TOFA analogs, sebum-reducing preparations containing said analogs, and cosmetic and / or therapeutic uses of said analogs as active principles for sebum reduction or sebum suppression - Patents.com

Abstract

A compound of general formula (1).

Description

[Technical field]

[0001] The present invention relates to a novel substance and its use as an active ingredient which is effective against oily and / or dirty skin and mild forms of acne and / or in oily hair, as well as to formulations containing said active ingredient.

[0002] Seborrhea is a predisposing condition characterized by hyperactivity of the sebaceous glands. In addition to the scalp, the skin of the face also appears greasy. The composition of seborrheic sebum differs from normal sebum. Seborrhea can be divided into three stages of development: 1. Simple seborrhea: In mild cases, the skin becomes sticky after 8 days. 2. Oily seborrhea: After 2-3 days, the skin becomes sticky. 3. Irreversible form: no recovery. Seborrhea: after one day already the hair looks oily.

[0003] The overproduction of the sebaceous glands can be caused, among other things, by androgen disorders (male hormone disorders) and has a negative aesthetic effect on the overall appearance of the hair. This disease can also lead to hair loss. Its precursor is always a seborrheic state of the scalp. Autonomic nervous system disorders and improper care further worsen the appearance of the skin and the condition of the hair. Even with seborrheic conditions, the hair itself can dry out due to a disturbance in the keratin structure. Dryness and damage of hair are often caused by external stresses, for example sunlight or chemical treatments. Too hot a blow dryer or not taking proper care of damaged hair can lead to damage.

[0004] The cause of oily hair is in the human body and is hormonal. Each hair has a sebaceous gland that produces fat (also called sebum). Sebum production is controlled by hormones and can be overproduced or underproduced depending on the hormone sensitivity of the sebaceous gland. Sebum itself keeps the scalp supple. From the sebaceous gland, sebum travels to the scalp and only then does it reach the hairline. There, it is generally absorbed by the hair shaft and is invisible to the eye. When there is too much sebum, the hair shaft can no longer absorb it. The sebum becomes visible as a greasy film on the hair. The result is streaky, sticky and shiny hair.

[0005] The fact that sebaceous glands are constantly producing oil and that their production is dependent on hormonal balance means that the root cause of oily hair problems cannot be addressed. Consistent care and a high-quality regimen remains the best way to combat oily hair.

[0006] Unfortunately, oily hair has a very troublesome consequence: the hair becomes streaky again already a short time after washing, making it difficult to keep the hairstyle in place.

[0007] Contrary to popular belief, washing your hair too frequently makes it get greasy faster is just a myth. A mild shampoo for oily hair will ensure that excess oil is removed. The hair and scalp will be provided with sufficient moisture, which will balance the overproduction of sebum glands.

[0008] Oily hair and dandruff are among the most common hair problems. These disorders are caused by the disturbance of the activity of the sebaceous glands. When the activity of the sebaceous glands becomes too active, it becomes seborrhea. Here, it is divided into two types: oily type (seborrhea oleosa) and dry type (seborrhea sicca).

[0009] Oily seborrhea: In this case, the sebaceous glands become overactive, producing too much sebum, making the skin oily, and the hair ends become sticky and streaky again 2-3 days after washing.

[0010] Dry seborrhea: This is also due to an overactivity of the sebaceous glands, but the sebum becomes drier and has a thicker consistency. Large flakes of sebum that rub off easily appear along with scales on the epidermis. The scalp acquires a waxy, shiny appearance, and the hair becomes oily only at the roots, dry and brittle in the lengths and especially the ends.

[0011] The first step in treating seborrhea is to wash the hair regularly and thoroughly, as necessary, with a special shampoo. It is advisable to simultaneously carry out the washing and massage of the connective tissue, as this will help to empty the sebaceous glands more and delay the re-oiling of the hair.

[0012] In the case of dirty skin and mild forms of acne, in addition to increased sebum production, other influences, such as secondary bacterial infections, are of etiological importance. One of the most important microorganisms associated with dirty skin is Propionibacterium acnes.

[0013] Dirty skin and / or comedones, even in mild cases, are detrimental to the health of the person affected. Virtually all young people suffer from some form of dirty skin, so many need to improve this condition. In this case, excessive sebum production is the essential factor, so in many cases the skin condition can be improved simply by using active ingredients that reduce sebum.

[0014] The problem of the present invention was therefore to find a formulation which is effective against oily and / or dirty skin, mild forms of acne and oily hair.

[0015] Some attempts to solve this problem are already known in the prior art, but not all of the advantages of the advances presented herein are known.

[0016] WO 2011 / 005660 discloses analogues of 5-(tetradecyloxy)-2-furancarboxylic acid (TOFA) and their antiseborrheic effects.

[0017] WO 2018 / 022797 discloses analogues of 5-(tetradecyloxy)-2-furancarboxylic acid (TOFA) and their effect on acne vulgaris.

[0018] WO 2019 / 115405 discloses analogues of pyrrole derivatives and their antiseborrheic effects.

[0019] However, the general formula (1) [ka] [In the formula, R represents n-tetradecyl; n is a number from 1 to 5. X represents O, N, NH or S; Y and Z, independently of one another, represent CH, N, NH, O or S, said groups being selected such that the five-membered ring has Hückel aromaticity; R 2 and R 3 cannot simultaneously form a double bond, R 1 , R 2 and R 3 are each independently -H, an oxo group, -C 1 ~C 24 -Alkyl (straight and branched), -C 1 ~C 24 -Alkenyl (straight and branched), -C 1 ~C 8 -cycloalkyl, -C 1 ~C 8 -cycloalkylalkylhydroxy, -C substituted with one or more hydroxyl groups and / or one or more primary, secondary and / or tertiary amino groups 1 ~C 24-C substituted with alkyl (linear and branched) and / or one or more optionally esterified carboxyl groups 1 ~C 24 -Alkyl (straight and branched), -C 1 ~C 24 -Alkylarylalkylhydroxy (linear and branched), -C 1 ~C 24 -Alkylheteroaryl (linear and branched), -C 1 ~C 24 -Alkyl-OC 1 ~C 24 -Alkyl (straight and branched), -C 1 ~C 24 -alkylmorpholino, -C 1 ~C 24 -Alkylpiperidino, -C 1 ~C 24 -Alkylpiperazino, -C 1 ~C 24 -alkylpiperazino-N-alkyl, oxo group (=O), However, the group R 1 , R 2 and R 3 of which at most one H atom is represented, and topical pharmaceutical or cosmetic preparations containing one or more of said compounds in effective concentrations. and the cosmetic use of one or more of said compounds for reducing sebum production in human skin. and the use of topical preparations containing one or more of said compounds for the treatment of oily and / or dirty skin and / or mild forms of acne and / or oily hair and / or oily scalp and / or seborrhea. However, it has surprisingly been found to improve upon the shortcomings of the prior art and this is a solution to the problem.

[0020] The sebaceous glands of the scalp and the face have the same structure and the same mechanism of sebum production, so the use according to the invention follows the same principle. Thus, by applying a sebum-reducing active ingredient to the scalp area, sebum production can be reduced, and as a result, the cosmetically undesirable condition of oily hair can be prevented.

[0021] According to the invention, the formulation is particularly advantageously characterized in that one or more compounds of general formula (1) are advantageously present in the aqueous phase and / or in the oily phase, respectively, in a concentration ranging from 0.0001 to 40.00% by weight, preferably from 0.005 to 20.00% by weight and particularly preferably from 0.001 to 6.00% by weight relative to the total weight of the composition.

[0022] Preferred compounds of formula (1) are as follows: [ka]

[0023] [ka]

[0024] Synthesis of TOFA(3) [ka]

[0025] Compound 3 (TOFA) To a suspension of alcohol (2) (25.3 g, 117.8 mM) in 400 ml of o-xylene was added NaH (60% in mineral oil, 7.85 g, 196.3 mM) at ambient temperature and the mixture was stirred under reflux cooling for 2 hours. The mixture was cooled to about 70° C. and acid (1) was added as a solid in one portion (15.0 g, 78.5 mM). The mixture was stirred under reflux cooling for 48 hours and cooled to ambient temperature. The mixture was diluted with aqueous KHSO 4 4 The mixture was quenched with ethyl acetate, extracted with EtOAc, and the organic layer was further purified with H 2 Wash with O and Na 2 SO 4The mixture was dried at 40° C. and evaporated. The residue was triturated with hexane to give compound (3) (7.1 g, 28%). This synthesis was repeated several times to obtain the required amount of TOFA (about 100 g).

[0026] [ka]

[0027] Compound (5) A solution of compound (4) (15.0 g, 150 mM) in EtOH (100 mL) was added with SOCl at 0 °C. 2 (34.6 g, 300 mM) was added in portions. The resulting mixture was heated under reflux for 12 h. The mixture was then allowed to cool at room temperature and concentrated in vacuo. After removal of the solvent, the residue was dissolved in aqueous NaHCO 3 The aqueous solution was extracted with DCM and the extract was poured into aqueous NaHCO 3 , H 2 Wash with O, saline, and then Na 2 SO 4 After concentration under reduced pressure, compound (5) (18.0 g, 94%) was obtained, which was used in the next step without purification.

[0028] Compound (6) Compound (5) (12.4 g, 150 mM) was dissolved in 160 ml of water. The solution was cooled in an ice bath and diluted with NaHCO in several steps. 3 (14.3 g, 170.2 mM). The reaction mixture was mixed in portions with a solution of chloroacetyl chloride (7.5 g, 66.6 mM) in 140 ml of toluene and then vigorously stirred at 20-25° C. for 3 hours. After phase separation, the aqueous phase was extracted with toluene. The solvent was removed from the combined organic phase to give compound (6) as a colorless oil (8.46 g, 55%).

[0029] Compound (7)(ZE33-0100)(BDF:T71e) To a solution of TOFA (3) (15.4 g, 47.0 mM) in DMF (150 ml) was added compound (6) (1.2 eq., 11.0 g, 56.0 mM) and triethylamine (2 eq., 9.5 ml, 94.0 l) at room temperature. After addition, the mixture was stirred at 50° C. for 18 h, after which the mixture was diluted with ether (250 ml) and washed with water (2×50 ml). The two layers were separated and the aqueous phase was extracted with dichloromethane (2×50 ml). The organic layers were combined and washed with anhydrous MgSO 4 The mixture was dried at 40° C. and evaporated under reduced pressure to give an orange oil, which was purified by silica gel column chromatography (eluting with 10-20% EtOAc / DCM) to produce compound (7) (ZE33-0100) as white crystals (9.0 g, 39%).

[0030] [ka]

[0031] Compound (9) A solution of compound (8) (2.0 g, 12.9 mM) in EtOH (20 mL) was added with SOCl at 0 °C. 2 (7.6 g, 64.5 mmol) was added in portions. The resulting mixture was heated under reflux for 12 hours. The mixture was then allowed to cool at room temperature and concentrated in vacuo. After removal of the solvent, the residue was dissolved in aqueous NaHCO 3 The aqueous solution was extracted with DCM and the extract was poured into aqueous NaHCO 3 , H 2 Wash with O, saline, and then Na 2 SO 4 After concentration under reduced pressure, compound (9) (2.2 g, 93%) was obtained as a colorless powder, which was used directly in the next reaction.

[0032] Compound (10) Compound (9) (2.2 g, 12.5 mM) was dissolved in 40 ml of water. The solution was cooled in an ice bath and added in several steps (2.6 g, 31.3 mM) of NaHCO 3The reaction mixture was mixed with a solution of chloroacetyl chloride (1.3 g, 11.9 mM) in 25 ml of toluene in small portions and then vigorously stirred at 20-25° C. for 3 h. After phase separation, the aqueous phase was extracted with toluene. The solvent was removed from the combined organic phase to give compound (10) as a colorless oil (2.5 g, 90%).

[0033] Compound (11)(ZE33-0101)(BDF:T105e) To a solution of compound (10) (10.0 g, 30.8 mM) in DMF (150 ml) was added 4 (1.1 eq., 7.6 g, 33.9 mM) and triethylamine (2 eq., 6.3 ml, 62.6 mM) at room temperature. After addition, the mixture was stirred at 50° C. for 18 h, after which the mixture was diluted with ether (300 ml) and washed with water (3×50 ml). The two layers were separated and the aqueous phase was extracted with dichloromethane (2×50 ml). The organic layers were combined and washed with anhydrous MgSO 4 The mixture was dried at rt and evaporated under reduced pressure to give an orange oil, which was purified by silica gel column chromatography (eluting with 10-20% EtOAc / DCM) to give compound (11) (ZE33-0101) as white crystals (10.0 g, 63.4%).

[0034] [ka]

[0035] Compound (13) A solution of compound (12) (14.0 g, 105.0 mM) in EtOH (200 mL) was added to the flask at 0° C. with SOCl 2 (16.3 g, 136.5 mmol) was added in portions. The resulting mixture was heated under reflux for 1 h. The mixture was then allowed to cool at room temperature and concentrated in vacuo. After removal of the solvent, the residue was dissolved in aqueous NaHCO 3 The aqueous solution was extracted with DCM and the extract was poured into aqueous NaHCO 3 , H 2 Wash with O, saline, and then Na 2 SO 4After concentration under reduced pressure, compound (13) (20.5 g, 98%) was obtained as a colorless powder, which was used directly in the next reaction.

[0036] Compound (14) Compound (13) (20.5 g, 103.7 mM) was dissolved in 400 ml of water. The solution was cooled in an ice bath and added in several steps (17.4 g, 207.4 mM) of NaHCO 3 The reaction mixture was mixed with a solution of chloroacetyl chloride (12.9 g, 114.0 mM) in 150 ml of toluene in small portions and then vigorously stirred at 20-25° C. for 3 hours. After phase separation, the aqueous phase was extracted with toluene. The solvent was removed from the combined organic phase to give compound (14) as a colorless oil (20.9 g, 85%).

[0037] Compound 15(ZE33-0102)(BDF:T106e) To a solution of TOFA (3) (12.0 g, 36.9 mM) in DMF (200 ml) was added compound (14) (1.2 eq., 10.5 g, 44.3 mM) and triethylamine (2 eq., 7.5 ml, 73.8 mM) at room temperature. After addition, the mixture was stirred at 50° C. for 18 h, after which the mixture was diluted with ether (300 ml) and washed with water (3×50 ml). The two layers were separated and the aqueous phase was extracted with dichloromethane (2×50 ml). The organic layers were combined and washed with anhydrous MgSO 4 The mixture was dried at 40° C. and evaporated under reduced pressure to give an orange oil, which was purified by silica gel column chromatography (eluting with 10-20% EtOAc / DCM) to give compound (15) (ZE33-0102) as white crystals (8.4 g, 43.2%).

[0038] [ka]

[0039] Compound (16) 450ml of CH 2 Cl 2 To a solution of TOFA(3) (14.3 g, 44 mM) in2 CH 2 COOt-Bu (9.1 g, 62 mM) was added, followed by EDCI (14.9 g, 77 mM) and DMAP (1.0 g, 8.2 mM). The mixture was stirred at ambient temperature for 20 h, evaporated and concentrated with Et 2 Redissolve in HO and H 2 Wash with O and Na 2 SO 4 The residue was purified by column chromatography on silica gel eluted with 5% EtOAc in hexane to give compound (16) (12.5 g, 62%).

[0040] Compound (17) 150ml of CH 2 Cl 2 To a solution of compound (16) (11.8 g, 26 mM) in 50 ml of TFA was added and the mixture was stirred at ambient temperature for 1 h. The solvent was evaporated and the residue was dissolved in CCl 4 Co-evaporation gave compound (17) (10.5 g, 100%).

[0041] Compounds (18) and (19) (ZE33-0104 and ZE33-0147) 500ml of CH 2 Cl 2 To a solution of compound (17) (11.1 g, 28 mM) in water was added sarcosine ethyl ester hydrochloride (5.6 g, 36.5 mM), followed by HOBt (4.2 g, 31 mM), DIPEA (11.6 g, 90 mM) and EDCI (7.6 g, 40 mM). The mixture was stirred at ambient temperature for 20 h, evaporated, redissolved in EtOAc and diluted with H 2 Wash with O and Na 2 SO 4 The residue was purified by column chromatography on silica gel eluted with 0-50% EtOAc in hexane to give compound (18) (ZE33-0104) (7.7 g, 56%) and compound (19) (ZE33-0147) (3.19 g, 20%).

[0042] [ka]

[0043] Compound (21) To a solution of Boc-glycine (20) (8.7 g, 50 mM) in 100 ml of DMF was added ethyl bromoacetate (8.5 g, 50 mM), followed by K 2 CO 3 (20.7 g, 150 mM) was added. The mixture was stirred at 50-60 °C for 15 h, cooled to ambient temperature, and then heated in H 2 Dilute with 200 mL of Et 2 The combined organic extracts were washed with Na 2 SO 4 and evaporated to give compound (21) (13.0 g, 99%), which was used in the next step without further purification.

[0044] Compound (22) 100ml of CH 2 Cl 2 To a solution of compound (21) (13.0 g, 5 mM) in 25 ml of TFA was added and the mixture was stirred at ambient temperature for 15 h. The volatiles were removed by evaporation and the residue was dissolved in aqueous NaHCO 3 The solution was made basic with CH 2 Cl 2 The combined organic extracts were extracted with Na 2 SO 4 and evaporated to give compound (22) (8.0 g, 98%), which was used in the next step without further purification.

[0045] Compound (23)(ZE33-0105) 200ml of CH 2 Cl 2 To a solution of compound (3) (TOFA) (5.3 g, 16 mM) and amine (22) (3.9 g, 24 mM) in water was added EDCI (6.3 g, 32 mM) followed by DMAP (4.4 g, 32 mM) and the mixture was stirred at ambient temperature for 24 h. The mixture was quenched with aqueous citric acid and the organic layer was washed with aqueous NaHCO 3 Wash with Na 2 SO 4and evaporated to give compound (23) (ZE33-0105) (6.6 g, 88%).

[0046] [ka]

[0047] Compound (25) To a suspension of imidazole-2-carboxylic acid (24) (51.4 g, 459 mmol) in 400 ml of MeOH was added SOCl 2 (109.1 g, 918 mmol) was added in portions. The mixture was stirred under reflux for 15 h, cooled to ambient temperature and evaporated. The residue was dissolved in aqueous K 2 CO 3 and basify with 1:1 t-BuOH-CHCl 3 The combined extracts were extracted with Na 2 SO 4 The mixture was dried at rt, evaporated, and co-evaporated twice with MeCN to give compound (25) (51.0 g, 88%).

[0048] Compound (26) To a mixture of compound (25) (51.0 g, 404 mM), benzyl alcohol (52.4 g, 485 mM) and PPh3 (127.3 g, 485 mM) in 500 ml of THF was added diisopropyl azadicarboxylate (98.1 g, 485 mM) in 100 ml of THF in small portions at 5-10 °C. The mixture was stirred at ambient temperature for 15 h and then evaporated. The residue was dissolved in EtOAc and the desired compound was extracted with 10% aqueous HCl. The combined aqueous extracts were concentrated to solid K at 5-10 °C. 2 CO 3 The mixture was carefully basified with EtOAc and the combined organic extracts were washed with Na 2 SO 4 The residue was purified by column chromatography on silica gel eluted with 25-50% EtOAc in hexane to give compound (26) (68.1 g, 78%).

[0049] Compound (27) A mixture of compound (26) (68.1 g, 315 mM) and N-chlorosuccinimide (42.0 g, 315 mM) in 350 ml of DMF was stirred at ambient temperature for 15 hours. The reaction mixture was diluted with aqueous NaHCO 3 Quench with Et 2 O and the combined organic extracts were washed with Na 2 SO 4 The mixture was dried at 40° C. and evaporated. The residue was purified by column chromatography on silica gel eluted with 1-10% EtOAc in hexane. The desired fraction was evaporated and the solid residue was washed with hexane to give compound (27) (32.8 g, 42%).

[0050] Compound (28) To a suspension of n-tetradecanol (70.1 g, 328 mM) in 600 ml of DMF, NaH (60% in mineral oil, 13.1 g, 328 mM) was added in small portions. The mixture was stirred at 50° C. for 2 hours and compound (27) (32.8 g, 131 mM) was added as a solid. The reaction mixture was stirred at 50° C. for 24 hours and then at ambient temperature for one weekend. The mixture was diluted with aqueous NH 4 The mixture was quenched with Cl, extracted with EtOAc, and the combined organic extracts were washed with Na 2 SO 4 The mixture was dried at 40° C. and evaporated. The residue was purified by column chromatography on silica gel eluted with 1-5% EtOAc in hexanes. The desired fractions were evaporated and the solid residue was washed with MeOH to give compound (28) (17.8 g, 22%).

[0051] Compound (29) MeOH-THF-H 2 Compound (28) (17.8 g, 29 mM) in 300 mL of LiOH H 2 The mixture was stirred at 80° C. for 15 h and then at ambient temperature for 24 h. The organic solvent was evaporated and the aqueous residue was diluted with aqueous KHSO 4 The mixture was extracted with EtOAc and the combined organic extracts were washed with Na 2 SO 4The mixture was dried at 40° C. and evaporated to dryness, and the solid residue was washed with hexane to give compound (29) (11.3 g, 93%).

[0052] Compound (30)(ZE33-0119) To a solution of compound (29) (0.31 g, 0.75 mM) in MeOH, first a few drops of concentrated HCl were added, followed by the addition of 10% Pd / C (30 mg). The mixture was hydrogenated at 7 MPa and 40° C. for 2 h. The catalyst was filtered off and the solvent was evaporated. The residue was redissolved in MeOH and made basic with Dowex 1X8 chloride form (strongly basic). The mixture was filtered through Celite and evaporated. The residue was suspended in hot MeCN, filtered off and dried to give compound (30) (ZE33-0119) (0.16 g, 67%).

[0053] Compound (32) Sarcosine ethyl ester hydrochloride (31) (50.00 g, 330 mM) was dissolved in 160 ml of water. The solution was cooled in an ice bath and added in several steps 2.5 eq (68.4 g, 830 mM) of NaHCO 3 The reaction mixture was mixed with (36.7 g, 330 mM) of chloroacetyl chloride in 140 ml of toluene in small portions and then stirred vigorously at 20-25° C. for 3 h. After phase separation, the aqueous phase was extracted with toluene. The combined organic phase was stripped of solvent. (53.5 g, 84.9%) of compound (32) was obtained as a colorless oil.

[0054] Compound (33) Compound (29) (11.3 g, 27 mM), chloroacetyl chloride (32) (6.9 g, 35 mM) and Et 3 The mixture was stirred at 60° C. for 15 h with aqueous NH 4 The mixture was quenched with Cl, extracted with EtOAc, and the combined organic extracts were washed with Na 2 SO 4 The residue was purified by column chromatography on silica gel, eluting with 20-75% EtOAc in hexanes. The desired fractions were evaporated and the solid residue was purified with hexanes.

[0055] Compound (34)(ZE33-0107) To a solution of compound (33) (11.6 g, 20.3 mM) in 150 ml of EtOAc, 2.32 g of 10% Pd / C was added and the mixture was hydrogenated at 5 MPa and 40-50° C. for 48 h. The catalyst was filtered off, the filtrate was evaporated and the residue was purified by column chromatography on silica gel, followed by elution with 20-50% EtOAc in hexane, 25% CHCl in EtOAc, and 10% hexane. 3 to give compound (34) (ZE33-0107) (5.82 g, 60%).

[0056] [ka]

[0057] Compound (37)(ZE33-0122) To a solution of n-tetradecanol (12.3 g, 57.5 mM) in 100 ml of THF was added 60% NaH (1.82 g, 46 mM). The mixture was stirred at 80° C. for 4 hours, cooled to 5° C., and a solution of chlorooxazole (35) (6.08 g, 28.9 mM) in 20 ml of THF was added. The mixture was stirred at ambient temperature for 15 hours and quenched with 5% HCl. The mixture was diluted with Et 2 O and the combined organic extracts were washed with Na 2 SO 4 The residue was washed with hexane and dried to give compound (36) (4.4 g), which was used in the next step without further purification. Compound (36) was redissolved in 250 ml of THF and 75 ml of MeOH, and diluted with 1.55 g of LiOH and 5 ml of H 2 O was added and the mixture was stirred at ambient temperature for 15 h. The organic components were evaporated and the residue was quenched with 1.5% HCl. The formed pellet was dissolved in H 2 O and dried to give compound (37) (ZE33-0122) (2.04 g, 22%).

[0058] Compound (38)(ZE33-0110) Compound (37) (6.1 g, 187 mM) and chloride (32) (9.0 g, 46 mM) in 200 mL of MTBE with Et 3 The mixture was stirred at 60° C. for 48 h with aqueous NH 4 The mixture was quenched with Cl, extracted with EtOAc, and the combined organic extracts were washed with Na 2 SO 4 The residue was purified by column chromatography on silica gel, eluting with 20-50% EtOAc in hexanes. The desired fractions were evaporated and the solid residue was purified by 10% Et 2 The mixture was washed with O to give compound (38) (ZE33-0110) (5.0 g, 55%).

[0059] [ka]

[0060] Compound (39) 800ml of CH 2 Cl 2 To a solution of n-tetradecanol (20.0 g, 92 mM) in 20% aqueous H2SO4 was added EDCI (21.6 g, 112 mM) followed by DMAP (1.12 g, 0.2 mM) and the mixture was stirred at ambient temperature for 24 hours. 2 SO 4 Quench the organic layer with aqueous NaHCO 3 Wash with Na 2 SO 4 Drying at rt and evaporation gave compound (39) (34.8 g, 100%).

[0061] Compound(40) 200ml of CH 2 Cl 2 To a solution of compound (39) (34.8 g, 92 mM) in 50 ml of TFA was added and the mixture was stirred at ambient temperature for 15 h. The volatiles were removed by evaporation and the residue was dissolved in aqueous NaHCO 3 The solution was made basic with CH 2 Cl 2 The combined organic extracts were extracted with Na2 SO 4 Drying at 40° C. and evaporation gave compound (40) (20.0 g, 80%).

[0062] Compound (41) CH 2 Cl 2 A solution of compound (40) (20.0 g, 72 mM) in 300 mL of Et 3 N (22.4 g, 216 mM) was added, followed by 40 ml CH 2 Cl 2 Ethyl oxalyl chloride (12.0 g, 88 mM) in water was added in small portions at 5° C. The reaction mixture was stirred at ambient temperature for 4 h, quenched with 10% HCl, and dissolved in CH 2 Cl 2 The combined organic extracts were extracted with Na 2 SO 4 The residue was purified by column chromatography on silica gel eluted with 5-30% EtOAc in hexane to give compound (41) (12.0 g, 43%).

[0063] Compound (42) CH under nitrogen 3 P in CN (150 ml) 2 O 5 A suspension of (84.4 g, 600 mM) was heated to 50 °C and added 30 ml of CH 3 The mixture was treated with compound (41) (36.8 g, 100 mM) dissolved in CN. The mixture was heated to 65° C. for 1.5 h and then cooled in an ice bath. Ice and brine were added to the reaction mixture, followed by EtOAc and the mixture was transferred to a separatory funnel. 3 The solid was dissolved by adding 100 ml of CHC1 3 and EtOAc, and the combined organic layers were washed with Na 2 SO 4 The residue was chromatographed on silica gel eluting with a gradient of 0-30% EtOAc / hexane to give the product as a colorless oil, which was further recrystallized from hexane to give compound (42) (27 g, 77%).

[0064] Compound (43) Solvent mixture THF / MeOH / H 2 A mixture of compound (42) (20.5 g, 60 mM) and LiOH (3.7 g, 90 mM) in 2H2O (50 ml, 4 ml, 150 ml) was stirred at 50° C. for 4 h. The reaction mixture was acidified to pH 2 with aqueous 2N HCl, and the resulting precipitate was filtered off and first diluted with H2O. 2 Washing with O and then EtOAc afforded compound (43) as a white solid, which was used in the next step without further purification (15.4 g, 82%).

[0065] Compound (44)(ZE33-0111) To a solution of compound 43 (15.4 g, 47 mM) in DMF (150 ml) was added compound (32) (11.0 g, 56 mM) and triethylamine (9.5 ml, 94 mM) at room temperature. After addition, the mixture was stirred at 50° C. for 18 hours, then the mixture was diluted with ether (250 ml) and washed with water (2×50 ml). The two layers were separated and the aqueous phase was extracted with dichloromethane (2×50 ml). The organic layers were combined and washed with anhydrous MgSO 4 The mixture was dried at 40° C. and evaporated under reduced pressure to give an orange oil. The residue was purified by silica gel column chromatography (eluting with 10-20% EtOAc / DCM) to give compound (44) (ZE33-0111) (9.0 g, 39%).

[0066] [ka]

[0067] Compound (47)(ZE33-0124) To a suspension of n-tetradecanol (41.7 g, 195 mM) in 200 ml of DMF, NaH (60% in mineral oil) was added in small portions (7.4 g, 185 mM). The mixture was stirred at 60° C. for 2 hours, and compound (45) (23.0 g, 97 mM) was added in 50 ml of DMF. The reaction mixture was stirred at 80° C. for 24 hours. The mixture was diluted with 10% aqueous H 2 SO 4The mixture was quenched with ethyl acetate, extracted with EtOAc, and the combined organic extracts were washed with Na 2 SO 4 The residue was washed with 10% MTBE in hexane to give compound (47) (ZE33-0124) (7.4 g, 22%).

[0068] Compound (48)(ZE33-0112) Compound (47) (7.4 g, 22 mM) and chloride (32) (4.6 g, 24 mM) in 200 ml of MTBE with Et 3 The mixture was stirred at 60° C. for 48 h with aqueous NH 4 The mixture was quenched with Cl, extracted with EtOAc, and the combined organic extracts were washed with Na 2 SO 4 The residue was diluted with 1:1 MeCN-H 2 Wash with O and then Et 2 O and dried to give compound (48) (8.8 g, 82%).

[0069] [ka]

[0070] Compound(50) To a solution of n-tetradecanol (60.0 g, 280 mM) in 500 ml of THF was added 60% NaH (8.0 g, 245 mM). The mixture was stirred at 80° C. for 4 hours, cooled to 5° C., and a solution of chlorooxazole (49) (19.5 g, 111 mM) in 50 ml of THF was added. The mixture was stirred at ambient temperature for 15 hours and quenched with 5% HCl. The mixture was diluted with Et 2 O and the combined organic extracts were washed with Na 2 SO 4 The residue was purified by column chromatography on silica gel (EtOAc-Hx, 0-75%) to give compound (50) (20.0 g, 35%).

[0071] Compound (51)(ZE33-0125) Compound (50) (19.6 g, 38 mM) was dissolved in 250 ml of THF and 75 ml of MeOH, and 4.6 g (190 mM) of LiOH and 20 ml of H 2 O was added and the mixture was stirred at ambient temperature for 15 h. The organic components were evaporated and the residue was quenched with 1.5% HCl. The mixture was diluted with CH 2 Cl 2 The combined organic extracts were extracted with Na 2 SO 4 The residue was purified by column chromatography on silica gel and purified by HCl. 2 Cl 2 Elution with 0-10% EtOAc in water afforded compound (51) (ZE33-0125) (19.6 g, 100%).

[0072] Compound (52)(ZE33-0113) Compound (51) (19.5 g, 38 mM), chloride (32) (11.0 g, 57 mM) and Et 3 The mixture was stirred at 60° C. for 48 h with aqueous NH 4 The mixture was quenched with Cl, extracted with EtOAc, and the combined organic extracts were washed with Na 2 SO 4 The residue was purified by column chromatography on silica gel, eluting with 20-50% EtOAc in hexanes. The desired fractions were evaporated and the solid residue was purified by elution with 10% Et 2 Washing with O gave compound (52) (ZE33-0113) (8.77 g, 48%).

[0073] [ka]

[0074] Compound (54) 400ml of CH 2 Cl 2To a solution of chlorothiophene carboxylic acid (53) (25 g, 154 mM) and n-tetradecanol (39.5 g, 185 mM) in 20% aqueous H2SO4 was added EDCI (35.4 g, 185 mM) followed by DMAP (3.8 g, 31 mM) and the mixture was stirred at ambient temperature for 5 h. 2 SO 4 The organic layer was quenched with Na 2 SO 4 Dry with SiO 2 Flooding and evaporation gave compound (54) (52.8 g, 96%).

[0075] Compound(55) To a suspension of n-tetradecanol (63.0 g, 294 mM) in 400 ml of DMF, NaH (60% in mineral oil) was added in small portions (11.2 g, 279 mM). The mixture was stirred at 60° C. for 3 hours, and compound (54) (52.8 g, 147 mM) was added in 100 ml of DMF. The reaction mixture was stirred at 80° C. for 24 hours. The mixture was diluted with 10% aqueous H 2 SO 4 The mixture was quenched with ethyl acetate, extracted with EtOAc, and the combined organic extracts were washed with Na 2 SO 4 The mixture was dried at 40° C. and evaporated. The residue was purified by column chromatography on silica gel eluted with 1-5% EtOAc in hexanes. The desired fractions were evaporated and the solid residue was washed with MeOH to give compound (55) (38.9 g, 49%).

[0076] Compound (56) (ZE33-0126) was obtained.

[0077] 1000ml 1:1 EtOH-H 2 To a solution of compound (55) (38.9 g, 72 mM) in 200 was added 50 ml of 10 N aqueous NaOH and the mixture was stirred at 120° C. for 15 h. MeOH was evaporated and Et 2 HO was added, the interlayer containing the compound of interest was separated and diluted with 10% aqueous HO. 2 SO 4 The combined ether extracts were acidified with Na 2 SO4 The solid residue was washed with hexane and dried to give compound (56) (ZE33-0126) (14.3 g, 58%).

[0078] Compound (57)(ZE33-0114) Compound (56) (7.2 g, 22 mM) and chloride (32) (4.0 g, 22 mM) in 200 ml of DMF with Et 3 The mixture was stirred at 60° C. for 15 h with aqueous NH 4 The mixture was quenched with Cl, extracted with EtOAc, and the combined organic extracts were washed with Na 2 SO 4 The residue was purified by column chromatography on silica gel, eluting with 20-30% EtOAc in hexanes. The desired fractions were evaporated and the solid residue was purified by 10% Et 2 Washing with O gave compound (57) (ZE33-0114) (7.38 g, 70%).

[0079] [ka]

[0080] Compound (59) To a solution of furan (58) (4.9 g, 72 mM) in 30 ml of THF was added portionwise 30 ml of 2.5 M n-BuLi in hexane at -70 °C. The mixture was stirred at -70 °C for 0.5 h and at 0 °C for 1 h, cooled to -70 °C, and mixed with a solution of n-pentadecyl bromide (18.0 g, 62 mM) in 20 ml of THF. The mixture was stirred at room temperature for 15 h and then diluted with aqueous NH 4 Quench with Cl and Et 2 O and the combined organic extracts were washed with Na 2 SO 4 The residue was purified by column chromatography on silica gel eluted with hexane to give compound (59) (11.9 g, 69%).

[0081] Compound (60)(ZE33-0127) To a solution of compound (59) (9.7 g, 35 mM) in 100 ml of THF was added 20 ml of 2.5 M n-BuLi in hexane in small portions at −30° C. The mixture was stirred at ambient temperature for 3.5 h, cooled to −35° C., and mixed with freshly crushed dry ice (approximately 400 g). The mixture was stirred at ambient temperature for 15 h and then diluted with aqueous KHSO. 4 The mixture was quenched with CH 2 Cl 2 The combined organic extracts were extracted with Na 2 SO 4 The solid residue was washed with hexane to give compound (60) (ZE33-0127) (9.5 g, 91%).

[0082] Compound (61)(ZE33-0115) Compound (60) (11.6 g, 36 mM), chloride (32) (11.7 g, 60 mM) and Et 3 The mixture was stirred at 60° C. for 24 h with aqueous NH 4 The mixture was quenched with Cl, extracted with EtOAc, and the combined organic extracts were washed with Na 2 SO 4 The residue was purified by column chromatography on silica gel and purified with CH 2 Cl 2 Elution with 0±5% EtOAc in water afforded compound (61) (ZE33-0115) (13.2 g, 76%).

[0083] [ka]

[0084] Compound (63) 500ml of CH 2 Cl 2To a solution of TOFA (3) (13.1 g, 40 mM) in 10 mL of 1000 ml ... 2 Wash with O and Na 2 SO 4 The residue was purified by column chromatography on silica gel eluted with 15% EtOAc in hexane to give compound (63) (9.43 g, 61%).

[0085] Compound (64) 120ml of CH 2 Cl 2 A solution of 9.43 g (25 mM) of compound (63) in 40 mL of CH 2 Cl 2 Trifluoroacetic anhydride (26.4 g, 126 mM) in water was added. The mixture was stirred at ambient temperature for 4 h, evaporated and the residue was dissolved in CCl 4 Co-evaporation gave compound (64) (14.5 g, 99%).

[0086] Compound (65)(ZE33-0116) 120 ml of CH at -55°C 2 Cl 2 A solution of compound (64) (14.5 g, 25 mM) in 100 ml of CH 2 Cl 2 A solution of pyridine (22 g) and MeOH (13 g) in was added in portions. The mixture was stirred at -30°C for 0.5 h and then at ambient temperature for 3 h. The mixture was evaporated and the residue was washed with hexane to give compound (65) (ZE33-0116) (9.85 g, 100%).

[0087] [ka]

[0088] Compound(67) 500ml of CH2 Cl 2 To a solution of TOFA (3) (7.9 g, 24 mM) in 10 mL of 1000 ml of 10 ... 2 Wash with O and Na 2 SO 4 The residue was purified by column chromatography on silica gel eluted with 15% EtOAc in hexane to give compound (67) (9.16 g, 86%).

[0089] Compound (68)(ZE33-0117) To a solution of compound (67) (8.78 g, 20 mM) in 400 ml of MeOH was added 0.4 ml of 3M HCl in dioxane and the mixture was stirred at ambient temperature for 0.5 h. The mixture was evaporated and then evaporated with MeOH to a volume of about 20 ml, and the resulting pellet was filtered off and dried to give compound (68) (ZE33-0117) (6.9 g, 87%).

[0090] The compounds according to the invention can be advantageously incorporated into cosmetic or dermatological preparations.

[0091] The preparation or use according to the invention can be in the form of a liquid composition that can be applied by brush or blade, roll-on device or nebulizer, as a stick, and in the form of a system that can be applied from conventional bottles and containers, such as creams, gels or lotions. The preparation or use according to the invention can be, for example, a solution, an emulsion of the water-in-oil (W / O) or oil-in-water (O / W) type, or a multiple emulsion, for example of the water-in-oil-in-water (W / O / W) or oil-in-water-in-oil (O / W / O) type, a gel, an aqueous dispersion, a lamellar phase, an isotropic liquid solution phase, a micellar phase, a solid or dispersed hexagonal phase or phases, a solid or dispersed cubic phase or phases, a lyotropic phase, a crystalline phase, a solid stick, or even an aerosol.

[0092] Furthermore, the preparations or uses according to the invention can advantageously be in the form of washes, tinctures, cleansing formulations, pads, cotton or wipes, as well as in the form of tonics or shampoos.

[0093] Advantageously, the pH value of the preparation or use according to the invention is adjusted to a slightly acidic to neutral range, preferably between 3.0 and 7.0, particularly preferably between 4.0 and 6.5.

[0094] The formulations according to the invention can be formulated in the usual way and can be used for the treatment of the skin and / or hair in the context of skin treatment or treatment in the context of cosmetic care products.However, the formulations according to the invention can also be used in make-up products in decorative cosmetics or in cosmetic or skin cleansing products.

[0095] It is well known to those skilled in the art that cosmetic preparations are usually not conceivable without common auxiliaries and additives.Therefore, the cosmetic and dermatological preparations according to the present invention can further comprise the cosmetic auxiliaries that are generally used in said preparations, such as consistency regulators, preservatives, stabilizers, fillers, fragrances, pigments with coloring effect, thickeners, suspending agents, buffer mixtures, surface-active substances, emulsifiers, emollients, moisturizing substances and / or humectants, anti-inflammatory substances, additional active ingredients, such as vitamins or proteins, sunscreens, insect repellents, bactericides, water, salts, antibacterial substances, proteolytic or keratolytic substances, pharmaceuticals, or other common ingredients of cosmetic or dermatological formulations, such as alcohols, polyols, polymers, foam stabilizers, organic solvents or even electrolytes.

[0096] The amount of carrier material to be used in each case can be easily determined by the skilled artisan by simple trials depending on the respective product type.

[0097] In addition to water, ethanol and isopropanol, glycerin and propylene glycol, skin-protecting fatty or fatty-like substances, such as decyl oleate, cetyl alcohol, cetylstearyl alcohol and 2-octyldodecanol, in the quantitative proportions customary for such preparations, as well as mucus-forming substances and thickeners, such as hydroxyethylcellulose or hydroxypropylcellulose, polyacrylic acid, polyvinylpyrrolidone, but also in addition small amounts of cyclic silicone oils (polydimethylsiloxanes) and low-viscosity liquid polymethylphenylsiloxanes, can be used as typical carrier substances for the production or use of the preparations according to the invention.

[0098] As emulsifiers for the production or use of the preparations according to the invention, which are advantageously applied to the desired skin area as liquid or solid preparations, and which can be used in the preparations in small amounts, for example 1-6% by weight based on the total composition, non-ionic types, such as polyoxyethylene fatty alcohol ethers, for example cetostearyl alcohol polyethylene glycol ethers with 12 or 20 ethylene oxide units per molecule, cetostearyl alcohol, as well as sorbitan esters and sorbitan ester-ethylene oxide compounds (for example sorbitan monostearate and polyoxyethylene sorbitan monostearate), as well as long-chain, higher molecular weight waxy polyglycol ethers have proven suitable. In addition to this, however, any other emulsifier or mixture of emulsifiers commonly used in cosmetic preparations is also suitable. These include, for example, but are not limited to, glyceryl citrate stearate, PEG-40 stearate or polyglyceryl(3)-methylglucose distearate, stearic acid, steareth-2 and steareth-21.

[0099] The oil phase of the preparation according to the invention is advantageously selected from the group of esters of saturated and / or unsaturated, branched and / or unbranched alkanecarboxylic acids having a chain length of 3 to 30 carbon atoms and saturated and / or unsaturated, branched and / or unbranched alcohols having a chain length of 3 to 30 carbon atoms, and the group of esters of aromatic carboxylic acids and saturated and / or unsaturated, branched and / or unbranched alcohols having a chain length of 3 to 30 carbon atoms.

[0100] Furthermore, the oil phase may advantageously be selected from the group of branched and unbranched hydrocarbons and waxes, silicone oils, dialkyl ethers, the group of saturated or unsaturated branched or unbranched alcohols and the group of fatty acid triglycerides, in particular the triglycerol esters of saturated and / or unsaturated branched and / or unbranched alkanecarboxylic acids having a chain length of 8 to 24, in particular 12 to 18 C atoms. The compounds of the oil phase may be of synthetic, semi-synthetic or natural origin.

[0101] Any mixture of such oil and wax components may also be used advantageously within the context of the present invention.

[0102] Advantageously, the content of the oily phase ranges from 1 to 50% by weight, preferably from 2 to 30% by weight and particularly preferably less than 10% by weight relative to the total weight of the formulation.

[0103] For use, the cosmetic and / or dermatological formulations according to the invention are applied in sufficient amounts to the skin, scalp and / or hair in the usual manner for cosmetic and dermatological preparations.

[0104] Lipid Assay for Testing the Effectiveness of TOFA Derivatives According to the Invention To measure the lipid-reducing effect of the active ingredients, primary cell lines of sebaceous glands from different human donors are used. The cells are cultured for a total of 7 days. After seeding on day 1, the treatment with the active ingredients is carried out on days 3 and 5. On day 7, the cells are stained with the dye AdipoRed, which allows the fluorescent staining and quantification of intracellular lipid droplets. In addition, the dye fluorescein diacetate (FDA), which is converted by live cells, is also used to monitor the vitality of the cells. The resulting fluorescent signal is likewise quantifiable. The effect of the active ingredients can be measured and displayed as the ratio of the fluorescent signal of AdipoRed and FDA to the corresponding solvent ratio. The test substances were dissolved in dimethyl sulfoxide (DMSO), so all results were normalized to the DMSO-treated control. [Brief description of the drawings]

[0105] [Figure 1] FIG. 1 shows the results of an assay of the present invention.

[0106] The following examples are intended to illustrate but not limit the invention. Unless otherwise stated, numerical data relate to % by weight.

[0107] [Table 1-1]

[0108] [Table 1-2]

Claims

1. General formula (1) 【Chemistry 1】 [In the formula, R represents n-tetradecyl; n represents a number from 1 to 5; X represents O, N, N-H or S; Y and Z, independently of one another, represent C-H, N, N-H, O or S, said groups being selected such that the five-membered ring has Hückel aromaticity; R ２ and R ３ cannot simultaneously form a double bond, R １ , R ２ and R ３ are each independently -H, an oxo group, -C １ ~C ２４ -Alkyl (linear and branched), -C １ ~C ２４ -alkenyl (straight chain and branched), -C １ ~C ８ -cycloalkyl, -C １ ~C ８ -cycloalkylalkylhydroxy, -C substituted with one or more hydroxyl groups and / or one or more primary, secondary and / or tertiary amino groups １ ~C ２４ -C substituted with alkyl (linear and branched) and / or one or more optionally esterified carboxyl groups １ ~C ２４ -Alkyl (linear and branched), -C １ ~C ２４ -alkylarylalkylhydroxy (linear and branched), -C １ ~C ２４ -alkylheteroaryl (linear and branched), -C １ ~C ２４ -Alkyl-O-C １ ~C ２４ -Alkyl (linear and branched), -C １ ~C ２４ -alkylmorpholino, -C １ ~C ２４ -Alkylpiperidino, -C １ ~C ２４ -Alkylpiperazino, -C １ ~C ２４ -alkylpiperazino-N-alkyl, oxo group (=O), However, the group R １ , R ２ and R ３ A compound of the formula: wherein at most one represents an H atom.

2. The compound is selected from the group consisting of: 【Chemistry 2-1】 【Chemistry 2-2】 2. The compound according to claim 1, characterized in that it is selected from the group:

3. 3. A topical pharmaceutical or cosmetic preparation containing one or more compounds of formula (1) according to claim 1 or 2 in an effective concentration.

4. 3. A topical pharmaceutical or cosmetic preparation comprising one or more compounds of formula (1) according to claim 1 or 2, each in a concentration of 0.0001 to 40.00% by weight, preferably 0.005 to 20.00% by weight, particularly preferably 0.001 to 6.00% by weight, based on the total weight of the composition.

5. 3. Cosmetic use of one or more compounds of formula (1) according to claim 1 or 2 for reducing sebum production in human skin.

6. 3. One or more compounds of formula (1) according to claim 1 or 2 for the therapeutic treatment of oily and / or dirty skin and / or mild forms of acne and / or oily hair and / or oily scalp and / or seborrhea.

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