Diarylbenzopyran derivatives as cyclooxygenase-2 inhibitors

Details Diarylbenzopyran derivatives as cyclooxygenase-2 inhibitors Diarylbenzopyran derivatives as cyclooxygenase-2 inhibitors

2001-02-20

2002-01-22

Huang, Evelyn Mei (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S255050, C514S365000, C514S374000, C514S406000, C514S443000, C514S444000, C514S456000, C544S405000, C546S283100, C548S235000, C548S203000, C548S364400, C549S058000, C549S060000, C549S401000

Reexamination Certificate

active

06340694

ABSTRACT:

BACKGROUND OF THE INVENTION
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.
SUMMARY OF THE INVENTION
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.
DETAILED DESCRIPTION OF THE INVENTION
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, burs

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