Compounds

Abstract

Novel biaromatic compounds, which are vitamin D analogs, processes for their preparation and cosmetic, dermatological and pharmaceutical preparations containing one or more of these compounds.

Claims

1. A compound according to formula (I): ##STR00004## wherein X and Y are either both CH.sub.2, or one of X and Y is CH.sub.2 and the other of X and Y O; R.sup.1 is a methyl group or an ethyl group; A is either a carbon moiety or oxygen; one of Z.sup.1 and Z.sup.2 represents a hydroxyl group and the other of Z.sup.1 and Z.sup.2 is a hydrogen atom; R.sup.2 and R.sup.3 represent a CF.sub.3 group, or R.sup.2 and R.sup.3, together with the carbon that R.sup.2 and R.sup.3 are bound to, form a cyclopropyl group; wherein the dotted/solid lines () represent either a single carbon-carbon bond or a double carbon-carbon bond, with the proviso that, if two of said bonds are double bonds, these bonds are conjugated; and wherein R.sup.4 represents a methyl group, an ethyl group, a propyl group or a (CH.sub.2).sub.nOR.sup.5 group where n is 1, 2, 3 or 4, and R.sup.5 represents a hydrogen atom, a methyl group, or an ethyl group.

2. The compound according to claim 1, wherein R.sup.1 is ethyl.

3. The compound according to claim 1, wherein R.sup.2 and R.sup.3 both represent a CF.sub.3 group.

4. The compound according to claim 1, wherein R.sup.4 represents a methyl group.

5. A compound according to formula (I-a): ##STR00005##

6. A cosmetic composition comprising the compound according to claim 1.

7. The cosmetic composition according to claim 6, wherein the compound of formula (I) is present in an amount within a range of 0.00001 to 0.1 wt.-%, based on total weight of the cosmetic composition.

8. A method to smoothen wrinkles and/or fine lines and/or to decrease volume and depth of wrinkles and/or fine lines, wherein the method comprises a step of applying the cosmetic composition according to claim 6 to an area of skin affected by wrinkles and/or fine lines.

9. A dermatological composition comprising at least one compound according to claim 1.

10. A pharmaceutical composition comprising at least one compound according to claim 1.

11. A process for preparing the compound of formula (I) according to claim 1, wherein the process comprises conducting hydroboration of a styrene derivative to form an organoborane, followed by a sp.sup.2-sp.sup.3 Suzuki cross coupling of the organoborane with an aryl halogenide.

Description

EXAMPLES

(1) Instruments and Materials

(2) Analytical chromatograms were measured on a Waters Acquity Ultra Performance Liquid Chromatography, equipped with an Acquity HSS T3 100 , 1.8 m 2.150 mm.sup.2 analytical column and a PDA detector operating in the 200-400 nm wavelength range. H.sub.2O+0.02% TFA (A phase) and MeCN+0.02% TFA (B phase) were used as eluents with a flow of 0.5 mL/min.

(3) Low-resolution mass-spectra were measured on a Waters Acquity I-Class Ultra Performance Liquid Chromatography, equipped with an Acquity HSS T3 100 , 1.8 m 2.150 mm.sup.2 analytical column and a PDA detector operating in the 200-400 nm wavelength range coupled to a Waters Single Quadrupole Detector mass spectrometer operating in positive electrospray ionization (ESI+) mode and detecting in the m/z range 100-1500. H.sub.2O+0.04% HCOOH (A phase) and MeCN+0.04% HCOOH (B phase) were used as eluents with a flow of 0.6 mL/min.

(4) Preparative purifications on reverse phase were performed on a Waters High Performance Liquid Chromatography LC-2525 equipped with a Waters 2767 Sample Manager and a Waters FCII automated fraction collector, using a Grom Saphir 110 C18 10 m 50300 mm.sup.2 preparative column and a Waters 2487 double wavelength UV-Vis detector operating at 220 and 254 nm.

(5) H.sub.2O+0.07% TFA (A phase) and MeCN+0.07% TFA (B phase) were used as eluents with a flow of 55 mL/min.

(6) Silica gel 60 (0.040-0.063 mm, Merck) was used as stationary phase for flash-chromatographic purifications.

(7) Nuclear magnetic resonance spectra were recorded on a Bruker Avance 300 spectrometer equipped with 5 mm BBO BB-1H probe head operating at 300 MHz for .sup.1H and 75.5 MHz for .sup.13C. Spectra were recorded in in deuterochlorophorm (CDCl.sub.3) or perdeuterated methyl sulfoxide (d.sub.6-DMSO) and were referenced to the residual solvent signal (CDCl.sub.3: 7.26 ppm, .sup.1H; 77.0 ppm, .sup.13C; d.sub.6-DMSO: 2.54 ppm, .sup.1H; 39.5 ppm .sup.13C).

(8) All air- and water-sensitive reactions were performed under argon, reaction vessels were dried overnight at 80 C. in the drying cabinet. THF was freshly distilled over sodium/benzophenone, DCM was desiccated over Na.sub.2SO.sub.4, all other reagents and solvents were used as received.

(9) Abbreviations

(10) TABLE-US-00001 AcOEt ethyl acetate DCM dichloromethane h hour Hex hexane LR-MS low resolution mass spectrometry MeCN acetonitrile MeOH methanol min minute MS mass spectrometry NMR nuclear magnetic resonance PDA photodiode array PPh.sub.3 triphenyl phosphine RP reverse phase sh shoulder THF Tetrahydrofurane TFA trifluoroacetic acid UPLC ultra high-performance liquid chromatography UV ultra-violet Vis Visible tr retention time

(11) Synthesis Protocols

(12) The products consist of a variable portion and a constant, alkylated or fluorinated portion connected by an ethylene bridge. The same three-step general procedure was used for the preparation of all products: a protected aryl bromide corresponding to the variable portion was converted in the corresponding styrene via Suzuki cross-coupling using potassium vinyltrifluoroborate as a vinyl source (step I); the styrene derivative was hydroborated and then employed for a Suzuki sp.sup.2-sp.sup.3 cross-coupling onto either the alkylated or the fluorinated constant portion as an aryl bromide (step II); the resulting protected product was deacetylated by saponification (step III), yielding the free product. General synthesis procedures for the three steps are given in the subsection below.

(13) Products having one asymmetric center were obtained as racemates, products having several asymmetric centers were obtained as mixtures of diastereomers. No attempts were made to preparatively separate the diastereomers; in case separation of the diastereoisomer signals occurred on the analytical instruments the approximate signal ratio is provided.

(14) General Synthesis Procedure

(15) Step I: Vinylation (Adapted from a Literature Procedure)

(16) G. A. Molander, A. R. Brown, J. Org. Chem., 71, 9681 (2006).

(17) The protected aryl bromide, potassium vinyltrifluoroborate (1.00 eq), Cs.sub.2CO.sub.3 (3.00 eq) and PPh.sub.3 (0.06 eq) were given in a pressure-tight reactor, 0.02 eq of a 10 mM PdCl.sub.2 solution in THF/H.sub.2O 9:1 were added, the reactor was closed tightly and heated to mild reflux under magnetic stirring overnight. The mixture was diluted with H.sub.2O (3 mL/mmol aryl bromide), extracted in AcOEt (24.5 mL/mmol), washed with brine (4.5 mL/mmol), dried on Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude product was purified by preparative RP-HPLC; after purification, the resulting styrene was added with 0.01 eq 2,6-di-tert-butyl-4-methylphenol and stored under argon at 18 C. to prevent spontaneous polymerization.

(18) Step II: sp2-sp3 Cross-Coupling (Adapted from a Literature Procedure)

(19) A. Frstner, A. Leitner, Synlett, 2, 290 (2001).

(20) The styrene obtained in step I (1.33 eq) was given in a reaction glass, which was evacuated and put under Ar pressure (3). 0.67 eq 9-bora-[3.3.1]-bicyclononane dimer and THF (2.0 mL/mmol aryl bromide coupling partner) were added and the mixture was stirred at room temperature. After 5 h potassium methylate (1.34 eq) was added. The aryl bromide coupling partner was diluted in THF (0.5 mL/mmol aryl bromide) and added to the reaction mixture. Palladium(II) acetate (0.03 eq) and 1,3-bis-(2,6-di-isopropyl-phenyl)-imidazolium chloride (0.06 eq) were given in a separate flask, THF (2.0 mL/mmol aryl bromide) was added and after stirring for 15 min at room temperature the resulting solution was added to the reaction mixture, which was then heated to mild reflux. After 2.5 h the mixture was cooled to room temperature and filtered over a celite pad, which was rinsed with several portions of THF. The mother liquors were concentrated under reduced pressure, taken-up in DCM (35 mL/mmol aryl bromide), washed with H.sub.2O (12 mL/mmol aryl bromide), the aqueous phase was back-extracted with DCM (26 mL/mmol aryl bromide), the pooled organic phases were washed with 15% NH.sub.4Cl (16 mL/mmol aryl bromide), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude protected product was purified by flash-chromatography (Hex/AcOEt).

(21) Step III: Final Deprotection

(22) The protected product obtained in step II was dissolved in MeOH (15 mL/mmol) and cooled to 0 C. under Ar. LiOH*H.sub.2O (3 eq) was dissolved in H.sub.2O (0.2 mL/mL MeOH) and added to the protected product solution under stirring. After saponification was completed, as judged by UPLC analysis, about half of the mixture was removed under reduced pressure and the residue taken up in AcOEt (4 mL/mL MeOH) and 5% NaHCO.sub.3 (2 mL/mL MeOH). The aqueous phase was extracted with AcOEt (1 mL/mL MeOH), the pooled organic extracts were washed with 5% NaHCO.sub.3 (2 mL/mL MeOH) and brine (2 mL/mL MeOH), dried over Na.sub.2SO.sub.4, concentrated under reduced pressure, taken-up with DCM and evaporated to dryness under reduced pressure.

Example 1: Compound According to the Formula I-a

(3E,5E)-1,1,1-trifluoro-6-(3-(3-(1-hydroxyethyl)-4-(hydroxymethyl)phenethyl)phenyl)-2-(trifluoromethyl)octa-3,5-dien-2-ol

(23) Step I

(24) From 2.24 g 2-(1-acetoxyethyl)-4-bromobenzyl acetate (7.1 mmol) and 970 mg potassium vinyltrifluoroborate (7.2 mmol) 1.43 g 2-(1-acetoxyethyl)-4-vinylbenzyl acetate (V5P) were obtained as an oil after preparative HPLC purification (77% yield).

(25) Characterization

(26) Analytical UPLC (0-100% B in A in 1.5 min, 100% B 1.5-2.5 min): 1.55 min.

(27) Analytical UPLC-MS (0-100% B in A in 1.5 min, 100% B 1.5-2.5 min): 1.54 min.

(28) Step II

(29) From 399 mg V5P (1.50 mmol) and 448 mg (3E,5E)-6-(3-bromophenyl)-1,1,1-trifluoro-2-trifluoromethyl-octa-3,5-dien-2-ol (FOH, 1.1 mmol) 165 mg 1-(4-(1-acetoxyethyl)-3-acetoxymethyl-phenyl)-2-(3-((3E,5E)-1,1,1-trifluoro-2-trifluoromethyl-octa-3,5-dien-2-ol-6-yl)-phenyl)-ethane (I-aAc) were obtained as an oil after flash-chromatographic purification in Hex/AcOEt 4:1 to 3:1 (24% yield, monohydrate according to NMR).

(30) Characterization

(31) Analytical UPLC (0-100% B in A in 1.5 min, 100% B 1.5-2.5 min): 1.90 min.

(32) Analytical UPLC-MS (0-100% B in A in 1.5 min, 100% B 1.5-2.5 min): 1.88 min.

(33) LR-MS: m/z 609.5 ([M+Na].sup.+, cic 609.21).

(34) Step III

(35) From 157 mg I-aAc (0.26 mmol) and 34 mg LiOH*H.sub.2O (0.79 mmol) 129 mg of the title compound I-a were obtained as a dry foam (95% yield, monohydrate according to NMR).

(36) Characterization

(37) Analytical UPLC (0-100% B in A in 1.5 min, 100% B 1.5-2.5 min): 1.67 min.

(38) Analytical UPLC-MS (0-100% B in A in 1.5 min, 100% B 1.5-2.5 min): 1.67 min.

(39) LR-MS: m/z 485.4 ([MOH].sup.+, cic 485.19).

Comparative Example

(40) Compound according to formula (Comp1)not according to the present invention:

(41) ##STR00003##

4E,6E)-3-ethyl-7-(3-(3-(1-hydroxyethyl)-4-(hydroxymethyl)phenethyl)phenyl)nona-4,6-dien-3-ol

(42) Step I

(43) From 2.24 g 2-(1-acetoxyethyl)-4-bromobenzyl acetate (7.1 mmol) and 970 mg potassium vinyltrifluoroborate (7.2 mmol) 1.43 g 2-(1-acetoxyethyl)-4-vinylbenzyl acetate (V5P) were obtained as an oil after preparative HPLC purification (77% yield).

(44) Characterization

(45) Analytical UPLC (0-100% B in A in 1.5 min, 100% B 1.5-2.5 min): 1.55 min.

(46) Analytical UPLC-MS (0-100% B in A in 1.5 min, 100% B 1.5-2.5 min): 1.54 min.

(47) Step II

(48) From 398 mg V5P (1.50 mmol) and 370 mg (4E,6E)-7-(3-bromophenyl)-3-ethyl-nona-4,6-dien-3-ol (LOH, 96%, 1.10 mmol) 250 mg 1-(4-(1-acetoxyethyl)-3-acetoxymethyl-phenyl)-2-(3-((4E,6E)-3-ethyl-nona-4,6-dien-3-ol-7-yl)-phenylyethane (Comp1Ac) were obtained as an oil after flash-chromatographic purification in Hex/AcOEt 4:1 (43% yield).

(49) Characterization

(50) Analytical UPLC (0-100% B in A in 1.5 min, 100% B 1.5-2.5 min): 1.98 min.

(51) Analytical UPLC-MS (0-100% B in A in 1.5 min, 100% B 1.5-2.5 min): 1.95 min.

(52) LR-MS: m/z 529.5 ([M+Na].sup.+, cic 529.29).

(53) Step III

(54) From 246 mg Comp1Ac (0.47 mmol) and 60 mg LiOH*H.sub.2O (1.41 mmol) 199 mg of the title compound Comp1 were obtained as an oil (quantitative yield).

(55) Characterization

(56) Analytical UPLC (0-100% B in A in 1.5 min, 100% B 1.5-2.5 min): 1.69 min.

(57) Analytical UPLC-MS (0-100% B in A in 1.5 min, 100% B 1.5-2.5 min): 1.68 min.

(58) LR-MS: m/z 405.5 ([MOH].sup.+, cic 405.28), 445.5 ([M+Na].sup.+, clc 445.27).

Comparative Example 2

(59) The compound according to Example 5 of US 2004/0224929 A1 was prepared (Comp2), as this compound is structurally close to the compounds according to the present invention.

(60) Testing of the Human Vitamin D Receptor (VDR) Agonist Activity of the Compounds

(61) The activities of all example compoundsthose according to the invention and those according to the comparative exampleshave been tested as follows.

(62) The transient transfections were performed in HEK293 cells (ATCC, Molsheim, France) grown in minimum essential medium (Eagle) with Earle's balanced salt solution without L-glutamine and supplemented with 10% fetal bovine serum (Sigma-Aldrich Corp., St. Gallen, Switzerland), 2 mM glutamax (Life Technologies AG, Basel, Switzerland), 0.1 mM non-essential amino acids (Life Technologies), and 1 mM sodium pyruvate (Life Technologies) at 37 C. in 5% CO.sub.2. For transfection, 7.5104 cells were plated per well (80 l) in white 96-well cell culture plates with clear bottom (Corning, Basel, Switzerland) in minimum essential medium (Eagle) with Earle's balanced salt solution without L-glutamine and without phenol red supplemented with 10% charcoal-treated fetal bovine serum (HyClone Laboratories, Inc., Logan, Utah, USA), 2 mM glutamax, 0.1 mM non-essential amino acids, and 1 mM sodium pyruvate. The cells were transiently transfected before stimulation the next day at >80% confluence by polyethylene-imine-based transfection. Compound stocks were prepared in DMSO, pre-diluted in PBS (0.45% final DMSO concentration), and added in the respective dilution 5 h after the addition of the transfection mixture onto the cells. The cells were again incubated for additional 16 h before firefly and renilla luciferases activity was measured sequentially in the same cell extract using buffers according to established protocols (Promega AG, Dbendorf, Switzerland). Transfection efficiency was controlled to the pRL-TK renilla luciferase reporter expression. The ligand-binding domain of VDR was expressed from a GATEWAY (Invitrogen, Zug, Switzerland)-compatible version of pCMV-BD (Stratagene Corp., Santa Clara, Calif., USA) as a fusion to the GAL4 DNA-binding domain (amino acids 1 to 147). pFR-Luc (Stratagene) was used as a reporter plasmid to determine the VDR agonist binding and transactivation.

(63) Results

(64) The results are given in table 1:

(65) TABLE-US-00002 TABLE 1 Effective concentrations of half maximal activation (EC.sub.50) compound EC.sub.50 (nM) 1,25 dihydrocholecalciferol (control) 0.65 Comp1 113 Comp2 17 I-a 8

(66) The results show the surprisingly much stronger activity of the compound of the invention with respect to the comparative compounds Comp1 and Comp2.

Example 2: Cosmetic Composition

(67) Table 2 outlines exemplary O/W emulsions, wherein one (or more) compound(s) according to the formulas I-a, I-b and/or I-c is (are) incorporated in the indicated amount (in wt.-%, based on the total weight of the composition).

(68) TABLE-US-00003 TABLE 2 Exemplary O/W emulsion O/W Emulsions 1 2 3 4 5 6 7 8 Glyceryl Stearate 2.5 2 1.2 1 1 1 PEG-40 Stearate 1 PEG-100 Stearate 2.5 1 Ceteareth-20 1 Glyceryl Stearate Citrate 0.5 Potassium Cetyl Phosphate 3 1.5 Stearic Acid 2.5 3 Cetearyl Alcohol 4 2 2 Stearyl Alcohol 2 1 Cetyl Alcohol 1 1 0.5 Acrylates/C.sub.10-30 Alkyl Acrylate 0.2 0.2 0.4 0.2 Crosspolymer Carbomer 0.1 0.2 Xanthan Gum 0.3 0.3 C.sub.12-15 Alkyl Benzoate 5 2 5 5 10 5 Petrolatum 5 3 Butylene Glycol 4 2 9 9 Dicaprylate/Dicaprate Hydrogenated Polydecene 3 2 2 Caprylic/Capric Triglyceride 1 3 5 5 5 Cyclomethicone 5 2 10 Methylpropanediol 2 3 3 Glycerine 4 7 3 4 3 5 3 Glyceryl Glucoside 3.5 3 1 1 2 2 Alcohol denat. 1 3 0.5 10 4 8 4 Butylene Glycol 3 Ascorbylglucoside 0.5 1.0 1.5 0.1 Ubiquinone (Coenzyme 10) 0.1 0.05 0.01 Hyaluronic acid 0.2 Bisabolol 0.5 0.2 Isotridecylsalicylate 1 3 5 2 3 5 Compound (1-a) 0.00001 0.025 0.0001 0.05 0.1 0.00002 0.03 0.002 Dibutyl Adipate 1.5 3 Diisopropyl sebacate 1 1 2 3 Ethylhexyl Benzoate 0.75 1.5 1 Titanium Dioxide (PARSOL TX) 0.5 2 Methylene Bis-Benztriazoyl 0.5 4 6 2 Tetramethylbutylphenol Ethylhexyl methoxycinnamate 2 Phenylbenzimidazole Sulfonic 2 2 2 Acid Butyl Methoxydibenzoylmethane 1 2 2 3 3 3 Methylbenzylidene Camphor 2 3 Octocrylene 5 2 10 Polysilicone-15 2 3 Ethylhexyl Salicylate 5 Homosalate 4 2 Bis-Ethylhexyloxyphenol 1.5 2 Methoxyphenyltriazine Silica 1 2.5 0.5 Silica & Methicone 4 1 2.5 Methyl Methacrylate 1 2 Crosspolymer Disodium EDTA 0.1 0.5 Fragrance, Preservatives q.s Sodium Hydroxide q.s. Water Ad 100