AU603380B2 - Compounds useful in the synthesis of 1-aziridinoalkyl nitroimidazoles - Google Patents

Description

COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952-69 COMPLETE SPECIFICATION

(ORIGINA'L)

Class Application Number., Lodged: I nt. Class Complete Specification Lodged: Accepted: Published: PriCority:,

I

1~ ~fl t Ut4 .7 Related Art Name of Applicant: Address of Applicant: Actual Inventor: Address for Service: NATIONAL RESEARCH DEVELOPMENT CORPORATION 101 Newington Causeway, London SEl 6BU, England ISRAR AH-MED, GERALD EDWARD ADMAS, IAN JAMES STRATFORD and DAVID GIBSON EDWD. WATERS SONS, 50 QUEEN STREET, MELBOURNE, AUSTRALIA, 3000.

Complete Specification for the invention entitled.' OP. CHEMOTHERAPY The following statement is a full description of this invention, including the best method of performing it known to :,US P7 1. 1 la COMPOUNDS USEFUL IN THE SYNTHESIS OF 1-AZIRIDINOALKYL NITfRiOIMIDAZOLES 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.

The present invention provides intermediates some which are active in their own right to a compound of formula R R2

S-CH

2

(CHOH)

n

CH

2 SR4 N I in which formula:

H

1 represents hydrogen or an alkyl C,-C, .15 alkyl) group; I I,

R

2 -Rs represent hydrogen, alkyl C -C 6 alkyl), S aryl, aralkyl or alkaryl group; and n is 1 or 2.

In compounds I, the nitro group is typically located at the 2-position on the imidazole ring and When an alkyl group, e.g. a methyl group, is usually disposed at the 5-position. Generally, at least two of R 2

-R

5 are Shydrogen and preferably at least one of R -R 5 is an alkyl, e.g. a methyl, ethyl or isopropyl group or a benzyl group.

S 25 Compounds wherein the group -NO 2 is located at the- 2-position, R represents hydrogen, n is 1 and R, R, R j and R. represent hydrogen or R and R, represent methyl and R) and R 5 represent hydrogen or R and R 4 represent methyl c. and R 3 and R represent hydrogen are of particular interest.

The compounds are useful in increasing the sensitivity of tumour cells to radiation in radiotherapy and s also in potentiating or enhancing damage to tumours by chemotherapeutic agents.

3 z *0ot 2 2 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 of formula III preferably in a polar solvent such as an alcohol.

RI

II N-CH(CHOH) n- 1

CH

t C 05 In a second process within the scope of the present invention i it Ys for the production of the compound I, the compound of formula II is reacted with a compound of formula IIIA:- S III HNCRRCR R t 3 wherein X represents a halogen, typically chlorine or bromine, Spreferably in the presence of an acid acceptor e.g. an alkal 10 metal hydroxide.

In a third process within the scope of the present invention for the production of the compound I, a compound IV Iv CIA2 2CK R nCH2 t CC i- NC R te metal hydroxide.

I 0 In a third process within the scope of the present invention for the production of the compound I, a compound IV IV 'C 2 (CaOH) nCl 2

Y

I -C02 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 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

R,

V CH CH (CHOH) CII -N

\R

RR

C I t C VI 2 preferably under neutral or basic conditions.

a compound of formula VII:- R1 vi 7 ,cnH 2 (CHOH)nCH 2

NHCR

2

R

3

CR

4

CR

5

Z

S 2 wherein Z represents a halogen, typically bromine Sor chlorine, is cyclised by treatment with a base, typically an alkali metal hydroxide e.g. potassium or sodium Shydroxide. Compounds of formula VII exhibit radiotherapeutic activity.

I

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;-

NO;L

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 diluent.

The compound may be included in a dosage form such as a tablet or capsule, for example a capsule comprising known formulation components auch as one or more of those described in Example A of U.K.

Patent Application 2003154A. The compound may also be formulated 2or 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 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 (l-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea). The invention is illustrated by the following Examples:- Example 1 1-(2-Nitro-1-imidazolyl)-3-(1-aziridino)-2-propanol A mixture of l-(2,3-epoxypropyl)-2-nitroimidazole prepared by the method described by Beaman (Beaman Tautz W. and Duschinsky 1967; Studies in the Nitroimidazole Series, Antimicrobial Agents and Chemotherapy p. 520-530), (5.10 g, 0.03 mol) and aziridine (2.60 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- 1-imidazolyl)-3-(l-aziridino)-2-propanol (3.57 g, 56%, m.p. 119-1210C) Sc 15 as a pale yellow crystalline solid. Recrystallization causes the decomposition of the product.

Example 2 and 3 4j In the following Examples, WHT mice in which the MT tumour has been implanted subcutaneously are administered the compound of Example I intraperitoneally 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 Senhancement 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 (MISO) and the compound Ro-03-8799. The asterisks against the results from treatment with the latter compounds indicate that the tumours =treated in these cases are intramuscular.

C TABLE I Example 2 Radiosensitization MISO 8799 Compound I Administered dose C -12 0-28 0.3.

mmoles/kg 3&-r 4.3- 38- Enhancement ratio 1.3 1.3 1.7 Example 3 Chemosensitization (melphalan) MISO 8799 Compound I Administered dose 0.72 Enhancement ratio 1.7* 2.2* Administered dose 0.72 0.08 Enhancement ratio 1.9 c~c Example 4 1-(2-Nitro-l-imidazolyl)-3-(2-methyl-l-aziridino)-2-propanol In a manner analogous to that described in Example 1 there is obtained by reaction of 2-methyl aziridine with 1-(2,3-epoxypropyl)-2- 03 nitroimidazole after crystallization from ethanol-ether, 1-(2-nitro-1imidazolyl)-3-(2-methyl-1-aziridino)-2-propanol in the form of a pale yellow crystalline solid (3.06g, 45%, m.p. 109-111 0

CQ.

Example 1- (2-Nitro-1-imidazolyl) (2-ethyl-l-aziridimo) -2-propanol In a manner analogous to that described in Example 1 there is obtained by reaction of 2-ethylaziridine with 1-(2,3-epoxypropyl)-2nitroimidazole after crystallization from ethanol-ether at -70 C, 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 1-(2-Nitro-l-iinidazolyl) -3-(2-benzyl-l-azirid ino)-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 with 1-(2,3-epoxypropyl)-2nitroiinidazole after column chromatography using silica gel as adsorbent, 1-(2-nitro-1-imidazolyl)-3-(2-benzyl-l-aziridino)-2propanol in the form of a pale yellow gum, in 72% yield.

,7 II-m Example 7 1-(2-Nitro-1-imidazolyl)-3-(2,2-dimethyl-1-aziridino)-2-propanol In a manner analogous to that described in Example 1, there is obtained from reaction of 2,2-dimethyl aziridine with 1-(2,3epoxypropyl)-2-nitroimidazole after crystallization from ethanolether, 1-(2-nitro-1-imidazolyl)-3-(2,2-dimethyl-1-aziridino)-2propanol in the form of a pale yellow crystalline solid of melting I0 point 101-103oC; yield 78%.

Example 8 1-(2-Nitro-l-imidazolyl)-3-(2-phenyl-1-aziridinou) -2-propanol The compound is preparable by reaction of l-(2,3-epoxypropyl)-2nitroimidazole with 2-phenylaziridine (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-1-imidazolyl)-3-(2-isopropyl-1-aziridino)-2-propano1 The compound is preparable by reaction of 1-(2,3-epoxypropyl-2nitroimidazole with 2-isopropylaziridine (K.Ichimura, Bull. Chem.

Soc. Japan 43 1443-50 (1970)) in methanol following the method described in Example 1.

Example 1-(2-Nitro-1-imidazolyl)-4-(1-aziridino) or substituted aziridino)-2,3-butane-diol. (I,R 1 IH, n=2, R 2

R

5 =H or alkyl, aryl, aralkyl or alkaryl).

1-(2-nitroimidazolyl)-2-hydroxy-3,4-epoxy butane 3-(2-Nitroimidazolyl)-2-hydroxy-1-butene (11.83 gns, m.p. 90 92 C, prepared by refluxing a mixture of azomycin, 1,3-butadiene monoxide and anydrous potassium carbonate in ethanol for 5 hours) is stirred overnight in 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 dichloroethane 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 and ethanol the eluent. The product is crystallised from ethanol as a pale yellow solid of m.p. 134 136oC. Yield 33%.

8-9 -8- The compound from is reacted with an aziridine of formula III in methanol to yield the required compound of formula I.

Example 11 1-(2-methyl-5-nitro-I-imidazolyl)-3-(1-aziridino or substituted aziridino)-2-propanol. (I,R 1

CH

3 n=1,R 2

R

5 H alkyl, aryl, aralkyl or alkaryl) 1-(2,3-epoxypropyl)-2-methyl-5-nitroimidazole Hoffer and E. Grunberg, J. Med. Chem. 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-l-imidazolyl)-3-(1-aziridino or substituted aziridino)-2-propanol. (I,R 1

I=CH

3 n=1,R 2

R

5 =H alkyl, aryl, c aralkyl or alkaryl) The procedure of Example 11 is repeated using 1-(2,3-epoxypropyl)-2-methyl-4-nitroimidazole Suwinski, E. Suwinska, A J. Watras (1974) and M. Widel, Acta Pol. Pharm., 15(5), 529 (1975)) to yield the required compound of formula I.

Examples 13 and 14 1-(2-Nitro-1-imidazolyl)-3-(2,3-dimethyl-1-aziridino)-2-propanoI (meso and dl forms) A mixture of meso and dl forms of 2,3-dimethylaziridine, prepared by the method of Dickey described in J. Amer. Chem Soc.

Vol. 74, p 944 (1952), is reacted with 1-(2,3-epoxypropyl)-2nitroimidazole in a manner analogous to that described in Example 1, to yield a mixture of the meso and dl forms of 1-(2- 2 nitro--imidazolyl)-3-(2,3-dimethy-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 and ethanol the eluant. The meso form has m.p. 84-50 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.

N TABLE II Sensitisation and toxicity data on Compounds described in the Examples Therapeutic ratiod relative to Compound of Example 1 Example number Position of R NO 2 group n R R 3

R

4

R

5

C

1 .6/mol dm 3

LD

5 0 /mmol/kgb

H

H

H

H

H

H

H

H

H

2-Me 2-Me

H

Me PhCH 2 Et Me Ph Me(meso) Me(dl)

H

H

H

1.0 x 8 x 10- 4 10x 10 4 x 10 5 x 10 4 x 10 5 x 10 x 10- 4 x 10 4 0.61 c 0.58 0.58 1.25 1.25 0.41 0.80 1.18 1 1.2 0.73 2.56 2.56 0.52 0.44 1.49 9 H 2 1 Me CH Me, H H H 1.3 x 10 4 aConcentration required to achieve an enhancement ratio of bDrugs administered i.p. to 0 WHT mice.

cFor Compound of Example I in e CRCD1 mice LD50 0.71 mmol 0.54 mmol d 4 Higher value is more efficacious LD-- 10 Higher value is more efficacious.

1.6 in irradiated hypoxic V79 mammalian cells.

e/kg 'administered LD 5 0 0 0.87 mmole/kg administered e/kg i.p. LD10 0.71 mmole/kg 3 i.v.

DV X C1.

6 0.61 1.6

Claims (5)

1. A compound of formula II R 1 -CH 2 (CHOH), CH. CH 2 NO 2 in which formula R, represents hydrogen or an alkyl group; and n is I-af.

2. teat t 4,1« a, 4 2. A compound of formula V a 2 R L R 2 t1-R SV CH 2 H (CHOH) CH 2 -N -R "4 wherein R -R 5 represent hydrogen, alkyul aryl, taralkyl or alkaryl group; and n is 1 or 2

3. A compound of formula VII VI -CH 2 (CHOH)nCH 2 NHCR 2 R 3 CR

4 CR

5 Z VII NO2 I t, i 11 wherein R 1 represents hydrogen or an alkyl group; R 2 -R 5 represents hydrogen, alkyl aryl, aralkyl or alkaryl group; and z represents a haltogen. DATED this 7th day of March, 1990 NATIONAL RESEARCH DEVELOPMENT CORPORATION ''CC C C CC C C C 4 CC 4 C *1tt CC C C CC C C ~.CC L7'r 4 'C C v WATERMARK PATENT TRADEMARK ATTORNEYS, 290 Burwood Road, HAWTHORN. VIC. 3122 AUSTRAL IA LCG:KS~jl9.19 to~