NZ797532B2 - Antitumoral Compounds - Google Patents
Antitumoral CompoundsInfo
- Publication number
- NZ797532B2 NZ797532B2 NZ797532A NZ79753218A NZ797532B2 NZ 797532 B2 NZ797532 B2 NZ 797532B2 NZ 797532 A NZ797532 A NZ 797532A NZ 79753218 A NZ79753218 A NZ 79753218A NZ 797532 B2 NZ797532 B2 NZ 797532B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- substituted
- unsubstituted
- cancer
- compound according
- compound
- Prior art date
Links
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
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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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D515/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D515/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains four or more hetero rings
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The present invention relates to compounds of Formula IE, pharmaceutical compositions containing them, methods for their manufacture and their use as antitumoral agents. The compounds disclosed are synthetic analogues of the ecteinascidins, particularly of ecteinascidin 736 (ET-736). The compounds exert their anticancer effect through the covalent modification of guanines in the DNA minor groove that eventually give rise to DNA double-strand break, S-phase arrest and apoptosis in cancer cells.
Claims (33)
1. A compound of formula IE, or a pharmaceutically acceptable salt or ester thereof: wherein: X is -NH- or -O-; R1 is -OH or -CN; R2 is a -C(=O)Ra group; R3 is hydrogen or a -ORb group; R4 is selected from -CH2NH2 and ProtNH; Ra is selected from hydrogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl, and substituted or unsubstituted C2-C12 alkynyl; Rb is selected from substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2- C12 alkenyl and substituted or unsubstituted C2-C12 alkynyl; and ProtNH is a carbamate protecting group for amino; wherein tuted groups are substituted at one or more available positions by one or more groups ed from OR’, =O, SR’, SOR’, SO2R’, NO2, NHR’, NR’R’, =N-R’. NHCOR’, N(COR’)2, NHSO2R’, NR’C(=NR’)NR’R’, CN, halogen, COR’, COOR’, OCOR’, OCONHR’, OCONR’R’, CONHR’, CONR’R’, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 l, aryl and heterocyclic group; where each of the R’ groups is independently selected from the group consisting of hydrogen, OH, NO2, NH2, SH, CN, halogen, COH, l, CO2H, C1- C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, aryl, and cyclic group.
2. The compound according to claim 1 selected from formula IEa or IEb, or a pharmaceutically acceptable salt or ester thereof: IEa IEb wherein: X is -NH- or -O-; R1 is -OH or -CN; R2 is a Ra group; R3 is hydrogen or a -ORb group; R4 is selected from -CH2NH2 and -CH2NHProtNH; Ra is ed from en, tuted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl, and substituted or unsubstituted C2-C12 alkynyl; Rb is selected from substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl, and substituted or unsubstituted C2-C12 alkynyl; and ProtNH is a carbamate protecting group for amino.
3. The compound according to claim 1 or 2 n X is -NH-.
4. The compound according to claim 1 or 2 wherein X is -O-.
5. The compound according to any one of claims 1 to 4, wherein R4 is -CH2NH2.
6. The compound according to any one of claims 1 to 5, wherein R1 is -OH.
7. The compound according to any one of claims 1 to 6, wherein R2 is a -C(=O)Ra group where Ra is tuted or unsubstituted C1-C6 alkyl; preferably wherein Ra is selected from substituted or unsubstituted methyl, substituted or tituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl and substituted or unsubstituted tertbutyl.
8. The compound according to claim 7 wherein R2 is acetyl.
9. The compound according to any one of claims 1 to 8, wherein R3 is hydrogen or -ORb wherein Rb is substituted or unsubstituted C1-C6 alkyl; preferably wherein Rb is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or tituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or tituted isobutyl, substituted or unsubstituted sec-butyl and tuted or unsubstituted tertbutyl.
10. The compound according to claim 9 wherein R3 is hydrogen.
11. The compound according to claim 9 wherein R3 is -ORb wherein Rb is substituted or unsubstituted C1-C6 alkyl; preferably n Rb is ed from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or tituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl and substituted or unsubstituted tert-butyl.
12. The compound according to claim 11 wherein R3 is methoxy.
13. The compound according to claim 1 of formula: , , , or a ceutically acceptable salt or ester thereof.
14. The compound according to claim 1 of formula: or a pharmaceutically acceptable salt or ester thereof.
15. The compound according to claim 1 of formula: or a pharmaceutically able salt or ester thereof.
16. The compound according to claim 1 of formula: or a pharmaceutically acceptable salt or ester thereof.
17. The compound according to claim 1 of formula: or a pharmaceutically acceptable salt or ester thereof.
18. A compound according to any one of claims 1 to 17, wherein the salt is selected from hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, acetate, trifluoroacetate, maleate, fumarate, citrate, oxalate, ate, tartrate, malate, mandelate, methanesulfonate, p- toluenesulfonate, sodium, potassium, calcium, ammonium, ethylenediamine, ethanolamine, N,N- dialkylenethanolamine, anolamine and basic cids.
19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt or ester f and a pharmaceutically acceptable carrier.
20. A dosage form comprising a pharmaceutical composition according to claim 19.
21. A compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt or ester thereof, or a ition according to claim 19, or a dosage form according to claim 20, for use as a medicament.
22. A compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt or ester thereof, or a composition according to claim 19, or a dosage form according to claim 20, for use in the ent of cancer.
23. The compound, composition or dosage form for use ing to claim 22, wherein the cancer is selected from lung cancer including non-small cell lung cancer and small cell lung cancer, colon cancer, ctal cancer, breast cancer, pancreas cancer, sarcoma, ovarian cancer and gastric cancer.
24. The compound, composition or dosage form for use according to claim 23, n the cancer is selected from lung cancer ing non-small cell lung cancer and small cell lung cancer, breast , pancreas cancer and colorectal cancer.
25. The compound, composition or dosage form for use according to claim 22, wherein the cancer is prostate cancer.
26. Use of a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt or ester f, or a composition according to claim 19, or a dosage form according to claim 20, in the manufacture of a medicament for the treatment of cancer.
27. The use according to claim 26, wherein the cancer is selected from lung cancer including non-small cell lung cancer and small cell lung cancer, colon cancer, ctal cancer, breast cancer, pancreas cancer, sarcoma, ovarian cancer and gastric cancer.
28. The use according to claim 27, wherein the cancer is selected from lung cancer including non-small cell lung cancer and small cell lung cancer, breast , pancreas cancer and colorectal cancer.
29. The use according to claim 26, wherein the cancer is prostate cancer.
30. A process for obtaining a compound as defined in any one of claims 1 to 18 or a pharmaceutically acceptable salt or ester thereof: comprising the step of reacting a compound of formula II with a compound of formula III to give a compound of formula IV: wherein (where allowed by possible substituent groups): X is -NH- or -O-; R2 is a -C(=O)Ra group; R3 is hydrogen or a -ORb group; R4 is -CH2NHProtNH; Ra is selected from hydrogen, substituted or unsubstituted C1-C12 alkyl, tuted or unsubstituted C2-C12 l, tuted or unsubstituted C2-C12 alkynyl; Rb is selected from substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2- C12 alkenyl, and substituted or unsubstituted C2-C12 alkynyl; and ProtNH is a carbamate ting group for amino; wherein substituted groups are substituted at one or more available positions by one or more groups selected from OR’, =O, SR’, SOR’, SO2R’, NO2, NHR’, NR’R’, =N-R’. NHCOR’, N(COR’)2, NHSO2R’, NR’C(=NR’)NR’R’, CN, halogen, COR’, COOR’, OCOR’, ’, R’, CONHR’, CONR’R’, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, aryl and heterocyclic group; where each of the R’ groups is independently selected from the group consisting of en, OH, NO2, NH2, SH, CN, halogen, COH, COalkyl, CO2H, C1- C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, aryl, and cyclic group.
31. The process according to claim 30, comprising the further step of replacing the cyano group in the compound of formula IV with a hydroxy group to give a compound of formula IE, where R1 is OH.
32. A kit comprising a therapeutically effective amount of a compound according to any one of claims 1 to 18 and a pharmaceutically acceptable carrier.
33. The kit according to claim 32 further sing instructions for use of the compound in the treatment of cancer, and more preferably a cancer selected from lung cancer, including non-small cell lung cancer and small cell lung cancer, colon cancer, breast cancer, pancreas cancer, sarcoma, ovarian cancer, prostate , colorectal cancer and gastric cancer. (tumur+lag) Median Lag 43-019: 0 T 14 21 28 35 42 Days at Treatment
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP17382228 | 2017-04-27 | ||
| EP17382497 | 2017-07-26 | ||
| NZ758490A NZ758490B2 (en) | 2018-04-27 | Antitumoral compounds |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| NZ797532A NZ797532A (en) | 2025-06-27 |
| NZ797532B2 true NZ797532B2 (en) | 2025-09-30 |
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