Derivatives hintline, the method of production thereof and pharmaceutical composition based on them

 

(57) Abstract:

Hintline derivatives of the formula (I), its pharmaceutically acceptable salt or ester, where R1- C1-C4-alkyl; R2is hydrogen, C1-C4- alkyl; R3- C1-C4- alkyl, C3-C4alkenyl, C3-C4- quinil; Ar is phenylene which may be optionally one or two substituent selected from halogen, C1-C4- alkyl, C1-C4- alkoxy, or pyridinyl, possess antitumor activity. Hintline ring may optionally be in one of 5-, 7 - and 8-positions Deputy selected from halogen and C1-C4-alkyl. The compound (I) is produced by interaction of the acid (II) with compound (III), where R1, R2, R3have the specified values, and R4is hydrogen or a protective group, R5- protective group, the protective group is removed in the traditional way. The compound (I) is used as active ingredient in pharmaceutical compositions. 3 S. and 9 C.p. f-crystals, 2 tab.

The invention relates to novel antitumor compounds, in particular to hinazolinam derivatives or their pharmaceutically acceptable salts or complex Echis their receipt, new pharmaceutical compositions containing these hintline derivatives, the use of these derivatives to obtain new drugs with the ability to produce anti-tumor response in a warm-blooded animal such as man.

One group of antitumor compounds is a antimetabolites, such as aminopterin, methotrexa, which are inhibitors of enzymes such as dihydrofolate-reductase affecting derivatives of folic acid. A compound known as CB3717, which was described and claimed in UK patent N 2065653B, showed promising results in its clinical trial. Despite significant efficiency CB3717 to use him against breast cancer, ovarian cancer and liver cancer, this tool proved to be toxic to humans, especially in the liver and kidney [Calvert, Alison, Harland, Robinson, Jackman, Jones, Newell, Siddik, Whiltshaw, Me Elwain, Swith and ish, J. Clin. Oncol., 1986, 4, 1245; Cantwell, Earnshaw and Harris, Cancer Treatment Reports, 1986, 70, 1335; Bassendine, Curtin, Loose, Harris and James, J. Hepatol., 1987, 4, 39; Vest, Bork and Hasen, Eur. J. Cancer. Clin. Oncol., 1988, 24, 201; Cantwell, Macaulay, Harris, Kaye, Smith, Milsted and Calvert, Eur. J. Cancer Clin. Oncol. , 1988, 24, 733; Sessa, Zucchetti, Ginier, Willems, D Incalci and Cavalli, Eur. J. Cancer Clin. Oncol., 1988, 24, 7For in the case is missing, or substituted one of the various alternative substituents as described in the patents great Britain N 2175903 and 2188319 respectively.

Obviously, the antitumor activity of compounds of the type CB3717 is not by inhibiting dehydropeptidase, and by inhibition of thymidylate synthase. The thymidylate synthase catalyzes methylation of deoxyuridines to obtain timeintensity, which is required for DNA synthesis. Anticancer activity CB3717 can be assessed in vitro by determining its inhibitory effect on the specified enzyme and in cell cultures by determining its inhibitory effect on the line of cancer cells, such as cell line L1210 leukemia mice, cell lines mouse lymphoma L U TK-/- and L U TK+/ - and cell line MCF-7 breast cancer man.

Anticancer activity of other compounds CB3717-type can therefore be determined and compared with the activity of CB3717, for example, against the same enzyme and the same cell lines.

Antimetabolites, such as aminopterin and methotrexate, are inhibitors of enzymes such as dihydrotetrazolo that affects the derivative of folic acid, can BT and psoriasis. So hintline derivatives of the present invention, which are also antimetabolites are a valuable therapeutic tools that can be used to treat, for example, allergic conditions, such as psoriasis.

Antimetabolites, such as methotrexate, has also shown activity in the treatment of various inflammatory diseases, such as inflammation of the joints (in particular, rheumatoid arthritis, osteoarthritis and gout), and inflammation of the gastrointestinal tract (in particular, intestinal inflammatory disease, ulcerative colitis and gastritis) (Weinblatt and others, New England J. Med., 1985, 312, 818; Andersen and others Ann. Internat. Med. 1985, 103, 489; Healey, Bull. Rheum. Dis., 1986, 36, 1). Thus, hintline derivatives of the present invention are valuable therapeutic tools that can be used, for example, for the treatment of inflammatory diseases such as rheumatoid arthritis.

In applications for Europatent N 0239362 and 0284338 revealed two series khinazolinov derivatives, which possess anti-cancer properties due to its ability to inhibit the thymidylate synthase. Examples of such derivatives are derivatives of N-{p-[N-(4-oxo-3,4-dihydroquinazolin-6-ileti CB3717, operate through metabolite produced when gamma polyglutamylation (Sikora and others, Biochem. Pharmacol. , 1988, 34, 4047; Jackman and others, Cancer Research, 1991, 51, 5579).

We unexpectedly found that structures are known derivatives of L-glutamic acid can be modified by removing the gamma-carboxyl group or by its replacement by tetrazol-5-ilen group to obtain compounds with improved inhibitory activity against the thymidylate synthase. In addition, the compounds of the present invention, it is obvious that apply directly, if the process of gamma glutaminovaya cannot take place. Such an alternative mode of action of the compounds of the present invention allows more accurate control of anti-cancer action since the beginning of this action manifests itself more quickly because of its independence from metabolic process, which may vary considerably in different patients. In addition, it is expected that the compounds of the present invention will be more useful in the treatment of those cases of cancer, where there is the process of gamma glutaminovaya than the previously described connections to enhance their anti-cancer action, ecologicaleconomic derivatives, antimetabolites, which cannot easily diffuse through the cell membrane. When useful anticancer action connection overlaps its adverse toxic effects, is highly undesirable, if an antimetabolite remains in normal cells due process polyglutamylation. Therefore, an alternative mechanism of action of the compounds of the present invention allows precise control of anti-cancer therapy of the patient.

The present invention relates to hinazolinam derivative of formula 1 (see the end of the text), where R1is (1-4C)alkyl; hintline ring may, but not necessarily, contain (one or two 5-, 7 - and 8-positions) one or two additional substituent selected from halogen (1-4C)alkyl and (1-4C)alkoxy; R2is hydrogen or (1-4C) alkyl; R3represents (1-4C)alkyl, (3-4C)alkenyl, (3-4C)quinil, hydroxy-(2-4C)alkyl, halogeno-(2-4C)alkyl or cyano-(1-4C)alkyl; and Ar represents a phenylene or heterocycle, which may, but not necessarily, to have one or two substituent selected from halogeno, (1-4C)alkyl and (1-4C)alkoxy; either present invention relates to a pharmaceutically acceptable salt or complex air ukazannoj is Oh or branched chain, however, refer to individual alkyl groups such as "propyl" are specific only for groups with a direct chain. The same remarks apply to other basic terms.

It should be noted that hintline derivative of the present invention has one or more asymmetric carbon atoms and therefore exist in optically active forms. Hence it is clear that the present invention includes any optically active form having antitumor activity; moreover, these optically active forms can be separated by known methods. The preferred form chineselanguage derivative of the present invention is derived enriched form having the (S)-configuration at the carbon atom that bears the carboxyl group, i.e., relation (S):(R) that is greater than 1:1. More preferably, if hintline derivative of the present invention has a predominantly (S)-configuration at this carbon atom, i.e., the ratio (S):(R) greater than 3: 2. And even more preferably, if the specified hintline derived mainly contains the form with (R)-configuration at this carbon atom. Used above the term "is citicolina not more than 2 wt.% any (R)-form.

It should also be noted that hintline derivatives of the present invention of formula (I) can detect the phenomenon of tautomerism. The formulae given in the present description, can represent only one of the possible tautomeric forms. In particular, tetrazol-5-ilen group can be, for example, in the form of 1H-tetrazol-5-ilen or 3H-tetrazol-5-ilen group. Therefore, the present invention encompasses any tautomeric form which has antitumor activity and is not limited to any one tautomeric form depicted in the presented formulas.

It should also be pointed out that some hintline derivatives of the formula (I) can exist in solvated and resolutiony forms, such as hydrates. It should be noted that the present invention includes all of the solvated forms, with antitumor activity.

Listed below are the appropriate values for the basic radicals specified above.

A suitable value for R1, R2and R3if it is (1-4C)alkyl or (1-4C)alkyl substituent which may be present on hinahayaan the ring or on Ar is, for example, methyl, Aristotle on hinazolinam ring or Ar, is, for example, fluorescent-, chloro-, or braugruppe.

A suitable value for the radical R3if it is a (3-4C)alkenyl is, for example, prop-2-Enel, but-2-enyl, but-3-enyl or 2-methylpropyl-2-enyl; if it is a (3-4C)quinil, then the appropriate value is, for example, prop-2-inyl or but-3-inyl; if he is a hydroxy-(2-4C)alkyl, then the appropriate value is, for example, 2-hydroxyethyl or 3-hydroxyethyl; if it is halogeno-(2-4C)alkyl, then the appropriate value is, for example, 2-toroidal, 2-chloroethyl, 2-bromoethyl, 3-forapril, 3-chloropropyl or 3-bromopropyl; and, finally, if he is a cyano-(1-4C)alkyl, then a suitable value, for example, is cyanomethyl, 2-cyanoethyl or 3-cyanopropyl.

If Ar is a phenylene, its appropriate value is 1,3 - or 1,4-phenylene.

If Ar is heterocycle, its appropriate value is, for example, 5 - or 6-membered ring (that is, fully unsaturated) heterocyclic ring which contains up to 3 heteroatoms selected from nitrogen atoms, and sulfur, such as difenidol, pyridinethiol, pyrimidinyl or diazolidinyl. If Ar drank, pyridine-2,5-diyl or thiazol-2,5-diyl.

Suitable pharmaceutically acceptable salts chineselanguage derivative of the present invention which is sufficiently basic, are acid additive salts formed with inorganic or organic acids, such as hydrochloric, Hydrobromic, sulfuric, phosphoric, triperoxonane, citric or maleic acid. In addition, suitable pharmaceutically acceptable salts chineselanguage derivative of the present invention which is sufficiently acidic, are salts of alkaline metal such as potassium or sodium salts of alkaline-earth metal such as calcium salts or magnesium salts of ammonium or Tetra-(2-hydroxyethyl)ammonium; or a salt formed with an organic base, bearing a physiologically acceptable cation, for example melaminovaya salt, trimethylamine salt or Tris-(2-hydroxyethyl)Eminova salt.

Suitable pharmaceutically acceptable esters chineselanguage derivative of the present invention are, for example, esters derived from (1-6C)alcohol, such as methyl, ethyl or tert-butyl methyl ether.

Conques where

a) R1represents methyl or ethyl; and Deputy chineselanguage rings R2, R3and Ar have any of the values defined above or in this section defining particular new compounds of the present invention;

b) hintline ring has a 7-position another Deputy, selected from fluorescent, chloro, bromo and methyl; and R1, R2, R3and Ar have any of the values defined above or in this section defining particular new compounds of the present invention;

c) R2is hydrogen; and R1, Deputy chineselanguage ring, R3and Ar have any of the values defined above or in this section defining particular new compounds of the present invention;

d) R3is stands, ethyl, propylene, prop-2-anilam, prop-2-inila, 2-hydroxyethyl, 2-feration, 2-bromoethyl or cyanomethyl; and R1, Deputy chineselanguage ring, R2and Ar have any of the values defined above or in this section defining particular new compounds of the present invention;

e) Ar is 1,4-phenylene, which may be, but not necessarily, one or two Deputy, jibraeel; and R1, Deputy chineselanguage ring, R2and R3have any of the values defined above or in this section defining particular new compounds of the present invention; or their pharmaceutically acceptable salts or esters.

Another specific compound of the present invention is hintline derivative of the formula (I), where R1is stands; hintline ring may, but not necessarily, have a 7-fluorescent-, 7-chloro, 7-bromo - or 7-methyl Deputy; R2represents hydrogen; R3represents methyl, ethyl, propyl, prop-2-enyl or prop-2-inyl; and Ar is a 1,4-phenylene, which may, but not necessarily, be of the fluorescent-Deputy, or Ar is a thiophene-2,5-diyl, thiazole-2,5-diyl (- CONH-group in 2-position) or pyridine-2,5-diyl (- CONH-group in 2-position);

or its pharmaceutically acceptable salt.

Another preferred compound of the present invention is hintline derivative of the formula (I), where R1is stands; hintline ring may have, but not necessarily, 7 -, fluorescent-, 7-chloro, 7-bromo - or 7-methyl Deputy; R2represents hydrogen; R3pre 1-position), or pyridine-2,5-diyl (- CONH-group in 2-position);

or its pharmaceutically acceptable salt.

Another preferred compound of the present invention is hintline derivative of the formula (I), where R1represents methyl; hintline ring may, but not necessarily, have a 7-fluorescent-, 7-chloro, 7-bromo - or 7-methyl Deputy; R2represents hydrogen; R3represents methyl, ethyl, propyl, prop-2-enyl or prop-2-inyl; and Ar is a 1,4-phenylene, which may, but need not be fluorescent-Deputy, or Ar is a thiophene-2,5-diyl or thiazol-2,5-diyl (- CONH-group in 2-position);

or its pharmaceutically acceptable salt.

Specific preferred hinazolinam derivative of the present invention is, for example, one of the following khinazolinov derivatives of the formula (I) or its pharmaceutically acceptable salt

2-{ p-[N-(2-methyl-4-hydroxy-3,4-dihydroquinazolin-6-ylmethyl)-N-(propyl-2-inyl)amino]benzamido}-4-(tetrazol-5-yl)butyric acid;

2-{ o-fluorescent-p-[N-(2-methyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl)-N-(prop-2-inyl)amino]benzamido}-4-tetrazol-5-yl)butyric acid;

2-{ p-[N-(2,7-dimethyl-4-oxo-3,4-dihydroquinazolin drogenation-6-yl - methyl)-N-methylamino]benzamido}-4-tetrazol-5-yl)butyric acid;

2-{ p-[N-(2,7-dimethyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl)-N-(propyl-2-inyl)amino]benzamido}-4-(tetrazol-5-)butyric acid;

2-{ o-fluorescent-p-[N-2,7-dimethyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl)-N-(prop-2-inyl)amino]benzamido}-4-(tetrazol-5-yl)-butyric acid;

2-{ p-[N - (7-chloro-2-methyl-4-oxo-3,4-dihydrothiazolo-6-ylmethyl)-N-(prop-2-inyl)amino]benzamido}-4-(tetrazol-5-yl)- butyric acid;

2-{ o-fluorescent-p-[N 7-chloro-2-methyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl)-N-(prop-2-inyl)amino]benzamido}-4-(tetrazol-5-yl)butyric acid, or

2{ p-[N-7-bromo-2-methyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl)-N-(prop-2-inyl)amino]benzamido}-4-tetrazol-5-yl)-butyric acid.

Other typical preferred hinazolinam derivative of the present invention is, for example, one of the following khinazolinov derivatives of the formula (I), its pharmaceutically acceptable salt

(2S)-2-{ p-[N-(2-methyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl-N-(prop-2-inyl)amino]benzamido}-4-(tetrazol-5-yl)butyric acid;

(2S)-2-{ o-fluorescent-p-[N-(2-methyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl)-N-(prop-2-inyl)amino]benzamido}-4-(tetrazol-5-yl)butyric acid;

(2S)-2-{ p-[N-(2,7-dimethyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl)-N-methylamino]benzamido}-4-tetrazol-5-yl)oil is l-5-yl)butyric acid;

(2S)-2-{ p-[N-(2,7-dimethyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl)-N-(prop-2-inyl)amino]benzamido}-4-(tetrazol-5-yl)butyric acid;

(2S)-2-{ o-fluorescent-p-[N-(2,7-dimethyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl)-N-(prop-2-inyl)amino]benzamido}-4-(tetrazol-5-yl)butyric acid;

(2S)-2-{ p-[N-(7-chloro-2-methyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl)-N-(prop-2-inyl)amino]benzamido}-40(tetrazol-5-yl)-butyric acid;

(2S)-2-{ o-fluorescent-p-[N-(7-chloro-2-methyl-4-oxo-3,4-dihydroquinazolin-6 - ylmethyl)-N-(prop-2-inyl)amino] benzamido} -4-(tetrazol-5-yl)butyric acid, or

(2S)-2-{ p-[N-(7-bromo-2-methyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl-N-(prop-2-inyl)amino]benzamido}-4-tetrazol-5-yl)butyric acid.

While this hintline derivative (S)-configuration can exist in the form of a mixture with the corresponding derivative of (R)-configuration, however, as mentioned above, it is preferable that the derivative (S)-configuration was present in larger quantities.

The following are typical preferred hinazolinam derivative of the present invention is, for example, one of the following khinazolinov derivatives of the formula (I) or its pharmaceutically acceptable salt

(2S)-2-{ o-fluorescent-p-[N-(2,7-dimethyl-4-oxo-3,4-dihydroquinazolin-6-elmet insulin-6-ylmethyl)-N-(prop-2-inyl)amino] pyridine-2-carboxamido} -4-(tetrazol-5-yl)butyric acid.

In another embodiment, the present invention relates to a group khinazolinov derivatives, which possess improved antitumor activity and which, furthermore, may have a better therapeutic index in comparison with the activity and therapeutic index known and structurally related derivatives of N-{p-[N-(4-oxo-3,4-dihydroquinazolin-6-ylmethyl)-N - alkylamino]benzoyl}-L-glutamic acid.

This group khinazolinov derivative preferably includes hintline derivative of the formula (I), where R1represents methyl; hintline ring has 7-methyl Deputy; R2represents hydrogen; R3represents methyl, ethyl or prop-2-inyl; and Ar is a 1,4-phenylene or 2-fluorescent-1,4-phenylene (- CONH-group at 1-position); or its pharmaceutically acceptable salt.

Alternative this group khinazolinov derivatives includes hintline derivative of the formula (I), where R1is stands; hintline ring has 7-methyl Deputy; R2represents hydrogen; R3represents methyl or prop-2-inyl; and Ar is a 1,4-phenylene, 2-fluorescent-1,4-phenylene (- CONH-group in 1 Polo is impactfully connection of this group khinazolinov derivative is 2-{ o-fluorescent-p-[N-(2,7-dimethyl-4-oxo-3,4 - dihydroquinazolin-6-ylmethyl)-N-methylamino]benzamido}-4-tetrazol-5 - yl)butyric acid or its pharmaceutically acceptable salt.

An alternative connection of this group khinazolinov derivative is (2S)-2-{ o-fluorescent-p-[N-(2,7-dimethyl-4-oxo-3,4 - dihydroquinazolin-6-ylmethyl)-N-(prop-2-inyl)amino] benzamido}-4- (tetrazol-5-yl)butyric acid or its pharmaceutically acceptable salt.

An alternative connection of this group khinazolinov derivative is (2S)-2-{ 5-N-(2,7-dimethyl-4-oxo-3,4-dihydrobenzoic-6-ylmethyl)-N-(prop-2-inyl)amine] pyridine-2-carboxamido}-4-(tetrazol-5-yl)butyric acid or its pharmaceutically acceptable salt.

Therapeutic index chineselanguage derivative of the present invention can be determined, for example, by comparing the dose that ensures effective antitumor activity in appropriate in vivo models, such as tumor L U TK +/- (Fisher and other Methods in Medical Research, 1964, 10, 247), in suitable animals, such as mice, dose, causing a significant loss in weight of the test animal.

The compound of the present invention, representing hintline derivative of the formula (I) or its pharmaceutically acceptable salt or ester may be obtained by any known method, which is usually used for structurally related etenia and illustrated below are typical examples, where R1, R2, R3and Ar (if it is not specifically mentioned) have the meanings given above. The alternative, where necessary, functional groups, use standard protective group, if only they do not prevent the correct process. Examples of such protective groups is given below. Any such protective groups can be removed, if necessary, any traditional way.

a) the reaction of the acid of formula (II) (below) or its reactive derivative, where R4is hydrogen or a protective group, with a compound of formula (III), where R5is a protective group, such as (1-4C) alkyl group, with the subsequent removal of the protective groups in the traditional way. Suitable reactive derivative of the acid of formula (II) may be, for example, Allgood, such as acylchlorides formed through reaction of the acid and an inorganic acid chloride, for example thionyl chloride; a mixed anhydride, for example the anhydride formed through reaction of the acid and chloroformate, such as isobutylacetate; active complex ester formed through reaction of the acid and a phenol, such as 1-hydroxybenzotriazole; acylated, such as the cyanide, formed through reaction of an acid and a cyanide such as diethylphosphoramidite; or the reaction product of the acid with a carbodiimide, such as dicyclohexylcarbodiimide.

This reaction is carried out preferably in the presence of an appropriate base, such as carbonate, alkoxide, hydroxide or hydride of an alkaline or alkaline-earth metal, for example sodium carbonate, potassium carbonate, ethoxide sodium, butoxide potassium, potassium hydroxide, sodium hydride or potassium hydride; or an organic amine base such as, for example, pyridine, 2,6-lutidine, kallidin, 4-dimethylaminopyridine, triethylamine, morpholine or diazabicyclo 5.40 unlac-7-ene. The reaction is also preferably carried out in a suitable inert solvent such as tetrahydrofuran, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidine-2-it, dimethylsulfoxide or acetone, at a temperature of about -78oC - 150oC, and preferably at a temperature close to ambient temperature.

A suitable value for the radical R4if it represents a protective group is, for example, pivellina group, which can then be removed by hydrosoil diluent, for example in methanol or ethanol.

A suitable value for the radical R5if it is a (1-4C)alkyl group is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl. R5can be removed, for example by hydrolysis, preferably in the presence of a base such as a hydroxide of an alkaline or alkaline-earth metal, such as lithium hydroxide, sodium hydroxide or potassium hydroxide. Alternatively, if R5represents a tert-boutelou group, it may be removed, for example, by treatment with the appropriate inorganic acid, such as hydrochloric, sulphuric or phosphoric acid, or organic acid, such as triperoxonane acid.

A suitable protecting group for hydroxy-(2-4C)alkyl group is, for example, alcoolica group such as acetyl group; arolina group, such as benzoline group; or arylmethylidene group such as benzyl group. Conditions of release for the above-mentioned protective groups will vary depending on the choice of protective groups. So, for example, acyl group, such as alcoolica or arolina group, can be compa the example lithium hydroxide or sodium. Alternatively, allmerica group such as benzyl group may be removed, for example by hydrogenation in the presence of a catalyst such as palladium charcoal.

The initial compounds of the formula (II) and formula (III) can be obtained by traditional methods of organic chemistry. Examples of obtaining the starting materials described in the examples below, which are only for illustrative purposes and should not be construed as a limitation of the present invention. Other necessary raw materials are obtained by procedures similar to those described, or using modifications of standard procedures known to the specialists in organic chemistry. So, for example, the source compound of formula (II) can be obtained by reaction of compounds of formula (IV), where Z is a substituted group, with an amine of the formula

HNR3-Ar1-CO2R5,

where R5is a protecting group, as defined above, which can then be removed with obtaining carboxylic acids.

In addition, the source compound of formula (III), where R5is hydrogen, having predominantly (S)-configuration at the carbon atom that carries amino, Carbo the AI in the traditional way with the formation of the compounds of formula (III), where R5is (1-4C)alkyl group. Alternatively, the open here is the link that has the structure of formula (III), where R5is stands, except that the amino group is protected benzyloxycarbonyloxy group, can be unlocked, for example by hydrogenolysis.

A suitable value for the substitutable group Z is, for example, halogeno or sulfonyloxy, such as chloro-, bromo-, methylsulfonate - or 4-toluensulfonate.

b) Reaction of compounds of formula (IV), where R4is hydrogen or a protecting group, as defined above, and Z is a substituted group, as defined above, with an amine of formula (V), where R5is a protecting group, as defined above, followed by removal of protective groups by conventional methods. This reaction is carried out preferably in the presence of an appropriate base, as defined above, in an appropriate inert solvent or diluent as defined above, and at a temperature of about, for example, 25 - 150oC, and preferably at about 90oC.

The initial compounds of formulas (IV) and (V) can be obtained by standard methods, usually used for the description of the example, which are only illustrated and in no way should be construed as limiting the invention. Other necessary raw materials can be obtained using procedures similar to those described, or by using a modification of standard procedures, well known to experts.

If you want to get a pharmaceutically acceptable salt of the new compounds of formula (I), this salt can be obtained, for example, through reaction of the compounds with the appropriate acid or base in accordance with the traditional technique. If you want to get a pharmaceutically acceptable ester of the new compounds of formula (I), the ester can be obtained, for example, through reaction of the compounds with the corresponding (1-6C) alcohol in accordance with the traditional technique. If you want to obtain optically active form of compounds of formula (I), it can be obtained by using one of the above methods using optically active starting material, or by separation of the racemic forms of the compounds using standard procedures.

As mentioned above, hintline derivative of the present janiem the procedures described below.

a) In vitro analysis to determine the ability of test compounds to inhibit the thymidylate synthase (enzyme). The thymidylate synthase was obtained from cells L 1210 murine leukemia particularly pure form, using the procedure described Jackman and others (Cancer Res., 1986, 46, 2810) and Sikora and others , (Biochem. Pharmacol., 1988, 37, 4047).

in the Analysis to determine the ability of test compounds to inhibit the growth of cell lines of leukemia L1210 cell culture. The tests were carried out in accordance with the descriptions in the patent UK N 206565B and Jones and others in J. Med. Chem. 1985, 28, 1468.

(C) Analysis to determine the ability of test compounds to inhibit the growth of cell lines MCF-7 breast cancer man in the cell culture. The tests were carried out in accordance with the description Lippman and others (Cancer Res., 1976, 36, 4595).

Although the pharmacological properties of hintline of the present invention vary depending on the structural dimension, but in tests (a) - (c) (see above) hintline the present invention generally have the following activity:

test (a) IC50for example, in the range 1 - 100 nm;

test (b) IC50for example, in the range from 0.01 to 10 microns;

test (c) IC50for example, in the range from 0.01 to 10 μm.

Results the s hintline of the present invention, which are preferred, mainly have the following activity:

test (a) IC50for example, in the range from 1 to 20 nm;

test (b) IC50for example, in the range from 0.01 to 1 μm;

test (c) IC50for example, in the range from 0.01 to 1 μm;

For example, the compound (2S)-2-{p-[N-(2-methyl-4-oxo-3, 4-dihydroquinazolin-6-ylmethyl)-N-(prop-2-inyl)amino]benzamido}-4- (tetrazol-5-yl) butyric acid has the IC5013 nm in test (a), IC50to 0.12 μm in test (b) and (IC500,04 µm in test (c); the compound (2S)-2-{o-fluorescent-p-[N-(2,7-dimethyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl)-N-methylamino]benzamido}-4-(tetrazol-5-yl) butyric acid has the IC502 nm in test (a), IC50of 0.07 μm in test (b) and (IC500,04 µm in test (c); the compound (2S)-2-{o-fluorescent-p-[N-(2,7-dimethyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl)-N-(prop-2-inyl)amino] benzamido}-4-(tetrazol-5-yl) butyric acid has the IC501 nm in test (a), IC50of 0.02 μm in test (b) and (IC500.01 µm in test (c).

Hintline derivative of the present invention, or its pharmaceutically acceptable salt or ester can be introduced warm-blooded animal, including man, in the form of a pharmaceutical composition, which contains hintline derivative or its pharmaceutically p">

This composition can be made in the form intended for oral administration, such as tablets, capsules, aqueous or oily solutions, suspensions or emulsion; for topical use, for example, in the form of creams, ointments, gels, or aqueous or oily solutions or suspensions; for intranasal, for example, in the form of a powder for inhalation through the nose, aerosol and droplets through the nose; for vaginal or rectal administration, for example, in the form of a suppository; for administration by inhalation, for example, in the form of an aerosol for spraying finely ground powder or a liquid aerosol; for sublingual or translocating introduction, for example, in the form of tablets or capsules; or, particularly preferably, for parenteral injection (including intravenous, subcutaneous, intramuscular and intravascular introduction or infusion), for example, in the form of a sterile aqueous or oily solutions, emulsions or suspensions. The above compositions can be obtained mainly by traditional methods using standard fillers.

In addition chineselanguage derivative of the present invention the composition may contain other antitumor agents, wybranie, carboplatin and cyclophosphamide; antimetabolites, for example 5-fluorouracil inside the body, citizenoriented and hydroxyurea; intercalary antibiotics, for example adriamycin and bleomycin; enzymes, for example asparaginase; topoisomerase inhibitors, for example etoposide; and biological response modifiers, for example interferon.

Warm-blooded animal hinzelin injected mainly in the form of a single dose of 50 - 500 mg/m2the body surface of the animal, i.e. approximately 1 to 100 mg/kg, and represents a normal therapeutically effective dose. Single dosage form such as tablet or capsule, may mainly contain, for example, from 1 to 250 mg of active ingredient. The preferred daily dose is 1 to 50 mg/kg, and more preferably 1 to 15 mg/kg, However, this daily dose may vary depending on the treated individual, the specific route of administration and the severity of the disease. Therefore, the treatment of each individual patient's optimal dose is prescribed by the treating physician.

Another distinguishing feature of the present invention to provide chineselanguage derivative of the formula (I) or its pharmaceutically acceptable salt, or a complex eternum characteristic of the present invention is a method of producing an antitumor response in a warm-blooded animal, for example the person in need of such treatment, by introducing a specified animal an effective amount of chineselanguage derivative of the present invention, or its pharmaceutically acceptable salt, or a complex ester.

The present invention also relates to the use chineselanguage derivative of the present invention, or its pharmaceutically acceptable salt, or a complex ester in the manufacture of a new drug intended for producing antitumor response in a warm-blooded animal such as man.

It can be expected that hinzelin the present invention has a broad spectrum of antitumor activity. SW showed promising activity against breast cancer, ovary and liver of man, and therefore it is assumed that hinzelin of the present invention will also have antitumor activity for these types of cancer. In addition, it is assumed that hinzelin of the present invention will possess activity against leukemia, malignant tumors of lymphoid tissues and solid tumors such as carcinomas and sarcomas. These tumors require the presence of timeintensity ka is subjective amount of an inhibitor of thymidylate synthase, such as chineselanguage derivative of the present invention, tumor growth is inhibited.

As mentioned above, hintline derivative of the present invention, or its pharmaceutically acceptable salt, or ester can also be used in the treatment of, for example, allergic conditions, such as psoriasis, or inflammatory diseases such as rheumatoid arthritis. When using hintline of the present invention for these purposes, this connection is mostly administered in the dose of that component of the 500 - 50000 mg/m2the body surface of the animal. In the treatment of allergic conditions, such as psoriasis, hinzelin of the present invention, it is preferable to use by external application. For example, for local use daily dosage can generally be 1 to 150 mg/kg, and preferably 1 to 80 mg/kg

For purposes of illustrating the present invention the following examples, which, however, should not be construed as a limitation of the present invention and in which (if it is not specifically mentioned)

I) the evaporation was carried out in vacuum using a rotary evaporator, and handling procedures were carried out after removal of the remaining atmosphere inert gas, such as argon;

III) column chromatography (by the flash procedure) and liquid chromatography medium pressure (GHSD) was performed on silica Merck Kieselgel (Art 9385) or reverse-phase silica Merck Lichroprep RP-18 (Art. 9303) obtained from E. Merck, Darmstadt, Zap. Germany;

IV) conclusions are given only for illustration and do not necessarily represent the maximum achievable level;

V) final products of the formula (I) showed satisfactory results when microanalysis, and their structures were confirmed by NMR analysis and mass spectroscopy [proton nuclear magnetic resonance spectrum was determined using a spectrometer JeoI FX 900 or Bruker AM200 operating at a field strength of 200 MHz; chemical shifts in NMR spectra are given in ppm relative to tetramethylsilane used as internal standard (-scale), and the multiplicity of the peaks are indicated as follows: s (singlet); d (doublet); DD (doublet of doublets), t (triplet); m (multiplet); data mass spectroscopy by fast atom bombardment (FAB) were obtained using analytical spectrometer (VG Analytical MS9) and xenon gas; and where possible, evidence of positive or negative by means of thin layer chromatography, infrared analysis (IR) or NMR analysis;

(VII) melting points, which are given without amendments, were determined using an automatic device for determining the melting temperature of Mettler SP62; devices with heated plates Koffler or device with an oil bath;

VIII) chiral purity of the final products of the formula (I) and intermediates such as compounds of formula (III), was estimated using NMR and chromatographic analysis;

IX) we used the following abbreviations:

THF - tetrahydrofuran;

DMF - N, N-dimethylformamide;

DMA is N, N-dimethylacetamide;

N - N-methylpyrrolidine-2-he;

DMSO - dimethyl sulfoxide.

Example 1. The mixture pentafluorophenyl o-fluorescent-p-[N-(2,7-dimethyl-4-oxo-3-(pivaloyloxymethyl)-3,4-dihydroquinazolin-6-ylmethyl)-N- (prop-2-inyl)amino] benzoate (2.5 g), methyl (2S)-2-amino-4-(tetrazol-5-yl)butyrate (0.32 g), N-hydroxybenzotriazole (0.05 g) and dimethylformamide (DMF) (100 ml) was stirred at room temperature for 24 h the resulting mixture was evaporated and the residue was purified by column chromatography, elwira mixture of methylene chloride and methanol (19:1 V/V). The mixture obtained in the form of gum, pereirae with diethyl ether, resulting in a recip is lmutil)-N-(prop-2-inyl)amino] benzamido} -4-(tetrazol-5-yl)butyrate with the release of 79%.

A mixture of the obtained product, 2 n sodium hydroxide solution (20 ml) and methanol (5 ml) was stirred at room temperature for 1 h the mixture was concentrated by evaporation of the methanol and the aqueous residue was acidified to pH 4 by addition of concentrated hydrochloric acid. The precipitate was isolated, washed with water and dried, resulting in the obtained (2S)-2-{ o-fluorescent-p-[N-(2,7-dimethyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl) -N-(prop-2-inyl)amino] benzamido} -4-(tetrazol-5-yl)butyric acid (1,21 g, 79%), so pl. 232-240oC.

NMR spectrum (CD3SOCD3); 2,12-2,21 (mn, 2H); 2,24 (c, 3H); 2,30 (c, 3H); to 2.94 (m, 2H), 3,20 (c, 1H); 4,28 (c, 2H); to 4.41 (m, 1H); 4,68 (c, 2H); 6,62 (m, 2H); 7,42 (c, 1H); 7,56 (t, 1H); to 7.67 (c, 1H); with 8.05 (t, 1H); a 12.03 (c, 1H).

Mass spectrum: mass spectroscopy by fast atom bombardment by positive ions (MC-FAB)m/e(P+I) 533.

Elemental analysis for C26H25FN8O40.9m NaCl:

Found, %: C 53,1; H 4,4; N 19,5;

Calculated, %: C 53,4; H 4,3; N 19,2.

In this example, methyl (2S)-2-amino-4-(tetrazol-5-yl)-butyrate was enriched form, with (S)-configuration at the carbon atom that bears methoxycarbonyl group (S):(R)=7:3, as determined by chromatographic analysis. This somervail-oxymethyl)-3,4-dihydroquinazolin-6-ylmethyl)-N-(prop-2-inyl) amino]benzoate, used as starting material was prepared as follows.

A mixture of tert-butyl o-fluorescent-p-(prop-2-inyl)aminobenzoate [0,882 g; obtained from 56% yield via reaction of tert-butyl - p-amino-o-porobotat (example 3 application Europatent N 0373891) propylbromide], 6-bromomethyl-2,7-dimethyl-3-(pivaloyloxymethyl) -3,4-dihydroquinazolin-4-it [0.9 g; example 13 application Europatent N 0459730], potassium carbonate (0,691 g), 18-crown-6-(0.005 g) and N (20 ml) was stirred and heated to 90oC for 6 hours the mixture is evaporated and the residue was distributed between ethyl acetate and water. The organic phase is washed with water, brine, dried (MgSO4) and evaporated. The obtained residue was purified by column chromatography, elwira constantly increasing polar mixtures of methylene chloride and ethyl acetate, which was obtained tert-butyl-o-fluorescent-p-[N-(2,7-dimethyl-4-oxo-3-(pivaloyloxymethyl) -3,4-dinitrobenzoyl-6-ylmethyl)-N-(prop-2-inyl)amino]benzoate (0.9 g).

The mixture thus obtained product and triperoxonane acid (20 ml) was stirred at room temperature for 1 h the resulting mixture was evaporated, and the residue was pereirae with diethyl ether, resulting in a received on-the fluoride is in the form of a solid (0.64 g).

Elemental analysis for C27H28FN3O50,1 CF3CO2H:

Found, %: C 64,7; H 5,5; N 8,2;

Calculated, %: C 64,7; H 5,6; N 8,3.

Dicyclohexylcarbodiimide 14.9 g) was added to a suspension of o-fluorescent-p- [N-(2,7-dimethyl-4-oxo-3-(pivaloyloxymethyl)3,4-dihydroquinazolin-6-ylmethyl)-N-(prop-2-inyl)amino] benzoic acid (23,8 g) pentafluorophenol (26,6 g) in DMF (200 ml) and the resulting mixture was stirred at room temperature for 18 hours the mixture was filtered, and the filtrate evaporated. The obtained residue was purified by column chromatography, elwira with a mixture of hexane and ethyl acetate (1:1 V/V). Thus obtained the required starting material (11 g), so pl. 163-165oC.

This methyl(2S)2-amino-4-(tetrazol-5-yl)butyrate (relationship (S):(R) = 7: 3), used as starting material was prepared as follows.

Sulfurylchloride (1 g) was added to a stirred mixture of N-benzyloxycarbonyl-L-glutamine (100 g) and methanol (1300 ml) and the resulting mixture was stirred at room temperature for 24 hours the mixture is evaporated and the received N-benzyloxycarbonyl-L-glutaminergic ester (105 g).

p-Taillored (85,8 g) was added in portions to a stirred mixture of the obtained product and/SUP>C for 90 minutes then the mixture was concentrated by evaporation of the pyridine and the residue was distributed between ethyl acetate and water. The organic phase was washed 2 N. aqueous solution of hydrochloric acid and water, then dried (MgSO4) and evaporated. The obtained residue was purified by column chromatography, elwira with a mixture of hexane and ethyl acetate (1:1 V/V). Thus obtained methyl (2S)-2-benzyloxycarbonylamino-4-cyanovaleric (81 g).

A mixture of the obtained product of sodium azide (22,2 g), ammonium chloride (18.3 g) and DMF (400 ml) was heated on the steam bath for 24 h the mixture was concentrated and to the residue was added water (55 ml). The resulting mixture was acidified to pH 1 by adding concentrated hydrochloric acid and was extracted with ethyl acetate. This organic extract was dried (MgSO4) and evaporated. The obtained residue was pereirae diethyl ether, the result was obtained methyl(2S)-2-benzyloxycarbonylamino-4-(tetrazol-5-yl)butyrate (36 g; (S):(R)=7:3).

NMR spectrum (CD3SOCD3); of 1.95 to 2.35 (m, 2H); 2.95 and (t, 2H); 3,64 (c, 3H); 4,15 (m, 1H); 5,04 (c, 2H); of 7.36 (c, 5H); 7,88 (d, 1H); 13,0 (c, 1H).

A mixture of part (17.1 g) of the obtained product, 10% palladium carbon (2.2 g) and ethanol (300 miltat evaporated. Then the obtained residue was pereirae with diethyl ether and was obtained methyl(2S)-2-amino-4-(tetrazol-5-yl)butyrate (11,75 g) respect (S):(R)=7: 3), so pl. 177-182oC.

Example 2. Repeating the procedure described in example 1, except that the appropriate pentafluorobenzoate was subjected to reaction with (2S)-2-amino-4-(tetrazol-5-yl)butyrate. Thus were obtained the compounds described in table. 2, the structures of which were confirmed by proton magnetic resonance, mass spectroscopy and elemental analysis. Unless specifically indicated, used part of methyl(2S)-2-amino-4-(tetrazol-5-yl)butyrate-enriched form having the (S)-configuration with respect (S):(R)=7:3.

Pentafluorophenyl p-[N-(2-methyl-4-oxo-3-(pivaloyloxymethyl)- 3,4-dihydroquinazolin-6-ylmethyl)-N-(prop-2-inyl)-amino]benzoate used as starting material, was obtained via the reaction of n-[N-(2-methyl-4-oxo-3-(pivaloyloxymethyl)-3,4 - dihydroquinazolin-6-ylmethyl)-N-(prop-2-inyl)-amino] benzoic acid (example 1 application Europatent N 459730) and pentafluorophenol using a procedure similar to that described in the portion of example 1 which relates to the production of raw materials.

This methyl(2S)-2-amino-4-(tetrazol-5-yl)butyrate, ispolzovaniya, described Tran and others, Tetrahedron, 1977, 33, 2299.

b) Elemental analysis showed that the resulting product contains 0.5 equivalents of water and 0.5 equivalents of sodium chloride.

This pentafluorophenyl o-fluorescent-p-[N-(2-methyl-4-oxo-3 - pivaloyloxymethyl)-3,4-dihydroquinazolin-6-ylmethyl)-N-(prop-2-inyl) amino] benzoate used as starting material, was obtained through the reaction of o-fluorescent-p-[N-(2-methyl-4-oxo-3- (pivaloyloxymethyl)-3,4-dihydroquinazolin-6-ylmethyl)-N-prop-2-inyl) amino]benzoic acid (example 13 application Europatent N 0459730) and pentafluorophenol using a procedure similar to that described in the portion of example 1 which relates to the production of raw materials.

c) the product Obtained had the following characteristic NMR spectra (CD3SOCD3): of 2.21 (m, 2H); of 2.33 (s, 3H); 2,96 (t, 2H); of 3.13 (s, 3H); 4,4 (m, 1H); 4,78 (s, 2H); is 6.78 (d, 2H); 7.5 to the 7.65 (m, 2H); 7,74 (d, 2H); a 7.85 (d, 1H); 8.3 (l, 1H).

This pentafluorophenyl p-[N-(2-methyl-4-oxo-3-(pivaloyloxymethyl)- 3,4-dihydroquinazolin-6-ylmethyl)-N-methylamino] benzoate used as starting material, was obtained from 6-bromoethyl-2-methyl-3- (pivaloyloxymethyl)-3,4-dihydroquinazolin-4-it [example 1 of the application for Europatent N 0239362] and tertbutyl p-methylaminophenol [obtained by the reaction Proc. of the example 1, which relates to the production of raw materials.

d) the product Obtained had the following characteristic NMR spectra (CD3SOCD3): a 2.0 to 2.25 (m, 2H); 2,3 (s,3H); 2,9-3,0 (t, 2H); 3,1 (s, 3H); 4,35 to 4.5 (m, 1H); and 4.8 (s, 2H); 6,7 (m, 2H); EUR 7.57 (m, 3H); to 7.9 (m, 2H); 12,08 (s, 1H).

This pentafluorophenyl o-fluorescent-p-[N-(2-methyl-4-oxo-3-(pivaloyloxymethyl)-3,4-dihydroquinazolin-6-ylmethyl)-N-methyl-amino] benzoate used as starting material, was obtained from 6-bromomethyl-2-methyl-3-(pivaloyloxymethyl)3,4-dihydroquinazolin-4-it and tert-butyl o-fluorescent-p-methylaminophenol [obtained by the reaction of tert-butyl p-amino-o-porobotat with methyliodide] using a procedure similar to that described in the portion of example 1 which relates to the production of raw materials.

This methyl (2S)-2-amino-4-(tetrazol-5-yl)butyrate, used to obtain this product, received in the form of mainly nestorgames (R)-configuration, in accordance with the procedure described Tran and others, Tetrahedron, 1977, 33, 2299.

e) Elemental analysis showed that this product contains 1.2 equivalents of water.

The resulting pentafluorophenyl p-[N-(2,7-dimethyl-4-oxo-3- (pivaloyloxymethyl)-3,4-dihydroquinazolin-6-ylmethyl)-N - methylamino] benzoate used in Kacha tert-butyl p-methylaminophenol, using a procedure similar to that described in the portion of example 1 which relates to the production of raw materials.

f) Elemental analysis showed that the product contains 0.5 equivalents of water and 0.45 equivalents of sodium chloride.

This pentafluorophenyl o-fluorescent-p-[N-(2,7-dimethyl-4-oxo-3-(pivaloyloxymethyl)-3,4-dihydroquinazolin-6-ylmethyl)- N-methylamino] benzoate used as starting material, was obtained from 6-bromomethyl-2,7-dimethyl-3-(pivaloyloxymethyl)- 3,4-dihydroquinazolin-4-she tert-butyl-o-fluorescent-p-methylaminophenol using a procedure similar to that described in the portion of example 1, which relates to the production of raw materials.

g) Elemental analysis showed that the resulting product contains 1 equivalent of water.

This pentafluorophenyl p-[N-2,7-dimethyl-4-oxo-3-(pivaloyloxymethyl)- 3,4-dihydroquinazolin-6-ylmethyl)-N-(prop-2-inyl-amino] benzoate used as starting material, was obtained via the reaction of n-[N-(2,7-dimethyl-4-oxo-3-(pivaloyloxymethyl)-3,4 - dihydroquinazolin-6-ylmethyl)-N-(prop-2-inyl)-amino] benzoic acid (example 13 application Europatent N 0459730) and pentafluorophenol using a procedure similar to that described in the portion of example 1 which regard is ACTRAV (CD3SOCD3): 2,2 (m, 2H); of 2.33 (s, 3H); 2.95 and (t, 2H); 3.15 in (s, 1H); 4,28 is 4.45 (m, 3H); 4,78 (s, 2H); 6,86 (d, 2H); to 7.35 (d, 1H); to 7.77 (d, 2H); a 7.92 (d, 1H); of 8.47 (m, 1H).

This pentafluorophenyl p-[N-(7-fluorescent-2-methyl-4-oxo-3- (pivaloyloxymethyl)3,4-dihydroquinazolin-6-ylmethyl)-N-(prop-2 - inyl)amino] benzoate used as starting material, was obtained via the reaction of n-[N-(7-fluorescent-2-methyl-4-oxo-3- (pivaloyloxymethyl)-3,4-dihydroquinazolin-6-ylmethyl)-N-(prop-2 - inyl)amino]benzoic acid (example 26 applications for Europatent N 0373891) and pentafluorophenol using a procedure similar to that described in the portion of example 1 which relates to the production of raw materials.

i) the product Obtained had the following characteristic NMR spectra (CD3SOCD3): 2,2(m, 2H); 2,32 (s, 3H); 2.95 and (t, 2H); 3,18 (s, 3H); 4,4 (m, 1H); was 4.76 (s, 2H): 6,72 (d, 2H); 7,72 (kV, 4H); at 8.36 (d, 1H).

The resulting pentafluorophenyl p-[N-(7-chloro-2-methyl-4-oxo - 3-(pivaloyloxymethyl)-3,4-dihydroquinazolin-6-ylmethyl)-N-methylamino] benzoate used as starting material, was obtained from 6-bromomethyl-7-chloro-2-methyl-3-(pivaloyloxymethyl)-3,4 - dihydroquinazolin-4-she tert-butyl-p-methylaminophenol using a procedure similar to that described in the portion of example 1, which relates to the production of raw materials.


7-Chloro-2,6-dimethyl-3,4-dihydroquinazolin-4-one (17 g) was added in portions to a stirred suspension of sodium hydride (60% W/W dispersion in mineral oil (2.9 g), rinsed with hexane to remove mineral oil) in DMSO (200 ml) which was cooled to 20oC. the resulting mixture was stirred at room temperature for 1 h Then added in portions chloromethylene (23,7 ml) and the mixture was stirred at room temperature for 15 hours the mixture was poured into water (150 ml) and was extracted with ethyl acetate (3 70 ml). These combined extracts were washed with water, dried (MgSO4) and evaporated. The obtained residue was pereirae with diethyl ether, resulting in the obtained 7-chloro-2,6-dimethyl - 3-(pivaloyloxymethyl)-3,4-dihydroquinazolin-4-one as a solid (17 g).

A mixture of the resulting product, N-bromosuccinimide (9,8 g), benzoyl peroxide (0.1 g) and carbon tetrachloride (400 ml) was heated under reflux for 4 hours the mixture was cooled to room temperature. Was filtered and the filtrate was concentrated to a volume of 200 ml. of This mixture was left at room t the substances (15 g), so pl. 160-164oC.

The NMR spectrum (CDCl3): 1,22 (s, 9H); to 2.66 (s, 3H); and 4.68 (s, 2H); 6,09 (s, 2H); 7,68 (s, 1H); 8,31 (s, 1H).

j) Elemental analysis showed that the resulting product contains 1 equivalent of water and 0.5 equivalents of sodium chloride.

This pentafluorophenyl p-[N-(7-chloro-2-methyl-4-oxo-3-(pivaloyloxymethyl) -3,4-dihydroquinazolin-6-ylmethyl)-N-(prop-2-inyl)amino] benzoate used as starting material, was obtained from 6-bromomethyl-7-chloro-2-methyl-3-(pivaloyloxymethyl)-3,4-dihydroquinazolin-4-it and tert-butyl n-(prop-2-inyl)aminobenzoate [obtained by the reaction of tert-butyl p-aminobenzoate with propylbromide] using a procedure similar to that described in the portion of example 1 which relates to the production of raw materials.

k) Elemental analysis showed that this product contains 1 equivalent of water, 0.25 equivalents of diethyl ether and 1.5 equivalents of sodium chloride.

This pentafluorophenyl-p-[N-(7-chloro-2-methyl-4-oxo-3-(pivaloyloxymethyl)- 3,4-dihydroquinazolin-6-ylmethyl)-N-(prop-2-inyl)amino] -o-porobotat used as starting material, was obtained from 6-bromomethyl-7-chloro-2-methyl-3-(pivaloyloxymethyl)3,4-dihydroquinazolin-4-it and tert-butyl o-fluorescent-p(prop-2-inyl)Amenhotep materials.

l) Elemental analysis showed that the resulting product contains 1.5 equivalents of water and 1 equivalent of sodium chloride.

This pentafluorophenyl p-[N - (7-bromo-2-methyl-4-oxo-3-(pivaloyloxymethyl)-3,4-dihydroquinazolin-6-ylmethyl)-N-methylamino]-o-porobotat used as starting material, was obtained from 7-bromo-6-bromomethyl-2-methyl-3-(pivaloyloxymethyl)-3,4-dihydroquinazolin-4-it (example 23 applications of Europatent N 0459730) and tert-butyl o-fluorescent-p-methylaminophenol using the procedure similar to that described in the portion of example 1 which relates to the production of raw materials.

m) Elemental analysis showed that the resulting product contains 1 equivalent of water and 0.6 equivalents of sodium chloride.

The product obtained had the following characteristic NMR spectra (CD3SOCD3): 2,2 (m, 2H); of 2.34 (s, 3H); 2.95 and (t, 2H); 3,2 (s, 1H); 4,4 (Shir. s, 3H); 4.7 in (s, 2H); 6,79 (d, 2H); 7,72-7,8 (kV, 4H); 8,46 (d, 1H); to 12.28 (s, 1H).

This pentafluorophenyl p-[N-(7-bromo-2-methyl-4-oxo-3- (pivaloyloxymethyl)-3,4-dihydroquinazolin-6-ylmethyl)-N-prop - 2-inyl)amino] benzoate used as starting material described in example 23 applications for Europatent N 0459730.

n) Elemental analysis showed that the resulting product contains 2 equibiaxial)-3,4-dihydroquinazolin-6-ylmethyl)-N-(prop-2-inyl)amino] -o-porobotat, used as starting material, was obtained from 7-bromo-6-bromomethyl-2-methyl-3- (pivaloyloxymethyl)-3,4-dihydroquinazolin-4-she tert-butyl-o-(prop-2-inyl)aminobenzoate using a procedure similar to that described in the portion of example 1 which relates to the production of raw materials.

Example 3. Using a similar procedure described in example 1, pentafluorophenyl o-fluorescent-p-[N - (2,7-dimethyl-4-oxo-3-(pivaloyloxymethyl)- 3,4-dihydroquinazolin-6-ylmethyl)-N-(prop-2-inyl)-amino] benzoate was subjected to reaction with methyl (2S)-2-amino-4-(tetrazol-5-yl)butyrate was obtained methylbutyrate hydrolyzed and received (2S)-2-{o-fluorescent-p- [N-(2,7-dimethyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl)-N-(prop - 2-inyl)amino] benzamido} -4-(tetrazol-5-yl)butyric acid (drained with azeotropic distillation of water from a mixture of toluene) to yield 76%.

NMR spectrum (CD3SOCD3): 2.06 to 2,28 (m, 2H); 2,31 (s, 3H); of 2.44 (s, 3H); of 2.97 (m, 2H); 3,21 (s, 1H); 4,30 (s, 2H); was 4.42 (m, 1H); 4,70 (s, 2H); of 6.65 (m, 2H); the 7.43 (s, 1H); to 7.59 (t, 1H); 7,71 (s, 1H); with 8.05 (t, 1H); 12,06 (s, 1H).

MC: (positive ion FAB) m/e (P + I) 533.

Elemental analysis for C26H25FN8O40,38 H2O 0,14 Na+0,045 Cl-x 0,04 CH3C6H5:

Found,%: C of 57.8; H 4,8; N 20,3;

Calculated,%: C 57,6; Reguraly in the relationship (S):(R) = 99:1 or more, as determined by chromatographic analysis. This isomeric ratio was maintained and the product of example 3.

This methyl (2S)-2-amino-4-(tetrazol-5-yl)butyrate (relationship (S):(R) = 99:1 or more) used as starting material was prepared as follows.

A solution of N-benzyloxycarbonyl-L-glutamylation of ester (25 g) in THF (500 ml) was added drop by drop to a stirred solution of triphenylphosphine (44,5 g) in carbon tetrachloride (1 liter). The resulting mixture was heated to 50oC for 2 hours Then the mixture evaporated. The obtained oily substance was pereirae in ethyl acetate. After that, the mixture was filtered, and the filtrate evaporated. The obtained residue was purified by column chromatography, elwira with a mixture of hexane and ethyl acetate (1:1), and was obtained methyl (2S)-2-benzyloxycarbonylamino-4-cyanovaleric (19,38 g, 83%).

A mixture of methyl (2S)-2-benzyloxycarbonylamino-4-cyanobacteria (10 g), azide three-p-butyanova [obtained in accordance with the method in Rees. Trav. Chim. Pay - as., 1963, 81, 286; 12 g] and THF (60 ml) was stirred and heated to a temperature of distillation for 40 hours Then the mixture evaporated. The obtained brown oily substance was pereirae in diethyl ether, which was us who started a methyl (2S)-2-benzyloxycarbonylamino-4-(tetrazol-5-yl)-butyrate (2,23 g, 32%).

NMR spectrum (CD3SOCD3): of 1.95 to 2.35 (m, 2H); 2.95 and (t, 2H); to 3.64 (s, 3H); 4,15 (m, 1H); 5,04 (s, 2H); of 7.36 (s, 5H); 7,88 (d, 1H); 13,0 (s, 1H).

A mixture of the obtained product was hydrogenosomal using the same procedure described in the last paragraph of example 1, and was obtained methyl (2S)-2-amino-4-(tetrazol-5-yl)butyrate with the release of 88%.

NMR spectrum (CD3SOCD3): 1,82-of 2.26 (m, 2H); 2,86-to 2.94 (t, 2H); to 3.67 (s, 3H); 3,7-of 3.85 (m, 1H); 5,28 (Shir. s, 2H).

Example 4. Diethylphosphoramidite (0.18 g) was added to a mixture of 5-[N-(2,7-dimethyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl)-N-(prop - 2-inyl)amino] pyridine-2-carboxylic acid (is 0.135 g), N-methylmorpholine (0,113 g) and DMF (10 ml). This mixture was stirred at room temperature for 1 h Then the solution was added a mixture of methyl (2S)-2-amino-4-(tetrazol-5-yl)butyrate (0.14 g) and N-methylmorpholine (0,113 g) in DMF (5 ml). The resulting mixture was stirred at room temperature for 64 hours and Then the mixture is evaporated and the residue was distributed between ethyl acetate and water. The organic phase is washed with water, dried (MgSO4) and evaporated, resulting in the obtained methyl (2S)-2-{ 5-N - (2,7-dimethyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl)-N- (prop-2-inyl)amino]pyridine-2-carboxamido}-4-(tetrazol-5-yl)butyrate (0.16 g).

NMR spectrum (CD3

A mixture of the obtained material and 2 n sodium hydroxide solution (3 ml) was stirred at room temperature for 1 h the mixture was acidified to pH 4 by adding concentrated hydrochloric acid. The precipitate was isolated, then washed successively with water, acetone and diethyl ether, then dried and obtained (2S)-2-{5-[N-(2,7-dimethyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl)-N-(prop - 2-inyl)amino] pyridine-2-carboxamido}-4-(tetrazol-5-yl)-butyric acid (0.124 g).

NMR spectrum (CD3SOCD3): 2,30 (m, 5H); of 2.45 (s, 3H); 2,82-2,89 (t, 2H); 4,39 (s, 2H); to 4.41-4,60 (m, 1H); was 4.76 (s, 2H); 7,2-7,31 (m, 1H); 7,45 (s, 1H); 7,73 (s, 1H); 7,8-7,9 (d, 1H); 8,15 (d, 1H); 8,32-8,61 (d, 1H).

MS: (positive ion FAB)m/e(P + 1) 515;

Elemental analysis for C25H25N9O41,5 NaCl 1,25 H2O:

Found, %: C 48,0; H 4,3; N 19,8;

Calculated, %: C 48,0; H 4,4; N 20,15.

In this example, methyl (2S)-2-amino-4-(tetrazol-5-yl)butyrate was enriched form, with (S)-configuration in the relationship (S):(R)=99:1 or more, as determined by chromatographic analysis. This isomeric ratio was maintained and the product of example 4.

This 5-[N-(2,7-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl-methyl)-N-(prop-2-IAP.

A mixture of 6-bromomethyl-2,7-dimethyl-3-(pivaloyloxymethyl)-3,4-dihydroquinazolin-4-it (1,11 g), methyl 5-[N-(prop-2-inyl)-amino]pyridine-2-carboxylate (0,61 g), obtained with a quantitative yield by treatment of methyl 5-[N-(tert-butoxycarbonyl)-N-(prop-2-inyl)amino] pyridine-2-carboxylate (J. Med. Chem, 1991 1594) triperoxonane acid at 0oC for 1 h, 2,6 lutidine (0,62 g), iodine sodium (0.005 g) and DMA (20 ml) was stirred and heated to 95oC for 7 hours the mixture is evaporated, and the residue was distributed between ethyl acetate and 2 N. hydrochloric acid. The acidity of the aqueous layer was lowered to pH 4 by adding 2 n sodium hydroxide solution and the solution was extracted with ethyl acetate. The organic layer was dried with magnesium sulfate and evaporated. The residue was purified by column chromatography, elwira with ethyl acetate. The result was obtained methyl 5-[N-(2,7-dimethyl-4-oxo-3-(pivaloyloxymethyl) -3,4-dihydroquinazolin-5-ylmethyl-N-(prop-2-inyl)amino]pyridine-2-carboxylate in the form of gum (0,262 g).

The mixture thus obtained complex ether, 2 n sodium hydroxide solution (20 ml) and methanol (10 ml) was stirred 16 h at room temperature. The methanol phase was evaporated and the remaining aqueous solution was acidified using dooi and diethyl ether, and then drained. In the described procedure was obtained 5-[N - (2,7-dimethyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl)-N-(prop-2-inyl) amino] pyridine-2-carboxylic acid (0,143 g).

NMR spectrum (CD3SOCD3): 2,30 (s, 3H); of 2.45 (s, 3H); or 3.28 (s, 1H); of 4.35 (s, 2H); 7,12-7,25 (m, 1H); 7,45 (s, 1H); 7,71 (s, 1H); 7,82-to $ 7.91 (d, 1H); 8.17 and is 8.22 (d, 1H).

Example 5. In accordance with the procedure described in example 1, pentafluorophenyl n-{N-[1-(2,7-dimethyl-4-oxo-3-(pivaloyloxymethyl)-3,4-dihydroquinazolin-6-yl) ethyl]-N-(prop-2-inyl)amino] benzoate was subjected to reaction with methyl (2S)-2-amino-4-(tetrazol-5-yl) by butyrate and received methylbutyrate hydrolyzed to obtain 2-p-N-[1-(2,7-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)-ethyl] -N-(prop-2-inyl) amino, benzamido-4-(tetrazol-5-yl) butyric acid with a yield of 25%, so pl. 207oC.

NMR spectrum (CD3SOCD3receive: 1.5 (d, 3H); to 2.25 (m, 2H); and 2.27 (s, 1H); of 2.34 (s, 3H); 2,9 (s, 1H); 3,0 (t, 2H); 3,7 (d, 1H); 3,95 (d, 1H); 4,4 (m, 1H), and 5.5 (m, 1H); 7,0 (d, 2H); to 7.4 (s, 1H); 7,8 (d, 2H); 8,1 (s, 1H); a 8.4 (d, 1H);

Elemental analysis of C27H28N8O41H2O 0,25 NaCl:

Found, %: C to 57.9; H 5,2; N 19,5;

Calculated, %: C 57,7; H 5,3; N 19,9.

In this example, methyl (2S)-2-amino-4-(tetrazol-5-yl)butyrate was enriched form, with (S)-configuration in the relationship (S) : (R) = 7:3. This isomeric ratio was preserved in Lin-6-yl)ethyl]-N-(prop-2-inyl)-amino}benzoate, used as starting material, was prepared as follows.

Bromine (9.4 g) was added drop by drop to a stirred solution of 4'-ethyl-3'-methylacetanilide in acetic acid (100 ml) which was heated to 45oC. the Mixture is stirred 30 min at 45oC. then the mixture is evaporated, and the residue was distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase is washed with water, dried with magnesium sulfate and evaporated. The residue was purified by column chromatography, elwira mixture 5:1 (by volume) of hexane and ethyl acetate. The result was obtained 2'-bromo-4'-ethyl-5-methylacetanilide (13,2 g), so pl. 92oC.

A mixture of the obtained compound, copper cyanide (6.8 g) and MP (100 ml) was stirred and heated to 120oC for 1 h Then the mixture was cooled to room temperature, poured into a mixture of aqueous ammonium hydroxide (0.88 g/ml, 300 ml) and ice (600 ml) and stirred 10 minutes the Precipitate was isolated and soften washed with water and ethyl acetate. The organic washings were washed with water and brine, dried with magnesium sulfate and evaporated. The result was obtained 2'-cyano-4'-ethyl-5-methylacetanilide (8 g), so pl. 121oC.

A mixture of the obtained product, Perek the ATEM and the mixture was cooled to room temperature and evaporated. To the residue was added water (200 ml) and the resulting solution was acidified to pH by adding dilute aqueous hydrochloric acid. The residue was isolated, washed and dried. As a result of this received 6-ethyl-2,7-dimethyl-3,4-dihydroquinazolin-4-one (6.7 g), so pl. 288o(decomposition).

NMR spectrum (CD3SOCD3): 1,2 (t, 3H), 2,3 (c, 3H); 2,35 (c, 3H); and 2.7 (q, 2H); 7,3 (c, 1H); 7,8 (c, 1H); 11,95 (Shir.s, 1H).

A solution of the obtained product in DMCO (50 ml) was added to a stirred mixture of sodium hydride (80% dispersion in mineral oil, 1.5 g, where the oil was washed with hexane) and DMCO (50 ml). The resulting mixture was stirred at room temperature for 30 minutes Then added chloromethylene (9.7 g) and the mixture stirred at room temperature for 20 hours the Mixture was distributed between ethyl acetate and a mixture of ice and water. The organic phase is washed with water, dried with magnesium sulfate and evaporated. The product was purified by column chromatography, elwira increasing amounts of polar mixtures of hexane and ethyl acetate. Thus obtained 6-ethyl-2,7-dimethyl-3-(pivaloyloxymethyl)-3,4-dihydroquinazolin-4-one (4.2-d), so pl. 104oC.

The mixture of the parts of the resulting product (3.2 g), N-bromosuccinimide (1,9 g), benzoyl peroxide (0.01 g) and tetrahedral temperature and filtered. The filtrate is evaporated and the residue was purified by column chromatography, elwira increasing amounts of polar mixtures of hexane and ethyl acetate. Thus obtained 6-(1-bromoethyl)-2,7-dimethyl-3-(pivaloyloxymethyl)-3,4-dihydroquinazolin-4-one (3,35 g), so pl. 132oC.

The NMR spectrum (CDCl3): 1,25 (c, 9H); 2,2 (d, 3H); 2,55 (c, 3H); 2,65 (c, 3H); 3,4 (kV, 1H); 6,1 (q, 2H); 7,43 (c, 1H); and 8.4 (c, 1H).

A mixture of the obtained product, tert-butyl p-aminobenzoate (4.8 g), calcium carbonate (3.3 g) and DMA (80 ml) was stirred and heated to 110oC for 3 hours the Mixture is evaporated and the residue was distributed between ethyl acetate and water. The organic phase was dried with magnesium sulfate and evaporated. The residue was purified by column chromatography, elwira increasing amounts of polar mixtures of hexane and ethyl acetate. Thus was obtained tert-butyl n-{N-[1-(2,7-dimethyl-4-oxo-3-(pivaloyloxymethyl)-3,4-dihydroquinazolin- -6-yl)ethyl]amino}benzoate (2,75 g), so pl. 220oC.

A mixture of a portion (1.5 g) obtained product, propylbromide (80% solution in toluene, 3,3 ml), calcium carbonate (1.5 g) and DMA (50 ml) was stirred and heated to 110oC for 8 hours the Mixture is evaporated, and the residue was distributed between ethyl acetate and water. The organic phase was dried Suu) of hexane and ethyl acetate. Thus was obtained tert-butyl n-{ N-[1-(2,7-dimethyl- -4-oxo-3-(pivaloyloxymethyl)-3,4-dihydroquinazolin-6-yl)ethyl]-N-(prop-2-inyl)amino}benzoate as a gum (0,78 g).

The NMR spectrum (CDCl3): 1,23 (c, 9H); 1.57 in (c, 9H); 1,72 (d, 3H); 2.0 (t, 1H); 2,3 (c, 3H); 2.63 in (c, 3H); 3,7 (m, 1H); 3.9 to (m, 1H); 5,3 (kV, 1H); 6,1 (c, 2H); to 6.95 (d, 2H); 7,42 (c, 1H); to 7.95 (d, 2H); 8.3 in (c, 1H).

A mixture of the obtained product and triperoxonane acid (20 ml) stirred at room temperature for 1 h Then the mixture is evaporated. To the mixture was added diethyl ether (100 ml) and the precipitate was isolated. Thus obtained n-{ N-[1-(2,7-dimethyl-4-oxo-3-(pivaloyloxymethyl)-3,4-dihydroquinazolin-6-yl)ethyl] -N-(prop-2-inyl)amino} benzoic acid triperoxonane salt (0.73 g), so pl. 217oC.

A mixture of the obtained product, pentafluorophenol (0.64 g), dicyclohexylcarbodiimide (0,717 g) and ethyl acetate (120 ml) was stirred at room temperature for 20 hours the Mixture was filtered and the filtrate evaporated. The residue was purified by column chromatography, elwira mixture (3:1, by volume) hexane and ethyl acetate. Thus obtained n-{N-[1-(2,7-dimethyl-4-oxo-3-(pivaloyloxymethyl)-3,4-dihydroquinazolin-6-yl)ethyl] -N-(prop-2 - inyl)amino}benzoate (0.68 g), so pl. 112oC.

Example 6. Below, in order Yevtushenko acceptable salt (compound X) and intended for the prevention or therapeutic treatment of a person:

a) Tablet I mg/tablet

Connection X - 100

Lactose Ph. Eur. - 182,75

Crosscarmellose-Na - 12,0

Tablet I mg/tablet

Corn starch paste (5 wt.%/about.) was 2.25

Magnesium stearate - 3,0

b) II Tablet mg/tablet

Connection X - 50

Lactose Ph.Eur. - 223,73

Crosscarmellose-Na - 6,0

Corn starch - 15,0

Polyvinylpyrrolidone pasta (5 wt.%/about.) was 2.25

Magnesium stearate - 3,0

(c) Tablet III mg/tablet

Connection X - 1,0

Lactose Ph.Eur. - 93,25

Crosscarmellose-Na - 4,0

Corn starch paste (5 wt.%/about.) - 0,75

Magnesium stearate - 1,0

d) Capsule mg/capsule

Connection X - 10,0

Lactose Ph.Eur. - 488,5

Magnesium stearate and 1.5

e) Injection I (50 mg/ml

Connection X - 5.0 wt.%/about.

The sodium hydroxide solution 1M - 15.0 wt.%/about.

Hydrochloric acid 0.1 M to bring the pH to 7.6

The polyethylene glycol 400 - 4.5 wt.%/about.

Water for injection to 100%

f) Injection II (10 mg/ml

Connection X - 1.0 wt.%/about.

Sodium phosphate BP 3.6 wt.%/about.

The sodium hydroxide solution of 1.0 M to 15.0 wt.%/about.

Water for injection to 100%

(g) Injection III - I mg/ml, buffered to pH 6

Compound X 0.1 wt.%/about.

Phosphate intothree the

Water for injection to 100%

The above compositions can be obtained by traditional methods commonly used in the pharmaceutical industry. The tablets (a)-(c) can be covered intersolubility coating in accordance with the standard technique, for example a coating of azettftalat pulp.

Schema of formulas I - V are given in the end of the text.

1. Hintline derivative of General formula (I)

< / BR>
where R1- C1- C4-alkyl, hintline ring may optionally have (in one of the 5-, 7 - and 8-positions) one Deputy, selected from halogen and C1- C4-alkyl;

R2is hydrogen or C1- C4-alkyl,

R3- C1- C4-alkyl, C3- C4alkenyl or3- C4-quinil;

Ar is phenylene which may be optionally one or two substituent selected from halogen, C1- C4-alkyl and C1- C4-alkoxy, or Ar - pyridinyl,

or its pharmaceutically acceptable salt, or ester.

2. Derived under item 1, where R1is methyl, hintline ring can be (but not necessarily) 7-fluoro, 7-chloro, 7-bromo-or 7-metaltometal;

R2is hydrogen;

R3is methyl, ethyl, prop is either Ar - pyridine-2,5-diyl (CONH-group in 2-position),

or its pharmaceutically acceptable salt.

3. Hintline derivative of the formula (I) under item 1, where R1is methyl, hintline ring may have, but not necessarily, 7-fluoro-, 7-chloro-, 7-bromo - or 7-metaltometal, R2is hydrogen, R3is methyl, ethyl or prop-2-inyl and Ar is 1,4-phenylene, 2-fluorescent-1,4-phenylene (- CONH-group at 1-position), or pyridine-2,5-diyl (- CONH-group in 2-position), or its pharmaceutically acceptable salt.

4. Derivative of formula (I) under item 1, where R1is methyl, hintline ring has 7-methyl Deputy, R2is hydrogen, R3is methyl, ethyl or prop-2-inyl and Ar is 1,4-phenylene or 2-fluorescent-1,4-phenylene (- CONH-group at 1-position), or its pharmaceutically acceptable salt.

5. Hintline derivative of the formula (I) under item 1, where R1is methyl, hintline ring has 7-methyl Deputy, R2is hydrogen, R3is methyl or prop-2-inyl and Ar is a 1,4-phenylene, 2-fluorescent-1,4-phenylene (- CONH-group at 1-position), or pyridine-2,5-diyl (- CONH-group in 2-position), or its pharmaceutically acceptable salt.

6. Hintline derivative of the formula I under item 1 or its pharmaceutically acceptable salt, selected from the group VK the azole-5-yl)butyric acid,

2-{ o-fluorescent-p-[N-( 2-methyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl)-N-(prop-2-inyl) amino]benzamido}-4- (tetrazol-5-yl)butyric acid,

2-{ p-[N-(2,7-dimethyl-4-oxo-3,4 - dihydroquinazolin-6-ylmethyl)-N-methylamino]benzamido} -4-(tetrazol-5-yl)butyric acid,

2-{ o-fluorescent-p-[N-(2,7-dimethyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl)-N-methylamino]benzamido} -4-(tetrazol-5-yl)butyric acid,

2-{ p-[N-(2,7-dimethyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl)-N-(prop-2-inyl)amino]benzamido}-4- (tetrazol-5-yl)butyric acid,

2-{ o-fluorescent-p-[N- (2,7-dimethyl-4-oxo-3,4 - dihydroquinazolin-6 - ylmethyl)-N-(prop-2-inyl)amino/benzamido} -4-(tetrazol-5-yl)butyric acid;

2-{ p-[N-(7-chloro-2-methyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl)-N-(prop-2-inyl)amino]benzamido }-4-(tetrazol-5-yl)butyric acid,

2-{ o-fluorescent-p-[N-(7-chloro-2-methyl-4-oxo - 3,4-dihydroquinazolin-6-ylmethyl)-N - (prop-2-inyl)amino] benzamido}-4-(tetrazol-5 - yl)butyric acid and

2-{ p-[N-(7-bromo-2-methyl-4-oxo-3,4-dihydroquinazolin-6 - ylmethyl)-N-(prop-2-inyl) amino]benzamido}-4-(tetrazol-5 - yl)butyric acid.

7. Hintline derivative of the formula (I) under item 1 or its pharmaceutically acceptable salt selected from the group comprising:

(2S)-2-p-[N-(2-methyl-4-oxo-3,4-dihydroquinazolin-6 - ylmethyl)-N-is Natolin-6-ylmethyl)-N-(prop-2-inyl)amino]benzamido} -4-(tetrazol-5-yl)butyric acid,

(2S)-2-{ p-[N-(2,7-dimethyl-4 - oxo-3,4-dihydroquinazolin-6-ylmethyl)-N-methylamino] benzamido}-4-( tetrazol-5-yl)butyric acid,

(2S)-2-{ o-fluorescent-p-[N-(2,7-dimethyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl)-N-methylamino/benzamido} -4-(tetrazol-5-yl)butyric acid,

(2S)-2-{ p-[N-(2,7-dimethyl-4-oxo-3,4-dihydroquinazolin - 6-ylmethyl)-N-(prop-2-inyl)amino] benzamido}-4-(tetrazol-5-yl)butyric acid,

(2S)-2-{ o-fluorescent-p- [N-(2,7 - dimethyl-4-oxo-3,4-dihydroquinazolin-6 - ylmethyl)-N-(prop-2-inyl) amino]benzamido}-4-(tetrazol-5-yl)butyric acid,

(2S)-2-{ p-[N-(7-chloro-2-methyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl)-N- (prop-2-inyl)amino]benzamido} -4-(tetrazol-5-yl)butyric acid,

(2S)-2-{ o-fluorescent-p- [N-(7-chloro-2-methyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl)-N-( prop-2-inyl)amino]benzamido}-4- (tetrazol-5-yl)butyric acid and

(2S)-2-{ p- [N-(7 - bromo-2-methyl-4-oxo-3,4 - dihydroquinazolin-6-ylmethyl)-N-(prop-2-inyl)amino] benzamido}-4- (tetrazol-5-yl)butyric acid.

8. Hintline derivative of the formula (I) under item 1 or its pharmaceutically acceptable salt,

(2S)-2-{ o-fluorescent-p-[N-(2,7-dimethyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl)-N-(prop-2-inyl) amino]benzamido}-4-(tetrazol-5-yl)butyric acid.

9. Connection on p. 1, representing (2S)-2-{ 5-(N-(2,7-dimethyl -4 is at or pharmaceutically acceptable salt of this compound.

10. The method of obtaining chineselanguage derivative of the formula (I) or its pharmaceutically acceptable salt, or a complex ester, stated in paragraph 1, characterized in that carry out the reaction of the acid of formula (II) or its reactive derivative

< / BR>
where R1, R2and R3have the values listed in paragraph 1;

R4is hydrogen or a protective group,

with the compound of the formula (III)

< / BR>
where R5- protective group,

then the protective group is removed by traditional methods.

11. Pharmaceutical composition having antitumor activity, comprising the active ingredient in combination with pharmaceutically acceptable diluent or carrier, characterized in that it contains as active ingredient an effective amount chineselanguage derivative of the formula (I) or its pharmaceutically acceptable salt, or a complex ester according to any one of paragraphs.1 to 9.

12. Hintline derivative of the formula (I) or its pharmaceutically acceptable salt or ester according to any one of paragraphs.1 to 9, with antitumor activity.

 

Same patents:

The invention relates to heterocyclic amines of formula I:

,

in which

X represents-CH2-group or-S-group;

B denotes a group selected from a number containing-CO -, - CH2OCO-, -CH2OCS-, -CH2NHCO - CH2NHCS-group;

D represents benzhydryl or phenyl group, optionally substituted by halogen atoms, and heterocyclic group, selected from a number containing 1,3,5-triazine-2-yl, pyridin-2-yl and pyrimidine-4-yl, and optionally substituted by one or two substituents selected from the group comprising amino, mono - or di-(C1C6) alkylamino, mono- (C3-C7)-alkynylamino, mono-(C3-C7)-quinil-amino group and pyrrolidin-1-yl group;

The is a simple carbon-carbon bond or a group of the formula: -CH2CH2or CRaRb-, where Raand Rbis a hydrogen atom, (C1-C3)alkyl, or taken together with the carbon atom to which they are attached, form a (C3-C6) cycloalkyl;

A is selected from the group comprising (a) carboxyl group optionally esterified (C1-C4) Ukrspirt the crystals: -CОNHRgOH, where Rcand Rdidentical or different, represent a hydrogen atom, (C1-C6) alkyl, benzyl, pyridin-2-yl, or taken together with the nitrogen atom to which they are bound, form piperidino, morpholino-, 4-thiomorpholine-, 4,5-diazepino, 4-(C1-C4)alkylpiperazine; Rfis a tolyl; Rgis a (C1-C4) alkyl;

(b) (C1-C3) alkyl;

(c) the group-NRcRdwhere Rcand Rddefined above,

(d) a cyano, if "y" does not mean a simple carbon-carbon bond

in the form of S-enantiomers, diastereomers, in the form of various racemic mixtures and their salts with pharmaceutically acceptable acids and bases

The invention relates to new biologically active chemical compounds, derived pyrazine formula I listed in the description, which is obtained by the interaction of the previously obtained through collaboration pyrazinamide with Amida sodium in liquid ammonia Na-salt pyrazin-2-carboxamide and 6-methyl-5-uracil sulfochloride in liquid ammonia

The invention relates to new derivatives of benzimidazolone, possessing valuable pharmacological properties, in particular derivatives benzimidazolone General formula

< / BR>
where R1and R2the same or different and mean a hydrogen atom, halogen atom, trifluoromethyl, alkyl with 1 to 6 carbon atoms, alkoxy with 1 to 6 carbon atoms, alkylthio with 1 to 6 carbon atoms, acyl of 1 to 6 carbon atoms, carboxyl, alkoxycarbonyl with 1 to 6 carbon atoms, hydroxy, nitro group or amino group, unsubstituted or N-mono - or disubstituted by alkyl with 1 to 4 carbon atoms, acylamino with 1 to 6 carbon atoms, alkoxycarbonyl with 1 to 6 carbon atoms, carbarnoyl, unsubstituted or N-mono - or disubstituted by alkyl with 1 to 4 carbon atoms, cyano, alkylsulfonyl with 1 to 6 carbon atoms, alkylsulfonyl with 1 to 6 carbon atoms, aminosulfonyl, unsubstituted or N-mono - or disubstituted by alkyl with 1 to 4 carbon atoms, or aminosulfonyl group, unsubstituted or N-mono - or disubstituted by alkyl with 1 to 4 carbon atoms;

R3a hydrogen atom, alkyl with 1 to 6 carbon atoms, alkenyl with 2-6 carbon atoms or quinil with 2-6 carbon atoms;

And the group-CO - or-CONH-, or the same As the ode;

m and n independently of one another denote an integer of 1 to 3;

R4phenyl, naphthyl or benzodioxan, unsubstituted or substituted by at least one Deputy from the group comprising halogen atom, trifluoromethyl, cyano, alkoxy with 1 to 3 carbon atoms and alkyl with 1 to 4 carbon atoms,

mixtures of their isomers or individual isomers and their acid additive salts

The invention relates to organic chemistry, in particular to a method of obtaining an individual stereoisomers of 4-diprosone glutamic acid of General formula

< / BR>
< / BR>
ALK is a lower alkyl

The invention relates to organic chemistry, and more specifically to new connections - hydrochloridum 2-aminoimidazole and 2-aminothiazole General formula (1),

< / BR>
aryl, the substituent in position 4 and a disulfide bridge in the position 5, where X is alkylamino, for example, methylamino, and R1-R2is hydrogen; X-methylaminopropyl, and R1-alkyl, for example methyl and R2is hydrogen; X-methylaminopropyl, and R1-alkoxygroup, for example, methoxy and R2is hydrogen; X-methylaminopropyl, and R1-ethoxypropan and R2is hydrogen; X-methylaminopropyl, and R1halogen, for example chlorine and RF2is hydrogen; X-methylaminopropyl, and R1-R2-alkoxygroup, for example, methoxy; X-atramentaria, and R1-alkoxygroup, for example, methoxy and R2is hydrogen; X is sulfur, and R1-alkoxygroup, for example, methoxy and R2is hydrogen; X is sulfur, and R1-R2-alkoxygroup, for example, methoxy; X is sulfur, and R1halogen, for example fluorine and R2-hydrogen

The invention relates to new biologically active chemical compounds, derived diaminodiphenylsulfone General formula;

< / BR>
which is obtained by the interaction equimolecular amounts of diaminodiphenylsulfone and orotovoy acid in water

The invention relates to new derivatives of 3-aminopyrazole possessing biological activity, and to their use in farbkomposition

The invention relates to the derivatives of tetrazole exhibiting inhibitory alsoreported activity, the method of production thereof and to compositions containing the derivative tetrazole as an effective component

The invention relates to the synthesis of heterocyclic compounds, and in particular to an improved process for the preparation of substituted 1(2)-benzyl-5-R-tetrazoles General formula I

Rwhere(A)< / BR>
R = phenyl, R1= A, R = 4-OCH3-phenyl, R1= A;

R = 3,4 - (OCH3)2-phenyl, R1= A; R = 3-pyridyl, R1= A;

R = 4-pyridyl, R1= A; R = 4-Cl-phenyl, R1= A;

R = 4-Br-phenyl, R1= A; R = NH2, R1= A;

R = N-phthalimido, R1= A; R = phenyl, R1= B;

R = 4-OCH3-phenyl, R1= B; R = 3,4-(OCH3)2-phenyl, R1= B;

R = 4-Br-phenyl, R1= B; R = 4-NO2-phenyl, R1= B

The invention relates to the synthesis of heterocyclic poliittisten compounds and can be used to obtain tetrazole in process variant

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compound of the formula (I) or its pharmaceutically acceptable salt or solvate wherein X represents CH or nitrogen atom (N); Z represents CH; R1 represents hydrogen atom; R2 and R3 can be similar or different and represent (C1-C6)-alkoxy-group that is optionally substituted with halogen atom, hydroxyl, (C1-C4)-alkoxycarbonyl, amino-group wherein one or two hydrogen atom are optionally replaced for (C1-C4)-alkyl that is optionally substituted with hydroxyl or (C1-C4)-alkoxy-group, the group R12R13N-C(=O)-O- wherein R12 and R13 can be similar or different and represent hydrogen atom or (C1-C4)-alkyl substituted optionally with (C1-C4)-alkoxy-group or the group R14-(S)m- wherein R14 represents phenyl or saturated or unsaturated 5-7-membered heterocyclic group substituted optionally with (C1-C4)-alkyl; m = 0 or 1; R4 represents hydrogen atom; R5, R6, R7 and R8 can be similar or different and represent hydrogen atom, halogen atom, (C1-C4)-alkyl, (C1-C4)-alkoxy-group or nitro-group under condition that R5, R6, R7 and R don't represent hydrogen atom simultaneously; R9 represents hydrogen atom, (C1-C6)-alkyl or (C1-C4)-alkylcarbonyl wherein alkyl fragment of indicated (C1-C6)-alkyl or (C1-C4)-alkylcarbonyl is optionally substituted with (C1-C4)-alkoxy-group; R10 represents hydrogen atom or (C1-C6)-alkyl; R11 represents (C1-C6)-alkyl, (C2-C6)-alkenyl or (C2-C6)-alkynyl (wherein each (C1-C6)-alkyl, (C2-C6)-alkenyl and (C2-C6)-alkynyl is substituted optionally with halogen atom or (C1-C6)-alkoxy-group), or R15-(CH2)n- wherein n is a whole number from 0 to 3; R15 represents naphthyl or 6-membered saturated or unsaturated carbocyclic or saturated or unsaturated 5-7-membered heterocyclic group that are substituted optionally with halogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy-group. Also, invention relates to variants of compounds of the formula (I). Compounds elicit antitumor activity and don't effect on cytomorphosis. Also, invention relates to pharmaceutical composition based on above described compounds, to a method for treatment of such diseases as malignant tumor, diabetic retinopathy, chronic rheumatism, psoriasis, atherosclerosis, Kaposi's sarcoma, and to a method for inhibition of vascular vessels angiogenesis.

EFFECT: valuable medicinal properties of compounds and composition.

22 cl, 4 tbl, 186 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to compounds of formula IId and their pharmacologically acceptable salts. In formula IId M represents -CH- or -N-; R2c bonded with carbon atom of 5-member ring and is selected from hydrogen and methyl; R2d is bonded with carbon atom from 6-member ring and selected from hydrogen and fluorine; one of R2a and R2b represents methoxy, and other is Q1X1, where X1 represents -O-, and values of other radicals are given in formula IId, to pharmaceutical composition, inhibiting antiogenesis and/or reducing vessel permeability, which contains as active component compound of formula IId, to application of invention compounds for preparation of medication and to compounds of 7-benzyloxy-4(4-fluorine-2-methylindol-5-iloxy)-6-methoxyquinazoline and 4-(4-fluorine-2- methylindol -5-yloxy)-7-hydroxy-6-methoxyquinazo-line.

EFFECT: development of effective method of obtaining quinazoline compounds.

12 cl, 54 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of general formula (I), where R1 - C1-C6alkyl, (C1-C6alkyl)C1-C6alkyl, di(C1-C6)C1-C6alkyl or C3-C6dicloalkyl; each R2 independently represents halogen, C1-C6alkyl, halogen-substituted C1-C6alkyl or cyano; R3 - hydrogen, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkinyl, hydroxyl, hydroxy-substituted C1-C6alkyl, C1-C6alkoxy, C3-C6cycloalkyl, cyano, C(=O)H, phenyl, (C3-C6cycloalkyl)C1-C6alkoxy, (C1-C6alkoxycarbonylamino)C1-C6alkoxy or (C1-C6alkylcarbonylamino)C1-C6alkoxy; R4 represents hydroxyl, C1-C6alkoxy, the group -NH(C=O)R4a, where R4a is halogen-substituted C1-C6alkyl, or the group -NH(CH2)2OR4b, where R4b is benzyl or phenyl ethyl; and m = 1 or 2 in a free form or in the form of pharmaceutically acceptable salt. Besides the invention refers to a pharmaceutical composition of the compounds applied for treatment or prevention of a disease or condition wherein vaniloid receptor activation acts the part or participates.

EFFECT: invention refers to application of the named compounds for preparing a drug to be applied for treatment or prevention of pain or gastrointestinal disturbance.

20 cl, 30 ex

FIELD: medicine.

SUBSTANCE: compounds can be used for treating neurological conditions, more specifically for treating neurodegenerative conditions, such as Alzheimer's disease. In a compound of formula I R2 represents H or CH2NR1R4 where R1 and R4 are independently selected from H, unsubstituted C1-6alkyl, substituted or unsubstituted C3-6 cycloalkyl, R3 represents H; substituted or unsubstituted C1-4alkyl; substituted or unsubstituted C2-4alkenyl; substituted or unsubstituted 6-members aryl condensed or uncondensed with substituted or unsubstituted 6-members aryl or 5-6-members heteroaryl, containing 1-2 nitrogen atoms in a cycle; substituted or unsubstituted saturated or unsaturated 5 or 6-members N-containing heterocycle which can additionally contain nitrogen, oxygen or the sulphur atom condensed or ucondensed with substituted or unsubstituted 6-members aryl or 5-6-members heteroaryl containing nitrogen in a cycle; (CH2)nR6 where n is an integer from 1 to 6, and the values of R6 and the values of other radicals are specified in the patent claim.

EFFECT: increased antiamyloidogenic action.

20 cl, 20 tbl, 6 dwg, 7 ex

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