Derivatives hintline or their pharmaceutically acceptable salts, method of production thereof and pharmaceutical composition based on them

 

(57) Abstract:

Derivatives hintline formula I (the values of the radicals listed in paragraph 1 of the claims) have inhibition of the receptor tyrosine kinase. 4 C. and 7 C.p. f-crystals, 1 Il., 1 PL.

The object of the present invention are derivatives of hintline or their pharmaceutically acceptable salts, which possess anti-cancer activity and are useful for the treatment of humans or animals. The present invention also relates to methods of producing these derivatives hintline containing their pharmaceutical compositions and to their use in the manufacture of medicinal products intended for the treatment of cancer in a warm-blooded animal such as man.

Many of the currently used schemes of cancer treatment include the use of compounds inhibiting DNA synthesis. Such compounds have a toxic effect on all cells, but they very effectively affect rapidly dividing cancer cells. Alternative approaches to creating cancer of the funds, which are not associated with inhibition of DNA synthesis, based on achieving high selectivity of vasculathe turning part of its DNA into an oncogene, that is, in the gene, which is under the action of activating factors leads to the formation of malignant cells (Bradshaw, Mutagenesis, 1986, 1, 91). Some of these oncogenes induce the formation of peptides, which are receptors for growth factors. The complex of receptors for growth factors then leads to increased cell proliferation. For example, it is known that some oncogenes encode different types of tyrosine kinase and that certain receptors for growth factors also represent different types of tyrosine kinase (Yarden and others, App. Rev. Biochem, 1988, 57, 443, Larsen and others Ann. Reports in Med., Chem 1989, Chapter 13).

Tyrosine kinase receptors play an important role in the transmission of biochemical signals that initiate cell replication. These enzymes are the major type block cell membrane and invade the extracellular binding region for such growth factors as a factor in the growth of the epidermis, and an intracellular portion, which functions as a kinase, phosphorylase tyrosinekinase in proteins, and thus affecting cell proliferation. It is known that these kinases are often present in cancer human cancers, such as breast cancer (Sainsbury and others, Brit J. Cancer, 1988, 58, 458; Gurin, etc. , Oncogene Res., 1988, 3, 21), cancer of the gastro-Kish is C (Konak and others, Cell, 1984, 37, 1035) and ovarian carcinoma, bronchial or pancreatic cancer (the description of the invention the European patent N 0400586). In the study of cancer tissues in relation to the activity of tyrosine kinase receptors is very likely that this is found to be widespread in other cancers, such as thyroid cancer and uterine cancer. It is also known that tyrosinekinase rarely active in normal cells, it is often found in cancer cells (hunter, Cell, 1987, 50, 823). It was recently demonstrated (C. J. Gallik, Brit. Med. Bull., 1991, 47, 87), which is the receptor for the growth factor of the epidermis, which is active tyrosine kinase, overly expressed in many cancers in humans, such as brain cancer, cancer of the squamous cell epithelium of the lung, bladder cancer, stomach cancer, breast cancer, head and neck cancer, esophageal cancer, cancer of the reproductive organs and thyroid cancer.

Thus, it was found that the inhibitor of the tyrosine kinase receptor should be very effective selective inhibitor of the growth of cancer cells in mammals (Eysh and others, Science, 1988, 242, 933). This view is confirmed by the fact that erbstein, the inhibitor of the tyrosine kinase receptor, apparatusthe tyrosinekinase receptor for the growth factor, epidermal (EGF), but no effect on the growth of other cancer, in which there is no tyrosinekinase receptor for EGF (Toi and others , Eur J. Cancer Clin. Oncol., 1990, 26, 722). Also indicates that various derivatives of styrene have any abscopal properties tyrosine kinase (a European patent application N 0211363, 0304493 and 0322738) and are useful antitumor agents. Inhibitory effect of two such derivatives of styrene was demonstrated in vivo in the growth of the cancer cells of the squamous epithelium of the person vaccinated "Nude" mice (Yoneda and others, Cancer Research, 1991, 51. 4430). Thus, it was found that inhibitors of tyrosine kinase receptors should be useful in the treatment of various cancers person. Various known tyrosine kinase inhibitors are discussed in a recently published review of T. R. Burke, Jr. (Drugs of the Future, 1992, 17, 119).

It was found that certain derivatives of hintline have anti-cancer properties, which, according to the applicant, directly associated with any abscopal inherent properties of tyrosine kinase receptors.

Currently known many derivatives chinsali voracova action due to their inhibitory properties against tyrosine kinase receptors.

Of patent applications in the UK N 2033894 it is known that certain derivatives of hintline possess analgesic and anti-inflammatory properties. Compounds and containing pharmaceutical compounds represented by the General formula II (below), in which R1mean hydrogen, halogen, trifluoromethyl or nitro;

R2represents hydrogen, halogen, alkyl or alkoxy, and

R3represents hydrogen or alkyl.

With one exception all examples of compounds described in this application, require that R1was represented by the Deputy, are not hydrogen. The exception is the connection, defined as 4-/N-methylaniline/hinzelin, in which each substituent R1and R2represent hydrogen, and R3is stands. Applicants believe that the following derivatives hintline not include any of the compounds described in the patent application UK N 2033894.

Other known derivatives of hintline specified in the application for patent in the UK N 2033894 include such compounds as 4-anilinoquinazoline and 4-aniline-6-chlorination (J. org. Chem., 1976, 41, 2646 and U.S. patent N 3985749), which are used when electioneering/ hintline were investigated in respect of antiarrhythmic properties. The connections defined as an intermediate chemical products include 4-/4'-hydroxyimino/-6-methoxyquinazoline and 4-/4'-hydroxyimino/-6,7-methylenedioxyaniline. From "Chemical Abstracts", vol. 70, abstract N 68419, it is known that certain derivatives of 4-aminoquinazolin have a bronchodilator and/or anti-hypertensive properties. One of the considered compound is 4-aniline-6,7-dimethoxyquinazolin/ From "Chemical Abstracts", vol. 92, abstract N 76445, it is also known that certain derivatives 6,7,8-trimethoxyaniline have antimalarial properties. One connection that is listed as a chemical intermediate is 4-/4'-hydroxyimino/-6,7,8-trimethoxybenzoyl.

From "Chemical Abstracts", vol 58, abstract N 9258, it is also known that certain derivatives of 4-/4'-isoamylene/hintline are dyes. The connection specified in the abstract as an intermediate product, is 6-amino-4-/4'-aminoaniline/hinzelin. Journal J. Chem, Soc., 1962, 4679, it is also known that 4-chloro-6-methylpyrazole interacts with the aniline with the formation of 4-aniline-6-methylinosine.

In accordance with one aspect of the present invention provides a derivative of hintline form the Roxy, amino, carboxy, carbarnoyl, ureido, /1-4C/-alkoxycarbonyl, N-/1-4C/-allylcarbamate, N, N-di-[/1-4C/alkyl] carbarnoyl, hydroxyamino, /2-4C/alkoxyamino, /2-4C/-alkanolamine, trifter-methoxy, /1-4C/alkyl, /1-4C/-alkoxy, /1-3C/alkylenedioxy, /1-4C/alkylamino, di-[/1-4C/alkyl]amino, pyrrolidin-1-yl, piperidino, morpholino, piperazine-1-yl, 4-/1-4C/alkylpiperazine-1-yl, /1-4C/alkylthio, /1-4C/alkylsulfanyl, /1-4C/alkylsulfonyl, halogen-/1-4C/alkyl (non-trifluoromethyl), hydroxy-/1-4C/alkyl, /2-4C/alkanoyloxy-/1-4C/alkyl, /1-4C/-alkoxy-/1-4C/alkyl, carboxy-/1-4C/alkyl, /1-4C/alkoxycarbonyl-/1-4C/alkyl, carbarnoyl-/1-4C/alkyl, N-/1-4C/-allylcarbamate-/1-4C/alkyl, N,N-di[/1-4C/alkyl]carbarnoyl-/1-4C-alkyl, amino-/1-4C/alkyl, /1-4C/alkylamino-/1-4C/alkyl, di-[/1-4C/alkyl]amino-/1-4C/alkyl, piperidino-/1-4C/alkyl, morpholino-/1-4C/alkyl, piperazine-1-Il-/1-4C/alkyl, 4-/1-4C/alkylpiperazine-1-yl-/2-4C/alkyl, hydroxy-/2-4C/alkoxy-/1-4C/alkyl, /1-4C/alkoxy-/2-4C/-alkoxy-/1-4C/alkyl, hydroxy-/2-4C/alkylamino-/1-4C/alkyl, /1-4C/alkoxy-/2-4C/alkylamino/1-4C/alkyl, /1-4C/alkylthio-/1-4C/alkyl, hydroxy-/2-4C/alkylthio-/1-4C/alkyl, /1-4C/alkoxy-/2-4C/alkylthio-/1-4C/alkyl, phenoxy-/1-4C/alkyl, aniline-/1-4C/alkyl, phenylthio-/1-4C/alkyl, cyano -,/1-4C/alkyl, halogen-/2-4C/alkoxy, hydroxy-/2-4C/alkoxy, /2-4C/alkanoyloxy-/2-4C/alkoxy, /1-4C/alkoxy-/2-4C/alkoxy, carboxy-/1-4C] carbarnoyl-/1-4C/alkoxy, amino-/2-4C/alkoxy, /1-4C/alkylamino-/2-4C/alkoxy, di[/1-4C/alkyl] amino-/2-4C/alkoxy, /2-4C/alkanoyloxy, hydroxy-/2-4C/alkanoyloxy, /1-4C/alkoxy-/2-4C/alkanoyloxy, phenyl-/1-4C/alkoxy, phenoxy-/2-4C/alkoxy, aniline-/2-4C/alkoxy, phenylthio-/2-4C/alkoxy, piperidino-/2-4C/alkoxy, morpholino-/2-4C/alkoxy, piperazine-1-Il-/2-4C/alkoxy, 4-/1-4C/alkylpiperazine-1-yl-/2-4C/alkoxy, halogen-/2-4C/alkylamino, hydroxy-/2-4C/alkylamino, /2-4C/alkanoyloxy-/2-4C/alkylamino, /1-4C/alkoxy-/2-4C/alkylamino, carboxy-/1-4C/alkylamino, /1-4C/alkoxycarbonyl-/1-4C/alkylamino, carbarnoyl-/1-4C/alkylamino, N-/1-4C/allylcarbamate-/1-4C/alkylamino, N, N-di-[/1-4C/alkyl] carbarnoyl-/1-4C/alkylamino, amino-/2-4C/alkylamino, /1-4C/alkylamino-/2-4C/alkylamino, di-[/1-4C/alkyl] amino-/2-4C/alkylamino, phenyl-/1-4C/alkylamino, phenoxy-/2-4C/alkylamino, aniline-/2-4C/alkylamino, phenylthio-/2-4C/alkylamino, /2-4C/alkanolamine, /1-4C/alkoxycarbonyl, /1-4C/alkylsulfonamides, benzamido, benzosulfimide, 3 phenylurea, 2-oxopyrrolidin-1-yl, 2,5-dioxopiperidin-1-yl, halogen-/2-4C/alkanolamine, hydroxy-/2-4C/alkanolamine, /1-4C/alkoxy-/2-4C/alkanolamine, carboxy-/2-4C/alkanolamine, /1-4C/alkoxycarbonyl-/2-4C/alkanolamine, carbarnoyl-/2-4C/alkanolamine, N-/1-4C/allylcarbamate-/2-4C/alkanolamine, N,N-di-[/1-4C/alkyl] carbarnoyl-/2-4C/elkano the which the said Deputy, representing benzamido or benzosulfimide, or any of aniline, phenoxy or phenyl group, the substituent R1can variant to include one or two Deputy representing halogen, /1-4C/alkyl /or 1-4C/alkoxy;

n denotes 1 or 2 and R2regardless of other elements represents hydrogen, hydroxy, halogen, trifluoromethyl, amino, nitro, cyano, /1-4C/alkyl, /1-4C/alkoxy, /1-4C/alkylamino, di-[/1-4C/alkyl] amino, /1-4C/alkylthio, /1-4C/alkylsulfanyl /or 1-4C/alkylsulfonyl, or its pharmaceutically acceptable salt;

except that the scope of the present invention does not include 4-/4'-hydroxyimino/-6-methoxyquinazoline, 4-/4'-hydroxyimino/-6,7-methylenedioxybenzene, 4-/4'-hydroxyimino/-6,7,8-trimethoxybenzoyl, 6-amino-/4-/4'-aminoaniline/hinzelin, 4-aniline-6-methylpyrazole or chloride-hydrogen salt and 4-aniline-6,7-dimethoxyquinazolin or chloride-hydrogen salt.

In accordance with another aspect of the present invention provides a derivative of hintline formula I, below, in which in addition to the above values of R2can provide /2-4C/alkanolamine, benzamido or /2-4C/alkanol and in which benzamidoxime may variant includes ramlila salt.

In accordance with another aspect of the present invention provides a derivative of hintline formula I, in which m denotes 1, 2 or 3 and R1regardless of other elements is hydroxy, amino, carboxy, carbarnoyl, ureido, /1-4C/alkoxycarbonyl, N-/1-4C/allylcarbamate, N,N-di-[/1-4C/alkyl] carbarnoyl, /1-4C/alkyl, /1-4C/alkoxy, /1-3C/alkylenedioxy, /1-4C/alkylamino, di-[/1-4C/alkyl]amino, /1-4C/alkylthio, /1-4C/alkylsulfanyl, /1-4C/alkylsulfonyl, halogen-/1-4C/alkyl (except trifloromethyl), hydroxy-/1-4C/alkyl, /2-4C/alkanoyloxy-/1-4C/alkyl, /1-4C/alkoxy-/1-4C/alkyl, carboxy-/1-4C/alkyl, /1-4C/alkoxycarbonyl-/1-4C/alkyl, carbarnoyl-/1-4C/alkyl, N-/1-4C/allylcarbamate-/1-4C/alkyl, N,N-di-[/1-4C/alkyl]carbarnoyl-/1-4C/alkyl, amino-/1-4C/alkyl, /1-4C/alkylamino-/1-4C/alkyl, di-[/1-4C/alkyl]amino-/1-4C/alkyl, piperidino-/1-4C/alkyl, morpholino-/1-4C/alkyl, piperazine-1-Il/1-4C/alkyl, 4-/1-4C/alkylpiperazine-1-yl-/1-4C/alkyl, hydroxy-/2-4C/alkoxy-/1-4C/alkyl, /1-4C/alkoxy-/2-4C/alkoxy-/1-4C/alkyl, hydroxy-/2-4C/alkylamino/1-4C/alkyl, /1-4C/alkoxy-/2-4C/alkylamino-/1-4C/alkyl, /1-4C/alkylthio-/1-4C/alkyl, hydroxy-/2-4C/alkylthio-/1-4C/alkyl, /1-4C/alkoxy-/2-4C/alkylthio-/1-4C/alkyl, halogen-/2-4C/alkoxy, hydroxy-/2-4C/alkoxy, /2-4C/alkanoyloxy-/2-4C/alkoxy, /1-4C/alkoxy-/2-4C/alkoxy, carboxy-/1-4C/alkoxy, /1-4C/alkoxycarbonyl the Ino-/2-4C/alkoxy, /1-4C/alkylamino-/2-4C/alkoxy, di-[/1-4C/alkyl] amino-/2-4C/alkoxy, halogen-/2-4C/alkylamino, hydroxy-/2-4C/alkylamino, /2-4C/alkanoyloxy-/2-4C/alkylamino, /1-4C/alkoxy-/2-4C/alkylamino, carboxy-/1-4C/alkylamino, /1-4C/alkoxycarbonyl-/1-4C/alkylamino, carbarnoyl-/1-4C/alkylamino, N-/1-4C/allylcarbamate-/1-4C/alkylamino, N, N-di-[/1-4C/alkyl]carbarnoyl-/1-4C/alkylamino, amino-/2-4C/alkylamino, /1-4C/alkylamino-/2-4C/alkylamino, di-[/1-4C/alkyl]amino-/2-4C/alkylamino, /2-4C/alkanolamine, /1-4C/alkoxycarbonyl, /1-4C/alkylsulfonamides, benzamido, benzosulfimide, halogen-/2-4C/alkanolamine, hydroxy-/2-4C/alkanolamine, /1-4C/alkoxy-/2-4C/alkanolamine, carboxy-/2-4C/alkanolamine, /1-4C/alkoxycarbonyl-/2-4C/alkanolamine, carbarnoyl-/2-4C/alkanolamine, N-/1-4C/allylcarbamate-/2-4C/alkanolamine, N, N-di-[/1-4C/alkyl] carbarnoyl-/2-4C/alkanolamine, amino-/2-4C/alkanolamine, /1-4C/alkylamino-/2-4C/alkanolamine or di-[/1-4C/alkyl] amino-/2-4C/alkanolamine and in which the said Deputy, representing benzamido or benzosulfimide, variant can include one or two substituent, represents halogen, /1-4C/alkyl /or 1-4C/alkoxy;

n denotes 1 or 2 and R2regardless of other elements represents hydrogen, hydroxy, halogen, trifluoromethyl, amino, nitro, cyano, the sludge, or its pharmaceutically acceptable salt;

except that the scope of the present invention does not include 4-/4'-hydroxyimino/-6-methoxyquinazoline, 4-/4'-hydroxyimino/-6,7-methylenedioxybenzene, 4-/4'-hydroxyimino/-6,7,8-trimethoxybenzoyl, 6-amino-/4-/4'-aminoaniline/hinzelin, 4-aniline-6-methylpyrazole or chloride-hydrogen salt and 4-aniline-6,7-dimethoxyquinazolin or chloride-hydrogen salt.

In accordance with another aspect of the present invention provides a derivative of hintline formula I, in which m denotes 1 or 2 and R1regardless of other elements is hydroxy, amino, carboxy, /1-4C/alkoxycarbonyl, /1-4C/alkyl, /1-4C/alkoxy, /1-3C/alkylenedioxy, /1-4C/alkylamino, di-[/1-4C/alkyl]amino, /1-4C/alkylthio, /1-4C/alkylsulfanyl, /1-4C/alkylsulfonyl, hydroxy-/1-4C/alkyl, /1-4C/alkoxy-/1-4C/alkyl, amino-/1-4C/alkyl, /1-4C/alkylamino-/1-4C/alkyl, di-[/1-4C/alkyl]amino-/1-4C/alkyl, hydroxy-/2-4C/alkoxy, /1-4C/alkoxy-/2-4C/alkoxy, carboxy-/1-4C/alkoxy, /1-4C/alkoxycarbonyl-/1-4C/alkoxy, /2-4C/alkanolamine, /1-4C/alkylsulfonamides, benzamido or benzosulfimide and in which these last 2 Deputy variant can include one or two Deputy representing halogen, /1-, is hydroxy, halogen, trifluoromethyl, amino, nitro, cyano, /1-4C/alkyl, /1-4C/alkoxy, /1-4C/alkylamino, di-[/1-4C/alkyl] amino, /1-4C/alkylthio, /1-4C/alkylsulfanyl /or 1-4C/alkylsulfonyl;

or its pharmaceutically acceptable salt;

except that the scope of the present invention does not include 4-/4'-hydroxyimino/-6-methoxyquinazoline, 4-/4'-hydroxyimino/-6,7-methylenedioxyaniline, 6-amino-/4-/4'-aminoaniline/hinzelin, 4-aniline-6-methylpyrazole or chloride-hydrogen salt and 4-aniline-6,7-dimethoxyquinazolin or chloride-hydrogen salt.

Chemical formulas, denoted in this proposal Roman numerals are for convenience on a separate sheet. In this description, the term "alkyl" includes an alkyl group with a straight or branched chain, but references to individual alkyl groups such as "propyl", refers to the variant of a straight chain. A similar condition applies to other generic terms.

It should be remembered that the scope of the present invention includes all tautomeric forms, formed by hinazolinam formula 1, with the figures of the formulas given in this description of the invention, can be represented only one of the possible tautomeric forms. It should be understood, a limited to any one tautomeric form, shown on the drawings formulas.

Hintline formula I are not replaced in the position of the atom 2. This is specifically shown in formula I by the presence of a hydrogen atom in the position of the atom 2. You must understand that the group R1are only in the position of the benzene nucleus chineselanguage rings.

You must also understand that certain hintline formula I can be solvated and nonsolvated forms, for example, hydrated forms. It should be remembered that the present invention includes all of solvated forms which possess anti-cancer effect.

Listed below are the acceptable values for the generic radicals discussed above.

A reasonable value for R1or R2when it is /1-4C-alkyl, can be, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl; when it is /1-4C/-alkoxy, such a value can be, for example, methoxy; ethoxy, propoxy, isopropoxy, or butoxy; when it is /1-4C/alkylamino, this value may be, for example, methylamino, ethylamino or propylamino; when it is di-[/1-4C/alkyl] amino, such a value can be, for example, dimethylamino, N-ethyl-what achenium maybe for example, methylthio, ethylthio or propylthio; when it is /1-4C/alkylsulfanyl, this value may be, for example, methylsulfinyl, ethylsulfinyl or propylsulfonyl; when it is /1-4C/alkylsulfonyl, this value may be, for example, methylsulphonyl, ethylsulfonyl or propylsulfonyl; and when it is /2-4C/alkanolamine, this value may be, for example, acetamido, propionamido or butyramide.

Acceptable values for each substituent R1that may be present in hinazolinam ring include, for example:

for /1-4C/alkoxycarbonyl: methoxycarbonyl, etoxycarbonyl, propoxycarbonyl and tert-butoxycarbonyl;

for N-/1-4C/allylcarbamate: N-methylcarbamoyl, N-ethylcarbazole and N-propellerblades;

for N, N-di[/1-4C-alkyl]-carbamoyl;N,N-dimethylcarbamoyl, N-ethyl-N-methyl-carbarnoyl and N,N-diethylcarbamoyl;

for /1-4C/alkoxyamino: methoxyamino, amoxilina, propoxyimino;

for /2-4C/alkanolamine: acetoacetamide, propionylacetate, butyraldoxime;

for /1-3C/alkylenedioxy: methylenedioxy, Ethylenedioxy, Propylenediamine;

5-/1-4C/alkylpiperazine-1-yl: 4-methylpiperazin-1-yl and 4-ethyl piperazine-1-yl;

for halogen/1-4C/Ala; the trifluoromethyl excluded from the scope of the invention;

for hydroxy-/1-4C/alkyl: hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl and 3-hydroxypropyl;

for /2-4C/alkanoyloxy-/1-4C/alkyl: acetoxymethyl, propionylacetate, butyrolactone, 2-acetoxyethyl and 3-acetoxypropionyl;

for /1-4C/alkoxy-/1-4C/alkyl: methoxymethyl, ethoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 2-ethoxyethyl and 3-methoxypropyl;

for carboxy-/1-4C/alkyl: carboxymethyl, 1-carboxyethyl, 2-carboxyethyl and 3-carboxypropyl;

for /1-4C/alkoxycarbonyl-/1-4C/alkyl; methoxycarbonylmethyl, ethoxycarbonylmethyl, tert - butoxycarbonylmethyl, 1-methoxycarbonylethyl, 1-ethoxycarbonylethyl, 2-methoxycarbonylethyl, 2-ethoxycarbonylethyl, 3-methoxycarbonylpropionyl and 3-ethoxycarbonylphenyl;

for carbarnoyl-/1-4C/alkyl: carbamoylmethyl, 1-carbamoylethyl, 2-carbamoylethyl and 3-carbamoylmethyl;

for N-/1-4C/allylcarbamate-/1-4C/alkyl: N-methylcarbamoylmethyl, N-ethylcarbazole, N-propylgallate, 1-/N-methylcarbamoyl/ ethyl, 1-/N-ethylcarbamate/ethyl, 2-/N-methylcarbamoyl/ethyl, 2-/N-ethylcarbamate/ethyl and 3-/N-methylcarbamoyl/propyl;

for N, N-di-[/1-4C/alkyl]-carbarnoyl-/1-4C/alkyl: N,N-dimethylcarbamoyl, N-ethyl-N-methylcarbamoylmethyl, N,N-diethylcarbamoyl, 1-/N,N-dimethylcarbamoyl/propyl;

for amino-/1-4C/alkyl: aminomethyl, 1-amino-ethyl, 2-amino-ethyl and 3-aminopropyl;

for /1-4C/alkylamino-/1-4C/alkyl: methylaminomethyl, ethylaminomethyl, 1-methylaminomethyl, 2-methylaminomethyl, 2-ethylaminomethyl and 3-methylaminopropyl;

for di-[/1-4C/alkyl]amino-/1-4C/alkyl: dimethylaminomethyl, diethylaminomethyl, 1-dimethylaminoethyl, 2-dimethylaminoethyl and 3-dimethylaminopropyl;

for piperidino-/1-4C/alkyl: piperidinomethyl and 2-piperidinoethyl;

for morpholino-/1-4C/alkyl: morpholinomethyl and 2-morpholinoethyl;

for piperazine-1-Il/1-4C)-alkyl: piperazine-1-ylmethyl and 2/piperazine-1-Il/ethyl;

4-/1-4C/alkylpiperazine-1-yl/1-4C/alkyl: 4-methylpiperazin-1-ylmethyl, 4-ethylpiperazin-1-ylmethyl, 2-/4-methylpiperazin-1-yl/ethyl and 2-/4-ethylpiperazin-1-yl/ethyl;

for hydroxy-/2-4C/alkoxy-/1-4C/alkyl: 2-hydroxyethoxyethyl, 3-hydroxypropoxy, 2-/2-hydroxyethoxy/ethyl and 2-/3-hydroxypropoxy/ethyl;

for /1-4C/alkoxy-/2-4C/-alkoxy-/1-4C/alkyl: 2-methoxyethoxymethyl, 2-toxicokinetic, 3-methoxypropionitrile, 3-ethoxypropionitrile, 2-/2-methoxyethoxy/ethyl 2-/2-ethoxyethoxy/ethyl;

for hydroxy-/2-4C/alkylamino-/1-4C/alkyl: 2-hydroxyethylaminomethyl, 3-hydroxypropylamino, 2-/2-hydroxyethylamino/ethyl and 2-/3-hydroxypropylamino/ethyl;

for /1-4C/alkylthio-1-4C/alkyl: methylthiomethyl, ethylthiomethyl, 2-methylthioethyl, 2-ethylthioethyl, 3-metaltipped and 3-ethylthiophen;

for hydroxy-/2-4C/alkylthio-/1-4C/alkyl: 2-hydroxyethylaminomethyl, 3-peroxidizability, 2-/2-hydroxyethylthio/ethyl and 2-/3-hydroxypropylamino/ethyl;

for /1-4C/alkoxy-/2-4C/-alkylthio-/1-4C/alkyl: 2-methoxyethoxymethyl, 2-amoxicilline, 3-methoxypropionate, 2-/2-Methoxyacetic/ethyl 2-/2-toxicity/ethyl;

for phenoxy-/1-4C/alkyl: phenoxymethyl, 2-phenoxyethyl and 3-phenoxypropan;

for the aniline-/1-4C/alkyl: anilinomethyl, 2-anilinomethyl and 3-onlinepool;

for phenylthio-/1-4C/alkyl: phenylthiomethyl, 2-phenylthiomethyl and 3-phenylthiomethyl;

for cyano-/1-4C/alkyl: cyanomethyl, 2-cyanoethyl and 3-cyanopropyl;

for halogen/2-4C/alkoxy: 2-floratone, 2-chloroethoxy, 2-bromoethoxy, 3 forproperty and 3 chloropropoxy;

for hydroxy-/2-4C/alkoxy: 2-hydroxyethoxy, 3 hydroxypropoxy and 4 hydroxybutane;

for /2-4C/alkanoyloxy-/2-4C/alkoxy: 2-acetoacetate, 2-propionylacetate, 2-butyrylacetate and 3 acetoxypropionyl;

for /1-4C/alkoxy-/2-4C/alkoxy: 2-methoxyethoxy, 2-ethoxyethoxy, 3 methoxypropane and 4 methoxyphenoxy;

DS/alkoxycarbonyl-/1-4C/alkoxy: ethoxycarbonylmethoxy, ethoxycarbonylmethoxy, 1 ethoxycarbonylmethoxy, 2-ethoxycarbonylmethoxy, 2-ethoxycarbonylmethoxy and 3 methoxycarbonylpropionyl;

for carbarnoyl-/1-4C/alkoxy: carbamoylphenoxy, 1 carbamoylethyl, 2-carbamoylethyl and 3 carbamoylphenoxy;

for N-/1-4C/allylcarbamate-/1-4C/alkoxy: N-methylcarbamoylmethyl, N-ethylcarbamate, 2-/N-methylcarbamoyl/ethoxy, 2-/N-ethylcarbamate/ethoxy and 3/N-methylcarbamoyl/proposi;

for N, N-di-[/1-4C/alkyl]carbarnoyl-/1-4C/alkoxy: N,N-dimethylcarbamoyl, N-ethyl-N-methylcarbamoylmethyl, N,N-diethylcarbamoyl, 2-/N, N-dimethylcarbamoyl/ethoxy, 2-/N,N-diethylcarbamoyl/ethoxy and 3/N,N-dimethylcarbamoyl/propoxy;

for amino-/2-4C/alkoxy: 2-aminoethoxy and 3 aminopropoxy;

for /1-4C/alkylamino-/2-4C/alkoxy: 2-methylaminoethanol, 2-ethylaminoethanol, 2-propylaminoethyl, 3 methylaminopropane and 3 Ethylenedioxy;

for di-[/1-4C/alkyl]amino/2-4C/alkoxy: 2-dimethylaminoethoxy, 2-N-ethyl-N-methyl/ethoxy, 2-diethylaminoethoxy, 2-dipropylamino, 3 dimethylaminopropoxy and 3 diethylaminopropyl;

for /2-4C/alkanoyloxy: acetoxy, propionyloxy, butyryloxy;

for hydroxy-/2-4C/alkanoyloxy: 2-hydroxyacetate, 3 hydroxypropionate and 4 hydroxybutyrate;

for /1-4C/alkoxysilane, 2 venlafaxi and 3 phenylpropoxy;

for phenoxy-/2-4C/alkoxy: 2-phenoxyethoxy, 3 phenoxypropane and 4 phenoxyethoxy;

for the aniline-/2-4C/alkoxy: 2-onlinetake, 3 onlinepropecia and 4 onlinebooks;

for phenylthio-/2-4C/alkoxy: 2-penilties, 3 phenylthiophene and 4 vinyltoluene;

for piperidino-/2-4C/alkoxy: 2-piperidineacetic and 3 piperidinyloxy;

for morpholino-/2-4C/alkoxy: 2-morpholinoethoxy and 3 morpholinopropan;

for piperazine-1-Il-/2-4C/alkoxy: 2-/piperazine-1-Il/ethoxy and 3/piperazine-1-Il/propoxy;

4-/1-4C/alkylpiperazine-1-yl-/2-4C/alkoxy: 2-/4-methylpiperazin-1-yl/ethoxy and 3-/4-methylpiperazin-1-yl/propoxy;

for halogen/2-4C/alkylamino: 2-Floridiana, 2-chloroethylamine, 2-bromethalin, 3 forprofile and 3 chloropropylamine;

for hydroxy-/2-4C/alkylamino: 2-hydroxyethylamino, 3 hydroxypropylamino and 4 hydroxyethylamino;

for /2-4C/alkanoyloxy-/2-4C/alkylamino: 2-acetoxyethyl, 2-propionylcarnitine, 2-butyrolacetone and 3 acetoxypropionyl;

for /1-4C/alkoxy-/2-4C/alkylamino: 2-methoxyethylamine, 2-ethoxyethylene, 3 methoxypropylamine and 3 ethoxypropylamine;

for carboxy-/1-4C/alkylamino: carboxymethylamino, 1 carboxymethylamino, 2-carboxymethylamino is animationen, 1 methoxycarbonylamino, 2-methoxycarbonylethyl, 2-ethoxycarbonylmethylene and 3 methoxycarbonylpropionyl;

for carbarnoyl-/1-4C/alkylamino: carbamoylmethyl, 1 carbamoylethyl, 2-carbamoylethyl and 3 carbamoylphosphate;

for N-/1-4C/allylcarbamate-/1-4C/alkylamino: N-methylcarbamoylmethyl, N-ethylcarbodiimide, 2-/N-methylcarbamoyl/ethylamino, 2-/N-ethylcarbamate/ethylamino and 3/N-methylcarbamoyl/propylamino;

for N, N-di-[/1-4C/alkyl] -carbarnoyl-1-4C/alkylamino: N,N-dimethylcarbamoyl, N-ethyl-N-methylcarbamoylmethyl, N,N-diethylcarbamoyl, 2-/N,N-dimethylcarbamoyl/ethylamino, 2-/N,N-diethylcarbamoyl/ethylamino and 3/N,N-dimethylcarbamoyl/propylamino;

for amino-/2-4C/alkylamino: 2-aminoethylamino, 3 aminopropylene and 4 aminoethylamino;

for /1-4C/alkylamino-/2-4C/alkylamino: 2-methylaminoethanol, 2-ethylaminoethanol, 2-Propylenediamine, 3 methylaminopropane, 3 ethylenepropylene and 4 methylaminopropane;

for di-[/1-4C/alkyl] amino-/2-4C/alkylamino: 2-diethylaminoethylamine, 2-N-ethyl-N-methylamino/ethylamino, 2-diethylaminoethylamine, 2-dipropylenetriamine, 3 dimethylaminopropylamine, 3 diethylaminopropylamine and 4 diethylaminoethylamine;

for phenyl-/1 the Mino and 3 phenoxypropylamine;

for the aniline-/2-4C/alkylamino: 2-anilinomethylene and 3 anilinopiperidine;

for phenylthio-/2-4C/alkylamino: 2-phenylethylamine and 3 phenylthiophene;

for /1-4C/alkoxycarbonyl: methoxycarbonylamino, ethoxycarbonylethyl, propoxycarbonyl;

for /1-4C/alkylsulfonamides: methylsulfonylamino, ethylsulfonyl, propylsulfonyl;

for halogen/2-4C/alkanolamine: 2-chloroacetamido, 2-bromoacetamide, 3 chlorpropamide and 3 bromopropionate;

for hydroxy-/2-4C/alkanolamine: 2-hydroxyacetamido, 3 hydroxypropylamino and 4 hydroxybutyrate;

for /1-4C/alkoxy-/2-4C/alkanolamine: 2-methoxyacetate, 2-ethoxyacetic, 2-propoxylated, 3 methoxypropylamine, 3 ethoxypropionate and 4 methoxybutyl;

for carboxy-/2-4C/alkanolamine: 2-carboxylated, 3 carboxypropyl and 4 carboxymethylamino;

for /1-4C/alkoxycarbonyl-/2-4C/alkanolamine: 2-methoxycarbonylethyl, 2-ethoxycarbonylethyl, 3 methoxycarbonylpropionyl and 3 ethoxycarbonylphenyl;

for carbarnoyl-/2-4C/alkanolamine: 2-carbamoylated, 3 carbamoylphosphate and 4 carbamoylating;

for N-/1-4C/allylcarbamate-/2-4C/alkanolamine: 2-/N-methylcarbamoyl/acetamido,oil/butyramide;

for N,N-di-[/1-4C/alkyl]-carbarnoyl-/2-4C/alkanolamine: 2-/N,N-dimethylcarbamoyl/acetamido, 2-N-ethyl-N-methylcarbamoyl/acetamido, 2-/N, N-diethylcarbamoyl/acetamido, 3-/N, N-dimethylcarbamoyl/propionamide, 3-/N,N-diethylcarbamoyl/propionamide and 4/N,N-dimethylcarbamoyl/butyramide;

for amino-/2-4C/alkanolamine: 2-aminoacetate, 3 aminopropionic and 4 aminobutyrate;

for /1-4C/alkylamino-/2-4C/alkanolamine: 2-methylaminoethanol, 2-ethylaminoethanol, 2-propylaminoethyl, 3 methylaminopropane, 3 ethylenepropylene and 4 methylaminomethyl;

for di-[/1-4C/alkyl]amino-/2-4C/alkanolamine: 2-dimethylaminoacetyl, 2-N-ethyl-N-methylamino/acetamido, 2-diethylaminoacetate, 3 dimethylaminopropylamine, 3 diethylaminopropylamine and 4 dimethylaminobutyric.

If R1is /1-3C/alkylenedioxy, oxygen atoms in each such group occupy adjacent positions in hinazolinam the ring.

Suitable values for substituents which may be present in the phenyl ring, if R1is benzamido or benzosulfimide, R2is benzamido, or in the substituent R1which contains aniline, phenoxy or phenyl group include, for example;

DL is propoxy.

A reasonable value for R2if it represents a halogen is fluorine, chlorine, bromine or iodine, and if it is /2-4C/alkanoyl, this value is, for example, acetyl, propionyl or butyryl.

A suitable pharmaceutically acceptable salt of the derivative hintline of the present invention is, for example, salt accession acid derived hintline which is sufficiently basic, formed by inorganic acid, in particular chloride-hydrogen, Hydrobromic, sulfuric, phosphoric, triperoxonane, citric or maleic acid. In addition a suitable pharmaceutically acceptable acid derived hintline of the present invention which is sufficiently acidic is an alkali metal salt, for example, sodium salt or potassium salt, alkaline-earth metal, for example, a salt of calcium or magnesium, ammonium salt or a salt formed with an organic base, which allows to obtain a physiologically acceptable cation, in particular salt formed by methylamine, dimethylamine, trimethylamine, piperidine, morpholine or Tris-/2-hydroxyethyl/Amin.

Certain of the new compounds according to the present invention bknyh exceptions where;

(a) m is 1 or 2 and R1regardless of other elements is hydroxy, /1-4C/alkoxycarbonyl, /1-4C/alkyl, /1-4C/alkoxy or /1-3C/alkylenedioxy; and n and R2have the values specified above or in this section in relation to certain novel compounds of the present invention:

(b) m is 1 or 2 and R1regardless of other elements is hydroxy, amino, /1-4C/alkoxycarbonyl, /1-4C/alkyl, /1-4C/alkoxy, /1-3C/alkylenedioxy, halogen/1-4C/alkyl (except trifloromethyl), /1-4C/alkylamino-/1-4C/alkyl, di-[/1-4C/alkyl]amino-/1-4C/alkyl, piperidino-/1-4C/alkyl, morpholino-/1-4C/alkyl, piperazine-1-Il-/1-4C/alkyl, hydroxy-/2-4C/alkylthio-/1-4C/alkyl, hydroxy-/2-4C/alkoxy, /1-4C/alkoxy-/2-4C/alkoxy, /1-4C/alkoxycarbonyl-/1-4C/alkoxy, carbarnoyl-/1-4C/alkoxy, /1-4C/alkylamino-/2-4C/alkoxy, di-[/1-4C/alkyl]amino-/2-4C/alkoxy, hydroxy-/2-4C/alkylamino, /1-4C/alkoxy-/2-4C/alkylamino, /1-4C/alkylamino-/2-4C/alkylamino, di-[/1-4C/alkyl]amino-/2-4C/alkylamino, /2-4C/alkanolamine, hydroxy-/2-4C/alkanolamine /or 1-4C/alkoxy-/2-4C/alkanolamine; and n and R2have the values specified above or in this section in relation to certain novel compounds of the present invention

(c) m is 1 or 2 and R1regardless of other cell battery (included) is oxycarbonyl-/1-4C/alkoxy, carbarnoyl-/1-4C/alkoxy or di-[/1-4C/alkyl]amino-/2-4C/alkoxy; and n and R2have the values specified above or in this section in relation to certain novel compounds of the present invention;

(d) m is 1 or 2 and R1regardless of other elements is amino, hydroxy-/2-4C/alkylamino, /1-4C/alkoxy-/2-4C/alkylamino, di-[/1-4A/alkyl] amino-/2-4C/alkylamino, /2-4C/alkanolamine, hydroxy-/2-4C/alkanolamine /or 1-4C/alkoxy-/2-4C/alkanolamine; and n and R2have the values specified above or in this section in relation to certain novel compounds of the present invention;

(e) m is 1, 2 or 3 and R1regardless of other elements is hydroxy, amino, carboxy, ureido, /1-4C/alkoxycarbonyl, hydroxyamino, triptoreline, /1-4C/alkyl, /1-4C/alkoxy, /1-3C/alkylenedioxy, /1-4C/alkylamino, di-[/1-4C/alkyl] amino, piperidine, morpholine, piperazine-1-yl, 4-/1-4C/alkylpiperazine-1-yl, /1-4C/alkylthio, halogen/1-4C/alkyl (except trifloromethyl), /1-4C/alkoxy-/1-4C/alkyl, /1-4C/alkylamino-/1-4C/alkyl, di-[/1-4C/alkyl] amino-/1-4C/alkyl, piperidino-/1-4C/alkyl, morpholino-/1-4C/alkyl, piperazine-1-Il-/1-4C/alkyl, hydroxy-/2-4C/alkoxy-/1-4C/alkyl, /1-4C/alkoxy-/2-4C/alkoxy-/1-4C/alkyl, /1-4C/alkylthio-/1-4C/alkyl, hydroxy-/2-4C/alkylthio-/1-4C/alkyl, alkoxy, /1-4C/alkoxycarbonyl-/1-4C/alkoxy, carbarnoyl-/1-4C/alkoxy, /1-4C/alkylamino-/2-4C/alkoxy, di-[/1-4C/alkyl] amino-/2-4C/alkoxy, /1-4C/alkoxy-/2-4C/alkanoyloxy, phenyl-/1-4C/alkoxy, phenoxy-/2-4C/alkoxy, aniline-/2-4C/alkoxy, piperidino-/2-4C/alkoxy, morpholino-/2-4C/alkoxy, piperazine-1-Il-/2-4C/alkoxy, hydroxy-/2-4C/alkylamino, /1-4C/alkoxy-/2-4C/alkylamino, /1-4C/alkylamino-/2-4C/alkylamino, di-[/1-4C/alkyl]amino-/2-4C/alkylamino, /2-4C/alkanolamine, benzamido, 3 phenylurea, 2-oxopyrrolidin-1-yl, halogen-/2-4C/alkanolamine, hydroxy-/2-4C/alkanolamine, /1-4C/alkoxy-/2-4C/alkanolamine /or 1-4C/alkoxycarbonyl-/2-4C/alkanolamine; and n and R2have the values specified above or in this section in relation to certain novel compounds of the present invention;

(f) m is 1 or 2 and R1regardless of other elements is hydroxy, amino, ureido, /1-4C/alkoxycarbonyl, triptoreline, /1-4C/alkyl, /1-4C/alkoxy, /1-3C/alkylenedioxy, /1-4C/alkylamino, di-[/1-4C/alkyl]amino, piperidino, morpholino, /1-4C/alkylthio, halogen/1-4C/alkyl (except trifloromethyl), cyano -,/1-4C/alkyl, halogen/2-4C/alkoxy, hydroxy-/2-4C/alkoxy, /1-4C/alkoxy-/2-4C/alkoxy, carbarnoyl-/1-4C/alkoxy, /1-4C/alkoxy-/2-4C/alkanoyloxy, phenyl-/1-4C/alkoxy, aniline-/2-4C/alkoxy, /1-4C/alkoxy-/2-4C/al is alkanolamine; and n and R2have the values specified above or in this section to certain new compounds of the present invention;

(g) n is 1 or 2 and R2regardless of other elements represents hydrogen, halogen, trifluoromethyl, nitro, cyano, /1-4C/alkyl, di-[/1-4C/alkyl] amino or /1-4C/alkylthio; and m and R1have the values specified above or in this section to certain new compounds of the present invention;

(h) n is 1 or 2 and R2regardless of other elements is halogen, trifluoromethyl or /1-4C/alkyl; and m and R1have the values specified above or in this section to certain new compounds of the present invention, or

(i) n is 1 or 2 and R2regardless of other elements represents hydrogen, hydroxy, halogen, trifluoromethyl, amino, nitro, cyano or /1-4C/alkyl; and m and R1have the values specified above or in this section to certain new compounds of the present invention.

The preferred compound of the present invention is derived hintline formula I, in which m denotes 1 or 2 and R1regardless of other elements is hydroxy, methyl, ethyl, methoxy, ethoxy or methylenedioxy;

Another preferred compound according to the present invention is derived hintline formula I, in which R1)mis 6-hydroxy, 7-hydroxy, 6,7-dihydroxy, 6-methyl, 7-methyl, 6-methoxy, 7-methoxy, 6,7-dimethoxy, or 6,7-methylenedioxy; and

(R2) n is 3'-chloro, 3'-bromo or 3'-methyl; or its pharmaceutically acceptable salt accession acid.

Especially preferred compound of the present invention is the following derived hintline formula I or its pharmaceutically acceptable salt accession acid:

6,7-dimethoxy-4-/3'-methylaniline/hinzelin,

6,7-dimethoxy-4-/3'-chloroanilino/hinzelin,

6,7-dimethoxy-4-/3'-bromoaniline/hinzelin,

6,7-methylenedioxy-4-/3'-methylaniline/hinzelin,

7-methoxy-4-/3'-methylaniline/hinzelin,

7-hydroxy-4-/3'-methylaniline/hinzelin,

6-methyl-4-/3'-methylaniline/hinzelin or

7-methoxycarbonyl-4-/3'-methylaniline/hinzelin.

Another preferred compound for this from other items means hydroxy, amino, methoxycarbonyl, etoxycarbonyl, methyl, ethyl, methoxy, ethoxy, methylenedioxy, dibromomethyl, dimethylaminomethyl, piperazine-1-ylmethyl, 2-gidroksietilimino, 2-hydroxyethoxy, 3 hydroxypropoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 3 methoxypropane, 3 ethoxypropane, ethoxycarbonylmethoxy, ethoxycarbonylmethoxy, carbamoylmethyl, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 2-hydroxyethylamino, 3 hydroxypropylamino, 2-methoxyethylamine, 2-ethoxyethylene, 3 methoxypropylamine, 3 ethoxypropylamine, 2-diethylaminoethylamine, 2-diethylaminoethylamine, 3 dimethylaminopropylamine, 3 diethylaminopropylamine, acetamido, propionamido, 2-methoxyacetate or 2-ethoxyacetic;

n denotes 1 or 2 and R2regardless of other elements represents fluorine, chlorine, bromine, trifluoromethyl, methyl or ethyl;

or its pharmaceutically acceptable salt.

Another preferred compound of the present invention is derived hintline formula I, in which R1)mis 6-hydroxy, 7-hydroxy, 6,7-dihydroxy, 6-amino, 7-amino, 6-methyl, 6,7-dimethyl, 7-methoxy, 6,7-dimethoxy, 6-hydroxy-7-methoxy, 7-hydroxy-6-methoxy, 6,7-methylenedioxy, 6-/2-hydroxyethylaminomethyl/, 7-/2-hydroxyethoxy/-6 is C/-6-methoxy, 6-/2-methoxyethylamine/, 6-acetamido, or 7/2-methoxyacetate/ while (R2)nis 4'-fluoro, 3'-chloro, 3'-bromo, 3'-methyl, 3'-trifluoromethyl or 4'-fluoro-3'-trifluoromethyl; or its pharmaceutically acceptable salt accession acid.

Another preferred compound of the present invention is derived hintline formula I, in which R1)mis 6-amino, 7-amino, 6-/2-methoxyethylamine/, 6-acetamido, or 7/2-methoxyacetate/ while (R2)nis 3'-chloro, 3'-methyl or 3'-trifluoromethyl;

or its pharmaceutically acceptable salt accession acid.

Another especially preferred compound of the present invention is the following derived hintline formula I or its pharmaceutically acceptable salt accession acid:

6,7-dimethoxy-4-/3'-triptoreline/hinzelin,

6-hydroxy-7-methoxy-4-/3'-methylaniline/hinzelin,

7-hydroxy-6-methoxy-4-/3'-methylaniline/hinzelin,

7-amino-4-/3'-methylaniline/hinzelin,

6-amino-4-/3'-methylaniline/hinzelin,

6-amino-/4-/3'-chloroanilino/hinzelin,

6-acetamido-/4-/3'-methylaniline/hinzelin,

6-/2-methoxyethylamine/-4-/3'-methylaniline/hinzelin,

7-/2-Li 7-/2-methoxyethoxy/-6-methoxy-4-/3'-methylaniline/hinzelin.

Another preferred compound of the present invention is derived hintline formula I, in which m denotes 1, 2 or 3 and R1regardless of other elements is hydroxy, amino, ureido, methoxycarbonyl, etoxycarbonyl, hydroxyamino, triptoreline, methyl, ethyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, methylenedioxy, Ethylenedioxy, methylamino, ethylamino, dimethylamino, diethylamino, piperidino, morpholino, methylthio, ethylthio, methyl bromide, dibromomethyl, methoxymethyl, piperidinomethyl, morpholinomethyl, piperazine-1-ylmethyl, methoxyethoxymethyl, methylthiomethyl, 2-hydroxyethylaminomethyl, anilinomethyl, phenylthiomethyl, cyanomethyl, 2-bromoethoxy, 2-hydroxyethoxy, 3 hydroxypropoxy, 2-methoxyethoxy, 2 ethoxyethoxy, 3 methoxypropane, 3 ethoxypropane, ethoxycarbonylmethoxy, ethoxycarbonylmethoxy, carbamoylmethyl, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 2-methoxyethoxy, benzyloxy, 2-onlinetake, 2-piperidinoethyl, 2-morpholinoethoxy, 2-/piperazine-1-Il/ethoxy, 2-hydroxyethylamino, 3 hydroxypropylamino, 2-methoxyethylamine, 2-ethoxyethylene, 3 methoxypropylamine, 3 ethoxypropylamine, 2-diethylaminoethylamine, 2-diethylaminoethylamine, 3 dimethylaminopropylamine, 3-the sludge, 2 hydroxyacetamido, 2-methoxyacetate or 2-ethoxyacetic;

n denotes 1 or 2 and R2regardless of other elements represents hydrogen, fluorine, chlorine, bromine, trifluoromethyl, nitro, cyano, methyl or ethyl;

or its pharmaceutically acceptable salt.

Another preferred compound of the present invention is derived hintline formula I, in which R1)mis 6-hydroxy, 7-hydroxy, 6,7-dihydroxy, 6-amino, 7-amino, 6-ureido, 6-triptoreline, 6-methyl, 6,7-dimethyl, 6-methoxy, 7-methoxy, 6,7-dimethoxy, 6,7-diethoxy, 6-hydroxy-7-methoxy, 7-hydroxy-6-methoxy, 6-amino-7-methoxy, 6-amino-7-methylthio, 5-amino-6,7-dimethoxy, 6-methoxy-7-isopropoxy, 6,7-methylenedioxy, 6,7-Ethylenedioxy, 6-dimethylamino, 6-methoxymethyl, 6-/2-methoxyethoxymethyl/ 6-cyanomethyl, 7-/2-hydroxyethoxy/-6-methoxy, 6,7-di-/2-hydroxyethoxy/, 6-/2-methoxyethoxy/, 6-methoxy-7-/2-methoxyethoxy/, 6,7-di-/2-methoxyethoxy/, 7-/2-bromoethoxy/-6-methoxy, 7-benzyloxy-6-methoxy, 6-/2-methoxyethylamine/, 6-acetamido, 6-/2-chloracetamide/, 6-/2-methoxyacetate/ or 7/2-methoxyacetate/, and (R2)nis hydrogen, 4'-fluoro, 3'-chloro, 3'-bromo, 3', 4'-dichloro, 4'-fluoro-3'-chloro, 3'-trifluoromethyl, 4'-fluoro-3'-trifluoromethyl, 3'-nitro, 3'-nitro-4'-chloro, 3'-neither is particularly preferred compound of the present invention is the following derived hintline formula I or its pharmaceutically acceptable salt accession acid:

4-/3'-chloro-4'-foranyone/-6,7-dimethoxyquinazolin,

4-/3',4'-dichloraniline/-6,7-dimethoxyquinazolin,

6,7-dimethoxy-4-/3'-nitroaniline/hinzelin,

6,7-diethoxy-4-/3 methylaniline/hinzelin,

6-methoxy-4-/3'-methylaniline/hinzelin,

4-/3'-chloroanilino/-6-methoxyquinazoline,

6,7-Ethylenedioxy-4-/3'-methylaniline/hinzelin,

6-amino-7-methoxy-4-/3'-methylaniline/hinzelin,

4-/3'-methylaniline/-6-ureidopenicillin or

6-/2-methoxyethoxymethyl/-4-/3'-methylaniline/hinzelin.

Another preferred compound of the present invention is derived hintline formula I, in which R1)mis 6-hydroxy, 7-hydroxy, 6,7-dihydroxy, 6-amino, 7-amino, 6-ureido, 6-triptoreline, 6-methyl, 6,7-dimethyl, 6-methoxy, 7-methoxy, 6,7-dimethoxy, 6,7-diethoxy, 6-hydroxy-7-methoxy, 7-hydroxy-6-methoxy, 6-amino-7-methoxy, 6-amino-7-methylthio, 5-amino-6,7-dimethoxy, 6-methoxy-7-isopropoxy, 6,7-methylenedioxy, 6,7-Ethylenedioxy, 6-methylamino, 7-methylamino, 6-dimethylamino, 6-amino-7-methylamino, 6-methoxymethyl, 6-methyl bromide, 6-/2-methoxyethoxymethyl/ 6-cyanomethyl, 6-methylthiomethyl, 6-phenylthiomethyl, 7-/2-hydroxyethoxy/-6-methoxy, 6,7-di/2 hydroxyethoxy/, 6-/2-bromoethoxy/, 6-/2-methoxyethoxy/, 6-methoxy-7-/2-metoxi-benzamide. 6-/2-chloracetamide/, 6-/2-methoxyacetate/ or 7/2-methoxyacetate/, and (R2)nis hydrogen, 4'-fluoro, 3'-chloro, 3'-bromo, 3',4'-dichloro, 4'-fluoro-3'-chloro, 3'-trifluoromethyl, 4'-fluoro-3'-trifluoromethyl, 3'-nitro, 3'-nitro-4'-chloro, 3'-nitro-4'-fluoro or 3'-methyl;

or its pharmaceutically acceptable salt accession acid.

Another especially preferred compound of the present invention is the following derived hintline formula I or its pharmaceutically acceptable salt accession acid:

6,7-di/2 methoxyethoxy/-4-/3'-methylaniline/hinzelin,

6-dimethylamino-4-/3'-methylaniline/hinzelin or

6 benzamido-4-/3'-methylaniline/hinzelin.

Derived hintline formula I or its pharmaceutically acceptable salt can be obtained using any known method, designed to produce compounds having a similar chemical structure. Acceptable method, for example, is considered in the patent application UK N 2033894. The methods used to obtain derived hintline formula I or its pharmaceutically acceptable salt, represent another aspect of the present invention and are illustrated by the following examples in which, if the formula I. The necessary starting materials may be obtained using standard methods of organic chemistry. The receipt of such starting materials is described in the accompanying examples, not limiting the scope of invention. Alternative necessary raw materials can be obtained in accordance with the procedures that are similar to those discussed in this application and are well known to the expert in the field of organic chemistry.

(a) Interaction of hintline formula (III) below), in which Z represents a substituted group, with an aniline of the formula IV in the presence of reasonable grounds.

Acceptable substituted by a group Z is, for example, halogen, alkoxy, aryloxy or sulfonyloxy, in particular chlorine, bromine, methoxy, phenoxy, methansulfonate or toluene-persulfonic group.

Acceptable base is, for example, an organic amine base such as pyridine, 2,6-lutidine, kallidin, 4-dimethylaminopyridine, triethylamine, morpholine, N-methylmorpholine or diazabicyclo-[5.4.0]under-7-ene, or a carbonate or hydroxide of an alkaline or alkaline-earth metal, e.g. sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide.

El, for example, alkanol or complex ether, such as methanol, ethanol, isopropanol or ethyl acetate, a halogenated solvent, in particular methylene chloride, chloroform or carbon tetrachloride, a simple ether, such as tetrahydrofuran or 1,4-dioxane, an aromatic solvent such as toluene, or a bipolar aprotic solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidine-2-one or dimethylsulfoxide. This reaction is usually carried out at a temperature in the range from 10 to 150oC, preferably in the range from 20 to 80oC.

In this way the derived hintline formula I can be obtained in the form of free base or alternatively in the form of a salt formed by the acid of the formula H-Z, in which Z has the above meaning. If necessary, obtain the free base from the salt this salt can be processed reasonable grounds specified above, using a known method.

(b) To obtain compounds of the formula I, in which R1or R2represents hydroxy, is splitting derived hintline formula I, in which R1or R2is /1-4C/alkoxy.

The cleavage reaction may be carried out by processing the derived hintline (1-4C/alkylsulfides alkali metal, such as attentional sodium, or diarylphosphino alkali metal such as lithium diphenylphosphide. Alternative cleavage reaction may be carried out by processing the derived hintline trihalogen boron or aluminum, such as tribromide boron. Such reactions are preferably carried out in the presence of acceptable inert solvent or diluent, as specified above, and at the corresponding temperature, are shown in the attached examples.

(c) To obtain compounds of the formula I, in which R1or R2is /1-4C/alkylsulfanyl /or 1-4C/alkylsulfonyl group, the oxidation of the derived hintline formula I, in which R1or R2is /1-4C/allylthiourea.

Acceptable oxidizing agent is any substance used for the oxidation of tigraphy in sulfinil and/or sulfonyl, for example, hydrogen peroxide, percolate (for example, 3-chloroperoxybenzoic or peroxidasa acid), peroxosulfates alkali metal (for example, peroxymonosulfate potassium, chromium trioxide or gaseous oxygen in the presence of platinum. The oxidation is usually performed under mild conditions with use of necessary stereoselectively groups. This reaction is usually carried out in an acceptable solvent or diluent such as methylene chloride, chloroform, acetone, tetrahydrofuran or tert-butyl methyl ether, at a temperature in the range from -25 to 50oC, typically at ambient temperature, i.e. in the range from 15 to 35oC. If necessary, obtain compounds containing sulfinyl group, you can also use a weaker oxidising agent, for example, metaperiodate sodium or potassium, typically in a polar solvent such as acetic acid or ethanol. If necessary, obtain the compounds of formula I containing /1-4C/alkylsulfonyl group, can be obtained by oxidation of the corresponding /1-4C/alkylsulfanyl connections as well as respective 1-4C/alkylthiophene.

(d) To obtain compounds of formula 1 in which R1represents amino, restores derived hintline formula I, in which R1represents nitro.

Recovery can be done using any of the numerous methods are available for this purpose. The recovery may be carried out by hydrogenation of a solution of nitro compounds in an inert solvent or R is or platinum. Other acceptable reducing agent is activated metal, for example, activated iron (obtained by leaching iron powder) diluted aqueous acid such as chloride-hydrogen acid). Thus, recovery can be effected by heating a mixture of nitro compounds, and the activated metal in the acceptable solution or diluent such as a mixture of water and alcohol, for example methanol or ethanol, to a temperature between 50 and 150oC, typically at a temperature of approximately 70oC.

(e) To obtain compounds of the formula I, in which R1is /2-4C/alkanolamine or substituted /2-4C/alkanolamines, ureido, 3 phenylurea or benzamido, or R2is acetamido or benzamido produce acylation derived hintline formula I, in which R1or R2represents the amino group.

Acceptable allermuir agent is any substance intended for acylation of amino groups in allmenalp, for example, allalone in particular /2-4C/alcoholclone or chloride, or benzoyl chloride or bromide, usually in the presence of reasonable grounds specified above, anhydride alanovoy acid or smiling the ID, the resulting interaction alanovoy acid /1-4C/alkoxycarbonylmethyl, for example, /1-4C/alkoxycarbonylmethyl, in the presence of reasonable grounds specified above. To obtain compounds of the formula I, in which R1is ureido or 3-phenylurea, use the appropriate allerease agent, for example, cyanate, such as an alkali metal cyanate, in particular the sodium cyanate or isocyanate, such as phenylisocyanate. The acylation is usually acceptable inert solvent or diluent as above, at a temperature in the range from -30 to 120oC, typically at ambient temperature.

(f) To obtain compounds of the formula I, in which R1is /1-4C/alkoxy or substituted /1-4C/alkoxy or R1is /1-4C/alkylamino or substituted /1-4C/alkylamino produce alkylation derived hintline formula I, in which F1represents hydroxy or amino group, preferably in the presence of reasonable grounds specified above.

Acceptable alkylating agent is any substance intended for alkylation of the hydroxyl group in the CNS group or substituted Liprimar, in alkylhalogenide or substituted alkylhalogenide, in particular in /1-4C/alkylchloride, bromide or iodide or a substituted /1-4C/alkylchloride, bromide or iodide, in the presence of reasonable grounds specified above, acceptable inert solvent or diluent as above, at a temperature in the range from 10 to 140oC, typically at ambient temperature.

(g) To obtain compounds of the formula I, in which R1represents carboxyl Deputy or Deputy comprising a carboxyl group produced by hydrolysis of the derivative hintline formula I, in which R1is /1-4C/alkoxycarbonyl Deputy or Deputy, include /1-4C/alkoxycarbonyl group.

The hydrolysis can be effected under alkaline conditions, described in the accompanying examples.

(h) To obtain compounds of the formula I, in which R1represents the amino-, hydroxy-, thio - or tiananamen /1-4C/alkyl substituent is interaction derived hintline formula I, in which R1is /1-4C/alkyl substituent, including substituted group above, with the appropriate amine, alcohol, thiol or a cyanide, preferably in pryemlemom inert solvent or diluent, above, at a temperature in the range from 10 to 100oC, typically at ambient temperature.

If necessary, obtain pharmaceutically acceptable salts derived hintline formula I produce the interaction of the compounds with the appropriate acid in accordance with known procedure.

Many mentioned here, the intermediate compounds are new, for example, the compounds of formula II and represent another aspect of the present invention. In addition, some of the original materials intended for use in the variant of method (d) described above, namely the compounds of formula I, in which m represents 2 or 3 and one of the groups R1represents nitro, are not only new, but also active inhibitors of tyrosine kinase receptors. Therefore, these compounds constitute another aspect of the present invention.

As mentioned above, the derived hintline of the present invention possesses anti-cancer action is a consequence of the inhibitory activity of this compound against tyrosinase receptors. These properties can be determined using one or more of the methods below:

(a) the Laboratory is Inez receptors. Tyrosinekinase receptors was obtained in partially purified form from cells A-431 (isolated from cancer of the external female genital organs) using methods described by carpenter and others, J. Biol. Chem. 1979, 254, 4884, Cohen and others, J. Biol, Chem. , 1982, 257, 1523 and brown and others, J. Biol, Chem., 1984, 259, 2051.

Cells A-431 were grown until confluence in a modified method of Dulbecco environment Needle (DMEM) containing 5% fetal calf serum (FCS). The obtained cells are homogenized in hypotonic buffer containing borate and ethylenediaminetetraacetic acid, with a pH of 10.1. The homogenate was centrifuged with a gradient of 400 for 10 minutes at a temperature of 0-4oC. the Supernatant was centrifuged with a gradient equal to 25000, for 30 minutes at a temperature of 0-4oC. Precipitated material suspended in 30 mmol buffer HEPES with a pH of 7.4, containing 5% glycerol, 4 mmole of benzamidine and 1% Triton X-100, stirred for 1 hour at a temperature of 0-4oC and again centrifuged with a gradient equal to 100000 for 1 hour at a temperature of 0-4oC. the Supernatant containing tyrosinekinase receptors in dissolved form, kept in liquid nitrogen.

When tested 40 μl of thus obtained of rest, ,1% Triton X-100, 10% glycerol, 200 μl water, 80 μl of 25 mmol of dithiothreitol and 80 μl of a mixture of 12.5 mmol of chloride of manganese, 125 mmol of magnesium chloride and distilled water. Thus was obtained a solution of the enzyme that is designed to test.

Each test compound was dissolved in dimethyl sulfoxide (DMSO), resulting in 50 mmol of a solution, which was diluted in 50 mmol buffer HEPES, containing 0.1% Triton X-100, 10% glycerol and 10% dimethyl sulfoxide, with the formation of 500 mcmole solution. Mixed equal volumes of this solution and of a solution of growth factor epidermal (EGF, 20 μg/ml).

[-32P]ATP /3000 Ci/mmol, 250 MK Ci/ was diluted to a volume equal to 2 ml by the addition of a solution of adenosine-5'-triphosphate (100 mcmole) in distilled water. Added an equal volume of 4 mg/ml solution of the peptide Arg-Arg-Leu-IIe-Glu-ASp-Ala-GIu-Tyr-Ala-Ala-Arg-GIy in a mixture of 40 mmol buffer HEPES with a pH of 7.4, 0.1% of Triton X-100 and 10% glycerol.

The solution mixture of the test compound and the growth factor of the epidermis (5 ml) was added to the enzyme solution (10 μl) and incubated the mixture at a temperature of 0-4oC for 30 minutes. Was added a mixture of adenosine-5'-triphosphate (ATP) and peptide (10 μl), and then incubated the mixture at OI acid (40 ml) and bovine serum albumin (BSA; 1 mg/ml, 5 μl). This mixture was left to set for 30 minutes at a temperature of 4oC, and then centrifuged. An aliquot (40 μl) of the supernatant liquid was placed on a strip phosphocellulose paper Whatman p-81". This strip was washed in 75 mmol of phosphoric acid (4x10 ml) and blotted to dry. The radioactivity of the filter paper was measured using a liquid scintillation counter (sequence A). Sequence reactions were repeated in the absence of growth factor epithelium (sequence B) and again in the absence of the test compounds (reaction sequence (C).

Inhibition of tyrosine kinase (RTK) receptors was calculated as follows:

< / BR>
The degree of inhibition was then determined depending on the concentrations of the test compounds with the goal of establishing a concentration of 50% inhibition (IC50mm).

(b) Laboratory analysis in order to determine the ability of the test compound in relation to inhibition of cell growth of nasopharyngeal cancer line KB.

The KB cells were sown in holes with a density of 1104-1,5104cells per well and grown for 24 hours in modified according to the method of Dolbec elali after incubation for 3 days according to the degree of metabolism tetrazolium dye MTT with the formation of a bluish color. Then cell growth was determined in the presence of the growth factor of the epidermis (100 ng/ml) or in the presence of the growth factor of the epidermis (100 ng/ml) and test compounds at various concentrations. Then we calculated the value of the concentration of 50% inhibition (IC50).

(c) Analysis of in vivo produced in relation to groups of male rats, which allows to determine the ability of the test compound (usually introduced orally in the form of ground in a ball mill, a suspension in 0.5% Polysorbate) to inhibit the growth of hepatocytes caused by the introduction of a growth factor (TGFa (injected subcutaneously in the amount of 400 mg/kg usually twice at 3 and 7 hours after administration of the test compound).

In the control group of rats introduction TGFa caused on average 5-fold stimulation of growth repetita.

Growth of cells in control and experimental animals was determined as follows.

The next morning, after administration of the test compounds (or 0.5% Polysorbate in the control group) animals were injected with bromodeoxyuridine (BrdU; administered intraperitoneally at 100 mg/kg). Four hours later the animals were killed and removed their liver. Did sections of each liver was determined absorption is 268 article, Goldsworthy and other in the book "cell Proliferation caused by chemicals: Assessment of risk factors", Wiley-Liss, Inc. 1991, pages 253-284.

Subsequent tests were made using different doses of the tested compounds with the aim of determining the dose of the agent, resulting in 50% increase effect. (ED50) in the inhibition of proliferation of hepatocytes, based on studies of slowing the absorption of BrdU.

Although the pharmacological properties of the compounds of formula 1 are changed depending on changes in the structure, activity, inherent in the compounds of formula I, may be demonstrated at the following concentrations or doses in the execution of one or more of the above tests (a), (b) and (c);

Test (a): IC50achieved in the dosing interval of 0.0005 - 1 μm

Test (b): IC50achieved in the dosing interval of 0.01-10 μm

Test (s): ED50achieved in the dosing interval 1-100 mg/kg

So, for example, 6,7-dimethoxy-4-/3'-methylaniline/-hintline was obtained the value of the IC50equal to 0.005 mcmole, in test (a), the value of the IC50equal to 0.05 µm in test (b) and the value of the ED50< 5 mg/kg in test (c); 6,7-dimethoxy-4-/3'-triptoreline/chinasol test (b); 6-amino-4-/3'-methylaniline/hintline was obtained the value of the IC50equal to 0.055 of µm in test (a), the value of the IC50equal to 1 µm in test (b) and the value of the ED50< 5 mg/kg in test (c); 6-acetamido-4-/3'-methylaniline/hintline was obtained the value of the IC50equal to 0.01 µm in test (a) and the value of the IC50equal to 0.65 µm in test (b); 7-/2-hydroxyethoxy/6-methoxy-4-/3'-methylaniline/ hintline was obtained the value of the IC50equal to 0.005 µm in test (a) and the value of the IC50equal to 0.14 µm in test (b).

As mentioned above, the compound 4-aniline-6,7-dimethoxyquinazoline is known and has bronchodilators or anti-hypertensive properties. There is no indication that other derivatives hintline, excluded from the scope of the present invention possess pharmacological properties.

In accordance with another aspect of the present invention provides a pharmaceutical composition comprising a derivative of hintline formula I or its pharmaceutically acceptable salt, above, or derived hintline selected from 4-/4'-hydroxyimino/-6-methoxyquinazoline, 4-/4'-hydroxyimino/-6,7-methylenedioxyaniline, is noinline/hintline and 4-aniline-6-methylinosine or chloride-hydrogen salt, together with a pharmaceutically acceptable diluent or carrier.

This composition may be in the form acceptable for oral administration, for example, in the form of a tablet or capsule, for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular injection or infusion) as a sterile solution, suspension or emulsion, for topical application in the form of ointment or cream or for rectal administration in the form of a suppository.

The above compounds can be produced by known methods using conventional fillers.

Hinzelin usually do a warm-blooded animal in the form of a uniform dose component 5-5000 mg per square meter of body size specified animal, i.e. approximately 0.1-100 mg/kg, and this number is typically a therapeutically effective dose. Uniform dosage form such as tablet or capsule, usually contains about 1-250 mg of the active ingredient. The preferred daily dose, part of 1-50 mg/kg, However, the daily dose usually varies depending on the condition of the patient, the route of administration and the severity of the disease to be treated. The optimal dose is determined by the treating physician.

We have found that compounds of the present invention and compounds excluded from the scope of the present invention possess anti-cancer properties, which are the result of an inhibitory effect against tyrosine kinase receptors.

In accordance with this aspect of the present invention provides for the use of the derived hintline formula I or its pharmaceutically acceptable salts listed above, or derived hintline selected from 4-/4'-hydroxyimino/-6-methoxyquinazoline, 4-/4'-hydroxyimino/-6,7-methylenedioxybenzene, 4-/4'-hydroxyimino/-6,7,8-trimethoxyaniline, 6-amino-4-/4'-aminoaniline/-hintline, 4-aniline-6-methylinosine or chloride-hydrogen salt, for the manufacture of a medicinal product intended for the treatment of cancer such a warm-blooded animal, such as man.

In accordance with another aspect of the present invention provides a way to achieve anti-cancer action in warm-blooded animal, such as man, in need of such treatment, which includes the introduction of specified animal is SHL, necessary for the prevention or treatment of a particular cancer will vary depending on the condition of the patient, method of selection and the severity of the disease. A uniform dose is usually 1-100 mg/kg, preferably 1-50 mg/kg

Cancer treatment, discussed above, can only be derived hintline according to the present invention may optionally include the use of one or more other anti-cancer funds, which represent, for example, mitotic inhibitors, in particular, vinblastine; alkylating funds, in particular, CIS-Platin, carboplatin and cyclophosphamide; antimetabolites, in particular 5-fluorouracil, citizenoriented and hydroxyurea, or one of the preferred antimetabolites addressed in the application for the European patent N 239362, such as N-{5-[N-/3,4-dihydro-2-methyl-4-oxoindole-6-ylmethyl/-N-methylamino-2-thenoyl}-L-glutamic acid; intercalating antibiotics such as adriamycin and bleomycin; enzymes, for example asparaginase; topoisomerase inhibitors, in particular etoposide; biological reaction modifiers, for example interferon; and antihormones such as antiestrogens, such as "NOLVA/trifluoromethyl/propionanilide/. Joint treatment may be carried out by simultaneous, sequential or separate introduction of specific drugs used for treatment. In accordance with this aspect of the present invention provides a pharmaceutical agent comprising the derivative hintline formula I, above, or derived hintline selected from 4-/4'-hydroxyimino/-6-methoxyquinazoline, 4-/4'-hydroxyimino/-6,7-methylenedioxyaniline, 6-amino-4-/4'-aminoaniline/hintline, 4-aniline-6-methylinosine or chloride-hydrogen salt and 4 anilino-6,7-dimethoxyquinazoline or chloride-hydrogen salt, and additional anti-cancer agent, above, for the joint treatment of cancer.

As mentioned above, the derived hintline of the present invention is an effective anti-cancer activity which is a consequence of the inhibitory effect against tyrosine kinase receptors. It is believed that the derived hintline of the present invention has a wide range of anti-cancer properties, as tyrosinekinase receptors is directly related to many of the cancer, such as is Syria, pancreas and ovary. Thus, it is assumed that the derived hintline of the present invention will possess anticancer activity against these cancers. Moreover, it is expected that hinzelin of the present invention have activity against several leukemia, malignant lymphomatosis and solid tumors such as carcinomas and sarcomas in tissues such as liver, kidney, prostate and pancreas.

The present invention is further illustrated by the following examples do not limit the invention in which, if no special instructions:

(1) evaporation produced by rotary evaporation under vacuum, and the processing was carried out after removal of residual solids such as drying by filtration;

(II) all operations were performed at ambient temperature, i.e. in the interval from 18 to 25oC, in an atmosphere of inert gas such as argon;

(III) chromatography on columns (in accordance with evaporatively) and liquid medium pressure chromatography (MPLC) was performed on silica gel Merck Kieselgel (N 9385) or on silica gel with reversed phase Merck likr what I illustration and do not necessarily represent the maximum value;

(V) the melting temperature was not adjusted and was determined using the instrument for automatic measurement of the melting temperature "by Mettler SP62, the device with oil bath or appliance with a heating plate Koffler;

(VI) the structures of the final products of formula I was determined by spectroscopy nuclear magnetic resonance (NMR) (usually proton) and mass spectrometry; the magnitude of the chemical shift for spectroscopy proton nuclear magnetic resonance was measured on a scale chemical shifts multipletness peaks were shown as follows: s, singlet; D., doublet; so, triplet; m , multiplet;

(VII) intermediate compounds is not fully characterised and purity was determined using thin-layer chromatography (TLC) analysis, infrared spectroscopy (IR) or nuclear magnetic resonance;

(VIII) used the following abbreviations:

DMF N,N-dimethylformamide,

DMA N,N-dimethylacetamide,

THF tetrahydrofuran.

Example 1.

A mixture of 4-chloro-6,7-dimethoxyquinazoline (0.3 g), 3-methylaniline (0,143 g) and isopropanol (5 ml) was stirred and heated to boiling point under reflux for 1 h the mixture was cooled to a temperature ackim was obtained chloride-hydrogen salt of 6,7-dimethoxy-4-/3'-methylaniline/hintline (0,226 g, 51%), melting point 248-249oC.

An NMR spectrum: (CD3SOCD3) a 2.36(s, 3H), 3,99(s, 3H), was 4.02(s, 3H), 7,13(d, 1H), 7,38(s, 1H), 7,39(t, 1H), 7,49(s, 2H), 8.34 per(s, 1H), 8,80(s, 1H).

Elemental analysis:

found: C 61,4, H 5,4, N 12,5

calculated for C17H13N3O2HCl: C 61,4, H 5,4; N 12,7%

4-Chloro-6,7-dimethoxyquinazolin used as starting material was prepared as follows:

A mixture of 4,5-dimethoxyaniline acid (19.7 g) and formamide (10 ml) was stirred and heated to a temperature of 190oC for 5 hours. This mixture was cooled to 80oC was added water (50 ml). The resulting mixture was stirred at ambient temperature for 3 hours. The precipitate was separated, washed with water and dried. Thus there was obtained 6,7-dimethoxyquinazolin-4-one (3,65 g).

A mixture of a portion (of 2.06 g) of the material so obtained, thionyl chloride (20 ml) and N,N-dimethylformamide (1 drop) was stirred and heated to boiling point under reflux for 2 hours. The resulting mixture was evaporated, and the residue was distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase is washed with water, dried (MgSO4) and evaporated. The residue was purified by HRO is her polarity. Thus was obtained the target source material (0.6 g, 27%).

Example 2.

Perform the procedure described in example 1, except that instead of 3-methylaniline used the appropriate aniline instead of 4-chloro-6,7-dimethoxyquinazoline used the corresponding substituted 4-chlorination. Thus in the form of chloride-hydrogen salts were obtained the compounds described in table I, according to the structures of which were confirmed by spectroscopy proton nuclear magnetic resonance and elemental analysis.

Notes to the table. I:

a. For this product the following results were obtained elemental analysis:

found: C 48,3, H 3,6, N 10,4

calculated for C16H14BrN3O2HCl: C 48,4, H 3,8, N 10,6%.

and the following data of the NMR spectrum: (CD3SOCD3) 4,0 (s, 3H), 4,22(s, 3H), of 7.36(s, 1H), 7.5(m, 2H), 7,76(m, 1H), 8,02(m, 1H), 8,35(s, 1H), 8,66(s, 1H).

b. For this product the following results were obtained elemental analysis:

found: C, 60,3, H 4,3, N 13,3

calculated for C16H13N3O21,08 HCl: C 60,2, H 4,4, N 13,2%.

and the following data of the NMR spectrum (CD3SOCD3) a 2.36 (s, 3H), 6,37(s, 2H), 7,13(d, 2H), 7,35(m, 1H), 7,37(s, 1H), 7,49(m, 2H), 8,28(s, 1H), 8,78(s, 1H).

santaniello acid using the same methods, described in example 1 on obtaining raw materials.

c. 4-Chloro-7-methoxyquinazoline used as starting material, was obtained from 4-methoxyestradiol acid using the same methods described in example 1 on obtaining raw materials.

d. The reaction mixture was heated to boiling point under reflux for 2 hours. Upon cooling the mixture to room temperature, there was no precipitation. This mixture was poured into water (50 ml) was added dropwise a saturated aqueous solution of ammonium hydroxide. The precipitate was separated, washed with water and dried. Thus there was obtained 7-methoxycarbonyl-4-/3'-methylaniline/hinzelin, the output of which amounted to 47%.

For this product there were obtained the following results of elemental analysis:

found: C 69,8, H 5,2, N 13,9

calculated for C17H15N3O2: C 69,6, H 5,2, N 14,3%.

and the following characteristic data of the NMR spectrum: (CD3SOCD3) a 2.36(s, 3H), of 3.95(s,3H), 6,98(d,1H), 7,29(m,1H), to 7.67(m,2H), 8,08(m,1H), 8,29(d,1H), 8,68(s,1H), to 8.70(s,1H).

4-Chloro-7-methoxycarbonylbenzyl used as starting material, was obtained seeduwa raw materials, 4-carboxyanhydride acid (14.2 g) was subjected to interaction with formamide, which allowed us to obtain 7-carboxyaniline-4-one (8.5 g). A mixture of a portion (4 g) of the material so obtained, methanol (40 ml) and concentrated sulfuric acid (2 ml) was stirred and heated to boiling point under reflux for 6 hours. The resulting mixture was cooled to ambient temperature and the precipitate was separated. Thus there was obtained 7-methoxycarbonylmethyl-4-one (5.7 g).

A mixture of a portion (0.5 g) of the material so obtained, phosphorylchloride (2 ml) and N,N-dimethylformamide (1 drop) was stirred and heated to boiling point under reflux for 2 hours. The resulting mixture was evaporated with the formation of 4-chloro-7-methoxycarbonylmethylene, which was used without further purification.

Example 3

A mixture of 4-chloro-6-methylinosine (0.5 g), 3-methylaniline (0.33 g) and isopropanol (10 ml) was stirred and heated to boiling point under reflux for 1 hour. The resulting mixture was cooled to ambient temperature. The precipitate was filtered and washed with cold isopropanol and simple diethyl ether. Was thus obtained 6-methyl-4-/3'-methyl is 8 (c, 3H), 2.57 m (c, 3H), 7,1 - 8,0 (m, 6H), 8,77 (s, 1H), 8,88 (c, 1H).

Elemental analysis:

found: C 67,0, H 5,5, N 14,5

calculated for C16H15N3HCl: C 67,2, H 5,6, N 14,7%.

4-Chloro-6-methylpyrazole used as starting material was prepared as follows:

A mixture of 6-methylpyrazole-4-it (10 g, J. Med.Chem. 1989, 32, 847), phosphorylchloride (12.5 ml), N,N-dimethylaniline (14,25 ml) and toluene (150 ml) was stirred and heated to boiling point under reflux for 2.5 hours. This mixture was poured on ice, the organic layer was separated, washed with water, dried (MgSO4) and evaporated. Thus was obtained the target source material in the form of a solid (10.4 g, 93%) which was used without further purification.

Example 4

A mixture of 7-methoxy-4-/3'-methylaniline/hintline (0,106 g), ethanolate sodium (0,336 g) and N,N-dimethylformamide (5 ml) was stirred and heated to a temperature of 140oC for 4 hours. The resulting mixture was evaporated, and the residue was purified by chromatography on columns using as eluent a mixture of water, methanol and triperoxonane acid with a volume ratio of 45: 55:0,2. Thus there was obtained 7-hydroxy-4-/3 methylaniline/hinzelin (0,068 g, 41%), temperature 5H13N3O1,4 CF3CO2H: C 52,0, H 3,5, N 10,2%.

Example 5

In accordance with the procedure described in example 4 6,7-dimethoxy-4-/3'-chloroanilino/hinzelin were subjected to interaction with acantilados sodium, which allowed us to obtain 6,7-dihydroxy-4-/3'-chloroanilino/hinzelin, the output of which amounted to 68%, melting point 233 - 235oC.

Elemental analysis:

found: C 46,3 H 2,7, N, 10,0

calculated for C14H10CIN3O21.18 CF3CO2H: C 46,6 H 2,7, N 10,0%

Example 6

Perform the procedure described in example 1, except that instead of 3-methylaniline used the appropriate aniline instead of 4-chloro-6,7-dimethoxyquinazoline used the corresponding substituted 4-chlorination. Thus in the form of chloride-hydrogen salts were obtained the compounds described in table II, according to the structures of which were confirmed by spectroscopy proton nuclear magnetic resonance and elemental analysis.

Notes to the table. II.

A. For this product the following results were obtained elemental analysis:

found: C 52,9, H, 4,0, N 10,6

calculated for C17H14F3N3O20,1(CH3)2CHOH: C 53,0, H, 4,0,, 1H), to 7.64 (d, 1H), 7,73 (t, 1H), of 8.09 (d, 1H), 8,16 (s, 1H), 8,39 (s, 1H), 8,89 (s, 1H), 11,59 (broad singlet, 1H).

b. For this product the following results were obtained elemental analysis:

found: C 50,3, H 3,7, N 9,9

calculated for C17H13F4N3O25EtOH: C 50,7, H 3,6, N 9.9% and the following characteristic data of the NMR spectrum: (CD3SOCD3) 4,0 (s, 3H), a 4.03 (s, 3H), 7,37 (s, 1H), 7,65 (t, 1H), 8,1 - of 8.25 (m, 2H), 8,44 (s, 1H), 8,89 (s, 1H), 11,76 (s, 1H).

c. This product originally obtained in the form of chloride-hydrogen salt, as follows transformed into the corresponding free base. This salt was distributed between ethyl acetate and 1 N. aqueous sodium hydroxide solution. The organic phase was washed with brine, dried (MgSO4) and evaporated. The resulting material was ground to a powder under a layer of ethyl acetate. Thus was obtained target free base, melting point 227 - 230oC.

An NMR spectrum: (CD3SOCD3) of 3.94 (s, 3H), 3,98 (s, 3H), 7,16 - 7,25 (m, 3H), of 7.7 to 7.8 (m, 3H), 8,40 (s, 1H), and 9.5 (s, 1H).

Elemental analysis:

found: C 64,1, H 4,7, N 13,8

calculated for C16H14FN3O2: C 64,2, H 4,7, N 14,0%.

d. To the reaction mixture was added two equivalents of triethylamine, and then p is waited until the ambient temperature and distributed between methylene chloride and water. The organic phase was dried (MgSO4) and evaporated. The residue was recrystallized from isopropanol with the formation of the target product.

e. For this product the following results were obtained elemental analysis:

found: C 70,7, H 6,3, N 14,3

Calculated for C17H17N30,7 HCl: C 70,7, H X 6.15, N Of 14.5%. and the following characteristic data of the NMR spectrum: (CD2SOCD3) a 2.36 (s, 3H), of 2.5 (s, 6H), and 7.1 to 7.7 (m, 5H), 8,56 (s, 1H), 8,77 (s, 1H),

4-Chloro-6,7-dimethylindoline used as starting material, was obtained from 4,5-dimethylacrylate acid (Acta Chemica Scand., 1967, 21, 983) in accordance with the methods described in the portion of example 1 which is concerned with obtaining raw materials.

f. For this product the following results were obtained elemental analysis:

found: C 58,2, H 5,9, N 10,6

calculated for C16H14ClN31,3HCl0,8/CH3/2CHOH: C 58,2, H 5,8, N 11.0% the following characteristic data of the NMR spectrum: (CD3SOCD3) to 2.5 (s, 6H), 7,37 (m, 1H), 7,51 (t, 1H), 7,73 (s, 1H), 7,78 (m, 1H), of 7.96 (t, 1H), total of 8.74 (m, 1H), of 8.92 (s, 1H), and 11.5 (Broad singlet, 1H).

g. For this product the following results were obtained elemental analysis:

found: C 41,4, H 3,4, N 9,1

calculated for C16H) of 2.38 (s, 3H), 7,18 (d, 1H), 7,40 (t, 1H), 7,49 (m, 2H), 7,51 (s, 1H), 7,94 (d, 1H), 8,29 (m, 1H), 8,91 (s, 1H), 9,10 (d, 1H), 11,7 (s, 1H).

4-Chloro-6-dibromodiphenyl used as starting material was prepared as follows:

A mixture of 4-chloro-6-methylinosine (7,3 g) (obtained as the result of the interaction of 6-methyl-4-oxo-3,4-dihydroquinazolin (application for European patent N 86304148.9) with thionyl chloride), N-bromosuccinimide (7,32 g), dibenzoylperoxide (0.1 g) and carbon tetrachloride (200 ml) was stirred and heated to boiling point under reflux for 6 hours. The resulting mixture was evaporated, and the residue was purified by chromatography on columns using as eluent mixtures of methylene chloride and ethyl acetate of increasing polarity. Thus in turn were obtained 4-chloro-6-dibromodiphenyl (0.5 g) and 6-methyl bromide-4-chlorination (4 g).

Example 7

The ammonium formate (3.6 g) was added to a stirred mixture of 4-/3'-methylaniline/-7-nitroquinazoline (4 g), a catalyst comprising 10% palladium charcoal (0.4 g), and ethanol, after which the resulting mixture was stirred at ambient temperature for 3 hours. This mixture was filtered, and the filtrate evaporated. The residue was distributed between metilen. Thus there was obtained 7-amino-4-/3'-methylaniline/hinzelin (3,39 g), melting point 196-197oC.

An NMR spectrum: (CD3SOCD3) 2,32 (s, 3H), 5,96 (broad singlet, 2H), 6,7-6,9 (m, 3H), of 7.23 (t, 1H), 7,6 (m, 2H), 8,21 (d, 1H), scored 8.38 (s, 1H).

Elemental analysis:

found: C 69,1, H 6,8, N, 19,0

calculated for C15H14N4C2H5OH: C 69,1, H 6,8, N 18,9%.

4-/3'-methylaniline/-7-nitroquinazoline used as starting material was prepared as follows:

In accordance with the procedure described in the portion of example 1 which is concerned with obtaining raw materials, 4-nitroanthranilic acid was converted into 4-chloro-7-nitroquinazoline. Perform the procedure described in example 1, except that the reagents were stirred together at ambient temperature for 20 minutes, 4-chloro-7-nitroquinazoline were subjected to interaction with 3-methyl-aniline production, which allowed us to obtain 4-/3'-methylaniline/-7-nitroquinazoline.

Example 8

In accordance with the procedure described in example 7, had been recovered 4-/3'-methylaniline/-6-nitroquinazoline with the formation of 6-amino-4-/3'-methylaniline/hintline, the output of which accounted for 43%, the melting point of 205-206oC.

the fair analysis:

found: C 71,7, H 5,7, N 22,4

calculated for C15H14N4: 72,0 C, H 5,6, N 22,4%.

4-/3'-methylaniline/-6-nitroquinazoline used as starting material was prepared as follows:

In accordance with the procedure described in the first paragraph of the portion of example 1 which is concerned with obtaining raw materials, 5-nitroanthranilic acid were subjected to interaction with formamide, which allowed us to obtain 6-nitroquinazoline-4-one, the output of which amounted to 82%, melting point 268-271oC.

A mixture of 6-nitroquinazoline-4-it (10 g), pentachloride phosphorus (16.4 g) and phosphorylchloride (20 ml) was heated to boiling point under reflux for 2 hours. The resulting mixture was cooled to ambient temperature and was added hexane (700 ml). This mixture was stood at 0oC for 16 hours. The precipitate was separated and distributed between chloroform (700 ml) and water (550 ml). The aqueous layer was podslushivaet adding 2 N. aqueous sodium hydroxide solution and was extracted with chloroform (CH ml). The combined organic solutions were dried (MgSO4) and evaporated. Was thus obtained 4-chloro-6-nitroquinazoline (1.6 g) which was used without further purification.

To see what camping was stirred and heated to boiling point under reflux for 2 hours. This mixture was cooled to ambient temperature and evaporated. The residue was purified by chromatography on columns using as eluent mixtures of hexane and ethyl acetate of increasing polarity. Thus was obtained an oil which hardened when crushed under a layer of simple mixture of diethyl ether and isopropanol. The result was obtained 4-/3'-methylaniline/-6-nitroquinazoline (0.09 g, 26%), melting point 248-249oC.

Mass spectrum: (P+1) m/e 281.

Elemental analysis:

found: C 64,0, H 4.5, N 18,6

calculated for C15H12N4O20,25/CH3/2CHOH: C 64,1, H 4,8, N 18,9%.

Example 9

In accordance with the procedure described in example 7, had been recovered 4-/3'-chloroanilino/-6-nitroquinazoline, which allowed us to obtain 6-amino-4-/3'-chloroanilino/hinzelin, the output of which amounted to 18% of the melting point of >150oC (decomposes).

An NMR spectrum: (CD3SOCD3) 7,27 (m, 1H), 7,39 (d, 1H), 7,45 (m, 2H), 7,66 (d, 1H), 7,74 (d, 1H), 7,97 (t, 1H), at 8.60 (s, 1H).

Elemental analysis:

found: C is 56.4, H 4.5, N 18,4

calculated for C14H11ClN40,5 HCl 0.5 H2O: C OF 56.4, H 4.2, N 18,8%.

4-/3'-Chloroanilino/-6-nitroquinazoline used eredi was added to a stirred mixture of 4-chloro-6-nitroquinazoline (5 g) and isopropanol (40 ml). The resulting mixture was stirred and heated to a temperature of 80oC for 1 hour. This mixture was cooled to ambient temperature, the precipitate was separated and washed simple diethyl ether. Thus was obtained the target source material (5,09 g). Melting point 272-274oC.

Example 10

In accordance with the procedure described in example 7, had been recovered 6-nitro-4-/3'-cryptomelane/hintline, which allowed us to obtain 6-amino-4-/3'-triptoreline/hinzelin, the output of which amounted to 38%, melting point 190-192oC.

An NMR spectrum: (CD3SOCD3) to 5.7 (broad singlet, 2H), 7,28 (m, 1H), 7,38 (d, 1H), 7,40 (d, 1H), 7,6 (m, 2H), 8,23 (d, 1H), 8,35 (s, 1H), 8,42 (s, 1H).

Elemental analysis:

found: C 57,4, H 3,6, N 17,6

calculated for C15H11F3N40.5 H2O: C OF 57.5, H 3,8, N 17,9%.

6-Nitro-4-/3'-cryptomelane/hinzelin used as starting material was prepared as follows:

The triethylamine (of 3.46 g) and 3-triptorelin (of 3.46 g) were added to a stirred mixture of 4-chloro-6-nitroquinazoline (4.5 g) and isopropanol (30 ml). The resulting mixture was heated up to 80oC for 1 hour. This mixture was cooled to a temperature ochrogaster was purified by chromatography on columns using as eluent mixtures of methylene chloride and ethyl acetate of increasing polarity. Thus was obtained the target source material (1,76 g), melting point 206-207oC.

Example 11

Acetic anhydride (0,204 g) was added to a stirred solution of 6-amino-4-/3'-methylaniline/hintline (0.5 g) in N,N-dimethylacetamide (5 ml), after which the mixture was stirred at ambient temperature for 24 hours. The resulting mixture was evaporated, and the residue was recrystallized from a mixture of isopropanol, acetone and water with a ratio of 4:1:2. Was thus obtained 6-acetamido-4-/3'-methylaniline/hinzelin (0,413 g).

An NMR spectrum: (CD3SOCD3) a 2.12 (s, 3H), of 2.33 (s, 3H), 6,93 (d, 1H), 7,28 (m, 1H), 7,6 (m, 2H), 7,73 (d, 1H), to 7.84 (m, 1H), 8,49 (s, 1H), 8,64 (d, 1H), 9,68 (s, 1H).

Elemental analysis:

found: C 69,6, H 5,5, N 19,1

calculated for C17H16N4O: C 69,8, H 5,5, N 19,2%.

Example 12

In accordance with the procedure described in example 11, 6-amino-4-/3'-chloroanilino/hinzelin were subjected to interaction with acetic anhydride, which allowed us to obtain 6-acetamido-4-/3'-chloroanilino/hinzelin, the output of which amounted to 50%, melting point 260-262oC.

An NMR spectrum: (CD3SOCD3) to 2.13 (s, 3H), 7,13 (m, 1H), 7,39 (t, 1H), and 7.8 (m, 3H), 8,03 (s, 1H), 8,56 (s, 1H), 8,66 (d, 1H), 9,87 (broad singlet, 1H), 10,24 (wide Singh is>O: C 61,4, H 4.2, N 17,9%.

Example 13

2-Methoxyacetanilide (0,094 g) was added to a stirred solution of 7-amino-4-/3'-methylaniline/-hintline (0,206 g) in N,N - dimethylacetamide (4 ml). The resulting mixture was stirred and heated to 100oC for 1 hour. This mixture was cooled to ambient temperature and was poured into a mixture of methylene chloride and water. The mixture was podslushivaet to pH 9 by adding a diluted aqueous solution of sodium hydroxide. The organic layer was dried (MgSO4) and evaporated. The residue was purified by chromatography on columns using as eluent first mixture of methylene chloride and ethanol with a ratio of 100: 1, and then mixtures of methylene chloride and ethanol with increasing polarity. Thus there was obtained 7-/2-methoxyacetate/-4-/3'-methylaniline/hintline (of 0.085 g), melting point 222oC.

An NMR spectrum: (CD3SOCD3) was 2.34 (s, 3H), 3,42 (s, 3H), 4,08 (s, 2H), 6,9 - 7,9 (m, 4H), 8,21 (d, 1H), 8,48 (d, 1H), charged 8.52 (s, 1H), and 9.6 (s, 1H), 10,2 (s, 1H).

Elemental analysis:

found: C 66,6, H 5,6, N 17,0

calculated for C18H18N4O20,1 H2O: C 66,7 H 5,6, N 17,3%

Example 14

In accordance with the procedure described in example 13, except that the reaction mixture peremeshali interaction with 2-methoxyacetanilide, that allowed us to obtain 6-/2-methoxyacetate/-4-/3'-chloroanilino/hinzelin, the output of which amounted to 41%, melting point 177 - 180oC.

An NMR spectrum: (CD3SOCD3) 3,44 (s, 3H), 4.09 to (s, 2H), 7,17 (m, 1H), 7,44 (t, 1H), 7,8 (m, 2H), 8,0 (m, 2H), 8,61 (s, 1H), 8,71 (d, 1H), 9,9 (C. 1H), of 10.05 (s, 1H).

Elemental analysis:

found: C 59,7, H 4,4 N 16,2

calculated for C18H18N4O2: C 59,6, H 4,4, N 16.3 PER CENT.

Example 15

Benzosulphochloride (0,158 g) was added to a stirred mixture of 7-amino-4-/3'-methylaniline/hintline (0.2 g), triethylamine (0,181 g) and methylene chloride (10 ml), previously cooled to 3oC. the resulting mixture was left to warm to ambient temperature and was stirred for 16 hours. This mixture is evaporated and the residue was purified by chromatography on columns using as eluent mixtures of methylene chloride and ethyl acetate of increasing polarity. Thus there was obtained 7-benzosulfimide-4-/3'-methylaniline/hinzelin (0.05 g), melting point 180 - 185oC (decomposes).

Elemental analysis:

found: C 61,5, H 4,8, N 13,4

calculated for C21H18N4O2S H2O: C 61,7, H 4,4, N 13,7%

Example 16

2-Bromoethanol (0,109 g of the resulting mixture was stirred and heated to 110oC for 1 hour. Periodically added to the remaining portions of 2-bromoethanol (h,109 g), after which the mixture was heated to 10oC for 5 hours the mixture is evaporated and the residue was purified by chromatography on columns using as eluent mixtures of methylene chloride and ethanol with increasing polarity. Thus obtained product was subjected to further purification by chromatography on columns with reversed phase when used as a first eluent mixture of methanol, water and triperoxonane acid with a ratio of 25: 75:0,2, and then a mixture of such solvent with the ratio of 50:50:0,2. Thus there was obtained 7-/2-hydroxyethylamino/-4-/3'-methylaniline/hinzelin (0,027 g).

An NMR spectrum (CD3SOCD3) a 2.36 (s, 3H), of 3.77 (t, 2H), 4,34 (t, 2H), 6,8 - 7,5 (m, 7H), of 8.37 (d, 1H), 8,61 (s, 1H), 10,79 (s, 1H).

Example 17

In accordance with the procedure described in example 16, 6-amino-4-/3'-methylaniline/hinzelin were subjected to interaction with 2-prommetalservis ether, which allowed us to obtain 6-/2-methoxyethylamine/-4-/3'-methylaniline/hinzelin, the output of which amounted to 20%, melting point 163 - 167oC.

An NMR spectrum: (CD3SOCD3+CD3CO2D) 2,39 (s, 3H), on 3.36 (s, 3H), 3,44 (t, 2H), 3,63 (t, 2H), 7,17 18H20N4OCF3CO2H: C 56,8, H, 5,0, N 13,3%

Example 18

In accordance with the procedure described in example 7, had been recovered 7-/3-dimethylaminopropylamine/-4-/3'-methylaniline/ -6-nitroquinazoline, which allowed us to obtain 6-amino-7-/3-dimethylaminopropylamine/-4-/3'-methylaniline/hinzelin, the output of which amounted to 56%, melting point 60 - 66oC.

An NMR spectrum (CD3SOCD3) of 1.84 (m, 2H), 2,28 (s, 6H), is 2.30 (s, 3H), 2,31 (m, 2H), 3,23 (m, 2H), return of 6.58 (s, 1H), for 6.81 (d, 1H), 7,19 (t, 1H), 7,31 (s, 1H), 7,63 (m, 2H), 8,24 (s, 1H).

Elemental analysis:

found: C 66,5, H 7,6, N 22,8

calculated for C20H26N60,66 H2O: C 66,3, H 7,6, N 23,2%.

7-/3-Dimethylaminopropylamine/-4-/3'-methylaniline/-6 - nitroquinazoline used as starting material was prepared as follows:

A mixture of 4-chlorantraniliprole acid (17,2 g) and formamide (10 ml) was stirred and heated to 130oC for 45 minutes and up to 175oC for 75 minutes. The resulting mixture was cooled to 100oC and added 2/2-ethoxyethoxy/ethanol (50 ml). The resulting solution was poured into a mixture (250 ml) of water with ice. The precipitate was separated, washed with water and dried. Thus there was obtained 7-chlorination-4-one (15.3 g, 85%).

A portion (6 g) Paul) and fuming nitric acid (12 ml). The resulting mixture was heated to 110oC for 30 minutes. This mixture was cooled to ambient temperature and poured into ice. The solid was separated, washed with water and dried. Thus there was obtained 7-chloro-6-nitroquinazoline-4-one (6,89 g, 92%).

A mixture of a portion (4 g) thus obtained material, thionyl chloride (30 ml), phosphorylchloride (5 ml) and N,N-dimethylformamide (10 drops) was stirred and heated to boiling point under reflux for 4 hours. The resulting mixture was evaporated. A mixture of the resulting residue, the 3'-methylaniline (1.89 g) and isopropanol (25 ml) was stirred and heated to boiling point under reflux for 2 hours. The resulting mixture was filtered, the solid was washed with isopropanol and simple diethyl ether. Thus there was obtained 7-chloro-4-/3'-methylaniline/-6-nitroquinazoline (3,74 g, 67%), melting point 271 - 274oC.

An NMR spectrum: (CD3SOCD3) is 2.37 (s, 3H), 7,13 (d, 1H), 7,47 (t, 1H), EUR 7.57 (m, 2H), to 8.20 (s, 1H), 8,83 (s, 1H), 9,72 (s, 1H).

3-Dimethylaminopropylamine (2,44 g) was added to a stirred solution of a portion (0.75 g) thus obtained material in N,N-dimethylacetamide (20 ml). This mixture was heated to 70oC for 1 hour and up to 90oC.

An NMR spectrum: (CD3SOCD3) to 1.61 (m, 2H), 2,2 - 2,3 (3 singlets, 9H), 2,39 (t, 2H), 3,39 (m, 2H), 6,93 (s, 1H), of 6.96 (d, 1H), 7,27 (t, 1H), to 7.61 (s, 1H), 7,63 (d, 1H), at 8.36 (t, 1H), 8,42 (s, 1H), 9,50 (s, 1H), 10,07 (broad singlet, 1H).

Example 19

A mixture of 6,7-dimethoxy-4-/3'-methylaniline/hintline (4 g), ethanolate sodium (9,8 g) and N,N-dimethylformamide (100 ml) was stirred and heated to 80oC for 6 hours. The mixture was cooled and poured into a mixture of ethyl acetate with water. This mixture was acidified to pH 7, was added a dilute aqueous solution of chloride-hydrogen acid. The organic phase was dried (MgSO4) and evaporated. The residue was purified by chromatography on columns using as eluent mixtures of methylene chloride and methanol with increasing polarity. The oil obtained was ground under a layer of simple diethyl ether with the formation of solids. Thus there was obtained 7-hydroxy-6-methoxy-4-/3'-methylaniline/hinzelin (1,02 g), melting point 139 - 14 is, 1H), 8,39 (s, 1H), 9,34 (broad singlet, 1H).

Elemental analysis:

found: C 66,5, H 5,7, N 13,7

calculated for C16H15N3O20,15 Et2O0,5 H2O: C 66,3, H 5,5, N, 14,0.

Example 20

A mixture of 6,7-dimethoxy-4-/3'-methylaniline/hintline (4 g), ethanolate sodium (9,8 g) and N,N-dimethylformamide (100 ml) was stirred and heated to 80oC for 3 hours. The resulting mixture was cooled to ambient temperature and acidified to pH 4 by adding glacial acetic acid. The mixture is evaporated and the residue was purified by chromatography on columns using as eluent mixtures of methylene chloride and methanol with increasing polarity. Was thus obtained 6-hydroxy-7-methoxy-4-/3'-methylaniline/hinzelin (0.3 g), melting point 265 - 267oC.

An NMR spectrum: (CD3SOCD3) 2,32 (s, 3H), of 3.97 (s, 3H), 6.90 to (m, 1H), 7,15 - 7,30 (m, 2H), 7,66 (m, 2H), 7,80 (s, 1H), to 8.41 (s, 1H), 9,24 (broad singlet, 1H), at 9.53 (broad singlet, 1H).

Elemental analysis:

found: C 65,2, H 5,2, N, 14,0

calculated for C16H15N3O20,67 H2O: C 65,5, H 5,6, N 14,3%

Example 21

Ethylbromoacetate (0,033 g) was added dropwise to a stirred mixture of 7-hydroxy-6-methoxy-4-/3'-methylaniline/gynazole (0,0 is her medium for 1 hour. The mixture is evaporated and the residue was purified by chromatography on columns using as eluent mixtures of methylene chloride and ethyl acetate of increasing polarity. Thus there was obtained 7-/ethoxycarbonylmethoxy/-6-methoxy-4-/3'-methylaniline/-hinzelin (0,051 g), melting point 165 - 168oC.

An NMR spectrum: (CD3SOCD3) to 1.24 (t, 3H), of 2.35 (s, 3H), 3,99 (s, 3H), 4,99 (square, 2H), 4,33 (s, 2H), 6,9 - 7,9 (m, 6H), 8,43 (s, 1H), 9,40 (s, 1H).

Elemental analysis:

found: C 64,8, H 5,9, N 10,9

calculated for C20H21N3O40,2 H2O: C 64,7, H 5,8, N 11.3 PER CENT.

Example 22

Perform the procedure described in example 21, except that instead of ethylbromoacetate used 2-todatetime. Thus there was obtained 7-/carbamoylphenoxy/6-methoxy-4-/3'-methylaniline/hinzelin, the output of which was 91%, melting point 214 - 222oC.

An NMR spectrum: (CD3SOCD3) to 2.35 (s, 3H), 3,99 (s, 3H) and 4.65 (s, 2H), 6,9 - 7,9 (m, 6H), to 8.45 (s, 1H).

Elemental analysis:

found: C 47,8, H is 4.9, N 11,9

calculated for C18H18N4O30,1 HI: C 47,5, H 4,8, N 12,3%

Example 23

A mixture of 7-hydroxy-6-methoxy-4-/3'-methylaniline/hinzelin (0,556 g), 2-bromoethanol (0,153 g), potassium carbonate (0,819 g)imali by chromatography on columns using as eluent mixtures of ethyl acetate and methanol with a ratio of 19 : 1. The obtained product was subjected to further purification by chromatography with reversed phase, using as eluent a mixture of ethanol, water and triperoxonane acid with a ratio of 50 : 50 : 0,2. Thus there was obtained 7-/2-hydroxyethoxy/-6-methoxy-4-/3'-methylaniline/hinzelin (0,154 g), melting point 122 - 124oC.

An NMR spectrum: (CD3SOCD3) to 2.35 (m, 3H), 3,81 (m, 2H), of 3.97 (s, 3H), 4,17 (t, 2H), 6,9 - 7,9 (m, 6H), to 8.45 (s, 1H).

Elemental analysis:

found: C 52,9 H 4,9, N 8,7

calculated for C18H19N3O31,1 CF3CO2H 0,5 H2O: C 52,7, H 4,6, N 9,1%

Example 24

Perform the procedure described in example 21, except that instead of ethylbromoacetate used 2-bromatology ether and the reaction mixture was stirred at ambient temperature for 16 hours. Was thus obtained 6-methoxy-7-/2-methoxyethoxy/-4-/3'-methylaniline/hinzelin in the form of a colorless oil. The resulting oil was dissolved in ethyl acetate (2 ml) was added a saturated solution of hydrogen chloride in simple ethyl ether. Thus was obtained chloride-hydrogen salt of the desired product, which was 73%, melting point 211 - 227oC.

The special

Elemental analysis:

found: C 61,2, H, 6,0, N 10,9

calculated for C19H21N3O30,9 HCl: C 61,2, H 5,9, N 11,3%

Example 25

A mixture of 7-/ethoxycarbonylmethoxy/-6-methoxy-4-/3'-methylaniline/hintline (0,262 g), 2 N. aqueous sodium hydroxide solution (2 ml) and 1,4-dioxane (2 ml) was stirred at ambient temperature for 3 hours. The mixture was acidified by adding 2 N. aqueous solution of a chloride-hydrogen acid, after which the acidity was reduced at pH 6 by adding an aqueous solution of ammonium hydroxide. The precipitate was separated and dried. Thus there was obtained 7-/carboxymethoxy/-6-methoxy-4-/3'-methylaniline/hinzelin (strength of 0.159 g), melting point 215 - 222oC.

An NMR spectrum: (CD3SOCD3) was 2.34 (s, 3H), of 3.95 (s, 3H), 4,33 (S., 2H), 6,9 - 7,9 (m, 6H), to 8.41 (S., 1H).

Elemental analysis:

found: C 53,5, H, 5,0, N 10,5

calculated for C18H16NaN3O42,3 H2O: C 53,6, H 5,1, N 10,4%

Example 26

A mixture of 7-/2-hydroxyethoxy/-6-methoxy-4- /3'-methylaniline/hintline (0,23 g), N,N-dimethylformamide (1 drop) and thionyl chloride (5 ml) was heated to boiling point under reflux for 2 hours. The resulting mixture was evaporated.

The residue was dissolved in N, N-DIMETHYLPROPANE to 100oC for 3 hours. The mixture is evaporated and the residue was purified by chromatography on columns with reversed phase, using as eluent a mixture of methanol, water and triperoxonane acid with a ratio of 50:50: 0,2. Thus there was obtained 7-/2-dimethylaminoethoxy/-6-methoxy-4-/3'-methylaniline/hinzelin (0.24 g), melting point 97 - 100oC.

An NMR spectrum: (CD3SOCD3) 2,37 (C., 3H), 2,93 (C., 6H), 3,66 (t, 2H), 3,98 (C., 3H), of 4.57 (t, 2H), of 7.1 - 8.2 (m, 6H), 7,78 (S., 1H), 10,82 (S., 1H).

Elemental analysis:

found: C 46,4 H 4.2, N 8,8%

calculated for C20H24N4O22,6 CF3CO2H: C 46,6, H 4,1, N 8,6%.

Example 27

2-Codetel (0,327 ml) was added to a mixture of 6,7-dihydroxy-4-/3'-methylaniline/hintline (0.534 g), potassium carbonate (1.1 g) and N,N-dimethylacetamide (10 ml). The resulting mixture was stirred at ambient temperature for 18 hours. This mixture is evaporated and the residue was purified by chromatography on columns with reversed phase, using as eluent a mixture of methanol, water and triperoxonane acid with a ratio of 50:50:0,2. Thus there was obtained 6,7-di/2 hydroxyethoxy/-4-/3'-methylaniline/hinzelin (0,049 g), melting point 96 - 102oC.

An NMR spectrum: (CD3 the elemental analysis:

found: C 49,2, H 4.5, N, 7,9

calculated for C19H31N4O41,6 CF3CO2H: C 49,5, H 4.2, N OF 7.8%.

6,7-Dihydroxy-4-/3'-methylaniline/hinzelin used as starting material, was obtained with the achievement of 77% exit 6,7-dimethoxy-4-/3'-methylaniline/hintline in accordance with the procedure described in example 4.

Example 28

A solution of 6-methyl bromide-4-/3'-methylaniline/hintline in N,N-dimethylformamide (3 ml) was saturated with gaseous dimethylamine, after which the resulting solution was stirred at ambient temperature for 16 hours. The resulting mixture was evaporated, and the residue was purified by chromatography on columns using as elution solvent a mixture of methylene chloride and methanol with a ratio of 17 : 3. The resulting solid (0,308 g) was subjected to further purification using chromatography on columns with reversed phase, using as eluent a mixture of water, methanol and triperoxonane acid with a ratio of 3:2:0,01. Was thus obtained 6-dimethylaminomethyl-4-/3'-methylaniline/hinzelin (0.172 g), melting point 174 - 177oC.

An NMR spectrum: (CD3SOCD3) 2,35 (C., 3H), 2,85 (C., 6H), 4,47 (S., 2H), between 7.0 and 8.1 (m, 6H), 8,66 (D., 1H), cent to 8.85 (S., 1H).

3CO2H: C 49,2, H 4,1, N 10,2%

Example 29

In accordance with the procedure described in example 28, 6-methyl bromide-4-chlorination were subjected to interaction with 3-methyl-aniline production, after which the resulting product was subjected to interaction with piperazine. Thus there was obtained 4-/3'-methylaniline/-6-/piperazine-1-ylmethyl/hinzelin, the output of which amounted to 45%, melting point 175 - 178oC.

An NMR spectrum: (CD3SOCD3) 2,38 (C., 3H), by 2.73 (m, 4H), 3,17 (m, 4H), 3,86 (S., 2H), and 7.1 to 8.1 (m, 6H), 8,66 (D., 1H), 8,90 (S., 1H).

Elemental analysis:

found: C 43,0, H 3,7, N, 9,0

calculated for C20H23N53,9 CF3CO2H : C 42,0, H 3,5, N, 9,0

Example 30.

In accordance with the procedure described in example 28, 6-methyl bromide-4-chlorination (0.5 g) was subjected to interaction with 3-methyl-aniline production (0,204 g). The mixture of the formed product and the sodium salt of 2-mercaptoethanol (resulting from the interaction of 2-mercaptoethanol (0,38 g) with sodium hydride (60% dispersion in mineral oil, 0.17 g) in N,N-dimethylacetamide (5 ml) was stirred at ambient temperature for 2 hours. This mixture is evaporated and the residue was purified by chromatography on columns with reversed phase, using as elasiticity/-4-/3'-methylaniline/hinzelin (0,38 g), the melting point of 93 - 94oC.

An NMR spectrum: (CD3SOCD3) 2,37 (c. 3H), 2,52 (m, 2H), of 3.56 (m, 2H), 3,98 (S., 2H), and 7.1 to 8.1 (m, 6H), at 8.60 (D., 1H), 8,84 (S., 1H).

Elemental analysis:

found: C 54,1, H 4.5, N 9,3

calculated for C18H19N3OS 1,1 CF3CO2H: C 53,8, H 4.5, N 9,3%.

Example 31

A mixture of 7-methoxycarbonyl-4-/3'-methylaniline/hintline (1.3 g) and 2 N. aqueous sodium hydroxide solution (10 ml) was stirred and heated to 40oC for 4 hours. The resulting mixture was cooled to ambient temperature and acidified to pH 6 by adding glacial acetic acid. The precipitate was separated, washed with water and dried. Thus there was obtained 7-carboxy-4-/3'-methylaniline/hinzelin (1,16 g), melting point > 280oC.

An NMR spectrum: (CD3SOCD3) 2,36 (C., 3H), 6,98 (D., 1H), 7,29 (t, 1H), 7,66 (m , 2H), 8,18 (m, 1H), 8,28 (D., 1H), 8,64 (S., 1H), 8,66 (D., 1H), 9,88 (S., 1H).

Elemental analysis:

found: C 67,3, H 4,8, N 14,8

calculated for C16H13N3O20,3 H2O: C 67,3, H 4,8, N 14,7%

Example 32.

Ethylchloride (0,146 g) and triethylamine (rate £ 0.162 g) were added to a stirred mixture of 7-carboxy-4-/3'-methylaniline/hintline (0.3 g) and tetrahydrofuran (5 ml). This mixture of peremeshivaya ambient temperature for 2 hours. The resulting mixture was acidified, was added 2 N. aqueous solution of chloride-hydrogen acid, and evaporated. The residue was dissolved in water and extracted with methylene chloride. The aqueous phase was podslushivaet to pH 9 by addition of a saturated aqueous solution of ammonium hydroxide and was extracted with ethyl acetate. The organic phase was dried (MgSO4) and evaporated. The residue was purified by chromatography on columns using as eluent mixtures of methylene chloride and methanol with increasing polarity. Thus there was obtained 7-hydroxymethyl-4-/3'-methylaniline/hinzelin (0.125 g), melting point 175 - 177oC.

An NMR spectrum (CD3SOCD3) 2,35 (C., 3H), 4,70 (D., 2H), of 5.45 (t, 1H), of 6.96 (D., 1H), of 7.2 to 7.7 (m, 5H), and 8.50 (S., 1H), 8,57 (S., 1H), for 9.64 (S., 1H).

Elemental analysis:

found: C 72,2, H 5,8, N 15,8

calculated for C16H15N3O: C 72,4, H 5,7, N 15,8%

Example 33

In accordance with the procedure described in example 11, 6-amino-4-/3'-triptoreline/hinzelin were subjected to interaction with acetic anhydride, which allowed us to obtain 6-acetamido-4-/3'-triptoreline/hinzelin, the output of which was 87%, in the form of a solid substance.

An NMR spectrum: (CD3SOCD3) 2,14 (C., 3H), 7,45 (D., 1H), to 7.64 (8,7, H 3,9, N 16,1

calculated for C17H13F3N4O: C 59,0, H 3,8, N 16,5%.

Example 34.

In accordance with the procedure described in example 1, the corresponding substituted 4-chlorination were subjected to interaction with the corresponding aniline, which allowed us to obtain in the form of chloride-hydrogen salts of the compounds listed in table III, according to the structures of which were confirmed by spectroscopy proton nuclear magnetic resonance and elemental analysis.

Notes to the table. III:

A. For this product the following results were obtained elemental analysis:

found: C 63,1, H 5,2, N 13,5

calculated for C16H15N3O 1,1 HCl: C 62,9, H 5,3, N 13,8%

and the following characteristic data of the NMR spectrum (CD3SOCD3) 2,37 (C., 3H), 4,01 (C., 3H), 7,16 (D., 1H), 7,38 (m, 1H), 7,52 (S., 2H), 7,73 (m, 1H), 7,94 (D., 1H), 8,43 (D.,1H), 8,84 (S., 1H), 11,63 (S., 1H).

4-Chloro-6-methoxyquinazoline used as starting material, was obtained from 5-methoxyestradiol acid in accordance with the procedures described in example 1 on obtaining raw materials.

5-Methoxyestradiol acid used as starting material, was prepared as brazomar boiling under reflux for 4 hours. The resulting mixture was evaporated. The resulting substance was added to a solution obtained by adding sodium (15.2 g) to methanol (250 ml). This mixture was heated to boiling point under reflux for 4 hours. The mixture is evaporated, and the residue was distributed with ethyl acetate and water. The organic layer was dried (MgSO4) and evaporated. The residue was purified by chromatography on columns using as eluent mixtures of methylene chloride and methanol with increasing polarity. Thus there was obtained methyl-5-methoxy-2-nitrobenzoate in the form of oil (22,5 g).

The mixture thus obtained material, the catalyst comprising 10% palladium carbon (2.1 g), ethanol (200 ml) and ammonium formate (25,2 g) was stirred and heated to 70oC for 2 hours. The mixture was filtered, and the filtrate evaporated. The residue was distributed between methylene chloride and dilute aqueous sodium bicarbonate solution. The organic layer was dried (MgSO4) and evaporated with the formation of methyl-2-amino-5-methoxybenzoate (15.2 g).

The mixture thus obtained material, 2 N. aqueous sodium hydroxide solution (150 ml) and 1,4-dioxane (50 ml) was stirred and heated to 40oC for 3 hours. The issue is ogorodnoi acid and was extracted with ethyl acetate solution. The organic phase was dried (MgSO4) and evaporated with the formation of 5-methoxyestradiol acid (14.1 g).

b. The reaction mixture was heated to boiling point under reflux for 3 hours. For this product the following results were obtained elemental analysis:

found: C 55,4, H, 4,0, N 12,8

calculated for C15H12ClN3O 1,1 HCl: C 55,2, H, 4,0, N 12,9%

and the following characteristic data of the NMR spectrum: (CD3SOCD3) was 4.02 (SD, 3H), 7,37 (m, 1H), 7,53 (m, 1H), to 7.67 (m, 2H), 7,95 (m, 2H), 8,51 (D., 1H), 8,91 (S., 1H), are 11.62 (S., 1H).

c. As required hintline used 6-acetoxy-4-chlorination and the reaction mixture was heated to boiling point under reflux for 2.5 hours. For this product the following results were obtained

elemental analysis:

found: C 58,6, H 5,3, N 13,4

calculated for C15H13N3O 1HCl 1H2O : C OF 58.9 H 5,2, N 13.7 PERCENT.

and the following characteristic data of the NMR spectrum: (CD3SOCD3) 2,36(C., 3H), 7,14(D. , 1H), was 7.36(t, 1H), 7,41(D., 1H), 7,41(D., 2H), 7,72(m, 1H), of 7.90(D., 1H), 8,07(D., 1H), 8,78(S., 1H), 10,42(S., 1H), 11,22 (..1H).

6-Acetoxy-4-chlorination used as starting material was prepared as follows:

In the Anthranilic acid was converted into 6-hydroxyquinazoline-4-one. To a mixture of 6-hydroxyquinazoline-4-it (2 g), triethylamine (1,37 g) and N,N-dimethylformamide (60 ml) was added dropwise acetic anhydride (1.38 in). The resulting mixture was stirred at ambient temperature for 1 hour. This mixture is evaporated with the formation of 6-acetoxymethyl-4-it, which was subjected to interaction with thionyl chloride according to the procedure described in example 1 on obtaining raw materials.

d. For this product the following results were obtained elemental analysis:

found: C 54,1, H 3,7 N 11,7

calculated for C16H12F3N3O 1HCl: C 54,0 H 3,7 11,8 N%

and the following characteristic data of the NMR spectrum: (CD3SOCD3) 2,37(C., 3H), 7,17(S. , 1H), 7,38(t, 1H), 7,51(D., 2H), 8,07(m, 2H), 8,91(m, 2H), of 11.45(S., 1H).

4-Chloro-6-cryptomaterial used as starting material, was obtained from 5-cryptomaterial acid in accordance with the procedures described in example 1 on obtaining raw materials.

e. The reaction mixture was heated to boiling point under reflux for 2 hours. For this product the following results were obtained elemental analysis:

found: C 5 is isticheskie data of the NMR spectrum: (CD3SOCD3) 4,01(C., 3H), of 4.04(SD,3H), 7,45(S.,1H), to 7.59(t,1H), to 7.84(m,1H), 8,1(m,1H), 8,51(S. ,1H), 8,93(S.,1H), 11,74(S.,1H).

f. The reaction mixture was heated to boiling point under reflux for 2 hours. For this product there were obtained the following characteristic data of the NMR spectrum: (CD3SOCD3) 4,04(C.,3H), 4,08(C.,3H), 7,35(S. , 1H), to $ 7.91(S.,1H), 8,03(D.,1H), 8,18(m,1H), of 8.47(D.,1H), total of 8.74(S., 1H), to 9.93(SD,1H).

g. The reaction mixture was heated to boiling point under reflux for 2 hours. For this product the following results were obtained elemental analysis:

found: C 49,7, H 3,7, N, 11,0

calculated for C16H13Cl2N3O21 HCl: C 49,7, H 3,65, N 10,9%

and the following characteristic data of the NMR spectrum: (CD3SOCD3) 4,01(C., 3H), of 4.04(SD , 3H), of 7.36(S. , 1H), 7,74(m,1H), 7,83(m,1H), 8,17(D.,1H), scored 8.38(S.,1H), 8,19(S.,1H), 11,55(S.,1H).

h. The reaction mixture was heated to boiling point under reflux for 2 hours. For this product the following data were obtained elemental analysis:

found: C 53,1, H 4.2, N 15,3

calculated for C16H14N4O41HCl: C 53,0, H 4.2, N 15.4% and the following characteristic data of the NMR spectrum: (CD3SOCD3) 4,0(C.,3H), of 4.04(SD,3H), 7,37(S. , 1H), of 7.75(t,1H), 8,1 who Tim refrigerator for 3 hours. For this product the following results were obtained elemental analysis:

found: C 59,1 H 5,0, N 12,7

calculated for C16H15N3O21 HCl 0,35 H2O: C 59,3, H 5,2, N, 13,0%

and the following characteristic data of the NMR spectrum: (CD3SOCD3) 3,99(C., 3H), was 4.02(SD , 3H), a 7.1 to 7.6(m,4H), 7.68 per to 7.75(m,2H), 8,43(S.,1H), 8,80(S., 1H).

j. The reaction mixture was heated to boiling point under reflux for 2 hours. For this product the following results were obtained elemental analysis:

found: C 48,3 H 3,5, N 13,5

calculated for C16H13CIN4O41HCl: C 48,4, H 3,5, N 14,1%

and the following characteristic data of the NMR spectrum:(CD3SOCD3) 4,01(C., 3H), 4,05(C. , 3H), 7,34(S. , 1H), 7,86(D. 1H), 7,88(D.,1H), 8,23(m. 1H), 8,48(S.,1H), 8,64(D.,1H), 8,94(S.,1H), 11.87 per(C.,1H).

k. For this product the following results were obtained elemental analysis:

found: C 50,7, H 3,4, N 14,2

calculated for C16H13FN4O41 HCl: C, 50,5, H 3,7, N 14,7%

and the following characteristic data of the NMR spectrum: (CD3SOCD3) 4,0(C., 3H), of 4.04(SD , 3H), 7,40(S. , 1H), 7,71(m,1H), 8,29(m,1H), 8,50(S.,1H), 8,65(m,1H), 8,92(S.,1H), 11,9(broad singlet, 1H).

Example 35

3-Methylaniline (0,123 g) was added dropwise to the mixed nature environment within 2 hours. Added simple diethyl ether (10 ml) and the separated precipitate. Was thus obtained 6-methyl bromide-4-/3'-methylaniline/hinzelin, the output of which amounted to 32%, melting point > 260oC (decomposes).

An NMR spectrum: (CD3SOCD3) 2,37(C.,3H), 4,98(S.,2H), 7,17(D.,1H), 7,39(t, 1H), 7,53(m , 2H), 7,95(D. , 1H), 8,15(m,1H), 8,93(S.,1H), 8,96(d. 1H), 11,59(broad singlet, 1H).

Elemental analysis:

Found: C 56,5, H 4,6, N 12,3

calculated for C16H14BrN30,25 HCl: C 56,9, H 4,3, N Of 12.4%.

6-methyl bromide-4-chlorination used as starting material, was obtained as described in note g to table II of example 6.

Example 36

In accordance with the procedure described in example 7, had been recovered 6,7-dimethoxy-4-/3'-methylaniline/-5-nitroquinazoline, which allowed us to obtain 5-amino-6,7-dimethoxy-4-/3'-methylaniline/hinzelin, which was purified by chromatography on columns using as eluent mixtures of methylene chloride and ethyl acetate of increasing polarity. Thus was obtained the desired product, the yield was 55%, melting point 181-182oC.

An NMR spectrum: (CD3SOCD3) 2,30(C.,3H), 3,70(C.,3H), 3,86(C.,3H), 6,51(S., 1H), 6,86(D.,1H), 7,10(m,2H), 7,19(t, 1H)B>4
O20,15 H2O: C 65,2, H 5,8, N 17,9%.

6,7-Dimethoxy-4-/3'-methylaniline/-5-nitroquinazoline used as starting material was prepared as follows:

6,7-Dimethoxyquinazolin-4-one (10 g) portions was added to a stirred mixture of concentrated sulfuric acid (30 ml) and fuming nitric acid (30 ml), which was pre-cooled to 0oC. the resulting mixture was stirred at ambient temperature for 1 hour. This mixture was poured into a mixture of ice water (500 ml). The precipitate was separated, washed with water and dried. Thus there was obtained 6,7-dimethoxy-5-nitropyrazole-4-one (9,51 g).

In accordance with the procedures described in example 1, the compound obtained was converted to 6,7-dimethoxy-4-/3'-methylaniline/-5-nitroquinazoline, the output of which amounted to 71%, melting point 151-155oC.

An NMR spectrum: (CD3SOCD3) 2,30(C.,3H), 3,86(C.,3H), was 4.02(SD,3H), 6.75 in(m, 2H), 6,88(D.,1H), 7,22(t,1H), 7,28(S.,1H), 7,85(S.,1H).

Example 37

In accordance with the procedure described in example 7, except that the reaction mixture was heated to 70oC for 2 hours, had been recovered 4-/3-methylaniline/ -7-methylthio-6-nitroquinazoline with the formation of 6-amino-4-/3'-methylaniline/-7-MEA mixtures of methylene chloride and ethyl acetate of increasing polarity. Thus was obtained the desired product, which was 22%, melting point 217-218oC.

An NMR spectrum: (CD3SOCD3) 2,33(C.,3H), 2,59(C.,3H), of 5.34(broad singlet, 2H), 6.90 to(doctor , 1H), 7,24(t , 1H), 7,44(c.1H), 7,50(S.,1H), 7,63(S.,2H), of 8.47(S.,1H).

Elemental analysis:

found: C 64,8, H 5,4, N 18,7

calculated for C16H16N4S: C 64,8, H 5,4, N 18,9%

4-/3'-methylaniline/-7-methylthio-6-nitroquinazoline used as starting material was prepared as follows:

A mixture of 4-chlorantraniliprole acid (17,2 g) and formamide (10 ml) was stirred and heated to 130oC for 45 minutes and up to 175oC for 75 minutes. The resulting mixture was cooled to 100oC was added 2-/2-ethoxyethoxy/ethanol (50 ml). The resulting solution was poured into a mixture (250 ml) of water with ice. The precipitate was separated, washed with water and dried. Thus there was obtained 7-chloro-hinzelin-4-one (15.3 g, 85%).

After re-run of this reaction 7-chlorination-4-one (30 g) servings were added to a stirred mixture of concentrated sulfuric acid (60 ml) and fuming nitric acid (60 ml), which was pre-cooled to 0oC. This mixture was stirred at ambient temperature for 1 hour, and then heating the ice (1 l). The precipitate was separated, washed with water and dried. Thus there was obtained 7-chloro-6-nitroquinazoline-4-one (38,1 d).

In accordance with the procedures described in example 1, the resulting material was converted to 7-chloro-4-/3'-methylaniline/-6-nitroquinazoline, the output of which amounted to 59%, melting point 271-274oC.

Portion (0.9 g) thus obtained substance was dissolved in N, N-dimethylacetamide (15 ml). Added meantioned sodium (0,44 g) and the mixture was stirred at ambient temperature for 1 hour. This mixture was acidified by adding glacial acetic acid. The mixture is evaporated and the residue triturated under a layer of methylene chloride. The obtained solid substance was distributed between methylene chloride and dilute aqueous ammonium hydroxide solution. The organic layer was dried (MgSO4) and evaporated with the formation of 4-/3'-methylaniline/-7-methylthio-6-nitroquinazoline (0,473 g), melting point of 230-231oC.

An NMR spectrum: (CD3SOCD3) 2,33 (c.3H), 2.63 in (c.3H), 6,97 (D.,1H), 7,28 (t,1H), to 7.61 (S., 1H), 7,63 (m,2H), 8,63 (S.,1H), 9,70 (S.,1H).

Elemental analysis:

found: C 58,6, H 4,6, N 17,2

calculated for C16H14N4O2S: C 58,8, H 4,3, N 17,1%

Example 38

A mixture of 7-methoxy-4/3'-methylaniline/6-nitro is Nola (20 ml) was stirred under atmospheric pressure, the generated hydrogen for 5 hours. The mixture was filtered, and the filtrate evaporated. The residue was purified by chromatography on columns of silica gel, reversed phase, using as eluent a mixture of methanol, water and triperoxonane acid and increasing polarity. Thus in turn were obtained 6-hydroxy-amino-7-methoxy-4-/3'-methylaniline/hinzelin (0,038 g), melting point 130-147oC.

An NMR spectrum: (CD3SOCD3) 2,35 (C., 3H), was 4.02 (SD, 3H), 7,12 (D., 1H), 7,19 (S., 1H), 7,34 (t,1H), of 7.48 (m, 2H), 8,10 (S., 1H), 8,70 (S., 1H)/

Elemental analysis:

found: C 44,0, H 3,5, N 10,5

calculated for C16H16N4O21H2O2CF3CO2H: C 44,3, H 3,7, N 10.7% of 6-amino-7-methoxy-4-/3'-methylaniline/hinzelin (0,049 g), melting point 85-95oC.

An NMR spectrum: (CD3SOCD3) 2,36(C.,3H), 4,03 (C.,3H), 7,12 (D., 1H), 7,18(S. ,1H), 7,35 (t,1H), 7,45 (m, 2H), 7.62mm (C. 1H), 8,69(C. 1H).

Elemental analysis:

found: C 52,3, H, 4,0, N, 13,0

calculated for C16H16N4O1,3CF3CO2H: C 52,1, H, 4,0, N 13,1%.

7-Methoxy-4-/3'-methylaniline/-6-nitroquinazoline used as starting material was prepared as follows:

7-Chloro-4-/3'-methylaniline/-6-nitroquinazoline (0.35 g) servings)). This mixture was stirred and heated to boiling point under reflux for 1 hour. Added a second portion of sodium (0,069 g) and the mixture was heated to boiling point under reflux for 5 hours. The mixture is evaporated and the residue was purified by chromatography on columns of silica gel, reversed phase, using as eluent first mixture of water, methanol and triperoxonane acid with a ratio of 50: 50:0.2 and then a mixture of water, methanol and triperoxonane acid with decreasing polarity. Thus there was obtained 7-methoxy-4-/3 '-methylaniline-6-nitroquinazoline (0,81 g), melting point 149-154oC.

Example 39

1,2-Dibromethane (10,9 g) was added to a stirred mixture of 7-hydroxy-6-methoxy-4-/3'-methylaniline/hintline (2.5 g), potassium carbonate (3,69 g) and N, N-dimethylformamide (60 ml). The resulting mixture was stirred at ambient temperature for 30 minutes and then was heated up to 80oC for 2 hours. The mixture is evaporated and the residue is distributed between methylene chloride and water. The organic phase was dried (MgSO4) evaporated. The residue was purified by chromatography on columns using as eluent mixtures of methylene chloride and methanol with the age of the tour melting 86-89oC.

An NMR spectrum: (CD3SOCD3) 2,35 (C., 3H), with 3.89 (t, 2H), 3,99 (c. 3H), 4,51 (t,2H), 7,21 (S.,1H), 7,28(t, 1H), 7,58 (S., 1H), 7.62mm (D., 1H), 7,88 (S., 1H), 8,46 (S., 1H), 8,94 (D.,1H), 9,46 (S., 1H).

Elemental analysis:

found: C 55,7, H 5,9, N 11,9

calculated for C18H18BrN3O20,75 H2O: C 69,6, H 6,2, N 13,5%

Example 41

A mixture of 7-/2-bromoethoxy/-6-methoxy-4-/3'-methylaniline/-hintline (0.25 g) and research (4 ml) was stirred at ambient temperature for 4 hours. The resulting mixture was evaporated, and the residue is distributed between methylene chloride and dilute aqueous sodium bicarbonate solution. The organic phase was dried (MgSO4) and evaporated. The residue is triturated under a layer of simple diethyl ether with the formation of 6-methoxy-4-/3'-methylaniline/-7-/2-morpholinoethoxy/hintline (0,198 g), melting point 168-170oC.

An NMR spectrum: (CD3SOCD3) + CD3CO2D) 2,35 (C., 3H), 3,15 (t, 4H), 3,81 (t , 4H), 3.96 points (C., 3H), 6,93 (D., 1H), 7,21 (S., 1H), 7,26 (t, 1H), 7,58 (S., 1H), 7,63 (D., 1H), 7,84 (S., 1H), 8,44(S., 1H), 9,58(S.,1H).

Elemental analysis:

found: C 64,3, H 6,9, N 13,8

calculated for C22H26N4O30,9 H2O: C 64,3, H 6,8, N 13,6%,

Example 42

2-Methoxyacetanilide (of 0.085 g) was added to a mixed restively at ambient temperature for 16 hours. Added a second portion of 2-methoxyacetanilide (of 0.085 g) and the mixture was heated to 45oC for 3 hours. The resulting mixture was cooled to ambient temperature and was added ethyl acetate (5 ml). The precipitate was separated, washed with ethyl acetate and simple diethyl ether, and then dried under vacuum. Was thus obtained 6-methoxy-7-/2-methoxyacetate/-4/3'-methylaniline/hinzelin (0,218 g), melting point 215-219oC.

An NMR spectrum: (CD3SOCD3) 2,37 (C. , 3H), 3.43 points (C., 3H), 4,06 (C., 3H), 4,45(S. , 2H), 7,16(D. , 1H), 7,33 (S.,1H), 7,38(t, 1H), 7,52(m, 2H), 8,83(S., 1H), 8,62(S., 1H).

Elemental analysis:

found: C 53,5, H 5,8, N, 10,0

calculated for C19H19N3O41HCl2H2O: C 53,5, H 5,6, N 9,9%

Example 43

A mixture of 6-amino-4-/3'-methylaniline/hintline (0.25 g), benzoyl chloride (0,148 g), triethylamine (2 ml) and N,N-dimethylformamide (2 ml) was stirred and heated to 100oC for 3 hours. Added another portion of benzoyl chloride (0,296 g) and the mixture was heated to 100oC for a further 3 hours. The resulting mixture was cooled to ambient temperature and distributed between methylene chloride and water. The organic phase was dried (MgSO4) and evaporated. The residue was purified by chromatography on a column of the Institute was obtained 6-benzamido-4-/3'-methylaniline/hinzelin (0,142 g), melting point 243 - 245oC.

An NMR spectrum: (CD3SOCD3) 2,34 (C., 3H), 6,95 (D., 1H), 7,27 (m, 1H), 7,6 (m , 5H), 7,79 (D., 1H), 8,01 (m, 1H), 8,04 (m, 2H), charged 8.52 (S., 1H), 8,90 (D., 1H), 9,80 (S., 1H), 10,55 (S., 1H).

Elemental analysis:

found: C 73,2, H, 5,0, N 15,4

calculated for C22H18N4O0,25 H2O: C 73,6, H 5,2, N 15.6 PER CENT.

Example 44

A mixture of 6-amino-4-/3'-methylaniline/hintline (0.75 g), methyl-3-chloroformiate (0,451 g), triethylamine (0,303 g) and toluene (6 ml) was stirred and heated to boiling point under reflux for 4 hours. This mixture is evaporated and the residue was purified by chromatography on columns, using as elution solvent a mixture of methylene chloride and methanol with increasing polarity. Was thus obtained 6-/3-methoxycarbonylpropionyl/-4-/3'-methylaniline/hinzelin (0,46 g), melting point 202 - 203oC.

An NMR spectrum: (CD3SOCD3) 2,34(C.,3H), 2,68 (m, 4H), 3,61(C., 3H), 6,95 (D. , 1H), 7,26 (t, 1H), 7,6 (S., 2H), 7,74 (D., 1H), to 7.84 (m, 1H), charged 8.52 (S., 1H), 8,70 (D., 1H), 9,8 (S., 1H), 10,3 (S., 1H).

Elemental analysis:

found: C 65,3, H 5,5, N 14,8

calculated for C20H20N4O3: C 65,2, H 5,5, N, 15,0%

Example 45

A mixture of 6-amino-4-/3'-methylaniline/hintline (0.5 g), methyl-4-hlei cooled from ambient temperature and distributed between methylene chloride and water. The organic layer was dried (MgSO4) and evaporated. The residue was purified by chromatography on columns, using as elution solvent a mixture of methylene chloride and methanol with a ratio of 20: 1. Was thus obtained 6-/3-methoxycarbonylpropionyl/-4-/3'-methylaniline/hinzelin (0.32 g).

An NMR spectrum: (CD3SOCD3) of 1.92 (m, 2H), 2,34 (C., 3H), 3,23 (m, 4H), 3,61 (C. , 3H), from 6.22 (t, 1H), 6,93 (D., 1H), 7,18 (D., 1H), 7,25 (m, 1H), 7,29 (t, 1H), 7,6 (S., 1H), 7,65 (D., 1H), 8,43 (S., 1H), 9,25 (S., 1H).

The mixture thus obtained material and simple diphenyl ether (0.5 ml) was stirred and heated to 160oC for 3 hours. The resulting mixture was cooled to ambient temperature and distributed between methylene chloride and water. The organic phase was dried (MgSO4) and evaporated. The residue was purified by chromatography on columns using as elution solvent a mixture of methylene chloride and methanol with a ratio of 20:1. Thus there was obtained 4-/3'-methylaniline/-6-/2-oxopyrrolidin-1-yl/hinzelin (0,053 g), melting point 212 - 215oC.

An NMR spectrum: (CD3SOCD3) to 2.15 (m, 2H), 2,35 (C., 3H), at 2.59 (t, 2H), 4,01 (t, 2H), 7,02 (D., 1H), 7,30 (t, 1H), 7,6 (m, 2H), 7,8 (D., 1H), 8,24 (D. , 1H), 8,55 (S., 1H), at 8.60 (m, 1H), 9,88 (S., 1H).

Elemental analysis:

found:example 46

Phenylisocyanate (0,193 g) was added to a stirred mixture of 6-amino-4-/3'-methylaniline/hintline (0.39 g) and tetrahydrofuran (15 ml), which was pre-cooled to -2oC. the resulting mixture was stirred at a temperature of 5oC for 10 minutes and then left to warm to ambient temperature. The mixture is evaporated and the residue was purified by chromatography on columns, using as elution solvent a mixture of methylene chloride and methanol with a ratio of 20:1. Thus there was obtained 4-/3'-methylaniline/-6-/3-phenylurea/hinzelin (0,335 g), melting point 224 - 226oC.

An NMR spectrum: (CD3SOCD3) 2,34 (C., 3H), 6,94 (D., 1H), 7,01 (m, 1H), 7,28 (m , 2H), 7,30 (t, 1H), 7,51 (m, 2H), 7.62mm (m, 2H), 7,73 (D., 1H), 7,92 (m , 1H), 8,46 (D., 1H), 8,49 (S., 1H), 8,90 (S., 1H), 8,94 (S., 1H), 9,75 (S., 1H)< / BR>
Elemental analysis:

found: C 65,2, H 5,5, N 17,2

calculated for C22H19N5O2H2O: 65,2, H 5,7, N 17,3%.

Example 47

A solution of sodium cyanate (of € 0.195 g) in water (3 ml) was added to a stirred solution of 6-amino-4-/3'-methylaniline/hintline (0.25 g) in water (5 ml) and acetic acid (0.1 ml). The resulting mixture was stirred at ambient temperature for 2 hours. The mixture is evaporated and the residue was purified by chromatography forexpros acid with a ratio of 30:70:0,2, and then the same mixture with a ratio of 45: 55: 0,2. Thus there was obtained 4-/3'-methylaniline/-6-ureidopenicillin (0,047 g), melting point > 230oC (decomposes).

An NMR spectrum: (CD3SOCD3) 2,36 (C., 3H), 6,18 (S., 2H), 7,12 (D., 1H), was 7.36 (m , 1H), of 7.48 (m, 2H), 7,79 (D., 1H), 8,01 (m, 1H), 8,65 (D., 1H), 8,75 (S., 1H), 9,11 (S., 1H), 11,12 (S., 1H).

Elemental analysis:

found: C to 48.8, H 4,1, N 15,4

calculated for C16H15N5O1H2O1,3CF3CO2H: C 48,6, H, 4,0, N 15,2%.

Example 48

Benzolamide (0,378 g) was added to a stirred mixture of 7-hydroxy-6-methoxy-4-/3'-methylaniline/hinzelin (0,281 g), potassium carbonate (0,414 g) and N, N-dimethylacetamide (4 ml). The resulting mixture was stirred at ambient temperature for 10 minutes and then was heated to 60oC for 1 hour. The mixture is evaporated and the residue was purified by chromatography on a column using as eluent first methylene chloride and then a mixture of methylene chloride and methanol with a ratio of 100:3. Was thus obtained 7-benzyloxy-6-methoxy-4-/3'-methylaniline/hinzelin (0,225 g), melting point 203 - 205oC.

An NMR spectrum: (CD3SOCD3) 2,34 (C., 3H), 3,97 (C., 3H), 5,28 (S., 2H), 6,93 (D., 1H), 7,27 (t, 1H), 7,28 (S., 1H), 7,22 - of 7.55 (m, 5H), 7,58 (S., 1H), 7,63 (D., 1H), 7,8723H21N3O2: C 74,4, H 5,7, N 11,3%

Example 49

Isopropylamine (0,246 g) was added to a stirred mixture of 7-hydroxy-6-methoxy-4-/3'-methylaniline/hintline (0,281 g), potassium carbonate (0,414 g) and N, N-dimethylacetamide (3 ml). The resulting mixture was stirred at ambient temperature for 30 minutes and then was heated to 70oC for 1 hour. This mixture was distributed between ethyl acetate and water. The organic phase was dried (MgSO4) and evaporated with the formation of 7-isopropoxy-6-methoxy-4-/3'-methylaniline/hintline (0.28 g), melting point 218 - 221oC.

An NMR spectrum: (CD3SOCD3) 1,36 (D., 6H), 2,34 (C., 3H), 3,94 (C., 3H), of 4.83 (m , 1H), 6,94 (D., 1H), 7,17 (S., 1H), 7,27 (t, 1H), EUR 7.57 (S., 1H), to 7.64 (D., 1H), 7,82 (S., 1H), 8,43 (S., 1H).

Elemental analysis:

found: C 69,4, H 6,7, N, 12,0

calculated for C19H21N3O20,3 H2O0,1EtOAC: C 69,0, H 6,6, N 12.4% OF

Example 50

Ethyliodide (0,624 g) was added to a stirred mixture of 6,7-dihydroxy-4-/3'-methylaniline/hintline (0.534 g), potassium carbonate (0.828 g) and N,N-dimethylacetamide (10 ml). The resulting mixture was heated to 50oC for 2 hours. Added second portion of ethyliodide (0,624 g) and the mixture was heated to 60oC for 2 hours. The mixture is evaporated and the residue was purified pore lorida and methanol with increasing polarity. Thus there was obtained 6,7-diethoxy-4-/3'-methylaniline/hinzelin (0.26 g), melting point 178 - 180oC.

An NMR spectrum: (CD3SOCD3) of 1.43 and 1.44 (2 triplet, 6H), 2,34 (C., 3H), 4,2 (m , 4H), 6,92 (D., 1H), 7,14 (S., 1H), 7,26 (t, 1H), EUR 7.57 (S., 1H), 7,63 (D., 1H), 7,82 (S., 1H), 8,42 (S., 1H).

Elemental analysis:

found: C 69,1, H 6,6, N 12,2

calculated for C19H21N3O20,48 H2O: C 68,7, H 6,6, N OF 12.6%.

Example 51.

2-Bromatology ether (0,834 g) was added to a stirred mixture of 6,7-dihydroxy-4-/3'-methylaniline/hintline (0.534 g), potassium carbonate (0.828 g) and N,N'-dimethylacetamide (10 ml). The resulting mixture was stirred at ambient temperature for 16 hours. The mixture is evaporated, and the residue was distributed between ethyl acetate and water. The organic layer was dried (MgSO4) and evaporated. The residue was purified by chromatography on columns using as eluent mixtures of methylene chloride and methanol with increasing polarity. The resulting resin was dissolved in ethyl acetate (4 ml) and acidified by adding a saturated solution of hydrogen chloride in simple diethyl ether. The precipitate was separated. Thus was obtained chloride-hydrogen salt of 6,7-di-/2-methoxyethoxy/-4-/3'-methylaniline/healozone (0., 4H), 4.1 and 4.5 (m , 4H), 7,14 (D., 1H), 7,37 (D., 1H), 7,40 (S., 1H), of 7.48 (m, 2H), 8,35 (S., 1H), 8,79 (S., 1H).

Elemental analysis:

found: C 59,8, H 6,4, N, 9,9

calculated for C21H25N3O41HCI: C 60,0, H 6,2, N 10,0%

Example 52

1,2-Dibromethane (0,376 g) was added to a stirred mixture of 6,7-dihydroxy-4-/3'-methylaniline/hintline (0,524 g), potassium carbonate (0.828 g) and N, N-dimethylacetamide (20 ml). The resulting mixture was heated to 100oC for 30 minutes. The mixture is evaporated and the residue was purified by chromatography on columns using as eluent mixtures of methylene chloride and ethyl acetate of increasing polarity. Thus there was obtained 6,7-Ethylenedioxy-4-/3'-methylaniline/hinzelin (0,23 g), melting point 223-226oC.

An NMR spectrum: (CD3SOCD3) 2,34 (C., 3H), 4,40 (C., 4H), 7,14 (D., 1H), 7,17 (S. , 1H), 7,26 (t, 1H), 7,66 (m, 2H), 8,10 (S., 1H), 8.34 per (C., 1H), 9,38 (S., 1H).

Elemental analysis:

found: C 67,5 H 5,1, N, 13,0

calculated for C17H15N3O20,33 H2O 0,25 EtOAc: C 67,2, H 5,5, N 13,1%

Example 53

A mixture of 6-methyl bromide-4-/3'-methylaniline/hintline (0,415 g) and research (2 ml) was stirred and heated to 60oC for 2 hours. The resulting mixture was cooled to ambient temperature and otdeleniya brine, dried (MgSO4) and evaporated. Was thus obtained 6-morpholinomethyl-4-/3'-methylaniline/hinzelin (of € 0.195 g), melting point 191-193oC.

An NMR spectrum: (CD3SOCD3) 2,34 (C., 3H), 2.49 USD (t, 4H), 3,62 (t, 4H), 3,69 (S. , 2H), of 6.96 (D.,1H), 7,29 (t, 1H), 7,69 (m, 2H), 7,74 (D., 1H), a 7.85 (m, 1H), 8,45 (S., 1H), 8,55 (S., 1H), 9,71 (S., 1H).

Elemental analysis:

found: C 71,2, H 6,8, N 16,2

calculated for C20H22N4O: C 71,2, H 6,6, N 16,6%.

Example 54

A mixture of 6-methyl bromide-4-/3'-methylaniline/hintline (0.3 g), aniline (of 0.085 g) and N,N-dimethylacetamide (5 ml) was stirred and heated to 80oC for 2 hours. The resulting mixture was evaporated, and the residue was purified by chromatography on columns using as eluent mixtures of methylene chloride and methanol with increasing polarity. Was thus obtained 6-anilinomethyl-4-/3'-methylaniline/hinzelin in the form of oil (0,254 g) which was dissolved in ethyl acetate. Was added a saturated solution of hydrogen chloride in simple diethyl ether and the precipitate was separated. Thus was obtained the dihydrochloride-6-anilinomethyl-4-/3'-methylaniline/hintline, melting point 216-221oC.

An NMR spectrum: (CD3SOCD3) 2,30 (C., 3H), 4,45 (S., 2H), and 6.6 (t, 1H), 6,7 (D. , 2H is:

found: C, 60,4, H 5,8, N 12,9

calculated for C22H20N42HCI 1,33 H2O: C, 60,4, H 5,6, N 12,8%

Example 55

The sodium methylate (0,073 g) was added to a stirred mixture of 6-methyl bromide-4-/3'-methylaniline/hintline (0.3 g) and methanol (5 ml). The resulting mixture was stirred at ambient temperature for 2 hours. The mixture is evaporated and the residue was purified by chromatography on columns using as eluent mixtures of methylene chloride and ethyl acetate of increasing polarity. Was thus obtained 6-methoxymethyl-4-/3'-methylaniline/hinzelin resin (0,045 g).

An NMR spectrum: (CD3SOCD3) 2,36 (C., 3H), 3,39 (C., 3H), 4,62 (S., 2H), 7,07 (D. , 1H), 7,35 (t, 1H), 7,58 (S., 2H), 7,82 (D., 1H), 7,92 (D., 1H), 8,65 (S., 1H), 8,76 (S., 1H).

Example 56

A mixture of 6-methyl bromide-4-/3'-methylaniline/hintline (0.5 g) and 2-methoxyethanol (2.5 ml) was stirred and heated to 80oC for 2 hours. The resulting mixture was cooled to ambient temperature and distributed between methylene chloride and water. The organic phase was washed with brine, dried (MgSO4) and evaporated. The residue was purified by chromatography on columns using as eluent mixtures of methylene chloride and ethyl acetate with increasing polar">

An NMR spectrum: (CD3SOCD3) 2,34 (C., 3H), 3.27 to (C., 3H), 3,53 (m, 2H), 3,63 (m, 2H), 4,67 (S., 2H), of 6.96 (D., 1H), 7,28 (t, 1H), and 7.7 (m, 2H), and 7.8 (m , 2H), 8,5 (S., 1H),8,57 (S., 1H), 9,8 (S., 1H).

Elemental analysis:

found: C 68,5, H 6,8, N 12,5

calculated for C19H21N3O2: C 68,6, H 6,7, N OF 12.6%.

Example 57

Meantioned sodium (0,141 g) was added to a stirred mixture of 6-methyl bromide-4-/3'-methylaniline/hintline (0.6 g), triethylamine (0,203 g) in N,N-dimethylformamide (2 ml). The resulting mixture was stirred at ambient temperature for 4 hours. The mixture is evaporated and the residue was purified by chromatography on columns using as eluent mixtures of methylene chloride and ethyl acetate of increasing polarity. Thus was obtained an oil which is triturated under a layer of a mixture of hexane and simple diethyl ether, which allowed us to obtain 4-/3'-methylaniline/-6-methylthiotetrazole (0,205 g), melting point 134-136oC.

An NMR spectrum: (CD3SOCD3) 2,01 (C., 3H), 2,34 (C., 3H), 3,88 (S., 2H), 6,97 (D. , 1H), 7,28 (t, 1H), 7,6 (m, 2H), 7,75 (D., 1H), 7,83 (m, 1H), 8,45 (D., 1H), 8,58 (S., 1H), 9,8 (Broad singlet, 1H).

Elemental analysis:

found: C 69,7, H 5,8, N 14,2

calculated for C17H17N3S 0.1 C6H14: but/hintline (0.33 g), bentolila (0.11 g) and N,N-dimethylacetamide (2 ml). The resulting mixture was stirred at ambient temperature for 5 hours. This mixture is evaporated and the residue was purified by chromatography on columns using as eluent mixtures of methylene chloride and ethyl acetate of increasing polarity. Thus there was obtained 4-/3'-methylaniline/-6-phenylthiohydantoin (0,155 g), melting point 145-148oC.

An NMR spectrum: (CD3SOCD3) 2,34 (C., 3H), to 4.41 (SD, 2H), of 6.96 (D., 1H), 7,24 (t , 1H), and 7.3 (SD, 5H), the 7.65 (m, 2H), 7,72 (D., 1H), 7,86 (m, 1H), 8,54 (D., 1H), 8,55 (S., 1H), 9,73 (S., 1H).

Elemental analysis:

found: C 73,7, H 5,3, N 11,5

calculated for C22H19N3S: C 73,9, H 5,4, N 11,8%.

Example 59

Succinyldicholine (0,207 g) was added to a mixture of 6-amino-4-/3'-methylaniline/hintline (0.33 g), triethylamine (0,128 g) and toluene (5 ml). The resulting mixture was stirred and heated to boiling point under reflux for 2 hours. The mixture is evaporated and the residue was purified by chromatography on columns using as eluent mixtures of methylene chloride and methanol with increasing polarity. Thus there was obtained 4-/3'-methylaniline/-6-/2,5-dioxopiperidin-1-yl/hinzelin (0,082 g), temn), to 7.61 (D., 2H), to 7.75 (m, 1H), 7,88 (D., 1H), 8,50 (D., 1H), 8,64 (S., 1H), 9,95 (S., 1H).

Elemental analysis:

found: C 64,9, H 5,2, N 15,2

calculated for C19H16N4O20,4 HCl 0,4 CH3OH: C 64,8, H, 5,0, N 15.6 PER CENT.

Example 60

3-Chlorocatechol (0,473 g) was added to a mixture of 6-amino-4-/3'-methylaniline/hintline (1 g), triethylamine (0,423 g) and N,N-dimethylformamide (5 ml). The resulting mixture was stirred and heated to 50oC for 2 hours. The resulting mixture was evaporated, and the residue was purified by chromatography on columns using as eluent mixtures of methylene chloride and methanol with increasing polarity. Was thus obtained 6-/2-chloracetamide/-4-/3'-methylaniline/hinzelin (0,775 g), melting point >290oC.

An NMR spectrum: (CD3SOCD3) 2,32 (C., 3H), 4,33 (S., 2H), 6,94 (D., 1H), 7,25 (t , 1H), 7,6 (m, 2H), 7,75 (D., 1H), to 7.84 (m, 1H), 8,50 (S., 1H), 8,68 (D., 1H), 9,80 (S., 1H), 10,57 (S., 1H).

Elemental analysis:

found: C 62,6, H 4.5, N, 17,1

calculated for C17H15ClN4O: C 62,5, H 4,6, N 17,1%.

Example 61

Lambrogini sodium (0.2 g) portions was added to a mixture of 6-amino-4-/3'-methylaniline/hintline (0.5 g), formaldehyde (37% solution in water, 0.8 ml) and acetonitrile (15 ml). The resulting mixture peremeshivanii acid and evaporated. The residue was distributed between methylene chloride and 2 N. aqueous sodium hydroxide solution. The organic phase was dried (MgSO4) and evaporated. The residue was purified by chromatography on columns using as eluent mixtures of methylene chloride and methanol with increasing polarity. Was thus obtained 6-dimethylamino-4-/3'-methylaniline/hinzelin (0,237 g), melting point >200oC (decomposes).

An NMR spectrum: (CD3SOCD3) 2,33 (C., 3H), 3,06 (C., 6H), 6,95 (D., 1H), 7,26 (t , 1H), 7,41 (S., 1H), of 7.48 (D., 1H), 7,6 (m, 2H), 7,65 (D., 1H), of 8.37 (S., 1H), 9,5 (S., 1H).

Elemental analysis:

found: C 71,2, H 6,3, N 19,4

calculated for C17H18N40,4 H2O: C 71,5, H 6,6, N 19,6%.

Example 62

In accordance with the procedure described in example 39, except that instead of N, N-dimethylformamide used N,N-dimethylacetamide and the reaction mixture was heated up to 80oC for 4 hours, 6-hydroxy-4-/3'-methylaniline/hinzelin were subjected to interaction with 1,2-dibromethane, which allowed us to obtain 6-/2-bromoethoxy/-4-/3'-methylaniline/hinzelin, the output of which was 47%, melting point 129-135oC.

An NMR spectrum: (CD3SOCD3) 2,35 (C., 3H), 3,92 (t, 2H), to 4.52 (t, 2H), 6,95 (D. , 1H), 7,28 (t, 1H)2, N 11,5

calculated for C17H16BrN3O: C 57,0, H 4.5, N 11,7%.

Example 63

Perform the procedure described in example 62, except that instead of 1,2-dibromethane used 2-bromatology ether. Was thus obtained 6-/2-methoxyethoxy/-4-/3'-methylaniline/hinzelin, the output of which amounted to 52%, melting point 177-179oC.

An NMR spectrum: (CD3SOCD3) 2,35 (C., 3H), 3,36 (C., 3H), 3,76 (t, 2H), 4,29 (t , 2H), 6,95 (D., 1H), 7,28 (m, 1H), 7,51 (m, 1H), 7.62mm (S., 1H), 7,65 (D., 1H), 7,72 (D., 1H), 7,95 (D., 1H), 8,49 (S., 1H).

Elemental analysis:

found: C 69,4, H 6,2, N 13,2

calculated for C18H19N3O20,1 H2O: C 69,4, H 6,2, N 13,5%.

Example 64

Gaseous dimethylamine was introduced into the stirred solution of 6-/2-bromoethoxy/-4-/3'-methylaniline/hintline (0,237 g) in N,N-dimethylacetamide (5 ml), after which the resulting mixture was stirred at ambient temperature for 16 hours. The mixture is evaporated and the residue was purified by chromatography on columns using as eluent mixtures of methylene chloride and methanol with increasing polarity. Thus was obtained Hydrobromic salt 6-/2-dimethylaminoethoxy/-4-/3'- methylaniline/hintline (0,177 g) temperature p,29 (m, 1H), 7,50 (m, 1H), 7.62mm (m, 2H), to 7.64 (D., 1H), 7,98 (D., 1H), 8,49 (S., 1H), 9,54 (S., 1H).

Elemental analysis:

found: C 56,6, H 5,9, N 13,6

calculated for C19H22N4O1HBr: C 56,6, H 5,7, N 13.9 Per Cent.

Example 65

Sodium cyanide (0,121 g) and triethylamine (0,303 g) were added to a mixture of 6-methyl bromide-4-/3'-methylaniline/hintline (0.3 g) and N,N-dimethylacetamide (5 ml). The resulting mixture was stirred at ambient temperature for 16 hours. The mixture is evaporated and the residue was purified by chromatography on columns using as elaenia mixtures of methylene chloride and ethyl acetate of increasing polarity. Was thus obtained 6-cyanomethyl-4-/3'-methylaniline/hinzelin in the form of solids (0,084 g).

An NMR spectrum: (CD3SOCD3) 2,34 (C., 3H), 4,24 (S., 2H), 6,98 (D., 1H), 7,29 (t, 1H), to 7.61 (m, 2H), 7,83 (S., 2H), 8,56 (S., 1H), 8,62 (S., 1H).

Elemental analysis:

found: C 72,7, H is 4.9, N 19,6

calculated for C17H14N40,33 H2O: C 72,8, H 5,2, N 20,0%.

Example 66

Di/1-imidazolyl/ketone (0,421 g) was added to a mixture of 7-carboxy-4-/3'-methylaniline/hintline (0,558 g) in tetrahydrofuran (40 ml) and N,N-dimethylformamide (20 ml). The resulting mixture was stirred and heated to 40oC for 90 minutes. The mixture of on and under water. The formed solid substance was separated and dried. Thus there was obtained 7-/N, N-dimethylcarbamoyl/-4-/3'-methylaniline/hinzelin (0.55 g), melting point 207-209oC.

An NMR spectrum: (CD3SOCD3+ CD3CO3D) 2,35 (C., 3H), 2,96 (C., 3H), of 3.07 (SD, 3H),? 7.04 baby mortality (D., 1H), 7,32 (t, 1H), 7,63 (m, 1H), 7,66 (S., 2H), 7,82 (D., 1H), 8,60 (D., 1H), 8,64 (S., 1H).

Elemental analysis:

found: C 69,6, H 5,8, N 18,1

calculated for C18H18N4O0,2H2O: C 69,8, H 5,9, N 18.1 PER CENT.

Example 67

In accordance with the procedure described in example 1, 4-chloro-6-morpholinopropan were subjected to interaction with 3-methyl-aniline production, which allowed to obtain the chloride-hydrogen salt 4-/3'-methylaniline/-6-morpholinopropan, which amounted to 76%, melting point 276-278oC.

An NMR spectrum: (CD3SOCD3) 2,38 (C., 3H), 3,41 (m, 4H), 3,82 (m, 4H), 7,18 (D. , 1H), 7,38 (m, 1H), of 7.48 (S., 1H), 7,50 (D., 1H), 7,87 (S., 2H), 8,08 (S., 1H), 8,75 (S., 1H).

Elemental analysis:

found: C 63,9, H, 6,0, N 15,4

calculated for C18H20N4O1HCl C 64,1, H 5,9, N 15,8%.

4-Chloro-6-morpholinopropan used as starting material was prepared as follows:

A mixture of 5-chloro-2-nitrobenzoic acid (20.2 g) and research (50 ml) paramashiva is. Was added water (100 ml) and acidified mixture to pH 2, giving it a concentrated chloride-hydrogen acid. The precipitate was separated, washed with water and dried. Thus there was obtained 2-nitro-5-morpholinomethyl acid (24.3 g).

A mixture of a portion (10 g) obtained material, the catalyst comprising 10% palladium carbon (1 g) and N,N-dimethylacetamide (150 ml) was heated to 40oC and was stirred in an atmosphere of hydrogen for 4 hours. The mixture was filtered, and the filtrate evaporated. The residue is triturated under a layer of simple diethyl ether with the formation of 5-morpholinoethyl acid (6,05 g).

A mixture of a portion (5.5 g) obtained material and formamide (20 ml) was stirred and heated to 170oC for 4 hours. The resulting mixture was cooled to ambient temperature, the precipitate was separated, in turn washed with formamide, ethyl acetate and simple diethyl ether and dried. Was thus obtained 6-morpholinomethyl-4-one (4.8 g), melting point 270 - 273oC.

Phosphorylchloride (0,664 g) was added to a stirred mixture of 6-morpholinosydnonimine (0.5 g), N,N-dimethylaniline (0,471 g) and toluene (10 ml). The resulting mixture was heated to boiling point under reflux for 1 hour. dnim solution of ammonium chloride. The organic phase was dried (MgSO4) and evaporated. The residue was purified by chromatography on columns, using as elution solvent a mixture of methylene chloride and ethyl acetate of increasing polarity. Was thus obtained 4-chloro-6-morpholinopropan in the form of a solid (0.52 g).

Example 68

A mixture of 4-chloro-6,7-dimethoxyquinazoline (0,449 g), 1,3-phenylenediamine (0,433 g) and tetrahydrofuran (16 ml) was stirred and heated to boiling point under reflux for 20 hours. The resulting mixture was cooled to ambient temperature. The precipitate was separated, washed simple diethyl ether and dried. Thus was obtained chloride-hydrogen salt 4-/3'-aminoaniline/- 6,7-dimethoxyquinazoline (0,367 g), melting point 242 - 243oC.

An NMR spectrum: (CD3SOCD3) 3,97 (C., 3H), 4.0 (with S., 3H), only 6.64 (m, 1H), 6,95 (D. , 1H), 7,02 (D., 1H), 7,16 (t, 1H), 7,87 (S., 1H), 8,25 (S., 1H), 8,72 (S., 1H), 10,99 (broad singlet, 1H).

Elemental analysis:

found: C 57,6, H, 5,0, N 16,4

calculated for C16H16N4O21HCl of 0.1 H2O:C 57,4, H 5,2, N 16,7%.

Example 69

In accordance with the procedure described in example 68, 4-chloro-6,7 - dimethoxyquinazolin were subjected to interaction with 3-aminophenol, clenia 256 - 257oC.

An NMR spectrum: 3,98 (C., 3H), was 4.02 (SD, 3H), 6.75 in (m, 1H), 7,12 (D., 1H), 7,14 (D. , 1H), 7,25 (t, 1H), 7,42 (S., 1H), of 8.37 (s, 1H), 8,80 (S., 1H), and 9.5 (broad peak, 1H), and 11.4 (broad singlet, 1H).

Elemental analysis:

found: C 57,1, H 4,8, N, 12,1

calculated for C16H15N3O31HCl 0,25 H2O: C 56,8, H IS 4.9, N 12.4% OF

Example 70

A mixture of 4-chloro-6-piperidinedione (0,371 g), 3,4-dichloraniline (0,243 g), isopropanol (3 ml) and tetrahydrofuran (4 ml) was stirred and heated to boiling point under reflux for 3 hours. The resulting mixture was cooled to room temperature. The precipitate was separated, washed with tetrahydrofuran and simple diethyl ether and dried. Thus was obtained chloride-hydrogen salt 4-/3',4'- dichloraniline/-6-piperidinedione (0,331 g, 54%), melting point >280oC.

An NMR spectrum: (CD3SOCD3) 1,68 (m, 6H), 3,49 (m, 4H), 7,7 - 8,0 (m, 5H), 8,13 (S., 1H), 8,81 (S., 1H).

Elemental analysis:

found: C of 56.4 H 4,7, N 13,6

calculated for C19H18Cl2N40,9 HCl: C 56,3, H 4,7, N 13,8%

4-Chloro-6-piperidinophenyl used as starting material was obtained as follows: t

A mixture of 5-chloro-2-nitrobenzoic acid (13,7 g), piperidine (perivale. The residue was dissolved in water and podslushivaet the resulting solution to pH 10 by adding 2 N. aqueous sodium hydroxide solution. The solution was extracted with ethyl acetate. The aqueous layer was acidified to pH 2 by adding concentrated chloride-hydrogen acid, and was extracted with ethyl acetate. The organic layer was dried (MgSO4) and evaporated with the formation of 2-nitro-5 - piperidinemethanol acid (16,25 g), melting point 130 - 140oC.

A mixture of a portion (10 g) obtained material, the catalyst comprising 10% palladium carbon (1 g) and N,N - dimethylacetamide (150 ml) was heated to 40oC and was stirred in an atmosphere of hydrogen for 4 hours. The mixture was filtered, and the filtrate evaporated. Thus there was obtained 5-piperidinoethyl acid in the form of oil (12.1 g), which was used without further purification.

A mixture of the obtained material and formamide (50 ml) was stirred and heated to 170oC for 90 minutes. The resulting mixture was cooled to ambient temperature. The precipitate was separated, washed with formamide and simple diethyl ether and dried. Was thus obtained 6-piperidinomethyl-4-one (5,95 g), melting point 160 - 166oC.

Phosphorylchloride (lower than the 5.37) was added to p is Ali up to the boiling temperature under reflux for 2 hours. The mixture was cooled to ambient temperature, diluted with toluene (80 ml) and was extracted with a dilute aqueous solution of ammonium chloride. The organic phase was dried (MgSO4) and evaporated. The residue was purified by chromatography on columns using as eluent mixtures of methylene chloride and ethyl acetate of increasing polarity. Was thus obtained 4-chloro-6-piperidinophenyl in the form of solids (2,01 g).

Example 71

A mixture of 7-methylamino-4-/3'-methylaniline/-6-nitroquinazoline (1 g), a catalyst comprising 10% palladium carbon (0.1 g) and N,N-dimethylacetamide (20 ml) was stirred and heated to 50oC in an atmosphere of hydrogen for 3 hours. The resulting mixture was cooled to ambient temperature and filtered. The filtrate is evaporated and the residue is distributed between methylene chloride and aqueous solution of ammonium hydroxide. The organic phase was dried (MgSO4) and evaporated. The residue was purified by chromatography on columns using as elution solvent a mixture of methylene chloride and methanol with increasing polarity. Was thus obtained 6-amino-7 - methylamino-4-/3'-methylaniline/hinzelin (0,056 g, 6%), melting point 229 - 232oC.

(D. 1H), 7,20 (m, 1H), 7,32 (S. , 1H), 7,60 (D. , 1H), 7.62mm (s, 1H), 8,29 (S., 1H), 9,10 (broad singlet, 1H).

Elemental analysis:

found: C 65,9, H 5,8 N 23,8

calculated for C16H17N50,1 H2O 0,15 CH2Cl2: C 66,2, H 5,9, N 23,7%

7. Methylamino-4-/3'-methylaniline/-6-nitroquinazoline used as starting material was prepared as follows:

A mixture of 7-chloro-4-/3'-methylaniline/-6-nitroquinazoline (10.5 g), a solution of methylamine in ethanol (30% weight to volume; 100 ml) and ethanol (100 ml) was stirred at ambient temperature for 16 hours. The resulting mixture was evaporated with the formation of the target source material, which was used without further purification.

Example 72

Tert-butylnitrite (0,051 g) was added to a mixture of 6-amino-4-/3'- methylaniline/-7-morpholinosydnonimine (0.167 g) and N,N-dimethylformamide (5 ml), which was pre-heated to 65oC. the resulting mixture was heated to 65oC for 30 minutes. Added second portion (0,051 g) tert-butylnitrite and stirred the mixture at ambient temperature for 65 hours. The mixture is evaporated and the residue was purified by chromatography on columns with reversed phase, using as eluent a mixture of methanol, water, and Tr is 6 g, 41%), melting point 227 - 229oC.

An NMR spectrum: (CD3SOCD3) 2,33 (C., 3H), 3,50 (m, 4H), 3,82 (m, 4H), 6,93 (D. , 1H), 7,14 (D., 1H), 7,56 (D., 1H), EUR 7.57 (S., 1H), to 7.59 (m, 1H), 8,49 (D., 1H), 8,75 (S., 1H), of 10.93 (broad singlet, 1H).

6-Amino-4-/3'-methylaniline/-7-morpholinopropan used as starting material was prepared as follows:

A mixture of 7-chloro-4-/3'-methylaniline/-6-nitroindoline (1 g) and research (0,306 ml) was stirred and heated to 70oC for 3 hours. The mixture is evaporated and the residue triturated under a layer of methylene chloride. Thus there was obtained 4-/3'-methylaniline/-7 - morpholino-6-nitroquinazoline (1,02 g), melting point 212 - 215oC.

An NMR spectrum: (CD3SOCD3) 2,34 (C., 3H), 3,11 (t, 4H), 3,74 (t, 4H), 6,97 (D. , 1H), 7,28 (i.e 1H), 7,31 (S., 1H), 7.62mm (S., 1H), to 7.64 (D., 1H), 8,58 (S., 1H), 9,19 (..1H), 9,90 (broad singlet), 1H).

Elemental analysis:

found: C 55,7, H 16,4, N 4,7

calculated for C19H19N5O30,73 CH2Cl2: C 55,4, H 16,4, N IS 4.6%.

In accordance with the procedure described in example 70, except that the reaction was carried out at ambient temperature, has been recovered 4-/3'-methylaniline/-7-morpholino-6-nitroquinazoline with the formation of 6-amino-4-/3'-methylaniline: (CD3SOCD3) 2,32 (C., 3H), 2,98 (m, 4H), of 3.84 (m, 4H), 5,24 (broad singlet, 2H), 6,92 (D., 1H), 7,18 (S., 1H), 7,25 (t, 1H), 7,52 (S. , 1H), 7.62mm (D., 2H), scored 8.38 (s, 1H), 9,37 (broad singlet, 1H).

Elemental analysis:

found: C 67,7, H 6,4, N 20,5

calculated for C19H21N5O: C 68,0, H 6,3, N 20,9%

Example 73

In accordance with the procedure described in example 1, except that the reaction mixture was heated to boiling point under reflux for 2 hours, the corresponding 4-chloro-hinzelin were subjected to interaction with the corresponding aniline, which allowed to obtain the chloride-hydrogen salt (if no special instructions) of the compounds listed in table IV, the compliance of the structures of which were confirmed by spectroscopy proton nuclear magnetic resonance and elemental analysis.

Notes to the table. IV:

A. This product originally obtained in the form of chloride-hydrogen salt was converted into the free base as follows.

Salt was treated with a mixture of methylene chloride and 1 N. aqueous sodium hydroxide solution. The resulting mixture was filtered, the separated solid was washed with a mixture of methylene chloride and methanol with a ratio of 10:1 and dried. Thus was obtained> 3,97 (C., 3H), 4.0 (with S., 3H), 7,22 (S., 1H), 7,55 (m , 1H), 7.62mm (m, 1H), 7,83 (S., 1H), 8,16 (m, 1H), scored 8.38 (m, 1H), 8,56 (S.,1H), 9,67 (broad singlet, 1H).

Elemental analysis:

found: C 66,0, H 4,6, N, 18,0

calculated for C17H14N4O20,2 H2O: C 65,9, H 4,7, N 18.1 PER CENT.

b. For this product the following results were obtained elemental analysis:

found: C 58,3, H, 5,0, N 11,2

calculated for C18H17N3O31HCl 0.5 H2O: C 58,6, H 5,2, N 11,4%.

and the following characteristic data of the NMR spectrum: 2,62 (C., 3H), 3,99 (C. , 3H), 4.04 the (..3H), 7,43 (S., 1H), 7.62mm (m, 1H), of 7.90 (m, 1H), with 8.05 (m , 1H), 8,29 (m , 1H), of 8.47 (S., 1H), 8,84 (S., 1H), 11,74 (broad singlet, 1H).

c. This product originally obtained in the form of chloride-hydrogen salt was converted into the free base as follows.

Salt was distributed between ethyl acetate and 1 N. aqueous sodium hydroxide solution. The organic phase was washed with brine, dried (MgSO4) and evaporated. The residue was purified by chromatography on columns, using as elution solvent a mixture of methylene chloride and methanol with a ratio of 19:1. Thus was obtained target free base, melting point > 240oC.

An NMR spectrum: (CD3SOCD3) 3,82 (who,6, H 4,1, N 13,4

calculated for C16H13F2N3O2: C, 60,6, H 4,1, N 13,2%.

d. For this product the following results were obtained elemental analysis:

found: C 67,8, H 6,9, N 15,3

calculated for C20H22N41,03 HCl: C 67,4, H 6,5, N, 15.7% OF

and the following characteristic data of the NMR spectrum: (CD3SOCD3) and 1.63 (m, 6H), 2,35 (C., 3H), of 3.45 (m, 4H), 7,13 (D., 1H), was 7.36 (m, 1H), 7,45 (m, 2H), 7,75 (D. , 1H), to 7.84 (m . 1H), 8,69 (S., 1H), 8,88 (D., 1H), and 11.2 (broad singlet, 1H).

Example 74

A mixture of 4-chloro-6,7-dimethoxyquinazoline (0,674 g), 1,2-phenylenediamine (0,649 g) and tetrahydrofuran (24 ml) was stirred and heated to boiling point under reflux for 40 hours. The resulting mixture was cooled to ambient temperature. The precipitate was separated, washed simple diethyl ether and dried. Thus was obtained chloride-hydrogen salt 4-/2'-aminoaniline/-6,7-dimethoxyquinazoline (0,83 g, 83%), melting point 241 - 243oC.

An NMR spectrum: (CD3SOCD3) 3,98 (C., 6H), of 6.68 (m, 1H), 6.87 in (D., 1H), 7,12 (m , 2H), 7,40 (S. , 1H), 8,29 (S., 1H), 8,68 (S., 1H), 11,05 (broad singlet, 1H).

Elemental analysis:

found: C 57,9, H 5,2, N 16,6

calculated for C16H16N4O21HCl: C 57,7, H 5,15, N 16,8%.

An NMR spectrum: (CD3SOCD3) 3,95 (C., 3H), 3,98 (C., 3H), 6.75 in (D., 2H), 7,35 (S. , 1H), 7,38 (D. , 2H), 8,25 (S., 1H), 8,67 (S., 1H), 11,05 (broad singlet, 1H).

Elemental analysis:

found: C 57,6, H, 5,0, N 16,9

calculated for C16H16N4O21HCl: C 57,7, H 5,15, N 16,8%.

Example 76

Lambrogini sodium (0,13 g) was added to a mixture of 6-amino-4-/3'-methylaniline/hintline (0.5 g), formaldehyde (37% solution in water, 0.16 ml) and N, N-dimethylacetamide (5 ml). The resulting mixture was stirred at ambient temperature for 1 hour. This mixture was neutralized by addition of glacial acetic acid. The mixture is evaporated and the residue was purified by chromatography on columns using as eluent mixtures of methylene chloride and methanol with increasing polarity. Was thus obtained 6-methylamino-4-/3'-methylaniline/hinzelin. (0.15 g, 28%), melting point 99 - 102oC.

An NMR spectrum: (CD3SOCD3) 2,34 (C., 3H), 2,85 (D., 3H), 6,32 (square, 1H), of 6.96 (D. , 1H), 7,20 (D., 1H), 7,28 (m, 2H), 7,54 (D., 1H), 7,6 (m, 2H), 8,48 (S., 1H), 9,52 (broad singlet, 1H).

Ale is, 20,6%

Example 77

A mixture of 6-amino-4-/3'-methylaniline/hintline (0.05 g), benzaldehyde (0,02 ml) and methanol (5 ml) was stirred and heated to boiling point under reflux for 1 hour. The resulting mixture was cooled to ambient temperature and portions were added borohydride sodium (0,0076 g). The mixture was stirred at ambient temperature for 16 hours. The mixture is evaporated and the residue was purified by chromatography on columns using as elution solvent a mixture of methylene chloride and ethyl acetate with a ratio of 4: 1. Was thus obtained 6-benzylamino-4-/3'-methylaniline/hinzelin (0,068 g).

An NMR spectrum: (CD3SOCD3) 2,35 (C., 3H), 4,36 (d, 1H), to 6.67 (t, 1H), 6,93 (D., 1H), of 7.2 to 7.7 (m, 1H), 8,33 (S., 1H), 9,26 (broad singlet, 1H).

Elemental analysis:

found: C 77,3, H 6,1, N, 16,0

calculated for C22H20N40,125 H2O: C 77,1, H 5,9, N 16,4%

Example 78

N, N-Dimethylacetamide (3 ml) was saturated with gaseous dimethylamine was added 6-,2-chloracetamide/-4-/3'-methylaniline/hinzelin (0.2 g). The resulting mixture was stirred at ambient temperature for 18 hours. The mixture is evaporated and the residue was purified by chromatography on columns, using as eaacatalog/-4-/3'-methylaniline/hinzelin (to 0.127 g, 62%), melting point 146 - 148oC.

An NMR spectrum: (CD3SOCD3) 2,32 (C., 9H), 3,14 (S., 2H), 6,94 (d, 1H), 7,26 (t , 1H), 7,65 (m, 2H), 7,75 (D., 1H), 8,13 (m, 1H), 8,53 (..1H), 8,61 (D., 1H), for 9.64 (broad singlet, 1H), of 9.89 (broad singlet, 1H).

Elemental analysis:

found: C 67,7, H 6,5, N 20,6

calculated for C19H21N5O: C 68,0, H 6,3, N 20,9%

Example 79

In accordance with the procedure described in example 11, chloride-hydrogen salt 4-/3'-aminoaniline/-6,7-dimethoxyquinazoline were subjected to interaction with acetic anhydride. The crude product was purified by chromatography on columns using as elution solvent a mixture of methylene chloride, methanol and ammonia with a ratio of 150 : 8 : 1. Thus there was obtained 4-/3'-acetamidoacrylic/-6,7-dimethoxyquinazolin, the output of which was 47%, melting point 252 - 255oC.

An NMR spectrum: (CD3SOCD3) to 2.06 (s, 3H), 3,94 (C., 3H), 3.96 points (C., 3H), 7,18 (with. . 1H), 7,27 - 7,35 (m, 2H), 7,45 (m, 1H), 7,87 (S., 1H), of 8.06 (s, 1H), 8,45 (S., 1H), and 9.5 (broad singlet, 1H), 9,9 (broad singlet, 1H).

Elemental analysis:

found: C 62,9, H 5,5, N 16,1

calculated for C18H18N4O30,25 H2O: C 63,1, H 5,4, N 16.3 PER CENT.

Example 80

A mixture of chloride-hydrogen salt of 4-(3'-amino is eremetical at ambient temperature for 20 hours. The resulting mixture was evaporated, and the residue was purified by chromatography on columns using as elution solvent a mixture of methylene chloride, methanol and ammonia 100 : 8 : 1. Was thus obtained 4-(3'-benzimidazolyl)-6,7-dimethoxyquinazolin (0.15 g, 15%), melting point 239 - 242oC.

An NMR spectrum: (CD3SOCD3) to 3.92 (C., 3H), 3.96 points (C., 3H), 7,18 (S., 1H), 7,34 (t, 1H), 7,45 - 7,63 (m, 5H), 7,87 (S., 1H), of 7.96 (m, 2H), compared to 8.26 (t, 1H), 8,45 (S., 1H), 9,52 (broad singlet, 1H), 10,29 (broad singlet, 1H).

Elemental analysis:

found: C 65,9 H 5,3 13,0 N

calculated for C23H20N4O30,3 CH3OH 0,75 H2O: C 66,1 H 5,4 N 13,2%

Example 81

The following illustrate typical pharmaceutical dosage forms containing the compound of formula 1 or its pharmaceutically acceptable salt (hereafter compound X, such as the compound of examples 1 to 80), which are intended to prevent or treat cancer in humans.

(a) Tablet I mg/tablet

Connection X - 100

Lactose (European Pharmacopoeia) - 182,75

Sodium croscarmellose to 12.0

Maize starch paste (paste 5% weight to volume) was 2.25

Magnesium stearate - 3,0

(b) Tablet II - mg/tablet

Ajmal - 15,0

Polyvinylpyrrolidone (pasta with a 5% weight to volume) was 2.25

Magnesium stearate - 3,0

(c) Tablet III mg/tablet

Connection X - 1,0

Lactose (European Pharmacopoeia) - 93,25

Sodium croscarmellose - 4,0

Maize starch paste (pasta with a 5% weight to volume - 0,75

Magnesium stearate - 1,0

(d) Capsule mg/capsule

Connection X - 10

Lactose (European Pharmacopoeia) - 488,5

Magnesium stearate and 1.5

(e) the Composition for injection I (50 mg/ml)

Compound X 5.0% weight to volume

1 M sodium hydroxide solution to 15.0% of the volume ratio of

0.1 M solution of chloride-hydrogen acid to bring the pH to 7.6)

Polyethylene glycol 400 was 4.5% weight to volume

Water for injection to 100%

(f) the Composition for injection II (10 mg/ml)

Compound X 1.0% weight to volume

Sodium phosphate (British Pharmacopoeia) and 3.6% weight to volume

0.1 M sodium hydroxide solution to 15.0% of the volume ratio of

Water for injection to 100%

(g) the Composition for injection III (1 mg/ml, buffered to pH 6)

Compound X 0.1% weight to volume

Sodium phosphate (British Pharmacopoeia) - of 2.26% weight to volume

Citric acid - 0,100%.

Note:

The above compositions can be obtained by conventional means, which are well known in pharmacology. The tablets (a) - (c) can be applied intersolubility coating using known methods, for example, the coating of acatitla cellulose.

1. Derivatives hintline formula I

< / BR>
in which m denotes 1, 2 or 3;

each R1independently represents a hydroxy, amino, carboxy, carbarnoyl, ureido, (1-4C)alicecullen, N-(1-4C)allylcarbamate, N,N-di[(1-4C)alkyl] carbarnoyl, hydroxyamino, triptoreline, (1-4C)alkyl, (1-4C)alkoxy, (1-3C)alkylenedioxy, (1-4C)alkylamino, di-[(1-(1-4C)alkyl]amino, pyrrolidin-1-yl, piperidino, morpholino, piperazine-1-yl, 4-(1-4C)alkylpiperazine-1-yl, (1-4C)alkylaryl, halogeno-(1-4C)alkyl (except trifloromethyl), hydroxy-(1-4C)alkyl, (1-4C)alkoxy(1-4C)alkyl, amino(1-4C)alkyl, (1-4C)alkylamino-(1-4C)alkyl, di-[(1-4C)alkyl]amino-(1-4C)alkyl, piperidino-(1-4C)alkyl, morpholino-(1-4C)alkyl, piperazine-1-yl-(1-4C)alkyl, 4-(1-4C)alkylpiperazine-1-yl-(1-4C)alkyl, hydroxy-(2-4C)alkoxy(1-4C)alkyl, (1-4C)alkoxy(2-4C)alkoxy(1-4C)alkyl, (1-4C)alkylthio-(1-4C)alkyl, hydroxy-(2-4C)alkylthio-(1-4C)alkyl, aniline-(1-4C)alkyl, phenylthio-(1-4C)alkyl, cyano-(1-4C)alkyl, halogeno-(2-4C)alkoxy, hydroxy(2-4C)alkoxy, (1-4C)Ala is XI, (1-4C)alkylamino-(2-4C)alkoxy, di[(1-4C)alkyl] amino-(2-4C)alkoxy, (1-4C)alkoxy(2-4C)alkanoyloxy, phenyl-(1-4C)alkoxy, aniline-(2-4C)alkoxy, piperidino-(2-4C)alkoxy, morpholino-(2-4C)alkoxy, piperazine-1-yl-(2-4C)alkoxy, 4-(1-4C)alkylpiperazine-1-yl(2-4C)alkoxy, hydroxy(2-4C)alkylamino, (1-4C)alkoxy(2-4C)alkylamino, amino(2-4C)alkylamino, (1-4C)alkylamino-(2-4C)alkylamino, di-[(1-4C)alkyl] amino-(2-4C)alkylamino, phenyl-(1-4C)alkylamino, (2-4C)alkanolamine, benzamido, benzosulfimide, 3 phenylurea, 2-oxopyrrolidin-1-yl, 2,5-dioxopiperidin-1-yl, halogeno-(2-4C)alkanolamine, hydroxy-(2-4C)alkanolamine, (1-4C)alkoxy(2-4C)alkanolamine, (1-4C)alkoxycarbonyl-(2-4C)alkanolamine, amino(2-4C)alkanolamine, (1-4C)alkylamino-(2-4C)alkanolamine or di-[(1-4C)alkyl] amino-(2-4C)alkanolamine;

n denotes 1 or 2;

R2independently represents hydrogen, hydroxy, halogeno, trifluoromethyl, amino, nitro, cyano, (1-4C)alkyl or (1-4C)alkoxy,

or their pharmaceutically acceptable salts;

except that the scope of the present invention does not include 4-(4'-hydroxyimino)-6-methoxyquinazoline, 4-(4'-hydroxyimino)-6,7-methylenedioxybenzene, 4-(4'-hydroxyimino)-6,7,8-trimethoxyaniline, 6-amino-4-(4'-aminoaniline)hinzelin, 4-aniline-6-meth is ü, 4-(4'-methoxyaniline)-8-methoxy-hinzelin, 4-(4'-chloroanilino)-8-methoxyquinazoline, 8-hydroxy-4-(4'-methoxyaniline)hinzelin and 4-(4'-chloroanilino)-8-hydroxyquinazoline.

2. Derivatives hintline formula I according to claim 1 wherein m is 1, 2 or 3, R1regardless of other elements is hydroxy, amino, carboxy, carbarnoyl, ureido, (1-4C)alkoxycarbonyl, N-(1-4C)allylcarbamate, N,N-di-[(1-4C)alkyl] carbarnoyl, (1-4C)alkyl, (1-4C)alkoxy, (1-3C)alkylenedioxy, (1-4C)alkylamino, di-[(1-4C)alkyl] amino, (1-4C)alkylthio, halogeno-(1-4C)alkyl (except trifloromethyl), hydroxy-(1-4C)alkyl; (1-4C)alkoxy(1-4C)alkyl, amino(1-4C)alkyl, (1-4C)alkylamino-(1-4C)alkyl, di-[(1-4C)alkyl] amino(1-4C)alkyl, piperidino-(1-4C)alkyl, morpholino-(1-4C)alkyl, piperazine-1-yl-(1-4C)alkyl, 4-(1-4C)alkylpiperazine-1-yl-(1-4C)alkyl, (1-4C)alkoxy(2-4C)alkoxy(1-4C)alkyl, (1-4C)alkylthio-(1-4C)alkyl, hydroxy-(2-4C)alkylthio-(1-4C)alkyl, halogeno-(2-4C)alkoxy, hydroxy(2-4C)alkoxy, (1-4C)alkoxy(2-4C)alkoxy, carboxy-(1-4C)alkoxy, (1-4C)alkoxycarbonyl-(1-4C)alkoxy, carbarnoyl-(1-4C)alkoxy, amino-(2-4C)alkoxy, (1-4C)alkylamino-(2-4C)alkoxy, di-[(1-4C)alkyl] amino-(2-4C)alkoxy, hydroxy(2-4C)alkylamino, (1-4C)alkoxy(2-4C)alkylamino, amino(2-4C)alkylamino, (1-4C)alkylamino-(2-4C)alkylamino, di-[(1-4C)alkyl]amino-(2-4C)Alki is about, (1-4C)alkoxy(2-4C)alkanolamine, (1-4C)alkoxycarbonyl-(2-4C)alkanolamine, amino(2-4C)alkanolamine, (1-4C)alkylamino-(2-4C)alkanolamine or di-[(1-4C)alkyl] amino-(2-4C)alkanolamine; n is 1 or 2, and R2independently represents hydrogen, hydroxy, halogeno, trifluoromethyl, amino, nitro, cyano, (1-4C)alkyl or (1-4C)alkoxy, or their pharmaceutically acceptable salts; except that the scope of the present invention is not 4-(4'-hydroxyimino)-6-methoxyquinazoline, 4-(4'-hydroxyimino)-6,7-methylenedioxybenzene, 4-(4'-hydroxyimino)-6,7,8-trimethoxybenzoyl, 6-amino-4-(4'-aminoaniline)hinzelin, 4-aniline-6-methylpyrazole or its hydrochloric salt and 4-aniline-6,7-dimethoxyquinazolin or its hydrochloric salt, 4-(4'-methoxyaniline)-8-methoxy-hinzelin, 4(4'-chloroanilino)-8-methoxyquinazoline, 8-hydroxy-4-(4'-methoxyaniline)hinzelin and 4(4'-chloroanilino)-8-hydroxyquinazoline.

3. Derivatives hintline formula I on p. 1, where m denotes 1 or 2, and R1independently represents hydroxy, amino, carboxy, (1-4C)alkoxycarbonyl, (1-4C)alkyl, (1-4C)alkoxy, (1-3C)alkylenedioxy, (1-4C)alkylamino, di-[(1-4C)alkyl] amino, (1-4C)alkylthio, hydroxy-(1-4C)alkyl, (1-4C)alkoxy(1-4C)alkyl, amino(1-4C)alkyl, (1-4C)alkylamino-(1-4C)alkyl, the carbonyl-(1-4C)alkoxy, (2-4C)alkanolamine, benzamido or benzosulfimide; n is 1 or 2, and R2independently represents hydrogen, hydroxy, halogeno, trifluoromethyl, amino, nitro, cyano, (1-4C) alkyl or (1-4C)alkoxy, or their pharmaceutically acceptable salts; except that the scope of the present invention does not include 4-(4'-hydroxyimino)-6-methoxyquinazoline, 4-(4'-hydroxyimino)-6,7-methylenedioxyaniline, 6-amino-4-(4'-aminoaniline)hinzelin, 4-aniline-6-methylpenicillin or its hydrochloric salt and 4-aniline-6,7-dimethoxyquinazolin or its hydrochloric salt, 4-(4'-methoxyaniline)-8-methoxyquinazoline, 4(4'-chloroanilino)-8-methoxyquinazoline, 8-hydroxy-4-(4'-methoxyaniline)hinzelin and 4(4'-chloroanilino)-8-hydroxyquinazoline.

4. Derivatives hintline formula I under item 1 subject to the conditions listed in paragraph 1, where m is 1 or 2 or 3 and R1independently represents hydroxy, amino, ureido, methoxycarbonyl, etoxycarbonyl, hydroxyamino, triptoreline, methyl, ethyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, methylenedioxy, Ethylenedioxy, methylamino, ethylamino, dimethylamino, diethylamino, piperidino, morpholino, methylthio, ethylthio, methyl bromide, dibromomethyl, methoxymethyl, piperidinomethyl, morpholinomethyl, pipermail, 2 bromoethoxy, 2-hydroxyethoxy, 3 hydroxypropoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 3 methoxypropane, 3 ethoxypropane, ethoxycarbonylmethoxy, ethoxycarbonylmethoxy, carbamoylmethyl, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 2-methoxyethoxy, benzyloxy, 2-onlinetake, 2-piperidinoethyl, 2-morpholinoethoxy, 2-(piperazine-1-yl)ethoxy, 2-hydroxyethylamino, 3 hydroxypropylamino, 2-methoxyethylamine, 2-ethoxyethylene, 3 methoxypropylamine, 3 ethoxypropylamine, 2-diethylaminoethylamine, 2 diethylaminoethylamine, 3 dimethylaminopropylamine, 3 diethylaminopropylamine, acetamido, propionamido, benzamido, 3 phenylurea, 2-chloroacetamido, 2-oxopyrrolidin-1-yl, 2-hydroxyacetamido, 2-methoxyacetate or 2-ethoxyacetic; n is 1 or 2, R2regardless of other elements represents hydrogen, fluorine, chlorine, bromine, trifluoromethyl, nitro, cyano, methyl or ethyl; or their pharmaceutically acceptable salts.

5. Derivatives hintline formula I on p. 1 taking into account the guidance given in paragraph 1, where (R1)mis 6-hydroxy, 7-hydroxy, 6,7-dihydroxy, 6-amino, 7-amino, 6-ureido, 6-triptoreline, 6-methyl, 6,7-dimethyl, 6-methoxy, 7-methoxy, 6,7-dimethoxy, 6,7-diethoxy, 6-hydroxy-7-methoxy, 7-hydroxy-6-methoxy, 6-a is 6-dimethylamino, 6-methoxymethyl, 6-(2-methoxyethoxymethyl), 6-cyanomethyl, 7-(2-hydroxyethoxy)-6-methoxy, 6,7-di-(2-hydroxyethoxy), 6-(2-methoxyethoxy), 6-methoxy-7-(2-methoxyethoxy), 6,7-di-(2-methoxyethoxy), 7-(2-bromoethoxy)-6-methoxy, 7-benzyloxy-6-methoxy, 6-(2-methoxyethylamine), 6-acetamido, 6-(2-chloroacetamido), 6-(2-methoxyacetate) or 7-(2-methoxyacetate); and (R2)nis hydrogen, 4'-fluoro, 3'-chloro, 3'-bromo, 3',4'-dichloro, 4'-fluoro-3'-chloro, 3'-trifluoromethyl, 4'-fluoro-3'-trifluoromethyl, 3'-nitro, 3'-nitro-4'-chloro, 3'-nitro-4'-fluoro or 3'-methyl; or pharmaceutically acceptable salt accession acid.

6. Derivatives hintline formula I or its pharmaceutically acceptable salt accession acid on p. 1, selected from the group including

4-(3'-chloro-4'-foronline)-6,7-dimethoxyquinazolin,

4-(3',4'-dichloraniline)-6,7-dimethoxyquinazolin,

6,7-dimethoxy-4-(3'-nitroaniline)hinzelin,

6,7-dimethoxy-4-(3'-methylaniline)hinzelin,

6-methoxy-4-(3'-methylaniline)hinzelin,

4-(3'-chloroanilino)-6-methoxyquinazoline,

6,7-Ethylenedioxy-4-(3'-methylaniline)hinzelin,

6-amino-7-methoxy-4-(3'-methylaniline)hinzelin,

4-(3'-methylaniline)-6-ureidopenicillin and

6-(2-methoxyethoxymethyl)-4-(3'-methylaniline)hinzelin.

7. P-hydroxy, 7-hydroxy, 6,7-dihydroxy, 6-amino, 7-amino, 6-ureido, 6-triptoreline, 6-methyl, 6,7-dimethyl, 6-methoxy, 7-methoxy, 6,7-dimethoxy, 6,7-diethoxy, 6-hydroxy-7-methoxy, 7-hydroxy-6-methoxy, 6-amino-7-methoxy, 6-amino-7-methylthio, 5-amino-6,7-dimethoxy, 6-methoxy-7-isopropoxy, 6,7-methylenedioxy, 6,7-Ethylenedioxy, 6-methylamino, 7-methylamino, 6-dimethylamino, 6-amino-7-methylamino, 6-methoxymethyl, 6-methyl bromide, 6-(2-methoxyethoxymethyl), 6-cyanomethyl, 6-methylthiomethyl, 6-phenylthiomethyl, 7-(2-hydroxyethoxy)-6-methoxy, 6,7-di-(2-hydroxyethoxy), 6-(2-bromoethoxy), 6-(2-methoxyethoxy), 6-methoxy-7-(2-methoxyethoxy), 6,7-di-(2-methoxyethoxy), 7-(2-bromoethoxy)-6-methoxy, 7-benzyloxy-6-methoxy, 6-(2-methoxyethylamine), 6-acetamido, 6-benzamido, 6-(2-chloroacetamido), 6-(2-methoxy-acetamido) or 7-(2-methoxyacetate); and (R2)nis hydrogen, 4'-fluoro, 3'-chloro, 3', 4'-dichloro, 4'-fluoro-3'-chloro, 3'-trifluoromethyl, 4' -fluoro-3'-trifluoromethyl, 3'-nitro, 3'-nitro-4'-chloro, 3'-nitro-4'-fluoro or 3'-methyl and 3'-bromo; or their pharmaceutically acceptable salts accession acid.

8. Derived hintline formula I or its pharmaceutically acceptable salt accession acid on p. 1, selected from the group including

6,7-di(2-methoxyethoxy)-4-(3'-methylaniline)hinzelin,

6-dimethylaminoethoxy of hintline formula I or their pharmaceutically acceptable salts according to any one of paragraphs. 1 to 8, characterized in that the interact of hintline formula III

< / BR>
in which Z represents a substitutable group;

R1and m have any of the values defined in paragraph 1,

with an aniline of the formula IV

< / BR>
where R2and n have the meanings given in paragraph 1,

subsequent, optional, perform the following steps:

a) break down the compound obtained of the formula I, in which R1or R2represents (1-4C)alkoxy, to obtain compounds of the formula I, in which R1or R2represents hydroxy;

in) acelerou derived hintline formula I, in which R1represents amino, to obtain compounds of the formula I, in which R1is (2-4C)alkanolamine or substituted (2-4C)alkanolamines, as defined in paragraph 1, ureido, 3 phenylurea or benzamido;

C) alkylate derived hintline formula I, in which R1represents hydroxy or amino, for producing compounds of the formula I, in which R1represents (1-4C)alkoxy or substituted (1-4C)alkoxy, as defined in paragraph 1, or R1represents (1-4C)alkylamino or substituted (1-4C)alkylamino, as defined in paragraph 1;

d) hydrolyzing the derivative hintline(1-4C)alkoxycarbonyl group, as defined in paragraph 1, to obtain compounds of the formula I, in which R1represents carboxyl Deputy or Deputy, including carboxyl group, as defined in paragraph 1;

e) derived hintline formula I, in which R1represents (1-4C)alkyl having substituted group, interact with the appropriate amine, alcohol, thiol or cyanide, to obtain compounds of the formula I, in which R1represents amino, hydroxy-, thio - or tiananamen (1-4C)alkyl, and, if necessary, obtain pharmaceutically acceptable salts derived hintline formula I interact the specified connection with acceptable acid in accordance with the known method.

10. The method of obtaining derivatives of hintline General formula I

< / BR>
or their pharmaceutically acceptable salts,

where R2, m and n have the meanings given in paragraph 1;

R1means an amino group.

characterized in that the restoring compound of General formula I, where R1means the nitrogroup, and a value of R2, m and n are specified in paragraph 1 and, if necessary, obtain pharmaceutically acceptable salts derived hintline formula I interact the specified connection with priemlemee tyrosine kinase, characterized in that it contains a derivative of hintline formula I or its pharmaceutically acceptable salt according to any one of paragraphs.1 - 8 in an effective amount, in combination with a pharmaceutically acceptable diluent or excipient.

Priority points:

under item 1: m is 1 or 2; R1is hydroxy, amino, carboxy, (1-4C)alkoxycarbonyl, (1-4C)alkyl, (1-4C)alkoxy, (1-3C)alkylenedioxy, (1-4C)alkylamino, di-[(1-4C)alkyl] amino, (1-4C)alkylthio, hydroxy-1-(1-4C)alkyl, (1-4C)alkoxy(1-4C)alkyl, amino(1-4C)alkyl, (1-4C)alkylamino-(1-4C)alkyl, di-[(1-4C)alkyl] amino-(1-4C)alkyl, hydroxy-(2-4C)alkoxy, (1-4C)alkoxy(2-4C)alkoxy, carboxy-(1-4C)alkoxy), (1-4C)alkoxycarbonyl-(1-4C)alkoxy, (2-4C)alkanolamine, benzamido, benzosulfimide; n is 1 or 2; R2is hydrogen, hydroxy, halogeno, trifluoromethyl, amino, nitro, cyano, (1-4C)alkyl or (1-4C)alkoxy - 20.01.92;

under item 9, in addition to stages b), C), (d) and (e) - 20.01.92;

under item 1: m means 3, R1- carbarnoyl, ureido, N-(1-4C)allylcarbamate, N, N-di-[(1-4C)alkyl)] carbarnoyl, halogeno-(1-4C)alkyl, piperidino-(1-4C)alkyl, morpholino-(1-4C)alkyl, piperazine-1-yl(1-4C)alkyl, 4-(1-4C)alkylpiperazine-1-yl-(1-4C)alkyl, hydroxy-(2-4C)alkoxy-(1-4C)alkyl, (1-4C)alkoxy(2-4C)alkoxy(1-4C)alkyl, (1-4C)alkylthio-(1-4C)alkyl, hydroxy-(2-4C)Ala[(1-4C)Alky]amino-(2-4C)alkoxy, hydroxy-(2-4C)alkylamino, (1-4C)alkoxy(2-4C)alkylamino, amino(2-4C)alkylamino, (1-4C)alkylamino-(2-4C)alkylamino, di-[(1-4C)Alky] amino-(2-4C)alkylamino, halogen-(2-4C)alkanolamine, hydroxy-(2-4C)alkanolamine, (1-4C)alkoxy(2-4C)alkanolamine, (1-4C)alkoxycarbonyl-(2-4C)alkanolamine, amino(2-4C)alkanolamine, (1-4C)alkylamino-(2-4C)alkanolamine or N, N-di-[(1-4C)alkyl] amino-(2-4C)alkanolamine - 26.06.92;

under item 9, in addition to stage a), and on p. 10 - 26.06.92;

under item 1: R1hydroxylamino, triptoreline, pyrrolidin-1-yl, piperidino, morpholino, piperazine-1-yl, 4-(1-4C)alkylpiperazine-1-yl, aniline-(1-4C)alkyl, phenylthio-(1-4C)alkyl, cyano-(1-4C)alkyl, (1-4C)alkoxy(2-4C)alkanoyloxy, phenyl-(1-4C)alkoxy, aniline-(2-4C)alkoxy, piperidino-(2-4C)alkoxy, morpholino-(2-4C)alkoxy, piperazine-1-yl(2-4C)alkoxy, 4-(1-4C)alkylpiperazine-1-yl-(2-4C)alkoxy, phenyl-(1-4C)alkylamino, 3 phenylurea, 2-oxopyrrolidin-1-yl, 2,5-dioxopiperidin-1-yl, and p. 11 - 12.11.92.

 

Same patents:

The invention relates to novel condensed derivative indana formula I

< / BR>
in which A represents an optionally substituted benzene ring, naphthalene ring or benzene ring condensed with the lowest alkylenedioxy; ring B represents an optionally substituted benzene, Y = -N= CR or CR=N-

The invention relates to new triazolylmethyl tertiary amine of the formula I, where A is a simple bond or lower Allenova group; B is a lower alkyl, a group (a), naphthyl, pyridyl, thienyl, thiazolyl, benzothiazolyl, hinely, benzofurazanyl or benzothiazolyl, possibly substituted with halogen or alkyl; D - ring group, (b) or benzofurazanyl; E - ring - 4H-1,2,4-triazole or 1H-1,2,4-triazolyl; R1- H, halogen, cyano-, nitro-group, CF3, lower alkyl or alkoxy; R2is hydrogen or halogen; R3- halogen, cyano-, nitro-, CF3or amino group, provided that when both R1and R2are chlorine atoms, And a methylene

The invention relates to new Amida 4 - oxoazetidin-2-sulphonic acids and their salts, to a process of obtaining

The invention relates to pyrazole derivative of the General formula I, where g2, g3and g6hydrogen; g4- chlorine atom or bromine, WITH1-C3-alkyl, trifluoromethyl, or phenyl; g5is hydrogen or chlorine atom; w2, w3, w5and w6is hydrogen or chlorine atom; w4is hydrogen, a chlorine atom, a C1-C3-alkyl, C1-C3-alkoxy or nitro; X is a direct bond or the group -(CH2)nN(R3)-, where R3is hydrogen or C1-C3-alkyl; n is 0 or 1; R4is hydrogen or C1-C3-alkyl and, when X is a direct bond, R is a group-NR1R2where R1is hydrogen, C1-C6-alkyl or cyclohexyl, and R2- C1-C6-alkyl, non-aromatic carbocyclic radical WITH3-C15possibly substituted by a hydroxyl group, one or more1-C5-alkilani,1-C5alkoxygroup or halogen; amino group WITH1-C4-alkyl in which the amino may dazamide1-C3-alkyl, cyclohexyl1-C3-alkyl; phenyl, unsubstituted or substituted with halogen, or WITH1-C5-alkyl; phenyl WITH1-C3-alkyl, diphenyl1-C3-Olinala, hinokitiol and oxybutylene, unsubstituted or substituted C1-C3-alkyl or benzyl; 1-adamantaneacetic; C1-C3-alkyl, substituted aromatic heterocycle selected from pyrrolyl, pyridyl or indolyl, unsubstituted or substituted C1-C5-alkyl, or R1and R2form together with the nitrogen atom to which they relate, pyrrolidinyl, piperidyl or morpholinyl; or the group R5that represents phenyl WITH1-C3-alkyl, unsubstituted or substituted C1-C5-alkyl; cyclohexyl1-C3-alkyl, or 2-norbornylene; when X represents a group -(CH2)nN(R3)-, R represents a group R2Athat represents a non-aromatic carbocyclic radical WITH3-C15; phenyl substituted by halogen; phenyl WITH1-C3-alkyl, possibly substituted with halogen; indolyl, possibly substituted C1-C5alkoxygroup; anthracene, or group with other2bin which R2b- cyclohexyl, substituted, phenyl, unsubstituted or substituted by one or two halogen atoms, WITH1-C5-alkyl or C1-C5alkoxygroup or their acid additive salts

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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

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