DD299062A5 - USE OF PTERIDINES AND METHOD FOR THE PRODUCTION THEREOF - Google Patents

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

Use of pteridines and process for their preparation

The invention relates to the use of pteridines for the prevention of primary and secondary resistance in chemotherapy.

In the treatment of neoplastic diseases include natural products, such. Vinca alkaloids such as vinblastine, vincristine or vindesine, epipodophyllotoxins such as etoposide or teniposide, and antibiotics such as dactinomycin, daunorubicin, doxorubicin, bleomycin, mithramycin or mitomycin (see Goodman and Gilman's, The Parmacoligical Basis of Therapeutics, Macmillan Publishing Company, New York, 7th ed Edition, pages 1 240-1 247 and 1 277-1 289 (1985).) In chemotherapy with the substances listed above, it is frequently observed that the tumors to be treated due to a primary resistance or because of a due ansp'rechen not a therapy vorgegangenen formed secondary resistance to therapy, or that therapy Rosi n stents tumor cells may remain latent after remission of Tumo. _a. These resistant tumor cells typically result in at a later time to relapse.

By the use of pteridines according to the invention resistant tumors are brought to remission.

The object of the present invention is to provide compounds which prevent therapy-resistant tumor cell subpopulations from surviving the therapy and lead to recurrence, as well as processes for the preparation of these compounds

 It has been found that by the application of a pteridine of the formula

in the

η is the number 0 or 1,

R _{3 is} a straight-chain or branched alkyl group having 2 to 6 carbon atoms, in which, with the exception of the carbon atom adjacent to the nitrogen atom, one or two carbon atoms are substituted by a hydroxy group,

R4 is a benzyl group or an alkyl group having 1 to 4 carbon atoms in which, except for the carbon adjacent to the nitrogen atom, a carbon atom may be substituted by a hydroxy group, or R _{3 is} an alkyl group having 1 to 3 carbon atoms and

R _{4 is} a phenylalkyl group having 1 to 3 carbon atoms in the alkyl part,

R ₂ and R ₇ , 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 is a hydrogen atom or a methyl group, one of its geometrical or optical isomers and its acid addition salt, in particular its physiologically tolerated acid addition salts with an inorganic or organic acid,

resistant tumors are brought to remission.

By the prior, simultaneous or subsequent administration of a pteridine of the above general formula I or its physiologically tolerated acid addition salt according to the invention sensitization of tumors with a primary or secondary resistance to the above-mentioned chemotherapeutic agents is achieved.

The present invention therefore relates to the preparation of a novel medicament containing a pteridine of the above general formula I, one of its geometric or optical isomers or its physiologically acceptable acid addition salt and at least one chemotherapeutic agent from the series of natural products, and the new use of the above pteridines for sensitization of tumors in chemotherapy with the above-mentioned chemotherapeutic agents from the series of natural products.

For the bsi of the definitions of the radicals mentioned in the beginning, for example, R ₂ and R _{7 are} each those of pyrrolidino, 2-methylpyrrolidino, 3-methylpyrrolidino, 3,3-dimethylpyrrolidino, 2-ethylpyrrolidino , 3-ethyl-pyrrolidino, 3,3-diethyl-pyrrolidino, piperidino, 2-methyl-piperidino, 3-methyl-piperidino, 4-methyl-piperidini-, 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-dimethylmorpholino, cis ^ .e-dimethyl-morpholino, trans-2,6-dimethyl-morpholino, 2,6-diethyl-morpholino, cis-2, 6-diethylmorpholino, trans-2,6-diethyl-morpholino, 3,5-dimethyl-morpholino or 3,5-diethyl-morpholino, for R ₃ those of 2-hydroxyethyl, 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-dihydr oxy-n-propyl, methyl, ethyl, n-propyl or isopropyl group,

for R _4, the benzyl, 2-phenyl-ethyl, 2-phenyl-n-propyl, 3-phenyl-propyl, 2-hydroxy-ethyl, 2-hydroxy-n-propyl, 3-hydroxypropyl , 4-hydroxy-butyl or 2-hydroxy-2-methyl-n-propyl group and for Rs that of the hydrogen atom or the methyl group into consideration

 Here, the pteridines of the abovementioned general formula I are new in which η is the number 0 or 1,

R ₂ and R ₇ , which are the same, each have a morpholino group or a 3,5-dimethyl-piperidino group which is substituted in the 2- or in the 2- and the 6-position by a methyl or ethyl group,

Ra is 2-hydroxyethyl, 2-hydroxy-n-propyl, 2,3-dihydroxy-n-propyl or 2-hydroxy-2-methyl-n-propyl, R4 is 2-hydroxy-2-methyl n-propyl group and R _{5 is} a hydrogen atom or a methyl group

or, when η is the number 0 and R _{6 is} a hydrogen atom or a methyl group. R ₂ and R ₇ , which are the same, each represents a 2,6-dimethyl or 2,6-diethylmorpholino group; Ra and R ₄ together with the intervening nitrogen atom represent an N-alkyl-phenylalkylamino group in which the alkyl portion has 1 to 3 carbon atoms each may contain an N-benzyl-ethanolamino, N-ethyl-ethanolamino, N-ethyl-isopropanolamino, ethanol-isopropanolamino or N- (2,3-dihydroxy-n-propyl) -ethano! amino group or one of Radicals R ₂ or R _{7 is} a morpholino group,

the other of R ₂ or R _{7 is} a 2,6-dimethyl or 2,6-diethylmorpholino group and R ₃ and R ₄ together represent an N- (2-hydroxy-2-methyl-n-propyl) -ethanolamino group or, if η is the number 0 and Rs is a methyl group, R ₂ and R _{7 are} each a 2-methylmorpholino group,

R ₃ and R ₄ together with the intervening nitrogen atom denote an ethanol-isopropanolamino group, their optical and geometric isomers and their acid addition salts, in particular their physiologically acceptable acid addition salts.

Processes for the preparation of the abovementioned novel pteridines and for the production of medicaments / containing these pteridines are a further subject of the present invention

 Preferred pteridines of the above general formula I here are those in which η is the number 0,

R ₂ and R ₇ , which may be the same or different, are a piperidino, 3,5-dimethyl-piperidino, morpholino, 2-methyl-morpholino, 2,6-dimethyl-morpholino, cis-2,6 Dimethyl-morpholino or trans-2,6-dimethylmethylmorpholino group, R _{3 is} a methyl, ethyl, benzyl, 2-hydroxyethyl, 2-hydroxy-n-propyl, 2,3-dihydroxy- n-propyl or 2-methyl-2-hydroxy-n-propyl group,

R _{4 is} a 2-hydroxyethyl, 2-hydroxy-n-propyl or 2-methyl-2-hydroxy-n-propyl group and R _{6 is} a hydrogen atom or a methyl group,

their optical and geometric isomers and their physiologically acceptable acid addition salts, the compounds 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-dimethylmorpholino) -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-isopropanoiamino) -2,7-bis ( 2-methyl-morpholino) -6- (o-tolyl) -pteridine, 4- [bis (2-hydroxy-2-methyl-n-propyl) -arnino] -2,7-bis (2,6-dimethyl- morpholino; -6-phenyl-pteridine, 4- (2,3-dihydroxy-n-propyl-ethanolamino) -2,7-bis (2,6-dimethylmorpholino) -6-phenyl-pteridine, 4- [N- ( 2-hydroxy-2-methyl-n-propyl) ethynolino] -2,7-bis (3,5-dimethyl-piperidino) -6-phenyl-pteridine, 4- (N-ethanol-benzylamino) -2, 7-bis (2,6-dimethyl-morpholino) -6-phenyl-pter idine, 4- [N- (2-hydroxy-2-methyl-n-propyl) -ethanolamino) -2,7-bis (cis-2,6-dimethyl-morpholino) -6-phenyl-ptericline, 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, e-dimethyl-morpholino) -2- (morpholino-6-phenyl-pteridine and 4- (N-ethyl benzylamino) -2,7-bis (2,6-dimethyl-morpholino) -6-phenyl-pteridine are new.

However, preferred new compounds are those in which

η is the number 0,

R ₂ and R _{7 are} each a 2,6-dimethyl-morpholino group or

one of R ₂ or R 7 is a morpholino group and

the other of the radicals R ₂ or R _{7 is} a 2,6-dimethylmorpholino group,

R3 and R4 together represent an N- (2-hydroxy-2-methyl-n-propyl) -ethanolamino group and Rs represent a hydrogen atom.

According to the invention, the following pteridines have proven to be particularly effective:

4- [N- (2-Hydroxy-2-methyl-n-propyl) -ethanol-amino-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-HydroAy-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- isopropanolami.io) -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 (2,6-dimethyl-morpholino) -6-phenyl-pteridine, 4- (2,3-dihydroxy -n-propyl-ethanolamino) -2,7-bis (2,6-dimethylmorpholino) -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-methyl-n-propyl) -ethanolamino] -2,7 bis (cis-2,6-dimethyl-morpholino) -6-phenyl-pteridine, 4- [N- (2-hydroxy-2-methyl-n-propyl) -ethanolamino) -2,7-bis (trans 2,6-dimathyl-morpholino) -6-phenyl-pteridine, 4- [N- (2-hydroxy-2-methyl-2-propyl) -ethanolamino] -2- (2,6-dimethyl-morpholino) - 7-morpholino-6-phenyl-pteridine and 4- [N- (2-hydroxy-2-methyl-n-propyl) -eth9nolaminol-7- (2,6-dimethyl-morpholino) -2-morpholino-6-phenyl pteridine, as well as their physiologically acceptable acid addition salts.

For example, sensitization by the compounds

A = 4-N- (2-hydroxy-2-methyl-propyl) -ethanolamino-2,7-bis (2,6-dimethyl-morpholino) -6-phenyl-pteridine, B = N-ethyl-ethanolamino-2 , 7-bis (2,6-dimethyl-morpholino) -6-phenyl-pteridine, C = 4-ethanol-isopropanolamino-2,7-bis (2,6-dimethyl-morpholino) -6-pheiiyl-pteridine, D = 4-diethanolamino-2,7-bis (2,6-dimethyl-morpholino) -6-plienyl-pteridine and E = 4- [N- (2-hydroxy-2-methyl-propyl) -ethanol-aminol-2,7 -bis (cis-2,6-dimethyl-morpholino) -6-phenyl-pteridine using the example of adriamycin-resistant cells as follows:

Proliferating, adriamycin-resistant S180 mouse sarcoma cells are cultured in the presence of different concentrations of test substances for six days. Cytotoxic or cytostatic concentrations of the test substances are indicated by reduced cell growth or cell death. The endpoint of the assay is the number of live cells per culture, which is determined indirectly by the property of vital cells, the dye MTT [= 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide] to the colored Exploiting formazan is exploited. IC 50 is the concentration of a test substance which reduces the number of vital cells per culture vessel to 50% of the untreated control.

The test substances are Adriarr in the absence of adriamycin as well as in the presence of a non-proliferation-inhibiting under Kuitur conditions. / a tested. Therefore, two IC 50 values are obtained per test substance, one in the presence (IC50 ADR) and the other in the absence (IC50) of adriamycin. The difference between the ten logarithms of the two IC50 values: Δ = IgC50-IgC50 ADR is a measure of the increase in the cytotoxicity of the test substance by adriamycin.

Experimental Procedure

Exponentially growing, adriamycin-resistant or adriamycin-sensitive S 180 cells are plated in 96-well flat bottom microtiter plates at 2000 cells per well in 100μΙ growth medium (RPMI-1640 containing 10% fetal bovine serum). The culture plates are incubated in the incubator at 37 ° C, 5% CO ₂ and 100% relative humidity. After 24 hours, 50 μl of growth medium containing different concentrations of test substance and 50 μl of growth medium with or without adriamycin are added per well. Following another six-day culture, 50μΙ of Totrazolium Saline | 5mg of 3- (4,5-dimethylthiazol-2-yl) -?, 5-diphenyltetrazolium bromide per ml of phosphate buffered saline solution, before use, is diluted 1: 5 (v / v) with RPMI -1640 diluted] into each well. After four hours of incubation, the culture medium is carefully aspirated and solubilized intracellular formazan by 150 μΙ dimethyl sulfoxide per hole. The plates are shaken briefly and the optical density measured at 570 nm with a photometer such as a Dynatech MR-600 instrument. The formation of the colored formazone by reduction of the tretrazolium salt is proportional to the number of living cells. The mean values of triplicate determinations were used in the calculation of IC50 values (dilution level: 1: 2).

Table 1

IC 50

substance ιυυυ \ μ ^ / ιΐιΐ; adriamycin 20.69 inng / ml 'U IC5025ng adriamycin O > 31.60 25 A 12.85 1.49 1.14 B 14,37 4.43 > 0.85 C 7.50 3.77 0.53 D 5.78 0.40 LJJ 0.50 1.18

Table 2

IC 50

substance IVsOU ΐμυΜΜΙ * adriamycin 20.69 inng / ml ¹ U IC 50100 ng adriamycin 0 > 31.60 100 A 12.85 <0.50 > 1.61 B 14,37 0.77 > 1.61 C 7.50 0.82 1.20 D 1.57 0.96 e 0.10 1.88

Airline of the above general formula I thus have a marked sensitization to adriamycin-resistant Satcuni.j. llnn and are therefore suitable in combination with vinca alkaloids, epipodophyllotoxins or antibiotics such as daunorubicin, doxorubicin, bleonycin, mithramycin or mitomycin for the treatment of neoplastic diseases In the case of tumors which are resistant to the above-mentioned chemotherapeutic agents, the pteridines of the formula I together with the chemotherapeutic agent prevent therapy-resistant tumor cell subpopulations from surviving the therapy and thus prevent their resistance to a corresponding chemotherapy. . can lead to recurrence.

The application of the pteridines, which are also well tolerated, is carried out separately or in combination with a chemotherapeutic agent administered in the usual dose; the dose 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 into 1 to 4 individual doses.

Combined with a corresponding chemotherapeutic agent is an intravenous dosage form such as ampoules and in a separate application, a parallel dosage form of tablets, Dragoes, suspensions, juices, capsules or suppositories into consideration.

Based on the literature application scheme of 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 1277-128911985]) is the first Administering a pteridine of the formula I or its physiologically acceptable acid addition salt, expediently together with or before the chemotherapeutic agent used or with or before a combination of several chemotherapeutic agents containing at least one of the abovementioned chemotherapeutic agents (see DeVita et al., Cancer, Principles & Practice of Oncology ", 2nd Edition, JB Lippincott Company Philadelphia).

The other applications of a pteridine of the formula I or its physiologically acceptable acid addition salt can be carried out according to the circumstances orally or also intravenously. >

An inventive for the i. Appropriately suitable combination of v.-application thus conveniently contains 1 to 25mg / kg, preferably 1 to 20mg / kg body weight of a pteridine of formula I or its physiologically acceptable acid addition salt and a suitable chemotherapeutic agent or a combination of various suitable chemotherapeutic agents, eg. B.

0.1-0.15 mg / kg vinblastine every 7 days, whereby the dose may be increased in steps of 0.05 mg / kg depending on the degree of adverse reactions,

approx. 2 mg / m ² body surface vincristine every 7 days for juvenile leukemia, whereas in adults therapy preferably begins at 0.01 mg / kg every 7 days and, depending on tolerability, to 0.02-0.05 mg / kg can be increased, 3-4 mg / m ² body area Vindesin every 7 days, 25-30μg / kg mithramycin daily or every 2 days, 60-75mg / m ² body surfaceAdriamycinalle21 days, 30-60mg / m ² body surface Daunorubicin daily for 3 days , 10-15pg / kg dactinomycin daily for 5 days, 50-100mg / m ² body surface etoposide daily for 5 days and

30mg / m ² body surface Teniposide daily up to 5 days, followed by 6-10 treatment cycles after each 10-day break.

The pteridines of general formula I are described in CA-A-912,556, US-A-3,557,105 and US-A-3,574,206 or can be prepared by the methods described therein.

The novel pteridines of the above formula I are obtained by reacting a pteridine of the formula

( ^CH 2 ^ n \ / (H)

in the

R ₃ to Rs and η are as defined above,

one of Z ₂ or Z _{7 is} a nucleophilically exchangeable group wio is a halogen atom, for. As a chlorine or bromine, represents

the other of the radicals Z ₂ or Z _{7 has} the meanings mentioned for R ₂ or R ₇ above, or also a nucleophilically exchangeable group such as a halogen atom, eg. As a chlorine or bromine atom, with an amine of the general formula

H-X (III)

in the

X has the meanings mentioned for R ₂ or R ₇ .

The reaction is conveniently carried out in a solvent such as tetrahydrofuran, dioxane, benzene, toluene, dimethyl sulfoxide or dimethyl glycol ether at temperatures between 0 and 150 ° C, preferably at temperatures between room temperature and the boiling point of the solvent used or in the melt. In this case, the use of an acid-binding agent such as sodium carbonate, triethylamine or pyridine may be advantageous.

The novel compounds obtained according to the invention can be converted into their acid addition salts, in particular into their physiologically tolerated salts with inorganic or organic acid clay. Suitable acids are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, citric acid, tartaric acid, succinic acid, maleic acid or fumaric acid.

The compounds of the general formula II and III used as starting material are for the most part known (see CA-A-912,556, US-A-3,557,105 and US-A-3,574,206) or they are obtained according to the in the US -A-2,940,972 or according to the methods described in the aforementioned patents.

If the compounds of the formula I contain at least one chiral center, these can be separated into their enantiomers by customary methods, for example by column chromatography on a chiral phase or by crystallization with optically active acids, eg. With D- or L-monomethyltartaric, D- or L-diacetyl-tartaric acid, D- or L-tartaric acid, D- or L-lactic acid or D- or L-camphoric acid.

In addition, the compounds of formula I, provided that they contain at least one geometric center such as a substituted by two methyl or ethyl groups pyrrolidino, piperidino or morpholino, but in particular at least one 2,6-dimethyl-morpholino, by conventional methods, for example by Chromatography, are separated or present in their cis / trans isomers.

The following examples are intended to explain the invention in more detail:

embodiments

Example 1 4 [N · (2-hydroxy-2-methyl-n-propyl) -thanolamino] -2,7-bis (2,6-dimethylmorpholino) 6-dimethylpteridine

a) 2,7-Dichloro-4- [N- (2-hydroxy-2-methyl-n-propyl) -ethanolamino] -6-phenyl-pteridine

15.5 g (0.005 mol) of 2,4,7-trichloro-6-phenyl-pteridine are dissolved in 100 ml of acetone and treated with 13.3 g (0.1 mol) of N- (2-hydroxy-2-methyl-propyl) After stirring at room temperature for 20 minutes, 200 ml of water are added to the resulting suspension and the precipitated product is filtered off with suction, washed with water and crystallized from methanol / water = 95: 5.

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 dioxane and washed with 3.5 g (0 , 08 mol) of 2,6-dimethyl-morpholine heated for 30 minutes at reflux. Subsequently, the reaction solution is poured into water, the precipitate was filtered off, washed with water and recrystallized from ethyl acetate.

Yield: 2.4g (84% of theory),

Melting point: 191-194 ⁰ C.

Example 2

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

Yield: 81% of theory,

Melting point: 128-138 ⁰ C (ethanol).

Example 3

Prepared from 4- (ethanol-isopropanolamino) -2,7-dichloro-6-phenyl-pteridine and 2,6-Dimetliyl-morpholin analogously to Example Yield: 60% of theory, Melting point: 192-193 ⁰ C (methanol / water = 4: 1).

Example 4

4-N (2-hydroxy-2-methoxy-n-propyl) -thanolamino] -2,7-bis (2-methyl-morpholino) 6-phenyl-p-noridine Prepared from 4- | N- (2-hydroxy-2 -metliyl-n-propyl) -ethanolamino] -2,7-dichloro-6-phenyl-pteridine and 2-methyl-morpholine in analogy to example yield: 74% of theory, melting point: 143-147 ⁰ C (Essigestar / petroleum ether).

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 morpholine analogously to example yield: 55% of theory, melting point: 100-105 ⁰ C.

Examples

4- (Ethanol-isopropanolamino) -2,7-bl (2-methyl-morpholino) -6- (o-tolyl) -pteridine Prepared from 4- (ethanol-isopropanolamino) -2,7-dichloro-6- (o -tolyl) pteridin and 2-methyl-morpholine in analogy to example yield: 85% of theory, melting point: 105-110 ⁰ C (reprecipitation from 0.1 N hydrochloric acid).

Example 7

4- [Bis (2-hydroxy-2-methyl-n-propyl) -amino] -2,7-bis (2,6-dimethyl-morpholino) -6-phenyl-pteridine Prepared from 4- [bis (2-hydroxy 2-methyl-n-propyl) -aminol-2,7-dichloro-6-phenyl-pteridine and 2,6-dimethyl-morpholine analog

Example 1.

Yield: 46% of theory, Melting point: 122-127 ⁰ C (reprecipitation from 0.1 N hydrochloric acid).

Example 8

4- (2,3-Dihydroxy-n-propyl-ethanolamino) -2,7-bis (2,6-dimethylmorpholino) -6-phenyl-pteridine Prepared from 4- (2,3-dihydroxy-n-propyl-ethanolamino ) -2,7-dichloro-6-phenyl-pteridine and 2,6-dimethyl-morpholine analog

Example 1.

Yield: 76% of theory, Melting point: 105-115 ⁰ C (reprecipitation from 0.1 N hydrochloric acid).

Example 9

4- [N- (2-hydroxy-2-methyl-n-propyl) -ethanolamino] -2,7-bls- (3,5-dimethyl-piperidino) -6-phenyl-pteridine Prepared from 4-lN- (2-Hydroxy-2-methyl-n-propyl) -ethanolamino] -2,7-dichloro-6-phenyl-pteridine and 3,5-dimethyl-piperidine analogous to Example 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-morpnoline analogously to Example Yield: 34% of theory, melting point: 200-202 ° C.

Example 11

4- [N- (2-hydroxy-2-methyl-n-propyl) -ethano! -Amino] -2,7-bis (cis-2,6-dimethyl-morpholino "o) -6-phenyl-pteridine Prepared from 4- [N- (2-hydroxy-2-methyl-n-propyl) -ethanolamino] -2,7-dichloro-6-pher. / L-pteridine and cis-2,6-dimethylmorpholine analogously to Example 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-methyl-n-propyl) -ethanolamino) -2- (2,6-dimethyl-morpholino) -7-chloro-6-phenyl-pteridine 2.0g (5 mmol ) 4- [N- (2-Hydroxy-2-methyl-n-propyl) -ethanolamino] -2,7-dichloro-6-phenyl-pteridine are dissolved in 30 ml dioxane and treated with 1.25 ml (10 mM MoI) 2.6 Dimethyl morpholine stirred for 2 hours at room temperature. The solution is then added to water and the first precipitate is filtered off with suction, dissolved in methylene chloride, dried and concentrated by rotary evaporation. The residue is chromatographed on a silica gel column with chloroform / methanol = 95: 5 chroamtographiert.

Yield: 1.1 g (45% of theory), m.p .: 125 ^° C.

Stopped 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) -thethanolamino] -7- (2,6 · dl-n-thyl · morpholino) -2-morpholino-6-phenyl-p-triazine

a) 4- [N (2 x -hydroxy-2 · methylthyl · n · propyl) · θthanolamino] -2-morpholino-7-chloro-6-phenylpaltylnol

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 ⁰ C.

b) 4- [N • (2-hydroxy-2-methylthyl-n-propyl) -thanolamino] -7- (12,6-dimethylthylmorpholino) -2-methylpholno 6-phylnylphenylthin Prepared from 4- [N- (2 -Hydroxy-2-methyl-n-propyl) -ethanolamino] -2-morpholino-7-chloro-6-ph8nyl-pteridine and 2,6-dimethylmorpholine analogously to Example 1.

Yield: 54% of theory, melting point: sintering at 125 ° C

Example 14

4- {M-Ethylbenzylamino) -2,7-bls (2,6-dimethyl-morpholino) -6-phenyl-pteridine Prepared from 4- (N-ethylbenzylamino) -2,7-dichloro-6-phenylpteridine and 2,6-dimethyl-morpholine analogously to Example Yield: 63% of theory, melting point: 96 ° C.

Example I

Dragos with 75 mg of 4- [N- (2-hydroxy-2-methyl-n-propyl) -ethanolamino] -2,7-bls (2,6-dimethyl-morpholino) -6-phenyl-pteridine

1 Dragoekern contains: 75,0mg active substance 93.0 mg calcium phosphate 35,5mg corn starch 10.0 mg polyvinylpyrrolidone 15.0 mg hydroxypropyl methylcellulose 1.5mg magnesium stearate

230.0 mg

production:

The active substance is mixed with calcium phosphate, corn starch, polyvinylpyrrolidone, hydroxypropylmethylcellulose and half of the stated amount of magnesium stearate. On a tabletting machine compacts are produced with a diameter of about 13 mm, these are ground on a suitable machine through a sieve with 1.5 mm mesh size and mixed with the remaining amount of magnesium stearate. This granulate is pressed on a tabletting machine into tablets of the desired shape.

Core weight: 230mg Stamp: 9mm, arched

The Dragäekerne thus prepared are coated with a film consisting essentially of hydroxypropylmethylcellulose. The finished film drags are shone with beeswax.

Dragao weight: 245mg.

Example If

Tablets containing 100 mg of 4- [N- (2-hydroxy-2-methyl-n-propyl) -ethanolamino] -2,7-bls (2,6-dimethyl-morpholino) -6-phenyl-pteridine

Composition: 100.0 mg 1 tablet contains: 80.0 mg active substance 34.0 mg lactose 4.0 mg corn starch 2.0 mg polyvinylpyrrolidone magnesium stearate

220,0mg

Production method:

Active ingredient, lactose and starch are mixed and uniformly moistened with an aqueous solution of polyvinylpyrrolidone. After sieving the moist mass (2.0 mm mesh size) and drying in a drying oven at 5O ⁰ C is again sieved (1.5 mm Mbschenwoito) and the lubricant mixed. The ready-to-use mixture is processed into tablets.

Tablet weight: 220mg

Diameter: 10mm, biplane with double-sided racette and one-sided part notch.

Example III

Tablets containing 150 mg of 4 × N-2-hydroxy-2-methyl-n-propyl-β-thanolaminol-2,7-bls (2,6 × dl-methyl-morpholino-6-phen-pentteridine

Composition: 150.0 mg 1 tablet contains: 89,0mg active substance 40.0 mg Milk sugar powder. 10.0 mg corn starch 10.0 mg Colloidal silicic acid 1.0 mg polyvinylpyrrolidone magnesium stearate

300.0 mg

production:

The active substance mixed with lactose, corn starch and silica is moistened with a 20% strength aqueous solution of polyvinylpyrrolidone and beaten through a sieve with a mesh size of 1.5 mm. The dried at 45 ⁰ C granules are rubbed again through the same sieve and mixed with the specified amount of magnesium stearate. From the mixture tablets are pressed.

Tablet weight: 300mg Stamp: 10mm, flat

Example IV

Hard gelatin capsules containing 150 mg of 4- [N- (2-hydroxy-2-methyl-n-propyl) -ethanolamino] -2,7-bis (2,6-dimethylmorphollno) -6-phenylpteridine

1 capsule contains:

Active ingredient 150.0 mg

Corn starch drink. about 180.0mg

Milk sugar powder approx. 87.0mg

Magnesium stearate 3.0 mg

about 420.0mg

production:

The active ingredient is mixed with the excipients, passed through a sieve of 0.75 mm mesh size and mixed homogeneously in a suitable device.

The final mixture is filled into size 1 hard gelatin capsules.

Capsule filling: approx. 320mg

Capsule shell: Hargelatine capsule size 1.

Example V

Suppositories with 150 mg of 4- [N- (2-hydroxy-2-methyl-n-propyl) -ethanolamino] -2,7-bis (2,6-diniethyl-morpholino) -6-phenylpteridine

1 suppository contains:

Active ingredient 150.0 mg

Polyethylene glycol 1500 550.0 mg

Polyethylene glycol 6000 460.0mg

Polyoxyethylene sorbitan monostearate 840.0 mg

2000.0 mg

production:

After the suppository mass has melted, the active ingredient is distributed homogeneously therein and the melt is poured into pre-cooled molds.

Example VI

Suspension with 50 mg of 4- [N- (2-hydroxy-2-methyl-n-propyl) -ethanolamino] -2,7-bls (2,6-dimethylmethylmorphiolio) -6-phenyl-pteridine

100ml suspension contain: 1.0g active substance 0.1g Carboxymethylcellulose-Na-salt 0.05 g p-hydroxybenzoate 0.01g p-hydroxybenzoate 10.0 g cane sugar 5.0 g glycerin 20.0 g Sorbitol solution 70% 0.3g Aroma ad 100ml Water dist.

production:

Dest. Water is heated to 7O ⁰ C. Herein, methyl p-hydroxybenzoate and propyl ester are dissolved with stirring while glycerin and carboxymethyl cellulose sodium salt are dissolved. It is cooled to room temperature and added with stirring, the active ingredient and dispersed homogeneously. After addition and dissolution of the sugar, the sorbitol solution and the aroma, the suspension is evacuated to vent with stirring.

5ml suspension contain 50mg active ingredient.

Example VII

Ampoules containing 10 mg of 4- [N * (2-hydroxy-2-methyl-n-propyl) -thanolamino] -2,7-bis (cia-2,6-dimethyl morpholino) 6-phenylpheridine

Composition:

Active ingredient 10.0mg

0.01 η hydrochloric acid s. q.

Aquabidest ad 2,0ml

production:

The active ingredient is dissolved in the required amount 0.01 η HCl, made isotonic with sodium chloride, sterile filtered and filled into 2 ml ampoules. Sterilization is carried out by 20 minutes heating to 121 ⁰ C.

Example VIII

50 mg ampoules of 4- [N- (2-hydroxy-2-methyl-n-propyl) -1-ethanolamino] -2,7-bis (2,6-dimethyl-morpholino) -6-phenyl-pteridine

Composition: 50.0 mg Wirkstott 0.01 η hydrochloric acid s. q. ad 10.0ml Aqua bidest

production:

The active ingredient is dissolved in the required amount 0.01 η HCl, made isotonic with sodium chloride, sterile filtered and filled into 10 ml ampoules. Sterilisaiton carried out by heating for 20 minutes at 121 ⁰ C.

Example IX

Dry ampoules containing 10 mg of doxorublins and 10 mg of 4- [N- (2-hydroxy-2-methyl-n-propyl) ethanolamine] -2,7'bis (2,6-dimethylmorpholino) -6-phenyl-pteridine

Composition of dry ampoule: Doxorubicin 10.0 mg

Active substance 10.0mg

production:

The two active substances are dissolved in the required amount of 0, C1 η HCl, filtered and lyophilized.

The solvent vial contains 5ml saline.

Before use, the lyophilizate is dissolved in the sterile physiological saline solution.

Example X

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-dimethylmorpholino) -6-phenyl-pteridine

Dry phase composition: Doxorubicin 50.0 mg

Active substance 50.0mg

production:

The two active substances are dissolved in the required amount 0.01 η KCl, sterile filtered and lyophilized.

The solvent ampule contains 25 ml saline.

Before use, the lyophilizate is dissolved in the sterile physiological saline solution.

Of course, all other compounds of general formula I can be used as active ingredients in the above galenic preparations.

Claims (11)

claims: 1. Use of pteridines of the formula I (D in the η is the number O or 1, R _{3 is} a straight-chain or branched alkyl group having 2 to 6 carbon atoms in which, with the exception of the carbon atom adjacent to the nitrogen atom, one or two carbon atoms are substituted by a hydroxy group, and R _{4 is} a benzylflupup ^<r > .r, an alkyl group having 1 to 4 carbon atoms, in which, with the exception of the carbon atom adjacent to the nitrogen atom, a carbon atom may be substituted by a hydroxy group, or R3 is an alkyl group having 1 to 3 carbon atoms and R 4 is a phenylalkyl group having 1 to 3 carbon atoms, R 2 and R _7, which may be identical or different, each represent an optionally substituted by one or two methyl or ethyl groups pyrrolidino, piperidino or morpholino group, and R ₅ is a hydrogen atom or a methyl group or their geometrical or optical isomers and their physiologically acceptable acid addition salts with an inorganic or organic acid, characterized in that they are suitable for the preparation of a medicament suitable for preventing primary and secondary resistance in chemotherapy with a chemotherapeutic agent from the natural product series , are used. 2. Use according to claim 1, characterized in that is used as a chemotherapeutic vinblastine, vincristine, vindesine, etoposide, teniposide, dactinomycin, daunorubicin, doxorubicin, bleomycin, mithramycin or mitomycin. 3. A process for the preparation of a medicament, characterized in that a pteridine of the formula I according to claim 1 or its physiologically acceptable acid addition salt is incorporated together with a chemotherapeutic agent from the series of natural products in one or more inert conventional carrier. 4. A process for the preparation of pteridines of the formula I in which η is the number 0 or 1, R ₂ and R ₇ , which are the same, each have a morpholino group or a 3,5-dimethylpiperidino group substituted in the 2- or in 2- and 6-position by a methyl or ethyl group, R _{3 is} 2-hydroxyethyl, 2 -Hydroxy-n-propyl, 2,3-diphydroxy-n-propyl or 2-hydroxy-2-methyl-n-propyl group, R4 is a 2-hydroxy-2-methyl-n-propyl group and R ₅ is a hydrogen atom or a methyl group or, if η ₅ represent the number 0 or R is a hydrogen atom or a methyl group, R ₂ and R _7, which are identical, each having a 2,6-dimethyl or 2,6-diethylmorpholino group, R ₃ and R ₄ together with the intervening nitrogen atom, an N-alkylphenylalkylamino group in which the alkyl moiety may each contain 1 to 3 carbon atoms, an N-benzyl-ethanolamino, N- Ethyl-ethanolamino, N-ethyl-isopropanolamino, ethanolisopropanolamino or N- (2,3-dihydroxy-n-propyl) -ethanolamino group or one of R ₂ or R _{7 is} a morpholino group, the other of the radicals R ₂ or R _{7 is} a 2,6-dimethyl or 2,6-diethylmorpholino group and R ₃ and R ₄ together form an N- (2-hydroxy-2-methyl-n-propyl) -ethanolamino group or, if η the number 0 or R _{5 represents} a methyl group, R ₂ and R ₇ each represent a 2-methylmorpholino group, R ₃ and R ₄ together with the intervening nitrogen atom denote an ethanolisopropanolamino group, their optical and geometric isomers and their acid addition salts, characterized in that a pteridine of the formula (II) in the R ₃ to R ₅ and η are as defined in claims 4 to 8, one of the radicals Z ₂ and Z _{7 represents} a nucleophilic exchangeable group and the other of the radicals Z ₂ or Z ₇ for R ₂ or R ₇ in the claims Has 4 to 8 mentioned meanings or also represents a nucleophil exchangeable group, with an amine of the general formula H-X (III) in the X has the meanings mentioned for R ₂ or R ₇ in claims 4 to 8, is reacted and then a compound thus obtained is optionally separated into their optical and geometric isomers and / or   a compound thus obtained is converted into its acid addition salt, in particular into its physiologically tolerated acid addition salt. 5. The method according to claim 4, characterized in that pteridines of the formula I are prepared in which P ^, R ₃ , R ₄ and R _{7 are} as defined in claim 4, η is the number 0 and R _{5 is} a V-hydrogen atom whose optical and geometric isomers and their addition salts. 6. Vei drive according to claim 4, characterized in that the following pteridines are prepared: 4- [N- (2-hydroxy-2-methyl-n-propyl) -ethanolamino] -2,7-bis (2,6-dimethyl morpholino) -6-phenylpteridine, 4- [N-ethyl-ethanolamino) -2,7bis (2,6-dimethylmorpholino) -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-phenylpteridine, 4- (Ethanol-isopropanolamino) -2,7-bis (2-methylmorpholino) 6-benzylpteridine, 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 (2,6-dimethyl-morpholino) -6-phenyl-pteridine, 4 - (2,3-dihydroxy-n-propyl-ethanolamino) -2,7-bis (2,6-dimethylmorpholino) -6-phenyl-pteridine, 4- [N- (2-hydroxy-2-methyl-n- propyl) -ethanolamino] -2,7-bis (3,5-dimethyl-piperidino) -6-phenylpteridine, 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) -ethanolaminol-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-ethylbenzylamino) -2,7-bis (2,6-dimethyl-morpholino) -6-phenyl-pteridine and its acid addition salts. 7. The method according to claim 4, characterized in that pteridines of the formula I are prepared, in the η and R _{5 are} as defined in claim 5, R ₂ and R _{7 are} each a 2,6-dimethyl-morpholino group or one of R 2 or R ₇ is a morpholino group and the other of R 2 or R _{7 is} a 2,6-dimethylmorpholino group, R ₃ and R ₄ together represent an N- (2-hydroxy-2-methyl-n-propyl) -ethanolamino group, their optical and geometric isomers and their acid addition salts. 8. The method according to claim 4, characterized in that the following compounds are prepared: 4- [N- (2-hydroxy-2-methyl-n-propyl) -ethanolamino] -2,7-bis (2,6-dimethyl-morpholino) -6-phenylpteridine, its optical and geometric isomers and its acid addition salts , 9. The method according to claim 4, characterized in that physiologically acceptable acid addition salts of the compounds according to at least one of claims 4 to 8 are prepared. 10. A process for the preparation of a medicament, characterized in that a pteridine according to at least one of claims 4 to 8 or a physiologically acidic acid addition salt according to claim 9 is incorporated into one or more inert carriers and / or diluents, 11. Use of a pteridine according to at least one of claims 4 to 8 or a physiologically acceptable acid addition salt according to claim 9, characterized in that it is used for the preparation of a medicament.