5′-deoxy-cytidine derivative administration to treat...

Details 5′-deoxy-cytidine derivative administration to treat... 5′-deoxy-cytidine derivative administration to treat...

2000-03-24

2001-04-03

Geist, Gary (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C536S028500, C536S028510, C536S028520, C536S028530, C536S028540, C536S028550

Reexamination Certificate

active

06211166

ABSTRACT:

FIELD OF THE INVENTION
The present invention is concerned with novel 5′-deoxy-cytidine derivatives, pharmaceutical compositions, a kit thereof for assisting a delivery of 5-fluorouracil selectively to tumor tissues and process for manufacturing the novel 5′-deoxy-cytidine derivatives.
BACKGROUND
Although 5-fluorouracil (5-FU) or its derivatives are clinically useful antitumor agents for the treatment of various solid tumors, in general they are still not satisfactory in terms of efficacy and safety. These drawbacks are mainly due to rapid inactivation of 5-FU by dihydropyrimidine dehydrogenase (DPD) and/or the unsatisfactory delivery of 5-FU to tumor tissues with respect to tumor selectivity. The attempts to enhance the antitumor activity of 5-FU or its derivatives by inhibition of DPD have already been reported: the co-administration of 5-FU or its derivative with a DPD inhibitor such as uracil [U.S. Pat. No. 4,328,229], 5-ethynyluracil [WO92/04901], 5-chloro-2,4-dihydroxypyridine [U.S. Pat. No. 5,525,603] etc. Such co-administration resulted in enhancement of the antitumor activity of 5-FU or its derivatives, but the safety profile was not so improved due to insufficient selectivity in delivering the DPD inhibitor to tumor tissues (as a consequence, 5-FU level is increased both in tumor and plasma).
SUMMARY OF THE INVENTION
The present invention relates to 5′-deoxy-cytidine derivatives of the formula (I),
wherein R
1
is a hydrogen atom or a group easily hydrolyzable under physiological conditions; R
2
is a hydrogen atom, or —CO—OR
4
group [wherein R
4
is a saturated or unsaturated, straight or branched hydrocarbon group consisting of one to fifteen carbon atoms, or a group of the formula —(CH
2
)
n
—Y (in which Y is cyclohexyl or phenyl; n is an integer from 0 to 4)]; R
3
is a hydrogen atom, bromo, iodo, cyano, a C
1-4
alkyl group [which may be substituted with halogen atom(s)], a vinyl or ethynyl group [which may be substituted with halogen atom(s), C
1-4
alkyl, cycloalkyl, aralkyl, or aromatic ring which may have one or more hetero atom(s)], or an aralkyl group which may be substituted; with the proviso that R
2
and R
3
do not simultaneously mean a hydrogen atom.
The present invention also relates to pharmaceutical compositions comprising a 5′-deoxy-cytidine derivative of formula (I) and a pharmaceutically acceptable inert carrier material.
In accordance with the present invention it has been found that the co-administration of a 5′-deoxy-cytidine derivative of the formula (I) with 5-FU or its derivative results in the significantly improved delivery of 5-FU selectively to tumor tissues as compared with the combination of 5-FU or its derivative with a known DPD inhibitor such as 5-ethynyluracil, and shows significantly improved antitumor activity in human cancer xenograft models.
The present invention also relates to pharmaceutical compositions comprising a 5′-deoxy-cytidine derivative of formula (I) and 5′-fluorouracil or a derivative thereof.
DETAILED DESCRIPTION OF THE INVENTION
The respective groups of the formula (I) are explained in more detail as follows;
Explanation of R
1
:
R
1
is a hydrogen atom or a group easily hydrolyzable under physiological condition.
In the above, the term “a group easily hydrolyzable under physiological condition” preferably means acetyl, propionyl, benzoyl, toluoyl, glycyl, alanyl, &bgr;-alanyl, valyl, lysyl, and the like. In the most preferred embodiment of the compounds in accordance with the present invention, R
1
means hydrogen, or acetyl.
Explanation of R
2
:
R
2
is a hydrogen atom, or —CO—OR
4
group [wherein R
4
is a saturated or unsaturated, straight or branched hydrocarbon group consisting of one to fifteen carbon atoms, or group of formura —(CH
2
)n—Y (in which Y is cyclohexyl or phenyl; n is an integer of from 0 to 4)].
In the above group R
4
, the term “a saturated or unsaturated, straight or branched hydrocarbon group consisting of one to fifteen carbon atoms” preferably means methyl, ethyl, 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-heptyl, n-octyl, 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, n-tridecyl and the like.
The term “a group of the formula —(CH
2
)
n
—Y (in which Y is cyclohexyl or phenyl; n is an integer from 0 to 4)” preferably means cyclohexyl, cyclohexylmethyl, 2-cyclohexylethyl, 3-cyclohexylpropyl, 4-cyclohexyl-butyl, phenyl, benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl and the like.
In the most preferred embodiment of the compounds in accordance with the present invention, R
4
means n-propyl, n-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3,3-dimethylbutyl, 2-ethylbutyl, phenylethyl, and cyclohexylmethyl.
Explanation of R
3
:
R
3
is a hydrogen atom, bromo, iodo, cyano, a C
1-4
alkyl group [which is unsubstituted or substituted with one or more halogen atom(s)], a vinyl or ethynyl group [which is unsubstituted or substituted with one or more halogen atom(s), C
1-4
alkyl, cycloalkyl, aralkyl, or aromatic ring which may have one or more hetero atom(s)], or an aralkyl group which is unsubstituted or substituted; with the proviso that R
2
and R
3
do not mean a hydrogen atom at the same time.
In the above, the term “a C
1-4
alkyl group which is unsubstituted or substituted with one or more halogen atom(s)” preferably means methyl, trifluoromethyl, ethyl, propyl and the like.
The term “a vinyl or ethynyl group [which is unsubstituted or substituted with one or more halogen atom(s), C
1-4
alkyl, cycloalkyl, aralkyl, or aromatic ring which may have one or more hetero atom(s)]” preferably means vinyl, 1-chlorovinyl, 2-bromovinyl, 2-bromo-1-chlorovinyl, ethynyl, prop-1-ynyl, but-1-ynyl, pent-1-ynyl, hex-1-ynyl, 3,3-dimethyl-but-1-ynyl, cyclopentylethynyl, cyclohexylethynyl, phenylethynyl, 3-phenylprop-1-ynyl, pyrid-2-ylethynyl, imidazol-2-ylethynyl, and the like. The most preferred group is ethynyl, vinyl and iodo.
The term “an aralkyl group which is unsubstituted or substituted” preferably means 3-(benzyloxy)benzyl, 3-methoxybenzyl, 3-bromobenzyl, 3-methylbenzyl, 3-hydroxybenzyl and the like.
Preferred 5′-deoxy-cytidine derivatives of the present invention are:
5′-deoxy-5-ethynylcytidine,
5′-deoxy-5-prop-1-ynylcytidine,
5-but-1-ynyl-5′-deoxycytidine,
5′-deoxy-5-pent-1-ynylcytidine,
5′-deoxy-5-hex-1-ynylcytidine,
5′-deoxy-5-iodocytidine,
5-bromo-5′-deoxycytidine,
5-(1-chlorovinyl)-5′-deoxycytidine,
5′-deoxy-5-vinylcytidine,
5′-deoxy-5-trifluoromethylcytidine
5-(3-benzyloxybenzyl)-5′-deoxycytidine,
5-cyano-5′-deoxycytidine,
5′-deoxy-N
4
-(n-pentyloxycarbonyl)cytidine,
5′-deoxy-N
4
-(n-pentyloxycarbonyl)-5-prop-1-ynylcytidine,
5-but-1-ynyl-5′-deoxy-N
4
-(n-pentyloxycarbonyl)cytidine,
5′-deoxy-5-pent-1-ynyl-N
4
-(n-pentyloxycarbonyl)cytidine,
5′-deoxy-5-hex-1-ynyl-N
4
-(n-pentyloxycarbonyl)cytidine,
5′-deoxy-5-iodo-N
4
-(n-pentyloxycarbonyl)cytidine,
5-bromo-5′-deoxy-N
4
-(n-pentyloxycarbonyl)cytidine,
5-(1-chlorovinyl)-5′-deoxy-N
4
-(n-pentyloxycarbonyl)cytidine,
N
4
-(ethoxycarbonyl)-5′-deoxy-5-vinylcytidine,
5′-deoxy-N
4
-(n-propoxycarbonyl)-5-vinylcytidine,
N
4
-(n-butoxycarbonyl)-5′-deoxy-5-vinylcytidine,
5′-deoxy-N
4
-(n-pentyloxycarbonyl)-5-vinylcytidine,
N
4
-(benzyloxycarbonyl)-5′-deoxy-5-vinylcytidine,
5′-deoxy-N
4
-(n-pentyloxycarbonyl)-5-trifluoromethylcytidine,
5-(3-benzyloxybenzyl)-5′-deoxy-N
4
-(n-pentyloxycarbonyl)cytidine,
5-cyano-5′-deoxy-N
4
-(n-pentyloxycarbonyl)cytidine,
5′-deoxy-5-ethynyl-N
4
-(methoxycarbonyl)cytidine
5′-deoxy-N
4
-(ethoxycarbonyl)-5-ethynylcytidine
5′-deoxy-5-ethynyl-N
4
-(n-propoxycarbonyl)cytidine,
5′-deoxy-5-ethyny

Affiliated with

Also associated with

Rating

5′-deoxy-cytidine derivative administration to treat... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with 5′-deoxy-cytidine derivative administration to treat..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and 5′-deoxy-cytidine derivative administration to treat... will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2463482