US20090163465A1 - Pyrimidines as PLK inhibitors - Google Patents
Pyrimidines as PLK inhibitors Download PDFInfo
- Publication number
- US20090163465A1 US20090163465A1 US12/366,075 US36607509A US2009163465A1 US 20090163465 A1 US20090163465 A1 US 20090163465A1 US 36607509 A US36607509 A US 36607509A US 2009163465 A1 US2009163465 A1 US 2009163465A1
- Authority
- US
- United States
- Prior art keywords
- group
- mmol
- mono
- pseudohalogen
- halogen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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- CPCFYUJKIUDIFA-UHFFFAOYSA-N NC1CC(N2CCCCC2)C1 Chemical compound NC1CC(N2CCCCC2)C1 CPCFYUJKIUDIFA-UHFFFAOYSA-N 0.000 description 1
- AVNCAJZLJQHHII-UHFFFAOYSA-N NC1CC(N2CCCOCC2)C1 Chemical compound NC1CC(N2CCCOCC2)C1 AVNCAJZLJQHHII-UHFFFAOYSA-N 0.000 description 1
- LDFRTROGBKHYSZ-UHFFFAOYSA-N NC1CC(N2CCN(CCC(F)(F)F)CC2)C1 Chemical compound NC1CC(N2CCN(CCC(F)(F)F)CC2)C1 LDFRTROGBKHYSZ-UHFFFAOYSA-N 0.000 description 1
- JAMSXZZVHDYKGK-UHFFFAOYSA-N NC1CC(N2CCN(CCN3CCCC3)CC2)C1 Chemical compound NC1CC(N2CCN(CCN3CCCC3)CC2)C1 JAMSXZZVHDYKGK-UHFFFAOYSA-N 0.000 description 1
- PZRIVFTUPHKMSW-UHFFFAOYSA-N NC1CC(N2CCOCC2)C1 Chemical compound NC1CC(N2CCOCC2)C1 PZRIVFTUPHKMSW-UHFFFAOYSA-N 0.000 description 1
- HCOZOMRFERPFIX-UHFFFAOYSA-N NCC1=C(CN2CCOCC2)NN=N1 Chemical compound NCC1=C(CN2CCOCC2)NN=N1 HCOZOMRFERPFIX-UHFFFAOYSA-N 0.000 description 1
- VILXMZMRFLRMJO-UHFFFAOYSA-N NCCCN1CC2=CC=CC(N)=C2C1=O Chemical compound NCCCN1CC2=CC=CC(N)=C2C1=O VILXMZMRFLRMJO-UHFFFAOYSA-N 0.000 description 1
- MMVCAWVNKSGFPP-UHFFFAOYSA-N NCCN1CC2=CC=CC(N)=C2C1=O Chemical compound NCCN1CC2=CC=CC(N)=C2C1=O MMVCAWVNKSGFPP-UHFFFAOYSA-N 0.000 description 1
- YIGNFXKOFMFNMB-UHFFFAOYSA-N NCCN1CC2CCC(C1)O2 Chemical compound NCCN1CC2CCC(C1)O2 YIGNFXKOFMFNMB-UHFFFAOYSA-N 0.000 description 1
- CLPVUDZYVCDMBZ-UHFFFAOYSA-N NCCN1CC2CCC1C2 Chemical compound NCCN1CC2CCC1C2 CLPVUDZYVCDMBZ-UHFFFAOYSA-N 0.000 description 1
- BVYNFUYPUXPMCI-UHFFFAOYSA-N NCCN1CCC(F)(F)CC1 Chemical compound NCCN1CCC(F)(F)CC1 BVYNFUYPUXPMCI-UHFFFAOYSA-N 0.000 description 1
- ZNLCTCNYKCENHP-UHFFFAOYSA-N NCCN1CCC(O)C1 Chemical compound NCCN1CCC(O)C1 ZNLCTCNYKCENHP-UHFFFAOYSA-N 0.000 description 1
- TVPOQFOCXVSORW-UHFFFAOYSA-N NCCN1CCC(O)CC1 Chemical compound NCCN1CCC(O)CC1 TVPOQFOCXVSORW-UHFFFAOYSA-N 0.000 description 1
- RIHYLJLIMZMKTQ-UHFFFAOYSA-N NCCN1CCC1 Chemical compound NCCN1CCC1 RIHYLJLIMZMKTQ-UHFFFAOYSA-N 0.000 description 1
- HHEKNWQXFVOUNJ-UHFFFAOYSA-N NCCN1CCCC1=O Chemical compound NCCN1CCCC1=O HHEKNWQXFVOUNJ-UHFFFAOYSA-N 0.000 description 1
- OKIPJNZTHGXISP-UHFFFAOYSA-N NCCN1CCCOCC1 Chemical compound NCCN1CCCOCC1 OKIPJNZTHGXISP-UHFFFAOYSA-N 0.000 description 1
- JCCWMSYGCHUCQE-ZETCQYMHSA-N NCCN1CCC[C@H]1CO Chemical compound NCCN1CCC[C@H]1CO JCCWMSYGCHUCQE-ZETCQYMHSA-N 0.000 description 1
- QAAAENOFEXNQEL-QWRGUYRKSA-N NC[C@@H]1CCC[C@@H]1N1CCCCC1 Chemical compound NC[C@@H]1CCC[C@@H]1N1CCCCC1 QAAAENOFEXNQEL-QWRGUYRKSA-N 0.000 description 1
- UQIGTMOVPSBIPL-NEPJUHHUSA-N NC[C@@H]1CCC[C@H](CN2CCCC2)C1 Chemical compound NC[C@@H]1CCC[C@H](CN2CCCC2)C1 UQIGTMOVPSBIPL-NEPJUHHUSA-N 0.000 description 1
- IFNKMASEQYBDOM-NXEZZACHSA-N NC[C@H]1CCC[C@H]1N1CCCC1 Chemical compound NC[C@H]1CCC[C@H]1N1CCCC1 IFNKMASEQYBDOM-NXEZZACHSA-N 0.000 description 1
- BPOPCKMMKGYPBH-MGCOHNPYSA-N N[C@H]1CC[C@H](CN2CCC2)CC1 Chemical compound N[C@H]1CC[C@H](CN2CCC2)CC1 BPOPCKMMKGYPBH-MGCOHNPYSA-N 0.000 description 1
- ZGJSSLUKZHVIDZ-XYPYZODXSA-N N[C@H]1CC[C@H](CN2CCCC2)CC1 Chemical compound N[C@H]1CC[C@H](CN2CCCC2)CC1 ZGJSSLUKZHVIDZ-XYPYZODXSA-N 0.000 description 1
- CFTCVDMEKQNGOO-XYPYZODXSA-N N[C@H]1CC[C@H](CN2CCOCC2)CC1 Chemical compound N[C@H]1CC[C@H](CN2CCOCC2)CC1 CFTCVDMEKQNGOO-XYPYZODXSA-N 0.000 description 1
- JHWXVHJNXAOZEW-LXHRWSGQSA-N N[C@H]1CC[C@H](N2CC3CCC(C2)O3)CC1 Chemical compound N[C@H]1CC[C@H](N2CC3CCC(C2)O3)CC1 JHWXVHJNXAOZEW-LXHRWSGQSA-N 0.000 description 1
- YAUYNQUPOXKDNI-MGCOHNPYSA-N N[C@H]1CC[C@H](N2CCCC2)CC1 Chemical compound N[C@H]1CC[C@H](N2CCCC2)CC1 YAUYNQUPOXKDNI-MGCOHNPYSA-N 0.000 description 1
- LBYALFWGJOLWMN-HDJSIYSDSA-N N[C@H]1CC[C@H](N2CCN(CC3CC3)CC2)CC1 Chemical compound N[C@H]1CC[C@H](N2CCN(CC3CC3)CC2)CC1 LBYALFWGJOLWMN-HDJSIYSDSA-N 0.000 description 1
- USUNCAQFNNEGBQ-MGCOHNPYSA-N N[C@H]1CC[C@H](N2CCOCC2)CC1 Chemical compound N[C@H]1CC[C@H](N2CCOCC2)CC1 USUNCAQFNNEGBQ-MGCOHNPYSA-N 0.000 description 1
- FVSXNELJDHDCPJ-UHFFFAOYSA-N O=C1NCC(Cc2ccccc2)c2cccc(I)c12 Chemical compound O=C1NCC(Cc2ccccc2)c2cccc(I)c12 FVSXNELJDHDCPJ-UHFFFAOYSA-N 0.000 description 1
- CXFFCXIZNWLQGH-DYCDLGHISA-N [2H]N1CCCN(C2=CC=C(NC3=NC=C(C(F)(F)F)C(NC4=CC=CC5=C4C(=O)N(CCF)C5C)=N3)C(OC)=C2)CC1 Chemical compound [2H]N1CCCN(C2=CC=C(NC3=NC=C(C(F)(F)F)C(NC4=CC=CC5=C4C(=O)N(CCF)C5C)=N3)C(OC)=C2)CC1 CXFFCXIZNWLQGH-DYCDLGHISA-N 0.000 description 1
- KSPFICONXINXKY-DYCDLGHISA-N [2H]N1CCN(C2=CC=C(NC3=NC=C(C(F)(F)F)C(NC4=CC=CC5=C4C(=O)N(CCF)C5C)=N3)C(OC)=C2)CC1 Chemical compound [2H]N1CCN(C2=CC=C(NC3=NC=C(C(F)(F)F)C(NC4=CC=CC5=C4C(=O)N(CCF)C5C)=N3)C(OC)=C2)CC1 KSPFICONXINXKY-DYCDLGHISA-N 0.000 description 1
- MWWATHDPGQKSAR-UHFFFAOYSA-N [H]C#CC Chemical compound [H]C#CC MWWATHDPGQKSAR-UHFFFAOYSA-N 0.000 description 1
- MWBULQNPGVGHKO-ZETCQYMHSA-N [H]C12CCN(CC1)C[C@@H]2C Chemical compound [H]C12CCN(CC1)C[C@@H]2C MWBULQNPGVGHKO-ZETCQYMHSA-N 0.000 description 1
- MWBULQNPGVGHKO-SSDOTTSWSA-N [H]C12CCN(CC1)C[C@H]2C Chemical compound [H]C12CCN(CC1)C[C@H]2C MWBULQNPGVGHKO-SSDOTTSWSA-N 0.000 description 1
- LRYQADKSTLWINM-PHIMTYICSA-N [H][C@@]12CN(CC)C[C@]1([H])CN(CCC)C2 Chemical compound [H][C@@]12CN(CC)C[C@]1([H])CN(CCC)C2 LRYQADKSTLWINM-PHIMTYICSA-N 0.000 description 1
- SUFONLJOTVIQLA-TXEJJXNPSA-N [H][C@@]12CN(CCC)C[C@]1([H])CN(C(C)C)C2 Chemical compound [H][C@@]12CN(CCC)C[C@]1([H])CN(C(C)C)C2 SUFONLJOTVIQLA-TXEJJXNPSA-N 0.000 description 1
- MQIBSXNUCYAMDD-BETUJISGSA-N [H][C@@]12CN(CCC)C[C@]1([H])CN(CC1CC1)C2 Chemical compound [H][C@@]12CN(CCC)C[C@]1([H])CN(CC1CC1)C2 MQIBSXNUCYAMDD-BETUJISGSA-N 0.000 description 1
- VQPNFKCQRQGJPG-DTORHVGOSA-N [H][C@@]12CNC[C@]1([H])CN(CCC)C2 Chemical compound [H][C@@]12CNC[C@]1([H])CN(CCC)C2 VQPNFKCQRQGJPG-DTORHVGOSA-N 0.000 description 1
- IWOIJZMBJYXKOF-YUMQZZPRSA-N [H][C@]12CN(CCC)[C@]([H])(CO1)C2 Chemical compound [H][C@]12CN(CCC)[C@]([H])(CO1)C2 IWOIJZMBJYXKOF-YUMQZZPRSA-N 0.000 description 1
- OESOAVWKEOJJNZ-BQBZGAKWSA-N [H][C@]12CN(CCN)[C@]([H])(CO1)C2 Chemical compound [H][C@]12CN(CCN)[C@]([H])(CO1)C2 OESOAVWKEOJJNZ-BQBZGAKWSA-N 0.000 description 1
- YHFFRDPMIOWQPH-HZGVNTEJSA-N [H][C@]12C[C@@H](O)CN1C(=O)C1=C(N)C=CC=C1NC2=O Chemical compound [H][C@]12C[C@@H](O)CN1C(=O)C1=C(N)C=CC=C1NC2=O YHFFRDPMIOWQPH-HZGVNTEJSA-N 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
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
-
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- 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
-
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- 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
- C07D403/14—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 three or more hetero rings
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
- C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- 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
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- C—CHEMISTRY; METALLURGY
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- 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
- C07D487/08—Bridged systems
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- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/08—Bridged systems
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- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
Definitions
- the present invention relates to new pyrimidines of general formula (1),
- Tumour cells wholly or partly elude regulation and control by the body and are characterised by uncontrolled growth. This is due on the one hand to the loss of control proteins such as for example Rb, p16, p21 and p53 and also to the activation of so-called accelerators of the cell cycle, the cyclin-dependent kinases.
- a murine cell line with a temperature-sensitive CDK-1 kinase mutant shows a rapid breakdown in CDK-1 kinase after temperature increase and a subsequent arrest in the G2/M phase (Th ⁇ ng et al. 1990 , Cell. 63(2):313-24).
- Aurora B has also been described as having an essential function during entry into mitosis.
- Aurora B phosphorylates histone H3 on Ser10 and thereby initiates chromosome condensation (Hsu et al. 2000, Cell 102:279-91).
- a specific cell cycle arrest in the G2/M phase may, however, also be initiated e.g. by inhibition of specific phosphatases such as e.g. Cdc25C (Russell and Nurse 1986, Cell 45:145-53).
- Cdc25C e.g. Cdc25C
- overexpression of Cdc25 leads to premature entry into the mitosis phase (Russell and Nurse, 1987, Cell 49:559-67).
- an arrest in the G2/M phase may also be initiated by inhibition of specific motor proteins, the so-called kinesins such as for example Eg5 (Mayer et al. 1999 , Science 286:971-4), or by microtubuli stabilising or destabilising agents (e.g. colchicin, taxol, etoposide, vinblastine, vincristine) (Schiff and Horwitz 1980 , Proc Natl Acad Sci USA 77:1561-5).
- kinesins such as for example Eg5 (Mayer et al. 1999 , Science 286:971-4)
- microtubuli stabilising or destabilising agents e.g. colchicin, taxol, etoposide, vinblastine, vincristine
- PLK-1 In addition to the cyclin-dependent and Aurora kinases the so-called polo-like kinases, a small family of serine/threonine kinases, also play an important role in the regulation of the eukaryotic cell cycle.
- PLK-1, PLK-2, PLK-3 and PLK-4 have been described in the literature.
- PLK-1 in particular has been found to play a central role in the regulation of the mitosis phase.
- PLK-1 is responsible for the maturation of the centrosomes, for the activation of phosphatase Cdc25C, as well as for the activation of the Anaphase Promoting Complex (Glover et al. 1998, Genes Dev.
- Pyrimidines are generally known as inhibitors of kinases.
- pyrimidines are described as an active component with an anticancer activity in International Patent Application WO 00/53595, which describes the use of 2,4,5-substituted pyrimidines with a heterocyclic group in the 4-position and an anilino group in the 2 position, which in turn comprises a side chain with the length of at least one n-propyl group.
- Antiviral 2,4,5-substituted pyrimidines wherein the groups R c and R d form a heteroaromatic five-membered ring at the nitrogen of the 4-position, are known from International Patent Application WO 99/41253.
- 2,4,5-substituted pyrimidines which carry (hetero)aryls in position 2 and 4 (WO00/27825) and also 2,4,5-substituted pyrimidines which carry a (hetero)aryl group functionalised with a nitrile group in position 2 or 4 (EP 0 945 443 A1) are described as having an antiviral activity.
- the aim of the present invention is therefore to indicate new active substances which may be used for the prevention and/or treatment of diseases characterised by excessive or anomalous cell proliferation.
- compounds of general formula (1) wherein the groups A, W, X, Y, R a , R b , R c , R 1 , R 2 and R 3 are defined as hereinafter, act as inhibitors of specific cell cycle kinases.
- the compounds according to the invention may be used for example for the treatment of diseases associated with the activity of specific cell cycle kinases and characterised by excessive or anomalous cell proliferation.
- the present invention relates to compounds of general formula (1)
- L denotes a bond or a group selected from among optionally mono- or polysubstituted C 1-16- alkyl, C 2-16- alkenyl, C 2-16- alkynyl, C 3-10- cycloalkyl, aryl, heterocyclyl and heteroaryl, while the substituent(s) may be identical or different and are selected from among halogen, —NO 2 , —OR 8 , —C( ⁇ O)R 8 , —C( ⁇ O)OR 8 , —C( ⁇ O)NR 8 R 9 , —NR 8 R 9 , —NR 8 C( ⁇ O)R 9 , —NR 8 C( ⁇ O)OR 9 , —NR 8 C( ⁇ O)NR 9 R 10 , —NR 8 C( ⁇ O)ONR 9 R 10 , —NR 8 SO 2 R 9 , —N ⁇ CR 8 R 9 , —SR 8 , —SOR 8 , —SO 2 R 8 , —SO 2
- the invention relates to compounds of general formula (1) wherein
- the invention relates to compounds of general formula (1), wherein
- the invention also relates to compounds of general formula (1), wherein
- the invention also includes compounds of general formula (1), wherein
- the invention relates to compounds of general formula (1), or the pharmaceutically active salts thereof, as pharmaceutical compositions.
- the invention relates to compounds of general formula (1), or the pharmaceutically active salts thereof, for use as pharmaceutical compositions with an antiproliferative activity.
- the invention includes compounds of general formula (1), or the pharmaceutically active salts thereof, for use as pharmaceutical compositions with an antiproliferative activity with a selective kinase-inhibiting mechanism of activity.
- the invention relates to the use of compounds of general formula (1), or the pharmaceutically active salts thereof, for preparing a pharmaceutical composition with an antiproliferative activity with a PLK inhibiting mechanism of activity.
- the invention relates to pharmaceutical preparations, containing as active substance one or more compounds of general formula (I), or the physiologically acceptable salts thereof, optionally in conjunction with conventional excipients and/or carriers.
- the invention relates to the use of one or more compounds of general formula (1) for preparing a pharmaceutical composition for the treatment and/or prevention of cancer, infections, inflammatory and autoimmune diseases.
- the invention relates to a pharmaceutical preparation containing at least one compound of general formula (1)
- alkyl substituents are meant in each case saturated, straight-chain or branched aliphatic hydrocarbon groups (alkyl group).
- alkenyl substituents are in each case straight-chain or branched, unsaturated alkyl groups which have at least one double bond.
- alkynyl substituents are meant in each case straight-chain or branched, unsaturated alkyl groups which have at least one triple bond.
- Haloalkyl refers to alkyl groups wherein one or more hydrogen atoms are replaced by halogen atoms.
- Haloalkyl includes both saturated alkyl groups and unsaturated alkenyl and alkynyl groups, such as for example —CF 3 , —CHF 2 , —CH 2 F, —CF 2 CF 3 , —CHFCF 3 , —CH 2 CF 3 , —CF 2 CH 3 , —CHFCH 3 , —CF 2 CF 2 CF 3 , —CF 2 CH 2 CH 3 , —CHFCH 2 CH 3 and —CHFCH 2 CF 3 .
- Halogen relates to fluorine, chlorine, bromine and/or iodine atoms.
- pseudohalogen are meant the following groups: —OCN, —SCN, —CF 3 and —CN.
- cycloalkyl is meant a mono- or bicyclic ring, while the ring system may be a saturated ring or an unsaturated, non-aromatic ring, which may optionally also contain double bonds, such as for example cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, norbornyl, norbornenyl, spiro[5.5]undecane, spiro[5.4]decane and spiro[4.4]nonane.
- Aryl relates to monocyclic or bicyclic rings with 6-12 carbon atoms such as for example phenyl and naphthyl.
- heteroaryl mono- or bicyclic rings which contain instead of one or more carbon atoms one or more identical or different heteroatoms, such as e.g. nitrogen, sulphur or oxygen atoms.
- heteroaryl mono- or bicyclic rings which contain instead of one or more carbon atoms one or more identical or different heteroatoms, such as e.g. nitrogen, sulphur or oxygen atoms.
- heteroaryl examples include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl and triazinyl.
- bicyclic heteroaryl groups are indolyl, isoindolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, indazolyl, isoquinolinyl, quinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl and benzotriazinyl, indolizinyl, oxazolopyridinyl, imidazopyridinyl, naphthyridinyl, indolinyl, isochromanyl, chromanyl, tetrahydroisoquinolinyl, isoindolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl, benzoxazolyl,
- Heterocyclyl relates to saturated or unsaturated, non-aromatic mono-, bicyclic or bridged bicyclic rings comprising 5-12 carbon atoms, which carry heteroatoms, such as nitrogen, oxygen or sulphur, instead of one or more carbon atoms.
- heterocyclyl groups are tetrahydrofuranyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, indolinyl, isoindolinyl, morpholinyl, thiomorpholinyl, homomorpholinyl, homopiperidyl, homopiperazinyl, thiomorpholinyl-S-oxide, thiomorpholinyl-S,S-dioxide, tetrahydropyranyl, piperidinyl, tetrahydrothienyl, homopiperidinyl, homothiomorpholinyl-S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidin
- the compounds according to the invention may be prepared according to methods of synthesis A to C described hereinafter, wherein the substituents of general formulae (I to XVI) have the meanings given hereinbefore.
- the intermediate compound III is prepared by substitution of a leaving group LG, for example halogen, SCN or methoxy, preferably chlorine, in a heteroaromatic system I by a nucleophile II.
- LG for example halogen, SCN or methoxy, preferably chlorine
- a solvent for example 1,4-dioxane, tetrahydrofuran, ethanol, isopropanal, N,N-dimethylformamide or N,N-dimethylacetamide.
- a base for example potassium carbonate, sodium carbonate, caesium carbonate, N-ethyl-N,N-diisopropylamine or triethylamine.
- the solvent is distilled off and the residue is combined with water which has been adjusted to a pH of between 1-4 with an inorganic acid, for example hydrochloric acid or sulphuric acid.
- an inorganic acid for example hydrochloric acid or sulphuric acid.
- This mixture is extracted two to three times with an organic solvent, for example diethyl ether, ethyl acetate or dichloromethane.
- the combined organic extracts are dried and the solvent is distilled off.
- the residue is purified by chromatography.
- the end compound V is prepared by substitution of a leaving group LG, for example halogen, SCN or methoxy, preferably chlorine, in a heteroaromatic system III by a nucleophile IV.
- LG for example halogen, SCN or methoxy, preferably chlorine
- 1 equivalent of the compound III and 1 to 3 equivalents of the compound IV are stirred in a solvent, for example 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide or N-methyl-2-pyrrolidinone.
- a solvent for example 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide or N-methyl-2-pyrrolidinone.
- 1 to 2 equivalents of an inorganic acid for example sulphuric acid or hydrochloric acid
- the intermediate compound VII is prepared by substitution of a leaving group LG, for example halogen, SCN, methoxy, preferably chlorine, in a heteroaromatic system I by a nucleophile VI.
- LG for example halogen, SCN, methoxy, preferably chlorine
- a base for example potassium carbonate, sodium carbonate, caesium carbonate, potassium hydrogen phosphate, N-ethyl-N,N-diisopropylamine or triethylamine are added.
- the reaction mixture is stirred for 6 to 72 h more at a temperature of 20 to 120° C.
- the reaction mixture is combined with water, which has been adjusted to a pH of 8 to 9 with an inorganic base, for example sodium hydrogen carbonate or potassium carbonate.
- This mixture is extracted two to three times with an organic solvent, for example diethyl ether or ethyl acetate.
- the intermediate compound VIII is prepared by substituting a leaving group LG, for example halogen, SCN, methoxy, preferably chlorine, in a heteroaromatic system VII by a nucleophile IV.
- LG for example halogen, SCN, methoxy, preferably chlorine
- 1 equivalent of the compound VII and 1 to 1.5 equivalents of the compound IV are stirred in a solvent, for example 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide or N-methyl-2-pyrrolidinone.
- a solvent for example 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide or N-methyl-2-pyrrolidinone.
- an acid for example sulphuric acid or hydrochloric acid
- the reaction mixture is stirred for another 12 to 72 h at a temperature of 20 to 100° C.
- the reaction mixture is stirred into water and the resulting precipitate is filtered off and dried.
- the precipitate may be purified by chromatography or crystallisation or used as the crude product in the next step.
- 1 equivalent of the compound VIII, 1 to 1.5 equivalents of the compound IX and 1 to 3 equivalents of a base, for example triethylamine or ethyldiisopropylamine, are stirred in a solvent, for example 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide or N-methyl-2-pyrrolidinone.
- a base for example triethylamine or ethyldiisopropylamine
- a coupling reagent for example N,N-dicyclohexylcarbodiimide, N,N-diisopropyl-carbodiimide, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-tetrafluoroborate or 1-(3-N,N-dimethylaminopropyl)-3-ethylcarbodiimide are added.
- the reaction mixture is stirred for another 4 to 24 h at a temperature of 15 to 25° C. Then the solvent is distilled off and the residue is purified by chromatography.
- the intermediate compound XI is prepared by substituting a leaving group LG, for example halogen, SCN, methoxy, preferably chlorine, at a heteroaromatic system I with a nucleophilic group IV.
- LG for example halogen, SCN, methoxy, preferably chlorine
- a base for example triethylamine or ethyldiisopropylamine
- a solvent for example 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide or N,N-dimethylacetamide.
- 0.8 to 1.5 equivalents of a compound IV are added.
- the reaction mixture is stirred for 6 to 72 h at a temperature of 15 to 75° C. Then the solvent is distilled off and the residue is purified by chromatography.
- the end compound V is prepared by substitution of a leaving group LG, for example halogen, SCN, methoxy, preferably chlorine, at a heteroaromatic system XI by a nucleophile II.
- LG for example halogen, SCN, methoxy, preferably chlorine
- 1 equivalent of the compound XI and 1 to 1.5 equivalents of the compound II are stirred in a solvent, for example 1,4-dioxane, N,N-dimethyl-formamide, N,N-dimethylacetamide or N-methyl-2-pyrrolidinone.
- a solvent for example 1,4-dioxane, N,N-dimethyl-formamide, N,N-dimethylacetamide or N-methyl-2-pyrrolidinone.
- 1 to 2 equivalents of an acid for example sulphuric acid or hydrochloric acid
- MLC medium pressure chromatography
- silica gel made by Millipore (name: Granula Silica Si-60A 35-70 ⁇ m) or C-18 RP-silica gel made by Macherey Nagel (name: Polygoprep 100-50 C18) is used.
- the measurement is carried out in deuterised dimethylsulphoxide-d6. If other solvents are used they are explicitly mentioned in the Examples or in the methods.
- the measurements are given on a delta scale in ppm. Tetramethylsilane is taken as the standard.
- the measurements are carried out on an Avance 400 (400 MHz NMR spectrometer) made by Messrs Bruker Biospin GmbH.
- the NMR spectra are given purely in a descriptive capacity. Basically, only the visible molecular signals are listed. If for example molecular signals are partly or completely masked by foreign signals such as for example water signals, DMSO signals or CDCl 3 signals they are not mentioned.
- the apparatus is constructed so that a diode array detector (G1315B made by Agilent) and a mass detector (1100 LS-MSD SL; G1946D; Agilent) are connected in series downstream of the chromatography apparatus (column: Zorbax SB-C8, 3.5 ⁇ m, 2, 1*50, Messrs. Agilent).
- the apparatus is operated with a flow of 0.6 ml/min. For a separation process a gradient is run through within 3.5 min (start of gradient: 95% water and 5% acetonitrile; end of gradient: 5% water and 95% acetonitrile; in each case 0.1% formic acid is added to the two solvents).
- reaction mixture is diluted with 250 ml of ethyl acetate and washed first with 300 ml aqueous 10% KHSO 4 solution, then with 300 ml saturated aqueous NaCl solution.
- the organic phase is dried with MgSO 4 and the solvent is eliminated in vacuo.
- the crude product is purified by column chromatography.
- the carrier used is silica gel and the eluant is a mixture of cyclohexane:ethyl acetate (75:25).
- the solvent is eliminated in vacuo and the crude product is purified by chromatography with C18-RP silica gel and an eluant mixture of acetonitrile and water in the ratio 5:95 to 95:5, to which 0.1% formic acid has been added.
- the combined organic phases are washed twice with 200 ml saturated sodium hydrogen carbonate solution and once with 150 ml distilled water. Then the organic phase is dried with MgSO 4 and the solvent is eliminated in vacuo.
- the crude product is dissolved in 250 ml of methanol and combined with 4.5 g Raney nickel. The reaction mixture is hydrogenated for 16 h at 3 bar H 2 pressure and 25° C. Then the catalyst is filtered off and the solvent is eliminated in vacuo.
- the crude product is purified by column chromatography.
- the carrier used is silica gel and the eluant used is a mixture of cyclohexane:ethyl acetate (75:25).
- N-indan-4-yl-acetamide 147 mg (0.84 mmol) N-indan-4-yl-acetamide are dissolved in 10 ml acetone and combined with 770 ⁇ l of a 15% aqueous magnesium sulphate solution. The solution is cooled to 0° C. and 397 mg (2.490 mmol) potassium permanganate are added batchwise. After 2 h the mixture is diluted with 50 ml of water, and extracted three times with 20 ml chloroform. The organic phase is dried with magnesium sulphate and the solvent is eliminated in vacuo and the crude product is purified by chromatography.
- the carrier used is silica gel and the eluant used is a mixture of cyclohexane:ethyl acetate (85:15).
- the organic phase is dried with magnesium sulphate, the solvent is eliminated in vacuo and the crude product is purified by chromatography.
- the carrier used is silica gel and the eluant used is a mixture of dichloromethane:methanol (95:5).
- the organic phase is dried with MgSO 4 and the solvent is eliminated in vacuo.
- the crude product is suspended in 10 ml n-hexane and refluxed.
- the precipitate is filtered off, suspended in 48 ml of a saturated aqueous sodium hydrogen carbonate solution and heated to 65° C. for 1 h. Then the solution is crystallised at 0° C.
- the precipitate is filtered off, the filtrate is acidified with 1 N aqueous hydrochloric acid and combined with 100 ml of ethyl acetate.
- the organic phase is separated off, dried with magnesium sulphate and the solvent is eliminated in vacuo. The residue is recrystallised from ethyl acetate.
- the carrier used is C18-RP-silica gel and a gradient is run through which consists of 95% water and 5% acetonitrile at the starting point and consists of 5% water and 95% acetonitrile at the finishing point. 0.1% formic acid is added in each case to both the water and to the acetonitrile.
- the carrier used is C18-RP-silica gel and a gradient is run through which consists of 95% water and 5% acetonitrile at the starting point and consists of 5% water and 95% acetonitrile at the finishing point. 0.1% formic acid is added to both the water and the acetonitrile. The suitable fractions are freeze-dried. 71 mg of the intermediate product thus obtained are dissolved in 50 ml of methanol and combined with 10 mg palladium on charcoal. The reaction mixture is stirred for 48 h at ambient temperature and 4.5 bar H 2 pressure. 50 ml dichloromethane are added to the reaction solution, the mixture is treated for 5 min in the ultrasound bath and then the catalyst is filtered off. The solvent is eliminated in vacuo.
- the residue is taken up in dichloromethane and washed with water.
- the organic phase is dried with magnesium sulphate, the solvent is eliminated in vacuo and the crude product is purified by chromatography.
- the carrier used is silica gel and the eluant used is a mixture of cyclohexane:ethyl acetate (70:30).
- the suction filter is washed batchwise with a total of 500 ml of a mixture of dichloromethane, methanol and aqueous conc. ammonia (90:9:1). The majority of the solvent is eliminated at a vacuum of 200 mbar and a sump temperature of approx. 50° C. The product is distilled at 69-71° C. and 10 mbar.
- the carrier used is C18-RP-silica gel and a gradient is run through which consists of 95% water and 5% acetonitrile at the starting point and consists of 20% water and 80% acetonitrile at the finishing point. 0.1% formic acid are added to both the water and to the acetonitrile. The suitable fractions are combined with dichloromethane, the organic phase is separated off, dried and the solvent is eliminated in vacuo.
- the following compounds are prepared analogously to this process.
- the aniline derivatives used are described in the supplements to method 2, in method 10 and in the supplements to method 10.
- the preparation of the 2,4-dichloropyrimidine derivatives is known from the literature or may be carried out by methods known from the literature.
- the reaction mixture is cooled, diluted with 100 ml of ethyl acetate and washed twice with 0.5 N sodium hydroxide solution.
- the organic phase is dried with magnesium sulphate and the solvent is eliminated in vacuo.
- the residue is taken up in dichloromethane and combined with 4 M dioxanic hydrochloric acid.
- the mixture is stirred for 72 h at ambient temperature. It is diluted with ethyl acetate and extracted 4 times with 1 N hydrochloric acid.
- the aqueous phases are combined and extracted once with ethyl acetate.
- the aqueous phase is made basic with sodium hydroxide solution and extracted three times with ethyl acetate.
- the organic phases are combined, dried and the solvent is eliminated in vacuo.
- enantiomer 1 The enantiomer that elutes first is known as enantiomer 1 and in the chemical formula bears the symbol *1:
- enantiomer 2 The enantiomer that elutes second is known as enantiomer 2 and in the chemical formula bears the symbol *2:
- the reaction mixture is diluted with dichloromethane and washed three times with concentrated aqueous ammonia solution.
- the organic phase is dried with magnesium sulphate and the solvent is eliminated in vacuo.
- the residue is purified by column chromatography.
- the carrier used is C18-RP-silica gel and a gradient is run through which consists of 98% water and 2% acetonitrile at the starting point and 2% water and 98% acetonitrile at the finishing point. 0.1% formic acid are added to both the water and to the acetonitrile.
- the suitable fractions are freeze-dried.
- This intermediate product is dissolved in 2 ml dioxane and combined with 5 ml concentrated hydrochloric acid.
- the reaction mixture is refluxed for 24 h with stirring. Then it is diluted with water and extracted three times with dichloromethane. The combined organic phases are again washed with water, dried and the solvent is removed. The residue is purified by column chromatography.
- the carrier used is silica gel and the eluant used is dichloromethane, to which 5% of a mixture of 90% methanol and 10% saturated aqueous ammonia solution have been added.
- the carrier used is C18-RP-silica gel and a gradient is run through which consists of 95% water and 5% acetonitrile at the starting point and 5% water and 95% acetonitrile at the finishing point. 0.1% formic acid are added to both the water and to the acetonitrile. The suitable fractions are freeze-dried. This intermediate product is dissolved in 50 ml of methanol combined with 10 mg palladium on charcoal and hydrogenated for 20 h at 5 bar hydrogen pressure and ambient temperature. Then the catalyst is filtered off and the solvent is eliminated in vacuo. The residue is purified by column chromatography.
- the carrier used is C18-RP-silica gel and a gradient is run through which consists of 95% water and 5% acetonitrile at the starting point and consists of 5% water and 95% acetonitrile at the finishing point. 0.1% formic acid are added to both the water and to the acetonitrile. The suitable fractions are freeze-dried.
- reaction mixture 1 1.9 g (47.577 mmol) sodium hydroxide are dissolved in 40 ml of water cooled to 0° C. and combined with 0.5 ml (28.899 mmol) bromine.
- reaction mixture 1 is slowly added dropwise to this solution. After 8 h the same amount of reaction mixture 1 is added again. The mixture is stirred for a further 48 h at RT. Then sodium sulphite solution is added, the mixture is stirred for 20 min and then acidified with potassium hydrogen sulphate solution. It is extracted three times with ethyl acetate. The combined organic phases are dried and the solvent is eliminated in vacuo. The residue is purified by column chromatography.
- the carrier used is silica gel and the eluant used is a mixture of cyclohexane:ethyl acetate (3:1).
- the carrier used is silica gel and the eluant used is dichloromethane, to which 5% of a mixture of 90% methanol and 10% saturated aqueous ammonia solution have been added.
- the concentrated crude product is again purified by column chromatography.
- the carrier used is C18RP-silica gel and a gradient is run through which consists of 80% water and 20% acetonitrile at the starting point and 60% water and 40% acetonitrile at the finishing point.
- the following compounds are prepared by an analogous method to that described in Example 53.
- the corresponding aniline is described in method 2, 7, 8, or 9 or known from the literature.
- the amine used to prepare the amide is commercially obtainable or is described in method 13.
- 2-(4-Carboxy-2-methoxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine may be prepared according to method 12 or 14.
- the corresponding aniline is described in the supplements to method 10.
- the amine used to prepare the amide is commercially obtainable or is described in method 13, in the supplements to method 13, 15 or 25.
- the following compounds are prepared by an analogous method to that described in Example 53.
- the preparation of 2-(4-carboxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine is described in method 14.
- the corresponding aniline is described in method 10.
- the amine used to prepare the amide is commercially obtainable or is described in method 13, 15 or 25.
- the carrier used is C18-RP-silica gel and a gradient is run through which consists of 95% water and 5% acetonitrile at the starting point and consists of 5% water and 95% acetonitrile at the finishing point. 0.1% formic acid are added to both the water and to the acetonitrile.
- This compound is prepared analogously to Example 167.
- the aniline used is described in method 10.
- the carrier used is C18-RP-silica gel and a gradient is run through which consists of 95% water and 5% acetonitrile at the starting point and 50% water and 50% acetonitrile at the finishing point. 0.1% formic acid are added to both the water and to the acetonitrile. The suitable fractions are combined with 500 ⁇ l of a 1 N hydrochloric acid and freeze-dried. The product is obtained as the dihydrochloride.
- Example 169 and 170 The following Examples are prepared analogously to Example 169 and 170.
- Example 169 and 170 The following Examples are prepared analogously to Example 169 and 170.
- the residue is taken up in 20 ml dichloromethane and 5 ml of methanol and filtered through aluminium oxide. The aluminium oxide is washed several times with a mixture of dichloromethane and methanol (4:1). The solvent of the combined fractions is eliminated in vacuo. The residue is dissolved in 5 ml dichloromethane and combined with 5 ml trifluoroacetic acid. This mixture is stirred for 3 h at 20° C. and then the solvent is eliminated in vacuo. The crude product is purified by column chromatography.
- the carrier material used is C18-RP-silica gel and a gradient is run through which consists of 90% water and 10% acetonitrile at the starting point and 5% water and 95% acetonitrile at the finishing point. 0.1% formic acid are added both to the water and to the acetonitrile. The suitable fractions are combined with 500 ⁇ l of a 1 N hydrochloric acid and freeze-dried. The product is obtained as the trihydrochloride.
- 2-(4-carboxy-2-methoxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine may be prepared according to method 12 or 14.
- the corresponding aniline is described in method 22.
- the amine used to prepare the amide is commercially obtainable, described in method 13, 15, 20, 21, 23, 24 and 25 or in J. Med. Chem. 2003, 46(5), 702-715.
- the carrier material used is C18-RP-silica gel and a gradient is run through which consists at the starting point of 90% water and 10% acetonitrile and at the finishing point of 55% water and 45% acetonitrile. 0.1% formic acid are added both to the water and to the acetonitrile. The suitable fractions are combined with 500 ⁇ l of a 1 M aqueous hydrochloric acid and freeze-dried. The product is obtained as the dihydrochloride.
- the mixture is stirred for 16 h at 100° C.
- the crude product is purified by column chromatography.
- the carrier material used is C18-RP-silica gel.
- a gradient is run through which consists at the starting point of 75% water and 25% acetonitrile and at the finishing point of 30% water and 70% acetonitrile. 0.1% ammonia is added to the water.
- 23 mg of this intermediate product and 0.018 g (0.094 mmol) p-toluenesulphonyl chloride are suspended in 0.9 ml of tetrahydrofuran and 0.02 ml (0.139 mmol) triethylamine and combined with 0.007 g (0.057 mmol) 4-dimethylamino-pyridine.
- This reaction mixture is stirred for 16 h at 20° C. Then it is combined with 0.36 ml (5.064 mmol) pyrrolidine and stirred for 16 h at 60° C.
- the crude product is purified by column chromatography.
- the carrier material used is C18-RP-silica gel. A gradient is run through which consists of 90% water and 10% acetonitrile at the starting point and of 60% water and 40% acetonitrile at the finishing point. 0.1% formic acid is added to the water.
- the residue is purified by column chromatography.
- the carrier material used is C18-RP-silica gel and within 15 min a gradient is run through which consists of 95% water and 5% acetonitrile at the starting point and 5% water and 95% acetonitrile at the finishing point. 0.1% formic acid are added both to the water and to the acetonitrile.
- the suitable fractions are combined with 500 ⁇ l of a 1 M aqueous hydrochloric acid and freeze-dried. The product is obtained as the dihydrochloride.
- 2-(4-Carboxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine may be prepared according to method 14.
- the corresponding aniline is described in method 22.
- the amine used to prepare the amide is commercially obtainable or described in method 13.
- the group R 3 ′ may be synthesised analogously to Example 639 by reductive amination.
- An amine is used which has another protected amino function in the side chain.
- the protective group used may be a tert-butoxycarbonyl, benzyloxycarbonyl or benzyl group. This protective group is cleaved by a procedure familiar to the skilled man and reductive amination (analogously to Example 639) or alkylation (analogously to method 34 or WO2004052857) are the last steps in this sequence.
- the carrier material used is C18-RP-silica gel and a gradient is run through within 20 min which consists of 95% water and 5% acetonitrile at the starting point and of 2% water and 98% acetonitrile at the finishing point. 0.1% formic acid are added both to the water and to the acetonitrile. The suitable fractions are combined with 500 ⁇ l of a 1 M aqueous hydrochloric acid and freeze-dried. The product is obtained as the dihydrochloride.
- a primary amine which has another protected amino function in the side chain is coupled to 2-(4-carboxy-2-methoxy-phenylamino)-4-[2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino]-5-trifluoromethyl-pyrimidine.
- the protective group used may be a tert-butoxycarbonyl, benzyloxycarbonyl or benzyl group. This protective group is cleaved using a procedure familiar to the skilled man and reductive amination (analogously to Example 639) or alkylation (analogously to method 34 or WO2004052857) are the final steps in this sequence.
- This intermediate product is combined with 70 mg (0.515 mmol) potassium carbonate and with 84 mg (0.506 mmol) potassium iodide and suspended in 2 ml acetonitrile. 20 ⁇ l (0.170 mmol) 1,4-dibromobutane are added to this mixture and it is stirred under reflux conditions for 16 h. Then the solvents are solvent eliminated in vacuo and the residue is purified by column chromatography.
- the carrier used is C18-RP-silica gel and within 15 min a gradient is run through which consists at the starting point of 90% water and 10% acetonitrile and at the finishing point of 50% water and 50% acetonitrile. 0.1% formic acid are added to both the water and to the acetonitrile. The suitable fractions are combined with 0.5 ml 1 N hydrochloric acid and freeze-dried. The product is obtained as the dihydrochloride.
- the following compounds are prepared by an analogous process to that described in Example 53.
- the corresponding aniline is described in method 31.
- the amine used to prepare the amide is commercially obtainable or is described in method 13, 21 or in method 25.
- the following compounds are prepared by an analogous process to that described in Example 53.
- the corresponding aniline is described in method 31.
- the amine used to prepare the amide is commercially obtainable, described in method 13, 15, 20, 21, 23, 24 and 25 or in J. Med. Chem. 2003, 46(5), 702-715.
- a primary amine which has another protected amino function in the side chain is coupled to 2-(4-carboxy-2-methoxy-phenylamino)-4-[2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino]-5-trifluoromethyl-pyrimidine Enantiomer 1.
- the protective group used may be a tert-butoxycarbonyl, benzyloxycarbonyl or benzyl group. This protective group is cleaved using a procedure familiar to the skilled man and reductive amination (analogously to Example 639) or alkylation (analogously to method 34 or WO2004052857) are the final steps in this sequence.
- eluant 25 ethanol/75 methanol (v/v) (0.03% triethylamine is added to each solvent)
- Enantiomer 1 The enantiomer that elutes first is referred to as Enantiomer 1 and bears the symbol *1 in the chemical formula.
- Enantiomer 2 The enantiomer that elutes second is referred to as Enantiomer 2 and bears the symbol *2 in the chemical formula.
- the following compounds are prepared by an analogous method to that described in Example 53.
- the corresponding aniline is described in method 22.
- the amine used to prepare the amide is commercially obtainable or is described in method 13.
- the following compounds are prepared by an analogous method to that described in Example 53.
- the corresponding aniline is described in method 32.
- the amine used to prepare the amide is commercially obtainable or described in method 13.
- the following compounds are prepared by an analogous method to that described in Example 53.
- the corresponding aniline is described in method 33.
- the amine used to prepare the amide is commercially obtainable or described in method 13 or 21.
- the following compounds are prepared by an analogous method to that described in Example 53.
- the corresponding aniline is described in method 10.
- the amine used to prepare the amide is commercially obtainable or described in method 13.
- the above-mentioned compound is prepared by a method analogous to that described in Example 53.
- the corresponding aniline is described in method 34.
- the amine used to prepare the amide is commercially obtainable.
- the substance is obtained as the dihydrochloride.
- the following compounds are prepared by an analogous method to that described in Example 1037.
- the aniline used is described in method 28.
- the amine used to prepare the amide is commercially obtainable or described in method 13.
- the following compounds are prepared by an analogous method to that described in Example 622 or 623 and 53.
- the corresponding aniline is described in method 28.
- the amine used to prepare the amide is commercially obtainable or described in method 13.
- the following compounds are prepared by an analogous method to that described in Example 1037.
- the corresponding aniline is described in method 28.
- the amine used to prepare the amide is commercially obtainable or described in method 13.
- the inhibition of proliferation brought about by the compounds according to the invention is mediated above all by the arrest of the cells in the G2/M phase of the cell cycle.
- the cells arrest depending on the type of cell used, for a specific length of time in this cell cycle phase before programmed cell death is initiated.
- An arrest in the G2/M phase of the cell cycle may be initiated e.g. by the inhibition of specific cell cycle kinases.
- the compounds of general formula I according to the invention their isomers and the physiologically acceptable salts thereof are suitable for treating diseases characterised by excessive or anomalous cell proliferation.
- Such diseases include for example: viral infections (e.g. HIV and Kaposi's sarcoma); inflammatory and autoimmune diseases (e.g. colitis, arthritis, Alzheimer's disease, glomerulonephritis and wound healing); bacterial, fungal and/or parasitic infections; leukaemias, lymphomas and solid tumours; skin diseases (e.g. psoriasis); bone diseases; cardiovascular diseases (e.g. restenosis and hypertrophy). They are also useful for protecting proliferating cells (e.g. hair, intestinal, blood and progenitor cells) from DNA damage caused by radiation, UV treatment and/or cytostatic treatment (Davis et al., 2001).
- the new compounds may be used for the prevention, short- or long-term treatment of the above-mentioned diseases, also in combination with other active substances used for the same indications, e.g. cytostatics, steroids or antibodies.
- the activity of the compounds according to the invention on various kinases was determined by in vitro kinase assays with recombinantly produced protein. In this assay the compounds exhibit a good to very good effect on PLK1, i.e. for example an IC50 value of less than 1 ⁇ mol/L, usually less than 0.1 ⁇ mol/L.
- Recombinant human PLK1 enzyme linked to GST at its N-terminal end is isolated from insect cells infected with baculovirus (Sf21). Purification is carried out by affinity chromatography on glutathione sepharose columns.
- the cell number is determined, the cells are removed by centrifuging (5 minutes, 4° C., 800 rpm) and washed 1 ⁇ with PBS (8 g NaCl/l, 0.2 g KCl/l, 1.44 g Na 2 HPO 4 /l, 0.24 g KH 2 PO 4 /l). After centrifuging again the pellet is flash-frozen in liquid nitrogen.
- the pellet is quickly thawed and resuspended in ice-cold lysing buffer (50 mM HEPES pH 7.5, 10 mM MgCl 2 , 1 mM DTT, 5 ⁇ g/ml leupeptin, 5 ⁇ g/ml aprotinin, 100 ⁇ M NaF, 100 ⁇ M PMSF, 10 mM ⁇ -glycerolphosphate, 0.1 mM Na 3 VO 4 , 30 mM 4-nitrophenylphosphate) to give 1 ⁇ 10 8 cells/17.5 ml. The cells are lysed for 30 minutes on ice.
- ice-cold lysing buffer 50 mM HEPES pH 7.5, 10 mM MgCl 2 , 1 mM DTT, 5 ⁇ g/ml leupeptin, 5 ⁇ g/ml aprotinin, 100 ⁇ M NaF, 100 ⁇ M PMSF, 10 mM ⁇ -glycerolphosphat
- the clear supernatant is combined with glutathione sepharose beads (1 ml resuspended and washed beads per 50 ml of supernatant) and the mixture is incubated for 30 minutes at 4° C. on a rotating board.
- the protein concentration is determined by Bradford Assay.
- the reaction is started by adding the ATP solution and continued for 45 minutes at 30° C. with gentle shaking (650 rpm on an IKA Schüttler MTS2).
- the reaction is stopped by the addition of 125 ⁇ l of ice-cold 5% TCA per well and incubated on ice for at least 30 minutes.
- the precipitate is transferred by harvesting onto filter plates (96-well microtitre filter plate: UniFilter-96, GF/B; Packard; No. 6005177), then washed four times with 1% TCA and dried at 60° C.
- 35 ⁇ l scintillation solution Ready-Safe; Beckmann
- the plate is sealed shut with sealing tape and the amount of P33 precipitated is measured with the Wallac Betacounter.
- the measured data are evaluated using the standard Graphpad software (Levenburg-Marquard Algorhythmus).
- the anti-proliferative activity of the compounds according to the invention is determined in the cytotoxicity test on cultivated human tumour cells and/or in a FACS analysis, for example on HeLa S3 cells. In both test methods the compounds exhibit good to very good activity, i.e. for example an EC50 value in the HeLa S3 cytotoxicity test of less than 5 ⁇ mol/L, generally less than 1 ⁇ mol/L.
- cells of cervical carcinoma tumour cell line HeLa S3 obtained from American Type Culture Collection (ATCC) are cultivated in Ham's F12 Medium (Life Technologies) and 10% foetal calf serum (Life Technologies) and harvested in the log growth phase. Then the HeLa S3 cells are placed in 96-well plates (Costar) at a density of 1000 cells per well and incubated overnight in an incubator (at 37° C. and 5% CO 2 ), while on each plate 6 wells are filled with medium alone (3 wells as the medium control, 3 wells for incubation with reduced AlamarBlue reagent).
- ATCC American Type Culture Collection
- the active substances are added to the cells in various concentrations (dissolved in DMSO; DMSO final concentration: 0.1%) (in each case as a triple measurement). After 72 hours incubation 20 ⁇ l AlamarBlue reagent (AccuMed International) are added to each well, and the cells are incubated for a further 5-7 hours. As a control, 20 ⁇ l reduced AlamarBlue reagent is added to each of 3 wells (AlamarBlue reagent, which is autoclaved for 30 min). After incubation the colour change of the AlamarBlue reagent in the individual wells is determined in a Perkin Elmer fluorescence spectrophotometer (excitation 530 nm, emission 590 nm, slits 15, integrate time 0.1).
- the amount of AlamarBlue reagent reacted represents the metabolic activity of the cells.
- the relative cell activity is calculated as a percentage of the control (HeLa S3 cells without inhibitor) and the active substance concentration which inhibits the cell activity by 50% (IC50) is derived.
- the values are calculated from the average of three individual measurements—with correction of the dummy value (medium control).
- Propidium iodide binds stoichiometrically to double-stranded DNA, and is thus suitable for determining the proportion of cells in the G1, S, and G2/M phase of the cell cycle on the basis of the cellular DNA content.
- Cells in the G0 and G1 phase have a diploid DNA content (2N), whereas cells in the G2 or mitosis phase have a 4N DNA content.
- HeLa S3 cells are seeded onto a 75 cm2 cell culture flask, and after 24 h either 0.1% DMSO is added as control or the substance is added in various concentrations (in 0.1% DMSO).
- the cells are incubated for 24 h with the substance or with DMSO before the cells are washed 2 ⁇ with PBS and then detached with trypsin/EDTA.
- the cells are centrifuged (1000 rpm, 5 min, 4° C.), and the cell pellet is washed 2 ⁇ with PBS before the cells are resuspended in 0.1 ml PBS. Then the cells are fixed with 80% ethanol for 16 hours at 4° C.
- the fixed cells are centrifuged (1000 rpm, 5 min, 4° C.), washed with PBS and then centrifuged again.
- the cell pellet is resuspended in 2 ml 0.25% Triton X-100 in PBS, and incubated on ice for 5 min before 5 ml PBS are added and the mixture is centrifuged again.
- the cell pellet is resuspended in 350 ⁇ l PI staining solution (0.1 mg/ml RNase A (Sigma, No. R-4875), 10 ⁇ g/ml prodium iodide (Sigma, No. P-4864) in 1 ⁇ PBS).
- the cells are incubated for 20 min in the dark with the staining buffer before being transferred into sample measuring containers for the FACS scan.
- the DNA measurement is carried out in a Becton Dickinson FACS Analyzer, with an argon laser (500 mW, emission 488 nm), and the DNA Cell Quest Programme (BD).
- the logarithmic PI fluorescence is determined with a band-pass filter (BP 585/42).
- the cell populations in the individual cell cycle phases are quantified using the ModFit LT Programme made by Becton Dickinson.
- the compounds according to the invention are also tested accordingly for other tumour cells.
- these compounds are effective on carcinomas of all kinds of tissue (e.g. breast (MCF7); colon (HCT116), head and neck (FaDu), lung (NCI-460), pancreas (BxPC-3), prostate (DU145)), sarcomas (e.g. SK-UT-1B), leukaemias and lymphomas (e.g. HL-60; Jurkat, THP-1) and other tumours (e.g. melanomas (BRO), gliomas (U-87MG)) and could be used for such indications.
- MCF7 breast
- HCT116 colon
- FaDu head and neck
- lung NCI-460
- pancreas BxPC-3
- prostate DU145
- sarcomas e.g. SK-UT-1B
- leukaemias and lymphomas e.g. HL-60; Jurkat, THP-1
- other tumours e.
- the compounds of general formula (I) may be used on their own or in conjunction with other active substances according to the invention, optionally also in conjunction with other pharmacologically active substances.
- Suitable preparations include for example tablets, capsules, suppositories, solutions, particularly solutions for injection (s.c., i.v., i.m.) and infusion, elixirs, emulsions or dispersible powders.
- the content of the pharmaceutically active compound(s) should be in the range from 0.1 to 90 wt.-%, preferably 0.5 to 50 wt.-% of the composition as a whole, i.e. in amounts which are sufficient to achieve the dosage range specified below.
- the doses specified may, if necessary, be given several times a day.
- Suitable tablets may be obtained, for example, by mixing the active substance(s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and/or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate.
- excipients for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and/or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate.
- excipients for example inert dilu
- Coated tablets may be prepared accordingly by coating cores produced analogously to the tablets with substances normally used for tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar.
- the core may also consist of a number of layers.
- the tablet coating may consist of a number or layers to achieve delayed release, possibly using the excipients mentioned above for the tablets.
- Syrups or elixirs containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g. a flavouring such as vanillin or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.
- a sweetener such as saccharine, cyclamate, glycerol or sugar
- a flavour enhancer e.g. a flavouring such as vanillin or orange extract.
- suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.
- Solutions for injection and infusion are prepared in the usual way, e.g. with the addition of isotonic agents, preservatives such as p-hydroxybenzoates, or stabilisers such as alkali metal salts of ethylenediamine tetraacetic acid, optionally using emulsifiers and/or dispersants, whilst if water is used as the diluent, for example, organic solvents may optionally be used as solvating agents or dissolving aids, and transferred into injection vials or ampoules or infusion bottles.
- isotonic agents e.g. with the addition of isotonic agents, preservatives such as p-hydroxybenzoates, or stabilisers such as alkali metal salts of ethylenediamine tetraacetic acid, optionally using emulsifiers and/or dispersants, whilst if water is used as the diluent, for example, organic solvents may optionally be used as solvating agents or dissolving aid
- Capsules containing one or more active substances or combinations of active substances may for example be prepared by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gelatine capsules.
- Suitable suppositories may be made for example by mixing with carriers provided for this purpose, such as neutral fats or polyethyleneglycol or the derivatives thereof.
- Excipients which may be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. groundnut or sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carriers such as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk), synthetic mineral powders (e.g. highly dispersed silicic acid and silicates), sugars (e.g. cane sugar, lactose and glucose) emulsifiers (e.g.
- lignin e.g. lignin, spent sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone
- lubricants e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulphate.
- the preparations are administered by the usual methods, preferably by oral or transdermal route, most preferably by oral route.
- the tablets may, of course contain, apart from the abovementioned carriers, additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gelatine and the like.
- lubricants such as magnesium stearate, sodium lauryl sulphate and talc may be used at the same time for the tabletting process.
- the active substances may be combined with various flavour enhancers or colourings in addition to the excipients mentioned above.
- solutions of the active substances with suitable liquid carriers may be used.
- the dosage for intravenous use is from 1-1000 mg per hour, preferably between 5 and 500 mg per hour.
- the finely ground active substance, lactose and some of the corn starch are mixed together.
- the mixture is screened, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet-granulated and dried.
- the granules, the remaining corn starch and the magnesium stearate are screened and mixed together.
- the mixture is compressed to produce tablets of suitable shape and size.
- the finely ground active substance, some of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is screened and worked with the remaining corn starch and water to form a granulate which is dried and screened.
- the sodiumcarboxymethyl starch and the magnesium stearate are added and mixed in and the mixture is compressed to form tablets of a suitable size.
- the active substance is dissolved in water at its own pH or optionally at pH 5.5 to 6.5 and sodium chloride is added to make it isotonic.
- the solution obtained is filtered free from pyrogens and the filtrate is transferred under aseptic conditions into ampoules which are then sterilised and sealed by fusion.
- the ampoules contain 5 mg, 25 mg and 50 mg of active substance.
Abstract
The present invention encompasses compounds of general formula (1),
wherein
A, W, X, Y, Z, Ra, Rb, Rc, R1 and R3 are defined as in claim 1, which are suitable for the treatment of diseases characterised by excessive or abnormal cell proliferation, and the use thereof for preparing a pharmaceutical composition having the above-mentioned properties.
A, W, X, Y, Z, Ra, Rb, Rc, R1 and R3 are defined as in claim 1, which are suitable for the treatment of diseases characterised by excessive or abnormal cell proliferation, and the use thereof for preparing a pharmaceutical composition having the above-mentioned properties.
Description
- This application is a continuation of U.S. application Ser. No. 11/206,703, filed on Aug. 17, 2005.
- The present invention relates to new pyrimidines of general formula (1),
- wherein the groups A, W, X, Y, Z, Ra, Rb, Rc, R1 and R3 have the meanings given in the claims and description, the isomers thereof, processes for preparing these pyrimidines and their use as pharmaceutical compositions.
- Tumour cells wholly or partly elude regulation and control by the body and are characterised by uncontrolled growth. This is due on the one hand to the loss of control proteins such as for example Rb, p16, p21 and p53 and also to the activation of so-called accelerators of the cell cycle, the cyclin-dependent kinases.
- Studies in model organisms such as Schizosaccharomyces pombe, Drosophila melanogaster or Xenopus laevis as well as investigations in human cells have shown that the transition from the G2 phase to mitosis is regulated by the CDK1/cyclin B kinase (Nurse 1990, Nature 344: 503-508). This kinase, which is also known as “mitosis promoting factor” (MPF), phosphorylates and regulates a plurality of proteins, such as e.g. nuclear lamina, kinesin-like motor proteins, condensins and Golgi Matrix Proteins, which play an important part in the breakdown of the nuclear coat, in centrosome separation, the structure of the mitotic spindle apparatus, chromosome condensation and breakdown of the Golgi apparatus (Nigg. E. 2001, Nat Rev Mol Cell Biol. 2(1):21-32). A murine cell line with a temperature-sensitive CDK-1 kinase mutant shows a rapid breakdown in CDK-1 kinase after temperature increase and a subsequent arrest in the G2/M phase (Th´ng et al. 1990, Cell. 63(2):313-24). The treatment of human tumour cells with inhibitors against CDK1/cyclin B, such as e.g. butyrolactone, leads to an arrest in the G2/M phase and subsequent apoptosis (Nishio, et al. 1996, Anticancer Res. 16(6B):3387-95).
- Moreover, the protein kinase Aurora B has also been described as having an essential function during entry into mitosis. Aurora B phosphorylates histone H3 on Ser10 and thereby initiates chromosome condensation (Hsu et al. 2000, Cell 102:279-91). A specific cell cycle arrest in the G2/M phase may, however, also be initiated e.g. by inhibition of specific phosphatases such as e.g. Cdc25C (Russell and Nurse 1986, Cell 45:145-53). Yeasts with a defective Cdc25 gene arrest in the G2 phase, whereas overexpression of Cdc25 leads to premature entry into the mitosis phase (Russell and Nurse, 1987, Cell 49:559-67). Moreover, an arrest in the G2/M phase may also be initiated by inhibition of specific motor proteins, the so-called kinesins such as for example Eg5 (Mayer et al. 1999, Science 286:971-4), or by microtubuli stabilising or destabilising agents (e.g. colchicin, taxol, etoposide, vinblastine, vincristine) (Schiff and Horwitz 1980, Proc Natl Acad Sci USA 77:1561-5).
- In addition to the cyclin-dependent and Aurora kinases the so-called polo-like kinases, a small family of serine/threonine kinases, also play an important role in the regulation of the eukaryotic cell cycle. Up till now the polo-like kinases PLK-1, PLK-2, PLK-3 and PLK-4 have been described in the literature. PLK-1 in particular has been found to play a central role in the regulation of the mitosis phase. PLK-1 is responsible for the maturation of the centrosomes, for the activation of phosphatase Cdc25C, as well as for the activation of the Anaphase Promoting Complex (Glover et al. 1998, Genes Dev. 12:3777-87; Qian et al. 2001, Mol Biol Cell. 12:1791-9). The injection of PLK-1 antibodies leads to a G2 arrest in untransformed cells, whereas tumour cells arrest during the mitosis phase (Lane and Nigg 1996, J. Cell Biol. 135:1701-13). Overexpression of PLK-1 has been demonstrated in various types of tumour, such as non-small-cell carcinoma of the lung, plate epithelial carcinoma, breast and colorectal carcinoma (Wolf et al. 1997, Oncogene 14:543-549; Knecht et al. 1999, Cancer Res. 59:2794-2797; Wolf et al. 2000, Pathol. Res. Pract. 196:753-759; Takahashi et al. 2003, Cancer Sci. 94: 148-52). Therefore, this category of proteins also presents an interesting point of attack for therapeutic intervention in proliferative diseases (Liu and Erikson 2003, Proc Natl Acad Sci USA 100:5789-5794).
- Pyrimidines are generally known as inhibitors of kinases. Thus, for example, pyrimidines are described as an active component with an anticancer activity in International Patent Application WO 00/53595, which describes the use of 2,4,5-substituted pyrimidines with a heterocyclic group in the 4-position and an anilino group in the 2 position, which in turn comprises a side chain with the length of at least one n-propyl group.
- Moreover, International Patent Application WO 00/39101 describes the use of 2,4,5-substituted pyrimidines as compounds with an anticancer activity which are linked in the 2- and 4-position with an aromatic or heteroaromatic ring, at least one of which comprises a side chain with the length of at least one n-propyl group.
- International Patent Application WO 97/19065 further proposes the use of 2,4,5-substituted pyrimidines with a 3,4-dialkoxyanilino group in position 2 as kinase inhibitors.
- International Patent Application WO 02/04429 describes 2,4,5-substituted pyrimidines with a cyano group in position 5 and their cell cycle inhibiting effect.
- International Patent Application WO 03/063794 describes the use of 2,4-pyrimidinediamines as inhibitors of the IgE and/or IgG receptor signal cascade.
- Antiviral 2,4,5-substituted pyrimidines, wherein the groups Rc and Rd form a heteroaromatic five-membered ring at the nitrogen of the 4-position, are known from International Patent Application WO 99/41253.
- 2,4,5-substituted pyrimidines which carry (hetero)aryls in position 2 and 4 (WO00/27825) and also 2,4,5-substituted pyrimidines which carry a (hetero)aryl group functionalised with a nitrile group in position 2 or 4 (EP 0 945 443 A1) are described as having an antiviral activity.
- The resistance of many types of tumour demands that new drugs be developed to fight the tumours. The aim of the present invention is therefore to indicate new active substances which may be used for the prevention and/or treatment of diseases characterised by excessive or anomalous cell proliferation.
- It has now been found that, surprisingly, compounds of general formula (1), wherein the groups A, W, X, Y, Ra, Rb, Rc, R1, R2 and R3 are defined as hereinafter, act as inhibitors of specific cell cycle kinases. Thus, the compounds according to the invention may be used for example for the treatment of diseases associated with the activity of specific cell cycle kinases and characterised by excessive or anomalous cell proliferation.
- The present invention relates to compounds of general formula (1)
- wherein
- W denotes N or C—R2,
- X denotes —NR1a, O or S,
- Y denotes CH or N,
- Z denotes hydrogen, halogen, —NO2, C1-3alkyl, C2-3alkenyl, C2-3alkynyl, halogen-C1-3alkyl, —COH, —C(═O)—C1-3alkyl, —C(═O)—C2-3alkenyl, —C(═O)—C2-3alkynyl, —C(═O)C1-3alkyl-halogen or pseudohalogen;
- A is selected from the formulae (i), (ii) or (iii)
- Q1 denotes mono- or bicyclic aryl compounds;
- B1, B2, B3 and B4 in each case independently of one another denote C—RgRh, N—Ri, O or S, while adjacent B1-B4 in each case do not represent —O—;
- R1 and R1a each independently of one another denote hydrogen or methyl,
- R2 denotes a group selected from among hydrogen, halogen, —OR4, —C(═O)R4, —C(═O)NR4R5, —NR4R5, —NR4C(═O)R5, —NR4SO2R5, —N═CR4R5, —C═NRi, —SR4, —SOR4, —SO2R4, —SO2NR4R5 and pseudohalogen, or an optionally mono- or polysubstituted group selected from among C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6-cycloalkyl, aryl, heterocyclyl and heteroaryl, while the substituent(s) may be identical or different and are selected from among halogen, —NO2, —OR4, —C(═O)R4, —C(═O)OR4, —C(═O)NR4R5, —NR4R5, —NR4C(═O)R5, —NR4C(═O)OR5, —NR4C(═O)NR5R6, —NR4SO2R5, —N═CR4R5, —SR4, —SOR4, —SO2R4, —SO2NR4R5, —NR4SO2NR5R6, —OSO2NR5R6 and pseudohalogen;
- Ra, Rb, Rc, Rd, Re, Rf, Rg and Rh in each case independently of one another denote a group selected from among hydrogen, halogen, ═O, —NO2, —OR4, —C(═O)R4, —C(═O)OR4, —C(═O)NR4R5, —NR4R5, —NR4C(═O)R5, —NR4C(═O)OR5, —NR4C(═O)NR5R6, —NR4SO2R5, —N═CR4R5, —C═NRi, —SR4, —SOR4, —SO2R4, —SO2NR4R5, —NR4SO2NR5R6, —OSO2NR5R6 and pseudohalogen; or an optionally mono- or polysubstituted group selected from among C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-6-cycloalkyl, aryl, heterocyclyl and heteroaryl, while the substituent(s) may be identical or different and are selected from among halogen, R8, —NO2, —OR4, —C(═O)R4, —C(═O)OR4, —C(═O)NR4R5, —NR4R5, —NR4C(═O)R5, —NR4C(═O)OR5, —NR4C(═O)NR5R6, —NR4SO2R5, —N═CR4R5, —SR4, —SOR4, —SO2R4, —SO2NR4R5, —NR4SO2NR5R6, —OSO2NR5R6 and pseudohalogen; and optionally the Rg and Rh located at the same or at adjacent C atoms may be attached in any combination to a common saturated or partially unsaturated 3-5-membered alkyl bridge which may contain one to two heteroatoms;
- Ri denotes a group selected from among hydrogen, ═O, —OR4, —C(═O)R4, —C(═O)OR4, —C(═O)NR4R5, —NR4R5, —NR4C(═O)R5, —NR4C(═O)OR5, —NR4C(═O)NR5R6, —NR4SO2R5, —N═CR4R5, —SR4, —SOR4, —SO2R4, —SO2NR4R5, —NR4SO2NR5R6, —OSO2NR5R6 and pseudohalogen; or an optionally mono- or polysubstituted group selected from among C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, aryl, heterocyclyl and heteroaryl, while the substituent(s) may be identical or different and are selected from among halogen, R8, —NO2, —OR4, —C(═O)R4, —C(═O)OR4, —C(═O)NR4R5, —NR4R5, —NR4C(═O)R5, —NR4C(═O)OR5, —NR4C(═O)NR5R6, —NR4SO2R5, —N═CR4R5, —SR4, —SOR4, —SO2R4, —SO2NR4R5, —NR4SO2NR5R6, —OSO2NR5R6 and pseudohalogen; and optionally the Ri groups located at adjacent N atoms may be joined together or Ri with Rg or Rh located at adjacent C atoms may be attached in any combination to a common saturated or partially unsaturated 3-5-membered alkyl bridge which may contain one to two heteroatoms;
- R3 is selected from the formulae (iv)-(x),
- R4, R5 and R6 each independently of one another denote hydrogen or a group selected from among optionally mono- or polysubstituted C1-5-alkyl, C2-5alkenyl, C2-5alkynyl, C3-10cycloalkyl, aryl, heterocyclyl and heteroaryl, while the substituent(s) may be identical or different and are selected from among C3-10-cycloalkyl, aryl, heterocyclyl, heteroaryl, halogen, —NO2, —OR8, —C(═O)R8, —C(═O)OR8, —C(═O)NR8R9, —NR8R9, —NR8C(═O)R9, —NR8C(═O)OR9, —NR8C(═O)NR9R10, —NR8C(═O)ONR9R10, —NR8SO2R9, —N═CR8R9, —SR8, —SOR8—SO2R8, —SO2NR8R9, —NR8SO2NR9R10, —OSO2NR8R9 and pseudohalogen;
- L denotes a bond or a group selected from among optionally mono- or polysubstituted C1-16-alkyl, C2-16-alkenyl, C2-16-alkynyl, C3-10-cycloalkyl, aryl, heterocyclyl and heteroaryl, while the substituent(s) may be identical or different and are selected from among halogen, —NO2, —OR8, —C(═O)R8, —C(═O)OR8, —C(═O)NR8R9, —NR8R9, —NR8C(═O)R9, —NR8C(═O)OR9, —NR8C(═O)NR9R10, —NR8C(═O)ONR9R10, —NR8SO2R9, —N═CR8R9, —SR8, —SOR8, —SO2R8, —SO2NR8R9, —NR8SO2NR9R10, —OSO2NR8R9 and pseudohalogen;
- Q2 and Q3 independently of one another denote a bond or a group selected from among optionally mono- or polysubstituted C1-16-alkyl, C2-16-alkenyl, C2-16 alkynyl, C3-10-cycloalkyl, aryl, heterocyclyl and heteroaryl while the substituent(s) may be identical or different and are selected from among halogen, —NO2, —OR8, —C(═O)R8, —C(═O)OR8, —C(═O)NR8R9, —NR8R9, —NR8C(═O)R9, —NR8C(═O)OR9, —NR8C(═O)NR9R10, —NR8C(═O)ONR9R10, —NR8SO2R9, —N═CR8R9, —SR8, —SOR8, —SO2R8, —SO2NR8R9, —NR8SO2NR9R10, —OSO2NR8R9 and pseudohalogen;
- R7 denotes hydrogen or a group selected from among optionally mono- or polysubstituted C1-16-alkyl, C2-16-alkenyl, C2-16-alkynyl, C3-10-cycloalkyl, aryl, heterocyclyl and heteroaryl, while the substituent(s) may be identical or different and are selected from among halogen, NO2, —OR8, —C(═O)R8, —C(═O)OR8, —C(═O)NR8R9, —NR8R9, —NR8COR9, —NR8C(═O)OR9, —NR8C(═O)NR9R10, —NR8C(═O)ONR9R10, —NR8SO2R9, —N═CR8R9, —SR8, —SOR8, —SO2R8, —SO2NR8R9, —NR8SO2NR9R10, —OSO2NR8R9 and pseudohalogen;
- R8, R9 and R10 each independently of one another denote hydrogen or a group selected from among optionally substituted C1-8-alkyl, C2-8-alkenyl, C2-8-alkynyl, C3-10-cycloalkyl, aryl, heterocyclyl and heteroaryl, while the substituent(s) may be identical or different and are selected from among halogen, methyl, ethyl, amino, methylamino, dimethylamino, —OH and pseudohalogen;
optionally in the form of the tautomers, racemates, enantiomers, diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof. - In one aspect the invention relates to compounds of general formula (1) wherein
- W denotes C—R2 and the other groups are as hereinbefore defined.
- In another aspect the invention relates to compounds of general formula (1), wherein
- X denotes —NR1a or oxygen,
- R1 and R1a denote hydrogen;
- R3 denotes formula (iv) or (x),
- and the other groups are as hereinbefore defined.
- In another aspect the invention relates to compounds of general formula (1), wherein
- Y denotes CH and
- Q1 denotes monocyclic aryl compounds and the other groups are as hereinbefore defined.
- In one aspect the invention relates to compounds of general formula (1), wherein
- Rc denotes a group selected from among hydrogen, —F, —Cl, methyl and ethyl and the other groups are as hereinbefore defined.
- In another aspect the invention relates to compounds of general formula (1), wherein
- Ra and Rb each independently of one another denote hydrogen or fluorine;
- or an optionally mono- or polysubstituted group selected from among C1-2-alkyl, C2-alkenyl, C2-alkynyl, C3-6-cycloalkyl, aryl, heterocyclyl and heteroaryl, while the substituent(s) may be identical or different and are selected from among hydrogen, halogen, —NO2, —OR4, —C(═O)R4, —C(═O)OR4, —C(═O)NR4R5, —NR4R5, —NR4C(═O)R5, —NR4C(═O)OR5, —NR4C(═O)NR5R6, —NR4SO2R5, —N═CR4R5, —SR4, —SOR5, —SO2R4, —SO2NR4R5, —NR4, —SO2NR4R5, —OSO2NR4R5 and pseudohalogen
and the other groups are as hereinbefore defined.
- or an optionally mono- or polysubstituted group selected from among C1-2-alkyl, C2-alkenyl, C2-alkynyl, C3-6-cycloalkyl, aryl, heterocyclyl and heteroaryl, while the substituent(s) may be identical or different and are selected from among hydrogen, halogen, —NO2, —OR4, —C(═O)R4, —C(═O)OR4, —C(═O)NR4R5, —NR4R5, —NR4C(═O)R5, —NR4C(═O)OR5, —NR4C(═O)NR5R6, —NR4SO2R5, —N═CR4R5, —SR4, —SOR5, —SO2R4, —SO2NR4R5, —NR4, —SO2NR4R5, —OSO2NR4R5 and pseudohalogen
- In another aspect the invention also relates to compounds of general formula (1), wherein
- Ra and Rb denote hydrogen or fluorine and the other groups are as hereinbefore defined.
- The invention also includes compounds of general formula (1), wherein
- Z denotes halogen-C1-3-alkyl, —COH, —C(═O)—C1-3-alkyl, —C(═O)—C2-3-alkenyl, —C(═O)—C2-3-alkynyl, —C(═O)C1-3-alkyl-halogen and pseudohalogen
and the other groups are as hereinbefore defined. - In one aspect the invention relates to compounds of general formula (1), or the pharmaceutically active salts thereof, as pharmaceutical compositions.
- In an essential aspect the invention relates to compounds of general formula (1), or the pharmaceutically active salts thereof, for use as pharmaceutical compositions with an antiproliferative activity.
- Moreover the invention includes compounds of general formula (1), or the pharmaceutically active salts thereof, for use as pharmaceutical compositions with an antiproliferative activity with a selective kinase-inhibiting mechanism of activity.
- In one aspect the invention relates to the use of compounds of general formula (1), or the pharmaceutically active salts thereof, for preparing a pharmaceutical composition with an antiproliferative activity with a PLK inhibiting mechanism of activity.
- In another aspect the invention relates to pharmaceutical preparations, containing as active substance one or more compounds of general formula (I), or the physiologically acceptable salts thereof, optionally in conjunction with conventional excipients and/or carriers.
- In another aspect the invention relates to the use of one or more compounds of general formula (1) for preparing a pharmaceutical composition for the treatment and/or prevention of cancer, infections, inflammatory and autoimmune diseases.
- In another aspect the invention relates to a pharmaceutical preparation containing at least one compound of general formula (1)
- wherein
- W denotes N or C—R2,
- X denotes —NR1a, O or S,
- Y denotes CH or N,
- Z denotes hydrogen, halogen, —NO2, C1-3-alkyl, C2-3-alkenyl, C2-3-alkynyl, halogen-C1-3-alkyl, —COH, —C(═O)—C1-3-alkyl, —C(═O)—C2-3-alkenyl, —C(═O)—C2-3-alkynyl, —C(═O)C1-3-alkyl-halogen and pseudohalogen;
- A is selected from the formulae (i), (ii) or (iii)
- Q1 denotes mono- or bicyclic aryl compounds;
- B1, B2, B3 and B4 in each case independently of one another represent C—RgRh, N—Ri, O or S, while adjacent B1-B4 in each case do not denote —O—;
- R1 and R1a each independently of one another denote hydrogen or methyl,
- R2 denotes a group selected from among hydrogen, halogen, —OR4, —C(═O)R4, —C(═O)NR4R5, —NR4R5, —NR4C(═O)R5, —NR4SO2R5, —N═CR4R5, —C═NR4, —SR4, —SOR4, —SO2R4, —SO2NR4R5 and pseudohalogen, or an optionally mono- or polysubstituted group selected from among C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-6-cycloalkyl, aryl, heterocyclyl and heteroaryl, while the substituent(s) may be identical or different and are selected from among halogen, —NO2, —OR4, —C(═O)R4, —C(═O)OR4, —C(═O)NR4R5, —NR4R5, —NR4C(═O)R5, —NR4C(═O)OR5, —NR4C(═O)NR5R6, —NR4SO2R5, —N═CR4R5, —SR4, —SOR4, —SO2R4, —SO2NR4R5, —NR4SO2NR5R6, —OSO2NR5R6 and pseudohalogen;
- Ra, Rb, Rc, Rd, Re, Rf, Rg and Rh in each case independently of one another denote a group selected from among hydrogen, halogen, ═O, —NO2, —OR4, —C(═O)R4, C═O)OR4, —C(═O)NR4R5, —NR4R5, —NR4C(═O)R5, —NR4C(═O)OR5, —NR4C(═O)NR5R6, —NR4SO2R5, —N═CR4R5, —C═NRi, —SR4, —SOR4, —SO2R4, —SO2NR4R5, —NR4SO2NR5R6, —OSO2NR5R6 and pseudohalogen; or an optionally mono- or polysubstituted group selected from among C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-6-cycloalkyl, aryl, heterocyclyl and heteroaryl, while the substituent(s) may be identical or different and are selected from among halogen, R8, —NO2, —OR4, —C(═O)R4, —C(═O)OR4, —C(═O)NR4R5, —NR4R5, —NR4C(═O)R5, —NR4C(═O)OR5—NR4C(═O)NR5R6, —NR4SO2R5, —N═CR4R5, —SR4, —SOR4, —SO2R4, —SO2NR4R5, —NR4SO2NR5R6, —OSO2NR5R6 and pseudohalogen; and optionally the Rg and Rh located at the same or at adjacent C atoms may be attached in any combination to a common saturated or partially unsaturated 3-5-membered alkyl bridge which may contain one to two heteroatoms;
- Ri denotes a group selected from among hydrogen, ═O)—OR4, —C(═O)R4, —C(═O)OR4, —C(═O)NR4R5, —NR4R5, —NR4C(═O)R5, —NR4C(═O)OR5, —NR4C(═O)NR5R6, —NR4SO2R5, —N═CR4R5, —SR4, —SOR4, —SO2R4, —SO2NR4R5, —NR4SO2NR5R6, —OSO2NR5R6 or an optionally mono- or polysubstituted group selected from among C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-6-cycloalkyl, aryl, heterocyclyl and heteroaryl, while the substituent(s) may be identical or different and are selected from among halogen, R8, —NO2, —OR4, —C(═O)R4, —C(═O)OR4, —C(═O)NR4R5, —NR4R5, —NR4C(═O)R5, —NR4C(═O)OR5, —NR4C(═O)NR5R6, —NR4SO2R5, —N═CR4R5, —SR4, —SOR4, —SO2R4, —SO2NR4R5, —NR4SO2NR5R6, —OSO2NR5R6 and pseudohalogen; and optionally the Ri groups located at adjacent N atoms may be joined together or to Rg and Rh located at adjacent C atoms in any combination with a common saturated or partially unsaturated 3-5-membered alkyl bridge which may contain one to two heteroatoms;
- R3 is selected from the formulae (iv)-(x),
- R4, R5 and R6 each independently of one another denote hydrogen or a group selected from among optionally mono- or polysubstituted C1-5-alkyl, C2-5-alkenyl, C2-5-alkynyl, C3-10-cycloalkyl, aryl, heterocyclyl and heteroaryl, while the substituent(s) may be identical or different and are selected from among C3-10-cycloalkyl, aryl, heterocyclyl, heteroaryl, halogen, —NO2, —OR8, —C(═O)R8, —C(═O)OR8, —C(═O)NR8R9, —NR8R9, —NR8C(═O)R9, —NR8C(═O)OR9, —NR8C(═O)NR9R10, —NR8C(═O)ONR9R10, —NR8SO2R9, —N═CR8R9, —SR8, —SOR8, —SO2R8, —SO2NR8R9, —NR8SO2NR9R10, —OSO2NR8R9 and pseudohalogen;
- L denotes a bond or a group selected from among optionally mono- or polysubstituted C1-16-alkyl, C2-16-alkenyl, C2-16-alkynyl, C3-10-cycloalkyl, aryl, heterocyclyl and heteroaryl, while the substituent(s) may be identical or different and are selected from among halogen, —NO2, —OR8, —C(═O)R8, —C(═O)OR8, —C(═O)NR8R9, —NR8R9, —NR8C(═O)R9, —NR8C(═O)OR9, —NR8C(═O)NR9R10, —NR8C(═O)ONR9R10, —NR8SO2R9, —N═CR8R9, —SR8, —SOR8, —SO2R8, —SO2NR8R9, —NR8SO2NR9R10, —OSO2NR8R9 and pseudohalogen;
- Q2 and Q3 independently of one another denote a bond or a group selected from among optionally mono- or polysubstituted C1-16-alkyl, C2-16-alkenyl, C2-16-alkynyl, C3-10-cycloalkyl, aryl, heterocyclyl and heteroaryl, while the substituent(s) may be identical or different and are selected from among halogen, —NO2, —OR8, —C(═O)R8, —C(═O)OR8, —C(═O)NR8R9, —NR8R9, —NR8C(═O)R9, —NR8C(═O)OR9, —NR8C(═O)NR9R10, —NR8C(═O)ONR9R10, —NR8SO2R9, —N═CR8R9, —SR8, —SOR8, —SO2R8, —SO2NR8R9, —NR8SO2NR9R10, —OSO2NR8R9 and pseudohalogen;
- R7 denotes hydrogen or a group selected from among optionally mono- or polysubstituted C1-16-alkyl, C2-16-alkenyl, C2-16-alkynyl, C3-10-cycloalkyl, aryl, heterocyclyl and heteroaryl, while the substituent(s) may be identical or different and are selected from among halogen, NO2, —OR8, —C(═O)R8, —C(═O)OR8, —C(═O)NR8R9, —NR8R9, —NR8COR9, —NR8C(═O)OR9, —NR8C(═O)NR9R10, —NR8C(═O)ONR9R10, —NR8SO2R9, —N═CR8R9, —SR8, —SOR8, —SO2R8, —SO2NR8R9, —NR8SO2NR9R10, —OSO2NR8R9 and pseudohalogen;
- R8, R9 and R10 each independently of one another denote hydrogen or a group selected from among optionally substituted C1-8-alkyl, C2-8-alkenyl, C2-8-alkynyl, C3-10-cycloalkyl, aryl, heterocyclyl and heteroaryl, while the substituent(s) may be identical or different and are selected from among halogen, —NH2, —OH and pseudohalogen;
optionally in the form of the tautomers, racemates, enantiomers, diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof, and
at least one other cytostatic or cytotoxic active substance, optionally in the form of the tautomers, racemates, enantiomers, diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof. - As used herein, the following definitions apply, unless stated otherwise.
- By alkyl substituents are meant in each case saturated, straight-chain or branched aliphatic hydrocarbon groups (alkyl group).
- The alkenyl substituents are in each case straight-chain or branched, unsaturated alkyl groups which have at least one double bond.
- By alkynyl substituents are meant in each case straight-chain or branched, unsaturated alkyl groups which have at least one triple bond.
- Haloalkyl refers to alkyl groups wherein one or more hydrogen atoms are replaced by halogen atoms. Haloalkyl includes both saturated alkyl groups and unsaturated alkenyl and alkynyl groups, such as for example —CF3, —CHF2, —CH2F, —CF2CF3, —CHFCF3, —CH2CF3, —CF2CH3, —CHFCH3, —CF2CF2CF3, —CF2CH2CH3, —CHFCH2CH3 and —CHFCH2CF3.
- Halogen relates to fluorine, chlorine, bromine and/or iodine atoms.
- By pseudohalogen are meant the following groups: —OCN, —SCN, —CF3 and —CN.
- By cycloalkyl is meant a mono- or bicyclic ring, while the ring system may be a saturated ring or an unsaturated, non-aromatic ring, which may optionally also contain double bonds, such as for example cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, norbornyl, norbornenyl, spiro[5.5]undecane, spiro[5.4]decane and spiro[4.4]nonane.
- Aryl relates to monocyclic or bicyclic rings with 6-12 carbon atoms such as for example phenyl and naphthyl.
- By heteroaryl are meant mono- or bicyclic rings which contain instead of one or more carbon atoms one or more identical or different heteroatoms, such as e.g. nitrogen, sulphur or oxygen atoms. Examples include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl and triazinyl. Examples of bicyclic heteroaryl groups are indolyl, isoindolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, indazolyl, isoquinolinyl, quinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl and benzotriazinyl, indolizinyl, oxazolopyridinyl, imidazopyridinyl, naphthyridinyl, indolinyl, isochromanyl, chromanyl, tetrahydroisoquinolinyl, isoindolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl, benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, phenoxazinyl, phenothiazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl, imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl, dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, cumarinyl, isocumarinyl, chromonyl, chromanonyl, pyridinyl-N-oxide, tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl, dihydroisoquinolinonyl, dihydrocumarinyl, dihydroisocumarinyl, isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyrrolyl-N-oxide, pyrimidinyl-N-oxide, pyridazinyl-N-oxide, pyrazinyl-N-oxide, quinolinyl-N-oxide, indolyl-N-oxide, indolinyl-N-oxide, isoquinolyl-N-oxide, quinazolinyl-N-oxide, quinoxalinyl-N-oxide, phthalazinyl-N-oxide, imidazolyl-N-oxide, isoxazolyl-N-oxide, oxazolyl-N-oxide, thiazolyl-N-oxide, indolizinyl-N-oxide, indazolyl-N-oxide, benzothiazolyl-N-oxide, benzimidazolyl-N-oxide, pyrrolyl-N-oxide, oxadiazolyl-N-oxide, thiadiazolyl-N-oxide, triazolyl-N-oxide, tetrazolyl-N-oxide, benzothiopyranyl-S-oxide and benzothiopyranyl-S,S-dioxide.
- Heterocyclyl relates to saturated or unsaturated, non-aromatic mono-, bicyclic or bridged bicyclic rings comprising 5-12 carbon atoms, which carry heteroatoms, such as nitrogen, oxygen or sulphur, instead of one or more carbon atoms. Examples of such heterocyclyl groups are tetrahydrofuranyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, indolinyl, isoindolinyl, morpholinyl, thiomorpholinyl, homomorpholinyl, homopiperidyl, homopiperazinyl, thiomorpholinyl-S-oxide, thiomorpholinyl-S,S-dioxide, tetrahydropyranyl, piperidinyl, tetrahydrothienyl, homopiperidinyl, homothiomorpholinyl-S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydrofuryl, dihydropyranyl, tetrahydrothienyl-S-oxide, tetrahydrothienyl-S,S-dioxide, homothiomorpholinyl-S-oxide, 2-oxa-5-azabicyclo[2.2.1]heptane, 8-oxa-3-aza-bicyclo[3.2.1]octane, 3,8-diaza-bicyclo[3.2.1]octane, 2,5-diaza-bicyclo[2.2.1]heptane, 3,8-diaza-bicyclo[3.2.1]octane, 3,9-diaza-bicyclo[4.2.1]nonane, 2,6-diaza-bicyclo[3.2.2]nonane, 2,7-diaza-spiro[3.5]nonane, 2,7-diaza-spiro[4.4]nonane, 2,8-diaza-spiro[4.5]decane, 3,9-diaza-spiro[5.5]undecane.
- The Examples that follow illustrate the present invention without restricting its scope:
- The compounds according to the invention may be prepared according to methods of synthesis A to C described hereinafter, wherein the substituents of general formulae (I to XVI) have the meanings given hereinbefore.
- The intermediate compound III is prepared by substitution of a leaving group LG, for example halogen, SCN or methoxy, preferably chlorine, in a heteroaromatic system I by a nucleophile II.
- 1 equivalent of compound I and 1 to 1.5 equivalents of compound II are stirred in a solvent, for example 1,4-dioxane, tetrahydrofuran, ethanol, isopropanal, N,N-dimethylformamide or N,N-dimethylacetamide. At a temperature of 15 to 25° C., 2 to 2.5 equivalents of a base, for example potassium carbonate, sodium carbonate, caesium carbonate, N-ethyl-N,N-diisopropylamine or triethylamine, are added. The reaction mixture is stirred for 6 to 72 h at a temperature of 20 to 100° C. Then the solvent is distilled off and the residue is combined with water which has been adjusted to a pH of between 1-4 with an inorganic acid, for example hydrochloric acid or sulphuric acid. This mixture is extracted two to three times with an organic solvent, for example diethyl ether, ethyl acetate or dichloromethane. The combined organic extracts are dried and the solvent is distilled off. The residue is purified by chromatography.
- The end compound V is prepared by substitution of a leaving group LG, for example halogen, SCN or methoxy, preferably chlorine, in a heteroaromatic system III by a nucleophile IV.
- 1 equivalent of the compound III and 1 to 3 equivalents of the compound IV are stirred in a solvent, for example 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide or N-methyl-2-pyrrolidinone. At a temperature of 15 to 40° C., 1 to 2 equivalents of an inorganic acid, for example sulphuric acid or hydrochloric acid, are added. The reaction mixture is stirred for another 12 to 72 h at a temperature of 20 to 100° C. Then the solvent is distilled off and the residue is purified by chromatography.
- The intermediate compound VII is prepared by substitution of a leaving group LG, for example halogen, SCN, methoxy, preferably chlorine, in a heteroaromatic system I by a nucleophile VI.
- 1 equivalent of the compound I and 1 to 1.5 equivalents of the compound VI are stirred in a solvent, for example 1,4-dioxane, tetrahydrofuran, ethanol, isopropanol, N,N-dimethylformamide or N,N-dimethylacetamide.
- At a temperature of 15 to 25° C., 2 to 2.5 equivalents of a base, for example potassium carbonate, sodium carbonate, caesium carbonate, potassium hydrogen phosphate, N-ethyl-N,N-diisopropylamine or triethylamine are added. The reaction mixture is stirred for 6 to 72 h more at a temperature of 20 to 120° C. The reaction mixture is combined with water, which has been adjusted to a pH of 8 to 9 with an inorganic base, for example sodium hydrogen carbonate or potassium carbonate. This mixture is extracted two to three times with an organic solvent, for example diethyl ether or ethyl acetate.
- The combined organic extracts are dried and the solvent is distilled off. The residue is purified by chromatography or repeated crystallisation.
- The intermediate compound VIII is prepared by substituting a leaving group LG, for example halogen, SCN, methoxy, preferably chlorine, in a heteroaromatic system VII by a nucleophile IV.
- 1 equivalent of the compound VII and 1 to 1.5 equivalents of the compound IV are stirred in a solvent, for example 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide or N-methyl-2-pyrrolidinone. At a temperature of 15 to 40° C., 0.2 to 1 equivalent of an acid, for example sulphuric acid or hydrochloric acid, is added. The reaction mixture is stirred for another 12 to 72 h at a temperature of 20 to 100° C. The reaction mixture is stirred into water and the resulting precipitate is filtered off and dried. The precipitate may be purified by chromatography or crystallisation or used as the crude product in the next step.
- Compounds VIII whose group R7 denotes hydrogen may be used directly for preparing the end compounds X, while a compound VIII is reacted with a compound IX.
- Compounds VIII whose group R7 does not denote hydrogen are converted beforehand by hydrolysis or similar methods known to the skilled man into the compounds wherein the group R7 denotes hydrogen.
- 1 equivalent of the compound VIII, 1 to 1.5 equivalents of the compound IX and 1 to 3 equivalents of a base, for example triethylamine or ethyldiisopropylamine, are stirred in a solvent, for example 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide or N-methyl-2-pyrrolidinone. At a temperature of 15 to 25° C., 1 to 1.5 equivalents of a coupling reagent, for example N,N-dicyclohexylcarbodiimide, N,N-diisopropyl-carbodiimide, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-tetrafluoroborate or 1-(3-N,N-dimethylaminopropyl)-3-ethylcarbodiimide are added. The reaction mixture is stirred for another 4 to 24 h at a temperature of 15 to 25° C. Then the solvent is distilled off and the residue is purified by chromatography.
- The intermediate compound XI is prepared by substituting a leaving group LG, for example halogen, SCN, methoxy, preferably chlorine, at a heteroaromatic system I with a nucleophilic group IV.
- 1 equivalent of the compound I and 1 to 3 equivalents of a base, for example triethylamine or ethyldiisopropylamine, are stirred in a solvent, for example 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide or N,N-dimethylacetamide. At a temperature of −60 to 0° C., 0.8 to 1.5 equivalents of a compound IV are added. The reaction mixture is stirred for 6 to 72 h at a temperature of 15 to 75° C. Then the solvent is distilled off and the residue is purified by chromatography.
- The end compound V is prepared by substitution of a leaving group LG, for example halogen, SCN, methoxy, preferably chlorine, at a heteroaromatic system XI by a nucleophile II.
- 1 equivalent of the compound XI and 1 to 1.5 equivalents of the compound II are stirred in a solvent, for example 1,4-dioxane, N,N-dimethyl-formamide, N,N-dimethylacetamide or N-methyl-2-pyrrolidinone. At a temperature of 15 to 40° C. 1 to 2 equivalents of an acid, for example sulphuric acid or hydrochloric acid, are added. The reaction mixture is stirred for another 6 to 72 h at a temperature of 20 to 100° C. Then the solvent is distilled off and the residue is purified by chromatography.
- For medium pressure chromatography (MPLC) silica gel made by Millipore (name: Granula Silica Si-60A 35-70 μm) or C-18 RP-silica gel made by Macherey Nagel (name: Polygoprep 100-50 C18) is used.
- For high pressure chromatography columns made by Waters (name: XTerra Prep. MS C18, 5 μM, 30*100 mm or Symmetrie C18, 5 μm, 19*100) are used.
- The measurement is carried out in deuterised dimethylsulphoxide-d6. If other solvents are used they are explicitly mentioned in the Examples or in the methods. The measurements are given on a delta scale in ppm. Tetramethylsilane is taken as the standard. The measurements are carried out on an Avance 400 (400 MHz NMR spectrometer) made by Messrs Bruker Biospin GmbH.
- The NMR spectra are given purely in a descriptive capacity. Basically, only the visible molecular signals are listed. If for example molecular signals are partly or completely masked by foreign signals such as for example water signals, DMSO signals or CDCl3 signals they are not mentioned.
- These data are generated using an HPLC-MS apparatus (high performance liquid chromatography with mass detector) made by Agilent.
- The apparatus is constructed so that a diode array detector (G1315B made by Agilent) and a mass detector (1100 LS-MSD SL; G1946D; Agilent) are connected in series downstream of the chromatography apparatus (column: Zorbax SB-C8, 3.5 μm, 2, 1*50, Messrs. Agilent). The apparatus is operated with a flow of 0.6 ml/min. For a separation process a gradient is run through within 3.5 min (start of gradient: 95% water and 5% acetonitrile; end of gradient: 5% water and 95% acetonitrile; in each case 0.1% formic acid is added to the two solvents).
-
- 5 g (21.9 mmol) 2,4-dichloro-5-trifluoromethyl-pyrimidine are dissolved in 50 ml 1,4-dioxane and combined with 5.5 g (21.9 mmol) 4-amino-3-methoxybenzoic acid-propylamide hydrochloride (Zhuangyu Zhang, et al. 1989, J Pharml Sci. 78(10):829-32). 7.5 ml (43.8 mmol) ethyldiisopropylamine are added to this reaction mixture and the mixture is stirred for 2 days at ambient temperature. Then the reaction mixture is diluted with 250 ml of ethyl acetate and washed first with 300 ml aqueous 10% KHSO4 solution, then with 300 ml saturated aqueous NaCl solution. The organic phase is dried with MgSO4 and the solvent is eliminated in vacuo. The crude product is purified by column chromatography. The carrier used is silica gel and the eluant is a mixture of cyclohexane:ethyl acetate (75:25).
- Yield: 2.30 g (5.9 mmol; 27%)
- 1H-NMR: 0.91 (t, 3H), 1.50-1.61 (m, 2H), 3.20-3.28 (m, 2H), 3.87 (s, 3H), 7.46-7.51 (m, 1H), 7.52-7.56 (m, 1H), 7.70-7.75 (m, 1H), 8.44 (t, 1H), 8.75 (s, 1H), 9.73 (s, 1H)
-
- 1.5 g (5.473 mmol) methyl 2-bromomethyl-6-nitro-benzoate are dissolved in 20 ml N,N-dimethylformamide and combined with 15 ml of methanolic ammonia (7 mmol/ml). After 20 h at 25° C. the mixture is diluted with 100 ml of ethyl acetate and extracted 3 times with saturated sodium hydrogen carbonate solution. The organic phase is dried with magnesium sulphate and the solvent is eliminated in vacuo.
- Yield: 960 mg (5.389 mmol, 99%)
- MS-ESI+: m/z=179 [M+H]+
- 960 mg (5.389 mmol) 7-nitro-2,3-dihydro-isoindol-1-one are dissolved in 100 ml of tetrahydrofuran and combined with 100 mg palladium on charcoal. Then the mixture is stirred for 20 h at 25° C. and 4 bar hydrogen pressure (H2 pressure). The catalyst is filtered off and the solvent is eliminated in vacuo.
- Yield: 734 mg (4.958 mmol, 92%)
- MS-ESI+: m/z=149 [M+H]+
- The following 7-amino-2,3-dihydro-isoindol-1-one derivatives are prepared analogously to this method. A corresponding amine is used instead of ammonia:
-
- 500 mg (3.1 mmol) 4-amino-isobenzofuran-1,3-dione and 1.13 g (3.1 mmol) (ethoxy-carbonylmethylene)-triphenylphosphorane are dissolved in 5 ml of tetrahydrofuran (THF) and refluxed for 3 h. Then the solvent is eliminated in vacuo. The crude product is purified by column chromatography. The carrier used is silica gel and the eluant used is a mixture of cyclohexane:ethyl acetate (75:25).
- Yield: 221 mg (0.95 mmol, 31%)
- MS-ESI+: m/z=234 [M+H]+
- 120 mg (0.51 mmol) ethyl(4-amino-3-oxo-3H-isobenzofuran-1-ylidene)-acetate are dissolved in 50 ml of methanol and combined with 50 mg palladium on activated charcoal (10% Pd). The reaction mixture is hydrogenated for 3 h at 2 bar H2 pressure and 25° C. Then the catalyst is filtered off and the solvent is eliminated in vacuo.
- Yield: 116 mg (0.49 mmol, 97%)
- MS (ESI): m/z=236 (M+H)+
- 1H-NMR: 1.17 (t, 3H), 2.68-2.78 (m, 1H), 3.08-3.16 (m, 1H), 4.10 (q, 2H), 5.67-5.74 (m, 1H), 6.28 (bs, 2H), 6.61-6.70 (m, 2H), 7.30-7.38 (m, 1H)
-
- 5 g (25.373 mmol) 2,6-dinitro-benzonitrile is combined with 20 ml of an aqueous 80% sulphuric acid and stirred for 2 h at 80° C. The reaction mixture is combined with 100 ml of tetrahydrofuran and neutralised with 10% aqueous sodium hydroxide solution. The organic phase is separated off, combined with another 100 ml of tetrahydrofuran and 200 mg palladium on charcoal and stirred for 20 h at 8 bar H2 pressure and 25° C. The solids are filtered off. The filtrate is combined with 300 ml of ethyl acetate and extracted with saturated potassium hydrogen carbonate solution. The organic phase is separated off, dried and the solvent is eliminated in vacuo. The residue is purified by chromatography. The carrier used is silica gel and the eluant used is dichloromethane, to which 7% of a mixture of 90% methanol and 10% saturated aqueous ammonia solution are added.
- Yield: 900 mg (5.958 mmol; 23%)
- MS (ESI): 152 (M+H)+
- 900 mg (5.958 mmol) 2,6-diaminobenzamide are dissolved in 3.6 ml N,N-dimethylacetamide and combined with 6.3 ml (57.01 mmol) trimethylorthoformate and 792 μl (8.865 mmol) 98% sulphuric acid. After 16 h at 25° C. the reaction mixture is taken up with 20 ml of methanol and the solvent is eliminated in vacuo. The residue is again taken up in 20 ml of methanol, neutralised with concentrated ammonia. The solvent is eliminated in vacuo and the residue purified by chromatography. The carrier used is silica gel and the eluant used is dichloromethane, to which 7% of a mixture of 90% methanol and 10% saturated aqueous ammonia solution are added.
- Yield: 782 mg (4.852 mmol; 81%)
- MS (ESI): 162 (M+H)+
-
- 500 mg (1.825 mmol) 2-bromomethyl-6-nitro-methylbenzoate are heated to 100° C. in 2 ml trimethyl phosphate for 5 h. 2-(dimethylphosphonomethyl)-6-nitromethylbenzoate is obtained by evaporation under a high vacuum and used further directly. The crude product is dissolved in 24 ml of tetrahydrofuran at −70° C. under N2, 2.7 ml (2.7 mmol) of a 1 M lithium hexamethyldisilazide solution in tetrahydrofuran is added dropwise and then 430 mg (2.70 mmol) tert.-butyl-N-(2-oxoethyl)-carbamate in 5 ml of tetrahydrofuran are added. The reaction mixture is slowly heated to ambient temperature, combined with 5 ml of 1 M HCl and extracted with ethyl acetate. The combined organic phases are concentrated by evaporation and, by chromatography on silica gel with a mixture of cyclohexane-ethyl acetate in the ratio 95:5 to 75:25, 338 mg (1.006 mmol, 55%) of the E-/Z mixture of 2-(3-tert.-butoxycarbonylamino-prop-1-en-1-yl)-6-nitro-methylbenzoate are obtained. This E-/Z-mixture is treated for 12 h with 10 ml of a saturated methanolic potassium hydroxide solution. After acidification with aqueous 1 M HCl and extraction with ethyl acetate 302 mg (0.938 mmol, 93%) of the E-/Z mixture of 2-(3-tert.-butoxycarbonylamino-prop-1-en-1-yl)-6-nitro-methylbenzoic acid are obtained. To this are added 20 mg Raney nickel in 100 ml of methanol and the mixture is hydrogenated at 5 bar H2 pressure. The catalyst is filtered off, the filtrate concentrated by evaporation and stirred overnight with a 1:1 mixture of trifluoroacetic acid and dichloromethane at ambient temperature. After elimination of the solvent 133 mg (0.686 mmol, 73%) 2-amino-6-(3-amino-propyl)-benzoic acid are obtained. The further reaction is carried out by dissolving in 10 ml THF and 10 ml DCM with the addition of 300 mg (1.570 mmol) N-(3-dimethylaminopropyl)-N4-ethylcarbodiimide hydrochloride and 134 μl (0.830 mmol) N,N-diisopropyl-ethylamine and 48 h stirring at ambient temperature. The solvent is eliminated in vacuo and the crude product is purified by chromatography with C18-RP silica gel and an eluant mixture of acetonitrile and water in the ratio 5:95 to 95:5, to which 0.1% formic acid has been added.
- Yield: 28 mg (0.160 mmol, 23%)
- MS (ESI): m/z=177 (M+H)+
-
- 5 g (27.5 mmol) 2-amino-6-nitro-benzoic acid are combined with 22.2 ml (225.3 mmol) concentrated HCl and 45 ml (30.0 mmol) 5% aqueous sodium nitrite solution and stirred for 1 h at ambient temperature. Then the suspension is diluted with 150 ml dist. H2O and added dropwise to 350 ml destilliertes water which has been saturated with sulphur dioxide. Sulphur dioxide is piped through the reaction mixture for a further 30 min. Then the reaction mixture is refluxed for 30 min and then left to cool slowly to 20° C. The resulting precipitate is filtered off.
- Yield: 1.7 g (9.5 mmol, 35%)
- MS (ESI): m/z=180 (M+H)+
- 306 mg (1.7 mmol) 4-nitro-1,2-dihydro-indazol-3-one are dissolved in 1 ml N,N-dimethyl-acetamide, combined with 150 μl (2.4 mmol) methyl iodide and 500 μl (2.32 mmol) of N-ethyldiisopropylamide and stirred for 2 h at ambient temperature. Then the reaction mixture is combined with 40 ml of a 1 N aqueous hydrochloric acid and extracted twice with 50 ml dichloromethane. Then the organic phase is dried with MgSO4, the solvent is eliminated in vacuo and the crude product is purified by chromatography. The carrier used is C18-RP-silica gel and a gradient is run through which consists of 95% water and 5% acetonitrile at the starting point and 5% water and 95% acetonitrile at the finishing point.
- Yield: 144 mg (0.7 mmol, 44%)
- MS (ESI): m/z=194 (M+H)+
- 1H-NMR: 3.90 (s, 3H), 7.47-7.52 (m, 1H), 7.68-7.73 (m, 1H), 7.88-7.93 (m, 1H), 10.53 (s, 1H)
- 140 mg (0.7 mmol) 1-methyl-4-nitro-1,2-dihydro-indazol-3-one are suspended in 6 ml of ethanol and combined with 600 mg (4.4 eq, 2.9 mmol) sodium dithionite, dissolved in 2 ml distilled water, and stirred for 15 min at 25° C. Then the reaction mixture is combined with distilled water and extracted twice with ethyl acetate. Then the organic phase is dried with MgSO4 and the solvent is eliminated in vacuo.
- Yield: 33 mg (0.2 mmol, 28%)
- MS (ESI): m/z=164 (M+H)+
- 4-amino-1,2-dihydro-indazol-3-one and the following compounds are prepared analogously to this method.
-
- 400 mg (1.8 mmol) methyl 2-cyanomethyl-6-nitro-benzoate are dissolved in 13 ml THF, combined with 114 μl (1.8 mmol) methyl iodide and the mixture is cooled to −20° C. under a nitrogen atmosphere. Then at this temperature 250 mg (2.2 mmol) potassium-tert-butoxide are added. After 1 h the solvent is eliminated in vacuo and the crude product is purified by chromatography. The carrier used is C18-RP-silica gel and a gradient is run through which consists of 95% water and 5% acetonitrile at the starting point and 5% water and 95% acetonitrile at the finishing point.
- Yield: 289 mg (1.2 mmol, 68%)
- MS (ESI): 233 (M−H)−
- 400 mg (1.8 mmol) methyl 2-(cyanomethyl-2-methyl)-6-nitro-benzoate are dissolved in 13 ml of methanol and combined with 50 mg Raney nickel. The reaction mixture is hydrogenated for 16 h at 4 bar H2 pressure and 25° C. Then the catalyst is filtered off and the solvent is eliminated in vacuo.
- Yield: 170 mg (0.8 mmol, 46%)
- MS (ESI): 177 (M+H)+
- 8-amino-3,4-dihydro-2H-isoquinolin-1-one and 8-amino-4,4-dimethyl-3,4-dihydro-2H-isoquinolin-1-one and the following compounds are prepared analogously to this method.
-
- 24 ml (349 mmol) 65% nitric acid are cooled to 0-5° C. 28 ml (518.5 mmol) of concentrated sulphuric acid are slowly added dropwise while cooling with ice. This solution is cooled to 5° C. and slowly added dropwise to 30 ml (232 mmol) indane cooled to 0-5° C., with vigorous stirring and further cooling with ice. The reaction mixture is stirred for 30 min at 0-5° C., and then heated to 25° C. for 1 h with stirring. Then the solution is added dropwise to 150 ml ice/water and stirred for 30 min. The aqueous phase is extracted three times with 200 ml diethyl ether. The combined organic phases are washed twice with 200 ml saturated sodium hydrogen carbonate solution and once with 150 ml distilled water. Then the organic phase is dried with MgSO4 and the solvent is eliminated in vacuo. The crude product is dissolved in 250 ml of methanol and combined with 4.5 g Raney nickel. The reaction mixture is hydrogenated for 16 h at 3 bar H2 pressure and 25° C. Then the catalyst is filtered off and the solvent is eliminated in vacuo. The crude product is purified by column chromatography. The carrier used is silica gel and the eluant used is a mixture of cyclohexane:ethyl acetate (75:25).
- Yield: 3.81 g (28.6 mmol, 12%)
- MS (ESI): 134 (M+H)+
- 1H-NMR: 1.90-2.00 (m, 2H), 2.61 (t, 2H), 2.76 (t, 2H), 4.73 (s, 2H), 6.33-6.38 (m, 1H), 6.39-6.45 (m, 1H), 6.76-6.83 (m, 1H)
- 226 mg (1.7 mmol) indan-4-ylamine are combined with 5 ml acetic anhydride. The suspension is stirred for 16 h at 70° C. The resulting solution is stirred into 40 ml distilled water, adjusted to pH 7 with sodium carbonate and extracted three times with 30 ml of ethyl acetate. Then the organic phase is dried with MgSO4, the solvent is eliminated in vacuo and the crude product is purified by chromatography. The carrier used is silica gel and the eluant used is a mixture of cyclohexane:ethyl acetate (70:30).
- Yield: 152 mg (0.9 mmol, 51%)
- MS (ESI): 176 (M+H)+
- 1H-NMR: 1.93-2.03 (m, 2H), 2.04 (s, 3H), 2.79 (t, 2H), 2.86 (t, 2H), 6.94-7.01 (m, 1H), 7.02-7.10 (m, 1H), 7.36-7.44 (m, 1H), 9.25 (s, 1H)
- 147 mg (0.84 mmol) N-indan-4-yl-acetamide are dissolved in 10 ml acetone and combined with 770 μl of a 15% aqueous magnesium sulphate solution. The solution is cooled to 0° C. and 397 mg (2.490 mmol) potassium permanganate are added batchwise. After 2 h the mixture is diluted with 50 ml of water, and extracted three times with 20 ml chloroform. The organic phase is dried with magnesium sulphate and the solvent is eliminated in vacuo and the crude product is purified by chromatography. The carrier used is silica gel and the eluant used is a mixture of cyclohexane:ethyl acetate (85:15).
- Yield: 95 mg (0.500 mmol, 60%)
- MS (ESI): 190 (M+H)+
- 500 mg (2.6 mmol) N-(3-oxo-indan-4-yl)-acetamide are dissolved in 5 ml of ethanol, combined with 5 ml 18% hydrochloric acid and stirred for 3 h at 70° C. Then the reaction mixture is stirred into 100 ml distilled water, adjusted to pH 7 with sodium carbonate and extracted three times with 30 ml of ethyl acetate. Then the organic phase is dried with magnesium sulphate and the solvent is eliminated in vacuo.
- Yield: 388 mg (2.6 mmol, 100%)
- 8-amino-3,4-dihydro-2H-naphthalen-1-one is prepared analogously to this method. 1,2,3,4-tetrahydronaphthalene is used as starting material instead of indane.
-
- a) 2-benzyloxy-N-(7-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-acetamide
- 870 mg (4.5 mmol) 2-amino-7-nitro-2,3-dihydro-isoindol-1-one (prepared analogously to method 2) are dissolved in 82 ml dichloromethane and 64 ml THF. The solution is combined with 2.8 ml (3.3 eq, 20 mmol) benzyloxyacetyl chloride, 4.8 ml (28.0 mmol) N-ethyldiisopropyl-amine and 10 mg N,N-dimethylaminopyridine and stirred for 3 h at 25° C. Then the reaction mixture is combined with 100 ml aqueous 0.1 N hydrochloric acid and extracted three times with 50 ml of ethyl acetate. The organic phase is dried with magnesium sulphate, the solvent is eliminated in vacuo and the crude product is purified by chromatography. The carrier used is silica gel and the eluant used is a mixture of dichloromethane:methanol (95:5).
- Yield: 910 mg (2.7 mmol, 59%)
- 790 mg (2.3 mmol) 2-benzyloxy-N-(7-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-acetamide are dissolved in 100 ml of methanol and combined with 80 mg palladium hydroxide. The reaction mixture is hydrogenated for 48 h at 4 bar H2 pressure and 25° C. Then the catalyst is filtered off and the solvent is eliminated in vacuo. The crude product is purified by chromatography. The carrier used is silica gel and the eluant used is a mixture of dichloromethane:methanol (90:10).
- Yield: 210 mg (0.1 mmol, 41%)
- MS (ESI): 222 (M+H)+
-
- 2.01 g (22 mmol) 1-amino-2-butanol are dissolved in 6.5 ml 1,4-dioxane, combined with 880 mg (7.8 mmol) sodium hydride and stirred for 30 min at ambient temperature. 2 g (14.7 mmol) of 2-amino-6-fluorobenzonitrile are added to this reaction mixture and it is stirred for 24 h at 50° C. Then the solvent is eliminated in vacuo and the crude product is purified by chromatography. The carrier used is silica gel and the eluant used is dichloromethane, to which 5% of a mixture of 90% methanol and 10% saturated aqueous ammonia solution has been added.
- Yield: 1.15 g (5.6 mmol, 38%)
- MS (ESI): 206 (M+H)+
- 1.15 g (5.6 mmol) 2-amino-6-(1-aminomethyl-propoxy)-benzonitrile are dissolved in 10 ml 20% ethanolic KOH and stirred for 24 h at 80° C. Then the solvent is eliminated in vacuo and the crude product is purified by chromatography. The carrier used is silica gel and the eluant used is dichloromethane, to which 12% of a mixture of 90% methanol and 10% saturated aqueous ammonia solution have been added.
- Yield: 262 mg (1.2 mmol, 21%)
- MS (ESI): 225 (M+H)+
- 262 mg (1.2 mmol) 2-amino-6-(1-aminomethyl-propoxy)-benzoic acid are dissolved in 26 ml THF, combined with 680 mg (3.5 mmol) 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride and 0.6 ml (3.5 mmol) diisopropyl-ethylamine and stirred for 3 h at 50° C. Then the solvent is eliminated in vacuo and the crude product is purified by chromatography. The carrier used is silica gel and the eluant used is dichloromethane, to which 4% of a mixture of 90% methanol and 10% saturated aqueous ammonia solution have been added.
- Yield: 50 mg (0.2 mmol, 21%)
- MS (ESI): 207 (M+H)+
- The following compounds are prepared analogously to this method. 1-amino-2-butanol was replaced by a corresponding aminoalcohol or by a corresponding 1,2-diaminoethylene.
-
- 1.18 g (6.5 mmol) 2-amino-6-nitrobenzoic acid, 1.0 g (4.6 mmol) D,L-phenylalanine-methylester hydrochloride, 4.05 ml (23.2 mmol) N-ethyldiisopropylamine are combined with 2.5 ml of tetrahydrofuran. 1.71 g (5.1 mmol) O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-tetrafluoroborate are added to this reaction mixture and it is heated for 12 h to 50° C. Then the solvent is eliminated in vacuo and the crude product is purified by chromatography. The carrier used is silica gel and the eluant used is a mixture of cyclohexane:ethyl acetate (50:50).
- Yield: 1.04 g (3.03 mmol, 65%)
- MS (ESI): 344 (M+H)+
- 1.04 g (3.03 mmol) methyl 2-(2-amino-6-nitro-benzoylamino)-3-phenyl-propionate are dissolved in 3 ml 20% ethanolic KOH and stirred for 1.5 h at 50° C. Then the solvent is eliminated in vacuo and the crude product is purified by chromatography. The carrier used is silica gel and the eluant used is dichloromethane, to which 15% of a mixture of 90% methanol and 10% saturated aqueous ammonia solution has been added.
- Yield: 636 mg (1.9 mmol, 64%)
- MS (ESI): 329 (M+H)+
- 1H-NMR: 2.86-2.94 (m, 1H), 3.17 (s, 1H), 3.22-3.29 (m, 1H), 4.30-4.38 (m, 1H),
-
- 6.63 (s, 2H), 6.89-6.96 (m, 1H), 6.97-7.02 (m, 1H), 7.12-7.21 (m, 2H), 7.21-7.27 (m, 2H), 7.28-7.35 (m, 2H), 8.33-8.43 (m, 1H)
- 410 mg (1.25 mmol) 2-(2-amino-6-nitro-benzoylamino)-3-phenyl-propionic acid are dissolved in 50 ml of methanol and combined with 40 mg palladium on charcoal (10% Pd). The reaction mixture is hydrogenated for 9 h at 5 bar H2 pressure and 25° C. Then the catalyst is filtered off, the solvent is eliminated in vacuo and the crude product is purified by chromatography. The carrier used is C18-RP-silica gel and a gradient is run through which consists of 95% water and 5% acetonitrile at the starting point and consists of 5% water and 95% acetonitrile at the finishing point.
- Yield: 88 mg (0.29 mmol, 24%)
- MS (ESI): 300 (M+H)+
- 88 mg (0.3 mmol) 2-(2,6-diamino-benzoylamino)-3-phenyl-propionic acid are dissolved in 2 ml THF, combined with 143 mg (0.9 mmol) 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride and 103 μl (0.6 mmol) diisopropyl-ethylamine and stirred for 17 h at 50° C. Then the solvent is eliminated in vacuo and the crude product is purified by chromatography. The carrier used is silica gel and the eluant used is dichloromethane, to which 5% of a mixture of 90% methanol and 10% saturated aqueous ammonia solution have been added.
- Yield: 22 mg (0.08 mmol, 27%)
- MS (ESI): 282 (M+H)+
- The following compounds are prepared analogously to method 11.
-
- 7.36 g (44 mmol) 4-amino-3-methoxybenzoic acid are suspended in 80 ml of an aqueous phosphate buffer solution (pH 6.3) and combined with 9.5 g (44 mmol) 2,4-dichloro-5-trifluoro-methyl-pyrimidine, which is dissolved in 240 ml 1,4-dioxane. After 4 h at 100° C. the reaction mixture is crystallised at 0° C. The precipitate is filtered off, the filtrate is combined with 150 ml of ethyl acetate and washed twice with 200 ml of a saturated aqueous sodium hydrogen carbonate solution. The organic phase is dried with MgSO4 and the solvent is eliminated in vacuo. The crude product is suspended in 10 ml n-hexane and refluxed. The precipitate is filtered off, suspended in 48 ml of a saturated aqueous sodium hydrogen carbonate solution and heated to 65° C. for 1 h. Then the solution is crystallised at 0° C. The precipitate is filtered off, the filtrate is acidified with 1 N aqueous hydrochloric acid and combined with 100 ml of ethyl acetate. The organic phase is separated off, dried with magnesium sulphate and the solvent is eliminated in vacuo. The residue is recrystallised from ethyl acetate.
- Yield: 330 mg (0.95 mmol, 2%)
- MS (ESI): 348 (M+H)+
- 1H-NMR: 1.55 (s, 1H), 4.01 (s, 3H), 7.61-7.64 (m, 1H), 7.79-7.85 (m, 1H), 8.34
-
- (s, 1H), 8.59-8.63 (m, 1H), 8.66 (s, 1H)
-
- 3.9 g (30 mmol) 4-dibenzylamino-cyclohexanone are dissolved in 100 ml dichloromethane and stirred with 3.9 g (45 mmol) morpholine and 9.5 g (45 mmol) sodium triacetoxyborohydride for 12 h at ambient temperature. Then water and potassium carbonate are added, the organic phase is separated off, dried and the solvent is eliminated in vacuo. The crude product is purified by column chromatography. The carrier used is silica gel and the eluant used is ethyl acetate, to which 10% of a mixture of 90% methanol and 10% saturated aqueous ammonia solution have been added. The suitable fractions are evaporated down in vacuo.
- Yield: 6.6 g (18 mmol, 60%) cis-isomer
-
- 2 g (5.4 mmol, 18%) trans-isomer.
- 7.2 g (16.4 mmol) trans-dibenzyl-4-morpholino-cyclohexylamine are dissolved in 100 ml of methanol and hydrogenated on 1.4 g palladium on charcoal (10% Pd) at 30-50° C. The solvent is eliminated in vacuo and the residue is crystallised from ethanol and concentrated hydrochloric acid.
- Yield: 3.9 g (15.2 mmol, 93%)
- melting point: 312° C.
- The following compounds are prepared analogously to Method 13:
-
- 2 g (9.217 mmol) 2,4-dichloro-5-trifluoromethylpyrimidine are dissolved in 4 ml dioxane and combined with 6.01 g (18.430 mmol) caesium carbonate and 2.16 g (7.363 mmol) benzyl 4-amino-3-methoxybenzoate (WO 9825901). This suspension is stirred for 30 h at 100° C. The suspension is combined with 50 ml dichloromethane and methanol and filtered to remove the insoluble constituents. The solvent is eliminated in vacuo and the residue is purified by column chromatography. The carrier used is silica gel and the eluant used is a mixture of 85% cyclohexane and 15% ethyl acetate.
- Yield: 1.03 g (2.360 mmol; 26%)
- UV max: 320 nm
- MS (ESI): 438/440 (M+H)+Cl distribution
-
- 436/438 (M−H)−Cl distribution
- 1 g (2.284 mmol) 2-(4-benzyloxycarbonyl-2-methoxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine are dissolved in 50 ml THF and combined with 100 mg palladium hydroxide. The reaction mixture is stirred for 16 h at ambient temperature and 4 bar hydrogen pressure. Then the catalyst is filtered off and the solvent is eliminated in vacuo.
- Yield: 0.76 g (2.192 mmol; 96%)
- UV max: 288 nm
- MS (ESI): 346/348 (M−H)−Cl distribution
- The following compounds are prepared analogously to this process:
- 2-(4-carboxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine
- MS (ESI): 316/318 (M−H)−Cl distribution
- 2-[4-(4-benzyloxycarbonyl-piperazin-1-yl)-phenylamino]-4-chloro-5-trifluoromethyl-pyrimidine
- MS (ESI): 492/494 (M+H)+Cl distribution
- 2-[4-(4-benzyloxycarbonyl-piperazin-1-yl)-2-methoxy-phenylamino]-4-chloro-5-trifluoromethyl-pyrimidine
- MS (ESI): 522/524 (M+H)+Cl distribution
-
- 9.28 g (45 mmol) 3-benzyloxy-cyclobutancarboxylic acid (Org. Lett. 6(11), 1853-1856, 2004) are suspended in 80 ml dry tert-butanol and combined with 5.1 g (50 mmol) triethylamine and 13.8 g (50 mmol) phosphoric acid diphenylester azide. The reaction mixture is stirred for 20 h under reflux conditions. The solvent is eliminated in vacuo and the residue is taken up in dichloromethane. The organic phase is washed three times with 2 N sodium hydroxide solution, dried with sodium sulphate and the dichloromethane is eliminated in vacuo. The crude product is recrystallised from acetonitrile (1 g crude product:5 ml acetonitrile).
- Yield: 5.98 g (22 mmol; 48%)
- MS (ESI): 178 (M+H-boc)+Boc cleaving in the mass detector
- 2.77 g (10 mmol) tert. butyl (3-benzyloxy-cyclobutyl)-carbamate are suspended in 100 ml of methanol and combined with 200 mg palladium hydroxide. The reaction mixture is stirred for 5 h at 45° C. and 45 bar H2 pressure. Then the catalyst is filtered off and the solvent is eliminated in vacuo. The residue is taken up in chloroform and washed three times with aqueous sodium hydrogen carbonate solution. The organic phase is dried with magnesium sulphate and the solvent is eliminated in vacuo.
- Yield: 1.53 g (8.2 mmol; 82%)
- MS (ESI): 188 (M+H)+
- 18.7 g (100 mmol) tert. butyl (3-hydroxy-cyclobutyl)-carbamate and 12.1 g (120 mmol) triethylamine are placed in 500 ml chloroform. 20.5 g (105 mmol) tosyl chloride, dissolved in 150 ml chloroform, is added dropwise to this solution at 0° C. with stirring. Then the mixture is left to come up to ambient temperature and stirred for 2 h. The organic phase is washed successively with water, dilute hydrochloric acid, sodium hydrogen carbonate solution and water. The organic phase is dried with magnesium sulphate and the solvent is eliminated in vacuo.
- Yield: 28.30 g (83 mmol; 83%)
- MS (ESI): 342 (M+H)+
- 34.1 g (100 mmol) tert. butyl (3-tosyl-cyclobutyl)-carbamate are dissolved in 750 ml pyrrolidine, and combined with a catalytic amount of DMAP. The reaction mixture is refluxed for 20 h with stirring. The pyrrolidine is eliminated in vacuo, the residue is taken up in 500 ml of ethyl acetate and washed twice with saturated sodium hydrogen carbonate solution. The organic phase is dried with magnesium sulphate and the solvent is eliminated in vacuo. The crude product consists—as in all the analogous reactions—of a mixture of 2 isomeric compounds which are separated by column chromatography. The stationary phase used is silica gel and the eluant used is dichloromethane, to which 9% of a mixture of 90% methanol and 10% saturated aqueous ammonia solution have been added.
- The substances that elute first are designated as follows:
- Yield product A: 1 g (4.17 mmol; 4%)
- RF value (silica gel; dichloromethane:methanol:conc. aqueous ammonia=90:9:1)=0.62
- The substances that elute second are designated as follows:
- Yield product C: 2.00 g (8.33 mmol; 8%)
- RF value (silica gel; dichloromethane:methanol:conc. aqueous ammonia=90:9:1)=0.53
-
- 1 g (4.17 mmol) tert. butyl (3-pyrrolidine-cyclobutyl)-carbamate (product A from precursor) are stirred in 20 ml of a 2 N aqueous hydrochloric acid solution for 2 h at 40° C. Then the solvent is eliminated in vacuo and the residue is recrystallised from ethanol.
- Yield: 0.43 g (2.786 mmol; 67%)
- MS (ESI): 141 (M+H)+
- The following compounds are prepared analogously to this process:
-
- 1 g (4.17 mmol) tert. butyl (3-pyrrolidine-cyclobutyl)-carbamate (product C from precursor) are stirred in 20 ml of a 2 N aqueous hydrochloric acid solution for 2 h at 40° C. Then the solvent is eliminated in vacuo and the residue is recrystallised from ethanol.
- Yield: 0.43 g (3.09 mmol; 74%)
- MS (ESI): 141 (M+H)+
- The following compounds are prepared analogously to this method:
-
- 1 g (3.15 mmol) 2-(4-carboxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine are dissolved in 5 ml DMF and combined batchwise with 3.36 g (18.89 mmol) N-bromosuccinimide. The reaction mixture is stirred for 16 h at ambient temperature. The solvent is eliminated in vacuo and the residue is purified by column chromatography. The carrier used is C18-RP-silica gel and a gradient is run through which consists of 95% water and 5% acetonitrile at the starting point and consists of 2% water and 98% acetonitrile at the finishing point. 0.1% formic acid is added in each case to both the water and to the acetonitrile.
- Yield: 0.57 g (1.44 mmol; 46%)
- MS (ESI): 396/398 (M−H)+Cl/Br distribution
-
- 500 mg (3.102 mmol) 5-amino-3H-quinazolin-4-one are combined with 2 ml (15.596 mmol) 1-bromo-2-fluoroethane. 125 mg (3.125 mmol) sodium hydride are added thereto and the mixture is stirred for 5 days at ambient temperature. The reaction mixture is diluted with 100 ml of ethyl acetate and washed with 100 ml saturated aqueous sodium chloride solution. The aqueous phase is combined with 50 ml 1 N sodium hydroxide solution and extracted 5 times with ethyl acetate. The combined organic phases are dried and the solvent is eliminated in vacuo. The residue is purified by column chromatography. The carrier used is C18-RP-silica gel and a gradient is run through which consists of 95% water and 5% acetonitrile at the starting point and consists of 5% water and 95% acetonitrile at the finishing point. 0.1% formic acid is added in each case to both the water and to the acetonitrile.
- Yield: 67 mg (0.323 mmol; 10%)
- MS (ESI): 208 (M+H)+
-
- 1.466 g (9.039 mmol) 8-amino-3,4-dihydro-2H-isoquinolin-1-one are dissolved in 15 ml DMF and combined with 3.226 g (23.340 mmol) potassium carbonate and with 3.808 ml (31.420 mmol) benzylbromide. This reaction mixture is stirred for 16 h at 50° C. The reaction mixture is diluted with ethyl acetate and extracted with sodium hydrogen carbonate solution. The organic phases are dried and the solvent is eliminated in vacuo.
- Yield: 1.670 g (4.877 mmol; 54%)
- MS (ESI): 343 (M+H)+
- 1.06 g (3.095 mmol) 8-dibenzylamino-3,4-dihydro-2H-isoquinolin-1-one are combined with 1.5 ml (12 mmol) 1-bromo-2-fluoro-ethane and at ambient temperature 780 mg (19.50 mmol) sodium hydride are added batchwise over a period of 30 h. The reaction mixture is diluted with ethyl acetate and extracted with sodium hydrogen carbonate solution. The organic phases are dried and the solvent is eliminated in vacuo. The crude product is purified by column chromatography. The carrier used is silica gel and the eluant used is dichloromethane, to which 5% of a mixture of 90% methanol and 10% saturated aqueous ammonia solution have been added.
- Yield: 0.83 g (2.136 mmol; 69%)
- MS (ESI): 389 (M+H)+
- 830 mg (2.136 mmol) 8-dibenzylamino-2-(2-fluoro-ethyl)-3,4-dihydro-2H-isoquinolin-1-one are dissolved in 50 ml of methanol and combined with 80 mg palladium hydroxide. The reaction mixture is stirred for 48 h at ambient temperature and 4.5 bar H2 pressure. Then the catalyst is filtered off and the solvent is eliminated in vacuo.
- Yield: 0.403 g (1.935 mmol; 91%)
- MS (ESI): 209 (M+H)+
- The following compounds are prepared analogously to this process:
-
- 250 mg (1.16 mmol) methyl 2-chloro-6-nitro-benzoate, 458 mg (1.392 mmol) caesium carbonate, 211 mg (1.218 mmol) 2-nitrophenylboric acid and 18 mg (0.035 mmol) bis(tri-tert-butylphosphin)palladium(0) are placed under argon and combined with 0.8 ml dioxane. This reaction mixture is stirred for 48 h at 80° C. The reaction mixture is diluted with ethyl acetate and extracted with 1 N hydrochloric acid. The organic phase is dried and the solvent is eliminated in vacuo. The crude product is purified by column chromatography. The carrier used is C18-RP-silica gel and a gradient is run through which consists of 95% water and 5% acetonitrile at the starting point and consists of 5% water and 95% acetonitrile at the finishing point. 0.1% formic acid is added to both the water and the acetonitrile. The suitable fractions are freeze-dried. 71 mg of the intermediate product thus obtained are dissolved in 50 ml of methanol and combined with 10 mg palladium on charcoal. The reaction mixture is stirred for 48 h at ambient temperature and 4.5 bar H2 pressure. 50 ml dichloromethane are added to the reaction solution, the mixture is treated for 5 min in the ultrasound bath and then the catalyst is filtered off. The solvent is eliminated in vacuo.
- Yield: 46 mg (0.221 mmol; 94%)
- MS (ESI): 211 (M+H)+
-
- 18.021 g (100 mmol) 1-azido-4-morpholino-2-butyne and 19.728 g (100 mmol) dibenzylamine are dissolved in 100 ml dioxane and heated to 80° C. with stirring. After stirring for 20 h at this temperature the solvent is eliminated in vacuo and the residue is purified by column chromatography. The carrier used is silica gel and the eluant used is dichloromethane, to which 5% of a mixture of 90% methanol and 10% saturated aqueous ammonia solution have been added. The suitable fractions are combined and the solvent is eliminated in vacuo. The residue is dissolved in 480 ml of methanol and combined with 30 ml concentrated aqueous hydrochloric acid and 1 g palladium on charcoal. This reaction mixture is stirred for 5 h at 50° C. and 50 bar H2 pressure. Then the catalyst is filtered off and the solvent is eliminated in vacuo.
- Yield: 8.588 g (28.00 mmol; 28%)
- MS (ESI): 198 (M+H)+
-
- 2.5 g (11 mmol) tert. butyl trans-(4-formyl-cyclohexyl)-carbamate dissolved in 25 ml dimethylacetamide are combined with 1 ml (11 mmol) morpholine and 0.7 ml acetic acid. 2.4 g (11.3 mmol) sodium triacetoxyborohydride dissolved in 12.5 ml dimethylacetamide is added to this mixture. The reaction mixture is stirred for 16 h at ambient temperature. Then the reaction mixture is added to 250 ml 10% potassium hydrogen carbonate solution and this mixture is extracted three times with 100 ml of ethyl acetate. The organic phases are combined, dried and then the solvent is eliminated in vacuo. The residue is taken up in 20 ml dichloromethane and 20 ml trifluoroacetic acid and stirred for 1 h at ambient temperature. The solvents are eliminated in vacuo.
- Yield: 4.22 g (9.9 mmol; 90%) (double trifluoroacetic acid salt)
- MS (ESI): 199 (M+H)+
- The following compounds are prepared analogously to this process:
-
- 10 g (42.157 mmol) methyl 2-acetyl-6-nitro-benzoate (J. Org. Chem. (1952), 17, 164-76), 6.06 g (54.804 mmol) 2-fluoroethylamine and 9.32 ml (54.804 mmol) N-ethyldiisopropylamine are suspended in 25 ml of toluene and refluxed for 40 h with stirring. The reaction mixture is diluted with 400 ml of methanol and combined with 2.5 g palladium on charcoal. Then the mixture is stirred for 48 h at ambient temperature and 5 bar H2 pressure. The catalyst is filtered off and the solvent is eliminated in vacuo. The residue is taken up in dichloromethane and washed with water. The organic phase is dried with magnesium sulphate, the solvent is eliminated in vacuo and the crude product is purified by chromatography. The carrier used is silica gel and the eluant used is a mixture of cyclohexane:ethyl acetate (70:30).
- Yield: 3.83 g (18.404 mmol, 43%)
- MS (ESI): 209 (M+H)+
- UV max: 318 nm
- The following compounds are prepared analogously to this process, using the corresponding methyl 6-nitro-benzoate derivative:
-
- 500 μl (7.49 mmol) azetidin are dissolved in 15 ml acetonitrile, combined with 4.831 g (34.822 mmol) potassium carbonate and 445 μl (7.038 mmol) chloroacetonitrile. This reaction mixture is stirred for 20 h at ambient temperature. To this reaction mixture are added 20 ml diethyl ether, the suspension is stirred for 10 min and filtered to separate the solid constituents. The filtrate is freed from solvents in vacuo. 463 mg (4.816 mmol) of this intermediate product are dissolved in 50 ml 7 N methanolic ammonia and Raney nickel is added. The reaction mixture is stirred for 2 h at 60° C. and 20 bar H2 pressure. The catalyst is filtered off and the solvent is eliminated in vacuo.
- Yield: 365 mg (3.664 mmol, 48%)
- MS (ESI): 101 (M+H)+
- The following compounds are prepared analogously to this process:
- Method 24
-
- 1 g (5.369 mmol) (S)-3-(Boc-amino)-pyrrolidine are dissolved in 20 ml acetonitrile and combined with 4.831 g (34.822 mmol) potassium carbonate and 322 μl (5.101 mmol) chloroacetonitrile. This reaction mixture is stirred for 20 h at ambient temperature. 20 ml diethyl ether are added to this reaction mixture, the suspension is stirred for 10 min and filtered to separate off the solid constituents. The filtrate is freed from the solvents in vacuo. The intermediate product is dissolved in 2 ml dioxane and combined with 13 ml of 4 N dioxanic hydrochloric acid and stirred overnight at RT. Then the solvent is eliminated in vacuo.
- Yield: 500 mg (3.995 mmol, 74%)
- MS (ESI): 126 (M+H)+
-
- 2 g (16.055 mmol) R-alaninamide hydrochloride, 6.67 g (16.083 mmol) potassium carbonate and 8 mg (0.048 mmol) potassium iodide are suspended in 50 ml acetonitrile and then combined with 1.921 ml (16.083 mmol) 1,4-dibromobutane. This reaction mixture is refluxed for 14 h with stirring. 100 ml 1 N hydrochloric acid and 100 ml dichloromethane are added to the reaction mixture. The organic phase is separated off and discarded. The aqueous phase is made basic with sodium hydroxide solution and extracted three times with dichloromethane. The organic phases are combined, dried and freed from the solvent in vacuo.
- Yield: 1.305 g (9.177 mmol, 57%)
- MS (ESI): 143 (M+H)+
- Under a nitrogen atmosphere 31.65 ml 1 M Lithiumaluminiumhydrid solution (THF) are taken and combined with 1 g (7.032 mmol) (R)-2-pyrrolidin-1-yl-propionamide, dissolved in 2 ml THF, at 0° C. The reaction mixture is stirred for 48 h at 50° C. The reaction mixture is combined with 100 ml of methanol and then with the same amount of dichloromethane while cooling with ice. Approx. 25 g silica gel are added to this mixture and the solvent is eliminated in vacuo. This silica gel applied to a suction filter which has previously been charged with approx. 75 g silica gel. The suction filter is washed batchwise with a total of 500 ml of a mixture of dichloromethane, methanol and aqueous conc. ammonia (90:9:1). The majority of the solvent is eliminated at a vacuum of 200 mbar and a sump temperature of approx. 50° C. The product is distilled at 69-71° C. and 10 mbar.
- Yield: 160 mg (1.248 mmol, 18%)
- MS (ESI): 129 (M+H)+
- The following compounds are prepared analogously to this process:
-
- 1.1 g (5.07 mmol) 2,4-dichloro-5-trifluoromethylpyrimidin are dissolved in 1 ml dioxane and combined with 0.9 g (4.322 mmol) 7-amino-2-(2-fluoro-ethyl)-3-methyl-2,3-dihydro-isoindol-1-one (method 22) and 0.9 ml (5.257 mmol) diisopropyethylamine. This mixture is stirred for 1 h at 80° C. Then the solvent is eliminated in vacuo. The crude product is purified by column chromatography. The carrier used is C18-RP-silica gel and a gradient is run through which consists of 95% water and 5% acetonitrile at the starting point and consists of 20% water and 80% acetonitrile at the finishing point. 0.1% formic acid are added to both the water and to the acetonitrile. The suitable fractions are combined with dichloromethane, the organic phase is separated off, dried and the solvent is eliminated in vacuo.
- Yield: 485 mg (1.250 mmol, 25%)
- MS (ESI): 389/391 (M+H)+; Cl distribution
- The following compounds are prepared analogously to this process. The aniline derivatives used are described in the supplements to method 2, in method 10 and in the supplements to method 10. The preparation of the 2,4-dichloropyrimidine derivatives is known from the literature or may be carried out by methods known from the literature.
-
- 25 g (150.504 mmol) 3-fluoro-4-nitrobenzonitrile and 25 g (462.757 mmol) sodium methoxide are dissolved in 125 ml THF at 0° C. This reaction mixture is stirred for 30 min. The reaction mixture is extracted with ethyl acetate and 1 N hydrochloric acid. The organic phase is dried with magnesium sulphate and the solvent is eliminated in vacuo.
- Yield: 25.092 g (140.852 mmol, 94%)
- UV max: 334 nm
- 99 ml (99 mmol) lithium-bis-trimethylsilylamide solution (1 mol/l in THF) are diluted with 640 ml THF, cooled to 10° C. and combined with 8.3 g (46.591 mmol) 3-methoxy-4-nitro-benzonitrile. The reaction mixture is stirred for 10 min at 20° C. The mixture is cooled to 0° C. and combined with 80 ml 3 N hydrochloric acid. The reaction mixture is evaporated down in vacuo and extracted with water and ethyl acetate. The aqueous phase is adjusted to pH 14 with 3 N sodium hydroxide solution. The product is then suction filtered.
- Yield: 14.30 g (crude product: 60% purity)
- MS (ESI): 196 (M+H)+
- UV max: 334 nm
- 7 g (60% purity, 21.519 mmol) 3-methoxy-4-nitro-benzamidine are dissolved in methanol and combined with 11 ml (44 mmol) 4 N dioxanic hydrochloric acid, the solvents are eliminated in vacuo. The residue and 6.13 g (44.384 mmol) potassium carbonate are suspended in 350 ml acetonitrile and combined with 3.24 ml (22.764 mmol) ethyl 4-chloracetoacetate and 880 mg (5.301 mmol) potassium iodide. The reaction mixture is stirred for 16 h at 45° C. The reaction mixture is diluted with water and combined with 1 N sodium hydroxide solution, and extracted with ethyl acetate. The aqueous phase is adjusted to pH 1 with 1 N HCL and saturated with sodium chloride. The product is then suction filtered.
- Yield: 1.45 g (5.230 mmol, 24%)
- MS (ESI): 278 (M+H)+
- UV max: 294 nm
- 1.45 g (5.23 mmol) [2-(3-methoxy-4-nitro-phenyl)-1H-imidazol-4-yl]-acetic acid are dissolved in 36 ml THF and cooled to 0° C. and combined with 10 ml (18 mmol) borane-THF complex (1.8 mol/l). After 1 h the mixture is heated to 20° C. and stirred for 16 h. Water is added until the development of gas has ended. Then the mixture is extracted twice with saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic phases are combined, dried and freed from the solvent in vacuo.
- Yield: 0.65 g (2.465 mmol, 47%)
- MS (ESI): 264 (M+H)+
- UV max: 298 nm
- 0.144 g (0.547 mmol) 2-[2-(3-methoxy-4-nitro-phenyl)-1H-imidazol-4-yl]-ethanol are dissolved in 100 ml of methanol and combined with 0.08 g (5%) palladium on charcoal. The reaction mixture is hydrogenated for 16 h at 20° C. and 4 bar H2 pressure. The palladium on charcoal is suction filtered and the methanol is eliminated in vacuo.
- Yield: 87 mg (0.373 mmol, 68%)
- MS (APCI): 234 (M+H)+
- UV max: 314 nm
- The following compounds are prepared analogously to this process:
- [2-(4-amino-3-methoxy-phenyl)-thiazole-5-yl]-ethanol is prepared analogously to the processes described above. For the cyclisation, 4-amino-3-methoxy-thiobenzamide is used (analogously to J. Am. Soc. 82, 2656, 1960) instead of 3-methoxy-4-nitro-benzamidine.
- MS (ESI): 251 (M+H)+
-
- 1 g (5.884 mmol) 4-fluoro-2-methoxy-1-nitro-benzene, 975 mg (7.369 mmol) 1-(3-aminopropyl)pyrrolidine and 1.5 ml (8.765 mmol) diisopropyethylamine are dissolved in 5 ml dioxane and stirred for 24 h at 95° C. The solvents are eliminated in vacuo and the crude product is purified by column chromatography. The carrier used is silica gel and the eluant used is dichloromethane, to which 15% of a mixture of 90% methanol and 10% saturated aqueous ammonia solution has been added.
- Yield: 1.07 g (3.827 mmol; 65%)
- MS (ESI): 280 (M+H)+
- 200 mg (0.716 mmol) (3-methoxy-4-nitro-phenyl)-(3-pyrrolidin-1-yl-propyl)-amine are dissolved in 10 ml of methanol and combined with 537 μl (2.148 mmol) dioxanic hydrochloric acid and 20 mg palladium on charcoal. The reaction mixture is stirred for 1 h at ambient temperature and 5 bar H2 pressure. The catalyst is filtered off and the solvent is eliminated in vacuo.
- Yield: 213 mg (0.661 mmol, 92%)
- MS (ESI): 250 (M+H)+
- The following compounds are prepared analogously to this process:
-
- 1 g (3.148 mmol) 2-(4-carboxy-2-methoxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine (method 12 or 14) are dissolved in 5 ml DMF and combined batchwise with 3.36 g (18.889 mmol) N-bromosuccinimide. This reaction mixture is stirred for 16 h at ambient temperature. Then the solvent is eliminated in vacuo and the residue is purified by column chromatography. The carrier used is C18-RP-silica gel and a gradient is run through which consists of 95% water and 5% acetonitrile at the starting point and consists of 2% water and 98% acetonitrile at the finishing point. 0.1% formic acid are added to both the water and to the acetonitrile.
- Yield: 571 mg (1.440 mmol, 46%)
- MS (ESI): 396/398 (M+H)+
-
- 1 g (1.925 mmol) 2-(4-carboxy-2-methoxy-phenylamino)-4-[2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino]-5-trifluoromethyl-pyrimidine (prepared analogously to Example 53) are dissolved in 2 ml of toluene and combined successively with 0.43 ml (2.503 mmol) diisopropylethylamine, with 1.8 ml tert-butanol and with 0.49 ml (2.310 mmol) diphenylphosphorylazide and heated to 80° C. for 18 h. The reaction mixture is cooled, diluted with 100 ml of ethyl acetate and washed twice with 0.5 N sodium hydroxide solution. The organic phase is dried with magnesium sulphate and the solvent is eliminated in vacuo. The residue is taken up in dichloromethane and combined with 4 M dioxanic hydrochloric acid. The mixture is stirred for 72 h at ambient temperature. It is diluted with ethyl acetate and extracted 4 times with 1 N hydrochloric acid. The aqueous phases are combined and extracted once with ethyl acetate. The aqueous phase is made basic with sodium hydroxide solution and extracted three times with ethyl acetate. The organic phases are combined, dried and the solvent is eliminated in vacuo.
- Yield: 606 mg (1.236 mmol, 64%)
- MS (ESI): 491 (M+H)+
- 311 mg (0.634 mmol) 2-(4-amino-2-methoxy-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine are dissolved in 10 ml THF and combined with 115 μl (0.824 mmol) triethylamine and 62 μl (0.761 mmol) acrylic chloride. This mixture is stirred for 1 h at ambient temperature. Then it is diluted with ethyl acetate and extracted three times with water. The organic phase is dried with magnesium sulphate and the solvent is eliminated in vacuo.
- Yield: 340 mg (0.625 mmol, 98%)
- MS (ESI): 545 (M+H)+
- The following compounds are prepared analogously to this process:
- The separation is carried out by preparative chromatography under the following conditions:
- column: 280×110 mm CHIRALPAK® AD 20 μm
- Eluant: 95% acetonitrile/5% isopropanol (v/v)
- Flow rate: 570 ml/min
- Temperature: ambient temperature
- The enantiomer that elutes first is known as enantiomer 1 and in the chemical formula bears the symbol *1:
-
- The enantiomer that elutes second is known as enantiomer 2 and in the chemical formula bears the symbol *2:
-
-
- 262 mg (1.364 mmol) copper iodide are taken and heated in an argon current. Then the copper iodide is suspended in ether and cooled to −78° C. At this temperature 0.8 ml of a 3 M ethylmagnesium bromide solution (in ether) are added and the mixture is stirred for 10 min and then left to thaw to 0° C. After 15 min stirring at this temperature the mixture is cooled to −78° C. again and 200 mg (0.802 mmol) N-(3-oxo-3H-inden-4-yl)-benzamide, dissolved in 9 ml THF, are added dropwise and the mixture is stirred for 1 h at 0° C. The reaction mixture is diluted with dichloromethane and washed three times with concentrated aqueous ammonia solution. The organic phase is dried with magnesium sulphate and the solvent is eliminated in vacuo. The residue is purified by column chromatography. The carrier used is C18-RP-silica gel and a gradient is run through which consists of 98% water and 2% acetonitrile at the starting point and 2% water and 98% acetonitrile at the finishing point. 0.1% formic acid are added to both the water and to the acetonitrile. The suitable fractions are freeze-dried. This intermediate product is dissolved in 2 ml dioxane and combined with 5 ml concentrated hydrochloric acid. The reaction mixture is refluxed for 24 h with stirring. Then it is diluted with water and extracted three times with dichloromethane. The combined organic phases are again washed with water, dried and the solvent is removed. The residue is purified by column chromatography. The carrier used is silica gel and the eluant used is dichloromethane, to which 5% of a mixture of 90% methanol and 10% saturated aqueous ammonia solution have been added.
- Yield: 70 mg (0.399 mmol; 29%)
- MS (ESI): 176 (M+H)+
- The following compounds are prepared analogously to this process:
-
- 250 mg (0.609 mmol) methyl 2-dibenzylamino-benzoate are combined under argon with 0.609 ml of a 1 M lithium chloride solution (THF). This solution is cooled to—ambient temperature and slowly 0.914 ml (1.827 mmol) of a 2 M isopropyl-magnesium chloride solution are metered in. After stirring for 16 h at this temperature, 45 μl (0.609 mmol) acetone are added dropwise and the mixture is stirred for 4 h at ambient temperature. The reaction solution is combined with sodium hydrogen carbonate solution and extracted three times with dichloromethane. The combined organic phases are dried and the solvent is eliminated in vacuo. The residue is purified by column chromatography. The carrier used is C18-RP-silica gel and a gradient is run through which consists of 95% water and 5% acetonitrile at the starting point and 5% water and 95% acetonitrile at the finishing point. 0.1% formic acid are added to both the water and to the acetonitrile. The suitable fractions are freeze-dried. This intermediate product is dissolved in 50 ml of methanol combined with 10 mg palladium on charcoal and hydrogenated for 20 h at 5 bar hydrogen pressure and ambient temperature. Then the catalyst is filtered off and the solvent is eliminated in vacuo. The residue is purified by column chromatography. The carrier used is C18-RP-silica gel and a gradient is run through which consists of 95% water and 5% acetonitrile at the starting point and consists of 5% water and 95% acetonitrile at the finishing point. 0.1% formic acid are added to both the water and to the acetonitrile. The suitable fractions are freeze-dried.
- Yield: 34 mg (0.192 mmol; 32%)
- MS (ESI): 178 (M+H)+
- The following compounds are prepared analogously to this process:
-
- 3 g (13.625 mmol) methyl 2-cyanomethyl-6-nitro-benzoate (WO 9518097) are dissolved in 20 ml THF combined with 4.33 ml (68.788 mmol) iodomethane and cooled to 0° C. At this temperature 40.87 ml of a 1 M potassium-tert-butoxide solution is slowly added dropwise. The mixture is heated to ambient temperature and stirred for 16 h at this temperature. The reaction mixture is diluted with ethyl acetate and extracted three times with 1 M hydrochloric acid. The combined organic phases are dried and the solvent is eliminated in vacuo.
- Yield: 3.11 g (12.535 mmol; 92%)
- 1 g (4.028 mmol) methyl 2-(cyano-dimethyl-methyl)-6-nitro-benzoate are suspended in 20% ethanolic potassium hydroxide solution and stirred for 24 h at ambient temperature.
- 1.9 g (47.577 mmol) sodium hydroxide are dissolved in 40 ml of water cooled to 0° C. and combined with 0.5 ml (28.899 mmol) bromine. reaction mixture 1 is slowly added dropwise to this solution. After 8 h the same amount of reaction mixture 1 is added again. The mixture is stirred for a further 48 h at RT. Then sodium sulphite solution is added, the mixture is stirred for 20 min and then acidified with potassium hydrogen sulphate solution. It is extracted three times with ethyl acetate. The combined organic phases are dried and the solvent is eliminated in vacuo. The residue is purified by column chromatography. The carrier used is silica gel and the eluant used is a mixture of cyclohexane:ethyl acetate (3:1).
- Yield: 67 mg (0.325 mmol, 8%)
- MS (ESI): 207 (M+H)+
- 67 mg (0.325 mmol) 3,3-dimethyl-7-nitro-2,3-dihydro-isoindol-1-one are dissolved in 50 ml of methanol and combined with 10 mg palladium on charcoal. The mixture is hydrogenated for 16 h at 4 bar H2 pressure and ambient temperature. Then the catalyst is filtered off and the solvent is eliminated in vacuo.
- Yield: 50 mg (0.284 mmol, 93%)
- MS (ESI): 177 (M+H)+
- 50 mg (0.284 mmol) 3,3-dimethyl-7-amino-2,3-dihydro-isoindol-1-one are dissolved in 0.5 ml DMF and combined with 141 mg (1.021 mmol) potassium carbonate and 10 mg (0.028 mmol) tetrabutylammonium iodide. The mixture is heated to 50° C. and 155 μl (1.277 mmol) benzylbromide are added dropwise thereto. After stirring for 16 h at this temperature the mixture is diluted with ethyl acetate and extracted three times with 1 M hydrochloric acid. The combined organic phases are dried and the solvent is eliminated in vacuo.
- Yield: 67 mg (0.188 mmol; 66%)
- MS (ESI): 357 (M+H)+
- 67 mg (0.188 mmol) 7-dibenzylamino-3,3-dimethyl-2,3-dihydro-isoindol-1-one are dissolved in 1 ml (7.877 mmol) 1-bromo-2-fluoroethane and combined with 52 mg (0.376 mmol) sodium hydride. After 4 h stirring at ambient temperature the mixture is diluted with ethyl acetate and extracted three times with 1 M hydrochloric acid. The combined organic phases are dried and the solvent is eliminated in vacuo.
- Yield: 75 mg (0.188 mmol; 100%)
- MS (ESI): 403 (M+H)+
- 75 mg (0.188 mmol) 7-dibenzylamino-2-(2-fluoro-ethyl)-3,3-dimethyl-2,3-dihydro-isoindol-1-one are dissolved in 50 ml of methanol and combined with 10 mg palladium on charcoal. The mixture is hydrogenated for 16 h at 5 bar H2 pressure and ambient temperature. Then the catalyst is filtered off and the solvent is eliminated in vacuo.
- Yield: 36 mg (0.162 mmol, 87%)
- MS (ESI): 223 (M+H)+
-
- 100 mg (0.257 mmol) 2-(2-methoxy-4-propylcarbamoyl-phenylamino)-4-chloro-5-trifluoro-methyl-pyrimidine (method 1) are dissolved in 1 ml N,N-dimethylacetamide and combined with 83 mg (0.565 mmol) 7-amino-2,3-dihydro-isoindol-1-one (method 2). 48 μl of a 4 molar solution of HCl (0.193 mmol) in 1,4-dioxane are metered into this reaction mixture. After two days at 50° C. the solvent is eliminated in vacuo. The crude product is purified by column chromatography. The carrier used is silica gel and the eluant used is dichloromethane, to which 5% of a mixture of 90% methanol and 10% saturated aqueous ammonia solution have been added. The concentrated crude product is again purified by column chromatography. The carrier used is C18RP-silica gel and a gradient is run through which consists of 80% water and 20% acetonitrile at the starting point and 60% water and 40% acetonitrile at the finishing point.
- Yield: 42 mg (0.084 mmol; 33%)
- UV max: 318 nm
- MS (ESI): 501 (M+H)+
- 1H-NMR: 0.92 (t, 3H), 1.51-1.63 (m, 2H), 3.21-3.29 (m, 2H), 3.86 (s, 3H), 4.37 (s, 2H), 7.14-7.21 (m, 1H), 7.33 (t, 1H), 7.47-7.54 (m, 1H), 7.55-7.60 (m, 1H), 7.73-7.82 (m, 1H), 8.35-8.50 (m, 3H), 8.75 (s, 1H), 9.09 (s, 1H), 10.66 (s, 1H)
- The following compounds are prepared by an analogous method as described in Example 1. 2-(2-Methoxy-4-propylcarbamoyl-phenylamino)-4-chloro-5-trifluoromethylpyrimidine and a corresponding 7-amino-2,3-dihydro-isoindol-1-one derivative (method 2) are used. N-methyl-2-pyrrolidinone or N,N-dimethylacetamide is used as solvent.
-
- 100 mg (0.257 mmol) 2-(2-methoxy-4-propylcarbamoyl-phenylamino)-4-chloro-5-trifluoro-methyl-pyrimidine (method 1) are dissolved in 1 ml N,N-dimethylacetamide and combined with 46 mg (0.308 mmol) 7-amino-3H-isobenzofuran-1-one (Safdar Hayat et al., Tetrahedron Lett 2001, 42(9): 1647-1649). 48 μl of a 4 molar solution of HCl (0.193 mmol) in 1,4-dioxane zudosiert metered into this reaction mixture. After 4 days at 50° C. the solvent is eliminated in vacuo. The crude product is purified by column chromatography. The carrier used is silica gel and the eluant used is dichloromethane, to which 4% of a mixture of 90% methanol and 10% saturated aqueous ammonia solution have been added.
- Yield: 26 mg (0.051 mmol; 20%)
- UV max: 322 nm
- MS (ESI): 502 (M+H)+
- 1H-NMR: 0.92 (t, 3H), 1.51-1.63 (m, 2H), 3.22-3.28 (m, 2H), 3.86 (s, 3H), 5.42 (s, 2H), 7.24-7.30 (m, 1H), 7.44-7.55 (m, 2H), 7.55-7.60 (m, H), 7.67-7.78 (m, 1H), 8.38-8.48 (m, 2H), 8.50 (s, 1H), 9.21 (s, 1H), 9.64 (s, 1H)
- The following compounds are prepared by analogous methods to those described in Example 1 and Example 18. 2-(2-methoxy-4-propylcarbamoyl-phenylamino)-4-chloro-5-trifluoromethylpyrimidine (method 1) is used. The corresponding aniline derivative is commercially obtainable, known from the literature or is prepared by the processes described in method 2 and 4 to 9. N-methyl-2-pyrrolidinone or N,N-dimethylacetamide is used as solvent.
-
- 50 mg (0.129 mmol) 2-(2-methoxy-4-propylcarbamoyl-phenylamino)-4-chloro-5-trifluoro-methyl-pyrimidine (method 1) are dissolved in 200 μl 1,4-dioxane and combined with 25 mg (0.13 mmol) 6-amino-4-methyl-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one (method 10). 36 μl of a 4 molar solution of HCl (0.144 mmol) in 1,4-dioxane are metered into this reaction mixture. After 4 days at 50° C. the solvent is eliminated in vacuo. The crude product is purified by column chromatography. The carrier used is silica gel and the eluant used is a mixture of dichloromethane and ethyl acetate (1:1).
- Yield: 23 mg (0.042 mmol; 33%)
- UV max: 318 nm
- MS (ESI): 545 (M+H)+
- 1H-NMR: 0.91 (t, 3H), 1.49-1.61 (m, 2H), 3.09 (s, 3H), 3.20-3.28 (m, 2H), 3.49 (t, 2H), 3.88 (s, 3H), 4.31 (t, 2H), 6.83-6.88 (m, 1H), 7.34-7.45 (m, 2H), 7.50-7.54 (m, 1H), 7.88-8.00 (m, 2H), 8.37-8.44 (m, 2H), 8.62 (s, 1H), 9.97 (s, 1H)
- The following compounds are prepared by analogous methods to those described in Example 1 and 18. 2-(2-methoxy-4-propylcarbamoyl-phenylamino)-4-chloro-5-trifluoromethylpyrimidine (method 1) is used. The corresponding aniline derivative is commercially obtainable, known from the literature or is prepared by the processes described in method 10 and 11. N-methyl-2-pyrrolidinone or N,N-dimethylacetamide is used as solvent.
-
- 102 mg (0.29 mmol) 2-(4-carboxyamino-2-methoxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine (method 12) are dissolved in 250 μl N-methyl-2-pyrrolidinone and combined with 47 mg (0.319 mmol) 7-amino-indan-1-one (method 8). 15 μl of a 4 M solution of HCl (0.058 mmol) in 1,4-dioxane are metered into this reaction mixture. After 16 h at 90° C. the reaction mixture is stirred into 150 ml of a aqueous 1 N hydrochloric acid. The precipitate is filtered off and dried in vacuo. 100 mg (0.174 mmol) of this precipitate, 150 μl (0.875 mmol) N-ethyldiisopropyl-amine, 68 mg (0.210 mmol) O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-tetrafluoroborate and 30 mg (0.163 mmol) trans-4-morpholin-4-yl-cyclohexylamine (method 13) are dissolved in 5 ml N,N-dimethylformamide. After 15 h at ambient temperature the solvent is eliminated in vacuo. The crude product is purified by column chromatography. The carrier used is silica gel and the eluant used is dichloromethane, to which 7% of a mixture of 90% methanol and 10% saturated aqueous ammonia solution have been added.
- Yield: 55 mg (0.100 mmol; 57%)
- UV max: 318 nm
- MS (ESI): 555 (M+H)+
- 1H-NMR: 1.55-1.69 (m, 2H), 1.74-1.84 (m, 2H), 1.91-2.02 (m, 2H), 2.18 (s, 3H), 2.69-2.75 (m, 2H), 2.75-2.84 (m, 2H), 3.03-3.10 (m, 2H), 3.70-3.83 (m, 1H), 3.86 (s, 3H), 7.15-7.21 (m, 1H), 7.36-7.46 (m, 1H), 7.48-7.54 (m, 1H), 7.54-7.58 (m, 1H), 7.71-7.79 (m, 1H), 8.18-8.25 (m, 1H), 8.30-8.45 (m, 1H), 8.48 (s, 1H), 9.16 (s, 1H), 10.59 (s, 1H)
- The following compounds are prepared by an analogous method to that described in Example 53. The corresponding aniline is described in method 2, 7, 8, or 9 or known from the literature. The amine used to prepare the amide is commercially obtainable or is described in method 13.
-
UV max MS (ESI) # A R3′ [nm] (M + H)+ 54 318 555 55 318 569 56 322 570 57 320 640 58 284, 322 556 59 282, 318 626 60 325 655 61 325 585 62 254, 286, 318 639 63 321 631 64 322 570 65 322 640 66 322 683 67 322 613 68 286, 322 654 69 286, 322 584 70 282, 322 627 71 322 670 72 286, 322 600 73 322 684 74 286, 322 614 75 322 557 76 330 732 77 325 654 - The following compounds are prepared by an analogous method to that described in Example 53. 2-(4-Carboxy-2-methoxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine may be prepared according to method 12 or 14. The corresponding aniline is described in the supplements to method 10. The amine used to prepare the amide is commercially obtainable or is described in method 13, in the supplements to method 13, 15 or 25.
-
UV max MS (ESI) # A R3′ [nm] (M + H)+ 78 318 308 79 326 346 80 318 706 81 318 584 82 318 614 83 318 776 84 318 626 85 318 348 86 318 718 87 318 684 88 318 353 89 322 346 90 318 686 91 310 621 92 318 746 93 318 676 94 318 316 95 318 696 96 282; 310 571 97 318 614 98 318 684 99 315 559 100 314 621 101 314 676 102 318 747 103 318 656 104 318 586 105 318 (M 106 318 730 107 322 674 108 318 640 109 322 640 110 282, 318 614 111 226, 282, 318 640 112 318 614 113 626 114 318 640 115 318 640 116 318 654 117 318 668 118 318 628 119 318 600 120 318-322 614 121 318 670 122 318 654 123 318 626 124 282, 318 668 125 282, 318 642 126 282, 318 693 127 318 680 128 318 654 129 318 705 130 226, 282, 318 628 131 318 668 132 318-322 642 133 318 693 134 318-322 642 135 318 682 136 318 698 137 318-322 656 138 318-322 707 139 318-322 640 140 318-322 628 - The following compounds are prepared by an analogous method to that described in Example 53. The preparation of 2-(4-carboxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine is described in method 14. The corresponding aniline is described in method 10. The amine used to prepare the amide is commercially obtainable or is described in method 13, 15 or 25.
-
UV max MS (ESI) # A R3′ [nm] (M + H)+ 141 302 596 142 302 610 143 302 596 144 302 584 145 302 610 146 302 638 147 298 654 148 302 610 149 302 650 150 298-302 666 151 302 584 152 302 624 153 298-302 640 154 302 598 155 298-302 649 156 302 598 157 302 638 158 298-302 654 159 302 612 160 302 663 161 302 612 162 302 652 163 298-302 668 164 302 677 165 302 626 166 302 624 -
- 500 mg (0.958 mmol) 2-[4-(4-benzyloxycarbonyl-piperazin-1-yl)-phenylamino]-4-chloro-5-trifluoromethyl-pyrimidine (method 14) are dissolved in 0.5 ml NMP, combined with 198 mg (0.960 mmol) 6-amino-3,3-dimethyl-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one (method 10) and with 25 μl (0.1 mmol) dioxanic hydrochloric acid. This reaction mixture is stirred for 1.5 h at 100° C. The solvent is eliminated in vacuo and the residue is purified by column chromatography. The carrier used is C18-RP-silica gel and a gradient is run through which consists of 95% water and 5% acetonitrile at the starting point and consists of 5% water and 95% acetonitrile at the finishing point. 0.1% formic acid are added to both the water and to the acetonitrile.
- Yield: 0.59 g (0.86 mmol; 90%)
- 0.59 g (0.86 mmol) of the above-mentioned intermediate products are dissolved in 50 ml of dimethylformamide and combined with a quantity of distilled water such that there is no precipitation. To this solution are added 60 mg palladium on charcoal and the mixture is hydrogenated at 7 bar H2 pressure and 20° C. for 6 h. The catalyst is filtered off and the solvent is eliminated in vacuo. The residue is purified by column chromatography. The carrier used is C18-RP-silica gel and a gradient is run through which consists at the starting point of 60% water and 40% acetonitrile and at the finishing point of 15% water and 85% acetonitrile. 10 mmol/l ammonium hydrogen carbonate and 20 mmol/l ammonia are dissolved in the water. The suitable fractions are freeze-dried. The residue is dissolved in acetonitrile and combined with 2 ml of a 1 M hydrochloric acid solution. Then the solvent is eliminated in vacuo. The substance is obtained as the dihydrochloride.
- Yield: 0.46 g (0.73 mmol; 85%)
- UV max: 284 nm
- MS (ESI): 558 (M+H)+
- 1H-NMR: 1.19 (s, 6H), 3.19-3.28 (m, 4H), 3.41-3.49 (m, 4H), 3.80 (s, 3H), 4.07 (s, 1H), 6.54-6.60 (m, 1H), 6.72-6.76 (m, 1H), 6.83-6.89 (m, 1H), 7.21-7.42 (m, 2H), 7.85-8.20 (m, 1H), 8.33-8.60 (m, 1H), 8.74 (s, 1H), 9.30-9.71 (m, 3H), 12.84 (s, 1H)
-
- This compound is prepared analogously to Example 167. The aniline used is described in method 10.
- Yield: 0.23 g (0.41 mmol; 91%)
- UV max: 282 nm
- MS (ESI): 570 (M+H)+
- 1H-NMR: 1.53-1.71 (m, 1H), 1.79-2.06 (m, 3H), 3.15-3.32 (m, 4H), 3.32-3.55 (m, 5H), 3.58-3.72 (m, 1H), 3.72-3.94 (m, 4H), 4.00-4.23 (m, 2H), 6.48-6.61 (m, 1H), 6.68-6.77 (m, 1H), 6.83-7.00 (m, 1H), 7.19-7.50 (m, 2H), 7.78-8.10 (m, 1H), 8.23-8.60 (m, 1H), 9.18-9.64 (m, 3H), 10.54-10.86 (m, 1H)
-
- 60 mg (0.11 mmol) 2-(2-methoxy-4-piperazin-1-yl-phenylamino)-4-((S)-4-oxo-2,3,10,10a-tetrahydro-1H,4H-9-oxa-3a-aza-benzo[f]azulen-5-ylamino-5-trifluoromethyl-pyrimidine (Example 168) are dissolved in 300 μl dimethylformamide and combined with 12 μl (0.21 mmol) acetaldehyde and 47 mg (0.21 mmol) sodium triacetoxyborohydride. This reaction mixture is stirred at 20° C. for 20 h. The solvent is eliminated in vacuo and the residue is purified by column chromatography. The carrier used is C18-RP-silica gel and a gradient is run through which consists of 95% water and 5% acetonitrile at the starting point and 50% water and 50% acetonitrile at the finishing point. 0.1% formic acid are added to both the water and to the acetonitrile. The suitable fractions are combined with 500 μl of a 1 N hydrochloric acid and freeze-dried. The product is obtained as the dihydrochloride.
- Yield: 49 mg (0.074 mmol; 71%)
- UV max: 282 nm
- MS (ESI): 598 (M+H)+
- 1H-NMR: 1.23-1.37 (m, 3H), 1.57-1.72 (m, 1H), 1.80-2.06 (m, 3H), 3.02-3.27 (m, 6H), 3.34-3.48 (m, 1H), 3.48-3.71 (m, 3H), 3.71-3.94 (m, 7H), 6.48-6.61 (m, 1H), 6.68-6.79 (m, 1H), 6.84-6.97 (m, 1H), 7.18-7.43 (m, 2H), 7.78-8.08 (m, 1H), 8.26-8.53 (m, 1H), 9.14-9.44 (m, 1H), 10.49-10.74 (m, 1H), 10.80-11.08 (m, 1H)
-
- To prepare this compound formaldehyde is used instead of acetaldehyde. Otherwise the method is as in Example 169.
- Yield: 16 mg (0.024 mmol; 28%)
- UV max: 278 nm MS (ESI): 584 (M+H)+
- 1H-NMR: 1.58-1.71 (m, 1H), 1.81-2.06 (m, 3H), 2.78-2.88 (m, 3H), 3.00-3.23 (m, 4H), 4.03-4.21 (m, 2H), 6.48-6.59 (m, 1H), 6.69-6.78 (m, 1H), 6.80-6.91 (m, 1H), 7.17-7.44 (m, 2H), 7.92-8.15 (m, 1H), 8.34 (s, 1H), 8.86-9.04 (m, 1H), 10.38-10.64 (m, 2H)
- The following Examples are prepared analogously to Example 169 and 170.
- The corresponding aniline is described in the supplements to method 10.
- The following compounds are prepared by an analogous process to that described in Example 53. 2-(4-Carboxy-2-methoxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine may be obtained according to method 12 or 14. The corresponding aniline is described in method 11. The amine used to prepare the amide is commercially obtainable or described in method 13, 15 and 25.
-
UV max MS (ESI) # A R3′ [nm] (M + H)+ 181 318, 282, 234 380 182 238 639 183 234; 318 709 184 318, 282, 248 558 185 318, 280 613 186 316, 282, 234 342 187 318, 284, 238 307 188 318, 282, 242 342 189 314, 282, 242 600 190 318, 282, 234 328 191 318 363 192 318, 230 650 193 314 634 194 318 634 195 318 671 196 318, 230 380 197 314, 282, 250 558 198 319 705 199 318, 226 775 200 318 634 201 314 634 202 230; 318 584 203 317 572 204 318, 230 697 205 318, 234 544 206 318 669 207 318, 230 650 208 317 627 209 318, 230 599 210 318, 230 705 211 230; 322 653 212 230; 322 655 213 230; 318 669 214 230, 282, 314 634 215 318 655 216 318, 234 725 217 314, 235 586 218 318, 230 641 219 318, 226 711 220 318, 230 640 221 318 765 222 318 600 223 315 673 224 319, 226 728 225 318, 226 798 226 318, 234 655 227 230; 322 653 228 230; 318 682 229 234; 318 639 230 318, 226 695 231 234, 282, 318 598 232 230, 282, 318 653 233 234, 282, 318 723 234 318, 222 673 235 318 725 236 318, 282, 226 798 237 230; 318 641 238 230; 318 711 239 234; 318 586 240 318, 226 745 241 322 703 242 320, 226 732 243 321, 221 694 244 230, 282, 318 652 245 234, 282, 318 707 246 230, 282, 318 777 247 230, 282, 318 630 248 234, 282, 318 685 249 234, 282, 318 755 250 230, 282, 318 630 251 230, 282, 318 685 252 230, 282, 318 755 253 230; 318 695 254 230; 318 70 255 230; 318 389 256 230; 318 652 257 230 357 258 230 784 259 230 659 260 319, 230 689 261 322 703 262 322 705 263 320 719 264 226 690 265 226; 318 760 266 230 635 267 230; 318 381 268 318 812 269 318 652 270 318 707 271 318, 226 777 272 318 659 273 318 714 274 315, 239 669 275 319, 222 723 276 318, 226 793 277 316 620 278 318 675 279 318, 226 745 280 317, 226 620 281 318 675 282 318, 230 745 283 318 784 284 318 758 285 318 688 286 238, 282, 314 616 287 230, 282, 318 671 288 230, 282, 318 741 289 234, 282, 318 616 290 226, 282, 318 671 291 234, 282, 318 741 292 234, 282, 318 648 293 230, 282, 318 703 294 226, 282, 318 773 295 226, 282, 318 893 296 226, 282, 318 727 297 226, 282, 318 754 298 230, 282, 318 823 299 282, 318 669 300 282, 318 613 301 282, 318 641 302 286, 318 639 303 286, 318 627 304 286, 318 655 305 286, 318 667 306 286, 318 717 307 286, 318 689 308 286, 318 665 309 230, 286, 318 653 310 230, 282, 318 715 311 286, 322 695 312 234, 286, 318 667 313 230, 282, 318 639 314 230, 282, 318 667 315 230, 282, 318 681 316 230, 282, 318 695 317 679 318 226, 284, 318 681 319 230, 284, 318 697 320 226, 284, 314 750 321 230, 286, 318 669 322 230, 282, 318 693 323 230, 282, 314 709 324 230, 286, 314 681 325 226, 286, 314 762 326 230, 282, 318 681 327 230, 282, 314 697 328 234, 282, 318 627 329 226, 282, 318 767 330 226, 282, 318 725 331 230, 286, 318 711 332 226, 282, 318 671 333 234, 282, 314 718 334 234, 282, 318 693 335 234, 286, 318 653 336 284, 318 706 337 230, 282, 318 641 338 230, 282, 314 667 339 283, 318 655 340 230, 286, 318 699 341 230, 282, 318 750 342 230, 282, 318 627 343 250, 282, 318 667 344 230, 282, 318 683 345 238, 282, 314 641 346 230, 314 692 347 282, 318 723 348 234, 286, 314 653 349 286, 318 667 350 234, 286, 314 718 351 230, 286, 318 685 - The following compounds are prepared by an analogous process to that described in Example 53 described, prepared. 2-(4-carboxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine may after method 14 prepared are. The corresponding aniline is in method 11 described. The amine used to prepare the amide is commercially obtainable or is in method 13, 15 or 25 described.
-
UV max MS (ESI) # A R3′ [nm] (M + H)+ 352 222, 302 688 353 246, 298 663 354 234, 298 679 355 234, 302 623 356 298 611 357 246, 302 676 358 651 359 667 360 246, 302 611 361 298 662 362 637 363 234, 298 653 364 226, 302 597 365 302 637 366 246, 302 625 367 302 695 368 302 711 369 302 669 370 302 720 371 300 693 372 242, 302 655 - The following Examples are prepared analogously to Example 169 and 170.
- The corresponding aniline is described in method 11.
- The following compounds are prepared by an analogous process to that described in Example 53. 2-(4-Carboxy-2-methoxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine may be prepared according to method 12 or 14. The corresponding aniline is described in method 4 or method 17. The amine used to prepare the amide is commercially obtainable.
- The following compounds are prepared by an analogous process to that described in Example 53. 2-(4-Carboxy-2-methoxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine may be prepared according to method 12 or 14. The corresponding aniline is described in method 7, in method 18 or 19. The amine used to prepare the amide is commercially obtainable or is described in method 13.
-
UV max MS (ESI) # A R3′ [nm] (M + H)+ 389 284, 322 668 390 230, 285, 325 698 391 280, 325 730 392 230, 285, 325 682 393 285, 325 630 394 284, 322 686 395 285, 325 616 396 285, 322 654 397 285, 325 584 398 285, 325 598 399 285, 325 668 400 285, 325 598 401 285, 325 612 402 285, 322 700 403 285, 322 630 404 262 688 -
- 1150 mg (3.308 mmol) 2-(4-carboxy-2-methoxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine (method 12 or 14) are dissolved in 2.5 ml N-methyl-2-pyrrolidinone and combined with 883 mg (4.161 mmol) 7-amino-2-(2,2-difluoro-ethyl)-2,3-dihydro-isoindol-1-one (method 2). 115 μl of a 4 M solution of HCl (0.460 mmol) in 1,4-dioxane are metered into this reaction mixture. After 16 h at 90° C. the reaction mixture is stirred into 150 ml of an aqueous 1 N hydrochloric acid. The precipitate is filtered off and dried in vacuo.
- Yield: 1626 mg (3.110 mmol; 94%)
- MS (ESI): 524 (M+H)+
- 100 mg (0.191 mmol) of this precipitate, 240 μl (1.402 mmol) N-ethyldiisopropyl-amine, 89 mg (0.279 mmol) O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-tetrafluoroborate and 76 mg (0.267 mmol) tert-butyl 4-amino-[1,4′]bipiperidinyl-1′-carboxylate are dissolved in 3 ml N,N-dimethylformamide. After 15 h at 20° C. the solvent is eliminated in vacuo. The residue is taken up in 20 ml dichloromethane and 5 ml of methanol and filtered through aluminium oxide. The aluminium oxide is washed several times with a mixture of dichloromethane and methanol (4:1). The solvent of the combined fractions is eliminated in vacuo. The residue is dissolved in 5 ml dichloromethane and combined with 5 ml trifluoroacetic acid. This mixture is stirred for 3 h at 20° C. and then the solvent is eliminated in vacuo. The crude product is purified by column chromatography. The carrier material used is C18-RP-silica gel and a gradient is run through which consists of 90% water and 10% acetonitrile at the starting point and 5% water and 95% acetonitrile at the finishing point. 0.1% formic acid are added both to the water and to the acetonitrile. The suitable fractions are combined with 500 μl of a 1 N hydrochloric acid and freeze-dried. The product is obtained as the trihydrochloride.
- Yield: 42 mg (0.053 mmol; 28%)
- UV max: 322 nm
- MS (ESI): 689 (M+H)+
- 1H-NMR: 1.92-2.19 (m, 6H), 2.28-2.37 (m, 2H), 2.86-3.00 (m, 2H), 3.07-3.19 (m, 3H), 3.84-4.18 (m, 7H), 4.59 (s, 2H), 6.15-6.47 (m, 1H), 7.23-7.28 (m, 1H), 7.35-7.43 (m, 1H), 7.54-7.64 (m, 2H), 7.75-7.82 (m, 1H), 8.40-8.64 (m, 3H), 8.90-9.01 (m, 1H), 9.10-9.25 (m, 2H), 10.40-10.47 (m, 1H), 10.91-11.27 (m, 1H)
- The following compounds are prepared by an analogous process to that described in Example 405.
-
- 70 mg (0.087 mmol) 2-[4-([1,4′]bipiperidinyl-4-ylcarbamoyl)-2-methoxy-phenylamino]-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine (Example 405) are dissolved in 3 ml of methanol, and combined with 8.5 μl (0.508 mmol) acetic acid and with 8 μl (0.107 mmol) of a 37% aqueous formaldehyde solution. Then at 20° C. 7.0 mg (0.112 mmol) sodium cyanoborohydride are added. This mixture is stirred for 16 h at 20° C. The solvent is eliminated in vacuo and the crude product is purified by column chromatography. The carrier material used is C18-RP-silica gel and a gradient is run through which consists at the starting point of 95% water and 5% acetonitrile and at the finishing point of 5% water and 95% acetonitrile. 0.1% formic acid are added both to the water and to the acetonitrile. The suitable fractions are combined with 500 μl of a 1 N hydrochloric acid and freeze-dried. The product is obtained as the trihydrochloride.
- Yield: 18 mg (0.022 mmol; 25%)
- UV max: 322 nm
- MS (ESI): 703 (M+H)+
- The following compounds are prepared by an analogous process to that described in Example 53. 2-(4-Carboxy-2-methoxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine may be prepared according to method 12 or 14. The corresponding aniline is described in method 2. The amine used to prepare the amide is commercially obtainable or is described in method 13, 20 or 21.
-
UV max MS (ESI) # A R3′ [nm] (M + H)+ 409 285, 320 584 410 322 716 411 326 703 412 558 413 282. 318 699 414 322, 286 668 415 322.3 724 416 322.3 362 417 322, 286 738 418 322, 286 738 419 282, 314 738 420 286, 314 738 421 286, 318 700 422 286, 322 698 423 286, 318 700 424 286, 322 712 425 286, 322 724 426 322, 286 672 427 282, 322 723 428 322, 285 602 429 326.3 616 430 322, 286 616 431 318, 286 645 432 321, 284 632 433 322, 286 618 434 318, 242 690 435 322, 282 708 436 322, 286 686 437 322, 284 722 438 322, 282 658 439 322, 285 547 440 322, 286 602 441 286.3 565 442 322, 286 620 443 322, 284 686 444 326.3 634 445 326, 286 634 446 322, 284 676 447 322.3 663 448 325.3 650 449 325.3 635 450 322, 282 620 451 322, 282 704 452 322, 282 665 453 326, 282 595 454 322, 284 677 455 322.3 664 456 326, 286 594 457 322, 282 743 458 326, 286 638 459 326, 283 681 460 318, 284 681 461 318, 286 627 462 322, 286 627 463 326, 286 648 464 322, 286 611 465 322, 286 723 466 322, 282 710 467 326, 286 654 468 326, 286 654 469 322, 284 683 470 326. 286 640 471 318, 283 710 472 326, 286 654 473 326, 286 654 474 321, 285 683 475 326, 286 630 476 322, 286 682 477 318, 286 612 478 318.3 606 479 322, 286 566 480 322, 286 621 481 318, 286 621 482 322, 286 606 483 326, 286 652 484 326, 286 648 485 322, 284 704 486 326, 286 634 487 322, 285 689 488 322, 285 703 489 322 698 490 322, 286 619 491 322, 286 689 - The following compounds are prepared by an analogous process to that described in Example 53. 2-(4-carboxy-2-methoxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine may be prepared according to method 12 or 14. The corresponding aniline is described in method 22. The amine used to prepare the amide is commercially obtainable, described in method 13, 15, 20, 21, 23, 24 and 25 or in J. Med. Chem. 2003, 46(5), 702-715.
-
UV max MS (ESI) # A R3′ R3″ [nm] (M + H)+ 492 H 286, 322 584 493 H 286, 322 826 494 H 284, 322 613 495 H 282, 322 640 496 H 286, 320 570 497 H 286, 322 584 498 H 282, 322 693 499 H 286, 322 686 500 H 286, 326 616 501 H 286, 326 630 502 H 282, 325 704 503 H 286, 326 634 504 H 286, 326 648 505 H 286, 322 712 506 H 322, 286 739 507 H 322, 286 645 508 H 326, 286 632 509 H 322, 286 672 510 H 322, 284 700 511 H 314, 286 616 512 H 286, 322 684 513 H 286, 322 670 514 H 282, 322 658 515 H 322, 286 632 516 H 326, 286 628 517 H 325, 286 628 518 H 326, 286 659 519 H 326 699 520 H 284, 326 616 521 H 234, 282, 314 630 522 H 326 660 523 H 326 657 524 H 645 525 H 326 627 526 H 326 660 527 H 326 659 528 H 326 692 529 H 326 644 530 H 326 628 531 H 322 662 532 H 326 699 533 H 326 602 534 H 646 535 H 326 666 536 H 326 646 537 H 326 — 538 H 322 616 539 H 318 630 540 H 318 630 541 H 274 644 542 H 326 658 543 H 286, 324 630 544 H 286, 326 658 545 H 286, 322 630 546 H 286, 326 642 547 H 286, 322 562 548 H 322-326 630 549 H 326 630 550 H 286, 322 607 551 H 646 552 H 644 553 H 326 644 554 H 322-326 658 555 H 322-326 658 556 H 286, 326 658 557 H 322-326 642 558 H 322-326 642 559 H 286, 322 656 560 H 286, 322 656 561 H 286, 322 671 562 H 286, 322 671 563 H 318 685 564 H 322-326 685 565 H 322-326 754 566 H 322-326 672 567 H 322 711 568 H 322-326 711 569 H 326 624 570 H 326 645 571 H 322-326 650 572 H 286, 326 684 573 H 286, 326 684 574 H 326 673 575 H 322 698 576 H 326, 286 646 577 H 286, 322 684 578 H 282, 322 658 579 H 322, 286 617 580 H 326, 286 644 581 H 326, 286 590 582 H 286, 326 673 583 H 326, 285 652 584 H 326, 282 722 585 H 326, 286 648 586 H 326, 285 718 587 H 326, 286 652 588 H 326, 284 652 589 H 325, 283 681 590 H 325.3 652 591 H 326.3 666 592 H 325, 283 666 593 H 325.3 648 594 H 325, 284 648 595 H 325, 284 677 596 H 325, 284 648 597 H 326, 285 662 598 H 325, 284 662 599 H 326, 282 720 600 314, 283 576 601 H 322, 286 714 602 H 286, 322 670 603 H 324, 285 614 604 H 324, 284 684 605 H 324, 285 628 606 H 324, 284 698 607 H 285, 322 630 608 H 325, 284 576 609 H 325, 284 576 610 H 326, 286 659 611 H 326, 286 646 612 H 325, 285 630 613 H 325, 284 630 614 H 325, 285 590 615 H 285, 325 642 616 H 325, 285 670 617 H 326, 286 684 618 H 326, 286 658 619 H 285, 324 684 620 H 326, 286 658 621 H 280, 320 631 -
- 73 mg (0.193 mmol) 3-(4-amino-3-methoxy-phenylamino)-N-(2-pyrrolidin-1-yl-ethyl)-propionamide hydrochloride (method 28) are dissolved in 3 ml 2-butanol and combined with 50 mg (0.129 mmol) 2-chloro-4-(2-(2-fluorethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine (method 26). This reaction mixture is stirred for 16 h at 100° C. The solvent is eliminated in vacuo and the residue is purified by column chromatography. The carrier material used is C18-RP-silica gel and a gradient is run through which consists at the starting point of 90% water and 10% acetonitrile and at the finishing point of 55% water and 45% acetonitrile. 0.1% formic acid are added both to the water and to the acetonitrile. The suitable fractions are combined with 500 μl of a 1 M aqueous hydrochloric acid and freeze-dried. The product is obtained as the dihydrochloride.
- Yield: 33 mg (0.045 mmol; 35%)
- UV max: 314 nm
- MS (ESI): 659 (M+H)+
- 1H-NMR: 1.35-1.48 (m, 3H), 1.64-1.78 (m, 4H), 2.37-2.46 (m, 2H), 3.48-3.75 (m, 4H), 3.97-4.14 (m, 1H), 4.50-4.78 (m, 3H), 5.55-5.71 (m, 1H), 6.14-6.42 (m, 2H), 6.96-7.32 (m, 3H), 7.86-7.98 (m, 1H), 8.32 (s, 1H), 8.84 (s, 1H), 10.41 (s, 1H)
-
- 0.07 g (0.3 mmol) 2-[2-(4-amino-3-methoxy-phenyl)-1H-imidazol-4-yl]-ethanol (method 27) are suspended in 2 ml dioxane and brought into solution in the ultrasound bath at 50° C. 0.8 ml (3.20 mmol) 4 N dioxanic hydrochloric acid are added. The dioxane is eliminated in vacuo, combined with 0.096 g (0.247 mmol) 7-(2-chloro-5-trifluoromethyl-pyrimidine-4-ylamine)-2-(2-fluoro-ethyl)-3-methyl-2,3-dihydro-isoindol-1-one and suspended in butanol. The mixture is stirred for 16 h at 100° C. The crude product is purified by column chromatography. The carrier material used is C18-RP-silica gel. A gradient is run through which consists at the starting point of 75% water and 25% acetonitrile and at the finishing point of 30% water and 70% acetonitrile. 0.1% ammonia is added to the water. 23 mg of this intermediate product and 0.018 g (0.094 mmol) p-toluenesulphonyl chloride are suspended in 0.9 ml of tetrahydrofuran and 0.02 ml (0.139 mmol) triethylamine and combined with 0.007 g (0.057 mmol) 4-dimethylamino-pyridine. This reaction mixture is stirred for 16 h at 20° C. Then it is combined with 0.36 ml (5.064 mmol) pyrrolidine and stirred for 16 h at 60° C. The crude product is purified by column chromatography. The carrier material used is C18-RP-silica gel. A gradient is run through which consists of 90% water and 10% acetonitrile at the starting point and of 60% water and 40% acetonitrile at the finishing point. 0.1% formic acid is added to the water.
- Yield: 7 mg (0.011 mmol, 28%)
- MS (ESI): 639 (M+H)+
- UV max: 330 nm
- NMR: 1.42-1.46 (m, 3H), 1.78-2.08 (m, 6H), 2.29 (s, 1H), 3.95-4.16 (m, 4H), 4.52-4.78 (m, 3H), 7.09-7.13 (m, 1H), 7.24-7.28 (m, 1H), 7.46-7.50 (m, 1H), 7.52-7.58 (m, 2H), 7.64-7.67 (m, 1H), 7.82-7.88 (m, 1H), 8.02-8.13 (m, 2H), 8.50-8.60 (m, 2H), 9.20-9.23 (m, 1H), 10.52-10.82 (m, 2H).
- The following compounds are prepared by an analogous process to that described in Example 622 or 623. The corresponding aniline is described in method 27 and 28.
-
- 50 mg (0.087 mmol) 2-(4-(4-[1,4]diazepan-1-yl)-2-methoxy-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine (method from Example 622, aniline from method 28) are dissolved in 0.5 ml dimethylacetamide and combined with 13 μl (0.174 mmol) acetone. 37 mg (0.175 mmol) sodium triacetoxyborohydride are added to this reaction mixture. After 16 h at 20° C. the solvent is eliminated in vacuo. The residue is purified by column chromatography. The carrier material used is C18-RP-silica gel and within 15 min a gradient is run through which consists of 95% water and 5% acetonitrile at the starting point and 5% water and 95% acetonitrile at the finishing point. 0.1% formic acid are added both to the water and to the acetonitrile. The suitable fractions are combined with 500 μl of a 1 M aqueous hydrochloric acid and freeze-dried. The product is obtained as the dihydrochloride.
- Yield: 51 mg (0.074 mmol; 85%)
- UV max: 314 nm
- MS (ESI): 616 (M+H)+
- 1H-NMR: 1.23-1.35 (m, 6H), 1.35-1.51 (m, 3H), 2.16-2.29 (m, 1H), 2.95-3.05 (m, 1H), 3.12-3.23 (m, 1H), 3.42-3.66 (m, 6H), 3.78 (s, 3H), 3.83-4.00 (m, 2H), 4.00-4.16 (m, 1H), 4.50-4.79 (m, 3H), 6.32-6.63 (m, 2H), 7.08-8.59 (m, 4H), 9.24-9.76 (m, 1H), 10.67 (s, 2H)
- The following compounds are prepared by an analogous process to that described in Example 639.
- The following compounds are prepared by an analogous process to that described in Example 639. For the reductive amination 2-(2-methoxy-4-piperazin-1-yl-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine is used. The aniline for preparing this compound is described in method 28.
- The following compounds are prepared by an analogous process to that described in Example 53. 2-(4-Carboxy-2-bromo-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine may be prepared according to method 29. The corresponding aniline is described in method 22. The amine used to prepare the amide is commercially obtainable or described in method 13.
- The following compounds are prepared by an analogous process to that described in Example 53. 2-(4-Carboxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine may be prepared according to method 14. The corresponding aniline is described in method 22. The amine used to prepare the amide is commercially obtainable or described in method 13. In addition, the group R3′ may be synthesised analogously to Example 639 by reductive amination. An amine is used which has another protected amino function in the side chain. The protective group used may be a tert-butoxycarbonyl, benzyloxycarbonyl or benzyl group. This protective group is cleaved by a procedure familiar to the skilled man and reductive amination (analogously to Example 639) or alkylation (analogously to method 34 or WO2004052857) are the last steps in this sequence.
-
- 63 mg (0.116 mmol) 2-(4-acryloylamino-2-methoxy-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine (method 30) are dissolved in 1 ml of methanol and combined with 70 mg (0.699 mmol) N-methyl-piperazine. After stirring for 48 h at 20° C. the solvent is eliminated in vacuo. The residue is purified by column chromatography. The carrier material used is C18-RP-silica gel and a gradient is run through within 20 min which consists of 95% water and 5% acetonitrile at the starting point and of 2% water and 98% acetonitrile at the finishing point. 0.1% formic acid are added both to the water and to the acetonitrile. The suitable fractions are combined with 500 μl of a 1 M aqueous hydrochloric acid and freeze-dried. The product is obtained as the dihydrochloride.
- Yield: 58 mg (0.081 mmol; 70%)
- UV max: 282 nm
- MS (ESI): 645 (M+H)+
- 1H-NMR: 1.42 (d, 3H), 2.18 (s, 3H), 2.29-2.43 (m, 4H), 2.65-2.70 (m, 2H), 3.50-3.62 (m, 1H), 3.72 (s, 3H), 4.00-4.12 (m, 1H), 4.52-4.76 (m, 3H), 7.12-7.17 (m, 1H), 7.12-7.42 (m 4H), 7.51 (s, 1H), 8.17 (s, 1H), 8.38 (s, 1H), 9.08 (s, 1H), 10.18 (s, 1H), 10.46 (s, 1H)
- The following compounds are prepared by an analogous process to that described in Example 682.
- The following compounds are prepared by an analogous process to that described in Example 682. 2-(4-(2-Bromo-acetylamino)-2-methoxy-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine or 2-(4-(2-bromo-acetylamino)-2-bromo-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine or 2-[5-(2-bromo-acetylamino)-pyridin-2-ylamino]-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine, which are described in method 30, are used as educt for the nucleophilic substitution.
-
- 70 mg (0.135 mmol) 2-(4-carboxy-2-methoxy-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine (analogously to Example 53) are dissolved in 2 ml of toluene and combined with 190 μl (1.348 mmol) triethylamine and 60 μl (0.270 mmol) diphenylphosphorylazide. This reaction mixture is stirred for 48 h at 20° C. Then the temperature of the suspension is adjusted to 95° C. for 2 h, whereupon a clear brown solution is formed. Then 31 mg (0.270 mmol) 1-(2-aminoethyl)-pyrrolidine are added and the mixture is again stirred for 1 h at 95° C. The solvent is eliminated in vacuo. The residue is purified by column chromatography. The carrier used is C18-RP-silica gel and within 15 min a gradient is run through which consists of 95% water and 5% acetonitrile at the starting point and consists of 2% water and 98% acetonitrile at the finishing point. 0.1% formic acid are added to both the water and to the acetonitrile. The suitable fractions are made basic with 5 M sodium hydroxide solution and extracted 4 times with 50 ml dichloromethane. The combined organic phases are dried and the solvent is eliminated in vacuo.
- Yield: 42 mg (0.067 mmol; 50%)
- UV max: 282 nm
- MS (ESI): 631 (M+H)+
- 1H-NMR: 1.42-1.48 (m, 3H), 1.69-1.79 (m, 4H), 3.22-3.28 (m, 2H), 3.49-3.62 (m, 1H), 3.70 (s, 3H), 3.99-4.12 (m, 1H), 4.53-4.76 (m, 3H), 6.17 (s, 1H), 6.84-6.91 (m, 1H), 7.15-7.33 (m, 3H), 7.40 (s, 1H), 8.36 (s, 1H), 8.76 (s, 1H), 9.01 (s, 1H), 10.44 (s, 1H)
-
- This compound is prepared analogously to Example 705.
- UV max: 282/314 nm
- MS (ESI): 534 (M+H)+
- 1H-NMR: 1.42 (d, 3H), 3.48-3.64 (m, 1H), 3.69 (s, 3H), 3.98-4.13 (m, 1H), 4.50-4.77 (m, 3H), 5.89 (s, 2H), 6.94 (d, 1H), 7.16-7.30 (m, 2H), 7.36 (s, 1H), 8.33-8.41 (m, 2H), 8.38 (s, 1H), 8.73 (s, 1H), 9.00 (s, 1H), 10.44 (s, 1H)
-
- Starting from 2-(4-amino-2-methoxy-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine (method 30) the above-mentioned product is prepared using an amide linking method familiar to the skilled man (cf. also Example 53 or 1032). The substance is obtained as a free base.
- UV max: 282 nm
- MS (ESI): 616 (M+H)+
- 1H-NMR (400 MHz, CDCl3): 1.51 (d, 3H), 2.25-2.32 (m, 1H), 2.36 (s, 3H), 3.00-3.07 (m, 2H), 3.53-3.65 (m, 1H), 3.92 (s, 3H), 4.13-4.27 (m, 1H), 4.56-4.77 (m, 3H), 6.84 (d, 1H), 7.07 (d, 1H), 7.44 (s, 1H), 7.47-7.54 (m, 1H), 7.57 (s, 1H), 7.62 (s, 1H), 8.16-8.24 (m, 1H), 8.39 (s, 1H), 8.60-8.68 (m, 1H), 10.42 (s, 1H)
- Using an analogous method to that described in Example 53 a primary amine which has another protected amino function in the side chain is coupled to 2-(4-carboxy-2-methoxy-phenylamino)-4-[2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino]-5-trifluoromethyl-pyrimidine. The protective group used may be a tert-butoxycarbonyl, benzyloxycarbonyl or benzyl group. This protective group is cleaved using a procedure familiar to the skilled man and reductive amination (analogously to Example 639) or alkylation (analogously to method 34 or WO2004052857) are the final steps in this sequence.
-
UV max MS (ESI) # R3′ [nm] (M + H)+ 708 285, 322 706 709 285, 322 656 710 285, 322 630 711 322, 286 644 712 325, 286 699 713 282, 318 644 714 326 685 715 326 658 716 326 699 717 326 630 718 326 644 719 322 644 720 326 656 721 326 678 722 314 630 723 322 641 724 326 712 725 326 642 726 322 642 727 318 672 728 301 686 729 326 588 730 326 642 731 326 670 732 326 642 733 326 630 734 326 699 735 310 616 736 326 656 737 322 630 738 326 656 739 326 656 740 266 652 741 326 629 742 326 671 743 326 630 744 326 642 745 326 602 746 326 628 747 326 616 748 326 602 749 322 652 750 326 646 751 326 672 752 326 616 753 326 616 754 326 685 755 322 616 756 318 713 757 286, 322 588 758 226, 286, 322 602 759 322-326 656 760 322-326 699 761 322-326 670 762 322-326 699 763 322 713 764 326 685 765 322 684 766 326 642 767 322-326 656 768 322-326 685 769 322-326 630 770 286, 322 670 771 286, 322 670 772 322-326 644 773 322 684 774 322-326 658 775 322 686 776 322-326 727 777 322-326 674 778 322-326 684 796 322-326 698 780 286, 322 630 781 282, 314 616 782 322, 286 686 783 326 684 784 324, 286 656 785 326, 286 685 786 322, 286 715 787 322, 286 673 788 285, 322 616 789 285, 322 630 790 285, 322 686 791 285, 322 686 792 326 644 793 322 630 794 326 631 795 326 660 -
- 200 mg (0.385 mmol) 2-(4-carboxy-2-methoxy-phenylamino)-4-[2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino]-5-trifluoromethyl-pyrimidine (analogously to Example 53) are dissolved in 1 ml of dimethylformamide cooled to 0° C. and combined with 520 μl (3.038 mmol) diisopropylethylamine and 160 mg (0.498 mmol) O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-tetrafluoroborate. This solution is slowly added dropwise after 10 min to 56 μl (0.539 mmol) 1,2-diamino-2-methylpropane, which is dissolved in 300 μl dimethylformamide. The reaction mixture is stirred for 24 h at 20° C. and then the solvent is eliminated in vacuo. The residue is purified by column chromatography. The carrier used is C18-RP-silica gel and within 15 min a gradient is run through which consists at the starting point of 90% water and 10% acetonitrile and at the finishing point of 50% water and 50% acetonitrile. 0.1% formic acid are added to both the water and to the acetonitrile. The suitable fractions are freeze-dried. This intermediate product is combined with 70 mg (0.515 mmol) potassium carbonate and with 84 mg (0.506 mmol) potassium iodide and suspended in 2 ml acetonitrile. 20 μl (0.170 mmol) 1,4-dibromobutane are added to this mixture and it is stirred under reflux conditions for 16 h. Then the solvents are solvent eliminated in vacuo and the residue is purified by column chromatography. The carrier used is C18-RP-silica gel and within 15 min a gradient is run through which consists at the starting point of 90% water and 10% acetonitrile and at the finishing point of 50% water and 50% acetonitrile. 0.1% formic acid are added to both the water and to the acetonitrile. The suitable fractions are combined with 0.5 ml 1 N hydrochloric acid and freeze-dried. The product is obtained as the dihydrochloride.
- Yield: 20 mg (0.032 mmol, 8%)
- UV max: 325 nm
- MS (ESI): 644 (M+H)+
- 1H-NMR (400 MHz): 1.30-1.47 (m, 9H), 1.85-2.01 (m, 4H), 3.20-3.31 (m, 2H), 3.91 (s, 3H), 3.99-4.15 (m, 1H), 4.51-4.78 (m, 3H), 7.23-7.29 (m, 1H), 7.39-7.47 (m, 1H), 7.63-7.69 (m, 1H), 7.73-7.77 (m, 1H), 7.79-7.87 (m, 1H), 8.40-8.59 (m, 2H), 8.75-8.82 (m, 1H), 9.16-9.21 (m, 1H), 10.50-10.63 (m, 2H)
- The following compounds are prepared by an analogous method to that described in Example 796:
- The following compounds are prepared by an analogous process to that described in Example 53. The corresponding aniline is described in method 31. The amine used to prepare the amide is commercially obtainable or is described in method 13, 21 or in method 25.
- The following compounds are prepared by an analogous process to that described in Example 53. The corresponding aniline is described in method 31. The amine used to prepare the amide is commercially obtainable, described in method 13, 15, 20, 21, 23, 24 and 25 or in J. Med. Chem. 2003, 46(5), 702-715.
-
UV max MS (ESI) # R3′ [nm] (M + H)+ 822 286, 322 686 823 325, 284 616 824 286, 326 630 825 286, 322 616 826 286, 318 712 827 286, 322 684 828 326 645 829 316 689 830 322 689 831 616 832 318 630 833 326 588 834 322 630 835 286, 322 630 836 658 837 322-326 602 838 322-326 616 839 322 616 840 322-326 616 841 322-326 630 842 322-326 630 843 286, 322 644 844 286, 322 642 845 286, 322 642 846 286, 322 656 847 282, 318 630 848 282, 322 630 849 286, 318 671 850 286, 322 630 851 286, 322 630 852 286, 322 644 853 322-326 672 854 322 672 855 286, 322 725 856 286, 322 725 857 322-326 685 858 286, 322 713 859 286, 322 713 860 286, 322 644 861 286, 322 644 862 318-322 645 863 286, 322 658 864 286, 322 699 865 286, 322 699 866 326 709 867 322 697 868 322 697 869 318 695 870 290.3 693 871 322 695 872 286, 322 753 873 286, 326 642 874 286, 322 645 875 322, 286 659 876 282, 322 684 877 324, 284 646 878 286, 322 670 879 325, 284 630 880 322, 286 630 881 322, 286 684 882 325, 286 670 883 322, 286 646 884 326, 286 644 885 325, 285 630 - The following compounds are prepared by an analogous process to that described in Example 622 or 623. The corresponding aniline is described in method 27 or 28.
- The following compounds are prepared by an analogous process to that described in Example 53. 2-(4-carboxy-2-bromo-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine is described in method 29. The corresponding aniline is described in method 31. The amine used to prepare the amide is commercially obtainable.
-
- Starting from 2-(4-amino-2-methoxy-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine enantiomer 1 (analogously to method 30) the above-mentioned product is prepared by an amide linking method familiar to the skilled man (cf. also Example 1032). It is obtained as the dihydrochloride.
- UV max: 310 nm
- MS (ESI): 616 (M+H)+
- 1H-NMR (500 MHz): 1.42 (d, 3H), 1.69-1.77 (m, 2H), 1.77-1.84 (m, 2H), 1.94-2.03 (m, 2H), 2.23 (s, 3H), 2.29-2.38 (m, 1H), 2.86-2.93 (m, 2H), 3.72 (s, 3H), 4.00-4.12 (m, 1H), 4.52-4.75 (m, 3H), 7.16 (d, 3H), 7.18-7.24 (m, 1H), 7.32-7.41 (m, 1H), 7.57 (s, 1H), 8.18 (s, 1H), 8.38 (s, 1H), 9.07 (s, 1H), 9.95 (s, 1H), 10.46 (s, 1H)
-
- Starting from 2-(4-amino-2-methoxy-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine Enantiomer 1 (analogously to method 30) the above-mentioned product is prepared by an amide linking method familiar to the skilled man (cf. also Example 1032). It is obtained as the dihydrochloride.
- UV max: 282 nm
- MS (ESI): 602 (M+H)+
- 1H-NMR (500 MHz): 1.43 (d, 3H), 1.87-2.00 (m, 2H), 2.00-2.10 (m, 2H), 3.12-3.22 (m, 2H), 3.74 (s, 3H), 4.00-4.13 (m, 1H), 4.28-4.32 (m, 2H), 4.53-4.76 (m, 3H), 7.19-7.49 (m, 4H), 7.51 (s, 1H), 8.41 (s, 1H), 9.26 (s, 1H), 10.20-10.31 (m, 1H), 10.54 (s, 1H), 10.86 (s, 1H)
- Using a method analogous to that described in Example 53 a primary amine which has another protected amino function in the side chain is coupled to 2-(4-carboxy-2-methoxy-phenylamino)-4-[2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino]-5-trifluoromethyl-pyrimidine Enantiomer 1. The protective group used may be a tert-butoxycarbonyl, benzyloxycarbonyl or benzyl group. This protective group is cleaved using a procedure familiar to the skilled man and reductive amination (analogously to Example 639) or alkylation (analogously to method 34 or WO2004052857) are the final steps in this sequence.
-
UV max MS (ESI) # R3′ [nm] (M + H)+ 897 672 898 322 644 899 326 630 900 326 630 901 322 644 902 322 642 903 322 658 904 326 615 905 322 656 906 326 658 907 326 644 908 322 644 909 322 670 910 306 686 911 326 630 912 666 913 286, 322 656 914 286, 322 656 915 286, 318 670 916 286, 322 713 917 286, 322 670 918 286.3 713 919 286, 322 642 920 286, 322 672 921 286, 322 672 922 286, 322 644 923 286, 322 670 924 286, 322 700 925 286, 322 700 926 286, 322 670 927 326 713 928 322-326 700 929 322-326 644 930 322 658 931 322-326 713 932 322 700 933 322-326 644 934 322 658 935 322-326 714 936 322 714 937 322 662 938 322-326 662 939 676 940 322-326 680 941 286, 322 648 942 230, 286, 318 662 943 284, 324 668 944 282, 322 670 945 282, 322 696 946 228, 284, 322 642 947 226, 286, 322 672 948 286, 322 644 949 324, 284 644 950 285, 322 616 951 285, 325 630 952 285, 325 616 - The following compounds are prepared by a method analogous to that described in Example 796:
-
- The racemic synthesis of the above-mentioned compound is carried out using by a method analogous to that described in Example 53. The corresponding aniline is described in method 22. The two enantiomers are isolated by preparative chromatography:
- column: 250×4.6 mm CHIRALPAKADH®
- eluant: 25 ethanol/75 methanol (v/v) (0.03% triethylamine is added to each solvent)
- flow rate: 0.5 ml/min
- temperature: 20° C.
- The enantiomer that elutes first is referred to as Enantiomer 1 and bears the symbol *1 in the chemical formula.
-
- retention time: 9.96 min
- The enantiomer that elutes second is referred to as Enantiomer 2 and bears the symbol *2 in the chemical formula.
-
- retention time: 12.60 min
- The following compounds are prepared by an analogous method to that described in Example 53. The corresponding aniline is described in method 22. The amine used to prepare the amide is commercially obtainable or is described in method 13.
-
UV max MS (ESI) # A R3′ [nm] (M + H)+ 960 280, 320 654 961 282, 318 962 286, 322 680 963 286, 326 630 964 286, 326 644 965 286, 326 630 966 286, 326 659 967 286, 326 630 968 286, 322 644 969 286, 326 644 970 286, 326 644 971 286, 326 714 972 286, 322 632 973 286, 326 646 974 286, 326 660 975 282, 326 685 976 282, 326 659 - The following compounds are prepared by an analogous method to that described in Example 53. The corresponding aniline is described in method 6. The amine used to prepare the amide is described in method 13.
- The following compounds are prepared by an analogous method to that described in Example 53. The corresponding aniline is described in method 32. The amine used to prepare the amide is commercially obtainable or described in method 13.
- The following compounds are prepared by an analogous method to that described in Example 53. The corresponding aniline is described in method 33. The amine used to prepare the amide is commercially obtainable or described in method 13 or 21.
-
UV max MS (ESI) # A R3′ [nm] (M + H)+ 1000 282, 322 614 1001 282, 322 841 1002 282, 326 571 1003 280, 322 655 1004 280, 325 655 1005 280, 322 669 1006 280, 325 599 1007 282, 327 613 1008 280, 322 697 1009 282, 325 627 1010 283, 328 641 1011 280, 325 585 1012 280, 325 599 1013 326, 283 585 1014 282, 327 599 1015 322-326 597 1016 326 611 1017 280, 325 585 1018 280, 325 614 1019 280, 325 585 1020 280, 322 599 1021 280, 325 641 1022 280, 325 599 1023 280, 325 585 1024 280, 322 653 - The following compounds are prepared by an analogous method to that described in Example 53. The corresponding aniline is described in method 10. The amine used to prepare the amide is commercially obtainable or described in method 13.
- The following compounds are prepared by an analogous method to that described in Example 53. The corresponding aniline is described in method 2. The amine used to prepare the amide is described in method 13.
-
- The above-mentioned compound is prepared by a method analogous to that described in Example 53. The corresponding aniline is described in method 34. The amine used to prepare the amide is commercially obtainable. The substance is obtained as the dihydrochloride.
- UV max: 326, 286 nm
- MS (ESI): 630 (M+H)+
- 1H-NMR (400 MHz): 1.44-1.50 (m, 6H), 1.84-1.95 (m, 2H), 1.98-2.07 (m, 2H), 3.02-3.12 (m, 2H), 3.62-3.70 (m, 4H), 3.71-3.76 (m, 1H), 3.77-3.81 (m, 1H), 3.89 (s, 3H), 4.57-4.61 (m, 1H), 4.69-4.73 (m, 1H), 7.27-7.31 (m, 1H), 7.39-7.45 (m, 1H), 7.55-7.59 (m, 1H), 7.63-7.66 (m, 1H), 7.84-7.88 (m, 1H), 8.44-8.55 (m, 2H), 8.77-8.82 (m, 1H), 9.11-9.15 (m, 1H), 9.91-10.03 (m, 1H), 10.51-10.55 (m, 1H)
-
- 50 mg (0.104 mmol) 2-(4-carboxy-2-methoxy-phenylamino)-4-(2-(2-fluoro-ethyl)-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-acetyl-pyrimidine (prepared by an analogous process to that described in Example 622 or 623) are dissolved in 0.5 ml of dimethylformamide and combined with 72 μl (0.520 mmol) and 34 mg (0.104 mmol) O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-tetrafluoroborate. After stirring for 20 min at 20° C., 23 mg (0.156 mmol) 2-(4-methylpiperazin-1-yl)-ethylamine are added. The reaction is completed after 2 h at 20° C. Then the solvent is eliminated in vacuo and the residue is purified by column chromatography. The carrier used is C18-RP-silica gel and a gradient is run through within 20 min which consists of 95% water and 5% acetonitrile at the starting point and consists of 5% water and 95% acetonitrile at the finishing point. 0.1% formic acid are added to both the water and to the acetonitrile. The suitable fractions are combined with 500 μl of a 1 M aqueous hydrochloric acid and freeze-dried. The product is obtained as the trihydrochloride.
- UV max: 326 nm
- MS (ESI): 605 (M+H)+
- 1H-NMR (500 MHz): 2.53-2.58 (m, 3H), 2.80-2.92 (m, 3H), 3.62-3.88 (m, 9H), 3.88-4.01 (m, 4H), 4.54 (s, 2H), 4.58-4.66 (m, 1H), 4.69-4.77 (m, 1H), 7.14-7.32 (m, 1H), 7.32-7.50 (m, 1H), 7.50-7.59 (m, 1H), 7.63-7.75 (m, 1H), 7.78-8.01 (m, 1H), 8.29-8.60 (m, 1H), 8.73-8.99 (m, 2H), 9.03-9.18 (m, 1H), 12.31-12.41 (m, 1H)
- The following compounds are prepared by an analogous method to that described in Example 1037. The aniline used is described in method 28. The amine used to prepare the amide is commercially obtainable or described in method 13.
-
UV max MS (ESI) # A R3′ [nm] (M + H)+ 1038 326 660 1039 326 646 1040 328 576 1041 318 672 1042 326 605 1043 330 590 1044 318 663 1045 330 604 1046 326 686 1047 326 604 1048 330 590 1049 326 713 1050 330 590 1051 250 614 1052 334-338 600 1053 334-338 614 1054 338 600 1055 338 670 1056 334 696 1057 330 622 1058 327 340 1059 330 608 1060 330 632 - The following compounds are prepared by an analogous method to that described in Example 622 or 623. The corresponding aniline is described in method 28.
- The following compounds are prepared by an analogous method to that described in Example 622 or 623 and 53. The corresponding aniline is described in method 28. The amine used to prepare the amide is commercially obtainable or described in method 13.
- The following compounds are prepared by an analogous method to that described in Example 1037. The corresponding aniline is described in method 28. The amine used to prepare the amide is commercially obtainable or described in method 13.
- As demonstrated by DNA staining followed by FACS analysis, the inhibition of proliferation brought about by the compounds according to the invention is mediated above all by the arrest of the cells in the G2/M phase of the cell cycle. The cells arrest, depending on the type of cell used, for a specific length of time in this cell cycle phase before programmed cell death is initiated. An arrest in the G2/M phase of the cell cycle may be initiated e.g. by the inhibition of specific cell cycle kinases. On the basis of their biological properties the compounds of general formula I according to the invention, their isomers and the physiologically acceptable salts thereof are suitable for treating diseases characterised by excessive or anomalous cell proliferation.
- Such diseases include for example: viral infections (e.g. HIV and Kaposi's sarcoma); inflammatory and autoimmune diseases (e.g. colitis, arthritis, Alzheimer's disease, glomerulonephritis and wound healing); bacterial, fungal and/or parasitic infections; leukaemias, lymphomas and solid tumours; skin diseases (e.g. psoriasis); bone diseases; cardiovascular diseases (e.g. restenosis and hypertrophy). They are also useful for protecting proliferating cells (e.g. hair, intestinal, blood and progenitor cells) from DNA damage caused by radiation, UV treatment and/or cytostatic treatment (Davis et al., 2001). The new compounds may be used for the prevention, short- or long-term treatment of the above-mentioned diseases, also in combination with other active substances used for the same indications, e.g. cytostatics, steroids or antibodies.
- The activity of the compounds according to the invention on various kinases, for example on serine-threonine kinase PLK-1, was determined by in vitro kinase assays with recombinantly produced protein. In this assay the compounds exhibit a good to very good effect on PLK1, i.e. for example an IC50 value of less than 1 μmol/L, usually less than 0.1 μmol/L.
- Recombinant human PLK1 enzyme linked to GST at its N-terminal end is isolated from insect cells infected with baculovirus (Sf21). Purification is carried out by affinity chromatography on glutathione sepharose columns.
- 4×107 Sf21 cells (Spodoptera frugiperda) in 200 ml of Sf-900 II Serum free insect cell medium (Life Technologies) are seeded in a spinner flask. After 72 hours' incubation at 27° C. and 70 rpm, 1×108 Sf21 cells are seeded in a total of 180 ml medium in a new spinner flask. After another 24 hours, 20 ml of recombinant Baculovirus stock suspension are added and the cells are cultivated for 72 hours at 27° C. at 70 rpm. 3 hours before harvesting, okadaic acid is added (Calbiochem, final concentration 0.1 μM) and the suspension is incubated further. The cell number is determined, the cells are removed by centrifuging (5 minutes, 4° C., 800 rpm) and washed 1× with PBS (8 g NaCl/l, 0.2 g KCl/l, 1.44 g Na2HPO4/l, 0.24 g KH2PO4/l). After centrifuging again the pellet is flash-frozen in liquid nitrogen. Then the pellet is quickly thawed and resuspended in ice-cold lysing buffer (50 mM HEPES pH 7.5, 10 mM MgCl2, 1 mM DTT, 5 μg/ml leupeptin, 5 μg/ml aprotinin, 100 μM NaF, 100 μM PMSF, 10 mM β-glycerolphosphate, 0.1 mM Na3VO4, 30 mM 4-nitrophenylphosphate) to give 1×108 cells/17.5 ml. The cells are lysed for 30 minutes on ice. After removal of the cell debris by centrifugation (4000 rpm, 5 minutes) the clear supernatant is combined with glutathione sepharose beads (1 ml resuspended and washed beads per 50 ml of supernatant) and the mixture is incubated for 30 minutes at 4° C. on a rotating board. Then the beads are washed with lysing buffer and the recombinant protein is eluted from the beads with 1 ml eluting buffer/ml resuspended beads (eluting buffer: 100 mM Tris/HCl pH=8.0, 120 mM NaCl, 20 mM reduced glutathione (Sigma G-4251), 10 mM MgCl2, 1 mM DTT). The protein concentration is determined by Bradford Assay.
- The following components are combined in a well of a 96-well round-bottomed dish (Greiner bio-one, PS Microtitre plate No. 650101):
-
- 10 μl of the compound to be tested in variable concentrations (e.g. beginning at 300 μM, and dilution to 1:3) in 6% DMSO, 0.5 mg/ml casein (Sigma C-5890), 60 mM β-glycerophosphate, 25 mM MOPS pH=7.0, 5 mM EGTA, 15 mM MgCl2, 1 mM DTT
- 20 μl substrate solution (25 mM MOPS pH=7.0, 15 mM MgCl2, 1 mM DTT, 2.5 mM EGTA, 30 mM β-glycerophosphate, 0.25 mg/ml casein)
- 20 μl enzyme dilution (1:100 dilution of the enzyme stock in 25 mM MOPS pH=7.0, 15 mM MgCl2, 1 mM DTT)
- 10 μl ATP solution (45 μM ATP with 1.11×106 Bq/ml gamma-P33-ATP).
- The reaction is started by adding the ATP solution and continued for 45 minutes at 30° C. with gentle shaking (650 rpm on an IKA Schüttler MTS2). The reaction is stopped by the addition of 125 μl of ice-cold 5% TCA per well and incubated on ice for at least 30 minutes. The precipitate is transferred by harvesting onto filter plates (96-well microtitre filter plate: UniFilter-96, GF/B; Packard; No. 6005177), then washed four times with 1% TCA and dried at 60° C. After the addition of 35 μl scintillation solution (Ready-Safe; Beckmann) per well the plate is sealed shut with sealing tape and the amount of P33 precipitated is measured with the Wallac Betacounter. The measured data are evaluated using the standard Graphpad software (Levenburg-Marquard Algorhythmus).
- The anti-proliferative activity of the compounds according to the invention is determined in the cytotoxicity test on cultivated human tumour cells and/or in a FACS analysis, for example on HeLa S3 cells. In both test methods the compounds exhibit good to very good activity, i.e. for example an EC50 value in the HeLa S3 cytotoxicity test of less than 5 μmol/L, generally less than 1 μmol/L.
- To measure cytotoxicity on cultivated human tumour cells, cells of cervical carcinoma tumour cell line HeLa S3 (obtained from American Type Culture Collection (ATCC)) are cultivated in Ham's F12 Medium (Life Technologies) and 10% foetal calf serum (Life Technologies) and harvested in the log growth phase. Then the HeLa S3 cells are placed in 96-well plates (Costar) at a density of 1000 cells per well and incubated overnight in an incubator (at 37° C. and 5% CO2), while on each plate 6 wells are filled with medium alone (3 wells as the medium control, 3 wells for incubation with reduced AlamarBlue reagent). The active substances are added to the cells in various concentrations (dissolved in DMSO; DMSO final concentration: 0.1%) (in each case as a triple measurement). After 72 hours incubation 20 μl AlamarBlue reagent (AccuMed International) are added to each well, and the cells are incubated for a further 5-7 hours. As a control, 20 μl reduced AlamarBlue reagent is added to each of 3 wells (AlamarBlue reagent, which is autoclaved for 30 min). After incubation the colour change of the AlamarBlue reagent in the individual wells is determined in a Perkin Elmer fluorescence spectrophotometer (excitation 530 nm, emission 590 nm, slits 15, integrate time 0.1). The amount of AlamarBlue reagent reacted represents the metabolic activity of the cells. The relative cell activity is calculated as a percentage of the control (HeLa S3 cells without inhibitor) and the active substance concentration which inhibits the cell activity by 50% (IC50) is derived. The values are calculated from the average of three individual measurements—with correction of the dummy value (medium control).
- Propidium iodide (PI) binds stoichiometrically to double-stranded DNA, and is thus suitable for determining the proportion of cells in the G1, S, and G2/M phase of the cell cycle on the basis of the cellular DNA content. Cells in the G0 and G1 phase have a diploid DNA content (2N), whereas cells in the G2 or mitosis phase have a 4N DNA content.
- For PI staining, for example, 1×106 HeLa S3 cells are seeded onto a 75 cm2 cell culture flask, and after 24 h either 0.1% DMSO is added as control or the substance is added in various concentrations (in 0.1% DMSO). The cells are incubated for 24 h with the substance or with DMSO before the cells are washed 2× with PBS and then detached with trypsin/EDTA. The cells are centrifuged (1000 rpm, 5 min, 4° C.), and the cell pellet is washed 2× with PBS before the cells are resuspended in 0.1 ml PBS. Then the cells are fixed with 80% ethanol for 16 hours at 4° C. or alternatively for 2 hours at −20° C. The fixed cells are centrifuged (1000 rpm, 5 min, 4° C.), washed with PBS and then centrifuged again. The cell pellet is resuspended in 2 ml 0.25% Triton X-100 in PBS, and incubated on ice for 5 min before 5 ml PBS are added and the mixture is centrifuged again. The cell pellet is resuspended in 350 μl PI staining solution (0.1 mg/ml RNase A (Sigma, No. R-4875), 10 μg/ml prodium iodide (Sigma, No. P-4864) in 1×PBS). The cells are incubated for 20 min in the dark with the staining buffer before being transferred into sample measuring containers for the FACS scan. The DNA measurement is carried out in a Becton Dickinson FACS Analyzer, with an argon laser (500 mW, emission 488 nm), and the DNA Cell Quest Programme (BD). The logarithmic PI fluorescence is determined with a band-pass filter (BP 585/42). The cell populations in the individual cell cycle phases are quantified using the ModFit LT Programme made by Becton Dickinson.
- The compounds according to the invention are also tested accordingly for other tumour cells. For example, these compounds are effective on carcinomas of all kinds of tissue (e.g. breast (MCF7); colon (HCT116), head and neck (FaDu), lung (NCI-460), pancreas (BxPC-3), prostate (DU145)), sarcomas (e.g. SK-UT-1B), leukaemias and lymphomas (e.g. HL-60; Jurkat, THP-1) and other tumours (e.g. melanomas (BRO), gliomas (U-87MG)) and could be used for such indications. This is evidence of the broad applicability of the compounds according to the invention for the treatment of all kinds of tumour types.
- The compounds of general formula (I) may be used on their own or in conjunction with other active substances according to the invention, optionally also in conjunction with other pharmacologically active substances.
- Suitable preparations include for example tablets, capsules, suppositories, solutions, particularly solutions for injection (s.c., i.v., i.m.) and infusion, elixirs, emulsions or dispersible powders. The content of the pharmaceutically active compound(s) should be in the range from 0.1 to 90 wt.-%, preferably 0.5 to 50 wt.-% of the composition as a whole, i.e. in amounts which are sufficient to achieve the dosage range specified below. The doses specified may, if necessary, be given several times a day.
- Suitable tablets may be obtained, for example, by mixing the active substance(s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and/or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets may also comprise several layers.
- Coated tablets may be prepared accordingly by coating cores produced analogously to the tablets with substances normally used for tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve delayed release or prevent incompatibilities the core may also consist of a number of layers. Similarly the tablet coating may consist of a number or layers to achieve delayed release, possibly using the excipients mentioned above for the tablets.
- Syrups or elixirs containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g. a flavouring such as vanillin or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.
- Solutions for injection and infusion are prepared in the usual way, e.g. with the addition of isotonic agents, preservatives such as p-hydroxybenzoates, or stabilisers such as alkali metal salts of ethylenediamine tetraacetic acid, optionally using emulsifiers and/or dispersants, whilst if water is used as the diluent, for example, organic solvents may optionally be used as solvating agents or dissolving aids, and transferred into injection vials or ampoules or infusion bottles.
- Capsules containing one or more active substances or combinations of active substances may for example be prepared by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gelatine capsules.
- Suitable suppositories may be made for example by mixing with carriers provided for this purpose, such as neutral fats or polyethyleneglycol or the derivatives thereof. Excipients which may be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. groundnut or sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carriers such as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk), synthetic mineral powders (e.g. highly dispersed silicic acid and silicates), sugars (e.g. cane sugar, lactose and glucose) emulsifiers (e.g. lignin, spent sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulphate).
- The preparations are administered by the usual methods, preferably by oral or transdermal route, most preferably by oral route. For oral administration the tablets may, of course contain, apart from the abovementioned carriers, additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gelatine and the like. Moreover, lubricants such as magnesium stearate, sodium lauryl sulphate and talc may be used at the same time for the tabletting process. In the case of aqueous suspensions the active substances may be combined with various flavour enhancers or colourings in addition to the excipients mentioned above.
- For parenteral use, solutions of the active substances with suitable liquid carriers may be used.
- The dosage for intravenous use is from 1-1000 mg per hour, preferably between 5 and 500 mg per hour.
- However, it may sometimes be necessary to depart from the amounts specified, depending on the body weight, the route of administration, the individual response to the drug, the nature of its formulation and the time or interval over which the drug is administered. Thus, in some cases it may be sufficient to use less than the minimum dose given above, whereas in other cases the upper limit may have to be exceeded. When administering large amounts it may be advisable to divide them up into a number of smaller doses spread over the day.
- The formulation examples which follow illustrate the present invention without restricting its scope:
-
-
A) Tablets per tablet active substance 100 mg lactose 140 mg corn starch 240 mg polyvinylpyrrolidone 15 mg magnesium stearate 5 mg 500 mg - The finely ground active substance, lactose and some of the corn starch are mixed together. The mixture is screened, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet-granulated and dried. The granules, the remaining corn starch and the magnesium stearate are screened and mixed together. The mixture is compressed to produce tablets of suitable shape and size.
-
B) Tablets per tablet active substance 80 mg lactose 55 mg corn starch 190 mg microcrystalline cellulose 35 mg polyvinylpyrrolidone 15 mg sodium-carboxymethyl starch 23 mg magnesium stearate 2 mg 400 mg - The finely ground active substance, some of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is screened and worked with the remaining corn starch and water to form a granulate which is dried and screened. The sodiumcarboxymethyl starch and the magnesium stearate are added and mixed in and the mixture is compressed to form tablets of a suitable size.
-
C) Ampoule solution active substance 50 mg sodium chloride 50 mg water for inj. 5 ml - The active substance is dissolved in water at its own pH or optionally at pH 5.5 to 6.5 and sodium chloride is added to make it isotonic. The solution obtained is filtered free from pyrogens and the filtrate is transferred under aseptic conditions into ampoules which are then sterilised and sealed by fusion. The ampoules contain 5 mg, 25 mg and 50 mg of active substance.
Claims (2)
1.) A method of treatment of a disease or condition responsive to an inhibitor of PLK, said disease or condition being selected from the group consisting of: cancer, infection, inflammation and an autoimmune disease, said method comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a compound of the following formula (1):
wherein
W denotes N or C—R2,
X denotes —NR1a, O or S,
Y denotes CH,
Z denotes —CF3;
A is selected from one of the following formulas (i), (ii) and (iii):
Q1 denotes that (i), (ii) and (iii) are mono- or bicyclic aryl;
B1, B2, B3 and B4 each independently of one another denote C—RgRh, N—Ri, O or S;
R1 and R1a each independently of one another denote hydrogen or methyl;
R2 denotes one of hydrogen, halogen, —OR4, —C(═O)R4, —C(═O)NR4R5, —NR4R5, —NR4C(═O)R5, —NR4SO2R5, —N═CR4R5, —C═NRi, —SR4, —SOR4, —SO2R4, —SO2NR4R5, pseudohalogen, and a mono- or polysubstituted group selected from the group consisting of C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6-cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the substituent(s) of the mono- or polysubstituted group are identical or different and are selected from the group consisting of halogen, —NO2, —OR4, —C(═O)R4, —C(═O)OR4, —C(═O)NR4R5, —NR4R5, —NR4C(═O)R5, —NR4C(═O)OR5, —NR4C(═O)NR5R6, —NR4SO2R5, —N═CR4R5, —SR4, —SOR4, —SO2R4, —SO2NR4R5, —NR4SO2NR5R6, —OSO2NR5R6 and pseudohalogen;
Ra, Rb, Rc, Rd, Re, Rf, Rg and Rh each independently of one another denote a group selected from the group consisting of hydrogen, halogen, ═O, —NO2, —OR4, —C(═O)R4, —C(═O)OR4, —C(═O)NR4R5, —NR4R5, —NR4C(═O)R5—NR4C(═O)OR5, —NR4C(═O)NR5R6, —NR4SO2R5, —N═CR4R5, —C═NRi, —SR4, —SOR4—SO2R4, —SO2NR4R5, —NR4SO2NR5R6, —OSO2NR5R6, pseudohalogen, and an unsubstituted or mono- or polysubstituted group selected from the group consisting of C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-6-cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the substituent(s) of the mono- or polysubstituted group are identical or different and are selected from the group consisting of halogen, R8, —NO2, —OR4, —C(═O)R4, —C(═O)OR4, —C(═O)NR4R5, —NR4R5, —NR4C(═O)R5, —NR4C(═O)OR5, —NR4C(═O)NR5R6, —NR4SO2R5, —N═CR4R5, —SR1, —SOR4, —SO2R4, —SO2NR4R5, —NR4SO2NR5R6, —OSO2NR5R6 and pseudohalogen; wherein Rg and Rh are optionally located at the same or at adjacent C atoms and are attached in any combination to a common saturated or partially unsaturated 3-5-membered alkyl bridge which contains one to two heteroatoms;
Ri denotes a group selected from the group consisting of hydrogen, —OR4, —C(═O)R4, —C(═O)OR4, —C(═O)NR4R5, —NR4R5, —NR4C(═O)R5—NR4C(═O)OR5, —NR4C(═O)NR5R6, —NR4SO2R5, —N═CR4R5, —SR4, —SOR4, —SO2R4, —SO2NR4R5, —NR4SO2NR5R6, —OSO2NR5R6, pseudohalogen and an unsubstituted or substituted mono- or polysubstituted group selected from the group consisting of C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the substituent(s) of the mono- or polysubstituted group are identical or different and are selected from the group consisting of halogen, R8, —NO2, —OR4, —C(═O)R4, —C(═O)OR4, —C(═O)NR4R5, —NR4R5, —NR4C(═O)R5, —NR4C(═O)OR5, —NR4C(═O)NR5R6, —NR4SO2R5, —N═CR4R5, —SR4, —SOR4, —SO2R4—SO2NR4R5, —NR4SO2NR5R6, —OSO2NR5R6 and pseudohalogen; wherein the Ri groups located at adjacent N atoms are optionally joined together or Ri with Rg or Rh located at adjacent C atoms are optionally attached in any combination to a common saturated or partially unsaturated 3-5-membered alkyl bridge which contains one to two heteroatoms;
R3 is selected from the following formulas (iv)-(x):
R4, R5 and R6 each independently of one another denote hydrogen or an unsubstituted or mono- or polysubstituted group selected from the group consisting of C1-5-alkyl, C2-5alkenyl, C2-5alkynyl, C3-10cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the substituent(s) of the mono- or polysubstituted group are identical or different and are selected from the group consisting of C3-10-cycloalkyl, aryl, heterocyclyl, heteroaryl, halogen, —NO2, —OR8, —C(═O)R8, —C(═O)OR8, —C(═O)NR8R9, —NR8R9, —NR8C(═O)R9, —NR8C(═O)OR9, —NR8C(═O)NR9R10, —NR8C(═O)ONR9R10, —NR8SO2R9, —N═CR8R9, —SR8, —SOR8, —SO2R8, —SO2NR8R9, —NR8SO2NR9R10, —OSO2NR8R9 and pseudohalogen;
L denotes a bond or an unsubstituted or mono- or polysubstituted group selected from the group consisting of C1-16-alkyl, C2-16-alkenyl, C2-16-alkynyl, C3-10-cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the substituent(s) of the mono- or polysubstituted group are identical or different and are selected from the group consisting of halogen, —NO2, —OR8, —C(═O)R8, —C(═O)OR8, —C(═O)NR8R9, —NR8R9, —NR8C(═O)R9, —NR8C(═O)OR9, —NR8C(═O)NR9R10, —NR8C(═O)ONR9R10, —NR8SO2R9, —N═CR8R9, —SR8, —SOR8, —SO2R8, —SO2NR8R9, —NR8SO2NR9R10, —OSO2NR8R9 and pseudohalogen;
Q2 and Q3 each independently of one another denote a bond or an unsubstituted or mono- or polysubstituted group selected from the group consisting of C1-16-alkyl, C2-16-alkenyl, C2-16-alkynyl, C3-10-cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the substituent(s) of the mono- or polysubstituted group are identical or different and are selected from the group consisting of halogen, —NO2, —OR8, —C(═O)R8, —C(═O)OR8, —C(═O)NR8R9, —NR8R9, —NR8C(═O)R9, —NR8C(═O)OR9, —NR8C(═O)NR9R10, —NR8C(═O)ONR9R10, —NR8SO2R9, —N═CR8R9, —SR8, —SOR8, —SO2R8, —SO2NR8R9, —NR8SO2NR9R10, —OSO2NR8R9 and pseudohalogen;
R7 denotes hydrogen or an unsubstituted or mono- or polysubstituted group selected from the group consisting of C1-16-alkyl, C2-16-alkenyl, C2-16-alkynyl, C3-10-cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the substituent(s) of the mono- or polysubstituted group are identical or different and are selected from the group consisting of halogen, NO2, —OR8, —C(═O)R8, —C(═O)OR8, —C(═O)NR8R9, —NR8R9, —NR8COR9, —NR8C(═O)OR9, —NR8C(═O)NR9R10, —NR8C(═O)ONR9R10, —NR8SO2R9, —N═CR8R9, —SR8, —SOR8, —SO2R8, —SO2NR8R9, —NR8SO2NR9R10, —OSO2NR8R9 and pseudohalogen; and
R8, R9 and R10 each independently of one another denote hydrogen or a substituted or unsubstituted group selected from the group consisting of C1-8-alkyl, C2-8-alkenyl, C2-8-alkynyl, C3-10-cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the substituent(s) of the substituted group are identical or different and are selected from the group consisting of halogen, methyl, ethyl, amino, methylamino, dimethylamino, —OH and pseudohalogen;
or a pharmacologically acceptable acid addition salt thereof
in an excipient or carrier.
2.) A method of prevention of a disease or condition responsive to an inhibitor of PLK, said disease or condition being selected from the group consisting of: infection, and inflammation; said method comprising administering a therapeutically effective amount of a pharmaceutical composition-comprising the compound the following formula (1):
wherein
W denotes N or C—R2,
X denotes —NR1a, O or S,
Y denotes CH,
Z denotes —CF3;
A is selected from one of the following formulas (i), (ii) and (iii):
Q1 denotes that (i), (ii) and (iii) are mono- or bicyclic aryl;
B1, B2, B3 and B4 each independently of one another denote C—RgRh, N—Ri, O or S;
R1 and R1a each independently of one another denote hydrogen or methyl;
R2 denotes one of hydrogen, halogen, —OR4, —C(═O)R4, —C(═O)NR4R5, —NR4R5, —NR4C(═O)R5, —NR4SO2R5, —N═CR4R5, —C═NR4, —SR4, —SOR4, —SO2R4, —SO2NR4R5, pseudohalogen, and a mono- or polysubstituted group selected from the group consisting of C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6-cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the substituent(s) of the mono- or polysubstituted group are identical or different and are selected from the group consisting of halogen, —NO2, —OR4, —C(═O)R4, —C(═O)OR4, —C(═O)NR4R5, —NR4R5, —NR4C(═O)R5, —NR4C(═O)OR5, —NR4C(═O)NR5R6, —NR4SO2R5, —N═CR4R5, —SR4, —SOR4, —SO2R4, —SO2NR4R5, —NR4SO2NR5R6, —OSO2NR5R6 and pseudohalogen;
Ra, Rb, Rc, Rd, Re, Rf, Rg and Rh each independently of one another denote a group selected from the group consisting of hydrogen, halogen, ═O, —NO2, —OR4, —C(═O)R4, —C(═O)OR4, —C(═O)NR4R5, —NR4R5, —NR4C(═O)R5, —NR4C(═O)OR5, —NR4C(═O)NR5R6, —NR4SO2R5—N═CR4R5, —C═NR4, —SR4, —SOR4, —SO2R4, —SO2NR4R5, —NR4SO2NR5R6, —OSO2NR5R6, pseudohalogen, and an unsubstituted or mono- or polysubstituted group selected from the group consisting of C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-6-cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the substituent(s) of the mono- or polysubstituted group are identical or different and are selected from the group consisting of halogen, R8, —NO2, —OR4, —C(═O)R4, —C(═O)OR4, —C(═O)NR4R5, —NR4R5, —NR4C(═O)R5, —NR4C(═O)OR5, —NR4C(═O)NR5R6, —NR4SO2R5, —N═CR4R5, —SR4, —SOR4, —SO2R4, —SO2NR4R5, —NR4SO2NR5R6, —OSO2NR5R6 and pseudohalogen; wherein Rg and Rh are optionally located at the same or at adjacent C atoms and are attached in any combination to a common saturated or partially unsaturated 3-5-membered alkyl bridge which contains one to two heteroatoms;
Ri denotes a group selected from the group consisting of hydrogen, —OR4, —C(═O)R4, —C(═O)OR4, —C(═O)NR4R5, —NR4R5, —NR4C(═O)R5, —NR4C(═O)OR5, —NR4C(═O)NR5R6, —NR4SO2R5, —N═CR4R5, —SR4, —SOR4, —SO2R4, —SO2NR4R5, —NR4SO2NR5R6, —OSO2NR5R6, pseudohalogen and an unsubstituted or substituted mono- or polysubstituted group selected from the group consisting of C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the substituent(s) of the mono- or polysubstituted group are identical or different and are selected from the group consisting of halogen, R8, —NO2, —OR4, —C(═O)R4, —C(═O)OR4, —C(═O)NR4R5, —NR4R5, —NR4C(═O)R5, —NR4C(═O)OR5, —NR4C(═O)NR5R6, —NR4SO2R5, —N═CR4R5, —SR4, —SOR4, —SO2R4, —SO2NR4R5, —NR4SO2NR5R6, —OSO2NR5R6 and pseudohalogen; wherein the Ri groups located at adjacent N atoms are optionally joined together or Ri with Rg or Rh located at adjacent C atoms are optionally attached in any combination to a common saturated or partially unsaturated 3-5-membered alkyl bridge which contains one to two heteroatoms;
R3 is selected from the following formulas (iv)-(x):
R4, R5 and R6 each independently of one another denote hydrogen or an unsubstituted or mono- or polysubstituted group selected from the group consisting of C1-5-alkyl, C2-5alkenyl, C2-5alkynyl, C3-10-cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the substituent(s) of the mono- or polysubstituted group are identical or different and are selected from the group consisting of C3-10-cycloalkyl, aryl, heterocyclyl, heteroaryl, halogen, —NO2, —OR8, —C(═O)R8, —C(═O)OR8, —C(═O)NR8R9, —NR8R9, —NR8C(═O)R9, —NR8C(═O)OR9, —NR8C(═O)NR9R10, —NR8C(═O)ONR9R10, —NR8SO2R9, —N═CR8R9, —SR8, —SOR8, —SO2R8, —SO2NR8R9, —NR8SO2NR9R10, —OSO2NR8R9 and pseudohalogen;
L denotes a bond or an unsubstituted or mono- or polysubstituted group selected from the group consisting of C1-16-alkyl, C2-16-alkenyl, C2-16-alkynyl, C3-10-cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the substituent(s) of the mono- or polysubstituted group are identical or different and are selected from the group consisting of halogen, —NO2, —OR8, —C(═O)R8, —C(═O)OR8, —C(═O)NR8R9, —NR8R9, —NR8C(═O)R9, —NR8C(═O)OR9, —NR8C(═O)NR9R10, —NR8C(═O)ONR9R10, —NR8SO2R9, —N═CR8R9, —SR8, —SOR8, —SO2R8, —SO2NR8R9, —NR8SO2NR9R10, —OSO2NR8R9 and pseudohalogen;
Q2 and Q3 each independently of one another denote a bond or an unsubstituted or mono- or polysubstituted group selected from the group consisting of C1-16-alkyl, C2-16-alkenyl, C2-16-alkynyl, C3-10-cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the substituent(s) of the mono- or polysubstituted group are identical or different and are selected from the group consisting of halogen, —NO2, —OR8, —C(═O)R8, —C(═O)OR8, —C(═O)NR8R9, —NR8R9, —NR8C(═O)R9, —NR8C(═O)OR9, —NR8C(═O)NR9R10, —NR8C(═O)ONR9R10, —NR8SO2R9, —N═CR8R9, —SR8, —SOR8, —SO2R8, —SO2NR8R9, —NR8SO2NR9R10, —OSO2NR8R9 and pseudohalogen;
R7 denotes hydrogen or an unsubstituted or mono- or polysubstituted group selected from the group consisting of C1-16-alkyl, C2-16-alkenyl, C2-16-alkynyl, C3-10-cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the substituent(s) of the mono- or polysubstituted group are identical or different and are selected from the group consisting of halogen, NO2, —OR8, —C(═O)R8, —C(═O)OR8, —C(═O)NR8R9, —NR8R9, —NR8COR9, —NR8C(═O)OR9, —NR8C(═O)NR9R10, —NR8C(═O)ONR9R10, —NR8SO2R9, —N═CR8R9, —SR8, —SOR8, —SO2R8, —SO2NR8R9, —NR8SO2NR9R10, —OSO2NR8R9 and pseudohalogen; and
R8, R9 and R10 each independently of one another denote hydrogen or a substituted or unsubstituted group selected from the group consisting of C1-8-alkyl, C2-8-alkenyl, C2-8-alkynyl, C3-10-cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the substituent(s) of the substituted group are identical or different and are selected from the group consisting of halogen, methyl, ethyl, amino, methylamino, dimethylamino, —OH and pseudohalogen;
or a pharmacologically acceptable acid addition salt thereof
in an excipient or carrier.
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Also Published As
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BRPI0514371A (en) | 2008-06-10 |
PL1781640T3 (en) | 2015-06-30 |
WO2006021544A1 (en) | 2006-03-02 |
DK1781640T3 (en) | 2015-04-20 |
CA2573371C (en) | 2013-02-19 |
IL181421A (en) | 2015-05-31 |
HUE025285T2 (en) | 2016-03-29 |
RU2404979C2 (en) | 2010-11-27 |
CN101044137A (en) | 2007-09-26 |
AR051195A1 (en) | 2006-12-27 |
TWI421248B (en) | 2014-01-01 |
TW200619218A (en) | 2006-06-16 |
ES2532611T3 (en) | 2015-03-30 |
AU2005276500B2 (en) | 2012-05-10 |
US20090149438A1 (en) | 2009-06-11 |
EP1781640B1 (en) | 2015-01-07 |
IL181421A0 (en) | 2007-07-04 |
US7521457B2 (en) | 2009-04-21 |
US20060148800A1 (en) | 2006-07-06 |
CA2573371A1 (en) | 2006-03-02 |
ZA200700084B (en) | 2008-02-27 |
RU2007109870A (en) | 2008-11-10 |
JP5060294B2 (en) | 2012-10-31 |
KR101277506B1 (en) | 2013-06-25 |
KR20070048757A (en) | 2007-05-09 |
AU2005276500A1 (en) | 2006-03-02 |
EP1781640A1 (en) | 2007-05-09 |
MX2007002055A (en) | 2007-03-29 |
JP2008510691A (en) | 2008-04-10 |
NZ553632A (en) | 2010-12-24 |
US20110086842A1 (en) | 2011-04-14 |
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