CA2633411A1 - Diaryl ureas for treating inflammatory skin, eye and/or ear diseases - Google Patents
Diaryl ureas for treating inflammatory skin, eye and/or ear diseases Download PDFInfo
- Publication number
- CA2633411A1 CA2633411A1 CA002633411A CA2633411A CA2633411A1 CA 2633411 A1 CA2633411 A1 CA 2633411A1 CA 002633411 A CA002633411 A CA 002633411A CA 2633411 A CA2633411 A CA 2633411A CA 2633411 A1 CA2633411 A1 CA 2633411A1
- Authority
- CA
- Canada
- Prior art keywords
- formula
- alkyl
- optionally substituted
- compound
- eye
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- -1 Diaryl ureas Chemical class 0.000 title claims abstract description 75
- 201000004624 Dermatitis Diseases 0.000 title claims abstract description 27
- 208000032625 disorder of ear Diseases 0.000 title claims abstract description 18
- 208000030533 eye disease Diseases 0.000 title claims abstract description 18
- 235000013877 carbamide Nutrition 0.000 title description 16
- 239000003814 drug Substances 0.000 claims abstract description 32
- 229940124597 therapeutic agent Drugs 0.000 claims abstract description 20
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims description 79
- 150000003839 salts Chemical class 0.000 claims description 25
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 24
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 22
- 238000000034 method Methods 0.000 claims description 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 22
- 125000001424 substituent group Chemical group 0.000 claims description 22
- 206010012442 Dermatitis contact Diseases 0.000 claims description 19
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 18
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 16
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims description 14
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 14
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 14
- 150000002367 halogens Chemical class 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 229940002612 prodrug Drugs 0.000 claims description 12
- 239000000651 prodrug Substances 0.000 claims description 12
- 238000011282 treatment Methods 0.000 claims description 12
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 12
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 10
- 229910052731 fluorine Inorganic materials 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 125000001624 naphthyl group Chemical group 0.000 claims description 10
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims description 9
- 229940079593 drug Drugs 0.000 claims description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- 239000011737 fluorine Substances 0.000 claims description 9
- 125000001153 fluoro group Chemical group F* 0.000 claims description 9
- 125000001188 haloalkyl group Chemical group 0.000 claims description 9
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 claims description 8
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 claims description 8
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 8
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 8
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 8
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 8
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 8
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 239000000460 chlorine Chemical group 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 125000001072 heteroaryl group Chemical group 0.000 claims description 8
- 208000027866 inflammatory disease Diseases 0.000 claims description 8
- 230000000622 irritating effect Effects 0.000 claims description 8
- 239000002207 metabolite Substances 0.000 claims description 8
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 8
- 239000012453 solvate Substances 0.000 claims description 8
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea group Chemical group NC(=O)N XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 8
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 claims description 7
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims description 7
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 7
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 7
- 206010046851 Uveitis Diseases 0.000 claims description 7
- 208000002029 allergic contact dermatitis Diseases 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 7
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 claims description 7
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 claims description 7
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
- 150000003536 tetrazoles Chemical class 0.000 claims description 7
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 claims description 7
- 229930192474 thiophene Natural products 0.000 claims description 7
- 150000003852 triazoles Chemical class 0.000 claims description 7
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
- 239000003246 corticosteroid Substances 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims description 6
- 125000004076 pyridyl group Chemical group 0.000 claims description 6
- 206010012438 Dermatitis atopic Diseases 0.000 claims description 5
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
- 201000008937 atopic dermatitis Diseases 0.000 claims description 5
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 239000001301 oxygen Chemical group 0.000 claims description 5
- 238000002560 therapeutic procedure Methods 0.000 claims description 5
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 5
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 5
- NQPJDJVGBDHCAD-UHFFFAOYSA-N 1,3-diazinan-2-one Chemical compound OC1=NCCCN1 NQPJDJVGBDHCAD-UHFFFAOYSA-N 0.000 claims description 4
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- OXBLVCZKDOZZOJ-UHFFFAOYSA-N 2,3-Dihydrothiophene Chemical compound C1CC=CS1 OXBLVCZKDOZZOJ-UHFFFAOYSA-N 0.000 claims description 4
- JKTCBAGSMQIFNL-UHFFFAOYSA-N 2,3-dihydrofuran Chemical compound C1CC=CO1 JKTCBAGSMQIFNL-UHFFFAOYSA-N 0.000 claims description 4
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 claims description 4
- 206010033078 Otitis media Diseases 0.000 claims description 4
- 201000004681 Psoriasis Diseases 0.000 claims description 4
- 206010038910 Retinitis Diseases 0.000 claims description 4
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 claims description 4
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims description 4
- YPWFISCTZQNZAU-UHFFFAOYSA-N Thiane Chemical compound C1CCSCC1 YPWFISCTZQNZAU-UHFFFAOYSA-N 0.000 claims description 4
- 125000005037 alkyl phenyl group Chemical group 0.000 claims description 4
- 229960001334 corticosteroids Drugs 0.000 claims description 4
- 125000005265 dialkylamine group Chemical group 0.000 claims description 4
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 150000004677 hydrates Chemical class 0.000 claims description 4
- 206010023332 keratitis Diseases 0.000 claims description 4
- 206010025135 lupus erythematosus Diseases 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000004043 oxo group Chemical group O=* 0.000 claims description 4
- KASDHRXLYQOAKZ-ZPSXYTITSA-N pimecrolimus Chemical compound C/C([C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@]2(O)O[C@@H]([C@H](C[C@H]2C)OC)[C@@H](OC)C[C@@H](C)C/C(C)=C/[C@H](C(C[C@H](O)[C@H]1C)=O)CC)=C\[C@@H]1CC[C@@H](Cl)[C@H](OC)C1 KASDHRXLYQOAKZ-ZPSXYTITSA-N 0.000 claims description 4
- 229960005330 pimecrolimus Drugs 0.000 claims description 4
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 claims description 4
- 150000003248 quinolines Chemical class 0.000 claims description 4
- 229910052705 radium Inorganic materials 0.000 claims description 4
- 229910052701 rubidium Inorganic materials 0.000 claims description 4
- 229960001967 tacrolimus Drugs 0.000 claims description 4
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 claims description 4
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 claims description 4
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 claims description 4
- 125000005034 trifluormethylthio group Chemical group FC(S*)(F)F 0.000 claims description 4
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 claims description 4
- 150000003973 alkyl amines Chemical class 0.000 claims description 3
- 229940111121 antirheumatic drug quinolines Drugs 0.000 claims description 3
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 claims description 2
- 108010036949 Cyclosporine Proteins 0.000 claims description 2
- 108010008165 Etanercept Proteins 0.000 claims description 2
- 241000283898 Ovis Species 0.000 claims description 2
- 241000700639 Parapoxvirus Species 0.000 claims description 2
- 101100054666 Streptomyces halstedii sch3 gene Proteins 0.000 claims description 2
- 229960002964 adalimumab Drugs 0.000 claims description 2
- 230000003110 anti-inflammatory effect Effects 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 229960001265 ciclosporin Drugs 0.000 claims description 2
- 229930182912 cyclosporin Natural products 0.000 claims description 2
- 229960000284 efalizumab Drugs 0.000 claims description 2
- 229960000403 etanercept Drugs 0.000 claims description 2
- 239000001530 fumaric acid Substances 0.000 claims description 2
- 229960002598 fumaric acid Drugs 0.000 claims description 2
- 229960000598 infliximab Drugs 0.000 claims description 2
- PQIOSYKVBBWRRI-UHFFFAOYSA-N methylphosphonyl difluoride Chemical group CP(F)(F)=O PQIOSYKVBBWRRI-UHFFFAOYSA-N 0.000 claims description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 9
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 6
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims 5
- 150000002431 hydrogen Chemical class 0.000 claims 3
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 2
- 229940121363 anti-inflammatory agent Drugs 0.000 claims 1
- 239000002260 anti-inflammatory agent Substances 0.000 claims 1
- 125000005490 tosylate group Chemical class 0.000 claims 1
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 abstract description 5
- 239000004202 carbamide Substances 0.000 abstract description 5
- 229960003787 sorafenib Drugs 0.000 abstract description 5
- 239000000203 mixture Substances 0.000 description 18
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 17
- 238000003786 synthesis reaction Methods 0.000 description 15
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- 238000002360 preparation method Methods 0.000 description 12
- 208000010247 contact dermatitis Diseases 0.000 description 10
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 10
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 9
- 229910052740 iodine Inorganic materials 0.000 description 9
- 239000002253 acid Substances 0.000 description 8
- 239000002585 base Substances 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- 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 description 8
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- 125000003545 alkoxy group Chemical group 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- 102000009929 raf Kinases Human genes 0.000 description 7
- 108010077182 raf Kinases Proteins 0.000 description 7
- GHMLBKRAJCXXBS-UHFFFAOYSA-N resorcinol Chemical compound OC1=CC=CC(O)=C1 GHMLBKRAJCXXBS-UHFFFAOYSA-N 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 6
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- 239000000890 drug combination Substances 0.000 description 6
- 125000005843 halogen group Chemical group 0.000 description 6
- 102000002574 p38 Mitogen-Activated Protein Kinases Human genes 0.000 description 6
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- 238000000844 transformation Methods 0.000 description 6
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 239000003599 detergent Substances 0.000 description 5
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 5
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 5
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- 229960003943 hypromellose Drugs 0.000 description 5
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical class OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
- 125000002619 bicyclic group Chemical group 0.000 description 4
- 239000004305 biphenyl Substances 0.000 description 4
- 235000010290 biphenyl Nutrition 0.000 description 4
- 125000001246 bromo group Chemical group Br* 0.000 description 4
- 239000011248 coating agent Substances 0.000 description 4
- 238000000576 coating method Methods 0.000 description 4
- 125000004122 cyclic group Chemical group 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
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- 238000009472 formulation Methods 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
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- 229940043355 kinase inhibitor Drugs 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 229910052751 metal Inorganic materials 0.000 description 4
- 239000002184 metal Substances 0.000 description 4
- 150000007522 mineralic acids Chemical class 0.000 description 4
- 125000004999 nitroaryl group Chemical group 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 235000019198 oils Nutrition 0.000 description 4
- 150000007524 organic acids Chemical class 0.000 description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 4
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 229960001755 resorcinol Drugs 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
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- LGZXYFMMLRYXLK-UHFFFAOYSA-N mercury(2+);sulfide Chemical compound [S-2].[Hg+2] LGZXYFMMLRYXLK-UHFFFAOYSA-N 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- CCRCUPLGCSFEDV-BQYQJAHWSA-N methyl trans-cinnamate Chemical compound COC(=O)\C=C\C1=CC=CC=C1 CCRCUPLGCSFEDV-BQYQJAHWSA-N 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 239000002324 mouth wash Substances 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 235000010460 mustard Nutrition 0.000 description 1
- 125000001421 myristyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-M naphthalene-2-sulfonate Chemical compound C1=CC=CC2=CC(S(=O)(=O)[O-])=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-M 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229960004927 neomycin Drugs 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 1
- LGQLOGILCSXPEA-UHFFFAOYSA-L nickel sulfate Chemical compound [Ni+2].[O-]S([O-])(=O)=O LGQLOGILCSXPEA-UHFFFAOYSA-L 0.000 description 1
- 229910000363 nickel(II) sulfate Inorganic materials 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 201000005111 ocular hyperemia Diseases 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- ATGUVEKSASEFFO-UHFFFAOYSA-N p-aminodiphenylamine Chemical compound C1=CC(N)=CC=C1NC1=CC=CC=C1 ATGUVEKSASEFFO-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- JRKICGRDRMAZLK-UHFFFAOYSA-L peroxydisulfate Chemical compound [O-]S(=O)(=O)OOS([O-])(=O)=O JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 229950000688 phenothiazine Drugs 0.000 description 1
- 229940096826 phenylmercuric acetate Drugs 0.000 description 1
- VUXSPDNLYQTOSY-UHFFFAOYSA-N phenylmercuric borate Chemical compound OB(O)O[Hg]C1=CC=CC=C1 VUXSPDNLYQTOSY-UHFFFAOYSA-N 0.000 description 1
- 229960000247 phenylmercuric borate Drugs 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 229960004838 phosphoric acid Drugs 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- 229950010765 pivalate Drugs 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 230000007096 poisonous effect Effects 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
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- 230000003389 potentiating effect Effects 0.000 description 1
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- 125000006239 protecting group Chemical group 0.000 description 1
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- 238000000746 purification Methods 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 229940079877 pyrogallol Drugs 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 229960000948 quinine Drugs 0.000 description 1
- 229960003110 quinine sulfate Drugs 0.000 description 1
- 238000011555 rabbit model Methods 0.000 description 1
- 235000009736 ragweed Nutrition 0.000 description 1
- 208000002574 reactive arthritis Diseases 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 208000008742 seborrheic dermatitis Diseases 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 231100000489 sensitizer Toxicity 0.000 description 1
- 239000002453 shampoo Substances 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 239000000344 soap Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000008275 solid aerosol Substances 0.000 description 1
- 239000004759 spandex Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 235000013599 spices Nutrition 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000011301 standard therapy Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000001384 succinic acid Chemical class 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229940032330 sulfuric acid Drugs 0.000 description 1
- 230000000475 sunscreen effect Effects 0.000 description 1
- 239000000516 sunscreening agent Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229940037128 systemic glucocorticoids Drugs 0.000 description 1
- 239000001648 tannin Substances 0.000 description 1
- 229920001864 tannin Polymers 0.000 description 1
- 235000018553 tannin Nutrition 0.000 description 1
- 239000011269 tar Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 206010043207 temporal arteritis Diseases 0.000 description 1
- 229910052718 tin Inorganic materials 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 229940026191 topical antipsoriatics tars Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 229940126702 topical medication Drugs 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 208000002419 toxicodendron dermatitis Diseases 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000010938 white gold Substances 0.000 description 1
- 229910000832 white gold Inorganic materials 0.000 description 1
- 210000002268 wool Anatomy 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- 229910052726 zirconium Inorganic materials 0.000 description 1
Classifications
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- 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
-
- 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
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/16—Otologicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
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- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Dermatology (AREA)
- Pulmonology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Ophthalmology & Optometry (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The present invention relates to pharmaceutical compositions for treating inflammatory skin, eye and/or ear diseases comprising at least a diaryl urea compound optionally combined with at least one additional therapeutic agent.
Useful combinations include e.g. BAY 43-9006 as a diaryl urea compound.
Useful combinations include e.g. BAY 43-9006 as a diaryl urea compound.
Description
DIARYL UREAS FOR TREATING INFLAMMATORY SKIN, EYE AND/OR EAR
DISEASES
The present invention relates to pharmaceutical compositions for treating inflammatory skin, eye and/or ear diseases comprising at least a diaryl urea compound optionally combined with at least one additional therapeutic agent. Useful combinations include e.g. BAY 43-9006 as a diaryl urea compound.
BAY 43-9006 refers to 4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-phenoxy}-pyridine-2-carboxylic acid methyl amide and is species of diaryl urea compounds which are potent anti-cancer and anti-angiogenic agents that possess various activities, including inhibitory activity on the VEGFR, PDGFR, raf, p38, and/or flt-3 kinase signaling molecules. See, e.g., WO
and WO 2005/000284.
Contact dermatitis is one of the most frequently occurred inflammatory skin, eye and/or ear diseases and is a kind of intolerance against e.g. external toxins (S.A.
Bucher, Kontaktdermatitis, Schweiz Med Forum, 2001, 18, 458) which can be differentiated in an allergic contact dermatitis and a toxic irritative one. The allergic contact dermatitis is a type IV
reaction according to Coombs and Gell und requires a specific sensitisation against specific environmental substances (D.
Belsito, J. Allergy Clin. Immunol. 2000, 105, 409). The irritative contact dermatitis is a primary inflammation of the skin in response to chemical or physical stimuli without immune reasons (H.
Loffler et la., Die irritative Kontaktdermatitis, Hautarzt, 2000, 51, 203).
The standard therapy of the contact dermatitis is a local application of glucocorticoids followed by an protective skin care (e.g. hydrating or fatty cremes). Recent therapeutic agents are pimecrolimus and tacrolimus which latter is also used for the treatment of atopic dermatitis and psoriasis.
It is known that 2,4-dinitrofluorbenzene - a highly sensitising agent -activates the ERK 1/2 and the MAPK signal pathway in antigen presenting dendritic cells which were extracted from mice skin (T.S. Matos, J. Dermatol. Sci. 2005, 39 113).
The present invention provides pharmaceutical compositions for treating inflammatory skin, eye and/or ear diseases comprising at least one compound of formula I and optionally at least one further therapeutic agent.
The present invention provides a therapeutic method which treat inflammatory skin, eye and/or ear diseases more effectively compared to current therapies and therefore is superior to current therapies. The present invention can be used e.g. by administering a diaryl urea compound of formula I and optionally a further therapeutic agent, pharmaceutically-acceptable salts thereof, and derivatives thereof, etc.
The compounds with the structure of formula (I), pharmaceutically acceptable salts, polymorphs, solvates, hydrates metabolites and prodrugs thereof, including diastereoisomeric forms (both isolated stereoisomers and mixtures of stereoisomers) are collectively referred to herein as the "compounds of formula P.
Formula (I) is as follows:
0 (RZ)m Zk Q
A-N N- B L
H H
wherein Q is -C(O)RX
RX is hydroxy, C14 alkyl, C14 alkoxy or NRaRb, Ra and Rb are independently :
a) hydrogen;
b) C14 alkyl, optionally substituted by - hydroxy, - C14 alkoxy, - a heteroaryl group selected from pyrrole, furan, thiophene, imidazole, pyrazole, thiazole, oxazole, isoxazole, isothiazole, triazole, tetrazole, thiadiazole, oxadiazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine, benzoxazole, isoquioline, quinolines and imidazopyrimidine - a heterocyclic group selected from tetrahydropyran, tetrahydrofuran, 1,3-dioxo-lane, 1,4-dioxane, morpholine, thiomorpholine, piperazine, piperidine, piperi-dinone, tetrahydropyrimidone, pentamethylene sulfide, tetramethylene sulfide, dihydropyrane, dihydrofuran, and dihydrothiophene, WO 2007/068381 _ PCT/EP2006/011691 - amino,-NH2, optionally substituted by one or two CI-4 alkyl groups, or - phenyl, c) phenyl optionally substituted with - halogen, or - amino,-NH2, optionally substituted by one or two C14 alkyl, or d) - a heteroaryl group selected from pyrrole, furan, thiophene, imidazole, pyrazole, thiazole, oxazole, isoxazole, isothiazole, triazole, tetrazole, thiadiazole, oxadiazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine, benzoxazole, isoquioline, quinoline and imidazopyrimidine;
A is optionally substituted phenyl, pyridinyl, naphthyl, benzoxazole, isoquioline, quinoline or imidazopyrimidine;
B is optionally substituted phenyl or naphthyl:
L is a bridging group which is -S- or -0-;
m is0,1,2or3,and each R2 is independently C1_5 alkyl, C1_5 haloalkyl, C 1_3 alkoxy, N-oxo or N-hydroxy.
Structures of optionally substituted phenyl moieties for A of formula (1) which are of particular interest include structures of formula lxx:
(R3 )n 1xx Structures of optionally substituted pyridinyl moieties for A of formula (1) which are of particular interest include structures of formula 1 x:
DISEASES
The present invention relates to pharmaceutical compositions for treating inflammatory skin, eye and/or ear diseases comprising at least a diaryl urea compound optionally combined with at least one additional therapeutic agent. Useful combinations include e.g. BAY 43-9006 as a diaryl urea compound.
BAY 43-9006 refers to 4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-phenoxy}-pyridine-2-carboxylic acid methyl amide and is species of diaryl urea compounds which are potent anti-cancer and anti-angiogenic agents that possess various activities, including inhibitory activity on the VEGFR, PDGFR, raf, p38, and/or flt-3 kinase signaling molecules. See, e.g., WO
and WO 2005/000284.
Contact dermatitis is one of the most frequently occurred inflammatory skin, eye and/or ear diseases and is a kind of intolerance against e.g. external toxins (S.A.
Bucher, Kontaktdermatitis, Schweiz Med Forum, 2001, 18, 458) which can be differentiated in an allergic contact dermatitis and a toxic irritative one. The allergic contact dermatitis is a type IV
reaction according to Coombs and Gell und requires a specific sensitisation against specific environmental substances (D.
Belsito, J. Allergy Clin. Immunol. 2000, 105, 409). The irritative contact dermatitis is a primary inflammation of the skin in response to chemical or physical stimuli without immune reasons (H.
Loffler et la., Die irritative Kontaktdermatitis, Hautarzt, 2000, 51, 203).
The standard therapy of the contact dermatitis is a local application of glucocorticoids followed by an protective skin care (e.g. hydrating or fatty cremes). Recent therapeutic agents are pimecrolimus and tacrolimus which latter is also used for the treatment of atopic dermatitis and psoriasis.
It is known that 2,4-dinitrofluorbenzene - a highly sensitising agent -activates the ERK 1/2 and the MAPK signal pathway in antigen presenting dendritic cells which were extracted from mice skin (T.S. Matos, J. Dermatol. Sci. 2005, 39 113).
The present invention provides pharmaceutical compositions for treating inflammatory skin, eye and/or ear diseases comprising at least one compound of formula I and optionally at least one further therapeutic agent.
The present invention provides a therapeutic method which treat inflammatory skin, eye and/or ear diseases more effectively compared to current therapies and therefore is superior to current therapies. The present invention can be used e.g. by administering a diaryl urea compound of formula I and optionally a further therapeutic agent, pharmaceutically-acceptable salts thereof, and derivatives thereof, etc.
The compounds with the structure of formula (I), pharmaceutically acceptable salts, polymorphs, solvates, hydrates metabolites and prodrugs thereof, including diastereoisomeric forms (both isolated stereoisomers and mixtures of stereoisomers) are collectively referred to herein as the "compounds of formula P.
Formula (I) is as follows:
0 (RZ)m Zk Q
A-N N- B L
H H
wherein Q is -C(O)RX
RX is hydroxy, C14 alkyl, C14 alkoxy or NRaRb, Ra and Rb are independently :
a) hydrogen;
b) C14 alkyl, optionally substituted by - hydroxy, - C14 alkoxy, - a heteroaryl group selected from pyrrole, furan, thiophene, imidazole, pyrazole, thiazole, oxazole, isoxazole, isothiazole, triazole, tetrazole, thiadiazole, oxadiazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine, benzoxazole, isoquioline, quinolines and imidazopyrimidine - a heterocyclic group selected from tetrahydropyran, tetrahydrofuran, 1,3-dioxo-lane, 1,4-dioxane, morpholine, thiomorpholine, piperazine, piperidine, piperi-dinone, tetrahydropyrimidone, pentamethylene sulfide, tetramethylene sulfide, dihydropyrane, dihydrofuran, and dihydrothiophene, WO 2007/068381 _ PCT/EP2006/011691 - amino,-NH2, optionally substituted by one or two CI-4 alkyl groups, or - phenyl, c) phenyl optionally substituted with - halogen, or - amino,-NH2, optionally substituted by one or two C14 alkyl, or d) - a heteroaryl group selected from pyrrole, furan, thiophene, imidazole, pyrazole, thiazole, oxazole, isoxazole, isothiazole, triazole, tetrazole, thiadiazole, oxadiazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine, benzoxazole, isoquioline, quinoline and imidazopyrimidine;
A is optionally substituted phenyl, pyridinyl, naphthyl, benzoxazole, isoquioline, quinoline or imidazopyrimidine;
B is optionally substituted phenyl or naphthyl:
L is a bridging group which is -S- or -0-;
m is0,1,2or3,and each R2 is independently C1_5 alkyl, C1_5 haloalkyl, C 1_3 alkoxy, N-oxo or N-hydroxy.
Structures of optionally substituted phenyl moieties for A of formula (1) which are of particular interest include structures of formula lxx:
(R3 )n 1xx Structures of optionally substituted pyridinyl moieties for A of formula (1) which are of particular interest include structures of formula 1 x:
(R3 )n iN
1x Structures of optionally substituted naphthyl moieties for A of formula (1) which are of particular interest include structures of formula ly:
( / \ ) (R3)n ly The structure ly represents that the substituents R3 can appear on any carbon atom in either ring which has a valence that is otherwise complete with a hydrogen atom as a substituent. The bond to the urea group can also be through any carbon atom on either ring which has a valence that is otherwise complete with a hydrogen atom as a substituent.
B is optionally substituted phenyl or naphthyl. Structures of optionally substituted phenyl or naphthyl moieties for B of formula (I) which are of particular interest include structures 2a and 2b:
(R')p and 2a 2b The structures 2a and 2b represent that the substituents R' can appear on any carbon atom in the structure which has a valence that is otherwise complete with a hydrogen atom as a substituent and the bond to the urea group can be through any carbon atom in the structure which has a valence that is otherwise complete with a hydrogen atom as a substituent.
In a class of embodiments of this invention, B is substituted by at least one halogen substituent. In another class of embodiments, R, is NRaRb, and Ra and Rb are independently hydrogen or C14 alkyl optionally substituted by hydroxy and L is a bridging group which is -S, or -0-.
1x Structures of optionally substituted naphthyl moieties for A of formula (1) which are of particular interest include structures of formula ly:
( / \ ) (R3)n ly The structure ly represents that the substituents R3 can appear on any carbon atom in either ring which has a valence that is otherwise complete with a hydrogen atom as a substituent. The bond to the urea group can also be through any carbon atom on either ring which has a valence that is otherwise complete with a hydrogen atom as a substituent.
B is optionally substituted phenyl or naphthyl. Structures of optionally substituted phenyl or naphthyl moieties for B of formula (I) which are of particular interest include structures 2a and 2b:
(R')p and 2a 2b The structures 2a and 2b represent that the substituents R' can appear on any carbon atom in the structure which has a valence that is otherwise complete with a hydrogen atom as a substituent and the bond to the urea group can be through any carbon atom in the structure which has a valence that is otherwise complete with a hydrogen atom as a substituent.
In a class of embodiments of this invention, B is substituted by at least one halogen substituent. In another class of embodiments, R, is NRaRb, and Ra and Rb are independently hydrogen or C14 alkyl optionally substituted by hydroxy and L is a bridging group which is -S, or -0-.
The variable p is 0, 1, 2, 3, or 4, typically 0 or 1. The variable n is 0, 1, 2, 3, 4, 5 or 6, typically 0,1,2,3 or 4. The variable m is 0,1,2 or 3, typically 0.
Each R' is independently: halogen, C1_5 haloalkyl, NO2, C(O)NR4R5, CI_6 alkyl, CI_6 dialkylamine, CI_3 alkylamine, CN, amino, hydroxy or C1_3 alkoxy. Where present, R' is more commonly halogen and of the halogens, typically chlorine or fluorine, and more commonly fluorine.
Each RZ is independently: C1_5 alkyl, C1_5 haloalkyl, C1_3 alkoxy, N-oxo or N-hydroxy. Where present, RZ is typically methyl or trifluoromethyl.
Each R3 is independently selected from halogen, R4, OR4, S(O)R4, C(O)R4, C(O)NR4R5, oxo, cyano or nitro (NO2).
R4 and R5 are independently selected from hydrogen, CI-6 alkyl, and up to per-halogenated C1_6 alkyl.
Other examples of A include: 3-tert butyl phenyl, 5-tert butyl-2-methoxyphenyl, 5-(trifluoromethyl)-2 phenyl, 3-(trifluoromethyl)-4-chlorophenyl, 3-(trifluoromethyl)-4-bromophe-nyl and 5-(trifluoromethyl)-4-chloro-2 methoxyphenyl.
Other examples of B include:
F
I \ \ \
F
F F
F Br \
F
\ \ \ \
and F F
F
Preferably the urea group -NH-C(O)-NH- and the bridging group, L, are not bound to contiguous ring carbons of B, but rather have 1 or 2 ring carbons separating them.
Examples of R' groups include fluorine, chorine, bromine, methyl, NO2, C(O)NH2, methoxy, SCH3, trifluoromethyl, and methanesulfonyl.
Each R' is independently: halogen, C1_5 haloalkyl, NO2, C(O)NR4R5, CI_6 alkyl, CI_6 dialkylamine, CI_3 alkylamine, CN, amino, hydroxy or C1_3 alkoxy. Where present, R' is more commonly halogen and of the halogens, typically chlorine or fluorine, and more commonly fluorine.
Each RZ is independently: C1_5 alkyl, C1_5 haloalkyl, C1_3 alkoxy, N-oxo or N-hydroxy. Where present, RZ is typically methyl or trifluoromethyl.
Each R3 is independently selected from halogen, R4, OR4, S(O)R4, C(O)R4, C(O)NR4R5, oxo, cyano or nitro (NO2).
R4 and R5 are independently selected from hydrogen, CI-6 alkyl, and up to per-halogenated C1_6 alkyl.
Other examples of A include: 3-tert butyl phenyl, 5-tert butyl-2-methoxyphenyl, 5-(trifluoromethyl)-2 phenyl, 3-(trifluoromethyl)-4-chlorophenyl, 3-(trifluoromethyl)-4-bromophe-nyl and 5-(trifluoromethyl)-4-chloro-2 methoxyphenyl.
Other examples of B include:
F
I \ \ \
F
F F
F Br \
F
\ \ \ \
and F F
F
Preferably the urea group -NH-C(O)-NH- and the bridging group, L, are not bound to contiguous ring carbons of B, but rather have 1 or 2 ring carbons separating them.
Examples of R' groups include fluorine, chorine, bromine, methyl, NO2, C(O)NH2, methoxy, SCH3, trifluoromethyl, and methanesulfonyl.
Examples of RZ groups include methyl, ethyl, propyl, oxygen, and cyano.
Examples of R3 groups include trifluoromethyl, methyl, ethyl, propyl, butyl, isopropyl, tert-butyl, chlorine, fluorine, bromine, cyano, methoxy, acetyl, trifluoromethanesulfonyl, trifluoromethoxy, and trifluoromethylthio.
j C(O)NRaRb _if A H H-B O II
iN
A class of compounds of interest are of formula II below wherein Ra and Rb are independently hydrogen and Cl-C4 alkyl, B of formula 11 is / ' \ \ \
F
F F
Br F \ \ \
F F
\ \ \
or F
wherein the urea group, NH-C(O)-NH-, and the oxygen bridging group are not bound to contiguous ring carbons of B, but rather have I or 2 ring carbons separating them, and A of formula (H) is (R3 )n (R3 )n or i N
1xx 1x wherein the variable n is 0, 1, 2, 3 or 4.
R3 is trifluoromethyl, methyl, ethyl, propyl, butyl, isopropyl, tert-butyl, chlorine, fluorine, bromine, cyano, methoxy, acetyl, trifluoromethanesulfonyl, trifluoromethoxy, or trifluoromethylthio.
In a subclass of such compounds, each R3 substituent on A of formula 11 is selected from chlorine, trifluoromethyl, tert-butyl or methoxy.
In another subclass of such compounds, A of formula II is F
~ ~
- CI or Br and B of formula II is phenylene, fluoro substituted phenylene or difluoro substituted phenylene.
Another class of compounds of interest includes compounds having the structure of formulae X
below wherein phenyl ring "B" optionally has one halogen substituent.
0 (R2)m C(O)NHCH3 ~
iN X
A H H % O
For the compounds of formula X, R2, m and A are as defined above for formula I. The variable "m" is preferably zero, leaving C(O)NHCH3 as the only substituent on the pyridinyl moiety.
Preferred values for A are substituted phenyl which have at least one substituent, W. R3 is preferably halogen, preferably Cl or F, trifluoromethyl and/or methoxy.
A subclass of compounds of interest includes compounds having the structure of formulas ZI and Z2 below :
Examples of R3 groups include trifluoromethyl, methyl, ethyl, propyl, butyl, isopropyl, tert-butyl, chlorine, fluorine, bromine, cyano, methoxy, acetyl, trifluoromethanesulfonyl, trifluoromethoxy, and trifluoromethylthio.
j C(O)NRaRb _if A H H-B O II
iN
A class of compounds of interest are of formula II below wherein Ra and Rb are independently hydrogen and Cl-C4 alkyl, B of formula 11 is / ' \ \ \
F
F F
Br F \ \ \
F F
\ \ \
or F
wherein the urea group, NH-C(O)-NH-, and the oxygen bridging group are not bound to contiguous ring carbons of B, but rather have I or 2 ring carbons separating them, and A of formula (H) is (R3 )n (R3 )n or i N
1xx 1x wherein the variable n is 0, 1, 2, 3 or 4.
R3 is trifluoromethyl, methyl, ethyl, propyl, butyl, isopropyl, tert-butyl, chlorine, fluorine, bromine, cyano, methoxy, acetyl, trifluoromethanesulfonyl, trifluoromethoxy, or trifluoromethylthio.
In a subclass of such compounds, each R3 substituent on A of formula 11 is selected from chlorine, trifluoromethyl, tert-butyl or methoxy.
In another subclass of such compounds, A of formula II is F
~ ~
- CI or Br and B of formula II is phenylene, fluoro substituted phenylene or difluoro substituted phenylene.
Another class of compounds of interest includes compounds having the structure of formulae X
below wherein phenyl ring "B" optionally has one halogen substituent.
0 (R2)m C(O)NHCH3 ~
iN X
A H H % O
For the compounds of formula X, R2, m and A are as defined above for formula I. The variable "m" is preferably zero, leaving C(O)NHCH3 as the only substituent on the pyridinyl moiety.
Preferred values for A are substituted phenyl which have at least one substituent, W. R3 is preferably halogen, preferably Cl or F, trifluoromethyl and/or methoxy.
A subclass of compounds of interest includes compounds having the structure of formulas ZI and Z2 below :
CI O /~ O NH1CH3 Z1 NN \ N
I I
H H
CI O a~-I O NH2 Z2 NJ~N N
I I
H H
Preferably used as compound of formula I according to the invention is 4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-phenoxy}-pyridine-2-carboxylic acid methyl amide (BAY 43-9006) or the p-toluenesulfonic acid salt of 4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-phenoxy}-pyridine-2-carboxylic acid methyl amide (tosylate salt of compound (I)). More prefer-ably the p-toluenesulfonic acid salt of 4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-phen-oxy}-pyridine-2-carboxylic acid methyl amide exists for at least 80% in the stable polymorph I.
Most preferably the p-toluenesulfonic acid salt of 4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-phenoxy}-pyridine-2-carboxylic acid methyl amide exists for at least 80% in the stable polymorph I and in a micronized form.
Micronization can be achieved by standard milling methods, preferably by air chat milling, known to a skilled person. The micronized form can have a mean particle size of from 0.5 to 10 m, preferably from 1 to 6 m, more preferably from 1 to 3 m. The indicated particle size is the mean of the particle size distribution measured by laser diffraction known to a skilled person (measuring device: HELOS, Sympatec).
The process for preparing the p-toluenesulfonic acid salt of 4{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-ureido]-phenoxy}-pyridine-2-carboxylic acid methyl amide and its stable polymorph I are described in the patent applications EP 04023131.8 and EP 04023130Ø
When any moiety is "substituted", it can have up to the highest number of indicated substituents and each substituent can be located at any available position on the moiety and can be attached through any available atom on the substituent. "Any available position" means any position on the moiety that is chemically accessible through means known in the art or taught herein and that does not create an unstable molecule, e.g., incapable of administration to a human.
When there are two WO 2007/068381 _ PCT/EP2006/011691 or more substituents on any moiety, each substituent is defined independently of any other substituent and can, accordingly, be the same or different.
The term "optionally substituted" means that the moiety so modified may be either unsubstituted, or substituted with the identified substituent(s).
It is understood that the term "hydroxy" as a pyridine substituent includes 2-, 3-, and 4-hy-droxypyridine, and also includes those structures referred to in the art as 1-oxo-pyridine, 1-hy-droxy-pyridine or pyridine N-oxide.
Where the plural form of the word compounds, salts, and the like, is used herein, this is taken to mean also a single compound, salt, or the like.
The term CI-6 alkyl, unless indicated otherwise, means straight, branched chain or cyclic alkyl groups having from one to six carbon atoms, which may be cyclic, linear or branched with single or multiple branching. Such groups include for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl and the like.
The term CI-6 haloalkyl, unless indicated otherwise, means a saturated hydrocarbon radical having up to six carbon atoms, which is substituted with a least one halogen atom, up to perhalo. The radical may be cyclic, linear or branched with single or multiple branching.
The halo substituent(s) include fluoro, chloro, bromo, or iodo. Fluoro, chloro and bromo are preferred, and fluoro and chloro are more preferred. The halogen substituent(s) can be located on any available carbon.
When more than one halogen substituent is present on this moiety, they may be the same or different. Examples of such halogenated alkyl substituents include but are not limited to chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, and 1,1,2,2-tetrafluoroethyl, and the like.
The term CI-6 alkoxy, unless indicated otherwise, means a cyclic, straight or branched chain alkoxy group having from one to six saturated carbon atoms which may be cyclic, linear or branched with single or multiple branching, and includes such groups as methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, pentoxy and the like. It also includes halogenated groups such as 2, 2-dichloroethoxy, trifluoromethoxy, and the like.
Halo or halogen means fluoro, chloro, bromo, or iodo. Fluoro, chloro and bromo are preferred, and fluoro and chloro are more preferred.
CI-3alkylamine, unless indicated otherwise, means methylamino, ethylamino, propylamino or isopropylamino.
I I
H H
CI O a~-I O NH2 Z2 NJ~N N
I I
H H
Preferably used as compound of formula I according to the invention is 4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-phenoxy}-pyridine-2-carboxylic acid methyl amide (BAY 43-9006) or the p-toluenesulfonic acid salt of 4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-phenoxy}-pyridine-2-carboxylic acid methyl amide (tosylate salt of compound (I)). More prefer-ably the p-toluenesulfonic acid salt of 4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-phen-oxy}-pyridine-2-carboxylic acid methyl amide exists for at least 80% in the stable polymorph I.
Most preferably the p-toluenesulfonic acid salt of 4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-phenoxy}-pyridine-2-carboxylic acid methyl amide exists for at least 80% in the stable polymorph I and in a micronized form.
Micronization can be achieved by standard milling methods, preferably by air chat milling, known to a skilled person. The micronized form can have a mean particle size of from 0.5 to 10 m, preferably from 1 to 6 m, more preferably from 1 to 3 m. The indicated particle size is the mean of the particle size distribution measured by laser diffraction known to a skilled person (measuring device: HELOS, Sympatec).
The process for preparing the p-toluenesulfonic acid salt of 4{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-ureido]-phenoxy}-pyridine-2-carboxylic acid methyl amide and its stable polymorph I are described in the patent applications EP 04023131.8 and EP 04023130Ø
When any moiety is "substituted", it can have up to the highest number of indicated substituents and each substituent can be located at any available position on the moiety and can be attached through any available atom on the substituent. "Any available position" means any position on the moiety that is chemically accessible through means known in the art or taught herein and that does not create an unstable molecule, e.g., incapable of administration to a human.
When there are two WO 2007/068381 _ PCT/EP2006/011691 or more substituents on any moiety, each substituent is defined independently of any other substituent and can, accordingly, be the same or different.
The term "optionally substituted" means that the moiety so modified may be either unsubstituted, or substituted with the identified substituent(s).
It is understood that the term "hydroxy" as a pyridine substituent includes 2-, 3-, and 4-hy-droxypyridine, and also includes those structures referred to in the art as 1-oxo-pyridine, 1-hy-droxy-pyridine or pyridine N-oxide.
Where the plural form of the word compounds, salts, and the like, is used herein, this is taken to mean also a single compound, salt, or the like.
The term CI-6 alkyl, unless indicated otherwise, means straight, branched chain or cyclic alkyl groups having from one to six carbon atoms, which may be cyclic, linear or branched with single or multiple branching. Such groups include for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl and the like.
The term CI-6 haloalkyl, unless indicated otherwise, means a saturated hydrocarbon radical having up to six carbon atoms, which is substituted with a least one halogen atom, up to perhalo. The radical may be cyclic, linear or branched with single or multiple branching.
The halo substituent(s) include fluoro, chloro, bromo, or iodo. Fluoro, chloro and bromo are preferred, and fluoro and chloro are more preferred. The halogen substituent(s) can be located on any available carbon.
When more than one halogen substituent is present on this moiety, they may be the same or different. Examples of such halogenated alkyl substituents include but are not limited to chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, and 1,1,2,2-tetrafluoroethyl, and the like.
The term CI-6 alkoxy, unless indicated otherwise, means a cyclic, straight or branched chain alkoxy group having from one to six saturated carbon atoms which may be cyclic, linear or branched with single or multiple branching, and includes such groups as methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, pentoxy and the like. It also includes halogenated groups such as 2, 2-dichloroethoxy, trifluoromethoxy, and the like.
Halo or halogen means fluoro, chloro, bromo, or iodo. Fluoro, chloro and bromo are preferred, and fluoro and chloro are more preferred.
CI-3alkylamine, unless indicated otherwise, means methylamino, ethylamino, propylamino or isopropylamino.
- 10 -.
Examples of CI-6 dialkylamine include but are not limited to diethylamino, ethyl-isopropylamino, methyl-isobutylamino and dihexylamino.
The term heteroaryl refers to both monocyclic and bicyclic heteroaryl rings.
Monocyclic heteroaryl means an aromatic monocyclic ring having 5 to 6 ring atoms and 1-4 hetero atoms selected from N, 0 and S, the remaining atoms being carbon. When more than one hetero atom is present in the moiety, they are selected independently from the other(s) so that they may be the same or different.
Monocyclic heteroaryl rings include, but are not limited to pyrrole, furan, thiophene, imidazole, pyrazole, thiazole, oxazole, isoxazole, isothiazole, triazole, tetrazole, thiadiazole, oxadiazole, pyridine, pyrimidine, pyridazine, pyrazine, and triazine.
Bicyclic heteroaryl means fused bicyclic moieties where one of the rings is chosen from the monocyclic heteroaryl rings described above and the second ring is either benzene or another monocyclic heteroaryl ring described above. When both rings in the bicyclic moiety are heteroaryl rings, they may be the same or different, as long as they are chemically accessible by means known in the art. Bicyclic heteroaryl rings include synthetically accessible 5-5, 5-6, or 6-6 fused bicyclic aromatic structures including, for example but not by way of limitation, benzoxazole (fused phenyl and oxazole), quinoline (fused phenyl and pyridine), imidazopyrimidine (fused imidazole and pyrimidine), and the like.
Where indicated, the bicyclic heteroaryl moieties may be partially saturated.
When partially saturated either the monocyclic heteroaryl ring as described above is fully or partially saturated, the second ring as described above is either fully or partially saturated or both rings are partially saturated.
The term "heterocyclic group", unless indicated otherwise, means monocyclic and bicyclic moieties containing at least one atom selected from oxygen, nitrogen and sulfur, which is saturated or partially saturated, and includes, by no way of limitation, tetrahydropyran, tetrahydrofuran, 1,3-dioxolane, 1,4-dioxane, morpholine, thiomorpholine, piperazine, piperidine, piperidinone, tetrahydropyrimidone, pentamethylene sulfide, tetramethylene sulfide, dihydropyrane, dihydrofuran, dihydrothiophene and the like.
The term "Cl-3 alkyl-phenyl" includes, for example, 2-methylphenyl, isopropylphenyl, 3-phenyl-propyl, or 2-phenyl-l-methylethyl. Substituted examples include 2-[2-chlorophenyl]ethyl, 3,4-di-methylphenylmethyl, and the like.
Examples of CI-6 dialkylamine include but are not limited to diethylamino, ethyl-isopropylamino, methyl-isobutylamino and dihexylamino.
The term heteroaryl refers to both monocyclic and bicyclic heteroaryl rings.
Monocyclic heteroaryl means an aromatic monocyclic ring having 5 to 6 ring atoms and 1-4 hetero atoms selected from N, 0 and S, the remaining atoms being carbon. When more than one hetero atom is present in the moiety, they are selected independently from the other(s) so that they may be the same or different.
Monocyclic heteroaryl rings include, but are not limited to pyrrole, furan, thiophene, imidazole, pyrazole, thiazole, oxazole, isoxazole, isothiazole, triazole, tetrazole, thiadiazole, oxadiazole, pyridine, pyrimidine, pyridazine, pyrazine, and triazine.
Bicyclic heteroaryl means fused bicyclic moieties where one of the rings is chosen from the monocyclic heteroaryl rings described above and the second ring is either benzene or another monocyclic heteroaryl ring described above. When both rings in the bicyclic moiety are heteroaryl rings, they may be the same or different, as long as they are chemically accessible by means known in the art. Bicyclic heteroaryl rings include synthetically accessible 5-5, 5-6, or 6-6 fused bicyclic aromatic structures including, for example but not by way of limitation, benzoxazole (fused phenyl and oxazole), quinoline (fused phenyl and pyridine), imidazopyrimidine (fused imidazole and pyrimidine), and the like.
Where indicated, the bicyclic heteroaryl moieties may be partially saturated.
When partially saturated either the monocyclic heteroaryl ring as described above is fully or partially saturated, the second ring as described above is either fully or partially saturated or both rings are partially saturated.
The term "heterocyclic group", unless indicated otherwise, means monocyclic and bicyclic moieties containing at least one atom selected from oxygen, nitrogen and sulfur, which is saturated or partially saturated, and includes, by no way of limitation, tetrahydropyran, tetrahydrofuran, 1,3-dioxolane, 1,4-dioxane, morpholine, thiomorpholine, piperazine, piperidine, piperidinone, tetrahydropyrimidone, pentamethylene sulfide, tetramethylene sulfide, dihydropyrane, dihydrofuran, dihydrothiophene and the like.
The term "Cl-3 alkyl-phenyl" includes, for example, 2-methylphenyl, isopropylphenyl, 3-phenyl-propyl, or 2-phenyl-l-methylethyl. Substituted examples include 2-[2-chlorophenyl]ethyl, 3,4-di-methylphenylmethyl, and the like.
Unless otherwise stated or indicated, the term "aryl" includes 6-12 membered mono or bicyclic aromatic hydrocarbon groups (e.g., phenyl, naphthalene, azulene, indene group ) having 0, 1, 2, 3, 4, 5 or 6 substituents.
The compounds of formula (1) may contain one or more asymmetric centers, depending upon the location and nature of the various substituents desired. Asymmetric carbon atoms may be present in the (R) or (S) configuration or (R,S) configuration. In certain instances, asymmetry may also be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds. Substituents on a ring may also be present in either cis or trans form. It is intended that all such configurations (including enantiomers and diastereomers), are included within the scope of the present invention.
Preferred compounds are those with the absolute configuration of the compound of formula (I) which produces the more desirable biological activity. Separated, pure or partially purified isomers or racemic mixtures of the compounds of this invention are also included within the scope of the present invention. The purification of said isomers and the separation of said isomeric mixtures can be accomplished by standard techniques known in the art.
The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers. Examples of appropriate acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid.
Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known in the art, for example, by chromatography or fractional crystallization. The optically active bases or acids are then liberated from the separated diastereomeric salts. A different process for separation of optical isomers involves the use of chiral chromatography (e.g., chiral HPLC columns), with or without conventional derivation, optimally chosen to maximize the separation of the enantiomers. Suitable chiral HPLC
columns are manufactured by Diacel, e.g., Chiracel OD and Chiracel OJ among many others, all routinely selectable. Enzymatic separations, with or without derivitization, are also useful. The optically active compounds of formula I can likewise be obtained by chiral syntheses utilizing optically active starting materials.
The present invention also relates to useful forms of the compounds as disclosed herein, such as pharmaceutically acceptable salts, metabolites and prodrugs. The term "pharmaceutically acceptable salt" refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the present invention. For example, see S. M. Berge, et al.
"Pharmaceutical Salts,"
J. Pharm. Sci. 1977, 66, 1-19. Pharmaceutically acceptable salts include those obtained by reacting the main compound, functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, camphor sulfonic acid, oxalic acid, maleic acid, succinic acid and citric acid.
Pharmaceutically acceptable salts also include those in which the main compound functions as an acid and is reacted with an appropriate base to form, e.g., sodium, potassium, calcium, mangnesium, ammonium, and choline salts. Those skilled in the art will further recognize that acid addition salts of the claimed compounds may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods. Alternatively, alkali and alkaline earth metal salts are prepared by reacting the compounds of the invention with the appropriate base via a variety of known methods.
Representative salts of the compounds of this invention include the conventional non-toxic salts and the quaternary ammonium salts which are formed, for example, from inorganic or organic acids or bases by means well known in the art. For example, such acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate, dodecyl-sulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, itaconate, lactate, maleate, mandelate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfo-nate, tartrate, thiocyanate, tosylate, trifluoromethanesulfonate, and undecanoate.
Base salts include alkali metal salts such as potassium and sodium salts, alkaline earth metal salts such as calcium and magnesium salts, and ammonium salts with organic bases such as dicyclo-hexylamine and N-methyl-D-glucamine. Additionally, basic nitrogen containing groups may be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and strearyl chlorides, bromides and iodides, aryl or aralkyl halides like benzyl and phenethyl bromides and others monosubstituted aralkyl halides or polysubstituted aralkyl halides.
Solvates for the purposes of the invention are those forms of the compounds where solvent molecules form a complex in the solid state and include, but are not limited to for example ethanol and methanol. Hydrates are a specific form of solvates, where the solvent molecule is water.
Certain pharmacologically active agents can be further modified with labile functional groups that are cleaved after in vivo administration to furnish the parent active agent and the pharma-cologically inactive derivatizing group. These derivatives, commonly referred to as prodrugs, can be used, for example, to alter the physicochemical properties of the active agent, to target the active agent to a specific tissue, to alter the pharmacokinetic and pharmacodynamic properties of the active agent, and to reduce undesirable side effects. Prodrugs of the invention include, e.g., the esters of appropriate compounds of this invention that are well-tolerated, pharmaceutically _ acceptable esters such as alkyl esters including methyl, ethyl, propyl, isopropyl, butyl, isobutyl or pentyl esters. Additional esters such as phenyl-CI-C5 alkyl may be used, although methyl ester is preferred.
Methods which can be used to synthesize other prodrugs are described in the following reviews on the subject, which are incorporated herein by reference for their description of these synthesis methods:
= Higuchi, T.; Stella, V. eds. Prodrugs As Novel Drug Delivery Systems. ACS
Symposium Series. American Chemical Society: Washington, DC (1975).
= Roche, E. B. Design of Biopharmaceutical Properties through Prodrugs and Analogs.
American Pharmaceutical Association: Washington, DC (1977).
= Sinkula, A. A.; Yalkowsky, S. H. JPharm Sci. 1975, 64, 181-210.
= Stella, V. J.; Charman, W. N. Naringrekar, V. H. Drugs 1985, 29, 455-473.
= Bundgaard, H., ed. Design ofProdrugs. Elsevier: New York (1985).
= Stella, V. J.; Himmelstein, K. J. J. Med. Chem. 1980, 23, 1275-1282.
= Han, H-K; Amidon, G. L. AAPS Pharmsci 2000, 2, 1- 11.
= Denny, W. A. Eur. J. Med. Chem. 2001, 36, 577-595.
= Wermuth, C. G. in Wermuth, C. G. ed. The Practice of Medicinal Chemistry Academic Press:
San Diego (1996), 697-715.
= Balant, L. P.; Doelker, E. in Wolff, M. E. ed. Burgers Medicinal Chemistry And Drug Discovery John Wiley & Sons: New York (1997), 949-982.
The metabolites of the compounds of this invention include oxidized derivatives of the compounds of formula I, II, X, Z1 and Z2, wherein one or more of the nitrogens are substituted with a hydroxy group; which includes derivatives where the nitrogen atom of the pyridine group is in the oxide form, referred to in the art as 1-oxo-pyridine or has a hydroxy substituent, referred to in the art as 1-hydroxy-pyridine.
General Preparative Methods The particular process to be utilized in the preparation of the compounds used in this embodiment of the invention depends upon the specific compound desired. Such factors as the selection of the specific substituents play a role in the path to be followed in the preparation of the specific compounds of this invention. Those factors are readily recognized by one of ordinary skill in the art.
The compounds of the invention may be prepared by use of known chemical reactions and procedures as described in the following published international applications WO 00/42012, W003/047579, WO 2005/009961, WO 2004/078747 and W005/000284 and European patent applications EP 04023131.8 and EP 04023130Ø
The compounds of the invention can be made according to conventional chemical methods, and/or as disclosed below, from starting materials which are either commercially available or producible according to routine, conventional chemical methods. General methods for the preparation of the compounds are given below.
The preparation of ureas of formula (1) can be prepared from the condensation of the two arylamine fragments and in the presence of phosgene, di-phosgene, tri-phosgene, carbonyl-diimidazole, or equivalents in a solvent that does not react with any of the starting materials, as described in one or more of these published. Alternatively, compounds of formula (I) can be synthesized by reacting amino compounds) with isocyanate compounds as described in one or more of the published international applications described above.
The isocyanates are commercially available or can be synthesized from heterocyclic amines according to methods commonly known to those skilled in the art [e.g. from treatment of an amine with phosgene or a phosgene equivalent such as trichloromethyl chloroformate (diphosgene), bis(trichloromethyl)carbonate (triphosgene), or N,N'-carbonyldiimidazole (CDI); or, alternatively by a Curtius-type rearrangement of an amide, or a carboxylic acid derivative, such as an ester, an acid halide or an anhydride].
Aryl amines of formulas are commercially available, or can be synthesized according to methods commonly known to those skilled in the art. Aryl amines are commonly synthesized by reduction of nitroaryls using a metal catalyst, such as Ni, Pd, or Pt, and H2 or a hydride transfer agent, such as formate, cyclohexadiene, or a borohydride (Rylander. Hydrogenation Methods;
Academic Press: London, UK (1985)). Nitroaryls may also be directly reduced using a strong hydride source, such as LiAlH4 (Seyden-Penne. Reductions by the Alumino- and borohydrides in Organic Synthesis; VCH Publishers: New York (1991)), or using a zero valent metal, such as Fe, Sn or Ca, often in acidic media. Many methods exist for the synthesis of nitroaryls (March. Advanced Organic Chemistry, 3d Ed.; John Wiley: New York (1985). Larock. Comprehensive Organic Transformations; VCH Publishers: New York (1989)). Nitro aryls are commonly formed by electrophilic aromatic nitration using HNO3, or an alternative NO2+ source.
Pyridine-l-oxides of formula (1) where the pyridine ring carries a hydroxy substituent on its nitrogen atom, and A, B, L are broadly defined as above can be prepared from the corresponding pyridines using oxidation conditions know in the art. Some examples are as follows:
= peracids such as meta chloroperbenzoic acids in chlorinated solvents such as dichloromethane, dichloroethane, or chloroform (Markgraf et al., Tetrahedron 1991, 47 183);
= (Me3SiO)2 in the presence of a catalytic amount of perrhenic acid in chlorinated solvents such as dichloromethane (Coperet et al., Terahedron Lett. 1998, 39, 761);
= Perfluoro-cis-2-butyl-3-propyloxaziridine in several combinations of halogenated solvents (Amone et al., Tetrahedron 1998, 54 7831);
= Hypofluoric acid - acetonitrile complex in chloroform (Dayan et al., Synthesis 1999, 1427);
= Oxone, in the presence of a base such as KOH, in water (Robker et al., J.
Chem. Res., Synop.
1993, 0 412);
= Magnesium monoperoxyphthalate, in the presence of glacial acetic acid (Klemm et al., J.
Heterocylic Chem. 1990, 6, 1537);
= Hydrogen peroxide, in the presence of water and acetic acid (Lin A.J., Org.
Prep. Proced. Int.
1991, 23(1), 114);
= Dimethyldioxirane in acetone (Boyd et al., J. Chem. Soc., Perkin Trans.
1991, 9 2189).
In addition, specific methods for preparing diaryl ureas and intermediate compounds are already described elsewhere in the patent literature, and can be adapted to the compounds of the present invention. For example, Miller S. et al, "Inhibition of p38 Kinase using Symmetrical and Unsymmetrical Diphenyl Ureas" PCT Int. Appl. WO 99 32463, Miller, S et al.
"Inhibition of raf Kinase using Symmetrical and Unsymmetrical Substituted Diphenyl Ureas" PCT
Int. Appl., WO 99 32436, Dumas, J. et al., "Inhibition of p38 Kinase Activity using Substituted Heterocyclic Ureas"
WO 2007/068381 . PCT/EP2006/011691 PCT Int. Appl., WO 99 32111, Dumas, J. et al., "Method for the Treatment of Neoplasm by Inhibition of raf Kinase using N-Heteroaryl-N'-(hetero)arylureas" PCT Int.
Appl., WO 99 32106, Dumas, J. et al., "Inhibition of p38 Kinase Activity using Aryl- and Heteroaryl- Substituted Heterocyclic Ureas" PCT Int. Appl., WO 99 32110, Dumas, J., et al., "Inhibition of raf Kinase 5_ using Aryl- and Heteroaryl- Substituted Heterocyclic Ureas" PCT Int._Appl., WO 99 32455, Riedl, B., et al., "O-Carboxy Aryl Substituted Diphenyl Ureas as raf Kinase Inhibitors" PCT Int. Appl., WO 00 42012, Riedl, B., et al., "O-Carboxy Aryl Substituted Diphenyl Ureas as p38 Kinase Inhibitors" PCT Int. Appl., WO 00 41698, Dumas, J. et al. "Heteroaryl ureas containing nitrogen hetero-atoms as p38 kinase inhibitors" U.S. Pat. Appl. Publ., US 20020065296, Dumas, J. et al.
"Preparation of N-aryl-N'-[(acylphenoxy) phenyl]ureas as raf kinase inhibitors" PCT Int. Appl., WO 02 62763, Dumas, J. et al. "Inhibition of raf kinase using quinolyl, isoquinolyl or pyridyl ureas" PCT Int. Appl., WO 02 85857, Dumas, J. et al. "Preparation of quinolyl, isoquinolyl or pyridyl-ureas as inhibitors of raf kinase for the treatment of tumors and/or cancerous cell growth"
U.S. Pat. Appl. Publ., US 20020165394. All the preceding patent applications are hereby incorporated by reference.
Synthetic transformations that may be employed in the synthesis of compounds of formula (1) and in the synthesis of intermediates involved in the synthesis of compounds of formula (1) are known by or accessible to one skilled in the art. Collections of synthetic transformations may be found in compilations, such as:
= J. March. Advanced Organic Chemistry, 4'b ed.; John Wiley: New York (1992);
= R.C. Larock. Comprehensive Organic Transformations, 2 d ed.; Wiley-VCH: New York (1999);
= F.A. Carey; R.J. Sundberg. Advanced Organic Chemistry, 2d ed.; Plenum Press:
New York (1984);
= T.W. Greene; P.G.M. Wuts. Protective Groups in Organic Synthesis, 3d ed.;
John Wiley:
New York (1999);
= L.S. Hegedus. Transition Metals in the Synthesis of Complex Organic Molecules, 2 d ed.;
University Science Books: Mill Valley, CA (1994);
= L.A. Paquette, Ed. The Encyclopedia of Reagents for Organic Synthesis; John Wiley: New York (1994);
The compounds of formula (1) may contain one or more asymmetric centers, depending upon the location and nature of the various substituents desired. Asymmetric carbon atoms may be present in the (R) or (S) configuration or (R,S) configuration. In certain instances, asymmetry may also be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds. Substituents on a ring may also be present in either cis or trans form. It is intended that all such configurations (including enantiomers and diastereomers), are included within the scope of the present invention.
Preferred compounds are those with the absolute configuration of the compound of formula (I) which produces the more desirable biological activity. Separated, pure or partially purified isomers or racemic mixtures of the compounds of this invention are also included within the scope of the present invention. The purification of said isomers and the separation of said isomeric mixtures can be accomplished by standard techniques known in the art.
The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers. Examples of appropriate acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid.
Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known in the art, for example, by chromatography or fractional crystallization. The optically active bases or acids are then liberated from the separated diastereomeric salts. A different process for separation of optical isomers involves the use of chiral chromatography (e.g., chiral HPLC columns), with or without conventional derivation, optimally chosen to maximize the separation of the enantiomers. Suitable chiral HPLC
columns are manufactured by Diacel, e.g., Chiracel OD and Chiracel OJ among many others, all routinely selectable. Enzymatic separations, with or without derivitization, are also useful. The optically active compounds of formula I can likewise be obtained by chiral syntheses utilizing optically active starting materials.
The present invention also relates to useful forms of the compounds as disclosed herein, such as pharmaceutically acceptable salts, metabolites and prodrugs. The term "pharmaceutically acceptable salt" refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the present invention. For example, see S. M. Berge, et al.
"Pharmaceutical Salts,"
J. Pharm. Sci. 1977, 66, 1-19. Pharmaceutically acceptable salts include those obtained by reacting the main compound, functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, camphor sulfonic acid, oxalic acid, maleic acid, succinic acid and citric acid.
Pharmaceutically acceptable salts also include those in which the main compound functions as an acid and is reacted with an appropriate base to form, e.g., sodium, potassium, calcium, mangnesium, ammonium, and choline salts. Those skilled in the art will further recognize that acid addition salts of the claimed compounds may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods. Alternatively, alkali and alkaline earth metal salts are prepared by reacting the compounds of the invention with the appropriate base via a variety of known methods.
Representative salts of the compounds of this invention include the conventional non-toxic salts and the quaternary ammonium salts which are formed, for example, from inorganic or organic acids or bases by means well known in the art. For example, such acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate, dodecyl-sulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, itaconate, lactate, maleate, mandelate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfo-nate, tartrate, thiocyanate, tosylate, trifluoromethanesulfonate, and undecanoate.
Base salts include alkali metal salts such as potassium and sodium salts, alkaline earth metal salts such as calcium and magnesium salts, and ammonium salts with organic bases such as dicyclo-hexylamine and N-methyl-D-glucamine. Additionally, basic nitrogen containing groups may be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and strearyl chlorides, bromides and iodides, aryl or aralkyl halides like benzyl and phenethyl bromides and others monosubstituted aralkyl halides or polysubstituted aralkyl halides.
Solvates for the purposes of the invention are those forms of the compounds where solvent molecules form a complex in the solid state and include, but are not limited to for example ethanol and methanol. Hydrates are a specific form of solvates, where the solvent molecule is water.
Certain pharmacologically active agents can be further modified with labile functional groups that are cleaved after in vivo administration to furnish the parent active agent and the pharma-cologically inactive derivatizing group. These derivatives, commonly referred to as prodrugs, can be used, for example, to alter the physicochemical properties of the active agent, to target the active agent to a specific tissue, to alter the pharmacokinetic and pharmacodynamic properties of the active agent, and to reduce undesirable side effects. Prodrugs of the invention include, e.g., the esters of appropriate compounds of this invention that are well-tolerated, pharmaceutically _ acceptable esters such as alkyl esters including methyl, ethyl, propyl, isopropyl, butyl, isobutyl or pentyl esters. Additional esters such as phenyl-CI-C5 alkyl may be used, although methyl ester is preferred.
Methods which can be used to synthesize other prodrugs are described in the following reviews on the subject, which are incorporated herein by reference for their description of these synthesis methods:
= Higuchi, T.; Stella, V. eds. Prodrugs As Novel Drug Delivery Systems. ACS
Symposium Series. American Chemical Society: Washington, DC (1975).
= Roche, E. B. Design of Biopharmaceutical Properties through Prodrugs and Analogs.
American Pharmaceutical Association: Washington, DC (1977).
= Sinkula, A. A.; Yalkowsky, S. H. JPharm Sci. 1975, 64, 181-210.
= Stella, V. J.; Charman, W. N. Naringrekar, V. H. Drugs 1985, 29, 455-473.
= Bundgaard, H., ed. Design ofProdrugs. Elsevier: New York (1985).
= Stella, V. J.; Himmelstein, K. J. J. Med. Chem. 1980, 23, 1275-1282.
= Han, H-K; Amidon, G. L. AAPS Pharmsci 2000, 2, 1- 11.
= Denny, W. A. Eur. J. Med. Chem. 2001, 36, 577-595.
= Wermuth, C. G. in Wermuth, C. G. ed. The Practice of Medicinal Chemistry Academic Press:
San Diego (1996), 697-715.
= Balant, L. P.; Doelker, E. in Wolff, M. E. ed. Burgers Medicinal Chemistry And Drug Discovery John Wiley & Sons: New York (1997), 949-982.
The metabolites of the compounds of this invention include oxidized derivatives of the compounds of formula I, II, X, Z1 and Z2, wherein one or more of the nitrogens are substituted with a hydroxy group; which includes derivatives where the nitrogen atom of the pyridine group is in the oxide form, referred to in the art as 1-oxo-pyridine or has a hydroxy substituent, referred to in the art as 1-hydroxy-pyridine.
General Preparative Methods The particular process to be utilized in the preparation of the compounds used in this embodiment of the invention depends upon the specific compound desired. Such factors as the selection of the specific substituents play a role in the path to be followed in the preparation of the specific compounds of this invention. Those factors are readily recognized by one of ordinary skill in the art.
The compounds of the invention may be prepared by use of known chemical reactions and procedures as described in the following published international applications WO 00/42012, W003/047579, WO 2005/009961, WO 2004/078747 and W005/000284 and European patent applications EP 04023131.8 and EP 04023130Ø
The compounds of the invention can be made according to conventional chemical methods, and/or as disclosed below, from starting materials which are either commercially available or producible according to routine, conventional chemical methods. General methods for the preparation of the compounds are given below.
The preparation of ureas of formula (1) can be prepared from the condensation of the two arylamine fragments and in the presence of phosgene, di-phosgene, tri-phosgene, carbonyl-diimidazole, or equivalents in a solvent that does not react with any of the starting materials, as described in one or more of these published. Alternatively, compounds of formula (I) can be synthesized by reacting amino compounds) with isocyanate compounds as described in one or more of the published international applications described above.
The isocyanates are commercially available or can be synthesized from heterocyclic amines according to methods commonly known to those skilled in the art [e.g. from treatment of an amine with phosgene or a phosgene equivalent such as trichloromethyl chloroformate (diphosgene), bis(trichloromethyl)carbonate (triphosgene), or N,N'-carbonyldiimidazole (CDI); or, alternatively by a Curtius-type rearrangement of an amide, or a carboxylic acid derivative, such as an ester, an acid halide or an anhydride].
Aryl amines of formulas are commercially available, or can be synthesized according to methods commonly known to those skilled in the art. Aryl amines are commonly synthesized by reduction of nitroaryls using a metal catalyst, such as Ni, Pd, or Pt, and H2 or a hydride transfer agent, such as formate, cyclohexadiene, or a borohydride (Rylander. Hydrogenation Methods;
Academic Press: London, UK (1985)). Nitroaryls may also be directly reduced using a strong hydride source, such as LiAlH4 (Seyden-Penne. Reductions by the Alumino- and borohydrides in Organic Synthesis; VCH Publishers: New York (1991)), or using a zero valent metal, such as Fe, Sn or Ca, often in acidic media. Many methods exist for the synthesis of nitroaryls (March. Advanced Organic Chemistry, 3d Ed.; John Wiley: New York (1985). Larock. Comprehensive Organic Transformations; VCH Publishers: New York (1989)). Nitro aryls are commonly formed by electrophilic aromatic nitration using HNO3, or an alternative NO2+ source.
Pyridine-l-oxides of formula (1) where the pyridine ring carries a hydroxy substituent on its nitrogen atom, and A, B, L are broadly defined as above can be prepared from the corresponding pyridines using oxidation conditions know in the art. Some examples are as follows:
= peracids such as meta chloroperbenzoic acids in chlorinated solvents such as dichloromethane, dichloroethane, or chloroform (Markgraf et al., Tetrahedron 1991, 47 183);
= (Me3SiO)2 in the presence of a catalytic amount of perrhenic acid in chlorinated solvents such as dichloromethane (Coperet et al., Terahedron Lett. 1998, 39, 761);
= Perfluoro-cis-2-butyl-3-propyloxaziridine in several combinations of halogenated solvents (Amone et al., Tetrahedron 1998, 54 7831);
= Hypofluoric acid - acetonitrile complex in chloroform (Dayan et al., Synthesis 1999, 1427);
= Oxone, in the presence of a base such as KOH, in water (Robker et al., J.
Chem. Res., Synop.
1993, 0 412);
= Magnesium monoperoxyphthalate, in the presence of glacial acetic acid (Klemm et al., J.
Heterocylic Chem. 1990, 6, 1537);
= Hydrogen peroxide, in the presence of water and acetic acid (Lin A.J., Org.
Prep. Proced. Int.
1991, 23(1), 114);
= Dimethyldioxirane in acetone (Boyd et al., J. Chem. Soc., Perkin Trans.
1991, 9 2189).
In addition, specific methods for preparing diaryl ureas and intermediate compounds are already described elsewhere in the patent literature, and can be adapted to the compounds of the present invention. For example, Miller S. et al, "Inhibition of p38 Kinase using Symmetrical and Unsymmetrical Diphenyl Ureas" PCT Int. Appl. WO 99 32463, Miller, S et al.
"Inhibition of raf Kinase using Symmetrical and Unsymmetrical Substituted Diphenyl Ureas" PCT
Int. Appl., WO 99 32436, Dumas, J. et al., "Inhibition of p38 Kinase Activity using Substituted Heterocyclic Ureas"
WO 2007/068381 . PCT/EP2006/011691 PCT Int. Appl., WO 99 32111, Dumas, J. et al., "Method for the Treatment of Neoplasm by Inhibition of raf Kinase using N-Heteroaryl-N'-(hetero)arylureas" PCT Int.
Appl., WO 99 32106, Dumas, J. et al., "Inhibition of p38 Kinase Activity using Aryl- and Heteroaryl- Substituted Heterocyclic Ureas" PCT Int. Appl., WO 99 32110, Dumas, J., et al., "Inhibition of raf Kinase 5_ using Aryl- and Heteroaryl- Substituted Heterocyclic Ureas" PCT Int._Appl., WO 99 32455, Riedl, B., et al., "O-Carboxy Aryl Substituted Diphenyl Ureas as raf Kinase Inhibitors" PCT Int. Appl., WO 00 42012, Riedl, B., et al., "O-Carboxy Aryl Substituted Diphenyl Ureas as p38 Kinase Inhibitors" PCT Int. Appl., WO 00 41698, Dumas, J. et al. "Heteroaryl ureas containing nitrogen hetero-atoms as p38 kinase inhibitors" U.S. Pat. Appl. Publ., US 20020065296, Dumas, J. et al.
"Preparation of N-aryl-N'-[(acylphenoxy) phenyl]ureas as raf kinase inhibitors" PCT Int. Appl., WO 02 62763, Dumas, J. et al. "Inhibition of raf kinase using quinolyl, isoquinolyl or pyridyl ureas" PCT Int. Appl., WO 02 85857, Dumas, J. et al. "Preparation of quinolyl, isoquinolyl or pyridyl-ureas as inhibitors of raf kinase for the treatment of tumors and/or cancerous cell growth"
U.S. Pat. Appl. Publ., US 20020165394. All the preceding patent applications are hereby incorporated by reference.
Synthetic transformations that may be employed in the synthesis of compounds of formula (1) and in the synthesis of intermediates involved in the synthesis of compounds of formula (1) are known by or accessible to one skilled in the art. Collections of synthetic transformations may be found in compilations, such as:
= J. March. Advanced Organic Chemistry, 4'b ed.; John Wiley: New York (1992);
= R.C. Larock. Comprehensive Organic Transformations, 2 d ed.; Wiley-VCH: New York (1999);
= F.A. Carey; R.J. Sundberg. Advanced Organic Chemistry, 2d ed.; Plenum Press:
New York (1984);
= T.W. Greene; P.G.M. Wuts. Protective Groups in Organic Synthesis, 3d ed.;
John Wiley:
New York (1999);
= L.S. Hegedus. Transition Metals in the Synthesis of Complex Organic Molecules, 2 d ed.;
University Science Books: Mill Valley, CA (1994);
= L.A. Paquette, Ed. The Encyclopedia of Reagents for Organic Synthesis; John Wiley: New York (1994);
= A.R. Katritzky; O. Meth-Cohn; C.W. Rees, Eds. Comprehensive Organic Functional Group Transformations; Pergamon Press: Oxford, UK (1995);
= G. Wilkinson; F.G A. Stone; E.W. Abel, Eds. Comprehensive Organometallic Chemistry;
Pergamon Press: Oxford, UK (1982);
= B.M. Trost; I. Fleming. Comprehensive Organic Synthesis; Pergamon Press:
Oxford, UK
(1991);
= A.R. Katritzky; C.W. Rees Eds. Comprehensive Heterocylic Chemistry; Pergamon Press:
Oxford, UK (1984);
= A.R. Katritzky; C.W. Rees; E.F.V. Scriven, Eds. Comprehensive Heterocylic Chemistry II;
Pergamon Press: Oxford, UK (1996); and = C. Hansch; P.G. Sammes; J.B. Taylor, Eds. Comprehensive Medicinal Chemistry:
Pergamon Press: Oxford, UK (1990).
In addition, recurring reviews of synthetic methodology and related topics include Organic Reactions; John Wiley: New York; Organic Syntheses; John Wiley: New York;
Reagents for Organic Synthesis: John Wiley: New York; The Total Synthesis of Natural Products; John Wiley:
New York; The Organic Chemistry of Drug Synthesis; John Wiley: New York;
Annual Reports in Organic Synthesis; Academic Press: San Diego CA; and Methoden der Organischen Chemie (Houben-Weyl); Thieme: Stuttgart, Germany. Furthermore, databases of synthetic transformations include Chemical Abstracts, which may be searched using either CAS OnLine or SciFinder, Handbuch der Organischen Chemie (Beilstein), which may be searched using SpotFire, and REACCS.
Further therapeutic agents The compounds of formula I according to the present invention can be combined with further therapeutic agents such as anti-inflammatory and/or known drugs for the therapy of inflammatory skin, eye and/or ear diseases.
The further therapeutic agents according to the invention include, but are not limited to, corticosteroids such as aldosterone, hydrocortisone, dexamethasone, prednisolone, methyl-prednisolone and cortisol; retinoids such as acitretin; cyclosporine, methothrexat, fumaric acid, efalizumab, etanercept, onecerpt, adalimumab, infliximab, pimecrolimus, tacrolimus, efomycin, elaiophyllin and parapoxvirus ovis.
= G. Wilkinson; F.G A. Stone; E.W. Abel, Eds. Comprehensive Organometallic Chemistry;
Pergamon Press: Oxford, UK (1982);
= B.M. Trost; I. Fleming. Comprehensive Organic Synthesis; Pergamon Press:
Oxford, UK
(1991);
= A.R. Katritzky; C.W. Rees Eds. Comprehensive Heterocylic Chemistry; Pergamon Press:
Oxford, UK (1984);
= A.R. Katritzky; C.W. Rees; E.F.V. Scriven, Eds. Comprehensive Heterocylic Chemistry II;
Pergamon Press: Oxford, UK (1996); and = C. Hansch; P.G. Sammes; J.B. Taylor, Eds. Comprehensive Medicinal Chemistry:
Pergamon Press: Oxford, UK (1990).
In addition, recurring reviews of synthetic methodology and related topics include Organic Reactions; John Wiley: New York; Organic Syntheses; John Wiley: New York;
Reagents for Organic Synthesis: John Wiley: New York; The Total Synthesis of Natural Products; John Wiley:
New York; The Organic Chemistry of Drug Synthesis; John Wiley: New York;
Annual Reports in Organic Synthesis; Academic Press: San Diego CA; and Methoden der Organischen Chemie (Houben-Weyl); Thieme: Stuttgart, Germany. Furthermore, databases of synthetic transformations include Chemical Abstracts, which may be searched using either CAS OnLine or SciFinder, Handbuch der Organischen Chemie (Beilstein), which may be searched using SpotFire, and REACCS.
Further therapeutic agents The compounds of formula I according to the present invention can be combined with further therapeutic agents such as anti-inflammatory and/or known drugs for the therapy of inflammatory skin, eye and/or ear diseases.
The further therapeutic agents according to the invention include, but are not limited to, corticosteroids such as aldosterone, hydrocortisone, dexamethasone, prednisolone, methyl-prednisolone and cortisol; retinoids such as acitretin; cyclosporine, methothrexat, fumaric acid, efalizumab, etanercept, onecerpt, adalimumab, infliximab, pimecrolimus, tacrolimus, efomycin, elaiophyllin and parapoxvirus ovis.
Preference is given to corticosteroids such as aldosterone, hydrocortisone, dexamethasone, prednisolone, methylprednisolone and cortisol; pimecrolimus and/or tacrolimus.
Indications The compounds and combinations according to the present invention can be used for manufacture of a medicament for treating inflammatory skin, eye and/or ear diseases. Also the present invention provides methods of treating inflammatory skin, eye and/or ear diseases, comprising administering effective amounts of at least one compound of formula I and optionally at least one further therapeutic agent according to the invention. An "effective amount" is the quantity of the compound that is useful to achieve the desired result, e.g., to treat the disease or condition. Any subject can be treated in accordance with the present invention, including, e.g., invertebrates, vertebrates, mammals (e.g., humans; non-human primates; monkeys; livestock, such as cows, pigs, and sheep; dogs; cats; rodents; rats; mice; guinea pigs), and birds (e.g., chicken; turkey; and ducks).
Diseases according to the present invention include, but are not limited to, contact dermatitis such as irritative or allergic contact dermatitis, psoriasis, atopic dermatitis, discoid Lupus erythema-todes, inflammatory diseases of the eye such as keratitis, uveitis or retinitis, and inflammatory diseases of the ear such as Otitis media.
Preference is given to contact dermatitis such as irritative or allergic contact dermatitis, atopic dermatitis, discoid Lupus erythematodes, inflammatory diseases of the eye such as keratitis, uveitis or retinitis, and inflammatory diseases of the ear such as Otitis media. More preferably contact dermatitis such as irritative or allergic contact dermatitis is to be mentioned as disease according to the invention.
The present invention also relates to the treatment and/or prophylaxis of contact dermatitis that is produced by contact with skin sensitizers. A skin sensitizer is any agent that can cause an allergic reaction after repeated exposure to it. Examples of contact dermatitis and the sensitizing agent include, e.g., neonatal contact dermatitis (e.g., diapers; metals; perfumes;
wool; polyester;
cosmetic preparations; medicated creams containing antibiotics, such as neomycin and penicillin, antihistamines, and corticosteroids); intertrigo; napkin dermatitis; cosmetic dermatitis (e.g.
perfumes; formaldehyde; balsams; flavoring agents; spices; fixatives, such as balsams, benzyl salicylates, and synthetic musk; methyl cinnamate; antioxidants; lanolins;
sunscreens; detergents, such as lauryl ether sulfate, and coconut diethanolamide; oils; creams;
powders; deodorants and antiperspirants, containing zinc salts, aluminum salts, zirconium preparations; chlorinated phenols, hexachlorophene, and hydroxyquinolines; hair dyes, such as phenylenediamine, toluenediamine, nitro-PPD, p-aminodiphenylamine, resorcinol and pyrogallol; hair lacquers, such as shellac, benzoin, and cyclohexanone-formaldehyde resin ; hair creams and gels; hair lotions, such as quinine, resorcinol, and hexamidine isethionate; hair detergents, such as azo dyes, hydroxyquinolines, and zinc pyrithium; hair sprays, such as lanolin, shellac, or gum Arabic; hair shampoos, such as tars, salicylic acid, resorcin, quinine sulfate, detergent, azo dyes, hydroxyquinolines, zinc pyrithium, cinchona, lanolin, paraben, p-phenylenediamine; hair dyes, such as p-toluenediamine, resorcinol, pyrogallol, and musk; lip preparations (e.g., rouge azo dyes, quinazoline yellow, and coloring and flavoring preparations; flavoring agents (e.g., mustard, cinnamon, vanilla, allspice, oil of juniper, and cloves; adhesives, such as rubber chemicals, acrylates, diphenyl-thiourea; epoxy resin; topical medications, such as benzoyl peroxide and parabens; phenothiazine; hydroxyquinolines; formaldehyde; tooth and mouthwashes, such as fluorine, antiseptics, essential oils, and flavorings); clothing dermatitis (e.g., dyes; finishings;
spandex; mercaptobenzothiazole; formaldehyde; chromate; tannin, paraphenylene diamine;
remnants of soaps); detergent dermatitis (detergents; surface-acting agents;
sulphonated oils;
wetting agents; emulsifiers; perborates; phosphates; bleaches; perfumes;
quaternary ammonium compounds; soda ash; plant dermatitis (e.g., grass; shrubs; oils of certain "poisonous" plants such as poison ivy, oak, and sumac; beeswax; poplar resin; cinnamic acid ester;
garlic, such as diallyldissulphide; essential oils; cinnamon oil; clove oil; lemon oil;
vanilla; furocourmaines;
pollens; epoxy resin); rhus dermatitis; lacquer dermatitis; metal dermatitis (e.g., chromium; nickel, such as nickel sulfate and nickel ammonium sulfate; gold salts and platinum;
mercury, such as mercuric salts, mercurochrome, phenyl mercuric borate, phenyl mercuric acetate, and red mercuric sulfide; arsenic and arsenic salts; white gold; chloride gold; iodine); shoe dermatitis; stocking dermatitis; seborrheic dermatitis. Any of the agents listed above can cause contact dermatitis.
The present invention also relates to treating and/or preventing any skin, eye, or ear inflaniunatory response, condition, or disease associated with immune cells, including dendritic cells (e.g., contact sensitizers have been shown to trigger DC cell maturation.
Compounds according to the present invention can be tested for their ability to treat and/or prevent inflammatory conditions of the present invention routinely. A number of in vivo and vitro models exist for inflammatory conditions. See, e.g., hairless guinea pig (e.g., Miyauchi and Horio, J.
Dermatol., 1992 Mar;19(3):140-5); induced on ears of BALB/c mice using dinitrofluorobenzene (e.g., Bhol and Schecter, Br. J. Dermatol. 2005 Jun;152(6):1235-42); hairless mouse model. See, also, Knight and Breheny, Altem Lab Anim. 2002 Jan-Feb;30(1):7-22.
The present invention also relates to inflammatory conditions, diseases, and disorders of the eye.
These include, but are not limited to, inflammation associated with ocular infection, immune WO 2007/068381 . PCT/EP2006/011691 disorders, and allergy. Uveitis is an example of an autoimmune disease that affects the eye.
Examples of autoimmune conditions that affect the eye include, but are not limited to, e.g., giant cell arteritis (associated with polymyalgia rheumatica); iritis (associated with ankylosing spondylitis); scleritis (associated with rheumatoid arthritis); and dry eyes (associated with Sjogren's syndrome). Reactive arthritis can also be associated with eye inflammation, including uveitis and conjunctivitis. See, e.g., Colmegna et al., Clin Microbiol Rev.
2004 Apr; 17(2): 348-369.
Other examples of inflammatory eyes conditions that can be treated in accordance with the present invention include, allergic conjunctivitis, infectious conjunctivitis, blepharitis, and red eye.
Chronic uveitis can be associated with a heterogeneous group of diseases, including arthritis, sarcoidosis and Behcet's syndrome. Intermediate uveitis can be associated with multiple sclerosis, sarcoidosis, syphilis, Lyme disease, and ocular lymphoma. Posterior uveitis (also known as also known as choroiditis and chorioretinitis) can be associated with many systemic diseases, including sarcoidosis, syphilis, Behcet's syndrome, and Vogt Koyanagi Harada syndrome, as well as purely ocular syndromes such as sympathetic ophthalmia and birdshot chorioretinopathy.
Models of eye inflammation are well-known in the art, including rabbit models;
experimental model of allergic conjunctivitis to ragweed in guinea pig (e.g., Merayo-Lloves et al., Curr Eye Res.
1995 Jun;14(6):487-94.
Administration Compounds or drug combinations of the present invention can be administered in any form by any effective route, including, e.g., oral, parenteral, enteral, intravenous, intraperitoneal, topical, transdermal (e.g., using any standard patches, plasters or bandages), ophthalmic, nasally, local, non-oral, such as aerosal, inhalation, subcutaneous, intramuscular, buccal, sublingual, rectal, vaginal, intra-arterial, and intrathecal, etc. They can be administered alone, or in combination with any ingredient(s), active or inactive.
Preference is given to an oral and/or topical administration.
Compounds or drug combinations of the present invention can be converted in a known manner into the usual formulations, which may be liquid or solid formulations e.g.
without limitation nonnal and enteric coated tablets, capsules, pills, powders, granules, elixirs, tinctures, solutions, suspensions, syrups, solid and liquid aerosols, cremes, ointments, gels, ear drops, eye drops and emulsions.
Indications The compounds and combinations according to the present invention can be used for manufacture of a medicament for treating inflammatory skin, eye and/or ear diseases. Also the present invention provides methods of treating inflammatory skin, eye and/or ear diseases, comprising administering effective amounts of at least one compound of formula I and optionally at least one further therapeutic agent according to the invention. An "effective amount" is the quantity of the compound that is useful to achieve the desired result, e.g., to treat the disease or condition. Any subject can be treated in accordance with the present invention, including, e.g., invertebrates, vertebrates, mammals (e.g., humans; non-human primates; monkeys; livestock, such as cows, pigs, and sheep; dogs; cats; rodents; rats; mice; guinea pigs), and birds (e.g., chicken; turkey; and ducks).
Diseases according to the present invention include, but are not limited to, contact dermatitis such as irritative or allergic contact dermatitis, psoriasis, atopic dermatitis, discoid Lupus erythema-todes, inflammatory diseases of the eye such as keratitis, uveitis or retinitis, and inflammatory diseases of the ear such as Otitis media.
Preference is given to contact dermatitis such as irritative or allergic contact dermatitis, atopic dermatitis, discoid Lupus erythematodes, inflammatory diseases of the eye such as keratitis, uveitis or retinitis, and inflammatory diseases of the ear such as Otitis media. More preferably contact dermatitis such as irritative or allergic contact dermatitis is to be mentioned as disease according to the invention.
The present invention also relates to the treatment and/or prophylaxis of contact dermatitis that is produced by contact with skin sensitizers. A skin sensitizer is any agent that can cause an allergic reaction after repeated exposure to it. Examples of contact dermatitis and the sensitizing agent include, e.g., neonatal contact dermatitis (e.g., diapers; metals; perfumes;
wool; polyester;
cosmetic preparations; medicated creams containing antibiotics, such as neomycin and penicillin, antihistamines, and corticosteroids); intertrigo; napkin dermatitis; cosmetic dermatitis (e.g.
perfumes; formaldehyde; balsams; flavoring agents; spices; fixatives, such as balsams, benzyl salicylates, and synthetic musk; methyl cinnamate; antioxidants; lanolins;
sunscreens; detergents, such as lauryl ether sulfate, and coconut diethanolamide; oils; creams;
powders; deodorants and antiperspirants, containing zinc salts, aluminum salts, zirconium preparations; chlorinated phenols, hexachlorophene, and hydroxyquinolines; hair dyes, such as phenylenediamine, toluenediamine, nitro-PPD, p-aminodiphenylamine, resorcinol and pyrogallol; hair lacquers, such as shellac, benzoin, and cyclohexanone-formaldehyde resin ; hair creams and gels; hair lotions, such as quinine, resorcinol, and hexamidine isethionate; hair detergents, such as azo dyes, hydroxyquinolines, and zinc pyrithium; hair sprays, such as lanolin, shellac, or gum Arabic; hair shampoos, such as tars, salicylic acid, resorcin, quinine sulfate, detergent, azo dyes, hydroxyquinolines, zinc pyrithium, cinchona, lanolin, paraben, p-phenylenediamine; hair dyes, such as p-toluenediamine, resorcinol, pyrogallol, and musk; lip preparations (e.g., rouge azo dyes, quinazoline yellow, and coloring and flavoring preparations; flavoring agents (e.g., mustard, cinnamon, vanilla, allspice, oil of juniper, and cloves; adhesives, such as rubber chemicals, acrylates, diphenyl-thiourea; epoxy resin; topical medications, such as benzoyl peroxide and parabens; phenothiazine; hydroxyquinolines; formaldehyde; tooth and mouthwashes, such as fluorine, antiseptics, essential oils, and flavorings); clothing dermatitis (e.g., dyes; finishings;
spandex; mercaptobenzothiazole; formaldehyde; chromate; tannin, paraphenylene diamine;
remnants of soaps); detergent dermatitis (detergents; surface-acting agents;
sulphonated oils;
wetting agents; emulsifiers; perborates; phosphates; bleaches; perfumes;
quaternary ammonium compounds; soda ash; plant dermatitis (e.g., grass; shrubs; oils of certain "poisonous" plants such as poison ivy, oak, and sumac; beeswax; poplar resin; cinnamic acid ester;
garlic, such as diallyldissulphide; essential oils; cinnamon oil; clove oil; lemon oil;
vanilla; furocourmaines;
pollens; epoxy resin); rhus dermatitis; lacquer dermatitis; metal dermatitis (e.g., chromium; nickel, such as nickel sulfate and nickel ammonium sulfate; gold salts and platinum;
mercury, such as mercuric salts, mercurochrome, phenyl mercuric borate, phenyl mercuric acetate, and red mercuric sulfide; arsenic and arsenic salts; white gold; chloride gold; iodine); shoe dermatitis; stocking dermatitis; seborrheic dermatitis. Any of the agents listed above can cause contact dermatitis.
The present invention also relates to treating and/or preventing any skin, eye, or ear inflaniunatory response, condition, or disease associated with immune cells, including dendritic cells (e.g., contact sensitizers have been shown to trigger DC cell maturation.
Compounds according to the present invention can be tested for their ability to treat and/or prevent inflammatory conditions of the present invention routinely. A number of in vivo and vitro models exist for inflammatory conditions. See, e.g., hairless guinea pig (e.g., Miyauchi and Horio, J.
Dermatol., 1992 Mar;19(3):140-5); induced on ears of BALB/c mice using dinitrofluorobenzene (e.g., Bhol and Schecter, Br. J. Dermatol. 2005 Jun;152(6):1235-42); hairless mouse model. See, also, Knight and Breheny, Altem Lab Anim. 2002 Jan-Feb;30(1):7-22.
The present invention also relates to inflammatory conditions, diseases, and disorders of the eye.
These include, but are not limited to, inflammation associated with ocular infection, immune WO 2007/068381 . PCT/EP2006/011691 disorders, and allergy. Uveitis is an example of an autoimmune disease that affects the eye.
Examples of autoimmune conditions that affect the eye include, but are not limited to, e.g., giant cell arteritis (associated with polymyalgia rheumatica); iritis (associated with ankylosing spondylitis); scleritis (associated with rheumatoid arthritis); and dry eyes (associated with Sjogren's syndrome). Reactive arthritis can also be associated with eye inflammation, including uveitis and conjunctivitis. See, e.g., Colmegna et al., Clin Microbiol Rev.
2004 Apr; 17(2): 348-369.
Other examples of inflammatory eyes conditions that can be treated in accordance with the present invention include, allergic conjunctivitis, infectious conjunctivitis, blepharitis, and red eye.
Chronic uveitis can be associated with a heterogeneous group of diseases, including arthritis, sarcoidosis and Behcet's syndrome. Intermediate uveitis can be associated with multiple sclerosis, sarcoidosis, syphilis, Lyme disease, and ocular lymphoma. Posterior uveitis (also known as also known as choroiditis and chorioretinitis) can be associated with many systemic diseases, including sarcoidosis, syphilis, Behcet's syndrome, and Vogt Koyanagi Harada syndrome, as well as purely ocular syndromes such as sympathetic ophthalmia and birdshot chorioretinopathy.
Models of eye inflammation are well-known in the art, including rabbit models;
experimental model of allergic conjunctivitis to ragweed in guinea pig (e.g., Merayo-Lloves et al., Curr Eye Res.
1995 Jun;14(6):487-94.
Administration Compounds or drug combinations of the present invention can be administered in any form by any effective route, including, e.g., oral, parenteral, enteral, intravenous, intraperitoneal, topical, transdermal (e.g., using any standard patches, plasters or bandages), ophthalmic, nasally, local, non-oral, such as aerosal, inhalation, subcutaneous, intramuscular, buccal, sublingual, rectal, vaginal, intra-arterial, and intrathecal, etc. They can be administered alone, or in combination with any ingredient(s), active or inactive.
Preference is given to an oral and/or topical administration.
Compounds or drug combinations of the present invention can be converted in a known manner into the usual formulations, which may be liquid or solid formulations e.g.
without limitation nonnal and enteric coated tablets, capsules, pills, powders, granules, elixirs, tinctures, solutions, suspensions, syrups, solid and liquid aerosols, cremes, ointments, gels, ear drops, eye drops and emulsions.
Examples of solid formulations for oral administration are described in US
provisional application Nos. 60/605,753 and 60/658,827.
The combinations of the present invention can be administered at any time and in any effective form. For example, the compounds can be administered simultaneously, e.g., as a single composition or dosage unit (e.g., a pill or liquid containing both compositions), or they can be administered as separate compositions, but at the same time (e.g., where one drug is administered intravenously and the other is administered orally or intramuscularly). The drugs can also be administered sequentially at different times. Agents can be formulated conventionally to achieve the desired rates of release over extended period of times, e.g., 12-hours, 24-hours. This can be achieved by using agents and/or their derivatives which have suitable metabolic half-lives, and/or by using controlled release formulations.
The drug combinations can be synergistic, e.g., where the joint action of the drugs is such that the combined effect is greater than the algebraic sum of their individual effects.
Thus, reduced amounts of the drugs can be administered, e.g., reducing toxicity or other deleterious or unwanted effects, and/or using the same amounts as used when the agents are administered alone, but achieving greater efficacy.
Compounds or drug combinations of the present invention can be further combined with any other suitable additive or pharmaceutically acceptable carrier. Such additives include any of the substances already mentioned, as well as any of those used conventionally, such as those described in Remington: The Science and Practice of Pharmacy (Gennaro and Gennaro, eds, 20th edition, Lippincott Williams & Wilkins, 2000); Theory and Practice of Industrial Pharmacy (Lachman et al., eds., 3rd edition, Lippincott Williams & Wilkins, 1986); Encyclopedia of Pharmaceutical Technology (Swarbrick and Boylan, eds., 2nd edition, Marcel Dekker, 2002).
These can be referred to herein as "pharmaceutically acceptable carriers" to indicate they are combined with the active drug and can be administered safely to a subject for therapeutic purposes.
In addition, compounds or drug combinations of the present invention can be administered with other active agents or other therapies that are utilized to treat any of the above-mentioned diseases and/or conditions.
The present invention provides also combinations of at least one compound of Formula I and at least one other therapeutic agent mentioned above useful in treating a disease or disorder.
"Combinations" for the purposes of the invention include:
provisional application Nos. 60/605,753 and 60/658,827.
The combinations of the present invention can be administered at any time and in any effective form. For example, the compounds can be administered simultaneously, e.g., as a single composition or dosage unit (e.g., a pill or liquid containing both compositions), or they can be administered as separate compositions, but at the same time (e.g., where one drug is administered intravenously and the other is administered orally or intramuscularly). The drugs can also be administered sequentially at different times. Agents can be formulated conventionally to achieve the desired rates of release over extended period of times, e.g., 12-hours, 24-hours. This can be achieved by using agents and/or their derivatives which have suitable metabolic half-lives, and/or by using controlled release formulations.
The drug combinations can be synergistic, e.g., where the joint action of the drugs is such that the combined effect is greater than the algebraic sum of their individual effects.
Thus, reduced amounts of the drugs can be administered, e.g., reducing toxicity or other deleterious or unwanted effects, and/or using the same amounts as used when the agents are administered alone, but achieving greater efficacy.
Compounds or drug combinations of the present invention can be further combined with any other suitable additive or pharmaceutically acceptable carrier. Such additives include any of the substances already mentioned, as well as any of those used conventionally, such as those described in Remington: The Science and Practice of Pharmacy (Gennaro and Gennaro, eds, 20th edition, Lippincott Williams & Wilkins, 2000); Theory and Practice of Industrial Pharmacy (Lachman et al., eds., 3rd edition, Lippincott Williams & Wilkins, 1986); Encyclopedia of Pharmaceutical Technology (Swarbrick and Boylan, eds., 2nd edition, Marcel Dekker, 2002).
These can be referred to herein as "pharmaceutically acceptable carriers" to indicate they are combined with the active drug and can be administered safely to a subject for therapeutic purposes.
In addition, compounds or drug combinations of the present invention can be administered with other active agents or other therapies that are utilized to treat any of the above-mentioned diseases and/or conditions.
The present invention provides also combinations of at least one compound of Formula I and at least one other therapeutic agent mentioned above useful in treating a disease or disorder.
"Combinations" for the purposes of the invention include:
- single compositions or dosage forms which contain at least one compound of Formula I
and at least one other therapeutic agent mentioned above;
- combination packs containing at least one compound of Formula I and at least one other therapeutic agent mentioned above to be administered concurrently or sequentially;
- kits which comprise at least one compound of Formula I and at least one other therapeutic agent mentioned above packaged separate from one another as unit dosages or as independent unit dosages, with or without instructions that they be administered concurrently or sequentially; and - separate independent dosage forms of at least one compound of Formula I and at least one other therapeutic agent mentioned above which cooperate to achieve a therapeutic effect, e.g., treatment of the same disease, when administered concurrently or sequen-tially.
The dosage of each agent of the combination can be selected with reference to the other and/or the type of disease and/or the disease status in order to provide the desired therapeutic activity. For example, the active agents in the combination can be present and administered in a fixed combination. "Fixed combination" is intended here to mean pharmaceutical forms in which the components are present in a fixed ratio that provides the desired efficacy.
These amounts can be determined routinely for a particular patient, where various parameters are utilized to select the appropriate dosage (e.g., type of disease, age of patient, disease status, patient health, weight, etc.), or the amounts can be relatively standard.
The amount of the administered active ingredient can vary widely according to such considerations as the particular compound and dosage unit employed, the mode and time of administration, the period of treatment, the age, sex, and general condition of the patient treated, the nature and extent of the condition treated, the rate of drug metabolism and excretion, the potential drug combinations and drug-drug interactions, and the like.
Preference is given to an amount of the compound of formula I from 20 to 2000 mg, preferably from 40 to 800 mg, more preferably from 50 to 600 mg.
Particular preference is given to an amount of p-toluenesulfonic acid salt of 4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-phenoxy}-pyridine-2-carboxylic acid methyl amide in the pharma-ceutical composition from 27 to 2740 mg, preferably from 54 to 1096, more preferably from 68 to 822 mg.
and at least one other therapeutic agent mentioned above;
- combination packs containing at least one compound of Formula I and at least one other therapeutic agent mentioned above to be administered concurrently or sequentially;
- kits which comprise at least one compound of Formula I and at least one other therapeutic agent mentioned above packaged separate from one another as unit dosages or as independent unit dosages, with or without instructions that they be administered concurrently or sequentially; and - separate independent dosage forms of at least one compound of Formula I and at least one other therapeutic agent mentioned above which cooperate to achieve a therapeutic effect, e.g., treatment of the same disease, when administered concurrently or sequen-tially.
The dosage of each agent of the combination can be selected with reference to the other and/or the type of disease and/or the disease status in order to provide the desired therapeutic activity. For example, the active agents in the combination can be present and administered in a fixed combination. "Fixed combination" is intended here to mean pharmaceutical forms in which the components are present in a fixed ratio that provides the desired efficacy.
These amounts can be determined routinely for a particular patient, where various parameters are utilized to select the appropriate dosage (e.g., type of disease, age of patient, disease status, patient health, weight, etc.), or the amounts can be relatively standard.
The amount of the administered active ingredient can vary widely according to such considerations as the particular compound and dosage unit employed, the mode and time of administration, the period of treatment, the age, sex, and general condition of the patient treated, the nature and extent of the condition treated, the rate of drug metabolism and excretion, the potential drug combinations and drug-drug interactions, and the like.
Preference is given to an amount of the compound of formula I from 20 to 2000 mg, preferably from 40 to 800 mg, more preferably from 50 to 600 mg.
Particular preference is given to an amount of p-toluenesulfonic acid salt of 4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-phenoxy}-pyridine-2-carboxylic acid methyl amide in the pharma-ceutical composition from 27 to 2740 mg, preferably from 54 to 1096, more preferably from 68 to 822 mg.
In another embodiment of the invention the compound of formula I is administered in combination with at least one further therapeutic agent in an amount that those of ordinary skill in the art can determine by their professional judgement.
The pharmaceutical composition according to the invention is administered one or more, preferably up to three, more preferably up to two times per day. Preference is given to an administration via the oral route. With each administration the number of tablets or capsules taken in at the same time should not exceed two.
Nevertheless, it may in some cases be advantageous to deviate from the amounts specified, depending on body weight, individual behaviour toward the active ingredient, type of preparation and time or interval over which the administration is effected. For instance, less than the aforementioned minimum amounts may be sufficient in some cases, while the upper limit specified has to be exceeded in other cases. In the case of administration of relatively large amounts, it may be advisable to divide these into several individual doses over the day.
The combination can comprise effective amounts of at least one compound of Formula I and at least one other therapeutic agent mentioned above, which achieves a greater therapeutic efficacy than when either compound is used alone. The combination can be useful to treat inflammatory skin, eye and/or ear diseases, where the therapeutic effect is not observed when the agents are used alone, or where an enhanced effect is observed when the combination is administered.
The relative ratios of each compound in the combination can also be selected based on their respective mechanisms of action and the disease biology. The relative ratios of each compound can vary widely and this invention includes combinations for treating inflammatory skin, eye and/or ear diseases where the amounts of the formula I compound and the other therapeutic agent can be adjusted routinely such that either is present in higher amounts.
The release of one or more agents of the combination can also be controlled, where appropriate, to provide the desired therapeutic activity when in a single dosage form, combination pack, kit or when in separate independent dosage forms.
Preference is given to a combination comprising at least one compound of formula I and at least one corticosteroid. More preferably a combination comprising 4{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-ureido]-phenoxy}-pyridine-2-carboxylic acid methyl amide (BAY 43-9006) or the p-toluenesulfonic acid salt of 4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-phenoxy}-pyridine-2-carboxylic acid methyl amide and at least one corticosteroid is used.
The pharmaceutical composition according to the invention is administered one or more, preferably up to three, more preferably up to two times per day. Preference is given to an administration via the oral route. With each administration the number of tablets or capsules taken in at the same time should not exceed two.
Nevertheless, it may in some cases be advantageous to deviate from the amounts specified, depending on body weight, individual behaviour toward the active ingredient, type of preparation and time or interval over which the administration is effected. For instance, less than the aforementioned minimum amounts may be sufficient in some cases, while the upper limit specified has to be exceeded in other cases. In the case of administration of relatively large amounts, it may be advisable to divide these into several individual doses over the day.
The combination can comprise effective amounts of at least one compound of Formula I and at least one other therapeutic agent mentioned above, which achieves a greater therapeutic efficacy than when either compound is used alone. The combination can be useful to treat inflammatory skin, eye and/or ear diseases, where the therapeutic effect is not observed when the agents are used alone, or where an enhanced effect is observed when the combination is administered.
The relative ratios of each compound in the combination can also be selected based on their respective mechanisms of action and the disease biology. The relative ratios of each compound can vary widely and this invention includes combinations for treating inflammatory skin, eye and/or ear diseases where the amounts of the formula I compound and the other therapeutic agent can be adjusted routinely such that either is present in higher amounts.
The release of one or more agents of the combination can also be controlled, where appropriate, to provide the desired therapeutic activity when in a single dosage form, combination pack, kit or when in separate independent dosage forms.
Preference is given to a combination comprising at least one compound of formula I and at least one corticosteroid. More preferably a combination comprising 4{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-ureido]-phenoxy}-pyridine-2-carboxylic acid methyl amide (BAY 43-9006) or the p-toluenesulfonic acid salt of 4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-phenoxy}-pyridine-2-carboxylic acid methyl amide and at least one corticosteroid is used.
Examnles=
Example 1: Immediate release tablet and optionally subsequent film-coating 1.1 Composition of tablets containing the p-toluenesulfonic acid salt of 4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-phenoxy}-pyridine-2-carboxylic acid methyl amide Composition [mg/tablet] Tablet A 50 mg Tablet B 200 mg Tablet C 200 mg Tablet D 400 mg Tablet core: step a), b) step a), b), c) ii Step a), b) c) i Step a), b) c) i Tosylate salt of compound68.5 mg 274.0 mg 274.0 mg 548.0 mg (I) micronized Microcrystalline cellulose 4.0 mg 16.0 mg 16.0 mg 32.0 mg Croscarmellose sodium 9.1 mg 36.4 mg 36.4 mg 72.8 mg Hypromellose (5 cP) 2.55 mg 10.2 mg 10.2 mg 20.4 mg Magnesium stearate 0.425 mg 1.7 mg 2.55 mg"1 5.10 mg (1.70 - 2.55 mg) Sodium lauryl sulfate 0.425 mg 1.7 mg 1.7 mg 3.4 mg Weight 85.0 mg 340.0 mg 340.85 mg 681.70 mg (340.0 - 340.85 mg) Film-coating:
Opadry Red YS2-15531#3 10.0 mg --"Z-- -"Z-Hypromellose (15 cP) ---- ----- 6.00 mg 9.0 mg (4.8 - 7.2 mg) (7.2-10.8 mg) Macrogol 3350---- --- 2.00 mg 3.0 mg (polyethylene gycol) (1.6 - 2.4 mg) (2.4-3.6 mg) Titanium dioxide ----- ----- 1.73 mg 1.6 mg (1.384 - 2.076 mg) (1.28-1.92 mg) WO 2007/068381 _ PCT/EP2006/011691 Ferric oxide (red) ---- ---- 0.27 mg ----(0.216 - 0.324 mg) Ferric oxide (yellow) ----- ----- ---- 1.4 mg (1.12-1.68 mg) Weight of film coat ----- 10.0 mg 10.0 mg 15.0 mg (8.0-12.0mg) (12.0 - 18.0 mg) 350.85 mg 696.7 mg Total tablet weight 85.0 mg 350.0 mg (348 - 352.85 mg) (348.0-352.85 mg) Tabletformat Round round round oval Dimensions of the tablet diameter: 6 mm diameter: 10 mm,diameter: 10 mm,Iength: 18 mm, height: 4.5 (f0.3)height: 4.5 ( 0.3) mm width: 8 mm mm #1 Range for Mg stearate may apply according to manufacturing conditions #2 Range for film coat may apply according to manufacturing conditions Fixed ratio of coating components 60 % (hypromellose) - 20 % (polyethylene glycol) - 17.3 %
(titanium dioxide) - 2.7 % ferric oxide #3 Opadry Red YS-15531 ready to use commercial coating system.
1.2 Process for manufacturing Step a) Granulation 4 {4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-phenoxy} -pyridine-2-carboxylic acid methyl amide micronized, microcrystalline cellulose, croscarmellose sodium, and hypromellose are mixed for 2 minutes in a high shear mixer in order to obtain a powder blend. Sodium lauryl sulfate is dissolved in water. The powder blend is granulated with the solution in a wet granulation process using a high-shear mixer. The granulation process is finished when the granulate achieves aõsnow .-27-ball like consistency". The wet granulation mass is sized using a 4 mm rasp and then dried in a fluidized bed dryer at an inlet air temperature of 80 - 100 C until a residual moisture of 0.3 up to 0.7% by weight (loss on drying) is reached. The dry granules are sieved using a 2 mm sieve size.
Step b) Tablet compression The granulate is blended with magnesium stearate and croscarmellose sodium using a tumbler blender for from 5 to 10 minutes. The blend is subdivided into single units and compressed to tablets using a standard rotary tablet press at typical tabletting speeds of from 25,000 to 250,000 tablets / hour.
Step c) Film-coating Alternative i:
Hypromellose, polyethylene glycol (Macrogol), titanium dioxide and ferric oxide red are combined with purified water to result in a homogenous coating suspension which is sprayed on the tablets in a perforated drum coater.
Alternative ii:
The commercially available Opadry Red YS-15531 is combined with purified water to result in a homogenous coating suspension which is sprayed on the tablets in a perforated drum coater.
Example 1: Immediate release tablet and optionally subsequent film-coating 1.1 Composition of tablets containing the p-toluenesulfonic acid salt of 4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-phenoxy}-pyridine-2-carboxylic acid methyl amide Composition [mg/tablet] Tablet A 50 mg Tablet B 200 mg Tablet C 200 mg Tablet D 400 mg Tablet core: step a), b) step a), b), c) ii Step a), b) c) i Step a), b) c) i Tosylate salt of compound68.5 mg 274.0 mg 274.0 mg 548.0 mg (I) micronized Microcrystalline cellulose 4.0 mg 16.0 mg 16.0 mg 32.0 mg Croscarmellose sodium 9.1 mg 36.4 mg 36.4 mg 72.8 mg Hypromellose (5 cP) 2.55 mg 10.2 mg 10.2 mg 20.4 mg Magnesium stearate 0.425 mg 1.7 mg 2.55 mg"1 5.10 mg (1.70 - 2.55 mg) Sodium lauryl sulfate 0.425 mg 1.7 mg 1.7 mg 3.4 mg Weight 85.0 mg 340.0 mg 340.85 mg 681.70 mg (340.0 - 340.85 mg) Film-coating:
Opadry Red YS2-15531#3 10.0 mg --"Z-- -"Z-Hypromellose (15 cP) ---- ----- 6.00 mg 9.0 mg (4.8 - 7.2 mg) (7.2-10.8 mg) Macrogol 3350---- --- 2.00 mg 3.0 mg (polyethylene gycol) (1.6 - 2.4 mg) (2.4-3.6 mg) Titanium dioxide ----- ----- 1.73 mg 1.6 mg (1.384 - 2.076 mg) (1.28-1.92 mg) WO 2007/068381 _ PCT/EP2006/011691 Ferric oxide (red) ---- ---- 0.27 mg ----(0.216 - 0.324 mg) Ferric oxide (yellow) ----- ----- ---- 1.4 mg (1.12-1.68 mg) Weight of film coat ----- 10.0 mg 10.0 mg 15.0 mg (8.0-12.0mg) (12.0 - 18.0 mg) 350.85 mg 696.7 mg Total tablet weight 85.0 mg 350.0 mg (348 - 352.85 mg) (348.0-352.85 mg) Tabletformat Round round round oval Dimensions of the tablet diameter: 6 mm diameter: 10 mm,diameter: 10 mm,Iength: 18 mm, height: 4.5 (f0.3)height: 4.5 ( 0.3) mm width: 8 mm mm #1 Range for Mg stearate may apply according to manufacturing conditions #2 Range for film coat may apply according to manufacturing conditions Fixed ratio of coating components 60 % (hypromellose) - 20 % (polyethylene glycol) - 17.3 %
(titanium dioxide) - 2.7 % ferric oxide #3 Opadry Red YS-15531 ready to use commercial coating system.
1.2 Process for manufacturing Step a) Granulation 4 {4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-phenoxy} -pyridine-2-carboxylic acid methyl amide micronized, microcrystalline cellulose, croscarmellose sodium, and hypromellose are mixed for 2 minutes in a high shear mixer in order to obtain a powder blend. Sodium lauryl sulfate is dissolved in water. The powder blend is granulated with the solution in a wet granulation process using a high-shear mixer. The granulation process is finished when the granulate achieves aõsnow .-27-ball like consistency". The wet granulation mass is sized using a 4 mm rasp and then dried in a fluidized bed dryer at an inlet air temperature of 80 - 100 C until a residual moisture of 0.3 up to 0.7% by weight (loss on drying) is reached. The dry granules are sieved using a 2 mm sieve size.
Step b) Tablet compression The granulate is blended with magnesium stearate and croscarmellose sodium using a tumbler blender for from 5 to 10 minutes. The blend is subdivided into single units and compressed to tablets using a standard rotary tablet press at typical tabletting speeds of from 25,000 to 250,000 tablets / hour.
Step c) Film-coating Alternative i:
Hypromellose, polyethylene glycol (Macrogol), titanium dioxide and ferric oxide red are combined with purified water to result in a homogenous coating suspension which is sprayed on the tablets in a perforated drum coater.
Alternative ii:
The commercially available Opadry Red YS-15531 is combined with purified water to result in a homogenous coating suspension which is sprayed on the tablets in a perforated drum coater.
Claims (18)
1. Use of a compound of formula I or a pharmaceutically acceptable salt, polymorph, solvate, hydrate, metabolite, prodrug or diastereoisomeric form thereof, for manufacture of a medicament for treatment of inflammatory skin, eye and/or ear diseases, wherein said compound of formula I is:
wherein Q is -C(O)R x R x is hydroxy, C1-4 alkyl, C1-4 alkoxy or NR a R b, R a and R b are independently :
a) hydrogen;
b) C1-4 alkyl, optionally substituted by - hydroxy, - C1-4 alkoxy, - a heteroaryl group selected from pyrrole, furan, thiophene, imidazole, pyrazole, thiazole, oxazole, isoxazole, isothiazole, triazole, tetrazole, thiadiazole, oxadiazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine, benzoxazole, isoquioline, quinolines and imidazopyrimidine - a heterocyclic group selected from tetrahydropyran, tetrahydrofuran, 1,3-dioxo-lane, 1,4-dioxane, morpholine, thiomorpholine, piperazine, piperidine, piperidi-none, tetrahydropyrimidone, pentamethylene sulfide, tetramethylene sulfide, dihy-dropyrane, dihydrofuran, and dihydrothiophene, - amino,-NH2, optionally substituted by one or two C1-4 alkyl groups, or - phenyl, c) phenyl optionally substituted with - halogen, or - amino,-NH2, optionally substituted by one or two C1-4 alkyl, or d) - a heteroaryl group selected from pyrrole, furan, thiophene, imidazole, pyrazole, thiazole, oxazole, isoxazole, isothiazole, triazole, tetrazole, thiadiazole, oxadiazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine, benzoxazole, isoquioline, quinoline and imidazopyrimidine;
A is an optionally substituted phenyl group of formula 1xx:
an optionally substituted pyridinyl group of formula 1x:
or an optionally substituted naphthyl moiety of formula 1y:
B is optionally substituted phenyl or naphthyl of formulas 2a and 2b:
L is a bridging group which is -S- or -O-, p is 0, 1, 2, 3, or 4, n is 0, 1, 2, 3, 4, 5 or 6, m is 0, 1, 2 or 3, each R1 is independently: halogen, C1-5 haloalkyl, NO2, C(O)NR4R5, C1-6 alkyl, dialkylamine, C1-3 alkylamine, CN, amino, hydroxy or C1-3 alkoxy.
each R2 is independently: C1-5 alkyl, C1-5 haloalkyl, C1-3 alkoxy, N-oxo or N-hydroxy, each R3 is independently: halogen, R4, OR4, S(O)R4, C(O)R4, C(O)NR4R5, oxo, cyano or nitro (NO2) and R4 and R5 are independently hydrogen, C1-6 alkyl, or up to per-halogenated C 1-6-alkyl.
wherein Q is -C(O)R x R x is hydroxy, C1-4 alkyl, C1-4 alkoxy or NR a R b, R a and R b are independently :
a) hydrogen;
b) C1-4 alkyl, optionally substituted by - hydroxy, - C1-4 alkoxy, - a heteroaryl group selected from pyrrole, furan, thiophene, imidazole, pyrazole, thiazole, oxazole, isoxazole, isothiazole, triazole, tetrazole, thiadiazole, oxadiazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine, benzoxazole, isoquioline, quinolines and imidazopyrimidine - a heterocyclic group selected from tetrahydropyran, tetrahydrofuran, 1,3-dioxo-lane, 1,4-dioxane, morpholine, thiomorpholine, piperazine, piperidine, piperidi-none, tetrahydropyrimidone, pentamethylene sulfide, tetramethylene sulfide, dihy-dropyrane, dihydrofuran, and dihydrothiophene, - amino,-NH2, optionally substituted by one or two C1-4 alkyl groups, or - phenyl, c) phenyl optionally substituted with - halogen, or - amino,-NH2, optionally substituted by one or two C1-4 alkyl, or d) - a heteroaryl group selected from pyrrole, furan, thiophene, imidazole, pyrazole, thiazole, oxazole, isoxazole, isothiazole, triazole, tetrazole, thiadiazole, oxadiazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine, benzoxazole, isoquioline, quinoline and imidazopyrimidine;
A is an optionally substituted phenyl group of formula 1xx:
an optionally substituted pyridinyl group of formula 1x:
or an optionally substituted naphthyl moiety of formula 1y:
B is optionally substituted phenyl or naphthyl of formulas 2a and 2b:
L is a bridging group which is -S- or -O-, p is 0, 1, 2, 3, or 4, n is 0, 1, 2, 3, 4, 5 or 6, m is 0, 1, 2 or 3, each R1 is independently: halogen, C1-5 haloalkyl, NO2, C(O)NR4R5, C1-6 alkyl, dialkylamine, C1-3 alkylamine, CN, amino, hydroxy or C1-3 alkoxy.
each R2 is independently: C1-5 alkyl, C1-5 haloalkyl, C1-3 alkoxy, N-oxo or N-hydroxy, each R3 is independently: halogen, R4, OR4, S(O)R4, C(O)R4, C(O)NR4R5, oxo, cyano or nitro (NO2) and R4 and R5 are independently hydrogen, C1-6 alkyl, or up to per-halogenated C 1-6-alkyl.
2. The use of claim 1 wherein A is 3-tert butyl phenyl, 5-tert butyl-2-methoxyphenyl, 5-(trifluoromethyl)-2phenyl, 3-(tri-fluoromethyl)-4-chlorophenyl, 3-(trifluoromethyl)-4-bromophenyl or 5-(trifluoro-methyl)-4-chloro-2 methoxyphenyl;
B is R1 is fluorine, chorine, bromine, methyl, NO2, C(O)NH2, methoxy, SCH3, trifluoromethyl, or methanesulfonyl;
R2 is methyl, ethyl, propyl, oxygen, or cyano and R3 is trifluoromethyl, methyl, ethyl, propyl, butyl, isopropyl, tert-butyl, chlorine, fluorine, bromine, cyano, methoxy, acetyl, trifluoromethanesulfonyl, trifluoro-methoxy, or trifluoromethylthio.
B is R1 is fluorine, chorine, bromine, methyl, NO2, C(O)NH2, methoxy, SCH3, trifluoromethyl, or methanesulfonyl;
R2 is methyl, ethyl, propyl, oxygen, or cyano and R3 is trifluoromethyl, methyl, ethyl, propyl, butyl, isopropyl, tert-butyl, chlorine, fluorine, bromine, cyano, methoxy, acetyl, trifluoromethanesulfonyl, trifluoro-methoxy, or trifluoromethylthio.
3. The use of any of claims 1 to 2 wherein the compound of formula I is also of formula II
below or salts, polymorphs, solvates, hydrates, metabolites, prodrugs or diastereoisomeric forms thereof:
wherein Ra and Rb are independently hydrogen and C1-C4 alkyl, B of formula II is wherein the urea group, -NH-C(O)-NH-, and the oxygen bridging group are not bound to contiguous ring carbons of B, but rather have 1 or 2 ring carbons separating them, and A of formula (II) is, or wherein the variable n is 0, 1, 2, 3 or 4, and R3 is trifluoromethyl, methyl, ethyl, propyl, butyl, isopropyl, tert-butyl, chlorine, fluorine, bromine, cyano, methoxy, acetyl, trifluoromethanesulfonyl, trifluoro-methoxy, or trifluoromethylthio.
below or salts, polymorphs, solvates, hydrates, metabolites, prodrugs or diastereoisomeric forms thereof:
wherein Ra and Rb are independently hydrogen and C1-C4 alkyl, B of formula II is wherein the urea group, -NH-C(O)-NH-, and the oxygen bridging group are not bound to contiguous ring carbons of B, but rather have 1 or 2 ring carbons separating them, and A of formula (II) is, or wherein the variable n is 0, 1, 2, 3 or 4, and R3 is trifluoromethyl, methyl, ethyl, propyl, butyl, isopropyl, tert-butyl, chlorine, fluorine, bromine, cyano, methoxy, acetyl, trifluoromethanesulfonyl, trifluoro-methoxy, or trifluoromethylthio.
4. The use of any of claims 1 to 3 wherein, each R3 substituent is chlorine, trifluoromethyl, tert-butyl or methoxy, A of formula II is and B of formula II is phenylene, fluoro substituted phenylene or difluoro substituted phenylene.
5. The use of any of claims 1 to 4 wherein the compound of formula I is also of formula X
below or salts, polymorphs, solvates, hydrates, metabolites, prodrugs or diastereoisomeric forms thereof:
wherein phenyl ring "B" optionally has one halogen substituent, A is an optionally substituted phenyl group of formula 1xx:
an optionally substituted pyridinyl group of formula 1x:
or an optionally substituted naphthyl moiety of formula 1y:
n is 0, 1, 2, 3, 4, 5 or 6, m is 0, 1, 2 or 3, each R2 is independently: C1-5 alkyl, C1-5 haloalkyl, C1-3 alkoxy, N-oxo or N-hydroxy, each R3 is independently: halogen, R4, OR4, S(O)R4, C(O)R4, C(O)NR4R5, oxo, cyano or nitro (NO2) and R4 and R5 are independently hydrogen, C1-6 alkyl, or up to per-halogenated C1-
below or salts, polymorphs, solvates, hydrates, metabolites, prodrugs or diastereoisomeric forms thereof:
wherein phenyl ring "B" optionally has one halogen substituent, A is an optionally substituted phenyl group of formula 1xx:
an optionally substituted pyridinyl group of formula 1x:
or an optionally substituted naphthyl moiety of formula 1y:
n is 0, 1, 2, 3, 4, 5 or 6, m is 0, 1, 2 or 3, each R2 is independently: C1-5 alkyl, C1-5 haloalkyl, C1-3 alkoxy, N-oxo or N-hydroxy, each R3 is independently: halogen, R4, OR4, S(O)R4, C(O)R4, C(O)NR4R5, oxo, cyano or nitro (NO2) and R4 and R5 are independently hydrogen, C1-6 alkyl, or up to per-halogenated C1-
6 alkyl.
6. The use of claim 5 wherein m is zero and A is substituted phenyl with at least one substituent R3.
6. The use of claim 5 wherein m is zero and A is substituted phenyl with at least one substituent R3.
7. The use of claim 6 wherein R3 is halogen, trifluoromethyl and/or methoxy.
8. The use of claim 1 wherein the compound of formula I also has the structure of one of formulas Z1 or Z2 below or a salt, polymorph, solvate, hydrate, metabolite, prodrug or diastereo-isomeric form thereof:
9. The use of claim 8 wherein the compound of formula I is the tosylate salt of the compound of formula Z1.
10. The use of any of claims 1 to 9 for the treatment of irritative or allergic contact dermatitis, psoriasis, atopic dermatitis, discoid Lupus erythematodes, inflammatory diseases of the eye such as keratitis, uveitis or retinitis, and inflammatory diseases of the ear such as Otitis media.
11. Combination comprising at least one compound of formula I as defined in any of claims 1 to 9 and at least one therapeutic agent selected from the group consisting of anti-inflammatory agents and known drugs for the therapy of inflammatory skin, eye and/or ear diseases.
12. Combination of claim 11 wherein the further therapeutic agent is selected from the group consisting of corticosteroids, retinoids, cyclosporine, methothrexat, fumaric acid, efalizumab, etanercept, onecerpt, adalimumab, infliximab, pimecrolimus, tacrolimus, efomycin, elaiophyllin and parapoxvirus ovis.
13. Use of a combination of any of claims 11 to 12 for manufacture of a medicament for treatment of inflammatory skin, eye and/or ear diseases.
14. The use of claim 13 for the treatment of irritative or allergic contact dermatitis, psoriasis, atopic dermatitis, discoid Lupus erythematodes, inflammatory diseases of the eye such as keratitis, uveitis or retinitis, and inflammatory diseases of the ear such as Otitis media.
15. Pharmaceutical composition comprising a combination as defined in any of claims 11 to 12.
16. Pharmaceutical composition of claim 15 for the treatment of inflammatory skin, eye and/or ear diseases.
17. A method for treating inflammatory skin, eye and/or ear diseases in a subject in need thereof comprising administering effective amounts of at least one compound of formula I or a pharmaceutically acceptable salt, polymorph, solvate, hydrate, metabolite, prodrug or diastereo-isomeric form thereof wherein said compound of formula I is:
wherein Q is -C(O)R x R x is hydroxy, C1-4 alkyl, C1-4 alkoxy or NR a R b, R a and R b are independently :
a) hydrogen;
b) C1-4 alkyl, optionally substituted by - hydroxy, - C1-4 alkoxy, - a heteroaryl group selected from pyrrole, furan, thiophene, imidazole, pyrazole, thiazole, oxazole, isoxazole, isothiazole, triazole, tetrazole, thiadiazole, oxadiazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine, benzoxazole, isoquioline, quinolines and imidazopyrimidine - a heterocyclic group selected from tetrahydropyran, tetrahydrofuran, 1,3-dioxo-lane, 1,4-dioxane, morpholine, thiomorpholine, piperazine, piperidine, piperidi-none, tetrahydropyrimidone, pentamethylene sulfide, tetramethylene sulfide, dihydropyrane, dihydrofuran, and dihydrothiophene, - amino,-NH2, optionally substituted by one or two C1-4 alkyl groups, or - phenyl, c) phenyl optionally substituted with - halogen, or - amino,-NH2, optionally substituted by one or two C1-4 alkyl, or d) - a heteroaryl group selected from pyrrole, furan, thiophene, imidazole, pyrazole, thiazole, oxazole, isoxazole, isothiazole, triazole, tetrazole, thiadiazole, oxadiazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine, benzoxazole, isoquioline, quinoline and imidazopyrimidine;
A is an optionally substituted phenyl group of formula 1xx:
an optionally substituted pyridinyl group of formula 1x:
or an optionally substituted naphthyl moiety of formula 1y:
B is optionally substituted phenyl or naphthyl of formulas 2a and 2b:
L is a bridging group which is -S- or -O-, p is 0, 1, 2, 3, or 4, n is 0, 1, 2, 3, 4, 5 or 6, m is 0, 1, 2 or 3, each R1 is independently: halogen, C1-5 haloalkyl, NO2, C(O)NR4R5, C1-6 alkyl,C1-6 dialkylamine, C1-3 alkylamine, CN, amino, hydroxy or C1-3 alkoxy.
each R2 is independently: C1-5 alkyl, C1-5 haloalkyl, C1-3 alkoxy, N-oxo or N-hydroxy, each R3 is independently: halogen, R4, OR4, S(O)R4, C(O)R4, C(O)NR4R5, oxo, cyano or nitro (NO2) and R4 and R5 are independently hydrogen, C1-6 alkyl, or up to per-halogenated C1-6-alkyl.
wherein Q is -C(O)R x R x is hydroxy, C1-4 alkyl, C1-4 alkoxy or NR a R b, R a and R b are independently :
a) hydrogen;
b) C1-4 alkyl, optionally substituted by - hydroxy, - C1-4 alkoxy, - a heteroaryl group selected from pyrrole, furan, thiophene, imidazole, pyrazole, thiazole, oxazole, isoxazole, isothiazole, triazole, tetrazole, thiadiazole, oxadiazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine, benzoxazole, isoquioline, quinolines and imidazopyrimidine - a heterocyclic group selected from tetrahydropyran, tetrahydrofuran, 1,3-dioxo-lane, 1,4-dioxane, morpholine, thiomorpholine, piperazine, piperidine, piperidi-none, tetrahydropyrimidone, pentamethylene sulfide, tetramethylene sulfide, dihydropyrane, dihydrofuran, and dihydrothiophene, - amino,-NH2, optionally substituted by one or two C1-4 alkyl groups, or - phenyl, c) phenyl optionally substituted with - halogen, or - amino,-NH2, optionally substituted by one or two C1-4 alkyl, or d) - a heteroaryl group selected from pyrrole, furan, thiophene, imidazole, pyrazole, thiazole, oxazole, isoxazole, isothiazole, triazole, tetrazole, thiadiazole, oxadiazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine, benzoxazole, isoquioline, quinoline and imidazopyrimidine;
A is an optionally substituted phenyl group of formula 1xx:
an optionally substituted pyridinyl group of formula 1x:
or an optionally substituted naphthyl moiety of formula 1y:
B is optionally substituted phenyl or naphthyl of formulas 2a and 2b:
L is a bridging group which is -S- or -O-, p is 0, 1, 2, 3, or 4, n is 0, 1, 2, 3, 4, 5 or 6, m is 0, 1, 2 or 3, each R1 is independently: halogen, C1-5 haloalkyl, NO2, C(O)NR4R5, C1-6 alkyl,C1-6 dialkylamine, C1-3 alkylamine, CN, amino, hydroxy or C1-3 alkoxy.
each R2 is independently: C1-5 alkyl, C1-5 haloalkyl, C1-3 alkoxy, N-oxo or N-hydroxy, each R3 is independently: halogen, R4, OR4, S(O)R4, C(O)R4, C(O)NR4R5, oxo, cyano or nitro (NO2) and R4 and R5 are independently hydrogen, C1-6 alkyl, or up to per-halogenated C1-6-alkyl.
18. The method of claim 17 wherein the compound of formula I is combined with at least one therapeutic agent selected from the group consisting of anti-inflammatory and/or known drugs for the therapy of inflammatory skin, eye and/or ear diseases.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
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EP05027469 | 2005-12-15 | ||
EP05027469.5 | 2005-12-15 | ||
EP06012788.3 | 2006-06-22 | ||
EP06012788 | 2006-06-22 | ||
PCT/EP2006/011691 WO2007068381A1 (en) | 2005-12-15 | 2006-12-06 | Diaryl ureas for treating inflammatory skin, eye and/or ear diseases |
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CA2633411A1 true CA2633411A1 (en) | 2007-06-21 |
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CA002633411A Abandoned CA2633411A1 (en) | 2005-12-15 | 2006-12-06 | Diaryl ureas for treating inflammatory skin, eye and/or ear diseases |
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EP (1) | EP1962842A1 (en) |
JP (1) | JP2009519266A (en) |
CA (1) | CA2633411A1 (en) |
WO (1) | WO2007068381A1 (en) |
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EP2156834A1 (en) * | 2008-08-08 | 2010-02-24 | S.I.F.I - Società Industria Farmaceutica Italiana - S.P.A. | Ophthalmic pharmaceutical compositions comprising Sorafenib for the treatment of neoangiogenic pathologies of the eye |
JP2014527511A (en) | 2011-06-24 | 2014-10-16 | アムジエン・インコーポレーテツド | TRPM8 antagonists and their use in therapy |
WO2012177896A1 (en) | 2011-06-24 | 2012-12-27 | Amgen Inc. | Trpm8 antagonists and their use in treatments |
CA2840491A1 (en) * | 2011-06-28 | 2013-01-03 | Bayer Healthcare Llc | Topical ophthalmological pharmaceutical composition containing sorafenib |
US8952009B2 (en) | 2012-08-06 | 2015-02-10 | Amgen Inc. | Chroman derivatives as TRPM8 inhibitors |
AR092439A1 (en) * | 2012-09-06 | 2015-04-22 | Bayer Healthcare Llc | PHARMACEUTICAL COMPOSITION COVERED WITH REGORAFENIB |
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ATE556713T1 (en) * | 1999-01-13 | 2012-05-15 | Bayer Healthcare Llc | OMEGA-CARBOXYARYL SUBSTITUTED DIPHENYL UREAS AS P38 KINASE INHIBITORS |
AU2003209116A1 (en) * | 2002-02-11 | 2003-09-04 | Bayer Pharmaceuticals Corporation | Aryl ureas with angiogenesis inhibiting activity |
TW200406374A (en) * | 2002-05-29 | 2004-05-01 | Novartis Ag | Diaryl urea derivatives useful for the treatment of protein kinase dependent diseases |
JP4777887B2 (en) * | 2003-07-23 | 2011-09-21 | バイエル、ファーマシューテイカルズ、コーポレイション | Fluoro-substituted omegacarboxyaryl diphenylureas for the treatment and prevention of diseases and conditions |
DE10334663A1 (en) * | 2003-07-30 | 2005-03-10 | Merck Patent Gmbh | urea derivatives |
-
2006
- 2006-12-06 EP EP06818988A patent/EP1962842A1/en not_active Withdrawn
- 2006-12-06 CA CA002633411A patent/CA2633411A1/en not_active Abandoned
- 2006-12-06 WO PCT/EP2006/011691 patent/WO2007068381A1/en active Application Filing
- 2006-12-06 JP JP2008544820A patent/JP2009519266A/en active Pending
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JP2009519266A (en) | 2009-05-14 |
EP1962842A1 (en) | 2008-09-03 |
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