethyl) chromene-4-ketone; 1H NMR (400MHz, DMSO-d 6) δ: 9.67 (s, 1H), 8.32 (d, 1H, J=8.4Hz), 8.25 (s, 1H), 8.17 (d, 1H, J=8.4Hz), 8.02 (d, 1H, J=8.4Hz), 7.54 (d, 1H, J=1.6Hz), 7.27 (dd, 1H, J=8.8,2.4Hz), 7.08 (d, 2H, J=8.0Hz), 6.82 (d, 2H, J=8.8Hz), 5.66 (s, 2H).(ESI)m/z?567(M+H) +
3-(4-hydroxyphenyl)-7-(5-[4-methoxyl group-3-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group)-2-(trifluoromethyl) chromene-4-ketone; (ESI) m/z 579 (M+H) +
3-{[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] methyl } cyanobenzene;
3-(3-{[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] methyl }-1,2,4-oxadiazole-5-yl) phenylformic acid.
3-(4-hydroxyphenyl)-7-({ 5-[3-(trifluoromethyl) phenyl] isoxazole-3-base } methoxyl group) chromene-4-ketone;
7-{[5-(trifluoromethyl) (3-pyridyl)] methoxyl group }-3-(4-{[6-(trifluoromethyl) (3-pyridyl)] methoxyl group } phenyl) chromene-4-ketone;
3-(4-hydroxyphenyl)-7-[(5-(3-pyridyl) (1,2,4-oxadiazole-3-yl)) methoxyl group] chromene-4-ketone;
3-(4-hydroxyphenyl)-7-[(5-(2-pyridyl) (1,2,4-oxadiazole-3-yl)) methoxyl group] chromene-4-ketone;
2-{[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] methyl }-1,3-oxazole-5-carboxylate methyl ester;
7-{[5-(4-fluorophenyl) (1,2,4-oxadiazole-3-yl)] methoxyl group }-the 3-{4-[(methylsulfonyl) amino]-phenyl } chromene-4-ketone;
2-{[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] methyl }-1,3-oxazole-5-carboxylic acid;
3-(3-[4-((1Z)-1-amino-2-methoxyl group-2-azepine vinyl) phenyl]-4-oxo chromene-7-base oxygen base } methyl) methyl benzoate;
7-{2-[4-(4-chloro-phenyl-) pyrazolyl] oxyethyl group }-3-(4-hydroxyphenyl) chromene-4-ketone;
3-(4-hydroxyphenyl)-7-[(6-pyrazolyl (3-pyridyl)) methoxyl group] chromene-4-ketone;
7-[(2R)-2-hydroxyl-3-({ [3-(trifluoromethyl) phenyl] methyl } amino) propoxy-]-3-(4-hydroxyphenyl) chromene-4-ketone;
3-(4-hydroxyphenyl)-7-[({[3-(trifluoromethyl) phenyl] methyl } amino) methoxyl group] chromene-4-ketone;
7-((2R)-3-{[(3,5-difluorophenyl) methyl] amino }-2-hydroxyl propoxy-)-3-(4-hydroxyphenyl) chromene-4-ketone;
7-(3-{[(1R)-1-(4-fluorophenyl) ethyl] amino }-the 2-oxopropoxy)-3-(4-hydroxyphenyl) chromene-4-ketone;
3-(4-hydroxyphenyl)-7-(3-phenyl propoxy-) chromene-4-ketone;
7-{[5-(3-fluorophenyl) (1,3,4-oxadiazole-2-yl)] methoxyl group }-3-(4-hydroxyphenyl) chromene-4-ketone;
3-(4-hydroxyphenyl)-7-{[3-(trifluoromethyl) phenyl] oxyethyl group } chromene-4-ketone;
3-(4-hydroxyphenyl)-7-(5-[3-(trifluoromethyl) phenyl] (1,3,4-oxadiazole-2-yl) } methoxyl group) chromene-4-ketone;
3-(4-hydroxyphenyl)-7-[(2-phenyl (1,3-oxazole-5-yl)) methoxyl group] chromene-4-ketone;
7-({ 5-[3,5-two (trifluoromethyl) phenyl] isoxazole-3-base } methoxyl group)-3-(4-hydroxyphenyl) chromene-4-ketone;
3-(4-hydroxyphenyl)-7-({ 5-[3-(trifluoromethyl) phenyl] isoxazole-3-base } methoxyl group) chromene-4-ketone;
The 3-{4-[(methylsulfonyl) amino] phenyl }-7-[(2-phenyl (1,3-oxazole-4-yl)) methoxyl group] chromene-4-ketone;
2-[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base]-N-[3-(trifluoromethyl) phenyl]-ethanamide;
7-{[5-(2-chloro-phenyl-) (1,3,4-thiadiazoles-2-yl)] methoxyl group }-3-(4-hydroxyphenyl) chromene-4-ketone;
4-[7-(4-methyl-2-[4-(trifluoromethyl) phenyl] (1,3-thiazoles-5-yl) } methoxyl group)-4-oxo chromene-3-yl] cyanobenzene;
The 3-{4-[(methylsulfonyl) amino] phenyl }-7-(4-methyl-2-[4-(trifluoromethyl) phenyl] (1,3-thiazoles-5-yl) } methoxyl group) chromene-4-ketone;
3-(6-methoxyl group (3-pyridyl))-7-(4-methyl-2-[4-(trifluoromethyl) phenyl] (1,3-thiazoles-5-yl) } methoxyl group) chromene-4-ketone;
4-[7-(5-[5-fluoro-3-(trifluoromethyl) phenyl] (1,3,4-oxadiazole-2-yl) } methoxyl group)-4-oxo chromene-3-yl] cyanobenzene;
4-[4-oxo-7-({ 3-[3-(trifluoromethyl) phenyl] isoxazole-5-base } methoxyl group) chromene-3-yl] cyanobenzene;
7-(5-[3-fluoro-5-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group)-the 3-{4-[(methylsulfonyl) amino] phenyl } chromene-4-ketone;
7-(5-[3-fluoro-5-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group)-3-[4-(methylsulfonyl) phenyl] chromene-4-ketone;
4-[7-(5-[3-fluoro-5-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group)-4-oxo chromene-3-yl] benzamide;
3-(3-acetylphenyl)-7-(5-[3-fluoro-5-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group) chromene-4-ketone;
7-(5-[3-fluoro-5-(trifluoromethyl) phenyl] (1,3,4-oxadiazole-2-yl) } methoxyl group)-3-(4-hydroxyphenyl) chromene-4-ketone;
7-(5-[3-fluoro-5-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group)-3-(5-hydrogen pyrazoles-4-yl) chromene-4-ketone;
3-[7-(3-[3-fluoro-5-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-5-yl) } oxyethyl group)-4-oxo chromene-3-yl] ethyl benzoate;
3-(4-hydroxyphenyl)-7-(2-[4-(trifluoromethyl) phenyl] (1,3-thiazoles-5-yl) } methoxyl group) chromene-4-ketone;
7-[2-(3-fluorophenyl)-2-oxo oxyethyl group]-3-(4-hydroxyphenyl) chromene-4-ketone;
7-(5-[3-fluoro-5-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } oxyethyl group)-3-(4-hydroxyphenyl) chromene-4-ketone;
7-(5-[3-fluoro-5-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group)-3-(4-{[(4-aminomethyl phenyl) alkylsulfonyl] amino } phenyl) chromene-4-ketone;
7-{[5-(2-chloro-phenyl-) (1,3,4-oxadiazole-2-yl)] methoxyl group }-3-(4-hydroxyphenyl) chromene-4-ketone;
7-{[5-(4-fluorophenyl) (1,3,4-oxadiazole-2-yl)] methoxyl group }-3-(4-hydroxyphenyl) chromene-4-ketone;
3-(4-hydroxyphenyl)-7-(4-pyridyl methoxyl group) chromene-4-ketone;
The 3-{4-[(methylsulfonyl) amino] phenyl }-7-(2-[4-(trifluoromethyl) phenyl] (1,3-thiazoles-5-yl) } methoxyl group) chromene-4-ketone;
2-[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base]-N-[2-(trifluoromethyl) phenyl]-ethanamide;
3-(4-hydroxyphenyl)-7-{2-oxo-2-[2-(trifluoromethyl) phenyl] oxyethyl group } chromene-4-ketone;
3-(1H-indazole-5-yl)-7-(5-[5-fluoro-3-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group) chromene-4-ketone;
3-(4-hydroxyphenyl)-7-(2-phenyl ethoxy) chromene-4-ketone;
2-[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] acetonitrile;
7-[2-(4-chlorophenoxy) oxyethyl group]-3-(4-hydroxyphenyl) chromene-4-ketone;
5-{4-[7-(5-[5-fluoro-3-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group)-4-oxo chromene-3-yl] phenyl }-1,3,5,6-tetrahydropyrimidine-2,4-diketone;
N-[(1R)-1-(4-fluorophenyl) ethyl]-2-[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] ethanamide;
3-(4-hydroxyphenyl)-7-(2-pyridyl methoxyl group) chromene-4-ketone;
2-fluoro-5-[7-(5-[5-fluoro-3-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group)-4-oxo chromene-3-yl] cyanobenzene;
7-(2-pyridyl methoxyl group)-3-[4-(2-pyridyl methoxyl group) phenyl] chromene-4-ketone;
3-(4-hydroxyphenyl)-7-[(5-(4-pyridyl) (1,2,4-oxadiazole-3-yl)) oxyethyl group] chromene-4-ketone;
3-(4-hydroxyphenyl)-7-[(5-(3-pyridyl) (1,2,4-oxadiazole-3-yl)) oxyethyl group] chromene-4-ketone;
3-(4-hydroxyphenyl)-7-[(5-(2-pyridyl) (1,2,4-oxadiazole-3-yl)) oxyethyl group] chromene-4-ketone;
3-(4-hydroxyphenyl)-7-{[5-(trifluoromethyl) (3-pyridyl)] methoxyl group } chromene-4-ketone;
7-{[5-(4-chloro-phenyl-) isoxazole-3-base] methoxyl group }-3-(4-hydroxyphenyl) chromene-4-ketone;
7-{[5-(3,4-dichlorophenyl) isoxazole-3-base] methoxyl group }-3-(4-hydroxyphenyl) chromene-4-ketone;
7-{[5-(4-chloro-phenyl-) isoxazole-3-base] methoxyl group }-3-(4-hydroxyphenyl) chromene-4-ketone;
7-[(2R)-2-hydroxyl-3-({ [3-(trifluoromethyl) phenyl] methyl } amino) propoxy-]-3-(4-hydroxyphenyl) chromene-4-ketone;
3-(4-hydroxyphenyl)-7-[2-({ [3-(trifluoromethyl) phenyl] methyl } amino) oxyethyl group] chromene-4-ketone;
7-((2R)-3-{[(3,5-difluorophenyl) methyl] amino }-2-hydroxyl propoxy-)-3-(4-hydroxyphenyl) chromene-4-ketone;
2-{[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] methyl }-1,3-oxazole-4-carboxylate methyl ester;
It is hydrolyzed under the standard hydrolysis condition to produce:
2-{[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] methyl }-1,3-oxazole-4-carboxylic acid;
N-[(1S)-1-(4-fluorophenyl) ethyl]-2-[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] ethanamide;
7-{[5-(4-fluorophenyl) (1,2,4-oxadiazole-3-yl)] methoxyl group }-3-(4-hydroxyphenyl) chromene-4-ketone;
7-{[5-(4-fluorophenyl) (1,2,4-oxadiazole-3-yl)] methoxyl group }-the 3-{4-[(methylsulfonyl)-amino] phenyl } chromene-4-ketone;
7-{3-[4-(4-chloro-phenyl-) pyrazolyl] propoxy-}-3-(4-hydroxyphenyl) chromene-4-ketone;
3-(4-hydroxyphenyl)-7-(3-phenyl propoxy-) chromene-4-ketone;
3-(4-hydroxyphenyl)-7-[(6-pyrazolyl (3-pyridyl)) methoxyl group] chromene-4-ketone;
7-((2R)-2-hydroxyl-3-phenyl propoxy-)-3-(4-hydroxyphenyl) chromene-4-ketone;
3-(4-hydroxyphenyl)-7-[(5-(3-pyridyl) (1,3,4-oxadiazole-2-yl)) methoxyl group] chromene-4-ketone;
3-[(2-hydroxyl-3-{4-[(methylsulfonyl) amino] phenyl }-4-oxo chromene-7-base oxygen base) methyl]-phenylformic acid;
7-{[5-(4-fluorophenyl) (1,3,4-oxadiazole-2-yl)] oxyethyl group }-3-(4-hydroxyphenyl) chromene-4-ketone;
3-(4-hydroxyphenyl)-7-[(5-(3-pyridyl) (1,3,4-oxadiazole-2-yl)) oxyethyl group] chromene-4-ketone;
3-(4-hydroxyphenyl)-7-[(3-(3-pyridyl) (1,2,4-oxadiazole-5-yl)) methoxyl group] chromene-4-ketone;
3-(4-hydroxyphenyl)-7-(3-[3-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-5-yl) } methoxyl group) chromene-4-ketone;
3-(4-hydroxyphenyl)-7-[(5-(3-pyridyl) (1,3,4-oxadiazole-2-yl)) oxyethyl group] chromene-4-ketone;
3-(4-hydroxyphenyl)-7-[(5-(4-pyridyl) (1,2,4-oxadiazole-3-yl)) oxyethyl group] chromene-4-ketone;
(2-{[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] methyl } (1,3-oxazole-4-yl))-the N-methylformamide;
4-{[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] methyl }-7-methoxyl group benzo pyran-2-one;
7-{[5-(4-fluorophenyl) (1,3,4-oxadiazole-2-yl)] methoxyl group }-the 3-{4-[(methylsulfonyl) amino]-phenyl } chromene-4-ketone;
7-{[5-(3-aminophenyl) (1,3,4-oxadiazole-2-yl)] methoxyl group }-3-(4-hydroxyphenyl) chromene-4-ketone;
1-{2-[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] ethyl } pyrazoles-4-carboxylic acid, ethyl ester;
7-{2-[4-(3-chloro-phenyl-) piperazinyl] oxyethyl group }-3-(4-hydroxyphenyl) chromene-4-ketone;
3-(4-hydroxyphenyl)-7-(2-{4-[3-(trifluoromethyl) phenyl] piperazinyl } oxyethyl group) chromene-4-ketone;
3-(4-hydroxyphenyl)-7-[(5-(2-pyridyl) isoxazole-3-base) methoxyl group] chromene-4-ketone;
7-(3-[3-fluoro-5-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-5-yl) } oxyethyl group)-3-(4-hydroxyphenyl) chromene-4-ketone;
7-[2-(4-fluorophenyl) oxyethyl group]-3-(4-hydroxyphenyl) chromene-4-ketone;
7-((1R)-1-{3-[3-fluoro-5-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-5-yl) } oxyethyl group)-3-(4-hydroxyphenyl) chromene-4-ketone;
7-((1S)-1-{3-[3-fluoro-5-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-5-yl) } oxyethyl group)-3-(4-hydroxyphenyl) chromene-4-ketone;
3-(4-hydroxyphenyl)-7-{2-[3-(trifluoromethyl) pyrazolyl] oxyethyl group } chromene-4-ketone; And
7-(1-{3-[3-fluoro-5-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-5-yl) }-isopropoxy)-3-(4-hydroxyphenyl) chromene-4-ketone.
D. The preparation of the compound of chemical formula (3)
Similarly, according to the step of above embodiment 5A or 5B, the commercially available isoflavones that is replaced by nitryl group with 3-phenyl group wherein replaces the 3-hydroxy-isoflavone and/or uses chemical formula R 1CH 2Other compound of X (R wherein 1With X as hereinbefore defined) replace that 3-chloromethyl-5-(3-trifluoromethyl)-[1,2,4] oxadiazoles have prepared the following compound of chemical formula (3).
3-{[3-(4-nitrophenyl)-4-oxo chromene-7-base oxygen base] methyl } methyl benzoate; (ESI) m/z 432 (M+H) +
3-(4-nitrophenyl)-7-(5-[3-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group) chromene-4-ketone; (ESI) m/z 510.5 (M+H) +
7-(5-[5-fluoro-3-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group)-3-(4-nitrophenyl) chromene-4-ketone; (ESI) m/z 528.1 (M+H) +
3-(3-{[3-(4-nitrophenyl)-4-oxo chromene-7-base oxygen base] methyl }-1,2,4-oxadiazole-5-yl) phenylformic acid third-2-alkene ester; (ESI) m/z 458 (M+H) +
3-{[3-(4-nitrophenyl)-4-oxo chromene-7-base oxygen base] methyl } cyanobenzene; (ESI) m/z 399 (M+H) +
3-{[3-(4-nitrophenyl)-4-oxo chromene-7-base oxygen base] methyl } methyl benzoate; (ESI) m/z 432 (M+H) +
7-(benzothiazole-2-ylmethoxy)-3-(4-hydroxyphenyl) chromene-4-ketone, and
3-[3-(4-nitrophenyl)-4-oxo chromene-7-base oxygen ylmethyl] the phenylformic acid allyl ester.
E The preparation of the compound of Formula I, wherein R 2 Be the 4-hydroxyl, R 3 Be hydrogen, X, Y and Z be-CH-, and V is an oxygen, and W is methylene radical, changes R 1
Similarly, according to the step of above embodiment 5A or 5B, the commercially available isoflavones that is replaced by nitryl group with 3-phenyl group wherein replaces the 3-hydroxy-isoflavone and/or uses chemical formula R 1CH 2Other compound of X (R wherein 1With X as hereinbefore defined) replace that 3-chloromethyl-5-(3-trifluoromethyl)-[1,2,4] oxadiazoles have prepared other compound of Formula I.
Embodiment 6
The preparation of the compound of Formula I
A. The preparation of the compound of Formula I, wherein R 1 Be (3-(1H-1,2,3,4-tetrazolium-5- Base) phenyl) 1,2,4-oxadiazole-5-yl), R 2 Be the 4-hydroxyl, R 3 Be hydrogen, X, Y and Z are -CH-, V are oxygen, and W is a methylene radical
Figure BPA00001185905000761
Under 150 ℃ 1, microwave treatment 3-in the 2-glycol dimethyl ether (0.6ml) (3-{[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] methyl }-1,2,4-oxadiazole-5-yl) cyanobenzene (51mg, 0.117mmol), dibutyl tin oxide (IV) (15mg, 0.059mmol, 0.5 equivalent) and azidotrimethylsilane (81mg, 0.702mmol, 6 equivalents) mixture 20 minutes.Then the dried prepacked column (use silica gel) that is loaded in of reaction mixture upward and by flash chromatography (silica gel, gradient, 100%CH2Cl2 and CH2Cl2/MeOH, 3: 1) is carried out purifying, to obtain the product by the trimethyl silyl protection of expectation.Be suspended in this intermediate in acetonitrile (2ml) and the water (1ml) and add a trifluoroacetic acid.Under vacuum, remove volatile solvent, so that 3-(4-hydroxyphenyl)-7-{[5-(3-(pyrrotriazole-5-yl) phenyl) (1,2,4-oxadiazole-3-yl) to be provided] methoxyl group } chromene-4-ketone (4mg).
1H?NMR(400MHz，DMSO-d 6)δ：9.57(s，1H)，8.82(s，1H)，8.42-8.33(m，3H)，8.09(d，1H，J＝8.8Hz)，7.92(m，1H)，7.41(m，3H)，7.24(dd，1H，J＝8.8，1.6Hz)，6.82(d，2H，J＝8.4Hz)，5.62(s，2H)。(ES-)m/z?479.2(M-1)
B The preparation of the compound of Formula I, wherein R 1 Be (3-(1H-1,2,3,4-tetrazolium-5- Base) R phenyl), 2 Be the 4-hydroxyl, R 3 Be hydrogen, X, Y and X be-CH-, and V is an oxygen, and And W is a methylene radical
Similarly, from 3-{[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] methyl } cyanobenzene begins and according to the step of above 6A, prepared 3-(4-hydroxyphenyl)-7-[(3-(1H-1,2,3,4-tetrazolium-5-yl) phenyl) methoxyl group] chromene-4-ketone.
1H?NMR(400MHz，DMSO-d 6)δ：9.56(s，1H)，8.39(s，1H)，8.21(s，1H)，8.06(m，2H)，7.73-7.67(m，2H)，7.40(d，2H，J＝8.4Hz)，7.31-6.81(m，5H)，5.42(s，2H)。(ESI)m/z?435(M+Na) +，(ES-)m/z411.1(M-1)
C. The preparation of the compound of Formula I, wherein R 1 Be (3-(1H-1,2,3,4-tetrazolium-5- Base) phenyl)
Similarly, from other compound of Formula I, wherein R 1The phenyl that is replaced by cyano group, and, prepared other compound of Formula I, wherein R according to the step of above 6A 1It is 3-(1H-1,2,3,4-tetrazolium-5-yl) phenyl.
Embodiment 7
The preparation of the compound of Formula I
A. The preparation of the compound of Formula I, wherein R 1 Be 3-phenylformic acid third-2-alkene ester also And R 2 Be amino
3-[3-(4-nitrophenyl)-4-oxo-4H-chromene-7-base oxygen ylmethyl the 60-65 ℃ of preparation of describing in heating as embodiment 5d down] phenylformic acid allyl ester (164.6mg, 0.36mmol), and V-Brite B (188mg, 1.08mmol) suspension in tetrahydrofuran (THF) (8ml) and water (4ml) is 1 hour.Through 2 hours with 5 parts add other V-Brite B (1.13g, 6.48mmol).Spend the night at 60-65 ℃ of following stirred reaction mixture.Reaction mixture 1H NMR shows, obtains product and do not have starting raw material.Reaction mixture is mixed with silica gel (2g), under reduced pressure remove and desolvate, then mixture is put on post.By flash chromatography, come the purifying silica-gel mixture, so that 3-{[3-(4-the aminophenyl)-4-oxo chromene-7-base oxygen base as yellow solid to be provided with methylene chloride (98/2) elution] methyl } phenylformic acid third-2-alkene ester (99.6mg, 65%).(ESI)m/z?428(M+H) +。
B. The replaceable preparation of the compound of Formula I, wherein R 1 Be 3-(tert.-butoxy carbonyl Base) phenyl methyl, and R 2 Be amino
In 3L 3-neck round-bottomed flask, with initial substance (58.00g, 122.50mmol, 3-((3-(4-nitrophenyl)-4-oxo-4H-chromene-7-base oxygen base) methyl) phenylformic acid tertiary butyl ester, 99.8% purity) be suspended in AcOH (348mL, Aldrich) in.In 30 minutes, in suspension, add Zn (40.04g, 612.50mmol, 5.0 equivalents, Aldrich).Make internal temperature can maintain between 20-35 ℃ with the ice-water bath cooling suspension, because reaction is extreme heat release.After adding Zn, remove ice-water bath, and make reaction vessel be heated to room temperature (22 ℃).After stirring in 30 minutes, the HPLC analysis revealed forms the product of expectation, 99.25%.Stirred reaction mixture is 1 hour under identical temperature.
(1800mL J.T.Baker), and stirred the mixture 20 minutes to add EtOAc in envrionment temperature in described reaction mixture.(30g, glass filter Aldrich) (350mL has meticulous lid) filter to remove by product, ZnOAc mixture by having diatomite subsequently.Washing the yellow residue of the gained that on diatomite, forms to produce yellow filtrate (filtrate 1, approximately 2100mL) with EtOAc (250mL) on the glass filter.Only remove the yellow residue on the diatomite, and be suspended among the EtOAc (1500mL).Suspension stirred 40 minutes.The glass filter that utilizes diatomite and use above, filtering suspension liquid.The yellow filtrate that the yellow residue of gained becomes clear with generation with EtOAc (250mL) washing on glass filter very much on the diatomite (filtrate 2, approximately 1800mL).
Merging filtrate 1 and filtrate 2 (approximately 3900mL) also are divided into 3 parts (approximately 1300mL).Each part is used salt solution (10%NaCl/H in the 2L separatory funnel 2O, 800mL) washing, and in 2L Erlen-Myer flask (x3), use Na 2SO 4(80g, Aldrich) dry 1 hour.Remove Na by filtering by a cotton 2SO 4After, under reduced pressure go down to desolventize at 50 ℃.The solvent of surplus is removed 6 hours to produce the expectation product (61.08g is polluted by the AcOH of about 100mol%) as yellow solid by high vacuum under 22 ℃.Repeat to have other three times of the similar reaction of similar scale to consume initial substance and final product is provided, 3-((3-(4-aminophenyl)-4-oxo-4H-chromene-7-base oxygen base) methyl) the phenmethyl tert-butyl ester.
C. The preparation of the compound of Formula I changes R 1
Similarly, replace 3-[3-(4-nitrophenyl)-4-oxo chromene-7-base oxygen ylmethyl with other compound of chemical formula (3)] the phenylformic acid allyl ester, and, prepared the following compound of chemical formula (4) according to the step of above 7A or 7B:
3-(4-aminophenyl)-7-(5-[3-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group) chromene-4-ketone; 1H NMR (400MHz, DMSO-d 6) δ: 8.46 (d, 1H, J=7.9Hz) 8.39 (s, 1H), 8.35 (s, 1H), 8.13 (d, 1H, J=7.6Hz), 8.07 (d, 1H, J=8.9Hz), 7.92 (dd, 1H, J=7.9Hz, J=7.9Hz), 7.37 (d, 1H, J=1.8Hz), 7.27 (d, 2H, J=8.3Hz), 7.21 (dd, 1H, J=1.8Hz, J=8.9Hz), 6.61 (d, 2H, J=8.3Hz), 5.60 (s, 2H), 5.23 (s, 2H); (ESI) m/z 480 (M+H) +
3-{[3-(4-aminophenyl)-4-oxo chromene-7-base oxygen base] methyl } methyl benzoate; (ESI) m/z402 (M+H) +
7-(5-[5-fluoro-3-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group)-3-(4-aminophenyl) chromene-4-ketone); (ESI) m/z 498.2 (M+H) +
3-{[3-(4-aminophenyl)-4-oxo chromene-7-base oxygen base] methyl } cyanobenzene; (ESI) m/z 369 (M+H) +
3-{[3-(4-aminophenyl)-4-oxo chromene-7-base oxygen base] methyl } benzamide; (ESI) m/z 387 (M+H) +
C. The preparation of the compound of Formula I changes R 1
Similarly, replace 3-[3-(4-nitrophenyl)-4-oxo-4H-chromene-7-base oxygen ylmethyl with other compound of chemical formula (3)] the phenylformic acid allyl ester, and, prepared other compound of Formula I according to the step of above 7A or 7B.
Embodiment 8
The preparation of the compound of Formula I
A. The preparation of the compound of Formula I, wherein R 1 It is 3-(third-2-thiazolinyl) phenylformic acid Ester, R 2 It is the 4-[(first Alkylsulfonyl) amino, R 3 Be hydrogen, X, Y and Z be-CH-, and V is an oxygen, And W is a methylene radical
Figure BPA00001185905000801
Under 0 ℃, the 3-{[3-of the preparation of in as embodiment 7A, describing (4-aminophenyl)-4-oxo chromene-7-base oxygen base] methyl } phenylformic acid third-2-alkene ester (169.5mg, 0.397mmol) and anhydrous pyridine (34.5mg, 0.44mmol) add in the mixture in exsiccant methylene dichloride (3ml) methylsulfonyl chloride (68.1mg, 0.60mmol).At room temperature stirred the mixture then 21 hours, and then mixed, and under reduced pressure remove and desolvate with silica gel.The flash chromatography silica-gel mixture is with methylene chloride (99.5/0.5) elution, so that the 3-[(3-{4-[(methylsulfonyl as white solid to be provided) amino] phenyl }-4-oxo chromene-7-base oxygen base) methyl] phenylformic acid third-2-alkene ester (160.9mg).(ESI)m/z?506(M+H) +。
B. The replaceable preparation of the compound of Formula I, wherein R 1 Be 3-(tert.-butoxy carbonyl Base) phenyl, R 2 Be the 4-[(methylsulfonyl) amino, R 3 Be hydrogen, X, Y and Z are-CH-V Be oxygen, and W is a methylene radical
In 3L 3-neck round-bottomed flask, will as the 3-that in embodiment 7B, prepares ((3-(4-aminophenyl)-4-oxo-4H-chromene-7-base oxygen base) methyl) t-butyl perbenzoate (474.05mmol) be dissolved in pyridine (1053mL, Aldrich) in to produce orange solution.In 10 minutes, in this solution, add MeSO 2Cl (81.45g, 711.08mmol, 1.5 equivalents, Aldrich).Use the ice-water bath reaction mixture, make internal temperature can maintain between 20-35 ℃, because described reaction is a slight exotherm.Adding MeSO 2Behind the Cl, remove ice-water bath, and make reaction vessel be heated to envrionment temperature (22 ℃).
After stirring 1 hour, HPLC analyzes product and the initial substance that shows expectation, is respectively 98.55% and 0.30%.After stirring in 1.5 hours, in the orange suspension that obtains, slowly add H 2O (1900mL is in the distillation of CVT place).Described suspension is divided into three parts (putting into three 3L round-bottomed flasks).In each flask, add H individually 2O (1185mL is in the distillation of CVT the place) (H of adding 2The total amount of O: 5455mL, 11.5mL/mmol).Mixture stirs down in envrionment temperature (22 ℃) and also passed through 2L filter funnel (thick) filtration at least in 30 minutes to collect crude product.Transfer to the crude product on the funnel in the 4LErlen-Myer flask and be suspended in H 2Among the O (2800mL).Stir after 20 minutes, suspension passes through 2L filter funnel (thick) filtration to collect crude product.Be suspended in the H in the 4L flask 2Among the O (2800mL), repeat again once to filter.Residue on the filter funnel is placed (the approximately volume of 500mL) (1162g at that point) on the exsiccant plate.
Moistening crude product is descended dry 54 hours to produce the dry raw product as light yellow bulk powder at 60 ℃ under high vacuum.Be placed on it in another 3L 3 neck round-bottomed flasks and be suspended in DMF (3mL/g, 729mL, Aldrich) in.Utilize heating jacket to add hot suspension, make internal temperature can reach 90 ℃.With water-bath cooling suspension 10 minutes.When internal temperature becomes 40 ℃, and adding MeOH (1000mL, Aldrich).Suspension is divided in 2 flasks (3L 3 neck round-bottomed flasks).In each flask, add MeOH (1322mL).(total amount of the MeOH of adding: 3644mL, 15mL/g).Stir after at least 1 hour, at ambient temperature by 2L filter funnel (medium) filtering suspension liquid.With the product on MeOH (total amount 1200mL) the washing and filtering device.Residue on the filter funnel is placed (approximately 500mL volume) (at this some 202.32g of place) on the exsiccant plate.Under high vacuum 60 ℃ down dry moistening products 4 hours to produce 3-((3-(4-(methyl sulfonamido) phenyl)-4-oxo-4H-chromene-7-base oxygen base) methyl) t-butyl perbenzoate as buff powder.
C. The preparation of the compound of Formula I, wherein R 2 Be the 4-[(methylsulfonyl) amino, R 3 Be hydrogen, X, Y and Z be-CH-, and V is an oxygen, and W is methylene radical, changes R 1
Similarly, replace 3-{[3-(4-aminophenyl)-4-oxo chromene-7-base oxygen base with other compound of chemical formula (4)] methyl } phenylformic acid third-2-alkene ester, and, prepared the following compound of Formula I, wherein R according to the step of above 8A or 8B 2Be the 4-[(methylsulfonyl) amino:
The 3-[(3-{4-[(methylsulfonyl) amino] phenyl }-4-oxo chromene-7-base oxygen base) methyl] methyl benzoate, 1H NMR (400MHz, DMSO-d 6) δ: 9.84 (br s, 1H), 8.46 (s, 1H), 8.10 (s, 1H), 8.07 (d, 1H, J=8.9Hz), 7.96 (d, 1H, J=7.8Hz), 7.80 (d, 1H, J=7.7Hz), 7.62-7.56 (m, 3H), 7.30 (s, 1H), 7.27 (d, 2H, J=8.1Hz), 7.20 (dd, 1H, J=1.5Hz, J=9.0Hz), 5.39 (s, 2H), 3.03 (s, 3H).(ESI)m/z?480(M+H) +。
The 3-{4-[(methylsulfonyl) amino] phenyl }-7-(5-[3-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group) chromene-4-ketone, 1H NMR (300MHz, DMSO-d 6) δ: 9.86 (s, 1H), 8.49 (s, 1H), 8.45 (d, 1H, J=7.8Hz), 8.38 (s, 1H), 8.12 (d, 1H, J=8.1Hz), 8.08 (d, 1H, J=9.0Hz), 7.91 (dd, 1H, J=7.9Hz, J=7.9Hz), 7.57 (d, 2H, J=8.6Hz), 7.41 (d, 1H, J=2.3Hz), 7.28-7.21 (m, 3H), 5.61 (s, 2H), 3.03 (s, 3H).(ESI)m/z558(M+H) +。
7-(5-[5-fluoro-3-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group)-the 3-{4-[(methylsulfonyl) amino] phenyl } chromene-4-ketone, 1H NMR (300MHz, DMSO-d 6) δ: 9.85 (s, 1H), 8.49 (s, 1H), 8.33-8.08 (m, 4H), 7.56 (d, 2H, J=8.7Hz), 7.42-7.22 (m, 4H), 5.62 (s, 2H), 3.02 (s, 3H).(ESI)m/z576.1(M+H) +。
The 3-[(3-{4-[(methylsulfonyl) amino] phenyl }-4-oxo chromene-7-base oxygen base) methyl]-cyanobenzene; 1H NMR (400MHz, DMSO-d 6) δ: 9.84 (s, 1H), 8.47 (s, 1H), 8.07 (d, 1H, J=9.2Hz), 8.00 (s, 1H), 7.86 (d, 2H, J=7.6Hz), 7.66 (dd, 1H, J=7.6,7.6Hz), 7.57 (d, 2H, J=8.8Hz), 7.31-7.20 (m, 4H), 5.36 (s, 2H), 3.03 (s, 3H).(ESI)m/z447(M+H) +。
3-{[3-(4-methylsulfonyl aminophenyl)-4-oxo chromene-7-base oxygen base] methyl } benzamide; 1H NMR (400MHz, DMSO-d 6) δ: 9.83 (s, 1H), 8.46 (s, 1H), 8.06 (d, 1H, J=8.9Hz), 8.01 (s, 2H), 7.87 (d, 1H, J=7.5Hz), 7.65 (d, 1H, J=7.9Hz), 7.57 (d, 2H, J=8.6Hz), 7.50 (dd, 1H, J=7.7,7.7Hz), 7.40 (br s, 1H), 7.30 (d, 1H, J=2.2Hz), 7.26 (d, 2H, J=8.6Hz), 7.19 (dd, 1H, J=2.2,8.9Hz), 5.33 (s, 2H), 3.02 (s, 3H).(ESI)m/z465(M+H) +。
Embodiment 9
The preparation of the compound of Formula I
A. The preparation of the compound of Formula I, wherein R 1 Be the 3-phenylformic acid, R 2 It is the 4-[(first Alkylsulfonyl) amino, R 3 Be hydrogen, X, Y and Z are-CH-that V is an oxygen, and W is inferior Methyl
Figure BPA00001185905000831
To the 3-[(3-{4-[(methylsulfonyl) amino] phenyl }-4-oxo chromene-7-base oxygen base) methyl] phenylformic acid third-2-alkene ester (88.8mg; 0.176mmol), tetrakis triphenylphosphine palladium (0) (10mg; 0.009mmol) add morpholine (77mg in the solution in exsiccant tetrahydrofuran (THF) (2ml); 0.88mmol), and under room temperature and argon gas, stirred the mixture 2 hours.Under reduced pressure remove then and desolvate, and residue is dissolved in the acetone, mix with silica gel, under reduced pressure remove and desolvate, then with methylene chloride (95/5) the elution silica gel that comprises 1% acetate, so that the 3-[(3-{4-[(methylsulfonyl to be provided) amino] phenyl }-4-oxo chromene-7-base oxygen base) methyl] phenylformic acid; 1H NMR (400MHz, DMSO-d 6) δ: 13.1 (br s, 1H), 9.84 (s, 1H), 8.47 (s, 1H), and 8.08-8.06 (m, 2H), 7.94 (d, 1H, J=7.8Hz), 7.76 (d, 1H, J=7.7Hz), 7.58-7.45 (m, 3H), 7.30 (d, 1H, J=1.8Hz), 7.27 (d, 2H, J=8.5Hz), 7.20 (dd, 1H, J=1.8Hz, J=8.9Hz), 5.38 (s, 2H), 3.03 (s, 3H).(ESI)m/z?466(M+H) +。
B. The replaceable preparation of the compound of Formula I, wherein R 1 Be 3-phenylformic acid, R 2 Be the 4-[(methylsulfonyl) amino, R 3 Be hydrogen, X, Y and Z be-CH-, and V is an oxygen, and W is a methylene radical
In 3L 3 neck round-bottomed flasks, (157.88g 302.70mmol) is suspended in HCO to t-butyl perbenzoate with 3-((3-(4-(methyl sulfonamido) phenyl)-4-oxo-4H-chromene-7-base oxygen base) methyl) 2H (1026mL, 6.5mL/g, Aldrich) in.Utilize heating jacket to descend heated mixt 1 hour at 50 ℃ (internal temperatures).The product and the initial substance of the expectation of HPLC analysis revealed are respectively 98.61% and 1.39%.At about 30 minutes internal temperature is increased to 80 ℃.Heating is after 2 hours down at 80 ℃, and the product and the initial substance of the expectation of HPLC analysis revealed are respectively 99.82% and 0.18%.Turn off heating jacket, and make suspension be cooled to envrionment temperature, stir 8 hours (product of expectation, 99.86%, and initial substance, 0.14%) then.
After stirring 8 hours, in room temperature (22 ℃) downhill reaction mixture, add H 2O (1104mL is in the distillation of CVT place).Mixture is divided into 2 parts (putting into 3L 3 neck flask x2).In each flask, add H 2O (1500mL).The total amount of the water that adds at this some place is 4104mL.Under the ice-water bath cooling, stirred suspension at least 1 hour.Come filtering suspension liquid by 2L filter funnel (medium).On strainer, use H 2O (1000mL altogether) washes residue.The residue that obtains is put into 4L Erlen-Myer flask and is suspended in H 2Among the O (3000mL).Mixture was stirred 20 minutes and filter by 2L filter funnel (medium).On strainer, use H 2O (500mL) washes residue.Be suspended in the H in the 4L flask 2Among the O (3000mL), and repeat again once to filter.The moistening material that obtains is 197.06g (a very shallow brown moistening powder).Place it on two exsiccant plates and under high vacuum 60 ℃ dry 18 hours down, so that the 3-[(3-{4-[(methylsulfonyl to be provided) amino] phenyl-4-oxo chromene-7-base oxygen base) methyl] phenylformic acid.
C. The recrystallize of the compound of Formula I, wherein R 1 Be 3-phenylformic acid, R 2 Be the 4-[(first Alkylsulfonyl) amino, R 3 Be hydrogen, X, Y and Z are-CH-that V is an oxygen, and W is inferior Methyl
3-[(3-{4-[(methylsulfonyl from embodiment 9B) amino] phenyl-4-oxo chromene-7-base oxygen base) methyl] phenylformic acid following from DMF (554mL, 4mL/g)-(4424mL is 32mL/g) by recrystallize for MeOH.Crude product is divided into 2 parts (each 69.25g puts into 3L 3 neck flask x2).(277mL is Aldrich) with dissolving crude product (light brown solution) to add DMF under envrionment temperature (22 ℃) in each flask.In 10 minutes, in every kind of solution, add MeOH (2216mL).The adding of MeOH makes solution become suspension (cream color).After stirring 1 hour, two suspension all filter by 2L glass filter (medium).With the residue on MeOH (1108mL altogether) the washing and filtering device.(very shallow orange moistening powder 465.79g) is transferred to the exsiccant plate, and descends dry 12 hours at 60 ℃ under high vacuum, to remove MeOH with the residue on the strainer.After dry 12 hours, obtain very shallow yellow powder (130.56g is polluted by DMF 12-14%).The product of this pollution under high vacuum under 175 ℃ by after drying 20 hours to remove DMF fully.End product obtains as very shallow yellow powder and pollutes without any DMF.
D. The preparation of the compound of Formula I, wherein R 1 Be the 3-phenylformic acid, R 3 Be hydrogen, X, Y and Z be-CH-, and V is an oxygen, and W is methylene radical, changes R 2
Similarly, use wherein R 1Other compound that is the Formula I of phenylformic acid third-2-alkene ester replaces the 3-[(3-{4-[(methylsulfonyl) amino] phenyl }-4-oxo chromene-7-base oxygen base) methyl] phenylformic acid third-2-alkene ester; and according to the step of above 9A or 9B; the following compound that has prepared Formula I, wherein R 1Be phenylformic acid:
3-{[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] methyl } phenylformic acid; 1HNMR (400MHz, DMSO-d 6) δ: 13.1 (br s, 1H), 9.59 (br s, 1H), 8.38 (s, 1H), 8.08 (s, 1H), 8.05 (d, 1H, J=9.0Hz), 7.94 (d, 1H, J=7.8Hz), 7.75 (d, 1H, J=7.7Hz), 7.56 (dd, 1H, J=7.5Hz, J=7.8Hz), 7.40 (d, 2H, J=8.7Hz), 7.29 (d, 1H, J=1.9Hz), 7.18 (dd, 1H, J=1.9Hz, J=9.0Hz), 6.82 (d, 2H, J=8.7Hz), 5.37 (s, 2H).(ESI)m/z?389(M+H) +。
3-(3-{[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] methyl }-1,2,4-oxadiazole-5-yl) phenylformic acid; 1H NMR (400MHz, DMSO-d 6) δ: 13.5 (s, 1H), 9.54 (br s, 1H), 8.62 (s, 1H), 8.40 (s, 1H), 8.36 (d, 1H, J=7.7Hz), 8.25 (d, 1H, J=7.8Hz), 8.08 (d, 1H, J=8.9Hz), 7.79 (dd, 1H, J=7.8Hz, J=7.8Hz), 7.42-7.40 (m, 3H), 7.23 (dd, 1H, J=1.6Hz, J=9.0Hz), 6.82 (d, 2H, J=8.4Hz), 5.59 (s, 2H).(ESI)m/z?457(M+H) +。
3-{[3-(4-aminophenyl)-4-oxo chromene-7-base oxygen base] methyl } phenylformic acid; (ESI) m/z 388 (M+H) +
Embodiment 10
The preparation of the compound of Formula I
A. The preparation of the compound of Formula I, wherein R 1 Be 3-((2-morpholinyl oxyethyl group) Carbonyl) benzyl, R 2 Be the 4-[(methylsulfonyl) amino, R 3 Be hydrogen, X, Y and Z be-CH-, V is an oxygen, and W is a methylene radical
Figure BPA00001185905000861
In the 100mL round-bottomed flask; under nitrogen atmosphere; the 3-[(3-{4-[(methylsulfonyl) amino] phenyl }-4-oxo chromene-7-base oxygen base) methyl] phenylformic acid (315.0mg; 0.677mmol) with the triethylamine (137.0mg, 1.354mmol, 2.0 equivalents) and 2 in THF (6mL); 4; 6-trichloro-benzoyl chloride (198.2mg, 0.812mmol, 1.2 equivalents) is handled.At room temperature stirred the mixture 1 hour.In mixture, add the solution of 4-hydroxyethyl morpholine (133.2mg, 1.016mmol, 1.5 equivalents) in THF (3mL) and dimethyl aminopyridine (82.7mg, 0.677mmol, 1.0 equivalents).Once more, at room temperature stirred the mixture 1 hour.In mixture, add H 2O (50mL), and whole with EtOAc (50mL * 3) extraction.Wash the organic layer that merges and use Na with salt solution (50mL) 2SO 4Dry.Under reduced pressure remove solvent to produce crude mixture.Crude mixture is by column chromatography purification (SiO 2=80g, 2.5%MeOH/CH 2Cl 2To 5%MeOH/CH 2Cl 2) to produce 3-((3-(4-(methyl sulfonamido) phenyl)-4-oxo-4H-chromene-7-base oxygen base) methyl) phenylformic acid 2-morpholinyl ethyl ester as colorless solid.
B. The preparation of the compound of Formula I, wherein R 2 Be the 4-[(methylsulfonyl) amino, R 3 Be hydrogen, X, Y and Z be-CH-, and V is an oxygen, and W is methylene radical, changes R 1
Similarly, replace the 4-hydroxyethyl morpholine with 1-(2-hydroxyethyl)-4-methylpiperazine, and, prepared 3-((3-(4-(methyl sulfonamido) phenyl)-4-oxo-4H-chromene-7-base oxygen base) methyl) phenylformic acid 2-(4-methylpiperazine) ethyl ester according to the step of top 10A.
C. The preparation of the compound of Formula I, wherein R 2 Be the 4-[(methylsulfonyl) amino, R 3 Be hydrogen, X, Y and Z be-CH-, and V is an oxygen, and W is methylene radical, changes R 1
Similarly, use chemical formula R 20Other compounds of OH replace the 4-hydroxyethyl morpholine, and according to the step of top 10A, have prepared other compounds of Formula I.
Embodiment 11
The preparation of the compound of Formula I
A. the preparation of the compound of Formula I, wherein R 1Be the 3-methyl benzoic acid ester, R 2Be the 4-[(methylamino) carbonylamino, R 3Be hydrogen, X, Y and Z are-CH-that V is an oxygen, and W is a methylene radical
With 3-{[3-(4-aminophenyl)-4-oxo chromene-7-base oxygen base] methyl } methyl benzoate (100mg, 0.25mmol) and the suspension of methyl isocyanate (57mg) in tetrahydrofuran (THF) (1ml) place sealed tube, and at room temperature stirred the mixture 3 days.Reaction mixture methylene dichloride furnishing slurry, and under reduced pressure remove and desolvate, so that thick 3-[(3-{4-[(methylamino to be provided) carbonyl amino] phenyl }-4-oxo chromene-7-base oxygen base) methyl] methyl benzoate.Solid is dissolved in the mixture of ethanol/methylene, mixes, remove and desolvate, use ethanol/methylene (3/97) elution silica gel then, so that the pure products of 90mg to be provided with silica gel.(ESI)m/z?459(M+H) +。
B. The preparation of the compound of Formula I, wherein R 1 Be phenylformic acid 3-methyl esters, R 2 Be The 4-kharophen, R 3 Be hydrogen, X, Y and Z are-CH-that V is an oxygen, and W is a methylene Base
Similarly, replace methyl isocyanate, and according to the step of above 11A, prepared 3-({ 3-[4-(kharophen) phenyl]-4-oxo chromene-7-base oxygen base } methyl) methyl benzoate with Acetyl Chloride 98Min..
Embodiment 12
The preparation of the compound of Formula I
A. The preparation of the compound of Formula I, wherein R 1 Be 2-[4-(4-p-methoxy-phenyl) Piperazinyl], R 2 Be the 4-hydroxyl, R 3 Be hydrogen, X, Y and Z be-CH-, and V is an oxygen, and And W is an ethylidene
Figure BPA00001185905000881
Step 1
1-(4-p-methoxy-phenyl) piperazine dissolved at N, in the dinethylformamide, and is added salt of wormwood and 1-bromo-2-monochloroethane.At room temperature stir the mixture overnight of gained, leach solid matter, under reduced pressure from filtrate, remove then and desolvate.By the biotage chromatography, with 3: 7 ethyl acetate: the hexane elution comes the purifying residue, so that 1-[4-(2-chloroethyl) piperazinyl to be provided]-the 4-anisole.
Step 2
To 1-[4-(2-chloroethyl) piperazinyl]-4-anisole (0.929mmo l) and 4, add 11% potassium hydroxide (0.5ml) in the solution of 7-dihydroxy isoflavone (0.929mmol) in acetone (10ml), and under reflux temperature, stirred the mixture 48 hours.Add enough methyl alcohol to precipitate unreacted parent material, it is leached, under reduced pressure from filtrate, remove then and desolvate.By the biotage column chromatography, come the purifying residue with 5% ethanol/methylene elution, so that pure 3-(4-hydroxyphenyl)-7-{2-[4-(4-p-methoxy-phenyl) piperazinyl to be provided] oxyethyl group chromene-4-ketone.
B.
Similarly, prepared following Piperazino derivs:
7-{2-[4-(4-fluorophenyl) piperazinyl] oxyethyl group }-3-(4-hydroxyphenyl) chromene-4-ketone;
3-(4-hydroxyphenyl)-7-(2-piperazinyl oxyethyl group) chromene-4-ketone;
N-(3-fluorophenyl) (4-{2-[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] ethyl }-piperazinyl) methane amide;
7-[2-(4-{[(3-fluorophenyl) amino] sulphomethyl } piperazinyl) oxyethyl group]-3-(4-hydroxyphenyl) chromene-4-ketone;
N-(2,4 difluorobenzene base) (4-{2-[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] ethyl } piperazinyl) methane amide;
Embodiment 13
The preparation of the compound of Formula I
A. The preparation of the compound of Formula I, wherein R 1 Be 2-[3-fluoro-5-(trifluoromethyl) Phenyl]-1, the 3-oxazole], R 2 Be the 4-hydroxyl, R 3 Be hydrogen, X, Y and Z are-CH-that V is Oxygen, and W is an ethylidene
Figure BPA00001185905000891
Step 1
In the 50ml round-bottomed flask, place diethyl malonate (3.72g, 23.25mmol, 5 equivalents) and N, dinethylformamide (10mL).At room temperature, through 10 minutes, in this solution, add sodium hydride (60% suspension in mineral oil, 744.0mg, 18.6mmol, 4.0 equivalents) in batches.After stirring 30 minutes, under 0 ℃,, add 4-(chloromethyl)-2-[5-fluoro-3-(trifluoromethyl) phenyl through 15 minutes]-1,3-oxazole (1.30g, 4.65mmol) at N, the solution in the dinethylformamide (10ml) is heated to envrionment temperature with reaction mixture then.At room temperature in described mixture, add sodium iodide (697.0mg, 4.65mmol, 1 equivalent).Stirred reaction mixture is 2 hours under uniform temp.Then water is joined in the reaction mixture (30mL) and also integral body is extracted with ethyl acetate (30mL * 3).Merge organic layer, (30mL) washs and uses dried over sodium sulfate with salt solution.Under reduced pressure remove 4 desolvate after, by silica gel column chromatography (SiO 2=80g, hexane: EtOAc=7: 1) repeat the purifying crude mixture.Acquisition is as the product of the expectation of colourless powder, 2-(2-[5-fluoro-3-(trifluoromethyl) phenyl] and-1,3-oxazole-4-yl } methyl) propane-1,3-two diethyl phthalates (1.75g).
Step 2
Use the product of step 1 and need not to be further purified.(606.7mg 1.50mmol) places the 50mL round-bottomed flask, and adds lithium chloride (127.6mmol, 3.01mmol, 2 equivalents), methyl-sulphoxide (5mL) and water (0.5mL), then 190-195 ℃ of following heated mixt 3 hours with product.Adding entry (30mL) in reaction mixture also extracts integral body with ethyl acetate (30mL * 3).Wash the organic layer that merges and use dried over sodium sulfate with salt solution (30mL).Under reduced pressure except that after desolvating, by silica gel column chromatography (SiO 2=80g, hexane: EtOAc=3: 1) come the purifying crude mixture.Acquisition is as the product of the expectation of light yellow oil, 3-{2-[5-fluoro-3-(trifluoromethyl) phenyl]-1,3-oxazole-4-yl } ethyl propionate (345.5mg).
Step 3
(330.0mg 0.996mmol) places 250mL round-bottomed flask and be dissolved in tetrahydrofuran (THF) (3mL) with the product of step 2.Under 0 ℃ and nitrogen atmosphere, use the lithium aluminum hydride treatment soln.After stirring 30 minutes, (3g) joins in the reaction mixture with diatomite, then adds methyl alcohol (5mL) and water (3mL) successively.Filter the suspension of gained by glass filter, and with the residue of ethyl acetate (50mL) washing on strainer.Under reduced pressure remove and desolvate, to produce water white oil (298.3mg).By silica gel column chromatography (SiO 2=80g, hexane: EtOAc=7: 1) come the purifying crude mixture, to produce 3-{2-[5-fluoro-3-(trifluoromethyl) phenyl as water white oil]-1,3-oxazole-4-yl } third-1-alcohol (255.3mg, 0.883mmol, 89%).
Step 4
To 3-{2-[5-fluoro-3-(trifluoromethyl) phenyl]-1,3-oxazole-4-yl } third-1-alcohol (250.3mg, 0.865mmol) the middle triphenylphosphate (295.4mg that adds, 0.952mmol, 1.1 equivalent) and the mixture of methyl-iodide (184.2mg, 1.298mmo l, 1.5 equivalents).At 130 ℃ of following heated mixt, add the methyl-iodide (184.2mg, 1.298mmol, 1.5 equivalents) of amount in addition simultaneously.Reacting by heating mixture 2 hours altogether is then by column chromatography (SiO 2=25g, hexane/EtOAc=7: 1) then by preparation property TLC (SiO 2=6 plates, hexane/EtOAc=15: 1) purifying in addition, to produce 2-[5-fluoro-3-(trifluoromethyl) phenyl as water white oil]-4-(3-iodine propyl group)-1,3-oxazole (116.1mg, 0.291mmol, 34%).
Step 5
With 4 ', the 7-dihydroxy isoflavone (31.3mg, 0.123mmol), 2-[5-fluoro-3-(trifluoromethyl) phenyl]-4-(3-iodine propyl group)-1,3-oxazole (48.9mg, 0.123mmol, 1.0 equivalents) and cesium carbonate (40.0mg, 0.123mmol, 1.0 equivalents) and place the 25mL flask.At room temperature in this flask, add methyl-sulphoxide (3mL) with the dissolving initial substance, and stirred reaction mixture 15 hours at room temperature.Adding entry (30mL) in mixture also extracts integral body with ethyl acetate (30mL * 3).Also use dried over sodium sulfate with the organic layer that salt solution (30mL) washing merges, to produce crude mixture (64.2mg) as water white oil.By column chromatography (SiO 2=80g, hexane/EtOAc=2: 1 to 1: 1) comes the purifying crude mixture, to produce 7-as clear crystal (2-{2-[3-fluoro-5-(trifluoromethyl) phenyl] (1,3-oxazole-5-yl) } oxyethyl group)-3-(4-hydroxyphenyl) chromene-4-ketone (49.1mg, 0.0934mmol, 76%).
Prepare 7-(3-{2-[3-fluoro-5-(trifluoromethyl) phenyl] (1,3-oxazole-4-yl) } propoxy-)-3-(4-hydroxyphenyl) chromene-4-ketone similarly.
Embodiment 14
The preparation of the compound of Formula I
A. The preparation of the compound of Formula I, wherein R 1 Be the 4-fluorophenyl, R 2 It is the 4-hydroxyl Base, R 3 Be hydrogen, X, Y and Z are-CH-that V is an oxygen, and W is-C (O) CH 2 -
Figure BPA00001185905000911
With dihydroxy isoflavone (0.2g 0.78mmol) is suspended in the acetone (10ml), and in this suspension, add 2-bromo-1-(4-fluorophenyl) second-1-ketone (0.16g, 0.75mmol) and 11% potassium hydroxide (0.78mmol).Backflow mixture 24 hours, and under reduced pressure remove and desolvate.Use the water treatment residue, supersound process is filtered, and air-dry.Use the methyl alcohol abrasive solid, filter, so that 7-[2-(4-fluorophenyl)-2-oxo oxyethyl group to be provided]-3-(4-hydroxyphenyl) chromene-4-ketone.If expectation can be by the preparation of lamina chromatography, be further purified product with methylene chloride 15/1 elution.
B.
Similarly,, replace 2-bromo-1-(4-fluorophenyl) second-1-ketone, prepared following compound with other halo acetophenone derivative according to the step of above embodiment 14A:
7-[2-(3-fluorophenyl)-2-oxo oxyethyl group]-3-(4-hydroxyphenyl) chromene-4-ketone;
3-(4-hydroxyphenyl)-7-{2-oxo-2-[2-(trifluoromethyl) phenyl] oxyethyl group } chromene-4-ketone;
3-(4-hydroxyphenyl)-7-{2-oxo-2-[2-(trifluoromethyl) phenyl] oxyethyl group } chromene-4-ketone.
Embodiment 15
The preparation of the compound of Formula I
A. The preparation of the compound of Formula I, wherein R 1 Be the 3-trifluoromethyl, R 2 Be the 4-hydroxyl, R 3 Be hydrogen, X, Y and Z are-CH-that V is an oxygen, and W is -NHC (O) CH 2 -
Figure BPA00001185905000921
With dihydroxy isoflavone (0.2g 0.78mmol) is suspended in the acetone (10ml), and adds 2-chloro-N-[3-(trifluoromethyl) phenyl in this suspension] ethanamide (0.18g, 0.78mmol) and 11% potassium hydroxide (0.78mmol).Backflow mixture 24 hours, and under reduced pressure remove and desolvate.Use the water treatment residue, supersound process is filtered, and air-dry.Use the methyl alcohol abrasive solid, filter, so that 2-[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base to be provided]-N-[3-(trifluoromethyl) phenyl] ethanamide.If expectation can be by the preparation of lamina chromatography, be further purified product with methylene chloride 15/1 elution.
B.
Similarly,, replace 2-chloro-N-[3-(trifluoromethyl) phenyl with other halogen acetamide derivative according to the step of above embodiment 15A] ethanamide, prepared following compound:
N-[(1S)-1-(4-fluorophenyl) ethyl]-2-[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] ethanamide;
2-[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base]-N-[2-(trifluoromethyl)-phenyl] ethanamide;
N-(3-fluorophenyl)-2-[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] ethanamide;
N-[(1R)-1-(4-fluorophenyl) ethyl]-2-[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] ethanamide.
Embodiment 16
The preparation of the compound of Formula I
A. The preparation of the compound of Formula I, wherein R 1 Be the 3-trifluoromethyl, R 2 Be the 4-hydroxyl, R 3 Be hydrogen, X, Y and Z are-CH-that V is an oxygen, and W is -CH 2 NHCH 2 CH (OH) CH 2 -
Figure BPA00001185905000931
Step 1
Under 80 ℃, stir 7-hydroxyl-3-(4-p-methoxy-phenyl) chromene-4-ketone (0.86g, 3.21mmol), Epicholorohydrin (1.25ml, 16mmol) and salt of wormwood (0.89g, 6.42mmol) mixture in dimethyl formamide (20ml) is 3 hours.Under reduced pressure, water is joined in the residue, and leach throw out, wash with water then except that after desolvating.By chromatography on silica gel, come the purifying crude product with ethyl acetate/hexane (1: 4 to 2: 3) elution, so that 3-(4-p-methoxy-phenyl)-7-(epoxy second-2-ylmethoxy) to be provided chromene-4-ketone.
Step 2
Under 78 ℃, in ethanol (15ml), stir 3-(4-p-methoxy-phenyl)-7-(epoxy second-2-ylmethoxy) chromene-4-ketone (0.24g, 0.74mmol), 3-(trifluoromethyl) benzylamine (0.11ml, 0.74mmol) and diisopropylethylamine (0.26g 1.47mmol) spends the night.Under reduced pressure remove and desolvate, and on silica gel the chromatography residue, with 5% ethanol/methylene elution, then from the ethyl acetate/hexane recrystallize, so that 7-[2-hydroxyl-3-({ [3-(trifluoromethyl) phenyl] methyl } amino) propoxy-to be provided]-3-(4-p-methoxy-phenyl) chromene-4-ketone.
Step 3
℃ under, to 7-[2-hydroxyl-3-({ [3-(trifluoromethyl) phenyl] methyl }-amino) propoxy-]-3-(4-p-methoxy-phenyl) chromene-4-ketone (38mg, 0.076mmol) add in the stirred suspension in methylene dichloride boron tribromide (1M, 0.38ml).At room temperature stir the mixture 4 hours of gained, under reduced pressure remove then and desolvate.By the preparation of lamina chromatography, come the purifying residue with 10% ethanol/methylene elution, so that 3-(4-hydroxyphenyl)-7-[2-hydroxyl-3-({ [3-(trifluoromethyl) phenyl] methyl } amino) propoxy-to be provided] chromene-4-ketone.
B.
Similarly, according to the step of above embodiment 16A, but with 3,5-two flunamines replace 3-(trifluoromethyl) benzylamine, have prepared following compound:
7-(3-{[(3,5-difluorophenyl) methyl] amino }-2-hydroxyl propoxy-)-3-(4-hydroxyphenyl) chromene-4-ketone; And
7-(2-{[(4-fluorophenyl) ethyl] amino } oxyethyl group)-3-(4-hydroxyphenyl) chromene-4-ketone.
Embodiment 17
The preparation of the compound of Formula I
A. The preparation of the compound of Formula I, wherein R 1 Be phenyl, R 2 Be the 4-hydroxyl, R 3 Be hydrogen, X, Y and Z are-CH-that V is an oxygen, and W is-CH 2 CH (OH) CH 2 -
Figure BPA00001185905000941
Step 1
Under-40 ℃, (0.14g 0.74mmol) drips at tetrahydrofuran (THF) (1M, 2.22ml, 2.22mmol) phenyl-magnesium-bromide in the solution in tetrahydrofuran (THF) (2ml) to cuprous iodide.After 5 minutes, (0.24g 0.74mmol), and stirred 1 hour down at-40 ℃ slowly to be added in 3-(4-p-methoxy-phenyl)-7-(epoxy second-2-ylmethoxy) chromene-4-ketone in the tetrahydrofuran (THF) (4ml).With saturated ammonium chloride and water chilled mixture, use ethyl acetate extraction, with salt water washing organic layer, use dried over sodium sulfate, under reduced pressure remove then and desolvate.By the preparation of lamina chromatography, with 10% ethanol/methylene, then come the purifying residue, so that 7-(2-hydroxyl-3-phenyl propoxy-)-3-(4-p-methoxy-phenyl) chromene-4-ketone to be provided with ethyl acetate/hexane 2/3 elution.
Step 2
As at embodiment 16, shown in the step 3, make the product and the boron tribromide reaction of step 1, then so that 3-(4-hydroxyphenyl)-7-(2-hydroxyl-3-phenyl propoxy-) to be provided chromene-4-ketone.
Embodiment 18
The preparation of the compound of Formula I
A. The preparation of the R enantiomorph of the compound of Formula I, wherein R 1 It is the 3-[5-fluorine -3-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-5-yl), R 2 Be the 4-hydroxyl, R 3 Be hydrogen, X, Y and Z are-CH-that V is an oxygen, and W is-CH (CH 3 )-
Figure BPA00001185905000951
Step 1
Will be as (28.04g, solution 126.24mmol) are dissolved in the tetrahydrofuran (THF) (40ml) and are cooled to-78 ℃ at [5-fluoro-3-(trifluoromethyl)-phenyl] (oxyimino) methylamine for preparing as shown in the embodiment 1.Under the atmosphere of drying nitrogen, dropping (1S)-1-(chloroformyl) ethyl acetate (20g, the 128.82mmol) solution in tetrahydrofuran (THF) (20ml), and after adding is finished, stirred 10 minutes.Drip diisopropylethylamine (27.0ml, solution 155mmol), and reaction mixture is heated to room temperature then.Stirred the mixture two hours, and under reduced pressure removed then and desolvate.Residue is poured in the ethyl acetate (150ml), water (2 * 50ml), salt solution (2 * 50ml) washing, use dried over sodium sulfate then.Under reduced pressure remove and desolvate, so that 2-amino-2-[3-fluoro-5-(trifluoromethyl) phenyl as light yellow oil to be provided]-1-azepine vinyl (2S)-2-acetoxyl group propionic ester (39.04g, MS mz 337.1 (M+H), it is used for next reaction and is not further purified.
Step 2
Under 0 ℃ and nitrogen to 2-amino-2-[3-fluoro-5-(trifluoromethyl) phenyl]-(5.19g 15.43mmol) drips the solution of 1M tetrabutylammonium in tetrahydrofuran (THF) (3ml) to 1-azepine vinyl (2S)-2-acetoxyl group propionic ester in the solution in anhydrous tetrahydro furan (20ml).0 ℃ of following stirred reaction mixture 3 hours, pour into then in the ethyl acetate (50ml), water (2 * 20ml), salt solution (30ml) washing, and use dried over sodium sulfate.Under reduced pressure remove and desolvate, and by the flash chromatography method, come the purifying residue with the methylene dichloride elution, so that (1S)-1-{3-[5-fluoro-3-(trifluoromethyl) phenyl to be provided] (1,2,4-oxadiazole-5-yl) ethyl acetate, LCMS319.1.
Step 3
Under-15 ℃, to (1S)-1-{3-[5-fluoro-3-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-5-yl) ethyl acetate (900mg, 2.83mmol) add in the solution in methyl alcohol (4ml) salt of wormwood the aqueous solution (10M, 10ml).Stirred the mixture 20 minutes, and with mixture heating up to room temperature, stirred 1 hour.(3 * 20ml) extract mixture, then water (10ml), the salt solution (organic phase that 2 * 20ml) washings merge with ethyl acetate.Desolvating, so that (1S)-1-{3-[5-fluoro-3-(trifluoromethyl) phenyl to be provided to removing under reducing pressure] (1,2,4-oxadiazole-5-yl) } second-1-alcohol, it is from the hexane crystallization, to produce white solid, LCMS277.2.
Step 4
Under-78 ℃, (262mg, (0.45ml 1mmol), stirred the mixture under-78 ℃ 30 minutes then 1mmol) to drip 40% diethylazodicarboxylate in toluene in the solution in anhydrous tetrahydro furan (15ml) to triphenylphosphine.Slow adding dihydroxy isoflavone (300mg, 1.14mmol) at tetrahydrofuran (THF) (8ml) and N, the solution in the mixture of dinethylformamide (3ml), and stirred the mixture 10 minutes.Drip (1S)-1-{3-[5-fluoro-3-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-5-yl) } (277mg, the 1mmol) solution in tetrahydrofuran (THF) (8ml) stirred the mixture under-78 ℃ 3 hours second-1-alcohol, was heated to room temperature then, stirred 36 hours.
Reaction mixture is poured in the ethyl acetate (40ml), and (dried over sodium sulfate is used in 2 * 10ml) washings, under reduced pressure removes then and desolvates for water (10ml), salt solution.The mixture of methylene dichloride/tetrahydrofuran (THF) (4ml/1ml) is joined in the yellow residue, and on silica gel the flash chromatography soluble part, with ethyl acetate (0-30%)/hexane elution, to produce white solid, it is by the preparation of lamina chromatography, be further purified with acetonitrile (2.597.5%/water) elution, so that 7-((1R)-1-{3-[5-fluoro-3-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-5-yl) } oxyethyl group)-3-(4-hydroxyphenyl) chromene-4-ketone to be provided; 245mg, 0.48mmol, 48%).MS mz 513.1 (M+H), analysis mode HPLC＞99%, Chiralcel OJ-RH hplc99.2%e.e. (mass detector), and 99.0%e.e. (UV detector) are in acetonitrile/water.
1H?NMR(400MHz；CDCl 3)δ8.25(d，1H，J＝9.0Hz)；8.18(s，1H)；7.99(m，1H)；7.91(s，1H)；7.49(m，1H)；7.42(d，2H，J＝8.6Hz)；7.09(dd，1H，J＝9.0，2.3Hz)；6.97(d，1H，J＝2.3Hz)；6.88(d，2H，J＝9.0Hz)；5.59(t，1H，J＝6.6Hz)；1.96(d，1H，J＝6.6Hz)。
Embodiment 19
The preparation of the prodrug of the compound of Formula I
A. The preparation of the phosphoric acid ester of the compound of Formula I, wherein R 1 It is 5-fluoro-3-(trifluoro Methyl) phenyl] (1,2-oxazole-5-yl), R 2 Be the 4-hydroxyl, R 3 Be hydrogen, X, Y and Z be-CH-, V is an oxygen, and W is CH 2 -
Figure BPA00001185905000981
Step 1
To 7-(2-[5-fluoro-3-(trifluoromethyl) phenyl] (1,3-oxazole-4-yl) } methoxyl group)-3-(4-hydroxyphenyl) chromene-4-ketone (1g, 2.01mmol) add 1-H-tetrazolium (3%wt in the solution in tetrahydrofuran (THF) (50mL), in acetonitrile, 65ml 22.1mmol), then adds di-t-butyl N, N-diethyl phosphoramidite (2.57ml, 4.6mmol).After at room temperature stirring 2 hours, wash with the methylene dichloride diluted reaction mixture and with saturated sodium bicarbonate.Separate organic layer, and with the dichloromethane extraction water layer more than twice.With the extract of dried over sodium sulfate merging, and under reduced pressure remove and desolvate.By the biotage column chromatography, come the purifying residue with ethyl acetate/hexane mixture (1: 4) elution, so that 3-{4-[two (tert.-butoxy) phosphine oxygen base to be provided] phenyl }-7-(2-[5-fluoro-3-(trifluoromethyl) phenyl] (1,3-oxazole-4-yl) } methoxyl group) chromene-4-ketone.
Step 2
To the product 3-{4-[two of step 1 (tert.-butoxy) phosphine oxygen base] phenyl }-add the tertbutyl peroxide (5M-6M) of 6ml in decane in 7-({ 2-[5-fluoro-3-(trifluoromethyl) phenyl] (1, the 3-oxazole-4-yl) } methoxyl group) solution of chromene-4-ketone in the mixture of tetrahydrofuran (THF) (20mL) and acetonitrile (10mL).At room temperature stirred reaction mixture is 1 hour, cools off in ice bath, and adds 5% sodium bisulfite of 50mL.The mixture of stirring gained 15 minutes is removed ice bath thereafter.Use the dichloromethane extraction mixture, use the dried over sodium sulfate organic extraction, and under reduced pressure remove and desolvate.By the biotage column chromatography, come the purifying residue with the elution of 1: 1 ethyl acetate/hexane mixture, so that 4-[7-({ 2-[5-fluoro-3-(trifluoromethyl) phenyl] (1,3-oxazole-4-yl) } methoxyl group)-4-oxo chromene-3-yl to be provided] the phosphenylic acid di tert butyl carbonate.
Step 3
3-{4-[two (tert.-butoxy) phosphine oxygen base to preparation in step 2] phenyl }-7-(2-[5-fluoro-3-(trifluoromethyl) phenyl] (1,3-oxazole-4-yl) } methoxyl group) add in the solution of chromene-4-ketone in methylene dichloride (60ml) trifluoroacetic acid (0.15ml, 1.99mmol).At room temperature stirred reaction mixture spends the night, leach solid, and use washed with dichloromethane, and with 4-[7-that 100% pure (passing through HPLC) is provided ({ 2-[5-fluoro-3-(trifluoromethyl) phenyl] (1,3-oxazole-4-yl) } methoxyl group)-4-oxo chromene-3-yl] phosphenylic acid two hydrogen esters.
Embodiment 20
The preparation of the prodrug of the compound of Formula I
A. The preparation of the methyl dihydrogen phosphate ester of the compound of Formula I, wherein R 1 Be 5- Fluoro-3-(trifluoromethyl) phenyl] (1,2-oxazole-5-yl), R 2 Be the 4-hydroxyl, R 3 Be hydrogen, X, Y With Z be-CH-, V is an oxygen, and W is CH 2 -
Figure BPA00001185905000991
The preparation of the step 1-chloromethyl di(2-ethylhexyl)phosphate tert-butyl ester
Make the 100mL round-bottomed flask be mounted with the di-t-butyl potassiumphosphate (1.0g, 4.03mmol), sodium bicarbonate (677.4mg, 8.06mmol), normal-butyl ammonium sulfate (68.2mg, 0.403mmol) water (10ml) and methylene dichloride (5ml).(797.9mg, the 4.84mmol) solution in methylene dichloride (5ml) at room temperature stirred the mixture 2 hours then to add chloromethyl chlorsulfonic acid ester in this mixture.In reaction product, add entry (30ml), and integral body is extracted with methylene dichloride (30ml * 3).With the organic layer that salt solution (30ml) washing merges, use Na 2SO 4Drying, and under reduced pressure remove and desolvate.Come the purifying residue by column chromatography (silica gel=80g, hexane/ethyl acetate=1: 1), to provide the chloromethyl di(2-ethylhexyl)phosphate tert-butyl ester as water white oil.
Step 2- (4-(7-((2-(3-fluoro-5-(trifluoromethyl) phenyl) oxazole-4-yl) methoxyl group)-4- Oxo-4H-chromene-3-yl) preparation of methyl acid phosphate di tert butyl carbonate phenoxy group)
In the 50mL round-bottomed flask, at N, there is potassium tert.-butoxide (67.8mg in the dinethylformamide (2ml), 0.604mmol, 1.0 equivalent) and sodium iodide (89.9mg, 0.604mmol, 1.0 under condition equivalent), with the chloromethyl di(2-ethylhexyl)phosphate tert-butyl ester (156.2mg, 0.604mmol, 1.0 equivalents) processing 7-(2-[5-fluoro-3-(trifluoromethyl) phenyl] (1,3-oxazole-4-yl) } methoxyl group)-3-(4-hydroxyphenyl) chromene-4-ketone (150.0mg, 0.302mmol), at room temperature stirred the mixture then 15 hours.In mixture, add entry (30ml), and integral body is extracted with ethyl acetate (30ml * 3).With the organic layer that salt solution (30ml) washing merges, use Na 2SO 4Drying, and under reduced pressure remove and desolvate, to provide crude mixture (345.1mg).By column chromatography (SiO 2=80g, hexane/EtOAc=1: 1) come purified mixture, to provide { 4-[7-({ 2-[5-fluoro-3-(trifluoromethyl) phenyl] (1,3-oxazole-4-yl) } methoxyl group)-4-oxo chromene-3-yl] phenoxy group } methyl acid phosphate di tert butyl carbonate as water white oil.
Step 3- (4-(7-((2-(3-fluoro-5-(trifluoromethyl) phenyl) oxazole-4-yl) methoxyl group)-4- Oxo-4H-chromene-3-yl) preparation of methyl dihydrogen phosphate ester phenoxy group)
In the 50mL round-bottomed flask, with the trifluoroacetic acid (37.9mg in the methylene dichloride (2ml), 0.332mmol, 2.0 equivalent) handle 4-[7-(2-[5-fluoro-3-(trifluoromethyl) phenyl] (1,3-oxazole-4-yl) } methoxyl group)-and 4-oxo chromene-3-yl] phenoxy group } the methyl acid phosphate di tert butyl carbonate (119.1mg, 0.166mmol).At room temperature stirred the mixture 18 hours, and added methylene dichloride (10ml), filter thus obtained suspension by glass filter then.Residue on the de-entrainment filter is to provide { 4-[7-({ 2-[5-fluoro-3-(trifluoromethyl) phenyl] (1,3-oxazole-4-yl) } methoxyl group)-4-oxo chromene-3-yl] phenoxy group } methyl dihydrogen phosphate ester.
Embodiment 21
Prepared the hard gelatin capsule that comprises following component:
Figure BPA00001185905001011
Mix above component and be filled in the hard gelatin capsule.
Embodiment 22
Utilize following component to prepare Tabules (prescription):
Figure BPA00001185905001012
Described composition (component) mixed and compression to form tablet.
Embodiment 23
Prepared the Foradil Aerolizer formoterol fumarate formulation that comprises following composition:
Component Weight %
Active ingredient 5
Lactose 95
Make active ingredient mix with lactose and mixture is joined in the Diskus.
Embodiment 24
Be prepared as follows the tablet that each comprises the 30mg active ingredient:
Figure BPA00001185905001021
Make active ingredient, starch and Mierocrystalline cellulose pass the U.S.'s the 20th mesh sieve and thorough mixing.Make the powder mixes of the solution and the gained of polyvinylpyrrolidone, make it pass the U.S.'s 16 mesh sieves then.The particles that drying is so produced under 50 ℃ to 60 ℃ also pass the U.S.'s 16 mesh sieves.Sodium starch glycolate, Magnesium Stearate and the talcum powder that will pass the U.S.'s the 30th mesh sieve then in advance join in the particle, and after mixing, the above-mentioned particle of compression on tabletting machine is to produce the tablet that each weight is 120mg.
Embodiment 25
Be prepared as follows the suppository that each comprises the active ingredient of 25mg:
Component Amount
Active ingredient 25mg
Saturated fatty acid glyceride to 2,000mg
Make active ingredient pass the U.S.'s the 60th mesh sieve and be suspended in the saturated fatty acid glyceride that before utilizes required minimum heat melts.Then mixture is poured in the suppository mould that nominal capacity is 2.0g and made its cooling.
Embodiment 26
Be prepared as follows the suspensoid of each active ingredient that comprises 50mg/5.0mL dosage:
Component Amount
Active ingredient 50.0mg
Xanthan gum 4.0mg
Xylo-Mucine (11%)
Microcrystalline Cellulose (89%) 50.0mg
Sucrose 1.75g
Sodium Benzoate 10.0mg
Sweetener and tinting material capacity (volume, q.v.)
Pure water is to 5.0mL
Mixed active component, sucrose and xanthan gum are passed the U.S.'s the 10th sieve, mix with the Microcrystalline Cellulose and the solution of Xylo-Mucine in water of previous preparation then.With some water dilution Sodium Benzoate, sweetener and tinting material, and under agitation add.Add enough water then to produce needed volume.
Embodiment 27
Can be prepared as follows subcutaneous dosage form:
Embodiment 28
Preparation has the injection formulations of following composition:
Component Amount
Active ingredient 2.0mg/ml
N.F,USP MANNITOL, USP 50mg/ml
Glyconic acid, USP capacity (pH 5-6)
Water (distillation, aseptic) capacity to 1.0
ml
Nitrogen, the NF capacity
Embodiment 29
Preparation has the topical formulations of following composition:
Component Gram
Active ingredient 0.2-10
This coils 60 2.0
Polysorbate60 2.0
Mineral oil 5.0
Vaseline 0.10
Methyl hydroxybenzoate 0.15
Propyl Hydroxybenzoate 0.05
BHA (butylated hydroxy anisole (BHA)) 0.01
Water capacity to 100
Merge all said components beyond dewatering, and under agitation be heated to 60 ℃.Under vigorous stirring, add 60 ℃ water of capacity then,, then add the water capacity to 100g with emulgate ingredient.
Embodiment 30
Sustained-release composition
Figure BPA00001185905001041
Be prepared as follows sustained release forms of the present invention: mix (do and mix) compound and pH dependent binder and any optional vehicle closely.To do mixed mixture then under the situation that strong alkali aqueous solution exists and make particle, described highly basic is sprayed into mixed powder.Particle is carried out drying, and screening mixes with optional lubricant (as talcum powder or Magnesium Stearate), is pressed into tablet then.Preferred strong alkali aqueous solution is the solution of the alkali metal hydroxide (as sodium hydroxide or potassium hydroxide, preferred sodium hydroxide) in water (comprising water-miscible solvent such as lower alcohol up to 25% alternatively).
Can be with the tablet of optional membrane-forming agent coating gained, be used for identification, taste masking purpose and be convenient to swallow.Membrane-forming agent will be usually with tablet weight 2% to 4% between the amount of scope exist.Suitable membrane-forming agent be well known in the art and comprise Vltra tears, positively charged ion alkylmethacrylate polymer (dimethylaminoethyl methacrylate/methacrylic acid methyl butyl ester multipolymer-
Figure BPA00001185905001051
Figure BPA00001185905001052
Pharma) etc.These membrane-forming agents can comprise tinting material, softening agent and other complementary elements alternatively.
Compressed tablets preferably has the hardness that is enough to bear 8Kp pressure.The big young pathbreaker of tablet depends primarily on the amount of compound in the tablet.Tablet will comprise 300 to 1100mg compound free alkali.Preferably, tablet will be included in the amount of the compound free alkali of 400-600mg, 650-850mg and 900-1100mg scope.
In order to influence dissolution rate, the time that wet-mixed is contained compound powder is controlled.Preferably, total powder mixes time, that is, powder is exposed to time of sodium hydroxide solution will be in 1 to 10 minute and preferred 2 to 5 minutes scope.After granulation, from tablets press, remove degranulation and place fluid bed dryer to be used under about 60 ℃, carrying out drying.
Embodiment 31
MAO and ALDH-2 analyze
The mitochondrial pellet that will obtain from the hamster liver of 5g is suspended in the 10mM sodium phosphate buffer (pH 7.4) of 10mL again, remains on ice, utilizes Branson Sonifier cell disruptor to carry out supersound process 3-15 second under the power of 90W.This suspension in Beckman L8 ultracentrifuge centrifugal 70 minutes with 105000g, and comprise the active supernatant liquor of ALDH-2 and be used for ALDH-2 and analyze.The throw out that mainly comprises mitochondrial membrane washes 3 times in 30mL TKK damping fluid (pH 7.4 for 10mM Tris, 10mM KCl and 10mM KPi).Only comprise MAO but do not have the active final throw out of ALDH-2 to be used for MAO and analyze.At 0.1M NaPPi, analyze the ALDH-2 activity among the pH 9.5, comprise 0.15M KCl, 1.2mM NAD+, 0.6mM formaldehyde, and the daidzin of specific concentrations or its analog.
Active passing through utilizes Varian Cary 1 spectrophotometer under 25 ℃, determine according to the increase of absorbancy at the 340nm place.Analyze the 23MAO activity in the TKK damping fluid, described damping fluid comprises daidzin or its analog and the MAO of 10 í M5-HT, 0.4mM sodium bisulfite, prescribed concentration.Enzyme reaction causes by adding enzyme, and allows to carry out under 37 ℃ 30 minutes.Described reaction is by at full throttle stopping by centrifugal 15 minutes down at 4 ℃ in Sorvall Microspin.Reaction product 5-HIAL exists with its stable hydrosulphite complex body in supernatant liquor, and by at 50mM NaPPi, 10-100-doubly dilutes supernatant liquor and is released among the pH 8.8, and analyzes by HPLC.Because 5-HIAL is unstable at alkaline pH, therefore 5-HIAL is released and is no more than 4 hours before HPLC analyzes.In analytic sample, measure the 5-HIAL of (enhancings) and the total yield of 5-HIAA is 0.78 and 0.86, and be 11.2% and 7.5% by analysis within variance coefficient with the definite analytical procedure of the sample of 2 micromolar analyte determinations separately with the standard analysis thing.Daidzin and analogue thereof are expressed as ALDH-2 and the active effect of MAO: per-cent (%) suppresses)=(Ao-Ae) * 100/Ao, wherein Ao and Ae be the test compounds shortage and in the presence of each self-metering enzymic activity.
The representative data of multiple compound of the present invention is listed in the following table 1.
Figure BPA00001185905001061
Figure BPA00001185905001071
Figure BPA00001185905001081
Figure BPA00001185905001091
Figure BPA00001185905001101
Figure BPA00001185905001111
Figure BPA00001185905001121
Figure BPA00001185905001131
Figure BPA00001185905001141
Figure BPA00001185905001151
Figure BPA00001185905001161
Figure BPA00001185905001171
Embodiment 32
The reduction of alcohol dependence
Animal
Under 21 ± 1 ℃ constant temperature and put upside down 12 hours bright-12 hours dark circulation (10:00-22:00 is dark), the kind of the rat of alcohol-preference is contained in the Stainless Steel Wire mesh cage (26 ' 34 ' 20cm) separately.These rats are than they check varieties separately: the selectivity-non-preference of nursing alcohol (NP), low alcohol-drink (LAD) rat and the Wistar rat consumes the alcohol of significantly Duoing.FH and P rat are from the Wistar rat.Unrestrictedly provide water and food (Agway Prolab Rat/Mouse/Hamster 3000formula, Agway, Syracuse, USA).
The foundation of baseline
According to standard method (Murphy et al., 1988; Rezvani and Grady, 1994; Rezvani et al., 1995), in the Richter pipe, the rat of alcohol-preference is given 1 day and obtains water, freely obtains 10% (v/v) ethanolic soln of originating as unique liquid in 3 days subsequently.Thereafter, for remaining research, rat is given the selection between alcohol and the water.All experiments relate to two-and bottle selects in the example freely to obtain in 24 hours food, water and alcohol.
Experimental program
Behind the stable baseline of setting up alcohol and water intake, animal is maintained at successive and selects example acquisition alcohol and water to reach about 2 months via two bottles.Then, at 09:30am, rat is accepted single i.p. injection of saline vehicle or test compounds.After injection, measured alcohol and water intake in 6 and 24 hours.Measured ingestion of food in back 24 hours in injection.
Chronic whole body gives
Carry out chronic test with bull P rat.Behind the stable baseline of setting up for alcohol and water intake, and according to cross-over design, i.p. gives testing drug or carrier, once a day, and 10 days of sustained continuous.After processing, measured alcohol and water intake in 6 and 24 hours, and measured ingestion of food in back 24 hours in processing.Each rat is accepted two kinds of processing, and gives 3 days removing phase between handling.
Statistical study
The result is expressed as the standard error (SEM) of mean value ± mean value.Volume by the alcohol that consumes multiply by 10% and 0.7893 (ethanol density)/the weight of animals (is unit with kg) and calculates alcohol picked-up (g/kg).Following calculation expression is the alcohol preference of percentage ratio:
(volume of the alcohol of the consumption of representing with ml/represent with ml total fluid intake) * 100 (Rezvani et al., 1990; Rezvani and Grady, 1994).The statistical discrepancy between does not on the same group utilize variance analysis to determine according to Newman-Keuls protected t-test.
Embodiment 33
The minimizing of cocaine dependence and recurrence
The operability oneself that intravenously Cocaine (0.35mg/kg/inj) is used in rat give with restoration model in.In this model, to the rat of cocaine habituation repeatedly presses lever to obtain intravenous dosages Cocaine (iv).When removing Cocaine, rat stops presses lever.Yet if stand not have usually the Cocaine of little intraperitoneal (ip) dosage (10mg/kg) of effect in the animal of not experiment, rat recovers to push (recovery) for the lever of Cocaine.This is effective animal model of recurrence of the mankind of cocaine habituation, and the compound of test Formula I is thirsted for the blocking-up Cocaine and the ability of recurrence.
Use has male Si-Dao mouse that jugular vein inserts conduit.Rat is given the selection of two levers in the test training chest.Active pressing of lever causes sending of Cocaine reinforcer, and pressing of nonactive lever do not cause strengthening.During initial 15 hours 1 training stages of fixed ratio (FR) (FR1 represent a lever to push equal a reinforcement send), the food ball is sent to active lever and pushes to promote lever, and each active lever push (the Noyes that sends that causes single 45mg food ball, Lancaster, NH).Reinforcer was converted into for the FR1 lever of Cocaine (0.35mg/kg/inj sent with 0.27 second) and pushed next day.Cocaine is strengthened and to be sent in the FR1 plan of revising so that illumination and the 20 seconds time outs of the stimulator on active lever are followed in each medicine injection, but active lever is pushed to be counted and do not caused reinforcer to be sent during time out.After 20 seconds, close thorn laser, and first lever is pushed and is caused medicine to be sent once more.Pressing of nonactive lever do not have any result.Training stage every day for each group continues 2 hours, or obtains 200 medicines injections up to the experimenter, and whichever reaches earlier.The experimenter maintains the medicine oneself and gives training mode, up to meeting acquisition standard (3 continuous training Day, on average pushing variation＜10% on the active lever).This spends 10-14 days usually.
Trained reflex weakens (extinction) and restores
Weaken (extinction) and restore experiment for trained reflex, rat is required to show stable replying (velocity of variation (variability) is not higher than 15% in two successive stage) in the FR1 plan of strengthening.After this standard of realization, trained reflex weakens (extinction) process and begins, and makes lever push and no longer causes sending of reinforcer.When cross on average replying of three condition of continuity hyporeflexia (extinction) stages fall into during keeping reply 15% the time, the tested recovery of experimenter.In the animal of Cocaine-experience, restore by non-accidental Cocaine injection (10mg/kg ip) before the recovery phase and cause immediately.In order to strengthen statistics strength and to reduce the animal use thus, began in 3-4 days in first back during second disappearance, it allows the comparison in the other experimenter.Training and testing method between the test operational phase, wherein animal is trained with the oneself and is given medicine.Their behavior disappears subsequently, causes in different skies then and restores.
The result
The 3-[(3-{4-[(methylsulfonyl) amino] phenyl }-4-oxo chromene-7-base oxygen base) first Base]-phenylformic acid (compd A) is to the effect of Cocaine inductive recurrence
ALDH-2 inhibitor 3-[(3-{4-[(methylsulfonyl) amino] phenyl }-4-oxo chromene-7-base oxygen base) methyl] recurrence of benzoic Ip injected dose dependency blocking-up Cocaine.Animal training gives Cocaine (0.35mg/kg/inj) with the oneself and reaches stable replying up to them.They are trained in identical chamber subsequently, but Cocaine is no longer obtained.Be reduced to minimum level (trained reflex weakens) in case they push their lever to reply, they are given the Cocaine (10mg/kg) of amount of initiator subsequently, and their lever of replying is pushed remarkable increase (recovery) thereupon.Those accept the 3-[(3-{4-[(methylsulfonyl before initiations of Cocaine injection) amino] phenyl }-4-oxo chromene-7-base oxygen base) methyl] the identical animal of phenylformic acid (7.5 with the 10mg/kg) lever that do not show them pushes the increase (not recurrence) aspect replying.
Table 2-lever is pushed (mean+/-standard error)
Figure BPA00001185905001201
#, weaken (extinction) with trained reflex significantly different, p＜0.01
*, significantly different with carrier, p＜0.05
Test the following compound of Formula I similarly, and obtained similar result:
7-(5-[3-fluoro-5-(trifluoromethyl) phenyl] (1,2,4-oxadiazole-3-yl) } methoxyl group)-3-(4-hydroxyphenyl) chromene-4-ketone; And
3-(3-{[3-(4-hydroxyphenyl)-4-oxo chromene-7-base oxygen base] methyl }-1,2,4-oxadiazole-5-yl) phenylformic acid.
When other compound of test Formula I, obtained similar result.
Embodiment 34
The reduction of nicotine dependence
Biomaterial
The male rat (250-300g) in Wistar-source one arrive the laboratory after, be divided into two groups and hold and with 12 hours: 12 hours photoperiod (0600h open-1800h close) is supported in the environment of temperature-control.Animal can freely obtain food and water during the custom phase in one week of laboratory.About the NIH guilding principle of using and nursing of laboratory animal, and the animal of using in the research is handled, holds and killed to all place, state and federal regulations that are suitable for and policy according at present.Animal is handled and reached several days so that they are desensitized to processing pressure every day before experiment test.Sample size (n=8) provides the reliable estimation of effect of drugs.
Drug treating:
The rat in Wistar-source is accepted the 3-[(3-{4-[(methylsulfonyl of (i.p.) several dosage that intraperitoneal gives) amino] phenyl }-4-oxo chromene-7-base oxygen base) methyl] phenylformic acid (0.00,7.5,10 and 15mg/kg); and positive control compound; mecamylamine (mecamylamine) (1.5mg/kg, subcutaneous (s.c.).Described compound gave during SA in preceding 30 minutes.The 3-[(3-{4-[(methylsulfonyl) amino] phenyl }-4-oxo chromene-7-base oxygen base) methyl] phenylformic acid gives with 2ml/kg for 7.5mg/kg (3.75mg/ml) and 10mg/kg (5mg/ml), and (5mg/ml) gives with 3ml/kg for 15mg/kg dosage.In Semen Maydis oil (VEH), and supersound process at least 30 minutes is up to giving preceding 2 hours with compound dissolution.Mecamylamine is dissolved in 0.09% isotonic saline solution, and gives with the volume of 1ml/kg.
Device:
Food training and Nicotine oneself occur in 8 standard C oulboum operation rooms.Each chamber is contained in the noise elimination box.Operation room is equipped with two levers, and 2cm on the ground is installed, and signal lamp is installed in the right lever top 2cm on the rear wall of described chamber.For the food training, the food hopper is positioned at a left side/right 2cm of arbitrary lever, is positioned at the centre of rear wall.Intravenously injects injection pump via the outside that is positioned at anechoic room, and (Razel CT) sends with the volume of 0.1ml 1 second interim.
The food training:
As by Hyytia et al., the lever of setting up that the method for (1996) is showed is pushed.At first, rat is limited the food (approximately 85% of their ad lib body weight) of 15g every day.After food restriction second day, rat are trained in fixed ratio 1 (FR1) plan of strengthening (pushing 1 food ball for each lever) down to food reaction, have 1 second time out (TO-1s) after each reinforcement.Be given twice every day training period, and the TO phase is increased to 20 seconds gradually.In case the stable baseline that the rat acquisition is replied with the FR1-TO20s plan of strengthening, they are preparing to return to random diet before the implant surgery of intravenously jugular vein conduit.
Operation:
With ketamine/xylazine mixture anesthetized rat, and chronic silicon rubber jugular vein conduit is inserted in the external jugular vein and subcutaneous passing arrives the polyethylene components that is installed on the animal back.Conduit tube component is formed (internal diameter 0.31mm by the long silicon catheter of 13-cm; External diameter 0.64mm), be connected to guiding sleeve with right-angle bending.Described sleeve pipe is embedded in the dental cement substrate also with the durable sieve aperture grappling of 2 * 2cm quadrate.Described conduit is subcutaneous by arriving jugular vein from rat back, and wherein it is inserted into and fixes with the nonabsorbable silk suture.After completing successfully operation, rat is given 3-5 days so that recover before the beginning during the oneself gives.During restoration, rat is kept random diet, and every day with the heparinized saline flushing line line that comprises the 66mg/ml Ticarcillin/Clavulanate Acid of 30 units/ml, in case hemostasis liquid solidify with conduit in infection.
Nicotine the oneself give:
After the recovering of success from the conduit implant surgery, rat by food deprivation once more to they free diet body weight 85%.In case the oneself gives the stage, the experimenter is trained, and IV oneself gives Nicotine in 1-hour baseline period, 5 days weekly, and under the FR1-TO-20 plan of strengthening, up to realizing stable replying.Stable reply be defined as through 3 successive stage less than 20% velocity of variation.After stable the replying that obtains Nicotine, utilize Latin square design in the subject to test the 3-[(3-{4-[(methylsulfonyl of various dosage) amino] phenyl }-4-oxo chromene-7-base oxygen base) methyl] phenylformic acid.Rat is at the 3-[(3-{4-[(methylsulfonyl with each dosage) amino] phenyl-4-oxo chromene-7-base oxygen base) methyl] phenylformic acid handles to reach and is allowed to the oneself behind 1 test phase and gives Nicotine, and subsequently during a test oneself gives the stage before next dosage is surveyed " baselined again " reach 1-3 days.According to the test of first compound, rat is accepted the positive control compound, and mecamylamine (1.5mg/kg) gives according to cross-over design.
During the SA stage, rat before test phase by normal saline washing guaranteeing catheter patency, and the heparinized saline with the 30 units/ml that comprises the 66mg/ml Ticarcillin/Clavulanate Acid washes once more behind test phase, in case hemostasis liquid solidify with conduit in infection.If there is query in catheter patency, then pass through moving of unexpected response rate, maybe can not show from the conduit blood drawing, inject the shortterm effect narcotic (Brevital) of 0.1ml.Has the animal of OD showed musculartone in 3 seconds rapid forfeiture.Test has rat removal from experiment of no longer open conduit according to Brevital.
Data analysis
From the online collection data of a plurality of operation rooms, and be reported as the average cumulative quantity of pushing for the rod of Nicotine.Utilize StatView statistical packages analytical data on the compatible computer of PC-.
The result
The 3-[(3-{4-[(methylsulfonyl) amino] phenyl }-4-oxo chromene-7-base oxygen base) first Base]-effect that phenylformic acid gives the Nicotine oneself
3-[(3-{4-[(methylsulfonyl as the increase dosage that gives described in the top scheme) amino] phenyl }-4-oxo chromene-7-base oxygen base) methyl] phenylformic acid reduces the quantity that the rod that gives for Nicotine is pushed, as shown in Figure 1.
When other compounds of test Formula I, obtained similar result.

Claims (25)

1. the compound of chemical formula below a kind:
Figure FPA00001185904900011
Formula I
Wherein:
R 1Be the heteroaryl of the phenyl of optional replacement, optional replacement or the heterocyclic radical of optional replacement;
R 2Be low alkyl group, cyano group, the heteroaryl of optional replacement, C (O) OR of the lower alkoxy of hydrogen, hydroxyl, halogen, optional replacement, optional replacement 5,-C (O) R 5,-SO 2R 15,-B (OH) 2,-OP (O) (OR 5) 2,-C (NR 20) NHR 22,-NHR 4, or C (O) NHR 5, wherein,
R 4Be hydrogen ,-C (O) NHR 5, or-SO 2R 15, or-C (O) R 5
R 5It is the low alkyl group of hydrogen, optional replacement;
R 15Be the low alkyl group of optional replacement or the phenyl of optional replacement; Or
R 2Be-O-Q-R 6, wherein Q is covalent linkage or low-grade alkylidene and R 6It is the heteroaryl of optional replacement;
R 3Be amino, low alkyl group, lower alkoxy or the halogen of hydrogen, cyano group, optional replacement;
X, Y and Z are selected from-CR 7-and-N-, wherein R 7Be hydrogen, low alkyl group, lower alkoxy or halogen;
V be oxygen, sulphur or-NH-; And
W is-Q 1-T-Q 2-, wherein
Q 1Be covalent linkage or alternatively by hydroxyl, lower alkoxy, amino, cyano group or=C that O replaces 1-6The straight or branched alkylidene group;
Q 2Be alternatively by hydroxyl, lower alkoxy, amino, cyano group or=C that O replaces 1-6The straight or branched alkylidene group; And
T be covalent linkage ,-O-or-NH-, or
T and Q 1Can form covalent linkage together,
R 20And R 22Be independently selected from by hydrogen, hydroxyl, C 1-15Alkyl, C 2-15Thiazolinyl, C 2-15The group that alkynyl, cycloalkyl, heterocyclic radical, aryl, benzyl and heteroaryl are formed,
Wherein said alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, benzyl and heteroaryl moieties are replaced by 1 to 3 substituting group alternatively, and described substituting group is independently selected from halogen, alkyl, alkyl monosubstituted amino or dialkyl amido, alkyl or aryl or heteroaryl amide, CN, O-C 1-6Alkyl, CF 3, COOH, OCF 3, B (OH) 2, Si (CH 3) 3, heterocyclic radical, aryl and heteroaryl.
2. compound according to claim 1, wherein,
R 1Replaced by 1 to 3 substituting group alternatively, described substituting group be independently selected from by alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, halogen ,=O, B (OH) 2, NO 2, CF 3, OCF 3, CN, OR 20, SR 20, N (R 20) 2, S (O) R 22, SO 2R 22, SO 2N (R 20) 2, S (O) 3R 20, P (O) (OR 20) 2, SO 2NR 20COR 22, SO 2NR 20CO 2R 22, SO 2NR 20CON (R 20) 2, NR 20COR 22, NR 20CO 2R 22, NR 20CON (R 20) 2, NR 20C (NR 20) NHR 22, COR 20, CO 2R 20, CON (R 20) 2, C (O) N (R 20) 2, C (S) N (R 20) 2, C (O) NR 20SO 2R 22, NR 20SO 2R 22, SO 2NR 20CO 2R 22, OCONR 20SO 2R 22, OC (O) R 20, C (O) OCH 2OC (O) R 20, and OCON (R 20) 2The group of forming, and
In addition wherein each optional alkyl, cycloalkyl, heteroaryl, aryl and heterocyclic radical substituting group further alternatively by aryl, heteroaryl, halogen, NO 2, alkyl ,=O, B (OH) 2, CF 3, OCF 3, Si (CH 3) 3, amino, alkyl monosubstituted amino or dialkyl amido, alkyl or aryl or heteroaryl amide, NR 20COR 22, NR 20SO 2R 22, COR 20, CO 2R 20, CON (R 20) 2, C (O) N (R 20) 2, C (S) N (R 20) 2, NR 20CON (R 20) 2, OC (O) R 20, OC (O) N (R 20) 2, S (O) 3R 20, P (O) (OR 20) 2, SR 20, S (O) R 22, SO 2R 22, SO 2N (R 20) 2, CN or OR 20Replace.
3. compound according to claim 2, wherein X, Y and Z are-CH-.
4. compound according to claim 3, wherein,
R 2And R 3Be independently alkyl, amino ,-B (OH) 2,-C (NR 20) NHR 22,-C (O) NHR 5,-C (O) R 5,-C (O) OR 5, cyano group, hydrogen, halogen, lower alkoxy ,-NHSO 2R 15, hydroxyl ,-OP (O) (OR 5) 2, or-SO 2R 5
5. compound according to claim 4, wherein, V is-O-.
6. compound according to claim 5, wherein, Q 1And/or Q 2Be branched alkylidene.
7. compound according to claim 5, wherein, Q 1Form covalent linkage together with T, and Q 2Be methylene radical, make that W is a methylene radical.
8. compound according to claim 7, wherein, R 2For hydroxyl or-NHSO 2CH 3, and R 3Be hydrogen.
9. compound according to claim 8, wherein, R 1For alternatively by COOR 20The phenyl that replaces.
10. compound according to claim 9, wherein, R 20Be the C that is replaced by 1 to 3 substituting group alternatively 1-3Alkyl, described substituting group are independently selected from halogen, alkyl monosubstituted amino or dialkyl amido and aryl, heteroaryl, cycloalkyl or heterocyclic radical, and described aryl, heteroaryl, cycloalkyl or heterocyclic radical are independently selected from halogen, CF by 1 to 3 alternatively 3, C 1-4Low alkyl group and C 1-3The substituting group of alkoxyl group replaces.
11. compound according to claim 10, wherein, R 20Be the C that is replaced by five yuan or single six-membered rings heterocyclic radical alternatively 1-3Alkyl, described heterocyclic radical are independently selected from halogen, CF by 1 to 3 alternatively 3, C 1-4Low alkyl group and C 1-3The substituting group of alkoxyl group replaces.
12. compound according to claim 11, wherein, R 20Be the ethyl that is replaced by five yuan or single six-membered rings heterocyclic radical alternatively, described heterocyclic radical is independently selected from halogen, CF by 1 to 3 alternatively 3, C 1-4Low alkyl group and C 1-3The substituting group of alkoxyl group replaces.
13. compound according to claim 12, wherein, described five yuan or single six-membered rings heterocyclic radical are selected from the group of being made up of tetrahydrofuran base, morpholinyl, oxathiane, thio-morpholinyl, tetrahydro-thienyl, THP trtrahydropyranyl, tetrahydro thiapyran base, piperidyl, triazolidinge, piperazinyl, dihydropyridine base, pyrrolidyl, imidazolidyl, hexahydropyrimidine, hexahydro-pyridazine and tetrahydroglyoxaline.
14. compound according to claim 13 is selected from the group of being made up of following:
3-((3-(4-(methyl sulfonamido) phenyl)-4-oxo-4H-chromene-7-base oxygen base) methyl) phenylformic acid 2-morpholinyl ethyl ester; And
3-((3-(4-(methyl sulfonamido) phenyl)-4-oxo-4H-chromene-7-base oxygen base) methyl) phenylformic acid 2-(4-methylpiperazine-1-yl) ethyl ester.
15. compound according to claim 10, wherein, R 20Be the C that is replaced by alkyl monosubstituted amino or dialkyl amido alternatively 1-3Alkyl.
16. compound according to claim 15, wherein, R 20Be the ethyl that is replaced by dialkyl amido.
17. compound according to claim 16, wherein, R 20Be the ethyl that is replaced by dimethylamino, that is, and 3-((3-(4-(methyl sulfonamido) phenyl)-4-oxo-4H-chromene-7-base oxygen base) methyl) phenylformic acid 2-(dimethylamino) ethyl ester.
18. compound according to claim 10, wherein, R 20It is unsubstituted alkyl.
19. compound according to claim 18, wherein, R 20Be ethyl, that is, and 3-((3-(4-(methyl sulfonamido) phenyl)-4-oxo-4H-chromene-7-base oxygen base) methyl) ethyl benzoate.
20. a pharmaceutical composition comprises described compound of the claim 1 for the treatment of significant quantity and pharmaceutical carrier.
21. a method for the treatment of habituation comprises the described compound of claim 1 of the Mammals treatment effective dose that needs it.
22. method according to claim 21, wherein, described habituation is to being selected from the medicament in the group of being made up of Cocaine, opium, Amphetamine, Nicotine and alcohol.
23. method according to claim 21, wherein, the described compound of claim 1 is the 3-[(3-{4-[(methylsulfonyl) amino] phenyl }-4-oxo chromene-7-base oxygen base) methyl] phenylformic acid.
24. compound according to claim 14, wherein, described compound is 3-((3-(4-(methyl sulfonamido) phenyl)-4-oxo-4H-chromene-7-base oxygen base) methyl) phenylformic acid 2-morpholinyl ethyl ester.
25. pharmaceutical composition according to claim 20, wherein, the described compound of claim 1 is 3-((3-(4-(methyl sulfonamido) phenyl)-4-oxo-4H-chromene-7-base oxygen base) methyl) phenylformic acid 2-morpholinyl ethyl ester.
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