GB2123816A - Nitrolmidazole derivatives - Google Patents

Nitrolmidazole derivatives Download PDF

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Publication number
GB2123816A
GB2123816A GB08314696A GB8314696A GB2123816A GB 2123816 A GB2123816 A GB 2123816A GB 08314696 A GB08314696 A GB 08314696A GB 8314696 A GB8314696 A GB 8314696A GB 2123816 A GB2123816 A GB 2123816A
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compound
formula
nitro
aziridino
propanol
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GB8314696D0 (en
GB2123816B (en
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Gerald Edward Adams
Israr Ahmed
David Gibson
Ian James Stratford
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National Research Development Corp UK
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National Research Development Corp UK
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/91—Nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Abstract

A compound of formula I <IMAGE> I in which formula: R1 represents hydrogen or an alkyl group; R2-R5 represent hydrogen, alkyl aryl, aralkyl or alkaryl group; and n is 1.

Description

1 GB 2 123 816 A 1
SPECIFICATION Improvements relating to compounds useful in radiotherapy or chemotherapy
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 5 and to methods of treating such patients.
Accordingly, the present invention comprises a compound of formula 1 R1 / 2 R3 N N CH2 (CHOH)n CH2 -N m \\ - R4 N02. R5 in which formula:
1 R, represents hydrogen or an alkyl (e.g. Cl-C, alkyl) group; F127-13., represent hydrogen, alkyl (e.g. Cl-C, alkyl), ary], aralkyl or alkaryl group; and n is 1 or 2.
In compounds 1, the nitro group is typically located at the 2-position on the imidazole ring and R,, when an alkyl group, e.g. a methyl group, is usually disposed at the 5-position. Generally, at least two of R,,--R, are hydrogen and preferably at least one of R--Rr, is an alkyl, e.g. a methyl, ethyl or isopropyl group or a benzyl group. Compounds wherein the group -N02'S located at the 2-position, R, represents hydrogen, n is 1 and R2, R3, R4 and R. represent hydrogen or R2 and R, represent methyl and R4 and R, represent hydrogen or R2 and R4 represent methyl and R3 and R, represent hydrogen are of particular interest.
The compounds are useful in increasing the sensitivity of tumour cells to radiation in radiotherapy and also in potentiating or enhancing damage to tumours by chemotherapeutic agents.
A compound 1 may be produced, in accordance with a further aspect of the present invention from compound 11 by treatment thereof with an aziridine of formula Ill preferably in a polar solvent such as an alcohol.
l 1- 1..10\ N 1 N"2("0')n-l M-M2 N02 R2 t' R3 HN R4 RS Ill In a second process within the scope of the present invention for the production of the compound 1, the compound of formula 11 is reacted with a compound of formula IIIA:- H2NCR2R3CR4Rg--X IIIA wherein X represents a halogen, typically chlorine or bromine, preferably in the presence of an acid 30 acceptor e.g. an alkali metal hydroxide.
In a third process within the scope of the present invention for the production of the compound 1, a compound W R1 N N CH2 (CHOH)n W2Y H02 IV 2 GB 2 123 816 A 2 wherein Y represents a halogen, typically bromine or chlorine, is reacted with an aziridine of formula Ill, 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 1, a compound V 2 0 - R3 C112-CH(CH011) CH2-N n-1 -R4 R5 is reacted with a compound of formula VI preferably under neutral or basic conditions.
V l Nyt,AH V1 In a fifth alternative process within the scope of the present invention for the production of the 10 compound 1, a compound of formula Vil- gl N /===\ NC2(C"')nCH2NHCR2R3CR4RSZ N02 VI1 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.
The above alternative processes are typically conducted in a polar solvent such as an alcohol.
When n is 2, compound 1 may be prepared by reaction of a compound of formula Vill with an 15 aziridine of formula Ill suitably in a polar solvent such as methanol.
R1 /=k=l\ / 0 \ N,5XNCH2 (CHOH) CH- CH2 N02 Vill Intermediate compounds of formula Vill 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 such as one or more of those described in Example A of U.K. Patent Application 20031 54A. 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 localised or metastatic cancer. Administration of the compound I is generally carried out prior 30 to or simultaneously with administration of the chemotherapeutic agent, for example mephalan, cyclophosphamide, 5-fluorouracil or CCNU (1 -(2-chloroethyl)-3-cyclohexyl- 1 -nitrosourea).
The invention is illustrated by the following Examples:- IQ 4 A k 3 GB 2 123 816 A 3 EXAMPLE 1 1-(2-Nitro-1 -imidazolyi)-3-(l -aziridino)-2-propanol A mixture of 1-(2,3-epoxypropyl)-2-nitoimidazole prepared by the method described by Beaman (Beaman A.G., Tautz W. and Duschinsky R., 1967; Studies in the Nitrolmidazole Series, Antimicrobial Agents and Chemotherapy p.-520-530), (5.10 g, 0.03 mol) and aziridine (2.60 g., 0.06 moll 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-(2Nitro-1 -imidazolyl)-3-(1 -azi rid ino)-2-propa nol (3.57 g, 56%, m.p. 119-121 OC) as a pale yellow 10 crystalline solid. Recrystallization causes the decomposition of the product.
EXAMPLE 2 AND 3 In the following Examples, WHT mice in which the MT tumour has been implanted subcutaneously are administered the compound of Example 1 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 enhancement is effected. The results of treatment with radiation 15 and the chemotherapeutic drug are set out respectively in Tables I and 11 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 turnours treated in these cases are intramuscular.
TABLE 1
EXAMPLE 2 RADIOSENSITIZATION MISO 8799 Compound 1 Administered dose mmoles/kg 3.8 3.8 3.8 Enhancement ratio 1.3 1.3 1.7 EXAMPLE 3 CHEMOSENSITIZATION (MELPHALAN) MISO 8799 Compound 1 Administered dose mmoles/kg Enhancement ratio Administered dose mmoles/kg 0.72 0.72 1.7 2.2 0.72 0.08 Enhancement ratio 1.9 3.0 EXAMPLE 4
1-(2-Nitro-1 -imidazoiyi)-3-(2-methyi-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-epoxypropyi)-2-nitroimidazole after crystallization from ethanol-ether, 1-(2-nitro 1-imidazolyi)-3-(2-methyi-l-aziridino)-2-propanoI in the form of a pale yellow crystalline solid (3.06 g, 20 45%, m.p. 109-111 'C).
EXAMPLE 5
1-(2-Nitro-1 -imidazoiyl)-3-(2-ethy]-1 -aziridino)-2-propanol In a manner analogous to that described in Example 1 there is obtained by reaction of 2- ethylaziridine with 1-(2,3-epoxypropyi)-2-nitrolmidazole after crystallization from ethanol-ether at -700C, 1-(2-nitro-1 -imidazoiyi)-3(2-ethyi-l -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-propanoI In a manner analogous to that described in Example 1, but using equimolar amounts of reagents, 30 4 GB 2 123 816 A 4 there is obtained from reaction of 2-benzyl aziridine with 1-(2,3- epoxypropyi)-2-nitroimidazole after column chromatography using silica gel as adsorbent, 1-(2-nitro-1 -imidazoiyi)-3-(2-benzy]-1 -aziridino)- 2-propanol in the form of a pale yellow gum, in 72% yield.
EXAMPLE 7
1-(2-Nitro-1 -imidazolyi)-3-(2,2-di methyl- 1 -aziridino)-2-propanol In a manner analogous to that described in Example 1, there is obtained from reaction of 2,2dimethyl aziridine with 1-(2,3-epoxypropyi)-2nitroimidazole after crystallization from ethanol-ether, 1 (2-nitro-1 -i m idazoiyi)-3-(2,2-di m ethyl- 1 -azi rid i no)-2-propanol in the form of a pale yellow crystalline solid of melting point 101-1 031C; yield 78%.
EXAMPLE8 1-(2-Nitro-l-imidazolyl)-3-(2-phenyi-l-aziridino)-2-propanoI The compound is preparable by reaction of 1-(2,3-epoxypropyi)- 2nitroimidazole with 2phenylazirldine (K. lchimura 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-11 -imidazoiyi)-3-(2-isopropy]-1 -aziridino)-2propanol The compound is preparable by reaction of 1-(2,3-epoxypropyi-2nitroimidazole with 2isopropylaziridine (K. Ichimura, Bull. Chem. Soc. Japan, 43 1443-50 (1970)) in methanol following the method described in Example 1.
EXAMPLE 10
1-(2-Nitro-1 -imidazolyl)-4-(1 -aziridino) or substituted aziridino)-2,3butane-diol. (1, R, = H, n = 2, Rj--R, = H or alkyl, aryl, aralkyl or alkaryl).
(a) 1-(2-nitroimidazolyl)-2-hydroxy-3,4-epoxy butane 3-(2-Nitroimidazolyl)-2-hydroxy-l-butene (11.83 gms), m.p. 90-921C, prepared by refluxing a mixture of azomycin, 1,3-butadiene monoxide and anhydrous 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 30 mixture of chloroform (90%) and ethanol 0 0%) the eluent. The product is crystallised from ethanol as a pale yellow solid of m.p. 134-1360C. Yield 33%.
(b) The compound from (a) is reacted with an aziridine of formula III in methanol to yield the required compound of formula 1.
EXAMPLE 11 1-(2-methyl-5-nitro-1 -imidazolyl)-3-(1 -aziridino or substituted aziridino)-2-propanol. (1, R, = CH., n = 1, 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 0 974)) is reacted with an aziridine of formula III in methanol to yield the required compound of formula 1.
EXAMPLE 12
1-(2-methy]-4-nitro-l-imidazolyi)-3-(1-aziridino orsubstituted aziridino)2-propanoi. (1, R, = CH3, n = 1, R,--R, = H aiky], aryi, aralkyl or alkaryl) The procedure of Example 11 is repeated using 1-(2,3-epoxypropyl)-2- methyi-4-nitroimidazole (J.
Suwinski, E. Suwinska, J. Watras (1974) and M. Wide[, Acta Pol. Pharm., 15(5), 529 (1975)) to yield 45 the required compound of formula 1.
EXAMPLES 13 AND 14 1-(2-Nitro-1 -imidazolyl)-3-(2,3-dimethyl-1 -aziridino)-2-propanol (meso and dl forms) A mixture of meso and dl forms of 2,3-di m ethyl aziridi n e, 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- 50 nitrolmidazole 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 -i m idazolyl)-3-(2,3-di m ethyl- 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 eluant. The meso form has m.p. 84-51 and the dl form is isolated as a waxy solid. 55 Sensitization and toxicity data for compounds described in the above Examples are set out in Table 11.
i 9 A TABLE 11
Sensitisation and toxicity data on Compounds described in the Examples Therapeutic ratiod Example Position of relative to Compound number R' NO, group n R2 R3 R4 R5 C,.,/mol dM-3a LD.Jmi-nol/kgb of Example 1 1 H 2 1 H H H H 1.0 X 10-4 0.61 c 1 4 H 2 1 Me H H H 8 x 10-5 0.58 < 1.2 6 H 2 1 PhCH2 H H H H 2 1 Et H H H 1.3 x 10-4 0.58 0.73 7 H 2 1 Me Me H H 8 x 10-5 1.25 2.56 8 H 2 1 Ph H H H 3 x 10-4 13 H 2 1 Me(meso) H Me H 8 X 1 0-, >1.25 2.56 14 H 2 1 Me(di) H Me H 8 X 10-, H 2 2 H H H H 1.3 x 10-4 0.41 0.52 11 2-Me 5 1 H H H H 3 x 10-4 0.80 0.44 12 2-Me 4 1 H H H H Me 9 H 2 1 CH H H H 1.3 x 10-4 1.49 Me aConcentration required to achieve an enhancement ratio of 1.6 in irradiated hypoxic V79 mammalian cells. b Drugs administered i.p. toy WHT mice. '.For Compound of Example 1 in CIRC131 mice LD ole/k d istered LD50 0 0.087 mmole/kg 1 administered d LD50 104 5.0.71 mm g} apmin 1-1310 0.54 mmole/kg i.. LDIO 0.71 mmoie/kg J i.v. C1.6 0.61 W G) m N) N W 00 CD X - Higher value is more efficacious.
W 6 GB 2 123 816 A 6

Claims (18)

1. A compound of formula 1 in which formula:
R3 N N CH2 (CHOH)n CH2 -N R4 N02 RS 1 R, represents hydrogen or an alkyl group; 132-13. represent hydrogen, alkyl aryl, aralkyl or alkaryl group; and n is 1 or 2.
2. A compound according to Claim 1 in which the nitro group is located at the 2-position in the imidazole ring.
3. A compound according to Claim 1 or 2, in which at least one of R-R. is an alkyl or benzyl group.
4. A compound according to any preceding claim, in which at least two of R2 R3 R4 and R. are C,-C6 alkyl groups.
5. A compound according to any preceding claim, in which n is one.
6. A compound according to any preceding claim, in which R, represents hydrogen.
7. A compound substantially as described in any one of the Examples.
8. 1-(2-Nitro-1 -imidazolyl)-3-(1 -aziridino)-2-propanol; 1-(2-Nitro-1 imidazolyi)-3-(2-isopropyl-1 - aziridino)-2-propanol; 1-(2-Nitro-1 -imidazolyl)-3-(2,3-dimethyl-1 - aziridino)-2-propanol; or 1-(2-Nitro 1 -imidazolyi)-3(2,2-dimethyl-1 -aziridino)-2-propanol.
9. An intermediate of formula 11, IV, V, VII or Vill, as hereinbefore described.
10. An intermediate according to Claim 9, substantially as decribed in any of the Examples.
11. A process for the production of a compound of formula I in which a compound of formula 11 is treated with an aziridine of formula III or a compound of formula 11 is reacted with a compound of formula IIIA or a comnound of formula IV is reacted with an aziridine of formula III or a compound of 9 1 formula V is reacted with a compound of formula VI ora compound of formula VII is cyclised by 25 treatment with a base or a compound of formula Vill is reacted with an aziridine of formula 111.
12. A process according to Claim 11, substantially as described in any of the Examples.
13. A formulation comprising a compound of formula I in association with a pharmaceutically compatible carrier or diluent.
14. A formulation according to Claim 13, in which the carrier or diluent is a saline drip.
15. A formulation according to Claim 13, in dosage form.
16. A method of treating a patient having a radiation sensitive cancer in which a compound of formula I is administered to the patient prior to irradiation of the cancer.
17. A method of treating a patient having a localised or metastatic cancer in which the patient is administered a compound of formula I before or simultaneously with administration of a chemotherapeutic agent.
18. A method according to claim 17, in which the chemotherapeutic agent is melphalan, cyclophosphamide, 5-fluorouracil or 1-(2-chloroethyl)-3-cyclohexyl-l- nitrosourea.
Printed for Her Majesty's Stationery Office by the Courier Press, Leamington Spa, 1984. Published by the Patent Office, Southampton Buildings, London, WC2A l AY, from which copies may be obtained.
GB08314696A 1982-05-27 1983-05-27 Nitrolmidazole derivatives Expired GB2123816B (en)

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EP0319329A2 (en) * 1987-12-04 1989-06-07 Btg International Limited Nitro-substituted aromatic or hetero-aromatic compounds for use in cancer treatment
US5521203A (en) * 1987-12-04 1996-05-28 British Technology Group Limited Nitro-substituted aromatic or hetero-aromatic compounds for use in cancer treatment

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US4815447A (en) * 1985-03-19 1989-03-28 Mills Randell L Mossbauer cancer therapy
CA1329206C (en) * 1987-06-10 1994-05-03 Tsutomu Kagiya Fluorine-containing nitroazole derivatives and radiosensitizer comprising the same
US5304654A (en) * 1987-06-10 1994-04-19 Yasunori Nishijima Fluorine-containing nitroimidazole compounds
US4797397A (en) * 1987-07-31 1989-01-10 Warner-Lambert Company 2-nitroimidazole derivatives useful as radiosensitizers for hypoxic tumor cells
US5177075A (en) * 1988-08-19 1993-01-05 Warner-Lambert Company Substituted dihydroisoquinolinones and related compounds as potentiators of the lethal effects of radiation and certain chemotherapeutic agents; selected compounds, analogs and process
US5073639A (en) * 1988-11-25 1991-12-17 Warner-Lambert Company Process for the synthesis of novel and known nitroimidazoles which are useful as sensitizing agents
US5036096A (en) * 1988-11-25 1991-07-30 Warner-Lambert Company Aziridino derivatives of nitroimidazoles and pharmaceutical compositions of selected derivatives
US5036089A (en) * 1988-11-25 1991-07-30 Warner-Lambert Company 2-oxazolidinone derivatives of nitroimidazoles and pharmaceutical compositions useful as sensitizing agents
US4954515A (en) * 1988-11-25 1990-09-04 Warner-Lambert Company Haloalkylaminomethyl-2-nitro-1H-imidazoles
EP0562306B1 (en) * 1992-03-06 1995-08-30 Zdzislaw Dr. Fiutowski Pharmaceutical composition having antiviral and antibacterial activity
MX9304399A (en) * 1992-07-31 1994-02-28 Warner Lambert Co NOVEL PROCESS TO PREPARE [[2-BROMOETHYL) -AMINO] METHYL] -2-NITRO-1H-IMIDAZOL-1-ETHANOL CHIRAL AND RELATED COMPOUNDS.
US6617100B2 (en) * 1998-09-25 2003-09-09 V.I. Technologies, Inc. Solid phase quenching systems
US6403359B1 (en) 1998-09-25 2002-06-11 V. I. TECHNOLOGIES, Inc. Solid phase quenching systems
US6794518B1 (en) 1998-12-18 2004-09-21 Bristol-Myers Squibb Pharma Company Vitronectin receptor antagonist pharmaceuticals
EP1296678A2 (en) * 2000-06-21 2003-04-02 Bristol-Myers Squibb Pharma Company Vitronectin receptor antagonist pharmaceuticals for use in combination therapy
US7842278B2 (en) * 2006-10-27 2010-11-30 Natural Pharmacia International, Inc. Hypoxia-selective, weakly basic 2-nitroimidazole delivery agents and methods of use thereof
US20110118191A1 (en) * 2009-11-14 2011-05-19 Reid Paul F Crotoxin Administration for Cancer Treatment and Pain Relief

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IE47132B1 (en) * 1977-08-19 1983-12-28 Roche Products Ltd Novel nitroimidazoles and pharmaceutical preparations containing these as well as their manufacture
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Cited By (4)

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Publication number Priority date Publication date Assignee Title
EP0319329A2 (en) * 1987-12-04 1989-06-07 Btg International Limited Nitro-substituted aromatic or hetero-aromatic compounds for use in cancer treatment
EP0319329A3 (en) * 1987-12-04 1990-03-07 National Research Development Corporation Nitro-substituted aromatic or hetero-aromatic compounds nitro-substituted aromatic or hetero-aromatic compounds for use in cancer treatment for use in cancer treatment
US5098921A (en) * 1987-12-04 1992-03-24 National Research Development Corporation Nitro-substituted aromatic or hetero-aromatic compounds for use in cancer treatment
US5521203A (en) * 1987-12-04 1996-05-28 British Technology Group Limited Nitro-substituted aromatic or hetero-aromatic compounds for use in cancer treatment

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US4581368A (en) 1986-04-08
JPH0649697B2 (en) 1994-06-29
EP0095906B1 (en) 1986-10-22
US4631289A (en) 1986-12-23
ATE23041T1 (en) 1986-11-15
JPS58225086A (en) 1983-12-27
AU567338B2 (en) 1987-11-19
EP0095906A1 (en) 1983-12-07
GB8314696D0 (en) 1983-07-06
US4596817A (en) 1986-06-24
GB2123816B (en) 1986-03-19
AU2702984A (en) 1985-10-24
US4757148A (en) 1988-07-12
DE3367092D1 (en) 1986-11-27

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