Aminobenzophenones as inhibitors of IL 1&bgr; and TNF-&agr;

Details Aminobenzophenones as inhibitors of IL 1&bgr; and TNF-&agr; Aminobenzophenones as inhibitors of IL 1&bgr; and TNF-&agr;

2001-03-20

2003-04-01

Richter, Johann (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Amino nitrogen containing

C564S431000, C564S266000, C564S253000, C558S411000, C558S412000, C558S415000, C558S418000, C558S422000

Reexamination Certificate

active

06541670

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to a hitherto unknown class of compounds which shows anti-inflammatory effects, to pharmaceutical preparations containing these compounds, to dosage units of such preparations, and to their use in the treatment and prophylaxis of asthma and allergy; inflammatory diseases, such as arthritis, including rheumatoid arthritis and spondyloarthritis, gout, atherosclerosis, chronic inflammatory bowel disease (Crohn's disease), uveitis, septic shock, and AIDS; proliferative and inflammatory skin disorders, such as psoriasis, atopic dermatitis, and acne; and osteoporosis.
BACKGROUND OF THE INVENTION
Previously, a series of closely related aminobenzophenones (e.g. 4-(2-amino-4-nitrophenylamino)benzophenone) have been described (Hussein, F. A. et al, Iraqi J. Sci., 22, 54-66 (1981)). However, there is no description of their uses. WO 98/32730 discloses aminobenzophenone inhibitors of interleukin 1&bgr; (IL-1&bgr;) and tumour necrosis factor &agr; (TNF-&agr;) secretion in vitro, said compounds being potentially useful for treatment of inflammatory diseases in which the production of cytokines is involved in the pathogenesis, e.g. asthma, rheumatoid arthritis, psoriasis, contact dermatitis, and atopic dermatitis. Furthermore the compounds of PCT/DK98/00008 were tested in vivo for anti-inflammatory properties in the 12-O-tetradecanoylphorbol-13-acetate (TPA) induced murine chronic skin inflammation model, (De Young, L. M. et al., Agents Actions, 26, 335-341 (1989); Carlson, R. P. et al., Agents Actions, 17, 197-204 (1985); Alford, J. G. et al., Agents Action, 37, (1992); Stanley, P. L. et al., Skin Pharmacol, 4, 262-271 (1991)). In this chronic skin inflammation model the compounds had the same potency compared to the reference compound hydrocortisone.
The purpose of the present invention is to provide further pharmacologically active benzophenone derivatives and related compounds.
It has surprisingly been found that novel aminobenzophenone derivatives according to the general formula I are potent inhibitors of interleukin 1&bgr; (IL-1&bgr;) and tumour necrosis factor &agr; (TNF-&agr;) secretion in vitro, making them potentially useful for treatment of inflammatory diseases, in which the secretion and regulation of cytokines or more specifically interleukin 1&bgr; (IL-1&bgr;) and tumour necrosis factor &agr; (TNF-&agr;) are involved in the pathogenesis. The inhibition or down regulation of the cytokines is possibly due to an inhibition of MAP kinases. The preparation of structurally related aminobenzophenones useful as dyes for textiles is disclosed in Man-Made Text. India (1987), 30(6), 275-6; Man-Made Text. India (1986), 29(5), 224-30; and Man-Made Text. India (1985), 28(11), 425, 427-9, 431; an related aminobenzophenone is disclosed in JP 81-61259 as a reactant in the preparation of fluoran color formers.
SUMMARY OF THE INVENTION
The compounds of the present invention are represented by the general formula I
wherein
R
1
represents a substituent selected from the group consisting of halogen, hydroxy, mercapto, trifluoromethyl, amino, (C
1
-C
3
)alkyl, (C
2
-C
3
)olefinic group, (C
1
-C
3
)alkoxy, (C
1
-C
3
)alkylthio, (C
1
-C
6
)alkylamino, (C
1
-C
3
)alkoxycarbonyl, cyano, —CONH
2
, phenyl, or nitro;
R
2
represents one or more, same or different substituents selected from the group consisting of hydrogen, halogen, hydroxy, mercapto, trifluoromethyl, amino, (C
1
-C
3
)alkyl, (C
2
-C
3
)olefinic group, (C
1
-C
3
)alkoxy, (C
1
-C
3
)alkylthio, (C
1
-C
6
)alkylamino, (C
1
-C
3
)alkoxycarbonyl, cyano, —CONH
2
, phenyl, or nitro;
R
3
represents one or more, same or different substituents selected from the group consisting of hydrogen, halogen, hydroxy, mercapto, trifluoromethyl, cyano, carboxy, carbamoyl, (C
1
-C
10
)alkyl, (C
2
-C
10
)olefinic group, (C
3
-C
8
)monocyclic hydrocarbon group, (C
1
-C
10
)alkoxy, (C
1
-C
10
)alkylthio, (C
1
-C
10
)alkoxycarbonyl, or phenyl;
R
4
represents hydrogen, (C
1
-C
6
)alkyl, (C
2
-C
6
)olefinic group, or (C
3
-C
6
)monocyclic hydrocarbon group;
R
5
represents one or more, same or different substituents selected from the group consisting of hydrogen and R
1
;
X represents oxygen, sulphur, or N—OH;
with the proviso that when X represents oxygen then R
1
, R
2
and R
5
together does not represent more than 8 fluorine substituents and with the proviso that the following compounds are not included in formula I:
2-Chloro-4′-(2-chlorophenylamino)benzophenone,
2-Chloro-4′-(phenylamino)benzophenone,
2-Hydroxy-4′-(phenylamino)benzophenone,
2-Hydroxy-4′-(4-hydroxyphenylamino)benzophenone,
2-Hydroxy-4′-(4-methoxyphenylamino)benzophenone,
2-Hydroxy-4′-(2-hydroxyphenylamino)benzophenone,
2-Hydroxy-4′-(2-methoxyphenylamino)benzophenone,
2-Methoxy-4′-(2-methoxyphenylamino)benzophenone, and
2-Methyl-4′-(4-methoxyphenylamino)benzophenone.
DETAILED DESCRIPTION OF THE INVENTION
Preferred embodiments of the invention
In compounds of formula I R
1
preferably represents a substituent selected from the group consisting of fluoro, chloro, bromo, hydroxy, trifluoromethyl, amino, (C
1
-C
2
)alkyl, (C
2
-C
3
)alkenyl, (C
1
-C
3
)alkoxy, (C
1
-C
3
)alkoxycarbonyl, cyano, and —CONH
2
;
R
2
represents one or more, same or different substituents selected from the group consisting of hydrogen, fluoro, chloro, bromo, hydroxy, trifluoromethyl, amino, (C
1
-C
3
)alkyl, (C
2
-C
3
)alkenyl, and (C
1
-C
3
)alkoxy.
R
3
represents one or more, same or different substituents selected from the group consisting of hydrogen, fluoro, chloro, bromo, hydroxy, trifluoromethyl, (C
1
-C
6
)alkyl, (C
2
-C
6
)alkenyl, (C
1
-C
6
)alkoxy, (C
1
-C
6
)alkoxycarbonyl, cyano, carboxy, and —CONH
2
.
R
4
represents hydrogen, (C
1
-C
4
)alkyl, or (C
2
-C
4
)olefinic group;
X represents oxygen or sulphur;
R
5
represents one or more, same or different substituents selected from the group consisting of hydrogen, fluoro, chloro, bromo, hydroxy, trifluoromethyl, amino, (C
1
-C
2
)alkyl, (C
2
-C
3
)alkenyl, (C
1
-C
3
)alkoxy, (C
1
-C
3
)alkoxycarbonyl, cyano, and —CONH
2
;
More preferably R
1
represents a substituent selected from the group consisting of fluoro, chloro, bromo, hydroxy, methyl, and methoxy;
R
2
represents one or more, same or different substituents selected from the group consisting of hydrogen, fluoro, chloro, bromo, hydroxy, methyl, and methoxy;
R
3
represents one or more, same or different substituents selected from the group consisting of hydrogen, fluoro, chloro, bromo, hydroxy, methyl, methoxy, cyano, and carboxy;
R
4
represents hydrogen, methyl, or ethyl;
R
5
represents one or more, same or different substituents selected from the group consisting of hydrogen, fluoro, chloro, bromo, hydroxy, trifluoromethyl, methyl, ethyl, and methoxy;
X represents oxygen;
The phenyl group of R
1
, R
2
, R
3
, and R
5
may optionally be substituted, e.g. with hydroxy; amino; nitro; cyano; halogen, preferably fluoro, chloro, or bromo; methyl; or methoxy.
A preferred embodiment of the invention is the formula VII:
wherein X, R
1
, R
2
, R
3
, R
4
, and R
5
have the meanings specified above except that R
2
does not represent hydrogen. Preferred compounds of formula VII are compounds wherein R
2
represents a halogen atom, preferably chlorine.
Specific compounds of formula I or VII of the invention are:
2-[[3-Chloro-4-(2-methylbenzoyl)]phenylamino]benzonitrile (Compound 101),
2-Chloro-2′-methyl-4-(2-methyl-phenylamino)benzophenone (Compound 102),
2-Chloro-2′-methyl-4-(phenylamino)benzophenone (Compound 103),
2-Chloro-4-(2-methoxy-phenylamino)-2′-methylbenzophenone (Compound 104),
2-Chloro-4-(2-fluoro-phenylamino)-2′-methylbenzophenone (Compound 105),
2-Chloro-4-(2-chloro-phenylamino)-2′-methylbenzophenone (Compound 106),
4-(2-tert-Butyoxy-phenylamino)-2-chloro-2′-methylbenzophenone (Compound 107),
2-Chloro-4-(2-hydroxy-phenylamino)-2′-methylbenzophenone (Compound 108),
2-Chloro-4-(3-chloro-phenylamino)-2′-methylbenzophenone (Comp

Affiliated with

Also associated with

Rating

Aminobenzophenones as inhibitors of IL 1&bgr; and TNF-&agr; does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Aminobenzophenones as inhibitors of IL 1&bgr; and TNF-&agr;, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Aminobenzophenones as inhibitors of IL 1&bgr; and TNF-&agr; will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3109477