Note: Descriptions are shown in the official language in which they were submitted.
Jo
23410-266
This invention relates to compounds useful in the treatment of
cancer patients by radiotherapy or chemotherapy to a process for the product
lion of such compounds, to formulations for administration and to methods of
treating such patients.
Accordingly the present invention comprises a compound of formula I
If R2
I \ / r R3
N N Cluck) SHEEHAN R
N02 'I
R5
in which formula:
Al represents hydrogen or an alkyd (e.g. Of - C6 alkyd) group;
R2 R5 represent hydrogen, alkyd (e.g. Of - C6 alkyd), aureole, aralkyl
or alkaryl group; and
n is 1 or 2.
; In compounds I, the vitro group is typically located at the 2-
position on the imidazole ring and Al, when an alkyd group, e.g. a methyl group,
is usually disposed at the 5-position. Generally, at least two of R2 R5 are
hydrogen and preferably at least one of R2 R5 is an alkyd, e.g. a methyl,
ethyl or isopropyl group or a bouncily group. Compounds wherein the group -NO
is located at the 2-position, Al represents hydrogen, n is 1 and R2, R3, I and
R5 represent hydrogen or R2 and R3 represent methyl and I and R5 represent
hydrogen or R2 and I represent methyl and R3 and R5 represent hydrogen are of
particular interest.
The compounds are useful in increasing the sensitivity of tumor
cells to radiation in radiotherapy and also in potentiating or enhancing damage
to tumors by chemotherapeutic agents.
A compound I may be produced, in accordance with a further aspect
of the present invention from compound II by treatment thereof with an aziridine
. .
r I
of formula III preferably in a polar solvent such as an alcohol.
Al
I I
II N - CH2~cHOll)n-lcll SHEA
N02 R2
III H N
I
R5
In a second process within the scope of the present invention for
the production of the compound I, the compound of formula II is reacted with a
compound of formula IIIA:-
IIIA H2NCR2R3C'~R5-X
wherein X represents a halogen, typically chlorine or bromide, preferably in
the presence of an acid acceptor e.g. an alkali metal hydroxide.
In a third process within the scope of the present invention for
the production of the compound I, a compound IV
I,
; IV NCH2(CHOH)2CH2Y
N02
wherein Y represents a halogen, typically bromide or chlorine, is reacted with
an a~iridine of formula III, preferably in the presence of an acid acceptor
e.g. an alkali metal hydroxide.
In a fourth process within the scope of the present invention for
the production of the compound I, a compound V
/ \ 3
V SUE CH(CHOH)n-l SHEEHAN
\ R4
R5
is reacted with a compound of formula VI
R
I
VI N' huh
N02
preferably under neutral or basic conditions.
In a fifth alternative process within the scope of the present
invention for the production of the compound I, a compound of formula VII:-
Al
VII NCE12(CEIOH) CE12NHCR2R3CR4CR5Z
N02
wherein Z represents a halogen, typically bromide or chlorine, is cyclised by
treatment with a base, typically an alkali metal hydroxide e.g. potassium or
sodium hydroxide.
The above alternative processes are typically conducted in a polar solvent such as an alcohol.
When n is 2, compound I may be prepared by reaction of a compound
of formula VIII with an aziridine of formula III suitably in a polar solvent
such as methanol:-
I I
VIII NCH2~CHOH)CH - SHEA
N02
-- 3 --
.,
I
Intermediate compounds of formula VIII also form part of the present
invention.
The compound I may be formulated in a manner appropriate to the
treatment for which it is to be used by bringing it into association with a
pharmaceutically compatible carrier or delineate. The compound may be included
in a dosage form such as a tablet or capsule, for example a capsule comprising
known formulation components such as one or more of those described in Example
A of US Patent Application AYE. The compound may also be formulated
for intravenous administration e.g. in a saline drip solution.
When employed as a radiation sensitizing agent, in accordance with
a further aspect of the present invention, the compound I is administered to
a patient having a radiation sensitive cancer prior to irradiation of said
cancer.
The compound I may, however, in yet a further aspect of the present
invention be employed for chemopotentiation of a chemotherapeutic agent by
administration of the compound I to a patient having a localized or metastatic
cancer. Administration of the compound I is generally carried out prior to or
simultaneously with administration of the chemotherapeutic agent, for example
melphalan, cyclophosphamide, 5-fluorouracil or CCNU (1-~2-chloroethyl)-3-
cyclohexyl-l-nitrosourea).
The invention is illustrated by the following Examples:-
Example 1
1-(2-Nitro-l-imidazolyl)-3-~1-aziridino)-2-propanoof
A mixture of 1-(2,3-epoxypropyl)-2-nitroimidazole prepared by the
method described by Berman IBeaman AGO., Taut W. and Duschinsky R., 1967;
Studies in the Nitroimidazole Series, Antimicrobial Agents and Chemotherapy
I
p. 520-530), ~5.10 g, 0.03 molt and aziridine (2.60 g., 0.06 molt in methanol
(70 ml) is heated under reflex for one hour. The reaction mixture is treated
with decolourising charcoal reflexed for 5 minutes and filtered. The solvent
is removed under reduced pressure to a yellow residue, which is dissolved in a
minimum quantity of ethanol and allowed to crystallize to give neutral-
imidazolyl)-3-(1-aziridino)-2-propanol (3.57 go 56%J mop. 119 - 121C) as a
pale yellow crystalline solid. Recrystallization causes the decomposition of
the product.
Examples 2 and 3
In the following Examples WRIT mice in which the MIX tumor has been
implanted subcutaneously are administered the compound of Example 1 intro-
peritoneal before treatment with radiation or with the chemotherapeutic agent
melphalan. The time before such treatment at which the drug is administered
is such that maximum enhancement is effected. The results of treatment with
radiation and the chemotherapeutic drug are set out respectively in Tables I
and II together with comparison results using misonidazole (MIST) and the come
pound Roy. The asterisks against the results from treatment with the
latter compounds indicate that the tumors treated in these cases are intro-
muscular.
TABLE I
Example 2
P~adiosensitization
MIST 8799 Compound I
Administered dose
mmoles/kg 0.38 0.38 0.38
Enhancement ratio 1.3 1.3 1.7
I
sample 3
Chemosensitization (mellhalan)
MIST 87999 Compound I
_ _ _ _
Administered dose mug 0.72 0.72
Enhancement ratio 1.7* 2.2*
-
Administered dose mug - 0.72 0.08
Enhancement ratio - 1.9 3.0
Example 4
1-(2-Nitro-l-imidazolyl)-3-(2-methyl-]-aziridino)--2-propanol
. _ _
In a manner analogous to -that described in Example 1 there is ox-
twined by reaction of 2-methyl aziridine with 1-(2,3-epoxypropyl)-2-nitro-
imidazole after crystallization from ethanol-ether, l-(2-nitro-1-imidazolyl)-
3-(2-methyl-1-aziridino)-2-propanol in the form of a pale yellow crystalline
solid (3.06g, 45%, mop. 109 - 111C).
Example 5
1-(2-Nitro-l-imidazolyl)-3-(2-ethyl-1-aziridino)-22-propanol
In a manner analogous to that described in Example 1 there is ox-
twined by reaction of 2-ethyl aziridine with 1-(2,3-epoxypropyl)-2-nitro-
imidazole after crystallization from ethanol-ether at -70C, nutria-
imidazolyl)-3-(2-ethyl-1-aziridino)-2-propanol in the form of a pale yellow
crystalline solid which changes to a yellow thick oil at room temperature:
yield 65%.
Example 6
1-(2-Nitro-l-imidazolyl)-3-(2-benzyl-l-aziridino)--2-propanol
In a manner analogous to -that described in Example 1, but using
equimolar amounts of reagents, there is obtained from reaction of bouncily
aziridine with 1-(2,3-epoxypropyl)-2-nitroimidazole after column chromatography
- 6 -
., .
SLY
using silica gel as adsorbent,1-(2-nitro-1-imidazolyl)-3-~2-benzyl-1-aziridino)--
2-propanol in the form of a pale yellow gum, in 72% yield.
example 7
1-(2-Nitro-l-imidazole)-3-(2,2-dimethyl-1-aziridinno)-2-propanol
.
In a manner analogous to that described in Example 1, there is ox-
twined from reaction of 2,2-dimethyl aziridine with 1-~2,3-epoxypropyl)-2-
nitroimidazole after crystallization from ethanol-ether, l-(2-nitro-1-imida-
zolyl)-3-~2,2-dimethyl-1-aziridino)-2-propanol in the form of a pale yellow
crystalline solid of melting point 101 - 103C; yield 78%.
Example 8
1-(2-Nitro-l-imidazolyl)-3-(2-phenyl-1-aziridino)--2-propanol
The compound is prepayable by reaction of 1-(2,3-epoxypropyl)-2-
nitroimidazole with phenol aziridine (K. Ichimura and M. Ought, Bull. Chum.
Sock Japan, 43 (5) 1443-50 (1970)) in methanol, following the method described
in Example 1.
Example 9
1-(2-Nitro-l-imidazolyl)-3-(2-isopropyl-1-aziridinno)-2-propanol
The compound is prepayable by reaction of 1-~2,3-epoxypropyl)-2-
nitroimidazole with 2-isopropylaziridine (K. Ichimura, Bull. Chum. Sock Japan
_ 1443-50 ~1970)) in methanol following the method described in Example 1.
1-(2-Nitro-l-imidazolyl)-4-(1-aziridino) or substituted aziridino)-2,3-butane-
dill. (I,Rl=H~ n-2, R2 R5=H or alkyd, aureole, aralkyl or alkaryl).
-
pa) 1-(2-nitroimidazolyl)-2-hydroxy-3,4-epoxy butane
3-(2-Nitroimidazolyl)-2-hydroxy-1-butene (11.83 gyms, mop. 90 - 92C,
prepared by refluxing a mixture of azomycin, 1,3-butadiene monoxide and
an hydrous potassium carbonate in ethanol for 5 hours) is stirred overnight in
31.~7~7;2~
dichloroethane with m-chloroperbenzoic acid in the presence of 3-tert.-butyl-
4-hydroxy-5-methylphenyl sulfide and after stirring the reaction mixture is
reflexed for 1 hour. The mixture is washed with saturated sodium carbonate
solution and the aqueous phase was extracted with chloroform. The combined dip
chloroethane and chloroform extracts are concentrated to a small volume and the
product is purified by column chromatography, in which silica gel is the
stationary phase and a mixture of chloroform (90%) and ethanol (10%) the fluent.
The product is crystallized from ethanol as a pale yellow solid of mop. 134 -
136C. Yield 33%.
(b) The compound from (a) is reacted with an aziridine of formula
III in methanol to yield the required compound of formula I.
Example 11
l-(2-Methyl-5-nitro-l-imidazolyl)-3-(l-aziridino or substituted aziridino)-2-
propanol (I, Rl=CH3, nil, R2 R5=H alkyd, aureole, aralkyl or alkaryl)
1-(2,3-Epoxypropyl)-2-methyl-5-nitroimidazole (M. Holler and E.
Greenberg, J. Med. Chum. 17, 1019 ~1974) is reacted with an aziridine of formula
III in methanol to yield the required compound of formula I.
Example 12
1-(2-Methyl-4-nitro-1-imidazolyl)-3-(1-aziridino or substituted aziridino)-2-
; 20 propanol. (I, Rl=CH3, nil, R2 R5=H alkyd, aureole, aralkyl or alkaryl)
The procedure of Example 11 is repeated using 1-(2,3-epoxypropyl)-
2-methyl-4-nitroimidazole (J. Cenozoic, E. Cenozoic, J. Waters (1974) and
M. Widely Act Pot. Harm., 15 (5), 529 (1975)) to yield the required compound
of formula I.
E my 13 and 14
_(2-Nitro-1-imidazolyl)-3-(2,3-dimethyl-1-aziridinno)-2-propanol (mess and_
do forms)
A mixture of mess and do forms of 2,3-dimethyl aziridine, prepared
by the method of Dickeys described in J. Amer. Chum. Sock Vol. 74, p 944 (1952),
is reacted with 1-(2,3-epoxypropyl)-2-nitroimidazole in a manner analogous to
that described in Example 1, to yield a mixture of the mess and do forms of
1-(2-nitro-1-imidazolyl)-3-(2,3-dimethyl-1-aziridiino)-2-propanol (isomers
reflect the presence of two choral centers in the aziridinyl moiety). The mess
and do forms are separated by column chromatography in which silica gel is the
stationary phase and a mixture of deathly ether (95%) and ethanol (5%) the
fluent. The mess form has mop. 84-5 and the do form is isolated as a waxy
solid.
Sensitization and toxicity data for compounds described in the above
Examples are set out in Table II.
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