NEW ISOBUTYRAMIDE DERIVATIVES, COSMETIC AND/OR DERMATOLOGICAL PREPARATIONS CONTAINING SAID COMPOUNDS, AND THEIR USE FOR THE PROPHYLAXIS AND TREATMENT OF SENSITIVE, IN PARTICULAR INFLAMED SKIN OR INFLAMMATORY SKIN CONDITIONS

Abstract

New isobutyramides.

Claims

1.-7. (canceled)

8. An isobutyramide of general formula: ##STR00016## wherein n: is an integer from 1 to 5 which indicates the number of radicals R.sup.1, R.sup.1: independently represents OH, CH.sub.3, O—CH.sub.3, O—(CO)—CH.sub.3, R.sup.2: represents H or C.sub.1-C.sub.4 alkyl, R.sup.3: represents H or CH.sub.3, the isobutyramide of formula ##STR00017## being excluded.

9. The isobutyramide of claim 8, i.e., one of the following compounds: ##STR00018## ##STR00019##

10. A cosmetic or dermatological preparation, wherein the preparation comprises one or more isobutyramides according to claim 8.

11. A cosmetic or dermatological preparation, wherein the preparation comprises one or more isobutyramides according to claim 9.

12. The preparation of claim 10, wherein the preparation comprises from 0.000001% to 10.0% by weight of the one or more isobutyramides, based on a total weight of the preparation.

13. The preparation of claim 12, wherein the preparation comprises from 0.0001% to 3.0% by weight of the one or more isobutyramides.

14. The preparation of claim 12, wherein the preparation comprises from 0.001% to 1% by weight of the one or more isobutyramides.

15. The preparation of claim 10, wherein the preparation is suitable for topical application to human skin.

16. The preparation of claim 10, wherein the preparation is present as an aqueous or aqueous/ethanolic solution.

17. The preparation of claim 10, wherein the preparation is present as an emulsion.

18. The preparation of claim 10, wherein the preparation is capable of prophylaxis and treatment of sensitive skin, itching, dry skin and/or inflammatory phenomena in human skin.

19. The preparation of claim 10, wherein the preparation is capable of reducing a production of sebum or a use of cyclodextrins to produce preparations for eliminating sebum.

20. The preparation of claim 10, wherein the preparation is capable of preventing a formation of comedones and/or acne.

21. The preparation of claim 10, wherein the preparation is capable of preventing or eliminating seborrheic phenomena.

22. The preparation of claim 10, wherein the preparation is capable of preventing or eliminating greasy hair.

23. The preparation of claim 10, wherein the preparation is capable of preventing or eliminating dandruff.

24. A method for the prophylaxis and treatment of sensitive skin, itching, dry skin and/or inflammatory phenomena in human skin, wherein the method comprises applying to skin in need thereof the preparation of claim 10.

25. A method for the prophylaxis and treatment of or for reducing the production of sebum or the use of cyclodextrins for producing preparations for eliminating sebum, wherein the method comprises employing an isobutyramide of claim 8 in making a cosmetic or dermatological preparation for topical application to skin.

26. A method of preventing the formation of comedones and/or acne, wherein the method comprises applying to skin in need thereof a preparation of claim 10.

27. A method of preventing or eliminating seborrheic phenomena, wherein the method comprises applying to skin in need thereof a preparation of claim 10.

Description

[0095] FIG. 1 demonstrates the reduction in LPS-stimulated PGE2 production in human dermal fibroblasts.

[0096] Leukotrienes, which also promote inflammation, can also be formed from arachidonic acid in the skin by migrating neutrophilic granulocytes. Therefore, a reduction in leukotrienes, especially LTB4, is also advised for efficient efficacy.

[0097] FIG. 2 demonstrates the reduction in Ca ionophore-stimulated LTB4.

[0098] Granulocytes are the first immune cells to migrate into the skin after an inflammatory stimulus. Although the “oxidative burst” of the granulocytes is very important for defence against infection, an excessive burst in the tissue can cause extensive collateral damage. In the case of severe inflammation, it may therefore be advisable to dampen this reaction with anti-inflammatory substances.

[0099] FIG. 3 demonstrates the reduction in the “oxidative burst” of fMLP-stimulated neutrophilic granulocytes.

[0100] It can be seen from FIGS. 1-3 that the isobutyramides claimed exhibit an extremely positive anti-inflammatory effect in the tests specified.

Synthetic Methods for Isobutyramides Selected by Way of Example:

Compound 1: N-(4-(2-Hydroxy-4-Methoxyphenyl)Thiazol-2-Yl)Isobutyramide

Step 01

[0101] ##STR00006##

[0102] 114 g (1.5 mol) of thiourea were initially charged in toluene (800 ml) and 80 g (0.75 mol) of isobutyryl chloride were added dropwise. The reaction solution was boiled under reflux for 3 hours, with 2 phases arising. The upper phase was decanted off and cooled. The precipitated white crystals were filtered off under suction and washed with toluene and dried under vacuum.

[0103] Yield: 62 g. .sup.1H-NMR (DMSO-D.sub.6): 11.03 (bs, 1H), 9.66 (bs, 1H), 9.35 (bs, 1H), 2.72 (m, 1H), 1.03 (2, 6H) ppm;

Step 02

[0104] ##STR00007##

Step 03

[0105] ##STR00008##

Compound 2: N-(4-(2,4-Bis(Methoxy)Phenyl)Thiazol-2-Yl)Isobutyramide

Step 01

[0106] ##STR00009##

Step 02

[0107] ##STR00010##

Step 03

[0108] ##STR00011##

Compounds 12 and 13

Step 01

[0109] ##STR00012##

Step 02

[0110] ##STR00013##

Step 03

[0111] ##STR00014##

Step 04

[0112] ##STR00015##

[0113] The examples below are intended to illustrate the present invention without limiting it. Unless otherwise stated, all quantitative data, fractions, and percentages are based on the weight and the total amount or on the total weight of the preparations.

Example Formulations

O/W Emulsions

[0114]

TABLE-US-00001 Example formulations 1 2 3 % by weight % by weight % by weight Stearic acid 2.50 2.00 2.00 Glyceryl stearate 1.00 1.00 1.00 C12-15 alkyl benzoate 3.00 5.00 3.00 Caprylic acid/capric 2.50 2.50 2.00 acid triglyceride Isopropyl palmitate 2.00 — — Cetyl stearyl alcohol 3.00 — 2.00 Cetyl alcohol — 2.00 — Stearyl alcohol — 2.00 1.00 Dibutyl adipate — — 1.50 Cyclomethicone 1.00 1.00 0.50 Dicaprylyl carbonate 2.00 2.00 2.00 Dimethicone 1.00 — 0.50 Compound 1 0.1  0.125 0.15 Glycerin 5.00 7.00 5.00 Ethylhexyl cocoate — — 1.00 Butylene glycol — — 2.0 Carbomer 0.15 0.10 0.15 Carrageenan 0.10 — 0.10 Xanthan gum — — 0.10 Acrylates/C10-30 Alkyl — 0.10 — Acrylate Crosspolymer Trisodium EDTA 0.20 0.20 0.20 Tapioca starch 1.50 1.00 — Polymethylsilsesquioxane — 1.00 1.00 Aluminum starch — — 1.00 octenylsuccinate Distarch phosphate 1.00 1.00 — Sodium hydroxide as as as required required required Water to 100 to 100 to 100 Example formulations 4 5 6 % by weight % by weight % by weight Stearic acid 2.50 2.00 2.00 Glyceryl stearate 1.00 1.00 1.00 C12-15 alkyl benzoate 3.00 5.00 3.00 Caprylic acid/capric 2.50 2.50 2.00 acid triglyceride Isopropyl palmitate 2.00 — — Cetyl stearyl alcohol 3.00 — 2.00 Cetyl alcohol — 2.00 — Stearyl alcohol — 2.00 1.00 Dibutyl adipate — — 1.50 Cyclomethicone 1.00 1.00 0.50 Dicaprylyl carbonate 2.00 2.00 2.00 Dimethicone 1.00 — 0.50 Compound 12 0.2  0.15 0.1 Glycerin 5.00 7.00 5.00 Ethylhexyl cocoate — — 1.00 Butylene glycol — — 2.0  Carbomer 0.15 0.10 0.15 Carrageenan 0.10 — 0.10 Xanthan gum — — 0.10 Acrylates/C10-30 Alkyl — 0.10 — Acrylate Crosspolymer Trisodium EDTA 0.20 0.20 0.20 Tapioca starch 1.50 1.00 — Polymethylsilsesquioxane — 1.00 1.00 Aluminum starch — — 1.00 octenylsuccinate Distarch phosphate 1.00 1.00 — Sodium hydroxide as as as required required required Water to 100 to 100 to 100

W/O Emulsions

[0115]

TABLE-US-00002 Example formulations 7 8 Chemical/INCI name % by weight % by weight Polyglyceryl-3 diisostearate 1.50 1.50 PEG-40 sorbitan perisostearate 2.50 2.50 Lanolin alcohol 0.50 0.50 Paraffinum Liquidum (mineral oil) 8.00 8.00 Cera Microcrystallina 2.50 2.50 Cyclomethicone 4.00 4.00 Isohexadecane 2.00 2.00 Isopropyl palmitate 5.00 5.00 Iodopropynyl butylcarbamate — 0.10 Compound 1 0.20 0.10 Glycerin 7   7 Perfume as required as required Water to 100 to 100 Example formulations 9 10 Chemical/INCI name % by weight % by weight Polyglyceryl-3 diisostearate 1.50 1.50 PEG-40 sorbitan perisostearate 2.50 2.50 Lanolin alcohol 0.50 0.50 Paraffinum Liquidum (mineral oil) 8.00 8.00 Cera Microcrystallina 2.50 2.50 Cyclomethicone 4.00 4.00 Isohexadecane 2.00 2.00 Isopropyl palmitate 5.00 5.00 Iodopropynyl butylcarbamate — 0.10 Compound 12 0.10 0.15 Glycerin 7   7 Perfume as required as required Water to 100 to 100

Aqueous-Ethanolic Solution for e.g., Pen/Applicator/Brush Application

[0116]

TABLE-US-00003 Example formulation 11 % by weight Sodium polyacrylates 1.00 Alcohol Denat. + Aqua 44.40 Glycerin 10.00 Compound 1 0.20 Water 44.40

TABLE-US-00004 Example formulation 12 % by weight Sodium polyacrylates 1.00 Alcohol Denat. + Aqua 44.40 Glycerin 10.00 Compound 12 0.20 Water 44.40