Use of physiological cooling active ingredients, and compositions comprising such active ingredients
11434220 · 2022-09-06
Assignee
Inventors
- Benoît Join (Holzminden, DE)
- Jekaterina Ongouta (Stadtoldendorf, DE)
- Michael Backes (Holzminden, DE)
- Rahim Brodhage (Höxter, DE)
- Arnold Machinek (Holzminden, DE)
- Hubert LOGES (Höxter, DE)
- Susanne Mundt (Holzminden, DE)
- Tom SOMERS (Holzminden, DE)
- Thomas Subkowski (Schriesheim, DE)
- Jens Wittenberg (Limburgerhof, DE)
- Martin Weisel (Mannheim, DE)
- Wolfgang Siegel (Limburgerhof, DE)
- Claus Bollschweiler (Heidelberg, DE)
- Ralf PELZER (Fürstenberg, DE)
Cpc classification
C07D409/12
CHEMISTRY; METALLURGY
A61Q11/00
HUMAN NECESSITIES
C07D307/14
CHEMISTRY; METALLURGY
A61K31/443
HUMAN NECESSITIES
C07C323/41
CHEMISTRY; METALLURGY
A23V2002/00
HUMAN NECESSITIES
A61K31/4436
HUMAN NECESSITIES
A61K31/165
HUMAN NECESSITIES
C07D213/75
CHEMISTRY; METALLURGY
A61K31/341
HUMAN NECESSITIES
C07D407/12
CHEMISTRY; METALLURGY
A61K31/34
HUMAN NECESSITIES
C07D405/12
CHEMISTRY; METALLURGY
A23G3/36
HUMAN NECESSITIES
A61K31/4155
HUMAN NECESSITIES
A61K31/444
HUMAN NECESSITIES
A61K31/36
HUMAN NECESSITIES
A61K8/494
HUMAN NECESSITIES
C07D307/22
CHEMISTRY; METALLURGY
International classification
C07D405/12
CHEMISTRY; METALLURGY
C07D213/75
CHEMISTRY; METALLURGY
C07D407/12
CHEMISTRY; METALLURGY
C07D307/14
CHEMISTRY; METALLURGY
C07D409/12
CHEMISTRY; METALLURGY
A61Q11/00
HUMAN NECESSITIES
A23L29/00
HUMAN NECESSITIES
A23L27/00
HUMAN NECESSITIES
A23G3/36
HUMAN NECESSITIES
Abstract
The invention relates primarily to a method of modulation, preferably of in vitro and/or in vivo modulation, of the cold menthol receptor TRPM8, wherein the receptor is contacted with at least one modulator selected from the group consisting of the compounds of the structure type 1 described herein. The present invention further relates to corresponding uses and compositions comprising such compounds.
Claims
1. A compound selected from the group consisting of the following compounds: TABLE-US-00018 Structure Name
2. A composition comprising the compound according to claim 1.
3. The composition according to claim 2, wherein the composition is selected from the group consisting of a) foods, b) oral care products, c) personal care products and d) foams and gels.
4. The composition according to claim 2, wherein the composition is selected from the group consisting of a) foods selected from the group consisting of ice cream, mousse, cream, drinks and confectionery, b) oral care products selected from the group consisting of toothpaste, mouthwash and chewing gum, and c) personal care products selected from the group consisting of skincare or haircare products.
5. The composition according to claim 2, wherein the composition is selected from the group consisting of aroma mixtures and formulations for nutrition, oral hygiene or cosmetic formulations, comprising one, two, three or more of the modulators wherein said modulator(s) is/are present in a (total) amount of 0.05 ppm to 10% by weight, based on the total weight of the aroma mixture or formulation.
6. The composition according to claim 2, wherein the composition additionally comprises: (1) one or more further substances having physiological cooling action, wherein the further substance or one, more than one or all of the further substances (i) cause(s) a flavoring effect or (ii) do(es) not cause a flavoring effect, and/or (2) one or more aromas with no physiological cooling effect, and/or (3) one or more substances having a trigeminal or mouthwatering effect with no physiological cooling effect, and/or (4) (iii) one compound or (iv) two or more compounds which, independently or collectively in case (iv), additionally cause(s) a flavor-modulating effect and/or a trigeminal and/or mouthwatering stimulus.
7. A composition comprising at least one compound as defined in claim 1 for use as a modulator of the TRPM8 receptor.
8. A non-therapeutic method of modulation of the cold menthol receptor TRPM8, which comprises contacting the receptor with at least one modulator selected from the group consisting of the compounds recited in claim 1, including salts of these compounds, and optionally the compounds in stereoisomerically pure form or mixtures of stereoisomers thereof.
9. The method according to claim 8, wherein the modulation is in vitro and/or in vivo modulation.
10. The method according to claim 8, wherein the receptor is contacted with at least one modulator which, in a cellular activity test using cells that recombinantly express the human TRPM8 receptor, modulates the permeability of these cells for Ca.sup.2+ ions.
11. The method according to claim 8, wherein the modulator has an agonistic or antagonistic effect on cellular Ca.sup.2+ ion permeability.
12. The method according to claim 8, wherein the modulator is a TRPM8 receptor agonist.
13. A process for non-therapeutic induction of a cold sensation in man and/or animals which comprises a modulator has an agonistic or antagonistic effect on cellular Ca.sup.2+ ion permeability, wherein the modulator is selected from the compounds recited in claim 1.
14. The process according to claim 13 for non-therapeutic induction of a cold sensation by means of a packing or textile comprising the modulator.
15. The process according to claim 13, wherein a composition comprising at least one, two, three or more of the modulators in a (total) amount of 0.1 ppm to 10% by weight, based on the total weight of the composition, is used to achieve a cooling effect on the skin or mucosa that has been prolonged compared to the cooling effect of a composition of the same constitution in which the modulator(s) has/have merely been exchanged for N-ethylmenthanecarboxamide in the same concentration, by at least 10 minutes, and/or a cooling effect that sets in earlier compared to the cooling effect of a composition of the same constitution in which the modulator(s) has/have merely been exchanged for FEMA 4809 or FEMA 4496 in the same concentration.
16. A process for non-therapeutic induction of a cold sensation in man and/or animals for achieving a physiological cooling effect on the skin and/or mucosa that has been prolonged by at least 10 minutes compared to the cooling effect of a composition of the same constitution in which the modulator(s) has/have merely been exchanged for N-ethylmenthanecarboxamide in the same concentration, and/or a cooling effect that sets in earlier compared to the cooling effect of a composition of the same constitution in which the modulator(s) has/have merely been exchanged for FEMA 4809 or FEMA 4496 in the same concentration, comprising the following step: applying an amount of a composition as defined in claim 2 which is sufficient for achieving a physiological cooling effect to the skin and/or mucosa.
Description
EXAMPLES
(1) The examples serve to illustrate the invention without restricting it thereby. Unless stated otherwise, all figures are based on weight.
(2) Active Production:
(3) The actives of structure type 1 used in accordance with the invention are either compounds known per se or can be prepared by the person skilled in the art in the field of organic synthesis on the basis of known synthesis methods.
(4) Cloning of Human TRPM8:
(5) The starting point for the cloning of the human TRPM8 receptor is an LnCaP cDNA bank. This is, for example, commercially available (for example from BioChain, Hayward, USA) or can be produced from the androgen-sensitive human prostate adenocarcinoma cell line (e.g. ATCC, CRL1740 or ECACC, 89110211) using standard kits.
(6) The encoding TRPM8 sequence (see, for example, http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=nuccore&id=09689694) can be PCR-amplified and cloned using standard methods. The human TRPM8 gene thus isolated was used for production of the plasmid plnd_M8.
(7) Alternatively, the TRPM8 gene can also be produced synthetically.
(8) Generation of the HEK293 Test Cells:
(9) The test cell system produced, with human TRPM8 DNA, was a stably transfected HEK293 cell line. Preference is given here to HEK293 which, via the plasmid introduced, offers the option of induction of TRPM8 expression by means of tetracycline.
(10) Methods of production of suitable test cell systems are known to the person skilled in the art. For instance, the production of the cells used can be inferred from the details in Behrendt H. J. et al., Br. J. Pharmacol. 141, 2004, 737-745 or the thesis by Behrendt “Vergleichende funktionale Untersuchungen des Hitze-Capsaicin-Rezeptors (TRPV1) und des Kälte-Menthol-Rezeptors (TRPM8) in rekombinanten und nativen Zellssystemen” [Comparative Functional Studies of the Heat Capsaicin Receptor (TRPV1) and the Cold Menthol Receptor (TRPM8) in Recombinant and Native Cell Systems], available for example at http://www-brs.ub.ruhr-uni-bochum.de/netahtml/HSS/Diss/BehrendtHansJoerg/diss.pdf. The disclosure of these publications is explicitly incorporated by reference.
(11) Assay for TRPM8 Modulators:
(12) A test comparable with the test already described in the literature by Behrendt H. J. et al., Br. J. Pharmacol. 141, 2004, 737-745, is conducted. The agonism or antagonism of the receptor can be quantified by means of a Ca.sup.2+-sensitive dye (e.g. FURA, Fluo-4 etc.). Agonists on their own result in an increase in the Ca.sup.2+ signal; antagonists in the presence of menthol, for example, result in a reduction in the Ca.sup.2+ signal (in each case detected by means of the Fluo-4 dye which is caused to have different fluorescence properties by Ca.sup.2+).
(13) First of all, in a manner known per se, a fresh culture of transformed HEK cells is produced in cell culture bottles. The HEK293-TRPM8 test cells are detached from the cell culture bottles by means of trypsin and 40 000 cells/well are sown with 100 μl of medium in 96-hole plates (Greiner #655948 poly-D-lysine-coated). For induction of the TRPM8 receptor, tetracycline is added to the growth medium (DMEM/HG, 10% FCS tetracycline-free, 4 mM L-glutamine, 15 μg/mL blasticidin, 100 μg/mL hygromycin B, 1 μg/mL tetracycline). The next day, the cells are laden with Fluo-4AM dye and the test is conducted. The procedure for this purpose is as follows: Adding to each well 100 μl/well C.sub.8-4 Kit staining solution (RB 141, Molecular Devices) for each 100 μl of medium (DMEM/HG, 10% FCS tetracycline-free, 4 mM L-glutamine, 15 μg/mL blasticidin, 100 μg/mL hygromycin B, 1 μg/mL tetracycline) Incubation in an incubator, 30 minutes/37° C./5% CO.sub.2, 30 minutes/RT Preparation of the test substances (different concentrations in 200 μl of HBSS buffer), and positive controls (different concentrations of menthol, icilin and ionomycin in 200 μl of HBSS buffer) and negative controls (200 μl of HBSS buffer only) Addition of the test substances in amounts of 50 μl/well and measurement of the change in fluorescence (for example in the FLIPR assay instrument, Molecular Devices, or NovoStar, BMG) at excitation 485 nm, emission 520 nm, and evaluation of the intensity of action of the different substances/concentrations and determination of the EC50 values.
(14) The test substances are used in the assay in triplicates in concentrations of 0.1-200 μM. Normally, the compounds are kept in DMSO solutions and diluted down for the assay to a maximum DMSO concentration of 2%.
(15) In-house evaluations in the case of performance of the assay described showed, surprisingly, that the compounds to be used in accordance with the invention (as described herein) are particularly suitable as agonists of TRPM8.
(16) The EC50 values ascertained for modulators of the invention selected by way of example are shown in the table below.
(17) TABLE-US-00007 Activity In vitro assay Structure Name (EC50)
Synthesis Examples
1) Preparation of N-ethyl-2-methylsulfanylethanamine
(18) ##STR00259##
(19) 1,1-Dimethoxy-2-(methylthio)ethane (21.5 mL, 161.07 mmol, 1.0 eq) is dissolved in HCl solution (0.5 M, 323 mL, 1.0 eq) and stirred at 50° C. for 1 h. The reaction mixture is cooled down to RT and extracted with CH.sub.2Cl.sub.2 (500 mL). The combined organic phases are dried over Na.sub.2SO.sub.4. The aldehyde solution is diluted with THF (500 mL), cooled to 0° C. and then admixed with ethylamine (70% solution in water, 15.57 mL, 241.61 mmol, 1.5 eq), acetic acid (9.1 mL, 161.07 mmol, 1.0 eq) and Na.sub.2SO.sub.4 (250 g). After 16 h, the reaction mixture is filtered through Na.sub.2SO.sub.4 and admixed with sodium triacetoxyborohydride (37.6 g, 177.17 mmol, 1.1 eq). The reaction mixture is stirred at RT for 16 h. The solids are filtered through kieselguhr and the solution is concentrated under reduced pressure. The crude product is distilled under reduced pressure (7 mbar, 60° C.). The compound is used without further analyses.
(20) Yield: 23%.
2) Preparation of N-ethyl 3-methylsulfanylpropan-1-amine
(21) ##STR00260##
(22) Methional (25.0 g, 240.0 mmol, 1.0 eq) is dissolved in THF (1000 mL), cooled to 0° C. and then admixed with ethylamine (70% solution in water, 23.2 mL, 360.0 mmol, 1.5 eq), acetic acid (13.6 mL, 240.0 mmol, 1.0 eq) and Na.sub.2SO.sub.4 (250 g). After 16 h, the reaction mixture is filtered through Na.sub.2SO.sub.4 and admixed with sodium triacetoxyborohydride (55.95 g, 264.0 mmol, 1.1 eq). The reaction mixture is stirred at RT for 16 h. The solids are filtered through kieselguhr and the solution is concentrated under reduced pressure. The crude product is distilled under reduced pressure (7 mbar, 60° C.). The compound is used without further analyses.
(23) Yield: 31%.
3) Preparation of N-pyridine-, N-phenyl- and N-1H-pyrazoleamines
(24) 1,1-Dimethoxy-2-(methylthio)ethane (1.0 eq) is dissolved in HCl solution (0.5 M, 1.0 eq) and stirred at 50° C. for 1 h. The reaction mixture is cooled down to RT and extracted with CH.sub.2Cl.sub.2 (3 mL/mmol in total). The combined organic phases are dried over Na.sub.2SO.sub.4. The aldehyde solution is cooled to 0° C. and then admixed with amine (1.0 eq), sodium triacetoxyborohydride (1.5 eq) and acetic acid (1.0 eq). The reaction mixture is stirred at RT for 16 h. The reaction is ended by the addition of NaHCO.sub.3 solution. The aqueous phase is extracted three times with CH.sub.2Cl.sub.2, and the combined organic phases are dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude product is purified by flash chromatography (hexane:EtOAc=19:1).
N-(2-methylsulfanylethyl)pyridine-2-amine
(25) ##STR00261##
84% yield
(26) The compound is used without further analyses.
N-(2-methylsulfanylethyl)aniline
(27) ##STR00262##
(28) Yield: 85%
(29) The compound is used without further analyses.
N-(2-methylsulfanylethyl)-1H-pyrazole-5-amine
(30) ##STR00263##
(31) Yield: 84%
(32) The compound is used without further analyses.
4) Preparation of N-(2-methoxyethyl)aniline
(33) ##STR00264##
(34) 1,1-Dimethoxy-2-(methyloxy)ethane (10 g, 83.23 mmol, 1.0 eq) is dissolved in HCl solution (0.5 M, 1.0 eq) and stirred at 50° C. for 1 h. The reaction mixture is cooled down to RT and extracted with CH.sub.2Cl.sub.2 (3 mL/mmol in total). The combined organic phases are dried over Na.sub.2SO.sub.4. The aldehyde solution is cooled to 0° C. and then admixed with aniline (7.75 g, 83.23 mmol, 1.0 eq), sodium cyanoborohydride (5.75 g, 91.55 mmol, 1.1 eq) and acetic acid (4.7 mL, 83.23 mmol, 1.0 eq). The reaction mixture is stirred at RT for 16 h. The reaction is ended by the addition of NaHCO.sub.3 solution. The aqueous phase is extracted three times with CH.sub.2Cl.sub.2, and the combined organic phases are dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude product is purified by flash chromatography (hexane:EtOAc=19:1).
(35) Yield: 19%
(36) The compound is used without further analyses.
5) Preparation of Cinnamides or Phenoxyacetamides of the Invention
(37) Method A
(38) Cinnamic acid or phenoxyacetic acid (1.5 eq) and N-methylformanilide (MFA) (1 drop) are dissolved in CH.sub.2Cl.sub.2 (5 mL/mmol), cooled to 0° C. and admixed with oxalyl chloride (3.0 eq). The reaction mixture is stirred at RT for 2 h and at 40° C. for 1 h and concentrated under reduced pressure. Triethylamine (4.0 eq) and the respective amine (1.0 eq) are dissolved in CH.sub.2Cl.sub.2 (4 ml/mmol) and cooled to 0° C. The crude product is dissolved in CH.sub.2Cl.sub.2 (1 mL/mmol) and slowly added dropwise. The reaction mixture is stirred at RT for 16 h. The reaction is ended by the addition of NaHCO.sub.3 solution. The aqueous phase is extracted with CH.sub.2Cl.sub.2 (3×), and the combined organic phase is dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude product is purified by flash chromatography.
(39) Method B:
(40) Cinnamic acid or phenoxyacetic acid (2.0 eq) and MFA (1 drop) are dissolved in CH.sub.2Cl.sub.2 (5 mL/mmol), cooled to 0° C. and admixed with oxalyl chloride (4.2 eq). The reaction mixture is stirred at RT for 2 h and at 40° C. for 1 h and concentrated under reduced pressure. Pyridine (2.0 eq) and the respective amine (1.0 eq) are dissolved in CH.sub.2Cl.sub.2 (4 mL/mmol) and cooled to 0° C. The crude product is dissolved in CH.sub.2Cl.sub.2 (1 mL/mmol) and slowly added dropwise. The reaction mixture is stirred at RT for 16 h. The reaction is ended by the addition of NaHCO.sub.3 solution. The aqueous phase is extracted with CH.sub.2Cl.sub.2 (3×), and the combined organic phase is dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude product is dissolved in ethanol (15 mL/mmol) and admixed with NaOH (5.0 eq). After 15 min, the solvent is removed under reduced pressure and the crude product is admixed with water and extracted three times with CH.sub.2Cl.sub.2. The combined organic phases are dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The product is purified by flash chromatography (EtOAc:hexane=25:75.fwdarw.45:55).
6) Preparation of (E)-3-(1,3-benzodioxol-5-yl)-N-(2-methylsulfanylethyl)-N-phenylprop-2-enamide
(41) ##STR00265##
(42) Method A: 71% yield
(43) .sup.1H NMR (400 MHz, chloroform-d) δ 7.59 (d, J=15.5 Hz, 1H), 7.49-7.41 (m, 2H), 7.41-7.35 (m, 1H), 7.28-7.22 (m, 2H), 6.85 (dd, J=8.1, 1.7 Hz, 1H), 6.73 (d, J=8.1 Hz, 1H), 6.73 (d, J=1.7 Hz, 1H), 6.10 (d, J=15.4 Hz, 1H), 5.93 (s, 2H), 4.06-3.99 (m, 2H), 2.74-2.68 (m, 2H), 2.16 (s, 3H).
7) Preparation of 2-(4-methylphenoxy)-N-(2-methylsulfanylethyl)-N-phenylacetamide
(44) ##STR00266##
(45) Method A: 87% yield
(46) .sup.1H NMR (400 MHz, chloroform-d) δ 7.46 (dd, J=8.3, 6.4 Hz, 2H), 7.43-7.37 (m, 1H), 7.30-7.23 (m, 2H), 7.01 (d, J=8.4 Hz, 2H), 6.67 (d, J=8.6 Hz, 2H), 4.34 (s, 2H), 3.98-3.90 (m, 2H), 2.70-2.61 (m, 2H), 2.25 (s, 3H), 2.13 (s, 3H).
8) Preparation of (E)-3-(1,3-benzodioxol-5-yl)-N-ethyl-N-(2-methylsulfanylethyl)prop-2-enamide
(47) ##STR00267##
(48) Method A: 31% yield
(49) .sup.1H NMR (400 MHz, chloroform-d) δ 7.63 (d, J=15.2 Hz, 2H), 7.06-6.96 (m, 4H), 6.81 (d, J=8.0 Hz, 2H), 6.66 (dd, J=15.0, 6.4 Hz, 2H), 6.00 (s, 4H), 3.62 (dd, J=8.6, 6.4 Hz, 4H), 3.52 (q, J=7.2 Hz, 4H), 2.78-2.68 (m, 4H), 2.19 (s, 6H), 1.26 (t, J=7.2 HZ, 3H), 1.19 (t, J=7.3 Hz, 3H).
9) Preparation of (E)-3-(1,3-benzodioxol-5-yl)-N-(2-methylsulfanylethyl)-N-(2-pyridyl)prop-2-enamide
(50) ##STR00268##
(51) Method A: 5% yield
(52) .sup.1H NMR (400 MHz, chloroform-d) δ 8.55 (ddd, J=4.9, 2.0, 0.9 Hz, 1H), 7.75 (td, J=7.7, 2.0 Hz, 1H), 7.64 (d, J=15.4 Hz, 1H), 7.23 (ddd, J=7.4, 2.7, 1.0 Hz, 2H), 6.90 (dd, J=8.2, 1.7 Hz, 1H), 6.81 (d, J=1.7 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 6.26 (d, J=15.4 Hz, 1H), 5.96 (s, 2H), 4.26-4.16 (m, 2H), 2.89-2.75 (m, 2H), 2.15 (s, 3H).
10) Preparation of (E)-N-(2-methylsulfanylethyl)-3-(p-tolyl)-N-(2-pyridyl)prop-2-enamide
(53) ##STR00269##
(54) Method A: 10% yield
(55) .sup.1H NMR (400 MHz, chloroform-d) δ 8.55 (dd, J=5.4, 2.0 Hz, 1H), 7.75 (td, J=7.8, 2.0 Hz, 1H), 7.71 (d, J=15.4 Hz, 1H), 7.29-7.21 (m, 4H), 7.12 (d, J=7.9 Hz, 2H), 6.40 (d, J=15.5 Hz, 1H), 4.30-4.16 (m, 2H), 2.87-2.74 (m, 2H), 2.33 (s, 3H), 2.15 (s, 3H).
11) Preparation of (E)-3-(1,3-benzodioxol-5-yl)-N-(2-methylsulfanylethyl)-N-(1H-pyrazol-3-yl)prop-2-enamide
(56) ##STR00270##
(57) Method B: 10% yield
(58) .sup.1H NMR (400 MHz, chloroform-d) δ 7.63 (d, J=15.2 Hz, 1H), 7.61 (d, J=2.4 Hz, 1H), 6.90 (d, J=7.9 Hz, 1H), 6.83 (s, 1H), 6.74 (d, J=8.0 Hz, 1H), 6.35 (d, J=14.7 Hz, 1H), 6.25 (s, 1H), 5.95 (s, 2H), 4.03 (t, J=7.3 Hz, 2H), 2.78 (t, J=7.6 Hz, 2H), 2.16 (s, 3H).
12) Preparation of (E)-N-ethyl-N-(2-methylsulfanylethyl)-3-(p-tolyl)prop-2-enamide
(59) ##STR00271##
(60) Method A: 41% yield
(61) Two rotamers at the nitrogen are apparent in the spectrum.
(62) .sup.1H NMR (400 MHz, chloroform-d) δ 7.69 (d, J=15.3 Hz, 2H), 7.42 (d, J=7.8 Hz, 4H), 7.18 (d, J=7.9 Hz, 4H), 6.79 (dd, J=15.4, 5.7 Hz, 2H), 3.67-3.57 (m, 4H), 3.53 (q, J=7.1 Hz, 4H), 2.78-2.68 (m, 4H), 2.37 (s, 6H), 2.19 (s, 6H), 1.27 (t, J=7.1 Hz, 3H), 1.20 (t, J=7.1 Hz, 3H).
13) Preparation of (E)-N-ethyl-3-(4-methoxyphenyl)-N-(2-methylsulfanylethyl)prop-2-enamide
(63) ##STR00272##
(64) Method A: 12% yield
(65) .sup.1H NMR (400 MHz, chloroform-d) δ 7.69 (d, J=15.3 Hz, 1H), 7.53-7.44 (m, 2H), 6.96-6.83 (m, 2H), 6.70 (d, J=15.3 Hz, 1H), 3.83 (s, 3H), 3.62 (dd, J=8.5, 6.6 Hz, 2H), 3.53 (q, J=7.1 Hz, 2H), 2.78-2.69 (m, 2H), 2.19 (s, 3H), 1.27-1.19 (m, 3H).
14) Preparation of (E)-N-(2-methylsulfanylethyl)-N-phenyl-3-(p-tolyl)prop-2-enamide
(66) ##STR00273##
(67) Method A: 79% yield
(68) .sup.1H NMR (400 MHz, chloroform-d) δ 7.65 (d, J=15.5 Hz, 1H), 7.48-7.41 (m, 2H), 7.41-7.35 (m, 1H), 7.29-7.23 (m, 2H), 7.19 (d, J=8.1 Hz, 2H), 7.08 (d, J=8.0 Hz, 2H), 6.23 (d, J=15.5 Hz, 1H), 4.07-3.99 (m, 2H), 2.75-2.67 (m, 2H), 2.31 (s, 3H), 2.16 (s, 3H).
15) Preparation of (E)-3-(4-methoxyphenyl)-N-(2-methylsulfanylethyl)-N-phenylprop-2-enamide
(69) ##STR00274##
(70) Method A: 85% yield
(71) .sup.1H NMR (400 MHz, chloroform-d) δ 7.64 (d, J=15.5 Hz, 1H), 7.48-7.41 (m, 2H), 7.42-7.34 (m, 1H), 7.28-7.21 (m, 4H), 6.82-6.78 (m, 2H), 6.15 (d, J=15.5 Hz, 1H), 4.06-4.00 (m, 2H), 3.78 (s, 3H), 2.75-2.67 (m, 2H), 2.16 (s, 3H). 16) Preparation of 2-(4-methoxyphenoxy)-N-(2-methylsulfanylethyl)-N-phenylacetamide
(72) ##STR00275##
(73) Method A: 89% yield
(74) .sup.1H NMR (400 MHz, chloroform-d) δ 7.50-7.41 (m, 2H), 7.40 (s, 1H), 7.29-7.22 (m, 2H), 6.76 (t, J=9.1 Hz, 2H), 6.71 (s, 2H), 4.32 (s, 2H), 3.99-3.88 (m, 2H), 3.73 (s, 3H), 2.72-2.59 (m, 2H), 2.13 (s, 3H).
17) Preparation of (E)-N-ethyl-N-(3-methylsulfanylpropyl)-3-(p-tolyl)prop-2-enamide
(75) ##STR00276##
(76) Method A: 50% yield
(77) Two rotamers at the nitrogen are apparent in the spectrum.
(78) .sup.1H NMR (400 MHz, chloroform-d) δ 7.69 (d, J=15.3 Hz, 2H), 7.47-7.39 (m, 4H), 7.18 (d, J=7.9 Hz, 4H), 6.93 (d, J=15.4 Hz, 1H), 6.79 (d, J=15.4 Hz, 1H), 3.51 (dt, J=14.2, 7.8 Hz, 8H), 2.55 (t, J=7.0 Hz, 4H), 2.37 (s, 6H), 2.11 (s, 6H), 1.99-1.87 (m, 4H), 1.39-1.08 (m, 6H).
18) Preparation of (E)-3-(1,3-benzodioxol-5-yl)-N-ethyl-N-(3-methylsulfanylpropyl)prop-2-enamide
(79) ##STR00277##
(80) Method A: 66% yield
(81) Two rotamers at the nitrogen are apparent in the spectrum.
(82) .sup.1H NMR (400 MHz, chloroform-d) δ 7.62 (d, J=15.3 Hz, 2H), 7.11-6.97 (m, 4H), 6.87-6.76 (m, 2H), 6.66 (d, J=15.3 Hz, 2H), 5.99 (s, 4H), 3.59-3.43 (m, 8H), 2.62-2.49 (m, 4H), 2.12 (s, 6H), 1.99-1.90 (m, 4H), 1.26 (t, J=7.1 Hz, 3H), 1.19 (t, J=7.1 Hz, 3H).
19) Preparation of (E)-3-(1,3-benzodioxol-5-yl)-N-(3-methylsulfanylpropyl)-N-phenylprop-2-enamide
(83) ##STR00278##
(84) Method A: 98% yield
(85) .sup.1H NMR (400 MHz, chloroform-d) δ 7.57 (d, J=15.4 Hz, 1H), 7.48-7.42 (m, 2H), 7.41-7.34 (m, 1H), 7.23-7.18 (m, 2H), 6.85 (dd, J=8.1, 1.7 Hz, 1H), 6.73-6.72 (m, 2H), 6.72 (d, J=8.0 Hz, 1H), 6.10 (d, J=15.4 Hz, 1H), 5.93 (s, 2H), 3.95-3.89 (m, 2H), 2.56-2.49 (m, 2H), 2.06 (s, 3H), 1.94-1.84 (m, 2H).
20) Preparation of (E)-3-(1,3-benzodioxol-5-yl)-N-(2-methoxyethyl)-N-phenylprop-2-enamide
(86) ##STR00279##
(87) Method A: 61% yield
(88) .sup.1H NMR (400 MHz, chloroform-d) δ 7.58 (d, J=15.5 Hz, 1H), 7.46-7.40 (m, 2H), 7.40-7.33 (m, 1H), 7.29-7.24 (m, 2H), 6.85 (dd, J=8.1, 1.6 Hz, 1H), 6.73 (d, J=1.8 Hz, 1H), 6.73 (d, J=8.0 Hz, 1H), 6.12 (d, J=15.4 Hz, 1H), 5.93 (s, 2H), 4.00 (t, J=5.8 Hz, 2H), 3.60 (t, J=5.8 Hz, 2H), 3.33 (s, 3H).
21) Preparation of (E)-3-(4-methoxyphenyl)-N-(2-methylsulfanylethyl)-N-(2-pyridyl)prop-2-enamide
(89) ##STR00280##
(90) Method A: 10% yield
(91) .sup.1H NMR (400 MHz, chloroform-d) δ 8.55 (d, J=5.7 Hz, 1H), 7.75 (td, J=7.7, 2.0 Hz, 1H), 7.69 (d, J=15.5 Hz, 1H), 7.35-7.28 (m, 2H), 7.23 (dd, J=7.5, 4.5 Hz, 2H), 6.94-6.73 (m, 2H), 6.31 (d, J=15.4 Hz, 1H), 4.26-4.18 (m, 2H), 3.80 (s, 3H), 2.85-2.76 (m, 2H), 2.15 (s, 3H).
22) Preparation of 2-(4-methylphenoxy)-N-(2-methylsulfanylethyl)-N-(2-pyridyl)acetamide
(92) ##STR00281##
(93) Method A: 19% yield
(94) .sup.1H NMR (400 MHz, chloroform-d) δ 8.50-8.44 (m, 1H), 7.77 (td, J=7.8, 2.0 Hz, 1H), 7.30-7.25 (m, 1H), 7.23 (ddd, J=7.3, 5.0, 0.7 Hz, 1H), 7.01 (d, J=8.3 Hz, 2H), 6.64 (d, J=8.5 Hz, 2H), 4.68 (s, 2H), 4.10-4.00 (m, 2H), 2.77-2.69 (m, 2H), 2.25 (s, 3H), 2.12 (s, 3H).
23) Preparation of (E)-N-(2-methylsulfanylethyl)-3-(p-tolyl)-N-(1H-pyrazol-3-yl)prop-2-enamide
(95) ##STR00282##
(96) Method B: 50% yield
(97) .sup.1H NMR (600 MHz, chloroform-d) δ 10.91 (s, 1H), 7.69 (d, J=15.5 Hz, 1H), 7.60 (d, J=1.6 Hz, 1H), 7.26 (d, J=5.5 Hz, 2H), 7.10 (d, J=7.5 Hz, 2H), 6.46 (d, J=14.6 Hz, 1H), 6.24 (s, 1H), 4.04 (t, J=13.1, 6.2 Hz, 2H), 2.78 (t, J=7.4 Hz, 2H), 2.32 (s, 3H), 2.16 (s, 3H).
24) Preparation of 2-(4-methylphenoxy)-N-(2-methylsulfanylethyl)-N-(1H-pyrazol-3-yl)acetamide
(98) ##STR00283##
(99) Method B: 64% yield
(100) .sup.1H NMR (400 MHz, chloroform-d) δ 7.57 (d, J=2.5 Hz, 1H), 7.00 (d, J=8.2 Hz, 2H), 6.71 (d, J=8.4 Hz, 2H), 6.23 (d, J=2.4 Hz, 1H), 4.53 (s, 2H), 4.01-3.83 (m, 2H), 2.77-2.62 (m, 2H), 2.23 (s, 3H), 2.11 (s, 3H).
25) Preparation of 2-(4-methoxyphenoxy)-N-(2-methylsulfanylethyl)-N-(1H-pyrazol-3-yl)acetamide
(101) ##STR00284##
(102) Method B: 53% yield
(103) .sup.1H NMR (400 MHz, chloroform-d) δ 10.72 (s, 1H), 7.58 (d, J=2.4 Hz, 1H), 6.77 (s, 4H), 6.24 (d, J=2.4 Hz, 1H), 4.54 (s, 2H), 3.93 (dd, J=8.5, 6.3 Hz, 2H), 3.73 (s, 3H), 2.72 (dd, J=8.6, 6.2 Hz, 2H), 2.13 (s, 3H).
26) Preparation of (E)-3-(1,3-benzodioxol-5-yl)prop-2-enoyl Chloride
(104) ##STR00285##
(105) An initial charge of 52.7 g (274.2 mmol) of 3,4-dioxymethylenecinnamic acid, 529 mL of toluene and 1.60 g of DMF is heated to 57° C. Within 30 min, 44.1 g (371 mmol) of thionyl chloride is added dropwise at 57 to 60° C. The solution is stirred at 60 to 65° C. for a further 1 h and then concentrated to a volume of about 300 mL. 3×289 mL of toluene is added, and each portion is distilled off again under standard pressure.
27) Preparation of (E)-3-(1,3-benzodioxol-5-yl)-N-phenyl-N-tetrahydrofuran-3-ylprop-2-enamide
(106) ##STR00286##
(107) To 0.72 g (3.4 mmol) of 3,4-methylenedioxycinnamoyl chloride in 7.5 g of toluene are added, at 50° C., 0.52 g (5.14 mmol) of triethylamine and then 0.52 g (3.19 mmol) of N-phenyloxolane-3-amine in 4 mL of toluene. The mixture is stirred at 60° C. for 8 h and cooled down to RT. The organic phase is washed with water, 1 N hydrochloric acid, water, saturated NaHCO.sub.3 solution and water again, dried over Na.sub.2SO.sub.4, filtered and concentrated.
(108) Yield: 39%
(109) .sup.1H NMR (500 MHz, CDCl.sub.3) δ 7.56 (d, J=15.4 Hz, 1H); 7.50-7.38 (m, 3H); 7.22-7.12 (m, 2H); 6.81 (dd, J=8.2, 1.6 Hz, 1H); 6.71 (d, J=8.0 Hz, 1H); 6.67 (d, J=1.6 Hz, 1H); 5.96-5.85 (m, 3H); 5.29 (dq, J=8.3, 5.5 Hz, 2H); 4.04 (dd, J=9.3, 6.7 Hz, 1H); 3.79 (dd, J=9.3, 5.1 Hz, 1H); 3.74-3.53 (m, 1H); 2.20-2.12 (m, 1H); 1.96-1.77 (m, 1H).
28) Preparation of (E)-N-phenyl-3-(p-tolyl)-N-tetrahydrofuran-3-ylprop-2-enamide
(110) ##STR00287##
(111) To a solution of 0.56 g (3.0 mmol) of 4-methylcinnamoyl chloride in 7.5 mL of toluene is added dropwise 0.46 g (4.5 mmol) of triethylamine. Subsequently, within 2 min, a suspension of 0.46 g (2.8 mmol) of N-phenyltetrahydrofuran-3-amine in 4 mL of toluene is metered in. The mixture is stirred at RT for 46 h and at 50° C. for 11 h. 20 mL of water is added for workup, and the organic phase is removed and concentrated on a rotary evaporator. The residue is recrystallized from ethyl acetate/heptane.
(112) Yield: 0.32 g of product
(113) .sup.1H NMR (500 MHz, CDCl.sub.3) δ 7.63 (d, 1H), 7.50-7.40 (m, 3H), 7.22 (d, 2H), 7.14 (d, 2H), 7.07 (d, 2H), 6.06 (d, 1H), 5.34-5.26 (m, 1H), 4.05 (t, 1H), 3.83-3.78 (m, 1H), 3.71 (dd, 1H), 3.61 (dd, 1H), 2.30 (s, 3H); 2.25-2.14 (m, 1H); 1.90-1.81 (m, 1H).
29) Preparation of N-phenyltetrahydrothiophene-3-amine
(114) ##STR00288##
(115) A reactor is initially charged with 91.1 g (0.968 mol) of 2-aminopyridine, 1591 mL of toluene, 98.4 g (0.963 mol) of tetrahydrothiophene-3-one and 81.6 g of acetic acid. At room temperature, 288 g (1.36 mol) of sodium triacetoxyborohydride is added in portions within 30 min. The residue is rinsed in with 115 mL of toluene and the mixture is stirred at room temperature for 21 h. Subsequently, the mixture is metered into 4.85 L of aqueous 10% Na.sub.2CO.sub.3 solution at 15° C. and admixed with a further 500 mL of toluene. Stirring is continued at 15-20° C. for about 20 minutes, and the aqueous phase is removed and extracted once again with 500 mL of toluene. The organic phases are combined and admixed with 2 L of water and 280 g of 10% HCl. The mixture is stirred for a further 10 min and the organic phase is removed and discarded. The aqueous phase is washed 2× with 500 mL each time of toluene, which are likewise discarded. Subsequently, the aqueous phase is admixed with 2 L of water and 1 L of toluene, and adjusted to pH 10.3 with 274 mL of 10% NaOH. The mixture is stirred for a further 10 min, the organic phase is removed and the aqueous phase is re-extracted once more with 250 mL of toluene. The combined organic phases are washed 1× with 200 mL of water, dried over Na.sub.2SO.sub.4 and concentrated.
(116) Residue: 45.3 g (28%)
30) Preparation of (E)-3-(1,3-benzodioxol-5-yl)-N-(2-pyridyl)-N-tetrahydrothiophen-3-ylprop-2-enamide
(117) ##STR00289##
(118) To a solution of about 57.7 g (274 mmol) of 3,4-methylenedioxycinnamoyl chloride in about 235 mL of toluene are added, at about 50° C., 41.6 g (0.411 mol) of triethylamine and 46.5 g (258 mmol) of N-phenyltetrahydrothiophene-3-amine in 264 mL of toluene. The mixture is stirred at 55° C. for 1 h and then at RT overnight. The suspension is cooled down to 0° C. and filtered. The filter residue is taken up in 2 L of ethyl acetate and, at 40° C., washed 3× with 500 mL of water each time. The mixture is concentrated to a volume level of about 600 mL at standard pressure, cooled down to about 0° C. within 3 h and stirred for a further 1 h. This is followed by filtering and washing of the filtercake with 80 mL of ice-cold ethyl acetate. The filtercake is dried, taken up in 1670 mL of isopropanol and heated to reflux (solution). The mixture is concentrated to a volume level of 670 mL, cooled down to 20° C. and filtered. The residue is washed with 50 mL of ice-cold i-PrOH and dried.
(119) Residue: 59.8 g (yield: 62%)
(120) .sup.1H NMR (500 MHz, CDCl.sub.3) δ 8.63 (d, 1H); 7.84 (td, J=7.7, 2.0 Hz, 1H); 7.60 (d, J=15.3 Hz, 1H); 7.39 (ddd, J=7.5, 4.9, 0.9 Hz, 1H); 7.22 (d, J=7.8 Hz, 1H), 6.82 (d, 1H); 6.72 (d, J=8.0 Hz, 1H); 6.68 (d, J=1.6 Hz, 1H); 5.94 (s, 2H); 5.80 (d, J=15.3 Hz, 1H); 5.32-5.15 (m, 1H); 3.12 (dd, J=10.1, 6.9 Hz, 1H); 2.94-2.81 (m, 2H); 2.72 (ddd, J=10.3, 7.8, 2.4 Hz, 1H); 2.35-2.25 (m, 1H); 1.90-1.79 (m, 1H).
31) Preparation of (E)-3-(p-tolyl)-N-(2-pyridyl)-N-tetrahydrothiophen-3-ylprop-2-enamide
(121) ##STR00290##
(122) To an initial charge of 0.74 g (4.1 mmol) of 4-methylcinnamoyl chloride in 10 mL of toluene is added 0.52 g (5.1 mmol) of triethylamine. Subsequently, 0.65 g 3.4 mmol) of N-tetrahydrothiophen-3-ylpyridine-2-amine in 4.8 mL of toluene is metered in and the mixture is stirred at 50° C. for 1 h. The mixture is quenched at RT with 20 mL of water. The precipitated solids are filtered off, washed with water and a little MTBE, and dried.
(123) Yield: 57%
(124) .sup.1H NMR (500 MHz, CDCl.sub.3) δ 8.64 (br s, 1H); 7.83 (td, J=7.7, 2.0 Hz, 1H); 7.67 (d, J=15.4 Hz, 1H); 7.39 (dd, J=7.5, 4.9 Hz, 1H); 7.22 (d, J=7.8 Hz, 1H); 7.16 (d, J=8.1 Hz, 2H); 7.07 (d, J=8.0 Hz, 2H); 5.94 (d, J=15.4 Hz, 1H); 5.32-5.20 (m, 1H); 3.13 (dd, J=10.2, 6.9 Hz, 1H); 2.96-2.80 (m, 2H); 2.78-2.66 (m, 1H); 2.40-2.23 (m, 4H); 1.94-1.78 (m, 1H).
32) Preparation of (E)-3-(4-methoxyphenyl)-N-(2-pyridyl)-N-tetrahydrothiophen-3-ylprop-2-enamide
(125) ##STR00291##
(126) To an initial charge of 0.81 g (4.1 mmol) of 4-methoxycinnamoyl chloride in 11 mL of toluene is added 0.52 g (5.1 mmol) of triethylamine. Subsequently, 0.65 g (3.4 mmol) of N-tetrahydrothiophen-3-ylpyridine-2-amine in 4.8 mL of toluene is metered in and the mixture is stirred at 50 to 60° C. for 1 h. The mixture is quenched at RT with 20 mL of water. The precipitated solids are filtered off, washed with water and a little MTBE, and dried.
(127) Yield: 69%
(128) .sup.1H NMR (500 MHz, CDCl.sub.3) δ 8.65 (d, 1H); 7.83 (td, J=7.7, 1.8 Hz, 1H); 7.65 (d, J=15.4 Hz, 1H); 7.39 (dd, J=7.3, 5.0 Hz, 1H); 7.22 (d, J=8.6 Hz, 3H); 6.80 (d, J=8.7 Hz, 2H); 5.85 (d, J=15.4 Hz, 1H); 5.32-5.20 (m. 1H), 3.78 (s, 3H); 3.13 (dd, J=10.1, 6.9 Hz, 1H); 2.97-2.80 (m, 2H); 2.75-2.69 (m, 1H); 2.35-2.25 (m, 1H); 1.94-1.74 (m, 1H).
33) Preparation of (E)-3-phenyl-N-(2-pyridyl)-N-tetrahydrothiophen-3-ylprop-2-enamide
(129) ##STR00292##
(130) To an initial charge of 0.68 g (4.1 mmol) of cinnamoyl chloride in 9 mL of toluene is added 0.52 g (5.1 mmol) of triethylamine. Subsequently, 0.65 g (3.4 mmol) of N-tetrahydrothiophen-3-ylpyridine-2-amine in 4.8 mL of toluene is metered in and the mixture is stirred at 50 to 60° C. for 1 h. The mixture is quenched at RT with 20 mL of water and the organic phase is washed once again with 20 mL of water. The organic phase is dried over Na.sub.2SO.sub.4, filtered and concentrated by rotary evaporation. This is followed by recrystallization from n-heptane/EtOAc.
(131) Yield: 50%
(132) .sup.1H NMR (500 MHz, CDCl.sub.3) δ 8.65 (dd, J=4.8, 1.8 Hz, 1H); 7.84 (td, J=7.7, 2.0 Hz, 1H); 7.70 (d, J=15.4 Hz, 1H); 7.42-7.35 (m, 1H); 7.32-7.12 (m, 6H); 5.99 (d, J=15.4 Hz, 1H); 5.35-5.13 (m, 1H); 3.14 (dd, J=10.2, 6.9 Hz, 1H); 2.97-2.81 (m, 2H); 2.72 (m, 1H); 2.31 (m, Hz, 1H); 1.99-1.70 (m, 1H).
34) Preparation of N-(tetrahydrofuran-2-ylmethyl)aniline
(133) ##STR00293##
(134) 96.1 g (1.0 mol) of furfural is initially charged in 400 g of methylene chloride. Subsequently, 111.8 g (1.2 mol) of aniline is added dropwise at 40° C. The mixture is cooled to 0° C., and 400 g of methanol and 56.7 g (1.5 mol) of sodium boronate are added cautiously, and the mixture is stirred at 0 to 5° C. for 1 h. The mixture is quenched with water, and methanol is distilled out. Thereafter, the mixture is neutralized with 450 g of HCl (10%) and extracted with MTBE. The organic phase is dried and condensed, and the product is distilled and used without further purification.
(135) 100 g of furfurylphenylamine is initially charged in 250 mL of ethanol, and 4 g of Pd/C is added. The reactor is supplied with hydrogen (10 bar) and the mixture is stirred at 50° C. for 18 h. The mixture is filtered at RT and distilled directly.
(136) Yield: 58%
Preparation of (E)-3-81,3-benzodioxo-5-yl)-N-phenyl-N-(tetrahydrofuran-2-ylmethyl)prop-2-enamide
(137) ##STR00294##
(138) 1.14 g (11.3 mmol) of triethylamine and 1.95 g (11 mmol) of 2-tetrahydrofurfurylphenylamine are initially charged in 30 g of toluene. Subsequently, 4.52 g (21.5 mmol) of 3,4-methylenedioxycinnamoyl chloride is metered in and the mixture is stirred at 100° C. for a further 2 h. The mixture is poured onto 50 g of water at RT and the solids are filtered off with suction. After phase separation, the organic phase is dried, filtered and concentrated by rotary evaporation. This is followed by passage through a silica gel column (AcOEt).
(139) Yield: 76%
(140) .sup.1H NMR (400 MHz, chloroform-d) δ 7.58 (d, J=15.5 Hz, 1H), 7.47-7.39 (m, 2H), 7.39-7.33 (m, 2H), 7.33-7.28 (m, 1H), 6.84 (dd, J=8.1, 1.7 Hz, 1H), 6.72 (d, J=1.6 Hz, 1H), 6.70 (d, J=7.9 Hz, 1H), 6.13 (d, J=15.5 Hz, 1H), 5.92 (s, 2H), 4.21-4.08 (m, 1H), 4.00 (dd, J=13.7, 4.8 Hz, 1H), 3.89-3.81 (m, 1H), 3.84-3.75 (m, 1H), 3.77-3.68 (m, 1H), 1.98 (ddd, J=6.9, 4.2, 1.9 Hz, 1H), 1.96-1.79 (m, 2H), 1.68-1.54 (m, 1H).
35) The Following Compounds can Also be Prepared Analogously to the Methods Described Above
(E)-3-(4-Methoxyphenyl)-N-phenyl-N-tetrahydrofuran-3-ylprop-2-enamide
(141) ##STR00295##
(142) .sup.1H NMR (500 MHz, CD.sub.2Cl.sub.2) δ 7.52 (d, 1H); 7.48-7.35 (m, 3H); 7.27-7.11 (m, 4H); 6.77 (d, 2H); 5.97 (d, 1H); 5.29-5.13 (m, 1H); 3.95 (dd, 1H); 3.74 (s, 3H); 3.70 (dd, 1H); 3.63 (q, 1H); 3.54 (td, 1H); 2.21-2.05 (m, 1H); 1.74-1.36 (m, 1H).
2-(4-Methylphenoxy)-N-phenyl-N-tetrahydrofuran-3-ylacetamide
(143) ##STR00296##
(144) .sup.1H NMR (500 MHz, CDCl.sub.3) δ 7.56-7.36 (m, 3H); 7.30-7.16 (m, 2H); 7.02 (d, 2H); 6.66 (d, 2H); 5.25-5.09 (m, 1H); 4.25 (d, 1H); 4.21 (d, 1H); 3.98 (dd, 1H); 3.78 (dd, 1H); 3.67 (td, 1H); 3.60-2.48 (m, 1H), 2.25 (s, 3H); 2.23-2.07 (m, 1H); 1.85-1.75 (m, 1H).
2-(4-Methylphenoxy)-N-phenyl-N-tetrahydrothiophen-3-ylacetamide
(145) ##STR00297##
(146) .sup.1H NMR (500 MHz, CDCl.sub.3) δ 7.55-7.35 (m, 3H); 7.24-7.15 (m, 2H); 7.02 (d, 2H); 6.66 (d, 2H); 5.34-4.97 (m, 1H); 4.22 (s, 2H); 3.04 (dd, 1H); 2.84 (td, 1H); 2.74-2.50 (m, 2H); 2.37-2.10 (m, 4H); 1.65 (qd, 1H).
(E)-N-Cyclohexyl-3-(4-methoxyphenyl)-N-(3-thienyl)prop-2-enamide
(147) ##STR00298##
(148) .sup.1H NMR (500 MHz, CDCl.sub.3) δ 7.60 (d, 1H); 7.37 (dd, 1H); 7.25 (d, 2H); 7.08 (dd, 1H); 6.88 (dd, 1H); 6.81 (d, 2H); 6.05 (d, 1H); 4.71-4.61 (m, 1H); 3.79 (s, 3H); 1.86 (d, 2H); 1.76 (d, 2H); 1.61 (d, 1H); 1.44 (qt, 2H); 1.13 (qd, 2H); 1.03-0.90 (m, 1H).
N-Cyclohexyl-2-(4-methylphenoxy)-N-(3-thienyl)acetamide
(149) ##STR00299##
(150) .sup.1H NMR (500 MHz, CDCl.sub.3) δ 7.45-7.30 (m, 1H); 7.16-7.08 (m, 1H); 7.02 (d, 2H); 6.87 (dd, 1H); 6.69 (d, 2H); 4.61-4.49 (m, 1H); 4.28 (s, 2H); 2.25 (s, 3H); 1.83 (m, 2H); 1.74 (d, 2H); 1.59 (d, 1H); 1.39 (q, 2H); 1.09 (qd, 2H); 0.94 (qt, 1H).
N-Cyclohexyl-2-(4-methoxyphenoxy)-N-(3-thienyl)acetamide
(151) ##STR00300##
(152) .sup.1H NMR (500 MHz, CDCl.sub.3) δ 7.38 (dd, 1H); 7.11 (dd, 1H); 6.87 (dd, 1H); 6.82-6.62 (m, 4H); 4.62-4.48 (m, 1H); 4.26 (s, 2H); 3.74 (s, 3H); 1.82 (d, 2H); 1.73 (d, 2H); 1.59 (d, 1H); 1.39 (qt, 2H); 1.09 (qd, 2H); 0.94 (qt, 1H).
(E)-3-(1,3-benzodioxol-5-yl)-N-(1H-pyrazol-3-yl)-N-(tetrahydrothiophen-2-ylmethyl)prop-2-enamide
(153) ##STR00301##
(154) .sup.1H NMR (500 MHz, CDCl.sub.3) δ 7.68-7.54 (m, 2H); 6.89 (d, 1H); 6.81 (s, 1H); 6.74 (d, 1H); 6.31 (d, 1H); 6.24 (s, 1H); 5.96 (s, 2H); 4.29-4.17 (m, 1H); 3.67 (br s, 2H); 2.92 (dt, 1H); 2.81 (dt, 1H); 2.18-1.81 (m, 4H).
(E)-3-(p-Tolyl)-N-(1H-pyrazol-3-yl)-N-(tetrahydrothiophen-2-ylmethyl)prop-2-enamide
(155) The preparation is effected using N-(tetrahydrothiophen-2-ylmethyl)-1-(2-trimethylsilylethoxymethyl)pyrazole-3-amine and final deprotection with tetrabutylammonium fluoride in THF.
(156) ##STR00302##
(157) .sup.1H NMR (500 MHz, CDCl.sub.3) δ 7.75-7.55 (m, 2H); 7.32-7.20 (m, 2H); 7.09 (d, 2H); 6.43 (d, 1H); 6.22 (s, 1H); 4.30-4.18 (m, 1H); 3.75-3.62 (m, 2H); 2.96-2.86 (m, 1H); 2.85-2.74 (m, 1H); 2.31 (s, 3H); 2.13-1.77 (m, 4H).
(E)-3-(4-methoxyphenyl)-N-(1H-pyrazol-3-yl)-N-(tetrahydrothiophen-2-ylmethyl)prop-2-enamide
(158) The preparation is effected using N-(tetrahydrothiophen-2-ylmethyl)-1-(2-trimethylsilylethoxymethyl)pyrazole-3-amine and final deprotection with tetrabutylammonium fluoride in THF.
(159) ##STR00303##
(160) .sup.1H NMR (500 MHz, CDCl.sub.3) δ 7.73 (d, 1H); 7.65 (s, 1H); 7.32 (d, 2H); 6.84 (d, 2H); 6.38 (d 11H); 6.26 (s, 1H); 4.37-4.21 (m, 1H); 3.79 (s, 3H); 3.75-3.61 (m, 2H); 3.00-2.89 (m, 1H); 2.89-2.79 (m, 1H); 2.18-1.83 (m, 4H).
2-(4-Methylphenoxy)-N-(1H-pyrazol-3-yl)-N-(tetrahydrothiophen-2-ylmethyl)acetamide
(161) ##STR00304##
(162) .sup.1H NMR (500 MHz, CDCl.sub.3) δ 7.57 (d, 1H); 7.00 (d, 2H); 6.71 (d, 2H); 6.24 (d, 1H); 4.55 (q, 2H); 4.18-4.04 (m, 1H); 3.68-3.50 (m, 2H); 2.93-2.67 (m, 2H); 2.23 (s, 3H); 2.08-1.80 (m, 4H).
2-(4-Methoxyphenoxy)-N-(1H-pyrazol-3-yl)-N-(tetrahydrothiophen-2-ylmethyl)acetamide
(163) ##STR00305##
(164) .sup.1H NMR (500 MHz, CDCl.sub.3) δ 7.58 (d, 1H); 6.76 (s, 4H), 6.24 (d, 1H); 4.53 (q, 2H); 4.13 (q, 1H); 3.72 (s, 3H); 3.65-3.46 (m, 2H); 2.94-2.84 (m, 1H); 2.84-2.74 (m, 1H); 2.09-1.73 (m, 4H).
(E)-3-(p-Tolyl)-N-(1H-pyrazol-3-yl)-N-tetrahydrothiophen-3-ylprop-2-enamide
(165) ##STR00306##
(166) .sup.1H NMR (500 MHz, CDCl.sub.3) δ 7.76-7.56 (m, 2H); 7.21 (d, 2H); 7.07 (d, 2H); 6.24 (d, 1H); 6.17 (d, 1H); 5.37-5.22 (m, 1H); 3.10 (dd, 1H); 2.92-2.80 (m, 1H); 2.76 (t, 1H); 2.69 (ddd, 1H); 2.36-2.22 (m, 4H); 1.78 (qd, 1H).
(E)-3-(4-Methoxyphenyl)-N-(1H-pyrazol-3-yl)-N-tetrahydrothiophen-3-yl)prop-2-enamide
(167) ##STR00307##
(168) .sup.1H NMR (500 MHz, CDCl.sub.3) δ 7.77-7.53 (m, 2H); 7.25 (d, 2H); 6.79 (d, 2H); 6.24 (d, 1H); 6.09 (d, 1H); 5.40-5.16 (m, 1H); 3.79 (s, 3H); 3.10 (dd, 1H); 2.92-2.82 (m, 1H); 2.76 (t, 1H); 2.75-2.65 (m, 1H); 2.31-2.22 (m, 1H); 1.85-1.70 (m, 1H). 2-(4-Methoxyphenoxy)-N-(1H-pyrazol-3-yl)-N-tetrahydrothiophen-3-ylacetamide
(169) ##STR00308##
(170) .sup.1H NMR (500 MHz, CDCl.sub.3) δ 7.62 (d, 1H); 6.76 (s, 4H); 6.23 (d, 1H); 5.25-5.14 (m, 1H); 4.35 (s, 2H); 3.73 (s, 3H); 3.07 (dd, 1H); 2.84 (dd, 1H); 2.78-2.59 (m, 2H); 2.34-2.15 (m, 1H); 1.84-1.70 (m, 1H).
(E)-3-(1,3-Benzodioxol-5-yl)-N,N-bis(2-pyridyl)prop-2-enamide
(171) ##STR00309##
(172) 7.25-7.16 (m, 2H); 6.92 (d, 1H); 6.80 (s, 1H); 6.77 (d, 1H); 6.19 (d, 1H); 5.97 (s, 2H).
(E)-3-(1,3-benzodioxol-5-yl)-N-(1H-pyrazol-3-yl)-N-(tetrahydrofuran-2-ylmethyl)prop-2-enamide
(173) ##STR00310##
(174) .sup.1H NMR (400 MHz, chloroform-d) δ 7.61 (d, J=15.5 Hz, 1H), 7.57 (d, J=2.1 Hz, 1H), 6.90 (d, J=7.7 Hz, 1H), 6.83 (s, 1H), 6.74 (d, J=8.0 Hz, 1H), 6.42 (d, J=15.2 Hz, 1H), 6.21 (s, 1H), 5.95 (s, 2H), 4.22 (qd, J=7.2, 4.2 Hz, 1H), 4.13 (dd, J=13.8, 4.1 Hz, 1H), 3.95-3.84 (m, 1H), 3.78 (td, J=7.9, 6.2 Hz, 1H), 3.68-3.60 (m, 1H), 2.10-1.96 (m, 1H), 1.99-1.82 (m, 2H), 1.62 (ddt, J=15.6, 12.0, 8.1 Hz, 1H).
(E)-3-(p-tolyl)-N-(1H-pyrazol-3-yl)-N-(tetrahydrofuran-2-ylmethyl)prop-2-enamide
(175) ##STR00311##
(176) .sup.1H NMR (400 MHz, chloroform-d) δ 11.26 (s, 1H), 7.68 (d, J=15.5 Hz, 1H), 7.56 (d, J=2.2 Hz, 1H), 7.27 (d, J=8.0 Hz, 2H), 7.10 (d, J=7.8 Hz, 2H), 6.55 (d, J=15.6 Hz, 1H), 6.21 (s, 1H), 4.22 (qd, J=7.1, 4.1 Hz, 1H), 4.18-4.10 (m, 1H), 3.90 (dt, J=8.3, 6.8 Hz, 1H), 3.78 (td, J=7.9, 6.1 Hz, 1H), 3.73-3.57 (m, 1H), 2.32 (s, 3H), 2.12-1.96 (m, 1H), 1.98-1.80 (m, 2H), 1.61 (ddt, J=12.0, 8.4, 7.2 Hz, 1H).
(E)-3-(4-methoxyphenyl)-N-(1H-pyrazol-3-yl)-N-(tetrahydrofuran-2-ylmethyl)prop-2-enamide
(177) ##STR00312##
(178) .sup.1H NMR (600 MHz, chloroform-d) δ 8.15 (d, J=3.0 Hz, 1H), 7.90 (d, J=15.8 Hz, 1H), 7.63-7.61 (m, 2H), 7.62 (d, J=15.9 Hz, 1H), 6.93 (d, J=8.7 Hz, 2H), 5.92 (d, J=3.0 Hz, 1H), 4.14 (qd, J=7.1, 3.6 Hz, 1H), 3.97-3.87 (m, 1H), 3.85 (s, 3H), 3.83-3.73 (m, 1H), 3.57-3.47 (m, 1H), 3.32-3.25 (m, 1H), 2.04 (dddt, J=9.5, 8.4, 6.9, 4.9 Hz, 1H), 1.98-1.88 (m, 2H), 1.69 (ddt, J=12.1, 8.6, 7.1 Hz, 1H).
2-(4-methylphenoxy)-N-(1H-pyrazol-3-yl)-N-(tetrahydrofuran-2-ylmethyl)acetamide
(179) ##STR00313##
(180) .sup.1H NMR (400 MHz, chloroform-d) δ 7.54 (d, J=2.4 Hz, 1H), 7.01 (d, J=8.1 Hz, 2H), 6.72 (d, J=8.0 Hz, 2H), 6.28 (s, 1H), 4.66-4.48 (m, 2H), 4.2-4.1 (m, 1H), 4.0-3.9 (m, 1H), 3.9-3.8 (m, 1H), 3.8-3.7 (m, 1H), 3.64 (dd, J=13.6, 7.7 Hz, 1H), 2.24 (s, 3H), 2.03-1.78 (m, 3H), 1.66-1.52 (m, 1H).
(E)-3-(1,3-benzodioxol-5-yl)-N-(2-pyridyl)-N-(tetrahydrofuran-2-ylmethyl)prop-2-enamide
(181) ##STR00314##
(182) .sup.1H NMR (600 MHz, chloroform-d) δ 8.53 (ddd, J=4.9, 2.0, 0.8 Hz, 1H), 7.75 (ddd, J=8.1, 7.4, 2.0 Hz, 1H), 7.63 (d, J=15.3 Hz, 1H), 7.33 (dt, J=8.1, 1.0 Hz, 1H), 7.22 (ddd, J=7.4, 4.9, 1.0 Hz, 1H), 6.89 (dd, J=8.1, 1.6 Hz, 1H), 6.80 (d, J=1.7 Hz, 1H), 6.75 (d, J=8.0 Hz, 1H), 6.27 (d, J=15.3 Hz, 1H), 5.95 (s, 2H), 4.24-4.18 (m, 2H), 4.04-3.98 (m, 1H), 3.73 (ddd, J=8.3, 7.2, 6.5 Hz, 1H), 3.67 (td, J=8.0, 5.9 Hz, 1H), 1.99 (dddd, J=11.9, 8.6, 6.5, 5.2 Hz, 1H), 1.94-1.87 (m, 1H), 1.87-1.79 (m, 1H), 1.63 (ddt, J=12.2, 8.6, 6.9 Hz, 1H).
(E)-3-(p-tolyl)-N-(2-pyridyl)-N-(tetrahydrofuran-2-ylmethyl)prop-2-enamide
(183) ##STR00315##
(184) .sup.1H NMR (600 MHz, chloroform-d) δ 8.53 (dt, J=4.8, 1.9, 0.7 Hz, 1H), 7.74 (td, J=7.7, 2.0 Hz, 1H), 7.69 (d, J=15.5 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.25 (s, 2H), 7.22 (ddd, J=7.4, 4.9, 0.9 Hz, 1H), 7.11 (d, J=8.0 Hz, 2H), 6.40 (d, J=15.4 Hz, 1H), 4.25-4.21 (m, 2H), 4.05-3.99 (m, 1H), 3.77-3.70 (m, 1H), 3.67 (td, J=8.0, 6.0 Hz, 1H), 2.33 (s, 3H), 2.04-1.96 (m, 1H), 1.96-1.87 (m, 1H), 1.87-1.78 (m, 1H), 1.64 (ddt, J=12.3, 8.5, 7.0 Hz, 1H).
(E)-3-(4-methoxyphenyl)-N-(2-pyridyl)-N-(tetrahydrofuran-2-ylmethyl)prop-2-enamide
(185) ##STR00316##
(186) .sup.1H NMR (400 MHz, chloroform-d) δ 8.53 (ddd, J=5.0, 2.0, 0.8 Hz, 1H), 7.74 (td, J=7.7, 2.0 Hz, 1H), 7.68 (d, J=15.4 Hz, 1H), 7.34 (dd, J=7.5, 1.0 Hz, 1H), 7.32-7.28 (m, 2H), 7.21 (ddd, J=7.4, 4.9, 1.0 Hz, 1H), 6.85-6.78 (m, 2H), 6.33 (d, J=15.4 Hz, 1H), 4.27-4.17 (m, 2H), 4.07-3.96 (m, 1H), 3.80 (s, 3H), 3.93-3.62 (m, 2H), 2.09-1.75 (m, 3H), 1.64 (ddt, J=11.6, 8.2, 6.7 Hz, 1H).
(E)-3-(1,3-benzodioxol-5-yl)-N-ethyl-N-(tetrahydrofuran-2-ylmethyl)prop-2-enamide
(187) ##STR00317##
(188) Two rotamers at the nitrogen are apparent in the spectrum.
(189) .sup.1H NMR (400 MHz, chloroform-d) δ 7.66-7.55 (m, 2H), 7.06-6.95 (m, 4H), 6.81-6.74 (m, 3H), 6.70 (d, J=15.3 Hz, 1H), 5.98 (s, 4H), 4.17-4.02 (m, 2H), 3.93-3.82 (m, 3H), 3.82-3.69 (m, 2H), 3.69-3.56 (m, 4H), 3.56-3.42 (m, 2H), 3.20 (dd, J=13.8, 7.3 Hz, 1H), 2.08-1.97 (m, 2H), 1.97-1.79 (m, 3H), 1.63-1.52 (m, 3H), 1.23 (t, J=7.0 Hz, 3H), 1.18 (t, J=7.1 Hz, 3H).
N-ethyl-2-(4-methoxyphenoxy)-N-(tetrahydrofuran-2-ylmethyl)acetamide
(190) ##STR00318##
(191) Two rotamers at the nitrogen are apparent in the spectrum,
(192) .sup.1H NMR (400 MHz, chloroform-d) δ 6.93-6.86 (m, 4H), 6.82 (dd, J=9.2, 1.7 Hz, 4H), 4.71 (dd, J=14.6, 1.3 Hz, 2H), 4.66 (dd, J=14.1, 1.0 Hz, 2H), 4.15-4.06 (m, 1H), 4.06-3.99 (m, 1H), 3.90-3.80 (m, 2H), 3.76 (s, 6H), 3.79-3.69 (m, 2H), 3.66-3.57 (m, 1H), 3.54 (q, J=7.1 Hz, 2H), 3.47-3.31 (m, 3H), 3.13 (dd, J=13.9, 7.5 Hz, 2H), 2.07-1.94 (m, 2H), 1.94-1.78 (m, 4H), 1.58-1.44 (m, 2H), 1.21 (t, J=7.1 Hz, 3H), 1.13 (t, J=7.1 Hz, 3H).
(E)-N-phenyl-3-(p-tolyl)-N-(tetrahydrofuran-2-ylmethyl)prop-2-enamide
(193) ##STR00319##
(194) .sup.1H NMR (400 MHz, chloroform-d) δ 7.65 (d, J=15.5 Hz, 1H), 7.45-7.38 (m, 2H), 7.38-7.33 (m, 1H), 7.33-7.28 (m, 2H), 7.18 (d, J=8.1 Hz, 2H), 7.06 (d, J=8.0 Hz, 2H), 6.26 (d, J=15.5 Hz, 1H), 4.21-4.14 (m, 1H), 4.01 (dd, J=13.7, 4.8 Hz, 1H), 3.88-3.69 (m, 3H), 2.30 (s, 3H), 2.02-1.78 (m, 3H), 1.67-1.56 (m, 1H).
(E)-3-(4-methoxyphenyl)-N-phenyl-N-(tetrahydrofuran-2-ylmethyl)prop-2-enamide
(195) ##STR00320##
(196) .sup.1H NMR (400 MHz, chloroform-d) δ 7.63 (d, J=15.5 Hz, 1H), 7.46-7.39 (m, 2H), 7.38-7.32 (m, 1H), 7.32-7.28 (m, 2H), 7.27-7.21 (m, 2H), 6.79 (d, J=8.8 Hz, 2H), 6.17 (d, J=15.5 Hz, 1H), 4.17 (qd, J=6.8, 4.9 Hz, 1H), 4.02 (dd, J=13.6, 4.9 Hz, 1H), 3.88-3.80 (m, 1H), 3.82-3.75 (m, 1H), 3.78 (s, 3H), 3.73 (ddd, J=8.3, 7.4, 5.8 Hz, 1H), 2.06-1.94 (m, 1H), 2.03-1.78 (m, 2H), 1.68-1.56 (m, 1H).
2-(4-methylphenoxy)-N-phenyl-N-(tetrahydrofuran-2-ylmethyl)acetamide
(197) ##STR00321##
(198) .sup.1H NMR (400 MHz, chloroform-d) δ 7.43 (dd, J=8.2, 6.4 Hz, 2H), 7.41-7.35 (m, 1H), 7.34-7.29 (m, 2H), 7.01 (d, J=8.3 Hz, 2H), 6.72-6.64 (m, 2H), 4.36 (d, J=14.6 Hz, 1H), 4.31 (d, J=14.7 Hz, 1H), 4.12 (qd, J=6.6, 4.6 Hz, 1H), 3.89-3.78 (m, 2H), 3.72 (td, J=7.8, 5.9 Hz, 2H), 2.24 (s, 3H), 2.04-1.78 (m, 3H), 1.62-1.53 (m, 1H).
2-(4-methoxyphenoxy)-N-phenyl-N-(tetrahydrofuran-2-ylmethyl)acetamide
(199) ##STR00322##
(200) .sup.1H NMR (400 MHz, chloroform-d) δ 7.47-7.40 (m, 2H), 7.40-7.34 (m, 1H), 7.34-7.28 (m, 2H), 6.77 (d, J=9.3 Hz, 2H), 6.72 (d, J=9.4 Hz, 2H), 4.38-4.24 (m, 2H), 4.17-4.06 (m, 1H), 3.88-3.78 (m, 2H), 3.78-3.69 (m, 2H), 3.73 (s, 3H), 2.05-1.77 (m, 3H), 1.64-1.53 (m, 1H).
(E)-3-(1,3-benzodioxol-5-yl)-N-ethyl-N-[2-(2-thienyl)ethyl]prop-2-enamide
(201) ##STR00323##
(202) .sup.1H NMR (400 MHz, chloroform-d) δ 7.65 (d, J=15.2 Hz, 1H), 7.54 (d, J=15.2 Hz, 1H), 7.18-7.10 (m, 2H), 7.06-6.98 (m, 2H), 6.97-6.89 (m, 4H), 6.88-6.83 (m, 2H), 6.79 (t, J=8.2 Hz, 2H), 6.66 (d, J=15.3 Hz, 1H), 6.44 (d, J=15.3 Hz, 1H), 5.98 (s, 4H), 3.66 (t, J=7.5 Hz, 4H), 3.50 (q, J=7.1 Hz, 2H), 3.37 (q, J=7.2 Hz, 2H), 3.19-3.09 (m, 4H), 1.19 (t, J=7.1 Hz, 6H).
(203) Sensory Assessment:
(204) Cooling Intensity of Inventive Amides Compared to FEMA 4809:
(205) Test solutions with 2 or 20 ppm of the inventive amides in a 5% sugar solution were sensorily assessed by trained panelists (n=10 to 11) and compared with a solution containing 2 ppm of the comparative compound FEMA 4809. What were assessed here were initial cooling intensity, overall cooling intensity and long-lasting action on a scale from 1 (very weak) to 9 (very strong).
(206) TABLE-US-00008 Initial Overall Dosage cooling cooling Long-lasting # ppm effect intensity action FEMA 4809 2 3.9 7.3 7.5 (E)-3-(1,3-benzodioxol- 20 5.8 7.8 7.9 5-yl)-N-phenyl-N-tetra- hydrofuran-3-yl-prop-2- enamide (E)-3-(1,3-benzodioxol- 2 4.1 6.1 6.9 5-yl)-N-phenyl-N-tetra- hydrofuran-3-yl-prop-2- enamide (E)-N-phenyl-3-(p-tolyl)- 20 4.3 5.7 6.1 N-tetrahydrofuran-3-yl- prop-2-enamide (E)-3-(1,3-benzodioxol- 20 6.6 8.3 7.9 5-yl)-N-(2-pyridyl)-N- tetrahydrothiophen-3-yl- prop-2-enamide (E)-3-(p-tolyl)-N-(2- 20 5.3 7.0 7.4 pyridyl)-N- tetrahydrothiophen- 3-yl-prop-2-enamide (E)-3-(4-methoxy- 20 4.1 5.6 5.9 phenyl)-N-(2-pyridyl)-N- tetrahydrothiophen-3-yl- prop-2-enamide (E)-3-phenyl-N-(2- 20 5.3 7.8 7.8 pyridyl)-N- tetrahydrothiophen- 3-yl-prop-2-enamide (E)-3-(1,3-benzodioxol- 20 3.1 5.0 5.3 5-yl)-N-phenyl-N- (tetrahydrofuran-2- ylmethyl)prop-2-enamide (E)-3-(1,3-benzodioxol- 20 2.7 4.7 4.7 5-yl)-N-(2-methyl- sulfanylethyl)-N-phenyl- prop-2-enamide 2-(4-methylphenoxy)-N- 20 2.2 2.8 2.8 (2-methylsulfanylethyl)- N-phenyl-acetamide (E)-3-(1,3-benzodioxol- 20 3.8 5 4.7 5-yl)-N-ethyl-N-(2- methylsulfanylethyl)prop- 2-enamide (E)-3-(1,3-benzodioxol- 20 6.2 7.8 7.5 5-yl)-N-(2-methyl- sulfanylethyl)-N-(2- pyridyl)prop-2-enamide (E)-3-(1,3-benzodioxol- 2 3.4 4.6 4.3 5-yl)-N-(2-methyl- sulfanylethyl)-N-(2- pyridyl)prop-2-enamide (E)-N-(2-methyl- 20 4 5.7 5.3 sulfanylethyl)-3-(p-tolyl)- N-(2-pyridyl)prop-2- enamide (E)-3-(1,3-benzodioxol- 20 3.7 6.6 6.6 5-yl)-N-(2-methyl- sulfanylethyl)-N-(1H- pyrazol-3-yl)prop-2- enamide (E)-3-(1,3-benzodioxol- 5 3.1 4.8 4.6 5-yl)-N-(2-methyl- sulfanylethyl)-N-(1H- pyrazol-3-yl)prop-2- enamide N.B.: The compounds were predissolved as a 1% ethanol solution.
(207) What are clearly apparent are the faster onset of the cooling effect, a clear cooling profile comparable to or better than the reference, and the distinctly long-lasting cooling effect for inventive amides.
(208) Time-Intensity Profile of Inventive Amides Compared to Reference Compounds (FEMA 4809, 4496) and WS3:
(209) To establish a time-intensity profile, the oral cavity of trained panelists (n=8 to 11) was rinsed for 40 seconds with a mouthful of a sample solution (2 ppm of FEMA 4809 or 50 ppm of FEMA 4496 or 50 ppm of 1) to 5)). Subsequently, the cooling intensity perceived was assessed at defined time intervals using a scale.
(210) TABLE-US-00009 Cooling intensity Time (sec.) # 0 40 70 100 130 160 190 220 250 280 310 340 640 940 1240 FEMA 0 2.7 2.8 2.5 2.6 2.6 2.7 2.8 2.7 2.8 2.9 2.8 2.6 2.6 2.1 4809 WS3 0 4.3 4.3 4.1 3.7 3.4 3.1 2.9 2.8 2.4 2.3 2.1 1.2 0.5 0.3 FEMA 0 1.9 2.3 2.4 2.3 2.3 2.3 2.2 2.2 2.2 2.1 2.1 2.0 1.5 1.2 4496 1) 0 6.1 6.4 6.4 6.2 6.0 6.0 5.8 5.7 5.5 5.4 5.3 4.8 3.9 2.9 2) 0.0 4.2 4.5 4.5 4.5 4.4 4.3 4.2 4.1 4.1 3.9 3.8 3.1 2.1 1.1 3) 0.0 4.0 4.0 4.0 3.9 3.7 3.7 3.5 3.4 3.3 3.2 3.2 2.2 1.3 0.7 4) 0.0 4.7 4.6 4.5 4.3 4.2 3.9 3.7 3.5 3.3 3.2 2.9 2.0 1.3 1.1 5) 0.0 5.7 6.2 6.0 5.6 5.6 5.2 5.0 4.9 4.6 4.5 4.3 3.1 1.9 1.1 1) (E)-3-(1,3-benzodioxol-5-yl)-N-phenyl-N-tetrahydrofuran-3-ylprop-2-enamide 2) (E)-3-(1,3-benzodioxol-5-yl)-N-(2-pyridyl)-N-tetrahydrothiophen-3-ylprop-2-enamide 3) (E)-3-(p-tolyl)-N-(2-pyridyl)-N-tetrahydrothiophen-3-ylprop-2-enamide 4) (E)-3-phenyl-N-(2-pyridyl)-N-tetrahydrothiophen-3-ylprop-2-enamide 5) (E)-3-(1,3-benzodioxol-5-yl)-N-(2-methylsulfanylethyl)-N-(2-pyridyl)prop-2-enamide
(211) For the inventive amides, distinctly more rapid or at least comparably rapid onset of cooling activity was found with respect to WS3. In addition, the cooling effect lasted for longer than for WS3 and for a comparatively long period to that for reference compounds (FEMA 4809, FEMA 4496), but these showed a distinctly retarded onset of the cooling action.
Use Examples
(212) Toothpaste
(213) Suitable toothpastes can be produced according to the following base formulation:
(214) TABLE-US-00010 % by Ingredient weight type Ingredient examples 0.05-0.2% Fluorides sodium fluoride, tin(II) fluoride, sodium monofluorophosphate 10-55% Humectants glycerol, sorbitol, propylene glycol, polyalkylene glycol 0-50% Polymer polyoxyalkylene block copolymers Mw 5000-30 000 10-50% Water 10-55% Abrasives calcium pyrophosphate, dicalcium phosphate, silicon oxide hydrate 2-10% Binder karaya gum, tragacanth USP, sodium alginate, Irish moss, methyl cellulose 2-8% Surfactant sodium lauryl sulfate, sodium- N-laurylsarcosinate, dioctylsodium sulfosuccinate, sodium lauryl sulfoacetate 0-10% Peroxygen hydrogen peroxide, inorganic compound peroxides 0.001-10% TRPM8 agonist 0-10% s.o. Further additives
(215) Evaluation of the Progression of the Cooling Intensities of Compounds for Use in Accordance with the Invention Over Time in Illustrative Toothpaste:
(216) The cooling substances for use in accordance with the invention were incorporated into toothpaste as follows:
(217) TABLE-US-00011 Deionized water 27.52 Sorbitol 700/0 45 Solbrol M Na salt 0.15 Trisodium phosphate 0.1 Saccharin 0.2 Sodium monofluorophosphate 1.12 PEG 1500 5 Sident 9 (abrasive silica) 10 Sident 22 S (thickening silica) 8 Sodium carboxymethyl 0.9 cellulose Titanium (IV) oxide 0.5 Sodium lauryl sulfate (SLS) 1.5 Respective cooling substance 0.01 Total 100
All Figures in % by Weight
(218) The sensory properties of the resulting toothpaste were evaluated by a trained panel (of 6 persons). For this purpose, the teeth were first cleaned with the toothpaste comprising the compounds of the invention for 30 seconds, then the toothpaste foam was spat out and the mouth was rinsed once with water. The testers assessed the intensity of the cold sensation on a scale from 0 (no cold sensation) to 9 (extremely strong cold sensation). The cold sensation was assessed after 30 seconds and after 1, 5, 10, 20, 30, 45 and 60 minutes.
(219) Compounds of the invention tested by way of example were the compounds (E)-N-phenyl-3-(p-tolyl)-N-tetrahydrofuran-3-ylprop-2-enamide, (E)-3-(4-methoxyphenyl)-N-(2-pyridyl)-N-tetrahydrothiophen-3-ylprop-2-enamide, (E)-3-(1,3-benzodioxol-5-yl)-N-phenyl-N-(tetrahydrofuran-2-ylmethyl)prop-2-enamide, (E)-3-(1,3-benzodioxol-5-yl)-N-(2-methylsulfanylethyl)-N-phenylprop-2-enamide, 2-(4-methylphenoxy)-N-(2-methylsulfanylethyl)-N-phenylacetamide, (E)-3-(1,3-benzodioxol-5-yl)-N-ethyl-N-(2-methylsulfanylethyl)prop-2-enamide and (E)-N-(2-methylsulfanylethyl)-3-(p-tolyl)-N-(2-pyridyl)prop-2-enamide, but especially the compounds (E)-3-(1,3-benzodioxol-5-yl)-N-(2-pyridyl)-N-tetrahydrothiophen-3-ylprop-2-enamide, (E)-3-(1,3-benzodioxol-5-yl)-N-(2-methylsulfanylethyl)-N-(2-pyridyl)prop-2-enamide, (E)-3-(p-tolyl)-N-(2-pyridyl)-N-tetrahydrothiophen-3-ylprop-2-enamide, (E)-3-phenyl-N-(2-pyridyl)-N-tetrahydrothiophen-3-ylprop-2-enamide, (E)-3-(1,3-benzodioxol-5-yl)-N-phenyl-N-tetrahydrofuran-3-ylprop-2-enamide and (E)-3-(1,3-benzodioxol-5-yl)-N-(2-methylsulfanylethyl)-N-(1H-pyrazol-3-yl)prop-2-enamide.
(220) By way of comparison, toothpastes with the same composition but comprising N-ethylmenthane-3-carboxamide (“WS 3”, see also U.S. Pat. No. 4,150,052) as conventional cooling substance were tested.
(221) The result showed that the cooling substances of the invention are distinctly superior to those used conventionally both in terms of rapidly perceptible intensity and in terms of duration of the perception of coolness. Thus, the cooling substances of the invention, even after 1 hour after the cleaning of the teeth, impart a very distinctly perceptible cold sensation, whereas this has already disappeared entirely after this time in the case of the conventional comparative compounds.
(222) Chewing Gum
(223) Suitable chewing gums can be produced according to the following base formulation:
(224) TABLE-US-00012 % by weight Ingredient 15-25% Chewing gum base 20-30% Glucose syrup 50-60% Icing sugar 0.001-10% TRPM8 agonist 1-2% Softener (e.g. glycerol) 3-6% Water
(225) For “sugar-free formulations”, it is also possible to replace the glucose syrup and the icing sugar with the sugar alcohols mannitol, xylitol and sorbitol, “Palatinit” and other synthetic sweeteners such as saccharin, cyclamate, acesulfame-K and aspartame.
(226) Cosmetic Sunscreen Formulation
(227) The formulations that follow describe a cosmetic sunscreen formulation comprising a combination of at least inorganic pigment and organic UV filter.
(228) The formulations specified hereinafter are produced in a customary manner known to the person skilled in the art.
(229) TABLE-US-00013 A 7.50 Uvinul MC 80 ethylhexyl cinnamate 2.00 Uvinul M 40 benzophenone-3 0.80 Rylo PG 11 polyglyceryl dimer soyate 1.00 Span 60 sorbitan stearate 0.50 Vitamin E acetate tocopheryl acetate 3.00 Dracorin 100 SE glyceryl stearate, PEG-100 stearate 1.00 Cremophor CO 410 PEG-40-hydrogenated castor oil B 3.00 T-Lite SF titanium dioxide, aluminum oxide hydrate, dimethicone/methicone copolymer 1.00 Cetiol SB 45 Butyrospermum parkii (shea butter) 6.50 Finsolv TN C.sub.12-15-alkyl benzoate C 5.00 butylene glycol butylene glycol 0.30 Keltrol xanthan gum 0.10 Edeta BD disodium EDTA 0.10 allantoin allantoin 66.20 water dem, aqua dem. D 1.00 Sepigel 305 polyacrylamide, C.sub.13-14 isoparaffin, Laureth-7 0.001-10% TRPM8 agonist q.s. preservative
Blancmange
(230) Recipe (for 100 ml)
(231) TABLE-US-00014 Ingredient Amount Fat-free powdered milk 10.715 g Sucrose 5 g Novelose starch, National Starch 7 g Vegetable oil mixture 2.2 g Carrageenan 0.016 g Vanilla flavoring 0.5 g Sodium stearoyl-2-lactylate 0.095 g Yellow dye 0.189 g Magnesium phosphate 0.165 g Vitamin premix 1.84 g Trace element premix 0.015 g Active ingredient 0.5 g Water 81.94 g
Preparation:
(232) Heat nine tenths of the water to 43.3° C. Dissolve skimmed milk powder in water. Heat oil to 60° C. and add carrageenan and oil-soluble vitamins to the oil. Mix oil into the product. Add the other constituents except for the modified starch, vanilla flavoring and vitamin premix. Homogenize the mixture. Add starch gradually. Add active ingredient, vitamins and flavoring. Standardize solids content. Heat in sterile units and pack in doses.
(233) Textile Modification with Actives of the Invention
(234) First of all, an aqueous slurry of amylose-containing starch is prepared by admixing 570 g of deionized water with 10 g of a standard commercial preservative. 20 g of carboxymethyl cellulose was dissolved therein, then 400 g of an amylose-containing starch having an amylose content of 50% by weight was added, and a slurry was produced while stirring.
(235) This was followed by the production of aqueous liquors with amylose-containing starch by one of the following two methods:
(236) Method 1: The respective slurry is adjusted to a starch content of 5% or 15% by weight by diluting with water.
(237) Method 2: The respective slurry is first diluted with water to a starch content of 5% or 15% by weight and then admixed with 30 g/L of a 30% by weight aqueous polyurethane dispersion (nonionogenic).
(238) This is followed by the modification of a woven fabric with amylose-containing starch and active of the invention.
(239) Specimen woven cotton fabric with a basis weight of 124 g/m.sup.2 is treated with one of the above-prepared liquors by means of a pad-mangle up to a liquor pickup of 80% by weight, based on the weight of the fabric. This is followed by drying at 120° C. for 2 min.
(240) Subsequently, the fabric specimens thus modified are treated with an aqueous active formulation by applying an aqueous emulsion/suspension of an active of the invention having an active content of 1% to 7% by weight to the fabric specimen by means of a pad-mangle up to a liquor pickup of 79-80% by weight. Subsequently, the fabric specimens thus treated are dried in a domestic drier down to a residual moisture content of 15%.
(241) The active-laden fabrics thus produced can then be examined further, for example for their cooling effect on contact with skin or the repellent effect thereof on insects.
(242) Mouthwash Flavorings
(243) Production of mouthwash flavorings with cooling action using the cooling substances of the invention:
(244) The following were mixed (all figures, unless stated otherwise, in % by weight):
(245) TABLE-US-00015 Batch Component a b c Anethole 30 30 30 Eucalyptol 25 25 25 L-Menthol 44.4 44.2 44.9 (E)-3-(1,3-benzodioxol-5-yl)-N- 0.6 phenyl-N-tetrahydrofuran-3- ylprop-2-enamide (E)-N-phenyl-3-(p-tolyl)-N-tetra- 0.8 hydrofuran-3-ylprop-2-enamide (E)-3-(1,3-benzodioxol-5-yl)-N- 0.1 (2-pyridyl)-N-tetrahydrothiophen- 3-yl-prop-2-enamide Total 100 100 100
(246) The flavorings were each incorporated into a ready-to-use mouthwash at a concentration of 0.15% by weight, or into a mouthwash concentrate at a concentration of 3% by weight. Sensory assessment by a trained panel of experts showed that the flavorings led to rapid onset of a very long-lasting fresh effect that lasted over a period of almost 1 h after use of the mouthwashes.
(247) Chewable Sweets
(248) Production of a chewable sweet with cooling raspberry flavor using the cooling substances of the invention.
(249) All figures, unless stated otherwise, in % by weight:
(250) TABLE-US-00016 Constituents 1 2 3 4 5 6 Water 7.8 7.79 7.805 7.8 7.815 7.81 C4 refined sugar 42.1 42.1 42.1 42.1 42.1 42.1 Dextrose 40 glucose syrup 37.3 37.3 37.3 37.3 37.3 37.3 Hydrogenated vegetable fat, 6.6 6.6 6.6 6.6 6.6 6.6 melting point 32-36° C. Lecithin emulsifier 0.3 0.3 0.3 0.3 0.3 0.3 (soya lecithin) Gelatin (pork gelatin) 0.8 0.8 0.8 0.8 0.8 0.8 Fondant type S30 4.8 4.8 4.8 4.8 4.8 4.8 Raspberry flavoring 0.22 0.22 0.22 0.22 0.22 0.22 Menthyl lactate 0.06 0.06 0.06 0.06 0.06 0.06 (E)-3-(p-tolyl)-N-(2-pyridyl)-N- 0.02 tetrahydrothiophen-3-ylprop- 2-enamide (E)-3-(4-methoxyphenyl)-N- 0.03 (2-pyridyl)-N-tetrahydrothiophen- 3-yl-prop-2-enamide (E)-3-phenyl-N-(2-pyridyl)-N- 0.015 tetrahydrothiophen-3-ylprop-2- enamide (E)-3-(1,3-benzodioxol-5-yl)-N- 0.02 phenyl-N-(tetrahydrofuran- 2-ylmethyl)prop-2-enamide (E)-3-(1,3-benzodioxol-5-yl)-N- 0.005 (2-methylsulfanylethyl)-N-phenyl- prop-2-enamide 2-(4-methylphenoxy)-N-(2-methyl- 0.01 sulfanylethyl)-N- phenyl-acetamide
Production Instructions: a) allow gelatin to swell with water (1.8 times the amount of the gelatin) at 70° C. for 2 hours; b) boil sugar, syrup, water, fat and lecithin at 123° C.; c) mix gelatin solution gradually with the boiled mixture; d) mix raspberry flavoring, menthyl lactate and the cooling substances of the invention and optionally stir in coloring; e) bring the resulting mass to about 70° C. on a refrigerated table, then add fondant and aerate on a pulling machine for about 3 minutes; f) then cut up the chewable sweet mixture and pack.
(251) On consumption of the chewable sweets, a fresh, cooling raspberry flavor is perceived while chewing.
(252) Fruit Gums
(253) Production of fruit gums with a long-lasting fresh cooling taste using the cooling substances of the invention.
(254) All figures, unless stated otherwise, in % by weight:
(255) TABLE-US-00017 Component 1 2 3 4 5 6 Water 23.6 23.6 23.6 23.6 23.6 23.6 Sucrose 34.5 34.5 34.5 34.5 34.5 34.5 Glucose syrup, DE 40 31.89 31.89 31.89 31.89 31.89 31.89 Iso Syrup C* Tru Sweet 01750 1.5 1.5 1.5 1.5 1.5 1.5 (Cerestar GmbH) Gelatin 240 Bloom 8.2 8.2 8.2 8.2 8.2 8.2 Yellow and red dye 0.01 0.01 0.01 0.01 0.01 0.01 Citric acid 0.2 0.2 0.2 0.2 0.2 0.2 (E)-3-phenyl-N-(2-pyridyl)-N-tet- 0.1 rahydrothiophen-3-ylprop-2- enamide (E)-3-(1,3-benzodioxol-5-yl)-N- 0.1 phenyl-N-(tetrahydrofuran-2- ylmethyl)prop-2-enamide (E)-3-(1,3-benzodioxol-5-yl)-N- 0.1 (2-methylsulfanylethyl)-N- phenyl-prop-2-enamide 2-(4-methylphenoxy)-N-(2- 0.1 methylsulfanylethyl)-N-phenyl- acetamide (E)-3-(1,3-benzodioxol-5-yl)-N- 0.1 phenyl-N-tetrahydrofuran-3-yl- prop-2-enamide (E)-N-phenyl-3-(p-tolyl)-N-tetra- 0.1 hydrofuran-3-ylprop-2-enamide
(256) The above use examples can be applied to other products from the respective product group—if appropriate via modifications that the person skilled in the art will not find it difficult to undertake. It is not difficult for the person skilled in the art to see on the basis of the present description that the compounds of the invention—possibly with minor modifications—are mutually interchangeable without any great complexity. The concentration of the compound or mixture of the invention used is also variable as readily apparent to the person skilled in the art. Moreover, the product-specific further constituents in the respective use example, in a manner readily appreciable to the person skilled in the art, are likewise exchangeable for other product-typical constituents or can be supplemented thereby. A multitude of such product-specific constituents is disclosed in the description above.