 |
Description  |
|
|
TECHNICAL FIELD
The present invention relates to novel pyrimidine nucleoside derivatives
having excellent antitumor activities.
BACKGROUND ART
As the commercially available antitumor agents of pyrimidine series
metabolism antagonistic agents, 5-fluorouracil (Duschinsky, R., et al., J.
Am. Chem. Soc., 79, 4559 (1957)), Tegafur (Hiller, SA., et al., Dokl.
Akad. Nauk USSR, 176, 332 (1967)), UFT (Fujii, S., et al., Gann, 69, 763
(1978)), Carmofur (Hoshi, A., et al., Gann, 67, 725 (1976)), Doxyfluridine
(Cook, A. F., et al., J. Med. Chem., 22, 1330 (1979)), Cytarabine (Evance,
J. S., et al., Proc. Soc. Exp. Bio. Med., 106, 350 (1961)), Ancytabine
(Hoshi, A., et al., Gann, 63, 353, (1972)), Enocytabine (Aoshima, M., et
al., Cancer Res., 36, 2726 (1976)), etc. are so far known.
As the pyrimidine mononucleoside having a cyano group at the ribose moiety,
3'-cyanothymine nucleoside and 3'-cyanouracil nucleoside derivatives are
only known (Japanese Unexamined Patent Publication Nos. Hei-2-83392,
Hei-2-104586 and Hei-2-503002).
DISCLOSURE OF THE INVENTION
The present inventors made extensive studies for a long period of time with
a view to developing an absolutely novel antimetabolites which is superior
to the existing antitumor agents described above to find that compounds
wherein a cyano group is introduced to the 2'-position of the sugar moiety
of pyrimidine series nucleosides have strong antitumor activities to
various tumor systems and such compounds can be intermediates for
producing such compounds having strong antitumor activities, and they
accomplished the present invention.
CONSTITUTION OF THE INVENTION
The novel pyrimidine nucleoside derivatives having strong antitumor
activities according to the present invention are compounds having the
general formula:
##STR3##
the general formula:
##STR4##
and pharmacologically acceptable nontoxic salts thereof.
In the above general formulae (1) and (2), R.sup.1 represents a hydroxyl
group or an amino group which may optionally have a substituent selected
from the following group A or B: R.sup.2 represents a hydrogen atom or an
alkyl group having 1 to 4 carbon atoms; R.sup.3 represents a hydrogen atom
or a hydroxyl group; and R.sup.4 and R.sup.5 each represent a hydrogen
atom or together may form a group --R.sup.6 R.sup.7 Si--O--SiR.sup.6'
R.sup.7' --(wherein R.sup.6, R.sup.7, R.sup.6' and R.sup.7' may be the
same or different from one another and each represent an alkyl group
having 1 to 4 carbon atoms).
Group A
Aliphatic acyl having 1 to 4 carbon atoms and aromatic acyl having 7 to 11
carbon atoms which may have a substituent on the ring.
Group B
Alkoxycarbonyl having a C.sub.1 -C.sub.4 alkyl, alkenyloxycarbonyl having a
C.sub.2 -C.sub.4 alkenyl, aralkyloxycarbonyl having 8 to 12 carbon atoms
which may have a substituent on the ring.
The aliphatic acyl having 1 to 4 carbon atoms as the substituent R.sup.1
mentioned above includes formyl, acetyl, propionyl, butyryl and
isopropionyl, preferably an aliphatic acyl having 1 to 2 carbon atoms. The
aromatic acyl having 7 to 11 carbon atoms includes benzoyl,
.alpha.-naphthoyl and .beta.-naphthoyl, preferably benzoyl. The
substituent moiety on the aromatic ring includes an alkyl having 1 to 4
carbon atoms, an alkoxy having 1 to 4 carbon atoms and an aliphatic acyl
having 1 to 4 carbon atoms, preferably methyl, ethyl, methoxy, ethoxy and
acetyl groups. The alkyl moiety of the alkoxycarbonyl having a C.sub.1
-C.sub.4 alkyl group includes methyl, ethyl, n-propyl, isopropyl, n-butyl,
isobutyl and t-butyl, preferably methyl and t-butyl. The alkenyl moiety of
the alkenyloxycarbonyl having a C.sub.2 -C.sub.4 alkenyl includes vinyl,
allyl, isopropenyl, 1-butenyl and 2-butenyl, preferably allyl. The aralkyl
moiety of the aralkyloxycarbonyl having 8 to 12 carbon atoms includes
benzyl, phenethyl, .alpha.-naphthylmethyl and .beta.-naphthylethyl,
preferably benzyl. The substituent on the aromatic ring includes an alkyl
having 1 to 4 carbon atoms, an alkoxy having 1 to 4 carbon atoms and an
aliphatic acyloxy having 1 to 4 carbon atoms, preferably methyl, ethyl,
methoxy, ethoxy and acetoxy.
R.sup.1 mentioned above preferably includes a hydroxyl group, an amino
group, an amino group substituted with a C.sub.1 -C.sub.2 aliphatic acyl,
an amino group substituted with an aromatic acyl having 7 carbon atoms
which may have a substituent on the ring, an amino group substituted with
an alkoxycarbonyl having a C.sub.1 -C.sub.4 alkyl, an amino group
substituted with an alkenyloxycarbonyl having a C.sub.3 alkenyl, an amino
group substituted with an aralkyloxycarbonyl having 8 carbon atoms which
may have a substituent on the ring, more preferably a hydroxyl group, an
amino group, an amino group substituted with an aliphatic acyl having 1 to
2 carbon atoms, an amino group substituted with an aromatic acyl having 7
carbon atoms, most preferably a hydroxyl group and an amino group.
The R.sup.2 alkyl group having 1 to 4 carbon atoms includes methyl, ethyl,
propyl, isopropyl, butyl, isobutyl and t-butyl groups, preferably a methyl
group.
R.sup.2 mentioned above preferably includes a hydrogen atom and a methyl
group.
The R.sup.6, R.sup.6', R.sup.7 or R.sup.7' alkyl group having 1 to 4 carbon
atoms includes methyl, ethyl, propyl, Isopropyl, butyl, isobutyl and
t-butyl groups, preferably isopropyl group.
R.sup.4 and R.sup.5 mentioned above each are a hydrogen atom or together
form a tetramethyldisiloxdiyl group, a tetraethyldisiloxdiyl group, a
tetrapropyldisiloxdiyl group, a tetraisopropyldisiloxdiyl group, a
tetrabutyldisiloxdiyl group, a diethyldiisopropyldisiloxdiyl group or a
dibutyldiisopropyldisiloxdiyl group, preferably a hydrogen atom or a
tetraisopropyldisiloxdiyl group, more preferably a hydrogen atom.
The pharmacologically acceptable nontoxic salts of the compounds having the
above general formulae (1) or (2) of the present invention can be
exemplified by salts of mineral acids such as hydrochloride, hydrobromide
and sulfate, organic sulfonates such as methane sulfonate and benzene
sulfonate, aliphatic carboxylates such as acetate, propionate, butyrate,
and caproate and aromatic carboxylates such as benzoate.
Among those salts, the salts of mineral acids (particularly hydrochloric
acid) and aliphatic carboxylates (particularly acetic acid) are preferred.
In Compounds (1) and (2), there may preferably be mentioned:
1) Compounds wherein R.sup.1 represents a hydroxyl group or an amino group
which may have a substituent selected from the following group A' or B';
R.sup.2 represents a hydrogen atom or an alkyl group having 1 to 4 carbon
atoms: R.sup.3 represents a hydrogen atom or a hydroxyl group; and R.sup.4
and R.sup.5 each represent a hydrogen atom or together form a
tetraisopropyldisiloxdiyl group.
Group A'
An aliphatic acyl having 1 to 2 carbon atoms and an aromatic acyl having 7
carbon atoms which may have a substituent on the ring.
Group B'
An alkoxycarbonyl having a C.sub.1 -C.sub.4 alkyl, an alkenyloxycarbonyl
having a C.sub.3 alkenyl and an aralkyloxycarbonyl having 8 carbon atoms
which may have a substituent on the ring.
2) Compounds wherein R.sup.1 represents a hydroxyl group or an amino group
which may have a substituent selected from the following group A'; R.sup.2
represents a hydrogen atom or a methyl group; R.sup.3 represents a
hydrogen atom or a hydroxyl group; and R.sup.4 and R.sup.5 each represent
a hydrogen atom.
Group A'
An aliphatic acyl having 1 to 2 carbon atoms and an aromatic acyl having 7
carbon atoms which may have a substituent on the ring.
3) Compounds wherein R.sup.1 represents a hydroxyl group or an amino group;
R.sup.2 represents a hydrogen atom or a methyl group; R.sup.3 represents a
hydrogen atom or a hydroxyl group; and R.sup.4 and R.sup.5 each represent
a hydrogen atom.
Compounds (1) and (2) of the present invention can typically be exemplified
by those listed in Table 1, Table 2 and Table 3, but the present invention
is not limited thereto.
Incidentally, Table 1, Table 2 and Table 3 show compounds of the formula A,
compounds of the formula B and compounds of the formula C, respectively.
In Table 1, Table 2 and Table 3, Et, Pr, tBu, AL, Ac, Bz, BzpMe, BzpOMe,
By and BypOAc mean an ethyl group, propyl group, tert-butyl group, allyl
group, acetyl group, benzoyl group, p-methylbenzoyl group,
p-methoxybenzoyl group, benzyl group and p-acetoxybenzyl group,
respectively.
##STR5##
TABLE 1
______________________________________
No. R.sup.1 R.sup.2 R.sup.7
R.sup.8
X
______________________________________
1-1 NH.sub.2 H H CN --
1-2 NH.sub.2 CH.sub.3 H CN --
1-3 NH.sub.2 CH.sub.3 CH.sub.2
H CN --
1-4 NH.sub.2 CH.sub.3 (CH.sub.2).sub.2
H CN --
1-5 NH.sub.2 (CH.sub.3).sub.2 CH
H CN --
1-6 NH.sub.2 CH.sub.3 (CH.sub.2).sub.3
H CN --
1-7 NH.sub.2 H H CN HC1
1-8 NH.sub.2 CH.sub.3 H CN HC1
1-9 NH.sub.2 CH.sub.3 CH.sub.2
H CN HC1
1-10 NH.sub.2 CH.sub.3 (CH.sub.2).sub.2
H CN HC1
1-11 NH.sub.2 (CH.sub.3).sub.2 CH
H CN HC1
1-12 NH.sub.2 CH.sub.3 (CH.sub.2).sub.3
H CN HC1
1-13 OH H H CN --
1-14 OH CH.sub.3 H CN --
1-15 OH CH.sub.3 CH.sub.2
H CN --
1-16 OH CH.sub.3 (CH.sub.2).sub.2
H CN --
1-17 OH (CH.sub.3).sub.2 CH
H CN --
1-18 OH CH.sub.3 (CH.sub.2).sub.3
H CN --
1-19 NH.sub.2 H CN OH --
1-20 NH.sub.2 CH.sub.3 CN OH --
1-21 NH.sub.2 CH.sub.3 CH.sub.2
CN OH --
1-22 NH.sub.2 CH.sub.3 (CH.sub.2).sub.2
CN OH --
1-23 NH.sub.2 (CH.sub.3).sub.2 CH
CN OH --
1-24 NH.sub.2 CH.sub.3 (CH.sub.2).sub.3
CN OH --
1-25 NH.sub.2 H CN OH HC1
1-26 NH.sub.2 CH.sub.3 CN OH HC1
1-27 NH.sub.2 CH.sub.3 CH.sub.2
CN OH HC1
1-28 NH.sub.2 CH.sub.3 (CH.sub.2).sub.2
CN OH HC1
1-29 NH.sub.2 (CH.sub.3).sub.2 CH
CN OH HC1
1-30 NH.sub.2 CH.sub.3 (CH.sub.2).sub.3
CN OH HC1
1-31 OH H CN OH --
1-32 OH CH.sub.3 CN OH --
1-33 OH CH.sub.3 CH.sub.2
CN OH --
1-34 OH CH.sub.3 (CH.sub.2).sub.2
CN OH --
1-35 OH (CH.sub.3).sub.2 CH
CN OH --
1-36 OH CH.sub.3 (CH.sub.2).sub.3
CN OH --
1-37 NH.sub.2 H CN H --
1-38 NH.sub.2 CH.sub.3 CN H --
1-39 NH.sub.2 CH.sub.3 CH.sub.2
CN H --
1-40 NH.sub.2 CH.sub.3 (CH.sub.2).sub.2
CN H --
1-41 NH.sub.2 (CH.sub.3).sub.2 CH
CN H --
1-42 NH.sub.2 CH.sub.3 (CH.sub.2).sub.3
CN H --
1-43 NH.sub.2 H CN H HC1
1-44 NH.sub.2 CH.sub.3 CN H HC1
1-45 NH.sub.2 CH.sub.3 CH.sub.2
CN H HC1
1-46 NH.sub.2 CH.sub.3 (CH.sub.2).sub.2
CN H HC1
1-47 NH.sub.2 (CH.sub.3).sub.2 CH
CN H HC1
1-48 NH.sub.2 CH.sub.3 (CH.sub.2).sub.3
CN H HC1
1-49 OH H CN H --
1-50 OH CH.sub.3 CN H --
1-51 OH CH.sub.3 CH.sub.2
CN H --
1-52 OH CH.sub.3 (CH.sub.2).sub.2
CN H --
1-53 OH (CH.sub.3).sub.2 CH
CN H --
1-54 OH CH.sub.3 (CH.sub.2).sub.3
CN H --
1-55 NH.sub.2 H OH CN --
1-56 NH.sub.2 CH.sub.3 OH CN --
1-57 NH.sub.2 CH.sub.3 CH.sub.2
OH CN --
1-58 NH.sub.2 CH.sub.3 (CH.sub.2).sub.2
OH CN --
1-59 NH.sub.2 (CH.sub.3).sub.2 CH
OH CN --
1-60 NH.sub.2 CH.sub.3 (CH.sub.2).sub.3
OH CN --
1-61 NH.sub.2 H OH CN HC1
1-62 NH.sub.2 CH.sub.3 OH CN HC1
1-63 NH.sub.2 CH.sub.3 CH.sub.2
OH CN HC1
1-64 NH.sub.2 CH.sub.3 (CH.sub.2).sub.2
OH CN HC1
1-65 NH.sub.2 (CH.sub.3).sub.2 CH
OH CN HC1
1-66 NH.sub.2 CH.sub.3 (CH.sub.2).sub.3
OH CN HC1
1-67 OH H OH CN --
1-68 OH CH.sub.3 OH CN --
1-69 OH CH.sub.3 CH.sub.2
OH CN --
1-70 OH CH.sub.3 (CH.sub.2).sub.2
OH CN --
1-71 OH (CH.sub.3).sub.2 CH
OH CN --
1-72 OH CH.sub.3 (CH.sub.2).sub.3
OH CN --
1-73 NHBz H H CN --
1-74 NHCOOtBu H H CN --
1-75 NHCOOBy H H CN --
1-76 NHCOOAL H H CN --
1-77 NHBz CH.sub.3 H CN --
1-78 NHBz CH.sub.3 CH.sub.2
H CN --
1-79 NHBz CH.sub.3 (CH.sub.2).sub.2
H CN --
1-80 NHBz (CH.sub.3).sub.2 CH
H CN --
1-81 NHBz CH.sub.3 (CH.sub.2).sub.3
H CN --
1-82 NHBz H CN H --
1-83 NHBz CH.sub.3 CN H --
1-84 NHBz CH.sub.3 CH.sub.2
CN H --
1-85 NHBz CH.sub.3 (CH.sub.2).sub.2
CN H --
1-86 NHBz (CH.sub.3).sub.2 CH
CN H --
1-87 NHBz CH.sub.3 (CH.sub.2).sub.3
CN H --
1-88 NHAc H H CN --
1-89 NHCOH H H CN --
1-90 NHCOEt H H CN --
1-91 NHCOPr H H CN --
1-92 NHAc CH.sub.3 H CN --
1-93 NHAc CH.sub.3 CH.sub.2
H CN --
1-94 NHAc CH.sub.3 (CH.sub.2).sub.2
H CN --
1-95 NHAc (CH.sub.3).sub.2 CH
H CN --
1-96 NHAc CH.sub.3 (CH.sub.2).sub.3
H CN --
1-97 NHAc H OH CN --
1-98 NHAc CH.sub.3 OH CN --
1-99 NHAc CH.sub.3 CH.sub.2
OH CN --
1-100 NHAc CH.sub.3 (CH.sub.2).sub.2
OH CN --
1-101 NHAc (CH.sub.3).sub.2 CH
OH CN --
1-102 NHAc CH.sub.3 (CH.sub.2).sub.3
OH CN --
1-103 NHAc H CN H --
1-104 NHAc CH.sub.3 CN H --
1-105 NHAc CH.sub.3 CH.sub.2
CN H --
1-106 NHAc CH.sub.3 (CH.sub.2).sub.2
CN H --
1-107 NHAc (CH.sub.3).sub.2 CH
CN H --
1-108 NHAc CH.sub.3 (CH.sub.2).sub.3
CN H --
______________________________________
TABLE 2
______________________________________
No. R.sup.1 R.sup.2 X
______________________________________
2-1 NH.sub.2 H --
2-2 NH.sub.2 CH.sub.3 --
2-3 NH.sub.2 CH.sub.3 CH.sub.2
--
2-4 NH.sub.2 CH.sub.3 (CH.sub.2).sub.2
--
2-5 NH.sub.2 (CH.sub.3).sub.2 CH
--
2-6 NH.sub.2 CH.sub.3 (CH.sub.2).sub.3
--
2-7 NH.sub.2 H HC1
2-8 NH.sub.2 CH.sub.3 HC1
2-9 NH.sub.2 CH.sub.3 CH.sub.2
HC1
2-10 NH.sub.2 CH.sub.3 (CH.sub.2).sub.2
HC1
2-11 NH.sub.2 (CH.sub.3).sub.2 CH
HC1
2-12 NH.sub.2 CH.sub.3 (CH.sub.2).sub.3
HC1
2-13 OH H --
2-14 OH CH.sub.3 --
2-15 OH CH.sub.3 CH.sub.2
--
2-16 OH CH.sub.3 (CH.sub.2).sub.2
--
2-17 OH (CH.sub.3).sub.2 CH
--
2-18 OH CH.sub.3 (CH.sub.2).sub.3
--
2-19 NHAc H --
2-20 NHAc CH.sub.3 --
2-21 NHAc CH.sub.3 CH.sub.2
--
2-22 NHAc CH.sub.3 (CH.sub.2).sub.2
--
2-23 NHAc (CH.sub.3).sub.2 CH
--
2-24 NHAc CH.sub.3 (CH.sub.2).sub.3
--
2-25 NHBzpMe H --
2-26 NHBzpOMe CH.sub.3 --
2-27 NHCOOtBu CH.sub.3 CH.sub.2
--
2-28 NHCOOBy CH.sub.3 (CH.sub.2).sub.2
--
2-29 NHCOOAL (CH.sub.3).sub.2 CH
--
2-30 NHCOOBypOAc CH.sub.3 (CH.sub.2).sub.3
--
2-31 NHBz H --
2-32 NHBz CH.sub.3 --
2-33 NHBz CH.sub.3 CH.sub.2
--
2-34 NHBz CH.sub.3 (CH.sub.2).sub.2
--
2-35 NHBz (CH.sub.3).sub.2 CH
--
2-36 NHBz CH.sub.3 (CH.sub.2).sub.3
--
2-37 NHAc H --
2-38 NHAc CH.sub.3 --
2-39 NHAc CH.sub.3 CH.sub.2
--
2-40 NHAc CH.sub.3 (CH.sub.2).sub.2
--
2-41 NHAc (CH.sub.3).sub.2 CH
--
2-42 NHAc CH.sub.3 (CH.sub.2).sub.3
--
______________________________________
TABLE 3
______________________________________
No. R.sup.1 R.sup.2 R.sup.7
R.sup.8
X
______________________________________
3-1 NH.sub.2 H H CN --
3-2 NH.sub.2 CH.sub.3 H CN --
3-3 NH.sub.2 CH.sub.3 CH.sub.2
H CN --
3-4 NH.sub.2 CH.sub.3 (CH.sub.2).sub.2
H CN --
3-5 NH.sub.2 (CH.sub.3).sub.2 CH
H CN --
3-6 NH.sub.2 CH.sub.3 (CH.sub.2).sub.3
H CN --
3-7 OH H H CN --
3-8 OH CH.sub.3 H CN --
3-9 OH CH.sub.3 CH.sub.2
H CN --
3-10 OH CH.sub.3 (CH.sub.2).sub.2
H CN --
3-11 OH (CH.sub.3).sub.2 CH
H CN --
3-12 OH CH.sub.3 (CH.sub.2).sub.3
H CN --
3-13 NH.sub.2 H CN OH --
3-14 NH.sub.2 CH.sub.3 CN OH --
3-15 NH.sub.2 CH.sub.3 CH.sub.2
CN OH --
3-16 NH.sub.2 CH.sub.3 (CH.sub.2).sub.2
CN OH --
3-17 NH.sub.2 (CH.sub.3).sub.2 CH
CN OH --
3-18 NH.sub.2 CH.sub.3 (CH.sub.2).sub.3
CN OH --
3-19 OH H CN OH --
3-20 OH CH.sub.3 CN OH --
3-21 OH CH.sub.3 CH.sub.2
CN OH --
3-22 OH CH.sub.3 (CH.sub.2).sub.2
CN OH --
3-23 OH (CH.sub.3).sub.2 CH
CN OH --
3-24 OH CH.sub.3 (CH.sub.2).sub.3
CN OH --
3-25 NH.sub.2 H CN H --
3-26 NH.sub.2 CH.sub.3 CN H --
3-27 NH.sub.2 CH.sub.3 CH.sub.2
CN H --
3-28 NH.sub.2 CH.sub.3 (CH.sub.2).sub.2
CN H --
3-29 NH.sub.2 (CH.sub.3).sub.2 CH
CN H --
3-30 NH.sub.2 CH.sub.3 (CH.sub.2).sub.3
CN H --
3-31 OH H CN H --
3-32 OH CH.sub.3 CN H --
3-33 OH CH.sub.3 CH.sub.2
CN H --
3-34 OH CH.sub.3 (CH.sub.2).sub.2
CN H --
3-35 OH (CH.sub.3).sub.2 CH
CN H --
3-36 OH CH.sub.3 (CH.sub.2).sub.3
CN H --
3-37 NH.sub.2 H OH CN --
3-38 NH.sub.2 CH.sub.3 OH CN --
3-39 NH.sub.2 CH.sub.3 CH.sub.2
OH CN --
3-40 NH.sub.2 CH.sub.3 (CH.sub.2).sub.2
OH CN --
3-41 NH.sub.2 (CH.sub.3).sub.2 CH
OH CN --
3-42 NH.sub.2 CH.sub.3 (CH.sub.2).sub.3
OH CN --
3-43 OH H OH CN --
3-44 OH CH.sub.3 OH CN --
3-45 OH CH.sub.3 CH.sub.2
OH CN --
3-46 OH CH.sub.3 (CH.sub.2).sub.2
OH CN --
3-47 OH (CH.sub.3).sub.2 CH
OH CN --
3-48 OH CH.sub.3 (CH.sub.2).sub.3
OH CN --
3-49 NHAc H H CN --
3-50 NHAc CH.sub.3 H CN --
3-51 NHAc CH.sub.3 CH.sub.2
H CN --
3-52 NHAc CH.sub.3 (CH.sub.2).sub.2
H CN --
3-53 NHAc (CH.sub.3).sub.2 CH
H CN --
3-54 NHAc CH.sub.3 (CH.sub.2).sub.3
H CN --
3-55 NHAc H CN OH --
3-56 NHAc CH.sub.3 CN OH --
3-57 NHAc CH.sub.3 CH.sub.2
CN OH --
3-58 NHAc CH.sub.3 (CH.sub.2).sub.2
CN OH --
3-59 NHAc (CH.sub.3).sub.2 CH
CN OH --
3-60 NHAc CH.sub.3 (CH.sub.2).sub.3
CN OH --
3-61 NHAc H CN H --
3-62 NHAc CH.sub.3 CN H --
3-63 NHAc CH.sub.3 CH.sub.2
CN H --
3-64 NHAc CH.sub.3 (CH.sub.2).sub.2
CN H --
3-65 NHAc (CH.sub.3).sub.2 CH
CN H --
3-66 NHAc CH.sub.3 (CH.sub.2).sub.3
CN H --
3-67 NHAc H OH CN --
3-68 NHAc CH.sub.3 OH CN --
3-69 NHAc CH.sub.3 CH.sub.2
OH CN --
3-70 NHAc CH.sub.3 (CH.sub.2).sub.2
OH CN --
3-71 NHAc (CH.sub.3).sub.2 CH
OH CN --
3-72 NHAc CH.sub.3 (CH.sub.2).sub.3
OH CN --
3-73 NHBz H H CN --
3-74 NHBz CH.sub.3 H CN --
3-75 NHBz CH.sub.3 CH.sub.2
H CN --
3-76 NHBz CH.sub.3 (CH.sub.2).sub.2
H CN --
3-77 NHBz (CH.sub.3).sub.2 CH
H CN --
3-78 NHBz CH.sub.3 (CH.sub.2).sub.3
H CN --
3-79 NHBz H CN OH --
3-80 NHBz CH.sub.3 CN OH --
3-81 NHBz CH.sub.3 CH.sub.2
CN OH --
3-82 NHBz CH.sub.3 (CH.sub.2).sub.2
CN OH --
3-83 NHBz (CH.sub.3).sub.2 CH
CN OH --
3-84 NHBz CH.sub.3 (CH.sub.2).sub.3
CN OH --
3-85 NHBz H CN H --
3-86 NHBz CH.sub.3 CN H --
3-87 NHBz CH.sub.3 CH.sub.2
CN H --
3-88 NHAc CH.sub.3 (CH.sub.2).sub.2
CN H --
3-89 NHBz (CH.sub.3).sub.2 CH
CN H --
3-90 NHBz CH.sub.3 (CH.sub.2).sub.3
CN H --
3-91 NHBz H OH CN --
3-92 NHBz CH.sub.3 OH CN --
3-93 NHBz CH.sub.3 CH.sub.2
OH CN --
3-94 NHBz CH.sub.3 (CH.sub.2).sub.2
OH CN --
3-95 NHBz (CH.sub.3).sub.2 CH
OH CN --
3-96 NHBz CH.sub.3 (CH.sub.2).sub.3
OH CN --
______________________________________
Among the above exemplary compounds, preferred are:
1-1, 1-2, 1-7, 1-8, 1-13, 1-14, 1-19, 1-20, 1-25, 1-26, 1-31, 1-32, 1-37,
1-38, 1-43, 1-44, 1-49, 1-50, 1-55, 1-56, 1-61, 1-62, 1-67, 1-68, 1-73,
1-77, 1-82, 1-83, 1-88, 1-89, 1-92, 1-97, 1-98, 1-103, 1-104, 2-1, 2- 2,
2- 7, 2- 8, 2-13, 2-14, 2-19, 2-20, 2-25, 2-26, 2-31, 2-32, 2-37, 2-38,
3-1, 3-2, 3-7, 3-8, 3-13, 3-14, 3-19, 3-20, 3-25, 3-26, 3-31, 3-32, 3-37,
3-38, 3-43, 3-44, 3-49, 3-50, 3-55, 3-56, 3-61, 3-62, 3-67, 3-68, 3-73,
3-74, 3-79, 3-80, 3-85, 3-86, 3-91 and 3-92.
Among the above exemplary compounds, more preferred are:
1-1, 1-2, 1-7, 1-8, 1-13, 1-14, 1-19, 1-20, 1-25, 1-26, 1-31, 1-32, 1-37,
1-38, 1-43, 1-44, 1-49, 1-50, 1-55, 1-56, 1-61, 1-62, 1-67, 1-68, 1-73,
1-77, 1-82, 1-83, 1-88, 1-89, 1-92, 1-97, 1-98, 1-103, 1-104, 2-1, 2-2,
2-7, 2-8, 2-13, 2-14, 2-19, 2-20, 2-25, 2-26, 2-31, 2-32, 2-37 and 2-38.
Among the above exemplary compounds, still more referred are:
1-1, 1-2, 1-7, 1-8, 1-13, 1-14, 1-19, 1-20, 1-25, 1-26, 1-31, 1-32, 1-37,
1-38, 1-43, 1-44, 1-49, 1-50, 1-55, 1-56, 1-61, 1-62, 1-67, 1-68, 2-1,
2-2, 2-7, 2- 8, 2-13 and 2-14.
Among the above exemplary compounds, most preferred are:
1-1, 1- 7, 1-13, 1-14, 1-19, 1-25, 1-31, 1-32, 1-37, 1-43, 1-49, 1-50,
1-55, 1-61, 1-67, 1-68, 2-1, 2- 7, 2-13 and 2-14.
##STR6##
##STR7##
##STR8##
##STR9##
Compounds (1) and (2) of the present invention can be prepared using uracil
or a 5-lower alkyluracil, a known compound (3), [M. Muraoka, A. Tanaka and
T. Ueda, Chem. Pharm. Bull., 18, 261 (1970)] following the reaction steps
shown in Reaction Schemes 1, 2, 3 and 4. In Schemes 1, 2, 3 and 4, R.sup.1
and R.sup.2 have the same meanings as defined above, R.sup.4a and R.sup.5a
together represent a group of the formula: --R.sup.6 R.sup.7
Si--O--SiR.sup.6' R.sup.7' --(wherein R.sup.6, R.sup.7, R.sup.6' and
R.sup.7' have the same meanings as defined above). R.sup.9 represents an
alkoxythiocarbonyl group having a C.sub.1 -C.sub.4 alkyl or an
aryloxythiocarbonyl group having a C.sub.6 -C.sub.10 aryl. The alkyl
having 1 to 4 carbon atoms includes methyl, ethyl propyl, butyl, etc., and
the aryl having 6 to 10 carbon atoms includes phenyl, naphthyl, etc.,
preferably methyl and phenyl, respectively. R.sup.10 represents a
triarylmethyl group wherein the aryl moiety may be substituted, whereas
the aryl moiety includes phenyl, naphthyl, etc., preferably phenyl. The
substituent for the aryl moiety includes an alkyl group having 1 to 4
carbon atoms such as methyl, ethyl, propyl and butyl, an alkoxy group
having 1 to 4 carbon atoms such as methoxy, ethoxy, propoxy and butoxy,
and an acyloxy group having 2 to 4 carbon atoms such as acetoxy, propyloxy
and butyryloxy, preferably methyl and methoxy group. X represents a
halogen atom, preferably chlorine or bromine. The respective reaction
steps will be explained below in detail.
Step 1
This step is for preparing Compound (4) by ribosylating Compound (3).
Ribosylation is generally carried out by methods customarily employed in
the art, for example, as follows: (i) A mercury salt of compound (3) to be
obtained by addition of an alcoholic solution of mercuric chloride to an
aqueous sodium hydroxide solution of compound (3) is reacted with a known
compound 2',3',5'-tri-O-benzoyl-D-ribosyl chloride in benzene. Sodium
methoxide is allowed to act on the resulting compound in methanol to
obtain Compound (4) [M. Muraoka, A. Tanaka and T. Ueda, Chem. Pharm.
Bull., 18, 261 (1970)] and
(ii) Compound (3) is reacted with trimethylsilyl chloride in benzene in the
presence of an organic amine such as triethylamine to obtain
bis(trimethylsilyl)uracil, which is reacted with
2',3',5'-tri-O-benzoyl-D-ribosyl chloride, followed by reaction of the
resulting compound with sodium methoxide in methanol to obtain Compound
(4) [T. Nishimura, B. Shimizu and I. Iwai, Chem. Pharm. Bull., 11, 1470
(1963)].
Step 2
This step is for preparing Compound (5) by converting the carbonyl moiety
at the 4-position of Compound (4) to an amino group.
The conversion to an amino group is generally carried out by methods
customarily employed in the art, for example, as follows:
(i) Hexamethyldisilazane and ammonium sulfate are allowed to act on
Compound (4) with heating in anhydrous formamide to obtain Compound (5)
[Compiled by Townsend and Tipson, Nucleic Acid Chemistry, 227 (1978)]
(ii) The hydroxyl groups at the 2'-, 3'- and 5'-positions of Compound (4)
are protected by acetylation or benzoylation. In chloroform containing no
alcohol, thionyl chloride and anhydrous dimethylformamide are acted on the
resulting compound, followed by treatment with a methanol solution of
ammonia to obtain Compound (5) [Compiled by Townsend and Tipson, Nucleic
Acid. Chemistry, 223 (1978)]
(iii) The hydroxyl groups at the 2'-, 3'- and 5'-positions of Compound (4)
are protected by acetylation or benzoylation, and diphosphorus
pentasulfide is acted thereon in pyridine to obtain a 4-thio compound. A
lower alkyl iodide such as methyl iodide and ethyl iodide and an alkali
metal hydroxide such as sodium hydroxide is acted on the resulting
compound to obtain a 4-alkylthio compound as an intermediate compound. The
4-alkylthio compound is further treated with a liquid ammonia to obtain
Compound (5) [J. J. Fox, N. Miller and I. Wenpen, Journal of Medicinal
Chemistry, 9, 101 (1966)].
Step 3
In this step, X--R.sup.6 R.sup.7 Si--O--SiR.sup.6' R.sup.7' --X is acted on
the 3'- and 5'-positions of Compound (4) and these positions are protected
at the same time to obtain Compound (5). This step is carried out by the
known method [M. J. Robins, J. S. Wilson, L. Sawyer and M. N. G. James,
Can. J. Chem., 61, 1911, (1983)].
As the solvent employable, there may preferably be mentioned a basic
solvent such as pyridine.
Reaction is carried out at a temperature of -10.degree. to 100.degree. C.,
preferably 0.degree. to 50.degree. C.
While the reaction time varies depending on the compound and reaction
temperature employed, it is usually from 1 hour to 30 hours, preferably 1
hour to 5 hours.
After completion of the reaction, for example, the solvent is distilled
off, and the reaction mixture is poured in water. The resulting mixture is
extracted with a water-immiscible solvent such as benzene, ether and ethyl
acetate and the solvent is distilled off from the extract to obtain a
compound. The thus obtained compound is used as such in the subsequent
step. If desired, the compound can be purified by isolation by means of
various chromatographic procedures or recrystallization.
Step 3'
This step is for acylating the amino group at the 4-position of Compound
(5) and for acting X--R.sup.6 R.sup.7 Si--O--SiR.sup.6' R.sup.7' --X on
the thus acylated compound to protect the 3'- and 5'-positions at the same
time whereby to obtain Compound (6). The 3'- and 5'-positions can be
protected in the same manner as in Step 3.
The acylation of the amino group at the 4-position is carried out by the
method generally employed in the art. For example, in the case of an
aliphatic acyl or aromatic acyl, the reactive derivative of the
corresponding carboxylic acid such as an acid halide or an acid anhydride
is allowed to react or the corresponding carboxylic acid is allowed to
react in the presence of a condensing agent: or in the case of
alkoxycarbonyl, alkenyloxycarbonyl or aralkyloxycarbonyl, a halogenoformic
acid ester having the corresponding alkoxy, alkenyloxy or aralkyloxy
group, or dialkyl dicarbonate, dialkenyl dicarbonate or diaralkyl
dicarbonate having the corresponding alkyl, alkenyl or aralkyl group is
allowed to react.
As the acid halide employable, there may be mentioned, for example, acid
chlorides and acid bromides.
As the condensing agent employable, there may be mentioned, for example,
N,N'-dicyclohexylcarbodiimide (DCC), 1,1'-oxalyldiimiazole,
2,2'-dipyridyldisulfide, N,N'-disuccinimidyl carbonate,
N,N'-bis(2-oxo-3-oxazolydinyl)-phosphinic chloride, N,N'-carbodiimidazole,
N,N'-disuccinimidyl oxalate (DSO), N,N'-diphthalimide oxalate (DPO),
N,N'-bis(norbornenylsuccinimidyl)oxalate (BNO), 1,1'-bis(benzotriazolyl)
oxalate (BBTO), 1,1'-bis(6-chlorobenzotriazolyl) oxalate (BCTO),
1,1'-bis(6-trifluoromethylbenzotriazolyl)oxalate (BTBO), etc.
The solvent employable is not particularly limited unless it inhibits the
reaction and includes aromatic hydrocarbons such as b | | |
