UA76233C2 - N-substituted pyrrolidine derivatives as dipeptidylpeptidase iv inhibitors - Google Patents

Info

Publication number

UA76233C2

UA76233C2 UA20040504003A UA20040504003A UA76233C2 UA 76233 C2 UA76233 C2 UA 76233C2 UA 20040504003 A UA20040504003 A UA 20040504003A UA 20040504003 A UA20040504003 A UA 20040504003A UA 76233 C2 UA76233 C2 UA 76233C2

Authority

UA

Ukraine

Prior art keywords

methyl

pyridin

acetyl

pyrrolidine

phenyl

Prior art date

2001-10-26

Links

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• -1 N-substituted pyrrolidine Chemical class 0.000 title claims description 370
• 229940124213 Dipeptidyl peptidase 4 (DPP IV) inhibitor Drugs 0.000 title 1
• 239000003603 dipeptidyl peptidase IV inhibitor Substances 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 428
• 150000003839 salts Chemical class 0.000 claims abstract description 126
• 238000011282 treatment Methods 0.000 claims abstract description 67
• 208000001072 type 2 diabetes mellitus Diseases 0.000 claims abstract description 19
• 208000002705 Glucose Intolerance Diseases 0.000 claims abstract description 17
• 201000009104 prediabetes syndrome Diseases 0.000 claims abstract description 17
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 13
• 201000010099 disease Diseases 0.000 claims abstract description 12
• 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 11
• 238000000034 method Methods 0.000 claims description 278
• 125000000217 alkyl group Chemical group 0.000 claims description 135
• 125000001424 substituent group Chemical group 0.000 claims description 87
• 229910052736 halogen Inorganic materials 0.000 claims description 78
• 150000002367 halogens Chemical class 0.000 claims description 78
• 125000003545 alkoxy group Chemical group 0.000 claims description 77
• 125000001072 heteroaryl group Chemical group 0.000 claims description 63
• 125000003118 aryl group Chemical group 0.000 claims description 52
• 229910052739 hydrogen Inorganic materials 0.000 claims description 36
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 34
• 238000006243 chemical reaction Methods 0.000 claims description 32
• 239000001257 hydrogen Substances 0.000 claims description 31
• 229910052799 carbon Inorganic materials 0.000 claims description 30
• 125000004076 pyridyl group Chemical group 0.000 claims description 23
• 125000000623 heterocyclic group Chemical group 0.000 claims description 22
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 22
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 21
• 125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 18
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 16
• 125000005329 tetralinyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 claims description 14
• 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 12
• 125000001544 thienyl group Chemical group 0.000 claims description 12
• 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims description 12
• 101150046432 Tril gene Proteins 0.000 claims description 11
• 230000002265 prevention Effects 0.000 claims description 11
• RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 11
• 208000001145 Metabolic Syndrome Diseases 0.000 claims description 10
• 208000008589 Obesity Diseases 0.000 claims description 10
• 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims description 10
• 238000004519 manufacturing process Methods 0.000 claims description 10
• 125000001624 naphthyl group Chemical group 0.000 claims description 10
• 235000020824 obesity Nutrition 0.000 claims description 10
• 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 claims description 10
• 125000000335 thiazolyl group Chemical group 0.000 claims description 10
• 206010009900 Colitis ulcerative Diseases 0.000 claims description 9
• 208000011231 Crohn disease Diseases 0.000 claims description 9
• 201000006704 Ulcerative Colitis Diseases 0.000 claims description 9
• 150000001721 carbon Chemical group 0.000 claims description 9
• 230000006806 disease prevention Effects 0.000 claims description 9
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 9
• 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 9
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
• 125000001715 oxadiazolyl group Chemical group 0.000 claims description 8
• 229910052760 oxygen Inorganic materials 0.000 claims description 8
• 229940126601 medicinal product Drugs 0.000 claims description 7
• 125000002971 oxazolyl group Chemical group 0.000 claims description 7
• 239000013543 active substance Substances 0.000 claims description 6
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
• SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 6
• 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 claims description 6
• 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 claims description 5
• 125000006289 hydroxybenzyl group Chemical group 0.000 claims description 5
• 125000002883 imidazolyl group Chemical group 0.000 claims description 5
• 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 claims description 5
• 125000001041 indolyl group Chemical group 0.000 claims description 5
• 125000005334 azaindolyl group Chemical group N1N=C(C2=CC=CC=C12)* 0.000 claims description 4
• 125000004190 benzothiazol-2-yl group Chemical group [H]C1=C([H])C([H])=C2N=C(*)SC2=C1[H] 0.000 claims description 4
• 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 4
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 4
• 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 3
• 125000005872 benzooxazolyl group Chemical group 0.000 claims description 3
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
• 125000002757 morpholinyl group Chemical group 0.000 claims description 3
• 125000003386 piperidinyl group Chemical group 0.000 claims description 3
• 125000001425 triazolyl group Chemical group 0.000 claims description 3
• 125000000972 4,5-dimethylthiazol-2-yl group Chemical group [H]C([H])([H])C1=C(N=C(*)S1)C([H])([H])[H] 0.000 claims description 2
• 241001465754 Metazoa Species 0.000 claims description 2
• 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
• 239000003937 drug carrier Substances 0.000 claims description 2
• 239000008194 pharmaceutical composition Substances 0.000 claims description 2
• 125000003373 pyrazinyl group Chemical group 0.000 claims description 2
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims 2
• 150000002431 hydrogen Chemical class 0.000 claims 2
• 125000001475 halogen functional group Chemical group 0.000 claims 1
• 125000005493 quinolyl group Chemical group 0.000 claims 1
• 238000012876 topography Methods 0.000 claims 1
• 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 abstract 1
• 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 abstract 1
• 238000011321 prophylaxis Methods 0.000 abstract 1
• AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 307
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 216
• 229940098779 methanesulfonic acid Drugs 0.000 description 129
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 111
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 110
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 90
• 150000001412 amines Chemical class 0.000 description 87
• AQEFLFZSWDEAIP-UHFFFAOYSA-N di-tert-butyl ether Chemical compound CC(C)(C)OC(C)(C)C AQEFLFZSWDEAIP-UHFFFAOYSA-N 0.000 description 84
• 238000003818 flash chromatography Methods 0.000 description 74
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical class CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 64
• 239000000203 mixture Substances 0.000 description 61
• 239000000243 solution Substances 0.000 description 56
• 239000000843 powder Substances 0.000 description 55
• 239000000047 product Substances 0.000 description 55
• 238000005160 1H NMR spectroscopy Methods 0.000 description 53
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 53
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 51
• 239000006260 foam Substances 0.000 description 48
• 239000007787 solid Substances 0.000 description 42
• 230000015572 biosynthetic process Effects 0.000 description 39
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 38
• 239000000741 silica gel Substances 0.000 description 38
• 229910002027 silica gel Inorganic materials 0.000 description 38
• OPCJOXGBLDJWRM-UHFFFAOYSA-N 1,2-diamino-2-methylpropane Chemical compound CC(C)(N)CN OPCJOXGBLDJWRM-UHFFFAOYSA-N 0.000 description 37
• 238000005481 NMR spectroscopy Methods 0.000 description 37
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 37
• 238000004587 chromatography analysis Methods 0.000 description 35
• 239000012458 free base Substances 0.000 description 35
• 239000007858 starting material Substances 0.000 description 35
• QSJXEFYPDANLFS-UHFFFAOYSA-N Diacetyl Chemical compound CC(=O)C(C)=O QSJXEFYPDANLFS-UHFFFAOYSA-N 0.000 description 34
• 239000003480 eluent Substances 0.000 description 33
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 31
• 239000003921 oil Substances 0.000 description 31
• 235000019198 oils Nutrition 0.000 description 31
• 238000003786 synthesis reaction Methods 0.000 description 31
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 30
• 239000012044 organic layer Substances 0.000 description 29
• 239000000126 substance Substances 0.000 description 29
• PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 25
• 239000002904 solvent Substances 0.000 description 24
• 239000011541 reaction mixture Substances 0.000 description 22
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
• 239000011780 sodium chloride Substances 0.000 description 21
• 239000000725 suspension Substances 0.000 description 20
• ZHXUWDPHUQHFOV-UHFFFAOYSA-N 2,5-dibromopyridine Chemical compound BrC1=CC=C(Br)N=C1 ZHXUWDPHUQHFOV-UHFFFAOYSA-N 0.000 description 19
• FEYDZHNIIMENOB-UHFFFAOYSA-N 2,6-dibromopyridine Chemical compound BrC1=CC=CC(Br)=N1 FEYDZHNIIMENOB-UHFFFAOYSA-N 0.000 description 19
• 238000010511 deprotection reaction Methods 0.000 description 19
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 18
• BHIWKHZACMWKOJ-UHFFFAOYSA-N methyl isobutyrate Chemical compound COC(=O)C(C)C BHIWKHZACMWKOJ-UHFFFAOYSA-N 0.000 description 18
• 239000002243 precursor Substances 0.000 description 18
• 238000003756 stirring Methods 0.000 description 18
• RIDWRQPRYKGWRO-UHFFFAOYSA-N 2-(carbamothioylamino)ethylcarbamic acid Chemical compound NC(=S)NCCNC(O)=O RIDWRQPRYKGWRO-UHFFFAOYSA-N 0.000 description 17
• BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 17
• SGNPIGAGPRLGEJ-UHFFFAOYSA-N oxathiazolidine-3-carboxylic acid Chemical compound OC(=O)N1CCOS1 SGNPIGAGPRLGEJ-UHFFFAOYSA-N 0.000 description 17
• 150000002460 imidazoles Chemical class 0.000 description 16
• 239000012267 brine Substances 0.000 description 15
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 15
• 230000009467 reduction Effects 0.000 description 15
• 238000006722 reduction reaction Methods 0.000 description 15
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 15
• HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 14
• 239000000543 intermediate Substances 0.000 description 14
• 238000005804 alkylation reaction Methods 0.000 description 13
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 12
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
• 239000002253 acid Substances 0.000 description 11
• 239000000969 carrier Substances 0.000 description 11
• HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 11
• JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 11
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• 238000010992 reflux Methods 0.000 description 10
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• 230000029936 alkylation Effects 0.000 description 9
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• HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
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• 229910052757 nitrogen Inorganic materials 0.000 description 5
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