CA1227211A - Nitro imidazolyl aziridino propanols - Google Patents
Nitro imidazolyl aziridino propanolsInfo
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- CA1227211A CA1227211A CA000453229A CA453229A CA1227211A CA 1227211 A CA1227211 A CA 1227211A CA 000453229 A CA000453229 A CA 000453229A CA 453229 A CA453229 A CA 453229A CA 1227211 A CA1227211 A CA 1227211A
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Abstract
ABSTRACT
A compound of formula I
in which formula:
R1 represents hydrogen or an alkyl group;
R2 - R5 represent hydrogen, alkyl, aryl, aralkyl or alkaryl group;
and n is 2. The compounds are useful in the treatment of cancer patients by radiotherapy or chemotherapy.
A compound of formula I
in which formula:
R1 represents hydrogen or an alkyl group;
R2 - R5 represent hydrogen, alkyl, aryl, aralkyl or alkaryl group;
and n is 2. The compounds are useful in the treatment of cancer patients by radiotherapy or chemotherapy.
Description
Jo 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
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
III H N
I
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
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 is reacted with a compound of formula VI
R
I
VI N' huh 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
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
., 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 ., .
SLY
using silica gel as adsorbent,1-(2-nitro-1-imidazolyl)-3-~2-benzyl-1-aziridino)--
Accordingly the present invention comprises a compound of formula I
If R2 I \ / r R3 N N Cluck) SHEEHAN R
N02 'I
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
III H N
I
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
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 is reacted with a compound of formula VI
R
I
VI N' huh 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
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
., 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 ., .
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
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-
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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4 Do ED N C:
O I No` Ill r .
I Al r-l 0~1 N O O I I 111 Jo $ En v 4J
I X
i 4 I I I
I r-l O E
m E it m m us o m o o 4) O UP I I N N m Jo o I
I Us O o o r1 I 0 0 I
a v Jo I I .
pa v .1 O O O O O o Ox O o pa C4 O 1 . I r-l I:
U) X X X X X X X X X X .
o I at I m I m m ED X
H 111 b Hi I; m I I I
En 3 Jo O O
~:~' m I o $ N O C u I: No I 4 æ I: a) æ JO .
, V C. o 1 r-l N I
. h N N N N N N N 4 or N 0 I 3 0 N 4) P; N N 3: X
at pa a 1~
X I: D I I m o N Q ' {
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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I Us O o o r1 I 0 0 I
a v Jo I I .
pa v .1 O O O O O o Ox O o pa C4 O 1 . I r-l I:
U) X X X X X X X X X X .
o I at I m I m m ED X
H 111 b Hi I; m I I I
En 3 Jo O O
~:~' m I o $ N O C u I: No I 4 æ I: a) æ JO .
, V C. o 1 r-l N I
. h N N N N N N N 4 or N 0 I 3 0 N 4) P; N N 3: X
at pa a 1~
X I: D I I m o N Q ' {
Claims (13)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a compound of formula I, in which formula:
R1 represents hydrogen or alkyl; and R2, R3, R4 and R5 each represent hydrogen, alkyl, aryl, aralkyl or alkaryl;
which process comprises either (a) reacting a compound of the formula II with an azi?idine com-pound of formula III, II III
in which R1, R2, R3, R4 and R5 are as defined above, in a polar solvent; or (b) reacting a compound of formula II, as given above, with a compound of formula IIIA
in which R2, R3, R4 and R5 are as defined above and X represents halogen , in a polar solvent and in the presence of an acid accep-tor; or (c) reacting a compound of the formula IV
IV
in which R1 is defined above and Y represents halogen, with an aziridine of formula III, as given above, in a polar solvent and in the presence of an acid acceptor; or (d) reacting a compound of the formula V with a compound of formu-la VI
V VI
in which R1, R2, R3, R4 and R5 are as defined above in a polar solvent; or (e) cyclizing a compound of formula VII
VII
in which R1, R2, R3, R4 and R5, are as defined above and Z repre-sents halogen, by treatment with a base.
R1 represents hydrogen or alkyl; and R2, R3, R4 and R5 each represent hydrogen, alkyl, aryl, aralkyl or alkaryl;
which process comprises either (a) reacting a compound of the formula II with an azi?idine com-pound of formula III, II III
in which R1, R2, R3, R4 and R5 are as defined above, in a polar solvent; or (b) reacting a compound of formula II, as given above, with a compound of formula IIIA
in which R2, R3, R4 and R5 are as defined above and X represents halogen , in a polar solvent and in the presence of an acid accep-tor; or (c) reacting a compound of the formula IV
IV
in which R1 is defined above and Y represents halogen, with an aziridine of formula III, as given above, in a polar solvent and in the presence of an acid acceptor; or (d) reacting a compound of the formula V with a compound of formu-la VI
V VI
in which R1, R2, R3, R4 and R5 are as defined above in a polar solvent; or (e) cyclizing a compound of formula VII
VII
in which R1, R2, R3, R4 and R5, are as defined above and Z repre-sents halogen, by treatment with a base.
2. A compound of the formula I, as defined in claim 1, whenever prepared by a process according to claim 1, or by an obvious chemical equivalent thereof.
3. A process according to claim 1 in which a halogen re-presented by X, Y, or Z is chosen from chlorine or bromine.
4. A process according to claim 1 in which the polar sol-vent is an alkanol.
5. A process according to claim 4 in which the solvent is methanol or ethanol.
6. A process according to claim 1 in which the acid accep-tor is an alkali metal hydroxide.
7. A process according to claim 6 in which the alkali metal hydroxide is sodium or potassium hydroxide.
8. A process according to claim 1 wherein the nitro group is located in the 2-position of the imidazole ring.
9. A compound of the formula I as defined in claim 1 wherein the nitro group is in the 2-position of the imidazole ring whenever prepared by the process of claim 8, or by an abvious chemi-cal equivalent thereof.
10. A process according to claim 1 in which at least one of R2, R3, R4 or R5 is an alkyl or benzyl group.
11. A compound of the formula I as defined in claim 1 where-in at least one of R2, R3, R4 or R5 is an alkyl or benzyl group, whenever prepared by the process of claim 10 or by an obvious chemi-cal equivalent thereof.
12. A process according to claim 1 in which at least two of R2, R3, R4 or R5 are C1-C6 alkyl groups.
13. A compound of the formula I as defined in claim 1 wherein at least two of R2, R3, R4 or R5 are C1-C6 alkyl groups, whenever prepared by the process of claim 12 or by an obvious chemical equivalent thereof.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000453229A CA1227211A (en) | 1982-05-27 | 1984-05-01 | Nitro imidazolyl aziridino propanols |
| AU78669/87A AU603380B2 (en) | 1982-05-27 | 1987-09-18 | Compounds useful in the synthesis of 1-aziridinoalkyl nitroimidazoles |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8215545 | 1982-05-27 | ||
| CA000453229A CA1227211A (en) | 1982-05-27 | 1984-05-01 | Nitro imidazolyl aziridino propanols |
| AU78669/87A AU603380B2 (en) | 1982-05-27 | 1987-09-18 | Compounds useful in the synthesis of 1-aziridinoalkyl nitroimidazoles |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1227211A true CA1227211A (en) | 1987-09-22 |
Family
ID=36915760
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000453229A Expired CA1227211A (en) | 1982-05-27 | 1984-05-01 | Nitro imidazolyl aziridino propanols |
Country Status (2)
| Country | Link |
|---|---|
| AU (1) | AU603380B2 (en) |
| CA (1) | CA1227211A (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1329206C (en) * | 1987-06-10 | 1994-05-03 | Tsutomu Kagiya | Fluorine-containing nitroazole derivatives and radiosensitizer comprising the same |
| ES2080726T3 (en) * | 1987-12-04 | 1996-02-16 | British Tech Group | NITROSUSSTITUTED AROMATIC OR HETEROAROMATIC COMPOUNDS FOR USE IN THE TREATMENT OF CANCER. |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IE47132B1 (en) * | 1977-08-19 | 1983-12-28 | Roche Products Ltd | Novel nitroimidazoles and pharmaceutical preparations containing these as well as their manufacture |
-
1984
- 1984-05-01 CA CA000453229A patent/CA1227211A/en not_active Expired
-
1987
- 1987-09-18 AU AU78669/87A patent/AU603380B2/en not_active Ceased
Also Published As
| Publication number | Publication date |
|---|---|
| AU7866987A (en) | 1987-12-24 |
| AU603380B2 (en) | 1990-11-15 |
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