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

2004-06-15

Aulakh, Charanjit S. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Nitrogen containing other than solely as a nitrogen in an...

C564S048000, C564S050000, C562S561000, C560S169000, C514S597000, C514S592000, C514S578000, C514S557000, C514S551000

Reexamination Certificate

active

06750253

ABSTRACT:

FIELD 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-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. PCT/DK98/00008 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 patho-genesis, 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 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 patho-genesis. 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, and 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
)olefinic group, (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;
Q represents a bond, —SO
2
—, or —C(R
6
)(R
7
)(—O—C═O)—, in which formula R
6
and R
7
independently represent hydrogen, trifluoromethyl, or (C
1
-C
4
)alkyl;
Y represents (C
1
-C
15
)alkyl, (C
2
-C
15
)olefinic group, (C
3
-C
10
)carbocyclic group, or phenyl, any of which is optionally substituted by one or more, same or different substituents represented by the formula R
5
; or Y represents a group of formula —(Z—O)
n
—Z, where Z is a (C
1
-C
3
)alkyl and 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, (C
1
-C
4
)alkyl, 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 —CONRR′ wherein R and R′ stands for (C
1
-C
3
)alkyl;
X represents oxygen or sulphur,
or a pharmaceutically acceptable salt thereof, or a hydrate or 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, or cyano; 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
2
)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, or carboxy; R
4
represents hydrogen, (C
1
-C
2
)alkyl, or allyl; X represents oxygen; Q represents a bond, or —-SO
2
—; Y represents (C
1
-C
6
)alkyl; (C
2
-C
6
)alkenyl; (C
3
-C
6
)cycloalkyl; (C
5
-C
8
)cycloalkene group; or phenyl; any of which is optionally substituted by one or more, same or different substituents selected from the group consisting of the formula R
5
as defined below, and R
5
represents fluoro, chloro, bromo, 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 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; preferably R
1
is methyl and most preferrably 2-methyl; R
2
represents one or more, same or different substituents selected from the group consisting of hydrogen, fluoro, chloro, bromo, hydroxy, methyl, or methoxy; preferably R
2
is Cl and most preferably 2-Cl; preferably R
3
represents hydrogen, methyl, methoxy, fluoro, chloro, or bromo; R
4
represents hydrogen; Y represents (C
1
-C
6
)alkyl, (C
3
-C
7
)cycloalkyl, or phenyl; any of which may be optionally substituted by one or more, same or different substituents selected from the group consisting of fluoro, chloro, bromo, hydroxy, amino, azido, (C
1
-C
3
)alkyl, (C
1
-C
2
)alkoxycarbonyl, cyano, —COOH, —CONH
2
, and CON(CH
3
)
2
. Most preferably Y represents methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, cyclohexyl, hexyl, 6-chloro-hexyl, —(CH
2
)
2
COOCH
2
CH
3
, (CH
2
)
2
COOH, tolyl, or phenyl.
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.
Specific Compounds of the Invention Includes
1-Cyclohexyl-3-[2-[3-chloro-4-(2-methylbenzoyl)-phenylamino]phenyl]urea (Compound 101),
1-Ethyl-3-[2-[3-chloro-4-(2-methylbenzoyl)-phenylamino]phenyl]urea (Compound 102),
1-[2-[3-Chloro-4-(2-methylbenzoyl)-phenylamino]phenyl]-3-phenylurea (Compound 103),
1-Butyl-3-[2-[3-chloro-4-(2-methylbenzoyl)-phenylamino]phenyl]urea (Compound 104),
1-[2-[3-Chloro-4-(2-methylbenzoyl)-phenylamino]phenyl]-3-(4-methylphenylsulfonyl)urea (Compound 105),
1-[2-[3-Chloro-4-(2-methylbenzoyl)-phenylamino]phenyl]-3-(phenylsulfonyl)urea (Compound 106),
1-tert-Butyl-3-[2-[3-chloro-4-(2-methylbenzoyl)-phenylamino]phenyl]urea (Compound 107),
1-[2-[3-Chloro-4-(2-methylbenzoyl)-phenylamino]phenyl]-3-iso-propylurea (Compound 108),
1-[2-[3-Chloro-4-(2-methylbenzoyl)-phenylamino]phenyl]-3-propylurea (Compound 109),
1-Methyl-3-[2-[3-chloro-4-(2-methylbenzoyl)-phenylamino]phenyl]urea (Compound 110),
Ethy

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