Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-06-12
1999-09-28
Dees, Jose' G.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
5462684, 544358, 544360, 544366, 544106, 544111, 544124, 514 89, 514133, 5142358, 5142315, 5142355, 514255, C07D40104, C07D40304, A61K 3144, A61K 3147
Patent
active
059591137
DESCRIPTION:
BRIEF SUMMARY
The invention is concerned with novel imidazole derivatives of the general formula ##STR2## wherein R.sup.1 signifies lower-alkyl or halogen, R.sup.2 signifies hydrogen, hydroxy, nitro, lower-alkoxycarbonyl, di(lower-alkyl) amino-lower-alkyl, morpholino-lower-alkyl or 4-methylpiperazinyl-lower-alkyl, R.sup.3 signifies hydrogen or lower-alkyl, R.sup.5 signifies amino or lower-alkyl, R.sup.7 signifies hydrogen or lower-alkyl, and R.sup.8 signifies hydrogen or halogen,
The term "lower-alkyl" used here, alone or in combination, signifies a straight-chain or branched alkyl group with 1-6 C atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, isobutyl, tert. butyl, n-pentyl and n-hexyl. The term "halogen" or "halo" embraces fluorine, chlorine, bromine and iodine.
Methyl and isopropyl are preferred lower-alkyl groups. Chlorine is a preferred halogen.
Examples of preferred compounds of formula I are:
methyl e, l!morpholine, dimethylamine, l!-4-methylpiperazine, ine, and
The compounds of formula I which contain acidic functions can form pharmaceutically usable salts with bases such as alkali metal hydroxides (e.g. sodium hydroxide and potassium hydroxide), alkaline earth metal hydroxides (e.g. calcium hydroxide and magnesium hydroxide) and ammonium hydroxide and the like. The compounds of formula I which contain basic functions can form pharmaceutically usable salts with acids. As such salts there come into consideration not only salts with inorganic acids such as hydrochloric acid or hydrobromic acid, sulphuric acid, nitric acid and phosphoric acid, but also salts with organic acids such as acetic acid, tartaric acid, succinic acid, fumaric acid, maleic acid, malic acid, salicylic acid, citric acid, methanesulphonic acid, p-toluenesulphonic acid etc.
The present invention is accordingly concerned with compounds of formula I and their pharmaceutically usable salts per se and for use as therapeutically active substances, a process for the manufacture of these compounds and their salts, medicaments which contain these compounds or salts and the production of these medicaments and the use of the compounds and their salts for the control of illnesses, especially hyperproliferative disorders such as atherosclerosis, psoriasis and tumours and for the treatment of alopecia, or for the production of a medicament for the treatment and prevention of such disorders.
The pharmacological activity of the compounds in accordance with the invention can be determined on the basis of their activity as protein kinase inhibitors and inhibitors of HaCaT-cell proliferation. In particular, the compounds in accordance with the invention are selective inhibitors of epidermal growth factor receptor (EGF-R) tyrosine kinase.
EGF-R plays a role in the development and metastation of certain human malignant diseases such as breast cancer, cancer of the liver and cancer of the prostate.
For all known functions and activities of EGF-R its tyrosine kinase activity is a determining factor. The inhibition of this enzymatic activity by the compound of formula I can therefore be looked upon as a measurement for the efficacy in the therapeutic treatment of EGF-R-mediated hyperproliferative diseases such as certain forms of cancer and psoriasis.
In contrast to the stimulating role of the EGF receptor in keratinocyte proliferation, in vitro and in vivo studies show that the activation of this receptor is a negative regulator of hair follicle activity. Thus, the injection of EGF inhibits hair growth in newborn mice (Moore et al., J. EGF induces a catagen-like state (Philpott et al., J. Cell Sci. 97, 463 that inhibition of EGF-R tyrosine kinase stimulates hair growth and lengthens the duration of the anagen phase of the hair cycle in vivo.
The biological activity of the compounds in accordance with the invention was tested in various test models which are described hereinafter.
The activity of EGF-receptor tyrosine kinase is determined by measuring the transfer of .sup.32 P-labelled phosphate from .sup.32 P-.gamma.-ATP (10 .mu.M) to the su
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Harmon Charles Stanford
Kamber Markus
Krasso Anna
Pirson Wolfgang
Wyss Pierre-Charles
Dees Jos,e G.
Hoffmann-La Roche Inc.
Johnston George W.
Qazi Sabiha N.
Rocha-Tramaloni Patricia S.
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