AP330A - Piperidine aectate derivatives. - Google Patents

Piperidine aectate derivatives. Download PDF

Info

Publication number: AP330A
Authority: AP; ARIPO
Prior art keywords: solvates; physiologically acceptable; piperazinyl; acceptable salts; formula
Prior art date: 1991-11-14

Application number

APAP/P/1992/000447A

Other languages

English (en)

Other versions

AP9200447A0 (en

Inventor

Barry Porter

Colin David Eldred

Henry Anderson Kelly

James Russell Wheatcroft

Original Assignee

Glaxo Group Ltd

Priority date (The priority date 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 date listed.)

1991-11-14

Filing date

1992-11-13

Publication date

1994-03-30

1991-11-14 Priority claimed from GB919124221A external-priority patent/GB9124221D0/en

1992-01-16 Priority claimed from GB929201052A external-priority patent/GB9201052D0/en

1992-11-13 Application filed by Glaxo Group Ltd filed Critical Glaxo Group Ltd

1993-01-31 Publication of AP9200447A0 publication Critical patent/AP9200447A0/xx

1994-03-30 Application granted granted Critical

1994-03-30 Publication of AP330A publication Critical patent/AP330A/en

Links

NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 title claims description 6
150000001875 compounds Chemical class 0.000 claims abstract description 328
150000003839 salts Chemical class 0.000 claims abstract description 125
239000012453 solvate Substances 0.000 claims abstract description 103
125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 32
125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims abstract description 16
239000001257 hydrogen Substances 0.000 claims abstract description 12
229910052739 hydrogen Inorganic materials 0.000 claims abstract description 12
125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 12
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 6
239000000460 chlorine Substances 0.000 claims abstract description 5
229910052801 chlorine Inorganic materials 0.000 claims abstract description 5
PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims abstract description 4
229910052731 fluorine Inorganic materials 0.000 claims abstract description 4
239000011737 fluorine Substances 0.000 claims abstract description 4
KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims abstract description 3
125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims abstract description 3
239000000203 mixture Substances 0.000 claims description 104
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 67
229910052757 nitrogen Inorganic materials 0.000 claims description 43
238000000034 method Methods 0.000 claims description 36
QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 33
238000006243 chemical reaction Methods 0.000 claims description 26
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 24
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 20
125000000217 alkyl group Chemical group 0.000 claims description 19
230000008569 process Effects 0.000 claims description 18
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 14
239000002253 acid Substances 0.000 claims description 14
239000003814 drug Substances 0.000 claims description 14
125000006239 protecting group Chemical group 0.000 claims description 13
238000011282 treatment Methods 0.000 claims description 13
238000002360 preparation method Methods 0.000 claims description 11
125000004193 piperazinyl group Chemical group 0.000 claims description 10
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
125000001841 imino group Chemical group [H]N=* 0.000 claims description 9
239000008194 pharmaceutical composition Substances 0.000 claims description 9
208000007536 Thrombosis Diseases 0.000 claims description 8
125000004005 formimidoyl group Chemical group [H]\N=C(/[H])* 0.000 claims description 8
229910021529 ammonia Inorganic materials 0.000 claims description 7
150000001412 amines Chemical class 0.000 claims description 6
RAIYODFGMLZUDF-UHFFFAOYSA-N piperidin-1-ium;acetate Chemical compound CC([O-])=O.C1CC[NH2+]CC1 RAIYODFGMLZUDF-UHFFFAOYSA-N 0.000 claims description 5
AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 4
230000015572 biosynthetic process Effects 0.000 claims description 4
125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 4
125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 4
PWIBJZBXBPVCAM-UHFFFAOYSA-N 2-[4-[4-(4-methanehydrazonoylphenyl)piperazin-1-yl]piperidin-1-yl]acetic acid Chemical compound C1=CC(C=NN)=CC=C1N1CCN(C2CCN(CC(O)=O)CC2)CC1 PWIBJZBXBPVCAM-UHFFFAOYSA-N 0.000 claims description 2
ONPCDIAVSPPJPN-UHFFFAOYSA-N 2-[4-[4-[4-[(ethoxycarbonylhydrazinylidene)methyl]phenyl]piperazin-1-yl]piperidin-1-yl]acetic acid Chemical compound C1=CC(C=NNC(=O)OCC)=CC=C1N1CCN(C2CCN(CC(O)=O)CC2)CC1 ONPCDIAVSPPJPN-UHFFFAOYSA-N 0.000 claims description 2
CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 2
241001465754 Metazoa Species 0.000 claims description 2
229910019142 PO4 Inorganic materials 0.000 claims description 2
235000010323 ascorbic acid Nutrition 0.000 claims description 2
125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
CEIPQQODRKXDSB-UHFFFAOYSA-N ethyl 3-(6-hydroxynaphthalen-2-yl)-1H-indazole-5-carboximidate dihydrochloride Chemical compound Cl.Cl.C1=C(O)C=CC2=CC(C3=NNC4=CC=C(C=C43)C(=N)OCC)=CC=C21 CEIPQQODRKXDSB-UHFFFAOYSA-N 0.000 claims description 2
JFCQEDHGNNZCLN-UHFFFAOYSA-N glutaric acid Chemical compound OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 claims description 2
150000003840 hydrochlorides Chemical class 0.000 claims description 2
238000004519 manufacturing process Methods 0.000 claims description 2
159000000000 sodium salts Chemical class 0.000 claims description 2
TUZXZKLQIBAYHZ-UHFFFAOYSA-N tert-butyl 2-[4-[4-(4-methanehydrazonoyl-2-methylphenyl)piperazin-1-yl]piperidin-1-yl]acetate Chemical compound CC1=CC(C=NN)=CC=C1N1CCN(C2CCN(CC(=O)OC(C)(C)C)CC2)CC1 TUZXZKLQIBAYHZ-UHFFFAOYSA-N 0.000 claims description 2
OKOSKHISHNRDHB-UHFFFAOYSA-N tert-butyl 2-[4-[4-(4-methanehydrazonoylphenyl)piperazin-1-yl]piperidin-1-yl]acetate Chemical compound C1CN(CC(=O)OC(C)(C)C)CCC1N1CCN(C=2C=CC(C=NN)=CC=2)CC1 OKOSKHISHNRDHB-UHFFFAOYSA-N 0.000 claims description 2
OSYLNIVYXONDEI-UHFFFAOYSA-N tert-butyl 2-[4-[4-(6-methanehydrazonoylpyridin-3-yl)piperazin-1-yl]piperidin-1-yl]acetate Chemical compound C1CN(CC(=O)OC(C)(C)C)CCC1N1CCN(C=2C=NC(C=NN)=CC=2)CC1 OSYLNIVYXONDEI-UHFFFAOYSA-N 0.000 claims description 2
ANCNTBUSBUODCH-UHFFFAOYSA-N tert-butyl 2-[4-[4-[4-[(diethoxyphosphorylhydrazinylidene)methyl]phenyl]piperazin-1-yl]piperidin-1-yl]acetate Chemical compound C1=CC(C=NNP(=O)(OCC)OCC)=CC=C1N1CCN(C2CCN(CC(=O)OC(C)(C)C)CC2)CC1 ANCNTBUSBUODCH-UHFFFAOYSA-N 0.000 claims description 2
CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims 2
VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims 2
XVOUMQNXTGKGMA-OWOJBTEDSA-N (E)-glutaconic acid Chemical compound OC(=O)C\C=C\C(O)=O XVOUMQNXTGKGMA-OWOJBTEDSA-N 0.000 claims 1
OHBXIRUZXOFBAZ-UHFFFAOYSA-N 2-[4-[4-(4-methanehydrazonoyl-2-methylphenyl)piperazin-1-yl]piperidin-1-yl]acetic acid Chemical compound CC1=CC(C=NN)=CC=C1N1CCN(C2CCN(CC(O)=O)CC2)CC1 OHBXIRUZXOFBAZ-UHFFFAOYSA-N 0.000 claims 1
GYBKMCAZLRWJHI-UHFFFAOYSA-N 2-[4-[4-(5-methanehydrazonoylpyridin-2-yl)piperazin-1-yl]piperidin-1-yl]acetic acid Chemical compound N1=CC(C=NN)=CC=C1N1CCN(C2CCN(CC(O)=O)CC2)CC1 GYBKMCAZLRWJHI-UHFFFAOYSA-N 0.000 claims 1
OXDSCIXIPQDVJW-UHFFFAOYSA-N 2-[4-[4-(6-methanehydrazonoylpyridin-3-yl)piperazin-1-yl]piperidin-1-yl]acetic acid Chemical compound C1=NC(C=NN)=CC=C1N1CCN(C2CCN(CC(O)=O)CC2)CC1 OXDSCIXIPQDVJW-UHFFFAOYSA-N 0.000 claims 1
LPUGHCBDVBQVMO-UHFFFAOYSA-N 2-[4-[4-[4-[(diethylphosphorylhydrazinylidene)methyl]phenyl]piperazin-1-yl]piperidin-1-yl]acetic acid Chemical compound C1=CC(C=NNP(=O)(CC)CC)=CC=C1N1CCN(C2CCN(CC(O)=O)CC2)CC1 LPUGHCBDVBQVMO-UHFFFAOYSA-N 0.000 claims 1
CQLQOTNRCDRHNQ-UHFFFAOYSA-N 2-[4-[4-[4-[(e)-n'-methoxycarbonylcarbamimidoyl]phenyl]piperazin-1-yl]piperidin-1-yl]acetic acid Chemical compound C1=CC(C(N)=NC(=O)OC)=CC=C1N1CCN(C2CCN(CC(O)=O)CC2)CC1 CQLQOTNRCDRHNQ-UHFFFAOYSA-N 0.000 claims 1
ALKYHXVLJMQRLQ-UHFFFAOYSA-M 3-carboxynaphthalen-2-olate Chemical compound C1=CC=C2C=C(C([O-])=O)C(O)=CC2=C1 ALKYHXVLJMQRLQ-UHFFFAOYSA-M 0.000 claims 1
QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims 1
KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims 1
FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims 1
VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims 1
JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 claims 1
AFVFQIVMOAPDHO-UHFFFAOYSA-M Methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 claims 1
QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical class [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims 1
230000002152 alkylating effect Effects 0.000 claims 1
229940072107 ascorbate Drugs 0.000 claims 1
239000011668 ascorbic acid Substances 0.000 claims 1
125000004429 atom Chemical group 0.000 claims 1
WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical class OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims 1
229940001447 lactate Drugs 0.000 claims 1
VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims 1
REGWVSTWPUXKJS-UHFFFAOYSA-N methyl 2-piperidin-1-ylacetate Chemical compound COC(=O)CN1CCCCC1 REGWVSTWPUXKJS-UHFFFAOYSA-N 0.000 claims 1
NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical class [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims 1
239000010452 phosphate Chemical class 0.000 claims 1
YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 claims 1
229960001860 salicylate Drugs 0.000 claims 1
229940086735 succinate Drugs 0.000 claims 1
KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims 1
IIACRCGMVDHOTQ-UHFFFAOYSA-M sulfamate Chemical compound NS([O-])(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-M 0.000 claims 1
229910021653 sulphate ion Inorganic materials 0.000 claims 1
229940095064 tartrate Drugs 0.000 claims 1
ABMKZZPZLHESEG-UHFFFAOYSA-N tert-butyl 2-[4-[4-(2-bromo-4-methanehydrazonoylphenyl)piperazin-1-yl]piperidin-1-yl]acetate Chemical compound C1CN(CC(=O)OC(C)(C)C)CCC1N1CCN(C=2C(=CC(C=NN)=CC=2)Br)CC1 ABMKZZPZLHESEG-UHFFFAOYSA-N 0.000 claims 1
LTJCGYZHVZQHTN-UHFFFAOYSA-N tert-butyl 2-[4-[4-(4-methanehydrazonoylphenyl)-2-methylpiperazin-1-yl]piperidin-1-yl]acetate Chemical compound CC1CN(C=2C=CC(C=NN)=CC=2)CCN1C1CCN(CC(=O)OC(C)(C)C)CC1 LTJCGYZHVZQHTN-UHFFFAOYSA-N 0.000 claims 1
DSZNMOPZHUMIGZ-UHFFFAOYSA-N tert-butyl 2-[4-[4-[4-(n'-hydroxycarbamimidoyl)phenyl]piperazin-1-yl]piperidin-1-yl]acetate Chemical compound C1CN(CC(=O)OC(C)(C)C)CCC1N1CCN(C=2C=CC(=CC=2)C(\N)=N\O)CC1 DSZNMOPZHUMIGZ-UHFFFAOYSA-N 0.000 claims 1
JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 claims 1
KQTIIICEAUMSDG-UHFFFAOYSA-N tricarballylic acid Chemical compound OC(=O)CC(C(O)=O)CC(O)=O KQTIIICEAUMSDG-UHFFFAOYSA-N 0.000 claims 1
210000001772 blood platelet Anatomy 0.000 abstract description 9
208000010110 spontaneous platelet aggregation Diseases 0.000 abstract description 6
102000008946 Fibrinogen Human genes 0.000 abstract description 4
108010049003 Fibrinogen Proteins 0.000 abstract description 4
150000001242 acetic acid derivatives Chemical class 0.000 abstract description 4
229940012952 fibrinogen Drugs 0.000 abstract description 4
230000001419 dependent effect Effects 0.000 abstract description 2
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 108
239000000543 intermediate Substances 0.000 description 95
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 90
239000007787 solid Substances 0.000 description 84
239000002904 solvent Substances 0.000 description 73
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 66
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 64
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 61
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 55
239000000243 solution Substances 0.000 description 51
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 46
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 45
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 42
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 42
238000010992 reflux Methods 0.000 description 41
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 35
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 34
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 30
-1 ptoluenesulphonates Chemical class 0.000 description 29
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 28
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 26
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 26
239000000377 silicon dioxide Substances 0.000 description 23
VFRSADQPWYCXDG-LEUCUCNGSA-N ethyl (2s,5s)-5-methylpyrrolidine-2-carboxylate;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CCOC(=O)[C@@H]1CC[C@H](C)N1 VFRSADQPWYCXDG-LEUCUCNGSA-N 0.000 description 21
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 21
239000003921 oil Substances 0.000 description 20
235000019198 oils Nutrition 0.000 description 20
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 20
229910052681 coesite Inorganic materials 0.000 description 19
229910052906 cristobalite Inorganic materials 0.000 description 19
229910052682 stishovite Inorganic materials 0.000 description 19
229910052905 tridymite Inorganic materials 0.000 description 19
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 18
238000001819 mass spectrum Methods 0.000 description 18
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 18
239000003054 catalyst Substances 0.000 description 17
239000000741 silica gel Substances 0.000 description 17
229910002027 silica gel Inorganic materials 0.000 description 17
HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 16
GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 15
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
125000003118 aryl group Chemical group 0.000 description 15
239000012267 brine Substances 0.000 description 15
INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 15
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
238000000746 purification Methods 0.000 description 14
229910000029 sodium carbonate Inorganic materials 0.000 description 14
229960000583 acetic acid Drugs 0.000 description 13
238000004458 analytical method Methods 0.000 description 13
239000012044 organic layer Substances 0.000 description 13
USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 12
239000005695 Ammonium acetate Substances 0.000 description 12
229940043376 ammonium acetate Drugs 0.000 description 12
235000019257 ammonium acetate Nutrition 0.000 description 12
JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 12
WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 10
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 10
239000003153 chemical reaction reagent Substances 0.000 description 10
239000000706 filtrate Substances 0.000 description 10
229910000027 potassium carbonate Inorganic materials 0.000 description 10
WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 9
OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 9
150000001409 amidines Chemical group 0.000 description 9
239000002585 base Substances 0.000 description 9
239000000284 extract Substances 0.000 description 9
239000007789 gas Substances 0.000 description 9
229910052763 palladium Inorganic materials 0.000 description 9
239000000843 powder Substances 0.000 description 9
239000011541 reaction mixture Substances 0.000 description 9
229910000030 sodium bicarbonate Inorganic materials 0.000 description 9
239000000725 suspension Substances 0.000 description 9
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 8
150000002148 esters Chemical class 0.000 description 8
238000003818 flash chromatography Methods 0.000 description 8
235000019359 magnesium stearate Nutrition 0.000 description 8
239000001267 polyvinylpyrrolidone Substances 0.000 description 8
229920000036 polyvinylpyrrolidone Polymers 0.000 description 8
235000013855 polyvinylpyrrolidone Nutrition 0.000 description 8
235000017557 sodium bicarbonate Nutrition 0.000 description 8
238000003756 stirring Methods 0.000 description 8
239000008346 aqueous phase Substances 0.000 description 7
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150000007530 organic bases Chemical class 0.000 description 1
MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
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230000002093 peripheral effect Effects 0.000 description 1
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GJQNVZVOTKFLIU-UHFFFAOYSA-N piperidin-1-ium-4-one;chloride Chemical compound Cl.O=C1CCNCC1 GJQNVZVOTKFLIU-UHFFFAOYSA-N 0.000 description 1
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239000002798 polar solvent Substances 0.000 description 1
229910052700 potassium Inorganic materials 0.000 description 1
239000011591 potassium Substances 0.000 description 1
230000003389 potentiating effect Effects 0.000 description 1
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QLULGIRFKAWHOJ-UHFFFAOYSA-N pyridin-4-ylboronic acid Chemical compound OB(O)C1=CC=NC=C1 QLULGIRFKAWHOJ-UHFFFAOYSA-N 0.000 description 1
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YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical class OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 1
150000003902 salicylic acid esters Chemical class 0.000 description 1
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239000013049 sediment Substances 0.000 description 1
239000011734 sodium Substances 0.000 description 1
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239000001509 sodium citrate Substances 0.000 description 1
239000012312 sodium hydride Substances 0.000 description 1
229910000104 sodium hydride Inorganic materials 0.000 description 1
230000003019 stabilising effect Effects 0.000 description 1
239000003381 stabilizer Substances 0.000 description 1
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IIACRCGMVDHOTQ-UHFFFAOYSA-N sulfamic acid Chemical class NS(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 description 1
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239000000375 suspending agent Substances 0.000 description 1
239000006188 syrup Substances 0.000 description 1
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DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 1
VOZUUIODSDMFDF-UHFFFAOYSA-N tert-butyl 2-[4-[4-(5-methanehydrazonoylpyridin-2-yl)piperazin-1-yl]piperidin-1-yl]acetate Chemical compound C1CN(CC(=O)OC(C)(C)C)CCC1N1CCN(C=2N=CC(C=NN)=CC=2)CC1 VOZUUIODSDMFDF-UHFFFAOYSA-N 0.000 description 1
JZXKPSCJKUEPFG-UHFFFAOYSA-N tert-butyl 2-[4-[4-[4-[(benzoylhydrazinylidene)methyl]phenyl]piperazin-1-yl]piperidin-1-yl]acetate Chemical compound C1CN(CC(=O)OC(C)(C)C)CCC1N1CCN(C=2C=CC(C=NNC(=O)C=3C=CC=CC=3)=CC=2)CC1 JZXKPSCJKUEPFG-UHFFFAOYSA-N 0.000 description 1
YDQGKUJOXTYOOT-UHFFFAOYSA-N tert-butyl 2-[4-[4-[5-[(e)-n'-hydroxycarbamimidoyl]pyridin-2-yl]piperazin-1-yl]piperidin-1-yl]acetate Chemical compound C1CN(CC(=O)OC(C)(C)C)CCC1N1CCN(C=2N=CC(=CC=2)C(\N)=N/O)CC1 YDQGKUJOXTYOOT-UHFFFAOYSA-N 0.000 description 1
VXKWYPOMXBVZSJ-UHFFFAOYSA-N tetramethyltin Chemical compound C[Sn](C)(C)C VXKWYPOMXBVZSJ-UHFFFAOYSA-N 0.000 description 1
238000004809 thin layer chromatography Methods 0.000 description 1
238000011200 topical administration Methods 0.000 description 1
230000009466 transformation Effects 0.000 description 1
238000002054 transplantation Methods 0.000 description 1
NHDIQVFFNDKAQU-UHFFFAOYSA-N tripropan-2-yl borate Chemical compound CC(C)OB(OC(C)C)OC(C)C NHDIQVFFNDKAQU-UHFFFAOYSA-N 0.000 description 1
HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
229940038773 trisodium citrate Drugs 0.000 description 1
208000019553 vascular disease Diseases 0.000 description 1
239000003981 vehicle Substances 0.000 description 1
SYOKIDBDQMKNDQ-XWTIBIIYSA-N vildagliptin Chemical compound C1C(O)(C2)CC(C3)CC1CC32NCC(=O)N1CCC[C@H]1C#N SYOKIDBDQMKNDQ-XWTIBIIYSA-N 0.000 description 1
239000011800 void material Substances 0.000 description 1
238000005406 washing Methods 0.000 description 1
239000008215 water for injection Substances 0.000 description 1
230000029663 wound healing Effects 0.000 description 1
229910052725 zinc Inorganic materials 0.000 description 1
239000011701 zinc Substances 0.000 description 1

Classifications

- 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
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom

Landscapes

Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Health & Medical Sciences (AREA)
General Health & Medical Sciences (AREA)
Life Sciences & Earth Sciences (AREA)
General Chemical & Material Sciences (AREA)
Diabetes (AREA)
Animal Behavior & Ethology (AREA)
Medicinal Chemistry (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Engineering & Computer Science (AREA)
Bioinformatics & Cheminformatics (AREA)
Hematology (AREA)
Pharmacology & Pharmacy (AREA)
Chemical Kinetics & Catalysis (AREA)
Public Health (AREA)
Veterinary Medicine (AREA)
Biochemistry (AREA)
Molecular Biology (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Hydrogenated Pyridines (AREA)
Plural Heterocyclic Compounds (AREA)

APAP/P/1992/000447A 1991-11-14 1992-11-13 Piperidine aectate derivatives. AP330A (en)

Applications Claiming Priority (2)

Application Number	Priority Date	Filing Date	Title
GB919124221A GB9124221D0 (en)	1991-11-14	1991-11-14	Chemical compounds
GB929201052A GB9201052D0 (en)	1992-01-16	1992-01-16	Chemical compounds

Publications (2)

Publication Number	Publication Date
AP9200447A0 AP9200447A0 (en)	1993-01-31
AP330A true AP330A (en)	1994-03-30

Family

ID=26299862

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
APAP/P/1992/000447A AP330A (en)	1991-11-14	1992-11-13	Piperidine aectate derivatives.

Country Status (10)

Country	Link
EP (2)	EP0542363A3 (is)
JP (1)	JPH07501063A (is)
CN (1)	CN1073169A (is)
AP (1)	AP330A (is)
AU (1)	AU2915892A (is)
IL (1)	IL103746A0 (is)
IS (1)	IS3945A (is)
MX (1)	MX9206541A (is)
TW (1)	TW221996B (is)
WO (1)	WO1993010091A2 (is)

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Also Published As

Publication number	Publication date
EP0612313A1 (en)	1994-08-31
IS3945A (is)	1993-05-15
EP0542363A3 (en)	1993-07-14
IL103746A0 (en)	1993-04-04
WO1993010091A2 (en)	1993-05-27
AP9200447A0 (en)	1993-01-31
CN1073169A (zh)	1993-06-16
AU2915892A (en)	1993-06-15
MX9206541A (es)	1993-04-01
WO1993010091A3 (en)	1993-06-24
JPH07501063A (ja)	1995-02-02
EP0542363A2 (en)	1993-05-19
TW221996B (is)	1994-04-01

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