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Patent 1260949 Summary

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(12) Patent: (11) CA 1260949
(21) Application Number: 587900
(54) English Title: NITROIMIDAZOLYL INTERMEDIATES USEFUL IN THE PREPARATION OF NITRO IMIDAZOLYL AZIRIDINO PROPANOLS
(54) French Title: PRODUITS INTERMEDIAIRES NITRO-IMIDAZOLYLIQUES UTILES POUR LA PREPARATION DE NITRO- IMIDAZOLYLAZIRIDINOPROPANOLS
Status: Expired
Bibliographic Data
(52) Canadian Patent Classification (CPC):
  • 260/315.2
(51) International Patent Classification (IPC):
  • C07D 233/91 (2006.01)
  • A61K 31/415 (2006.01)
  • C07D 403/06 (2006.01)
(72) Inventors :
  • AHMED, ISRAR (United Kingdom)
  • STRATFORD, IAN J. (United Kingdom)
  • ADAMS, GERALD E. (United Kingdom)
(73) Owners :
  • NATIONAL RESEARCH DEVELOPMENT CORPORATION (Not Available)
(71) Applicants :
(74) Agent: FETHERSTONHAUGH & CO.
(74) Associate agent:
(45) Issued: 1989-09-26
(22) Filed Date: 1984-05-01
Availability of licence: N/A
(25) Language of filing: English

Patent Cooperation Treaty (PCT): No

(30) Application Priority Data: None

Abstracts

English Abstract






ABSTRACT OF THE DISCLOSURE
A compound of formula (VII)


Image (VII)

wherein
R1 represents hydrogen or alkyl;
R2, R3, R4, and R5 each represent hydrogen, alkyl,
aryl, alkaryl or aralkyl;
Z represents halogen. These compounds are useful
as intermediates in the preparation of nitro imidazolyl aziridino
propanols useful in treatment of cancer patients by radiotherapy
or chemotherapy.


Claims

Note: Claims are shown in the official language in which they were submitted.


11
THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A compound of formula (VII)

Image (VII)

wherein
R1 represents hydrogen or alkyl;
R2, R3, R4, and R5 each represent hydrogen, alkyl,
aryl, alkaryl or aralkyl;
Z represents halogen.


2. A compound of formula (VII) as defined in claim 1
wherein the nitro group is at the 2-position in the imidazole
ring.


3. A compound of formula (VII) as defined in claim 1
wherein at least one of R2-R5 is an alkyl or benzyl group.


4. A compound of formula (VII) as defined in claim 1
wherein at least two of R2, R3, R4 and R5 are C1-C6 alkyl groups.


5. A compound of formula (VII) as defined in claim 1
wherein R1 represents hydrogen.



6. A compound of formula (VII) as defined in claim 1
wherein Z represents chlorine or bromine.


Description

Note: Descriptions are shown in the official language in which they were submitted.


23410-267D

~ his application is a divisional of application No.
453,230 filed on May 1st, 1984.
~ his invention relates to intermediates useful in the
preparation of 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.
Accordingly, the invention of the parent application
comprises a compound of formula I

Rl R2
I ~ ~ R3

1~ N N CH2(CHOH)nCH2-N ~ R4
NO2 R5

in which formula:
Rl represents hydrogen or an alkyl (e.g. Cl - C6
alkyl) group;
R2 ~ R5 represent hydrogen, alkyl (e.g. Cl - C6 alkyl),
~ryl, aralkyl or alkaryl group; and
n is 1
In compounds I, the nitro group is typically located
at the 2-position on the imidazole ring and Rl, 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 iso-
propyl group or a benzyl group. Compounds wherein the group -NO2
is located at the 2-position, Rl represents hydrogen, n is 1 and
R2, R3, R4 and R5 represent hydrogen or R2 and R3 represent methy]
and R4 and R5 represent hydrogen or R2 and R4 represent methyl


23410-267D


and R3 and R5 represent hydrogen are of particular interest.
The eompounds are useful in increasing -the sensitivity
of tumour eells to radiation in radiotherapy and also in
potentiating or enhancing damage to tumours by chemotherapeutic
agents.
A compound I may be produced from compound II by
~eatment thereof with an aziridine of formula III preferably in
a polar solvent such as an alcohol.
Rl
,p /'\
II ~ N - CH2(cHoH)n-lcH CH~
N02


/ R3
la III H N

\ - R4
R5

In a second proeess for the produetion of the com-
pound I, the eompound of formula II is reacted with a compound of
~ormula IIIA:-

IIIA 2 2 3CR4R5 Xwherein X represents a halogen, typically chlorine or bromine,
preferably in the presence of an acid aceeptor e.g. an alkali
metal hydroxide.
In a third process for the production of the eompound
I, a eompound IV




-- 2

23410-267D
Rl
,~,
IV N NCH2(CHOH)2CH2Y
~'
N02
wherein Y represents a halogen, typically bromine or chlorine, is
reacted with an aziridine of formula III, preferably in the pre-
sence of an acid acceptor e.g. an alkali metal hydroxide~
In a fourth process for the production of the
compound I, a compound V R2

/ O \ / R3
V CH2 ~ CH(CHOH)n_l CH2-N ~5 R4




is reacted with a compound of formula VI
R
VI ~

~ NH
N02
preferably under neutral or basic conditions.
In a fifth alternative process for the production of
the compound I, a compound of formula VII:-


Rl

VII ~ NCH2(CHH) CH2NHCR2R3CR4CR Z
N02
wherein Z represents a halogen, typically bromine or chlorine,is cyclised by treatment with a base, typically an alkali metal
hydroxide e.g. potassium or sodium hydroxide. These compounds


~2~
23410-267D
of formula VII are the subject of this divisional application.
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 ~ / \
N NcH2(cHoH)cH - - CH2
N02

The compound I may be formulated in a manner approp-
riate to the treatment for which it is to be used by bringing it
1~ into association with a pharmaceutically compatible carrier or
diluent. 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.
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 sen-
sitive 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


~6~
23410-267D



patient having a localised or metastatic cancer. Administration
of the compound I is generally carried out prior to or simul-
taneously with administration of the chemotherapeutic agent,
for example melphalan, cyclophosphamide, 5-fluorouracil or CCNU
(1-~2-chloroethyl) ~-cyclohexyl-l-nitrosourea).
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 Beaman (Beaman A.G., Tautz
W. and Duschinsky R., 1967; Studies in the Nitroimi.dazole Series,
Antimicrobial Agents and Chemotherapy




- 4a -

~ ~.'6#.9g~

p. 5~0-530), (S.10 g, 0.03 mol) and aziridine (2.60 g., 0.06 mol) in methanol
~70 ml) is heatccl 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-
imida~olyl)-3-(1-aziridino)-2-propanol (3.57 g, 56%, m.p. 119 - 121C) as a
~ale yello~Y crystalline solid. Recrystallizal:ion causes tlle decomllosition of
the product.
~amL~les ~ and 3
1~ In the following Examples, Ill~lT mice in which the ~1 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 ma~cimum enhancement is effected. The results of treatment with
rndiation and the chemotherapeutic drug are set out respectively in Tables I
and II together with comparison results using misonidazole (MIS0) and the com-
~ound 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~nm~le ~ -
R~diosensitization
MIS0 8799 Compound I

Administered dose
mmoles~kg 0.38 0.38 0.38

Enllancement ratio 1.3 1.3 1.7

~;26~

Example 3

Chem_sensitizatioll (melphalan)
hlIS0 87999 Compound I

Administered dose mg/g 0.72 0.72

Enhancement ratio 1.7* 2.2*
. . . _ . . . _ _ . _ _ _ _ _
Administered dose mg/g - 0.72 0.08

Enllancemcllt ratio - 1.9 3.0
_ _ . . . . .. .. . _
E~amplc ~
1-~2-Nitro-l-imidazolyl)-3-~2-methyl-1-aziridino)-2-propanol
1~ 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, 1-(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).
E~am~)le 5
1-(2-lNitr_-l-imidazolyl)-3-~2-ethyl-l-aziridino)-2-propanol
In a malmer analogous to that described in Example 1 there is ob-
~ained ~y reaction of 2-ethyl aziridine with 1-(2,3-epoxypropyl)-2-nitro-
in~idazole 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 challges to a yellow thick oil at room temperature:
yield 65~.
E~nmple 6
1-(2-Nitro-l-imidazolyl)-3-(2-benzyl-1-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 2-benzyl
aziridine witll 1-(2,3-epoxypropyl)-2-nitroimidazole after column chromatography


-- 6 --

using silica gel as adsorbent, 1-(2-nitro-l-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-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, 1-(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
l-(2-Nitro-l-imidazolyl)-3-(2-phenyl-1-aziridino)-2-propanol
The compound is preparable by reaction of 1-(2,3-epoxypropyl)-2-
nitroimidazole with 2-phenyl azi~idine (K. 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-l-aziridino)-2-propanol
The compound is preparable by reaction of 1-(2,3-epoxypropyl)-2-
nitroimidazole with 2-isopropylaziridine ~K. Ichimura, Bull. Chem. Soc. Japan
~0 43 1443-50 ~1970)) in methanol following the method described in Example 1.
Example 10
1-~2-Nitro-l-imidazolyl)-4-~1-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-hydroxy-1-butene (11.83 gms, m.p. 90 - 92C,
prepared by rcfluxing a mixture of azomycin, 1,3-butadicno monoxide ?nd
anhydrous potassium carbonate in ethanol for 5 hours) is stirred overnight in


~Z~ 9

dichloroethane with m-chloroperbenzoic acid in the presence o 3-tert -butyl-
4-hydroxy-5-methylpllellyl sulfide and after stirring thc reaction mixture is
refluxed for 1 hour. The mlxture is washed with saturated sodium carbonate
solution and the aqueous phase was extracted with chloroform. The combined di-
chloroetllane 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 ~]0%) the eluent.
The product is crystall.ised 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 metllanol to yield the required compound of fornlula I.
Example 11
1-(2-Metllyl-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 (M. Hoffer and E.
Grunberg, J. Med. Chem. 17, 1019 (1974) is reacted with an aziridine of formuia
III in methanol to yield the required compound of formula I.
Example 12
1-~2-Methyl-4-nitro-1-imidazol~1)-3-(1-aziridino_or substituted a~iridino)-2-
propanol. (I, Rl-CH3, n=l, R2 - R5=l-l 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
M. I~idel, Acta Pol. Pharm., 15 (5), 529 (1975)) to yield the required compound
o~ formula I.


J

~ 9


Examples 13 and 14
1-~2-Nitro-l-imidazolyl)-3-(2,3-dimethyl-1-aziridino)-2-propanol ~meso and
dl forms)
____
A mixture o~ 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 1-~2,3-epoxypropyl~-2-nitroimidazole in a manner analogous to
that described in Example l, to yield a mixture of the meso and dl forms o
l-(2-nitro-l-imidazolyl?-3-(2,3-dimethyl-l-aziridino)-2-propanol (isomers
reflec~ the presence of two chiral cen~res 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. 8~-5 and the dl form is isolated as a waxy
solid.
Sensitisation and toxicity data for compounds described in the above
Examples are set out in Table II.




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Administrative Status

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Administrative Status

Title Date
Forecasted Issue Date 1989-09-26
(22) Filed 1984-05-01
(45) Issued 1989-09-26
Expired 2006-09-26

Abandonment History

There is no abandonment history.

Payment History

Fee Type Anniversary Year Due Date Amount Paid Paid Date
Application Fee $0.00 1989-01-10
Owners on Record

Note: Records showing the ownership history in alphabetical order.

Current Owners on Record
NATIONAL RESEARCH DEVELOPMENT CORPORATION
Past Owners on Record
None
Past Owners that do not appear in the "Owners on Record" listing will appear in other documentation within the application.
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Document
Description 
Date
(yyyy-mm-dd) 
Number of pages   Size of Image (KB) 
Drawings 1993-09-09 1 16
Claims 1993-09-09 1 27
Abstract 1993-09-09 1 14
Cover Page 1993-09-09 1 18
Description 1993-09-09 11 322