US 20190040020A1 ( 19) United States (12 ) Patent Application Publication ( 10) Pub . No. : US 2019 / 0040020 A1 Eriksson et al. (43 ) Pub . Date : Feb . 7 , 2012019 ( 54 ) TETRAZOLE DERIVATIVES AS A61K 45 / 06 (2006 .01 ) CYTOCHROME P450 INHIBITORS A61L 31/ 16 (2006 . 01) ( 52 ) U . S . CI. ( 71 ) Applicant : C26 Bioscience AB , Örebro (SE ) CPC .. .. CO7D 257/ 04 ( 2013 .01 ) ; A61L 31/ 16 ( 72 ) Inventors : Leif Eriksson , Göteborg (SE ); Allan ( 2013 .01 ) ; A61K 45 / 06 ( 2013 .01 ) ; A61K 31/ 41 Sirsjö , Örebro (SE ) ; Åke Strid , Örebro (2013 . 01 ) (SE ) (57 ) ABSTRACT ( 21 ) Appl. No. : 16 /076 , 571 According to the invention there is provided a compound of formula I , wherein Rl and R2 have meanings given in the ( 22 ) PCT Filed : Feb . 10 , 2017 description , which compounds are useful in the treatment of ( 86 ) PCT No .: PCT/ GB2017 /050361 skin disorders and other diseases . $ 371 ( C ) ( 1 ), ( 2 ) Date : Aug . 8, 2018 (30 ) Foreign Application Priority Data Feb . 12 , 2016 (GB ) .. .. 1602572 .8 Publication Classification (51 ) Int. Ci. C07D 257704 ( 2006 .01 ) A61K 31 /41 ( 2006 .01 ) Patent Application Publication Feb . 7 , 2019 Sheet 1 of 5 US 2019 /0040020 A1 0.001 * 0.01 * 0.1 Material(UM)Test 1AFigure * 1 * 10 Control . 2 0 values relative CYP26B1 Patent Application Publication Feb . 7 , 2019 Sheet 2 of 5 US 2019 / 0040020 A1 * 0.001 * 0.01 .1 * 0 TestMaterial(UM) Figure1B * 1 * 10 Control values relative RARB Patent Application Publication Feb . 7 , 2019 Sheet 3 of 5 US 2019 /0040020 A1 * combination bothof new candidate Figure2B * atRA Control values relative RARB * ofboth * newcandidatecombination Figure2A * atRA Control attention a nd wewwwww values relative CYP26B1 Patent Application Publication Feb . 7 , 2019 Sheet 4 of 5 US 2019 / 0040020 A1 * empty vector * 10um Figure3B * lum CYP26B1 30000 25000 20000 15000 10000 5000 protein mg/ dpm RA] H [ * 10um * lum Figure3A Control 60000 50000 40000 30000 20000 10000 protein mg/ dpm RA] H [ Patent Application Publication Feb . 7 , 2019 Sheet 5 of 5 US 2019 / 0040020 A1 Newcandidate5uM+50nMatRA *Newcandidate25uM+50nMatRA control resepigeratRA50nM - 10min 5min Figure4 min1 me www. 30sec tortutofoto r httsuttuto 10sec secO 25000 20000 15000 10000 5000 DPM atRA ] BH[ US 2019 /0040020 A1 Feb . 7 , 2019 TETRAZOLE DERIVATIVES AS has been suggested that the therapeutic effects of atRA are CYTOCHROME P450 INHIBITORS undermined by its rapid in vivo metabolism and catabolism by cytochrome P450 enzymes (CYPs ) . FIELD OF THE INVENTION [ 0009 ] Emerging evidence , both clinical and molecular, [ 0001 ] The present invention relates to new compounds indicates that retinoids may also be used to treat atheroscle and their use in medicine . More specifically , it relates to the rotic lesions and restenosis phenomena in cardiovascular use of compounds in the treatment of diseases and condi disease . Although the data from clinical trials examining the tions in which a retained cellular level of endogenous effect of vitamin A and vitamin A precursors on cardiac all - trans retinoic acid (atRA ) is beneficial through the inhi events have been contradictory , these data do suggest that bition of the enzyme CYP26B1 responsible for degradation retinoids do influence fundamental processes relevant to of atRA . atherosclerosis . Preclinical cellular and animal model stud ies support these concepts . Retinoids exhibit complex effects BACKGROUND OF THE INVENTION on proliferation , growth , differentiation and migration of [0002 ] Retinoic acid (RA ) is a critical signaling molecule vascular smooth muscle cells (VSMC ), including responses in both embryonic development and in post -natal life . RA is to injury and atherosclerosis . Retinoids also appear to exert the active metabolite of Vitamin A (retinol ) and exists in important inhibitory effects on thrombosis and inflammatory several isoforms, of which all - trans RA ( atRA ) , 13 - cisRA responses relevant to atherogenesis . Recent studies suggest and 9 , 13 - dicisRA are those most commonly detected in the that retinoids may also be involved in vascular calcification human body . Endogenous RA isomers are essential for stem and endothelial function , for example , by modulating nitric cell and neuronal differentiation , in regulating insulin stimu oxide pathways. lated glucose secretion , in regulating cell cycles and apop tosis , and in the maintenance of healthy skin , epithelia and 0010 ] Treatment by addition of exogenous atRA or one of the immune system . A high level of cellular atRA has its isoforms is therefore often the main treatment or a efficient antiproliferatory effects . co - treatment for these conditions . 10003 ] The biological activity of the RAs is mainly mani 10011 ] Although atRA - treatment as such is a successful fested by their binding to nuclear RA receptors (RARS ) , treatmentmodality , excessive intake of Vitamin A leads to a which leads to increased transcription of the target genes . syndrome known as hypervitaminosis A or retinoic acid The observed effects on gene transcription are thus depen syndrome, characterized by erythema , weight and hair loss , dent on cellular concentrations of atRA and on the expres bone pain , liver problems, build - up of fluid in lungs and in sion levels of the three RAR isoforms. Catabolism of the rest of the body , kidney failure , skin and eye irritations , cellular atRA is achieved by members of the cytochrome and teratogenicity . In addition , patients may also develop P450 family 26 (CYP26 ) , and in particular CYP26A1 in the RA resistance during treatment. liver and CYP26B1 in other adult human tissues. Inhibition [0012 ] To overcome these severe and unwanted side of members of the CYP26 family may therefore provide a effects, the use of selective CYP26 inhibitors has been means to ensure elevated levels of endogenous atRA in the proposed , possibly together with mild addition of exogenous cells . Such inhibitors are referred to as retinoic acid metabo atRA . The most common and well - studied of these RAM lism blocking agents , RAMBAS . BAs are ketoconazole , liarozole and talarozole . Albeit suc 10004 ] A number of indications have been shown to lead cessful to varying degrees in cell tests , animal models , and to local up -regulation of atRA degrading enzymes and to clinical trials , their efficacy is not extraordinary. The main respond favorably to treatment using exogenous atRA ( or focus for all three RAMBAs has in this context been to target one of its isoforms) due to its ability to down - regulate cell CYP26A1 for treatment of psoriasis , the rare disease kera proliferation . tinocytic ichthyosis , and prostate cancer . [ 0005 ] These indications include dermatological condi tions such as severe acne /rosacea , psoriasis , and keratino [0013 ] The listing or discussion of an apparently prior cytic ichthyosis . Synthetic vitamin A derivatives ( retinoids ) published document in this specification should not neces have long been the mainstay of treatment for several disor sarily be taken as an acknowledgement that the document is ders of keratinization , notably the ichthyoses and severe part of the state of the art or is common general knowledge . acne . Some forms of psoriasis also respond well . [0014 ] The inventors have surprisingly found that the [ 0006 ]. In terms of cosmetic anti -aging applications , pre compounds disclosed herein may be useful as inhibitors of scribed creams containing atRA ( intended for treatment of CYP26 , in particular the CYP26B1 isoform . acne ) , are the only preparations with proven effect against fine lines and wrinkles . [ 0007 ] Recent studies have shown that retinoic acid pro SUMMARY OF THE INVENTION tects against intestinal inflammation mainly by shifting the Treg / Th17 profile , allowing for the treatment of inflamma [ 0015 ] According to the present invention , there is pro tory bowel diseases . vided a compound of formula I : [0008 ] atRA has been successful in the chemotherapy treatment of various cancer forms such as neuroblastoma (NBI ) , acute promyelocytic leukaemia (APL ), prostate can cer and to some extent post -menopausal breast cancer . One of the most impressive effects of atRA has been observed in the treatment of APL . Treatment of patients suffering from APL with high dose of atRA resulted in complete remission . Furthermore , several experiments in animals have demon strated that atRA inhibited the induction and caused the N disappearance of prostate tumors. In spite of these encour N aging results , knowledge of the effects of prolonged atRA therapy on human cancers in the clinic has been scarce . It US 2019 /0040020 A1 Feb . 7 , 2019 wherein : the proviso above will become redundant ( for example , R represents hydrogen or C1- 2 alkyl , which alkyl group is where it is stated that R is a C1- 2 alkyl group substituted by optionally substituted by one or more fluorine atoms; and one or more fluorine atoms, or R is a group other than R ? represents hydrogen or a carboxylic acid protecting hydrogen ) . group ; 10023 ] In an embodiment of the invention , there is pro or a pharmaceutically acceptable salt thereof , vided a compound of formula I wherein R is a methyl provided that the compound or pharmaceutically acceptable group , optionally substituted by one or more fluorine atoms . salt thereof is not the compound of formula II : For example , in a further embodiment, R represents methyl or trifluoromethyl. [ 0024 ] In an alternative embodiment, R ' represents hydro gen , methyl or ethyl.