GB2493914A - Flurbiprofen and related compounds for the treatment of skin diseases - Google Patents

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

Flurhiprofen and Related Compounds for the Treatment of Skin Diseases The present invention relates to the use of a compound according to the following formula (1) (R4)n_____f__ II (R5)m__f_._ II (1), wherein R or R2 is a group selected from H. -CH1. -CH2CH3, -CH2CH2CH3, and - CH2CH2CH2CI-13 or can be taken together with another to give a eyelopropyl ring, a cyclobu- tyl 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)4-0N02, -COO-PhOCft-C2H2-COO-(CH2)4-0N02, tetrazolyl, and a -COOH bioisos- tere, R.4 or R5 is a group selected from -Cl, -F, -Br, -I, -CE3, -OCF3, -SCF3, -OCH3, - OCI-12CH3, -CN, -CH=CH2, -CH2OI-1, and -NO2, R 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)-eriantiomer thereof, such as Tarenflurbil ((R)-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 "inflamma- tion". Therefore, dermatitis denotes an inflammation of the skin, often occurring in the con-text 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.

I

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 derma-titis.

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 from of an ointment, cream or spray. Such pharmaceutical compositions include corticosteroids and antihistamines as active compounds. None pharmacological treat-ments include wet compresses and the avoiding of allergens and irritants -such instructions are part of most treatment plans. Other pharmaceutically active compounds used are nonster- oidal medications which however help to relieve signs and symptoms and do not cure the dis-ease.

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 topi- cally applied medicaments in the form of ointments, creams or sprays. Also orally adminis-tercd anti-itch drugs exist, but arc usually only available under prescription. Pharmaceutically active components included in these medicaments are antihistamines, such as diphenhy-dramine, corticosteroids, such as hydrocortisonc 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 itch-ing and/or dermatitis.

Alternative therapies, such as phototherapy is successfully used against severe itching, espe-cially 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 ((R)-Flurbiprofen) (chemical name (R)-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.

(R)-Flurbiprofen, together with, for example, Ibuprofen and Naproxen, belongs to the group of 2-aryl propionic acids (profens). Just like Ibuprofen, (R)-Flurbiprofen is a by-product of thc marketed racemie Flurbiprofen, the active agent of which is thought to be the (S)-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 com-prising about 0.5 to 10% flurbiprofen; and methods for delivering flurbiprofen-eontaining compositions through the skin. The fiurbiprofea compositions show enhanced permeability of the skin and therefore are useful for the treatment of conditions in the joints or soft tissue be-neath 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 cffect of the topical administration of the drug was assessed, but no correlation observed between the clinical ef-fects 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 of the present invention, this object of the present invention is solved by of a compound according to the following formula (I) R2 (R4)fl {Rs)m__I__ II (I), wherein R1 or R2 is a group selected from H, -CH3, -CH2CH, -CI-I2CH2CH3, 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, - COOR6, -CON El2, -CONHR5, -CON R6R7, -CONHSO2R6, -COO-(CH2)3-CH2OH, -COO- (CH2)4-0N02, -COO-PhOCH-C2H2-COO-(CH2)4-ONO2, tetrazolyl, and a -COOH bioisos- tere, R4 or R5 is a group selected from -Cl, -F, -Br, -I. -CF3, -OCF2, -SCF3. -OCH1. - OCH2CH3, -CN, -CHCH2, -CH2OH, and -NO2, R6 ot R7 is a group selected from -CH3, -CI-12CH3, -CI-I2CH2CH3, and -CI-12C1-I2CH2CI-13, and morn is an integer selected from 0, 1, 2, and 3, or a nitro-variant of said compound, such as (R)-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 (R)-enantiomer of a compound of the present invention.

Preferably, R1 is selected from 1-1. Further preferred is the use of a compound according to the present invention which is selected from the group of (R)-2-(2-fluoro-4-phenylphenyl)propionic acid.

(R)-2-(2-fluoro-biphenyl-4-yl)propionic acid 4-nitrooxybutyl ester, (R)-1,1 -biphenyl)-4-aeetic acid 2-fluoro-a-methyl-4-hydroxybutylester, (R)-3-[4-(2-fluoro-a-methyl-[ 1,1 -biphenyl]-4-acetyloxy)-3-methoxyphenyl-2-propenoic acid 4-nitrooxybutyl ester, (R)-2-methyl-2(2-fluoro-4'-trifluoromethyfljiphen-4-yl)propionic acid, (R)-2-methyl-2(2-fluoro-4'eyelohexylbiphen-4-yl)propion ic acid, (R)-2-(2-fluoro-3',5'-bis(chloro)biphen-4-yfl propionic acid amide, (R)-2-(2-fl uoro-4'-trifluoromcthy lbiphen-4-yl)propionic acid, (R)-2-(2-fl uoro-3'-trifluoromethy lbiphen-4-yl) propionic acid, (R)-2-(2-fluoro-3',5'-bis(trifluoromethyl)biphcn-4-yl)propionic acid, (R)-2-(4'-cyclohexyl-2-fl uorobiphen-4-yl)propionic acid, (R)-2-(2-Fluoro-1,1 -biphenyl-4-yl) -2-methylpropanoic acid, and (R)-5 -[1 -(2-Fluoro-biphenyl-4-yl)-1-methyl-ethyl] -2H-tetrazole.

Further preferred is (R)-Flurhiprofen or Nitro-(R)-Fiurhiproien for use in the treatment of a skin disease. Even frirther preferred is the use of a compound as above, preferably (R)-FAuliprofen or Nitro-(R)-Flurhiproferi 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 invcntion, and preferably (R)-Fiurbiprofen or Nitro..(R)-Flurbiprofen. The primary aims of therapy according to the present invention are to reduce inflammation of the skin, and specifically to reduce the itching symptom, and thereby to bring relieve to a patient who suffers from dermatitis and to reduce the occurrence of inju-ries 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 dis- eases of the dermis, most preferably inflammatory disease of the dermis like dermatitis. Al-ternatively, 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 atopie dermatitis or ncurodcrmitis; itchiness caused by dermatitis; idiopathic itchiness; itchi-ness caused by the use of medicamcnts, 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 (R)-enantiomer of a profen-compound, namely (R)-F'lurhiprofen, reducesiftihihits the occurrence of ml animation of the skin. This provides a new avenue to tackle dermatitis Furthermore, it was surprisingly found that the treatment with a compound of the invention, preferably an (Th-enantiomer of a pro- fen-compound, namely (R)--Flurbiprofen, resulted in reduced itching. Therefore, the com- pounds of the present invention may he used for treating the itching symptom in a patient suf-fering from a skin or neurological disease.

In contra-st to its S-isomer, R-Flurhiprofen does not inhibit the eyciooxygenases and has no effect on the prostaglandin synthesis. Even at high daily 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 cyclooxygenases and has no effect on the prostaghindin synthesis, comprising administering to a patient in need thereof a therapeuti- cally effective amount of a compound according to the present invention, and preferably R-Flurhiprofen or Nitro-R-Fluthiprofen.

Even at high daily dosage and long-term therapy, no essential toxicity of (R)-Flurbiprofen is known. Thus, generally arty dosage of a compound according to the present invention, and preferably (R)-Flurhiprofen or Nitro-(R)-Fiurbiprofen, can be used which exhibits an advan-tageous 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 (R)-ilurhiprotèn or Niuo-(1{)-Fiurbiprofen, according to the invention, wherein said compound according to the present invention, and preferably (R)-Flurbiprofen or Nitro-(R)-Flurhiprofen, is provided in an amount of between 50 mg to 3000 mg, preferably of between 100 mg to 1500 mg, more pref-erably between 300 mg to 1200 mg per dosage form. Further preferred is a use, wherein said compound according to the present invention, and preferably (/fl-Fiurbiprofen or Nitro-(R)-Flurhiprofen, is provided in a dosage of between 5 mg/kg of body weight to 15 mg/kg of body weight of the patient to be treated per day.

In general, a compound according to the present invention, and preferably (R)-Fiurbiprofen or Nitro-(R)-Fhirhiprofen. 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. Further-more, the compound according to the present invention, and preferably (k)-Ffturhiprofen or Nilro-(R)-Flurbipmfen, can be provided to the patient in any suitable and effective pharma- ceutically acceptable form, such as in the form of a tablet, capsule, dragée, powder, supposi-tory, gel, cream, spray, ointment and/or as solution for iijection.

The compound according to the present invention, and preferably (R)-Flurbiprofen or Nitro- (R)-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 derma-titis, 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 com-pounds and treatments that are available Jbr 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 (R)-Flurbiprofen or Nitro-(R)-Flurbiprofen, wherein said a compound according to the present invention, and preferably (R)-Flurbipmfen or Nitro-(R)-Flurbipmfen, is provided in combination with least one additional therapeutic against a skin disease is selected from the group consisting of antihistamines, such as diphen- hydramine; corticosteroids, such as hydrocortisone; counterirritants, such as mint oil, men-thol, or camphor; crotamiton; and local anesthetics such as benzocaine.

Pharmaceutical formulations according to the present invention, preferably pharmaceutical fbrmulations comprising (R)-Flurbipmfen or Nitro-(R)-Flurbiprofen, lbr the use in the treat-ment of dermatitis, further comprise pharmaceutically acceptable carriers and/or exipients.

The present invention 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 (R)-Flurbipmfen or Nitro-(R)-Flurbiprofen, as described herein.

The main advantage of a compound according to the present invention, and preferably (R)- Flurbiprofen or Nitro-(R)-Flurbiprofen, is its low toxicity, which is sufficiently proven for R- Flurbiprofen. Even with a long-term therapy in old patients no significant side-effects oe-cuned. 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 (R)-Flurbiprofen or Nitro-(R)-Fiurbiprofen, wherein the dermatitis is resistant to standard dermatitis treatments, or wherein the patient suffers fitm 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 embodi-ment said standard dermatitis treatment comprises the administnition of antihistanilnes 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 inven- tion, all references as cited herein are incorporated by reference in their entireties. In the Fig-ures, Figure 1: shows the scratching behavior after subcutaneous injection of compound 48/80 (50 pg in 100 p1 Ringer solution) in C57BL6 mice (m, 8-10 weeks). Treat-ments: R-Flurbiprofen 3 x 5 mg/kg orally with 12h interval, last dose 30 miii before Compound 48/80. Controls received vehicle. (A)Timc 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 sensiti-zation with DNFB. DNFB was applied (0.2 %, 50 p1) 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

1. In a mouse model of IgE mediated type 1 allergic dermatitis (R)-Flurbiprofen reduced scratching behavior.

Compound 48/80 evoked itching dermatitis (model for igE-mediated type-i aHergic dermati- tis, itch evoked by insect bites, drug induced itch e.g. by morphine, non-allergic chronic pruri-tus). Mice were pretreated with R-Flurbiprofen or vehicle. They received 3 doses of 5 mg/kg body weight perorally in DM50/water with 12h intervals. The last dose was administered 30 mm before injection of compound 48/80. Control animals received equal volumes of the vehi-cle. 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 mm 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 jig compound 48/80 in 100 pi 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 mm. The time mice spent scratching the back surrounding the injection site with a hind leg was recorded with a stop watch in 5 mm inter-vals. 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 1A) 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 atopie dermatitis, contact allergic der- matitis, delayed type 4 hypersensitivity) CS7BL6 mice were sensitized by 2,4-dinitro-i-fluorobenzene, DNFB application (50 t1 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 -10 -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 R1 was injected into the tail vein 30 mm 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.

HI. Flurbiprofen reduced skin inflammation in a model for non-allergic dermatitis with-out itching.

Unilateral hind paw inflammation was induced by subcutaneous injection of 0.625 mg zymo-san suspended in 100 p1 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 vehi- cle was administered. Six rats were used in each group. The drugs were administered 15 min-utes before zymosan. S-Flurbiprofcn was used as positive control.

(R)-flurbiprofen significantly reduced the inflammatory edema and showed stronger efficacy in this model than the (S)-enantiomer (Figure 3). -11 -

Claims (1)

1. <claim-text>Claims 1. A compound according to the following formula (I) (R4)n_____f__ II (R5)m__f_._ II (1), 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, -COOR5, -CONH2, -CONHR6, -CONR5R7, - CONHSO2R6, -COO-(CU2)-CH2OH, -COO-(Cl-12)4-0N02, -COO-PhOCH1-C2H2-COO- (CH2)4-0N02, tetrazolyl, and a -COOH bioisostcre, R4 or R5 is a group selected from -Cl, -F, -Br, -I, -CF3, -OCF3, -SCF3, -OCH3, -OCH2CH3, -CN, -CH=CH2, -CH2OH, and -NO2, R ot R7 is a group selected from -CH3, -CH2CH3, -CH2CI-12C1-13, and -CH2CF]2CH2CH3, 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.</claim-text> <claim-text>2. The compound according to claim 1, wherein said compound is an (R) enantiomer, prefera-bly selected from (R)-Fiurhiprofen (Tarenflurbil) or Nifro-(R)-Fiurbiprotèn.-12 - 3. The compound according to claim 1 or 2, wherein said skin disease is characterized by the occurrence of itchiness.</claim-text> <claim-text>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 neurodermitis; itchiness caused by dermatitis; idiopathic itchiniss; itchiness caused by the use of medicaments, such as morphine; itchincss caused by diseases of the liver or kidney, such as liver insufficiency or renal failure; non infectious local inflamma-tion of the skin and pcrioral dcrmatitis.</claim-text> <claim-text>4. The compound according to any of claims ito 3, wherein said compound is provided in an amount of between 50 mg to 3000 mg, preferably between 100 mg to 1500 mg.</claim-text> <claim-text>5. The compound according to any of claims I to 3, whcrcin said compound is providcd in a dosage of between 5 mg/kg of body weight to 15 mg!kg of body weight per day.</claim-text> <claim-text>6. The compound according to any of claims Ito 5, wherein said compound is administered orally, rectally or by injection.</claim-text> <claim-text>7. The compound according to any of claims ito 6, wherein said compound is provided in form of a tablet, capsule, dragée, powder, suppository, gd or solution for injection.</claim-text> <claim-text>8. The compound according to any of claims ito 7, wherein said compound is provided in combination with at least one additional therapeutic against a skin discase.</claim-text> <claim-text>9. The compound according to claim 8, wherein the at least one additional therapeutic against a skin disease is selected from the group consisting of antihistamines, such as diphenhy-dramine; corticosteroids, such as hydrocortisone; counterirritants, such as mint oil, menthol, or camphor; crotamiton; and local anesthetics such as benzocaine.</claim-text>