Aminobenzophenones

Details Aminobenzophenones Aminobenzophenones

2002-02-22

2003-09-23

Davis, Brian (Department: 1621)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C564S328000

Reexamination Certificate

active

06624199

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to novel pharmacologically active aminobenzophenones and related compounds, a novel medical prophylaxis and treatment of acne and acne related skin diseases with aminobenzophenones, and novel compounds effective in the treatment, as well as pharmaceutical preparations containing these compounds and dosage units of such preparations.
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 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.
Acne is a skin condition which is a multifactorial disease affecting the pilosebaceous follicles, characterised in increased sebum production, the formation of comedones, bacterial colonisation by especially Propionibacterium acnes, and localised inflammation. Acne vulgaris is the most common skin disorder among teenagers, but substantial numbers of adults aged 20-40 are also affected by acne. Currently available drugs for the treatment of acne include benzoyl peroxide, azelaic acid, topical and systemic antibiotics, such as fusidic acid (Fucidin®), clindamycin, erythromycin, and tetracyclin, retinoids, such as adapalene, tretinoin, isotretinoin, and hormones, such as estrogen. There are, however, serious drawbacks with these medications including teratogenicity, skin irritation, photosensibilisation, etc., cf. Table 1 below.
Because of the negative psychosocial consequences for the affected individual, and the relatively limited numbers of drugs available for topical treatment of acne and the severity of the known side effects of these drugs, the provision of new medicaments for adequate therapy of acne is very important.
The present inventors have surprisingly found that selected aminobenzophenones including novel compounds having the general formula I below are effective anti-acne agents in both in vitro and in vivo models of acne and acne related disorders with a further potential for being useful as MAP kinase inhibitors and in the treatment of diseases connected with interleukin 1 &bgr; (IL-1 &bgr;) and tumour necrosis factor &agr; (TNF-&agr;) secretion. These findings suggest that an inhibitor of interleukin 1 &bgr; (IL-1 &bgr;) and/or tumour necrosis factor &agr; (TNF-&agr;) secretion (or an inhibitor of intra/extra-cellular? MAP kinase) is useful in the preparation of a medicament for the treatment and/or prophylaxis of acne and related skin disorders.
SUMMARY OF THE INVENTION
The present invention is directed to novel compounds represented by the general formula I
wherein R
1
represents one or more, similar or different substituents selected from the group consisting of hydroxy, halogen including F, Cl, Br, and I, (C
1
-C
5
)alkyl, (C
1
-C
5
)-alkoxy, (C
1
-C
5
)alkylthio, and cyano; R
2
represents hydrogen, hydroxy, halogen including F, Cl, Br, and I, (C
1
-C
5
)alkyl, (C
1
-C
5
)alkoxy, (C
1
-C
5
)alkylthio, or cyano; R
3
represents one or more, similar or different substituents selected from the group consisting of halogen, including F, Cl, Br, and I, hydroxy, mercapto, trifluoromethyl, (C
1
-C
5
)alkyl, (C
1
-C
5
)alkoxy, (C
1
-C
5
)alkylthio, and cyano; and R
6
represents hydrogen or methyl; and salts thereof with pharmaceutically acceptable acids, hydrates, and solvates.
DETAILED DESCRIPTION OF THE INVENTION
Preferred Embodiments
In compounds of formula I it is preferred that R
1
, R
2
and R
3
independently represent similar or different substituents selected from the group consisting of halogen including F, Cl, Br, and I, and (C
1
-C
5
)alkyl. More preferably R
1
represents methyl, R
2
and R
3
represent halogen, preferably F, Cl, or Br, and R
6
represent hydrogen.
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 formula I are:
4-(2-Amino-4-bromophenylamino)-2-chloro-2′-methylbenzophenone (Compound 101);
4-(2-Amino-4-fluorophenylamino)-2-chloro-2′-methylbenzophenone (Compound 102);
4-(2-Aminophenylamino)-2,2′-dichloro-4′-methoxybenzophenone (Compound 112);
4′-(2-Aminophenylamino)-2,2′,3-trichloro-4-methoxybenzophenone (Compound 113);
4′-(2-Aminophenylamino)-2,2′,6-trichloro-4-methoxybenzophenone (Compound 114);
4-(2-Aminophenylamino)-2-chloro-2′-hydroxybenzophenone (Compound 115);
4-(2-Aminophenylamino)-2-chloro-2′-fluorobenzophenone (Compound 116);
4-(2-Aminophenylamino)-2,2′-dichloro-4′-hydroxybenzophenone (Compound 117);
4-(2-Amino-4-bromophenylamino)-2-chloro-4′-ethoxy-2′-methylbenzophenone (Compound 118);
4-(2-Amino-4-bromophenylamino)-2-ethoxy-2′-methylbenzophenone (Compound 119);
4′-(2-Aminophenylamino)-2,2′,4-trichloro-6-hydroxybenzophenone (Compound 120);
4-(2-Amino-5-hydroxyphenylamino)-2-chloro-2′-methylbenzophenone (Compound 121);
4-(2-Aminophenylamino)-2-fluoro-2′-methoxybenzophenone (Compound 122);
4-(2-Aminophenylamino)-2-fluoro-2′-methylbenzophenone (Compound 123);
4-(2-Amino-5-methoxyphenylamino)-2-chloro-2′-methylbenzophenone (Compound 124);
4-(2-Amino-5-chlorophenylamino)-2-chloro-2′-methylbenzophenone (Compound 125);
4-(2-Amino-
4-(trifluoromethyl)phenylamino)-2-chloro-2′-methylbenzophenone (Compound 126);
4-(2-Amino-3-fluorophenylamino)-2-chloro-2′-methylbenzophenone (Compound 127);
4-(2-Amino-N-methyl-phenylamino)-2-chloro-2′-methylbenzophenone (Compound 128);
4-(2-Aminophenylamino)-2,2′-dimethylbenzophenone (Compound 129);
4-(2-Amino-4-fluoro-N-methyl-phenylamino)-2-chloro-2′-methylbenzophenone (Compound 130);
4-(2-Amino-6-methylphenylamino)-2-chloro-2′-methylbenzophenone (Compound 131);
4-(2-Amino-4-methoxyphenylamino)-2-chloro-2′-methylbenzophenone (Compound 132);
4-(2-Aminohenylamino)-2-chloro-3′-fluoro-2′-methylbenzophenone (Compound 133);
4-(2-Amino-4-bromophenylamino)-2-chloro-2′,3′-dimethylbenzophenone (Compound 134);
4-(2-Amino-4-bromophenylamino)-4′-n-butyl-2-chloro-2′-methylbenzophenone (Compound 135);
4-(2-Amino-4-bromophenylamino)-2,4′-dichloro-2′-methylbenzophenone (Compound 136);
4-(2-Amino-4-bromophenylamino)-2-fluoro-2′-methylbenzophenone (Compound 137);
4′-(2-Amino-4-bromophenylamino)-2′-chloro-2,4,5-trimethylbenzophenone (Compound 138);
4-(2-Amino-4-bromophenylamino)-2-chloro-4′-fluoro-2′-methylbenzophenone (Compound 139);
4-(2-Amino-4-bromophenylamino)-2-chloro-2′,5′-dimethylbenzophenone (Compound 140);
4-(2-Amino-4-bromophenylamino)-2,3′-dichloro-2′-methylbenzophenone (Compound
4-(2-Amino-4-bromophenylamino)-2-fluoro-4′-methoxy-2′-methylbenzophenone Compound 142), and their salts with pharmaceutically acceptable acids, hydrates, and solvates.
The compounds of formula I are useful in the treatment and/or prophylaxis of acne and acne related skin disorders.
Furthermore, the present invention is directed to the use of com

Affiliated with

Also associated with

Rating

Aminobenzophenones 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, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Aminobenzophenones will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3034208