N.sup.4 -(substituted-oxycarbonyl)-5'-deoxy-5-fluorocytidine compounds, compositions and methods of using same

• US 5,472,949 A
• Filed: 12/14/1993
• Issued: 12/05/1995
• Est. Priority Date: 12/18/1992
• Status: Expired due to Term

• Current Assignee: Hoffmann-La Roche Incorporated (Roche Holding AG)
• Original Assignee: Hoffmann-La Roche Incorporated (Roche Holding AG)
• Inventors: Shimma, Nobuo, Ishitsuka, Hideo, Murasaki, Chikako, Kuruma, Isami, Arasaki, Motohiro, Umeda, Isao, Miwa, Masanori
• Primary Examiner(s): Robinson, Douglas W.
• Assistant Examiner(s): Wilson, James O.
• Application Number:
  US08/167,392
• Time in Patent Office: 721 Days
• Field of Search: 514/49, 514/50, 536/28.5, 536/28.52
• US Class Current: 514/49
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07H 19/06 Pyrimidine radicals
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention relates to N⁴ -(substituted-oxycarbonyl)-5'"'"'-deoxy-5-fluorocytidine derivatives which are useful as an agent for treating tumors, pharmaceutical compositions including the same, a method of treating tumors and a method of preparing N⁴ -(substituted-oxycarbonyl)-5'"'"'-deoxy-5-fluorocytidine derivatives for treating tumors.

Compounds of formula (I), ##STR1## wherein R¹ is a saturated or unsaturated, straight or branched hydrocarbon radical wherein the number of carbon atoms in the longest straight chain of this hydrocarbon radical ranges from three to seven, or is a radical of the formula --(CH₂)n--^Y wherein Y is a cyclohexyl radical, a C₁ -C₄ alkoxy radical or a phenyl radical and wherein when Y is a cyclohexyl radical n is an integer from 0 to 4, and when Y is C₁ -C₄ alkoxy radical or a phenyl radical n is an integer from 2 to 4, and R² is a hydrogen atom or a radical easily hydrolyzable under physiological conditions,

or a hydrate or solvate thereof. Compounds of formula (I) are useful in the treatment of tumors.

Claims

1. A compound of formula (I), ##STR6## wherein R¹ is a saturated straight or branched hydrocarbon radical wherein the number of carbon atoms in the longest straight chain of this hydrocarbon radical ranges from three to seven, or is a radical of the formula --(CH₂)n--^Y wherein Y is a cyclohexyl radical, a C₁ -C₄ alkoxy radical or a phenyl radical and wherein when Y is a cyclohexyl radical n is an integer from 0 to 4, and when Y is C₁ -C₄ alkoxy radical or a phenyl radical n is an integer from 2 to 4, and R² is a hydrogen atom or a radical easily hydrolyzable under physiological conditions,

or a hydrate or solvate thereof.

2. The compounds according to claim 1, wherein R¹ is selected from the group consisting of n-propyl, 1-isopropyl-2-methylpropyl, 1,1,2-trimethylpropyl, n-butyl, isobutyl, 2-ethylbutyl, 3,3-dimethylbutyl, n-pentyl, isopentyl, neopentyl, 2-propylpentyl, n-hexyl, 2-ethylhexyl, n-hetpyl, cyclohexyl, cyclohexylbutyl, 2-methoxyethyl, 2-ethoxyethyl, 3-methoxypropyl, 3-ethoxypropyl, 4-methoxybutyl, 4-ethoxybutyl, phenethyl, 3-phenyl-propyl and 4-phenylbutyl.

3. The compounds according to claim 1, selected from a group consisting of:

5'"'"'-deoxy-5-fluoro-N⁴ -(propoxycarbonyl)cytidine,

5'"'"'-deoxy-5-fluoro-N⁴ -(hexyloxycarbonyl)cytidine,

5'"'"'-deoxy-5-fluoro-N⁴ -(isopentyloxycarbonyl)cytidine,

5'"'"'-deoxy-5-fluoro-N⁴ -(neopentyloxycarbonyl)cytidine,

5'"'"'-deoxy-5-fluoro-N⁴ -[(1,1,2-trimethylpropoxy)carbonyl]cytidine,

5'"'"'-deoxy-N⁴ -[(3,3-dimethylbutoxy)carbonyl]-5-fluorocytidine,

5'"'"'-deoxy-5-fluoro-N⁴ -[(1-isopropyl-2-methylpropoxy)carbonyl]cytidine,

5'"'"'-deoxy-N⁴ -[(2-ethylbutyl)oxycarbonyl]-5-fluorocytidine,

N⁴ -[(cyclohexylmethoxy)carbonyl]-5'"'"'-deoxy-5-fluorocytidine,

5'"'"'-deoxy-5-fluoro-N⁴ -[(2-phenylethoxy)carbonyl]cytidine,

2'"'"',3'"'"'-di-O-acetyl-5'"'"'-deoxy-5-fluoro-N⁴ -(propoxycarbonyl)cytidine,

2'"'"',3'"'"'-di-O-acetyl-N⁴ -(butoxycarbonyl)-5'"'"'-deoxy-5-fluorocytidine,

2'"'"',3'"'"'-di-O-benzoyl-N⁴ -(butoxycarbonyl)-5 '"'"'-deoxy-5-fluorocytidine,

2'"'"',3'"'"'-di-O-acetyl-5'"'"'-deoxy-5-fluoro-N⁴ -(pentyloxycarbonyl)cytidine,

2'"'"',3'"'"'-di-O-acetyl-5'"'"'-deoxy-5-fluoro-N⁴ -(isopentyloxycarbonyl)cytidine,

2'"'"',3'"'"'-di-O-acetyl-5'"'"'-deoxy-5-fluoro-N⁴ -(hexyloxycarbonyl)cytidine,

2'"'"',3'"'"'-di-O-acetyl-5'"'"'-deoxy-N⁴ -[(2-ethylbutyl)oxycarbonyl]-5-fluorocytidine,

2'"'"',3'"'"'-di-O-acetyl-N⁴ -[(cyclohexylmethoxy)carbonyl]-5'"'"'-deoxy-5-fluorocytidine,

2'"'"',3'"'"'-di-O-acetyl-5'"'"'-deoxy-5-fluoro-N⁴ -[(2-phenylethoxy)carbonyl]cytidine,

5'"'"'-deoxy-5-fluoro-N⁴ -(isobutoxycarbonyl)cytidine,

5'"'"'-deoxy-5-fluoro-N⁴ -[(2-propylpentyl)oxycarbonyl]cytidine,

'"'"' -deoxy-N⁴ -[(2-ethylhexyl)oxycarbonyl]-5'"'"'-fluorocytidine,

5'"'"'-deoxy-5-fluoro-N⁴ -(heptyloxycarbonyl)cytidine,

N⁴ -[(2-cyclohexylethoxy)carbonyl]-5'"'"'-deoxy-5-fluorocytidine,

N⁴ -[(3-cyclohexylpropyl)oxycarbonyl]-5'"'"'-deoxy-5-fluorocytidine,

N⁴ -(cyclohexyloxycarbonyl)-5'"'"'-deoxy-5-fluorocytidine,

5'"'"'-deoxy-5-fluoro-N⁴ -[(3-phenylpropyl)oxycarbonyl]cytidine,

5'"'"'-deoxy-5-fluoro-N⁴ -[(2-methoxyethoxy)carbonyl]cytidine,

N⁴ -(butoxycarbonyl)-5'"'"'-deoxy-5-fluorocytidine and

5'"'"'-deoxy-5-fluoro-N⁴ -(pentyloxycarbonyl)cytidine.

6. The compound according to claim 1, 5'"'"'-deoxy-5-fluoro-N⁴ -(pentyloxycarbonyl)cytidine.

4. A pharmaceutical composition comprising a therapeutically effective amount of one or more compounds of formula (I) ##STR7## wherein R¹ is a saturated straight or branched hydrocarbon radical wherein the number of carbon atoms in the longest straight chain of the hydrocarbon radical ranges from three to seven, or is a radical of the formula --(CH₂)_n --Y wherein Y is a cyclohexyl radical, a C₁ -C₄ alkoxy radical or a phenyl radical and wherein when Y is a cyclohexyl radical n is an integer from 0 to 4 and when Y is a C₁ -C₄ alkoxy radical or a phenyl radical n is an integer from 2 to 4, and R² is a hydrogen atom or a radical easily hydrolyzable under physiological conditions,

or a hydrate or solvate thereof, and an inert carrier.

5. A method of treating tumors comprising administering to a host in need of such treatment an effective amount of a compound of formula (I) ##STR8## wherein R¹ is a saturated straight or branched hydrocarbon radical wherein the number of carbon atoms in the longest straight chain of the hydrocarbon radical ranges from three to seven, or is a radical of the formula --(CH₂)_n --Y wherein Y is a cyclohexyl radical, a C₁ -C₄ alkoxy radical or a phenyl radical and wherein when Y is a cyclohexyl radical n is an integer from 0 to 4 and when Y is a C₁ -C₄ alkoxy radical or a phenyl radical n is an integer from 2 to 4, and R² is a hydrogen atom or a radical easily hydrolyzable under physiological conditions,

or a hydrate or solvate thereof.