HRP950609A2 - Piperazine derivatives, medicaments containing the same, their use and processes for preparing the same - Google Patents

Piperazine derivatives, medicaments containing the same, their use and processes for preparing the same Download PDF

Info

Publication number: HRP950609A2
Authority: HR; Croatia
Prior art keywords: group; alkyl; piperidinyl; piperazin; acid
Prior art date: 1994-12-23

Application number

HR19533639.9A

Other languages

English (en)

Croatian (hr)

Inventor

Helmut Pieper

Volkhard Austel

Frank Himmelsbach

Guenter Linz

Brian Guth

Johannes Weisenberger

Original Assignee

Thomae Gmbh Dr K

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.)

1994-12-23

Filing date

1995-12-20

Publication date

1997-10-31

1994-12-23 Priority claimed from DE19944446301 external-priority patent/DE4446301A1/de

1995-12-20 Application filed by Thomae Gmbh Dr K filed Critical Thomae Gmbh Dr K

1997-10-31 Publication of HRP950609A2 publication Critical patent/HRP950609A2/hr

Links

238000000034 method Methods 0.000 title claims description 11
150000004885 piperazines Chemical class 0.000 title claims description 9
229940066771 systemic antihistamines piperazine derivative Drugs 0.000 title claims description 9
239000003814 drug Substances 0.000 title claims description 5
230000008569 process Effects 0.000 title claims description 3
-1 C1-3-alkoxycarbonyl Chemical group 0.000 claims description 164
125000004744 butyloxycarbonyl group Chemical group 0.000 claims description 159
150000001875 compounds Chemical class 0.000 claims description 103
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 101
QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 93
125000004432 carbon atom Chemical group C* 0.000 claims description 68
125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 67
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 64
125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 62
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 60
238000006243 chemical reaction Methods 0.000 claims description 49
230000002829 reductive effect Effects 0.000 claims description 49
229910052757 nitrogen Inorganic materials 0.000 claims description 43
125000004433 nitrogen atom Chemical group N* 0.000 claims description 42
125000000217 alkyl group Chemical group 0.000 claims description 37
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 35
239000002253 acid Substances 0.000 claims description 32
125000004430 oxygen atom Chemical group O* 0.000 claims description 32
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 32
XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 31
239000000203 mixture Substances 0.000 claims description 29
150000003839 salts Chemical class 0.000 claims description 29
125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 25
125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 25
238000002360 preparation method Methods 0.000 claims description 25
125000000753 cycloalkyl group Chemical group 0.000 claims description 24
229910052740 iodine Inorganic materials 0.000 claims description 24
125000003118 aryl group Chemical group 0.000 claims description 23
125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 21
229910052799 carbon Inorganic materials 0.000 claims description 18
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 18
125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 17
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims description 16
125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 15
125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 14
125000004956 cyclohexylene group Chemical group 0.000 claims description 12
150000002148 esters Chemical class 0.000 claims description 12
238000001727 in vivo Methods 0.000 claims description 12
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 11
125000003545 alkoxy group Chemical group 0.000 claims description 11
125000001841 imino group Chemical group [H]N=* 0.000 claims description 11
235000019260 propionic acid Nutrition 0.000 claims description 11
IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 11
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 10
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 10
125000004076 pyridyl group Chemical group 0.000 claims description 10
230000000269 nucleophilic effect Effects 0.000 claims description 9
125000006705 (C5-C7) cycloalkyl group Chemical group 0.000 claims description 8
125000004955 1,4-cyclohexylene group Chemical group [H]C1([H])C([H])([H])C([H])([*:1])C([H])([H])C([H])([H])C1([H])[*:2] 0.000 claims description 8
125000001140 1,4-phenylene group Chemical group [H]C1=C([H])C([*:2])=C([H])C([H])=C1[*:1] 0.000 claims description 8
235000001014 amino acid Nutrition 0.000 claims description 8
150000001413 amino acids Chemical class 0.000 claims description 8
125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 8
125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 8
150000001602 bicycloalkyls Chemical group 0.000 claims description 8
GCFAUZGWPDYAJN-UHFFFAOYSA-N cyclohexyl 3-phenylprop-2-enoate Chemical compound C=1C=CC=CC=1C=CC(=O)OC1CCCCC1 GCFAUZGWPDYAJN-UHFFFAOYSA-N 0.000 claims description 8
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 7
125000006526 (C1-C2) alkyl group Chemical group 0.000 claims description 6
125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 6
125000002030 1,2-phenylene group Chemical group [H]C1=C([H])C([*:1])=C([*:2])C([H])=C1[H] 0.000 claims description 6
239000005977 Ethylene Substances 0.000 claims description 6
125000002252 acyl group Chemical group 0.000 claims description 6
125000003342 alkenyl group Chemical group 0.000 claims description 6
125000000304 alkynyl group Chemical group 0.000 claims description 6
150000001412 amines Chemical class 0.000 claims description 6
125000003277 amino group Chemical group 0.000 claims description 6
125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 6
229910052794 bromium Inorganic materials 0.000 claims description 6
125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 6
229910052801 chlorine Inorganic materials 0.000 claims description 6
239000000460 chlorine Substances 0.000 claims description 6
125000000392 cycloalkenyl group Chemical group 0.000 claims description 6
125000003884 phenylalkyl group Chemical group 0.000 claims description 6
125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 6
125000001424 substituent group Chemical group 0.000 claims description 6
BNPJOIFXNVGADN-UHFFFAOYSA-N 2-[4-[(4-piperidin-4-ylpiperazine-1-carbonyl)amino]phenoxy]acetic acid Chemical compound C1=CC(OCC(=O)O)=CC=C1NC(=O)N1CCN(C2CCNCC2)CC1 BNPJOIFXNVGADN-UHFFFAOYSA-N 0.000 claims description 5
ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 5
KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 5
125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 5
125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
230000007062 hydrolysis Effects 0.000 claims description 5
238000006460 hydrolysis reaction Methods 0.000 claims description 5
125000006559 (C1-C3) alkylamino group Chemical group 0.000 claims description 4
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 4
101100294102 Caenorhabditis elegans nhr-2 gene Proteins 0.000 claims description 4
125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 4
125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 4
LEQAOMBKQFMDFZ-UHFFFAOYSA-N glyoxal Chemical compound O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 claims description 4
238000004519 manufacturing process Methods 0.000 claims description 4
UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 4
125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 claims description 4
125000006239 protecting group Chemical group 0.000 claims description 4
125000005551 pyridylene group Chemical group 0.000 claims description 4
125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 4
125000006698 (C1-C3) dialkylamino group Chemical group 0.000 claims description 3
125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 3
125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
239000003085 diluting agent Substances 0.000 claims description 3
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
238000007327 hydrogenolysis reaction Methods 0.000 claims description 3
150000007522 mineralic acids Chemical class 0.000 claims description 3
150000007524 organic acids Chemical class 0.000 claims description 3
235000005985 organic acids Nutrition 0.000 claims description 3
238000001149 thermolysis Methods 0.000 claims description 3
125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 2
125000006704 (C5-C6) cycloalkyl group Chemical group 0.000 claims description 2
NDZFNTHGIIQMQI-UHFFFAOYSA-N 1-benzylpyridin-1-ium Chemical group C=1C=CC=C[N+]=1CC1=CC=CC=C1 NDZFNTHGIIQMQI-UHFFFAOYSA-N 0.000 claims description 2
DHQHLYLHMXCVNZ-UHFFFAOYSA-N 3-[1-(4-piperidin-4-ylpiperazine-1-carbonyl)piperidin-4-yl]oxypropanoic acid Chemical compound C1CC(OCCC(=O)O)CCN1C(=O)N1CCN(C2CCNCC2)CC1 DHQHLYLHMXCVNZ-UHFFFAOYSA-N 0.000 claims description 2
HTWMCCBHJPNIGR-UHFFFAOYSA-N 3-[[4-(4-piperidin-4-ylpiperazine-1-carbonyl)piperidin-1-yl]amino]propanoic acid Chemical compound N1CCC(CC1)N1CCN(CC1)C(=O)C1CCN(CC1)NCCC(=O)O HTWMCCBHJPNIGR-UHFFFAOYSA-N 0.000 claims description 2
CMZYQGKFUWWEDM-UHFFFAOYSA-N 4-[1-(4-piperidin-4-ylpiperazine-1-carbonyl)piperidin-4-yl]butanoic acid Chemical compound C1CC(CCCC(=O)O)CCN1C(=O)N1CCN(C2CCNCC2)CC1 CMZYQGKFUWWEDM-UHFFFAOYSA-N 0.000 claims description 2
125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 2
MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 2
PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
150000004260 O,O-acetals Chemical class 0.000 claims description 2
DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 2
125000005236 alkanoylamino group Chemical group 0.000 claims description 2
125000003302 alkenyloxy group Chemical group 0.000 claims description 2
125000005078 alkoxycarbonylalkyl group Chemical group 0.000 claims description 2
125000005036 alkoxyphenyl group Chemical group 0.000 claims description 2
125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 2
125000003282 alkyl amino group Chemical group 0.000 claims description 2
235000008206 alpha-amino acids Nutrition 0.000 claims description 2
125000004391 aryl sulfonyl group Chemical group 0.000 claims description 2
125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
125000004465 cycloalkenyloxy group Chemical group 0.000 claims description 2
125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 2
125000005112 cycloalkylalkoxy group Chemical group 0.000 claims description 2
125000004663 dialkyl amino group Chemical group 0.000 claims description 2
125000004473 dialkylaminocarbonyl group Chemical group 0.000 claims description 2
230000006806 disease prevention Effects 0.000 claims description 2
229940079593 drug Drugs 0.000 claims description 2
FPIQZBQZKBKLEI-UHFFFAOYSA-N ethyl 1-[[2-chloroethyl(nitroso)carbamoyl]amino]cyclohexane-1-carboxylate Chemical compound ClCCN(N=O)C(=O)NC1(C(=O)OCC)CCCCC1 FPIQZBQZKBKLEI-UHFFFAOYSA-N 0.000 claims description 2
125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 2
229910052731 fluorine Inorganic materials 0.000 claims description 2
239000011737 fluorine Substances 0.000 claims description 2
ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 2
229940015043 glyoxal Drugs 0.000 claims description 2
125000003104 hexanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
125000004356 hydroxy functional group Chemical group O* 0.000 claims description 2
230000003993 interaction Effects 0.000 claims description 2
125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 claims description 2
150000002576 ketones Chemical class 0.000 claims description 2
125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 2
125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
229910052760 oxygen Inorganic materials 0.000 claims description 2
239000001301 oxygen Substances 0.000 claims description 2
125000001148 pentyloxycarbonyl group Chemical group 0.000 claims description 2
125000002071 phenylalkoxy group Chemical group 0.000 claims description 2
125000004742 propyloxycarbonyl group Chemical group 0.000 claims description 2
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
229920002554 vinyl polymer Polymers 0.000 claims description 2
239000000969 carrier Substances 0.000 claims 2
BXWVIIXLVUQTCG-UHFFFAOYSA-N 2-[4-[2-(4-piperidin-4-ylpiperazin-1-yl)acetyl]phenoxy]acetic acid Chemical compound C1=CC(OCC(=O)O)=CC=C1C(=O)CN1CCN(C2CCNCC2)CC1 BXWVIIXLVUQTCG-UHFFFAOYSA-N 0.000 claims 1
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 942
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 891
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 312
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 252
239000000741 silica gel Substances 0.000 description 252
229910002027 silica gel Inorganic materials 0.000 description 252
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 159
229910021529 ammonia Inorganic materials 0.000 description 156
238000001819 mass spectrum Methods 0.000 description 147
239000000243 solution Substances 0.000 description 136
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 128
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 119
238000002844 melting Methods 0.000 description 104
230000008018 melting Effects 0.000 description 104
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 102
150000004702 methyl esters Chemical class 0.000 description 86
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 82
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 78
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 75
239000002904 solvent Substances 0.000 description 66
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 65
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 57
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 56
238000000354 decomposition reaction Methods 0.000 description 54
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 52
235000002639 sodium chloride Nutrition 0.000 description 49
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 44
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 41
238000005984 hydrogenation reaction Methods 0.000 description 41
229960000583 acetic acid Drugs 0.000 description 39
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 39
235000019439 ethyl acetate Nutrition 0.000 description 37
239000007787 solid Substances 0.000 description 36
239000000126 substance Substances 0.000 description 35
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 33
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 32
239000001257 hydrogen Substances 0.000 description 32
229910052739 hydrogen Inorganic materials 0.000 description 32
239000011780 sodium chloride Substances 0.000 description 31
239000003054 catalyst Substances 0.000 description 28
239000003921 oil Substances 0.000 description 27
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 26
238000003756 stirring Methods 0.000 description 26
NZNMSOFKMUBTKW-UHFFFAOYSA-N cyclohexanecarboxylic acid Chemical compound OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 description 25
239000012074 organic phase Substances 0.000 description 25
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 24
239000012071 phase Substances 0.000 description 24
DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 22
101000610640 Homo sapiens U4/U6 small nuclear ribonucleoprotein Prp3 Proteins 0.000 description 22
101001110823 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 60S ribosomal protein L6-A Proteins 0.000 description 22
101000712176 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 60S ribosomal protein L6-B Proteins 0.000 description 22
102100040374 U4/U6 small nuclear ribonucleoprotein Prp3 Human genes 0.000 description 22
KXKVLQRXCPHEJC-UHFFFAOYSA-N methyl acetate Chemical compound COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 22
SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 21
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 18
125000004494 ethyl ester group Chemical group 0.000 description 17
229960002449 glycine Drugs 0.000 description 17
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 16
238000010992 reflux Methods 0.000 description 16
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
239000004471 Glycine Substances 0.000 description 15
RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 15
DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 15
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 14
239000012043 crude product Substances 0.000 description 14
239000003480 eluent Substances 0.000 description 14
IHTYTYHXCRAMAV-UHFFFAOYSA-N acetic acid;dihydrochloride Chemical compound Cl.Cl.CC(O)=O IHTYTYHXCRAMAV-UHFFFAOYSA-N 0.000 description 13
239000002585 base Substances 0.000 description 13
238000009835 boiling Methods 0.000 description 13
229910000027 potassium carbonate Inorganic materials 0.000 description 13
239000000725 suspension Substances 0.000 description 13
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 13
WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 12
VZFUCHSFHOYXIS-UHFFFAOYSA-N cycloheptane carboxylic acid Natural products OC(=O)C1CCCCCC1 VZFUCHSFHOYXIS-UHFFFAOYSA-N 0.000 description 12
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238000011065 in-situ storage Methods 0.000 description 1
230000001939 inductive effect Effects 0.000 description 1
239000011261 inert gas Substances 0.000 description 1
150000007529 inorganic bases Chemical class 0.000 description 1
230000008611 intercellular interaction Effects 0.000 description 1
238000001990 intravenous administration Methods 0.000 description 1
PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
239000011630 iodine Substances 0.000 description 1
230000002427 irreversible effect Effects 0.000 description 1
GJRQTCIYDGXPES-UHFFFAOYSA-N isobutyl acetate Chemical compound CC(C)COC(C)=O GJRQTCIYDGXPES-UHFFFAOYSA-N 0.000 description 1
238000002955 isolation Methods 0.000 description 1
239000004310 lactic acid Substances 0.000 description 1
235000014655 lactic acid Nutrition 0.000 description 1
235000019359 magnesium stearate Nutrition 0.000 description 1
VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
239000011976 maleic acid Substances 0.000 description 1
239000001630 malic acid Substances 0.000 description 1
235000011090 malic acid Nutrition 0.000 description 1
229960002510 mandelic acid Drugs 0.000 description 1
239000011159 matrix material Substances 0.000 description 1
229940098779 methanesulfonic acid Drugs 0.000 description 1
UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
KRDTUMQGDPZWMF-UHFFFAOYSA-N methyl 1-aminocyclohexane-1-carboxylate Chemical compound COC(=O)C1(N)CCCCC1 KRDTUMQGDPZWMF-UHFFFAOYSA-N 0.000 description 1
PYSYDGVIWZCWSC-UHFFFAOYSA-N methyl 2-(4-acetylphenyl)acetate Chemical compound COC(=O)CC1=CC=C(C(C)=O)C=C1 PYSYDGVIWZCWSC-UHFFFAOYSA-N 0.000 description 1
RVMIGVAYAAAZBT-UHFFFAOYSA-N methyl 2-(4-aminoanilino)acetate Chemical compound COC(=O)CNC1=CC=C(N)C=C1 RVMIGVAYAAAZBT-UHFFFAOYSA-N 0.000 description 1
PZUTXFJKMUIAKA-UHFFFAOYSA-N methyl 2-(4-benzylpiperazin-1-yl)acetate Chemical compound C1CN(CC(=O)OC)CCN1CC1=CC=CC=C1 PZUTXFJKMUIAKA-UHFFFAOYSA-N 0.000 description 1
QJDVHHUSFFIXCO-UHFFFAOYSA-N methyl 2-[(1-benzylpiperidin-4-yl)-[(2-methylpropan-2-yl)oxycarbonyl]amino]acetate;dihydrochloride Chemical compound Cl.Cl.C1CC(N(CC(=O)OC)C(=O)OC(C)(C)C)CCN1CC1=CC=CC=C1 QJDVHHUSFFIXCO-UHFFFAOYSA-N 0.000 description 1
WQTZUOFFUPMIPZ-UHFFFAOYSA-N methyl 2-[(1-benzylpiperidin-4-yl)-methylamino]acetate;dihydrochloride Chemical compound Cl.Cl.C1CC(N(C)CC(=O)OC)CCN1CC1=CC=CC=C1 WQTZUOFFUPMIPZ-UHFFFAOYSA-N 0.000 description 1
SAQHLMVVQFAKRH-QRPNPIFTSA-N methyl 2-[1-[(2s)-2-aminopropanoyl]piperidin-4-yl]oxyacetate;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.COC(=O)COC1CCN(C(=O)[C@H](C)N)CC1 SAQHLMVVQFAKRH-QRPNPIFTSA-N 0.000 description 1
CMZPKTDCECCYKP-UHFFFAOYSA-N methyl 2-[2-(2-methoxy-2-oxoethoxy)-4-nitrophenoxy]acetate Chemical compound COC(=O)COC1=CC=C([N+]([O-])=O)C=C1OCC(=O)OC CMZPKTDCECCYKP-UHFFFAOYSA-N 0.000 description 1
FKHCPSBMORHQGF-UHFFFAOYSA-N methyl 2-[4-[(4-piperidin-4-yl-2,3,4a,5-tetrahydroquinoxaline-1-carbonyl)amino]phenoxy]acetate Chemical compound C1=CC(OCC(=O)OC)=CC=C1NC(=O)N1C2=CC=CCC2N(C2CCNCC2)CC1 FKHCPSBMORHQGF-UHFFFAOYSA-N 0.000 description 1
DOVAXCATWCGLKB-UHFFFAOYSA-N methyl 2-[4-amino-2-(2-methoxy-2-oxoethoxy)phenoxy]acetate;hydrochloride Chemical compound Cl.COC(=O)COC1=CC=C(N)C=C1OCC(=O)OC DOVAXCATWCGLKB-UHFFFAOYSA-N 0.000 description 1
LIXYDSMWHZOXJJ-UHFFFAOYSA-N methyl 2-[acetyl-(1-benzylpiperidin-4-yl)amino]acetate;hydrochloride Chemical compound Cl.C1CC(N(CC(=O)OC)C(C)=O)CCN1CC1=CC=CC=C1 LIXYDSMWHZOXJJ-UHFFFAOYSA-N 0.000 description 1
VSDUZFOSJDMAFZ-UHFFFAOYSA-N methyl 2-amino-3-phenylpropanoate Chemical compound COC(=O)C(N)CC1=CC=CC=C1 VSDUZFOSJDMAFZ-UHFFFAOYSA-N 0.000 description 1
NFFOXPLOXZDPPD-UHFFFAOYSA-N methyl 3-(4-aminophenyl)propanoate;hydrochloride Chemical compound Cl.COC(=O)CCC1=CC=C(N)C=C1 NFFOXPLOXZDPPD-UHFFFAOYSA-N 0.000 description 1
IPKVQGGDPYOWLK-UHFFFAOYSA-N methyl 3-[acetyl-(1-benzylpiperidin-4-yl)amino]propanoate;hydrochloride Chemical compound Cl.C1CC(N(CCC(=O)OC)C(C)=O)CCN1CC1=CC=CC=C1 IPKVQGGDPYOWLK-UHFFFAOYSA-N 0.000 description 1
BVNFBHOJDPAZAX-UHFFFAOYSA-N methyl 3-piperazin-1-ylpropanoate Chemical compound COC(=O)CCN1CCNCC1 BVNFBHOJDPAZAX-UHFFFAOYSA-N 0.000 description 1
SHYJOEYGNQPMQV-UHFFFAOYSA-N methyl 4-(methoxyamino)benzoate Chemical compound CONC1=CC=C(C(=O)OC)C=C1 SHYJOEYGNQPMQV-UHFFFAOYSA-N 0.000 description 1
LHNNWRSHBMGXCI-UHFFFAOYSA-N methyl acetate;dihydrochloride Chemical compound Cl.Cl.COC(C)=O LHNNWRSHBMGXCI-UHFFFAOYSA-N 0.000 description 1
RZVWBASHHLFBJF-UHFFFAOYSA-N methyl piperidine-4-carboxylate Chemical compound COC(=O)C1CCNCC1 RZVWBASHHLFBJF-UHFFFAOYSA-N 0.000 description 1
239000008108 microcrystalline cellulose Substances 0.000 description 1
235000019813 microcrystalline cellulose Nutrition 0.000 description 1
229940016286 microcrystalline cellulose Drugs 0.000 description 1
238000002156 mixing Methods 0.000 description 1
208000010125 myocardial infarction Diseases 0.000 description 1
GSLWSSUWNCJILM-UHFFFAOYSA-N n,n-dibenzyl-2-chloroethanamine Chemical compound C=1C=CC=CC=1CN(CCCl)CC1=CC=CC=C1 GSLWSSUWNCJILM-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
GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 1
230000010807 negative regulation of binding Effects 0.000 description 1
OTKCDFNVBPBSNB-UHFFFAOYSA-N nitric acid;propane-1,2,3-triol Chemical compound O[N+]([O-])=O.OCC(O)CO OTKCDFNVBPBSNB-UHFFFAOYSA-N 0.000 description 1
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
RXCVUXLCNLVYIA-UHFFFAOYSA-N orthocarbonic acid Chemical compound OC(O)(O)O RXCVUXLCNLVYIA-UHFFFAOYSA-N 0.000 description 1
150000002905 orthoesters Chemical class 0.000 description 1
MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
238000005192 partition Methods 0.000 description 1
WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
229960003424 phenylacetic acid Drugs 0.000 description 1
239000003279 phenylacetic acid Substances 0.000 description 1
239000002571 phosphodiesterase inhibitor Substances 0.000 description 1
125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 1
230000036470 plasma concentration Effects 0.000 description 1
229910003446 platinum oxide Inorganic materials 0.000 description 1
229920001223 polyethylene glycol Polymers 0.000 description 1
239000001267 polyvinylpyrrolidone Substances 0.000 description 1
229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
239000000843 powder Substances 0.000 description 1
230000002265 prevention Effects 0.000 description 1
150000003141 primary amines Chemical class 0.000 description 1
229960000856 protein c Drugs 0.000 description 1
238000000746 purification Methods 0.000 description 1
239000002516 radical scavenger Substances 0.000 description 1
238000011084 recovery Methods 0.000 description 1
238000001953 recrystallisation Methods 0.000 description 1
239000010948 rhodium Substances 0.000 description 1
MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
QBERHIJABFXGRZ-UHFFFAOYSA-M rhodium;triphenylphosphane;chloride Chemical compound [Cl-].[Rh].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 QBERHIJABFXGRZ-UHFFFAOYSA-M 0.000 description 1
LMHHRCOWPQNFTF-UHFFFAOYSA-N s-propan-2-yl azepane-1-carbothioate Chemical compound CC(C)SC(=O)N1CCCCCC1 LMHHRCOWPQNFTF-UHFFFAOYSA-N 0.000 description 1
238000007127 saponification reaction Methods 0.000 description 1
108010073863 saruplase Proteins 0.000 description 1
238000003345 scintillation counting Methods 0.000 description 1
239000013049 sediment Substances 0.000 description 1
230000035939 shock Effects 0.000 description 1
LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 description 1
229910001958 silver carbonate Inorganic materials 0.000 description 1
229910001923 silver oxide Inorganic materials 0.000 description 1
229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
235000017557 sodium bicarbonate Nutrition 0.000 description 1
NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
235000009518 sodium iodide Nutrition 0.000 description 1
238000000638 solvent extraction Methods 0.000 description 1
239000011877 solvent mixture Substances 0.000 description 1
239000000600 sorbitol Substances 0.000 description 1
208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
239000007921 spray Substances 0.000 description 1
239000007858 starting material Substances 0.000 description 1
229960005202 streptokinase Drugs 0.000 description 1
239000005720 sucrose Substances 0.000 description 1
235000000346 sugar Nutrition 0.000 description 1
239000000829 suppository Substances 0.000 description 1
238000003786 synthesis reaction Methods 0.000 description 1
239000003826 tablet Substances 0.000 description 1
RMSFFUYFWWLAGV-UHFFFAOYSA-N tert-butyl 4-(2-methoxy-2-oxoethoxy)piperidine-1-carboxylate Chemical compound COC(=O)COC1CCN(C(=O)OC(C)(C)C)CC1 RMSFFUYFWWLAGV-UHFFFAOYSA-N 0.000 description 1
WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 1
ISXSCDLOGDJUNJ-UHFFFAOYSA-N tert-butyl prop-2-enoate Chemical compound CC(C)(C)OC(=O)C=C ISXSCDLOGDJUNJ-UHFFFAOYSA-N 0.000 description 1
150000003509 tertiary alcohols Chemical class 0.000 description 1
125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
LFQCEHFDDXELDD-UHFFFAOYSA-N tetramethyl orthosilicate Chemical compound CO[Si](OC)(OC)OC LFQCEHFDDXELDD-UHFFFAOYSA-N 0.000 description 1
150000007970 thio esters Chemical class 0.000 description 1
239000003868 thrombin inhibitor Substances 0.000 description 1
230000002537 thrombolytic effect Effects 0.000 description 1
RZWIIPASKMUIAC-VQTJNVASSA-N thromboxane Chemical compound CCCCCCCC[C@H]1OCCC[C@@H]1CCCCCCC RZWIIPASKMUIAC-VQTJNVASSA-N 0.000 description 1
231100000331 toxic Toxicity 0.000 description 1
230000002588 toxic effect Effects 0.000 description 1
230000009466 transformation Effects 0.000 description 1
125000001425 triazolyl group Chemical group 0.000 description 1
YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-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
238000005292 vacuum distillation Methods 0.000 description 1
210000003462 vein Anatomy 0.000 description 1
229940019333 vitamin k antagonists Drugs 0.000 description 1
238000003809 water extraction Methods 0.000 description 1

Classifications

- 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
- 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
- C07D211/34—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 carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Landscapes

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

HR19533639.9A 1994-12-23 1995-12-20 Piperazine derivatives, medicaments containing the same, their use and processes for preparing the same HRP950609A2 (en)

Applications Claiming Priority (3)

Application Number	Priority Date	Filing Date	Title
DE19944446301 DE4446301A1 (de)	1994-12-23	1994-12-23	Piperazinderivate, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung
DE19526678A DE19526678A1 (de)	1994-12-23	1995-07-21	Piperazinderivate, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung
DE1995133639 DE19533639A1 (de)	1994-12-23	1995-09-12	Piperazinderivate, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung

Publications (1)

Publication Number	Publication Date
HRP950609A2 true HRP950609A2 (en)	1997-10-31

Family

ID=27207101

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
HR19533639.9A HRP950609A2 (en)	1994-12-23	1995-12-20	Piperazine derivatives, medicaments containing the same, their use and processes for preparing the same

Country Status (20)

Country	Link
US (1)	US5922717A (fr)
EP (1)	EP0799202A1 (fr)
JP (1)	JPH10511374A (fr)
CN (1)	CN1183770A (fr)
AR (1)	AR002950A1 (fr)
AU (1)	AU4432496A (fr)
BG (1)	BG101582A (fr)
BR (1)	BR9510360A (fr)
CA (1)	CA2207618A1 (fr)
CZ (1)	CZ189197A3 (fr)
EE (1)	EE9700141A (fr)
FI (1)	FI972646L (fr)
HR (1)	HRP950609A2 (fr)
IL (1)	IL116517A0 (fr)
MX (1)	MX9704745A (fr)
NO (1)	NO972881L (fr)
PL (1)	PL321003A1 (fr)
SK (1)	SK79797A3 (fr)
TR (1)	TR199501634A2 (fr)
WO (1)	WO1996020173A1 (fr)

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US5889006A (en) *	1995-02-23	1999-03-30	Schering Corporation	Muscarinic antagonists
JPH11513382A (ja) *	1995-10-20	1999-11-16	ドクトルカルルトーマエゲゼルシャフトミットベシュレンクテルハフツング	５員複素環化合物、これらの化合物を含む医薬品、それらの使用及びそれらの調製方法
UY25225A1 (es)	1997-10-29	2000-12-29	Smithkline Beecham Plc	Derivados de pleuromutilina utiles como agentes antimicrobianos
WO1999052894A1 (fr) *	1998-04-09	1999-10-21	Meiji Seika Kaisha, Ltd.	Composes heterocycliques a base d'azote anti-agregation plaquettaire et leur utilisation medicale
CZ20011872A3 (cs) *	1999-09-29	2002-03-13	Ortho-Mcneil Pharmaceutical, Inc.	Isonipekotamidy pro léčbu onemocnění zprostředkovaných integriny
EP1533310A1 (fr) *	1999-09-29	2005-05-25	Ortho-McNeil Pharmaceutical, Inc.	isonipecotamides destinées au traitement de maladies provoquées par l'integrine
GB9923748D0 (en)	1999-10-07	1999-12-08	Glaxo Group Ltd	Chemical compounds
USRE39921E1 (en)	1999-10-07	2007-11-13	Smithkline Beecham Corporation	Chemical compounds
GB0025354D0 (en)	2000-10-17	2000-11-29	Glaxo Group Ltd	Chemical compounds
EP1389205B1 (fr) *	2001-04-09	2005-12-21	Ortho-McNeil Pharmaceutical Research Inc.	Quinazoline et composes similaires a la quinazoline pour traiter des troubles dus a l'integrine
US7763620B2 (en)	2001-08-24	2010-07-27	Yale University	Piperazinone compounds as anti-tumor and anti-cancer agents and methods of treatment
FR2829766A1 (fr) *	2001-09-14	2003-03-21	Lipha	Derives d'oxamates comportant un heterocycle azote diversement substitue
GB0203022D0 (en)	2002-02-08	2002-03-27	Glaxo Group Ltd	Chemical compounds
GB0203020D0 (en)	2002-02-08	2002-03-27	Glaxo Group Ltd	Chemical compounds
WO2003066589A1 (fr)	2002-02-08	2003-08-14	Glaxo Group Limited	Derives piperidylcarboxamide, et leur utilisation dans le traitement des maladies dont la mediation est assuree par les tachykinines
CA2558585C (fr) *	2004-02-27	2010-10-12	Amgen Inc.	Composes, compositions pharmaceutiques et procedes d'utilisation dans le traitement de troubles metaboliques
US7851474B2 (en) *	2005-08-02	2010-12-14	Neurogen Corporation	Dipiperazinyl ketones and related analogues
AU2006309050B2 (en)	2005-10-28	2012-08-16	Merck Sharp & Dohme Corp.	Piperidine glycine transporter inhibitors
AU2007265467C1 (en)	2006-06-28	2013-11-07	Amgen Inc.	Glycine transporter-1 inhibitors
WO2008013622A2 (fr) *	2006-07-27	2008-01-31	E. I. Du Pont De Nemours And Company	Amides azocycliques fongicides
US9090604B2 (en)	2006-07-27	2015-07-28	E I Du Pont De Nemours And Company	Fungicidal azocyclic amides
EP2397477B1 (fr) *	2007-01-16	2014-03-05	Purdue Pharma LP	Composés de pipéridine hétérocycliques substitués et leurs utilisations
MY150602A (en)	2007-08-31	2014-01-30	Purdue Pharma Lp	Subtituted-quinoxaline-type piperidine compounds and the uses thereof
WO2010081851A1 (fr)	2009-01-14	2010-07-22	Genoscience Pharma	Composés de pipéridin-4-ylpipérazine pour le traitement d'une infection à vhc
EP2723718A1 (fr)	2011-06-24	2014-04-30	Amgen Inc.	Antagonistes de trpm8 et leur utilisation dans le cadre thérapeutique
JP2014527511A (ja)	2011-06-24	2014-10-16	アムジエン・インコーポレーテツド	Ｔｒｐｍ８拮抗剤及び治療におけるそれらの使用
CN104334541A (zh) *	2012-02-16	2015-02-04	纽约大学	使用低聚氧代哌嗪非肽螺旋模拟物对低氧诱导基因表达的控制
US8952009B2 (en)	2012-08-06	2015-02-10	Amgen Inc.	Chroman derivatives as TRPM8 inhibitors
WO2014113794A2 (fr)	2013-01-19	2014-07-24	New York University	Oligooxopipérazines pour la réactivation du p53
US10787424B2 (en)	2014-05-21	2020-09-29	New York University	Oxopiperazine helix mimetics for control of Hypoxia-Inducible gene expression
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DE4035961A1 (de) *	1990-11-02	1992-05-07	Thomae Gmbh Dr K	Cyclische iminoderivate, diese verbindungen enthaltende arzneimittel und verfahren zu ihrer herstellung
DE4213919A1 (de) *	1992-04-28	1993-11-04	Thomae Gmbh Dr K	Cyclische iminoderivate, verfahren zu ihrer herstellung und diese verbindungen enthaltende arzneimittel
DE4332168A1 (de) *	1993-02-22	1995-03-23	Thomae Gmbh Dr K	Cyclische Derivate, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung
EP0690847A1 (fr) *	1993-03-29	1996-01-10	Zeneca Limited	Composes heterocycliques en tant qu'inhibiteurs de l'agregation plaquettaire
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DE4324580A1 (de) *	1993-07-22	1995-01-26	Thomae Gmbh Dr K	Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung
DE4326344A1 (de) *	1993-08-05	1995-02-09	Thomae Gmbh Dr K	Carbonamide, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung
US5814636A (en) *	1994-07-15	1998-09-29	Meiji Seika Kabushiki Kaisha	Compounds with platelet aggregation inhibitor activity
IL115420A0 (en) *	1994-09-26	1995-12-31	Zeneca Ltd	Aminoheterocyclic derivatives

1995
- 1995-12-19 EP EP95943168A patent/EP0799202A1/fr not_active Withdrawn
- 1995-12-19 SK SK797-97A patent/SK79797A3/sk unknown
- 1995-12-19 FI FI972646A patent/FI972646L/fi not_active Application Discontinuation
- 1995-12-19 JP JP8520188A patent/JPH10511374A/ja active Pending
- 1995-12-19 WO PCT/EP1995/005031 patent/WO1996020173A1/fr not_active Ceased
- 1995-12-19 EE EE9700141A patent/EE9700141A/xx unknown
- 1995-12-19 CZ CZ971891A patent/CZ189197A3/cs unknown
- 1995-12-19 BR BR9510360A patent/BR9510360A/pt not_active Application Discontinuation
- 1995-12-19 CN CN95196854A patent/CN1183770A/zh active Pending
- 1995-12-19 PL PL95321003A patent/PL321003A1/xx unknown
- 1995-12-19 MX MX9704745A patent/MX9704745A/es unknown
- 1995-12-19 CA CA002207618A patent/CA2207618A1/fr not_active Abandoned
- 1995-12-19 AU AU44324/96A patent/AU4432496A/en not_active Abandoned
- 1995-12-20 HR HR19533639.9A patent/HRP950609A2/hr not_active Application Discontinuation
- 1995-12-21 US US08/576,528 patent/US5922717A/en not_active Expired - Fee Related
- 1995-12-21 TR TR95/01634A patent/TR199501634A2/xx unknown
- 1995-12-22 AR ARP950100727A patent/AR002950A1/es unknown
- 1995-12-22 IL IL11651795A patent/IL116517A0/xx unknown
1997
- 1997-06-06 BG BG101582A patent/BG101582A/xx unknown
- 1997-06-20 NO NO972881A patent/NO972881L/no unknown

Also Published As

Publication number	Publication date
FI972646A7 (fi)	1997-08-19
NO972881D0 (no)	1997-06-20
TR199501634A2 (tr)	1996-07-21
SK79797A3 (en)	1997-11-05
AU4432496A (en)	1996-07-19
FI972646A0 (fi)	1997-06-19
PL321003A1 (en)	1997-11-24
FI972646L (fi)	1997-08-19
EE9700141A (et)	1997-12-15
CN1183770A (zh)	1998-06-03
JPH10511374A (ja)	1998-11-04
IL116517A0 (en)	1996-03-31
WO1996020173A1 (fr)	1996-07-04
NO972881L (no)	1997-06-20
MX9704745A (es)	1997-10-31
BR9510360A (pt)	1997-12-23
AR002950A1 (es)	1998-05-27
US5922717A (en)	1999-07-13
CA2207618A1 (fr)	1996-07-04
CZ189197A3 (cs)	1998-01-14
EP0799202A1 (fr)	1997-10-08
BG101582A (bg)	1998-01-30

Legal Events

Date	Code	Title	Description
1997-10-31	A1OB	Publication of a patent application
1999-03-04	ODBC	Application rejected

Publication	Publication Date	Title
HRP950609A2 (en)	1997-10-31	Piperazine derivatives, medicaments containing the same, their use and processes for preparing the same
US5700801A (en)	1997-12-23	Piperazine derivatives, pharmaceutical compositions containing these compounds, their use and processes for preparing them
SK107293A3 (en)	1994-08-10	Carboxylic acid derivatives, drugs containing these compounds and method of their production
US5994356A (en)	1999-11-30	Carboxylic acid derivatives, medicaments comprising these compounds, their use and processes for their production
US4791102A (en)	1988-12-13	Derivatives of the N α-arylsulphonylaminoacyl-p-amidinophenylalaninamides, their preparation process, their use as medicaments and the pharmaceutical compositions containing them
WO1997015567A1 (fr)	1997-05-01	Heterocycles a 5 chainons, medicaments contenant ces composes, utilisation et procede de production correspondants
EP0608858A1 (fr)	1994-08-03	Dérivés hétérocycliques à 5 chaînons comme inhibiteurs d'aguégation
US20020183316A1 (en)	2002-12-05	Amidoalkyl-piperidine and amidoalkyl-piperazine derivatives useful for the treatment of nervous system disorders
DE4219158A1 (de)	1993-12-16	Biphenylderivate, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung
DE19533639A1 (de)	1997-03-13	Piperazinderivate, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung
AU703946B2 (en)	1999-04-01	Substituted phenylamidines, pharmaceutical compositions containing these compounds and processes for preparing them
DE19548798A1 (de)	1997-07-03	5-gliedrige Heterocyclen, diese Verbindungen enthaltende Arzneimittel und deren Verwendung sowie Verfahren zu ihrer Herstellung
ES2199587T3 (es)	2004-02-16	Fenilamidinas sustituidas con efecto antitrombotico.
ES2348290T3 (es)	2010-12-02	Amidas n-(4-ariloxipiperidin-1-ilalquil) cinámicas como antagonistas del receptor de ccr3-3.
DE19533224A1 (de)	1997-03-13	Piperazinderivate, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung
DE19607436A1 (de)	1997-09-04	Carbonsäurederivate, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung
CA2244860A1 (fr)	1997-10-16	Derives d'acides carboxyliques a effet inhibant l'agregation
WO2004013128A1 (fr)	2004-02-12	Nouveaux carboxamides substitues, leur production et leur utilisation en tant que medicaments
JPS59500963A (ja)	1984-05-31	新規フェニルオキソアルキルピペリジン、その製法並びにこれらを含む薬理組成物
DE4424974A1 (de)	1996-01-18	Harnstoff- und Carbaminsäurederivate, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung
WO2004013115A2 (fr)	2004-02-12	Nouveaux carboxamides, leur production et leur utilisation en tant que medicaments