FI92699B - Process for the preparation of pharmacologically valuable pteridine - 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

x 92699

Method for the preparation of pharmacologically valuable pteridine Förfarande för framställning av pharmacologiskt värdefull pteridin

The invention relates to a process for the preparation of a pharmacologically valuable pteridine of the formula (I) wherein R is a number 0 or 1, R2 and R7, which may be be the same or different, are in each case 2- or 2- and 6-position substituted by methyl or ethyl morpholino groups or 3,5-dimethylpiperidino groups, and R3 is 2-hydroxyethyl, 2-hydroxy-n-propyl -, 2,3-dihydroxy-n-propyl or 2-hydroxy-2-methyl-n-propyl, and R 4 is a 2-hydroxy-2-methyl-n-propyl group, and R 5 is a hydrogen atom or a methyl group, or when n = O R2 and R7 are the same and denote a 2,6-dimethyl or 2,6-diethylmorpholino group, R3 and R4 together with the nitrogen atom in between are an N-alkylphenylalkylamino group in which the alkyl moiety contains 1 to 3 carbon atoms, N- benzylethanolamino, N-ethylethanolamino, N-ethylisopropanolamino, ethanol isopropanol. an amino or N- (2,3-dihydroxy-n-propyl) ethanolamino group, or one of R2 or R7 is a morpholino group, one of R2 or R7 is a 2,6-dimethyl or 2,6-diethylmorpholino group, and R3 and R4 together is an N- (2-hydroxy-2-methyl-n-propyl) -ethanol-amino group, or 92699 2 when n is O and R5 is a methyl group R2 and R7 is a 2-methylmorpholino group, R3 and R4 together are a nitrogen atom has an ethanol-isopropanolamino group, a geometric or optical isomer thereof as well as a physiologically acceptable acid addition salt thereof with an inorganic or organic acid.

In the treatment of tumor diseases, e.g. natural products such as vinca alkaloids such as vinblastine, vincristine or vindesine, epipodophyllotoxins such as etoposide or teniposide and antibiotics such as bactinomycin, daunoru-bicin, doxorubicin, bleomycin, mithramycin or Mitomycin and Mtsomycin (kts. , Macmillan Publishin Company, New York, 7th Edition, pp. 1240-1247 and 1277-1289 (1985)). In chemotherapy with the above-mentioned agents, it is generally found that the tumors to be treated do not respond to treatment due to primary resistance or previous therapy, or that the tumor cells resistant to the treatment remain latent after the tumors have alleviated. These resistant tumor cells usually lead to recurrence of the disease at a later stage.

By administering the pteridine of the above formula I or a physiologically acceptable acid addition salt thereof before, simultaneously with or after the invention, sensitization of tumors with primary or secondary resistance to the above-mentioned chemotherapeutic agents is achieved according to the invention.

The invention thus relates to novel medicaments comprising a pteridine of the above formula I, a geometric or optical isomer thereof or a physiologically acceptable acid addition salt thereof and at least one chemotherapeutic agent from natural products, and a new use of the above pteridines for sensitizing tumors to chemotherapeutic agents. chemotherapeutic agents.

II

92699 3

For the purposes of defining the groups already mentioned, for example, R2 and R7 are in each case pyrrolidino, 2-methylpyrrolidino, 3-methylpyrrolidino, 3,3-dimethylpyrrolidino, 2-ethylpyrrolidino, 3-ethylpyrrolidino, 3, 3-diethylpyrrolidino, piperidino, 2-methylpiperidino, 3-methylpiperidino, 4-methylpiperidino, 2-ethylpiperidino, 3-ethylpiperidino, 4-ethylpiperidino, 3,5-dimethylpiperidino , 3,5-diethylpiperidino, morpholino, 2-methylmorpholino, 2-ethylmorpholino, 3-methylmorpholino, 3-ethylmorpholino, 2,6-dimethylmorpholino, cis-2,6-dimethylmorpholino, trans-2,6-dimethylmorpholino, 2,6-diethylmorpholino, cis-2,6-diethylmorpholino or 3,5-diethylmorpholino group, for R 3 2-hydroxyethyl, 2-hydroxy-n-propyl, 2-hydroxyisopropyl, 3- hydroxypropyl, 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, R4: benzyl, 2-phenylethyl, 2-phenyl-n-propyl, 3-phenylpropyl, 2-hydroxyethyl, 2-hydroxy-n-propyl, 3-hydroxypropyl, 4-hydroxy-n -butyl or 2-hydroxy-2-methyl-n-propyl group and for R5 a hydrogen atom or a methyl group.

Preferred pteridines of the above general formula I are those in which n is the number 0, R2 and R7, which may be the same or different, are piperidino, 3,5-dimethylpiperidino, morpholino, 2-methylmorpholidino, 2, 6-dimethylmorpholino, cis-2,6-dimethylmorpholino or trans-2,6-dimethylmorpholino group, R3 is methyl, ethyl, benzyl, 2-hydroxyethyl, 2-hydroxy-n-propyl, 2 , A 3-dihydroxy-n-propyl or 2-methyl-2-hydroxy-n-propyl group, R4 is a 2-hydroxyethyl, 2-hydroxy-n-propyl or 2-methyl-2-hydroxy-n-propyl group, and R5 is a hydrogen atom or a methyl group, 92699 4 their optical and geometric isomers as well as their physiologically acceptable acid addition salts, the novel compounds being 4- [N- (2-hydroxy-2-methyl-n-propyl) ethanolamino] -2,7-bis - (2,6-dimethylmorpholino) -6-phenylpteridine, 4- [N-ethylethanolamino] -2,7-bis- (2,6-dimethylmorpholino) -6-phenylpteridine, 4- (ethanol-isopropanolamino) -2 , 7-bis - (2,6-dimethylimo Folino) -6-phenylpteridine, 4- [N- (2-hydroxy-2-methyl-n-propyl) ethanolamino] -2,7-bis- (2-methylmorpholino) -6-phenylpteridine, 4- (ethanol-isopropanolamino) ) -2,7-bis- (2-methylmorpholino) -6-benzylpteridine, 4- (ethanol-isopropanolamino) -2,7-bis- (2-methylmorpholino) -6- (o-tolyl) pteridine, 4- [ bis (2-hydroxy-2-methyl-n-propyl) amino] -2,7-bis- (2-dimethylmorpholino) -6-phenylpteridine, 4- [2,3-dihydroxy-n-propyl) ethanolamino] -2,7-bis - (2-dimethyllimorpholino) -6-phenylpteridine, 4- [N- (2-hydroxy-2-methyl-n-propyl) ethanolamino] -2,7-bis- (3,5 -dimethylpiperidino) -6-phenylpteridine, 4- (N-ethanol-benzylamino) -2,7-bis- (2,6-dimethylmorpholino) -6-phenylpteridine, 4- [N- (2-hydroxy-2-methyl- n-propyl) ethanolamino] -2,7-bis- (cis-2,6-dimethylmorpholino) -6-phenylpteridine, η 4 - [N- (2-hydroxy-2-methyl-n-propyl) ethanolamino] - 2- (2,6-Dimethylmorpholino) -7-morpholino-6-phenylpteridine, 92699 5 4- [N- (2-hydroxy-2-methyl-n-propyl) ethanolamino] -7- (2,6- di-methyl morpholino) -2-morpholino-6-phenylpteridine and 4- (N-ethylbenzylamino) -2,7-bis- (2,6-methylmorpholino) -6-phenylpteridine.

However, those in which n is the number 0, R2 and R7 are in each case a 2,6-dimethylmorpholino group or one of R2 and R7 are preferred. is a morpholino group and one of R2 and R7 is a 2,6-dimethylmorpholino group, R3 and R4 together are an N- (2-hydroxy-2-methyl-n-propyl) -ethanolamino group and R5 is a hydrogen atom.

The following pteridines have proven to be particularly effective according to the invention: 4- [N- (2-hydroxy-2-methyl-n-propyl) ethanolamino] -2,7-bis- (2,6-dimethylmorpholino) -6-phenylpteridine, 4- (N-ethyl-ethanolamino) -2,7-bis- (2,6-methylmorpholino) -6-phenylpteridine, 4- (ethanol-isopropanolamino) -2,7-bis- (2,6-methylmorpholino) -6- phenylpteridine, 4- (diethanolamino) -2,7-bis- (2,6-methylmorpholino) -6-phenyl-. pteridine, 4- [N- (2-hydroxy-2-methyl-n-propyl) ethanolamino] -2,7-bis- (2-methylmorpholino) -6-phenylpteridine, 92699 6 4- (ethanol-isopropanolamino) -2 , 7-bis- (2-methylmorpholino) -6-benzylpteridine, 4- (ethanol-isopropanolamino) -2,7-bis- (2-methyl-morpholino) -6-phenylpteridine, 4- (ethanol-isopropanolamino) -2.7 -bis- (2-methylmorpholino) -6- (o-tolyl) pteridine, 4- (N-benzylethanolamino) -2,7-dimorpholino-6-phenylpiperidine, 4- [bis (2-hydroxy-2 -methyl-n-propyl) amino] -2,7-bis (2,6-dimethylmorpholino) -6-phenylpteridine, 4- (2,3-dihydroxy-n-propylethanolamino) -2,7-bis (2 , 6-dimethylmorpholino) -6-phenylpteridine, 4- (diethanolamino) -2,7-dipiperidino-6-phenylpteridine, 4- (diethanolamino) -2,7-dimorpholino-6-phenylpteridine, 4- (N-ethyl -ethanolamino) -2,7-dimorpholino-6-phenylpteridine, 4- (N-methylethanolamino) -2,7-dimorpholino-6-phenylpteridine, 4- [N- (2-hydroxy-2-methyl-n- propyl) ethanolamino] -2,7-bis- (3,5-dimethylpiperidino) -6-phenyl teridine, 4- (N-ethanol-benzylamino) -2,7-bis (2,6-dimethylmorpholino) -6-phenylpteridine,

II

4- [N- (2-hydroxy-2-methyl-n-propyl) ethanolamino] -2,7-bis- (cis-2,6-dimethylmorpholino) -6-phenylpteridine, 7 y 2 6 9 v 4- [N- (2-hydroxy-2-methyl-n-propyl) -ethanolamino] -2,7- (trans-2,6-dimethylmorpholino) -6-phenylpteridine, 4- [N- (2-hydroxy-2- Methyl-n-propyl) -ethanolamino] -2- (2,6-dimethyl-morpholino) -7-morpholino-6-phenyl-pteridine and 4- [N- (2-hydroxy-2-methyl-n-propyl) -ethanolamino] - 7- (2,6-dimethylmorpholino) -2-morpholino-6-phenylpteridine, as well as their physiologically acceptable acid addition salts.

Sensitization was tested, for example, with compounds A = 4- [N- (2-hydroxy-2-methyl-propyl) -ethanolamino] -2,7-bis (2,6-dimethylmorpholino) -6-phenylpteridine, B = 4-ethyl-ethanolamino -2,7-bis (2,6-dimethylmorpholino) -6-phenylpteridine, C = 4-ethanol-isopropanolamino-2,7-bis (2,6-dimethyl-morpholino) -6-phenylpteridine, D = 4-diethanolamino- 2,7-bis (2,6-dimethylmorpholino) -6-phenyl lipteridine and E = 4- [N- (2-hydroxy-2-methylpropyl) ethanolamino] -2,7-bis (cis-2, 6-dimethylmorpholino) -6-phenylpteridine = 7-benzylamino-4-morpholino-6-phenyl-2-piperazinopteridine (e.g. 33) and V2 = 4,7-dimorpholino-6-phenyl-2-piperazino-pteridine ( eg 34)

As an example against adriamycin-resistant cells as follows (compounds V1 and V2 are reference compounds, and described in FI 82 696):

New growth adriamycin-resistant S 180 mouse sarcoma cells were cultured in the presence of varying concentrations of test substances for 8 days. Cytotoxic or cytostatic concentrations of test compounds were manifested by decreased cell growth or cell death. The endpoint of the assay was the number of viable cells per culture, which was implicitly exploited by the ability of viable cells to reduce the dye to MTT [= 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide] to colored formazan. The IC50 was the concentration of test substance that reduced the number of viable cells by 50% from the untreated control. Test substances were tested both in the absence of adriamycin and with the amount of adriamycin that does not inhibit neoplasm under culture conditions. Thus, two IC50 values were obtained for the test substance, one in the presence of adriamycin (IC50 ADR), the other without (IC50). Ten-log difference of both IC50 values: = IgIC50 to IgIC50 ADR is a measure of the increase in cytotoxicity of a test substance via adriamycin.

To complete the experiment:

Exponentially growing, adriamycin-resistant S 180 cells were plated in a 96-well flat-bottom microtiter plate at 2000 cells per well in 100 μl of growth medium (RPMI-1640m containing 10% fetal bovine serum). The culture plates were incubated in an incubation cabinet at 37 ° C, 5% CO 2 and 100% relative humidity. After 24 h, 50 μΐ of medium with varying concentrations of test substance and 50 μΐ of medium with or without adriamycin were added per well. At the end of a further 6 days of incubation, 50 μΐ of a tetrazolium solution [5 mg of 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide in ml of phosphate buffered saline was pipetted into each well, diluted to 15 (v / v) before use. RPMI 1640]. After 4 h of incubation, the culture medium was carefully aspirated and the intracellularly formed formazan was dissolved in 150 μΐ of dimethyl sulfoxide per well. The plates were shaken for a short time and the optical density was measured on a li 92699 9570 nm photometer such as Dynatech MR-600 alite. The formation of colored formazan by reduction of the tetrazolium salt is proportional to the number of living cells: the mean of the triplicate (dilution ratio: 1: 2) was used to calculate IC 50 values.

Table 1 IC50 [Mg / ml] Ig_IC50_ compound adriamycin [ng / ml] IC50 25 n9 adriamycin _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 [μg / ml] Ig _IC50_ compound adriamycin [ng / ml] IC50 100 n9 adriamycin _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 νχ 3.00 1.00 0.477 V2 10.00 3.00 0.477

The pteridines of the above general formula I thus had a clear sensitizing effect on adriamycin-resistant tumor cells and are therefore suitable in combination with vinca alkaloids, epipodophyllotoxins or antibiotics such as daunorubicin, doxorubicin, mitramycin or mitomycin. chemotherapy and thus cause deterioration in tumors resistant to these substances. Thus, in tumors sensitized to said chemotherapeutic agents, the pteridines of the formula I, together with the chemotherapeutic agent, prevent the survival of the therapy-resistant tumor cell populations and their ability to cause disease recurrence.

The administration of pteridines, which are also very physiologically acceptable, takes place alone or in combination with a chemotherapeutic agent administered in the usual dose; this dose of pteridine used is then between 1 and 50 mg / kg of body weight per day, preferably 3 to 20 mg / kg of body weight per day, divided into 1 to 4 single doses.

In combination with a corresponding chemotherapeutic agent, it is suitable for intravenous administration such as ampoules and, in separate administration, for parallel administration of tablets, granules, suspensions, juices, capsules or suppositories.

According to a known formula for the administration of natural products for the chemotherapy of tumor diseases (see Goodman and Gilman's, The Pharmacological Basis of Therapies, Macmillan Publishing Company, New York, 7th Edition, pp. 1240-1247 and 1277-1289 (1985)), pteridine of formula I or its the administration of the physiologically acceptable acid addition salt is conveniently performed together with or before the chemotherapeutic agent used or together or before a combination of several therapeutic agents containing at least one of the aforementioned chemotherapeutic agents (see DeVita et al., Cancer, Principles, & Practices of Oncology, 2nd Edition); , JB Lippincott Company Philadelphia).

92699 11

Other administrations of the pteridine of the formula I or its physiologically acceptable acid addition salt may take place orally or possibly intravenously, depending on the circumstances.

The combination suitable for intravenous administration according to the invention thus suitably contains from 1 to 25 mg / kg, preferably from 1 to 20 mg / kg of body weight of pteridine of the formula I or a physiologically acceptable acid addition salt thereof and a suitable chemotherapeutic agent or combination of various suitable chemotherapeutic agents, e.g. , 1 to 0.15 mg / kg vinblastine every 7 days, which may be increased in 0.05 mg / kg steps depending on the degree of side effects, approximately 2 mg / m2 body surface area vinctristine every 7 days in juvenile leukemia, treatment in adults preferably starts at a dose of 0.01 mg / kg every 7 days and can be increased to 0.01 to 0.05 mg / kg according to physiological acceptability.

3-4 mg / m2 body surface area vindesine every 7 days, 25-30 Mg / kg mitramycin daily or every 2 days, 60-75 mg / m2 body surface area adriamycin every 21 days.

.. day, 30 to 60 mg / m2 body surface area daunorubicin daily for 3 days, 10 to 15 mg / kg dactinomycin daily for 5 days, 50 to 100 mg / m2 body surface area etoposide daily for 5 days, and 30 mg / m2 body surface area teniposide daily for up to 5 days, with 6 to 10 treatment cycles added after each 10-day break.

12,92699

The pteridines of the 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 method described therein.

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

In R3 to R5 and n are as defined above, one of Z2 or Z7 is a nucleophilic displaceable group such as a halogen atom, for example a chlorine or bromine atom, and the other of Z2 or Z7 is for R2 or R7 or a nucleophilic substituent such as a halogen atom, for example a chlorine or bromine atom, with an amine of general formula III

H - X III

in which X has the meaning already mentioned for R2 and R7.

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, it may be advantageous to use an acid-binding agent such as sodium carbonate, triethylamine or pyridine.

92699 13

The novel compounds obtained according to the invention can be formed with their inorganic or organic acids into their physiological salts. Examples of suitable acids are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, citric acid, viric acid, succinic acid, maleic acid or fumaric acid.

The compounds of the general formulas II and III used as starting materials are for the most part known (see patents CA-A-912,556, US-A-3,557,105 and US-A-3,754,206) or are obtained according to US-A-2,940,972. or in accordance with the methods described in the aforementioned patent publications.

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 from optically active acids, for example D- or L-monomethyltartaric acid, D- or L-diacetyltartaric acid, or L-tartaric acid, D- or L-lactic acid or D- or L-camphoric acid.

In addition, compounds of the formula I may be separated if they contain at least one geometric center, such as a pyrrolidino, piperidino or morpholino group substituted by two methyl or ethyl groups, in particular a 2,6-dimethylmorpholino group, by customary methods, for example chromatography, cis / trans isomers, or may exist as their cis / trans isomers.

The following examples further illustrate the invention: 4- [N- (2-hydroxy-2-methyl-n-propyl) -ethanolamino] -2,7-bis- (2,6-dimethylmorpholino) -6-phenyllipteridine ____ 92699

Example 1 14 a) 2,7-Dichloro-4- [N- (2-hydroxy-2-methyl-n-propyl) -ethanolamino] -6-phenylpteridine 15.5 g (0.005 mol) of 2,4,7- trichloro-6-phenylpteridine was dissolved in 100 ml of acetone and 13.3 g (0.1 mol) of N- (2-hydroxy-2-methyl-n-propyl) ethanolamine were added. After stirring for 20 min at room temperature, 200 ml of water were added to the corresponding suspension. The precipitated product was 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-dimethylmorpholino) -6-phenylpteridine 2.0 g (0.005 mol) 2, 7-Dichloro-4- [N- (2-hydroxy-2-methyl-n-propyl) -ethanolamino] -6-phenylpteridine was dissolved in 20 ml of dioxane and heated at 3.5 g (0.08 mol) for 30 min. ) With 2,6-dimethylmorpholine. Finally, the reaction solution was poured into water, the precipitated precipitate was filtered off with suction, and recrystallized from ethyl acetate.

Yield: 2.4 g (84% of theory)

Melting point: 191-194 ° C.

Example 2 4- [N-Ethyl-ethanolamino] -2,7-bis (2,6-dimethyl-morpholino) -6-phenyl-pteridine________

Prepared from 4- [N-ethyl-ethanolamino] -2,7-dichloro-6-phenyl-lipteridine and 2,6-dimethyl-morpholine as in Example 1 •.

92699 15

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

Example 3 4- [N-Ethanol-isopropanolamino] -2,7-bis (2,6-dimethyl-morpholino) -6-phenylpteridine

Prepared from 4- (ethanol-isopropanolamino) -2,7-dichloro-6-phenyl-pteridine and 2,6-dimethyl-morpholine as in Example 1.

Yield: 60% of theory

Melting point: 192-193 ° C (methanol / water = 4: 1).

Example 4 4- [N- (2-Hydroxy-2-methyl-n-propyl) -ethanolamino] -2,7-bis (2-methylmorpholino) -6-phenylpteridine_

Prepared from 4- [N- (2-hydroxy-2-methyl-n-propyl) ethanolamino] -2,7-dichloro-6-phenylpteridine and 2-methylmorpholine as in Example 1.

Yield: 74% of theory

Melting point: 143-147 ° C (ethyl acetate / petroleum ether). Example 5 4- (Ethanol-isopropanolamino) -2,7-bis (2-methyl-morpholino) -6-benzyl-lipteridine_

Prepared from 4- (ethanol-isopropanolamino) -2,7-dichloro-6-benzylpteridine and 2-methylmorpholine as in Example 1.

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

92699

Example 6 16 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-methylmorpholine as in Example 1.

Yield: 85% of theory

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

Example 7 4- [Bis (2-hydroxy-2-methyl-n-propyl) amino] -2,7-bis (2,6-dimethylmorpholino) -6-phenylphenidine

Prepared from 4- [bis (2-hydroxy-2-methyl-n-propyl) amino] -2,7-dichloro-6-benzylpteridine and 2,6-dimethylmorpholine as in Example 1.

Yield: 46% of theory

Melting point: 122-127 ° C (reprecipitation from 0.1 N hydrochloric acid).

Example 8 1- (2,3-Dihydroxy-n-propylethanolamino) -2,7-bis (2,6-dimethyllimorpholino) -6-phenylpteridine_

Prepared from 4- (2,3-dihydroxy-n-propylethanolamino] -2,7-dichloro-6-benzylpteridine and 2,6-dimethylmorpholine as in Example 1.

Yield: 76% of theory

Melting point: 105-115 ° C (reprecipitation from 0.1 N hydrochloric acid).

II 4- [N- (2-Hydroxy-2-methyl-n-propyl) -ethanolamino) -2,7-bis- (3,5-dimethylpiperidino) -6-phenyl] -pteridine_ 92699

Example 9 17

Prepared from 4- (N- (2-hydroxy-2-methyl-n-propyl) ethanolamino] -2,7-dichloro-6-phenylpteridine and 3,5-dimethylpiperidine as in Example 1.

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

Example 10 4- [N-ethanol-benzylamino) -2,7-bis (2,6-dimethylmorpholino) -6-phenylpteridine_

Prepared from 4- (N-ethanol-benzylamino) -2,7-dichloro-6-phenylpteridine and 2,6-dimethylmorpholine as in Example 1.

Yield: 34% of theory Melting point: 200-202 ° C.

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-phenylpteridine and cis-2,6-dimethylmorpholine as in 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-dimethylmorpholino) -7-morpholino-6-phenylpteridine__ 9269? 18 a) 4- [N- (2-hydroxy-2-methyl-n-propyl) ethanolamino) -2- (2,6-dimethylmorpholino) -7-chloro-6-phenylpteridine 2.0 g (5 mmol) 4- (N- (2-Hydroxy-2-methyl-n-propyl) -ethanolamino] -2,7-dichloro-6-phenylpteridine was dissolved in 30 ml of dioxane and stirred for 2 h at room temperature in 1.25 ml ( 10 mmol) with 2,6-dimethylmorpholine, the solution was then added to water and the solidified precipitate was filtered off with suction, dissolved in methylene chloride, dried and evaporated on a rotary evaporator, and the residue was 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-dimethylmorpholino) -7-morpholino-6-phenylpteridine was prepared from 4- [N- (2- hydroxy-2-methyl-n-propyl) -ethanolamino) -2- (2,6-dimethylmorpholino) -7-chloro-6-phenylpiperidine and morpholine as in Example 1.

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

Example 13 4- [N- (2-Hydroxy-2-methyl-n-propyl) -ethanolamino) -7- (2,6-dimethylmorpholino) -2-morpholino-6-phenylpteridine) 4- [N- (2- -hydroxy-2-methyl-n-propyl) -ethanolamino) -2-morpholino-7-chloro-6-phenylpteridine 11,92699 19

Prepared as in Example 12 a) from 4- (N- (2-hydroxy-2-methyl-n-propyl) ethanolamino] -2,7-dichloro-6-phenylpiperidine and morpholine.

Yield: 64% of theory Melting point: 152-155 ° C.

b) 4- [N- (2-Hydroxy-2-methyl-n-propyl) -ethanolamino) -7- (2,6-dimethylmorpholino) -2-morpholino-6-phenylpteridine

Prepared from 4- [N- (2-hydroxy-2-methyl-n-propyl) ethanolamino) -2-morpholino-7-chloro-6-phenylpteridine and 2,6-dimethylmorpholine as in Example 1.

Yield: 54% of theory Melting point: sintered at 125 ° C.

Example 14 4- (N-Ethyl-benzylamino] -2,7-bis (2,6-dimethyl-morpholino) -6-phenylpteridine_

Prepared from 4- [N-ethylbenzylamino) -2,7-dichloro-6-phenylpteridine and 2,6-dimethylmorpholine as in Example 1.

Yield: 63% of theory Melting point: 96 ° C.

Claims (3)

A process for the preparation of pharmacologically valuable pteridine tried formula (I) .... X.1 JLA R £ Tl. r7 where n is the number 0 or 1, R 2 and R 2, which may be the same or different, are respectively in the 2- or 2- and 6-position with a methyl or ethyl group substituted morpholine group or 3,5-dimethyl -piperidino group, and R 3 is 2-hydroxy-ethyl, 2-hydroxy-n-propyl, 2,3-dihydroxy-n-propyl or 2-hydroxy-2-methyl-n-propyl, and R 4 is a 2 -hydroxy-2-methyl-n-propyl group, and R5 is a hydrogen atom or methyl group or when n = 0 R2 and R7 are the same and refer to a 2,6-dimethyl or 2,6-diethyltin group, R3 and R 4 together with the intermediate nitrogen atom is an N-alkyl-phenylalkylamino group, wherein the alkyl moiety contains 1-3 carbon atoms, an N-benzylethanolamino, N-ethylethanolamino, N-ethyl-isopropanolamino, ethanol-isopropanolamino or N- (2 , 3-dihydroxy-n-propyl) -ethanolamino group, or one of groups R 2 or R 7 is a morpholino group, the other of groups R 2 or R 7 is a 2,6-dimethyl or 2,6-diethylmorpholino group and R 3 and R 4 together is an N- (2-hydroxy-2-methyl) 1-propyl) -ethanolamino group, or where 0 is and R5 is a methyl group, then R 2 and R 7 are a 2-methyl-morpholino group, R 3 and R 4 are, together with the intermediate nitrogen atom, an ethanol-isopropanol amino group, its geometric or optical isomers such as also its physiologically acceptable acid addition salts with inorganic or organic acids, characterized in that a pteridine of formula II III x = y, (II) where R3 - R5 and n are as defined above, one of the groups Z2 or Z7 is a nucleophilic substitutable group and the other of the groups Z2 or Z7 has the meaning mentioned for R2 or R7 or is also a nucleophilic substitutable group, reacted with an amine of the general formula III H - X (III) where X has the meaning given for R2 or R7 above. and, if necessary, the said obtained compound is separated into its optical or geometric isomers and / or the so obtained compound is optionally converted to its acid addition salt, in particular its physiologically acceptable surface addition salt. Process according to Claim 1, characterized in that the compound is 4- [N- (2-hydroxy-2-methyl-n-propyl) -ethanolamino] -2,7-bis (2,6-dimethylmorpholino) -6- phenylpteridine, its optical or geometric isomer, or its acid addition salt. Process according to claim 1, characterized in that the pteridine produced is: - [N- (2-hydroxy-2-methyl-n-propyl) -ethanolamino] -2,7-bis - (2, 6-dimethylmorpholino) -6-phenylpteridine, 4- (N-ethyl-ethanolamino) -2,7-bis (2,6-dimethylmorpholino) -6-phenyl-pteridine, 4- (ethanol-isopropanolamino) -2,7- bis (2,6) dimethylmorpholino) -6-phenylpteridine, 4 - [N- (2-hydroxy-2-methyl-n-propyl) -ethanolamino] -2,7-bis (2-methylmorpholino) - 6- phenylpteridine, 4- (ethanol-isopropanolamino) -2,7-bis (2-methylmorpholino) -6-benzylpteridine, 4- (ethanol-isopropanolamino) -2,7-bis (2-methylmorpholino) -6- (o -tolyl) pteridine, 4 - [bis (2-hydroxy-2-methyl-n-propyl) amino] -2,7-bis (2-methylmorpholino) - 6-phenylpteridine, 4- (2,3-dihydroxy) -n-propyl-ethanolamino) -2,7-bis (methylmorpholino) -6-phenylpteridine, 4- [N- (2-hydroxy-2-methyl-n-propyl) -ethanolamino] -2,7-bis (3 5-Dimethylpiperidino) -6-phenylpteridine, 4- (N-ethanol-benzylamino) -2,7-bis (2,6-dimethylmorpholino) -6-phenylpteridine, 4- [N- (2-hydroxy-2) methyl-n-propyl) ethanolamine o] -2,7-bis (cis-2,6-dimethylmorpholino) -6-phenylpteridine, 4- [II- (2-hydroxy-2-methyl-n-propyl) -ethanolamino] -2- (2.6 -dimethyl-morpholino) -7-morpholino-6-phenylpteridine, 4- [N- (2-hydroxy-2-methyl-n-propyl) -ethanolamino] -7- (2,6-dimethyl-morpholino) - 2-morpholino-6-phenylpteridine, 4- (λ'-ethylbenzylamino) -2,7-bis (2,6-dimethylmorpholino) -6-phenylpteridine, or their acid addition salts.