ZA200608741B - Proline derivatives and their use as dipeptidyl peptidase IV inhibitors - Google Patents
Proline derivatives and their use as dipeptidyl peptidase IV inhibitors Download PDFInfo
- Publication number
- ZA200608741B ZA200608741B ZA200608741A ZA200608741A ZA200608741B ZA 200608741 B ZA200608741 B ZA 200608741B ZA 200608741 A ZA200608741 A ZA 200608741A ZA 200608741 A ZA200608741 A ZA 200608741A ZA 200608741 B ZA200608741 B ZA 200608741B
- Authority
- ZA
- South Africa
- Prior art keywords
- pyrrolidin
- compound
- mmol
- piperazin
- alkyl
- Prior art date
Links
- 229940124213 Dipeptidyl peptidase 4 (DPP IV) inhibitor Drugs 0.000 title description 2
- 239000003603 dipeptidyl peptidase IV inhibitor Substances 0.000 title description 2
- 150000003147 proline derivatives Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 165
- -1 -NR*R® Chemical group 0.000 claims description 63
- 239000000651 prodrug Substances 0.000 claims description 54
- 229940002612 prodrug Drugs 0.000 claims description 54
- 150000003839 salts Chemical class 0.000 claims description 45
- 125000000217 alkyl group Chemical group 0.000 claims description 30
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 20
- 125000003545 alkoxy group Chemical group 0.000 claims description 13
- 239000012453 solvate Substances 0.000 claims description 13
- 229910052684 Cerium Inorganic materials 0.000 claims description 12
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 150000002367 halogens Chemical class 0.000 claims description 11
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 10
- 125000001072 heteroaryl group Chemical group 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 8
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 229910052792 caesium Inorganic materials 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 125000002393 azetidinyl group Chemical group 0.000 claims description 3
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 125000004193 piperazinyl group Chemical group 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 114
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 54
- 239000000203 mixture Substances 0.000 description 51
- 239000000243 solution Substances 0.000 description 49
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 39
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 37
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 36
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 36
- 239000000047 product Substances 0.000 description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 30
- 238000000034 method Methods 0.000 description 29
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 23
- 206010012601 diabetes mellitus Diseases 0.000 description 23
- 235000019439 ethyl acetate Nutrition 0.000 description 23
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 description 20
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 20
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 20
- 238000006243 chemical reaction Methods 0.000 description 20
- 239000003112 inhibitor Substances 0.000 description 20
- 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 description 20
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 19
- 239000011541 reaction mixture Substances 0.000 description 19
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 19
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 18
- 235000019341 magnesium sulphate Nutrition 0.000 description 18
- 238000002360 preparation method Methods 0.000 description 18
- 239000012267 brine Substances 0.000 description 17
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 17
- 239000007787 solid Substances 0.000 description 17
- 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 16
- 239000008103 glucose Substances 0.000 description 16
- 239000002904 solvent Substances 0.000 description 16
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 14
- 206010020772 Hypertension Diseases 0.000 description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 13
- 150000001412 amines Chemical class 0.000 description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- 125000004432 carbon atom Chemical group C* 0.000 description 12
- 239000008194 pharmaceutical composition Substances 0.000 description 12
- 208000008589 Obesity Diseases 0.000 description 11
- 239000003472 antidiabetic agent Substances 0.000 description 11
- 201000010099 disease Diseases 0.000 description 11
- 235000020824 obesity Nutrition 0.000 description 11
- 241000124008 Mammalia Species 0.000 description 10
- 241000699670 Mus sp. Species 0.000 description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- 239000002253 acid Substances 0.000 description 10
- 239000003085 diluting agent Substances 0.000 description 10
- 239000003814 drug Substances 0.000 description 10
- 102000004877 Insulin Human genes 0.000 description 9
- 108090001061 Insulin Proteins 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 229910052799 carbon Inorganic materials 0.000 description 9
- 238000002425 crystallisation Methods 0.000 description 9
- 230000008025 crystallization Effects 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- 229940125396 insulin Drugs 0.000 description 9
- 239000003921 oil Substances 0.000 description 9
- 235000019198 oils Nutrition 0.000 description 9
- 230000036470 plasma concentration Effects 0.000 description 9
- 239000007858 starting material Substances 0.000 description 9
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 8
- 201000001320 Atherosclerosis Diseases 0.000 description 8
- 208000031226 Hyperlipidaemia Diseases 0.000 description 8
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 229940125708 antidiabetic agent Drugs 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- 238000004587 chromatography analysis Methods 0.000 description 8
- 239000003937 drug carrier Substances 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 8
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- 208000001132 Osteoporosis Diseases 0.000 description 7
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 7
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 7
- 241000700159 Rattus Species 0.000 description 7
- 239000007864 aqueous solution Substances 0.000 description 7
- 239000008280 blood Substances 0.000 description 7
- 210000004369 blood Anatomy 0.000 description 7
- 239000000284 extract Substances 0.000 description 7
- 239000006260 foam Substances 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 7
- 239000010410 layer Substances 0.000 description 7
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 7
- 229960002429 proline Drugs 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 239000000758 substrate Substances 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- 208000011580 syndromic disease Diseases 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 108010004460 Gastric Inhibitory Polypeptide Proteins 0.000 description 6
- 102100039994 Gastric inhibitory polypeptide Human genes 0.000 description 6
- 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 6
- 101800000224 Glucagon-like peptide 1 Proteins 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 6
- 102100040918 Pro-glucagon Human genes 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 239000005557 antagonist Substances 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 230000008878 coupling Effects 0.000 description 6
- 238000010168 coupling process Methods 0.000 description 6
- 238000005859 coupling reaction Methods 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 239000000546 pharmaceutical excipient Substances 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 108090000765 processed proteins & peptides Proteins 0.000 description 6
- 125000003373 pyrazinyl group Chemical group 0.000 description 6
- 125000000714 pyrimidinyl group Chemical group 0.000 description 6
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 238000002560 therapeutic procedure Methods 0.000 description 6
- 239000003981 vehicle Substances 0.000 description 6
- 125000004485 2-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 description 5
- 208000004476 Acute Coronary Syndrome Diseases 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- 239000007821 HATU Substances 0.000 description 5
- 208000031773 Insulin resistance syndrome Diseases 0.000 description 5
- 239000008346 aqueous phase Substances 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- 125000004429 atom Chemical group 0.000 description 5
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 5
- 208000035475 disorder Diseases 0.000 description 5
- 238000003818 flash chromatography Methods 0.000 description 5
- 238000001030 gas--liquid chromatography Methods 0.000 description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 5
- 201000001421 hyperglycemia Diseases 0.000 description 5
- 239000012442 inert solvent Substances 0.000 description 5
- 238000004811 liquid chromatography Methods 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 102000004196 processed proteins & peptides Human genes 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 4
- CKYGSXRXTIKGAJ-ZETCQYMHSA-N Boc-L-Pro(4-oxo) Chemical compound CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(O)=O CKYGSXRXTIKGAJ-ZETCQYMHSA-N 0.000 description 4
- 208000010392 Bone Fractures Diseases 0.000 description 4
- 208000002177 Cataract Diseases 0.000 description 4
- 208000036119 Frailty Diseases 0.000 description 4
- 208000002705 Glucose Intolerance Diseases 0.000 description 4
- 208000001145 Metabolic Syndrome Diseases 0.000 description 4
- 208000029725 Metabolic bone disease Diseases 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 208000025865 Ulcer Diseases 0.000 description 4
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 4
- 206010003549 asthenia Diseases 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 4
- 230000015556 catabolic process Effects 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 238000006731 degradation reaction Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 208000002551 irritable bowel syndrome Diseases 0.000 description 4
- 150000002576 ketones Chemical class 0.000 description 4
- WSFSSNUMVMOOMR-BJUDXGSMSA-N methanone Chemical compound O=[11CH2] WSFSSNUMVMOOMR-BJUDXGSMSA-N 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 230000003647 oxidation Effects 0.000 description 4
- 238000007254 oxidation reaction Methods 0.000 description 4
- 230000036961 partial effect Effects 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000002002 slurry Substances 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 231100000397 ulcer Toxicity 0.000 description 4
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 3
- YYVPZQADFREIFR-UHFFFAOYSA-N 3,3-difluoropyrrolidine;hydrochloride Chemical compound [Cl-].FC1(F)CC[NH2+]C1 YYVPZQADFREIFR-UHFFFAOYSA-N 0.000 description 3
- 208000010444 Acidosis Diseases 0.000 description 3
- 208000019901 Anxiety disease Diseases 0.000 description 3
- 229940123208 Biguanide Drugs 0.000 description 3
- 206010065687 Bone loss Diseases 0.000 description 3
- 208000000094 Chronic Pain Diseases 0.000 description 3
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 3
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 3
- 208000032781 Diabetic cardiomyopathy Diseases 0.000 description 3
- 206010012689 Diabetic retinopathy Diseases 0.000 description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
- 206010061818 Disease progression Diseases 0.000 description 3
- 208000030814 Eating disease Diseases 0.000 description 3
- 208000019454 Feeding and Eating disease Diseases 0.000 description 3
- 206010018473 Glycosuria Diseases 0.000 description 3
- 206010056438 Growth hormone deficiency Diseases 0.000 description 3
- 239000005909 Kieselgur Substances 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Chemical compound 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 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- 206010027417 Metabolic acidosis Diseases 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 206010049088 Osteopenia Diseases 0.000 description 3
- 208000002193 Pain Diseases 0.000 description 3
- 208000020221 Short stature Diseases 0.000 description 3
- 206010049416 Short-bowel syndrome Diseases 0.000 description 3
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 3
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 230000036506 anxiety Effects 0.000 description 3
- 206010003246 arthritis Diseases 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 3
- 150000004283 biguanides Chemical class 0.000 description 3
- 239000013058 crude material Substances 0.000 description 3
- 208000033679 diabetic kidney disease Diseases 0.000 description 3
- 235000014632 disordered eating Nutrition 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 206010015037 epilepsy Diseases 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 206010016256 fatigue Diseases 0.000 description 3
- 230000035780 glucosuria Effects 0.000 description 3
- 230000036512 infertility Effects 0.000 description 3
- 208000000509 infertility Diseases 0.000 description 3
- 231100000535 infertility Toxicity 0.000 description 3
- 230000002757 inflammatory effect Effects 0.000 description 3
- 206010022437 insomnia Diseases 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 230000008991 intestinal motility Effects 0.000 description 3
- 125000002950 monocyclic group Chemical group 0.000 description 3
- 238000007410 oral glucose tolerance test Methods 0.000 description 3
- 201000010065 polycystic ovary syndrome Diseases 0.000 description 3
- 201000009104 prediabetes syndrome Diseases 0.000 description 3
- GCYXWQUSHADNBF-AAEALURTSA-N preproglucagon 78-108 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(=O)NCC(O)=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 GCYXWQUSHADNBF-AAEALURTSA-N 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 235000018102 proteins Nutrition 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 125000004076 pyridyl group Chemical group 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 230000009466 transformation Effects 0.000 description 3
- JNTMAZFVYNDPLB-PEDHHIEDSA-N (2S,3S)-2-[[[(2S)-1-[(2S,3S)-2-amino-3-methyl-1-oxopentyl]-2-pyrrolidinyl]-oxomethyl]amino]-3-methylpentanoic acid Chemical compound CC[C@H](C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)CC)C(O)=O JNTMAZFVYNDPLB-PEDHHIEDSA-N 0.000 description 2
- BENKAPCDIOILGV-RQJHMYQMSA-N (2s,4r)-4-hydroxy-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(O)=O BENKAPCDIOILGV-RQJHMYQMSA-N 0.000 description 2
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 208000007848 Alcoholism Diseases 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- 101100117236 Drosophila melanogaster speck gene Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 102000051325 Glucagon Human genes 0.000 description 2
- 108060003199 Glucagon Proteins 0.000 description 2
- 229940121931 Gluconeogenesis inhibitor Drugs 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 102000007390 Glycogen Phosphorylase Human genes 0.000 description 2
- 108010046163 Glycogen Phosphorylase Proteins 0.000 description 2
- 238000010268 HPLC based assay Methods 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 229940122199 Insulin secretagogue Drugs 0.000 description 2
- 108010041872 Islet Amyloid Polypeptide Proteins 0.000 description 2
- 102000036770 Islet Amyloid Polypeptide Human genes 0.000 description 2
- 108010009384 L-Iditol 2-Dehydrogenase Proteins 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- AYCPARAPKDAOEN-LJQANCHMSA-N N-[(1S)-2-(dimethylamino)-1-phenylethyl]-6,6-dimethyl-3-[(2-methyl-4-thieno[3,2-d]pyrimidinyl)amino]-1,4-dihydropyrrolo[3,4-c]pyrazole-5-carboxamide Chemical compound C1([C@H](NC(=O)N2C(C=3NN=C(NC=4C=5SC=CC=5N=C(C)N=4)C=3C2)(C)C)CN(C)C)=CC=CC=C1 AYCPARAPKDAOEN-LJQANCHMSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 2
- YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-UHFFFAOYSA-N 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- 102100026974 Sorbitol dehydrogenase Human genes 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 229940100389 Sulfonylurea Drugs 0.000 description 2
- 239000012042 active reagent Substances 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 239000003288 aldose reductase inhibitor Substances 0.000 description 2
- 229940090865 aldose reductase inhibitors used in diabetes Drugs 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 125000005206 alkoxycarbonyloxymethyl group Chemical group 0.000 description 2
- 125000003282 alkyl amino group Chemical group 0.000 description 2
- 239000000908 ammonium hydroxide Substances 0.000 description 2
- 230000003243 anti-lipolytic effect Effects 0.000 description 2
- 239000000883 anti-obesity agent Substances 0.000 description 2
- 239000003524 antilipemic agent Substances 0.000 description 2
- 229940125710 antiobesity agent Drugs 0.000 description 2
- 238000011914 asymmetric synthesis Methods 0.000 description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 2
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 210000000988 bone and bone Anatomy 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 125000001589 carboacyl group Chemical group 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
- 229940082638 cardiac stimulant phosphodiesterase inhibitors Drugs 0.000 description 2
- 150000005829 chemical entities Chemical class 0.000 description 2
- 239000011651 chromium Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 108010054812 diprotin A Proteins 0.000 description 2
- 230000006806 disease prevention Effects 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 229940088598 enzyme Drugs 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- QMMMCTXNYMSXLI-UHFFFAOYSA-N fast blue B Chemical compound C1=C([N+]#N)C(OC)=CC(C=2C=C(OC)C([N+]#N)=CC=2)=C1 QMMMCTXNYMSXLI-UHFFFAOYSA-N 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 125000000524 functional group Chemical group 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
- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(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](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)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(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 description 2
- 229960004666 glucagon Drugs 0.000 description 2
- 230000010030 glucose lowering effect Effects 0.000 description 2
- 239000003324 growth hormone secretagogue Substances 0.000 description 2
- 208000019622 heart disease Diseases 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 150000003840 hydrochlorides Chemical class 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 238000007327 hydrogenolysis reaction Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 229940126904 hypoglycaemic agent Drugs 0.000 description 2
- 230000002218 hypoglycaemic effect Effects 0.000 description 2
- 150000002462 imidazolines Chemical class 0.000 description 2
- 150000002466 imines Chemical class 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000000099 in vitro assay Methods 0.000 description 2
- 238000005462 in vivo assay Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 125000001786 isothiazolyl group Chemical group 0.000 description 2
- 125000000842 isoxazolyl group Chemical group 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 2
- 229960003105 metformin Drugs 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 208000010125 myocardial infarction Diseases 0.000 description 2
- 239000006199 nebulizer Substances 0.000 description 2
- 239000003538 oral antidiabetic agent Substances 0.000 description 2
- 229940127209 oral hypoglycaemic agent Drugs 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000002571 phosphodiesterase inhibitor Substances 0.000 description 2
- HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical class OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 2
- 125000004943 pyrimidin-6-yl group Chemical group N1=CN=CC=C1* 0.000 description 2
- 125000000168 pyrrolyl group Chemical group 0.000 description 2
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 238000007127 saponification reaction Methods 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 2
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 2
- NHXLMOGPVYXJNR-ATOGVRKGSA-N somatostatin Chemical class C([C@H]1C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CSSC[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(=O)N1)[C@@H](C)O)NC(=O)CNC(=O)[C@H](C)N)C(O)=O)=O)[C@H](O)C)C1=CC=CC=C1 NHXLMOGPVYXJNR-ATOGVRKGSA-N 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- AKEJUJNQAAGONA-UHFFFAOYSA-N sulfur trioxide Chemical compound O=S(=O)=O AKEJUJNQAAGONA-UHFFFAOYSA-N 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 238000003419 tautomerization reaction Methods 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 125000001113 thiadiazolyl group Chemical group 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 125000004306 triazinyl group Chemical group 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- LSGOVYNHVSXFFJ-UHFFFAOYSA-N vanadate(3-) Chemical compound [O-][V]([O-])([O-])=O LSGOVYNHVSXFFJ-UHFFFAOYSA-N 0.000 description 2
- 150000003681 vanadium Chemical class 0.000 description 2
- AOFUBOWZWQFQJU-SNOJBQEQSA-N (2r,3s,4s,5r)-2,5-bis(hydroxymethyl)oxolane-2,3,4-triol;(2s,3r,4s,5s,6r)-6-(hydroxymethyl)oxane-2,3,4,5-tetrol Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O.OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@@H]1O AOFUBOWZWQFQJU-SNOJBQEQSA-N 0.000 description 1
- LENYOXXELREKGZ-WCCKRBBISA-N (3s)-3-fluoropyrrolidin-1-ium;chloride Chemical compound Cl.F[C@H]1CCNC1 LENYOXXELREKGZ-WCCKRBBISA-N 0.000 description 1
- FHUDAMLDXFJHJE-UHFFFAOYSA-N 1,1,1-trifluoropropan-2-one Chemical compound CC(=O)C(F)(F)F FHUDAMLDXFJHJE-UHFFFAOYSA-N 0.000 description 1
- IRFSXVIRXMYULF-UHFFFAOYSA-N 1,2-dihydroquinoline Chemical compound C1=CC=C2C=CCNC2=C1 IRFSXVIRXMYULF-UHFFFAOYSA-N 0.000 description 1
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 1
- MRBFGEHILMYPTF-UHFFFAOYSA-N 1-(2-Pyrimidyl)piperazine Chemical compound C1CNCCN1C1=NC=CC=N1 MRBFGEHILMYPTF-UHFFFAOYSA-N 0.000 description 1
- 125000005846 1-(alkanoyloxy)ethyl group Chemical group 0.000 description 1
- 125000005848 1-(alkoxycarbonyloxy)ethyl group Chemical group 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- YMXAILYGDPCVFW-UHFFFAOYSA-N 1-benzhydryl-3-fluoroazetidine;hydrochloride Chemical compound Cl.C1C(F)CN1C(C=1C=CC=CC=1)C1=CC=CC=C1 YMXAILYGDPCVFW-UHFFFAOYSA-N 0.000 description 1
- ZQXCQTAELHSNAT-UHFFFAOYSA-N 1-chloro-3-nitro-5-(trifluoromethyl)benzene Chemical compound [O-][N+](=O)C1=CC(Cl)=CC(C(F)(F)F)=C1 ZQXCQTAELHSNAT-UHFFFAOYSA-N 0.000 description 1
- LDMOEFOXLIZJOW-UHFFFAOYSA-N 1-dodecanesulfonic acid Chemical class CCCCCCCCCCCCS(O)(=O)=O LDMOEFOXLIZJOW-UHFFFAOYSA-N 0.000 description 1
- 125000005849 1-methyl-1-(alkoxycarbonyloxy)ethyl group Chemical group 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- OQHQOOLVQDEIGL-UHFFFAOYSA-N 2-methyl-2,7-diazaspiro[4.4]nonane Chemical compound C1N(C)CCC11CNCC1 OQHQOOLVQDEIGL-UHFFFAOYSA-N 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- KPTMFLKIYHWQPB-UHFFFAOYSA-N 3,3,4,4-tetrafluoropyrrolidine;hydrochloride Chemical compound Cl.FC1(F)CNCC1(F)F KPTMFLKIYHWQPB-UHFFFAOYSA-N 0.000 description 1
- CDBAEFXTCRKJPZ-UHFFFAOYSA-N 3,3-difluoroazetidine;hydron;chloride Chemical compound Cl.FC1(F)CNC1 CDBAEFXTCRKJPZ-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-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
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 102100026189 Beta-galactosidase Human genes 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- YNXLOPYTAAFMTN-SBUIBGKBSA-N C([C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)C1=CC=C(O)C=C1 Chemical compound C([C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)C1=CC=C(O)C=C1 YNXLOPYTAAFMTN-SBUIBGKBSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241001631457 Cannula Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- OKTJSMMVPCPJKN-NJFSPNSNSA-N Carbon-14 Chemical compound [14C] OKTJSMMVPCPJKN-NJFSPNSNSA-N 0.000 description 1
- 208000031229 Cardiomyopathies Diseases 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- RKWGIWYCVPQPMF-UHFFFAOYSA-N Chloropropamide Chemical compound CCCNC(=O)NS(=O)(=O)C1=CC=C(Cl)C=C1 RKWGIWYCVPQPMF-UHFFFAOYSA-N 0.000 description 1
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 206010010071 Coma Diseases 0.000 description 1
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 1
- 206010012335 Dependence Diseases 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 239000004338 Dichlorodifluoromethane Substances 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- 108010016626 Dipeptides Proteins 0.000 description 1
- 101710087092 Dipeptidyl-peptidase 5 Proteins 0.000 description 1
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 1
- 101710198144 Endopolygalacturonase I Proteins 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 206010017943 Gastrointestinal conditions Diseases 0.000 description 1
- 101000930822 Giardia intestinalis Dipeptidyl-peptidase 4 Proteins 0.000 description 1
- 206010018429 Glucose tolerance impaired Diseases 0.000 description 1
- 102000004366 Glucosidases Human genes 0.000 description 1
- 108010056771 Glucosidases Proteins 0.000 description 1
- 241000282575 Gorilla Species 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 239000004705 High-molecular-weight polyethylene Substances 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 208000013016 Hypoglycemia Diseases 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 208000025814 Inflammatory myopathy with abundant macrophages Diseases 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- 150000008575 L-amino acids Chemical class 0.000 description 1
- 108010059881 Lactase Proteins 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 208000007177 Left Ventricular Hypertrophy Diseases 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- 125000001429 N-terminal alpha-amino-acid group Chemical group 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 108090000189 Neuropeptides Proteins 0.000 description 1
- 102000003797 Neuropeptides Human genes 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 description 1
- 239000012425 OXONE® Substances 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 241000282579 Pan Species 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 102100029909 Peptide YY Human genes 0.000 description 1
- 108010088847 Peptide YY Proteins 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 101710168595 Probable dipeptidyl-peptidase 5 Proteins 0.000 description 1
- 101710191566 Probable endopolygalacturonase I Proteins 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 208000017442 Retinal disease Diseases 0.000 description 1
- 206010038923 Retinopathy Diseases 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- 108010022999 Serine Proteases Proteins 0.000 description 1
- 102000012479 Serine Proteases Human genes 0.000 description 1
- 244000000231 Sesamum indicum Species 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 239000005708 Sodium hypochlorite Substances 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- 230000006044 T cell activation Effects 0.000 description 1
- QYTDEUPAUMOIOP-UHFFFAOYSA-N TEMPO Chemical group CC1(C)CCCC(C)(C)N1[O] QYTDEUPAUMOIOP-UHFFFAOYSA-N 0.000 description 1
- 229940123464 Thiazolidinedione Drugs 0.000 description 1
- JLRGJRBPOGGCBT-UHFFFAOYSA-N Tolbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=C(C)C=C1 JLRGJRBPOGGCBT-UHFFFAOYSA-N 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- WXIONIWNXBAHRU-UHFFFAOYSA-N [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylidene]-dimethylazanium Chemical compound C1=CN=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 WXIONIWNXBAHRU-UHFFFAOYSA-N 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229960001466 acetohexamide Drugs 0.000 description 1
- VGZSUPCWNCWDAN-UHFFFAOYSA-N acetohexamide Chemical compound C1=CC(C(=O)C)=CC=C1S(=O)(=O)NC(=O)NC1CCCCC1 VGZSUPCWNCWDAN-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 206010000891 acute myocardial infarction Diseases 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 125000005042 acyloxymethyl group Chemical group 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000000278 alkyl amino alkyl group Chemical group 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000003178 anti-diabetic effect Effects 0.000 description 1
- 235000021229 appetite regulation Nutrition 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000005251 aryl acyl group Chemical group 0.000 description 1
- 125000004566 azetidin-1-yl group Chemical group N1(CCC1)* 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000005872 benzooxazolyl group Chemical group 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- CTOUWUYDDUSBQE-UHFFFAOYSA-N benzyl piperazine-1-carboxylate Chemical compound C1CNCCN1C(=O)OCC1=CC=CC=C1 CTOUWUYDDUSBQE-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
- 108010005774 beta-Galactosidase Proteins 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 230000037118 bone strength Effects 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 235000014121 butter Nutrition 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- FATUQANACHZLRT-KMRXSBRUSA-L calcium glucoheptonate Chemical compound [Ca+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C([O-])=O FATUQANACHZLRT-KMRXSBRUSA-L 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 208000015114 central nervous system disease Diseases 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 229960001761 chlorpropamide Drugs 0.000 description 1
- 229910052804 chromium Inorganic materials 0.000 description 1
- 229940117975 chromium trioxide Drugs 0.000 description 1
- WGLPBDUCMAPZCE-UHFFFAOYSA-N chromium trioxide Inorganic materials O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 1
- GAMDZJFZMJECOS-UHFFFAOYSA-N chromium(6+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Cr+6] GAMDZJFZMJECOS-UHFFFAOYSA-N 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 230000001010 compromised effect Effects 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- MOVRKLZUVNCBIP-RFZYENFJSA-N cortancyl Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)CC2=O MOVRKLZUVNCBIP-RFZYENFJSA-N 0.000 description 1
- 239000007822 coupling agent Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- UVJHQYIOXKWHFD-UHFFFAOYSA-N cyclohexa-1,4-diene Chemical compound C1C=CCC=C1 UVJHQYIOXKWHFD-UHFFFAOYSA-N 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 125000002576 diazepinyl group Chemical group N1N=C(C=CC=C1)* 0.000 description 1
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 1
- 235000019404 dichlorodifluoromethane Nutrition 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 1
- 238000000113 differential scanning calorimetry Methods 0.000 description 1
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 description 1
- 231100000676 disease causative agent Toxicity 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- POULHZVOKOAJMA-UHFFFAOYSA-M dodecanoate Chemical compound CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 150000002081 enamines Chemical class 0.000 description 1
- 230000003628 erosive effect Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 229910052731 fluorine Chemical group 0.000 description 1
- 239000011737 fluorine Chemical group 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- NMUZMGPHYASFRU-UHFFFAOYSA-N formaldehyde;dihydrochloride Chemical compound Cl.Cl.O=C NMUZMGPHYASFRU-UHFFFAOYSA-N 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000011953 free-radical catalyst Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 125000005643 gamma-butyrolacton-4-yl group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 230000014101 glucose homeostasis Effects 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 125000003147 glycosyl group Chemical group 0.000 description 1
- 230000005802 health problem Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002373 hemiacetals Chemical group 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- RCBVKBFIWMOMHF-UHFFFAOYSA-L hydroxy-(hydroxy(dioxo)chromio)oxy-dioxochromium;pyridine Chemical compound C1=CC=NC=C1.C1=CC=NC=C1.O[Cr](=O)(=O)O[Cr](O)(=O)=O RCBVKBFIWMOMHF-UHFFFAOYSA-L 0.000 description 1
- 150000004806 hydroxypyridines Chemical class 0.000 description 1
- 208000006575 hypertriglyceridemia Diseases 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- MGXWVYUBJRZYPE-YUGYIWNOSA-N incretin Chemical class C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C(C)C)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](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(O)=O)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=1C=CC(O)=CC=1)[C@@H](C)O)[C@@H](C)CC)C1=CC=C(O)C=C1 MGXWVYUBJRZYPE-YUGYIWNOSA-N 0.000 description 1
- 239000000859 incretin Substances 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 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
- 238000002955 isolation Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 229940116108 lactase Drugs 0.000 description 1
- 229940099584 lactobionate Drugs 0.000 description 1
- JYTUSYBCFIZPBE-AMTLMPIISA-N lactobionic acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O JYTUSYBCFIZPBE-AMTLMPIISA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229940070765 laurate Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- DIDCDJTVKPODTM-UHFFFAOYSA-N n-ethylpiperazine-1-carboxamide Chemical compound CCNC(=O)N1CCNCC1 DIDCDJTVKPODTM-UHFFFAOYSA-N 0.000 description 1
- 125000005487 naphthalate group Chemical group 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- BPGXUIVWLQTVLZ-OFGSCBOVSA-N neuropeptide y(npy) Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=C(O)C=C1 BPGXUIVWLQTVLZ-OFGSCBOVSA-N 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 238000003305 oral gavage Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000011164 ossification Effects 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000004287 oxazol-2-yl group Chemical group [H]C1=C([H])N=C(*)O1 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 239000002831 pharmacologic agent Substances 0.000 description 1
- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 description 1
- ICFJFFQQTFMIBG-UHFFFAOYSA-N phenformin Chemical compound NC(=N)NC(=N)NCCC1=CC=CC=C1 ICFJFFQQTFMIBG-UHFFFAOYSA-N 0.000 description 1
- 229960003243 phenformin Drugs 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 229960005095 pioglitazone Drugs 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 125000005575 polycyclic aromatic hydrocarbon group Chemical group 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 230000003234 polygenic effect Effects 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- OKBMCNHOEMXPTM-UHFFFAOYSA-M potassium peroxymonosulfate Chemical compound [K+].OOS([O-])(=O)=O OKBMCNHOEMXPTM-UHFFFAOYSA-M 0.000 description 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- 150000008318 pyrimidones Chemical class 0.000 description 1
- 125000006085 pyrrolopyridyl group Chemical group 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000004549 quinolin-4-yl group Chemical group N1=CC=C(C2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000002207 retinal effect Effects 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 229960004586 rosiglitazone Drugs 0.000 description 1
- 230000036186 satiety Effects 0.000 description 1
- 235000019627 satiety Nutrition 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- 238000010583 slow cooling Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 229940114926 stearate Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Chemical group 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- UOUFRTFWWBCVPV-UHFFFAOYSA-N tert-butyl 4-(2,4-dioxo-1H-thieno[3,2-d]pyrimidin-3-yl)piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(CC1)n1c(=O)[nH]c2ccsc2c1=O UOUFRTFWWBCVPV-UHFFFAOYSA-N 0.000 description 1
- FQFILJKFZCVHNH-UHFFFAOYSA-N tert-butyl n-[3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCCNC1=NC(Cl)=NC=C1Br FQFILJKFZCVHNH-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- CBXCPBUEXACCNR-UHFFFAOYSA-N tetraethylammonium Chemical compound CC[N+](CC)(CC)CC CBXCPBUEXACCNR-UHFFFAOYSA-N 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 150000001467 thiazolidinediones Chemical class 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000004588 thienopyridyl group Chemical group S1C(=CC2=C1C=CC=N2)* 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 238000003354 tissue distribution assay Methods 0.000 description 1
- 229960005371 tolbutamide Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrrole Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
PROLINE DERIVATIVES AND THEIR USB AS DIPEPTIDYL PEPTIDASE IV INHIBITORS
The invention relates to selective inhibitors of the enzyme dipeptidyl peptidase-IV (OPP-1V), pharmaceutical compositions thereof, and uses thereof for treating diseases and conditions associated with proteins that are subject to processing by DPP-IV.
DPP-IV (EC 3.4.14.5) is a serine protease that preferentially hydrolyzes an N-terminal dipeptide from proteins having proline or alanine in the 2-position. DPP-1V is believed to be involved in diabetes, glucose tolerance, obesity, appetite regulation, lipidemia, osteoporosis, neuropeptide metabolism and T- cell activation, among others. Accordingly, administration of DPP-IV inhibitors in vivo prevents N- terminal degradation of substrate peptides, thereby resulting in higher circulating concentrations of such peptides, and therapeutic benefits associated with such elevated concentrations.
DPP-IV has been implicated in the control of glucose homeostasis because its substrates include the incretin peptides glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP). Cleavage of the N-terminal amino acids from these peptides renders them functionally inactive. GLP-1 has been shown to be an effective anti-diabetic therapy in Type 2 diabetic patients and to reduce the meal-related insulin requirement in Type 1 diabetic patients. GLP-1 and/or GIP are believed to regulate satiety, lipidemia and osteogenesis. Exogenous GLP-1 has been proposed as a treatment for patients sutfering from acute coronary syndrome, angina and Ischemic heart disease.
Administration of DPP-IV inhibitors in vivo prevents N-terminal degradation of GLP-1 and GIP, resulting in higher circulating concentrations of these peptides, increased insulin secretion and improved glucose tolerance. On the basis of these observations, DPP-IV inhibitors are regarded as agents for the treatment of Type 2 diabetes, a disease in which glucose tolerance is impaired. In addition, treatment with DPP-IV inhibitors prevents degradation of Neuropeptide Y (NPY), a peptide associated with a variety of central nervous system disorders, and Peptide YY which has been linked to gastrointestinal conditions such as ulcers, irritable bowel disease, and inflammatory bowel disease.
In spite of the early discovery of insulin and its subsequent widespread use in the treatment of diabetes, and the later discovery of and use of sulfonylureas (e.g. chlorpropamide, tolbutamide, acetohexamide, biguanides (e.g., phenformin), metformin, thiazolidinediones (e.g., rosiglitazone), and pioglitazone as oral hypoglycemic agents, the treatment of diabetes remains less than satisfactory.
The use of insulin, necessary in Type 1 diabetic patients and about 10% of Type 2 diabetic patients in whom currently available oral hypoglycemic agents are ineffective, requires multiple daily doses, usually by seif-injection. Determination of the appropriate dosage of insulin necessitates frequent estimations of the glucose concentration in urine or blood. The administration of an excess dose of insulin causes hypoglycemia, with consequences ranging from mild abnormalities in blood glucose to coma, or even death.
Treatment of Type 2 diabetes usually comprises a combination of diet, exercise, oral agents, and in 40 more severe cases, insulin. However, the clinically available hypoglycemics can have side effects that limit their use. A continuing need for hypoglycemic agents, which may have fewer side effects or succeed where others fail, is clearly evident.
Poorly controlled hyperglycemia is a direct cause of the multiplicity of complications (cataracts, neuropathy, nephropathy, retinopathy, cardiomyopathy) that characterize advanced Type 2 diabetes. In addition, Type 2 diabetes is & comorbid disease that frequently confounds hyperlipidemia, atherosclerosis and hypertension, adding significantly to the overall morbidity and mortality attributable to those diseases.
Epidemiological evidence has firmly established hyperlipidemia as a primary risk factor for cardiovascular disease (CVD) due to atherosclerosis. Atherosclerosis is recognized to be a leading cause of death in the United States and Western Europe. CVD is especially prevalent among diabetic subjects, at least in part because of the existence of multiple independent risk factors such as glucose intolerance, left ventricular hypertrophy and hypertension in this population. Successful treatment of hyperlipidemia in the general population, and in diabetic subjects in particular, is therefore of exceptional medical importance. .
Hypertension (high blood pressure) is a condition that can occur in many patients in whom the causative agent or disorder is unknown. Such “essential” hypertension is often associated with disorders such as obesity, diabetes, and hypertriglyceridemia and it is known that hypertension is positively associated with heart failure, renal failure, and stroke. Hypertension can also contribute to the development of atherosclerosis and coronary disease. Hypertension, together with insulin resistance and . hyperlipidemia, comprise the constellation of symptoms that characterize metabolic syndrome, also known as insulin resistance syndrome (IRS) and Syndrome X. .
Obesity is a well-known and common risk factor for the development of atherosclerosis, hypertension, and diabetes. The incidence of obesity and its related sequelae is increasing worldwide.
Currently, few pharmacological agents are available that reduce adiposity effectively and acceptably.
Osteoporosis is a progressive systemic disease characterized by low bone density and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. Osteoporosis and the consequences of compromised bone strength are a significant cause of frailty, and of increased morbidity and mortality.
Heart disease is a major health problem throughout the world. Myocardial infarctions are a significant source of mortality among those individuals with heart disease. Acute coronary syndrome denactes patients who have or are at high risk of developing an acute myocardial infarction (MI).
Though there are therapies available for the treatment of diabetes, hyperglycemia, hyperlipidemia, hypertension, obesity, and osteoporosis there is a continuing need for alternative and improved therapies.
Various indications for DPP-V inhibitors are discussed in Augustyns, et al., Curr. Medicinal Chem., 6, 311 (1999); Ohnuki, et al., Drugs of the Future, 1998, 24, 665-670 (1999); Villhauer, et al., Annual
Reports in Medicinal Chemistry, 36, 191-200 (2001); Drucker, Expert Opin. Invest. Drugs, 12, 87-100 (2003); and Weideman, et al., Curr. Opin. Invest. Drugs, 4, 412-420 (2003).
Orally administered compounds that inhibit DPP-IV have recently been prepared, such as those disclosed in International Application WO 02/14271. : :
DPP-IV inhibitors, such as those disclosed in WO 02/14271, are believed to act by inhibiting the 40 degradation of the natural hormones, GLP-1 and GIP. Therefore, it is important that a suitable concentration of the DPP-IV inhibitor be avaitable in plasma to inhibit DPP-IV coincidently with the secretion of these GLP-1 and GIP hormones. To achieve such plasma concentrations, It is preferred that the DPP-IV inhibitor compounds maintain a higher plasma concentration over time than that which would be expected for other DPP-1V inhibitor compounds, such as those disclosed in WO 02/14271.
Therefore, what is needed is an orally administered DPP-IV inhibitor compound that has equivalent or better DPP-IV inhibitory activity and that maintains a higher plasma concentration over time.
The present invention relates to compounds having the structure of Formula (1) ’ "
HET R?
N~(
Nooo zy or a prodrug thereof, or a pharmaceutically acceptable salt of said compound or prodrug, or a solvate of said compound, prodrug or salt, wherein:
R' is {(Cy-Ca)alkyl, -(Cy-Cy)alkoxy, {C:-Ce)arylalkyl, -NRR", hydroxy, cyano, aryl, or heteroaryl, wherein said -(C,-Ce)alkyl, said aryl, or said heteroaryl is optionally substituted independently with one to three -COOH, -C(0)(C1-Cs)alkoxy, -C(O)(Cy-Celalkyl, -C(O)NR'R’, cyano, halogen, nitro, trifluoromethy|, -(Cy-Ce)alkyl, -(Cy-Ce)alkoxy, (Cs-Ce)cycloalkyl, or phenyl, and wherein R* and R® are, independently, hydrogen, -(C-Cs)alkyl, aryl, or heteroaryl, or R* and R°, taken together with the nitrogen atom to which they are attached, form a four- to six-membered heterocyclic ring, wherein said ring optionally - Incorporates an additional one or two nitrogen, oxygen, or sulfur ring heteroatoms;
R? and R? are, independently, hydrogen, halogen, -(C,-Ce)alkyl, or (C3-Cs)cycloalkyl;
Q is a covalent bond, -C(O)-, or -SO,-;
HET is a heterocycloalkyl ring moiety, optionally substituted with: (A) one to four -(C,-Cg)alkyl, optionally substituted with one to six halogen atoms, -(C,-Ce)alkoxy, cyano, halogen, hydroxy, or NR'R, or (B) -(C,-Ce)arylalkyl, optionally substituted with one to six halogen atoms, -(C,-Cg)alkoxy, cyano, halogen, hydroxy, or -NR*R® n is zero or one;
X is -CH,-, -CHF-, or -CF2- and Y is -CHz-, -CHF-, or -CF,-, provided that when nis one X and Y are not both CH, and when n is zero X is -CH,-; and
Z is hydrogen or cyano.
The present invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention, or a prodrug thereof, or a pharmaceutically acceptable salt of the compound or prodrug, or a solvate of the compound, prodrug or salt, and a pharmaceutically acceptable carrier, vehicle, diluent or excipient.
The present invention further relates to a method of treating diabetes comprising administering to a mamma! in need of such treatment a therapeutically effective amount of a compound of the present invention, or a prodrug thereof, or a pharmaceutically acceptable salt of the compound or of the prodrug, or a solvate of the compound, prodrug or salt. Preferably, the type of diabetes treated is Type 2 diabetes.
The present invention additionally relates to a method of treating a condition mediated by dipeptidyl peptidase-1V in a mammal comprising administering to said mammal in need of such treatment a therapeutically effective amount of a compound of the present invention, or a prodrug thereof, or a pharmaceutically acceptable salt of said compound or prodrug, or a solvate of said compound, prodrug or salt.
The compounds, and pharmaceutical compositions, of the present invention are useful for the treatment of diabetes, preferably Type 2 diabetes.
The compounds, and pharmaceutical compositions, of the present invention are also useful for the treatment of dipeptidyl peptidase-1V related conditions which include, but are not limited to, Type 2 diabetes; Type 1 diabetes, impaired glucose tolerance, hyperglycemia, metabolic syndrome (syndrome X and/or insulin resistance syndrome), glucosuria, metabolic acidosis, arthritis, cataracts, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, obesity, conditions exacerbated by obesity, hypertension, hyperlipidemia, atherosclerosis, osteoporosis, osteopenia, frailty, bone loss, bone fracture, acute coronary syndrome, short stature due to growth hormone deficiency, infertility due to polycystic ovary syndrome, anxiety, depression, insomnia, chronic fatigue, epilepsy, eating disorders, chronic pain, alcohol addiction, diseases associated with intestinal motility, ulcers, irritable bowel syndrome, inflammatory bowel syndrome; short bowel syndrome; and the prevention of disease progression in Type 2 diabetes.
The terms usad to describe the present invention have the following meanings herein.
The phrase "pharmaceutically acceptable” indicates that the designated carrier, vehicle, diluent, excipient(s), and/or salt is generally chemically and/or physically compatible with the other ingredients comprising the formulation, and physiologically compatible with the recipient thereof. ~The carbon atom content of the various hydrocarbon-containing moieties herein may be indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, for example, the prefixes (C,-Cp)alkyl, and C,.palkyl, indicate an alkyl moiety of the integer “a* to "b" carbon atoms, inclusive. Thus, for example, (C;-Ce)alkyl and C,.salkyi refer to an alkyl group of one to six carbon atoms inclusive.
The term “alkyl” denotes a straight or branched chain of carbon atoms, wherein the alkyl group optionally incorporates one or more double or triple bonds, or a combination of double bonds and triple bonds. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, vinyl, ally, 2- methylpropenyl, 2-butenyl, 1,3-butadienyl, sthynyl, propargyl, and the like.
The term "alkoxy" refers to straight or branched, monovalent, saturated aliphatic chains of carbon atoms bonded to an oxygen atom that is attached to a core structure. Examples of alkoxy groups include methoxy, ethoxy, propoxy, butoxy, iso-butoxy, tert-butoxy, and the like.
The term "cycloalkyl® denotes a saturated monocyclic or bicyclic cycloalkyl group. Cycloalkyl groups may be optionally fused to aromatic hydrocarbons such as benzene to form fused cycloalkyl groups, such as indanyl and the like. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
The term “halogen” or “halo” represents chioro, bromo, fluoro, and iodo atoms and substituents.
The term “aryl” denotes a monocyclic or polycyclic aromatic hydrocarbon group, for example, anthracenyl, fluorenyl, naphthyl, phenanthrenyl, phenyl, and the like.
The term “arylalkyl” means an alkyl group, as defined hereinabove, wherein at least one of the hydrogen atoms thereof has been substituted with an aryl group, also as defined hereinabove. Examples of arylalkyl groups include, inter alia, benzyl groups.
The term *heterocycloalkyl”, as employed with reference to HET hereinabove, refers to a saturated four- to eight-membered heterocyclic ring system, optionally fused to a tive- or six-membered aromatic or heteroaromatic ring system. Examples of heterocycioalky! groups comprise homopiperazinyl, piperazinyl, piperidyl, pyrrolidinyl, azetidinyl, 2-aza-bicyclo[2.2.1]heptanyl, 3-aza-bicycio[3.1.0Jhexanyl, 2,5-diaza- bicyclo{2.2.1}heptanyl, 5,6,7,8-tetrahydro-2H-imidazo{1,2-a]pyrazinyl, 5.6,7,8- tetrahydro[1,2,4]triazolo{4,3-a]pyrazinyl, 4,5,6,7-tetrahydropyrazolo{1,5-a]pyrazinyl, 5,6,7.8- tetrahydropyrido{3,4-d)pyrimidyl, 5,6,7,8-tetrahydropyrido{4,3-d}pyrimidyl, octahydropyrrolo{3,4-b)pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyt, 6-azabicyclo{3.2.1]octany!, 3,8-diazabicyclo{3.2.1Joctanyl, 2,3- dihydrospiro{indene-1,4'-piperidyl], spiro{lindene-1,4'-piperidyl], 1-oxa-8-azaspiro{4.5]decanyl, 8- azabicyclo{3.2.1]octanyl, 2,3,4,5-tetrahydrobenzoff){1,4]oxazepinyl, hexahydro-2H-pyrroiof3,4- dJisothiazolyl-1,1-dioxide, 2,7-diazaspiro{4.4jnonanyl, 6,7,8,9-tetrahydro-5H-[1,2,4]triazolo{4,3- gl(1,4]diazepinyl, 5,6-dihydro-8H-imidazo[1,2-a]pyrazinyl, 5,6-dihydro-8H-{1,2,4]triazolo{4,3-a)pyrazinyl, 7.8-dihydro-5H-pyrido{4,3-a)pyrimidy!, 7,8-dihydro-5H-pyrido{4,3-d]pyrimidyl, pyrazolof1,5-a)pyrimidyl, and the like. :
The term “heteroaryl” denotes a monocyclic or polycyclic aromatic heterocyclic ring system.
Exampies of heteroaryl groups comprise benzoisothiazolyl, benzisoxazolyl, benzooxazolyl, benzothiazotyl, benzofuranyl, benzothienyl, benzimidazolyl, cinnolinyl, furanyl, furopyridyl, imidazolopyrimidyl, imidazolyl, indazolyl, indolyl, isoquinolyl, isothiazolyl, isoxadiazolyl, isoxazolyl, oxazolopyridyl, oxadiazolyl, oxazolyl, phthalazinyl, pteridinyl, pyrazinyl, pyridazinyl, pyrrolopyrimidyl, pyrrolopyridyl, pyrazolopyrimidyl, pyrazolyl, pyridyl, pyrimidyl, pyrrolyl, quinazolyl, quinolyl, quinoxalinyl, tetrazolyl, thiazolyl, thiadiazolyl, thiazolopyridyl, thienopyridyl, thienyl, triazinyl, triazolyl, 1,1-dioxo-1H- 1,2-benzoiscthiazolyl, oxazolopyridyl, and the like.
The term "oxo", means a carbonyl group formed by the combination of a carbon atom and an oxygen atom.
The term "substituted® means that a hydrogen atom on a molecuie has been replaced with a different atom or molecule. The atom or molecule replacing the hydrogen atom is denoted as a “substituent.”
The symbol °-" represents a covalent bond.
The phrase “inert solvent" refers to a solvent, or mixture of solvents, that does not interact with starting materials, reagents, intermediates, or products in a manner that adversely affects their desired properties.
The terms “treating”, "treated", or “treatment” as employed herein includes preventative (e.g., prophylactic), palliative, and curative uses or results. 40 The phrase "therapettically effective amount® means an amount of a compound of the present invention that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates,
ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein.
The term *mammal® is an individual animal that is a member of the taxonomic class Mammalia. The class Mammalia includes, for example, humans, monkeys, chimpanzees, gorillas, cattie, swine, horses, sheep, dogs, cats, mice and rats. In the present invention, the preferred mammal is a human.
Preferably, the compounds of the present invention have the structure of Formula (1) wherein:
R' is aryl or heteroaryl, optionally substituted independently with one to three cyano, halogen, nitro, trifluoromethyl, -(C,-Cg)alkyl, -(C:-Cg)alkoxy, -(Cs-Ce)cycloalkyl, or phenyl;
R?is -H or -(C,-Ce)alkyl;
R® is -H -(C,-Ce)alkyl; and :
HET is azetidinyl, piperaziny!, piperidinyl, pyrrolidinyl, 5,6-dihydro-8H-imidazo{1.2-a}pyrazin-7-yl, 5,6-dihydro-8H-{1,2,4]triazolo{4,3-a)pyrazin-7-yl, or 7,8-dihydro-5H-pyrido{4,3-a]pyrimidin-6-yl.
More preferably, the compounds of the present invention have the structure of Formula (1A) \
NY
A,
N~( :
N lo) r4 (1A) wherein R' is benzoisothiazolyl, benzisoxazolyl, isothiazolyl, isoxazolyl, oxazolopyridyl, pyrazinyl, pyridinyl, pyrimidinyl, quinolinyl, quinoxalinyl, thiadiazolyl, triazinyl, or 1,1-dioxo-1H-1,2-benzoisothiazolyi.
In the present invention, it is preferred, for the compounds of Formula (IA), that R' is pyridinyl or pyrimidinyl and more preferred that R' is pyridiny! or pyrimidinyl, nis 1, Xis -CF.- and Y is -CH;-. . in the present invention, the compound (3,3-difluoropyrrolidin-1-yl)-((2S,45)-4-(4-(pyrimidin-2- yl)piperazin-1-yl)pyrrolidin-2-ylymethanons, or a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug, is most preferred.
In an altemate embodiment, a compound selected from the group consisting of: ((2S,45)-4-(3-(trifluoromethyl)-5,6-dihydro-[ 1,2,4]triazolo{4,3-a]pyrazin-7(8H)-yl)pyrrolidin-2-yt)-(3,3- difluoropyrrolidin-1-yl)-methanone, (3,3-difluoropyrrolidin-1-yi)-((2 S,4 S)-4-(4-(oxazolo[5, 4-b]pyridin-2-yl)piperazin-1-yi)pyrrolidin-2-yl)- methanone, (3,3-difluoropyrrolidin-1-yi)-((25,4 S)-4-(4-(4-methyipyrimidin-2-yl)piperazin-1-yl)pyrrolidin-2-yl)- methanone, {(25,45)-4-(2-(trifluoromethy!)-7,8-dihydropyrido{4, 3-d)pyrimidin-6(5H)-yl)pyrrolidin-2-y1)-(3,3- difluoropyrrolidin-1-yl)-methanone, ({(S)-3-tluoro-pyrrolidin-1-yl)-{(2S,4 S)-4-[4-(3-trif luoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyrrolidin-2- yl}-methanone,
((S)-3-tiuoro-pyrrolidin-1-yl)-[(2 S,45)~4-(2-trifluoromethy\-7,8-dihydro-5H-pyrido{4,3-djpyrim idin-6-yl)- pyrrolidin-2-ylj-methanone, (3,3-difluoro-pyrrolidin-1 -yi)-[(25,45)-4-(4-oxazolo[4,5-cipyridin-2-yl-piperazin-1 -yl)-pyrrolidin-2-yi}- methanone, . [(25,45)-4-(2-cyclopropyl-7,8-dihydro-5H-pyrido{4,3-dlpyrimidin-6-yl)-pyrrolidin-2-yi]-(3-fluoro- azetidin-1-yl)-methanone, (3,3-difluoro-pyrrolidin-1-yl)-{(2 S,45)-4-(2-athoxy-7,8-dihydro-5H-pyrido[4,3-djpyrimidin-6-yl)- pyrrolidin-2-yl]-methanone, 2-{4-[(35.55)-5-(3-fluoro-azetidine-1 -carbonyl)-pyrrolidin-3-y!}-piperazin-1-yl}-nicotinonitrile, ((S)-3-fluoro-pyrrolidin-1 -yl)-{(2S,48)-4-(4-oxazolo[5,4-b)pyridin-2-yl-piperazin-1 -yl)-pyrrolidin-2-yl]- methanone, (3-fluoro-azetidin-1 -yl){(25,45)-4-(2-trifluoromethy|-7,8-dihydro-6H-pyrido[4,3-dlpyrimidin-6-yl)- pyrrolidin-2-yl]-methanone, 2-{4-{(3S,55)-5-((S)-3-fluoro-pyrrolidine-1 -carbonyl)-pyrrolidin-3-yl]-piperazin-1-yl}-nicotinonitrile, (3-tluoro-azetidin-1 -yl)-{(2S,45)-4{4-(2-trifluoromethyl-quinolin-4-yl)-piperazin-1 -yl]-pyrroiidin-2-yl}- methanone, ((3A",45*)-3,4-difluoro-pyrrolidin-1 -yIH(25.45)-4-(2-trifluoromethyl-7,8-dihydro-SH-pyrido{4,3- dpyrimidin-6-yl)-pyrrolidin-2-yl-methanone, and ((3R",45*)-3,4difluoro-pyrrolidin-1 -yl)-[(2S,4S)-4-(4-0xazolo[5,4-b]pyridin-2-yl-piperazin-1-yl)- pyrrolidin-2-yl)-methanons, or a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug, is preferred. :
The compounds of the present invention contain all contain at least two stereogenic centers, specifically the (2S, 4S) pyrrolidin-2-yl, stereogenic centers shown below in Formula (1). "=
HET R2 ~
Ho 2
The compounds of the present invention may be resolved into the pure enantiomers by methods known to those skilled in the art, for example by formation of diastereoisomeric salts which may be separated, for example, by crystallization; formation of diasterecisomeric derivatives or complexes which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic esterification; or gas- liquid or liquid chromatography in a chiral environment, for example on a chiral support for example silica with a bound chiral ligand or in the presence of a chiral solvent. It will be appreciated that where the desired stereoisomer is converted into another chemical entity by one of the separation procedures described above, a further step is required to liberate the desired enantiomeric form. Alternatively, the specific stereoisomers may be synthesized by using an optically active starting material, by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one stereoisomer into the other by asymmetric transformation.
Wherein said compounds contain one or more additional stereogenic centers, those skilled in the art will appreciate that all diasterecisomers and diastereoisomeric mixtures of the compounds illustrated and discussed herein are within the scope of the present invention. These diasterecisomers may be isolated by methods known to those skilled in the art, for example, by crystallization, gas-liquid or liquid chromatography. Altenatively, intermediates in the course of the synthesis may exist as racemic mixtures and be subjected to resolution by methods known to those skilled in the art, for example by formation of diastereoisomeric salts which may be separated, for example, by crystallization; formation of diastereoisomeric derivatives or complexes which may be separated, for example, by crystallization, gas- liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic esterification; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support for example silica with a bound chiral ligand or in the presence of a chiral solvent. it will be appreciated that where the desired stereocisomer is converted into another chemical entity by one of the separation procedures described above, a further step is required - to liberate the desired enantiomeric form. Alternatively, specific stereoisomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one stereoisomer into the other by asymmetric transformation.
Certain compounds of Formula (I) may exist in different stable conformational forms which may be separable. Torsional asymmetry due to restricted rotation about an asymmetric single bond, for example because of steric hindrance or ring strain, may permit separation of different conformers. The present invention includes each conformational isomer of compounds of Formula (1) and mixtures thereof.
Practitioners will appreciate that certain compounds of Formula (I) may exist in tautomeric form, i.e., that an equilibrium exists between two isomers which are in rapid equilibrium with each other. A common example of tautomerism is keto-enol tautomerism, i.e.,
Ax _— LS° 0) 0 :
Examples of such compounds of the present invention include, inter alla, hydroxypyridines (pyridones) and hydroxypyrmidines (pyrimidones). In particular, a person skilled in the art will recognize that a hydroxypyridine of the instant invention can exist as two separate tautomers, e.g.,
NR 2
ZN _ | NH
OH o
The degree to which one tautomer is prasent over the other depends upon various factors, including substitution pattern and solvent type. Other examples in accordance with the present invention will be recognized by those skilled in the art. All tautomeric forms of Formula (1) are included within the scope of the claimed invention.
The compounds of the present invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace unsolvated forms, solvated forms and mixtures of solvated forms.
Certain compounds of Formula (1) and their salts and solvates may axist in more than one crystal form. Polymorphs of compounds represented by Formula (I) form part of this invention and may be prepared by crystallization of a compound of Formula (1) under different conditions. For example, using different solvents or different solvent mixtures for recrystallization; crystallization at different temperatures; various modas of cooling, ranging from very fast to very slow cooling during crystallization.
Polymorphs may also be obtained by heating or meiting a compound ot Formula (1) followed by gradual or fast cooling. The presence of polymorphs may be determined by solid probe nmr spectroscopy, ir spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques.
This invention also includes isotopically-labeled compounds, which are identical to those described by Formula (1), but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur and fluorine, such as 2H, *H, iC, ¥C, *N, **0, 0, ®s, *CI, "#1, '®), and "°F respectively. Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of the compounds or of the prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes such as *H and '‘C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated (i.e., %H), and carbon- 14 (i.e., '*C), isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (ie., 2H), can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds of
Formula (I) of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes and/or in the Examples below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
Phamaceutically acceptable salts, as used herein in relation to compounds of the prasent invention, include pharmaceutically acceptable inorganic and organic salts of said compound. These salts can be prepared in situ during the final isolation and purification of a compound, or by separately reacting the compound or prodrug with a suitable organic or inorganic acid and isolating the salt thus formed.
Representative salts include, but are not limited to, the hydrobromide, hydrochloride, hydroiodide, sulfate, bisulfate, nitrate, acetate, trifluoroacetate, oxalate, besylate, palmitate, pamoate, malonate, stearate, laurate, malate, borate, benzoate, lactate, phosphate, hexafluorophosphate, benzene sulfonate, tosylate, formate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate and laurylsulphonate salts, and the like. These may also include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to, 40 ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine,
triethylamine, ethylamine, and the like. For additional examples see, for example, Berge, et al.. J.
Pharm. Sci., 86, 1-19 (1977).
The compounds of the present invention may be isolated and used per se or in the form of their pharmaceutically acceptable salts or solvates. In accordance with the present invention, compounds with multiple basic nitrogen atoms can form salts with varying number of equivalents of acid. It will be understood by practitioners that all such salts are within the scope of the present invention.
A prodrug of a compound of Formula (I) may be one formed in a conventional manner with a functional group of the compound, such as with an amino, hydroxy or carboxy group. The term “prodrug” means a compound that is transformed in vivo to yield a compound of Formula m ora pharmaceutically acceptable salt or solvate of the compound. The transformation may occur by various mechanisms, such as through hydrolysis in blood. A discussion of the use of prodrugs is provided by T.
Higuchi and W. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical
Association and Pergamon Press, 1987.
For example, if a compound of the present invention incorporates an amine tunctional group, a prodrug can be formed by the replacement of a hydrogen atom: in the amine group with a group such as
R-carbonyl, RO-carbonyl, NRR'-carbonyl where R and R' are each independently (C-Cio)alkyl, (Cs-
Cr)cycloalkyl, benzyl, or R-carbonyi is a natural a-aminoacyi or natural a-aminoacyi-natural a-aminoacy!, -C(OH)C(O)OY' wherein Y' is H, (C,-Cs)aikyl or benzyl, -C(OYo)Y, wherein Yg is (C1-Co) alkyl and Y; is (Ci-Ce)alkyl, carboxy(Cy-Calalkyl, amino(C;-Caalkyl or mono-N- or di-N,N-(Cy-Ce)alkylaminoalkyl, -
C(Y2)Y; wherein Y2 is H or methyl and Y; is mono-N- or di-N,N-(C,-Cs)alkylamino, morpholino, piperidin- 1-yl or pyrrolidin-1-yi.
Similarty, if a compound of the present invention contains an aicohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as (Cy- Ce)alkanoyloxymethyi, 1-((Ci-Ce)alkanayloxy)ethyl, 1-methyl-1-((C,-Ce)alkanoyloxy)ethyl, (C,-
Ce)alkoxycarbonyloxymethyl, N-(C,-Cs)alkoxycarbonylaminomethyl, succinoyl, (C.-Cg)alkanoyl, a- amino(C,-C.)alkanoyl, arylacyl and a-aminoacyl, or a-aminoacyl-o-aminoacyl, where each a-aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH)z, -P(O)(O(C,-
Ce)alky!l), or glycosyl (the radical resulting from the removal of a hydroxy! group of the hemiacetal form of a carbohydrate).
If a compound of the prasent invention contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as (C,-Cg)alky!, (C2-Cyz)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 8 carbon atoms, 1- methyi-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1- (alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyi)aminomethyl having from 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyt)amino)ethy! having from 4 to 10 carbon atoms, 3-phthalidyl, 4- crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(C,-C,)alkylamino(C,-C;)alkyt (such as f- ’ dimethylaminoethyl), carbamoyl-(C,-C)alkyl, N,N-di(C,-C.)alkylcarbamoyl-(C,-C.)alkyl and piperidino-, 40 pyrrolidino- or morpholino(C,-Cs)alky!.
in general, the compounds of Formula (1) of this invention may be prepared by methods that include processes known in the chemical arts, particularly in light of the description contained herein. Certain processes for the manufacture of the compounds of Formula (1) of this invention are illustrated by the following reaction schemes. Other processes are described in the experimental section. The methods disclosed in the instant Schemes and Examples are are intended for purposes of exemplifying the instant invention, and are not to be construed in any manner as limitations thereon.
Some of the starting compounds for the reactions described in the schemes and Examples are prepared as illustrated herein. All other starting compounds may be obtained from general commercial sources, such as Sigma-Aldrich Corporation, St. Louis, MO.
In the discussions below, the following abbreviations are used: BOC (tert-butoxycarbonyl), Cbz (benzyloxycarbonyl), DMF (N,N-dimethylformamide), NMP (N-methyl-2-pyrrolidinone), DMAC (N,N- dimethylacetamide), DME (dimethoxyethane), DMSO (dimethyisulfoxide), EtOAC (ethyl acetate), EtOH ~ (ethanol), MeOH (methanol), TFA (trifluoroacetic acid), TFAA (trifluoroacetic anhydride), TEA (triethylamine), THF (tetrahydrofuran), DIPEA (diisopropylethyiamine), EDC (1-(3-dimethylaminopropyl)- 3-carbodiimide)), DCC (dicyclohexylcarbodiimide), CDI (1,1'-carbonyidiimidazole), HATU (O-(7- azabenzotriazol-1-yl)-N,N,N’,N'-tetramethyluronium hexafiuorophosphate), HOAT (1-hydroxy-7- azabenzotriazole), HOBT (N-hydroxybenzotriazole), and EEDQ (2-ethoxy-1-ethoxycarbonyi-1,2- . dihydroquinoline).
A generalized method for preparing the compounds of formula (1) is depicted in Scheme 1' 20. hereinbelow.
Scheme 1 rm R “Ee LE
X,
N. 1 am (i) 0)
In Scheme 1, a compound of formula (It), prepared as described in Scheme 2, wherein P represents a nitrogen-protecting group, is deprotected according to known methods. If P represents BOC, deprotection is typically effected by first treating (il), dissolved in a solvent such as EtOAc, ether dioxane or water, with optional cooling at a suitable temperature, such as about 0°C, with acid (e.g., hydrogen chloride) for a suitable time, such as about 5 minutes to about an hour. The solution is allowed to warm to room temperature (RT), followed by stirring for an additional amount of time, typically an additional 30 minutes to about 16 hours. Preferably, the reaction mixture Is stirred about 15 minutes, allowed to reach room temperature, then stirred an additional 30 minutes. Alternatively, (Il) is dissolved in TFA and, after a suitable time (e.g., about 30 min to about 24 hours), excess TFA is removed in vacuo, and the residual product is triturated with a solvent such as ether. If P represents Cbz, deprotection may be performed by hydrogenolysis in the presence of catalyst, such as 10% palladium or palladium hydroxide, in a suitable solvent such as EtOH or EtOAC at a pressure of about 30 psi to about 60 psi, for a sufficient period of time, usually overnight, at a temperature of between about 20° C and about 80° C. Preferably, hydrogenolysis is effected at a pressure of about 45 psi at room temperature.
The compounds of formula (Il) may be prepared by coupling an appropriately-substituted carboxylic acid derivative (Ill) with an appropriately-substituted amine derivative (IV) as depicted herainbelow in
Scheme 2.
Scheme 2 a—0 Rl—"
ELE s od Fon, ( n
PG I (Iv) b (ny (0)
P4
The coupling is typically accomplished by combining (Ili) and (IV) ina reaction-inert solvent, preferably an aprotic solvent such as acetonitrile, dichloromethane, DMF, THF, or chloroform. A coupling agent, such as EDC, HATU, DCC, EEDQ, CDI, pivaloyl chloride or diethylphosphoryicyanide is then added, optionally in the presence of a base, such as TEA or pyridine, and an optional adjuvant, such as
HOBT or HOAT. The coupling is typically effected at a temperature of between about 0° C and about 50°
C, for a suitable time, such as from about one hour and about 24 hours, for example about 16 hours. For a discussion of other conditions useful for coupling carboxylic acids see Houben-Weyl, Vol. XV, Part li, E.
Wunsch, Ed., G. Theime Verlag, (1974), Stuttgart; M. Bodansky, “Principles of Peptide Synthesis”, -
Springer-Verlag Berlin (1984); and “The Peptides: Analysis, Synthesis and Biology” (ed. E. Gross and J.
Meienhoter), Vols. 1-5 (Academic Press NY 1979-1983). The compounds of formulae (lil) and (IV) may be prepared by known methods or, altematively, according to the exemplary preparative procedures "described hereinbelow. For exemplary preparations of formula (IV) amines, see PCT International
Application Publication No. WO 2003/101958 and U.S. Pat. No. 6,710,040, the disclosure of which is incorporated herein by reference.
Alternatively, the compounds of formula (1) may be prepared as described below in Scheme 3.
Scheme 3
Rr'—Q 0) R? R® x Te) R2 , x
TX — Tg 0 7 Rp'—Q 1S } v1) \ ~X v) a
In Scheme 3, the compounds of formula (il) are prepared by reductive amination of a protected ketone (V), prepared as described hereinbelow in Scheme 4, with an appropriately-substituted heterocycloalkylamine (VI). Such amination reactions are well-known to one skilled in the art. See, for example, A.F. Abdel-Magid, et al., J. Org. Chem., 61, 3848 (1996); R.F. Borch, et al., J. Am. Chem.
Soc., 93, 2897 (1971); and S. Bhattacharyya, et al; "Synlett, 1079 (1995). The formula (Vi) amines are well-known in the relevant art and may be obtained commercially or prepared by known methods. See,
for example, D.A. Horton, et al., Chem. Rev., 103, 893-930 (2003), H. Fukui, et al, Heterocycles, 56, 257- 264 (2002), M.Y. Chu-Moyer, et al., J. Org. Chem., 60, 5721-5725 (1995), and J.P. Yevich, et al., J. Med.
Chem., 29, 359-369 (19886).
Typically, (V) and (VI) are condensed in the presence of a reducing agent such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, tetramethylammonium triacetoxyborohydride, or hydrogen in the presence of a catalyst (10% Pd/C, platinum oxide, etc.), optionally in the presence of an acid (e.g. acetic acid (AcOH), hydrochloric acid, etc.). The coupling is normally effected in a reaction-inert solvent, such as 1,2-dichloroethane, THF, DMF, EtOH, or MeOH.
The reaction is performed at a suitable temperature, such as 0 to 50°C, for a suitable period of time, such as between about one to about 24 hours, for example, about 16 hours, :
The compounds of formula (V) may be prepared as described hereinbelow in Scheme 4, beginning with, as appropriate, commercially available carboxylic acid (V1), ketocarboxylic acid (IX), or ketoester (X). : Scheme 4
HO, HO, \
N any N. z po© Ry b© (VID av 2 (vin)
Step 2 0 ° Xs o F x
J a UT /
N XS N Y N ~ \ (Fem yf iL © \ F4 p HN—, P P ax) avy’ (Va) R*=R’<H) wv) pe hydrolysis 0 fe) R? 3 Step 7 coupling
D> Step 5 [pu bp © L 0 XD
In Scheme 4, Step 1, protected acid (Vil) is coupled with amine (IV) as described hereinabove in
Scheme 2 to afford alcohol (VIII). in Scheme 4, Step 2, alcohol (VIII) is oxidized to ketone (Va) by treating (Vil) with an oxidizing agent in a reaction-inert solvent. Examples of appropriate oxidizing agents comprise pyridine/sulfur trioxide in DMSO; aqueous sodium hypochlorite in the presence of sodium bromide and TEMPO (2,2,6,6- tetramethyl-1-piperidinyloxy) free radical catalyst; chromium based reagents, such as chromium trioxide, pyridinium dichromate, or pyridinium chiorochromate; and oxalyl chloride in DMSO in the presence of a tertiary amine. Examples of reaction-inert solvents comprise dichloromethane, EtOAc, toluene, or pyridine. The oxidation is typically conducted at a temperature of between about -78°C and about 50°C,
for between about one and about 24 hours, for example, about 16 hours. Such oxidations are well-known to one skilled in the art. See, for example, M. Tamaki, et al., J. Org. Chem., 66, 3593 (2001) and X-I. Qiu, et al., J. Org. Chem., 67, 7162 (2002).
In Scheme 4, Step 3, protected ketocarboxylic acid (IX) is first coupled with amine (IV), as described hereinabove in Scheme 2, to afford (Va), which is then alkylated to atford ketone (V). The alkylation is typically effected by first forming an enamine by reacting ketone (Va) with a secondary amine, for example, pyrrolidine, piperidine or morpholine, followed by treatment with an alkylating agent, optionally in the presence of a base, such as potassium carbonate. Typically, the reaction is effected in a solvent such as benzene, toluene, acetonitrile, or dioxane. Such conversions are weli-known to one skilled in the art. See, for example, G. Stork, et al., J. Am. Chem. Soc., 85, 207 (1963); M.W. Holladay, et al, J. Med.
Chem.. 34, 455 (1991); and P. Barraclough, et al., Tetrahedron, 51, 4195 (1995).
In Scheme 4, Step 5, protected ketoester (X), wherein R represents an alkyl or arylalkyl moiety, Is alkylated under the conditions previously described in Step 4 to afford ketoester (X1).
In Scheme 4, Step 6, ketoester (XI) is saponified to yield the corresponding carboxylic acid which, in
Step 7, is coupled with an appropriately-substituted amine (IV), as previousty described hereinabove in
Scheme 2. The saponification step is typically accomplished by dissolving (XI) in a water-miscible solvent, such as MeOH or EtOH, and water in the presence of a base, such as lithium hydroxide or sodium hydroxide. The saponification is effected at suitable temperature, such as between about 0 °C and about 100 °C, preferably room temperature, for a suitable time, such as between about one and about 24 hours, for example, about 16 hours.
Preferably, a pharmaceutical composition of the present invention comprises a therapeutically effective amount of a compound of Formula (1A), or a prodrug thereof, or a pharmaceutically acceptable salt of the compound or prodrug, or a solvate of the compound, prodrug or salt, and a pharmaceutically acceptable carrier, vehicle, diluent or excipient.
More preferably, a pharmaceutical compasition of the present invention comprises a therapeutically effective amount of the compound (3.3-difluoropyrrolidin-1-y)-((2S,45)~4-(4-(pyrimidin-2-yl)piperazin-1- yi)pyrrotidin-2-yl)methanone, or a prodrug thereof, or a pharmaceutically acceptable salt of said compound or prodrug, or a solvate of said compound, prodrug or salt; and a pharmaceutically acceptable carrier, vehicle, diluent or excipient.
The pharmaceutical compositions formed by combining the compounds of this invention and the pharmaceutically acceptable carriers, vehicles or diluents are then readily administered in a variety of dosage forms such as tablets, powders, lozenges, syrups, injectable solutions and the like. These pharmaceutical compositions can, it desired, contain additional ingredients such as flavorings, binders, excipients and the like.
Thus, for purposes of oral administration, tablets containing various excipients such as sodium citrate, calcium carbonate and/or calcium phosphate, may be employed along with various disintegrants such as starch, alginic acid and/or certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and/or acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and taic are often useful for tabletting purposes. Solid compositions of a 40 similar type may also be employed as fillers in soft and hard filled gelatin capsules. Preferred materials for this include lactase or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the active pharmaceutical agent therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, it desired, emulsifying or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin and/or combinations thereof.
For parenteral administration, solutions of the compounds or compositions of this invention in sesame or peanut oil, aqueous propylene glycol, or in sterile aqueous solutions may be employed. Such aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. In this connection, the sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
For intranasal administration or administration by inhalation, the compounds or compositions of the invention are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant, 6.g., dichlorodifluoromethane, trichlorofiuoromethane, dichlorotetrafiuoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurized container or nebulizer may contain a solution or suspension of a compound of this invention. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated containing a powder mix of a compound or compounds of the invention and a suitable powder base such as lactose or starch.
Methods of preparing various pharmaceutical compositions with a certain amount of active ingredient are known, or will be apparent in light of this disclosure, to those skilled in this art. For examples of methods of preparing pharmaceutical compositions, see Remington's Pharmaceutical .
Sciences, Mack Publishing Company, Easton, Pa., 19th Edition (1985). in another aspect, the invention is directed to a pharmaceutical composition, which comprises a therapeutically effective amount of a first compound of Formula (1), a prodrug thereof or a pharmaceutically acceptable salt of the compound or the prodrug; a second compound that is an antidiabetic agent selected from insulin and insulin analogs; insulinotropin; biguanides; 0g-antagonists and imidazolines; glitazones; aldose reductase inhibitors; glycogen phosphorylase inhibitors; sorbitol dehydrogenase inhibitors; fatty acid oxidation inhibitors; a-glucosidase inhibitors; B-agonists; phosphodiesterase inhibitors; lipid-lowering agents; antiobesity agents; vanadate and vanadium complexes and peroxovanadium complexes; amylin antagonists; glucagon antagonists; growth hormone secretagogues; gluconeogenesis inhibitors; somatostatin analogs; antilipolytic agents; a prodrug of the antidiabetic agents, or a pharmaceutically acceptable salt of the antidiabetic agents and the prodrugs.
In another aspect, the invention is directed to a kit comprising: a first dosage torm comprising a compound of Formula (1), or a prodrug thereof, or a pharmaceutically acceptable sait of the compound or prodrug, or a solvate of the compound, prodrug or salt; and a second dosage form comprising an antidiabetic agent selected from insulin and insulin analogs; insulinotropin; biguanides; a;-antagonists 40 and imidazolines; glitazones; aldose reductase inhibitors; glycogen phosphorylase inhibitors; sorbitol dehydrogenase inhibitors; fatty acid oxidation inhibitors; a-glucosidase inhibitors; B-agonists;
phosphodiesterase inhibitors; lipid-lowering agents; antiobesity agents; vanadate and vanadium complexes and peroxovanadium complexes; amylin antagonists; glucagon antagonists; growth hormone secretagogues; gluconeogenesis inhibitors; somatostatin analogs; antilipolytic agents; prodrugs of the antidiabetic agents, or a pharmaceutically acceptable salte of the antidiabetic agents and the prodrug; § and a container for containing said first dosage (a) and said second dosage (b). In a preferred embodiment of the kit, both the first and the second dosage forms independently comprise a pharmaceutically acceptable carrier or diluent.
In another aspect, the invention is directed to a therapeutic method of inhibiting dipeptidyl peptidase-
IV comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Formula (I), or a prodrug thereof, or a pharmaceutically acceptable salt of the compound or of the prodrug, or a solvate of the compound, prodrug or salt; either alone or in combination with an antidiabetic agent as described above.
In another aspect, the invention is directed to a method of treating a condition mediated by dipeptidyl peptidase-1V inhibition comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Formula (!), or a prodrug thereof, or a pharmaceutically acceptable sait of the compound or of the prodrug, or a solvate of the compound, prodrug or salt; either alone or in combination with an antidiabetic agent as described above.
In one embodiment, the condition treated is Type 2 diabetes, Type 1 diabetes, impaired glucose tolerance, hyperglycemia, metabolic syndrome (syndrome X and/or insulin resistance syndrome), glucosuria, metabolic acidosis, arthritis, cataracts, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, obesity, conditions exacerbated by obesity, hypertension, hyperlipidemia, atherosclerosis, osteoporosis, osteopenia, frailty, bone loss, bone fracture, acute coronary syndrome, short stature due to growth hormone deficiency, infertility due to polycystic ovary syndrome, anxiety, depression, insomnia, chronic fatigue, epilepsy, eating disorders, chronic pain, alcohol addiction, diseases associated with intestinal motility, ulcers, irritable bowel syndrome, inflammatory bowel syndrome; short bowel syndrome; and.the prevention of disease progression in Type 2 diabetes.
In a preferred embodiment, the condition treated is Type 2 diabetes.
In another aspect, the invention is directed to a method of identifying an insulin secretagogue agent for diabetes, comprising: administering an agent of Formula (i) to a fasted, diabetic KK/H1J symptomatic mouse; and assessing a response in the mouse to a subsequent oral glucose challenge, wherein, if said mouse demonstrates an improvement in the symptoms, said agent is identified as a treatment for Type 2 diabetes, Type 1 diabetes, impaired glucose tolerance, hyperglycemia, metabolic syndrome (syndrome X and/or insulin resistance syndrome), glucosuria, metabolic acidosis, arthritis, cataracts, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, obesity, conditions exacerbated by obesity, hypertension, hyperlipidemia, atherosclerosis, osteoporosis, osteopenia, frailty, bone loss, bone fracture, acute coronary syndrome, short stature due to growth hormone deficiency, infertility due to polycystic ovary syndrome, anxiety, depression, insomnia, chronic fatigue, epilepsy, eating disorders, chronic pain, alcoho! addiction, diseases associated with intestinal motility, ulcers, 40 irritable bowel syndrome, inflammatory bowel syndrome; short bowel syndrome, and to prevent disease progression in Type 2 diabetes.
The present invention also relates to therapeutic methods for treating or preventing the above described conditions in a mammal, including a human, wherein a compound of Formula (1) of this invention is administered as part of an appropriate dosage regimen designed to obtain the benefits of the therapy. The appropriate dosage regimen, the amount of each dose administered and the intervals between doses of the compound will depend upon the compound of Formula (1) of this invention being used, the type of pharmaceutical compositions being used, the characteristics of the subject being treated and the severity of the conditions. :
In general, an effective dosage for the compounds of the present invention is in the range of 0.01mg/kg/day to 30 mg/kg/day, preferably 0.01 mg/kg/day to 5 mg/kg/day of active compound in single or divided doses. Some variation in dosage will necessarily occur, however, depending on the condition of the subject being treated. The Individual responsible for dosing will, in any event, determine the appropriate dose for the individual subject. Practitioners will appreciate that “kg” refers to the weight of the patient measured in kilograms.
The compounds or compositions of this invention may be administered in single (s.g., once daily) or multiple doses or via constant infusion. The compounds of this invention may also be administered alone or in combination with pharmaceutically acceptable carriers, vehicles or diluents, In either singie or multiple doses. Suitable pharmaceutical carriers, vehicles and diluents include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents.
The compounds or compositions of the present invention may be administered to a subject in need of treatment by a variety of conventional routes of administration, including orally and parenterally, (e.g., intravenously, subcutaneously or intramedullary). Further, the pharmaceutical compositions of this invention may be administered intranasally, as a suppository, or using a “flash” formulation, i.e., allowing the medication to dissolve in the mouth without the need to use water.
EXEMPLIFICATION
Unless noted otherwise, all reactants were obtained commercially.
Flash chromatography was performed according to the method described by W.C. Still et al. in J.
Org. Chem. 1978, 43, 2823.
PREPARATIVE EXPERIMENTAL
The compounds and intermediates of the present invention were generally named according to the
IUPAC (International Union for Pure and Applied Chemistry) recommendations on Nomenclature of
Organic Chemistry and the CAS Index rules.
Preparation 1
Step1 - tert-butyl-(2S,4R)-2-{(3.3-Difluoropyrrolidin-1-yl)carbonyll-4-hydroxypyrrolidine-1-carboxylate
TEA (0.77 mL, 5.5 mmol) was added to a suspension of 3,3-difluoropyrrolidine hydrochloride (0.79 g, 5.5 mmol; Synlett, 55 (1995)), in 10 mL of dichloromethane. After five min, (4R)-1-(tert-butoxycarbonyl)- 4-hydroxy-L-proline (1.16 g, 5 mmol), HOBt (0.74 g, 5.5 mmol), and EDC (1.05 g, 5.5 mmol) were added.
After stirring the reaction overnight, the mixture was washed sequentially with saturated sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and concentrated. The residue was 40 purified by chromatography (Biotage® Flash 40S (A Dynax Corp.; Charlottesville, VA), 9:1 dichloromethane:methanol) to afford 1.07 g of a light pink foam. Additional product (0.26 g) was obtained by repeated dichloromethane extractions of the aqueous layer to provide an overall yield of 1.33 g (83%).
MS m/z 321 (MH). . Step 2
DMSO (0.57 mL, 8 mmol) in 3 mL dichloromethane was added dropwise to a solution of oxalyl chloride (0.38 mL, 4.4 mmol) in 10 mL dichloromethane at - 65 °C. After five min, a solution of the product of Step 1 (1.28 g, 4 mmol) in 20 mL dichloromethane was added. After 15 min, TEA (2.79 mL, 20 mmol) was added. The reaction mixture was allowed to warm to RT. After 2 hr, the mixture was poured onto ice. The organic layer was separated, washed sequentially with 10% NaHCO; solution and brine, dried (MgSO.), and concentrated. The residue was purified by chromatography (Biotage® Flash 40S, 95:5 dichloromethane:MeOH) to afford 765 mg (60%) of the title compound. MS m/z 319 (MH").
Alternatively, tert-butyl-(25)-2-{(3,3-difluoropyrrolidin-1 -yl)carbonyl]-4-oxopyrrolidine-1-carboxylate may be prepared according to the foliowing procedure. 1-(tert-Butoxycarbonyt)-4-oxo-L-proline (6.88 g, 30 mmol), HOBt (4.46 g, 33 mmol), EDC (6.326 g, 33 mmol), and 3,3-difluoropyrrolidine hydrochloride (4:52 g, 31.5 mmol) were dissolved in 100 mL of dichloromethane and the reaction mixture was cooled to 0° C in an ice bath before adding TEA (8.4 mL, 60 mmol). The reaction mixture was then allowed to warm to RT. After stirring overnight, saturated sodium bicarbonate (100 mL) was added and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by chromatography (Biotage® Flash 40M, eluting with 1:10 dichloromethane:hexanes) to afford the title compound 7.85 g (82% yield). MS (El) m/z 319.3 (MH"). tort-Butyl (25)-2-{[(3R* 4S 1-3.4-difluoropytrolidin-1-yl]carbonyl}-4-oxopyrrolidine-1-carboxylate
Step 1 - tert-Butyl (25.4-2-{[(3R* 459-3. 4difluoropyrrolidin-1-yl]carbonyl}-4-hydroxypyrrolidine-1- . carboxylate (4R)-1-(tert-butoxycarbonyl)-4-hydroxy-L-proline (2.31 g, 10 mmol), was coupled with (3A,45)-ret- 3,4-difluoropyrrolidine hydrochloride (1.44 g, 10 mmol, Preparation 4), in a manner analogous to that described in Preparation 1, Step 1, to afford 2.15 g (67%) of the title product as an off-white foam. MS m/z 321 (MH).
Step 2
The product of Step 1 (1.97 g, 6.15 mmol) was oxidized in a manner analogous to that described in
Preparation 1, Step 2, to afford 0.74 g (38%) of the title compound as a tight yellow solid. MS m/z 319 (MH").
Preparation 3 {45)-1-{tert-Butoxycarbonyl)-4-(4-pyrimidin-2-yipiperazin-1-yl)-L -proling 1-(teri-Butoxycarbonyl)-4-oxo-L-proline (1.0 g, 4.4 mmol), 2-piperazin-1-yipyrimidine (0.73 g, 4.4 mmol), and acetic acid (275 ul, 4.6 mmol) were dissolved in.20 mL of anhydrous 1,2-dichlorosthane and sodium triacetoxyborohydride (1.85 g, 8.7 mmol) was added. After agitating at RT for 24 hr, the reaction mixture was quenched with saturated NaHCO,. The pH was adjusted to pH 7 by addition of solid
NaHCO; and concentrated HCI, the mixture was extracted with dichloromethane, dried over MgSO, 10 filtered, and concentrated to afford 1.0 (61%) of crude material that was sufficiently pure for further use.
MS m/z 378 (MH").
Preparation 4 (3R.4S)-ret-3.4-Ditiyoro-pyrrolidine hydrochloride 3-Pyrroline (10 g, 0.145 mol) was added to a slurry of sodium bicarbonate (14 g, 0.17 mol) in toluene (100 mL). The mixture was cooled to 0° C and benzyl! chioroformate (23 mL, 0.16 mol) was added dropwise. After stirring overnight the solution was diluted with dichloromethane, washed with cold water and brine, dried over magnesium sulfate, and concentrated to a pale yeliow oil that was distilled in vacuo.
Bp 119-126 °C (0.32 mm).
The title compound of Step 1 (3.0 g, 15 mmol) was dissolved in a mixture of acetonitrile (100 mL) and water (70 mL) containing ethylenediamine tetraacetate, disodium salt dihydrate (11 mg, 0.03 mmol).
The solution was cooled to 0°C and 1,1,1-trifluoroacetone (14.5 mL, 160 mmol) was added over 10 min.
Potassium peroxymonosulfate (45 g, 74 mmol) was added portionwise over 40 min while maintaining the pH at 7 by adding sodium bicarbonate. The mixture was stirred at 0°C for 1.5 hr then poured into water and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and concentrated to a colorless oil (3.45 g, 100%).
A mixture of TEA trihydrofluoride (1.95 mL, 12 mmol) and the title compound of Step 2 (2.62 g, 12 mmol) was heated to 155 °C for three hr, cooled, and partitioned between water and dichloromethane.
The aqueous phase was extracted again with dichloromethane and the combined organic extracts were washed with brine, dried over magnesium sultate and concentrated. The residue was purified by flash- chromatography (1% methanol in dichloromethane) to give the title compound as a pale oil (1.14 g, 40%).
Step 4 - (3R.4)-rel-3.4-Difluoro-pyrrolidine-1-carboxviic acid benzyl ester
A solution of the title compound of Step 3 in dichloromethane (15 mL) was cooled to -50 °C and [bis{2-methoxyethyl)amino]sultur trifluoride (1.3 mL, 6.9 mmol) was added. The solution was warmed to room temperature over 18 hr then partitioned between water and EtOAc. The aqueous phase was extracted again with EtOAc and the combined organic extracts were washed with brine, dried over magnesium sulfate, and concentrated. The residue was purified by flagsh-chromatography (dichloromethane) to give the product as a brown oil (1.14 g, 40%).
Step 5
A solution of the title compound of Step 4 (675 mg, 2.8 mmol) in EtOH (10 mL) containing 10% Pd/C (200 mg) was hydrogenated at 40 psi in a Parr apparatus for 18 hr. The solution was filtered over diatomaceous earth and the filtrate was concentrated to dryness, leaving a yellow solid (400 mg, 100%).
Preparation 5 (S)-2-3-Fluoro-azetidine-1-carbonyl}-4-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester
Step 1 - Benzhydryl-3-fluoro-azetidine hydrochloride 1-Benzyhydryl-azetidin-3-o! (5.0 g, 20.9 mmol) was dissolved in 50 mL of benzene, the solution cooled to 15 °C, and (diethylamino)sulfur trifluoride (10.1 g, 62.7 mmol) was added dropwise. After 40 stirring overnight at room temperature, saturated sodium bicarbonate was added. The mixture was extracted with EtOAc, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by chromatography (Biotage® 40S, 10% EtOAc/hexanes). The product was dissolved in EtOAc, treated with HCI (15 mL, 2N in ether), heated briefly, and concentrated. The solid was triturated with ether, . filtered, and dried to provide 2.58 g of the title compound. MS m/z 242.3 (MH*).
Step 2 - 3-Fluoro-azetidine hydrochloride
A solution of the product of Step 1 (2.58 g, 9.3 mmol) in 30 mL of methanol containing 10% Pd/C (0.38 g) was hydrogenated at 30-50 psi in a Parr apparatus tor 60 hr. The solution was filtered over diatomaceous earth and the filtrate concentrated to dryness. The solid was recrystallized from
MeOH/EtOAC to furnish 0.62 g (60%) of the title compound.
Step 3
N-tert-Boc-4-oxo-L-proline (917 mg, 4 mmol), the title compound of Step 2 (446 mg, 4 mmol), and
HATU (1.673 g, 4.4 mmol) were mixed under nitrogen in anhydrous methylene chloride. The solution was cooled in an ice bath before the addition of DIEA (1.4 mL, 8 mmol). The reaction mixture was allowed to warm to RT and stirred overnight. Saturated sodium bicarbonate was added, the phases were separated and the aqueous phase was extracted with methylene chloride. The combined organic portions were washed with brine and dried over magnesium sulfate. The crude product (2.11 g) was purified by chromatography (Biotage® Flash 40S, 95:5 EtOAc:MeOH) to give the title product as light pink foam (1.06 g, 92%). MS m/z 287.3 (MH").
Preparation 6 (S)-2-((S)-3-Fluore-pyrrolidine-1-carbonyl)-4-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester
N-tert-Boc-4-oxo-L-proline (2.29 g, 10 mmol), (S)-3-fluoropyrrolidine hydrochloride (1.38 g, 11 mmol) and TEA (2.09 mL, 15 mmol) were mixed in anhydrous methylene chloride (30 mL) under nitrogen.
HOBT (2.03 g, 15 mmol) was added and the mixture cooled to 0°C in an ice bath before addition of EDC (2.10, 11 mmol). The reaction mixture was allowed to warm to RT and stirred overnight. The mixture was washed with saturated sodium bicarbonate and brine and dried over magnesium sulfate. The crude material (3.15 g) was recrystallized from hexane:EtOAc (2:1) to give the title compound as light yellow needles (2.18 g, 73%}. MS m/z 301.3 (MH").
Preparation 7 } (25,45)-2-(3,3-Ditluoro-pyrrolidine-1-carbonyl)-4-piperazin-1-yl-pyrrolidine-1 carboxylic acid tert-butyl ester
Step 1 - 4-[(35.,55)-1-ten-Butoxycarbonyl-5-(3. 3-difluoro-pyrralidine- 1 -carbonyl}-pyrrolidin-3-yi}- piperazine-1-carboxylic acid benzyl ester
To a solution of the title compound of Preparation 1 (1.59 g, 5 mmol) and 1- (benzyloxycarbonyl)piperazine (1.21 g, 5.5 mmol) in 1,2-dichloroethane (20mL) was added AcOH (0.3 mL, 1.05 equiv.), followed by sodium triacetoxyborohydride (2.119 g, 10 mmol). The reaction mixture was stirred at RT for 4 hr. Saturated sodium bicarbonate was added and the product extracted with methylene chloride. The organic phase was washed with brine and dried over magnesium sulfate. After evaporation, the crude product (2.28 g yellow foam) was purified by flash chromatography eluting with
EtOAc to give title compound as white foam (1.28 g, 49%). MS m/z 523.3 (MH").
Step 2 40 The product of Step 1 (1g, 1.91 mmol) was dissolved in EtOH (50 mL) and 10% Pd/C (1g, 1 equiv. w/w) was carefully added, followed by 1,4-cyclohexadiene (1.81 mL, 10 equiv.). The mixture was stirred gently in a tightty-capped flask at RT overnight. The reaction mixture was filtered through diatomaceous earth and concentrated to give the product as yellow semisolid (758 mg, 100%). MS m/z 389.4 (MH").
Preparation § oo (S)-2-(3,3-Difiuoro-azetidine-1-carbonyl)-4-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester
N-tert-BOC-4-oxo-L-proline (458 mg, 2 mmol), 3,3-difluoroazetidine hydrochloride (258 mg, 2 mmot)(prepared as described in WO 2000/47582), and DIPEA (0.35 mL, 2 mmol) were mixed in : anhydrous methylene chioride (10 mL) and cooled to 0°C. HOBT (405 mg, 3 mmol) was then added In one portion followed by EDC hydrochloride (422 mg, 2.2 mmol). The resulting mixture was allowed to warm to RT and stirred overnight. Saturated sodium bicarbonate was added, the organic layer was separated, and the aqueous phase extracted with methylene chloride. The combined organic extracts were washed twice with brine, dried over magnesium sulfate, filtered, and concentrated. The crude product (570 mg) was triturated with hexanes:methylene chloride (10:1), filtered, and dried in a vacuum oven to afford 510 mg (84% yield) of the title product as a light orange powder. MS (m/z): 305.1 (MH"). p tion 9 {25.4 5)-4-Fluoro-pyrrolidine-2-carbonitrile hydrochloride
Step 1 - (25.49)-4-Flyoro-pyrrolidine-1,2-dicarbo hoxylic acid 2- tert-butyl ester 1-(2.5-dioxo-pyrrolidin-1-vi) ester
To a solution of N-ter-BOC-cis-4-fluoro-L-proline (700 mg, 3 mmol) in anhydrous DMF (8 mL) was at 0°C added N-hydroxysuccinimide (380 mg, 3.3 mmol) in one portion, followed by 1.3 diisopropylcarbodiimide (391 mg, 3.1 mmol) in small portions. The reaction was aliowed to warm to RT and stirred overnight. The mixture was diluted with 100 mL of water, the precipitate was collected, washed with cold water, and dried in a vacuum oven overnight. The product (1.093 g) was used without further purification. MS m/z 331.3 (MH").
Step 2 - (25.45)-2-Carbamoyl-4-fluoro-pyrrolidine-1-carboxylic acid tert-Dutyl ester
The title compound of Step 1 (1.03 g, 3.12 mmo!) was dissolved in dioxane (12 mL) at RT and the solution was treated with concentrated aqueous ammonium hydroxide (10 mmol) dropwise. The resulting thick solution was stirred at RT for three hr, then acidified with 6N HCI to pH 4-5, and extracted with methylene chloride (2x). The combined extracts were washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and concentrated to afford 562 mg (78% yield) of a clear oil. MS m/z 233.3 (MH").
Step 3 - (25,45)-2-Cyano-4-fluoro-pyrrolidine-1-carboxvlic acid_ tert-butyl ester
To a solution of the title compound of Step 2 (550 mg, 2.37 mmol) and dry pyridine (0.4 mL, 2 equiv.) in anhydrous methylene chloride (15 mL) at 0°C was added a solution of TFAA in 2 mL of methylene chloride under nitrogen. The solution was stirred at 0°C for two hr and then at RT for one hr.
The reaction mixture was washed with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel to give 458 mg (90% yield) of an oil that solidified on standing. MS m/z 215.3 (MH").
Step 4
The title compound of Step 3 (400 mg) was dissolved in dry acetonitrile (8 mL) and 0.5 mL of 4N HCI 40 in dioxane was added under nitrogen. The resulting solution was stirred at RT ovemight and the white precipitate that formed was filtered and dried in a vacuum oven to yield 128 mg (46% yield) of the title compound. MS m/z 115.1 (MH"). Additional product could be obtained from the filtrate.
Preparation 10
Step 1- N-tert-BOC-4.4-Difluorgpyrrolidine-2-carbonitrile
To a solution of N-tert-BOC-4,4-difluoropyrrolidine-L-proline amide (250 mg, 1 mmol) and dry pyridine (97 pL, 1.2 equiv.) in anhydrous methylene chloride at 0°C was added a solution of TFAA (252 mg, 1.2 equiv.) in 1 mL of anhydrous methylene chloride. The solution was allowed to warm to RT and stirred for 36 hr. The reaction was quenched with saturated ammonium chloride, the organic phase was washed successively with 1N HC), saturated sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and concentrated to afford 252 mg of a white semisolid. MS m/z 233.1 (MH").
Step 2
The title compound of Step 1 (245 mg) was dissolved in dry acetonitrile (10 mL) and 0.5 mL of 4N
HC! was added. The resulting solution was stirred at RT for five hr and the solvents were removed. The residue was triturated with EtOAc, the solid was filtered, and then dried under high-vacuum to afford 105 (59% yield) of the title compound as a white solid. MS m/z 133.2 (MH.
The compounds of formula (i), the sterecisomers thereof, and the pharmaceutically acceptable salts of the compounds and stereoisomers, may be prepared as described in the following Examples. The free base compounds of the present invention may be obtained from their salt forms by conventional means such as disclosed in Example 113, herein.
Example 1 methanone dihydrochloride phenyllpiperazin-1-yllpyrroliding-1-carboxylate
The title compound of Preparation 1 (96 mg, 0.3 mmol), 1-[3-(trifluoromethyl)phenyi]piperazine (70 mg, 0.3 mmol) and AcOH (18 pL, 0.3 mmo!) were dissolved in 8 mL anhydrous 1,2-dichloroethane.
Sodium triacetoxyborohydride (127 mg, 0.6 mmol) was added. After stirring the reaction at RT tor 3 hr, the reaction was quenched with saturated sodium bicarbonate, extracted with EtOAc, washed with brine, dried over magnesium sulfate, filtered, and concentrated. The crude material was purified by chromatography (Biotage® Flash 40S, 95:5 dichloromethane:MeOH) to afford 126 mg (79%) of the title compound as a white foam. MS m/z 533 (MH").
Step 2
The product of Step 1 (120 mg, 0.225 mmol) was treated with 4N HCI in dioxane (5 mL). After two hr at RT, the mixture was concentrated to dryness, triturated with ether, filtered, and dried in vacuo to provide 92 mg of the title compound as a white solid. MS m/z 433 (MH").
Using appropriate starting materials, the hydrochioride salts of the compounds of Examples 2 to 112, disclosed in Table 1 hereinbelow, were prepared in a manner analogous to that described in
Example 1.
Jable1
CEs | Maw [wom] ((25,45)-4-(4-(5-(Tritluoromethyl)pyridi n-2-yl)piperazin-1-
IR i eiiriienil I ((25,45)-4-(4-(5-(Trifluoromethyl)pyridin-2-yi)-1,4-diazepan-1- erento. | sa ((25.45)-4-(4-(3-(Trifluoromethyl)phenyl)piperazin-1- yhpyrrolidin-2-yl)-((3F*,4 S*)-3,4-difluoropyrrolidin-1-yt)-
Te | = ((2S,45)-4-(4-(2-(Tritluoromethyl)quinolin-4-yl)piperazin-1 -
I soil (3.3-Difluoropyrrolidin-1-yl)-{((2S,45)-4-(4-(5-nitropyridin-2- ot ((2S,4 5)-4-(4-(3-Cyanopyridin-2-yl)piperazin-1-yl)pyrrolidin-2-yl)- 391 .
IE rice I ((2S,45)-4-(4-(5-(Trifluoromethyl)pyridin-2-yl)piperazin-1- yl)pyrrolidin-2-yl)-((3A,4S")-3,4-difluoropyrrolidin-1-yl)- methanone ((2S,4 S)-4-(4-(3-Cyanopyridin-2-yl)piperazin- 1-yl)pyrrolidin-2-yl)-
I ints ail Il ((25,45)-4-(4-(3-Cyanopyrazin-2-yl)piperazin-1-yl)pymolidin-2- 0 | Ceres r | w ((25,4 S)-4-(4-(4-(Trifluoromethyl)pheny!)piperazin-1- yl)pyrrolidin-2-yl)-((3R*.4 5") -3,4-difluoropyrrolidin-1-yl)- - methanone ((2S.45)-4-(2-(Trifluoromethyl)-5,6-dihydroimidazo[1,2-a]pyrazin- [Femi methanone ((2S,45)-4-(4-(3-Cyanopyrazin-2-yl)piperazin-1-yl)pyrrolidin-2- oe rs ((25,45)-4-(2-(Trifluoromethyt)-5,6-dihydroimidazo| 1,2-a)pyrazin- 14 7(8H)-yl)pyrrolidin-2-yl)-(3,3-difluoropyrrolidin-1-yl)-methanone 394 ((3R".45")-3,4-difluoropyrrolidin-1-y1)-((2S,4 S)-4-(4-(pyrimidin-2-
IE nits (25,4 5)-4-(4-(2-(Trifluoromethyl)phenyl)piperazin-1- :
IER eis omni ((25,45)-4-((1S,5R,6 A)-6-Amino-3-aza-bicyclof3.1.0]Jhexan-3-
((2S,45)-4-(4-Cyano-4-phenylpiperidin-1 -yl)pyrrolidin-2-yl)-(3,3- 389
I ives Bell ((2S.45)-4-(4-(1,1-Dioxo-1H-1,2-benzo]d]isothiazol-3-yl)- piperazin-1-yl)pyrrolidin-2-yl)-(3,3-difluoro-pyrrolidin-1-yl)-
Tem— ((25,45)-4-(4-(5-(Trifluoromethyl)-1,3,4-thiadiazol-2-yl)piperazin- 0 | remorse | 41 (3,3-Difluoropyrrolidin-1-yl)-((2S,4S)-4-(4-(isothiazol-3- 372 a | eres (3.3-Difluoropymalidin-1-yl)-((25,4 S)-4-(4-(8-methyl- [1,2,4]triazolo[4, 3-a]pyrazin-3-yl)piperazin-1-yl)pyrrolidin-2-yl)- e | @ ((25,45)-4-(3-(Trifluoromethyl)-5,6-dihydro-{1,2,4]triazolof4,3- ajpyrazin-7(8H)-yl)pyrrolidin-2-yl)-(3,3-difluoropyrrolidin-1 -yl)- —m— (3,3-Difluoropyrrolidin-1-yl)-((2S,45)-4-(4-(2,6-dimethylpyrimidin- a | mas ((2S,4.5)-4-(4-(Benzo{d]isothiazol-3-yt)piperazin-1-yi)pyrrolidin-2-
IE ives ll IP ((2S,45)-4-(4-(4-(Trifluoromethyl)-6-methylpyridin-2-yi)piperazin- e rensossmn rn (3,3-Diflucropyrrolidin-1-yl)-((2S,4S)-4-(4-(oxazolof5,4-b]pyridin- (3,3-Difluoropyrrolidin-1-yl)-((2S5,4 S)-4-(4-(4-methylpyrimidin-2- e | meee, | = (28,4 5)-4-(4-(4-Cyanopyridin-2-yl)piperazin-1-yl)pyrrolidin-2-yl})-
BER i ecw I ((2 S.45)-4-(4-(7-(Trifluoromethyl)quinolin-4-yl)piperazin-1- omens (2 5,4 5)-4-(4-(5-Cyanopyridin-2-y|)piperazin-1-yl)pyrrolidin-2-yl)-
IER ar scsi a (3,3-Ditluoropyrrolidin-1-yl)-((2S,4 S)-4-(4-(pyridin-2-yl)piperazin- 366 wT me ((25,45)-4-(4-(6-(Trifluoromethyl)quinolin-4-yl)piperazin-1- o | msemosommm aes (3.3-Ditluoropyrrolidin-1-yl)-((2S,4 S)-4-(4-(5-methylpyridin-2- eee ((2S,4 5)-4-(4-(4-(Tritluoromethyl)pyrimidin-2-yl)piperazin-1- | emepasmensen ees
(3.3-Difluoropyrrolidin-1-yt)-((2S,4 5)-4-(4-(3-methyl-1,2,4- e | imams | so (3,3-Difluoropyrrolidin-1-yl)-{(2S,45)-4-(4-(quinolin-2- emo (3,3-Difluoropyrrolidin-1-yl)-((25,4S)-4-(4-(6-methoxypyridin-2- e | eee (3.3-Difluoropyrrolidin-1-yl)-((25,4 5)-4-(4-(5-methyi-1,2,4-
IE ity sl IE (3,3-Ditluoropyrrolidin-1-yl)-((2S,45)-4-(4-(quinolin-8-
IE iil (3,3-Diftuoropyrrolidin-1-yl)-((2S,4 5)-4-(4-(1-phenyl-1H-imidazol-
IE iio gl (3,3-Ditluoropyrrolidin-1-yl)-((2 5,4 5)4-(4-(quinoxalin-5- 417 a | ranean ((2S.4S)-4-(4-(Benzo[d)isoxazo!-3-yl)piperazin-1-yl)pyrrolidin-2-
I Revol I (3,3-Difluoro-pyrrolidin-1-yl)-[(2S,4 5)-4-(8-trifluoromethyl-3,4- dihydro-1H-benzo[4,5}imidazo[1,2-a}pyrazin-2-yl)-pyrrolidin-2-yi}- = a ha (3,3-Difluoropyrrolidin-1-yi)-((25,4 5)-4-(4-phenyipiperidin-1-
IE Bc oil ((2S,45)-4-(4-(3-(Trifluoromethyl)phenyl)piperidin-1 —yl)pyrrolidin- oe | mm oes ((28,495)-4-(4-(3-(Trifluoromethy!)pyridin-2-yl)piperazin-1- 0 | emeenosmmmn ie (25,4 5)-4-(4-(4-(Trifluoromethyl)quinolin-2-yl)piperazin-1-
Smmecnsseemnnen | a ((285,45)-4-(2-(Trifluoromethyl)-7,8-dihydropyrido{4,3- d)pyrimidin-6(5H)-yl)pyrrolidin-2-yl)-(3,3-difluoropyrrolidin-1-yi)- e (3,3-Difluoropyrrolidin-1-yl)-((2S,4 S)-4-(4-(4-methyl-6- 6 | moments visser (25,4 5)-4-(4-(1H-Benzo[d][1,2,3]triazol-1-yl)piperidin-1- 0 | rss (3,3-Difluoropyrrolidin-1-yl)((2S,4 S)-4-(4-(thiazol-2-yl)piperazin- 372
IE eer (3,3-Diflucropyrrolidin-1-yl}-((2S,4 S5)-4-(4~(3-methylpyridin-2-
IE Resi dion Bl
((25.45)-4-(4-(Benzo|d]oxazol-2-yl)piperazin-1 -yl)pyrrolidin-2-yl)- [arm (3,3-Difluoropyrrolidin-1-yl)-((2S,4 S)-4-(4-(6-phenylpyridin-2- a | emi (3,3-Difluoropyrrolidin-1-yl)-((2S,45)-4-((3R,55)-3,5-dimethyl-4- (4,6-dimethyl-1,3,5-triazin-2-yl)piperazin-1-yl)pyrrolidin-2-yl)- [ [(25,4S)-4-(2-Cyclopropyl-7,8-dihydro-5H-pyridof4,3-d]pyrimidin- (3,3-Difluoro-pyrmrolidin-1-yl)-{(2 5,4 S5)4-(2-methoxy-7,8-dihydro- 0 | meteor | 1 (3.3-Difluoro-pymolidin-1-yl)-[(2S,4 S)-4-(2-pheny|-7,8-dihydro- 0 | setae (3,3-Difluoro-pyrrolidin-1-yl)-[(2S, 45)-4-(4-oxazolo{4,5-C]pyridin-
I iret sii IPT (3,3-Difluoro-pyrrolidin-1-yl)-{(25,4 S)-4-(4-oxazolof5,4-clpyridin- 407.4
IE Resid I (3,3-Difluoro-pyrrolidin-1-yl)-{(2S,45)-4(2,3.4,5-tetrahydro- e | irom | 1 {(2S,45)-4-14-(3,5-Dichloro-pyridin-4-yl)-piperazin-1-yl}- © | omaresssmomroimnee | se (3,3-Difluoro-pyrrolidin-1-yl)-{(2S5,4 S)-4-(4-quinoxalin-2-yl- 417.4 : e ome 4-[(38,55)-5-(3,3-Ditluoro-pyrrolidine-1-carbonyl)-pyrrolidin-3-yl}- e | nessa | ms [(2S,4S)-4-(2-Amino-7,8-dihydro-5H-pyridof4,3-d]pyrimidin-6-yl)-
Tre (3,3-Difluoro-pyrrolidin-1-yl)-[ (25,4 5)-4-(2-methyi-4-pyrimidin-2- (3,3-Difluoro-pyrrolidin-1-yl)-{(2 S,4 S)-4-[4-(5-ethyl-pyrimidin-2-
IE fet wmosis oil {(2S,4 S)-4-{4-(5-Bromo-pyrimidin-2-yl)-piperazin- 1 -yl}-pyrrolidin-
BEN ervey 4-((3S5,59)-5-(3,3-Difluoro-pyrrolidine-1-carbonyl)-pyrrolidin-3-yl)- on | ces ((2S,4S)-4-(2-(4-Chlorophenyt)-7,8-dihydropyrido[4,3- dlpyrimidin-6(5H)-y!)pyrralidin-2-yt)(3,3-difluoropyrralidin-1- 448.4 mie
(3,3-Difluoropyrrolidin-1-yl)((2S,4S)-4-(7,8-dihydro-2- {2 S,45)-4-[4-(5-Chloro-benzooxazol-2-yl)-piperazin-1 yi} pyrrolidin-2-yl}-(3,3-difluoro-pyrrolidin-1 -yl)-methanone (3,3-Difluoro-pyrrolidin-1 -y)-[(2S,45)-4+((2-pyridin-2-yl)-7,8- dihydro-5H-pyrido[4,3-d}pyrimidin-6-yl)-pyrrolidin-2-yl}- (3.3-Difluoro-pyrrolidin-1-yl)-[(2S,45)-4-(2-pyridin-4-y|-7 8- dihydro-5H-pyrido{4,3-d]pyrimidin-6-yl)-pyrrolidin-2-yl]- memes (3.3-Difluoro-pyrrolidin-1-yi)-{(2S,4 S)-4-[4-(S-methyi- .
IE iii aint {(2S,45)-4-[4-(6-Chloro-benzooxazol-2-yl)-piperazin-1-yl}- (3.3-Difluoro-pyrrolidin-1-yl)-{(2S,4S)-4-(7,8-dihydro-5H- ((S)-3-Fluoro-pyrrolidin-1-yl)-{(2 S,45)~4-(4-oxazolo[$,4-C]pyridin- 3804 on | oman 4-[(38,55)-5-((S)-3-Fluoro-pyrrolidine-1-carbonyl)-pyrrolidin-3- 3744 0 | rsssommmom sano : ((8S)-3-Fluoro-pyrrolidin-1-yl)-{(2S,4 5)-4-[4-(5-trifluoromethyl- 416.4 0 | Cm orsaroyraaes ((S)-3-Fluoro-pyrrolidin-1-yl)-{(2 S,45)-4-(4-oxazolofS,4-b]pyridin- 360.4
IP reivihaves gl Ral 2-{4-{(35,55)-5-((S)-3-Fluoro-pyrrolidine-1-carbonyl)-pyrrolidin-3- 373.4
IP ees Tl ((S)-3-Fluoro-pyrrolidin-1-yl)-{(25,4S)-4-{4-(3-trifluoromethyi- uo | Ceremonies ((2S,4S)-4-(2-(Trifluoromethyl)-7,8-dihydropyrido(4,3- d)pyrimidin-6(5H)-yl)pyrrolidin-2-y)((S)-3-fluoropyrrolidin-1- 388.4 yl)methanone ((S)-3-Fluoro-pyrrolidin-1-yl)-{(2S,4 5)-4-[4-(4-methyl-pyrimidin-2- eT erosion ((S)-3-Fluoropyrrolidin-1-yl)((2S,4 5)-4-(4-(pyrazin-2-yi)piperazin- oT mes [(25,45)-4-(2-Cyclopropyl-7,8-dihydro-5H-pyrido{4,3-djpyrimidin- ((S)-3-Fluoro-pyrroidin-1-y1)-{(2S,4S)-4-[4-(2-Triflucromethyl-
IE i iraits won Bl
(3-Fluoroazetidin-1-y!)((2 5,45)-4-(4-(pyrazin-2-yl)piperazin-1- 335.4
I iil Baill 44(35,59)-5-(3-Fluoro-azetidine-1 -carbonyl)-pyrrolidin-3-yi}- 360.4 a [mm (3-Fluoro-azetidin-1 -yl)-[(2S,4S)-4-(4-0xazolo[5,4-b)pyridin-2-yl- 375.4
I ei (3-Fluoro-azetidin-1 -yh)-{(2S,45)-4-{4-(3-trifluoromethyl-pyridin-2-
I ie ll (3-Fluoro-azetidin-1-yl)-{(25,45)~4-(4-oxazolo{5,4-c}pyridin-2-yl- 375.4
I iil I [(2S,4S)-4-(2-Cyclopropy|-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin- e | ermmeneonoomsnpmees | sas 2-{4{(3S,55)-5-(3-Fluoro-azetidine-1-carbonyi)-pyrrolidin-3-yl}- ee (3-F luoroazatidin-1 -y1)((2S.4S)-4-(4-(5-(trifluoromethyl)pyridin-2- a pane (3-Fluoro-azetidin-1-y!)-{(25,45)-4-(2-trifluoromethyi-7,8-dibydro- 0 | erraomecesomaesrene | 55s (3-Fluoro-azetidin-1-yl)-{(25,45)-4-[4-(4-methyl-pyrimidin-2-yl)- 349.4 mm (3-Fluoro-azetidin-1-yl)-{(2S,45)-4-[4-(2-trifluoromethyl-quinolin- wo | omnes [(2S,45)-4-(4-Benzooxazolo-2-ylpiperazin-1-yl)-pyrrolidin-2-yl}- 406.4 0 |r non ((3R*,4S5"%)-3,4-Difluoro-pyrrolidin-1-yi)-[(25,45) 4-(2- trifluoromethyl-7,8-dihydro-5H-pyrido{4,3-d]pyrimidin-6-yt)- 406.4 e— ((3R",45")-3,4-Difluoro-pyrrolidin-1-yl)-[(2S,4 5)-4-(4-oxazolo{5,4- ((3R*.45")-3,4-Difluoro-pyrrolidin-1-yl)-[(2S,45)-4-(4-0xazolofS 4- wn | errermenmorsineene | re ((3F*,45")-3,4-Ditluoro-pyrrolidin-1-y1)-{(25,4 S)-4-[4-(4-methyl- (3,3-Difluoro-azetidin-1-yl)-{(25,45)-4-[4-(3-trifluoromethyl- we | Comrememartorsniree : 2-(4-{(3S,55)-5-(3,3-Ditluoro-azetidin-1-carbonyl)-pyrrolidin-3-yl]- 377.2 ow [ee (3,3-Difluoro-azetidin-1-y1)-{(2S,45)-4-(2-trifluoromethyl-7,8- e |omimsamnms momar | sms
(3,3-Difluoro-azetidin-1-yi)-{(2S,4 5)-4-[4-(2-triflucromethyl- 470.2
I eeveiinivionoil IN (3,3-Difluoro-azetidin-1-yl)-[{(2S,4 5)-4-(4-oxazolo{5,4-c]pyridin-2-
IE eine ll {(2S,45)-4-[5-{4-Chloro-phenyl)-2-aza-bicyciof2.2. 1)hept-2-yl]- on |rerenasonoomartn (3.3-Difluoro-pyrrolidin-1-yl)-[(25,4 S)-4-(2-trifluoromethyl-5,8- dihydro-6H-pyrido(3,4-d)pyrimidin-7-yt)-pyrrolidin-2-yl]- - 406.1 112 methanone
Example 113 (3,3-Diflucropyrrolidin-1-yl)-((25,45)-4-{4-(pyrimidin-2-yl)piperazin-1-yl)pyrrolidin:2-yi)-methanone 5 .
F
~Q
N oO
No
O
(S)-4-Oxo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (6.6 kg, 1.0 equivalent) was charged to a reactor, followed by addition of dichloromethane (15 volumes). The reaction mixture was cooled to 0°C. Triethylamine (4.82 liters, 1.2 equiv) was added over 30 minutes. The mixture tumed from suspension to a clear solution at the end of triethylamine addition. The mixture was held at 0°C to 5°C for 10 minutes.
Pivaloyl chloride (3.65 kg, 1.05 equivalents) was added slowly while keeping the reaction temperature at 0°C to 5°C. The reaction mixture turned back to aslurry. The reaction mixture was sampled for completion by HPLC (using diethylamine to derivatize) after held for 1 hour at 0°C to §°C. 3,3-Difluoro- pyrrolidine hydrochloride (4.13 kg, 1.0 equivalent) was charged to the above mixture over 10 minutes at - 10°C to 0°C. Triethylamine (4.0 liters, 1.0 equiv) was introduced slowly over 70 minutes at -10°C to 0°C. Upon completion of triethylamine addition, the mixture was stirred for 1h at 0 to 5°C. The reaction was complete by HPLC assay (~1% starting material). The reaction was quenched with water (10 volumes) at 0°C to 5 °C. The mixture was heated to 20°C to 25 °C. The layers were separated, and the organic layer was washed with 0.5 M HCI (5S volumes). The organic layer was again washed with combined 5% NaHCO; (2 volumes) and half saturated brine solution (1.64 M, 3 volumes). The organic solution was concentrated atmospherically to a low stirrable volume (approximately 20 liters). Ethyl acetate (12.6 volumes, 82.8 liters) was added, the solution was concentrated atmospherically to ~6 volumes. The mixture was held at 60°C to 65 °C for 2 hours and cooled to room temperature over 3 . hours. The mixture was held at 20°C to 25 °C for 8 hours. Heptane (8 volumes) was added, and the mixture was granulated for a minimum of 2 hours. The solid was filtered, rinsed with 2:1 heptane/ethy! acetate (1 volume), and dried in a tray dryer at 25°C to 35°C for a minimum of 12 h. Yield: 7.26 kg, 79%.
HPLC purity: 99.7%. The mother liquor (86 liters) was concentrated to 12 liters under partial vacuum at 65°C to 70°C. The mixture was cooled to 60°C to 65 °C. Ethyl acetate (4.0 liters) was added slowly over 15 minutes. The mixture was cooled to 20°C to 25 °C over 2 hours and was held at that temperature for at least 2 hours. The solid was filtered and rinsed with haptane/ethyl acetate (3:1 v/v, 1.7 iiters). Drying in a tray dryer for 12 hours at 35°C to 45 °C yielded 435 grams of product. HPLC purity: 96.4%. carboxylic acid tert-butyl ester
A reactor was charged with THF (20 volumes), 2-piperazin-1-yl-pyrimidine (2.17 kg, 1.05 equivalents) and the product from Step 1 (4.00 kg, 1.0 equivalent). The mixture was held at 20°C to 25°C until all material was dissolved over 30 minutes. Acetic acid (0.792 kg, 1.05 equivalents) as added. The mixture was stirred for 1 hour during which the reaction mixture tumed to cloudy. The reaction mixture was refluxed for 30 minutes and then concentrated at 60°C to 70°C until a steady temperature of 66.9°C was observed in the overheads indicating compiete removal of water from the system. More THF was added as necessary. At the end, THF was added to bring the total volume in the reactor to 15 volumes of the limit reagent. The reaction mixture was cooled to -3°C to 7°C and sampled for complete formation of imine by HPLC (using sodium triacetoxyborohydride to reduce imine). Sodium triacetoxyborohydride (5.33 kg, 2.0 equivalents) was added portion-wise to the suspension at -5°C to 15°C. The reaction mixture was heated to 20°C to 25°C and held for 12 hours. HPLC results confirmed the reaction was compiete by 99.8%. Sodium bicarbonate aqueous solution (10% w/w, 10 volumes) was added. The slurry was concentrated to remove 10 volumes of THF under partial vacuum at 30°C to 60°C. Ethyl acetate (10 volumes) was added to the suspension after it cooled to 20°C to 25°C. The organic phase was separated and the aqueous phase was checked by HPLC. It contained less than 2% of the product. The organic phase was washed with water (5 volumes), saturated brine solution (5 volumes) and concentrated to a small volume (2 volumes) under partial vacuum at 45°C to 50°C. To the siurry was added heptane (10 volumes) at 45°C to 50°C over 30 minutes. The mixture was cooled to 20°C to 25°C and granulated for 2 hours. Solid was collected by filtration, rinsed with heptane (2 volumes).
Drying in a tray dryer for 12 hours at 35°C to 45°C yield 5.35 kg (91.3%) of the product.
Step 3 - (3.3-Difluoro-pyrrolidin-1-y1)-{(2 5,4 S)-4-(4-pyrimidin-2-yi-piperazin-1-yl)-pyrrolidin-2-yl]- methanone
Water (19 liters, 2 volumes) was charged to a reactor followed by the product from Step 2 (9.57 kg. 1.0 equivalent). To the slurry was added concentrated HCI (37 wt% in water, 19.1 liters, 2 volumes) slowly at 20°C to 30°C over 4 hours. The slurry went into solution after 12 liters of HCl was added. After the addition completion, the reaction was complete by HPLC assay. The reaction mixture was cooled to 5°C to 15°C. To the mixture was added 50% NaOH aqueous solution slowly with 40 agitation to pH 10 to pH 11. The pH was monitored with a pH meter closely during the neutralization.
The total volume of 50% NaOM added was 12.45 liters. The mixture was warmed to 20°C to 25°C and extracted with ethyl acetate twice (115 liters, 12 volumes and 57 liters, 6 volumes, respectively). The sample from aqueous layer after second extraction was analyzed by HPLC and showed only 1% of the product in that aqueous solution. The organic layers were combined and treated with magnesium sulfate (5 kg) for 1 hour. The mixture was filtered. The filter cake was rinsed with ethyl acetate (10 titers). The filtrate was charged back to the reactor via a 0.2 micron in-line filter for speck free operation. (The following operations were performed under speck free conditions.) The solution was concentrated to 20 liters (2 volumes) under partial vacuum at 50°C to 60°C. The mixture was cooled to 20°C to 25°C over 30 minutes. Upon cooling to room temperature, crystallization occurred. The mixture was held for 30 minutes. Hexanes (20 liters, 2 volumes) was added slowly over 1 hour. The mixture was granulated for 2 hours. The solid product was collected by filtration and rinsed with hexanes/ethyl acetate (10 liters, 1:1 viv). The filter was blown dry with nitrogen for & minimum of 2 hours. The product was dried in a tray dryer at 44°C for 12 hours. Yield: 5.7 kg, 75.9%. m.p. 156°C. MS m/z 367 (MH"). "HNMR (400 MHz,
D;0): 68.15(d, 2H, J = 5.0 Hz, CH of pyrimidine), 6.55 (t, 1H, J = 4.8 Hz, CH of pyrimidine), 3.87-3.81 (dd, 1H, Ha, of proline, rotomeric), 3.78-3.50 (m, 4H, N-CH; of pyrrolidide), 3.55-3.40 (m, 4H, N-CH_ of piperazine), 2.97 (dd, 1H, J = 10.2, 6.6 Hz, Hs, of proline), 2.85-2.75 (m, 1H, He, of proline), 2.68 (dd, 1H,
J = 10.0, 8.1 Hz, Hg, of proline), 2.55-2.20 (m, 7H, overlapping N-CH; of piperazine, CH, of pyrrolidide and Hy, of proline), 1.47-1.38 (m, 1H, Ha, of proline).
Alternatively, the dihydrochloride salt of the titled compound was prepared according to the method of Example 1.
Example 114 {(25.49)-{4-(4-Pyrimidin-2-y|-piperazin-1-yi)-pyrrolicin-2-yil}-(3,3.4,4-tetratluore-pvrrolidin-1-yl)- methanong dihydrochloride
Step 1 - tort-Butyl (25.4 9)-4-(4-pyrimidin-2-ylpiperazin-1-yl)-2-[(3.3.4,4-tetrafluoropyrrolidin-1- ylicarbonyl]pyrrolidine-1-carboxyiate
DIPEA (261 mL, 1.5 mmol) was added dropwise to a suspension of the title compound of
Preparation 3 (114 mg, 0.3 mmol), HATU (128 mg, 0.33 mmol), and 3,3,4,4-tetrafluoropyrrolidine hydrochloride (54 mg, 0.3 mmol) in 5 mL dichloromethane. After stirring overnight, saturated sodium bicarbonate solution was added, the mixture was extracted with dichloromethane, the extracts dried over magnesium sulfate, and concentrated. The residue was purified by chromatography (Biotage® Flash 40S,
EtOAc) to afford the title compound. MS m/z 503 (MH").
Step 2
An EtOAc/MeOH solution of the product from Step 1 was treated with 4M HCI in dioxane (ca. 5 mL).
After 18 hr, the solvent was removed and the residue was taken up in acetonitrile and concentrated. The solid was taken up in hexanes, filtered, and dried to afford 50 mg (33%, two steps) of the title compound.
MS m/z 403 (MH").
Using appropriate starting materials, the hydrochloride salts of the compounds of Examples 11510. 122, disclosed in Table 2, were prepared in a manner analogous to that described in Example 114.
Table 2 eae [aw [WMD] (3-Fluoroazetidin-1 Y)-((25,45)-4-(4-(pyrimidin-2-yl)piperazin-1 - yh)pyrrolidin-2-yl)-methanone * ((3R", 4R")-3,4-Difluoropyrrolidin-1 -y1)-{(25.45)-4-(4-(pyrimidin-2-
IE leer I ((S)-3-Fluoropyrrolidin-1 y1)-((25,45)-4-(4-(pyrimidin-2-
Tommie ((R)-3-Fluoropyrrolidin-1 -yl)-((25.45)-4-(4-(pyrimidin-2-
Cn | moron (3.3-Difluoroazetidin-1 -y1)((4S)-4-(4-(pyrimidin-2-y!)piperazin-1 - [| = (25,4 5)-4-Fluoro-1 (2S, 4S)-4-(4-pyrimidin-2-yi-piperazin-1-yl)- 374.1 pyrrolidine-2-carbonyi]-pyrrolidine-2-carbonitrile TY (S)-4,4-Difluoro-1 {(25,45)-4-(2-tritluoromethyi-7,8-dihydro-5H- pyridof4,3-d]pyrimidin-8-yl)-pyrrolidine-2-carbonyl]-pyrrolidine-2- e — or (25,45)-4-Fluoro-1 {(25,45)4-(2-trifluoromethyt-7,8-dihydro-5H- pyrido{4, 3-d}pyrimidin-6-yl)-pyrrolidine-2-carbonyl}-pyrrolidine-2- carbonitrile (Azetidin-1-yl) ((2S,4S)-4-(4-(pyrimidin-2-yl)piperazin-1 - © 317
I eG I
Example 124 ((2S.3R.4S)-4-(4-(3-(T rifluoromethylpyridin-2-yl)piperazin-1 -yl)-3-methylpyrrolidin-2-y|}(3,3- difluoropyrrolidin-1-ylymethanone dihydrochloride
Step 1
The title compound of Preparation 1 (5.6 g, 20 mmol) was dissolved in benzene (50 mL) containing 4
A molecular sieves (7.9 g) and treated with pyrrolidine (2.0 mL, 24 mmol). The solution was filtered and concentrated to dryness, leaving an orange foam (7.0 g, 100% yield).
Step2
A solution of the product of Step 1 (7.0 g, 20 mmol) in acetonitrile (100 mL) was added to crushed potassium carbonate (5.2 g, 38 mmol) and treated with methyl iodide (1.5 mL, 24 mmol). The mixture was heated to 90° C for 16 hrs, cooled to RT, and concentrated. The residue was taken up in chloroform (150 mL) and a mixture of AcOH (5 mL) and water (45 mL) was added. After three hr at RT, the layers were separated, the aqueous layer was extracted with chloroform (3 x 25 mL), and the combined organic phases were washed with saturated sodium bicarbonate (2 x 25 mL) and brine, and concentrated to a brown oil. The oil was dissolved in ether (75 mL), filtered, and concentrated to a pale brown solid (0.97 g, 16% yield).
Step 3
To a mixture of the product of Step 2 (74 mg, 0.25 mmol), 1-(3-trifluoromethyl)pyridin-2-yl-piperazine (63 mg, 0.28 mmol), AcOH (16 uL), and sodium acetate (23 mg, 0.28 mmol) in MeOH (1 mL) was added sodium cyanoborohydride (21 mg, 0.28 mmol). The mixture was stirred at RT for 65 hr and then concentrated. The residue was taken up in EtOAc (20 mL) and the solution was washed with 1N sodium hydroxide (2 x 3 mL) and brine (5 mL), dried over magnesium sulfate, and concentrated to dryness. The residue was purified by preparative HPLC (Shimadzu, Columbia, MD; 30 x 50 cm Waters-Xterra® C18 column - Waters Instrument Co., Milford, MA; 30 mL/min gradient of 15% acetonitrile with 0.1% ammonium hydroxide over 10 min) to afford a colorless solid (35.7 mg, 26% Yield).
Step4
HCI (4M) in dioxane (0.5 mL) was added to a solution of the product of Step 3 (35 mg, 0.064 mmol) in acetonitrile (1 mL). After 16 hr, the mixture was concentrated to dryness and the residue was triturated with ether (2 mL). The title compound was obtained as a solid (32 mg, 96% yield). MS m/z 448.4 (MH).
Using appropriate starting materials, the hydrochloride salts of the compounds of Examples 125 to 127, disclosed in Table 3 hereinbelow, were prepared in a manner analogous to that described in
Example 124.
Table 3
I EE. — LIC ((2S,3R,45)-4-(4-(2-tert-Butyl-5-(trifluoromethyi)pyrazolof 1 5 apyrimidin-7-yl)piperazin-1 -yl)-3-methylpyrrolidin-2-y1)(3.3- ’ [es (3.3-Difluoro-pyrrolidin-1 -y1)-{(25,3R,45)-3-methyl-4-[4-(5- 448.4 trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyrrolidin-2-yl}- methanone : (3,3-Difluoro-pyrrolidin-1-yl)-{(2S,3R.45)-3-methyl-4-(4- pyrimidin-2-yi-piperazin-1-yl)-pyrrolidin-2-yl]-methanone
Example 128 oo (2.4-Ditluoro-phenyl)-{4-[(35,5S)-5-(3.3-difluoro-pyrrolidine-1 -carbonvi)-pyrrolidin-3-yl}-piperazin-1-yi}- methanone dihydrochloride
Step 1 - (25.45)-4-[4-(2.4-Diftuoro-benzoyl)-piperazin-1-y!]-2-(3,3-difluoro-pyrrolidine-1-carbony)-
The title compound of Preparation 7 (37 mg, 0.25 mmol), 2,4-difiuorobenzoic acid (40 mg, 0.25 mmol) and HATU (95 mg, 0.3 mmol) were mixed in anhydrous methylene chloride under nitrogen and cooled to 0 °C in and ice bath before addition of DIEA (32 mg, 45uL, 0.3 mmol). The reaction mixture was allowed to warm to RT and stirred overnight. The reaction was quenched with saturated sodium bicarbonate and the aqueous layer was extracted with methylene chloride. The combined organic extracts were washed with brine and dried over magnesium sulfate. The crude product was purified by flash chromatography using methylene chloride.MeOH (95:5) to give the final product as white powder (132 mg, 100%). MS m/z 529.4 (MH").
Step 2 - An acetonitrile solution of the product of Step 1 (120 mg) was treated with 4N HC! in dioxane (1 mL). The reaction was stirred at RT overnight and evaporated. The residue was dissolved in water, filtered, and lyophilized overnight to afford the title product as white powder (110 mg, 96%). MS m/z 429.2 (MH+).
Using appropriate starting materials, thehydrochloride salts of the compounds of Examples 129 to 133, disclosed in Table 4, were prepared in a manner analogous to that described in Example 128.
Table 4 eae [tw [Wt] (3,3-Difluoro-pyrrolidin-1 -y1)-1(2S,4S)-4-[4-(toluene-4-sulfonyl)-
Cn | epee (3-Amino-pyrazin-2-y)-{4(35,55)-5-(3,3-difiuoro-pyrralidine-1 - carbonyl)-pyrrolidin-3-yl]-piperazin-1 -yl}-methanone - oe (4738 55)-5-(3,3-Difluro-pyrrolidine-1-carbonyl)-pyrrolidin-3- yi)-piperazin-1-yl}-quinolin-4-yl-methanone 0 4(35,55)-5-(3.3 Difluoro-pyrrolidine-1-carbonyl)-pyrrolidin-3-yl}- 360.2 : piperazine-1-carboxylic acid-ethylamide - 4-[(35,55)-5-(3,3-Difluoro-pymolidine-1 -carbonyl)-pyrrolidin-3-y]- piperazine-1-carboxylic aci d-(4-fluoro-phenyl)-amide hil
BIOLOGICAL METHODOLOGIES
The utility of the compounds of formula (1), the prodrugs and stereoisomers thereof, and the pharmaceutically acceptable salts of the compounds, prodrugs, and stereoisomers, in the treatment or pravention of the conditions enumerated hereinabove in mammals may be demonstrated in conventional assays known to one of ordinary skill in the relevant art, including the in vivo and in vitro assays described below. Such assays also provide a means by which the activities of the compounds of formula (I), the prodrugs, and stereoisomers thereof, and the pharmaceutically acceptable salts of the compounds, prodrugs, and stereoisomers, may be compared with the activities of other compounds.
In Vitro Assay for DPP-IV Inhibition
DPP-IV inhibition may be demonstrated in vitro by the following assay, which is adapted from methods of
Scharpe, et al., A. Clin. Chem., 2299 (1988) and Lodja, Z. Czechoslovak Medicine, 181 (1988). 150 uL of an enzyme-substrate solution is pipetted into microtiter wells of a polystyrene 96-well plate, and maintained at 4°C. The enzyme-substrate solution comprises 50 uM Gly-Pro-4-methoxy-f-naphthylamide hydrochloride in SOmM Tris assay butter pH 7.3 containing 0.1M sodium chloride, 0.1% (v/v) Triton and 50 pU/mL DPP-IV (MP Biomedicals, Livermore, CA: DPP-IV 5 mU/mL stock). 5 pL per well of the compound of formula (!) is added, bringing the final concentrations of the formula (I) compound to between 3 uM and 10 nM per well.
Controls. Enzyme is omitted from four (4) wells, as a reagent blank. 5 pL of 3 mM Diprotin A {Bachem
Bioscience, Inc.; King of Prussia, PA) is added to four wells as a positive quality control, providing a final
Diprotin A concentration of 100 UM. To measure total enzyme activity (i.e., a negative control), without the influence of any compounds of tormula (1), 5 nL of distilled water is added to tour wells.
The entire assay is incubated overnight (between 14 and 18 hours) at 37 °C. The reaction is quenched by adding 10 pL of Fast Blue B solution (0.5 mg/mL Fast Blue B in a butfer comprising 0.1M sodium acetate pH 4.2 and 10% (v/v) Triton X-100 to each well, followed by shaking for approximately 5 min at room temperature. The plates may be analyzed on a Spectramax spectrophotometer (Molecular
Devices; Sunnyvale, CA), or equivalent equipment, (absorption maximum at 525 nm). ICs, data for compounds may be obtained by measuring the activity of DPP-IV over a range of compound concentrations from 10nM to 3uM.
In Vivo Assay for Glucose Lowering
The glucose lowering effects of DPP-1V inhibitors, including the compounds of formula (I), may be exemplified in 4-6 week old KK/H1J mice (Jackson Labs; Bar Harbor, ME) in the context of an oral glucose tolerance test. .
Oral glucose tolerance tests (OGTT) have been in use in humans since, at least, the 1830s, as described by Pincus, et al., Am. J. Med. Sai., 782 (1934), and are routinely used in the diagnosis of human diabetes, though not to evaluate the efficacy of therapeutic agents in patients.
KK mice have been used to evaluate (i) glitazones (Fujita et al. Diabetes, 804 (1983); Fujiwara, et al,
Diabetes, 1549 (1988); and Izumi, et al., Biopharm Drug. Dispos., 247 (1997)); (ii) metformin (Reddi, et al., Diabet. Metabol., 44 (1993)); (iil) glucosidase inhibitors (Hamada, et al., Jap. Pharmacol. Ther., 17 (1988) and Matsuo, et al., Am. J. Clin. Nutr., 314S (1992), and (iv) extra-pancreatic effects of sulfonylureas (Kameda, et al., Arzneim. Forsch./Drug Res., 39044 (1982) and Muller et al., Horm.
Metab. Res., 469 (1990)).
KK mice are derived from an inbred line first established and described by Kondo, et al., Bull. Exp.
Anim., 107 (1957). These mice spontaneously develop a hereditary form of polygenic diabetes that progresses to cause renal, retinal, and neurological complications analogous to those seen in human diabetic subjects, however, they do not require insulin or other medication for survival.
Another aspect of the invention is directed to the use of KK mice to evaluate the effects of insulin secretagogue agents in the context of an oral glucose toierance test. The mice are fasted overnight (about 14 to about 18 hr), but allowed free access to water. After fasting, (time “t* = 0), 25 uL of blood is drawn from the retro-orbital sinus and added to 0.025% heparinized saline (100 ul) on ice. The mice (10 per group) are then orally dosed with a solution of a compound of formula (1) in 0.5% methyiceliulose (0.2 mU/mousa). Two controls groups receive only 0.5% methylcellulose. Att = 15 min, the mice are bled, as described above, and then dosed with 1 mg/kg glucose in distilled water (0.2 mL/mouse). The first control group is dosed with glucose. The second control group is dosed with water. Att = 45 min, the mice are again bled, as described above. The blood samples are centrifuged, the plasma collected and analyzed for glucose content on a Roche-Hitachi 912 glucose analyzer (Roche Diagnostics Corp.; Indianapolis, IN). 10 The data may be expressed as percent (%) inhibition of glucose excursion relative to the two control groups (i.e., the glucose level in the animals receiving glucose but no test compound representing 0%
inhibition and the glucose concentration in the animals receiving only water representing 100% inhibition).
The compounds of formula (1) generally exhibit inhibitory activity, expressed as ICso's, against DPP-
IV that are <1,000 nM. Generally preferred compounds have ICso’s <100 NM. For example, ((2S,4S)-4- (4-(3-cyanopyrazin-2-yl)piperazin-1 -yl)pyrrolidin-2-yl)-((3R*,45-3,4-difluoropyrrolidin-1 -yl)}-methanone dihydrochloride has an ICs of 3.5 nM. :
Comparative Rat Pharmacokinetics Experiments
Rat Pharmacokinetics experiments were performed to demonstrate the improvement in plasma concentrations maintained over time for a compound of the present invention as compared to a structurally similar prior art compound generically disclosed in International Application WO 02/14271.
Specifically, plasma concentrations over time were measured for rats administered (a) the dihydrochloride salt of (3,3-difluoropyrrolidin-1 -y1)-((2S,45)-4-(4-(pyrimidin-2-y!)piperazin-1 -yl)pyrrolidin-2- yl)-methanone (hereinafter “CPD 1137), which was prepared as described in Example 113, and (b) the comparative dihydrochloride salt of ((25,48)-4-(4-(pyrimidin-2-yl)piperazin-1 -yl)pyrrolidin-2-yl)}(pyrrolidin- 1-yl)methanone (hereinafter “comparator”), which may be prepared according to the method of Example 1 or as generally described in WO 02/14271.
In this experiment, male Sprague-Dawley rats (200-250 grams) implanted with jugular vein cannulas (JVC) were obtained from Charles River Laboratories. Each compound was administered to two rats or by oral gavage. The oral dose was administered as a solution in 0.5% methycellulose with a dose volume of 10 ml/kg. The amount of each compound administered was 5 mg/kg body weight. Blood samples (0.25mL) were collected at multiple time points from 0-24 hours and placed into tubes containing lithium heparin (Becton Dickinson, Microtainer®). The blood samples were then centrifuged at 12000 rpm for 10 minutes). Plasma aliquots were taken for determination of compound plasma concentrations (pharmacokinetic analysis). The plasma samples were frozen at -70°C until analysis.
The rat plasma samples were analyzed for compound concentrations by LC/MS/MS (Applied
Biosystems AP| 4000 mass spectrometer). In brief, compound standard curves were prepared in control rat plasma with a dynamic range of 1.0-2000 ng/mL. Aliquots (0.02mL) of both standards and samples were placed into Marsh™ tubes in a 96-well block. Proteins were precipitated by addition of 0.1mL acetonitrile containing 0.1 ug/mL of intemal standard. The 96-well blocks were vortexed and then centrifuged at 3000rpm for 5 minutes. The resulting supernatant was removed and placed into a new 96- well block and taken to dryness at 50°C under a nitrogen stream. Residues were reconstituted in mobile phase (60% 5mM ammonium acetate and 40% acetonitrile). Aliquots (0.01mL) were then injected onto the LC/MS/MS for analysis.
The average plasma concentrations, measured are provided in the following table.
Compound/ CPD 113 Std dev Comparator Std dev
Time (hr) Mean Plasma Mean = ET E- ng/ml ng/ml om | wo | seo | 48] 7 os | ees | wes | as | te om | wer | wo | sv | we — | mr | ews | ws | wes
I LJ DOL NCI EL ws | we | ws | WE]
LA I NN NAN I
| ws | @&s | ee | ee
As shown by their despective plasma concentrations, CPD 113 achieved and maintained significantly higher plasma concentrations than did the comparator compound.
Claims (2)
1. A compound of formula (1) 1 "= HET R? “~ N 6 2 or a prodrug thereof, or a pharmaceutically acceptable salt of said compound or prodrug, or a solvate of said compound, prodrug or salt, wherein: R' is -(C1-Ca)alkyl, -(Cs-Cs)alkoxy, -(C:-Ce)arylalkyl, -NR*R®, hydroxy, cyano, aryl, of heteroaryl, wherein said -(C,-Ce)alkyl, said aryl, or said heteroaryl is optionally substituted independently with one to three -COOH, -C(O)(C1-Celalkoxy, -C(O)(C,-Ce)alkyt, -C(O)NR*R®, cyano, halogen, nitro, trifluoromethyl, -(C;-Ce)alkyl, -(C:-Cs)alkoxy, -(Cx-Ce)cycioalkyl, or phenyl, wherein: R* and R® are, independently, hydrogen, -(Ci-Ce)alkyl, aryl, or heteroaryl, or R® and R®, taken together with the nitrogen atom to which they are attached, form a four- to six- membered heterocyclic ring, wherein said ring optionally incorporates an additional one or two nitrogen, oxygen, or sulfur ring heteroatoms; : : R? and R? are, independently, hydrogen, halogen, -(C,-Ce)alkyl, or -(Cs-Cs)cycloalkyl; Q is a covalent bond, -C(O)-, or -SO;-; HET is a heterocycloalkyl ring moiety, optionally substituted with: (A) one to four -(C4-Cgalkyl, optionally substituted with one to six halogen atoms, -(C,-Ce)alkoxy, cyano, halogen, hydroxy, or -NR*R®, or (B) -(Cy-Ce)arylalkyl, optionally substituted with one to six halogen atoms, -(C:-Ce)alkoxy, cyano, halogen, hydroxy, or -NRR”; nisOor1; when nis 0, X is -CH,-, and Y is -CH.-, -CHF-, or -CFz-, or when n is 1, X is -CH,-, -CHF-, or -CF5-; and Y is -CH,-, -CHF-, or -CF-, provided that X and Y are not both -CH,-; and Z is hydrogen or cyano.
2. The compound of claim 1, wherein: : R' is aryl or heteroaryl, optionally substituted independently with one to three cyano, halogen, nitro, trifluoromethyl, -(C,-Ce)alkyl, -(Ci-Ce)alkoxy, -(Cs-Cs)cycioalkyl, or phenyl; Ris -H or -(C,-Celalkyl; R* is -H or -(C,-Cs)alkyl; and HET is azetidinyl, piperazinyl, piperidiny!, pyrrolidinyl, 5,6-dihydro-8H-imidazo{1,2-a]
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US57030004P | 2004-05-12 | 2004-05-12 |
Publications (1)
Publication Number | Publication Date |
---|---|
ZA200608741B true ZA200608741B (en) | 2008-07-30 |
Family
ID=38077110
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
ZA200608741A ZA200608741B (en) | 2004-05-12 | 2006-10-19 | Proline derivatives and their use as dipeptidyl peptidase IV inhibitors |
Country Status (5)
Country | Link |
---|---|
CN (1) | CN1968949B (en) |
HN (1) | HN2005000205A (en) |
TN (1) | TNSN06366A1 (en) |
UA (1) | UA83133C2 (en) |
ZA (1) | ZA200608741B (en) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107108610B (en) * | 2014-12-30 | 2019-06-04 | 豪夫迈·罗氏有限公司 | For treating and preventing the new tetrahydropyridine and pyrimidine and tetrahydropyridine and pyridine compounds that hepatitis b virus infects |
JP6462155B2 (en) * | 2015-05-04 | 2019-01-30 | エフ.ホフマン−ラ ロシュ アーゲーF. Hoffmann−La Roche Aktiengesellschaft | Tetrahydropyridopyrimidines and tetrahydropyridopyridines as inhibitors of HBsAg (HBV surface antigen) and HBV DNA production for the treatment of hepatitis B virus infection |
CN114213504B (en) * | 2021-12-24 | 2023-05-09 | 西南医科大学 | Compound with antidiabetic activity and application thereof |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7074794B2 (en) * | 2000-08-10 | 2006-07-11 | Mitsubishi Pharma Corporation | Proline derivatives and the use thereof as drugs |
GB0115517D0 (en) * | 2001-06-25 | 2001-08-15 | Ferring Bv | Novel antidiabetic agents |
-
2005
- 2005-04-29 CN CN2005800152588A patent/CN1968949B/en active Active
- 2005-04-29 UA UAA200611856A patent/UA83133C2/en unknown
- 2005-05-10 HN HN2005000205A patent/HN2005000205A/en unknown
-
2006
- 2006-10-19 ZA ZA200608741A patent/ZA200608741B/en unknown
- 2006-11-10 TN TNP2006000366A patent/TNSN06366A1/en unknown
Also Published As
Publication number | Publication date |
---|---|
HN2005000205A (en) | 2009-10-30 |
CN1968949B (en) | 2011-05-04 |
TNSN06366A1 (en) | 2008-02-22 |
UA83133C2 (en) | 2008-06-10 |
CN1968949A (en) | 2007-05-23 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2566108C (en) | Proline derivatives and their use as dipeptidyl peptidase iv inhibitors | |
US7485641B2 (en) | Substituted 3-amino-pyrrolidino-4-lactams | |
CN108349940B (en) | Bruton's tyrosine kinase inhibitors | |
KR20210077719A (en) | Bifunctional compounds to degrade BTK via the ubiquitin proteosome pathway | |
CN107011330B (en) | Bruton's tyrosine kinase inhibitors | |
AU2021201018A1 (en) | Substituted thiohydantoin derivatives as androgen receptor antagonists | |
US20050234065A1 (en) | Dipeptidyl peptidase-IV inhibitors | |
KR20160058188A (en) | Substituted nicotinimide inhibitors of btk and their preparation and use in the treatment of cancer, inflammation and autoimmune disease | |
CZ20033437A3 (en) | N-aroyl cyclic amine derivatives functioning as orexin receptor antagonists | |
CN115485278A (en) | Degradation of Bruton's Tyrosine Kinase (BTK) by conjugation of BTK inhibitors with E3 ligase ligands and methods of use thereof | |
WO2024002284A1 (en) | Five-membered and six-membered nitrogen-containing compound, and intermediate, preparation method and use thereof | |
CA3204318A1 (en) | N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-quinoline-4-carboxamides | |
WO2008100620A2 (en) | Bicyclic aminopropyl tetrahydro-pyrazolo-pyridine modulators of cathepsin s | |
CN116981675A (en) | Degradation of Bruton's Tyrosine Kinase (BTK) by conjugation of BTK inhibitors to E3 ligase ligands and methods of use | |
WO2006008644A1 (en) | Antidiabetic compounds | |
ZA200608741B (en) | Proline derivatives and their use as dipeptidyl peptidase IV inhibitors | |
WO2024032689A1 (en) | Compound based on isoindoline-substituted glutarimide backbone and use thereof | |
CN115557946A (en) | Heterocyclic lactam compound, pharmaceutical composition containing same and application thereof | |
CN116615417A (en) | 1, 4-diheterocycle substituted aromatic ring or aromatic heterocyclic compound and application thereof | |
EA038420B1 (en) | Positive allosteric modulators of the muscarinic acetylcholine receptor m4 |