Derivatives of 4-(substituted phenylamino)hintline or their pharmaceutically acceptable salt, a method of inhibiting receptor tyrosine kinase and pharmaceutical composition

 

(57) Abstract:

The proposed derivatives of 4-(substituted phenylamino)hintline formula 1 in which m is 1 or 2, n represents 1 or 2; each R1independently selected from the group consisting of halogen; cyano; hydroxy; R5; nitro; amino; trifloromethyl; C(=O)O R5, R5O, optionally substituted with halogen, hydroxy, (1-4)alkoxy, acetoxy, (1-4)With alkylpiperazine, morpholinium, imidazolyl, 4-oxopyridine or S(1-3)C - alkyl, optionally substituted by carboxy; SO2R5; SR5, optionally substituted by cyano, (1-4)alkyl, S(1-4)alkyl or 4-cyanophenyl group; toluensulfonate, NHSO2R5; benzylmorphine or phenylsulfonyl, optionally substituted by 1-2 halogen atoms; phenoxy, optionally substituted with 1-2 substituents selected from halogen, (1-4)alkyl, (1-4) - alkoxy, methanesulfonyl, methanesulfonyl and halogenbenzonitriles; arylsulfonyl; vinyloxy, guanidino, phthalimido (1-4)With alkylsulfonamides; or two R1fragment, taken together, 6 and 7 positions of hintline form methylenedioxy, where the alkyl groups and alkyl fragments of these alkoxygroup can be p is P> is hydrogen, each R3group independently selected from hydrogen, halogen and (1-4)alkyl, R4is azido or (2-4)With quinil where specified quinil optionally substituted by hydroxy, amino or aminomethyl group, R5is (1-4)alkyl, or their pharmaceutically acceptable salts. These compounds inhibit the receptor tyrosinekinase and can be useful in the treatment of hyperproliferative diseases, such as malignant tumors in mammals. In addition, the proposed method of inhibiting receptor tyrosine kinase and a pharmaceutical composition having anti-proliferative activity. 3 S. and 4 C.p. f-crystals, 2 tab.

This invention relates to derivatives of 4- (substituted phenylamino)hintline, which are useful in the treatment of hyperproliferative diseases, such as malignant tumors (cancer) in mammals.

Many of the current methods of treating cancer using compounds that inhibit DNA synthesis. Such compounds are usually toxic to cells, but their toxic effect on rapidly dividing tumor cells may be beneficial. Were developed alternative approaches to anti-cancer agents, Vija against cancer cells.

It is known that cells can become cancerous due to the transformation of a portion of its DNA into an oncogene (i.e., genes that upon activation lead to the formation of malignant tumor cells). Many oncogenes encode proteins that are aberrant tyrosine kinases that can cause transformation of cells. Alternatively, overexpression of normal protooncogene tyrosine kinase may also result in proliferative disorders, sometimes resulting in a malignant phenotype.

Receptor tyrosine kinase are large enzymes that span the cell membrane and possess an extracellular binding domain for growth factors such as epidermal growth factor, a transmembrane domain and an intracellular part, which functions as a kinase, phosphorylase specific the tyrosine residues in proteins and, consequently, affecting cell proliferation. It is known that these kinases are often aberrant expressed in normal cancerous human tumors, such as breast cancer, cancer of the gastrointestinal tract, such as cancer of the colon, cancer of the rectum or stomach, leukemia, and ovarian cancer, bronchial or pancrea tyrosine kinase, motirola and/or sverkhekspressiya in many cancerous human tumors, such as tumors of the brain, lung, squamous cell, bladder, gastric, breast, head and neck, esofagului, gynecological and thyroid tumors.

Respectively, was recognized that inhibitors of receptor tyrosinekinase are useful as selective inhibitors of the growth of cancer cells in mammals. For example, erbstein, a tyrosine kinase inhibitor that selectively attenuatum (TERS) in animicheskih naked mice transplanted growth of breast carcinoma person, which expresses the receptor tyrosinekinase of epidermal growth factor (EGFR), but has no effect on the growth of other carcinomas, which does not expresses the EGF receptor.

It was also shown that any abscopal properties tyrosine kinase possess various other compounds, such as derivatives of styrene. Most recently, in five European patent publications, namely, EP 0 566 226 A1, EP 0 602 851 A1, EP 0 635 507 A1, EP 0 635 498 A1 and EP 0 520 722 A1, it has been described that some derivatives of hintline possess anti-cancer properties that result from their properties of inhibiting tyrosine kinase. In PCT publication WO 92/20 insincerity.

Although the above-described anti-cancer compounds make an important contribution in this area of technology, in this branch of engineering is the ongoing search for improved anticancer pharmaceutical substances.

This invention is directed to 4-substituted, phenylamino/hintline derivatives of the formula

< / BR>
and their pharmaceutically acceptable salts and prodrugs, where:

m represents 1, 2 or 3;

each R1independently selected from hydrogen, halogen, hydroxy, amino, hydroxyamino, carboxy, (1-4)C - alkoxycarbonyl, nitro, guanidino, ureido, carbamoyl, cyano, trifloromethyl, (R6)2N-carbonyl and phenyl-W-alkyl, where W is selected from a single bond, O, S and NH;

or each R1independently selected from cyano-(1-4)C alkyl and R9where R9selected from the group consisting of R5, R5O, (R6)2N, R7C(=O) R5ONH, A and R5Y; R5is (1-4)C alkyl; R6represents hydrogen or R5where the symbols R5are the same or different; R7is R5, R5O or (R6)2N; A is selected from piperidino , morpholino, pyrrolidino and 4-R6-piperazine-1-yl imidazol-1-yl, 4-pyridone-1-yl, carboxy-(1-4)C-alkyl, phenoxy,global fragments in (R6)2N are optionally substituted by halogen, or R9where R9has the values defined above, and alkyl fragments in5and R5O are optionally substituted by halogen, R6O or R9where R6and R9have the meanings defined above, and where the resulting group optionally substituted by halogen, or R9assuming that the atom is nitrogen, oxygen or sulfur and another heteroatom may not be attached to the same carbon atom, and with the additional condition that no more than three "R9" link can be included in R1;

or each R1independently selected from R5- sulfonylamino, phthalimido-(1-4)C alkylsulfonyl, benzamido, benzosulfimide, 3 phenylurea, 2-oxopyrrolidin-1-yl, 2,5 - dioxopiperidin-1-yl, and R10-(2-4)C alkanolamine, where R10selected from halogen, R6O, (2-4)C-alkanoyloxy, R7C(=), and (R6)2N; and where specified benzamido, or benzosulfimide, or phenyl, or phenoxy, or aniline, or phenylsulfanyl Deputy in R1may optionally bear one or two of halogen, (1-4)alkyl, cyano, methanesulfonyl or (1-4)alkoxy substituent;

or labeause, at least one or two heteroatoms selected from oxygen, sulfur or nitrogen; and where the alkyl groups or the alkyl part of alkoxy or alkylamino groups can be straight chain, or, if they are composed of at least three carbon atoms, they may be branched or cyclic;

R2selected from hydrogen and optionally substituted (1-6)C - alkyl;

n represents 1 or 2, and each R3independently selected from hydrogen, optionally substituted (1-6)C-alkyl, optionally substituted amino, halogen, hydroxy, optionally substituted by hydroxy;

R4is azido or R11-ethinyl, where R11selected from hydrogen, optionally substituted (1-6) C-alkyl, where the substituents are selected from hydrogen, amino, hydroxy, R5O, R5NH and (R5)2N

More particularly this invention relates to compounds of the formula I, in which m, n, R1and R3have the meanings defined above, and R2represents hydrogen, and R4is R11-ethinyl, where R11selected from hydrogen, optionally substituted (1 - 6)C-alkyl, where the substituents are selected from hydrogen, amino, hydroxy, R5O, R5NH and (R5)2N, or R4performance is defined above, and m represents 1 or 2; each R1independently selected from hydrogen, hydroxy, amino, hydroxyamino, carboxy, nitro, carbamoyl, ureido;

R5, optionally substituted by halogen, R6OH, HOC(=O) (R6)2NC(=O), A and (R6)2N;

R12O, where R12is HK, and K represents the (2-4)C-alkyl, optionally substituted by halogen, R6O, (2-4)C - alkanoyloxy, HOC(=O), A and (R6)2N, R6OKO, R6OKNH, CN and phenyl;

R5NH, optionally substituted by halogen, (2-4)C - alkanoyloxy, R6O, R7C(=O) (R6)2N, A, R6OKO, R6OKNH, C6H5Y, CN;

(R6)2N(C= O), R5ONH, R5S, (1-4) C-alkylsulfonamides, phthalimido-(1-4)C-alkylsulfonamides: 3-phenylurea, 2-oxopyrrolidin-1-yl, 2,5-dioxopiperidin-1-yl, halogen-(2-4)C-alkanolamine, hydroxy-(2-4)C-alkanolamine, (2-4) C-alkanoyloxy-(2-4)C-alkanolamine, (1-4)alkoxy-(2-4) C-alkanolamine, carboxy-(2-4)C-alkanolamine, (1-4) C-alkoxycarbonyl-(2 - 4)C-alkanolamine, carbarnoyl-(2-4) C-alkanolamine, N-(1-4)C-allylcarbamate- (2-4)C-alkanolamine, N, N-di[(1-4)alkyl]-carbarnoyl-(2-4)C-alkanolamine, amino- (2-4)C-alkanolamine, (1-4)C-alkylamino-(2-4)C-alkanolamine, di- (1-4)C-alkylamino-(2-4)C-alkanolamine, and where specified phenyl is or (1-4)C-alkoxy substituent; or any two of R1taken together with the carbon atoms to which they are attached, form a 5-8-membered ring including at least one or two heteroatoms selected from oxygen, sulfur or nitrogen; and where the alkyl groups and the alkyl part of alkoxy or alkylamino groups can be straight chain, or, if they are composed of at least three carbon atoms, they may be branched or cyclic;

each R3independently selected from hydrogen, methyl, ethyl, amino, halogen and hydroxy;

R4is R11-ethinyl, where R11represents hydrogen.

Most particularly this invention relates to compounds of the formula I, in which m, n, R1, R2and R3have the meanings defined above, and each R1independently selected from hydrogen, hydroxy, amino, hydroxyamino, nitro, carbamoyl, ureido, R5, optionally substituted by halogen, R6O, HOC(=O), H2NC(=O);

R5O, optionally substituted with halogen, R6Oh, (2-4)C-alkanoyloxy HOC(= O) (R6)2N, A, phenyl;

R5NH, (R5)2N, R5NH2, (R5)2NH, R5NHC(=O) (R5)2NC(=O) R5S, phenyl-(2-4)C-alkoxy, and where specified fees; or any two of R1taken together with the carbon to which they are attached, form a 5-8-membered ring including at least one or two heteroatoms selected from oxygen, sulfur or nitrogen; and where the alkyl groups and the alkyl part of alkoxy or alkylamino groups can be straight chain, or, if they are composed of at least three carbon atoms, they may be branched or cyclic.

This invention most particularly relates to compounds of formula I, selected from the group consisting of the following:

(6,7-dimethoxyquinazolin-4-yl)- (3-ethynylphenyl)-amine;

(6,7-dimethoxyquinazolin-4-yl)- [3-(3'-hydroxypropyl-1-yl) phenyl]-amine,

(6,7-dimethoxyquinazolin-4-yl)- [(3-(2'-(aminomethyl)-ethinyl)phenyl] -amine;

[(3-ethynylphenyl)- (6-nitroquinazoline-4-yl)]-amine,

(6,7-dimethoxyquinazolin-4-yl)- (4-ethynylphenyl)-amine,

(6,7-dimethoxyquinazolin-4-yl)- (3-ethinyl-2-were)-amine, (6-aminoquinazolin-4-yl)- (3-ethynylphenyl)-amine,

(3-ethynylphenyl)- (6-methanesulfonylaminoethyl - 4-yl)-amine,

(3-ethynylphenyl)- (6,7-methylenedioxyaniline-4-yl)- amine,

(6,7-dimethoxyquinazolin-4-yl)- (3-ethinyl-6-were) -amine,

(3-ethynylphenyl)- (7-nitroquinazoline-4-yl) -amine,

(3-ethynylphenyl) is] hinzelin-4-yl}- amine,

(3-ethynylphenyl)- (6-guanidinopentanoic-4-yl)-amine,

(7-aminoquinazolin-4-yl)- (3-ethynylphenyl)-amine,

(3-ethynylphenyl)- (7-methoxyquinazoline-4-yl)-amine,

(6-carbomethoxybiphenyl-4-yl)- (3-ethynylphenyl)-amine,

(7-carbomethoxybiphenyl-4-yl)- (3-ethynylphenyl)-amine,

[6,7-bis(2-methoxyethoxy) hinzelin-4-yl]- (3-ethynylphenyl) amine,

(3-azidophenyl)- (6,7-dimethoxyquinazolin-4-yl) -amine,

(4-azidophenyl)- (6,7-dimethoxyquinazolin-4-yl) amine,

(3 azido-5-chlorophenyl)- (6,7-dimethoxyquinazolin-4-yl) amine,

(3-ethynylphenyl)- (6-methanesulfonyl-hinzelin-4-yl)- amine,

(6-econsultancy - hinzelin-4-yl)- (3-ethynylphenyl)-amine,

(6,7-dimethoxy - hinzelin-4-yl)- (3-ethinyl-4-fluoro-phenyl) -amine,

(6,7-dimethoxy - hinzelin-4-yl)- (3-propyne-1-yl-phenyl)- amine,

[6,7-bis-(2-methoxy-ethoxy) -hinzelin-4-yl] - (5-ethinyl-2-were) -amine,

[6,7-bis-(2 - methoxy-ethoxy) -hinzelin-4-yl] - (3-ethinyl-4-forfinal) -amine,

[6,7-bis-(2-chloro-ethoxy) -hinzelin-4-yl]- (3-ethinyl - phenyl)-amine,

[6-(2-chloro-ethoxy)-7- (2-methoxy-ethoxy) -hinzelin-4-yl]- (3-ethinyl-phenyl) -amine,

[6,7-bis-(2-acetoxy-ethoxy) -hinzelin-4-yl]- (3-ethinyl-phenyl) -amine,

2-[4-(3-ethinyl-phenylamino)- 7-(2-hydroxy-ethoxy) -hinzelin-6-yloxy] -ethanol,

[6-(2-acetoxy-ethoxy) -7-(2-meetinr-phenyl) -amine,

[7-(2-acetoxy-ethoxy) -6-(2-methoxy-ethoxy) -hinzelin-4 - yl]- (3-ethinyl-phenyl)-amine,

2-[4-(3-ethinyl-phenylamino)- 6-(2-hydroxy-ethoxy) -hinzelin-7-yloxy] -ethanol,

2-[4-(3-ethinyl-phenylamino) -7-(2-methoxy-ethoxy) -hinzelin-6-yloxy] -ethanol,

2-[4-(3-ethinyl-phenylamino) -6-(2-methoxy-ethoxy) -hinzelin-7-yloxy] -ethanol,

[6-(2-acetoxy-ethoxy)- 7-(2-methoxy-ethoxy)- hinzelin-4-yl]- (3-ethinyl-phenyl) -amine,

(3-ethinyl-phenyl)- { 6-(2-methoxy-ethoxy)-7-[2- (4-methyl-piperazine-1-yl)-ethoxy] -hinzelin-4-yl}-amine,

(3-ethinyl-phenyl)- [7-(2-methoxy-ethoxy)-6- (2-morpholine-4-yl) -ethoxy)-hinzelin-4-yl] -amine,

(6,7-detoxification-1-yl) -(3-ethynylphenyl)-amine,

(6,7-dimetocsibenzoy-1-yl) -(3-ethynylphenyl) -amine,

(6,7-diisopropylaniline-1-yl) -(3-ethynylphenyl)-amine,

(6,7-detoxification-1-yl) -(3-ethinyl-2-methyl-phenyl) -amine,

[6,7-bis-(2-metoxi-ethoxy) -hinzelin-1-yl] - (3 - ethinyl-2-were) -amine,

(3-ethynylphenyl)- [6-(2-hydroxy-ethoxy) -7-(2-methoxy-ethoxy) -hinzelin-1-yl] -amine,

[6,7-bis-(2-hydroxy-ethoxy) -hinzelin-1-yl]- (3-ethinyl-2 - were) -amine and

2-[4-(3-ethinyl-phenylamino)- 6-(2-methoxy-ethoxy)- hinzelin - 7-yloxy] -ethanol.

Another aspect of the invention is a process for obtaining compounds of the forms of the people, hydroxy, amino, hydroxyamino, carboxy, (1-4)C-alkoxycarbonyl, nitro, guanidino, ureido, carbamoyl, cyano, trifloromethyl, (R6)2N-carbonyl and phenyl-W-alkyl, where W is selected from a single bond, O, S and NH;

or each R1independently selected from cyano-(1-4)C-alkyl, and R9where R9selected from the group consisting of R5, R5O, (R6)2N, R7C(=O) R5ONH, A and R5Y; where R5is (1-4)C-alkyl; R6represents hydrogen or R5where the radicals R5are the same or different; R7is R5, R5O or (R6)2N; A is selected from piperidino, morpholino, pyrrolidino and 4-R6-piperazine-1-yl imidazol-1-yl, 4-pyridone-1-yl, carboxy-(1-4)C-alkyl, phenoxy, phenyl, phenylsulfanyl, (2-4)C-alkenyl, (R6)2-N-carbonyl-(1 - 4)C-alkyl; and Y is selected from S, SO, SO2; alkyl fragments (R6)2N are optionally substituted by halogen, or R9where R9has the values defined above, and alkyl fragments in5and R5O are optionally substituted by halogen, R6O or R9where R6and R9have the meanings defined above, and where the resulting groups are Euroatom cannot be attached to the same carbon atom, and with the additional condition that no more than three "R9" link can be R1;

or each R1independently selected from R5- sulfonylamino, phthalimido-(1-4)C-alkylsulfonamides, benzamido, benzosulfimide, 3 phenylurea, 2-oxopyrrolidin-1-yl, 2,5 - dioxopiperidin-1-yl, and R10-(2-4)C-alkanolamine, where R10selected from halogen, R6O, (2-4)C-alkanoyloxy, R7C(=O) and (R6)2N; and where specified benzamido or benzosulfimide, or phenyl or phenoxy; or aniline or phenylsulfanyl Deputy in R1may optionally bear one or two of halogen, (1-4)alkyl, cyano, methanesulfonyl or (1-4)C-alkoxy substituent;

or any two of R1taken together with the carbon to which they are attached, form a 5-8-membered ring including at least one or two heteroatoms selected from oxygen, sulfur or nitrogen; and where the alkyl groups and the alkyl part of alkoxy or alkylamino groups can be straight chain, or, if they are composed of at least three carbon atoms, they may be branched or cyclic;

R2selected from hydrogen and optionally substituted (1-6) C-alkyl;

n represents 1 or 2, and each but halogen, hydroxy, optionally substituted by hydroxy;

R4is azido or R11-ethinyl, where R11selected from hydrogen, optionally substituted (1-6) C-alkyl, where the substituents are selected from hydrogen, amino, hydroxy, R5O, R5NH and (R5)2N, which includes

a) treatment of compounds of formula

< / BR>
or

< / BR>
where R1and m have the meanings given above,

with CCl4and optionally substituted by triarylphosphines, optionally deposited on inert polymer of the formula Ar3P, where each Ar is optionally substituted (6-10) C-aryl group, and each of the substituents independently selected from (1-6)C-alkyl; and

b) treatment of the product of stage a) of the compound of the formula

< / BR>
where R2, R3and n have the meanings defined above, and J represents Y or R4where R5has the values defined above, provided that when J is Y, then the product of stage b) must then be processed by Alcina.

Another aspect of the present invention is directed to a method of treatment of hyperproliferative diseases in mammals by assigning to a mammal suffering from a hyperproliferative disease, joint is eenie also directed to pharmaceutical compositions for the treatment of hyperproliferative diseases in mammals, which include effective for the treatment of hyperproliferative diseases of the amount of the compounds of formula I and a pharmaceutically acceptable carrier.

Halogen means chlorine, bromine, iodine or fluorine.

Under the alkyl is meant a hydrocarbon fragment with a straight-chain, cyclic or branched, saturated or unsaturated, provided that the alkyl must include three or more carbon atoms, if it is branched, or cyclic.

In the same sense as it is used here, the expression "reaction-inert solvent" refers to a solvent which does not react with the starting materials, reagents, intermediates or products in any way that adversely affects the yield of the desired product.

Other characteristics and advantages of the invention will be seen from the description and claims which describe the invention.

Detailed description of the invention

The compounds of formula I, their pharmaceutically acceptable salts and prodrugs (hereafter called active compounds) can be obtained using any process known in relation to the production of chemically related compounds.

As shown in the diagram (see the end of the description), the corresponding 4-substituted hinzelin 2, in which X represents a suitable displacement of the deleted group, such as halogen, aryloxy, alkylsulfanyl, alkylsulfonyl, such as tripterocalyx, arylsulfonyl, arylsulfonyl, siloxy, cyano, pyrazolo, triazolo or tetrazole, preferably 4-chlorination, undergoes reaction with the appropriate amine or hydrochloride (hydrochloride) amine 4 or 5, where R4matter described above, and Y represents bromine, iodine or triptorelin-sulfonyloxy, in a solvent such as (1-6)C-alcohol, dimethylformamide (DMF), N-methylpyrrolidine-2-he, chloroform, acetonitrile, tetrahydrofuran (THF), 1-4-dioxane, pyridine or other aprotic solvent. The reaction may be conducted in the presence of a base, preferably a carbonate or hydroxide of alkali or alkaline earth metal or tertiary amine bases such as pyridine, 2,6-lutidine, kallidin, N - methyl-morpholine, triethylamine, 4-dimethylamino-pyridine or N,N - dimethylaniline. These reasons then here are referred to the appropriate bases. The reaction mixture is maintained at a temperature from about ambient temperature to the temperature is still essentially will not be able to find the remaining 4-haloinhalation, in a typical case, from about 2 to 24 hours. Preferably, the reaction is carried out in an inert atmosphere such as dry nitrogen.

Typically, the reactants are combined in stoichiometric quantities. When using amine base for those compounds, when used salt (usually HCl salt) amine 4 or 5, it is preferable to use an excess of amine base, usually an additional equivalent of amine base. (Alternatively, if the amine base is not used, can be used an excess of amine 4 or 5).

For those connections that use spatial (steric) hindered amine 4 (such as 2-alkyl-3-itinerary) or very reactive 4-haloinhalation; it is preferable to use tert-butyl alcohol or a polar aprotic solvent, such as DMF or N-methyl-pyrrolidin-2-he, as a solvent.

Alternatively, a 4-substituted hinzelin 2, in which X represents hydroxyl or oxo (2-nitrogen gidrirovanny), is subjected to reaction with carbon tetrachloride, and optionally substituted by triarylphosphines, which is optionally deposited on inert polymer (for example, triphenylphosphine, deposited on the polymer. Cat. Aldrich N 36645-5 to retele, such as carbon tetrachloride, chloroform, dichloroethane, tetrahydrofuran, acetonitrile or other aprotic solvent or a mixture of them. The reaction mixture is maintained at a temperature approximately equal to ambient temperature to the temperature of reflux distilled, preferably, from about 35oC to the temperature of reflux distilled, for 2-24 hours. This mixture is subjected to reaction with an appropriate amine or amine hydrochloride 4 or 5 either directly or after removal of the solvent, for example, by vacuum evaporation, and add a suitable alternative solvent, such as (1-6)C-alcohol, DMF, N-methylpyrrolidine-2-it, pyridine or 1-4 dioxane. Then, the reaction mixture is maintained at a temperature from about ambient temperature to the temperature of reflux distilled solvent, preferably from approximately 35oC to the temperature of reflux distilled, until then, until it is achieved essentially complete formation of the product, usually from about 2 to 24 hours. Preferably the reaction is carried out in an inert atmosphere such as dry nitrogen.

When as a starting material in the reaction with hinazolinam 2 uses the connection 4, in which Y represents bromine, iodine € value described above. Compound 3 is converted into compounds of the formula I, in which R4is R11-ethinyl, and R11has the values defined above, by reaction with a suitable palladium reagent, such as tetrakis(triphenylphosphine) palladium or bis(triphenylphosphine)palladium-dichloride, in the presence of a suitable Lewis acid, such as copper chloride, and a suitable alkyne, such as trimethylsilylacetamide, propargilovyh alcohol or 3-(N,N-dimethylamino)-propyne in a solvent such as diethylamine or triethylamine. Compound 3, in which Y represents NH2can be transformed into compounds 1, in which R4represents azide, using a processing connection 3 diastereomer agent such as acid and nitrite (for example, acetic acid and NaNO2with subsequent treatment of the resulting product azide such as sodium azide (NaN3).

To obtain those compounds of formula I in which R1represents amino or hydroxyamino the group applies the recovery of the corresponding compounds of formula I in which R1is nitro.

Recovery may conveniently be carried out using any of the many procedures known for such promotional inert solvent, in the presence of a suitable metal catalyst, such as palladium, platinum or Nickel. Additional suitable regenerating agent is, for example, activated metal, such as activated iron (obtained by leaching iron powder diluted aqueous acid, such as hydrochloric acid). For example, the recovery may be carried out by heating a mixture of the nitro compound and the activated metal with concentrated hydrochloric acid in a solvent such as a mixture of water and alcohol, for example methanol or ethanol, to a temperature in the range of, for example, 50 to 150oC the easy way at equal or close to the 70oC. Another suitable class of reducing agents are dithionite alkali metal, such as dithionite sodium, which can be used in (1-4)C-alkanovykh acids, (1-6)C-alkanols, water or mixtures of them.

To obtain those compounds of formula I in which R2or R3includes primary or secondary amine fragment (other than the amino group is intended for reaction with hinazolinam), the free amino group is preferably protected prior to the above reaction with a subsequent removal of the well-known groups, protecting the nitrogen. Such groups include (1-6)C-alkoxycarbonyl, optionally substituted benzyloxycarbonyl, aryloxyalkyl, tritill, vinyloxycarbonyl, O-nitrophenyloctyl, diphenylphosphinyl, p-toluene-sulfonyl and benzyl. Adding nitrogen protecting group may be carried out in a chlorinated hydrocarbon solvent such as methylene chloride or 1,2 - dichloroethane, or in an ether solvent such as glyme, diglyme or THF, in the presence or absence of a tertiary amine base, such as triethylamine, diisopropylethylamine or pyridine, preferably triethylamine, at a temperature of from about 0oC to 50oC, preferably at about ambient temperature. Alternatively, the protective group of the easy way join using the conditions of the Schotten's-Baumann.

After the reaction described above for the attachment of compounds 2 and 5, the protective group can be removed using the methods of release is known to the experts in this field, such as processing triperoxonane acid in methylene chloride, for products that are protected tert-butoxycarbonyl.

As for descriptions of protective groups and their use, see the publication by T. W. Greene and P. G. H. Wuts, "ProtI, in which R1or R2represents hydroxy, preferred cleavage of compounds of formula I in which R1or R2is (1-4)C-alkoxy.

The cleavage reaction may conveniently be carried out using any of the many procedures known for such a transformation. Treatment of the protected derivative of the formula I with molten pyridine hydrochloride (20-30 equiv.) at 150 - 175oC can be used for reactions of O-dealkylation. Alternatively, the cleavage reaction can be carried out, for example, by processing protected chineselanguage derivative (1 - 4)C-alkylsulfides alkali metal, such as attentional sodium, or by treatment with diarylphosphino alkali metal such as lithium diphenylphosphide. The cleavage reaction may also conveniently be carried out by processing a protected derivative hintline trihalogen boron or aluminum, such as trichromacy Bor. Such reactions are preferably carried out in the presence of a reaction-inert solvent at a suitable temperature.

The compounds of formula I in which R1or R2is (1-4)C-alkylsulfonyl or (1-4)C-alkylsulfonyl, preferably obtained with the help. For oxidation of sulfanyl in sulfinil and/or sulfonyl suitable oxidizing agents are well known in the art, for example, hydrogen peroxide, percolate (such as 3-chloroperoxybenzoic or peroxidasa acid), peroxosulfates alkali metal (such as peroxymonosulfate potassium, chromium trioxide or gaseous oxygen in the presence of platinum. The oxidation is usually carried out in as possible mild conditions using a stoichiometric amount of oxidizing agent, in order to reduce the risk of pereokislenie and damage to other functional groups. Typically, this reaction is carried out in a suitable solvent, such as methylene chloride, chloroform, acetone, tetrahydrofuran or tert-butyl methyl ether and at a temperature of from about -25 to 50oC, preferably at a temperature equal to or close to ambient temperature, i.e. in the range of 15 - 35oC. When it is desirable connection, support sulfonyloxy group, you should use a milder oxidizing agents, such as metaperiodate sodium or potassium hydroxide, conveniently in a polar solvent, such as acetic acid or ethanol. The compounds of formula I containing (1-4)C-alkylsulfonyl group, can-4)C-alkylsulfanyl connection.

The compounds of formula I in which R1is optionally substituted (2-4)C-alkanolamine, ureido, 3 phenylurea, benzamido or sulfonamide can be obtained by acylation or sulfonylamine the corresponding compounds in which R1represents amino. Suitable allerease agents are any agents known in the art for the acylation of amino to acylamino, for example, acylhomoserine, for example, (2-4) C-alcoholclone or chloride, or benzoyl chloride or-bromide, anhydrides alkanovykh acids or mixed anhydrides, for example acetic anhydride or mixed anhydride formed by the reaction alanovoy acid and (1-4)C-alkoxycarbonylmethyl, for example (1-4)C-alkoxycarbonylmethyl, in the presence of a suitable base. To obtain those compounds of formula I in which R1is ureido or 3-phenylurea suitable allermuir agent is, for example, cyanate, for example, alkali metal cyanate such as sodium cyanate or isocyanate, such as phenylisocyanate. Reaction of N-sulfonylurea can be carried out with suitable sulphonylchloride or sulfanilamide in the presence of a tertiary amine base. Typically, the acylation or sulfo what about the 120oC, conveniently at a temperature equal to or close to the ambient temperature.

The compounds of formula I in which R1is (1-4)alkoxy or substituted (1-4)C-alkoxy, or R1is (1 - 4)C-alkylamino or substituted mono-N - or di-N,N-(1-4)C - alkylamino, retrieved using the alkylation, preferably in the presence of a suitable base, of a corresponding compound in which R1represents hydroxy or amino, respectively. Suitable alkylating agents include alkyl - or substituted alkylhalogenide, for example, optionally substituted (1-4)C - alkylchloride, -bromide or-iodide, in the presence of a suitable base in a reaction-inert solvent and at a temperature in the range of about 10 to 140oC, conveniently at equal or close to ambient temperature.

To obtain those compounds of formula I in which R1represents amino, hydroxy or cyano-substituted (1-4)C-alkyl substituent, the corresponding compound in which R1is (1-4)C-alkyl substituent bearing a group which can be replaced or substituted amino, alkoxy or cyano group, undergoes reaction with the corresponding aminoethyl in a reaction-inert solvent or diluent, at a temperature in the range of about 10 - 100oC, preferably at equal to or close to ambient temperature.

The compounds of formula I in which R1represents carboxy Deputy or Deputy, which includes a carboxy group, obtained via hydrolysis of the corresponding compounds in which R1is (1-4)C-alkoxycarbonyl Deputy or Deputy, which includes (1-4)C - alkoxy-carbonyl group. The hydrolysis may conveniently be carried out, for example, in basic conditions, for example, in the presence of a hydroxide of an alkali metal, such as is illustrated in the accompanying examples.

The compounds of formula I in which R1represents amino, (1-4)C-alkylamino, di-[(1-4)alkyl] amino, pyrrolidin-1-yl, piperidino, morpholino, piperazine-1-yl, 4-(1-4)C-alkylpiperazine - 1-yl or (1-4)C-alkylsulfanyl can be obtained through reaction, in the presence of a suitable base, of a corresponding compound in which R1group substituted with an amine or thiol, with the appropriate amine or thiol. The reaction preferably is carried out in a reaction-inert solvent or diluent and at a temperature in the range of approximately 10 to 180oC, the preferred is Raiden-1-yl or 2-oxopiperidin-1-yl, obtained using a cyclization in the presence of a suitable base, of a corresponding compound in which R1represents a halogen-(2-4) C-alkanolamine group. The reaction preferably is carried out in a reaction-inert solvent or diluent at a temperature in the range of about 10 - 100oC the easy way, with equal or close to ambient temperature.

To obtain compounds of the formula I, in which R1is carbarnoyl, substituted carbarnoyl, alkanoyloxy or substituted, alkanoyloxy, comfortable is carbamylcholine or acylation of the corresponding compounds in which R1represents hydroxy.

Suitable alleluya agents known in the art for acylation hydroxyaryl fragments in alkanoyloxy groups include, for example, (2-4)C - alkanolamine, (2-4)C-alkanolamide and mixed anhydrides, as described above, and may apply appropriate their substituted derivatives, typically in the presence of a suitable base. Alternatively, (2-4)C-alcamovia acid or appropriately substituted derivatives can join the compound of formula I, in which R1is gidroog R1is carbarnoyl or substituted carbarnoyl, suitable carbamoyloximes agents are, for example, cyanate or alkyl or arylisocyanate, in the typical case, in the presence of a suitable base. Alternatively, a suitable intermediate connections, such as chloroformic or carbonyldiimidazole derivative compounds of formula I in which R1is hydroxy, can be obtained, for example, by processing the specified derivative with phosgene (or poshtovam equivalent) or carbonyl diimidazol. The resulting intermediate compound can then be subjected to reaction with an appropriate amine or substituted amine to obtain the desired karamolegos derived.

The compounds of formula I in which R1is aminocarbonyl or substituted aminocarbonyl can be obtained using aminolysis appropriate intermediate compounds in which R1represents carboxy.

Activation and connection of the compounds of the formula I, in which R1is carboxy, may be performed using a wide variety of methods known to experts in this field. Suitable methods include activating the CSOs of ester appropriate reactivity for combination with the desired amine. Examples of such types of intermediate compounds and their preparation and use in the reactions of addition or combination with amines, can be found widely in the literature, e.g., M. Bodansky and A. Bodansky, "The Practice of Peptide Synthesis; Springer.-Verlag, New York, 1984. The resulting compounds of formula I can stand out and be purified using standard methods, such as removal of solvent and recrystallization or chromatography.

The raw materials for the above described reaction schemes (e.g., amines, heatline and amine protecting groups) are readily available or can be easily synthesized by specialists in the field using conventional methods of organic synthesis. For example, 2,3-dihydro-1,4-benzoxazinone derivatives described in R. C. Elderfield, Todd, S. Gerber, CH. 12, "Heterocylic Compounds" vol. 6, R. C. Elderfield, ed, John Willy & sons, Inc, new York, 1957. Substituted 2,3 - dihydro-benzothiazoline compounds described by the authors R. C. Elderfield and E. E. Harris in the main 13 volume 6 books Elderfield "Heterocyclic Compounds".

Some hintline formula I may exist in solvated, and resolutional forms, such as hydrated forms. It should be understood that the invention encompasses all such with the main diseases.

A suitable pharmaceutically acceptable salt of the compounds of formula I is for example an acid additive salt of the corresponding compound which is sufficiently basic, for example an acid additive salt, for example, from inorganic or organic acid, such as hydrochloric, Hydrobromic, sulfuric, phosphoric, methansulfonate, benzolsulfonat, triperoxonane, citric, lactic or maleic acid. Suitable pharmaceutically acceptable additive salt of the base compounds of formula I, which is acidic, is a salt with alkaline metal such as lithium, sodium or potassium salt; salt with alkaline earth metal, e.g. calcium or magnesium salt; ammonium salt; or a salt with an organic base, which gives a physiologically acceptable cation, for example, a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or Tris-(2-hydroxy-ethyl) - amine. All such salts are within the scope of the present invention, and they can be obtained using conventional methods. For example, they can be obtained simply by entering in contact with acidic or basic molecules, usually in a stoichiometric ratio, or in aqueous or non-aqueous, Denmark; deposition aristotelem, preferably ether or hydrocarbon solvent, followed by filtration and evaporation of the solvent, or, in the case of aqueous solutions, by lyophilization.

Some of the compounds of formula I have asymmetric carbon atoms. Such diastereomer mixture can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known per se, e.g. by chromatography and/or fractional crystallization. Enantiomers can be separated by turning enantiomeric mixtures in diastereomeric mixture by reaction with an appropriate optically active compound (e.g., alcohol), separating the diastereomers and converting (e.g., by hydrolysis) the individual diastereomers to the corresponding pure enantiomers. All such isomers, including diastereomeric mixtures and pure enantiomers, are considered part of this invention.

The active compounds of this invention are powerful inhibitors of erb family oncogenic B and protooncogene the protein tyrosinekinase, such as the receptor for epidermal growth factor (EGFR), erb B2, HER3, or HER4, and thus all applicable DL is apicauda, especially people. In particular, the compounds of this invention are therapeutic or prophylactic agents for the treatment of various human cancers (renal, liver, kidneys, bladder, breast, stomach, ovary, rectum, prostate, pancreas, lung, external female genital organs, thyroid, hepatic carcinomas, sarcomas, glioblastomas, various head and neck tumors), and other hyperplastic conditions such as benign hyperplasia of the skin (e.g. psoriasis) or prostate (e.g., BPH). In addition to the stated expected hintline of the present invention may have activity against a number of leukemias and lymphoid malignancies.

You can also expect that the active compounds are useful in the treatment of additional disorders that involve aberrant expression of ligand/receptor interactions, activation of signaling events associated with various protein tyrosine kinases, whose activity is inhibited by agents of formula I.

Such disorders can include violations of neuronal, glial, astrocytic hypothalamic character and other glands, macracantha function, expression or signaling erb B tyrosinekinase. In addition, the compounds of formula I may be therapeutically useful in inflammatory angiogenic and immunologic disorders involving both identified and yet unidentified tyrosine kinase that is inhibited by compounds of formula I.

Activity in vitro active compounds in the inhibition of receptor tyrosine kinase (and thus subsequent proliferative response, for example, cancer) can be determined using the procedure, described in detail below.

The activity of the active compounds in vitro can be determined by the degree of inhibition of the test compounds in relation to monitoring the phosphorylation of exogenous substrate (e.g., LyS3-gastrin or poly Glu Tyr (4: 1) random copolymer (J. Posner et al. J. Biol>Chem. 267 (29), 20638-47 (1992)) receptor kinase of epidermal growth factor on tyrosine.

Cleared due soluble human EGF receptor (96 ng) is obtained in accordance with the procedure described in G. N. Gill, W. Weber, Methods in Enzymology 146, 82-88 (1987) from A431 cells (American type collection of cultures, Rockville MD) and pre-incubated in microcentrifuge tube with EGF (2 µg/total volume of 10 ál, for 20-30 minutes at room temperature. The test compound dissolved in dimethyl sulfoxide (DMSO), diluted PBV, and 10 μl mixed with a mixture of EGF receptor/EGF and incubated for 10-30 minutes at 30oC. the phosphorylation Reaction is initiated by adding 20 ál of a mixture of33P-ATP/substrate (120 μm LyS3-gastrin (a sequence of one-letter code for amino acids, KKKGPWEEEEEYGWLDF), 50 mm Hepes, pH 7.4, 40 μm ATP, 2 MX -[33P]-ATP) to a mixture of the EGF receptor/EGF and incubated for 20 minutes at room temperature. The reaction is stopped by adding 10 μl of stop solution (0.5 M EDTA, pH 8; 2 mm ATP) and 6 ál 2 N. HCl. Tubes centrifugeuse at 14000 rpm./min, 4oC, for 10 minutes. 35 μl of the supernatant from each tube is withdrawn by pipette 2.5 cm circle paper Whatman P81, mass is washed four times with 5% acetic acid, 1 liter wash, and then dried in air. This results in binding of the substrate paper with the loss of free ATP after washing. Included [33P] is measured using liquid scintillation counting. Inclusion in the absence of substrate (e.g., LyS3-gastrin) is subtracted from all values in the background and the percentage of inhibition vechicles is possible with a range of doses of test compounds allow you to determine the approximate IC50the value for inhibition of in vitro activity of EGFR kinase. Although inhibiting properties of the compounds of formula I, as expected, vary with structural change, the activity shown under the action of these agents, as measured by the method described above, is in the interval IC50= 0.0001 - 30 µm (IC50= 50% inhibitory concentration). (Table 2).

The activity of the active compounds in vivo may be determined by the degree of inhibition of tumor growth under the effect of the test compound relative to the control. Inhibitory effect on tumor growth of various compounds measured in accordance with the methodology Corbett and other "Tumor Induction Relationships in Development of Transplantable Cancers of the Colon in Mice for Chemotherapy Assays, with a Note on Cancinogen Structure", Cancer Res., 35, 2434-2439 (1975) and Corbett, T. H., and others, "A Mouse Colon-tumor Model for Experimental Therapy", Cancer Chemother. Rep. (Part 2)", 5, 169-186 (1975), with minor modifications. Tumors are induced in the left side by subcutaneous injection cultured in 1 of 106log phase of tumor cells (carcinoma cells human breast MDA-MB-468 or carcinoma of the head and neck of a person HN5), suspended in 0.10 ml of RPM1 1640. Upon passage of a sufficient period of time to oukhoudane (converted into ready preparative form by dissolving in DMSO usually in a concentration of from 50 to 100 mg/ml and then 1:9 dilution with saline or alternatively, a 1:9 dilution of 0.1% Pluronic P105 in 0.9% saline) using intraperitoneal (i.R.) or oral (po) assign twice a day (i.e. every 12 hours) for 5 days in a row. To determine the antitumor activity, measured the tumor in mm using Vernier calipers in two diameters, and the size of the tumor (mg) is calculated using the following formula: tumor Weight = (length [width]2)/2, according to the methodology Geran, R. 1., and other "Protocols for Screening Chemical Agents and Natural Products Against Animal Tumors and Other Biological Systems", Third edition, Cancer Chemother Rep., 3, 1-104 (1972). The results are expressed as percent inhibition according to the formula: Inhibition (%) = (Weight of tumorcontrol-Weight tumorexperienced) / Tumor weightcontrol100%.

The boundaries of the area of implantation of the tumor give reproducible effect depending on dose to a variety of chemotherapeutic agents, and the method of measurement (diameter of the tumor) is a reliable method to assess the rates of tumor growth.

The purpose of the active compounds can be carried out by any method that enables delivery of the compounds to the site of action (e.g., cancer cells). These methods include oral is s, subcutaneous, intramuscular, intravascular injection or infusion), topical or local mode of appointment etc.

Assign the number of active connections will, of course, depend on the subject being treated, on the severity of the disease, mode of appointment and from opinion or qualification prescribing physician. However, an effective dosage is approximately in the range of 0.001-100 mg/kg, preferably 1-35 mg/kg in single or divided doses. For a person weighing 70 kg would amount to 0.05 to 7 g/day, preferably 0.2 - 2.5 g/day.

The composition may be, for example, in a form suitable for oral purposes, such as tablets, pills, powders, ready-made forms of the drug with the delayed drug release; in the form of solutions, suspensions; for parenteral injection as a sterile solution, suspension or emulsion; for topical or local destination in the form of ointment or cream or for rectal destination in the form of suppositories or medical candles. The pharmaceutical composition may be in the form of a unit dose, appropriate for a single destination with accurate dosage. The pharmaceutical composition typically includes conventional pharmaceutical nose the data it may include other medicinal or pharmaceutical agents, carriers, adjuvant, etc.

The pharmaceutical compositions according to the invention may contain 0.1 to 95% of the compound, preferably 1-70%. In any event, the composition or finished form of the drug, intended for use, contains the active compound in an amount effective to alleviate or reduce symptoms of the disease in the subject to be treated, i.e., symptoms of hyperproliferative diseases, throughout the course of treatment.

Examples of parenteral forms for appointment include solutions or suspensions of the active compounds in sterile aqueous solutions, for example, in aqueous solutions of propylene glycol or dextrose. Such dosage forms, if necessary, can appropriately be supererogatory.

Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents. Pharmaceutical compositions, if necessary, may contain additional ingredients, such as flavoring or flavoring additives, binders, excipients and similar. So, for oral assignments can be used tablets containing various excipients such as citric acid, together with a variety of the relevant agents, such as sucrose, gelatin and gum acacia. For the purposes of tabletting often useful advanced lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc. Solid compositions of a similar type may also be used in filled them soft or hard gelatin capsules. Preferred materials include lactose or milk sugar and glycols of high molecular weight. When oral assignments desirable aqueous suspensions or elixirs, the active compound may be combined with various sweetening or flavoring agents, coloring agents or dyes, and, if desired, emulsifying agents or suspendresume agents, together with diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof.

Methods of obtaining various pharmaceutical compositions with a specific number of active compounds are known or are obvious to a person skilled in the art. For example, see Remington''s Pharmaceutical Sciences. , Mack Publishing Company, Easter, PA., 15th edition (1975).

The treatment of hyperproliferative diseases, described above, can be used ugogo antitumor substances. Such joint treatment can be achieved by simultaneous, sequential, cyclic or separate dosing of the individual components of treatment.

Liquid chromatography high pressure (ghvd) used in the following examples and receipts, were performed in accordance with the following method, if it has not been modified in some examples. Cartridge column Perkin-Elmer Peckover SHSS (3 mm x 3 cm, C18; supplied by the company Perkin Elmer Corp. Norwalk, CT 06859) precolonial Brownlie (trade mark) RP-8 Newgard (7 μm, 3.2 mm x 15 mm, supplied by the firm Applid of Biosystems Inc. San Tose CA 95134), which was pre-equilibrated at pH 4.50, 200 mm ammonium acetate buffer. The samples were loirevalley using a linear gradient of 0-100% acetonitrile/pH 4.50, 200 mm ammonium acetate over 10 minutes, with a flow rate of 3.0 ml/min Chromatogram was obtained in the range of 240-400 nm using a diode radiation detector.

It should be understood that the invention is not limited to the specific embodiments shown and described herein, and may employ various changes and modifications without deviating from the essence and scope of the present invention, opredelenn-yl) -amine

4-Chloro-6,7-dimethoxyquinazolin (250 mg, 1.12 mmole) and 4-azidoaniline hydrochloride (200 mg, 1.11 mmole) was heated under conditions of reflux distilled in 10 ml of isopropyl alcohol for 0.5 hour, cooled and filtered, giving a solid target product, which was washed with 10 ml of isopropyl alcohol and dried in vacuum at 70oC, 392 mg (98%); so pl. 200 - 205oC (Razlog.).

Example 2

Hydrochloride (6,7-dimethoxyquinazolin-4-yl)-(3-ethynylphenyl) -amine

4-Chloro-6,7-dimethoxyquinazolin (250 mg, 1.12 mmole) and 3-itinerary (137 mg, 1.17 mmole) was heated under conditions of reflux distilled in 10 ml of isopropyl alcohol for 0.5 hour, cooled and filtered, giving a solid target product, which was washed with 10 ml of isopropyl alcohol and dried in vacuum at 70oC, 338 mg (99%); so pl. 269-270oC.

Example 3

(6,7-dimethoxyquinazolin-4-yl) [3-(3'-hydroxypropyl-1-yl) phenyl]-amine

A mixture of the hydrochloride (3'-bromophenyl)-(6,7-dimethoxyquinazolin-4 - yl)-amine (250 mg, 0,591 mmole), tetrakis (triphenylphosphine) palladium (100 mg), propargilovyh alcohol (600 μl), 7 ml of dry nitrogen purged of diethylamine and copper iodide (10 mg) was heated under conditions of reflux distilled for 5 hours, cooled and filtered, giving a solid target product, which is Ola, giving pure target product after drying in vacuum at 70oC, 73 mg (37%); so pl. 267-268oC.

Example 4

Hydrochloride [(3-(2'-aminomethyl-ethinyl)phenyl]-(6, 7-dimethoxy-hinzelin-4-yl)-amine

The target product of example 3 (50 mg, 0.149 mmole), triphenylphosphine (60 mg, 0.225 mmole), phthalimide (165 mg, 1.12 mmole) and diethylazodicarboxylate (36 μl, 0.228 mmole) were mixed at room temperature in 3 ml of dry tetrahydrofuran for 16 hours. The reaction mixture was concentrated to solids and subjected to flash chromatography on silica gel, blueroom a mixture of 15% acetone:methylene chloride, giving a clean solid [3-(2'- {phthalimidomethyl} -ethinyl)phenyl]- (6,7-dimethoxyquinazolin-4 - yl) amine, which was turned into his chlorhydrate salt by adding 1 ml of anhydrous 1 M HCl in methanol, and then 3 ml of isopropyl alcohol. Salt was collected by filtration, dried and used immediately in the next stage; 15 mg. Data 15 mg, 0.0323 mmole, was treated with 0.5 ml of hydrazine hydrate is added and 1 ml of methanol for 0.5 hours. The reaction mixture was evaporated in vacuo, and the product was separated using flash chromatography with elution with 10% methanol in methylene chloride. Pure target product stood out after converting it into chlorhydrate (HYDR vacuum; 5.6 mg (47%), so pl. 275oC decomp.

Example 5

Hydrochloride (3-ethynylphenyl)-(6-nitroquinazoline-4 - yl)-amine

4-Chloro-6-nitroquinazoline (1.06 g, 5.00 mmol) and 3 - itinerary (1.00 g, 5.30 mmole) was heated under conditions of reflux distilled in 10 ml of isopropyl alcohol for 3 hours, cooled and after 16 hours of finding at room temperature was filtered, giving a solid target product, which was washed with 10 ml of isopropyl alcohol and dried in vacuum at 70oC, 1.27 g (78%); so pl. 255-258oC.

Example 6

(6,7-Dimethoxyquinazolin-4-yl)- (4-ethynylphenyl)- amine

The target product was obtained using the following three-stage sequence of reactions without purification of intermediate products. 4 - Chloro-6,7-dimethoxyquinazolin (250 mg, 1.113 mmole) and 4-iodoaniline (268 mg, 1.224 mmole) was heated under conditions of reflux distilled in 10 ml of isopropyl alcohol for 3 hours, cooled to room temperature and filtered, giving a solid hydrochloride (4 - itfeel)-(6,7-Dimethoxyquinazolin-4-yl)amine, which was rinsed with 10 ml of isopropyl alcohol and dried in vacuum at 70oC, 396 mg (76%). A mixture consisting of hydrochloride (4'-itfeel)-(6,7 - dimethoxy-hinzelin-4-yl)-amine (250 mg, 0.564 mmole), tetrakis(triphenylphosphine)Palladia mg) was heated under conditions of reflux distilled for 2 hours, was cooled and concentrated under vacuum giving a residue that was distributed between chloroform and 1 N. HCl. Solid [4-(2'-{ trimethylsilyl} atenil)phenyl] -(6,7 - dimethoxyquinazolin-4-yl)-amine, formed at the interface of two liquid phases were filtered and dried in a vacuum; 170 mg(80%) [4-(2'-{Trimethylsilyl}-ethinyl)phenyl]-(6,7 - dimethoxyquinazolin-4-yl)amine (100 mg, 0.265 mmole) and anhydrous potassium carbonate (125 mg, 0.906 mmole) were mixed in 3 ml of methanol and 1 ml of water at room temperature for 2.5 hours. The reaction mixture was concentrated in vacuum and were distributed between 20 ml of chloroform and 20 ml of 1 N. hydrochloric acid. The organic layer was dried with magnesium sulfate, filtered and evaporated in vacuo, giving the desired product, which was pulverized with diethyl ether and dried in vacuum at 70oC; 81 mg (90%), so pl. 239oC decomp.

Example 7

(6,7-dimethoxyquinazolin-4-yl)-(3-ethinyl-2-were)-amine

The target product was obtained using the following three-stage sequence of procedures without purification of intermediate products. A mixture of 3-bromo-2-methylaniline (1.00 g, 5.37 mmole), tetrakis(triphenylphosphine)palladium (200 mg), trimethylsilylacetamide (1.053 g, 10.75 mmole), 10 ml of dry nitrogen purged dimoulas in vacuum, giving a residue, which was distributed between chloroform and 1 N. HCl. The organic layer was washed with salt solution, dried by magnesium sulfate and evaporated in vacuo giving a residue, 3-[2'-(trimethylsilyl)ethinyl] -2-methylaniline, which was purified using flash chromatography on silica gel, blueroom a mixture of 1:1 hexane: methylene chloride; 200 mg (18%).

4-Chloro-6,7-dimethoxyquinazolin (104 mg, 0,466 mmole) and 3- [2'-(trimethylsilyl)ethinyl] -2-methylaniline (100 mg, 0.491 mmole) was heated under conditions of reflux distilled in 3 ml of isopropyl alcohol for 16 hours, cooled to room temperature and filtered, giving a solid residue hydrochloride { 3-[2'- (trimethylsilyl)ethinyl]-2-were}-(6,7-dimethoxyquinazolin-4 - yl) amine, which were washed with 10 ml of isopropyl alcohol and were pulverized for 16 hours with diethyl ether. Thin layer chromatography on silica gel, blueroom a mixture of 9:1 chloroform:methanol, showed that the residue was the crude or crude product. The residue was purified using flash chromatography on silica gel, blueroom a mixture of 9:1 methylene chloride; methanol, giving after concentration and drying under vacuum clean the product, 64 mg (33%). The product was dissolved in 3 ml of methanol and was treated with 64 mg of anhydrous carbonate of clash between 1 to N. HCl and chloroform. Hard target product was formed at the interface of two liquid phases and was filtered and dried in a vacuum; 40 mg (84%), so pl. 225oC decomp.

Example 8

(6-Amino-hinzelin-4-yl)-(3-ethynylphenyl)-amine

(3-Ethinyl-phenyl)-(6-nitro-hinzelin-4-yl)-amine hydrochloride (500 mg, 1.50 mmole) was dissolved in 10 ml of formic acid and processed portions dithionite sodium (1.10 g, 6.28 mmole) at room temperature. After 2 hours, the mixture was extinguished 120 ml of water and filtered. The filtrate was evaporated in vacuo to a residue, which was dissolved in 100 ml of a mixture of 1:1 methanol: chloroform, filtered and evaporated in vacuo to another residue. This substance was pulverized with 200 ml of 5% sodium bicarbonate for 30 minutes, filtered, rinsed with water and dried in vacuum for 16 hours. Flash chromatography on silica gel, blueroom with ethyl acetate gave pure (6-amino - hinzelin-4-yl)-(3-ethynylphenyl)-amine; 140 mg (34%); so pl. 165oC decomp.

Example 9

(3-Ethynylphenyl)- (6-methanesulfonylaminoethyl - 4-yl)amine

The target product of example 8 (100 mg, 0.384 mmole), pyridine (140 μl, 1.68 mmole) and methanesulfonamide (99 μl, 1.26 mmole) was heated under reflux in 10 ml of 1,2-dichloroethane during what was intervals and dried in vacuum, giving (3-ethynylphenyl)-(6 - methanesulfonylaminoethyl-4-yl)-amine; 102 mg (78%), so pl. 248oC decomp.

Example 10

Hydrochloride (3-ethynylphenyl)-(6,7-methylenedioxyaniline-4-yl) -amine

4-Chloro-6,7 - methylenedioxyaniline (200 mg, 1.04 mmole) and 3-itinerary (127 mg, 1.09 mmole) was heated under conditions of reflux distilled in 5 ml of isopropyl alcohol for 16 hours, cooled, filtered, giving a solid target product, which was washed with 10 ml of isopropyl alcohol and dried in vacuum at 70oC, 266 mg (79%); so pl. above 350oC.

Example 11

Hydrochloride ((6,7-dimethoxyquinazolin-4-yl)-3-ethinyl-6-were) -amine

The target product was obtained in the following three-stage sequence of procedures without purification of intermediate products. A mixture of 4-bromo-2-nitrotoluene (1.50 g, 6.94 mmole), tetrakis(triphenylphosphine)palladium (750 mg), trimethylsilylacetamide (3.00 ml, 21.21 mol) and copper iodide (20 mg) in 20 ml of nitrogen purged dry diethylamine was heated under conditions of reflux distilled for 2 hours, cooled and concentrated under vacuum giving a residue that was distributed between 100 ml ethyl acetate and 100 ml of 1 N. HCl. The organic layer was washed twice with 50 ml of 1 N. HCl, then brine, sushils ml of petroleum ether. The solids were filtered off, and the oil obtained after evaporation of the filtrate in vacuo, hardened, giving 4-[2'-(trimethylsilyl) ethinyl]-2-nitrotoluene. This product was restored to the amino product by treatment with iron powder (1.76 g, 98.5 mmole) in 30 ml of methanol and 5 ml of concentrated hydrochloric acid at 80oC for 2 hours. The cooled reaction mixture was filtered through celite, and the filtrate was evaporated in vacuum. The residue was distributed between ethyl acetate and 5% aqueous sodium bicarbonate. The organic layer was washed with salt solution, dried by magnesium sulfate, filtered and evaporated in vacuo, yielding an oil, 5-[2'-(trimethylsilyl)ethinyl]- 2-methylaniline, which hardened on standing; 1.37 g

The above-mentioned product (185 mg, 0.909 mmole) and 4-chloro-6,7-dimethoxyquinazolin (200 mg, 0.890 mmole) was heated under conditions of reflux distilled in tert-butyl alcohol for 16 hours. After cooling, the reaction mixture was filtered, giving a net hydrochloride [2-methyl-5-(2'-{trimethylsilyl}-ethinyl)-phenyl]-(6, 7-dimethoxyquinazolin-4-yl)-amine after simple washing with ether and drying in a vacuum; 326 mg (85%). Trimethylsilyl group was removed by dissolving the above product in 5 ml of methanol and tribals in vacuum. The residue, thus obtained, was distributed between 100 ml of methylene chloride and 100 ml of 1 N. HCl. The aqueous layer was extracted an additional 100 ml of methylene chloride. Chilled organic layers were dried with magnesium sulfate, filtered and evaporated in vacuo to a residue, which was dissolved in anhydrous 1 N. HCl in methanol, concentrated and precipitated with ether. Hard target product was collected by filtration and were washed with diethyl ether, then dried in vacuum at 70oC; 236 mg (88%), pl. 266-267oC.

Example 12

Hydrochloride (3-ethynylphenyl)-(7-nitroquinazoline-4-yl)-amine

4-Chloro-7-nitroquinazoline (7.97 g, 38.0 mmol) and 3-itinerary (4.54 g, 38.8 mmol) was heated under conditions of reflux distilled in 125 ml of tert-butyl alcohol for 3 hours, cooled to room temperature and filtered, giving the desired product in the form of solids, which were washed with 10 ml of isopropyl alcohol and dried in vacuum at 70oC, 9.95 g (80%); so pl. 209-210oC decomp.

Example 13

Hydrochloride (3-ethynylphenyl)-[6-(4'-toluensulfonyl) -hinzelin-4-yl] -amine

The target product of example 8 (0.201 mg, 0.771 mmole) and 4 - toluensulfonate (0.441 mg, 2.31 mmole) was heated under conditions of reflux distilled in 3 ml of 1,2-dichlo the ü 75 ml ethyl acetate and was washed two times 75 ml of water, once with 75 ml of 3% sodium bicarbonate and once with 75 ml of saline solution. The organic layer was dried over magnesium sulfate, filtered and evaporated in vacuo to a residue, which was purified via chromatography using Chromatotron (trade mark), aliremove with ethyl acetate, giving a solid target product; 86.7 mg (27%), so pl. 220 - 222oC.

Example 14

Hydrochloride (3-ethynylphenyl)-{ 6-[2'-phthalimido-Ethan-1'- ylsulphonyl] hinzelin-4-yl}amine.

The target product of example 8 (0.20 mg, 0.768 mmole) and 2-phthalimido-1-acanaloniidae (0.615 mg, 2.25 mmole) was heated under conditions of reflux distilled in 2 ml of 1,2-dichloroethane and 0.5 ml of pyridine for 16 hours, cooled to room temperature, it was diluted with 100 ml of chloroform and washed with 50 ml of 3% aqueous sodium bicarbonate and 50 ml of saline solution. The organic layer was dried with magnesium sulfate, filtered and evaporated in vacuo to a residue, which was dissolved in a minimal amount of methylene chloride and precipitated with petroleum ether, 188 mg. Residue was purified using chromatography using chromatotron, aliremove with ethyl acetate, giving the desired product in the form of solids; 53.4 mg (14%), so pl. 197-200oC.

Example 15

the - dimethylpyrazol-1-carboxamidine (0,328 mg, 2.36 mmole) was heated under conditions of reflux distilled in 10 ml of 1,2-dichloroethane and 0.97 ml of acetic acid for 24 hours, cooled to room temperature and filtered, giving the crude acetate of the desired product. The product was dissolved in 35 ml of methanol and processed 15 ml of anhydrous 1 N. HCl in methanol for 15 minutes, and then were precipitated with 75 ml of diethyl ether. Hard target product was collected by filtration and dried in vacuum at 70oC; 91.2 mg (23%), so pl. above 400oC.

Example 16

(7-Aminoquinazolin-4-yl)-(3-ethynylphenyl)Amin

The target product of example 12 (1.039 g, 3.18 mmole) was dissolved in 50 ml of tetrahydrofuran, 10 ml of methanol and 5 ml of chloroform at 50oC. was Added monopotassium postit sodium (NaH2PO2, 3.822 g, 36 mmol) and 10% palladium on coal (0,19 g), followed by adding dropwise 10 ml of water. When it was added 3 ml of water, the mixture has become much more homogeneous. After 1 hour, the mixture was filtered through celite. Celite was washed thoroughly with methanol and chloroform. The combined organic solutions were evaporated in vacuo to a residue, which was pulverized with water, 3% aqueous sodium bicarbonate and filtered. Hard target product was rinsed with water, then diethyl ether and silseth hot ethanol and water, giving after removal of the minor from the first harvest of the impurity substance pure target product (43%), so pl. 180oC (Razlog.)

Example 17

Hydrochloride (3-ethynylphenyl)-(7-methoxyquinazoline-4-yl)amine

4-Chloro-7-methoxyquinazoline (274 mg, 3.72 mmole) and 3 - itinerary (436 mg, 3.72 mmole) was heated under reflux in 15 ml of tert-butyl alcohol for 3 hours, cooled and filtered, giving a solid target product, which was washed with 10 ml of isopropyl alcohol and dried in vacuum at 70oC, 977 mg (84%), so pl. 229-231oC.

Example 18

Hydrochloride (6-carbomethoxybiphenyl-4-yl)-(3-ethynylphenyl)-amine

4-Chloro-6-carbamidomethylation (100 mg, 0.450 mmole) and 3-itinerary-hydrochloride (53.4 mg, 0.456 mmole) was heated under conditions of reflux distilled in 2 ml of tert-butyl alcohol for 2 hours, cooled, it was diluted with 2 ml of isopropyl alcohol and filtered, giving a solid target product, which was washed with 10 ml of diethyl ether, and dried in vacuum at 70oC, 122 mg (80%); so pl. 232-233oC (decomposition).

Example 19

Hydrochloride (7-carbomethoxybiphenyl-4-yl)-(3-ethynylphenyl) -amine

4-Chloro-7-carbamidomethylation (202 mg, 0.907 mmole) and 3 - itinerary (110 mg, 0.939 mmole) was heated epilogo alcohol and filtered, giving solid target product, which was washed with 10 ml of diethyl ether, and dried in vacuum at 70oC, 248 mg (80%); so pl. 219.5-221oC.

Example 20

Hydrochloride [6,7-bis-(2-methoxyethoxy)-hinzelin-4-yl] - (3-ethynylphenyl)-amine

3-Itinerary (37 mg, 0.32 mmole) and 4-chloro-6,7-bis- (2-methoxyethoxy)-hinzelin (90 mg, 0.29 mmole) was added to isopropanol (1.5 ml) containing pyridine (25 μl, 0.32 mmole) and the mixture was heated under conditions of reflux distilled for 4 hours in a dry nitrogen atmosphere. The solvent was removed in vacuo, and the residue was distributed between 10% methanol in CHCl3and saturated aqueous sodium bicarbonate. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuum. The residue was subjected to flash chromatography on silica gel using 30% acetone in hexano, yielding 81 mg of the free base of the desired product as a pale yellow solid. The free base was dissolved in minimum amount of CHCl3was diluted with several volumes of ether, and pulverized with 1 M HCl in ether with the deposition of the desired product in the form of its chlorhydrate salt; 90 mg, 71%; so pl. 228-230oC.

Example 21

(3-Azidophenyl)- (6,7-dimethoxyquinazolin - 4-yl)- amine

4-X4.6 mmole) in delegateuser isopropanol (100 ml) in a dry nitrogen atmosphere. After the addition was completed, the mixture was heated at the temperature of reflux distilled for 4 hours. The mixture was cooled to 20oC, and the precipitate was filtered, washed with chilled isopropanol and dried in vacuum, giving 6.97 g (93%) of hydrochloride (3-AMINOPHENYL)-(6,7-dimethoxyquinazolin-4-yl)-amine ( C-MC: 297 (MH+). To a solution of the above product (50 mg, 0.169 mmole) in a mixture of 80% acetic acid/water (2 ml) at 0oC was added a solution of NaNO2(18.4 mg, 0.186 mmole) in water (100 μl). After stirring for 10 minutes at 0oC was added a solution of sodium azide (12 mg, 0.185 mmole) in water (100 μl). The mixture was left to run until 20oC and stirred for 1.5 hours. The reaction mixture was liabilities, and the residue was distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was then rinsed with saline, dried over sodium sulfate, filtered and concentrated in vacuum. Recrystallization from a mixture of CHCl3/hexane gave 36 mg of the desired product as white solids; so pl. 110-113oC.

Example 22

(3 Azido-5-chlorophenyl)- (6,7-dimethoxyquinazolin - 4-yl)-amine

4-Chloro-6,7-dimethoxyquinazolin (200 mg, 0.89 mmole) and 5 - amino-3-chloron is in a dry nitrogen atmosphere. After cooling to 20oC the mixture was diluted with methanol (5 ml) and the resulting precipitate was filtered and dried in vacuum, giving 252 mg (77%) of hydrochloride (3-amino-5-chlorophenyl)-(6,7-dimethoxy-hinzelin-4-yl) amine (so pl. 298-301oC, C-MC, 331 (MH+)). Part of this product (175 mg, 0.476 mmole) was dissolved in a mixture of 80% acetic acid/water (12 ml), cooled to 0oC, was added a solution of sodium nitrite (NaNO2) (36 mg, 0.516 mmole) in water (300 μl). The solution was mixed for 10 minutes at 0oC. was added NaN3(33 mg, 0.50 mmole) in water (300 μl). The reaction mixture was left to run until 20oC and stirred for 16 hours. The resulting precipitate was filtered off and dissolved in 10% methanol in CHCl3and the solution was washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered and concentrated in vacuo, giving 59 mg (35%) of the desired product as a yellow solid; T. pl. 205-206oC.

Example 23

Hydrochloride (3-ethynylphenyl)-(6-methanesulfonyl - hinzelin-4-yl)-amine

6-Methanesulfonyl-hinzelin-4-one (200 mg, 0.89 mmole), triphenylphosphine (566 mg, 2.15 mmole) and carbon tetrachloride (815 μl, 8.92 mmole) NAA balance. This substance was dissolved in 5 ml of isopropyl alcohol and 3-itineraria (156 mg, 1.33 mmole) and heated under conditions of reflux distilled for 16 hours. The cooled reaction mixture was filtered, washed with minimum amount of cold isopropyl alcohol and dried in vacuum at 70oC for 16 hours, giving a pure target product; 63 mg (20%), so pl. 281-282oC.

Example 24

Hydrochloride (6-econsultancy-hinzelin-4-yl)-(3 - ethynylphenyl)-amine

6-Econsultancy-hinzelin-4-one (100 mg, 0.48 mmole), triphenylphosphine (305 mg, 1.16 mmole) and 3 ml of carbon tetrachloride was heated under conditions of reflux distilled for 16 hours. The solvent was evaporated in vacuo giving a residue. This residue was dissolved in 5 ml of isopropyl alcohol and 3-itineraria (68 mg, 0.58 mmole) and heated under conditions of reflux distilled for 1 hour. The cooled reaction mixture was filtered, washed with minimum amount of cold isopropyl alcohol and dried in vacuum at 70oC for 16 hours, giving a pure target product; 70 mg (42%), so pl. 239-240oC.

Example 25

Hydrochloride (6,7-dimethoxy-hinzelin-4-yl)- (3 - ethinyl-4-forfinal)-amine

4-Chloro-6,7-dimethoxyquinazolin (500 mg, 2.23 mmole) and 3-(2 PIRT for 16 hours, was cooled and filtered, giving a solid hydrochloride (6,7-dimethoxy-hinzelin-4-yl)-(3'- ethynylphenyl)-amine, which was rinsed with 10 ml of isopropyl alcohol and dried in vacuum at 70oC, 832 mg (83%). This material was subjected to reaction in 10 ml of methanol and 1 drop of water containing 250 mg of potassium carbonate for 3 hours. The mixture was filtered, and the filtrate was evaporated in vacuum. The residue was pulverized for 1 hour with 1 N. hydrochloric acid, filtered and washed with minimum amount of water, then with methanol and dried in a vacuum; 506 mg (63%), so pl. 229oC, Razlog.

3-(2'-Trimethylsilyl-ethinyl) -4-ftoranila used above was obtained from 3-bromo-4-foronline (7.0 g, 36.8 mmole), tetrakis(triphenylphosphine)palladium (1.4 g), trimethylsilyl-acetylene (7.2 g, 74 mmole) and copper iodide (40 mg) in 140 ml of nitrogen purged dry diethylamine when heated under conditions of reflux distilled for 16 hours. The cooled reaction mixture was filtered through celite, and the celite was rinsed with ether. The combined filtrates were evaporated in vacuo to a residue, which was purified using flash chromatography on silica gel, blueroom 35% hexane in methylene chloride. The fractions containing pure 3-(2'-trimethylsilyl-ethinyl)-4-ftoranila, vepari the rat (6,7-dimethoxy-hinzelin-4-yl)-[3- (propyl-1-yl)phenyl]-amine

4-Chloro-6,7-dimethoxyquinazolin (585 mg, 2.60 mmole) and 3-(propyne-1-yl)-aniline (361 mg, 2.74 mmole) was heated under conditions of reflux distilled in 5 ml of tert-butyl alcohol for 16 hours, cooled and filtered, giving a solid (6,7 - dimethoxy-hinzelin-4-yl)- [3-(propyne-1-yl) phenyl]-amine - hydrochloride, which was filtered and 5 ml of isopropyl alcohol and 25 ml of ether, then were dried in vacuum at 70oC, 869 mg (94%); so pl. 260 - 261oC.

3-(Propyne-1-yl)aniline used above was obtained from 3-bromo-nitrobenzene in four stages. 3-bromo-nitrobenzene (5.0 g, 24.7 mmole), tetrakis(triphenylphosphine)palladium (1.0 g), trimethylsilyl-acetylene (3.6 g, 37 mmol) and copper iodide (20 mg) in 20 ml dry diethylamine, nitrogen purged, when heated under conditions of reflux distilled for 16 hours. The cooled reaction mixture was evaporated in vacuo, diluted with 50 ml of methylene chloride and 50 ml of 1 N. hydrochloric acid and filtered. The organic layer was collected and dried with magnesium sulfate, filtered and evaporated in vacuo to a residue. 3-Trimethylsilylmethylamine was purified using flash chromatography on silica gel, blueroom a mixture of 2:1 hexane: methylene chloride. The fractions containing pure material were evaporated in vacuo, giving a clean 3-trimetals is potassium carbonate. After one hour, the mixture was evaporated in vacuo and diluted with 100 ml of methylene chloride. The organic layer was washed with 100 ml of 1 N. hydrochloric acid, dried with magnesium sulfate, filtered and evaporated in vacuo to a residue (2.96 g). 790 mg of the substance was dissolved in 10 ml of benzene and processed finely sprayed 87% potassium hydroxide (377 mg, 5.91 mmole), methyliodide (2 ml) and 10 mg of 18-crown-6 (Aldrich) under the conditions of reflux distilled for 16 hours. Added additional 0.5 ml under the conditions, and heating under conditions of reflux distilled continued for additional 2 hours. The cooled reaction mixture was evaporated in vacuo to a residue, which was diluted with 100 ml of methylene chloride and was washed with 100 ml of 1 N. hydrochloric acid, dried with magnesium sulfate, filtered and evaporated in vacuo to an oil. This oil was purified using flash chromatography on silica gel, blueroom a mixture of 1:1 hexane: methylene chloride. The fractions containing pure 3-(propyne-1-yl) nitrobenzene was evaporated in vacuo to an oil which was used without further purification; 530 mg (61%), 3-(Propyne-1-yl)-nitrobenzene (530 mg, 3.3 mmole), iron powder (400 mg, 7.27 mmole), 3 ml of concentrated hydrochloric acid and 10 ml of methanol was heated under conditions of reflux distilled for 1 hour is DN 100 ml of methylene chloride and 100 ml of 1 N. of sodium hydroxide. Two phases were filtered, and then the organic phase was separated, dried with magnesium sulfate, filtered and evaporated in vacuum to an oil, which was used directly in obtaining the target product; 321 mg (78%).

Example 27

Hydrochloride [6,7-Bis- (2-methoxy-ethoxy)- hinzelin-4-yl]- (3-ethinyl-4-forfinal) -amine

4-Chloro-6,7-bis- (2-methoxy-ethoxy)- hinzelin (140 mg, 0.446 mmole) and 3-ethinyl-4-ftoranila (66 mg, 0.452 mmole) was subjected to reaction in delegateuser isopropanol (3 ml) in a nitrogen atmosphere for 16 hours. The solvent was removed in vacuo, and the residue was distributed between CHCl3and saturated aqueous sodium bicarbonate. The organic extracts were washed with saline, dried over sodium sulfate, filtered and concentrated in vacuum. The crude product was chromatographically on silica using a mixture of 40% acetone/methylene chloride, yielding 116 mg of pure desired product in the form of its free base. This oil was dissolved in minimum amount of CHCl3was diluted with several volumes of ether, and pulverized with 1M HCl in ether with the deposition of the desired product as a white solid (99 mg, 50%, so pl. 170-190oC (decomp.), C-MS: 412 (MH+
4-Chloro-6,7-bis- (2-methoxy-ethoxy)- hinzelin (153 mg, 0.49 mmole), pyridine (40 μl) and 3-ethinyl-6-methylaniline (71 mg, 0.54 mmole) was subjected to reaction in DMF (3 ml) at 110oC in nitrogen atmosphere for 36 hours. The solvent was removed in vacuo, and the residue was distributed between chloroform and saturated aqueous sodium bicarbonate. The organic extracts were washed with saline, dried over sodium sulfate, filtered and concentrated in vacuum. The crude product was chromatographically on silica using a mixture of 40% acetone/methylene chloride, yielding 40 mg (19%) of pure product in the form of its free base. This oil was dissolved in a minimal volume of chloroform, it was diluted with several volumes of ether, and pulverized with 1M HCl in ether with the deposition of the desired product as a white solid (so pl. 170-185oC (decomp.), C-MS: 408 (MH+), the analysis RP18-ihvd RT: 3.93 min).

Example 29

Hydrochloride [6,7-bis-(2-chloro-ethoxy)-hinzelin-4-yl]- (3-ethinyl-phenyl)-amine

4-Chloro-6,7-bis-(2-chloroethoxy)-hinzelin (600 mg, 1.87 mmole) and 3-ethinyl-aniline (219 mg, 1.87 mmole) was subjected to reaction in delegateuser isopropanol (15 ml) under nitrogen atmosphere for 2.5 hours. The mixture was cooled is the Aquum. (707 mg, 86%, so pl. 230-240oC (decomp.), C-MS: 402 (MH+), the analysis RP18-ihvd RT: 5.35 min).

Example 30

Hydrochloride [6-(2-chloro-ethoxy)-7-(2-methoxy-ethoxy)-hinzelin - 4-yl] -(3-ethinyl-phenyl)-amine

The target product was obtained from 4-chloro-6-(2-chloro-ethoxy)-7- (2-methoxy-ethoxy)-hintline (399 mg, 1.26 mmole) and 3-ethinyl - aniline (147 mg, 1.26 mmole) as described in example 29 (515 mg, 94%, so pl. 215-225oC (decomp.), C-MS: 398 (MH+), the analysis RP18-ihvd RT: 4.85 min

Example 31

6,7-Bis(2-acetoxy-ethoxy)- 4-(3-ethinyl-phenylamino)- hinzelin

The target product of example 29 (200 mg, 0.456 mmole) was treated with cesium acetate (1.75 g, 9.12 mmole) in DMF (3 ml) at 120oC in nitrogen atmosphere for 16 hours. The reaction mixture was distributed between brine and chloroform, and the organic extract was washed with saline, dried over sodium sulfate, filtered and concentrated in vacuo, yielding an oil (277 mg), which was precrystallization from a mixture of methylene chloride/hexane (184 mg, 90%, so pl. 137-138oC, C-MS: 450 (MH+), the analysis RP18-ihvd RT: 4.64 min).

Example 32

Hydrochloride of 2-[4-(3-ethinyl-phenylamino)-7-(2 - hydroxy-ethoxy)-hinzelin-6-yloxy]-ethanol

6,7-Bis-(2-acetoxy-ethoxy)-4-(3-ethinyl-phenyl-amino)- hinzelin (199 mg, 0.443 mmole) in melenium of the solvent in vacuo. The solid residue was rinsed with water to remove salts, and dried azeotrope by dissolving twice in acetonitrile and concentration under vacuum, yielding 116 mg of the desired product in the form of its free base. This substance is turned into its HCl salt according to the method used in example 28 (115 mg, 65%, so pl. 215-218oC (decomp.), C-MS: 366 (MH+), the analysis RP18-ihvd RT: 3.08 min).

Example 33

6-(2-Acetoxy-ethoxy)- 4-(3-ethinyl-phenylamino)- 7-(2-methoxy-ethoxy) -hinzelin

The target product of example 30 (160 mg, 0.368 mmole) was treated with cesium acetate (707 mg, 3.68 mmole) in DMF (3 ml) at 120oC in nitrogen atmosphere for 16 hours. The reaction mixture was distributed between brine and chloroform, and the organic extract was washed with saline, dried over sodium sulfate, filtered and concentrated in vacuum giving a residue (285 mg), which was precrystallization from a mixture of ethyl acetate/hexane (134 mg, so pl. 84-87oC, C-MC: 422 (MH+), the analysis RP18-ihvd RT: to 4.38 min).

Example 34

Hydrochloride [7-(2-chloro-ethoxy)-6-(2-methoxy-ethoxy)-hinzelin-4-yl] - (3-ethinyl-phenyl)amine

This product was obtained from 4-chloro-7-(2-chloro-ethoxy)-6- (2-methoxy-ethoxy)-hintline (600 mg, 1.89 mmole) and 3-ethinyl-Ani is .89 min).

Example 35

7-(2-Acetoxy-ethoxy)-4- (3-ethinyl-phenylamino)- 6-(2-methoxy-ethoxy) -hinzelin

The target product of example 34 (160 mg, 0.368 mmole) was treated with cesium acetate (707 mg, 3.68 mmole) in DMF (3 ml) at 120oC in nitrogen atmosphere for 16 hours. The reaction mixture was distributed between brine and chloroform, and the organic extract was washed with saline, dried over sodium sulfate, filtered and concentrated in vacuum giving a residue (288 mg), which was precrystallization from a mixture of ethyl acetate/hexane (134 mg, so pl. 134-135oC, C-MC: 422 (MH+), the analysis RP18-ihvd RT: 4.43 min.)

Example 36

Hydrochloride of 2-[4-(3-ethinyl-phenylamino)-6-(2 - methoxy-ethoxy)-hinzelin-7-yl-oxy]-ethanol

The target product of example 35 (149 mg, 0.354 mmole) in methanol (3 ml) was treated with 5 M aqueous KOH (0.25 ml). The mixture was mixed at 20oC for 30 minutes before removing the solvent in vacuo. The solid residue was rinsed with water to remove salts and dried by azeotropic dissolution twice in acetonitrile and concentration under vacuum, giving 100 mg of the target product in the form of its free base. This substance is turned into its HCl salt according to the method used in example 28 (87 mg, 59%, t is tiny-phenyl)-{ 6-[2-methoxy-ethoxy)-7-[2-(4-methylpiperazin-1-yl) -ethoxy]-hinzelin-4-yl}-amine

The target product of example 34 (110 mg, 0.253 mmole) in DMF (2 ml) was treated with N-methyl-piperazine (281 μl, 2.53 mmole) at 110oC for 16 hours. The reaction mixture was distributed between chloroform and saturated aqueous sodium bicarbonate. The organic extracts were washed with saline, dried over sodium sulfate, filtered and concentrated in vacuum. The crude product was chromatographically on silica using 15% methanol/methylene chloride, yielding 56 mg of pure product in the form of its free base. This white solid was dissolved in a minimal volume of chloroform and were pulverized with 2 EQ. 1 M HCl in ether to precipitate the desired product as a white solid (65 mg, 48%, so pl. 130-142oC (decomp. ), C-MS: 462 (MH+), the analysis RP18-ihvd RT: 3,69 min).

Example 38

Dichlorhydrate (3-ethinyl-phenyl)-[7-(2-imidazol-1 - yl-ethoxy)-6-(2-methoxy-ethoxy)hinzelin-4-yl]-amine

Target product from example 34 (110 mg, 0.253 mmole) in DMF (2 ml) was treated with imidazole (172 mg, 2.53 mmole) at 110oC for 48 hours. The reaction mixture was distributed between chloroform and saturated aqueous sodium bicarbonate. The organic extracts were washed with saline, dried over sulfate is silicon using a mixture of 10% methanol: methylene chloride, giving 85 mg of pure desired product in the form of its free base. This white solid was dissolved in minimum amount of chloroform, and were pulverized with 2 EQ. 1M HCl in ether, with precipitation of the desired product as a white solid (95 mg, 75%, so pl. 220-227oC (decomp.), C-MS: 430 (MH+), the analysis RP18-ihvd RT: 3.75 min.)

Example 39

Dichlorhydrate (3-ethinyl-phenyl)-[6-(2-imidazol - 1-yl-ethoxy)-7-(2-methoxy-ethoxy)-hinzelin-4-yl]-amine

The target product of example 30 (110 mg, 0.253 mmole) in DMF (2 ml) was treated with imidazole (172 mg, 2.53 mmole) at 110oC for 48 hours. The reaction mixture was distributed between chloroform and saturated aqueous sodium bicarbonate. The organic extracts were washed with saline, dried over sodium sulfate, filtered and concentrated in vacuum. The crude product (125 mg) was chromatographically on silica using a mixture of 10% methanol/methylene chloride, giving 86 mg of pure desired product in the form of its free base. This white solid was dissolved in a minimal volume of chloroform and were pulverized with 2 EQ. 1M HCl in ether with the deposition of the desired product as a white solid diclorhidrato salt (95 mg, 78%, so pl. 85-100oC (decomp.), C-MC: C)- 6-(2-morpholine-4-yl-ethoxy)-hinzelin-4-yl]-amine

Target product from example 30 (107 mg, 0.245 mmole) in DMF (2 ml) was treated with morpholine (214 μl, 2.45 mmole) at 80oC for 24 hours. The reaction mixture was distributed between chloroform and saturated aqueous sodium bicarbonate. The organic extracts were washed with saline, dried over sodium sulfate, filtered and concentrated in vacuum. The crude product (168 mg) was chromatographically on silica using a mixture of 7.5% methanol/methylene chloride, yielding 65 mg of pure desired product as free base. This white solid was dissolved in a minimal volume of chloroform and were pulverized with 2 EQ. 1M HCl in ether with the deposition of the desired product as a white solid (88 mg, 59%, so pl. 115 - 130oC (decomp.), C-MS: 449 (MH+), the analysis of RP-18-ihvd RT: 4.00 min).

Example 41

Hydrochloride of 2-[4-(3-ethinyl-phenylamino)-7-(2-methoxy-ethoxy) -hinzelin-6-yloxy]-ethanol

Target product from example 33 (149 mg, 0.354 mmole) in methanol (3 ml) was treated with 5M aqueous KOH (0.25 ml). The mixture was mixed at 20oC for 30 minutes before removing the solvent in vacuo. The solid residue was rinsed with water to remove salts and dried azeotrope by dissolving twice in ACE who has been turned into its HCl salt in accordance with the method, used in example 28 (89 mg, 61%, so pl. 190-215oC (decomp.), C-MC: 380 (MH+), the analysis RP18-ihvd RT: 3.66 min).

Example 42

Hydrochloride (6,7-diethoxy-hinzelin-4-yl)-(3 - ethinyl-phenyl)-amine

6,7-Detoxification-4-one (120 mg, 0.512 mmole), triphenylphosphine (295 mg, 1.126 mmole) in 3 ml of carbon tetrachloride was heated under conditions of reflux distilled for 16 hours. The reaction mixture was concentrated in vacuo to a residue, which was diluted to 3 ml of isopropyl alcohol and 3-itineraries (66 mg, 0.562 mmole) and heated under conditions of reflux distilled for 3 hours. The cooled reaction mixture was filtered, giving a solid target product, which was washed with 10 ml of isopropyl alcohol and dried in vacuum at 70oC, 140 mg (75%), so pl. 269-270oC.

Example 43

Hydrochloride (6,7-diethoxy-hinzelin-4-yl)-(3-ethinyl-2-methyl-phenyl) -amine

4-Chloro-6,7-detoxification (200 mg, 0,792 mmole) and 3-(2' -trimethylsilylethynyl)-2-methyl-aniline (168 mg, 0.871 mmole) in 4 ml of butyl alcohol was heated under conditions of reflux distilled for 16 hours. The cooled reaction mixture was diluted with 5 ml of ethyl ether and filtered, giving a solid hydrochloride (6,7-diethoxy-hinzelin-4-yl)- (3-(2'-trimethylsilyl-ethinyl)- 2-methyl-phenyl)-amine, eposredstvenno processing 2 ml of methanol, containing 1 drop of water and 100 mg of potassium carbonate, in a period of 0.5 hours. The heterogeneous reaction mixture was filtered through celite and evaporated in vacuo to a residue, which was dissolved in excess of 1 N. HCl in methanol, precipitated with ethyl ether, filtered and dried in vacuum at 70oC, giving the desired product; 160 mg (75%), so pl. 258-259,5oC.

Example 44

Hydrochloride (3-ethinyl-phenyl)-(6-methyl-hinzelin - 4-yl)-amine

6-Methyl-hinzelin-4-one (350 mg, 2.18 mmole) was added to a suspension of precipitated polymer triphenylphosphine (from Fluka, 3,63 g to about 3 mmol P/g resin; 10.9 mmole) in a mixture of CCl4(3.35 g, 21.80 mmol) and 1,2-dichloroethane (10 ml). The mixture was heated to 60oC for 2 hours, and then the polymer was removed by filtration and was rinsed with dichloroethane. The filtrate was collected in a flask containing 3-ethinyl-aniline (0.644 g, 2.18 mmole) and concentrated to 5 ml by evaporation. After a 4-hour heat under reflux distilled in a nitrogen atmosphere and then cooled to 20oC target product was collected by filtration (551 mg, 86%, so pl. 256-257oC, C-MC: 260 (MN+), the analysis of RP-ihvd RT: to 4.41 min).

Example 45

Ammonium salt 2-{ 2-[4-(3-ethinyl-phenylamino)-6-(2 - methoxy-ethoxy)-hinzelin-7-yloxy]-atlanfa the slots (100 μl, 1.14 mmole) and KOH (150 mg, 2.7 mmole) in degassed DMF (5 ml)/water (0.5 ml). The reaction mixture was stirred at 50oC in nitrogen atmosphere for 72 hours, and then cooled to room temperature. The pH of the mixture was brought to about 4.0 with acetic acid and then the mixture was distributed between chloroform and brine. The organic extracts were washed with saline, dried over sodium sulfate, filtered and concentrated in vacuum. The crude product was purified using preparative RP18 jhud with a gradient of 15% to 100% CH3CN/pH 4.5, 50 mm ammonium acetate, followed by lyophilization of the appropriate pure fractions, giving the desired product (28 mg, 18%, so pl. 95-103oC (decomp.), C-MS: 468 (MH+), the analysis of RP-ihvd RT: 3.57 min.)

Example 46

Ammonium salt of {2-[4-(3-ethinyl-phenylamino)-6-(2-methoxy - ethoxy)-hinzelin-7-yloxy]ethylsulfanyl}-acetic acid

The target product was obtained from the target product of example 34 and mercaptohexanol acid according to the method of example 45 (3%, C-MS: 454 (MH+), the analysis of RP-ihvd RT: 3.37 min).

Example 47

4-(3-Ethinyl-phenylamino)- 6-(2-methoxy-ethoxy) -hinzelin-7-ol

This product stood out as more lipophilic product is: 336 (MH+), the analysis of RP-ihvd RT: 3,60 min).

Example 48

(3-Ethinyl-phenyl)-[7-(2-methoxy-ethoxy)-6 - vinyloxy-hinzelin-4-yl]amine hydrochloride and [6-(2-ethoxy-ethoxy) -7-(2-methoxy-ethoxy)-hinzelin-4-yl]-(3-ethinyl-phenyl) -amine

The target product of example 30 (107 mg, 0.245 mmole) was treated with sodium ethylate (0.582 mmole) in delegateuser ethanol (3 ml) for 24 hours. The solvent was removed in vacuo, and the product was separated using flash chromatography on silica using a mixture of 10% acetone/methylene chloride, yielding 30 mg of 6 - vinyloxy product (33%, so pl. 113-114oC, C-MS: 362 (MH+), the analysis of RP-ihvd RT: 4.84 min), 6-(2-ethoxy-ethoxy) was derived loirevalley in the form of a more polar product (45 mg) and turned into its HCl salt according to the procedure described for example 28 (43%, so pl. 220-225oC (decomp. C-MS: 408 (MH+), the analysis of RP-ihvd RT: 4.35 min.)

Example 49

The hydrochloride of 4-(3-ethinyl-phenylamino)-7-(2 - methoxy-ethoxy) -hinzelin-6-ol

(3-Ethinyl-phenyl)-[7-(2-methoxy-ethoxy)-6-vinyloxy - hinzelin-4-yl]-amine (20 mg, from example 48) hydrolizable processing 6M hydrochloric acid/methanol (30: 70, 3 ml) at 50oC for 5 days. The solution was concentrated in vacuo, and the residue was distributed between chloroform and brine p is the n and concentrated in vacuum, giving the desired product in the form of its free base (15 mg), which was transformed into its HCl salt according to the procedure described for example 28 (so pl. 135-150oC (decomp.), C-MS: 336 (MH+), the analysis of RP-ihvd RT: 3.77 min).

Example 50

Hydrochloride 1-{ 2-[4-(3-ethinyl-phenylamino)-6- (2-methoxy-ethoxy)-hinzelin-7-yloxy]-ethyl}-1H-pyridin-4-one

Sodium hydride (30 mg, 60% in mineral oil, 0.77 mmole) was added to anhydrous DMF (2.0 ml) followed by the addition of pyrid-4-it (79 mg, 0.83 mmole). The mixture was mixed for 40 minutes at 22oC up until all solids were dissolved and did not stop the release of hydrogen. Added target product of example 34 (120 mg, 0.28 mmole) and tetrabutylammonium (15 mg) and the reaction mixture stirred at 22oC for 7 days under nitrogen atmosphere. Additional number of pyrid-4-it (79 mg) and NaH (30 mg, 60%) was dissolved in DMF (2 ml) and the solution was added to the reaction mixture. After stirring for 4 days, the mixture was distributed between chloroform and brine. The organic extracts were dried over sodium sulfate, filtered and concentrated in vacuum. The crude product was purified using flash chromatography on silica using the on-clorhidrato) salt according to the procedure described for example 28 (66 mg, so pl. 240-248oC (decomp.), C-MS: 457 (MH+), the analysis of RP-ihvd RT: 3.23 min.)

Example 51

Hydrochloride 1-{ 2-[4-(3-ethinyl-phenylamino)-7- (2-methoxy-ethoxy)-hinzelin-6-yloxy]-ethyl}-1H-pyridin-4-one

The free base of this product was obtained from the target product of example 30 and sodium salt of pyrid-4, as described for example 50. The free base was separated using flash chromatography using a mixture of 15% methanol/chloroform and turned into a target product in accordance with the procedure described for example 28 (32%, so pl. 155-168oC (decomp.), C-MS: 457 (MH+), the analysis of RP-ihvd RT: 3.45 min.)

Example 52

Hydrochloride (3-ethinyl-phenyl)-(6-methoxy-hinzelin-4-yl)-amine

25 mm solution of 6-methoxy-3H-hinzelin-4-she in 1,2-dichloroethane was added to the precipitated polymer to triphenylphosphine (from Fluka, about 3 mmole P/g polymer, 2.5 mol.EQ.) and carbon tetrachloride (10 mol. EQ.). The reaction mixture was heated with shaking at 60oC for 21 hours, cooled to 22oC, and added a 30 mm solution of 3-itineraria (1.5 mol. EQ.) in tert-butanol. The resulting mixture then was heated with shaking at 60oC for 18 hours with subsequent cooling gap is bilalis to the filtrate, and the solution was concentrated in vacuo, giving the desired product (73%, C-MC: 276 (MH+), the analysis RP18-ihvd RT: 5.82 min). For these cases, analytical RP18-ihvd system consisted of a waters 717 (trade mark) auto sampler, waters 996 photodiode Radiation Detector (trade mark) and a waters 600 Quaternary system of delivery of solvent and controlled using software Millennium (trade mark). Aliquots of the samples or the samples was chromatographically using a linear gradient 0 to 100% acetonitrile/0.2 M AMMONIATING buffer (pH 4.5) for ten minutes at a flow rate of 3 ml/min using a C18 column Perkin-Elmer Pecover (trade mark) (3 mm x 3 cm).

Connection examples 53-94 in the form of their chlorhydrate salts were prepared similarly to the method of example 52 from the corresponding 3H-hinzelin-4-about derivative and 3-ethinyl-aniline.

Example 95

Hydrochloride (6,7-dibutoxy-hinzelin-4-yl)- (3-ethinyl-phenyl)-amine

6,7-dibutoxy-hinzelin-4-one (105 mg, 0,362 mmole), triphenyl phosphine (208 mg, coefficient was 0.796 mmole) and 5 ml of carbon tetrachloride was heated under reflux for 16 hours, and the reaction mixture was concentrated in vacuo, giving OST the fridge for 3 hours. The cooled reaction mixture was filtered, giving a solid hydrochloride (6,7-dibutoxy-hinzelin-4-yl)- (3-ethinyl-phenyl)-amine, which was rinsed with 10 ml of isopropyl alcohol and dried in vacuum at 70oC, in the amount of 92 mg (60%); so pl. 247-248oC.

Example 96

Hydrochloride (6,7-diisopropoxide-hinzelin-4-yl)- (3-ethinyl-phenyl)-amine

6,7-diisopropylaniline-4-one (55 mg, 0,210 mmole), triphenylphosphine (121 mg, 0,462 mmole) and 3 ml of carbon tetrachloride was heated under conditions of reflux distilled for 16 hours, and the reaction mixture was concentrated in vacuo to obtain a residue, which was diluted to 3 ml of isopropyl alcohol and 3-itineraria (30 mg, 0,257 mmole) and heated under reflux for 3 hours. The cooled mixture was perivolas in vacuo, giving the desired product, which was chromatographically on silicagel column during elution with 5% acetone in methylene chloride containing 0.25% triethylamine. The fractions containing pure product were concentrated in vacuo to obtain a solid, which was dissolved in 2 ml of 1 N. HCl in methanol, precipitated with ethyl ether, filtered and dried in vacuum at 70oC, giving the desired product in the amount of 140 mg (75%); so pl. phenyl)amine

6-chloro-7-(2-methoxyethylamine)-hinzelin-4-one (200 mg, 0,739 mmole), triphenylphosphine (427 mg, and 1.63 mmole) and 0.7 ml of carbon tetrachloride was heated under conditions of reflux distilled in 4 ml of 1,2-dichloroethane for 4 hours, concentrated in vacuo before the residue was diluted with 4 ml of isopropyl alcohol and 3-itineraria (129 mg, 1,104 mmole) and heated under reflux for 16 hours. The hot reaction mixture was filtered to separate the crude product, which was subjected to column chromatography on silica gel with elution with 5% methanol in chloroform. The fractions containing pure product were concentrated in vacuo, giving the desired product in the form of a solid substance in an amount of 23 mg (8.4 per cent); so pl. 230-232oC.

Example 98

(6,7-bis-[2-methoxyethoxy] - hinzelin-4-yl)- (3-ethinyl-2-methyl-phenyl) -amine

6,7-bis-[2-methoxyethoxy] -4-chloro-hinzelin (90 mg, in 0.288 mmole) and 3-(2'-trimethylsilylethynyl)-2-methyl-aniline (62 mg, MX 0.317 mmole) was heated under reflux in 4 ml of tert-butyl alcohol for 16 hours. The cooled reaction mixture was diluted with 1 ml of isopropyl alcohol and filtered, giving a solid hydrochloride (6,7-bis- (methoxyethoxy)-hinzelin-4-yl)-(3-(2'-trimethylsilylethynyl-1 - yl)-2-methyl-phenyl who was eSellerate by processing in 3 ml of methanol, containing 1 drop of water and 50 mg of potassium carbonate, within half an hour at room temperature. The heterogeneous reaction mixture was filtered through celite and perivolas in a vacuum to residue, which was dried in vacuum at 70oC, giving the desired product in the form of a dry foam in the amount of 38 mg (75%); so pl. 232oC.

Example 99

Hydrochloride (6,7-bis-[2-methoxyethoxy] -hinzelin-4-yl)- (3-ethinyl-5-fluoro-phenyl)-amine

6,7-bis-(2-methoxyethoxy)- 4-chloro-hinzelin (90 mg, in 0.288 mmole) and 3-(2'-triethylsilanol)-5-fluoro-aniline (69 mg, MX 0.317 mmole) in 3 ml of butyl alcohol was heated under conditions of reflux distilled for 5 hours. The cooled reaction mixture was diluted with 2 ml of isopropyl alcohol and filtered, giving a solid hydrochloride (6,7-bis-methoxyethoxymethyl-4-yl)-(3-(2'-trimethylsilyl - ethinyl)-5'-fluoro-phenyl)-amine, which was filtered and 10 ml of ethanol and dried in vacuum at 70oC; 131 mg All this stuff was desilicious by dissolving in 3 ml of methanol containing 1 drop of water and 35 mg of potassium carbonate, within half an hour at room temperature. The pH of the reaction mixture was brought to 2.5 with an aqueous solution of 1 N. hydrochloric acid, and the mixture was filtered. The solid was dried in vacuum, giving 92 mil-phenyl)-amine.

Hydrochloride 7-propylsulfonyl - hinzelin-4-one (300 mg, about 1.36 mmole), triphenylphosphine (785 mg, 2,99 mmole), 1.31 ml of carbon tetrachloride and 5 ml of chloroform was heated under reflux for 16 hours, and the reaction mixture was concentrated in vacuo to a residue, which was diluted with 5 ml of isopropyl alcohol and 3-itineraria (175 mg, 1,49 mmole) and heated under conditions of reflux distilled for 3 hours. The cooled reaction mixture was concentrated in vacuo, and the residue was purified column chromatography on silica gel with elution with 10% methanol in chloroform. The fractions containing the pure target product, in the form of a free amine, concentrated in vacuo, giving a solid which was added to 3 ml of 1 N. HCl in methanol. This solution was supariwala in a vacuum to residue, which was pulverized with 4 ml of hot isopropyl alcohol, cooled and filtered. The thus obtained solid substance was dried in vacuum at 70oC, giving 239 mg of pure desired product (55%), so pl. 229-230oC.

Example 101

Hydrochloride [7-(2-methoxyethylamine)-hinzelin-4-yl] - (3-ethinyl-phenyl)-amine

In the same way as in example 42, hydrochloride [7- (2-methoxyethylamine) -hinzelin-4-yl]-(3-ethinyl - Veolia) and 3 ml of carbon tetrachloride to yield 74%; 233 mg, so pl. 208 - 209oC.

Example 102

Hydrochloride (7-chloro-6-nitro-hinzelin-4-yl)-(3 - ethinyl-phenyl)-amine

7-chloro-6-nitro-hinzelin-4-one (1,002 g of 4.44 mmole), phosphorus oxychloride (11.5g, 7,51 mmole) and pentachloride phosphorus (1,62 g, 7,74 mmole) was heated under reflux for 2 hours, and the reaction mixture was concentrated in vacuo to a residue, which was pulverized with toluene, and then again with chloroform and dried in vacuo, giving crude 4,7-dichloro-6-nitro-hinzelin. The latter was dissolved in 35 ml of isopropyl alcohol and 3-itineraria (639 mg, the 5.45 mmole) and heated under conditions of reflux distilled for 3 hours. The cooled reaction mixture was filtered, giving the target compound in the form of solids, which were washed with 10 ml of isopropyl alcohol and dried in vacuum at 70oC, of 1.055 g (66%); so pl. to 230.8-232,6oC.

Example 103

Hydrochloride (6-amino-7-chloro-hinzelin-4-yl)-(3-ethinyl-phenyl)-amine

Hydrochloride (7-chloro-6-nitro-hinzelin-4-yl)-(3-ethinyl-phenyl)-amine (166 mg, 0,295 mmole) and dithionite sodium (207 mg, 1,19 mmole) were mixed in 1.5 ml of formic acid for 4 hours at room temperature. 45 ml of methanol was added to the reaction mixture, which was left for 16 hours at room is within half an hour and filtered. The solid was dissolved in 20 ml of 1 N. HCl in methanol and precipitated with 200 ml of ethyl ether. This substance was filtered and dried in vacuum at 70oC, yielding 72 mg of the desired product (83%); so pl. 260-265oC.

Example 104

(3-ethinyl-phenyl)- (7-methoxy-6-nitro - hinzelin - 4-yl)-amine

Hydrochloride (7-chloro-6-nitro-hinzelin-4-yl)-(3 - ethinyl-phenyl)-amine (100 mg, 0,306 mmole) and dry sodium methylate (120 mg, 2,22 mmole) were mixed in 2 ml of dry 2-methyl - pyrrolidin-1-it for 8 hours at 30oC. To the cooled reaction mixture was added with 0.93 ml of 3 N. hydrochloric acid and 1 ml of water. The mixture was diluted with 60 ml water and was extracted twice with 60 ml of ethyl acetate. The combined organic layers were washed three times with 50 ml water and 50 ml of saline solution, dried by magnesium sulfate, filtered and mariveles in vacuum, yielding 80 mg of the desired product as a solid (82%); so pl. 213-218oC decomp.

Example 105

Ammonium salt of { 2-[4-(3-ethinyl-phenylamino)-7-(2-methoxy-ethoxy)- hinzelin-6-yloxy]-ethylsulfanyl}-acetic acid

This substance was obtained from the target product of example 30 and mercaptohexanol acid at the 22oC for 10 days in accordance with the method described in example 45 (16%, so pl. 98-113oC (p>To ethyl-3,4-dihydroxybenzoate cases (36.4 g, 0.200 mole), potassium carbonate (60.8 g, 0.44 mol) and tetrabutylammonium (750 mg) in degassed acetone (400 ml) was added 2-bromatology ether (69.5 g, 47 ml). The mixture was stirred in nitrogen atmosphere at reflux for 64 hours. To the mixture was added ether (600 ml) and after stirring for 30 minutes at 20oC precipitated salt was removed by filtration. The filtrate was concentrated in vacuo, and the residue was pulverized with hexane (500 ml) for 30 minutes and the white solid ethyl 3,4-bis(2-methoxy-ethoxy)benzoate was filtered off and dried in vacuum (of 55.5 g, 93%, so pl. 50-51oC). Part of this product (45.7 g, 0.158 mol) in acetic acid (150 ml) was treated dropwise with concentrated nitric acid (40 ml) at 5oC, and the solution was mixed for 24 hours before pouring into cold water (1.6 l). The mixture was extracted with ethyl acetate (1.1 l) and the organic phase was washed three times with 200 ml of water and brine and were dried over sodium sulfate, filtered and concentrated in vacuo, giving ethyl 4,5-bis(2-methoxy-ethoxy)-2-nitrobenzoate (54.3 g) as a brown oil. This nitro product (52.0 g, 0.15 mol) was dissolved in ethanol (1000 ml) containing 1 EQ. HCl (the very, and the mixture was gerasoulis under hydrogen pressure of 45 lb./square inch (3.164 kg/cm2within 6 hours. The catalyst was removed by filtration through celite, and the filtrate was concentrated in vacuo to a thick suspension which was diluted with ether (400 ml). Solid white chlorhydrate salt of ethyl 2-amino-4,5-bis-(2-methoxy-ethoxy)benzoate was filtered off and dried in vacuum (44.7 g, 88%). Part of this substance (42 g, 0.12 mol) and ammonium formate (7.6 g, 0.12 mol) was dissolved in formamide (63 ml) and the stirred mixture was heated to 160-165oC in nitrogen atmosphere for 3 hours. Water was added (200 ml), and after cooling, the precipitated crude target product was separated by filtration, were washed with cold water and dried in vacuum. The filtrate was extracted five times with chloroform, and the combined organic extracts were washed with saline, dried over sodium sulfate and concentrated in vacuum. The residue and the precipitated crude hintline United, were pulverized in hot acetonitrile (250 ml) for 30 minutes, cooled to 20oC and was treated with ether (250 ml). After cooling to 4oC white solid was filtered and dried in vacuum (30.4 g, 86%, GC-MS m/z 294 (M+)).

Getting 2

4-Chloro what hloroform (10 ml), containing one drop of DMF, was added oxalicacid (490 μl, 5.6 mmole) in several portions over 5 minutes. After foaming ceased, the solution was heated under reflux for 1.5 hours. The solvent was removed in vacuo, and the residue was dissolved in 1,2-dichloroethane (20 ml) and was washed twice with 80 ml of saturated aqueous sodium carbonate. The organic phase was dried over sodium sulfate and concentrated in vacuo giving a solid target product (520 mg, 92%, so pl. 108-109oC).

Getting 3

4-Chloro-6,7-bis-(2-chloro-ethoxy)-hinzelin, 4 - chloro-6-(2-chloro-ethoxy)-7-(2-methoxy-ethoxy)-hinzelin, 4-chloro - 6,7-bis-(2-methoxy-ethoxy)-hinzelin and 4-chloro-7-(2-chloro-ethoxy)-6- (2-methoxy-ethoxy)-hinzelin

6,7-Bis (2-methoxy-ethoxy) hinzelin (5.4 g, 18.3 mmole) of a 1 and pyridine (3.0 ml, 37 mmol) was heated in delegateuser POCl3(22 ml) in a dry nitrogen atmosphere for 2.5 hours. After concentrating the mixture in vacuo at 60oC the residue was dissolved in chloroform (150 ml) and carefully added in portions with stirring to a cold saturated aqueous sodium bicarbonate (100 ml). The mixture was mixed for 10 minutes after completion of the adding, and the organic phase was attilalongoria flash chromatography on silica using a gradient of 20 60% ethyl acetate/hexane, giving 3.41 g of 4-chloro-6,7-bis-(2-methoxy-ethoxy) -hintline, 234 mg of 4-chloro-6-(2-chloro-ethoxy)- 7-(2-methoxy-ethoxy)- hintline, 532 mg 4-chloro-7-(2-chloro-ethoxy)-6- (2-methoxy-ethoxy)- hintline 330 mg of 4-chloro-6,7-bis (2-chloro-ethoxy)- hintline.

The results of the test compounds shown in table 2.

1. Derivatives of 4-(substituted phenylamino)hintline formula

< / BR>
in which m represents 1 or 2,

n represents 1 or 2,

each R1independently selected from the group consisting of halogen; cyano; hydroxy; R5, nitro; amino; trifloromethyl, C(=O)OR5, R5O, optionally substituted with halogen, hydroxy, (1-4)alkoxy, acetoxy, (1-4)With alkylpiperazine, morpholinium, imidazolyl, 4-oxopyridine or S(1-3)alkyl, optionally substituted by carboxy; SO2R5, SR5, optionally substituted by cyano, (1-4)alkoxy, S(1-4)alkyl or 4-cyanophenyl group; toluensulfonate, NHSO2R5benzylmorphine or phenylsulfonyl, optionally substituted by 1-2 halogen atoms; phenoxy, optionally substituted with 1-2 substituents selected from halogen, (1-4)alkyl, (1-4)alkoxy, methanesulfonyl, methanesulfonyl and halogenbenzonitriles; the and, taken together, 6 and 7 positions of hintline form methylenedioxy; and where the alkyl groups or the alkyl fragments of these alkoxygroup may have a straight chain, and if they are made at least three carbon atoms, may be branched;

R2represents hydrogen;

each group R3independently selected from hydrogen, halogen and (1-4)alkyl;

R4is azido or (2-4)With quinil where specified quinil optionally substituted by hydroxy, amino or aminomethyl group;

R5is (1-4)alkyl;

or their pharmaceutically acceptable salts.

2. Connection on p. 1, in which R3is hydrogen, R4is ethinyl or azido, each R1independently selected from carbomethoxy and (1-4)alkoxy, where the alkoxy optionally substituted by hydroxy, halogen, (1-4)alkoxy or acetoxy.

3. Connection on p. 1, selected from the group consisting of:

(6,7-dimethoxyquinazolin-4-yl)-(3-ethynylphenyl)-amine,

(6,7-dimethoxyquinazolin-4-yl)-[3-(3'-hydroxypropyl-1-yl)phenyl]-amine,

[3-(2'-(aminomethyl)ethinyl)phenyl]-(6,7-dimethoxyquinazolin-4-yl)-amine,

[3-ethynylphenyl]-(6-nitroquinazoline-4-yl)-amine,

(6,7-dimethoxyquinazolin the-4-yl)-(3-ethynylphenyl)-amine,

(3-ethynylphenyl)-(6-methanesulfonylaminoethyl-4-yl)-amine,

(3-ethynylphenyl)-(6,7-methylenedioxyaniline-4-yl)-amine,

(6,7-dimethoxyquinazolin-4-yl)-(3-ethinyl-6-were)-amine,

(3-ethynylphenyl)-(7-nitroquinazoline-4-yl)-amine,

(3-ethynylphenyl)-[6-(4'-toluensulfonate)hinzelin-4-yl)-amine,

hydrochloride (3-ethynylphenyl)-{6-[2'-phthalimido-1'-ethyl-sulfonyl-amino]hinzelin-4-yl}-amine,

(3-ethynylphenyl)-(6-guanidinopentanoic-4-yl)-amine,

(7-aminoquinazolin-4-yl)-(3-ethynylphenyl)-amine,

(3-ethynylphenyl)-(7-methoxyquinazoline-4-yl)-amine,

(6-caramelisation-4-yl)-(3-ethynylphenyl)-amine,

(7-carbomethoxybiphenyl-4-yl)-(3-ethynylphenyl)-amine,

[6,7-bis(2-methoxyethoxy)hinzelin-4-yl]-(3-ethynylphenyl)-amine,

(3-azidophenyl)-(6,7-dimethoxyquinazolin-4-yl)-amine,

(3 azido-5-chlorophenyl)-(6,7-dimethoxyquinazolin-4-yl)-amine,

(4-azidophenyl)-(6,7-dimethoxyquinazolin-4-yl)-amine,

(3-ethynylphenyl)-(6-methanesulfonyl-hinzelin-4-yl)-amine,

(6-econsultancy-hinzelin-4-yl)-(3-ethynylphenyl)-amine,

(6,7-dimethoxyquinazolin-4-yl)-(3-ethinyl-4-fluoro-phenyl)-amine,

(6,7-dimethoxyquinazolin-4-yl)-[3-(propyne-1'-yl-phenyl)]-amine,

[6,7-bis(2-methoxy-ethoxy)-hinzelin-4-yl] -(5-ethinyl-2-methyl-phenyl)-amine,

[6,7-bis(2-methods the min

[6-(2-chloro-ethoxy)-7-(2-methoxy-ethoxy)hinzelin-4-yl)-(3-ethynylphenyl)-amine,

[6,7-bis-(2-acetoxy-ethoxy)-hinzelin-4-yl]-(3-ethynylphenyl)-amine,

2-[4-(3-ethinyl-phenylamino)-7-(2-hydroxy-ethoxy)-hinzelin-6-yl-oxy] -ethanol,

6-(2-acetoxy-ethoxy)-4-(3-ethinyl-phenylamino)-7-(2-methoxy-ethoxy)-hinzelin,

[7-(2-chloro-ethoxy)-6-(2-methoxy-ethoxy)-hinzelin-4-yl] -(3-ethynylphenyl)-amine,

[7-(2-acetoxy-ethoxy)-6-(2-methoxy-ethoxy)-hinzelin-4-yl]-(3-ethynylphenyl)-amine,

2-[4-(3-ethinyl-phenylamino)-7-(2-methoxy-ethoxy)-hinzelin-6-yl-oxy] -ethanol,

2-[4-(3-ethinyl-phenylamino)-6-(2-methoxy-ethoxy)-hinzelin-7-yl-oxy] -ethanol,

(3-ethynylphenyl)-{ 6-(2-methoxy-ethoxy)-7-[2-(4-methyl-piperazine-1-yl)-ethoxy]-hinzelin-4-yl}-amine,

(3-ethynylphenyl)-[7-(2-methoxy-ethoxy)-6-(2-morpholine-4-yl)-ethoxy)-hinzelin-4-yl]-amine,(6,7-detoxification-4-yl)-(-3-ethynylphenyl)-amine,

(6,7-dimetocsibenzoy-4-yl)-(3-ethynylphenyl)-amine,

(6,7-diisopropylaniline-4-yl)-(3-ethynylphenyl)-amine,

(6,7-detoxification-4-yl)-(3-ethinyl-2-methyl-phenyl)-amine,

[6,7-bis(2-methoxy-ethoxy)hinzelin-4-yl]-(3-ethinyl-2-methyl-phenyl)-amine,

4. Connection on p. 1, selected from the group consisting of:

(6,7-dipropoxy-hinzelin-4-yl)-(3-ethynylphenyl)-amine,

(6,7-diethoxy-x is etoxy-hinzelin-4-yl)-(5-ethinyl-2-methyl-phenyl)-amine,

(6,7-diethoxy-hinzelin-4-yl)-(3-ethinyl-4-methyl-phenyl)-amine,

(6-aminomethyl-7-methoxy-hinzelin-4-yl)-(3-ethynylphenyl)-amine

(6-aminocarbonylmethyl-7-methoxy-hinzelin-4-yl)-(3-ethynylphenyl)-amine,

(6-aminocarbonylmethyl-7-methoxy-hinzelin-4-yl)-(3-ethynylphenyl)-amine,

(6-aminocarbonylmethyl-7-ethoxy-hinzelin-4-yl)-(3-ethynylphenyl)-amine,

(6-aminocarbonylmethyl-7-ethoxy-hinzelin-4-yl)-(3-ethynylphenyl)-amine,

(6-aminocarbonylmethyl-7-isopropoxy-hinzelin-4-yl)-(3-ethynylphenyl)-amine,

(6-aminocarbonylmethyl-7-propoxy-hinzelin-4-yl)-(3-ethynylphenyl)-amine,

(6-aminocarbonylmethyl-7-isopropoxy-hinzelin-4-yl)-(3-ethynylphenyl)-amine,

(6-aminocarbonylmethyl-7-propoxy-hinzelin-4-yl)-(3-ethynylphenyl)-amine.

5. Connection on p. 3, selected from the group consisting of:

(6,7-detoxification-4-yl)-(3-ethynylphenyl)-amine,

(3-ethynylphenyl)-[6-(2-hydroxy-ethoxy)-7-(2-methoxy-ethoxy)-hinzelin-4-yl]-amine,

[6,7-bis-(2-hydroxy-ethoxy)-hinzelin-4-yl]-(3-ethynylphenyl)-amine,

[6,7-is-(2-methoxy-ethoxy)-hinzelin-4-yl]-(3-ethynylphenyl)-amine,

(6,7-dimethoxyquinazolin-4-yl)-(3-ethynylphenyl)-amine,

(3-ethynylphenyl)-(6 methanesulfonamido-hinzelin-4-yl)-amine,

(6-amino-hinzelin-4-yl)-(3-ethynylphenyl)-amine.

7. Pharmaceutical composition having anti-proliferative activity and containing an active agent and a pharmaceutically acceptable carrier, wherein the active agent it contains a therapeutically effective amount of the compounds under item 1.

Priority points:

30.03.1995 - PP. 1, 6 and 7, with the exception of compounds where R1selected from cyano, tolyloxy, arylsulfonyl, vinyloxy;

06.06.1995 - PP. 1, 6 and 7, where in the compounds R1selected from cyano, tolyloxy, arylsulfonyl, vinyloxy.

 

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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 derivatives of N-sulfanilimide formula I, where R1and R2denote hydrogen, halogen, C1-4alkyl, C1-4alkoxycarbonyl or phenyl which can be substituted one to three times, equal or different residues from the group comprising halogen, C1-4alkyl, trifluoromethyl; R3- halogen, cyano, trifluoromethyl; R4- 4-isoxazolyl, pyrazolyl, which may be substituted with halogen, C1-4the alkyl, amino group, cycloalkyl, as well as their acid-salt additive

The invention relates to new derivatives of 4.1-benzoxazepin-2-she is of the formula (I), where R1lower alkyl, substituted by at least one optionally substituted hydroxyl group, R2and R3independently of one another is hydrogen or phenyl, which is substituted by 1-3 substituents selected from the group consisting of lower C1-C4alkoxygroup; X is a bond, methylene group or a linking group with a chain length of 1-7 atoms, selected from the group consisting of -(CH2)m-E-(CHR6)n-, where m and n = 1 or 2 independently from each other: E-bond or an oxygen atom, -NR5-, -CONR7-, where R5-methylsulphonyl, R6and R7independently of one another(i) hydrogen, (ii) lower alkyl, which is not substituted or substituted by substituents selected from the group consisting of piperidine, indolyl, possibly esterified carboxypropyl, (iii) benzyl, Y is optionally substituted carbarnoyl and/or the substituents on the N atom of carbamoyl, taken together, form a ring which may be substituted, or tetrazolyl, or piperidine, and the ring And is substituted by 1-3 substituents selected from the group consisting of atoms of Halogens or their salts

The invention relates to arylalkylamines formula I, where In - unsubstituted pyridyl, pyrazinyl, isoxazolyl or thienyl; Q - CH2; X - CH2or S; R1and R2each - H; and R3- OR5; R4OA; R5- Or cycloalkyl with 4-6 C atoms; And the alkyl with 1-6 C-atoms, and their physiologically acceptable salts

- aminohydroxylation and carboxylic acid" target="_blank">

The invention relates to new compounds of General formula I, where Q, A, R1n, m are listed in the value formula

The invention relates to a derivative of 7- (alkoxycarbonyl-substituted) -10-hydroxy-taxan following formula 3b:

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in which R1, R2, R4, R5, R6and R14defined above

The invention relates to a method for producing compounds of formula (I) consists in the fact that the compound of formula (IX):

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in which R1' has the abovementioned meaning and M represents a hydrogen atom or the radical R2' which has the values specified above for R2in which the possible reactive functions can be protected by a protective group, is subjected to reaction with the compound of the formula (VIII) defined above, to obtain a product of formula (X):

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in which R1' M and R4' have the above values, the obtained compound of formula (X), if M implies R2' defined above, is subjected to a halogenation reaction, to obtain the product of formula (XI):

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in which R1', R2', R4' and Hal have the above values, which is subjected to the reaction of the exchange of the halogen-metal, then the reaction with the compound of the formula (XII):

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in which R9' matter referred to in paragraph 1 for R9where possible reaction ф�g/rupat4/200110/01/2174513-36t.gif" ALIGN="ABSMIDDLE">< / BR>
in which R1', R2', R4' and R9' have the above meanings and, if necessary, or interact product of formula (I2) with the compound of the formula (XV):

O=C=N-R6' (XV)

in which R6' matter referred to in paragraph 1 for R6in which the possible reactive functions can be protected by a protective group, to obtain a product of formula (I3):

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in which R1', R2', R4', R6' and R9' have the above meanings, or the product of formula (I2) is subjected to a saponification reaction with the product of formula (I4):

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in which R1', R2', R4' and R9' have the above meanings, is subjected to reaction with COCl2to obtain a product of formula (I5):

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in which R1', R2', R4' and R9' have the above meanings, or the product of formula (X), provided that M denotes a hydrogen atom, is subjected to a halogenation reaction to obtain a product of formula (XIV):

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in which R1', R4'Hal and R3" have the above values, the compound obtained is subjected to the reaction of the exchange of the halogen-metal, then the processing of the compound of formula (IVa') (IVb'), (IVc'), (IVd') or (IVe') defined above, to obtain a product of formula (I7):

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in which R1', R4', R2and R3" have the above meanings; then the above products of formula I2, I3, I4, I5, I6, I7that are a product of the formula I, allocate or subjected, if necessary, one or more reactions of transformation to other products of the formula I, in any order:

a) esterification of the acid function,

(b) saponification functions of ester to acid functions,

C) transforming functions of ester function acyl,

d) transforming Sinopoli in an acid function,

e) conversion of the acid function to an alcohol function,

g) transforming functions alkoxy function hydroxyl or hydroxyl function in the function alkoxy,

h) oxidation of the alcohol function to the aldehyde, acid or keto-function

i) the conversion of the formyl radical in the radical carbarnoyl,

j) turning radical carbarnoyl in the nitrile radical,

k) converting the nitrile radical in tetrazolyl,

l) oxidation of ancilliary or aristocraty to the corresponding sulfoxide or sulfone,

m) the transformation function sulfide, sulfoxide or sulfone function corresponding sulfoximine,

n) the transformation function oxo function of thioxo,

a) transforming radical

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in radical

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p) conversion of the acid function in function

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q) is the transformation function of beta-keto-sulfoxide in the function of alpha-ketotioefir,

r) the conversion of carbamate into urea and, in particular, sulfonylamino in the sulfonylurea,

s) removal of protective groups, which can protect the reaction functions,

t) salt formation using mineral or organic cisisomer, enantiomers and diastereoisomers
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