MX2007002176A - Thiazolo-naphthyl acids as inhibitors of plasminogen activator inhibitor-1 - Google Patents
Thiazolo-naphthyl acids as inhibitors of plasminogen activator inhibitor-1Info
- Publication number
- MX2007002176A MX2007002176A MXMX/A/2007/002176A MX2007002176A MX2007002176A MX 2007002176 A MX2007002176 A MX 2007002176A MX 2007002176 A MX2007002176 A MX 2007002176A MX 2007002176 A MX2007002176 A MX 2007002176A
- Authority
- MX
- Mexico
- Prior art keywords
- phenyl
- alkyl
- naphthyl
- cycloalkyl
- thiazol
- Prior art date
Links
- 108010022233 Plasminogen Activator Inhibitor 1 Proteins 0.000 title claims abstract description 54
- 102000012335 Plasminogen Activator Inhibitor 1 Human genes 0.000 title claims abstract 6
- 230000002401 inhibitory effect Effects 0.000 title description 16
- 239000003112 inhibitor Substances 0.000 title description 8
- 201000010099 disease Diseases 0.000 claims abstract description 55
- 230000014509 gene expression Effects 0.000 claims abstract description 18
- 230000000051 modifying Effects 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims description 119
- -1 jalkoxyaryl Chemical group 0.000 claims description 69
- 125000000217 alkyl group Chemical group 0.000 claims description 53
- 229910052736 halogen Inorganic materials 0.000 claims description 41
- 150000002367 halogens Chemical class 0.000 claims description 41
- 239000002253 acid Substances 0.000 claims description 40
- 239000001257 hydrogen Substances 0.000 claims description 36
- 229910052739 hydrogen Inorganic materials 0.000 claims description 36
- 150000003839 salts Chemical class 0.000 claims description 36
- 239000011780 sodium chloride Substances 0.000 claims description 36
- 150000002148 esters Chemical group 0.000 claims description 34
- 230000000694 effects Effects 0.000 claims description 32
- 238000000034 method Methods 0.000 claims description 31
- 125000003545 alkoxy group Chemical group 0.000 claims description 28
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 27
- 125000003118 aryl group Chemical group 0.000 claims description 26
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 25
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 25
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 23
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 20
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 20
- 239000003814 drug Substances 0.000 claims description 17
- 125000005010 perfluoroalkyl group Chemical group 0.000 claims description 17
- 229920001774 Perfluoroether Polymers 0.000 claims description 15
- 230000015572 biosynthetic process Effects 0.000 claims description 13
- 125000001072 heteroaryl group Chemical group 0.000 claims description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims description 13
- 125000002541 furyl group Chemical group 0.000 claims description 12
- 125000001544 thienyl group Chemical group 0.000 claims description 12
- 125000003342 alkenyl group Chemical group 0.000 claims description 11
- 125000000304 alkynyl group Chemical group 0.000 claims description 11
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 11
- 230000003480 fibrinolytic Effects 0.000 claims description 10
- 239000003527 fibrinolytic agent Substances 0.000 claims description 10
- 230000003278 mimic Effects 0.000 claims description 9
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 9
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 8
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 125000001624 naphthyl group Chemical group 0.000 claims description 8
- 239000012453 solvate Substances 0.000 claims description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- 125000001041 indolyl group Chemical group 0.000 claims description 7
- 125000000335 thiazolyl group Chemical group 0.000 claims description 7
- 206010003658 Atrial fibrillation Diseases 0.000 claims description 6
- 208000008787 Cardiovascular Disease Diseases 0.000 claims description 6
- 206010012601 Diabetes mellitus Diseases 0.000 claims description 6
- 208000007536 Thrombosis Diseases 0.000 claims description 6
- 201000011510 cancer Diseases 0.000 claims description 6
- 238000005755 formation reaction Methods 0.000 claims description 6
- 238000001356 surgical procedure Methods 0.000 claims description 6
- 206010001897 Alzheimer's disease Diseases 0.000 claims description 5
- 208000003067 Myocardial Ischemia Diseases 0.000 claims description 5
- 125000005418 aryl aryl group Chemical group 0.000 claims description 5
- 239000004202 carbamide Substances 0.000 claims description 5
- 229960000539 carbamide Drugs 0.000 claims description 5
- 235000013877 carbamide Nutrition 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 201000002793 renal fibrosis Diseases 0.000 claims description 5
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 5
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 4
- 206010008132 Cerebral thrombosis Diseases 0.000 claims description 4
- 206010051055 Deep vein thrombosis Diseases 0.000 claims description 4
- 230000003143 atherosclerotic Effects 0.000 claims description 4
- KXDHJXZQYSOELW-UHFFFAOYSA-M carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 4
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 201000001429 intracranial thrombosis Diseases 0.000 claims description 4
- 201000010065 polycystic ovary syndrome Diseases 0.000 claims description 4
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 3
- 206010003178 Arterial thrombosis Diseases 0.000 claims description 3
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 3
- 206010047249 Venous thrombosis Diseases 0.000 claims description 3
- 201000010874 syndrome Diseases 0.000 claims description 3
- 208000001072 Type 2 Diabetes Mellitus Diseases 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000000546 pharmaceutic aid Substances 0.000 claims description 2
- 150000003536 tetrazoles Chemical class 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 8
- 208000006011 Stroke Diseases 0.000 claims 4
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 4
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 claims 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- 206010016654 Fibrosis Diseases 0.000 claims 1
- 102000004877 Insulin Human genes 0.000 claims 1
- 108090001061 Insulin Proteins 0.000 claims 1
- 210000004072 Lung Anatomy 0.000 claims 1
- 208000004361 Obstructive Lung Disease Diseases 0.000 claims 1
- 230000001684 chronic Effects 0.000 claims 1
- 230000001419 dependent Effects 0.000 claims 1
- 230000004761 fibrosis Effects 0.000 claims 1
- 230000002611 ovarian Effects 0.000 claims 1
- 230000002685 pulmonary Effects 0.000 claims 1
- 239000000203 mixture Substances 0.000 description 73
- 239000007787 solid Substances 0.000 description 54
- 102100007015 SERPINE1 Human genes 0.000 description 49
- 230000002829 reduced Effects 0.000 description 48
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 45
- 125000004432 carbon atoms Chemical group C* 0.000 description 45
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 45
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 44
- 238000006243 chemical reaction Methods 0.000 description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 29
- 235000002639 sodium chloride Nutrition 0.000 description 28
- 229910052757 nitrogen Inorganic materials 0.000 description 26
- 239000000243 solution Substances 0.000 description 23
- 239000002904 solvent Substances 0.000 description 23
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
- 238000000921 elemental analysis Methods 0.000 description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 20
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 17
- 238000007792 addition Methods 0.000 description 15
- 239000003795 chemical substances by application Substances 0.000 description 14
- 239000003921 oil Substances 0.000 description 14
- 235000019198 oils Nutrition 0.000 description 14
- 102000004169 proteins and genes Human genes 0.000 description 14
- 108090000623 proteins and genes Proteins 0.000 description 14
- 125000005309 thioalkoxy group Chemical group 0.000 description 13
- 239000000284 extract Substances 0.000 description 12
- 238000001914 filtration Methods 0.000 description 12
- 239000010410 layer Substances 0.000 description 12
- 125000001424 substituent group Chemical group 0.000 description 12
- 229940079593 drugs Drugs 0.000 description 11
- 239000000725 suspension Substances 0.000 description 11
- 238000004166 bioassay Methods 0.000 description 10
- 229910052740 iodine Inorganic materials 0.000 description 10
- 210000004369 Blood Anatomy 0.000 description 9
- 239000008280 blood Substances 0.000 description 9
- 125000004093 cyano group Chemical group *C#N 0.000 description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 9
- 230000001965 increased Effects 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- 229910004373 HOAc Inorganic materials 0.000 description 8
- 150000007513 acids Chemical class 0.000 description 8
- 125000003710 aryl alkyl group Chemical group 0.000 description 8
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 8
- 230000002265 prevention Effects 0.000 description 8
- 238000000746 purification Methods 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- YHTFFXDPPBHYNF-UHFFFAOYSA-N 1-bromo-6-(2-phenyl-1,3-thiazol-4-yl)naphthalen-2-ol Chemical compound C1=CC2=C(Br)C(O)=CC=C2C=C1C(N=1)=CSC=1C1=CC=CC=C1 YHTFFXDPPBHYNF-UHFFFAOYSA-N 0.000 description 7
- 125000004423 acyloxy group Chemical group 0.000 description 7
- 150000001338 aliphatic hydrocarbons Chemical group 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M buffer Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
- 239000000969 carrier Substances 0.000 description 7
- 210000004027 cells Anatomy 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 7
- 239000003480 eluent Substances 0.000 description 7
- 239000008079 hexane Substances 0.000 description 7
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 7
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 7
- 235000019341 magnesium sulphate Nutrition 0.000 description 7
- 239000006187 pill Substances 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 230000002194 synthesizing Effects 0.000 description 7
- 210000001519 tissues Anatomy 0.000 description 7
- FJDQFPXHSGXQBY-UHFFFAOYSA-L Caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 6
- WQZGKKKJIJFFOK-GASJEMHNSA-N D-Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 6
- CZMRCDWAGMRECN-UGDNZRGBSA-N D-sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 6
- 210000002381 Plasma Anatomy 0.000 description 6
- CZMRCDWAGMRECN-GDQSFJPYSA-N Sucrose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1)[C@@]1(CO)[C@H](O)[C@@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-GDQSFJPYSA-N 0.000 description 6
- 229960004793 Sucrose Drugs 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 239000000443 aerosol Substances 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 239000000839 emulsion Substances 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 239000008103 glucose Substances 0.000 description 6
- 201000001421 hyperglycemia Diseases 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 239000005720 sucrose Substances 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 5
- 125000002947 alkylene group Chemical group 0.000 description 5
- 125000000266 alpha-aminoacyl group Chemical group 0.000 description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 5
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 150000004702 methyl esters Chemical class 0.000 description 5
- 210000000056 organs Anatomy 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 239000000651 prodrug Substances 0.000 description 5
- 229940002612 prodrugs Drugs 0.000 description 5
- 235000000346 sugar Nutrition 0.000 description 5
- 125000004495 thiazol-4-yl group Chemical group S1C=NC(=C1)* 0.000 description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 5
- 125000004953 trihalomethyl group Chemical group 0.000 description 5
- 108010010803 Gelatin Proteins 0.000 description 4
- FBPFZTCFMRRESA-KVTDHHQDSA-N Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 4
- 125000004442 acylamino group Chemical group 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- 239000007900 aqueous suspension Substances 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 239000007859 condensation product Substances 0.000 description 4
- 230000002354 daily Effects 0.000 description 4
- 235000014113 dietary fatty acids Nutrition 0.000 description 4
- 239000000194 fatty acid Substances 0.000 description 4
- 150000004665 fatty acids Chemical class 0.000 description 4
- 239000000796 flavoring agent Substances 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 239000008273 gelatin Substances 0.000 description 4
- 229920000159 gelatin Polymers 0.000 description 4
- 235000019322 gelatine Nutrition 0.000 description 4
- 235000011852 gelatine desserts Nutrition 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 230000036961 partial Effects 0.000 description 4
- 239000000825 pharmaceutical preparation Substances 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 150000003254 radicals Chemical class 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- FZWLAAWBMGSTSO-UHFFFAOYSA-N thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 4
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 4
- REXUYBKPWIPONM-UHFFFAOYSA-N 2-bromoacetonitrile Chemical compound BrCC#N REXUYBKPWIPONM-UHFFFAOYSA-N 0.000 description 3
- IOJUPLGTWVMSFF-UHFFFAOYSA-N Benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 3
- 125000005915 C6-C14 aryl group Chemical group 0.000 description 3
- 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 3
- FBPFZTCFMRRESA-KAZBKCHUSA-N D-Mannitol Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KAZBKCHUSA-N 0.000 description 3
- 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 3
- 229940012957 Plasmin Drugs 0.000 description 3
- 208000005069 Pulmonary Fibrosis Diseases 0.000 description 3
- 229920001615 Tragacanth Polymers 0.000 description 3
- 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 3
- 239000012190 activator Substances 0.000 description 3
- 239000007853 buffer solution Substances 0.000 description 3
- 239000001768 carboxy methyl cellulose Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000015271 coagulation Effects 0.000 description 3
- 239000003086 colorant Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 201000008739 coronary artery disease Diseases 0.000 description 3
- 230000000875 corresponding Effects 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 235000013355 food flavoring agent Nutrition 0.000 description 3
- 235000003599 food sweetener Nutrition 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- 125000005842 heteroatoms Chemical group 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 230000003902 lesions Effects 0.000 description 3
- 239000002502 liposome Substances 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 230000003000 nontoxic Effects 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 108020004707 nucleic acids Proteins 0.000 description 3
- 150000007523 nucleic acids Chemical class 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- IAYPIBMASNFSPL-UHFFFAOYSA-N oxane Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 3
- 125000004043 oxo group Chemical group O=* 0.000 description 3
- 230000000896 plasminic Effects 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 230000002035 prolonged Effects 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 3
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- 235000010356 sorbitol Nutrition 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- 239000000375 suspending agent Substances 0.000 description 3
- 239000003765 sweetening agent Substances 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- 230000001225 therapeutic Effects 0.000 description 3
- 230000001732 thrombotic Effects 0.000 description 3
- 230000000699 topical Effects 0.000 description 3
- GGWCZBGAIGGTDA-UHFFFAOYSA-N 1-(6-methoxynaphthalen-2-yl)ethanone Chemical compound C1=C(C(C)=O)C=CC2=CC(OC)=CC=C21 GGWCZBGAIGGTDA-UHFFFAOYSA-N 0.000 description 2
- WPVJILDZUWUUOX-UHFFFAOYSA-N 1-bromo-6-(5-bromo-2-phenyl-1,3-thiazol-4-yl)naphthalen-2-ol Chemical compound C1=CC2=C(Br)C(O)=CC=C2C=C1C(=C(S1)Br)N=C1C1=CC=CC=C1 WPVJILDZUWUUOX-UHFFFAOYSA-N 0.000 description 2
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Chemical compound C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 description 2
- HCQVOEBHAJXJSJ-UHFFFAOYSA-N 2-(4-methylmorpholin-4-ium-4-yl)ethanol Chemical compound OCC[N+]1(C)CCOCC1 HCQVOEBHAJXJSJ-UHFFFAOYSA-N 0.000 description 2
- ZCRIIJKMPPZJNP-UHFFFAOYSA-N 2-[6-(2-phenyl-1,3-thiazol-4-yl)naphthalen-2-yl]oxyacetonitrile Chemical compound C1=CC2=CC(OCC#N)=CC=C2C=C1C(N=1)=CSC=1C1=CC=CC=C1 ZCRIIJKMPPZJNP-UHFFFAOYSA-N 0.000 description 2
- MONMFXREYOKQTI-UHFFFAOYSA-M 2-bromopropanoate Chemical compound CC(Br)C([O-])=O MONMFXREYOKQTI-UHFFFAOYSA-M 0.000 description 2
- PFEULDGKFCBBIJ-UHFFFAOYSA-N 6-(2-phenyl-1,3-thiazol-4-yl)naphthalen-2-ol Chemical compound C1=CC2=CC(O)=CC=C2C=C1C(N=1)=CSC=1C1=CC=CC=C1 PFEULDGKFCBBIJ-UHFFFAOYSA-N 0.000 description 2
- 206010002383 Angina pectoris Diseases 0.000 description 2
- 235000003911 Arachis Nutrition 0.000 description 2
- 240000005781 Arachis hypogaea Species 0.000 description 2
- 206010062599 Arterial occlusive disease Diseases 0.000 description 2
- 206010003210 Arteriosclerosis Diseases 0.000 description 2
- 208000006673 Asthma Diseases 0.000 description 2
- 241000416162 Astragalus gummifer Species 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 241000283707 Capra Species 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- 208000004981 Coronary Disease Diseases 0.000 description 2
- 206010012289 Dementia Diseases 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 229950003499 FIBRIN Drugs 0.000 description 2
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 2
- 102000009123 Fibrin Human genes 0.000 description 2
- 108010073385 Fibrin Proteins 0.000 description 2
- 229920000084 Gum arabic Polymers 0.000 description 2
- 208000001083 Kidney Disease Diseases 0.000 description 2
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 description 2
- 206010024324 Leukaemias Diseases 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 206010029149 Nephropathy Diseases 0.000 description 2
- 206010029151 Nephropathy Diseases 0.000 description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N Oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 2
- 102000013566 Plasminogen Human genes 0.000 description 2
- 108010051456 Plasminogen Proteins 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 229940005550 Sodium alginate Drugs 0.000 description 2
- JNYAEWCLZODPBN-CTQIIAAMSA-N Sorbitan Chemical compound OCC(O)C1OCC(O)[C@@H]1O JNYAEWCLZODPBN-CTQIIAAMSA-N 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N Stearic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Tris Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- 239000000205 acacia gum Substances 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 125000004171 alkoxy aryl group Chemical group 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 201000001320 atherosclerosis Diseases 0.000 description 2
- 230000027455 binding Effects 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 230000000271 cardiovascular Effects 0.000 description 2
- 201000001084 cerebrovascular disease Diseases 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 238000005345 coagulation Methods 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 238000000502 dialysis Methods 0.000 description 2
- 239000002270 dispersing agent Substances 0.000 description 2
- 239000008298 dragée Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 235000020828 fasting Nutrition 0.000 description 2
- 239000006260 foam Substances 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 230000013632 homeostatic process Effects 0.000 description 2
- 239000003906 humectant Substances 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 230000036571 hydration Effects 0.000 description 2
- 238000006703 hydration reaction Methods 0.000 description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N 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 2
- 239000003446 ligand Substances 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 150000002739 metals Chemical class 0.000 description 2
- NLWBJPPMPLPZIE-UHFFFAOYSA-N methyl 4-(bromomethyl)benzoate Chemical compound COC(=O)C1=CC=C(CBr)C=C1 NLWBJPPMPLPZIE-UHFFFAOYSA-N 0.000 description 2
- 239000004005 microsphere Substances 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- SJRJJKPEHAURKC-UHFFFAOYSA-N n-methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 150000002829 nitrogen Chemical group 0.000 description 2
- 239000000346 nonvolatile oil Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 230000002093 peripheral Effects 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 230000002335 preservative Effects 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000004952 protein activity Effects 0.000 description 2
- RWRDLPDLKQPQOW-UHFFFAOYSA-N pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 2
- 231100000486 side effect Toxicity 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 235000015424 sodium Nutrition 0.000 description 2
- MSXHSNHNTORCAW-UHFFFAOYSA-M sodium 3,4,5,6-tetrahydroxyoxane-2-carboxylate Chemical compound [Na+].OC1OC(C([O-])=O)C(O)C(O)C1O MSXHSNHNTORCAW-UHFFFAOYSA-M 0.000 description 2
- 235000010413 sodium alginate Nutrition 0.000 description 2
- 239000000661 sodium alginate Substances 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 239000012439 solid excipient Substances 0.000 description 2
- 230000002459 sustained Effects 0.000 description 2
- 239000002562 thickening agent Substances 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 230000003442 weekly Effects 0.000 description 2
- FIWSRSRCWYARAJ-SQOFCNSWSA-N (2R,3R,4R,5S)-hexane-1,2,3,4,5,6-hexol;(Z)-octadec-9-enoic acid Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.CCCCCCCC\C=C/CCCCCCCC(O)=O FIWSRSRCWYARAJ-SQOFCNSWSA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2R,3R,4S,5R,6S)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2S,3R,4S,5R,6R)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2R,3R,4S,5R,6R)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- FKASFBLJDCHBNZ-UHFFFAOYSA-N 1,3,4-oxadiazole Chemical compound C1=NN=CO1 FKASFBLJDCHBNZ-UHFFFAOYSA-N 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N 1,4-Butanediol, dimethanesulfonate Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- OXHNLMTVIGZXSG-UHFFFAOYSA-N 1-Methylpyrrole Chemical group CN1C=CC=C1 OXHNLMTVIGZXSG-UHFFFAOYSA-N 0.000 description 1
- KJCVRFUGPWSIIH-UHFFFAOYSA-N 1-Naphthol Chemical compound C1=CC=C2C(O)=CC=CC2=C1 KJCVRFUGPWSIIH-UHFFFAOYSA-N 0.000 description 1
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 1
- FGYADSCZTQOAFK-UHFFFAOYSA-N 1-methylbenzimidazole Chemical compound C1=CC=C2N(C)C=NC2=C1 FGYADSCZTQOAFK-UHFFFAOYSA-N 0.000 description 1
- OMAFFHIGWTVZOH-UHFFFAOYSA-N 1-methyltetrazole Chemical compound CN1C=NN=N1 OMAFFHIGWTVZOH-UHFFFAOYSA-N 0.000 description 1
- 125000004343 1-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C([H])([H])[H] 0.000 description 1
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 1H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 1
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- KZTWONRVIPPDKH-UHFFFAOYSA-N 2-(piperidin-1-yl)ethanol Chemical compound OCCN1CCCCC1 KZTWONRVIPPDKH-UHFFFAOYSA-N 0.000 description 1
- RVQSHKHHIAIERU-UHFFFAOYSA-N 2-(trifluoromethylsulfonyloxy)propanoic acid Chemical compound OC(=O)C(C)OS(=O)(=O)C(F)(F)F RVQSHKHHIAIERU-UHFFFAOYSA-N 0.000 description 1
- JWAZRIHNYRIHIV-UHFFFAOYSA-N 2-Naphthol Chemical compound C1=CC=CC2=CC(O)=CC=C21 JWAZRIHNYRIHIV-UHFFFAOYSA-N 0.000 description 1
- UUKQZEMZUBDTGU-UHFFFAOYSA-N 2-[(2,6-dichlorophenyl)methyl]-4-(6-methoxynaphthalen-2-yl)-1,3-thiazole Chemical compound C1=CC2=CC(OC)=CC=C2C=C1C(N=1)=CSC=1CC1=C(Cl)C=CC=C1Cl UUKQZEMZUBDTGU-UHFFFAOYSA-N 0.000 description 1
- VUKAUDKDFVSVFT-UHFFFAOYSA-N 2-[6-[4,5-bis(2-hydroxypropoxy)-2-(2-hydroxypropoxymethyl)-6-methoxyoxan-3-yl]oxy-4,5-dimethoxy-2-(methoxymethyl)oxan-3-yl]oxy-6-(hydroxymethyl)-5-methoxyoxane-3,4-diol Chemical compound COC1C(OC)C(OC2C(C(O)C(OC)C(CO)O2)O)C(COC)OC1OC1C(COCC(C)O)OC(OC)C(OCC(C)O)C1OCC(C)O VUKAUDKDFVSVFT-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- HHHKEQGAGUAOQI-UHFFFAOYSA-N 2-bromo-1-(6-methoxynaphthalen-2-yl)ethanone Chemical compound C1=C(C(=O)CBr)C=CC2=CC(OC)=CC=C21 HHHKEQGAGUAOQI-UHFFFAOYSA-N 0.000 description 1
- WYKHSBAVLOPISI-UHFFFAOYSA-N 2-phenyl-1,3-thiazole Chemical compound C1=CSC(C=2C=CC=CC=2)=N1 WYKHSBAVLOPISI-UHFFFAOYSA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N 289-95-2 Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- VOXXWSYKYCBWHO-UHFFFAOYSA-N 3-phenyllactic acid Chemical compound OC(=O)C(O)CC1=CC=CC=C1 VOXXWSYKYCBWHO-UHFFFAOYSA-N 0.000 description 1
- 125000006201 3-phenylpropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- VAJZCFLYJRMBFN-UHFFFAOYSA-N 4,4-dimethylmorpholin-4-ium Chemical compound C[N+]1(C)CCOCC1 VAJZCFLYJRMBFN-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
- YJISHJVIRFPGGN-UHFFFAOYSA-N 5-[5-[3,4-dihydroxy-6-(hydroxymethyl)-5-methoxyoxan-2-yl]oxy-6-[[3,4-dihydroxy-6-(hydroxymethyl)-5-methoxyoxan-2-yl]oxymethyl]-3,4-dihydroxyoxan-2-yl]oxy-6-(hydroxymethyl)-2-methyloxane-3,4-diol Chemical compound O1C(CO)C(OC)C(O)C(O)C1OCC1C(OC2C(C(O)C(OC)C(CO)O2)O)C(O)C(O)C(OC2C(OC(C)C(O)C2O)CO)O1 YJISHJVIRFPGGN-UHFFFAOYSA-N 0.000 description 1
- 125000004070 6 membered heterocyclic group Chemical group 0.000 description 1
- BTRCQAOBLPXGAT-UHFFFAOYSA-N 6-[2-[(2,6-dichlorophenyl)methyl]-1,3-thiazol-4-yl]naphthalen-2-ol Chemical compound C1=CC2=CC(O)=CC=C2C=C1C(N=1)=CSC=1CC1=C(Cl)C=CC=C1Cl BTRCQAOBLPXGAT-UHFFFAOYSA-N 0.000 description 1
- 208000010444 Acidosis Diseases 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- XJKJWTWGDGIQRH-BFIDDRIFSA-N Alginic acid Chemical compound O1[C@@H](C(O)=O)[C@@H](OC)[C@H](O)[C@H](O)[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](C)[C@@H](O)[C@H]1O XJKJWTWGDGIQRH-BFIDDRIFSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 206010002388 Angina unstable Diseases 0.000 description 1
- 206010003119 Arrhythmia Diseases 0.000 description 1
- 206010003246 Arthritis Diseases 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N Aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 229960003438 Aspartame Drugs 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N Benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- JYZIHLWOWKMNNX-UHFFFAOYSA-N Benzimidazole Chemical compound C1=C[CH]C2=NC=NC2=C1 JYZIHLWOWKMNNX-UHFFFAOYSA-N 0.000 description 1
- IANQTJSKSUMEQM-UHFFFAOYSA-N Benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- FCEHBMOGCRZNNI-UHFFFAOYSA-N Benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 1
- WGQKYBSKWIADBV-UHFFFAOYSA-N Benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 230000035639 Blood Levels Effects 0.000 description 1
- 210000001772 Blood Platelets Anatomy 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 102000025380 C-Reactive Protein Human genes 0.000 description 1
- 108010074051 C-Reactive Protein Proteins 0.000 description 1
- QQLOAGCNXLDDQH-UHFFFAOYSA-N C1(=CC=CC=C1)C=1SC=C(N=1)C1=C(C=CC2=CC=CC=C12)O Chemical compound C1(=CC=CC=C1)C=1SC=C(N=1)C1=C(C=CC2=CC=CC=C12)O QQLOAGCNXLDDQH-UHFFFAOYSA-N 0.000 description 1
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate dianion Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 206010007521 Cardiac arrhythmias Diseases 0.000 description 1
- 206010007554 Cardiac failure Diseases 0.000 description 1
- 210000000170 Cell Membrane Anatomy 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N Cetyl alcohol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- 206010009802 Coagulopathy Diseases 0.000 description 1
- 240000007170 Cocos nucifera Species 0.000 description 1
- 235000013162 Cocos nucifera Nutrition 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- MTCFGRXMJLQNBG-UWTATZPHSA-N D-serine Chemical compound OC[C@@H](N)C(O)=O MTCFGRXMJLQNBG-UWTATZPHSA-N 0.000 description 1
- 208000007342 Diabetic Nephropathy Diseases 0.000 description 1
- 206010061835 Diabetic nephropathy Diseases 0.000 description 1
- 206010012689 Diabetic retinopathy Diseases 0.000 description 1
- PXBRQCKWGAHEHS-UHFFFAOYSA-N Dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 1
- 239000004338 Dichlorodifluoromethane Substances 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N Diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 229940021019 Disal Drugs 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 229940088598 Enzyme Drugs 0.000 description 1
- 102000010911 Enzyme Precursors Human genes 0.000 description 1
- 108010062466 Enzyme Precursors Proteins 0.000 description 1
- 210000002744 Extracellular Matrix Anatomy 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 241000282324 Felis Species 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N Furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 206010056819 Gastric disease Diseases 0.000 description 1
- 229940093915 Gynecological Organic acids Drugs 0.000 description 1
- 229940031574 HYDROXYMETHYL CELLULOSE Drugs 0.000 description 1
- 206010019280 Heart failure Diseases 0.000 description 1
- NAQMVNRVTILPCV-UHFFFAOYSA-N Hexamethylenediamine Chemical compound NCCCCCCN NAQMVNRVTILPCV-UHFFFAOYSA-N 0.000 description 1
- 210000001624 Hip Anatomy 0.000 description 1
- 229940088597 Hormone Drugs 0.000 description 1
- 206010060378 Hyperinsulinaemia Diseases 0.000 description 1
- 206010020718 Hyperplasia Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 229940102223 Injectable Solution Drugs 0.000 description 1
- 229940102213 Injectable Suspension Drugs 0.000 description 1
- 206010022114 Injury Diseases 0.000 description 1
- 206010022489 Insulin resistance Diseases 0.000 description 1
- AWJUIBRHMBBTKR-UHFFFAOYSA-N Isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 1
- 210000001503 Joints Anatomy 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- 229940067606 Lecithin Drugs 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 206010024627 Liposarcoma Diseases 0.000 description 1
- 208000009856 Lung Disease Diseases 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N Meglumine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 206010054949 Metaplasia Diseases 0.000 description 1
- UMELTKSLWXJXNZ-UHFFFAOYSA-N Methyl 3,5-dinitrosalicylate Chemical compound COC(=O)C1=CC([N+]([O-])=O)=CC([N+]([O-])=O)=C1O UMELTKSLWXJXNZ-UHFFFAOYSA-N 0.000 description 1
- PQBAWAQIRZIWIV-UHFFFAOYSA-N Methylpyridinium Chemical compound C[N+]1=CC=CC=C1 PQBAWAQIRZIWIV-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 206010028537 Myelofibrosis Diseases 0.000 description 1
- 208000010125 Myocardial Infarction Diseases 0.000 description 1
- UQFQONCQIQEYPJ-UHFFFAOYSA-N N-methylpyrazole Chemical compound CN1C=CC=N1 UQFQONCQIQEYPJ-UHFFFAOYSA-N 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 206010029113 Neovascularisation Diseases 0.000 description 1
- 206010029164 Nephrotic syndrome Diseases 0.000 description 1
- 108009000551 Nephrotic syndrome Proteins 0.000 description 1
- 206010029331 Neuropathy peripheral Diseases 0.000 description 1
- 108091005503 Nucleic proteins Proteins 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- 229920000272 Oligonucleotide Polymers 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 206010049088 Osteopenia Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 208000005764 Peripheral Arterial Disease Diseases 0.000 description 1
- 206010062585 Peripheral arterial occlusive disease Diseases 0.000 description 1
- 206010034636 Peripheral vascular disease Diseases 0.000 description 1
- XHXFXVLFKHQFAL-UHFFFAOYSA-N Phosphoryl chloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 1
- 102000001938 Plasminogen Activators Human genes 0.000 description 1
- 108010001014 Plasminogen Activators Proteins 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 206010036049 Polycystic ovary Diseases 0.000 description 1
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 208000003476 Primary Myelofibrosis Diseases 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N Propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 206010037437 Pulmonary thrombosis Diseases 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N Quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 210000000664 Rectum Anatomy 0.000 description 1
- 206010038435 Renal failure Diseases 0.000 description 1
- 206010038932 Retinopathy Diseases 0.000 description 1
- 206010038923 Retinopathy Diseases 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N Saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 Saccharin Drugs 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 206010040070 Septic shock Diseases 0.000 description 1
- 210000002966 Serum Anatomy 0.000 description 1
- 241000580858 Simian-Human immunodeficiency virus Species 0.000 description 1
- 229940005581 Sodium Lactate Drugs 0.000 description 1
- NGSFWBMYFKHRBD-UHFFFAOYSA-M Sodium lactate Chemical compound [Na+].CC(O)C([O-])=O NGSFWBMYFKHRBD-UHFFFAOYSA-M 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 240000001016 Solanum tuberosum Species 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 206010041349 Somnolence Diseases 0.000 description 1
- 208000007718 Stable Angina Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 241000862969 Stella Species 0.000 description 1
- 108060008443 TPPP Proteins 0.000 description 1
- YUKQRDCYNOVPGJ-UHFFFAOYSA-N Thioacetamide Chemical compound CC(N)=S YUKQRDCYNOVPGJ-UHFFFAOYSA-N 0.000 description 1
- 229940116362 Tragacanth Drugs 0.000 description 1
- 206010052779 Transplant rejections Diseases 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H Tricalcium phosphate Chemical class [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N Trifluoromethanesulfonic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N Trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
- PRXNKYBFWAWBNZ-UHFFFAOYSA-N Trimethylphenylammonium tribromide Chemical compound Br[Br-]Br.C[N+](C)(C)C1=CC=CC=C1 PRXNKYBFWAWBNZ-UHFFFAOYSA-N 0.000 description 1
- 229940035504 Tromethamine Drugs 0.000 description 1
- 208000007814 Unstable Angina Diseases 0.000 description 1
- 206010047116 Vascular inflammations Diseases 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Vitamin C Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- NWGKJDSIEKMTRX-HSACVWGTSA-N [(2R)-2-[(2R,3R,4S)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl] (E)-octadec-9-enoate Chemical compound CCCCCCCC\C=C\CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-HSACVWGTSA-N 0.000 description 1
- VQWATWIYRYSPQI-UHFFFAOYSA-M [Cl-].CCCCCC=C Chemical compound [Cl-].CCCCCC=C VQWATWIYRYSPQI-UHFFFAOYSA-M 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 125000004062 acenaphthenyl group Chemical group C1(CC2=CC=CC3=CC=CC1=C23)* 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000003213 activating Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000001154 acute Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000000240 adjuvant Effects 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000005083 alkoxyalkoxy group Chemical group 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 125000005213 alkyl heteroaryl group Chemical group 0.000 description 1
- 125000005263 alkylenediamine group Chemical group 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminum Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 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 1
- 230000000879 anti-atherosclerotic Effects 0.000 description 1
- 230000002429 anti-coagulation Effects 0.000 description 1
- 230000000111 anti-oxidant Effects 0.000 description 1
- 230000000798 anti-retroviral Effects 0.000 description 1
- 102000004965 antibodies Human genes 0.000 description 1
- 108090001123 antibodies Proteins 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 230000003078 antioxidant Effects 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- 239000000305 astragalus gummifer gum Substances 0.000 description 1
- 125000004429 atoms Chemical group 0.000 description 1
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-M benzoate Chemical compound [O-]C(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-M 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 125000001231 benzoyloxy group Chemical group C(C1=CC=CC=C1)(=O)O* 0.000 description 1
- 229950011260 betanaphthol Drugs 0.000 description 1
- 238000006065 biodegradation reaction Methods 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 125000002529 biphenylenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C12)* 0.000 description 1
- 239000010836 blood and blood product Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- 235000014121 butter Nutrition 0.000 description 1
- PUPZLCDOIYMWBV-UHFFFAOYSA-N butylene glycol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L cacl2 Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 235000011148 calcium chloride Nutrition 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 230000035602 clotting Effects 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 229960005188 collagen Drugs 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 239000012059 conventional drug carrier Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- 230000003111 delayed Effects 0.000 description 1
- 238000000586 desensitisation Methods 0.000 description 1
- 238000003795 desorption Methods 0.000 description 1
- 230000001809 detectable Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000001627 detrimental Effects 0.000 description 1
- 229940042935 dichlorodifluoromethane Drugs 0.000 description 1
- 235000019404 dichlorodifluoromethane Nutrition 0.000 description 1
- SPWVRYZQLGQKGK-UHFFFAOYSA-N dichloromethane;hexane Chemical compound ClCCl.CCCCCC SPWVRYZQLGQKGK-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- ROSDSFDQCJNGOL-UHFFFAOYSA-N dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000013080 embryo development ending in birth or egg hatching Effects 0.000 description 1
- 230000013144 embryo development ending in seed dormancy Effects 0.000 description 1
- 239000003974 emollient agent Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000012202 endocytosis Effects 0.000 description 1
- 230000003511 endothelial Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002708 enhancing Effects 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N ethanolamine Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N ethyl amine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000011737 fluorine Chemical group 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N fluorine atom Chemical group [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000004407 fluoroaryl group Chemical group 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical compound OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000002496 gastric Effects 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 229920000591 gum Polymers 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 239000000852 hydrogen donor Substances 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 230000003451 hyperinsulinaemic Effects 0.000 description 1
- 201000008980 hyperinsulinism Diseases 0.000 description 1
- 239000012216 imaging agent Substances 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 238000001114 immunoprecipitation Methods 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000010874 in vitro model Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 230000002757 inflammatory Effects 0.000 description 1
- 200000000018 inflammatory disease Diseases 0.000 description 1
- 230000000977 initiatory Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 201000004332 intermediate coronary syndrome Diseases 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000011630 iodine Chemical group 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 230000003211 malignant Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000003340 mental Effects 0.000 description 1
- 230000015689 metaplastic ossification Effects 0.000 description 1
- 200000000023 metastatic cancer Diseases 0.000 description 1
- FUKUFMFMCZIRNT-UHFFFAOYSA-M methanol;chloride Chemical compound [Cl-].OC FUKUFMFMCZIRNT-UHFFFAOYSA-M 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- BAVYZALUXZFZLV-UHFFFAOYSA-N methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 1
- XGZVLEAZGCUUPH-UHFFFAOYSA-N methylamino(methylimino)methanesulfonic acid Chemical compound CNC(=NC)S(O)(=O)=O XGZVLEAZGCUUPH-UHFFFAOYSA-N 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000006011 modification reaction Methods 0.000 description 1
- QDHHCQZDFGDHMP-UHFFFAOYSA-N monochloramine Chemical compound ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 description 1
- YNAVUWVOSKDBBP-UHFFFAOYSA-N morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 1
- 229940113083 morpholine Drugs 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 230000002107 myocardial Effects 0.000 description 1
- 238000010984 neurological examination Methods 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 230000003287 optical Effects 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003204 osmotic Effects 0.000 description 1
- 230000016087 ovulation Effects 0.000 description 1
- 125000004430 oxygen atoms Chemical group O* 0.000 description 1
- 239000012057 packaged powder Substances 0.000 description 1
- 239000003973 paint Substances 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 235000011837 pasties Nutrition 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- GLUUGHFHXGJENI-UHFFFAOYSA-N piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 1
- 229920002312 polyamide-imide Polymers 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000002062 proliferating Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- UORVCLMRJXCDCP-UHFFFAOYSA-M propynoate Chemical compound [O-]C(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-M 0.000 description 1
- 238000000575 proteomic Methods 0.000 description 1
- 230000003331 prothrombotic Effects 0.000 description 1
- 201000004681 psoriasis Diseases 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- SMWDFEZZVXVKRB-UHFFFAOYSA-N quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000001105 regulatory Effects 0.000 description 1
- 230000000268 renotropic Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 200000000008 restenosis Diseases 0.000 description 1
- 230000000250 revascularization Effects 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 230000036573 scar formation Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000036303 septic shock Effects 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- BZKBCQXYZZXSCO-UHFFFAOYSA-N sodium hydride Inorganic materials [H-].[Na+] BZKBCQXYZZXSCO-UHFFFAOYSA-N 0.000 description 1
- 239000001540 sodium lactate Substances 0.000 description 1
- 235000011088 sodium lactate Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 239000008347 soybean phospholipid Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000001954 sterilising Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000004434 sulfur atoms Chemical group 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000003698 tetramethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 201000005665 thrombophilia Diseases 0.000 description 1
- 230000002588 toxic Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 230000003966 vascular damage Effects 0.000 description 1
- 231100000216 vascular lesion Toxicity 0.000 description 1
- 238000007631 vascular surgery Methods 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
- 230000036642 wellbeing Effects 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
Abstract
The present invention relates to thiazolo-naphthyl acids of the formula (I) and methods of using them to modulate PAI-1 expression and to treat PAI-1 related disorders.
Description
ACIDOS DE TIAZOLO-NAFTILO
FIELD OF THE INVENTION The present invention relates, in general, to thiazolo-naphthyl acids and methods for using them. BACKGROUND OF THE INVENTION The p-rotease serine inhibitor PAI-1 is one of the primary inhibitors of the fibrinolytic system. The fibrinolytic system comprises the plasminogen of proenzymes, which is converted to the active enzyme, plasmin, by one of two tissue-type plasminogen activators, t-PA or u-PA. PAI-1 is the main physiological inhibitor of t-PA or u-PA. One of the main functions of plasmin in the fibibolytic system is to digest fibrin at the site of the vascular lesion. However, the fibrinolytic system is not only responsible for the elimination of fibrin from the circulation but is also involved in several other biological processes including ovulation, embryogenesis, intimal proliferation, angiogenesis, tumorigenesis and atherosclerosis. Elevated levels of PAI-1 have been associated with a variety of diseases and conditions including those associated with insufficiency of the fibrinolytic system. For example, elevated levels of PAI-1 have been implicated in thrombotic diseases, for example, diseases in which the thrombus obstructs local blood circulation or deviates and embolizes to occlude. l blood flow down
(Krishnamurti, Blood 69, 798 (1987), Reilly, Arteriesclerosis and thrombosis, 11, 1276 (1991), Carmeliet, Journal of Clinical
use them in order to modulate the activity or expression of
PAI-1, for example, in the treatment of disorders associated with high levels of PAI-1. BRIEF DESCRIPTION OF THE INVENTION In iere aia acids
F o or a solvate, hydrate or pharmaceutically acceptable salt or ester form thereof, wherein: Ar is aryl or heteroajryl; Ri is hydrogen, Ci-Ci2 alkyl, C6-14 aryl, C6-i4 ar (Ci-6) 1 alkyl, - (CH2) p-heteroaryl, -CH2) p-CO-aryl, - (CH2) P - CO-1 heteroaryl, - (CH2) P -CO- (Ci-C6) alkyl, C2 C7 alkenyl, C2 C7 alkynyl, C3-C3 cycloalkyl, halogen Ci-C3 perfluoroalkyl or Ci-C3j perfluoroalkoxy; I R2 and R3 are independently hydrogen, Ci-Ci2 alkyl, C6-14 aryl, C6-i4 ar (Ci_6) alkyl, - (CH2) p-heteroaryl, halogen, Ci-C3 j perfluoroalkyl, Ci-C3 perfluoroalkoxy, Ci- C3 lalkoxy, alkoxyaryl, nitro, carboxy
(Ci-Ce) alkyl, carbamide, carbamate or C3-C8 cycloalkyl; R4 is -CH (R6) (CH2) nR1, -C (CH3) 2R6, -CH (R5) (CH2) nR6, -CH (R5) C6H4R6, -CH (R5) C6H3 (C02k) 2, CH ( R5) C6H2 (C02H) 3 or a mimic acid; R5 is hydrogen, Ci-C6 alkyl, C6-i2 aryl, aralkyl,
C3 - C8 cycloalkyl or - (CH2) n (R7) i
a is from 0 to 6. The present invention furthermore discloses, inter alia, methods for using thiazolo-naphthyl acids to, for example, modulate the activity and / or expression of PAI-1. In some I procedures, a therapeutically effective amount of one or more compounds of the present invention is administered to a subject to treat a disorder related to PAI-1. Exemplary procedures are those that involve inhibition of PAI-1 activity in the subject, such as those associated with insufficiency of the fibrinolytic system. In some embodiments, one or more compounds of the present invention are administered to a subject to treat thrombosis, for example, venous thrombosis, arterial thrombosis, cerebral thrombosis and deep vein thrombosis, atrial fibrillation, pulmonary fibrosis, thromboembolic complications of the surgery, cardiovascular disease, for example, myocardial ischemia, formation of atherosclerotic plaques, chronic obstructive pulmonary disease, renal fibrosis, polycystic ovary syndrome, and Alzheimer's disease or cancer. DETAILED DESCRIPTION OF THE INVENTION t I A. GENERAL VISION | The present invention provides compounds that inhibit the activity of PAI-lj, processes for preparing said compounds, pharmaceutical compositions containing said compounds and methods for using said compounds, for example, in medical therapies. Preferred compounds have properties which are useful for the prevention and / or inhibition of a wide range of diseases and disorders involving the production and / or action of PAI-1. Compounds of the present invention can be used to treat insufficiency of the fibrinolytic system, including, without limitation, thrombosis, coronary heart disease, renal fibrosis, formation of atherosclerotic plaques, pulmonary disease, myocardial ischemia, atrial fibrillation, pulmonary fibrosis, thromboembolic complications of surgery, peripheral arterial occlusion and pulmonary fibrosis. Other disorders treatable by the compounds of the present invention include, if limitation, polycystic ovary syndrome, Alzheimer's disease and cancer. The terms "alkyl" and "alkylene" as used herein, used alone or as part of another group, refer to substituted or unsubstituted aliphatic hydrocarbon chains, the difference being that the alkyl groups are monovalent (ie say, terminals) by their very nature while the alkylene groups are divalent and often serve as liaison elements. Both include, without limitation, straight and branched chains containing from 1 to 12 carbon atoms, (preferably 1 to 6 carbon atoms, unless otherwise explicitly specified.) For example, methyl, ethyl, propyl, isopropyl, encompassed by the term within the definition of "alkyl" are the aliphatic hydrocarbon chains which are optionally substituted.As a consequence, the alkyl groups, described herein, refer to both substituted and unsubstituted groups. Representative I include, without limitation, halogens, -CN, hydroxy, oxo (= 0), acyloxy, alkoxy, amino, amino substituted by one or two alkyl groups of 1 to 6 carbon atoms, aminoacyl, acylamino, thioalkoxy, 1 to 6 carbon atoms, substituted thioalkoxy of 1 to 6 carbon atoms and trihalomethyl Preferred substituents include halogens, -CN, -OH, oxo (= 0) and amino groups The number of carbon atoms , as used in the definitions given herein, refers to carbon skeletons and carbon branching, but does not include the carbon atoms of | substituents, such as alkoxy substitutions and the like. The term "alkenyl" as used herein, used alone or as part of another group, refers to a chain of substituted or unsubstituted aliphatic hydrocarbons and includes, without limitation, straight and branched chains having 2 to 10 atoms of carbon (unless explicitly specified otherwise) and containing at least one double bond Preferably, the alkenyl molecule part has 1 or 2 double bonds Preferably, the part of the alkenyl molecule has approximately 2 to 7 carbon atoms, said molecular alkenyl moieties may exist in the E or Z conformations and the compounds i of this invention j include both conformations.
Specifically included j within the definition of i "alekinyl" are the chains of aliphatic hydrocarbons that I. They are optionally replaced. Accordingly, the alkenyl groups described herein refer to substituted or unsubstituted groups, j Representative optional substituents include, without limitation, halogens, -CN, hydroxy, acyloxy, alkoxy, amino, amino substituted by one or two alkyl groups of lj to 6 carbon atoms, aminoacyl, acylamino, thioalkoxy of 6 to 6 carbon atoms, substituted thioalkoxy of 1 to 6 carbon atoms and trialomethyl. The heteroatoms, such as! 0 or S bound to an alkenyl, not I must be attached to a carbon atom that is linked to a double bond. Preferred substituents include halogens, -CN, -OH and amino groups. ! The term "alkynyl", as used herein, used alone or as part of another group, refers to a chain of substituted or unsubstituted aliphatic hydrocarbons and includes, without limitation,! straight and branched chains that I have 2 to 10 carbon atoms (unless explicitly specified otherwise) and that contain at least one triple bond. Preferentially, the alkynyl molecule part has from 2 to 7 carbon atoms. In some embodiments, the akinyl may contain more than one triple bond and, in such cases, the alkynyl group must contain at least 4 carbon atoms. Specifically included within the definition of "alkynyl" are the aliphatic hydrocarbon chains which are optionally substituted. Accordingly, the alkynyl groups described herein refer to substituted or unsubstituted groups. Substituents i! representative optionals include, without limitation, halogens, -CN, hydroxy, acyloxy, alkoxy, amino, amino substituted by one or two alkyl groups of 1 to 6 carbon atoms, aminoacyl, acyamino, thioalkoxy of 1 to 6 carbon atoms, thioalkoxy substituted from 1 to 6 carbon atoms and trihalomethyl. Preferred substituents include halogens, -i CN, -OH and amino groups. Heteroatoms, such as 0 or S attached to an alkynyl, should not be attached to a carbon that is bound to a triple bond. The term "cycloalkyl" as used herein, only I or as part of another group, refers to a group of substituted or unsubstituted alicyclic hydrocarbons having 3 to 20 carbon atoms (unless otherwise specified). i explicitly otherwise), preferably 3 to 8 carbon atoms and more preferably, 3 to 6 carbon atoms. Specifically included within the definition of "cycloalkyl" are the groups of alicyclic hydrocarbons which are optionally substituted. Accordingly, the cycloalkyl groups herein described refer to substituted or unsubstituted groups. Representative optional substituents include, without limitation, halogens, -CN, hydroxy, oxo (= 0), acyloxy, alkoxy, amino, amino substituted by one or two alkyl groups of 1 to 6 carbon atoms, aminoacyl, acyamino , thioalkoxy of 1 to 6 carbon atoms, I thioalkoxy substituted of | 1 to 6 carbon atoms and i
trihalomethyl. The term "aryl", as used herein, used only I or as part of another group, is defined as a group of i rings of substituted or unsubstituted aromatic hydrocarbons having from 5 to 50 carbon atoms (a not to be explicitly specified otherwise) with the preferred embodiment of 6 to 14 carbon atoms and more preferably, of 6 to 12 carbon atoms. The group
"Aryl" can have a single ring I or multiple fused rings. The term "aryl" includes, without limitation, I phenyl, α-naphthyl,: β-naphthyl, biphenyl, anthryl, tetrahydronaphthyl, fluorenyl, indanyl, biphenylenyl and acenaphthenyl. Specifically included within the definition of "aryl" are the aromatic gjupos that are optional substituted. Accordingly, the aryl groups (e.g., phenyl, naphthyl and fluoroaryl), described herein, refer to substituted or unsubstituted groups. In representative embodiments of the present invention, the "aryl" groups are optionally substituted with from 1 to 5 substituents I selected from the group | consisting of acyloxy, hydroxy, acyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 and carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, C3-C6 cycloalkyl , - (CH2) p-C3 - C6 cycloalkyl, halogen, Ci-C3 perfluoroalkyl, Ci-C3 perfluoroalkoxy, | - (CH2) p-phenyl, -O (CH2) p-phenyl, amino, amino substituted by one or two alkyl groups of 1 to 6 carbon atoms, aminoacyl, acylamino, azido, cyano, halo, nitro, trioalkoxy 1 to 6 carbon atoms, substituted thioalkoxy of 1 to 6 carbon atoms and trihalomethyl. For example, the "aryl" groups can optionally be substituted with one of three groups selected from Ci-Ce alkyl, Ci-C6 alkoxy, hydroxy, C3-C6 cycloalkyl, - (CH2) P- C3-C6 cycloalkyl, halogen, Ci-C3 perfluoroalkyl, Ci-C3 perfluoroalkoxy, i (CH2) p-phenyl and -0 (CH2) p-phenyl. The phenyl group of - (CH 2) pj phenyl and -O (CH 2) p-phenyl may be optionally substituted with, for example, from 1 to 3 groups j selected from Ci-C6 alkyl, Ci-C6 alkoxy, - (CH2 P-phenyl, halogen, trifluoromethyl or trifluoromethoxy. P is a
halo, cyano, nitro, trihalomethyl and Ci-C6 thioalkoxy. As used herein, the term "heteroaryl", used alone or as part of another group, is defined as a system of substituted or non-substituted heterocyclic and aromatic rings. The groups! heteroaryl can have, for example, from 3 to 50 carbon atoms (unless otherwise explicitly specified), with from 4 to 10 carbon atoms as a preferred embodiment. In some embodiments, the heteroaryl groups are methylpyrrole, pyrazole, N-methylpyrazole, 1,3,4-oxadiazole, 1,2 systems.
4-triazole, 1-methyl-1,1,2,4-triazole, 1H-tetrazole, 1-methyltetrazole, benzthiazole, benzothiazole, benzofuran, benzothiophene, benzothiazole, benzimidazole, N-methylbenzimidazole, azabenzimidazole, indazole, quinazoline, quinoline and isoquinoline I Bicyclic aromatic heteroaryl groups include phenyl, pyridine, pyrimidine or pyridicine rings that are (a) fused with a 6-membered heterocyclic and aromatic ring | (unsaturated) that have a single nitrogen atom; (b) fused to an aromatic heterocyclic ring of 5 or 6 elements (unsaturated) having two I atoms of nitrogen; (c) | fused to an aromatic (unsaturated) heterocyclic ring of 5 elements having a single nitrogen atom together with an oxygen atom or a sulfur atom or (d) fused to an aromatic (unsaturated) heterocyclic ring of 5 elements which has a heteroatom selected from 0, N or js. Specifically included within the definition of "heteroaryl" are the aromatic groups that are optionally substituted. Accordingly, the alkoxy, phenyl, halogen, trifluoromethyl or trifluoromethoxy.
P is an integer number from 0 to 3. Preferred heteroaryls i of the present invention include furanyl,? thienyl, benzofuranyl, benzothienyl, thiophenyl, indolyl, pyrazolyl and thiazolyl substituted and unsubstituted. The term "alkoxy" as used herein refers to the group Ra-0- wherein Ra is an alkyl group as defined above. The term "thioalkoxy", as used herein, refers to the group -0-Ra-S where Ra is an alkyl group as defined above. Specifically I. . . , included within the definition of "alkoxy" and "thioalkoxy" are the groups that j are optionally substituted. Preferred substituents! in the alkoxy and thioalkoxy groups include halogens, -CN, j-OH and amino groups. The term "alkoxyaryl", as used herein, refers to the group Ra-O-aryl wherein Ra is an alkyl group as defined above and aryl is as previously defined. The term "arylalkyloyl" or "aralkyl" refers to the group Ra-Rb where Ra is, an alkylene group as defined! previously, replaced; by Rb an aryl group. Preferred alalkyl groups include the groups of Ce ar (Ci alkyl) The aralkyl groups of the present invention are optionally substituted For example, in preferred embodiments, the benzyl groups of the present invention are optionally substituted with from 1 to 3 groups selected from Ci-C6 alkyl, Ci-C6 alkoxy, hydroxy, C3-Ce cycloalkyl, - (CH2) P | L C3 - Ce cycloalkyl, halogen, Ci-C3 perfluoroalkyl, Ci - | c3 perfluoroalkoxy, - (CH2) P - phenyl and -0 (CH2) p-phenyl Axles of parts of the arylalkyl molecule include, without limitation, benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl and the like. "perfluoroalkyl", as used herein, used alone or as part of another group, refers to a saturated aliphatic hydrocarbon having 1 to 6 carbon atoms and two or more fluorine atoms and includes, without limitation, Straight or branched chains, such as -CF3- I
CH2CF3, -CF2CF3 and -CH (CF3) 2l I The term "halogen" I or "halo" refers to chlorine, bromine, fluorine and iodine. The term "carbamide", as used here, refers to the group -C (0) R'R "wherein R 'and R" are independently hydrogen, alkyl, aryl or cycloalkyl as defined herein. The term "carbamate", as used herein, refers to the group -OC (O) NR 'R "wherein R' and R" are independently hydrogen, alkyl, aryl or cycloalkyl as defined herein . The term "acyl" refers to a radical of the formula RC (O) -, where R is hydrogen, alkyl, aryl or cycloalkyl as defined herein. Suitable acyl radicals include formyl, acetyl, propioryl and the like. The term "acyloxy" refers to radicals of the formula RC (0) 0- where R is hydrogen, alkyl, aryl or cycloalkyl as defined herein. Suitable acyloxy racials include
CH3COO-, CH3CH2COO-, benzoyloxy and the like. The term "acylamino" refers to radicals of the formula RC (0) NH- where R is hydrogen, alkyl, aryl or? cycloalkyl as defined herein. The term "amino acid" refers to radicals of the formula I (R) 0-3C (O) H 2 where R is alkylene as described above. The term "treat" or "treatment" refers to any indication of success in the improvement of an injury, pathology or condition, including any objective or subjective parameter such as relief, remission, diminution of symptoms or the lesion, pathology or condition more tolerable for the patient, decelerating the rate of degeneration or decline, making the end point of degeneration less debilitating or improving the physical or mental well-being of a subject. it can be based on objective or subjective parameters, including the results of a physical examination, neurological examination and / or psychiatric evaluation, etc. The term "treat" or "treatment of a disorder related to PAI-1" includes prevention ij
of the initiation of symptoms in a subject who may be predisposed to a condition related to PAI-1, but who still does not experience or show symptoms of the disorder (prophylactic treatment), inhibit the symptoms of the disorder (slowing or stopping its development), provide relief of the symptoms or side effects of the disorder (including palliative treatment) and / or relieve the symptoms of disorder (causing regression). Accordingly, the term j "treat" includes the administration of the compounds or agerites of the present invention to a subject to prevent or delay, to alleviate or to stop or inhibit the development of symptoms or conditions associated with disorders related to PAI- 1, for example, tumor growth! associated with cancer. An experienced medical professional will know how to use standard procedures to determine if a patient is suffering from a disease associated with increases in PAI-1 levels and / or activity, for example, by examining the patient and determining if the patient is suffering from a disease known as j associated with high levels of I
PAI-1 or its activity or testing the levels of PAI-1 in blood plasma or tissue of the person suspected of suffering from PAI-1-related disease and comparing levels of PAI-1 in the blood plasma or tissue the person suspected of suffering a disease related to II PAI-1 with levels of PAI-jl in the blood plasma or tissue of a healthy person. Methods known in the art for the detection of nucleic acids and proteins can be used to determine! PAI-1 levels in a subject, eg, PCR, so-called Northern blots and Southern blots, spot jblots (macular transfers), matrix configurations of nucleic acids, Western blots, immunoassays such as immunoprecipitation, ELISA (bound immunosolvent assay to enzymes), proteomic assays and the like. The increased i levels of PAI-1 are indicative of disease. In healthy subjects, the! PAI-1 is found at low levels in the plasma (for example, approximately 5-10 ng / mL),
Plasma is also elevated, for example, in post-menopausal women and has been proposed to contribute to the increased incidence of cardiovascular disease in this population (Koh K et al, Ñ Engl J Med 336: 683-690, 1997 ). The term "disease or disorder related to PAI-1" refers to any disease or condition that is associated with the increase or amplification of the expression or activity of PAI-1 or increase or extension of the expression or activity of a PAI. -1 gene encoder. Examples of said increase in expression activity include the following: j protein activity or expression of the gene encoding the protein is increased by a fraction of the level of normal subjects; the activity of the protein or expression of the gene encoding the protein is in an organ, tissue or cell where its presence is not normally detected in normal subjects (eg, spatial distribution of the protein or expression of the gene encoding the protein is modified); i Protein activity or expression of the gene encoding the protein is increased when the activity of the protein or expression is increased when the activity of the protein or I expression of the gene encoding the protein is present in an organ, tissue or cell for a longer period than in a normal subject (p. ^., the duration of activity of the protein b expression of the gene encoding the protein is increased). A normal subject is a person who does not suffer from a disorder related to PAI-1, which is not associated with hyperglycemia is a disorder, for example, that is not caused by elevated blood glucose levels. The term "pharmaceutically acceptable excipient" I means an excipient which is useful for preparing a pharmaceutical composition which is generally safe, non-toxic and desirable and includes excipients that are acceptable for further veterinary use for human pharmaceutical use. Said excipients may be solid, liquid, semisolid or, in the case of an aerosol composition, gaseous. The term "pharmaceutically acceptable salts and esters" refers to salts and esters that are pharmaceutically acceptable and have the desired pharmacological properties.
Said salts include, for example, salts that can be formed where the protons and acids present in the compounds i are capable of reacting | with organic or inorganic bases. Suitable inorganic salts include, for example, those formed with the alkali metals or alkaline and toric metals, for example, sodium and potassium, magnesium, calcium and aluminum. Suitable organic salts include, for example, those formed with orthogonal bases such as the amine bases such as the amino bases, for example, ethanolamine, I-diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like. The pharmaceutically acceptable salts may also include acid addition salts formed from the reaction of molecular fractions of amines in the matrix compound with inorganic acids (eg, hydrochloric and hydrobromic acids) and organic acids (eg, acetic acid, citric acid). , maleic acid and the alkane and sulfonic acid acids, such [as methane sulphonic acid and benzenesulfonic acid]. The pharmaceutically acceptable esters include the esters formed from carboxy, sulfonyloxy and phosphonoxy groups present in the compounds, e.g. esters of Ci-? alkyl! When there are two acid groups present, a pharmaceutically acceptable salt or ester can be an ester or monosal j of monoacid or an ester or disal and
said compounds are (intended to include all unique stereisomers and all mixtures (racemic or other) of said stereoisomers.j The terms "inhibitors", "activators"
"Modulators", as used in relation to expression or activity, refer to inhibitory, activating or modulating molecules, respectively. The inhibitors of the present invention are compositions that inhibit PAI-1 expressions or bind to block, partially or totally, the stimulation, decrease, prevention, delayed activation, inactivation, desensitization or regulation of PAI-1 activity. The samples or assays comprising PAI-1 can be treated with a composition according to the present invention and compared with the control samples without a composition of the present invention. Control samples (not treated with compositions according to the present invention) can be assigned a relative activity value of 100%. In some embodiments, inhibition of PAI-1 is achieved when the value j of the activity relative to the control is about 80% or less, optionally 50% or 25%, 10%, 5% or 1%. i The terms J "pharmaceutically acceptable",
"Physiologically tolerable" and its grammatical variations, when referring to compounds, carriers, diluents and reagents, are used! interchangeably and indicate that the materials are capable of administration to a human patient without the production of undesirable physiological effects, such as nausea, drowsiness, gastric disorders and the like, which could be of a degree that would prohibit the administration of the compound. A "therapeutically effective amount" or a "pharmaceutically effective amount" means an amount that, when administered to a subject to treat a disease, is sufficient to effect treatment for said disease. I Excepted when so indicated, the terms "subject" or
"patient" are used interchangeably and refer to mammals, such as human patients and non-human primates as well as experimental animals such as rabbits, rats and mice and other animals. Accordingly, the term "subject" or "patient" as used herein means any patient or mammal subject to which the compounds according to the invention can be administered. In an exemplary embodiment! of the present invention, to identify patients! subjects for treatment according to! In accordance with methods of the invention, accepted screening procedures are used to determine the risk factors associated with a suspected or suspected condition or disease or to determine the status of the condition or disease existing in a subject. These selection procedures include, for example, conventional work to determine the risk factors that may be associated with the disease or imminent or suspected condition. These and other routine procedures allow the clinical technician to select patients in need of therapy using the methods and formulations according to the present invention. In some embodiments of the present invention, the subject to be treated with the methods of the invention does not have hyperglycemia and / or a disease that has been caused by hyperglycemia. Procedures for determining whether a subject has hyperglycemia are known in the prior art and include, for example, performing a glucose test that measures the blood glucose level. Two exemplary tests that can be used to measure the presence of excess blood glucose levels include a test that measures the amount of blood glucose after an overnight fast and a test that measures the body's ability to process an excess of sugar presented after . I drink a high glucose test. Under normal conditions, a subject who has a fasting sugar level (sugar level after a nighttime ayujno) of approximately 64 to 110 mg / day does not have hyperglycemia, while a person who has a higher fasting blue level than 110 mg
/ di presents elevated blood sugar levels. A value of i above 140 mg / di on at least two occasions usually means that the patient has diabetes.
When any variable occurs more than once in any constituent or in any formula, its definition in each occurrence is (independent of its definition in any other occurrence.) Combinations of substituents and / or variables are admissible only if such combinations result in stable compounds B. TIAZOLO ACIDS 4- NAFTILO I As indicated above, the compounds of the present invention include those of the following formula:
acceptable or an Ar is aryl or heteroaryl; Ri is hydrogen, Ci-pi2 alkyl, C6-14 aryl, Ce-1 ar (Ci_6) 1 alkyl, - (CH2) p-heteroaryl, -CH2) p-CO-aryl, - (CH2) P -CO-1 heteroaryl, - (CH2) P -CO- (Gi-C6) alkyl, C2 C7 alkenyl, C2-C7 alkynyl, C3-Cs and cycloalkyl, halogen or Ci-C3 perfluoroalkoxy; R2 and R3 are independently hydrogen, Ci-Ci2 alkyl, C6-i4 aryl, C6-i4 ar (Ci-6) alkyl, (CH2) p-heteroaryl, halogen, Ci-C3 alkoxy, kalkoxyaryl, nitro, carboxy (Ci C6 alkyl), carbamide, carbamate or C3-Ce cycloalkyl; R4 is -CH (R6) (CH2) nR5 -C (CH3) 2R6, -CH (R5) (CH2) nR6, -CH (R5) C6H4R6, -CH (R5) C6H3 (C02H) 2, CH (R5) C6H2 (C02H) 3 or a mimic acid; R5 is hydrogen, Ci-C6 alkyl, C6-i2 aryl, C6-i ar (Ci-6 > alkyl, C3-Cs cycloalkyl or - (CH2) n (R7) R6 is C02H, tetrazole or P03H; R7 is
n is from 0 to 6; j p is from 0 to 3; B is from 0 to 6 and | A is from 0 to 6 j In some forms of realization, when b is from 1 to
6, Ar is phenyl, furanyl, thienyl, pyrazolyl, thiazolyl or fluorenyl. In some forms of realization, in the definition of Ri i, R2 or R3 said Ci-C12 alkyl is Ci-C3 perfluoroalkyl and i said Ci-C6 alkoxy is Ci C3 perfluoroalkoxy. The thiazolo-naphthyl acids include the following compounds:! ??
Formula 5
Formula 6 i II or solvates, hydrates or their forms of esters or pharmaceutically acceptable salts, wherein: Ar, Rx, R2, R3, R4, b, in and p are as defined above and R8 and R9 R10, 1 Rn and R12 are, independently, hydrogen, Ci-C6 alkyl, Ci-C6 alkoxy, hydroxy, p3-C6 cycloalkyl, - (CH2) P-C3-C6 I cycloalkyl, halogen, -j (CH2) p-phenyl or -O ( CH2) P-phenyl. In some embodiments, Ci-C6 alkyl is Ci-C3 perfluoroalkyl or said Ci-C6 alkoxy is Ci-C3 perfluoroalkoxy. In some compound examples, R8, Rg, Rio Ruy R12 are independently hydrogen or halogen. Compounds examples of formulas 1 to 3 include compounds in which arylo is phenyl, naphthyl, furanyl, thienyl, benzofuranyl, benzothienyl, indolyl, pyrazolyl, thiazolyl or fluorenyl. Exemplary compounds of formulas 1 to 6 include those in which: j Ri is hydrogen, jCi-C6 alkyl, Ci-C3 perfluoroalkyl, halogen or - (CH2) P-phenyl. R2 and R3 are independently hydrogen, Ci-C6 alkyl, phenyl- (CH2) P-, halogen Ci-C3 perfluoroalkyl; R4 is -CHR5 C02H, -CH2-tetrazole or a mimic acid; R5 is hydrogen, or optionally substituted benzyl; I Ar is phenyl, naphyl, furanyl, thienyl, benzofuranyl, benzothienyl, indolyl, pyrazolyl, thiazolyl or fluorenyl or I alternatively, Ar j is phenyl, furanyl, thienyl, i-purolyl, thiazolyl or fluorenyl or solvates, hydrates or their I forms of pharmaceutically acceptable esters or salts. Exemplary compounds of formulas 1 to 6 include those in which the definitions have one or more, for example all, the following values: Ri is hydrogen or halogen, R2 and R3 are independently hydrogen or halogen;! R4 is -CHR5 C02H, -CH2 -tetrazole or a mimic acid; R5 is optionally substituted hydrogen or benzyl; and Ar is unsubstituted phenyl or substituted phenyl with from 1 to 3 selected groups of Ci-C6 alkyl, Ci-C6 alkoxy, hydroxy, C3- G6 cycloalkyl, - (CH2) P-C3-Ce cycloalkyl, halogen, Cij-C3 perfluoroalkyl, Ci-C3 perfluoroalkoxy, - (CH2) p-fjenyl and -O (CH2) phenyl.In some embodiments, when b is from 1 to
i1 6, Ar is phenyl, furanyl, thienyl, pyrazolyl, thiazole or fluorenyl and when b is 0, Ar is furanyl, benzofuranyl, benzothienyl, indolyl, pyrazolyl, thiazole or fluorenyl. The compounds of the present invention also include prodrugs and stereoisomers of formulas 1 to 6. In some compounds Ri is hydrogen, halogen, Ci-C12 alkyl, Ci-C3 perfluoroalkyl or - (CH2) P-phenyl, wherein i the ring of phenyl is optionally substituted with Ci-C6 alkyl, Ci-C6 alkoxy, halogen, trifluoromethyl or 1 I trifluoromethoxy. In some embodiments of the present invention, Ri is hydrogen or halogen. For example, in some embodiments, Ri is hydrogen or bromine. ! In some compounds according to the present invention, R 2 and R 3 1 are independently hydrogen, Ci-Ci 2 alkyl, halogen, Ci-C 3 perfluoroalkyl or - (CH 2) P-phenyl where the phenyl ring is optionally substituted with Ci. C6-alkyl, Ci-C6 alkoxy, halogen, trifluoromethyl or trifluoromethoxy. In some embodiments of the present invention, R 2 is hydrogen and R 3 is hydrogen or j halogen. For example, R3 is hydrogen or bromine. In some compounds,! R4 is-CHR5C02H, CH2-tetrazole, CH (R5) C6H4C02H, -CH (R5) C6H4 (p02H or a mimic acid In some embodiments, R4 jes CH2COOH, unsubstituted, substituted CH2COOH-CH2-tetrazole or CH ( R5) C6H4C02H In some embodiments, for example, R4 is unsubstituted CH2COOH;
I substituted, naphthyl, furanyl, thienyl, benzofuranyl, benzothienyl, indolyl, pyrazolyl, thiazole or fluorenyl. In some embodiments, Ar is substituted or non-substituted phenyl. In some compounds of the present invention, OR4 i substituent is in position j relative to the thiazolo ring (the numbering system used is represented in formula 3). Examples of the thiazolo-naphthyl acids of the present invention include, without limitation, 3-phenyl-2-II ( { [6 - (2-phenyl-1,3; thiazol-4-yl) - 2-naphthylloxy.) Propanic or one of its ester forms or pharmaceutically acceptable salt; 5 - [(. {6- [2- (2-phenyl-1,3-y thiazol-4-yl) -2- Naphthyl.} oxy) methyl] -1H tetraazole or one of its pharmaceutically acceptable salt or ester forms, 2- {[[[bromo-6-i (2-phenyl-1,3-thiazol-4-yl} ) - its forms of { [1-bromo-6 acetic or one acceptable, - 5- ( { [1-bromo-6 - (2 -! phenyl-1,3-thiazol-4-yl) - 2-naphthyl] oxy} methyl) -l H-tetraazole or one of its ester forms or pharmaceutically acceptable salt; (6- {2 - (2,6 I-dichorobenzyl) -1,3 acid tiaz'pl-4-yl] -2- naphthyl-oxy) -acetic I or one of its pharmaceutically acceptable salt or ester forms, 2 - { [1 -i-bromo-6- (5-bromo-2- phenyl I-1,3-thiazole - 4 | - il) - 2 -naphthyl] oxy} - 3-phenylpropanoic acid or one of its salt or ester forms and 4 - (. { [1-bromo-6 - - 4 - yl) - 2 -naphthyl] oxy} methyl)
its pharmaceutically acceptable salt or ester forms. The present invention also discloses compositions comprising the thiazolo-naphthyl acids of the present invention, including the compounds of formulas 1 to 6 or a stereoisomer or one of its pharmaceutically acceptable solvate, hydrate, salt or ester forms. acceptable and one or more carriers, excipients or pharmaceutically acceptable diluents. Said compositions include pharmaceutical compositions for treating or controlling disease states or conditions associated with increases of | the activity of PAI-1. In some I embodiments, the compositions comprise mixtures of one or more thiazolo-naphthyl acids. j Some of the compounds of formulas 1 to 6 contain stereogenic carbon atoms or other chiral elements and thus, give rise! to the formation of stereoisomers, including enantiomers! and diastereomers. The present invention includes all stereoisomers of formulas 1 to 7 and I as well as mixtures of stereoisomeric mixtures. Through all! this application, the name of the product, where the absolute configuration of an asymmetric center is not indicated, is intended to encompass the individual stereoisomers as well as mixtures of stereoisomers. Where an enantiomer is preferred, it may, in some embodiments, be provided substantially free of the corresponding enantiomer. Thus, a substantially free enantiomer of the corresponding enantiomer refers to a compound that is isolated or separated by techniques of separation or free preparation of the corresponding enantiomer. The term "substantially free", as used herein, means that the compound is replaced by a significantly greater proportion of an enantiomer. In preferred embodiments, the compound is composed of at least 90% by weight of a preferred antimer. In another embodiment of the invention, the compound consists of at least 99%, for example, in Jacques, | et al, Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen,
S.H., et al, Tetrahedron 33: 2725 (1977); Eliel, E.L. Sterochemistry of Carbon iCompounds (cGraw-Hill, NY 1962) and i Wilen S.H. Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed. J Univ., Of Notre Dame Loans, Notre Dame, IN 1972). Exemplary salt forms of these compounds include, without limitation, sodium salts and potassium salts. Other salt forms of examples of; These compounds include, without limitation, those formed! with pharmaceutically acceptable organic or inorganic acids and bases known in the prior art. Acids include, for example, acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, maleic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, naphthalenesulfonic, benzenesulfonic, toluenosul phonic, fieldsurfonic and similarly known acceptable aids when a compound of this invention contains a basic molecular moiety. Forms of salts prepared using inorganic bases include hydroxides, carbonates or bicarbonates of alkaline metals or alkaline earth metals which are therapeutically acceptable, such as sodium, potassium, magnesium, calcium and the like. Acceptable organic bases include amines, such as benzylamine, mono-, di- and tnalkyl amines, preferably those having alkyl groups of 1 to 6 carbon atoms, preferably from 1 to 3 carbon atoms, such as methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, mono-, di- and triethanolamine. Examples of salts include also alkylene diamines containing up to 6 carbon atoms, such as hexamethylenediamine; cyclic bases saturated or unsaturated j containing up to 6j carbon atoms including pyrrolidine, peperidine,! morpholine, piperazine and its N-alkyl and N-hydroxy alkyl derivatives, such as N-methyl-morpholine and N- (2-hydroxyethyl) -piperidine or pyridine. Quaternary salts may also be formed, such as tetralkyl1 forms, such as tetramethyl forms, alkyl-alkanoyl forms, such as methyl triethanol or trimethyl monoethanol and cyclic ammonium salt forms, such as N-methylpyridinium. , N-, methyl-N- (2-hydroxyethyl) -morpholinium, N, N-di-methylmorpholinium, N-methyl-N- (2-hydroxyethyl) -morpholinium or N, N-dimethyl-piperidine salt forms. These salt forms can be prepared using the acidic compounds of formulas 1 to 6 and methods known in the art. Exemplary ester forms of the compounds of this invention include, without limitation, straight chain alkyl esters having from 1 to 6 carbon atoms or branched chain alkyl groups containing 1 to 6 carbon atoms.
alkyl of 1 to 6 carbon atoms. The mimic acids and acids, according to the invention, are defined as proton or hydrogen donor groups. I Mimic acids or mimetic examples of the present invention and they R. rug cos gone
wherein R18 is Ci alkyl, C2-C6 alkenyl,
- C6 cycloalkyl, -CH2-r (C3 cycloalkyl), C3 cycloalkenyl, -CH2- (C3-C6 cloalkenyl), aryl or heteroaryl groups optionally substituted or -aryl groups (Ci-Cs) alkyl-heteroaryl (Ci-C6) ) alkyl, optionally substituted] with the aryl and heteroaryl groups I as defined herein. The preferred compounds of the present invention inhibit the activity of PAI-1. Accordingly, compounds can be used for the treatment, including prevention, inhibition / or improvement of disorders related to PAI-1 in a subject including, for example, in the treatment of non-insulin-dependent diabetes mellitus, in the treatment of disease cardiovascular and in t treatment episodes, thrombotic associated with cerebrovascular disease and coronary artery disease. Using the methods of the present invention, an experienced medical technician will know how to administer the compounds of the present invention, including the! represented by formulas 1 to 6, to a subject suffering from any of the diseases associated with the increaseof the activity or expression of PAI-1, for example, cardiovascular disease or diabetes, in order to carry out the treatment for said disease. In an exemplary embodiment, the compounds of the present invention are administered to a subject to be able to treat disease processes involving thrombotic or pro-thrombotic states including, without limitation, the formation of arteriosclerotic plaques, thrombosis venous and arterial, myocardial ischemia, atrial fibrillation, deep vein thrombosis, coagulation syndromes, pulmonary thrombosis, cerebral thrombosis, thromboembolic complications of surgery (such as hip or joint replacement) and peripheral arterial occlusion. Any disease or condition that is associated with an increase in the activity or expression of PAI-1 in a subject can be treated using the compounds of the present invention, diseases and conditions. Example conditions include stroke, for example, stroke associated with or resulting from atrial fibrillation; diseases associated with extracellular matrix accumulation including, but not limited to, renal fibrosis, chronic obstructive pulmonary disease, polycystic ovarian syndrome, restenosis, renovascular disease, and organ transplant rejection; diseases associated with neoangiogenesis including, without limitation, diabetic retinopathy; Alzheimer's disease, for example, by increasing or normalizing levels | of plasmin concentration in a subject; myelofibrosis with mileoid metaplasia, for example, regulating the hyperplasia Ide extromares cells and increases in extracellular matrix proteins.
The compounds of the present invention can be used to treat, for example, diabetic nephropathy and renal dialysis associated with nephropathy; tumors or cancers including, without limitation, leukemia, breast cancer and ovarian cancer; tumors, including, without limitation, liposarcomas and epithelial tumors; septicemia; obesity; insulin resistance; proliferative diseases including, without limitation, psoriasis, and conditions associated with abnormal clotting homeostasis; low grade vascular inflammation; Cerebrovascular diseases; hypertension; dementia; opsteoporosis; arthritis, asthma; heart failure, arrhythmia; angina including, without limitation, angina pectoris; atherosclerosis and sequelae; kidney failure; multiple sclerosis; j steoporosis; osteopenia; dementia; peripheral vascular disease; Peripheral arterial disease; acute vascular syndromes; microvascular diseases including, without limitation, nephropathy, neuropathy, retinopathy and nephrotic syndrome; hipértensión, type I and II diabetes and I related diseases; hyperglycemia, hyperinsulinemia; malignant lesions; Premalignant lesions; gastrointestinal tumors; coronary heart disease including, without limitation, primary and secondary prevention of myocardial infarction; Stable and unstable angina, primary prevention! of coronary episodes and secondary prevention of cardiovascular events and inflammatory diseases including, without limitation, septic shock and the vascular damage associated with i • nf * ections. The compounds of the present invention can also be administered to a subject in combination with a second therapeutic agent, including, without limitation, I prothrombolytic agents, fibrinobes and anticoagulants or in conjunction with other therapies, for example, protease inhibitor. containing very active antiretroviral therapy
(HAART) for the treatment of diseases that have their origin in fibrinolytic insufficiency and the hypercoagulability of patients infected with HIV -1. In some embodiments,! The compounds of the present invention can be administered in conjunction with, and / or following processes and procedures involving maintaining patency or patency including, without limitation, vascular surgery, vascular graft and stent patency.
(endoprosthesis), implantation of organs, tissues and cells and transplant. The compounds of the present invention can also be used for the treatment of blood and blood products used in dialysis, storage I of the blood in the filtrate phase, especially aggregation of platelets ex vivo. The compounds of the present invention can also be administered to a subject as a hormone replacement agent or to reduce inflammatory or C-reactive protein markers. The compounds can be administered to improve coagulation homeostasis, to improve endothelial function or as a topical application for wound healing, for example, the prevention of scar formation. The compounds of the present invention can be administered to a subject to reduce the risk of undergoing a myocardial revascularization procedure. The present compounds are! They can also be added to human plasma during blood chemistry analysis in hospital facilities to determine their fibrinolytic capacity. In some embodiments, the compounds of the present invention can be used as imaging agents for the identification of metastatic cancers. C. GENERAL VIEW OF THE SYNTHESIS The compounds of the present invention can be prepared by those skilled in the art of organic synthesis using conventional methods using reagents and readily available starting materials.
Representative compounds; of the present invention can be prepared using the following synthetic reaction scheme. Professionals experienced in this technique will know how to make use of variants of these stages of the process that by themselves are well known in this technique. In the following reaction reaction schemes, the substituents are selected from the previously defined groups I 43. Reaction scheme 1
D. PHARMACEUTICAL COMPOSITIONS The present invention provides thiazolo-naphthyl acids as pharmaceutical products. In a preferred embodiment, the compounds of the present invention are formulated as pharmaceuticals to treat diseases, for example, those associated with the increased activity of PAI-1, eg, by inhibiting the activity of PAI-1 in a subject. In general, the compounds of the present invention can be administered as pharmaceutical compositions by any method known in the art for administering therapeutic drugs including oral, buccal, topical, systemic (p.Je., transdermal, intranasal or suppository) or parenteral ( eg, intramuscular, subcutaneous or intravenous injection)! The compositions can take the form of pills, pills, capsules, semi-solids, powders, sustained-release formulations, solutions, suspensions, emulsions, syrups, elixirs, aerosols or
in this technique and said excipients, and methods for formulating the compositions, can be found in standard references such as Alfonso AR: Remington's I Pharmaceutical Sciences, jl7th ed. , Mack Publishing Company, i I Easton PA, 1985. Suitable liquid carriers, especially for injectable solutions, include water, aqueous saline solution, aqueous desorption solution and glycols. In some embodiments of the present invention, suitable thiazolo-naphthyl acids! for use in the practice of this invention they will be administered individually or in combination with at least one other compound of this invention.
Thiazolo-naphthyl acids can also be administered with at least one other conventional therapeutic agent for the disease to be treated. The aqueous suspensions of the invention may contain thiazolo-naphthyl acids in mixture with excipients I suitable for obtaining aqueous suspensions. Said excipients may include, for example, a suspending agent, such as | sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and acacia gum and dispersing agents o. humectants, such as naturally occurring phosphatide (eg, lecithin), a condensation product of an alkylene oxide with a long-chain aliphatic alcohol (eg, heptadecaethylene oxypetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol (eg, polyoxyethylene sorbitol mono-oleate) or a condensation product of ethylene oxide with a partial ester derived from fatty acid and a hexitol anhydride (eg, polyoxyethylene mono-oleate sorbitan) . The aqueous suspension i may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more sweetening agents and one or more flavoring agents, such as sucrose, aspartame or saccharin. The formulations can be adjusted for osmolarity. I Oily suspensions may be formed by suspending a thiazolo-naphthyl acid in a vegetable oil such as arachis oil, olive oil, sesame oil or coconut oil or in a mineral oil, such as liquid paraffin or a mixture The suspensions in oil may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol, Sweetening agents may be added to provide an oral preparation with a pleasant taste, such as glycerol, sorbitol or sucrose. These I formulations can be preserved by the addition of an antioxidant such as ascorbic acid.As an example of an injectable oil vehicle, see Minto, J. Pharmacol,
Exp. Ther. 281: 93 L 102, 1997. The pharmaceutical formulations of the invention may also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil or a mineral oil, previously described or a mixture of them. Suitable emulsifying agents include natural occurring gums, such as acacia gum and tragacanth gum, naturally occuring phosphatic compounds, such | such as soy lecithin, esters or partial esters derived from 1-hexitol anhydrides and fatty acids, such as sorbitan mono-oleate and condensation products of these partial esters with ethylene oxide, such as pplioxyethylene mono-oleate sorbitan. The emulsion may also contain j sweetening agents and flavoring agents I, as in the formulation of syrups and elixirs. Said formulations may also contain a demulcent, a condom or a coloring agent. The compound of choice, alone or in combination with other suitable components, can be obtained in aerosol formulations (ie, they can be "nebulized") to be administered by inhalation. The aerosol formulations can be placed in acceptable pressurized propellants, such as dichlorodifluoromethane, protopane, nitrogen and the like. Formulations suitable for parenteral administration, such as, for example, by intraarticular (in the joints), intravenous, intramuscular, intradermal, intraperitoneal and subcutaneous routes include isotonic, aqueous and non-aqueous sterile injection solutions which may contain antioxidants, solutions and I buffers, bacteriostats and solutes that make the formulation isotonic with the blood of the intended recipient and sterile aqueous and non-aqueous suspensions, which may include suspending agents, solubilizers, thickening agents, stabilizers and preservatives. Among vehicles and acceptable solvents, which | can be used, are water and Ringer's solution, uni sodium chloride isotonic. In addition, sterile fixed oils can be conventionally employed as a suspending medium or solvent. For this purpose, any insipid, fixed oil can be used i including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can be used analogously in the preparation of injectables. These solutions are sterile J and generally free of undesirable matter. When the! The compounds are sufficiently soluble, they can be dissolved directly in normal brine with or without the use of suitable organic solvents, such as propylene glycol or polyethylene glycol. Dispersions of the finely divided compounds can be obtained in the solution of sodium carboxymethyl cellulose or starch in the aqueous state or in suitable oil, such as arachis oil. These formulations can be sterilized by conventional well-known sterilization techniques. The formulations may contain substantial pharmaceutically acceptable adjuvants when required to approximate the conditions; physiological agents such as pH adjusting and buffered agents; toxicity adjusting agents, I for example, isodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like. The concentration of thiazolo-naphthyl acids j in these formulations can vary greatly and will be primarily selected on the basis of volumes of fluids, viscosities, body pejso and the like, in accordance with the particular mode of administration selected and the needs of the patient. patient. For IV administration, the formulation may be a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known art using said suitable dispersing agents or humectants and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic, non-toxic solvent or solvent, such as a solution of 1,3-butanediol. The recommended formulations can be presented in single-dose or multi-dose sealed containers, such as ampoules and vials. j Can be prepared! suspensions and injection solutions, for example,] from sterile powders, granules and pellets of the kind described above. Suitable compounds! for use in the practice of this invention can be administered orally. The amount of a compound of the present invention in the composition can vary widely depending on type of composition, size of a unit dose, class of excipients and other factors well known to those of ordinary skill in the prior art. In general, the final composition may comprise, for example, 0.0001% by weight (% w) to 10% by weight of the compound, preferably 0.00001% by weight to 1% by weight, with the remainder being jel excipient or excipients. Pharmaceutical formulations for oral administration can be formulated using pharmaceutically acceptable carriers well known in this technique in doses suitable for oral administration. Said carriers enable the pharmaceutical formulations to be formulated in dosage unit forms such as pills, pills, powders, dragees, capsules, syrups, pasty solutions, suspensions, ejtc. suitable for ingestion by the patient. Formulations suitable for oral administration may consist of (a) liquid solutions, such as an effective amount of the packaged nucleic acid suspended in diluents, such as water, brine or PEG 400; (b) capsules, sachets or pills, each containing a predetermined amount ij of the active ingredient, such as liquids, solids, granules or gelatin; (c) suspensions in a suitable liquid and (d) suitable jemulsions. Pharmaceutical preparations for oral use can be obtained by combining the compounds of the present invention with solid excipient, optionally by grinding a resulting mixture and processing the mixture of granules, after adding additional suitable compounds, if desired, to obtain pills or dragee cores. Solid excipients! Suitable include fillers! proteins or carbohydrates and include, without limitation, sugars including lactose, sucrose, mannitol or sorbitol; corn starch, wheat, rice, potato and other plants; cellulose such as mefeilcelulose, hydroxymethylcellulose, hydroxypropylmethylcellulosk or sodium carboxymethylcellulose and gums including arabica and tragacanth as well as proteins such as gelatin and collagen. If so desired, disintegrating or solubilizing agents can be added, such as
• crosslinked polyvinyl pyrrolidone, agar, alginic acid or one of its salts, such as sodium alginate. The tablet forms may include, for example, one or more of lactose, sucrose, mannitol, sorbitol, calcium phosphates, corn starch, potato starch, microcrystalline cellulose, gelatin, colloidal silicon dioxide, talc, magnesium stearate, stearic acid. and other pharmaceutically compatible excipients, colorants, buffering agents, flavoring agents, ntegrants and carriers. The tablet forms may comprise the active ingredient in a flavor, for example, sucrose, as well as tablets comprising the active ingredient in an inert base, such as gelatin and glycerin or acacia and sucrose emulsions, gels and similar elements containing, in addition to the active ingredient, carriers known in this art.1 II The compounds of the present invention can also be administered in the form of suppositories for rectal administration of the drug. These formulations can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures, but liquid at rectal temperatures and will therefore melt in the rectum to release the drug. These materials are coconut butter and polyethylene glycols. ! The compounds of the present invention can be administered intranasally, intraocularly, intravaginally and intrarectally including suppositories, insufflation, powders and aerosol formulations (eg, of steroid inhalants), see Rohat gi, J. Clin. Pharmacol. 35: 1187- i 1193, 1995; Tjwa, Ann. Altiergy Asthma Immunol. 75: 107-111, 1995). The compounds of the present invention can be administered in controlled or sustained release dosage forms (eg, employing a biodegradable slow release delivsystem), including reservoir injections, osmotic pumps (such as the implant). of Alzet manufactured by Alza), transdermal transdermal and transdermal pills (including electrotransport) and the like for prolonged administration at a predetermined rate, preferably in the form of unit doses suitable for the single administration of precise doses. The compositions will normally include a conventional pharmaceutical carrier, the invention, in addition, these other active agents,. The compounds of the present invention can be delivered transdermally, via a topical route, formulated as rod applicators, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders and aerosols. Encapsulating materials can also be used with the compounds of the present invention and the term "composition" is intended to include the active ingredient in combination with an encapsulating material as a formulation with or without other carriers. For example, the compounds of the present invention can also be delivered as microspheres for slow release into the body.
of injectable and injectable drugs (see Gao, Pharm, Res 12: 857-63, 1995); or as microspheres for oral administration (see e.g., Eyles J. Pharm, Pharmacol 49: 6 69-674,
1997). Both transdermal and intradermal routes can provide a constant delivfor weeks or months. Wafers can also be used in the delivof the compounds of the present invention, for example, anti-atherosclerotic drugs. In another embodiment, the compounds of the present invention can be delivered through the use of liposomes that are fused with the cell membrane or are endocytosed, for example, by using ligands attached to the liposora or incorporated directly into the oligonucleotide, which binds with the receptors of superficial membrane proteins of the cell giving rise to endocytosis.
By using liposomes in particular where the surface of the liposome supports ligands specific for target cells or are otherwise preferentially directed to a specific organ, the compound delivery can be concentrated in the target cells in vivo (see eg, Al-Muhammed, J. Microencapsul 13: 293-306, 1996, Chonn, Curr Opin, Biotechnol 6: 698-708, 1995, Ostro, Am. J. Hosp. Pharm 46: 1576-1587, 1989). In other cases, the preferred preparation may be a lyophilized powder in, for example, 1 M-50 mM histidine, 0.1% sucrose-2%, 2% -7% mannitol in a pH range of 4, 5 to 5.5, which is combined with buffer solution before use. ·; A pharmaceutical composition of the invention may optionally contain, in addition to oxaxol naphthyl acids, at least one other therapeutic agent useful in the treatment of a disease or condition associated with the increase of PAI-1 activity. | The pharmaceutical compositions are generally formulated as sterile, substantially isotonic and in full compliance with all Good Manufacturing Practice (GMP) standards of the U.S. Food and Drug Administration (North American Agency of the Medicine). E. DETERMINATION OF DOSAGE REGIMES For treatment purposes, the compositions or compounds given here | knowing can be administered to the subject in a single bolus delivery, by continuous delivery (eg, continuous delivery, transdermal, mucosal or intravenous) for a prolonged period of time or in a repeated protocol of administration (eg, by means of an hourly, daily or weekly and repeated administration protocol). The pharmaceutical formulations of the present invention can be administered, for example, once or more times a day, 3 times a week or weekly. In a preferred embodiment of the present invention, the pharmaceutical formulations of the present invention are I administer orally once or twice a day. Within this context, a therapeutically effective dose of the biologically active agents may include repeated doses within! of a prolonged treatment regimen that will provide clinically significant results to alleviate p plus symptoms or detectable conditions associated with the increased activity of PAI-1. The determination of effective doses in this context is usually based on studies of animal models followed by human clinical tests! and is guided by determining effective doses and administration protocols that significantly reduce the occu- pation or severity of symptoms of objective exposure or conditions in the subject. Suitable models for this respect include, for example, murine, rat, porcine, feline, non-human primate and other subjects of accepted animal models known in this art. Alternatively, effective doses can be determined using in vitro models (e.g., immunological and histopathological assays). Using such models, only ordinary calculations and adjustments may be needed to determine an adequate concentration and the appropriate dose to administer a therapeutically effective amount of the biologically active agents (ie, amounts that are intranasally effective, transdermally effective, and intravenously effective). or intramuscularly effective to elicit a desired response). In alternative embodiments, an "effective amount" or "therapeutically effective dose of biologically active agents will simplify, inhibit or enhance one or more biological activities selected in correlation with a disease or condition, as set forth above, for therapeutic or therapeutic purposes. The actual dosage of biologically active agents will vary, of course, according to factors such as magnitude of exposure and particular state of the subject (eg, the age of the subject, size, physical state, extent of symptoms, susceptibility, etc.), time and route of administration as well as other drugs or treatments that are administered simultaneously Dosage regimens can be adjusted to provide an optimal prophylactic or therapeutic response The term "therapeutically effective dose" means here a dose that produces the effects
1992); Lloyd, 1999, The Art, Science and Technology of
Pharmacéutical Compounding and · Pickar, 1999, Dosage
Calculations). A therapeutically effective dose is also a dose at which any toxic or detrimental side-effect of the active agent is compensated in clinical terms for therapeutically beneficial effects. In addition, it should be noted that for each particular subject, specific regimens should be evaluated and adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compounds.
In an exemplary embodiment of the present invention, unit dosage forms of the compounds are prepared for standard administration regimens. In this way, the composition can easily be subdivided into smaller doses according to the doctor's guidelines. For example, unit doses can be set in packaged powders, flasks, ampoules and preferably in the form of a capsule or tablet. The active compound present in these 1 unit dosage forms of the composition may be present in one! amount of, for example, from about one gram! to about fifteen grams or more, for administration; daily simple or multiple, according to the I particular need of: patient. Starting the treatment regimen with a minimum daily dose of approximately one gram, blood levels of PAI-1 and the analysis of symptomatic relief of? The agent can be used to determine if a higher or lower dose is indicated. The effective administration of the compounds of this invention can be provided in the oral dose of, for example, I about 0.1 mg / kg / day to about 1,000 mg / kg / day. Preferably, the administration will be from about 10 mg / kg / day to 600 mg / kg / day, more preferably from 25 to 200 mg / kg / day and even more preferably from 50 mg / kg / day to 100 mg / kg / day . In some embodiments, a daily dose of about 1 mg / kg to 250 mg / kg is provided. The present invention compounds can also be solvated, especially hydrated. Hydration can occur during the manufacture of the compounds or compositions comprising the compounds or hydration can occur over time due to the hygroscopic nature of the compounds. In some embodiments, the present invention relates to prodrugs of the compounds of formulas 1 to 6. The term "prodrug", as used herein, means, a compound that is convertible in vivo by
Presss (1985); Krogsgaard-Larsen, et al. (Ed.) "Design and I Application of Prodrugs, Textbook of Drug Design and
Development, chapter 5, 113-191 (1991), Bundgaard, et al, i Journal of Drug Delivery Reviews, 8: 1-38 (1992), i Bundgaard, J of Pharmaceutical Sciences, 77 .: 285 et seq. I (1988) and Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975).
The compound of the present invention can be placed in a suitable container and labeled for treatment of a related disorder with PAI-1, for example, leukemia. In addition, another pharmaceutical product comprising at least one other therapeutic agent useful in the treatment of the PAI-1 related disorder can be placed in the container as well as labeled for treatment of the indicated disease. I For the administration! of pharmaceutical products that
Step 1: 2-bromo-J 1 - (6-methoxy-2-naphthyl) ethanone. Phenyltrimethylammonium tribromide (9.45 g, 25.1 mmol) was added under nitrogen in portions for about 2 hours, to a solution of 1- (6-methoxy-naphthalene-2-yl) -ethanone (5.05 g). , 25.2 mmol) in 50 mL of anhydrous THF (tetrahydrofuran) at room temperature. After the addition] the reaction was stirred at room temperature for 0.5 hour and then, 250 mL of cold water was added. The solid present was collected by filtration, rinsed with | 50 mL of water and drying under reduced pressure to obtain ß |, 66 g of a solid tanning agent. Recrystallization of the solid by isopropyl alcohol i provided 2-bromo-1; - (6-methoxy-2-naphthyl) ethanone (4.07 g, 58%) as a! Brown solid, mp 109-116a C. Elemental analysis for j Ci3H Br02 calculated: C, 55.94, H,
C. After the addition] the reaction was refluxed for 2 hours. The solid was collected by filtration, rinsed with absolute ethanol and dried, under reduced pressure, to obtain phosphorous oxychloride was extracted under reduced pressure to obtain 4 - (- (6-methoxy-2-naphthyl) -2-phenyl 1,3-thiazole (909 mg, 88%), as a white solid, mp 191-193a C. Elemental analysis for calculated C20H15NOS: C, 5j, 68; H, 4.76; N, 4.41; Found: C, 75.37; H, 4.65; N, 4.3-J, I Step 3: 6 - (2-phenyl-1,3-thiazol-4-yl) -2-naphthol. suspension of 4 - (6-methoxy-2-naph il) -2-phenyl-1,3-thiazole (804 mg, 2.53 mmol), prepared in the previous step, in 50 mL | of HOAc glacial acid plus 25 mL of 48% I HBr was stirred under nitrogen at 120 ° C. for 3 hours.The solvent was removed under reduced pressure and the residue was parked between 10% methanol chloride and 5% aHC03. (Note: The solid that did not dissolve in one or another layer was collected by filtration and stored as HGL salt of the desired product). The aqueous layer was separated and extracted 3 times with methanol-methylene chloride. The combined extracts were dried (MgSO.sub.4), filtered and the solvent extracted under reduced pressure to obtain 6 - | (2-phenyl-1,3-thiazol-4-yl) -2-naphthol (650 mg, 85%) as a light brown solid, mp 194 - 1972 C.! Elemental analysis for calculated C19H13NOS: C, 75.22; H, 41, 32; N, 4.62, Found: C, 74.22; H H, 4.12; N, 4.43. 1 Step 4: methyl ester of 2-hydroxy-3-phenyl-propinoic acid. Hydrogen chloride was bubbled for 15 minutes in a solution of 2-hydroxy-3-phenyl-propionic acid (10.0 g, 60 mmol) in 100 mL of methanol at room temperature. The vessel was sealed and then stirred overnight at room temperature. The reaction was made basic by the addition of 5% NaHCO 3 and then concentrated under reduced pressure to extract the methanol. The residue was diluted with water and extracted with ethyl acetate. The organic layer was extracted with saturated NaCl, dried (MgSO 4), filtered and the solvent extracted under reduced pressure to obtain methyl ester of 2-hydroxy-3-phenyl-propinoic acid (9.7 g, 90 %) as 1 yellow oil, S m / z 180 [M] +. Elemental analysis for calculated C10H12O3: C; 66, 65; H, 6.71; N, 0.00; Found: C, j 66.52; H, 6.86; N, 0.29. '1 j Step 5: methyl ester of 3-phenyl-2-1 trifluoromethanesulfonyloxy-propionic acid. Triethylamine (93 iL, 6.68 mmol) was added under nitrogen to a solution of methyl ester of 2-hydroxy-3-phenyl-propynoic acid (1.00 g, 5.57 mmol), prepared in step above, in 20 mL of chloroform (99.9%, free of ethanol) at the temperature of acetone! - dry ice. Then, anhydride was added dropwise for 15 minutes. I trifluoromethanesulfonic acid 1 (1.03 mL, 6.13 mmol). The I cooling bath was removed! and the reaction was stirred overnight at room temperature. The reaction was extracted with 1 N HCl, 5% NaHCO 3, dried (MgSO 4), filtered and the solvent removed under reduced pressure to obtain 1.53 g of a brown oil. Purification of the oil in 100 g of silica gel (230-400 mesh) using 3: 1 methylene-hexane chloride as the eluent,
I thiazol-4-yl) -2-naphthyl.oxi} propanoate. A mix of
6 -. 6 - (2-phenyl-1,3-thiazol-4-yl) -2-naphthol (247 mg, I 0.814 mmol), prepared in step 3, methyl ester of 2-hydroxy-3-y acid phenyl-prophiic (387 mg, 1.24 mmol), prepared in the previous step and cesium carbonate (532 mg, 1.63 mmol) in 1 mL of acetone was stirred under nitrogen at room temperature for 17 hours. The reaction was concentrated under reduced pressure to remove acetone. The residue was partitioned between methylene chloride and water. The aqueous layer was separated and extracted 3 times with Imethylene chloride. The combined extracts were dried (MgSO4), filtered and the solvent removed under reduced pressure to obtain 449 mg of a brown oil. Purification of the oil in 300 g of silica gel (230-400 mesh) using 1: 1 to 3: 2 methylene chloride: hexane as the eluent provided methyl 3-phenyl i -2-. { [6 - (2-phenyl I-1,3-thiazol-4-yl) -2-naphthyl] oxy} propanoate (3 ^ 3 mg, 88%) as a white foam, MS (ESI) m / z 466 [M + h] +. Elemental analysis for calculated C29H23F3 03S: C; 74.82; H, 4.98; N, 3.01; Found: C, 74.46; H, 4.96; N, 2.81. Step 7: acid 3 - 2 ¡-. { [6 - (2-phenyl-1,3-thiazol-4-yl) -2-naphthyl] -oxijpropanoic acid. A mixture of methyl 3-phenyl-2 -. { [6 - (2-f nyl-1,3-thiazol-4-yl) -2-naphthyl-oxy} Propanoate (260 mg, 0.559 mmol), prepared in the previous step, and, and 1 N NaOH (839 mL, 0.839 mmol) in 40 mL of THF, 10 mL of water was refluxed under nitrogen for 3.5 hours and then heated overnight. , maintained overnight at room temperature. Through TLC, material from the game remained. 559 yL (0.559 mmol) of 1 N NaH and the refluxing mixture) was added over 3 hours. The reaction was acidified by the addition of 2 mL of 1N HCl and then concentrated, under pressure; reduced, to eliminate the THF. The gum present was dissolved in methylene chloride and the mixture concentrated under pressure! reduced. The solid present was I collected by filtration, r rinsed with water and dried under reduced pressure to obtain the title compound (234 mg, 92%) as a yellow solid, mp 154-160s.
- thiazol-4-yl) - | 2-naphthol (300 mg, 0.990 mmol), prepared in step 3 of example 1, bromoacetonitrile (83 μl, 1.19 mmol) and carbonatp potassium (684 mg, 4, 95 mmol) in 15 mL of DMF was stirred under nitrogen at room temperature for 21 hours. Through TLC, some starting material remained. 34 pL (0.488 mmol) of additional bromoacetonitrile was added and the reaction stirred at room temperature for 3 days. The reaction was partitioned between ethyl acetate and water. The formed emulsion was separated by the addition of saturated sodium chloride. The organic layer was separated, extracted several times with water, dried (MgSO), filtered and the solvent removed under reduced pressure to obtain 311 mg of a brown solid. [Purification of the solid in 250 g of silica gel (230-400 mesh) using 1: 1 to 3: 2 methylene chloride: hexane as the eluent provided. { [6 - (2-phenyl-1,3-thiazol-4-yl) -2-naphthyl] oxy} acetonitrile (256 mg, 76%), as a white solid, mp 113-117s C. Elemental analysis! for calculated C2iHi4N2OS: C; 73.66; H, 4.12; N, 8.18; Found: C, 72.83; H, 4.18; N, 8.03. Step 2: 5 - ( { [6 - (2-phenyl-1,3-thiazol-4-yl) -2-naphthyl] oxy} methyl-1H-tetraazole A mixture of { 6 - (2-phenyl-1,3-thiazol-4-yl) -2-naphthyl-oxy} -acetonitrile (204 mg, 0.596 mmol), prepared in step j above sodium azide (119 mg, 1 , 82 mmol) and ammonium chloride (98 mg, 1.82 mmol) in 10 ml of DMF was stirred under nitrogen at 100 ° C. for 5 hours.j The reaction was partitioned between 10% methylene-methylene chloride and 1%. N HC1 The organic layer was separated, extracted three times with water, dried
(MgSO), filtered and the solvent extracted under reduced pressure to obtain the title compound (87 mg, 37%) as a white solid, p'm 226-2288 C. Elemental analysis I for C2iHi5N5OS calculated1: C; 64.74; H, 4, 00; N, 17, 98; I Found: C, 63, 46; H, 4, 08; N, 16, 95. Example 3: Synthesis of 2 - acid. { [1-Bromo-6 - (2-phenyl, -1,3-thiazol-4-yl) -2-naphthyl > oxy } - 3-phenylpropanoic. | I Step 1: 1-bromo-6- (2-phenyl-1,3-thiazol-4-yl) -2-naphthol. Bromine (547 yL, 10, 7 mmol) in 250 mL of glacial HOAc was added, under nitrogen drip, for about 7 hours at! a solution of 1-bromo-6 - (2
phenyl-1,3-thiazol-yl) -2-naphthol (3.24 g, 10.7 mmol), prepared in the country 3 of Example 1, in 600 mL of
Glacial HOAc at room temperature. After the addition, the reaction was stirred at room temperature and overnight. The solid was collected by filtration, I rinsed with glacial HOAc and dried under reduced pressure to obtain 4.74 g of yellow solid jun. The solid was dissolved in 500 mL of 20% methanol-methylene chloride and -1 neutralized with 5% NaH03. The aqueous layer was separated and extracted 3 times with 20% methanol-methylene chloride. The combined extracts were dried (MgSO 4), filtered and the solvent removed under reduced pressure to obtain 3.99 g of a light brown solid. Purification of the solid in 1 kg of silica gel (230-400 mesh) using 3: 1 hexane: methylene chloride to 3: 1 methylene chloride: hexane, as the eluents, provided 1-bromo-6 - (2 - phenyl-1,3-thiazol-4-yl) -2-naphthol (1.74 g, 43%) as a brown solid, p17 176-1832 C. Elemental analysis for calculated Ci9H12BrNOS: C; 59.70; H, 3.16; N, 3.66; Found: C, 59.16; H, 3.12; N, 3.48. Step 2: Methyl 2. { [II-Bromo-6 (2-phenyl-1,3-thiazol-4-yl) -2-naphthyl] oxy} - 3 - phenylpropanoate. A mixture of 1-bromo-6 - (2-phenyl-1,3-thiazol-4-yl) -2-naphthol (303 mg, 0.792 mmol), prepared in the previous step, methyl ester of 3-acid phenyl-2-trifluoromethanesulfonyloxy-propinoic acid (378 mg, 1.21 mmol), i prepared in step 5 of example 1 and cesium carbonate i (517 mg1.59 mmol) in 25 mL of acetone was stirred under nitrogen at room temperature for 18 hours. The reaction was concentrated under reduced pressure to remove acetone. The residue was partitioned between methylene chloride and water. The aqueous layer was separated and extracted 3 times with methylene chloride. The combined extracts were dried (MgSO4), filtered and the solvent removed under reduced pressure to obtain 514 mg of a light yellow oil. Purification of the oil in 300 g of silica gel (230-400 mesh) using 3: 2 to 1: 1 hexane: methylene chloride as the eluents afforded Methyl 2. { [1 I-Bromo-6 (2-phenyl-1,3-thiazol-4-yl) -2-naphthyl] oxy} - 3 - phenylpropanoate (372 mg, 86%) as a matt solid I, p.m. 96 -! 101a C. Elemental analysis for
C29H22BrN03S calculated: C; 63.97; H, 4.07; N, 2.57; Found: I C, 63.87; H, 4.01; N, 2.44. Step 3: acid 2 -. { [! - Bromo-6 - (2-phenyl-1,3-I thiazol-4-yl) -2-naphthyl-oxy} - 3 - phenylpropanoic. A mixture of Methyl 2. { [1-bromo-6 (2-phenyl-1,3-thiazol-4-yl) -2- 197 mg,
0.363 mmol), pre OH (544 L, 0.544 mmol) plus 10 mL of water was 3 hard. The reaction was filtered, acidified by the addition of 2 mL of 1 N HC1 and then concentrated under reduced pressure. The solid was collected by filtration, rinsed with water and dried under reduced pressure to obtain the title compound (178 pg, 92%) as a white solid, mp 220-2242 C. Elemental analysis for calculated C28H20BrNO3S: C; 63.02; H, 3.85; N, 2.62; Found: C, 63.13; H, 3.70; N, 2, 54.
Example 4: Synthesis of acid. { [1-Bromo-6 - (2-phenyl-1, -1,3-thiazol-4-yl) j-2-naphthyl] oxy} acetic. Step 1: Methyl. { [1-j bromo-6 - (2-phenyl-1,3-thiazol-4-yl) -2-naphthyl] oxy} acetate. A mixture of 1-bromo-6- (2-phenyl-1,3-thiazol-4-yl) -2-naphthol I (356 mg, 0.931 mmol), prepared in step 1 of Example 3, methyl bromoacetate (106 [mu] g, 1.12 mmol) and cesium carbonate (457 mg, 1.40 mmol) in 25 mL of acetone was stirred under nitrogen at room temperature for 19 hours. The reaction was concentrated under reduced pressure to remove acetone. The residue was partitioned between methylene chloride and water. The aqueous layer was separated and extracted several times with methylene chloride. The combined organic extracts were dried (MgSO.sub.4), filtered and the solvent removed under reduced pressure to obtain Methyl.
. { [1-Bromo-6 - (2-phehyl-1,3-thiazol-4-yl) -2-naphthyl] oxy} acetate (401 mg, 5%) as a white matte solid, mp 156-159 a C. Elemental analysis for calculated C22Hi6BrN03S: C; 58.16; H, 3.55; N, 3.08; Found: C, 57.87; I H, 3.43; N, 2.94. 'Step 2: acid. { [1 - bromo-6 - (2-phenyl-1,3-thiazole
- 4 - yl) -2-naphthyl] oxdi} acetic. A mixture of Methyl. { [1-Bromo-6 - (2-phenyl-1,3-thiazol-4-yl) -2-naphthyl-oxy} acetate (217 jmg, 0.477 mmol), prepared in the previous step and 1N NaOH (716 pL, 0.716 mmol) in 20 mL of THF plus 20 mL of methanol plus 10 mL of water was refluxed under nitrogen for 2j25 hours. The reaction was filtered, acidified by the addition of 3 mL of 1 N HC1 and then concentrated under reduced pressure. The solid formed was collected by filtration, rinsed with water and dried under reduced pressure to obtain the title compound (195 mg, 92%) as a white solid, mp 222-2309 C. Elemental analysis for calculated jC2iHi BrN03S: C; 56.94; H,
3.25; N, 3.16; Found-C, 57.19; H, 3.18; N, 3.04. Example 5. Synthesis of 5 - ( { [1-bromo-6 - (2-phenyl)
- 1,3-thiazol-4-yl) -2-naphthyl] oxy} methyl) - 1 H -tetraazole. ! Step 1: . { [1-bromo-6 - (2-phenyl-1,3-thiazole-4
- il) - 2 - naphthyl] oxy} methyl) acetonitrile. A mixture of 1-bromo-6 - (2-phenyl-1, 3-thiazol-4-yl) -2-naphthol
(351 mg, 0.918 mmol), prepared in step 1 of Example 3, i bromoacetonitrile (77 pL, 1.11 mmol) and cesium carbonate i (1.505 g, 4.62 mmol) in 125 mL of acetone was stirred under I nitrogen at room temperature for 19 hours (from one day to another). The reaction was concentrated under reduced pressure to remove acetone. The residue partitioned between methylene chloride and water. The aqueous layer was separated and extracted three times with methylene chloride. The combined extracts were dried (MgSO4), filtered and the extracted solvent reduced in reduced pressure to obtain. { [1-bromo-6- (2-phenyl-1,3-thiazole naphthyl] oxy) methyl) acetonitrile (382 mg, 99%) as a light brown solid, mp 157-1609 C. Elemental analysis for C2iHi3BrN02S calculated: C; 59.87; H, 3.11; N, 6.65; Found: C, 59.56; H, 3.28; N, 6.56. Step 2: 5 - ( { [1-brjomo-6 - (2-phenyl-1,3-thiazol-4-yl) -2-naphthyl] oxy} methyl) -1H-tetraazole. A mix of . { [1-Bromo-6 - (2-phenyl-1,3-thiazol-4-yl) -2-naphthyl] oxy} mptil) acetonitrile (277 mg, 0.658 mmol), prepared in the previous step, sodium azide (128 mg,
dried under reduced pressure to obtain the title compound (276 mg, 82%) as a white matt solid, 227-231 aC. Elemental analysis for C2iHi BrN5OS + 0.48 C3H7NO + 0.47 H20 t i calculated: C; 53.07; H, 3? 63; N, 15.11; Found: C, 53.08; H, 3.61; N, 14.91. ! Example 6: Synthesis | (. {6 - [2 - (2,6-dichlorobenzyl) -1,3-thiazol-4-yl] -2-naphthyl} oxy) acetic acid. Step 1: 2- (2,6-Dichlorobenzyl) -4- (6-methoxy-2-naphthyl) -1,3-thiazole. A suspension of (2-bromo-1- (6-methoxy-2-naphthyl) ethanone (500 mg, 1.79 mmol), prepared in step 1 of Example 1, in 25 mL of absolute ethanol was heated under nitrogen At this point, all the solid had been dissolved, and at the reflux temperature 2 - (2, - dichlorophenyl) ethanethioamide (395 mg, 1.79 mmol) was added and the reaction was added. reflux for 3 hours.After cooling to room temperature, the solid was collected by filtration, rinsed with absolute ethanol and dried under reduced pressure to obtain 575 mg of a dull white solid.The solid was dissolved in 20% methanol. j- methylene chloride An excess of 5% NaHC03 was added to convert the amine salt to the free base.The aqueous layer was separated and extracted 3 times with 20% methanol-methylene chloride.The combined organic extracts were dried (MgSO4), filtered and the solvent extracted under reduced pressure to obtain 2- (2,6-dichlorobenzyl) -! - (6-methoxy-2-naphthyl) -1,3-do pale, calculated mp: H, 3.67; N,
- thiazole - 4 chlorobenzyl) 90 mg, 0.975 mL of glacial HOAc plus 25 mL of HBr al 48% was stirred under nitrogen at 120a C for 3.5 hours and then maintained, overnight, at ambient temperature. The reaction was concentrated under reduced pressure. The residue was dissolved in 20% methanol-methylene chloride and neutralized with the addition of an excess of 5% NaHCO3. The aqueous layer was separated and extracted 3 times with 20% methanol-methylene chloride.
The combined extracts were dried (MgSO4), filtered and i the solvent extracted under reduced pressure to obtain 6 I - [2- (2,6-dichlorobenzyl) -1,3-thiazol-4-yl] -2-naphthol as a brown solid, pm 191 - 1932 C.
Elemental analysis for! C2oHi3Cl2NOS calculated: C; 62.19; H,
3.39; N, 3.63; Found 'C, 61.31; H, 3.30; N, 3.42. I Step 3: methyl (. {6-j [2 - (2,6-dichlorobenzyl) -1,3-thiazol-4-yl] -2-naphyl} oxy) acetate. A mixture of 6 - [2 - (2,6-dichlorobenzyl) -1,3-thiazol-4-yl] -2-naphthol (269 mg, 0.696 mmol), prepared in the previous step, methyl bromoacetate (79 0.835 mmol) and cesium carbonate (341 mg, 1.05 mmol) in 25 mL of acetone was stirred under nitrogen at room temperature for 4 hours. The reaction was concentrated 1 under reduced pressure to extract the acetone. The residue was partitioned between methylene chloride and water. The aqueous layer was separated and extracted 3 times with methylene chloride. The combined extracts were dried (MgSO4), filtered and the solvent removed under reduced pressure to obtain 298 mg of a brown solid. The solid was triturated several times with hexane and then dried under reduced pressure to obtain methyl (. {6 - [2 - i (2,6-dichlorobenzyl) -j 1,3-thiazol-4-yl] -2 -nafil Oxy) acetate (298 μg, 93%) as a brown solid, mp 174-177 ° C. (Elemental analysis for C23H17CI2 O3S calculated: C, 60.27; H, 3.74; N, 3 , 06; Found: C, 59.03;
H, 3.70; N, 2.88. ! Step 4: Acid (. {6 - [2 - (2,6-dichlorobenzyl) -1,3-thiazol-4-yl] -2-jnaphthyl} oxy) acetic acid. A mixture of methyl (. {6 - [2 - (2,6-dichlorobenzyl) -1,3-thiazol-4-yl] -2-naphyl} oxy) acetate (205 mg, 0.447 mmol), prepared in the previous step, and 1 N NaOH (671 μ? _, 0.671 mmol), in 20 mL of THF plus 20 mL of methanol plus 10 mL of water was refluxed under nitrogen! for 2.5 hours. The reaction was filtered, acidified by the addition of 3 mL of 1 N HC1 and then concentrated under reduced pressure to extract the THF and the methanol. The solid present was collected by filtration, rinsed with water and dried under reduced pressure to obtain the title compound (150 mg, 74%) as a matt white solid, mp 205 - j 207s C. Elemental analysis for C22H15CI2NO3S + 0, 30 H20! calculated: C; 58.75; H, 3.50; N, 3.11; Found: C, 59.09; H, 3.58; N, 2.92.
I I Example 7: Synthesis of 2 - acid. { [1-Bromo-6 - (5-bromo-2-phenyl-1,3-thiazol-4-yl) -2-naphthyl] oxy} > - 3 - phenylpropanoic. | Step 1: 1-bromo-6 - (5-bromo-2-phenyl-1,3-thiazol-4-yl) -2-naphthol. Bromine (547 pL, 10.7 mmol) in I 250 mL of glacial HOAc was added under nitrogen by dripping for about 7 hours to a solution of 6 - (2-phenyl-1,3-thiazole - | 4-yl) Naphthol 83.24 g, 10.7 mmol), prepared in step 3 of Example 1 in 600 mL of glacial HOAc at room temperature. After the addition, the reaction was stirred at room temperature overnight. The solid was collected by filtration, rinsed with
Glacial HOAc and drying under reduced pressure to obtain 4.74 i! g of a yellow solid. The solid was dissolved in 500 mL of 20% methanol-methylene chloride and neutralized with 5% j NaHCO 3. The aqueous layer was separated and extracted 3 times with
% methanol - methylene chloride. The combined extracts were dried (MgSO.sub.4), filtered and the solvent extracted i under reduced pressure to obtain 3.99 g of a light brown solid I. Purification of solid dejl in 1 kg of silica gel
(230-400 mesh) using 3: 1 hexane: methylene chloride ia 3: 1 methylene chloride: hexane as the eluents, i provided 1-bromo-6j- (5-bromo-2-phenyl-1,3-thiazole - 4 - yl) -2-naphthol (178 mg, 4%) as a matt white solid, mp 198-1200s C. Elemental analysis for calculated Ci9HiiBr2NOS: C; J. 49, 48; H, 2.40; N, 3, 04; Found: C, 49, 83; H, 2.36; N, 2, 81. Step 2: Methyl 2 -. { (1-Bromo-6 - (5-bromo-2-phenyl-1,3-thiazol-4-yl) -2-naphthyl] oxy} - 3-phenylpropanoate A mixture of 1-bromo-6 - (5 - Bromo-2-phenyl-1,3-thiazol-4-yl) -2-naphthol (132 mg, I 0, 286 mmol), prepared in the previous step, 3-phenyl-2-trifluoromethanesulfonyloxy-methyl ester The propynoate (136 mg, 0.43 mmol), prepared in step 5 of Example 1 and jasium carbonate (188 mg, 0.577 mmol) in 15 mL of acetone was stirred under nitrogen at room temperature for 20 h. After 5 minutes, the starting material was left in. An additional quantity of 43.8 mg (0. 140 mmol) of 3-phenyl-2-trifluoromethanesulfonyloxy! -propionic acid methyl ester was added and the reaction was continued. The reaction was concentrated under reduced pressure to extract the acetone, the residue partitioned between methylene chloride and water. and separated and extracted 3 times with methylene ilide. The combined extracts were dried! (MgSO 4), filtered and the solvent removed under reduced pressure to obtain 235 mg of a yellow oil. Purification of the oil on silica gel i (230-400 mesh) using 3: 2 hexane-methylene chloride as the eluent provided methyl 2 -. { (1-Bromo-6 - (5-bromo-2-phenyl-1,3-thiazol-4-yl) -2-naphthyl] oxy} -. 3-phenijlpropanoate (125 mg, 70%) as a foam yellow, MS (ESI) m / z 622/624/626 [M + H] + Elemental analysis for calculated C29H2iBr2N03S: C: 55.88; H, 3.40; N, 2.25; Found ^ C, 56 , 33; H, 3, 33; N, 2, 14. Step 3: 2 - { [1 - bromo - 6 - (5-bromo-2-phenyl-1,3-thiazol-4-yl) acid) - 2 - naphthyl] oxy} - 3 - I phenylpropanoic A mixture of Methyl 2 -. {(1 - bromo - 6 - (5 i - bromo - 2 - phenyl - i 1, 3 - thiazole - 4 - il) -2-j naphthyl] oxy.} - 3-pheylpropropanoate (134 mg, 0.21 mmol), prepared in the previous step and 1 N NaOH (323 L, 0.323 mmol) in 10 mL of THF plus 10 mL of methanol plus 5 mL of water was refluxed under nitrogen for 2 hours.The reaction was filtered, acidified with 1 N HCl and then concentrated under reduced pressure to remove THF and methanol.The solid present was collected by filtration , rinsed c on water and drying under reduced pressure to obtain the title compound (68 mg, 52%) as a yellow solid, mp 221-223a C. Elemental analysis for C28Hi9Br2 N05S calculated: C; 55.19; H, i 3.14; N, 2.30; Found: C, 56.17; H, 3.45; N, 2.05. Example 8: Synthesis of 4 - ( { [1-bromo-6- (2-phenyl-1,3-thiazol-4-yl) -2-naphthyl] oxy} benzoic acid Step 1: methyl 4 - ( { [i-Bromo-6 - (2-phenyl-1,3-thiazol-4-yl) -2-naphthyl-oxy} -methyl) -benzoate A mixture of 1-bromo-6- (2-phenyl-1,3-thiazol-4-yl) -2-naphthol (0.43 mg, 1.12 mmol), prepared in step 1 of Example 3, methyl 4 - (bromomethyl) benzoate (259) , 7 mg, 1.13 mmol) and cesium carbonate (551.9 mg, 1.69 mmol) in 25 mL of acetone was stirred under (nitrogen at room temperature I for 18 hours.) The reaction was concentrated under reduced pressure. to remove the acetone The reaction was partitioned between methylene chloride and water.The aqueous layer was separated and extracted 3 times with methylene chloride.
The combined extracts were dried (MgSO4), filtered and the solvent removed under reduced pressure to obtain 514.0 mg of a yellow solid. The purification of the solid in! 300 g of silica gel (230-400 mesh) using hexane: methylene chloride to 3: 2 methylene chloride: hexane as
63.40; H, 3.80; N, 2.64; Found: C, 62.99; H, 4.15; N, I 2.50. ! Step 2: 4 - ( { [1-Bromo-6- (2-phenyl-1,3-l thiazol-4-yl) -2-naphthyl] oxy} methyl) benzoic acid. A mixture of methyl 4 - ( { [Lj-bromo-6- (2-phenyl-1,3-thiazol-4-yl) -2-naphthoxy] methyl] benzoate (214.8 mg, 0.405 mmol), prepared in the previous step and 1 N NaOH (608 μ?, 0.608 mmol) in 40 mL of THF plus 40 mL of methanol plus 10 mL of water was stirred for 24 hours. An additional amount of 608 yL (0.608 mmol) of 1 N NaOH was added and the mixture subjected to reflux for 24 hours. After cooling to room temperature, the reaction was filtered through TLC. acidified by the addition of 5 mL of 1 N HCl and then concentrated under reduced pressure to remove THF and methanol.The solid present was collected by filtration, washed with water and I dried under reduced pressure to obtain the compound of title (152.9 mg, 73%) such as a white solid, mp 268-2702 C. Elemental analysis for C27Hi8Br 03S calculated: C; 62.36; H, 3.57; N, 2.69; Found: C , 62.38; H, 3.54; N, 2, 62. Example 9: Primary selection for inhibition of PAI-1 The test compounds are dissolved in DMSO I (dimethylsulfoxide) at a final concentration of 10 M and t then, diluted 100X in physiological buffer solution, the inhibitor assay is initiated by the addition of the assay (final concentration 1 - 100 μ ?, maximum concentration i DMSO 0.2%) in a pH 6.6 buffer containing 140 nM of recombinant human plasminogen activator inhibitor - 1 (PAI-lj Molecular Innovations, Royal Oak, MI). After a 1-hour incubation at room temperature, 70 nM of recombinant human plasminogen tissue activator (tPA) is added and the combination in the molar ratio used (2: 1) and the absence of any effect of the test compound About tPA alone. I Example 10: Assay to determine the IC50 value of inhibition of PAI-1 This assay is based on the non-SDS dissociable interaction between tPA and active PAI-1. The test plates are initially coated with human tPA (10 pg / ml). The test compounds of the present invention are dissolved in 10 mM DMSO and then, diluted with physiological buffer solution (pH 7.5) to a final concentration of 1-50 μ. i Test compounds1 are incubated with human PAI-1 (50 i ng / ml) for 15 minutes at room temperature. The plate coated with tPA s washed with a solution of 0.05% I I Tween 20 and 0.1% BSA and then, the plate is blocked by a solution of 3% BSA. An aliquot of the thiazole-naphthylcocid / PAI-1 acid solution is added to the plate at room temperature for 1 hour (Molecular Innovations, Royal Oak, MI). The plate is again washed and dried. add a goat rat-alkaline phosphatase IgG-alkaline phosphatase solution at a dilution of 1; 50,000 in goat serum. The plate is incubated 30 minutes at room temperature, washed and a phosphatase and alkaline substrate solution is added. The plate is incubated for 45 minutes at room temperature and color development is determined at OD4o5nm- The quantification of active PAI-1 bound to tPA at varying concentrations of the test compound is used to determine the IC50 value. The results are analyzed using a logarithmic optimal fit equation. The sensitivity of the assay is 5 ng / ml of human PAI-1 as determined from a standard curve ranging from 0 to 100 ng / ml. The compounds of Ta present invention inhibited the plasminogen-1 activator inhibitor as summarized in Table 1.! · Table 1
to. The value of IC50 | was determined by the antibody assay as described above. Although the above invention has been described in detail by way of example for purposes of clarity of understanding, it will be apparent to the person skilled in the art that some changes and modifications can be made and can be implemented without undue experimentation within the scope of the invention. of the appended claims, which are presented by way of illustrative and not limitedjr. All publications and patent documents cited above are hereby incorporated by reference in their entirety for all purposes to the same extent as if they were I indicated individually. It is noted that with respect to this date, the best method known to the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention.
Claims (21)
- precedes, rec the following re 1
- Formula 1 or a solvate, hydrate or pharmaceutically acceptable salt or ester form thereof, characterized in that: Ar is aryl or heteroaryl; Ri is hydrogen, Ci - C12 alkyl, C6-i4 aryl, Ce-n ar (Ci-6 < alkyl, - (CH2) p-heteroaryl, -CH2) p-CO-aryl, - (CH2) P -CO-t heteroaryl, - (CH2) P -CO- (Ci-C6) alkyl, C2 C7 alkenyl, C2 I C7 alkynyl, C3-Ca cycloalkyl, halogen or Ci-C3 1 perfluoroalkoxy; J i R2 and R3 are independently hydrogen, Ci-Ci2 alkyl, 1-14 aryl, C6-1 ar (Ci-6 > alkyl, - (CH2) p-heteroaryl, halogen, Ci-C3 alkoxy, jalkoxyaryl, nitro, carboxy (Ci-C6) alkyl, carbamide, carbjamate or C-Cs cycloalkyl; R4 is -CH (R6) (CH2) nR5-C (CH3) 2R6, -CH (R5) (CH2) nR6, -CH (R5) C6H4R6, -CH (R5) C6H3 (C02H) 2, CH (R5) C6H2 (C02H) 3 or a mimic acid; I R5 is hydrogen, Ci4 C6 alkyl, C6-12 aryl, Ce-14 ar (Ci-6) " alkyl, C3-C8 cycloalkyl or - (CH2) n (R7) i R6 is C02H, tetrazole or P03H;
- that when b: from 1 to 6, Ar is phenyl, furanyl, thienyl, pyrazolyl-1-thiazolyl or fluorenyl. j 1 2. Compound in accordance with claim 1
- Ci-C6 alkyl, phenyl- (CH2) P-halogeno perfluoroalkyl unsubstituted. 5. Compound in accordance with any of the
- unsubstituted benzyl or benzyl substituted with from 1 to 3 groups selected from Ci-C6 alkyl, Ci-C6 alkoxy, hydroxy, C3-Ce cycloalkyl, - (CH2) P-C3-C6 cycloalkyl, halogen,
- Ci-C3 perfluoroalkyl, Ci-C3 perfluoroalkoxy, ~ (CH2) P-phenyl and -O (CH2) P-phenyl doride p is from 1 3. I 7. Compound of conformity with any of claims 1 to 6, characterized because it has the formula
- or a solvate, hydrate or its pharmaceutically acceptable salt or ester form. 1 8. Compound according to any of claims 1 to 6, characterized in that it has the formula 3:
- Formula or a solvate, hydrate or its pharmaceutically acceptable salt or ester form. 9. Compound according to any of claims 1 to 8,! characterized in that Ar is phenyl, naphthyl, furanyl, thienyl, benzofuranyl, benzothienyl,
- i claims 1 a | 6, characterized in that it has the
- salt or ester i0, Rn and Ri2
- ilo, Ci-C6 alkoxy, hydroxy, C3-C6 cycloalkyl, - (CH2) P-C3-C6 cycloalkyl, halogen, - | (CH2) P-phenyl or -0 (CH2) P-phenyl. a of the formula
- or ester R11 and i2 are independently hydrogen, Ci-C6 alkyl, Ci-C6 alkoxy, hydroxy, cycloalkyl, - (CH2) P-C3-C6 cycloalkyl, halogen, - CK2) p-phenyl or -0 (CH2) P -phenyl 12. Compound according to claim 10 or 11, characterized in that the C1-6 alkyl is Ci-3 perfluoroalkyl and said Ci_6 alkoxy is Ci-3 perfluoroalkoxy.
- 13. Compound according to any of claims 1 to 1, characterized in that Ri is hydrogen. !
- 14. Compound according to any one of claims 1 to 13, characterized in that R4 is -CHR5C02H, CH2-tetrazole or -CH (R5) C6HJCO2H.
- 15. Compound according to claim 1, characterized in that it is 3-phenyl-2- ( { [6 - (2-phenyl-1,3-thiazol-4-yl) -2-naphthyl] oxy} acid} propanic; i 2- {[[l-bromo-6- (2-phenyl-1,3-thiazol-4-yl) -2-naphthyl} oxy} phenylpronaic acid; acid { [1-bromo -6 - (2-phenyl-1,3-thiazol-4-yl) -2-naphthyl} oxy) acetic; 5- ( { [1-bromo-6 - (2-phenyl-1,3-thiazol-4-yl] -2-naphthyl] oxy} methyl) -lH-tetraazole or one of its forms ester or pharmaceutically acceptable salt
- 16. Compound according to claim 1, characterized in that it is 2 - { [1-bromo-6 - (5-bromo-2-phenyl-thiazol-4-yl) -2-acid. -naphthyl] oxy} -3-phenylpropanoic acid (. {6 - [2- (2,6-dichlorobenzyl) -1,3-thiazol-4-yl] -2-naphthyl} oxy) acetic acid 4 - ( { [1-bromo-6 - (2-phenyl-1,3-thiazol-4-yl) -2-naphthyl] oxy} methyl) benzoium or one of its salt forms or Pharmaceutically eptable ester
- 17. Process characterized in that it comprises administering a compound according to any of claims 1 to 16 to a subject
- 18. Method according to claim 17, characterized because! comprises, determining a level of PA1 activity in a subject. I •
- 19. Method of conformance with 18 characterized in that the determination is made before the administration of said compound.
- 20. Procedure of! according to claim 18, characterized in that | the determination is made after the administration of a compound.
- 21. Procedure for modulating PAI-1 activity characterized in that it comprises identifying a subject in need of PAI-1 modulation and administering to the subject an effective amount of a compound of formula 1:pharmaceutically acceptable salt or an ester form of ellaj, wherein: Ar is aryl or heteroaryl; Ri is hydrogen, Ci-Ci2 alkyl, C6-i4 aryl, Ce-14 ar (Ci-6) alkyl, - (CH2) p-heteroaryl, -CH2) p-CO-aryl, - (CH2) P -CO- heteroaryl, - (CH2) P -CO-. { Ci-C6) alkyl, C2 C7 alkenyl, C2 and C7 alkynyl, C3-c [cycloalkyl, halogen or Ci-C3 perfluoroalkoxy; I R2 and R3 are independently hydrogen, Ci-Ci2 alkyl, C6-i4 aryl, in ar (jCi-6) alkyl, - (CH2) p-heteroaryl, I halogen, Ci-C3 alkoxy, laxaryl, nitro, carboxy (Ci-Ce) -alkyl, carbamide, carbamate or C3-Ca cycloalkyl; R4 is -CH (R6) (CH2) nR5 |, -C (CH3) 2R6, -CH (R5) (CH2) nR6, -CH (R5)C6H4R6, -CH (R5) C6H3 (C02H) 2, CH (R5) C6H2 (C02H) 3 or a mimic acid;R5 2 aryl, Ce ar (Ci-6) alkyl R6 R7n is from 0 to 6; I p is from 0 to 3; 'I b is from 0 to 6 and I a is from 0 to 6 j 22. Process according to claim I 21, characterized in that in the definition of Ri, R2 and R3 said Ci-C12 Ci-C3 alkyl perfluoroalkyl and said Ci-Ce alkoxy is Ci-j c3 perfluoroalkoxy. 2. 3 . Procedure of compliance with the claims21 or 22, characterized in that Ar is phenyl, naphthyl, furanyl, thienyl, benzofuranyl, benzothienyl, indolyl, pyrazolyl, thiazolyl or! fluorenyl. 1 I 24 Process according to any of claims 21 to 23, characterized in that Ar is unsubstituted phenyl or phenyl substituted with from 1 to 3 groups selected from j Ci-C6 alkyl, Ci-C6 alkoxy, hydroxy, C3-Ce and cycloalkyl , - (CH2) P C3 C6 cycloalkyl, halogen, | - (CH2) P - phenyl or -0 (CH2) p-phenyl.2 5. Process according to claim 24, characterized in that the Ci-Ce alkyl is Ci-C3 perfluoroalkyl or dicijo Ci-C6 alkoxy is Ci-C6 perfluoroalkoxy. 2 6. Procedure in accordance with the claim21, characterized in that! Ar is phenyl, naphthyl, furanyl, thienyl, benzofuranyl, benzothienyl, indolyl, pyrazolyl, thiazolyl or fluorenylRi is hydrogen, halogen, Ci_ C6 alkyl, or - (CH2) p-phenyl R2 and R3 are independently hydrogen, Ci-C unsubstituted alkyl, phenyl- | (CH2) p-, halogen or Ci-C3 perfluoroalkyl; R4 is -CHR5C02H, -CH2. etrazole or -CH (R5) C6H4C02H or a mimic acid and! R5 is hydrogen or benzyl; or a solvate, hydrate or pharmaceutically acceptable salt I or an ester form thereof. 27 Process characterized in that it is to treat the insufficiency of the fibrinolytic system, thrombosis, atrial fibrillation, lung jfibrosis, thromboembolic complication of surgery, stroke, myocardial ischemia, stroke, thromboembolic complication of surgery, cardiovascular disease, formation of atherosclerotic plaques, obstructive pulmonary disease chronic, renal fibrosis, Alzheimer's disease, (cancer of diabetes or arterial ovarian syndrome, cerebral thrombosis and deep vein thrombosis) 30. Procedure according to claim 27, characterized by that cardiovascular disease is caused by diabetes mellitus not dependent on Insulin 31. Pharmaceutical composition characterized in that it comprises a compound according to any of claims 1 to 16 Jo 21 to 26, or one of its pharmaceutically acceptable salt or ester forms and a pharmaceutically acceptable excipient or carrier. from a compound as defined in any of Claims 1 to 116 or 21 to 26 in the manufacture of a medicament for treating fibrinolytic system insufficiency, thrombosis, atrial fibrillation, fibrosis? pulmonary, thromboembolic complication I surgery, stroke, myocardial ischemia, atherosclerotic plaque formation, cardiovascular disease, chronic obstructive pulmonary disease, polycystic ovary syndrome, stroke, diabetes, Alzheimer's disease, cancer or renal fibrosis. 33. Use according to claim 32, wherein the thrombosis is selected from the group consisting of venous thrombosis, arterial thrombosis, cerebral thrombosis and deep vein thrombosis. 34. Use according to claim 32, wherein the cardi-vascular disease is caused by non-insulin-dependent diabetes mellitus.The thiazolo-naphthyl present of the formula (I) and the procedures for i use them to modulate the expression of PAI-1 and to treat the disordersIii! I Ii II
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US60/603,739 | 2004-08-23 |
Publications (1)
Publication Number | Publication Date |
---|---|
MX2007002176A true MX2007002176A (en) | 2008-10-03 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US7186749B2 (en) | Pyrrolo-naphthyl acids and methods for using them | |
US7754747B2 (en) | Oxazolo-naphthyl acids | |
US7605172B2 (en) | Thiazolo-naphthyl acids | |
US7351726B2 (en) | Substituted oxadiazolidinediones | |
US20090054484A1 (en) | Substituted heteroaryl benzofuran acids | |
US7163954B2 (en) | Substituted naphthyl benzothiophene acids | |
MXPA06003246A (en) | Substituted indole acid derivatives and their use as pai-1 inhibitors. | |
MXPA06003251A (en) | 4- (1h-indol-3-yl-methylideneaminoxy-propoxy) -benzioc acid derivatives and related compounds as pai-1 inhibitors for the treatment of impairment of the fibrinolytic system and of thrombisis. | |
MXPA06003254A (en) | Substituted oxadiazolidinediones als pai-1 inhibitors. | |
MXPA06003256A (en) | Biphenyloxy-acids. | |
MXPA06003247A (en) | 4-(phenyl-ethylideneaminoxy-propoxy) -phenyl-acetic acid derivatives and related compounds as pai-1 inhibitors for the treatment of impairment of the fibrinolytic system and of thrombosis. | |
MXPA06003244A (en) | Heterocyclic- or aryloxy, -thio or -amino substituted indoles-2-carboxylic acids or esters as pai-1. | |
MX2007002176A (en) | Thiazolo-naphthyl acids as inhibitors of plasminogen activator inhibitor-1 |