WO2013026772A1 - Flurbiprofen and related compounds for the treatment of skin diseases - Google Patents
Flurbiprofen and related compounds for the treatment of skin diseases Download PDFInfo
- Publication number
- WO2013026772A1 WO2013026772A1 PCT/EP2012/066034 EP2012066034W WO2013026772A1 WO 2013026772 A1 WO2013026772 A1 WO 2013026772A1 EP 2012066034 W EP2012066034 W EP 2012066034W WO 2013026772 A1 WO2013026772 A1 WO 2013026772A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- compound according
- flurbiprofen
- dermatitis
- coo
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 55
- 238000011282 treatment Methods 0.000 title claims abstract description 39
- 208000017520 skin disease Diseases 0.000 title claims abstract description 21
- 229960002390 flurbiprofen Drugs 0.000 title claims description 43
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 title description 11
- 201000004624 Dermatitis Diseases 0.000 claims abstract description 48
- SYTBZMRGLBWNTM-SNVBAGLBSA-N (R)-flurbiprofen Chemical compound FC1=CC([C@H](C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-SNVBAGLBSA-N 0.000 claims abstract description 15
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 8
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims abstract description 8
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims abstract description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 5
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims abstract description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims abstract description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims abstract description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims abstract description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 4
- 150000003839 salts Chemical class 0.000 claims abstract description 4
- 229950005628 tarenflurbil Drugs 0.000 claims abstract description 4
- 125000003831 tetrazolyl group Chemical group 0.000 claims abstract description 4
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims abstract description 4
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims abstract description 4
- 239000003814 drug Substances 0.000 claims description 15
- 230000005722 itchiness Effects 0.000 claims description 15
- 201000008937 atopic dermatitis Diseases 0.000 claims description 11
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 claims description 10
- 208000010668 atopic eczema Diseases 0.000 claims description 10
- 201000010099 disease Diseases 0.000 claims description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 9
- 239000007924 injection Substances 0.000 claims description 9
- 238000002347 injection Methods 0.000 claims description 9
- 206010012434 Dermatitis allergic Diseases 0.000 claims description 6
- 229940125715 antihistaminic agent Drugs 0.000 claims description 6
- 239000000739 antihistaminic agent Substances 0.000 claims description 6
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 claims description 6
- BLFLLBZGZJTVJG-UHFFFAOYSA-N benzocaine Chemical compound CCOC(=O)C1=CC=C(N)C=C1 BLFLLBZGZJTVJG-UHFFFAOYSA-N 0.000 claims description 5
- 230000037396 body weight Effects 0.000 claims description 5
- 239000003246 corticosteroid Substances 0.000 claims description 5
- 229960001334 corticosteroids Drugs 0.000 claims description 5
- 239000006071 cream Substances 0.000 claims description 5
- 206010012438 Dermatitis atopic Diseases 0.000 claims description 4
- 206010020751 Hypersensitivity Diseases 0.000 claims description 4
- DNTGGZPQPQTDQF-XBXARRHUSA-N crotamiton Chemical compound C/C=C/C(=O)N(CC)C1=CC=CC=C1C DNTGGZPQPQTDQF-XBXARRHUSA-N 0.000 claims description 4
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 claims description 4
- 239000002674 ointment Substances 0.000 claims description 4
- 239000007921 spray Substances 0.000 claims description 4
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 claims description 3
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical compound C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 claims description 3
- 241000723346 Cinnamomum camphora Species 0.000 claims description 3
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 claims description 3
- 235000006679 Mentha X verticillata Nutrition 0.000 claims description 3
- 235000002899 Mentha suaveolens Nutrition 0.000 claims description 3
- 235000001636 Mentha x rotundifolia Nutrition 0.000 claims description 3
- 208000001647 Renal Insufficiency Diseases 0.000 claims description 3
- 208000026935 allergic disease Diseases 0.000 claims description 3
- 229960000846 camphor Drugs 0.000 claims description 3
- 229930008380 camphor Natural products 0.000 claims description 3
- 229960003338 crotamiton Drugs 0.000 claims description 3
- 229960000520 diphenhydramine Drugs 0.000 claims description 3
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical compound C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 claims description 3
- 201000006370 kidney failure Diseases 0.000 claims description 3
- 239000003589 local anesthetic agent Substances 0.000 claims description 3
- 229960005015 local anesthetics Drugs 0.000 claims description 3
- 229940041616 menthol Drugs 0.000 claims description 3
- 229960005181 morphine Drugs 0.000 claims description 3
- 229940060184 oil ingredients Drugs 0.000 claims description 3
- 230000001225 therapeutic effect Effects 0.000 claims description 3
- 208000000857 Hepatic Insufficiency Diseases 0.000 claims description 2
- 208000009675 Perioral Dermatitis Diseases 0.000 claims description 2
- 230000007815 allergy Effects 0.000 claims description 2
- 230000001363 autoimmune Effects 0.000 claims description 2
- 229960005274 benzocaine Drugs 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 239000008298 dragée Substances 0.000 claims description 2
- 239000000499 gel Substances 0.000 claims description 2
- 229960000890 hydrocortisone Drugs 0.000 claims description 2
- 208000015181 infectious disease Diseases 0.000 claims description 2
- 230000002458 infectious effect Effects 0.000 claims description 2
- 210000003734 kidney Anatomy 0.000 claims description 2
- 210000004185 liver Anatomy 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- 239000000243 solution Substances 0.000 claims description 2
- 239000000829 suppository Substances 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 229910004679 ONO2 Inorganic materials 0.000 abstract 2
- 208000003251 Pruritus Diseases 0.000 description 20
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 16
- 238000006748 scratching Methods 0.000 description 15
- 230000002393 scratching effect Effects 0.000 description 15
- 230000007803 itching Effects 0.000 description 14
- 210000003491 skin Anatomy 0.000 description 12
- 230000000694 effects Effects 0.000 description 10
- 235000019260 propionic acid Nutrition 0.000 description 9
- 208000024891 symptom Diseases 0.000 description 9
- 229940079593 drug Drugs 0.000 description 8
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 8
- LOTKRQAVGJMPNV-UHFFFAOYSA-N 1-fluoro-2,4-dinitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(F)C([N+]([O-])=O)=C1 LOTKRQAVGJMPNV-UHFFFAOYSA-N 0.000 description 7
- 206010061218 Inflammation Diseases 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- 229920002055 compound 48/80 Polymers 0.000 description 6
- 230000004054 inflammatory process Effects 0.000 description 6
- 229920000392 Zymosan Polymers 0.000 description 5
- 210000002683 foot Anatomy 0.000 description 5
- 238000002560 therapeutic procedure Methods 0.000 description 5
- 239000003981 vehicle Substances 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- 230000006399 behavior Effects 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 150000003180 prostaglandins Chemical class 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000000763 evoking effect Effects 0.000 description 3
- 238000012153 long-term therapy Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 3
- SYTBZMRGLBWNTM-JTQLQIEISA-N (S)-flurbiprofen Chemical compound FC1=CC([C@@H](C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-JTQLQIEISA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 238000011740 C57BL/6 mouse Methods 0.000 description 2
- 239000012891 Ringer solution Substances 0.000 description 2
- 206010070834 Sensitisation Diseases 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 2
- 235000010290 biphenyl Nutrition 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 230000007012 clinical effect Effects 0.000 description 2
- 210000004207 dermis Anatomy 0.000 description 2
- 239000003651 drinking water Substances 0.000 description 2
- 235000020188 drinking water Nutrition 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 210000000548 hind-foot Anatomy 0.000 description 2
- 229960001680 ibuprofen Drugs 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 230000037390 scarring Effects 0.000 description 2
- 230000035807 sensation Effects 0.000 description 2
- 230000008313 sensitization Effects 0.000 description 2
- 239000007929 subcutaneous injection Substances 0.000 description 2
- 238000010254 subcutaneous injection Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000011200 topical administration Methods 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- XQDQRCRASHAZBA-UHFFFAOYSA-N 2,4-dinitro-1-thiocyanatobenzene Chemical compound [O-][N+](=O)C1=CC=C(SC#N)C([N+]([O-])=O)=C1 XQDQRCRASHAZBA-UHFFFAOYSA-N 0.000 description 1
- 206010063409 Acarodermatitis Diseases 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 206010052804 Drug tolerance Diseases 0.000 description 1
- 206010013786 Dry skin Diseases 0.000 description 1
- 208000006877 Insect Bites and Stings Diseases 0.000 description 1
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 201000009053 Neurodermatitis Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 241000447727 Scabies Species 0.000 description 1
- 208000028990 Skin injury Diseases 0.000 description 1
- 206010040880 Skin irritation Diseases 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- 206010042674 Swelling Diseases 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000013566 allergen Substances 0.000 description 1
- 208000002029 allergic contact dermatitis Diseases 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000003908 antipruritic agent Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229940046428 benzocaine topical cream Drugs 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000003920 cognitive function Effects 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000037336 dry skin Effects 0.000 description 1
- 229940063164 eurax Drugs 0.000 description 1
- 230000026781 habituation Effects 0.000 description 1
- 229940009977 hydrocortisone topical cream Drugs 0.000 description 1
- 230000009610 hypersensitivity Effects 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000011503 in vivo imaging Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000002085 irritant Substances 0.000 description 1
- 231100000021 irritant Toxicity 0.000 description 1
- 208000001875 irritant dermatitis Diseases 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 229940099430 lanacane Drugs 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 208000010658 metastatic prostate carcinoma Diseases 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 229960002009 naproxen Drugs 0.000 description 1
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 238000011458 pharmacological treatment Methods 0.000 description 1
- 238000001126 phototherapy Methods 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 208000005687 scabies Diseases 0.000 description 1
- 208000037974 severe injury Diseases 0.000 description 1
- 230000009528 severe injury Effects 0.000 description 1
- 238000007390 skin biopsy Methods 0.000 description 1
- 230000036556 skin irritation Effects 0.000 description 1
- 231100000475 skin irritation Toxicity 0.000 description 1
- 206010040882 skin lesion Diseases 0.000 description 1
- 231100000444 skin lesion Toxicity 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- 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
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- 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
- A61P17/04—Antipruritics
Definitions
- the present invention relates to the use of a compound according to the following formula (I)
- Ri or R 2 is a group selected from H, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , and - CH 2 CH 2 CH 2 CH 3 or can be taken together with another to give a cyclopropyl ring, a cyclobu- tyl ring, a cyclopentyl ring, or a cyclohexyl ring
- R 3 is a group selected from -COOH, - COORs, -CONH2, -CONHRs, -CONRgRy, -CONHSO2R6, -COO-(CH 2 ) 3 -CH 2 OH, -COO- (CH 2 ) 4 -ON0 2 , -COO-PhOCH 3 -C 2 H 2 -COO-(CH 2 ) 4 -ON0 2 , tetrazolyl, and a -COOH bioisos- tere
- R 4 or R 5 is
- dermatitis is derived from the Greek words for derma "skin” and -itis "inflammation”. Therefore, dermatitis denotes an inflammation of the skin, often occurring in the context of allergic reactions. Further, the term dermatitis describes eczema or dermatitis eczema, which are skin irritations often indicative for an atopic dermatitis, one of many types of the disease. There are several forms of dermatitis known which are classified according to their underlying cause of the skin inflammation. Symptoms of dermatitis can be different and range from mild irritations to the occurrence of lesions or blistering of the skin.
- dermatitis Although symptoms vary between the different classes of the disease, there are common indications for dermatitis, including redness of the skin, swelling, skin lesions and injuries, dry skin, scarring and in particular itchiness. Also, the local area of the skin on which the symptoms are observed may differ between the various types of dermatitis.
- Classical treatments comprise the topically application of medicaments to the affected area of the skin, for example in the form of an ointment, cream or spray.
- Such pharmaceutical compositions include corticosteroids and antihistamines as active compounds. None pharmacological treatments include wet compresses and the avoiding of allergens and irritants - such instructions are part of most treatment plans.
- Other pharmaceutically active compounds used are nonsteroidal medications which however help to relieve signs and symptoms and do not cure the disease.
- Pharmaceutically active components included in these medicaments are antihistamines, such as diphenhydramine, corticosteroids, such as hydrocortisone topical cream, counterirritants, such as mint oil, menthol, or camphor; crotamiton (trade name Eurax®) is an antipruritic agent available as a cream or lotion often used to treat scabies, and local anesthetics such as benzocaine topical cream (Lanacane®). Many of the above substances are known to induce severe side effects, thus creating a continuous need for the development of further alternative treatments of itching and/or dermatitis.
- antihistamines such as diphenhydramine
- corticosteroids such as hydrocortisone topical cream
- counterirritants such as mint oil, menthol, or camphor
- crotamiton trade name Eurax®
- crotamiton is an antipruritic agent available as a cream or lotion often used to treat scabies
- local anesthetics such
- Tarenflurbil (( ?)-Flurbiprofen) (chemical name (i?)-2-(2-fluoro-4-phenylphenyl)propionic acid) was tested in 2008 as a potential candidate for the treatment of Alzheimer's disease. Nevertheless, the further development for this indication was stopped after an insufficient improvement of cognitive functions was found.
- ( ?)-Flurbiprofen together with, for example, Ibuprofen and Naproxen, belongs to the group of 2-aryl propionic acids (profens). Just like Ibuprofen, ( ?)-Flurbiprofen is a by-product of the marketed racemic Flurbiprofen, the active agent of which is thought to be the (5)-enantiomer. Flurbiprofen is currently in clinical trials for the treatment of metastatic prostate cancer.
- flurbiprofen-containing compositions for topical administration comprising about 0.5 to 10% flurbiprofen; and methods for delivering flurbiprofen-containing compositions through the skin.
- the flurbiprofen compositions show enhanced permeability of the skin and therefore are useful for the treatment of conditions in the joints or soft tissue beneath the skin.
- Kassis et al 1981 examined the effect of topical flurbiprofen on the prostaglandin synthesis in human skin biopsies in primary irritant dermatitis.
- the anti- inflammatory effect of the topical administration of the drug was assessed, but no clinical effect of the treatment observed. Also no correlation was observed between the poor clinical effects of the drug and the reduction of the prostaglandin synthesis.
- Ri or R 2 is a group selected from H, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , and - CH 2 CH 2 CH 2 CH 3 or can be taken together with another to give a cyclopropyl ring, a cyclobu- tyl ring, a cyclopentyl ring, or a cyclohexyl ring
- R 3 is a group selected from -COOH, - COORs, -CONH2, -CONHRs, -CONRgRy, -CONHSO2R6, -COO-(CH 2 ) 3 -CH 2 OH, -COO- (CH 2 ) 4 -ON0 2 , -COO-PhOCH 3 -C 2 H 2 -COO-(CH 2 ) 4 -ON0 2 , tetrazolyl, and a -COOH bioisos- tere
- R 4 or R 5 is
- Ri is selected from H.
- a compound according to the present invention which is selected from the group of
- (i?)-Flurbiprofen or it ro-( /? )- F I urb i pro fen for use in the treatment of a skin disease.
- Even further preferred is the use of a compound as above, preferably (R )- Flurbiprofen or N i t ro - (/?)- F 1 u rb i p o f e n for the production of a medicament for the treatment of a skin disease.
- Another aspect of the present invention relates to a method for treating of a skin disease, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to the present invention, and preferably ( ⁇ -Flurbiprofen or it vo-(R )- F i u rb i pro fen .
- the primary aims of therapy according to the present invention are to reduce inflammation of the skin, and further to reduce the itching symptom, and thereby to bring relieve to a patient who suffers from dermatitis and to reduce the occurrence of injuries caused by scratching.
- treatment shall include both preventive and/or actual treatment of the disease symptoms of dermatitis, specifically itching, as described herein, which can be alleviated and/or even completely removed using said treatment.
- skin disease shall refer to any pathological condition of the skin, preferably diseases of the dermis, most preferably inflammatory disease of the dermis like dermatitis. Alternatively, the term shall comprise conditions which involve inflammation of the skin and/or itchiness as a symptom.
- the skin disease is selected from the group consisting of allergic dermatitis, such as contact allergy; autoimmune dermatitis, such as an atopic dermatitis or neurodermitis; itchiness caused by dermatitis; idiopathic itchiness; itchiness caused by the use of medicaments, such as morphine; itchiness caused by diseases of the liver or kidney, such as liver insufficiency or renal failure; non infectious local inflammation of the skin and perioral dermatitis.
- the present invention is based on the surprising finding that an (i?)-enantiomer of a profen- compound, namely (/? (-Flurbiprofen, reduces inhibits the occurrence of inflammation of the skin .
- the compounds of the present invention may be used for treating the itching symptom in a patient suffering from a skin or neurological disease.
- Another aspect of the present invention thus relates to a method for treating dermatitis which is free from inhibiting cyciooxygenases and has no effect on the prostaglandin synthesis, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to the present invention, and preferably R- Fiurbiprofen or Nitro-R-Flurbiprofen.
- any dosage of a compound according to the present invention and preferably (/? (-Fl urbiprofen, o itro-( ?)-Fi u rb i pro fen , can be used which exhibits an advantageous effect on the skin disease to be treated.
- Respective effective dosages can be readily determined by the person of skill and/or the attending physician. Preferred is the use of a compound according to the present invention, and preferably (/?
- a compound according to the present invention and preferably (/? (-Flurbiprofen, or it Y -(R )- F I u rb i pro fen , can be provided to the patient in any suitable and effective manner, such as topically, orally, rectally or by injection. Preferred is topically and orally. Furthermore, the compound according to the present invention, and preferably (/? (-Flurbiprofen, or it Y -(R )- F I u rb i pro fen , can be provided to the patient in any suitable and effective manner, such as topically, orally, rectally or by injection. Preferred is topically and orally. Furthermore, the compound according to the present invention, and preferably (/? (-Flurbiprofen, or it Y -(R )- F I u rb i pro fen , can be provided to the patient in any suitable and effective manner, such as topically, orally, rect
- (-Flurbiprofen, or Nitro-(i?)-Flurbiprofen can be provided to the patient in any suitable and effective pharmaceutically acceptable form, such as in the form of a tablet, capsule, dragee, powder, suppository, gel, cream, spray, ointment and/or as solution for injection.
- the compound according to the present invention and preferably (/? (-Flurbiprofen, or Nitro- (/? (-Flurbiprofen, can be used alone or in combination with other compounds and treatments that are available for the therapy and/or treatment of inflammation of the skin, such as dermatitis, and/or itchiness.
- the combination includes a simultaneous or spaced apart use of the compounds and treatments.
- the combination also includes any synergistic effect of the compounds and treatments that are available for the therapy and/or treatment of skin diseases and/or itchiness. Therefore, another aspect of the present invention is the use of a compound according to the present invention, and preferably (/? (-Flurbiprofen, or itro-( ?)-F!
- a compound according to the present invention and preferably (/? (-Flurbiprofen, or it o-( R )- F 1 u rb i pro fen , is provided in combination with least one additional therapeutic against a skin disease is selected from the group consisting of antihistamines, such as diphenhydramine; corticosteroids, such as hydrocortisone; counterirritants, such as mint oil, menthol, or camphor; crotamiton; and local anesthetics such as benzocaine.
- antihistamines such as diphenhydramine
- corticosteroids such as hydrocortisone
- counterirritants such as mint oil, menthol, or camphor
- crotamiton and local anesthetics such as benzocaine.
- compositions according to the present invention preferably pharmaceutical formulations comprising (/? (-Flurbiprofen or Nitro-(i?)-Flurbiprofen, for the use in the t eatment of dermatitis, further comprise pharmaceutically acceptable carriers and/or exipients.
- the present inv ention not only comprises the use of the inventive compounds described in pharmaceuticals but also in cosmetic preparations.
- Another aspect of the present invention relates to a method for treating, and in particular reducing, the symptoms of skin diseases, preferably itchiness, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to the present invention, and preferably (/? (-Flurbiprofen or Nitro-(i?)-Flurbiprofen, as described herein.
- Flurbiprofen or Nitro-(i?)-Flurbiprofen is its low toxicity, which is sufficiently proven for R- Flurbiprofen. Even w i th a long-term therapy in old patients no significant side-effects oc- currcd. Usually, mild side-effects do not lead to a termination of the therapy. Therefore the preferable side effect profile of the compound of the invention makes the treatments described herein advantageous over state of the art remedies, specifically the use of antihistamines and corticoids.
- the invention relates in a further aspect to a treatment of dermatitis using a compound according to the invention, specifically (/ ⁇ -Flurbiprofen or Nitro-(i?)-Flurbiprofen, wherein the dermatitis is resistant to standard dermatitis treatments, or wherein the patient suffers from mild to severe side effects of a standard dermatitis treatment, specifically wherein the patient suffers from severe side effects of a standard dermatitis treatment.
- said standard dermatitis treatment comprises the administration of antihistamines and/or corticosteroids.
- Figure 1 shows the scratching behavior after subcutaneous injection of compound 48/80
- Figure 2 shows representative images of each two mice per treatment group (R- Flurbiprofen 10 mg/kg/d in the drinking water versus vehicle) after the sensitization with DNFB.
- DNFB was applied (0.2 %, 50 ⁇ ) onto a shaved 2 x 2 cm area on the back without occlusion at day 1, 7 and 14..
- Figure 3 shows time course of zymosan evoked paw skin inflammation in rats treated with R- flurbiprofen, Sflurbiprofen or placebo.
- the paw volume increase as compared to baseline was analyzed with a plethysmometer.
- Compound 48/80 evoked itching dermatitis (model for IgE-mediated type-1 allergic dermatitis, itch evoked by insect bites, drug induced itch e.g. by morphine, non-allergic chronic pruritus).
- Mice were pretreated with R-Flurbiprofen or vehicle. They received 3 doses of 5 mg/kg body weight perorally in DMSO/water with 12h intervals. The last dose was administered 30 min before injection of compound 48/80. Control animals received equal volumes of the vehicle. All animals were placed into white acrylic chambers (20 x 20 x 20 cm), with a clear acrylic front panel and a mirrored back panel, for 30 min to acclimate to the observational environment.
- mice were briefly removed from the chambers, and injected subcutaneously with 50 ⁇ g compound 48/80 in 100 ⁇ Ringer solution under the scruff at the most dorsal point of the back just beneath the head and were returned to the chambers for 30 min. The time mice spent scratching the back surrounding the injection site with a hind leg was recorded with a stop watch in 5 min intervals. Eight animals were treated in each group. Data are reported as mean +/- SEM and were analyzed for statistical significance using Student's t test. Resulting p values of less than 0.05 were considered significant.
- DNTB induced allergic dermatitis in mice (model for atopic dermatitis, contact allergic dermatitis, delayed type 4 hypersensitivity) C57BL6 mice were sensitized by 2,4-dinitro-l- fluorobenzene, DNFB application (50 ⁇ of 0.2% DNFB ) onto a shaved area on the back (2 x 2 cm). DNFB was diluted in acetone/olive oil (4: 1) immediately before use. Applications were repeated 7 and 14 days after the first sensitization. Skin inflammation was documented on day 9 and 16 (i.e. 48 h after 2nd and 3rd challenges) by photography and analysis of the scratching response.
- MMPSense 680 Vehicles were used to assess the skin inflammation. MMPSense 100 ⁇ was injected into the tail vein 30 min before the imaging. Animals were treated with RFlurbi- profen in the drinking water (10 mg/kg daily), starting on day 1 after the first application of DNFB.
- Flurbiprofen reduced skin inflammation in a model for non-allergic dermatitis without itching.
- Unilateral hind paw inflammation was induced by subcutaneous injection of 0.625 mg zymosan suspended in 100 ⁇ phosphate buffer into the midplantar region of the right hind paw in rats.
- the paw volume was measured before zymosan injection (time 0) and repeatedly after induction of the inflammation up to 24h using a plethysmometer. At each time point five measurements of the paw volume were taken and the average was used to calculate the net paw volume increase as compared to the value before zymosan injection.
- Animals were treated with an intraperitoneal injection of 9 mg/kg R- flurbiprofen or S-flurbiprofen.
- the drugs were dissolved in 1 ml phosphate buffer. In control rats the respective volume of vehicle was administered. Six rats were used in each group. The drugs were administered 15 minutes before zymosan. S-Flurbiprofen was used as positive control.
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Dermatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The present invention relates to the use of a compound according to the following formula (I), wherein R1 or R2 is a group selected from H, -CH3, -CH2CH3, -CH2CH2CH3, and - CH2CH2CH2CH3 or can be taken together with another to give a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring, or a cyclohexyl ring, R3 is a group selected from -COOH, - COOR6, -CONH2, -CONHR6, -CONR6R7, -CONHSO2R6, -COO-(CH2)3-CH2OH, -COO- (CH2)4-ONO2, -COO-PhOCH3-C2H2-COO-(CH2)4-ONO2, tetrazolyl, and a -COOH bioisostere, R4 or R5 is a group selected from -Cl, -F, -Br, -I, -CF3, -OCF3, -SCF3, -OCH3, - OCH2CH3, -CN, -CH=CH2, -CH2OH, and -NO2, R6 ot R7 is a group selected from -CH3, - CH2CH3, -CH2CH2CH3, and -CH2CH2CH2CH3, and m or n is an integer selected from 0, 1, 2, and 3, or a nitro-variant of said compound, and pharmaceutically acceptable salts of said compound, preferably an (R)-enantiomer thereof, such as Tarenflurbil ((R)-Flurbiprofen), for use in the treatment of skin diseases, preferably for the treatment of dermatitis.
Description
Flurbiprofen and Related Compounds for the Treatment of Skin Diseases
The present invention relates to the use of a compound according to the following formula (I)
(I),
wherein Ri or R2 is a group selected from H, -CH3, -CH2CH3, -CH2CH2CH3, and - CH2CH2CH2CH3 or can be taken together with another to give a cyclopropyl ring, a cyclobu- tyl ring, a cyclopentyl ring, or a cyclohexyl ring, R3 is a group selected from -COOH, - COORs, -CONH2, -CONHRs, -CONRgRy, -CONHSO2R6, -COO-(CH2)3-CH2OH, -COO- (CH2)4-ON02, -COO-PhOCH3-C2H2-COO-(CH2)4-ON02, tetrazolyl, and a -COOH bioisos- tere, R4 or R5 is a group selected from -CI, -F, -Br, -I, -CF3, -OCF3, -SCF3, -OCH3, - OCH2CH3, -CN, -CH=CH2, -CH2OH, and -N02, Rg ot R7 is a group selected from -CH3, - CH2CH3, -CH2CH2CH3, and -CH2CH2CH2CH3, and m or n is an integer selected from 0, 1, 2, and 3, or a nitro-variant of said compound, and pharmaceutically acceptable salts of said compound, preferably an (i?)-enantiomer thereof, such as Tarenflurbil. ((i?)-Flurbiprofen), for use in the treatment of skin diseases, preferably for the treatment of dermatitis.
The term dermatitis is derived from the Greek words for derma "skin" and -itis "inflammation". Therefore, dermatitis denotes an inflammation of the skin, often occurring in the context of allergic reactions. Further, the term dermatitis describes eczema or dermatitis eczema, which are skin irritations often indicative for an atopic dermatitis, one of many types of the disease. There are several forms of dermatitis known which are classified according to their underlying cause of the skin inflammation.
Symptoms of dermatitis can be different and range from mild irritations to the occurrence of lesions or blistering of the skin. Although symptoms vary between the different classes of the disease, there are common indications for dermatitis, including redness of the skin, swelling, skin lesions and injuries, dry skin, scarring and in particular itchiness. Also, the local area of the skin on which the symptoms are observed may differ between the various types of dermatitis.
Depending on the type of dermatitis diagnosed, different treatments are prescribed. Classical treatments comprise the topically application of medicaments to the affected area of the skin, for example in the form of an ointment, cream or spray. Such pharmaceutical compositions include corticosteroids and antihistamines as active compounds. None pharmacological treatments include wet compresses and the avoiding of allergens and irritants - such instructions are part of most treatment plans. Other pharmaceutically active compounds used are nonsteroidal medications which however help to relieve signs and symptoms and do not cure the disease.
Common to all forms of skin diseases is the occurrence of itchiness. Itching is a sensation that urges to scratch. In the context of dermatitis, in particular of chronic forms of such a disease, the continuous urge to scratch, which is a hardly controllable reflex in response to itching, often results in severe injuries and permanent scarring of the affected area of the skin. For the treatment of itching a variety of drugs are on the market. Usually anti-itch remedies are topically applied medicaments in the form of ointments, creams or sprays. Also orally administered anti-itch drugs exist, but are usually only available under prescription. Pharmaceutically active components included in these medicaments are antihistamines, such as diphenhydramine, corticosteroids, such as hydrocortisone topical cream, counterirritants, such as mint oil, menthol, or camphor; crotamiton (trade name Eurax®) is an antipruritic agent available as a cream or lotion often used to treat scabies, and local anesthetics such as benzocaine topical cream (Lanacane®). Many of the above substances are known to induce severe side effects, thus creating a continuous need for the development of further alternative treatments of itching and/or dermatitis.
Alternative therapies, such as phototherapy is successfully used against severe itching, especially if caused by renal failure. The common type of light used is UVB. Isolated itches may
be treated using scratching devices, since scratching sometimes results in a relieve. However, the scratching mostly does not cure the itching but leads to an increased itching sensation, which is counter productive and may result in a positive feedback circle of itching and scratching.
Tarenflurbil (( ?)-Flurbiprofen) (chemical name (i?)-2-(2-fluoro-4-phenylphenyl)propionic acid) was tested in 2008 as a potential candidate for the treatment of Alzheimer's disease. Nevertheless, the further development for this indication was stopped after an insufficient improvement of cognitive functions was found.
( ?)-Flurbiprofen, together with, for example, Ibuprofen and Naproxen, belongs to the group of 2-aryl propionic acids (profens). Just like Ibuprofen, ( ?)-Flurbiprofen is a by-product of the marketed racemic Flurbiprofen, the active agent of which is thought to be the (5)-enantiomer. Flurbiprofen is currently in clinical trials for the treatment of metastatic prostate cancer.
US 5,807,568 describes flurbiprofen-containing compositions for topical administration comprising about 0.5 to 10% flurbiprofen; and methods for delivering flurbiprofen-containing compositions through the skin. The flurbiprofen compositions show enhanced permeability of the skin and therefore are useful for the treatment of conditions in the joints or soft tissue beneath the skin.
Kassis et al 1981 examined the effect of topical flurbiprofen on the prostaglandin synthesis in human skin biopsies in primary irritant dermatitis. The anti- inflammatory effect of the topical administration of the drug was assessed, but no clinical effect of the treatment observed. Also no correlation was observed between the poor clinical effects of the drug and the reduction of the prostaglandin synthesis.
In view of the above, an ongoing demand exists for the development of new and effective alternative treatments of skin diseases, specifically for the treatment of dermatitis.
In a first aspect, the object of the present invention is solved by a compound according to the following formula (I)
(I),
wherein Ri or R2 is a group selected from H, -CH3, -CH2CH3, -CH2CH2CH3, and - CH2CH2CH2CH3 or can be taken together with another to give a cyclopropyl ring, a cyclobu- tyl ring, a cyclopentyl ring, or a cyclohexyl ring, R3 is a group selected from -COOH, - COORs, -CONH2, -CONHRs, -CONRgRy, -CONHSO2R6, -COO-(CH2)3-CH2OH, -COO- (CH2)4-ON02, -COO-PhOCH3-C2H2-COO-(CH2)4-ON02, tetrazolyl, and a -COOH bioisos- tere, R4 or R5 is a group selected from -CI, -F, -Br, -I, -CF3, -OCF3, -SCF3, -OCH3, - OCH2CH3, -CN, -CH=CH2, -CH2OH, and -N02, Rg ot R7 is a group selected from -CH3, - CH2CH3, -CH2CH2CH3, and -CH2CH2CH2CH3, and m or n is an integer selected from 0, 1 , 2, and 3, or a nitro-variant of said compound, such as (i?)-2-(2-fluoro-biphenyl-4-yl)propionic acid 4-nitrooxybutyl ester, and pharmaceutically acceptable salts of said compound for use in the treatment of diseases of the skin, preferably for reducing itchiness.
Preferred is the use of an ( ?)-enantiomer of a compound of the present invention.
Preferably, Ri is selected from H. Further preferred is the use of a compound according to the present invention which is selected from the group of
(i?)-2-(2-fluoro-4-phenylphenyl)propionic acid,
(i?)-2-(2-fluoro-biphenyl-4-yl)propionic acid 4-nitrooxybutyl ester,
(R)- 1 , 1 '-biphenyl)-4-acetic acid 2-fluoro-a-methyl-4-hydroxybutylester,
(i?)-3-[4-(2-fluoro-a-methyl-[ 1 , 1 '-biphenyl]-4-acetyloxy)-3-methoxyphenyl]-2-propenoic acid 4-nitrooxybutyl ester,
(i?)-2-methyl-2(2-fluoro-4'-trifluoromethylbiphen-4-yl)propionic acid,
(i?)-2-methyl-2(2-fluoro-4'cyclohexylbiphen-4-yl)propionic acid,
(i?)-2-(2-fluoro-3',5'-bis(chloro)biphen-4-yl) propionic acid amide,
(i?)-2-(2-fluoro-4'-trifluoromethylbiphen-4-yl)propionic acid,
(i?)-2-(2-fluoro-3'-trifluoromethylbiphen-4-yl) propionic acid,
(i?)-2-(2-fluoro-3',5'-bis(trifluoromethyl)biphen-4-yl)propionic acid,
(i?)-2-(4'-cyclohexyl-2-fluorobiphen-4-yl)propionic acid,
(i?)-2-(2-Fluoro-l , l'-biphenyl-4-yl) -2-methylpropanoic acid,
and ( ?)-5-[ 1 -(2-Fluoro-biphenyl-4-yl)- 1 -methyl-ethyl]-2H-tetrazole.
Further preferred is (i?)-Flurbiprofen or it ro-( /? )- F I urb i pro fen for use in the treatment of a skin disease. Even further preferred is the use of a compound as above, preferably (R )- Flurbiprofen or N i t ro - (/?)- F 1 u rb i p o f e n for the production of a medicament for the treatment of a skin disease. Another aspect of the present invention relates to a method for treating of a skin disease, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to the present invention, and preferably (^-Flurbiprofen or it vo-(R )- F i u rb i pro fen . The primary aims of therapy according to the present invention are to reduce inflammation of the skin, and further to reduce the itching symptom, and thereby to bring relieve to a patient who suffers from dermatitis and to reduce the occurrence of injuries caused by scratching.
In the context of the present invention, treatment shall include both preventive and/or actual treatment of the disease symptoms of dermatitis, specifically itching, as described herein, which can be alleviated and/or even completely removed using said treatment.
The term "skin disease" shall refer to any pathological condition of the skin, preferably diseases of the dermis, most preferably inflammatory disease of the dermis like dermatitis. Alternatively, the term shall comprise conditions which involve inflammation of the skin and/or itchiness as a symptom. In another embodiment the skin disease is selected from the group consisting of allergic dermatitis, such as contact allergy; autoimmune dermatitis, such as an atopic dermatitis or neurodermitis; itchiness caused by dermatitis; idiopathic itchiness; itchiness caused by the use of medicaments, such as morphine; itchiness caused by diseases of the liver or kidney, such as liver insufficiency or renal failure; non infectious local inflammation of the skin and perioral dermatitis.
The present invention is based on the surprising finding that an (i?)-enantiomer of a profen- compound, namely (/? (-Flurbiprofen, reduces inhibits the occurrence of inflammation of the skin . This provides a new avenue to tackle dermatitis. Furthermore, it was surprisingly found that the treatment with a compound of the invent ion, preferably an (i?)-enantiomer of a pro- fen-compound, namely (/? (-Flurbiprofen, resulted in reduced itching. Therefore, the compounds of the present invention may be used for treating the itching symptom in a patient suffering from a skin or neurological disease.
In contrast to its 5- isomer, /^-Flurbiprofen does not inhibit the cyciooxygenases and has no effect on the prostaglandin synthesis. Even at h igh dai ly dosage and long-term therapy, no essential toxicity is known. Another aspect of the present invention thus relates to a method for treating dermatitis which is free from inhibiting cyciooxygenases and has no effect on the prostaglandin synthesis, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to the present invention, and preferably R- Fiurbiprofen or Nitro-R-Flurbiprofen.
Even at high daily dosage and long-term therapy, no essential toxicity of (/? (-Flurbiprofen is known . Thus, general ly any dosage of a compound according to the present invention, and preferably (/? (-Fl urbiprofen, o itro-( ?)-Fi u rb i pro fen , can be used which exhibits an advantageous effect on the skin disease to be treated. Respective effective dosages can be readily determined by the person of skill and/or the attending physician. Preferred is the use of a compound according to the present invention, and preferably (/? (-Flurbiprofen or N itro-(/?(- Flurbiprofen, according to the invention, wherein said compound according to the present invention, and preferably (/? (-Flurbiprofen, or N it ro-( /? )- F I u rb i pro fen , i s prov i d ed i n a n amount of between 50 mg to 3000 mg, preferably of between 100 mg to 1500 mg, more preferably between 300 mg to 1200 mg per dosage form. Further preferred is a use, wherein said compound according to the present invention, and preferably (/? (-Flurbiprofen, o it o-(/?(- Flurbiprofen, is provided in a dosage of between 5 mg/kg of body weight to 1 5 mg/kg of body weight of the patient to be treated per day.
In general, a compound according to the present invention, and preferably (/? (-Flurbiprofen, or it Y -(R )- F I u rb i pro fen , can be provided to the patient in any suitable and effective manner, such as topically, orally, rectally or by injection. Preferred is topically and orally. Furthermore, the compound according to the present invention, and preferably (/? (-Flurbiprofen, or
Nitro-(i?)-Flurbiprofen, can be provided to the patient in any suitable and effective pharmaceutically acceptable form, such as in the form of a tablet, capsule, dragee, powder, suppository, gel, cream, spray, ointment and/or as solution for injection.
The compound according to the present invention, and preferably (/? (-Flurbiprofen, or Nitro- (/? (-Flurbiprofen, can be used alone or in combination with other compounds and treatments that are available for the therapy and/or treatment of inflammation of the skin, such as dermatitis, and/or itchiness. The combination includes a simultaneous or spaced apart use of the compounds and treatments. The combination also includes any synergistic effect of the compounds and treatments that are available for the therapy and/or treatment of skin diseases and/or itchiness. Therefore, another aspect of the present invention is the use of a compound according to the present invention, and preferably (/? (-Flurbiprofen, or itro-( ?)-F! u rb i pro fen , wherein said a compound according to the present invention, and preferably (/? (-Flurbiprofen, or it o-( R )- F 1 u rb i pro fen , is provided in combination with least one additional therapeutic against a skin disease is selected from the group consisting of antihistamines, such as diphenhydramine; corticosteroids, such as hydrocortisone; counterirritants, such as mint oil, menthol, or camphor; crotamiton; and local anesthetics such as benzocaine.
Pharmaceutical formulations according to the present invention, preferably pharmaceutical formulations comprising (/? (-Flurbiprofen or Nitro-(i?)-Flurbiprofen, for the use in the t eatment of dermatitis, further comprise pharmaceutically acceptable carriers and/or exipients.
The present inv ention not only comprises the use of the inventive compounds described in pharmaceuticals but also in cosmetic preparations.
Another aspect of the present invention then relates to a method for treating, and in particular reducing, the symptoms of skin diseases, preferably itchiness, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to the present invention, and preferably (/? (-Flurbiprofen or Nitro-(i?)-Flurbiprofen, as described herein.
The main advantage of a compound according to the present invention, and preferably (/? )-
Flurbiprofen or Nitro-(i?)-Flurbiprofen, is its low toxicity, which is sufficiently proven for R- Flurbiprofen. Even w i th a long-term therapy in old patients no significant side-effects oc-
currcd. Usually, mild side-effects do not lead to a termination of the therapy. Therefore the preferable side effect profile of the compound of the invention makes the treatments described herein advantageous over state of the art remedies, specifically the use of antihistamines and corticoids.
Hence, the invention relates in a further aspect to a treatment of dermatitis using a compound according to the invention, specifically (/^-Flurbiprofen or Nitro-(i?)-Flurbiprofen, wherein the dermatitis is resistant to standard dermatitis treatments, or wherein the patient suffers from mild to severe side effects of a standard dermatitis treatment, specifically wherein the patient suffers from severe side effects of a standard dermatitis treatment. In one preferred embodiment said standard dermatitis treatment comprises the administration of antihistamines and/or corticosteroids.
The present invention will now be explained in the following examples with reference to the accompanying figures, without being limited thereto. For the purposes of the present invention, all references as cited herein are incorporated by reference in their entireties. In the Figures,
Figure 1: shows the scratching behavior after subcutaneous injection of compound 48/80
(50 μg in 100 μΐ Ringer solution) in C57BL6 mice (m, 8-10 weeks). Treatments: R-Flurbiprofen 3 x 5 mg/kg orally with 12h interval, last dose 30 min before Compound 48/80. Controls received vehicle. (A)Time courses of the scratching behavior. (B) The total scratching time.
Figure 2: shows representative images of each two mice per treatment group (R- Flurbiprofen 10 mg/kg/d in the drinking water versus vehicle) after the sensitization with DNFB. DNFB was applied (0.2 %, 50 μΐ) onto a shaved 2 x 2 cm area on the back without occlusion at day 1, 7 and 14..
Figure 3: shows time course of zymosan evoked paw skin inflammation in rats treated with R- flurbiprofen, Sflurbiprofen or placebo. The paw volume increase as compared to baseline was analyzed with a plethysmometer.
Examples
I. In a mouse model of IgE mediated type 1 allergic dermatitis (^-Flurbiprofen reduced scratching behavior.
Compound 48/80 evoked itching dermatitis (model for IgE-mediated type-1 allergic dermatitis, itch evoked by insect bites, drug induced itch e.g. by morphine, non-allergic chronic pruritus). Mice were pretreated with R-Flurbiprofen or vehicle. They received 3 doses of 5 mg/kg body weight perorally in DMSO/water with 12h intervals. The last dose was administered 30 min before injection of compound 48/80. Control animals received equal volumes of the vehicle. All animals were placed into white acrylic chambers (20 x 20 x 20 cm), with a clear acrylic front panel and a mirrored back panel, for 30 min to acclimate to the observational environment.
Experiments were done in a climate controlled and sound restricted room and white noise was applied during habituation and experiments. For injection of Compound 48/80 animals were briefly removed from the chambers, and injected subcutaneously with 50 μg compound 48/80 in 100 μΐ Ringer solution under the scruff at the most dorsal point of the back just beneath the head and were returned to the chambers for 30 min. The time mice spent scratching the back surrounding the injection site with a hind leg was recorded with a stop watch in 5 min intervals. Eight animals were treated in each group. Data are reported as mean +/- SEM and were analyzed for statistical significance using Student's t test. Resulting p values of less than 0.05 were considered significant.
Time courses of the scratching behavior differed significantly between groups (Figure 1 A) and the total scratching time was significantly reduced by R-Flurbiprofen treatment, p < 0.05, n = 8 per group (Figure IB).
II. (R)-Flurbiprofen reduces signs of inflammation and scratching.
DNTB induced allergic dermatitis in mice (model for atopic dermatitis, contact allergic dermatitis, delayed type 4 hypersensitivity) C57BL6 mice were sensitized by 2,4-dinitro-l- fluorobenzene, DNFB application (50 μΐ of 0.2% DNFB ) onto a shaved area on the back (2 x 2 cm). DNFB was diluted in acetone/olive oil (4: 1) immediately before use. Applications
were repeated 7 and 14 days after the first sensitization. Skin inflammation was documented on day 9 and 16 (i.e. 48 h after 2nd and 3rd challenges) by photography and analysis of the scratching response. Near infrared in vivo imaging of the inflammation with MMPSense 680 (ViSen Medical - PerkinElmer) was used to assess the skin inflammation. MMPSense 100 μΐ was injected into the tail vein 30 min before the imaging. Animals were treated with RFlurbi- profen in the drinking water (10 mg/kg daily), starting on day 1 after the first application of DNFB.
Signs of inflammation and scratching injuries were reduced in the R-Flurbiprofen group as shown in Figure 2.
III. Flurbiprofen reduced skin inflammation in a model for non-allergic dermatitis without itching.
Unilateral hind paw inflammation was induced by subcutaneous injection of 0.625 mg zymosan suspended in 100 μΐ phosphate buffer into the midplantar region of the right hind paw in rats. The paw volume was measured before zymosan injection (time 0) and repeatedly after induction of the inflammation up to 24h using a plethysmometer. At each time point five measurements of the paw volume were taken and the average was used to calculate the net paw volume increase as compared to the value before zymosan injection. Animals were treated with an intraperitoneal injection of 9 mg/kg R- flurbiprofen or S-flurbiprofen. The drugs were dissolved in 1 ml phosphate buffer. In control rats the respective volume of vehicle was administered. Six rats were used in each group. The drugs were administered 15 minutes before zymosan. S-Flurbiprofen was used as positive control.
(i?)-flurbiprofen significantly reduced the inflammatory edema and showed stronger efficacy in this model than the (5)-enantiomer (Figure 3).
Claims
1. A compound according to the following formula (I)
(I),
wherein
Ri or R2 is a group selected from H, -CH3, -CH2CH3, -CH2CH2CH3, and -CH2CH2CH2CH3 or can be taken together with another to give a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring, or a cyclohexyl ring,
R3 is a group selected from -COOH, -COORe, -CONH2, -CONHRs, -CONReRy, - CONHS02Rs, -COO-(CH2)3-CH2OH, -COO-(CH2)4-ON02, -COO-PhOCH3-C2H2-COO- (CH2)4-ON02, tetrazolyl, and a -COOH bioisostere,
R4 or R5 is a group selected from -CI, -F, -Br, -I, -CF3, -OCF3, -SCF3, -OCH3, -OCH2CH3, - CN, -CH=CH2, -CH2OH, and -N02,
Rs ot R7 is a group selected from -CH3, -CH2CH3, -CH2CH2CH3, and -CH2CH2CH2CH3, and m or n is an integer selected from 0, 1 , 2, and 3,
or a nitro-variant of said compound, and pharmaceutically acceptable salts of said compound for use in the treatment of a skin disease.
2. The compound according to claim 1 , wherein said compound is an (R ) enantiomer, preferably selected from (i?)-Flurbiprofen (Tarenflurbil ) or N it ro-( /? )- Fl u rb i pro fen .
3. The compound according to claim 1 or 2, wherein said skin disease is characterized by the occurrence of itchiness.
4. The compound according to claim 1 or 2, wherein said skin disease is selected from the group consisting of allergic dermatitis, such as contact allergy; autoimmune dermatitis, such as an atopic dermatitis or neurodermatitis; itchiness caused by dermatitis; idiopathic itchiniss; itchiness caused by the use of medicaments, such as morphine; itchiness caused by diseases of the liver or kidney, such as liver insufficiency or renal failure; non infectious local inflammation of the skin and perioral dermatitis.
5. The compound according to any of claims 1 to 4, wherein said compound is provided in an amount of between 50 mg to 3000 mg, preferably between 100 mg to 1500 mg.
6. The compound according to any of claims 1 to 4, wherein said compound is provided in a dosage of between 5 mg/kg of body weight to 15 mg/kg of body weight per day.
7. The compound according to any of claims 1 to 6, wherein said compound is administered orally, topically, rectally or by injection.
8. The compound according to any of claims 1 to 7, wherein said compound is provided in form of a tablet, capsule, dragee, powder, suppository, gel, cream, spray, ointment and/or solution for injection.
9. The compound according to any of claims 1 to 8, wherein said compound is provided in combination with at least one additional therapeutic against a skin disease.
10. The compound according to claim 9, wherein the at least one additional therapeutic against a skin disease is selected from the group consisting of antihistamines, such as diphenhydramine; corticosteroids, such as hydrocortisone; counterirritants, such as mint oil, menthol, or camphor; crotamiton; and local anesthetics such as benzocaine.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB1114289.0A GB2493914A (en) | 2011-08-19 | 2011-08-19 | Flurbiprofen and related compounds for the treatment of skin diseases |
| GB1114289.0 | 2011-08-19 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2013026772A1 true WO2013026772A1 (en) | 2013-02-28 |
Family
ID=44800539
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP2012/066034 WO2013026772A1 (en) | 2011-08-19 | 2012-08-16 | Flurbiprofen and related compounds for the treatment of skin diseases |
Country Status (2)
| Country | Link |
|---|---|
| GB (1) | GB2493914A (en) |
| WO (1) | WO2013026772A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2017066074A (en) * | 2015-09-30 | 2017-04-06 | 三笠製薬株式会社 | Atopic dermatitis therapeutic agent |
| WO2017080989A1 (en) | 2015-11-09 | 2017-05-18 | Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. | (r)-fluriprofen for the prevention and/or treatment of diabetes |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019099294A1 (en) | 2017-11-14 | 2019-05-23 | Merck Sharp & Dohme Corp. | Novel substituted biaryl compounds as indoleamine 2,3-dioxygenase (ido) inhibitors |
| MX2020004930A (en) | 2017-11-14 | 2020-08-27 | Merck Sharp & Dohme | Novel substituted biaryl compounds as indoleamine 2,3-dioxygenase (ido) inhibitors. |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995011017A1 (en) * | 1993-10-20 | 1995-04-27 | The Boots Company Plc | Ibuprofen and flurbiprofen as anti-pruritic agents |
| US5807568A (en) | 1994-12-27 | 1998-09-15 | Mcneil-Ppc, Inc. | Enhanced delivery of topical compositions containing flurbiprofen |
| US20050042284A1 (en) * | 2003-07-11 | 2005-02-24 | Myriad Genetics, Incorporated | Pharmaceutical methods, dosing regimes and dosage forms for the treatment of Alzheimer's disease |
| US20110082164A1 (en) * | 2009-10-01 | 2011-04-07 | Amira Pharmaceuticals, Inc. | Polycyclic compounds as lysophosphatidic acid receptor antagonists |
| EP2468270A1 (en) * | 2010-12-21 | 2012-06-27 | GALENpharma GmbH | (R)-2-(3-fluoro-4-phenylphenyl)propionic acid for use in the treatment of skin diseases |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2944587A1 (en) * | 1978-11-08 | 1980-05-22 | Upjohn Ltd | PHARMACEUTICAL COMPOSITION FOR USE ON THE SKIN |
| US20030143165A1 (en) * | 2002-01-25 | 2003-07-31 | Allan Evans | NSAID-containing topical formulations that demonstrate chemopreventive activity |
-
2011
- 2011-08-19 GB GB1114289.0A patent/GB2493914A/en not_active Withdrawn
-
2012
- 2012-08-16 WO PCT/EP2012/066034 patent/WO2013026772A1/en active Application Filing
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995011017A1 (en) * | 1993-10-20 | 1995-04-27 | The Boots Company Plc | Ibuprofen and flurbiprofen as anti-pruritic agents |
| US5807568A (en) | 1994-12-27 | 1998-09-15 | Mcneil-Ppc, Inc. | Enhanced delivery of topical compositions containing flurbiprofen |
| US20050042284A1 (en) * | 2003-07-11 | 2005-02-24 | Myriad Genetics, Incorporated | Pharmaceutical methods, dosing regimes and dosage forms for the treatment of Alzheimer's disease |
| US20110082164A1 (en) * | 2009-10-01 | 2011-04-07 | Amira Pharmaceuticals, Inc. | Polycyclic compounds as lysophosphatidic acid receptor antagonists |
| EP2468270A1 (en) * | 2010-12-21 | 2012-06-27 | GALENpharma GmbH | (R)-2-(3-fluoro-4-phenylphenyl)propionic acid for use in the treatment of skin diseases |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2017066074A (en) * | 2015-09-30 | 2017-04-06 | 三笠製薬株式会社 | Atopic dermatitis therapeutic agent |
| WO2017080989A1 (en) | 2015-11-09 | 2017-05-18 | Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. | (r)-fluriprofen for the prevention and/or treatment of diabetes |
Also Published As
| Publication number | Publication date |
|---|---|
| GB201114289D0 (en) | 2011-10-05 |
| GB2493914A (en) | 2013-02-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP3390367B1 (en) | Method for preventing and/or treating aging-associated cognitive impairment and neuroinflammation | |
| JP2002516262A (en) | Pain control with exogenous cannabinoids | |
| WO2013026772A1 (en) | Flurbiprofen and related compounds for the treatment of skin diseases | |
| US20110160306A1 (en) | Use of alkanedicarboxylic acids and retinoids for treatment of rosacea and other inflammatory skin diseases | |
| US8431601B2 (en) | Topical compositions comprising telmesteine for treating dermatological disorders | |
| JP2011506505A (en) | Medicament and its production method and use in the treatment of painful neuropathy | |
| Zhong et al. | Efficacy of a new non-drug acne therapy: Aloe Vera gel combined with ultrasound and soft mask for the treatment of mild to severe facial acne | |
| JP6842794B2 (en) | Topical skin preparation | |
| US10835584B2 (en) | Systems for treating dermal inflammatory conditions | |
| Cantisani et al. | New patents on topical anesthetics | |
| Vinik et al. | Efficacy and tolerability of tapentadol extended release (ER) in patients with chronic, painful diabetic peripheral neuropathy (DPN): results of a phase 3, randomized-withdrawal, placebo-controlled study | |
| US20150119434A1 (en) | Method for Topically Treating Actinic Keratosis with ingenol 3-(3,5-diethylisoxazole-4-carboxylate) | |
| CA2489705A1 (en) | Use of amide derivative of ge 2270 factor a3 for the treatment of acne | |
| CA2809793C (en) | Treatment of fungal infections | |
| Nille et al. | Effect of an Ayurveda treatment in palmoplantar psoriasis: A case study | |
| JP6188784B2 (en) | Compositions for the treatment of inflammatory and immune diseases | |
| KR20190039735A (en) | Compositions and their uses for the treatment or prevention of rubella | |
| JP2002241308A (en) | Therapeutic agent for pruritus cutaneus | |
| RU2313327C1 (en) | Method for treating acne | |
| RU2663452C1 (en) | Pharmaceutical composition in gel medicinal form for local use on the basis of n-(2-adamantil)-hexamethylenemine hydrochloride | |
| EP4403164A1 (en) | Gel composition for prevention or treatment of atopic dermatitis | |
| JP2017114816A (en) | Antipruritic drugs | |
| JPS6229529A (en) | Manufacture of medicine for disease | |
| Doba et al. | Pharmacological Effects of Dexpanthenol | |
| WO2024102219A1 (en) | Compositions including caffeic acid phenethyl ester |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 12747928 Country of ref document: EP Kind code of ref document: A1 |
|
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 12747928 Country of ref document: EP Kind code of ref document: A1 |