Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-06-16
2001-07-24
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S396000, C514S458000
Reexamination Certificate
active
06265425
ABSTRACT:
The present invention is concerned with the use of a tocopherol, more in particular vitamin E, for the manufacture of a medicament for avoiding, alleviating, suppressing or overcoming the adverse side-effects of therapy with a RAMBA, i.e. a Retinoic Acid Metabolism Blocking Agent, more particularly a 4-(heteroaryl-methyl)aniline compound, especially a N-[4-(heteroaryl-methyl)phenyl]-benzothiazolamine compound. The present invention is also concerned with the combination of 4-(heteroaryl-methyl)anilines with vitamin E and its use as a medicine.
Compounds suppressing the metabolism of retinoids, also denoted as Retinoic Acid Metabolism Blocking Agents (RAMBAs), can be used to control the rate of growth and differentiation of normal, preneoplastic and neoplastic epithelial cells, control the rate of growth and differentiation of normal, preneoplastic and neoplastic cells, whether they are epithelial or mesenchymal; whether they are of ectodermal, endodermal or mesodermal origin, thus making these compounds useful in the treatment of carcinoma and keratinization disorders. They are particularly useful in the treatment of carcinomas, such as, for example, prostate cancer, breast cancer, head- and neck cancer, cervix cancer, skin tumors, lung cancer, esophageal cancer, gastrointestinal cancers, anal cancer, penile cancer, bladder cancer, renal cancer; or keratinization disorders, such as, for example, ichthyosis, psoriasis and severe psoriasis, rosacea, acne, plantar warts, callosities, acanthosis nigricans, lichen planus, molluscum, melasma, corneal epithelial abrasion, geographic tongue, Fox-Fordyce disease, cutaneous metastatic melanoma and keloids, epidermolytic hyperkeratosis, Darier's disease, pityriasis rubra pilaris, congenital ichthyosiform erythroderma, hyperkeratosis palmaris et plantaris, melasma, hyperpigmentation and premalignant lesions, such as, for example, Morbus Bowden, pin (prostate intraepithelial neoplasia), cin (cervical intraepithelial neoplasia), leukoplakia.
EP-0,371,559 discloses the use of (1H-imidazol-1-yl)methyl-1H-benzimidazoles as RAMBAs, i.e. they suppress the metabolism of retinoids. Amongst the compounds mentioned therein, 5-[3-chlorophenyl]-1H-imidazol-1-ylmethyl]-1H-benzimidazole has been tested clinically and is known as liarozole.
Vitamin E , &agr;-tocopherol, is a phenol that is widespread in plant materials. It appears to have several functions in animals, but one important function seems to be as a radical scavenger. Vitamin E has the following structure:
The chemical systematic name of vitamin E is 3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-2H-1-benzopyran-6-ol. In literature, vitamin E may refer to various alpha-tocopherol derivatives, stereoisomers and mixtures thereof. Vitamin E is commercially available as various alpha-tocopherol derivatives, stereoisomers and mixtures thereof and also as e.g. the acetate or the succinate.
Other interesting tocopherols are beta-tocopherol, i.e. 3,4-dihydro-2,7,8-trimethyl-2-(4,8,12-trimethyltridecyl)-2H-1-benzopyran-6-ol; gamma-tocopherol, i.e. 3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-2H-1-benzopyran-6-ol; delta-tocopherol, i.e. 3,4-dihydro-2,8-dimethyl-2-(4,8,12-trimethyltridecyl)-2H-1-benzo-pyran-6-ol; epsilon-tocopherol, 3,4-dihydro-2,5,8-trimethyl-2-(4,8,12-trimethyl-3,7,11-tridecatrienyl)-2H-1-benzopyran-6-ol; zeta-1-tocopherol, i.e. 3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyl-3,7,11-tridecatrienyl)-2H-1-benzopyran-6-ol; zeta-2-tocopherol, i.e. 3,4-dihydro-2,5,7-trimethyl-2-(4,8,12-trimethyltridecyl)-2H-1-benzopyran-6-ol; eta-tocopherol, i.e. 3,4-dihydro-2,7-dimethyl-2-(4,8,12-trimethyltridecyl)-2H-1-benzopyran-6-ol.
For the purpose of this invention actually also a prodrug of a tocopherol and in particular of vitamin E will do.
The term “prodrug” refers to a product that releases a tocopherol or, in particular, vitamin E once administered to the patient. The term “prodrug” may refer to another compound wherein there is a covalent bond between the tocopherol and the rest of the compound, said covalent bond being a bond which is easily broken once administered to the patient. Examples of such bonds which are easily broken are ester bonds or amide bonds. The term “prodrug” may also refer to inclusion complexes or other types of complexes which release a tocopherol, in particular, vitamin E once it is administered to the body.
Aside from relieving symptoms of its deficiency in animals, vitamin E displays no notable pharmacological effects or toxicity. Numerous contradictory findings and claims for the actions and mechanisms of action characterize the literature on vitamin E. In acting as an antioxidant, vitamin E presumably prevents oxidation of essential cellular constituents, such as ubiquinone (coenzyme Q), or prevents the formation of toxic oxidation products , such as peroxidation products from unsaturated fatty acids that have been detected in its absence. Diets high in polyunsaturated fatty acids increase an animal's requirement for vitamin E. However, other chemically unrelated substances, such as synthetic antioxidants, selenium, some sulfur-containing amino acids, and the coenzyme Q group, are able to prevent or reverse some of the symptoms of vitamin E deficiency in animal species. In animals vitamin E also affords protection against various drugs, metals and chemicals that can initiate free-radical formation. However, no such protection has been observed in man. Some symptoms of vitamin E deficiency in animals are not relieved by other antioxidants, and it is presumed in these cases that the vitamin is acting in a more specific way.
There is an apparent relationship between vitamin A and E. The intestinal absorption of vitamin A is enhanced by vitamin E, and hepatic and other cellular concentrations of vitamin A are elevated; this may be related to its protection by the antioxidant properties of vitamin E. In addition, vitamin E seems to protect against various effects of hypervitaminosis A. (
Goodman and Gilman, The Pharmacological Basis of Therapeutics,
seventh edition, page 1587).
Vitamin E is commercially available, for instance, in nutritional supplements often in the form of a cocktail of several vitamins and other ingredients.
It is known that liarozole, as a prominent member of the retinoic acid metabolism blocking agents (RAMBAs), has some particular side-effects, such as nausea, vomiting or fatigue. Furthermore patients taking liarozole show symptoms of skin or mucosa linked toxicities, such as, for example, dry skin, peeling skin, flaking skin, pruritus, dry lips, cheilitis, dry mouth. However, liarozole does not show several toxicities seen with hypervitaminosis A or administration of exogenous retinoids such as influence on lipid metabolism, retinoic acid syndrome or visus disturbances.
Unexpectedly, it has been found that administering a tocopherol, in particular, vitamin E or a prodrug thereof ameliorates the retinoic acid metabolism blocking agent (RAMBA) related adverse effects.
The present invention encompasses the combination of a tocopherol, in particular vitamin E, or a prodrug thereof and a retinoic acid metabolism blocking agent (RAMBA).
The present invention encompasses the combination of a tocopherol, in particular, vitamin E and a retinoic acid metabolism blocking agent (RAMBA), more in particular, 4-(heteroaryl-methyl)anilines of formula (I) and (II), the N-oxides, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, said 4-(heteroaryl-methyl)anilines having the formula
wherein:
R
1
represents hydrogen, hydroxy, C
1-6
alkyl or aryl;
R
2
represents hydrogen; C
1-12
alkyl; C
3-7
cycloalkyl; C
2-8
alkenyl; aryl; pyrrolidinyl optionally substituted with C
1-4
algyl or C
1-4
alkyloxycarbonyl; or C
1-12
alkyl substituted with one or two substituents selected from C
3-7
cycloalkyl, hydroxy, C
1-4
alkyloxy, cyano, amino, mono- and di(C
1-4
alkyl)amino, mono- and di(aryl)-amino, arylC
1-4
alkylamino, (C
1-4
alkyl)(arylC
1-4
alkyl)amino, pyrrol
Bruynseels Jan Paul Jozef Michel
De Porre Peter Marie-Zoë Robert
Wouters Walter Boudewijn Leopold
Appollina Mary
Henley III Raymond
Janssen Pharmaceutica N.V.
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