SG188644A1 - Matrix metalloproteinase inhibitors - Google Patents
Matrix metalloproteinase inhibitors Download PDFInfo
- Publication number
- SG188644A1 SG188644A1 SG2013021696A SG2013021696A SG188644A1 SG 188644 A1 SG188644 A1 SG 188644A1 SG 2013021696 A SG2013021696 A SG 2013021696A SG 2013021696 A SG2013021696 A SG 2013021696A SG 188644 A1 SG188644 A1 SG 188644A1
- Authority
- SG
- Singapore
- Prior art keywords
- compound
- phenyl
- formula
- carbamoyl
- oxy
- Prior art date
Links
- 239000003771 matrix metalloproteinase inhibitor Substances 0.000 title description 2
- 229940121386 matrix metalloproteinase inhibitor Drugs 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 559
- -1 sulfone acetic acid derivatives Chemical class 0.000 claims abstract description 114
- 208000027866 inflammatory disease Diseases 0.000 claims abstract description 12
- 229940124761 MMP inhibitor Drugs 0.000 claims abstract description 7
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims abstract description 6
- 201000001320 Atherosclerosis Diseases 0.000 claims abstract description 4
- 201000004681 Psoriasis Diseases 0.000 claims abstract description 4
- 208000003556 Dry Eye Syndromes Diseases 0.000 claims abstract description 3
- 206010013774 Dry eye Diseases 0.000 claims abstract description 3
- 206010019280 Heart failures Diseases 0.000 claims abstract description 3
- 206010027476 Metastases Diseases 0.000 claims abstract description 3
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 3
- 206010035664 Pneumonia Diseases 0.000 claims abstract description 3
- 201000001263 Psoriatic Arthritis Diseases 0.000 claims abstract description 3
- 208000036824 Psoriatic arthropathy Diseases 0.000 claims abstract description 3
- 208000006011 Stroke Diseases 0.000 claims abstract description 3
- 208000006673 asthma Diseases 0.000 claims abstract description 3
- 208000007565 gingivitis Diseases 0.000 claims abstract description 3
- 230000000302 ischemic effect Effects 0.000 claims abstract description 3
- 208000017169 kidney disease Diseases 0.000 claims abstract description 3
- 230000009401 metastasis Effects 0.000 claims abstract description 3
- 201000008482 osteoarthritis Diseases 0.000 claims abstract description 3
- 230000035755 proliferation Effects 0.000 claims abstract description 3
- 208000005069 pulmonary fibrosis Diseases 0.000 claims abstract description 3
- 208000037803 restenosis Diseases 0.000 claims abstract description 3
- 206010039073 rheumatoid arthritis Diseases 0.000 claims abstract description 3
- 206010039083 rhinitis Diseases 0.000 claims abstract description 3
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 221
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 111
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 60
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 54
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 42
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 41
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 38
- 125000000217 alkyl group Chemical group 0.000 claims description 36
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 34
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 32
- 125000001072 heteroaryl group Chemical group 0.000 claims description 27
- 125000003118 aryl group Chemical group 0.000 claims description 25
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 18
- 125000003342 alkenyl group Chemical group 0.000 claims description 16
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 14
- 239000003112 inhibitor Substances 0.000 claims description 14
- 229910052736 halogen Inorganic materials 0.000 claims description 13
- 150000002367 halogens Chemical class 0.000 claims description 13
- 125000000623 heterocyclic group Chemical group 0.000 claims description 13
- 239000002253 acid Substances 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 claims description 11
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 11
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 11
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 11
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 11
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 125000000304 alkynyl group Chemical group 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 10
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 9
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 8
- 201000010099 disease Diseases 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 238000011282 treatment Methods 0.000 claims description 8
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 230000003301 hydrolyzing effect Effects 0.000 claims description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- 230000002757 inflammatory effect Effects 0.000 claims description 7
- 229910052740 iodine Inorganic materials 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 6
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 5
- RMMKVAPUDOBVRP-UHFFFAOYSA-N 4-[(4-chlorophenyl)carbamoyloxy]-2-(4-chlorophenyl)sulfanylbutanoic acid Chemical compound C=1C=C(Cl)C=CC=1SC(C(=O)O)CCOC(=O)NC1=CC=C(Cl)C=C1 RMMKVAPUDOBVRP-UHFFFAOYSA-N 0.000 claims description 5
- 125000004860 4-ethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 125000005213 alkyl heteroaryl group Chemical group 0.000 claims description 5
- 150000001356 alkyl thiols Chemical class 0.000 claims description 5
- 208000026935 allergic disease Diseases 0.000 claims description 5
- 125000004104 aryloxy group Chemical group 0.000 claims description 5
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 5
- 125000004367 cycloalkylaryl group Chemical group 0.000 claims description 5
- 125000001207 fluorophenyl group Chemical group 0.000 claims description 5
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 5
- 150000003573 thiols Chemical class 0.000 claims description 5
- YPZRUQWTOKHJDF-UHFFFAOYSA-N 2-(4-nitrophenyl)sulfonyl-4-phenylmethoxybutanoic acid Chemical compound C=1C=C([N+]([O-])=O)C=CC=1S(=O)(=O)C(C(=O)O)CCOCC1=CC=CC=C1 YPZRUQWTOKHJDF-UHFFFAOYSA-N 0.000 claims description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 4
- 239000004072 C09CA03 - Valsartan Substances 0.000 claims description 4
- 229910052792 caesium Inorganic materials 0.000 claims description 4
- 125000001108 carbamothioyl group Chemical group C(N)(=S)* 0.000 claims description 4
- 125000004188 dichlorophenyl group Chemical group 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 4
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims description 4
- RMMXLENWKUUMAY-UHFFFAOYSA-N telmisartan Chemical compound CCCC1=NC2=C(C)C=C(C=3N(C4=CC=CC=C4N=3)C)C=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C(O)=O RMMXLENWKUUMAY-UHFFFAOYSA-N 0.000 claims description 4
- 229960004699 valsartan Drugs 0.000 claims description 4
- SJSNUMAYCRRIOM-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SJSNUMAYCRRIOM-QFIPXVFZSA-N 0.000 claims description 4
- FUWYGORBNNYYIQ-UHFFFAOYSA-N 2-(4-chlorophenyl)sulfanyl-4-[(4-fluorophenyl)carbamoyloxy]butanoic acid Chemical compound C=1C=C(Cl)C=CC=1SC(C(=O)O)CCOC(=O)NC1=CC=C(F)C=C1 FUWYGORBNNYYIQ-UHFFFAOYSA-N 0.000 claims description 3
- UNIUKGWXMCOSEN-UHFFFAOYSA-N 2-[4-[(4-chlorobenzoyl)amino]phenyl]sulfonyl-4-[(5-fluoro-2-methylphenyl)carbamoyloxy]butanoic acid Chemical compound CC1=CC=C(F)C=C1NC(=O)OCCC(C(O)=O)S(=O)(=O)C(C=C1)=CC=C1NC(=O)C1=CC=C(Cl)C=C1 UNIUKGWXMCOSEN-UHFFFAOYSA-N 0.000 claims description 3
- JXGOHGWDBUYUFH-UHFFFAOYSA-N 4-[(4-chlorophenyl)carbamoyloxy]-2-(4-chlorophenyl)sulfonylbutanoic acid Chemical compound C=1C=C(Cl)C=CC=1S(=O)(=O)C(C(=O)O)CCOC(=O)NC1=CC=C(Cl)C=C1 JXGOHGWDBUYUFH-UHFFFAOYSA-N 0.000 claims description 3
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 3
- 150000004820 halides Chemical group 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 125000003944 tolyl group Chemical group 0.000 claims description 3
- PMUNTYGNFLTHNY-UHFFFAOYSA-N 2-(4-chlorophenyl)sulfonyl-4-[(4-fluorophenyl)carbamoyloxy]butanoic acid Chemical compound C=1C=C(Cl)C=CC=1S(=O)(=O)C(C(=O)O)CCOC(=O)NC1=CC=C(F)C=C1 PMUNTYGNFLTHNY-UHFFFAOYSA-N 0.000 claims description 2
- CRHKBXWSIKOIDS-UHFFFAOYSA-N 2-[4-[(4-chlorobenzoyl)amino]phenyl]sulfanyl-4-[(3-chlorophenyl)carbamoyloxy]butanoic acid Chemical compound C=1C=C(NC(=O)C=2C=CC(Cl)=CC=2)C=CC=1SC(C(=O)O)CCOC(=O)NC1=CC=CC(Cl)=C1 CRHKBXWSIKOIDS-UHFFFAOYSA-N 0.000 claims description 2
- 239000005541 ACE inhibitor Substances 0.000 claims description 2
- 239000002083 C09CA01 - Losartan Substances 0.000 claims description 2
- 239000002080 C09CA02 - Eprosartan Substances 0.000 claims description 2
- 239000002947 C09CA04 - Irbesartan Substances 0.000 claims description 2
- 239000002053 C09CA06 - Candesartan Substances 0.000 claims description 2
- 239000005537 C09CA07 - Telmisartan Substances 0.000 claims description 2
- 101100296719 Caenorhabditis elegans pde-4 gene Proteins 0.000 claims description 2
- 229940127291 Calcium channel antagonist Drugs 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
- 108010036949 Cyclosporine Proteins 0.000 claims description 2
- 108010061435 Enalapril Proteins 0.000 claims description 2
- 102000000589 Interleukin-1 Human genes 0.000 claims description 2
- 108010002352 Interleukin-1 Proteins 0.000 claims description 2
- 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 2
- 239000000867 Lipoxygenase Inhibitor Substances 0.000 claims description 2
- 108010007859 Lisinopril Proteins 0.000 claims description 2
- 241001465754 Metazoa Species 0.000 claims description 2
- 108700023400 Platelet-activating factor receptors Proteins 0.000 claims description 2
- 101100545004 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) YSP2 gene Proteins 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 239000000556 agonist Substances 0.000 claims description 2
- 229940051880 analgesics and antipyretics pyrazolones Drugs 0.000 claims description 2
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 claims description 2
- 239000005557 antagonist Substances 0.000 claims description 2
- 229940121363 anti-inflammatory agent Drugs 0.000 claims description 2
- 239000002260 anti-inflammatory agent Substances 0.000 claims description 2
- 230000003110 anti-inflammatory effect Effects 0.000 claims description 2
- 239000002220 antihypertensive agent Substances 0.000 claims description 2
- 229940030600 antihypertensive agent Drugs 0.000 claims description 2
- 229940111136 antiinflammatory and antirheumatic drug fenamates Drugs 0.000 claims description 2
- 229960002170 azathioprine 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
- 239000000480 calcium channel blocker Substances 0.000 claims description 2
- 229960000932 candesartan Drugs 0.000 claims description 2
- SGZAIDDFHDDFJU-UHFFFAOYSA-N candesartan Chemical compound CCOC1=NC2=CC=CC(C(O)=O)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SGZAIDDFHDDFJU-UHFFFAOYSA-N 0.000 claims description 2
- 125000000068 chlorophenyl group Chemical group 0.000 claims description 2
- 229960001265 ciclosporin Drugs 0.000 claims description 2
- 239000003246 corticosteroid Substances 0.000 claims description 2
- 229960001334 corticosteroids Drugs 0.000 claims description 2
- 229940111134 coxibs Drugs 0.000 claims description 2
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 claims description 2
- 229930182912 cyclosporin Natural products 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
- GBXSMTUPTTWBMN-XIRDDKMYSA-N enalapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)CC1=CC=CC=C1 GBXSMTUPTTWBMN-XIRDDKMYSA-N 0.000 claims description 2
- 229960000873 enalapril Drugs 0.000 claims description 2
- 229960004563 eprosartan Drugs 0.000 claims description 2
- OROAFUQRIXKEMV-LDADJPATSA-N eprosartan Chemical compound C=1C=C(C(O)=O)C=CC=1CN1C(CCCC)=NC=C1\C=C(C(O)=O)/CC1=CC=CS1 OROAFUQRIXKEMV-LDADJPATSA-N 0.000 claims description 2
- 229940125721 immunosuppressive agent Drugs 0.000 claims description 2
- 239000003018 immunosuppressive agent Substances 0.000 claims description 2
- 229960002198 irbesartan Drugs 0.000 claims description 2
- YCPOHTHPUREGFM-UHFFFAOYSA-N irbesartan Chemical compound O=C1N(CC=2C=CC(=CC=2)C=2C(=CC=CC=2)C=2[N]N=NN=2)C(CCCC)=NC21CCCC2 YCPOHTHPUREGFM-UHFFFAOYSA-N 0.000 claims description 2
- GWNVDXQDILPJIG-NXOLIXFESA-N leukotriene C4 Chemical compound CCCCC\C=C/C\C=C/C=C/C=C/[C@H]([C@@H](O)CCCC(O)=O)SC[C@@H](C(=O)NCC(O)=O)NC(=O)CC[C@H](N)C(O)=O GWNVDXQDILPJIG-NXOLIXFESA-N 0.000 claims description 2
- YEESKJGWJFYOOK-IJHYULJSSA-N leukotriene D4 Chemical compound CCCCC\C=C/C\C=C/C=C/C=C/[C@H]([C@@H](O)CCCC(O)=O)SC[C@H](N)C(=O)NCC(O)=O YEESKJGWJFYOOK-IJHYULJSSA-N 0.000 claims description 2
- OTZRAYGBFWZKMX-JUDRUQEKSA-N leukotriene E4 Chemical compound CCCCCC=CCC=C\C=C\C=C\[C@@H](SC[C@H](N)C(O)=O)[C@@H](O)CCCC(O)=O OTZRAYGBFWZKMX-JUDRUQEKSA-N 0.000 claims description 2
- 150000002617 leukotrienes Chemical class 0.000 claims description 2
- 229960002394 lisinopril Drugs 0.000 claims description 2
- RLAWWYSOJDYHDC-BZSNNMDCSA-N lisinopril Chemical compound C([C@H](N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(O)=O)C(O)=O)CC1=CC=CC=C1 RLAWWYSOJDYHDC-BZSNNMDCSA-N 0.000 claims description 2
- 229960004773 losartan Drugs 0.000 claims description 2
- KJJZZJSZUJXYEA-UHFFFAOYSA-N losartan Chemical compound CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C=2[N]N=NN=2)C=C1 KJJZZJSZUJXYEA-UHFFFAOYSA-N 0.000 claims description 2
- 229960000485 methotrexate Drugs 0.000 claims description 2
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 claims description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 claims description 2
- 102000002574 p38 Mitogen-Activated Protein Kinases Human genes 0.000 claims description 2
- 108010068338 p38 Mitogen-Activated Protein Kinases Proteins 0.000 claims description 2
- 229960002702 piroxicam Drugs 0.000 claims description 2
- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 claims description 2
- 102000030769 platelet activating factor receptor Human genes 0.000 claims description 2
- 150000004672 propanoic acids Chemical class 0.000 claims description 2
- 235000019260 propionic acid Nutrition 0.000 claims description 2
- JEXVQSWXXUJEMA-UHFFFAOYSA-N pyrazol-3-one Chemical class O=C1C=CN=N1 JEXVQSWXXUJEMA-UHFFFAOYSA-N 0.000 claims description 2
- JSDRRTOADPPCHY-HSQYWUDLSA-N quinapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CC2=CC=CC=C2C1)C(O)=O)CC1=CC=CC=C1 JSDRRTOADPPCHY-HSQYWUDLSA-N 0.000 claims description 2
- 229960001455 quinapril Drugs 0.000 claims description 2
- 239000002464 receptor antagonist Substances 0.000 claims description 2
- 229940044551 receptor antagonist Drugs 0.000 claims description 2
- 150000003873 salicylate salts Chemical class 0.000 claims description 2
- 229960005187 telmisartan Drugs 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 8
- 230000008878 coupling Effects 0.000 claims 5
- 238000010168 coupling process Methods 0.000 claims 5
- 238000005859 coupling reaction Methods 0.000 claims 5
- 230000001590 oxidative effect Effects 0.000 claims 4
- 238000004519 manufacturing process Methods 0.000 claims 3
- OYVGUTYAKIUJBH-UHFFFAOYSA-N 2-[4-[(4-chlorobenzoyl)amino]phenyl]sulfanyl-4-[(3,5-dimethoxyphenyl)carbamoyloxy]butanoic acid Chemical compound COC1=CC(OC)=CC(NC(=O)OCCC(SC=2C=CC(NC(=O)C=3C=CC(Cl)=CC=3)=CC=2)C(O)=O)=C1 OYVGUTYAKIUJBH-UHFFFAOYSA-N 0.000 claims 1
- 102000008873 Angiotensin II receptor Human genes 0.000 claims 1
- 108050000824 Angiotensin II receptor Proteins 0.000 claims 1
- 229940122142 Lipoxygenase inhibitor Drugs 0.000 claims 1
- 206010038687 Respiratory distress Diseases 0.000 claims 1
- 230000001154 acute effect Effects 0.000 claims 1
- 230000000172 allergic effect Effects 0.000 claims 1
- 208000010668 atopic eczema Diseases 0.000 claims 1
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 claims 1
- 108010033380 cathepsin-6 Proteins 0.000 claims 1
- 125000004802 cyanophenyl group Chemical group 0.000 claims 1
- 125000004212 difluorophenyl group Chemical group 0.000 claims 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims 1
- 201000006417 multiple sclerosis Diseases 0.000 claims 1
- 238000011321 prophylaxis Methods 0.000 claims 1
- 208000011580 syndromic disease Diseases 0.000 claims 1
- 102000002274 Matrix Metalloproteinases Human genes 0.000 abstract description 19
- 108010000684 Matrix Metalloproteinases Proteins 0.000 abstract description 19
- 238000003786 synthesis reaction Methods 0.000 abstract description 12
- 238000000034 method Methods 0.000 abstract description 11
- 230000004913 activation Effects 0.000 abstract description 7
- 230000008569 process Effects 0.000 abstract description 5
- 230000002018 overexpression Effects 0.000 abstract description 3
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 abstract description 2
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 abstract description 2
- 201000000028 adult respiratory distress syndrome Diseases 0.000 abstract description 2
- 239000008196 pharmacological composition Substances 0.000 abstract description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 107
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 102
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 87
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 57
- 239000000243 solution Substances 0.000 description 49
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 48
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 42
- 239000011541 reaction mixture Substances 0.000 description 39
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 36
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 30
- 238000006243 chemical reaction Methods 0.000 description 29
- 238000002360 preparation method Methods 0.000 description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 27
- 239000012043 crude product Substances 0.000 description 25
- 239000012044 organic layer Substances 0.000 description 25
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 24
- 229910052938 sodium sulfate Inorganic materials 0.000 description 24
- 235000011152 sodium sulphate Nutrition 0.000 description 24
- 239000003480 eluent Substances 0.000 description 21
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 239000000203 mixture Substances 0.000 description 17
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 14
- 239000002904 solvent Substances 0.000 description 14
- 239000000741 silica gel Substances 0.000 description 13
- 229910002027 silica gel Inorganic materials 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 12
- 125000004432 carbon atom Chemical group C* 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- 239000012300 argon atmosphere Substances 0.000 description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 238000012746 preparative thin layer chromatography Methods 0.000 description 9
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- 230000007062 hydrolysis Effects 0.000 description 8
- 238000006460 hydrolysis reaction Methods 0.000 description 8
- 102000004190 Enzymes Human genes 0.000 description 7
- 108090000790 Enzymes Proteins 0.000 description 7
- 102100030412 Matrix metalloproteinase-9 Human genes 0.000 description 7
- 108010015302 Matrix metalloproteinase-9 Proteins 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- 230000003647 oxidation Effects 0.000 description 7
- 238000007254 oxidation reaction Methods 0.000 description 7
- 125000006239 protecting group Chemical group 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- 239000002585 base Substances 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- 239000006196 drop Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 6
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 239000004289 sodium hydrogen sulphite Substances 0.000 description 5
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 5
- XEZNGIUYQVAUSS-UHFFFAOYSA-N 18-crown-6 Chemical compound C1COCCOCCOCCOCCOCCO1 XEZNGIUYQVAUSS-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- 206010061218 Inflammation Diseases 0.000 description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 206010012601 diabetes mellitus Diseases 0.000 description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- 230000004054 inflammatory process Effects 0.000 description 4
- 150000007529 inorganic bases Chemical class 0.000 description 4
- 150000007530 organic bases Chemical class 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 4
- 239000004296 sodium metabisulphite Substances 0.000 description 4
- 235000010262 sodium metabisulphite Nutrition 0.000 description 4
- 229910052717 sulfur Inorganic materials 0.000 description 4
- 239000011701 zinc Substances 0.000 description 4
- NWRMZZZPRYCMAY-UHFFFAOYSA-N 2-[4-[(4-chlorophenyl)carbamoyl]phenyl]sulfanyl-4-[(4-fluorophenyl)carbamoyloxy]butanoic acid Chemical compound C=1C=C(C(=O)NC=2C=CC(Cl)=CC=2)C=CC=1SC(C(=O)O)CCOC(=O)NC1=CC=C(F)C=C1 NWRMZZZPRYCMAY-UHFFFAOYSA-N 0.000 description 3
- FEXMFAPYCAAWIH-UHFFFAOYSA-N 2-[4-[(4-methylbenzoyl)amino]phenyl]sulfonyl-4-phenylmethoxybutanoic acid Chemical compound C1=CC(C)=CC=C1C(=O)NC1=CC=C(S(=O)(=O)C(CCOCC=2C=CC=CC=2)C(O)=O)C=C1 FEXMFAPYCAAWIH-UHFFFAOYSA-N 0.000 description 3
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 3
- 208000023275 Autoimmune disease Diseases 0.000 description 3
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000003638 chemical reducing agent Substances 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 210000002808 connective tissue Anatomy 0.000 description 3
- 125000004415 heterocyclylalkyl group Chemical group 0.000 description 3
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 230000008506 pathogenesis Effects 0.000 description 3
- 239000006187 pill Substances 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 125000006413 ring segment Chemical group 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- XQTLDIFVVHJORV-UHFFFAOYSA-N tecnazene Chemical compound [O-][N+](=O)C1=C(Cl)C(Cl)=CC(Cl)=C1Cl XQTLDIFVVHJORV-UHFFFAOYSA-N 0.000 description 3
- 229940124597 therapeutic agent Drugs 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 230000002110 toxicologic effect Effects 0.000 description 3
- 231100000027 toxicology Toxicity 0.000 description 3
- 229910052725 zinc Inorganic materials 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
- ADAKRBAJFHTIEW-UHFFFAOYSA-N 1-chloro-4-isocyanatobenzene Chemical compound ClC1=CC=C(N=C=O)C=C1 ADAKRBAJFHTIEW-UHFFFAOYSA-N 0.000 description 2
- MVXVYAKCVDQRLW-UHFFFAOYSA-N 1h-pyrrolo[2,3-b]pyridine Chemical compound C1=CN=C2NC=CC2=C1 MVXVYAKCVDQRLW-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- AYLSBTXXNXCGKN-UHFFFAOYSA-N 2-[4-(cyclohexanecarbonylamino)phenyl]sulfanyl-4-[[4-(trifluoromethyl)phenyl]carbamoyloxy]butanoic acid Chemical compound C=1C=C(NC(=O)C2CCCCC2)C=CC=1SC(C(=O)O)CCOC(=O)NC1=CC=C(C(F)(F)F)C=C1 AYLSBTXXNXCGKN-UHFFFAOYSA-N 0.000 description 2
- VXODVQRLOHRIDC-UHFFFAOYSA-N 2-[4-[(2,4-dichlorobenzoyl)amino]phenyl]sulfanyl-4-[[4-(trifluoromethyl)phenyl]carbamoyloxy]butanoic acid Chemical compound C=1C=C(NC(=O)C=2C(=CC(Cl)=CC=2)Cl)C=CC=1SC(C(=O)O)CCOC(=O)NC1=CC=C(C(F)(F)F)C=C1 VXODVQRLOHRIDC-UHFFFAOYSA-N 0.000 description 2
- KATPMMAAQWMCBC-UHFFFAOYSA-N 2-[4-[(2-ethoxybenzoyl)amino]phenyl]sulfanyl-4-[[4-(trifluoromethyl)phenyl]carbamoyloxy]butanoic acid Chemical compound CCOC1=CC=CC=C1C(=O)NC(C=C1)=CC=C1SC(C(O)=O)CCOC(=O)NC1=CC=C(C(F)(F)F)C=C1 KATPMMAAQWMCBC-UHFFFAOYSA-N 0.000 description 2
- UABBATIKABYMIU-UHFFFAOYSA-N 2-[4-[(2-fluorobenzoyl)amino]phenyl]sulfonyl-4-phenylmethoxybutanoic acid Chemical compound C=1C=C(NC(=O)C=2C(=CC=CC=2)F)C=CC=1S(=O)(=O)C(C(=O)O)CCOCC1=CC=CC=C1 UABBATIKABYMIU-UHFFFAOYSA-N 0.000 description 2
- XRRQKFGUOMULJJ-UHFFFAOYSA-N 2-[4-[(2-methylbenzoyl)amino]phenyl]sulfanyl-4-[[4-(trifluoromethyl)phenyl]carbamoyloxy]butanoic acid Chemical compound CC1=CC=CC=C1C(=O)NC(C=C1)=CC=C1SC(C(O)=O)CCOC(=O)NC1=CC=C(C(F)(F)F)C=C1 XRRQKFGUOMULJJ-UHFFFAOYSA-N 0.000 description 2
- UTTVRXFNYOKMRV-UHFFFAOYSA-N 2-[4-[(3,4-dichlorobenzoyl)amino]phenyl]sulfanyl-4-[[4-(trifluoromethyl)phenyl]carbamoyloxy]butanoic acid Chemical compound C=1C=C(NC(=O)C=2C=C(Cl)C(Cl)=CC=2)C=CC=1SC(C(=O)O)CCOC(=O)NC1=CC=C(C(F)(F)F)C=C1 UTTVRXFNYOKMRV-UHFFFAOYSA-N 0.000 description 2
- CNSZHFUHBXOQJQ-UHFFFAOYSA-N 2-[4-[(3-chlorobenzoyl)amino]phenyl]sulfonyl-4-phenylmethoxybutanoic acid Chemical compound C=1C=C(NC(=O)C=2C=C(Cl)C=CC=2)C=CC=1S(=O)(=O)C(C(=O)O)CCOCC1=CC=CC=C1 CNSZHFUHBXOQJQ-UHFFFAOYSA-N 0.000 description 2
- BRJIWOFPKZEDKZ-UHFFFAOYSA-N 2-[4-[(3-fluorobenzoyl)amino]phenyl]sulfonyl-4-phenylmethoxybutanoic acid Chemical compound C=1C=C(NC(=O)C=2C=C(F)C=CC=2)C=CC=1S(=O)(=O)C(C(=O)O)CCOCC1=CC=CC=C1 BRJIWOFPKZEDKZ-UHFFFAOYSA-N 0.000 description 2
- XDURELWBMFNAGQ-UHFFFAOYSA-N 2-[4-[(3-methoxybenzoyl)amino]phenyl]sulfonyl-4-phenylmethoxybutanoic acid Chemical compound COC1=CC=CC(C(=O)NC=2C=CC(=CC=2)S(=O)(=O)C(CCOCC=2C=CC=CC=2)C(O)=O)=C1 XDURELWBMFNAGQ-UHFFFAOYSA-N 0.000 description 2
- HEISSDOHTILWNS-UHFFFAOYSA-N 2-[4-[(4-chlorobenzoyl)amino]phenyl]sulfanyl-4-[(3-ethoxyphenyl)carbamoyloxy]butanoic acid Chemical compound CCOC1=CC=CC(NC(=O)OCCC(SC=2C=CC(NC(=O)C=3C=CC(Cl)=CC=3)=CC=2)C(O)=O)=C1 HEISSDOHTILWNS-UHFFFAOYSA-N 0.000 description 2
- SMUXPWNUGIBPQX-UHFFFAOYSA-N 2-[4-[(4-chlorobenzoyl)amino]phenyl]sulfanyl-4-[(4-chlorophenyl)carbamothioyloxy]butanoic acid Chemical compound C=1C=C(NC(=O)C=2C=CC(Cl)=CC=2)C=CC=1SC(C(=O)O)CCOC(=S)NC1=CC=C(Cl)C=C1 SMUXPWNUGIBPQX-UHFFFAOYSA-N 0.000 description 2
- OQXDPFDKWONWQN-UHFFFAOYSA-N 2-[4-[(4-chlorobenzoyl)amino]phenyl]sulfanyl-4-[(4-fluorophenyl)carbamoyloxy]butanoic acid Chemical compound C=1C=C(NC(=O)C=2C=CC(Cl)=CC=2)C=CC=1SC(C(=O)O)CCOC(=O)NC1=CC=C(F)C=C1 OQXDPFDKWONWQN-UHFFFAOYSA-N 0.000 description 2
- UQJBJBFBUSAQQM-UHFFFAOYSA-N 2-[4-[(4-chlorobenzoyl)amino]phenyl]sulfonyl-4-[(2-fluorophenyl)carbamoyloxy]butanoic acid Chemical compound C=1C=C(NC(=O)C=2C=CC(Cl)=CC=2)C=CC=1S(=O)(=O)C(C(=O)O)CCOC(=O)NC1=CC=CC=C1F UQJBJBFBUSAQQM-UHFFFAOYSA-N 0.000 description 2
- SYJKBOHRTCAASQ-UHFFFAOYSA-N 2-[4-[(4-chlorobenzoyl)amino]phenyl]sulfonyl-4-[(3-chloro-4-methoxyphenyl)carbamoyloxy]butanoic acid Chemical compound C1=C(Cl)C(OC)=CC=C1NC(=O)OCCC(C(O)=O)S(=O)(=O)C(C=C1)=CC=C1NC(=O)C1=CC=C(Cl)C=C1 SYJKBOHRTCAASQ-UHFFFAOYSA-N 0.000 description 2
- GTMAULQASXFNRQ-UHFFFAOYSA-N 2-[4-[(4-chlorobenzoyl)amino]phenyl]sulfonyl-4-[(3-chlorophenyl)carbamoyloxy]butanoic acid Chemical compound C=1C=C(NC(=O)C=2C=CC(Cl)=CC=2)C=CC=1S(=O)(=O)C(C(=O)O)CCOC(=O)NC1=CC=CC(Cl)=C1 GTMAULQASXFNRQ-UHFFFAOYSA-N 0.000 description 2
- QWDIYGGVQCFMHE-UHFFFAOYSA-N 2-[4-[(4-chlorobenzoyl)amino]phenyl]sulfonyl-4-[(3-cyanophenyl)carbamothioyloxy]butanoic acid Chemical compound C=1C=C(NC(=O)C=2C=CC(Cl)=CC=2)C=CC=1S(=O)(=O)C(C(=O)O)CCOC(=S)NC1=CC=CC(C#N)=C1 QWDIYGGVQCFMHE-UHFFFAOYSA-N 0.000 description 2
- XUDWKZOIOZWEPY-UHFFFAOYSA-N 2-[4-[(4-chlorobenzoyl)amino]phenyl]sulfonyl-4-[(4-fluorophenyl)carbamoyloxy]butanoic acid Chemical compound C=1C=C(NC(=O)C=2C=CC(Cl)=CC=2)C=CC=1S(=O)(=O)C(C(=O)O)CCOC(=O)NC1=CC=C(F)C=C1 XUDWKZOIOZWEPY-UHFFFAOYSA-N 0.000 description 2
- XMEQZXOTCKYKGI-UHFFFAOYSA-N 2-[4-[(4-chlorophenyl)carbamoyl]phenyl]sulfanyl-4-(pentylcarbamoyloxy)butanoic acid Chemical compound C1=CC(SC(CCOC(=O)NCCCCC)C(O)=O)=CC=C1C(=O)NC1=CC=C(Cl)C=C1 XMEQZXOTCKYKGI-UHFFFAOYSA-N 0.000 description 2
- MPKLEOHJAVQKTC-UHFFFAOYSA-N 2-[4-[(4-chlorophenyl)carbamoyl]phenyl]sulfanyl-4-[(4-ethylphenyl)carbamoyloxy]butanoic acid Chemical compound C1=CC(CC)=CC=C1NC(=O)OCCC(C(O)=O)SC1=CC=C(C(=O)NC=2C=CC(Cl)=CC=2)C=C1 MPKLEOHJAVQKTC-UHFFFAOYSA-N 0.000 description 2
- WULSHLHMHHWLTO-UHFFFAOYSA-N 2-[4-[(4-chlorophenyl)carbamoyl]phenyl]sulfanyl-4-[(4-methoxyphenyl)carbamoyloxy]butanoic acid Chemical compound C1=CC(OC)=CC=C1NC(=O)OCCC(C(O)=O)SC1=CC=C(C(=O)NC=2C=CC(Cl)=CC=2)C=C1 WULSHLHMHHWLTO-UHFFFAOYSA-N 0.000 description 2
- XAFFADULGPYEDT-UHFFFAOYSA-N 2-[4-[(4-chlorophenyl)carbamoyl]phenyl]sulfanyl-4-[(4-methylphenyl)carbamoyloxy]butanoic acid Chemical compound C1=CC(C)=CC=C1NC(=O)OCCC(C(O)=O)SC1=CC=C(C(=O)NC=2C=CC(Cl)=CC=2)C=C1 XAFFADULGPYEDT-UHFFFAOYSA-N 0.000 description 2
- BYIIYNQFVWJUSG-UHFFFAOYSA-N 2-[4-[(4-chlorophenyl)carbamoyl]phenyl]sulfanyl-4-[(4-propan-2-ylphenyl)carbamoyloxy]butanoic acid Chemical compound C1=CC(C(C)C)=CC=C1NC(=O)OCCC(C(O)=O)SC1=CC=C(C(=O)NC=2C=CC(Cl)=CC=2)C=C1 BYIIYNQFVWJUSG-UHFFFAOYSA-N 0.000 description 2
- WWFDJUJGAOHLRH-UHFFFAOYSA-N 2-[4-[(4-chlorophenyl)carbamoyl]phenyl]sulfanyl-4-[[4-(trifluoromethyl)phenyl]carbamoyloxy]butanoic acid Chemical compound C=1C=C(C(=O)NC=2C=CC(Cl)=CC=2)C=CC=1SC(C(=O)O)CCOC(=O)NC1=CC=C(C(F)(F)F)C=C1 WWFDJUJGAOHLRH-UHFFFAOYSA-N 0.000 description 2
- NXISWVNBHQZKJN-UHFFFAOYSA-N 2-[4-[(4-chlorophenyl)carbamoyl]phenyl]sulfonyl-4-[(2,6-dichlorophenyl)carbamoyloxy]butanoic acid Chemical compound C=1C=C(C(=O)NC=2C=CC(Cl)=CC=2)C=CC=1S(=O)(=O)C(C(=O)O)CCOC(=O)NC1=C(Cl)C=CC=C1Cl NXISWVNBHQZKJN-UHFFFAOYSA-N 0.000 description 2
- XRHJSHZBJVOBMR-UHFFFAOYSA-N 2-[4-[(4-chlorophenyl)carbamoyl]phenyl]sulfonyl-4-[(2-methylphenyl)carbamoyloxy]butanoic acid Chemical compound CC1=CC=CC=C1NC(=O)OCCC(C(O)=O)S(=O)(=O)C1=CC=C(C(=O)NC=2C=CC(Cl)=CC=2)C=C1 XRHJSHZBJVOBMR-UHFFFAOYSA-N 0.000 description 2
- RHAXVYKYKDTWGX-UHFFFAOYSA-N 2-[4-[(4-chlorophenyl)carbamoyl]phenyl]sulfonyl-4-[(4-methylphenyl)carbamoyloxy]butanoic acid Chemical compound C1=CC(C)=CC=C1NC(=O)OCCC(C(O)=O)S(=O)(=O)C1=CC=C(C(=O)NC=2C=CC(Cl)=CC=2)C=C1 RHAXVYKYKDTWGX-UHFFFAOYSA-N 0.000 description 2
- JPWKGDWHOMGXKG-UHFFFAOYSA-N 2-[4-[(4-ethoxybenzoyl)amino]phenyl]sulfanyl-4-[[4-(trifluoromethyl)phenyl]carbamoyloxy]butanoic acid Chemical compound C1=CC(OCC)=CC=C1C(=O)NC(C=C1)=CC=C1SC(C(O)=O)CCOC(=O)NC1=CC=C(C(F)(F)F)C=C1 JPWKGDWHOMGXKG-UHFFFAOYSA-N 0.000 description 2
- AKWFVZSCNKLATD-UHFFFAOYSA-N 2-[4-[(4-methoxybenzoyl)amino]phenyl]sulfanyl-4-[[4-(trifluoromethyl)phenyl]carbamoyloxy]butanoic acid Chemical compound C1=CC(OC)=CC=C1C(=O)NC(C=C1)=CC=C1SC(C(O)=O)CCOC(=O)NC1=CC=C(C(F)(F)F)C=C1 AKWFVZSCNKLATD-UHFFFAOYSA-N 0.000 description 2
- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- YPQGKDWVROJUBQ-UHFFFAOYSA-N 4-(butylcarbamoyloxy)-2-[4-[(4-chlorophenyl)carbamoyl]phenyl]sulfonylbutanoic acid Chemical compound C1=CC(S(=O)(=O)C(C(O)=O)CCOC(=O)NCCCC)=CC=C1C(=O)NC1=CC=C(Cl)C=C1 YPQGKDWVROJUBQ-UHFFFAOYSA-N 0.000 description 2
- GZIOCXYPPCYQNW-UHFFFAOYSA-N 4-(tert-butylcarbamoyloxy)-2-[4-[(4-chlorophenyl)carbamoyl]phenyl]sulfonylbutanoic acid Chemical compound C1=CC(S(=O)(=O)C(C(O)=O)CCOC(=O)NC(C)(C)C)=CC=C1C(=O)NC1=CC=C(Cl)C=C1 GZIOCXYPPCYQNW-UHFFFAOYSA-N 0.000 description 2
- GBRNGKXUAWGDEN-UHFFFAOYSA-N 4-(tert-butylcarbamoyloxy)-2-[4-[(4-methoxybenzoyl)amino]phenyl]sulfanylbutanoic acid Chemical compound C1=CC(OC)=CC=C1C(=O)NC1=CC=C(SC(CCOC(=O)NC(C)(C)C)C(O)=O)C=C1 GBRNGKXUAWGDEN-UHFFFAOYSA-N 0.000 description 2
- PZEJVIXSQRUYHB-UHFFFAOYSA-N 4-(tert-butylcarbamoyloxy)-2-[4-[(4-methoxybenzoyl)amino]phenyl]sulfonylbutanoic acid Chemical compound C1=CC(OC)=CC=C1C(=O)NC1=CC=C(S(=O)(=O)C(CCOC(=O)NC(C)(C)C)C(O)=O)C=C1 PZEJVIXSQRUYHB-UHFFFAOYSA-N 0.000 description 2
- QYSIWAODUJWUTH-UHFFFAOYSA-N 4-[(2-fluorophenyl)carbamoyloxy]-2-[4-[(4-methoxybenzoyl)amino]phenyl]sulfonylbutanoic acid Chemical compound C1=CC(OC)=CC=C1C(=O)NC1=CC=C(S(=O)(=O)C(CCOC(=O)NC=2C(=CC=CC=2)F)C(O)=O)C=C1 QYSIWAODUJWUTH-UHFFFAOYSA-N 0.000 description 2
- BTPXRUMJFIPPMJ-UHFFFAOYSA-N 4-[(2-fluorophenyl)carbamoyloxy]-2-[4-[(4-methylbenzoyl)amino]phenyl]sulfanylbutanoic acid Chemical compound C1=CC(C)=CC=C1C(=O)NC(C=C1)=CC=C1SC(C(O)=O)CCOC(=O)NC1=CC=CC=C1F BTPXRUMJFIPPMJ-UHFFFAOYSA-N 0.000 description 2
- NZXHODFGOOMNLQ-UHFFFAOYSA-N 4-[(3,4-dichlorophenyl)carbamoyloxy]-2-[4-[(4-methoxybenzoyl)amino]phenyl]sulfanylbutanoic acid Chemical compound C1=CC(OC)=CC=C1C(=O)NC(C=C1)=CC=C1SC(C(O)=O)CCOC(=O)NC1=CC=C(Cl)C(Cl)=C1 NZXHODFGOOMNLQ-UHFFFAOYSA-N 0.000 description 2
- NBBZMYJBDCOHGA-UHFFFAOYSA-N 4-[(3,4-dichlorophenyl)carbamoyloxy]-2-[4-[(4-methylbenzoyl)amino]phenyl]sulfanylbutanoic acid Chemical compound C1=CC(C)=CC=C1C(=O)NC(C=C1)=CC=C1SC(C(O)=O)CCOC(=O)NC1=CC=C(Cl)C(Cl)=C1 NBBZMYJBDCOHGA-UHFFFAOYSA-N 0.000 description 2
- SDCCUNIBLOFCBS-UHFFFAOYSA-N 4-[(3,4-dichlorophenyl)carbamoyloxy]-2-[4-[(4-methylbenzoyl)amino]phenyl]sulfonylbutanoic acid Chemical compound C1=CC(C)=CC=C1C(=O)NC1=CC=C(S(=O)(=O)C(CCOC(=O)NC=2C=C(Cl)C(Cl)=CC=2)C(O)=O)C=C1 SDCCUNIBLOFCBS-UHFFFAOYSA-N 0.000 description 2
- MVKIAUCJHQZKJC-UHFFFAOYSA-N 4-[(3-chlorophenyl)carbamoyloxy]-2-[4-[(4-chlorophenyl)carbamoyl]phenyl]sulfanylbutanoic acid Chemical compound C=1C=C(C(=O)NC=2C=CC(Cl)=CC=2)C=CC=1SC(C(=O)O)CCOC(=O)NC1=CC=CC(Cl)=C1 MVKIAUCJHQZKJC-UHFFFAOYSA-N 0.000 description 2
- XNNDRDUHFGDTHE-UHFFFAOYSA-N 4-[(3-fluorophenyl)carbamoyloxy]-2-[4-[(4-methoxybenzoyl)amino]phenyl]sulfanylbutanoic acid Chemical compound C1=CC(OC)=CC=C1C(=O)NC(C=C1)=CC=C1SC(C(O)=O)CCOC(=O)NC1=CC=CC(F)=C1 XNNDRDUHFGDTHE-UHFFFAOYSA-N 0.000 description 2
- QWMCBZAOTSPLNN-UHFFFAOYSA-N 4-[(3-fluorophenyl)carbamoyloxy]-2-[4-[(4-methylbenzoyl)amino]phenyl]sulfanylbutanoic acid Chemical compound C1=CC(C)=CC=C1C(=O)NC(C=C1)=CC=C1SC(C(O)=O)CCOC(=O)NC1=CC=CC(F)=C1 QWMCBZAOTSPLNN-UHFFFAOYSA-N 0.000 description 2
- GPSQZBJAMACRBV-UHFFFAOYSA-N 4-[(3-fluorophenyl)carbamoyloxy]-2-[4-[(4-methylbenzoyl)amino]phenyl]sulfonylbutanoic acid Chemical compound C1=CC(C)=CC=C1C(=O)NC1=CC=C(S(=O)(=O)C(CCOC(=O)NC=2C=C(F)C=CC=2)C(O)=O)C=C1 GPSQZBJAMACRBV-UHFFFAOYSA-N 0.000 description 2
- MKVXAFAMSQICJV-UHFFFAOYSA-N 4-[(4-chlorophenyl)carbamoyloxy]-2-[4-[(4-methoxybenzoyl)amino]phenyl]sulfonylbutanoic acid Chemical compound C1=CC(OC)=CC=C1C(=O)NC1=CC=C(S(=O)(=O)C(CCOC(=O)NC=2C=CC(Cl)=CC=2)C(O)=O)C=C1 MKVXAFAMSQICJV-UHFFFAOYSA-N 0.000 description 2
- IDMSBJUMAVOTCD-UHFFFAOYSA-N 4-[(4-ethylphenyl)carbamoyloxy]-2-[4-[(4-methoxybenzoyl)amino]phenyl]sulfanylbutanoic acid Chemical compound C1=CC(CC)=CC=C1NC(=O)OCCC(C(O)=O)SC(C=C1)=CC=C1NC(=O)C1=CC=C(OC)C=C1 IDMSBJUMAVOTCD-UHFFFAOYSA-N 0.000 description 2
- DGZGQNQSMGOPFM-UHFFFAOYSA-N 4-[(4-ethylphenyl)carbamoyloxy]-2-[4-[(4-methoxybenzoyl)amino]phenyl]sulfonylbutanoic acid Chemical compound C1=CC(CC)=CC=C1NC(=O)OCCC(C(O)=O)S(=O)(=O)C(C=C1)=CC=C1NC(=O)C1=CC=C(OC)C=C1 DGZGQNQSMGOPFM-UHFFFAOYSA-N 0.000 description 2
- AXBVSRMHOPMXBA-UHFFFAOYSA-N 4-nitrothiophenol Chemical compound [O-][N+](=O)C1=CC=C(S)C=C1 AXBVSRMHOPMXBA-UHFFFAOYSA-N 0.000 description 2
- 229920002785 Croscarmellose sodium Polymers 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- 102000010911 Enzyme Precursors Human genes 0.000 description 2
- 108010062466 Enzyme Precursors Proteins 0.000 description 2
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 2
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 102000000380 Matrix Metalloproteinase 1 Human genes 0.000 description 2
- 108010016113 Matrix Metalloproteinase 1 Proteins 0.000 description 2
- 102000005741 Metalloproteases Human genes 0.000 description 2
- 108010006035 Metalloproteases Proteins 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- 229920000881 Modified starch Polymers 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 102000035195 Peptidases Human genes 0.000 description 2
- 108091005804 Peptidases Proteins 0.000 description 2
- 239000007868 Raney catalyst Substances 0.000 description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 2
- 229910000564 Raney nickel Inorganic materials 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- AYJRCSIUFZENHW-UHFFFAOYSA-L barium carbonate Chemical compound [Ba+2].[O-]C([O-])=O AYJRCSIUFZENHW-UHFFFAOYSA-L 0.000 description 2
- 125000004622 benzoxazinyl group Chemical group O1NC(=CC2=C1C=CC=C2)* 0.000 description 2
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 239000004305 biphenyl Chemical group 0.000 description 2
- 235000010290 biphenyl Nutrition 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 229960001681 croscarmellose sodium Drugs 0.000 description 2
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 2
- 125000006165 cyclic alkyl group Chemical group 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 229940000406 drug candidate Drugs 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- KYHRMDZMWJWBCC-UHFFFAOYSA-N ethyl 2-(4-nitrophenyl)sulfonyl-4-phenylmethoxybutanoate Chemical compound C=1C=C([N+]([O-])=O)C=CC=1S(=O)(=O)C(C(=O)OCC)CCOCC1=CC=CC=C1 KYHRMDZMWJWBCC-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 210000002744 extracellular matrix Anatomy 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- 150000002430 hydrocarbons Chemical group 0.000 description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- PQNFLJBBNBOBRQ-UHFFFAOYSA-N indane Chemical compound C1=CC=C2CCCC2=C1 PQNFLJBBNBOBRQ-UHFFFAOYSA-N 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- 229910052742 iron Inorganic materials 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 239000003865 nucleic acid synthesis inhibitor Substances 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 2
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 2
- 125000004193 piperazinyl group Chemical group 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920006316 polyvinylpyrrolidine Polymers 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 235000019833 protease Nutrition 0.000 description 2
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 238000007634 remodeling Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 2
- 125000003831 tetrazolyl group Chemical group 0.000 description 2
- 239000011135 tin Substances 0.000 description 2
- 229910052718 tin Inorganic materials 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 1
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 description 1
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 description 1
- UXTZUUVTGMDXNG-UHFFFAOYSA-N 1,2-benzoxazine-3,4-dione Chemical compound C1=CC=C2C(=O)C(=O)NOC2=C1 UXTZUUVTGMDXNG-UHFFFAOYSA-N 0.000 description 1
- 229940058015 1,3-butylene glycol Drugs 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 1
- DMSSTTLDFWKBSX-UHFFFAOYSA-N 1h-1,2,3-benzotriazin-4-one Chemical group C1=CC=C2C(=O)N=NNC2=C1 DMSSTTLDFWKBSX-UHFFFAOYSA-N 0.000 description 1
- KLIDCXVFHGNTTM-UHFFFAOYSA-N 2,6-dimethoxyphenol Chemical group COC1=CC=CC(OC)=C1O KLIDCXVFHGNTTM-UHFFFAOYSA-N 0.000 description 1
- IEQAICDLOKRSRL-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-dodecoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical compound CCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO IEQAICDLOKRSRL-UHFFFAOYSA-N 0.000 description 1
- ZRKMQNCJUOPFKS-UHFFFAOYSA-N 2-[4-(cyclopropanecarbonylamino)phenyl]sulfanyl-4-[[4-(trifluoromethyl)phenyl]carbamoyloxy]butanoic acid Chemical compound C=1C=C(NC(=O)C2CC2)C=CC=1SC(C(=O)O)CCOC(=O)NC1=CC=C(C(F)(F)F)C=C1 ZRKMQNCJUOPFKS-UHFFFAOYSA-N 0.000 description 1
- DELATDGSLLNTTJ-UHFFFAOYSA-N 2-[4-[(2,6-dimethoxybenzoyl)amino]phenyl]sulfanyl-4-[[4-(trifluoromethyl)phenyl]carbamoyloxy]butanoic acid Chemical compound COC1=CC=CC(OC)=C1C(=O)NC(C=C1)=CC=C1SC(C(O)=O)CCOC(=O)NC1=CC=C(C(F)(F)F)C=C1 DELATDGSLLNTTJ-UHFFFAOYSA-N 0.000 description 1
- HXPCCAQEXHBWJU-UHFFFAOYSA-N 2-[4-[(2-fluorobenzoyl)amino]phenyl]sulfanyl-4-[[4-(trifluoromethyl)phenyl]carbamoyloxy]butanoic acid Chemical compound C=1C=C(NC(=O)C=2C(=CC=CC=2)F)C=CC=1SC(C(=O)O)CCOC(=O)NC1=CC=C(C(F)(F)F)C=C1 HXPCCAQEXHBWJU-UHFFFAOYSA-N 0.000 description 1
- RFUZLFOZRVDVEV-UHFFFAOYSA-N 2-[4-[(4-chlorobenzoyl)amino]phenyl]sulfanyl-4-[(2-fluorophenyl)carbamoyloxy]butanoic acid Chemical compound C=1C=C(NC(=O)C=2C=CC(Cl)=CC=2)C=CC=1SC(C(=O)O)CCOC(=O)NC1=CC=CC=C1F RFUZLFOZRVDVEV-UHFFFAOYSA-N 0.000 description 1
- SBSARAUACUEKCX-UHFFFAOYSA-N 2-[4-[(4-chlorobenzoyl)amino]phenyl]sulfanyl-4-[(3-chloro-4-methoxyphenyl)carbamoyloxy]butanoic acid Chemical compound C1=C(Cl)C(OC)=CC=C1NC(=O)OCCC(C(O)=O)SC(C=C1)=CC=C1NC(=O)C1=CC=C(Cl)C=C1 SBSARAUACUEKCX-UHFFFAOYSA-N 0.000 description 1
- YIZGQIBKRMUGMA-UHFFFAOYSA-N 2-[4-[(4-chlorobenzoyl)amino]phenyl]sulfanyl-4-[(3-cyanophenyl)carbamothioyloxy]butanoic acid Chemical compound C=1C=C(NC(=O)C=2C=CC(Cl)=CC=2)C=CC=1SC(C(=O)O)CCOC(=S)NC1=CC=CC(C#N)=C1 YIZGQIBKRMUGMA-UHFFFAOYSA-N 0.000 description 1
- OBJYFCNDTXZIHU-UHFFFAOYSA-N 2-[4-[(4-chlorobenzoyl)amino]phenyl]sulfanyl-4-[(4-chlorophenyl)carbamoyloxy]butanoic acid Chemical compound C=1C=C(NC(=O)C=2C=CC(Cl)=CC=2)C=CC=1SC(C(=O)O)CCOC(=O)NC1=CC=C(Cl)C=C1 OBJYFCNDTXZIHU-UHFFFAOYSA-N 0.000 description 1
- KNHMHYKZUXDUCN-UHFFFAOYSA-N 2-[4-[(4-chlorobenzoyl)amino]phenyl]sulfanyl-4-[(5-fluoro-2-methylphenyl)carbamoyloxy]butanoic acid Chemical compound CC1=CC=C(F)C=C1NC(=O)OCCC(C(O)=O)SC(C=C1)=CC=C1NC(=O)C1=CC=C(Cl)C=C1 KNHMHYKZUXDUCN-UHFFFAOYSA-N 0.000 description 1
- AANGGSVALJDQQP-UHFFFAOYSA-N 2-[4-[(4-chlorobenzoyl)amino]phenyl]sulfanyl-4-[[2-fluoro-5-(trifluoromethyl)phenyl]carbamoyloxy]butanoic acid Chemical compound C=1C=C(NC(=O)C=2C=CC(Cl)=CC=2)C=CC=1SC(C(=O)O)CCOC(=O)NC1=CC(C(F)(F)F)=CC=C1F AANGGSVALJDQQP-UHFFFAOYSA-N 0.000 description 1
- XRKGPHUHNWLOSZ-UHFFFAOYSA-N 2-[4-[(4-chlorobenzoyl)amino]phenyl]sulfanyl-4-[[4-(trifluoromethyl)phenyl]carbamoyloxy]butanoic acid Chemical compound C=1C=C(NC(=O)C=2C=CC(Cl)=CC=2)C=CC=1SC(C(=O)O)CCOC(=O)NC1=CC=C(C(F)(F)F)C=C1 XRKGPHUHNWLOSZ-UHFFFAOYSA-N 0.000 description 1
- ABURBYLXDGNTFF-UHFFFAOYSA-N 2-[4-[(4-chlorobenzoyl)amino]phenyl]sulfonyl-4-[[2-fluoro-5-(trifluoromethyl)phenyl]carbamoyloxy]butanoic acid Chemical compound C=1C=C(NC(=O)C=2C=CC(Cl)=CC=2)C=CC=1S(=O)(=O)C(C(=O)O)CCOC(=O)NC1=CC(C(F)(F)F)=CC=C1F ABURBYLXDGNTFF-UHFFFAOYSA-N 0.000 description 1
- AGVYFWPCQSIIRW-UHFFFAOYSA-N 2-[4-[(4-chlorophenyl)carbamoyl]phenyl]sulfanyl-4-[(2,4-difluorophenyl)carbamoyloxy]butanoic acid Chemical compound C=1C=C(C(=O)NC=2C=CC(Cl)=CC=2)C=CC=1SC(C(=O)O)CCOC(=O)NC1=CC=C(F)C=C1F AGVYFWPCQSIIRW-UHFFFAOYSA-N 0.000 description 1
- IJCWOZVQNWQQOF-UHFFFAOYSA-N 2-[4-[(4-chlorophenyl)carbamoyl]phenyl]sulfanyl-4-[(2,6-dichlorophenyl)carbamoyloxy]butanoic acid Chemical compound C=1C=C(C(=O)NC=2C=CC(Cl)=CC=2)C=CC=1SC(C(=O)O)CCOC(=O)NC1=C(Cl)C=CC=C1Cl IJCWOZVQNWQQOF-UHFFFAOYSA-N 0.000 description 1
- IRUORIDTECXBCS-UHFFFAOYSA-N 2-[4-[(4-chlorophenyl)carbamoyl]phenyl]sulfanyl-4-[(2-fluorophenyl)carbamoyloxy]butanoic acid Chemical compound C=1C=C(C(=O)NC=2C=CC(Cl)=CC=2)C=CC=1SC(C(=O)O)CCOC(=O)NC1=CC=CC=C1F IRUORIDTECXBCS-UHFFFAOYSA-N 0.000 description 1
- UURIOHRUAVNOQM-UHFFFAOYSA-N 2-[4-[(4-chlorophenyl)carbamoyl]phenyl]sulfanyl-4-[(2-methylphenyl)carbamoyloxy]butanoic acid Chemical compound CC1=CC=CC=C1NC(=O)OCCC(C(O)=O)SC1=CC=C(C(=O)NC=2C=CC(Cl)=CC=2)C=C1 UURIOHRUAVNOQM-UHFFFAOYSA-N 0.000 description 1
- IZMWZRMLRXFSFU-UHFFFAOYSA-N 2-[4-[(4-chlorophenyl)carbamoyl]phenyl]sulfanyl-4-[(3,4-dichlorophenyl)carbamoyloxy]butanoic acid Chemical compound C=1C=C(C(=O)NC=2C=CC(Cl)=CC=2)C=CC=1SC(C(=O)O)CCOC(=O)NC1=CC=C(Cl)C(Cl)=C1 IZMWZRMLRXFSFU-UHFFFAOYSA-N 0.000 description 1
- ZIKGEFQESZPJLD-UHFFFAOYSA-N 2-[4-[(4-chlorophenyl)carbamoyl]phenyl]sulfanyl-4-[(3-fluorophenyl)carbamoyloxy]butanoic acid Chemical compound C=1C=C(C(=O)NC=2C=CC(Cl)=CC=2)C=CC=1SC(C(=O)O)CCOC(=O)NC1=CC=CC(F)=C1 ZIKGEFQESZPJLD-UHFFFAOYSA-N 0.000 description 1
- JSSRGGYPLBDLHI-UHFFFAOYSA-N 2-[4-[(4-chlorophenyl)carbamoyl]phenyl]sulfonyl-4-(pentylcarbamoyloxy)butanoic acid Chemical compound C1=CC(S(=O)(=O)C(C(O)=O)CCOC(=O)NCCCCC)=CC=C1C(=O)NC1=CC=C(Cl)C=C1 JSSRGGYPLBDLHI-UHFFFAOYSA-N 0.000 description 1
- MUVYYAIWZVVVQC-UHFFFAOYSA-N 2-[4-[(4-chlorophenyl)carbamoyl]phenyl]sulfonyl-4-[(2,4-difluorophenyl)carbamoyloxy]butanoic acid Chemical compound C=1C=C(C(=O)NC=2C=CC(Cl)=CC=2)C=CC=1S(=O)(=O)C(C(=O)O)CCOC(=O)NC1=CC=C(F)C=C1F MUVYYAIWZVVVQC-UHFFFAOYSA-N 0.000 description 1
- APWAUSWAFRNKCG-UHFFFAOYSA-N 2-[4-[(4-chlorophenyl)carbamoyl]phenyl]sulfonyl-4-[(2-fluorophenyl)carbamoyloxy]butanoic acid Chemical compound C=1C=C(C(=O)NC=2C=CC(Cl)=CC=2)C=CC=1S(=O)(=O)C(C(=O)O)CCOC(=O)NC1=CC=CC=C1F APWAUSWAFRNKCG-UHFFFAOYSA-N 0.000 description 1
- PLXQACLYRNHRBV-UHFFFAOYSA-N 2-[4-[(4-chlorophenyl)carbamoyl]phenyl]sulfonyl-4-[(3,4-dichlorophenyl)carbamoyloxy]butanoic acid Chemical compound C=1C=C(C(=O)NC=2C=CC(Cl)=CC=2)C=CC=1S(=O)(=O)C(C(=O)O)CCOC(=O)NC1=CC=C(Cl)C(Cl)=C1 PLXQACLYRNHRBV-UHFFFAOYSA-N 0.000 description 1
- BVDDXJIYEDDNGU-UHFFFAOYSA-N 2-[4-[(4-chlorophenyl)carbamoyl]phenyl]sulfonyl-4-[(4-ethylphenyl)carbamoyloxy]butanoic acid Chemical compound C1=CC(CC)=CC=C1NC(=O)OCCC(C(O)=O)S(=O)(=O)C1=CC=C(C(=O)NC=2C=CC(Cl)=CC=2)C=C1 BVDDXJIYEDDNGU-UHFFFAOYSA-N 0.000 description 1
- QFJIGPGTNFPRPY-UHFFFAOYSA-N 2-[4-[(4-chlorophenyl)carbamoyl]phenyl]sulfonyl-4-[(4-fluorophenyl)carbamoyloxy]butanoic acid Chemical compound C=1C=C(C(=O)NC=2C=CC(Cl)=CC=2)C=CC=1S(=O)(=O)C(C(=O)O)CCOC(=O)NC1=CC=C(F)C=C1 QFJIGPGTNFPRPY-UHFFFAOYSA-N 0.000 description 1
- SCLJSFNULGSMJQ-UHFFFAOYSA-N 2-[4-[(4-chlorophenyl)carbamoyl]phenyl]sulfonyl-4-[[4-(trifluoromethyl)phenyl]carbamoyloxy]butanoic acid Chemical compound C=1C=C(C(=O)NC=2C=CC(Cl)=CC=2)C=CC=1S(=O)(=O)C(C(=O)O)CCOC(=O)NC1=CC=C(C(F)(F)F)C=C1 SCLJSFNULGSMJQ-UHFFFAOYSA-N 0.000 description 1
- SPAWCTUPOLDCOH-UHFFFAOYSA-N 2-[4-[(4-methoxybenzoyl)amino]phenyl]sulfanyl-4-[(4-methoxyphenyl)carbamoyloxy]butanoic acid Chemical compound C1=CC(OC)=CC=C1NC(=O)OCCC(C(O)=O)SC(C=C1)=CC=C1NC(=O)C1=CC=C(OC)C=C1 SPAWCTUPOLDCOH-UHFFFAOYSA-N 0.000 description 1
- BXDLPFRXTLCFPI-UHFFFAOYSA-N 2-[4-[(4-methoxybenzoyl)amino]phenyl]sulfonyl-4-[(2-methylphenyl)carbamoyloxy]butanoic acid Chemical compound C1=CC(OC)=CC=C1C(=O)NC1=CC=C(S(=O)(=O)C(CCOC(=O)NC=2C(=CC=CC=2)C)C(O)=O)C=C1 BXDLPFRXTLCFPI-UHFFFAOYSA-N 0.000 description 1
- PNLLRJJDOUGNIO-UHFFFAOYSA-N 2-[4-[(4-methoxybenzoyl)amino]phenyl]sulfonyl-4-[[4-(trifluoromethyl)phenyl]carbamoyloxy]butanoic acid Chemical compound C1=CC(OC)=CC=C1C(=O)NC1=CC=C(S(=O)(=O)C(CCOC(=O)NC=2C=CC(=CC=2)C(F)(F)F)C(O)=O)C=C1 PNLLRJJDOUGNIO-UHFFFAOYSA-N 0.000 description 1
- VKUYLANQOAKALN-UHFFFAOYSA-N 2-[benzyl-(4-methoxyphenyl)sulfonylamino]-n-hydroxy-4-methylpentanamide Chemical compound C1=CC(OC)=CC=C1S(=O)(=O)N(C(CC(C)C)C(=O)NO)CC1=CC=CC=C1 VKUYLANQOAKALN-UHFFFAOYSA-N 0.000 description 1
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical compound C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 description 1
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 1
- RAZVFEJOZHRSAC-UHFFFAOYSA-N 3-(4-chlorophenyl)sulfanyloxolan-2-one Chemical compound C1=CC(Cl)=CC=C1SC1C(=O)OCC1 RAZVFEJOZHRSAC-UHFFFAOYSA-N 0.000 description 1
- YGAMTFWLEVVXIX-UHFFFAOYSA-N 3-(4-nitrophenyl)sulfanyloxolan-2-one Chemical compound C1=CC([N+](=O)[O-])=CC=C1SC1C(=O)OCC1 YGAMTFWLEVVXIX-UHFFFAOYSA-N 0.000 description 1
- HJBLUNHMOKFZQX-UHFFFAOYSA-N 3-hydroxy-1,2,3-benzotriazin-4-one Chemical compound C1=CC=C2C(=O)N(O)N=NC2=C1 HJBLUNHMOKFZQX-UHFFFAOYSA-N 0.000 description 1
- PCYBGEKXCCDMAU-UHFFFAOYSA-N 4-(2-oxooxolan-3-yl)sulfanylbenzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1SC1C(=O)OCC1 PCYBGEKXCCDMAU-UHFFFAOYSA-N 0.000 description 1
- UDLKXKBFRQOJOT-UHFFFAOYSA-N 4-(butylcarbamoyloxy)-2-[4-[(4-chlorophenyl)carbamoyl]phenyl]sulfanylbutanoic acid Chemical compound C1=CC(SC(CCOC(=O)NCCCC)C(O)=O)=CC=C1C(=O)NC1=CC=C(Cl)C=C1 UDLKXKBFRQOJOT-UHFFFAOYSA-N 0.000 description 1
- LFUQRGHHUBLHIB-UHFFFAOYSA-N 4-(tert-butylcarbamoyloxy)-2-[4-[(4-chlorophenyl)carbamoyl]phenyl]sulfanylbutanoic acid Chemical compound C1=CC(SC(CCOC(=O)NC(C)(C)C)C(O)=O)=CC=C1C(=O)NC1=CC=C(Cl)C=C1 LFUQRGHHUBLHIB-UHFFFAOYSA-N 0.000 description 1
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 description 1
- ZIGQZQTUMAKIBI-UHFFFAOYSA-N 4-[(2,4-difluorophenyl)carbamoyloxy]-2-[4-[(4-methoxybenzoyl)amino]phenyl]sulfanylbutanoic acid Chemical compound C1=CC(OC)=CC=C1C(=O)NC(C=C1)=CC=C1SC(C(O)=O)CCOC(=O)NC1=CC=C(F)C=C1F ZIGQZQTUMAKIBI-UHFFFAOYSA-N 0.000 description 1
- YVRANOBWAOGKRE-UHFFFAOYSA-N 4-[(2,4-difluorophenyl)carbamoyloxy]-2-[4-[(4-methoxybenzoyl)amino]phenyl]sulfonylbutanoic acid Chemical compound C1=CC(OC)=CC=C1C(=O)NC1=CC=C(S(=O)(=O)C(CCOC(=O)NC=2C(=CC(F)=CC=2)F)C(O)=O)C=C1 YVRANOBWAOGKRE-UHFFFAOYSA-N 0.000 description 1
- ANOXFJLYFCRGAV-UHFFFAOYSA-N 4-[(2,4-difluorophenyl)carbamoyloxy]-2-[4-[(4-methylbenzoyl)amino]phenyl]sulfanylbutanoic acid Chemical compound C1=CC(C)=CC=C1C(=O)NC(C=C1)=CC=C1SC(C(O)=O)CCOC(=O)NC1=CC=C(F)C=C1F ANOXFJLYFCRGAV-UHFFFAOYSA-N 0.000 description 1
- HBSNNBUPECSCHD-UHFFFAOYSA-N 4-[(2,4-difluorophenyl)carbamoyloxy]-2-[4-[(4-methylbenzoyl)amino]phenyl]sulfonylbutanoic acid Chemical compound C1=CC(C)=CC=C1C(=O)NC1=CC=C(S(=O)(=O)C(CCOC(=O)NC=2C(=CC(F)=CC=2)F)C(O)=O)C=C1 HBSNNBUPECSCHD-UHFFFAOYSA-N 0.000 description 1
- BPXIFCARYCRHPB-UHFFFAOYSA-N 4-[(2,6-dichlorophenyl)carbamoyloxy]-2-[4-[(4-methoxybenzoyl)amino]phenyl]sulfanylbutanoic acid Chemical compound C1=CC(OC)=CC=C1C(=O)NC(C=C1)=CC=C1SC(C(O)=O)CCOC(=O)NC1=C(Cl)C=CC=C1Cl BPXIFCARYCRHPB-UHFFFAOYSA-N 0.000 description 1
- KBTOIAQESYTZKA-UHFFFAOYSA-N 4-[(2,6-dichlorophenyl)carbamoyloxy]-2-[4-[(4-methoxybenzoyl)amino]phenyl]sulfonylbutanoic acid Chemical compound C1=CC(OC)=CC=C1C(=O)NC1=CC=C(S(=O)(=O)C(CCOC(=O)NC=2C(=CC=CC=2Cl)Cl)C(O)=O)C=C1 KBTOIAQESYTZKA-UHFFFAOYSA-N 0.000 description 1
- LMZVAKVGSTZNTO-UHFFFAOYSA-N 4-[(2-fluorophenyl)carbamoyloxy]-2-[4-[(4-methoxybenzoyl)amino]phenyl]sulfanylbutanoic acid Chemical compound C1=CC(OC)=CC=C1C(=O)NC(C=C1)=CC=C1SC(C(O)=O)CCOC(=O)NC1=CC=CC=C1F LMZVAKVGSTZNTO-UHFFFAOYSA-N 0.000 description 1
- NHCJBOVRKHIGPX-UHFFFAOYSA-N 4-[(3,4-dichlorophenyl)carbamoyloxy]-2-[4-[(4-methoxybenzoyl)amino]phenyl]sulfonylbutanoic acid Chemical compound C1=CC(OC)=CC=C1C(=O)NC1=CC=C(S(=O)(=O)C(CCOC(=O)NC=2C=C(Cl)C(Cl)=CC=2)C(O)=O)C=C1 NHCJBOVRKHIGPX-UHFFFAOYSA-N 0.000 description 1
- JTYPCOOMIYUPNS-UHFFFAOYSA-N 4-[(3-chlorophenyl)carbamoyloxy]-2-[4-[(4-chlorophenyl)carbamoyl]phenyl]sulfonylbutanoic acid Chemical compound C=1C=C(C(=O)NC=2C=CC(Cl)=CC=2)C=CC=1S(=O)(=O)C(C(=O)O)CCOC(=O)NC1=CC=CC(Cl)=C1 JTYPCOOMIYUPNS-UHFFFAOYSA-N 0.000 description 1
- WXIMMVCQAVHHOW-UHFFFAOYSA-N 4-[(5-chloro-2-methoxyphenyl)carbamoyloxy]-2-[4-[(4-methoxybenzoyl)amino]phenyl]sulfonylbutanoic acid Chemical compound C1=CC(OC)=CC=C1C(=O)NC1=CC=C(S(=O)(=O)C(CCOC(=O)NC=2C(=CC=C(Cl)C=2)OC)C(O)=O)C=C1 WXIMMVCQAVHHOW-UHFFFAOYSA-N 0.000 description 1
- GAMYYCRTACQSBR-UHFFFAOYSA-N 4-azabenzimidazole Chemical compound C1=CC=C2NC=NC2=N1 GAMYYCRTACQSBR-UHFFFAOYSA-N 0.000 description 1
- QSNSCYSYFYORTR-UHFFFAOYSA-N 4-chloroaniline Chemical compound NC1=CC=C(Cl)C=C1 QSNSCYSYFYORTR-UHFFFAOYSA-N 0.000 description 1
- VZXOZSQDJJNBRC-UHFFFAOYSA-N 4-chlorobenzenethiol Chemical compound SC1=CC=C(Cl)C=C1 VZXOZSQDJJNBRC-UHFFFAOYSA-N 0.000 description 1
- RKIDDEGICSMIJA-UHFFFAOYSA-N 4-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=C(Cl)C=C1 RKIDDEGICSMIJA-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- LMJXSOYPAOSIPZ-UHFFFAOYSA-N 4-sulfanylbenzoic acid Chemical compound OC(=O)C1=CC=C(S)C=C1 LMJXSOYPAOSIPZ-UHFFFAOYSA-N 0.000 description 1
- 229940124125 5 Lipoxygenase inhibitor Drugs 0.000 description 1
- GOZMBJCYMQQACI-UHFFFAOYSA-N 6,7-dimethyl-3-[[methyl-[2-[methyl-[[1-[3-(trifluoromethyl)phenyl]indol-3-yl]methyl]amino]ethyl]amino]methyl]chromen-4-one;dihydrochloride Chemical compound Cl.Cl.C=1OC2=CC(C)=C(C)C=C2C(=O)C=1CN(C)CCN(C)CC(C1=CC=CC=C11)=CN1C1=CC=CC(C(F)(F)F)=C1 GOZMBJCYMQQACI-UHFFFAOYSA-N 0.000 description 1
- 102100026802 72 kDa type IV collagenase Human genes 0.000 description 1
- 101710151806 72 kDa type IV collagenase Proteins 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000000884 Airway Obstruction Diseases 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
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 235000003276 Apios tuberosa Nutrition 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- 235000010777 Arachis hypogaea Nutrition 0.000 description 1
- 235000010744 Arachis villosulicarpa Nutrition 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 description 1
- XUVGEXCGIRYVRH-UHFFFAOYSA-N COC(=O)C(CCO)SC1=CC=C(Cl)C=C1 Chemical compound COC(=O)C(CCO)SC1=CC=C(Cl)C=C1 XUVGEXCGIRYVRH-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 102000005600 Cathepsins Human genes 0.000 description 1
- 108010084457 Cathepsins Proteins 0.000 description 1
- 229940123982 Cell wall synthesis inhibitor Drugs 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 102000029816 Collagenase Human genes 0.000 description 1
- 108060005980 Collagenase Proteins 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 240000006890 Erythroxylum coca Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 102000013382 Gelatinases Human genes 0.000 description 1
- 108010026132 Gelatinases Proteins 0.000 description 1
- 102000002068 Glycopeptides Human genes 0.000 description 1
- 108010015899 Glycopeptides Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-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
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 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
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 102100027998 Macrophage metalloelastase Human genes 0.000 description 1
- 101710187853 Macrophage metalloelastase Proteins 0.000 description 1
- 235000019759 Maize starch Nutrition 0.000 description 1
- 102100030417 Matrilysin Human genes 0.000 description 1
- 108090000855 Matrilysin Proteins 0.000 description 1
- 108010076557 Matrix Metalloproteinase 14 Proteins 0.000 description 1
- 102100030216 Matrix metalloproteinase-14 Human genes 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 102000036436 Metzincins Human genes 0.000 description 1
- 108091007161 Metzincins Proteins 0.000 description 1
- 101150101095 Mmp12 gene Proteins 0.000 description 1
- 229920000715 Mucilage Polymers 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 240000007817 Olea europaea Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229940123573 Protein synthesis inhibitor Drugs 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 102100030416 Stromelysin-1 Human genes 0.000 description 1
- 101710108790 Stromelysin-1 Proteins 0.000 description 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 229940126575 aminoglycoside Drugs 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 1
- 229910001863 barium hydroxide Inorganic materials 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 229960002903 benzyl benzoate Drugs 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 239000004067 bulking agent Substances 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- 235000014121 butter Nutrition 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
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 150000005829 chemical entities Chemical class 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- BFPSDSIWYFKGBC-UHFFFAOYSA-N chlorotrianisene Chemical compound C1=CC(OC)=CC=C1C(Cl)=C(C=1C=CC(OC)=CC=1)C1=CC=C(OC)C=C1 BFPSDSIWYFKGBC-UHFFFAOYSA-N 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
- 239000011248 coating agent Substances 0.000 description 1
- 235000008957 cocaer Nutrition 0.000 description 1
- ZPUCINDJVBIVPJ-LJISPDSOSA-N cocaine Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 description 1
- 230000037369 collagen remodeling Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- UKJLNMAFNRKWGR-UHFFFAOYSA-N cyclohexatrienamine Chemical group NC1=CC=C=C[CH]1 UKJLNMAFNRKWGR-UHFFFAOYSA-N 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 239000012351 deprotecting agent Substances 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 125000004598 dihydrobenzofuryl group Chemical group O1C(CC2=C1C=CC=C2)* 0.000 description 1
- 125000004852 dihydrofuranyl group Chemical group O1C(CC=C1)* 0.000 description 1
- 125000001070 dihydroindolyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000005048 dihydroisoxazolyl group Chemical group O1N(CC=C1)* 0.000 description 1
- 125000004655 dihydropyridinyl group Chemical group N1(CC=CC=C1)* 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 125000005805 dimethoxy phenyl group Chemical group 0.000 description 1
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000003221 ear drop Substances 0.000 description 1
- 229940047652 ear drops Drugs 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000013020 embryo development Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- UDFBWDNLJBHCNA-UHFFFAOYSA-N ethyl 2-(4-aminophenyl)sulfonyl-4-phenylmethoxybutanoate Chemical compound C=1C=C(N)C=CC=1S(=O)(=O)C(C(=O)OCC)CCOCC1=CC=CC=C1 UDFBWDNLJBHCNA-UHFFFAOYSA-N 0.000 description 1
- RUFWJCXCVXSNQN-UHFFFAOYSA-N ethyl 2-(4-nitrophenyl)sulfanylacetate Chemical compound CCOC(=O)CSC1=CC=C([N+]([O-])=O)C=C1 RUFWJCXCVXSNQN-UHFFFAOYSA-N 0.000 description 1
- IADNJKLOCURMTC-UHFFFAOYSA-N ethyl 2-(4-nitrophenyl)sulfonylacetate Chemical compound CCOC(=O)CS(=O)(=O)C1=CC=C([N+]([O-])=O)C=C1 IADNJKLOCURMTC-UHFFFAOYSA-N 0.000 description 1
- 229940093499 ethyl acetate Drugs 0.000 description 1
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 239000003885 eye ointment Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 239000003188 fatty acid synthesis inhibitor Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- WJRBRSLFGCUECM-UHFFFAOYSA-N hydantoin Chemical compound O=C1CNC(=O)N1 WJRBRSLFGCUECM-UHFFFAOYSA-N 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000011630 iodine Chemical group 0.000 description 1
- 208000023589 ischemic disease Diseases 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 230000037356 lipid metabolism Effects 0.000 description 1
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 1
- 229910052808 lithium carbonate Inorganic materials 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000005906 menstruation Effects 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- 125000001421 myristyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- GUAQVFRUPZBRJQ-UHFFFAOYSA-N n-(3-aminopropyl)-2-methylprop-2-enamide Chemical compound CC(=C)C(=O)NCCCN GUAQVFRUPZBRJQ-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- UMRZSTCPUPJPOJ-KNVOCYPGSA-N norbornane Chemical compound C1C[C@H]2CC[C@@H]1C2 UMRZSTCPUPJPOJ-KNVOCYPGSA-N 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000011164 ossification Effects 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- NIXKBAZVOQAHGC-UHFFFAOYSA-N phenylmethanesulfonic acid Chemical compound OS(=O)(=O)CC1=CC=CC=C1 NIXKBAZVOQAHGC-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- IJAPPYDYQCXOEF-UHFFFAOYSA-N phthalazin-1(2H)-one Chemical compound C1=CC=C2C(=O)NN=CC2=C1 IJAPPYDYQCXOEF-UHFFFAOYSA-N 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 229960004063 propylene glycol Drugs 0.000 description 1
- 239000000007 protein synthesis inhibitor Substances 0.000 description 1
- 239000003806 protein tyrosine phosphatase inhibitor Substances 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000009711 regulatory function Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229940080313 sodium starch Drugs 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000001119 stannous chloride Substances 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 108091007196 stromelysin Proteins 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000005309 thioalkoxy group Chemical group 0.000 description 1
- 125000004001 thioalkyl group Chemical group 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 150000008648 triflates Chemical class 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
- 150000003952 β-lactams Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
- C07C317/46—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/57—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing carboxyl groups bound to the carbon skeleton
- C07C309/60—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing carboxyl groups bound to the carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/325—Carbamic acids; Thiocarbamic acids; Anhydrides or salts thereof
-
- 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
- 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
- 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
- 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
- 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
- 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
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/04—Artificial tears; Irrigation solutions
-
- 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
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- 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
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C321/00—Thiols, sulfides, hydropolysulfides or polysulfides
- C07C321/24—Thiols, sulfides, hydropolysulfides, or polysulfides having thio groups bound to carbon atoms of six-membered aromatic rings
- C07C321/28—Sulfides, hydropolysulfides, or polysulfides having thio groups bound to carbon atoms of six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/52—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C333/00—Derivatives of thiocarbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C333/02—Monothiocarbamic acids; Derivatives thereof
- C07C333/08—Monothiocarbamic acids; Derivatives thereof having nitrogen atoms of thiocarbamic groups bound to carbon atoms of six-membered aromatic rings
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pulmonology (AREA)
- Rheumatology (AREA)
- Immunology (AREA)
- Urology & Nephrology (AREA)
- Epidemiology (AREA)
- Cardiology (AREA)
- Neurology (AREA)
- Oncology (AREA)
- Ophthalmology & Optometry (AREA)
- Otolaryngology (AREA)
- Heart & Thoracic Surgery (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Biomedical Technology (AREA)
- Pain & Pain Management (AREA)
- Neurosurgery (AREA)
- Dermatology (AREA)
- Vascular Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The present invention relates to certain sulfone acetic acid derivatives of formula I as MMP inhibitor and processes for its syntheses. The invention also relates to pharmacological compositions containing the compounds of the present invention and methods of treating asthma, rheumatoid arthritis, COPD, rhinitis, osteoarthritis, psoriatic arthritis, psoriasis, pulmonary fibrosis, pulmonary inflammation, acute respiratory distress syndrome, perodontitis, multiple scleorisis, gingivitis, atherosclerosis, dry eye, neointimal proliferation which leads to restenosis and ischemic heart failure, stroke, renal disease, tumor metastasis, and other inflammatory disorders characterized by over expression and over activation of a matrix metalloproteinase using the compounds.
Description
MATRIX METALLOPROTEINASE INHIBITORS
The present invention relates to certain sulfone acetic acid derivatives as MMP inhibitor and processes for its syntheses. The invention also relates to pharmacological compositions containing the compounds of the present invention and methods of treating asthma, rheumatoid arthritis, COPD, rhinitis, osteoarthritis, psoriatic arthritis, psoriasis, pulmonary fibrosis, pulmonary inflammation, acute respiratory distress syndrome, perodontitis, multiple scleorisis, gingivitis, atherosclerosis, dry eye, and neointimal proliferation which leads to restenosis and ischemic heart failure, stroke, renal disease, tumor metastasis, and other inflammatory disorders characterized by over expression and over activation of a matrix metalloproteinase using the compounds.
Metalloproteinases (MMPs) are a naturally occurring superfamily of proteinases (enzymes) found in most mammals. The superfamily is composed of at least 26 members of zinc-containing enzymes produced by many cell types; sharing structural and functional features. Based on structural and functional considerations proteinases have been classified into different families and subfamilies (Vartak et al., J. Drug Targeting, 15, p. 1-20 (2007), and Hopper, FEBS, 354, p. 1-6 (1994), such as collagenases (MMP-1, -8 and -13), gelatinases (MMP-2, and -9), metalloelastases (MMP-12), the MT-MMPs (MMP-14, -15,-16, -17, -24 and -25), matrilysins (MMP-7 and -26), stromelysins (MMP-3, -10 and -11) and sheddases such as TNF-converting enzymes (TACE, and ACE).
Metalloproteinases are believed to be important in physiological disease processes that involve remodeling such as embryonic development, bone formation and uterine remodeling during menstruation. One major biological function of MMPs is to catalyze the breakdown of connective tissues or extra-cellular matrix by their ability to hydrolyze various components of tissue or matrix. Apart from their role in degrading connective tissue, MMPs are involved in the activation of zymogen (pro) forms of other MMPs thereby inducing MMP activation. They are also involved in the biosynthesis of TNF- alpha which is implicated in many pathological conditions.
MMP-9 (gelatianse B) has been implicated in pathogenesis of COPD, MS and other inflammatory disorders. MMP-9 is secreted as proenzyme and upon activation, exhibits distinct roles in the progression of both disease states. For example, leukocyte mediated activation of MMP-9 exhibits during the inflammatory response associated with
COPD, marks the onset of processes linked to airway obstruction. MMP-9 is the primary pro-inflammatory mediator of the inflammation and its expression goes higher in all inflammatory diseases, like COPD, MS, arthritis, psoriasis, etc. Other MMPs are also involved in some vital and regulatory functions of the cell, so an MMP-9 selective inhibitor would only target the inflammation component of the disease and would be free of undesirable toxicity.
Over-expression or over-activation of an MMP, or an imbalance between an MMP and a natural (i.e., endogenous) tissue inhibitor of a matrix metalloproteinase (TIMP) has been linked to a pathogenesis of diseases characterized by the breakdown of connective tissue or extracellular matrix.
Inhibition of the activity of one or more MMPs may be of benefit in treatment of various inflammatory, autoimmune and allergic diseases such as, inflammation of the joint, inflammation of the GI tract, inflammation of the skin, collagen remodeling, wound healing disorders, etc.
The design and therapeutic application of MMP inhibitors has revealed that the requirement of a molecule to be an effective inhibitor of MMP class of enzymes is a functional group (e.g., carboxylic acid, hydroxamic acid or sulphydryl) capable of chelating to the active site Zn** jon (Whittaker et al., Chem. Rev., 99; p. 2735-76 (1999).
WO 03/82841 discloses new 5-substituted 1,1-dioxo-1,2,5-thiazolidine-3-one derivatives as protein tyrosine phosphatase inhibitors used for treating, e.g., diabetes, metabolic disorders, obesity and ischemic disease. EP 0 507 238 discloses R- and S- carboxylic acids in the treatment of diabetes, especially diabetes mellitus. EP 0 279 162 discloses new 2-substituted thio-alkanoic acid derivatives useful for treating diabetes, atherosclerosis, and diseases of lipid metabolism.
Research has been carried out into the identification of inhibitors that are selective, e.g, for afew of the MMP subtypes. An MMP inhibitor of improved selectivity would avoid potential side effects associated with inhibition of MMPs that are not involved in the pathogenesis of the disease being treated.
Further, use of more selective MMP inhibitors would require administration of a lower amount of the inhibitor for treatment of disease than would otherwise be required and, after administration, partitioned in vivo among multiple MMPs. Still further, the administration of a lower amount of compound would improve the margin of safety between the dose of the inhibitor required for therapeutic activity and the dose of the inhibitor at which toxicity is observed.
Many drugs exist as asymmetric three-dimensional molecules, i.e., chiral and will therefore have several stereoisomers depending upon the number of chiral centers present.
The importance of evaluating new chemical entities having chiral centers as single isomers is to understand their effect on pharmacological and toxicological aspects. There are often pharmacodynamic, pharmacokinetic and/or toxicological differences between enantiomers/diastercomers. Even if natural physiological mediators are achiral, based on their target environment, their receptors/enzymes may demonstrate a preference for only one optically pure enantiomer of agonists, antagonists or inhibitors. From a pharmacokinetics point of view, chirality can have an influence on drug absorption, distribution, metabolism and elimination. Pure single isomers may also offer advantages in terms of these pharmacokinetic parameters thus enabling better developability of such molecules as drug candidates. It is also known that chirality has a significant effect of the physicochemical properties and crystallinity of a chiral molecule which in turn have profound effects on the pharmacokinetics and developability of the molecule. Besides those mentioned above, regulatory principles guide one to preferably develop single isomers as drug candidates in order to avoid any pharmacological, pharmacokinetic and toxicological problems that may arise due to interactions of an unwanted isomer with undesirable molecular targets.
In this context, synthetic strategies to produce pure single isomers offer advantages over analytical techniques of separation of isomer not only in terms of cost and efficiency but larger amounts of compound can be prepared for elaborate pharmaceutical testing.
Thus, compounds of present invention, which are single chiral isomers, have improved potency, improved pharmacokinetics and/or improved physicochemical properties as compared to racemic compounds.
The present invention is directed to overcoming problems encountered in the art.
The present invention provides sulfone acetic acid derivatives as matrix metalloproteinase-9 inhibitors which are effective therapeutic or prophylactic agents for the treatment of various inflammatory and allergic diseases. Also provides are processes for synthesizing such compounds.
The compounds of the present invention are useful for the treatment of inflammatory and autoimmune diseases.
Pharmaceutical compositions containing such compounds are provided together with the pharmaceutically acceptable carriers or diluents, which can be used for the treatment or prevention of inflammatory and autoimmune diseases. These pharmaceutical compositions may be administered or co-administered by a wide variety of routes including, for example, oral, topical, rectal, intranasal or by parenteral route. The composition may also be administered or co-administered in slow release dosage forms.
Although, the specific enantiomers have been shown by way of examples, racemates, diastereomers, and pharmaceutically acceptable salts are also provided.
Pharmaceutical compositions comprising such compounds, their racemates, enantiomers, diastereomers, and pharmaceutically acceptable salts are also included.
The therapeutically effective amount of one or more compounds of the present invention can be used in combination with one or more other therapeutic agents, for example, protein synthesis inhibitors, amino glycosides, cell wall synthesis inhibitor (glycopeptides, beta-lactams, etc.), RNA, and DNA synthesis inhibitors or fatty acid synthesis inhibitors.
Other objects will be set forth in accompanying description and in the part will be apparent from the description or may be by the practice of the invention.
In accordance with one aspect there is provided a compounds having structure of
Formula I:
RECTIFIED SHEET (RULE 91) ISA/EP
X R1
Formula I including racemates, enantiomers and diastereomers, thereof or a pharmaceutically acceptable salts thereof. 5 Wherein,
X can be 8, SO or SO»;
L! can be selected from bond, -0-, -§-, -SO, -SO,, -CH,, -NR*, -NHCO(CH3),-, -(CH;).CONH-, -NHCONH-, -SO;NH-, -NHSO,-, -NHCQ(O)-, -O-(CH3),, -(CH3)a-O-, -OC(O)NH-, -C(S)NH-, -NHC(S), -NHC(S)NH-, -COO- wherein n can be zero or an integer between 1 and 2;
R! can be -OCONHR?, OCSNHR?, OCH,R’;
When R! is OCONHR? or OCSNHR? then R? can be hydrogen, C;-Cealkyl, hydroxyl, C,-Csalkoxy, cyano, nitro, halogen, halogeno C,-Cgalkyl, Cs-C); aryl,
Ci3-Cyeycloalkyl, Cs-Cyz heteroaryl wherein Cs-C)2 aryl, Cs-Cgcycloalkyl, Cs-C 2 heteroaryl is optionally substituted with one or more times with R®;
When R' is OCH;R?, then R? can be Cs-C, aryl, C5-Cs cycloalkyl, Cs-Ciz heteroaryl;
Ris alkyl, alkenyl, alkynyl, Cs-Ci2 aryl, Cs-Cg cycloalkyl, Cs-C); heteroaryl, Cs-
C12 heterocyclyl which may optionally be substituted one or more times with R?;
R* can be H, C,.6alkyl, C,qalkylaryl;
R® can be selected from alkyl, alkenyl, alkynyl, cyano, nitro, halogen, halogeno-
C-Cs alkyl, halogeno-C,-Cs alkoxy, azido, thiol, alkylthiol, (CH,),-OR;¢, -C(=0)-
Rg, -COORg, -NRRg, -(CH2)n-C(=O)NRgR, -(CH,),-NHC(=0)-Ry, -(CH;)n- O-
C(=0)}-NRRy, (CHz)a NHC(=O)NRR,, -(CH2)a-O-C(=0)- Ry, (CH,),-NH-C(=0)-
Rs or -(CH,),S(=0)m-NRR, {wherein Ry and Rq are independently selected from hydrogen, alkyl, alkenyl, cycloalkyl aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and alkylheterocyclyl, n is as define earlier and m is an integer 0-2};
RECTIFIED SHEET (RULE 91) ISA/EP
In one aspect the invention encompasses compounds that include, for example, 4-{[(4-Chlorophenyl)carbamoyl]oxy}-2-[(4-chlorophenyl)sulfanyl ]butanoic acid (Compound no. 1); 2-[(4-Chlorophenyl)sulfanyl]-4-{[(4-fluorophenyl)carbamoyl]oxy}butanoic acid
(Compound no. 2); 4-{[(4-Chlorophenyl)carbamoyl]oxy}-2-[(4-chlorophenyl)sulfonyl]butanoic acid (Compound no. 3); 2-[(4-Chlorophenyl)sulfonyl]-4-{[(4-fluorophenyl)carbamoyl]oxy} butanoic acid (Compound no. 4);
2-[(4-{[(4-Chlorophenyl)carbonyl]amino } phenyl)sulfanyl]-4-{[(4-fluorophenyl carbamoyl]oxy}butanoic acid (Compound no. 5); 2-[(4-{[(4-Chlorophenyl)carbonyl]amino} phenyl)sulfanyl]-4-({[2-fluoro-5- (trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 6); 2-[(4-{[(4-Chlorophenyl)carbonyl]amino} phenyl)sulfanyl]-4-{[(3,5-
dimethoxyphenyl)carbamoyl]oxy}butanoic acid (Compound no. 7); 2-[(4-{[(4-Chlorophenyl)carbonyl]amino} phenyl )sulfanyl]-4-{[(5-fluoro-2-methyl phenyl)carbamoyl]oxy} butanoic acid (Compound no. 8); 2-[(4-{[(4-Chlorophenyl)carbonyl]amino} phenyl)sulfanyl]-4-{[(2-fluorophenyl) carbamoyl]oxy}butanoic acid (Compound no. 9);
4-{[(3-Chloro-4-methoxyphenyl)carbamoyl]oxy}-2-[(4-{[(4-chloropheny]) carbonyl]amino} phenyl)sulfanyl]butanoic acid (Compound no. 10); 2-[(4-{[(4-Chlorophenyl)carbonyl]amino} phenyl)sulfanyl]-4-{[(3- ethoxyphenyl)carbamoyl]oxy}butanoic acid (Compound no. 11); 4-{[(3-Chlorophenyl)carbamoyl]oxy}-2-[(4-{[(4-
chlorophenyl)carbonyl]amino} phenyl)sulfanylJbutanoic acid (Compound no. 12); 4-{[(4-Chlorophenyl)carbamothioyl]oxy}-2-[(4-{[(4-chlorophenyl)carbonyl] amino} phenyl)sulfanyl]butanoic acid (Compound no. 13); 2-[(4-{[(4-Chlorophenyl)carbonyl]amino} phenyl)sulfanyl]-4- {[(3-cyanophenyl) carbamothioyl]oxy}butanoic acid (Compound no. 14);
2-[(4-{[(4-Chlorophenyl)carbonyl]amino} phenyl)sulfonyl]-4-{[(4-fluorophenyl) carbamoyl]oxy}butanoic acid (Compound no. 15); 2-[(4-{[(4-Chlorophenyl)carbonylJamino} phenyl)sulfonyl]-4-({[2-fluoro-5- (trifluoromethyl)phenyl]carbamoyl} oxy)butanoic acid (Compound no. 16); 2-[(4-{[(4-Chlorophenyl)carbonyl]amino} phenyl )sulfonyl]-4-{[(5-fluoro-2-methyl phenyl)carbamoyl]oxy}butanoic acid (Compound no. 17); 4-{[(3-Chloro-4-methoxyphenyl)carbamoyl]oxy}-2-[(4-{[(4- chlorophenyl)carbonyl]amino} phenyl)sulfonyl]butanoic acid (Compound no. 18); 2-[(4-{[(4-Chlorophenyl)carbonyl]amino} phenyl)sulfonyl]-4-{[ (2- fluorophenyl)carbamoyl]oxy} butanoic acid (Compound no. 19);
4-{[(3-Chlorophenyl)carbamoyl]oxy}-2-[(4-{[(4-chlorophenyl)carbonyl] amino} phenyl)sulfonyl]butanoic acid (Compound no. 20); 2-[(4-{[(4-Chlorophenyl)carbonyl]amino } phenyl)sulfonyl]-4-{[(3-cyanophenyl) carbamothioyl]oxy}butanoic acid (Compound no. 21);
4-(Benzyloxy)-2-[(4-{[(4-methylphenyl)carbonyl]amino} phenyl)sulfonyl]butanoic acid (Compound no. 22;) 4-(Benzyloxy)-2-[(4-{[(3-fluorophenyl)carbonyl]amino} phenyl)sulfonyl]butanoic acid (Compound no. 23); 4-(Benzyloxy)-2-[(4-{[(3-chlorophenyl)carbonyl]amino} phenyl)sulfonyl]butanoic acid (Compound no. 24); 4-(Benzyloxy)-2-[(4-{[(4-ethylphenyl)carbonyl]amino} phenyl)sulfonyl}butanoic acid (Compound no. 25); 4-(Benzyloxy)-2-[(4-{[(3-methoxyphenyl)carbonyl]amino} phenyl) sulfonyl]butanoic acid (Compound no. 26);
4-(Benzyloxy)-2-[(4-{[(2-fluorophenyl)carbonyl]amino} phenyl)sulfonyl]butanoic acid (Compound no. 27) 4-(Benzyloxy)-2-[(4-nitrophenyl)sulfonyl ]butanoic acid (Compound no. 28); 4-{[(2-Fluorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methylphenyl) carbonyl]amino} phenyl)sulfanyl]butanoic acid (Compound no. 29);
4-{[(3-Fluorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methylphenyl) carbonyl]amino}phenyl)sulfanyl]butanoic acid (Compound no. 30); 4-{[(3-Fluorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methylphenyl) carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 31); 4-{[(4-Chlorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl)
carbonyl]amino } phenyl)sulfanyl]butanoic acid (Compound no. 32); 4-{[(4-Ethylphenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl) carbonyl]amino}phenyl)sulfanyl]butanoic acid (Compound no. 33); 2-[(4-{[(4-Methoxyphenyl)carbonyl]amino } phenyl)sulfanyl]-4-({[4- (trifluoromethyl)phenyl]carbamoyl }oxy)butanoic acid (Compound no. 34);
4-{[(2,6-Dichlorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl) carbonylJamino}phenyl)sulfanyl]butanoic acid (Compound no. 35); 2-[(4-{[(4-Methoxyphenyl)carbonyl]Jamino} phenyl)sulfanyl]-4-{[(2-methylphenyl) carbamoyl]oxy}butanoic acid (Compound no. 36); 4-{[(4-Methoxyphenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl)
carbonyl]amino} phenyl)sulfanyl]butanoic acid (Compound no. 37); 4-[(tert-Butylcarbamoyl)oxy]-2-[(4-{[(4-methoxyphenyl) carbonyl]amino} phenyl)sulfanyl]butanoic acid (Compound no. 38); 4-{[(2,4-Difluorophenyl)carbamoyljoxy} -2-[(4-{[(4-methoxypheny]) carbonyl]amino}phenyl)sulfanyl]butanoic acid (Compound no. 39);
4-{[(2-Fluorophenyl)carbamoyl]oxy }-2-[(4-{[(4-methoxypheny]) carbonyl]amino} phenyl)sulfanyl]butanoic acid (Compound no. 40); 4-{[(3-Fluorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl) carbonyl]amino} phenyl)sulfanyl]butanoic acid (Compound no. 41);
4-{[(3,4-Dichlorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl) carbonyl]amino} phenyl)sulfanyl]butanoic acid (Compound no. 42); 4-{[(3,4-Dichlorophenyl)carbamoyl]oxy }-2-[(4-{[(4-methylphenyl) carbonyl]amino}phenyl)sulfanyl]butanoic acid (Compound no. 43); 4-{[(2,4-Difluorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methylphenyl)
carbonyl]amino}phenyl)sulfanyl]butanoic acid (Compound no. 44); 4-{[(4-Chlorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl) carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 45); 4-{[(4-Ethylphenyl)carbamoyl]oxy }-2-[(4-{[(4-methoxyphenyl) carbonyl]amino} phenyl)sulfonyl]butanoic acid (Compound no. 46);
2-[(4-{[(4-Methoxyphenyl)carbonyl]Jamino}phenyl)sulfonyl]-4-({[4- (trifluoromethyl)phenyl]carbamoyl} oxy)butanoic acid (Compound no. 47); 4-{[(2,6-Dichlorophenyl)carbamoyl]oxy }-2-[(4- {[(4-methoxyphenyl) carbonyl]aminophenyl)} sulfonyl]butanoic acid (Compound no. 48); 2-[(4-{[(4-Methoxyphenyl)carbonyl]amino} phenyl)sulfonyl]-4-{[(2-
methylphenyl)carbamoyl]oxy}butanoic acid (Compound no. 49); 4-[(tert-Butylcarbamoyl)oxy]-2-[(4-{[(4-methoxyphenyl) carbonyl]amino} phenyl)sulfonyl]butanoic acid (Compound no. 50); 4-{[(2,4-Difluorophenyl)carbamoyljoxy}-2-[(4-{[(4-methoxyphenyl) carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 51);
4-{[(2-Fluorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl) carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 52); 4-{[(3-Fluorophenyl)carbamoyl]oxy}-2-[(4- {[(4-methoxyphenyl) carbonyl}amino}phenyl)sulfonyl]butanoic acid (Compound no. 53); 4-{[(5-Chloro-2-methoxyphenyl)carbamoyl]oxy}-2-[(4- {[(4-methoxyphenyl)
carbonyl]amino } phenyl)sulfonyl]butanoic acid (Compound no. 54); 4-{[(3,4-Dichlorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl) carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 55); 4-{[(3,4-Dichlorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methylphenyl) carbonyl]amino} phenyl)sulfonyl]butanoic acid (Compound no. 56);
4-{[(2,4-Difluorophenyl)carbamoyljoxy}-2-[(4-{[(4-methylphenyl) carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 57); 4-{[(2-Fluorophenyl)carbamoyljoxy}-2-[(4-{[(4-methylphenyl) carbonyl]amino} phenyl)sulfonyl]butanoic acid (Compound no. 58); 2-({4-[(4-Chlorophenyl)carbamoyl Jphenyl} sulfanyl)-4- {[(2-
40 fluorophenyl)carbamoyl]oxy } butanoic acid (Compound no. 59);
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfanyl)-4-{[(4- ethylphenyl)carbamoyl]oxy}butanoic acid (Compound no. 60); 2-({4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfanyl)-4-({[4-(propan-2-yl)phenyl] carbamoyl }oxy)butanoic acid (Compound no. 61);
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfanyl)-4-{[(4-methoxyphenyl) carbamoyl]oxy}butanoic acid (Compound no. 62); 2-({4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfanyl)-4-{[ (2- methylphenyl)carbamoyl]oxy}butanoic acid (Compound no. 63); 2-({4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfanyl)-4-{[(3-
fluorophenyl)carbamoyl]oxy } butanoic acid (Compound no. 64); 2-({4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfanyl)-4-{[(4- methylphenyl)carbamoyl]oxy}butanoic acid (Compound no. 65); 2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfanyl)-4-({[4- (trifluoromethyl)phenyl]carbamoyl} oxy)butanoic acid (Compound no. 66);
2-({4-[(4-Chlorophenyl)carbamoyl phenyl} sulfanyl)-4-{[(2,4- difluorophenyl)carbamoyl]oxy}butanoic acid (Compound no. 67); 2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfanyl)-4-{[(4- fluorophenyl)carbamoylJoxy} butanoic acid (Compound no. 68); 2-({4-[(4-Chlorophenyl)carbamoyl] phenyl} sulfanyl)-4-{[(2,6-
dichlorophenyl)carbamoyl]oxy}butanoic acid (Compound no. 69); 4-[(tert-Butylcarbamoyl)oxy]-2-({4-[(4-chlorophenyl)carbamoyl] phenyl} sulfanyl)butanoic acid (Compound no. 70); 2-({4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfanyl)-4-{[(3,4- dichlorophenyl)carbamoyl]oxy}butanoic acid (Compound no. 71);
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfanyl)-4- [(pentylcarbamoyl)oxy]butanoic acid (Compound no. 72); 4-{[(3-Chlorophenyl)carbamoyl]oxy}-2-({4-[(4-chlorophenyl) carbamoyl]phenyl}sulfanyl)butanoic acid (Compound no. 73); 4-[(Butylcarbamoyl)oxy]-2-({4-[(4-chlorophenyl)
carbamoyl]phenyl}sulfanyl)butanoic acid (Compound no. 74); 2-({4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfonyl)-4-{[(2- fluorophenyl)carbamoyl]oxy}butanoic acid (Compound no. 75); 2-({4-[(4-Chlorophenyl)carbamoyl phenyl} sulfonyl)-4-{[(4- ethylphenyl)carbamoyl]oxy}butanoic acid (Compound no. 76);
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfonyl)-4-{[(2- methylphenyl)carbamoyl]oxy} butanoic acid (Compound no. 77); 2-({4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfonyl)-4-{[(4- methylphenyl)carbamoyl]oxy}butanoic acid (Compound no. 78); 2-({4-[(4-Chlorophenyl)carbamoyl]phenyl } sulfonyl)-4-({[4-
40 (trifluoromethyl)phenyl]carbamoyl }oxy)butanoic acid (Compound no. 79);
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfonyl)-4-{[(2,4- difluorophenyl)carbamoyl]oxy} butanoic acid (Compound no. 80); 2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfonyl)-4-{[ (4- fluorophenyl)carbamoyl oxy} butanoic acid (Compound no. 81);
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfonyl)-4-{[(2,6- dichlorophenyl)carbamoyl]oxy}butanoic acid (Compound no. §2); 4-[(tert-Butylcarbamoyl)oxy]-2-({4-[(4-chlorophenyl)carbamoyl] phenyl} sulfonyl)butanoic acid (Compound no. 83); 2-({4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfonyl)-4-{[(3,4-dichlorophenyl)
carbamoyl]oxy}butanoic acid (Compound no. 84); 2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfonyl)-4- [(pentylcarbamoyl)oxy]butanoic acid (Compound no. 85); 4-{[(3-Chlorophenyl)carbamoyl]oxy}-2-({4-[(4-chlorophenyl)carbamoyl] phenyl} sulfonyl)butanoic acid (Compound no. 86);
4-[(Butylcarbamoyl)oxy]-2-({4-[(4- chlorophenyl)carbamoyl]phenyl} sulfonyl)butanoic acid (Compound no. 87); 2-[(4-{[(2-Fluorophenyl)carbonyl]amino} phenyl)sulfanyl]-4-({[4-(trifluoromethyl) phenyl]carbamoyl}oxy)butanoic acid (Compound no. 88); 2-[(4-{[(4-Chlorophenyl)carbonyl]Jamino}phenyl)sulfanyl]-4-({[4-
(trifluoromethyl)phenyl]carbamoyl }oxy)butanoic acid (Compound no. 89); 2-[(4-4 [(2,6-Dimethoxyphenyl)carbonyl] amino} phenyl)sulfanyl]-4-({[4- (trifluoromethyl)phenyl]carbamoyl} oxy)butanoic acid (Compound no. 90); 2-({4-[(Cyclopropylcarbonyl)amino]phenyl } sulfanyl)-4-({[4- (trifluoromethyl)phenyl carbamoyl} Joxy)butanoic acid (Compound no. 91);
2-[(4-{[(2-Methylphenyl)carbonyl]amino} phenyl)sulfanyl]-4-({[4- (trifluoromethyl)phenyl]carbamoyl }oxy)butanoic acid (Compound no. 92); 2-[(4-{[(2-Ethoxyphenyl)carbonyl]amino}phenyl)sulfanyl]-4-({[4- (trifluoromethyl)phenyl]carbamoyl} oxy)butanoic acid (Compound no. 93); 2-[(4-{[(2,3-Difluorophenyl)carbonylJamino} phenyl)sulfanyl]-4-( {[4-
(trifluoromethyl)phenyl]carbamoyl }oxy)butanoic acid (Compound no. 94); 2-[(4-{[(3,4-Dichlorophenyl)carbonyl]amino} phenyl)sulfanyl]-4-({[4- (trifluoromethyl)phenyl]carbamoyl }oxy)butanoic acid (Compound no. 95); 2-[(4-{[(4-Ethoxyphenyl)carbonyl]amino} phenyl)sulfanyl]-4-({[4- (trifluoromethyl)phenyl]carbamoyl} oxy)butanoic acid (Compound no. 96);
2-({4-[(Cyclohexylcarbonyl)amino]phenyl}sulfanyl)-4-({[4-(trifluoromethyl) phenyl]carbamoyl} oxy)butanoic acid (Compound no. 97); 2-[(4-{[(2,4-Dichlorophenyl)carbonyl]amino} phenyl)sulfanyl]-4-({[4- (trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 98).
In another aspect, provided herein, are pharmaceutical compositions comprising therapeutically effective amounts of one or more compounds described herein together with one or more pharmaceutically acceptable carriers, excipients or diluents.
In another aspect, provided herein are methods for treating or preventing various inflammatory and allergic diseases comprising administering to a mammal in need thereof therapeutically effective amount of one or more compounds of Formula 1 described herein.
In yet another aspect, the present invention relates to the therapeutically effective amount of compounds of Formula I in combination with one or more of other therapeutic agents used in treating various inflammatory and allergic diseases. Examples of such therapeutic agents includes but are not limited to: a) anti-inflammatory agents, experimental or commercial (i) such as nonsteroidal anti-inflammatory agents piroxicam, diclofenac, propionic acids, fenamates, pyrazolones, salicylates, PDE-4/p38 MAP Kinase/Cathepsin inhibitors, (ii) leukotrienes LTC4/LTD4/LTE4/LTBA4-Inhibitors, 5- lipoxygenase inhibitor and PAF-receptor antagonists, (iii) Cox-2 inhibitors, (iv) MMP inhibitors, and (v) interleukin-I inhibitors; b) antihypertensive agents, (i) ACE inhibitors, e.g., enalapril, lisinopril, valsartan, telmisartan and quinapril, (ii) angiotensin II receptor antagonists and agonists, e.g., losartan, candesartan, irbesartan, valsartan, and eprosartan, (iii) B-blockers, and (iv) calcium channel blockers. c) immunosuppressive agents such as cyclosporine, azathioprine and methotrexate, and anti inflammatory corticosteroids.
The following definitions apply to terms as used herein.
The term “alkyl” unless otherwise specified, refers to a monoradical branched or unbranched saturated hydrocarbon chain having from 1 to 20 carbon atoms. This term can be exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-decyl, tetradecyl, and the like.
The term “alkenyl” unless otherwise specified, refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group having from 2 to 20 carbon atoms with cis, trans or geminal geometry.
The term “alkyny]” unless otherwise specified, refers to a monoradical of an unsaturated hydrocarbon, having from 2 to 20 carbon atoms.
The term “cycloalkyl” unless otherwise specified, refers to cyclic alkyl groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings, which may optionally contain one or more olefinic bonds, unless otherwise constrained by the definition. Such cycloalkyl groups can include, for example, single ring structures, including cyclopropyl, cyclobutyl, cyclooctyl, cyclopentenyl, and the like or multiple ring structures, including adamantanyl, and bicyclo [2.2.1] heptane or cyclic alkyl groups to which is fused an aryl group, for example, indane, and the like. Spiro and fused ring structures can also be included.
The term “aryl” unless otherwise specified, refers to aromatic system having 6 to 14 carbon atoms, wherein the ring system can be mono-, bi- or tricyclic and are carbocyclic aromatic groups. For example, aryl groups include, but are not limited to, phenyl, biphenyl, anthryl or naphthyl ring and the like, optionally substituted with 1 to 3 substituents selected from halogen (e.g., F, Cl, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, acyl, aryloxy, CF3, cyano, nitro, COOR,, NHC(=O)R;, -NR;R,, -C(=O)NRiR,, -NHC(=O)NR)Ry, -O-C(=O)NR:R, -SOnR,, carboxy, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl or amino carbonyl amino, mercapto, haloalkyl, optionally substituted aryl, optionally substituted heterocyclylalkyl, thioalkyl, -CONHRg, -OCORy, -COR,, -NHSO2R,: or —-SO;NHR, (wherein R;, R, m and Ry are the same as defined earlier). Aryl groups optionally may be fused with a cycloalkyl group, wherein the cycloalkyl group may optionally contain heteroatoms selected from O, N or S.
Groups such as phenyl, naphthyl, anthryl, biphenyl, and the like exemplify this term.
The term “aralkyl” unless otherwise specified, refers to alkyl-aryl linked through an alkyl portion (wherein alkyl is as defined above) and the alkyl portion contains 1-6 carbon atoms and aryl is as defined above. Examples of aralkyl groups include benzyl, ethylphenyl, propylphenyl, naphthylmethyl, and the like.
RECTIFIED SHEET (RULE 91) ISA/EP
The term “aryloxy” denotes the group O-aryl wherein aryl is the same as defined above.
The term “heteroaryl” unless otherwise specified, refers to an aromatic ring structure containing 5 or 6 ring atoms or a bicyclic or tricyclic aromatic group having from 8to 10 ring atoms, with one or more heteroatom(s) independently selected from N, O or S.
Unless otherwise constrained by the definition, the substituents are attached to a ring atom, i.e., carbon or heteroatom in the ring. Examples of heteroaryl groups include oxazolyl, imidazolyl, pyrrolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, thiazolyl, oxadiazolyl, benzoimidazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, triazinyl, furanyl, benzofuranyl, indolyl, benzthiazinyl, benzthiazinonyl, benzoxazinyl, benzoxazinonyl, quinazonyl, carbazolyl phenothiazinyl, phenoxazinyl, benzothiazolyl or benzoxazolyl, and the like.
The term “heterocyclyl” unless otherwise specified, refers to a non-aromatic monocyclic or bicyclic cycloalkyl group having 5 to 10 atoms wherein 1 to 4 carbon atoms in aring are replaced by heteroatoms selected from O, S or N, and optionally are benzofused or fused heteroaryl! having 5-6 ring members. Examples of heterocyclyl groups include benzotriazinone, isoindoledione, pyrimidinedione, aza- spiro[4.5]decanedione, benzo-oxazinedione, imidazolidinedione, phthalazinone, oxazolidinyl, tetrahydrofuranyl, dihydrofuranyl, benzoxazinyl, benzthiazinyl, imidazolyl, benzimidazolyl, tetrazolyl, carbaxolyl, indolyl, phenoxazinyl, phenothiazinyl, dihydropyridinyl, dihydroisoxazolyl, dihydrobenzofuryl, azabicyclohexyl, thiazolidinyl, dihydroindolyl, pyridinyl, isoindole 1,3-dione, piperidinyl, tetrahydropyranyl, piperazinyl, 3H-imidazo[4,5-b]pyridine, isoquinolinyl, 1H-pyrrolo[2,3-b]pyridine or piperazinyl, and the like.
The term “cycloalkylalkyl” refers to cycloalkyl group linked through alkyl portion, wherein the alkyl having 1 to 6 carbon atoms and cycloalkyl are the same as defined earlier.
The term “heteroarylalkyl” refers to heteroaryl group linked through alkyl portion, wherein the alkyl having 1 to 6 carbon atoms and heteroaryl are the same as defined earlier.
The term “heterocyclylalkyl” refers to heterocyclyl group linked through alkyl portion, wherein the alkyl having 1 to 6 carbon atoms and heterocyclyl are the same as defined earlier.
The term “amino” refers to —NH;
The term “halogen or Halo” refers to fluorine, chlorine, bromine or iodine;
The term “leaving group” refers to groups that exhibit or potentially exhibit the properties of being labile under the synthetic conditions and also, of being readily separated from synthetic products under defined conditions. Examples of leaving groups include, but are not limited to, halogen (e.g., F, Cl, Br, I), triflates, tosylate, mesylates, alkoxy, thioalkoxy, or hydroxy radicals, and the like.
The term “protecting groups” refers to moieties that prevent chemical reaction at a location of a molecule intended to be left unaffected during chemical modification of such molecule. Unless otherwise specified, protecting groups may be used on groups, such as hydroxy, amino, or carboxy. Examples of protecting groups are found in T.W. Greene and P.G.M. Wuts, “Protective Groups in Organic Synthesis”, 2" Ed., John Wiley and Sons,
New York, N.Y., which is incorporated herein by reference. The species of the carboxylic protecting groups, amino protecting groups or hydroxy protecting groups employed are not critical, as long as the derivatised moieties/moiety is/are stable to conditions of subsequent reactions and can be removed without disrupting the remainder of the molecule.
The compounds of this invention can contain one asymmetric carbon atom and thus may occur as racemic mixtures, enantiomers and diasteromers. These compounds can also exist as conformers/rotamers. All such isomeric forms of these compounds are included in the present invention. Each stereogenic carbon atom may be of the R or § configuration. Although the specific compounds exemplified in this application may be depicted in a particular sterochemical configuration, compounds having either the opposite stereochemistry at any given chiral center or mixture thereof are envisioned as part of the invention.
The term “pharmaceutically acceptable salts” forming part of this invention includes the salts of carboxylic acids moiety, which can be prepared by reacting the compound with appropriate base to provide corresponding base addition salts. Examples of such base are alkali metal hydroxide including potassium hydroxide, sodium hydroxide, and lithium hydroxide; alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide. Further, the salts of organic bases such as lysine, arginine, guanidine, ethanolamine, choline and the like, inorganic bases, e.g., ammonium or substituted ammonium salts are also included. Wherever appropriate, compounds with pharmaceutically acceptable organic and inorganic acids, e.g., hydro halides, such as hydrochloride, hydrobromide, hydroiodide; other mineral acids and their corresponding salts, such as sulphate, nitrate, phosphate etc. and alkyl and mono-arylsulphonates, such as ethane sulphonate, toluene sulphonate and benzene sulphonate; and other organic acids and their corresponding salts, such as acetate, tartaratae, maleate, succinate, citrate, etc.
In another aspect, the compounds disclosed herein may be prepared by following reaction sequences as depicted in Schemes I, and II.
Scheme 1 . R? R’
SH When Y is COOH R2 R'-Hal \ O or . Br a oy o_o — _N
Y Y R'NH, — Formula 4' x Se
Formula 3' Oo
Formula 5
Formula 2 Formula 3 Path A : .
When Y is NO, Formula 4 R3N=C=Z
Path B When Y is Hal Formula 6
Path C
J R'-Hal R? _R'
BO Formula 4' \ o
N
H H
Formula 10 \ Oo 0, 2 ar So 2 R3—
Ru Hal H
Formula 11 OH Formula 7 “Xp Formula 17 x RIN=C=Z 2 J 2
BH | Formula 6 R oH
Formula 12 HN
Oo 0,
R'-Hal o® =z
Formula 4' ry R3-N
Hal H o Formula 8 2 - rN
R? 3 H
OH Formula 18 Q
Formula 13 R?
RIN=C=Z | \ A IY oH ~~
Formula 6 H T S oC - 3
LOT
R? 0.
H 0 =z Formula 9 rz R? -N Formula I when Lis
RS AN H -CONH and R! is OC(Z)NHR?
H Formula 19
Formula 14
Q
2 OAC
R? Hal
H 0 0 rz =z rN ri-N
H H
Formula 15 Formula 20
Formula I when L! is 0 bond and R'is OC(Z)NHR? [¥otie o
R2
H
0 rz
R*-N
H
Formula 16
Formula I when L! is -NHCO and R!is OC(Z)NHR?
The compound of Formula 8 (Path A), Formula 9 (Path A), Formula 15 (Path B),
Formula 16 (Path B), Formula 19 (Path C) and Formula 20 (Path C) can be prepared according to Scheme I. Thus, reacting a compound of Formula 2 (wherein Y is NO,, Hal and COOH) with alpha bromo lactone gives a compound of Formula 3. The compound of
Formula 3 can react in three ways to give a compound of Formula 8, Formula 9, Formula 15, Formula 16, Formula 19 and Formula 20.
Path A (when Y is COOH): The reaction of a compound of Formula 3 with a compound of Formula 3’ (where R? is same as defined earlier) to give a compound of Formula 4 which upon reaction with a compound of Formula 4’ (wherein R’ is alkyl, allyl, benzyl, butyl, silyl and Hal is F, Cl, Br, I) gives a compound of Formula 5. The reaction of a compound of Formula 5 with a compound of Formula 6 (where R’ is same as defined earlier and Z is O or S) gives a compound of Formula 7. The hydrolysis of a compound of
Formula 7 gives a compound of Formula 8 which upon oxidation gives a compound of
Formula 9.
Path B (when Y is NO): The reduction of a compound of Formula 3 gives a compound of Formula 10 which upon reaction with a compound of Formula 11 (wherein R? is same as defined earlier and U is a leaving group such as halide, alkyloxy, aryloxy) gives a compound of Formula 12. The compound of Formula 12 upon reaction with a compound of Formula 4’ (wherein R’ and Hal are same as defined earlier) gives a compound of
Formula 13. The reaction of a compound of Formula 13 with a compound of Formula 6 (wherein R® and Z are same as defined earlier) gives a compound of Formula 14. The hydrolysis of a compound of Formula 14 gives a compound of Formula 15 which upon oxidation gives a compound of Formula 16.
Path C (when Y is halogen): The reaction of a compound of Formula 3 with a compound of Formula 4’ (wherein R’ and Hal is same as defined earlier) gives a compound of
Formula 17 which upon reaction with a compound of Formula 6 (wherein R® and Z are same as defined as earlier) gives a compound of Formula 18. The hydrolysis of a compound of Formula 18 gives a compound of Formula 19 which upon oxidation gives a compound of Formula 20.
The reaction of a compound of Formula 2 with alpha bromo lactone to give a compound of Formula 3 can be carried out in the presence of organic base, for example,
triethylamine, pyridine, N,N’-dimethylaminopyridine, 2,6-lutidine, 1-methylpiperidine, N- ethyldiisopropylamine or N-methylmorpholine in a solvent selected from, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, or mixture(s) thereof.
The reaction of a compound of Formula 3 (Path A) with a compound of Formula 3° to give a compound of Formula 4 can be carried out using base selected from triethylamine, pyridine, N,N-dimethylaminopyridine, 2,6-lutidine, 1-methylpiperidine, N- ethyldiisopropylamine or N-methylmorpholine, in the presence of a additives, for example, hydroxybenzotriazole, 3-hydroxy-3,4-dihydro-4-oxo-1,2,3-benzotriazine, 2- hydroxypyridine, N-hydroxysuccinimide or 1-hydroxy-7-azabenzotriazole, with a suitable condensing agent, for example, dicyclohexyl carbodiimide, 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride, chlorotripyrrolidinophosphonium hexafluorophosphate or (benzotriazol-1-yloxy)tris-(dimethylamino)phosphonium hexafluorophosphate.
The reaction of a compound of Formula 4 with a compound of Formula 4’ to give a compound of Formula 5 can be carried out in the presence of 18-crown-6 using one or more inorganic base selected from sodium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide in the presence of a solvent, selected from, N, N’- dimethylformamide, methanol, ethanol, propanol, butanol, tetrahydrofuran, acetonitrile, water, or mixture thereof.
The reaction of a compound of Formula 5 with a compound of Formula 6 to give a compound of Formula 7 can be carried out in the presence of organic base selected from, for example, triethylamine, pyridine, N,N’-dimethylaminopyridine, 2,6-lutidine, 1- methylpiperidine, N-ethyldiisopropylamine or N-methylmorpholine in a solvent selected from tetrahydrofuran, dimethylsulfoxide, acetonitrile, N, N’-dimethylformamide, or mixture(s) thereof.
The hydrolysis of a compound of Formula 7 to give a compound of Formula 8 can be carried out in the presence of inorganic base selected from, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide in solvents for example, tetrahydrofuran, acetonitrile, methanol, ethanol, propanol, dimethylsulfoxide, or mixture(s) thereof.
The oxidation of a compound of Formula 8 to give a compound of Formula 9 can be carried out with oxidizing agents, for example, meta-chloroperbenzoic acid or oxone in a solvent, selected from, chloroform, dichloromethane, methanol, water, carbon tetrachloride, or mixture(s) thereof.
The reduction of a compound of Formula 3 (Path B) to give a compound of
Formula 10 can be carried out using reducing agent selected from, for example, Pd/C, lithium aluminum hydride, Raney Nickel in the presence of hydrazine hydrate, zinc, tin or iron in the presence of hydrochloric acid in a solvent selected from tetrahydrofuran, methanol, ethanol, dichloromethane, or mixture(s) thereof.
The reaction of a compound of Formula 10 with a compound of Formula 11 to give a compound of Formula 12 can be carried out in the presence of organic base, for example, triethylamine, pyridine, N,N’-dimethylaminopyridine, 2,6-Iutidine, 1- methylpiperidine, N-ethyldiisopropylamine or N-methylmorpholine in a solvent selected from, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, or mixture(s) thereof.
The ring opening of a compound of Formula 12 with a compound of Formula 4’ to give a compound of Formula 13 can be carried out under similar conditions as described for the reaction of a compound of Formula 4 with a compound of Formula 4’ to give a compound of Formula 5.
The reaction of a compound of Formula 13 with a compound of Formula 6 to give a compound of Formula 14 can be carried out under similar conditions as described for the reaction of a compound of Formula 5 with a compound of Formula 6 to give a compound of Formula 7.
The hydrolysis of a compound of Formula 14 to give a compound of Formula 15 can be carried out under similar conditions as described for the reaction of a compound of
Formula 7 to give a compound of Formula 8.
The oxidation of a compound of Formula 15 to give a compound of Formula 16 can be carried out under similar conditions as described for the compound of Formula 8 to give a compound of Formula 9.
The reaction of a compound of Formula 3 (Path C) with a compound of Formula 4° to give a compound of Formula 17 can be carried out under similar conditions as described for the reaction of compound of Formula 4 with a compound of Formula 4’ to give a compound of Formula 5.
The reaction of a compound of Formula 17 with a compound of Formula 6 to give a compound of Formula 18 can be carried out under similar conditions as described for the reaction of a compound of Formula 5 with a compound of Formula 6 to give a compound of Formula 7.
The hydrolysis of a compound of Formula 18 to give a compound of Formula 19 can be carried out under similar conditions as described for the hydrolysis of a compound of Formula 7 to give a compound of Formula 8.
The oxidation of a compound of Formula 19 to give a compound of Formula 20 can be carried out under similar conditions as described for the compound of Formula 8 to give a compound of Formula 9.
Scheme II ?
SH 0 s _R' ie R’ iy oR
ON 0, ON Formula 25 OBn
Formula 26
Formula 21 Formula 22 Formula 23 Formula 24
Path y/ oe D ; foo A Ae hd
OH 0 0
WR TECH 9 Cet det JO
H OBn H OBn Formula 11 *°2 OBn OBn
Formula 30 Formula 29 Formula 28 Formula 27
Formula 1 when L! is -NHCO and R! is OBn
The compound of Formula 27 (Path D) and Formula 30 (Path E) can be prepared according to Scheme II. Thus, reaction of a compound of Formula 21 with a compound of
Formula 22 (wherein R’ and Hal are same as defined earlier) gives a compound of
Formula 23 which upon oxidation gives a compound of Formula 24. The reaction of a compound of Formula 24 with a compound of Formula 25 (Bn is benzyl group and Hal is same as defined earlier) forms a compound of Formula 26. The compound of Formula 26 can be reacted in two ways to give a compound of Formula 27 and Formula 30.
Path D: The hydrolysis of a compound of Formula 26 gives a compound of Formula 27.
Path E: The reduction of a compound of Formula 26 gives a compound of Formula 28 which upon reaction with a compound of Formula 11 (wherein R* and U are same as defined earlier) gives a compound of Formula 29. The compound of Formula 29 upon hydrolysis gives a compound of Formula 30.
The reaction of a compound of Formula 21 with a compound of Formula 22 to give a compound of Formula 23 can be carried out in the presence of organic base selected from, for example, triethylamine, pyridine, N,N’-dimethylaminopyridine, 2,6-lutidine, 1- methylpiperidine, N-ethyldiisopropylamine or N-methylmorpholine in a solvent selected from dichlormethane, dichloroethane, carbon tetrachloride, chloroform, tetrahydrofuran, dimethylsulfoxide, acetonitrile, N, N’-dimethylformamide, or mixture(s) thereof.
The oxidation of a compound of Formula 23 to form a compound of Formula 24 can be carried out under similar conditions as described for the compound of Formula 8 to give a compound of Formula 9.
The reaction of a compound of Formula 24 with a compound of Formula 25 to give a compound of Formula 26 can be carried out using tetrabutylammonium iodide in the presence of inorganic base selected from lithium carbonate, sodium carbonate, potassium carbonate, barium carbonate using a solvent selected from, N,N’-dimethylformamide, acetonitrile, tetrahydrofuran, dimethylsulfoxide, or mixture(s) thereof.
The hydrolysis of a compound of Formula 26 (Path D) to give a compound of
Formula 27 can be carried out under similar conditions as described for the compound of
Formula 7 to give a compound of Formula 8.
The reduction of a compound of Formula 26 (Path E) to give a compound of
Formula 28 can be carried out using reducing agent selected from, for example, lithium aluminum hydride, Raney Nickel in hydrazine hydrate or ammonium formate, zinc, tin or iron in the presence or in the absence of hydrochloric acid.
The reaction of a compound of Formula 28 with a compound of Formula 11 to give a compound of Formula 29 can be carried out under similar conditions as described for the reaction of a compound of Formula 10 with a compound of Formula 11 to give a compound of Formula 12.
The hydrolysis of a compound of Formula 29 to give a compound of Formula 30 can be carried out under similar conditions as described for the compound of Formula 7 to give a compound of Formula 8.
In the above schemes, where specific reagents, for example, bases, acids, solvents, condensing agents, hydrolyzing agents, catalysts, etc., as mentioned, is to be understood that other reagents, e.g., other acids, bases, solvents, condensing agents, reducing agent, deprotecting agent, hydrolyzing agents, catalysts, etc., known to one of ordinary skill in the art may be used. Similarly, reaction temperatures and durations may be adjusted according to the desired needs without undue experimentation and well within the abilities of one of ordinary skill in the art.
The compounds described herein may be administered to an animal for treatment orally, topically, rectally, internasally or by parenteral route. Pharmaceutical compositions disclosed herein comprise pharmaceutically effective amounts of compounds described herein formulated together with one or more pharmaceutically acceptable carriers, excipients or diluents.
Solid form preparations for oral administration include capsules, tablets, pills, powder, granules, lozenges, troches, cachets and suppositories. For solid form preparations, active compounds can be mixed with one or more inert, pharmaceutically acceptable excipients or carrier. Tablets and capsules for oral administration may contain conventional excipients, such as binding agents and/or dissolution enhancers, for example, polyvinyl pyrrolidine, cellulose, mucilage of starch, gelatin, sorbitol, syrup, acacia or tragacanth; fillers or bulking agents, for example, microcrystalline cellulose, sugar, maize-starch, calcium phosphate, sorbitol or lactose; lubricants, for example, talc, silica, polyethyleneglycol, magnesium stearate or stearic acid; disintegrating agents and binder, for example, croscarmellose sodium, pregelatinized starch, sodium starch gylcollate or potato starch; glidants, for example, colloidal silicon dioxide or talc; antiadherants, for example, magnesium stearate or sodium luaryl sulfate; and coating materials.
Capsules, tablets or pills may also comprise buffering agents.
Tablets, capsules, pills or granules can be prepared using one or more coatings or shells to modulate the release of active ingredients, for example, enteric coatings or other coatings known to one of ordinary skill in the art.
General Example
A formulation of a tablet could typically contain from 0.01 mg to 500 mg of active compound whilst tablet fill weight may range from 50 mg to 1000 mg. An example is illustrated below.
Ingredients Amount % w/w
Active Compound 0.01 to 20 mg
Microcrystalline Cellulose about 50% to about 90%
Croscarmellose Sodium about 1% to about 10%
Pregelatinized Starch about 1% to about 15%
Polyvinyl Pyrrolidone (K-30) about 5% to about 12%
Talc about 0.1% to about 2%
Magnesium Stearate about 0.1% to about 2%
Colloidal Silicon Dioxide about 0.1% to about 2%
Liquid form preparations for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs. In such liquid form preparations, active compounds can be mixed with water or one or more non-toxic solvents, solubilizing agents or emulsifiers, for example, water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, for example, cottonseed, groundnut, corn, germ, olive, castor and sesame oil, glycerol, fatty acid esters of sorbitan, or mixtures thereof. Oral compositions can also include one or more adjuvants, for example, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, or mixtures thereof.
Injectable preparations, for example, sterile injections, and aqueous suspensions may be formulated according to methods known to one of ordinary skill in the art, and in particular, using one or more suitable dispersing or wetting and suspending agents.
Acceptable vehicles and solvents that may be employed include one or more of water,
Ringer’s solution, isotonic sodium chloride, or mixtures thereof.
Suppositories for rectal administration of the compound of this invention can be prepared by mixing the drug with suitable nonirritating excipients such as coca butter and polyethylene glycols, which are solid at ordinary temperatures but liquid at body temperature and which therefore melt in the rectum and release the drug.
Dosage forms for topical or transdermal administration of a compound of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. Active compounds can be admixed under sterile condition with one or more pharmaceutically acceptable carriers and optionally any preservatives or buffers as may be required. Ophthalmic formulations, eardrops, eye ointments, powders and solutions are also encompassed within the scope of this invention.
Pharmaceutical preparations may be in unit dosage form. In unit dosage form, the preparations can be subdivided into unit doses containing appropriate quantities of active components. Unit dosage forms can be packaged preparations containing discrete capsules, powders, in vials or ampoules, ointments, capsules, sachets, tablets, gels, creams or any combination and number of such packaged forms.
The following examples are set forth to demonstrate general synthetic procedures for the preparation of representative compounds of the present invention. The examples are provided to illustrate particular aspect of the disclosure and do not limit the scope of the present invention.
Experimental
Various solvents, for example, dimethylformamide, benzene, tetrahydrofuran, etc., were dried using various drying reagents according to procedure as described in the literature.
Example 1: Synthesis of 2-({4-[(4-chlorophenyl)carbamoyl]phenyl}sulfanyl)-4-{[(4- fluoro phenyl)carbamoyl]oxy}butanoic acid (Compound no. 68) (Scheme I, Path A,
Formula 8)
Step a: Preparation of 4-[(2-oxotetrahydrofuran-3-yl)sulfanyl]benzoic acid
To an ice cooled solution of 4-mercaptobenzoicacid (0.5 g, 0.003 moles) in dichloromethane (5 mL) under argon atmosphere were added triethylamine (0.909 g, 0.009 moles) and a solution of bromo lactone (0.53 g, 0.003 moles) in dichloromethane (5 mL) drop wise. The reaction mixture was allowed to stir for about 30 minutes. After completion, reaction mixture was diluted by adding water and extracting in dichloromethane. The combined organic layer was dried over anhydrous sodium sulphate and concentrated to get crude product which was purified by silica gel column using 70% ethyl acetate in hexane as eluent to get desired compound.
Yield: 0.800 g
LCMS: 239.16 (M+1)
Step b: Preparation of N-(4-chlorophenyl)-4-[(2-oxotetrahydrofuran-3-yl)sulfanyl] benzamide
To the solution of compound obtained from Step a (15.0 g, 0.0630 moles) in dichloromethane (150 mL) were added 1-ethyl-3~(3-dimethylaminopropyl)carbodiimide) (EDCI, 18.0 g, 0.0942 moles), hydroxybenzotriazole (HOBT 10.2 g, 0.0689 moles), 4- dimethylaminopyridine (DMAP 1.5 g, 0.0122 moles) and stirred for about 30 minutes under argon atmosphere. After 30 minutes, 4-chloroaniline (8.0 g, 0.0630 moles) was added and again stirred for about 12 hours at room temperature. After completion, reaction mixture was diluted by adding water and extracting in dichloromethane. The combined organic layer was dried over anhydrous sodium sulphate and concentrated to get crude compound which was purified by column chromatography using 40% ethyl acetate in hexane as eluent to get desired compound.
Yield: 13.0g
LCMS: 348.05 (M+1)
Step c: Preparation of methyl 2-({4-[(4-chlorophenyl)carbameyl|phenyl}sulfanyl)-4- hydroxybutanoate
To a solution of compound obtained from Step b (13.0 g, 0.037 mole) in N,N’- dimethylformamide (52 mL) and water (13 mL) was added sodium hydroxide (1.70 g, 0.044 moles). The reaction mixture was allowed to stir for about 30 minutes at room temperature. After 30 minutes, sodium bicarbonate (3.7 g, 0.044 moles), 18 crown 6 (0.970 g, 0.0037 moles) and methyl iodide (7.80 g, 0.055 moles) were added and stirred for overnight. After completion, reaction mixture was diluted by adding water and extracting in ethyl acetate. The combined organic layer was dried over anhydrous sodium sulphate and concentrated to get crude product which was purified by silica gel column using 30% ethyl acetate in hexane as eluent to get desired compound.
Yield: 8.0 g
Step d: Preparation of methyl 2-({4-[(4-chlorophenyl)carbamoyl]|phenyl}sulfanyl)-4- {[(4-fluorophenyl)carbamoyl]oxy}butanoate
To a solution of compound obtained from Step ¢ (0.500 g, 0.0013 moles) in tetrahydrofuran (5 mL) under argon atmosphere were added triethylamine (0.393 g, 0.0038 moles) and 4-fluoro-isocyanate (0.213 g, 0016moles) and stirred for about 2 hours at room temperature. After completion, reaction mixture was diluted by adding water and extracting in ethyl acetate. The combined organic layer was dried over anhydrous sodium sulphate and concentrated to get crude product which was purified by silica gel column using 30% ethyl acetate in hexane as eluent to afford desired compound.
Yield: 0.3 g
Step e: Preparation of 2-({4-[(4-chlorophenyl)carbamoyl]phenyl}sulfanyl)-4-{[(4- fluorophenyl)carbamoyl]oxy}butanoic acid
To a solution of compound obtained from Step d (0.300 g, 0.0005 moles) in tetrahydrofuran (5Sml)/methanol (Sml) was added a solution of lithium hydroxide (0.036 g, 0.0006 moles) in water (1 mL) and stirred for about one hour at room temperature. After completion, reaction mixture was acidify by adding sodium bisulphite solution and extracted in ethyl acetate. The combined organic layer was dried over anhydrous sodium sulphate and concentrated to get a compound which was purified by preparative TLC eluted using 10% methanol in dichloromethane.
Yield: 0.050 g
LCMS: 501.15 (M-1) "HNMR (400 MHz, DMSO-ds)-8:10.28 - 10.35 (1H, s), 9.67 (1H, s), 7.76 - 7.78 (4H, m), 7.53 - 7.55 (2H, m), 7.32 - 7.44 (3H, m), 7.07 - 7.20 (3H, m), 4.18 - 4.21 (2H, m), 3.98 - 4.02 (1H, m), 1.90 -2.23 (2H, m).
The following compounds can be prepared by following the above synthetic route. 2-({4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfanyl)-4-{[(2- fluorophenyl)carbamoyl]oxy } butanoic acid (Compound no. 59);
LCMS: 501.17 (M-1) 2-({4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfanyl)-4- {[(4- ethylphenyl)carbamoyl]oxy}butanoic acid (Compound no. 60);
LCMS: 511.22 (M-2) 2-({4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfanyl)-4-( {[4-(propan-2-yl)phenyl] carbamoyl }oxy)butanoic acid (Compound no. 61);
LCMS: 525.19 (M-2) 2-({4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfanyl)-4-{[(4-methoxyphenyl) carbamoyl]oxy }butanoic acid (Compound no. 62);
LCMS: 513.18 (M-1) 2-({4-[(4-Chlorophenyl)carbamoyl]phenyl} sul fanyl)-4-{[(2- methylphenyl)carbamoyl]oxy}butanoic acid (Compound no. 63);
LCMS: 497.18 (M-1) 2-({4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfanyl)-4-{[(3-fluoro phenyl) carbamoyl]oxy}butanoic acid (Compound no. 64);
LCMS: 501.16 (M-1) 2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfanyl)-4-{[(4-methylphenyl) carbamoyl]oxy}butanoic acid (Compound no. 65);
LCMS: 417.17 (M-1) 2-({4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfanyl)-4-({[4- (trifluoromethyl)phenyl]carbamoyl } oxy)butanoic acid (Compound no. 66);
LCMS: 551.09 (M-1) 2-({4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfanyl)-4-{[(2,4-difluorophenyl) carbamoyl]oxy } butanoic acid (Compound no. 67);
LCMS: 519.15 (M-1) 2-({4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfanyl)-4-{[(2,6- dichlorophenyl)carbamoyl]oxy} butanoic acid (Compound no. 69);
LCMS: 553.06 (M) 4-[(tert-Butylcarbamoyl)oxy]-2-({4-[(4-chlorophenyl)carbamoyl]phenyl} sulfanyl butanoic acid (Compound no. 70);
LCMS: 463.20 (M-1) 2-({4-[(4-Chlorophenyl)carbamoyl phenyl} sulfanyl)-4-{[(3,4- dichlorophenyl)carbamoyl]oxy}butanoic acid (Compound no. 71);
LCMS: 553.03 (M) 2-({4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfanyl)-4- [(pentylcarbamoyl)oxy]butanoic acid (Compound no. 72);
LCMS: 477.19 (M-1)
4-{[(3-Chlorophenyl)carbamoyl]oxy}-2-({4-[(4-chlorophenyl)carbamoyl]phenyl} sulfanyl)butanoic acid (Compound no. 73);
LCMS: 519.10 (M) 4-[(Butylcarbamoyl)oxy]-2-({4-[(4- chlorophenyl)carbamoyl]phenyl}sulfanyl)butanoic acid (Compound no. 74);
LCMS: 463.17 (M-1)
Example 2: Synthesis of 2-({4-[(4-chlorophenyl)carbamoyl]phenyl}sulfonyl)-4-{[(4- fluorophenyl)carbamoyl]oxy}butanoic acid (Compound no. 81) (Scheme I, Path A,
Formula 9)
To an ice-cooled solution of 2-({4-[(4-chlorophenyl)carbamoyl]phenyl}sulfanyl)- 4-{[(4-fluorophenyl)carbamoyl]oxy} butanoic acid (0.050 g, 0.00009 moles) in chloroform (5 mL) was added metachloroperbenzoic acid (0.065 g, 0.00037 moles) and stirred for 1 hour at room temperature. The reaction mixture was quenched by adding sodium metabisulphite solution and then extracted in dichloromethane. The combined organic layer was dried over anhydrous sodium sulphate and concentrated to get crude product which was purified by preparative TLC eluted in 12% methanol in dichloromethane.
Yield: 0.030 g
LCMS: 533.18 (M-1) 'H NMR (400 MHz, DMSO-ds) -8: 10.63 - 10.71 (1H, s), 9.10 (1H, s), 8.10 - 8.12 (2H, d,
J=8.0Hz), 7.96-7.98 (2H, d, J=8.0 Hz), 7.83 - 7.86 (2H, m), 7.41 - 7.44 (4H, m), 7.10 - 7.21 (2H, m), 4.17 (2H, m), 3.86 (1H, m), 2.11 (2H, m).
The following compounds can be prepared by following the above synthetic route. 2-({4-[(4-Chlorophenyl)carbamoyl phenyl} sulfonyl)-4-{[(2- fluorophenyl)carbamoyl]oxy} butanoic acid (Compound no. 75);
LCMS: 533.21 (M-1) 2-({4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfonyl)-4-{[(4- ethylphenyl)carbamoyl]oxy}butanoic acid (Compound no. 76);
LCMS: 543.24 (M-2) 2-( {4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfonyl)-4-{[(2- methylphenyl)carbamoyl]oxy } butanoic acid (Compound no. 77);
LCMS: 529.22 (M-1) 2-({4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfonyl)-4-{[(4- methylphenyl)carbamoyl]oxy } butanoic acid (Compound no. 78);
LCMS: 529.20 (M-1)
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfonyl)-4-({[4- (trifluoromethyl)phenyl]carbamoyl } oxy)butanoic acid (Compound no. 79);
LCMS: 583.21 (M-1) : 2-({4-[(4-Chlorophenyl)carbamoyl phenyl} sulfonyl)-4-{[(2,4- difluorophenyl)carbamoyl]oxy} butanoic acid (Compound no. 80);
LCMS: 551.19 (M-1) 2-({4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfonyl)-4-{[(2,6-dichlorophenyl) carbamoyl]oxy}butanoic acid (Compound no. 82);
LCMS: 541.11 (M-44) 4-[(tert-Butylcarbamoyl)oxy]-2-({4-[ (4-chlorophenyl)carbamoyl]phenyl} sulfonyl)butanoic acid (Compound no. 83);
LCMS: 451.19 (M-45) 2-({4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfonyl)-4-{[(3,4-dichlorophenyl) carbamoyl]oxy}butanoic acid (Compound no. 84);
LCMS: 585.09 (M) 2-({4-[(4-Chlorophenyl)carbamoyl phenyl} sulfonyl)-4- [(pentylcarbamoyl)oxy]butanoic acid (Compound no. 85);
LCMS: 509.24 (M-1) 4-{[(3-Chlorophenyl)carbamoyl]oxy}-2-({4-[(4-chlorophenyl)carbamoyl]phenyl} sulfonyl butanoic acid (Compound no. 86);
LCMS: 551.11 (M) 4-[(Butylcarbamoyl)oxy]-2-({4-[(4-chlorophenyl)carbamoyl]phenyl} sulfonyl)butanoic acid (Compound no. 87);
LCMS: 495.24
Example 3: Synthesis of 2-[(4-{[(4-chlorophenyl)carbonyl]amino} phenyl)sulfanyl]-4- {[(4-fluoro phenyl)carbamoyl]oxy}butanoic acid (Compound no. 5) (Scheme I, Path B,
Formula 15)
Step a: Preparation of 3-[(4-nitrophenyl)sulfanyl]dihydrofuran-2(3H)-one
To an ice-cooled solution of p-nitro thiophenol (10.0 g, 0.0645 moles) in dichloromethane (75 mL) under argon atmosphere were added triethylamine (19.4 g, 0.1935 moles) and a solution of bromo-lactone (11.1 g, 0.067 moles) in dichloromethane (75 mL) drop wise. The reaction mixture was allowed to stir for about 30 minutes at room temperature. After completion, reaction mixture was diluted with water and extracted in dichloromethane. The combined organic layer was dried over anhydrous sodium sulphate and concentrated to get a crude product. The crude product so obtained was purified by silica gel column using 30% ethyl acetate in hexane as eluent to get title compound.
Yield: 11 g
Step b: Preparation of 3-[(4-aminophenyl)sulfanyl|dihydrofuran-2(3H)-one
To the solution of compound obtained from Step a (10.0 g, 0.04184 moles) in tetrahydrofuran/methanol (100 mL:100 mL) was added Pd/C (4 g) under vacuum and hydrogen pressure was applied using balloon. The reaction mixture was allowed to stir for about 2 hours at room temperature. After completion, reaction mixture was filtered through celite and concentrated to get desired compound. Yield:5.0g
LCMS: 210 (M+1)
Step c: Preparation of 4-chloro-N-{4-[(2-oxotetrahydrofuran-3-yl)sulfanyl] phenyl} benzamide
To a solution of compound obtained from Step b (4.86 g, 0.0232 moles) in dichloromethane (100 mL) under argon atmosphere was added triethylamine (7.04 g, 0.0697 moles) and cooled to 0°C and then 4-chlorobenzoyl chloride (4.27 g, 0.024 moles) was added slowly drop wise. The reaction mixture was allowed to stir for 10 minutes at room temperature. After completion, reaction mixture was diluted with water and extracting in dichloromethane. The organic layer was washed with sodium bicarbonate and separated. The organic layer was dried over anhydrous sodium sulphate and concentrated to obtain a crude product. The crude product obtained was purified by silica gel column using 10% ethyl acetate in hexane as eluent.
Yield: 4.0 g
LCMS: 348 (M+1)
Step d: Preparation of methyl 2-[(4-{|(4-chlorophenyl)carbonyl]amino} phenyl) sulfanyl]-4-hydroxybutanoate
To a solution of compound obtained from Step ¢ (8.2 g, 0.0236 moles) in N, N°- dimethylformamide (32 mL) and water (8 mL) was added sodium hydroxide (1.12 g, 0.0283 moles). The reaction mixture was allowed to stir for about 30 minutes at room temperature. After 30 minutes, sodium bicarbonate (2.3 g, 0.0283 moles), 18 crown 6 (0.620 g, 0.0023 moles) and methyl iodide (5.02 g, 0.0354 moles) were added to reaction mixture and stirred for overnight at room temperature. After completion, reaction mixture was diluted by adding water and extracting in ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated to get a crude product which was purified by silica gel column using 8% ethyl acetate in hexane as eluent.
Yield: 8.0 g
Step e: Preparation of methyl 4-{[(4-chlorophenyl)carbamoyl]oxy}-2-[(4-{[(4- chlorophenyl)carbonyl]amino}phenyl)sulfanyl|butanoate
To a solution of compound obtained from Step d (0.500 g, 0.00131 moles) in tetrahydrofuran (10 mL) under argon atmosphere were added triethylamine (0.266 g, 0.0026 moles) and 1-chloro-4-isocyanatobenzene (0.211 g, 0.0015 moles) and stirred for about 2 hours at room temperature. After completion, reaction mixture was diluted by adding water and extracting in ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated to get crude product which was purified by silica gel column using 15% ethyl acetate in hexane as eluent.
Yield: 0.4 g
Step f: Preparation of 4-{[(4-chlorophenyl)carbamoyl]oxy}-2-[(4-{[(4-chlorophenyl) carbonyl]amino}phenyl)sulfanyl]butanoic acid
To a solution of compound obtained from Step e (0.300 g, 0.0005 moles) in tetrahydrofuran /methanol (5 mL:5 mL) was added a solution of lithium hydroxide (0.034 g, 0.0008 moles) in water and stirred at room temperature for about one hour. After completion, reaction mixture was acidify with sodium bisulphite solution and then extracted in ethyl acetate. The combined organic layer was dried over anhydrous sodium sulphate and concentrated to get crude product which was purified by preparative TLC using 10% methanol/dichloromethane as eluent.
Yield: 0.080 g
LCMS: 503 (M+1), 520 (M+18) 'H NMR (400 MHz, DMSO-ds) 8 10.4 (1H, s), 9.66 (1H, s), 7.95 - 7.97 (2H, d, J= 8.4
Hz), 7.73-7.76 2H, d, J=8.4 Hz), 7.59 - 7.61 2H, d, J=8.4 Hz), 7.43 - 7.49 (4H, d, J =
8.4 Hz), 7.06 - 7.15 (2H, d, J= 4.0 Hz), 5.7 (1H, s), 4.12 - 4.23 (2H, m), 3.72 - 3.76 (1H, m), 2.07 - 2.12 (1H, m), 1.89 -1.96 (1H, m).
The following compounds can be prepared by following the above synthetic route. 2-[(4-{[(4-Chlorophenyl)carbonyl]Jamino} phenyl)sulfanyl]-4-({[2-fluoro-5- (trifluoro methyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 6);
LCMS: 571.11 (M+1) 2-[(4-{[(4-Chlorophenyl)carbonyl]Jamino} phenyl)sulfanyl]-4-{[(3,5- dimethoxyphenylcarbamoyl]oxy} butanoic acid (Compound no. 7);
LCMS: 545.11 (M) 2-[(4-{[(4-Chlorophenyl)carbonyl]Jamino}phenyl)sulfanyl]-4-{[(5-fluoro-2-methyl phenyl)carbamoyl]oxy}butanoic acid (Compound no. 8);
LCMS: 517.17 (M+1) 2-[(4-{[(4-Chlorophenyl)carbonyl]Jamino}phenyl)sulfanyl]-4-{[(2- fluorophenyl)carbamoyl]oxy } butanoic acid (Compound no. 9);
LCMS: 503.11 (M+1) 4-{[(3-Chloro-4-methoxyphenyl)carbamoyl]oxy}-2-[(4-{[(4-chlorophenyl) carbonyl]amino}phenyl)sulfanyl]butanoic acid (Compound no. 10);
LCMS: 549.03 (M) 2-[(4-{[(4-Chlorophenyl)carbonyl]amino} phenyl)sulfanyl]-4-{[(3-ethoxyphenyl) carbamoyl]oxy }butanoic acid (Compound no. 11);
LCMS: 529.15 (M), 546.19 (M+17) 4-{[(3-Chlorophenyl)carbamoyl]oxy}-2-[(4-{[(4-chlorophenyl)carbonyl]amino} phenyl)sulfanyl]butanoic acid (Compound no. 12);
LCMS: 519.07 (M), 536.11 (M+17) 4-{[(4-Chlorophenyl)carbamothioyl]oxy}-2-[(4-{[(4-chlorophenyl)carbonyl] amino }phenyl)sulfanyl]butanoic acid (Compound no. 13);
LCMS: 535.03 (M) 2-[(4-{[(4-Chlorophenyl)carbonyl]amino} phenyl)sul fanyl]-4-{[(3- cyanophenyl)carbamothioyl]oxy }butanoic acid (Compound no. 14);
LCMS: 527.12 (M+1) 4-{[(2-Fluorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methylphenyl)carbonyl]amino} phenyl)sulfanyl]butanoic acid (Compound no. 29) ;
LCMS: 483.14 (M+1) 4-{[(3-Fluorophenyl)carbamoyl]oxy}-2-[ (4-{[(4-methylphenyl)carbonyl]amino} phenyl)sulfanyl]butanoic acid (Compound no. 30);
LCMS: 483.21 (M+1)
4-{[(4-Chlorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl)carbonyl amino} phenyl)sulfanyl]butanoic acid (Compound no. 32);
LCMS: 513.22 (M-1) 4-{[(4-Ethylphenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl)carbonyl] amino} phenyl)sulfanyl]butanoic acid (Compound no. 33);
LCMS: 507.28 (M-1) 2-[(4-{[(4-Methoxyphenyl)carbonyl]amino} phenyl)sulfanyl]-4-({[4- (trifluoromethyl)phenyl]carbamoyl} oxy)butanoic acid (Compound no. 34);
LCMS: 547.20 (M-1) 4-{[(2,6-Dichlorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl) carbonyl]amino} phenyl)sulfanyl]butanoic acid (Compound no. 35);
LCMS: 547.3 (M-2) 2-[(4-{[(4-Methoxyphenyl)carbonyl]amino} phenyl)sulfanyl]-4-{[(2-methylphenyl) carbamoyl oxy} butanoic acid (Compound no. 36);
LCMS: 493.22 (M-1) 4-{[(4-Methoxyphenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl)carbonyl] amino} phenyl)sulfanyl]butanoic acid (Compound no. 37);
LCMS: 509.26 (M-1) 4-[(tert-Butylcarbamoyl)oxy]-2-[(4-{[(4-methoxyphenyl)carbonyl]amino} phenyl) sulfanyl]butanoic acid (Compound no. 38);
LCMS: 459.24 (M-1) 4-{[(2,4-Difluorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl)carbonyl] amino} phenyl)sulfanyl]butanoic acid (Compound no. 39);
LCMS: 515.20 (M-1) 4-{[(2-Fluorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl)carbonyl]amino} phenyl)sulfanyl]butanoic acid (Compound no. 40);
LCMS: 497.25 (M-1) 4-{[(3-Fluorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl)carbonyl]amino} phenyl)sulfanyl]butanoic acid (Compound no. 41);
LCMS: 497.25 (M-1) 4-{[(3,4-Dichlorophenyl)carbamoyl]oxy }-2-[(4-{[(4-methoxyphenyl) carbonyl]amino} phenyl)sulfanyl]butanoic acid (Compound no. 42);
LCMS: 547.14 (M-2) 4-{[(3,4-Dichlorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methylphenyl) carbonyl]amino}phenyl)sulfanyl]butanoic acid (Compound no. 43);
LCMS: 535.09 (M+2) 4-{[(2,4-Difluorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methylphenyl) carbonyl]amino} phenyl)sulfanyl]butanoic acid (Compound no. 44);
LCMS: 501.15 (M+1) 2-[(4-{[(2-Fluorophenyl)carbonyl]amino} phenyl)sulfanyl}-4-({[4-(trifluoromethyl) phenyl]carbamoyl} oxy)butanoic acid (Compound no. 88);
LCMS: 535.27 (M-1) 2-[(4-{[(4-Chlorophenyl)carbonyl]amino} phenyl)sulfanyl]-4-({[4- (trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 89);
LCMS: 551.27 (M-1) 2-[(4-{[(2,6-Dimethoxyphenyl)carbonyl]amino} phenyl)sulfanyl]-4-({[4- (trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 90);
LCMS: 577.29 (M-1) 2-({4-[(Cyclopropylcarbonyl)amino]phenyl} sulfanyl)-4-({[4- (trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 91);
LCMS: 483.19 (M+1) 2-[(4-{[(2-Methylphenyl)carbonyl]amino } phenyl)sulfanyl]-4-({[4- (trifluoromethyl)phenyl] carbamoyl} oxy)butanoic acid (Compound no. 92);
LCMS: 531.25 (M-1) 2-[(4-{[(2-Ethoxyphenyl)carbonyl]amino} phenyl)sulfanyl]-4-({[4- (trifluoromethyl) phenyl]carbamoyl}oxy)butanoic acid (Compound no. 93);
LCMS: 561.27 (M-1) 2-[(4-{[(2,3-Difluorophenyl)carbonyl}amino} phenyl)sulfanyl]-4-({[4- (trifluoromethyl)phenyl]carbamoyl } oxy)butanoic acid (Compound no. 94);
LCMS: 553.21 (M-1) 2-[(4-{[(3,4-Dichlorophenyl)carbonyl]amino } phenyl)sulfanyl]-4-({[4- (trifluoromethyl)phenyl]carbamoyl} oxy)butanoic acid (Compound no. 95);
LCMS: 585.21 (M-2) 2-[(4-{[(4-Ethoxyphenyl)carbonyl]amino } phenyl)sulfanyl]-4-({[4- (trifluoromethyl)phenyl]carbamoyl } oxy)butanoic acid (Compound no. 96);
LCMS: 561.28 2-({4-[(Cyclohexylcarbonyl)amino]phenyl} sulfanyl)-4-({[4-(trifluoromethyl) phenyl]carbamoyl} oxy)butanoic acid (Compound no. 97);
LCMS: 523.33 (M-1) 2-[(4-{[(2,4-Dichlorophenyl)carbonyl]amino} phenyl)sulfanyl]-4-({[4- (trifluoromethyl)phenyl]carbamoyl} oxy)butanoic acid (Compound no. 98);
LCMS: 585.19 (M-2), 587.15 (M).
Example 4: Synthesis of 2-[(4-{[(4-chlorophenyl)carbonyl]amino}phenyl)sulfonyl]-4- {[(4-fluoro phenyl)carbamoyl]oxy}butanoic acid (Compound no. 15) (Scheme 1, Path B,
Formula 16)
To an ice-cooled solution of 4-{[(4-fluorophenyl)carbamoyl]oxy}-2-[(4-{[(4- chlorophenyl)carbonyl]amino} phenyl)sulfanyl]butanoic acid (0.080 g, 0.00015 moles) was added meta-chloroperbenzoic acid (0.101 g, 0.00059 moles) and stirred for about one hour at room temperature. After completion, reaction mixture was quenched by adding sodium metabisulphite solution and then extracted in dichloromethane. The organic layer was dried over anhydrous sodium sulphate and concentrated to obtain a crude product which was purified by preparative TLC using 10% methanol in dichloromethane as eluent.
Yield: 0.020 g
LCMS: 535 (M+1), 557 (M+23)
NMR (400 MHz, DMSO-de)-8 11.00 (1H, s), 9.67 (1H, s), 7.98 - 8.05 (4H, d, J = 8.4 Hz), 7.78 -7.80 (2H, d, J=9.2 Hz), 7.57 - 7.60 (2H, d, J= 8.4 Hz), 7.42 - 7.45 (2H, d, J= 8.8
Hz), 7.05 - 7.10 (2H, d, J= 8.8 Hz), 4.17 - 4.19 (1H, m), 3.97 - 4.03 (1H, m), 3.70 - 3.79 (1H, m), 2.07 - 2.11 (2H, m).
The following compounds can be prepared by following the above synthetic route. 2-[(4-{[(4-Chlorophenyl)carbonyl]amino} phenyl)sulfonyl]-4-({[2-fluoro-5- (trifluoromethyl)phenyl]carbamoyl } oxy)butanoic acid (Compound no. 16);
LCMS: 603.22 (M+1), 620.22 (M+18) 2-[(4-{[(4-Chlorophenyl)carbonyl]amino} phenyl)sulfonyl]-4-{[(5-fluoro-2-methyl phenyl)carbamoyl]oxy}butanoic acid (Compound no. 17);
LCMS: 548.03 (M) 4-{[(3-Chloro-4-methoxyphenyl)carbamoyl]oxy}-2-[(4-{[(4- chlorophenyl)carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 18);
LCMS: 581.33 (M), 603.08 (M+1) 2-[(4-{[(4-Chlorophenyl)carbonyl]amino} phenyl)sulfonyl]-4-{[(2-fluorophenyl) carbamoyl]oxy}butanoic acid (Compound no. 19);
LCMS: 535.22 (M+1), 552.28 (M+18) 4-{[(3-Chlorophenyl)carbamoyl]oxy}-2-[(4-{[(4-chlorophenyl)carbonyl]amino} phenyl)sulfonyl]butanoic acid (Compound no. 20);
LCMS: 552.01 (M+1), 573.14 (M+22) 2-[(4-{[(4-Chlorophenyl)carbonyl]amino} phenyl)sulfonyl]-4- {[(3-cyanophenyl) carbamothioyl]oxy }butanoic acid (Compound no. 21);
LCMS: 564.12 (M+6), 542.24 (M-16) 4-{[(3-Fluorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methylphenyl)carbonyl] amino} phenyl)sulfonyl]butanoic acid (Compound no. 31);
LCMS: 515.09 (M+1) 4-{[(4-Chlorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl)carbonyl] amino} phenyl)sulfonyl]butanoic acid (Compound no. 45);
LCMS: 547.20 (M+1) 4-{[(4-Ethylphenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl)carbonyl]amino} phenyl)sulfonyl]butanoic acid (Compound no. 46);
LCMS: 540.25 (M) 2-[(4-{[(4-Methoxyphenyl)carbonyl]amino} phenyl)sulfonyl]-4-({[4- (trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 47);
LCMS: 579.24 (M-1) 4-{[(2,6-Dichlorophenyl)carbamoyl]oxy} -2-[(4-{[(4-methoxyphenyl)carbonyl] amino} phenyl)sulfonyl]butanoic acid (Compound no. 48);
LCMS: 579.18 (M-20) 2-[(4-{[(4-Methoxyphenyl)carbonyl]amino} phenyl)sulfonyl]-4-{[(2- methylphenyl)carbamoyl]oxy } butanoic acid (Compound no. 49);
LCMS: 525.24 (M-1) 4-[(tert-Butylcarbamoyl)oxy]-2-[(4-{[(4-methoxyphenyl)carbonyl]amino} phenyl) sulfonyl]butanoic acid (Compound no. 50);
LCMS: 491.29 (M-1) 4-{[(2,4-Difluorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl)carbonyl] amino} phenyl)sulfonyl]butanoic acid (Compound no. 51);
LCMS: 547.22 (M-1) 4-{[(2-Fluorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl)carbonyl]amino} phenyl)sulfonyl]butanoic acid (Compound no. 52);
LCMS: 529.22 (M-1) 4-{[(3-Fluorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl)carbonyl]Jamino} phenyl)sulfonyl]butanoic acid (Compound no. 53);
LCMS: 529.25 (M-1) 4-{[(5-Chloro-2-methoxyphenyl)carbamoyl]oxy} -2-[(4-{[ (4-methoxyphenyl) carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 54);
LCMS: 575.23 (M-2), 577.17 (M) 4-{[(3,4-Dichlorophenyl)carbamoyl]oxy }-2-[(4-{[(4-methoxypheny]) carbonyl]amino} phenyl)sulfonyl]butanoic acid (Compound no. 55);
LCMS: 579.14 (M-2), 581.16 (M) 4-{[(3,4-Dichlorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methylphenyl) carbonyl]amino} phenyl)sulfonyl]butanoic acid (Compound no. 56);
LCMS: 565.06 (M)
4-{[(2,4-Difluorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methylphenyl) carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 57);
LCMS: 533.10 (M+1) 4-{[(2-Fluorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methylphenyl)carbonyl Jamino} phenyl)sulfonyl]butanoic acid (Compound no. 58);
LCMS: 515.15 (M+1)
Example 5: Synthesis of 4-{[(4-chlorophenyl)carbamoyl]oxy}-2-[(4-chlorophenyl) sulfanyl]butanoic acid (Compound no. 1) (Scheme I, Path C, Formula 19)
Step a: Preparation of 3-[(4-chlorophenyl)sulfanyl]dihydrofuran-2(3H)-one
To an ice cooled solution of p-chloro thiophenol (10.0 g, 0.069 moles) in dichloromethane (75 mL) under argon atmosphere were added triethylamine (21.0 g, 0.208 moles) and a solution of bromo lactone (12.0 g, 0.072 moles) in dichloromethane (75 mL) drop wise. The reaction mixture was allowed to stir for about 30 minutes at 0°C.
After completion, reaction mixture was diluted by adding water and extracting in dichloromethane. The organic layer was dried over anhydrous sodium sulphate and concentrated to get a crude product which was purified by silica gel column using 10% ethyl acetate in hexane as eluent.
Yield: 139 ¢g
Step b: Preparation of methyl 2-[(4-chlorophenyl)sulfanyl]-4-hydroxybutanoate
To a solution of compound obtained from Step a (5.0 g, 0.0219 moles) in N, N’- dimethylformamide (20ml) and water (Sm!) was added sodium hydroxide (1.05 g, 0.0263 moles). The reaction mixture was allowed to stir for about 30 minutes at room temperature. After 30 minutes, sodium bicarbonate (1.74 g, 0.0208 moles), 18 crown 6 (0.45 g, 0.0017 moles) and methyl iodide (3.68 g, 0.0259 moles) were added to reaction mixture and again stirred for overnight at room temperature. After completion, reaction mixture was diluted by addition of water and extracting in ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated to obtain a crude product which was purified by silica gel column using 8% ethyl acetate in hexane as eluent to get a title compound.
Yield:3.5¢g
Step c: Preparation of methyl 4-{[(4-chlorophenyl)carbamovljoxy}-2-[(4- chlorophenylsulfanyl|butanoate
To a solution of compound obtained from Step & (0.425 g, 0.0016 moles) in tetrahydrofuran (10 mL) under argon atmosphere were added triethylamine (0.323 g, 0.0032 moles) and 1-chloro-4-isocyanatobenzene (0.293 g, 0.0019 moles) and stirred for about 2 hours at room temperature. After completion, reaction mixture was diluted by adding water and extracting in ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated to get crude product which was purified by silica gel column using 15% ethyl acetate in hexane as eluent to get desired compound.
Yield: 0.600 g
Step d: Preparation of 4-{[(4-chlorophenyl)carbamoyl]oxy}-2-[(4-chlorophenyl) sulfanyl]butaneic acid
To a solution of compound obtained from Step ¢ (0.600 g, 0.0014 moles) in tetrahydrofuran/methanol (5ml:5ml) was added a solution of lithium hydroxide (0.090 g, 0.0021 moles) in water (1 mL) and stirred for about one hour at room temperature. After completion, reaction mixture was acidify with sodium bisulphite solution and then extracted in ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated to get crude product which was purified by preparative TLC using 10% methanol in dichloromethane as eluent to obtain the desired compound.
Yield: 0.100 g
LCMS: 401.23(M+1)
NMR- (400 MHz, DMSO-dg) 8: 9.73 (1H, s), 7.45 - 7.53 (6H, d, J= 8.4 Hz), 7.15 - 7.19 (2H, d, J=8.4 Hz), 4.17 - 4.30 (2H, m), 3.91 - 3.95 (1H, t, J= 7.2 Hz), 2.15 - 2.24 (1H, m), 1.97 - 2.06 (1H, m).
The following compounds can be prepared by following the above synthetic route. 2-[(4-Chlorophenyl)sulfanyl]-4-{[(4-fluorophenyl)carbamoyl]oxy } butanoic acid (Compound no. 2);
LCMS: 384.22 (M™+1)
Example 6: Synthesis of 4-{[(4-chlorophenyl)carbamoyl]oxy}-2-[(4- chlorophenyl)sulfonyl]butanoic acid (Compound no. 3) (Scheme I, Path C, Formula 20)
To an ice-cooled solution of 4-{[(4-chlorophenyl)carbamoyl]oxy}-2-[(4- chlorophenyl)sulfanyl]butanoic acid (0.100 g, 0.0002 moles) in chloroform (10 mL) was added meta-chloroperbenzoic acid (0.172 g, 0.001 moles) and stirred at room temperature for about one hour. After completion, reaction mixture was quenched by sodium metabisulphite solution and extracted in dichloromethane. The organic layer was dried over anhydrous sodium sulphate and concentrated to get crude product which was purified by preparative TLC using 10% methanol in dichloromethane as eluent to get desired compound.
Yield: 0.090 g
LCMS: 432.12 (M), 434 (M+2), 449.17 (M+18)
NMR-(400 MHz, DMSO-dp) 8: 9.79 (1H, s), 7.73 - 7.82 (2H, d, J = 8.8 Hz), 7.60 - 7.63 (2H, d, J=8.8 Hz), 7.44- 7.46 (2H, d, /J= 8.8 Hz), 7.29 - 7.31 (2H, d, J = 8.8 Hz), 4.07 - 4.19 (1H, m), 3.97 - 4.03 (1H, m), 3.75 - 3.76 (1H, m), 2.03 - 2.10 (2H, m).
The following compounds can be prepared by following the above synthetic route. 2-[(4-Chlorophenyl)sulfonyl]-4-{[(4-fluorophenyl)carbamoyljoxy} butanoic acid (Compound no. 4);
LCMS: 416.13 (M+1)
Example 7: Synthesis of 4-(benzyloxy)-2-[(4-nitrophenyl)sulfonyl]butanoic acid (Compound no. 28 (Scheme II, Path D, Formula 27)
Step a: Synthesis of ethyl [(4-nitrophenyl)sulfanyl]acetate
To an ice-cooled solution of p-nitro thiophenol (5 g, 0.0322 moles) in dichloromethane (50 mL) under argon atmosphere were added triethylamine (9.7 g, 0.0967 moles) and a solution of ethyl bromoacetate (6.4 g, 0.0387 moles) drop wise. The reaction mixture was allowed to stir for about 5 hours at room temperature. After completion, reaction mixture was diluted with water and extracted in dichloromethane.
The organic layer was dried over sodium sulphate and concentrated to get a crude product.
The crude product obtained was purified by silica gel column using 10% ethyl acetate in hexane as eluent.
Yield: 6.5 ¢g
LCMS: 242 (M+1)
Step b: Preparation of ethyl [(4-nitrophenyl)sulfonyl]acetate
To an ice-cooled solution of compound obtained from Step a (6.5 g, 0.0269 moles) in chloroform (70 mL) was added meta-chloroperbenzoic acid (18 g, 0.107 moles) and stirred at room temperature for about one hour. After completion, reaction mixture was quenched with sodium metabisulphite solution and then extracted in dichloromethane.
The organic layer was dried over anhydrous sodium sulphate and concentrated to get crude product which was purified by preparative TLC using 10% methanol in dichloromethane as eluent to obtain a crude product.
Yield: 6.7 g
LCMS:274 (M+1)
Step c: Preparation of ethyl 4-(benzyloxy)-2-[(4-nitrophenyl)sulfonyl]butanoate
To a solution of compound obtained from Step » (0.500 g, 0.0018 moles) in N, N’- dimethylformamide (5 mL) under argon atmosphere were added potassium carbonate (0.745 g, 0.0054 moles), tetrabutylammonium iodide (0.067 g, 0.00018 moles) and O- benzyl ethyl bromide (0.550 g, 0.0027 moles). The reaction mixture was heated to 50° C and stirred at same temperature for about 4 hours. After completion, reaction mixture was diluted by adding water and extracting in ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated to get a crude product which was purified by silica gel column using 8% ethyl acetate in hexane as eluent to get title compound.
Yield: 0.450 g
LCMS: 408 (M+1)
Step d: Preparation of 4-(benzyloxy)-2-[(4-nitrophenyl)sulfonyl]butanoic acid
To a solution of compound obtained from Step ¢ (0.100 g, 0.00024 moles) in tetrahydrofuran/methanol (5 mL:5 mL) was added a solution of lithium hydroxide (0.015 g, 0.00036 moles) in water (1 mL). The reaction mixture was allowed to stir at room temperature for about one hour. After completion, reaction mixture was acidify with sodium bisulphite solution and then extracted in ethyl acetate. The combined organic layer was dried over anhydrous sodium sulphate and concentrated to get a crude product which was purified by preparative TLC using 10% methanol in dichloromethane as eluent to get title compound.
Yield: 0.040 g
LCMS: 402.12 (M+23)
NMR-(400 MHz, DMSO-dy) 6: 8.35 - 8.46 (2H, d, J= 8.8 Hz), 8.07 - 8.20 (2H, d, /= 8.8
Hz), 7.28 - 7.33 (SH, m, J= 5.6 Hz), 4.41 (2H, s), 3.80 - 3.84 (1H, m), 3.45 - 3.51 (4H, m),2.05-2.09 (3H, m), 1.83 (1H, m).
Example 8: Synthesis of 4-(benzyloxy)-2-[(4-{[(4-methylphenyl)carbonyl]amino} phenyl)sulfonyl]butanoic acid (Compound no. 22) (Scheme II, Path E, Formula 30)
Step a: Preparation of ethyl 2-[(4-aminophenyl)sulfonyl]-4-(benzyloxy)butanoate
To a solution of ethyl 4-(benzyloxy)-2-[(4-nitrophenyl)sulfonyl]butanoate (0.500 g, 0.0012 moles) in ethyl acetate (10 mL) was added stannous chloride (0.829 g, 0.0036 moles) and stirred at 80°C for about 2 hours. After completion, reaction mixture was quenched by adding sodium bicarbonate solution and then extracted in ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to get desired compound.
Yield: 0.450 g
LCMS: 378 (M+1)
Step b: Preparation of ethyl 4-(benzyloxy)-2-[(4-{[(4-methylphenyl)carbonyl] amino}phenyl)sulfonyl|butanoate
To a solution of compound obtained from Step a (0.500 g, 0.0013 moles) in dichloromethane (10 mL) under argon atmosphere was added pyridine (0.314 g, 0.0039 moles) and cooled to 0°C. To this cooled solution was added 4-methylbenzoy! chloride (0.220 g, 0.0014 moles) slowly drop wise. After completion, reaction mixture was quenched by adding water and extracting in dichloromethane. The organic layer was washed with sodium bicarbonate, dried over anhydrous sodium sulphate and concentrated to get crude product which was purified by silica gel column using 10% ethyl acetate in hexane as eluent to get desired compound.
Yield: 0.400 g
LCMS: 348 (M+1)
Step c: Preparation of 4-(benzyloxy)-2-[(4-{[(4-methylphenyl)carbonyl] amino} phenyl)sulfonyl]butanoic acid
To a solution of compound obtained from Step b (0.100 g, 0.00020 moles) in tetrahydrofuran/methanol (5 mL:5ml) was added a solution of lithium hydroxide (0.012 g, 0.00030 moles) in water (1 mL) and stirred at room temperature for about one hour. After completion, reaction mixture was acidify by adding sodium bisulphite solution and then extracted in ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated to get crude product which was purified by preparative TLC using 10% methanol in dichloromethane as eluent to afford desired compound.
Yield: 0.050 g
LCMS: 467.93 (M), 484.95 (M+17) 'H NMR (400 MHz, DMSO-d) 8: 10.6 (1H, s), 7.98 - 8.00 (2H, d, J = 8.8 Hz), 7.89 - 7.91 (2H, d,J=8.0 Hz), 7.76 - 7.78 (2H, d, J= 8.4 Hz), 7.24 - 7.35 (7TH, d. J = 8.0 Hz), 4.36 (2H, s), 3.77 (1H, m), 3.46 - 3.49 (1H, m), 2.38 (3H, s), 1.99 - 2.01 (2H, t, J= 6.8 Hz), 121-122 (3H, t, J = 4.0Hz).
The following compounds can be prepared by following the above synthetic route. 4-(Benzyloxy)-2-[(4-{[(3-fluorophenyl)carbonyl]amino} phenyl)sulfonyl]butanoic acid (Compound no. 23);
LCMS: 470.07 (M-1) 4-(Benzyloxy)-2-[(4-{[(3-chlorophenyl)carbonyl]amino} phenyl)sulfonyl]butanoic acid (Compound no. 24);
LCMS: 486.04 (M-1) 4-(Benzyloxy)-2-[(4-{[(4-ethylphenyl)carbonylJamino} phenyl)sulfonyl]butanoic acid (Compound no. 25);
LCMS: 480.14 (M-1) 4-(Benzyloxy)-2-[(4-{[(3-methoxyphenyl)carbonyl]amino} phenyl) sulfonyl ]butanoic acid (Compound no. 26);
LCMS: 483.98 (M), 500.97 (M+17) 4-(Benzyloxy)-2-[(4-{[(2-fluorophenyl)carbonyl]amino} phenyl)sulfonyl]butanoic acid (Compound no. 27)
LCMS: 470.07 (M-1)
Assay for Matrix Metallo Proteinases (MMPs)
NCEs/standards were prepared (stock 10 mM) in 100% DMSO and subsequent dilutions were made in 50% DMSO-50% TCNB (50 mM Tris, 10 mM CaCl,, 150 mM
NaCl, 0.05% Brij-35, pH 7.5). 1 pl of the compound and 88 pl of TCNB was added to wells of 96 well plate to achieve the desired final concentration of NCE (final DMSO concentration should not exceed 0.5%). 1 pl of activated, recombinant MMPs was added to each well (20-100 ng/100 pl reaction mixture) except the “negative well”. (MMP-1, 9 &14 enzymes require prior activation. For this, supplied enzyme was incubated with either APMA, final concentration 1 mM, for a time period of 1 hour at 37°C). Incubation was done at room temperature (~ 25°C) for 4 minutes to 5 minutes. Reaction was initiated with 10 pl of 100 pM substrate (ES001: Aliquots were freshly diluted in TCNB; stock: 2 mM) and increase in florescence was monitored at excitation wavelength 320 nm followed by emission at 405 nm for 25-30 cycles. Increase in florescence (RFU) was calculated for positive, negative and NCE/standard wells. The percent inhibition compared to controls was calculated and ICs values determined using Graph-prism software.
Activities for MMP-9 provided ICs values below 10 nanomolar-10 micromolar.
Claims (1)
- We claim: I 1 A compound of Formula [: 1 X R 3 Formula I 4 including racemates, enantiomers and diastereomers, thereof or a pharmaceutically 5 acceptable salts thereof, wherein, 6 X is S, SO or SO; 7 Lis selected from bond, -O-, -S-, -SO, -SO,, -CHz, -NR*, -NHCO(CH3),-, 8 -(CH;),CONH-, -NHCONH-, -SO,NH-, -NHSQO>-, -NHCO(0)-, -O-(CH3)x, 9 -(CH;),-0O-, -OC(O)NH-, -C(S)NH-, -NHC(S), -NHC(S)NH-, -COO- wherein n is zero or an integer between 1 and 2; 1 R! is -OCONHR?, OCSNHR?, OCH;R?; 12 When R' is OCONHR® or OCSNHR? then R? is hydrogen, C1-Csalkyl, hydroxyl, 13 C;-Csalkoxy, cyano, nitro, halogen, halogeno C,-Cgalkyl, C¢-Ci; aryl, Cs- 14 Cgcycloalkyl, Cs-C; heteroaryl wherein Ce-C;; aryl, C3-Cscycloalkyl, Cs-Ci2 * heteroaryl is optionally substituted with one or more times with R’; 16 When R' is OCH;R?, then R? is C¢-C) aryl, C3-Cg cycloalkyl, Cs-C; heteroaryl; 17 R’ is alkyl, alkenyl, alkynyl, Cs-C 2 aryl, C;-C; cycloalkyl, Cs-Ci, heteroaryl, Cs- 18 C2 heterocyclyl which is optionally substituted one or more times with R’; 19 R'is H, Cysalkyl, Cj.alkylaryl; RS is selected from alkyl, alkenyl, alkynyl, cyano, nitro, halogen, halogeno-C;-Cg 21 alkyl, halogeno-C,-Cs alkoxy, azido, thiol, alkylthiol, (CH,),-OR¢ -C(=0)-Rg, 22 -COORy, -NRRg, -(CH;),-C(=0)NRRg, -(CH2),-NHC(=0)-R¢, -(CH3),- O- 23 C(=0)»NRR,, (CH2)n NHC(FO)NRR,, -(CH,),-O-C(=0) Rg, -(CH;),-NH-C(=0)- 24 R¢ or -(CH2)aS(=0)n-NRR4 {wherein R; and R, are independently selected from hydrogen, alkyl, alkenyl, cycloalkyl aryl, heteroaryl, heterocyclyl, alkylaryl, 26 alkylheteroaryl and alkylheterocyclyl, n is as define earlier and m is an integer 0-2}. RECTIFIED SHEET (RULE 91) ISA/EP1 2. A compound of Formula I, which is: 2 4-{[(4-Chlorophenyl)carbamoyl]oxy}-2-[(4-chlorophenyl)sulfanyl]butanoic acid 3 (Compound no. 1); 4 2-[(4-Chlorophenyl)sulfanyl]-4-{[(4-fluorophenyl)carbamoyl]oxy} butanoic acid (Compound no. 2); ) 4-{[(4-Chlorophenyl)carbamoyl]oxy}-2-[(4-chlorophenyl)sulfonyl]butanoic acid 7 (Compound no. 3); 8 2-[(4-Chlorophenyl)sulfonyl]-4-{[(4-fluorophenyl)carbamoyl]oxy} butanoic acid 9 (Compound no. 4); 2-[(4-{[(4-Chlorophenyl)carbonyl]amino} phenyl)sulfanyl]-4-{[(4-fluorophenyl 11 carbamoyl ]oxy } butanoic acid (Compound no. 5); 12 2-[(4-{[(4-Chlorophenyl)carbonyl]amino} phenyl)sulfanyl]-4-({[2-fluoro-5- 13 (trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 6); 14 2-[(4-{[(4-Chlorophenyl)carbonyl]amino} phenyl)sulfanyl]-4-{[(3,5- dimethoxyphenyl)carbamoyl]oxy} butanoic acid (Compound no. 7); 16 2-[(4-{[(4-Chlorophenyl)carbonyl]amino} phenyl)sulfanyl]-4-{[(5-fluoro-2-methyl 17 phenyl)carbamoyl]oxy} butanoic acid (Compound no. 8); 18 2-[(4-{[(4-Chlorophenyl)carbonyl]amino} phenyl)sulfanyl]-4-{[(2-fluoro phenyl) 19 carbamoyl ]oxy}butanoic acid (Compound no. 9); 4-{[(3-Chloro-4-methoxyphenyl)carbamoyl]oxy} -2-[(4-{[(4-chlorophenyl) 21 carbonyl]amino}phenyl)sulfanyl]butanoic acid (Compound no. 10); 22 2-[(4-{[(4-Chlorophenyl)carbonyl]Jamino} phenyl)sulfanyl]-4-{[(3- 23 ethoxyphenyl)carbamoyl]oxy} butanoic acid (Compound no. 11); 24 4-{[(3-Chlorophenyl)carbamoyl]oxy}-2-[(4-{[(4-chlorophenyl)carbonyl] amino} phenyl)sulfanyl]butanoic acid (Compound no. 12); 26 4-{[(4-Chlorophenyl)carbamothioyl]oxy}-2-[ (4-{[(4-chlorophenyl)carbonyl] 27 amino} phenyl)sulfanyl]butanoic acid (Compound no. 13); 28 2-[(4-{[(4-Chlorophenyl)carbonyl]amino} phenyl)sulfanyl]-4-{[(3-cyanophenyl) 29 carbamothioyl]oxy}butanoic acid (Compound no. 14); 2-[(4-{[(4-Chlorophenyl)carbonyl]amino} phenyl)sulfonyl]-4- {[(4-fluorophenyl) 31 carbamoyl ]oxy }butanoic acid (Compound no. 15); 32 2-[(4-{[(4-Chlorophenyl)carbonyl]amino} phenyl)sulfonyl]-4-({[2-fluoro-5- 33 (trifluoromethyl)phenyl]carbamoyl} oxy)butanoic acid (Compound no. 16); 34 2-[(4-{[(4-Chlorophenyl)carbonyl]amino} phenyl)sulfonyl]-4- {[(5-fluoro-2-methyl phenyl)carbamoyl]oxy}butanoic acid (Compound no. 17); 36 4-{[(3-Chloro-4-methoxyphenyl)carbamoyl]oxy}-2-[(4-{[(4- 37 chlorophenyl)carbonyl]amino} phenyl)sulfonyl]butanoic acid (Compound no. 18); 38 2-[(4-{[(4-Chlorophenyl)carbonyl]amino} phenyl)sulfonyl]-4-{[(2- 39 fluorophenyl)carbamoyl]oxy } butanoic acid (Compound no. 19);40 4-{[(3-Chlorophenyl)carbamoyl]oxy}-2-[(4-{[(4-chlorophenyl)carbonyl] 41 amino} phenyl)sulfonyl]butanoic acid (Compound no. 20); 42 2-[(4-{[(4-Chlorophenyl)carbonyl]amino} phenyl)sulfonyl]-4-{[(3- 43 cyanophenyl)carbamothioyl]oxy} butanoic acid (Compound no. 21); 44 4-(Benzyloxy)-2-[(4-{[(4-methylphenyl)carbonyl]amino} phenyl)sulfonyl]butanoic 45 acid (Compound no. 22;) 46 4-(Benzyloxy)-2-[(4-{[(3-fluorophenyl)carbonyl]Jamino} phenyl)sulfonyl]butanoic 47 acid (Compound no. 23); 48 4-(Benzyloxy)-2-[(4-{[(3-chlorophenyl)carbonyl]amino} phenyl)sulfonyl]butanoic 49 acid (Compound no. 24); 50 4-(Benzyloxy)-2-[(4-{[(4-ethylphenyl)carbonyl]amino} phenyl)sulfonyl]butanoic 51 acid (Compound no. 25); 52 4-(Benzyloxy)-2-[(4-{[(3-methoxyphenyl)carbonyl]amino} phenyl) 53 sulfonyl]butanoic acid (Compound no. 26); 54 4-(Benzyloxy)-2-[(4-{[(2-fluorophenyl)carbonyl]amino} phenyl)sulfonyl]butanoic 55 acid (Compound no. 27) 56 4-(Benzyloxy)-2-[(4-nitrophenyl)sulfonyl]butanoic acid (Compound no. 28); 57 4-{[(2-Fluorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methylphenyl)carbonyl]amino} 58 phenyl)sulfanyl]butanoic acid (Compound no. 29); 59 4-{[(3-Fluorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methylphenyl)carbonyl] 60 amino} phenyl)sulfanyl]butanoic acid (Compound no. 30); 61 4-{[(3-Fluorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methylphenyl)carbonyl] 62 amino} phenyl)sulfonyl]butanoic acid (Compound no. 31); 63 4-{[(4-Chlorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl)carbony]] 64 amino} phenyl)sulfanyl]butanoic acid (Compound no. 32); 65 4-{[(4-Ethylphenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl)carbonyl] 66 amino} phenyl)sulfanyl]butanoic acid (Compound no. 33); 67 2-[(4-{[(4-Methoxyphenyl)carbonylJamino} phenyl)sulfanyl]-4-({[4- 68 (trifluoromethyl)phenyl]carbamoyl} oxy)butanoic acid (Compound no. 34); 69 4-{[(2,6-Dichlorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl) 70 carbonyl]amino} phenyl)sulfanyl]butanoic acid (Compound no. 35); 71 2-[(4-{[(4-Methoxyphenyl)carbonyl]amino} phenyl)sulfanyl]-4-{[(2-methylphenyl) 72 carbamoyl]oxy} butanoic acid (Compound no. 36); 73 4-{[(4-Methoxyphenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl)carbonyl] 74 amino }phenyl)sulfanyl]butanoic acid (Compound no. 37); 75 4-[(tert-Butylcarbamoyl)oxy]-2-[(4-{[(4-methoxyphenyl)carbonyl] 76 amino} phenyl)sulfanyl]butanoic acid (Compound no. 38); 77 4-{[(2,4-Difluorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl) 78 carbonyl]amino} phenyl)sulfanyl]butanoic acid (Compound no. 39);79 4-{[(2-Fluorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl)carbonyl] 80 amino} phenyl)sulfanyl]butanoic acid (Compound no. 40); 81 4-{[(3-Fluorophenyl)carbamoyljoxy}-2-[(4-{[(4-methoxyphenyl)carbonyl] 82 amino }phenyl)sulfanyl]butanoic acid (Compound no. 41); 83 4-{[(3,4-Dichlorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl) 84 carbonyl]Jamino} phenyl)sulfanyl]butanoic acid (Compound no. 42); 85 4-{[(3,4-Dichlorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methylphenyl)carbonyl] 86 amino } phenyl)sulfanyl]butanoic acid (Compound no. 43); 87 4-{[(2,4-Difluorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methylphenyl)carbonyl] 88 amino }phenyl)sulfanyl]butanoic acid (Compound no. 44); 89 4-{[(4-Chlorophenyl)carbamoyl]oxy }-2-[(4-{[(4-methoxyphenyl)carbonyl] 90 amino } phenyl)sulfonyl]butanoic acid (Compound no. 45); 91 4-{[(4-Ethylphenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl)carbonyl] 92 amino} phenyl)sulfonyl]butanoic acid (Compound no. 46); 93 2-[(4-{[(4-Methoxyphenyl)carbonyl]amino}phenyl)sulfonyl]-4-({[4- 94 (trifluoromethyl)phenyljcarbamoyl} oxy)butanoic acid (Compound no. 47); 95 4-{[(2,6-Dichlorophenyl)carbamoyl]oxy }-2-[(4- {[(4-methoxyphenyl) 96 carbonyl]aminophenyl)} sulfonyl]butanoic acid (Compound no. 48); 97 2-[(4-{[(4-Methoxyphenyl)carbonyl]amino} phenyl)sul fonyl]-4- {[(2- 98 methylphenyl)carbamoyl]oxy}butanoic acid (Compound no. 49); 99 4-[(tert-Butylcarbamoyl)oxy]-2-[(4-{[(4-methoxyphenyl)carbonyl] 100 amino } phenyl)sulfonyl]butanoic acid (Compound no. 50); 101 4-{[(2,4-Difluorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl) 102 carbonyl]amino }phenyl)sulfonyl]butanoic acid (Compound no. 51); 103 4-{[(2-Fluorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl)carbonyl]amino} 104 phenyl)sulfonyl]butanoic acid (Compound no. 52); 105 4-{[(3-Fluorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl)carbonyl] 106 amino } phenyl)sulfonyl]butanoic acid (Compound no. 53); 107 4-{[(5-Chloro-2-methoxyphenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl) 108 carbonyl]amino} phenyl)sulfonyl]butanoic acid (Compound no. 54); 109 4-4[(3,4-Dichlorophenyl)carbamoyljoxy}-2-[(4-{[(4-methoxyphenyl) 110 carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 55); 111 4-{[(3,4-Dichlorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methylphenyl) 112 carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 56); 113 4-{[(2,4-Difluorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methylpheny]) 114 carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 57); 115 4-{[(2-Fluorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methylphenyl) 116 carbonyl]amino} phenyl)sulfonyl]butanoic acid (Compound no. 58); 117 2-({4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfanyl)-4-{[(2- 118 fluorophenyl)carbamoyl]oxy} butanoic acid (Compound no. 59);119 2-({4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfanyl)-4-{[(4-ethylpheny])120 carbamoyl]oxy }butanoic acid (Compound no. 60);121 2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfanyl)-4-({[4-(propan-2-yl)phenyl] 122 carbamoyl} oxy)butanoic acid (Compound no. 61);123 2-({4-1(4-Chlorophenyl)carbamoyl]phenyl} sulfanyl)-4- {[(4-methoxyphenyl) 124 carbamoyl]oxy } butanoic acid (Compound no. 62);125 2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfanyl)-4- {[(2-126 methylphenyl)carbamoyl]oxy} butanoic acid (Compound no. 63);127 2-({4-[(4-Chlorophenyl)carbamoyl phenyl} sulfanyl)-4-{[(3-fluorophenyl) 128 carbamoyl]oxy}butanoic acid (Compound no. 64);129 2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfanyl)-4- {[(4-methylphenyl) 130 carbamoyl]oxy}butanoic acid (Compound no. 65);131 2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfanyl)-4-({[4-(trifluoromethyl) 132 phenyl]carbamoyl}oxy)butanoic acid (Compound no. 66);133 2-({4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfanyl)-4- {[(2,4-difluorophenyl) 134 carbamoyl]oxy } butanoic acid (Compound no. 67);135 2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfanyl)-4-{[(4-fluorophenyl) 136 carbamoyl]oxy}butanoic acid (Compound no. 68);137 2-({4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfanyl)-4-{[(2,6-138 dichlorophenyl)carbamoyl]oxy}butanoic acid (Compound no. 69);139 4-[(tert-Butylcarbamoyl)oxy]-2-({4-[(4-chlorophenyl)carbamoyl]140 phenyl} sulfanyl)butanoic acid (Compound no. 70);141 2-({4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfanyl)-4-{[(3,4-142 dichlorophenyl)carbamoyl]oxy} butanoic acid (Compound no. 71);143 2-({4-[(4-Chlorophenyl)carbamoyl]phenyl } sulfanyl)-4-[(pentylcarbamoyl) 144 oxy Jbutanoic acid (Compound no. 72);145 4-{[(3-Chlorophenyl)carbamoyl]oxy}-2-({4-[(4-chlorophenyl)146 carbamoyl]phenyl}sulfanyl)butanoic acid (Compound no. 73);147 4-[(Butylcarbamoyl)oxy]-2-({4-[(4-chlorophenyl)carbamoyl]148 phenyl} sulfanyl)butanoic acid (Compound no. 74);149 2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfonyl)-4-{[(2-fluorophenyl) 150 carbamoyl]oxy}butanoic acid (Compound no. 75);151 2-({4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfonyl)-4-{[(4-ethylphenyl)152 carbamoyl]oxy } butanoic acid (Compound no. 76);153 2-({4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfonyl )-4-{[(2-methylphenyl) 154 carbamoyl]oxy }butanoic acid (Compound no. 77);155 2-({4-[(4-Chlorophenyl)carbamoyl phenyl} sulfonyl)-4-{[(4-methylphenyl) 156 carbamoyl]oxy} butanoic acid (Compound no. 78);157 2-({4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfonyl)-4-({[4-(trifluoromethyl) 158 phenyl]carbamoyl}oxy)butanoic acid (Compound no. 79);159 2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfonyl)-4-{[(2,4- 160 difluorophenyl)carbamoyl]oxy}butanoic acid (Compound no. 80); 161 2-({4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfonyl)-4-{[(4- 162 fluorophenyl)carbamoyl]oxy}butanoic acid (Compound no. 81); 163 2-({4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfonyl)-4-{[(2,6- 164 dichlorophenyl)carbamoyl]oxy}butanoic acid (Compound no. 82); 165 4-[(tert-Butylcarbamoyl)oxy]-2-({4-[(4-chlorophenyl)carbamoyl] 166 phenyl} sulfonyl)butanoic acid (Compound no. 83); 167 2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfonyl)-4-{[(3,4-dichlorophenyl) 168 carbamoyl]oxy }butanoic acid (Compound no. 84); 169 2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfonyl)-4-[(pentylcarbamoyl) 170 oxy ]butanoic acid (Compound no. 85); 171 4-{[(3-Chlorophenyl)carbamoyljoxy}-2-({4-[(4-chlorophenyl)carbamoyl] 172 phenyl} sulfonyl)butanoic acid (Compound no. 86); 173 4-[(Butylcarbamoyl)oxy]-2-( {4-[(4-chlorophenyl)carbamoyl]phenyl} 174 sulfonyl)butanoic acid (Compound no. 87); 175 2-[(4-{[(2-Fluorophenyl)carbonyl]amino} phenyl)sulfanyl]-4-({[4-(trifluoromethyl) 176 phenyl]carbamoyl} oxy)butanoic acid (Compound no. 88); 177 2-[(4-{[(4-Chlorophenyl)carbonyl]amino} phenyl)sulfanyl]-4-({[4- 178 (trifluoromethyl)phenyl]carbamoyl} oxy)butanoic acid (Compound no. 89); 179 2-[(4-{[(2,6-Dimethoxyphenyl)carbonyl]amino} phenyl)sulfanyl]-4-({[4- 180 (trifluoromethyl)phenyl]carbamoyl} oxy)butanoic acid (Compound no. 90); 181 2-({4-[(Cyclopropylcarbonyl)amino]phenyl} sulfanyl)-4-({[4- 182 (trifluoromethyl)phenylcarbamoyl} Joxy)butanoic acid (Compound no. 91); 183 2-[(4-{[(2-Methylphenyl)carbonyl]amino} phenyl)sulfanyl]-4-({[4- 184 (trifluoromethyl)phenyljcarbamoyl}oxy)butanoic acid (Compound no. 92); 185 2-[(4-{[(2-Ethoxyphenyl)carbonyl]amino} phenyl)sulfanyl]-4-({[4- 186 (trifluoromethyl)phenyl]carbamoyl} oxy)butanoic acid (Compound no. 93); 187 2-[(4-{[(2,3-Difluorophenyl)carbonyl]amino} phenyl)sulfanyl]-4-({[4- 188 (trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 94); 189 2-[(4-{[(3,4-Dichlorophenyl)carbonylJamino} phenyl)sulfanyl]-4-({[4- 190 (trifluoromethyl)phenyljcarbamoyl} oxy)butanoic acid (Compound no. 95); 191 2-[(4-{[(4-Ethoxyphenyl)carbonyl]amino} phenyl)sulfanyl]-4-( {[4- 192 (trifluoromethyl)phenyl]carbamoyl} oxy)butanoic acid (Compound no. 96); 193 2-({4-[(Cyclohexylcarbonyl)amino]phenyl}sulfanyl)-4-( {[4-(trifluoromethyl) 194 phenyl]carbamoyl}oxy)butanoic acid (Compound no. 97); 195 2-[(4-{[(2,4-Dichlorophenyl)carbonyl]amino} phenyl)sulfanyl]-4-({[4- 196 (trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 98).1 3. A pharmaceutical composition comprising a therapeutically effective amount of 2 one or more of compound of Formula I according to claims 1 and 2, together with one or 3 more pharmaceutically acceptable carrier, excipient or diluents.1 4. A compound according to any one of claims 1-2, for use in the treatment or 2 prophylaxis of an animal or a human suffering from an inflammatory or allergic disease.1 5. A compound according to claim 4, wherein the inflammatory disease or allergic 2 disease is asthma, rheumatoid arthritis, COPD, rhinitis, osteoarthritis, psoriatic arthritis, 3 psoriasis, pulmonary fibrosis, pulmonary inflammation, acute respiratory distress 4 syndrome, perodontitis, multiple sclerosis, gingivitis, atherosclerosis, dry eye, neointimal proliferation associated with restenosis and ischemic heart failure, stroke, renal disease or 6 tumor metastasis.1 6. A pharmaceutical composition according to claim 3, further comprising one or 2 more of additional active ingredients selected from: 3 a) anti-inflammatory agents, experimental or commercial, selected from (i) the 4 nonsteroidal anti-inflammatory agents piroxicam, diclofenac, propionic acids, 5 fenamates, pyrazolones, salicylates, PDE-4/p38 MAP Kinase/Cathepsin 6 inhibitors, (ii) leukotrienes LTC4/LTD4/LTE4/LTB4-Inhibitors, 5- 7 lipoxygenase inhibitor and PAF-receptor antagonists, (iii) Cox-2 inhibitors, 8 (iv) other MMP inhibitors, and (v) interleukin-I inhibitors; 9 b) antihypertensive agents, selected from (i) the ACE inhibitors, enalapril, lisinopril, valsartan, telmisartan and quinapril, (ii) the angiotensin II receptor 11 antagonists and agonists, losartan, candesartan, irbesartan, valsartan, and 12 eprosartan, (iii) B-blockers, and (iv) calcium channel blockers. 13 ¢) immunosuppressive agents selected from, cyclosporine, azathioprine and 14 methotrexate, and anti inflammatory corticosteroids.1 7. A process for preparing a compound of Formula 9 (Formula I when L' is ~-CONH-, 2 Xis SO; and R' is OC(Z)NHR?) comprising; 3 a) reacting a compound of Formula 2 with alpha bromolactone to give a 4 compound of Formula 3;. oO oc" OC Y Y 6 Formula 2 Formula 3 7 b) reacting a compound of Formula 3 (where Y is COOH) with a compound of 8 Formula 3’ to give a compound of Formula 4; dh No 9 R2NH, oO Formula 3° Formula 4 11 c) coupling a compound of Formula 4 with a compound of Formula 4’ to give a 12 compound of Formula 5; 0) R? OC oR H’ N 13 R'-Hal Oo OH 14 Formula 4° Formula 5 d) reacting a compound of Formula 5 with a compound of Formula 6 to give a 16 compound of Formula 7; 0 OC i oO oO =z 17 R3N=C=Z RN, 18 Formula 6 Formula 7 19 e) hydrolyzing a compound of Formula 7 to give a compound of Formula 8;0 R Se “Co uN 0 Or, R3-N 21 H 22 Formula 8 23 f) oxidizing a compound of Formula 8 to give a compound of Formula 9; 0 0O Lor ry O Ov, RN 24 H Formula 9 26 wherein, 27 R%is hydrogen, C;-Csalkyl, hydroxyl, C,-Csalkoxy, cyano, nitro, halogen, 28 halogeno C;-Csalkyl, Cs-C;; aryl, C3-Cscycloalkyl, Cs-C,2 heteroaryl wherein 29 C6-Ci2 aryl, Cs5-Cgcycloalkyl, Cs-Ci, heteroaryl is optionally substituted with one or more times with R>; 31 R’is alkyl, alkenyl, alkynyl, Cs-C;; aryl, C3-Cg cycloalkyl, Cs-C,; heteroaryl, 32 C3-Ci2 heterocyclyl optionally substituted one or more times with R’; 33 R°® is selected from alkyl, alkenyl, alkynyl, cyano, nitro, halogen, halogeno- 34 C;-Cs alkyl, halogeno-C;-Cs alkoxy, azido, thiol, alkylthiol, (CH),-OR;, - C(=0)-R; -COORy, -NRR, (CH2)p-C(=O)NRR, (CH2)o-NHC(=0)-Ry, 36 -(CHz)p- O-C(=0)-NRRg, (CHz)n NHC(FO)NRR, (CH2)r-O-C(=0)- Ry; - 37 (CH2)p-NH-C(=0)-R¢ or (CH), S(=O)m-NR{R, {wherein Rrand Rqare 38 independently selected from hydrogen, alkyl, alkenyl, cycloalkyl aryl, 39 heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and alkylheterocyclyl}; 40 n is zero or an integer between 1 and 2; 41 m is an integer 0-2; 42 R’ is alkyl, allyl, benzyl, t-butyl, silyl;43 HalisF, Cl, Br, I; and 44 ZisO,S.1 8. A process for preparing a compound of Formula 16 (Formula I when L'is— 2 NHCO-, X is SO; and R' is OC(Z)NHR?), Formula 20 (Formula I when L' is bond, X is 3 SO;and R'is OC(Z)NHR?) comprising: 4 a) reducing a compound of Formula 3 (where Y is NO») to give a compound of Formula 10; 1 R oe oho 6 Y HN 7 Formula 3 Formula 10 8 b) coupling a compound of Formula 10 with a compound of Formula 11 to give 9 a compound of Formula 12; 04 0 9 2 R2 R? 11 Formula 11 Formula 12 12 c) reacting a compound of Formula 12 with a compound of Formula 4’ to give a 13 compound of Formula 13; 0 s A Rr LITT R2 N 14 R'-Hal OH Formula 4’ Formula 13 16 d) coupling a compound of Formula 13 with a compound of Formula 6 to give a 17 compound of Formula 14;0 TC" RAN H Oo =z 37 N{ 1 R3N=C=Z Ry 2 Formula 6 Formula 14 3 e) hydrolyzing a compound of Formula 14 to give a compound of Formula 15; 0 2 2” 'N R H 3 =z rN 4 H Formula 15 6 f) oxidizing a compound of Formula 15 to give a compound of Formula 16; Q oO i J R OH AN © R2 N 0 =z R-N 7 H 8 Formula 16 9 or 2) reacting a compound of Formula 3 (wherein Y is Hal) with a compound of 11 Formula 4°; 1 ome; 12 Y R'-Hal 13 Formula 3 Formula 4° 14 to give a compound of Formula 17;0 oe LC 16 OH 17 Formula 17 18 h) coupling a compound of Formula 17 with a compound of Formula 6 to give a 19 compound of Formula 18; oO oe Hal T ON, R3N=C=Z BN, 21 Formula 6 Formula 18 22 i) hydrolyzing a compound of Formula 18 to give a compound of Formula 19; 0 oC Hal T oO, rR:-N 23 H 24 Formula 19 j) oxidizing a compound of Formula 19 to give a compound of Formula 20; 2 oC Hal oO, rR>-N 26 H 27 Formula 20 28 wherein, 29 Ris alkyl, alkenyl, alkynyl, C¢-C2 aryl, C5-Cs cycloalkyl, Cs-C,2 heteroaryl, C3-Cy; heterocyclyl optionally substituted one or more times with R’; 31 R?is hydrogen, C;-Cealkyl, hydroxyl, C;-Csalkoxy, cyano, nitro, halogen, 32 halogeno C;-Cealkyl, Cs-C;2 aryl, C3-Cgcycloalkyl, Cs-Ci, heteroaryl,33 wherein Cs-C;; aryl, C3-Cscycloalkyl, C¢-Ci2 heteroaryl is optionally 34 substituted with one or more times with R>; 35 R® is selected from alkyl, alkenyl, alkynyl, cyano, nitro, halogen, halogeno- 36 C1-Cs alkyl, halogeno-C,;-Cs alkoxy, azido, thiol, alkylthiol, -(CH,).-ORy, - 37 C(=0)-Rg, -COORy, -NRRg, (CH)n-C(=O)NRRg, -(CH2),-NHC(=O)-Rg, 38 -(CHy)n- O-C(=0)-NRRg, (CHz)n NHC(=O)NRRq, -(CH2)a-O-C(=0)- Rs - 39 (CH),-NH-C(=0)-R¢ or -(CH2),S(=O)m-NRR, {wherein R¢and Rqeach 40 independently represent hydrogen, alkyl, alkenyl, cycloalkyl aryl, heteroaryl, 41 heterocyclyl, alkylaryl, alkylheteroaryl and alkylheterocyclyl}; 42 n is zero or an integer between 1 and 2; 43 m is an integer 0-2; 44 HalisF, Cl, Br, I; 45 U is halide, alkyloxy, aryloxy; 46 R’ is alkyl, allyl, benzyl, #-butyl, silyl; and 47 ZisO,S.1 9. A process for preparing compounds of Formula 27 (Formula I when L' is bond, X 2 is SO, R?is NO, and R' is -OBn) and 30 (Formula I when L' is -NHCO, X is SO, and R! 3 is -OBn) comprising: 4 a) reacting a compound of Formula 21 with a compound of Formula 22 oo { $ O,N Hal PN OR! 6 Formula 21 Formula 22 7 to give a compound of Formula 23; ors oR’ 0 O,N 9 Formula 23 b) oxidizing a compound of Formula 23 to give a compound of Formula 24;Q 0 SA oR re 1 O,N 12 Formula 24 13 ¢) coupling a compound of Formula 24 with a compound of Formula 25 to give 14 a compound of Formula 26; 2 Lor Le ON Bno~-Hal 2 OBn 16 Formula 25 Formula 26 17 d) hydrolyzing a compound of Formula 26 to give a compound of Formula 27; 0 0 $ ISG O,N 18 OBn 19 Formula 27 or 21 e) reducing a compound of Formula 26 to give a compound of Formula 28; Q 0 0S .R' S .R' CRC Ce O,N H,N 22 OBn OBn 23 Formula 26 Formula 28 24 f) reacting a compound of Formula 28 with a compound of Formula 11 to give a compound of Formula 29; 0 0 S R' Nei 1 ely 26 R2 U H OBn 27 Formula 11 Formula 29 28 g) hydrolyzing a compound of Formula 29 to give a compound of Formula 30;0 0 g LOC RAN 29 H OBn Formula 30 31 wherein, 32 R? is hydrogen, Ci-Cealkyl, hydroxyl, C,-Csalkoxy, cyano, nitro, halogen, 33 halogeno C,-Cealkyl, Cs-C;; aryl, C3-Cscycloalkyl, Cs-Ci2 heteroaryl wherein 34 Cs-C2 aryl, C5-Cgeycloalkyl, Cs-C,2 heteroaryl is optionally substituted with one or more times with R’; 36 R’ is selected from alkyl, alkenyl, alkynyl, cyano, nitro, halogen, halogeno- 37 C,-Cs alkyl, halogeno-C,-Cs alkoxy, azido, thiol, alkylthiol, (CH2)s-ORs, - 38 C(=0)-Ry, -COORy, -NRR, (CH)n-C(=O)NRR, (CH2),-NHC(=O)-R;, 39 -(CHp)p- O-C(=0)-NRR, (CH), NHC(=O)NRR,, -(CH),-O-C(=0)- R; - 40 (CH2)p-NH-C(=0)-R or -(CH2)nS(=O)n-NR{R {wherein Rs and Ry each 41 independently represent hydrogen, alkyl, alkenyl, cycloalkyl aryl, heteroaryl, 42 heterocyclyl, alkylaryl, alkylheteroaryl and alkylheterocyclyl}; 43 n is zero or an integer between 1 and 2; 44 m is an integer 0-2; 45 HalisF, Cl, Br, I; 46 U is halide, alkyloxy, aryloxy; 47 Bn is benzyl; and 48 R’ is alkyl, allyl, benzyl, t-butyl, silyl.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN2278DE2010 | 2010-09-24 | ||
PCT/IB2011/054228 WO2012038943A1 (en) | 2010-09-24 | 2011-09-26 | Matrix metalloproteinase inhibitors |
Publications (1)
Publication Number | Publication Date |
---|---|
SG188644A1 true SG188644A1 (en) | 2013-05-31 |
Family
ID=44903305
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
SG2013021696A SG188644A1 (en) | 2010-09-24 | 2011-09-26 | Matrix metalloproteinase inhibitors |
Country Status (11)
Country | Link |
---|---|
EP (1) | EP2619177A1 (en) |
JP (1) | JP2013538820A (en) |
KR (1) | KR20130137174A (en) |
CN (1) | CN103221386A (en) |
AU (1) | AU2011306397A1 (en) |
BR (1) | BR112013006929A2 (en) |
CA (1) | CA2812361A1 (en) |
EA (1) | EA201390405A1 (en) |
MX (1) | MX2013003360A (en) |
SG (1) | SG188644A1 (en) |
WO (1) | WO2012038943A1 (en) |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP6360039B2 (en) | 2012-05-03 | 2018-07-18 | カラ ファーマシューティカルズ インコーポレイテッド | Composition comprising a plurality of coated particles, pharmaceutical composition, pharmaceutical formulation and method of forming the particles |
US9827191B2 (en) | 2012-05-03 | 2017-11-28 | The Johns Hopkins University | Compositions and methods for ophthalmic and/or other applications |
US11596599B2 (en) | 2012-05-03 | 2023-03-07 | The Johns Hopkins University | Compositions and methods for ophthalmic and/or other applications |
EP2844227B1 (en) | 2012-05-03 | 2020-11-18 | Kala Pharmaceuticals, Inc. | Pharmaceutical nanoparticles showing improved mucosal transport |
WO2014127214A1 (en) | 2013-02-15 | 2014-08-21 | Kala Pharmaceuticals, Inc. | Therapeutic compounds and uses thereof |
ES2831625T3 (en) | 2013-02-20 | 2021-06-09 | Kala Pharmaceuticals Inc | Therapeutic compounds and their uses |
US9688688B2 (en) | 2013-02-20 | 2017-06-27 | Kala Pharmaceuticals, Inc. | Crystalline forms of 4-((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)-1-(2-oxa-7-azaspiro[3.5]nonan-7-yl)butan-1-one and uses thereof |
JP6426194B2 (en) | 2013-11-01 | 2018-11-21 | カラ ファーマシューティカルズ インコーポレイテッド | Crystalline forms of therapeutic compounds and uses thereof |
US9890173B2 (en) | 2013-11-01 | 2018-02-13 | Kala Pharmaceuticals, Inc. | Crystalline forms of therapeutic compounds and uses thereof |
EP3509421A4 (en) | 2016-09-08 | 2020-05-20 | Kala Pharmaceuticals, Inc. | Crystalline forms of therapeutic compounds and uses thereof |
US10392399B2 (en) | 2016-09-08 | 2019-08-27 | Kala Pharmaceuticals, Inc. | Crystalline forms of therapeutic compounds and uses thereof |
US10253036B2 (en) | 2016-09-08 | 2019-04-09 | Kala Pharmaceuticals, Inc. | Crystalline forms of therapeutic compounds and uses thereof |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3700729A1 (en) | 1987-01-13 | 1988-07-21 | Boehringer Mannheim Gmbh | NEW CARBONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS |
DE4111026A1 (en) | 1991-04-05 | 1992-10-08 | Boehringer Mannheim Gmbh | OPTICALLY ACTIVE CARBONIC ACIDS AND THESE MEDICINAL PRODUCTS |
ATE534637T1 (en) | 2002-04-03 | 2011-12-15 | Novartis Ag | 5-SUBSTITUTED 1,1-DIOXO-1,2,5 THIAZOLIDINE-3-ONE DERIVATIVES AS PTPASE 1B INHIBITORS |
-
2011
- 2011-09-26 MX MX2013003360A patent/MX2013003360A/en unknown
- 2011-09-26 AU AU2011306397A patent/AU2011306397A1/en not_active Abandoned
- 2011-09-26 CA CA2812361A patent/CA2812361A1/en not_active Abandoned
- 2011-09-26 SG SG2013021696A patent/SG188644A1/en unknown
- 2011-09-26 KR KR1020137010202A patent/KR20130137174A/en not_active Application Discontinuation
- 2011-09-26 EA EA201390405A patent/EA201390405A1/en unknown
- 2011-09-26 EP EP11776884.6A patent/EP2619177A1/en not_active Withdrawn
- 2011-09-26 WO PCT/IB2011/054228 patent/WO2012038943A1/en active Application Filing
- 2011-09-26 BR BR112013006929A patent/BR112013006929A2/en not_active IP Right Cessation
- 2011-09-26 CN CN2011800564174A patent/CN103221386A/en active Pending
- 2011-09-26 JP JP2013529762A patent/JP2013538820A/en not_active Withdrawn
Also Published As
Publication number | Publication date |
---|---|
EP2619177A1 (en) | 2013-07-31 |
JP2013538820A (en) | 2013-10-17 |
MX2013003360A (en) | 2013-06-05 |
AU2011306397A1 (en) | 2013-05-02 |
CN103221386A (en) | 2013-07-24 |
WO2012038943A1 (en) | 2012-03-29 |
CA2812361A1 (en) | 2012-03-29 |
KR20130137174A (en) | 2013-12-16 |
EA201390405A1 (en) | 2014-05-30 |
BR112013006929A2 (en) | 2016-07-12 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
SG188644A1 (en) | Matrix metalloproteinase inhibitors | |
EP2890375B1 (en) | Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis b | |
SG188641A1 (en) | Matrix metalloproteinase inhibitors | |
SG187654A1 (en) | Matrix metalloproteinase inhibitors | |
SG188642A1 (en) | Matrix metalloproteinase inhibitors | |
CA2598518C (en) | 5-phenyl-pentanoic acid derivatives as matrix metalloproteinase inhibitors for the treatment of asthma and other diseases | |
KR19990072009A (en) | Metalloproteinase inhibitors, pharmaceutical compositions comprising them and their use as medicaments and intermediates useful in the preparation and the preparation thereof | |
EP1147095B1 (en) | 2, 3, 4, 5-tetrahydro-1h-[1, 4] benzodiazepine-3-hydroxamic acids as matrix metalloproteinase inhibitors | |
AU2006321349A1 (en) | Spirocyclic quinazoline derivatives as PDE7 inhibitors | |
JP2003505367A (en) | 3-arylsulfonyl-2- (substituted methyl) propanoic acid derivatives as matrix metalloproteinase inhibitors | |
SK5082002A3 (en) | Beta disubstituted metalloprotease inhibitors | |
US6544984B1 (en) | 2,3,4,5-tetrahydro-1H-(1,4)benzodiazepine-3-hydroxamic acids | |
RAUF et al. | International Bureau | |
CA2274889A1 (en) | Bis-sulfonomides hydroxamic acids as mmp inhibitors | |
CZ309499A3 (en) | Sulfonyl compounds of bivalent aryl or heteroaryl hydroxamic acids |