GB2257360A

GB2257360A - Substituted quinoxalines useful for treating tumours

Info

Publication number: GB2257360A
Application number: GB9214239A
Authority: GB
Inventors: Gerald Edward Adams; Edward Martin Fielden; Matthew Alexander Naylor; Ian James Stratford
Original assignee: British Technology Group Ltd
Current assignee: BTG International Ltd
Priority date: 1991-07-03
Filing date: 1992-07-03
Publication date: 1993-01-13
Also published as: GB9214239D0; WO1993000904A1; GB9114426D0; AU2197992A

Abstract

Dihydropyrimido-quinoxalines and dihydropyrimido-pyridopyrazines of general formula (1) are useful in the treatment of cancer, in particular hypoxic tumours:- <IMAGE> in which Ar forms, together with the carbon atoms to which is attached, a fused benzene ring optionally substituted by halogen or trifluoromethyl or a group of formula (II> <IMAGE> where one of X, Y and Z is -N= and the other two are -CH=, R<1> and R<2> are the same or different and each is hydrogen, halogen, alkyl of 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms; and R<3> and R<4> are the same or different and each is alkyl of 1 to 6 carbon atoms or together R<3> and R<4> form a group: <IMAGE> where n is from 0 to 4; or a pharmaceutically acceptable salt thereof.

Description

COMPOUNDS USEFUL FOR TREATING TUMOURS The present invention relates to the use of dihydropyrimido-quinoxalines and dihydropyrimidopyridopyrazines in the manufacture of medicaments useful in the treatment of cancer.

EP-A-256,545 and EP-A-257,508 disclose quinoxaline and pyridopyrazine derivatives which are useful as anti-anaerobic agents, for the treatment of diseases related to anaerobic bacteria. Such diseases include for example, post-operative sepsis following lower gastrointestinal surgery or female urinogenital surgery, pelvic inflammatory disease, ulcers, gangrene, trichomonal vaginitis, non-specific vaginitis, amoerbiasis, giardiasis, periodontal disease, acne, and the like.

Accordingly the present invention provides the use in the manufacture of a medicament, for use the treatment of a tumour, such as a hypoxic tumour, of a compound of formula (I)

in which Ar forms, together with the carbon atoms to which is attached, a fused benzene ring optionally substituted by halogen (i.e. fluorine, chlorine, bromine or iodine) or trifluoromethyl or a group of formula (II)

where one of X, Y and Z is -N= and the other two are -CH=, Rl and R2 are the same or different and each is hydrogen, halogen, i.e. fluorine, chlorine, bromine or iodine, alkyl of 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms; and R3 and R4 are the same or different and each is alkyl of 1 to 6 carbon atoms or together R3 and R4 form a group:

where n is from 0 to 4; and and pharmaceutically acceptable salts thereof.

According to a further feature the present invention provides a method for the treatment of a human or animal patient suffering from a tumour, such as a hypoxic tumour, which method comprises administering to the patient an effective amount of a compound of Formula (I), as hereinbefore defined, or a pharmaceutically acceptable salt thereof.

The invention provides, as a further feature, products comprising a compound of Formula (I) as hereinbefore defined or a pharmaceutically acceptable salt thereof, for use in the treatment of a tumour, such as a hypoxic tumour.

The invention provides, as yet a further feature, a pharmaceutical agent for use in the treatment of a tumour, such as a hypoxic tumour, which agent comprises a compound of Formula (I) as hereinbefore defined, or a pharmaceutically acceptable salt thereof.

In the compounds of formula (I), the alkyl and alkoxy groups may be either straight or branched.

It is preferred that any alkyl groups in the compounds of formula (I) (including alkyl groups which form part of alkoxy groups) be alkyl groups of 1 to 4 carbon atoms, ie methyl, ethyl, n-propyl, isopropyl, n-butyl, secbutyl or tert-butyl.

The most preferred alkyl substituents are methyl and ethyl.

In the compounds of formula (I) the phenyl ring bearing the groups Rl and R2 may be substituted in any position by 1 or 2 substituents selected from halogen atoms e.g. bromine, chlorine or fluorine atoms, and alkyl, e.g. methyl, and alkoxy, e.g. methoxy, groups. The following substituted phenyl groups are illustrative of such groups: 4chlorophenyl, 4-fluorophenyl, 2,4-dichlorophenyl, 2,4 difluorophenyl, 3 -bromophenyl, 3-chlorophenyl, 2methoxyphenyl, 4-methoxypenyl, 3-methoxyphenyl, 2- ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 3,4dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4-diethoxyphenyl, 3,5-diethoxyphenyl, 2-chloro-4-methoxyphenyl, 4-methylphenyl and 2,4-dimethylphenyl.

Preferred compounds of formula (I) are those in which Rl and R2 are both hydrogen i.e. the phenyl ring bearing Rl and R2 is unsubstituted.

Also preferred are compounds of formula (I) in which R3 and R4 are methyl or ethyl, and more preferably R3 and R4 are both methyl or both ethyl. Most preferably R3 and R4 are both methyl.

Preferably Ar is a group of formula (II). More preferably X is -CH= and one of Y and Z is -N= and the other -CH=. Still more preferably, X and Z are -CH= and Y is -N=.

Of the compounds of formula (I) 2,3-dihydro-2,2 dimethyl-5-phenyl-lH-pyrimidol, 2-a)pyrido[3 , 4-epyrazine-6- oxide and 2,3-dihydro-2,2-diethyl-5-phenyl-lH-pyrimido[1,2- a]pyrido [3,4e]pyrazine-6-oxide may be specifically mentioned as particularly preferred. Of these two the dimethyl compound is more preferable.

Salts of the compounds of formula (I) used in the present invention may be any pharmaceutically acceptable acid addition salts. Examples of suitable salts include, salts of inorganic acids such as chlorides, bromides, iodides, phosphates and sulphates and salts of organic acids such as acetates, citrates, lactates and tartrates.

The compounds of Formula (I) may, according to the invention, be used in uncomplexed form or in the form of a complex such as a complex formed with one or more molecules of organic solvent, water (i.e. a hydrate) or hydrogen halide, e.g. hydrogen chloride.

The compounds used in the present invention are known compounds which may be prepared using known methods. In particular they may be prepared according to procedures described in EP-A-256,545 and EP-A-257,508.

The compounds of formula (I) are useful in increasing the sensitivity of tumour cells to radiation in radiotherapy and as bioreductive agents. A compound is administered to a patient having a radiation-treatable cancer, prior to or after, more typically shortly after irradiation of the tumour, in an amount effective to increase the sensitivity of the tumour cells to the effects of the irradiation.

Any solid tumour, which may have regions where cells are radiobiologically hypoxic and become resistant to ionising radiation, may be treated. Examples of such tumours are epithelial tumours of the head, neck, thorax and abdomen, soft tissue sarcomas and brain tumours. The compounds of formula (I) can therefore be employed in the radiotherapy of all such solid tumours where hypoxic cells are known or suspected to exist.

The compounds of formula (I) may also be used where an agent having differential hypoxic cytotoxicity is required.

The compounds can be employed for chemopotentiation of a chemotherapeutic agent or as a chemotherapeutic by administration of a compound (I) to a patient having a localised or metastatic cancer. Administration is carried out prior to simultaneously with or after administration, typically prior to or simultaneously with, of a chemotherapeutic agent such as melphalan, cyclophosphamide, 5-fluorouracil, adriamycin, CCNU(1-(2-chloroethyl)-3- cyclohexyl-1-nitrosourea) or tumour necrosis factor (TNF).

Any solid tumours, such as above, which are primary or secondary deposits, where it is known or suspected that hypoxic cells are present can therefore benefit from treatment employing a compound of formula (I).

The compounds of formula (I) are useful in particular for the treatment of hypoxic tumours. However the compounds of formula (I) may also be useful in the treatment of other tumours rich in enzymes required to activate the compounds of formula (I) as bioreductive agents or radiosensitisers. Such enzymes may include cytochrome P450, NADPH dependent cytochrome p450 reductase, DT-diaphorase and xanthine oxidase.

The compounds of formula (I) and salts thereof may be administered orally or intravenously. The amount administered depends on factors such as the cancer, the condition of the patient and the body weight of the patient.

Typically, however, doses of 50 to 1000 mg/m2, of a patient's body area may be employed.

A compound of formula (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 suitable for bolus injection or such as a tablet or capsule, for example a capsule comprising known formulation components. The compound may also be formulated for intravenous administration e.g. in a saline drip solution.

The following Example illustrates the invention.

EXAMPLE 1 The toxicity of RB 90008X [2,3-dihydro-2,2-diethyl-5phenyl-lH-pyrimido [1, 2-a]pyrido [3,4-e] pyrazine-6-oxide] towards aerobic or hypoxic V79 cells in vitro is shown in Table 2 and comparison is made with SR 4233 [3-amino-1,2,4- benzotriazine 1,4-dioxide. Toxicity was determined by the use of the modified MTT assay (Stratford and Stephens (1989), Int. J. Radiat. Oncol. Biol. Phys. 16, 973-976). Values quoted represent concentrations of drug required to reduce proliferation of treated cultures by 50%. Cells are treated with various drug doses for 3 hours at 370C under aerobic or hypoxic conditions, following drug removal cells are allowed to proliferate for 3 days prior to assay.

TABLE 2 Compound C air C N2 Ratio mmol dm3 RB 90008X 3.0 0.3 10 SR 4233 0.3 0.006 50 Clearly RB90008X is substantially more toxic to hypoxic compared with aerobic cells. While the differential is higher for SR 4233, the aerobic toxicity of the mono-N-oxide is considerably less.

Claims

1. Use in the manufacture of a medicament, for use in the treatment of a tumour, of a compound of formula (I)

in which Ar forms, together with the carbon atoms to which is attached, a fused benzene ring optionally substituted by halogen or trifluoromethyl or a group of formula (11)

where one of X, Y and Z is -N= and the other two are -CH=, Rl and R2 are the same or different and each is hydrogen, halogen, alkyl of 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms; and R3 and R4 are the same or different and each is alkyl of 1 to 6 carbon atoms or together R3 and R4 form a group:

where n is from 0 to 4; or a pharmaceutically acceptable salt thereof.

2. Use according to claim 1 of a compound of formula (I) in which Rl and R2 are both hydrogen, or a pharmaceutically acceptable salt thereof.

3. Use according to claim 1 or 2 of a compound of formula (I) in which R3 and R4 are the same or different and each is methyl or ethyl, or a pharmaceutically acceptable salt thereof.

4. Use according to claim 3 of a compound of formula (I) in which R3 and R4 are both methyl or both ethyl or a pharmaceutically acceptable salt thereof.

5. Use according to any one of claims 1 to 4 of a compound of formula (I) in which Ar is a group of formula (II) in which X and Z are -CH= and Y is -N= or a pharmaceutically acceptable salt thereof.

6. Use according to claim 1 of a compound of formula (I) which is 2,3-dihydro-2,2-dimethyl-5-phenyl-lH- pyrimido[1,2-a]pyrido[3,4-e]pyrazine-6-oxide or 2, 3-dihydro- 2,2-diethyl-5-phenyl-1H-pyrimido[l,2-a]pyrido[3,4e]pyrazine- 6-oxide or a pharmaceutically acceptable salt thereof.

7. Use according to claim 6 of a compound of formula (I) which is 2, 3-dihydro-2,2-dimethyl-5-phenyl-lH- pyrimido[1,2-a]pyrido[3,4e]pyrazine-6-oxide or a pharmaceutically acceptable salt thereof.

8. Use according to any one of the preceding claims, for use in the treatment of a hypoxic tumour.