CN1803797A - 二肽基肽酶iv抑制剂 - Google Patents
二肽基肽酶iv抑制剂 Download PDFInfo
- Publication number
- CN1803797A CN1803797A CNA2005101377754A CN200510137775A CN1803797A CN 1803797 A CN1803797 A CN 1803797A CN A2005101377754 A CNA2005101377754 A CN A2005101377754A CN 200510137775 A CN200510137775 A CN 200510137775A CN 1803797 A CN1803797 A CN 1803797A
- Authority
- CN
- China
- Prior art keywords
- compound
- tertbutyloxycarbonyl
- tetramethyleneimine
- group
- formonitrile hcn
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000003112 inhibitor Substances 0.000 title abstract description 19
- 102000016622 Dipeptidyl Peptidase 4 Human genes 0.000 title abstract 2
- 101000930822 Giardia intestinalis Dipeptidyl-peptidase 4 Proteins 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 54
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 13
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 11
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 claims abstract description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 6
- 229910052717 sulfur Inorganic materials 0.000 claims abstract 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 67
- 239000000460 chlorine Substances 0.000 claims description 30
- -1 Sauerstoffatom Chemical group 0.000 claims description 27
- 125000001072 heteroaryl group Chemical group 0.000 claims description 18
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 15
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims description 13
- 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 claims description 12
- 239000008103 glucose Substances 0.000 claims description 12
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 11
- 239000001301 oxygen Substances 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- 125000002252 acyl group Chemical group 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- 239000005864 Sulphur Substances 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- 206010012601 diabetes mellitus Diseases 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 125000003107 substituted aryl group Chemical group 0.000 claims description 4
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 4
- 125000003435 aroyl group Chemical group 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- 206010056438 Growth hormone deficiency Diseases 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 230000005784 autoimmunity Effects 0.000 claims description 2
- 125000002619 bicyclic group Chemical group 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 208000027866 inflammatory disease Diseases 0.000 claims description 2
- 125000002950 monocyclic group Chemical group 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 201000010065 polycystic ovary syndrome Diseases 0.000 claims description 2
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims 2
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims 1
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 abstract description 8
- 208000001072 type 2 diabetes mellitus Diseases 0.000 abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 122
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 95
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 93
- 239000003921 oil Substances 0.000 description 57
- 235000019198 oils Nutrition 0.000 description 57
- 239000000243 solution Substances 0.000 description 53
- OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 description 42
- 235000019439 ethyl acetate Nutrition 0.000 description 41
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 40
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 32
- 238000005406 washing Methods 0.000 description 32
- 238000001704 evaporation Methods 0.000 description 31
- 239000003480 eluent Substances 0.000 description 30
- 230000008020 evaporation Effects 0.000 description 30
- 238000003818 flash chromatography Methods 0.000 description 30
- 238000000746 purification Methods 0.000 description 30
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 28
- 239000011734 sodium Substances 0.000 description 28
- 239000012266 salt solution Substances 0.000 description 27
- 238000000034 method Methods 0.000 description 25
- 239000000203 mixture Substances 0.000 description 24
- 239000007787 solid Substances 0.000 description 23
- 229920006395 saturated elastomer Polymers 0.000 description 22
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 20
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 19
- 125000000217 alkyl group Chemical group 0.000 description 19
- 239000002585 base Substances 0.000 description 19
- 230000008569 process Effects 0.000 description 17
- 238000002360 preparation method Methods 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- 239000002253 acid Substances 0.000 description 14
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 14
- MPGQQQKGAXDBDN-UHFFFAOYSA-N 1,3-thiazolidin-3-ium;chloride Chemical compound Cl.C1CSCN1 MPGQQQKGAXDBDN-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- 201000010099 disease Diseases 0.000 description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 11
- 230000000694 effects Effects 0.000 description 10
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 8
- 229960002429 proline Drugs 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
- PRSDPVKGJUBIAA-UHFFFAOYSA-N 1,3-thiazolidine-4-carbonitrile Chemical compound N#CC1CSCN1 PRSDPVKGJUBIAA-UHFFFAOYSA-N 0.000 description 7
- 229940073608 benzyl chloride Drugs 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 230000003203 everyday effect Effects 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 6
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 5
- 150000001408 amides Chemical class 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 238000010790 dilution Methods 0.000 description 5
- 239000012895 dilution Substances 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 102100040918 Pro-glucagon Human genes 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- 239000000654 additive Substances 0.000 description 4
- 230000000996 additive effect Effects 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- 230000000903 blocking effect Effects 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- NIPZZXUFJPQHNH-UHFFFAOYSA-N pyrazine-2-carboxylic acid Chemical compound OC(=O)C1=CN=CC=N1 NIPZZXUFJPQHNH-UHFFFAOYSA-N 0.000 description 4
- 150000003556 thioamides Chemical class 0.000 description 4
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 4
- SWTCRXVGKJOXJA-DFWYDOINSA-N (4r)-1,3-thiazolidine-4-carboxamide;hydrochloride Chemical compound Cl.NC(=O)[C@@H]1CSCN1 SWTCRXVGKJOXJA-DFWYDOINSA-N 0.000 description 3
- RXTRRIFWCJEMEL-UHFFFAOYSA-N 2-chloropyridine-3-carbonyl chloride Chemical compound ClC(=O)C1=CC=CN=C1Cl RXTRRIFWCJEMEL-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- ZKRHHAYAEBQZSK-UHFFFAOYSA-N C1CSCN1.OC(=O)C(F)(F)F Chemical compound C1CSCN1.OC(=O)C(F)(F)F ZKRHHAYAEBQZSK-UHFFFAOYSA-N 0.000 description 3
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 3
- ACBRDXYEZXNEIR-UHFFFAOYSA-N FC(C(=O)O)(F)F.C=N.C=N.C=N.C=N Chemical compound FC(C(=O)O)(F)F.C=N.C=N.C=N.C=N ACBRDXYEZXNEIR-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 101000908391 Homo sapiens Dipeptidyl peptidase 4 Proteins 0.000 description 3
- VLJNHYLEOZPXFW-BYPYZUCNSA-N L-prolinamide Chemical compound NC(=O)[C@@H]1CCCN1 VLJNHYLEOZPXFW-BYPYZUCNSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- FCLZCOCSZQNREK-UHFFFAOYSA-N Pyrrolidine, hydrochloride Chemical compound Cl.C1CCNC1 FCLZCOCSZQNREK-UHFFFAOYSA-N 0.000 description 3
- 210000001744 T-lymphocyte Anatomy 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 239000004202 carbamide Substances 0.000 description 3
- 229940125898 compound 5 Drugs 0.000 description 3
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 229960003104 ornithine Drugs 0.000 description 3
- 150000003141 primary amines Chemical class 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 150000003512 tertiary amines Chemical class 0.000 description 3
- NTNKNFHIAFDCSJ-UHFFFAOYSA-N (2-nitrophenyl) thiohypochlorite Chemical compound [O-][N+](=O)C1=CC=CC=C1SCl NTNKNFHIAFDCSJ-UHFFFAOYSA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 101710198884 GATA-type zinc finger protein 1 Proteins 0.000 description 2
- 101800000221 Glucagon-like peptide 2 Proteins 0.000 description 2
- 239000000095 Growth Hormone-Releasing Hormone Substances 0.000 description 2
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 2
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 235000019502 Orange oil Nutrition 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 102100022831 Somatoliberin Human genes 0.000 description 2
- 101710142969 Somatoliberin Proteins 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- GNVMUORYQLCPJZ-UHFFFAOYSA-M Thiocarbamate Chemical compound NC([S-])=O GNVMUORYQLCPJZ-UHFFFAOYSA-M 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 150000001263 acyl chlorides Chemical class 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 125000003368 amide group Chemical group 0.000 description 2
- 229940024606 amino acid Drugs 0.000 description 2
- 150000003862 amino acid derivatives Chemical class 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N anhydrous methyl chloride Natural products ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
- 230000003178 anti-diabetic effect Effects 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 125000004104 aryloxy group Chemical group 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 150000001718 carbodiimides Chemical class 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- TWSALRJGPBVBQU-PKQQPRCHSA-N glucagon-like peptide 2 Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(O)=O)[C@@H](C)CC)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)CC)C1=CC=CC=C1 TWSALRJGPBVBQU-PKQQPRCHSA-N 0.000 description 2
- 201000001421 hyperglycemia Diseases 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 210000004072 lung Anatomy 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
- 238000012423 maintenance Methods 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 239000010502 orange oil Substances 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 239000000813 peptide hormone Substances 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- HDOUGSFASVGDCS-UHFFFAOYSA-N pyridin-3-ylmethanamine Chemical compound NCC1=CC=CN=C1 HDOUGSFASVGDCS-UHFFFAOYSA-N 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 125000002072 seryl group Chemical group 0.000 description 2
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 2
- 229940124530 sulfonamide Drugs 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- BJFPYGGTDAYECS-UHFFFAOYSA-N (3-chlorophenyl)methanamine Chemical compound NCC1=CC=CC(Cl)=C1 BJFPYGGTDAYECS-UHFFFAOYSA-N 0.000 description 1
- FJWNZTPXVSWUKF-LURJTMIESA-N (4r)-3-[(2-methylpropan-2-yl)oxycarbonyl]-1,3-thiazolidine-4-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CSC[C@H]1C(O)=O FJWNZTPXVSWUKF-LURJTMIESA-N 0.000 description 1
- CZMRCDWAGMRECN-UHFFFAOYSA-N 2-{[3,4-dihydroxy-2,5-bis(hydroxymethyl)oxolan-2-yl]oxy}-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound OCC1OC(CO)(OC2OC(CO)C(O)C(O)C2O)C(O)C1O CZMRCDWAGMRECN-UHFFFAOYSA-N 0.000 description 1
- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 description 1
- GRFNBEZIAWKNCO-UHFFFAOYSA-N 3-pyridinol Chemical compound OC1=CC=CN=C1 GRFNBEZIAWKNCO-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- CKDWPUIZGOQOOM-UHFFFAOYSA-N Carbamyl chloride Chemical compound NC(Cl)=O CKDWPUIZGOQOOM-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- VVNCNSJFMMFHPL-VKHMYHEASA-N D-penicillamine Chemical compound CC(C)(S)[C@@H](N)C(O)=O VVNCNSJFMMFHPL-VKHMYHEASA-N 0.000 description 1
- 108010016626 Dipeptides Proteins 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- 101800000224 Glucagon-like peptide 1 Proteins 0.000 description 1
- 102400000326 Glucagon-like peptide 2 Human genes 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 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
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 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
- 229930182821 L-proline Natural products 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- WYNCHZVNFNFDNH-UHFFFAOYSA-N Oxazolidine Chemical compound C1COCN1 WYNCHZVNFNFDNH-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 101000886298 Pseudoxanthomonas mexicana Dipeptidyl aminopeptidase 4 Proteins 0.000 description 1
- 108010022999 Serine Proteases Proteins 0.000 description 1
- 102000012479 Serine Proteases Human genes 0.000 description 1
- 230000005867 T cell response Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 150000001348 alkyl chlorides Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- JHVLLYQQQYIWKX-UHFFFAOYSA-N benzyl 2-bromoacetate Chemical compound BrCC(=O)OCC1=CC=CC=C1 JHVLLYQQQYIWKX-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 125000001246 bromo group Chemical group Br* 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
- 239000002775 capsule Substances 0.000 description 1
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 125000000259 cinnolinyl group Chemical class N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 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
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 description 1
- 125000004639 dihydroindenyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- LUIQLXHVYAPLBK-UHFFFAOYSA-N formamido thiohypochlorite Chemical compound ClSNC=O LUIQLXHVYAPLBK-UHFFFAOYSA-N 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 230000002584 immunomodulator Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- AWJUIBRHMBBTKR-UHFFFAOYSA-N iso-quinoline Natural products C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 150000002668 lysine derivatives Chemical class 0.000 description 1
- 125000001288 lysyl group Chemical group 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229910000000 metal hydroxide Inorganic materials 0.000 description 1
- 150000004692 metal hydroxides Chemical class 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- HOGDNTQCSIKEEV-UHFFFAOYSA-N n'-hydroxybutanediamide Chemical compound NC(=O)CCC(=O)NO HOGDNTQCSIKEEV-UHFFFAOYSA-N 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 230000000474 nursing effect Effects 0.000 description 1
- 238000007410 oral glucose tolerance test Methods 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N ornithyl group Chemical group N[C@@H](CCCN)C(=O)O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 150000003140 primary amides Chemical class 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 238000009738 saturating Methods 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 229960001153 serine Drugs 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 150000005622 tetraalkylammonium hydroxides Chemical class 0.000 description 1
- 150000005621 tetraalkylammonium salts Chemical class 0.000 description 1
- UWYZHKAOTLEWKK-UHFFFAOYSA-N tetrahydro-isoquinoline Natural products C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- ZWZVWGITAAIFPS-UHFFFAOYSA-N thiophosgene Chemical compound ClC(Cl)=S ZWZVWGITAAIFPS-UHFFFAOYSA-N 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/06—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
- A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Immunology (AREA)
- Emergency Medicine (AREA)
- Obesity (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Gynecology & Obstetrics (AREA)
- Pregnancy & Childbirth (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Pyridine Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pyrrole Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
Abstract
根据通式(1)的化合物是新的,其中R1是H或CN;X1是S、O、SO2或CH2;X2是O、S或CH2;X3是NR5或者羰基或硫代羰基;R4是R6R7N、R8 (CH2) q OC(=O)、R8 (CH2) q OC(=S)、R6R7NC(=O)、R6R7NC(=S)、R8 (CH2) qC(=O)、R8 (CH2) qC(=S)或R8 (CH2) qSO2;m是1-3;n是0-4。本发明化合物是二肽基肽酶IV的抑制剂。本发明化合物或其药学上可接受的盐的药物组合物尤其可用于治疗2型糖尿病。
Description
本申请是申请日为2001年4月26日、申请号为01808504.0、发明名称为“二肽基肽酶IV抑制剂”的中国专利申请的分案申请。
本发明涉及一系列新颖的化合物,它们是二肽基肽酶IV的抑制剂,还涉及包含这些抑制剂的药物组合物和这类组合物在人疾病治疗中的用途。
背景
二肽基肽酶IV在本文简称DP-IV(以及DAP-IV或DPP-IV),已知分类为EC.3.4.14.5,是一系列从开始于序列H-Xaa-Pro(其中Xaa是任意氨基酸,不过优选为亲脂性者,Pro是脯氨酸)的肽裂解N-末端二肽的丝氨酸蛋白酶。它也接受开始于序列H-Xaa-Ala(其中Ala是丙氨酸)的肽作为底物。DP-IV首先被鉴定为一种膜结合蛋白。最近已经鉴定了一种可溶形式。
人们最初对DP-IV的兴趣集中于它在T淋巴细胞活化中的作用。DP-IV等同于T细胞蛋白CD26。有人提出DP-IV抑制剂将能够调节T细胞应答能力,因此可以开发成为新颖的免疫调节剂。有人进一步暗示CD26是HIV所必要的辅受体,因而DP-IV抑制剂可以用于AIDS的治疗。
DP-IV在免疫系统之外的作用也令人关注。公认的是DP-IV在若干肽类激素的降解中具有关键作用,包括生长激素释放激素(GHRH)和胰高血糖素样肽-1与-2(GLP-1和GLP-2)。由于已知GLP-1对胰岛素在食后血糖水平控制中的作用具有加强效果,显然DP-IV抑制剂也许也可用于II型糖尿病和葡萄糖耐量减低的治疗。目前至少有两种DP-IV处于临床试验阶段,以探究这种可能性。
若干组DP-IV抑制剂已被公开。尽管有些是从随机筛选程序中发现的,不过本领域的主要工作致力于底物类似物的研究。作为底物类似物的DP-IV抑制剂例如公开在US 5,462,928、US 5,543,396、WO95/15309(等同于US 5,939,560和EP 0731789)、WO 98/19998(等同于US 6,011,155)、WO 99/46272和WO 99/61431中。最有效的抑制剂是氨基酰基吡咯烷硼酸类,但是它们是不稳定的,趋向于环化,而更稳定的吡咯烷与噻唑烷衍生物对酶的亲和性较低,因此在临床情形中需要大剂量。吡咯烷腈类似乎提供良好的折衷方案,因为它们既对酶具有较高的亲和性,又在游离碱的溶液中具有长短适中的半衰期。不过,仍然需要性质得到改善的DP-IV抑制剂。
发明的简要说明
本发明涉及一系列DP-IV抑制剂,它们提高了对酶的亲和性。这些化合物能够用于大量人疾病的治疗,包括葡萄糖耐量减低和II型糖尿病。因此,本发明进一步涉及这些化合物在药物组合物制备中的用途、这类组合物本身和这类组合物在人疗法中的用途。本发明的化合物如通式1所述。
通式1中,X1选自-S-、-O-、-SO-、-SO2-和-CH2-;X2选自-O-、-S-、-NH-和-CH2-;X3是-NR5-或者>C=O或>C=S基团;R1是H或-CN;R2和R3独立地选自H和低级烷基,或者可以一起是-(CH2)p-;若X3是-NR5-,则R4是R4A,若X3是>C=O或>C=S,则R4是R4B;R4A选自R6R7NC(=O)、R6R7NC(=S)、R8(CH2)qC(=O)、R8(CH2)qC(=S)、R8(CH2)qSO2、R8(CH2)qOC(=S)和R8(CH2)qOC(=O);R4B是R6R7N;R5是H或低级烷基;R6和R7各自独立地是R8(CH2)q,或者它们一起是-(CH2)2-Z-(CH2)2-;R8选自H、烷基、可选被取代的芳基、可选被取代的芳酰基、可选被取代的芳基磺酰基和可选被取代的杂芳基;Z选自共价键、-(CH2)r、-O-、-SOt和-N((CH2)qR8)-;n是0-4;p是2-5;q是0-3;r是1或2;t是0-2。
发明的详细说明
本发明在第一方面包含一系列新颖的化合物,它们是DP-IV的抑制剂,可用于人某些疾病的治疗。这些化合物如通式1所述。
通式1中,X1是二价基团,选自硫原子(-S-)、氧原子(-O-)、亚磺酰基(-SO-)、磺酰基(-SO2-)和亚甲基(-CH2-)。X2是二价基团,选自氧原子(-O-)、硫原子(-S-)和亚甲基(-CH2-)。X3是取代的亚氨基(-NR5-)或者羰基(>C=O)或硫代羰基(>C=S)。
R1是氢原子(H)或腈基(-CN)。
R2和R3可以彼此独立地是氢原子或低级烷基,或者它们可以一起是二至五个亚甲基单元的链(-(CH2)p-,其中p是2-5),以便与它们所连接的碳原子构成三、四、五或六元环。m的值可以是1、2或3。若m大于1,则每个CR2R3单元可以是相同或不同的。例如,若m是2,则(CR2R3)2可以是CH2CH2、CH2C(Me)2、C(Me)2CH2等。
R4的性质取决于X3的特性,以致这两个基团通过酰胺(CO-N)、硫代酰胺(CS-N)或磺酰胺(SO2-N)键连接。因此,若X3是取代的亚氨基(-NR5),则R4是R4A,其中R4A选自氨基甲酰基(R6R7NC(=O))、硫代氨基甲酰基(R6R7NC(=S))、可选被修饰的酰基(R8(CH2)qC(=O))、可选被修饰的硫代酰基(R8(CH2)qC(=S))、磺酰基(R8(CH2)qSO2)、可选被修饰的(烷基或芳氧基)羰基(R8(CH2)qOC(=O))和可选被修饰的(烷基或芳氧基)硫代羰基(R8(CH2)qOC(=S))。本文所用的术语“可选被修饰”表示有些R8的实施方式超出术语“烷基”、“酰基”和“芳基”的范围。R4A定义的范围由R8定义的范围决定。作为替代选择,若X3是羰基(>C=O)或硫代羰基(>C=S),则R4是R4B,其中R4B是取代的氨基(R6R7N)。
R5是氢原子(H)或低级烷基。优选地,R5是H。
R6和R7可以彼此独立地是R8(CH2)q。作为替代选择,它们可以一起是基团-(CH2)2-Z1-(CH2)2-或-CHR9-Z2-CH2-CR10-。这里Z1是共价键、亚甲基或亚乙基(-(CH2)r-,其中r是1或2)、氧原子(-O-)、硫或氧化的硫原子(-SOt-,其中t是0、1或2)或取代的亚氨基(-N((CH2)qR8)-),以致基团NR6R7是吡咯烷、哌啶、全氢氮杂、吗啉、可选被氧化的硫代吗啉或取代的哌嗪环。Z2是邻-亚苯基部分(-C6H4-),以致基团NR6R7是四氢异喹啉。
R8选自氢原子(H)、低级烷基、苯并稠合的低级环烷基(例如二氢茚基)、酰基(低级烷基-CO)、二(低级烷基)氨基、二(低级烷基)氨基甲酰基、N-(低级烷基)哌啶基、可选被取代的α-烷基苄基、可选被取代的苯基、萘基或杂芳基和可选被取代的芳酰基(芳基-CO)或芳基磺酰基(芳基-SO2)。上文中,适合的可选的取代基是低级烷基、可以进一步被一或多个甲基或三氟甲基取代的芳基、羟基、低级烷氧基、低级烷基磺酰基、酰基、全氟酰基、氨基、低级烷基氨基、二(低级烷基)氨基、氨基亚烷基、氟、氯、溴、三氟甲基、硝基、氰基、氨基甲酰基、羧基和低级烷氧基羰基。另外,两个相邻的取代基可以连接构成与母体芳基或杂芳基环稠合的环。
R9和R10独立地选自氢、氨基甲酰基、羟甲基和氰基甲基。
整数n选自0至4,q选自0至3。
某些化合物特别要从本发明的范围中排除。若X2是亚甲基,X3是NH,R4是R8(CH2)qO(CO),q=1,则R8不可以是未取代的苯基或被硝基取代的苯基。一般优选的是若X2是亚甲基,X3是NH,R4是R8(CH2)qO(CO),q是1,R8是取代的苯基,则该取代基应当选自氯、甲氧基和三氟甲基。
在本文公开的内容中,术语低级烷基本身或者在诸如低级烷氧基的组合中都打算包含一至六个碳原子的直链、支链和环状饱和烃基。低级烷基的实例包括但不限于甲基、乙基、异丙基、叔丁基、新戊基、环己基、环戊基甲基、2-(环丙基)乙基、3,3-二甲基环丁基和二环并[3.1.0]己基。
术语杂芳基包括单环的五元和六元芳族基团,具有一或两个杂原子,选自氮、氧和硫。因而,杂芳基包括吡啶基、哒嗪基、嘧啶基、吡嗪基、吡咯基、噻吩基、呋喃基、咪唑基、吡唑基、噻唑基、异噻唑基、噁唑基和异噁唑基。杂芳基进一步包括这些环的苯并稠合衍生物,例如喹啉基、异喹啉基、喹喔啉基、喹唑啉基、酞嗪基、噌啉基、吲哚基、异吲哚基、苯并噻唑基等,和由两个这类单环杂芳基稠合形成的二环基团。
术语芳基包括苯基、萘基和杂芳基。
通式1化合物具有至少一个立体中心,因此可以存在旋光异构现象。在本发明的范围内包括所有这样的异构体,包括对映异构体、非对映异构体和差向异构体。此外,本发明包括单一的异构体和混合物,包括外消旋物。某些根据通式1的化合物可以以互变体形式存在,包括杂芳基携带羟基或氨基取代基的那些。这些互变体无论单独还是作为混合物都被视为在本发明的范围内。
根据通式1的化合物具有至少一个碱性官能团。它们因此可以与酸生成加成盐。在本发明的范围内包括与药学上可接受的酸生成的那些加成盐。适合的酸的实例包括乙酸、三氟乙酸、柠檬酸、富马酸、苯甲酸、扑酸、甲磺酸、盐酸、硝酸、硫酸、磷酸等。
某些根据通式1的化合物具有酸性基团,因此能够与碱生成盐。这类盐的实例包括钠、钾和钙的盐,它们是通过酸与对应的金属氢氧化物、氧化物、碳酸盐或碳酸氢盐的反应而生成的。类似地,四烷基铵盐可以通过酸与四烷基铵氢氧化物的反应而生成。伯胺、仲胺和叔胺、例如三乙胺可以与酸生成加成盐。这种情况的特例是内加成盐,它是在同一分子的酸性基团与伯胺基团之间生成的,也称两性离子。只要是药学上可接受的,在本发明的范围内包括所有这些盐。
在优选的发明实施方式中,R1是腈基。在这种实施方式中,优选的是该腈基的立体化学如通式2所示。
按照标准的命名法,若X1是亚甲基,则它是S构型,但是若X1是硫、氧、亚磺酰基或磺酰基,则它是R构型。
在另一种优选的实施方式中,与伯胺相邻的中心的立体化学如通式3所示。若X2是氧原子或者亚甲基或亚氨基,则它是S构型,若X2是硫原子,则它是R构型。
在这种实施方式中,更优选的是R1应当是腈基,进而更优选的是它应当具有通式4所示的绝对构型。
在另一种优选的发明实施方式中,m是1。更优选地,m是1,R2和R3独立地是氢原子或甲基。若X2是亚甲基,则更优选的是R2和R3都是氢。若X2是氧原子,则更优选的是R2和R3之一是氢,另一个是甲基。若X2是硫原子,则更优选的是R2和R3都是甲基。
在另一种优选的实施方式中,X1是S或亚甲基。更优选地,X1是S,R1是H,或者X1是亚甲基,R1是CN。
在另一种优选的实施方式中,X3是NH。更优选地,X3是NH,m是1,R2和R3都是H,X2是亚甲基,n是1或2。
在另一种优选的实施方式中,R4是R8NHCO或R8CO,R8是可选被取代的杂芳基。更优选地,R8是未取代的杂芳基或者被一或两个选自低级烷基、低级烷氧基、氟、氯和三氟甲基的基团取代的杂芳基。
在另一种优选的实施方式中,X3是CO,R4是R8NH。更优选地,R8是可选被取代的杂芳基。更优选地,R8是未取代的杂芳基或者被一或两个选自低级烷基、低级烷氧基、氟、氯和三氟甲基的基团取代的杂芳基。
在另一种优选的实施方式中,X3是NH,R4选自R6R7N(CO)、R8(CH2)qCO和R8(CH2)qSO2。
在本发明内特别优选的化合物包括:
(2S)-1-[Nω-(吡嗪基-2-羰基)-L-鸟氨酰基]吡咯烷-2-甲腈,
(2S)-1-[Nω-(吡嗪基-2-羰基)-L-赖氨酰基]吡咯烷-2-甲腈,
(2S)-1-[(2’S)-2’-氨基-4’-(吡嗪基-2″-羰基氨基)丁酰基]吡咯烷-2-甲腈,
(4R)-3-[Nω-(吡嗪基-2-羰基)-L-赖氨酰基]噻唑烷-4-甲腈,
(2S)-1-[Nω-(吡啶基-3-甲基)-L-谷氨酰胺酰基]吡咯烷-2-甲腈,
1-[Nω-(吡嗪基-2-羰基)-L-鸟氨酰基]吡咯烷,
(2S)-1-[S-(乙酰氨基甲基)-L-半胱氨酰基]吡咯烷-2-甲腈,
3-[Nω-(2-氯吡啶基-3-羰基)-L-鸟氨酰基]噻唑烷,
1-[Nω-(2-氯吡啶基-3-羰基)-L-鸟氨酰基]吡咯烷,
(2S)-1-[Nω-(2-氯吡啶基-3-羰基)-L-鸟氨酰基]吡咯烷-2-甲腈,
3-[Nω-(吡嗪基-2-羰基)-L-鸟氨酰基]噻唑烷,
3-[Nω-(2-喹喔啉酰基)-L-赖氨酰基]噻唑烷,
3-[Nω-(2-喹喔啉酰基)-L-鸟氨酰基]噻唑烷,
(2S)-1-[Nω-(2-喹喔啉酰基)-L-鸟氨酰基]吡咯烷-2-甲腈,
3-[Nω-(6-甲基吡嗪基-2-羰基)-L-鸟氨酰基]噻唑烷,
3-[Nω-(异喹啉-3-羰基)-L-鸟氨酰基]噻唑烷,
3-[Nω-(6-三氟甲基烟酰基)-L-鸟氨酰基]噻唑烷,
(2S)-1-[(2’R)-3’-(乙酰氨基甲硫基)-2’-氨基-3’-甲基丁酰基]吡咯烷-2-甲腈,
(2S)-1-[S-(3-甲基吡啶基氨基甲酰基甲基)-L-半胱氨酰基]吡咯烷-2-甲腈,
3-[Nω-(3-吡啶氧基羰基)-L-鸟氨酰基]噻唑烷,
3-[O-(3-氯苄基氨基甲酰基)丝氨酰基]噻唑烷,和
3-[(2’S)-2’-氨基-5’-氧代-5’-(1″,2″,3″,4″-四氢异喹啉-2″-基)戊酰基]噻唑烷。
本发明在第二方面包含用于人治疗用途的药物组合物。该组合物的特征在于它具有至少一种上述化合物作为活性成分。这样一种组合物可用于人疾病的治疗。该组合物一般将包括一或多种额外的组分,选自药学上可接受的赋形剂和除本发明以外的药物活性成分。
组合物可以是固体或液体制剂,这取决于预期的给药途径。固体制剂的实例包括用于口服给药的丸剂、片剂、胶囊剂和粉剂,用于直肠或阴道给药的栓剂,用于鼻或肺给药的粉剂,和用于透皮或透黏膜(例如颊)给药的贴剂。液体制剂的实例包括用于静脉内、皮下或肌内注射和口服、鼻或肺给药的溶液和悬液。特别优选的剂型是用于口服给药的片剂。另一种优选的剂型是用于静脉内注射的无菌溶液,特别是用于紧急情况和危象护理。
组合物包含至少一种根据前述说明的化合物。组合物可以含有一种以上这样的化合物,但是一般优选的是它仅应包含一种。化合物在组合物中的用量将是这样的,活性成分的总每日剂量可以分一至四个适宜的剂量单元给药。例如,组合物可以是片剂,化合物的含量等于必要的总每日剂量,所述片剂每天服用一次。作为替代选择,片剂可以含有每日剂量的一半(或三分之一或四分之一),每天服用两次(或三次或四次)。这样一种片剂还可以刻以划线,有利于分剂量服用,例如包含完整每日剂量的片剂可以分成两半,分两次给药。优选地,片剂或其他单位剂型将含有0.1mg至1g活性化合物。更优选地,它将含有1mg至250mg。
组合物一般将包括一或多种赋形剂,选自公认为药学上可接受的那些。适合的赋形剂包括但不限于填充剂、粘合剂、稀释剂、溶剂、防腐剂和矫味剂。改变组合物释放特征的试剂在本发明内容中也被视为适合的赋形剂,例如在肠内选择性溶解的聚合物(“肠溶衣”)。
除了本发明的化合物以外,组合物还可以包含第二种药物活性成分。例如,组合物可以包括抗糖尿病剂、生长促进剂、抗炎剂或抗病毒剂。不过,一般优选的是组合物仅包含一种活性成分。
本发明在第三方面包含上述化合物与组合物在人疾病治疗中的用途。这方面同样可以被视为包含这类疾病的治疗方法。对治疗敏感的疾病是其中DP-IV或CD26的抑制直接或间接导致临床有益效果的那些。直接的作用包括T淋巴细胞活化的阻滞。间接的作用包括通过防止肽类激素的降解,加强这些激素的活性。疾病的实例包括但不限于自体免疫与炎性疾病,例如炎性肠疾病和类风湿性关节炎,引起身材矮小的生长激素缺乏,多囊性卵巢综合征,葡萄糖耐量减低和2型糖尿病。特别优选的是化合物和组合物在葡萄糖耐量减低和2型糖尿病治疗中的用途,同样和这些疾病的治疗方法,包含有效量的前述化合物或组合物的给药。
治疗的确切细节、包括给药方案将由主治医师在考虑患者的一般状况和疾病的严重性之后加以确定。关于活动型疾病急性期与静止期间隔的炎性肠疾病等,医师可以在急性期间选择相对高的剂量,在静止期选择较低的维持剂量。关于慢性疾病,例如2型糖尿病和葡萄糖耐量减低,剂量可能需要长期维持在同一水平。在这样一种情况下典型的给药方案可以是每天一至四片,每片包含0.1mg至1g(优选为1mg至250mg)活性化合物。
根据本发明的化合物可以按照本领域已知的方法制备。所选择的途径将取决于存在于目标分子中的取代基的特性。在下列一般说明中,概述了其中m是1的化合物的合成途径。m=2或3的化合物一般可以通过相似途径制备。
原料通常将是α,ω-二氨基酸衍生物
5或氨基二羧酸衍生物
6。
PG1和PG2是“正交”保护基团——屏蔽胺基的反应性并且各自能够在另一者的存在下被选择性除去的基团。适合的基团在文献中是熟知的。PG3和PG4是羧酸保护基团。它们是这样选择的,以便它们彼此并且与氨基保护基团是正交的。适合的PG3和PG4的可能性在文献中也是熟知的。根据通式5的二氨基酸衍生物和根据通式6的氨基二羧酸衍生物是商业产品,或者可以遵照文献所述方法制备。在实践中,根据所选择的策略,原料将仅具有三个保护基团中的两个。要么PG3将不存在,以便引入吡咯烷(或噻唑烷或噁唑烷)残基,要么PG1或PG4将不存在,以便确立侧链。
流程A阐述吡咯烷(或噻唑烷或噁唑烷)基的引入,作为本发明化合物制备的第一步。
流程A
化合物5A和6A相当于PG3是氢原子(也就是没有保护基团)的化合物
5和
6。游离羧酸可以与吡咯烷衍生物
7反应,得到酰胺
8或
9。实现这种转化的反应条件在文献中是熟知的。适合的试剂包括碳二亚胺类、磷试剂和烷基氯甲酸酯类,该反应通常受一种叔胺的催化,例如三乙胺或二甲氨基吡啶。
流程A所述反应可用于所有R1与X1的组合。不过,关于R1是腈基或者X1是亚磺酰基或磺酰基的情况,如流程B和C所述改进的方案可能是有利的。
流程B
流程C
流程B中,R1是作为伯酰胺引入的,随后受到脱水剂的作用转化为腈,例如三氟乙酸酐。流程C中,X1是作为硫醚引入的,随后受到氧化剂的作用转化为亚砜(a=1)或砜(a=2),例如高碘酸钠。如果X2是硫原子,那么由流程C提供的方案改变是不可能的。
流程D
流程D中,化合物
5 D是其中ω-保护基团是氢原子的二氨基酸衍生物
5。游离胺基容易与磺酰氯、酰氯和硫代酰氯反应,通常在一种叔胺的存在下,分别生成磺酰胺
14、酰胺
15和硫代酰胺
16。试剂一般是本身可得到的,或者可以从对应的酸制备。流程D的反应一般适用于基团R8(CH2)q的所有变化,其条件是作为R8选项的苯基与杂芳基环的某些取代基可能需要保护。这类取代基和适当的保护一般对熟悉本领域的人员来说将是显而易见的。
流程E
试剂:i)COCl2;ii)CSCl2;iii)R8(CH2)qOH;iv)R6R7NH;v)R8(CH2)qOCOCl;vi)R8(CH2)qOCSCl;vii)R6R7NCOCl;viii)R6R7NCSCl.
流程E阐述
5 D的确立,得到氨基甲酸酯和脲,和它们的硫代类似物。若R5不是氢原子,则化合物
5 D可以通过与光气或硫代光气的反应转化为对应的氨基甲酰氯
17或硫代氨基甲酰氯
18。其他试剂在本领域已知的,它们在功能上等同于这些毒性试剂,也是可以使用的。若R5是氢,则所生成的中间体是异氰酸酯或异硫氰酸酯,但是它在功能上充当相应氯化物的等价物。中间体
17和
18通常是不分离的,而是直接用醇处理,得到氨基甲酸酯
19和硫代氨基甲酸酯
20。将这些相同的中间体用胺处理,生成脲
21和硫脲
22。作为替代选择,5D可以直接与氯甲酸酯或氯硫代甲酸酯反应,得到氨基甲酸酯或硫代氨基甲酸酯,或者若R6和R7都不是氢,则与氯甲酰胺或氯硫代甲酰胺反应,得到脲或硫脲。若R6或R7是氢原子,则氯甲酰胺或氯硫代甲酰胺将趋向于不稳定,在这种情况下使用异氰酸酯(例如R6-NCO)或异硫氰酸酯(例如R6-NCS)。正如前面流程D所讨论的,在R8实施方式中的某些取代基可能需要适当的保护。
流程F
流程F阐述氨基二羧酸系列的侧链的确立。ω-去保护的酸
6 F可以在各种条件下与胺反应,得到酰胺
23。脱水剂可以促进缩合作用,例如碳二亚胺或磷试剂。作为替代选择,酸可以转化为反应性更高的衍生物,例如用草酰氯或亚硫酰氯处理,得到对应的酰氯,后者将直接与胺反应。将酰胺
23用Lawesson试剂处理,可以得到硫代酰胺
24。
当所有基团都已经确立后,除去最后的保护基团,分离产物,利用标准工艺纯化。
下列非限制性实施例进一步阐述这些通用方法。
实施例
缩写
使用下列缩写。
DMF N,N-二甲基甲酰胺
h 小时
hplc 高效液相色谱法
min 分钟
石油醚 沸点60-80℃的石油醚部分
PyBOP (苯并三唑-1-基氧基)三吡咯烷基鏻六氟磷酸盐
PyBroP 溴代三吡咯烷基鏻六氟磷酸盐
TFA 三氟乙酸
实施例1
(2S)-1-[Nω-(吡嗪基-2-羰基)-L-鸟氨酰基]吡咯烷-2-甲腈三氟乙酸盐
A.N-(2-硝基苯硫基)-L-脯氨酸
将L-脯氨酸(25g,217mmol)溶于2M NaOH(110mL,220mol)和二噁烷(120mL)。缓慢加入2-硝基苯硫基氯(2-nitrobenzenesulphenylchloride)(42g,222mmof)的二噁烷(60mL)溶液,同时加入2M NaOH(110mL,220mmol)。在室温下2h后,将反应混合物倒入水(500mL)中,滤出固体。滤液的pH用2M HCl调至pH3,溶液用乙酸乙酯萃取(3×500mL)。合并有机萃取液,用水(4×200mL)和盐水(1×200mL)洗涤,干燥(Na2SO4),在真空中蒸发,得到橙色固体,经鉴定为N-(2-硝基苯硫基)-L-脯氨酸(58.1g,217mmol,100%)。
B.N-(2-硝基苯硫基)-L-脯氨酸琥珀酰亚氨基酯
将N-(2-硝基苯硫基)-L-脯氨酸(57.9g,216mol)溶于CH2Cl2/DMF(9∶1,500mL)。加入N-羟基琥珀酰亚胺(37.3g,324mol)和水溶性碳二亚胺(51.8g,260mol)。在室温下18h后,在真空中除去溶剂,将残余物溶于乙酸乙酯(1000mL)。溶液用水(4×200mL)和盐水(1×200mL)洗涤,干燥(Na2SO4),在真空中蒸发,得到黄色固体,经鉴定为N-(2-硝基苯硫基)-L-脯氨酸琥珀酰亚氨基酯(78.9g,216mol,100%)。
C.N-(2-硝基苯硫基)-L-脯氨酰胺
将N-(2-硝基苯硫基)-L-脯氨酸琥珀酰亚氨基酯(78.5g,215mmol)溶于二噁烷(500mL)。加入氨(35%,100mL)。在室温下搅拌2h后,将反应混合物倒入水(700mL)中。滤出沉淀,用水(200mL)洗涤,经P2O5干燥,从乙酸乙酯/石油醚中重结晶,得到黄色固体,经鉴定为N-(2-硝基苯硫基)-L-脯氨酰胺(49.6g,185mmol,86%)。
D.(2S)-N-(2-硝基苯硫基)吡咯烷-2-甲腈
将N-(2-硝基苯硫基)-L-脯氨酰胺(49g,183mmol)溶于无水THF(300mL)。将该溶液冷却至0℃,加入三乙胺(36.7g,367mol),然后缓慢加入三氟乙酸酐(77g,367mol)。用三乙胺调节pH 9。30min后,将反应混合物用乙酸乙酯(500mL)稀释,用水(1×200mL)和盐水(1×200mL)洗涤,干燥(Na2SO4),在真空中蒸发,得到橙色的油,经过快速色谱纯化(洗脱剂:80%石油醚,20%乙酸乙酯),得到黄色固体,经鉴定为(2S)-N-(2-硝基苯硫基)吡咯烷-2-甲腈(38.9g,150mol,82%)。
E.(2S)-吡咯烷-2-甲腈盐酸盐
将(2S)-N-(2-硝基苯硫基)吡咯烷-2-甲腈(38.5g,149mmol)溶于二乙醚(200mL)。缓慢加入4M HCl/二噁烷(150mL,600mmol)。在室温下2h后,将反应混合物倒入二乙醚(1000mL)中。滤出固体,用二乙醚(500mL)洗涤,从甲醇/二乙醚中重结晶,得到白色固体,经鉴定为(2S)-吡咯烷-2-甲腈盐酸盐(18.9g,142.5mmol,96%)。
F.(2S)-1-[Nα-(叔丁氧羰基)-Nω-(吡嗪基-2-羰基)-L-鸟氨酰基]-吡咯烷-2-甲腈
将Nα-(叔丁氧羰基)-Nω(吡嗪基-2-羰基)-L-鸟氨酸(2.5g,7.4mmol)溶于CH2Cl2(50mL)。将该溶液冷却至0℃,加入(2S)-吡咯烷-2-甲腈盐酸盐(1.2g,9.1mmol)和PyBOP(4.3g,8.23mmol),用三乙胺调节pH 9。在0℃至室温下18h后,在真空中除去溶剂,将残余物溶于乙酸乙酯(200mL)。该溶液用0.3M KHSO4(2×50mL)、饱和NaHCO3(2×50mL)、水(2×50mL)和盐水(1×50mL)洗涤,干燥(Na2SO4),在真空中蒸发,得到黄色的油。经过快速色谱纯化(洗脱剂:80%乙酸乙酯,20%石油醚),得到无色的油,经鉴定为(2S)-1-[Nα-(叔丁氧羰基)-Nω-(吡嗪基-2-羰基)-L-鸟氨酰基]-吡咯烷-2-甲腈(2.98g,7.16mmol,97%)。
G.(2S)-1-[Nω-(吡嗪基-2-羰基)-L-鸟氨酰基]吡咯烷-2-甲腈三氟乙酸盐
将(2S)-1-[Nα-(叔丁氧羰基)-Nω-(吡嗪基-2-羰基)-L-鸟氨酰基]-吡咯烷-2-甲腈(2.8g,6.7mmol)溶于三氟乙酸(5mL)。在室温下1h后,在真空中除去溶剂。残余物经过制备型hplc纯化(Vydac C18,从5至50%0.1%TFA/乙腈到0.1%TFA/水历经40min,3mL/min)。冷冻干燥含有产物的部分,得到无色的油,经鉴定为(2S)-1-[Nω-(吡嗪基-2-羰基)-L-鸟氨酰基]吡咯烷-2-甲腈三氟乙酸盐(1.5g,3.48mmol,52%)。
[M+H]+=317.3
实施例2
(2S)-1-[Nω-(吡嗪基-2-羰基)-L-赖氨酰基]吡咯烷-2-甲腈三氟乙酸盐
A.(Nα-(叔丁氧羰基)-Nω-(9-芴基甲氧羰基)-L-赖氨酰基)-L-脯氨酰胺
将Nα-(叔丁氧羰基)-Nω-(9-芴基甲氧羰基)-L-赖氨酸(5g,10.7mmol)溶于CH2Cl2(100mL)。将溶液冷却至0℃,加入L-脯氨酰胺(1.78g,11.7mmol)和PyBOP(6.7g,12.8mmol),用三乙胺调节pH9。在0℃至室温下18h后,在真空中除去溶剂,将残余物溶于乙酸乙酯(200mL)。将该溶液用0.3M KHSO4(2×50mL)、饱和NaHCO3(2×50mL)、水(2×50mL)和盐水(1×50mL)洗涤,干燥(Na2SO4),在真空中蒸发。残余物经过快速色谱纯化(洗脱剂:2%甲醇,98%氯仿),得到无色的油,经鉴定为(Nα-(叔丁氧羰基)-Nω-(9-芴基甲氧羰基)-L-赖氨酰基)-L-脯氨酰胺(4.05g,7.2mmol,67%)。
B.(2S)-1-(Nα-(叔丁氧羰基)-Nω-(9-芴基甲氧羰基)-L-赖氨酰基)吡咯烷-2-甲腈
将(Nα-(叔丁氧羰基)-Nω-(9-芴基甲氧羰基)-L-赖氨酰基)-L-脯氨酰胺(3.95g,7.02mmol)溶于无水THF(100mL)。将该溶液冷却至0℃,加入三乙胺(1.4g,14mmol),然后缓慢加入三氟乙酸酐(2.97g,14.1mmol)。用三乙胺调节pH 9。30min后,将反应混合物用乙酸乙酯(100mL)稀释,用水(1×50mL)和盐水(1×50mL)洗涤,干燥(Na2SO4),在真空中蒸发,得到橙色的油。残余物经过快速色谱纯化(洗脱剂:60%石油醚,40%乙酸乙酯),得到无色的油,经鉴定为(2S)-1-(Nα-(叔丁氧羰基)-Nω-(9-芴基甲氧羰基)-L-赖氨酰基)吡咯烷-2-甲腈(3.3g,6.11mmol,87%)。
C.(2S)-1-(Nα-(叔丁氧羰基)-L-赖氨酰基)吡咯烷-2-甲腈
将(2S)-1-(Nα-(叔丁氧羰基)-Nω-(9-芴基甲氧羰基)-L-赖氨酰基)吡咯烷-2-甲腈(3.1g,5.7mmol)溶于THF(80mL)。加入二乙胺(20mL)。在室温下2h后,在真空中除去溶剂。残余物经过快速色谱纯化(洗脱剂:90%氯仿,7%甲醇,3%三乙胺),得到无色的油,经鉴定为(2S)-1-(Nα-(叔丁氧羰基)-L-赖氨酰基)吡咯烷-2-甲腈(1.63g,5.03mmol,89%)。
D.(2S)-1-(Nα-(叔丁氧羰基)-Nω-(吡嗪基-2-羰基)-L-赖氨酰基)吡咯烷-2-甲腈
将(2S)-1-(Nα-(叔丁氧羰基)-L-赖氨酰基)吡咯烷-2-甲腈(100mg,0.31mmol)溶于CH2Cl2/DMF(9∶1,20mL)。在0℃下向该溶液加入1-羟基苯并三唑水合物(84mg,0.62mol)、水溶性碳二亚胺(76mg,0.38mmol)、2-吡嗪羧酸(43mg,0.35mmol)和三乙胺(65mg,0.65mol)。在0℃至室温下18h后,在真空中除去溶剂,将残余物溶于乙酸乙酯(70mL)。将该溶液用0.3M KHSO4(2×20mL)、饱和NaHCO3(2×20mL)、水(2×20mL)和盐水(1×20mL)洗涤,干燥(Na2SO4),在真空中蒸发,得到黄色的油。残余物经过快速色谱纯化(洗脱剂:2%甲醇,98%氯仿),得到无色的油,经鉴定为(2S)-1-(Nα-(叔丁氧羰基)-Nω-(吡嗪基-2-羰基)-L-赖氨酰基)吡咯烷-2-甲腈(124mg,0.29mmol,93%)。
E.(2S)-1-[Nω-(吡嗪基-2-羰基)-L-赖氨酰基]吡咯烷-2-甲腈三氟乙酸盐
将(2S)-1-(Nα-(叔丁氧羰基)-Nω-(吡嗪基-2-羰基)-L-赖氨酰基)吡咯烷-2-甲腈(110mg,0.26mmol)溶于三氟乙酸(5mL)。在室温下1h后,在真空中除去溶剂。残余物经过制备型hplc纯化(Vydac C18,从5至50%0.1%TFA/乙腈到0.1%TFA/水历经40min,3mL/min)。冷冻干燥含有产物的部分,得到无色的油,经鉴定为(2S)-1-[Nω-(吡嗪基-2-羰基)-L-赖氨酰基]吡咯烷-2-甲腈三氟乙酸盐(66mg)。
[M+H]+=331.1
实施例3
(4R)-3-[Nω-(吡嗪基-2-羰基)-L-赖氨酰基]噻唑烷-4-甲腈三氟乙酸盐
A.(4R)-3-(叔丁氧羰基)噻唑烷-4-甲酰胺
将(4R)-3-(叔丁氧羰基)噻唑烷-4-羧酸(12.5g,54.1mmol)溶于CH2Cl2/DMF(9∶1,150mL)。在0℃下向该溶液加入1-羟基苯并三唑水合物(14.6g,108mol)和水溶性碳二亚胺(13.0g,65mol)。在0℃下1h后,加入氨(35%,50mL)。在0℃至室温下18h后,在真空中除去溶剂,将残余物溶于乙酸乙酯(500mL)。将溶液用0.3M KHSO4(2×100mL)、饱和NaHCO3(2×100mL)、水(2×100mL)和盐水(1×100mL)洗涤,干燥(Na2SO4),在真空中蒸发,得到黄色的油。残余物经过快速色谱纯化(洗脱剂:2%甲醇,98%氯仿),得到无色的油,经鉴定为(4R)-3-(叔丁氧羰基)噻唑烷-4-甲酰胺。
B.(4R)-噻唑烷-4-甲酰胺盐酸盐
将(4R)-3-(叔丁氧羰基)噻唑烷-4-甲酰胺(8.6g,37.1mmol)溶于4M HCl/二噁烷(50mL)。在室温下1h后,在真空中蒸发溶剂,得到白色固体,经鉴定为(4R)-噻唑烷-4-甲酰胺盐酸盐(6.2g,36.8mmol,99%)。
C.(4R)-3-[Nα-(叔丁氧羰基)-Nω-(9-芴基甲氧羰基)-L-赖氨酰基]-噻唑烷-4-甲酰胺
将Nα-(叔丁氧羰基)-Nω-(9-芴基甲氧羰基)-L-赖氨酸(5g,10.7mmol)溶于CH2Cl2(100mL)。将该溶液冷却至0℃,加入(4R)-噻唑烷-4-甲酰胺盐酸盐(1.78g,11.7mmol)和PyBOP(6.7g,12.8mmol),用三乙胺调节pH 9。在0℃至室温下18h后,在真空中除去溶剂,将残余物溶于乙酸乙酯(200mL)。将溶液用0.3M KHSO4(2×50mL)、饱和NaHCO3(2×50mL)、水(2×50mL)和盐水(1×50mL)洗涤,干燥(Na2SO4),在真空中蒸发,得到黄色的油。残余物经过快速色谱纯化(洗脱剂:2%甲醇,98%氯仿),得到无色的油,经鉴定为(4R)-3-[Nα-(叔丁氧羰基)-Nω-(9-芴基甲氧羰基)-L-赖氨酰基]-噻唑烷-4-甲酰胺(2.81g,4.8mmol,44%)。
D.(4R)-3-[Nα-(叔丁氧羰基)-Nω-(9-芴基甲氧羰基)-L-赖氨酰基]-噻唑烷-4-甲腈
将(4R)-3-[Nα-(叔丁氧羰基)-Nω-(9-芴基甲氧羰基)-L-赖氨酰基]-噻唑烷-4-甲酰胺(2.7g,4.7mmol)溶于无水THF(100mL)。将该溶液冷却至0℃,加入三乙胺(1.0g,10mmol),然后缓慢加入三氟乙酸酐(2.0g,9.5mmol)。用三乙胺调节pH 9。30min后,将反应混合物用乙酸乙酯(100mL)稀释,用水(1×50mL)和盐水(1×50mL)洗涤,干燥(Na2SO4),在真空中蒸发。残余物经过快速色谱纯化(洗脱剂:60%石油醚,40%乙酸乙酯),得到无色的油,经鉴定为(4R)-3-[Nα-(叔丁氧羰基)-Nω-(9-芴基甲氧羰基)-L-赖氨酰基]-噻唑烷-4-甲腈(2.14g,3.81mmol,82%)。
E.(4R)-3-[Nα-(叔丁氧羰基)-L-赖氨酰基]-噻唑烷-4-甲腈
将(4R)-3-[Nα-(叔丁氧羰基)-Nω-(9-芴基甲氧羰基)-L-赖氨酰基]-噻唑烷-4-甲腈(1.9g,3.4mmol)溶于THF(40mL)。加入二乙胺(10mL)。在室温下2h后,在真空中除去溶剂。残余物经过快速色谱纯化(洗脱剂:90%氯仿,7%甲醇,3%三乙胺),得到无色的油,经鉴定为(4R)-3-[Nα-(叔丁氧羰基)-L-赖氨酰基]-噻唑烷-4-甲腈(863mg,2.5mmol,75%)。
F.(4R)-3-[Nα-(叔丁氧羰基)-Nω-(吡嗪基-2-羰基)-L-赖氨酰基]-噻唑烷-4-甲腈
将(4R)-3-[Nα-(叔丁氧羰基)-L-赖氨酰基]-噻唑烷-4-甲腈(100mg,0.29mmol)溶于CH2Cl2(20mL)。在0℃下向该溶液加入2-吡嗪羧酸(43mg,0.35mmol)和PyBOP(170mg,0.33mmol),用三乙胺调节pH 9。在0℃至室温下18h后,在真空中除去溶剂,将残余物溶于乙酸乙酯(70mL)。将该溶液用0.3M KHSO4(2×20mL)、饱和NaHCO3(2×20mL)、水(2×20mL)和盐水(1×20mL)洗涤,干燥(Na2SO4),在真空中蒸发。残余物经过快速色谱纯化(洗脱剂:2%甲醇,98%氯仿),得到无色的油,经鉴定为(4R)-3-[Nα-(叔丁氧羰基)-Nω-(吡嗪基-2-羰基)-L-赖氨酰基]-噻唑烷-4-甲腈(112mg,0.25mmol,86%)。
G.(4R)-3-[Nω-(吡嗪基-2-羰基)-L-赖氨酰基]噻唑烷-4-甲腈三氟乙酸盐
将(4R)-3-[Nα-(叔丁氧羰基)-Nω-(吡嗪基-2-羰基)-L-赖氨酰基]-噻唑烷-4-甲腈(110mg,0.26mmol)溶于三氟乙酸(1mL)。在室温下1h后,在真空中除去溶剂。残余物经过制备型hplc纯化(Vydac C18,从5至50%0.1%TFA/乙腈到0.1%TFA/水历经40min,3mL/min)。冷冻干燥含有产物的部分,得到无色的油,经鉴定为(4R)-3-[Nω-(吡嗪基-2-羰基)-L-赖氨酰基]噻唑烷-4-甲腈三氟乙酸盐(57mg)。
[M+H]+=349.1
实施例4
(2S)-1-[Nω-(吡啶基-3-甲基)-L-谷氨酰胺酰基]吡咯烷-2-甲腈二盐酸盐
A.(2S)-1-[N-(叔丁氧羰基)-Oω-甲基-L-谷氨酰基]吡咯烷-2-甲腈
将N-(叔丁氧羰基)-Oω-甲基-L-谷氨酸(1.0g,3.83mmol)溶于CH2Cl2/DMF(9∶1,20mL)。在0℃下向该溶液加入1-羟基苯并三唑水合物(788mg,5.84mmol)、水溶性碳二亚胺(877mg,4.38mmol)、(2S)-吡咯烷-2-甲腈盐酸盐(609mg,4.6mmol)和三乙胺(65mg,0.65mol)。在0℃至室温下18h后,在真空中除去溶剂,将残余物溶于乙酸乙酯(70mL),将该溶液用0.3M KHSO4(2×20mL)、饱和NaHCO3(2×20mL)、水(2×20mL)和盐水(1×20mL)洗涤,干燥(Na2SO4),在真空中蒸发。残余物经过快速色谱纯化(洗脱剂:50%乙酸乙酯,50%石油醚),得到褐色的油,经鉴定为(2S)-1-[N-(叔丁氧羰基)-Oω甲基-L-谷氨酰基]吡咯烷-2-甲腈(290mg,0.86mmol,22%)。
B.(2S)-1-[N-(叔丁氧羰基)-L-谷氨酰基]吡咯烷-2-甲腈
将(2S)-1-[N-(叔丁氧羰基)-Oω-甲基-L-谷氨酰基]吡咯烷-2-甲腈(250mg,0.74mmol)溶于二噁烷(5mL)。加入1M氢氧化锂(1.1mL,1.1mmol)。在室温下1h后,在真空中除去溶剂,将残余物溶于乙酸乙酯(70mL)。将该溶液用1M KHSO4(2×20mL)、水(2×20mL)和盐水(1×20mL)洗涤,干燥(Na2SO4),在真空中蒸发,得到无色的油,经鉴定为(2S)-1-[N-(叔丁氧羰基)-L-谷氨酰基]吡咯烷-2-甲腈(200mg,0.61mmol,83%)。
C.(2S)-1-[Nα-(叔丁氧羰基)-Nω-(吡啶基-3-甲基)-L-谷氨酰胺酰基]吡咯烷-2-甲腈
将(2S)-1-[N-(叔丁氧羰基)-L-谷氨酰基]吡咯烷-2-甲腈(30mg,0.093mmol)溶于CH2Cl2/DMF(9∶1,10mL)。在0℃下向该溶液加入1-羟基苯并三唑水合物(21mg,0.16mol)、水溶性碳二亚胺(21mg,0.105mmol)、3-(氨基甲基)吡啶(11mg,0.1mmol)和三乙胺(20mg,0.2mmol)。在0度至室温下18h后,在真空中除去溶剂,将残余物溶于乙酸乙酯(70mL)。将该溶液用0.3M KHSO4(2×20mL)、饱和NaHCO3(2×20mL)、水(2×20mL)和盐水(1×20mL)洗涤,干燥(Na2SO4),在真空中蒸发,得到黄色的油。残余物经过快速色谱纯化(洗脱剂:5%甲醇,97%氯仿),得到无色的油,经鉴定为(2S)-1-[Nα-(叔丁氧羰基)-Nω-(吡啶基-3-甲基)-L-谷氨酰胺酰基]吡咯烷-2-甲腈(16.6mg,0.04mmol,44%)。
D.(2S)-1-[Nω-(吡啶基-3-甲基)-L-谷氨酰胺酰基]吡咯烷-2-甲腈二盐酸盐
将(2S)-1-[Nα-(叔丁氧羰基)-Nω-(吡啶基-3-甲基)-L-谷氨酰胺酰基]吡咯烷-2-甲腈(17mg,0.04mmol)溶于4M HCl/二噁烷(5mL)。在室温下1h后,在真空中除去溶剂,得到白色固体,经鉴定为(2S)-1-[Nω-(吡啶基-3-甲基)-L-谷氨酰胺酰基]吡咯烷-2-甲腈二盐酸盐(17mg,0.04mmol,100%)。
[M+H]+=316.2
实施例5
1-[Nω-(吡嗪基-2-羰基)-L-鸟氨酰基]吡咯烷三氟乙酸盐
A.1-[Nω-(苄氧羰基)-Nα-(叔丁氧羰基)-L-鸟氨酰基]吡咯烷将Nω-(苄氧羰基)-Nα-(叔丁氧羰基)-L-鸟氨酸(5.49g,15mmol)溶于CH2Cl2/DMF(9∶1,100mL)。在0℃下向该溶液加入1-羟基苯并三唑水合物(3.37g,22mmol)、水溶性碳二亚胺(3.46g,18mmol)、吡咯烷(1.28g,18mmol)和三乙胺(200mg,20mmol)。在0度至室温下18h后,在真空中除去溶剂,将残余物溶于乙酸乙酯(200mL)。将该溶液用0.3M KHSO4(2×50mL)、饱和NaHCO3(2×50mL)、水(2×50mL)和盐水(1×50mL)洗涤,干燥(Na2SO4),在真空中蒸发。残余物经过快速色谱纯化(洗脱剂:90%乙酸乙酯,10%石油醚),得到无色的油,经鉴定为1-[Nω-(苄氧羰基)-Nα-(叔丁氧羰基)-L-鸟氨酰基]吡咯烷(5.15g,12.3mmol,82%)。
B.1-[Nα-(叔丁氧羰基)-L-鸟氨酰基]吡咯烷
将1-[Nω-(苄氧羰基)-Nα-(叔丁氧羰基)-L-鸟氨酰基]吡咯烷(2.15g,5.13mmol)溶于甲醇(80mL)。该溶液经10%Pd/C(400mg)氢化。2h后,滤出催化剂,用甲醇(50mL)洗涤。合并滤液,在真空中蒸发,得到不完全白色固体,经鉴定为1-[Nα-(叔丁氧羰基)-L-鸟氨酰基]吡咯烷(1.35g,4.74mmol,94%)。
C.1-[Nα-(叔丁氧羰基)-Nω-(吡嗪基-2-羰基)-L-鸟氨酰基]吡咯烷
将1-[Nα-(叔丁氧羰基)-L-鸟氨酰基]吡咯烷(100mg,0.35mmol)溶于CH2Cl2(20mL)。在0℃下向该溶液加入PyBroP(195mg,0.4mmol)、2-吡嗪羧酸(50mg,0.4mmol)和三乙胺(100mg,1.0mmol)。在0℃至室温下18h后,在真空中除去溶剂,将残余物溶于乙酸乙酯(70mL)。将该溶液用0.3M KHS04(2×20mL)、饱和NaHCO3(2×20mL)、水(2×20mL)和盐水(1×20mL)洗涤,干燥(Na2S04),在真空中蒸发。残余物经过快速色谱纯化(洗脱剂:3%甲醇,97%氯仿),得到粘性白色固体,经鉴定为1-[Nα-(叔丁氧羰基)-Nω-(吡嗪基-2-羰基)-L-鸟氨酰基]吡咯烷(90mg,0.25mmol,66%)。
D.1-[Nω-(吡嗪基-2-羰基)-L-鸟氨酰基]吡咯烷三氟乙酸盐
将1-[Nα-(叔丁氧羰基)-Nω-(吡嗪基-2-羰基)-L-鸟氨酰基]吡咯烷(90mg,0.23mmol)溶于4M HCl/二噁烷(15mL)。在室温下45min后,在真空中除去溶剂。残余物经过制备型hplc纯化(Vydac C18,从5至50%0.1%TFA/乙腈到0.1%TFA/水历经40min,3mL/min)。冷冻干燥含有产物的部分,得到无色的油,经鉴定为1-[Nω-(吡嗪基-2-羰基)-L-鸟氨酰基]吡咯烷三氟乙酸盐(51mg)。
[M+H]+=292.1
实施例6
3-[Nω-(吡嗪基-2-羰基)-L-鸟氨酰基]噻唑烷三氟乙酸盐
A.3-[Nα-(叔丁氧羰基)-Nω-(9-芴基甲氧羰基)-L-鸟氨酰基]噻唑烷
将Nα-(叔丁氧羰基)-Nω-(9-芴基甲氧羰基)-L-鸟氨酸(2.73g,6mmol)溶于CH2Cl2/DMF(9∶1,100mL)。在0℃下向该溶液加入1-羟基苯并三唑水合物(1.53g,10mmol)、水溶性碳二亚胺(1.34g,7mmol)、噻唑烷(1.28g,18mmol)和三乙胺(80mg,8mmol)。在0C至室温下18h后,在真空中除去溶剂,将残余物溶于乙酸乙酯(100mL)。将该溶液用0.3M KHSO4(2×25mL)、饱和NaHCO3(2×25mL)、水(2×25mL)和盐水(1×25mL)洗涤,干燥(Na2SO4),在真空中蒸发。残余物经过快速色谱纯化(洗脱剂:75%乙酸乙酯,25%石油醚),得到白色固体,经鉴定为3-[Nα-(叔丁氧羰基)-Nω-(9-芴基甲氧羰基)-L-鸟氨酰基]噻唑烷(2.55g,4.85mmol,81%)。
B.3-[Nα-(叔丁氧羰基)-L-鸟氨酰基]噻唑烷
将3-[Nα-(叔丁氧羰基)-Nω-(9-芴基甲氧羰基)-L-鸟氨酰基]噻唑烷(1.15g,2.13mmol)溶于乙腈(20mL)。加入二乙胺(5mL)。在室温下90min后,在真空中除去溶剂,残余物经过快速色谱纯化(洗脱剂:90%氯仿,7%甲醇,3%三乙胺),得到淡黄色油,经鉴定为3-[Nα-(叔丁氧羰基)-L-鸟氨酰基]噻唑烷(530mg,1.67mmol,78%)。
C.3-[Nα-(叔丁氧羰基)-Nω-(吡嗪基-2-羰基)-L-鸟氨酰基]噻唑烷
将3-[Nα-(叔丁氧羰基)-L-鸟氨酰基]噻唑烷(80mg,0.27mmol)溶于CH2Cl2(20mL)。在0℃下向该溶液加入PyBroP(146mg,0.3mmol)、2-吡嗪羧酸(37mg,0.3mmol)和三乙胺(90mg,0.9mmol)。在0℃至室温下18h后,在真空中除去溶剂,将残余物溶于乙酸乙酯(70mL)。将该溶液用0.3M KHSO4(2×20mL)、饱和NaHCO3(2×20mL)、水(2×20mL)和盐水(1×20mL)洗涤,干燥(Na2SO4),在真空中蒸发。残余物经过快速色谱纯化(洗脱剂:3%甲醇,97%氯仿),得到粘性白色固体,经鉴定为3-[Nα-(叔丁氧羰基)-Nω-(吡嗪基-2-羰基)-L-鸟氨酰基]噻唑烷(45mg,0.11mmol,41%)。
D.3-[Nω-(吡嗪基-2-羰基)-L-鸟氨酰基]噻唑烷三氟乙酸盐
将3-[Nα-(叔丁氧羰基)-Nω-(吡嗪基-2-羰基)-L-鸟氨酰基]噻唑烷溶于4M HCl/二噁烷(10mL)。在室温下45min后,在真空中除去溶剂。残余物经过制备型hplc纯化(Vydac C18,从5至50%0.1%TFA/乙腈到0.1%TFA/水历经40min,3mL/min)。冷冻干燥含有产物的部分,得到无色的油,经鉴定为3-[Nω-(吡嗪基-2-羰基)-L-鸟氨酰基]噻唑烷三氟乙酸盐(14mg)。
[M+H]+=310.0
实施例7
(2S)-1-[S-(乙酰氨基甲基)-L-半胱氨酰基]吡咯烷-2-甲腈三氟乙酸盐
A.(2S)-1-[S-(乙酰氨基甲基)-N-(叔丁氧羰基)-L-半胱氨酰基]吡咯烷-2-甲腈
将S-(乙酰氨基甲基)-N-(叔丁氧羰基)-L-半胱氨酸(660mg,2.26mmol)溶于CH2Cl2(30mL)。在0℃下向该溶液加入(2S)-吡咯烷-2-甲腈盐酸盐(250mg,1.89mmol)和PyBOP(1.3g,2.49mmol),用三乙胺调节pH9。在0℃至室温下18h后,在真空中除去溶剂,将残余物溶于乙酸乙酯(150mL)。将该溶液用0.3M KHSO4(2×30mL)、饱和NaHCO3(2×30mL)、水(2×30mL)和盐水(1×30mL)洗涤,干燥(Na2SO4),在真空中蒸发。残余物经过快速色谱纯化(洗脱剂:75%乙酸乙酯,25%石油醚),得到无色的油,经鉴定为(2S)-1-[S-(乙酰氨基甲基)-N-(叔丁氧羰基)-L-半胱氨酰基]吡咯烷-2-甲腈(650mg,1.76mmol,78%)。
B.(2S)-1-[S-(乙酰氨基甲基)-L-半胱氨酰基]吡咯烷-2-甲腈三氟乙酸盐
将(2S)-1-[S-(乙酰氨基甲基)-N-(叔丁氧羰基)-L-半胱氨酰基]吡咯烷-2-甲腈(610mg,1.65mmol)溶于三氟乙酸(30mL)。在室温下1h后,在真空中除去溶剂,得到无色的油,经鉴定为(2S)-1-[S-(乙酰氨基甲基)-L-半胱氨酰基]吡咯烷-2-甲腈三氟乙酸盐(620mg,1.61mmol,98%)。
[M+H]+=271.0
实施例8
(2S)-1-[(2’R)-3’-(乙酰氨基甲硫基)-2’-氨基-3’-甲基丁酰基]吡咯烷-2-甲腈三氟乙酸盐
A.(2S)-1-[(2’R)-3’-(乙酰氨基甲硫基)-2’-(叔丁氧羰基氨基)-3’-甲基丁酰基]吡咯烷-2-甲腈
将S-(乙酰氨基甲基)-N-(叔丁氧羰基)青霉胺(720mg,2.25mmol)溶于CH2Cl2(30mL)。在0℃下向该溶液加入(2S)-吡咯烷-2-甲腈盐酸盐(270mg,2.04mmol)和PyBOP(1.3g,2.49mmol),用三乙胺调节pH 9。在0℃至室温下18h后,在真空中除去溶剂,将残余物溶于乙酸乙酯(150mL)。将该溶液用0.3M KHSO4(2×30mL)、饱和NaHCO3(2×30mL)、水(2×30mL)和盐水(1×30mL)洗涤,干燥(Na2SO4),在真空中蒸发。残余物经过快速色谱纯化(洗脱剂:75%乙酸乙酯,25%石油醚),得到无色的油,经鉴定为(2S)-1-[(2’R)-3’-(乙酰氨基甲硫基)-2’-(叔丁氧羰基氨基)-3’-甲基丁酰基]吡咯烷-2-甲腈(742mg,1.86mmol,83%)。
B.(2S)-1-[(2’R)-3’-(乙酰氨基甲硫基)-2’-氨基-3’-甲基丁酰基]吡咯烷-2-甲腈
将(2S)-1-[(2’R)-3’-(乙酰氨基甲硫基)-2’-(叔丁氧羰基氨基)-3’-甲基丁酰基]吡咯烷-2-甲腈(710mg,1.78mmol)溶于三氟乙酸(30mL)。在室温下1h后,在真空中除去溶剂,得到无色的油,经鉴定为(2S)-1-[(2’R)-3’-(乙酰氨基甲硫基)-2’-氨基-3’-甲基丁酰基]吡咯烷-2-甲腈(560mg,1.36mmol,76%)。
[M+H]+=299.1
实施例9
(2S)-1-[Nω-(2-氯吡啶基-3-羰基)-L-鸟氨酰基]吡咯烷-2-甲腈三氟乙酸盐
A.(2S)-1-(Nα-(叔丁氧羰基)-L-鸟氨酰基)吡咯烷-2-甲腈
按照实施例2赖氨酸衍生物所述方法制备(2S)-1-(Nα-(叔丁氧羰基)-L-鸟氨酰基)吡咯烷-2-甲腈。
B.(2S)-1-(Nα-(叔丁氧羰基)-Nω-(2-氯吡啶基-3-羰基)-L-鸟氨酰基)吡咯烷-2-甲腈
将(2S)-1-(Nα-(叔丁氧羰基)-L-鸟氨酰基)吡咯烷-2-甲腈(80mg,0.26mmol)溶于CH2Cl2(20mL)。向该溶液加入2-氯吡啶-3-碳酰氯(55mg,0.32mmol),用三乙胺调节pH 9。在室温下18h后,在真空中除去溶剂,将残余物溶于乙酸乙酯(70mL)。将该溶液用0.3M KHSO4(2×20mL)、饱和NaHCO3(2×20mL)、水(2×20mL)和盐水(1×20mL)洗涤,干燥(Na2SO4),在真空中蒸发。残余物经过快速色谱纯化(洗脱剂:95%乙酸乙酯,5%石油醚),得到无色的油,经鉴定为(2S)-1-(Nα-(叔丁氧羰基)-Nω-(2-氯吡啶基-3-羰基)-L-鸟氨酰基)吡咯烷-2-甲腈(60mg,0.14mmol,53%)。
C.(2S)-1-[Nω-(2-氯吡啶基-3-羰基)-L-鸟氨酰基]吡咯烷-2-甲腈三氟乙酸盐
将(2S)-1-(Nα-(叔丁氧羰基)-Nω-(2-氯吡啶基-3-羰基)-L-鸟氨酰基)吡咯烷-2-甲腈(60mg,0.14mmol)溶于三氟乙酸(5mL)。在室温下1h后,在真空中除去溶剂。残余物经过制备型hplc纯化(Vydac C18,从5至50%0.1%TFA/乙腈到0.1%TFA/水历经40min,3mL/min)。冷冻干燥含有产物的部分,得到白色固体,经鉴定为(2S)-1-[Nω-(2-氯吡啶基-3-羰基)-L-鸟氨酰基]吡咯烷-2-甲腈三氟乙酸盐(52mg)。
[M+H]+=350.1
实施例10
1-[Nω-(2-氯吡啶基-3-羰基)-L-鸟氨酰基]吡咯烷盐酸盐
A.1-(Nα-(叔丁氧羰基)-Nω-(2-氯吡啶基-3-羰基)-L-鸟氨酰基)吡咯烷
将1-(Nα-(叔丁氧羰基)-L-鸟氨酰基)吡咯烷(20mg,0.069mmol)溶于CH2Cl2(5mL)。向该溶液加入2-氯吡啶-3-碳酰氯(14mg,0.076mmol),用三乙胺调节pH 9。在室温下1h后,在真空中除去溶剂,将残余物溶于乙酸乙酯(70mL)。将该溶液用0.3M KHSO4(2×20mL)、饱和NaHCO3(2×20mL)、水(2×20mL)和盐水(1×20mL)洗涤,干燥(Na2SO4),在真空中蒸发。残余物经过快速色谱纯化(洗脱剂:10%甲醇,90%二氯甲烷),得到无色的油,经鉴定为1-(Nα-(叔丁氧羰基)-Nω-(2-氯吡啶基-3-羰基)-L-鸟氨酰基)吡咯烷(19mg,0.045mmol,63%)。
B.1-[Nω-(2-氯吡啶基-3-羰基)-L-鸟氨酰基]吡咯烷盐酸盐
将1-(Nω-(叔丁氧羰基)-Nω-(2-氯吡啶基-3-羰基)-L-鸟氨酰基)吡咯烷(19mg,0.045mmol)溶于4M HCl/二噁烷(10mL)。在室温下45min后,在真空中除去溶剂,得到白色固体,经鉴定为1-[Nω-(2-氯吡啶基-3-羰基)-L-鸟氨酰基]吡咯烷盐酸盐(15mg)。
[M+H]+=325。
实施例11
3-[Nω-(2-氯吡啶基-3-羰基)-L-鸟氨酰基]噻唑烷盐酸盐
A.3-(Nα-(叔丁氧羰基)-Nω-(2-氯吡啶基-3-羰基)-L-鸟氨酰基)噻唑烷
将3-(Nα-(叔丁氧羰基)-L-鸟氨酰基)噻唑烷(136mg,0.45mmol)溶于CH2Cl2(10mL)。向该溶液加入2-氯吡啶-3-碳酰氯(88mg,0.5mmol),用三乙胺调节pH 9。在室温下1h后,在真空中除去溶剂,将残余物溶于乙酸乙酯(70mL)。将该溶液用0.3M KHSO4(2×20mL)、饱和NaHCO3(2×20mL)、水(2×20mL)和盐水(1×20mL)洗涤,干燥(Na2SO4),在真空中蒸发。残余物经过快速色谱纯化(洗脱剂:1.5%甲醇,98.5%二氯甲烷),得到无色的油,经鉴定为3-(Nα-(叔丁氧羰基)-Nω-(2-氯吡啶基-3-羰基)-L-鸟氨酰基)噻唑烷(30mg,0.068mmol,15%)。
B.3-[Nω-(2-氯吡啶基-3-羰基)-L-鸟氨酰基]噻唑烷盐酸盐
将3-(Nα-(叔丁氧羰基)-Nω-(2-氯吡啶基-3-羰基)-L-鸟氨酰基)噻唑烷(30mg,0.068mmol)溶于4M HCl/二噁烷(10mL)。在室温下45min后,在真空中除去溶剂,得到白色固体,经鉴定为3-[Nω-(2-氯吡啶基-3-羰基)-L-鸟氨酰基]噻唑烷盐酸盐(25mg)。
[M+H]+=342.1。
实施例12
(2S)-1-[S-(3-甲基吡啶基氨基甲酰基甲基)-L-半胱氨酰基]吡咯烷-2-甲腈三氟乙酸盐
A.S-(苄氧羰基甲基)-N-(叔丁氧羰基)-L-半胱氨酸
将N-(叔丁氧羰基)-L-半胱氨酸(3.5g,15.8mmol),2-溴乙酸苄基酯(3.7g,16.1mmol)和三乙胺(1.8g,18.0mmol)溶于THF(100mL)。在室温下18h后,将反应混合物用乙酸乙酯(100mL)稀释,用0.3MKHSO4、饱和NaHCO3、水和盐水洗涤,干燥(Na2O4),蒸发。残余物经过快速色谱纯化(洗脱剂:95%氯仿,4%甲醇,1%乙酸),得到无色的油,经鉴定为S-(苄氧羰基甲基)-N-(叔丁氧羰基)-L-半胱氨酸(5.2g,14.1mmol,89%)。
B.(2S)-1-[S-(苄氧羰基甲基)-N-(叔丁氧羰基)-L-半胱氨酰基]-吡咯烷-2-甲腈
将S-(苄氧羰基甲基)-N-(叔丁氧羰基)-L-半胱氨酸(5.10g,13.8mmol)溶于CH2Cl2(200mL)。将该溶液冷却至0℃,加入(2S)-吡咯烷-2-甲腈盐酸盐(2.1g,15.8mmol)和PyBOP(8.0g,15.3mmol),用三乙胺调节pH 9。在0℃至室温下18h后,在真空中除去溶剂,将残余物溶于乙酸乙酯(150mL)。)。将该溶液用0.3M KHSO4(1×50mL)、饱和NaHCO3(1×50mL)、水(1×50mL)和盐水(1×50mL)洗涤,干燥(Na2SO4),在真空中蒸发,得到黄色的油。经过快速色谱纯化(洗脱剂:40%乙酸乙酯,60%石油醚),得到无色的油,经鉴定为(2S)-1-[S-(苄氧羰基甲基)-N-(叔丁氧羰基)-L-半胱氨酰基]-吡咯烷-2-甲腈(5.82g,13.0mmol,94%)。
C.(2S)-1-[N-(叔丁氧羰基)-S-(羧甲基)-L-半胱氨酰基]-吡咯烷-2-甲腈
将(2S)-1-[S-(苄氧羰基甲基)-N-(叔丁氧羰基)-L-半胱氨酰基]-吡咯烷-2-甲腈(1.31g,2.9mmol)溶于THF(100mL)。加入氢氧化锂水溶液(1M,3.5mL,3.5mmol)。在室温下3小时后,将反应混合物用乙酸乙酯(100mL)稀释,用1M柠檬酸、水和盐水洗涤,干燥(Na2SO4),在真空中蒸发,得到无色的油。经过快速色谱纯化(洗脱剂:97%氯仿,2%甲醇,1%乙酸),得到无色的油,经鉴定为(2S)-1-[N-(叔丁氧羰基)-S-(羧甲基)-L-半胱氨酰基]-吡咯烷-2-甲腈(860mg,2.4mmol,82%)。
D.(2S)-1-[N-(叔丁氧羰基)-S-(3-甲基吡啶基氨基甲酰基甲基)-L-半胱氨酰基]-吡咯烷-2-甲腈
将(2S)-1-[N-(叔丁氧羰基)-S-(羧甲基)-L-半胱氨酰基]-吡咯烷-2-甲腈(150mg,0.42mmol)溶于CH2Cl2(20mL)。将该溶液冷却至0℃,加入3-(氨基甲基)吡啶(53mg,0.5mmol)和PyBOP(270mg,0.52mmol),用三乙胺调节pH 9。在0℃至室温下18h后,在真空中除去溶剂,将残余物溶于乙酸乙酯(70mL)。)。将该溶液用0.3M KHSO4(1×20mL)、饱和NaHCO3(1×20mL)、水(1×20mL)和盐水(1×20mL)洗涤,干燥(Na2SO4),在真空中蒸发,得到黄色的油。经过快速色谱纯化(洗脱剂:96%氯仿,4%甲醇),得到无色的油,经鉴定为(2S)-1-[N-(叔丁氧羰基)-S-(3-甲基吡啶基氨基甲酰基甲基)-L-半胱氨酰基]-吡咯烷-2-甲腈(170mg,0.38mmol,91%)。
E.(2S)-1-[S-(3-甲基吡啶基氨基甲酰基甲基)-L-半胱氨酰基]-吡咯烷-2-甲腈三氟乙酸盐
将(2S)-1-[N-(叔丁氧羰基)-S-(3-甲基吡啶基氨基甲酰基甲基)-L-半胱氨酰基]-吡咯烷-2-甲腈(130mg,0.29mmol)溶于三氟乙酸(10mL)。在室温下1小时后,在真空中除去溶剂,得到白色固体,经鉴定为(2S)-1-[S-(3-甲基吡啶基氨基甲酰基甲基)-L-半胱氨酰基]-吡咯烷-2-甲腈三氟乙酸盐(116mg,0.25mmol,86%)。
[M+H]+=348.2
实施例13
3-[Nω-(2-喹喔啉酰基)-L-赖氨酰基]噻唑烷盐酸盐
A.3-[Nα-(叔丁氧羰基)-Nω-(2-喹喔啉酰基)-L-赖氨酰基]噻唑烷
将3-[Nα-(叔丁氧羰基)赖氨酰基]噻唑烷(128mg,0.4mmol)溶于CH2Cl2(10mL)。加入2-喹喔啉酰氯(85mg,0.44mmol)和碳酸钾(45.8mg,0.3mmol)。将反应混合物在室温下搅拌18小时,在真空中除去溶剂。残余物经过快速色谱纯化(洗脱剂:99.5%氯仿,0.5%甲醇),得到无色的油,经鉴定为3-[Nα-(叔丁氧羰基)-Nω-(2-喹喔啉酰基)-L-赖氨酰基]噻唑烷(140mg,0.296mmol,74%)。
B.3-[Nω-(2-喹喔啉酰基)-L-赖氨酰基]噻唑烷盐酸盐
将3-[Nα-(叔丁氧羰基)-Nω-(2-喹喔啉酰基)-L-赖氨酰基)噻唑烷(140mg,0.296mmol)溶于4M HCl/二噁烷(20mL)。在室温下1小时后,在真空中除去溶剂,得到白色固体,经鉴定为3-[Nω-(2-喹喔啉酰基)-L-赖氨酰基]噻唑烷盐酸盐(128mg,0.296mol,100%)。
[M+H]+=374.2
实施例14
3-[Nω-(3-吡啶氧羰基)-L-鸟氨酰基]噻唑烷盐酸盐
A.3-[Nα-(叔丁氧羰基)-Nω-(3-吡啶氧羰基)-L-鸟氨酰基]噻唑烷
将3-羟基吡啶(14.9mg,0.138mmol)溶于CH2Cl2(20mL)。在0℃下加入光气(20%甲苯溶液,0.335mL,0.685mmol)和吡啶(14mg,0.182mmol)。90min后,在真空中除去溶剂将残余物溶于CH2Cl2(20mL)。加入3-[Nα-(叔丁氧羰基)鸟氨酰基]噻唑烷(42mg,0.138mmol)和三乙胺(28mg,0.28mmol)。将反应混合物在室温下搅拌18小时,在真空中除去溶剂。残余物经过快速色谱纯化(洗脱剂:97%氯仿,3%甲醇),得到无色的油,经鉴定为3-[Nα-(叔丁氧羰基)-Nω-(3-吡啶氧羰基)-L-鸟氨酰基]噻唑烷(16mg,0.038mmol,27%)。
B.3-[Nω-(3-吡啶氧羰基)-L-鸟氨酰基]噻唑烷盐酸盐
将3-[Nα-(叔丁氧羰基)-Nω-(3-吡啶氧羰基)-L-鸟氨酰基]噻唑烷(16mg,0.038mmol)溶于4M HCl/二噁烷(20mL)。在室温下1小时后,在真空中除去溶剂,得到白色固体,经鉴定为3-[Nω-(3-吡啶氧羰基)-L-鸟氨酰基]噻唑烷盐酸盐(14mg,0.038mmol,100%)。
[M+H]+=325.1
实施例15
3-[O-(3-氯苄基氨基甲酰基)丝氨酰基]噻唑烷盐酸盐
A.3-[N-(叔丁氧羰基)-L-丝氨酰基]噻唑烷
将N-(叔丁氧羰基)-L-丝氨酸(2.1g,10.2mmol)溶于CH2Cl2/DMF(9∶1,50mL)。在0℃下加入噻唑烷(650mg,11.2mmol)、羟基苯并三唑(2.8g,20.7mmol)和水溶性碳二亚胺(3.9g,19.5mmol)。用N-甲基吗啉调节pH 8。将反应混合物在室温下搅拌18小时,在真空中除去溶剂,将残余物溶于乙酸乙酯(150mL)。将该溶液用0.3M KHSO4(1×50mL)、饱和NaHCO3(1×50mL)、水(1×50mL)和盐水(1×50mL)洗涤,干燥(Na2SO4),在真空中蒸发,得到白色固体,经鉴定为3-[N-(叔丁氧羰基)-L-丝氨酰基]噻唑烷(2.15g,7.78mmol,76%)。
B.3-[N-(叔丁氧羰基)-O-(3-氯苄基氨基甲酰基)-L-丝氨酰基]噻唑烷
将3-[N-(叔丁氧羰基)-L-丝氨酰基]噻唑烷(110mg,0.48mmol)溶于DMF(10mL),加入1,1’-羰基二咪唑(71mg,0.43mmol)。在室温下2小时后,加入3-氯苄胺(62mg,0.4mmol)。18小时后,加入EtOAc(200mL)。将该溶液用0.3M KHSO4(1×50mL)、饱和NaHCO3(1×50mL)、水(4×50mL)和盐水(1×50mL)洗涤,干燥(Na2SO4),在真空中蒸发,得到黄色的油。经过快速色谱纯化(洗脱剂:40%乙酸乙酯,60%石油醚),得到无色的油,经鉴定为3-[N-(叔丁氧羰基)-O-(3-氯苄基氨基甲酰基)-L-丝氨酰基]噻唑烷(158mg,0.36mmol,90%)。
C.3-[O-(3-氯苄基氨基甲酰基)-L-丝氨酰基]噻唑烷盐酸盐
将3-[N-(叔丁氧羰基)-O-(3-氯苄基氨基甲酰基)-L-丝氨酰基]噻唑烷(140mg,0.32mmol)溶于4M HCl/二噁烷(20mL)。在室温下1小时后,在真空中除去溶剂,得到白色固体,经鉴定为3-[O-(3-氯苄基氨基甲酰基)-L-丝氨酰基]噻唑烷盐酸盐(115mg,0.3mmol,94%)。
[M+H]+=344.1
按照类似于上述的方法制备下列所列实施例。
表1:实施例16-162
表2:实施例163-250
表3:实施例251-266
表4:实施例267-318
表5:实施例319-378
实施例 | R4B | R1 | X1 |
319 | NH2 | CN | CH2 |
表6:实施例379-418
表7:实施例419-438
表8:实施例439-450
实施例451
活性的测定
按照WO 95/15309所述方法测定化合物是DP-IV抑制剂。上述实施例所述全部化合物都是竞争性DP-IV抑制剂,Ki值小于300nM。
实施例452
体内活性的测定
利用标准口服葡萄糖耐量试验,在Zucker肥胖大鼠中证明选定化合物的抗糖尿病作用。通过口管饲法向对照大鼠给以葡萄糖溶液,测定血浆葡萄糖水平。证明这些大鼠有显著的高血糖。将根据本发明的化合物按不同浓度溶于葡萄糖溶液,以便可以在葡萄糖攻击的同时向大鼠给以不同剂量的化合物。在接受0.1与100mg/kg之间的DP-IV抑制剂的动物中,以剂量依赖性方式减少了高血糖的发生。
实施例453
药物制剂
如下制备片剂,含有100mg实施例1化合物作为活性成分:
实施例1化合物 200.0g
玉米淀粉 71.0g
羟丙基纤维素 18.0g
羧甲基纤维素钙 13.0g
硬脂酸镁 3.0g
乳糖 195.0g
总计 500.0g
将原料混合,然后压片,得到2000片,片重250mg,每片含有100mg实施例1化合物。
上文证明根据本发明的化合物是DP-IV抑制剂,因此预期可用作治疗剂,用于治疗葡萄糖耐量减低、II型糖尿病和抑制该酶可改善病状或症状的其他疾病。
下列权利要求书进一步限定本发明。
Claims (13)
1、式1化合物,或其药学上可接受的盐
其中:
X1选自硫原子、氧原子、亚磺酰基、磺酰基和亚甲基;
X2选自O、S和亚甲基;
X3是硫代羰基;
R1是氢原子或腈基;
R2和R3独立地选自H和C1-C6烷基,或者可以一起是-(CH2)p-;
R4是R6R7N;
R5是H或C1-C6烷基;
R6和R7独立地选自R8(CH2)q或者它们一起是-(CH2)2-Z1-(CH2)2-或-CHR9-Z2-CH2-CHR10-;
R8选自H、C1-C4烷基、苯并稠合的环C1-C6烷基、酰基、二C1-C6烷基氨基甲酰基、二C1-C6烷基氨基、N-C1-C6烷基哌啶基、可选被取代的芳基、可选被取代的α-C1-C6烷基苄基、可选被取代的芳酰基、可选被取代的芳基磺酰基和可选被取代的杂芳基,其中杂芳基表示单环的五元和六元芳族基团,具有一或两个选自氮、氧和硫的杂原子;这些环的苯并稠合衍生物;和由两个这类单环杂芳基稠合形成的二环基团;R9和R10独立地选自H、氨基甲酰基、羟甲基和氰基甲基;
Z1选自共价键、-(CH2)r-、-O-、-SOt-和-N((CH2)qR8)-;
Z2是可选被取代的邻-亚苯基基团;
m是1-3;
n是0-4;
p是2-5;
q是0-3;
r是1或2;
t是0-2;
其中,可选的取代基选自C1-C6烷基、可以进一步被一或多个甲基或三氟甲基取代的芳基、羟基、C1-C6烷氧基、C1-C6烷基磺酰基、酰基、全氟酰基、氨基、C1-C6烷基氨基、二(C1-C6烷基)氨基、氨基C1-C6亚烷基、氟、氯、溴、三氟甲基、硝基、氰基、氨基甲酰基、羧基和C1-C6烷氧基羰基和/或当存在两个相邻的取代基时,所述两个相邻的取代基可以连接构成与母体芳基或杂芳基环稠合的环。
2、根据权利要求1的化合物,其中R1是腈基。
5、根据权利要求4的化合物,其中R1是腈基,该腈基的立体化学如式4所示
6、根据前述权利要求1至5任一项的化合物,其中m是1。
7、根据前述权利要求1至5任一项的化合物,其中R2和R3独立地是H或甲基。
8、根据前述权利要求1至5任一项的化合物,其中m是1,X2是-CH2-,R2和R3都是氢。
9、根据权利要求1至5任一项的化合物,其中m是1,X2是-O-,R2和R3之一是氢,另一个是甲基。
10、根据权利要求1至5任一项的化合物,其中m是1,X2是-S-,R2和R3都是甲基。
11、根据权利要求1的化合物,其中R1是CN,X1是CH2。
12、根据权利要求1的化合物,其中R1是H,X1是S。
13、化合物用于制备药物组合物的用途,该药物组合物用于治疗2型糖尿病、葡萄糖耐量减低、生长激素缺乏、多囊性卵巢综合征和自体免疫与炎性疾病,该化合物为根据权利要求1的化合物或其药学上可接受的盐。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB0010183.2A GB0010183D0 (en) | 2000-04-26 | 2000-04-26 | Inhibitors of dipeptidyl peptidase IV |
GB0010183.2 | 2000-04-26 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB018085040A Division CN100355728C (zh) | 2000-04-26 | 2001-04-26 | 二肽基肽酶iv抑制剂 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1803797A true CN1803797A (zh) | 2006-07-19 |
Family
ID=9890555
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNA2005101377754A Pending CN1803797A (zh) | 2000-04-26 | 2001-04-26 | 二肽基肽酶iv抑制剂 |
CNB018085040A Expired - Fee Related CN100355728C (zh) | 2000-04-26 | 2001-04-26 | 二肽基肽酶iv抑制剂 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB018085040A Expired - Fee Related CN100355728C (zh) | 2000-04-26 | 2001-04-26 | 二肽基肽酶iv抑制剂 |
Country Status (23)
Country | Link |
---|---|
US (1) | US7189728B2 (zh) |
EP (2) | EP1693365A1 (zh) |
JP (1) | JP2003531191A (zh) |
KR (1) | KR20020093913A (zh) |
CN (2) | CN1803797A (zh) |
AU (1) | AU781245B2 (zh) |
BR (1) | BR0110267A (zh) |
CA (1) | CA2407663A1 (zh) |
CZ (1) | CZ20023514A3 (zh) |
EE (1) | EE200200604A (zh) |
GB (1) | GB0010183D0 (zh) |
HR (1) | HRP20020812A2 (zh) |
HU (1) | HUP0300542A2 (zh) |
IL (2) | IL151588A0 (zh) |
MX (1) | MXPA02010438A (zh) |
NO (1) | NO324364B1 (zh) |
NZ (1) | NZ521166A (zh) |
PL (1) | PL357820A1 (zh) |
RU (1) | RU2283303C2 (zh) |
SK (1) | SK15282002A3 (zh) |
UA (1) | UA75592C2 (zh) |
WO (1) | WO2001081304A1 (zh) |
ZA (1) | ZA200207739B (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101357921B (zh) * | 2007-08-02 | 2011-01-12 | 山东轩竹医药科技有限公司 | 新的二肽酶-iv抑制剂化合物 |
CN101723947B (zh) * | 2008-10-21 | 2012-05-30 | 山东轩竹医药科技有限公司 | 二肽酶-ⅳ抑制剂化合物 |
Families Citing this family (71)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE60223920T2 (de) * | 2001-06-27 | 2008-11-13 | Smithkline Beecham Corp. | Pyrrolidine als dipeptidyl-peptidase-inhibitoren |
US7183290B2 (en) | 2001-06-27 | 2007-02-27 | Smithkline Beecham Corporation | Fluoropyrrolidines as dipeptidyl peptidase inhibitors |
HUP0400321A2 (hu) | 2001-06-27 | 2004-08-30 | Smithkline Beecham Corp. | Fluorpirrolidin-származékok mint dipeptidil-dipeptidáz inhibitorok és ezeket tartalmazó gyógyszerkészítmények |
GB0125446D0 (en) | 2001-10-23 | 2001-12-12 | Ferring Bv | Novel anti-diabetic agents |
CN100383129C (zh) * | 2002-10-18 | 2008-04-23 | 默克公司 | 用于治疗或预防糖尿病的β-氨基杂环二肽酰肽酶抑制剂 |
US20060052382A1 (en) * | 2002-12-20 | 2006-03-09 | Duffy Joseph L | 3-Amino-4-phenylbutanoic acid derivatives as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes |
EP1608317B1 (en) | 2003-03-25 | 2012-09-26 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
US20040229848A1 (en) * | 2003-05-05 | 2004-11-18 | Hans-Ulrich Demuth | Glutaminyl based DP IV-inhibitors |
PL1620082T3 (pl) | 2003-05-05 | 2010-10-29 | Probiodrug Ag | Medyczne zastosowanie inhibitorów cyklazy glutaminylowej i glutaminianowej do leczenia choroby Alzheimera i zespołu Downa |
US7371871B2 (en) | 2003-05-05 | 2008-05-13 | Probiodrug Ag | Inhibitors of glutaminyl cyclase |
CN101837127A (zh) | 2003-05-05 | 2010-09-22 | 前体生物药物股份公司 | 谷氨酰胺酰基和谷氨酸环化酶效应物的应用 |
US7678909B1 (en) | 2003-08-13 | 2010-03-16 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
US7169926B1 (en) | 2003-08-13 | 2007-01-30 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
US7470700B2 (en) | 2003-08-13 | 2008-12-30 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
JP2007505121A (ja) | 2003-09-08 | 2007-03-08 | 武田薬品工業株式会社 | ジペプチジルぺプチダーゼ阻害剤 |
CN102302781A (zh) | 2003-10-15 | 2012-01-04 | 前体生物药物股份公司 | 谷氨酰胺酰基环化酶效应物和谷氨酸环化酶效应物的应用 |
CA2544573A1 (en) | 2003-11-03 | 2005-06-02 | Probiodrug Ag | Combinations useful for the treatment of neuronal disorders |
CN1905876B (zh) | 2003-11-17 | 2010-06-09 | 诺瓦提斯公司 | 二肽基肽酶iv抑制剂的用途 |
EP1715893B8 (en) | 2004-01-20 | 2009-12-16 | Novartis Ag | Direct compression formulation and process |
CA2554809C (en) | 2004-02-05 | 2014-04-29 | Probiodrug Ag | Novel n-alkyl thiourea- and thioamide-substituted imidazolyl inhibitors of glutaminyl cyclase |
US7732446B1 (en) | 2004-03-11 | 2010-06-08 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
AU2004318013B8 (en) | 2004-03-15 | 2011-10-06 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
JP2008501714A (ja) | 2004-06-04 | 2008-01-24 | 武田薬品工業株式会社 | ジペプチジルペプチダーゼインヒビター |
WO2006019965A2 (en) | 2004-07-16 | 2006-02-23 | Takeda San Diego, Inc. | Dipeptidyl peptidase inhibitors |
AU2005267093B2 (en) * | 2004-07-23 | 2009-10-01 | Nuada Llc | Peptidase inhibitors |
JP2008524331A (ja) | 2004-12-21 | 2008-07-10 | 武田薬品工業株式会社 | ジペプチジルペプチダーゼ阻害剤 |
DOP2006000008A (es) | 2005-01-10 | 2006-08-31 | Arena Pharm Inc | Terapia combinada para el tratamiento de la diabetes y afecciones relacionadas y para el tratamiento de afecciones que mejoran mediante un incremento de la concentración sanguínea de glp-1 |
CN101277949A (zh) | 2005-04-22 | 2008-10-01 | 阿兰托斯制药控股公司 | 二肽基肽酶-ⅳ抑制剂 |
CN101232873A (zh) * | 2005-08-11 | 2008-07-30 | 霍夫曼-拉罗奇有限公司 | 含有dpp-iv抑制剂的药物组合物 |
CA2622472C (en) | 2005-09-14 | 2013-11-19 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors for treating diabetes |
CN101360723A (zh) | 2005-09-16 | 2009-02-04 | 武田药品工业株式会社 | 制备嘧啶二酮衍生物的方法 |
DE102005054700B4 (de) * | 2005-11-16 | 2009-01-08 | Imtm Gmbh | Neue duale Peptidase-Inhibitoren als Prodrugs zur Therapie von entzündlichen und anderen Erkrankungen |
GB0526291D0 (en) | 2005-12-23 | 2006-02-01 | Prosidion Ltd | Therapeutic method |
WO2007112347A1 (en) | 2006-03-28 | 2007-10-04 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
DK1971862T3 (da) | 2006-04-11 | 2011-02-14 | Arena Pharm Inc | Fremgangsmåder til anvendelse af GPR119-receptor til identificering af forbindelser anvendelige til øgning af knoglemasse hos en person |
PE20071221A1 (es) | 2006-04-11 | 2007-12-14 | Arena Pharm Inc | Agonistas del receptor gpr119 en metodos para aumentar la masa osea y para tratar la osteoporosis y otras afecciones caracterizadas por masa osea baja, y la terapia combinada relacionada a estos agonistas |
EA200802054A1 (ru) | 2006-04-12 | 2009-04-28 | Пробиодруг Аг | Ингибиторы фермента |
AU2007296556B2 (en) * | 2006-09-13 | 2013-09-19 | Takeda Pharmaceutical Company Limited | Use of 2-6- (3-Amino-piperidin-1-yl) -3-methyl-2, 4-dioxo-3, 4-dihydro-2H-pyrimidin-1-ylmethyl-4-fluoro-benzonitrile |
US8324383B2 (en) | 2006-09-13 | 2012-12-04 | Takeda Pharmaceutical Company Limited | Methods of making polymorphs of benzoate salt of 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]-benzonitrile |
WO2008055945A1 (en) | 2006-11-09 | 2008-05-15 | Probiodrug Ag | 3-hydr0xy-1,5-dihydr0-pyrr0l-2-one derivatives as inhibitors of glutaminyl cyclase for the treatment of ulcer, cancer and other diseases |
TW200838536A (en) | 2006-11-29 | 2008-10-01 | Takeda Pharmaceutical | Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor |
SI2091948T1 (sl) | 2006-11-30 | 2012-07-31 | Probiodrug Ag | Novi inhibitorji glutaminil ciklaze |
US8093236B2 (en) | 2007-03-13 | 2012-01-10 | Takeda Pharmaceuticals Company Limited | Weekly administration of dipeptidyl peptidase inhibitors |
ES2529149T3 (es) | 2007-04-03 | 2015-02-17 | Mitsubishi Tanabe Pharma Corporation | Una combinación de inhibidor de dipeptidil peptidasa IV y edulcorante para uso en el tratamiento de la obesidad |
EP2142514B1 (en) | 2007-04-18 | 2014-12-24 | Probiodrug AG | Thiourea derivatives as glutaminyl cyclase inhibitors |
CL2008003653A1 (es) | 2008-01-17 | 2010-03-05 | Mitsubishi Tanabe Pharma Corp | Uso de un inhibidor de sglt derivado de glucopiranosilo y un inhibidor de dppiv seleccionado para tratar la diabetes; y composicion farmaceutica. |
EP2108960A1 (en) | 2008-04-07 | 2009-10-14 | Arena Pharmaceuticals, Inc. | Methods of using A G protein-coupled receptor to identify peptide YY (PYY) secretagogues and compounds useful in the treatment of conditons modulated by PYY |
AR077642A1 (es) | 2009-07-09 | 2011-09-14 | Arena Pharm Inc | Moduladores del metabolismo y el tratamiento de trastornos relacionados con el mismo |
ES2548913T3 (es) | 2009-09-11 | 2015-10-21 | Probiodrug Ag | Derivados heterocíclicos como inhibidores de glutaminil ciclasa |
JP6026284B2 (ja) | 2010-03-03 | 2016-11-16 | プロビオドルグ エージー | グルタミニルシクラーゼの阻害剤 |
JP5688745B2 (ja) | 2010-03-10 | 2015-03-25 | プロビオドルグ エージー | グルタミニルシクラーゼ(qc、ec2.3.2.5)の複素環阻害剤 |
JP2013523819A (ja) | 2010-04-06 | 2013-06-17 | アリーナ ファーマシューティカルズ, インコーポレイテッド | Gpr119レセプターのモジュレーターおよびそれに関連する障害の処置 |
WO2011131748A2 (en) | 2010-04-21 | 2011-10-27 | Probiodrug Ag | Novel inhibitors |
KR101871011B1 (ko) | 2010-09-22 | 2018-06-25 | 아레나 파마슈티칼스, 인크. | Gpr119 수용체의 조절제 및 그와 관련된 장애의 치료 |
WO2012123563A1 (en) | 2011-03-16 | 2012-09-20 | Probiodrug Ag | Benz imidazole derivatives as inhibitors of glutaminyl cyclase |
WO2012135570A1 (en) | 2011-04-01 | 2012-10-04 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
WO2012145361A1 (en) | 2011-04-19 | 2012-10-26 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
US20140038889A1 (en) | 2011-04-22 | 2014-02-06 | Arena Pharmaceuticals, Inc. | Modulators Of The GPR119 Receptor And The Treatment Of Disorders Related Thereto |
WO2012145604A1 (en) | 2011-04-22 | 2012-10-26 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
WO2012170702A1 (en) | 2011-06-08 | 2012-12-13 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
WO2013055910A1 (en) | 2011-10-12 | 2013-04-18 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
WO2014074668A1 (en) | 2012-11-08 | 2014-05-15 | Arena Pharmaceuticals, Inc. | Modulators of gpr119 and the treatment of disorders related thereto |
CN105492444B (zh) | 2013-07-02 | 2018-09-07 | 百时美施贵宝公司 | 作为rock抑制剂的三环吡啶-甲酰胺衍生物 |
JP6522602B2 (ja) | 2013-07-02 | 2019-05-29 | ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company | Rock阻害剤としての三環式ピリド−カルボキサミド誘導体 |
US9488286B2 (en) | 2013-10-24 | 2016-11-08 | Ecolab Usa Inc. | Single piece three-way elastomeric valve |
GB201415598D0 (en) | 2014-09-03 | 2014-10-15 | Univ Birmingham | Elavated Itercranial Pressure Treatment |
CA2979033A1 (en) | 2015-03-09 | 2016-09-15 | Intekrin Therapeutics, Inc. | Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy |
WO2018162722A1 (en) | 2017-03-09 | 2018-09-13 | Deutsches Institut Für Ernährungsforschung Potsdam-Rehbrücke | Dpp-4 inhibitors for use in treating bone fractures |
US11253508B2 (en) | 2017-04-03 | 2022-02-22 | Coherus Biosciences, Inc. | PPARy agonist for treatment of progressive supranuclear palsy |
EP3461819B1 (en) | 2017-09-29 | 2020-05-27 | Probiodrug AG | Inhibitors of glutaminyl cyclase |
CA3204318A1 (en) | 2020-12-17 | 2022-06-23 | Astrazeneca Ab | N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-quinoline-4-carboxamides |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4623715A (en) * | 1984-10-22 | 1986-11-18 | Hoechst Aktiengeselleschaft | Novel peptides which are active on the central nervous system and have an action on the cholinergic system |
EP0490379A3 (de) * | 1990-12-13 | 1992-06-24 | BERLIN-CHEMIE Aktiengesellschaft | Diaminosäurederivate und pharmazeutische Zusammensetzungen |
IL111785A0 (en) * | 1993-12-03 | 1995-01-24 | Ferring Bv | Dp-iv inhibitors and pharmaceutical compositions containing them |
US6011155A (en) * | 1996-11-07 | 2000-01-04 | Novartis Ag | N-(substituted glycyl)-2-cyanopyrrolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV |
TW492957B (en) * | 1996-11-07 | 2002-07-01 | Novartis Ag | N-substituted 2-cyanopyrrolidnes |
DE19823831A1 (de) * | 1998-05-28 | 1999-12-02 | Probiodrug Ges Fuer Arzneim | Neue pharmazeutische Verwendung von Isoleucyl Thiazolidid und seinen Salzen |
DE19826972A1 (de) | 1998-06-18 | 1999-12-23 | Univ Magdeburg Tech | Verwendung von Enzyminhibitoren und pharmazeutische Zubereitung zur Therapie von dermatologischen Erkrankungen mit follikulären und epidermalen Hyperkeratosen und einer verstärkten Keratinozytenproliferation |
DE19940130A1 (de) * | 1999-08-24 | 2001-03-01 | Probiodrug Ges Fuer Arzneim | Neue Effektoren der Dipeptidyl Peptidase IV zur topischen Anwendung |
FR2822826B1 (fr) * | 2001-03-28 | 2003-05-09 | Servier Lab | Nouveaux derives sulfonyles d'alpha-amino-acides, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
-
2000
- 2000-04-26 GB GBGB0010183.2A patent/GB0010183D0/en not_active Ceased
-
2001
- 2001-04-26 NZ NZ521166A patent/NZ521166A/en unknown
- 2001-04-26 CA CA002407663A patent/CA2407663A1/en not_active Abandoned
- 2001-04-26 HU HU0300542A patent/HUP0300542A2/hu unknown
- 2001-04-26 UA UA2002108483A patent/UA75592C2/uk unknown
- 2001-04-26 EP EP06075990A patent/EP1693365A1/en not_active Withdrawn
- 2001-04-26 CZ CZ20023514A patent/CZ20023514A3/cs unknown
- 2001-04-26 WO PCT/GB2001/001888 patent/WO2001081304A1/en not_active Application Discontinuation
- 2001-04-26 BR BR0110267-2A patent/BR0110267A/pt not_active IP Right Cessation
- 2001-04-26 PL PL01357820A patent/PL357820A1/xx not_active Application Discontinuation
- 2001-04-26 SK SK1528-2002A patent/SK15282002A3/sk not_active Application Discontinuation
- 2001-04-26 CN CNA2005101377754A patent/CN1803797A/zh active Pending
- 2001-04-26 CN CNB018085040A patent/CN100355728C/zh not_active Expired - Fee Related
- 2001-04-26 AU AU50544/01A patent/AU781245B2/en not_active Ceased
- 2001-04-26 EE EEP200200604A patent/EE200200604A/xx unknown
- 2001-04-26 EP EP01923861A patent/EP1282600A1/en not_active Withdrawn
- 2001-04-26 RU RU2002131640/04A patent/RU2283303C2/ru not_active IP Right Cessation
- 2001-04-26 KR KR1020027013781A patent/KR20020093913A/ko not_active Application Discontinuation
- 2001-04-26 IL IL15158801A patent/IL151588A0/xx not_active IP Right Cessation
- 2001-04-26 US US10/221,129 patent/US7189728B2/en not_active Expired - Fee Related
- 2001-04-26 MX MXPA02010438A patent/MXPA02010438A/es active IP Right Grant
- 2001-04-26 JP JP2001578399A patent/JP2003531191A/ja active Pending
-
2002
- 2002-09-03 IL IL151588A patent/IL151588A/en unknown
- 2002-09-26 ZA ZA200207739A patent/ZA200207739B/en unknown
- 2002-10-10 HR HRP20020812 patent/HRP20020812A2/hr not_active Application Discontinuation
- 2002-10-22 NO NO20025079A patent/NO324364B1/no unknown
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101357921B (zh) * | 2007-08-02 | 2011-01-12 | 山东轩竹医药科技有限公司 | 新的二肽酶-iv抑制剂化合物 |
CN101723947B (zh) * | 2008-10-21 | 2012-05-30 | 山东轩竹医药科技有限公司 | 二肽酶-ⅳ抑制剂化合物 |
Also Published As
Publication number | Publication date |
---|---|
KR20020093913A (ko) | 2002-12-16 |
MXPA02010438A (es) | 2003-04-25 |
NZ521166A (en) | 2003-10-31 |
US20030216450A1 (en) | 2003-11-20 |
BR0110267A (pt) | 2003-02-18 |
EE200200604A (et) | 2004-04-15 |
EP1282600A1 (en) | 2003-02-12 |
NO20025079L (no) | 2002-12-18 |
CN100355728C (zh) | 2007-12-19 |
EP1693365A1 (en) | 2006-08-23 |
ZA200207739B (en) | 2003-05-22 |
CZ20023514A3 (cs) | 2003-04-16 |
HRP20020812A2 (en) | 2004-12-31 |
AU5054401A (en) | 2001-11-07 |
JP2003531191A (ja) | 2003-10-21 |
UA75592C2 (en) | 2006-05-15 |
AU781245B2 (en) | 2005-05-12 |
WO2001081304A1 (en) | 2001-11-01 |
CA2407663A1 (en) | 2001-11-01 |
NO324364B1 (no) | 2007-10-01 |
US7189728B2 (en) | 2007-03-13 |
GB0010183D0 (en) | 2000-06-14 |
HUP0300542A2 (hu) | 2003-06-28 |
PL357820A1 (en) | 2004-07-26 |
SK15282002A3 (sk) | 2003-05-02 |
RU2283303C2 (ru) | 2006-09-10 |
RU2002131640A (ru) | 2004-03-27 |
CN1426395A (zh) | 2003-06-25 |
IL151588A0 (en) | 2003-04-10 |
NO20025079D0 (no) | 2002-10-22 |
IL151588A (en) | 2008-03-20 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1803797A (zh) | 二肽基肽酶iv抑制剂 | |
CN1249056C (zh) | 二肽基肽酶iv抑制剂 | |
CN1044117C (zh) | 用于抑制人免疫缺陷病毒蛋白酶的化合物及其制备方法和药物用途 | |
CN1164573C (zh) | 新的α-氨基酸化合物、其制备方法和包含它们的药物组合物 | |
CN1242995C (zh) | 化合物,它们的用途和制备方法 | |
CN1101380C (zh) | 作为法尼基转移酶抑制剂的4-巯基吡咯烷衍生物 | |
CN1039321C (zh) | 新的β-氨基-α羟基羧酸的制备方法 | |
CN1468217A (zh) | 脂肪族含氮五员环化合物 | |
CN1310179A (zh) | 作为impdh抑制剂的草酰胺 | |
CN1040003C (zh) | 三氟甲基酮衍生物的制备方法 | |
CN1481377A (zh) | 作为基质金属蛋白酶和TNF-α的抑制剂的环β-氨基酸衍生物 | |
CN1922139A (zh) | 双环酰胺衍生物 | |
CN1040986A (zh) | 环烷基取代的戊二酰胺衍生物的制备 | |
CN1845921A (zh) | 金刚烷和氮杂双环-辛烷及壬烷衍生物、其制备方法及其作为dpp-iv抑制剂的用途 | |
CN1387514A (zh) | 芳族砜异羟肟酸金属蛋白酶抑制剂 | |
CN1350452A (zh) | 糖尿病的预防或治疗药 | |
CN86102761A (zh) | N-吲哚基乙基-磺酰胺类其制备方法及用途 | |
CN1845900A (zh) | 作为嗜中性白细胞弹性蛋白酶抑制剂的喹啉衍生物及它们的用途 | |
CN1136556A (zh) | 芳香族取代的w-氨基链烷酸酰胺和链烷酸二酰胺 | |
CN1714078A (zh) | 可用于治疗雄激素受体相关疾病的吲哚类化合物 | |
CN1585763A (zh) | 哌啶衍生物及其作为趋化因子受体(尤其是ccr5)活性调节剂的用途 | |
CN1204889C (zh) | 粘附受体拮抗剂 | |
CN1303377A (zh) | 作为整合素αvβ3拮抗剂的氨基哌啶衍生物 | |
CN101080389A (zh) | 具有抗增殖活性的茚满酰胺 | |
CN1054071A (zh) | 口服的活性肾素抑制剂 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
WD01 | Invention patent application deemed withdrawn after publication |