Dioxolane analogues of uridine for the treatment of cancer
Inventors
Bethell, Richard • Eneroth, Anders • KLASSON, Bjorn • Oberg, Fredrik
Assignees
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Publication Number
US-11447511-B2
Publication Date
2022-09-20
Expiration Date
Abstract
The invention provides compounds of the formula:R1 is OR11, or NR5R5′;R2 is H or F;R5 is H, C1-C6alkyl, OH, C(═O)R6, O(C═O)R6 or O(C═O)OR6;R5′ is H or C1-C6alkyl;R6 is C1-C6alkyl or C3-C7cycloalkyl;R13 is H, phenyl, pyridyl, benzyl, indolyl or naphthyl wherein the phenyl, pyridyl, benzyl, indolyl and naphthyl is optionally substituted with 1, 2 or 3 R22; and the other variables are as defined in the claims, which are of use in the treatment of cancer, and related aspects.
Core Innovation
The invention is directed to a method for the treatment of liver cancer by oral administration to a warm blooded animal of a therapeutically effective amount of a compound of formula Ia, including pharmaceutically acceptable salts and/or solvates thereof. The compound of formula Ia includes a defined substituent set for R1, R2, R13, R15, R16, and independently selected substituents R22, with R1 being NH2 and R2 being H.
The formula Ia substitution pattern is characterized by R13 being phenyl or naphthyl optionally substituted with R22 groups, R15 being methyl, and R16 being C3-C7 cycloalkyl. Each R22 is independently selected from the listed substituents, with an option that any two R22 groups on adjacent ring carbon atoms can combine to form —O—(CR23R23′)1-6—O—.
Claims Coverage
The claim coverage centers on an oral method for treating liver cancer in a warm-blooded animal using a therapeutically effective amount of a specifically defined compound of formula Ia. The independent and dependent claim features identify the chemical definition of formula Ia and narrow the liver-cancer indication and patient population.
Oral liver-cancer treatment with a compound of formula Ia
A method for the treatment of liver cancer comprising oral administration to a warm blooded animal of a therapeutically effective amount of a compound of the formula Ia, including pharmaceutically acceptable salts and/or solvates thereof.
Formula Ia substituent pattern definition
The compound of formula Ia where R1 is NH2, R2 is H, R13 is phenyl or naphthyl optionally substituted with one, two or three R22, R15 is methyl, R16 is C3-C7 cycloalkyl, and each R22 is independently selected from the listed substituents, with the optional combination of two adjacent ring-carbon R22 groups to form —O—(CR23R23′)1-6—O—.
Secondary liver-cancer indication
The method wherein the liver cancer is secondary liver cancer, the cancer originating in another organ and metastasised to the liver.
Metastatic source from colon, lung, or breast
The method wherein the cancer has metastasised to the liver from colon, lung or breast.
Human patient among warm-blooded animals
The method wherein the warm blooded animal is human.
Overall, the claims cover oral administration of a therapeutically effective amount of a specifically defined formula Ia compound to treat liver cancer in a warm-blooded animal, with dependent coverage narrowing to secondary liver cancer, metastatic source organs, and humans.
Stated Advantages
Improved oral suitability.
Improved delivery to the liver via gastric stability and liver-enzyme metabolism to an active triphosphate.
Minimizing exposure and toxicity in non-target organs.
Possible effects in the tumor microenvironment, including anti-angiogenesis effects.
Documented Applications
Treatment of liver cancer by oral administration of a therapeutically effective amount of a compound of formula Ia to a warm blooded animal.
Treatment of secondary liver cancer, where the cancer originates in another body organ and metastasises to the liver.
Treatment of cancers that have metastasised to the liver from colon, lung, or breast.
Treatment of liver cancer in humans.
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