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;

2002-02-22

2003-05-20

Kumar, Shailendra (Department: 1621)

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

Organic compounds

Amino nitrogen containing

C564S050000, C564S074000, C564S214000, C564S328000, C562S441000, C560S027000, C560S034000, C560S043000, C560S045000, C554S036000, C514S488000, C514S534000, C514S535000, C514S538000, C514S539000, C514S563000, C514S597000, C514S599000, C514S628000, C514S648000

Reexamination Certificate

active

06566554

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 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 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 with the novel aminobenzophenone derivatives according to the general formula I that are found to be 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
, R
2
, and R
3
represents 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, —CONH
2
, phenyl, or nitro; further R
2
can be hydrogen, and R
3
can be carboxy and carbamoyl;
R
4
represents hydrogen, (C
1
-C
3
)alkyl, or allyl;
X represents oxygen or sulphur;
Q represents —(CO)—, —(CS)—, or a bond;
Y represents (C
5
-C
15
)alkyl; (C
2
-C
15
)olefinic group; (C
3
-C
10
)monocyclic hydrocarbon group; or phenyl; any of which may be optionally substituted by one or more, same or different substituents selected from the group consisting of the formula R
5
defined below; (C
1
-C
4
)alkyl substituted by one or more substituents selected from the group R
5
; or a group of the formula —(Z—O)
n
—Z, wherein Z is a (C
1
-C
3
)alkyl, n is an integer >1; and no continuous linear sequence of atoms in the group Y exceeds 15;
R
5
represents halogen, hydroxy, mercapto, trifluoromethyl, amino, (C
1
-C
3
)alkoxy, (C
1
-C
3
)alkylthio, (C
1
-C
6
)alkylamino, (C
1
-C
3
)alkoxycarbonyl, cyano, azido, nitro, —COOH, —CONH
2
, —CONHR′, or —COONR′R′ wherein R′ represents (C
1
-C
3
)alkyl;
or a salt thereof with a pharmaceutically acceptable acid, a hydrate or a solvate thereof.
In compounds of formula I R
1
preferably 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, halogen, 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;
X represents oxygen or sulphur;
Q represents —(CO)—, or a bond.
Y represents (C
5
-C
10
)alkyl; (C
2
-C
10
)alkenyl; (C
3
-C
8
)cycloalkyl; (C
5
-C
8
)cycloalkene group; or phenyl; any of which may be optionally substituted by one or more, same or different substituents selected from the group consisting of the formula R
5
defined below; (C
1
-C
4
)alkyl substituted by one or more substituents with the formula R
5
; or a group of formula —(Z—O)
n
—Z, wherein Z is a (C
1
-C
3
)alkyl, n is an integer >1; and no continuous linear sequence of atoms in the group Y exceeds 9;
R
5
represents halogen, hydroxy, amino, (C
1
-C
2
)alkoxy, (C
1
-C
4
)alkylamino, (C
1
-C
3
)alkoxycarbonyl, cyano, azido, —COOH, —CONH
2
, —CONHR′, or —CONR′R′ wherein R′ represents (C
1
-C
2
)alkyl.
More preferably 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 hydrogen, fluoro, chloro, bromo, hydroxy, methyl, or methoxy; R
4
represents hydrogen; X represents oxygen; Q represents —(CO)—, or bond; Y represents (C
5
-C
7
)alkyl; (C
2
-C
4
)alkenyl; any of which may be optionally substituted by one or more, same or different substituents selected from the group consisting of the formula R
5
, (C
1
-C
4
)alkyl, substituted by one or more substituents with the formula R
5
, and a group of formula —CH
2
—O—CH
2
—CH
2
—O—CH
3
; R
5
preferably represents fluoro, chloro, bromo, hydroxy, amino, (C
1
-C
2
)alkoxycarbonyl, —COOH, —CONH
2
, CON(CH
3
)
2
.
It is preferred that Q does not represent —(CO)— in compounds of the formula I where Y is —CF
3
.
The phenyl group of R
1
and R
2
may optionally be substituted, e.g. with hydroxy; amino; nitro; cyano; halogen, preferably fluoro, chloro, or bromo; methyl; or methoxy.
Specific compounds of formula I are:
N-[2-[3-Chloro-4-(2-methylbenzoyl)-phenylamino]phenyl]-succinamic acid (Compound 101),
2′-[3-Chloro-4-(2-methylbenzoyl)-phenylamino]octananilide (Compound 102),
4-Bromo-2′-[3-chloro-4-(2-methylbenzoyl)-phenylamino]butananilide (Compound 103),
Ethyl 2′-[3-chloro-4-(2-methylbenzoyl)-phenylamino]succinanilate (Compound 104),
2-(2-Methoxy-ethoxy)-2′-[3-chloro-4-(2-methylbenzoyl)-phenylamino]acetanilide (Compound 105),
N,N-dimethyl-N′-2-[3-chloro-4-(2-methylbenzoyl)-phenylamino]phenylsuccinamide (Compound 106),
2-Hydroxy-2′-[3-chloro-4-(2-methoxybenzoyl)-phenylamino]acetanilide (Compound 107),
2-Hydroxy-2′-[3-chloro-4-(2-methylbenzoyl)-phenylamino]acetanilide (Compound 108),
2-Hydroxy-2′-[3-fluoro-4-(2-methylbenzoyl)-phenylamino]acetanilide (Compound 109),
2-Amino-2′-[3-chloro-4-(2-methylbenzoyl)-phenylamino]acetanilide (Compound 110),
Ethyl 2-[2-[3-chloro-4-(2-methylbenzoyl)-phenylamino]anilino]acetate (Compound 111),
2-Chloro-4-&lsq

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-3019681