TW509674B - N-(substituted glycyl)-2-cyanopyrrolidine derivatives - Google Patents
N-(substituted glycyl)-2-cyanopyrrolidine derivatives Download PDFInfo
- Publication number
- TW509674B TW509674B TW088121371A TW88121371A TW509674B TW 509674 B TW509674 B TW 509674B TW 088121371 A TW088121371 A TW 088121371A TW 88121371 A TW88121371 A TW 88121371A TW 509674 B TW509674 B TW 509674B
- Authority
- TW
- Taiwan
- Prior art keywords
- amino
- patent application
- scope
- cyano
- adamantyl
- Prior art date
Links
- -1 N-(substituted glycyl)-2-cyanopyrrolidine Chemical class 0.000 title claims description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 70
- 150000003839 salts Chemical class 0.000 claims abstract description 36
- 239000002253 acid Substances 0.000 claims abstract description 27
- 239000003814 drug Substances 0.000 claims abstract description 11
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 9
- 239000001257 hydrogen Substances 0.000 claims abstract description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
- 208000008589 Obesity Diseases 0.000 claims abstract description 5
- 235000020824 obesity Nutrition 0.000 claims abstract description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 3
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 claims abstract 7
- 101000930822 Giardia intestinalis Dipeptidyl-peptidase 4 Proteins 0.000 claims abstract 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 17
- 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 description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 8
- 230000001105 regulatory effect Effects 0.000 claims description 8
- 102000004877 Insulin Human genes 0.000 claims description 7
- 108090001061 Insulin Proteins 0.000 claims description 7
- 150000001412 amines Chemical class 0.000 claims description 7
- 229940125396 insulin Drugs 0.000 claims description 7
- 206010012601 diabetes mellitus Diseases 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 239000004480 active ingredient Substances 0.000 claims description 5
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 5
- 229910001573 adamantine Inorganic materials 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 201000010099 disease Diseases 0.000 claims description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 2
- 150000003254 radicals Chemical class 0.000 claims description 2
- 229940079593 drug Drugs 0.000 claims 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 4
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims 3
- FICQFRCPSFCFBY-UHFFFAOYSA-N 2-[bis(methylsulfanyl)methylidene]propanedinitrile Chemical compound CSC(SC)=C(C#N)C#N FICQFRCPSFCFBY-UHFFFAOYSA-N 0.000 claims 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims 1
- 125000003368 amide group Chemical group 0.000 claims 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims 1
- 239000000825 pharmaceutical preparation Substances 0.000 claims 1
- 229940127557 pharmaceutical product Drugs 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 6
- 229910052736 halogen Inorganic materials 0.000 abstract description 3
- 150000002367 halogens Chemical class 0.000 abstract description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 abstract description 3
- 208000001072 type 2 diabetes mellitus Diseases 0.000 abstract description 3
- 208000001132 Osteoporosis Diseases 0.000 abstract description 2
- 206010003246 arthritis Diseases 0.000 abstract description 2
- 208000002705 Glucose Intolerance Diseases 0.000 abstract 1
- 230000001404 mediated effect Effects 0.000 abstract 1
- 201000009104 prediabetes syndrome Diseases 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 238000007792 addition Methods 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 20
- 238000012360 testing method Methods 0.000 description 14
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 238000000034 method Methods 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- 238000004458 analytical method Methods 0.000 description 7
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 239000008103 glucose Substances 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 4
- ORILYTVJVMAKLC-UHFFFAOYSA-N adamantane Chemical compound C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 125000006309 butyl amino group Chemical group 0.000 description 4
- 230000006362 insulin response pathway Effects 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 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
- GLNDAGDHSLMOKX-UHFFFAOYSA-N coumarin 120 Chemical compound C1=C(N)C=CC2=C1OC(=O)C=C2C GLNDAGDHSLMOKX-UHFFFAOYSA-N 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 229940088597 hormone Drugs 0.000 description 3
- 239000005556 hormone Substances 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 229920001592 potato starch Polymers 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000003127 radioimmunoassay Methods 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- 102100025101 GATA-type zinc finger protein 1 Human genes 0.000 description 2
- 101710198884 GATA-type zinc finger protein 1 Proteins 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 2
- 102400000326 Glucagon-like peptide 2 Human genes 0.000 description 2
- 101800000221 Glucagon-like peptide 2 Proteins 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 108091005804 Peptidases Proteins 0.000 description 2
- 102000035195 Peptidases Human genes 0.000 description 2
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 208000029742 colonic neoplasm Diseases 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- NIHNNTQXNPWCJQ-UHFFFAOYSA-N fluorene Chemical compound C1=CC=C2CC3=CC=CC=C3C2=C1 NIHNNTQXNPWCJQ-UHFFFAOYSA-N 0.000 description 2
- 238000005187 foaming Methods 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- TWSALRJGPBVBQU-PKQQPRCHSA-N glucagon-like peptide 2 Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(O)=O)[C@@H](C)CC)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)CC)C1=CC=CC=C1 TWSALRJGPBVBQU-PKQQPRCHSA-N 0.000 description 2
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 2
- 229910052737 gold Inorganic materials 0.000 description 2
- 239000010931 gold Substances 0.000 description 2
- 230000000968 intestinal effect Effects 0.000 description 2
- 239000012948 isocyanate Substances 0.000 description 2
- 150000002513 isocyanates Chemical class 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose 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
- 239000012044 organic layer Substances 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 235000019833 protease Nutrition 0.000 description 2
- 229910052710 silicon Inorganic materials 0.000 description 2
- 239000010703 silicon Substances 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- QRBHVARIMDDOOV-UHFFFAOYSA-N 1-(isocyanatomethyl)-4-methoxybenzene Chemical compound COC1=CC=C(CN=C=O)C=C1 QRBHVARIMDDOOV-UHFFFAOYSA-N 0.000 description 1
- GEUYACYJMUQXCF-UHFFFAOYSA-N 1-ethyl-2-(2-phenylethenyl)benzene Chemical compound CCC1=CC=CC=C1C=CC1=CC=CC=C1 GEUYACYJMUQXCF-UHFFFAOYSA-N 0.000 description 1
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 1
- BHNQPLPANNDEGL-UHFFFAOYSA-N 2-(4-octylphenoxy)ethanol Chemical compound CCCCCCCCC1=CC=C(OCCO)C=C1 BHNQPLPANNDEGL-UHFFFAOYSA-N 0.000 description 1
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 1
- DYAQXLDQUHCRBU-UHFFFAOYSA-N 2-chloroacetamide;hydrochloride Chemical compound Cl.NC(=O)CCl DYAQXLDQUHCRBU-UHFFFAOYSA-N 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- TYMLOMAKGOJONV-UHFFFAOYSA-N 4-nitroaniline Chemical compound NC1=CC=C([N+]([O-])=O)C=C1 TYMLOMAKGOJONV-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 108010039627 Aprotinin Proteins 0.000 description 1
- 101100175474 Arabidopsis thaliana GLP4 gene Proteins 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 241000195493 Cryptophyta Species 0.000 description 1
- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical group O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 description 1
- 108010016626 Dipeptides Proteins 0.000 description 1
- 101710087078 Dipeptidyl peptidase 1 Proteins 0.000 description 1
- 102100029921 Dipeptidyl peptidase 1 Human genes 0.000 description 1
- 101710087092 Dipeptidyl-peptidase 5 Proteins 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- PNKUSGQVOMIXLU-UHFFFAOYSA-N Formamidine Chemical compound NC=N PNKUSGQVOMIXLU-UHFFFAOYSA-N 0.000 description 1
- DCXXMTOCNZCJGO-UHFFFAOYSA-N Glycerol trioctadecanoate Natural products CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- 229930182821 L-proline Natural products 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- FGBCVJWWRHTXEL-AYXGTZKJSA-N OC12CC3(CC(CC(C1)C3)C2)NC(=C)N2[C@@H](CCC2)C#N Chemical compound OC12CC3(CC(CC(C1)C3)C2)NC(=C)N2[C@@H](CCC2)C#N FGBCVJWWRHTXEL-AYXGTZKJSA-N 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- 206010033799 Paralysis Diseases 0.000 description 1
- 101710167374 Peptidase 1 Proteins 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- 101710168595 Probable dipeptidyl-peptidase 5 Proteins 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 description 1
- WOLHOYHSEKDWQH-UHFFFAOYSA-N amantadine hydrochloride Chemical compound [Cl-].C1C(C2)CC3CC2CC1([NH3+])C3 WOLHOYHSEKDWQH-UHFFFAOYSA-N 0.000 description 1
- 229960001280 amantadine hydrochloride Drugs 0.000 description 1
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 229960004405 aprotinin Drugs 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 229910052797 bismuth Inorganic materials 0.000 description 1
- JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth atom Chemical compound [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000012888 bovine serum Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 1
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 150000004292 cyclic ethers Chemical class 0.000 description 1
- 230000009849 deactivation Effects 0.000 description 1
- 238000011033 desalting Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 125000004915 dibutylamino group Chemical group C(CCC)N(CCCC)* 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- PXEDJBXQKAGXNJ-QTNFYWBSSA-L disodium L-glutamate Chemical compound [Na+].[Na+].[O-]C(=O)[C@@H](N)CCC([O-])=O PXEDJBXQKAGXNJ-QTNFYWBSSA-L 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 229960002442 glucosamine Drugs 0.000 description 1
- 230000005283 ground state Effects 0.000 description 1
- 229960004198 guanidine Drugs 0.000 description 1
- 150000004820 halides Chemical group 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 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 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 150000002431 hydrogen Chemical group 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 238000002649 immunization Methods 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 239000002933 immunoreactive insulin Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- ZPNFWUPYTFPOJU-LPYSRVMUSA-N iniprol Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@H]2CSSC[C@H]3C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC=4C=CC=CC=4)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC2=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]2N(CCC2)C(=O)[C@@H](N)CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N2[C@@H](CCC2)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N3)C(=O)NCC(=O)NCC(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H](C(=O)N1)C(C)C)[C@@H](C)O)[C@@H](C)CC)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 ZPNFWUPYTFPOJU-LPYSRVMUSA-N 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 230000002934 lysing effect Effects 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000010907 mechanical stirring Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000004066 metabolic change Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 235000013923 monosodium glutamate Nutrition 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- HNHVTXYLRVGMHD-UHFFFAOYSA-N n-butyl isocyanate Chemical group CCCCN=C=O HNHVTXYLRVGMHD-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 208000021090 palsy Diseases 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- DGTNSSLYPYDJGL-UHFFFAOYSA-N phenyl isocyanate Chemical compound O=C=NC1=CC=CC=C1 DGTNSSLYPYDJGL-UHFFFAOYSA-N 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 229960002429 proline Drugs 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- ALSCEGDXFJIYES-UHFFFAOYSA-N pyrrolidine-2-carbonitrile Chemical compound N#CC1CCCN1 ALSCEGDXFJIYES-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 230000003938 response to stress Effects 0.000 description 1
- 235000021003 saturated fats Nutrition 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229940073490 sodium glutamate Drugs 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 229910052712 strontium Inorganic materials 0.000 description 1
- CIOAGBVUUVVLOB-UHFFFAOYSA-N strontium atom Chemical compound [Sr] CIOAGBVUUVVLOB-UHFFFAOYSA-N 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 125000004953 trihalomethyl group Chemical group 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Diabetes (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Endocrinology (AREA)
- Child & Adolescent Psychology (AREA)
- Emergency Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrrole Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Plural Heterocyclic Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
509674 五、發明說明（1) — 本發明係提供對於治療由Dpp_IV調節之症狀有效之 二肽-肽酶-IV (DPP-IV)抑制劑。最近，發現DPP〜Iv 、 胰島血糠激素肽酶一 1 (GLP4)去活性之原因。由於盯^員 為胰臟胰島素分泌之主要促激素，且對葡萄糖分布具 接有益作用’ DPP- I v抑制作用似乎表示對於治療如與 島素相關之糖尿病（NIDDM)症狀有效之方法。 本發明係關於呈游離態或酸加成鹽態之下式I之 N —(經取代之甘氨基）2_氰基喵嘻烧： 之
其中 R為經取代之金剛烷基；及 η為〇至3。 式I化合物可以呈游離基態或酸加成鹽態存在。 :藥上可接受(例如，無毒性’生理上可接受)之鹽好雖气 ς他鹽亦可用於例如使本發明之化合物分離或純化。雖^ 較佳之酸加成鹽為鹽酸鹽，但亦可使用甲烷磺酸、炉；、 &酸、檸檬酸、乳酸及醋酸之鹽。 本發明之化合物可以以光學活性異構物或非對映異 =形式存在’且可以以一般之技術分離及回收，如層析 下列為用於敘述本發明之各名詞之定義。此等名詞琴
509674 五、發明說明（2) ^ 或較大群之部份均以該定義用於筇日士 中有其他限制。 於-明中’除非在特定實例 “烷基”一詞係指具有i至1 〇個碳原子， 原子，且最好1至5個碳原子之直 車乂好1至7個板 *〜人说* 7盆 直鍵或分支烴基。列舉之炫 基、異丁基、戊基、己基等。 正丁基、苐三丁 “碳醯基”係指烷基-c ( 0 ) -。 “經取代之金剛烷基，，係指以一 ^ Ά m? $ NR R r甘1 η 或夕個（例如二個）選自 烧基、厲或-脚3 (其中彼此獨 (h-cv烷醯基）、胺基甲醯基' ,ΓΛ md ^认现泰n雄 ☆幺锶敗获i 土， 次—C0 — NR4R5 (其中1及1獨 Α Θ P 基，且其中1及1之一 為鼠，或K4及K5 趣代表C9_C7#p：mi、、 /v ㈣基，即卜或卜金剛^7伸坑基））之取代基取代之金 “芳基，’ -詞較好代表苯基。經取代之苯基較好為以二 ί多ΓΛ如Λ 自例如烷基、烷氧基、齒素及三氟甲 基之取代基取代之笨基。 “烷氧基” 一詞係指烷基。 ::函素” f “齒，，-詞係指氟、氯、溴及姨。 伸烷基一詞係指2至7個碳原子，較好3至6個碳原 子’且最好5個碳原子之直鏈橋。 本發明較佳類化合物為式ί化合物，其令金剛烷基上之 取代基係鍵結在橋接頭或與橋接頭相鄰之亞▼基上。式j 化合物令之甘氨醯基氰基吡咯烷部分與橋接頭鍵結， 則金剛烷基上之R’取代基較好為3—羥基。式丨化合物中之 第6頁
' ， u
p Λ中ri ’代表羥基、Cl_C?-院氧基、H院酸氧基、或 RAN-CO-O-，其中R4及Rs獨立為Ci_C7_烷基或未經取代或上 ί 茉烧烷氧基、鹵素及三氟甲基取代基耳 U ^ R4另可為氫；认及1—起代表C3-Ce伸 土’ R代表氫，或R，及R丨，分別代表CrC7烷基。 美)本裁發臭明：甲合其物可藉由例如包括使反應性(2~氰基吡咯烷 土）叛土亞甲基化合物與適當之經取代胺偶合之方法製
:合i特別的是’對製備式1化合物而言，其包括使式II 〇
II
γ II 、CN 其中Υ為反應性基（鉍& & 之化
合物反應： 較好為鹵素如溴、氯或碘）與式IU
III
NH“CH2)n 〜R 509674 五、發明說明（4) 其中R定義如上，且回收呈游離基態或酸加成鹽態之式I化 合物。 本發明方法可以以一般方式進行。例如，式I I化合物與 1至3當量，較好3當量之式I I I 一級胺反應。該反應一般係 在惰性有機溶劑（如二氣甲烷、或環狀醚，如四氫呋喃）存 在下進行。溫度較好為約0 °C至約3 5 °C，且較好在約0 °C至 約2 5 °C之間。 本發明化合物可以自反應混合物分離，且以習知方式 (如層析）純化。 起始物亦可以習知方式製備。式I I化合物可藉由下列二 步驟反應之反應圖製備·· 步驟1 步驟2 Ο II ·、、、'、 \ π Υ
II Ο NH, H-N^ γ丨丨
IV 步驟1包含式IV之唯哈烧與略莫爾過量之鹵乙酿鹵化物 (如溴乙醯溴或氯乙醯氯）及鹼（如碳酸鉀或三乙胺）反應。 該反應一般係在惰性有機溶劑（如四氫咲喃）或氯化脂族烴 (如二氯甲烷）存在下，在約0°c至約25 °C之温度下，較好 在約0 °C至約1 5 °C之溫度下進行。 步驟2關於步驟1中製備之式V化合物以1至2當量之三氟 乙酸酐（TF A A )脫水。脫水較好在惰性有機溶劑（如四氫呋
第8頁 509674 五、發明說明（5) 喃）或氯化之脂族烴（如二氯甲烷）存在下，在約〇 °C至約2 5 °C之溫度下，較好在約0 °C至約1 5 °C之溫度下進行。 製法在此處無特別敘述時，則作為起始物質之化合物為 已知或可由已知化合物，以已知方式或類似已知方法，或 類似實施例中敘述之方法製備。 例如，式I I I之一級胺化合物為已知，且可藉由文獻（例 如，Khim· -Farm.Zh.( 1 9 8 6 )， 20(7)， 810- 15)中提出之程 序製備。 可以呈游離態或其鹽態（若存有形 化合物可轉換成酸加成鹽，尤其是 鹽。此等係以例如無機酸（如礦物 氫氯酸），或以有機羧酸形成。較 〇 鹽形式之化合物間密切之關係觀 何種化合物，其亦包含相對應之 提供之鹽。 亦可呈其水和物態，或包含其結晶 〇 以抑制D P P - I V之醫藥組合物，包括 稀釋劑，及治療上有效量之式I化 之酸加成鹽。 提供抑制DPP-IV之方法，包括對需 療有效量之式I化合物或其醫藥上 後，本發明化合物 之基）而製得。 有鹼性基之本發明 上可接受之酸加成 例如硫酸、鱗酸或 與氫氯酸形成之鹽 游離基化合物與其 無論說明書中表示 或在該環境下可能 化合物（包含其鹽） 中所用之其他溶劑 發明亦包含例如用 上可接受之載劑或 或其醫藥上可接受 具體例中，本發明 療之哺乳類投與治 最 成鹽 具 醫藥 酸， 好為 由 之， 鹽， 該 作用 本 醫藥 合物 另一 此治
O:\6i\61273.ptd 第9頁 509674 五、發明說明（6) 可接受之酸加成鹽。 又另一具體例中，本發明提供一種治療由Dpp_丨v抑制 用調節之病症之方法，包括對需此治療之哺乳類投與汐2 有效量之上式I化合物或其醫藥上可接受之酸加成鹽。/σ、 本發明亦關於本發明化合物或其醫藥上可接受之鹽用γ 製造例如預防或治療與高量DPP—丨V有關之疾病或症狀之3 物之用途。 “ 如上所示，所有式I化合物及其對應之醫藥上可接受之 酸加成鹽可用以抑制DPP ― I V。式I化合物及其對應之醫藥 上可接受之酸加成鹽抑制DPP—ίν之能力可使用Caco —2 DPP -1 V分析（其係由人類結腸癌細胞萃取物測量試驗化合 物抑制DPP- I V之能力）測量。人類結腸癌細胞Caco - 2係得 自美國菌種收集中心（ATCC HTB 37)。細胞分化誘使 DPP-IV表現如述於 Reisher 等人在proc. Natl. Acad·
Sci·，第90卷，第5757 - 5761頁（ 1 9 9 3 )標題“腸細胞系 Caco-2之增加表現”般完成。細胞萃取物之製備係使細胞 溶解在 10mM Tris HC1、0. 15M NaCl、〇· 〇4 t. i· u·抑肽 酶、〇· 5% nonidet-P40，pH 8· 0，係在 4°C 下於 35, 00 0 g 離心3 0分鐘而移除細胞碎片。此分析細籍由將2 0微克溶解 之Caco - 2蛋白質（以分析緩衝液（25 mM Tris HC1 pH 7.4, 140 mM NaCl， 10 mM KC1，1%牛血清蛋白）稀釋至125微升 之終體積）添加至微滴定盤洞中。在室溫培育60分鐘後’ 反應藉由添加25微升之1 mM基質（H -丙氨酸—脯氨酸-PNA; ρΝΑ為對-硝基苯胺）起始。反應在室溫下進行1〇分鐘，隨
第10頁 509674 五、發明說明（7) 後，添加1 9微升體積之2 5 %冰醋酸終止反應。試驗化合物 一般係添加3 0微升，且分析緩衝體積降低至9 5微升。^離 對-硝基苯胺之標準曲線係使用0 -5 0 0 // Μ含游離pNA之分；I：斤 缓衝液溶液產生。所產生之曲線為直線，且作為基質消耗 插入（催化活性，n m ο 1 e基材斷裂/分鐘）。終點係藉由在分 子裝置U V M a X微滴定盤讀取機中，於4 0 5 n m下測量吸收度 而測定。 作為DPP- IV抑制劑之試驗化合物效力（以I k表示）係使 用4 -參數對數函數，由8 -點劑量反應曲線計算。 ” 得到下列I C5Q : 化合物 Caco_2 DPP-IV(nM) — 實例1 3.5±1.5 — 實例4 8
式I化合物及其對應醫藥上可接受之酸加成鹽抑制 DPP-I V之能力亦可藉由測量試驗化合物對人類及老鼠血漿 中之DPP-IV之作用（使用Kubota等人在臨床實驗免疫學第$ 89卷，第1 9 2 - 1 9 7頁（ 1 9 9 2 )中標題“二肽醯肽酶iv於體内 之相關免疫反應”）證明。簡言之，係將5微升之血漿添加 於96-洞平底微滴定盤（i?alcon)中，接著添加5微升之80 mM 含MgCl2 之培育緩衝液（25 mMHEPES，140 mM NaCl， 1 % RIA級BSA，pH 7.8)。在室溫培育60分鐘後，反應藉由 添加10微升之0.1 mM基質（H-丙氨酸-脯氨酸-AMC ;AMC為 7-胺基-4-甲基香豆精）起始。盤以鋁箔覆蓋（或保持在暗 處）及在室溫培育20分鐘。反應20分鐘後，使用Cyt〇Flu〇r
O:\61\61273.ptd 第11頁 509674 五、發明說明（8) 2~3 5 0勞光計測量螢光（激發38〇㈣發射46〇 nm;敏感度設 定4) °試驗化合物一般係添加2微升，且分析緩衝體積降 低至13微升。游離amc之螢光濃度曲線係使用0 —5〇 # ^含 AMC之%分析緩衝液溶液產生。所產生之曲線為直線，且作 為基貝消耗插入（催化活性，nm〇丨e基材斷裂/分鐘）。如前 述分析’作為DPP- I V抑制劑之試驗化合物效力（以丨Cs〇表 不）係使用4-參數對數函數，由8 _點劑量反應曲線計算。 得到下列I C5(): 化合物 人類血漿DPP-IV(nM) 老鼠血漿DPP-IV(nM) 實例1 2.7±0.1 2.3±0.1 實例8 6 12 〜π π w ur r - v心聪刀蜆之，式1化合物及其對應之醫 藥可接受性酸加成鹽可用以治療受DPP—H抑制作用所調節 之病況。基於上述及文獻中之發現，預期本發明化合物可 用以治療如非胰島素相關性糖尿病、關節炎、過胖症、異 體移植及降鈣素-骨骼疏鬆症之病況。此外，基於類胰島、 血糖激素肽酶（如GLP-1及GLP-2)及其與DPP-IV抑制作用之 相關性，預期本發明化合物可用於例如產生鎮靜或解營效 果之目的，或減弱術後代謝改變及對壓力之激素反應，或 降低心肌梗塞後之死亡率及發病率，或用以治療與上述可 受GLP-1及GLP-2量調節之效果有關之病況。 詳&之’式I化合物及其對應醫藥可接受性酸加成鹽可 改良對口氟^葡萄糖挑戰之早期胰島素反應且因此可用以治 療非胰島素相關之糖尿病。式I化合物及其對應醫藥可接
第12頁 509674
五、發明說明（9) 受性酸加成鹽可改良對口氟葡萄糖挑戰之早期胰島素反應 之能力可由下列方法於胰島素抗性老鼠中測量：
已餵與高脂肪食物（飽和脂肪=57%卡）2_3週之雄性史帕 奇-道利老鼠在測試當天禁食約2小時，分成8_1〇組，及以 i〇微莫耳/公斤之劑量口服投與試驗化合物（於CMC中）。試 驗化合物直接投入測試動物胃中後3〇分鐘口服投與】克/公 斤之葡萄糖球。在各種時間點自慢性頸靜脈導管獲得之金 液樣品分析血漿葡萄糖及免疫反應性胰島素（Ri)濃度及血 聚DPP-IV活性。使用得自Linc〇研究中心（聖路易，m〇)之 特定抗老鼠胰^素抗體藉雙抗體放射免疫分析（ia)方法分 析血漿胰島素篁。RIA之偵測下限為〇. 5以u/毫升分析内 及分析外偏，小於5%。數據以對對照組動物平均增加％表 不。口服投藥後，各試驗化合物擴大早期胰島素反應，其 可改善胰島素抗性試驗動物之葡萄糖耐受性。得下列結 化合物 之胰島素反應增加 實例1 -- 欲用以涪療受DPP-IV抑制作用調節之病況之式！化合物 ^其對應醫藥可接文性酸加成鹽之精確劑量視數種因素而 疋，包含欲治療宿主、病況性質及嚴重性、投藥模式及使 =之特定化合物。然而通常當式丨化合物或其對應醫藥可 接雙性酸加成鹽經腸投藥，如以日劑量〇〇〇2〜5，較好 0二0 2〜2 · 5氅克/公斤體重或對更大動物以日劑量〇.丨_ 2 5 〇， 車^好1 - 1 0 0耄克口服或非經腸道如靜脈内，較好口服投藥 寸可有效治療文1 ^抑制作用調節之病況。典型之口
509674 五、發明說明（ίο) 服劑量單元為0 . 0 1 - 0 . 7 5毫克/公斤，每日1至3次。一般， 最初投與較小劑量且逐漸增加劑量直至對宿主治療達到最 適劑量。劑量上限為可強制副作用且可由欲治療之宿主嘗 試而決定。 式I化合物及其對應醫藥可接受性酸加成鹽可與一或多 種醫藥可接受性載劑及視情況之一或多種習知醫藥佐劑組 合及經腸以錠劑、膠囊、藥囊等口服投藥，或以無菌可注 射溶液或懸浮液非經腸道如靜脈内投藥。經腸及非經腸道 投藥可以習知方式製備。 式I化合物及其對應醫藥可接受性酸加成鹽可調配成經 腸及非經腸道之醫藥組合物，其含有有效治療受DPP-IV抑 制作用調節之病況之量，此組合物成單位劑量劑型且此組 合物包括醫藥可接受載劑。 式I化合物（包含其附屬範圍及其實例）可以‘對映異構物 純態（如ee > 9 8%，較好> 99%)或與1對映異構物一起投 藥，如消旋態。上述劑量範圍係依據式I化合物為準（排除 R對映異構物量）。 下列實例顯示本發明包含之代表性化合物及其合成。然 而需清楚了解其僅用以說明目的。
吡咯烷，1-[( 3-羥基-1-金剛烷基）胺基]乙醯基-2-氰 基，（S)
第14頁 509674 五、發明說明（ll) L·__L^·麼基金剛烧-3 -醇： 可使用見於 Khim - Farm· Zh· ( 1 9 8 6 )，20(7)，810 - 15 之 略修飾合成法。 含96%濃硫酸（2 1 0毫升，3, 943毫莫耳）及65%硝酸（2 1 · 〇 宅升’ 217.0毫莫耳）之快速攪拌透明且無色之冰水冷卻之 混合物中’以30分鐘内少量添加2ΐ·〇克（112.0毫莫耳）1-金剛烧胺HC 1 ( 9 9 % )。添加金剛烷胺鹽酸鹽時，略產生發 泡且反應略放熱。起泡後，黃色溶液在冰水溫度下攪拌約 2小時接著在室溫攪拌3 0小時。此透明但黃色反應接著倒 入約1 0 0克冰中且所得溶液為透明之綠藍色。 溶液置於冰水浴上並擾拌30分鐘。接著於45分鐘内少量 添加約550克89%純度之](011(8.74莫耳）。添加期間，反應 放熱達80°C併產生多量棕色Ν〇2氣體。添加結束時，反應 含白色固體且稠（產物及鹽兩者）。所得白色糊漿倒至磁漏 斗/砍藻土墊上且以1· 2升CHJl2洗滌。自水層萃取CH2Cl2層 且以NaJO4脫水。接著過濾溶液並濃縮獲得丨—胺基金剛烷 一 3-醇白色固體。 L 1 _氮乙醯基-2-氰基吡咯饺
於含20.0克（180.0¾莫耳）氯乙醯氣及97克（〇?〇亳莫 耳）碳酸鉀之150毫升四氫呋喃機械攪拌溶液中以45分鐘滴 加含L-脯醯胺20.0克（180.0毫莫耳）之5〇〇毫升四氫呋喃溶 液。反應在室溫再機械授拌2小時。過濾、反應移除卸鹽且 濾液以硫酸鈉脫水。過濾移除硫酸鈉且於無色濾液中一次 添加三氣乙酸針（25.0宅升’ο.! 8〇毫莫耳）。接著反應在
509674 五、發明說明（12) 室溫機械攪拌1小時且所得透明黃色/橘色溶液經旋轉蒸發 器濃縮。添加乙酸乙酯於濃油中並經旋轉蒸發器再濃縮而 移除過量三氟乙酸酐。此移除操作進行3次。 所得油分配於乙酸乙酯及水之間。接著產物萃取至乙酸 乙酯且水層再以乙酸乙酯洗滌2次。接著合併之有機層依 序以水及食鹽水洗满：，以硫酸錢脫水，過濾並濃縮獲得1 -氣乙醯基-2 -氰基吡咯烷黃色固體。 C. 吡咯烷，1-[ (3-羥基-1 -金剛烷基）胺基1乙醯基-2-氰 基，（S) 於含標題A化合物（卜胺基金剛烷-3-醇）（5.80克，34.7 毫莫耳）之CH2C12 (68.0毫升）均質溶液中添加9.6克（69亳 莫耳）K 2 C 0 3。此均質混合物在冰水浴中冷卻且以3 0分鐘内 滴加溶於25. 0亳升（：112(：12之3. 0克（17亳莫耳）標題B化合物 (-氯乙醯基-2-氰基吡咯烷）。所得混合物在0 °C攪拌2小時 及在室溫攪拌6天。接著濃縮反應獲得黃色糊漿物質，其 於矽膠上利用SIMS/Biot age快速層析系統及以7°/g曱醇於二 氣甲烷之溶液作為溶離液純化，獲得游離鹼態之標題化合 物之白色結晶固體（溶點1 3 8 -1 40 °C，i3CNMR ( ppm )= 119.59) «
第16頁 509674 五、發明說明（13) 實例2至1 2 類似於實例1般至備下列化合物（尤其是步驟C):
509674 五、發明說明（14) 4 \ § 口比洛院，H[(3·甲氧基-1-金剛烷基)胺基] 乙醯基I-2-氰基1-, (S)- 92-94 (HCI) 5 對掌性 认A。 点 吡咯烷，H[[3-[[(第三丁胺基)羰基]氧基] -1-金剛烷基]胺基]乙酿ϊ]-2·ϋ·，（S)- 210-212 (HCI) 6 212-214 ϋ。 對掌性 h i ^ N (HCI) ’众Jig . ^ , ·* * 吡咯烷，l-[【[3-[[[(4-甲氧苯基)胺基]羰基]氧基I -1-金剛烷基]胺基]乙酸基]冬氰基，（s> η 1H1 第18頁 509674 五、發明說明（15)
im 第19頁 509674 五、發明說明（16)
(HC1 )鹽酸鹽 第20頁 509674 五、發明說明（17) ^ 終產物之所有鹽酸鹽籍由使HC 1氣體通過游離^、 呋喃之0 · 1溶液直至溶液明顯為酸性接著移除溶:於四氫 發器/泵）而製備。 _ ( %轉蒸 胺基金剛烷起始物為文獻中已知者或可如下般製 3. 5 -二甲基-卜金之製造述於醫藥各康又_備· -— —* 子期刊2 5 · 1 ； 1982 ； 51-56 ° ’ 3 -乙基-1-金剛烧躁^之製造述於醫藥化學期刊2 5 · 1982 ； 51-56 ° ? ? 3-甲氣基-：ί-金岡iAAf如下製備： 於含氫化奸（0.680克’ 5.95毫莫耳）之15·〇臺4 卜 毛开四氫0# 喃攪拌冰水冷卻懸浮液中，於3 0分鐘内滴加含丨〜胺美 χ 烷-3-醇（1· 00克，5· 95毫莫耳）及15· 0毫升四土金剛 風吹喃之混 合物。所得混合物再攪拌3 0分鐘接著於1分鐘内滴加蛾 烷（0· 3 7 0毫升，5· 95毫莫耳）。所得濁狀白色反應^室溫 攪拌1 8小時。接著混合物以50毫升二氣甲烷稀釋及過遽1以 移除無機雜質。濾異接著濃縮並在矽膠上利用 SIMS/Biotage裝置及含19%甲醇及1%氫氧化銨之二氣甲烧 作為溶離液純化，獲得3 -甲氧基-1 -金剛烷胺濁油。 3 -「f (第三丁吃羞丄幾基]氧1 1 -卜胺基金之合成·· 於含1-胺基金剛燒-3-醇（5.00克，30.0毫莫耳）及碳酸 鉀（6· 20克，45毫莫耳）之1 50毫升四氫呋喃混合物中，以 10分鐘期間滴加氯甲酸〒g旨（4.70克，33.0毫莫耳）。接著 混合物在室溫攪拌2小時及分配在乙酸乙酯及水之間。接 著產物萃取至乙酸乙I旨終及水層以乙酸乙_ (100¾升）洗2
第21頁 509674 五、發明説明、（is) 次。合併之有機層依序以100毫升2 N氫氧化鈉、水及食鹽 水洗滌’以琉酸鈉脫水、過濾及濃縮（旋轉蒸發器/泵）， 獲得卜胺甲醯基金剛烷—3 —醇之白色固體，產率85 %。 於含1 - T基胺甲醯基金剛烷一 3 -醇（ι·〇〇克，3.32亳莫 耳）及異氰酸第三丁酯（380微升，3·32毫莫耳）之30毫升二 氯甲炫透明溶液中以針筒添加三甲矽烷氯（2 〇 · 〇微升， 〇 · 1 7毫莫耳）。接著反應在室溫攪拌丨8小時，濃縮（旋轉蒸 發器）及並在矽膠上利用SIMS/Biot age裝置及含20%乙酸= 酉旨之己烧=為溶離液純化，獲得3 —[[(第三丁胺基）羰基] 氧基]- 1-卞基胺甲醯基金剛烷之白色固體，定量產率。 於各3 [[(第三丁胺基）羰基]氧基]_丨-苄基胺甲醯基金 剛烧（古1· 50克’ 3· 75毫莫耳）及10%鈀/碳（400毫克）之乙醇 (150宅升）之1升帕耳氫化瓶中加入氫氣（50psi )。接著蜀 ίϊίίί:搖晃24小時。嫌由砍藻土過濾反應二 S All美1 (旋轉蒸發器/泵），獲得3-[[(第三丁胺基） 4-[[[(甲4盆金剛烧透明油，"％產率。 合 暴]氧暴1- 之 金剛烷之程床同3-[[(第三丁胺基）叛基]氧基]-卜胺基 代異氰酸第三;^第二步驟中等量異氰酸4_甲氧基苄輯替 甲烷及反應使用丨，2—二氯乙烷作為溶劑替代二氣 物。 c授拌1 8小時。獲得油狀之最終胺中間 本1 一胺基金H之合成程序基 二丁胺基）羰基]氧基]-1-胺基金剛烷之程
第22頁 509674 五、發明說明（19) 序’但第二步驟中等量異氰酸苯酯替代異氰酸第三丁酿， 使用1，2-二氣乙烧作為溶劑替代二氣甲烷及反應在5〇艺攪 拌1 8小時。獲得透明油狀之最終胺中間物。
第23頁 509674 五、發明說明（20) 調配例： 如下製備各含5 0毫克活性成分例如（S) 1 - [(3 -羥基-1 -金 剛烷基）胺基]乙醯基-2 -氰基吡咯烷之錠劑： 組成（對1 0，0 0 0顆錠劑） 活性成分 500·0克 乳糖 500·0克 馬鈴薯澱粉 352·0克 明膠 8· 0克 滑石 60· 0 克 硬脂酸鎮 10· 0 克 氧化矽（高度分散） 20.0 克 乙醇 適量 活性成分與乳糖及2 9 2克馬鈴薯澱粉混合及混合物使用
明膠之醇溶液濕潤及藉過篩而造粒。乾燥後，混合剩餘之 馬鈴薯澱粉、滑石、硬脂酸鎂及高度分散之氧化矽，且混 合物經壓縮獲得各重14 5. 0毫克及活性成分含量為5 0. 0毫 克之錠劑，其若需要可壓碎提供調整更小劑量。
第24頁 509674
O:\61\61273.ptc 第25頁 2002. 03. 07. 025
Claims (1)
- 509674 六、申請專利範圍 1 · 一種下式（I A )或（I B )之化合物 R，O c 丨f (I A)〇 ， (IB) 其中R’代表羥基、q - C7-烧氧基、Ci - C8 -烧驢氧基、 R5M-C0-0-或Ci-C、-烷基，其中R4為氫或Cl-C7-烷基及R5為 烧基、環03-C广烧基或未經取代或以一個匕-^-烧氧 基取代之苯基；且其中Rn代表氫；其係呈游離基態或醫藥 上可接受之酸加成鹽態。 2.根據申請專利範圍第1項之化合物，其係選自下列組 群之化合物： (S) 1-[[(3, 5-二甲基-1-金剛烷基）胺基]乙醯基]-2- 氰基-D比洛烧； (S) 1-[[(3-乙基-1-金剛烧基）胺基]乙驢基]-2- 氰基-吡咯烷； (S) 1-[[(3-甲氧基-卜金剛烷基）胺基]乙醯基]-2-氰 基-吡咯烷； (S) 1-[[[3-[[(第三丁胺基）I炭基]氧基]- 1-金剛烧 基]胺基]乙酿基]-2 -氰基-卩比洛烧； (s) 1- [[[3-[[[(4-曱氧笨基）胺基]羰基]氧基]-卜金O:\61\61273.ptc 第1頁 2002. 03. 07. 026 509674 案號 88121371 月 曰 修正 六、申請專利範圍 剛烷基]胺基]乙醯基]-2-氰基-吡咯烷； (S) 1-[[[3-[[(苯基胺基）羰基]氧基]-1-金剛烧基] 胺基]乙酿基]-2-氰基-¾0各烧； (S) 1-[[(5-羥基-2-金剛烷基）胺基]乙醯基]-2 -氰基 -吡咯烷； (S) 1-[[(3-乙醯氧基-1-金剛烷基）胺基]乙醯基]-2- 氰基-D比洛烧； (S) 1-[[[3-[[[(二異丙基）胺基]羧基]氧基]-1-金剛 烷基]胺基]乙醯基]-2 -氰基-吡咯烷； (S) 1-[[[3-[[[(環己基）胺基]幾基]氧基]-1 -金剛烧 基]胺基]乙酿基]- 2-氰基-吼17各烧；及 (S) 1-[[(3-乙氧基-1-金剛烷基）胺基]乙醯基]-2-氰 基-吼咯烧； 或其醫藥可接受性鹽。 3 .根據申請專利範圍第1項之化合物，其係（S) 1 - [( 3 - 羥基-1-金剛烷基）胺基]乙醯基]-2 -氰基-吡嘻烷或其醫藥 可接受性鹽。 ，其係用於製造供 藥可接受性酸加成 ，其係用於製造治 況之醫藥品，或其 ，其係用於製造治 4. 根據申請專利範圍第1項之化合物 抑制二肽基肽酶-I V之醫藥品，或其醫 鹽。 5. 根據申請專利範圍第4項之化合物 療受二肽基肽酶- I V抑制作用調節之病 醫藥上可接受性酸加成鹽。 6. 根據申請專利範圍第5項之化合物O:\61\61273.ptc 第2頁 2002. 03. 07. 027 509674 案號 88121371 曰 修正 六、申請專利範圍 療非胰島素相關性糖尿病之醫藥品。 · 7 ·根據申請專利範圍第5項之化合物，其係用於製造治 療過胖症之醫藥品。 8.根據申請專利範圍第3項之化合物，其係用於治療非 胰島素相關性糖尿病。 9 .根據申請專利範圍第3項之化合物，其係用於治療過 胖症。 1 0 . —種用於抑制二肽基肽酶-I V之醫藥組合物，其包含 根據申請專利範圍第1項之化合物作為主要活性成份，其 係呈游離態或醫藥可接受性酸加成鹽態，及一種醫藥可接受性載劑或稀釋劑。 1 1 .根據申請專利範圍第1 0項之醫藥組合物，其係用於 治療受二肽基肽酶-I V抑制作用調節之病況。 1 2.根據申請專利範圍第11項之醫藥組合物，其係用於 治療非胰島素相關性糖尿病。 1 3.根據申請專利範圍第11項之醫藥組合物，其係用於 治療過胖症。O:\61\61273.ptc 第3頁 2002. 03. 08. 028
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US20906898A | 1998-12-10 | 1998-12-10 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| TW509674B true TW509674B (en) | 2002-11-11 |
Family
ID=22777194
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TW088121371A TW509674B (en) | 1998-12-10 | 1999-12-07 | N-(substituted glycyl)-2-cyanopyrrolidine derivatives |
Country Status (34)
| Country | Link |
|---|---|
| US (1) | US6166063A (zh) |
| EP (1) | EP1137635B1 (zh) |
| JP (2) | JP3681110B2 (zh) |
| KR (2) | KR100509311B1 (zh) |
| CN (1) | CN1160330C (zh) |
| AR (1) | AR023719A1 (zh) |
| AT (1) | ATE307112T1 (zh) |
| BR (1) | BRPI9915985B8 (zh) |
| CA (1) | CA2350609C (zh) |
| CO (1) | CO5150173A1 (zh) |
| CY (3) | CY1105355T1 (zh) |
| CZ (1) | CZ299151B6 (zh) |
| DE (3) | DE122008000017I1 (zh) |
| DK (1) | DK1137635T3 (zh) |
| ES (1) | ES2251847T3 (zh) |
| FR (1) | FR08C0005I2 (zh) |
| HK (1) | HK1040394B (zh) |
| HU (1) | HU226769B1 (zh) |
| ID (1) | ID28796A (zh) |
| IL (2) | IL143091A0 (zh) |
| LU (2) | LU91409I2 (zh) |
| MY (1) | MY123244A (zh) |
| NL (2) | NL300333I2 (zh) |
| NO (3) | NO318741B1 (zh) |
| NZ (1) | NZ511935A (zh) |
| PE (1) | PE20001317A1 (zh) |
| PL (1) | PL199443B1 (zh) |
| RU (1) | RU2251544C2 (zh) |
| SK (1) | SK286635B6 (zh) |
| TR (1) | TR200101478T2 (zh) |
| TW (1) | TW509674B (zh) |
| UY (1) | UY25843A1 (zh) |
| WO (1) | WO2000034241A1 (zh) |
| ZA (1) | ZA200104581B (zh) |
Families Citing this family (303)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6376549B1 (en) * | 1998-09-17 | 2002-04-23 | Akesis Pharmaceuticals, Inc. | Metforimin-containing compositions for the treatment of diabetes |
| AU6044699A (en) * | 1998-09-17 | 2000-04-03 | Akesis Pharmaceuticals, Inc. | Compositions and methods for treatment of glucose metabolism disorders |
| DE19940130A1 (de) * | 1999-08-24 | 2001-03-01 | Probiodrug Ges Fuer Arzneim | Neue Effektoren der Dipeptidyl Peptidase IV zur topischen Anwendung |
| AU1916401A (en) * | 1999-11-12 | 2001-06-06 | Guilford Pharmaceuticals Inc. | Dipeptidyl peptidase iv inhibitors and methods of making and using dipeptidyl peptidase iv inhibitors |
| US20040152745A1 (en) * | 1999-11-12 | 2004-08-05 | Guilford Pharmaceuticals, Inc. | Dipeptidyl peptidase IV inhibitors and methods of making and using dipeptidyl peptidase IV inhibitors |
| GB9928330D0 (en) * | 1999-11-30 | 2000-01-26 | Ferring Bv | Novel antidiabetic agents |
| NZ519231A (en) * | 1999-12-23 | 2004-05-28 | Novartis Ag | Use of nateglinide as an insulin secretion enhancer for treating impaired glucose metabolism |
| US6380398B2 (en) | 2000-01-04 | 2002-04-30 | Novo Nordisk A/S | Therapeutically active and selective heterocyclic compounds that are inhibitors of the enzyme DPP-IV |
| PT1248604E (pt) * | 2000-01-21 | 2007-01-31 | Novartis Ag | Associações compreendendo inibidor de dipeptidilpeptidase-iv |
| US20080076811A1 (en) * | 2000-01-21 | 2008-03-27 | Bork Balkan | Combinations comprising depeptidypeptidase-iv inhibitors and antidiabetic agents |
| WO2001055105A1 (en) * | 2000-01-24 | 2001-08-02 | Novo Nordisk A/S | N-substituted 2-cyanopyroles and -pyrrolines which are inhibitors of the enzyme dpp-iv |
| US6395767B2 (en) | 2000-03-10 | 2002-05-28 | Bristol-Myers Squibb Company | Cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV and method |
| US6432969B1 (en) | 2000-06-13 | 2002-08-13 | Novartis Ag | N-(substituted glycyl)-2 cyanopyrrolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV |
| AU2001268958B2 (en) | 2000-07-04 | 2006-03-09 | Novo Nordisk A/S | Heterocyclic compounds, which are inhibitors of the enzyme dpp-iv |
| AR033390A1 (es) * | 2000-08-22 | 2003-12-17 | Novartis Ag | Una composicion farmaceutica que comprende un antagonista del receptor at1 y un potenciador de la secrecion de insulina, el uso de dicha composicion para la fabricacion de un medicamento y un kit de partes |
| US20060089389A1 (en) | 2000-08-22 | 2006-04-27 | Malcolm Allison | Combination |
| EP1970072A1 (en) | 2000-09-18 | 2008-09-17 | Sanos Bioscience A/S | Use of GLP-2 peptides for the treatment of hyperparathyroidism |
| US20080249016A1 (en) * | 2000-09-18 | 2008-10-09 | Sanos Bioscience A/S | Use of GLP-2 in a combination treatment for bone-related disorders |
| US7371721B2 (en) * | 2000-09-18 | 2008-05-13 | Sanos Bioscience A/S | Use of GLP-2 and related compounds for the treatment, prevention, diagnosis, and prognosis of bone-related disorders and calcium homeostasis related syndromes |
| US20070135345A1 (en) * | 2000-09-18 | 2007-06-14 | Henriksen Dennis B | Use of GLP-2 for the treatment or prevention, of bone-related disorders |
| ES2312471T3 (es) | 2000-10-06 | 2009-03-01 | Mitsubishi Tanabe Pharma Corporation | Compuestos de anillo de 5 miembros que contienen nitrogeno. |
| TWI243162B (en) * | 2000-11-10 | 2005-11-11 | Taisho Pharmaceutical Co Ltd | Cyanopyrrolidine derivatives |
| UA74023C2 (en) * | 2000-11-10 | 2005-10-17 | Taisho Pharmaceutical Co Ltd | Cyanopyrrolidine derivatives |
| EP1354882A1 (en) * | 2000-12-27 | 2003-10-22 | Kyowa Hakko Kogyo Co., Ltd. | Dipeptidyl peptidase iv inhibitor |
| GB0109146D0 (en) * | 2001-04-11 | 2001-05-30 | Ferring Bv | Treatment of type 2 diabetes |
| US20030060494A1 (en) * | 2001-05-18 | 2003-03-27 | Nobuyuki Yasuda | Pharmaceutical use of N-carbamoylazole derivatives |
| DE60209348T2 (de) | 2001-06-20 | 2006-10-12 | Merck & Co., Inc. | Dipeptidylpeptidase-hemmer zur behandlung von diabetes |
| AU2002344820B2 (en) | 2001-06-20 | 2006-12-14 | Merck & Co., Inc. | Dipeptidyl peptidase inhibitors for the treatment of diabetes |
| US7183290B2 (en) * | 2001-06-27 | 2007-02-27 | Smithkline Beecham Corporation | Fluoropyrrolidines as dipeptidyl peptidase inhibitors |
| AU2002322344C1 (en) * | 2001-06-27 | 2006-02-16 | Smithkline Beecham Corporation | Fluoropyrrolidines as dipeptidyl peptidase inhibitors |
| ATE380175T1 (de) | 2001-06-27 | 2007-12-15 | Smithkline Beecham Corp | Pyrrolidine als dipeptidyl peptidase inhibitoren |
| US6709651B2 (en) * | 2001-07-03 | 2004-03-23 | B.M.R.A. Corporation B.V. | Treatment of substance P-related disorders |
| UA74912C2 (en) * | 2001-07-06 | 2006-02-15 | Merck & Co Inc | Beta-aminotetrahydroimidazo-(1,2-a)-pyrazines and tetratriazolo-(4,3-a)-pyrazines as inhibitors of dipeptylpeptidase for the treatment or prevention of diabetes |
| US6861440B2 (en) | 2001-10-26 | 2005-03-01 | Hoffmann-La Roche Inc. | DPP IV inhibitors |
| JP2005507261A (ja) * | 2001-10-31 | 2005-03-17 | ノバルティス アクチエンゲゼルシャフト | Ｔｃｆ１遺伝子における多型に基づく糖尿病および関連状態の治療方法 |
| US20050101638A1 (en) * | 2002-11-08 | 2005-05-12 | Webb Randy L. | Combination of organic compounds |
| US20030135663A1 (en) * | 2002-01-16 | 2003-07-17 | Sun Microsystems, Inc. | Method, system, and program for including device parameters from a device driver in a configuration file |
| MXPA04007743A (es) | 2002-02-13 | 2004-10-15 | Hoffmann La Roche | Nuevos derivados de piridina y quinolina. |
| BR0307665A (pt) | 2002-02-13 | 2005-01-04 | Hoffmann La Roche | Compostos, processo para a sua manufatura, composições farmacêuticas que compreendem os mesmos, método para o tratamento e/ou profilaxia de enfermidades associadas com dpp iv e utilização dos compostos |
| DE60304911D1 (de) | 2002-02-25 | 2006-06-08 | Eisai Co Ltd | Xanthin-Derivate als DPP-IV-Inhibitoren |
| US7307164B2 (en) * | 2002-03-25 | 2007-12-11 | Merck & Co., Inc. | β-amino heterocyclic dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes |
| PT1513519E (pt) * | 2002-06-03 | 2009-05-06 | Novartis Ag | Uso de cianopirrolidinas substituídas e preparações de combinações que as contêm para tratar hiperlipidemia e doenças associadas |
| US6710040B1 (en) | 2002-06-04 | 2004-03-23 | Pfizer Inc. | Fluorinated cyclic amides as dipeptidyl peptidase IV inhibitors |
| JP2004026678A (ja) * | 2002-06-24 | 2004-01-29 | Microbial Chem Res Found | ２型糖尿病治療剤 |
| WO2004007446A1 (ja) * | 2002-07-10 | 2004-01-22 | Yamanouchi Pharmaceutical Co., Ltd. | 新規なアゼチジン誘導体又はその塩 |
| WO2004007468A1 (en) | 2002-07-15 | 2004-01-22 | Merck & Co., Inc. | Piperidino pyrimidine dipeptidyl peptidase inhibitors for the treatment of diabetes |
| TW200401635A (en) * | 2002-07-23 | 2004-02-01 | Yamanouchi Pharma Co Ltd | 2-Cyano-4-fluoropyrrolidine derivative or salt thereof |
| US7407955B2 (en) | 2002-08-21 | 2008-08-05 | Boehringer Ingelheim Pharma Gmbh & Co., Kg | 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions |
| DK1560811T3 (da) * | 2002-09-19 | 2007-12-10 | Abbott Lab | Farmaceutiske sammensætninger som inhibitorer af dipeptidylpeptidase-IV (DPP-IV) |
| EP1554280B1 (en) | 2002-10-07 | 2007-08-15 | Merck & Co., Inc. | Antidiabetic beta-amino heterocyclic dipeptidyl peptidase inhibitors |
| AU2003298596B2 (en) * | 2002-10-18 | 2008-12-18 | Merck Sharp & Dohme Corp. | Beta-amino heterocyclic dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes |
| MXPA05004890A (es) | 2002-11-07 | 2005-07-22 | Merck & Co Inc | Derivados de fenilalanina como inhibidores de dipeptidilpeptidasa para el tratamiento o prevencion de diabetes. |
| CA2508487A1 (en) * | 2002-12-04 | 2004-06-17 | Merck & Co., Inc. | Phenylalanine derivatives as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes |
| EP1583534A4 (en) * | 2002-12-20 | 2007-08-29 | Merck & Co Inc | 3-AMINO-4-PHENYLBUTANIC ACID DERIVATIVES AS DIPEPTIDYL-PEPTIDASE INHIBITORS FOR THE TREATMENT OR PREVENTION OF DIABETES |
| CN102558155A (zh) | 2003-01-14 | 2012-07-11 | 阿伦纳药品公司 | 作为代谢调节剂的芳基和杂芳基衍生物及其所涉及的疾病如糖尿病和高血糖症的预防和治疗 |
| JP4564952B2 (ja) * | 2003-01-17 | 2010-10-20 | メルク・シャープ・エンド・ドーム・コーポレイション | 糖尿病の治療および予防のためのジペプチジルペプチダーゼ阻害薬としての３−アミノ−４−フェニルブタン酸誘導体 |
| CA2513684A1 (en) | 2003-01-31 | 2004-08-19 | Merck & Co., Inc. | 3-amino-4-phenylbutanoic acid derivatives as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes |
| CN1894234A (zh) | 2003-03-25 | 2007-01-10 | 武田药品工业株式会社 | 二肽基肽酶抑制剂 |
| GB0308854D0 (en) * | 2003-04-16 | 2003-05-21 | Novartis Ag | Organic compounds |
| PE20050021A1 (es) * | 2003-04-16 | 2005-03-15 | Novartis Ag | Procedimiento para la preparacion de 2-cianopirrolidina n-sustituida |
| JP2007511467A (ja) | 2003-05-14 | 2007-05-10 | タケダ サン ディエゴ インコーポレイテッド | ジペプチジルペプチダーゼインヒビター |
| ATE447574T1 (de) * | 2003-05-14 | 2009-11-15 | Merck & Co Inc | 3-amino-4-phenylbutansäurederivate als dipeptidylpeptidase-hemmer zur behandlung oder vorbeugung von diabetes |
| AU2004247068A1 (en) * | 2003-06-06 | 2004-12-23 | Merck & Co., Inc. | Fused indoles as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes |
| US7456204B2 (en) * | 2003-06-17 | 2008-11-25 | Merck & Co., Inc. | Cyclohexylglycine derivatives as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes |
| PT1638970E (pt) | 2003-06-20 | 2010-12-13 | Hoffmann La Roche | Derivados de pirid(2,1-a)isoquinolina como inibidores de dpp-iv |
| CN101090901B (zh) | 2003-06-20 | 2010-12-15 | 霍夫曼-拉罗奇有限公司 | 作为dpp-iv抑制剂的六氢吡啶并异喹啉类 |
| CN1882551A (zh) | 2003-07-31 | 2006-12-20 | 麦克公司 | 用作用于治疗或预防糖尿病的二肽基肽酶－iv酶抑制剂的六氢二氮杂吖庚因酮 |
| US6995183B2 (en) | 2003-08-01 | 2006-02-07 | Bristol Myers Squibb Company | Adamantylglycine-based inhibitors of dipeptidyl peptidase IV and methods |
| US7169926B1 (en) | 2003-08-13 | 2007-01-30 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
| US7678909B1 (en) | 2003-08-13 | 2010-03-16 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
| KR20060041309A (ko) | 2003-08-13 | 2006-05-11 | 다케다 야쿠힌 고교 가부시키가이샤 | ４-피리미돈 유도체 및 펩티딜 펩티다제 저해제로서의 그의용도 |
| JP2007505121A (ja) | 2003-09-08 | 2007-03-08 | 武田薬品工業株式会社 | ジペプチジルぺプチダーゼ阻害剤 |
| AR046330A1 (es) * | 2003-09-09 | 2005-12-07 | Japan Tobacco Inc | Inhibidor de dipeptidilpeptidasa iv |
| WO2005033099A2 (en) * | 2003-10-03 | 2005-04-14 | Glenmark Pharmaceuticals Ltd. | Novel dipeptidyl peptidase iv inhibitors; processes for their preparation and compositions thereof |
| EP1680120A2 (en) * | 2003-11-03 | 2006-07-19 | Probiodrug AG | Combinations useful for the treatment of neuronal disorders |
| WO2005044195A2 (en) * | 2003-11-04 | 2005-05-19 | Merck & Co., Inc. | Fused phenylalanine derivatives as dipeptidyl peptidase-iv inhibitors for the treatment or prevention of diabetes |
| US7576121B2 (en) * | 2003-11-12 | 2009-08-18 | Phenomix Corporation | Pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-IV |
| US7317109B2 (en) | 2003-11-12 | 2008-01-08 | Phenomix Corporation | Pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-IV |
| SI1689757T1 (sl) | 2003-11-12 | 2015-01-30 | Sino-Med International Alliance, Inc. | Heterociklične spojine boronske kisline |
| US7767828B2 (en) * | 2003-11-12 | 2010-08-03 | Phenomix Corporation | Methyl and ethyl substituted pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-IV |
| KR20060109911A (ko) * | 2003-11-17 | 2006-10-23 | 노파르티스 아게 | 디펩티딜 펩티다제 ⅳ 억제제의 용도 |
| ES2332920T3 (es) * | 2004-01-20 | 2010-02-15 | Novartis Ag | Proceso y formulacion de compresion directa. |
| CN101684089A (zh) * | 2004-02-05 | 2010-03-31 | 杏林制药株式会社 | 双环酯类衍生物 |
| US7560569B2 (en) * | 2004-02-18 | 2009-07-14 | Kyorin Pharmaceutical Co., Ltd | Bicycloamide derivative |
| US7501426B2 (en) | 2004-02-18 | 2009-03-10 | Boehringer Ingelheim International Gmbh | 8-[3-amino-piperidin-1-yl]-xanthines, their preparation and their use as pharmaceutical compositions |
| US20090017015A1 (en) * | 2004-02-20 | 2009-01-15 | Thomas Edward Hughes | Dpp-iv inhibitors for treating neurodegeneration and cognitive disorders |
| US7514571B2 (en) * | 2004-02-27 | 2009-04-07 | Kyorin Pharmaceutical Co., Ltd. | Bicyclo derivative |
| US7687504B2 (en) * | 2004-03-09 | 2010-03-30 | National Health Research Institutes | Pyrrolidine compounds |
| US7732446B1 (en) | 2004-03-11 | 2010-06-08 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
| AU2004318013B8 (en) | 2004-03-15 | 2011-10-06 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
| TW200604167A (en) * | 2004-04-27 | 2006-02-01 | Astellas Pharma Inc | Pyrrolidine derivatives |
| AU2005241056A1 (en) | 2004-05-04 | 2005-11-17 | Merck & Co., Inc. | 1,2,4-oxadiazole derivatives as dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes |
| CN1960990A (zh) * | 2004-05-18 | 2007-05-09 | 默克公司 | 作为用于治疗或预防糖尿病的二肽基肽酶－ⅳ抑制剂的环己基丙氨酸衍生物 |
| WO2005118555A1 (en) | 2004-06-04 | 2005-12-15 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
| US7935723B2 (en) * | 2004-06-04 | 2011-05-03 | Novartis Pharma Ag | Use of organic compounds |
| EP1778220A1 (en) | 2004-07-12 | 2007-05-02 | Phenomix Corporation | Constrained cyano compounds |
| WO2006019965A2 (en) | 2004-07-16 | 2006-02-23 | Takeda San Diego, Inc. | Dipeptidyl peptidase inhibitors |
| ATE553077T1 (de) * | 2004-07-23 | 2012-04-15 | Nuada Llc | Peptidaseinhibitoren |
| TW200608967A (en) | 2004-07-29 | 2006-03-16 | Sankyo Co | Pharmaceutical compositions containing with diabetic agent |
| AR050615A1 (es) | 2004-08-27 | 2006-11-08 | Novartis Ag | Composiciones farmaceuticas para la administracion oral |
| AU2005293266B2 (en) * | 2004-10-12 | 2011-09-29 | Glenmark Pharmaceuticals S.A. | Novel dipeptidyl peptidase IV inhibitors, pharmaceutical compositions containing them, and process for their preparation |
| US20090253752A1 (en) * | 2004-10-25 | 2009-10-08 | Bryan Burkey | Combination of dpp-iv inhibitor, ppar antidiabetic and metmorfin |
| DE102004054054A1 (de) | 2004-11-05 | 2006-05-11 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Verfahren zur Herstellung chiraler 8-(3-Amino-piperidin-1-yl)-xanthine |
| US7411093B2 (en) | 2004-12-20 | 2008-08-12 | Hoffman-La Roche Inc. | Aminocycloalkanes as DPP-IV inhibitors |
| RU2396257C2 (ru) | 2004-12-20 | 2010-08-10 | Ф.Хоффманн-Ля Рош Аг | Производные 4-аминопиперидина |
| EP1828192B1 (en) | 2004-12-21 | 2014-12-03 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
| DOP2006000008A (es) | 2005-01-10 | 2006-08-31 | Arena Pharm Inc | Terapia combinada para el tratamiento de la diabetes y afecciones relacionadas y para el tratamiento de afecciones que mejoran mediante un incremento de la concentración sanguínea de glp-1 |
| GT200600008A (es) * | 2005-01-18 | 2006-08-09 | Formulacion de compresion directa y proceso | |
| JP2008024592A (ja) * | 2005-01-28 | 2008-02-07 | Taisho Pharmaceut Co Ltd | シアノピロリジン誘導体含有固形製剤用組成物、それを含有する固形製剤及びその製造方法 |
| WO2006090244A1 (en) * | 2005-02-22 | 2006-08-31 | Glenmark Pharmaceuticals S.A. | New adamantane derivatives as dipeptidyl, peptidase iv inhibitors, processes for their preparation, and pharmaceutical compositions containing them |
| TWI357902B (en) | 2005-04-01 | 2012-02-11 | Lg Life Science Ltd | Dipeptidyl peptidase-iv inhibiting compounds, meth |
| BRPI0608469A2 (pt) | 2005-04-22 | 2010-01-05 | Alantos Pharmaceuticals Holding Inc | inibidores de dipeptidil peptidase-iv |
| US7825139B2 (en) | 2005-05-25 | 2010-11-02 | Forest Laboratories Holdings Limited (BM) | Compounds and methods for selective inhibition of dipeptidyl peptidase-IV |
| EP2356997A1 (en) | 2005-06-06 | 2011-08-17 | Georgetown University | Compositions and methods for lipo modeling |
| MY152185A (en) | 2005-06-10 | 2014-08-29 | Novartis Ag | Modified release 1-[(3-hydroxy-adamant-1-ylamino)-acetyl]-pyrrolidine-2(s)-carbonitrile formulation |
| WO2006134613A2 (en) * | 2005-06-17 | 2006-12-21 | Aurigene Discovery Technologies Limited | Novel 5-substituted indole derivatives as dipeptidyl peptidase iv (dpp-iv) inhibitors |
| MX2008000468A (es) * | 2005-07-12 | 2008-03-11 | Novartis Ag | Combinacion de un inhibidor de dipeptidil-peptidasa-iv y un antagonista del receptor canabinoide cb1. |
| DE102005035891A1 (de) | 2005-07-30 | 2007-02-08 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | 8-(3-Amino-piperidin-1-yl)-xanthine, deren Herstellung und deren Verwendung als Arzneimittel |
| WO2007019255A2 (en) * | 2005-08-04 | 2007-02-15 | Novartis Ag | Salts of vildagliptin |
| GT200600381A (es) | 2005-08-25 | 2007-03-28 | Compuestos organicos | |
| CA2622472C (en) | 2005-09-14 | 2013-11-19 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors for treating diabetes |
| US8222411B2 (en) | 2005-09-16 | 2012-07-17 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
| TW200738266A (en) * | 2005-09-29 | 2007-10-16 | Sankyo Co | Pharmaceutical agent containing insulin resistance improving agent |
| JOP20180109A1 (ar) * | 2005-09-29 | 2019-01-30 | Novartis Ag | تركيبة جديدة |
| US20090054314A1 (en) * | 2005-10-07 | 2009-02-26 | Antonio Cruz | Combined use of DPP-IV inhibitors and gastrin compounds |
| GB0526291D0 (en) | 2005-12-23 | 2006-02-01 | Prosidion Ltd | Therapeutic method |
| BRPI0706423A2 (pt) * | 2006-01-06 | 2011-03-29 | Novartis Ag | uso de compostos orgánicos |
| CA2645154C (en) | 2006-03-08 | 2011-11-29 | Kyorin Pharmaceutical Co., Ltd. | Method for producing aminoacetylpyrrolidinecarbonitrile derivative and production intermediate thereof |
| JP5412273B2 (ja) | 2006-03-21 | 2014-02-12 | アミリン・ファーマシューティカルズ，リミテッド・ライアビリティ・カンパニー | ペプチド−ぺプチダーゼ阻害剤及びその使用 |
| WO2007112347A1 (en) | 2006-03-28 | 2007-10-04 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
| DK2004601T3 (da) * | 2006-04-03 | 2011-06-27 | Matrix Lab Ltd | Nye dipeptidylpeptidase-IV-inhibitorer samt fremgangsmåder til deres fremstilling og farmaceutiske sammensætninger indeholdende dem |
| US7985759B2 (en) * | 2006-04-03 | 2011-07-26 | Matrix Laboratories Ltd. | Dipeptidyl peptidase IV inhibitors and processes for their preparation and pharmaceutical compositions containing them |
| RS51745B (en) | 2006-04-11 | 2011-10-31 | Arena Pharmaceuticals Inc. | PROCEDURE FOR USING GPR119 RECEPTORS FOR INDENTIFICATION OF UNITS USEFUL FOR BONE WEIGHT INCREASE |
| PE20071221A1 (es) | 2006-04-11 | 2007-12-14 | Arena Pharm Inc | Agonistas del receptor gpr119 en metodos para aumentar la masa osea y para tratar la osteoporosis y otras afecciones caracterizadas por masa osea baja, y la terapia combinada relacionada a estos agonistas |
| EP1852108A1 (en) | 2006-05-04 | 2007-11-07 | Boehringer Ingelheim Pharma GmbH & Co.KG | DPP IV inhibitor formulations |
| PE20110235A1 (es) | 2006-05-04 | 2011-04-14 | Boehringer Ingelheim Int | Combinaciones farmaceuticas que comprenden linagliptina y metmorfina |
| BRPI0711558A2 (pt) | 2006-05-04 | 2011-11-08 | Boeringer Ingelheim Internat Gmbh | polimorfos |
| KR20090031368A (ko) | 2006-05-26 | 2009-03-25 | 아밀린 파마슈티칼스, 인크. | 울혈성 심부전 치료용 조성물 및 방법 |
| MEP8509A (en) | 2006-09-07 | 2011-12-20 | Combination treatment for diabetes mellitus | |
| US8324383B2 (en) | 2006-09-13 | 2012-12-04 | Takeda Pharmaceutical Company Limited | Methods of making polymorphs of benzoate salt of 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]-benzonitrile |
| KR20090088854A (ko) * | 2006-09-13 | 2009-08-20 | 다케다 야쿠힌 고교 가부시키가이샤 | 2-6-(3-아미노-피페리딘-엘-일)-3-메틸-2,4-디옥소-3,4-디하이드로-2h-피리미딘-1-일메틸-4-플루오로-벤조니트릴의 용도 |
| TW200838536A (en) | 2006-11-29 | 2008-10-01 | Takeda Pharmaceutical | Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor |
| AR064833A1 (es) * | 2007-01-10 | 2009-04-29 | Medichem Sa | Un procedimiento para la preparacion de vildagliptin |
| US8093236B2 (en) | 2007-03-13 | 2012-01-10 | Takeda Pharmaceuticals Company Limited | Weekly administration of dipeptidyl peptidase inhibitors |
| US20080064701A1 (en) * | 2007-04-24 | 2008-03-13 | Ramesh Sesha | Anti-diabetic combinations |
| EP2123636B1 (en) | 2007-03-22 | 2012-03-21 | Kyorin Pharmaceutical Co., Ltd. | Method for producing aminoacetylpyrrolidinecarbonitrile derivative |
| EP2143443B1 (en) | 2007-04-03 | 2014-11-19 | Mitsubishi Tanabe Pharma Corporation | A combination of dipeptidyl peptidase iv inhibitor and sweetener for use in the treatment of obesity |
| DE102007022007A1 (de) * | 2007-05-08 | 2008-11-13 | Schebo Biotech Ag | Neuartike Pharmazeutika, Verfahren zu ihrer Herstellung und ihre Verwendung in der Prophylaxe und Therapie von ZNS-Erkrankungen und Diabetes |
| EA201401193A1 (ru) | 2007-06-04 | 2015-08-31 | Бен-Гурион Юниверсити Оф Дзе Негев Рисерч Энд Дивелопмент Оторити | Триарильные соединения и композиции, их содержащие |
| CL2008002427A1 (es) | 2007-08-16 | 2009-09-11 | Boehringer Ingelheim Int | Composicion farmaceutica que comprende 1-cloro-4-(b-d-glucopiranos-1-il)-2-[4-((s)-tetrahidrofurano-3-iloxi)bencil]-benceno combinado con 1-[(4-metilquinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-(r)-aminopiperidin-1-il)xantina; y su uso para tratar diabetes mellitus tipo 2. |
| EP2190434B1 (en) * | 2007-08-17 | 2019-04-17 | Boehringer Ingelheim International GmbH | Purin derivatives for use in the treatment of fap-related diseases |
| US8338450B2 (en) * | 2007-09-21 | 2012-12-25 | Lupin Limited | Compounds as dipeptidyl peptidase IV (DPP IV) inhibitors |
| US20090082420A1 (en) * | 2007-09-25 | 2009-03-26 | Protia, Llc | Deuterium-enriched vildagliptin |
| US8598314B2 (en) * | 2007-09-27 | 2013-12-03 | Amylin Pharmaceuticals, Llc | Peptide-peptidase-inhibitor conjugates and methods of making and using same |
| CN101918423B (zh) | 2007-11-30 | 2013-05-15 | 诺瓦提斯公司 | 二肽基肽酶-iv抑制剂 |
| KR20100098683A (ko) * | 2007-12-12 | 2010-09-08 | 아스트라제네카 아베 | 펩티딜 니트릴, 및 디펩티딜 펩티다제 ｉ 억제제로서의 그의 용도 |
| WO2009082134A2 (en) | 2007-12-21 | 2009-07-02 | Lg Life Sciences, Ltd. | Dipeptidyl peptidase-iv inhibiting compounds, methods of preparing the same, and pharmaceutical compositions containing the same as active agent |
| CL2008003653A1 (es) | 2008-01-17 | 2010-03-05 | Mitsubishi Tanabe Pharma Corp | Uso de un inhibidor de sglt derivado de glucopiranosilo y un inhibidor de dppiv seleccionado para tratar la diabetes; y composicion farmaceutica. |
| US8551524B2 (en) * | 2008-03-14 | 2013-10-08 | Iycus, Llc | Anti-diabetic combinations |
| PE20091730A1 (es) | 2008-04-03 | 2009-12-10 | Boehringer Ingelheim Int | Formulaciones que comprenden un inhibidor de dpp4 |
| EP2146210A1 (en) | 2008-04-07 | 2010-01-20 | Arena Pharmaceuticals, Inc. | Methods of using A G protein-coupled receptor to identify peptide YY (PYY) secretagogues and compounds useful in the treatment of conditions modulated by PYY |
| PE20100156A1 (es) * | 2008-06-03 | 2010-02-23 | Boehringer Ingelheim Int | Tratamiento de nafld |
| WO2009155309A1 (en) * | 2008-06-19 | 2009-12-23 | Concert Pharmaceuticals, Inc. | Substituted cyanopyrrolidine derivatives |
| KR20190016601A (ko) | 2008-08-06 | 2019-02-18 | 베링거 인겔하임 인터내셔날 게엠베하 | 메트포르민 요법이 부적합한 환자에서의 당뇨병 치료 |
| UY32030A (es) | 2008-08-06 | 2010-03-26 | Boehringer Ingelheim Int | "tratamiento para diabetes en pacientes inapropiados para terapia con metformina" |
| JP5476305B2 (ja) * | 2008-08-07 | 2014-04-23 | 杏林製薬株式会社 | ビシクロ［２．２．２］オクチルアミン誘導体の製造方法 |
| US20110152342A1 (en) * | 2008-08-14 | 2011-06-23 | Hiroshi Uchida | Stabilized pharmaceutical composition |
| EP2326326B1 (en) * | 2008-08-15 | 2019-10-09 | Boehringer Ingelheim International GmbH | Dpp-4 inhibitors for use for the treatment of wound healing in diabetic patients |
| CZ2008512A3 (cs) | 2008-08-26 | 2010-03-10 | Zentiva, A. S | Zpusob prípravy vysoce cistého vildagliptinu |
| RU2011113823A (ru) | 2008-09-10 | 2012-10-20 | БЕРИНГЕР ИНГЕЛЬХАЙМ ИНТЕРНАЦИОНАЛЬ ГмбХ (DE) | Комбинированная терапия, предназначенная для лечения диабета и связанных с ним состояний |
| CN102850330B (zh) * | 2008-09-23 | 2014-10-15 | 成都地奥制药集团有限公司 | 经溴代的制备n取代的吡咯烷衍生物的方法 |
| US20200155558A1 (en) | 2018-11-20 | 2020-05-21 | Boehringer Ingelheim International Gmbh | Treatment for diabetes in patients with insufficient glycemic control despite therapy with an oral antidiabetic drug |
| JO2870B1 (en) | 2008-11-13 | 2015-03-15 | ميرك شارب اند دوهم كورب | Amino Tetra Hydro Pirans as Inhibitors of Peptide Dipeptide IV for the Treatment or Prevention of Diabetes |
| KR20110103968A (ko) | 2008-12-23 | 2011-09-21 | 베링거 인겔하임 인터내셔날 게엠베하 | 유기 화합물의 염 형태 |
| TW201036975A (en) | 2009-01-07 | 2010-10-16 | Boehringer Ingelheim Int | Treatment for diabetes in patients with inadequate glycemic control despite metformin therapy |
| JP2012514630A (ja) | 2009-01-09 | 2012-06-28 | オーキッド リサーチ ラボラトリーズ リミテッド | ジペプチジルペプチダーゼｉｖ阻害剤 |
| TWI466672B (zh) | 2009-01-29 | 2015-01-01 | Boehringer Ingelheim Int | 小兒科病人糖尿病之治療 |
| US20120094894A1 (en) | 2009-02-13 | 2012-04-19 | Boehringer Ingelheim International Gmbh | Antidiabetic medications comprising a dpp-4 inhibitor (linagliptin) optionally in combination with other antidiabetics |
| AP2011005794A0 (en) | 2009-02-13 | 2011-08-31 | Boehringer Ingelheim Int | Pharmaceutical composition comprising a SGLT2 inhibitor, a DPP-IV inhibitor and optionally a furtherantidiabetic agent and uses thereof. |
| EP2412370A4 (en) | 2009-03-27 | 2013-05-22 | Kyorin Seiyaku Kk | MATRIX-LIKE EXTENDED RELEASE PREPARATION CONTAINING A BASIC ADDITIVE |
| AU2010244218B2 (en) | 2009-05-07 | 2012-07-19 | Astrazeneca Ab | Substituted 1-cyanoethylheterocyclylcarboxamide compounds 750 |
| EP2429995B1 (en) | 2009-05-15 | 2014-01-22 | Novartis AG | Aryl pyridine as aldosterone synthase inhibitors |
| EA201101621A1 (ru) | 2009-05-15 | 2012-05-30 | Новартис Аг | Производные бензоксазолона в качестве ингибиторов альдостеронсинтазы |
| CA2763565A1 (en) | 2009-05-28 | 2010-12-02 | Novartis Ag | Substituted aminobutyric derivatives as neprilysin inhibitors |
| ES2523734T3 (es) | 2009-05-28 | 2014-12-01 | Novartis Ag | Derivados aminopropiónicos sustituidos como inhibidores de neprilisina |
| US8748457B2 (en) | 2009-06-18 | 2014-06-10 | Lupin Limited | 2-amino-2- [8-(dimethyl carbamoyl)- 8-aza- bicyclo [3.2.1] oct-3-yl]-exo- ethanoyl derivatives as potent DPP-IV inhibitors |
| AR077642A1 (es) | 2009-07-09 | 2011-09-14 | Arena Pharm Inc | Moduladores del metabolismo y el tratamiento de trastornos relacionados con el mismo |
| WO2011014520A2 (en) | 2009-07-29 | 2011-02-03 | Irm Llc | Compounds and compositions as modulators of gpr119 activity |
| SI2459531T1 (sl) | 2009-07-31 | 2020-02-28 | Krka, D.D., Novo Mesto | Granulat, ki obsega vildagliptin, in postopek njegove priprave |
| CN102595897A (zh) | 2009-09-02 | 2012-07-18 | 默沙东公司 | 作为用于糖尿病的治疗或预防的二肽基肽酶-iv抑制剂的氨基四氢吡喃 |
| MX2012002274A (es) | 2009-09-03 | 2012-09-07 | Bioenergenix | Compuestos heterociclicos para la inhibicion de pask. |
| US20110160159A1 (en) | 2009-09-15 | 2011-06-30 | John Ryan | Treatment of cancer |
| EP2295083A1 (de) | 2009-09-15 | 2011-03-16 | Ratiopharm GmbH | Pharmazeutische Zusammensetzung mit den Wirkstoffen Metformin und Sitagliptin oder Vildagliptin |
| HUP0900638A2 (en) | 2009-10-07 | 2011-05-30 | Egyt Gyogyszervegyeszeti Gyar | Adducts of inorganic salts basea on vildaelitpin applicable for preparation of pharmaceutical compositions |
| JP2013507366A (ja) | 2009-10-09 | 2013-03-04 | アイアールエム・リミテッド・ライアビリティ・カンパニー | Ｇｐｒ１１９活性モジュレーターとしての化合物および組成物 |
| EP2308847B1 (en) | 2009-10-09 | 2014-04-02 | EMC microcollections GmbH | Substituted pyridines as inhibitors of dipeptidyl peptidase IV and their application for the treatment of diabetes and related diseases |
| JP5654608B2 (ja) | 2009-11-17 | 2015-01-14 | ノバルティス アーゲー | アルドステロンシンターゼ阻害剤としてのアリール−ピリジン誘導体 |
| JO2967B1 (en) | 2009-11-20 | 2016-03-15 | نوفارتس ايه جي | Acetic acid derivatives of carbamoyl methyl amino are substituted as new NEP inhibitors |
| EA201200617A1 (ru) | 2009-11-23 | 2012-11-30 | Серулин Фарма Инк. | Полимеры на основе циклодекстрина для доставки лекарственных средств |
| MX364651B (es) | 2009-11-27 | 2019-05-03 | Boehringer Ingelheim Int Gmbh Star | Inhibidores de dpp-iv, tales como la linagliptina, y composiciones farmacéuticas o combinaciones que comprenden los mismos, para usarse en el tratamiento de pacientes diabéticos tipificados genéticamente. |
| CN102666535B (zh) | 2009-11-30 | 2015-02-25 | 诺华股份有限公司 | 作为醛固酮合酶抑制剂的咪唑衍生物 |
| US8394858B2 (en) | 2009-12-03 | 2013-03-12 | Novartis Ag | Cyclohexane derivatives and uses thereof |
| WO2011078101A1 (ja) | 2009-12-22 | 2011-06-30 | 塩野義製薬株式会社 | アダマンタンアミン誘導体 |
| WO2011090940A1 (en) | 2010-01-19 | 2011-07-28 | Cerulean Pharma Inc. | Cyclodextrin-based polymers for therapeutic delivery |
| US8853212B2 (en) | 2010-02-22 | 2014-10-07 | Merck Sharp & Dohme Corp | Substituted aminotetrahydrothiopyrans and derivatives thereof as dipeptidyl peptidase-IV inhibitors for the treatment of diabetes |
| CN101798270B (zh) * | 2010-02-25 | 2013-04-17 | 东华大学 | 一种3-氨基-1-金刚烷醇的制备方法 |
| WO2011113947A1 (en) | 2010-03-18 | 2011-09-22 | Boehringer Ingelheim International Gmbh | Combination of a gpr119 agonist and the dpp-iv inhibitor linagliptin for use in the treatment of diabetes and related conditions |
| WO2011127051A1 (en) | 2010-04-06 | 2011-10-13 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
| EP2566469B1 (en) | 2010-05-05 | 2022-12-21 | Boehringer Ingelheim International GmbH | Combination therapy |
| US8980929B2 (en) | 2010-05-21 | 2015-03-17 | Merck Sharp & Dohme Corp. | Substituted seven-membered heterocyclic compounds as dipeptidyl peptidase-iv inhibitors for the treatment of diabetes |
| CN102260265B (zh) | 2010-05-24 | 2015-09-02 | 上海阳帆医药科技有限公司 | 六氢吡咯[3,4-b]吡咯衍生物、其制备方法及其用途 |
| CN101870671B (zh) * | 2010-06-11 | 2012-06-27 | 漆又毛 | 金刚烷基吡咯烷衍生物及制备和应用 |
| EP2585101A1 (en) | 2010-06-24 | 2013-05-01 | Boehringer Ingelheim International GmbH | Diabetes therapy |
| IT1400714B1 (it) | 2010-07-06 | 2013-06-28 | Chemelectiva S R L | Processo ed intermedi per la preparazione di un principio attivo. |
| US8697739B2 (en) | 2010-07-29 | 2014-04-15 | Novartis Ag | Bicyclic acetyl-CoA carboxylase inhibitors and uses thereof |
| TWI511958B (zh) * | 2010-08-09 | 2015-12-11 | Shionogi & Co | 胺基金剛烷胺基甲酸酯衍生物之製造方法 |
| HU231050B1 (hu) | 2010-08-19 | 2020-02-28 | Egis Gyógyszergyár Nyrt. | Eljárás gyógyszerhatóanyag előállítására |
| US10894787B2 (en) | 2010-09-22 | 2021-01-19 | Arena Pharmaceuticals, Inc. | Modulators of the GPR119 receptor and the treatment of disorders related thereto |
| US9034883B2 (en) | 2010-11-15 | 2015-05-19 | Boehringer Ingelheim International Gmbh | Vasoprotective and cardioprotective antidiabetic therapy |
| US8673974B2 (en) | 2010-11-16 | 2014-03-18 | Novartis Ag | Substituted amino bisphenyl pentanoic acid derivatives as NEP inhibitors |
| US8877815B2 (en) | 2010-11-16 | 2014-11-04 | Novartis Ag | Substituted carbamoylcycloalkyl acetic acid derivatives as NEP |
| TR201107482A1 (tr) | 2010-12-21 | 2012-07-23 | Sanovel İlaç San.Ve Ti̇c.A.Ş. | Vildagliptin ve gliklazidin iki tabakalı kombinasyon kompozisyonu. |
| TR201010683A1 (tr) | 2010-12-21 | 2012-07-23 | Sanovel İlaç San. Ve Ti̇c. A.Ş. | Vildagliptin formülasyonları. |
| EP2468268B1 (en) | 2010-12-21 | 2017-12-13 | Sanovel Ilaç Sanayi Ve Ticaret Anonim Sirketi | Combination composition of vildagliptin and gliclazide |
| TR201101809A1 (tr) | 2010-12-21 | 2012-07-23 | Sanovel İlaç Sanayi̇ Ve Ti̇caret Anoni̇m Şi̇rketi̇ | Vildagliptin ve glimepirid kombinasyonları. |
| KR20130128451A (ko) | 2011-01-31 | 2013-11-26 | 카딜라 핼쓰캐어 리미티드 | 지방이상증의 치료 |
| JP6139415B2 (ja) | 2011-03-02 | 2017-05-31 | バイオエナジェニックス | Ｐａｓｋの阻害のための複素環化合物 |
| WO2012135570A1 (en) | 2011-04-01 | 2012-10-04 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
| WO2012145361A1 (en) | 2011-04-19 | 2012-10-26 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
| WO2012145603A1 (en) | 2011-04-22 | 2012-10-26 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
| US20140051714A1 (en) | 2011-04-22 | 2014-02-20 | Arena Pharmaceuticals, Inc. | Modulators Of The GPR119 Receptor And The Treatment Of Disorders Related Thereto |
| WO2012170702A1 (en) | 2011-06-08 | 2012-12-13 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
| WO2013006526A2 (en) | 2011-07-05 | 2013-01-10 | Merck Sharp & Dohme Corp. | Tricyclic heterocycles useful as dipeptidyl peptidase-iv inhibitors |
| MX366629B (es) | 2011-07-15 | 2019-07-17 | Boehringer Ingelheim Int | Quinazolinas sustituidas, su preparación y su uso en composiciones farmacéuticas. |
| US20140302150A1 (en) | 2011-09-07 | 2014-10-09 | Umit Cifter | Dpp-iv inhibitor formulations |
| EP2572704A1 (en) | 2011-09-22 | 2013-03-27 | Sanovel Ilac Sanayi ve Ticaret A.S. | Orally-Disintegrating Formulations of Vildagliptin |
| EP2578208B1 (en) | 2011-10-06 | 2014-05-21 | Sanovel Ilac Sanayi ve Ticaret A.S. | DPP-IV inhibitor solid dosage formulations |
| WO2013055910A1 (en) | 2011-10-12 | 2013-04-18 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
| ITMI20112224A1 (it) | 2011-12-06 | 2013-06-07 | Chemelectiva S R L | Nuovo processo ed intermedi per la sintesi di vildagliptin |
| CN102491928A (zh) * | 2011-12-13 | 2012-06-13 | 临海天宇药业有限公司 | 一种制备(2s)-n-氯乙酰基-2-氰基四氢吡咯的方法 |
| US9115082B2 (en) | 2012-01-18 | 2015-08-25 | Catherine Yang | Dipeptidyl-peptidase-IV inhibitors for treatment of type 2 diabetes complex with hypertension |
| WO2013122920A1 (en) | 2012-02-17 | 2013-08-22 | Merck Sharp & Dohme Corp. | Dipeptidyl peptidase-iv inhibitors for the treatment or prevention of diabetes |
| US9555001B2 (en) | 2012-03-07 | 2017-01-31 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition and uses thereof |
| CN102617434B (zh) * | 2012-03-29 | 2014-07-23 | 中国科学院上海有机化学研究所 | 一锅法制备维达列汀 |
| WO2013179300A2 (en) | 2012-05-04 | 2013-12-05 | Megafine Pharma (P) Ltd. | A process for the preparation of vildagliptin and its intermediate thereof |
| EP3685839A1 (en) | 2012-05-14 | 2020-07-29 | Boehringer Ingelheim International GmbH | Linagliptin for use in the treatment of albuminuria and kidney related diseases |
| WO2013174767A1 (en) | 2012-05-24 | 2013-11-28 | Boehringer Ingelheim International Gmbh | A xanthine derivative as dpp -4 inhibitor for use in modifying food intake and regulating food preference |
| EP2874622A4 (en) | 2012-07-23 | 2015-12-30 | Merck Sharp & Dohme | TREATMENT OF DIABETES WITH DIPEPTIDYLPEPTIDASE IV INHIBITORS |
| WO2014020462A1 (en) * | 2012-08-01 | 2014-02-06 | Alembic Pharmaceuticals Limited | Improved process for preparation of vildagliptin intermediate |
| WO2014052619A1 (en) | 2012-09-27 | 2014-04-03 | Irm Llc | Piperidine derivatives and compositions as modulators of gpr119 activity |
| TWI500613B (zh) | 2012-10-17 | 2015-09-21 | Cadila Healthcare Ltd | 新穎之雜環化合物 |
| WO2014074668A1 (en) | 2012-11-08 | 2014-05-15 | Arena Pharmaceuticals, Inc. | Modulators of gpr119 and the treatment of disorders related thereto |
| UY35144A (es) | 2012-11-20 | 2014-06-30 | Novartis Ag | Miméticos lineales sintéticos de apelina para el tratamiento de insuficiencia cardiaca |
| CN103922986B (zh) * | 2013-01-16 | 2017-02-15 | 上海彩迩文生化科技有限公司 | 维大列汀及其类似物、中间体及其制备方法和应用 |
| LT2956464T (lt) | 2013-02-14 | 2018-07-10 | Novartis Ag | Pakeisti bisfenilbutanoinės fosfonrūgšties dariniai, kaip nep (neutralios endopeptidazės) inhibitoriai |
| EP2988736A1 (en) | 2013-04-22 | 2016-03-02 | Cadila Healthcare Limited | A novel composition for nonalcoholic fatty liver disease (nafld) |
| ES2889916T3 (es) | 2013-05-30 | 2022-01-14 | Cadila Healthcare Ltd | Un procedimiento para la preparación de pirroles con actividades hipolipidémicas e hipocolesterémicas |
| CN103304502B (zh) * | 2013-06-02 | 2015-03-04 | 张远强 | 一类抗糖尿病化合物、其制备方法和用途 |
| TW201513857A (zh) | 2013-07-05 | 2015-04-16 | Cadila Healthcare Ltd | 協同性組成物 |
| MX2016001021A (es) | 2013-07-25 | 2016-08-03 | Novartis Ag | Bioconjugados de polipeptidos de apelina sinteticos. |
| TN2016000031A1 (en) | 2013-07-25 | 2017-07-05 | Novartis Ag | Cyclic polypeptides for the treatment of heart failure |
| IN2013MU02470A (zh) | 2013-07-25 | 2015-06-26 | Cadila Healthcare Ltd | |
| IN2013MU02905A (zh) | 2013-09-06 | 2015-07-03 | Cadila Healthcare Ltd | |
| CN106061940A (zh) | 2013-11-05 | 2016-10-26 | 本古里安大学内盖夫研究发展局 | 治疗糖尿病和由其引发的并发疾病的化合物 |
| CN103641761A (zh) * | 2013-11-22 | 2014-03-19 | 沈阳化工大学 | 一种维格利汀的制备方法 |
| EP3110449B1 (en) | 2014-02-28 | 2023-06-28 | Boehringer Ingelheim International GmbH | Medical use of a dpp-4 inhibitor |
| EP2915528A1 (en) | 2014-03-06 | 2015-09-09 | Sanovel Ilac Sanayi ve Ticaret A.S. | Vildagliptin formulation process under inert gas atmosphere |
| CN103992257B (zh) * | 2014-05-16 | 2016-03-30 | 苏州天马精细化学品股份有限公司 | 一种维格列汀粗品的纯化方法 |
| CN105439873A (zh) * | 2014-08-20 | 2016-03-30 | 天津药物研究院 | 3-羟基-1-金刚烷胺的制备方法 |
| GB201415598D0 (en) | 2014-09-03 | 2014-10-15 | Univ Birmingham | Elavated Itercranial Pressure Treatment |
| CN105884669B (zh) * | 2014-09-15 | 2020-05-15 | 深圳翰宇药业股份有限公司 | 制备取代的(s)-吡咯烷-2-甲腈及维格列汀的方法 |
| KR20230151072A (ko) | 2015-01-06 | 2023-10-31 | 아레나 파마슈티칼스, 인크. | S1p1 수용체와 관련된 상태의 치료 방법 |
| CN104529857B (zh) * | 2015-01-13 | 2016-03-30 | 佛山市赛维斯医药科技有限公司 | 卤代金刚烷酰胺类衍生物、其制备方法和用途 |
| AU2016209968B2 (en) | 2015-01-23 | 2018-11-29 | Novartis Ag | Synthetic apelin fatty acid conjugates with improved half-life |
| KR20220070057A (ko) | 2015-03-09 | 2022-05-27 | 인테크린 테라퓨틱스, 아이엔씨. | 비알코올성 지방간 질환 및/또는 지방이영양증의 치료 방법 |
| CN104761456B (zh) * | 2015-03-10 | 2020-04-10 | 上海威智医药科技有限公司 | 3-氨基-1-金刚烷醇的制备方法 |
| CN104817482B (zh) * | 2015-03-17 | 2017-05-10 | 宁波百思佳医药科技有限公司 | 2‑取代吡咯烷类化合物、制备方法及其在制备维格列汀中的应用 |
| HUE060476T2 (hu) | 2015-06-22 | 2023-03-28 | Arena Pharm Inc | (R)-2-(7-(4-ciklopentil-3-(trifluormetil)benziloxi)-1,2,3,4- tetrahidrociklopenta[B]indol-3-il)ecetsav kristályos L-arginin-sója S1P1 receptorral kapcsolatos rendellenességek esetén való alkalmazásra |
| US10385017B2 (en) | 2015-10-14 | 2019-08-20 | Cadila Healthcare Limited | Pyrrole compound, compositions and process for preparation thereof |
| RU2628573C2 (ru) * | 2015-11-27 | 2017-08-21 | Общество с ограниченной ответственностью "Аллель Центр Инновационных Биотехнологий" | Ингибитор дипептидилпептидазы-4 для лечения сахарного диабета 2-го типа |
| BR112018013195A2 (pt) | 2015-12-28 | 2018-12-11 | Wockhardt Ltd | composição farmacêutica osmótica oral de vildagliptina |
| WO2017211979A1 (en) | 2016-06-10 | 2017-12-14 | Boehringer Ingelheim International Gmbh | Combinations of linagliptin and metformin |
| DE102016116130A1 (de) | 2016-08-30 | 2018-03-01 | Universität Bielefeld | Verfahren zur Herstellung chiraler Aminonitrile |
| WO2018050892A1 (en) | 2016-09-16 | 2018-03-22 | Galenicum Health S.L. | Vildagliptin pharmaceutical compositions |
| JOP20190086A1 (ar) | 2016-10-21 | 2019-04-18 | Novartis Ag | مشتقات نافثيريدينون جديدة واستخدامها في معالجة عدم انتظام ضربات القلب |
| WO2018104916A1 (en) | 2016-12-09 | 2018-06-14 | Cadila Healthcare Limited | Treatment for primary biliary cholangitis |
| WO2018162722A1 (en) | 2017-03-09 | 2018-09-13 | Deutsches Institut Für Ernährungsforschung Potsdam-Rehbrücke | Dpp-4 inhibitors for use in treating bone fractures |
| AU2018249822A1 (en) | 2017-04-03 | 2019-10-31 | Coherus Biosciences Inc. | PPArgamma agonist for treatment of progressive supranuclear palsy |
| GR1009406B (el) | 2017-10-03 | 2018-11-26 | Φαρματεν Αβεε | Φαρμακευτικο σκευασμα που περιλαμβανει βιλνταγλιπτινη και μεθοδος για την παρασκευη αυτου |
| UY38072A (es) | 2018-02-07 | 2019-10-01 | Novartis Ag | Compuestos derivados de éster butanoico sustituido con bisfenilo como inhibidores de nep, composiciones y combinaciones de los mismos |
| KR102622198B1 (ko) | 2018-03-30 | 2024-01-09 | 한미약품 주식회사 | 빌다글립틴을 함유하는 경구용 고형제제 및 그의 제조 방법 |
| GR1009644B (el) | 2018-09-25 | 2019-11-12 | Φαρματεν Α.Β.Ε.Ε. | Φαρμακευτικο σκευασμα που περιλαμβανει βιλνταγλιπτινη και μετφορμινη και μεθοδος για την παρασκευη αυτου |
| WO2020110011A1 (en) | 2018-11-27 | 2020-06-04 | Novartis Ag | Cyclic peptides as proprotein convertase subtilisin/kexin type 9 (pcsk9) inhibitors for the treatment of metabolic disorders |
| UY38485A (es) | 2018-11-27 | 2020-06-30 | Novartis Ag | Compuestos tetrámeros cíclicos como inhibidores de proproteína convertasa subtilisina/kexina tipo 9 (pcsk9), método de tratamiento, uso y su preparación |
| WO2020110008A1 (en) | 2018-11-27 | 2020-06-04 | Novartis Ag | Cyclic pentamer compounds as proprotein convertase subtilisin/kexin type 9 (pcsk9) inhibitors for the treatment of metabolic disorder |
| JP7461735B2 (ja) * | 2019-12-02 | 2024-04-04 | 日本ジェネリック株式会社 | ビルダグリプチン含有錠剤 |
| CN113527167B (zh) * | 2020-04-14 | 2024-01-19 | 威智医药股份有限公司 | 一种维格列汀的生产方法 |
| WO2021234430A1 (en) | 2020-05-17 | 2021-11-25 | Lotus International Pte. Ltd. | Modified release dosage form comprising vildagliptin and process for manufacturing the same |
| WO2022003405A1 (en) | 2020-07-03 | 2022-01-06 | Savoi Guilherme | One-pot process to obtain a pyrrolidine-2-carbonitrile intermediate compound and industrial scale telescopic process to prepare (2s)-1-[n-(3-hydroxyadamantan-1-yl)glycyl]-2-pyrrolidinecarbonitrile (vildagliptin) using same |
| EP4192509A1 (en) | 2020-08-05 | 2023-06-14 | Ellipses Pharma Ltd | Treatment of cancer using a cyclodextrin-containing polymer-topoisomerase inhibitor conjugate and a parp inhibitor |
| US20240174675A1 (en) * | 2021-01-21 | 2024-05-30 | The Scripps Research Institute | Small molecule regulators of alveolar type 2 cell proliferation for the treatment of pulmonary diseases |
| WO2023084449A1 (en) | 2021-11-12 | 2023-05-19 | Novartis Ag | Diaminocyclopentylpyridine derivatives for the treatment of a disease or disorder |
| AR127698A1 (es) | 2021-11-23 | 2024-02-21 | Novartis Ag | Derivados de naftiridinona para el tratamiento de una enfermedad o un trastorno |
Family Cites Families (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE296075C (zh) * | ||||
| DE158109C (zh) * | ||||
| FR2572399B1 (fr) * | 1984-10-31 | 1987-01-16 | Panmedica Sa | Nouveaux derives de l'adamantanamine, leurs procedes de preparation et medicaments les contenant |
| WO1990012005A1 (en) * | 1989-04-13 | 1990-10-18 | Japan Tobacco Inc. | New amino acid derivatives having prolylendopeptidase inhibitor activity |
| ES2099158T3 (es) * | 1990-04-14 | 1997-05-16 | New England Medical Center Inc | Tratamiento del rechazo de trasplantes o de enfermedades autoinmunitarias y complejo de la formula general x-pro-y-boropro asociada al mismo. |
| JPH07504158A (ja) * | 1991-10-22 | 1995-05-11 | ニュー イングランド メディカル センター ホスピタルズ インク | ジペプチジル−アミノペプチダーゼｉｖ型のインヒビタ |
| PH31294A (en) * | 1992-02-13 | 1998-07-06 | Thomae Gmbh Dr K | Benzimidazolyl derivatives, pharmaceutical compositions containing these compounds and process for preparing them. |
| WO1995011689A1 (en) * | 1993-10-29 | 1995-05-04 | Trustees Of Tufts College | Use of inhibitors of dipeptidyl-aminopeptidase to block entry of hiv into cells |
| HUT74733A (en) * | 1993-11-09 | 1997-02-28 | Merck & Co Inc | Piperidines, pyrrolidines and hexahydro-1h-azepines promote release of growth hormone |
| IL111785A0 (en) * | 1993-12-03 | 1995-01-24 | Ferring Bv | Dp-iv inhibitors and pharmaceutical compositions containing them |
| FR2719049B1 (fr) * | 1994-04-22 | 1996-06-14 | Pasteur Institut | Multireprésentation d'un analogue peptidique du substrat de la DPPIV, notamment de type KPR, afin d'inhiber l'entrée du HIV dans les cellules. |
| US5543396A (en) * | 1994-04-28 | 1996-08-06 | Georgia Tech Research Corp. | Proline phosphonate derivatives |
| WO1995034538A2 (en) * | 1994-06-10 | 1995-12-21 | Universitaire Instelling Antwerpen | Purification of serine proteases and synthetic inhibitors thereof |
| TW492957B (en) * | 1996-11-07 | 2002-07-01 | Novartis Ag | N-substituted 2-cyanopyrrolidnes |
| AU8174398A (en) * | 1997-06-27 | 1999-01-19 | Penn State Research Foundation, The | Agrobacterium-mediated transformation and efficient regeneration of cacao |
| EP2433623A1 (en) * | 1998-02-02 | 2012-03-28 | Trustees Of Tufts College | Use of dipeptidylpeptidase inhibitors to regulate glucose metabolism |
| JP2003190202A (ja) * | 2001-12-28 | 2003-07-08 | Yoshinobu Sekizawa | 使い捨てカイロ目的別貼付位置及び禁止位置表示付き下着 |
| AU2003240076A1 (en) * | 2002-06-08 | 2003-12-22 | Ian Robert Thomson | Delivery system for a medicament or well-being enhancing composition |
-
1999
- 1999-12-02 CO CO99075802A patent/CO5150173A1/es unknown
- 1999-12-07 TW TW088121371A patent/TW509674B/zh active
- 1999-12-07 AR ARP990106231A patent/AR023719A1/es active IP Right Grant
- 1999-12-07 PE PE1999001213A patent/PE20001317A1/es not_active IP Right Cessation
- 1999-12-09 CN CNB998142026A patent/CN1160330C/zh not_active Expired - Lifetime
- 1999-12-09 IL IL14309199A patent/IL143091A0/xx active Protection Beyond IP Right Term
- 1999-12-09 KR KR10-2001-7007227A patent/KR100509311B1/ko active IP Right Grant
- 1999-12-09 CA CA002350609A patent/CA2350609C/en not_active Expired - Lifetime
- 1999-12-09 CZ CZ20012028A patent/CZ299151B6/cs not_active IP Right Cessation
- 1999-12-09 EP EP99959396A patent/EP1137635B1/en not_active Expired - Lifetime
- 1999-12-09 ID IDW00200101155A patent/ID28796A/id unknown
- 1999-12-09 JP JP2000586689A patent/JP3681110B2/ja not_active Expired - Lifetime
- 1999-12-09 WO PCT/EP1999/009708 patent/WO2000034241A1/en active IP Right Grant
- 1999-12-09 TR TR2001/01478T patent/TR200101478T2/xx unknown
- 1999-12-09 ES ES99959396T patent/ES2251847T3/es not_active Expired - Lifetime
- 1999-12-09 KR KR1020057007771A patent/KR20050047561A/ko not_active Application Discontinuation
- 1999-12-09 DE DE122008000017C patent/DE122008000017I1/de active Pending
- 1999-12-09 RU RU2001118826/04A patent/RU2251544C2/ru active Protection Beyond IP Right Term
- 1999-12-09 HU HU0104495A patent/HU226769B1/hu active Protection Beyond IP Right Term
- 1999-12-09 MY MYPI99005359A patent/MY123244A/en unknown
- 1999-12-09 BR BRPI9915985A patent/BRPI9915985B8/pt not_active IP Right Cessation
- 1999-12-09 PL PL348043A patent/PL199443B1/pl unknown
- 1999-12-09 AT AT99959396T patent/ATE307112T1/de active
- 1999-12-09 DE DE69927844T patent/DE69927844T2/de not_active Expired - Lifetime
- 1999-12-09 US US09/458,224 patent/US6166063A/en not_active Expired - Lifetime
- 1999-12-09 DK DK99959396T patent/DK1137635T3/da active
- 1999-12-09 DE DE122008000007C patent/DE122008000007I1/de active Pending
- 1999-12-09 SK SK789-2001A patent/SK286635B6/sk not_active IP Right Cessation
- 1999-12-09 NZ NZ511935A patent/NZ511935A/en not_active IP Right Cessation
- 1999-12-10 UY UY25843A patent/UY25843A1/es not_active IP Right Cessation
-
2001
- 2001-05-10 IL IL143091A patent/IL143091A/en active Protection Beyond IP Right Term
- 2001-06-05 ZA ZA200104581A patent/ZA200104581B/en unknown
- 2001-06-08 NO NO20012853A patent/NO318741B1/no not_active IP Right Cessation
-
2002
- 2002-01-28 HK HK02100662.5A patent/HK1040394B/zh not_active IP Right Cessation
-
2005
- 2005-01-17 JP JP2005008992A patent/JP2005112864A/ja active Pending
-
2006
- 2006-01-18 CY CY20061100065T patent/CY1105355T1/el unknown
-
2008
- 2008-01-16 LU LU91409C patent/LU91409I2/fr unknown
- 2008-01-17 NL NL300333C patent/NL300333I2/nl unknown
- 2008-01-23 FR FR08C0005C patent/FR08C0005I2/fr active Active
- 2008-01-25 NO NO2008001C patent/NO2008001I1/no not_active IP Right Cessation
- 2008-01-25 CY CY200800002C patent/CY2008002I1/el unknown
- 2008-05-09 NO NO2008004C patent/NO2008004I1/no unknown
- 2008-05-09 LU LU91435C patent/LU91435I2/fr unknown
- 2008-05-12 CY CY2008011C patent/CY2008011I2/el unknown
- 2008-05-14 NL NL300345C patent/NL300345I1/nl unknown
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TW509674B (en) | N-(substituted glycyl)-2-cyanopyrrolidine derivatives | |
| RU2180901C2 (ru) | N-замещенные 2-цианопирролидины | |
| TW200825058A (en) | Cysteine protease inhibitors | |
| EA014425B1 (ru) | Терапевтические соединения | |
| JP2010279372A (ja) | Ｐｔｈ産生に対する被験物質の作用をアッセイする方法 | |
| CN101684089A (zh) | 双环酯类衍生物 | |
| JPH0421665B2 (zh) | ||
| CN105143183A (zh) | 联芳基取代的4-氨基丁酸衍生物及其制备方法和用途 | |
| WO2007142253A1 (ja) | ２－シアノピロリジン誘導体 | |
| US20080293618A1 (en) | Cyclopropyl-fused pyrrolidine derivatives as dipeptidyl peptidase iv inhibitors | |
| CN110234636B (zh) | 包含哌醋甲酯前药的组合物，其制造和使用方法 | |
| WO2024060911A1 (zh) | 苯并异噻唑化合物及其药物组合物和应用 | |
| JPH01143897A (ja) | チアゾリジン誘導体 | |
| WO2006070780A1 (ja) | Ｐａｒ－２アゴニスト | |
| JPH05504146A (ja) | シクロアルキル置換グルタルアミド降圧剤 | |
| WO2005116012A1 (ja) | ピロリジン誘導体 | |
| WO2022125614A1 (en) | Phosphonates as inhibitors of enpp1 and cdnp | |
| KR20130018623A (ko) | Ｎ1-고리아민-ｎ2-치환된 바이구아나이드 유도체, 이의 제조방법 및 이를 유효성분으로 함유하는 약학 조성물 | |
| JPH0832704B2 (ja) | プロリルエンドペプチダーゼ阻害剤 | |
| JPH0670023B2 (ja) | チアゾリジン誘導体 | |
| US20230117289A1 (en) | Compositions comprising methylphenidate-prodrugs, processes of making and using the same | |
| JPS62123171A (ja) | 血栓塞栓性疾患に対し薬理学的活性を示す４−メトキシ−イソフタル酸誘導体およびその製法 | |
| JPH1160484A (ja) | Ｔｎｆ産生阻害剤 | |
| WO2022125613A1 (en) | Phosphonates as inhibitors of enpp1 and cdnp | |
| CN117736201A (zh) | 靶向组蛋白去乙酰化酶8蛋白水解嵌合体、制备方法及其应用 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| GD4A | Issue of patent certificate for granted invention patent |