CA2103324C - N-oxycarbonyl substituted 5'-deoxy-5-fluorcytidines - Google Patents
N-oxycarbonyl substituted 5'-deoxy-5-fluorcytidinesInfo
- Publication number
- CA2103324C CA2103324C CA002103324A CA2103324A CA2103324C CA 2103324 C CA2103324 C CA 2103324C CA 002103324 A CA002103324 A CA 002103324A CA 2103324 A CA2103324 A CA 2103324A CA 2103324 C CA2103324 C CA 2103324C
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- Prior art keywords
- deoxy
- cytidine
- fluoro
- fluorocytidine
- radical
- Prior art date
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- 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
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Solid-Sorbent Or Filter-Aiding Compositions (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Medicinal Preparation (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Compounds represented by the general formula (I), ( I )
Description
; ~
2~3332~
~ ~060/166 The present invention relates to N4-(substituted-o~y~ l)onyl~-5'-deo~y-~-fluorocytidine derivatives, and a pharmaceutical composition containing the same for treating tumors.
More particularly, the present invention relate8 to N4-(substituted-5 o~call~onyl)-~'-deo~y-6-fluorocytidine de~vatives represen~e~l by the general ~ormula (I), -o J~ ~R
HN O
N~
H3C ~ N ~I ( 1 ) ~O\
wherein Rl is a saturated or llnR~t~lra~d, ~traight or branched hydrocarbon radical [wherein the number of carbon atoms in the 0 longest ~traight chain of this hydrocar~on radical range~ from three to seYen], or a radical of the formula -(CH2)n-Y [in which n i3 an integer from 0 to 4, when Y is a cyclohexyl radical, or n is an integer from 2 to 4, when Y is a lower alko~y radical having 1 to 4 carbon atom(s) or a phenyl radi~al], and R2 i9 a hy~lo~en atom or a radical easily hydrolyzable under physiological conditions, as well as hydrates or solvates of the compounds of the general formula (I), and a pharmaceutical composition cont~ining the same with ~c~llent pharmacokinetic profiles for treating tumor~ with high safety margin.
It is known that many l.rec~lsors of 5-fluorouracil (~-FU) are useful as aD antitumor agents, but in general their bioconversion efficiency is still insufficient for the tre~t,ment of patients sufEering ~rom tumors and they M~So 12.10.93 ,,~ .. , .. . , ... -- - - . . .. . . ..
~ 2~s~
cause intestinal toxicities and imrnunosuppressive toxicities, which are their major and dose limiting toxicities.
USP 4,966,891 discloses precursors of 5-FU which are iln~oved in the above mentioned aspect of bioconversion efficiency and to~cities. They are 5 converted to 5'-deoxy-5-fluorocytidine (5'-DFCR) by acyl~mi~ e~, to 5'-deoxy-5-fluoroundine (5'-DFUR) by cytidine ~lef~min~e, and then to 5-FU by pyrimidine nucleotide phosphoryla~e in vivo which is l,re~er~lltially 1OC~
in the liver, small intestin and tumor tissues. During intensive studies on the pharmArokinetic profiles of the precursors of 5-FU, particularly of N4-lo (substituted-o~ycarbonyl)-5'-deoxy-5-fluoroc~tidine derivatives, the inventors found that certain specific precursors are selectively liollve. ~ed into 5'-DFCRby an acylamidase isozyme that is preferentially located at the liver but not the other organs of hllm~n~, and e~hibited more improved pharm~cokinet;c profiles than the other compounds tested. The filrther studies based on the 15 above fin~in~R enabled the inventors of the present invention to identify that the sperific N4-(substituted-o~ycar~onyl)-5'-deoxy-5-fluorocytidine derivatives (hereinafter referred to as N4-(substituted-oa:ycarbonyl)-5'-DFCR) represented by the above mentioned general formula (I) have selectively oved pharmacokinetic profiles in monkeys, viz. 4 to 7 time~ higher ao maximum concentration (Cmax) of 5'-DFUR and 4 times larger higher area under the curve (AUC) of 5'-DFUR in blood than the other compounds, and less intestinal toxicity, and thus completed the present invention.
The respective radicals of the general formula (I) which are defined above a.e ~ plP~inecl in more detail as follows;
25 F.~pl~nP.t;on of Rl:
Rl is a saturated or un~t~rated, straight or branched hydrocarbon radical ~wherein the n~nber of carbon atoms in the longest straight chain of this hydrocarbon radical ranges from three to seven], or a radical of the formula -(CH2)n-Y [in which n i8 an integer from O to 4, when Y is a 30 cyclohexyl radical, or n is an integer from 2 to 4, when Y i9 a lower alkoxy radical having 1 to 4 carbon atom(s) or a phenyl radical].
In the above, the term "a saturated or lln~?.tllrated, straight or br~nfhe~l hydrocarbon radical twherein the number of carbon a~ms in the longest straight chain of this hydrocarbon radical ranges from three to 36 seven]" preferably signifies n-propyl, l-isoylopyl-2-methylpropyl, 1,1,2-" .. . . .
. ~ -.
. . ~ . - . - . . . - .
2~ 3~
~ ~060/166 The present invention relates to N4-(substituted-o~y~ l)onyl~-5'-deo~y-~-fluorocytidine derivatives, and a pharmaceutical composition containing the same for treating tumors.
More particularly, the present invention relate8 to N4-(substituted-5 o~call~onyl)-~'-deo~y-6-fluorocytidine de~vatives represen~e~l by the general ~ormula (I), -o J~ ~R
HN O
N~
H3C ~ N ~I ( 1 ) ~O\
wherein Rl is a saturated or llnR~t~lra~d, ~traight or branched hydrocarbon radical [wherein the number of carbon atoms in the 0 longest ~traight chain of this hydrocar~on radical range~ from three to seYen], or a radical of the formula -(CH2)n-Y [in which n i3 an integer from 0 to 4, when Y is a cyclohexyl radical, or n is an integer from 2 to 4, when Y is a lower alko~y radical having 1 to 4 carbon atom(s) or a phenyl radi~al], and R2 i9 a hy~lo~en atom or a radical easily hydrolyzable under physiological conditions, as well as hydrates or solvates of the compounds of the general formula (I), and a pharmaceutical composition cont~ining the same with ~c~llent pharmacokinetic profiles for treating tumor~ with high safety margin.
It is known that many l.rec~lsors of 5-fluorouracil (~-FU) are useful as aD antitumor agents, but in general their bioconversion efficiency is still insufficient for the tre~t,ment of patients sufEering ~rom tumors and they M~So 12.10.93 ,,~ .. , .. . , ... -- - - . . .. . . ..
~ 2~s~
cause intestinal toxicities and imrnunosuppressive toxicities, which are their major and dose limiting toxicities.
USP 4,966,891 discloses precursors of 5-FU which are iln~oved in the above mentioned aspect of bioconversion efficiency and to~cities. They are 5 converted to 5'-deoxy-5-fluorocytidine (5'-DFCR) by acyl~mi~ e~, to 5'-deoxy-5-fluoroundine (5'-DFUR) by cytidine ~lef~min~e, and then to 5-FU by pyrimidine nucleotide phosphoryla~e in vivo which is l,re~er~lltially 1OC~
in the liver, small intestin and tumor tissues. During intensive studies on the pharmArokinetic profiles of the precursors of 5-FU, particularly of N4-lo (substituted-o~ycarbonyl)-5'-deoxy-5-fluoroc~tidine derivatives, the inventors found that certain specific precursors are selectively liollve. ~ed into 5'-DFCRby an acylamidase isozyme that is preferentially located at the liver but not the other organs of hllm~n~, and e~hibited more improved pharm~cokinet;c profiles than the other compounds tested. The filrther studies based on the 15 above fin~in~R enabled the inventors of the present invention to identify that the sperific N4-(substituted-o~ycar~onyl)-5'-deoxy-5-fluorocytidine derivatives (hereinafter referred to as N4-(substituted-oa:ycarbonyl)-5'-DFCR) represented by the above mentioned general formula (I) have selectively oved pharmacokinetic profiles in monkeys, viz. 4 to 7 time~ higher ao maximum concentration (Cmax) of 5'-DFUR and 4 times larger higher area under the curve (AUC) of 5'-DFUR in blood than the other compounds, and less intestinal toxicity, and thus completed the present invention.
The respective radicals of the general formula (I) which are defined above a.e ~ plP~inecl in more detail as follows;
25 F.~pl~nP.t;on of Rl:
Rl is a saturated or un~t~rated, straight or branched hydrocarbon radical ~wherein the n~nber of carbon atoms in the longest straight chain of this hydrocarbon radical ranges from three to seven], or a radical of the formula -(CH2)n-Y [in which n i8 an integer from O to 4, when Y is a 30 cyclohexyl radical, or n is an integer from 2 to 4, when Y i9 a lower alkoxy radical having 1 to 4 carbon atom(s) or a phenyl radical].
In the above, the term "a saturated or lln~?.tllrated, straight or br~nfhe~l hydrocarbon radical twherein the number of carbon a~ms in the longest straight chain of this hydrocarbon radical ranges from three to 36 seven]" preferably signifies n-propyl, l-isoylopyl-2-methylpropyl, 1,1,2-" .. . . .
. ~ -.
. . ~ . - . - . . . - .
2~ 3~
trimethylplol,yl, n-butyl, isobutyl, 2-ethylbutyl, 3,3-dimethylbutyl, n-pen~yl, isopentyl, neopentyl, 2-p~,yyl~entyl, n-hexyl, 2-ethylhexyl, n-heptyl, allyl, 2-buten-1-yl, 3-buten-1-yl, 3-penten-1-yl, 4-penten-1-yl, 3-hexen-1-yl, 4-hexeIl-1-yl, 5-hexen-1-yl, and the like.
The term "a radical of the ~ormula -(CH2)n-Y [in which n iB an integer from O to 4, when Y is a cyclohexyl radical, or n is an integer from 2 to 4, when Y is a lower alkoxy radical having from 1 to 4 carbon atom(s) or a phenyl radical]" pref~rably fiignifies cyclohe~yl, cyclohexylmethyl, 2-cyclohexylethyl, 3-cyclohe;Kylp.~,~yl, 4-cyclohe~ylbutyl, 2-methoxyethyl, 2-0 ethoxyethyl, 2-p~opo~yethyl, 3-met~l)xy~l~o~ 3-etho~y~lo~l, 4-methoxy-butyl, 4-etho~yLulyl, ph~T~etllyl, 3-phenyly~ yl, 4-phenylbutyl, and the like.
In the most preferred embodiment of the coTnpounds in accordance with $he present invention, Rl signifies n-propyl, n-butyl, n-pentyl, isopentyl,neopentyl, 3,3-dimethylbutyl, n-hexyl, 2-ethylbutyl, phenylethyl, and L5 cyclohexylmethyl.
n~tion of R2 R2 is a hydrogen atom or a radical easily hydrolyzable under physiological condition.
In the above, the term "a radical easily hydrolyzable under physiological condition" preferably signifies acetyl, propionyl, benzoyl, toluoyl, ~-alanyl, valyl, and the like.
Preferred N4-(substituted-o~ycalllonyl)-5'-DFCRs of the present invention are:
~ '-deoxy-5-fluoro-N4-(propoxycarbonyl)cytidine, 2~ N4-(buto~yc~ 1,onyl)-5'-deoxy-5-fluorocytidine, 6'-deoxy-5-fluoro-N4~(pentyloxycarbonyl)cytidine, 5'-deoxy-5-fluoro-N4-(hexyloxycarbonyl)cytidine, 5'-deoxy-5-fluoro-N4-(isopentylo~ycarbonyl)cytidine, 5'-deoxy-5-nuoro-N4-(neopentyloxycarbonyl)cytidine, ~'-deoxy-5-fluoro-N4-[(1,1,2-trimethyl~ol~oxy)carbonyl]cytidine, 5'-deoxy-N4-[(3,3-dimethylbuto~y)carbonyl]-5-fluorocytidine, 5'-deoxy-5-fluoro-N4-[(1-isopropyl-2-methylpropoxy)car~onyl~cytidine, 5'-deoxy-N4-[(2-ethylbutoxy)carbonyl~-5-fluorocytidine, ..
The term "a radical of the ~ormula -(CH2)n-Y [in which n iB an integer from O to 4, when Y is a cyclohexyl radical, or n is an integer from 2 to 4, when Y is a lower alkoxy radical having from 1 to 4 carbon atom(s) or a phenyl radical]" pref~rably fiignifies cyclohe~yl, cyclohexylmethyl, 2-cyclohexylethyl, 3-cyclohe;Kylp.~,~yl, 4-cyclohe~ylbutyl, 2-methoxyethyl, 2-0 ethoxyethyl, 2-p~opo~yethyl, 3-met~l)xy~l~o~ 3-etho~y~lo~l, 4-methoxy-butyl, 4-etho~yLulyl, ph~T~etllyl, 3-phenyly~ yl, 4-phenylbutyl, and the like.
In the most preferred embodiment of the coTnpounds in accordance with $he present invention, Rl signifies n-propyl, n-butyl, n-pentyl, isopentyl,neopentyl, 3,3-dimethylbutyl, n-hexyl, 2-ethylbutyl, phenylethyl, and L5 cyclohexylmethyl.
n~tion of R2 R2 is a hydrogen atom or a radical easily hydrolyzable under physiological condition.
In the above, the term "a radical easily hydrolyzable under physiological condition" preferably signifies acetyl, propionyl, benzoyl, toluoyl, ~-alanyl, valyl, and the like.
Preferred N4-(substituted-o~ycalllonyl)-5'-DFCRs of the present invention are:
~ '-deoxy-5-fluoro-N4-(propoxycarbonyl)cytidine, 2~ N4-(buto~yc~ 1,onyl)-5'-deoxy-5-fluorocytidine, 6'-deoxy-5-fluoro-N4~(pentyloxycarbonyl)cytidine, 5'-deoxy-5-fluoro-N4-(hexyloxycarbonyl)cytidine, 5'-deoxy-5-fluoro-N4-(isopentylo~ycarbonyl)cytidine, 5'-deoxy-5-nuoro-N4-(neopentyloxycarbonyl)cytidine, ~'-deoxy-5-fluoro-N4-[(1,1,2-trimethyl~ol~oxy)carbonyl]cytidine, 5'-deoxy-N4-[(3,3-dimethylbuto~y)carbonyl]-5-fluorocytidine, 5'-deoxy-5-fluoro-N4-[(1-isopropyl-2-methylpropoxy)car~onyl~cytidine, 5'-deoxy-N4-[(2-ethylbutoxy)carbonyl~-5-fluorocytidine, ..
N4-t~cyclohexylmethoxy)carbonyl]-5'-deoxy-5-fluorocytidine, 5'-deoxy-S-fluoro N4-[(2-phenylethoxy)carbonyl]cytidine, 2',3'-di-0-acetyl-5'-deoxy-~-fluoro-N4-(propo~y~ ~ll,onyl)cytidine, 2',3'-di-0-acetyl-N4-(but.oxycarbonyl)-5'-deo~y-5-fluorocytidine, 2',3'-di-0-benzoyl-N4-(buto~ycarbonyl)-5'-deoxy-5-iluorocytidine, 2',3'-di-0-acetyl-5'-deo~y-5-fluoro-N4-(pentylo~y~ ~lI)onyl)cytidine, 2',3'-di-0-acetyl-5'-deo~y-5-fluoro-N4-~i~opentylo~yca~l,onyl)-cytidine, 2',3'-di-O-acetyl-5'-d~o~y-5-fluoro-N4-(he~yluxy~all~onyl)-cytidine~
2',3'-di-0-acetyl-5'-deoxy-N4-[(2-ethylbutyl~o~y~all)onyl~-5-fluorocytidine, 0 2',3'-di-0-acetyl-N4-[(cyclohe~cylmethoxy)carbonyl]-5'-deo~y-5-fluorocytidine, 2' ,3'-di-0-acetyl-5 '-deoxy-5-fluoro-N4-[(2-phenylethoxy)-carbonyl]cytidine, 5'-deoxy-5-~uoro-N4-(isobuto~ycarbonyl)cytidiIIe, 5'-deoxy-5-fluoro-N4-[(2-p~ o~ylpentyl)oxycarbonyl]cy~idiIle, ~'-daoxy-N4-[(2-ethylhexyl)oxycarbonyl]-5-fluorocytidine, 5'-deoxy-5-fluoro-N4-(heptylux,~ ~,all)onyl)cytidine, N4-[(2-cyclohexylethoxy)carbonyl]-5'-deoxy S-fluorocytidine, N4-[(3-cyclohexyl~l opyl)oxycarbonyl~-5'-deoxy-5-fluorocytidine, aD N4-(cyclohexyloxycarbonyl)-5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluoro-N4-[(3-phenyll~o~yl)o,~ycall~onyl]cytidine, and 5'-deoxy-5-fluoro-N4-[(2-mPt~o-ryethoxy)carbonyl]cytidine.
and their hydrates or solvates, and the like.
Among the above compolmllR, particularly pre~erred N4-(substituted-25 oxycarbonyl~-5'-DFCRs of the present invention are:
5'-deoxy-5-fluoro-N4-(propoxycarbonyl)cytidine, 5'-deoxy-~-fluoro-N4-(isopentyloxyc~ll,onyl)cytidine, 5'-daoxy-~-fluoro-N4-(hexyls~ arbonyl)cytidine, 5 '-deoxy-N4-[(2-ethylbutyl)oxycarbonyl]-5-fluorocytidine, 5'-deoxy-5-fluoro-N4-~neopentyloxycarbonyl)cytidine, 5'-deoxy-N4-[(3 ,3-dimethylbutoxy)carbonyl]-5-fluorocytidine, - S'-deo~y-5-fluoro-N4-[~2-phenylethoxy)carbonyl]cytidine, N4-[(cyclohe~ylmethoxy)carbor~yl]-5'-deoxy-5-fluorocytidine, ~peci~ly :, ~
- 5 - 2 ~ 2 ~
N4-(butoxycarbonyl)-5'-deoxy-5-fluorocytidine, 5'-deo~y-6-fluoro-N4-(pentylo~y~ onyl)cytidine, and their hydrates or solvates, and the like.
The N4-(substituted-o~;y~llJonyl)-5'-DFCR~ represen~ed by the general s fiormula (I) as well as their hydrate~ or solvates can be plepared by a reaction of a compound represented by the general formula tII), H3C ~ N ( II ) ~0~
R40 oR4 wherein R4 is a llydlo;~y-protecting radical such as acetyl, benzoyl, trimethylsilyl, tert-butyldimethylsilyl, and the like, with a compound represçntçd by the general ~ormula (III), R1OCOCl (III) wherein Rl is the same as ~lefinPd above, followed, if necess~ry~ by removal of a protecting radical.
The compound~ represen$ed by the above general formula (II) can be prepared by 2',3'-di-0-acylation or silylation of ~'-deoxy-5-fluorocytidine [J.
Med. Chem., ~, 1330 (1979)] as described in USP 4,966,891 or by direct coupling of 5-fluorocytosine with 1,2,3-t}i-0-acetyl-5-deoxyribofuranose according to the procedure similar to that described in the literature ; ~ [Syn~hesis, 748 (1981)].
2D The reaction of~he co~lpuul~d ofthe abo~e general formula (II)~nth the com pound ofthe above general form ula ~III) can be carried out in a solvent such as pyridine, dio~ane, tetrahydrofuran, acetonitrile, chloroform, dichloromethane and the like in the presence of acid acceptor such as ~ triethyl~qmine, pyridine, picoline, 4-(N,N-dimethylamino)pyridine, lutidine 25 and the like. The reaction can be carned out at a temperatllre between 0 and 30~C.
-,, ~3~
2',3'-di-0-acetyl-5'-deoxy-N4-[(2-ethylbutyl~o~y~all)onyl~-5-fluorocytidine, 0 2',3'-di-0-acetyl-N4-[(cyclohe~cylmethoxy)carbonyl]-5'-deo~y-5-fluorocytidine, 2' ,3'-di-0-acetyl-5 '-deoxy-5-fluoro-N4-[(2-phenylethoxy)-carbonyl]cytidine, 5'-deoxy-5-~uoro-N4-(isobuto~ycarbonyl)cytidiIIe, 5'-deoxy-5-fluoro-N4-[(2-p~ o~ylpentyl)oxycarbonyl]cy~idiIle, ~'-daoxy-N4-[(2-ethylhexyl)oxycarbonyl]-5-fluorocytidine, 5'-deoxy-5-fluoro-N4-(heptylux,~ ~,all)onyl)cytidine, N4-[(2-cyclohexylethoxy)carbonyl]-5'-deoxy S-fluorocytidine, N4-[(3-cyclohexyl~l opyl)oxycarbonyl~-5'-deoxy-5-fluorocytidine, aD N4-(cyclohexyloxycarbonyl)-5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluoro-N4-[(3-phenyll~o~yl)o,~ycall~onyl]cytidine, and 5'-deoxy-5-fluoro-N4-[(2-mPt~o-ryethoxy)carbonyl]cytidine.
and their hydrates or solvates, and the like.
Among the above compolmllR, particularly pre~erred N4-(substituted-25 oxycarbonyl~-5'-DFCRs of the present invention are:
5'-deoxy-5-fluoro-N4-(propoxycarbonyl)cytidine, 5'-deoxy-~-fluoro-N4-(isopentyloxyc~ll,onyl)cytidine, 5'-daoxy-~-fluoro-N4-(hexyls~ arbonyl)cytidine, 5 '-deoxy-N4-[(2-ethylbutyl)oxycarbonyl]-5-fluorocytidine, 5'-deoxy-5-fluoro-N4-~neopentyloxycarbonyl)cytidine, 5'-deoxy-N4-[(3 ,3-dimethylbutoxy)carbonyl]-5-fluorocytidine, - S'-deo~y-5-fluoro-N4-[~2-phenylethoxy)carbonyl]cytidine, N4-[(cyclohe~ylmethoxy)carbor~yl]-5'-deoxy-5-fluorocytidine, ~peci~ly :, ~
- 5 - 2 ~ 2 ~
N4-(butoxycarbonyl)-5'-deoxy-5-fluorocytidine, 5'-deo~y-6-fluoro-N4-(pentylo~y~ onyl)cytidine, and their hydrates or solvates, and the like.
The N4-(substituted-o~;y~llJonyl)-5'-DFCR~ represen~ed by the general s fiormula (I) as well as their hydrate~ or solvates can be plepared by a reaction of a compound represented by the general formula tII), H3C ~ N ( II ) ~0~
R40 oR4 wherein R4 is a llydlo;~y-protecting radical such as acetyl, benzoyl, trimethylsilyl, tert-butyldimethylsilyl, and the like, with a compound represçntçd by the general ~ormula (III), R1OCOCl (III) wherein Rl is the same as ~lefinPd above, followed, if necess~ry~ by removal of a protecting radical.
The compound~ represen$ed by the above general formula (II) can be prepared by 2',3'-di-0-acylation or silylation of ~'-deoxy-5-fluorocytidine [J.
Med. Chem., ~, 1330 (1979)] as described in USP 4,966,891 or by direct coupling of 5-fluorocytosine with 1,2,3-t}i-0-acetyl-5-deoxyribofuranose according to the procedure similar to that described in the literature ; ~ [Syn~hesis, 748 (1981)].
2D The reaction of~he co~lpuul~d ofthe abo~e general formula (II)~nth the com pound ofthe above general form ula ~III) can be carried out in a solvent such as pyridine, dio~ane, tetrahydrofuran, acetonitrile, chloroform, dichloromethane and the like in the presence of acid acceptor such as ~ triethyl~qmine, pyridine, picoline, 4-(N,N-dimethylamino)pyridine, lutidine 25 and the like. The reaction can be carned out at a temperatllre between 0 and 30~C.
-,, ~3~
The protçct;n~ radical may, if necessary, bs removed at~er the reaction by the proc~dures l~nown to those skilled in the art ~P, ~ecl~ue Groups in Organic Syn~hesis, John Wiley &r, Son~, New York, Can. J. Chem., 9f!d.. 493 (1971) and USP 4,966,891], e.g. by basic or acidic hydrolysis.
The compounds of the above general ~ormula (I) can e~i~t as un~olvated as well as solvated foIms, including hydrated fo~ . The hydration can be effected in the course of the manufacturing process or can occur gradually as a result of hygroscopic properties of an initially anhydrnus product.
Solvates wil~ pharmaceutically acceptable ~olvents such a~ ethanol can be obtained during, for P~mI~le, cryst~ ion.
N4-(Substituted-oxycarobonyl)-5'-DFCR derivatives represented by the general formula (I) as well a3 hydrates or solvate~ of the co~l,owld~ of the general formula (I) prepared by the present invention exhibit activity ~qE~qin~thuman colon cancer CXF280 and gastric cancer GXF97 xenografts, mouse colon 26 carcinom~ mouse Lewis lung car~inomA~ ~d the like in mice over a very wide range of do8age3 both orally and parenterally and are useful as antitumor agent~. They are efficiently converted to 5'-DFCR by an acylamidase isozyme, to 5'-DFIJR by cytidine dç~min~Re and then to the active metabolite 5-FU by pyrimidine nucleoside pho~phorylase.
ao The present i~ven~on further relates to a pharTn~ce~t;c~l composition, particularly for the treatment of tumors characterized by containing a compound of the above general ~ormula (I).
The N4-(substituted-oxycarbonyl)-5'-DFCR~ of the present invention can be ~q~mini.~tered orally or non-orally ~o human being~ by variou~
2; convent;on~l ~flmini~tration methods. Moreover, the N4-(~ubstituted-o~ycarbonyl)-~'-DFCRs according to the present invention are uaed singly or formulated with a comr~t;hle pharmaceutical carrier material~ ThiB carrier material can be an organic or inorganic inert carrier material suitable for enteral, percutaneous or parenteral ~Amini~tration such as, water, gelatin, 30 gum arabic, l~to~e, starch, m~nesium ~tearate, talc, vegetable oils, polyalkylene-glycol~ or petroleum jelly. The pharmaceutical composition can be made up in a solid fiorm (e.g. as tablets, dragees, enteric coating t?hlets, granulars, er~enc co~t;ne granulars, suppositor~es, capsules or enter~c capsule6) in a semi-solid form (e.g. as salves) or in a liquid form ~e.g. as 36 solutions, suspen~ion~ or emulsions). The pharmaceuticsl composition may be sterilized and/or may contain filrther adjuvants such as preserv~ng, st~hili7in~, setting or emulsifying agents, flavor-improviIIg agents, salts for variation of the osmotic pressure or substances acting as buffers. The pharmaceutical composition can be prepared in a convçn~ ns~l mslnner.
The N4-(substituted-oxycarbonyl)-5'-DFCR~ according to the present invention can be used alone or a~ mixtures of two or more different N4-(substituted-o~y~a~l~onyl)-5'-DFCRs and the amount of the N4-(substituted-oxycarbonyl}5'-DFCRs is about 0.1 to 99.5%, preferably 0.6 to 95% based on the weight of the pharmaceutical composition.
The pharmaceutical composition according to the present invention 0 may be formulated in a comhin~tion with other conventional antitumor agent.
Susceptibility to acyla~nidase of the N4-(substituted-o~ycal~)onyl~5'-DFCRs of the present invention al~d the;r pharrr ~cokinetic profiles in the monkey are shown as follows:
1. Susceptibility to human and monkey acylamidases The N4-(substituted-o~y~all~onyl3-~'-DFCRs of the present invention were in(~llh~te~ with crude extracts of monkey and human liver in the presence of an inhibitor of cytidine ~le~min~e~ tetrahy.lloulidine (0.4 mM) at 37~C for 6û min. Thereaf~er, the product 5'-DFCR was separated by HPLC
aD and the enzyme susceptibility wa~ te~l ~rom the amount of the product. As Table 1 shows, the compounds provided in the present invention were highly susceptible to the human liver acyl~mill~se, suggesting that they are efflciently biotransformed to 5'-DFCR in human.
;, ,. , ~ . , . ~ , ,. ... . , - . , - , .
2~ ~32,~i Table 1. Susceptibility to monkey and human asylamidase in the liver ~dase a~,~iv;ly (~ ol/mg px~) (~r~ 3U- ~-ld I~r 11 ~D 71 12 2~ L90 13 47 ~ao 14 3~ 74 16 3~ 210 17 ~2 160 ao ~9 21 a6 ~32 ~4 18 6~
~13 1~0 26 ~D 5~0 ~9 110 28 ~5 52 2. Pharmacokinetic profiles in monkeys The compounds of the present invention were orally ~rlministered into groups of 2 to 5 cynomolgous monkeys (3-4 kg). At vaIious times after the s~Aminist~ation, plasma was taken for determination of ~lood concentrations of intact molecule~ and their active metabolite 6'-DFUR.
Metabolites in the plasma were separated by HPLC and their concentrations were calc~ te~ As Table 2 shows, the compounds of t~e pre~ent invention gave hi~h levels in CmaX and AUC of tlhe active met~holite 5'-DFUR in the pl~m~ These results indicate that the compounds prov~ded in the present invention can be effectively lltili~e~ for the tre~t~n~nt of various tumors in human beings.
-: - . - . .~ .
.~ - .: . ~ --.. - .
2~32l~
The compounds of the above general ~ormula (I) can e~i~t as un~olvated as well as solvated foIms, including hydrated fo~ . The hydration can be effected in the course of the manufacturing process or can occur gradually as a result of hygroscopic properties of an initially anhydrnus product.
Solvates wil~ pharmaceutically acceptable ~olvents such a~ ethanol can be obtained during, for P~mI~le, cryst~ ion.
N4-(Substituted-oxycarobonyl)-5'-DFCR derivatives represented by the general formula (I) as well a3 hydrates or solvate~ of the co~l,owld~ of the general formula (I) prepared by the present invention exhibit activity ~qE~qin~thuman colon cancer CXF280 and gastric cancer GXF97 xenografts, mouse colon 26 carcinom~ mouse Lewis lung car~inomA~ ~d the like in mice over a very wide range of do8age3 both orally and parenterally and are useful as antitumor agent~. They are efficiently converted to 5'-DFCR by an acylamidase isozyme, to 5'-DFIJR by cytidine dç~min~Re and then to the active metabolite 5-FU by pyrimidine nucleoside pho~phorylase.
ao The present i~ven~on further relates to a pharTn~ce~t;c~l composition, particularly for the treatment of tumors characterized by containing a compound of the above general ~ormula (I).
The N4-(substituted-oxycarbonyl)-5'-DFCR~ of the present invention can be ~q~mini.~tered orally or non-orally ~o human being~ by variou~
2; convent;on~l ~flmini~tration methods. Moreover, the N4-(~ubstituted-o~ycarbonyl)-~'-DFCRs according to the present invention are uaed singly or formulated with a comr~t;hle pharmaceutical carrier material~ ThiB carrier material can be an organic or inorganic inert carrier material suitable for enteral, percutaneous or parenteral ~Amini~tration such as, water, gelatin, 30 gum arabic, l~to~e, starch, m~nesium ~tearate, talc, vegetable oils, polyalkylene-glycol~ or petroleum jelly. The pharmaceutical composition can be made up in a solid fiorm (e.g. as tablets, dragees, enteric coating t?hlets, granulars, er~enc co~t;ne granulars, suppositor~es, capsules or enter~c capsule6) in a semi-solid form (e.g. as salves) or in a liquid form ~e.g. as 36 solutions, suspen~ion~ or emulsions). The pharmaceuticsl composition may be sterilized and/or may contain filrther adjuvants such as preserv~ng, st~hili7in~, setting or emulsifying agents, flavor-improviIIg agents, salts for variation of the osmotic pressure or substances acting as buffers. The pharmaceutical composition can be prepared in a convçn~ ns~l mslnner.
The N4-(substituted-oxycarbonyl)-5'-DFCR~ according to the present invention can be used alone or a~ mixtures of two or more different N4-(substituted-o~y~a~l~onyl)-5'-DFCRs and the amount of the N4-(substituted-oxycarbonyl}5'-DFCRs is about 0.1 to 99.5%, preferably 0.6 to 95% based on the weight of the pharmaceutical composition.
The pharmaceutical composition according to the present invention 0 may be formulated in a comhin~tion with other conventional antitumor agent.
Susceptibility to acyla~nidase of the N4-(substituted-o~ycal~)onyl~5'-DFCRs of the present invention al~d the;r pharrr ~cokinetic profiles in the monkey are shown as follows:
1. Susceptibility to human and monkey acylamidases The N4-(substituted-o~y~all~onyl3-~'-DFCRs of the present invention were in(~llh~te~ with crude extracts of monkey and human liver in the presence of an inhibitor of cytidine ~le~min~e~ tetrahy.lloulidine (0.4 mM) at 37~C for 6û min. Thereaf~er, the product 5'-DFCR was separated by HPLC
aD and the enzyme susceptibility wa~ te~l ~rom the amount of the product. As Table 1 shows, the compounds provided in the present invention were highly susceptible to the human liver acyl~mill~se, suggesting that they are efflciently biotransformed to 5'-DFCR in human.
;, ,. , ~ . , . ~ , ,. ... . , - . , - , .
2~ ~32,~i Table 1. Susceptibility to monkey and human asylamidase in the liver ~dase a~,~iv;ly (~ ol/mg px~) (~r~ 3U- ~-ld I~r 11 ~D 71 12 2~ L90 13 47 ~ao 14 3~ 74 16 3~ 210 17 ~2 160 ao ~9 21 a6 ~32 ~4 18 6~
~13 1~0 26 ~D 5~0 ~9 110 28 ~5 52 2. Pharmacokinetic profiles in monkeys The compounds of the present invention were orally ~rlministered into groups of 2 to 5 cynomolgous monkeys (3-4 kg). At vaIious times after the s~Aminist~ation, plasma was taken for determination of ~lood concentrations of intact molecule~ and their active metabolite 6'-DFUR.
Metabolites in the plasma were separated by HPLC and their concentrations were calc~ te~ As Table 2 shows, the compounds of t~e pre~ent invention gave hi~h levels in CmaX and AUC of tlhe active met~holite 5'-DFUR in the pl~m~ These results indicate that the compounds prov~ded in the present invention can be effectively lltili~e~ for the tre~t~n~nt of various tumors in human beings.
-: - . - . .~ .
.~ - .: . ~ --.. - .
2~32l~
Table ~. Pharmacokinetic Profiles in Monkeys Plasma 6' I~FUR
le No.) Cmax AIJC
(~lg/ml) (~lgohr~
1.44 2.03 11 1.57 2.0 12 2.10 2.9~
~3 1.50 1.96 14 1.80 2.40 2.60 .89 16 1.40 2.52 17 1.6~ 2.66 28 1.0~
~ 2.~0 2.09 The ~qntitllmQr activities of the compounds of the present invention are shown as follows:
5 3. Antitumor testing against human colon cancer xenograf~ C~280 CXF280 tumor tabout 2 x 2 mm piece~ was implante~ hcllt~ ou8ly into BALB/c nu/nu mice (21- 22 g) on day 0. When tumor volume bec~m~ 100 mm3 on day around 14, the co~ 4unds of th2 present invention were orally lmin;~tered daily for 3 weeks. At one day after the last tre~tm~nt, tumor o volume was calculated.
i~,.
~r,rl i~:
;j, '?.
. ., :l .
'' 2-.~ !3 3~3~ L
le No.) Cmax AIJC
(~lg/ml) (~lgohr~
1.44 2.03 11 1.57 2.0 12 2.10 2.9~
~3 1.50 1.96 14 1.80 2.40 2.60 .89 16 1.40 2.52 17 1.6~ 2.66 28 1.0~
~ 2.~0 2.09 The ~qntitllmQr activities of the compounds of the present invention are shown as follows:
5 3. Antitumor testing against human colon cancer xenograf~ C~280 CXF280 tumor tabout 2 x 2 mm piece~ was implante~ hcllt~ ou8ly into BALB/c nu/nu mice (21- 22 g) on day 0. When tumor volume bec~m~ 100 mm3 on day around 14, the co~ 4unds of th2 present invention were orally lmin;~tered daily for 3 weeks. At one day after the last tre~tm~nt, tumor o volume was calculated.
i~,.
~r,rl i~:
;j, '?.
. ., :l .
'' 2-.~ !3 3~3~ L
Table 3. Antitumor Ef~ects of Fluorinated Pyrimidine~ in ~ALB/c nu/nu Mice Bearing CXF280 Human Colon Carcinoma C~mpound Do~e ~ 21 % Growth Fecal ~n~I~le No.) (mmoVh~ y) Exp. 1 Vehicle - N
12 0.13 68 0.3 ~
0.67 ~6 1.0 86 1.5 ~8 N
13 0.13 ~;9 0.3 ~6 0.67 7g 1.0 91 1.~ 94 N
- 24 0.13 37 0.3 0.67 75 1.0 ~
1.5 8~ N
Reference compound 5-FU 0.089 2~3 N
û.13 ~ N
0.2 7E~ L
' :
., :
, ~. . - ., - ~- - - - - .
.~, ; . , .
. x . . .. ; - . .
"~ ;,. .. . . :
3 3 ~, ~
.
CompoundDose ~c 21 % Grow~ Fecal ~n~I~le No.)(mmo~h~/~y) i~b;~o~
~2 Vehicle - N
0.13 39 .3 5B
0.~7 75 1.5 ~6 2.25 93 N
12 0.13 68 0.3 ~
0.67 ~6 1.0 86 1.5 ~8 N
13 0.13 ~;9 0.3 ~6 0.67 7g 1.0 91 1.~ 94 N
- 24 0.13 37 0.3 0.67 75 1.0 ~
1.5 8~ N
Reference compound 5-FU 0.089 2~3 N
û.13 ~ N
0.2 7E~ L
' :
., :
, ~. . - ., - ~- - - - - .
.~, ; . , .
. x . . .. ; - . .
"~ ;,. .. . . :
3 3 ~, ~
.
CompoundDose ~c 21 % Grow~ Fecal ~n~I~le No.)(mmo~h~/~y) i~b;~o~
~2 Vehicle - N
0.13 39 .3 5B
0.~7 75 1.5 ~6 2.25 93 N
11 0.13 ~6 0.3 72 0.67 84 1.5 ~36 2.25 100 N
14 0.13 6B
0.3 6B
0.67 ~5 1.6 94 N
2.25 100 N
27 0.13 ~6 0.3 72 0.67 ~
1.5 94 N
2.25 103 N
Reference compound 5-FU 0.089 NE N
0.13 ao N
0.2 58 L
NE: NotEf~ec~ve, * Fecal observation (N: normal feces, L: loose passage) 2~32~
14 0.13 6B
0.3 6B
0.67 ~5 1.6 94 N
2.25 100 N
27 0.13 ~6 0.3 72 0.67 ~
1.5 94 N
2.25 103 N
Reference compound 5-FU 0.089 NE N
0.13 ao N
0.2 58 L
NE: NotEf~ec~ve, * Fecal observation (N: normal feces, L: loose passage) 2~32~
The percent inhibition of tumor growth given in Table 3 above was calculated ~rom the formula:
% Inhibition = ~1- (T - Vo)/(C - Vo)) x 100 Vo = volume of tumor before tre~t~ent was ~tarted, T= volume OI the tumors s from the treated group, C = volume of the tumor from the control group.
As Table 3 shows, the compounds provided in the present invention were safely 2r1mini.~tered without c~ ing intes~;n~l toxicity and were much more ef~ective than ~~FU.
4. Antitumor and anticache~ia activity against mouse colon 26 carcinoma Antitumor activity of a representative compound (li Y~mrle 13), of the - present ;nvention, was me~llred as follows. Mice (CDF1) were subcutaneously inoculated with colon 26 carcinoma (106 cells) on day 0. The compound was ~lmini~tered daily for 7 times from day 21 when the ~ni7n~1 became c~qchectic. One day a~er the last tre~t~nent, tumor weight gain, 5 carcass weight gain, adipose tissue weight, concerltrations of glucose and the acute phase re~ct~nt IAP (immunosu~ essive acidic protein) in the serum were m~ red. As Table 4 shows, mice treated with vehicle were abno~nal in cP~rhe~ parameter~ such as adipose tissue weight, serum glucose and LAP levels, whereas treatment with the compound of F.ll~m~le ao 13 suppressed ~umor growth and ill~pl~ved c~che~
"
~, .
.~
2 .L~3 2 '~
% Inhibition = ~1- (T - Vo)/(C - Vo)) x 100 Vo = volume of tumor before tre~t~ent was ~tarted, T= volume OI the tumors s from the treated group, C = volume of the tumor from the control group.
As Table 3 shows, the compounds provided in the present invention were safely 2r1mini.~tered without c~ ing intes~;n~l toxicity and were much more ef~ective than ~~FU.
4. Antitumor and anticache~ia activity against mouse colon 26 carcinoma Antitumor activity of a representative compound (li Y~mrle 13), of the - present ;nvention, was me~llred as follows. Mice (CDF1) were subcutaneously inoculated with colon 26 carcinoma (106 cells) on day 0. The compound was ~lmini~tered daily for 7 times from day 21 when the ~ni7n~1 became c~qchectic. One day a~er the last tre~t~nent, tumor weight gain, 5 carcass weight gain, adipose tissue weight, concerltrations of glucose and the acute phase re~ct~nt IAP (immunosu~ essive acidic protein) in the serum were m~ red. As Table 4 shows, mice treated with vehicle were abno~nal in cP~rhe~ parameter~ such as adipose tissue weight, serum glucose and LAP levels, whereas treatment with the compound of F.ll~m~le ao 13 suppressed ~umor growth and ill~pl~ved c~che~
"
~, .
.~
2 .L~3 2 '~
Table 4 Impro~ement of Tumor C~che~i~ with Fluorinated Pyrimidines in Mice Bearing Colon 26 Adenoc~rcinoma 7 nlmor wt. Ca~8 wt. ~9dipoae &~lJm Serllm N~ g/ml) ( g)(g) (mg)(m~/dl) Vehicle 1.65 -1.5 11 91 1167 13 0.125 1.24 1.6~ 22~ 118~ 1195 0.25 0.91~~.4* 42* 120* 1~20 0.5 0.79~4.2* 63* 147~ 805~
0.0065.6* 85* 127* 795*
* P<0.05 versus corresponding value of vehicle group The toxicity (LDso) of the representat*e compound~ (~.Y~mrle 13,14, and 17) of the present invention was eY~mined by oral ~ mini~ration daily for 21 days in mice. The represent~t;v0 LDso value~ obtained from the experiments were more than 600 mglkg/day.
A dosage per day to a patient of the N4-(subsiiluted-o,~ l,onyl)-5'-0 DFCRs of the present invention may be varied ~lepen~ling upon his weight and state to be remedied, but generally is in the range of 0.5 to 500 mg per 1 kg of weight, preferably about 2 to 200 mg. It should be noted l~at the compound of the invention can be expected to have 3-5 times higher activity than those of the compounds ~ rlosecl in USP 4,966,891 in h~lm~n~, when 5 taking into consideration of the data of C,ma,~ and AUC OI 5'-DFUR after oral :~lmini~tration of the present compounds iIl monkeys. From the same reason, the compounds of the present invention can be expected to show sufficient activity at the 3-5 times lower dosage than those of the compounds of said U.S. Patent. The present invention can provide a pharmaceutical ao composition for treating tumors with high safety margin.
The following l~ mples are intended to illustrate the present invention in more detail, but are not int~nllel3 to limit its scope in any m~nner.
Reference PY~mple Preparation of starting material 2'~ '~332'~
0.0065.6* 85* 127* 795*
* P<0.05 versus corresponding value of vehicle group The toxicity (LDso) of the representat*e compound~ (~.Y~mrle 13,14, and 17) of the present invention was eY~mined by oral ~ mini~ration daily for 21 days in mice. The represent~t;v0 LDso value~ obtained from the experiments were more than 600 mglkg/day.
A dosage per day to a patient of the N4-(subsiiluted-o,~ l,onyl)-5'-0 DFCRs of the present invention may be varied ~lepen~ling upon his weight and state to be remedied, but generally is in the range of 0.5 to 500 mg per 1 kg of weight, preferably about 2 to 200 mg. It should be noted l~at the compound of the invention can be expected to have 3-5 times higher activity than those of the compounds ~ rlosecl in USP 4,966,891 in h~lm~n~, when 5 taking into consideration of the data of C,ma,~ and AUC OI 5'-DFUR after oral :~lmini~tration of the present compounds iIl monkeys. From the same reason, the compounds of the present invention can be expected to show sufficient activity at the 3-5 times lower dosage than those of the compounds of said U.S. Patent. The present invention can provide a pharmaceutical ao composition for treating tumors with high safety margin.
The following l~ mples are intended to illustrate the present invention in more detail, but are not int~nllel3 to limit its scope in any m~nner.
Reference PY~mple Preparation of starting material 2'~ '~332'~
Preparation of 2'.3'-di-O-acetvl-B'-deoxv-5-fluorocYtidine (a) From 5'-deol~y-5-fluorocytidine 5'-Deoxy-5-fluorocytidine (50 mg) was dissolved in dry pyridine (1.3 ml).
To the solution was added acetic anhydride (39 ml) with stirring at 0~C. The 5 reaction ~ re was stirred for 3 hours at 0~C. Af~er removal of the solvent under reduced pressure, the residue WaB partitioned between ethyl acetate and ice cooled water. The ethyl acetate layer was dried over m~ne.~ium sulfate and concentrated under reduced pressure. The resudie was purified by silica gel column chr~m~tography (dichloromethanelmethanol=9/1 as an lo eluent) followed by recryst~ tion from isopropanol to give 37 mg of 2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine: 191.5-193~C, FAB-MS m/z 330 (MH~).
(b) From 5-fluorocytosine and 1,2,3-tri-O-acetyl-5-deo~y-,B-D-ribofuranose A solution of sodium iodide (3.6 g) and chlorotrimethylsilane (79d,~ ml~ in dry acetonitrile (15 ml) was stirred with molec~ r sieves 4A (200 mg) at 0~C
To the solution was added acetic anhydride (39 ml) with stirring at 0~C. The 5 reaction ~ re was stirred for 3 hours at 0~C. Af~er removal of the solvent under reduced pressure, the residue WaB partitioned between ethyl acetate and ice cooled water. The ethyl acetate layer was dried over m~ne.~ium sulfate and concentrated under reduced pressure. The resudie was purified by silica gel column chr~m~tography (dichloromethanelmethanol=9/1 as an lo eluent) followed by recryst~ tion from isopropanol to give 37 mg of 2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine: 191.5-193~C, FAB-MS m/z 330 (MH~).
(b) From 5-fluorocytosine and 1,2,3-tri-O-acetyl-5-deo~y-,B-D-ribofuranose A solution of sodium iodide (3.6 g) and chlorotrimethylsilane (79d,~ ml~ in dry acetonitrile (15 ml) was stirred with molec~ r sieves 4A (200 mg) at 0~C
15 for ~ min (colorless sodium chlo~de deposited during stirring). 1,2,3-Tri-O-acetyl-5-deoxy-~-D-ribofuranose (2.0 g) was added and the ~llix~ a was stirrPd at 0~C for 30 min. Then, a solution of the trimethylsilylated 5-fluorocytosine, freshly prepared from 5-fluorocytosine (1.12 g), in dry acetonitrile (~ ml) was added at 0~C and stirring wa~ continued for 3 h at 20 room temperature. The ~i~lule wa3 filtered, the filtrate wa~ concentrated in vacuo, and the residue was partitioned between dichloromethane and saturated aq. sodium bicarbonate solution. ~he aqueous layer was extracted with CH2C12/MeOH ~10:1). The combined organic layers were dried over anhydrous sodium sulfate and t7vapolated under reduced pressure. The 25 resudie was purified by silica gel chromatogTaphy using CH2C12/MeOH
(15:1) as an eluent, followed by recrystallization from isopropanol to give 1.24g of 2',3'-di-O-acetyl-5'-deoxy-6-fluorocytidine.
~ ., ., . . . ~ . . .
mnle 1 Pre~aration of 2'~3'-di-O-acetyl-5'-deoxy-5-fluoro-N4-(pro~Qxycarbon~l)-cvti~ine To a solution of 2',3'-di O-acety1-5'-deoxy-5-fluorocytidine (2 g) in CH2Cl~ (15 ml) and dry pyridine (983 ml) was added dropwise n-propyl chloroformate (957 ml) with stirring and cooling on ice bath Af~er stirring for 30 min at room te~ eiature, the mixture was evaporated to dlyness under reduced pressure. ~ e residue wa~ par~oned bet~een ether and saturated aqueou5 ~olution of sodium bicarbon~te. The organic layer was washed unth b~ne, dned over anhydrous sodium sulfate and filtered.
The filtrate was evaporated to give 2',3'-d~-0-acetyl-5'-deoxy-5-fluoro-N4-(propo~y~ onyl)cytidine (2.5 g): EI-MS m/z 415(M+); 1H-NMR(d6-DMSO) ~ 0.92 (3H, t, J=7.3 Hz), 1.37 (3H, d, J=6.3 Hz), 1.63 (2H, sex, J=7.3 Hz), 4.06-4.14 (3H, m), 5.11 (1H, t, J=6.3 Hz), 5.47 (lH, d.d., J=4.6 ~c 6.3 Hz), .81 (lH, d, J=4.6 Hz), 8.31 (lH, br. 8), 10.63 (lH, br.s) The follounng compounds were obtained according to a m~nner analogous to that of FA~r~mrle 1 (Rl and R2 are the same with thosein the general formula (I~). The compound of ~ mrle 9 was prepared from t~e known 2',3'-di-O-benzoyl-5'-deoxy-5-fluorocytidine (USP 4,966,891) by the :~D similar ms~nn~r to that of F~r:~mr~le 1.
., ' .-: ~ :' : J
- ~ - F~B-MS
FY~ e NO. Rl R2 IH NMR ( m/ z ) (m solvent l or 2) 2 n-butyl ac~ 0.87 (3H, t, J=7.3Hz), 1.36 (SH, m),1.59 (2H, m), .05 (3H, s), 2.07 (3H, s), 4.12 ~3H, m ), 5.1 1 ~lH, br.t), 430 (MH+~
5.47 (lH, br.t), 5.81 ~lH, d, J-4.3Hz)1 8.34 (lH, br.s), 10.60 (1H,br.s) 3 n-pentyl ace~l ~(1): 0.88 (3H, t, J=7.3Hz), 1.31 (5H, m),1.36 (3H, d, J=6.3Hz), 1.61 (lH, m), 2.06 (3H, s), 2.07 (3H, s), 444 (MH+) . - 4.07~4.14 (3H, m), S.l l (lH, t, J=6.3Hz~, 5.47 ~lH, d.d, J=6.3 & 4.6Hz), 5.80 (lH, d, J=4.6Hz), 8.28 (1E~, br.s), lû.63 ( lH, br.s) r~ :
4 n-hexyl ace~l ~(1). 0.87 (3H, t, J=6.9Hz), 1.30 ~6H,m),1.36 (3H, d, J=6.3Hz), l.S9 (2H, m), 2.06 (3H, s), 2.07 (3H, s), 458 (MH~3 ~' ~ 4.07~4.14 (3H, m), S.ll (lH, t, J=6.3Hz),5.45 (lH, -- ~ d.d, J=6.3 & 4.6Hz), 5.80 (lH, d, J-~1.6Hz), 8.28 (lH, - ..
~r s~, 10.63 (lH, br.s~
! - : S,.. ~ :
. ~ ~ 5 isu~e,~ acet~ 0.90 (6H, d, J=6.9Hz), 1.36 (3H, d, J=6.3Hz~, ~ 3 1.51 (2H, q, J=6.9Hz), 1.68 (lH, m), 2.06 (3H, s), 444 (MH+) 2.07 ~3H, s), 4.09~4.20 (3H, m), S.l l (lH, t, J=6.3 Hz), c.~:~
5.46 (lH, d.d, J=6.3 & 4.3Hz), 5.80 (lH, d, J=4.3Hz), r ~, t, ' ~ 8.28 ~lH, br.s), 10.63(1H, br.s) NMR: solvent I = d6-DMSO, Solvent 2 = CDCI3 , ~.
:~.
.
ExampleNo. Rl R2 Qn solvHcn~oRr2) FAB-MS
r,~ , 6 2-ethylbutyl acet I ~ 0.87 (6H,t,J=7.3Hz), 1.23~1.45(7H,m), 1.51 (lH, m), 458 (MH+) ~' ' .-~ ; ' 2.06 (3H, s), 2.07 (3H, s~, 4.04 ~2H, br. d ), 4.12 (lH, t, =6.3Hz), 5.11 (lH, t, J=6.3Hz), 5.46 (1H,d.d, J=6.3 &
4.6Hz), 5.81 (d,1=4.6Hz), 8.32 (IH,br.s), 10.61 (lH,br.s) - 7 ~ L."~yl- ace~l ~(1): 1.00(2H,m), 1.11~1.29(4H,m),1.36(3H,d,J=6.3Hz), 470(M~) methyl 1.57-1.77 (SHs m), 2.06 (3H, s), 2.07 (3H, s), 3.92 (2H, br.s), 9 ~ 4.12 ( 1H, m), 5.11 ( lH, ~, 3=6.3Hz), 5.46 ( 1H, d.d, J=6.3&
4.0Hz), 5.81 (lH, d, 1=4.0Hz), 8.33 (lH, br.s),10.61 (lH, br.s) 8 phenethyl ~cetyl ~(1): 1.36 (3H, d, 1=6.3Hz), 2.U6 (3H, s), 2.07 (3H, s), 2.94 478 (MH+) (2H, t, J=6.8Hz), 4.12 (lH, m), 4.32 (2H, br. t), 5.11 (lH, t, 1=6.3Hz), 5.46 (lH, d.d, 1=6.3 & 4.3Hz), 5.81 (lH, d, J=4.3Hz), 7.16-7.37 (SH, m), 8.32 (lH, br.s), 10.67 ~lH, br.s) - .~ . . . . .
. :
9 n-butyl benzoyl ~(2): 0.95 (3H, t~ J=7.3Hz), 1.42 (2H, m)l.58 (3E~, d, J=6.3Hz~, 554 (MH~
1.68 (2H, m),4.16 (2H, br.s), 4.52 (IH, d.q, J=5.8 &6.3Hz), 5.40 (IH, t, J=5.~Hz), 5.65 (lH, d.d, J=4.6 & 5.8Hz), 6.16 (lH, c~
d, J-4.6Hz), 7.35-7.98 (1 lH, m), I l.9(1H, br.s) . ~
. .
- - - ~ , ~ NMR: solvent I = d6-DMSO7 Solvent 2 = CDCl3 ,. ~., .
--18- ~ I a~21~
Exam~le 10 Preparation OI 5'-deoxv-5-fluoro-N4-(~ro~oxycarbonyl)cvti-lin~
To a solution of 2',3'-di 0-acetyl-5'-deoxy-5-fluoro-N4-(propoxy-carbonyl)cytidine (2.5 g) in CH2Cl2 (17 ml) was added dropvvi~e lN NaOH (17 5 ml) with stir~ng and cooling with ice bath. Afl;er stirring for 1 hr at 0~C, MeOH (0.9 ml) was added to the mixture. And pH of the reaction ~ UI ~
was adjusted to 6 by the addition of concentrated HCl and partitioned. Th8 aqueous layer was extracted with a mixed solvent of CH2Cl~/MeOH(95/5) successively ~40 ml ~ 10). T~e co~nhine~ organic layers were dried over 0 anhydrous sodium sulfate and filtered. The solution was evaporated, and the residue was CFyst~ 7etl from ethyl acetate to give ~'-deoxy-5-fluoro-N4-(propoxycarbonyl)cytidine as colorless ClyStalB (1.6 g, y. 79.8%): mp. 125-126.5~ C; EI-MS m/z 331 (M~).
The following compounds were obtained according to a m~nner ~s analogous to that of ~Y~mple 10 (Rl and R2 are the same with $hose in the general formula (1)).
- .~ .
~ 2 ~
r ~ - Rl R~ P~ ; FAB-MS
No. (~C) ~a~on ~olvent m/z 11 n-butyl H 11~120 AcOEt 346 ~MH~) 12 n-pentyl H 11~121 AcOEt EI 359 (Mt) 13 n-hexyl H 114116 AcOEt EI 373 ~+) 14 isopentyl H 11~120 AcOEt 360 (MH+~
2 ~ yl~u~l H amorphou3~ - 374 ~H+) lfi cycl~hexyl- H 1~127 AcOEt 386(M H~) methyl 17 ph~nethyl H 144145 AcOEt-MeO~I 394 (MH~) 1~ allyl H 118.~120 AcOEt 330 (MH+) * 1H-NMR(d6-DMSO)of~.Y~mp~e16: ~ 0.87(6E,t,J=7Hz), 1.25-1.45 (7H, m), 1.~3 (lH, m), 3.68 (lH, q., J=6 Hz), 3.89 (lH, br. t, J=6 Hz), 4.02 (2H, d, J-6 H~), 4.10 (lH, m), 5.0~ (1H, d, J=6 Hz), 6.4 (lH, d, J=6 Hz), 5.67 (lH, d, J=3 Hz), 8.00 (1H, br. s), 10.55 & 11.6û (total lH, br. s each).
Examl~le 19 Pre~aration of N4-(cyclohexyloxycarbonyl)-5'-deoxy-5-fluorocvtidine 5'-Deoxy-5-fluorocytidine (2.6 g) was dis~olved in dry pyridine (20 ml). To the llliXI,Ul'e, trimethylsilyl chloride (3.4 ml) was added dropwise a$ O~C, andstirred for 30 min at room temperature. To the reaction ~ix~e, cyclohexyl chloro~ormate (2.0 ml) was added in one portion at O~C. After stirring of the mixture for 1 hour at room temperature, pyridine was evaporated under reduced pressure. The residue wa~ then partitioned between saturated 5 aqueous NaHCO3 and ether. The organic layer was washed with brine, dried over anhydrous MgSO4 and concentrated under reduced pressure. To the residue were added citric acid (2.0 g) and methanol (50 ml). The l~ixlu~e was stirred at room temperature overnight. Afl;er removal of the solvent - ~~ - 2 ,~ tJ ~
under reduced pressure, the residue was dissolved in CH2Cl2/MeOH (95:5) and neutralized by aqueous NaOH. The organic layer was dried over anhydrous Na2SO4 and concen~rated under reduced pressure. The residue wa~ purified by silica gel chromatography using CH2Cl2/MeoH (20:1) a~ an 5 eluent, followed by recryst~l7i7.~t;on ~rom ethyl acetate to give N4-(cyclohexyloxycarbony~)-5'-deoxy-5-fluorocytidine (3.47g: 92% yield): mp.
134-136~C, FAB-MS m/z 372 (MH+).
The following compounds were obtained according to a mannelo analogous to that of ~ 19 (Rl and R2 are the same w~th those in the 0 general ~ormula (I)).
r , ~ Rl R2 Melt;ingpoillt Re~rstalli- F~B MS
No. (~C~ ion solventm/z 2-cyclohexyl- H 128-129.5 AcOEt 400 (MH+) ethyl 21 3-cyclohexyl- H amorphous* - 414 (MH~) propyl 22 3-phenyl- H 12~121 AcOEt 408 (MH~) pr~pyl 23 2-methoxy- H ~mo~phous~* - 348 ~qH~) ethyl ,:
2~ isobutyl H 132-134 AcOEt 346 (MH+~
2-propylethyl H 11~118 AcOEt 40~ (MH+) .. a6 2-ethylhexyl H amorphous~* - 402 (MH+) Z7 n-heptyl H 115.5-117.5 AcOEt 388 (MH+) ;' * lH-NMR (d6-DMSO) of F,Y~ 1e 21:
~ 0.78-û.93(2H, m), 1.16-1.27(6H, m), 1.31 (3H, d, J=7 H~), 1.~9-1.75 (7H, m), 3.68 (lH, q, J-6 Hz~, 3.89 (lH, br. t, J=6Hz), 4.01-4.14 (3H, m), 5.04 (lH, d, J=6Hz), 5.40 (lH, d, J=6 Hz), 5.67 (1H, d, J=2 Hz), 8.00 (lH, br. s), 10.03 & 10.53 (total lH, br. s each).
.:~
-; :
~ .l O j 3 ~ ~
** lH-NMR (d6-DMSO) of F.Y~mrle 23:
~ 1.31 (3H, d, J=5.9 Hz), 3.28 (3H, s), 3.56 (2H, br. t), 3.69 (lH, t, J=6 Hz), 3.89 (lH, m), 4.06 (lH, m), 4.22 (2H, br. t), 5.05 (lH, d, J=6 Hz), 5.40 (1H, br. s), 5.67 (1H, d, J=3 Hz), 8.06 (lH, br. s), 10.65 (lH, br. B).
5 *** lH-NMR (d6-DMSO) of ~ m~le 26:
o 0.85-0.88 (6H, m), 1.27-1.38 (llH, m), 1.57 (lH, br. d, J=6 Hz), 3.68 (lH, q, J=6 Hz), 3.89-4.02 (4H, m), 5.05 (lH, br. s), 5.41(1H, br. s), .67 (lH, d, J=3 Hz)~ 8.û6 (lH, br. s), 10.52 (lH, br. s).
e ~8 0 Prel?aration of 5'-deoxy-5-fluoro-N4-(neo~entyloxycarbonyl)cytidine 5'-Deoxy-2',3'-di-O-acetyl-5-fluorocytidine (1.5 g) and dry pyridine (0.74 ml) were dissolved in d~ dichloromethane (15 ml). To the mixture, toluene solution of neopentyl chloroformate (3 eq.) was added dropwise at 0~C, and stirred at room temperature for 1 hr. Afl;er the solvent was removed 5 under reduced pressure, the residue was partitioned between ether and saturated aqueous solution of sodium carbonate. The organic layer was successiYely washed with water and brine, dried over anhydrous sodium sul&te and con~entrated under reduced pressure to give crude 2',3'-di-O-acetyl-5'-deoxy-5-fluoro-N4-(neopentyloxyrarbonyl)cytidine a~ pale yellow oil.
ao Thi~ crude product was dissolved in ethanol (15 ml) and cooled on ice-bath.
Then lN aqueous sodiurn hydroxide solution was added dropwise while m~in~ininE the t~mperature below 15~C. Af~cer the addi~on was completed9 the re~t~f.n ~ Lure was neutralized ~;vith conc. ~ )chloric acid at 0~C.
The solution was concentrated under reduced pressure, and the concentrate 2~ was partitioned between water and a mixed solution of CH2Cl2/MeOH (95:5).
The aa4ueous layer was back-extracted with CH~Cl2/M~OH (95:53 ten times ~20 ml each). All organic layers wer~ combined, d~ed over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chrom~t~raphy using cH2c~ MeOH (20:1) as 30 an eluent to give 5'-deoxy-5-fluoro-N4-(neopentyloxycarbonyl)cytidine (1.37 g:
8~% yield) as ~norphous powd~r: FAB-MS m/z 360 (MH~ H-NMR (d6-DMSO) ~ 0.93 ~9H, s), 1.31 (3H, d,J=6.3Hz), 3.68 (lH,q,J=5.9Hz), 3.81 (2H, br.
s), 3.87-3.92 (lH, m), 4.04-4.09 (lH, m), 5.05 (lH,d,J=5.9Hz), 5.41 (lH, br. d, J=5.3Hz), 5.67 (1~,llsl,~=1.3,3.6Hz), 8.04 ~lH, br. s~, 10.53 (~lH, br. s).
: ' . ', ~ ~ : : : . ,' . ' : :. : : . :, .
2~ 3~
- ~2-le ~
5'-Deo~y-N4-r(3 ,3-~limethylbutoxy)carbonyll-5-fluorocvti~line was obtained according to a n~nnçr analogou~ to that of ~mrle 28 except that 3,3-dimethylbutyl chloroformate wa~ used as the acylating 5 ag~nt ~qm~rphou~ powder (71% yield); FAB-MS m/z 374 (~+); lH-NMR
(d6-DMSO) ~ 0.93 (9H, s), 1.31 (3H,d,J=6.3Hz), 1.55 (2E,t,J=7.3Hz), 3.68 (lH,q,J=5.9Hz), 3.84-3.93 (lH, m), 4.03-4.09 (lH, m), 4.15 (2H,t,J-7.3Hz), 5.05 (lH,d,J=5.9Hz), 5.40 (lH, br, d,J=5.3Hz), 5.67 l1~-1d"T=l.3~4.oHz)~ 8.00 (~H, br. B), 10.53 (-lH, br. s).
lD The following a~ample~ illu~trate pharmaceutical preparation6 contsining a compound provided by the present invention.
Exam~le A:
Interlocking gelatin capsules each containing the following ingre-3içn~g were manufactured in a n~nnçr known per se:
N4-(Buto~ all~onyl)-5'-den~y-5-fluorocytidine100 mg Corn starch 20 mg Titanium dioxide 385 mg Magnesium stearate 5 mg l?ilm 20 mg ao PEG6000 3 mg Talc 10 mg 543 mg .-,. . .. ~ . .
, .--~ : r : . : :
~ - :
~ 2~3~?~
- ~3 -Exam~le B:
Tablets each containing the following ingredients were m~nuf~ctured in a m~nner known per se:
N4-(Butoxycarbonyl)-5'-deoxy-5-fluorocytidine100 mg T~ctose 25 mg Corn starch 20.2 mg Hydroxy~lo~ylmethyl cellulose 4 mg MAE~nesium stearate 0.8 mg ~ilm 10 mg lo PE:G6000 1.5 mg Talc 4.5 mg , 1~6 mg ]e C:
~5D~y parenteral dosage forms were manu~actllred in a ms~nn~r known per ~e:
(1~ A total 5 g of N4-(buto~ a~l onyl)-5'-deoxy-5-fluorocyti~ine was dissolved in 76 ml of distilled water, the 60lution was subjected to a bacterio~o~io~l filtration, and then divided aseptically into lO ste~le vials. I~e solution was then freeze-dried to yield 500 mg of sterile dry solid per vial.
~: (2) Clean N4-(butoxycarbonyl)-5'-deoxy-5-fluorocytidine in the amount of 500 mg per vial or ampoule was sealed in the Lece~tacle and heat-sterilized.
2~The above dry dosage ~orms were reconstitut~d before use by adding a suitalble sterile aqueous solvent such as water for injection or isotonic sodium chloride or ~% dextrose fo~ parenteral a~lmini~tration.
(15:1) as an eluent, followed by recrystallization from isopropanol to give 1.24g of 2',3'-di-O-acetyl-5'-deoxy-6-fluorocytidine.
~ ., ., . . . ~ . . .
mnle 1 Pre~aration of 2'~3'-di-O-acetyl-5'-deoxy-5-fluoro-N4-(pro~Qxycarbon~l)-cvti~ine To a solution of 2',3'-di O-acety1-5'-deoxy-5-fluorocytidine (2 g) in CH2Cl~ (15 ml) and dry pyridine (983 ml) was added dropwise n-propyl chloroformate (957 ml) with stirring and cooling on ice bath Af~er stirring for 30 min at room te~ eiature, the mixture was evaporated to dlyness under reduced pressure. ~ e residue wa~ par~oned bet~een ether and saturated aqueou5 ~olution of sodium bicarbon~te. The organic layer was washed unth b~ne, dned over anhydrous sodium sulfate and filtered.
The filtrate was evaporated to give 2',3'-d~-0-acetyl-5'-deoxy-5-fluoro-N4-(propo~y~ onyl)cytidine (2.5 g): EI-MS m/z 415(M+); 1H-NMR(d6-DMSO) ~ 0.92 (3H, t, J=7.3 Hz), 1.37 (3H, d, J=6.3 Hz), 1.63 (2H, sex, J=7.3 Hz), 4.06-4.14 (3H, m), 5.11 (1H, t, J=6.3 Hz), 5.47 (lH, d.d., J=4.6 ~c 6.3 Hz), .81 (lH, d, J=4.6 Hz), 8.31 (lH, br. 8), 10.63 (lH, br.s) The follounng compounds were obtained according to a m~nner analogous to that of FA~r~mrle 1 (Rl and R2 are the same with thosein the general formula (I~). The compound of ~ mrle 9 was prepared from t~e known 2',3'-di-O-benzoyl-5'-deoxy-5-fluorocytidine (USP 4,966,891) by the :~D similar ms~nn~r to that of F~r:~mr~le 1.
., ' .-: ~ :' : J
- ~ - F~B-MS
FY~ e NO. Rl R2 IH NMR ( m/ z ) (m solvent l or 2) 2 n-butyl ac~ 0.87 (3H, t, J=7.3Hz), 1.36 (SH, m),1.59 (2H, m), .05 (3H, s), 2.07 (3H, s), 4.12 ~3H, m ), 5.1 1 ~lH, br.t), 430 (MH+~
5.47 (lH, br.t), 5.81 ~lH, d, J-4.3Hz)1 8.34 (lH, br.s), 10.60 (1H,br.s) 3 n-pentyl ace~l ~(1): 0.88 (3H, t, J=7.3Hz), 1.31 (5H, m),1.36 (3H, d, J=6.3Hz), 1.61 (lH, m), 2.06 (3H, s), 2.07 (3H, s), 444 (MH+) . - 4.07~4.14 (3H, m), S.l l (lH, t, J=6.3Hz~, 5.47 ~lH, d.d, J=6.3 & 4.6Hz), 5.80 (lH, d, J=4.6Hz), 8.28 (1E~, br.s), lû.63 ( lH, br.s) r~ :
4 n-hexyl ace~l ~(1). 0.87 (3H, t, J=6.9Hz), 1.30 ~6H,m),1.36 (3H, d, J=6.3Hz), l.S9 (2H, m), 2.06 (3H, s), 2.07 (3H, s), 458 (MH~3 ~' ~ 4.07~4.14 (3H, m), S.ll (lH, t, J=6.3Hz),5.45 (lH, -- ~ d.d, J=6.3 & 4.6Hz), 5.80 (lH, d, J-~1.6Hz), 8.28 (lH, - ..
~r s~, 10.63 (lH, br.s~
! - : S,.. ~ :
. ~ ~ 5 isu~e,~ acet~ 0.90 (6H, d, J=6.9Hz), 1.36 (3H, d, J=6.3Hz~, ~ 3 1.51 (2H, q, J=6.9Hz), 1.68 (lH, m), 2.06 (3H, s), 444 (MH+) 2.07 ~3H, s), 4.09~4.20 (3H, m), S.l l (lH, t, J=6.3 Hz), c.~:~
5.46 (lH, d.d, J=6.3 & 4.3Hz), 5.80 (lH, d, J=4.3Hz), r ~, t, ' ~ 8.28 ~lH, br.s), 10.63(1H, br.s) NMR: solvent I = d6-DMSO, Solvent 2 = CDCI3 , ~.
:~.
.
ExampleNo. Rl R2 Qn solvHcn~oRr2) FAB-MS
r,~ , 6 2-ethylbutyl acet I ~ 0.87 (6H,t,J=7.3Hz), 1.23~1.45(7H,m), 1.51 (lH, m), 458 (MH+) ~' ' .-~ ; ' 2.06 (3H, s), 2.07 (3H, s~, 4.04 ~2H, br. d ), 4.12 (lH, t, =6.3Hz), 5.11 (lH, t, J=6.3Hz), 5.46 (1H,d.d, J=6.3 &
4.6Hz), 5.81 (d,1=4.6Hz), 8.32 (IH,br.s), 10.61 (lH,br.s) - 7 ~ L."~yl- ace~l ~(1): 1.00(2H,m), 1.11~1.29(4H,m),1.36(3H,d,J=6.3Hz), 470(M~) methyl 1.57-1.77 (SHs m), 2.06 (3H, s), 2.07 (3H, s), 3.92 (2H, br.s), 9 ~ 4.12 ( 1H, m), 5.11 ( lH, ~, 3=6.3Hz), 5.46 ( 1H, d.d, J=6.3&
4.0Hz), 5.81 (lH, d, 1=4.0Hz), 8.33 (lH, br.s),10.61 (lH, br.s) 8 phenethyl ~cetyl ~(1): 1.36 (3H, d, 1=6.3Hz), 2.U6 (3H, s), 2.07 (3H, s), 2.94 478 (MH+) (2H, t, J=6.8Hz), 4.12 (lH, m), 4.32 (2H, br. t), 5.11 (lH, t, 1=6.3Hz), 5.46 (lH, d.d, 1=6.3 & 4.3Hz), 5.81 (lH, d, J=4.3Hz), 7.16-7.37 (SH, m), 8.32 (lH, br.s), 10.67 ~lH, br.s) - .~ . . . . .
. :
9 n-butyl benzoyl ~(2): 0.95 (3H, t~ J=7.3Hz), 1.42 (2H, m)l.58 (3E~, d, J=6.3Hz~, 554 (MH~
1.68 (2H, m),4.16 (2H, br.s), 4.52 (IH, d.q, J=5.8 &6.3Hz), 5.40 (IH, t, J=5.~Hz), 5.65 (lH, d.d, J=4.6 & 5.8Hz), 6.16 (lH, c~
d, J-4.6Hz), 7.35-7.98 (1 lH, m), I l.9(1H, br.s) . ~
. .
- - - ~ , ~ NMR: solvent I = d6-DMSO7 Solvent 2 = CDCl3 ,. ~., .
--18- ~ I a~21~
Exam~le 10 Preparation OI 5'-deoxv-5-fluoro-N4-(~ro~oxycarbonyl)cvti-lin~
To a solution of 2',3'-di 0-acetyl-5'-deoxy-5-fluoro-N4-(propoxy-carbonyl)cytidine (2.5 g) in CH2Cl2 (17 ml) was added dropvvi~e lN NaOH (17 5 ml) with stir~ng and cooling with ice bath. Afl;er stirring for 1 hr at 0~C, MeOH (0.9 ml) was added to the mixture. And pH of the reaction ~ UI ~
was adjusted to 6 by the addition of concentrated HCl and partitioned. Th8 aqueous layer was extracted with a mixed solvent of CH2Cl~/MeOH(95/5) successively ~40 ml ~ 10). T~e co~nhine~ organic layers were dried over 0 anhydrous sodium sulfate and filtered. The solution was evaporated, and the residue was CFyst~ 7etl from ethyl acetate to give ~'-deoxy-5-fluoro-N4-(propoxycarbonyl)cytidine as colorless ClyStalB (1.6 g, y. 79.8%): mp. 125-126.5~ C; EI-MS m/z 331 (M~).
The following compounds were obtained according to a m~nner ~s analogous to that of ~Y~mple 10 (Rl and R2 are the same with $hose in the general formula (1)).
- .~ .
~ 2 ~
r ~ - Rl R~ P~ ; FAB-MS
No. (~C) ~a~on ~olvent m/z 11 n-butyl H 11~120 AcOEt 346 ~MH~) 12 n-pentyl H 11~121 AcOEt EI 359 (Mt) 13 n-hexyl H 114116 AcOEt EI 373 ~+) 14 isopentyl H 11~120 AcOEt 360 (MH+~
2 ~ yl~u~l H amorphou3~ - 374 ~H+) lfi cycl~hexyl- H 1~127 AcOEt 386(M H~) methyl 17 ph~nethyl H 144145 AcOEt-MeO~I 394 (MH~) 1~ allyl H 118.~120 AcOEt 330 (MH+) * 1H-NMR(d6-DMSO)of~.Y~mp~e16: ~ 0.87(6E,t,J=7Hz), 1.25-1.45 (7H, m), 1.~3 (lH, m), 3.68 (lH, q., J=6 Hz), 3.89 (lH, br. t, J=6 Hz), 4.02 (2H, d, J-6 H~), 4.10 (lH, m), 5.0~ (1H, d, J=6 Hz), 6.4 (lH, d, J=6 Hz), 5.67 (lH, d, J=3 Hz), 8.00 (1H, br. s), 10.55 & 11.6û (total lH, br. s each).
Examl~le 19 Pre~aration of N4-(cyclohexyloxycarbonyl)-5'-deoxy-5-fluorocvtidine 5'-Deoxy-5-fluorocytidine (2.6 g) was dis~olved in dry pyridine (20 ml). To the llliXI,Ul'e, trimethylsilyl chloride (3.4 ml) was added dropwise a$ O~C, andstirred for 30 min at room temperature. To the reaction ~ix~e, cyclohexyl chloro~ormate (2.0 ml) was added in one portion at O~C. After stirring of the mixture for 1 hour at room temperature, pyridine was evaporated under reduced pressure. The residue wa~ then partitioned between saturated 5 aqueous NaHCO3 and ether. The organic layer was washed with brine, dried over anhydrous MgSO4 and concentrated under reduced pressure. To the residue were added citric acid (2.0 g) and methanol (50 ml). The l~ixlu~e was stirred at room temperature overnight. Afl;er removal of the solvent - ~~ - 2 ,~ tJ ~
under reduced pressure, the residue was dissolved in CH2Cl2/MeOH (95:5) and neutralized by aqueous NaOH. The organic layer was dried over anhydrous Na2SO4 and concen~rated under reduced pressure. The residue wa~ purified by silica gel chromatography using CH2Cl2/MeoH (20:1) a~ an 5 eluent, followed by recryst~l7i7.~t;on ~rom ethyl acetate to give N4-(cyclohexyloxycarbony~)-5'-deoxy-5-fluorocytidine (3.47g: 92% yield): mp.
134-136~C, FAB-MS m/z 372 (MH+).
The following compounds were obtained according to a mannelo analogous to that of ~ 19 (Rl and R2 are the same w~th those in the 0 general ~ormula (I)).
r , ~ Rl R2 Melt;ingpoillt Re~rstalli- F~B MS
No. (~C~ ion solventm/z 2-cyclohexyl- H 128-129.5 AcOEt 400 (MH+) ethyl 21 3-cyclohexyl- H amorphous* - 414 (MH~) propyl 22 3-phenyl- H 12~121 AcOEt 408 (MH~) pr~pyl 23 2-methoxy- H ~mo~phous~* - 348 ~qH~) ethyl ,:
2~ isobutyl H 132-134 AcOEt 346 (MH+~
2-propylethyl H 11~118 AcOEt 40~ (MH+) .. a6 2-ethylhexyl H amorphous~* - 402 (MH+) Z7 n-heptyl H 115.5-117.5 AcOEt 388 (MH+) ;' * lH-NMR (d6-DMSO) of F,Y~ 1e 21:
~ 0.78-û.93(2H, m), 1.16-1.27(6H, m), 1.31 (3H, d, J=7 H~), 1.~9-1.75 (7H, m), 3.68 (lH, q, J-6 Hz~, 3.89 (lH, br. t, J=6Hz), 4.01-4.14 (3H, m), 5.04 (lH, d, J=6Hz), 5.40 (lH, d, J=6 Hz), 5.67 (1H, d, J=2 Hz), 8.00 (lH, br. s), 10.03 & 10.53 (total lH, br. s each).
.:~
-; :
~ .l O j 3 ~ ~
** lH-NMR (d6-DMSO) of F.Y~mrle 23:
~ 1.31 (3H, d, J=5.9 Hz), 3.28 (3H, s), 3.56 (2H, br. t), 3.69 (lH, t, J=6 Hz), 3.89 (lH, m), 4.06 (lH, m), 4.22 (2H, br. t), 5.05 (lH, d, J=6 Hz), 5.40 (1H, br. s), 5.67 (1H, d, J=3 Hz), 8.06 (lH, br. s), 10.65 (lH, br. B).
5 *** lH-NMR (d6-DMSO) of ~ m~le 26:
o 0.85-0.88 (6H, m), 1.27-1.38 (llH, m), 1.57 (lH, br. d, J=6 Hz), 3.68 (lH, q, J=6 Hz), 3.89-4.02 (4H, m), 5.05 (lH, br. s), 5.41(1H, br. s), .67 (lH, d, J=3 Hz)~ 8.û6 (lH, br. s), 10.52 (lH, br. s).
e ~8 0 Prel?aration of 5'-deoxy-5-fluoro-N4-(neo~entyloxycarbonyl)cytidine 5'-Deoxy-2',3'-di-O-acetyl-5-fluorocytidine (1.5 g) and dry pyridine (0.74 ml) were dissolved in d~ dichloromethane (15 ml). To the mixture, toluene solution of neopentyl chloroformate (3 eq.) was added dropwise at 0~C, and stirred at room temperature for 1 hr. Afl;er the solvent was removed 5 under reduced pressure, the residue was partitioned between ether and saturated aqueous solution of sodium carbonate. The organic layer was successiYely washed with water and brine, dried over anhydrous sodium sul&te and con~entrated under reduced pressure to give crude 2',3'-di-O-acetyl-5'-deoxy-5-fluoro-N4-(neopentyloxyrarbonyl)cytidine a~ pale yellow oil.
ao Thi~ crude product was dissolved in ethanol (15 ml) and cooled on ice-bath.
Then lN aqueous sodiurn hydroxide solution was added dropwise while m~in~ininE the t~mperature below 15~C. Af~cer the addi~on was completed9 the re~t~f.n ~ Lure was neutralized ~;vith conc. ~ )chloric acid at 0~C.
The solution was concentrated under reduced pressure, and the concentrate 2~ was partitioned between water and a mixed solution of CH2Cl2/MeOH (95:5).
The aa4ueous layer was back-extracted with CH~Cl2/M~OH (95:53 ten times ~20 ml each). All organic layers wer~ combined, d~ed over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chrom~t~raphy using cH2c~ MeOH (20:1) as 30 an eluent to give 5'-deoxy-5-fluoro-N4-(neopentyloxycarbonyl)cytidine (1.37 g:
8~% yield) as ~norphous powd~r: FAB-MS m/z 360 (MH~ H-NMR (d6-DMSO) ~ 0.93 ~9H, s), 1.31 (3H, d,J=6.3Hz), 3.68 (lH,q,J=5.9Hz), 3.81 (2H, br.
s), 3.87-3.92 (lH, m), 4.04-4.09 (lH, m), 5.05 (lH,d,J=5.9Hz), 5.41 (lH, br. d, J=5.3Hz), 5.67 (1~,llsl,~=1.3,3.6Hz), 8.04 ~lH, br. s~, 10.53 (~lH, br. s).
: ' . ', ~ ~ : : : . ,' . ' : :. : : . :, .
2~ 3~
- ~2-le ~
5'-Deo~y-N4-r(3 ,3-~limethylbutoxy)carbonyll-5-fluorocvti~line was obtained according to a n~nnçr analogou~ to that of ~mrle 28 except that 3,3-dimethylbutyl chloroformate wa~ used as the acylating 5 ag~nt ~qm~rphou~ powder (71% yield); FAB-MS m/z 374 (~+); lH-NMR
(d6-DMSO) ~ 0.93 (9H, s), 1.31 (3H,d,J=6.3Hz), 1.55 (2E,t,J=7.3Hz), 3.68 (lH,q,J=5.9Hz), 3.84-3.93 (lH, m), 4.03-4.09 (lH, m), 4.15 (2H,t,J-7.3Hz), 5.05 (lH,d,J=5.9Hz), 5.40 (lH, br, d,J=5.3Hz), 5.67 l1~-1d"T=l.3~4.oHz)~ 8.00 (~H, br. B), 10.53 (-lH, br. s).
lD The following a~ample~ illu~trate pharmaceutical preparation6 contsining a compound provided by the present invention.
Exam~le A:
Interlocking gelatin capsules each containing the following ingre-3içn~g were manufactured in a n~nnçr known per se:
N4-(Buto~ all~onyl)-5'-den~y-5-fluorocytidine100 mg Corn starch 20 mg Titanium dioxide 385 mg Magnesium stearate 5 mg l?ilm 20 mg ao PEG6000 3 mg Talc 10 mg 543 mg .-,. . .. ~ . .
, .--~ : r : . : :
~ - :
~ 2~3~?~
- ~3 -Exam~le B:
Tablets each containing the following ingredients were m~nuf~ctured in a m~nner known per se:
N4-(Butoxycarbonyl)-5'-deoxy-5-fluorocytidine100 mg T~ctose 25 mg Corn starch 20.2 mg Hydroxy~lo~ylmethyl cellulose 4 mg MAE~nesium stearate 0.8 mg ~ilm 10 mg lo PE:G6000 1.5 mg Talc 4.5 mg , 1~6 mg ]e C:
~5D~y parenteral dosage forms were manu~actllred in a ms~nn~r known per ~e:
(1~ A total 5 g of N4-(buto~ a~l onyl)-5'-deoxy-5-fluorocyti~ine was dissolved in 76 ml of distilled water, the 60lution was subjected to a bacterio~o~io~l filtration, and then divided aseptically into lO ste~le vials. I~e solution was then freeze-dried to yield 500 mg of sterile dry solid per vial.
~: (2) Clean N4-(butoxycarbonyl)-5'-deoxy-5-fluorocytidine in the amount of 500 mg per vial or ampoule was sealed in the Lece~tacle and heat-sterilized.
2~The above dry dosage ~orms were reconstitut~d before use by adding a suitalble sterile aqueous solvent such as water for injection or isotonic sodium chloride or ~% dextrose fo~ parenteral a~lmini~tration.
Claims (9)
1. Compounds represented by the general formula (I), ( I ) 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 a radical of the formula -(CH2)n-Y [in which n is an integer from 0 to 4, when Y is a cyclohexyl radical, or n is an integer from 2 to 4, when Y is a lower alkoxy radical having 1 to 4 carbon atom(s) or a phenyl radical], and R2 is a hydrogen atom or a radical easily hydrolyzable under physiological conditions, as well as hydrates or solvates of the compounds of the general formula (I).
2. The compounds according to claim 1, wherein R1 is selected from the group consisting of n-propyl, 1-isoproyl-2-methylpropyl, 1,1,2-trimethyl-propyl,n-butyl, isobutyl, 2-ethylbutyl, 3,3-dimethylbutyl, n-pentyl, isopentyl, neopentyl, 2-propylpentyl, n-hexyl, 2-ethylhexyl, n-heptyl, allyl, 2-buten-1-yl,3-buten-1-yl, 3-penten-1-yl, 4-penten-1-yl, 3-hexen-1-yl, 4-hexen-1-yl, 5-hexen-1-yl, cyclohexyl, cyclohexylmethyl, 2-cyclohexylethyl, 3-cyclohexylpropyl, 4-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'-d;-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, 5'-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, and 5'-deoxy-5-fluoro-N4-[(2-methoxyethoxy)carbonyl]cytidine, particularly N4-(butoxycarbonyl)-5'-deoxy-5-fluorocytidine and 5'-deoxy-5-fluoro-N4-(pentyloxycarbonyl)cytidine.
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'-d;-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, 5'-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, and 5'-deoxy-5-fluoro-N4-[(2-methoxyethoxy)carbonyl]cytidine, particularly N4-(butoxycarbonyl)-5'-deoxy-5-fluorocytidine and 5'-deoxy-5-fluoro-N4-(pentyloxycarbonyl)cytidine.
4. Compounds according to claim 1, 2 or 3 for use as therapeutically active substances, particularly for use as antitumor active substances.
5. A process for producing the compounds according to claim 1, 2 or 3, which comprises reacting a compound represented by the general formula (II), ( II ) wherein R4 is a hydroxy-protecting radical, with a compound represented by the general formula (III), R1OCOCl (III) wherein R1 is the same as defined above, and, if necessary, removing the protecting radicals.
6. A pharmaceutical composition, particularly for the treatment of tumors characterized by containing a compound of the general formula (I), as in claim 1, or a hydrate or solvate of the compound of the general formula (I), as an active ingredient.
7. The use of the compounds of claim 1, 2 or 3 for the manufacture of an antitumor agent.
8. Compounds according to claim 1, 2 or 3, whenever prepared by the process of claim 5, or by an obvious chemical equivalent thereof.
9. The invention as hereinbefore described, particularly with reference to the Examples.
***
***
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