Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C409/00—Peroxy compounds
  • C07C409/32—Peroxy compounds the —O—O— group being bound between two >C=O groups
  • C07C409/34—Peroxy compounds the —O—O— group being bound between two >C=O groups both belonging to carboxylic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
  • A61K8/38—Percompounds, e.g. peracids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
  • A61K8/42—Amides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/10—Anti-acne agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q19/00—Preparations for care of the skin
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C409/00—Peroxy compounds
  • C07C409/40—Peroxy compounds containing nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
  • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
  • C07C2601/14—The ring being saturated
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2603/00—Systems containing at least three condensed rings
  • C07C2603/56—Ring systems containing bridged rings
  • C07C2603/58—Ring systems containing bridged rings containing three rings
  • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
  • C07C2603/74—Adamantanes

Definitions

• Novel peroxide derivatives their process of preparation and their use in human medicine and in cosmetics for the treatment or prevention of acne
• Acne affects 90% of all adolescents but also men and women aged from about twenty to about thirty years, or it can even persist throughout adulthood.
• the process of development of acne has been described by W. J. Cunliffe in 'New Approaches to Acne Treatment', published by Martin Dunitz, London, 1989.
• Acne vulgaris is a chronic disorder of the pilosebaceous follicles (apparati) which is characterized by comedones (blackheads), papules, pustules, cysts, nodules and often scars which appear in the most visible regions of the skin, in particular the face, chest, back and sometimes the neck and top of the arms .
• the pilosebaceous apparatus is largely placed under the control of endogenous hormones (mainly androgens) which are present at unusually high concentrations in the blood during adolescence and puberty and are reflected by an excessive production of sebum.
• endogenous hormones mainly androgens
• This state of affairs can worsen due to a concomitant increase in the degree of keratinization of the cornea layer of the skin (stratum corneum) .
• the horny cells proliferate, they can form an occlusive plug or comedo which, in combination with the increased production of sebum, constitutes an ideal medium for the proliferation of the strains resident in the skin, such as the Gram positive anaerobic bacterium Propionibacterium acnes.
• the exposed follicles may assume a dark colour due to the deposition of pigment originating from the damaged cells of the deep layer of the skin.
• Acne is a condition comprising several stages and, in its severest form, results in the hospitalization of the patient and significant discomfort with the long- term presence of skin scars.
• the treatment of acne involves topical formulations in the form of creams, gels, emulsions or lotions comprising chosen agents.
• agents comprise, for example, hormones or hormone agonists and antagonists (EPAI 0 563 813 and US 5 439 923), antimicrobial agents (US 4 446 145, GB 2 088 717, GB 2 090 135, GB 1 054 124 and US 5 409 917) or salicylic acid (US 4 514 385, US 4 355 028, EPAI 0 052 705, FR-A 2 581 542 and FR-A 2 607 498) .
• hormones or hormone agonists and antagonists EPAI 0 563 813 and US 5 439 923
• antimicrobial agents US 4 446 145, GB 2 088 717, GB 2 090 135, GB 1 054 124 and US 5 409 91
• salicylic acid US 4 514 385, US 4 355 028, EPAI 0 052 705, FR-A 2 581 542 and FR-A 2 607 498) .
• the problems associated with the topical treatment of acne using creams, gels, emulsions or lotions comprise the lack of preciseness of the application and the absence of precise control of the dose at the site targeted.
• the application of a cream, of a gel, of an emulsion or of a lotion is reflected by the exposure of a surface area considerably greater than that covered by the lesion, which has the effect of exposing normal healthy skin to the antiacne formulation.
• salicylic acid is irritating to normal skin in the case of prolonged exposure, in particular at high concentrations .
• the administration by the oral route of antiacne agents is commonly provided in severe cases of acne. These have been reviewed by Sykes N. I. and Webster G. in 'Acne, A Review of Optimum Treatment', Drugs, 48, 59-70 (1994) . Numerous side effects have been described in the context of the administration of antiacne active compounds by the oral route.
• isotretinoin which is a vitamin A derivative, exhibits associated risks of teratogenicity and it can constitute a risk to women of reproductive age.
• antibiotics suitable for the treatment of acne can be accompanied by the appearance of side effects, such as abdominal cramps, glossophytia, coughing, diarrhoea, fatigue, buccal irritation and other undesirable symptoms.
• the present invention proposes to provide novel peroxide derivatives having a better antiacne effectiveness resulting, for example, from a better bactericidal activity than the compounds of the prior art, such as benzoyl peroxide, while controlling the potential sensitizing effect and the irritant effect and while not adding an antiinflammatory activity component.
• a subject-matter of the present invention is compounds of following general formula (I) : in which:
• Rl represents a lower alkyl, a higher alkyl, a cycloalkyl, a cycloalkylalkyl , a lower alkoxy, a higher alkoxy, a cycloalkyloxy, a cycloalkylalkoxy, an aryl, an aryloxy or a mono- or dialkylamino;
• A represents a hydrogen or the following sequence:
• R2 represents a lower alkoxy, a higher alkoxy, a cycloalkyloxy, a cycloalkylalkoxy, an aryloxy or a mono- or dialkylamino.
• the preferred compounds corresponding to the general formula (I) are those which exhibit the following characteristics:
• -Rl represents a lower alkyl, a cycloalkyl, a cycloalkylalkyl, a lower alkoxy, a cycloalkyloxy or a mono- or dialkylamino;
• A represents a hydrogen or a defined group of such type :
• -Rl represents a lower alkyl, a cycloalkyl, cycloalkylalkyl , a lower alkoxy or a cycloalkyloxy;
• A represents a hydrogen or a defined group of type :
• -R2 represents a lower alkoxy or a cycloalkyloxy.
• a lower alkyl denotes a saturated and linear or branched hydrocarbon chain comprising from 2 to 4 carbon atoms.
• a higher alkyl denotes a saturated and linear or branched hydrocarbon chain comprising from 5 to 10 carbon atoms .
• a cycloalkyl denotes a saturated and cyclic, bicyclic or tricyclic hydrocarbon chain comprising from 3 to 10 carbon atoms .
• a cycloalkylalkyl denotes an alkyl substituted by a cycloalkyl .
• a lower alkoxy denotes an oxygen atom substituted by a lower alkyl.
• a higher alkoxy denotes an oxygen atom substituted by a higher alkyl.
• an aryl denotes an unsubstituted phenyl or naphthyl .
• an aryloxy denotes an oxygen atom substituted by an aryl.
• a cycloalkylalkoxy denotes an oxygen atom substituted by a cycloalkyl (lower alkyl) .
• a cycloalkoxy denotes an oxygen atom substituted by a cycloalkyl .
• a mono- or dialkylamino denotes an amino substituted by one or two identical or different lower alkyls.
• Example 3 Bis (2- (ethoxycarbonyloxy) benzoyl) peroxide
• Example 4 Bis (2- (tert-butoxycarbonyloxy) benzoyl) peroxide
• Example 10 (2- (Isobutyryloxy) benzoyl) benzoyl peroxide
• Example 11 (2- (Cyclohexanecarbonyloxy) benzoyl) benzoyl peroxide
• Example 31 (2- ( Methylcarbamoyloxy) benzoyl) benzoyl peroxide
• Example 32 (2- Ethylcarbamoyloxy) benzoyl) benzoyl peroxide
• Example 53 Bis [2- ( 3-methylbutyryloxy) benzoyl ] peroxide
• Example 54 Bis [2- (2-methylbutyryloxy) benzoyl] peroxide
• Example 55 Bis (2- (dimethylcarbamoyloxy) benzoyl) peroxide
• Example 57 Bis (2- (methylcarbamoyloxy) benzoyl) peroxide
• Example 58 Bis (2- (ethylcarbamoyloxy) benzoyl) peroxide
• Example 59 Bis (2- (isopropylcarbamoyloxy) benzoyl) peroxide
• Example 60 Bis (2-propylcarbamoyloxy) benzoyl) peroxide
• Example 61 Bis (2- ( (isopropyl) (methyl ) carbamoyloxy) - benzoyl) peroxide
• Example 62 Bis (2- ( (ethyl) ( isopropyl ) carbamoyloxy) - benzoyl) peroxide
• Example 90 (2- (Cyclohexyloxycarbonyloxy) benzoyl) 2- (tert-butyryloxy) benzoyl peroxide
• Example 91 (2- (Cyclohexyloxycarbonyloxy) benzoyl)
• the acid chlorides of general formula (III) are prepared from the carboxylic acid (II) by methods chosen from those known to a person skilled in the art (EP 121 968 2) . They comprise the use of thionyl chloride and pyridine in a solvent, such as toluene or dichloromethane, for example.
• the compounds of general formula (V) can be prepared by coupling between the acyl chlorides of formula (III) and the peracid of formula (IV) by using, as base, pyridine in a solvent mixture, such as dichloromethane and chloroform (Evanochko, W. T. and Shevlin, P. B . ; J. Org. Chem. , 1979, 44(24), 4426-4430) .
• a solvent mixture such as dichloromethane and chloroform
• the peracid of general formula (IV) is prepared from benzoyl peroxide according to the method described in Scheme 11.
• the peroxides of general formula (V) are prepared by coupling between the carboxylic acids of formula (II) and the peracid of formula (IV) by using, for example, as coupling agent, N, N' -dicyclohexylcarbodiimide in a mixture of solvents, such as diethyl ether and dichloromethane ( Spantulescu, M. D.; Jain, R. P.; Derksen, D. J. and Vederas, J. C . ; Org. Lett., 2003 , 5(16), 2963-2965).
• solvents such as diethyl ether and dichloromethane
• the carboxylic acids of general formula (II) are commercially available or are prepared according to the methods described in Schemes 7 and 8.
• the peracid of general formula (IV) is prepared from benzoyl peroxide according to the method described in Scheme 11.
• the acid chlorides of general formula (VII) are prepared from the carboxylic acid (VI) by methods chosen from those known to a person skilled in the art (EP 121 968 2) . They comprise the use of thionyl chloride and pyridine in a solvent, such as toluene or dichloromethane, for example.
• the compounds of general formula (VIII) can be prepared by coupling between two acyl chlorides of formula (VII) by methods chosen from those known to a person skilled in the art (EP 0 108 821) . They comprise the use of hydrogen peroxide and sodium bicarbonate in a solvent, such as tetrahydrofuran, for example .
• the peroxides of general formula (VIII) are prepared by reaction between two carboxylic acids of formula (VI) by using, for example, as, N, N' -dicyclohexylcarbodiimide and hydrogen peroxide, for example in a mixture of solvents, such as diethyl ether and dichloromethane ( Spantulescu, M. D.; Jain, R. P.; Derksen, D. J.; Vederas, J. C . ; Org. Lett., 2003 , 5(16), 2963-2965).
• solvents such as diethyl ether and dichloromethane
• the acid chlorides of general formula (III) are prepared from the carboxylic acid (II) by methods chosen from those known to a person skilled in the art (EP 121 968 2) . They comprise the use of thionyl chloride and pyridine in a solvent, such as toluene or dichloromethane, for example.
• the compounds of general formula (X) can be prepared by coupling between the acyl chlorides of formula (III) and the peracid of formula (IX) by using, as base, pyridine, for example in a mixture of solvents, such as dichloromethane and chloroform.
• the peracid of general formula (IX) is prepared according to the method described in Scheme 12 starting from the peroxide of formula (VIII) .
• the peroxides of general formula (X) are prepared by coupling between the carboxylic acids of formula (II) and the peracid of formula (IX) by using, for example, as coupling agent, N, ⁇ ' -dicyclohexylcarbodiimide in a mixture of solvents, such as diethyl ether and dichloromethane, for example.
• the peracid of general formula (IX) is prepared according to the method described in Scheme 12 starting from the defined peroxide of formula (VIII) .
• the carboxylic acids of formula (II) can be prepared according to Reaction Scheme 7 or 8.
• the carboxylic acids of formula (II) are prepared from salicylic acid (XI) by methods chosen from those known to a person skilled in the art (Lima, S . ; Kumar, S . ; Gawandi, V.; Momany, C. and Phillips, R. S . ; J. Med. Chem. , 2009, 52 (2), 389- 396, and Sessions, E. H. and Jacobi, P. A.; Org. Lett., 2006, 8(18), 4125-4128).
• They comprise the use of the acid chloride of formula (XII) and of bases, such as N, -dimethylaniline, triethylamine or pyridine, in a solvent, such as toluene or dichloromethane, for example .
• the acid chlorides of formula (XII) are available commercially .
• the aldehydes of formula (XV) are prepared from salicylaldehyde (XIII) by methods chosen from those known to a person skilled in the art (Lima, S . ; Kumar, S . ; Gawandi, V.; Momany, C . ; Phillips, R. S . ; J. Med. Chem. , 2009, 52 (2), 389-396, and Sessions, E. H. and Jacobi, P. A.; Org. Lett., 2006, 8(18), 4125-4128).
• They comprise the use of the acid chloride of formula (XII) or of anhydrides of formula (XIV) and of bases, such as triethylamine or pyridine, in a solvent, such as acetone or dichloromethane, for example.
• the carboxylic acids of general formula (II) can be prepared by oxidation of the aldehydes of formula (XV) with sodium perchlorite in a mixture of solvents, such as water and tert-butanol (Marsini, M. A.; Gowin, K. M. ; Pettus, T. R. R.; Org. Lett., 2006, 8(16), 3481-3483).
• solvents such as water and tert-butanol
• the carboxylic acids of formula (VI) can be prepared according to Reaction Scheme 9 or 10.
• They comprise the use of the acid chloride of formula (XVI) and of bases, such as N, -dimethylaniline, triethylamine or pyridine, in a solvent, such as toluene or dichloromethane, for example .
• the aldehydes of formula (XVIII) are prepared from salicylaldehyde (XIII) by methods chosen from those known to a person skilled in the art (Lima, S . ; Kumar, S . ; Gawandi, V.; Momany, C . ; Phillips, R. S . ; J. Med. Chem. 2009, 52 (2), 389-396, and Sessions, E. H. and Jacobi, P. A.; Org. Lett., 2006, 8(18), 4125-4128).
• They comprise the use of the acid chloride of formula (XVI) or of anhydrides of formula (XVII) and of bases, such as triethylamine or pyridine, in a solvent, such as acetone or dichloromethane, for example.
• the carboxylic acids of general formula (VI) can be prepared by oxidation of the aldehydes of formula (XVIII) with sodium perchlorite in a mixture of solvents, such as water and tert-butanol .
• the peracid of formula (IV) can be prepared according to Reaction Scheme 11.
• the peracid of formula (IV) is prepared from dibenzoyl peroxide (XIX) by methods chosen from those known to a person skilled in the art (US 3 075 921) . They comprise the use of dibenzoyl peroxide (XIX) and of sodium in a mixture of solvents, such as methanol and chloroform.
• the peracids of formula (IX) can be prepared accor
• the peracids of formula (IX) are prepared from the peroxide of formula (VIII) by methods chosen from those known to a person skilled in the art (US 3 075 921) . They comprise the use of a peroxide (VIII) and of sodium in a mixture of solvents, such as methanol and chloroform. Study of the sensitivity of the peroxides to
• the aim is to evaluate the antibacterial activity of the peroxides by measuring the Minimum Inhibitory Concentrations (MICs) .
• MICs Minimum Inhibitory Concentrations
• the products are dissolved at 1280 mg/1 in an absolute ethanol/sterile Tween 80/sterile Wilkins- Chalgren broth mixture (5/10/85 v/v/v) .
• the dilution ranges produced are an adaptation of the method described by the CLSI for methods of diluting in a liquid medium.
• the range is composed of 10 concentrations from 2.5 mg/1 to 1280 mg/1 with an interval of ratio 2.
• the suspension of P. acnes is prepared in Wilkins- Chalgren broth and is calibrated at an optical density of approximately 0.4 at a wavelength 525 nm. It is subsequently diluted to l/10 th in Wilkins-Chalgren broth and then dispensed into the test wells so as to obtain a final suspension of approximately 10 5 -10 6 cfu/ml in each test well.
• the solutions of the test products are distributed on a 96-well microplate and incubated at 36°C ⁇ 2°C under an anaerobic atmosphere for a time of at least 72 h.
• the first well for which there is no growth visible to the naked eye is regarded as the MIC.
• the aim is to evaluate the anti ⁇ inflammatory activity of the peroxides by measuring the thickness of mouse ear after TPA topical application.
• the anti-inflammatory activity is defined as a inhibition percentage of the TAP-induced ear oedema.
• the objective of the study was to demonstrate the anti- inflammatory effect of New peroxide in comparison to BPO (Benzoyl peroxide) .
• Ear thickness was measured at T6h.
• Results are expressed in percentages based on the inhibition on the oedema induced by the TPA application .
• Benzoyl peroxide (BPo) was tested 2 times as a reference peroxide.
• the aim of this study was to demonstrate the anti- inflammatory effect of New peroxides after a single topical application in the TPA-induced ear oedema mouse model .
• Ex5 and Ex6 demonstrate a stronger anti-inflammatory effect.
• 2- (ethoxycarbonyloxy) benzoyl chloride 5.9 g (28 mmol) of 2- (ethoxycarbonyloxy) benzoic acid are dissolved in 30 ml of toluene with a few drops of pyridine. 2.15 ml (29 mmol) of thionyl chloride are added dropwise and the mixture is stirred at ambient temperature for 18 h and then concentrated to dryness. The residue is precipitated from pentane. The solid is filtered off and then dried. 5.2 g of 2- (ethoxycarbonyloxy) benzoyl chloride are obtained in the form of a white solid with a yield of 80%.
• the white solid obtained is precipitated from heptane at 0°C.
• the precipitate is filtered off and then rinsed with heptane and dried.
• 15.8 g of 2- (tert-butoxycarbonyloxy) benzoic acid are obtained in the form of a white powder with a yield of 70%.
• Example 6 bis (2- (isopropoxycarbonyloxy) benzoyl) peroxide
• 6-1 bis (2- (isopropoxycarbonyloxy) benzoyl) peroxide
• Example 4-1 Analogously to Example 4-1, 2.4 g of bis (2- (cyclohexyloxycarbonyloxy) benzoyl) peroxide are obtained, from 4 g (15.1 mmol) of 2- (cyclohexyloxy ⁇ carbonyloxy) benzoic acid (prepared as described in Example 7-2), in the form of a white solid with a yield of 60%.
• Example 12 [2- (2- (adamantan-l-yl) acetoxy) benzoyl] benzoyl peroxide 12-1: 2- (2- (adamantan-l-yl) acetoxy) benzoic acid

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