CN101932571B - 具有crth2拮抗活性的化合物 - Google Patents
具有crth2拮抗活性的化合物 Download PDFInfo
- Publication number
- CN101932571B CN101932571B CN200980103456.8A CN200980103456A CN101932571B CN 101932571 B CN101932571 B CN 101932571B CN 200980103456 A CN200980103456 A CN 200980103456A CN 101932571 B CN101932571 B CN 101932571B
- Authority
- CN
- China
- Prior art keywords
- compound
- disease
- crth2
- methyl
- medicament
- 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.)
- Expired - Fee Related
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 171
- 230000000694 effects Effects 0.000 title claims description 19
- 229940124003 CRTH2 antagonist Drugs 0.000 title claims description 13
- 239000000203 mixture Substances 0.000 claims abstract description 51
- 208000006673 asthma Diseases 0.000 claims abstract description 32
- -1 -C3-C8 cycloalkyl Chemical group 0.000 claims abstract description 26
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- 206010012438 Dermatitis atopic Diseases 0.000 claims abstract description 11
- 201000008937 atopic dermatitis Diseases 0.000 claims abstract description 11
- 208000026935 allergic disease Diseases 0.000 claims abstract description 9
- 201000010099 disease Diseases 0.000 claims description 40
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 40
- 239000003795 chemical substances by application Substances 0.000 claims description 39
- 239000000370 acceptor Substances 0.000 claims description 32
- 239000003814 drug Substances 0.000 claims description 32
- 230000001737 promoting effect Effects 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 25
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 25
- 238000002360 preparation method Methods 0.000 claims description 21
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 20
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 19
- 239000000556 agonist Substances 0.000 claims description 17
- 239000003112 inhibitor Substances 0.000 claims description 16
- 238000006243 chemical reaction Methods 0.000 claims description 14
- 206010016654 Fibrosis Diseases 0.000 claims description 13
- 230000004761 fibrosis Effects 0.000 claims description 13
- 206010061218 Inflammation Diseases 0.000 claims description 12
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 12
- 230000004054 inflammatory process Effects 0.000 claims description 12
- 239000005557 antagonist Substances 0.000 claims description 9
- 239000002585 base Substances 0.000 claims description 9
- 230000002757 inflammatory effect Effects 0.000 claims description 9
- 102000005962 receptors Human genes 0.000 claims description 9
- 108020003175 receptors Proteins 0.000 claims description 9
- 210000003491 skin Anatomy 0.000 claims description 9
- 208000011580 syndromic disease Diseases 0.000 claims description 9
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 claims description 8
- 206010020751 Hypersensitivity Diseases 0.000 claims description 7
- 230000007815 allergy Effects 0.000 claims description 7
- 208000024711 extrinsic asthma Diseases 0.000 claims description 7
- 150000002475 indoles Chemical class 0.000 claims description 7
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 claims description 7
- 102100040247 Tumor necrosis factor Human genes 0.000 claims description 6
- 208000024780 Urticaria Diseases 0.000 claims description 6
- 208000002205 allergic conjunctivitis Diseases 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 6
- 235000013305 food Nutrition 0.000 claims description 6
- 230000001225 therapeutic effect Effects 0.000 claims description 6
- 208000035285 Allergic Seasonal Rhinitis Diseases 0.000 claims description 5
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 5
- 208000011231 Crohn disease Diseases 0.000 claims description 5
- 102000004127 Cytokines Human genes 0.000 claims description 5
- 108090000695 Cytokines Proteins 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- 206010048908 Seasonal allergy Diseases 0.000 claims description 5
- 210000000621 bronchi Anatomy 0.000 claims description 5
- 208000008585 mastocytosis Diseases 0.000 claims description 5
- UFWIBTONFRDIAS-UHFFFAOYSA-N naphthalene-acid Natural products C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 5
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 claims description 4
- CNIIGCLFLJGOGP-UHFFFAOYSA-N 2-(1-naphthalenylmethyl)-4,5-dihydro-1H-imidazole Chemical compound C=1C=CC2=CC=CC=C2C=1CC1=NCCN1 CNIIGCLFLJGOGP-UHFFFAOYSA-N 0.000 claims description 4
- 206010002198 Anaphylactic reaction Diseases 0.000 claims description 4
- 102100022718 Atypical chemokine receptor 2 Human genes 0.000 claims description 4
- 102100025074 C-C chemokine receptor-like 2 Human genes 0.000 claims description 4
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 4
- 206010010744 Conjunctivitis allergic Diseases 0.000 claims description 4
- 206010012442 Dermatitis contact Diseases 0.000 claims description 4
- 206010065563 Eosinophilic bronchitis Diseases 0.000 claims description 4
- 206010014989 Epidermolysis bullosa Diseases 0.000 claims description 4
- 101000678892 Homo sapiens Atypical chemokine receptor 2 Proteins 0.000 claims description 4
- 102000014150 Interferons Human genes 0.000 claims description 4
- 108010050904 Interferons Proteins 0.000 claims description 4
- 208000009388 Job Syndrome Diseases 0.000 claims description 4
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 claims description 4
- 241000283973 Oryctolagus cuniculus Species 0.000 claims description 4
- 206010039094 Rhinitis perennial Diseases 0.000 claims description 4
- YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-UHFFFAOYSA-N 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
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 4
- NDAUXUAQIAJITI-UHFFFAOYSA-N albuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 claims description 4
- 230000036783 anaphylactic response Effects 0.000 claims description 4
- 208000003455 anaphylaxis Diseases 0.000 claims description 4
- 208000024998 atopic conjunctivitis Diseases 0.000 claims description 4
- 208000010247 contact dermatitis Diseases 0.000 claims description 4
- 229940111134 coxibs Drugs 0.000 claims description 4
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 claims description 4
- 201000001564 eosinophilic gastroenteritis Diseases 0.000 claims description 4
- 206010051040 hyper-IgE syndrome Diseases 0.000 claims description 4
- 229960000905 indomethacin Drugs 0.000 claims description 4
- 229940079322 interferon Drugs 0.000 claims description 4
- 239000003199 leukotriene receptor blocking agent Substances 0.000 claims description 4
- 229960000485 methotrexate Drugs 0.000 claims description 4
- 201000006417 multiple sclerosis Diseases 0.000 claims description 4
- BEEDODBODQVSIM-UHFFFAOYSA-N oxymetazoline hydrochloride Chemical compound Cl.CC1=CC(C(C)(C)C)=C(O)C(C)=C1CC1=NCCN1 BEEDODBODQVSIM-UHFFFAOYSA-N 0.000 claims description 4
- 208000022719 perennial allergic rhinitis Diseases 0.000 claims description 4
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 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
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical group O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 claims description 4
- 206010003645 Atopy Diseases 0.000 claims description 3
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 claims description 3
- 206010030216 Oesophagitis Diseases 0.000 claims description 3
- 230000003750 conditioning effect Effects 0.000 claims description 3
- 208000006881 esophagitis Diseases 0.000 claims description 3
- 210000003630 histaminocyte Anatomy 0.000 claims description 3
- 229960001680 ibuprofen Drugs 0.000 claims description 3
- 150000002617 leukotrienes Chemical class 0.000 claims description 3
- 208000015768 polyposis Diseases 0.000 claims description 3
- 230000002265 prevention Effects 0.000 claims description 3
- 230000004044 response Effects 0.000 claims description 3
- RDJGLLICXDHJDY-NSHDSACASA-N (2s)-2-(3-phenoxyphenyl)propanoic acid Chemical compound OC(=O)[C@@H](C)C1=CC=CC(OC=2C=CC=CC=2)=C1 RDJGLLICXDHJDY-NSHDSACASA-N 0.000 claims description 2
- QUPFKBITVLIQNA-KPKJPENVSA-N (5e)-2-sulfanylidene-5-[[5-[3-(trifluoromethyl)phenyl]furan-2-yl]methylidene]-1,3-thiazolidin-4-one Chemical compound FC(F)(F)C1=CC=CC(C=2OC(\C=C\3C(NC(=S)S/3)=O)=CC=2)=C1 QUPFKBITVLIQNA-KPKJPENVSA-N 0.000 claims description 2
- OLZHFFKRBCZHHT-SNVBAGLBSA-N 1-[(2r)-4-[5-(4-fluorophenoxy)furan-2-yl]but-3-yn-2-yl]-1-hydroxyurea Chemical compound O1C(C#C[C@@H](C)N(O)C(N)=O)=CC=C1OC1=CC=C(F)C=C1 OLZHFFKRBCZHHT-SNVBAGLBSA-N 0.000 claims description 2
- MMSNEKOTSJRTRI-LLVKDONJSA-N 1-[(2r)-4-[5-[(4-fluorophenyl)methyl]thiophen-2-yl]but-3-yn-2-yl]-1-hydroxyurea Chemical compound S1C(C#C[C@@H](C)N(O)C(N)=O)=CC=C1CC1=CC=C(F)C=C1 MMSNEKOTSJRTRI-LLVKDONJSA-N 0.000 claims description 2
- MWXPQCKCKPYBDR-UHFFFAOYSA-N 1-[4-[3-(4-fluorophenoxy)phenyl]but-3-yn-2-yl]-1-hydroxyurea Chemical compound NC(=O)N(O)C(C)C#CC1=CC=CC(OC=2C=CC(F)=CC=2)=C1 MWXPQCKCKPYBDR-UHFFFAOYSA-N 0.000 claims description 2
- SXERGJJQSKIUIC-UHFFFAOYSA-N 2-Phenoxypropionic acid Chemical compound OC(=O)C(C)OC1=CC=CC=C1 SXERGJJQSKIUIC-UHFFFAOYSA-N 0.000 claims description 2
- YGWFCQYETHJKNX-UHFFFAOYSA-N 2-[(4-tert-butyl-2,6-dimethylphenyl)methyl]-4,5-dihydro-1h-imidazol-3-ium;chloride Chemical compound [Cl-].CC1=CC(C(C)(C)C)=CC(C)=C1CC1=NCC[NH2+]1 YGWFCQYETHJKNX-UHFFFAOYSA-N 0.000 claims description 2
- ZKLPARSLTMPFCP-OAQYLSRUSA-N 2-[2-[4-[(R)-(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]ethoxy]acetic acid Chemical compound C1CN(CCOCC(=O)O)CCN1[C@@H](C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZKLPARSLTMPFCP-OAQYLSRUSA-N 0.000 claims description 2
- PFWLFWPASULGAN-UHFFFAOYSA-N 7-methylxanthine Chemical compound N1C(=O)NC(=O)C2=C1N=CN2C PFWLFWPASULGAN-UHFFFAOYSA-N 0.000 claims description 2
- MBUVEWMHONZEQD-UHFFFAOYSA-N Azeptin Chemical compound C1CN(C)CCCC1N1C(=O)C2=CC=CC=C2C(CC=2C=CC(Cl)=CC=2)=N1 MBUVEWMHONZEQD-UHFFFAOYSA-N 0.000 claims description 2
- KUVIULQEHSCUHY-XYWKZLDCSA-N Beclometasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)COC(=O)CC)(OC(=O)CC)[C@@]1(C)C[C@@H]2O KUVIULQEHSCUHY-XYWKZLDCSA-N 0.000 claims description 2
- 102100039705 Beta-2 adrenergic receptor Human genes 0.000 claims description 2
- 101710152983 Beta-2 adrenergic receptor Proteins 0.000 claims description 2
- VOVIALXJUBGFJZ-KWVAZRHASA-N Budesonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(CCC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O VOVIALXJUBGFJZ-KWVAZRHASA-N 0.000 claims description 2
- 102100031172 C-C chemokine receptor type 1 Human genes 0.000 claims description 2
- 101710149814 C-C chemokine receptor type 1 Proteins 0.000 claims description 2
- 102100031151 C-C chemokine receptor type 2 Human genes 0.000 claims description 2
- 101710149815 C-C chemokine receptor type 2 Proteins 0.000 claims description 2
- 102100024167 C-C chemokine receptor type 3 Human genes 0.000 claims description 2
- 101710149862 C-C chemokine receptor type 3 Proteins 0.000 claims description 2
- 102100037853 C-C chemokine receptor type 4 Human genes 0.000 claims description 2
- 101710149863 C-C chemokine receptor type 4 Proteins 0.000 claims description 2
- 102100035875 C-C chemokine receptor type 5 Human genes 0.000 claims description 2
- 101710149870 C-C chemokine receptor type 5 Proteins 0.000 claims description 2
- 102100036301 C-C chemokine receptor type 7 Human genes 0.000 claims description 2
- 102100036305 C-C chemokine receptor type 8 Human genes 0.000 claims description 2
- 102100036166 C-X-C chemokine receptor type 1 Human genes 0.000 claims description 2
- 102100028989 C-X-C chemokine receptor type 2 Human genes 0.000 claims description 2
- 102100028990 C-X-C chemokine receptor type 3 Human genes 0.000 claims description 2
- 102100031650 C-X-C chemokine receptor type 4 Human genes 0.000 claims description 2
- ZKLPARSLTMPFCP-UHFFFAOYSA-N Cetirizine Chemical compound C1CN(CCOCC(=O)O)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZKLPARSLTMPFCP-UHFFFAOYSA-N 0.000 claims description 2
- 102000009410 Chemokine receptor Human genes 0.000 claims description 2
- 108050000299 Chemokine receptor Proteins 0.000 claims description 2
- DBAKFASWICGISY-BTJKTKAUSA-N Chlorpheniramine maleate Chemical compound OC(=O)\C=C/C(O)=O.C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 DBAKFASWICGISY-BTJKTKAUSA-N 0.000 claims description 2
- LUKZNWIVRBCLON-GXOBDPJESA-N Ciclesonide Chemical compound C1([C@H]2O[C@@]3([C@H](O2)C[C@@H]2[C@@]3(C[C@H](O)[C@@H]3[C@@]4(C)C=CC(=O)C=C4CC[C@H]32)C)C(=O)COC(=O)C(C)C)CCCCC1 LUKZNWIVRBCLON-GXOBDPJESA-N 0.000 claims description 2
- 206010010741 Conjunctivitis Diseases 0.000 claims description 2
- 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
- IECPWNUMDGFDKC-UHFFFAOYSA-N Fusicsaeure Natural products C12C(O)CC3C(=C(CCC=C(C)C)C(O)=O)C(OC(C)=O)CC3(C)C1(C)CCC1C2(C)CCC(O)C1C IECPWNUMDGFDKC-UHFFFAOYSA-N 0.000 claims description 2
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 claims description 2
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 claims description 2
- 101000798902 Homo sapiens Atypical chemokine receptor 4 Proteins 0.000 claims description 2
- 101000777558 Homo sapiens C-C chemokine receptor type 10 Proteins 0.000 claims description 2
- 101000716068 Homo sapiens C-C chemokine receptor type 6 Proteins 0.000 claims description 2
- 101000716065 Homo sapiens C-C chemokine receptor type 7 Proteins 0.000 claims description 2
- 101000716063 Homo sapiens C-C chemokine receptor type 8 Proteins 0.000 claims description 2
- 101000716070 Homo sapiens C-C chemokine receptor type 9 Proteins 0.000 claims description 2
- 101000947174 Homo sapiens C-X-C chemokine receptor type 1 Proteins 0.000 claims description 2
- 101000916050 Homo sapiens C-X-C chemokine receptor type 3 Proteins 0.000 claims description 2
- 101000922348 Homo sapiens C-X-C chemokine receptor type 4 Proteins 0.000 claims description 2
- 108060003951 Immunoglobulin Proteins 0.000 claims description 2
- 102000003996 Interferon-beta Human genes 0.000 claims description 2
- 108090000467 Interferon-beta Proteins 0.000 claims description 2
- 108090000978 Interleukin-4 Proteins 0.000 claims description 2
- 102100039897 Interleukin-5 Human genes 0.000 claims description 2
- 108010002616 Interleukin-5 Proteins 0.000 claims description 2
- 108010018951 Interleukin-8B Receptors Proteins 0.000 claims description 2
- ZRVUJXDFFKFLMG-UHFFFAOYSA-N Meloxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=NC=C(C)S1 ZRVUJXDFFKFLMG-UHFFFAOYSA-N 0.000 claims description 2
- UCHDWCPVSPXUMX-TZIWLTJVSA-N Montelukast Chemical compound CC(C)(O)C1=CC=CC=C1CC[C@H](C=1C=C(\C=C\C=2N=C3C=C(Cl)C=CC3=CC=2)C=CC=1)SCC1(CC(O)=O)CC1 UCHDWCPVSPXUMX-TZIWLTJVSA-N 0.000 claims description 2
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 claims description 2
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 claims description 2
- JAUOIFJMECXRGI-UHFFFAOYSA-N Neoclaritin Chemical compound C=1C(Cl)=CC=C2C=1CCC1=CC=CN=C1C2=C1CCNCC1 JAUOIFJMECXRGI-UHFFFAOYSA-N 0.000 claims description 2
- WZYRHMVOCDVECK-UHFFFAOYSA-N O1C(=CC=C1)C(=O)O.C(CC)(=O)O Chemical compound O1C(=CC=C1)C(=O)O.C(CC)(=O)O WZYRHMVOCDVECK-UHFFFAOYSA-N 0.000 claims description 2
- VQDBNKDJNJQRDG-UHFFFAOYSA-N Pirbuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=N1 VQDBNKDJNJQRDG-UHFFFAOYSA-N 0.000 claims description 2
- 102100038277 Prostaglandin G/H synthase 1 Human genes 0.000 claims description 2
- 108050003243 Prostaglandin G/H synthase 1 Proteins 0.000 claims description 2
- 206010061494 Rhinovirus infection Diseases 0.000 claims description 2
- GIIZNNXWQWCKIB-UHFFFAOYSA-N Serevent Chemical compound C1=C(O)C(CO)=CC(C(O)CNCCCCCCOCCCCC=2C=CC=CC=2)=C1 GIIZNNXWQWCKIB-UHFFFAOYSA-N 0.000 claims description 2
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 claims description 2
- 108060008683 Tumor Necrosis Factor Receptor Proteins 0.000 claims description 2
- YEEZWCHGZNKEEK-UHFFFAOYSA-N Zafirlukast Chemical compound COC1=CC(C(=O)NS(=O)(=O)C=2C(=CC=CC=2)C)=CC=C1CC(C1=C2)=CN(C)C1=CC=C2NC(=O)OC1CCCC1 YEEZWCHGZNKEEK-UHFFFAOYSA-N 0.000 claims description 2
- MKFFGUZYVNDHIH-UHFFFAOYSA-N [2-(3,5-dihydroxyphenyl)-2-hydroxyethyl]-propan-2-ylazanium;sulfate Chemical group OS(O)(=O)=O.CC(C)NCC(O)C1=CC(O)=CC(O)=C1.CC(C)NCC(O)C1=CC(O)=CC(O)=C1 MKFFGUZYVNDHIH-UHFFFAOYSA-N 0.000 claims description 2
- RYVJQEZJUFRANT-UHFFFAOYSA-N [3-[4-(3-ethoxy-2-hydroxypropoxy)anilino]-3-oxopropyl]-dimethylsulfanium;4-methylbenzenesulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1.CCOCC(O)COC1=CC=C(NC(=O)CC[S+](C)C)C=C1 RYVJQEZJUFRANT-UHFFFAOYSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 229960003556 aminophylline Drugs 0.000 claims description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 2
- 230000001387 anti-histamine Effects 0.000 claims description 2
- 230000002924 anti-infective effect Effects 0.000 claims description 2
- 239000003429 antifungal agent Substances 0.000 claims description 2
- 239000000739 antihistaminic agent Substances 0.000 claims description 2
- GXDALQBWZGODGZ-UHFFFAOYSA-N astemizole Chemical compound C1=CC(OC)=CC=C1CCN1CCC(NC=2N(C3=CC=CC=C3N=2)CC=2C=CC(F)=CC=2)CC1 GXDALQBWZGODGZ-UHFFFAOYSA-N 0.000 claims description 2
- AUJRCFUBUPVWSZ-XTZHGVARSA-M auranofin Chemical compound CCP(CC)(CC)=[Au]S[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O AUJRCFUBUPVWSZ-XTZHGVARSA-M 0.000 claims description 2
- 229960005207 auranofin Drugs 0.000 claims description 2
- WOIIIUDZSOLAIW-NSHDSACASA-N azapropazone Chemical compound C1=C(C)C=C2N3C(=O)[C@H](CC=C)C(=O)N3C(N(C)C)=NC2=C1 WOIIIUDZSOLAIW-NSHDSACASA-N 0.000 claims description 2
- 229960001671 azapropazone Drugs 0.000 claims description 2
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 claims description 2
- 229960002170 azathioprine Drugs 0.000 claims description 2
- 229960004574 azelastine Drugs 0.000 claims description 2
- 108010051210 beta-Fructofuranosidase Proteins 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- HODFCFXCOMKRCG-UHFFFAOYSA-N bitolterol mesylate Chemical compound CS([O-])(=O)=O.C1=CC(C)=CC=C1C(=O)OC1=CC=C(C(O)C[NH2+]C(C)(C)C)C=C1OC(=O)C1=CC=C(C)C=C1 HODFCFXCOMKRCG-UHFFFAOYSA-N 0.000 claims description 2
- 229960000585 bitolterol mesylate Drugs 0.000 claims description 2
- 229960004436 budesonide Drugs 0.000 claims description 2
- 229960000590 celecoxib Drugs 0.000 claims description 2
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 claims description 2
- 229960001803 cetirizine Drugs 0.000 claims description 2
- HRYZWHHZPQKTII-UHFFFAOYSA-N chloroethane Chemical compound CCCl HRYZWHHZPQKTII-UHFFFAOYSA-N 0.000 claims description 2
- 229960003291 chlorphenamine Drugs 0.000 claims description 2
- 229960003728 ciclesonide Drugs 0.000 claims description 2
- VNFPBHJOKIVQEB-UHFFFAOYSA-N clotrimazole Chemical compound ClC1=CC=CC=C1C(N1C=NC=C1)(C=1C=CC=CC=1)C1=CC=CC=C1 VNFPBHJOKIVQEB-UHFFFAOYSA-N 0.000 claims description 2
- 229960004022 clotrimazole Drugs 0.000 claims description 2
- 229960000265 cromoglicic acid Drugs 0.000 claims description 2
- 239000003260 cyclooxygenase 1 inhibitor Substances 0.000 claims description 2
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 claims description 2
- 229960001271 desloratadine Drugs 0.000 claims description 2
- 229960001259 diclofenac Drugs 0.000 claims description 2
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 claims description 2
- VLARUOGDXDTHEH-UHFFFAOYSA-L disodium cromoglycate Chemical compound [Na+].[Na+].O1C(C([O-])=O)=CC(=O)C2=C1C=CC=C2OCC(O)COC1=CC=CC2=C1C(=O)C=C(C([O-])=O)O2 VLARUOGDXDTHEH-UHFFFAOYSA-L 0.000 claims description 2
- DLNKOYKMWOXYQA-UHFFFAOYSA-N dl-pseudophenylpropanolamine Natural products CC(N)C(O)C1=CC=CC=C1 DLNKOYKMWOXYQA-UHFFFAOYSA-N 0.000 claims description 2
- 239000003889 eye drop Substances 0.000 claims description 2
- 229940012356 eye drops Drugs 0.000 claims description 2
- 229950002170 fenleuton Drugs 0.000 claims description 2
- 229960001419 fenoprofen Drugs 0.000 claims description 2
- 229960003592 fexofenadine Drugs 0.000 claims description 2
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 claims description 2
- 229960000676 flunisolide Drugs 0.000 claims description 2
- 229960002390 flurbiprofen Drugs 0.000 claims description 2
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 claims description 2
- 229960002714 fluticasone Drugs 0.000 claims description 2
- MGNNYOODZCAHBA-GQKYHHCASA-N fluticasone Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)SCF)(O)[C@@]2(C)C[C@@H]1O MGNNYOODZCAHBA-GQKYHHCASA-N 0.000 claims description 2
- XTULMSXFIHGYFS-VLSRWLAYSA-N fluticasone furoate Chemical compound O([C@]1([C@@]2(C)C[C@H](O)[C@]3(F)[C@@]4(C)C=CC(=O)C=C4[C@@H](F)C[C@H]3[C@@H]2C[C@H]1C)C(=O)SCF)C(=O)C1=CC=CO1 XTULMSXFIHGYFS-VLSRWLAYSA-N 0.000 claims description 2
- 229960001469 fluticasone furoate Drugs 0.000 claims description 2
- 229960002848 formoterol Drugs 0.000 claims description 2
- BPZSYCZIITTYBL-UHFFFAOYSA-N formoterol Chemical compound C1=CC(OC)=CC=C1CC(C)NCC(O)C1=CC=C(O)C(NC=O)=C1 BPZSYCZIITTYBL-UHFFFAOYSA-N 0.000 claims description 2
- 229960004675 fusidic acid Drugs 0.000 claims description 2
- IECPWNUMDGFDKC-MZJAQBGESA-N fusidic acid Chemical compound O[C@@H]([C@@H]12)C[C@H]3\C(=C(/CCC=C(C)C)C(O)=O)[C@@H](OC(C)=O)C[C@]3(C)[C@@]2(C)CC[C@@H]2[C@]1(C)CC[C@@H](O)[C@H]2C IECPWNUMDGFDKC-MZJAQBGESA-N 0.000 claims description 2
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 claims description 2
- 239000010931 gold Substances 0.000 claims description 2
- 229910052737 gold Inorganic materials 0.000 claims description 2
- 239000000938 histamine H1 antagonist Substances 0.000 claims description 2
- 239000003396 histamine H4 receptor antagonist Substances 0.000 claims description 2
- 229960004171 hydroxychloroquine Drugs 0.000 claims description 2
- XXSMGPRMXLTPCZ-UHFFFAOYSA-N hydroxychloroquine Chemical compound ClC1=CC=C2C(NC(C)CCCN(CCO)CC)=CC=NC2=C1 XXSMGPRMXLTPCZ-UHFFFAOYSA-N 0.000 claims description 2
- 102000018358 immunoglobulin Human genes 0.000 claims description 2
- 239000002955 immunomodulating agent Substances 0.000 claims description 2
- 239000003018 immunosuppressive agent Substances 0.000 claims description 2
- 229960004078 indacaterol Drugs 0.000 claims description 2
- QZZUEBNBZAPZLX-QFIPXVFZSA-N indacaterol Chemical compound N1C(=O)C=CC2=C1C(O)=CC=C2[C@@H](O)CNC1CC(C=C(C(=C2)CC)CC)=C2C1 QZZUEBNBZAPZLX-QFIPXVFZSA-N 0.000 claims description 2
- 108091006086 inhibitor proteins Proteins 0.000 claims description 2
- 229960001388 interferon-beta Drugs 0.000 claims description 2
- 238000007918 intramuscular administration Methods 0.000 claims description 2
- 235000011073 invertase Nutrition 0.000 claims description 2
- 206010023332 keratitis Diseases 0.000 claims description 2
- 201000010666 keratoconjunctivitis Diseases 0.000 claims description 2
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 claims description 2
- 229960000991 ketoprofen Drugs 0.000 claims description 2
- 229960000681 leflunomide Drugs 0.000 claims description 2
- VHOGYURTWQBHIL-UHFFFAOYSA-N leflunomide Chemical compound O1N=CC(C(=O)NC=2C=CC(=CC=2)C(F)(F)F)=C1C VHOGYURTWQBHIL-UHFFFAOYSA-N 0.000 claims description 2
- 229960001508 levocetirizine Drugs 0.000 claims description 2
- 229960003088 loratadine Drugs 0.000 claims description 2
- JCCNYMKQOSZNPW-UHFFFAOYSA-N loratadine Chemical compound C1CN(C(=O)OCC)CCC1=C1C2=NC=CC=C2CCC2=CC(Cl)=CC=C21 JCCNYMKQOSZNPW-UHFFFAOYSA-N 0.000 claims description 2
- 229960003464 mefenamic acid Drugs 0.000 claims description 2
- HYYBABOKPJLUIN-UHFFFAOYSA-N mefenamic acid Chemical compound CC1=CC=CC(NC=2C(=CC=CC=2)C(O)=O)=C1C HYYBABOKPJLUIN-UHFFFAOYSA-N 0.000 claims description 2
- 229960001929 meloxicam Drugs 0.000 claims description 2
- LMOINURANNBYCM-UHFFFAOYSA-N metaproterenol Chemical compound CC(C)NCC(O)C1=CC(O)=CC(O)=C1 LMOINURANNBYCM-UHFFFAOYSA-N 0.000 claims description 2
- 229960005127 montelukast Drugs 0.000 claims description 2
- 239000003149 muscarinic antagonist Substances 0.000 claims description 2
- 229960005016 naphazoline Drugs 0.000 claims description 2
- 229960002009 naproxen Drugs 0.000 claims description 2
- 229960002657 orciprenaline Drugs 0.000 claims description 2
- 229960005162 oxymetazoline hydrochloride Drugs 0.000 claims description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims description 2
- DLNKOYKMWOXYQA-APPZFPTMSA-N phenylpropanolamine Chemical compound C[C@@H](N)[C@H](O)C1=CC=CC=C1 DLNKOYKMWOXYQA-APPZFPTMSA-N 0.000 claims description 2
- 229960000395 phenylpropanolamine Drugs 0.000 claims description 2
- 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 2
- 229960005330 pimecrolimus Drugs 0.000 claims description 2
- GLBJJMFZWDBELO-UHFFFAOYSA-N pimobendane Chemical compound C1=CC(OC)=CC=C1C1=NC2=CC=C(C=3C(CC(=O)NN=3)C)C=C2N1 GLBJJMFZWDBELO-UHFFFAOYSA-N 0.000 claims description 2
- 229960005414 pirbuterol Drugs 0.000 claims description 2
- 229960002702 piroxicam Drugs 0.000 claims description 2
- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical group OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 claims description 2
- 229960005205 prednisolone Drugs 0.000 claims description 2
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[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 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 claims description 2
- 229960004618 prednisone Drugs 0.000 claims description 2
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 claims description 2
- 229960000786 propylhexedrine Drugs 0.000 claims description 2
- JCRIVQIOJSSCQD-UHFFFAOYSA-N propylhexedrine Chemical compound CNC(C)CC1CCCCC1 JCRIVQIOJSSCQD-UHFFFAOYSA-N 0.000 claims description 2
- KWGRBVOPPLSCSI-WCBMZHEXSA-N pseudoephedrine Chemical compound CN[C@@H](C)[C@@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WCBMZHEXSA-N 0.000 claims description 2
- 229960003908 pseudoephedrine Drugs 0.000 claims description 2
- MIXMJCQRHVAJIO-TZHJZOAOSA-N qk4dys664x Chemical compound O.C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O.C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O MIXMJCQRHVAJIO-TZHJZOAOSA-N 0.000 claims description 2
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 claims description 2
- 210000000664 rectum Anatomy 0.000 claims description 2
- 229960000371 rofecoxib Drugs 0.000 claims description 2
- RZJQGNCSTQAWON-UHFFFAOYSA-N rofecoxib Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=C(C=2C=CC=CC=2)C(=O)OC1 RZJQGNCSTQAWON-UHFFFAOYSA-N 0.000 claims description 2
- MNDBXUUTURYVHR-UHFFFAOYSA-N roflumilast Chemical compound FC(F)OC1=CC=C(C(=O)NC=2C(=CN=CC=2Cl)Cl)C=C1OCC1CC1 MNDBXUUTURYVHR-UHFFFAOYSA-N 0.000 claims description 2
- 229960002586 roflumilast Drugs 0.000 claims description 2
- 229960004586 rosiglitazone Drugs 0.000 claims description 2
- 229960002052 salbutamol Drugs 0.000 claims description 2
- 229960004889 salicylic acid Drugs 0.000 claims description 2
- 229960004017 salmeterol Drugs 0.000 claims description 2
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 claims description 2
- 229960002930 sirolimus Drugs 0.000 claims description 2
- 239000003381 stabilizer Substances 0.000 claims description 2
- 238000007920 subcutaneous administration Methods 0.000 claims description 2
- 229960000894 sulindac Drugs 0.000 claims description 2
- MLKXDPUZXIRXEP-MFOYZWKCSA-N sulindac Chemical compound CC1=C(CC(O)=O)C2=CC(F)=CC=C2\C1=C/C1=CC=C(S(C)=O)C=C1 MLKXDPUZXIRXEP-MFOYZWKCSA-N 0.000 claims description 2
- 229940036185 synagis Drugs 0.000 claims description 2
- XYKWNRUXCOIMFZ-UHFFFAOYSA-N tepoxalin Chemical compound C1=CC(OC)=CC=C1N1C(C=2C=CC(Cl)=CC=2)=CC(CCC(=O)N(C)O)=N1 XYKWNRUXCOIMFZ-UHFFFAOYSA-N 0.000 claims description 2
- 229950009638 tepoxalin Drugs 0.000 claims description 2
- 229960000278 theophylline Drugs 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims description 2
- 229960002117 triamcinolone acetonide Drugs 0.000 claims description 2
- YNDXUCZADRHECN-JNQJZLCISA-N triamcinolone acetonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O YNDXUCZADRHECN-JNQJZLCISA-N 0.000 claims description 2
- 102000003298 tumor necrosis factor receptor Human genes 0.000 claims description 2
- 210000001215 vagina Anatomy 0.000 claims description 2
- 229960002004 valdecoxib Drugs 0.000 claims description 2
- LNPDTQAFDNKSHK-UHFFFAOYSA-N valdecoxib Chemical compound CC=1ON=C(C=2C=CC=CC=2)C=1C1=CC=C(S(N)(=O)=O)C=C1 LNPDTQAFDNKSHK-UHFFFAOYSA-N 0.000 claims description 2
- 208000018464 vernal keratoconjunctivitis Diseases 0.000 claims description 2
- 229940028445 visine Drugs 0.000 claims description 2
- 229960001095 xylometazoline hydrochloride Drugs 0.000 claims description 2
- 229960004764 zafirlukast Drugs 0.000 claims description 2
- MWLSOWXNZPKENC-SSDOTTSWSA-N zileuton Chemical compound C1=CC=C2SC([C@H](N(O)C(N)=O)C)=CC2=C1 MWLSOWXNZPKENC-SSDOTTSWSA-N 0.000 claims description 2
- 229960005332 zileuton Drugs 0.000 claims description 2
- 108050000258 Prostaglandin D receptors Proteins 0.000 claims 6
- 102100024218 Prostaglandin D2 receptor 2 Human genes 0.000 claims 6
- 239000003406 5-lipoxygenase-activating protein inhibitor Substances 0.000 claims 1
- BSYNRYMUTXBXSQ-FOQJRBATSA-N 59096-14-9 Chemical compound CC(=O)OC1=CC=CC=C1[14C](O)=O BSYNRYMUTXBXSQ-FOQJRBATSA-N 0.000 claims 1
- 102100031658 C-X-C chemokine receptor type 5 Human genes 0.000 claims 1
- 101000922405 Homo sapiens C-X-C chemokine receptor type 5 Proteins 0.000 claims 1
- 229940080774 Peroxisome proliferator-activated receptor gamma agonist Drugs 0.000 claims 1
- FQPFAHBPWDRTLU-UHFFFAOYSA-N aminophylline Chemical compound NCCN.O=C1N(C)C(=O)N(C)C2=C1NC=N2.O=C1N(C)C(=O)N(C)C2=C1NC=N2 FQPFAHBPWDRTLU-UHFFFAOYSA-N 0.000 claims 1
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 claims 1
- 238000007911 parenteral administration Methods 0.000 claims 1
- 125000003118 aryl group Chemical group 0.000 abstract description 12
- 229940002612 prodrug Drugs 0.000 abstract description 10
- 239000000651 prodrug Substances 0.000 abstract description 10
- 125000001072 heteroaryl group Chemical group 0.000 abstract description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 8
- 125000001424 substituent group Chemical group 0.000 abstract description 6
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 5
- 239000001257 hydrogen Substances 0.000 abstract description 5
- 239000012453 solvate Substances 0.000 abstract description 3
- 125000001309 chloro group Chemical group Cl* 0.000 abstract description 2
- 125000004093 cyano group Chemical group *C#N 0.000 abstract description 2
- 125000001153 fluoro group Chemical group F* 0.000 abstract description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 3
- 206010039085 Rhinitis allergic Diseases 0.000 abstract 1
- 101100372601 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) POR2 gene Proteins 0.000 abstract 1
- 101100099673 Zea mays TIP2-3 gene Proteins 0.000 abstract 1
- 201000010105 allergic rhinitis Diseases 0.000 abstract 1
- 125000005843 halogen group Chemical group 0.000 abstract 1
- 150000004677 hydrates Chemical class 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 35
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 21
- 239000000243 solution Substances 0.000 description 20
- 210000000222 eosinocyte Anatomy 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- 238000012360 testing method Methods 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 11
- 239000007788 liquid Substances 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- 230000001154 acute effect Effects 0.000 description 10
- 235000019439 ethyl acetate Nutrition 0.000 description 10
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- 229940125904 compound 1 Drugs 0.000 description 9
- 238000009472 formulation Methods 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 8
- 206010047115 Vasculitis Diseases 0.000 description 8
- 238000004458 analytical method Methods 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 8
- OMFXVFTZEKFJBZ-HJTSIMOOSA-N corticosterone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@H](CC4)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OMFXVFTZEKFJBZ-HJTSIMOOSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 7
- 208000002193 Pain Diseases 0.000 description 7
- 238000000338 in vitro Methods 0.000 description 7
- 238000001727 in vivo Methods 0.000 description 7
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 206010011224 Cough Diseases 0.000 description 6
- 206010063837 Reperfusion injury Diseases 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 206010012601 diabetes mellitus Diseases 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 206010039083 rhinitis Diseases 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 201000004624 Dermatitis Diseases 0.000 description 5
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 201000009594 Systemic Scleroderma Diseases 0.000 description 5
- 206010042953 Systemic sclerosis Diseases 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 238000013016 damping Methods 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 239000012530 fluid Substances 0.000 description 5
- 229910052731 fluorine Chemical group 0.000 description 5
- 239000011737 fluorine Chemical group 0.000 description 5
- 208000036971 interstitial lung disease 2 Diseases 0.000 description 5
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 5
- 210000004698 lymphocyte Anatomy 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 231100000241 scar Toxicity 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 201000004595 synovitis Diseases 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- 208000030507 AIDS Diseases 0.000 description 4
- 208000023275 Autoimmune disease Diseases 0.000 description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 4
- 208000002691 Choroiditis Diseases 0.000 description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 4
- 208000007465 Giant cell arteritis Diseases 0.000 description 4
- 206010019668 Hepatic fibrosis Diseases 0.000 description 4
- 208000003971 Posterior uveitis Diseases 0.000 description 4
- 206010037549 Purpura Diseases 0.000 description 4
- 241001672981 Purpura Species 0.000 description 4
- 241000725643 Respiratory syncytial virus Species 0.000 description 4
- 206010039710 Scleroderma Diseases 0.000 description 4
- 208000006011 Stroke Diseases 0.000 description 4
- 208000007536 Thrombosis Diseases 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 150000001299 aldehydes Chemical class 0.000 description 4
- CKMXBZGNNVIXHC-UHFFFAOYSA-L ammonium magnesium phosphate hexahydrate Chemical compound [NH4+].O.O.O.O.O.O.[Mg+2].[O-]P([O-])([O-])=O CKMXBZGNNVIXHC-UHFFFAOYSA-L 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 239000011575 calcium Substances 0.000 description 4
- 229910052791 calcium Inorganic materials 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 230000001684 chronic effect Effects 0.000 description 4
- 229940125782 compound 2 Drugs 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- 208000015181 infectious disease Diseases 0.000 description 4
- 210000004072 lung Anatomy 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 201000009240 nasopharyngitis Diseases 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 230000003389 potentiating effect Effects 0.000 description 4
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 4
- 201000000306 sarcoidosis Diseases 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 229910052567 struvite Inorganic materials 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- 206010043207 temporal arteritis Diseases 0.000 description 4
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 4
- 244000215068 Acacia senegal Species 0.000 description 3
- 208000002874 Acne Vulgaris Diseases 0.000 description 3
- 206010000748 Acute febrile neutrophilic dermatosis Diseases 0.000 description 3
- 208000032671 Allergic granulomatous angiitis Diseases 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- 208000006344 Churg-Strauss Syndrome Diseases 0.000 description 3
- 208000018428 Eosinophilic granulomatosis with polyangiitis Diseases 0.000 description 3
- 229920000084 Gum arabic Polymers 0.000 description 3
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 3
- 208000036824 Psoriatic arthropathy Diseases 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 3
- 208000021386 Sjogren Syndrome Diseases 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- 208000010265 Sweet syndrome Diseases 0.000 description 3
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 3
- 208000035222 X-linked skeletal dysplasia-intellectual disability syndrome Diseases 0.000 description 3
- 235000010489 acacia gum Nutrition 0.000 description 3
- 239000000205 acacia gum Substances 0.000 description 3
- 206010000496 acne Diseases 0.000 description 3
- 230000002052 anaphylactic effect Effects 0.000 description 3
- 230000003042 antagnostic effect Effects 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- 230000027455 binding Effects 0.000 description 3
- 206010006451 bronchitis Diseases 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 3
- 229940126214 compound 3 Drugs 0.000 description 3
- 238000010230 functional analysis Methods 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- 125000001041 indolyl group Chemical group 0.000 description 3
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 3
- 206010025135 lupus erythematosus Diseases 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 201000008482 osteoarthritis Diseases 0.000 description 3
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 230000001185 psoriatic effect Effects 0.000 description 3
- 125000004076 pyridyl group Chemical group 0.000 description 3
- 239000002287 radioligand Substances 0.000 description 3
- 229940044551 receptor antagonist Drugs 0.000 description 3
- 239000002464 receptor antagonist Substances 0.000 description 3
- 210000002345 respiratory system Anatomy 0.000 description 3
- 206010039073 rheumatoid arthritis Diseases 0.000 description 3
- 239000012266 salt solution Substances 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 208000025869 skeletal dysplasia-intellectual disability syndrome Diseases 0.000 description 3
- 230000000638 stimulation Effects 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 230000009885 systemic effect Effects 0.000 description 3
- 230000002792 vascular Effects 0.000 description 3
- 230000009385 viral infection Effects 0.000 description 3
- 238000010792 warming Methods 0.000 description 3
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 2
- URLVCROWVOSNPT-XOTOMLERSA-N (2s)-4-[(13r)-13-hydroxy-13-[(2r,5r)-5-[(2r,5r)-5-[(1r)-1-hydroxyundecyl]oxolan-2-yl]oxolan-2-yl]tridecyl]-2-methyl-2h-furan-5-one Chemical compound O1[C@@H]([C@H](O)CCCCCCCCCC)CC[C@@H]1[C@@H]1O[C@@H]([C@H](O)CCCCCCCCCCCCC=2C(O[C@@H](C)C=2)=O)CC1 URLVCROWVOSNPT-XOTOMLERSA-N 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- KHPAGGHFIDLUMB-UHFFFAOYSA-N 2-chloropyridine-3-carbaldehyde Chemical compound ClC1=NC=CC=C1C=O KHPAGGHFIDLUMB-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- 208000026872 Addison Disease Diseases 0.000 description 2
- 229940118148 Aldose reductase inhibitor Drugs 0.000 description 2
- 201000004384 Alopecia Diseases 0.000 description 2
- 208000035939 Alveolitis allergic Diseases 0.000 description 2
- 208000028185 Angioedema Diseases 0.000 description 2
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 2
- 208000003343 Antiphospholipid Syndrome Diseases 0.000 description 2
- 206010002921 Aortitis Diseases 0.000 description 2
- 206010053555 Arthritis bacterial Diseases 0.000 description 2
- 206010003267 Arthritis reactive Diseases 0.000 description 2
- 201000002909 Aspergillosis Diseases 0.000 description 2
- 208000036641 Aspergillus infections Diseases 0.000 description 2
- 201000001320 Atherosclerosis Diseases 0.000 description 2
- 208000023328 Basedow disease Diseases 0.000 description 2
- 208000009137 Behcet syndrome Diseases 0.000 description 2
- 208000020084 Bone disease Diseases 0.000 description 2
- 229940124638 COX inhibitor Drugs 0.000 description 2
- 206010007882 Cellulitis Diseases 0.000 description 2
- 206010065559 Cerebral arteriosclerosis Diseases 0.000 description 2
- 206010008190 Cerebrovascular accident Diseases 0.000 description 2
- 208000000094 Chronic Pain Diseases 0.000 description 2
- 208000015943 Coeliac disease Diseases 0.000 description 2
- 229940126657 Compound 17 Drugs 0.000 description 2
- 241000711573 Coronaviridae Species 0.000 description 2
- 201000003883 Cystic fibrosis Diseases 0.000 description 2
- 206010012289 Dementia Diseases 0.000 description 2
- 206010012468 Dermatitis herpetiformis Diseases 0.000 description 2
- 208000006926 Discoid Lupus Erythematosus Diseases 0.000 description 2
- 206010058314 Dysplasia Diseases 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 206010014561 Emphysema Diseases 0.000 description 2
- 206010015150 Erythema Diseases 0.000 description 2
- 206010015218 Erythema multiforme Diseases 0.000 description 2
- 206010016207 Familial Mediterranean fever Diseases 0.000 description 2
- 208000027445 Farmer Lung Diseases 0.000 description 2
- 206010016228 Fasciitis Diseases 0.000 description 2
- 241000233866 Fungi Species 0.000 description 2
- 208000005232 Glossitis Diseases 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 201000005569 Gout Diseases 0.000 description 2
- 208000015023 Graves' disease Diseases 0.000 description 2
- 239000007995 HEPES buffer Substances 0.000 description 2
- 208000030836 Hashimoto thyroiditis Diseases 0.000 description 2
- 102100029100 Hematopoietic prostaglandin D synthase Human genes 0.000 description 2
- 101000988802 Homo sapiens Hematopoietic prostaglandin D synthase Proteins 0.000 description 2
- 206010048643 Hypereosinophilic syndrome Diseases 0.000 description 2
- 201000003838 Idiopathic interstitial pneumonia Diseases 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- 208000004575 Infectious Arthritis Diseases 0.000 description 2
- 206010061217 Infestation Diseases 0.000 description 2
- 206010022941 Iridocyclitis Diseases 0.000 description 2
- 208000003456 Juvenile Arthritis Diseases 0.000 description 2
- 206010059176 Juvenile idiopathic arthritis Diseases 0.000 description 2
- 208000002260 Keloid Diseases 0.000 description 2
- 206010023330 Keloid scar Diseases 0.000 description 2
- 206010024229 Leprosy Diseases 0.000 description 2
- 208000007820 Lichen Sclerosus et Atrophicus Diseases 0.000 description 2
- 206010024434 Lichen sclerosus Diseases 0.000 description 2
- 208000032298 Lymphoma cutis Diseases 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- 208000003250 Mixed connective tissue disease Diseases 0.000 description 2
- 206010028594 Myocardial fibrosis Diseases 0.000 description 2
- 208000009525 Myocarditis Diseases 0.000 description 2
- 201000002481 Myositis Diseases 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 206010065673 Nephritic syndrome Diseases 0.000 description 2
- 208000012902 Nervous system disease Diseases 0.000 description 2
- 206010033645 Pancreatitis Diseases 0.000 description 2
- 206010034277 Pemphigoid Diseases 0.000 description 2
- 241000721454 Pemphigus Species 0.000 description 2
- 208000004362 Penile Induration Diseases 0.000 description 2
- 208000037581 Persistent Infection Diseases 0.000 description 2
- 208000020758 Peyronie disease Diseases 0.000 description 2
- 208000007048 Polymyalgia Rheumatica Diseases 0.000 description 2
- 206010036774 Proctitis Diseases 0.000 description 2
- 208000007893 Salpingitis Diseases 0.000 description 2
- 206010039793 Seborrhoeic dermatitis Diseases 0.000 description 2
- 208000009359 Sezary Syndrome Diseases 0.000 description 2
- 208000021388 Sezary disease Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 206010041303 Solar dermatitis Diseases 0.000 description 2
- 208000006045 Spondylarthropathies Diseases 0.000 description 2
- 108010069102 Thromboxane-A synthase Proteins 0.000 description 2
- 208000031737 Tissue Adhesions Diseases 0.000 description 2
- 241000169121 Toxicum Species 0.000 description 2
- 229920001615 Tragacanth Polymers 0.000 description 2
- 208000025865 Ulcer Diseases 0.000 description 2
- 208000025851 Undifferentiated connective tissue disease Diseases 0.000 description 2
- 208000017379 Undifferentiated connective tissue syndrome Diseases 0.000 description 2
- 206010046798 Uterine leiomyoma Diseases 0.000 description 2
- 208000036142 Viral infection Diseases 0.000 description 2
- QUHYUSAHBDACNG-UHFFFAOYSA-N acerogenin 3 Natural products C1=CC(O)=CC=C1CCCCC(=O)CCC1=CC=C(O)C=C1 QUHYUSAHBDACNG-UHFFFAOYSA-N 0.000 description 2
- BKSFTNBSMIREGF-UHFFFAOYSA-N acetic acid;3-methyl-1h-indole Chemical compound CC(O)=O.C1=CC=C2C(C)=CNC2=C1 BKSFTNBSMIREGF-UHFFFAOYSA-N 0.000 description 2
- 208000005298 acute pain Diseases 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 230000032683 aging Effects 0.000 description 2
- 239000003288 aldose reductase inhibitor Substances 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 208000004631 alopecia areata Diseases 0.000 description 2
- 201000004612 anterior uveitis Diseases 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 230000001754 anti-pyretic effect Effects 0.000 description 2
- 239000000427 antigen Substances 0.000 description 2
- 102000036639 antigens Human genes 0.000 description 2
- 108091007433 antigens Proteins 0.000 description 2
- 229940054051 antipsychotic indole derivative Drugs 0.000 description 2
- 206010003230 arteritis Diseases 0.000 description 2
- 239000000305 astragalus gummifer gum Substances 0.000 description 2
- 201000004984 autoimmune cardiomyopathy Diseases 0.000 description 2
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 210000001772 blood platelet Anatomy 0.000 description 2
- 210000000481 breast Anatomy 0.000 description 2
- 201000009267 bronchiectasis Diseases 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 description 2
- 206010007604 cardiac sarcoidosis Diseases 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 201000002676 cerebral atherosclerosis Diseases 0.000 description 2
- 230000002490 cerebral effect Effects 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 2
- 201000001352 cholecystitis Diseases 0.000 description 2
- 208000002849 chondrocalcinosis Diseases 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 208000013116 chronic cough Diseases 0.000 description 2
- 208000025302 chronic primary adrenal insufficiency Diseases 0.000 description 2
- 201000009151 chronic rhinitis Diseases 0.000 description 2
- 235000019504 cigarettes Nutrition 0.000 description 2
- 208000019425 cirrhosis of liver Diseases 0.000 description 2
- 210000000795 conjunctiva Anatomy 0.000 description 2
- 208000004921 cutaneous lupus erythematosus Diseases 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 230000003412 degenerative effect Effects 0.000 description 2
- 201000001981 dermatomyositis Diseases 0.000 description 2
- URLVCROWVOSNPT-QTTMQESMSA-N desacetyluvaricin Natural products O=C1C(CCCCCCCCCCCC[C@@H](O)[C@H]2O[C@@H]([C@@H]3O[C@@H]([C@@H](O)CCCCCCCCCC)CC3)CC2)=C[C@H](C)O1 URLVCROWVOSNPT-QTTMQESMSA-N 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000000428 dust Substances 0.000 description 2
- 230000004064 dysfunction Effects 0.000 description 2
- 150000002066 eicosanoids Chemical class 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 206010014665 endocarditis Diseases 0.000 description 2
- 206010014801 endophthalmitis Diseases 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 201000010063 epididymitis Diseases 0.000 description 2
- 231100000321 erythema Toxicity 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 201000001155 extrinsic allergic alveolitis Diseases 0.000 description 2
- 208000022195 farmer lung disease Diseases 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 208000007565 gingivitis Diseases 0.000 description 2
- 230000035876 healing Effects 0.000 description 2
- 208000006454 hepatitis Diseases 0.000 description 2
- 231100000283 hepatitis Toxicity 0.000 description 2
- 208000002672 hepatitis B Diseases 0.000 description 2
- 150000002430 hydrocarbons Chemical group 0.000 description 2
- 208000022098 hypersensitivity pneumonitis Diseases 0.000 description 2
- 230000000642 iatrogenic effect Effects 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- PQNFLJBBNBOBRQ-UHFFFAOYSA-N indane Chemical compound C1=CC=C2CCCC2=C1 PQNFLJBBNBOBRQ-UHFFFAOYSA-N 0.000 description 2
- 230000004968 inflammatory condition Effects 0.000 description 2
- 206010022000 influenza Diseases 0.000 description 2
- 201000005851 intracranial arteriosclerosis Diseases 0.000 description 2
- 201000010659 intrinsic asthma Diseases 0.000 description 2
- 210000001117 keloid Anatomy 0.000 description 2
- 201000011486 lichen planus Diseases 0.000 description 2
- 210000001853 liver microsome Anatomy 0.000 description 2
- 239000007937 lozenge Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 206010063344 microscopic polyangiitis Diseases 0.000 description 2
- 210000001589 microsome Anatomy 0.000 description 2
- 239000007758 minimum essential medium Substances 0.000 description 2
- 239000007932 molded tablet Substances 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 206010028417 myasthenia gravis Diseases 0.000 description 2
- 201000005962 mycosis fungoides Diseases 0.000 description 2
- 208000010125 myocardial infarction Diseases 0.000 description 2
- 208000031225 myocardial ischemia Diseases 0.000 description 2
- 208000004296 neuralgia Diseases 0.000 description 2
- 208000029974 neurofibrosarcoma Diseases 0.000 description 2
- 208000021722 neuropathic pain Diseases 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 229960000402 palivizumab Drugs 0.000 description 2
- 208000012111 paraneoplastic syndrome Diseases 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 208000008494 pericarditis Diseases 0.000 description 2
- 201000001245 periodontitis Diseases 0.000 description 2
- 230000000505 pernicious effect Effects 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 208000001297 phlebitis Diseases 0.000 description 2
- 210000002381 plasma Anatomy 0.000 description 2
- 239000003495 polar organic solvent Substances 0.000 description 2
- 201000006292 polyarteritis nodosa Diseases 0.000 description 2
- 208000005987 polymyositis Diseases 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- BHMBVRSPMRCCGG-OUTUXVNYSA-N prostaglandin D2 Chemical compound CCCCC[C@H](O)\C=C\[C@@H]1[C@@H](C\C=C/CCCC(O)=O)[C@@H](O)CC1=O BHMBVRSPMRCCGG-OUTUXVNYSA-N 0.000 description 2
- BHMBVRSPMRCCGG-UHFFFAOYSA-N prostaglandine D2 Natural products CCCCCC(O)C=CC1C(CC=CCCCC(O)=O)C(O)CC1=O BHMBVRSPMRCCGG-UHFFFAOYSA-N 0.000 description 2
- 201000007094 prostatitis Diseases 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 208000002815 pulmonary hypertension Diseases 0.000 description 2
- 208000009954 pyoderma gangrenosum Diseases 0.000 description 2
- 238000003653 radioligand binding assay Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 208000002574 reactive arthritis Diseases 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 201000002793 renal fibrosis Diseases 0.000 description 2
- 230000000241 respiratory effect Effects 0.000 description 2
- 208000023504 respiratory system disease Diseases 0.000 description 2
- 208000037803 restenosis Diseases 0.000 description 2
- 201000003068 rheumatic fever Diseases 0.000 description 2
- 239000012047 saturated solution Substances 0.000 description 2
- 208000008742 seborrheic dermatitis Diseases 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 201000001223 septic arthritis Diseases 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 201000000849 skin cancer Diseases 0.000 description 2
- 201000008261 skin carcinoma Diseases 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 201000005671 spondyloarthropathy Diseases 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 239000000021 stimulant Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 208000020408 systemic-onset juvenile idiopathic arthritis Diseases 0.000 description 2
- 210000002435 tendon Anatomy 0.000 description 2
- 230000001732 thrombotic effect Effects 0.000 description 2
- 201000008827 tuberculosis Diseases 0.000 description 2
- 231100000397 ulcer Toxicity 0.000 description 2
- 241000701161 unidentified adenovirus Species 0.000 description 2
- 208000000143 urethritis Diseases 0.000 description 2
- 208000001319 vasomotor rhinitis Diseases 0.000 description 2
- 208000010484 vulvovaginitis Diseases 0.000 description 2
- MEIRRNXMZYDVDW-MQQKCMAXSA-N (2E,4E)-2,4-hexadien-1-ol Chemical compound C\C=C\C=C\CO MEIRRNXMZYDVDW-MQQKCMAXSA-N 0.000 description 1
- ZIDQIOZJEJFMOH-JKSUJKDBSA-N (3R,4S)-BW 245C Chemical compound C([C@@H](O)C1CCCCC1)CN1[C@@H](CCCCCCC(O)=O)C(=O)NC1=O ZIDQIOZJEJFMOH-JKSUJKDBSA-N 0.000 description 1
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 1
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 1
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- QOPBEBWGSGFROG-UHFFFAOYSA-N 2-(1h-indol-2-yl)acetic acid Chemical class C1=CC=C2NC(CC(=O)O)=CC2=C1 QOPBEBWGSGFROG-UHFFFAOYSA-N 0.000 description 1
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 1
- XXSPGBOGLXKMDU-UHFFFAOYSA-N 2-bromo-2-methylpropanoic acid Chemical class CC(C)(Br)C(O)=O XXSPGBOGLXKMDU-UHFFFAOYSA-N 0.000 description 1
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 description 1
- MSYGAHOHLUJIKV-UHFFFAOYSA-N 3,5-dimethyl-1-(3-nitrophenyl)-1h-pyrazole-4-carboxylic acid ethyl ester Chemical compound CC1=C(C(=O)OCC)C(C)=NN1C1=CC=CC([N+]([O-])=O)=C1 MSYGAHOHLUJIKV-UHFFFAOYSA-N 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 102000004023 5-Lipoxygenase-Activating Proteins Human genes 0.000 description 1
- 108090000411 5-Lipoxygenase-Activating Proteins Proteins 0.000 description 1
- HQULYFAKUZDRPB-UHFFFAOYSA-N 6-bromo-2-[4-(trifluoromethoxy)phenoxy]-1,3-benzothiazole Chemical class BrC1=CC2=C(N=C(S2)OC2=CC=C(C=C2)OC(F)(F)F)C=C1 HQULYFAKUZDRPB-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 101100230376 Acetivibrio thermocellus (strain ATCC 27405 / DSM 1237 / JCM 9322 / NBRC 103400 / NCIMB 10682 / NRRL B-4536 / VPI 7372) celI gene Proteins 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 241000167854 Bourreria succulenta Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 206010006482 Bronchospasm Diseases 0.000 description 1
- 241000459479 Capsula Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 102000000844 Cell Surface Receptors Human genes 0.000 description 1
- 108010001857 Cell Surface Receptors Proteins 0.000 description 1
- 102000019034 Chemokines Human genes 0.000 description 1
- 108010012236 Chemokines Proteins 0.000 description 1
- 241000699802 Cricetulus griseus Species 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 101100296720 Dictyostelium discoideum Pde4 gene Proteins 0.000 description 1
- 241000709661 Enterovirus Species 0.000 description 1
- 108090000371 Esterases Proteins 0.000 description 1
- KGWDUNBJIMUFAP-KVVVOXFISA-N Ethanolamine Oleate Chemical compound NCCO.CCCCCCCC\C=C/CCCCCCCC(O)=O KGWDUNBJIMUFAP-KVVVOXFISA-N 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 238000012413 Fluorescence activated cell sorting analysis Methods 0.000 description 1
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 1
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- DCXXMTOCNZCJGO-UHFFFAOYSA-N Glycerol trioctadecanoate Natural products CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 description 1
- 239000008859 Grazax Substances 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 244000178870 Lavandula angustifolia Species 0.000 description 1
- 235000010663 Lavandula angustifolia Nutrition 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 244000246386 Mentha pulegium Species 0.000 description 1
- 235000016257 Mentha pulegium Nutrition 0.000 description 1
- 235000004357 Mentha x piperita Nutrition 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- ILRKKHJEINIICQ-OOFFSTKBSA-N Monoammonium glycyrrhizinate Chemical compound N.O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@H]1CC[C@]2(C)[C@H]3C(=O)C=C4[C@@H]5C[C@](C)(CC[C@@]5(CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C)C)C(O)=O)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O ILRKKHJEINIICQ-OOFFSTKBSA-N 0.000 description 1
- 201000002795 Muckle-Wells syndrome Diseases 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 108010016731 PPAR gamma Proteins 0.000 description 1
- 102100038825 Peroxisome proliferator-activated receptor gamma Human genes 0.000 description 1
- 241001483078 Phyto Species 0.000 description 1
- 102000012335 Plasminogen Activator Inhibitor 1 Human genes 0.000 description 1
- 108010022233 Plasminogen Activator Inhibitor 1 Proteins 0.000 description 1
- 101100082610 Plasmodium falciparum (isolate 3D7) PDEdelta gene Proteins 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 1
- 240000000111 Saccharum officinarum Species 0.000 description 1
- 235000007201 Saccharum officinarum Nutrition 0.000 description 1
- 102000005473 Secretory Phospholipases A2 Human genes 0.000 description 1
- 108010031873 Secretory Phospholipases A2 Proteins 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- NSOXQYCFHDMMGV-UHFFFAOYSA-N Tetrakis(2-hydroxypropyl)ethylenediamine Chemical compound CC(O)CN(CC(C)O)CCN(CC(C)O)CC(C)O NSOXQYCFHDMMGV-UHFFFAOYSA-N 0.000 description 1
- 210000004241 Th2 cell Anatomy 0.000 description 1
- 208000032109 Transient ischaemic attack Diseases 0.000 description 1
- 208000034327 Tumor necrosis factor receptor 1 associated periodic syndrome Diseases 0.000 description 1
- 102000011017 Type 4 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 description 1
- 108010037584 Type 4 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 description 1
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- ZEEBGORNQSEQBE-UHFFFAOYSA-N [2-(3-phenylphenoxy)-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound C1(=CC(=CC=C1)OC1=NC(=CC(=C1)CN)C(F)(F)F)C1=CC=CC=C1 ZEEBGORNQSEQBE-UHFFFAOYSA-N 0.000 description 1
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 1
- 230000009285 allergic inflammation Effects 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- PECIYKGSSMCNHN-UHFFFAOYSA-N aminophylline Chemical compound NCCN.O=C1N(C)C(=O)N(C)C2=NC=N[C]21.O=C1N(C)C(=O)N(C)C2=NC=N[C]21 PECIYKGSSMCNHN-UHFFFAOYSA-N 0.000 description 1
- 239000003945 anionic surfactant Substances 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000003097 anti-respiratory effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 201000003308 autosomal dominant familial periodic fever Diseases 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- DCBDOYDVQJVXOH-UHFFFAOYSA-N azane;1h-indole Chemical compound N.C1=CC=C2NC=CC2=C1 DCBDOYDVQJVXOH-UHFFFAOYSA-N 0.000 description 1
- 210000003651 basophil Anatomy 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 230000007885 bronchoconstriction Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 230000020411 cell activation Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000036755 cellular response Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 235000019693 cherries Nutrition 0.000 description 1
- 210000000038 chest Anatomy 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- NKLPQNGYXWVELD-UHFFFAOYSA-M coomassie brilliant blue Chemical compound [Na+].C1=CC(OCC)=CC=C1NC1=CC=C(C(=C2C=CC(C=C2)=[N+](CC)CC=2C=C(C=CC=2)S([O-])(=O)=O)C=2C=CC(=CC=2)N(CC)CC=2C=C(C=CC=2)S([O-])(=O)=O)C=C1 NKLPQNGYXWVELD-UHFFFAOYSA-M 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 208000022993 cryopyrin-associated periodic syndrome Diseases 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- 210000003317 double-positive, alpha-beta immature T lymphocyte Anatomy 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 229910001651 emery Inorganic materials 0.000 description 1
- 201000009580 eosinophilic pneumonia Diseases 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 230000003176 fibrotic effect Effects 0.000 description 1
- 229960000289 fluticasone propionate Drugs 0.000 description 1
- WMWTYOKRWGGJOA-CENSZEJFSA-N fluticasone propionate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)SCF)(OC(=O)CC)[C@@]2(C)C[C@@H]1O WMWTYOKRWGGJOA-CENSZEJFSA-N 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- FVIZARNDLVOMSU-UHFFFAOYSA-N ginsenoside K Natural products C1CC(C2(CCC3C(C)(C)C(O)CCC3(C)C2CC2O)C)(C)C2C1C(C)(CCC=C(C)C)OC1OC(CO)C(O)C(O)C1O FVIZARNDLVOMSU-UHFFFAOYSA-N 0.000 description 1
- 239000003365 glass fiber Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000001685 glycyrrhizic acid Substances 0.000 description 1
- 210000003714 granulocyte Anatomy 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 235000001050 hortel pimenta Nutrition 0.000 description 1
- 229940042795 hydrazides for tuberculosis treatment Drugs 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 230000001969 hypertrophic effect Effects 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 150000002469 indenes Chemical class 0.000 description 1
- 238000007373 indentation Methods 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229960001317 isoprenaline Drugs 0.000 description 1
- 229940039009 isoproterenol Drugs 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000001102 lavandula vera Substances 0.000 description 1
- 235000018219 lavender Nutrition 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000005389 magnetism Effects 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000037323 metabolic rate Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 230000003228 microsomal effect Effects 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- WOFMFGQZHJDGCX-ZULDAHANSA-N mometasone furoate Chemical compound O([C@]1([C@@]2(C)C[C@H](O)[C@]3(Cl)[C@@]4(C)C=CC(=O)C=C4CC[C@H]3[C@@H]2C[C@H]1C)C(=O)CCl)C(=O)C1=CC=CO1 WOFMFGQZHJDGCX-ZULDAHANSA-N 0.000 description 1
- 229960002744 mometasone furoate Drugs 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 239000002324 mouth wash Substances 0.000 description 1
- 229940051866 mouthwash Drugs 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- CMWTZPSULFXXJA-VIFPVBQESA-M naproxen(1-) Chemical compound C1=C([C@H](C)C([O-])=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-M 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000000414 obstructive effect Effects 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 235000010603 pastilles Nutrition 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 210000001428 peripheral nervous system Anatomy 0.000 description 1
- 102000013415 peroxidase activity proteins Human genes 0.000 description 1
- 108040007629 peroxidase activity proteins Proteins 0.000 description 1
- 208000017983 photosensitivity disease Diseases 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 201000009732 pulmonary eosinophilia Diseases 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 238000001525 receptor binding assay Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 229930002330 retinoic acid Natural products 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000007790 scraping Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 229910000077 silane Inorganic materials 0.000 description 1
- 229920002545 silicone oil Polymers 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- YPURUCMVRRNPHJ-UHFFFAOYSA-M sodium;3-[3-tert-butylsulfanyl-1-[(4-chlorophenyl)methyl]-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoate Chemical compound [Na+].C12=CC=C(OCC=3N=C4C=CC=CC4=CC=3)C=C2C(SC(C)(C)C)=C(CC(C)(C)C([O-])=O)N1CC1=CC=C(Cl)C=C1 YPURUCMVRRNPHJ-UHFFFAOYSA-M 0.000 description 1
- JFXAUUFCZJYLJF-UHFFFAOYSA-M sodium;4-chlorobenzenesulfinate Chemical compound [Na+].[O-]S(=O)C1=CC=C(Cl)C=C1 JFXAUUFCZJYLJF-UHFFFAOYSA-M 0.000 description 1
- VDDUCRSPMBZLMH-UHFFFAOYSA-M sodium;4-fluorobenzenesulfinate Chemical compound [Na+].[O-]S(=O)C1=CC=C(F)C=C1 VDDUCRSPMBZLMH-UHFFFAOYSA-M 0.000 description 1
- 125000006850 spacer group Chemical group 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- SRJQTHAZUNRMPR-UYQKXTDMSA-N spinosyn A Chemical compound O([C@H]1CCC[C@@H](OC(=O)C[C@H]2[C@@H]3C=C[C@@H]4C[C@H](C[C@H]4[C@@H]3C=C2C(=O)[C@@H]1C)O[C@H]1[C@@H]([C@H](OC)[C@@H](OC)[C@H](C)O1)OC)CC)[C@H]1CC[C@H](N(C)C)[C@@H](C)O1 SRJQTHAZUNRMPR-UYQKXTDMSA-N 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000035882 stress Effects 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- LERNTVKEWCAPOY-DZZGSBJMSA-N tiotropium Chemical compound O([C@H]1C[C@@H]2[N+]([C@H](C1)[C@@H]1[C@H]2O1)(C)C)C(=O)C(O)(C=1SC=CC=1)C1=CC=CS1 LERNTVKEWCAPOY-DZZGSBJMSA-N 0.000 description 1
- 229940110309 tiotropium Drugs 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000011830 transgenic mouse model Methods 0.000 description 1
- 201000010875 transient cerebral ischemia Diseases 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 230000029069 type 2 immune response Effects 0.000 description 1
- 229940116269 uric acid Drugs 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000009637 wintergreen oil Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/14—Antitussive agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/10—Drugs for disorders of the urinary system of the bladder
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
-
- 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
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- 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
- A61P17/00—Drugs for dermatological disorders
- A61P17/10—Anti-acne agents
-
- 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
- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- 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
- 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
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pulmonology (AREA)
- Dermatology (AREA)
- Immunology (AREA)
- Urology & Nephrology (AREA)
- Virology (AREA)
- Diabetes (AREA)
- Neurology (AREA)
- Physical Education & Sports Medicine (AREA)
- Rheumatology (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Hematology (AREA)
- Communicable Diseases (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Endocrinology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pain & Pain Management (AREA)
- Obesity (AREA)
- Oncology (AREA)
- Molecular Biology (AREA)
- Gynecology & Obstetrics (AREA)
- Ophthalmology & Optometry (AREA)
- Child & Adolescent Psychology (AREA)
- Vascular Medicine (AREA)
Abstract
本发明涉及一种通式(I)的化合物,其中,W为氯或氟,R1是苯基,该苯基可任选地被一个或多个取代基取代,这些取代基选自卤素、-CN、-C1-C6烷基、-SOR3、-SO2R3、-SO2N(R2)2、-N(R2)2、-NR2C(O)R3、-CO2R2、-CONR2R3、-NO2、-OR2、-SR2、-O(CH2)pOR2和-O(CH2)pO(CH2)qOR2,其中每个R2独立为氢、-C1-C6烷基、-C3-C8环烷基、芳基或杂芳基;每个R3独立为-C1-C6烷基、-C3-C8环烷基、芳基或杂芳基;p与q分别独立为1至3的整数;及该通式(I)的化合物药学上可接受的盐、水合物、溶剂合物、络合物或前药,可以以口服给药的组合物形式用于治疗变应性疾病,例如哮喘、变应性鼻炎和特应性皮炎。
Description
技术领域
本发明涉及用作药剂的化合物,及制备这些化合物的方法,并涉及含有这些化合物的组合物及其在治疗和预防过敏性疾病中的用途,这些疾病例如:哮喘、变应性鼻炎和特应性皮炎和由作用于CRTH2受体的前列腺素D2(PGD2)或其他激动剂所介导的其他炎症性疾病,这些受体位于包括嗜酸性粒细胞、嗜碱性粒细胞和Th2淋巴细胞等细胞上。
背景技术
PGD2是一种类二十烷酸,一种由细胞响应局部组织损伤、常规刺激或激素刺激,或者通过细胞活化途径而合成的化学介质。类二十烷酸结合至体内多种组织上的特异性细胞表面受体并介导这些组织中的多种效应。已知PGD2由肥大细胞、巨噬细胞和Th2淋巴细胞产生,且检测到其在受抗原激发的哮喘患者呼吸道中的浓度比较高(Murray等,(1986),N.Engl.J.Med.315:800-804)。将PGD2滴注到呼吸道中可引起包括支气管收缩(Hardy等,(1984)N.Engl.J.Med.311:209-213;Sampson等,(1997)Thorax 52:513-518)和嗜酸性粒细胞聚集(Emery等,(1989)J.Appl.Physiol.67:959-962)在内的多种哮喘反应特征。
外源使用PGD2引发炎症性反应的可能性已经通过使用过表达人类PGD2合酶的转基因小鼠而得到证实,这些小鼠表现出加重的嗜酸性粒细胞肺炎和响应抗原产生的Th2细胞因子(Fujitani等,(2002)J.Immunol.168:443-449)。
针对PGD2所发现的第一个受体是DP受体,其与细胞内cAMP水平的升 高有关。然而,业内认为,PGD2通过与称为CRTH2(表达于Th2细胞上的趋化因子受体-同源分子)的G蛋白偶联受体相互作用而调节其多种炎性活性,CRTH2由Th2淋巴细胞、嗜酸性粒细胞和嗜碱性粒细胞表达(Hirai等,(2001)J.Exp.Med.193:255-261,及EP0851030与EP-A-1211513,以及Bauer等,EP-A-1170594)。似乎很清楚,PGD2对Th2淋巴细胞和嗜酸性粒细胞活化的影响通过CRTH2进行介导,其原因在于选择性CRTH2激动剂13,14二氢-15-酮-PGD2(DK-PGD2)和15R-甲基-PGD2可引发此反应且PGD2效应由抗-CRTH2抗体阻断(Hirai等,2001;Monneret等,(2003)J.Pharmacol.Exp.Ther.304:349-355)。相比之下,选择性DP激动剂BW245C不会促进Th2淋巴细胞或嗜酸性粒细胞迁移(Hirai等,2001;Gervais等,(2001)J.Allergy Clin.Immunol.108:982-988)。基于这种迹象,作用于CRTH2受体的拮抗PGD2是一种治疗Th2-依赖性过敏性疾病(例如哮喘、变应性鼻炎和特应性皮炎)的炎症组分的颇具吸引力的方法。
EP-A-1170594提出,其所涉及的方法可用来鉴定用于治疗下列疾病的化合物:变应性哮喘、特应性皮炎、变应性鼻炎、自身免疫性疾病、再灌注损伤和多种炎症性病况,这些全部均由作用于CRTH2受体的PGD2或其他激动剂介导。
WO-A-03066046和WO-A-03066047中描述了结合至CRTH2的化合物。这些化合物以及类似化合物并非新发现的,但却首次在GB 1356834、GB 1407658和GB 1460348中公开,在这些文献当中,这些化合物被认为具有消炎、止痛和退热活性。WO-A-03066046和WO-A-03066047中所涉及的化合物是CRTH2受体活性的调节剂且因此用于治疗或预防阻塞性呼吸道疾病,例如:哮喘、慢性阻塞性肺疾病(COPD)和包括下列各项器官和组织的病变的多种其他疾病:骨与关节、皮肤与眼睛、胃肠道、中枢与周围神经系统和其他组织以及排斥反应。这些化合物是在吲哚环的3-位上具有乙酸取代基的所有吲哚衍生物。
PL 65781与JP 43024418还涉及吲哚-3乙酸衍生物,其结构与吲哚美辛类似,且被认为像吲哚美辛一样具有消炎和退热活性。因而,尽管当这些文献出版时这一点可能还没有被了解,但是其所描述的化合物是COX抑制剂,其活性与本发明化合物的活性完全不同。实际上,COX抑制剂在治疗多种疾病和病况时是禁忌,例如本发明的化合物用于哮喘和炎症性肠病,但有时可用来治疗关节炎。
另一项现有技术涉及吲哚-1-乙酸化合物,但这些化合物并未作为CRTH2拮抗剂进行描述。举例而言WO-A-9950268、WO-A-0032180、WO-A-0151489和WO-A-0164205均涉及为吲哚-1-乙酸衍生物的化合物,但这些化合物被认为是用来治疗糖尿病的醛糖还原酶抑制剂(WO-A-9950268、WO-A-0032180和WO-A-0164205)或降尿酸剂(WO-A-0151849)。在这些文献的任何一个文献中均未暗示,这些化合物可用来治疗由PGD2或其他CRTH2受体激动剂所介导的疾病和病况。
US 4,363,912涉及吲哚-1-烷基羧酸衍生物(包括吲哚-1-乙酸类似物),该化合物被认为是血栓烷合成酶的抑制剂且用来治疗诸如血栓形成、缺血性心脏病和脑卒中等病况。这些化合物在与通式(I)的吡啶基等同的位置上具有未经取代的3-吡啶基或4-吡啶基取代基。对属于US 4,363,912的权利要求书的范围内且与本发明化合物最接近的类似物(5-氟-2-甲基-3-(吡啶-3-基甲基)-吲哚-1-基)-乙酸)的评价表明,该化合物作为CRTH2拮抗剂的活性明显不如本发明的化合物。与本发明的化合物(其全部是吲哚-1-乙酸衍生物)相比而言,US 4,363,912中优选的化合物是3-(吲哚-1-基)-丙酸衍生物。
WO-A-9603376涉及被认为是sPLA2抑制剂的化合物,该化合物用于治疗支气管哮喘和变应性鼻炎。这些化合物均具有酰胺或酰肼取代基而非本发明化合物的羧酸衍生物。
JP 2001247570涉及一种生成3-苯并噻唑甲基吲哚乙酸的方法,该3-苯并噻唑甲基吲哚乙酸被认为是醛糖还原酶抑制剂。
US 4,859,692涉及被认为是白三烯拮抗剂的化合物,该化合物用于治疗诸如哮喘、花粉症和变应性鼻炎等病况以及诸如支气管炎、特应性和异位性湿疹等某些炎症性病况。该文献中的某些化合物是吲哚-1-乙酸,但该作者在J.Med.Chem.,33,1781-1790(1990)中教示,在吲哚氮上具有乙酸基团的化合物没有明显的肽白三烯(peptidoleukotriene)活性。
US 4,273,782涉及吲哚-1-乙酸衍生物,该化合物被认为可用于治疗诸如血栓形成、缺血性心脏病、脑卒中、短暂性脑缺血发作、偏头痛和糖尿病的血管并发症等病况。在该文献中未提及由作用于CRTH2受体的PGD2或其他激动剂所介导的病况。
US 3,557,142涉及3-经取代-1-吲哚羧酸与酯,该化合物被认为可用于治疗炎症性病况。
WO-A-03/097598涉及为CRTH2受体拮抗剂的化合物。这些化合物在吲哚-3位上没有芳基取代基。
文献(Cross等,J.Med.Chem.29,342-346(1986))涉及从相应酯制备吲哚-1-乙酸衍生物的方法。该文献所涉及的化合物被认为是血栓烷合成酶的抑制剂。
EP-A-0539117涉及为白三烯拮抗剂的吲哚-1-乙酸衍生物。
US 2003/0153751涉及为sPLA2抑制剂的吲哚-1-乙酸衍生物。然而,该文献中所有示例的化合物在吲哚系统的2-位和5-位均具有庞大的取代基,从而与本发明化合物极为不同。
US 2004/0116488公开为PAI-1抑制剂的吲哚-1-乙酸衍生物。但并未暗示这些化合物可具有CRTH2拮抗活性。
WO 2004/058164涉及被认为是哮喘和过敏性炎症调节剂的化合物。活性被证实的仅有的化合物在结构上完全不同于本发明的吲哚-1-乙酸衍生物。
WO-A-03/097042和WO-A-03/097598公开了结合至CRTH2受体的化合物。这些化合物是吲哚乙酸,但在WO-A-03/097042中吲哚系统的2-3位稠合到5-7元碳环上。在WO-A-03/097598中,吲哚3-位上是吡咯烷基。
WO-A-03/101981、WO-A-03/101961和WO-A-2004/007451均涉及被认为是CRTH2拮抗剂的吲哚-1-乙酸衍生物,但其结构与通式(I)的化合物不同,因为不存在间隔基团,或者是与吲哚3-位连接的是-S-或-SO2-基团而非本发明化合物的CH2基团,如下文所述。
WO-A-2005/019171还描述吲哚-1-乙酸衍生物,该化合物被认为是CRTH2拮抗剂且被认为可用于治疗各种呼吸性疾病。这些化合物均具有通过氧间隔基团连接至吲哚-3位的取代基。
WO-A-2005/094816再次描述了吲哚-1-乙酸化合物,此次在吲哚环的3-位上具有脂肪族取代基。这些化合物被认为是CRTH2拮抗剂。
WO-A-2006/034419涉及CRTH2拮抗剂吲哚化合物,该化合物具有杂环或杂芳基取代基,该取代基与吲哚环系统的3-位直接连接。
在先前的申请WO-A-2005/044260中,我们描述了作用于CRTH2受体的PGD2拮抗剂的化合物。这些化合物是在3-位上经基团CR8R9取代的吲哚-1-乙酸衍生物,其中R9为氢或烷基且R8为可被一个或多个取代基取代的芳基基团。该文献中所阐述的化合物是活体外作用于CRTH2受体的PGD2的强效拮抗剂。然而,我们发现,当在活体内测试时,某些化合物的药代动力学并非最佳且在全血嗜酸性粒细胞形变测试中其效价通常比可自活体外结合结果所期望的效价稍微偏低,该效价可给出活体内化合物可能活性的指示。
在另一个先前申请WO2006/095183中,吲哚-1-乙酸衍生物在3-位经1-苯磺酰基-1H-吡咯-2-基甲基基团取代,其中苯磺酰基部分的苯基基团可经取代。这些化合物是极具活性的CRTH2拮抗剂,但被迅速代谢掉,如通过与人类微粒体制剂一起培育所测定的那样。
申请WO2008/012511还涉及CRTH2拮抗剂化合物,这次涉及在3-位经2-苯基磺酰基苄基基团取代的吲哚-1-乙酸衍生物。文献中发现,苯基磺酰基取代基的位置对化合物的活性及其药代动力学具有显著影响。
发明内容
本发明涉及WO2008/012511的化合物的吡啶基类似物。这些化合物不具有WO2006/095183化合物的代谢稳定性缺点,且令人惊奇地发现,特定吡啶基的位置异构体(regioisomers)及其取代物可得到效价与药物动力学特性的最佳平衡。特别地,发现将苯基磺酰基取代基引至吡啶-3-基位置异构体的2-位上,可提供在活体外功能分析中具有良好效价并且在活体内具有良好药物动力学的化合物。这种组合应当产生高度有益的特性组合,但这组合并不明显且并没有在与CRTH2拮抗剂有关的文献和专利申请中描述。特别令人惊奇地,2-苯磺酰基-吡啶-3-基化合物在受体结合分析和活体外功能分析两种分析中均是CRTH2受体的强效和特效拮抗剂,因为我们发现3-苯磺酰基-吡啶-2-基类似物明显不大强效且3-苯磺酰基-吡啶-4-基类似物在活体外功能分析中呈现出比可自其受体结合活性所期望的活性低的活性。因此,看来吡啶基氮的位置在本发明化合物中 特别重要。
因此,本发明涉及新的化合物,其结合至CRTH2受体且因此可用于治疗由作用于CRTH2受体的PGD2活性所介导的疾病和病况。
在本发明中,提供通式(I)的化合物,
其中
W是氯或氟;
R1是苯基,该苯基可任选地被一个或多个取代基取代,这些取代基选自:卤素、-CN、-C1-C6烷基、-SOR3、-SO2R3、-SO2N(R2)2、-N(R2)2、-NR2C(O)R3、-CO2R2、-CONR2R3、-NO2、-OR2、-SR2、-O(CH2)pOR2和-O(CH2)pO(CH2)qOR2,其中
每个R2独立为氢、-C1-C6烷基、-C3-C8环烷基、芳基或杂芳基;
每个R3独立为-C1-C6烷基、-C3-C8环烷基、芳基或杂芳基;
p和q分别独立为1-3的整数;
或者该通式(I)的化合物药学上可接受的盐、水合物、溶剂合物、络合物或前药。
通式(I)的化合物是作用于CRTH2受体的拮抗剂且用于治疗由结合至CRTH2的PGD2或其他激动剂所介导的病况。这些病况包括过敏性疾病、哮喘病况和炎症性疾病,其实例为哮喘,包括变应性哮喘、支气管哮喘、哮喘恶化 和由病毒感染引起的相关过敏性疾病,特别是那些由鼻病毒和呼吸道合胞病毒引起的恶化,内源性哮喘、外源性哮喘、运动诱发的哮喘、药物诱发的哮喘和粉尘诱发的哮喘;治疗咳嗽,包括与呼吸道炎症和分泌状况有关的慢性咳嗽和医源性咳嗽;急性和慢性鼻炎,包括药物性鼻炎、血管运动性鼻炎、常年性变应性鼻炎、季节性变应性鼻炎、鼻息肉病;急性病毒感染,包括普通感冒、由呼吸道合胞病毒、流行性感冒、冠状病毒和腺病毒引起的感染;特应性皮炎、接触过敏(包括接触性皮炎)、湿疹性皮炎、植物性皮炎(phyto dermatitis)、光照性皮炎(photo dermatitis)、脂溢性皮炎、疱疹样皮炎、扁平苔藓、硬化萎缩性苔藓、坏疽性脓皮病、皮肤肉样瘤(skin sarcoid)、盘状红斑狼疮、天疱疮、类天疱疮、大疱性表皮松解症荨麻疹(epidermolysis bullosa urticaria)、血管性水肿、血管炎、中毒性红斑、皮肤嗜酸性粒细胞增多症、斑秃、男性型脱发、Sweet综合征(急性发热性嗜中性皮病)、韦-克二氏综合征(Weber-Christian syndrome)、多形性红斑、蜂窝组织炎、脂膜炎、皮肤淋巴瘤、非黑色素性皮肤癌和其他发育不良型病损;眼睑结膜炎、尤其是变应性结膜炎、前葡萄膜炎及后葡萄膜炎、脉络膜炎、自身免疫、影响视网膜的退化性或炎症性病症、眼炎;支气管炎,包括感染性和嗜酸粒细胞性支气管炎、肺气肿、支气管扩张症、农民肺、过敏性肺炎、特发性间质性肺炎、肺移植并发症、肺脉管系统的脉管炎和血栓性病症、肺动脉高血压、食物过敏、牙龈炎、舌炎、牙周炎、食道炎(包括反流)、嗜酸粒细胞性胃肠炎、直肠炎、pruris ani、乳糜泻疾病、与食物有关的过敏症、炎症性肠病、溃疡性结肠炎和克罗恩氏病(Crohn’s disease),肥大细胞增多症以及其他CRTH2介导的疾病,例如自身免疫疾病,例如高IgE综合征、乔本氏甲状腺炎、格雷夫斯氏病、阿狄森氏病、糖尿病、特发性血小板减少性紫癜病、嗜酸粒细胞性筋膜炎、抗磷脂综合征和 系统性红斑狼疮、艾滋病(AIDS)、麻风病、塞扎里综合征、肿瘤伴随综合征、混合性结缔组织病和未分化结缔组织病、炎性肌病包括皮肌炎和多肌炎,风湿性多肌痛、幼年型关节炎、风湿热、血管炎包括巨细胞性动脉炎、高安式动脉炎、丘-施二氏综合征(Churg-Strauss syndrome)、结节性多发性动脉炎、微型多动脉炎、颞动脉炎、重症肌无力、急性和慢性疼痛、神经性疼痛综合征、恶性中枢及周边神经系统并发症、感染性或自身免疫过程、腰痛、家族性地中海热、穆-韦二氏综合征(Muckle-Wells syndrome)、家族性爱尔兰人热(Familial Hibernian fever)、菊池病、银屑病、痤疮、多发性硬化症、同种异体移植排斥、再灌注损伤、慢性阻塞性肺疾病、以及类风湿性关节炎、斯蒂尔病、强直性脊柱炎、反应性关节炎、未分化型脊椎关节病、银屑病关节炎、脓毒性关节炎和其他与感染有关的关节痛和骨病和骨关节炎;急性和慢性晶体性滑膜炎(crystal-induced synovitis),包括尿酸盐痛风、焦磷酸钙沉积疾病、与钙肽(calcium paptite)有关的肌腱综合征、和滑膜炎,贝切特氏病、原发性及继发性斯耶格伦综合征系统性硬化病(primary and secondary Sjogren’s syndrome systemic sclerosis)和局限性硬皮病;肝炎、肝硬化、胆囊炎、胰腺炎、肾炎、肾炎综合征、膀胱炎和杭纳氏溃疡、急性和慢性尿道炎、前列腺炎、附睾炎、卵巢炎、输卵管炎、外阴阴道炎、佩罗尼氏病、勃起功能障碍、阿兹海默氏病及其他痴呆症;心包炎、心肌炎、炎症性和自身免疫性心肌病,包括心脏结节病、缺血再灌注损伤、心内膜炎、瓣膜炎、主动脉炎、静脉炎、血栓形成;治疗常见癌症和纤维化病况,例如特发性肺纤维化,包括隐原性纤维化肺泡炎、疤痕疙瘩、过度纤维化疤痕/术后粘连、肝纤维化(包括与肝炎B和C有关的肝纤维化)、子宫肌瘤、肉瘤病(sarcoidosis)(包括神经肉瘤病)、硬皮病、由糖尿病导致的肾纤维化、与RA(维甲酸)有关的纤维化、动脉粥样硬化(包 括脑动脉粥样硬化)、脉管炎、由心肌梗死导致的心肌纤维化、囊性纤维化、再狭窄症、系统性硬化病、迪皮特朗氏病、抗肿瘤治疗并发的纤维化和慢性感染(包括结核病和曲霉病和其他真菌感染)、和脑卒中后的CNS(中枢神经系统)纤维化,或促进愈合且不留纤维化疤痕。
通式(I)的化合物在全血嗜酸性粒细胞形变测试中改善的效价和药代动力学特别令人惊奇,因为WO-A-2005/044260中结构与通式(I)的化合物最接近的某些化合物不具有这些有利特性。具体而言,WO-A-2005/044260中实例17化合物与本发明化合物类似且预测可具有相似特性。然而,在狗活体内实施的实验中,用通式(I)的化合物中的2-(苯磺酰基)吡啶-3-基甲基基团替代WO-A-2005/044260实例17中的4-甲基磺酰基苄基基团对化合物的药物动力学具有明显影响,因为当WO-A-2005/044260的化合物17以口服给药时,其活体内药代动力学不如通式(I)的化合物的药代动力学有利。
另外,对于WO-A-2005/044260中的多数化合物而言,发现其活体外全血嗜酸性粒细胞形变活性通常低于自其活体外活性所预测的活性,如由与CRTH2受体结合的放射性配体实验所测量的那样。
此外,活性改善完全是针对通式(I)的化合物的基团而言。即使与WO-A-2005/044260中所具体公开的化合物密切相关的化合物也不具有这样的有利特性。举例而言,其中SO2R基团在吡啶环上的位置不与连接的亚甲基部分(与吲哚基骨架的3-位连接)毗邻的通式(I)的类似物在活体外全血嗜酸性粒细胞形变测试中活性较低。
在本发明说明书中,“C1-C6烷基”是指具有1-6个碳原子且任选地经一个或多个卤素取代基和/或一个或多个C3-C8环烷基基团取代的饱和直链或支链烃链。实例包括甲基、乙基、正丙基、异丙基、叔丁基、正己基、三氟甲基、2- 氯乙基、亚甲基环丙基、亚甲基环丁基、亚甲基环丁基和亚甲基环戊基。
术语“C1-C18烷基”具有与上文类似的含义,只是其指具有1-18个碳原子的饱和直链或支链烃链。
在本发明说明书中,“C3-C8环烷基”是指具有3-8个环原子且任选地经一个或多个卤素取代基取代的饱和碳环基团。实例包括环丙基、环戊基、环己基和4-氟环己基。
在本发明说明书中,“卤素”是指氟、氯、溴或碘。
在本发明说明书的上下文中,术语“芳基”是指具有5-14个环碳原子且含有多达三个环的具有芳香性特性的环系统。其中芳基基团含有一个以上环,但并非所有环都必须具有完全的芳香性特性。芳香族部分的实例是苯、萘、二氢化茚和茚。
在本说明书的上下文中,术语“杂芳基”是指具有5-14个环原子,其中至少有一个原子是选自N、O和S的杂原子,且含有多达3个环的具有芳香性特性的环系统。其中杂芳基基团含有一个以上的环,但并非所有环都必须具有完全的芳香性特性。杂芳基基团的实例包括吡啶、嘧啶、吲哚、苯并呋喃、苯并咪唑和吲哚烯液。
通式(I)的化合物适当的药学上和兽医学上可接受的盐包括碱加成盐,例如钠、钾、钙、铝、锌、镁和其他金属盐以及胆碱、二乙醇胺、乙醇胺、乙二胺、葡甲胺(megulmine)和其他众所周知的碱加成盐,如文献(Paulekuhn等,(2007)J.Med.Chem.50:6665-6672)中所概述的,和/或本领域技术人员所熟知的碱加成盐。
药学上或兽医学上不可接受的盐作为中间体仍然是有价值的。
前药是在活体内释放通式(I)的活性母体药物的任何以共价键结合的化合 物。前药的实例包括通式(I)的化合物的烷基酯,例如下文通式(II)的酯。
在特别适宜的通式(I)的化合物中,W为氟取代基且苯基基团R1未经取代或经单个卤素取代基、通常为氟或氯取代,该取代基一般位于苯基基团R1的4-位上。
本发明具体的活性化合物是:
(3-{[2-(苯磺酰基)吡啶-3-基]甲基}-5-氟-2-甲基吲哚-1-基)-乙酸;
[5-氟-3-({2-[(4-氟苯)磺酰基]吡啶-3-基}甲基)-2-甲基吲哚-1-基]-乙酸;
[3-({2-[(4-氯苯)磺酰基]吡啶-3-基}甲基)-5-氟-2-甲基吲哚-1-基]-乙酸;
或者上述化合物的C1-C6烷基、芳基、(CH2)mOC(=O)C1-C6烷基、((CH2)mO)nCH2CH2X、(CH2)mN(R5)2或CH((CH2)mO(C=O)R6)2酯;
m为1或2;
n为1-4;
X是OR5或N(R5)2;
R5是氢或甲基;
R6是C1-C18烷基。
在本发明另一方面中,提供通式(II)的化合物:
其中W与R1均如通式(I)所定义;且
R4是C1-C6烷基、经芳基取代的C1-C6烷基、芳基、(CH2)mOC(=O)C1-C6烷 基、((CH2)mO)nCH2CH2X、(CH2)mN(R5)2或CH((CH2)mO(C=O)R6)2;
m为1或2;
n为1-4;
X是OR5或N(R5)2;
R5是氢或甲基;
R6是C1-C18烷基;
或该通式(II)的化合物药学上可接受的盐、水合物、溶剂合物、络合物或前药。
通式(II)的化合物是新的且可用作通式(I)的化合物的前药。当通式(II)的化合物用作前药时,其随后通过患者血液或组织中酯酶的作用转化为药物。
当通式(II)的化合物用作前药时,特别适宜的R4基团的实例包括:甲基、乙基、丙基、苯基、-O(CH2)2O(CH2)2OR5、-O(CH2)2O(CH2)2O(CH2)2OR5、-O(CH2)2O(CH2)2NR5 2、-O(CH2)2O(CH2)2O(CH2)2NR5 2、-CH2OC(=O)tBu、-CH2CH2N(Me)2、-CH2CH2NH2或-CH(CH2O(C=O)R6)2,其中R5与R6均如上文所定义。
其中R4是C1-C6烷基或苄基的通式(II)的化合物除用作前药外,还可用于通式(I)的化合物的制备过程中,该过程包括使通式(II)的化合物与碱(例如氢氧化钠或氢氧化锂)反应。该反应可在水溶剂或有机溶剂或二者的混合物中发生。该反应所使用的典型溶剂是四氢呋喃与水的混合物。
通式(II)的化合物可由通式(III)的化合物与通式(IV)的醛反应制备:
通式(III)的化合物中,其中W如通式(I)中所定义,且R4如通式(II)中所定义;通式(IV)的醛如下:
其中R1如针对通式(I)所定义。该反应可在三氟甲磺酸三甲基硅酯(TMSOTf)参与下在非极性有机溶剂中及还原温度(例如-5到10℃,通常为0℃)下实施。随后(例如)用三烷基硅烷(例如三乙基硅烷)还原中间产物。
通式(III)的化合物的制备程序已为本领域技术人员所公知,且一般而言包括在1-位用α-溴乙酸盐衍生物或有关的烷基化试剂烷基化5-卤素-吲哚衍生物。5-卤素-吲哚衍生物容易获得或者可根据现有方法制备。
通式(IV)的化合物可通过通式(V)的化合物与通式(VI)的化合物的反应制备:
其中X是离去基团,例如卤素,尤其氟或氯;
通式(VI)的化合物如下:
R1-SO2Na (VI)
其中R1如通式(I)所定义。
该反应可在极性有机溶剂(例如DMSO)中在高温下(通常为回流温度) 反应较长时间(例如48-120小时)来实现。
通式(V)及(VI)的化合物可在市面上购得。
通式(I)的化合物是CRTH2受体拮抗剂且通式(II)的化合物是通式(I)的化合物的前药。因此,通式(I)及(II)的化合物可用于治疗由作用于CRTH2受体的PGD2或其他激动剂所介导的疾病和病况的方法中,该方法包括向有此治疗需要的患者施与适宜量的通式(I)或(II)化合物。
在本发明的第三方面中,提供用于药用的通式(I)或(II)的化合物,特别地用于治疗或预防由PGD2或其他CRTH2受体激动剂所介导的疾病和病况。
此外,本发明还提供通式(I)或(II)的化合物在制备药剂中的用途,该药剂用于治疗或预防由CRTH2受体激动剂、特别是PGD2介导的疾病和病况。
如上所述,这些疾病和病况包括变应性疾病、哮喘病况和炎症性疾病,这些疾病和病况的实例为哮喘,包括变应性哮喘、支气管哮喘、内源性哮喘、外源性哮喘、运动诱发的哮喘、药物诱发的哮喘和粉尘诱发的哮喘;治疗咳嗽,包括与呼吸道炎症和分泌状况有关的慢性咳嗽和医源性咳嗽;急性和慢性鼻炎,包括药物性鼻炎、血管运动性鼻炎、常年性变应性鼻炎、季节性变应性鼻炎、鼻息肉病;急性病毒感染,包括普通感冒、由呼吸道合胞病毒、流行性感冒、冠状病毒和腺病毒引起的感染;特应性皮炎、接触过敏(包括接触性皮炎)、湿疹性皮炎、植物性皮炎、光照性皮炎、脂溢性皮炎、疱疹样皮炎、扁平苔藓、硬化萎缩性苔藓、坏疽性脓皮病、皮肤肉样瘤、盘状红斑狼疮、天疱疮、类天疱疮、大疱性表皮松解症荨麻疹、血管性水肿、血管炎、中毒性红斑、皮肤嗜酸性粒细胞增多症、斑秃、男性型脱发、Sweet综合征、韦-克二氏综合征、多形性红斑、蜂窝组织炎、脂膜炎、皮肤淋巴瘤、非黑色素性皮肤癌和其他发育不良型病损;眼睑结膜炎、尤其是变应性结膜炎、前葡萄膜炎及后葡萄膜炎、 脉络膜炎、自身免疫、影响视网膜的退化性或炎症性病症、眼炎;支气管炎,包括感染性和嗜酸粒细胞性支气管炎、肺气肿、支气管扩张症、农民肺、过敏性肺炎、特发性间质性肺炎、肺移植并发症、肺脉管系统的脉管炎和血栓性病症、肺动脉高血压、食物过敏、牙龈炎、舌炎、牙周炎、食道炎(包括反流)、嗜酸粒细胞性胃肠炎、直肠炎、pruris ani、乳糜泻疾病、与食物有关的过敏症、炎症性肠病、溃疡性结肠炎和克罗恩氏病,肥大细胞增多症以及其他CRTH2介导的疾病,例如自身免疫疾病,例如高IgE综合征、乔本氏甲状腺炎、格雷夫斯氏病、阿狄森氏病、糖尿病、特发性血小板减少性紫癜病、嗜酸粒细胞性筋膜炎、抗磷脂综合征和系统性红斑狼疮、AIDS、麻风病、塞扎里综合征、肿瘤伴随综合征、混合性结缔组织病和未分化结缔组织病、炎性肌病包括皮肌炎和多肌炎,风湿性多肌痛、幼年型关节炎、风湿热、血管炎包括巨细胞性动脉炎、高安式动脉炎、丘-施二氏综合征、结节性多发性动脉炎、微型多动脉炎、颞动脉炎、重症肌无力、急性和慢性疼痛、神经性疼痛综合征、恶性中枢及周边神经系统并发症、感染性或自身免疫过程、腰痛、家族性地中海热、穆-韦二氏综合征、家族性爱尔兰人热、菊池病、银屑病、痤疮、多发性硬化症、同种异体移植排斥、再灌注损伤、慢性阻塞性肺疾病以及类风湿性关节炎、斯蒂尔病、强直性脊柱炎、反应性关节炎、未分化型脊椎关节病、银屑病关节炎、脓毒性关节炎和其他与感染有关的关节痛和骨病和骨关节炎;急性和慢性晶体性滑膜炎,包括尿酸盐痛风、焦磷酸钙沉积疾病、与钙肽有关的肌腱综合征、和滑膜炎,贝切特氏病、原发性及继发性斯耶格伦综合征系统性硬化病和局限性硬皮病;肝炎、肝硬化、胆囊炎、胰腺炎、肾炎、肾炎综合征、膀胱炎和杭纳氏溃疡、急性和慢性尿道炎、前列腺炎、附睾炎、卵巢炎、输卵管炎、外阴阴道炎、佩罗尼氏病、勃起功能障碍、阿兹海默氏病及其他痴呆症;心包炎、心 肌炎、炎症性和自身免疫性心肌病,包括心脏结节病、缺血再灌注损伤、心内膜炎、瓣膜炎、主动脉炎、静脉炎、血栓形成;治疗常见癌症和纤维化病况,例如特发性肺纤维化,包括隐原性纤维化肺泡炎、疤痕疙瘩、过度纤维化疤痕/术后粘连、肝纤维化(包括与肝炎B和C有关的肝纤维化)、子宫肌瘤、肉瘤病(包括神经肉瘤病)、硬皮病、由糖尿病导致的肾纤维化、与RA有关的纤维化、动脉粥样硬化(包括脑动脉粥样硬化)、脉管炎、由心肌梗死导致的心肌纤维化、囊性纤维化、再狭窄症、系统性硬化病、迪皮特朗氏病、抗肿瘤治疗并发的纤维化和慢性感染(包括结核病和曲霉病和其他真菌感染)、和脑卒中后的CNS纤维化。这些化合物还用于促进愈合且不留纤维化疤痕。
当这些化合物用于治疗或预防下列疾病时特别有效:变应性哮喘、常年性变应性鼻炎、季节性变应性鼻炎、特应性皮炎、接触过敏(包括接触性皮炎)、结膜炎、尤其是变应性结膜炎、春季角结膜炎和特应性角结膜炎、嗜酸粒细胞性支气管炎、食物过敏、嗜酸粒细胞性胃肠炎、炎症性肠病、溃疡性结肠炎和克罗恩氏病、肥大细胞增多症以及其他PGD2介导的疾病,例如自身免疫疾病,例如高IgE综合征和系统性红斑狼疮、银屑病、痤疮、多发性硬化症、同种异体移植排斥、再灌注损伤、慢性阻塞性肺疾病以及类风湿性关节炎、银屑病关节炎、骨关节炎和由Th2免疫响应引起/加重的纤维化疾病,例如特发性肺纤维化和肥大性疤痕。
通式(I)或(II)化合物须以适当的方式进行配制,视其需要治疗的疾病或病况而定。
因此,在本发明的再一方面中,提供包含通式(I)或(II)化合物以及医药赋形剂或载体的医药组合物。当认为对正治疗或预防的疾病或病况适当或可取时,还可存在其他活性材料。
在与配制物中的其他成分相容且对接受者无害方面,载体或(若存在一个以上载体)载体中的每一个均必须是可接受的。
配制物包括那些适合用于口、直肠、鼻、支气管(吸入)、局部(包括滴眼剂、颊内和舌下)、阴道或非肠胃(包括皮下、肌内、静脉内和真皮内)给药,且配制物可由药学技术领域中众所周知的任何方法来制备。
给药方式应视欲治疗的病况而定,但优选为组合物经配制以用于口、鼻、支气管或局部给药。
组合物可通过使上文所定义的活性剂与载体结合来制备。一般而言,通过使活性剂与液体载体或固体粉末载体或两者的组合均匀而紧密地结合来制备配制物,且随后视需要使产物成形。本发明提供制备医药组合物的方法,该方法包括使通式(I)或(II)的化合物与医药上或兽医学上可接受的载体或媒剂联合或结合。
本发明中口服给药配制物可以下列形式存在:离散单元,例如胶囊、囊剂或片剂,每个均含有预定量的活性剂;以粉末或颗粒形式;以活性剂存于水溶液或非水溶液中的溶液或悬浮液形式;或以水包油液体乳液或油包水液体乳液形式;或以弹丸等形式存在。
对于口服给药组合物(例如片剂和胶囊)而言,术语“可接受的载体”包含媒剂,例如常见赋形剂,例如粘结剂,例如糖浆、阿拉伯胶、凝胶、山梨醇、黄蓍胶、聚乙烯吡咯烷酮(聚维酮)、甲基纤维素、乙基纤维素、羧甲基纤维素钠、羟基丙基甲基纤维素、蔗糖和淀粉;填充剂和载体,例如玉米淀粉、凝胶、乳糖、蔗糖、微晶纤维素、高岭土、甘露醇、磷酸氢钙、氯化钠和海藻酸;及润滑剂,例如硬脂酸镁、硬脂酸钠和其他金属的硬脂酸盐、硬脂酸甘油酯、硬脂酸、硅油、滑石粉蜡、油和胶态二氧化硅。还可使用矫味剂,例如薄荷、 冬青油、樱桃矫味剂及类似物。理想地也可添加着色剂以便于辨别剂型。也可根据本领域中公知的方法对片剂实施包衣。
可通过任选地与一种或多种配合剂一起压制或模制来制备片剂。压制片剂可通过下列方法来制备:在适宜机器中压制呈自由流动形式(例如粉末或颗粒)的活性剂,该活性剂任选地混合有粘结剂、润滑剂、惰性稀释剂、防腐剂、表面活性剂或分散剂。模制片剂可通过在适宜机器中模制经惰性液体稀释剂润湿的粉末状化合物的混合物来制备。任选地可对片剂实施包衣或刻痕,且可经配制以提供活性剂的缓慢或受控释放。
适合口服给药的其他配制物包括锭剂,该锭剂包含存于矫味基质中的活性剂,通常为蔗糖和阿拉伯胶或黄蓍胶;糖果锭剂,包含存于惰性基质例如凝胶和甘油中的活性剂、或蔗糖和阿拉伯胶;及漱口剂,其包含存于适宜液体载体中的活性剂。
对于局部施用于皮肤而言,可将通式(I)或(II)化合物制成乳霜、软膏、凝胶、溶液或悬浮液等。可用于药物的乳霜或软膏配制物是本领域中众所周知的常规配制物,举例而言,如标准制药课本(例如英国药典(British Pharmacopoeia))中所述。
通式(I)或(II)化合物可通过经鼻、经支气管或颊内给药(例如)气溶胶或喷雾剂以用于治疗呼吸道,这些气溶胶或喷雾剂可将药理活性成分分散成粉末形式或溶液或悬浮液的滴剂形式。具有粉末分散特性的医药组合物除活性成分外还通常含有沸点低于室温的液体推进剂及(若需要)诸如液态或固态非离子或阴离子表面活性剂和/或稀释剂等助剂。其中药理活性成分呈溶液形式的医药组合物除此之外还含有适宜的推进剂和进一步(若需要)额外的溶剂和/或稳定剂。也可使用压缩空气替代推进剂,这可根据需要借助于适宜的压缩和膨胀装 置来产生。
非肠胃配制物通常无菌。
典型地,化合物的剂量为约0.01-100毫克/千克;以使血浆中的药物浓度保持在有效抑制作用于CRTH2受体的PGD2的浓度。达到有效治疗的通式(I)或(II)化合物的精确量和该化合物给药的最佳方式应由所属技术领域人员通过比较血液的药剂含量与达到治疗效果所需的浓度而容易地确定。
通式(I)或(II)化合物可与一种或多种用于治疗上文所列的疾病和病况的活性剂组合使用,但这些活性剂未必是作用于CRTH2受体的PGD2的抑制剂。
因此,上述药剂组合物可另外含有这些活性剂中的一或多种。
本发明还提供通式(I)或(II)的化合物在制备药剂中的用途,该药剂用于治疗由CRTH2受体激动剂,尤其是PGD2所介导的疾病和病况,其中该药剂还包含用于治疗同一疾病和病况的额外的活性剂。
这些额外的活性剂可以是其他的CRTH2受体拮抗剂或者可具有完全不同的作用模式。其包括现有的用于过敏性和其他炎症性疾病的治疗,包括:
甲磺司特及类似化合物;
β2肾上腺素受体激动剂,例如间羟异丙肾上腺素、异丙肾上腺素(isoproterenol、isoprenaline)、沙丁胺醇、羟甲叔丁肾上腺素、福莫特罗、沙美特罗、茚达特罗、特普他林、奥西那林、双甲苯喘定甲磺酸盐和吡布特罗或甲基黄嘌呤(methylxanthanines),例如茶碱和氨茶碱,肥大细胞稳定剂,例如色甘酸钠,或毒蕈碱性受体拮抗剂,例如噻托溴胺(tiotropium);
抗组胺,例如组胺H1受体拮抗剂,例如氯雷他定、西替利嗪、地氯雷他定、左西替利嗪、非索非那定、阿司咪唑、氮卓斯汀和氯苯那敏或H4受体拮抗剂;
α1及α2肾上腺素受体激动剂,例如六氢脱氧麻黄碱、苯肾上腺素、苯丙醇 胺、假麻黄碱、盐酸萘甲唑林、盐酸羟甲唑啉、盐酸四氢萘唑啉、盐酸赛洛唑啉和盐酸乙基去甲肾上腺素;
趋化因子受体功能的调节剂,例如CCR1、CCR2、CCR2A、CCR2B、CCR3、CCR4、CCR5、CCR6、CCR7、CCR8、CCR9、CCR10和CCR11(对于C-C族)或CXCR1、CXCR2、CXCR3、CXCR4和CXCR5(对于C-X-C族)和CX3CR1(对于C-X3-C族);
白三烯拮抗剂,例如孟鲁司特和扎鲁司特;
白三烯生物合成抑制剂,例如5-脂氧合酶抑制剂或5-脂氧合酶活化蛋白(FLAP)抑制剂,例如齐留通、ABT-761、芬留顿、替泊沙林、Abbott-79175、N-(5-经取代)-噻吩-2-烷基磺酰胺、2,6-二-叔丁基苯酚腙、甲氧基四氢吡喃,例如ZD2138、SB-210661,吡啶基-经取代-2-氰基萘化合物,例如L-739010,2-氰基喹啉化合物,例如L-746,530,吲哚和喹啉化合物,例如MK-591、MK-886和BAY x 1005;
磷酸二脂酶抑制剂,包括PDE4(磷酸二酯酶-4)抑制剂,例如罗氟司特;
抗-IgE抗体治疗,例如奥马佐单抗;
抗感染药,例如夫西地酸(特别用于治疗特应性皮炎);
抗真菌药,例如克霉唑(特别用于治疗特应性皮炎);
免疫抑制剂,例如他克莫司及特别是针对炎症性皮肤病情况的吡美莫司,或者可替代的FK-506、雷帕霉素、环孢菌素、硫唑嘌呤或甲氨蝶呤;
免疫治疗剂,包括过敏原免疫治疗,例如格瑞萨斯(Grazax);
皮质类固醇,例如泼尼松、泼尼松龙、氟尼缩松、曲安奈德、二丙酸倍氯米松、布地奈德、丙酸氟替卡松-糠酸莫米松(fluticasone propionate mometasone furoate)和促进Th1细胞因子响应的糠酸氟替卡松药物,例如干扰素、TNF或 GM-CSF。
CRTH2拮抗剂也可与针对炎症适应症所开发的治疗剂结合使用,这些治疗剂包括:
作用于其他受体的PGD2的其他拮抗剂,例如DP拮抗剂;
调节细胞因子产生的药物,例如TNFα转化酶(TACE)抗-TNF单克隆抗体的抑制剂;TNF受体免疫球蛋白分子;其他TNF异构体的抑制剂;非选择性COX-1/COX-2抑制剂,例如吡罗昔康、双氯芬酸;丙酸类,例如萘普生、氟苯布洛芬、非诺洛芬、酮洛芬和布洛芬(ibuprofen);芬那酯类,例如甲芬那酸、吲哚美辛、舒林酸和阿扎丙宗;吡唑啉酮类,例如苯丁唑酮;水杨酸类,例如阿司匹林;COX-2抑制剂,例如美洛昔康、塞来考昔、罗非考昔、伐地考昔和艾托考昔、低剂量甲氨蝶呤、来氟米特、环索奈德、羟氯喹、D-青霉胺、金诺芬或非肠胃或口服金;
调节Th2细胞因子IL-4和IL-5活性的药物,例如阻断单克隆抗体和可溶性受体;
PPAR-γ(过氧化物酶增殖体激活受体-γ)激动剂,例如罗格列酮;或采用抗-RSV(抗呼吸道合胞病毒)抗体,例如Synagis(帕利珠单抗(palivizumab)和将来可用于治疗鼻病毒感染的药剂,例如干扰素-α、干扰素-β或其他干扰素。
在本发明的又一方面中,提供包括通式(I)或(II)的化合物与一种或多种上文所列的作为组合制剂的药剂的产品,该产品在治疗由作用于CRTH2受体的PGD2所介导的疾病或病况中同时、单独或依次使用。
在本发明的再一方面中,提供一种套组,用于治疗由作用于CRTH2受体的PGD2所介导的疾病或病况,该套组包括第一外壳,该第一外壳包含通式(I)或(II)的化合物,以及第二外壳,该第二外壳包含一种或多种上文所列的活性 剂。
具体实施方式
现在参照以下非限制性实例更加详细地阐述本发明。
在实例1中,使用BrukerAdvance II光谱仪在300MHz下操作得到1H NMR谱。所有信号均相对于残余质子溶剂作为参照。
在实例2与3中,在Jeol JNM-GSX光谱仪上收集NMR谱,该光谱仪对于 1H NMR数据采集在400MHz下操作且对于13C NMR数据采集在100MHz下操作。
在实例1中,在Gilson 321HPLC上实施HPLC-CAD-MS,由ESA Corona CAD和Finnigan AQA质谱仪实施检测且以正离子电喷雾离子化模式操作。HPLC柱为Phenomenex Gemini C1850x4.6mm 3μ,且流动相梯度介于水中100%0.1%甲酸,与乙腈中100%0.1%甲酸之间,运行2.5分钟,且总运行时间为6.5分钟。在某些情况下,使用上述设备仅获得MS。
在实例2与3中,在Agilent 1050HPLC上实施HPLC,且在220纳米下由UV实施检测。HPLC柱为YMC-Pack、ODS-A 150x4.6mm 5μ,且流动相梯度介于水中100%-0.01%三氟乙酸,与乙腈中100%-0.01%三氟乙酸之间,运行16分钟,且总运行时间为21分钟。
实例1:(3-{[2-(苯磺酰基)吡啶-3-基]甲基}-5-氟-2-甲基吲哚-1-基)-乙酸(化合物1)的制备
2-(苯磺酰基)异烟醛
向在DMSO(45毫升)中溶有苯亚磺酸钠盐(9.36克,0.057摩尔)的搅拌悬浮液中添加2-氟-3-吡啶甲醛(5.20毫升,0.052摩尔)。将产生的混合物在100℃下搅拌94小时。冷却至室温后,使反应混合物在乙酸乙酯与水之间分溶。分离有机层并用乙酸乙酯(3x150毫升)进一步萃取含水层。合并的有机萃取物用水(100毫升)和盐水(100毫升)洗涤,用无水MgSO4干燥,过滤并进行蒸发。根据柱色谱法用乙酸乙酯∶己烷为0∶100至60∶40(v/v)的溶液洗脱而对所产生的固体进行纯化,以得到6.56克(51%)标题化合物(LCMS RT=5.63分钟,MH+248)。
1H NMR(DMSO):10.89(1H,d,J 0.68Hz),8.82(1H,dd,J 1.7,4.7Hz),8.32(1H,dd,J 1.7,7.9Hz),8.08-8.02(2H,m),7.85(1H,dd,J 7.9,0.7Hz),7.81(1H,dt,J1.3,7.5Hz),7.73-7.65(2H,m)。
[3-(2-苯磺酰基-吡啶-3-基甲基)-5-氟-2-甲基-吲哚-1-基]-乙酸乙酯
在N2下将在干燥二氯甲烷(45毫升)中溶有如WO/2006/092579实例1中制备的(5-氟-2-甲基-吲哚-1-基)-乙酸乙酯(0.95克,4.04毫摩尔)与2-(苯磺酰基)异烟醛(1.0克,4.04毫摩尔)的溶液,缓慢添加(经5分钟)到在干燥二氯甲烷(12.5毫升)中溶有TMSOTf(1.46毫升,8.08毫摩尔)的冷却至0℃ 的搅拌溶液中。将该混合物搅拌15分钟并一次性添加三乙基硅烷(1.94毫升,12.12毫摩尔)。将反应混合物搅拌2小时30分钟,温热到室温,并通过缓慢添加NaHCO3饱和水溶液(10毫升)淬灭。用二氯甲烷萃取所产生的两相混合物。合并的有机层用盐水洗涤,用无水MgSO4干燥,过滤并进行蒸发。根据柱色谱法用乙酸乙酯∶己烷为0∶100至60∶40(v/v)的溶液洗脱而对所产生的固体进行纯化,以得到1.21克(64%)标题化合物(LCMS RT=6.63分钟,MH+466.8)。
1H NMR(CDCl3):8.38(1H,dd,J 1.6,4.5Hz),8.14-8.07(2H,m),7.67(3H,ddt,J 1.3,27.7,7.4Hz),7.40-7.34(1H,m),7.22(1H,dd,J 4.6,7.9Hz),7.12(1H,dd,J 4.2,8.9Hz),6.90(1H,dt,J 2.5,9.0Hz),6.72(1H,dd,J 2.4,9.5Hz),4.82(2H,s),4.62(2H,s),4.24(2H,q,J 7.2Hz),2.30(3H,s),1.29(3H,t,J 7.2Hz)。
(3-{[2-(苯磺酰基)吡啶-3-基]甲基}-5-氟-2-甲基吲哚-1-基)-乙酸(化合物1)
向在THF(26毫升)中溶有[3-(2-苯磺酰基-吡啶-3-基甲基)-5-氟-2-甲基-吲哚-1-基]-乙酸乙酯(1.20克,2.56毫摩尔)的搅拌溶液中添加氢氧化钾水溶液,该氢氧化钾水溶液含氢氧化钾(0.43克,7.68毫摩尔)和水(9毫升)。将产生的溶液在室温下搅拌3.5小时。在真空下除去THF并用HCl水溶液(0.1M,25毫升)酸化剩余水层。过滤收集产物,将产物用水洗涤且在真空下进行干燥,得到1.12克(100%)标题化合物(LCMS RT=4.58分钟,M+-H 437.2)。
1H NMR(DMSO):8.41-8.27(1H,m),8.06-7.91(2H,m),7.84-7.62(3H,m), 7.50-7.31(3H,m),6.93-6.78(2H,m),4.99(2H,s),4.55(2H,s),2.27(3H,s)。
实例2-[5-氟-3-({2-[(4-氟苯)磺酰基]吡啶-3-基}甲基)-2-甲基吲哚-1-基]-乙酸(化合物2)的制备
2-(4-氟苯磺酰基)-吡啶-3-甲醛
将2-氯-3-吡啶甲醛(4.04克,2.86毫摩尔)和4-氟苯亚磺酸钠盐(5.73克,3.14毫摩尔)溶于DMSO(100毫升)中并将混合物在100℃氮气下加热72小时。冷却至环境温度后,用水(500毫升)稀释混合物并用EtOAc(3x)萃取。合并的有机物用水、盐水洗涤,(采用MgSO4)干燥并蒸发到干燥状态,得到7.89克粗产物。将粗产物预先吸附到硅石上并根据干垫抽吸柱色谱法(dry pad suction column chromatography)使用庚烷及EtOAc梯度洗脱,得到4.14克(41%)呈黄色固体(薄片)的期望产物(MP=131-131.3℃;IR=1691cm-1;HPLC=7.21分钟>99%)。
1H NMR(400MHz;CDCl3):7.23-7.29(2H,m)7.60(1H,dd)8.05-8.10(2H,m)8.37(2H,dd)8.67(1H,dd)11.1(1H,s)。
13C NMR(100MHz,CDCl3):116.6(d)116.8(d)127.3(d)130.7(s)132.6(d)134.0(s)137.9(d)152.5(s)159.7(s)165.1(s)167.7(s)188.5(d)。
[5-氟-3-({2-[(4-氟苯)磺酰基]吡啶-3-基}甲基)-2-甲基吲哚-1-基]-乙酸乙酯
在0℃下将在干燥DCM(50毫升)中溶有(5-氟-2-甲基-吲哚-1-基)-乙酸乙酯(1.0克,4.4毫摩尔)与2-(4-氟苯磺酰基)-吡啶-3-甲醛(1.13克,4.3毫摩尔)的溶液经5-10分钟添加到在干燥DCM(15毫升)中溶有TMSOTf的搅拌溶液中。将混合物老化15分钟,然后一次性添加纯三乙基硅烷(2.05毫升,12.8毫摩尔)。将混合物再搅拌15小时并使其温热到环境温度。通过逐滴添加NaHCO3饱和溶液(10毫升)淬灭反应并用DCM(2x50毫升)萃取两相混合物。合并的有机物用盐水(50毫升)洗涤,随后(采用MgSO4)干燥并蒸发到干燥状态。以相同规模重复反应并分别纯化两种粗产物。根据柱色谱法使用庚烷与乙酸乙酯梯度对粗反应产物进行纯化,分别得到0.90克(43%)与1.50克(72%)具有不同纯度(根据HPLC为96.0%与94.5%)的呈淡紫色固体与褐色固体的期望化合物(MP=150.5-151.5℃,IR=1751cm-1;HPLC=12.24分钟)。
1H NMR(400MHz;CDCl3):1.26(3H,t)2.29(3H,s)4.22(2H,q)4.62(2H,s)4.80(2H,s)6.79(1H,dd)6.86(1H,ddd)7.10(1H,dd)7.19(1H,dd)7.23-7.28(2H,m)7.36(1H,dd)8.05-8.11(2H,m)8.29(1H,dd)。
13C NMR(100MHz,CDCl3):10.4(q)14.2(q)25.3(t)45.2(t)61.9(t)103.4(d)103.6(d)108.0(s)108.1(s)109.1(d)109.2(d)109.5(d)109.8(d)116.2(d)116.4(d)127.0(d)128.5(s)128.6(s)132.2(d)132.3(d)133.3(s)135.1(s)136.4(s)136.6(s)139.4(d)146.2(d)156.2(s)157.0(s)159.4(s)164.7(s)167.3(s)168.6(s)。
[5-氟-3-({2-[(4-氟苯)磺酰基]吡啶-3-基}甲基)-2-甲基吲哚-1-基]-乙酸(化合物2)
将KOH(0.34克,5.94毫摩尔)溶于水(7毫升)中,并将该KOH水溶液在氮气及环境温度下添加到在THF(21毫升)中溶有[5-氟-3-({2-[(4-氟苯)磺酰基]吡啶-3-基}甲基)-2-甲基吲哚-1-基]-乙酸乙酯(0.96克,1.98毫摩尔)的剧烈搅拌的溶液中。由TLC和LCMS监测反应。2小时后,在真空下除去溶剂,然后使用0.1M HCl溶液将pH调节到1.5。将沉淀物剧烈搅拌15分钟,然后通过抽吸过滤进行分离。用水且随后用MTBE洗涤所收集固体,在空气中抽干且随后在真空50℃下进行干燥,得到870毫克(97%)呈粉红色固体的产物(MP=125-126℃;IR=1729cm-1;HPLC=10.80分钟99.3%)。
1H NMR(400MHz;DMSO):2.29(3H,s)4.56(2H,s)4.97(2H,s)6.85-6.91(2H,m)7.37-7.7.45(2H,m)7.47(1H,dd)7.51-7.57(2H,m)8.06-8.15(2H,m)8.36(1H,dd)。
13C NMR(100MHz,DMSO):10.5(q)25.0(t)45.5(t)102.7(d)102.9(d)107.7(s)107.8(s)108.8(d)109.1(d)110.9(d)111.0(d)117.1(d)117.3(d)128.1(d)128.2(d)128.3(d)132.7(d)132.8(d)133.8(d)135.5(s)136.8(s)138.1(s)140.4(d)147.0(d)155.9(s)156.6(s)158.9(s)164.6(s)167.1(s)171.1(s)。
实例3-[3-({2-[(4-氯苯)磺酰基]吡啶-3-基}甲基)-5-氟-2-甲基吲哚-1-基]-乙 酸(化合物3)的制备
2-(4-氯苯磺酰基)-吡啶-3-甲醛
在氮气下将2-氯-3-吡啶甲醛(5.0克,35.0毫摩尔)和4-氯苯亚磺酸钠盐(7.75克,38.8毫摩尔)溶于DMSO(120毫升)中并将混合物在100℃下加热72小时。冷却至环境温度后,用水(500毫升)稀释混合物并用EtOAc(3x)进行萃取。合并的有机物用水、盐水洗涤,(采用MgSO4)干燥且蒸发到干燥状态,得到8.1克粗产物。将粗产物物预先吸附到硅石上且根据干垫抽吸柱色谱法用庚烷及EtOAc梯度洗脱,得到4.62克(61%)呈白色粉末状固体的期望产物(MP=100.5-101℃;IR=1698cm-1;HPLC=8.00分钟>99%)。
1H NMR(400MHz;CDCl3):7.56(1H,dd)7.60(1H,dd)7.99(1H,dd)8.38(1H,dd)8.67(1H,dd)11.1(1H,s)。
13C NMR(100MHz,CDCl3):127.3(d)129.6(d)130.8(s)131.1(d)136.5(s)138.0(d)141.4(s)152.5(d)159.5(s)188.4(d)。
[3-({2-[(4-氯苯)磺酰基]吡啶-3-基}甲基)-5-氟-2-甲基-吲哚-1-基]-乙酸乙酯
在0℃下将在干燥DCM(50毫升)中溶有(5-氟-2-甲基-吲哚-1-基)-乙酸乙酯(1.0克,4.25毫摩尔)与2-(4-氯苯磺酰基)-吡啶-3-甲醛(1.19克,4.22毫摩 尔)的溶液经5-10分钟添加到在干燥DCM(15毫升)中溶有TMSOTf的搅拌溶液中。将混合物老化15分钟,然后一次性添加纯三乙基硅烷(2.05毫升,12.7毫摩尔)。将混合物再搅拌15小时并使其温热到环境温度。通过逐滴添加NaHCO3饱和溶液(10毫升)淬灭反应并用DCM(2x 50毫升)萃取两相混合物。合并的有机物用盐水(50毫升)洗涤,随后(采用MgSO4)干燥并蒸发到干燥状态。以相同规模重复反应且合并两粗产物。根据柱色谱法使用庚烷和乙酸乙酯梯度对粗反应产物进行纯化,得到1.80克(42%)呈浅橙色固体的期望化合物(MP=124.6-124.9℃;IR=1741cm-1;HPLC=12.75分钟97.3%)。
1H NMR(400MHz;CDCl3):1.26(3H,t)2.29(3H,s)4.20(2H,q)4.62(2H,s)4.80(2H,s)6.80(1H,dd)6.87(1H,ddd)7.10(1H,dd)7.19(1H,dd)7.37(1H,dd)7.54(2H,dd)8.00(2H,dd)8.28(1H,dd)。
13C NMR(100MHz,CDCl3):10.4(q)14.3(q)25.3(t)45.2(t)61.9(t)103.4(d)103.6(d)108.0(s)108.1(s)109.2(d)109.2(d)109.5(d)109.8(d)127.0(d)128.5(s)128.6(s)129.3(d)130.8(d)133.3(s)136.4(s)136.6(s)137.6(s)139.4(d)140.5(s)146.2(d)156.1(s)157.0(s)159.4(s)168.6(s)。
[3-({2-[(4-氯苯)磺酰基]吡啶-3-基}甲基)-5-氟-2-甲基吲哚-1-基]-乙酸(化合物3)
将KOH(0.60克,10.7毫摩尔)溶于水(14毫升)中,且将该KOH水溶 液在氮气及环境温度下添加到在THF(40毫升)中溶有[3-({2-[(4-氯苯)磺酰基]吡啶-3-基}甲基)-5-氟-2-甲基吲哚-1-基]-乙酸乙酯(1.17克,3.49毫摩尔)的剧烈搅拌的溶液中。由TLC和LCMS监测反应。2小时后,在真空下除去溶剂,然后使用0.1M HCl溶液将pH调节到1.5。将沉淀物剧烈搅拌15分钟,然后通过抽吸过滤进行分离。用水且随后用MTBE洗涤所收集固体,在空气中抽干且随后在真空50℃下干燥,得到1.31克(78%)呈粉红色固体的标题化合物(MP=125.2-126℃;IR=1729cm-1;HPLC=11.37分钟>99%)。
1H NMR(400MHz;DMSO):2.29(3H,s)4.56(2H,s)4.96(2H,s)6.85-6.91(2H,m)7.39(1H,dd)7.44(1H,dd)7.49(1H,dd)7.76-7.79(2H,m)8.00-8.8.03(2H,m)8.36(1H,dd)。
13C NMR(100MHz,DMSO):10.5(q)25.0(t)45.6(t)102.7(d)102.9(d)107.6(s)107.7(s)108.8(d)109.0(d)110.9(d)111.0(d)128.1(d)130.0(d)131.4(d)133.9(d)136.9(s)138.1(d)139.8(s)140.5(s)147.1(d)155.7(s)156.5(s)158.9(s)171.1(s)。
在以下实例中,对照以下比较化合物对化合物1-3进行测试:
化合物B、C和E是使用与化合物1所使用方法类似的方法来制备的。化合物A是WO 2005/044260的化合物17且该化合物的制备方法在该文献的实例1中进行了说明。化合物D是WO 2006/095183的化合物1且其制备方法阐述于该文献的实例1中。
实例4-CRTH2拮抗活性的测量
材料与方法
材料
单体聚合分解(Monopolyresolving)培养基来自日本大阪Dainippon Pharmaceuticals(大日本制药)。Macs抗-CD16微珠来自萨里比斯利(Bisley,Surrey)Miltenyi biotec(米尔泰尼生物技术)。ChemoTx板购自MD盖瑟斯堡(Gaithersburg,MD)Neuroprobe。经聚-D-赖氨酸涂布的96-孔板来自英国格洛斯特郡(Gloucestershire,UK)Greiner(格雷纳)。[3H]PGD2来自英国白金汉郡(Buckinghamshire,UK)Amersham Biosciences(阿麦斯罕生物科学)。[3H]SQ29548购自英国白金汉郡(Buckinghamshire,UK)Perkin Elmer Life Sciences(珀金埃尔默生命科学)。除非另有说明,否则所有其他试剂均来自英国多塞特(Dorset,UK)Sigma-Aldrich(西格玛-奥尔德里奇)。
方法
细胞培养
用CRTH2或DP受体(CHO/CRTH2与CHO/DP)转染中国仓鼠卵巢细胞,并在潮湿气氛37℃(5%CO2)下将该细胞保持在最小基础培养基(MEM,Minimum Essential Medium)中进行培养,该培养基补充有10%胎牛血清、2mM谷氨酰胺和1mg·ml-1活性G418。每2-3天对细胞进行传代培养。对于放射性配体结合分析,在三角瓶或175em2方瓶(对于膜制备)中制备细胞。
细胞膜的制备
从CHO/CRTH2和CHO/DP细胞、或者从血小板(作为TP受体源)制备膜。用PBS洗涤生长至融合状态的CHO细胞并使用维尔烯(Versene)溶液(15毫升/瓶)分离。当细胞在175cm2方瓶中生长时,通过刮擦收集于PBS中。对细胞悬浮液进行离心(1,700rpm,10分钟,4℃)并再悬浮于15毫升缓冲液(1xHBSS,补充有10mM HEPES,pH 7.3)中。随后使用试管分散机(Ultra Turrax)在4-6档下将细胞悬浮液均匀搅拌20秒。使均匀混合物在1,700rpm下离心10分钟且收集上清液并在4℃及20,000rpm下离心1小时。将所产生沉淀物薄片再悬浮于缓冲液中且以200-500微升小份储存在-80℃下。根据考马斯亮兰法(Bradford)(1976)使用牛血清白蛋白作为标准测定蛋白质浓度。通过在600xg下离心10分钟来洗涤血小板且再悬浮于冰冷分析缓冲液(10mMTris-HCl,pH 7.4,5mM葡萄糖,120mM NaCl,10μM吲哚美辛)中并在4℃及20,000rpm下直接离心30分钟。对所产生沉淀物薄片进行处理,如上所述。
放射性配体结合分析
在上述所制备的膜上进行[3H]PGD2(160Ci/mmol)结合实验。在最终体积100微升缓冲液(1XHBSS/HEPES 10mM,pH 7.3)中进行分析。使细胞膜(15微克)在室温下与不同浓度的竞争配体一起预培育15分钟。随后添加[3H]PGD2并在室温下再继续培育1小时。将200微升冰冷分析缓冲液添加到各孔中终止反应,随后借助Unifilter细胞收集器(PerkinElmer Life Sciences(珀金埃尔默生命科学))通过Whatman GF/B玻璃纤维过滤器迅速过滤,并用300微升冰冷缓冲液洗涤6次。将Unifilter板在室温下干燥至少1小时且在液闪计数器(Beta Trilux counter)(PerkinElmer Life Sciences(珀金埃尔默生命科学))上测定过滤器上所保留的放射性,随后添加40微升Optiphase Hi-Safe 3(Wallac)闪烁液。在10μM未标记的PGD2存在下定义非特异性结合。一式两份实施分析。
表1中显示了针对CRTH2的放射性配体结合实验的结果。
表1-放射性配体结合数据(CRTH2受体上,Ki)
化合物 | Ki(nM) |
化合物1 | 2 |
化合物2 | 2 |
化合物3 | 7 |
化合物A | 7 |
化合物B | 1 |
化合物C | 979 |
化合物D | 1 |
化合物E | 258 |
化合物C与E仅极其微弱地结合至CRTH2受体且因此不再进行测试。
实例5-人体全血嗜酸性粒细胞形变分析
分析化合物1-3对PGD2引起的嗜酸性粒细胞形变的影响并与对比化合物A、B和D进行比较。
方法
全血中的形变分析
将化合物(1微升,200x最终浓度)直接添加到200微升全血中,混合均匀并在37℃与5%CO2下培育15分钟。随后,通过添加300微升CytofixTM缓冲液(BD Biosciences(BD生物科学))固定细胞形状,在冰上固定15分钟。在室温下将10毫升RBC溶胞缓冲液添加到固定细胞中,培育5分钟,且在300xg下离心5分钟。除去上清液(含有裂解的红细胞)并重复溶胞步骤。将白细胞再悬浮于250微升RPMI/10%FCS中并由FACS分析形变。根据嗜酸性粒细 胞的自体荧光将其弃出且每个样品计数为2000个嗜酸性粒细胞事件。一式三份对数据进行分析。
表2中显示了嗜酸性粒细胞形变分析的结果。
表2-人体全血中测试化合物对10nM PGD2引起的嗜酸性粒细胞形变的影响的IC50值
化合物 | 值(nM) |
1 | 9 |
2 | 2.5 |
3 | 10 |
A | 8 |
B | 34 |
D | 8 |
在嗜酸性粒细胞形变测试中,最适合用作药剂的化合物的IC50值介于约1与10nM之间。因此,尽管化合物B特异性地结合至CRTH2受体(表1),但其在生理条件下不是特别强效的CRTH2拮抗剂。
特别值得注意的是,结构与化合物1最接近的对比化合物是化合物B和C。这些化合物当中,化合物C未特异性结合至CRTH2受体且化合物B远不如化合物1强效。
实例6-微粒体稳定性
测试化合物的微粒体稳定性根据以下方法测定。
使1微摩尔测试化合物与人体肝微粒体(总蛋白质浓度0.3毫克/毫升)一起培育60分钟。1小时后测量样品中剩余测试化合物的百分比,以测定测试化 合物的代谢速率。结果显示在表3中,表3给出两个实验的结果并得到平均值。
表3-微粒体稳定性测试结果
化合物 | 测试浓度(M) | 平均剩余的母体(%) |
1 | 1x10-6 | 96 |
2 | 1x10-6 | 98 |
B | 1x10-6 | 69 |
C | 1x10-6 | 90 |
D | 1x10-6 | 24 |
表3中所显示的结果表明,120分钟后,96%的化合物1与98%的化合物2在人体肝微粒体中未被代谢。将其分别与化合物B与C(化合物B与C是化合物1的位置异构体)的值69%与90%进行比较,且化合物D的值仅为24%。
因此,总而言之,这些实例中所描述的实验表明,化合物C与E未强烈地结合至CRTH2受体,化合物B在全血嗜酸性粒细胞形变分析中的活性远不如化合物1,且化合物D在人类微粒体中具有较低的稳定性,这限制了其作为药剂的效用性。化合物1-3作为CRTH2拮抗剂的活性令人惊奇且与其结构上最为密切相关的化合物相比令人惊奇地稳定。
此外,与化合物A相比,本发明化合物在狗活体内具有明显改善的药代动力学。化合物1与2的血浆半衰期分别为3小时与5小时,而化合物A的半衰期仅为1小时。
Claims (20)
1.一种化合物,所述化合物选自(3-{[2-(苯磺酰基)吡啶-3-基]甲基}-5-氟-2-甲基吲哚-1-基)-乙酸、[5-氟-3-({2-[(4-氟苯)磺酰基]吡啶-3-基}甲基)-2-甲基吲哚-1-基]-乙酸或它们的药学上可接受的盐。
2.一种化合物,所述化合物选自(3-{[2-(苯磺酰基)吡啶-3-基]甲基}-5-氟-2-甲基吲哚-1-基)-乙酸和[5-氟-3-({2-[(4-氟苯)磺酰基]吡啶-3-基}甲基)-2-甲基吲哚-1-基]-乙酸的C1-6烷基酯或苄基酯。
3.一种用于制备权利要求1所述的化合物的方法,该方法包括使权利要求2所述的化合物与碱反应。
4.一种根据权利要求1所述的化合物在制备药剂中的用途,所述药剂用来治疗或预防:变应性哮喘、常年性变应性鼻炎、季节性变应性鼻炎、特应性皮炎、接触过敏、结膜炎、嗜酸粒细胞性支气管炎、食物过敏、嗜酸粒细胞性胃肠炎、炎症性肠病、肥大细胞增多症、高IgE综合征、多发性硬化症、慢性阻塞性肺疾病、纤维化病况、鼻息肉病、大疱性表皮松解症荨麻疹、食道炎、肥大细胞增多症和穆-韦二氏综合症。
5.一种包含权利要求1所述的化合物作为活性成分,以及医药赋形剂或载体的医药组合物。
6.如权利要求5所述的组合物,该组合物经配制用于口、直肠、鼻、支气管、局部、阴道或非肠胃给药。
7.如权利要求5或6所述的组合物,该组合物含有一种或多种额外的活性剂,该活性剂用于治疗由作用于所述CRTH2受体的PGD2或其他激动剂所介导的疾病及病况。
8.如权利要求7所述的组合物,其特征在于,所述额外的活性剂选自:
其他CRTH2拮抗剂;
甲磺司特及类似化合物;
β2肾上腺素受体激动剂;
抗组胺;
α1与α2肾上腺素受体激动剂;
趋化因子受体功能的调节剂;
白三烯拮抗剂;
白三烯生物合成抑制剂;
磷酸二脂酶抑制剂,;
抗-IgE抗体治疗;
抗感染药;
抗真菌药;
免疫抑制剂;
免疫治疗剂,;
皮质类固醇;
CRTH2拮抗剂与针对炎症适应症所开发的治疗剂结合使用,该治疗剂选自:
作用于其他受体的PGD2的其他拮抗剂;
调节细胞因子产生的药物;
调节Th2细胞因子IL-4与IL-5活性的药物;
PPAR-γ激动剂;或采用
抗-RSV抗体。
9.一种用于制备权利要求5-8中任一项所述的医药组合物的方法,该方法包括使权利要求1所述的化合物与医药上或兽医学上可接受的载体或媒剂联合或结合。
10.一种包含权利要求1所述的化合物与一种或多种权利要求8中所列的作为组合制剂的药剂的产品,该产品在治疗由作用于CRTH2受体的PGD2或其他激动剂所介导的疾病或病况中同时、单独或依次使用。
11.如权利要求4所述的用途,其特征在于,所述药剂还包含额外的活性剂,该活性剂用于治疗由作用于所述CRTH2和/或DP受体的PGD2或其他激动剂所介导的疾病及病况。
12.如权利要求11所述的用途,其特征在于,所述额外的活性剂是权利要求8中所列的药剂中的一种。
13.一种用于治疗由作用于CRTH2受体的PGD2所介导的疾病或病况的套组,该套组包括:
(a)第一外壳,该外壳包含权利要求1所述的化合物;及
(b)第二外壳,该外壳包含额外的药剂,该额外的药剂用于治疗由作用于所述CRTH2受体的PGD2或其他激动剂所介导的疾病或病况。
14.如权利要求13所述的套组,其特征在于,所述额外的活性剂选自权利要求8中所列的药剂。
15.如权利要求4所述的用途,用于制备用来治疗或预防:接触性皮炎、变应性结膜炎、春季角结膜炎、特应性角结膜炎、溃疡性结肠炎和克罗恩氏病的药剂。
16.如权利要求6所述的组合物,该组合物经配制用于支气管吸入、滴眼剂、颊内、舌下、皮下、肌内、静脉内或真皮内给药。
17.如权利要求8所述的组合物,所述额外的活性剂选自间羟异丙肾上腺素、异丙肾上腺素、沙丁胺醇、羟甲叔丁肾上腺素、福莫特罗、沙美特罗、茚达特罗、特普他林、奥西那林、双甲苯喘定甲磺酸盐、吡布特罗或甲基黄嘌呤、肥大细胞稳定剂或毒蕈碱性受体拮抗剂,组胺H1受体拮抗剂或H4受体拮抗剂,六氢脱氧麻黄碱、苯肾上腺素、苯丙醇胺、假麻黄碱、盐酸萘甲唑林、盐酸羟甲唑啉、盐酸四氢萘唑啉、盐酸赛洛唑啉、盐酸乙基去甲肾上腺素,CCR1、CCR2、CCR2A、CCR2B、CCR3、CCR4、CCR5、CCR6、CCR7、CCR8、CCR9、CCR10和对于C-C族的CCR11或CXCR1、CXCR2、CXCR3、CXCR4和对于C-X-C族的CXCR5和对于C-X3-C族的CX3CR1,孟鲁司特、扎鲁司特,5-脂氧合酶抑制剂或5-脂氧合酶活化蛋白抑制剂,罗氟司特,奥马佐单抗,夫西地酸,克霉唑,他克莫司及针对炎症性皮肤病情况的吡美莫司,或者可替代的FK-506、雷帕霉素、环孢菌素、硫唑嘌呤或甲氨蝶呤,格瑞萨斯,泼尼松、泼尼松龙、氟尼缩松、曲安奈德、二丙酸倍氯米松、布地奈德、丙酸氟替卡松-糠酸莫米松和促进Th1细胞因子响应的糠酸氟替卡松药物。
18.如权利要求17所述的组合物,所述额外的活性剂选自茶碱和氨茶碱、色甘酸钠或噻托溴胺;氯雷他定、西替利嗪、地氯雷他定、左西替利嗪、非索非那定、阿司咪唑、氮卓斯汀和氯苯那敏;齐留通、ABT-761、芬留顿、替泊沙林、Abbott-79175、N-(5-经取代)-噻吩-2-烷基磺酰胺、2,6-二-叔丁基苯酚腙、甲氧基四氢吡喃,吡啶基-经取代-2-氰基萘化合物、2-氰基喹啉化合物、吲哚和喹啉化合物,干扰素、TNF或GM-CSF。
19.如权利要求8所述的组合物,所述治疗剂选自DP拮抗剂,TNFα转化酶抗-TNF单克隆抗体的抑制剂、TNF受体免疫球蛋白分子、其他TNF异构体的抑制剂、非选择性COX-1/COX-2抑制剂、双氯芬酸、丙酸类、芬那酯类、吡唑啉酮类、水杨酸类和COX-2抑制剂,阻断单克隆抗体和可溶性受体,罗格列酮,Synagis与将来可用于治疗鼻病毒感染的药剂。
20.如权利要求19所述的组合物,所述治疗剂选自吡罗昔康、萘普生、氟苯布洛芬、非诺洛芬、酮洛芬和布洛芬、甲芬那酸、吲哚美辛、舒林酸和阿扎丙宗、苯丁唑酮、阿司匹林、美洛昔康、塞来考昔、罗非考昔、伐地考昔和艾托考昔、低剂量甲氨蝶呤、来氟米特、环索奈德、羟氯喹、D-青霉胺、金诺芬或非肠胃或口服金,干扰素-α、干扰素-β或其他干扰素。
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0800874A GB0800874D0 (en) | 2008-01-18 | 2008-01-18 | Compounds having CRTH2 antagonist activity |
GB0800874.0 | 2008-01-18 | ||
GB0820526.2 | 2008-11-10 | ||
GB0820526A GB0820526D0 (en) | 2008-11-10 | 2008-11-10 | Compounds having crth2 antagonist activity |
PCT/GB2009/000142 WO2009090414A1 (en) | 2008-01-18 | 2009-01-19 | Compounds having crth2 antagonist activity |
Publications (2)
Publication Number | Publication Date |
---|---|
CN101932571A CN101932571A (zh) | 2010-12-29 |
CN101932571B true CN101932571B (zh) | 2014-04-23 |
Family
ID=40473418
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN200980103456.8A Expired - Fee Related CN101932571B (zh) | 2008-01-18 | 2009-01-19 | 具有crth2拮抗活性的化合物 |
Country Status (25)
Country | Link |
---|---|
US (1) | US20090186923A1 (zh) |
EP (1) | EP2250161B1 (zh) |
JP (2) | JP2011509988A (zh) |
KR (1) | KR101644170B1 (zh) |
CN (1) | CN101932571B (zh) |
AU (1) | AU2009204700B2 (zh) |
BR (1) | BRPI0906786B1 (zh) |
CA (1) | CA2712017C (zh) |
CY (1) | CY1114748T1 (zh) |
DK (1) | DK2250161T3 (zh) |
ES (1) | ES2442717T3 (zh) |
HK (1) | HK1145175A1 (zh) |
HR (1) | HRP20140045T1 (zh) |
IL (1) | IL206959A (zh) |
MA (1) | MA32075B1 (zh) |
MX (1) | MX2010007833A (zh) |
MY (1) | MY155133A (zh) |
NZ (1) | NZ587251A (zh) |
PL (1) | PL2250161T3 (zh) |
PT (1) | PT2250161E (zh) |
RS (1) | RS53142B (zh) |
RU (1) | RU2503672C2 (zh) |
SI (1) | SI2250161T1 (zh) |
WO (1) | WO2009090414A1 (zh) |
ZA (1) | ZA201005799B (zh) |
Families Citing this family (50)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6962940B2 (en) | 2002-03-20 | 2005-11-08 | Celgene Corporation | (+)-2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione: methods of using and compositions thereof |
GB0324763D0 (en) | 2003-10-23 | 2003-11-26 | Oxagen Ltd | Use of compounds in therapy |
US20100298368A1 (en) * | 2007-11-06 | 2010-11-25 | Amira Pharmaceuticals, Inc. | Antagonists of pgd2 receptors |
WO2009061676A2 (en) * | 2007-11-06 | 2009-05-14 | Amira Pharmaceuticals, Inc. | Antagonists of pgd2 receptors |
US20110124683A1 (en) * | 2007-11-13 | 2011-05-26 | Oxagen Limited | Use of CRTH2 Antagonist Compounds |
US7750027B2 (en) * | 2008-01-18 | 2010-07-06 | Oxagen Limited | Compounds having CRTH2 antagonist activity |
MX2010007833A (es) * | 2008-01-18 | 2010-08-11 | Oxagen Ltd | Compuestos que tienen actividad antagonista de crth2. |
JP2011509991A (ja) * | 2008-01-22 | 2011-03-31 | オキサジェン リミテッド | Crth2アンタゴニスト活性を有する化合物 |
WO2009093026A1 (en) * | 2008-01-22 | 2009-07-30 | Oxagen Limited | Compounds having crth2 antagonist activity |
BRPI0907364A2 (pt) | 2008-02-01 | 2015-07-14 | Amira Pharmaceuticals Inc | Antagonistas aminoalquilbifenil n,n-disubstituídos de receptores d2 de prostaglandina |
US8242145B2 (en) * | 2008-02-14 | 2012-08-14 | Panmira Pharmaceuticals, Llc | Cyclic diaryl ether compounds as antagonists of prostaglandin D2 receptors |
US8497381B2 (en) | 2008-02-25 | 2013-07-30 | Panmira Pharmaceuticals, Llc | Antagonists of prostaglandin D2 receptors |
WO2009145989A2 (en) * | 2008-04-02 | 2009-12-03 | Amira Pharmaceuticals, Inc. | Aminoalkylphenyl antagonists of prostaglandin d2 receptors |
US20110112134A1 (en) * | 2008-05-16 | 2011-05-12 | Amira Pharmaceuticals, Inc. | Tricyclic Antagonists of Prostaglandin D2 Receptors |
US8501959B2 (en) * | 2008-06-24 | 2013-08-06 | Panmira Pharmaceuticals, Llc | Cycloalkane[B]indole antagonists of prostaglandin D2 receptors |
US20110190227A1 (en) * | 2008-07-03 | 2011-08-04 | Amira Pharmaceuticals, Inc. | Antagonists of Prostaglandin D2 Receptors |
GB2463788B (en) * | 2008-09-29 | 2010-12-15 | Amira Pharmaceuticals Inc | Heteroaryl antagonists of prostaglandin D2 receptors |
US8378107B2 (en) | 2008-10-01 | 2013-02-19 | Panmira Pharmaceuticals, Llc | Heteroaryl antagonists of prostaglandin D2 receptors |
WO2010042652A2 (en) | 2008-10-08 | 2010-04-15 | Amira Pharmaceuticals, Inc. | Heteroalkyl biphenyl antagonists of prostaglandin d2 receptors |
GB2465062B (en) * | 2008-11-06 | 2011-04-13 | Amira Pharmaceuticals Inc | Cycloalkane(B)azaindole antagonists of prostaglandin D2 receptors |
WO2010057118A2 (en) | 2008-11-17 | 2010-05-20 | Amira Pharmaceuticals, Inc. | Heterocyclic antagonists of prostaglandin d2 receptors |
CN102596199A (zh) * | 2009-07-31 | 2012-07-18 | 潘米拉制药公司 | Dp2受体拮抗剂的眼用医药组合物 |
MX2012001542A (es) * | 2009-08-05 | 2012-06-19 | Panmira Pharmaceuticals Llc | Antagonista dp2 y usos del mismo. |
KR20120115989A (ko) | 2010-01-06 | 2012-10-19 | 판미라 파마슈티칼스, 엘엘씨 | Dp2 길항제 및 이의 용도 |
SI2558447T1 (sl) | 2010-03-22 | 2015-01-30 | Actelion Pharmaceuticals Ltd. | Derivati 3-(heteroaril-amino)-1,2,3,4-tetrahidro-9h-karbazola in njihova uporaba kot modulatorji prostaglandinskega receptorja d2 |
GB201103837D0 (en) | 2011-03-07 | 2011-04-20 | Oxagen Ltd | Amorphous (5-Fluoro-2-Methyl-3-Quinolin-2-Ylmethyl-Indol-1-Yl)-acetic acid |
PT2697223T (pt) | 2011-04-14 | 2016-10-14 | Actelion Pharmaceuticals Ltd | Derivados de ácido 7-(heteroaril-amino)-6,7,8,9-tetraidropirido[1,2-a]indolacético e utilização dos mesmos como moduladores do recetor d2 de prostaglandina |
SI2781508T1 (sl) * | 2011-11-17 | 2019-03-29 | Kbp Biosciences Co., Ltd. | Zlite obročne spojine, ki vsebujejo dušik za uporabo kot antagonisti CRTH2 |
GB201121557D0 (en) | 2011-12-15 | 2012-01-25 | Oxagen Ltd | Process |
CN104114169A (zh) * | 2011-12-16 | 2014-10-22 | 阿托佩斯治疗有限公司 | 用于治疗嗜酸细胞性食管炎的crth2拮抗剂和质子泵抑制剂的组合物 |
WO2014009302A1 (en) * | 2012-07-10 | 2014-01-16 | F. Hoffmann-La Roche Ag | Novel indazoles for the treatment and prophylaxis of respiratory syncytial virus infection |
WO2014088113A1 (en) | 2012-12-04 | 2014-06-12 | Millennium Pharmaceuticals, Inc. | Prophylactic or therapeutic method for sjogren's syndrome using specific ccr9 receptor inhibitors/antagonists |
NZ628320A (en) * | 2013-03-14 | 2017-04-28 | Celgene Corp | Treatment of psoriatic arthritis using apremilast |
GB201322273D0 (en) * | 2013-12-17 | 2014-01-29 | Atopix Therapeutics Ltd | Process |
AU2014373683B2 (en) * | 2013-12-31 | 2020-05-07 | Rapamycin Holdings, Llc | Oral rapamycin nanoparticle preparations and use |
CN106103435B (zh) | 2014-03-17 | 2018-11-16 | 爱杜西亚药品有限公司 | 氮杂吲哚乙酸衍生物及彼等作为前列腺素d2受体调节剂的用途 |
WO2015140701A1 (en) | 2014-03-18 | 2015-09-24 | Actelion Pharmaceuticals Ltd | Azaindole acetic acid derivatives and their use as prostaglandin d2 receptor modulators |
GB201407807D0 (en) * | 2014-05-02 | 2014-06-18 | Atopix Therapeutics Ltd | Polymorphic form |
GB201407813D0 (en) * | 2014-05-02 | 2014-06-18 | Atopix Therapeutics Ltd | Polymorphic form |
GB201407820D0 (en) * | 2014-05-02 | 2014-06-18 | Atopix Therapeutics Ltd | Polymorphic form |
JPWO2015190316A1 (ja) * | 2014-06-09 | 2017-04-20 | 住友化学株式会社 | ピリジン化合物の製造方法 |
US10092541B2 (en) | 2014-08-15 | 2018-10-09 | Celgene Corporation | Methods for the treatment of diseases ameliorated by PDE4 inhibition using dosage titration of apremilast |
CN108026093B (zh) | 2015-09-15 | 2021-11-16 | 爱杜西亚药品有限公司 | 结晶形式 |
RU2020106383A (ru) | 2017-08-14 | 2021-09-16 | Аллерган, Инк. | 3,4-двузамещенные 3-циклобутен-1,2-дионы и их применение |
WO2020143793A1 (zh) * | 2019-01-10 | 2020-07-16 | 石药集团中奇制药技术(石家庄)有限公司 | 杂环化合物盐及其应用 |
CN114796264A (zh) * | 2021-01-27 | 2022-07-29 | 北京北工大科技园有限公司 | 金络合物在制备治疗新型冠状病毒肺炎的药物中的应用 |
KR20230024976A (ko) * | 2020-06-12 | 2023-02-21 | 누크미토 파마슈티컬스 컴퍼니, 리미티드 | 인덴 화합물, 이의 약제학적 조성물, 및 이의 치료학적 적용 |
CN117916215A (zh) * | 2021-05-15 | 2024-04-19 | 藤济(厦门)生物医药科技有限公司 | 茚化合物、其药物组合物及其治疗应用 |
CN115192584A (zh) * | 2022-06-09 | 2022-10-18 | 南方科技大学 | 一种纳米药物及其制备方法和应用 |
WO2024104384A1 (en) * | 2022-11-16 | 2024-05-23 | Nucmito Pharmaceuticals Co. Ltd. | Indene compounds, pharmaceutical compositions thereof, and their therapeutic applications |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0054417A1 (en) * | 1980-12-15 | 1982-06-23 | Pfizer Limited | Indole thromboxane synthetase inhibitors, processes for their preparation, and pharmaceutical compositions containing them |
WO2005044260A1 (en) * | 2003-10-23 | 2005-05-19 | Oxagen Limited | Use of crth2 antagonist compounds in therapy |
WO2006095183A1 (en) * | 2005-03-11 | 2006-09-14 | Oxagen Limited | 1-acetic acid-indole derivatives with pgd2 antagonist activity |
WO2009077728A1 (en) * | 2007-12-14 | 2009-06-25 | Argenta Discovery Limited | Indoles and their therapeutic use |
Family Cites Families (37)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3557142A (en) | 1968-02-20 | 1971-01-19 | Sterling Drug Inc | 4,5,6,7-tetrahydro-indole-lower-alkanoic acids and esters |
BE790679A (fr) | 1971-11-03 | 1973-04-27 | Ici Ltd | Derives de l'indole |
GB1407658A (en) | 1973-03-06 | 1975-09-24 | Ici Ltd | Process for the manufacture of indole derivatives |
GB1460348A (en) | 1974-02-04 | 1977-01-06 | Ici Ltd | Quinazoline derivativesa |
DK151884C (da) | 1979-03-07 | 1988-06-13 | Pfizer | Analogifremgangsmaade til fremstilling af 3-(1-imidazolylalkyl)indolderivater eller farmaceutisk acceptable syreadditionssalte deraf |
GB8607294D0 (en) | 1985-04-17 | 1986-04-30 | Ici America Inc | Heterocyclic amide derivatives |
GB9122590D0 (en) | 1991-10-24 | 1991-12-04 | Lilly Industries Ltd | Pharmaceutical compounds |
DE69734141T2 (de) | 1996-06-05 | 2006-07-13 | Bml Inc. | PROTEIN, DAS FÜR MENSCHLICHE Th2-ZELLEN SPEZIFISCH IST, DAFÜR KODIERENDES GEN UND KORRESPONDIERENDE TRANSFORMANTE, REKOMBINANTER VEKTOR UND MONOKLONALER ANTKÖRPER |
US6916841B2 (en) | 1998-02-25 | 2005-07-12 | Genetics Institute, Llc | Inhibitors of phospholipase enzymes |
OA11622A (en) | 1998-03-31 | 2004-09-16 | Inst For Pharm Discovery Inc | Substituted indolealkanoic acids. |
TNSN99224A1 (fr) | 1998-12-01 | 2005-11-10 | Inst For Pharm Discovery Inc | Methodes de reduction des niveaux de glucose et triglyceride en serum et pour suppression de l'antigenese utilisant les acides la indolealkanoique |
GB9902461D0 (en) * | 1999-02-05 | 1999-03-24 | Zeneca Ltd | Chemical compounds |
WO2001014882A1 (fr) | 1999-08-23 | 2001-03-01 | Bml, Inc. | Identification des proprietes d'une substance pour les recepteurs de prostaglandine d |
KR20010113739A (ko) | 2000-01-14 | 2001-12-28 | 요트.게.아. 롤페즈 | 디스플레이 디바이스 |
WO2001064205A2 (en) | 2000-03-02 | 2001-09-07 | The Institutes For Pharmaceutical Discovery, Llc | Compositions containing a substituted indolealkanoic acid and an angiotensin converting enzyme inhibitor |
JP2001247570A (ja) | 2000-03-08 | 2001-09-11 | Japan Tobacco Inc | インドール酢酸化合物及びその製造方法 |
US6878522B2 (en) | 2000-07-07 | 2005-04-12 | Baiyong Li | Methods for the identification of compounds useful for the treatment of disease states mediated by prostaglandin D2 |
SE0200411D0 (sv) | 2002-02-05 | 2002-02-05 | Astrazeneca Ab | Novel use |
SE0200356D0 (sv) | 2002-02-05 | 2002-02-05 | Astrazeneca Ab | Novel use |
WO2003097042A1 (fr) | 2002-05-16 | 2003-11-27 | Shionogi & Co., Ltd. | Antagoniste de recepteur de pdg2 |
WO2003097598A1 (fr) | 2002-05-16 | 2003-11-27 | Shionogi & Co., Ltd. | Composé comprenant un antagonisme du récepteur de pdg2 |
TW200307542A (en) | 2002-05-30 | 2003-12-16 | Astrazeneca Ab | Novel compounds |
SE0201635D0 (sv) | 2002-05-30 | 2002-05-30 | Astrazeneca Ab | Novel compounds |
US7364647B2 (en) | 2002-07-17 | 2008-04-29 | Eksigent Technologies Llc | Laminated flow device |
SE0202241D0 (sv) | 2002-07-17 | 2002-07-17 | Astrazeneca Ab | Novel Compounds |
MXPA05006701A (es) | 2002-12-20 | 2006-03-30 | Amgen Inc | Moduladores de asma y de inflacion alergica. |
JP4324418B2 (ja) | 2003-08-05 | 2009-09-02 | 株式会社日立国際電気 | 基板処理装置および半導体デバイスの製造方法 |
SE0302232D0 (sv) | 2003-08-18 | 2003-08-18 | Astrazeneca Ab | Novel Compounds |
RU2006109108A (ru) * | 2003-10-14 | 2007-11-20 | Оксаген Лимитед (GB) | Соединения, обладающие активностью антагонистов crth2 рецепторов |
BRPI0508579A (pt) | 2004-03-11 | 2007-08-14 | Actelion Pharmaceuticals Ltd | composto, composição farmacêutica, e, uso de um composto |
JP2007533725A (ja) * | 2004-04-20 | 2007-11-22 | ファイザー・インク | Crth2受容体アンタゴニストを用いたニューロパシー性疼痛処置方法 |
CA2581338A1 (en) | 2004-09-21 | 2006-03-30 | Athersys, Inc. | Indole acetic acids exhibiting crth2 receptor antagonism and uses thereof |
GB0504150D0 (en) | 2005-03-01 | 2005-04-06 | Oxagen Ltd | Microcrystalline material |
PL65781Y1 (pl) | 2005-08-16 | 2012-02-29 | Katarzyna Kawczyńska | Wkładka kosmetyczna |
PL2046740T3 (pl) * | 2006-07-22 | 2012-10-31 | Oxagen Ltd | Związki o aktywności antagonisty CRTH2 |
GB0722203D0 (en) * | 2007-11-13 | 2007-12-19 | Oxagen Ltd | Use of CRTH2 antagonist compounds |
MX2010007833A (es) * | 2008-01-18 | 2010-08-11 | Oxagen Ltd | Compuestos que tienen actividad antagonista de crth2. |
-
2009
- 2009-01-19 MX MX2010007833A patent/MX2010007833A/es active IP Right Grant
- 2009-01-19 PT PT97025985T patent/PT2250161E/pt unknown
- 2009-01-19 ES ES09702598.5T patent/ES2442717T3/es active Active
- 2009-01-19 RU RU2010129027/04A patent/RU2503672C2/ru active
- 2009-01-19 DK DK09702598.5T patent/DK2250161T3/da active
- 2009-01-19 RS RS20140016A patent/RS53142B/en unknown
- 2009-01-19 WO PCT/GB2009/000142 patent/WO2009090414A1/en active Application Filing
- 2009-01-19 AU AU2009204700A patent/AU2009204700B2/en not_active Ceased
- 2009-01-19 NZ NZ587251A patent/NZ587251A/en not_active IP Right Cessation
- 2009-01-19 CN CN200980103456.8A patent/CN101932571B/zh not_active Expired - Fee Related
- 2009-01-19 JP JP2010542688A patent/JP2011509988A/ja active Pending
- 2009-01-19 SI SI200930822T patent/SI2250161T1/sl unknown
- 2009-01-19 PL PL09702598T patent/PL2250161T3/pl unknown
- 2009-01-19 MY MYPI2010003390A patent/MY155133A/en unknown
- 2009-01-19 EP EP09702598.5A patent/EP2250161B1/en active Active
- 2009-01-19 CA CA2712017A patent/CA2712017C/en active Active
- 2009-01-19 KR KR1020107017661A patent/KR101644170B1/ko active IP Right Grant
- 2009-01-19 BR BRPI0906786-8A patent/BRPI0906786B1/pt not_active IP Right Cessation
- 2009-01-21 US US12/356,822 patent/US20090186923A1/en not_active Abandoned
-
2010
- 2010-07-12 IL IL206959A patent/IL206959A/en active IP Right Grant
- 2010-08-13 ZA ZA2010/05799A patent/ZA201005799B/en unknown
- 2010-08-13 MA MA33081A patent/MA32075B1/fr unknown
- 2010-12-14 HK HK10111663.1A patent/HK1145175A1/xx not_active IP Right Cessation
-
2014
- 2014-01-15 HR HRP20140045AT patent/HRP20140045T1/hr unknown
- 2014-01-15 CY CY20141100031T patent/CY1114748T1/el unknown
- 2014-05-07 JP JP2014095946A patent/JP5855162B2/ja not_active Expired - Fee Related
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0054417A1 (en) * | 1980-12-15 | 1982-06-23 | Pfizer Limited | Indole thromboxane synthetase inhibitors, processes for their preparation, and pharmaceutical compositions containing them |
WO2005044260A1 (en) * | 2003-10-23 | 2005-05-19 | Oxagen Limited | Use of crth2 antagonist compounds in therapy |
WO2006095183A1 (en) * | 2005-03-11 | 2006-09-14 | Oxagen Limited | 1-acetic acid-indole derivatives with pgd2 antagonist activity |
WO2009077728A1 (en) * | 2007-12-14 | 2009-06-25 | Argenta Discovery Limited | Indoles and their therapeutic use |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN101932571B (zh) | 具有crth2拮抗活性的化合物 | |
US8980927B2 (en) | Compounds having CRTH2 antagonist activity | |
RU2412934C2 (ru) | Применение антагонистов crth2 в терапии | |
EP1856045B1 (en) | 1-acetic acid-indole derivatives with pgd2 antagonist activity | |
WO2009093026A1 (en) | Compounds having crth2 antagonist activity | |
JP2011509991A (ja) | Crth2アンタゴニスト活性を有する化合物 | |
GB2407318A (en) | Substituted Indol-3-yl acetic acid derivatives | |
TW201808945A (zh) | 磷脂酸肌醇3-激酶γ的新穎抑制劑 | |
US9951042B2 (en) | Polymorphic form of [5-fluoro-3-({2-[(4-fluorobenzene) sulfonyl] pyridin-3-yl}methyl)-2-methylindol-1-yl]-acetic acid | |
GB2457040A (en) | 1-Acetic acid indole derivatives with PGD2 activity |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
ASS | Succession or assignment of patent right |
Owner name: ATOPIX THERAPEUTICS LTD. Free format text: FORMER OWNER: OXAGEN LTD. Effective date: 20140819 |
|
C41 | Transfer of patent application or patent right or utility model | ||
TR01 | Transfer of patent right |
Effective date of registration: 20140819 Address after: London, England Patentee after: OXAGEN LTD. Address before: Oxfordshire Patentee before: Oxagen Ltd. |
|
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20140423 |
|
CF01 | Termination of patent right due to non-payment of annual fee |