Perfume ketones

Abstract

A compound of the formula (I) ##STR00001##
in which, independently, R.sub.1 is selected from H and methyl; R.sub.2 is selected from H, and methyl; R.sub.3 is selected from H, methyl and ethyl; R.sub.4 is selected from H, methyl and ethyl; or R.sub.3 and R.sub.4 together form a ring in which n is 1 or 2. The compounds have the characteristic desirable odour qualities of the Damascone molecules, but lack their disadvantageous skin sensitization effects.

Claims

1. A compound of the formula (I) ##STR00005## in which, independently, R.sub.1 is selected from H, and methyl; R.sub.2 is selected from H, and methyl; R.sub.3 is selected from H, methyl and ethyl; R.sub.4 is selected from H, methyl and ethyl; or R.sub.3 and R4 together form a ring in which n is 1 or 2.

2. The compound according to claim 1, wherein both R.sup.1 and R.sup.2 are hydrogen.

3. The compound according to claim 2, wherein R.sup.4 is selected from methyl and ethyl, or wherein R.sup.3 and R.sup.4 together form a cyclopentyl ring (n=1).

4. The compound according to claim 3 selected from the group consisting of (2E,1R*,2S*)-2-methyl-1-(2,6,6-trimethylcyclohex-3-en-1-yl)but-2-en-1-one, (2E,1R*,2R*)-2-methyl-1-(2,6,6-trimethylcyclohex-3-en-1-yl)but-2-en-1-one, (2E,6R*,7S*)-2-methyl-1-(7-methylspiro[4.5]dec-8-en-6-yl)but-2-en-1-one, (2E,6R*,7R*)-2-methyl-1-(7-methylspiro[4.5]dec-8-en-6-yl)but-2-en-1-one, (2E)-1-(2,6-dimethylcyclohex-3-en-1-yl)-2-methylbut-2-en-1-one, (2E)-1-(6-ethyl-2-methylcyclohex-3-en-1-yl)-2-methylbut-2-en-1-one, (2E)-2-methyl-1-(1,2,6-trimethylcyclohex-3-en-1-yl)but-2-en-1-one, (2E,1R*,2S*)-2-methyl-1-(2-methylcyclohex-3-en-1-yl)but-2-en-1-one, and (2E,1R*,2R*)-2-methyl-1-(2-methylcyclohex-3-en-1-yl)but-2-en-1-one.

5. (2E,1R*,2S*)-2-methyl-1-(2,6,6-trimethylcyclohex-3-en-1-yl)but-2-en-1-one.

6. A method comprising using in a fragrance composition or incorporating in a fragrance application as a fragrance ingredient, a compound or compounds of formula (I) according to claim 1.

7. A fragrance composition comprising a compound according to claim 1 and at least one other fragrance ingredient.

8. A perfumed product comprising a perfumed product base and at least one compound according to claim 1.

9. The perfumed product according to claim 8, selected from fine perfumery, fabric care, household products, beauty and personal care products and air care products.

10. A precursor capable of generating a compound according to Formula (I) as defined in claim 1, having the Formula (II): ##STR00006## in which X is selected from SR.sup.5, NHR.sup.6 and NR.sup.6R.sup.7; R.sup.5, R.sup.6 and R.sup.7 being selected from linear or branched C.sub.1-C.sub.15 alkyl, a C.sub.3-C.sub.8 cycloalkyl or an aryl substituent, both optionally substituted with linear or branched C.sub.1-C.sub.7 alkyl groups or, in the case of NR.sup.6R.sup.7, R.sup.6 and R.sup.7, together with the nitrogen atom to which they are attached, form part of a polymeric entity.

11. A method of providing in a fragrance application a compound of Formula (I) according to claim 1, comprising (i) preparing a precursor compound according to Formula II ##STR00007## in which X is selected from SR.sup.5, NHR.sup.6 and NR.sup.6R.sup.7; R.sup.5, R.sup.6 and R.sup.7 being selected from linear or branched C.sub.1-C.sub.15 alkyl, a C.sub.3-C.sub.8 cycloalkyl or an aryl substituent, both optionally substituted with linear or branched C.sub.1C.sub.7 alkyl groups or, in the case of NR.sup.6R.sup.7, R.sup.6 and R.sup.7, together with the nitrogen atom to which they are attached, form part of a polymeric entity; (ii) adding the precursor compound of Formula II to an application; and (iii) subjecting the application to conditions that will result in the generation of a compound according to Formula (I).

12. A method comprising adding in a fragrance application, a compound according to Formula II ##STR00008## in which X is selected from SR.sup.5, NHR.sup.6 and NR.sup.6R.sup.7; R.sup.5, R.sup.6 and R.sup.7 being selected from linear or branched C.sub.1-C.sub.15 alkyl, a C.sub.3C.sub.8 cycloalkyl or an aryl substituent, both optionally substituted with linear or branched C.sub.1-C.sub.7 alkyl groups or, in the case of NR.sup.6R.sup.7, R.sup.6 and R.sup.7, together with the nitrogen atom to which they are attached, form part of a polymeric entity; for the in situ generation of a compound according to claim 1.

13. A method of providing in a fragrance application a fruity-floral fragrance note with reduced skin sensitization, comprising the addition to a fragrance application base of a compound according to claim 1.

14. The method according to claim 13, wherein both R.sup.1 and R.sup.2 are hydrogen.

15. The method according to claim 14, wherein R.sup.4 is selected from methyl and ethyl, or wherein R.sup.3 and R.sup.4 together form a cyclopentyl ring (n=1).

16. The method according to claim 15, in which the compound is selected from the group consisting of: (2E,1R*,2S*)-2-methyl-1-(2,6,6-trimethylcyclohex-3-en-1-yl)but-2-en-1-one, (2E,1R*,2R*)-2-methyl-1-(2,6,6-trimethylcyclohex-3-en-1-yl)but-2-en-1-one, (2E,6R*,7S*)-2-methyl-1-(7-methylspiro[4.5]dec-8-en-6-yl)but-2-en-1-one, (2E,6R*,7R*)-2-methyl-1-(7-methylspiro[4.5]dec-8-en-6-yl)but-2-en-1-one, (2E)-1-(2,6-dimethylcyclohex-3-en-1-yl)-2-methylbut-2-en-1-one, (2E)-1-(6-ethyl-2-methylcyclohex-3-en-1-yl)-2-methylbut-2-en-1-one, (2E)-2-methyl-1-(1,2,6-trimethylcyclohex-3-en-1-yl)but-2-en-1-one, (2E,1R*,2S*)-2-methyl-1-(2-methylcyclohex-3-en-1-yl)but-2-en-1-one, and (2E,1R*,2R*)-2-methyl-1-(2-methylcyclohex-3-en-1-yl)but-2-en-1-one.

17. The method according to claim 16, in which the compound is (2E,1R*,2S*)-2-methyl-1-(2,6,6-trimethylcyclohex-3-en-1-yl)but-2-en-1-one.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 shows the gene-induction and cell viability curves for Damascone delta and Example 1, in which the black diamonds indicate the induction of the luciferase activity and the open squares Cellular viability.

(2) FIGS. 2 (peptide depletion) and 3 (adduct formation on a logarithmic scale) compare the peptide reactivity of two commercial damascones with the compound of Example 1 (Example).

(3) Example 1 did not induce luciferase activity above the 1.5-fold threshold, and is thus rated as non-sensitizing by this assay. Damascone delta on the other hand clearly induces the luciferase gene already at 4 micromolar, indicating it is a significantly sensitizing compound and maximal gene induction reaches 8.7-fold over control. These results show that Example 1 can be used in perfume formulations for reduced sensitization risk to the consumer. Table 1 shows the results of other compounds according to this disclosure, as compared with Damascone delta. With the exception of example 6, none of the inventive compounds induced the gene above the threshold of 1.5-fold at non-cytotoxic concentrations, while the maximal gene induction was at 8.7 for Damascone delta. A marginal gene induction (1.67-fold at 125 M only) was noted for example 6. This indicates that all inventive compounds have a strongly reduced sensitization potential as compared to Damascone delta.

(4) TABLE-US-00007 Imax (fold Concentration for 1.5- Concentration for 50% maximal gene fold gene induction Cytotoxicity induction) (EC 1.5 in M) (in M) Damascone delta 8.77 3.96 40.47 Compound of Example 1 1.09 n.i. 90.3 Compound of Example 2 1.28 n.i. 112.1 (2E,6R*,7R*)-2-Methyl- 1.12 n.i. 48.8 1-(7-methylspiro[4.5]dec- 8-en-6-yl)but-2-en-1-one (Example 3) (2E,6R*,7S*)-)-2-Methyl- 1.19 n.i. 21.4 1-(7-methylspiro[4.5]dec- 8-en-6-yl)but-2-en-1-one (Example 3) Compound of Example 4 1.36 n.i. 176.2 Compound of Example 5 1.51 Induction only 77.5 below 70% viability Compound of Example 6 1.64 48.8 89.3 (2E,1R*,2S*)-2-Methyl- 1.26 n.i. 339.8 1-(2-methylcyclohex-3- en-1-yl)but-2-en-1-one (Example 7) (2E,1R*,2R*)-2-Methyl- 1.35 n.i. 316.4 1-(2-methylcyclohex-3- en-1-yl)but-2-en-1-one (Example 8) n.i. no induction above threshold of 1.5

EXAMPLE 13

(5) Compounds Tested in the a Peptide Reactivity Assay for Skin Sensitization

(6) A second method to determine allergenic potential of chemicals is the DPRA direct peptide assay (OECD TG 442c). It is based on the fact that allergenic chemicals must react with a peptide/protein in order to be immunogenic.

(7) A peptide reactivity assay (A. Natsch, H. Gfeller, Toxicol. Sci 2008, 106, 464-478) was conducted similarly to the DPRA assay: The test chemicals were dissolved to a final concentration of 4 mM in acetonitrile and 250 l of this solution were added to 2 ml HPLC vials. The test peptide Cor1C-420 with the sequence Ac-NKKCDLF (Genscript Inc., Piscataway, N.J., USA), was dissolved at 0.133 mM in 20 mM phosphate buffer at pH 7.5, and 750 l of this solution were added to each test vial (final concentrations: 1 mM of test chemical and 0.1 mM of peptide in 25% acetonitrile; ratio 1:10 as in the DPRA assay). The samples were incubated for 1-24 h at 37 C. and at regular intervals they were analysed by LC-MS analysis on a VELOS PRO Mass spectrometer (Thermo SCIENTIFIC, San Jose, Calif., U.S.A.) operated in the ESl(+) mode. The temperature of the capillary was kept at 275 C. Mass spectra were recorded from 200-2000 amu. A ZORBAX Eclipse XDB-C18 column, 2.1 mm ID, 150 mm, 5-Micron (Agilent Technologies) was used. The mobile phase consisted of H.sub.2O (A) and methanol (B) each containing 0.1% formic acid (v/v). The solvent flow was 250 l/min and the following gradient (ratio A: B) was used: 0 min, 95:5; 2 min, 40:60; 10 min, 2:98; 12 min, 2:98. The integration was performed with Xcalibur Quan Browser.

(8) Two endpoints are measured with this assay: a) Depletion of the parent peptide. The mass of the protonated parent peptide is measured and the corresponding peak integrated (% depletion; FIG. 2). Depletion of the parent peptide is indicative of reactivity and is described as endpoint in OECD guideline 442c. b) Formation of modified peptides. The specific ion trace for a new adduct with the mass of the test chemical added to the test peptide is extracted, and the peak of the peptide-adduct is integrated (FIG. 3). Peptide adduct formation is a particular sensitive endpoint to determine reactive, and thus allergenic nature of compounds.

(9) FIGS. 2 (peptide depletion) and 3 (adduct formation on a logarithmic scale) compare the 5 peptide reactivity of two commercial damascones with the compound of Example 1 (Example 1). After 1 h, Example 1 produces 3200-fold lower levels of peptide adducts as compared to Damascone delta, and no significant peptide depletion is noted over the 24 h experiment, indicating a dramatic and unexpected reduction of reactivity (and thus allergenicity) for Example 1.