HEXYL CYCLE CARBAMATE, ITS USE, AND COSMETIC OR PHARMACEUTICAL COMPOSITION FOR TOPICAL USE

专利摘要:
"cyclohexyl carbamates, their use, and cosmetic or pharmaceutical composition for topical use". The present invention relates to the cosmetic, dermatological or therapeutic use of certain cyclohexyl carbamates compounds of the formula (I) given below, preferably as anti-cellulite actives. the invention further relates to cosmetic, dermatological or therapeutic compositions and products comprising such compounds of formula (I), which are preferably suitable for prophylaxis (prevention) and cosmetic treatment (combat) of cellulite in humans, corresponding methods and new compounds of formula (i) wherein a denotes in x, y and z independently of each other denote hydrogen, alkyl-c1-c4 or alkenyl-c2-c4, wherein optionally two of the radicals x, y and z are covalently bonded together to form a system bicyclic ring, in such a bicyclic ring system two of the radicals x, y and z together preferably form a radical having 1 to 4 carbon atoms, preferably a hydrocarbon having a radical of 1 to 3 carbon atoms, b denotes nr1r2, where r1 denotes hydrogen or having an organic radical of 1 to 14 carbon atoms, r2 denotes an organic radical having 1 to 14 carbon atoms, and wherein optionally r1 and r2 are covalently linked together, preferably so that b is a 3 to 8 membered ring.
公开号:BR112012029927B1
申请号:R112012029927-1
申请日:2010-05-25
公开日:2021-07-20
发明作者:Imke Meyer；Heiko Oertling；Nadine Hillebrand；Claudia Gömann；Rahim Brodhage
申请人:Symrise Ag；
IPC主号:

专利说明:

[0001] The present invention relates to the cosmetic, dermatological or therapeutic use of certain cyclohexyl carbamates compounds of Formula (I) provided below, preferably as anti-cellulite actives. The invention further relates to cosmetic, dermatological or therapeutic compositions and products comprising such compounds of Formula (I), which are preferably suitable for prophylaxis (prevention) and cosmetic treatment (combat) of cellulite in humans, corresponding methods and new compounds of Formula (I).
[0002] Cellulite is also known under the synonyms protrusio cutis and colloquially as orange peel skin. It is a cosmetic and aesthetic problem that is accompanied by the formation of dimples and indentations in the skin and the formation of nodules in the subcutaneous adipose tissue. Cellulite can occur on any part of the human body, but the outside and behind the thighs as well as the buttocks are most often affected. Breasts, under the stomach, arms or neck are sometimes also affected by cellulite.
[0003] Cellulite can be regularly found in parts of the human body with excessive fat deposits, but overweight is not a prerequisite for its occurrence. Thin women also increasingly have pronounced cellulite symptoms. However, there is probably a correlation between the severity of cellulite and the percentage of fat in the tissue.
[0004] The gender-specific anatomical structure of the skin of humans (humans) has a great influence on the development of cellulite. Thus, for example, cellulite may only rarely be seen in men, whereas, on the other hand, approximately 80% to 90% of all women are affected, in particular Caucasian women. The structure of the dermis, especially, has an effect on the skin's relief. Thus, the fat chambers in men, when the skin is pressed together, are retained by the intersection of connective tissue septa and the similar delineation of the adipose cell clamp attached to them. On the other hand, in women, the fat chambers separate from each other in a tubular shape, which are delimited by actinomorphic extension of connective tissue septa, becoming prominent when pressed together.
[0005] Furthermore, the visible model of cellulite is based on an increase in fat pads in the subcutis and a reduction in the conditions of circulation in lymphatic and blood vessels. The cause is, therefore, in part a predisposed weakening of connective tissue with concurrent occurrence of enlarged fat cell chambers with stress, sports activity, smoking, pregnancies and female hormones (estrogen and progesterone) playing a role, in addition to genetic factors .
[0006] Infectious cellulitis must be clearly separated and distinguished from the cosmetic phenomenon of cellulitis. Infectious cellulitis is a bacterial infection of the subcutaneous tissue, which in many cases can be a serious disease, and in contrast to cellulitis, it has to be treated therapeutically.
[0007] As mentioned above, even healthy women are affected by cellulite. It should be noted that cellulitis itself is not a disease and therefore its treatment should not be considered as therapy. Mild or moderate cellulite, which is considered healthy skin, is not a condition or deformity that requires medication and is not considered a pathological condition. In contrast to this, severe cellulitis may be accompanied by side effects or later effects such as pain or other medical symptoms. Medical specialists can clearly distinguish between mild or moderate cellulite and severe cellulite, and medical specialists also decide whether cellulite treatment in the medical sense is advisable or necessary.
[0008] In the context of the present invention, a cosmetic use or a cosmetic method does not have any therapeutic (side) effect.
[0009] In the context of the present invention, a therapeutic or pharmaceutical use or method is considered as medical treatment, optionally with cosmetic (side) effects.
[00010] Conventional cellulite treatment methods attempt to stimulate blood circulation to relevant skin parts and positively influence connective tissue structure, for example, by massage, lymphatic drainage, diet, sport, magnetic fields or liposuction (removal of fat by suction).
[00011] In the literature, the use of various cosmetic products is described for prophylaxis and treatment of cellulite. But its effectiveness is often very limited because of the very complex mechanism of fat cell metabolism. It is not enough to focus on a mechanism involved in lipid storage in adipose tissue.
[00012] Fat metabolism in human adipose tissue, in order to reduce the amount of stored lipids, can in principle be regulated by three Ways: Route (i): inhibition of preadipocyte differentiation
[00013] The differentiation of precursor cells from adipose cells called pre-adipocytes to true adipose cells, called adipocytes, which can store triglycerides, can be inhibited. More simply expressed, an inhibition of Pathway (i) prevents the accumulation of cellulite because the number of fat cells does not increase. This process of differentiating from preadipocytes to adipocytes is called adipogenesis. Route (ii): inhibition of lipogenesis in adipocytes
[00014] Storage of triglycerides in adipocytes (also called lipogenesis) can be prevented or inhibited. More simply expressed, an inhibition of Pathway (ii) prevents the storage of additional triglycerides (fats) in the cell, and existing fat cells do not store any new fat. Due to the natural metabolism of fat, when Via (ii) is inhibited, the fat content in the cell is reduced. Route (iii): stimulation of lipolysis in adipocytes
[00015] An increased/increased hydrolysis of lipids already stored in adipocytes - also called lipolysis - is possible by targeted stimulation. Expressed more simply, the stimulation of Pathway (iii) increases the breakdown of fats already present in the cell while an inhibition, ie, an antagonistic effect with respect to Pathway (iii) on the other hand inhibits or prevents the breakdown of fats.
[00016] Cell differentiation is the modification of the control of the gene activity of a cell so that various protein stores are provided in cells through transcription and protein biosynthesis and cells differentiate according to appearance and function . Thus, adipocytes only express enzymes that are necessary for fat storage, after differentiation. In their precursor cells, the undifferentiated preadipocytes, these enzymes are not expressed or only to a very small extent.
[00017] Cosmetic preparations that have the prophylaxis and treatment of cellulite as a goal have already been proposed in the literature. They mostly influence adipose tissue or adipocytes by a specific activity.
[00018] EP 1 234 572 describes a cosmetic preparation of at least one isoflavone aglycone, in particular genistein and/or daidzein, for treating cellulite. The aglycone isoflavone is in this case combined with an algae extract. Genistein is described as an active ingredient, which inhibits the multiplication of fat precursor cells and in addition the enzyme phosphodiesterase.
[00019] A cosmetic preparation of certain bioquinones and isoflavonoids, preferably genistein, is described for cellulite prophylaxis in DE 10 2004 032 837. It is stated that the effect of this preparation takes place through an improvement in cell metabolism. It cannot be seen which cellular metabolism mechanism is improved. It also cannot be inferred whether the adipose tissue is under the effect of the cosmetic preparation.
[00020] Preparations containing certain isoflavones are also described in DE 100 09 423, isoflavones which are described as materials with an anti-estrogen effect and used because of this effect. Daidzein, genistein, glycitein, formononetin and others are preferred isoflavones.
[00021] WO 2006/063714 teaches compositions for topical administration, containing a PDE3 inhibitor as active ingredient, for use in the treatment of cellulite and proposes pharmaceutical compositions comprising drugs such as anagrelide, cilostazol, pimobendan, milrinone, amrinone, olprinone, enoximon, cilostamide, vesnarinone and trequinsin.
[00022] The effectiveness of the substances proposed in the state of the art so far is often very limited.
[00023] Cellulite and adipocyte metabolism are a very complex mechanism that requires the alteration of different pathways within fat metabolism to be effective. Influencing only one of the different pathways is generally not effective in humans because they influence other pathways in parallel which in turn lead to an increase in the amount of stored lipid, leading to an adverse effect.
[00024] It was, therefore, the object of the invention to describe active ingredients and corresponding preparations that show activity, preferably improved, with respect to the prophylaxis and treatment of cellulite.
[00025] It has surprisingly been found that this object can be achieved using the compounds of the Formula (I) or a cosmetically acceptable salt of a compound of the Formula (I) or a mixture containing two or more of these compounds or salts thereof (i ) for the prevention, treatment or cosmetic reduction of cellulite, and/or (ii) for cosmetic (non-therapeutic) - reduction of the amount of lipid contained in the subcutaneous adipose tissue, and/or - stimulation of lipolysis in adipocytes, and/or - inhibition of pre-adipocyte differentiation, and/or - inhibition of lipogenesis in adipocytes, and/or (iii) as cosmetic anti-cellulite active,
where to denote
wherein X, Y and Z independently of each other denote hydrogen, C1-C4-alkyl or C2-C4-alkenyl, wherein optionally two of the radicals X, Y and Z are covalently bonded together to form a ring system bicyclic, in such a bicyclic ring system two of the radicals X, Y and Z together preferably form a radical having 1 to 4 carbon atoms, preferably a hydrocarbon having a radical of 1 to 3 carbon atoms, B denotes NR1R2 , wherein R1 denotes hydrogen or an organic radical having 1 to 14 carbon atoms, R2 denotes an organic radical having 1 to 14 carbon atoms, wherein optionally R1 and R2 are covalently bonded together, preferably so that B is a 3 to 8 member ring.
[00026] The compounds of Formula (I) thus are cyclohexyl carbamates (Carb-I)
wherein R1, R2 and X, Y and Z have the meanings indicated above or below.
[00027] As is common in the art, in the context of the present invention, the X, Y, and Z substituents may in each case occupy - as indicated in the different Structural Formulas - any position on the cyclohexyl ring, i.e., at the ipso position , ortho, meta or para to the cyclohexyl-carbon atom bonded to the oxygen of the group A.
[00028] It is evident, therefore, that two of the substituents X, Y, and Z - with the exception of the ipso position - can be bonded with the same carbon atom of the cyclohexyl ring of the group A.
[00029] The compounds of Formula (I) show a pronounced effect in the treatment of cellulite, recognizable by means of the ultrasound determination of the thickness of the subcutis layer, in particular to prevent the increased formation of fat deposits on the skin and/or cellulite , in which the lipid content in human subcutaneous adipose tissue is reduced. The invention, therefore, relates to cosmetic preparations (compositions) containing a corresponding effective amount of one or more compounds of the Formula (I), in particular for the topical treatment and prevention of the increased formation of fat deposits on the skin and/ or cellulite.
[00030] The compounds of Formula (I) structurally belong to the group of cyclohexyl carbamates. Some of these compounds have been described in the prior art.
[00031] As is common in the art, in the context of the present invention, abbreviations of certain chemical groups are used, for example, Me = methyl, E = ethyl, Pr = propyl, Bu = butyl, Ph = phenyl.
[00032] For the sake of clarity, it is emphasized that the present invention does not relate to substances as such or mixtures of substances as such that have been described or disclosed in the prior art.
[00033] The following compounds of Formula (I) and more specifically of Formula (Carb-II-R1H) as defined below have been described in the literature. WO 2007/016441, WO 2008/051514 and WO 2008/051475 mention
WO 2008/051514 describes
Bioorganic & Medicinal Chemistry Letters (2005), 15 (9), 2209-2213 describes
Organic Preparations and Procedures International (2004), 36 (2), 141-149 describes
US 5,892,100 mentions
JP06-072036-A describes
JP04-029964-A describes
US 5,260,474 mentions
Doklady - Akademiya Nauk Azerbaidzhanskoi SSR (1980), 36 (2), 63-66 describes
FR 2 259 589 mentions
DE 20500 87 describes
Journal of Agricultural and Food Chemistry (1967), 15(6), 1022-1029 describes
Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya (1966), (5), 922-924 describes

FR 1 401 219 mentions
The collection of Czechoslovak Chemical Communications (1965), 30(2), 585-598 and 599-604 describes
Annales Pharmaceutiques Francaises (1958), 16, 408-13 and Journal of Organic Chemistry (1958), 23, 1590-1591 describe
Annales Pharmaceutiques Francaises (1958), 16, 408-13 Mention
Azarbaycan Neft Tasarrufati (1933), (No. 3), 66-75 describes
Synthetic Communications 2001, 31 (24), 3759-3773 Describe
Journal of Medicinal Chemistry 1983, 26 (9), 1215-18 describes
Journal of Chromatography 1982, 239, 227-31 describes
Ecotoxicology and Environmental Safety 2008, 71 (3), 889 894 describe
Chirality 2010, 22 (2), 267-274 describes
Synthesis 1989, (2), 131-132 describes
Various Menthyl Carbamates of Formula (MH) have been described in the prior art
wherein R2 has the respective meaning indicated earlier or later as defined for Formula (I) and more specifically as defined for (Carb-II-R1H) given below.
[00034] Also, various compounds of Formulas (I), (Carb-II) and (Carb-II-R1H) in which X, Y, and Z each denotes H have been described in the prior art.
[00035] Furthermore, various compounds of Formulas (I), (Carb-II) and more specifically of Formula (Carb-II-R1H) as defined below wherein R2 denotes phenyl or naphthyl have been described in the prior art.
[00036] Additionally, some bicyclic carbamates of Formulas (Carb-II) and (Carb-II-R1H) as defined below wherein two of the radicals X, Y and Z are covalently bonded together to form a bicyclic ring system in the which R2 contains a -COOH group and/or a =CH2 have been described in the prior art.
[00037] WO 2004/033422 refers to compounds that inhibit fatty acid amide hydrolase (FAAH). Methods are described in this application for controlling appetite and treating appetite disorders by administering FAAH inhibitors, thereby reducing body fat or body weight. WO 2004/033422 describes a very broad generic chemical formula of carbamates which also encompasses a vast number of substituted or unsubstituted cycloalkyl carbamates. The only specific compounds described in WO 2004/033422 of relevance in the context of the present invention are as follows:

[00038] International Journal of Obesity (December 22, 2009) doi:10.1038/ijo.2009.262 investigated the effect of FAAH deficiency in mice on energy storage and appetite. Appetite and food intake were shown not to change with FAAH deficiency. The authors also measured an increased body weight, fat content and insulin resistance in FAAH-deficient mice compared to wild mice with the same caloric intake. An increased lipogenesis in FAAH-deficient mice is given here as a reason for this observation.
[00039] WO 2004/033422 does not relate to combating or preventing cellulite. There is no connection between FAAH inhibition and appetite reduction described in WO 2004/033422 and the prophylaxis and cosmetic treatment of cellulite in humans.
[00040] EP 1 284 145 describes the use of N-2-(3,4-dihydroxyphenyl)ethyl-substituted carbonic acid derivatives as radical scavengers and antioxidants. EP 1 284 145 further describes cosmetic preparations containing said carbonic acid derivatives. The effect of these compounds on adipose cell metabolism or human body weight has not been investigated. The only compound explicitly mentioned in EP 1 284 145 of relevance in view of Formula (I) of the present invention is N-[2-(3,4-dihydroxyphenyl)ethyl-O-(1R, 3R, 4S) -menthyl]carbamate. According to EP 1 284 145, preparations for nutrition or satisfaction may additionally comprise bitter substances, such as caffeine.
[00041] In a preferred embodiment, a cosmetic or pharmaceutical preparation according to the present invention is free of N-[2-(3,4-dihydroxyphenyl)ethyl-O-(1R,3R,4S)-menthyl ] carbamate. In another preferred embodiment, compounds of Formula (I) according to the present invention, more specifically compounds of Formula (Carb-II-R1H), are excluded in which R2 denotes the radical 2-(3,4-di -hydroxyphenyl)ethyl. In another preferred embodiment, compounds of Formula (I) according to the present invention, more specifically compounds of Formula (Carb-II-R1H), are excluded in which R2 denotes a radical containing a 3,4-di-group hydroxyphenyl. In another preferred embodiment, cosmetic or pharmaceutical preparations according to the present invention are free from the compounds of the Formula (I) according to the present invention, more specifically from the compounds of the Formula (Carb-II-R1H), in which R2 denotes the 2-(3,4-dihydroxyphenyl)ethyl radical. In another preferred embodiment, cosmetic or pharmaceutical preparations according to the present invention are free from the compounds of the Formula (I) according to the present invention, more preferably from the compounds of the Formula (Carb-II-R1H), in which R2 denotes a radical containing a 3,4-dihydroxyphenyl group.
[00042] There is no indication so far that the compounds used according to the present invention are suitable for the prophylaxis and treatment (preferably cosmetic) of cellulite in humans.
[00043] Compounds of Formula (I) and preparations (compositions) according to the invention, comprising one or more compounds of Formula (I) influence cellulite as to the amount of stored lipids, since the lipid content in beings humans is reduced.
[00044] Thus, according to the present invention, cellulite is prevented, treated or reduced by a preparation (composition) containing one or more compounds of the Formula (I) influencing the above-described Routes (i) and/or (ii) and/or (iii), even more preferably influencing the above-described Pathways (i) and (ii) and (iii).
[00045] The (preferred) compounds of Formula (I) stimulate lipolysis (Via (iii)).
[00046] Preferred compounds of Formula (I) according to the present invention influence in at least two, preferably all three mentioned Routes (i), (ii) and (iii).
[00047] Thus, preferred anti-cellulite active compounds of Formula (I) stimulate lipolysis (Route (iii)) and additionally exhibit activity in Route (i) and/or (ii).
[00048] To determine whether a compound exhibits an activity with respect to the present invention corresponding to Routes (i) and/or (ii) and/or (iii), preferably tests are carried out according to Examples 2, 3.2, and 4.1 of the dos below:
[00049] Route (i): Inhibition of adipogenesis (pre-adipocyte differentiation) is preferably tested using the assay as described in Example 2, below.
[00050] Route (ii): Inhibition of lipogenesis in adipocytes is preferably tested using the assay as described in Example 3.2, below.
[00051] Route (iii): stimulation of lipolysis in adipocytes is preferably tested using the assay as described in Example 4.1, below. More preferably, additionally, stimulation of lipolysis in adipocytes is tested using the assay as described in Example 4.2, below.
[00052] In the investigations, it was found that the compounds of Formula (I) in which X, Y and Z each denote hydrogen were less effective as to the effects to be achieved in the context of the present invention. Compounds of Formula (I) in which X, Y and Z each denote hydrogen inhibit adipogenesis (Via (i) and stimulate lipolysis (Via (iii)) but are not inhibitors or are very weak inhibitors of lipogenesis (Via (ii)) Accordingly, compounds of Formula (I) in which one, two or all of the X, Y and Z substituents are not hydrogen are preferred.
[00053] A regulatory mechanism of pre-adipocytes and adipocytes is inter alia the expression of SIRT1 (Sirtuin 1), a NAD+-dependent histone deacetylase (nicotinamide adenine dinucleotide) that regulates senescence and metabolism as well as modulates life expectancy . It is generally known (see Picard, F., M. Kurtev, et al. "Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma", Nature 2004, 429, 771-6) that SIRT1 influences adipocyte metabolism by inhibiting adipogenesis, Route (i) mentioned above, and stimulates lipolysis, Route (iii) mentioned above. Thus, stimulating the expression of SIRT1, Via (i) and Via (iii) are influenced, resulting in prevention and reduction of cellulite.
[00054] Surprisingly it has been found that the compounds of Formula (I) stimulate the expression of SIRT1 which inter alia influences Routes (i) and Route (iii) mentioned above.
[00055] Advantageous for anti-cellulite actives is also a proliferation inhibition. By inhibiting preadipocyte proliferation, the number of precursor cells is reduced and the process of adipogenesis (Route (i) is indirectly reduced resulting in a lower number of adipocytes). Surprisingly it has been found that the compounds of Formula (I) inhibit the proliferation of preadipocytes.
[00056] The compounds according to the invention of Formula (I), depending on the meaning of X, Y, Z, R1 and R2, can exist in different stereoisomeric forms and can be used in the context of the present invention as stereoisomers, enantiomers , diastereomers, syn-/anti-isomers, endo-/exo-isomers, cis-/trans-isomers or epimers.
[00057] As common in the art, Structural Formula "flat", ie Structural Formula that does not convey any stereochemical information, includes and encompasses all stereoisomers of said Structural Formula.
[00058] The compounds of Formula (I) can be used in the context of the present invention in the form of pure cis- or trans-, syn- or anti-diastereomer or in the form of any mixture of diastereomers. The compounds of Formula (I) can also be used in the context of the present invention in the form of pure enantiometers or in the form of any mixture of enantiometers, in the latter case, racemates being preferred.
[00059] In the case where R1 does not denote hydrogen, R1 and R2 independently of each other preferably denote an optionally substituted radical selected from the group consisting of alkyl, heteroalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, cycloalkenyl, cycloalkenylalkyl, alkynyl, cycloalkylalkynyl , aryl, heteroaryl, arylalkyl, cycloalkylaryl, cycloalkenylaryl, cycloalkylheteroaryl, heterocycloalkylaryl, heterocycloalkenylaryl, heterocycloalkenylheteroaryl and heteroarylalkyl.
[00060] In the case where R1 does not denote hydrogen, R1 and R2 independently of one another more preferably denote an optionally substituted alkyl-C1-C14 radical, heteroalkyl-C1-C14, cycloalkyl-C3-C14, cycloalkylalkyl-C4-C14, alkenyl- C2-C14, cycloalkenyl-C3-C14, cycloalkenylalkyl-C4-C14, alkynyl-C2-C14, cycloalkylalkynyl-C5-C14, aryl-C3-C14, heteroaryl-C2-C14, arylalkyl-C4-C14, cycloalkylaryl- C8-C14, cycloalkenylaryl-C8-C14, cycloalkyl-heteroaryl-C5-C14, heterocycloalkylaryl-C8-C14, heterocycloalkenylaryl-C8-C14, heterocycloalkenyl-heteroaryl-C8-C14 and heteroarylalkyl-C3-C14.
[00061] Heteroalkyl, heteroaryl, cycloalkyl-heteroaryl, heterocycloalkylaryl, heterocycloalkenylaryl, heterocycloalkenyl-heteroaryl and heteroarylalkyl radicals in the context of the present invention preferably contain at least one heteroatom, optionally up to four heteroatoms, independently selected from the group consisting of O, S and /or N. Preferred radicals are heteroalkyl, heteroaryl, cycloalkyl-heteroaryl, heterocycloalkylaryl, heterocycloalkenylaryl, heterocycloalkenyl-heteroaryl and heteroarylalkyl containing one, two or three heteroatoms, independently selected from the group consisting of O, S and/ or No.
[00062] Preferably, the X, Y, and Z substituents in each case occupy any desired position on the cyclohexyl ring in the ortho, meta or para position relative to the cyclohexyl-carbon atom attached to the oxygen of the carbamate group. Thus, preferably A denotes

[00063] The corresponding preferred compounds of Formula (I) are cyclohexyl carbamates of Formula (Carb-II):
wherein R1, R2 and X, Y and Z have the meanings indicated above or below.
[00064] In preferred compounds of Formula (I), (Carb-I) and (Carb-II), R1 denotes hydrogen. In our investigations, these compounds were generally found to have higher activity and efficacy with regard to the prophylaxis and treatment of cellulite compared to compounds of Formula (I) wherein R1 denoted having a radical of 1 to 14 carbon atoms.
[00065] Thus, the most preferred compounds of Formula (I) are cyclohexyl carbamates of Formula (Carb-II-R1H):
where X, Y and Z have the meaning indicated above or below.
[00066] Substituents X, Y and Z independently of each other preferably denote hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, ethenyl, prop-2-en- 1-yl, prop-1-en-1-yl, prop-1-en-2-yl, but-1-en-1-yl, but-1-en-2-yl, but-1-en- 3-yl, but-2-en-1-yl, but-3-en-1-yl, but-2-en-2-yl, 2-methylprop-1-en-1-yl or 2-methylprop- 2-en-1-ila.
[00067] In a preferred embodiment, the X, Y and Z substituents independently of each other denote hydrogen or C1-C4-alkyl. In another preferred embodiment, at least one of the X, Y and Z substituents denotes C 1 -C 4 -alkyl, that is, at least one of the X, Y and Z substituents does not denote hydrogen.
[00068] In another preferred embodiment, two of the substituents X, Y and Z independently of each other denote hydrogen or C1-C4-alkyl and at least one of the X, Y and Z substituents denotes C1-C4-alkyl.
[00069] In preferred compounds of Formula (I), (Carb-I), (Carb-II) and (Carb-II-R1H), R2 denotes an organic radical having from 1 to 12 carbon atoms, preferably having a radical organic of 1 to 10 carbon atoms, more preferably having an organic radical of 1 to 8 carbon atoms.
[00070] In more preferred compounds of Formula (I), (Carb-I), (Carb-II) and (Carb-II-R1H), R2 denotes an optionally substituted C1-C10-alkyl radical, C1-C10-heteroalkyl , C3-C10-cycloalkyl, C4-C10-cycloalkyl, C2-C10-alkenyl, C3-C10-cycloalkenyl, C4-C10-cycloalkenyl, C2-C10-alkynyl, C5-C10-cycloalkylalkynyl, C3-aryl -C10, heteroaryl-C2-C10, arylalkyl-C4-C10, cycloalkylaryl-C8-C10, cycloalkenylaryl-C8-C10, cycloalkyl-heteroaryl-C5-C10, heterocycloalkylaryl-C8-C10, heterocycloalkenylaryl-C8-C10 , heterocycloalkenyl-C8-C10 heteroaryl and heteroaryl-C3-C10 alkyl.
[00071] In the most preferred compounds of Formula (I), (Carb-I), (Carb-II) and (Carb-II-R1H), R2 denotes an optionally substituted radical chosen from the group consisting of C1-alkyl -C8, cycloC3-C8 cycloalkyl, cycloalkyl-C4-C12 alkyl, alkenyl-C2-C8, cycloalkenyl-C3-C8, cycloalkenyl-alkyl-C4-C8, aryl-C3-C8, heteroaryl-C2-C8, arylalkyl - 1a-C4-C8, cycloalkyl-heteroaryl-C5-C8 and heteroaryl-C4-C8-alkyl.
[00072] If the radicals R1 and/or R2 are substituted, R1 and/or R2 each may contain one or more heteroatoms, preferably independently selected from the group consisting of O, S, N, Si and F. are selected from the group consisting of O, S and N, the radicals R1 and/or R2 each preferably contain one, two or three heteroatoms independently selected from the group consisting of O, S and/or N.
[00073] If the radicals R1 and/or R2 are substituted, the following substituents are preferred: hydroxyl, fluoride, C1-C8-alkyl, preferably methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl , tert-butyl, C3-C12-cycloalkyl, preferably cyclopropyl, cyclopentyl, cyclohexyl, cyclooctyl, cyclododecyl, C2-C-alkynyl, preferably ethynyl, propynyl, perfluoroalkyl-C1-C8, preferably trifluoromethyl, nonafluorobutyl, alkoxy -C1-C8, preferably methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy, C3-C8 cycloalkoxy, preferably C3-cycloalkoxy, C5-cycloalkoxy, C6-cycloalkoxy , C8-cycloalkoxy, C1-C10-alkoxyalkyl, in which 1 to 3 CH2 groups are replaced by oxygen, preferably -[-O-CH2-CH2-]VQ or -[-O-CH2-CHMe-]VQ, in wherein Q is OH or CH3 and wherein v denotes an integer from 1 to 3, Acyl-C1-C4, preferably acetyl, Acetal-C1-C-, preferably dimethylacetal, diethylacetal or a group m ethylenedioxy-O-CH2-O-. carboxyl-C1-C4, preferably CO2Me, CO2Et, CO2iso-Pr, CO2tert-Bu, acyloxy-C1-C4, preferably acetyloxy, silyl-Si1-Si10, and siloxy-Si1-Si30 or polysiloxy. Cosmetically or pharmaceutically acceptable preferred salts of compounds of Formula (I) are those in which one or more counterions (neutralizing cation) is selected from the group consisting of Na+, K+, NH4+, trialkylammonium NHRi3+, Ca2+, Mg2+, Zn2+ and Al3+ .
[00074] In trialkylammonium NHRi3+, preferably each Riinde pendant to other radicals Ri denotes an alkyl group having from 1 to 30 C atoms, preferably having 4 to 22 C atoms.
[00075] Particular preferred counterions are Na+, K+, Ca2+ and/or Mg2+.
[00076] In the case where two different compounds of Formula (I) are used as a mixture, generally the weight ratio of the two compounds is chosen in the range of 10:1 to 1:10, preferably in the range of 5:1 to 1:5, more preferably in the range 3:1 to 1:3, the counterion, if present, is not included in the case of salts.
[00077] In the context of the present invention, a wavy line in the Structural Formulas means that the double bond can be in the (E) or (Z) configuration.
[00078] Preferred compounds of Formula (I), (Carb-I), (Carb-II) and (Carb-II-R1H) are those in which A denotes a radical chosen from the following list "CiO":




























[00079] Preferred compounds of Formula (I), (Carb-I), (Carb-II) and (Carb-II-R1H) are those in which B denotes NR1R2, wherein preferably R1 denotes hydrogen, and wherein NR2is radical chosen from the following list "N"







[00080] The code CiO-N- as defined and used below specifies a single individual compound of the Formula (Carb-II-R1H) according to the present invention. A specific compound is defined by the code CiO-N- by selecting a radical from the list "CiO" as substituent A in Formula (I) and selecting at substituent B a radical from the list "N" as group NR2, whereby R1 do substituent B denotes hydrogen.
[00081] By way of example, said CiO-N- code is illustrated by the following compounds:


[00082] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, wherein NR2 corresponds to radical 1 of the list "N", above, and A of Formula (I) denotes a radical selected from the list " CiO", above.
[00083] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 2 of the list "N", above, and A of Formula (I) denotes a radical selected from the list " CiO", above.
[00084] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 3 of the list "N", above, and A of Formula (I) denotes a radical selected from the list " CiO", above.
[00085] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 4 of the list "N", above, and A of Formula (I) denotes a radical selected from the list " CiO", above.
[00086] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 5 of the list "N", above, and A of Formula (I) denotes a radical selected from the list " CiO", above.
[00087] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 6 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[00088] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 7 of the list "N", above, and A of Formula (I) denotes a radical selected from the list " CiO", above.
[00089] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 8 of the list "N", above, and A of Formula (I) denotes a radical selected from the list " CiO", above.
[00090] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 9 of the list "N", above, and A of Formula (I) denotes a radical selected from the list " CiO", above.
[00091] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 10 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[00092] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 11 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[00093] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 12 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[00094] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 13 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[00095] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, wherein NR2 corresponds to radical 14 of the list "N" above, and A of Formula (I) denotes a radical selected from the "CiO" list above.
[00096] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 15 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[00097] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 16 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[00098] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 17 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[00099] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 18 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000100] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 19 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000101] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 20 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000102] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 21 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000103] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 22 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000104] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 23 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000105] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 24 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000106] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 25 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000107] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 26 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000108] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 27 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000109] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 28 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000110] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, wherein NR2 corresponds to radical 29 of the list "N" above, and A of Formula (I) denotes a radical selected from the "CiO" list above.
[000111] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 30 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000112] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 31 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000113] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 32 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000114] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 33 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000115] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 34 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000116] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 35 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000117] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 36 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000118] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 37 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000119] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 38 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000120] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 39 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000121] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 40 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000122] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 41 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000123] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 42 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000124] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 43 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000125] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 44 of the list "N" above, and A of Formula (I) denotes a radical selected from the "CiO" list above.
[000126] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 45 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000127] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 46 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000128] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 47 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000129] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 48 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000130] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 49 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000131] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 50 from the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000132] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 51 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000133] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 52 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000134] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 53 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000135] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 54 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000136] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 55 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000137] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 56 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000138] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 57 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000139] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 58 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000140] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, wherein NR2 corresponds to radical 59 of the list "N" above, and A of Formula (I) denotes a radical selected from the "CiO" list above.
[000141] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 60 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000142] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 61 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000143] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 62 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000144] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 63 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000145] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 64 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000146] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 65 from the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000147] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 66 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000148] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 67 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000149] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 68 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000150] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 69 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000151] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 70 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000152] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 71 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000153] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 72 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000154] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 73 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000155] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 74 of the list "N" above, and A of Formula (I) denotes a radical selected from the "CiO" list above.
[000156] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 75 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000157] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 76 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000158] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 77 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000159] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 78 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000160] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 79 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000161] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 80 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000162] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 81 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000163] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 82 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000164] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 83 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000165] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 84 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000166] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 85 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000167] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 86 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000168] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 87 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000169] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 88 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000170] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 89 of the list "N", above, and A of Formula (I) denotes a radical selected from the "CiO" list above.
[000171] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 90 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000172] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 91 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000173] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 92 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000174] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 93 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000175] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 94 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000176] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 95 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000177] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 96 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000178] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 97 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000179] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 98 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000180] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 99 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000181] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, where NR2 corresponds to radical 100 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000182] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, wherein NR2 corresponds to radical 101 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000183] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, wherein NR2 corresponds to radical 102 of the list "N" above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000184] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, wherein NR2 corresponds to radical 103 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000185] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, wherein NR2 corresponds to radical 104 of the "N" list above, and A of Formula (I) denotes a radical selected from the "CiO" list above.
[000186] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, wherein NR2 corresponds to radical 105 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000187] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, wherein NR2 corresponds to radical 106 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000188] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, wherein NR2 corresponds to radical 107 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000189] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, wherein NR2 corresponds to radical 108 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000190] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, wherein NR2 corresponds to radical 109 of the list "N" above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000191] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, wherein NR2 corresponds to radical 110 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000192] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, wherein NR2 corresponds to radical 111 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000193] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, wherein NR2 corresponds to radical 112 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000194] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, wherein NR2 corresponds to radical 113 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000195] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, wherein NR2 corresponds to radical 114 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000196] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, wherein NR2 corresponds to radical 115 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000197] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, wherein NR2 corresponds to radical 116 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000198] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, wherein NR2 corresponds to radical 117 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000199] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, wherein NR2 corresponds to radical 118 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000200] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, wherein NR2 corresponds to radical 119 of the list "N" above, and A of Formula (I) denotes a radical selected from the "CiO" list above.
[000201] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, wherein NR2 corresponds to radical 120 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000202] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, wherein NR2 corresponds to the radical 121 of the list "N" above, and A of Formula (I) denotes a radical selected from the "CiO" list above.
[000203] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, wherein NR2 corresponds to radical 122 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000204] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, wherein NR2 corresponds to radical 123 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000205] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, wherein NR2 corresponds to radical 124 of the list "N" above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000206] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, wherein NR2 corresponds to radical 125 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000207] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, wherein NR2 corresponds to radical 126 of the list "N" above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000208] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, wherein NR2 corresponds to radical 127 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000209] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, wherein NR2 corresponds to radical 128 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000210] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, wherein NR2 corresponds to radical 129 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000211] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, wherein NR2 corresponds to radical 130 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000212] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, wherein NR2 corresponds to radical 131 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000213] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, wherein NR2 corresponds to radical 132 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000214] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, wherein NR2 corresponds to radical 133 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000215] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, wherein NR2 corresponds to radical 134 of the list "N" above, and A of Formula (I) denotes a radical selected from the "CiO" list above.
[000216] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, wherein NR2 corresponds to radical 135 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000217] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, wherein NR2 corresponds to radical 136 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000218] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, wherein NR2 corresponds to radical 137 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000219] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, wherein NR2 corresponds to radical 138 of the list "N" above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000220] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, wherein NR2 corresponds to radical 139 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000221] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, wherein NR2 corresponds to radical 140 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000222] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, wherein NR2 corresponds to radical 141 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000223] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, wherein NR2 corresponds to radical 142 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000224] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, wherein NR2 corresponds to radical 143 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000225] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, wherein NR2 corresponds to radical 144 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000226] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, wherein NR2 corresponds to radical 145 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000227] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, wherein NR2 corresponds to radical 146 of the list "N" above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000228] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, wherein NR2 corresponds to radical 147 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000229] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, wherein NR2 corresponds to radical 148 of the list "N" above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000230] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, wherein NR2 corresponds to radical 149 of the list "N" above, and A of Formula (I) denotes a radical selected from the "CiO" list above.
[000231] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, wherein NR2 corresponds to radical 150 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000232] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, wherein NR2 corresponds to radical 151 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000233] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, wherein NR2 corresponds to radical 152 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000234] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, wherein NR2 corresponds to radical 153 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000235] Additional preferred compounds of Formula (I) are those in which B denotes NHR2, wherein NR2 corresponds to radical 154 of the list "N", above, and A of Formula (I) denotes a radical selected from the list "CiO" above.
[000236] However, in the context of the present invention, and depending on the circumstances, each individual compound of the compounds of the Formula (Carb-II-R1H), in particular those defined by the code CiO-N-, may for technical or non-technical reasons , as the case may be, in some embodiments is more or less preferred than other compounds of the Formula (Carb-II-R1H), particularly those defined by the code C10-N-. Thus, in some cases, the compounds of Formula (Carb-II-R1H) as defined by the code CiO-N- do not necessarily share the same level of preference.
[000237] Various compounds of Formula (I), in particular the preferred compounds according to the present invention, are identified and referred to using an arbitrary internal reference numbering system like "BIO", followed by a four-digit number.
[000238] In one embodiment, the compounds of Formula (I), (Carb-I), (Carb-II) and Carb-II-R1H) are those in which X, Y and Z each de-notehydrogen (corresponding to CyO - radical AA).
[000239] Such cyclohexyl carbamates are derived from unsubstituted cyclohexanols, thus for compounds of Formula (I) in which A denotes:

[000240] A particularly preferred cyclohexyl carbamate derived from unsubstituted cyclohexanol is: BIO1741: cyclohexyl ester of phenylcarbamic acid (corresponding to code CiO-N-AA35)

[000241] In the investigations it was found that the compounds of Formula (I) in which X, Y and Z each denote hydrogen (that is, those in which the radical CiO - denotes AA) were less effective in terms of the effects to be achieved in the context of the present invention compared to compounds of Formula (I) derived from mono-, di- or tri-substituted cyclohexanols as described below. Thus, compounds of Formula (I) in which one, two or all of the X, Y and Z substituents are not hydrogen are preferred.
[000242] In a preferred embodiment, the preferred compounds of Formula (I), (Carb-I), (Carb-II) and (Carb-II-R1H), are those in which X denotes C1-C4-alkyl or alkenyl-C2-C4 and Y and Z both dene-tamhydrogen.
[000243] Such cyclohexyl carbamates are derived from monosubstituted cyclohexanols, thus for compounds of Formula (I) in which A denotes
where X has the meaning given above.
[000244] Preferably, X denotes C1-C4-alkyl, more preferably X denotes methyl, isopropyl or tert-butyl.
[000245] In the investigations themselves it was found that the compounds of Formula (I) in which A denotes
wherein Rortoé methyl were less effective than those where Rorto was C 2 -C 4 -alkyl, in particular less active than those compounds of Formula (I) where Rorto was iso-propyl or tert-butyl. Accordingly, compounds of Formula (I) in which Rorto denotes isopropyl or tert-butyl, are preferred in this context. Even more preferably A denotes

[000246] Particularly preferred cyclohexyl carbamates of the Formula (Carb-II-R1H), derived from monosubstituted cyclohexanols, are as follows:


[000247] The (preferred) compounds of Formula (I) derived from monosubstituted cyclohexanols, in particular those explicitly listed above, were particularly active as to the effects to be achieved in the context of the present invention.
[000248] In another preferred embodiment, preferred compounds of Formula (I), (Carb-I), (Carb-II) and Carb-II-R1H), are those in which X and Y independently of each other denote C1-alkyl C4 or alkenyl-C2-C4 and Z denotes hydrogen.
[000249] Such cyclohexyl carbamates are derived from disubstituted cyclohexanols, thus for compounds of Formula (I) in which A denotes
where X and Y have the meaning given above.
[000250] Preferably, X and Y independently of each other denote have C1-C4-alkyl, more preferably methyl, isopropyl or tert-butyl. In a preferred embodiment, X or Y denotes methyl.
[000251] More preferably, X and Y independently of each other denote methyl or isopropyl, most preferably A denotes

[000252] Particularly preferred cyclohexyl carbamates of the Formula (Carb-II-R1H), derived from disubstituted cyclohexanols, are as follows:



[000253] The (preferred) compounds of Formula (I) derived from disubstituted cyclohexanols, in particular those explicitly listed above, were particularly active as to the effects to be achieved in the context of the present invention.
[000254] In another preferred embodiment, the preferred compounds of Formula (I), (Carb-I), (Carb-II) and Carb-II-R1H) are those in which X, Y and Z independently of each other denote alkyl -C1-C4 or alkenyl-C2-C4.
[000255] Such cyclohexyl carbamates are derived from trisubstituted cyclohexanols, thus for compounds of Formula (I) in which A denotes
where X, Y and Z have the meaning given above.
[000256] Preferably, X, Y and Z independently of each other denote C1-C4-alkyl, more preferably methyl, isopropyl or tert-butyl. In a preferred embodiment, at least one X, Y or Z substituent denotes methyl.
[000257] More preferably, X, Y and Z independently of each other denote methyl or isopropyl, most preferably X, Y and Z each denotes that it methyl, in particular A denotes

[000258] Also preferred cyclohexyl carbamates are derivatives of trisubstituted cyclohexanols are those in which X of methyl note and Y and Z together form a radical (a bridge) with 3 carbon atoms.
[000259] Among the compounds of Formula (I) derived from bicyclic cyclohexanols, those in which A denotes
(ie borneil or isoborneil) were particularly active, in particular those of the Formula (Carb-II-R1H).
[000260] Particularly preferred cyclohexyl carbamates of the Formula (Carb-II-R1H), derived from trisubstituted cyclohexanols, are as follows:

[000261] The (preferred) compounds of Formula (I) derived from trisubstituted cyclohexanols, in particular those explicitly listed above, were particularly active as to the effects to be achieved in the context of the present invention.
[000262] The following compounds of the Formula (Carb-II-R1H) are particularly preferred since they were among the most active and effective compounds tested in the three Routes (i), (ii) and (iii):
[000263] BIO1617, BIO1851, BIO1823, BIO1581, BIO1841, BIO1745, BIO1844, BIO1748, BIO1845, BIO1616, BIO1743, BIO1747, BIO1842, BIO1840, BIO1615, BIO1573.
[000264] The compounds of Formula (I) of the present invention can generally be obtained by procedures well known in chemical synthesis. For example, reaction from
on what
[000265] A, R1 and R2 denote a radical (preferred) as defined above, preferably R1 denotes H, and Hal denotes a halide, preferably chloride or bromide.
[000266] In order to facilitate the dehydrohalogenation step and the formation of a compound of Formula (I) it is preferable to carry out said reaction in the presence of a base, preferably a tertiary amine.
[000267] Preferred compounds of Formula (I) in which R1 of note H can be preferably obtained by reacting a cyclohexanol of Formula AH with a corresponding isocyanate O=C=N-R2, as illustrated in the following reaction scheme:
wherein A and R2 denote a (preferred) radical as defined above. The reaction of the isocyanate and the cyclohexanol of Formula AH can be carried out in the absence (see example 1.1.1, below) or in the presence of an inert solvent (see example 1.3.2, below).
[000268] The present invention also relates to a cosmetic or pharmaceutical product, preferably topical, composition for preventing, treating or reducing cellulite, comprising (a) an effective amount of one, two or more compounds, preferably of the preferred compounds, of Formula (I) as defined in this application and/or a cosmetically or pharmaceutically acceptable salt thereof, - to reduce the amount of lipid contained in subcutaneous adipose tissue, and/or - to stimulate lipolysis in adipocytes, and/ or - to inhibit preadipocyte differentiation, and/or - to inhibit lipogenesis in adipocytes, and one or more compounds selected from the following groups (b) and/or (c): (b) one or more stimulants of lipolysis, preferably selected from the (bi) group of phosphodiesterase inhibitors, and/or (b-ii) group of beta-adrenergic receptor agonists, and/or (c) one or more stimulants of fatty acid transport or oxidation free, preferably nt selected from the (c-i) group of promoters of free fatty acid transport in the mitochondria, preferably coenzyme A, and/or (c-ii) group of beta-oxidation stimulants, preferably L-carnitine.
[000269] In the context of the present invention an effective amount of compounds of Formula (I), preferably of preferred compounds of Formula (I), refers to a sum total of one, two or more compounds, preferably of preferred compounds, of Formula (I) sufficient to exhibit an activity in the above-described Routes (i) and/or (ii) and/or (iii), i.e. to influence one or more of said Routes in the manner desired with respect to the present invention .
[000270] Preferably, an effective amount of the (preferred) compounds of Formula (I) refers to a total sum of one, two or more compounds, preferably of preferred compounds, of Formula (I) sufficient to stimulate lipolysis (Via ( iii)), more preferably exhibit an activity in at least two, preferably all three of the above-mentioned Ways (i), (ii) and (iii).
[000271] A composition (preparation), preferably a topical composition, according to the present invention preferably contains one or more compounds of Formula (I) (including all stereoisomers, enantiomers, diastereomers, cis/trans-isomers and epimers, without considering possible counterions) in a total amount of 0.001 - 10% by weight, preferably 0.005 - 5% by weight and particularly preferably 0.01 - 2% by weight and even more preferably 0.05 - 1% by weight, in each case based on the total weight of the preparation (composition).
[000272] The compounds of Formula (I) can be easily incorporated at these concentrations into common cosmetic or dermatological formulations such as pump sprays, aerosol sprays, creams, ointments, dyes, lotions and the like. The (preferred) compounds of Formula (I) also stimulate lipolysis (Via (iii)). However, it is also possible and in many cases advantageous to combine the compounds of Formula (I) with additional active ingredients to increase the stimulation of lipolysis (Via (iii)).
[000273] The invention in one aspect of the present invention preferably relates to cosmetic (improved) preparations (compositions) containing: (a) one or more compounds of Formula (I), and (b) one or more stimulants of lipolysis.
[000274] Lipolysis stimulants are active ingredients that stimulate lipolysis (Via (iii)) and are preferably selected from the group (bi) of phosphodiesterase inhibitors, and/or group (b-ii) of receptor agonists beta-adrenergic,
[000275] Preferably, the lipolysis stimulant is present in an amount sufficient to stimulate lipolysis.
[000276] The invention in another aspect of the present invention relates to cosmetic (improved) preparations (compositions) containing: (a) one or more compounds of Formula (I), and (c) one or more transport or oxidation stimulants of free fatty acids.
[000277] The stimulants of transport or oxidation of free fatty acids are preferably selected from the group (ci) of promoters of free fatty acid transport in the mitochondria, preferably coenzyme A, and/or group (c-ii) of beta-oxidation stimulants, preferably L-carnitine.
[000278] Preferably, one or more stimulants of the transport or oxidation of free fatty acids are present in an amount sufficient to stimulate the transport or oxidation of free fatty acids.
[000279] An advantageous preparation according to the invention additionally contains anti-cellulite active ingredients from the group (bi) of phosphodiesterase inhibitors selected from the group of xanthines, preferably selected from the group of 3,7- or 3,9- optionally substituted dihydro-1H-purin-2,6-diones of Formula (Xa):
where R9, R10 and R11, independently of one another, denote hydrogen or methyl.
[000280] The xanthines, in particular those of Formula (Xa), can preferably be used as pure materials or in the form of plant extracts.
[000281] Methyl xanthines are preferably caffeine (R9 = R10 = R11 = CH3), theobromine (R9 = H, R10 = R11 = CH3) and theophylline (R9 = R10 = CH3, R11 = H); the most preferred xanthine in connection with the present invention is caffeine. Also preferred is the theophylline aminophylline derivative.
[000282] Particularly preferably, a preferably topical cosmetic preparation according to the invention contains one or more compounds of Formula (Xa), in turn caffeine is preferred in this application, preferably in a total amount of 0.005 - 10% by weight, preferably 0.05 - 5% by weight, particularly preferably 0.5 - 2.5% by weight, in each case based on the total weight of the preparation, counterions of the compounds of Formula (Xa) not being included.
[000283] The preferred weight ratios of the total amount of the compound of Formula (I) to the total amount of xanthines of Formula (Xa), caffeine being preferred in this application, in the preparations according to the invention are preferably 20:1 to 1:500, more preferably from 1:1 to 1:50, also without considering possible counterions.
[000284] Also preferred preparations contain combinations of the compound of Formula (I) with an adipocyte beta-adrenergic receptor agonist. Preferred beta-adrenergic receptor agonists are β-phenylethylamines of the Formula (PhEA):
wherein R12 and R13, independently of one another, signify hydrogen, hydroxy or methoxy, R14 means hydrogen, hydroxy or methyl, R15 means hydrogen or methyl, R16 and R17, independently of one another, signify hydrogen or C1-C4-alkyl.
[000285] The Formula β-phenylethylamines (PhEA) can be preferably used as pure substances, in the form of their respective hydrochlorides or in the form of plant extracts.
[000286] The preferred agonists of beta-adrenergic receptors are adrenaline, noradrenaline, metanephrine, macromerine, normachromerine, hordenine, N-methyltyramine, dopamine, octopamine, tyramine, 2-phenylethylamine, phenylethanolamine, epinine (N-methyldopamine), synephrine , ephedrine, pseudoephedrine, norephedrine and isoprenaline.
[000287] Some of these compounds had already been investigated in the literature for their activity on the beta-3-adrenergic receptor in human and mammalian adipose cells (Naunyn-Schmiedeberg's Archives of Pharmacology 1999, 359, 310-321).
[000288] The compounds of the Formula (PhEA) in which R17 = H and R16 means hydrogen or C1-C4-alkyl, preferably hydrogen, methyl or isopropyl are preferred. Most preferred are compounds of the Formula (PhEA), where additionally R15 = H.
[000289] In a further preferred configuration, beta-adrenergic receptor agonists are those compounds where R12 and R17 = H.
[000290] Particularly preferred beta-adrenergic receptor agonists correspond to Formula (PhEA-i), and in turn preferred here are tyramine, N-methyltyramine, octopamine and synephrine.
wherein residues R14 and R16 have the aforementioned (preferred) significance.
[000291] The most preferred agonist of a beta-adrenergic receptor is synephrine (R14 = OH, R16 = CH3 in the Formula (PhEA-i)), preferably racemic or pure enantiometer, in this case the preferred form is (-) . Also particularly preferred are extracts containing synephrine, such as, for example, orange blossom extract.
[000292] A cosmetic preparation preferably topical (with position) according to the invention particularly preferably contains a beta adrenergic receptor agonist, in this case preferably synephrine, preferably in a total amount of 0.0001 - 0.10% by weight preferably 0.001 - 0.05% by weight, more preferably 0.002 - 0.02% by weight, in each case based on the total weight of the preparation, the counterion of the agonist which is not included in the case of salts.
[000293] The weight ratios of the total amount of the compound of Formula (I) to the total amount of agonists of a beta-adrenergic receptor, in particular synephrine, in preparations according to the invention are preferably selected from 1000:1 to 1:5, more preferably from 500:1 to 1:1.
[000294] As the occurrence of cellulite, in addition to an increased storage of fat in adipose tissue, is also generally accompanied by a collapse of connective tissue, preferred cosmetic preparations according to the invention containing one or more compounds of Formula (I) they preferably also contain active ingredients that prevent connective tissue collapse. Such preparations show improved efficacy in the prophylaxis and cosmetic treatment of cellulite.
[000295] The active ingredients are advantageous in this application as they inhibit matrix metalloproteinases (MMPs). Such preparations are particularly effective in the prophylaxis and cosmetic treatment of cellulite. These enzymes are in a position to disrupt extracellular matrix (ECM)/connective tissue macromolecules, also including collagens, proteolytically. In particular, matrix metalloproteinase-1 (MMP-1), matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) are responsible for the breakdown of skin connective tissue. An inhibition of MMPs is possible, for example, by the addition of ursolic acid, retinyl palmitate, propyl gallate, precocious, 6-hydroxy-7-methoxy-2,2-dimethyl-1(2H)-benzopyran, 3,4 -dihydro-6-hydroxy-7-methoxy-2,2-dimethyl-1(2H)-benzopyran. An addition of peptides, which inhibit MMPs, to preparations according to the invention is also advantageous for inhibiting MMPs. Soy proteins or glycoproteins and hydrolyzed rice, pea or lupine proteins also inhibit MMPs and are therefore a suitable addition. A combination with a plant extract, which inhibits MMPs, is also advantageous. To be mentioned in this application by way of example is an extract of shitake mushrooms. The combination with extracts from the leaves of the Rosaceae family, subfamily Rosoideae, is also advantageous. Quite particularly advantageous is the use of blackberry leaf extract, in particular as described in WO 2005/123101 A1 .
[000296] The MMP inhibitors to be preferably used in combination within the scope of the present invention are retinyl palmitate, propyl gallate, preconos, 6-hydroxy-7-methoxy-2,2-dimethyl-1(2H)-benzopyran, 3, 4-dihydro-6-hydroxy-7-methoxy-2,2-dimethyl-1(2H)-benzopyran, benzamidine hydrochloride, cysteine proteinase inhibitors N-ethylmalemide and epsilon-amino-n-caproic acid inhibited serine protease res: phenylmethylsufonyl-fluoride, colhibin (Pentapharm company; INCI: hydrolyzed rice protein), oenoterol (Soliance company; INCI: propylene glycol, aqua, Oenothera biennis root extract, ellagic acid and elagitanins, for example, da pomegranate), phosphoramidone hinokitiol, EDTA, galardin, EquiStat (Collaborative Group company; apple extract, soy seed extract, ursolic acid, soy isoflavones and soy proteins), sage extracts, MDI (with Atrius company; INCI: glycoaminoglycans), fermiskin (Silab/Mawi company; INCI: water and lentinus extract edodes), actimp 1.9.3 (with Expanscience/Rahn company; INCI: hydrolyzed lupine protein), lipobelle soyaglucone (Mibelle company; INCI: alcohol, polysorbate 80, lecithin and soy isoflavones), green and black tea extracts and numerous additional plant extracts, which are listed in WO 02/069992 ( see table 1-12 there).
[000297] In order to counteract the collapse of connective tissue, the combination of active ingredients, which stimulate the formation of collagen in the tissue (collagen synthesis stimulants, collagen stimulants), is furthermore advantageous in cosmetic preparations preferred compounds according to the invention containing one or more compounds of the Formula (I). Such preparations are particularly effective in the prophylaxis and cosmetic treatment of cellulite. Individual substances often used to increase collagen synthesis are, for example, ingredients such as ascorbic acid and its derivatives, retinol and retinol derivatives, or plant extracts such as, for example, extracts from aloe and centella species. Furthermore, peptide materials and their derivatives, such as, for example, carnitine, carnosine, creatine, matriquine peptides (for example, lysyl-threonyl-threonyl-lysyl-serine) and even peptide structures, such as palmitoylated pentapeptides (for example , matrixil/company Sederma) or the oligopeptide with the trade name Vincipeptide (company Vincience/France) are also included in the frequently used active ingredients that increase collagen synthesis. In addition, compounds such as asian acid, madecassic acid, madecassoside, asiaticosides, extracts of Centella asiatica, niacinamide, astaxanthin, glycans eg from yeast and oats, soy extracts and soy isoflavones such as genistein and daidzein, rutin, chrysin, morin, betel nut alkaloids, forskolin, betulinic acid, Plantago species extracts, TGF-beta, Ginkgo biloba extracts, glutamine and glycolic acid are also used as collagen synthesis stimulants. Particularly preferred in this application is the addition of a combination of Aloe vera extract, raspberry extract and magnesium ascorbyl phosphate.
[000298] Thus, more preferred cosmetic or pharmaceutical preparations, preferably topical, according to the invention containing one or more compounds of Formula (I) further additionally comprise - one or more matrix metalloproteinase inhibitors, and/or - one or more collagen synthesis stimulants.
[000299] Other preferred cosmetic or pharmaceutical preparations, preferably topical, according to the invention containing one or more compounds of Formula (I) still additionally comprise - one or more agents that stimulate and/or depolarize C-nerve fibers, preferably selected from the group consisting of capsaicin, vanilyl-nonilamide and derivatives thereof or extracts containing one or more of these substances as extracts obtainable from various species of the genus Capsicum (such as Capsicum annum), and/or - one or more agents that stimulate microcirculation or drainage, preferably selected from the group consisting of sourdough extract or its active component ruscogenin, horse chestnut extract or its active component escina, ivy extract and/or pineapple extract.
[000300] Such preparations are particularly effective in the prophylaxis and cosmetic treatment of cellulite.
[000301] The present invention further relates to novel compounds of the Formula (Carb-II-R1H) or a cosmetically acceptable salt thereof
wherein R2 denotes having a radical of 1 to 14 carbon atoms, wherein R2 consists of carbon, hydrogen and optionally oxygen and optionally silicon, preferably R2 consists of carbon, hydrogen and optionally oxygen, X, Y and Z independently of each other denote hydrogen, C1-C4-alkyl or C2-C4-alkenyl, wherein optionally two of the radicals X, Y and Z are covalently bonded together in forming a bicyclic ring system, in such a bicyclic ring system two of the radicals X, Y and Z together preferably form a radical having 1 to 4 carbon atoms, preferably a hydrocarbon having a radical of 1 to 3 carbon atoms, wherein the compound of Formula (Carb-II-R1H) contains a maximum number of 24 carbon atoms and has a molecular weight of at most 500 g/mol, preferably a molecular weight of at most 450 g/mol, with the proviso that the following compounds of the Formula (Carb-II-R1H) are excluded: (i) Menthyl Carbamates of Formula (MH) given above, wherein R2 has the meaning as in (Carb-II-R1H), (ii) compounds of the Formula (Carb-II-R1H) in which R2is phenyl or naphthyl, (iii) compounds of the Formula (Carb-II- R1H) in which X, Y, and Z each denotes H, (iv) compounds of the Formula (Carb-II-R1H) in which two of the radicals X, Y, and Z are covalently bonded together to form a bicyclic ring system and wherein R 2 contains one or both of the following groups: -COOH and/or =CH 2 , and (v) compounds known from the prior art of the Formulas given above.
[000302] For the sake of clarity, it is noted that mentyl-carbamates of Formula (MH) include all stereoisomeric forms of carbamates of Formula (MH), ie menthyl-, neomenthyl-, isomentyl- and neoisomenthyl-carbamates , including their respective enantiomeric forms.
[000303] Preferably, the compounds of Formula (I), in particular the new compounds of Formula (Carb-II-R1H), are anti-cellulite actives (according to the definition and preferred embodiments given above).
[000304] Preferably, from the new compounds the following compounds are excluded: the compounds of the Formula (Carb-II-R1H) in which X, Y and Z each denote hydrogen, the compounds of the Formula (Carb-II-R1H) in which R2is phenyl, 3-Me-phenyl, naphthyl, biphenyl, p-hydroxyphenyl, p-carboxyphenyl, methyl, and the compounds of the Formula (Carb-II-R1H) in which R2 contains one, several or all of the following groups: -COOH na alpha position of N, =CH2, carbon-carbon triple bond, - COOR at alpha- or beta position of N, where R is a C1-C4-alkyl radical, - O(CO)-Ph at alpha position of N.
[000305] The new preferred anti-cellulite compounds or a cosmetically acceptable salt thereof exhibit an anti-cellulite activity in at least two of the following Routes, preferably exhibiting an activity in Route (iii), more preferably exhibiting an activity in all three of the following Routes - Route (i) - inhibition of preadipocyte differentiation, - Route (ii) - inhibition of lipogenesis in adipocytes, - Route (iii) - stimulation of lipolysis in adipocytes.
[000306] The (particularly) preferred compounds of Formula (I) of the present invention are preferably used in the preferred compositions indicated above or below.
[000307] The (particularly) preferred aspects and embodiments mentioned above or hereinafter referring to compounds of Formula (I) or compositions (preparations) comprising one or more compounds of Formula (I) according to the present invention also apply to (particularly) preferred aspects and embodiments, uses and methods in accordance with the present invention.
[000308] The present invention further relates to a method of (i) prevention, treatment or cosmetic reduction of cellulite, and/or (ii) - reduction of the amount of lipid contained in subcutaneous adipose tissue, and/or - stimulation of lipolysis in adipocytes, and/or - inhibition of preadipocyte differentiation, and/or - inhibition of lipogenesis in adipocytes, comprising the following step: - application, preferably topical application, of a cosmetically effective amount of a compound of Formula (I ) or a cosmetically acceptable salt of a compound of Formula (I) or a mixture containing two or more of these compounds or salts thereof as defined in this application or of a cosmetic composition as defined in this application.
[000309] Preferably, said method comprises the step of topical application to the skin, in particular the thighs (in particular the outer side and the back of the thighs) and/or the buttocks, of a human being, preferably a woman.
[000310] A further aspect of the present invention is the use of a compound of the Formula (I) or a pharmaceutically acceptable salt of a compound of the Formula (I) or a mixture containing two or more of these compounds or the salts thereof as defined in this application - for the preparation of a pharmaceutical composition, preferably topical, for the prevention, treatment or reduction of cellulite.
[000311] The present invention further relates to a compound of Formula (I) or a pharmaceutically acceptable salt of a compound of Formula (I) or a mixture containing two or more of these compounds or salts thereof as defined in this application as a drug , in particular (i) as an active for the prevention, treatment or reduction of cellulite, and/or (ii) - to reduce the amount of lipid contained in the subcutaneous adipose tissue, and/or - to stimulate lipolysis in adipocytes, and/or - to inhibit pre-adipocyte differentiation, and/or - to inhibit lipogenesis in adipocytes.
[000312] The present invention further relates to a pharmaceutical composition comprising a pharmaceutically active amount of one or more compounds of Formula (I) as defined in this application, preferably for preventing, treating or reducing cellulite.
[000313] Furthermore, the present invention also relates to a method for the treatment of cellulite, comprising the following step: - application, preferably topical application, of a pharmaceutically effective amount of a compound of Formula (I) or a salt pharmaceutically acceptable of a compound of Formula (I) or a mixture containing two or more of these compounds or salts thereof as defined in this application or of a pharmaceutical composition as defined in this application.
[000314] Substances and auxiliaries which may additionally contain a preparation according to the invention containing one or more compounds of Formula (I) are, for example: preservatives, in particular those described in US 2006/0089413, antimicrobial agents, such as such as antibacterial agents or agents to treat yeasts and fungi, in particular those described in WO 2005/123101, anti-acne and sebum reducing agents, in particular those described in WO 2008/046791, anti-aging compounds of the skin, in particular those described in WO 2005/123101, additional anti-cellulite agents, in particular those described in WO 2007/077541, anti-dandruff agents, in particular those described in WO 2008/046795, anti-irritant substances (anti-inflammatory agents, irritation preventing agents, irritation inhibiting agents), in particular those described in WO 2007/042472 and US 2006/0089413, antioxidants, in particular those described in WO 2005/123101, carrier materials, in particular Among those described in WO 2005/123101, chelating agents, in particular those described in WO 2005/123101, deodorizing and antiperspirant agents, in particular those described in WO 2005/123101, moisture regulators (moisture donating agents, moisturizing substance, substances moisture retainers), in particular those described in WO 2005/123101, osmolytes, in particular those described in WO 2005/123101, compatible solutes, in particular those described in WO 01/76572 and WO 02/15868, proteins and protein hydrolysates, in particular those described in WO 2005/123101 and WO 2008/46676, skin lightening agents, in particular those described in WO 2007/110415, skin tanning agents, in particular those described in WO 2006/045760 , cooling agents, in particular those described in WO 2005/123101, skin cooling agents, in particular those described in WO 2005/123101, skin warming agents, in particular those described in WO 2005/123101, skin warming agents. UV absorption, powder articulate those described in WO 2005/123101, UV filters, in particular those described in WO 2005/123101, the compound benzylidene-beta-dicarbonyl as per WO 2005/107692 and alpha-benzoyl-cinnamic acid nitriles as per WO 2006/015954 , insect repellents, in particular those described in WO 2005/123101, plant parts, plant extracts, in particular those described in WO 2005/123101, vitamins, in particular those described in WO 2005/123101, emulsifiers, in particular those described in WO 2005/123101, coagulating agents, in particular those described in WO 2005/123101, oils in particular those described in WO 2005/123101, waxes in particular those described in WO 2005/123101, fats in particular those described in WO 2005/ 123101, phospholipids, in particular those described in WO 2005/123101, saturated fatty acids and mono- or poly-unsaturated fatty acids and α-hydroxy-acids and poly-hydroxy-fatty-acids and branched and/or unbranched alkane esters saturated and/or unsaturated carboxylic acids the, in particular those described in WO 2005/123101, surface active substances (surfactants) in particular those described in WO 2005/123101, skin repair agents comprising cholesterol and/or fatty acids and/or ceramides and/or pseudoceramides , in particular those described in WO 2006/053912, dyes and dyes and pigments, in particular those described in WO 2005/123101, aroma and flavor chemicals and fragrances, in particular those described in S. Arctander, Perfume and Flavor Chemicals, private publishing house, Montclair, NJ 1969 and Surburg, Panten, Common Fragrance and Flavor Materials, 5th Edition, Wiley-VCH, Weinheim 2006, preferably those explicitly mentioned in US 2008/0070825, alcohols and polyols, in particular those described in WO 2005/123101, organic solvents, in particular those described in WO 2005/123101, silicone and silicone oils and silicone derivatives in particular those described in WO 2008/046676, virucides, abrasives, astringents, agents a antiseptics, antistatics, binders, tampons, cell stimulants, cleansing agents, assisting agents, depilatory agents, tranquilizers, enzymes, essential oils, in particular those described in US 2008/0070825, fibers, film-forming agents, fixatives, forming agents foaming agents, foam stabilizers, suds preventing substances, foaming aids, gel-forming agents, hair growth activators, hair growth inhibitors, hair care agents, hair adjusting agents, hair setting agents, straighteners capillaries, bleaching agents, strengthening agents, stain removing agents, optical brightening agents, impregnating agents, dirt repelling agents, friction reducing agents, lubricants, opacifying agents, plasticizing agents, coating agents, gloss , brightening agents, polymers in particular those described in WO 2008/046676, powders, peptides, mono-, di- and oligosaccharides, re-lubricating agents, eroding agents, skin soothing agents, skin cleansing agents, skin assisting agents, skin tanning agents, skin protecting agents, skin softening agents, smoothing agents of skin, skin nourishing agents, skin warming agents, stabilizers, detergents, tissue conditioning agents, spreading agents, thickeners, yeast extracts, algae or microalgae extracts, animal extracts, liquefiers, protective agents. color, and electrolytes.
[000315] In a preferred embodiment, a preparation according to the present invention comprises one or more compounds of Formula (I) and one or more hair growth modulating assets, in particular one or more agents to stimulate hair growth.
[000316] Preferred agents for stimulating hair growth selected from the group consisting of pyrimidine derivatives, in particular 2,4-diaminopyrimidine-3-oxide (Aminexil), 2,4-diamino-6-piperidinopyrimidine-3- oxide (Minoxidil) and derivatives thereof, 6-amino-1,2-dihydro-1-hydroxy-2-imino-4-piperidinopyrimidine and its derivatives, xanthine alkaloids, in particular caffeine, theobromine and theophylline and derivatives thereof, quercetin and derivatives, dihydroquercetin (taxifolin) and derivatives, potassium channel openers, antiandrogenic agents, synthetic or natural 5-reductase inhibitors, nicotinic acid esters, in particular tocopheryl nicotinate, nicotinate of benzyl and C1-C6 alkyl nicotinate, proteins, in particular the tripeptide Lys-Pro-Val, diphencyprene, hormones, finasteride, dutasteride, flutamide, bicalutamide, pregnane derivatives, progesterone and its derivatives, cyproterone acetate, spironolactone and other diuretics s, calcineurin inhibitors, in particular FK506 (Ta crolimus, Fujimycin) and its derivatives, Cyclosporin A and derivatives thereof, zinc and zinc salts, polyphenols, procyanidins, proanthocyanidins, phytosterols, in particular beta-sitosterol, biotin, eugenol, (±) - beta-citronellol, panthenol, glycogen, in particular from mussels, rice hydrolysates, wheat hydrolysates, and extracts from microorganisms, algae, microalgae or plants and plant parts, in particular from generosdent Dandelion (Leontodon or Taraxacum), Orthosiphon, Vitex, Coffea, Paullinia, Theobroma, Asiasarum, Cucurbita or Styphnolobium, Serenoa repens (saw palmetto), Sophora flavescens, Pygeum africanum, Panicum miliaceum, Cimicifuga racemosa Eugenia caryophyllata, Cotinus coggygria, Hibiscus rosa-sinensis, Camelia sinensis, Ilex paraguariensis, licorice, grape, apple, barley and hops.
[000317] In another preferred embodiment, a preparation according to the present invention comprises one or more compounds of Formula (I) and one or more agents for inhibiting hair growth.
[000318] Preferred agents for inhibiting hair growth are selected from the group consisting of activin, activin derivatives or activin agonists, ornithine decarboxylase inhibitors, in particular alpha-difluoromethylomithine or pentacyclic triterpenes, in particular ursolic acid, betulin, betulinic acid, oleanolic acid and derivatives thereof, 5alpha-reductase inhibitors, androgen receptor antagonists, S-adenosylmethionine decarboxylase inhibitors, gamma-glutamyl transpeptidase inhibitors, trans glutaminase inhibitors, derived serine protease inhibitors from soybean, and extracts from microorganisms, algae, microalgae or plants and vegetative parts, in particular from the families Leguminosae, Solanaceae, Graminae, Asclepiadaceae or Cucurbitaceae, genera Chondrus, Gloiopeltis, Ceramium, Durvillea, Glycine max, Sanguisorba officinalis, Caledula offi cinalis, Hamamelis virginiana, Arnica montana, Salix alba, Hypericum perforatum and Gymne but sylvestre.
[000319] Preparations according to the invention which are administered orally, e.g. in the form of tablets (eg tablets with film), coated tablets, capsules (eg gelatin capsules), granules, are also advantageous juices, solution emulsions, microemulsions, sprays or products that can be consumed orally in another form, or in the form of food, which, because of the compound(s) contained in this application of Formula (I) bring about "internal beauty" .
[000320] Most preferred osmolytes, which can be a component of a preparation according to the invention, is phosphate diglycerol or ectoin.
[000321] Preferred cosmetic carrier materials, which can be a component of a preparation according to the invention, are solid or liquid at 25°C and 1013 mbar (including highly viscous substances).
[000322] Preferred liquid carrier substances which may be a component of a preparation according to the invention are selected from the group consisting of glycerol, 1,2-propylene glycol, 1,2-butylene glycol, 1,3-butylene glycol, 1 ,2-pentanediol, 1,2-hexanediol, 1,2-octanediol, 1,2-decanediol, ethanol, water and mixtures of two or more of said liquid carrier materials with water. Optionally, these preparations according to the invention can be produced using preservatives, solubilizers or antioxidants.
[000323] Preferred solid carrier materials, which can be a component of a preparation according to the invention are hydrocolloids, such as starches, degraded starches, chemically or physically modified starches, dextrins, maltodextrins (powders) (preferably with a dextrose equivalent value from 5 to 25, preferably from 10 to 20), lactose, silicon dioxide, glucose, modified celluloses, gum arabic, gum ghatti, tragacanth, karaya, carrageenan, pullulan, curdlan, xanthan gum, gellan gum , guar gum, locust bean flour, alginates, agar, pectin and inulin and mixtures of two or more of these solids, in particular maltodextrins (preferably with a dextrose equivalent value of 15 - 20), lactose, silicon dioxide and/or glucose.
[000324] In addition, preparations according to the invention may be present in encapsulated form, which are preferably encapsulated with a solid covering material, which is preferably selected from chemically or physically degraded or modified starches (in particular dextrins and maltodextrins), gelatin, gum arabic, agar, ghatti gum, gellan gum, modified and unmodified celluloses, pullulan, curdlan, carrageenan, alginic acid, alginates, pectin, inulin, xanthan gum and mixtures of two or more of said substances.
[000325] The solid coating material is preferably selected from gelatin (preferably are pork, beef, chicken and/or fish gelatins and mixtures thereof, preferably comprising at least one gelatin with a bloom value greater than or equal to 200, preferably with a bloom value greater than or equal to 240), maltodextrin (preferably obtained from corn (maize), wheat, tapioca or potato, preferred maltodextrins have a DE value of 10 - 20), modified cellulose (eg ether of cellulose), alginates (eg Na-alginate), carrageenan (beta - iota - lambda - and/or kappa carrageenan), gum arabic, curdlan and/or agar. Gelatin is preferentially used, especially because of its good availability at different bloom values. Particularly preferred, especially for oral use are seamless gelatin or alginate capsules, the covering of which dissolves very quickly in the mouth or chewing burst. Production can be carried out, for example, as described in EP 0 389700, US 4,251,195, US 6,214,376, WO 03/055587 or WO 2004/050069.
[000326] Important areas of application of the preparations according to the invention are cosmetics, in particular dermatological preparations, which are compounded as conventional (apart from the compound(s) of Formula (I)) and are used for cosmetics, in particular. ocular dermatological protection against light, for the treatment, care and cleansing of skin and/or hair or as a make-up product in decorative cosmetics. Consequently, preparations of this type, depending on their structure, can be used, for example, as day protection cream, day or night cream, eye cream, sunscreen or after-sun lotion, nourishing cream, a more face treatment, gel pads, tonic treatment, facial moist and cleaning tissues, cleaning milk, cleaning soap, foam or bath, deodorant, antiperspirant, hair shampoo, hair care agent, hair conditioner, colorant hair, hair styling agent and in this case it is preferably present as an emulsion, lotion, milk, fluid, cream, dispersion hydrogel, balm, spray, alcoholic or aqueous/alcoholic solution, foam, powder, liquid soap, piece of soap, shampoo, roll-on, stick or makeup. In hair care agents, use is preferably directed to the hair base or the scalp.
[000327] One or more substances with a physiological cooling effect (cooling agents), which can be used in combination with one or more compounds of Formula (I) according to the invention, are preferably selected in this application from the following list: menthol and menthol derivatives (eg, L-menthol, D-menthol, racemic menthol, isomenthol, neoisomenthol, neomenthol) mentyl ethers (eg, (I-menthoxy)-1,2-propandiol, (1- mentoxy)-2-methyl-1,2-propandiol, 1-menthyl-methylether), mentylesters (eg, menthylformate, menthylacetate, menthylisobutyrate, mentylactates, L-menthyl-L-lactate, L-menthyl-D-lactate , menthyl-(2-methoxy)acetate, menthyl-(2-methoxyethoxy)acetate, menthylpyroglutamate), menthylcarbonates (eg menthylpropylene glycol carbonate, menthylethylene glycol carbonate, menthylglycerol carbonate or mixtures thereof), menthol hemi-esters with a dicarboxylic acid or derivatives thereof themselves (eg, mono-menthylsuccinate, mono-menthylglutarate, monom nthylmalonate, N,N-(dimethyl)amide ester of O-menthyl succinic acid, O-menthyl amide of succinic acid ester), amides of menthanecarboxylic acid (in this case preferably N-ethylamide of menthanecarboxylic acid [WS3] or Nα-(menthanecarbonyl)glycineethylester [WS5], as described in US 4,150,052, menthanecarboxylic acid (4-cyanophenyl)amide or menthanecarboxylic acid (4-cyanomethylphenyl)amide as described in WO 2005/049553 , (alkoxyalkyl) methanecarboxylic acid amides), menthone and menthone derivatives (eg glycerol L-menthone ketal), 2,3-dimethyl-2-(2-propyl)-butyric acid derivatives (by example, 2,3-dimethyl-2-(2-propyl)butyric acid N-methylamide [WS23]), isopulegol or its esters (I(-)-isopulegol, I(-)-isopulegolacetate), mentthane derivatives ( for example, p-menthane-3,8-diol), cubeball or synthetic or natural mixtures containing cubebol, pyrrolidone derivatives of cycloalkyldione derivatives (eg 3-methyl-2 (1-pyrrolidinyl) -2-cyclopenten-1-one) or tetrahydropyrimidine-2-one (eg icillin or related compounds as described in WO 2004/026840), plus carboxamides (eg N-(2-( pyridin-2-yl)ethyl)-3-p-menthanecarboxamide or related compounds), oxamates (preferably those described in EP 2033688 A2).
[000328] One or plurality of substances with a physiological cooling effect, which can be used in combination with one or more compounds of the Formula (I) according to the invention, in particular are preferably substances, which at least substantially cause a physiological cooling effect. Such preferred substances are: mentylethers (eg, propandiol, (1-menthoxy)-2-methyl-1,2-propandiol), (eg, mentyl-acetates, L-menthyl-D-lactate, menthyl-(2-methoxy) acetate, xi)acetate, menthylpyroglutamate), menthylcarbonates (eg menthyl-propyleneglycolcarbonate, menthylethyleneglycolcarbonate, menthylglycerolcarbonate), menthol semi-esters with a dicarboxylic acid or derivatives thereof (eg, mono- menthylsuccinate, monomenthylglutarate, monomenthylma-lonate, O-menthyl ester of N-succinic acid, N-(dimethyl)amide, O-menthyl succinic acid esteramide), not according to the invention, menthane carboxylic acid amides ( for example, menthane N-ethyl carboxylic acid amide [WS3], Nα-(menthanecarbonyl)glycineethylester [WS5], menthane(4-cyanophenyl)carboxylic acid amide, menthane(alkoxyalkyl) carboxylic acid amides), derivatives of menthone (eg glycerol L-menthone ketal), derivatives of 2,3-dimethyl-2-(2-propyl)-butyric acid (eg ample, 2,3-dimethyl-2-(2-propyl)butyric acid N-methylamide), pyrrolidone derivatives of cycloalkyldione derivatives (eg, 3-methyl-2(1-pyrrolidinyl)-2-cyclopentene- 1-one) or tetrahydropyrimidine-2-ones (for example icillin or related compounds, which are described in WO 2004/026840).
[000329] The total amount of substances having a physiological cooling effect (one or more compounds) in the preparations according to the invention preferably is in the range of 0.05 - 5% by weight, more preferably in the range of 0. 1 - 3% by weight, in particular in the range of 0.25 - 1.5% by weight, in each case based on the total weight of the preparation.
[000330] Components that cause a hot, subtle, throbbing or prickly sensation on the skin or mucous membranes, in particular flavors with an effect that produces heat and/or compounds of subtle taste (subtle substances) that, apart from one or more compounds of the Formula (I), which can be a component of a preparation according to the invention, are mentioned in WO 2005/123101.
[000331] Furthermore, combinations with compounds that reduce skin nerve hypersensitivity based on their action as TRPV1 antagonists, eg trans-4-tert-butyl cyclohexanol (as described in WO 2009/087242) , or indirect modulators of TRPV1 by an activation of the µ-receptor, eg, acetyl tetrapeptide-15, are preferred.
[000332] For use in the conventional manner of cosmetics and pharmaceuticals, the compounds of Formula (I) are applied to the skin and/or hair in a suitable amount. Particular advantages are offered in this application by cosmetic and dermatological preparations containing one or more compounds of Formula (I) and additionally acting as a means of sun protection. Advantageously, these preparations contain at least one UVA filter and/or at least one UVB filter and/or at least one inorganic pigment. The preparations may be present in this application in various forms such that they are conventionally used for sun protection preparations. Thus, they can be in the form of a solution, a water-in-oil (W/O) or oil-in-water (O/W) emulsion or multiple emulsion, for example, "water-in-oil-in-water" type (W/ O/W), a gel, a hydrodispersion, a solid stick or an aerosol.
[000333] The preparations according to the invention in the field of pharmaceuticals and cosmetics, containing one or more compounds of Formula (I), are particularly advantageously combined with substances that absorb or reflect UV radiation, especially for cosmetic purposes or skin protection (in other words not for oral hygiene purposes), the total amount of UV filter substances which are from 0.01% by weight to 40% by weight, preferably 0.1% to 10% by weight , in particular 1.0 to 5.0% by weight, in each case based on the total weight of the preparations, in order to provide cosmetic preparations which protect the hair or skin from ultraviolet radiation. These preparations advantageously contain at least one UVA filter and/or at least one UVB filter and/or at least one inorganic pigment, therefore a light protection factor (sun protection factor, SPF) of 2 or higher (preferably 5 or higher) is reached. These preparations according to the invention can, in this case, be present in various forms such as, for example, they are conventionally used for sun protection preparations. They can be, for example, a solution, a water-in-oil (W/O) or oil-in-water (O/W) emulsion or multiple emulsion, for example, of the "water-in-oil-in-water" type (W /O/W), a gel, a hydrodispersion, a solid stick or an aerosol.
[000334] Advantageous UV filters and inorganic light shielding pigments are mentioned in WO 2005/123101. Particularly suitable UV absorbers for the combination are also mentioned in WO 2005/123101.
[000335] Advantageous inorganic light shielding pigments are metal oxides and finely dispersed metal salts which are also mentioned in WO 2005/123101. The total amount of inorganic pigments, in particular hydrophobic inorganic micropigments in the finished cosmetic preparation according to the present invention is advantageously 0.1 to 30% by weight, preferably 0.5 to 10.0, in each case based on the total weight of the preparation.
[000336] A combination with (metal)-chelating agents may also be advantageous in some preparations. (Metal)-chelating agents to be preferably used are the compounds mentioned in WO 2005/123101.
[000337] Furthermore, it is advantageous to combine compounds of Formula (I) with active ingredients that penetrate the skin and protect the skin cells from the inside against damage induced by sunlight, such as skin aging, skin inflammation and cancer of skin. The respective ingredients, hence called aryl hydrocarbon receptor antagonists, are described in WO 2007/128723. It is preferred 2-benzylidene-5,6-dimethoxy-3,3-dimethylindan-1-one.
[000338] Preferred cosmetic preparations according to the invention may also contain anti-inflammatory and/or active ingredients that improve redness and/or itching. The compounds mentioned in WO 2005/123101 are advantageously used as anti-inflammatory or active ingredients that improve redness and/or itching.
[000339] The total amount of anti-irritant substances (one or more compounds) in the preparations according to the invention is preferably in the range of 0.0001 - 20% by weight, more preferably in the range of 0.0001 - 10% by weight, in particular in the range of 0.001 - 5% by weight, in each case based on the total weight of the preparation.
[000340] One or more compounds of the Formula (I) can be advantageously used, especially, in cosmetic and dermatological preparations in combination with insect repellents such as, for example, DEET, IR 3225, DragorepelTM (Symrise GmbH & Co. KG).
[000341] A compound or more compounds of the Formula (I) can be advantageously used in particular in cosmetic and dermatological preparations in combination with hair treatment agents and anti-dandruff active ingredients (eg climbazol, ketoconazol, piroctone oleamine, zinc -pyrithione).
[000342] The compounds of Formula (I) can also be used to advantage in numerous cases in combination with one or more preservatives in preparations according to the invention. The preservatives mentioned in WO 2005/123101 are preferably selected in this application.
[000343] The preparations according to the invention, apart from one or more compounds of Formula (I), may also contain plant extracts that can be used for cosmetic purposes. Vegetable extracts are preferably selected from the table of substances listed beginning on page 44 of the third edition of the manual on the clarification of contents of cosmetic agents, published by Industreverband Korperpflegemittel und Waschmittel e. V. (IKW), Frankfurt. The extracts mentioned in WO 2005/123101 are also particularly advantageous.
[000344] Cosmetic preparations containing one or more compounds of the Formula (I) may, in particular if crystalline or microcrystalline solid bodies such as, for example, inorganic micropigments are to be incorporated in the preparations, according to the invention, also contain anionic, cationic, nonionic and/or amphoteric surfactants mentioned in WO 2005/123101.
[000345] The surface active substance can be present in a concentration between 1 and 98% by weight in the preparations according to the invention, based on the total weight of the preparations.
[000346] The oil phase of preparations according to the invention, containing one or more compounds of the Formula (I) can be advantageously selected from the groups of substances mentioned in WO 2005/123101.
[000347] In preferred embodiments, composition according to the present invention comprises one or more cosmetically acceptable vehicles selected from the group consisting of (i) (alkane)diols having 3 to 10 carbon atoms, preferably selected from the group consisting of 1,2-propylene glycol, 2-methylpropane-1,3-diol, 1,2-butylene glycol, 1,3-butanediol, 1,2-pentanediol, 1,3-pentanediol, 1,5- pentanediol, 2,4-pentanediol, 2-methyl-pentane-2,4-diol, 1,2-hexanediol, 1,6-hexanediol, 1,2-octanediol, dipropylene glycol, preferably of 1,2-butylene glycol, 1,2-pentanediol glycol and/or dipropylene, and/or (ii-1) esters having 6 to 36 carbon atoms, preferably monoesters, diesters or triesters, preferably selected from the group consisting of diethyl phthalate, diethyl- hexyl 2,6-naphthalate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, isopropyl oleate, n-butyl stearate, n-hexyl laurate, n-decyl oleate, isooctyl stear rat, isononyl stearate, isononyl isononanoate, 3,5,5-trimethyl-hexyl 3,5,5-trimethyl-hexanoate, 2-ethyl-hexyl isononanoate, 2-ethyl-hexyl 3,5,5-trimethyl-hexanoate, 2 -ethylhexyl 2-ethylhexanoate, 2-ethylhexyl palmitate, 2-ethylhexyl laurate, 2-hexyldecyl stearate, cetearyl ethylhexanoate, stearyl heptanoate, stearyl caprylate, 2-octyldodecyl palmitate, oleyl oleate, oleyl erucate , erucil oleate, erucil erucate, 2-ethylhexyl isostearate, isotridecyl isononanoate, 2-ethylhexyl cocoate, C12-15 alkyl benzoate, cetyl palmitate, triethyl citrate, triacetin (triacetyl citrate), benzyl benzoate, benzyl acetate vegetable oils (preferably olive oil, sunflower oil, soybean oil, peanut oil, rapeseed oil, almond oil, palm oil, coconut oil, palm core oil) and triglycerides, in particular glyceryl stearate , glyceryl triisononanoate, glyceryl laurate or triglycerides with identical or different fatty acid radicals C6 to C10 (so called trig medium chain lycerides, in particular caprylic/capric triglyceride, such as glyceryl tricaprylate, glyceryl tricaprate), and/or (ii-2) branched and unbranched alkyl or alkenyl alcohols, preferably selected from the group consisting of decanol , decenol, octanol, octenol, dodecanol, dodecenol, octadienol, decadienol, dodecadienol, oleyl alcohol, ricinoleyl alcohol, erucyl alcohol, stearyl alcohol, isostearyl alcohol, cetyl alcohol, lauryl alcohol, myristyl alcohol, arachidyl alcohol, arachidyl alcohol linolenyl, hexyldecanol, octyldodecanol (in particular 2-octyl-1-dodecanol) and cetearyl alcohol and behenyl alcohol, and/or (ii-3) branched and unbranched hydrocarbons and waxes, cyclic or linear silicone oils and dialkyl ethers having 6 to 24 carbon atoms, preferably selected from the group consisting of jojoba oil, isoeicosane, dicaprilyl ether, mineral oil, petrolatum, squalane, squalene , cyclomethicone, decamethylcyclopentasiloxane, undecamethylcyclotrisiloxane, polydimethylsiloxane and poly(methylphenyl)siloxane.
[000348] In other preferred embodiments, composition according to the present invention comprises one or more actives providing a benefit to the skin, in particular other skin irritation reducing agents or skin soothing agents, preferably if selected to from the group consisting of anti-inflammatory agents, itching relieving compounds and/or redness relieving compounds which are suitable for cosmetic and/or dermatological applications, in which one or more actives are preferably selected from the groups consisting of: - steroidal anti-inflammatory substances like corticosteroids, in particular hydrocortisone, hydrocortisone derivatives, such as hydrocortisone, butyrate, dexamethasone, dexamethasone phosphate, methylprednisolone or cortisone; and/or - natural or naturally occurring anti-inflammatory substances or substances that alleviate redness and/or itching, in particular extracts or fractions of chamomile, Aloe vera, Commiphora species, Rubia species, willow, willow grass, oats, ca. - leendula, arnica, St. John's wort, honeysuckle, Rosemary, Passiflora incarnata, hazel, ginger or Echinacea; preferably selected from the group consisting of extracts or fractions of chamomile, Aloe vera, oat, calendula, arnica, honeysuckle, Rosemary, hazel, ginger or Echinacea, and/or - pure substances, preferably alpha-bisabolol, apigenin, apigenin -7-glycoside, gingerols, shogaols, gingerdiols, dehydrogingerdiones, paradollars, natural avenanthramides, non-natural avenanthramides, preferably dihydroavenanthramide D, boswellic acid, phytosterols, glycyrrhizin, glabridine and lychalcone; preferably selected from the group consisting of alpha-bisabolol, gingerols, shogaols, gingerdiols, dehydrogingerdiones, paradols, natural avenanthramides, unnatural avenantramides, preferably dihydroavenanthramide D, boswellic acid, phytoglycerols, and glycyrrhizinols; and/or - skin treatment agents, preferably skin moisture retention regulators or skin repair agents, preferably selected from the group consisting of sodium lactate, urea and derivatives, glycerol, 1,2-pentanediol, collagen, elastin or hyaluronic acid, diacyl adipates, petrolatum, urocanic acid, lecithin, allantoin, panthenol, phytantriol, lycopene, (pseudo-)ceramides [referably Ceramide 2, hydroxypropyl bispalmitamide MEA, cetyloxypropyl glyceryl methoxypropyl myristamide, N -hexadecanoyl)-4-hydroxy-L-proline ester (1-hexadecyl), hydroxyethyl palmityl oxyhydroxypropyl palmitamide], glycosphingolipids, cholesterol, phytosterols, chitosan, chondroitin sulfate, lanolin, lanolin esters, amino acids, vitamin E and derivatives (preferably tocopherol, tocopheryl acetate), alpha-hydroxy acids (preferably citric acid, lactic acid, malic acid) and derivatives thereof, mono-, di- and oligosaccharides, preferably te glucose, galactose, fructose, mannose, laevulose and lactose, polysugars such as β-glycans, in particular 1,3-1,4-β-glycan from oat, alpha-hydroxy-fatty acids, triterpenic acids, such as such as betulic acid or ursolic acid, and seaweed extracts, preferably selected from the group consisting of glycerol, 1,2-pentanediol, urea, hyaluronic acid, allantoin, panthenol, lanolin, alpha-hydroxy acids (preferably citri- co,lactic acid), vitamin E and derivatives (preferably tocopherol, tocopheryl acetate).
[000349] Preferred embodiments and additional aspects of the present invention emerge from the related patent claims and the following examples.
[000350] The examples describe the invention in more detail, without limiting the scope of protection of the claims. Unless otherwise stated, all data, in particular amounts and percentages, refer to weight. Examples 1: Synthesis of compounds of Formula (I) Examples 1.1: Disubstituted cyclohexyl carbamates Example 1.1.1: 2,3-dimethyl-cyclohexyl ester of sec-butyl-carbamic acid (BIO1845)
[000351] 50.7 g (0.5 mol) of sec-butyl isocyanate were placed in a 500 ml vessel at room temperature and 64.1 g (0.5 mol) of 2,3-dimethylcyclohexanol were added . The reaction mixture was heated for 5 h at 150 °C, cooled and then 100 mL of water was added. After refluxing for an hour, the solution was cooled, the phases separated and extracted once with MTBE (methyl tert-butyl ether). The crude product was purified by distillation to yield 60.2 g of product as a mixture of isomers with a purity of 99.6%.

[000352] main signals of the mixture of isomers: 1H-NMR (400 MHz, CDCl3, TMS): δ = 4.66 (m, H), 4.41 (m, H), 3.62 (m, H) , 2.06 (m, H), 1.68 (m, H), 1.44 (m, 2 H), 1.12 (d, 6.6 Hz, 3 H), 0.91 (t, 7.3Hz, 3H), 0.89 (d, 6.9Hz, 3H), 0.80 (d, 7.0Hz, 3H) ppm. 13C-NMR (400 MHz, CDCl3, TMS): δ = 156.2 (s), 76.2 (d), 48.2 (d), 37.8 (d), 34.2 (d), 30 .0 (t), 20.8 (q), 19.1 (q), 10.3 (q), 6.1 (q) ppm. MS (EI, major isomer): m/z = 227 (not detected), 198 (27), 111 (71), 95 (20), 81 (18), 69 (100), 55 (37), 44 ( 94), 41 (31).
[000353] The following cyclohexyl carbamates were produced analogously to the methodology of BIO1845 as described in example 1.1.1 or BIO1824 as described in example 1.3.2., below. Cyclohexyl carbamates were obtained in comparable yields and purity (generally >99%, depending on structure as a mixture of stereoisomers): Example 1.1.2: 2,3-dimethyl-cyclohexyl butyl acid ester -carbamic (BIO1842)

[000354] main signals of the mixture of isomers: 1H-NMR (400 MHz, CDCl3, TMS): δ = 4.66 (m, 2 H), 3.17 (q, 6.3 Hz, 2 H), 2 .05 (m, H), 1.24-1.80 (m, 11H), 0.92 (t, 7.3Hz, 3H), 0.89 (d, 6.6Hz, 3H ), 0.79 (d, 6.9 Hz, 3H) ppm. 13C-NMR (400 MHz, CDCl3, TMS): δ = 156.8 (s), 76.3 (d), 40.6 (t), 37.4 (d), 34.8 (t), 34 .2 (d), 32.2 (t), 27.4 (t), 25.6 (t), 20.0 (t), 19.1 (q), 13.8 (q), 6, 1(q) ppm.
[000355] MS (EI, main isomer): m/z = 227 (<1), 118 (100), 111 (49), 110 (88), 95 (53), 81 (55), 69 (83) , 57(35), 55(54), 41(35). Example 1.1.3: 2,3-dimethyl-cyclohexyl ester of ethyl carbamic acid (BIO1581)

[000356] main signals of the mixture of isomers: 1H-NMR (400 MHz, CDCl3, TMS): δ = 4.60-4.72 (m, 2 H), 3.21 (d, q, 5.3 Hz) , 7.2Hz, 2H), 2.05 (m, H), 1.25-1.81 (m, 7H), 1.14 (t, 7.2Hz, 3H), 0, 89 (d, 6.7Hz, 3H), 0.79 (d, 7.2Hz, 3H) ppm. 13C-NMR (400 MHz, CDCl3, TMS): δ = 156.2 (s), 76.3 (d), 37.5 (d), 35.7 (t), 34.8 (t), 34 .2(d), 27.4(t), 25.6(t), 19.1(q), 15.3(q), 6.2(q) ppm. MS (EI, major isomer): m/z = 200 (<1), 199 (<1), 127 (3), 110 (100), 95 (62), 90 (74), 81 (67), 69 (65), 55 (37), 41 (24). Example 1.1.4: 2,3-dimethyl-cyclohexyl ester of (2-hydroxy-phenyl)-carbamic acid (BIO1643)

[000357] main signals of the mixture of isomers: 1H-NMR (400 MHz, CDCl3, TMS): δ = 7.93 (m, H), 7.15 (d, 7.5 Hz, H), 7.05 (d, d, 7.7 Hz, 8.1 Hz, H), 6.97 (d, 8.1 Hz, H), 6.87 (d, d, 7.3 Hz, 7.7 Hz, H), 6.7 (m, H), 4.81 (t, d, 4.5 Hz, 11.6 Hz, H), 1.10-2.18 (m, 8 H), 0.92 (d , 6.9 Hz, 3H), 0.86 (d, 7.1Hz, 3H) ppm. 13C-NMR (400 MHz, CDCl3, TMS): δ = 155.4 (s), 147.2 (s), 125.6 (d), 125.4 (s), 121.2 (d), 120 .9 (d), 118.6 (d), 78.6 (d), 37.3 (d), 34.6 (t), 34.2 (d), 27.2 (t), 25, 4(t), 19.1(q), 6.2(q) ppm. MS (EI): m/z = 263 (15), 153 (100), 135 (15), 110 (21), 109 (64), 95 (9), 81 (9), 69 (51), 55 (27), 41 (11). Example 1.1.5: 3,5-dimethyl-cyclohexyl ester (4-ethyl-phenyl)-carbamic acid (BIO1823)

[000358] ααα, main signals of the mixture of isomers: 1H-NMR (400 MHz, CDCl3, TMS): δ = 7.27 (m, 2 H), 7.13 (m, 2 H), 6.46 ( s, H), 4.17 (t, t 4.3 Hz, 11.4 Hz, H), 2.60 (q, 7.6 Hz, 2 H), 2.03 (d, 12.1 Hz , 2H), 1.62 (d, 14.4Hz, H), 1.55 (m, 2H), 1.21 (t, 7.6Hz, 3H), 0.94 (d, 6.5Hz, 6H), 0.94 (q, 11.9Hz, 2H), 0.56 (q, 12.0Hz, H) ppm. 13C-NMR (400 MHz, CDCl3, TMS): δ = 153.4 (s), 137.8 (s), 137.2 (s), 128.0 (d), 128.0 (d), 118 .5 (d), 118.5 (d), 72.7 (d), 42.9 (t), 40.4 (t), 40.4 (t), 30.4 (d), 30, 4(d), 27.9(t), 22.1(q), 22.1(q), 15.9(q)ppm. MS (EI, minor isomer): m/z = 275 (22), 165 (100), 150 (26), 132 (21), 121 (41), 111 (11), 106 (42), 69 (52 ), 55 (22), 41 (13). Example 1.1.6: 3,5-dimethyl-cyclohexyl ester of cyclohexyl-carbamic acid (BIO1743)

[000359] main signals of the mixture of isomers: 1H-NMR (400 MHz, CDCl3, TMS): δ = 4.59 (m, H), 4.47 (m, H), 3.47 (m, H) , 1.94 (m, 2H), 1.69 (d, 13.5Hz, H), 1.52 (m, 2H), 1.00 1.40 (m, 10H), 0. 92 (d, 6.5Hz, 6H), 0.86 (m, 2H), 0.52 (q, 11.9Hz, H) ppm. 13C-NMR (400 MHz, CDCl3, TMS): δ = 156.8 (s), 73.0 (d), 49.1 (d), 43.1 (t), 40.5 (t), 40 .5 (t), 33.5 (t), 33.5 (t), 30.6 (d), 30.6 (d), 25.5 (t), 25.5 (t), 24, 8(t), 22.2(q), 22.2(q) ppm. MS (EI, minor isomer): m/z = 253 (2), 144 (100), 111 (26), 110 (33), 95 (61), 82 (32), 69 (96), 56 (59 ), 55 (71), 41 (50). MS (EI, major isomer): m/z = 253 (3), 144 (91), 111 (47), 110 (11), 95 (32), 82 (31), 69 (100), 56 (66 ), 55 (60), 41 (42). Example 1.1.7: 3,5-dimethyl-cyclohexyl ester of benzyl-carbamic acid (BIO1745)

[000360] main signals of the mixture of isomers: 1H-NMR (400 MHz, CDCl3, TMS): δ = 7.34 (m, 2H), 7.28 (m, 2H), 7.27 (m, H), 4.92 (m, H), 4.65 (t, t, 4.3 Hz, 11.4 Hz, H), 4.36 (d, 5.5 Hz, 2H), 1, 98 (d, 12.1Hz, 2H), 1.60 (d, 14.5Hz, H), 1.52 (m, 2H), 0.92 (d, 6.5Hz, 6H ), 0.86 (m, 2H), 0.53 (q, 11.9 Hz, H) ppm. 13C-NMR (400 MHz, CDCl3, TMS): δ = 156.3 (s), 138.7 (s), 128.6 (d), 128.6 (d), 127.5 (d), 127 .4 (d), 127.4 (d), 73.6 (d), 45.0 (t), 43.0 (t), 40.4 (t), 40.4 (t), 30, 6(d), 30.6(d), 22.2(q), 22.2(q) ppm. MS (EI, minor isomer): m/z = 261 (2), 151 (100), 150 (93), 106 (29), 95 (72), 91 (59), 69 (55), 55 (43 ), 41 (31). MS (EI, major isomer): m/z = 261 (2), 151 (78), 150 (100), 106 (24), 95 (38), 91 (55), 69 (63), 55 (37 ), 41 (26). Example 1.1.8: 3,5-dimethyl-cyclohexyl ester of ethyl carbamic acid (BIO1561)

[000361] main signals of the mixture of isomers: 1H-NMR (400 MHz, CDCl3, TMS): δ = 4.61 (m, 2 H), 3.20 (m, 2 H), 1.96 (d, 11.9 Hz, 2 H), 1.60 (d, 14.4 Hz, H), 1.52 (m, 2 H), 1.13 (t, 7.2 Hz, 3 H), 0, 92 (d, 6.6 Hz, 6H), 0.80-1.05 (m, 2H), 0.53 (q, 11.9Hz, H) ppm. 13C-NMR (400 MHz, CDCl3, TMS): δ = 156.3 (s), 73.1 (d), 43.1 (t), 40.5 (t), 40.5 (t), 38 .4(t), 30.6(d), 30.6(d), 22.2(q), 22.2(q), 15.3(q)ppm. MS (EI, major isomer): m/z = 199 (not detected), 127 (4), 95 (41), 90 (100), 69 (65), 55 (39), 41 (62), 29 ( 26). Example 1.1.9: p-tolyl-carbamic acid 3,5-dimethyl-cyclohexyl ester (BIO1822)

[000362] main signals of the mixture of isomers: 1H-NMR (400 MHz, CDCl3, TMS): δ = 7.25 (d, 8.1 Hz, 2H), 7.10 8d, 8.3 Hz, 2 H), 6.45 (m, H), 4.71 (t, t, 4.4 Hz, 11.3 Hz, H), 2.30 (s, 3 H), 2.03 (d, 12 .0Hz, 2H), 1.62 (d, 14.1Hz, H), 1.55 (m, 2H), 0.97 (q, 11.3Hz, 2H), 0.94 (d, 6.6Hz, 6H), 0.56 (d,t, 11.5Hz, 12.6Hz, H) ppm. 13C-NMR (400 MHz, CDCl3, TMS): δ = 153.4 (s), 135.5 (s), 132.8 (s), 129.5 (d), 129.5 (d), 118 .7 (d), 118.7 (d), 73.9 (d), 43.0 (t), 40.3 (t), 40.3 (t), 30.6 (d), 30, 6(d), 22.2(q), 22.2(q), 20.7(q) ppm. MS (EI): m/z = 262 (5), 261 (24), 151 (100), 107 (72), 106 (20), 69 (45), 55 (20), 41 (11). Example 1.1.10: 3,5-dimethyl-cyclohexyl ester of n-butyl-carbamic acid (BIO1840)

[000363] main signals of the mixture of isomers: 1H-NMR (400 MHz, CDCl3, TMS): δ = 4.58 (m, 2 H), 3.14 (q, 6.3 Hz, 2 H), 1 .94 (d, 11.7Hz, 2H), 1.58 (d, 12.6Hz, H), 1.40-1.54 (m, 4H), 1.32 (m, 2H) ), 0.90 (d, 6.5Hz, 6H), 0.90 (t, 7.2Hz, 3H), 0.89 (q, 11.8Hz, 2H), 0.50 (q, 12.0 Hz, H) ppm. 13C-NMR (400 MHz, CDCl3, TMS): δ = 156.4 (s), 73.1 (d), 43.1 (t), 40.6 (t), 40.5 (t), 40 .5 (t), 32.1 (t), 30.6 (d), 30.6 (d), 22.2 (q), 22.2 (q), 19.9 (t), 13. 7(q) ppm. MS (EI): m/z = 227 (1), 184 (1), 118 (100), 111 (43), 95 (28), 69 (77), 55 (28), 41 (29), 30 (19). Example 1.1.11: 3,5-dimethyl-cyclohexyl ester of phenyl-carbamic acid (BIO1685)

[000364] main signals of the mixture of isomers: 1H-NMR (400 MHz, CDCl3, TMS): δ = 7.37 (d, 7.9 Hz, 2H), 7.30 (m, 2H), 7 .05 (m, H), 6.53 (m, H), 4.72 (t, t, 4.3 Hz, 11.4 Hz, H), 2.04 (d, 11.7 Hz, 2 H), 1.63 (d, 12.5 Hz, H), 1.55 (m, 2 H), 0.94 (q, 11.7 Hz, 2 H), 0.94 (d, 6, 5Hz, 6H), 0.56 (d, t, 11.6Hz, 12.6Hz, H) ppm. 13C-NMR (400 MHz, CDCl3, TMS): δ = 153.2 (s), 138.1 (s), 129.0 (d), 129.0 (d), 123.2 (d), 118 .6 (d), 118.6 (d), 74.0 (d), 43.0 (t), 40.3 (t), 40.3 (t), 30.6 (d), 30, 6(d), 22.1(q), 22.1(q) ppm. MS (EI): m/z = 248 (3), 247 (15), 137 (29), 111 (29), 95 (34), 93 (84), 69 (100), 55 (47), 41 (35). Example 1.1.12: 3,4-dimethyl-cyclohexyl ester of ethyl carbamic acid (BIO1582)

[000365] main signals of the mixture of isomers: 1H-NMR (400 MHz, CDCl3, TMS): δ = 4.60 (m, 2 H), 3.20 (d, q, 5.2 Hz, 7.2 Hz, 2H), 0.95-2.10 (m, 8H), 1.14 (t, 7.2Hz, 3H), 0.83 (d, 6.9Hz, 3H), 0.88 (d, 6.4Hz, 3H) ppm. 13C-NMR (400 MHz, CDCl3, TMS): δ = 156.2 (s), 73.7 (d), 35.7 (t), 34.5 (t), 33.3 (d), 31 0.9 (d), 30.7 (t), 26.3 (t), 19.2 (q), 15.3 (q), 11.9 (q) ppm. MS (EI, main isomer): m/z = 200 (<1), 127 (4), 110 (20), 95 (21), 90 (100), 81 (20), 69 (49), 55 ( 22), 41 (16). Example 1.1.13: Ethyl-carbamic acid 4-isopropyl-3-methyl-cyclohexyl ester (BIO1560)

[000366] main signals of the mixture of isomers: 1H-NMR (400 MHz, CDCl3, TMS): δ = 4.78 (t, t, 4.2 Hz, 11.2 Hz, H), 4.61 (m , H), 0.81-2.20 (m, 9H), 1.12 (t, 7.2Hz, 3H), 0.89 (d, 7.0Hz, 6H), 0. 87 (d, 6.6 Hz, 3H) ppm. 13C-NMR (400 MHz, CDCl3, TMS): δ = 156.4 (s), 70.0 (d), 46.8 (d), 39.6 (t), 35.7 (t), 32 .8 (t), 30.1 (d), 26.7 (d), 23.2 (t), 21.6 (q), 21.6 (q), 15.1 (q), 12, 6(q) ppm. MS (EI): m/z = 227 (not detected), 123 (9), 109 (4), 95 (55), 90 (100), 83 (19), 69 (16), 55 (21) 41 (15). Example 1.1.14: 2-isopropenyl-5-methyl-cyclohexyl butyl-carbamic acid ester (BIO1615)

[000367] main signals of the mixture of isomers: 1H-NMR (400 MHz, CDCl3, TMS): δ = 4.73 (m, 2H), 4.65 (d, t, 4.3 Hz, 10.9 Hz, H), 4.54 (m, H), 3.13 (d, t, 6.0 Hz, 6.0 Hz, 2H), 2.07 (m, 2H), 1.63- 1.73 (m, 2H), 1.69 (t, 1.2Hz, 3H), 1.56 (m,H), 1.26 1.49 (m, 5H), 0.87 -1.02 (m, 2H), 0.92 (d, 6.5Hz, 3H), 0.91 (t, 7.2Hz, 3H) ppm. 13C-NMR (400 MHz, CDCl3, TMS): δ = 156.4 (s), 146.8 (s), 111.5 (t), 73.8 (d), 51.0 (d), 41 .0 (t), 40.6 (t), 34.2 (t), 32.1 (t), 31.4 (d), 30.7 (t), 22.0 (q), 19, 9(t), 19.5(q), 13.7(q) ppm. MS (EI, major isomer): m/z = 254 (1), 253 (4), 136 (100), 118 (87), 107 (35), 93 (40), 81 (56), 67 (20 ), 57 (20), 41 (32), 29 (10). Examples 1.2: unsubstituted cyclohexyl carbamates Example 1.2.1: phenylcarbamic acid cyclohexyl ester (BIO1741)
1H-NMR (400 MHz, CDCl3, TMS): δ = 7.38 (m, 2H), 7.30 (m, 3H), 7.05 (m,H), 6.51 (m,H) ), 4.76 (t, t, 3.9 Hz, 9.0 Hz, H), 1.94 (m, 2 H), 1.75 (m, 2 H), 1.56 (m, H ), 1.42 (m, 4H), 1.27 (m,H) ppm. 13C-NMR (400 MHz, CDCl3, TMS): δ = 153.2 (s), 138.1 (s), 129.0 (d), 129.0 (d), 123.2 (d), 118 .5 (d), 118.5 (d), 73.7 (d), 31.9 (t), 31.9 (t), 25.4 (t), 23.8 (t), 23, 8(t) ppm. MS (EI): m/z = 220 (4), 219 (25), 137 (59), 132 (15), 119 (30), 93 (100), 83 (54), 67 (24), 55 (83), 41 (40). Examples 1.3: mono-substituted cyclohexyl carbamates Example 1.3.1: butyl-carbamic acid 3-methyl-cyclohexyl ester (BIO1821)

[000368] main signals of the mixture of isomers: 1H-NMR (400 MHz, CDCl3, TMS): δ = 4.57 (m, 2 H), 3.16 (m, 2 H), 1.98 (d, 11.4 Hz, H), 1.75 (d, 13.5 Hz, H), 1.61 (d, 13.0 Hz, H), 1.47 (m, 2 H), 1.34 ( m, 2H), 1.25-1.56 (m, 3H), 1.16 (m,H), 0.93 (m,H), 0.92 (t, 7.3Hz, 3 H), 0.92 (d, 7.0Hz, 3H), 0.80 (q, 12.6Hz, H) ppm. 13C-NMR (400 MHz, CDCl3, TMS): δ = 156.3 (s), 73.4 (d), 41.0 (t), 40.6 (t), 34.1 8t), 32, 1 (t), 32.0 (t), 31.4 (d9, 24.0 (t), 22.3 (q), 19.9 (t), 13.7 (q) ppm. MS (EI , minor isomer): m/z = 214 (1), 213 (1), 170 (2), 126 (2), 118 (100), 97 (32), 81 (14), 55 (31), 41 (10), 30 (14). MS (EI, main isomer): m/z = 214 (1), 213 (2), 170 (3), 126 (9), 118 (100), 97 (45) , 81 (11), 55 (36), 41 (11), 30 (12) Example 1.3.2: p-tolyl-carbamic acid 2-isopropyl-cyclohexyl ester (BIO1824) 75.6 g (0 .56 mol) of para-tolylisocyanate were placed with 500 ml of toluene in a one liter vessel and then 73.4 g (0.51 mol) of 2-isopropylcyclohexanol were added. for 6 hours. After cooling to room temperature 50 g of water were added and the mixture refluxed for another hour. After phase separation, the solvent was evaporated and the crude product recrystallized from 235 g of n-heptane . The product (79.8 g) was obtained in the form of cr off-white crystals in 99.2% purity. This corresponds to a theoretical yield of 56%.

[000369] main signals of the mixture of isomers: 1H-NMR (400 MHz, CDCl3, TMS): δ = 7.28 (m, 2H), 7.10 (m, 2H), 6.50 (m, H), 5.19 (m, H); 2.30 (s, 3H), 2.07 (m,H), 1.70-1.81 (m, 2H), 1.22-1.55 (m, 6H), 1.07 (m, H), 0.92 (d, 6.7Hz, 3H), 0.90 (d, 6.7Hz, 3H) ppm. 13C-NMR (400 MHz, CDCl3, TMS): δ = 153.4 (s), 135.6 (s), 132.7 (s), 129.5 (d), 129.5 (d), 118 .6 (d), 118.6 (d), 71.7 (d), 47.2 (d), 30.9 (t), 29.5 (d), 26.0 (t), 25, 1(t), 20.8(q), 20.7(q), 20.7(q), 20.4(t) ppm. MS (EI): m/z = 276 (5), 275 (30), 151 (89), 125 (17), 107 (100), 83 (32), 69 (74), 57 (21), 41 (18). Example 1.3.3: Butyl-carbamic acid 2-isopropyl-cyclohexyl ester (BIO1841)

[000370] main signals of the mixture of isomers: 1H-NMR (400 MHz, CDCl3, TMS): δ = 5.06 (m, H), 4.65 (m, H), 3.17 (q, 6, 4Hz, 2H), 2.01 (t, 13.8Hz, H), 1.74 (m, H), 1.68 (d, 10.3Hz, H), 1.41-1, 53 (m, 3H), 1.35 (m, 2H), 1.26 (m, H), 1.24 (m, H), 1.02 (m, H), 0.93 (t , 7.3 Hz, 3H), 0.90 (d, 6.5Hz, 6Hz) ppm. 13C-NMR (400 MHz, CDCl3, TMS): δ = 156.5 (s), 70.8 (d), 47.2 (d), 40.7 (t), 32.2 (t), 31 .1 (t), 29.5 (d), 26.1 (t), 25.0 (t), 20.8 (q), 20.7 (q), 20.5 (t), 19, 9(t), 13.8(q) ppm. MS (EI, major isomer): m/z = 241 (<1), 198 (2), 124 (84), 118 (100), 109 (36), 99 (26), 81 (64), 69 ( 71), 57 (61), 41 (37). MS (EI, minor isomer): m/z = 241 (<1), 198 (1), 124 (100), 118 (97), 109 (41), 99 (12), 81 (65), 69 ( 71), 57 (61), 41 (41). Example 1.3.4: n-hexyl-carbamic acid 2-isopropyl-cyclohexyl ester (BIO1851)

[000371] main signals of the mixture of isomers: 1H-NMR (400 MHz, CDCl3, TMS): δ = 5.06 (m, H), 4.61 8 m, H), 3.15 (m, 2 H) ), 1.99 (d, 13.5 Hz, H), 1.64-1.78 (m, 2 H), 1.47 (m, 4 H), 1.19-1.40 (m, 10H), 1.02 (m, H), 0.90 (d, 7.0Hz, 6H), 0.89 (t, 6.6Hz, 3H) ppm. 13C-NMR (400 MHz, CDCl3, TMS): δ = 156.6 (s), 70.7 (d), 47.3 (d), 41.0 (t), 31.6 (t), 31 .1 (t), 31.0 (t), 29.5 (d), 26.5 (t), 26.1 (t), 25.0 (t), 22.6 (t), 20, 8(q), 20.8(q), 20.5(t), 14.0(q) ppm. MS (EI, major isomer): m/z = 269 (<1), 146 (95), 124 (86), 109 (34), 81 (59), 69 (100), 57 (45), 43 ( 52), 41 (40). MS (EI, minor isomer): m/z = 269 (<1), 146 (90), 124 (97), 109 (38), 81 (54), 69 (100), 57 (44), 43 ( 52), 41 (44). Example 1.3.5: Benzyl-carbamic acid 2-isopropyl-cyclohexyl ester (BIO1748)

[000372] main signals of the mixture of isomers: 1H-NMR (400 MHz, CDCl3, TMS): δ = 7.34 (m, 2 H), 7.28 (m, 2 H), 7.27 (m, H), 5.12 (m, H), 4.93 (m, H), 4.38 (m, 2 H), 2.03 (m, H), 1.64-1.76 (m, 2H), 0.99-1.52 (m, 7H), 0.89 (d, 6.3Hz, 6H) ppm. 13C-NMR (400 MHz, CDCl3, TMS): δ = 156.5 (s), 138.8 (s), 128.6 (d), 18.6 (d), 127.5 (d), 127 .5 (d), 127.4 (d), 71.3 (d), 47.2 (d), 45.0 (t), 31.0 (t), 29.5 (t), 26, 0 (d), 25.0 (t), 20.8 (q), 20.8 (q), 20.4 (t) ppm. MS (EI, major isomer): m/z = 275 (<1), 151 (59), 150 (44), 124 (44), 109 (34), 106 (35), 91 (53), 81 ( 100), 69 (56), 55 (26), 41 (31). MS (EI, minor isomer): m/z = 275 (<1), 151 (64), 150 (65), 124 (50), 109 (39), 106 (30), 91 (69), 81 ( 100), 69 (60), 55 (30), 41 (42). Example 1.3.6: (2-Methoxy-phenyl)-carbamic acid 2-isopropyl-cyclohexyl ester (BIO1744)

[000373] main signals of the mixture of isomers: 1H-NMR (400 MHz, CDCl3, TMS): δ = 8.12 (m, H), 7.18 (d, 7.4 Hz, H), 6.98 (m, H), 6.95 (m, H), 6.85 (m, H), 5.21 (m, H), 3.88 (s, 3 H), 2.04-2.15 (m, 2H), 1.15-1.82 (m, 7H), 1.08 (m,H), 0.92 (d, 6.9Hz, 3H), 0.92 (d , 7.0 Hz, 3H) ppm. 13C-NMR (400 MHz, CDCl3, TMS): δ = 153.3 (s), 147.4 (s), 128.0 (s), 122.5 (d), 121.1 (d), 118 .0 (d), 109.9 (d), 71.6 (d), 55.6 (q), 47.2 (d), 30.9 (t), 29.4 (d), 26, 0 (t), 25.1 (t), 20.8 (q), 20.8 (q), 20.4 (t) ppm. MS (EI, major isomer): m/z = 292 (3), 291 (21), 167 (45), 123 (100), 108 (46), 81 (46), 69 (87), 55 (29 ), 41 (36). MS (EI, minor isomer): m/z = 292 (3), 291 (21), 167 (43), 123 (100), 108 (38), 81 (35), 69 (76), 55 (25 ), 41 (32). Example 1.3.7: 4-tert-butyl-cyclohexyl ester of cyclohexyl-carbamic acid (BIO1747)

[000374] main signals of the mixture of isomers: 1H-NMR (400 MHz, CDCl3, TMS): δ = 4.44-4.54 (m, 2 H), 3.47 (m, H), 2.05 (d, 12.3Hz, 2H), 1.92 (d, 12.3Hz, 2H), 1.79 (d, 13.2Hz, 2H), 1.69 (d,13, 2Hz, 2H), 1.59 (d, 12.8Hz, H), 0.95-1.46 (m, 9H), 0.97 (d, 11.7Hz, H), 0 .85 (s, 9H) ppm. 13C-NMR (400 MHz, CDCl3, TMS): δ = 155.5 (s), 73.7 (d), 49.6 (d), 47.2 (d), 33.5 (t), 33 .5 (t), 32.6 (t), 32.6 (t), 32.3 (s), 27.6 (q), 27.6 (q), 27.6 (q), 25.5 (t), 25.5 (t), 25.5 (t), 24.8 (t) ppm. MS (EI, minor isomer): m/z = 281 (not detected), 144 (84), 83 (25), 82 (36), 67 (31), 57 (100), 56 (24), 41 ( 32). MS (EI, major isomer): m/z = 281 (<1), 144 (93), 83 (33), 82 (32), 67 (33), 57 (100), 56 (36), 41 ( 31). Examples 1.4: tri-substituted cyclohexyl carbamates Example 1.4.1: 2,3,6-trimethyl-cyclohexyl n-butyl-carbamic acid ester (BIO1617)

[000375] main signals of the mixture of isomers: 1H-NMR (400 MHz, CDCl3, TMS): δ = 4.72 (m, H), 4.15 (t, 10.2 Hz, H), 3.18 (m, 2H), 1.92 (m, H), 1.49 (m, 2H), 1.35 (m, 2H), 0.92-1.78 (m, 6H), 0.85-0.95 (m, 12H) ppm. 13C-NMR (400 MHz, CDCl3, TMS): δ = 157.4 (s), 82.7 (d), 40.7 (t), 40.6 (d), 36.6 (d), 34 .6 (t), 32.9 (t), 32.2 (t), 20.0 (q), 19.9 (d), 19.9 (t), 18.6 (q), 15, 1(q), 13.8(q) ppm. MS (EI, main): m/z = 241 (8), 198 (5), 124 (73), 118 (100), 109 (39), 95 (31), 82 (31), 69 (65) , 55 (23), 41 (22). Example 1.4.2: 2,3,6-trimethyl-cyclohexyl ester of (2-methoxy-phenyl)-carbamic acid (BIO1701)

[000376] main signals of the mixture of isomers: 1H-NMR (400 MHz, CDCl3, TMS): δ = 8.13 (m, H), 7.24 (m, H), 6.92-7.00 ( m, 2H), 6.85 (m, H), 4.29 (t, 10.0 Hz, H), 3.86 (s, 3H), 0.99-1.76 (m, 7 H), 0.94 (d, 6.4Hz, 6H), 0.94 (d, 6.6Hz, 3H) ppm. 13C-NMR (400 MHz, CDCl3, TMS): δ = 154.0 (s), 147.5 (s), 128.1 (s), 122.4 (d), 121.1 (d), 118 .0 (d), 109.9 (d), 83.4 (d), 55.6 (q), 44.4 (d), 38.1 (d), 37.8 (d), 34, 6(t), 32.9(t), 20.0(q), 18.6(q), 15.2(q)ppm. MS (EI, major isomer): m/z = 291 (50), 190 (5), 167 (55), 150 (12), 123 (100), 108 (25), 83 (19), 69 (57 ), 55 (21), 41 (14). Example 1.4.3: 3,3,5-trimethyl-cyclohexyl ester of sec-butyl-carbamic acid (BIO1844)

[000377] main signals of the mixture of isomers: 1H-NMR (400 MHz, CDCl3, TMS): δ = 4.75 (t, t, 4.1 Hz, 11.5 Hz, H), 4.38 (m , H), 3.60 (m, H), 2.00 (d, 11.4 Hz, H), 1.70 (d, 12.3 Hz, H), 1.66 (m, H), 1.43 (m, 2H), 1.31 (d, 13.2 Hz, H), 1.10 (d, 6.8 Hz, 3H), 1.04 (m, H), 0, 93 (s, 6H), 0.89 (t, 7.5Hz, 3H), 0.89 (d, 6.5Hz, 3H), 0.80 (m,H), 0.76 (t, 12.5 HZ, H) ppm. 13C-NMR (400 MHz, CDCl3, TMS): δ = 155.8 (s), 71.1 (d), 48.2 (d), 47.6 (t), 44.4 (t), 41 .0 (t), 33.1 (q), 32.2 (s), 30.0 (t), 27.1 (d), 25.6 (q), 22.3 (q), 20, 7(q), 10.3(q) ppm. MS (EI, major isomer): m/z = 241 (not detected), 226 (<1), 212 (38), 168 (28), 125 (35), 109 (23), 83 (39), 69 (100), 57 (31), 44 (86), 41 (32). Example 1.4.4: n-3,3,5-trimethyl-cyclohexyl butyl-carbamic acid ester (BIO1616)

[000378] main signals of the mixture of isomers: 1H-NMR (400 MHz, CDCl3, TMS): δ = 4.77 (t, t, 4.1 Hz, 11.6 Hz, H), 4.64 (m , H), 3.16 (q, 6.3 Hz, 2 H), 2.01 (d, 11.6 Hz, H), 1.63 1.75 (m, 3 H), 1.47 ( m, 2H), 1.29-1.39 (m, 3H), 1.03 (m, H), 0.94 (s, 6H), 0.92 (t, 7.3Hz, 3H), 0.90 (d, 6.5Hz, 3H), 0.71-0.85 (m, 2H) ppm. 13C-NMR (400 MHz, CDCl3, TMS): δ = 156.4 (s), 71.2 (d), 47.6 (t), 44.4 (t), 40.9 (t), 40 .6 (t), 33.1 (q), 32.2 (t), 32.1 (s), 27.1 (d), 25.5 (q), 22.3 (q), 19, 9(t), 13.7(q) ppm. MS (EI): m/z = 242 (<1), 241 (<1), 125 (17), 118 (100), 109 (36), 83 (29), 69 (57), 57 (18) , 55 (17), 41 (21). Example 1.4.5: 3,3,5-trimethyl-cyclohexyl ester of (2-methoxy-phenyl)-carbamic acid (BIO1703)

[000379] main signals of the mixture of isomers: 1H-NMR (400 MHz, CDCl3, TMS): δ = 8.09 (m, H), 7.17 (m, H), 6.96 (m, 2 H) ), 6.84 (m, H), 4.89 (t, t, 4.4 Hz, 11.6 Hz, H), 3.85 (s, 3 H), 2.08 (d, 12, 0 Hz, H), 1.78 (d, 12.1 Hz, H), 1.73 (m, H), 1.35 (d, 13.2 Hz, H), 1.14 (t, 12 .0Hz, H), 0.97 (s, 3H), 0.96 (s, 3H), 0.92 (d, 6.5Hz, 3H), 0.90 (m,H) , 0.80 (t, 12.7 Hz, H) ppm. 13C-NMR (400 MHz, CDCl3, TMS): δ = 153.2 (s), 147.5 (s), 127.9 (s), 122.5 (d), 121.1 (d), 118 .1 (d), 109.9 (d), 71.9 (d), 55.6 (q), 47.6 (t), 44.3 (t), 40.8 (t), 33, 1(q), 32.3(s), 27.1(d), 25.5(q), 22.3(q) ppm. MS (EI): m/z = 292 (12), 291 (62), 167 (53), 123 (100), 108 (31), 83 (18), 69 (52), 55 (17), 41 (19). Example 1.4.6: 3,3,5-trimethyl-cyclohexyl ester of n-hexyl-carbamic acid (BIO1850)

[000380] main signals of the mixture of isomers: 1H-NMR (400 MHz, CDCl3, TMS): δ = 4.77 (t, 11.5 Hz, H), 4.62 (m, H), 3.15 (q, 6.5Hz, 2H), 2.00 (d, 11.4Hz, H), 1.62-1.75 (m, 2H), 1.47 (m, 2H), 1.24-1.35 (m, 8H), 1.04 (m, H), 0.94 (s, 6H), 0.90 (d, 6.4Hz, 3H), 0. 88 (t, 6.9Hz, 3H), 0.76 (m,H) ppm. 13C-NMR (400 MHz, CDCl3, TMS): δ = 156.4 (s), 71.2 (d), 47.6 (t), 44.5 (t), 41.0 (t), 41 .0 (t), 33.1 (q), 32.2 (s), 31.5 (t), 30.0 (t), 27.1 (d), 26.4 (t), 25, 6(q), 22.6(t), 22.3(q), 14.0(q) ppm. MS (EI, minor isomer): m/z = 270 (<1), 269 (1), 146 (100), 125 (16), 109 (35), 83 (36), 69 (82), 55 ( 23), 41 (32), 30 (24). MS (EI, major isomer): m/z = 270 (<1), 269 (1), 146 (100), 125 (28), 109 (34), 83 (39), 69 (89), 55 ( 23), 41 (28), 30 (24). Example 1.4.7: Ethyl-carbamic acid 1,7,7-trimethyl-bicyclo[2.2.1] hept-2-yl ester (BIO1573)

[000381] main signals of the mixture of isomers: 1H-NMR (400 MHz, CDCl3, TMS): δ = 4.83 (d, d, d, 10.0 Hz, 3.4 Hz, 2.0 Hz, H ), 4.63 (m, H), 3.22 (d, q, 5.9 Hz, 7.2 Hz, 2°), 2.33 (m, H), 1.88 (m, H), 1.73 (m, H), 1.66 (m, H), 1.17-1.32 (m, 2 H), 1.15 (t, 7.2 Hz, 3 H), 1.01 (m, H), 0.90 (s, 3H), 0.86 (s, 3H), 0.84 (s, 3H) ppm. 13C-NMR (400 MHz, CDCl3, TMS): δ = 157.0 (s), 79.9 (d), 48.7 (s), 47.8 (s), 44.9 (d), 36 0.9 (t), 35.8 (t), 28.1 (t), 27.1 (t), 19.8 (q), 18.8 (q), 15.3 (q), 13. 5(q) ppm. MS (EI): m/z = 226 (2), 225 (12), 136 (49), 121 (34), 108 (21), 95 (100), 55 (12), 41 (19), 29 (13). Example 2: Adipogenesis assay (in vitro)
[000382] 3T3-L1 cells (adipocyte cell line similar to mouse embryonic fibroblast) are seeded in a 48-well plate coated with collagen I at a concentration of 3 x 104 cells/well. After 72 hours' cultivation at 37°C and 5% CO2 in DMEM (Dulbecco's Modified Eagle Medium), enriched with 10% calf serum, various concentrations of the test substances in DMEM, enriched with 10% fetal calf serum and to which 1 μg/ml insulin, 0.25 μM dexamethasone and 0.5 mM IBMX (3-isobutyl-1-methylxanthine) are added, added and incubated for a further 48 hours. A media modification is carried out, in which DMEM, enriched with 10% fetal calf serum and by added 1 µg/ml insulin, are applied. After renewed culture for 48 hours, an additional media modification is performed, in which DMEM, enriched with 10% fetal calf serum, is applied.
[000383] After an additional 72 hour incubation, intracellularly stored lipids are quantified as a measure of cell differentiation by measuring fluorescence after labeling the lipids with the fluorescent dye Red Nile.
[000384] Inhibition of adipogenesis in the presence of test substances is calculated according to the following equation: Inhibition of adipogenesis [100%]=100 - [(RFU test substance — control RFU without cells)/( RFU control - RFU control without cells)] x 100 where RFU test substance = relative fluorescent units from wells with test substance and with control RFU cells = relative fluorescent units from wells without test substance, but with RFU control cells without cells = relative fluorescent units from wells without test substance and no cells
[000385] IC50 is calculated from inhibition of adipogenesis [%] over a series of test sample dilutions. This is the concentration at which adipogenesis is 50% inhibited. Table 2: Inhibition of adipogenesis of individual substances (mean values of at least 2 independent tests)



[000386] Lipogenesis is perceived as the storage of triglycerides in adipocytes. The inhibition of this storage can be accomplished by inhibiting the activity of extracellular lipoprotein lipase (LPL) in which the hydrolysis of extracellular triglycerides and therefore the absorption of free fatty acids by adipocytes are reduced. As a preliminary test, pancreatic lipase (PL) inhibition is investigated. Example 3.1: Inhibition of PL
[000387] PL (Sigma-Aldrich), in the presence of test substances at different use concentrations has methylumbelliferyl oleate (MUF oleate) added as a substrate. Fluorescent methylumbelliferone (MUF) is produced by hydrolysis of MUF oleate by PL and is quantified. Inhibition of MUF oleate hydrolysis is a measure of inhibition of PL activity. Inhibition of PL [100%]=100 - [(MUF test substance - MUF control without PL)/( MUF control - MUF control without PL)] x 100 where MUF test substance = MUF concentration of the wells with the test substance and with PL MUF control = MUF concentration from wells without test substance, but with PL MUF control without PL = MUF concentration from wells without test substance and without PL
[000388] The IC50 is calculated from the inhibition of PL [%] in a series of test sample dilutions. That is, the concentration at which PL activity is 50% inhibited. Table 3.1: Inhibition of PL by individual substances (mean values of at least 2 independent tests)


Example 3.2: LPL inhibition
[000389] PL inhibition results are used as a preliminary test and are confirmed in LPL. To obtain LPL, 3T3-L1 cells (adipocyte cell line similar to mouse embryonic fibroblast) are seeded in a 6-well plate coated with collagen I at a concentration of 3 x 105 cells/well. Cell cultivation and differentiation are carried out analogously to the details in Example 2 (adipogenesis assay). During differentiation, LPL is increasingly expressed. LPL is present in a membrane-bound state and is released by a one-hour incubation with heparin solution at 2 - 8°C to the cell supernatant.
[000390] The LPL obtained in this way, in the presence of test substances at different usage concentrations, has methylumbelliferyl oleate (MUF oleate) added as the substrate. Fluorescent methylumbelliferyl (MUF) is produced by the hydrolysis of MUF oleate by LPL and is quantified. Inhibition of MUF oleate hydrolysis is a measure of inhibition of LPL activity and hence lipogenesis. LPL inhibition [100%]=100 - [(MUF test substance — MUF control without LPL)/( MUF control - MUF control without LPL)] x 100 where MUF test substance = MUF concentration of the wells with the test substance and with LPL MUF control = MUF concentration from the wells without the test substance, but with LPL MUF control without LPL = MUF concentration from the wells without the test substance and without LPL
[000391] IC50 is calculated from LPL inhibition [%] in a series of test sample dilutions. That is, the concentration at which LPL activity and hence lipogenesis is 50% inhibited. Table 3.2: LPL inhibition by individual substances (mean values of at least 2 independent tests)

Example 4: Lipolysis Assay Example 4.1: In vitro experiment with 3T3-L1 cells
[000392] 3T3-L1 cells (adipocyte cell line similar to mouse embryonic fibroblast) are seeded in a 48-well plate coated with collagen I at a concentration of 3 x 104 cells/well. Cell culture and differentiation are carried out analogously to the details in Example 2 (adipogenesis assay).
[000393] Various concentrations of the test substances are applied to the cells in DMEM, with the bovine serum albumen added. After approximately 20 hours of incubation, quantification of free glycerol in the cell supernatant is performed, which is released by the cells after hydrolysis of triglycerides in the cells and is a measure of cell lipolysis. Quantification of free glycerol is performed based on an enzymatic method with a free glycerol reagent.
[000394] The stimulation of lipolysis in the presence of test substances is calculated according to the following equation: Stimulation of lipolysis [100%]= {[(The test substance — The test substance without cells)/( The control — A control without cells)] X 100} — 100 where Test substance = absorption of wells with test substance and cells A test substance without cells = absorption of wells with test substance without cells (absorbent control) A control = absorption of wells without test substance but with cells A control without cells = absorption of wells without test substance and without cells
[000395] The EC50 is calculated from the stimulation of lipolysis [%] in a series of test sample dilutions. That is, the concentration at which lipolysis is 50% stimulated. Table 4.1: Stimulation of lipolysis by individual substances (mean values from at least 2 independent tests).

Example 4.2: Experiments using an ex vivo pigskin model
[000396] Full thickness pieces of pigskin (pigskin model including the subcutis fat layer as described in EP 1939279) are excised from the dorsal part of the young dead pig for meat. The ex vivo pigskin models have a size of 7 x 3 mm (diameter x height). They are placed in a titanium grate dipped in culture medium. On the skin, the sample formulations are applied. In parallel to a cosmetic test preparation containing one or more compounds of Formula (I) a placebo preparation without any compound of Formula (I) is applied as reference (blank).
[000397] After 24 hours of incubation, quantification of free glycerol in the medium surrounding the pig skin models was performed. Glycerol is released by cells after hydrolysis of triglycerides in adipose tissue cells and is a measure of lipolysis in pig skin models. Quantification of free glycerol is performed based on an enzymatic method with a free glycerol reagent. Cosmetic test preparation:
Production:
[000398] Phases A and B are heated to 70°C separately. Pemulen TR1 as well as Ultrez-21 are dispersed in phase B when heated to 70°C. Phase B/C is added to phase A by mixing with an Ultra Turrax, followed by emulsification. Phase D is slowly added to phase A/B/C using a paddle mixer and a pH 5.5 - 6 is adjusted. The formulation is cooled by mixing with a paddle mixer. Phase E is prepared by dissolving one or more compounds of Formula (I) in Hydrolite-5. Subsequently, phase E is added to the mixture of phase A-D.
[000399] The stimulation of lipolysis in the presence of test substances is calculated according to the following equation: Stimulation of lipolysis [%]= {[(The test substance)/(The placebo)] x 100} - 100 where The substance test = absorption of wells with medium from ex vivo skin models, in which the formulation containing the test substance was applied A placebo = absorption of wells with medium from ex vivo skin models, in which placebo without test substance was applied
[000400] Table 4.2 shows the individual stimulation results of BIO1617, BIO1823, BIO1841 and BIO1845 when used separately in the cosmetic test preparation specified above. Table 4.2: Stimulation of lipolysis by individual substances

Example 5: SIRT1 test
[000401] NHDF cells (normal human dermal fibroblasts) were seeded in 96-well plates. After 24 hours cultivation at 37°C and 5% CO2 in DMEM (Dulbecco's Modified Eagle Medium), the cells were treated with test substances for another 48 hours. After washing the cells with PBS (phosphate buffered saline), the cells were fixed with paraformaldehyde and permeabilized. Then they were washed again and blocked with BSA (bovine serum album), followed by incubation with the secondary antibody. After extensive washing, fluorescence is measured on a microplate reader and fluorescence images were recorded on a fluorescence microscope with a closed-loop exposure camera connected.
[000402] Stimulation of SIRT1 expression was calculated by: Stimulation of SIRT1 expression [%]= {[(RFU test substance — Reference RFU)/(Control RFU — reference RFU)] X 100} — 100 RFU test substance = Relative Fluorescent Units of Wells with Test Substance, Fully Labeled Control RFU = Relative Fluorescent Units of Wells without Test Substance, Fully Labeled Reference RFU = Relative Fluorescent Units of Wells without Test Substance, Labeled with Secondary Antibody Only. Table 5.1: Stimulation of SIRT1 expression by individual substances (mean values of at least 2 independent tests)
Example 6: ATP Assay
[000403] 3T3 cells (mouse melanoma fibroblasts) were seeded in 96-well plates. After culture for 24 hours at 37°C and 5% CO2 in DMEM (Dulbecco's Modified Eagle Medium), the cells were treated with test substances for another 48 hours. Microscopic observation is performed for 24 hours and 48 hours after application of test substances to discriminate between cytotoxicity and inhibition of proliferation. ATP content in cells is measured by
[000404] Proliferation inhibition was calculated by: Proliferation inhibition [%]= 100 - {[(RLU test substance — control RLU without cells)/( RLU control - RLU control without cells)] x 100} Where RLU substance test = relative luminescent units of wells with test substance and with RLU control cells = relative luminescent units of wells without test substance, but with control RLU cells without cells = relative luminescent units of wells without test substance and without cells
[000405] IC50 is calculated from inhibition of proliferation [%] in a series of non-cytotoxic dilutions of tested samples. That is, the concentration at which proliferation is 50% inhibited. Table 6.1: Inhibition of proliferation by individual substances (mean values from at least 2 independent tests)

Example 7:
[000406] Each of the four substances BIO1617, BIO1823, BIO1841 and BIO1845 was used separately in the following cosmetic preparation. The effectiveness of each of four different preparations according to the invention containing BIO1617, BIO1823, BIO1841 or BIO1845 at a final concentration of 0.5% by weight was tested by a panel of 30 healthy women (Caucasian type).
[000407] Each of the test subjects treated one leg for two months with a preparation according to the invention as provided below and treated another leg with a control preparation without cyclohexyl carbamates according to Formula (I). After two months a test panel of 3 trained examiners rated the improvement in cellulite appearance using a scale of 1 (only noticeable improvement) to 5 (complete elimination of cellulite model). On average, an improvement of approximately 2 was achieved.
Production:
[000408] Allow Pemulen TR2 to swell in water and pre-dissolve BIO1617, BIO1823, BIO1841 or BIO1845 in Hydrolite-5 (1,2-pentanediol). Mix Phase A. Add phase C to phase A then add phase B to phase A/C and emulsify with Homorex. Continue stirring the O/W emulsion with the paddle mixer and add phase D. Formulation examples:'List A compound"
[000409] Unless otherwise indicated in the respective formulation example, each compound of the following List A was formulated separately in each unique formulation of Formulation Example 1 - 10 and F1 - F10 given below. List A: BIO1617, BIO1851, BIO1823, BIO1581, BIO1841, BIO1745, BIO1844, BIO1748, BIO1845, BIO1616, BIO1743, BIO1747, BIO1842, BIO1840, BIO1615, BIO1573.
[000410] Additionally, various formulations were produced including mixtures of two, three of four different compounds selected from list A. In such a case, the amount used in the formulation example refers to the sum of the compounds selected from list one used therein.
[000411] In the case where two different compounds from list A are used as a mixture in the formulation examples provided in this application, generally the weight ratio of the two compounds has been chosen in the range of 10:1 to 1:10, preferably in the range from 5:1 to 1:5, more preferably in the range from 3:1 to 1:3.

[000412] In Formulation Examples 1 - 5, 7, 8 and 10, the following two perfume oils PFO1 and PFO2 were each used as a fragrance (DPG = dipropylene glycol). PFO1 perfume oil with rose scent
PFO2 perfume oil with white flower and musk scent







Examples: F1 - F10: Examples of orally consumable use [ "Interior beauty"] Example F1: fruit gums

Example F2: Caramel
Example F3: gelatine capsules suitable for direct consumption


[000413] Flavor G had the following composition (in % by weight): 0.1% neotam powder, 29.3% arvensis peppermint oil, piperta Willamette peppermint oil 29.35%, sucralose 2.97%, 2.28% triacetin, 5.4% diethyl tartrate, 12.1% yakima peppermint oil, 0.7% ethanol, 5.77% D-limonene 2-hydroxypropylmenthylcarbonate 3.0%, 2-hydroxyethylmenthylcarbonate 3.36%, L-menthylacetate 5.67%.
[000414] Gelatin capsules I, II, III suitable for direct consumption were produced according to WO 2004/050069 and in each case had a diameter of 5 mm and the weight ratio of main material to shell material was 90:10. The capsules in each case opened in the mouth in less than 10 seconds and completely dissolved in less than 50 seconds. Example F4: Tablets in round tablet form
Example F5: Gum (with sugar and without sugar)

[000415] Flavor P1 had the following composition (in % by weight): 0.05% isobutyraldehyde, 0.05% 3-octanol, 0.05% dimethylsulfide, 0.1% trans-2-hexanal, 0 .1% cis-3-hexanol, 0.1% natural 4-terpineols, 0.1% isopulegol, 0.2% natural piperiton, 0.3% linalool, 1.0% isoamyl alcohol, 1.0% isovaleraldehyde , 2.5% natural alpha-pinene, 2.5% natural beta-pinene, 8.0% eucalyptol, 7.0% l-mentylacetate, 12.0% l-menthone, 5.0% isomentone, 20.5 % l-carvone, 39.45% l-menthol. The following table refers to Examples F6-F10: Example F6 = Powdered instant drink Example F7 = Powdered instant drink, without sugar Example F8 = Carbonated lemonade (soda) Example F9 = Soy fruit drink Example F10 = Yogurt of reduced fat

* Carbon dioxide is added after filling in bottles.

权利要求:
Claims (18)
[0001]
1. Cosmetic or pharmaceutical composition for topical use, for the prevention, treatment or reduction of cellulite, and/or for reducing the amount of lipid contained in subcutaneous adipose tissue, and/or for stimulating lipolysis in adipocytes, and/or for inhibiting differentiation of preadipocytes, and/or for inhibition of lipogenesis in adipocytes, said composition being characterized by the fact that it comprises: a compound of Formula (I), or a cosmetically or pharmaceutically acceptable salt of a compound of Formula (I), or a mixture containing two or more such compounds or salts thereof,
[0002]
2. Cosmetic or pharmaceutical composition, according to claim 1, characterized in that R1 denotes hydrogen and/or where A denotes
[0003]
3. Cosmetic or pharmaceutical composition, according to claim 1, characterized in that A denotes:
[0004]
4. Cosmetic or pharmaceutical composition, according to claim 3, characterized in that A denotes:
[0005]
5. Cosmetic or pharmaceutical composition, according to claim 1, characterized in that A denotes:
[0006]
6. Cosmetic or pharmaceutical composition, according to claim 5, characterized in that A denotes:
[0007]
7. Cosmetic or pharmaceutical composition, according to claim 1, characterized in that A denotes:
[0008]
8. Cosmetic or pharmaceutical composition, according to claim 7, characterized in that A denotes:
[0009]
9. Cosmetic or pharmaceutical composition, according to any one of claims 1 to 8, characterized in that it further comprises one or more compounds selected from the following groups (b) and/or (c): (b) one or more lipolysis stimulants selected from: (bi) from the group of phosphodiesterase inhibitors, and/or (b-ii) from the group of beta-adrenergic receptor agonists, and/or (c) from one or more stimulants of transport or oxidation of free fatty acids.
[0010]
10. Cosmetic or pharmaceutical composition, according to claim 9, characterized in that one, a plurality of, or all of the lipolysis stimulants of component (b) are: - a compound of Formula (Xa), or a salt cosmetics or group (bi),
[0011]
11. Cosmetic or pharmaceutical composition, according to claim 10, characterized in that one, a plurality of, or all of the compounds of the Formula (PhEA) are compounds of the Formula (PhEA-i) and the cosmetically acceptable salts thereof , in which the radical R14 denotes hydrogen, hydroxy or methyl, and the radical R16 denotes hydrogen or C1-C4-alkyl.
[0012]
12. Cosmetic or pharmaceutical composition, according to any one of claims 9 to 11, characterized in that it further comprises: - one or more agents that stimulate and/or depolarize fibers of the C nerve, and/or
[0013]
13. Cosmetic or pharmaceutical composition, according to any one of claims 9 to 12, characterized in that: - the total amount of compounds of Formula (I) is in the range of 0.001 to 10% by weight, and/or - the total amount of phosphodiesterase (bi) inhibitors, preferably the compounds of Formula (Xa), is in the range of 0.005 to 10% by weight, and/or - the total amount of beta-adrenergic receptor agonists (b-ii) it is in the range of 0.0001 to 0.10% by weight, in each case, based on the total weight of the composition.
[0014]
14. Cosmetic or pharmaceutical composition, according to any one of claims 9 to 13, characterized in that: the proportion by weight of the total amount of compounds of Formula (I) to the total amount of phosphodiesterase (bi) inhibitors, preferably the compounds of Formula (Xa), is in the range of 20:1 to 1:500, and/or the weight ratio of the total amount of compounds of Formula (I) to the total amount of beta-adrenergic receptor agonists (b- ii) is in the range of 1000:1 to 1:5.
[0015]
15. Compound, characterized by the fact that it has Formula (I), or a cosmetic or pharmaceutically acceptable salt thereof,
[0016]
16. Compound according to claim 15, characterized in that it has the condition that the following compounds are excluded: the compounds of Formula (I), in which R2 is phenyl, 3-Me-phenyl, naphthyl, biphenyl, p-hydroxyphenyl and methyl.
[0017]
17. A compound, or a cosmetic or pharmaceutically acceptable salt thereof, according to claim 15 or 16, characterized in that it is selected from the group consisting of:
[0018]
18. Use of a compound, or a cosmetically or pharmaceutically acceptable salt thereof, as defined in any one of claims 15 to 17, or a mixture containing two or more of these compounds or salts thereof, characterized in that which is for preparing a cosmetic or pharmaceutical composition for topical use for preventing, treating or reducing cellulite.

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同族专利:

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公开号 | 公开日

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BR112012029927A2|2021-05-18|

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US20130137710A1|2013-05-30|

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WO2010097479A3|2011-04-14|

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CN103002868B|2016-05-04|

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JP5838497B2|2016-01-06|

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KR20130109982A|2013-10-08|

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JP2013533218A|2013-08-22|

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法律状态:
2020-09-08| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2021-05-25| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2021-07-20| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 25/05/2010, OBSERVADAS AS CONDICOES LEGAIS. PATENTE CONCEDIDA CONFORME ADI 5.529/DF, QUE DETERMINA A ALTERACAO DO PRAZO DE CONCESSAO. |

优先权:

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申请号 | 申请日 | 专利标题

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PCT/EP2010/057112|WO2010097479A2|2010-05-25|2010-05-25|Cyclohexyl carbamate compounds as active anti-cellulite ingredients|

---