WO1998030550A1 - 2,4-diaminopyrimidine compounds as anti-cancer agents - Google Patents
2,4-diaminopyrimidine compounds as anti-cancer agents Download PDFInfo
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- WO1998030550A1 WO1998030550A1 PCT/GB1998/000111 GB9800111W WO9830550A1 WO 1998030550 A1 WO1998030550 A1 WO 1998030550A1 GB 9800111 W GB9800111 W GB 9800111W WO 9830550 A1 WO9830550 A1 WO 9830550A1
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- YAAWASYJIRZXSZ-UHFFFAOYSA-N pyrimidine-2,4-diamine Chemical class NC1=CC=NC(N)=N1 YAAWASYJIRZXSZ-UHFFFAOYSA-N 0.000 title description 6
- 239000002246 antineoplastic agent Substances 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 36
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 23
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 20
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 18
- 125000003277 amino group Chemical group 0.000 claims abstract description 15
- 201000011510 cancer Diseases 0.000 claims abstract description 15
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 13
- 125000001188 haloalkyl group Chemical group 0.000 claims abstract description 13
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 13
- -1 aralkoxy Chemical group 0.000 claims abstract description 12
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims abstract description 11
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 11
- 150000002367 halogens Chemical class 0.000 claims abstract description 10
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 7
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 7
- 238000004519 manufacturing process Methods 0.000 claims abstract description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 6
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 6
- 150000003839 salts Chemical class 0.000 claims abstract description 6
- 150000001204 N-oxides Chemical class 0.000 claims abstract description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000003118 aryl group Chemical group 0.000 claims abstract description 5
- 239000003814 drug Substances 0.000 claims abstract description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 3
- 239000001301 oxygen Substances 0.000 claims abstract description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 20
- 210000001072 colon Anatomy 0.000 claims description 7
- 125000001691 aryl alkyl amino group Chemical group 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 125000003282 alkyl amino group Chemical group 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- 208000029742 colonic neoplasm Diseases 0.000 claims description 4
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 3
- 239000005864 Sulphur Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 2
- 125000000262 haloalkenyl group Chemical group 0.000 claims description 2
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 2
- 210000005265 lung cell Anatomy 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims 1
- 125000004429 atom Chemical group 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 230000000694 effects Effects 0.000 description 15
- 210000004027 cell Anatomy 0.000 description 10
- 108010022394 Threonine synthase Proteins 0.000 description 7
- 102000004419 dihydrofolate reductase Human genes 0.000 description 7
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 7
- 102000016914 ras Proteins Human genes 0.000 description 7
- 108010014186 ras Proteins Proteins 0.000 description 7
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 7
- 125000001309 chloro group Chemical group Cl* 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 206010009944 Colon cancer Diseases 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 239000003430 antimalarial agent Substances 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 230000024245 cell differentiation Effects 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 230000009036 growth inhibition Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- VQJHOPSWBGJHQS-UHFFFAOYSA-N metoprine, methodichlorophen Chemical compound CC1=NC(N)=NC(N)=C1C1=CC=C(Cl)C(Cl)=C1 VQJHOPSWBGJHQS-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 108700042226 ras Genes Proteins 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 210000004881 tumor cell Anatomy 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 1
- 125000006201 3-phenylpropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 0 CC(C)(CCC1N*)CC[C@]1N=*C Chemical compound CC(C)(CCC1N*)CC[C@]1N=*C 0.000 description 1
- 102000013446 GTP Phosphohydrolases Human genes 0.000 description 1
- 108091006109 GTPases Proteins 0.000 description 1
- 208000005045 Interdigitating dendritic cell sarcoma Diseases 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 208000028018 Lymphocytic leukaemia Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 101000957678 Mus musculus Cytochrome P450 7B1 Proteins 0.000 description 1
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- 102000043276 Oncogene Human genes 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 101000957679 Rattus norvegicus 25-hydroxycholesterol 7-alpha-hydroxylase Proteins 0.000 description 1
- 206010044708 Trypanosomal infections Diseases 0.000 description 1
- 101150044453 Y gene Proteins 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 230000002682 anti-psoriatic effect Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 210000003855 cell nucleus Anatomy 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000004052 folic acid antagonist Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 208000003747 lymphoid leukemia Diseases 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 230000000684 melanotic effect Effects 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- WKSAUQYGYAYLPV-UHFFFAOYSA-N pyrimethamine Chemical compound CCC1=NC(N)=NC(N)=C1C1=CC=C(Cl)C=C1 WKSAUQYGYAYLPV-UHFFFAOYSA-N 0.000 description 1
- 229960000611 pyrimethamine Drugs 0.000 description 1
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 description 1
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 1
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 208000029922 reticulum cell sarcoma Diseases 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 1
- 231100000004 severe toxicity Toxicity 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000001302 tertiary amino group Chemical group 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/655—Azo (—N=N—), diazo (=N2), azoxy (>N—O—N< or N(=O)—N<), azido (—N3) or diazoamino (—N=N—N<) compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Definitions
- This invention relates to the use of 2,4-diaminopyrimidine compounds in the treatment of certain cancers associated with ras mutations.
- Antifolate agents such as methotrexate
- diaminopyrimidine compounds have also been developed which have inherent species selectivity as antibacterial and antimalarial agents.
- WO 88/04293 discloses compounds of this class with inhibition of dihydrofolate reductase (DHFR) comparable to or greater than metoprine but which are relatively less toxic.
- DHFR dihydrofolate reductase
- the present inventors have now identified a group of these diaminopyrimidine compounds which have a previously unidentified property in so far as they have activity against mutant-ras associated tumours independent of tumour DHFR inhibitor activity.
- the Ras, R o, Rac and Rab proteins make up a large family of monomeric GTPases.
- the Ras proteins are anchored to the cytoplasmic face of the plasma membrane and relay signals from receptor tyrosine kinases to the cell nucleus in order to stimulate cell proliferation or differentiation.
- Ras proteins are produced by ras genes, mutants of which promote cancer by disrupting this control of cell proliferation and differentiation. It is believed that about 30% of human cancers involve mutant-ras genes.
- F. McCormick is to found on pages 125-145 of 'Oncogenes and the Molecular Origins of Cancer" Edited by R. A. Weinberg and published b ⁇ Cold Spring ICDCbour Laboratory Press (1989). Further details of the biochemistry of this mechanism are to be found in 'Molecular Biology of the Cell, by Alberts et al. 3rd Edition (1994) published by Garland Publishing Inc. New York and London: see pages 763-767 and 1276-1289. Other relevant publications include those by Feig..
- the prior art ascribes the activity of the aforesaid 2,4-diaminopyrimidine compounds to their dihydrofolate reductase (DF1FR) inhibiting activity, and particularly suggests their use in treatment of malignancies of the central nervous system and as antipsoriatic, antibacterial and antimalarial agents.
- Activity against a wide variety of murine tumour cell lines is demonstrated including lymphocytic leukaemia P388 and
- L1210 melanotic melanoma B 16, colon 38.
- TLX5 lymphoma W3129 myeloma, Walker 256 and M5076 reticulum cell sarcoma.
- DHFR inhibitor activity which is specific against mutant-/ « cancer cells and, in particular those of non-small cell lung cancer (NSCL), colon cancer and pancreatic cancer.
- NSCL non-small cell lung cancer
- Such activity is of particular use where it is suspected or confirmed that a mutant ras cancer is present.
- R 1 and R 2 are independently selected amino groups
- R 3 is C,_ 6 alkyl or haloalkyl
- X is N, CH or CR 9
- R 8 is C,. 6 alkyl or is aralkyl or R 4 and R 5 together with the benzene ring to which they are attached form a group of formula III
- R 9 is aryl or aralkyl or a salt or N-oxide of any such compound for the manufacture of a medicament for the treatment of mutani-r-/.y gene associated cancer.
- R 4 and R 5 form a group of formula II or III with the benzene ring to which they are attached, that group is of formula IV or V
- a particularly preferred medicament for which the compounds of formula I may be used in manufacture is for the treatment of mutant-ray gene associated cancers selected from non-small lung cell (NSCL), colon and pancreatic cancers, although it will be understood that other forms of mutant-ra y associated cancer will also be treatable with such compounds.
- NSC non-small lung cell
- pancreatic cancers although it will be understood that other forms of mutant-ra y associated cancer will also be treatable with such compounds.
- amino includes primary, secondary, tertiary and quaternary amino groups, but preferred groups are unsubstituted, mono or disubstituted amino groups, including those amino groups forming part of a heterocyclic ring, particularly a ring consisting of from 3 to 7 carbon, nitrogen, sulphur and/or oxygen atoms or as defined for -NR 6 R 7 above, more preferably being of carbon and nitrogen atoms only.
- Amino groups are generally substituted by one or two alkyl or aralkyl groups in which the alkyl group or moiety preferably contains 1 -6 carbon atoms.
- R' and R 2 are preferably unsubstituted primary amino groups or secondary or tertiary amino substituted by C alkyl groups. Where one or more of R 4 , R 5 , R l ⁇ or R" is an amino group, the following groups are of particular interest: C M alkyl amino, di-C alkyl amino, C ⁇ .l0 aralkyl amino. C alkyl C 6 . l() aralkyl amino, di-C 6 . 10 aralkyl amino.
- All of the aforesaid groups may be substituted; e.g. by halogen or C alkyl, particularly by chloro.
- the group includes a benzene ring. e.g. an aralkyl amino group, that ring may be substituted one or more times, preferably 1 or 2 times, and most preferably substituted with halogen, e.g. chloro.
- R 5 , R 10 and R are selected from -NHCH,. -NHCT L. -NH(nC 4 H 9 ), -NHCH 2 CH,PhenyI. -NHCI LPhcnyl. -N(CH,)CH,Phenyl. -N(CH,Phenyl) 2 , -N(C 2 H 5 )CH 2 Phcnyl and -NHCH(CH,)Phenyl.
- Substituents on aryl rings may conveniently be halogen, C,_ 6 alkyl or haloalkyl, C 2 . alkenvl or haloalkenyl, C,_ 6 alkoxy or haloalkoxy. nitro, or -C0 2 R 12 where R' 2 is h> drogen. C,. 6 alkyl or C, ⁇ alkoxyalkyl. It is found that a -CONHCH-, substitution of these phe 1 groups at the 4 position is not desirable as it appears to lead to loss of anti-ra.s activit ⁇ . However, substitution with halo. e.g. chloro, especially 3.4 dichloro. results in best activity, e.g. see compound 1 of the Examples.
- a group is designated as aralkyl that is preferably a C,. 4 alkylene group in association with a benzene ring, eg. phenylmethyl, 2-phenylethyl, 3-phenylpropyl or
- the group R 3 is preferably C,. 6 alkyl. preferably methyl or ethyl.
- R'° are mono or disubstituted amino groups such as -NR' 2 R ⁇ groups where R' 2 is H or C alkyl and R 13 is aralkyl, most preferably unsubstituted or halo substituted aralkyl and most particularly R 10 is -N(CH 3 )CH 2 Phenyl, -N(CH,)-CH 2 -(3,4 dichloroPhenyl), -NH-CH,-Phenyl or -NH-CH 2 -(3.4-dichloroPhenyl).
- R ⁇ and R are most preferably nitro. although azido also leads to good activit ⁇ .
- one of R 10 and R 1 ' is nitro and the other halogen, particularly chloro. activity is good regardless of position. Similar position independent activity is expected with azido
- the compounds used in the manufacture as described by the present invention are all accessible by methods known in the art with all the examples described herein being known compounds.
- the compounds described in WO 88/04293 (US 4992444) are cited herein as particular compounds for use in the present manufacture, as are those of WO 94/02469 and WO 84/0446 where they fall within the formula disclosed above.
- DHFR inhibitor compounds were selected for screening for anti-tumour activity using the NCI-In Vitro Anticancer Drug Discovery Screen. This is described in detail in a number of publications, particularly by Boyd and Paul in Drug Development Research (1995) 34:91 -109. These compounds are set out in Table I below in terms of their values R 1 to R" of formula VI. Et in Table 1 represents ethyl.
- the screen measures effect of a given compound on a cell line through to optical density changes which it interprets as changes in percent growth, growth inhibition (GI) and LC 5 ⁇ .
- Non-small cell lung cancer lines included are A 549/ATCC, EKVX, HOP-62.
- HOP-92 NCI-H226. NCI-H23. NCI-H322M. NCI-H460, NCI-H522.
- Colon cancer cell lines include COLO-205. HCC-2998, HCT-1 16. HCT-15, HT-29. KM- 12 and SW-620.
- Table 2 Pearson coefficients shown in Table 2 below as a measure of positive correlation of effect with anti ras-mutant seed cell efficacy for both NSCL and Colon ras types, the results in that table being at Log concentration -4 M. These correlations compare to values of less than 0.3 at the same concentration for a full 59 cell line screen.
- the anti-ra.y activity of the compounds for the use of the present invention is illustrated further in Table 3 where individual ra.y v. wild type (Wt) cell efficacies are given and in Table 4 where activity against pancreatic ras lines is given.
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- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Use of a compound of general formula (I) wherein R?1 and R2¿ are independently selected amino groups; R3 is C¿1-6? alkyl or haloalkyl; R?4¿ is selected from alkoxy, aralkoxy, haloalkyl, halogen and amino; and R5 is selected from nitro, amino, azido or a group -N=X-NR6R7 where R?6 and R7¿ are independently C¿1-6? alkyl or are aralkyl or together with the nitrogen to which they are attached form a heterocyclic ring with the proviso that one or both R?6 and R7¿ or the heterocyclic ring carries or includes or carries and includes at least one oxygen or sulphur atom, and X is N or CH or CR?9; or R4 and R5¿ together with the benzene ring to which they are attached form a group of formula (II), wherein X is N, CH or CR?9, and R8¿ is C¿1-6? alkyl or is aralkyl; or R?4 and R5¿ together with the benzene ring to which they are attached form a group of formula (III) wherein R9 is aryl or aralkyl; or a salt or N-oxide of any such compound, for the manufacture of a medicament for the treatment of mutant-ras gene associated cancer.
Description
2,4-DIAMINOPYRIMIDINE COMPOUNDS AS ANTI-CANCER AGENTS
This invention relates to the use of 2,4-diaminopyrimidine compounds in the treatment of certain cancers associated with ras mutations.
Antifolate agents, such as methotrexate, have been used as antitumour agents for many years and in 1954 metoprine (compound of formula A where R'=C1, R2=C1, R3=Me) entered clinical trials.
Although severe toxicity associated with this agent precluded further evaluation, the use of pyrimethamine (A. R'=C1 R2=H R3=Et) has been explored and diaminopyrimidine compounds have also been developed which have inherent species selectivity as antibacterial and antimalarial agents. WO 88/04293 (US 4992444) discloses compounds of this class with inhibition of dihydrofolate reductase (DHFR) comparable to or greater than metoprine but which are relatively less toxic. These compounds are described as of interest as antiproliferative agents useful in the treatment of tumours, psoriasis and bacterial, malarial and trypanosomal infections and are noted to act via DHFR inhibition. Certain of these compounds were also disclosed as intermediates in WO 84/04746 which relates to azido-substituted pyrimidine derivatives. WO 94/02469 discloses other related compounds, where R2 is -N=N-NR8R9 for use in treatment of inter alia AIDS associated infections.
The present inventors have now identified a group of these diaminopyrimidine compounds which have a previously unidentified property in so far as they have activity against mutant-ras associated tumours independent of tumour DHFR inhibitor activity. The Ras, R o, Rac and Rab proteins make up a large family of monomeric GTPases. The Ras proteins are anchored to the cytoplasmic face of the plasma membrane and relay signals from receptor tyrosine kinases to the cell nucleus in order to stimulate cell proliferation or differentiation.
These Ras proteins are produced by ras genes, mutants of which promote cancer by disrupting this control of cell proliferation and differentiation. It is believed that about 30% of human cancers involve mutant-ras genes. A review of this mechanism by F. McCormick is to found on pages 125-145 of 'Oncogenes and the Molecular Origins of Cancer" Edited by R. A. Weinberg and published b\ Cold Spring I Iarbour Laboratory Press (1989). Further details of the biochemistry of this mechanism are to be found in 'Molecular Biology of the Cell, by Alberts et al. 3rd Edition (1994) published by Garland Publishing Inc. New York and London: see pages 763-767 and 1276-1289. Other relevant publications include those by Feig.. Journal of the National Cancer fnstitute ( 1993) Vol 85. No 16: 1266-1268: Feig and Schaffhausen.. Nature (1994) 1 8: 508-9; Mars, Science (1993) Vol 260: 1588-90: Pretlow et al., Journal of the National Cancer fnstitute (1993) Vol 85 No 24:2004-2007: and Fearon.. Journal of the National Cancer Institute (1993) Vol 85 No 24: 1978-1980.
The prior art ascribes the activity of the aforesaid 2,4-diaminopyrimidine compounds to their dihydrofolate reductase (DF1FR) inhibiting activity, and particularly suggests their use in treatment of malignancies of the central nervous system and as antipsoriatic, antibacterial and antimalarial agents. Activity against a wide variety of murine tumour cell lines is demonstrated including lymphocytic leukaemia P388 and
L1210, melanotic melanoma B 16, colon 38. TLX5 lymphoma, W3129 myeloma, Walker 256 and M5076 reticulum cell sarcoma.
The present inventors have now determined that these compounds have an activity independent of that of their DHFR inhibitor activity which is specific against mutant-/ « cancer cells and, in particular those of non-small cell lung cancer (NSCL), colon cancer
and pancreatic cancer. Such activity is of particular use where it is suspected or confirmed that a mutant ras cancer is present.
Thus, in a first aspect of the present invention there is provided the use of a compound of general formula (I)
wherein R1 and R2 are independently selected amino groups R3 is C,_6 alkyl or haloalkyl
W is selected from alkoxy, aralkoxy. haloalkyl, halogen and amino and R5 is selected from nitro, amino. azido or a group -N=X-NR6R7 where R6 and R7 are independently C,_6 alkyl or are aralkyl or together with the nitrogen to which they are attached form a heterocyclic ring with the proviso that one or both R6 and R7 or the heterocyclic ring carries or includes or carries and includes at least one oxygen or sulphur atom, and X is N or CH or CR9 or R4 and R5 together with the benzene ring to which they are attached form a group of formula II
wherein X is N, CH or CR9, and R8 is C,.6 alkyl or is aralkyl
or R4 and R5 together with the benzene ring to which they are attached form a group of formula III
wherein R9 is aryl or aralkyl or a salt or N-oxide of any such compound for the manufacture of a medicament for the treatment of mutani-r-/.y gene associated cancer.
More preferably, where R4 and R5 form a group of formula II or III with the benzene ring to which they are attached, that group is of formula IV or V
Particularly preferred compounds for the use of the invention are those of formula VI
wherein R1, R2 and R3 are as defined for formula I
R10 and R" are selected from haloalkyl, halogen, amino, nitro, azido or a group -N=X-NR6R7 or, together with the benzene ring to which they are attached, form a group of formula IV or V, w ith the proviso that if one of R10 and R" is selected from haloalkyl and halo then the other is selected from amino, nitro, azido or a group -N=X-NR6R7- or a salt or N-oxide of any such compound. In all of the formulae I to VI hereinabove the term amino includes primary, secondary, tertiary and quaternary amino groups, but preferred groups are unsubstituted, mono or disubstituted amino groups, including those amino groups forming part of a heterocyclic ring, particularly a ring consisting of from 3 to 7 carbon, nitrogen, sulphur and/or oxygen atoms or as defined for -NR6R7 above, more preferably being of carbon and nitrogen atoms only. Amino groups are generally substituted by one or two alkyl or aralkyl groups in which the alkyl group or moiety preferably contains 1 -6 carbon atoms. R' and R 2 are preferably unsubstituted primary amino groups or secondary or tertiary amino substituted by C alkyl groups.
Where one or more of R4, R5, Rlϋ or R" is an amino group, the following groups are of particular interest: CM alkyl amino, di-C alkyl amino, C ή.l0aralkyl amino. C alkyl C6.l() aralkyl amino, di-C6.10 aralkyl amino.
All of the aforesaid groups may be substituted; e.g. by halogen or C alkyl, particularly by chloro. Where the group includes a benzene ring. e.g. an aralkyl amino group, that ring may be substituted one or more times, preferably 1 or 2 times, and most preferably substituted with halogen, e.g. chloro.
Particularly preferred amino groups at R4. R 5, R 10 and R "are selected from -NHCH,. -NHCT L. -NH(nC4H9), -NHCH2CH,PhenyI. -NHCI LPhcnyl. -N(CH,)CH,Phenyl. -N(CH,Phenyl)2, -N(C2H5)CH2Phcnyl and -NHCH(CH,)Phenyl.
Substituents on aryl rings may conveniently be halogen, C,_6 alkyl or haloalkyl, C2. alkenvl or haloalkenyl, C,_6 alkoxy or haloalkoxy. nitro, or -C02R12 where R'2 is h> drogen. C,.6 alkyl or C, ή alkoxyalkyl. It is found that a -CONHCH-, substitution of these phe 1 groups at the 4 position is not desirable as it appears to lead to loss of anti-ra.s activit} . However, substitution with halo. e.g. chloro, especially 3.4 dichloro. results in best activity, e.g. see compound 1 of the Examples.
Thus where a group is designated as aralkyl that is preferably a C,.4 alkylene group in association with a benzene ring, eg. phenylmethyl, 2-phenylethyl, 3-phenylpropyl or
4-phenylbutyl. Where a group is designated as haloalkyl it is preferably trifluoromethyl. When R4 is an alkoxy group it is preferably a C,_6 alkoxy group. OQ-L,. OC2H, and
0-nC I I9 being particularly preferred.
The group R3 is preferably C,.6 alkyl. preferably methyl or ethyl.
Most preferred groups R'° are mono or disubstituted amino groups such as -NR'2Rπ groups where R'2 is H or C alkyl and R13 is aralkyl, most preferably unsubstituted or halo substituted aralkyl and most particularly R10 is -N(CH3)CH2Phenyl, -N(CH,)-CH2-(3,4 dichloroPhenyl), -NH-CH,-Phenyl or -NH-CH2-(3.4-dichloroPhenyl).
R\ and R", are most preferably nitro. although azido also leads to good activit} . Where one of R10 and R1 ' is nitro and the other halogen, particularly chloro. activity is good regardless of position. Similar position independent activity is expected with azido
The compounds used in the manufacture as described by the present invention are all accessible by methods known in the art with all the examples described herein being known compounds. The compounds described in WO 88/04293 (US 4992444) are cited herein as particular compounds for use in the present manufacture, as are those of WO 94/02469 and WO 84/0446 where they fall within the formula disclosed above.
Details of preparative methods for obtaining compounds for use of the invention are to be found in the aforesaid patent documents as well as the following papers: Griffin et al (1985) J. Chem. Soc, Perkin Trans. I :2267; Griffin et al (1989) J. Medicinal Chem 32: 2468-2474; Griffin et al ( 1990) Anti-Cancer Drug Design, 5: 210-21 1. In a second aspect of the present invention there is provided a method of treatment of a patient having mutant-ra.y associated cancer, preferably of the NSCL. colon or pancreatic types, comprising administering to them an effective dose of a compound as described according to formula I or formula VI above.
The amount of these compounds used in the manufacture or method of the invention w ill of course vary with the type of cancer to be treated and the individual concerned.
Dosage forms and route of administration are more fully considered in the PCT application publications referred to above and their associated literature, as are forms such as salts suitable for administration. (See e.g. WO 94/02469 pages 6-9). The corresponding US applications US 4992444 and Serial No 08/374508 are incorporated herein by reference for that purpose and for their teaching of preparation of compounds for use in the method of the invention. The doses of such compounds may be conveniently assessed by reference to the relative efficacy evidenced against ras and wild type cancer cells shown in the Examples below.
The present invention will now be illustrated further by reference to the following non-limiting examples. Further embodiments falling within the scope of the invention will occur to those skilled in the art in the light of these.
EXAMPLES
A number of known DHFR inhibitor compounds were selected for screening for anti-tumour activity using the NCI-In Vitro Anticancer Drug Discovery Screen. This is described in detail in a number of publications, particularly by Boyd and Paul in Drug Development Research (1995) 34:91 -109. These compounds are set out in Table I below in terms of their values R1 to R" of formula VI. Et in Table 1 represents ethyl.
In brief, the screen measures effect of a given compound on a cell line through to optical density changes which it interprets as changes in percent growth, growth inhibition (GI) and LC5ϋ. Non-small cell lung cancer lines included are A 549/ATCC, EKVX, HOP-62.
HOP-92. NCI-H226. NCI-H23. NCI-H322M. NCI-H460, NCI-H522. Colon cancer cell lines include COLO-205. HCC-2998, HCT-1 16. HCT-15, HT-29. KM- 12 and SW-620. On analysis of screening results it was found that the compounds 1 to 13 of Table 1 above gave the Pearson coefficients shown in Table 2 below as a measure of positive correlation of effect with anti ras-mutant seed cell efficacy for both NSCL and Colon ras types, the results in that table being at Log concentration -4 M. These correlations compare to values of less than 0.3 at the same concentration for a full 59 cell line screen.
The anti-ra.y activity of the compounds for the use of the present invention is illustrated further in Table 3 where individual ra.y v. wild type (Wt) cell efficacies are given and in Table 4 where activity against pancreatic ras lines is given.
TABLE 1
Compound R1 R2 R3 R1 R11
1 -NH2 -NH2 Et 4-(N-(3',4'-dichlorobenzyl)arnino) 3-NO2
2 -NH2 -NH2 Et 4-(N-benzyl N-methylamino) 3-NO2
3 -NH2 -NH2 Et 4-C1 3-NO2 n c 4 -NH2 -NH2 Et 4-NO2 3-C1
DO O)
-4 5 -NH2 -NH2 Et formula V where R9 is phenyl
H
C 6 -NH2 -NH2 Et 4-C1 3-N, H m
(Λ I 7 -NH2 -NH2 Et 4-N-methylamino 3-NO2
I m I m 8 -NH2 -NH2 Et 4-N-(2-phenylethyl)amino 3-NO2
H
9 -NH2 -NH2 Et 4-(4-methylpiperazin- 1 -yl) 3-NO2 c m 10 -NH2 -NH2 Et 4-C1 3-N=CH-NMe2 r σ> 11 -NH2 -NH2 Et 4-N-benzylamino 3-NO2
12 -NH2 -NH2 Et formula IV wherein X is N and R8 is benzyl
13 -NH2 -NH2 Et 4-NO2 3-N-benzylamino
14 -NH2 -NH2 Et 4-NO2 3-(N-benzyl,N-methylami
15 -NH2 -NH, Et 4-C1 3-NH,
TABLE 2
PARTIAL RAS SEED - NSCL AND COLON
POSITIVE CORRELATION IS FOR RAS MUTANT SEED CELLS
WITH SENSITIVE CELLS FROM DATABASE
TABLE 3
ω c σ cn
H
H C H m ω z m m
H c r m r σ>
TABLE 4
Actiλ'ity of compounds agaisnt the pancreatic tumour cell line M l - mutant Ki-Ras gene 7 day assay.
Claims
Use of a compound of general formula (I)
wherein
R] and R2 are independently selected amino groups R1 is C,.6 alkyl or haloalkyl 5 R4 is selected from alkoxy, aralkoxy. haloalkyl, halogen and amino and
Rs is selected from nitro, amino. azido or a group -N=X-NR6R7 where R6 and R7 are independently C,_6 alkyl or are aralkyl or together with the nitrogen to which they are attached form a heterocyclic ring with the proviso that one or both R6 and R7 or the heterocyclic ring carries or includes or carries and includes at least one oxygen or sulphur
[ 0 atom, and X is N or CH or CR9 or R'1 and R5 together with the benzene ring to which they are attached form a group of formula II
wherein X is N, CH or CR9, and Rs is C,_6 alkyl or is aralkyl
l J-
or R4 and R3 together with the benzene ring to which they are attached form a group of formula III
wherein R9 is aryl or aralkyl or a salt or N-oxide of any such compound for the manufacture of a medicament for the treatment of mutant-ras gene associated cancer.
2. Use as claimed in claim 1 characterised in that R4 and R5 form a group of formula
II or III with the benzene ring to which they are attached and that group is of formula IV or V
R8
3. Use as claimed in claim 1 or 2 characterised in that the medicament manufactured is for the treatment of mutant-ras gene associated cancers selected from non-small lung cell (NSCL), colon and pancreatic cancers.
4. Use as claimed in any one of claims 1 to 3 characterised in that the compound is of formula VI
wherein R'° and R" are selected from haloalkyl, halogen, amino, nitro, azido or a group - N=X-NR6R7 or, together with the benzene ring to which they are attached, form a group of formula IV or V, with the provisio that if one one of R10 and R" is selected from haloalkyl and halo then the other is selected from amino. nitro, azido or a group -N=X-NR6Rλ or a salt or N-oxide of any such compound.
5. Use as claimed in any one of the preceding claims characterised in that the amino groups are selected from unsubstituted, mono and disubstituted amino groups, including those amino groups forming part of a heterocylic ring.
6. Use as claimed in claim 5 characterised in that the amino group comprises part of a ring consisting of from 3 to 7 carbon, nitrogen, sulphur and/or oxygen atoms.
7. Use as claimed in claim 6 characterised in that the ring is of carbon and nitrogen atoms only.
8. Use as claimed in any one of the preceding claims characterised in that when R4,
R3, R10 or R" are amino groups they are independently selected from C alkyl amino, di-CM alkyl amino, C6.l0 aralkyl amino, C,_4 alkyl C6.,0 aralkyl amino or di-C6.10 alkyl amino.
9. Use as claimed in claim 8 characterised in that when R4, R5, R10 or R" are aralkyl amino groups they are halo substituted on the phenyl ring.
10. Use as claimed in any one of the preceding claims characterised in that when R4. R5. R'° or R" are amino. one or more of them are independently selected from -NHCHV -NHC2H5, -NH(nC4H9) -NHCH,CH2Phenyl, -NHCH2Phenyl. -N(CH3)CH2Phenyl, -N(CH2Phenyl)2. -N(C2H5)CH2Phenyl and -NHCH(CH,)Phenyl.
1 1. Use as claimed in claim 10 characterised in that the aryl group, if present, is substituted by halogen, C,_6 alkyl or haloalkyl. C2.6 alkenyl or haloalkenyl, C,.6 alkoxy or haloalkoxy, nitro, or -C0 R]2 where R12 is hydrogen alkyl or alkoxyalkyl or C,_6
12 Use as claimed in any one of the preceding claims characterised in that R5 or R", is nitro or azido and R4 or R'° is amino.
13. Use as claimed in any one of the claims 4 to 12 characterised in that one of R10 and R" is nitro or azido and the other is halogen.
14. Use as claimed in claim 1 characterised in that the compound is one of 2.4-Diamino-5-[4-(3,4-dichlorobenzylamino)-3-nitrophenyl]-6-ethylpyrimidine,
2.4-Diamino-5-[4-benzylamino-3-nitrophenyl]-6-ethylpyrimidine, 2.4-Diamino-5-[4-chloro-3-nitrophenyl]-6-ethylpyrimidine, 2.4-Diamino-5-f4-nitiO-3-chlorophenyl|-6-ethylpyrimidine 2.4-Diamino-5-[4-chloro-3-azidophenyl]-6-ethylpyrimidine, and 2.4-Diamino-5-[4-N-methylamino-3-nitrophenyl]-ethylpyrimidine.
15. A method of treatment of a patient having mutant-ras associated cancer comprising administering to them a compound as defined according to fonnula I or formula VI above.
16. A method as claimed in claim 12 wherein the cancer is of the NSCL. colon or pancreatic types.
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU55690/98A AU5569098A (en) | 1997-01-14 | 1998-01-14 | 2,4-diaminopyrimidine compounds as anti-cancer agents |
| CA002275566A CA2275566A1 (en) | 1997-01-14 | 1998-01-14 | 2,4-diaminopyrimidine compounds as anti-cancer agents |
| EP98900602A EP0961772A1 (en) | 1997-01-14 | 1998-01-14 | 2,4-diaminopyrimidine compounds as anti-cancer agents |
| JP53067698A JP2001509149A (en) | 1997-01-14 | 1998-01-14 | 2,4-diaminopyrimidine compounds as anticancer agents |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9700664.7 | 1997-01-14 | ||
| GBGB9700664.7A GB9700664D0 (en) | 1997-01-14 | 1997-01-14 | Anti-cancer agents |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1998030550A1 true WO1998030550A1 (en) | 1998-07-16 |
Family
ID=10805951
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/GB1998/000111 WO1998030550A1 (en) | 1997-01-14 | 1998-01-14 | 2,4-diaminopyrimidine compounds as anti-cancer agents |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0961772A1 (en) |
| JP (1) | JP2001509149A (en) |
| AU (1) | AU5569098A (en) |
| CA (1) | CA2275566A1 (en) |
| GB (1) | GB9700664D0 (en) |
| WO (1) | WO1998030550A1 (en) |
| ZA (1) | ZA98306B (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006079556A3 (en) * | 2005-01-31 | 2006-09-21 | Basf Ag | Substituted 5-phenyl pyrimidines i in therapy |
| WO2008024974A1 (en) * | 2006-08-24 | 2008-02-28 | Serenex, Inc. | Pyrimidine and pyrazine derivatives |
| US7524849B2 (en) | 2003-09-24 | 2009-04-28 | Wyeth Holdings Corporation | 5-arylpyrimidines as anticancer agents |
| WO2010036917A1 (en) * | 2008-09-26 | 2010-04-01 | Takeda Pharmaceutical Company Limited | Prevention and treatment of cancer with ras gene mutation |
| WO2014145386A2 (en) * | 2013-03-15 | 2014-09-18 | University Of Florida Research Foundation Incorporated | Novel allosteric inhibitors of thymidylate synthase |
| US10835524B2 (en) | 2015-06-24 | 2020-11-17 | University Of Florida Research Foundation, Incorporated | Compositions for the treatment of pancreatic cancer and uses thereof |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005026148A1 (en) * | 2003-09-08 | 2005-03-24 | Takeda San Diego, Inc. | Dipeptidyl peptidase inhibitors |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1984004746A1 (en) * | 1983-05-26 | 1984-12-06 | Univ Birmingham | Pyrimidine derivatives |
| WO1988004293A1 (en) * | 1986-12-02 | 1988-06-16 | Malcolm Francis Graham Stevens | Antifolate agents |
| GB2268741A (en) * | 1992-07-15 | 1994-01-19 | British Tech Group | Pyrimidines useful against parasitic infections |
-
1997
- 1997-01-14 GB GBGB9700664.7A patent/GB9700664D0/en active Pending
-
1998
- 1998-01-14 JP JP53067698A patent/JP2001509149A/en active Pending
- 1998-01-14 ZA ZA9800306A patent/ZA98306B/en unknown
- 1998-01-14 CA CA002275566A patent/CA2275566A1/en not_active Abandoned
- 1998-01-14 WO PCT/GB1998/000111 patent/WO1998030550A1/en not_active Application Discontinuation
- 1998-01-14 AU AU55690/98A patent/AU5569098A/en not_active Abandoned
- 1998-01-14 EP EP98900602A patent/EP0961772A1/en not_active Withdrawn
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1984004746A1 (en) * | 1983-05-26 | 1984-12-06 | Univ Birmingham | Pyrimidine derivatives |
| WO1988004293A1 (en) * | 1986-12-02 | 1988-06-16 | Malcolm Francis Graham Stevens | Antifolate agents |
| GB2268741A (en) * | 1992-07-15 | 1994-01-19 | British Tech Group | Pyrimidines useful against parasitic infections |
Non-Patent Citations (5)
| Title |
|---|
| ANTICANCER DRUG DESIGN, vol. 2, no. 3, 1987, ENGL., pages 311 - 318 * |
| CHEMICAL ABSTRACTS, vol. 108, no. 1, 1988, Columbus, Ohio, US; abstract no. 142960k, STEVENS,GRIFFIN: "THE AROMATIC AZIDO GROUP IN ANTICANCER DRUG DESIGN." page 31; column 2; XP002043860 * |
| CHEMICAL ABSTRACTS, vol. 110, no. 7, 1989, Columbus, Ohio, US; abstract no. 50642w, F.KAMALI ET AL.: "MEDICINAL AZIDES.PART 3." page 8; XP002043861 * |
| E.BLISS,R.GRIFFIN: "STRUCTURAL STUDIES ON BIO-ACTIVE COMPOUNDS.PART 5.", JOURNAL OF THE CHEMICAL SOCIETY, PERKIN TRANSACTIONS 1., no. 10, 1987, LETCHWORTH GB, pages 2217 - 2227, XP002043859 * |
| XENOBIOTICA, vol. 18, no. 10, 1988, ENGL, pages 1157 - 1164 * |
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7524849B2 (en) | 2003-09-24 | 2009-04-28 | Wyeth Holdings Corporation | 5-arylpyrimidines as anticancer agents |
| WO2006079556A3 (en) * | 2005-01-31 | 2006-09-21 | Basf Ag | Substituted 5-phenyl pyrimidines i in therapy |
| EA014098B1 (en) * | 2005-01-31 | 2010-08-30 | Басф Акциенгезелльшафт | Substituted 5-phenyl pyrimidines i in cancer therapy, a pharmaceutical composition based thereon and a method for cancer treatment in animal |
| AU2006208621B2 (en) * | 2005-01-31 | 2011-08-11 | Basf Se | Substituted 5-phenyl pyrimidines I in therapy |
| WO2008024974A1 (en) * | 2006-08-24 | 2008-02-28 | Serenex, Inc. | Pyrimidine and pyrazine derivatives |
| WO2010036917A1 (en) * | 2008-09-26 | 2010-04-01 | Takeda Pharmaceutical Company Limited | Prevention and treatment of cancer with ras gene mutation |
| WO2014145386A2 (en) * | 2013-03-15 | 2014-09-18 | University Of Florida Research Foundation Incorporated | Novel allosteric inhibitors of thymidylate synthase |
| WO2014145386A3 (en) * | 2013-03-15 | 2014-12-24 | University Of Florida Research Foundation Incorporated | Novel allosteric inhibitors of thymidylate synthase |
| US20160067240A1 (en) * | 2013-03-15 | 2016-03-10 | University Of Florida Research Foundation, Inc. | Novel allosteric inhibitors of thymidylate synthase |
| US10420761B2 (en) | 2013-03-15 | 2019-09-24 | University Of Florida Research Foundation, Inc. | Allosteric inhibitors of thymidylate synthase |
| US10835524B2 (en) | 2015-06-24 | 2020-11-17 | University Of Florida Research Foundation, Incorporated | Compositions for the treatment of pancreatic cancer and uses thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA98306B (en) | 1999-07-14 |
| GB9700664D0 (en) | 1997-03-05 |
| CA2275566A1 (en) | 1998-07-16 |
| EP0961772A1 (en) | 1999-12-08 |
| JP2001509149A (en) | 2001-07-10 |
| AU5569098A (en) | 1998-08-03 |
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