AU2006239929B2 - Dipeptidyl peptidase-IV inhibitors - Google Patents
Dipeptidyl peptidase-IV inhibitors Download PDFInfo
- Publication number
- AU2006239929B2 AU2006239929B2 AU2006239929A AU2006239929A AU2006239929B2 AU 2006239929 B2 AU2006239929 B2 AU 2006239929B2 AU 2006239929 A AU2006239929 A AU 2006239929A AU 2006239929 A AU2006239929 A AU 2006239929A AU 2006239929 B2 AU2006239929 B2 AU 2006239929B2
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- Prior art keywords
- alkyl
- mixture
- title compound
- afford
- pct
- Prior art date
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- 229940124213 Dipeptidyl peptidase 4 (DPP IV) inhibitor Drugs 0.000 title description 2
- 239000003603 dipeptidyl peptidase IV inhibitor Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 610
- 238000000034 method Methods 0.000 claims abstract description 60
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims abstract description 17
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 4
- 150000003839 salts Chemical class 0.000 claims description 36
- 238000011282 treatment Methods 0.000 abstract description 41
- 239000003112 inhibitor Substances 0.000 abstract description 28
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 22
- 230000002401 inhibitory effect Effects 0.000 abstract description 19
- 238000002360 preparation method Methods 0.000 abstract description 13
- 201000010099 disease Diseases 0.000 abstract description 10
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 abstract description 6
- OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 abstract description 4
- 230000001404 mediated effect Effects 0.000 abstract description 4
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 abstract 3
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 abstract 3
- 238000010189 synthetic method Methods 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 340
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 287
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 270
- 239000002904 solvent Substances 0.000 description 234
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 164
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 160
- 235000019439 ethyl acetate Nutrition 0.000 description 138
- 239000000243 solution Substances 0.000 description 128
- 125000000217 alkyl group Chemical group 0.000 description 123
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- -1 S 2 NR Chemical group 0.000 description 93
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- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 79
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- 125000001072 heteroaryl group Chemical group 0.000 description 74
- 125000003118 aryl group Chemical group 0.000 description 71
- 239000000047 product Substances 0.000 description 68
- 125000000753 cycloalkyl group Chemical group 0.000 description 65
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- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 63
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 62
- 238000000746 purification Methods 0.000 description 62
- 229910052757 nitrogen Inorganic materials 0.000 description 57
- 125000000304 alkynyl group Chemical group 0.000 description 56
- 239000002585 base Substances 0.000 description 55
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 55
- 125000003710 aryl alkyl group Chemical group 0.000 description 53
- 125000003709 fluoroalkyl group Chemical group 0.000 description 53
- 125000005885 heterocycloalkylalkyl group Chemical group 0.000 description 53
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- 125000004446 heteroarylalkyl group Chemical group 0.000 description 52
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 52
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 52
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- 239000012267 brine Substances 0.000 description 51
- 229910052739 hydrogen Inorganic materials 0.000 description 51
- 125000004103 aminoalkyl group Chemical group 0.000 description 50
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 48
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 48
- 102000016622 Dipeptidyl Peptidase 4 Human genes 0.000 description 46
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 46
- 101000930822 Giardia intestinalis Dipeptidyl-peptidase 4 Proteins 0.000 description 46
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- 125000004183 alkoxy alkyl group Chemical group 0.000 description 43
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 42
- 238000003756 stirring Methods 0.000 description 41
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 36
- 239000001257 hydrogen Substances 0.000 description 35
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 35
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 31
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 30
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 30
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- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 29
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- 238000010992 reflux Methods 0.000 description 28
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- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 24
- 235000019341 magnesium sulphate Nutrition 0.000 description 24
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 23
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 22
- 229910052736 halogen Inorganic materials 0.000 description 21
- 150000002367 halogens Chemical class 0.000 description 21
- 229920006395 saturated elastomer Polymers 0.000 description 20
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-dimethylaminopyridine Substances CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 19
- 238000005160 1H NMR spectroscopy Methods 0.000 description 18
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 18
- 150000001299 aldehydes Chemical class 0.000 description 18
- 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 18
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- 101100294115 Caenorhabditis elegans nhr-4 gene Proteins 0.000 description 17
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- 239000003054 catalyst Substances 0.000 description 16
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- 229910052799 carbon Inorganic materials 0.000 description 15
- 229940086542 triethylamine Drugs 0.000 description 15
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 14
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 13
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- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 12
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 12
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| DE102004054054A1 (de) | 2004-11-05 | 2006-05-11 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Verfahren zur Herstellung chiraler 8-(3-Amino-piperidin-1-yl)-xanthine |
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- 2006-04-21 BR BRPI0608469-9A patent/BRPI0608469A2/pt not_active IP Right Cessation
- 2006-04-21 EP EP06758484.7A patent/EP1888562B1/en active Active
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- 2006-04-21 CN CNA2006800134175A patent/CN101277949A/zh active Pending
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- 2007-10-22 CR CR9462A patent/CR9462A/es not_active Application Discontinuation
- 2007-11-22 NO NO20075973A patent/NO20075973L/no not_active Application Discontinuation
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| US3297709A (en) * | 1965-11-19 | 1967-01-10 | American Home Prod | Certain substituted tetrazole derivatives |
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| US20100009961A1 (en) | 2010-01-14 |
| EP1888562A2 (en) | 2008-02-20 |
| ES2477868T3 (es) | 2014-07-18 |
| AU2010201511B2 (en) | 2012-02-16 |
| CN101277949A (zh) | 2008-10-01 |
| US20110112051A1 (en) | 2011-05-12 |
| JP2008538574A (ja) | 2008-10-30 |
| NO20075973L (no) | 2008-01-21 |
| CA2599419A1 (en) | 2006-11-02 |
| IL186607A0 (en) | 2008-01-20 |
| JP2010150273A (ja) | 2010-07-08 |
| BRPI0608469A2 (pt) | 2010-01-05 |
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| ZA200708179B (en) | 2009-12-30 |
| US20060270701A1 (en) | 2006-11-30 |
| TNSN07244A1 (en) | 2008-11-21 |
| AU2010201511A1 (en) | 2010-05-06 |
| EP1888562B1 (en) | 2014-06-18 |
| MA29387B1 (fr) | 2008-04-01 |
| JP4568361B2 (ja) | 2010-10-27 |
| JP5198494B2 (ja) | 2013-05-15 |
| WO2006116157A2 (en) | 2006-11-02 |
| WO2006116157A9 (en) | 2007-03-01 |
| EA200702208A1 (ru) | 2008-04-28 |
| CR9462A (es) | 2008-04-16 |
| WO2006116157A3 (en) | 2007-04-19 |
| US7553861B2 (en) | 2009-06-30 |
| KR20080000665A (ko) | 2008-01-02 |
| MX2007011453A (es) | 2008-02-12 |
| US8076330B2 (en) | 2011-12-13 |
| AP2007004234A0 (en) | 2007-12-31 |
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