IL96531A - History of Acid N- (Diomeric-H1-Pyrolo] D-2,3 [Pyrimidine-3-Ilacyl (-glutamic, preparation and pharmaceutical preparations containing them) - Google Patents

History of Acid N- (Diomeric-H1-Pyrolo] D-2,3 [Pyrimidine-3-Ilacyl (-glutamic, preparation and pharmaceutical preparations containing them)

Info

Publication number: IL96531A
Authority: IL; Israel
Prior art keywords: hydroxy; pyrrolo; hydrogen; ethyl; pyrimidin
Prior art date: 1989-12-11

Application number

IL9653190A

Other languages

English (en)

Hebrew (he)

Other versions

IL96531A0 (en

Original Assignee

Univ Princeton

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.)

1989-12-11

Filing date

1990-12-04

Publication date

1995-08-31

Family has litigation

First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=27503964&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=IL96531(A) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.

1990-05-24 Priority claimed from US07/528,805 external-priority patent/US4996206A/en

1990-12-04 Application filed by Univ Princeton filed Critical Univ Princeton

1991-09-16 Publication of IL96531A0 publication Critical patent/IL96531A0/xx

1995-08-31 Publication of IL96531A publication Critical patent/IL96531A/en

Links

238000002360 preparation method Methods 0.000 title claims description 8
239000008194 pharmaceutical composition Substances 0.000 title claims description 5
-1 chloro, fluoro, methyl Chemical group 0.000 claims description 122
150000001875 compounds Chemical class 0.000 claims description 111
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 70
229910052739 hydrogen Inorganic materials 0.000 claims description 41
239000001257 hydrogen Substances 0.000 claims description 41
229960002989 glutamic acid Drugs 0.000 claims description 37
125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 34
238000000034 method Methods 0.000 claims description 28
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 24
125000006239 protecting group Chemical group 0.000 claims description 24
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 20
125000004432 carbon atom Chemical group C* 0.000 claims description 17
125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 17
150000003839 salts Chemical class 0.000 claims description 15
206010028980 Neoplasm Diseases 0.000 claims description 13
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 13
230000005764 inhibitory process Effects 0.000 claims description 10
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 10
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 10
125000000217 alkyl group Chemical group 0.000 claims description 9
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 9
WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 8
229910052799 carbon Inorganic materials 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 7
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
230000008569 process Effects 0.000 claims description 7
150000001721 carbon Chemical group 0.000 claims description 6
125000004356 hydroxy functional group Chemical group O* 0.000 claims description 6
108010022394 Threonine synthase Proteins 0.000 claims description 5
125000001989 1,3-phenylene group Chemical group [H]C1=C([H])C([*:1])=C([H])C([*:2])=C1[H] 0.000 claims description 4
WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims description 4
102000005497 Thymidylate Synthase Human genes 0.000 claims description 4
125000005236 alkanoylamino group Chemical group 0.000 claims description 4
238000005859 coupling reaction Methods 0.000 claims description 4
235000013922 glutamic acid Nutrition 0.000 claims description 4
239000004220 glutamic acid Substances 0.000 claims description 4
230000012010 growth Effects 0.000 claims description 4
241000124008 Mammalia Species 0.000 claims description 3
125000004423 acyloxy group Chemical group 0.000 claims description 3
239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 3
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
150000001768 cations Chemical class 0.000 claims description 2
230000008878 coupling Effects 0.000 claims description 2
238000010168 coupling process Methods 0.000 claims description 2
239000003937 drug carrier Substances 0.000 claims 1
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 54
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 48
125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 46
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 25
239000000203 mixture Substances 0.000 description 22
125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 20
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 19
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 17
FDGQSTZJBFJUBT-UHFFFAOYSA-N hypoxanthine Chemical compound O=C1NC=NC2=C1NC=N2 FDGQSTZJBFJUBT-UHFFFAOYSA-N 0.000 description 17
229940049906 glutamate Drugs 0.000 description 15
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 14
230000002401 inhibitory effect Effects 0.000 description 14
DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 description 13
CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 13
IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 13
239000007787 solid Substances 0.000 description 13
229940104230 thymidine Drugs 0.000 description 13
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
150000002431 hydrogen Chemical group 0.000 description 11
239000000243 solution Substances 0.000 description 11
KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 10
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 10
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
238000001914 filtration Methods 0.000 description 10
238000012360 testing method Methods 0.000 description 10
UGQMRVRMYYASKQ-UHFFFAOYSA-N Hypoxanthine nucleoside Natural products OC1C(O)C(CO)OC1N1C(NC=NC2=O)=C2N=C1 UGQMRVRMYYASKQ-UHFFFAOYSA-N 0.000 description 9
230000015572 biosynthetic process Effects 0.000 description 9
210000004027 cell Anatomy 0.000 description 9
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
230000002829 reductive effect Effects 0.000 description 8
239000000741 silica gel Substances 0.000 description 8
229910002027 silica gel Inorganic materials 0.000 description 8
229940126062 Compound A Drugs 0.000 description 7
IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 7
NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 7
239000003054 catalyst Substances 0.000 description 7
239000011541 reaction mixture Substances 0.000 description 7
238000010992 reflux Methods 0.000 description 7
OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 6
OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 6
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
229960000583 acetic acid Drugs 0.000 description 6
WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 6
238000004587 chromatography analysis Methods 0.000 description 6
229930195712 glutamate Natural products 0.000 description 6
238000005984 hydrogenation reaction Methods 0.000 description 6
238000001727 in vivo Methods 0.000 description 6
239000003112 inhibitor Substances 0.000 description 6
239000000543 intermediate Substances 0.000 description 6
229910052763 palladium Inorganic materials 0.000 description 6
239000000047 product Substances 0.000 description 6
LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 6
239000002904 solvent Substances 0.000 description 6
238000003786 synthesis reaction Methods 0.000 description 6
229940086542 triethylamine Drugs 0.000 description 6
RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
229910021595 Copper(I) iodide Inorganic materials 0.000 description 5
XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Natural products P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 5
YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 5
230000010261 cell growth Effects 0.000 description 5
LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 5
OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 5
238000000338 in vitro Methods 0.000 description 5
229910052757 nitrogen Inorganic materials 0.000 description 5
125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 5
150000003003 phosphines Chemical class 0.000 description 5
229910000073 phosphorus hydride Inorganic materials 0.000 description 5
239000000126 substance Substances 0.000 description 5
125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 4
102000004190 Enzymes Human genes 0.000 description 4
108090000790 Enzymes Proteins 0.000 description 4
LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 4
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
231100000135 cytotoxicity Toxicity 0.000 description 4
230000003013 cytotoxicity Effects 0.000 description 4
239000012362 glacial acetic acid Substances 0.000 description 4
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
239000000377 silicon dioxide Substances 0.000 description 4
DVNYTAVYBRSTGK-UHFFFAOYSA-N 5-aminoimidazole-4-carboxamide Chemical compound NC(=O)C=1N=CNC=1N DVNYTAVYBRSTGK-UHFFFAOYSA-N 0.000 description 3
ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
JJTNLWSCFYERCK-UHFFFAOYSA-N 7h-pyrrolo[2,3-d]pyrimidine Chemical compound N1=CN=C2NC=CC2=C1 JJTNLWSCFYERCK-UHFFFAOYSA-N 0.000 description 3
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical class C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 3
KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 3
239000002253 acid Substances 0.000 description 3
125000002252 acyl group Chemical group 0.000 description 3
238000006243 chemical reaction Methods 0.000 description 3
125000004122 cyclic group Chemical group 0.000 description 3
230000000694 effects Effects 0.000 description 3
238000001704 evaporation Methods 0.000 description 3
230000008020 evaporation Effects 0.000 description 3
239000000706 filtrate Substances 0.000 description 3
235000019152 folic acid Nutrition 0.000 description 3
239000011724 folic acid Substances 0.000 description 3
229910052740 iodine Inorganic materials 0.000 description 3
239000011777 magnesium Substances 0.000 description 3
IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 3
PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 3
238000001953 recrystallisation Methods 0.000 description 3
159000000000 sodium salts Chemical class 0.000 description 3
229910052717 sulfur Inorganic materials 0.000 description 3
230000004614 tumor growth Effects 0.000 description 3
FBMZEITWVNHWJW-UHFFFAOYSA-N 1,7-dihydropyrrolo[2,3-d]pyrimidin-4-one Chemical compound OC1=NC=NC2=C1C=CN2 FBMZEITWVNHWJW-UHFFFAOYSA-N 0.000 description 2
LFZJRTMTKGYJRS-UHFFFAOYSA-N 1-chloro-4-ethynylbenzene Chemical compound ClC1=CC=C(C#C)C=C1 LFZJRTMTKGYJRS-UHFFFAOYSA-N 0.000 description 2
PTRUTZFCVFUTMW-UHFFFAOYSA-N 1-ethynyl-3-fluorobenzene Chemical compound FC1=CC=CC(C#C)=C1 PTRUTZFCVFUTMW-UHFFFAOYSA-N 0.000 description 2
QXSWHQGIEKUBAS-UHFFFAOYSA-N 1-ethynyl-4-fluorobenzene Chemical compound FC1=CC=C(C#C)C=C1 QXSWHQGIEKUBAS-UHFFFAOYSA-N 0.000 description 2
VKUSYWHFVAFWSN-UHFFFAOYSA-N 2,2-dimethyl-n-(4-oxo-1,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)propanamide Chemical compound N1=CNC2=NC(NC(=O)C(C)(C)C)=CC2=C1O VKUSYWHFVAFWSN-UHFFFAOYSA-N 0.000 description 2
125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 2
HQAXHIGPGBPPFU-UHFFFAOYSA-N 2-prop-2-ynoxyoxane Chemical compound C#CCOC1CCCCO1 HQAXHIGPGBPPFU-UHFFFAOYSA-N 0.000 description 2
KSZVOXHGCKKOLL-UHFFFAOYSA-N 4-Ethynyltoluene Chemical compound CC1=CC=C(C#C)C=C1 KSZVOXHGCKKOLL-UHFFFAOYSA-N 0.000 description 2
QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
108091003079 Bovine Serum Albumin Proteins 0.000 description 2
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
102100024746 Dihydrofolate reductase Human genes 0.000 description 2
QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 2
241001465754 Metazoa Species 0.000 description 2
OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 2
208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 2
239000012980 RPMI-1640 medium Substances 0.000 description 2
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
230000002378 acidificating effect Effects 0.000 description 2
125000003545 alkoxy group Chemical group 0.000 description 2
125000005907 alkyl ester group Chemical group 0.000 description 2
125000003277 amino group Chemical group 0.000 description 2
230000001399 anti-metabolic effect Effects 0.000 description 2
239000002585 base Substances 0.000 description 2
208000035269 cancer or benign tumor Diseases 0.000 description 2
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
GGRHYQCXXYLUTL-UHFFFAOYSA-N chloromethyl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OCCl GGRHYQCXXYLUTL-UHFFFAOYSA-N 0.000 description 2
YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 2
239000003814 drug Substances 0.000 description 2
QUPDWYMUPZLYJZ-UHFFFAOYSA-N ethyl Chemical compound C[CH2] QUPDWYMUPZLYJZ-UHFFFAOYSA-N 0.000 description 2
239000012091 fetal bovine serum Substances 0.000 description 2
229960000304 folic acid Drugs 0.000 description 2
150000002224 folic acids Chemical class 0.000 description 2
125000002541 furyl group Chemical group 0.000 description 2
150000002306 glutamic acid derivatives Chemical class 0.000 description 2
125000000268 heptanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
VPFMEXRVUOPYRG-UHFFFAOYSA-N hex-5-ynoic acid Chemical compound OC(=O)CCCC#C VPFMEXRVUOPYRG-UHFFFAOYSA-N 0.000 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 description 2
IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
229910000041 hydrogen chloride Inorganic materials 0.000 description 2
238000007912 intraperitoneal administration Methods 0.000 description 2
239000011630 iodine Substances 0.000 description 2
208000032839 leukemia Diseases 0.000 description 2
208000003747 lymphoid leukemia Diseases 0.000 description 2
230000007246 mechanism Effects 0.000 description 2
230000002503 metabolic effect Effects 0.000 description 2
JPGRSTBIEYGVNO-UHFFFAOYSA-N methyl 4-ethynylbenzoate Chemical compound COC(=O)C1=CC=C(C#C)C=C1 JPGRSTBIEYGVNO-UHFFFAOYSA-N 0.000 description 2
229910000510 noble metal Inorganic materials 0.000 description 2
NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].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.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 2
150000004943 pyrrolo[2,3-d]pyrimidines Chemical class 0.000 description 2
230000002441 reversible effect Effects 0.000 description 2
125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 2
239000012312 sodium hydride Substances 0.000 description 2
229910000104 sodium hydride Inorganic materials 0.000 description 2
239000011550 stock solution Substances 0.000 description 2
239000000758 substrate Substances 0.000 description 2
FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
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Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
- 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
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/582—Recycling of unreacted starting or intermediate materials

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

IL9653190A 1989-12-11 1990-12-04 History of Acid N- (Diomeric-H1-Pyrolo] D-2,3 [Pyrimidine-3-Ilacyl (-glutamic, preparation and pharmaceutical preparations containing them) IL96531A (en)

Applications Claiming Priority (4)

Application Number	Priority Date	Filing Date	Title
US44874289A	1989-12-11	1989-12-11
US47965590A	1990-02-08	1990-02-08
US07/528,805 US4996206A (en)	1989-12-11	1990-05-24	N-(pyrrolo[2,3-d]pyrimidin-3-ylacyl)-glutamic acid derivatives
US07/528,155 US5028608A (en)	1989-12-11	1990-05-24	N-(6-Amino-(pyrrolo(2,3-d)pyrimidin-3-ylacyl) )-glutamic acid derivatives

Publications (2)

Publication Number	Publication Date
IL96531A0 IL96531A0 (en)	1991-09-16
IL96531A true IL96531A (en)	1995-08-31

Family

ID=27503964

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
IL9653190A IL96531A (en)	1989-12-11	1990-12-04	History of Acid N- (Diomeric-H1-Pyrolo] D-2,3 [Pyrimidine-3-Ilacyl (-glutamic, preparation and pharmaceutical preparations containing them)

Country Status (22)

Country	Link
EP (1)	EP0432677B1 (de)
JP (1)	JP3016876B2 (de)
CN (1)	CN1030608C (de)
AR (1)	AR245129A1 (de)
AT (1)	ATE135007T1 (de)
AU (1)	AU640182B2 (de)
CA (1)	CA2031890C (de)
CY (1)	CY2076B1 (de)
DE (2)	DE69025723T2 (de)
DK (1)	DK0432677T3 (de)
ES (1)	ES2084639T4 (de)
GR (1)	GR3019784T3 (de)
HK (1)	HK1000920A1 (de)
HU (1)	HU218483B (de)
IE (1)	IE904445A1 (de)
IL (1)	IL96531A (de)
LU (1)	LU91147I2 (de)
NL (1)	NL300181I2 (de)
NZ (1)	NZ236385A (de)
PT (1)	PT96140B (de)
RU (1)	RU2057131C9 (de)
SG (1)	SG48098A1 (de)

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EP2316468A1 (de)	2002-02-22	2011-05-04	Shire LLC	Abgabesystem und Verfahren zum Schutz und zur Verabreichung von Dextroamphetamin
CN100344615C (zh) *	2004-11-25	2007-10-24	重庆医药工业研究院有限责任公司	制备N－(吡咯并[2,3－d]嘧啶－5－基)酰基谷氨酸衍生物的方法及中间体
CN101146532B (zh)	2005-01-21	2012-05-09	阿斯泰克斯治疗有限公司	药物化合物
EP2270012A1 (de)	2006-08-14	2011-01-05	Sicor, Inc.	Kristalline Formen von Pemetrexed-Disäure und Herstellungsverfahren dafür
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JP2008543975A (ja)	2006-08-14	2008-12-04	シコールインコーポレイティド	高度に純粋なペメトレキセド二酸およびその調製方法
KR101083230B1 (ko)	2006-08-14	2011-11-11	시코르, 인크.	페메트렉세드 이산의 동결 건조된 약학적 허용염의 제조 방법
EP2073807A1 (de)	2006-10-12	2009-07-01	Astex Therapeutics Limited	Pharmazeutische kombinationen
WO2008044041A1 (en)	2006-10-12	2008-04-17	Astex Therapeutics Limited	Pharmaceutical combinations
CN101417998B (zh)	2007-10-24	2012-10-24	重庆医药工业研究院有限责任公司	一种培美曲塞盐的纯化方法
ME02273B (me) *	2008-06-06	2016-02-20	Boehringer Ingelheim Int	Farmaceutska kombinacija
AU2015210337B2 (en) *	2008-06-06	2017-02-02	Boehringer Ingelheim International Gmbh	Pharmaceutical combination
CN101684121B (zh) *	2008-09-22	2013-04-03	重庆医药工业研究院有限责任公司	培美曲塞二酸的新晶型及其制备方法
EP2504341A1 (de)	2009-11-24	2012-10-03	Azad Pharmaceutical Ingredients AG	Neue kristalline form von pemetrexed-dinatrium
EP3210629A1 (de)	2012-05-30	2017-08-30	Fresenius Kabi Oncology Ltd	Pharmazeutische zusammensetzungen aus pemetrexed
ITRM20120398A1 (it)	2012-08-08	2014-02-09	Berlin Chemie Ag	Procedimento di sintesi pemetrexed e suo sale di lisina.
US20160051679A1 (en)	2013-04-12	2016-02-25	Actavis Group Ptc Ehf.	Pemetrexed Formulation
WO2014185797A1 (en)	2013-05-17	2014-11-20	Instytut Farmaceutyczny	Process for the preparation of high purity amorphous pemetrexed disodium and crystalline forms of n-[4-[2-(2-amino-4,7-dihydro-4-oxo-3h-pyrrolo[2,3- d] pyrimidin-5-yl)ethyl] benzoyl]-l-glutamic acid
US20160145260A1 (en)	2013-06-14	2016-05-26	Synthon B.V.	Stable pemetrexed arginine salt and compositions comprising it
EP3021849B1 (de) *	2013-07-16	2019-10-09	Dr. Reddy's Laboratories Ltd.	Neuartige kristalline formen von pemetrexed-tromethamin-salzen
NZ630292A (en)	2013-11-25	2015-02-27	Shilpa Medicare Ltd	Process for crystalline pemetrexed dipotassium salt
PT3206666T (pt)	2014-10-16	2020-03-11	Synthon Bv	Composição farmacêutica líquida compreendendo pemetrexedo
CN104672241B (zh) *	2015-01-29	2018-04-24	王磊	吡咯并[2,3-d]嘧啶类化合物及其用途
FR3037956B1 (fr) *	2015-06-23	2017-08-04	Servier Lab	Nouveaux derives d'acide amine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
ES3057783T3 (en)	2016-03-15	2026-03-04	Oryzon Genomics Sa	Combinations of lsd1 inhibitors for use in the treatment of neoplastic diseases
EP3675864A4 (de) *	2017-08-31	2022-02-16	Duquesne University of The Holy Spirit	Erste vertreter von shmt2- und mthfd2-inhibitoren als antitumormittel
CN110305137A (zh) *	2018-03-20	2019-10-08	鲁南制药集团股份有限公司	一种培美曲塞二钠中间体及其制备方法
CN110305134B (zh) *	2018-03-20	2022-02-22	鲁南制药集团股份有限公司	一种培美曲塞二钠中间体及其制备方法
CN110305136A (zh) *	2018-03-20	2019-10-08	鲁南制药集团股份有限公司	一种培美曲塞二钠中间体及其制备方法
CN110305135B (zh) *	2018-03-20	2022-02-22	鲁南制药集团股份有限公司	一种培美曲塞二钠中间体及其制备方法

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US4818819A (en) *	1986-10-20	1989-04-04	The Trustees Of Princeton University	Process for the preparation of fused pyridine compounds
NO169490C (no) *	1988-03-24	1992-07-01	Takeda Chemical Industries Ltd	Analogifremgangsmaate for fremstilling av terapeutisk aktive pyrrolopyrimidinderivater
DK172753B1 (da) *	1988-05-25	1999-06-28	Lilly Co Eli	N-(5,6,7,8-tetrahydropyrido[2,3--d]pyrimidin-6-yl-alkanoyl)-glutaminsyrederivater, deres anvendelse, farmaceutiske præparat
US4883799A (en) *	1988-06-29	1989-11-28	The Trustees Of Princeton University	N-(4-(1-hydroxy-3-(5,6,7,8-tetrahydropyrido(2,3,-d)-pyrimidin-6-yl)prop-2-yl)benzoyl)glutamic acid derivatives

1990
- 1990-12-04 IL IL9653190A patent/IL96531A/en active Protection Beyond IP Right Term
- 1990-12-05 AU AU67791/90A patent/AU640182B2/en not_active Expired
- 1990-12-07 NZ NZ236385A patent/NZ236385A/en unknown
- 1990-12-10 SG SG1996007025A patent/SG48098A1/en unknown
- 1990-12-10 DK DK90123671.1T patent/DK0432677T3/da active
- 1990-12-10 PT PT96140A patent/PT96140B/pt not_active IP Right Cessation
- 1990-12-10 AR AR90318580A patent/AR245129A1/es active
- 1990-12-10 AT AT90123671T patent/ATE135007T1/de active
- 1990-12-10 DE DE69025723T patent/DE69025723T2/de not_active Expired - Lifetime
- 1990-12-10 DE DE200512000012 patent/DE122005000012I2/de active Active
- 1990-12-10 IE IE444590A patent/IE904445A1/en not_active IP Right Cessation
- 1990-12-10 CA CA002031890A patent/CA2031890C/en not_active Expired - Lifetime
- 1990-12-10 HU HU147/90A patent/HU218483B/hu unknown
- 1990-12-10 EP EP90123671A patent/EP0432677B1/de not_active Expired - Lifetime
- 1990-12-10 ES ES90123671T patent/ES2084639T4/es not_active Expired - Lifetime
- 1990-12-11 JP JP2409992A patent/JP3016876B2/ja not_active Expired - Lifetime
- 1990-12-11 CN CN90110125A patent/CN1030608C/zh not_active Ceased
1991
- 1991-02-07 RU SU4894454/04A patent/RU2057131C9/ru active Protection Beyond IP Right Term
1996
- 1996-04-29 GR GR960401164T patent/GR3019784T3/el unknown
1997
- 1997-12-22 HK HK97102541A patent/HK1000920A1/en not_active IP Right Cessation
1998
- 1998-09-11 CY CY9802076A patent/CY2076B1/xx unknown
2005
- 2005-03-14 LU LU91147C patent/LU91147I2/fr unknown
- 2005-03-16 NL NL300181C patent/NL300181I2/nl unknown

Also Published As

Publication number	Publication date
AU6779190A (en)	1991-06-13
HUT58335A (en)	1992-02-28
NZ236385A (en)	1992-05-26
SG48098A1 (en)	1998-04-17
NL300181I1 (nl)	2005-05-02
DE122005000012I2 (de)	2006-02-09
HK1000920A1 (en)	1998-05-08
CA2031890C (en)	2000-07-25
AU640182B2 (en)	1993-08-19
HU908147D0 (en)	1991-06-28
RU2057131C9 (ru)	2006-04-10
DE69025723D1 (de)	1996-04-11
CA2031890A1 (en)	1991-06-12
ATE135007T1 (de)	1996-03-15
PT96140B (pt)	1997-06-30
IE904445A1 (en)	1991-06-19
DE69025723T2 (de)	1996-10-31
ES2084639T4 (es)	2013-06-11
EP0432677B1 (de)	1996-03-06
NL300181I2 (nl)	2005-06-01
AR245129A1 (es)	1993-12-30
HU218483B (hu)	2000-09-28
LU91147I2 (fr)	2005-05-17
DE122005000012I1 (de)	2005-06-23
CN1055182A (zh)	1991-10-09
IL96531A0 (en)	1991-09-16
JP3016876B2 (ja)	2000-03-06
DK0432677T3 (da)	1996-04-09
RU2057131C1 (ru)	1996-03-27
ES2084639T3 (es)	1996-05-16
CN1030608C (zh)	1996-01-03
JPH083166A (ja)	1996-01-09
PT96140A (pt)	1991-09-30
CY2076B1 (en)	1998-09-11
EP0432677A1 (de)	1991-06-19
GR3019784T3 (en)	1996-07-31

Legal Events

Date	Code	Title
1997-04-15	KB	Patent renewed
2001-06-14	KB	Patent renewed
2005-01-24	EXTP	Application for extension order is pending
2005-02-20	KB	Patent renewed
2009-07-20	KB	Patent renewed
2010-11-30	EXTG	Extension of patent term granted
2011-06-30	EXTN	Extension order renewed
2012-06-28	EXTN	Extension order renewed
2013-06-27	EXTN	Extension order renewed
2014-06-30	EXTN	Extension order renewed

Publication	Publication Date	Title
CA2031890C (en)	2000-07-25	N-(pyrrolo[2,3-d]pyrimidin-3-ylacyl)-glutamic acid derivatives
US5344932A (en)	1994-09-06	N-(pyrrolo(2,3-d)pyrimidin-3-ylacyl)-glutamic acid derivatives
US4996206A (en)	1991-02-26	N-(pyrrolo[2,3-d]pyrimidin-3-ylacyl)-glutamic acid derivatives
HK1000920B (en)	1998-05-08	N-(pyrrolo[2,3-d]pyrimidin-3-ylacyl)-glutamic acid derivatives
DK173980B1 (da)	2002-03-25	Pyrimidinderivater, fremgangsmåde til fremstilling deraf og deres anvendelse som antitumormidler
Taylor et al.	1992	A dideazatetrahydrofolate analog lacking a chiral center at C-6: N-[4-[2-(2-amino-3, 4-dihydro-4-oxo-7H-pyrrolo [2, 3-d] pyrimidin-5yl) ethyl [benzoyl]-L-glutamic acid is an inhibitor of thymidylate synthase
DeGraw et al.	1992	Synthesis and antifolate properties of 5, 10-ethano-5, 10-dideazaaminopterin
EP0215063B1 (de)	1993-11-03	Pyrido-(-2,3-d-)-pyrimidinabkömmlinge
HRP950033A2 (en)	1997-10-31	Tricyclic compounds capable of inhibiting tryosine kinases of the epidermal growth factor receptor family
US5663339A (en)	1997-09-02	Process for preparing 5-substituted pyrrolo-[2,3-D] pyrimidines
JPH01226886A (ja)	1989-09-11	ピリド〔２，３―ｄ〕ピリミジン誘導体
US4536575A (en)	1985-08-20	2-Amino-4(3H)-oxopyrido[2,3-d]pyrimidino
US4833145A (en)	1989-05-23	4(3H)-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine derivatives
CA2091978A1 (en)	1993-09-25	Pharmaceutical compounds
US5354754A (en)	1994-10-11	Pyrrolopyrimidines, their production and use
EP0638079B1 (de)	1999-12-15	Deazaaminopterine für behandlung von entzündungen
EP0530579A1 (de)	1993-03-10	Kondensierte Pyrimidinderivate als Antitumorverbindungen
US4526964A (en)	1985-07-02	2,4-Diamino-6-(hydroxymethyl)pyrido[2,3-d]pyrimidine
Badawey et al.	1995	Synthesis of some new imidazo [1, 2‐a] pyrimidin‐5 (1H)‐ones as potential antineoplastic agents
US5536724A (en)	1996-07-16	Antiinflammatory and antineoplastic 5-deazaaminopterins and 5,10-dideazaaminopterins
KR950011740B1 (ko)	1995-10-09	축합된 피리미딘 유도체
JPH04211063A (ja)	1992-08-03	縮合三環性複素環化合物、その製造法、用途及び中間体
EP0075880B1 (de)	1987-07-22	Pyrido(2,3-d)pyrimidine
US4628089A (en)	1986-12-09	Pyrido(2,3-D)pyrimidines
Gangjee et al.	1991	Synthesis and biological activity of 5, 11-methylenetetrahydro-5-deazahomofolic acid