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;

2002-03-15

2003-04-29

Kumar, Shailendra (Department: 1621)

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

Organic compounds

Amino nitrogen containing

C564S212000, C564S214000, C514S628000, C514S629000, C514S630000

Reexamination Certificate

active

06555710

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, allergy, arthritis, including rheumatoid arthritis and spondyloarthritis, gout, atherosclerosis, chronic inflammatory bowel disease (Crohn's disease), proliferative and inflammatory skin disorders, such as psoriasis and atopic dermatitis, uveitis, septic shock, AIDS, and acne.
BACKGROUND OF THE INVENTION
Previously, a series of closely related aminobenzophenones (e.g. 4-(2-amino-4-nitro-phenylamino)benzophenone) have been described (Hussein, F. A. et al, Iraqi J. Sci., 22, 54-66 (1981)). However, there is no description of their uses. PCT/DK98/00008 discloses aminobenzophenone inhibitors of interleukin 1&bgr; (IL-1&bgr;) and tumour necrosis factor a (TNF-&agr;) secretion in vitro, said inhibitors 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 was 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 aminobenzophenone derivatives and related compounds.
This purpose is achieved by providing novel aminobenzophenone derivatives according to the general formula I that 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.
SUMMARY OF THE INVENTION
The compounds of the present invention are represented by the general formula I below
wherein R
1
and R
2
independently represent one or more, same or different substituents 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, carbamoyl, phenyl, or nitro; R
2
further being represented by hydrogen;
R
3
represents hydrogen, halogen, hydroxy, mercapto, trifluoromethyl, amino, (C
1
-C
3
)alkyl, (C
2
-C
3
)alkenyl, (C
1
-C
3
)alkoxy, (C
1
-C
3
)alkylthio, (C
1
-C
6
)alkylamino, (C
1
-C
3
)alkoxycarbonyl, phenyl, cyano, carboxy, or carbamoyl;
R
4
represents hydrogen, (C
1
-C
3
)alkyl, or allyl;
X represents oxygen or sulphur;
with the proviso that formula I does not comprise the compound 2,2,2-Trifluoro-N-[2-[3-chloro-4-(2-methylbenzoyl)-phenylamino]phenyl]acetamide wherein R
1
is 2-methyl, R
2
is 2′-chloro, R
3
and R
4
is hydrogen, and X is oxygen,
or a salt thereof with a pharmaceutically acceptable acid, a hydrate or a solvate thereof.
DETAILED DESCRIPTION OF THE INVENTION
Preferred Embodiments of the Invention
In compounds of the invention it is preferred that R
1
represents one or more, same or different substituents 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, or —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, (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
3
)alkyl, (C
2
-C
3
)alkenyl, (C
1
-C
3
)alkoxy, (C
1
-C
3
)alkoxycarbonyl, cyano, carboxy, or —CONH
2
; R
4
represents hydrogen, (C
1
-C
2
)alkyl, or allyl; and X represents oxygen.
More preferred are compounds of formula I wherein R
1
represents one or more, same or different substituents selected from the group consisting of fluoro, chloro, bromo, hydroxy, methyl, or methoxy; R
2
represents one or more, same or different substituents selected from the group consisting of hydrogen, fluoro, chloro, bromo, hydroxy, methyl, or methoxy; R
3
represents one or more, same or different substituents selected from the group consisting of fluoro, chloro, bromo, hydroxy, methyl, or methoxy; R
4
represents hydrogen or (C
1
-C
2
)alkyl.
Further preferred compounds of general formula I are compounds wherein R
1
, R
2
, and R
3
represent one substituent. R
1
and R
2
preferably being in the ortho position.
Even more preferred are compounds of formula I wherein R
1
is in the 2-position and represents 2-methyl; wherein R
2
is in the 2-position and represents 2-chloro or 2-methyl; wherein R
3
is in the 4-position and represents 4-Br or 4-F; and wherein R
4
is hydrogen.
Specific compounds of the invention are:
2,2,2-Trifluoro-N-[5-bromo-2-[3-chloro-4-(2-methylbenzoyl)-phenylamino]-phenyl]acetamide (Compound 101),
2,2,2-Trifluoro-N-[2-[3-chloro-4-(2-methylbenzoyl)-phenylamino]-5-fluoro-phenyl]acetamide (Compound 102),
2,2,2-Trifluoro-N-[5-bromo-2-[3-chloro-4-(2,3-dimethylbenzoyl)-phenylamino]phenyl]acetamide (Compound 103),
2,2,2-Trifluoro-N-[5-bromo-2-[3-chloro-4-(4-n-butyl-2-methylbenzoyl)-phenylamino]-phenyl]acetamide (Compound 104),
2,2,2-Trifluoro-N-[5-bromo-2-[3-chloro-4-(4-chloro-2-methylbenzoyl)-phenylamino]-phenyl]acetamide (Compound 105),
2,2,2-Trifluoro-N-[5-bromo-2-[3-fluoro-4-(2-methylbenzoyl)-phenylamino]phenyl]-acetamide (Compound 106),
2,2,2-Trifluoro-N-[5-bromo-2-[3-chloro-4-(2,4,5-trimethylbenzoyl)-phenylamino]phenyl]-acetamide (Compound 107),
2,2,2-Trifluoro-N-[5-bromo-2-[3-chloro-4-(4-fluoro-2-methylbenzoyl)-phenylamino]-phenyl]acetamide (Compound 108),
2,2,2-Trifluoro-N-[5-bromo-2-[3-chloro-4-(2,5-dimethylbenzoyl)-phenylamino]phenyl]-acetamide (Compound 109),
2,2,2-Trifluoro-N-[5-bromo-2-[3-chloro-4-(3-chloro-2-methylbenzoyl)-phenylamino]-phenyl]acetamide (Compound 110),
2,2,2-Trifluoro-N-[5-bromo-2-[3-fluoro-4-(4-methoxy-2-methylbenzoyl)-phenylamino]-phenyl]acetamide (Compound 111),
2,2,2-Trifluoro-N-[5-bromo-2-[3-chloro-4-(4-ethoxy-2-methylbenzoyl)-phenylamino]-phenyl]acetamide (Compound 112),
2,2,2-Trifluoro-N-[5-bromo-2-[3-ethoxy-4-(2-methylbenzoyl)-phenylamino]phenyl]-acetamide (Compound 113),
and salts thereof with pharmaceutically acceptable acids, hydrates and solvates.
As used in the specification, unless specified to the contrary, the following terms have the meaning indicated:
“Alkyl” refers to any univalent group derived from an alkane by removal of a hydrogen atom from any carbon atom, and includes the subclasses of normal alkyl (n-alkyl), and primary, secondary and tertiary alkyl groups respectively, and having the number of carbon atoms specified, including for example (C
1
-C
3
)alkyl, methyl, ethyl, n-propyl, isopropyl. Alkane refers to an acyclic branched or unbranched hydrocarbon having the general formula C
n
H
2n+2
, and therefore consisting entirely of hydrogen atoms and saturated carbon atoms.
“Olefinic group” refers to

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-3016938