MEDICAMENTS CONTENANT DES 5-ALKYL-PYRIMIDINE NUCLEOSIDES, ET LEUR EMPLOI COMME AGENTS CYTOSTATIQUES ET VIROSTATIQUES

MEDICAMENTS CONTAINING 5-ALKYL-PYRIMIDINE NUCLEOSIDES AND USE AS CYTOSTATIC AND VIROSTATIC AGENTS

Abrégé anglais

ABSTRACT OF THE DISCLOSURE
5-Alkyl-pyrimidine nucleosides of the formula:
<IMG> ( I )
in which R represents alkyl having 2 to 10 carbon atoms, x represents hydrogen
or hydroxy and y represents a variety of functional carbonyl-containing groups
are disclosed for use in medicaments for the treatment of malignant diseases,
in immunosuppressive therapy, and as cytostatic and virostatic agents. They
may also be used for potentiating the action of 5-fluorouracil. Also disclosed
are medicaments containing a 5-alkyl-pyrimidine nucleoside of formula I,
either alone or in combination with 5-fluorouracil, in a pharmaceutically
acceptable carrier.

Revendications

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A composition for the treatment of malignant disease or for immunosupp-
ressive therapy, cytostatic and virostatic action, comprising an effective amount
of a 5-alkyl-pyrimidine nucleoside of the general formula I:
<IMG> (I)
where:
R = alkyl with 2-10 C-Atoms;
x = H or OH;
y = _?_R1,
<IMG>
<IMG>
where R1 = C1-C6-alkyl, straight-chain or branched, for example methyl,
ethyl, propyl, butyl, isobutyl, pentyl or hexyl;
<IMG>
<IMG> , where R2 = -NH2, -COOH,
n = 1-4,

-C-(CH2) -CN, where n = 1-4
<IMG> where Hal = F or Cl,
Ol o
( 2)n ~ where n = 1-4 and
A denotes a pyrimidine nucleoside of the Formula:
<IMG>
in which R and X have the meanings stated above,
in which the y-residues can be esterified if desired with the OH group in the 3'-
position instead of with the 5'-OH-group, together with a pharmaceutically compa-
tible carrier or diluent.
2. A composition according to claim 1, wherein a compound of formula I is
employed in which R is ethyl, isopropyl or isobutyl.
3. A composition according to claim 1 or 2, and also containing 5-fluoro-
uracil.

Description

' ^' 1 ' '':''" " '
:-; ll~S3
This invention relates to certain pharmacologically
active 5-alkyl-pyrimidine nucleosides and to medicaments containing
them, alone or in combination with 5-fluorouracil, as well as the
use of said medicaments for treatment of malignant diseases, in
immunosuppressive therapy, and as cytostatic and virostatic agents.
5-Fluorouracil is known as a cytostatically active
substance. According to present knowledge, it is converted in
the organism to fluorouracil riboside monophosphate and in major
part built into the RNA. Only a small fraction of the fluorouracil
riboside monophosphate is transformed into 5-fluorouracil deoxy-
riboside monophosphate by the action of the enzyme pyridine
nucleotide reductase and then phosphorylated into the corresonding
triphosphate. For cytostatic action, it is known that fluorouracil
deoxyriboside triphosphate is responsible. Namely, it is a strong
inhibitor of thymidilate kinase and thus inhibits DNA synthesis.
This process is schematically shown below.

- -
;; ~16~
~ ~ dT~lP-~ dTDP ~__dTTP --~DNS
O ~ N ~ ~
(FU = Fluorouracil) O O O ~ N
Nucleoside H2O3P-O-P-O-PI-O-cH2
phosphorylase OH OH V
U~03~ -O - H~C ~ F
I Reductase
H/ H2O3P-OH2C o
HO OH /
\~
RNS HO
The abbreviations;-are defined as follows:
d = deoxy
dTPM = d-thymidine monophosphate
dTDP = d~thymidine diphosphate
dTTP = d-thymidine triphosphate
DNA = d-ribonucleic aeid
The disadvantages of therapy with fluorouracil is
precisely that fluorouracil is mainly built into the RNA and
is available only in small amounts for conversion to the
cytostatically active compound, fluorouracil deoxyriboside
triphosphate.
To inc~ease the cytostatie effectiveness of 5~fluoro-
uracil, the latter is administered in combination ~ith
thymidine. Here thymine arises in the organism from the

: i~853
thymidine, but however leads to toxic byproducts, since it is
not excreted unchanged from the organ~sm but is decomposed
and thus wastes importar.t enz:ymes~ This.decomposition of
thymine is shown by the following reaction scheme:
HN~ ~CCH
N~
H
o
HN~ ~CHCH 3
OC~ ~CH2
H DHT
o
COH
H2N~ ~CHCH3
N~
H BUIB
o
COH
CHCH 3
CH2
H2N~ BAIB
The abbreviations are de~ined as follows:
DHT = dihydrothymine
BUIB = ~-ureido-isobutyric acid
B~IB = ~-amino~isobutyric acid
This decomposition of thymine is a heav~ additional
load for the organism,

iZtSS3
S~ARY OF:THE INVENTION
.. . .
It has now been surprisingly found that 5-alkyl-
pyrimidine nucleosides of the general for~ula I
o
~N~
N
O ~ (I)
y-O-C~4 o~}
H
OH x
where:
R = Alkyl with 2-10 C-Atoms;
x = H or OE;
o
y =--~--Rl
O O
--C--CH2--O--C--R
O O
10 - C -CH- O -C -O -R1,
C~I 3
where Rl = Cl-C6-Alkyl, straight-chain or branched, for
example Methyl, Ethyl, Propyl, Butyl, Isobutyl,
Pentyl or Hexyl, in particular Ethyl, Isopropyl
or Isobutyl;
O
y = -C ~
- C -(CH2)n ~ R2, where R2 = -NH2, ~COO~I,
n = 1-4,

~6ZF~S3
-5-
o
- C -(CH2)n- CN, where n = 1-4
O Hal
11 /
-C -C -Hal, where Hal = F or Cl,
~al
O O
il 11
-C -(CH2~n- C -A, where n = 1-4 and
A denotes a pyrimldine
nucleoside of Formula:
o
R
o~J
--OH2C~ o ~
HO X
in which R and Y, have the
meanings stated above,
where the y-residues can be esterified with the OH-group in
the 3'-position if desired, instead of with the 5'-OH group,
considerably increase the cytostatic action of fluorouracil~
Apart from this, they have a virostatic action.
Examples of suitable residues R are ethyl, propyl,
butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl residues,
which can be straight-chain or branched.
The invention, in one aspect, is directed to a method
for acco~plishing at least one of the following purposes,
treat~ent of malignant diseases, i~unosuppressive therapy,
cytostatic and virostatic action, which method comprises
administering to a mammal, in need of such treatment, an
effective amount of a 5-alkyl-pyrimidine nucleoside of the
general formula I as defined above, The compound may be
administered before, after or in combination with 5-fluorouracil,
to a mammal requiring fluorouracil treatment. In another aspect,

~B53.
--6--
the invention relates to a medicament containing a compound
of the formula I, alone or in combination with 5-~luorouracil,
in a pharmaceutically compatible carrier or diluent.
DETAILED DESCRIPTION
The compounds described here can ~e produced
analogously to the process of DE--OS 2,807,588, in which a
nucleoside of the general formula II:
\ ~
O ~ N~ II
H0
~3
R
where R is as above and R3 stands for H or a conventional
protective group, in particular for the acetyl or propionyl
residue, is reacted with a functional carbonyl derivative,
~7hich is derived from one of the a~ove~de~ined residues of
- formula y, in particular a halocarbonyl derivative of
formula y-Cl, in a basic medium at a temperature between
about 0C and room temperature.
As functional carbonyl derivative there can be
used a conventional, easily transesterifiable ester.
Pyridine, triethylamine, or dimethyl formamide can
be used as the base-~
The starting compounds of formula II can be prepared
according to DE-OS 1,620,185.
The medicament is characteri~ed in that it contains
at least one compound of general formula I in a conventional
pharmaceutical carrier, such as used with 5~fluorouracil,
and also if necessary other additivesO
The testing of the action of the compound according
to the invention for cytostatic effectiveness was performed
on Ehrlich ascites tumors and L1210 ~mouse leukemia~. The
survival period or the inhibition of the ascites tumor were
, ..

~ii21S~;~
-7~
taken as the measure for cytostatic effectiveness, The test
compol~nds were administered intraperitoneally or subcutaneously.
The results of these investigations are collected in
the following table:
TABLE
Tumor, Ehrlich Ascites ~ Beginning of Treatment 6 Days Post-
Inoculation, Application: suhcutaneous,
Substance Dose Tumor Surviving No~ of ani- Mouse
mg/kg wt,,g mice of 6 tumor or tu- Strain
mo~r below lg
.
Piv-~x-du20012.04 5 - BALB
Piv-Hx-du2003.20 4
+ Fu 5
Fu 514,43 5
Piv-ADU 20013,48 6
Control 12~84 5
Piv-Hx-du = 5'-pivaloyl-5-hexyl-deoxyuridine
Piv-ADU = 5'-pivaloyl-5-ethyl-deoxyuridine
FU = 5-fluorouracil
The data in the table show the effects on the already
developed tumors. Treatment was begun on the 6th day after
inoculation and continued until the 10th day (total of 5
treatments),
The combination Piv-~-du ~200 mg/kg) and FU (5 mg/
kg) led to the surprising result that the tumor weight was
reduced from 12.84 g to 3.2 g, although each component was
inef~ective on its own.
The administration of the substances according to
the invention can be effected orally or parentally in
combination with a conventional, pharmaceutically compatible
diluent or carrier, such as used with 5-fluorouracil, and
in fact can ~e administered before, at the time of, or after

~16~;3
--8--
the administration of the fluorouracil. One aspect of the
present invention is thus also a new medicament which contains
fluorouracil in combination with 5-alkyl-pyrimidine nucleo-
sides in a pharmaceutically compatible carrier or diluent.
Production Ex'ample
5-etnyl-2'-deoxyuridine-5~-O--pivaloate
A solution of 25,8 g ~0.1 moll of 5-ethyl-2~-deoxy~
uridine in 150 ml of dry pyridine is dropped slowly, with
stirring and cooling in an ice bath, into a solution of 12 g
~0.1 mol) of pivaloyl chloride in 80 ml of pyridine. The
reaction solution is stirred for 4 hours at room temperature
then the mixture is concentrated in vacuum and the residue is
taken up in methylene chloride. This solution is extracted
first with 1% aqueous sulfuric acid and then with 5% aqueous
sodium carbonate solution, The methylene chloride solution
is dried over sodium sulfate and then concentrated. The
residue is purified on a silica gel column, using chloroform/
methanol (98/2~. Thin layer homogeneous fractions are
collected and concentrated~ The desired product is obtained
in pure form, Yield 19.5 g. Melting point: 181C (after
temporary melting).
In the same way, there is obtained from 5n-hexyl-
2'-deoxyuridine, 5-n-hexyl-2'-deoxyuridine-5'-O-pivaloate
with melting point 143C, in 65% yield.
The other compounds used according to the invention
can be produced in an analogous manner.