IL91814A

IL91814A - Pharmaceutical compositions comprising 6-phenyl (methyl)-2,7-bis (cyclic amino)-4- pteridinamines, certain novel such pteridines and their preparation

Info

Publication number: IL91814A
Application number: IL9181489A
Authority: IL
Original assignee: Thomae Gmbh Dr K
Priority date: 1988-10-01
Filing date: 1989-09-28
Publication date: 1994-02-27
Also published as: JPH02256676A; ATE106728T1; FI92699C; DE3833393A1; EP0362645B1; DE58907824D1; NO893879L; AU4174989A; NO175979B; EP0362645A2; FI92699B; FI894615A0; IL91814A0; EP0362645A3; PT91836B; AU620645B2; HU205761B; DD299062A5; HUT52504A; NZ230833A

Abstract

The invention relates to medicaments containing a pteridine of the formula <IMAGE> in which n is the number 0 or 1, R2 and R7 are each a pyrrolidino, piperidino or morpholino group which is optionally substituted by one or two methyl groups, R3 is a straight-chain or branched alkyl group in which one or two carbon atoms, excepting the carbon atom adjacent to the nitrogen atom, can be substituted by a hydroxyl group, R<4> is an alkyl or phenylalkyl group, in which one carbon atom, excepting the carbon atom adjacent to the nitrogen atom, can be substituted by a hydroxyl group, and R5 is a hydrogen atom or a methyl group, or the acid addition salts thereof and at least one chemotherapeutic from the natural product series, and to the use of the above pteridines for sensitisation of tumours during chemotherapy with the abovementioned chemotherapeutics, and to pteridines, process for the preparation thereof and medicaments containing these pteridines.

Description

91814/2 -/÷-( >^> inN)o>a-2,7-( >nO)i?> o nn mnpi-i >-ι>νηη Pharmaceutical compositions comprising 6-phenyl (methyl ) -2,7-bis( cyclic amino )-it-pteridinamines, certain novel such pteridines and their preparation C: 78528 DR. KARL THOMAE GMBH 91814/2 1 The present invention relates to pteridine -containing pharmaceutical compositions, to certain novel pteridines and to their preparation.

In the treatment of neoplastic diseases, some natural products are used, e.g. Vinca alkaloids such as vinblastine, vincristine or vindesine, epipodophyllo-toxins such as etoposide or teniposide and antibiotics such as dactinomycin, daunorubicin, doxorubicin, bleomycin, mithramycin or mitomycin (see Goodman and Gilman's "The Pharmacological Basis of Therapeutics", Macmillan Publishing Company, New York, 7th Edition, pages 1240-1247 and 1277-1289 (1985)). In chemotherapy using these substances, it is frequently found that the tumours being treated are not responding because of either a primary resistance or a secondary resistance built up as a result of a previous treatment, or that therapy-resistant tumour cells may possibly remain latent after remission of the tumours. These resistant tumour cells generally cause a relapse at a later date.

It has now been found that tumours may be brought into remission by the administration of a certain pteridines.

More particularly, it has been found that administration of certain pteridines previous to, together with or subsequent to administration of such chemotherapeutic agents results in tumours with primary or secondary resistance being sensitized to such agents.

Viewed from one aspect therefore the present invention provides a pharmaceutical composition for use in combatting primary and secondary resistance in chemotherapy with a natural product chemotherapeutic agent, said composition comprising a compound of formula 1. (wherein n represents the number 0 or 1; R3 represents a straight-chained or branched C2.6 alkyl group in which one or two non-nitrogen-attached carbon atoms are substituted by a hydroxy group and R4 represents a benzyl group or a Cj_4 alkyl group in which a non-nitrogen-attached carbon atom may be substituted by a hydroxy group, or R3 represents a alkyl group and R4 represents a phenyl (C^) alkyl group; R2 and R7 which may be the same or different, each represents a pyrrolidino, piperidino or morpholino group optionally substituted by one or two methyl or ethyl groups ; and Rs represents a hydrogen atom or a methyl group) , or a geometrical or optical isomer thereof or a physiologically acceptable acid addition salt thereof, together with at least one natural product chemotherapeutic agent. 91814/4 - 3 - As examples of the definitions of the groups mentioned hereinbefore, R2 and R7 each may represent a pyrrolidino, 2-methyl- pyrrolidino, 3-methyl-pyrrolidino, 3 , 3-dimethyl- pyrrolidino, 2-ethyl-pyrrolidino, 3-ethyl-pyrrolidino, 3 , 3-diethyl-pyrrolidino, piperidino, 2-methyl- piperidino, 3-methyl-piperidino , 4-methyl-piperidino , 2- ethyl-piperidino, 3-ethyl-piperidino , 4-ethyl- piperidino, 3 , 5-dimethyl-piperidino , 3 , 5-diethyl- piperidino, morpholino, 2-methyl-morpholino, 2-ethyl- morpholino, 3-methyl-morpholino, 3-ethyl-morpholino, 2 , 6-dimethyl-morpholino, cis-2 , 6-dimethyl-morpholino, trans-2 , 6-dimethyl-morpholino, 2 , 6-diethyl-morpholino , cis-2 , 6-diethyl-morpholino, trans-2 , 6-diethyl- morpholino, 3 , 5-dimethyl-morpholino or 3,5-diethyl- morpholino group, R3 may represent a 2-hydroxy-ethyl , 2-hydroxy-n-propyl , 2-hydroxy-isopropyl , 3 -hydroxy-propyl , 4-hydroxy-n- butyl, 2-hydroxy-2-methyl-n-propyl , 5-hydroxy-n-pentyl , 6-hydroxy-n-hexyl , 2 , 3-dihydroxy-n-propyl , methyl, ethyl, n-propyl or isopropyl group, R may represent a benzyl , 2-phenyl-ethyl , 2-phenyl-n- propyl, 3 -phenyl-propyl , 2-hydroxy-ethyl, 2-hydroxy-n- propyl, 3 -hydroxy-propyl, 4-hydroxy-n-butyl or 2- hydroxy-2-methyl-n-propyl group and R5 may represent a hydrogen atom or a methyl group.

Some of the pteridines of formula (I) are described in U.S. Patent No. 3,574,206, which corresponds to German Patents Nos. (620,498 and 1,795,515 as being useful as coronary dilators. Furthermore some pteridines of formula (la) below fall within the generic scope of the aforementioned Patents but were not specifically named therein. 91814 / 1 - 3a - German Patent No. 3,445,298 discloses entirely different pteridines, namely 2-piperazino-pteridines, stated to exhibit metastase-inhibitory and tumor-growth limiting activities. Tests conducted with certain compounds of this publication, by the procedure described on page 11 herein, showed them to be devoid of any activity against the resistance of tumor cells to chemotherapeutic agents, or to possess only a very low such activity.

Certain of the pteridines of formula I are novel and thus in themselves provide another aspect of the present invention. Viewed from this aspect, the present invention provides compounds of formula la (wherein n represents the number 0 or 1, R2 and R7/ which are identical, each represents a morpholino group substituted by a methyl or ethyl group in the 2-position or in the 2 and 6-positions, or a 3,5-dimethyl-piperidino group, R3 represents a 2-hydroxy-ethyl , 2-hydroxy-n-propyl , 2,3-dihydroxy-n-propyl or 2-hydroxy-2-methyl-n-propyl group, R4 represents a 2-hydroxy-2-methyl-n-propyl group, and R5 represents a hydrogen atom or a methyl group; or n represents the number 0 and R5 represents a hydrogen atom or a methyl group, and R2 and R7, which are identical, each represents a 2,6-dimethylmorpholino, or 2 , 6-diethylmorpholino group, R3 and R¾ together with the intervening nitrogen atom represent an N- (C^alkyl) -phenyl (Chalky1) amino, N-benzyl-ethanolamino, N-ethyl-ethanolamino, ethanol-isopropanolamino , N-ethyl-isopropanolamino or N-(-2,3-dihydroxy- n-propyl )-ethanol amino group , 91814/2 5 or one of the groups R2 and R7 represents a morpholino group , the other group R2 or R7 represents a 2,6-dimethylmorpholino or 2 , 6-diethylmorpholino group and R3 and R* together with the intervening nitrogen atom represent an N- (2-hydroxy-2-methyl-n-propyl) -ethanolamino group; or n represents the number 0,· Rs represents a methyl group, R2 and R7 each represents a 2-methyl-morpholino group and R3 and 4 together with the intervening nitrogen atom represent an ethanol-isopropanolamino group) , or n represents the number 0, R5 represents a hydrogen atom, R2 and R7 each represents a 2-methyl-morpholino group, and R3 and R4 represent with the intervening nitrogen atom an ethanol-2,3-dihydroxy-propylamino group, the optical and geometrical isomers thereof and the acid addition salts thereof, particularly the physiologically acceptable acid addition salts thereof, e.g. with organic or inorganic acids.

Preferred compounds for use according to the invention include pteridines of formula I wherein represents the number 91814/1 - 5a - R2 and R7, which may be the same or different, each represents a piperidino, 3 , 5-dimethyl-piperidino, morpholino, 2-methyl-morpholino, 2 , 6-dimethyl-morpholino, cis-2 , 6-dimethyl-morpholino or trans-2,6-dimethyl-morpholino group, R4 represents a methyl, ethyl, benzyl, 2-hydroxy-ethyl , 2-hydroxy-n-propyl, 2 , 3-dihydroxy-^n-propyl .or 2-methyl- 6 2-hydroxy-n-propyl group, R3 represents a 2-hydroxy-ethyl , 2-hydroxy-n-propyl or methyl-2-hydroxy-n-propyl group and R5 represents a hydrogen atom or a methyl group, and the optical and geometric isomers and physiologically acceptable acid addition salts thereof The following novel compounds according to the invention- may be mentioned in particular: ~ · 4r- [N- (2-hydroxy-2-methylm-propyl) -ethanolamino] -2 , 7-bis (2 , 6-dimethyl-morpholino) -6-phenyl-pteridine; 4- (N-ethyl-ethaholamino)-2 , 7-bis (2 , 6-dimethyl-morpholino) -6-phenyl-pteridine; 4- (ethanol-isopropanolamino) -2 , 7-bis (2 , 6-dimethyl-morpholino) -6-phenyl-pteridine; 4-[N- (2-hydroxy-2-methyl-n-propyl) -ethanolamino] -2 , 7-bis (2-methyl-morpholino) -6-phenyl-pteridine; 4- (ethanol-isopropanolamino) -2 , 7-bis (2-methyl-morpholino) -6-benzyl-pteridine ; 4- (ethanol-isopropanolamino) -2 , 7-bis (2-methyl-morpholino) -6-(o-tolyl) -pteridine; 4- [bis ( 2-hydroxy-2-methyl-n-propyl) -amino] -2 , 7-bis >(2-methyl-morpholino)-6-phenyl-pteridine; 4- (2 , 3-dihydroxy-n-propyl-ethanolamino) -2 , 7-bis (2-methyl-mo holino)-6-phenyl-pteridine; 4- [N- (2-hydroxy-2-methyl-n-propyl) -ethanolamino] -2 , 7- 1 J' bis- (3 , 5-dimethyl-piperidino) -6-phenyl-pteridine; 4-[N-ethanol-benzylamino] -2 , 7-bis (2 , 6-dimethyl-morpholino) -6-phenyl-pteridine; 4- [N- (2-hydroxy-2-methyl-n-propyl) -ethanolamino] -2 , 7-bis (cis-2 , 6-dimethyl-morpholino) -6-phenyl-pteridine ; 4- [N- (2-hydroxy-2-methyl-n-propyl) -ethanolamino] -2- (2 , 6-dimethyl-morpholino) -7-morpholino-6-phenyl-pteridine ; 4- [N- (2-hydroxy-2-methyl-n-propyl) -ethanolamino] -7- (2 , 6-dimethyl-morpholinb) -2-morpholino-6-phenyl-pteridine ; 4- (N-ethyl-benzylamino) -2 , 7-bis (2 , 6-dimethyl-morpholino) -6-phenyl-pteridine; and the isomers and salts thereof. .

Preferred novel compounds according to the invention include compounds of formula la wherein: n represents the number 0; R2 and R7 each represents a 2 , 6-dimethyl-morpholino group or one of the groups R2 or R7 represents a morpholino group and the other group R2 or R7 represents a~2 , 6-dimethyl-morpholino group; R3 and R4 together with the intervening nitrogen atom represent an N- (2-hydroxy-2-methyl-n-propyl) -ethanolamino group; 91814/2 8 R5 represents a hydrogen atom; and the isomers and salts thereof.

The following pteridines have proved particularly effective for use according to the invention: 4-[N- (2-hydroxy-2-methyl-n-propyl) -ethanolamino] -2,7-bis (2 , 6-dimethyl-morpholino) -6-phenyl-pteridine; 4- (N-ethyl-ethanolamino) -2 , 7-bis (2 , 6-dimethyl-morpholino) -6-phenyl-pteridine; 4- (ethanol-isopropanolamino) -2 , 7-bis (2 , 6-dimethyl-morpholino) -6-phenyl-pteridine; 4- (diethanolamino) -2 , 7-bis (2 , 6-dimethyl-morpholino) -6-phenyl-pteridine ; 4- [N- ( 2-hydroxy-2-methyl-n-propyl) -ethanolamino] -2 ,7-bis (2-methyl-morpholino) -6-phenyl-pteridine; 4- (ethanol-isopropanolamino) -2 , 7-bis (2-methyl-morpholino) -6-benzyl-pteridine ; 4- (ethanol-isopropanolamino) -2 , 7-bis (2-methyl-morpholino) -6-phenyl-pteridine; 4- (ethanol-isopropanolamino) -2 , 7-bis (2-methyl-morpholino) -6-(o-tolyl) -pteridine; 4- (N-benzyl-ethanolamino) -2 , 7-dimorpholino-6-phenyl-pteridine; 4- [bis (2-hydroxy-2-methyl-n-propyl) -amino] -2 , 7-bis (2- Γηεί1ιγ1-ιιιο Κο1ίηο)-6-ρ1ΐ6ηγ1-ρΙεπ(ϋηε; 91814/2 9 4- (2 , 3-dihydroxy-n-propyl-ethanolamino) -2 , 7-bis (2-methyl-morpholino)-6-phenyl-pteridine; 4- (diethanolamino) -2 , 7-dipiperidino-6-phenyl-pteridine; 4- (diethanolamino) -2 , 7-dimorpholino-6-phenyl-pteridine ; 4- (N-ethyl-ethanolamino) -2 , 7-dimorpholino-6-phenyl-pteridine; 4- (N-methyl-ethanolamino) -2 , 7-dimorpholino-6-phenyl-pteridine ; 4-[N-(2-hydroxy-2-methyl-n-propyl) -ethanolamino] -2 , 7-bis- (3 , 5-dimethyl-piperidino) -6-phenyl-pteridine; 4- (N-ethanol-benzylamino) -2 , 7-bis (2 , 6-dimethyl-morpholino) -6-phenyl-pteridine; 4- [N- (2-hydroxy-2-methy1-n-propy1 ) -ethanolamino] -2 , 7-bis (cis-2 , 6-dimethyl-morpholino) -6-phenyl-pteridine; 4- [N- ( 2-hydroxy-2-methy1-n-propy1 ) -ethanolamino] -2 , 7-bis (trans-2 , 6-dimethyl-morpholino) -6-phenyl-pteridine ; 4- [N-( 2-hydroxy-2-methyl-n-propy1) -ethanolamino] -2- (2 , 6-dimethyl-morpholino) -7-morpholino-6-phenyl-pteridine ; 4- [N- (2-hydroxy-2-methy1-n-propy1) -ethanolamino] -7- (2 , 6-dimethyl-morpholino) -2-morpholino-6-phenyl-pteridine ; and the physiologically acceptable acid addition salts thereof.

By way of example, sensitisation on cells resistant to adriamycin was tested using the following compounds: A 4- [N- ( 2-hydroxy-2-methyl-propyl) -ethanolamino] -2 , 7- bis (2 , 6-dimethyl-morpholino) -6-phenyl-pteridine, B 4-(N-ethy†-ethanolamino)--2^b1f{2,6-^'imethyl- **£..·-.- morpholino) -6-phenyl-pteridine, C 4- (ethanol-isopropanolamino) -2 , 7-bis (2 , 6-dimethyl- morpholino) -6-phenyl-pteridine, D 4- (diethanolamino) -2 , 7-bis(2 , 6-dimethyl-morpholino) - 6-phenyl-pteridine, and E 4- [N- ( 2-hydroxy-2-methyl-propyl) -ethanolamino ] -2 , 7- bis- (cis-2 , 6-dimethyl-morpholino) -6-phenyl-pteridine by the following method: Proliferating S 180 mouse sarcoma cells resistant to adriamycin were cultivated for six days in the presence of varying concentrations of test substances.

Concentrations of the test substances having a cytotoxic or cytostatic activity are indicated by reduced cell growth or by the dying off of the cells. The end point of the assay is the number of living cells for each culture, which is determined indirectly by making use of the property of vital cells of reducing the dye MTT [= 3- (4 , 5-dimethylthiazol-2-yl) -2 , 5-diphenyltetrazolium-bromide] to the coloured formazan. The concentration of a test substance which reduces the number of vital cells of each culture vessel to 50% of the untreated control is termed the IC50. The test substances are tested both in the absence of adriamycin and also in the presence of a quantity of adriamycin which does not have the effect of inhibiting proliferation under the culture conditions. Therefore, two IC50 values are obtained for each test substance, one in the presence of adriamycin (IC5o ADR) , the other in the absence of adriamycin • 11 (ICJO) . The difference between the logarithms to the base ten of the two IC50 values, Δ = logIC50-logICS0 ADR, is a measurement of the increase in the cytotoxicity of the test substance brought about by adriamycin.

Description of experiment: Adriamycin-resistant or adriamycin-sensitive S 180 cells in exponential growth are plated out in 96-well flat bottomed microtitre plates in a quantity of 2000 cells per well in 100 μΐ of growth medium (RPMI-1640, containing 10% foetal calf serum) . The culture dishes are incubated in an incubator at 3 'C under 5% C02 (% by volume)' ■ - and at 100% relative humidity. After 24 hours, 50 μΐ of growth medium, containing different concentrations of test substance, and 50 μΐ of growth medium with or without adriamycin are added to each well. After a further six days' cultivation, 50 μΐ of tetrazolium salt solution (5 mg of 3- (4, 5-dimethylthiazol-2-yl) -2 , 5-diphenyltetrazoliumbromide per ml of phosphate-buffered saline solution, diluted 1:5 (v/v) with RPMI-1640 before use) are pipetted into each well. After 4 hours' incubation, the culture medium is carefully removed by aspiration and intracellularly formed formazan is solubilised using 150 μΐ of dimethylsulphoxide for each well. The plates are briefly shaken and the optical density is measured at 570 n with a photometer such as a Dynatech MR-600 apparatus. The formation of the coloured formazan by reduction of the tetrazolium salt is proportional to the number of living cells. The averages of three measurements are used when calculating the IC50 values (dilution ratio 1:2) .

The following tables show the results found for two different quantities of added adriamycin. 12 Table 1 [Mg/ml] . n IC50. log IC50 25 ng Adriamycin Substance Adriamycin in ng/ml 0 25 A 20.69 1.49 1.14 B >31.60 4.43 > 0.85 C 12.85 3.77 0.53 D 14.37 5.78 0.40 E 7.50 0.50 1.18 Table 2 IC50 Og/ml] log —50 IC50 100 ng Adriamycin Substance Adriamycin in ng/ml 0 100 A 20.69 <0.50 > 1.61 B >31.60 0.77 > 1.61 C 12.85 0.82 1.20 D 14.37 1.57 0.96 E 7.50 0.10 1.88 The pteridines of formula I : above thus have an excellent sensitising effect on adriamycin-resistant sarcoma cells and are therefore suitable for treating neoplastic diseases in conjunction with natural product chemotherapeutic agents such as for example Vinca alkaloids, epipodophyllotoxins or antibiotics such as daunorubicin, doxorubicin, bleomycin, mithramycin or mitomycin, in order to eliminate resistance to 91814/2 13 chemotherapy and thus bring about the remission of tumours resistant to these substances. In tumours sensitive to the above-mentioned chemotherapeutics , the pteridines of formula I, together with the chemotherapeutic agent, prevent therapy-resistant sub-populations of tumour cells from surviving the therapy and possibly leading to a relapse.

Viewed from another aspect, the present invention provides a pharmaceutical composition for use in combating primary or secondary resistance in chemotherapy with a natural product chemotherapeutic agent, comprising a compound of formula la as herein described, or an isomer or physiologically acceptable acid addition salt thereof, together with at least one pharmaceutical carrier or excipient.

For pharmaceutical use, the compounds of formula I or isomers or salts thereof may be incorporated in a conventional manner into customary pharmaceutical preparation forms, such as solutions, suppositories, 14 plain or coated tablets, capsules or infusions. The pteridines, which are moreover well tolerated, may be administered separately or in conjunction with a chemotherapeutic agent administered in the usual dosage; the dosage of pteridine used is between 1 and 50 mg/kg of body weight per day, preferably between 3 and 20 mg/kg of body weight per day, divided up into 1 to 4 single doses.

When the pteridines are administered in conjunction with a chemotherapeutic agent, they may be administered in intravenous form such as from ampoules and, when they are administered separately, they may be given in a parallel form such as for example plain or coated tablets, suspensions, syrups, capsules or suppositories.

On the basis of the plan of administration known from the literature for the natural products used in the chemotherapy of neoplastic diseases (see Goodman and Gilman's "The Pharmacological Basis of Therapeutics", Macmillan Publishing Company, New York, 7th Edition, pages 1240-1247 and 1277-1289 (1985)), the first dose of a pteridine of formula I or a physiologically acceptable acid addition salt thereof would conveniently be given together with or before the chemotherapeutic agent used or together with or before a combination of several chemotherapeutic agents which contains at least one of the above-mentioned natural product chemotherapeutic agents (see DeVita et al. in "Cancer, Principles & Practice of Oncology", 2nd Edition, J.B. Lippincott Company Philadelphia) .

The other doses of a pteridine of formula I or of an isomer or physiologically acceptable acid addition salt thereof may be given by oral route or possibly by intravenous route, depending on the particular circumstances .

Thus, a combination suitable for i.v. administration expediently contains 1 to 25 mg/kg, preferably 1 to 20 mg/kg of body weight, of a pteridine 15 of formula I or an isomer or physiologically acceptable acid addition salt thereof together with a suitable chemotherapeutic agent or a combination of different suitable chemotherapeutic agents, e.g. 0.1 to 0.15 mg/kg of vinblastine every 7 days (the dosage may be increased in stages of 0.05 mg/kg depending on the severity of the side effects) , about .2 mg/m2 of body surface of vincristine every 7 days for juvenile leukaemia (in adults the therapy preferably begins with 0.01 mg/kg every 7 days and can be increased to 0.02 - 0.05 mg/kg depending on tolerance), 3 - 4 mg/m2 of body surface area of vindesine every 7 days, 25 - 30 Mg/kg of mithramycin daily or every 2 days, 60 - 75 mg/m2 of body surface area of adriamycin every 21 days , 30 - 60 mg/m2 of body surface area of daunorubicin every day for 3 days, 10 - 15 Mg/kg of dactinomycin every day for 5 days, 50 - 100 mg/m2 of body surface area of etoposide daily for 5 days and 30 mg/m2 of body surface area of teniposide every day up to 5 days, followed, after a 10-day break, by 6 - 10 treatment cycles.

Pteridines of formula I are described in CA-A-912556, US-A-3557105 and US-A-3574206 or may be prepared by the methods described therein. 16 Viewed from a yet further aspect therefore, the present invention also provides a process for the preparation of the new compounds of the present invention, said process comprising at least one of the following steps: (a) reacting a pteridine of formula II (wherein R3 to R5 and n as hereinbefore defined, one of the groups Z2 or Z7 represents a nucleophilically exchangeable group such as a halogen atom, e.g. a chlorine or bromine atom, and the other group Z2 or Z7 has the meanings given for R2 or R7 hereinbefore or may also represent a nucleophilically exchangeable group such as a halogen atom, e.g. a chlorine or bromine atom) with an amine of formula III H - X (III) (wherein X has the meanings given for R2 or R7 hereinbefore) ; b) converting a compound of formula la into an acid addition salt thereof or converting an acid addition salt of a compound of formula la into the free base; and c) resolving a compound of formula la or salt thereof into its optical or geometric isomers. 17 The reaction of step (a) is conveniently carried out in a solvent such as tetrahydrofuran, dioxan, benzene, toluene, dimethylsulphoxide or dimethylglycolether at temperatures of between 0 and 150 "C, preferably at temperatures of between ambient temperature and the boiling temperature of the solvent used or in a melt. It may be advantageous to use an acid binding agent such as sodium carbonate, triethylamine or pyridine.

The new compounds of formula la thus obtained may be converted into the acid addition salts thereof, particularly the physiologically acceptable salts thereof, with inorganic or organic acids. Examples of such acids include hydrochloric, hydrobromic, sulphuric, phosphoric, lactic, citric, tartaric, succinic, maleic and fumaric acids.

The compounds of formulae II and III used as starting materials are known for the most part (see for example CA-A-912556, US-A-3557105 and US-A-3574206) or may be obtained by methods described in US-A-2940972 or in accordance with the methods described in the above-mentioned patent specifications.

If the compounds of formula la have at least one chiral centre, they may be resolved by conventional methods into the enantiomers thereof, for example by column chromatography on a chiral phase or by crystallisation with optically active acids, e.g. with D- or L-monomethyltartaric acid, D- or L-diacetyl-tartaric acid, D- or L-tartaric acid, D- or L-lactic acid or D- or L-camphoric acid.

In addition, if the compounds of formula la have at least one geometric centre such as a pyrrolidino, piperidino or morpholino group substituted by two methyl or ethyl groups, but more particularly if they contain at least one 2 , 6-dimethyl-morpholino group, they may be separated by conventional methods such as chromatography into the cis/trans isomers thereof or they may occur in 18 the form of these isomers.

The Examples which follow are provided to illustrate the invention. All percentages, parts and ratios are by weight unless otherwise indicated.

Example 1 4-[N- (2-Hydroxy-2-methyl-n-propyl) -ethanolamino] -2 , 7-bis ( 2 .6-dimethyl-morpholino) -6-phenyl-pteridine a) 2 , 7-dichloro-4-[N- (2-hydroxy-2-methyl-n-propyl) - ethanolamino] -6-phenyl-pteridine 15.5 g (0.005 mol) of 2 , , 7-trichloro-6-phenyl-pteridine are dissolved in 100 ml of acetone and 13.3 g (0.1 mol) of N- (2-hydroxy-2-methyl-n-propyl) -ethanolamine are added. After being stirred for 20 minutes at ambient temperature the suspension formed is combined with 200 ml of water. The product precipitated is suction filtered, washed with water and crystallised from methanol/water = 95:5¾ ( by vol ume ) : Yield: 19.9 g (97% of theory), Melting point: 145 - 147 "C. b) 4- [N- (2-hydroxy-2-methyl-n-propyl) -ethanolamino] -2 , 7- bis (2 , 6-dimethyl-morpholino) -6-phenyl-pteridine 2.0 g (0.005 mol) of 2 , 7-dichloro-4-[N-(2-hydroxy~ 2-methyl-n-propyl) -ethanolamino] -6-phenyl-pteridine are dissolved in 20 ml of dioxan and refluxed for 30 minutes with 3.5 g (0.08 mol) of 2 , 6-dimethyl-morpholine. The reaction solution is then poured into water, the precipitate formed is suction filtered, washed with water and recrystallised from ethyl acetate.

Yield: 2.4 g (84% of theory), Melting point: 191 - 194 °C.

Example 2 4- (N-Et yl-ethanolamino) -2 , 7-bis (2 , 6-dimethyl-morpholino) -6-phenyl-pteridine Prepared from 4- (N-ethyl-et anolamino) -2 , 7-dichloro-6-phenyl-pteridine and 2 , 6-dimethyl-morpholine analogously to Example 1.

Yield: 81% of theory, Melting point: 128 - 138"C (ethanol) .

Example 3 4- (Ethanol-isopropanolamino) -2 ,*7-bis (2 , 6-dimethyl-morpholino) -6-phenyl-pteridine Prepared from 4- (ethanol-isopropanolamino) -2 , 7-dichloro-6-phenyl-pteridine and 2 , 6-dimethyl-morpholine analogously to Example 1.

Yield: 60% of theory, Melting point: 192 - 193°C (methanol/water = 4:1 by volume) Example 4 4- [N- (2-Hydroxy-2-methyl-n-propyl) -ethanolamino] -2 , 7-bis ( 2-methyl-morpholino) -6-phenyl-pteridine Prepared from 4-[N- (2-hydroxy-2-methyl-n-propyl) -ethanolamino] -2 , 7-dichloro-6-phenyl-pteridine and 2-methyl-morpholine analogously to Example 1.

Yield: 74% of theory, Melting point: 143 - 147 °C (ethyl acetate/petroleum ether) . 91814/2 21 Example 5 4- (Ethanol-isopropanolamino) -2 , 7-bis (2-methyl-morpholino) -6-benzyl-pteridine Prepared from 4- (ethanol-isopropanolamino) -2 , 7-dichloro-6-benzyl-pteridine and 2-methyl-mo pholine analogously to Example 1.

Yield: 55% of theory, Melting point: 100 - 105°C.

Example 6 4- (Ethanol-isopropanolamino) -2 , 7-bis (2-methyl-morpholino) -6- (o-tolyl) -pteridine Prepared from 4- (ethanol-isopropanolamino) -2 , 7-dichloro-6- (o-tolyl) -pteridine and 2-methyl-morpholine analogously to Example 1.

Yield: 85% of theory,.

Melting point: 105 - 110 °C (precipitation from 0.1 N hydrochloric acid) .

Example 7 4- [Bis (2-hydroxy-2-methyl-n-propyl) -amino] -2 , 7-bis (2-methyl-morpholino) 6-phenyl-pteridine; Prepared from 4-[bis (2-hydroxy-2-methyl-n-propyl) -amino] -2 , 7-dichloro-6-phenyl-pteridine and 2— ! methyl-morpholine analogously to Example 1.

Yield: 46% of theory, Melting point: 122 - 127 °C (precipitation from 0.1 N hydrochloric acid) . 22 Example 8 4- (2 , 3-Dihydroxy-n-propyl-ethanolamino) -2 , 7-bis < (2-methyl-morpholino)-6-phenyl-pteridine; . Prepared from 4- (2 , 3-dihydroxy-n-propyl-ethanolamino) -2 , 7-dichloro-6-phenyl-pteridine and 2- '.' '.methyl-morpholine analogously to Example 1.

Yield: 76% of theory, Melting point: 105 - 115 °C (precipitation from 0.1 N hydrochloric acid) .

Example 9 4- [N- (2-Hydroxy-2-methyl-n-propyl) -ethanolamino] -2 , 7-bis- ( 3 , 5-dimethyl-piperidino) -6-phenyl-pteridine Prepared from 4- [N- (2-hydroxy-2-methyl-n-propyl) -ethanolamino] -2 , 7-dichloro-6-phenyl-pteridine and 3,5-dimethyl-piperidine analogously to Example 1.

Yield: 50% of theory, Melting point: 206-209 "C.

Example 10 4- (N-Ethanol-benzylamino) -2 , 7-bis (2 , 6-dimethyl-morpholino^ -6-phenyl-pteridine Prepared from 4- (N-ethanol-benzylamino) -2 , 7-dichloro-6-phenyl-pteridine and 2 , 6-dimethyl-morpholine analogously to Example 1.

Yield: 34% of theory, Melting point: 200-202 °C. 23 Example 11 4-[N- (2-Hydroxy-2-methyl-n-propyl) -ethanolamino] -2 , 7-bis (cis-2.6-dimethyl-morpholino) -6-phenyl-pteridine Prepared from 4-[N- (2-hydroxy-2-methyl-n-propyl) -ethanolamino] -2 , 7-dichloro-6-phenyl-pteridine and cis-2 , 6-dimethyl-morpholine analogously to Example 1.

Yield: 60% of theory, Melting point: 206-209 °C (isopropanol) .

Example 12 4-[N- (2-Hydroxy-2-methyl-n-propyl) -ethanolamino] -2- (2 , 6-dimethyl-morpholino) -7-morpholino-6-phenyl-pteridine a) 4- [N- (2-hydroxy-2-methy1-n-propy1) -ethanolamino] -2- (2.6-dimethyl-morpholino) -7-chloro-6-phenyl-pteridine 2.0 g (5 mitiol) of 4-[N- (2-hydroxy-2-methyl-n-propyl) -ethanolamino] -2 , 7-dichloro-6-phenyl-pteridine are dissolved in 30 ml of dioxan and stirred with 1.25 ml (10 mmol) of 2 , 6-dimethyl-morpholine for 2 hours at ambient temperature. Then the solution is added to water and the precipitate which hardens is suction filtered, dissolved in methylene chloride, dried and concentrated by rotary evaporation. The residue is chromatographed on a silica gel column with chloroform/methanol 95:5.

Yield: 1.1 g (45% of theory).

Melting point: 125°C b) 4- [N-( 2-hydroxy-2-methyl-n-propyl) -ethanolamino] -2- (2 , 6-dimethyl-morpholino) -7-morpholino-6-phenyl- pteridine Prepared from 4- [N- (2-hydroxy-2-methyl-n-propyl) -ethanolamino] -2- (2 , 6-dimethyl-morpholino) -7-chloro-6-phenyl-pteridine and morpholine analogously to Example 1.

Yield: 93% of theory, Melting point: 125 °C.

Example 13 4-[N- (2-Hydroxy-2-methyl-n-propyl) -ethanolamino] -7- (2 , 6-dimethyl-morpholino) -2-morpholino-6-phenyl-pteridine a) 4-[N-(2-hydroxy-2-methyl-n-propyl) -ethanolamino] -2- morpholino-7-chloro-6-phenyl-pteridine Prepared analogously to Example 12a) from 4-[N-(2-hydroxy-2-methyl-n-propyl) -ethanolamino] -2 , 7-dichloro-6-phenyl-pteridine and morpholine.

Yield: 64% of theory, Melting point: 152-155 "C. b) 4-[N-(2-hydroxy-2-methyl-n-propyl) -ethanolamino] -7- (2, 6-dimethyl-morpholino) -2-morpholino-6-phenyl- teridine Prepared from 4- [N- (2-hydroxy-2-methyl-n-propyl) -ethanolamino] -2-morpholino-7-chloro-6-phenyl-pteridine and 2 , 6-dimethyl-morpholine analogously to Example 1. Yield: 54% of theory, Melting point: sintering at 125 'C.

Example 14 4- (N-Ethyl-benzylamino) -2 , 7-bis (2 , 6-dimethyl-morpholino) -6-phenyl-pteridine Prepared from 4- (N-ethyl-benzylamino) -2 , 7-dichloro- 6-phenyl-pteridine and 2 , 6-dimethyl-morpholine analogously to Example 1.

Yield: 63% of theory, Melting point: 96 "C. 26 The following non-limiting Examples of pharmaceutical compositions are provided as further illustration of the invention: Example I Coated tablets containing 75 mg of 4-[N- (2-hydroxy-2-methyl-n-propyl) -ethanolamino] -2 , 7-bis (2 , 6-dimethyl-morpholino) -6-phenyl-pteridine ; 1 tablet core contains: Active substance 75. 0 mg Calcium phosphate 93. 0 mg Corn starch 35. 5 mg Polyvinylpyrrolidone 10. 0 mg Hydroxypropylmethylcellulose 15. 0 mg Magnesium stearate 1. 5 mq 230. 0 mg The active substance is mixed with calcium phosphate, corn starch, polyvinylpyrrolidone, hydroxypropylmethylcellulose and half the specified amount of magnesium stearate. In a tablet making machine, compressed blanks with a diameter of about 13 mm are produced which are pressed through a 1.5 mm mesh screen in a suitable apparatus and mixed with the remainder of the magnesium stearate. These granules are compressed in a tablet making machine using a 9mm convex punch to form tablets of the desired shape of 230 mg weight. The tablet cores thus produced are coated with a film consisting essentially of hydroxypropylmethylcellulose. The finished film-coated tablets are polished with beeswax to form tablets of 245 mg weight.

Example II Tablets containing 100 mg of 4-[N- (2-hydroxy-2-methyl-n-propyl) -ethanolamino] -2 , 7-bis (2 , 6-dimethyl-morpholino) -6-phenyl-pteridine Composition: 1 tablet contains: Active substance Lactose Corn starch Polyvinylpyrrolidone Magnesium stearate The active substance, lactose and starch are mixed together and evenly moistened with an aqueous solution of polyvinylpyrrolidone. After screening of the moist mass (2.0 mm mesh size) and drying in a rack dryer at 50 °C, the mass is screened again (1.5 mm mesh size) and the lubricant is added. The mixture ready for compression is processed to form tablets of weight 220 mg and diameter 10 mm, which are biplanar, facetted on both sides and provided with a dividing notch on one side.

Example III Tablets containing 150 mg of 4- [N- (2-hydroxy-2-methyl-n-propyl) -ethanolamino] -2 , 7-bis (2 , 6-dimethyl-morpholino) -6-phenyl-pteridine Composition: 1 tablet contains: Active substance 150.0 mg Powdered lactose 89.0 mg Corn starch 40.0 mg 28 Colloidal silicic acid 10.0 mg Polyvinylpyrrolidone 10.0 mg Magnesium stearate 1.0 ma 300.0 mg The active substance mixed with the lactose, corn starch and silicic acid is moistened with a 20% aqueous polyvinylpyrrolidone solution and passed through a 1.5 mm mesh screen. The granules dried at 45 °C are passed through the same screen again and mixed with the specified amount of magnesium stearate. Tablets are compressed from the mixture with a 10 mm flat punch to form tablets of weight 300 mg.

Example IV Hard gelatine capsules containing 150 mg of 4-[N-(2-hydroxy-2-methyl-n-propyl) -ethanolamino] -2 , 7-bis (2 , 6-dimethyl-morpholino¾ -6-phenyl-pteridine 1 capsule contains: Active substance 150.0 mg Dried corn starch approx. 180.0 mg Powdered lactose approx. 87.0 mg Magnesium stearate 3.0 ma approx . 420.0 mg The active substance is mixed with the excipients, passed through a 0.75 mm mesh sieve and homogeneously mixed in a suitable apparatus. The finished mixture is packed into size 1 hard gelatine capsules.

Capsule contents: about 320 mg Capsule shell: hard gelatine capsule, size 1.

Example V Suppositories containing 150 mg of 4- [N- ( 2-hydroxy-2- 29 methyl-n-propyl) -ethanolamino] -2 , 7-bis (2 , 6-dimethyl-morpholino) -6-phenyl-pteridine 1 suppository contains: Active substance 150.0 mg Polyethyleneglycol 1500 550.0 mg Polyethyleneglycol 6000 460.0 mg Polyoxyethylene sorbitan monostearate 840.0 mg 2,000.0 mg After the suppository mass has been melted, the active substance is homogeneously distributed therein and the melt is poured into chilled moulds.

Example VI Suspension containing 50 mg of 4- [N- ( 2-hydroxy-2-methyl-n-propyl) -ethanolamino] -2 , 7-bis (2 , 6-dimethyl-morpholino) -6-phenyl-pteridine 100 ml of suspension contain: Active substance Sodium carboxymethylcellulose Methyl p-hydroxybenzoate Propyl p-hydroxybenzoate Glucose Glycerol 70% sorbitol solution Flavouring Distilled water ad Distilled water is heated to 70 °C. The methyl and propyl p-hydroxybenzoates as well as the glycerol and sodium carboxymethylcellulose are dissolved therein with stirring. The solution is cooled to ambient temperature and the active substance is added and homogeneously dispersed therein with stirring. After the sugar, 30 sorbitol solution and flavouring have been added and dissolved therein, the suspension is evacuated with stirring to eliminate air. 5 ml of suspension contains 50 mg of active substance .

Example VII Ampoules containing 10 mg of 4-[N-(2-hydroxy-2-methyl-n-propyl) -ethanolamino] -2 , 7-bis (cis-2 , 6-dimethyl-morpholino) -6-phenyl-pteridine Composition: Active substance 10.0 mg 0.01 N hydrochloric acid q.s.

Twice distilled water ad 2.0 ml The active substance is dissolved in the required amount of 0.01 N HC1, made isotonic with common salt, filter sterilised and transferred into 2 ml ampoules. Sterilisation is effected by heating to 121 °C for 20 minutes . 31 Example VIII Ampoules containing 50 mg of 4-[N- (2-hydroxy-2-methyl-n-propyl) -ethanolamino] -2 , 7-bis (2 , 6-dimethyl-morpholino) -6-phenyl-pteridine Composition: Active substance 50.0 mg 0.01 N hydrochloric acid q.s.

Twice distilled water ad 10.0 ml The active substance is dissolved in the required amount of 0.01 N HC1, made isotonic with common salt, filter sterilised and transferred into 10 ml ampoules. Sterilisation is carried out by heating to 121"C for 20 minutes .

Example IX Dry ampoules containing 10 mg of doxorubicin and 10 mg of 4- [N- (2-hydroxy-2-methyl-n-propyl) -ethanolamino] -2 , 7-bis ( 2.6-dimethyl-morpholino) -6-phenyl-pteridine Content per dry ampoule Doxorubicin 10.0 mg Active substance 10.0 mg The doxorubicin and the pteridine active substance are dissolved in the required amount of 0.01 N HC1, filtered sterile and lyophilised.

A solvent ampoule containing 5 ml of saline solution is also prepared.

Before use the lyophilised material is dissolved in the sterile physiological saline solution.

Example X 32 Dry ampoules containing 50 mg of doxorubicin and 50 mg of 4-[N- (2-hydroxy-2-methyl-n-propyl) -ethanolamino] -2 , 7-bis (2 , 6-dimethyl-morpholino) -6-phenyl-pteridine Content of the dry ampoule Doxorubicin 50.0 mg Active substance 50.0 mg The doxorubicin and the pteridine active substance are dissolved in the required amount of 0.01 N HC1, filtered sterile and lyophilised.

A solvent ampoule containing 25 ml of saline solution is also prepared.

The other compounds of general formula I may of course be used as active substances in the galenic preparations described hereinbefore. - 33- 91814/2

Claims

1. A pharmaceutical composition for use in combatting primary and secondary resistance in chemotherapy with a natural product chemothera-peutic agent said composition comprising a compound of formula I (wherein n represents the number 0 or 1; R3 represents a straight-chained or branched C2.6 alkyl group in which one or two non-nitrogen-attached carbon atoms are substituted by a hydroxy group and R4 represents a benzyl group or a cx. alkyl group in which a non-nitrogen-attached carbon atom may be substituted by a hydroxy group, or R3 represents a alkyl group and R* represents a phenyl (C^) alkyl group; R2 and R7, which may be the same or different, each represents a pyrrolidino, piperidino or morpholino group optionally substituted by one or two methyl or ethyl groups ; and R5 represents a hydrogen atom or a methyl group) , or a geometric or optical isomer thereof or a physiologically acceptable acid addition salt thereof. -34- 91814/

2. A composition according to claim 1, further comprising at least one natural product chemotherapeutic agent.

3. A composition as claimed in claim 2 wherein said chemotherapeutic agent is selected from vinblastine, vincristine, vindesine, etoposide, teniposide, dactinomycin, daunorubicin, doxorubicin, bleomycin, mithramycin and mitomycin.

4. A compound of formula (wherein n represents the number 0 or .1, R2 and R7, which are identical, each represent a morpholino group substituted by a methyl or ethyl group in the 2-position or in the 2 and 6-positions, or a 3,5- dimethyl-piperidino group, R3 represents a 2-hydroxy-ethyl, 2-hydroxy-n-propyl , 2,3- dihydroxy-n-propyl or 2-hydroxy-2-methyl-n-propyl group, R_ represents a 2-hydroxy-2-methyl-n-propyl group and R5 represents a hydrogen atom or a methyl group; 91814/2 35 or n represents the number 0 and s represents a hydrogen atom or a methyl group, and R2 and R7, which are identical, each represents a 2,6-dimethylmorpholino or 2, 6-diethylmorpholino group, R3 and R<, together with, the intervening nitrogen atom represent an N- (Chalky1) -phenyl (Chalky1) amino , N-benzyl-ethanolamino, N-ethyl-ethanolamino, ethanol-isopropanolamino, (Methyl -isopropanol amino or N-(2',3-dihydroxy-n-prbpyl-ethanolamino group, or one of the groups R2 and R7 represents a morpholino group, the other group R2 or R7 represents a 2 , 6-dimethyl-morpholino or 2, 6-diethylmorpholino group and R3 and R4 together with the intervening nitrogen atom represent an N- ( 2-hydroxy-2-methyl-n-propyl) -ethanolamino group; or n represents the number 0, R5 represents a methyl grou , Rz and R7 each represents a 2-methyl-morpholino group, and R3 and (, together with the intervening nitrogen atom represent an ethanol-isopropanolamino group) , 91814/1 - 35a - or n represents the number 0, R5 represents a hydrogen atom, R2 and R7 each represents a 2-methyl-morpholino group, and R3 and R4 represent with the intervening nitrogen atom an ethanol-2,3-dihydroxy-propylamino group, ..·· or an optical or geometrical isomer or acid addition salt thereof.

5. A compound of formula la as claimed in claim 4 wherein 91814/2 36 R2 R3/ R4 and R7 are as defined in claim 4, n represents the number 0 and R5 represents a hydrogen atom, or an optical or geometric isomer or acid addition salt thereof.

6. A compound as claimed in claim 4 being: 4- [N- (2-hydroxy-2-methyl-n-propyl) -ethanolamino] -2 , 7-bis (2 , 6-dimethyl-morpholino) -6-phenyl-pteridine; 4- (N-ethyl-ethanolamino) -2 , 7-bis (2 , 6-dimethyl-morpholino) -6-phenyl-pteridine; 4- (ethanol-isopropanolamino) -2 , 7-bis (2 , 6-dimethyl-morpholino) -6-phenyl-pteridine; 4-[N- (2-hydroxy-2-methyl-n-propyl) -ethanolamino] -2 , 7-bis (2-methyl-morpholino) -6-phenyl-pteridine; 4- (ethanol-isopropylamino) -2 , 7-bis (2-methyl-morpholino) -6-benzyl-pteridine ; 4- (ethanol-isopropanolamino) -2 , 7-bis (2-methyl-morpholino) -6- (o-tolyl) -pteridine; 4-[bis (2-hydroxy-2-methyl-n-propyl) -amino] -2 , 7-bis (2-methyl-morpholino)-6-phenyl-pteridine; 4- (2 , 3-dihydroxy-n-propyl-ethanolamino) -2 , 7-bis (2-■methyl-morpholino)-6-phenyl-pteridine; 4- [N- (2-hydroxy-2-methyl-n-propyl) -ethanolamino] -2 , 7- 37 bis (3 , 5-dimethyl-piperidino) -6-phenyl-pteridine; 4- (N-ethanol-benzylamino) -2 , 7-bis ( 2 , 6-dimethyl-morpholino) -6-phenyl-pteridine 4- [N- (2-hydroxy-2-methyl-n-propy1) -ethanolamino] -2 , 7-bis (cis-2 , 6-dimethyl-morpholino) -6-phenyl-pteridine ; 4- [N- (2-hydroxy-2-methyl-n-propyl) -ethanolamino] -2- (2 , 6-dimethyl-morpholino) -7-morpholino-6-phenyl-pteridine; 4- [N- (2-hydroxy-2-methyl-n-propyl) -ethanolamino] -7- (2 , 6-dimethyl-morpholino) -2-morpholino-6-phenyl-pteridine; 4- (N-ethyl-benzylamino) -2 , 7-bis ( 2 , 6-dimethyl-morpholino) -6-phenyl-pteridine; or an acid addition salt thereof.

7. A compound of formula la as claimed in claim 4 wherein n and R5 are defined as in claim 5, R2 and R7 each represent a 2 , 6-dimethyl-morpholino group or one of the groups R2 or R7 represents a morpholino group and the other group R2 or R7 represents a 2 , 6-dimethyl-morpholino group, and R3 and R4 together with the intervening nitrogen atom represent an N-(2-hydroxy-2-methyl-n-propyl)-ethanolamino group, or an optical or geometric isomer or acid addition salt thereof. 38

8. A compound as claimed in claim 4 being 4-[N-(2-hydroxy-2-methyl-n-propyl) -ethanolamino] -2 , 7-bis (2 , 6-dimethyl-morpholino) -6-phenyl-pteridine, or an optical or geometric isomer or acid addition salt thereof.

9. A compound as claimed in any one of claims 4 to 8 being a physiologically acceptable acid addition salt of a compound of formula la.

10. A process for preparing compounds as claimed in claims 4 to 9, said process comprising at least one of the following steps: a) reacting a pteridine of formula II (wherein R3 to R5 and n are defined as in any one of claims 4 to 8, one of the groups Z2 or Z7 represents a nucleophilically exchangeable group and the other group Z2 or Z7 has the meanings given for R2 or R7 in claims 4 to 8 or also represents a nucleophilically exchangeable group) with an amine of formula III H - X (III) (wherein X has the meanings given for R2 or R7 in claims 4 to 8) ; 39 b) converting a compound of formula la into an acid addition salt thereof or converting an acid addition salt of a compound of formula la into the free base; and c) resolving a compound of formula la or salt thereof into its optical or geometric isomers.

11. A pharmaceutical composition according to claim 1 comprising a compound of formula la (as defined in any one of claims 4 to 8), or an isomer or physiologically acceptable acid addition salt thereof, together with at least one pharmaceutical carrier or excipient.

12. A compound of formula la as defined in claim 4 substantially as herein disclosed in any one of the Examples .

13. A pharmaceutical composition comprising a compound of formula I as defined in claim 1 substantially as herein disclosed in any one of the Examples. PARTNERS ND/mr