Diarylbenzopyran derivatives as cyclooxygenase-2 inhibitors

This application is the national phase of PCT/KR99/00469 filed on Aug. 20, 1999.

1. Field of the Invention

The present invention relates to diarylbenzopyran derivatives or their pharmaceutically acceptable salts and cyclooxygenase-2 inhibitor composition containing same.

2. Description of the Related Arts

Non-steroidal, antiinflammatory drugs(NSAIDs), which have been most prevalently used all over the world, have a problem of causing serious side-effects such as gastrointestinal tract or nephro-toxicity. NSAIDs inhibit the activity of cyclooxygenase(hereinafter “COX”), which is an enzyme involved in prostagladin synthesis, resulting in the inhibition of the biosynthesis of prostaglandin not only in inflammatory loci but also in stomach and kidney. It has been found that COX exists in the form of isoenzymes: COX-1 and COX-2[Cell, 83,345, (1995)]. COX-1 exists in normal cells and keeps cell homeostasis and controlls the function of stomach and kidney, while COX-2 is expressed by mitogens or cytokines in pain sites where inflammation and other imrunoreactions occur [J. Biol. Chem., 271,33157(1996)] and is involved in pathologic phenomenon. Therefore the toxicity of NSAIDs is due to its inhibition of the coexisting COX-1's.

To avoid this problem, selective inhibitors of COX-2 has been investigated [Nature, 367, 215(1995)]. The selective inhibitors (i) have suitable antiinflammation, pain-relieving action, antipyretic action; (ii) remove toxicity from and reduce bleeding time in gastrointestinal tract and kidney; (iii) show potential anticancer activity and reduce the induction of mechanism-related side-effect; and also (iv) lower the induction of asthma in asthmatic patients who are sensitive to conventional NSAIDs. These selective inhibitors of COX-2 also show inhibition effect on smooth muscle constriction and could be used in treating Alzheimer's disease and osteoporosis of women after menopausa.

Active researches have been made on the selective inhibitors of COX-2. For example, WO 9606840, Bioorg, Med. Chem. Lett. 5, 2377(1995), Ann. Report. Med. Chem., 211(1997) and many other publications report COX-2 inhibitors having heterocyclic moiety as a base structure.

The present inventors made extensive researches to provide a new compound capable of inhibiting the COX-2's action selectively and strongly, and as a result found out that the diarylbenzopyran derivatives fulfill the requirements.

Therefore, an object of the present invention is to provide diarylbenzopyran derivatives represented by the following general formula (I):

wherein

Y is an oxygen atom or a sulfur atom;

R 1 and R 2 , identical to or different from each other, are independently a hydrogen atom, a halogen atom, a C 1 -C 6 lower alkyl group, a trifluoromethyl group, an alkoxy group, a hydroxy group, a nitro group, a nitrile group, or a carboxyl group;

R 3 is a group of a formula: S(O)nR 5 wherein n is an integer of 0˜2, R 5 is a hydrogen atom, a C 1 -C 6 lower alkyl group, or a group of a formula: NR 6 R 7 wherein R 6 and R 7 , identical to or different from each other, are independently a hydrogen atom, or a C 1 -C 6 lower alkyl group; and

R 4 is oxazolyl, benzo[b]thienyl, furanyl, thienyl, naphthyl, thiazolyl, indolyl, pyrolyl, benzofuranyl, pyrazolyl, pyrazolyl substituted with a C 1 -C 6 lower alkyl group, indanyl, pyrazinyl, or a substituted group presented by the following structures:

wherein

R 8 through R 12 , identical to or different from one another, are independently a hydrogen atom, a halogen atom, a C 1 -C 6 lower alkyl group, a trifluoromethyl group, an alkoxy group, a hydroxy group, a hydroxyalkyl group, a nitro group, a group of a formula: S(O)nR 5 ′ a group of a formula: NR 6 R 7 , a trifluoromethoxy group, a nitrile group a carboxyl group, an acetyl group, or a formyl group, wherein n, R 5 , R 6 and R 7 have the same meaning as defined by R 3 above; and

R 13 is a hydrogen atom, a halogen atom, A C 1 -C 6 lower alkyl group, a trifluoromethyl group, an alkoxy group, a hydroxy group, a trifluoromethoxy group, a carboxyl group, or an acetyl group;

Another object of the present invention is to provide a cyclooxygenase-2-inhibitor-composition comprising an effective amount of a compound represented by the above general formula(I) or a pharmaceutically acceptable salt thereof.

The diarylbenzopyran derivatives or their pharmaceutically acceptable salts of the present invention effectively and selectively inhibit COX-2's action of biosynthesizing the prostagladin, which plays a more important role in progress of inflammation than COX-1.

The diarylbenzopyran derivatives of the present invention, which are useful as selective COX-2's inhibitor drugs, are represented by the following general formula(I)

wherein

Y is an oxygen atom or a sulfur atom;

R 1 and R 2 , identical to or different from each other, are independently a hydrogen atom, a halogen atom, a C 1 -C 6 lower alkyl group, a trifluromethyl group, an alkoxy group, a hydroxy group, a nitro group, a nitrile group, or a carboxyl group;

R 3 is a group of a formula: S(O)nR 5 wherein n is an integer of 0˜2, R 5 is a hydrogen atom, a C 1 -C 6 lower alkyl group, or a group of a formula: NR 6 R 7 wherein R 6 and R 7 , identical to or different from each other, are independently a hydrogen atom, or a C 1 -C 6 lower alkyl group;

R 4 is oxazolyl, benzo[b]thienyl, furanyl, thienyl, naphthyl, thiazolyl, indolyl, pyrolyl, benzofuranyl, pyrazolyl, pyrazolyl substituted with a C 1 -C 6 lower alkyl group, indanyl, pyrazinyl, or a substituted group presented by the following structures:

wherein

R 8 through R 12 , identical to or different from one another, are independently a hydrogen atom, a halogen atom, a C 1 -C 6 lower alkyl group, a trifluromethyl group, an alkoxy group, a hydroxy group, a hydroxyalkyl group, a nitro group, a 3,4-methylenedioxy group, a group of a formula: S(O)nR 5 , a group of a formula: NR 6 R 7 , a trifluromethoxy group, a nitrile group, a carboxyl group, an acetyl group, or a formyl group, wherein n, R 5 , R 6 and R 7 have the same meaning as defined X and R 3 above; and

R 13 is a hydrogen atom, a halogen atom, a C 1 -C 6 lower alkyl group, a trifluromethyl group, a alkoxy group, a hydroxy group, a trifluromethoxy group, a carboxyl group, or an acetyl group.

Also, the diarylbenzopyran derivatives of the above-described general formula(I) could form pharmaceutically acceptable salts, which generally refer to the salts that could form alkaline-metal salts, acid-addition salts, or base-addition salts and are pharmaceutically acceptable because of their non-toxicity. The pharmaceutically acceptable acid-addition salts of the compound(I) are derived from the organic acid or inorganic acid. The inorganic acid used in the present invention, for example, is hydrochloric acid, bromic acid, iodic acid, nitric acid, carbonic acid, sulfuric acid or phosphoric acid. The organic acid used in the present invention, for example, is formic acid, acetic acid, propionic acid, succinic acid, aspartic acid, ascorbic acid, benzoic acid, benzenesulfonic acid, methylsulfonic acid, p-toluenesulfonic acid or salicylic acid.

The pharmaceutically acceptable base-addition salts of the compound(I) are metal salts derived from Al, Ca, Li, Mg, K, Na and Zn or organic salts derived from N, N′-dibenzylethylenediamine, choline, chloroprocaine, diethanolamine, ethylenediamine, N-methylglucamine and procaine.

Even though the use of diarylbenzopyran derivatives(I) of the present invention is not particulary limited, it is useful for treating, for example inflammatory diseases, or as analgesia for labor pain, headache or as antifebrile. The compound(I) of the present invention, not particularly limited, is also useful for treating arthritis such as rheumatic arthritis, spondylitis ankylopoietica, gouty arthritis, osteoarthritis. And the compound(I) of the present invention is useful for treating asthma, bronchitis, dysmenorrhea, tendinitis, bursitis and also useful for treating skin-related diseases such as psoriasis, eczema, bum and dermatitis. Also, the compound(I) of the present invention is useful for treating diseases such as peptic ulcer, gastritis, topical enteritis, colic diverticulitis, gastrointestinal bleeding, and the like. Also the compound(I) of the present invention coud be used in treating cancer by inhibiting the transformation of cell and the growth of metastatic cancer. Moreover, it could be used in treating and preventing diseases, which show abnormality in cyclooxygenase-involving proliferation such as diabetic retinopathy and cancerous vascularization. And it is effective in treating Alzheimer's disease and used in preventing osteoporosis and in treating glaucoma.

Also, the compound(I) of the present invention can be used as a substitute drug for conventional non-steroidal antiinflammatory drugs because it shows high activity and specificity on COX-2. Particulary, the compound of the present invention could be used as a substitute drug in treating patients who are suffering from hypoprothrombinemia, hemophilia or kidney disease, or waiting for surgery or has recurrent gastrointestinal tract disorders such as agglutination abnormality cause by anticoagulant uptake.

In addition to that the compound of the present invention, as we described above, is useful for treating human diseases, it also could be used in treating warm-blooded animals such as mice, house mice, horses, lambs, dogs, cats and etc.

Also, the compound (I) of the present invention can be used for substituting all or parts of active ingredients in the existing non-steroidal inflammatory preparations. In other words, diarylbenzopyran derivatives or their pharmaceutically acceptable salts could be used alone or combined with one of or some of the following components:

(i) pain relievers containing acetoaminophen or phenacetin;

(ii) potentiators containing caffeine;

(iii) H 2 -antagonists;

(iv) decongestants containing aluminum hydroxide, magnesium hydroxide, simethicone, phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline, propylhexedrine or levodeoxyephedrine;

(v) antitussives containing codeine, hydrocodone, caramiphene, carbetapentane or dextramethorphan;

(vi) prostaglandins containing misoprostol, enprostil, riprostil, ornoprostol or rosaprostol;

(vii) diuretics;

(viii) antihistamines having or without having sedative action:

The preferred compound(I) of the present invention includes one of the following compounds:

2-(4-(Methylsulfonyl)phenyl)-3-phenyl-4H-1-benzopyran-4-one,

2-(4-(Methylsulfonyl)phenyl)-3-(4-(methylthio)phenyl)-4H-1-benzopyran-4-one,

3-(2-Methoxyphenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,

3-(4-Fluorophenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,

3-(2-Chlorophenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,

3-(4-(N,N-Dimethylamino)phenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,

3-(4-(N-Methylamino)phenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,

2-(4-(Methylsulfonyl)phenyl)-3-(4-trifluoromethoxyphenyl)-4H-1-benzopyran-4-one,

3-(3-Methoxyphenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,

3-(4-Isopropylphenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,

3-(4-Ethylphenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,

3-(4-Hydroxymethylphenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,

2-(4-(Methylsulfonyl)phenyl)-3-(4-trifluoromethylphenyl)-4H-1-benzopyran-4-one,

3-(4-Hydroxyphenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,

3-(2,3-Difluorophenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,

3-(3,5-Difluorophenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,

3-(2Hydroxyphenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,

3-(2,4-Difluorophenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,

3-(4-Methylphenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,

3-(2,4-Dichlorophenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,

3-(4-Acetylphenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,

3-(2,4-Dimethylphenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,

3-(4-Formylphenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,

3-(4-Carboxyphenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,

3-(4-Chloro-3-fluorophenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,

3-(4-Methoxyphenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,

3-(3,4-Dichlorophenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,

3-(2-Fluorophenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,

3-(4-Fluorophenyl)-5-methoxy-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,

3-(4-Fluorophenyl)-5-hydroxy-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,

3-(3,5-Dichlorophenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,

3-(N-methyl-3-pyrazolyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,

3-(4-Chlorophenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,

6-Chloro-3-(4-fluorophenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,

2-(4-(methylsulfonyl)phenyl)-3-(3-nitrophenyl)-4H-1-benzopyran-4-one,

3-(3,4-Difluorophenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,

2-(4-(methylsulfonyl)phenyl)-3-(1-naphthyl)-4H-1-benzopyran-4-one,

3-(3-Methylphenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,

3-(2-Methylphenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,

3-(3-Chloro-4-fluorophenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,

3-(4-Bromophenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,

3-(2,3-Dichlorophenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,

3-(3-Fluorophenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,

3-(3-Chlorophenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,

2-(4-(Methylsulfonyl)phenyl)-3-(2-oxazolyl)-4H-1-benzopyran-4-one,

6-Fluoro-2-(4-fluorophenyl)-3-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,

3-(2-Benzo[b]thienyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,

3-(2-Chloro-5-pyridinyl)-7-fluoro-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,

7-Fluoro-2-(4-(methylsulfonyl)phenyl)-3-(3-pyridinyl)-4H-1-benzopyran-4-one,

2-(4-(Methylsulfonyl)phenyl)-3-(2-pyridinyl)-4H-1-benzopyran-4-one,

2-(4-(Methylsulfonyl)phenyl)-3-(3-pyridinyl)-4H-1-benzopyran-4-one,

2-(4-(Methylsulfonyl)phenyl)-3-(4-pyridinyl)-4H-1-benzopyran-4-one,

6-Fluoro-2-(4-(methylsulfonyl)phenyl)-3-(3-pyridinyl)-4H-1-benzopyran-4-one,

7-Fluoro-3-(2-methoxy-5-pyridinyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,

3-((3,4-methylenedioxy)phenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4one,

2-(4-(Methylsulfonyl)phenyl)-3-(2-thiazolyl)-4H-1-benzopyran-4-one,

3-(Benzofuran-2-yl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,

2-(4-(Methylsulfonyl)phenyl)-3-(2-thienyl)-4H-1-benzopyran-4-one,

2-(4-(Methylsulfonyl)phenyl)-3-(2-pyrazinyl)-4H-1-benzopyran-4-one,

3-(2-Methyl-5-pyridinyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,

3-(2-Methoxy-5-pyridinyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,

6-Fluoro-3-(2-methyl-5-pyridinyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,

6-Fluoro-3-(2-methoxy-5-pyridinyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,

3-(2-Chloro-5-pyridinyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,

3-(2-Chloro-5-pyridinyl)-6-fluoro-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,

3-(2-Fluoro-5-pyridinyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,

6-fluoro-3-(2-fluoro-5-pyridinyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,

7-fluoro-3-(2-fluoro-5-pyridinyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,

3-(4-Chloro-3-pyridinyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,

3-(4-Fluorophenyl)-6-methoxy-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,

2-(4-(Methylsulfonyl)phenyl)-3-(2-trifluoromethyl-5-pyridinyl)-4H-1-benzopyran-4-one,

3-(2-Fluoro-3-pyridinyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,

3-(2-Chloro-3-pyridinyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,

3-(5-Bromo-3-pyridinyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,

3-(2-Furyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,

3-(5-Indanyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,

3-(4-Fluorophenyl)-6-methyl-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,

3-(4-Fluorophenyl)-6-hydroxy-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,

2-(4-(Aminosulfonyl)phenyl)-3-(2-methylphenyl)-4H-1-benzopyran-4-one,

2-(4-(Aminosulfonyl)phenyl)-3-phenyl-4H-1-benzopyran-4-one,

2-(4-(Aminosulfonyl)phenyl)-3-(3,4-difluorophenyl)-4H-1-benzopyran-4-one,

2-(4-(Aminosulfonyl)phenyl)-3-(4-chloro-3-fluorophenyl)-4H-1 benzopyran-4-one,

2-(4-(Aminosulfonyl)phenyl)-3-(3-chloro-4-fluorophenyl)-4H-1-benzopyran-4-one,

2-(4-(Aminosulfonyl)phenyl)-3-(3,4-dichlorophenyl)-4H-1-benzopyran-4-one,

2-(4-(Aminosulfonyl)phenyl)-3-(2-chlorophenyl)-4H-1-benzopyran-4-one,

2-(4-(Aminosulfonyl)phenyl)-3-(3-chlorophenyl)-4H-1-benzopyran-4-one,

2-(4-(Aminosulfonyl)phenyl)-3-(4-chlorophenyl)-4H-1-benzopyran-4-one,

2-(4-(Aminosulfonyl)phenyl)-3-((4-methylthio)phenyl)-4H-1-benzopyran-4-one,

2-(4-(Aminosulfonyl)phenyl)-3-((3,4-methylenedioxy)phenyl)-4H-1-benzopyran-4-one,

2-(4-(Aminosulfonyl)phenyl)-3-(2,3-difluorophenyl)-4H-1-benzopyran-4-one,

2-(4-(Aminosulfonyl)phenyl)-3-(3-fluorophenyl)-4H-1-benzopyran-4-one,

2-(4-(Aminosulfonyl)phenyl)-3-(2-fluorophenyl)-4H-1-benzopyran-4-one,

2-(4-(Aminosulfonyl)phenyl)-3-(2,4-difluorophenyl)-4H-1-benzopyran-4-one,

2-(4-(Aminosulfonyl)phenyl)-3-(3-methylphenyl)-4H-1-benzopyran-4-one,

2-(4-(Aminosulfonyl)phenyl)-3-(2-methoxyphenyl)-4H-1-benzopyran-4-one,

2-(4-(Aminosulfonyl)phenyl)-6-fluoro-3-(2-fluoro-5-pyridinyl)-4H-1-benzopyran-4-one,

2-(4-(Aminosulfonyl)phenyl)-3-(4-methylphenyl)-4H-1-benzopyran-4-one,

2-(4-(Aminosulfonyl)phenyl)-3-(4-methoxyphenyl)-4H-1-benzopyran-4-one,

2-(4-(Aminosulfonyl)phenyl)-7-fluoro-3-(2-methoxy-5-pyridinyl)-4H-1-benzopyran-4-one,

2-(4-(Aminosulfonyl)phenyl)-3-(3-methoxyphenyl)-4H-1-benzopyran-4-one,

2-(4-(Aminosulfonyl)phenyl)-3-(4-fluorophenyl)-4H-1-benzopyran-4-one,

2-(4-(Aminosulfonyl)phenyl)-3-(2-chloro-5-pyridinyl)-7-fluoro-4H-1-benzopyran-4-one,

2-(4-(Aminosulfonyl)phenyl)-3-(3,5-difluorophenyl)-4H-1-benzopyran-4-one,

2-(4-(Aminosulfonyl)phenyl)-3-(2-pyridinyl)-4H-1-benzopyran-4-one,

2-(4-(Aminosulfonyl)phenyl)-3-(3-pyridinyl)-4H-1-benzopyran-4-one,

2-(4-(Aminosulfonyl)phenyl)-6-fluoro-3-(3-pyridinyl)-4H-1-benzopyran-4-one,

2-(4-(Aminosulfonyl)phenyl)-7-fluoro-3-(3-pyridinyl)-4H-1-benzopyran-4-one,

2-(4-(Aminosulfonyl)phenyl)-3-(2-chloro-5-pyridinyl)-4H-1-benzopyran-4-one,

2-(4-(Aminosulfonyl)phenyl)-3-(2-chloro-5-pyridinyl)-6-fluoro-4H-1-benzopyran-4-one,

2-(4-(Aminosulfonyl)phenyl)-3-(2-fluoro-5-pyridinyl)-4H-1-benzopyran-4-one,

2-(4-(Aminosulfonyl)phenyl)-7-fluoro-3-(2-fluoro-5-pyridinyl)-4H-1-benzopyran-4-one,

2-(4-(Aminosulfonyl)phenyl)-3-(2-methyl-5-pyridinyl)-4H-1-benzopyran-4-one,

2-(4-(Aminosulfonyl)phenyl)-3-(2-methoxy-5-pyridinyl)-4H-1-benzopyran-4-one,

2-(4-(Aminosulfonyl)phenyl)-6-fluoro-3-(2-methoxy-5-pyridinyl)-4H-1-benzopyran-4-one,

2-(4-(Arninosulfonyl)phenyl)-3-(4-pyridinyl)-4H-1-benzopyran-4-one,

2-(4-(Aminosulfonyl)phenyl)-3-(2-thienyl)-4H-1-benzopyran-4-one,

2-(4-(Aminosulfonyl)phenyl)-3-(2-furyl)-4H-1-benzopyran-4-one,

2-(4-(Aminosulfonyl)phenyl)-6-fluoro-3-(4-fluorophenyl)-4H-1-benzopyran-4-one,

2-(4-(Aminosulfonyl)phenyl)-6-fluoro-3-phenyl-4H-1-benzopyran-4-one,

2-(4-(Aminosulfonyl)phenyl)-6-fluoro-3-(4-methylphenyl)-4H-1-benzopyran-4-one,

2-(4-(Aminosulfonyl)phenyl)-6-fluoro-3-(4-chlorophenyl)-4H-1-benzopyran-4-one,

2-(4-(Aminosulfonyl)phenyl)-6-fluoro-3-(3-fluorophenyl)-4H-1-benzopyran-4-one,

2-(4-(Aminosulfonyl)phenyl)-7-fluoro-3-(4-fluorophenyl)-4H-1-benzopyran-4-one,

2-(4-(Aminosulfonyl)phenyl)-7-fluoro-3-(3-fluorophenyl)-4H-1-benzopyran-4-one,

2-(4-(Aminosulfonyl)phenyl)-7-fluoro-3-(2-fluorophenyl)-4H-1-benzopyran-4-one,

2-(4-(Aminosulfonyl)phenyl)-7-fluoro-3-(3,4-dichlorophenyl)-4H-1-benzopyran-4-one,

2-(4-(Aminosulfonyl)phenyl)-8-chloro-3-(4-fluorophenyl)-5-hydroxy-4H-1-benzopyran-4-one,

2-(4-(Aminosulfonyl)phenyl)-8-chloro-3-(4-fluorophenyl)-5-methoxy-4H-1-benzopyran-4-one,

2-(4-(Aminosulfonyl)phenyl)-6-methoxy-3-(4-fluorophenyl)-4H-1-benzopyran-4-one,

2-(4-(Aminosulfonyl)phenyl)-7-methoxy-3-(4-fluorophenyl)-4H-1-benzopyran-4-one,

2-(4-(Aminosulfonyl)phenyl)-6-hydroxy-3-(4-fluorophenyl)-4H-1-benzopyran-4-one,

2-(4-(Methylsulfonyl)phenyl)-3-phenyl-4H-1-benzopyran-4-thione,

3-(4-Fluorophenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-thione,

6-Fluoro-3-(4-fluorophenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-thione,

3-(2-Fluorophenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-thione,

7-Fluoro-2-(4-(methylsulfonyl)phenyl)-3-(3-pyridinyl)-4H-1-benzopyran-4-thione,

3-(3-Fluorophenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-thione,

3-(2-Methylphenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-thione,

3-(4-Methylphenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-thione,

3-(3-Methylphenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-thione,

3-(4-Methoxyphenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-thione,

6-Fuoro-2-(4-(methylsulfonyl)phenyl)-3-(3-pyridinyl)-4H-1-benzopyran-4-thione,

3-(2-Chlorophenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-thione,

3-(2,3-Dichlorophenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-thione,

3-(3,4-Dichlorophenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-thione,

3-(3-Chlorophenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-thione,

3-(4-Chlorophenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-thione,

3-(3-Methoxyphenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-thione,

2-(4-(Methylsulfonyl)phenyl)-3-(4-trifluoromethylphenyl)-4H-1-benzopyran-4-thione,

3-(3-Chloro-4-fluorophenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-thione,

2-(4-(Methylsulfonyl)phenyl)-3-(3-pyridinyl)-4H-1-benzopyran-4-thione,

2-(4-(Aminosulfonyl)phenyl)-6-fluoro-3-(3-pyridinyl)-4H-1-benzopyran-4-thione,

2-(4-(Aminosulfonyl)phenyl)-3-(3-pyridinyl)-4H-1-benzopyran-4-thione,

2-(4-(Aminosulfonyl)phenyl)-3-(4-fluorophenyl)-4H-1-benzopyran-4-thione,

2-(4-(Aminosulfonyl)phenyl)-3-(2-fluorophenyl)-4H-1-benzopyran-4-thione,

2-(4-(Aminosulfonyl)phenyl)-3-(4-chlorophenyl)-4H-1-benzopyran-4-thione,

2-(4-(Aminosulfonyl)phenyl)-3-phenyl-4H-1-benzopyran-4-thione,

2-(4-(Aminosulfonyl)phenyl)-6-fluoro-3-(4-fluorophenyl)-4H-1-benzopyran-4-thione,

2-(4-(Aminosulfonyl)phenyl)-7-fluoro-3-(3-pyridinyl)-4H-1-benzopyran-4-thione

The diarylbenzop,ran derivatives of the present invention can be prepared by reaction schemes 1 through 6. Wherein R 1 , R 2 , R 3 and R 4 in the reaction schems have the same meanings as defined above.

[Reaction Scheme 1]

It represents a four-step reaction of preparing diarylbenzopyran derivative. In Step 1, chalcone(3) is prepared by condensation of substituted acetophenon(1) and substituted aldehyde(2) in the presence of KOH base. In Step 2, flavone derivative is prepared by cyclization of calcone(3) by adding I 2 as a catalyst. A suitable solvent of this step is dimethyl sulfoxide(DMSO). In Step 3, 3-halogenized flavone derivative is prepared by reaction of flavone derivative(4) either with I 2 or N-bromosuccinimide(NBS). In Step 4, benzopyran derivative(7) in which R 4 group at position 3 is substituted is prepared by cross-coupling reaction of substituted flavone derivative(5) with R 4 group substituted boronic acid using Paladium as a catalyst[(Synth. Commun., 11, 513(1981)].

[Reaction Scheme 2]

It represents a 3-step transformed reaction of preparing diarylbenzopyran derivative. In Step 1, compound(8) is prepared by the reaction of flavone derivative(4) having methylthio group as R 3 with I 2 in the presence of Lithium diisopropylamide(LDA) base, at a temperature of −78° C. [J. Chem. Soc. Perkin Trans. I. 799(1985)]. In Step 2, methylsulfonylflavone(10) is prepared by oxidation with oxone(potassium peroxymonosulfate) or 3-chloroperoxybenzoic acid(MCPBA). In Step 3, benzopyran derivative(11) is prepared by cross-coupling reaction of compound(10) with boronic acid(6) using paladium as catalyst.

Alternatively, compound(11) could be prepared by the following method: First, methylsulfonyl group substituted flavone derivative(9) is prepared by oxidizing compound(4) having methylthio group as R 3 with oxone; and then compound(10) is prepared by reacting compound(9) with I 2 and [Bis(trifluoroacetoxy)iodo]benzene(BTI); and benzopyran derivative(11) is prepared by Step 3 of the above reaction.

[Reaction Scheme 3]

It represents the 3-step modified reaction of preparing diarylbenzopyran derivative. In Step 1, bromoflavone(12) is prepared by refluxing flavone derivative(4) having methylthio group as R 3 in chloroform in the presence of N-bromosuccinimide(NBS). In Step 2, methylsulfonylflavone(13) is prepared by oxidation with oxone or MCPBA. In Step 3, benzopyran derivative(11) is substituted is prepared by cross-coupling reaction of compound(13) with boronic acid(6) using paladium catalyst.

[Reaction Scheme 4]

It represents the 1-step reaction of preparing diarylbenzopyranthione derivative. Benzopyranthione derivative(14) is prepared by refluxing diarylbenzopyran derivative with Lawesson reagent(2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphentan-2,4-disulfate; Org. Synth. Coll., 7, 372(1990)) or P 4 S 10 in toluenet.

[Reaction Scheme 5]

It represents the 3-step reaction of preparing diarylbenzopyran derivative. In Step 1, methylsulfinylflavone derivative(15) is prepared by oxidizing compound(5) with oxone or MCPBA. In Step 2, aminosulfonylflavone derivative is prepared by reacting flavone derivative(15) with trifluoroacetic anhydride(TFAA), chlorine gas, ammonium hydroxide. In Step 3, benzopyran derivative(17) is prepared by cross-coupling reaction of aminosulfonylflavone deriative(16) with boronic acid(6) using paladium catalyst.

[Reaction Scheme 6]

It represents the modified reaction of preparing diarylbenzopyran derivative. In Step 1, benzopyran derivative(18) is prepared by cross-coupling reaction of flavone derivative(15) prepared in reaction scheme 5, Step 1 with boronic acid(6) using paladium catalyst. In next step, benzopyran derivatives(17) is prepared by having the same condition of the reaction scheme 5, Step 2.

The present invention will be described in more detail by the following examples and experimental examples, but it must not to be construed that this invention is confined by them.

3-(4-Fluorophenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzo-pyran-4-one

To a solution of 2′-hydroxyacetophenone(10.88 g, 80 mmol) and 4-(methylthio)benzaldehyde(12.16 g, 80 mmol) in ethanol(120 ml) at a temperature of 0° C. was added a solution of KOH (8.96 g, 2.0 equivalent) in water(40 ml) dropwise. The mixture was stirred at room temperature for 24 hours. The solution was acidified with 3N HCl(88 ml) and extracted two times with CH 2 Cl 2 (100 ml per each). The organic layer was washed with saturated NaCl and dried over anhydrous MgSO 4 and filtered and concentrated under reduced pressure. The recrystallization of the residue with CH 2 Cl 2 and petroleum ether yielded the title compound as a yellow solid (42.01 g, 65%).

mp: 98˜100° C.

1 H NMR(CDCl 3 , 300 MHz): δ7.94˜7.86(2H, m), 7.65˜7.47(6H, m), 7.29˜7.25(2H, m), 7.05˜6.92(2H, m), 2.53(3H, s)

IR(KBr): 2911, 1658, 1433, 1306, 1090, 1013 cm −1

2′-hydroxy-4-(methylthio)chalcone(9.5 g, 35.15 mmol) from Step 1 and catalytic amount of I 2 was dissolved in dimethylsulfoxide(;DMSO, 100 ml) and the resulting mixture was stirred at a temperature of 180° C. for half an hour. After identifying the reaction being complete by TLC, the resulting dark solution was poured into excessive ice-water(about 300 ml) and stirred for 10 minutes. The mixture was extracted two times with CH 2 Cl 2 (100 ml per each). And the organic layer was washed with saturated Na 2 S 2 O 3 (100 ml), brine and dried over anhydrous MgSO 4 and filtered and concentrated under reduced pressure. The recrystallization of the residue with CH 2 Cl 2 and petroleum ether yielded the title compound as a light yellow solid(7.54 g, 80%).

mp: 110˜112° C.

1 H NMR(CDCl 3 , 300 MHz): δ8.25˜8.22(m, 1H), 7.86˜7.83(m, 2H), 7.73˜7.66(1H, m), 7.58˜7.55(m, 1H), 7.45˜7.40(1H, m), 7.37˜7.33(2H, m), 6.83(1H, s), 2.55(3H, s)

IR(KBr): 1654, 1594, 1464, 1379, 1099 cm −1

To a solution of 2-(4-(methylthio)phenyl)-4H-1-benzopyran-4-one(0.20 g, 0.75 mmol) from Step 2 in anhydrous tetrahydrofluran(THF, 15 ml) was added 2M LDA (0.38 ml, 1 equivalent) by syringe with stirring at a temperature of −78° C. for 15 minutes under Argon gas atmosphere and then iodine(0.19 g, 0.75 mmol) in THF(5 ml) was added. The mixture was warmed to room temperature and then stirred for 12 hours. After the reaction being complete, the reaction mixture was poured into saturated Na 2 S 2 O 3 (100 ml) and stirred for 1 hour, and the mixture was extracted two times with CH 2 Cl 2 (30 ml per each) and the organic layer was washed with brine and dried over anhydrous MgSO 4 and filtered. The residue was subjected to flash chromatography using a mixture of hexane:ethyl acetate(7:1) as an eluant to afford the title compound as a pale yellow solid(0.23 g, 78%).

mp: 150˜152° C.

1 H NMR(CDCl 3 , 300 MHz): δ8.30˜8.27(1H, m), 7.77˜7.74(2H, m), 7.73˜7.70(1H, m), 7.51˜7.44(2H, m), 7.38˜7.35(2H, m), 2.57(3H, s)

IR(KBr): 3032, 2912, 1646, 1599, 1490, 1330, 1060, 752 cm −1

To a solution of 3-iodo-2-(4-(methylthio)phenyl)-4H-1-benzopyran-4-one(0.34 g, 0.86 mmol) from Step 3 in MeOH(10 ml) and THF(10 ml) was added a solution of Oxone (1.59 g, 2.59 mmol) in H 2 O(10 ml) dropwise at a temperature of 0° C. The resulting mixture was stirred for 3 hours. And the solution was extracted two times with CH 2 Cl 2 (20 ml per each), and the organic layer was washed with brine and dried over anhydrous MgSO 4 . And the resulting solution was filtered and concentrated under reduced pressure. Recrystallization of the resulting residue with CH 2 Cl 2 and petroleum ether yielded the title compound as a white solid(0.33 g, 90%)

mp: 164˜165° C.

1 H NMR(CDCl 3 , 300 MHz): δ8.33˜8.29(1H, m), 8.15˜8.12(2H, m), 8.03˜7.99(2H, m), 7.80˜7.74(1H, m), 7.53˜7.49(2H, m), 3.16(3H, s)

IR(KBr): 1643, 1470, 1301, 1151, 960, 750 cm −1

To a solution of 3-iodo-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one (0.33 g, 90%) from Step 4, 4-fluorobenzeneboronic acid(0.036 g, 0.26 mmol) in toluene(1 ml) and EtOH(1 ml) was added 2M aqueous sodium carbonate (0.61 ml) and then tetrakis(triphenylphosphine)palladium(0.014 g, 0.012 mmol) and was stirred at a temperature of 90° C. for 4 hours. After being concentrated under reduced pressure, it was dissolved in dichloromethane(10 ml) and washed with water, brine. The organic layer was dried over anhydrous MgSO 4 . And the resulting solution was filtered and concentrated under reduced pressure. The residue was subjected to flash chromatography using a mixture of hexane:ethyl acetate(1:1) as an eluant to yield the title compound as a pale yellow solid(0.046 g, 59%).

mp: 208˜210° C.

1 H NMR(CDCl 3 , 300 MHz): δ8.32˜8.30(1H, m), 7.90˜7.87(2H, d), 7.79˜7.73(1H, m), 7.62˜7.60(2H, d), 7.57˜7.54(1H, d), 7.51˜7.46(1H, m), 7.21˜7.16(2H, m), 7.07˜7.01(2H, m), 3.07(3H, s)

IR(KBr): 3017,2922, 1640,1509,1468, 1378, 1290, 1230, 1155, 1142,770 cm −1

The inventive compounds of Examples 2-21 were produced by the same procedure described in Example 1, but substituting appropriate boronic acid or boronate for 4-fluorobenzeneboronic acid in Example 1, step 5. These compounds and their physical properties are shown in Table 1.

3-(3-Methylphenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one

A solution of (4-(methylthio)phenyl)-4H-1-benzopyran-4-one(0.50 g, 1.86 mmol) and NBS(0.36 g, 2.05 mmol) in CHCl 3 (30 ml) was heat to reflux for 5 hours. The resulting mixture was washed with saturated NaHCO 3 , brine and dried over anhydrous MgSO 4 , and filtered, and concentrated under reduced pressure. The residue was subjected to flash chromatography using a mixture of hexane: ethyl acetate(4:1) as an eluant to yield the title compound as a pale yellow solid(0.60 g, 93%).

mp: 162˜163° C.

1 H NMR(CDCl 3 , 300 MHz): δ8.30˜8.27(1H, m), 7.84˜7.80(2H, m), 7.74˜7.69(1H, m), 7.51˜7.43(2H, m), 7.38˜7.34(2H, m), 2.55(3H, s)

IR(KBr): 1658, 1611, 1463, 1331, 1065, 753 cm −1

Following the same oxidation procedure of Example 1, Step 4, but replacing 3-iodo-2-(4-(methylthio)phenyl)-4H-1-benzopyran-4-one by 3-bromo-2-(4-(methylthio)-phenyl)-4H-1-benzopyran-4-one(0.6 g, 0.86 mmol) from Step 1, the 4H-1-benzopyran-4-one(0.6 g, 0.86 mmol) from Step 1, the title compound was obtained as a solid(0.59 g, 90%).

mp: 211˜213° C.

1 H NMR(CDCl 3 , 300 MHz): δ8.34˜8.30(1H, m), 8.15˜8.05(4H, m), 7.80˜7.74(1H, m), 7.54˜7.49(2H, m), 3.15(3H, s)

IR(KBr): 1646, 1310, 1146, 1075 cm −1

Following the procedure of Example 1, Step 5, but substituting 3-bromo-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one(0.18 g,0.47 mmol) for 3-iodo 2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one and m-tolylboronic acid(0.071 g, 0.52 mmol) for 4-fluorobenzeneboronic acid, the title compound was obtained as a solid(0.13 g, 70%).

mp: 178˜179° C.

1 H NMR(CDCl 3 , 300 MHz): δ8.31 8.29(1H, m), 7.87˜7.84(2H, m), 7.76˜7.72(1H, m), 7.64˜7.61(2H, m), 7.56˜7.44(2H, m), 7.22˜7.06(2H, m), 6.96˜6.93(1H, m), 3.05(3H, s), 2.31(3H, s)

IR(KBr): 2920, 1639, 1465, 1377, 1299, 1149, 771 cm −1

Following the procedure of Example 1, Step 5, but substituting 3-bromo-2-(4-(methylthio)phenyl)-4H-1-benzopyran-4-one(0.1 g, 0.29 mmol) for 3-iodo-2-(4-(methylsulfonyl)phenyl) and 4-chlorobenzeneboronic acid(0.05 g, 0.32 mmol) for 4-fluorobenzeneboronic acid, the title compound was obtained as a solid(0.02 g, 20%).

mp: 145˜147° C.

1 H NMR(CDCl 3 , 300 MHz): δ8.30˜8.26(1H, m), 7.73˜7.72(1H, m), 7.55˜7.44(3H, m), 7.33˜7.29(3H, m), 7.20˜7.12(4H, m), 2.48(3H, s)

IR(KBr): 1636, 1594, 1465, 1092 cm −1

Following the procedure of Example 1, Step 4, but replacing 3-iodo-2-(4-(methylthio)phenyl)-4H-1-benzopyran-4-one by 3-(4-chlorophenyl)-2-(4-(methylthio)phenyl)-4H-1-benzopyran-4-one(0.05 g, 0.122 mmol), the title compound was obtained as a solid(0.048 g, 89%).

mp: 187˜188° C.

1 H NMR(CDCl 3 , 300 MHz): δ8.32˜8.28(1H, m), 7.91˜7.89(2H, m), 7.79˜7.73(1H, m), 7.63˜7.61(2H, m), 7.57˜7.46(2H, m), 7.34˜7.27(2H, m), 7.17˜7.14(2H, m), 3.08(3H, s)

IR(KBr): 3083, 2926, 1617, 1465, 1377, 1301, 1157, 1091, 770 cm −1

Following the procedure of Example 1, Step 5, but substituting 3,5-dichlorobenzeneboronic acid(0.067 g, 0.35 mmol) for 4-fluorobenzeneboronic acid and 3-bromo-2-(4-(methylthio)phenyl)-4H-1-benzopyran-4-one(0.1 g, 0.29 mmol) for 3-iodo-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one, the title compound was obtained as a solid(0.043 g, 36%).

mp: 198˜200° C.

1 H NMR(CDCl 3 , 300 MHz): δ8.29˜8.25(1H, m), 7.77˜7.70(1H, m), 7.57˜7.43(2H, m), 7.35˜7.14(5H, m), 6.94˜6.92(1H, m), 6.75˜6.74(1H, m), 2.50(3H, s)

IR(KBr): 2880, 1650, 1430, 1253, 950 cm −1

Following the same oxidation procedure of Example 1, Step 4, but replacing 3-iodo-2-(4-(methylthio)phenyl)-4H-1-benzopyran-4-one by 3-(3,5-dichlorophenyl)-2-(4-(methylthio)phenyl)-4H-1-benzopyran-4-one(0.04 g, 0.096 mmol), the title compound was obtained as a solid(0.02 g, 47%).

mp: 258˜260° C.

1 H NMR(CDCl 3 , 300 MHz): δ8.32˜8.28(1H, m), 7.97˜7.93(2H, m), 7.81˜7.75(1H, m), 7.66˜7.62(2H, m), 7.59˜7.48(2H, m), 7.35˜7.33(1H, m), 7.11˜7.10(2H, m), 3.08(3H, s)

IR(KBr): 3011, 2920, 1628, 1580, 1453, 1373, 1305, 1299, 1155, 961, 764 cm −1

3-(2-Chloro-5-pyridinyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one and 3-(4-Chloro-3-pyridinyl)-2-(4-(methylsulfonyl)-phenyl)-4H-1-benzopyran-4-one

A solution of 2-(4-(methylsulfonyl)phenyl)-3-(3-pyridinyl)-4H-1-benzopyran-4-one(0.2 g, 0.54 mmol) from Example 15 and MCPBA(0.18 g, 0.6 mmol) in CH 2 Cl 2 (20 mL) was refluxed for 1.5 hours. Then the mixture was cooled to room temperature and washed with 1N NaOH solution. The organic layer was dried and concentrated in vacuo to yield the title compound as a pale yellow solid(0.2 g).

mp: 231˜232° C.

1 H NMR(CDCl 3 , 300 MHz): δ8.32˜8.28(1H, m), 8.18˜8.15(1H, m),8.04˜8.03(1H, m), 7.99˜7.95(2H, m), 7.83˜7.76(1H, m), 7.69˜7.65(2H, m), 7.60˜7.50(2H, m), 7.33˜7.21(2H, m), 3.11(3H, s)

IR(KBr): 2923,1641,1467,1385, 1303,1261,1144,760 cm −1

compound A: 3-(2-Chloro-5-pyridinyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one

compound B: 3-(4-Chloro-3-pyridinyl)-2-(4-(methylsulfonyl)-phenyl)-4H-1-benzopyran-4-one

A solution of 2-(4-(methylsulfonyl)phenyl)-3-(N-oxo-3-pyridinyl)-4H-1-benzopyran-4-one(0.2 g, 0.5 mmol) in POCl 3 (2 mL) was heated at a temperature of 110° C. for 6.5 hours. After evaporating the excess POCl 3 , the residue was poured into ice and made alkaline with NH 4 OH and extracted with CH 2 Cl 2 . After the solvent being evaporated, the residue was subjected to flash chromatography to yield the title compound as a pale yellow solid(A; 0.092 g, B; 0.03 g).

compound A;

mp: 232˜233° C.

1 H NMR(CDCl 3 , 300 MHz): δ8.31˜8.28(1H, m), 8.14˜8.06(2H, m), 7.96˜7.93(2H, m), 7.82˜7.75(1H, m), 7.73˜7.69(1H, m), 7.64˜7.48(4H, m), 7.42˜7.36(1H, m), 3.09(3H, s)

IR(KBr): 2920,1647,1465,1308,1140,760 cm −1

compound B;

mp: 235˜236° C.

1 H NMR(CDCl 3 , 300 MHz): δ8.51˜8.49(1H, m), 8.33˜8.29(2H, m), 7.92˜7.89(2H, m), 7.83˜7.76(1H, m), 7.63˜7.42(5H, m), 3.06(3H, s)

IR(KBr): 2925,1643,1466,1307,1145,767 cm −1

2-(4-(Methylsulfonyl)phenyl)-3-(2-pyridinyl)-4H-1-benzopyran-4-one

A solution of 3-bromo-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one (0.5 g, 1.32 mmol) from Example 22, Step 2 and 2-tributylstannylpyridine(0.58 g, 1.58 mmol) and tetrakis(triphenylphosphine)palladium(0.15 g, 0.13 mmol) in N-methyl-2-pyrrolidine(50 ml) and ethanol(1 ml) was heated at a temperature of 100° C. for 24 hours. Then the mixture was cooled to room temperature and diluted with ethyl acetate and filtered through a pad of celite. The mixture was washed with 5% aqueous KF, dried and concentrated. The residue was subjected to flash chromatography to yield the title compound as a pale yellow solid(0.27 g).

mp: 203˜204° C.

1 H NMR(CDCl 3 , 300 MHz): δ8.55˜8.52(1H, m), 8.33˜8.29(1H, m),7.88˜7.84(2H, m), 7.79˜7.73(2H, m), 7.60˜7.55(3H, m), 7.51˜7.46(2H, m), 7.29˜7.24(1H, m), 3.05(3H, s)

IR(KBr): 3058, 1642, 1467, 1382, 1303, 1146, 769 cm −1

6-Fluoro-2-(4-(methylsulfonyl)phenyl)-3-(3-pyridinyl)-4H-1-benzopyran-4-one

The title compound was prepared from 4-(methylthio)benzaldehyde and 5′-fluoro-2′-hydroxyacetophenone by the same method as described in Step 1 of Example 1.

mp: 147˜148° C.

1 H NMR(CDCl 3 , 300 MHz): δ7.92(1H, d, J=15.6 Hz), 7.61˜7.57(3H, m), 7.50(2H, d, J=15.3 Hz), 7.30˜7.21(2H, m), 7.03˜6.98(1H, m), 2.54(3H, s)

IR(neat): 1640, 1573, 1482, 1359, 1170, 1097, 776 cm −1

The title compound was prepared from 5′-fluoro-2′-hydroxy-4-(methylthio)chcalcone and iodine by the same method as described in Step 2 of Example 1.

mp: 177˜178° C.

1 H NMR(CDCl 3 , 300 MHz): δ7.88˜7.81(3H, m), 7.59˜7.55(1H, m), 7.45˜7.39(1H, m), 7.37˜7.33(2H, m), 6.78(1H, s), 2.55(3H, s)

IR(neat): 1639, 1579, 1261,818 cm −1

The title compound was prepared from 6-fluoro-2-(4-(methylthio)phenyl)-4H-1-benzopyran-4-one by the same method as described in Step 4 of Example 1.

1 H NMR(CDCl 3 , 300 MHz): δ8.16˜8.08(4H, m), 7.91˜7.87(1H, m), 7.65˜7.60(1H, m), 7.51˜7.44(1H, m), 6.89(1H, s), 3.12(3H, s)

A solution of 6-fluoro-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one(3.5 g, 11 mmol), iodine(2.8 g, 11 mmol) and [bis(trifluoroacetoxy)iodo]-benzene (3.5 g, 11 mmol) in CH 2 Cl 2 (250 ml) was stirred at room temperature for 24 hours. The resulting mixture was washed with saturated Na 2 S 2 O 3 (100 ml), saturated NaHCO 3 (100 ml) and then washed with brine and dried over anhydrous MgSO 4 and concentrated. Recrystallization of the resulting residue by CH 2 Cl 2 and petroleum ether yielded the title compound as a white solid(2.5 g, 71%).

1 H NMR(CDCl 3 , 300 MHz): δ8.14˜8.10(2H, m), 8.01˜7.91(3H, m),7.55˜7.44(2H, m), 3.15(3H, s)

The title compound was prepared from 6-fluoro-3-iodo-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one and lithium trimethoxy-3-pyridinylboronate by the same method as described in Step 5 of Example 1.

mp: 233˜234° C.

1 H NMR(CDCl 3 , 300 MHz): δ8.60˜8.54(1H, m), 8.36˜8.28(1H, m), 7.96˜7.88(3H,m), 7.77˜7.73(1H, m), 7.62˜7.47(4H, m), 7.40˜7.34(1H, m), 3.07(3H, s)

IR(neat): 2928, 1642, 1483, 1272, 1152, 766 cm −1

A solution of 6-fluoro-2-(4-(methylthio)phenyl)-4H-1-benzopyran-4-one(7.43 g, 25.95 mmol) from Example 34, Step 2 and NBS(6.93 g, 38.93, mmol) in CHCl 3 (100 ml) was refluxed for 20 hours. The resulting mixture was washed with saturated NaHCO 3 , brine and dried over anhydrous MgSO 4 . Recrystallization of the resulting residue by CH 2 Cl 2 and petroleum ether yielded the title compound as a solid(7.38 g, 78%).

mp: 228˜229° C.

1 H NMR(CDCl 3 , 300 MHz): δ7.93(1H. dd, J=7.8,3.0 Hz), 7.84˜7.79(2H, m), 7.5˜7.50(1H, m), 7.48˜7.41(1H, m), 7.39˜7.34(2H, m), 2.56(3H, s)

IR(KBr): 1651, 1477, 1261, 1062, 823 cm −1

To a solution of 3-bromo-6-fluoro-2-(4-(methylthio)phenyl)-4H-1-enzopyran-4-one(7.3 g, 19.9 mmol) from Step 1 in CH 2 Cl 2 (700 ml) was added a solution of MCPBA(4.0 g, 19.9 mmol) in CH 2 Cl 2 (200 ml) at a temperature of 0° C. for 2 hours. The solution was washed two times with saturated Na 2 CO 3 (100 ml per each) and the organic layer was washed with H 2 O , brine and dried over anhydrous MgSO 4 . After the solvent being evaporated, the resulting solid was subjected to flash chromatography using a mixture of ethyl acetate CH 2 Cl 2 (1:1) as an eluant to yield the title compound as a solid(6.1 g, 80%).

mp: 172˜174° C.

1 H NMR(CDCl 3 , 300 MHz): δ8.05˜8.01(2H, m), 7.96˜7.93(1H, m), 7.86˜7.82(2H, m), 7.57˜7.44(2H, m), 2.83(3H, s)

IR(neat): 2988, 1657, 1481, 1275, 1261, 1081 cm −1

A solution of 3-bromo-6-fluoro-2-(4-(methylsulfinyl)phenyl)-4H-1-benzopyran-4-one(6.17 g, 16.18 mmol) in TFAA(trifluoroacetic anhydride, 100 ml) was refluxed for 2 hours. The solvent was removed and the resulting residue was coevaporated three times with using a triethylamine/MeOH solution(50 ml, 1:1) to yield oil. The oil was dissolved in AcOH(100 ml) and treated at room temperature with Cl 2 in AcOH(50 ml). After stirring for 2 hours, the solvent was removed and THF(100 ml) was added to the resulting product. After excessive amount of NH 4 OH solution was added at a temperature of 0° C., the reaction mixture was stirred for 2 hours at room temperature. Water was added and the product was extracted two times with ethyl acetate(100 ml per each). The extract was dried over anhydride MgSO 4 and concentrated. Recrystallization of the resulting residue by CH 2 Cl 2 and petroleum ether yielded the title compound as a solid(3.83 g, 60%).

mp: 266˜267° C.

1 H NMR(CDCl 3 —MeOH-d 4 , 300 MHz): δ8.12˜8.10(2H, m), 8.02˜7.99(2H, m), 7.92(1H, dd, J=8.1, 3.0 Hz), 7.64˜7.51(2H, m)

IR(KBr): 3300, 3236, 1647, 1552, 1481, 1333, 1163, 1081, 755 cm −1

Following the procedure of Example 1, Step 5, but substituting benzeneboronic acid(0.056 g, 0.459 mmol) for 4-fluorobenzeneboronic acid and 2-(4-(aminosulfonyl)phenyl)-3-bromo-6-fluoro-4H-1-benzopyran-4-one(0.153 g, 0.38 mmol) for 3-iodo-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one, the title compound was obtained as a solid(0.08 g, 53%).

mp: 265˜267° C.

1 H NMR(DMSO-d 6 , 300 MHz): δ8.22˜8.19(2H, m), 7.96˜7.94(2H, m), 7.82˜7.75(1H, m), 7,60(1H, d, J=8.4 Hz), 7.54(2H, bs, NH 2 ), 7.46(1H, m), 7.32˜7.19(5H, m)

IR(KBr): 3358, 3268, 3069, 2924, 1691, 1481, 1306, 1164, 750 cm −1

EXAMPLES 48-58

The inventive compounds of Examples 48-58 were produced by the same procedure described in Example 47, step 4, but substituting appropriate boronic acid or boronate for benzeneboronic acid and in case of Example 52-58, the requisite starting material, 2-(4-(aminosulfonyl)phenyl)-3-bromo4H-1-benzopyran-4-one was prepared in the same way to 6-fluoro analog from 2-(4-(methylthio)phenyl)-4H-1-benzopyran-4-one. These compounds and their physical properties are shown in Table 3.

2-(4-(Aminosulfonyl)phenyl)-7-fluoro-3-(4-fluorophenyl)-4H-1-benzopyran-4-one

Following the procedure of Example 1, Step 5, but replacing 3-iodo-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one by of 3-bromo-7-fluoro-2-(4-(methylsulfinyl)phenyl)-4H-1-benzopyran-4-one(0.3 g, 0.79 mmol) prepared from 7-fluoro-2-(4-(methylthio)phenyl)-4H-1-benzopyran-4-one in an analogous way to 6-fluoro analog of Step 1, and Step 2 in Example 47, the title compound was obtained(0.26 g, 82%).

1 H NMR(CDCl 3 , 300 MHz): δ8.33˜8.30(1H, m), 7.70˜7.63(2H, m), 7.50˜7.43(2H, m), 7.61(1H, brs), 7.28˜7.25(1H, m), 7.23˜7.16(2H, m), 7.05˜6.99(2H, m), 2.73(3H, s)

Following the procedure of Example 47, Step 3, but substituting 7-fluoro-3-(4-fluorophenyl)-2-(4-(methylsulfinyl)phenyl)-4H-1-benzopyran-4-one(0.18 g, 0.454 mmol) for 3-bromo-6-fluoro-2-(4-(methyl-sulfinyl)phenyl)-4H-1-benzopyran-4-one, the title compound was obtained as a solid(0.07 g, 37%).

mp: 214˜215° C.

1 H NMR(CDCl 3 , 300 MHz): δ8.34˜8.29(1H, m), 7.88˜7.85(2H, m), 7.55˜7.52(2H, m), 7.25˜7.15(4H, m), 7.07˜7.01(2H, m), 4.94(2H, s)