NITRO-IMIDAZOLYLAZIRIDINOPROPANOLS

NITRO IMIDAZOLYL AZIRIDINO PROPANOLS

Abrégé anglais

ABSTRACT OF THE DISCLOSURE
A compound of formula I
<IMG>
in Which formula:
R1 represents hydrogen or an alkyl group;
R2-R5 represent hydrogen, alkyl aryl, aralkyl or alkaryl group; and
n is 1. The compounds are useful in the treatment of cancer patients
by radiotherapy or chemotherapy.

Revendications

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a compound of formula
I
<IMG>
in which:
R1 represents hydrogen or alkyl; and
R2, R3, R4 and R5 each represent hydrogen, alkyl, aryl,
alkaryl, or aralkyl;
which process comprises either:
(a) reacting a compound of the formula II with an aziridine com-
pound of formula III
<IMG> <IMG>
(II) (III)
- 11 -

in which R1, R2, R3, R4 and R5 are as defined above; or
(b) reacting a compound of the formula II as given above with a
compound of formula III-A
H2NCR2R3CR4R5-X III-A
in which R2, R3, R4 and R5 are as defined above and X represents
halogen; or
(c) reacting a compound of formula IV
<IMG> IV
in which R1 is as defined above and Y represents halogen with an
aziridine of formula III, as given above, or
(d) reacting a compound of formula V with a compound of formula
VI
<IMG> <IMG>
VI V
- 12 -

in which R1, R2, R3, R4, and R5 are as defined above; or
(e) cyclising a compound of formula VII
<IMG> VII
in which R1, R2, R3, R4 and R5 are as defined above and Z represents
halogen, by treatment with a base.
2. A process according to Claim 1 in which the nitro
group is located at the 2-position in the imidazole ring.
3. A process according to Claim 1, in which at least one
of R2-R5 is an alkyl or benzyl group.
4. A process according to claim 1, in which at least two
of R2, R3, R4 and R5 are C1-C6 alkyl groups.
5. A process according to claim 1, in which R1 represents
hydrogen.
- 13 -

6. A compound of the formula (I)
<IMG> (I)
in which
R1 represents hydrogen or alkyl; and
R2, R3, R4, and R5 each represent hydrogen, alkyl,
aryl, alkaryl, or aralkyl
7. A compound of the formula (Ia)
<IMG> (Ia)
wherein R1, R2, R3, R4, and R5 are as defined in claim 6.
8. A compound according to claim 6 wherein at least one
of R2 - R5 is an alkyl or benzyl group.
9. A compound according to claim 6 wherein at least two
of R2, R3, R4, and R5 are C1-C6 alkyl groups.
10. A compound according to claim 6 in which R1 represents
hydrogen.
- 14 -

11. A compound of the formula (I)
<IMG> (I)
in which R1 represents hydrogen or alkyl; and
R2, R3, R4, and R5 each represent hydrogen, alkyl,
aryl, alkaryl or aralkyl or a salt thereof.
12. A pharmaceutically acceptable salt of a compound of
formula (I) as defined in claim 11.
13. 1-(2-Nitro-1-imidazolyl)-3-(1-aziridino) -2-propanol.
14. 1-(2-Nitro-1-imidazolyl)-3-(2-methyl-1-aziridino)-2-
propanol.
15. 1-(2-Nitro-1-imidazolyl)-3-(2,2-dimethyl-1-aziridino)-
2-propanol.
16. 1-(2-Nitro-1-imidazolyl)-3-(2-isopropyl-1-aziridino)-
2-propanol.
17. 1-(2-Nitro-1-imidazolyl)-3-(2,3-dimethyl-1-aziridino)-
2-propanol.
18. A pharmaceutical composition which comprises a
compound of formula I as defined in claim 6 as active ingredient
in association with a pharmaceutically compatible diluent or
carrier.
- 15 -

-16-
19. A pharmaceutical composition which comprises a
compound of formula I as defined in claim 6 as active ingredient
in association with a chemotherapeutic agent, and, if required,
in association with a pharmaceutically acceptable diluent or
carrier.
20. A pharmaceutical composition which comprises a
compound of formula I as defined in claim 6 or a pharmaceutically
acceptable salt thereof as active ingredient in association with
a pharmaceutically compatible diluent or carrier.
21. A pharmaceutical composition according to claim 18 or
19 wherein said active ingredient is as defined in claim 7.
22. A pharmaceutical composition according to claim 18 or
19 wherein said active ingredient is as defined in claim 8.
23. A pharmaceutical composition according to claim 18 or
19 wherein said active ingredient is as defined in claim 9.
24. A pharmaceutical composition according to claim 18 or
19 wherein said active ingredient is as defined in claim 10.
25. A pharmaceutical composition according to claim 19,
wherein said chemotherapeutic agent is selected from melphalan,
cyclophosphamide, 5-fluorouracil and 1-(2-chloroethyl)-3-
cyclohexyl-1-nitrosourea.
26. A pharmaceutical composition according to claim 18,
19 or 25 wherein said diluent or carrier comprises an aqueous
saline solution.

27. A pharmaceutical composition according to claim 18,
19 or 25 wherein said active ingredient comprises 1-(2-nitro-1-
imidazolyl)-3-(1-aziridino)-2-propanol.
28. A pharmaceutical composition according to claim 18,
19 or 25 wherein said active ingredient comprises 1-(2-nitro-1-
imidazolyl)-3-(2-methyl-1-aziridino)-2-propanol.
29. A pharmaceutical composition according to claim 18,
19 or 25 wherein said active ingredient comprises 1-(2-nitro-1-
imidazolyl)-3-(2,2-dimethyl-1-aziridino)-2-propanol.
30. A pharmaceutical composition according to claim 18,
19 or 25 wherein said active ingredient comprises 1-(2-nitro-1-
imidazolyl)-3-(2-isopropyl-1-aziridino)-2-propanol.
31. A pharmaceutical composition according to claim 18,
19 or 25 wherein said active ingredient comprises meso-1-(2-nitro-
1-imidazolyl)-3-(2,3-dimethyl-1-aziridino)-2-propanol.
32. A process for preparing a pharmaceutical composition
comprising a compound of formula (I) as defined in claim 6 as
active ingredient which process comprises admixing said active
ingredient with at least one of a pharmaceutically acceptable
diluent or carrier and a chemotherapeutic agent.
- 17 -

Description

~25421g
23410-267
This invention relates to compounds useful in the
treatment of cancer patients by radiotherapy or chemotherapy, to a
process for the production of such compounds, to formulations for
administration and to methods of treating such patients. A
divisional application is directed to intermediates of the formula
VII (see below), useful in the preparation of such compounds.
Accordingly, the present invention comprises a compound
of formula I
N ~ N CH2(CHOH)nCH2-N
NO2 R5
in which formula:
R1 represents hydrogen or an alkyl (e.g. C1 - C6 alkyl)
group;
R2 ~ R5 represent hydrogen, alkyl (e.g. C1 - C6), aryl,
aralkyl or alkaryl group; and
n is 1.
In compounds I, the nitro group is ~ypically located at
the 2-position on the imidazole ring and R1, when an alkyl 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 alkyl, e.g. a methyl, ethyl or
isopropyl group or a benzyl group. Compounds wherein the group -
NO2 is located at the 2-position, R1 represents hydrogen, n is 1
1:~

~:~S42~9
23~ 267
and R2, R3, R4 and R5 represent hydrogen or R2 and R3 represent
methyl and R~ and R5 represent hydrogen or R2 and R4 represent
methyl and R3 and R5 represent hydrogen are of particular
interest.
The compounds are useful in inc~easing the sensitivity
of tumour cells to radiation in radiotherapy and also in
potentiating or enhancing damage to tumours 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

~L~25~L9
of formula III preferably in a polar solvent such as an alcohol.
Rl
II ~ N - CH2~CHOH)n_lCH C~2
~: NO2
I '2
/ - R3
III H N
\ - R4
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 H2NCR2R3CR4R5-X
wherein X represents a halogen, typically chlorine or bromine, 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
IV ~ NC112(CHOH)2CH2Y
N02
wherein Y represents a halogen, typically bromine or chlorine~ is reacted with
an aziridine of formula III, preferably in the presence of an acid acceptor
e.g. an alkali metal hydroxide.
In a fourth process witllin the scope of the present invelltion for
. . ,

~25~19
23~10-267
the production of the compound I, a compound V
V / 0 \ / _ R3
H2 CH(CHOH)n_l CH-N
~ R4
R5
is reacted with a compound of formula VI
~IRl
VI ~
N ~ NH
N02
preferably under neutral or basic conditions.
In a fifth alternative process within the scope of ~he
present invention for the production of the com~ound I, a compound
of formula VII:-
Rl
VII ~
N ~ H2(CHOH)nCH2NHCR2R3CR4CR5z
N02
wherein Z represen~s a halogen, ~ypically bromine or chlorine, iscycli~ed by treatment with a base, typically an alkali metal
hydroxide e.g. potassium or sodium hydroxide. These compounds of
formula VII are the sub~ect of a divisional application.

5~219
23~10-267
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:-
Rl
VIII /~\ / \
NCH2 (CHOH) CH--CH2
N02
3a~-!

~2~
Intermediate compounds of formula VIII also form part of the present
invention.
The compound I may be formulated in a malmer appropriate to the
treatment for which it is to be used by bringing it into association with a
pharmaceutically compatible carrier or cliluent. 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 U.K. Patent Application 2003154A. The compound may also be formulated
for intravenous administration e.g. in a saline drip solution.
IYhen 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 localised 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-propanol
A mixture of 1-(2,3-epoxypropyl)-2-nitroimidazole prepared by the
method described by Beamall (Beamall A.G., Tautz IY. and Duschinsky R., 1967;
Studies in thc Nitroimid.lzole Series, Alltilllicrobi.ll Agents and Chemotllerapy

~5~g
p. 520-530), (5.10 g, O.Q3 mol) and aziridine (2.60 g., 0.06 mol) in methanol
(70 ml) is heated under reflux for one hour. The reaction mixture is treated
with decolourising charcoal, refluxed 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 crystallise to give 1-(2-Nitro-l-
imidazolyl)-3-(1-aziridino)-2-propanol (3.57 g, 56%, m.p. 119 - 121C) as a
pale yellow crystalline solid. Recrystallization causes the decomposition of
the product.
Examples 2 and 3
In the following Examples, WHT mice in which the h~l tumour has been
implanted subcutaneously are administered the compound of Example 1 intra-
peritoneally 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 (~IIS0) and the com-
pound Ro-03-8799. The asterisks against the results from treatment with the
latter compounds indicate that the tumours treated in these cases are intra-
muscular.
TABLE I
E~ample ~
Radiosensitization
~IIS0 8799 Compound I
. . .
Administered dose
mmoles/kg 0.38 0.38 0.3S
Enhancement ratio 1.3 1.3 1.7

~5~
Example 3
Chemosensitization (melphalan)
MIS0 87999 Compound I
_ _ _ _
Administered dose mg/g 0.72 0.72
Enhancement ratio 1.7* 2.2*
. . _ _ . _ _ . _
Administered dose mg/g - 0.72 O.OS
Enhancement ratio - 1.9 3.0
.
Example 4
1-~2-Nitro-l-imidazolyl)-3-~2-methyl-1-aziridino)-2-propanol
In a manner analogous to that described in Example 1 there is ob-
tained 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%, m.p. 109 - 111C).
Example 5
1-(2-Nitro-l-imidazolyl)-3-~2-ethyl-1-aziridino)-2-propanol
In a manner analogous to that described in Example 1 there is ob-
tained by reaction of 2-ethyl aziridine with 1-~2,3-epoxypropyl)-2-nitro-
imidazole after crystallization from ethanol-ether at -70C, 1-(2-nitro-1-
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-1-aziridino)-2-prop~mol
. .
In a manner analogous to that described in Example 1, but using
equimolar amounts of reagents, there is obtained from reaction of 2-benzyl
aziridine with 1-~2,3-epoxypropyl)-2-nitroimidazole after column chromatography

~5~
using silica gel as adsorbent, l-(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-dimethyl-l-aziridino)-2-propanol
In a manner analogous to that described in Example 1, there is ob-
tained 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 meltin~ point 101 - 103C; yield 78%.
Example 8
1-(2-Nitro-l-imidazolyl)-3-~2-phenyl-l-aziridino)-2-propanol
The compound is preparable by reaction of 1-(2,3-epoxypropyl)-2-
nitroimidazole with 2-phenyl aziridine (~. Ichimura and M. Ohta, Bull. Chem.
Soc. 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-aziridino)-?-propanol
The compound is preparable by reaction of 1-~2,3-epoxypropyl)-2-
nitroimidazole with 2-isopropylaziridine ~. Ichimura, Bull. Chem. Soc. Japan
43 1443-50 (1970)) in methanol following the method described in Example 1.
Example 10
1-(2-Nitro-l-imidazolyl)-~ l-aziridino) or substituted aziridino)-2,3-butane-
diol- (I,Rl=H, n-2, R2 ~ R5=H or alkyl, aryl, aralkyl or alkaryl~.
_ _ .
~a) 1-(2-nitroimidazolyl)-2-hydroxy-3,4-epoxy butane
3-~2-Nitroimidazolyl)-2-hydro~y-1-butene ~11.83 gms, m.p. 90 - 92~C,
prepared by reflu~ing a mixture of azomycin, 1,3-butadiene monoxide and
anhydrous potassium carbonate in ethanol for 5 hours) is stirred overnight in

~5~
dichloroethane with m-chloroperbenzoic acid in the presence of 3-tert.-butyl-
4-hydroxy-5-methylphenyl sulfide and after stirring the reaction mixture is
refluxed for 1 hour. The mixture is washed with saturated sodium carbonate
solution and the aqueous phase was extracted with chloroform. The combined di-
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 eluent.
The product is crystallised from ethanol as a pale yellow solid of m.p. 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
1-(2-~lethyl-5-nitro-1-imidazolyl)-3-(1-aziridino or substituted aziridino)-2-
propanol. ~I, Rl=CH3, n=l, R2 ~ R5=H alkyl, aryl, aralkyl or alkaryl)
1-(2,3-Epoxypropyl)-2-methyl-5-nitroimidazole (~1. Hoffer and E.
Grunberg, J. ~led. Chem. 17, 1019 ~1974) is reacted with an aziridine of formula
III in methanol to yield the re~uired compound of formula I.
Example 12
1-~2-~1ethyl-4-nitro-1-imidazolyl)-3-~1-aziridlno or substituted aziridino)-2-
propanol. (I, Rl=CH3, n=l, R2 ~ R5=H alkyl, aryl, aralkyl or alkaryl)
The procedure of Example 11 is repeated using 1-(2,3-epoxypropyl)-
2-methyl-4-nitroimidazole (J. Suwinski, E. Suwinska, J. Watras (1974) and
~l. lYidel, Acta Pol. Pharm., 15 (5), 529 (1975)) to yield the required compound
of formula I.

~25~2~9
Examples 13 and 14
1-~2-Nitro-l-imidazolyl)-3-(2,3-dimethyl-l-aziridino)-~propanol (meso and
dl forms)
A mixture of meso and dl forms of 2,3-dimethyl aziridine, prepared
by the method of Dickey described in J. Amer. Chem. Soc. Vol. 74, p 944 ~1952),
is reacted with l-(2,3-epoxypropyl)-2-nitroimidazole in a manner analogous to
that described in Example 1, to yield a mixture of the meso and dl forms of
1-~2-nitro-1-imidazolyl?-3-~2,3-dimethyl-1-aziridino)-2-propanol ~isomers
reflect the presence of two chiral centres in the aziridinyl moiety). The meso
and dl forms are separated by column chromatography in which silica gel is the
stationary phase and a mixture of diethyl ether ~95%) and ethanol ~5%) the
eluent. The meso form has m.p. 84-5 and the dl form is isolated as a waxy
solid.
Sensitisation and toxicity data for compounds described in the aboye
Examples are set out in Table II.

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