DE4225353A1 - Novel pteridines, medicaments containing these compounds and processes for their preparation - Google Patents

Abstract

Pteridine derivs. of formula (I) and their geometric and optical isomers and salts are new. R3 = opt. branched 2-6C alkyl (in which 1-2C, but not the C next to N are opt. substd. with OH), and R4 = benzyl, 1-4C alkyl (in which 1C, but not the C next to N is opt. substd. with OH) or R3 = 1-3C alkyl, and R4 = phenyl (1-3C)alkyl, R2, R7 = pyrrolidino, piperidino or morpholino (each opt. substd. with 1-2C Me or Et gps.), R5 = H, F, Cl, Br, Me or CF3, R6 = NO2, NH2 or azido. Suitable daily doses of (I) are 1-50 (esp. 3-20) mg/kg. divided into 1-4 unit doses, taken orally or intravenously and administered with the chemotherapeutic. E.g. ampoules could be made to contain 10.00 mg. dioxorubicin and 10.00 mg. (Ia). USE/ADVANTAGE - (I) sensitise tumours with primary or secondary resistance to chemotherapeutics such as vinca alkaloids and are thus able to bring esp. resistant tumours to remission. (I) are esp. effective at sensitising adriamycin-resistant sarcoma cells. (I) are well tolerated by the body.

Description

In the treatment of neoplastic diseases will be Cytostatics u. a. Natural products, eg. B. Vinca alkaloids such Vinblastine, vincristine or vindesine, epipodophyllotoxins like etoposide or teniposide and antibiotics like actinomycin, Dactinomycin, Daunorubicin, Doxorubicin, Bleomycin, Mithra mycin or mitomycin (see Goodman and Gilman's, The Phar Macoligical Basis of Therapeutics, Macmillan Publishing Com pany, New York, 7th Edition, pages 1240-1247 and 1277-1289 (1985)) or synthetic cytostatic agents such as 5-fluorouracil, Methotrexate or cytarabine (cytosine arabinoside) used. In chemotherapy with the substances listed above It is often observed that the tumors to be treated due to a primary resistance or due to a Secondary Re formed due to a previous therapy resistance to therapy, or that after Remission of tumors therapy-resistant tumor cells pos may remain latent. These resistant tumor cells usually lead to relapse at a later date.

It has been found that the pteridines of the general formula I

their geometric or optical isomers and their Säu Readditionssalze, in particular their physiologically tolerated acid addition salts with an inorganic or or ganic acid, have valuable properties, esp bring special resistant tumors to remission.

By the prior, simultaneous or later administration of a Pteridine of the above general formula I or its phy a biologically compatible acid addition salt is invented According sensitized tumors with a pri or secondary resistance to those mentioned above Chemotherapeutica scored.

The subject of the present invention are therefore the new ones Pteridines of the above general formula I, these Ver containing compounds and methods for their Production.

Another object of the present invention are new A pharmaceutical composition containing a pteridine of the above general Formula I, one of its geometric or optical isomers or its physiologically acceptable acid addition salts, and at least one chemotherapeuticum from the series of Na turmeric products, as well as the use of the above pteridines Sensitization of tumors in chemotherapy with the above-mentioned chemotherapeutics from the series of Na turprodukte.

In the above general formula I mean
R _{3 is} a straight-chain or branched alkyl group having 2 to 6 carbon atoms, in which, except for the nitrogen atom adjacent to the carbon atom, one or two carbon atoms are substituted by a hydroxy group, and
R _{4 is} a benzyl group or an alkyl group having 1 to 4 carbon atoms, in which, except for the nitrogen atom adjacent to the carbon 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, depending Weil an optionally substituted by one or two methyl or ethyl groups pyrrolidino, piperidino or morpholino,
R _{5 is} a hydrogen, fluorine, chlorine or bromine atom, a methyl or trifluoromethyl group and
R _{6 is} a nitro, amino or azido group.

The new compounds of the above general formula I, in which R _{6 represents} a nitro or amino group, are valuable intermediates and the remaining compounds of formula I above, their geometrical or optical isomers and their physiologically acceptable acid addition salts with an inorganic or organic Acid, have valuable pharmacological properties. For the meanings mentioned in the definition of the radicals at the outset, for example
R ₂ and R _{7 are} each those of pyrrolidino, 2-methyl-pyrrolidino, 3-methylpyrrolidino, 3,3-dimethyl-pyrrolidino, 2-ethyl-pyrrolidino, 3-ethyl-pyrrolidino, 3 , 3-diethyl-pyrrolidino, piperidino, 2-methylpiperidino, 3-methylpiperidino, 4-methylpiperidino, 2-ethylpiperidino, 3-ethylpiperidino, 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- Diethylmorpholino, trans-2,6-diethyl-morpholino, 3,5-dimethyl-morpholino or 3,5-diethyl-morpholino group,
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-dihydroxy-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 Hydroxy-propyl, 4-hydroxy-n-butyl or 2-hydroxy-2-methyl-n-propyl group,
for R ₅ those of the hydrogen, fluorine, chlorine or bromine atom, the methyl or trifluoromethyl group and
for R ₆ those of the nitro, amino or azido group into consideration.

Preferred pteridines of the above general formula I here are those in which
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-dimethyl-morpholino 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 _{5 is} a hydrogen atom or a methyl group and
R _{6 is} a nitro, amino or azido group, their optical and geometric isomers and their physiologically acceptable acid addition salts.

However, particularly preferred compounds are those in which
R ₂ and R _{7 are} each a 2,6-dimethyl-morpholino group or
one of the radicals 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,
R ₃ and R ₄ together represent an N- (2-hydroxy-2-methyl-n-propyl) -ethanolamino group and
R _{5 is} a hydrogen atom and
R _{6 is} an azido group, in particular the compound 4- (N- (2-hydroxy-2-methyl-propyl) -ethanolamino] -2,7-bis (cis-2,6-dimethylmorpholin-4-yl) -6- (4-azido-phenyl) -pteridine and its salts.

According to the invention, the compounds are obtained according to the following Method:

• a) For the preparation of a compound of general formula I in which R _{6 represents} a nitro group:
• Nitration of a compound of general formula II in the
  R ₂ to R ₅ and R _{7 are} as defined above.
• The nitration is concentrated using up to semi-concentrated nitric acid in water, glacial acetic acid or Acetic anhydride, using a mixture of conc trated nitric acid and concentrated sulfuric acid, with Nitrous pentoxide in carbon tetrachloride and in counter were of phosphorus pentoxide, with ethyl nitrate, optionally in the presence of a Lewis or Bronsted acid, with sodium nitrite in the presence of trifluoroacetic acid or under Ver use of a nitronium salt, for. B. Nitronium tetrafluoro borate or nitronium trifluoromethanesulfonate, at temperatures between 0 and 100 ° C, preferably at temperatures between 20 and 50 ° C, performed.
• b) For the preparation of a compound of general formula I in which R _{6 represents} an amino group:
• Reduction of a compound of general formula III, in the
  R ₂ to R ₅ and R _{7 are} as defined above.
• The reduction of the nitro group is preferably in a Lö such as water, water / ethanol, methanol, glacial acetic acid, Essigsäurethylester or dimethylformamide expediently with hydrogen in the presence of a hydrogenation catalyst like Raney nickel, platinum or palladium / carbon, with metals such as iron, tin or zinc in the presence of an acid, with sal such as ferrous sulfate, tin (II) chloride, sodium sulfide, Sodium hydrogen sulfite or sodium dithionite, or with Hydra  zin in the presence of Raney nickel at temperatures between O and 80 ° C, but preferably at temperatures between 20 and 40 ° C, performed.
• c) For the preparation of a compound of general formula I in which R _{6 represents} an azido group:
• Diazotization of a compound of general formula IV, in the
  R ₂ to R ₅ and R ₇ are defined as mentioned above, and closing reaction of the diazonium salt thus obtained with an alkali azide, z. With sodium azide.
• The diazotization is conveniently carried out in a geeigne th solvent, z. In water / hydrochloric acid, methanol / salt acid, ethanol / hydrochloric acid or dioxane / hydrochloric acid, by order tion of a corresponding amino compound with a Ni trit, z. As sodium nitrite or an ester of nitrous Acid, at low temperatures, e.g. At temperatures between -10 and 5 ° C.
• The reaction of a diazonium salt, for. B. the tetrafluoro borate, hydrosulfate in sulfuric acid, hydrochloride or the hydroiodide, if necessary in the presence of Copper or a corresponding copper (I) salt such as Kup ferric chloride / hydrochloric acid or copper (I) bromide / bromine water substance acid, with an alkali azide, z. As sodium azide occurs at temperatures between -15 and 100 ° C, preferably in a suitable solvent such as water / methanol, water / Acetone, ethanol, tetrahydrofuran or dioxane, e.g. B. at Tem  temperatures between 0 and 50 ° C, preferably at room temp temperature.
• d) For the preparation of a compound of the general formula I in which R ₂ and R ₇ , which may be identical or different, each represent a pyrrolidino, piperidino or morpholino group which is optionally substituted by one or two methyl or ethyl groups:
• Reaction of a compound of general formula V in the
  R ₃ to R _{6 are} as defined above,
  one of Z ₂ or Z _{7 is} a nucleophilically exchangeable group such as a halogen atom, for. B. is a chlorine or bromine atom, and
  the other of the radicals Z ₂ or Z _{7 has} the meanings mentioned above for R ₂ or R ₇ or likewise a nucleophilically exchangeable group such as a halogen atom, eg. A chlorine or bromine atom, with an amine of the general formula H-X (VI) in the
  X sitting at the beginning of R ₂ or R ₇ meanings be sitting.

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 the Raumtempe temperature and the boiling point of the solvent used or in the melt. Here, the Verwen an acid-binding agent such as sodium carbonate, tri ethylamine or pyridine may be beneficial.

In the reactions described above can give If present, reactive groups such as hydroxyl, amino or alkylamino groups during the reaction by conventional Protecting groups are protected, which after the reaction be split off again.

For example, comes as a protective group for a hydroxy group the trimethylsilyl, acetyl, benzoyl, methyl, ethyl, tert-butyl, benzyl or tetrahydropyranyl group, and as Protecting group for an amino, alkylamino or imino group Acetyl, benzoyl, ethoxycarbonyl, phthalyl or benzyl group into consideration.

The optional subsequent cleavage of a use The protective moiety is preferably carried out hydrolytically in one aqueous solvents, for. In water, isopropanol / water, Tetrahydrofuran / water or dioxane / water, in the presence of egg ner acid such as hydrochloric acid or sulfuric acid or in the presence an alkali base such as sodium hydroxide or potassium hydroxide Temperatures between 0 and 100 ° C, preferably at the you Detemperatur of the reaction mixture. The splitting off of a Benzylrestes is preferably hydrogenolytically, z. With hydrogen in the presence of a catalyst such as Palladium / carbon in a solvent such as methanol, ethanol, Ethyl acetate or glacial acetic acid, if appropriate under Zu Set an acid such as hydrochloric acid at temperatures between 0 and 50 ° C, but preferably at room temperature, and a  Hydrogen pressure of 1 to 7 bar, but preferably of 3 up to 5 bar.

The compounds used as starting material of the general my formula II and VI are for the most part known (see EP-A 0 362 645, 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 those mentioned in the above Patents described method.

For example, the sensitization by the connec tion
A = 4- [N- (2-hydroxy-2-methyl-propyl) -ethanolamino] -2,7-bis (cis-2,6-dimethylmorpholin-4-yl) -6- (4-azido-phenyl ) - pteridine
using the example of adriamycin-resistant cells as follows:
Proliferating, adriamycin-resistant S 180 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 death of the cells. The end point 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] zum exploiting colored formazan is exploited. As IC ₅₀ , the concentration of a test substance is called net, which reduces the number of vital cells per culture vessel to 50% of the untreated control. The test substances are tested both in the absence of adriamycin and in the presence of a non-proliferative inhibiting amount of adriamycin under culture conditions. Therefore, two IC ₅₀ values are obtained per test substance, one in presence (IC ₅₀ ADR) and the other in the absence (IC ₅₀ ) of adriamycin. The difference of the ten logarithms of the two IC ₅₀ values: Δ = IgIC _50- IgIC ₅₀ ADR is a measure of the increase in the cytotoxicity of the test substance by adriamycin.

Temptation implementation

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 100 μl 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 per well of growth medium containing different concentrations of test substance and 50 μl growth medium with or without adriamycin are added per well. Subsequent to a further six-day cultivation, 50 μl of tetrazolium salt solution [5 mg of 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide per ml of phosphate-buffered saline solution, before use 1: 5 (v / v) diluted with RPMI-1640] pipetted in each hole. After four hours of incubation, the culture medium is carefully aspirated and solubilized intracellular formed Formazan by 150 ul dimethyl sulfoxide per hole solubilized. 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 formazan by reduction of the tetrazolium salt is proportional to the number of living cells. The mean values of triplicate determinations were used in the calculation of the IC ₅₀ values (dilution stage: 1: 2).

Table 1

Table 2

The pteridines of the above general formula I thus have a pronounced sensitization to adriamycin-resistant Sarcoma cells and are therefore suitable in combination with Vinca alkaloids, epipodophyllotoxins or antibiotics like Actinomycin, daunorubicin, doxorubicin, bleomycin or sub such as 5-fluorourcil, methothrexate or cytarabine (Cyctosine arabinoside), mithramycin or mitomycin, Be treatment of neoplastic diseases for their resistance to suspend such chemotherapy and thus the remission of these substances resi cause stent tumors. When compared to the mentioned Chemotherapeutic sensitive tumors prevent the pteridines  of formula I so together with the chemotherapeuticum that therapy-resistant tumor cell subpopulations the therapy survive and lead to recurrence.

The application of pteridine, which is also well tolerated are carried out separately or combined with a in the üb dose of chemotherapeuticum; the dose of used pteridine is between 1 and 50 mg / kg Body weight per day, preferably between 3 to 20 mg / kg Body weight per day, divided into 1 to 4 single doses.

Combined with an appropriate chemotherapeuticum comes Here, an intravenous dosage form such as ampoules and in a separate application, a parallel administration form of tablets, dragees, suspensions, juices, capsules or suppositories.

Due to the literature-known application schema at chemotherapy of neoplastic diseases natural products (see Goodman and Gilman's, The Pharmaco ligical Basis of Therapeutics, Macmillan Publishing Company, New York, 7th Edition, pages 1240-1247 and 1277-1289 (1985)) the first application is a pteridine of formula I. or its physiologically acceptable acid addition salt expediently together with or before the used Che motherapeuticum or with or before a combination of several Chemotherapeutica containing at least one of the above he mentioned chemotherapeutica (see DeVita et al "Cancer, Principles & Practice of Oncology", 2nd Edition, J. Lippincott Company Philadelphia).

The remaining applications of a pteridine of formula I or its physiologically acceptable acid addition salt Kings According to the circumstances, either orally or intra venous.  

A com bination suitable for the iv application according to the invention thus advantageously contains 1 to 25 mg / kg, preferably 1 to 20 mg / kg body weight of a pteridine of the formula I or its physiologically acceptable acid addition salt and a suitable chemotherapeutic or a combination of various suitable chemotherapeutic ca, z. B.
0.1-0.15 mg / kg vinblastine every 7 days, with the dose being 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 in juvenile leukemia, whereby in adults the therapy preferably begins with 0.01 mg / kg every 7 days and can be increased up to 0.02-0.05 mg / kg depending on the tolerability,
3-4 mg / m ² body area Vindesin every 7 days,
2 mg / m ² body area mitomycin every 5 days,
10-15 pg / kg actinomycin every 5 days,
25-30 kg / kg mithramycin daily or every 2 days,
60-75 mg / m ² body surface adriamycin every 21 days,
30-60 mg / m ² body surface daunorubicin daily for 3 days,
10-15 kg / kg dactinomycin daily for 5 days,
12 mg / kg 5-fluorouracil daily for 4 days,
2.5-10 mg methotrexate daily for 5 days,
100-200 mg / m ² cytarabine (cytosine arabinoside) daily for 7 days,
50-100 mg / m ² body surface etoposide daily for 5 days and
30 mg / m ² body surface Teniposide daily up to 5 days, followed by 6 - 10 treatment cycles after each 10-day break.

Leave the novel compounds obtained according to the invention into their acid addition salts, especially in their phy biologically compatible salts with inorganic or orga transfer niche acids. As acids come for example Hydrochloric acid, hydrobromic acid, sulfuric acid, phosphorus acid, lactic acid, citric acid, tartaric acid, succinic acid, Maleic acid or fumaric acid.

If the compounds of the formula I contain at least one chi Center, so they can be by conventional metho the separated into their enantiomers, for example by Column chromatography on a chiral phase or by Crystallization with optically active acids, e.g. B. with D or L-monomethyltartaric acid, D- or L-diacetyltartaric acid, D- or L-tartaric acid, D- or L-lactic acid or D- or L-camphor Acid.

In addition, the compounds of formula I, if these at least one geometric center like one through two Methyl- or ethyl-substituted pyrrolidino-, piperi Contain dino or morpholino, but especially at least one 2,6-dimethyl-morpholino group, by means of übli chen methods, for example, by chromatography, in their Cis / trans isomers are separated or present.

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

example 1 4- [N- (2-hydroxy-2-methyl-propyl) -ethanolamino] -2,7-bis (cis 2,6-dimethyl-morpholin-4-yl) -6- (4-nitrophenyl) pteridin

12 g (0.021 mol) of 4- [N- (2-hydroxy-2-methyl-propyl) -ethanol-amino] -2,7-bis (cis-2,6-dimethylmorpholin-4-yl) -6-phenylpteridine are dissolved in 80 ml of methylene chloride and concentrated at -25 ° C for 2-3 minutes to 42 ml. Nitric acid in 1.5 l Me methylene chloride added dropwise. After the solution was stirred for 1.5 hours at -10 ° C, shaken with 500 ml of ice water, the organic phase is dried over sodium sulfate and concentrated to dryness. The residue is then taken up in 500 ml of ethyl acetate, extracted by shaking with aqueous sodium bicarbonate solution, dried and concentrated. The remaining material can be chromatographed for further purification on a silica gel column with ethyl acetate / methanol 20: 1 and recrystallized from ethyl acetate.
Yield: 6.5 g (75% of theory)

Example 2 4- [N- (2-hydroxy-2-methyl-propyl) -ethanolamino] -2,7-bis (cis 2,6-dimethyl-morpholin-4-yl) -6- (4-aminophenyl) pteridin

9.5 g (0.015 mol) of 4- [N- (2-hydroxy-2-methyl-propyl) -ethanol-amino] -2,7-bis (cis-2,6-dimethylmorpholin-4-yl) -6- (4-nitro-phenyl) -pteridine are dissolved in 150 ml of methanol. To this is added 40 ml of dioxane / HCl and then hydrogenated using palladium carbon as catalyst at room temperature and 50 psi hydrogen pressure. After 30 minutes, the catalyst is filtered off and the solution is evaporated. The initially oily residue is determined. The mixture is then stirred with ether and filtered with suction.
Yield: 10.3 g (95% of theory)
Melting point: from 105 ° C (decomp.)
Calc .:
C 55,12; H 7.09; 17.14%
Found .:
C 55.75; H, 6.91; N 16.83%

Example 3 4- [N- (2-hydroxy-2-methyl-propyl) -ethanolamino] -2,7-bis (cis 2,6-dimethyl-morpholin-4-yl) -6- (4-azidophenyl) pteridin

1.3 g (0.002 mol) of 4- [N- (2-hydroxy-2-methyl-propyl) -ethanol-amino] -2,7-bis (cis-2,6-dimethylmorpholin-4-yl) -6- (4-Amino-phenyl) -pteridine hydrochloride are treated with 4 ml of water and 2.3 ml of conc. Hydrochloric acid and cooled to 2 ° C. Then added dropwise 0.145 g of sodium nitrite in 0.5 ml of water and stirred for 1 hour at 0 ° C. Then, add 0.13 g of sodium azide in 0.5 ml of water and stirred for another hour, while nitrogen escapes. Finally, it is diluted with water to 80 ml and the solution is stirred for 80 to 100 minutes at room temperature. In the process, further nitrogen is split off. Subsequently, the solution is neutralized with sodium bicarbonate, the precipitated product is filtered off with suction, washed and dried.
Yield: 80% of theory
Melting point: 160 ° C (decomp., Sinters between 140-146 ° C).

Example I Drag'es with 75 mg of 4- [N- (2-hydroxy-2-methyl-propyl) -ethanol amino] -2,7-bis (cis-2,6-dimethylmorpholine-4-yl) -6- (4-azidophe nyl) pteridin

1 drag core contains: Active substance | 75,0 mg calcium phosphate 93.0 mg corn starch 35.5 mg polyvinylpyrrolidone 10.0 mg hydroxypropyl methylcellulose 15.0 mg magnesium stearate  1.5 mg 230.0 mg

manufacturing

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 a mesh size of 1.5 mm 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: 230 mg
Stamp: 9 mm, curved.

The Drag'ekerne thus prepared are coated with a film consisting essentially of hydroxypropylmethylcellulose. The finished film drags are glazed with beeswax.
Drag'e weight 245 mg.

Example II Tablets containing 100 mg of 4- [N- (2-hydroxy-2-methyl-propyl) -etha nolamino] -2,7-bis (cis-2,6-dimethylmorpholine-4-yl) -6- (4-azido phenyl) pteridin

composition 1 tablet contains: Active ingredient | 100.0 mg lactose 80.0 mg corn starch 34.0 mg polyvinylpyrrolidone 4.0 mg magnesium stearate  2.0 mg 220.0 mg

manufacturing process

Active ingredient, lactose and starch are mixed and uniformly moistened with an aqueous solution of polyvinylpyrrolidone. After sieving the wet mass (2.0 mm mesh width) and drying in a rack oven at 50 ° C is sieved again (1.5 mm mesh size) and admixed with the lubricant. The ready for pressing mixture is working to tablets ver.
Tablet weight: 220 mg
Diameter: 10 mm, biplan with facet on both sides and one-sided part notch.

Example III Tablets containing 150 mg of 4- [N- (2-hydroxy-2-methyl-propyl) -etha nolamino] -2,7-bis (cis-2,6-dimethylmorpholine-4-yl) -6- (4-azido phenyl) pteridin

composition 1 tablet contains: Active substance | 150,0 mg Milk sugar powder. 89.0 mg corn starch 40.0 mg Colloidal silicic acid 10.0 mg polyvinylpyrrolidone 10.0 mg magnesium stearate  1.0 mg 300.0 mg

manufacturing

The mixed with lactose, corn starch and silica Active substance is mixed with a 20% aqueous polyvinylpyr solution and moistened through a sieve of 1.5 mm diameter narrowed.

The dried granules at 45 ° C is again rubbed through the same sieve and mixed with the stated amount of magnesium stearate. From the mixture tablets are pressed.
Tablet weight: 300 mg
Stamp: 10 mm, flat.

Example IV Hard gelatin capsules containing 100 mg of 4- [N- (2-hydroxy-2-methyl-pro pyl) -ethanolamino] -2,7-bis (cis-2,6-dimethylmorpholine-4-yl) - 6- (4-azidophenyl) pteridin

1 capsule contains: Active ingredient | 150.0 mg Corn starch drink. about 180.0 mg Milk sugar powder. about 87.0 mg magnesium stearate  3.0 mg about 420.0 mg

manufacturing

The active ingredient is mixed with the excipients, by a Sieve of 0.75 mm mesh size and given in a geeigne unit mixed homogeneously.

The final mixture is filled into hard gelatin capsules of size 1.
Capsule filling: approx. 320 mg
Capsule shell: hard gelatin capsule size 1.

Example V Suppositories containing 150 mg of 4- [N- (2-hydroxy-2-methylpropyl) - ethanolamino] -2,7-bis (cis-2,6-dimethylmorpholine-4-yl) - 6- (4-azidophenyl) pteridin

1 suppository contains: Active ingredient | 150.0 mg Polyethylene glycol 1500 550.0 mg Polyethylene glycol 6000 460.0 mg Polyoxyäthylensorbitanmonostearat  840.0 mg 2000.0 mg

manufacturing

After melting the suppository mass of the Wirk The material is homogeneously distributed in it and the melt in pre-cooled Poured molds.

Example VI Suspension with 50 mg of 4- [N- (2-hydroxy-2-methyl-propyl) -etha nolamino] -2,7-bis (cis-2,6-dimethylmorpholine-4-yl) -6- (4-azido phenyl) pteridin

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

manufacturing

Dest. Water is heated to 70 ° C. Herein, methyl p-hydroxybenzoate and propyl ester are dissolved with stirring, whereby glycerol and carboxymethylcellulose 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.
5 ml of suspension contain 50 mg of active ingredient.

Example VII Ampoules containing 10 mg of 4- [N- (2-hydroxy-2-methyl-propyl) -ethanol amino] -2,7-bis (cis-2,6-dimethylmorpholine-4-yl) -6- (4-azido phenyl) pteridin

composition Active substance | 10.0 mg 0.01 n hydrochloric acid s.p. Aqua bidest ad 2.0 ml

manufacturing

The active substance is added in the required amount 0.01 N HCl dissolved, isotonic with saline, sterile filtered and filled in 2 ml ampoules. The sterilization takes place by heating at 121 ° C for 20 minutes.

Example VIII Ampoules containing 50 mg of 4- [N- (2-hydroxy-2-methyl-propyl) -ethanol amino] -2,7-bis (cis-2,6-dimethylmorpholine-4-yl) -6- (4-azido phenyl) pteridin

composition Active ingredient | 50.0 mg 0.01 n hydrochloric acid s.p. Aqua bidest ad 10.0 ml

manufacturing

The active substance is added in the required amount 0.01 N HCl dissolved, isotonic with saline, sterile filtered and filled in 10 ml ampoules. The sterilization takes place by heating at 121 ° C for 20 minutes.  

Example IX Dry ampoules containing 10 mg doxorubicin and 10 mg 4- [N- (2-Hy droxy-2-methyl-propyl) -ethanolamino] -2,7-bis (cis-2,6-dimethyl morpholin-4-yl) -6- (4-azidophenyl) pteridin

Composition of dry ampoule Doxorubicin | 10.0 mg active substance 10.0 mg

manufacturing

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

The solvent vial contains 5 ml saline.

Before use, the lyophilisate in the sterile phy dissolved in saline solution.

Example X Dry ampoules containing 50 mg doxorubicin and 50 mg 4- [N- (2-Hy droxy-2-methyl-propyl) -ethanolamino] -2,7-bis (cis-2,6-dimethyl morpholin-4-yl) -6- (4-azidophenyl) pteridin

Composition of dry ampoule Doxorubicin | 50.0 mg active substance 50.0 mg

manufacturing

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

The solvent vial contains 25 ml saline.

Before use, the lyophilisate in the sterile phy dissolved in saline solution.

Of course, all other connections of the all Formula I as active ingredients in the above galen are used.

Claims (10)

1. Pteridines of the general formula I. in the
R _{3 is} a straight-chain or branched alkyl group having 2 to 6 carbon atoms, in which, except for the nitrogen atom adjacent to the carbon atom, one or two carbon atoms are substituted by a hydroxy group, and
R _{4 is} a benzyl group or an alkyl group having 1 to 4 carbon atoms, in which, except for the nitrogen atom adjacent to the carbon 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, depending Weil an optionally substituted by one or two methyl or ethyl groups pyrrolidino, piperidino or morpholino,
R _{5 is} a hydrogen, fluorine, chlorine or bromine atom, a methyl or trifluoromethyl group and
R _{6 represents} a nitro, amino or azido group,
their geometric or optical isomers and their salts. 2. Pteridines of the general formula I according to claim 1, in which
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-dimethyl-morpholino 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 _{5 is} a hydrogen atom or a methyl group and
R _{6 represents} a nitro, amino or azido group,
their optical and geometric isomers and their salts. 3. Pteridines of the general formula I according to claim 1, in which
R ₂ and R _{7 are} each a 2,6-dimethylmorpholino group or one of the radicals 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,
R ₃ and R ₄ together represent an N- (2-hydroxy-2-methyl-n-propyl) -ethanolamino group and
R _{5 is} a hydrogen atom and
R _{6 is} an azido group,
their geometric or optical isomers and their salts. 4. 4- [N- (2-hydroxy-2-methyl-propyl) -ethanolamino] -2,7-bis- (Cis-2,6-dimethylmorpholine-4-yl) -6- (4-azido-phenyl) pteridin and its salts. 5. Physiologically acceptable acid addition salts of Ver Compounds according to at least one of claims 1 to 4 with inorganic or organic acids. 6. A pharmaceutical composition containing a compound after at least one of claims 1 to 4 or a physiologically acceptable Lich salt according to claim 5 besides optionally one or several inert carriers. 7. Medicament according to claim 7, characterized that this for the treatment of neoplastic diseases suitable is. 8. Medicaments according to claims 6 and 7, characterized marked records that these additionally one or more cytostatics contain. 9. Process for the preparation of the medicaments according to the An Spells 6 to 8, characterized in that notche Mixed way connect to at least one of the claims 1 to 5 and optionally one or more Cytosta tika in one or more inert carriers and / or Ver be incorporated thinning agent. 10. A process for the preparation of pteridines according to the entitlements 1 to 5, characterized in that

• a) for the preparation of a compound of general formula I in which R _{6 represents} a nitro group, a compound of general formula II in the
  R ₂ to R ₅ and R ₇ as defined in claims 1 to 4 defi ned, or is
• b) for the preparation of a compound of general formula I in which R _{6 is} an amino group, a compound of general formula III, in the
  R ₂ to R ₅ and R ₇ as defined in claims 1 to 4 defi ned, is reduced or
• c) for preparing a compound of general formula II in which R _{6 represents} an azido group, a compound of general formula IV, in the
  R ₂ to R ₅ and R _{7 are defined} as defined in claims 1 to 4, diazotized and then the diazonium salt thus obtained is reacted with an alkali azide or
• d) for the preparation of a compound of the general formula I in which 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, Pipe ridino- or Morpholino group, a compound the general formula V in the
  R ₃ to R _{6 are} as defined in claims 1 to 4,
  one of Z ₂ or Z _{7 is} a nucleophilically exchangeable group and
  the other of the radicals Z ₂ or Z _{7 has} the meanings mentioned for R ₂ or R ₇ in claims 1 to 4 or also represents a nucleophilically exchangeable group with an amine of the general formula
  HX (VI)
  in the
  X has the meanings mentioned for R ₂ or R ₇ in claims 1 to 4, is reacted and
  if desired, a compound of general formula I thus obtained in its acid addition salt, in particular in its physiologically acceptable acid addition salts, with anor ganic or organic acids is converted.