WO2013092936A2 - Use of 5-aminolevulinic acid and esters, in combination with a vitamin d derivative or analog in photochemotherapy, and their uses in treating acne - Google Patents
Use of 5-aminolevulinic acid and esters, in combination with a vitamin d derivative or analog in photochemotherapy, and their uses in treating acne Download PDFInfo
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- WO2013092936A2 WO2013092936A2 PCT/EP2012/076524 EP2012076524W WO2013092936A2 WO 2013092936 A2 WO2013092936 A2 WO 2013092936A2 EP 2012076524 W EP2012076524 W EP 2012076524W WO 2013092936 A2 WO2013092936 A2 WO 2013092936A2
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- WO
- WIPO (PCT)
- Prior art keywords
- ethyl
- methyl
- methanol
- ala ester
- hydroxymethylphenyl
- Prior art date
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- 206010000496 acne Diseases 0.000 title claims abstract description 56
- 208000002874 Acne Vulgaris Diseases 0.000 title claims abstract description 47
- 150000003710 vitamin D derivatives Chemical class 0.000 title claims abstract description 18
- 150000002148 esters Chemical class 0.000 title claims description 119
- ZGXJTSGNIOSYLO-UHFFFAOYSA-N 88755TAZ87 Chemical compound NCC(=O)CCC(O)=O ZGXJTSGNIOSYLO-UHFFFAOYSA-N 0.000 title claims description 31
- 229960002749 aminolevulinic acid Drugs 0.000 title claims description 17
- 239000003504 photosensitizing agent Substances 0.000 claims abstract description 47
- 229940046008 vitamin d Drugs 0.000 claims abstract description 9
- 229930003316 Vitamin D Natural products 0.000 claims abstract description 7
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 claims abstract description 7
- 235000019166 vitamin D Nutrition 0.000 claims abstract description 7
- 239000011710 vitamin D Substances 0.000 claims abstract description 7
- -1 4-[t-butyl]benzyl Chemical group 0.000 claims description 46
- 125000000217 alkyl group Chemical group 0.000 claims description 44
- 150000001875 compounds Chemical class 0.000 claims description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 28
- 238000011282 treatment Methods 0.000 claims description 27
- 125000003118 aryl group Chemical group 0.000 claims description 25
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 23
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 13
- 125000004432 carbon atom Chemical group C* 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 230000002265 prevention Effects 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 claims description 5
- 125000002528 4-isopropyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- 125000006181 4-methyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])C([H])([H])* 0.000 claims description 5
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 claims description 5
- 125000004847 2-fluorobenzyl group Chemical group [H]C1=C([H])C(F)=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000006179 2-methyl benzyl group Chemical group [H]C1=C([H])C(=C(C([H])=C1[H])C([H])([H])*)C([H])([H])[H] 0.000 claims description 4
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000006284 3-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(F)=C1[H])C([H])([H])* 0.000 claims description 4
- 125000006180 3-methyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C(=C1[H])C([H])([H])[H])C([H])([H])* 0.000 claims description 4
- 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 claims description 4
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 4
- 229940043215 aminolevulinate Drugs 0.000 claims description 4
- 125000006268 biphenyl-3-yl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C1=C([H])C(*)=C([H])C([H])=C1[H] 0.000 claims description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 claims description 4
- 125000006218 1-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000005916 2-methylpentyl group Chemical group 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
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- UHKVWIUFRVKVCH-UHFFFAOYSA-N 2-[4-[5-[[3,4-bis(hydroxymethyl)phenyl]methoxy]-2-methylphenyl]-3-propylphenyl]-1,1,1,3,3,3-hexafluoropropan-2-ol Chemical compound CCCC1=CC(C(O)(C(F)(F)F)C(F)(F)F)=CC=C1C1=CC(OCC=2C=C(CO)C(CO)=CC=2)=CC=C1C UHKVWIUFRVKVCH-UHFFFAOYSA-N 0.000 claims description 2
- VUPWQHUPXLAHFU-UHFFFAOYSA-N 2-[4-[5-[[3,4-bis(hydroxymethyl)phenyl]methyl-ethylamino]-2-methylphenyl]-3-propylphenyl]-1,1,1,3,3,3-hexafluoropropan-2-ol Chemical compound CCCC1=CC(C(O)(C(F)(F)F)C(F)(F)F)=CC=C1C1=CC(N(CC)CC=2C=C(CO)C(CO)=CC=2)=CC=C1C VUPWQHUPXLAHFU-UHFFFAOYSA-N 0.000 claims description 2
- WYACMJYRZLYMGF-UHFFFAOYSA-N 2-[4-[5-[[3,4-bis(hydroxymethyl)phenyl]methyl-propylamino]-2-ethylphenyl]-3-propylphenyl]-1,1,1,3,3,3-hexafluoropropan-2-ol Chemical compound C=1C=C(CC)C(C=2C(=CC(=CC=2)C(O)(C(F)(F)F)C(F)(F)F)CCC)=CC=1N(CCC)CC1=CC=C(CO)C(CO)=C1 WYACMJYRZLYMGF-UHFFFAOYSA-N 0.000 claims description 2
- COSVUHTWMJBCBU-UHFFFAOYSA-N 2-[4-[5-[[3,4-bis(hydroxymethyl)phenyl]methyl-propylamino]-2-methylphenyl]-3-propylphenyl]-1,1,1,3,3,3-hexafluoropropan-2-ol Chemical compound C=1C=C(C)C(C=2C(=CC(=CC=2)C(O)(C(F)(F)F)C(F)(F)F)CCC)=CC=1N(CCC)CC1=CC=C(CO)C(CO)=C1 COSVUHTWMJBCBU-UHFFFAOYSA-N 0.000 claims description 2
- PGTLUOYZLPFEKC-UHFFFAOYSA-N 2-[4-[5-[[3,4-bis(hydroxymethyl)phenyl]methylamino]-2-methylphenyl]-3-propylphenyl]-1,1,1,3,3,3-hexafluoropropan-2-ol Chemical compound CCCC1=CC(C(O)(C(F)(F)F)C(F)(F)F)=CC=C1C1=CC(NCC=2C=C(CO)C(CO)=CC=2)=CC=C1C PGTLUOYZLPFEKC-UHFFFAOYSA-N 0.000 claims description 2
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- SHGAZHPCJJPHSC-NUEINMDLSA-N Isotretinoin Chemical compound OC(=O)C=C(C)/C=C/C=C(C)C=CC1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-NUEINMDLSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
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- 230000003213 activating effect Effects 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000005194 alkoxycarbonyloxy group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000006696 biosynthetic metabolic pathway Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 150000004035 chlorins Chemical class 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 208000037893 chronic inflammatory disorder Diseases 0.000 description 1
- WZHCOOQXZCIUNC-UHFFFAOYSA-N cyclandelate Chemical compound C1C(C)(C)CC(C)CC1OC(=O)C(O)C1=CC=CC=C1 WZHCOOQXZCIUNC-UHFFFAOYSA-N 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 231100000321 erythema Toxicity 0.000 description 1
- 238000004299 exfoliation Methods 0.000 description 1
- 230000001815 facial effect Effects 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 210000001061 forehead Anatomy 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 150000002390 heteroarenes Chemical class 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 230000009610 hypersensitivity Effects 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 229960005280 isotretinoin Drugs 0.000 description 1
- 230000007803 itching Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000013307 optical fiber Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 238000012261 overproduction Methods 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- 230000002186 photoactivation Effects 0.000 description 1
- 230000019612 pigmentation Effects 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 229950003776 protoporphyrin Drugs 0.000 description 1
- 150000004492 retinoid derivatives Chemical class 0.000 description 1
- 201000004700 rosacea Diseases 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 230000037390 scarring Effects 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 1
- 150000002266 vitamin A derivatives Chemical class 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
- A61K41/0061—5-aminolevulinic acid-based PDT: 5-ALA-PDT involving porphyrins or precursors of protoporphyrins generated in vivo from 5-ALA
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
Definitions
- the invention relates to the use in the field of photodynamic therapy (PDT) of a photosensitizer (PS) combined to the use of a vitamin D analog or derivative for treating acne. Said vitamin d analog or derivative is applied before the PS.
- PDT photodynamic therapy
- PS photosensitizer
- acne is a superficial disorder which is accompanied by slight, spotty irritations.
- bacterial invasion of or about the pilosebaceous follicles occurs resulting in the formation of pustules, infected cysts, etc. These lesions may become extensive and often leave permanent, disfiguring scars.
- spots Blackheads, whiteheads, papules, pustules and cysts are commonly referred to as "spots". Each type of spot may be present to a different degree in any acne sufferer and most commonly a range of different types are found. Spots generally occur on the face and back, especially the facial skin areas (e.g. on the chin, nose and forehead) where sebaceous glands are the largest, most prevalent and most active.
- Established treatments of acne are designed to prevent the formation of new lesions and to facilitate the healing of existing lesions.
- Conventional treatments include, for example, the systemic and topical administration of antibiotics which aim to reduce the bacterial population of the pilosebaceous follicles and the topical application of peroxides, e.g. benzoyl peroxide, which are both anti-bacterial and mildly comedolytic. Vitamin A analogs, such as retinoids, are comedolytic and have also been used with a some degree of success in topical acne treatment compositions.
- peroxides such as benzoyl peroxide are often unstable and therefore have limited shelf-life. Their efficacy also tends to decrease over time. Antibiotic resistance of Proprionibacterium acnes is also increasing and this severely reduces efficacy.
- Retinoid drugs e.g. isotretinoin
- isotretinoin though effective, often cause unpleasant, and sometimes severe, side-effects and contraindications often limit their acceptability and use. There is therefore a need for the development of alternative treatments for acne.
- Photodynamic therapy is a relatively new technique which has been used in the treatment of various abnormalities or disorders of the skin or other epithelial organs or mucosa, especially cancer or pre-cancerous lesions, as well as certain non-malignant lesions such as psoriasis.
- PDT involves the administration of photosensitizing agents followed by exposure to photoactivating light in order to activate the photosensitizing agents and convert them into cytotoxic form resulting in the destruction of cells and thus treatment of the disease.
- photosensitizing agents are known and described in the literature, for example various porphyrins psoralens, chlorins, phthalocyanines, as well as 5-aminolevulinic acid (5-ALA) and certain derivatives thereof, e.g. 5-ALA esters.
- PDT has focused primarily on treatment of cancer and pre-cancerous stages, there are some reports relating to the use of PDT in treating acne.
- the invention is based, in part, on the discovery that the application of a vitamin D derivative or analog enhances the production of PPIX within the cells of interest, especially in sebaceous glands.
- the invention features a method of treating acne in a subject.
- the method includes: inducing PPIX formation in deep layer of the skin e.g., by administration of a vitamin D analog or derivative, providing said skin with a photosensitizer (PS); and activating said PS, thereby treating acne lesions.
- PS photosensitizer
- the invention relates to a photosensitiser (PS) which is a derivative of 5-aminolevulinic acid (5-ALA), or a pharmaceutically acceptable salt thereof in combination with a vitamin D derivative or analog, for use in the prevention or treatment of acne, wherein said vitamin D analog or derivative is applied before the photosensitizer.
- PS photosensitiser
- a photosensitiser which is a derivative of 5-aminolevulinic acid (5-ALA), or a pharmaceutically acceptable salt thereof in combination with a vitamin D derivative or analog , in the manufacture of a medicament for use in the prevention or treatment of acne, wherein said vitamin D analog or derivative is applied before the photosensitizer.
- a PS or the metabolic precursor of a PS and a vitamin D derivative or analog are administered to the subject, or are applied to a sample of the subject.
- the invention provides the use of a photosensitizer (PS) which is a derivative of 5-aminolevulinic acid (5-ALA), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the prevention or treatment of acne, wherein said photosensitiser is a compound of general formula I:
- R ** 2 2N-CH 2COCH 2-CH 2CO-OR ** 1 (I) (wherein R ** 1 represents an unsubstituted alkyl group (preferably C 1 -8 alkyl, e.g. C 1 -6 alkyl) or an alkyl group (e.g. C 1 -2 alkyl, especially C 1 alkyl) substituted by an aryl group; and each R ** 2 independently represents a hydrogen atom or an optionally substituted alkyl group).
- the 5-ALA derivatives which are used in accordance with the invention may be capable of forming protoporphyrin IX (PplX) or any other photosensitiser (e.g. a PplX derivative) in vivo.
- PplX protoporphyrin IX
- a PplX derivative e.g. a Pip ester
- Suitable precursors of PplX or PplX derivatives include 5-ALA prodrugs which might be able to form 5-ALA in vivo as an intermediate in the biosynthesis of PplX or which may be converted (e.g. enzymatically) to porphyrins without forming 5-ALA as an intermediate.
- 5-ALA esters are among the preferred compounds for use in the methods herein described.
- Esters of 5-aminolevulinic acid and N-substituted derivatives thereof are used as photosensitisers in the invention.
- Those compounds in which the 5-amino group is unsubstituted i.e. the ALA esters
- Such compounds are generally known and described in the literature (see, for example, W096/28412 and WO02/10120 to PhotoCure ASA, the contents of which are incorporated herein by reference).
- Photosensitisers for use in the invention are compounds of general formula I: R ** 2 2N-CH 2COCH 2-CH 2CO-OR ** 1 (I) wherein R ** 1 represents an unsubstituted alkyl group or an alkyl group substituted by an aryl group; and each R ** 2 independently represents a hydrogen atom or an optionally substituted alkyi group, e.g. a group R ** 1 , and pharmaceutically acceptable salts thereof.
- alkyi includes any long or short chain, cyclic, straight-chained or branched aliphatic saturated or unsaturated hydrocarbon group.
- the unsaturated alkyi groups may be mono- or polyunsaturated and include both alkenyl and alkynyl groups. Unless stated otherwise, such groups may contain up to 40 atoms. However, alkyi groups containing up to 30, preferably up to 10, particularly preferably up to 8, especially preferably up to 6, e.g. up to 4 carbon atoms are preferred.
- the substituted alkyi R ** 1 and R ** 2 groups maybe mono or poly-substituted. Suitable substituents may be selected from hydroxy, alkoxy, acyloxy, alkoxycarbonyloxy, amino, aryl, nitro, oxo, fluoro, -SR 3, -NR ** 3 2 and -PR ** 3 2 groups, and each alkyi group may be optionally interrupted by one or more -0-, -NR 3-, -S-or -PR 3- groups, in which R ** 3 is a hydrogen atom or a C 1 -6 alkyi group).
- Particularly preferred for use in the invention are those compounds of formula I in which at least one R ** 2 represents a hydrogen atom. In especially preferred compounds each R ** 2 represents a hydrogen atom.
- R ** 1 represents an unsubstituted alkyi group (preferably C 1 -8 alkyi, e.g. C 1 -6 alkyi) or more preferably an alkyi group (e.g. C 1 -2 alkyi, especially C 1 alkyi) substituted by an aryl group such as phenyl are also preferred.
- Unsubstituted alkyi groups which may be used in the invention include both branched and straight-chained hydrocarbon groups.
- R ** 1 is a C 4-8, preferably a C 5-8, straight chain alkyi group which is branched by one or more C 1 -6 (e.g. C 1 -2 alkyi) groups are preferred.
- Suitable unsubstituted branched alkyi groups include 2-methylpentyl, 4-methylpentyl, 1 -ethylbutyl and 3,3-dimethyl-1 -butyl. 4-methylpentyl is particularly preferred.
- R ** 1 is a C 1 -10 straight-chained alkyi group
- suitable unsubstituted alkyi groups include methyl, ethyl, propyl, butyl, pentyl, hexyl and octyl (e.g. n-propyl, n-butyl, n-pentyl, n-hexyl and n-octyl).
- Hexyl, especially n-hexyl is a particularly preferred group.
- Methyl is also particularly preferred.
- R ** 1 represents a C 1 -2 alkyl group (preferably a C 1 alkyl group) optionally substituted by an aryl group.
- R ** 1 represents an alkyl group (e.g. C 1 -2 alkyl, especially C 1 alkyl) substituted by an aryl group (e.g. phenyl).
- Preferred substituted alkyl R ** 1 groups which may be present in compounds of formula I include C 1 -6 alkyl, preferably C 1 -4 alkyl, particularly preferably C 1 or C 2 alkyl (e.g. C 1 alkyl) substituted (preferably terminally substituted) by an optionally substituted aryl group.
- an "aryl group” is meant a group which is aromatic.
- Preferred aryl groups comprise up to 20 carbon atoms, more preferably up to 12 carbon atoms, for example, 10 or 6 carbon atoms.
- Aryl groups which may be present in the compounds of the invention may be heteroaromatic (e.g. 5-7 membered heteroaromatics) but are preferably non-heteroaromatic.
- non-heteroaromatic is meant an aryl group having an aromatic system comprising electrons originating solely from carbon atoms.
- Preferred aryl groups include phenyl and napthyl, especially phenyl.
- one or two aryl groups may be present, preferably one.
- the invention provides the use of a photosensitiser which is a compound of formula I wherein R ** 1 represents an aryl substituted C 1 -4 alkyl group (preferably C 1 -2, e.g. C 1 ), preferably wherein said aryl group comprises up to 20 carbon atoms (e.g. up to 12 carbon atoms, especially 6 carbon atoms) and is itself optionally substituted, and each R ** 2 is as hereinbefore defined (e.g. each R ** 2 is hydrogen), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the prevention or treatment of acne.
- R ** 1 represents an aryl substituted C 1 -4 alkyl group (preferably C 1 -2, e.g. C 1 ), preferably wherein said aryl group comprises up to 20 carbon atoms (e.g. up to 12 carbon atoms, especially 6 carbon atoms) and is itself optionally substituted, and each R ** 2 is as hereinbefore defined (e.g. each R ** 2 is hydrogen),
- Aryl groups which may be present in the compounds of the invention may optionally be substituted by one or more (e.g. 1 to 5), more preferably one or two, groups (e.g. one group).
- the aryl group is substituted at the meta or para position, most preferably the para position.
- Suitable substituent groups may include haloalkyl (e.g. trifluoromethyl), alkoxy (i.e. -OR groups wherein R is preferably a C 1 -6 alkyl group), halo (e.g. iodo, bromo, more especially chloro and fluoro), nitro and C 1 -6 alkyl (preferably C 1 -4 alkyl).
- Preferred C 1 -6 alkyl groups include methyl, isopropyl and t-butyl, particularly methyl. Particularly preferred substituent groups include chloro and nitro. Still more preferably the aryl group is unsubstituted.
- Preferred photosensitizer (PS) for use in the invention include methyl ALA ester, ethyl ALA ester, propyl ALA ester, butyl ALA ester, pentyl ALA ester, hexyl ALA ester, octyl ALA ester, 2-methylpentyl ALA ester, 4-methylpentyl ALA ester, 1 -ethylbutyl ALA ester, 3,3-dimethyl-1 -butyl ALA ester, benzyl ALA ester, 4-isopropylbenzyl ALA ester, 4-methylbenzyl ALA ester, 2-methylbenzyl ALA ester, 3-methylbenzyl ALA ester, 4-[t-but
- Still further preferred photosensitizer (PS) for use in the invention include methyl ALA ester, ethyl ALA ester, benzyl ALA ester, 4-isopropylbenzyl ALA ester, 4-methylbenzyl ALA ester, 2-methylbenzyl ALA ester, 3-methylbenzyl ALA ester, 4-[t-butyl]benzyl ALA ester, 4-[trifluoromethyl]benzyl ALA ester, 4-methoxybenzyl ALA ester, 3,4-[di-chloro]benzyl ALA ester, 4-chlorobenzyl ALA ester, 4-fluorobenzyl ALA ester, 2-fluorobenzyl ALA ester, 3-fluorobenzyl ALA ester, 2,3,4,5,6-pentafluorobenzyl ALA ester, 3-nitrobenzyl ALA ester, 4-nitrobenzyl ALA ester, 2-phenylethyl ALA ester, 4-phenyl
- Particularly preferred photosensitizer (PS) for use in the invention include benzyl ALA ester, 4-isopropylbenzyl ALA ester, 4-methylbenzyl ALA ester, 2-methylbenzyl ALA ester, 3-methylbenzyl ALA ester, 4-[t-butyl]benzyl ALA ester, 4-[trifluoromethyl]benzyl ALA ester, 4-methoxybenzyl ALA ester, 3,4-[di-chloro]benzyl ALA ester, 4-chlorobenzyl ALA ester, 4-fluorobenzyl ALA ester, 2-fluorobenzyl ALA ester, 3-fluorobenzyl ALA ester, 2,3,4,5,6-pentafluorobenzyl ALA ester, 3-nitrobenzyl ALA ester, 4-nitrobenzyl ALA ester, 2-phenylethyl ALA ester, 4-phenylbutyl ALA ester, 3-pyridinyl-methyl
- Especially preferred photosensitizer (PS) for use in the methods herein described include benzyl ALA ester, 4-isopropylbenzyl ALA ester and 4-methylbenzyl ALA ester, especially benzyl ALA ester.
- 4-Nitrobenzyl ALA ester, 4-chlorobenzyl ALA ester and benzyl ALA ester are especially preferred.
- the term "acne” includes both inflammatory and non-inflammatory diseases of the pilosebaceous unit. Primarily, however, the methods herein described will be used for treating the more inflammatory types of acne where bacterial invasion of the pilosebaceous unit or follicles has occurred. As previously noted, the precise cause of acne is unknown though it is commonly associated with increased production of sebum (lipids secreted by the androgen-sensitive sebaceous glands), proliferation of bacteria such as Propionibacterium (e.g. P. acnes, P. granulosum and P. avidum), increased turnover of epithelial cells and/or the development of inflammation (e.g. redness, swelling and/or pus).
- the compounds described herein are preferably used for the treatment or prevention (preferably for the treatment) of acne associated with Propionibacterium acnes.
- Acne can manifest itself in a number of different ways (see attached Fig. Figure 1 ).
- Common characteristics of acne include blackheads (comedones) and whiteheads. These are caused by pores becoming clogged (e.g. with sebum and/or dead cells). If the pore stays open, a blackhead results (Fig. Figure 1 (i)), whereas if the pore closes and bulges out a whitehead is produced (Fig. Figure 1 (ii)).
- Papules, pustules and cysts are believed to be produced if the pore wall becomes damaged and bacteria infect the pore. In a papule the pus lies fairly close to the surface of the skin (Fig.
- Acne is categorized into different forms depending, for example, on the nature, severity and/or location of the blackheads, whiteheads, papules, pustules and/or cysts.
- Representative types of acne which may be treated according to the invention include acne vulgaris, acne rosacea, acne conglobate, acne papulosa and premenstrual acne, preferably acne vulgaris which is a chronic inflammatory disease of the pilosebaceous apparatus.
- Acne may occur on the back, chest, upper arms and/or face; the compounds described herein may be used for treating any of these areas of the body, especially the face.
- Certain milder forms of acne may not always be considered to be a "disease" and treatment thereof may be carried out purely for cosmetic reasons. This might be the case, for example, when acne is relatively infrequent and/or not widespread (i.e. few spots occur).
- the invention provides a method of cosmetic treatment of acne (e.g. on the face), said method comprising administering (e.g. topically applying) to an affected site a photosensitiser which is a derivative (e.g. an ester) of 5-aminolevulinic acid (5-ALA) as hereinbefore defined, or a pharmaceutically acceptable salt thereof, and photoactivating said photosensitiser at the affected site.
- a photosensitiser which is a derivative (e.g. an ester) of 5-aminolevulinic acid (5-ALA) as hereinbefore defined, or a pharmaceutically acceptable salt thereof
- the present invention relates to compounds that can be represented by the general formula (II): in which:
- R1 represents a hydrogen atom, a CH 3 radical or a radical - (CH2) r-OR 4,
- R2 represents a radical - (CH2) S-OR5
- r, s, R4 and R5 are as defined below,
- XY is a bond selected from the bonds of formulas (a) to (d) the following can be read from left to right or vice versa (R6 and W have the meanings given below,
- Ar1 represents a cycle of formula (e) (i)
- R7, R8 and R9 are as defined below,
- Ar2 is a cycle of formula (j) (n)
- R3 represents a radical of the formula:
- R and s are the same or different 1 or 2,
- R4 and R5 are identical or different represent a hydrogen atom, an acetyl, a benzoyl radical, a radical trimethylsilyl, tert-butyldimethylsilyl radical or a radical tetrahydropyranyl
- R6 is hydrogen or lower alkyl
- W represents an oxygen, sulfur, a radical or a radical CH2 NH may be substituted with lower alkyl
- R7 and R10 are identical or different represent a hydrogen atom or lower alkyl
- R8, R9, R1 1 and R12 are identical or different represent a hydrogen atom, lower alkyl, halogen, a radical-OR16, a polyether radical, a radical CF3, N02 radical or an amino which may be substituted with one or two lower alkyl radicals,
- T is 0 or 1
- R13 and R14 are identical or different represent a hydrogen atom, lower alkyl, a cycloalkyl group, a CF3 radical or a radical C 2 F5,
- R15 represents a hydrogen atom, an acetyl group, a trimethylsilyl radical, a tert-butyldimethylsilyl radical or a radical tetrahydropyranyl
- R16 represents a hydrogen atom or lower alkyl
- the invention is also the optical and geometric isomers of said compounds of formula (I) and their salts where XY represents a bond of formula (a) and W is a radical-NH-optionally substituted lower alkyl.
- the compounds of the invention are in the form of salts, it is pharmaceutically or cosmetically acceptable salts obtained by addition of an inorganic or organic acid, especially hydrochloric acid, sulfuric acid, fumaric hemisuccinic, maleic and mandelic.
- lower alkyl a linear or branched radical having 1 to 6 carbon atoms, and preferably methyl, ethyl, isopropyl, butyl and hexyl.
- cycloalkyl is meant a cyclic alkane radical containing 3 to 6 carbon atoms.
- the cycloalkyl is selected from cyclopropyl cyclopentyl or cyclohexyl.
- halogen preferably means a fluorine, chlorine or bromine.
- poiyether radical means a radical having from 2 to 5 carbon atoms interrupted by at least two atoms of oxygen radicals, such as methoxymethoxy, methoxyethoxy and methoxyethoxymethoxy.
- the compounds of formula (II) more particularly preferred are those for which at least one and preferably all of the following conditions are met:
- R1 represents the radical CH3 or CH 2 OH
- R2 represents the radical CH 2 OH
- XY is a bond of formula (a) or (c)
- R3 is the radical C (R13) (R14) OH.
- the present invention only relates to compounds, characterized by the fact that they are taken, or in mixtures, in the group consisted:
- the site of the wound is exposed to light to achieve the desired photosensitizing effect.
- the length of time following administration, at which the light exposure takes place will depend on the nature of the composition, the condition to be treated and the form of administration.
- the photosensitizer should reach an effective tissue concentration at the site of the wound prior to photoactivation. This can generally take in the region of from 1 to 24 hours.
- the photosensitizer (s) is/are applied to the wound followed by irradiation after a period of about 3 hours. If necessary, this procedure may be repeated, e. g. up to a further 3 times, at intervals of up to 14 days (e. g. 7-14 days). In those cases where this procedure does not lead to complete healing of the wound, an additional treatment may be performed several months later.
- the irradiation will in general be applied at a dose level of 40 to 200 Joules/cm2, for example at 100 Joules/cm2.
- the wavelength of light used for irradiation may be selected to achieve a more efficacious photosensitizing effect.
- the most effective light is light in the wavelength range 300-800 nm, typically 400-700 nm.
- a further aspect of the invention thus provides a method of treating a wound in a mammal (e. g. a human), said method comprising administering to the site of the wound a composition as hereinbefore defined, and exposing said surface to light, preferably to light in the wavelength region 300-800 nm, for example 400-700 nm.
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Abstract
The invention relates to the use in the field of photodynamic therapy (PDT) of a photosensitizer (PS) combined to the use of a vitamin D analog or derivative for treating acne. Said vitamin d analog or derivative is applied before the PS.
Description
USE OF 5-AMINOLEVULINIC ACID AND ESTERS, IN COMBINATION WITH A VITAMIN D DERIVATIVE OR ANALOG IN PHOTOCHEMOTHERAPY, AND THEIR USES IN TREATING
ACNE
Field of the invention
The invention relates to the use in the field of photodynamic therapy (PDT) of a photosensitizer (PS) combined to the use of a vitamin D analog or derivative for treating acne. Said vitamin d analog or derivative is applied before the PS.
Background of the invention
Acne is one of the most common skin disorders throughout the world.
Although particularly prevalent during puberty, it may continue for many years. It affects approximately 83-95% of 16 year olds of both sexes in the UK and about 20% of sufferers seek help from a clinician. It can in some cases cause permanent scarring and is often the source of considerable emotional distress.
In its milder forms, acne is a superficial disorder which is accompanied by slight, spotty irritations. However, in the more inflammatory types of acne, bacterial invasion of or about the pilosebaceous follicles occurs resulting in the formation of pustules, infected cysts, etc. These lesions may become extensive and often leave permanent, disfiguring scars.
The precise cause of acne is not fully understood although obstruction of the pilosebaceous canal is believed to be a primary factor. This may be caused by overproduction of sebum, increased turnover of epithelial cells and/or the proliferation of bacteria (e.g. Propionibacterium acnes). It is believed, for example, that excess sebum production and increased turnover of epithelial cells may cause clogging or blockage of the skin's pores and lead to formation of comedones (blackheads) and whiteheads. If certain bacteria are present in combination with these factors, inflammatory lesions such papules, pustules and cysts may form.
Blackheads, whiteheads, papules, pustules and cysts are commonly referred to as "spots". Each type of spot may be present to a different degree in any acne sufferer and most commonly a range of different types are found. Spots generally occur on the face and back, especially the facial skin areas (e.g. on the chin, nose and forehead) where sebaceous glands are the largest, most prevalent and most active.
Established treatments of acne are designed to prevent the formation of new lesions and to facilitate the healing of existing lesions. Conventional treatments include, for example, the systemic and topical administration of antibiotics which aim to reduce the bacterial population of the pilosebaceous follicles and the topical application of peroxides, e.g. benzoyl peroxide, which are both anti-bacterial and mildly comedolytic. Vitamin A analogs, such as retinoids, are comedolytic and have also been used with a some degree of success in topical acne treatment compositions.
There are, however, problems emerging with such conventional treatments.
For instance, peroxides such as benzoyl peroxide are often unstable and therefore have limited shelf-life. Their efficacy also tends to decrease over time. Antibiotic resistance of Proprionibacterium acnes is also increasing and this severely reduces efficacy. Retinoid drugs (e.g. isotretinoin), though effective, often cause unpleasant, and sometimes severe, side-effects and contraindications often limit their acceptability and use. There is therefore a need for the development of alternative treatments for acne.
One method which has recently been proposed for the treatment of acne is photodynamic therapy (PDT) using photosensitizing agents. Photodynamic therapy (PDT) is a relatively new technique which has been used in the treatment of various abnormalities or disorders of the skin or other epithelial organs or mucosa, especially cancer or pre-cancerous lesions, as well as certain non-malignant lesions such as psoriasis. PDT involves the administration of photosensitizing agents followed by exposure to photoactivating light in order to activate the photosensitizing agents and convert them into cytotoxic form resulting in the destruction of cells and thus treatment of the disease. Several photosensitizing agents are known and described in the literature, for example various porphyrins psoralens, chlorins, phthalocyanines, as well as 5-aminolevulinic acid (5-ALA) and certain derivatives thereof, e.g. 5-ALA esters.
Although PDT has focused primarily on treatment of cancer and pre-cancerous stages, there are some reports relating to the use of PDT in treating acne.
Such methods, however, have enjoyed only limited success. For example, Itoh, Y. et al. (Brit. J. Dermatology, 2001 , 144, 575-579) and Hongcharau, W. et al. (J. Invest. Dermatology, 2000, 1 15, 183-192) both describe trials on PDT treatment of acne using 5-ALA as a photosensitiser. Both studies conclude that ALA-PDT may be effective for treatment of acne but note that significant adverse effects are associated with the treatment. These include discomfort, burning, itching and stinging during the irradiation, oedematous erythema and epidermal exfoliation shortly after PDT, and prolonged irritation and hypersensitivity to physical stimulation for up to 10 days following
the treatment. Pigmentation was also reported in a number of cases and patients' skin took up to a month to return to normal.
Compared to superficial lesions like actinic keratosis, sebaceous glands are located deeper in the epidermis. To have sufficient PPIX accumulation in sebaceous glands is a key factor for achieving efficient treatment. One reason that PDT faced limited success is due to the fact that, by simply applying a photosensitiser (PS) on the skin before exposing the treated area to blue or red light, do not provide enough PPIX formation in the deeper layer of the skin. Summary of the invention
The invention is based, in part, on the discovery that the application of a vitamin D derivative or analog enhances the production of PPIX within the cells of interest, especially in sebaceous glands.
Accordingly, the invention features a method of treating acne in a subject. The method includes: inducing PPIX formation in deep layer of the skin e.g., by administration of a vitamin D analog or derivative, providing said skin with a photosensitizer (PS); and activating said PS, thereby treating acne lesions.
In an embodiment, the invention relates to a photosensitiser (PS) which is a derivative of 5-aminolevulinic acid (5-ALA), or a pharmaceutically acceptable salt thereof in combination with a vitamin D derivative or analog, for use in the prevention or treatment of acne, wherein said vitamin D analog or derivative is applied before the photosensitizer.
In a preferred embodiment the use of a photosensitiser (PS) which is a derivative of 5-aminolevulinic acid (5-ALA), or a pharmaceutically acceptable salt thereof in combination with a vitamin D derivative or analog , in the manufacture of a medicament for use in the prevention or treatment of acne, wherein said vitamin D analog or derivative is applied before the photosensitizer. In a preferred embodiment, a PS or the metabolic precursor of a PS and a vitamin D derivative or analog are administered to the subject, or are applied to a sample of the subject.
Photosensitisers In preferred embodiments the invention provides the use of a photosensitizer (PS) which is a derivative of 5-aminolevulinic acid (5-ALA), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the prevention or treatment of acne, wherein said
photosensitiser is a compound of general formula I:
R **2 2N-CH 2COCH 2-CH 2CO-OR **1 (I) (wherein R **1 represents an unsubstituted alkyl group (preferably C 1 -8 alkyl, e.g. C 1 -6 alkyl) or an alkyl group (e.g. C 1 -2 alkyl, especially C 1 alkyl) substituted by an aryl group; and each R **2 independently represents a hydrogen atom or an optionally substituted alkyl group).
The use of derivatives of 5-ALA (5-amino-4-oxo-pentanoic acid, otherwise known as 5-aminolevulinic acid) in PDT is well known in the scientific and patent literature (see, for example, J.C. Kennedy et al., J. Clin. Laser Med. Surg. (1996) 14: 289-304, US-A-5,079,262, US-A-5,21 1 ,938, US-A-5,234,940, US-A-5,422,093, US-A-6,034,267, WO91/01727 and W096/28412, the contents of which are incorporated herein by reference). All such derivatives of 5-ALA which are encompassed by general formula I as herein defined and their pharmaceutically acceptable salts are suitable for use in the methods herein described.
The 5-ALA derivatives which are used in accordance with the invention may be capable of forming protoporphyrin IX (PplX) or any other photosensitiser (e.g. a PplX derivative) in vivo. Typically, such derivatives will be a precursor of Pip or of a Pip derivative (e.g. a Pip ester) in the biosynthetic pathway for home and which are therefore capable of inducing an accumulation of Pip at the site of the acne following administration in vivo. Suitable precursors of PplX or PplX derivatives include 5-ALA prodrugs which might be able to form 5-ALA in vivo as an intermediate in the biosynthesis of PplX or which may be converted (e.g. enzymatically) to porphyrins without forming 5-ALA as an intermediate. 5-ALA esters are among the preferred compounds for use in the methods herein described.
Esters of 5-aminolevulinic acid and N-substituted derivatives thereof are used as photosensitisers in the invention. Those compounds in which the 5-amino group is unsubstituted (i.e. the ALA esters) are particularly preferred. Such compounds are generally known and described in the literature (see, for example, W096/28412 and WO02/10120 to PhotoCure ASA, the contents of which are incorporated herein by reference).
Photosensitisers for use in the invention are compounds of general formula I: R **2 2N-CH 2COCH 2-CH 2CO-OR **1 (I) wherein R **1 represents an unsubstituted alkyl group or an alkyl group substituted by an aryl
group; and each R **2 independently represents a hydrogen atom or an optionally substituted alkyi group, e.g. a group R **1 , and pharmaceutically acceptable salts thereof.
As used herein, the term "alkyi", unless stated otherwise, includes any long or short chain, cyclic, straight-chained or branched aliphatic saturated or unsaturated hydrocarbon group. The unsaturated alkyi groups may be mono- or polyunsaturated and include both alkenyl and alkynyl groups. Unless stated otherwise, such groups may contain up to 40 atoms. However, alkyi groups containing up to 30, preferably up to 10, particularly preferably up to 8, especially preferably up to 6, e.g. up to 4 carbon atoms are preferred.
The substituted alkyi R **1 and R **2 groups maybe mono or poly-substituted. Suitable substituents may be selected from hydroxy, alkoxy, acyloxy, alkoxycarbonyloxy, amino, aryl, nitro, oxo, fluoro, -SR 3, -NR **3 2 and -PR **3 2 groups, and each alkyi group may be optionally interrupted by one or more -0-, -NR 3-, -S-or -PR 3- groups, in which R **3 is a hydrogen atom or a C 1 -6 alkyi group).
Particularly preferred for use in the invention are those compounds of formula I in which at least one R **2 represents a hydrogen atom. In especially preferred compounds each R **2 represents a hydrogen atom.
Compounds of formula I in which R **1 represents an unsubstituted alkyi group (preferably C 1 -8 alkyi, e.g. C 1 -6 alkyi) or more preferably an alkyi group (e.g. C 1 -2 alkyi, especially C 1 alkyi) substituted by an aryl group such as phenyl are also preferred. Unsubstituted alkyi groups which may be used in the invention include both branched and straight-chained hydrocarbon groups. Compounds of formula I in which R **1 is a C 4-8, preferably a C 5-8, straight chain alkyi group which is branched by one or more C 1 -6 (e.g. C 1 -2 alkyi) groups are preferred. Representative examples of suitable unsubstituted branched alkyi groups include 2-methylpentyl, 4-methylpentyl, 1 -ethylbutyl and 3,3-dimethyl-1 -butyl. 4-methylpentyl is particularly preferred.
Compounds of formula I in which R **1 is a C 1 -10 straight-chained alkyi group are also preferred. Representative examples of suitable unsubstituted alkyi groups include methyl, ethyl, propyl, butyl, pentyl, hexyl and octyl (e.g. n-propyl, n-butyl, n-pentyl, n-hexyl and n-octyl). Hexyl, especially n-hexyl, is a particularly preferred group. Methyl is also particularly preferred.
Particularly preferred for use in the invention are those compounds of formula I in which R **1
represents a C 1 -2 alkyl group (preferably a C 1 alkyl group) optionally substituted by an aryl group.
Still further preferred for use in the invention are those compounds of formula I in which R **1 represents an alkyl group (e.g. C 1 -2 alkyl, especially C 1 alkyl) substituted by an aryl group (e.g. phenyl). Preferred substituted alkyl R **1 groups which may be present in compounds of formula I include C 1 -6 alkyl, preferably C 1 -4 alkyl, particularly preferably C 1 or C 2 alkyl (e.g. C 1 alkyl) substituted (preferably terminally substituted) by an optionally substituted aryl group. By an "aryl group" is meant a group which is aromatic. Preferred aryl groups comprise up to 20 carbon atoms, more preferably up to 12 carbon atoms, for example, 10 or 6 carbon atoms.
Aryl groups which may be present in the compounds of the invention may be heteroaromatic (e.g. 5-7 membered heteroaromatics) but are preferably non-heteroaromatic. By "non-heteroaromatic" is meant an aryl group having an aromatic system comprising electrons originating solely from carbon atoms. Preferred aryl groups include phenyl and napthyl, especially phenyl. In preferred compounds for use in the invention one or two aryl groups may be present, preferably one.
In a preferred aspect the invention provides the use of a photosensitiser which is a compound of formula I wherein R **1 represents an aryl substituted C 1 -4 alkyl group (preferably C 1 -2, e.g. C 1 ), preferably wherein said aryl group comprises up to 20 carbon atoms (e.g. up to 12 carbon atoms, especially 6 carbon atoms) and is itself optionally substituted, and each R **2 is as hereinbefore defined (e.g. each R **2 is hydrogen), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the prevention or treatment of acne.
Aryl groups which may be present in the compounds of the invention may optionally be substituted by one or more (e.g. 1 to 5), more preferably one or two, groups (e.g. one group). Preferably the aryl group is substituted at the meta or para position, most preferably the para position. Suitable substituent groups may include haloalkyl (e.g. trifluoromethyl), alkoxy (i.e. -OR groups wherein R is preferably a C 1 -6 alkyl group), halo (e.g. iodo, bromo, more especially chloro and fluoro), nitro and C 1 -6 alkyl (preferably C 1 -4 alkyl). Preferred C 1 -6 alkyl groups include methyl, isopropyl and t-butyl, particularly methyl. Particularly preferred substituent groups include chloro and nitro. Still more preferably the aryl group is unsubstituted. Preferred photosensitizer (PS) for use in the invention include methyl ALA ester, ethyl ALA ester, propyl ALA ester, butyl ALA ester, pentyl ALA ester, hexyl ALA ester, octyl ALA ester, 2-methylpentyl ALA ester, 4-methylpentyl ALA ester, 1 -ethylbutyl ALA ester, 3,3-dimethyl-1 -butyl
ALA ester, benzyl ALA ester, 4-isopropylbenzyl ALA ester, 4-methylbenzyl ALA ester, 2-methylbenzyl ALA ester, 3-methylbenzyl ALA ester, 4-[t-butyl]benzyl ALA ester, 4-[trifluoromethyl]benzyl ALA ester, 4-methoxybenzyl ALA ester, 3,4-[di-chloro]benzyl ALA ester, 4-chlorobenzyl ALA ester, 4-fluorobenzyl ALA ester, 2-fluorobenzyl ALA ester, 3-fluorobenzyl ALA ester, 2,3,4,5,6-pentafluorobenzyl ALA ester, 3-nitrobenzyl ALA ester, 4-nitrobenzyl ALA ester, 2-phenylethyl ALA ester, 4-phenylbutyl ALA ester, 3-pyridinyl-methyl ALA ester, 4-diphenyl-methyl ALA ester and benzyl-5-[(1 -acetyloxyethoxy)-carbonyl]amino levulinate.
Still further preferred photosensitizer (PS) for use in the invention include methyl ALA ester, ethyl ALA ester, benzyl ALA ester, 4-isopropylbenzyl ALA ester, 4-methylbenzyl ALA ester, 2-methylbenzyl ALA ester, 3-methylbenzyl ALA ester, 4-[t-butyl]benzyl ALA ester, 4-[trifluoromethyl]benzyl ALA ester, 4-methoxybenzyl ALA ester, 3,4-[di-chloro]benzyl ALA ester, 4-chlorobenzyl ALA ester, 4-fluorobenzyl ALA ester, 2-fluorobenzyl ALA ester, 3-fluorobenzyl ALA ester, 2,3,4,5,6-pentafluorobenzyl ALA ester, 3-nitrobenzyl ALA ester, 4-nitrobenzyl ALA ester, 2-phenylethyl ALA ester, 4-phenylbutyl ALA ester, 3-pyridinyl-methyl ALA ester, 4-diphenyl-methyl ALA ester and benzyl-5-[(1 -acctyloxyethoxy)-carbonyl]amino levulinate
Particularly preferred photosensitizer (PS) for use in the invention include benzyl ALA ester, 4-isopropylbenzyl ALA ester, 4-methylbenzyl ALA ester, 2-methylbenzyl ALA ester, 3-methylbenzyl ALA ester, 4-[t-butyl]benzyl ALA ester, 4-[trifluoromethyl]benzyl ALA ester, 4-methoxybenzyl ALA ester, 3,4-[di-chloro]benzyl ALA ester, 4-chlorobenzyl ALA ester, 4-fluorobenzyl ALA ester, 2-fluorobenzyl ALA ester, 3-fluorobenzyl ALA ester, 2,3,4,5,6-pentafluorobenzyl ALA ester, 3-nitrobenzyl ALA ester, 4-nitrobenzyl ALA ester, 2-phenylethyl ALA ester, 4-phenylbutyl ALA ester, 3-pyridinyl-methyl ALA ester, 4-diphenyl-methyl ALA ester and benzyl-5-[(1 -acetyloxyethoxy)-carbonyl]amino levulinate.
Especially preferred photosensitizer (PS) for use in the methods herein described include benzyl ALA ester, 4-isopropylbenzyl ALA ester and 4-methylbenzyl ALA ester, especially benzyl ALA ester. 4-Nitrobenzyl ALA ester, 4-chlorobenzyl ALA ester and benzyl ALA ester are especially preferred.
Acne
As used herein, the term "acne" includes both inflammatory and non-inflammatory diseases of the pilosebaceous unit. Primarily, however, the methods herein described will be used for treating the more inflammatory types of acne where bacterial invasion of the pilosebaceous unit or follicles has occurred. As previously noted, the precise cause of acne is unknown though it is
commonly associated with increased production of sebum (lipids secreted by the androgen-sensitive sebaceous glands), proliferation of bacteria such as Propionibacterium (e.g. P. acnes, P. granulosum and P. avidum), increased turnover of epithelial cells and/or the development of inflammation (e.g. redness, swelling and/or pus). The compounds described herein are preferably used for the treatment or prevention (preferably for the treatment) of acne associated with Propionibacterium acnes.
Acne can manifest itself in a number of different ways (see attached Fig. Figure 1 ). Common characteristics of acne include blackheads (comedones) and whiteheads. These are caused by pores becoming clogged (e.g. with sebum and/or dead cells). If the pore stays open, a blackhead results (Fig. Figure 1 (i)), whereas if the pore closes and bulges out a whitehead is produced (Fig. Figure 1 (ii)). Papules, pustules and cysts are believed to be produced if the pore wall becomes damaged and bacteria infect the pore. In a papule the pus lies fairly close to the surface of the skin (Fig. Figure 1 (iii)) whereas in a pustule the pus is present deeper inside the pore (Fig. Figure 1 (iv)). Cysts are generally larger and deeper than pustules and contain large amounts of pus. The compounds described herein may be used for the treatment or prevention of one or more of the following: blackheads, whiteheads, papules, pustules and cysts.
Acne is categorized into different forms depending, for example, on the nature, severity and/or location of the blackheads, whiteheads, papules, pustules and/or cysts. Representative types of acne which may be treated according to the invention include acne vulgaris, acne rosacea, acne conglobate, acne papulosa and premenstrual acne, preferably acne vulgaris which is a chronic inflammatory disease of the pilosebaceous apparatus. Acne may occur on the back, chest, upper arms and/or face; the compounds described herein may be used for treating any of these areas of the body, especially the face.
Certain milder forms of acne (e.g. blackheads and/or whiteheads) may not always be considered to be a "disease" and treatment thereof may be carried out purely for cosmetic reasons. This might be the case, for example, when acne is relatively infrequent and/or not widespread (i.e. few spots occur).
Thus, viewed from a further aspect the invention provides a method of cosmetic treatment of acne (e.g. on the face), said method comprising administering (e.g. topically applying) to an affected site a photosensitiser which is a derivative (e.g. an ester) of 5-aminolevulinic acid (5-ALA) as hereinbefore defined, or a pharmaceutically acceptable salt thereof, and photoactivating said photosensitiser at the affected site.
Vitamin D derivative or analog
In another embodiment the present invention relates to compounds that can be represented by the general formula (II): in which:
in which:
R1 represents a hydrogen atom, a CH 3 radical or a radical - (CH2) r-OR 4,
R2 represents a radical - (CH2) S-OR5
r, s, R4 and R5 are as defined below,
XY is a bond selected from the bonds of formulas (a) to (d) the following can be read from left to right or vice versa (R6 and W have the meanings given below,
Ar1 represents a cycle of formula (e) (i)
R7, R8 and R9 are as defined below,
Ar2 is a cycle of formula (j) (n)
R10, R1 1 and R12 having the meanings given below,
R3 represents a radical of the formula:
R and s are the same or different 1 or 2,
R4 and R5 are identical or different represent a hydrogen atom, an acetyl, a benzoyl radical, a radical trimethylsilyl, tert-butyldimethylsilyl radical or a radical tetrahydropyranyl
R6 is hydrogen or lower alkyl,
W represents an oxygen, sulfur, a radical or a radical CH2 NH may be substituted with lower alkyl,
R7 and R10 are identical or different represent a hydrogen atom or lower alkyl,
R8, R9, R1 1 and R12 are identical or different represent a hydrogen atom, lower alkyl, halogen, a radical-OR16, a polyether radical, a radical CF3, N02 radical or an amino which may be substituted with one or two lower alkyl radicals,
R16 having the meanings given below,
T is 0 or 1
R13 and R14 are identical or different represent a hydrogen atom, lower alkyl, a cycloalkyl group, a CF3 radical or a radical C 2 F5,
R15 represents a hydrogen atom, an acetyl group, a trimethylsilyl radical, a tert-butyldimethylsilyl radical or a radical tetrahydropyranyl
R16 represents a hydrogen atom or lower alkyl,
The invention is also the optical and geometric isomers of said compounds of formula (I) and their salts where XY represents a bond of formula (a) and W is a radical-NH-optionally substituted lower alkyl.
When the compounds of the invention are in the form of salts, it is pharmaceutically or
cosmetically acceptable salts obtained by addition of an inorganic or organic acid, especially hydrochloric acid, sulfuric acid, fumaric hemisuccinic, maleic and mandelic.
According to the present invention, the term lower alkyl, a linear or branched radical having 1 to 6 carbon atoms, and preferably methyl, ethyl, isopropyl, butyl and hexyl.
By cycloalkyl is meant a cyclic alkane radical containing 3 to 6 carbon atoms. Preferably, the cycloalkyl is selected from cyclopropyl cyclopentyl or cyclohexyl.
By halogen, preferably means a fluorine, chlorine or bromine.
By poiyether radical, means a radical having from 2 to 5 carbon atoms interrupted by at least two atoms of oxygen radicals, such as methoxymethoxy, methoxyethoxy and methoxyethoxymethoxy.
According to the present invention, the compounds of formula (II) more particularly preferred are those for which at least one and preferably all of the following conditions are met:
R1 represents the radical CH3 or CH 2 OH,
R2 represents the radical CH 2 OH,
XY is a bond of formula (a) or (c)
R3 is the radical C (R13) (R14) OH.
Thus, the present invention only relates to compounds, characterized by the fact that they are taken, or in mixtures, in the group consisted:
-1 (1 R,3S) - 5 - [2 - [(1 R,3aR,7aS) - 1 - [(2R) - 6 - hydroxyl - 6 - methyl - heptan - 2 - yl] - 7a - methyl - 2, 3, 3a, 5, 6, 7 - hexahydro - 1 H - inden - 4 - ylidene]ethylidene] - 4 - methylidene - cyclohexane - 1 ,3-diol
-2 (1 R,3S,5E) - 5 - {2 - [(1 R,3aS,4Z,7aR) - 1 - [(2R,3E) - 5 - cyclopropyl - 5 - hydroxypent - 3 - en - 2 - yl] - 7a - methyl - octahydro - 1 H - inden - 4 - ylidene]ethylidene} - 4 - methylidenecyclohexane - 1 ,3 - diol
- 3 {5 [4 ' - (1 -Ethyl-1 -hydroxypropyl) - 6-methyl-2'-propylbiphenyl-3-yloxymethyl] - 2-hydroxymethylphenyl} methanol;
4 {5 [6.2 ' - Diethyl-4'- (1 -ethyl-1-hydroxypropyl) biphenyl-3-yloxymethyl] 2-hydroxymethyl-phenyl} methanol;
- 5 {4 [6-Ethyl-4'- (1 -ethyl-1 -hydroxypropyl) - 2 ' - propylbiphenyl-3-yloxymethyl] - 2-hydroxymethylphenyl} methanol;
- 6 {4 [6-Ethyl-4'- (1 -ethyl-1 -hydroxypropyl) - 2 ' - isopropylbiphenyl-3-yloxymethyl] - 2-hydroxymethylphenyl} methanol;
- 7 (4 {2 [4 ' - (1 -Ethyl-1 -hydroxypropyl) - 6-methyl-2'-propylbiphenyl-3-yl] ethyl} - 2-hydroxymethylphenyl) methanol;
- 8 {4 [4 ' - (1 -Ethyl-1 -hydroxypropyl) - 6-methyl-2'-propylbiphenyl-3-ylmethoxy] -
2-hydroxymethylphenyl} methanol;
- 9 (4 {[4 ' - (1 -Ethyl-1 -hydroxypropyl) - 6-methyl-2'-propylbiphenyl-3-ylamino] methyl} - 2-hydroxymethylphenyl) methanol;
- 10 [4 ({[4 ' - (1 -Ethyl-1 -hydroxypropyl) - 6-methyl-2'-propylbiphenyl-3-yl] methylamino} methyl) - 2-hydroxymethylphenyl] methanol;
- 1 1 [4 ({Ethyl- [4 ' - (1 -ethyl-1 -hydroxypropyl) - 6-methyl-2'-propylbiphenyl-3-yl] amino} methyl) - 2-hydroxymethylphenyl] methanol;
- 12-4- ({[4 ' - (1 -Ethyl-1 -hydroxypropyl) - 6-methyl-2'-propylbiphenyl-3-yl] propylamino} methyl) - 2-hydroxymethylphenyl] methanol;
- 13 (2-Hydroxymethyl-4- {2 [6-methyl-2'-propyl-4'
(2, 2, 2-trifluoro-1 -hydroxy-1 -trifluoromethyl-ethyl) biphenyl-3-yl] ethyl} phenyl) methanol;
- 14 {2-Hydroxymethyl-4- [6-methyl-2'-propyl-4' (2,2,2-trifluoro-1 -hydroxy-1 -trifluoromethyl-ethyl) biphenyl-3-yloxymethyl] phenyl} methanol;
- 15 {2-Hydroxymethyl-4- [6-methyl-2'-propyl-4' (2,2,2-trifluoro-1 -hydroxy-1 -trifluoromethyl-ethyl) biphenyl-3-ylmethoxylphenyl} methanol;
- 16 (2-Hydroxymethyl-4- {[6-methyl-2'-propyl-4' (2,2,2-trifluoro-1 -hydroxy-1 -trifluoromethyl-ethyl) biphenyl-3-ylamino] methyl} phenyl) methanol;
17 [2-Hydroxymethyl-4- ({N-Methyl [6-methyl-2'-propyl-4'
(2,2,2-trifluoro-1 -hydroxy-1 -trifluoromethyl-ethyl) biphenyl-3-yl] amino} methyl) phenyl] methanol; - 18 [4 ({N-Ethyl [6-methyl-2'-propyl-4' (2,2,2-trifluoro-1 -hydroxy-1 -trifluoromethylethyl) biphenyl-3-yl] amino} methyl) - 2-hydroxymethylphenyl] methanol;
- 19 [2-Hydroxymethyl-4- ({[6-methyl-2'-propyl-4' (2,2,2-trifluoro-1 -hydroxy-1 -trifluoromethyl-ethyl) biphenyl-3-yl] N-propyl-amino} methyl) phenyl] methanol;
- 20 (4 {2 [6-Ethyl-4'- (1 -ethyl-1 -hydroxypropyl) - 2 ' propylbiphenyl-3-yl] ethyl} - 2-hydroxymethylphenyl) methanol;
- 21 {4 [6-Ethyl-4 - (1 -ethyl-1 -hydroxypropyl) - 2 ' - propylbiphenyl-3-ylmethoxy] - 2-hydroxymethylphenyl} methanol;
- 22 (4 {[6-Ethyl-4 - (1 -ethyl-1 -hydroxypropyl) - 2 ' - propylbiphenyl-3-ylamino] methy} - 2-hydroxymethylphenyl) methanol;
- 23 [4 ({[6-Ethyl-4'- (1 -ethyl-1 -hydroxypropyl) - 2 ' - propylbiphenyl-3-yl] methylamino} methyl) - 2-hydroxymethylphenyl] methanol;
- 24 [4 ({Ethyl- [6-ethyl-4 - (1 -ethyl-1 -hydroxypropyl) - 2 ' - propylbiphenyl-3-yl] amino} methyl) - 2-hydroxymethylphenyl] methanol;
- 25 [4 ({[6-Ethyl-4 - (1 -ethyl-1 -hydroxypropyl) - 2 ' - propylbiphenyl-3-yl] propylamino} methyl) - 2-hydroxymethylphenyl] methanol;
- 26 (4 {2 [6-Ethyl-2'-propyl-4'- (2,2,2-trifluoro-1 -hydroxy-1 -trifluoromethylethyl) biphenyl-3-yl] ethyl} - 2-hydroxymethylphenyl) methanol;
27- {4 [6-Ethyl-2'-propyl-4'- (2,2,2-trifluoro-l -hydroxy-l -trifluoromethyl-ethyl) biphenyl-3-yloxymethyl] - 2-hydroxymethylphenyl} methanol;
28- {4 [6-Ethyl-2'-propyl-4'- (2,2,2-trifluoro-1 -hydroxy-1 -trifluoromethyl-ethyl) biphenyl-3-ylmethoxy] - 2-hydroxymethylphenyl} methanol;
- 29- (4 {[6-Ethyl-2'-propyl-4'- (2,2,2-trifluoro-1 -hydroxy-1 -trifluoromethyl-ethyl) biphenyl-3-ylamino] methyl} - 2-hydroxymethylphenyl) methanol;
- 30- [4 ({[6-Ethyl-2'-propyl-4'- (2,2,2-trifluoro-1 -hydroxy-1 -trifluoromethyl-ethyl) biphenyl-3-yl] methylamino} methyl) - 2-hydroxymethylphenyl] methanol;
- 31 - [4 ({N-Ethyl [6-ethyl-2'=propyl-4'- (2,2,2-trifluoro-1 -hydroxy-1 -trifluoromethylethyl) biphenyl-3-yl] amino} methyl) - 2-hydroxymethylphenyl] methanol;
- 32 [4 ({[6-Ethyl-2'-propyl-4'- (2,2,2-trifluoro-1 -hydroxy-1 -trifluoromethyl-ethyl) biphenyl-3-yl] - N-propyl-amino} methyl) - 2-hydroxymethylphenyl] methanol;
- 33- (4 {[4 ' - (1 -Ethyl-1 -hydroxypropyl) - 6.2 ' - dimethylbiphenyl-3-ylamino] methyl} - 2-hydroxymethylphenyl) methanol.
Photodynamic therapy
After administration of a pharmaceutical formulation containing the photosensitizer (s), with or without removing the pharmaceutical formulation containing the vitamin D derivative or analog, the site of the wound is exposed to light to achieve the desired photosensitizing effect. The length of time following administration, at which the light exposure takes place will depend on the nature of the composition, the condition to be treated and the form of administration.
Generally, it is necessary that the photosensitizer should reach an effective tissue concentration at the site of the wound prior to photoactivation. This can generally take in the region of from 1 to 24 hours.
In a preferred treatment procedure, the photosensitizer (s) is/are applied to the wound followed by irradiation after a period of about 3 hours. If necessary, this procedure may be repeated, e. g. up to a further 3 times, at intervals of up to 14 days (e. g. 7-14 days). In those cases where this procedure does not lead to complete healing of the wound, an additional treatment may be performed several months later.
The irradiation will in general be applied at a dose level of 40 to 200 Joules/cm2, for example at 100 Joules/cm2.
The wavelength of light used for irradiation may be selected to achieve a more efficacious
photosensitizing effect. The most effective light is light in the wavelength range 300-800 nm, typically 400-700 nm.
A further aspect of the invention thus provides a method of treating a wound in a mammal (e. g. a human), said method comprising administering to the site of the wound a composition as hereinbefore defined, and exposing said surface to light, preferably to light in the wavelength region 300-800 nm, for example 400-700 nm.
Methods for irradiation of different areas of the body, eg. by lamps or lasers are well known in the art (see for example Van den Bergh, Chemistry in Britain, May 1986 p. 430-439). For inaccessible regions this may conveniently be achieved using optical fibers.
Claims
Claims:
1 . A photosensitiser which is a derivative of 5-aminolevulinic acid (5-ALA), or a pharmaceutically acceptable salt thereof, in combination with a vitamin D derivative or analog, for use in the prevention or treatment of acne, wherein said vitamin D analog or derivative is applied before the photosensitizer.
2. The photosensitizer for use as claimed in claim 1 , wherein said photosensitiser is a compound of general formula I: R **2 2N-CH 2COCH 2CH 2CO-OR **1 (I) wherein R **1 represents an unsubstituted alkyl group or an alkyl group substituted by an aryl group; and each R **2 independently represents a hydrogen atom or an optionally substituted alkyl group.
3. The photosensitizer for use as claimed in claim 1 , wherein in formula I, R **1 represents an unsubstituted C 1 -8 alkyl group (e.g. C 1 -6 alkyl) or a C 1 -2 alkyl group (especially C 1 alkyl) substituted by an aryl group.
4. The photosensitizer for use as claimed in claim 1 or claim 2, wherein in formula I each R **2 represents a hydrogen atom.
5. The photosensitizer for use as claimed in any one of claims 1 to 3, wherein in formula I, R **1 represents a C 1 -2 alkyl group (preferably a C 1 alkyl group) optionally substituted by an aryl group.
6. The photosensitizer for use as claimed in claim 4, wherein said compound is selected from methyl ALA ester, benzyl ALA ester or substituted benzyl ALA ester.
7. The photosensitizer for use as claimed in any one of claims 1 to 3, wherein in formula I, R **1 represents an alkyl group (e.g. C 1 -2 alkyl, especially C 1 ) substituted by an aryl group (e.g. phenyl).
8. The photosensitizer for use as claimed in any one of claims 1 to 3, wherein in formula I, R **1 represents an aryl substituted C 1 -4 alkyl group (preferably C 1 -2 alkyl, e.g. C 1 alkyl), preferably wherein said aryl group comprises up to 20 carbon atoms (e.g. up to 12 carbon atoms) and is itself optionally substituted, and each R **2 is as defined in claim 1 (e.g. each R **2 is hydrogen).
9. The photosensitizer for use as claimed in claim 8, wherein said compound is selected from benzyl ALA ester, 4-isopropylbenzyl ALA ester, 4-methylbenzyl ALA ester, 2-methylbenzyl ALA ester, 3-methylbenzyl ALA ester, 4-[t-butyl]benzyl ALA ester, 4-[trifluoromethyl]benzyl
ALA ester, 4-methoxybenzyl ALA ester, 3,4-[di-chloro]benzyl ALA ester, 4-chlorobenzyl ALA ester, 4-fluorobenzyl ALA ester, 2-fluorobenzyl ALA ester, 3-fluorobenzyl ALA ester,
2,3,4,5,6-pentafluorobenzyl ALA ester, 3-nitrobenzyl ALA ester, 4-nitrobenzyl ALA ester, 2-phenylethyl ALA ester, 4-phenylbutyl ALA ester, 3-pyridinyl-methyl ALA ester, 4-diphenyl-methyl ALA ester and benzyl-5-[(1 -acetyloxyethoxy)-carbonyl]amino levulinate.
10. The photosensitizer for use as claimed in claim 9, wherein said compound is selected from methyl ALA ester, ethyl ALA ester, propyl ALA ester, butyl ALA ester, pentyl ALA ester, hexyl ALA ester, octyl ALA ester, 2-methylpentyl ALA ester, 4-methylpentyl ALA ester, 1 -ethylbutyl ALA ester, 3,3-dimethyl-1 -butyl ALA ester.
1 1 . The photosensitizer for use as claimed in claim 1 , wherein said vitamin D derivative or analog
is a compound of general formula II: (II)
in which R1 represents a hydrogen atom, a CH3 radical or a radical - (CH2) r-OR 4,
R2 represents a radical - (CH2) S-OR5
r, s, R4 and R5 are as defined below,
XY is a bond selected from the bonds of formulas (a) to (d) the following can be read from left to right or vice versa (R6 and W have the meanings given below,
Ar1 represents a cycle of formula (e) (i)
R10, R1 1 and R12 having the meanings given below,
R3 represents a radical of the formula:
t, R13, R14 and R15 having the meanings given below,
R and s are the same or different 1 or 2,
R4 and R5 are identical or different represent a hydrogen atom, an acetyl, a benzoyl radical, a radical trimethylsilyl, tert-butyldimethylsilyl radical or a radical tetrahydropyranyl
R6 is hydrogen or lower alkyl,
W represents an oxygen, sulfur, a radical or a radical CH2 NH may be substituted with lower alkyl,
R7 and R10 are identical or different represent a hydrogen atom or lower alkyl,
R8, R9, R1 1 and R12 are identical or different represent a hydrogen atom, lower alkyl, halogen, a radical-OR16, a polyether radical, a radical CF3, N02 radical or an amino which may be substituted with one or two lower alkyl radicals,
R16 having the meanings given below,
T is 0 or 1
R13 and R14 are identical or different represent a hydrogen atom, lower alkyl, a cycloalkyl group, a CF3 radical or a radical C 2 F5,
R15 represents a hydrogen atom, an acetyl group, a trimethylsilyl radical, a tert-butyldimethylsilyl radical or a radical tetrahydropyranyl
R16 represents a hydrogen atom or lower alkyl.
2. The photosensitizer for use as claimed in claim 1 , wherein the vitamin D derivative or analog of formula II in which R1 represents the radical CH 3 or CH 2 OH, R2 represents the radical CH 2 OH, XY is a bond of formula (a) or (c) R3 is the radical C (R13) (R14) OH
3. The photosensitizer for use as claimed in claim 1 , wherein the vitamin D analog or derivative is selected from the list: -1 (1 R,3S) - 5 - [2 - [(1 R,3aR,7aS) - 1 - [(2R) - 6 - hydroxyl - 6 - methyl - heptan - 2 - yl] - 7a - methyl - 2, 3, 3a, 5, 6, 7 - hexahydro - 1 H - inden - 4 - ylidene]ethylidene] - 4 - methylidene - cyclohexane - 1 ,3-diol
-2 (1 R,3S,5E) - 5 - {2 - [(1 R,3aS,4Z,7aR) - 1 - [(2R,3E) - 5 - cyclopropyl - 5 - hydroxypent - 3 - en - 2 - yl] - 7a - methyl - octahydro - 1 H - inden - 4 - ylidene]ethylidene} - 4 - methylidenecyclohexane - 1 ,3 - diol
- 3 {5 [4 ' - (1 -Ethyl-1 -hydroxypropyl) - 6-methyl-2'-propylbiphenyl-3-yloxymethyl] - 2-hydroxymethylphenyl} methanol;
- 4 {5 [6.2 ' - Diethyl-4'- (1 -ethyl-1 -hydroxypropyl) biphenyl-3-yloxymethyl] - 2-hydroxymethyl-phenyl} methanol;
- 5 {4 [6-Ethyl-4'- (1 -ethyl-1 -hydroxypropyl) - 2 ' - propylbiphenyl-3-yloxymethyl] - 2-hydroxymethylphenyl} methanol;
- 6 {4 [6-Ethyl-4'- (1 -ethyl-1 -hydroxypropyl) - 2 ' - isopropylbiphenyl-3-yloxymethyl] - 2-hydroxymethylphenyl} methanol;
- 7 (4 {2 [4 ' - (1 -Ethyl-1 -hydroxypropyl) - 6-methyl-2'-propylbiphenyl-3-yl] ethyl} -
2-hydroxymethylphenyl) methanol;
- 8 {4 [4 ' - (1 -Ethyl-1 -hydroxypropyl) - 6-methyl-2'-propylbiphenyl-3-ylmethoxy] - 2-hydroxymethylphenyl} methanol;
- 9 (4 {[4 ' - (1 -Ethyl-1 -hydroxypropyl) - 6-methyl-2'-propylbiphenyl-3-ylamino] methyl} - 2-hydroxymethylphenyl) methanol;
- 10 [4 ({[4 ' - (1 -Ethyl-1 -hydroxypropyl) - 6-methyl-2'-propylbiphenyl-3-yl] methylamino} methyl) - 2-hydroxymethylphenyl] methanol;
- 1 1 [4 ({Ethyl- [4 ' - (1 -ethyl-1 -hydroxypropyl) - 6-methyl-2'-propylbiphenyl-3-yl] amino} methyl) - 2-hydroxymethylphenyl] methanol;
- 12-4- ({[4 ' - (1 -Ethyl-1 -hydroxypropyl) - 6-methyl-2'-propylbiphenyl-3-yl] propylamino} methyl) - 2-hydroxymethylphenyl] methanol;
13 (2-Hydroxymethyl-4- {2 [6-methyl-2'-propyl-4'
(2, 2, 2-trifluoro-1 -hydroxy-1 -trifluoromethyl-ethyl) biphenyl-3-yl] ethyl} phenyl) methanol;
14 {2-Hydroxymethyl-4- [6-methyl-2'-propyl-4' (2,2,2-trifluoro-1 -hydroxy-1 -trifluoromethyl-ethyl) biphenyl-3-yloxymethyl] phenyl} methanol;
15 {2-Hydroxymethyl-4- [6-methyl-2'-propyl-4' (2,2,2-trifluoro-1 -hydroxy-1 -trifluoromethyl-ethyl) biphenyl-3-ylmethoxylphenyl} methanol;
16 (2-Hydroxymethyl-4- {[6-methyl-2'-propyl-4' (2,2,2-trifluoro-1 -hydroxy-1 -trifluoromethyl-ethyl) biphenyl-3-ylamino] methyl} phenyl) methanol;
17 [2-Hydroxymethyl-4- ({N-Methyl [6-methyl-2'-propyl-4'
(2,2,2-trifluoro-1 -hydroxy-1 -trifluoromethyl-ethyl) biphenyl-3-yl] amino} methyl) phenyl] methanol;
- 18 [4 ({N-Ethyl [6-methyl-2'-propyl-4' (2,2,2-trifluoro-1 -hydroxy-1 -trifluoromethylethyl) biphenyl-3-yl] amino} methyl) - 2-hydroxymethylphenyl] methanol;
19 [2-Hydroxymethyl-4- ({[6-methyl-2'-propyl-4'
(2,2,2-trifluoro-1 -hydroxy-1 -trifluoromethyl-ethyl) biphenyl-3-yl] N-propyl-amino} methyl) phenyl] methanol;
- 20 (4 {2 [6-Ethyl-4'- (1 -ethyl-1 -hydroxypropyl) - 2 ' propylbiphenyl-3-yl] ethyl} - 2-hydroxymethylphenyl) methanol;
- 21 {4 [6-Ethyl-4'- (1 -ethyl-1 -hydroxypropyl) - 2 ' - propylbiphenyl-3-ylmethoxy] - 2-hydroxymethylphenyl} methanol;
- 22 (4 {[6-Ethyl-4'- (1 -ethyl-1 -hydroxypropyl) - 2 ' - propylbiphenyl-3-ylamino] methy} - 2-hydroxymethylphenyl) methanol;
- 23 [4 ({[6-Ethyl-4'- (1 -ethyl-1 -hydroxypropyl) - 2 ' - propylbiphenyl-3-yl] methylamino} methyl)
- 2-hydroxymethylphenyl] methanol;
- 24 [4 ({Ethyl- [6-ethyl-4'- (1 -ethyl-1 -hydroxypropyl) - 2 ' - propylbiphenyl-3-yl] amino} methyl)
- 2-hydroxymethylphenyl] methanol;
- 25 [4 ({[6-Ethyl-4'- (1 -ethyl-1 -hydroxypropyl) - 2 ' - propylbiphenyl-3-yl] propylamino} methyl)
- 2-hydroxymethylphenyl] methanol;
- 26 (4 {2 [6-Ethyl-2'-propyl-4'- (2,2,2-trifluoro-1 -hydroxy-1 -trifluoromethylethyl) biphenyl-3-yl] ethyl} - 2-hydroxymethylphenyl) methanol;
27- {4 [6-Ethyl-2'-propyl-4'- (2,2,2-trifluoro-1 -hydroxy-1 -trifluoromethyl-ethyl) biphenyl-3-yloxymethyl] - 2-hydroxymethylphenyl} methanol;
28- {4 [6-Ethyl-2'-propyl-4'- (2,2,2-trifluoro-1 -hydroxy-1 -trifluoromethyl-ethyl) biphenyl-3-ylmethoxy] - 2-hydroxymethylphenyl} methanol;
- 29- (4 {[6-Ethyl-2'-propyl-4'- (2,2,2-trifluoro-1 -hydroxy-1 -trifluoromethyl-ethyl) biphenyl-3-ylamino] methyl} - 2-hydroxymethylphenyl) methanol;
- 30- [4 ({[6-Ethyl-2'-propyl-4'- (2,2,2-trifluoro-1 -hydroxy-1 -trifluoromethyl-ethyl) biphenyl-3-yl] methylamino} methyl) - 2-hydroxymethylphenyl] methanol;
- 31 - [4 ({N-Ethyl [6-ethyl-2'=propyl-4'- (2,2,2-trifluoro-1 -hydroxy-1 -trifluoromethylethyl) biphenyl-3-yl] amino} methyl) - 2-hydroxymethylphenyl] methanol;
- 32 [4 ({[6-Ethyl-2'-propyl-4'- (2,2,2-trifluoro-1 -hydroxy-1 -trifluoromethyl-ethyl) biphenyl-3-yl]
- N-propyl-amino} methyl) - 2-hydroxymethylphenyl] methanol;
- 33- (4 {[4 ' - (1 -Ethyl-1 -hydroxypropyl) - 6.2 ' - dimethylbiphenyl-3-ylamino] methyl} - 2-hydroxymethylphenyl) methanol.
14. The photosensitizer for use as claimed in any one of claims 1 to 13, wherein said acne is selected from acne vulgaris, acne conglobate, acne papulosa and premenstrual acne, preferably acne vulgaris.
15. A photosensitiser as defined in any one of claims 1 to 1 1 , or a pharmaceutically acceptable salt thereof, together with a second photosensitiser for use in the prevention or treatment of acne.
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