Oxazolo- and thiazolo-[4,5-c]-quinoline-4-amines, intermediate compounds, pharmaceutical composition based on thereof and method for stimulating biosynthesis of cytokinins (cytokines)

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to oxazolo- and thiazolo-[4,5-c]-quinoline-4-amines of the general formula (I)

wherein R1 is taken among group consisting of oxygen and sulfur atoms; R2 is taken among hydrogen atom, alkyl, alkyl-OH (hydroxyalkyl), alkyl-X-alkyl, alkyl-O-C(O)-N(R5)2, morpholinyl, pyrrolidinyl, alkyl-X-aryl radical, alkenyl-X-aryl radical; each substitute R3 and R4 represents hydrogen atom or substitutes R3 and R4 taken in common form the condensed aromatic or [1,5]-naphthiridine system; X represents -O- or a single bond; R5 represents hydrogen atom. Also, invention describes intermediate compounds, pharmaceutical composition and a method for stimulating biosynthesis of cytokinins (cytokines) based on these compounds. Invention provides preparing new compounds eliciting valuable biological properties.

EFFECT: valuable properties of compounds.

21 cl, 2 tbl, 64 ex

 

The scope of the invention

The present invention relates to oxazole-, thiazole and selenatol[4,5-C]quinoline-tetrahydroquinolin-4-amines and analogs, as well as to intermediate compounds used for the synthesis of these products. The invention relates also to pharmaceutical compositions comprising the above compounds and to the use of these compounds as immunomodulators and to stimulate tsitogeneticheskogo biosynthesis, including the biosynthesis of interferon-α and(or) the biosynthesis of factor-α tumor necrosis.

The background to the invention and equivalents

In the first report on the synthesis of 1H-imidazo[4,5-C]quinoline cyclic system Taskmap etc., I. Org. hm. 15, 1278-1284 (1950)reported the synthesis of 1-(6-methoxy-8-chinoline)-2-methyl-1H-imidazo[4,5-C]quinoline and about the possible use of this compound as an antimalarial drug. Later it was reported the synthesis of various substituted 1H-imidazo[4,5-C]quinoline. For example, Jin etc., J. d. hm. 11, 87-92 (1968), synthesized the compound 1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-C]quinoline as a possible anti-seizure drugs and cardiovascular drugs. In addition, sheep and others, h.bs. 85, 94362 (1976), and Weepu etc., J. trlic hm. 18, 1537-1540 (1981)also reported the synthesis of some 2-accomidate[4,5-C]quinoline.

On the basis of the above works would be what about the installed that 1H-imidazo[4,5-C]quinoline-4-amine and 1 - and 2-substituted derivatives of these compounds are effective anti-virus tools, bronchodilators means and immunomodulators. Such compounds are described in U.S. patents№№ 4689338, 4698348, 4929624, 5037986, 5266675, 5268376, 5346905, 5389640, 5605899, 5352784, 5446153 and 5482936. Shen and others in the U.S. patent No. 4038396 and 4131677 describe some oxazolo and triazolopyridine, possessing anti-inflammatory, analgesic and antipyretic properties.

A brief statement of the substance of the invention

Oxazolo and thiazolo[4,5-C]quinoline-4-amines of the formula I:

characterized in that

Deputy R1selected from the group consisting of oxygen atoms and sulfur;

Deputy R2selected from the group consisting of

- hydrogen atom;

- alkyl;

- alkyl-HE (hydroxyalkyl);

- alkyl-S-alkyl;

- alkyl-O-C(O)-N(R5)2;

- morpholinyl, pyrrolidinyl;

- alkyl-X-aryl radical;

alkenyl-X-aryl radical;

each of the substituents R3and R4independently represents a hydrogen atom or taken together substituents R3and R4form a condensed aromatic or [1,5]naphthyridine system;

X represents-O - or a simple bond;

R5represents a hydrogen atom,

as well as the pharmaceutical is acceptable salt based on these compounds.

The second object of the present invention are pharmaceutical compositions containing therapeutically effective amounts of compounds of General formula(ia) and pharmaceutically acceptable filler.

Pharmaceutical compositions for stimulating the formation of cytokines in human cells containing a therapeutically effective amount of the compounds of General formula I(a):

where substituent R1selected from the group consisting of oxygen atoms and sulfur;

Deputy R2selected from the group consisting of

- hydrogen atom;

- alkyl;

- alkyl-HE (hydroxyalkyl);

- alkyl-S-alkyl;

- alkyl-O-C(O)-N(R5)2;

- morpholinyl, pyrrolidinyl;

- alkyl-X-aryl radical;

alkenyl-X-aryl radical;

each of the substituents R3and R4independently represents a hydrogen atom or taken together substituents R3and R4form a condensed aromatic or [1,5]naphthyridine system;

X represents-O - or a simple bond;

R5represents a hydrogen atom,

as well as pharmaceutically acceptable salts based on these compounds.

In the invention described also pharmaceutically acceptable salt based compounds I(a).

Compounds of General formula I(a) is capable of stimulating the SQL cytogenetically biosynthesis in animals and in particular, in the human body. Cytokines that can be stimulated specified in the invention compounds include, but are not limited to only these examples, the synthesis of interferons, in particular interferon-α and factor-α tumor necrosis. In this regard, in the invention described is also a way to encourage tsitogeneticheskogo biosynthesis in an animal by introducing into the animal body an effective amount of a composition containing a compound of formula I(a). Due to its ability to stimulate cytogenetically biosynthesis is given in the invention compounds are effective drugs for the treatment of various diseases, including viral diseases and various tumors. In addition, the invention provides a method of treating such diseases by introducing into the organism a therapeutically effective quantity of a composition which includes a compound of formula I(a).

Another object of the present invention are intermediate compounds of General formula II

characterized in that

Deputy R1selected from the group consisting of oxygen atoms and sulfur;

Deputy R2selected from the group consisting of

- alkyl;

- alkyl-HE;

- alkyl-S-alkyl;

- alkyl-X-aryl;

- morpholinyl;

which each of the substituents R 3and R4independently represents a hydrogen atom or taken together substituents R3and R4form a condensed aromatic or [1,5]naphthyridine system;

X represents-O - or a simple link.

Detailed description of the invention

The present invention includes compounds of General formula I, pharmaceutical compositions containing the compounds of General formula I(a), and therapeutic methods of using compounds of formula I(a), as well as the intermediate compounds of General formula II used for the synthesis of compounds of formulas I and Ia.

Used in this description, the terms “alkyl” and “alkenyl” refers to linear or branched hydrocarbon group or a cyclic group (for example, cycloalkyl and cycloalkenyl), which contains from 1 to 20, preferably from 1 to 10 and most preferably from 1 to 8 carbon atoms, unless otherwise specified. Typical alkyl groups are, for example, methyl, ethyl, n-sawn, ISO-propyl, n-bucilina, isobutylene, second-bucilina, tert-bucilina, n-pencilina, n-exilda, n-heptylene, n-aktiline and other similar groups. Examples of cyclic groups are cyclopropyl, cyclopentamine, tsiklogeksilnogo, cyclohexadiene and adamantly group. In those cases, when using suf is x “Ala”, for example, “alkoxy” and other similar cases, it has the same value.

The term “aryl” (“aryl radical”refers to carbocyclic aromatic cycle or cyclical. The aryl group preferably represents a six-membered ring such as a phenyl group, or a polycyclic aromatic system such as naftalina group. The most preferred aryl group is a phenyl group which may be unsubstituted or substituted by one or more substituents, as described below. Other examples of aryl groups are biphenylene, fluoroaniline and angenlina group.

Suitable heteroaryl groups include follow, thienyl, pyridyloxy, hyalinella, tetrazolyl, imidazole groups, etc. In cases where the substituents R3and R4used together and form a five - or six-membered heteroaromatic cycles, as heteroatom use nitrogen, oxygen or sulfur, and the cycle may contain one or more of such atoms. Preferably as heteroatom use nitrogen or sulfur. Preferred heteroaromatic cycles formed with participation of R3and R4illustrated in the following formulas, in which the two lines indicate the location at which oterom is condensation.

The terms “heterocyclic” and “heterocyclic radical” refers to non-aromatic cycles or cyclic systems containing one or more heteroatoms (such as O, S, N). Examples of heterocyclic groups include pyrrolidinyl, tetrahydrofuranyl, morpholinyl, piperidino, pieperazinove, diazolidinylurea, imidazolidinone and other similar groups.

All of the above cycles or cyclic systems can be unsubstituted or contain one or more substituents selected from the group consisting of such radicals as alkyl, CNS, alkylthiomethyl, hydroxyl, halide atom, keloidalis, polygamously, fergaliciousally (for example, triptoreline), triptorelin (for example, triptoreline), nitrile, aminoacyl, alkylamines, dialkylamines, alkylcarboxylic, alkenylboronic, arylcarboxylic, heteroarylboronic, aryl, arylalkyl, heteroaryl, heteroarylboronic, heterocyclyl, heterologously, nitrile and alkoxycarbonyl. Preferred substituents are1-4alkyl, C1-4CNS, halide atoms, amine, alkylamine, dialkylamino, hydroxyl, C1-4alkoxymethyl triptoreline radicals.

The term “galaida” refers to a halogen atom such as fluorine, chlorine, bromine or iodine.

The present invention includes compounds described herein in any of their pharmaceutically acceptable form, including isomers such as diastereomers and enantiomers, salts, solvate, different polymorphic status, etc.

As noted above, the compounds having formula I and I(a)can form a “pharmaceutically acceptable salt”. Pharmaceutically acceptable salts of the compounds I and I(a) include salts derived from such non-toxic inorganic acids as hydrochloric, nitric, phosphoric, sulfuric, Hydrobromic, itestosterone, hydrofluoric, phosphorous acid, and salts derived from such non-toxic organic acids as aliphatic mono - and dicarboxylic acids, phenylsilane fatty acids, hydroxyalkanoate acid, valkanova acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. So such salts include the sulfates, pyrosulfite, bisulfate, sulfites, bisulfite, nitrates, phosphates, primary and secondary acidic phosphates metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, triptoreline, propionate, caprylate, isobutyrate, oxalates, malonate, succinate, salt, cork acid, Sabatini, fumarate, maleate, the Oli almond acid, benzoate, chlorobenzoate, methylbenzoate, hydroxynaphthoate, xinafoate, dinitrobenzoate, phthalates, bansilalpet, toluensulfonate, phenylacetate, salt, citric acid, lactates, maleate, tartratami, methansulfonate etc. are Also available salts of amino acids such as arginate and gluconate, galacturonase (see, for example, Verde and others, “Pharmaceutical salts”, J. hrm. Sci. 1977; 66:1).

Salts of the compounds were obtained using conventional methods in the interaction of the free base with the desired quantity of the selected acid. Connection in the form of free base can be obtained by treating the salt forms of these compounds and the subsequent allocation of the free base using conventional methods.

Preferred compounds I and I(a) are such compounds in which the substituent R1represents an oxygen atom or sulfur. Preferred substituents R2are alkyl and alkoxyalkyl Deputy, and especially preferred are substituents with1-4alkyl group.

Preferably, the substituents R3and R4used together, form a condensed benzene ring or the pyridine cycle, which may be substituted or unsubstituted.

The most preferred compounds are compounds of the forms of the crystals of III or IV

in which the substituent R2selected as defined above, and the substituent R represents a hydrogen atom, alkyl, CNS, alkylthiols, hydroxyl, halide, haloethanol, polyalkylene, perhelomailuun (for example, triptorelin), triptorelin (for example, triptoreline), nitrile, amine, alkylamino, dialkylamino, alkylcarboxylic, alkenylboronic, arylcarbamoyl, heteroarylboronic, aryl, arylalkyl, heteroaryl, heteroallyl, heterocyclyl, geterotsyklicescoe, nitrile and alkoxycarbonyl group.

Examples of these compounds are:

2-methylthiazole[4,5-C]quinoline-4-amine;

thiazolo[4,5-C]quinoline-4-amine;

2-utilizalo[4,5-C]quinoline-4-amine;

2-propitiatio[4,5-C]quinoline-4-amine;

2-intellisol[4,5-C]quinoline-4-amine;

2-butylthiazole[4,5-C]quinoline-4-amine;

2-(1-methylethyl)thiazolo[4,5-C]quinoline-4-amine;

2-(2-phenyl-1-ethynyl)thiazolo[4,5-C]quinoline-4-amine;

2-(2-phenyl-1-ethyl)thiazolo[4,5-C]quinoline-4-amine;

2-(4-aminothiazolo[4,5-C]quinoline-2-yl)-1,1-dimethylthiocarbamate;

2-(ethoxymethyl)thiazolo[4,5-C]quinoline-4-amine;

2-(methoxymethyl)thiazolo[4,5-C]quinoline-4-amine;

2-(2-methylpropyl)thiazolo[4,5-C]quinoline-4-amine;

2-benzilate[4,5-C]hin the Lin-4-amine;

8-methyl-2-propitiatio[4,5-C]quinoline-4-amine;

(4-aminothiazolo[4,5-C]quinoline-2-yl)methanol;

2-methoxazole[4,5-C]quinoline-4-amine;

2-ethyloxazole[4,5-C]quinoline-4-amine;

2-butylanisole[4,5-C]quinoline-4-amine;

2-propitiatio[4,5-C]quinoline-4,8-diamine;

2-propiconazole[4,5-C]quinoline-4-amine;

8-bromo-2-propitiatio[4,5-C]quinoline-4-amine;

7-methyl-2-propitiatio[4,5-C]quinoline-4-amine;

2-butyl-7-methoxazole[4,5-C]quinoline-4-amine;

7-methyl-2-propiconazole[4,5-C]quinoline-4-amine;

7-fluoro-2-propiconazole[4,5-C]quinoline-4-amine;

7-fluoro-2-propitiatio[4,5-C]quinoline-4-amine;

2-propyl-7-(trifluoromethyl)thiazolo[4,5-C]quinoline-4-amine;

2-(4-morpholino)thiazolo[4,5-C]quinoline-4-amine;

2-(1-pyrrolidino)thiazolo[4,5-C]quinoline-4-amine;

2-butylthiazole[4,5-C][1,5]naphthiridine-4-amine;

2-propitiatio[4,5-C][1,5]naphthiridine-4-amine;

7-chloro-2-propitiatio[4,5-C]quinoline-4-amine;

7-methoxy-2-propitiatio[4,5-C]quinoline-4-amine

and pharmaceutically acceptable salts on the basis of these compounds, especially hydrochloric acid salt based on these compounds.

Getting connections

Compounds according to the present invention can be obtained according to scheme 1, in which the substituents R1, R2, R3and R4are selected as defined above.

At the stage (1) of the process according to scheme Ia, the compound V is treated with a carboxylic acid illiquidity her connection resulting in the receive connection of the formula VI. Suitable substitutes carboxylic acid include acid anhydrides, acid chlorides, orthoepy and 1,1-dualcarriageway. Carboxylic acid or its substitute is chosen in such a way as to obtain the desired substituent R2in connection VI. For example, when using triethylorthoformate will be obtained compound VI, in which the substituent R2is a hydrogen atom, and when using acetic anhydride will be obtained compound VI, in which the substituent R2represents a methyl group. The reaction may proceed in the absence of a solvent in the presence of acid, such as polyphosphoric acid, or preferably in the presence of a carboxylic acid of General formula R2(O)HE. The reaction is carried out under sufficient heat necessary for the distillation of alcohol or water formed as a by-product. Connection V connection is available or can be obtained in the usual way (see, for example, hmn and others, Journal of the American hmil Sity, 69, str-371 (1947); mbrogi etc., Synthesis, SCR-658 (1992); dler and others, Journal of the Chemical Societly, str-1797 (1960); Sus, etc., Justus Liebis nnln dr hmi, 583, str-160 (1953), and Sus, etc., Justus Liebigs nnln dr hmi, 593, p.91-126 (1955).

At stage (2) of reaction scheme Ia carried out the oxidation of compounds VI, financial p is Tata which receive N-oxide, having the formula II. The oxidation is performed under the action of the usual oxidizing agents capable of forming N-oxides. Preferred conditions for the reaction are in the processing solution of compound VI in chloroform 3-chloroperbenzoic acid at room temperature. The oxidation can also be carried out using peracetic acid in a suitable solvent, such as ethyl or methyl acetate.

At stage (3) of the process according to scheme I spend amination of N-oxide (II), resulting in a receive connection formula I. stage (3) includes (i) reaction of compound (II) with allermuir agent and (ii) subsequent processing of the obtained product aminimum agent. Phase (i) stage (3) is in the processing of N-oxide of formula II allermuir agent. Suitable allerease agents are acid chlorides alkyl - or arylsulfonic acids (for example, benzosulphochloride, methanesulfonate, p-toluensulfonate). Arylsulfonamides are preferred allerease agents. The most preferred of them is a pair-toluensulfonate. Phase (ii) phase (3) is in the interaction product formed in phase (i), with excess amineralo agent. Suitable ominiruyuschim agents are ammonia (for example, in the form of ammonium hydroxide) and ammonium salts (for example, carbon is tons of ammonium, ammonium bicarbonate, ammonium phosphate). It is preferable to use ammonium hydroxide. The reaction preferably by dissolving or dispersive N-oxide of formula II in an inert solvent such as dichloromethane or chloroform, adding to the solution or suspension miniraise agent and then slowly adding allerease agent. The formed product or a pharmaceutically acceptable salt on its basis can be isolated from the reaction mixture by conventional means.

According to another method stage (3) can be performed (i) treating the N-oxide of formula II with isocyanate, and then (ii) carrying out the hydrolysis of the resulting product. Phase (i) involves the reaction of N-oxide with an isocyanate in which the isocyanate group is linked to a carbonyl group. The preferred isocyanates are trichlorotriazine and abolitionary, such as benzoylation. The reaction of the isocyanate with N-oxide is carried out in practically anhydrous conditions by adding the isocyanate to a solution of N-oxide in an inert solvent such as dichloromethane. Phase (ii) is the hydrolysis product formed in phase (i). The hydrolysis is carried out using conventional methods such as heating in the presence of water or a lower alcohol in the presence of a catalyst, such as a lower alkoxide of an alkali metal or ammonium.

Scheme Reaktsii

Provided in the invention compounds in which the substituent R1is oxygen atom or sulfur and the substituents R3and R4form an aromatic ring, can be obtained in accordance with scheme II, in which the nature of the substituents R and R2selected as defined above.

At the stage (1) of reaction scheme II, carried out the reaction of 3-aminoquinoline-4-ol or 3-aminoquinoline-4-thiol (compound VII) with a carboxylic acid or equivalent connection, resulting in a gain oxazolo or thiazolo[4,5-C]quinoline having the formula VIII. Suitable substitutes carboxylic acid include acid anhydrides, acid chlorides of the acids, orthoepy and 1,1-dualcarriageway. Carboxylic acid or its substitute is chosen in such a way as to obtain the desired substituent R2in connection VIII. For example, when using triethylorthoformate will be obtained compound VIII in which the substituent R2is a hydrogen atom, and when using acetic anhydride will be obtained compound VIII in which the substituent R2represents a methyl group. The reaction may proceed in the absence of solvent, in the presence of acid, such as polyphosphoric acid, or preferably in the presence of a carboxylic acid of General formula R2WITH)IT. The reaction is carried out under sufficient heat necessary for the distillation of alcohol or water formed as a by-product. 3-Aminoquinoline-4-ol or 3-aminoquinoline-4-thiol (compound VII) are the available products or can be obtained by known methods.

At stage (2) of reaction scheme II, oxidation oxazolo or thiazolo[4,5-C]quinoline (VIII), leading to the formation of oxazole or thiazole[4,5-C]quinoline-5N-oxide (compound IX), which is a precursor of compound II. The oxidation is performed under the action of the usual oxidizing agents capable of forming N-oxides. Preferred conditions for the reaction are in the processing solution of compound VIII in chloroform 3-chloroperbenzoic acid at room temperature. The oxidation can also be performed using peracetic acid in a suitable solvent, such as ethyl or methyl acetate.

At stage (3) of reaction scheme II spend amination of N-oxide (IX) to oxazolo[4,5-C]quinoline-4-amine (compound III) or thiazolo[4,5-C]quinoline-4-amine (compound IV); both of these compounds are derivatives of the compounds I. stage (3) includes (i) the reaction of the compound (IX) with allermuir agent and (ii) subsequent processing of the obtained product aminimum agent. Phase (i) stage (3) is in the processing of N-oxide of formula IX acilius the m agent. Suitable allerease agents are acid chlorides alkyl - or arylsulfonic acid (for example, benzosulphochloride, methanesulfonate, p-toluensulfonate). Arylsulfonamides are preferred allerease agents. The most preferred of them is a pair-toluensulfonate. Phase (ii) phase (3) is in the interaction product formed in phase (i), with excess amineralo agent. Suitable ominiruyuschim agents are ammonia (for example, in the form of ammonium hydroxide) and ammonium salts (e.g. ammonium carbonate, ammonium bicarbonate, ammonium phosphate). Preferably using ammonium hydroxide. The reaction preferably by dissolving or dispersive N-oxide (compound IX) in an inert solvent such as dichloromethane or chloroform, adding to the solution or suspension miniraise agent and then slowly adding allerease agent. The formed product or a pharmaceutically acceptable salt on its basis can be isolated from the reaction mixture by conventional means.

According to another method stage (3) can be performed (i) treating the N-oxide of formula IX with the isocyanate and then (ii) carrying out the hydrolysis of the resulting product. Phase (i) involves the reaction of N-oxide with an isocyanate in which the isocyanate group is associated with CARBONYLS the th group. The preferred isocyanates are trichlorotriazine and abolitionary, such as benzoylation. The reaction of the isocyanate with N-oxide is carried out in the absence of water, adding the isocyanate to a solution of N-oxide in an inert solvent such as dichloromethane. Phase (ii) is the hydrolysis product formed in phase (i). The hydrolysis is carried out using conventional methods such as heating in the presence of water or a lower alcohol in the presence of a catalyst, such as a lower alkoxide of an alkali metal or ammonium.

Scheme II reactions

Provided in the invention compounds in which the substituent R1is a sulfur atom, can be obtained in accordance with scheme III, in which the substituents R2, R3and R4are selected as defined above.

At the stage (1) of reaction scheme III a compound of formula X is treated haloidoargentum compound of General formula R2C(O)Z, in which the substituent R2selected as defined above, and Z is a chlorine atom or bromine. The result of this treatment, get amide of formula XI. The reaction can be carried out in the presence of a tertiary amine, adding a controlled rate (e.g., dropwise) kaleidotile connection to the solution or suspension of compound X in a suitable solvent, such as pyridine Yedigaryan.

At stage (2) of reaction scheme III amide of formula XI is reacted with paternity phosphorus with the formation of compound XII. For reaction paternity phosphorus are added to a solution or suspension of compound XI in an appropriate solvent, such as pyridine, and heated the mixture.

Stage (3) and (4) of reaction scheme III can be performed in the same manner as steps (2) and (3) the reactions according to scheme I. the result is respectively N-oxide of formula XIII, which is a precursor of compound II, and compound XIV, which is a precursor compounds I.

Scheme III reactions

Provided in the invention compounds in which the substituent R1is a sulfur atom, and the substituents R3and R4form a substituted aromatic ring, can be obtained in accordance with scheme IV reaction, in which the substituents R and R2are selected as defined above.

At the stage (1) of reaction scheme IV, a compound of formula XV is treated haloidoargentum compound of General formula R2C(O)Z, in which the substituent R2selected as defined above, and Z is a chlorine atom or bromine. As a result of this processing gain N-(4-hydroxyquinolin-3-yl)amide of formula XVI. The reaction can be conducted by adding a controlled rate (e.g., dropwise) kaleidotile with the Association to the solution or suspension of compound XV in a suitable solvent, such as dichloromethane, and the reaction is carried out in the presence of a tertiary amine.

At stage (2) of reaction scheme IV N-(4-hydroxyquinolin-3-yl)amide of formula XVI is reacted with paternity phosphorus with education thiazolo[4,5-C]quinoline (compound XVII). For reaction paternity phosphorus are added to a solution or suspension of compound XVI in an appropriate solvent, such as pyridine, and heated the mixture.

Stage (3) and (4) of reaction scheme IV can be performed in the same manner as steps (2) and (3) of reaction scheme II. The result is accordingly thiazolo[4,5-C]quinoline-5N-oxide of formula XVIII, which is a precursor of compound II, and thiazolo[4,5-C]quinoline-4-amine (compound IV), which is a precursor compounds I.

Scheme IV reactions

The substituents in position 2 can be introduced due to the interaction of compounds XIX

in which the substituent R1represents an oxygen atom or sulfur, and the substituent R is selected as defined above, with a corresponding literalism agent such as diisopropylamide lithium and n-utility, in a polar aprotic solvent. The result of this interaction leads to the formation of compounds having liftirovaniyu 2-methyl group. After that, the obtained laister is ASEE compound can react with an appropriate reagent, containing a functional group that can substitute liftirovaniyu 2-methyl group. Examples of suitable reagents are halides such as methyl iodide or chloromethylation ether, aldehydes, such as benzaldehyde, and ketones, such as acetone. The compounds obtained can be subjected to oxidation and aminating using the methods described above in the synthesis of compounds III and IV.

Some compounds of General formula I can be obtained directly from other compounds I. for Example, narisovanie 2-propitiatio[4,5-C]quinoline-4-amine leads to the formation of 8-nitro-2-propitiatio[4,5-C]quinoline-4-amine, and recovering this nitrocompounds gives 2-propitiatio[4,5-C]quinoline-4,8-diamine.

Pharmaceutical composition and biological activity

The pharmaceutical compositions according to the present invention contain a therapeutically effective amount of compound I(a) together with a pharmaceutically acceptable filler.

Used in this description, the term “therapeutically effective amount” means an amount of compound sufficient to promote the desired therapeutic effect, such as cytogenetically biosynthesis, antitumor activity and(or) antiviral activity. Precise amounts of active compounds used farmatsevticheskii composition according to the present invention, will vary widely depending on various factors such as the physical and chemical nature of the compounds, as well as the nature of the filler composition, the prescribed dosage and, in addition, the severity of the disease. However, I believe that proposed in the invention composition contains a sufficient amount of the active ingredient to provide a dose of 100 ng per 1 kg of patient's weight to about 50 mg/kg, preferably from 10 μg/kg to 5 mg/kg weight of the patient. The pharmaceutical compositions can be used in any form, namely in the form of tablets, pellets, compositions for parenteral administration, syrups, creams, ointments, aerosols, various adhesives, etc. Used dosage form will also depend on the characteristics of the composition, which must be entered in the body. For example, some compounds I(a), particularly those compounds in which the substituent R1use a sulfur atom, have a relatively low oral bioavailability and quickly undergo metabolism when injected into the blood. These properties make these compounds particularly effective for the treatment of such diseases in which it is desirable local introduction connections, modifying the immune response. These diseases include asthma, basal cell carcinoma, cervical intraepithelial novobrdo the project, etc.

It is shown that given in the invention compounds contribute to the formation of some cytokines in experiments performed in accordance with the following testing Methods. These results suggest that such compounds may be effective as modifiers of the immune response that is able to modulate the immune response in various ways, and thus can be effective drugs for treatment of various disorders.

Cytokines, which are formed by introducing into the organism described in the invention compounds generally include interferon-α (IFN-α and(or) factor-α tumor necrosis (NF-α ), as well as certain interleukins (IL). Cytokinins, whose biosynthesis may be stimulated described in the invention compounds include IFN-α , NF-α , IL-1,6, 10 and 12, and various other cytokines. Cytokines inhibit formation of virus and tumor cell growth, making described in the invention compounds are effective agents for the treatment of tumors and viral diseases.

In addition to the ability to stimulate the formation of cytokines described in the invention compounds also affect other aspects of the innate immune response. For example, with the introduction of cytokines can be stimulated activity of natural “killer cells”. These compounds may that which activate macrophages, which, in turn, stimulate the release of nitric oxide and the formation of additional cytokines. In addition, these compounds are able to induce the proliferation and differentiation of b-lymphocytes and thus can be useful for maturation in vitro dendritic cells.

Compounds described in the present invention, also have implications for acquired immune response. For example, although I believe that they have no direct effect on T cells or the production of T-limfozitah cytokines, these connections are mediated through the cytokine T-phage-helper type 1 (Th1) affect the formation of IFN-γ , while at the expense of cytokine T-phage-helper type 2 (Th2 dysbalance) is the inhibition of the formation of IL-4, IL-5 and IL-13. This fact indicates that these compounds are effective in the treatment of diseases where it is desirable enhancing the role of Th1 and reduction of the role of Th2 dysbalance. Given the ability of the compounds Ia to inhibit an immune response Th2 dysbalance, it can be expected that these compounds will be effective in the treatment of atopy, such as allergic dermatitis, asthma, allergies, allergic rhinitis and lupus erythematosus; to enhance cellular immunity, and possibly for the treatment of recurrent fungal diseases and trichomonosis.

The modifying effect of compounds on the immune response makes them useful drugs to treat the hypoxia diseases. Having the ability to stimulate cytokines, such as INF-α and(or) NF-α , these compounds are particularly useful for the treatment of viral diseases and tumors. This immunomodulating activity suggests that described in this invention, the compounds are useful for the treatment of, inter alia, diseases such as viral diseases such as genital warts, common warts, plantar warts, hepatitis b, hepatitis C, herpes simple type I and II, molluscum contagiosum, HIV, cytomegaly virus and varicella, cervical intraepithelial neoplasia, viral papilloma of the person and its related neoplasms; fungal infections, such as aspergillosis, cryptococcal meningitis; cancers, such as basal cell carcinoma, leukemia hair cells, Kaposi's sarcoma, cancer kidney, squamous cell carcinoma, myelogenous leukemia, multiple myeloma, melanoma, lymphoma, not by Hodgkin's lymphoma, cutaneous lymphoma, T-cell and other cancers; parasitic diseases, such as pneumonia, cryptosporidia, histoplasmosis, toxoplasmosis, Trypanosoma infection, leishmaniasis and bacterial infectious diseases, such as tuberculosis, Mycobacterium avium. In addition to treatment of the above diseases described in the present invention compounds can be used also DL the treatment of such diseases, as eczema, eosinophilia, primary thrombocytosis, leprosy, multiple sclerosis, Ommen's syndrome, rheumatoid arthritis, systemic lupus erythematosus, discoid lupus, Bowen's disease, papules Bowen's; these compounds can speed up or stimulate the healing of wounds, including chronic wounds.

Thus, the present invention provides a method of stimulating tsitogeneticheskogo biosynthesis in vivo, which consists in introducing into the animal an effective amount of compound Ia. The number of compounds effective to stimulate tsitogeneticheskogo biosynthesis is an amount sufficient for one or more types of cells, such as monocytes, macrophages, dendritic cells and b-cells were able to form one or more cytokines, such as IFN-α , TNF-α , IL-1, 6, 10 and 12, in excess of background a number of these cytokines. The exact amount will vary depending on various factors, but it is expected that the dose of a compound will be in the range of 100 ng per 1 kg of patient's weight to 50 mg/kg, preferably from about 10 μg/kg to 5 mg/kg Invention also provides a method of treating a viral infection in an animal's body, which consists in the introduction of an effective amount of compound Ia in the body of the animal. The effective amount for cured the I or prevention of viral infections - it is the quantity that leads to decrease one or more symptoms of a viral infection, such as viral damage, viral load, rate of formation of the virus and the death of the virus, compared with the situation observed in control animals. The exact amount will vary depending on various factors, but it is expected that the dose of a compound will be in the range from 100 ng/kg to 50 mg/kg, preferably from about 10 μg/kg to 5 mg/kg

In the present invention compounds can be introduced into the body as the sole therapeutic agent or they can be part of a therapeutic compound in combination with one or more other agents. Examples of suitable agents which may be used in combination with the present invention, compounds modifying the immune response, are, among other substances, analgesics, antibacterial agents, antifungal, anti-inflammatory, anticancer agents, anti-virus, bronchodilators, drugs and steroid drugs.

The following examples are given to illustrate the invention, which, however, is in no way limited to these examples.

EXAMPLES

Example 1

2-Methylthiazole[4,5-C]quinoline-5N-oxide

Part a

A suspension of 12 g of C-aminoquinoline-4-thiol in a mixture of acetic anhydride (150 ml) and acetic acid (300 ml) was boiled under reflux overnight. The reaction mixture was filtered to remove fine sediment. The filtrate was evaporated in vacuum. The residue was diluted with ethanol and boiled under reflux for 30 minutes. The resulting solution was concentrated in vacuo, and the residue was diluted with water. The aqueous layer was podslushivaet sodium hydroxide and then was extracted with diethyl ether. The ether extracts were combined together, dried over magnesium sulfate and filtered. The filtrate was evaporated and the obtained 12.8 g of the crude product. 800 mg of this product was recrystallized from hexane; got 2 methylthiazole[4,5-C]quinoline as a yellow needle-like crystals, melting point which was 95.5-97,5° C. Analysis: calculated for C11H8N2S: %S, 65,97; %N, 4,03; %N, 13,99. Found: %C, 65,96; %N, 4,16; %N, 14,08.

Part b

5.0 g (25 mmol) 2-methylthiazole[4,5-C]quinoline, 9.5 g of 3-chloroperbenzoic acid (50-60%aqueous solution) and 150 ml of dichloromethane was stirred at room temperature for 3 hours. The reaction solution was diluted with 300 ml of dichloromethane and then was extracted with aqueous sodium carbonate solution to remove the acid. Organic is the cue layer was washed with water, was diluted with ethyl acetate to remove Muti, dried over magnesium sulfate and then concentrated in vacuum. The result was obtained 4.5 g of crude product. A small portion of this product was recrystallized from methanol. Received a yellow needles hydrate 2-methylthiazole[4,5-C]quinoline-5N-oxide; melting point of the pure product 150-160° C. Analysis: calculated for C11H8N2OS+0,75 H2O: %C, 57,50; %N, 4,17; %N, 12,19. Found: %C, 57,58; %N, 4,10; %N, 11,93.

Example 2

2-Methylthiazole[4,5-C]quinoline-4-amine

1.5 g of 2-methylthiazole[4,5-C]quinoline-5N-oxide (6,9 mmol) was added to a mixture of 10 ml dichloromethane and 25 ml of ammonium hydroxide. Under vigorous stirring to the reaction mixture solution was added 2.0 g of tosylchloramide (10.4 mmol) in 10 ml of dichloromethane. The reaction mixture is boiled under reflux, adding an additional amount of dichloromethane and ammonium hydroxide to complete the reaction, which is judged according to thin-layer chromatography. The resulting mixture is kept dichloromethane and remaining aqueous fraction was filtered yellow solid product. It was washed with water and dried. The result was obtained 1.2 g of the crude substance. This product was dissolved in dilute hydrochloric acid, the solution was passed over activated charcoal and then filtered. The filtrate Podlachia and diluted sodium hydroxide solution. The precipitate was filtered off, washed with water and recrystallized from a mixture of methanol with dichloromethane. The result was 0,46 g 2-methylthiazole[4,5-C]quinoline-4-amine as a white powder, melting point which was 184-187° C. Analysis: calculated for C11H9N3S: %S, 61,37; %N, 4,21; %N, 19,52. Found: %C, 61,32; %N, To 4.52; %N, 19,68.

Example 3

An alternative method of synthesis of 2-methylthiazole[4,5-C]quinoline-4-amine

Trichlorotriazine (2.0 ml, is 16.8 mmol) was added to a suspension of 2-methylthiazole[4,5-C]quinoline-5N-oxide (3.03 g, 14.0 mmol) in dichloromethane (150 ml). The reaction mixture was stirred at room temperature for 50 minutes. Dichloromethane was concentrated in vacuo, resulting in the obtained crude N-(2-methylthiazole[4,5-C]quinoline-4-yl)trichloroacetamide. This amide was dissolved in methanol, to the solution was added sodium methylate (1 ml of 25%solution of sodium methylate in methanol and boiled with reflux for 40 minutes. Thereafter, the methanol was evaporated in vacuum. The remaining brown solid product was washed with water and dried; the result was 2.85 g of the crude product. This product was treated with activated charcoal and then recrystallized from ethyl acetate. The obtained solid 2-methylthiazole[4,5-C]quinoline-4-amine had a melting point of 184-186° C. Analysis: caters the o 11H9N3S: %S, 61,37; %N, 4,21; %N, 19,52. Found: %C, 61,48; %N, 4,17; %N, 19,60.

Example 4

Hydrochloric acid 2-methylthiazole[4,5-C]quinoline-4-amine

To a solution of 0.5 g of 2-methylthiazole[4,5-C]quinoline-4-amine in 15 ml of methanol was added 0.2 ml of concentrated (12.1 M) hydrochloric acid, and then 15 ml of isopropanol. The mixture was heated to boiling to remove the main part of the methanol. The obtained precipitate was filtered, washed with isopropanol and dried. The result was hydrochloric acid 2-methylthiazole[4,5-C]quinoline-4-amine in the form of a solid product, melting at 323-325° C. Analysis: calculated for C11H9N3S· Hcl: %C, 52,48; %N, 4,00; %N, 16,69. Found: %C, 52,46; %N, 4,08; %N, 16,52.

Example 5

Hydrate hydrochloric acid thiazolo[4,5-C]quinoline-4-amine

Part a

Approximately 18.5 g of 3-aminoquinoline-2-thiol was added to 26,0 ml triethylorthoformate. The mixture was heated on the steam bath for 20 minutes. Was added thereto 400 ml of formic acid and then boiled under reflux during the night. Formic acid was evaporated in vacuum. The residue was combined with ethanol and boiled under reflux for 30 minutes, after which the ethanol was evaporated in vacuum. The residue is suspended in water and the suspension was podslushivaet by adding sodium hydroxide, thus formed precipitate, which was extracted with several portions of dichloromethane. Extracts from Denali, was dried over magnesium sulfate and concentrated. He got a yellow solid, after recrystallization from a mixture of hexanol got to 13.1 g of yellow crystalline thiazolo[4,5-C]quinoline, melting at 104-106° C.

Part b

To a suspension thiazolo[4,5-C]quinoline (12.5 g, 67 mmol) in methyl acetate (300 ml) was added 21 ml of peracetic acid (32%solution in acetic acid; 100 mmol). The mixture was heated under reflux overnight and then cooled to room temperature. The precipitate was filtered and suspended in water (100 ml). To the suspension was added 100 ml of an aqueous solution of sodium bicarbonate and the mixture was stirred for 1 hour. Solid thiazolo[4,5-C]quinoline-5N-oxide was filtered, washed with water and dried.

The part With

to 0.72 ml trichloroacetimidate (6.0 mmol) was added to a suspension of 1.10 g thiazolo[4,5-C]quinoline-5N-oxide (5.4 mmol) in 100 ml of dichloromethane. The reaction mixture was stirred at room temperature for 45 minutes, after which the dichloromethane was evaporated in vacuum and obtained crude N-(thiazolo[4,5-C]quinoline-4-yl)trichloroacetamide. This amide was stirred at room temperature for 2 hours in 2M ammonia solution in methanol; the methanol was evaporated in vacuum. The resulting residue is suspended in water, was added sodium carbonate and stirred for 10 minutes. The resulting solid is th brown product was washed with water and dried. Then suspended in water, was added 100 ml of 6 N hydrochloric acid and the mixture was heated on the steam bath. The mixture was filtered and the filtrate was slowly cooled to room temperature. The precipitate was filtered and dried, resulting in the received 0.75 g of product as a brown needle-shaped crystals. This product was dissolved by heating in 100 ml of water, to the solution was added activated charcoal and the mixture was stirred for 5 minutes. Then the mixture was filtered through a layer lite®. The filtrate was heated on a steam bath to remove most of the water and then cooled to room temperature. Formed upon cooling, the precipitate was filtered and dried, resulting in a received 0,30 g of white crystalline hydrate hydrochloric acid thiazolo[4,5-C]quinoline-4-amine; melting point of this substance 284-285° C. Analysis: calculated for C10H3S· Hcl· N2O: %C, 46,97; %N, 3,94; %N, 16,43. Found: %C, 46,96; %N, 3,99; %N, 16,34.

Example 6

Thiazolo[4,5-C]quinoline-4-amine

Part a

8.7 g thiazolo[4,5-C]quinoline-2-thiol (0,04 mol) suspended in an aqueous solution containing 1.4 g of sodium hydroxide (0,04 mol). To the suspension was added a few drops of 50%sodium hydroxide solution to dissolve the solid product. The flask with the reaction mixture was lowered into a bath of cold water and maintaining the temperature of the mixture in the range of 25-35° With dropwise within 30 minutes was added to 13.5 ml of 30%hydrogen peroxide (0,08 mol). Bath was removed and the reaction mixture was stirred for 15 minutes. After this was added 2.5 g 95,98%sulfuric acid. After 30 minutes the reaction mixture was podslushivaet 50%sodium hydroxide solution to a pH of 9-9,5. Then the reaction mixture was acidified with hydrochloric acid to a pH of 2.5 was observed the precipitation of a brown solid product. After heating the mixture on a steam bath for 15 minutes, the precipitate was dissolved. After cooling the solution to room temperature again formed precipitate. The mixture was podslushivaet 50%sodium hydroxide to pH 9. The resulting oily product was extracted with ethyl acetate. The extracts were combined, washed with water, dried over magnesium sulfate and concentrated in vacuum to obtain 3,3 g thiazolo[4,5-C]quinoline as a brown solid, melting point which was 104,4-105° C. Analysis: calculated for C10H6N2S: %S, 64,19; %N, 3,25; %N, 15,04. Found: %C, 64,15; %N, 3,26; %N, 14,9.

Part b

To a solution of thiazolo[4,5-C]quinoline (2.8 g) in methyl acetate was added to 4.7 ml of 32%peracetic acid. Within a few minutes was observed sediment. The reaction mixture was heated to boiling and then diluted by adding 10 ml of acetate. A large part of the sediment at this R what was storalasi. After 1 hour, to the mixture was added 3.1 ml of peracetic acid. After that the reaction mixture was heated overnight and then cooled to room temperature. Methyl acetate and acetic acid were removed in the azeotropic distillation with heptane. The remaining oily product is suspended in water. The mixture was podslushivaet a saturated solution of bicarbonate sodium and then was extracted with ethyl acetate. The extracts were combined, washed with water, dried over magnesium sulfate and then concentrated in vacuo to obtain 0.6 g thiazolo[4,5-C]quinoline-5N-oxide as an orange solid product, melting at to 178.4° C (decomposition).

The part With

To a cooled to 5° suspension thiazolo[4,5-C]quinoline-5]N-oxide (0.3 g) in a mixture of ammonium hydroxide (5 ml) and dichloromethane (50 ml) was added dropwise a solution of tosylchloramide (0.3 g) in water while maintaining the temperature within 4-6° C. Upon completion of addition of tosylchloramide the reaction mixture was stirred at room temperature for 4 hours. Analysis using the method of thin layer chromatography indicates the presence of a mixture of starting material. Therefore, the reaction mixture was cooled and was added 1 equivalent of Teilhard. The reaction mixture was stirred at room temperature for 20 hours. Then dichloromethane was evaporated in vacuum. Estato is suspended in a small amount of water. The mixture was filtered. Selected solid product was washed with water, dried and then recrystallized from isopropanol. Received 0.2 g thiazolo[4,5-C]quinoline-4-amine as an orange powder. Melting point 172,4° C (decomposition). Analysis: calculated for C10H7N3S: %S, 59,68; %N, 3,50; %N TO 20.88. Found: %C, To 59.82; %N, 3,20; %N, 19,50.

Example 7

2-Utilizalo[4,5-C]quinoline-5N-oxide

Part a

1.0 g of 2-methylthiazole[4,5-C]quinoline (10.0 mmol; example 2 or 3) in nitrogen atmosphere were placed in a dried flask. Added 50 ml of anhydrous tetrahydrofuran, and the reaction mixture was cooled to -78° With bath with dry ice. To the mixture was added dropwise to 6.7 ml of a 1.5 M solution of diisopropylamide lithium (10.0 mmol) in hexane. After 30 minutes, was added to 0.95 ml iodotope bromide (15.0 mmol). After 40 minutes the mixture was heated to room temperature and poured into water, and then was extracted with diethyl ether (250 ml). The extract was washed with three portions of water, 100 ml each), dried over magnesium sulfate and concentrated in vacuum to obtain 2.8 g of a brown oil. This product was purified by the method of high performance liquid chromatography, using as eluent 3:1 mixture of hexane and ethyl acetate. The result was 1.47 g of 2-utilizalo[4,5-C]quinoline as a yellow oil.

Part b

To a solution-utilizalo[4,5-C]quinoline (0,53 g) in 20 ml of chloroform was added to 0.44 g of 3-chloroperbenzoic acid. The mixture was stirred for 2 hours at room temperature and then diluted with 20 ml dichloromethane, washed with aqueous sodium bicarbonate solution, three portions of water, 100 ml each), dried over magnesium sulfate and then concentrated in vacuum. After recrystallization of the resulting yellow solid product from ethyl acetate obtained 0.32 g of solid 2-utilizalo[4,5-C]quinoline-5N-oxide, melting point 128 which° C. Analysis: calculated for C12H10N2OS: % C, 62,59; % N, TO 4.38; % N, 12,16. Found: % C, 62,59; % N, 4,27; % N, 12,12.

Example 8

2-Utilizalo[4,5-C]quinoline-4-amine

Part a

To a suspension of 0.90 g of 2-utilizalo[4,5-C]quinoline-5N-oxide (3.9 mmol) in 60 ml dichloromethane was added 0.51 ml trichloroacetimidate (4.3 mmol). The mixture was stirred at room temperature for 30 minutes and then concentrated in vacuo to obtain 1.80 g of N-(2-utilizalo[4,5-C]quinoline-4-yl)trichloroacetamide in the form of a yellow solid.

Part b

N-(2-Utilizalo[4,5-C]quinoline-4-yl)trichloroacetamide (0.40 g) suspended in 20 ml of 2 M solution of ammonia in methanol and then stirred at room temperature for 30 minutes. The reaction mixture was concentrated in vacuum. The residue was washed with water and dried, resulting in a received 0,19 g of the crude product, which paracrystals is provided from a mixture of ethyl acetate and hexane. The obtained 2-utilizalo[4,5-C]quinoline-4-amine has the appearance of brown needle-like crystals, melting point which is 170-172° C. Analysis: calculated for C12H11N3S: % S, 62,85; % N, A 4.83; % N, 18,32. Found: % C, 62,58; % N, 4,78; % N, 18,08.

Example 9

An alternative method of synthesis of 2-utilizalo[4,5-C]quinoline-4-amine

Part a

To a suspension of 3-aminoquinoline-4-thiol (15 g) in propionic acid (100 ml) was added 20 ml of propionic anhydride acid. The reaction mixture is boiled under reflux overnight and then filtered to remove the precipitate. The filtrate was concentrated in vacuum. The residue was washed with 200 ml dichloromethane, washed first with an aqueous solution of sodium bicarbonate and then with water and dried over magnesium sulfate. The resulting solution was passed through a layer of silica gel, using as eluent first 1:1 mixture of ethyl acetate with hexane, and then pure ethyl acetate. The filtrate was evaporated and obtained 2.6 g of 2-utilizalo[4,5-C]quinoline as a yellow oil.

Part b

To a solution of 5 g of 2-utilizalo[4,5-C]quinoline in 100 ml of ethyl acetate was added to 7.4 ml of 32% peracetic acid. The mixture was stirred at room temperature for two days. The precipitate was filtered off, washed with hexane and dried. The result obtained 3.4 g of 2-utilizalo[4,5-C]quinoline-5N-oxide.

The part With

To a suspension of 2-triazolo[4,5-C]quinoline-5N-oxide (9.0 g, 39,1 mmol) in 500 ml of dichloromethane was added to 6.5 ml trichloroacetimidate (54 mmol). The mixture was stirred at room temperature for 2 hours and then concentrated it in a vacuum to obtain crude N-(2-utilizalo[4,5-C]quinoline-4-yl)trichloroacetamide. This product was added to a solution of ammonia in methanol (500 ml, 2 M solution) and stirred at room temperature for 2 hours, after which the reaction mixture was concentrated in vacuum. The residue was washed with dichloromethane. Washed with two portions of 150 ml each of an aqueous solution of sodium bicarbonate, and then with three portions of 150 ml of water, dried over magnesium sulfate and concentrated in vacuum. After recrystallization of the resulting residue from 1,2-dichlorethane received substance in the form of a brown needle-shaped crystals. This material is suspended in water, was added to a suspension of one equivalent of concentrated hydrochloric acid and the mixture was heated to dissolve the solid product. The solution was treated with activated charcoal and then filtered. The filtrate was chilled and podslushivaet sodium carbonate. The precipitate was filtered and washed with water. After recrystallization from 1,2-dichloroethane got 2 utilizalo[4,5-C]quinoline-4-amine in the form of yellow needle-shaped crystals; melting point 169-171 ° C. Analysis: calculated for C12H11N 3S: % S, 62,85; % N, A 4.83; % N, 18,32. Found:% C, 62,79; % N, 4,86; % N, 18,22.

Example 10

Hydrochloric acid 2-utilizalo[4,5-C]quinoline-4-amine

To a solution of 2-utilizalo[4,5-C]quinoline-4-amine (4,25 g) in warm isopropanol was added concentrated hydrochloric acid (18.5 mmol). The mixture was boiled under reflux for reducing the overall volume and remove water and then cooled to room temperature. The precipitate was filtered and dried. The obtained solid hydrochloric acid 2-utilizalo[4,5-C]quinoline-4-amine had a melting point 268-270 ° C. Analysis: calculated for C12H11N3S • Hcl: % C, 54,23; % N, 4,55; % N, 15,81. Found:% C, 54,25; % N, 4,63; % N, 15,71.

Example 11

2-Propitiatio[4,5-C]quinoline-5 N-oxide

Part a

Using the methodology described in part a of example 7, first carried out the reaction between 2-methylthiazole[4,5-C]quinoline (2.50 g, 12.5 mmol) and Diisopropylamine lithium. Subsequent processing of the obtained product ethyl iodide resulted in the receipt of 0.28 g of 2-propitiatio[4,5-C]quinoline as a yellow crystalline substance with a melting point of 54° C. Analysis: calculated for C13H12N3S: % S, 68,39; % N, 5,30; % N, 12,27. Found: % C, 68,41; % N, 5,19; % N, 12,31.

Part b

Using the methodology described in part b of example 7, 2-propitiatio[4,5-C]quinoline (1,05 g, 4.6 mmol) Ocala and 3-chloroperbenzoic acid to 2-propitiatio[4,5-C]quinoline-5M-oxide. Obtained 0.65 g of the desired product as a yellow solid with a melting point 123° C. Analysis: calculated for C13H12N2OS: % C, 63,91; % N, 4,95; % N, 11,47. Found: % C, 63,53; % N, 4,88; % N, 11,44.

Example 12

2-Propitiatio[4,5-C]quinoline-4-amine

Using the methodology described in example 8, the reaction of 2-propitiatio[4,5-C]quinoline-5N-oxide (0,63 g) with trichlorotriazine and received an intermediate amide was subjected to hydrolysis using as gidrolizuemye agent solution of ammonia in methanol. The result was 0,22 g of white crystalline 2-propitiatio[4,5-C]quinoline-4-amine, melting point which was 140-142 ° C. Analysis: calculated for C13H13N3S: % S, 64,17; % N, 5,38; % N, 17,27. Found: % C, 64,31; % H, 5,39; % N, 17,13.

Example 13

An alternative method of synthesis of 2-propitiatio[4,5-C]quinoline-4-amine

Part a

Using the methodology described in part a of example 9, a suspension of 15 g of 3-aminoquinoline-4-thiol oil acid was treated with butyric acid anhydride, resulting in a yellow oily 2-propitiatio[4,5-C]quinoline.

Part b

Using the methodology described in part b of example 9, 2-propitiatio[4,5-C]quinoline (46 g) was oxidized peracetic acid to 2-propitiatio[4,5-C]quinoline-5N-oxide, predstavljajushej is a yellow crystalline solid.

The part With

To a solution of 20 g of 2-propitiatio[4,5-C]quinoline-5N-oxide in 500 ml of chloroform was added 50 ml of ammonium hydroxide. The mixture was cooled in an ice bath and then was added dropwise a solution of 16 g of tosylchloramide in chloroform. After adding taillored the reaction mixture is boiled under reflux for 2 hours and then diluted with additional chloroform and water. Separated aqueous and organic layers. The organic layer was washed with an aqueous solution of sodium bicarbonate, dried over magnesium sulfate and then concentrated in vacuum. After recrystallization of the residue of 1,2-dichloroethane was obtained 2-propitiatio[4,5-C]quinoline-4-amine as brown solid substance with a melting point 140-142 ° C. Analysis: calculated for C13H13N3S: % S, 64,17; % N, 5,38; % N, 17,27. Found:% C, 64,10; % N,5,47; % N, 17,29.

Example 14

Hydrochloric acid 2-propitiatio[4,5-C]quinoline-4-amine

Using the methodology described in example 10, of 1.75 g of 2-propitiatio[4,5-C]quinoline-4-amine was treated with 1 equivalent of concentrated hydrochloric acid. The result obtained yellowish-white crystalline product, representing hydrochloric acid 2-propitiatio[4,5-C]quinoline-4-amine; melting point 234-237 ° C. Analysis: calculated for C13H13N3S • Hcl: % C, 55,81; % N, 5,04; % N, 15,02. Found Is: % S, 55,86; % N, 5,02; % N, 14,99.

Example 15

2 Intitiate[4,5-C]quinoline-5N-oxide

Part a

Using the methodology described in part a of example 7, first carried out the reaction between 2-methylthiazole[4,5-C]quinoline (2.0 g, 10 mmol) and Diisopropylamine lithium (5.5 ml of 2 M solution in benzene), and then processed the resulting product is 1-iodobutane (1.8 ml). The result was obtained 1.1 g of yellow solid product, which represents a 2-intellisol[4,5-C]quinoline; melting point 62-64 ° C.

Part b

To a suspension of 1.25 g of 2-intellisol[4,5-C]quinoline in 50 ml of methyl acetate was added 1.50 ml of a 32%solution of peracetic acid in acetic acid. The reaction mixture is boiled under reflux for 6 hours, then cooled to room temperature, diluted with dichloromethane and washed first with an aqueous solution of sodium bicarbonate and then with water. The organic layer was dried over magnesium sulfate and concentrated in vacuum. The result was 1.20 g of a pale-yellow solid product. After recrystallization of this material from the ethyl acetate was obtained from 0.90 g of white crystalline 2-intellisol[4,5-C]quinoline-5N-oxide, melting point which was 142-144° C. Analysis: calculated for C15H16N2OS: %C, 66,14; %N, OF 5.92; %N, 10,19. Found: %C, 65,63; %N, Of 5.83; %N, 10,28.

Example 16

<> 2-Intellisol[4,5-C]quinoline-4-amine

To a solution 0,78 g 2-intellisol[4,5-C]quinoline-5N-oxide in 50 ml of dichloromethane was added 0.51 ml trichlorotriazine. The reaction mixture was stirred at room temperature for 75 minutes and then concentrated in vacuum. As a result, were obtained crude N-(2-intellisol[4,5-C]quinoline-4-yl)trichloroacetamide. To amide was added 40 ml of 2 M solution of ammonia in methanol and then dichloromethane to translate the entire product solution. Upon completion of the reaction, as judged according to the analysis by the method of thin-layer chromatography, the reaction mixture was concentrated in vacuum. The residue was mixed with dichloromethane and aqueous sodium bicarbonate solution. The organic layer was separated, washed first with an aqueous solution of sodium bicarbonate and then with water, dried over magnesium sulfate and then concentrated in vacuo to obtain a white solid product. After recrystallization of this material from the ethyl acetate was obtained yellowish-white crystalline substance, which represents a 2-intellisol[4,5-C]quinoline-4-amine, melting at 119-121° C. Analysis: calculated for C15H17N3S: %S, 66,39; %N, OF 6.31; %N, 15,48. Found: %C, 66,21; %N, 6.35mm; %N, 15,39.

Example 17

2-Butylthiazole[4,5-C]quinoline-5N-oxide

Part a/p>

Using the methodology described in part a of example 7, first carried out the reaction between 2-methylthiazole[4,5-C]quinoline (2.50 g, 12.5 mmol) and Diisopropylamine lithium (7,0 ml of 2 M solution in benzene), and then processed the resulting product is 1-iodopropane (3.0 g). The result obtained 1.19 g of a yellow oily product, which represents a 2-butylthiazole[4,5-C]quinoline.

Part b

Using the methodology described in part b of example 15, 2-butylthiazole[4,5-C]quinoline (1,33 g) was oxidized peracetic acid. The result was obtained 0.5 g of solid 2-butylthiazole[4,5-C]quinoline-5N-oxide, melting point which was 133-135 °C.

Example 18

2-Butylthiazole[4,5-C]quinoline-4-amine

Using the methodology described in example 16, 2-butylthiazole[4,5-C]quinoline-5N-oxide (0.50 g) was converted into the corresponding amide, which is then subjected to hydrolysis, resulting in the received 0.25 g of yellow crystalline 2-butylthiazole[4,5-C]quinoline-4-amine, melting point which was 149-151 ° C. Analysis: calculated for C14H15N3S: %S, 65,34; %N, BY 5.87; %N, 16,33. Found: %C, 64,88; %N, Of 5.84; %N, 16,03.

Example 19

2-( 1-Methylethyl)thiazolo[4,5-C]quinoline-5N-oxide

Part a

Using the methodology described in part a of example 7, 2-methylthiazole[4,5-C]quinoline (1.50 g, 7.5 mmol) of CH is first processed by diisopropylamide lithium (15.0 ml 2M solution in benzene), and then idestam the stands (2.4 ml). The result has been 0.97 g of a yellow oily product, which represents a 2-(1-methylethyl)thiazolo[4,5-C]quinoline.

Part b

Using the methodology described in part b of example 15, 2-(1-methylethyl)thiazolo[4,5-C]quinoline (0.95 g) was oxidized peracetic acid. The result was obtained 0.84 g of the solid product is yellow, representing 2-(1-methylethyl)thiazolo[4,5-C]quinoline-5N-oxide; melting point 161-162° C.

Example 20

2-( 1-Methylethyl)thiazolo[4,5-C]quinoline-4-amine

Using the methodology described in example 16, 2-(1-methylethyl)thiazolo[4,5-C]quinoline-5N-oxide (0.84 g) was converted into the corresponding amide and then subjected to hydrolysis, resulting in the obtained 0.16 g of yellow product having the form of needle-shaped crystals, and represents a 2-(1-methylethyl)thiazolo[4,5-C]quinoline-4-amine, melting point which was 163-165° C. Analysis: calculated for C13H13N3S:%S, 64,17; %N, 5,38; %N, 17,27. Found: %C, 63,49; %N, Are 5.36; %N, 17,09.

Example 21

2-(2-Phenyl-1-ethynyl)thiazolo [4,5-C]quinoline-5N-oxide

Part a

Using the methodology described in part a of example 7, 2-methylthiazole[4,5-C]quinoline (5.0 g, 25 mmol) was first treated with diisopropylamide lithium (15.0 ml of 2 M solution in benzene), and then benzalde the house (3.8 ml). The result was received with 5.3 g of a yellow solid of 1-phenyl-2-thiazolo[4,5-C]quinoline-2-yl-1-ethanol; melting point 147-148° C.

Part b

To a suspension of 2.16 g of 1-phenyl-2-thiazolo[4,5-C]quinoline-2-yl-1-ethanol in 40 ml of water by heating on the steam bath was added dropwise concentrated hydrochloric acid to dissolve the solid product. Heating of the reaction mixture was continued until the reaction is completed, as judged by the results of the analysis of the reaction system by the method of thin-layer chromatography. Then the reaction mixture was cooled to room temperature, it was observed the formation of a precipitate. The mixture was neutralized by adding sodium carbonate, then with stirring, was added dichloromethane to dissolve the precipitate. Separated organic and aqueous phase. The aqueous layer was extracted with dichloromethane. The organic layer was combined with dichlormethane extracts were washed with water, dried over magnesium sulfate and concentrated in vacuum to obtain 22 g of solid product green. After recrystallization of this product from ethyl acetate obtained 1.55 g green crystalline 2-(2-phenyl-1-ethynyl)thiazolo[4,5-C]quinoline. Analysis: calculated for C18H12N3S: %S, 74,97; %N, 4,19; %N, 9,71. Found: %C, 74,89; %N, 4,17; %N, 9,72.

The part With

To a suspension of 1.20 g of 2-(2-phenyl-1-ethynyl)enous the lo[4,5-C]quinoline in 50 ml of methyl acetate was added to 1.32 ml of a 32%solution of peracetic acid in acetic acid; the process resulted in the sediment. To the reaction mixture were added ethanol in an amount necessary to dissolve the precipitate, after which the mixture was boiled under reflux overnight and then cooled to room temperature. The precipitate was filtered, dried and then recrystallized from methanol/dichloromethane. The result was a solid 2-(2-phenyl-1-ethynyl)thiazolo[4,5-C]quinoline-5N-oxide yellow; the melting point of the oxide 268-270° C. Analysis: calculated for C18H12N2OS: %C, 71,03; %N, 3,97;%N, 9,20. Found: %C, 69,94; %N, A 3.87; %N, 9,05.

Example 22

2-(2-Phenyl-1-ethynyl)thiazolo[4,5-C]quinoline-4-amine

Using the methodology described in example 16, 2-(2-phenyl-1-ethynyl)thiazolo[4,5-C]quinoline-5N-oxide (0,67 g) was converted into the corresponding trichloroacetamide and then subjected to hydrolysis, resulting in received of 0.43 g of yellow crystalline 2-(2-phenyl-1-ethynyl)thiazolo[4,5-C]quinoline-4-amine, melting point which was 239-241 °C. Analysis: calculated for C18H13N3S: %S, 71,26; %N, 4,32; %N, 13,85. Found: %C, 70,73; %N, 4,15; %N, 13,68.

Example 23

2-(2-Phenyl-1-ethyl)thiazolo[4,5-C]quinoline-5N-oxide

Part a

To a suspension of 1.16 g of 2-(2-phenyl-1-ethynyl)thiazolo[4,5-C]quinoline (example 21, part b) in 200 ml of acetic key is lots added a small amount of catalyst (5% palladium, deposited on activated carbon). The mixture in the day were subjected to recovery in the Parr apparatus under a hydrogen pressure of 3.5 kg/cm2. Thereafter, the catalyst was filtered, the filtrate was concentrated in vacuo and the residue was dissolved in dichloromethane, washed first with an aqueous solution of sodium bicarbonate and then with water, dried over magnesium sulfate and concentrated in vacuum. The result was obtained 0.88 g of oily solid 2-(2-phenyl-1-ethyl)thiazolo[4,5-C]quinoline.

Part b

Using the methodology described in part b of example 15, 2-fenilatilamina[4,5-C]quinoline (from 0.90 g) was oxidized peracetic acid. He got to 0.63 g of orange solid 2-(2-phenyl-1-ethyl)thiazolo[4,5-C]quinoline-5N-oxide; melting point 165 to 169° C. Analysis: calculated for C18H14N2OS: %C, 70,56; %N, 4,60; %N, 9,14. Found: %C, 69,59; %N, 4,50; %N, 9,04.

Example 24

2-(2-Phenyl-1-ethyl)thiazolo[4,5-C]quinoline-4-amine

Using the methodology described in example 16, 2-(2-phenyl-1-ethyl)thiazolo[4,5-C]quinoline-5N-oxide (0,63 g) was converted into the corresponding trichloroacetamide, which was then subjected to hydrolysis, resulting in the obtained 0.21 g of 2-(2-phenyl-1-ethyl)thiazolo[4,5-C]quinoline-4-amine as a yellow crystalline substance, melting point which was 158-159° C. Analysis: calculated for C18the 15N3S: %S, 70,79; %N, 4,95; %N OF 13.75. Found: %C, 70,29; %N, 4,90; %N, 13,66.

Example 25

2-Methyl-1 -(thiazolo[4,5-C]quinoline-2-yl)-2-propanol-5N-oxide

Part a

In a dry flask, which was of 8.40 g of 2-methylthiazole[4,5-C]quinoline, in an atmosphere of nitrogen was introduced 150 ml of anhydrous tetrahydrofuran. The reaction mixture was cooled with dry ice to -78° and was added dropwise thereto, 23 ml of a 2.0 M solution of diisopropylamide lithium in benzene. Approximately 50 min to the mixture was added 5 ml of acetone and heated it up to 10° C. After several hours the mixture was treated with water, diluted with chloroform and then washed with water. The organic layer was dried over magnesium sulfate and concentrated in vacuum. The residue was dispersible in 200 ml of water, the mixture was heated and slowly added concentrated hydrochloric acid (6 N) to dissolve the solid product. To the solution was added activated charcoal and under stirring, the solution was heated for 5 minutes. Activated charcoal was filtered, the filtrate was neutralized with sodium bicarbonate and then extracted with chloroform. The chloroform extract is washed several times with water, dried over magnesium sulfate and then concentrated in vacuo to obtain 8.0 g of light brown solid product. After recrystallization of this product from a mixture of dichloromethane and of hexanol received 5.0 g of yellow crystalline 2-methyl-1-(thiazolo[4,5-C]quinoline-2-yl)-2-propanol, the melting point of which was 155-157° C. Analysis: calculated for C14H14N2OS: %C, 65,08; %N, 5,46; %N, 10,84. Found: %C, 64,97; %N, 5,33; %N 10,90.

Part b

To a suspension of 3.0 g of 2-methyl-1-(thiazolo[4,5-C]quinoline-2-yl)-2-propanol in 200 ml of methyl acetate was added to 4.8 ml of a 32%solution of peracetic acid in acetic acid. The reaction mixture is boiled under reflux overnight, then cooled to room temperature and concentrated in vacuum. The residue was dissolved in dichloromethane, to the solution was added sodium bicarbonate and thoroughly mixed. The precipitate was filtered and dissolved in a mixture of methanol and dichloromethane. This solution was concentrated in vacuo, the residue after distillation of the solvent was added to dichloromethane and then the resulting mixture was filtered to remove nerastvorimogo product. The filtrate was concentrated in vacuum and the result was obtained 2.6 g of the target N-oxide. After recrystallization of a small portion of this product (0.2 g) from a mixture of methanol/water received solid 2-methyl-1 -(thiazolo[4,5-C]quinoline-2-yl)-2-propanol-5N-oxide, melting point which was 187-189° C. Analysis: calculated for C14H14N2About2S • 1/3 H2ABOUT: %S, 59,98; %N, 5,27; %N, 9,99. Found: %C, 60,09; %N, 5,03; %N, 10,00.

Example 26

2-(4-Aminothiazolo[4,5-C]quinoline-2-yl)-1,1-dimethyl shall talkabout

To a solution of 2.4 g of 2-methyl-1-(thiazolo[4,5-C]quinoline-2-yl)-2-propanol-5N-oxide in 250 ml of dichloromethane was added 3.2 ml trichlorotriazine. The reaction mixture was stirred at room temperature for 1 hour and then concentrated in vacuum. The residue was stirred for 2 hours with 2 M solution of ammonia in methanol (150 ml), then methanol drove in a vacuum. Remaining after distillation, the product was dispersively in a mixture of dichloromethane and ethyl acetate and then washed with an aqueous solution of sodium bicarbonate. Nerastvorim product was filtered, washed first with water and then with dichloromethane, and then recrystallized from a mixture of methanol and dichloromethane. The result was obtained 1.6 g of solid 2-(4-aminothiazolo[4,5-C]quinoline-2-yl)-1,1-dimethylthiocarbamate, the melting point of which was 222-223° C. Analysis: calculated for C15H16N4O2S: %S, 56,94; %N, 5,09; %N, 17,70. Found: %C, 56,71; %H, 5,08; %N, 17,52.

Example 27

2-(Ethoxymethyl)thiazolo[4,5-C]quinoline-5N-oxide

Part a

To a suspension of 4.6 g C-aminoquinoline-4-thiol (26,1 mmol) in 50 ml detoxicates acid was added 6 ml of ethoxyacetylene (53.8 mmol). The mixture was heated at 60° C overnight, and then concentrated in vacuum to remove part detoxicates acid. the ri is added to the residue 100 ml of water was formed precipitate. The mixture was podslushivaet 50%sodium hydroxide solution. The precipitate was filtered, washed with water and dried. Got fluffy solid of 2-(ethoxymethyl)thiazolo[4,5-C]quinoline green color.

Part b

To a solution of 1.0 g of 2-(ethoxymethyl)thiazolo[4,5-C]quinoline in ethanol was added 1.0 ml of a 32%solution of peracetic acid in acetic acid. The reaction mixture was stirred for one week at room temperature, then concentrated in vacuo and subjected to azeotropic distillation with heptane to remove acetic acid. The residue was dissolved in dichloromethane, washed first with an aqueous solution of sodium bicarbonate and then with water, dried over magnesium sulfate and concentrated in vacuum. After recrystallization of the remaining product from isopropanol received a yellow crystalline 2-(ethoxymethyl)thiazolo[4,5-C]quinoline-5N-oxide; melting point 138-140° C. Analysis: calculated for C13H12N2O2S: %S, 59,98; %N, 4,65; %N 10,76. Found: %C, 59,85; %N, 4,66; %N, 10,71.

Example 28

2-(Ethoxymethyl)thiazolo[4,5-C]quinoline-4-amine

To a solution of 1.0 g of 2-(ethoxymethyl)thiazolo[4,5-C]quinoline-5N-oxide in 50 ml of dichloromethane was added 0.7 ml trichlorotriazine and the mixture was stirred at room temperature for 2 hours, then concentrated in vacuo to obtain N-(2-(ethoxymethyl)is Iesolo[4,5-C]quinoline-4-yl)trichloroacetamide. Amide was treated with methanol and was added 1 equivalent of sodium methylate. The reaction mixture was stirred 30 min at room temperature and then concentrated in vacuum. The reaction was carried out once using 2 g of N-oxide. Obtained in both experiments, the products were combined together and recrystallize from isopropanol. The result was 2.25 g slightly yellow 2-(ethoxymethyl)thiazolo[4,5-C]quinoline-4-amine, having the form of needle crystals. The melting point of this product 149-151° C. Analysis: calculated for C13H13N3OS: %C, 60,21; %N, OF 5.05; %N, 16,20. Found: %C, 59,86; %N, Equal To 4.97; %N, 16,16.

Example 29

2-(Methoxymethyl)thiazolo[4,5-C]quinoline-5N-oxide

Part a

To a mixture of 2.8 g C-aminoquinoline-4-thiol and 15 ml methoxybutanol acid was added 1.8 ml of methoxyacetanilide, the reaction mixture was stirred for 1 hour at 140° and then cooled to room temperature. After this was added a small amount of water was podslushivaet mixture of 10%sodium hydroxide solution and then was extracted with 300 ml dichloromethane. The extract was washed first with an aqueous solution of sodium bicarbonate, then with water, dried over magnesium sulfate and finally concentrated in vacuo to obtain the crude dark oily product. The oil was dissolved in dichloromethane and purified by chromatography is graficheskiy column of silica gel, using as eluent a 1:1 mixture of hexane and ethyl acetate. The eluate was concentrated in vacuo and the result was obtained 2.3 g of solid orange 2-(methoxymethyl)thiazolo[4,5-C]quinoline.

Part b

Using the methodology described in part b of example 27, carried out the oxidation of 2-(methoxymethyl)thiazolo[4,5-C]quinoline (1.7 g). The result was obtained 1.8 g of yellow crystalline 2-(methoxymethyl)thiazolo[4,5-C]quinoline-5N-oxide, melting point which was 151-153° C. Analysis: calculated for C12H10N2OS: %C, 58,52; %H, 4.09 TO; %N, 11,37. Found: %C, 57,95; %N, 3,98; %N, 11,3.

Example 30

2-(Methoxymethyl)thiazolo[4,5-C]quinoline-4-amine

Using the methodology described in example 28, in the processing of 2-(methoxymethyl)thiazolo[4,5-C]quinoline-5N-oxide (1.3 g) was obtained the relevant trichloroacetamide which was subsequently subjected to hydrolysis, which received light yellow needle crystals of 2-(methoxymethyl)thiazolo[4,5-C]quinoline-4-amine. The melting point of the obtained product was 183-185° C. Analysis: calculated for C12H11N30S: %S, 58,76; %N, TO 4.52; %N, 17,13. Found: %C, 58,69; %N, 4,34; %N, 17,14.

Example 31

2-(2-Methylpropyl)thiazolo[4,5-C]quinoline-5N-oxide

Part a

4.6 g C-aminoquinoline-4-thiol was added to 80 g of polyphosphoric acid. To allali additional 3.5 ml of isovalerianic acid and the mixture was heated at 140° C for 2 hours, then poured it into 300 ml of ice water. The mixture was filtered through a layer lite® to remove insoluble material. The filtrate was cooled with ice water and podslushivaet 50%sodium hydroxide solution, and then was extracted with chloroform. The extract was washed with water, dried over magnesium sulfate and then concentrated in vacuo to obtain an oily product. The oil was dissolved in dichloromethane and subjected to chromatographic purification on silica gel, using as eluent a 1:1 mixture of ethyl acetate and hexanol. The eluate was concentrated in vacuo and obtained 2-(2-methylpropyl)thiazolo[4,5-C]quinoline.

Part b

Using the methodology described in part b of example 27, carried out the oxidation of 2-(2-methylpropyl)thiazolo[4,5-C]quinoline (5,2 g). The result was obtained 2.5 g of yellow solid 2-(2-methylpropyl)thiazolo[4,5-C]quinoline-5N-oxide.

Example 32

2-(2-Methylpropyl)thiazolo[4,5-C]quinoline-4-amine

Using the methodology described in example 28, the processing of 2-(2-methylpropyl)thiazolo[4,5-C]quinoline-5N-oxide (2.5 g) was obtained the relevant trichloroacetamide which was subsequently subjected to hydrolysis, which received light yellow plate-like crystals of 2-(2-methylpropyl)thiazolo[4,5-C]quinoline-4-amine. The melting point of the obtained product SOS is alala 123-125° C. Analysis: calculated for C14H15N3S: %S, 65,34; %N, BY 5.87; %N, 16,33. Found: %C, 64,87; %N, 5,79; %N, 16,18.

Example 33

2-Benzilate[4,5-C]quinoline-5N-oxide

Part a

To a cooled solution of 2 g of phenylacetic acid in 10 ml of dichloromethane was added dropwise to 1.5 g of thionyl chloride. The mixture was stirred for one hour at room temperature, and receive a solution containing phenylacetylene. To a suspension of 3-aminoquinoline-4-ol in 10 ml of dichloromethane was added 4.3 ml of triethylamine and the resulting mixture was cooled in an ice bath. To this cooled mixture was added dropwise pre-prepared solution of phenylacetylene. The reaction mixture was stirred at room temperature overnight. The obtained sticky oily residue was diluted with water (10 ml) and then was rapidly stirred for 1 hour. The mixture was filtered. According to thin-layer chromatography target product contained in the highlighted during the filtration of the solid product, and in the filtrate. The filtrate was diluted with dichloromethane and water. The organic layer was separated, dried over magnesium sulfate and concentrated in vacuum. The residue was combined with the previously obtained solid product was recrystallized from a mixture of 80:20 isopropanol:water. The result was obtained 1.3 g of N-(hydroxyquinolin-3-yl)Fe is ylacetamide in the form of needle crystals. Melting point 253-255° C. Analysis: calculated for C17H14N2About2: %S, 73,37; %N, 5,07; %N, 10,07. Found: %C, 73,16; %N, 5,03; %N, 10,07.

Part b

To a suspension of 1.0 g of N-(4-hydroxyquinolin-3-yl)phenylacetamide in pyridine was added 1.6 g paternostro phosphorus. The mixture is boiled under reflux until the reaction is completed, after which the reaction mixture was concentrated in vacuo and subjected to azeotropic distillation with water to remove pyridine. The residue was combined with water, neutralized with sodium carbonate and then extracted with dichloromethane. The extract was washed with water, dried over magnesium sulfate and concentrated in vacuo to obtain a solid 2-benzilate[4,5-C]quinoline.

The part With

Using the methodology described in part b of example 27, 2-benzilate[4,5-C]quinoline (3.3 grams) was oxidized to obtain 2.1 g of 2-benzilate[4,5-C]quinoline-5N-oxide. The target product was obtained as a yellow solid, the melting point of which was 185-186° C. Analysis: calculated for C17H12N2OS: %C, 69,84; %N, 4,14; %N 9,58. Found: %C, 69,51; %N, 4,06; %N, Of 9.55.

Example 34

Hydrochloric acid 2-benzilate[4,5-C]quinoline-4-amine

1.2 ml trichloroacetimidate of 10.3 mmol) was added to a solution of 2.0 g of 2-benzilate[4,5-C]quinoline-5N-oxide (6.8 mmol) in 100 ml of dichloromethane. The mixture is eremetical 2 hours at room temperature and then concentrated. The result obtained crude N-(2-benzilate[4,5-C]quinoline-4-yl)trichloroacetamide. This amide was dissolved in methanol and to the solution was added 1 equivalent of sodium methylate. The reaction mixture was heated for 30 minutes on the steam bath and then cooled to room temperature. The precipitate was filtered and was dispersively in a mixture of methanol and isopropanol. To the suspension was added 1 equivalent of hydrochloric acid, when this happened the dissolution of solid product. When standing was crystallized white solid. It was filtered, washed with isopropanol and dried. The result was obtained 1.5 g of hydrochloric acid 2-benzilate[4,5-C]quinoline-4-amine, melting point which was 152-155° C. Analysis: calculated for C17H13N3S • Hcl: %C, 62,28; %N, 4,30; %N, 12,82. Found: %C, 62,05; %N, 4,23; %N, 12,82.

Example 35

8-Methyl-2-propitiatio[4,5-C]quinoline-5N-oxide

Part a

To a solution of 1 g of 6-methyl-3-nitroanilin-4-ol in 25 ml of ethanol and 0.5 ml of ammonium hydroxide was added 0.10 g of catalyst comprising an activated carbon coated with a platinum (10%). Recovery of 6-methyl-3-nitroanilin-4-ol was carried out in an atmosphere of hydrogen in a Parr apparatus at room temperature. After recovery of the catalyst was filtered and the reactions is nnow the mixture was concentrated in vacuum. The residue was combined with water and heated. For the complete dissolution of the solid product to the mixture was added dropwise hydrochloric acid and then the solution was added activated charcoal. After some time the mixture was filtered and to the filtrate was added 2 ml of concentrated (12 N) hydrochloric acid. This recrystallization was performed three times, resulting in a received 0.50 g of hydrochloric acid 3-amino-6-methylinosine-4-ol. The melting point of this product exceeded 310° C. Analysis: calculated for C10H10N2O· HCl: %C, 57,02; %N, 5,26; %N, 13,30. Found: %C, 56,92; %N, 5,16; %N, 13,24.

Part b

To a suspension of hydrochloric acid 3-amino-6-methylinosine-4-ol in 400 ml of dichloromethane was added first 11,46 ml of triethylamine, and then to 4.46 ml of acid chloride of acid oil. The mixture was heated on the steam bath for 30 min, then was diluted with sodium bicarbonate and filtered. The filtrate was washed with an aqueous solution of sodium bicarbonate and then concentrated in vacuum. After recrystallization of the residue from isopropanol received hemihydrate 3 butylamino-5-methylinosine-4-ol; melting point 274-277° C. Analysis: calculated for C14H16N2O2·1/2 H2O: %C, 66,39; %N, 6,76; %N, 11,06. Found: %C, 66,56; %N, 6,46; %N, 11,03.

The part With

To a mixture of 7,12 g hemihydrate 3 butylamino-6-methylinosine-4-ol in pyridine was added 12.9 g of the heels of the sulfur phosphorus. The reaction mixture is boiled under reflux for 90 min, then added to it a mixture of ice and sodium carbonate and was extracted with dichloromethane. The extract was concentrated in vacuum. The residue was diluted with toluene and again concentrated in vacuo to obtain a crude solid. The resulting product was purified through column chromatography using as eluent 20%solution of dichloromethane in ethyl acetate. The result was a solid 8-methyl-2-propitiatio[4,5-C]quinoline yellow.

Part D

Using the methodology described in part b of example 27, 8-methyl-2-propitiatio[4,5-C]quinoline (4.0 g) was oxidized with 3-chloroperbenzoic acid. The crude product (4,19 g) was recrystallized from isopropanol and as a result received 2.0 g solid 8-methyl-2-propitiatio[4,5-C]quinoline-5N-oxide; melting point 143-145° C. Analysis: calculated for C14H14N2OS: %C, 65,09; %N, 5,46; %N, 10,84. Found: %C, 64,86; %N, 5,40; %N 10,88.

Example 36

8-Methyl-2-propitiatio[4,5-C]quinoline-4-amine

Using the methodology described in example 28, was transformed 8-methyl-2-propitiatio[4,5-C]quinoline-5N-oxide of N-(8-methyl-2-propitiatio[4,5-C]quinoline-4-yl)trichloroacetamide which was subsequently subjected to hydrolysis, which received 1,32 g solid to istoricheskogo 8-methyl-2-propitiatio[4,5-C]quinoline-4-amine; the melting point of the obtained product was 147-149° C. Analysis: calculated for C14H15N3S: %S, 65,34; %N, BY 5.87; %N, 16,33. Found: %C, 64,97; %N, 5,76; %N, 16,25.

Example 37

(4-Aminothiazolo[4,5-C]quinoline-2-yl)methanol

Part a

To a suspension of 5 g of 3-aminoquinoline-4-ol in 50 ml of dichloromethane was added 7.3 ml of triethylamine. The mixture was cooled in an ice bath and was added dropwise to 3 ml of acetoacetanilide, then stirred at room temperature for 2 hours. The obtained residue was diluted with water (10 ml)was rapidly stirred for 10 min and was filtered. According to thin-layer chromatography, the target substance contained in the solid product, and in the filtrate. The filtrate was concentrated in vacuo, the resulting residue was mixed with water and was filtered. The solid product obtained in both stages were combined together and recrystallized from a mixture of 80:20 isopropanol : water. The result was obtained N-(4-hydroxyquinolin-3-yl)acetoacetamide; melting point 224-225° C.

Part b

Using the methodology described in part b of example 33, spent the reaction between N-(4-hydroxyquinolin-3-yl)acetoacetamide (5.3g) and paternity phosphorus. The result was obtained 2.9 g of solid thiazolo[4,5-C]quinoline-2-yl-acetate.

The part With

Using IU is the odik, listed in part b of example 27, 2.8 g thiazolo[4,5-C]quinoline-2-yl-acetate was oxidized with peracetic acid in the solid crystalline product is brown in color, representing thiazolo[4,5-C]quinoline-2-yl-acetate-5N-oxide.

Part D

0,65 ml trichloroacetimidate was added to a solution of 1.0 g thiazolo[4,5-C]quinoline-2-yl-acetate-5N-oxide in 50 ml of dichloromethane. The mixture was stirred 2 hours at room temperature and then concentrated in vacuum. The residue was dissolved in methanol. To the solution was added 1 equivalent of sodium methylate and the mixture was stirred over night at room temperature. The precipitate was filtered and dried. He got to 0.68 g of a white solid (4-aminothiazolo[4,5-C]quinoline-2-yl)methanol; melting point 247-249° C. Analysis: calculated for C11H9N3OS: %C, 57,13; %N, 3,92; %N, 18,17. Found: %C, 56,85; %N, 3,96; %N, 17,83.

Example 38

2-Methoxazole[4,5-C]quinoline-4-amine

Part a

6 g of 3-aminoquinoline-4-ol boiled with 8 equivalents of acetic anhydride to the reaction is completed, which was determined by the method of thin-layer chromatography. The reaction mixture was cooled, diluted with ice water and podslushivaet 10%sodium hydroxide solution, and then was extracted with dichloromethane. The extract was washed with water and solely the solution, was dried over magnesium sulfate and concentrated in vacuum. The residue was purified through column chromatography (silica gel; eluent a mixture of methanol with ethyl acetate). The result was of 5.1 g of 2-methoxazole[4,5-C]quinoline.

Part b

A mixture of 5.0 g of 2-methoxazole[4,5-C]quinoline, 5 equivalents of peracetic acid and ethanol was stirred at room temperature. After 2 hours, was added an additional amount of peracetic acid (2 equivalents) and stirring was continued for further 3 hours. The reaction mixture was concentrated in vacuum. The residue was subjected to azeotropic distillation with heptane, after which he received of 4.2 g of 2-methoxazole[4,5-C]quinoline-5N-oxide.

The part With

3.6 ml trichloroacetimidate was slowly added to a cooled mixture of 4.0 g of 2-methoxazole[4,5-C]quinoline-5N-oxide and dichloromethane. The reaction mixture was stirred for several hours and then concentrated in vacuum. To the obtained crude N-(2-methoxazole[4,5-C]quinoline-4-yl)trichloroacetamide was added 2 M solution of ammonia in methanol and the mixture was stirred for 1 hour. The reaction mixture was concentrated in vacuum, diluted with water and then was extracted with dichloromethane. The extract was washed with water and brine, dried over magnesium sulfate and again concentrated in vacuo. The residue was purified through column chromatography (silica gel; eluent a mixture of ethyl acetate is hexane). The result was obtained 1.2 g of solid 2-methoxazole[4,5-C]quinoline-4-amine; melting point 195-197° C. Analysis: calculated for C11H9N3ABOUT: %S, 66,32; %N, 4,55; %N, 21,09. Found: %C, 65,96; %N, Of 4.44; %N, 20,68.

Example 39

2-Ethyloxazole[4,5-C]quinoline-4-amine

Part a

6 g of hydrochloric acid 3-aminoquinoline-4-ol was heated under reflux with 8 equivalents of propionic anhydride to the reaction is completed, which was determined by the method of thin-layer chromatography. The reaction mixture was cooled, diluted with ice water and podslushivaet 10%sodium hydroxide solution, and then was extracted with dichloromethane. The extract was washed with water and brine, dried over magnesium sulfate and concentrated in vacuum. The residue was purified through column chromatography (silica gel; eluent a mixture of methanol with ethyl acetate). The result was obtained 4.0 g of 2-ethyloxazole[4,5-C]quinoline.

Part b

A mixture of 3.5 g of 2-ethyloxazole[4,5-C]quinoline, and 4.5 ml of a 32%solution of peracetic acid in acetic acid and 40 ml of methyl acetate was heated for several hours at 50° With, then concentrated in vacuo. The residue was mixed with hexane and after filtration was obtained 2.5 g of solid 2-ethyloxazole[4,5-C]quinoline-5N-oxide.

The part With

2 ml trichloroacetimidate was slowly added to the cooled to a mixture of 2-ethyloxazole[4,5-C]quinoline-5N-oxide (2.5 g) and dichloromethane. The reaction mixture was stirred for several hours and then concentrated in vacuum. To the obtained crude N-(2-ethyloxazole[4,5-C]quinoline-4-yl)trichloroacetamide was added 2 M solution of ammonia in methanol and the mixture was stirred for 1 hour. The reaction mixture was concentrated in vacuum, diluted with water and then was extracted with dichloromethane. The extract was washed with water and brine, dried over magnesium sulfate and again concentrated in vacuo. The residue was purified through column chromatography (silica gel; eluent a mixture of ethyl acetate with hexane). The result was a solid 2-ethyloxazole[4,5-C]quinoline-4-amine; melting point 175-178° C. Analysis: calculated for C12H11N3ABOUT: %S, 67,59; %N, 5,20; %N, 19,71. Found: %C, 67,19; %N, 4,86; %N, 20,43.

Example 40

2-Butylanisole[4,5-C]quinoline-5N-oxide

Part a

A mixture of 1.97 g of hydrochloric acid C-aminoquinoline-4-ol (10.0 mmol), 1.01 g of triethylamine (10.1 mmol) and 9.3 g of anhydride walerianowo acid (50.0 mmol) was boiled under reflux for 18 hours, then cooled to room temperature and poured into ice. Using 10%sodium hydroxide solution the pH of the mixture was brought to 12. The mixture was stirred until then, until melted all the ice, and then was extracted with diethyl ether. The ether extracts were dried over magnesium sulfate, concentri is ovale in vacuo to obtain a brown solid product. This product was purified by way of flash chromatography, using as eluent a mixture of 3:2 ethyl acetate and dichloromethane. The result obtained 1.45 g of 2-butylanisole[4,5-C]quinoline.

Part b

With stirring to a solution of 1.4 g of 2-butylanisole[4,5-C]quinoline (6.2 mmol) in 50 ml of ethanol was added 1.6 g of a 32%solution of peracetic acid in acetic acid (6.8 mmol). The mixture was stirred at room temperature for 3 days and then were decontaminated by adding a saturated solution of potassium carbonate. Separated organic and aqueous layers. The organic layer was concentrated in vacuo to obtain a brown solid product. This product was mixed with diethyl ether and then filtered. The result was obtained 0.6 g of 2-butylanisole[4,5-C]quinoline-5N-oxide, melting point which was 120-121° C. Analysis: calculated for C14H14N2O2: %S, 69,41; %N, OF 5.82; %N, TO 11.56. Found: %C, 69,22; %N, 5,76; %N,11,59.

Example 41

2-Butylanisole[4,5-C]quinoline-4-amine

0.6 g trichloroacetimidate (3,40 mmol) under nitrogen atmosphere was added under stirring to a solution of 0.55 g of 2-butylanisole[4,5-C]quinoline-5N-oxide of 2.27 mmol) in 20 ml of anhydrous dichloromethane. The reaction mixture was stirred for 2 hours at room temperature and then concentrated in vacuo to obtain neocide the aqueous oily N-(2-butylanisole[4,5-C]quinoline-4-yl)trichloroacetamide. This product was transferred into 25 ml of methanol and to the solution was added 0,49 ml of 25%solution of sodium methylate (of 2.27 mmol). The reaction mixture is boiled under reflux for 2 hours and then concentrated in vacuum. The residue was washed with ethyl acetate and washed with water. The organic layer was concentrated in vacuo to obtain a solid product of orange color. This product was twice purified by way of flash chromatography, using as eluent when the first cleaning ethyl acetate, and the second 30%solution of dichloromethane in ethyl acetate. The result was obtained 0.15 g of 2-butylanisole[4,5-C]quinoline-4-amine; melting point 96-98° C. Analysis: calculated for C14H15N3ABOUT: %S, 69,69; %N, 6,27; %N, 17,41. Found: %C, 69,23; %N, 6,06; %N, 17,07.

Example 42

2-Propitiatio[4,5-C]quinoline-4,8-diamine

Part a

To a solution of 2-propitiatio[4,5-C]quinoline-4-amine (1 g, 4,11 mmol; from example 12) in sulfuric acid (10 ml) was added and 0.46 g of sodium nitrate (to 4.52 mmol). The mixture was stirred 30 min at room temperature, then poured into ice, neutralized (to pH 7) with ammonium hydroxide (150 ml) and was extracted with dichloromethane. The extract was washed with an aqueous solution of sodium bicarbonate, dried over magnesium sulfate and then concentrated in vacuo to obtain 1 g of the yellow solid product. After re is cristallization this product from a mixture of isopropanol/water was obtained 0.84 g of solid yellow 8-nitro-2-propitiatio[4,5-C]quinoline, having a melting point 228-230° C. Analysis: calculated for C13H12N4About2S: %S, EUR 54.15; %N, 4,20; %N, 19,43. Found: %C, 54,22; %N, 4,05; %N, 19,04.

Part b

To a solution of 1.31 g of 8-nitro-2-propitiatio[4,5-C]quinoline in ethanol was added to 0.13 g of catalyst (palladium deposited on activated carbon). The mixture was reduced by hydrogen in a Parr apparatus. Thereafter, the catalyst was filtered and washed it on the filter with ethanol. The filtrate was concentrated in vacuum at 50° and then dried in nitrogen atmosphere. The result obtained yellow crystals of 2-propitiatio[4,5-C]quinoline-4,8-diamine; melting point 190-192° C. Analysis: calculated for C13H14N4S: %S, 60,44; %N, 5,46; %N, 21,69. Found: %C, 60,11; %N, The 5.45; %N 21,96.

Example 43

2-Propiconazole[4,5-C]quinoline-4-amine

Part a

A mixture of 1.97 g of hydrochloric acid C-aminoquinoline-4-ol (10.0 mmol)and 3.15 g of butyric acid anhydride (20 mmol) and 25 ml of pyridine was heated under reflux overnight, then cooled and poured into ice. The mixture was podslushivaet 1 N sodium hydroxide solution (to pH 11) and then was extracted with three portions of diethyl ether, 100 ml each. The precipitate was filtered. The ether extracts were combined together, dried over magnesium sulfate and then concentrated to obtain 1.1 g of solid 2-propilot the azolo[4,5-C]quinoline yellowish-white in color.

Part b

To a solution of 1.0 g of 2-propiconazole[4,5-C]quinoline (4.7 mmol) in 30 ml of chloroform under stirring was added 3-chloroperbenzoic acid (1 equivalent; in the form of a 60%aqueous solution). The mixture was stirred at room temperature overnight and then were decontaminated by adding a saturated solution of potassium carbonate. Separated organic and aqueous layers. The aqueous layer was extracted with dichloromethane. The organic layers were combined together and concentrated. The obtained product was purified by way of flash chromatography, using as eluent 8:2 mixture of ethyl acetate and dichloromethane. The result was obtained 1.0 g of solid 2-propiconazole[4,5-C]quinoline-5N-oxide brown.

The part With

0.9 g trichloroacetimidate (the 5.25 mmol) under stirring was added to a solution of 0.8 g of 2-propiconazole[4,5-C]quinoline-5N-oxide (3.5 mmol) in 30 ml of chloroform. The reaction mixture was stirred for 2.5 hours at room temperature and then concentrated in vacuo to obtain crude N-(2-propiconazole[4,5-C]quinoline-4-yl)trichloroacetamide. This amide was dissolved in 50 ml of methanol, was added to a solution of 1 equivalent of sodium methylate (25%solution) and the mixture is boiled under reflux for 2 hours. The reaction mixture was concentrated in vacuo, the residue was washed with diethyl ether and water. The ether layer was separated and who has koncentrirebuli in vacuo to obtain a brown solid product. This product was purified by way of flash chromatography, using two chromatographic column (the first column as the eluent used a 8:2 mixture of ethyl acetate with dichloromethane, the second 1:1 mixture of ethyl acetate and dichloromethane). The result was 0.1 g 2-propiconazole[4,5-C]quinoline-4-amine as a yellow powder; melting point 159,0-160,0° C. Analysis: calculated for C13H13N3ABOUT: %S, 68,71; %N, 5,77; %N, BE 18.49. Found: %C, 68,03; %N, 5,77; %N, 18,14.

Example 44

8-Bromo-2-propitiatio[4,5-C]quinoline-4-amine

1.0 g of 2-propitiatio[4,5-C]quinoline-4-amine (0.41 mmol) was added to 15 ml of acetic acid and the mixture was heated to 60° C. Then was added dropwise to 0.10 ml of bromine (1.94 mmol), the mixture was stirred at 60° C for 18 hours, then diluted with water and the resulting precipitate was filtered. The result was obtained 0.25 g of yellow solid 8-bromo-2-propitiatio[4,5-C]quinoline-4-amine; melting point 177-180° C. Analysis: calculated for C13H12rN3S: %S, 48,46; %N, 3,75; %N, 13,04. Found: %C, 47,98; %N, 3,95; %N, 12,70.

Example 45

7-Methyl-2-propitiatio[4,5-C]quinoline-4-amine

Part a

A mixture of 37.8 ml diethylethylenediamine (187 mmol) and 20 ml of m-toluidine (187 mmol) was heated at 100° C for about 3 hours. Upon cooling the mixture to room the second temperature it is hardened. This solidified mixture was added 350 ml of solvent Dowtherm a and the resulting solution was boiled under reflux for about 30 minutes, after which the mixture was cooled to room temperature. The precipitate was filtered, washed with acetone and dried. The result was 33 g of powder ethyl-4-hydroxy-7-methyl-3-chinainternational brown.

Part b

32 g of ethyl-4-hydroxy-7-methyl-3-chinainternational (138 mmol) was dispersible in 500 ml of 10%aqueous sodium hydroxide solution and then boiled under reflux for about 30 minutes. The resulting mixture was cooled to room temperature and acidified it with concentrated hydrochloric acid. The resulting precipitate was filtered, well washed with water and then dried in an oven. The result was 28 g of 4-hydroxy-7-methyl-3-quinoline-carboxylic acid. 2 g of this product is twice recrystallized from N,N-dimethylformamide, got fluffy white solid, melting point which was 264-265° C. Analysis: calculated for C11H9NO3: %S, 65,02; %N, 4,46;%N, 6,89. Found: %C, 65.22 Per; %N, 4,42; %N, 6,88.

The part With

32 g of 4-hydroxy-7-methyl-3-quinoline-carboxylic acid were loaded into a round bottom flask. Then the flask was heated in a bath filled with molten alloy wood, 310° during the course the e few minutes until until the product is completely melted with the formation of a light brown viscous liquid and does not stop the allocation of bubbles. Then the reaction mixture was cooled to room temperature and the product was recrystallized from a mixture of ethyl acetate and ethanol. The result has been of 9.8 g of 7-methyl-4-chinoline. In the process of recrystallization of the solid part of the product did not dissolve; this material was filtered and then recrystallized, thus obtained 1.1 g of 7-methyl-4-chinoline in the form of a yellow-brown plate crystals; melting point 233-235° C. Analysis: calculated for C10H9NR: %S, 75,45; %N, 5,70; %N, 8,80. Found: %C, 75,23; %N, 5,54; %N, 8,76.

Part D

To a hot solution (125° (C) and 10.5 g of 7-methyl-4-chinoline in 125 ml of propionic acid was slowly added to 6 ml of 70%nitric acid. The mixture was stirred for about 1.5 hours and then cooled to room temperature. The obtained precipitate was filtered, well washed with ethanol and water and dried. The result was of 6.9 g of slightly yellow solid 7-methyl-Z-nitro-4-chinoline.

Part E.

Mixture of 11.8 g of 7-methyl-3-nitroquinoline (58 mmol), 300 ml of methanol, 50 ml of ammonium hydroxide and 1 g of catalyst (10% palladium deposited on activated carbon)were loaded into a Parr apparatus and carried out the reaction of recovery in the atmosphere in Dorada (at a pressure of 2.4 - 2.8 kg/cm2within about 1 hour. The reaction mixture was passed through a layer of filter material lite® and a solid residue on the filter was thoroughly washed with methanol. The filtrate was treated with activated charcoal and then concentrated in vacuo to obtain a fluffy solid pale green color. After processing this product acetonitrile was obtained 8.5 g of 3-amino-7-methyl-4-chinoline.

Part F

To a suspension of 800 mg of 3-amino-7-methyl-4-chinoline (4.6 mmol) in 30 ml of dichloromethane under nitrogen atmosphere was added first to 0.71 ml of triethylamine (5.1 mmol), and then of 0.53 ml of acid chloride of butyric acid (5.1 mmol). The mixture was stirred at room temperature for about 2 hours. After that, using the method of thin-layer chromatography (silica gel, eluent is a mixture of 9:1 dichloromethane-methanol) was established that the reaction mixture still contained the original product. Therefore, the reaction mixture was heated to boiling and then allowed it to dry for about 30 minutes. After this has introduced additional amount of solvent and the mixture is boiled under reflux for 1 hour. After this analysis using thin-layer chromatography showed the presence of starting material in the reaction mixture. The obtained precipitate was filtered, washed with dichloromethane and water and received 650 mg pale to michnevich crystalline plates of N-(4-hydroxy-7-methylinosine-4-yl)butyramide.

Part G

To a mixture of 630 mg of N-(4-hydroxy-7-methylinosine-4-yl)butyramide (2.6 mmol) in 20 ml of pyridine under nitrogen atmosphere was added to 1.15 g paternostro phosphorus (2.6 mmol) and the mixture was heated to boiling. The reaction mixture became bright yellow, and all the solid went into solution. The mixture was boiled under reflux for about 2 hours,and then cooled to room temperature and was extracted with water, aqueous sodium bicarbonate solution and dichloromethane. The organic layer was treated with saturated copper sulfate solution, dried over magnesium sulfate and concentrated in vacuo to obtain an oily product. This product was dried in high vacuum and the result was 410 mg of solid orange 7-methyl-2-propitiatio[4,5-C]quinoline.

Part N

To a mixture of 2 g of 7-methyl-2-propitiatio[4,5-C]quinoline and 100 ml of chloroform was added 2.4 g of 3-chloroperbenzoic acid (57-86%solution). The mixture was stirred 2 hours at room temperature. Analysis by thin-layer chromatography showed no evidence of any source material in the reaction mixture, but found two new products. The mixture was stirred at room temperature for 1 hour and then was extracted with dichloromethane and aqueous sodium bicarbonate solution. The organic layer was dried over magnesium sulfate and concentrated in vacuum on the receiving yellow-orange oil. This oil was dried under high vacuum and the obtained 2.1 g of solid 7-methyl-2-propitiatio[4,5-C]quinoline-5N-oxide.

Part I

To a mixture of 2.1 g of 7-methyl-2-propitiatio[4,5-C]quinoline-5N-oxide (8.1 mmol) and 100 ml of dichloromethane in an atmosphere of nitrogen was added to 1.4 ml trichloroacetimidate (12.1 mmol). The obtained dark brown solution was stirred at room temperature for about 2 hours, after which the reaction mixture was concentrated in vacuo to obtain an oily N-(7-methyl-2-propitiatio[4,5-C]quinoline-4-yl)trichloroacetamide. To this oil was added methanol and 1.9 ml of 25%solution of sodium methylate in methanol (8.1 mmol) and stirred at room temperature for 1 hour. The precipitate was filtered and recrystallized twice from isopropanol. In the received 500 mg of 7-methyl-2-propitiatio[4,5-C]quinoline-4-amine as a yellow-brown powder; melting point of 186-187° C. Analysis: calculated for C14H15N3S: %S, 65,34; %N, BY 5.87; %N, 16,33. Found: %C, 64,95; %N, 5,77; %N, 16,08.

Example 46

2-Butyl-7-methoxazole[4,5-C]quinoline-4-amine

Part a

A mixture of 5 g of 3-amino-7-methyl-4-chinoline (28.7 mmol) and 28 ml Valerian anhydride (143,5 mmol) was boiled under reflux in nitrogen atmosphere for about 20 hours. After that, the mixture was cooled to room temp the atmospheric temperature, was podslushivaet 10%sodium hydroxide solution and stirred for another 1 hour, and then was extracted with dichloromethane. The extract was dried over magnesium sulfate and concentrated in vacuo to obtain a dark brown liquid. This liquid was subjected to chromatographic purification (column with silica gel as the eluent used a mixture of 3:2 ethyl acetate: dichloromethane) and the result obtained 4.7 g of a dark brown semi-solid connection. Part of this compound (700 mg) was purified on a chromatographic column filled with silica gel (eluent used a mixture of 95:5 dichloromethane: methanol). Thus purified product was a 2-butyl-7-methoxazole[4,5-C]quinoline, melting point which was 52-55° C. Analysis: calculated for C15H16N2ABOUT: %S, 74,97; %N, OF 6.71; %N, 11,66. Found: %C, 74,80; %N, 6.73 X; %N 11,53.

Part b

To a solution of 3.9 g of 2-butyl-7-methoxazole[4,5-C]quinoline (16.2 mmol) in 100 ml of chloroform was added 4.6 g of 3-chloroperbenzoic acid (57-86%solution). The mixture was stirred 4 hours at room temperature, then washed with aqueous sodium bicarbonate solution, dried over magnesium sulfate and concentrated in vacuum to obtain of 4.2 g of a dark brown-orange oil, which represents the 2-butyl-7-methoxazole [4,5-C]quinoline-5N-oxide.

The part With

The MCA is and 4.2 g of 2-butyl-7-methoxazole[4,5-C]quinoline-5N-oxide (16 mmol) and 100 ml of dichloromethane in a nitrogen atmosphere were added to 2.9 ml trichloroacetimidate (24 mmol). The mixture was stirred at room temperature for about 3 hours, then concentrated in vacuo. The resulting residue was washed with methanol and combined with a 3.7 ml of 25%solution of sodium methylate in methanol (16 mmol)and then stirred at room temperature overnight. The methanol was evaporated and the remaining residue was purified through column chromatography (silica gel; eluent a mixture of 95:5 dichloromethane:methanol). The result obtained brown solid substance. Recrystallization of this substance from acetonitrile gave 550 mg of small needle-shaped crystals, brown, representing 2-butyl-7-methoxazole[4,5-C]quinoline-4-amine; melting point 187-188° C. Analysis: calculated for C15H17N3About + 0.1 to H2O: %C, 70,07; %N, 6,74; %N, 16,34. Found: %C, 70,07; %N, Of 6.49; %N, 16,58.

Example 47

7-Methyl-2-propiconazole[4,5-C]quinoline-4-amine

Part a

A mixture of 3.4 g of 3-amino-7-methyl-4-chinoline (20 mmol) and 16 ml of butyric anhydride was heated under reflux under nitrogen atmosphere overnight. After that, the mixture was cooled to room temperature and poured into ice, and then podslushivaet to pH 12 10%sodium hydroxide solution and was extracted with dichloromethane. The extract was dried over magnesium sulfate and concentrated in vacuum. The residue after extraction still contains the al some number of source anhydride, so it was added 10%sodium hydroxide solution and stirred for 1 hour at room temperature. The mixture was again extracted with dichloromethane; the extract was dried over magnesium sulfate and concentrated in vacuo to obtain a brown oil. After purification of this oil through column chromatography (silica gel; eluent a mixture of 3:2 ethyl acetate: dichloromethane) was obtained 3.1 g of 7-methyl-2-propiconazole[4,5-C]quinoline as a light brown oil which hardened on standing; the melting temperature of 65-68° C. Analysis: calculated for C14H14N2ABOUT: %S, 74,31; %N, 6,24; %N, 12,38. Found: %C, at 73.69; %N, 6,07; %N, 12, and 15.

Part b

To a solution of 3 g of 7-methyl-2-propiconazole[4,5-C]quinoline in 100 ml of chloroform was added 3.8 g of 3-chloroperbenzoic acid (57-86%solution). The mixture was stirred at room temperature overnight, then washed twice with an aqueous solution of sodium bicarbonate, dried over magnesium sulfate and concentrated in vacuum to obtain 3.1 g of a pale-orange solid 7-methyl-2-propiconazole [4,5-C]quinoline-5N-oxide.

The part With

To a solution of 3.1 g of 7-methyl-2-propiconazole[4,5-C]quinoline-5N-oxide (12.8 mmol) in 100 ml dichloromethane under nitrogen atmosphere were added to 2.3 ml trichloroacetimidate (19.2 mmol). The mixture was stirred at room temperature for 3 hours and then concentrated in vacuum. To obrazovavshemusya orange residue was added successively with 100 ml of methanol and 2.9 ml of 25%solution of sodium methylate in methanol (12.8 mmol), then was stirred at room temperature overnight. The precipitate was filtered and recrystallized from isopropanol. In the received 450 mg of a white crystalline 7-methyl-2-propiconazole[4,5-C]quinoline-4-amine; melting point 188-189° C. Analysis: calculated for C14H15N3O + 0,2 H2ABOUT: %S, 68,66; %N, 6,34; %N, 17,16. Found: %C, 68,44; %N, 6,11; %N, 17,42.

Example 48

7-fluoro-2-propiconazole[4,5-C]quinoline-4-amine

Part a

A mixture of 50.0 g of 3-foronline (0.45 mol) and 91 ml of diethylethylenediamine (0.45 mol) was heated at 100° C in nitrogen atmosphere for 3 hours. After cooling the mixture to room temperature it was hardened. To the mixture was added 200 ml of solvent Dowtherm a And heated it under 240° C for 4 hours and then cooled to room temperature. The precipitate was filtered off, washed with hexane and dried in a vacuum drying Cabinet. He got to 71.5 g of ethyl-7-fluoro-4-hydroxy-Z-chinainternational.

Part b

A suspension of 65 g of ethyl-7-fluoro-4-hydroxy-3-chinainternational (0.28 mol) in 250 ml of 10%sodium hydroxide solution was boiled under reflux for 3 hours, the suspension turned into a solution. The resulting mixture was cooled to room temperature and filtered through filter paper in which the Aquum. The filtrate was acidified with concentrated hydrochloric acid. The precipitate was collected, washed with water and dried. He got to 53.5 g of white solid 7-fluoro-4-hydroxy-3-quinoline-carboxylic acid.

The part With

25 g of 7-fluoro-4-hydroxy-3-quinoline-carboxylic acid were placed in a round bottom flask and heated to 330-350° C. In the heating process was observed carbon dioxide gas, and the substance was liquid. After approximately 2 minutes were added 25 g of 7-fluoro-4-hydroxy-3-quinoline-carboxylic acid. Heating was continued for another 4-6 minutes, during this re-heating was not observed excretion of carbon dioxide. The solution was cooled to room temperature, the formed solid product was filtered and the result was 36,6 g solid pink 7-fluoro-4-chinoline.

Part D

To a hot solution (125° (C) 35 g of 7-fluoro-4-chinoline (214 mmol) in 200 ml of propionic acid was added 20 ml of 70%nitric acid. The mixture was stirred at 125° With about 1.5 hours and then cooled to room temperature. The obtained yellow precipitate was filtered, washed successively with water and ethanol and then recrystallized from a mixture of N,N-dimethylformamide/water. The result obtained 18 g of 7-fluoro-3-nitro-4-chinoline.

Part E.

A mixture containing 17 g of 7-fluoro-3-nitro-4-chinoline (81,7 mmol), 80 ml hydrox is Yes ammonium, 200 ml of methanol and 1 g of catalyst (10%palladium deposited on activated carbon)were loaded into a Parr apparatus and within 1 hour the reaction was performed recovery in the atmosphere of hydrogen at a pressure of 2.1 kg/cm2). Thereafter, the catalyst was filtered. The filtrate was treated with activated charcoal and then concentrated in vacuo to obtain a solid dark brown color, which made it even darker in the drying process. This product was dissolved in methanol and added to it a solution of hydrochloric acid in diethyl ether. Almost immediately formed a grey precipitate. The suspension was stirred several hours at room temperature. Then the precipitate was filtered and thoroughly washed with ether. The result obtained 6.6 g of hydrochloric acid, Z-amino-7-fluoro-4-chinoline.

Part F

A mixture of 3.4 g of hydrochloric acid 3-amino-7-fluoro-4-chinoline (19,1 mmol), to 2.9 ml of triethylamine (21,0 mmol) and 15.6 ml of butyric acid anhydride (95.5 mmol) under nitrogen atmosphere was heated under reflux for 18 hours. After that, the mixture was poured into ice and brought the pH to 12 by adding 10%sodium hydroxide solution. The resulting suspension was stirred until complete melting of the ice and then the mixture was extracted with dichloromethane. The extract was dried over magnesium sulfate and then concentrated in vacuo to obtain matloob asnago product. This oil was purified on a chromatographic column filled with silica gel, using as eluent first dichloromethane and then a mixture of 9:1 dichloromethane : methanol. The result was obtained 2.6 g of light brown solid 7-fluoro-2-propiconazole[4,5-C]quinoline.

Part G

A mixture of 2.6 g of 7-fluoro-2-propiconazole[4,5-C]quinoline (11.3 mmol), and 3.3 g of 3-chloroperbenzoic acid (57-86%aqueous solution) and 90 ml of chloroform was stirred for about 3 hours at room temperature. Analysis using the method of thin-layer chromatography showed the presence of starting material in the reaction mixture. So I added another 0.5 equivalent of 3-chloroperbenzoic acid and the mixture was additionally stirred at room temperature for 2 hours. After this thin layer chromatography showed the presence in the reaction mixture no source material. The reaction mixture was diluted with dichloromethane and washed twice with an aqueous solution of sodium bicarbonate. The organic layer was dried over magnesium sulfate and concentrated in vacuum. The result was obtained 2.8 g solid 7-fluoro-2-propiconazole[4,5-C]quinoline-5N-oxide as an orange-yellow solid oily substance.

Part N

To a solution of 2.8 g of 7-fluoro-2-propiconazole[4,5-C]quinoline-5N-oxide (11.3 mmol) in 50 ml of dichloromethane under nitrogen atmosphere was added 2.0 ml of trichloroacetimidate the Nata (17 mmol). The reaction mixture was stirred at room temperature for 3 hours, then dichloromethane drove in a vacuum. The residue was dissolved in methanol, was added to a solution of 2.4 ml of a 25%aqueous solution of sodium methylate in methanol (11.3 mmol) and stirred at room temperature overnight, then was filtered a small amount of solid product. The filtrate was concentrated in vacuum. The residue was dissolved in dichloromethane, dried over magnesium sulfate and then concentrated in vacuo to obtain a brown oil. This product was purified through column chromatography with silica gel, using as eluent a mixture of 95:5 dichloromethane : methanol. The obtained pale-brown sticky solid material was recrystallized from acetonitrile and as a result received 200 mg of 7-fluoro-2-propiconazole[4,5-C]quinoline-4-amine in the form of a rust-colored powder; melting point 184-187° C. Analysis: calculated for C13H12FN3ABOUT: %S, 63,67; %N, 4,93; %N, 17,13. Found: %C, 63,43; %N, 4,57; %N, 16,74.

Example 49

7-fluoro-2-propitiatio[4,5-C]quinoline-4-amine

Part a

To a suspension of 3 g of hydrochloric acid 3-amino-7-fluoro-4-chinoline (14.0 mmol) in 50 ml of tetrahydrofuran in a nitrogen atmosphere at room temperature was added first to 6.4 ml of triethylamine (46.2 mmol)and then dropwise 1.6 ml of acid chloride of butyric acid (to 15.4 mmol). Reaction the second mixture was stirred for 4 hours, was added thereto an aqueous solution of sodium bicarbonate and stirring continued for another 1 hour. The resulting biphasic mixture was filtered to remove solids. These solids were washed with diethyl ether and was isolated as a pale pink powder. After removal of the solvent in vacuo from tertrahydrofuran ring layer was obtained a dark pink solid product. All solid products were combined together and received from them, 3.0 g of N-(7-fluoro-4-hydroxyquinolin-3-yl)butanamide. After recrystallization from a mixture of ethyl acetate/ethanol portion of this product (300 mg) was obtained fluffy pale gray solid, melting at 306-30° C. Analysis: Calculated for C13H13FN2O2: %S, 62,90; %N, 5,28; %N, 11,28. Found: %C, 62,95; %N, 5,43; %N, 11,14.

Part b

To a mixture of 2.6 g of N-(7-fluoro-4-hydroxyquinolin-3-yl)butanamide (10.5 mmol) and 80 ml of pyridine under nitrogen atmosphere was added 4.7 g paternostro phosphorus (10.5 mmol). The mixture was boiled under reflux for 2 hours and then cooled to room temperature and was extracted with aqueous sodium bicarbonate solution and dichloromethane. The organic layer was separated, washed twice with water, dried over magnesium sulfate and concentrated in vacuum. The result has been a solid rust color, which after recrystallization from methanol gave 1.8 g of the plate crystal is 7-fluoro-2-propitiatio[4,5-C]quinoline, painted in the color of rust.

The part With

To a solution of 1.8 g of 7-fluoro-2-propitiatio[4,5-C]quinoline (7,3 mmol) in 50 ml of chloroform was added 2.1 g of 3-chloroperbenzoic acid (57-86%aqueous solution) and the mixture was stirred at room temperature. Analysis using the method of thin layer chromatography (elution on silica gel with a mixture of dichloromethane/methanol in the ratio 95:5) showed the presence of starting material in the reaction mixture, so I added another 0.5 equivalent of 3-chloroperbenzoic acid and the mixture was stirred at room temperature overnight. The reaction mixture was twice washed with an aqueous solution of sodium bicarbonate, dried over magnesium sulfate and concentrated in vacuum. The result was obtained 1.8 g of a pale-orange solid 7-fluoro-2-propitiatio[4,5-C]quinoline-5N-oxide.

Part D

To a mixture of 1.8 g of 7-fluoro-2-propitiatio[4,5-C]quinoline-5N-oxide (6,9 mmol) and 50 ml of dichloromethane under nitrogen atmosphere was added 1.2 ml trichloroacetimidate (10.4 mmol). The reaction mixture was stirred at room temperature for 2 hours, then concentrated in vacuo to obtain N-(7-fluoro-2-propitiatio[4,5-C]quinoline-4-yl)trichloroacetamide in the form of an orange oil. This oil was dissolved in methanol and added to a solution of 1.5 ml of 25%aqueous solution of sodium methylate in methanol. The reaction mixture was stirred at room is the temperature for 3 hours. The precipitate was filtered and recrystallized first from acetonitrile and then from methanol. The result was obtained 1.1 g of 7-fluoro-2-propitiatio[4,5-C]quinoline-4-amine in the form of a brownish powder; melting point 192.5 kg-of 193.5° C. Analysis: calculated for C13H12FN3S: %S, 59,75; %N, 4,63; %N, 16,08. Found: %C, 59,55; %N, 4,69; %N, 16,12.

Example 50

2-Propyl-7-(trifluoromethyl)thiazolo[4,5-C]quinoline-4-amine

Part a

A mixture of 40 ml of 3-(trifluoromethyl)aniline (0.32 mmol) and diethylethylenediamine was heated in nitrogen atmosphere at 100° C for 3 hours. After cooling to room temperature the solution became solid and was obtained 102 g of solid diethyl-2-{[3-(trifluoromethyl)aniline]methylene}malonate painted in cream color.

Part b

A mixture of 80 g of 2-{[3-(trifluoromethyl)aniline]methylene}malonate (0.24 mol) and solvent And Dowtherm heated in nitrogen atmosphere up to 240° and was stirred for 3 hours. Then the reaction mixture was cooled to room temperature and stirring continued for 16 hours. The solid products were separated from solution by filtration and washed with hexane. The result of 47.5 g of solid ethyl-4-hydroxy-7-(trifluoromethyl)-3-chinainternational yellowish-white in color.

The part With

A mixture of 43.4 g of ethyl-4-hydroxy-7-(cryptomite is)-3-chinainternational (0,521 mol) and 150 ml of 10%sodium hydroxide solution was heated to boiling under reflux. To facilitate dissolution of the ether to the mixture over one hour was added 150 ml of methanol. After boiling for 2 hours got the homogeneous solution. This solution was heated for another 2 hours and then left overnight to cool to room temperature. Methanol drove under reduced pressure and the remaining aqueous solution was acidified with concentrated hydrochloric acid. The precipitate was filtered, washed with water and then dried in a vacuum drying Cabinet at 120° C for 24 hours. The result of 38.5 g of solid 4-hydroxy-7-(trifluoromethyl)-3-quinoline-carboxylic acid white color.

Part D

to 34.1 g of 4-hydroxy-7-(trifluoromethyl)-3-quinoline-carboxylic acid (0,132 mol) were placed in a round bottom flask. Then the flask was heated in a bath of molten alloy wood within 5 minutes; in the process of heating was observed carbon dioxide emissions and the melting of the solid product. After 5 minutes, the carbon dioxide evolution ceased, therefore, the flask was removed from the heating bath and cooled to room temperature. Was filtered, the resulting solid product, representing 27,75 g 7-(trifluoromethyl)-4-chinoline.

Part E.

A mixture of 22.7 g of 7-(tryptomer)-4-chinoline (0,106 mol) and 106 ml of propionic acid was heated to 120° C, was added dropwise 10 ml of 70%nitric acid and heating etc which was continued for another 2 hours. The reaction mixture was cooled to room temperature, the precipitate was filtered and washed with water and diethyl ether. The result was obtained 13.3 g of solid 3-nitro-7-(trifluoromethyl)-4-chinoline yellowish-white in color.

Part F

In a Parr apparatus was loaded with 40 ml of methanol, 10 ml of ammonium hydroxide, 12.8 g of 3-nitro-7-(trifluoromethyl)-4-chinoline (49,6 mmol), 1 g of palladium catalyst (10% palladium deposited on activated carbon) and within 4 hours spent reaction recovery apparatus Parra in the atmosphere of hydrogen at a hydrogen pressure of 2.8 kg/cm2. Upon completion of the reduction reaction of the mixture was filtered and the catalyst washed with methanol and dichloromethane. Combined organic solutions were concentrated in vacuo and the result has been a solid green color. This product was dissolved in methanol and was added 150 ml of 1 N hydrochloric acid in anhydrous diethyl ether. Immediately after addition of the acid was observed in the sediment. The reaction mixture was stirred for 16 hours, the precipitate was filtered off, washed with diethyl ether and then dried in a vacuum drying Cabinet at 80° C. the result was obtained 9.3 g of solid hydrochloric acid 3-amino-7-(trifluoromethyl)-4-chinoline yellowish-white in color.

Part G

To a mixture of 3.5 g of hydrochloric acid 3-nitro-7-(reformer)-4-chinoline (13,2 mmol), of 6.1 ml of triethylamine (43,6 mmol) and 30 ml of anhydrous tetrahydrofuran was added dropwise 1.5 ml of acid chloride of butyric acid (14.5 mmol) and the mixture was stirred for 16 hours. After this was added a small amount of aqueous sodium bicarbonate solution and stirring was continued for another 0.5 hour. Tetrahydrofuran drove in vacuo, the remaining solid product was stirred with diethyl ether, then filtered off, washed with water and diethyl ether and during the night was dried in a vacuum drying Cabinet at 80° C. resulted In a 3.3 g of solid N-[4-hydroxy-7-(trifluoromethyl)quinoline-3-yl]butanamide painted in cream color.

Part N

A mixture of 3.0 g of N-[4-hydroxy-7-(trifluoromethyl)quinoline-3-yl]butanamide (10.05 mmol), 4.5 g paternostro phosphorus (10.05 mmol) and 30 ml of pyridine was heated under reflux for 6 hours, after which the solution was cooled to room temperature and diluted with dichloromethane and aqueous sodium bicarbonate solution. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and concentrated in vacuo to obtain a yellow solid product. This product was treated with hexane and after filtration was obtained 1.7 g of solid 2-propyl-7-(trifluoromethyl)thiazolo[4,5-C]quinoline, painted in brown color. From the hexane filtrate after evaporation RA is the God received another 0.6 g of yellow solid product.

Part I

To a mixture of 2.0 g of 2-propyl-7-(trifluoromethyl)thiazolo[4,5-C]quinoline (of 6.75 mmol) and 30 ml of chloroform was added 1,93 g of 3-chloroperbenzoic acid (6,88 mmol) and the resulting solution was stirred for 24 hours. Then the reaction mixture was diluted with aqueous sodium bicarbonate solution and was extracted with dichloromethane. The organic layer was separated, dried over magnesium sulfate and concentrated in vacuum. The result was 1.98 g yellow solid 2-propyl-7-(trifluoromethyl)thiazolo[4,5-C]quinoline-5N-oxide.

Part J

To a mixture of 1.3 g of 2-propyl-7-(trifluoromethyl)thiazolo[4,5-C]quinoline-5N-oxide (4,16 mmol) and 20 ml of anhydrous dichloromethane in a nitrogen atmosphere was added 0.75 ml trichloroacetimidate (6,24 mmol) and stirred the reaction mixture at room temperature for 16 hours, after which the solvent was removed under reduced pressure. The residue was dissolved in 40 ml of methanol and added to a solution of 1.43 ml of 25%solution of sodium methylate (6,24 mmol) in methanol. The reaction mixture was stirred at room temperature for 16 hours. The precipitate was filtered off, washed with a small amount of methanol and dried for 16 hours in a vacuum drying Cabinet at 80° C. the result obtained 0.96 g of white solid 2-propyl-7-(trifluoromethyl)thiazolo[4,5-C]quinoline-4-amine; melting point 215-216° C. Analysis: calculated the La 14H12F3N3S: %S, 54,01; %N, 3,89; %N, 13,50. Found: %C, 53,82; %N, 3,66; %N, 13,37.

Example 51

2-(Methylsulphonyl)thiazolo[4,5-C]quinoline-5N-oxide

Part a

To 5,4 g of N4-(2-methylpropyl " quinoline-3,4-diamine (25 mmol) was added to 9 ml of carbon disulfide (150 mmol) and 55 ml of ethanol and the mixture on the steam bath was heated under reflux for 2 hours. The precipitate was filtered off, washed with ethanol and dried in the air. The result was obtained 4.4 g of the crude product. 1 g of this product was dissolved in hot sodium hydroxide solution and then besieged acetic acid. The precipitate was filtered while hot, washed with hexane and after air drying has been solid thiazolo[4,5-C]quinoline-2-thiol; melting point 282-284° C. Analysis: calculated for C10H6N2S2: %S, 55,02; %N, 2,77; %N 12,83. Found: %C, 54,96; %N, 2,69; %N, 12,74.

Part b

To a solution 13,65 g thiazolo[4,5-C]quinoline-2-thiol (63 mmol) in 160 ml of methanol was added to 15.8 ml of 25%solution of sodium methylate (69 mmol) in methanol and 3.9 ml iodotope bromide (63 mmol). The mixture was heated on the steam bath for 1 hour, after which the solvent is kept in vacuum. The remaining bright greenish-yellow solid was mixed with water, was filtered and washed with water. The result of 9.8 g neocidin is on the product. After recrystallization of 1 g of this product from methanol obtained 2-(methylthio)thiazolo[4,5-C]quinoline having a melting point of 116 to 119° C. Analysis: calculated for C11H8N2S2: %S, 56,87; %N, 3,47; %N, 12,06. Found: %C, 57,09; %N, 3,57; %N, 12,04.

The part With

To a mixture of 7.7 g of 2-(methylthio)thiazolo[4,5-C]quinoline (33 mmol) and 100 ml of acetic acid was added 27.8 ml of 32%peracetic acid (132 mmol), the mixture was heated for 4 hours at 60° and then during the night kept at room temperature. The precipitate was filtered and obtained 5.6 g of the crude product. The filtrate was concentrated in vacuo and the residue was diluted with 100 ml of toluene. After removal of the toluene in vacuo received an additional 4 g of the crude product. 1 g of this product was recrystallized from N,N-dimethylformamide and the result has been solid 2-(methylsulphonyl)thiazolo[4,5-C]quinoline-5N-oxide, painted yellow; melting point 245-247° C. Analysis: calculated for C11H8N2About3S2: %S, 47,13; %N, 2,88; %N, 9,99. Found: %C, 47,08; %N, Is 3.08; %N, 10,14.

Example 52

2-(4-Morpholino)thiazolo[4,5-C]quinoline-5N-oxide

A mixture of 2.5 g of 2-(methylsulphonyl)thiazolo[4,5-C]quinoline-5N-oxide (8.9 mmol) and approximately 50 ml of the research was heated on the steam bath for 9 hours. The resulting OS the dock was filtered and obtained 0.9 g yellow solid crude product. The filtrate was cooled in an ice bath. The result was obtained 0.8 g of yellow solid crude product. These solid products were combined together and a small portion of this material (0.5 g) was recrystallized from methanol. The result is a solid 2-(4-morpholino)thiazolo[4,5-C]quinoline-5N-oxide, having a melting point 241-242° C. Analysis: calculated for C14H13N4About2S: %S, 58,52; %N, 4,56; %N, 14,62. Found: %C, 58,24; %N, To 4.38; %N, 14,43.

Example 53

2-(4-Morpholino)thiazolo[4,5-C]quinoline-4-amine

To a mixture of 1.2 g of 2-(4-morpholino)thiazolo[4,5-C]quinoline-5N-oxide (4.2 mmol) and 24 ml of dichloromethane was added 18 ml of ammonium hydroxide. The mixture was cooled and slowly added to it a solution of 0.88 g of tosylchloramide (4.6 mmol) in 10 ml of dichloromethane. After that, the mixture was heated to room temperature and was stirred overnight. The organic phase was separated, washed with aqueous sodium bicarbonate solution, dried over magnesium sulfate and concentrated in vacuo to obtain a yellow solid product. This product was purified through column chromatography, and then was dissolved in hydrochloric acid and perioadele sodium hydroxide. The precipitate was filtered and was perioadele from methanol. The result was obtained 0.26 g of solid 2-(4-morpholino)thiazolo[4,5-C]quinoline-4-amine, melting point of which is accounted for 225-227° C. Analysis: calculated for C14H14N4OS: %C, 58,72; %N, 4,93; %N, 19,57. Found: %C, 58,47; %N, 4,63; %N, 19,23.

Example 54

2-(1-Pyrrolidino)thiazolo[4,5-C]quinoline-4-amine

Part a

A mixture of 2.5 g of 2-(methylsulphonyl)thiazolo[4,5-C]quinoline-5N-oxide (8.9 mmol) and approximately 70 ml of pyrrolidine boiled under reflux on a steam bath for 3 days. The resulting yellow precipitate was filtered and was obtained 0.4 g of 2-(4-pyrrolidino)thiazolo[4,5-C]quinoline-5N-oxide. The filtrate was cooled in an ice bath. The resulting precipitate was filtered. The result was obtained 0.7 g yellow solid 2-(1-pyrrolidino)thiazolo[4,5-C]quinoline-5N-oxide. These products were combined together.

Part b

To a mixture of 0.8 g of 2-(1-pyrrolidino)thiazolo[4,5-C]quinoline-5N-oxide (2,95 mmol) and 50 ml of dichloromethane was added 12 ml of ammonium hydroxide. The mixture was cooled and slowly added to it a solution of 0.6 g of tosylchloramide (3.2 mmol) in 10 ml of dichloromethane. After that, the mixture was heated to room temperature and was stirred overnight. The organic phase was separated, washed with aqueous sodium bicarbonate solution, dried over magnesium sulfate and concentrated in vacuo to obtain a yellow solid crude product. This product was purified by way of flash chromatography, then mixed with hot methanol, cooled and outfilter ivali. The result was obtained 0.14 g of solid 2-(1-pyrrolidino)thiazolo[4,5-C]quinoline-4-amine; melting point 259-261° C. Analysis: calculated for C14H14N4S: %S, 62,20; %N, 5,22; %N, 20,49. Found: %C, 61,76; %N, 5,25; %N, 20,72.

Example 55

Xinafoate 2-propitiatio[4,5-C]quinoline-4-amine

3.0 g of 2-propitiatio[4,5-C]quinoline-4-amine (12.3 mmol) and 2.3 g of 1-hydroxy-2-naphthoic acid (12.3 mmol) were separately dissolved in methanol, optionally using additives dichloromethane. These two solutions were combined together, and the resulting solution was evaporated to reduce the volume. The precipitate was filtered. The result was obtained 3.6 g of colorless crystalline xinafoate 2-propitiatio[4,5-C]quinoline-4-amine; melting point of this product 185-189° C (decomposition). Analysis: calculated for C24H21N3About3S: %S, 66,80; %N, 4,91; %N, 9,74. Found: %C, 66,18; %N, 5,07; %N, 9,78.

Example 56

3-Hydroxy-2-aftout 2-propitiatio[4,5-C]quinoline-4-amine

A solution of 1.9 g of 3-hydroxy-2-naphthoic acid (10 mmol) in 30 ml of methanol was added to a solution of 2.4 g of 2-propitiatio[4,5-C]quinoline-4-amine (10 mmol) in 70 ml of hot methanol. Immediately upon addition of the formed precipitate. The mixture was heated for another 5 minutes and then cooled to room temperature. The sediment on filytrovali, washed with methanol and dried. The result was obtained 4.0 g of brown powder. This product was recrystallized from methanol/dichloromethane and obtained 3.2 g of white powdery Z-hydroxy-2-naphthoate 2-propitiatio[4,5-C]quinoline-4-amine. Analysis: calculated for C24H21N3About3S: %S, 66,80; %N, 4,91; %N, 9,74. Found: %C, 66,28; %N, 4,92; %N, 9,59.

Example 57

2-Butylthiazole[4,5-C][1,5]naphthiridine-5N-oxide

Part a

A mixture containing 7.5 g of 3-nitro[1,5]naphthiridine-4-ol, 200 ml of methanol, 50 ml of ammonium hydroxide and 0.75 g of platinum catalyst (5% platinum deposited on charcoal), kept in the Parr apparatus for 6 hours. After the reaction mixture was filtered to remove the catalyst, and then again filtered through a filter lite® . The filtrate was concentrated in vacuum and the result was of 6.1 g of brown solid 3-amino[1,5]naphthiridine-4-ol.

Part b

To a suspension of 5.2 g of 3-amino[1,5]naphthiridine-4-ol (32 mmol) in 100 ml of pyridine was added dropwise 4.3 g of acid chloride of valerianic acid (35 mmol) and the mixture is boiled under reflux for 2 hours. The pyridine was removed. The residue was washed with hot water and then cooled. The resulting gray precipitate was filtered, thoroughly washed with hot water and dried in a drying Cabinet. The result p is obtained 2.3 g of solid N-(4-hydroxy[1,5]naphthiridine-3-yl)pentamid gray.

The part With

To a suspension of 2.3 g of N-(4-hydroxy[1,5]naphthiridine-3-yl)pentamine (9.4 mmol) in 150 ml of pyridine was added to 4.2 g paternostro phosphorus (9.4 mmol). The mixture was boiled under reflux for 2 hours. The pyridine was removed. The residue was washed with a mixture of water, 10%sodium carbonate solution and 10%aqueous sodium hydroxide solution (in an amount sufficient to provide a pH of the mixture over 8) and then was extracted twice with dichloromethane. The dichloromethane extracts were combined together, washed with brine, dried and concentrated in vacuum. The residue was diluted with toluene and then concentrated in vacuum. The result was obtained 2 g of black sticky substance. This material was purified on a chromatographic column filled with silica gel, and the result was obtained 1.4 g of 2-butylthiazole[4,5-C][1,5]naphthiridine in the form of amber liquid. The analysis method of mass spectrometry high resolution (EI): calculated for C13H13N3S (M+) 243,0830. Found 243,0825.

Part D

To a solution of 1.4 g of 2-butylthiazole[4,5-C][1,5]naphthiridine (5.8 mmol) in 100 ml of chloroform was added 1.1 g of 3-chloroperbenzoic acid (57-86%aqueous solution) in 50 ml of chloroform. The mixture was stirred at room temperature for 2.5 hours and then diluted it dichloromethane, twice washed with 10%sodium hydroxide solution, washed with brine, who left the house taking and concentrated in vacuum to obtain a light yellow syrup-like substance, which hardened on standing. After purification of this substance on a chromatographic column with silica gel obtained 1.2 g of a pale-yellow solid product. Recrystallization of this material from a mixture of petroleum ether (15 ml) and hexanol (100 ml) allowed to obtain 2-butylthiazole[4,5-C][1,5]naphthiridine-5N-oxide, melting point which was 65-69° C. Analysis: calculated for C13H13N3OS: %C, 60,21; %N, OF 5.05; %N, 16,20. Found: %C, 60,43; %N, 5,17; %N, 16,18. The analysis method of mass spectrometry high resolution (EI): calculated for C13H13N3OS (M+) 259,0779. Found 259,0789.

Example 58

2-Butylthiazole[4,5-C][ 1,5]naphthiridine-4-amine

A solution of 0.5 g of 2-butylthiazole[4,5-C][1,5]naphthiridine-5N-oxide (1.9 mmol) in 100 ml dichloromethane was cooled in an ice bath and was added dropwise thereto a solution of 0.4 g trichloroacetimidate (2.1 mmol) in 25 ml dichloromethane. The mixture was stirred for 8 hours at room temperature and then was added a solution of ammonia in methanol in an amount such that the mixture had an alkaline reaction, and then kept her in for the night. After that, the mixture was diluted with more dichloromethane, twice washed with 10%sodium hydroxide solution, once with brine, dried and concentrated in vacuum to obtain 0.6 g of pale yellow solid. This product was purified normalisations column with silica gel and then recrystallized from acetonitrile (8 ml). The result was obtained 0.15 g of white crystalline 2-butylthiazole[4,5-C] [1,5]naphthiridine-4-amine, melting point which was 136-138° C. Analysis: calculated for C13H14N4S: %S, 60,44; %N, 5,46; %N, 21,69. Found: %C, 60,12; %N, 5,42; %N, 21,51. Mass spectrometry high resolution (EI): calculated for C13H13N4S (M+) 258,0941. Found 258,0939. The signals in the NMR spectrum in Dl3(ppm): 8,637 (DD) (1H, J=3,6; 1.2 Hz), 8,048 DD (1H, J=8,5; 1.2 Hz), 7,486 DD (1H, J=8,5; and 3.6 Hz), 5,691 ussingle (2N), 3,196 t (2N, J=7 Hz), 1,918 quintet (2H, J=7 Hz), 1,509 sextet (2H, J=7 Hz), 1,003 tons (3H, J=7 Hz).

Example 59

2-Propitiatio[4,5-C][1,5]naphthiridine-5N-oxide

Part a

Using the methodology described in part b of example 57, 1.8 g of 3-amino[1,5]naphthiridine-4-ol in (11.2 mmol) was treated with 1.3 g of acid chloride of butyric acid (12.3 mmol), which was obtained 1.2 g of N-(4-hydroxy[1,5]naphthiridine-3-yl)butanamide in a gray carbon powder, melting point exceeding 360° C.

Part b

The reaction between 1.2 g of N-(4-hydroxy[1,5]naphthiridine-3-yl)butanamide (5.2 mmol) and 2.3 g paternostro phosphorus (5.2 mmol) was performed according to methodology described in part C of example 57. The result was obtained 0.9 g of 2-propitiatio[4,5-C][1,5]naphthiridine in the form of syrup amber color.

The part With

Oxidation of 0.9 g of 2-propitiatio[4,5-C][1,5]naphthiridine about what the Odile according to the method listed in part D of example 57; as a result, there was obtained 0.7 g of solid pale yellow 2-propitiatio[4,5-C][1,5]naphthiridine-5N-oxide, melting point which was 139-142° C. Analysis: calculated for C12H11N3OS: %C, 58,76; %N, TO 4.52; %N, 17,13. Found: %C, 58,66; %N, 4,59; %N, 17,16. Mass spectrometry high resolution (EI): Calculated for C12H11N3OS (M+) 245,0623. Found 245,0612.

Example 60

2-Propitiatio[4,5-C][1,5]naphthiridine-4-amine

Using the General methodology described in example 58, 0.5 g of 2-propitiatio[4,5-C][1,5]naphthiridine-5N-oxide (2 mmol) was minirovali to 2-propitiatio[4,5-C][1,5]naphthiridine-4-amine. The yield of the target product, representing needle crystals ivory was 0.2 g, melting point 135-136° C. Analysis: calculated for C12H12N4S: %S, 58,99; %N, 4,95; %N, 22,93. Found: %C, 59,06; %N, 4,96; %N, 22,97. Mass spectrometry high resolution (EI): calculated for C12H12N4S (M+) 244,0783. Found 244,0785.

Example 61

2 Profileid[3,4-d][1,3]thiazole-5N-oxide

Part a

A suspension of 1.0 g of 3-nitropyridine-4-ol (7.1 mmol) in 110 ml of methanol and a small amount is used as a catalyst of Raney Nickel were loaded into a Parr apparatus and was subjected to hydrogenation for 4 hours the Reaction mixture was acidified with a solution of hydrochloric acid in ethanol and then filtered to remove the catalyst. The filtrate is again passed through the filter lite® and then concentrated in vacuo to obtain 1.2 g of a brown powder of 3-aminopyridine-4-ol. The melting point of the obtained alcohol 199-200° C.

Part b

To a suspension of 8.5 g of 3-aminopyridine-4-ol (46 mmol) in 100 ml dichloromethane was added first 33 ml of N,N-diisopropylethylamine (180 mmol)and then dropwise a solution of 5.4 g of acid chloride of butyric acid (51 mmol) in 100 ml of dichloromethane. The reaction mixture was stirred 3 hours at room temperature, then boiled under reflux for 3 hours. After that, the mixture was filtered to remove a black precipitate, and the filtrate was concentrated in vacuum. Light brown residue was treated with 250 ml of hot ethyl acetate and then left to cool over night. The mixture was filtered to remove the formed solid product (9.1 g) and these products were washed with fresh ethyl acetate. The filtrate was concentrated in vacuo, resulting in received 13 g of a light amber syrup. This syrup was dissolved in water and was extracted twice with ethyl acetate. The extracts were combined together, washed with brine, dried and concentrated in vacuum to obtain 2.5 g of an amber syrup-like product. After purification through column chromatography was obtained 1.2 g of a light amber syrup-like N-(4-gidroksipinan-3-yl)butane is Yes, which became solid on standing.

The part With

Using the methodology described in part C of example 57, 1.1 g of N-(4-gidroksipinan-3-yl)butanamide (6.1 mmol) was treated with 2.7 g paternostro phosphorus (6.1 mmol) and was obtained 0.4 g of 2-propylpyridine[3,4-d1][1,3]thiazole in the form of an amber syrup, which became solid on standing. Melting point 44-47° C.

Part D

Using the methodology described in part D of example 57, 0.4 g of 2-propylpyridine[3,4-d][1,3]thiazole (2.2 mmol) was oxidized to 2-propylpyridine[3,4-d1][1,3]thiazole-5N-oxide (0.2 g), which after recrystallization from ethyl acetate (7 ml) was kind of short needle-shaped crystals, ivory, melting point which was 137-139° C. Analysis: calculated for C9H10N2OS: %C, 55,65; %N, 5,19; %N, 14,42. Found: %C, 55,47; %N, 5,25; %N, 14,34.

Example 62

Triptorelin 2 profileid[3,4-d][1,3]thiazole-4-amine

A solution of 0.11 g trichloroacetimidate (0.6 mmol) in 5 ml of dichloromethane was added dropwise to cooled in an ice bath to a solution of 0.1 g of 2-propylpyridine[3,4-d][1,3]thiazole-5N-oxide (0.5 mmol) in 20 ml of dichloromethane. The reaction mixture was stirred at room temperature for 5 hours, after which was added 0.2 g trichlorotriazine and stirring at room temperature was continued overnight. Then the reaction mixture n is gravely to the boil under reflux, kept for a short time at this temperature and then was stirred at room temperature for another 3 hours. Through the mixture for 1 hour at room temperature was barbotirovany ammonia, and then the mixture was diluted with dichloromethane, twice washed with 10%sodium hydroxide solution and once with brine, dried and concentrated in vacuo to obtain a syrup-like product amber color. The reaction was repeated one more time. The reaction products were combined together, they received a total of 0.1 g of an amber syrup-like substance. This material was purified using the method prepreparation liquid chromatography system equipment Gilson (column Rainin C18 Microsobr, 21,4× 250 mm, particle size 8 μm, pore size 60A, the feed rate of solution 10 ml/min, gradient elution from 2 to 95% b for 5 min, where A=0.1%solution triperoxonane acid in water and B=0.1%solution triperoxonane acid in acetonitrile, detection of fractions by absorption at 254 nm). Resulting from this prepreparation method of dividing fractions were analyzed by way of line with an-ART/MS and the appropriate fractions were freeze-dried to obtain the target product as a salt triperoxonane acid; melting point 160-162° C. Analysis: calculated for C9H11N4S + CF3COOH: %S, 42,99; %N, 3,94; %N, 13,67. Found: %C, 4284; %N, 3,98; %N, 13,52. Mass spectrometry high resolution (EI): calculated for C9H11N4S (M+) 193,0674. Found 193, 0681.

Example 63

7-Chloro-2-propitiatio[4,5-C]quinoline-4-amine

Part a

A mixture of 35 g of 7-chloro-4-hydroxyquinoline solution (of € 0.195 mol; product ldrich, Milwaukee, Wisconsin) and 350 ml of 70%nitric acid was boiled under reflux for 75 min, after which the hot reaction mixture was poured into ice. The resulting bright yellow precipitate was filtered and three times washed with boiling ethyl acetate. The result is a 17.3 g of solid pale yellow 7-chloro-3-nitro-4-hydroxyquinoline solution.

Part b

The mixture 4,48 g of 7-chloro-3-nitro-4-hydroxyquinoline solution (20 mmol), and 22.6 g of dihydrate tin chloride (II) (100 mmol) and 200 ml of ethanol was boiled under reflux for 4 hours, then cooled to room temperature and poured into 250 ml of water. Using a saturated solution of sodium bicarbonate the pH of the mixture was brought to neutral values, and then the mixture was filtered to remove salt of tin. The filtrate was extracted with ethyl acetate; the combined organic fractions were dried over magnesium sulfate, filtered and then concentrated in vacuo to obtain 1.8 g of green powder 3-amino-7-chloro-4-hydroxyquinoline solution.

The part With

0,76 ml of acid chloride of butyric acid (7.3 m is ol) under nitrogen atmosphere was added dropwise to a mixture of 1.3 g of 3-amino-7-chloro-4-hydroxyquinoline solution (6.7 mmol), 3.0 ml of triethylamine (21.5 mmol) and 20 ml of anhydrous tetrahydrofuran. The reaction mixture was stirred at room temperature overnight, the precipitate was filtered, washed first with water and then with tetrahydrofuran, and then dried in vacuum. The result of this treatment was received of 1.05 g of a brown powder of N-(7-chloro-4-hydroxyquinolin-3-yl)butanamide.

Part D

A mixture of 0.9 g of N-(7-chloro-4-hydroxyquinolin-3-yl)butanamide (3.4 mmol), 1.51 g paternostro phosphorus (3.4 mmol) and 25 ml of pyridine was heated under reflux for 2.5 hours under nitrogen atmosphere, then cooled to room temperature. The reaction mixture was stirred with 100 ml dichloromethane and 100 ml saturated sodium bicarbonate solution, when this happened the distribution of the reaction mixture between organic and aqueous phases. The aqueous layer was extracted with two portions of dichloromethane, 100 ml each. The organic fractions were combined together, washed with water, dried over magnesium sulfate, filtered and then concentrated in vacuo to obtain the crude reaction product. This material was purified on a chromatographic column with silica gel (eluent used a mixture of 97:3 dichloromethane:methanol; the amount of silica gel 10 g) and as a result got to 0.62 g of 7-chloro-2-propitiatio[4,5-C]quinoline in the form of a Golden yellow solid fuel is Dogo substances.

Part E.

In the atmosphere of nitrogen 0.7 g of 3-chloroperoxybenzoic acid (57-86%aqueous solution) was added to a mixture of 0.5 g of 7-chloro-2-propitiatio[4,5-C]quinoline (1.9 mmol) and 20 ml of chloroform. After 2 hours of incubation of this mixture at room temperature, thereto was added 0.2 g of 3-chloroperbenzoic acid and the mixture was stirred at room temperature for another 14 hours. After the reaction mixture was diluted with dichloromethane and washed twice with a saturated solution of sodium bicarbonate. The organic fraction was dried over magnesium sulfate, filtered and concentrated in vacuo to obtain 0.52 g of solid orange 7-chloro-2-propitiatio[4,5-C]quinoline-5N-oxide.

Part F

To a mixture of 0.50 g of 7-chloro-2-propitiatio[4,5-C]quinoline-5N-oxide (1.8 mmol) and 20 ml of dichloromethane under nitrogen atmosphere was added 0,32 ml trichloroacetimidate (2.7 mmol), the mixture was stirred at room temperature for 2 hours, then concentrated in vacuo. The obtained oily residue was dissolved in 10 ml of methanol was added 1 ml of 25%solution of sodium methylate (4.4 mmol) and the mixture was stirred at room temperature for 2.5 days. The precipitate was filtered and washed with hexane. The result was obtained 0.28 g of the desired product in the form of a Golden yellow powder. 50 mg of this product was recrystallized from methanol and received twardy-chloro-2-propitiatio[4,5-C]quinoline-4-amine Golden yellow color; melting point 159-160° C. Data1H NMR (300 MHz, DMSO-d6): δ of 7.82 (d,J=8,5; Hz, 1H), 7,60 (d,J=2.0 Hz, 1H), 7,27 (DD,J=8,5; and 2.1 Hz, 1H), 7,10 (s, 2H), and 3.16 (t, J=7.4 Hz, 2H), 1,87 (sextet, J=7.4 Hz, 2H), of 1.02 (t, J=7.4 Hz, 3H). MS (EI) m/e 277,0441 (277,0440 calculated for C13H12lN3S).

Example 64

7-Methoxy-2-propitiatio[4,5-C]quinoline-4-amine

Part a

A mixture of 12.3 g of 3-methoxyaniline (0.1 mol) and 21.6 g of diethylethoxymethylenemalonate (0.1 mol) was heated at 120° C for 3 hours, then cooled to room temperature and kept in vacuum during the night. The result of 28.5 g of diethyl-2-[3-(methoxyaniline)methylene]malonate in the form of an orange oil.

Part b

In a flask equipped with a magnetic stirrer, inlet for input of nitrogen trap Dean-stark and reflux condenser, was filled with approximately 200 ml of solvent Dowtherm A. the Solvent was heated to intense boiling and added to 20.0 g of 2-[3-(methoxyaniline)methylene]malonate (68 mmol). The mixture was heated for 0.5 hour, after which the obtained brown solution was cooled to room temperature. The precipitate was filtered, washed with acetone and dried in the air. The result was obtained 12.5 g of ethyl-4-hydroxy-7-methoxyquinoline-3-carboxylate as a yellow powder.

The part With

A suspension of 12.0 g these is-4-hydroxy-7-methoxyquinoline-3-carboxylate (48 mmol) in 200 ml of 10%aqueous sodium hydroxide solution was boiled under reflux for 1.5 hours. Then the reaction mixture was cooled to room temperature and brought the pH value of the mixture to 3 by adding dropwise concentrated hydrochloric acid. The obtained precipitate was filtered, washed twice with water and dried overnight in a vacuum drying Cabinet at 80° C. Obtained 10.4 g of 4-hydroxy-7-methoxyquinoline-3-carboxylic acid.

Part D

A suspension of 4.0 g of 4-hydroxy-7-methoxyquinoline-3-carboxylic acid in 75 ml of Dowtherm And boiled under reflux for 2 hours. The obtained brown solution was slowly cooled to room temperature. The precipitate was filtered and dried in a vacuum drying Cabinet at 80° C for 2.5 days. The result was obtained 3.1 g of a solid light brown 7-methoxyquinoline-4-ol.

Part E.

A mixture of 5.0 g of 7-methoxyquinoline-4-ol (28.5 mmol) and 50 ml of propionic acid was heated to boiling under reflux, then for 15 min was added dropwise thereto with 3.2 ml of 70%nitric acid (50 mmol) and the mixture is boiled under reflux for 2 hours, then cooled to room temperature. The precipitate was filtered, washed first with cold ethanol and then hexane and dried. The result of 3.9 g of solid gray 7-methoxy-3-nitroanilin-4-ol.

Part F

A mixture of 4.5 g of 7-methoxy-3-nitroanilin-4-ol (from 20.4 mmol), 250 ml of m is of canola, 5 ml of ammonium hydroxide and 400 mg of palladium catalyst (10% palladium deposited on activated carbon) were loaded into a Parr apparatus and carried out the hydrogenation in a hydrogen atmosphere (hydrogen pressure of 2.8 kg/cm2within 2 hours. After the reaction mixture was filtered. The filtrate was concentrated in vacuo to obtain a solid green color. This product was dissolved in 20 ml of methanol and to the solution was added 75 ml of 1 N hydrochloric acid in diethyl ether. The precipitate was filtered and dried. The result was obtained 2.6 g of solid hydrochloric acid 3-amino-7-methoxyquinoline-4-ol pink color.

Part G

To a solution containing 1.0 g of hydrochloric acid 3-amino-7-methoxyquinoline-4-ol (5,26 mmol), 2.35 ml of triethylamine (16,8 mmol), 30 ml of dichloromethane and 10 ml of N,N-dimethylformamide was added dropwise 0.63 ml of acid chloride of butyric acid (6.1 mmol). The mixture was stirred over night at room temperature, after which the N,N-dimethylformamide drove in vacuum and the remaining solid substance was distributed between 100 ml of dichloromethane and 100 ml of water. The organic fraction was washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo to obtain 0,86 g of N-(4-hydroxy-7-methoxyquinoline-3-yl)butanamide in a solid brown color.

Part N

A mixture of 0.66 g of N-(4-hydroxy-7-amoxicillin-3-yl)butanamide (2.54 mmol), 20 ml of pyridine and 1.13 g paternostro phosphorus (2.54 mmol) was boiled under reflux in a nitrogen atmosphere and then cooled to room temperature. The mixture was filtered and the filtrate was distributed between 100 ml of dichloromethane and 100 ml of saturated aqueous sodium bicarbonate solution. The aqueous fraction was extracted with 100 ml dichloromethane. The organic fractions were combined together, washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo to obtain a solid product. This product was purified on a chromatographic column filled with silica gel (15 g SiO2as the eluent used a mixture of 95:5 dichloromethane:methanol) and obtained 0.45 g of 7-methoxy-2-propitiatio[4,5-C]quinoline as a pale yellow powder.

Part I

Using the method described in part E of example 63, was oxidized 0.40 g of 7-methoxy-2-propitiatio[4,5-C]quinoline (1.55 mmol) to 7-methoxy-2-propitiatio[4,5-C]quinoline-5N-oxide, which are solid orange product.

Part J

Using the method described in part F of example 63 N-oxide obtained in part I of this example was treated trichlorotriazine and the resulting amide was subjected to hydrolysis. The result was obtained 190 mg target yellowish-white solid product. When recrystallization of this product from methanol obtained 7-methoxy-2-properties what about[4,5-C]quinoline-4-amine in the form of yellowish-white needle-shaped crystals; melting point 152-154° C. Data1H NMR spectroscopy (300 MHz, DMSO-d6): δ to 7.67 (d, J=8.7 Hz, 1H), 7,06 (d, J=2.4 Hz, 1H), 6,91 (DD, J=8,7; 2,5 Hz, 1H), PC 6.82 (s, 2H), 3,86 (s, 3H), 3,11 (t, J=7.4 Hz, 2H), 1,85 (sextet, J=7.4 Hz, 2H), 1,01 (t, J=7.4 Hz, 3H). MS (EI) m/e 273,0934 (273,0936 calculated for C14H15N3OS).

The STIMULATION of the synthesis of INTERFERON (α ) IN HUMAN CELLS

To assess the stimulation of interferon synthesis of the compounds described in this invention, used a system of human blood cells in vitro. Activity was determined based on the number of interferon secreted in the medium of culture. The number of interferon was determined by evaluating the bioactivity of the sample.

Preparation of culture on the basis of blood cells

Whole blood was collected by venipuncture in special vials containing EDTA. Mononuclear cells from peripheral blood (RWM) was separated from whole blood using the system LeucoPREPTM(obtained from Becton Dickinson) or with a solution of Ficoll-Paque® (obtained from the company Pharmacia LKB Biotechnology Inc.,, Piscataway, new Jersey). RWM in number 1· 106cells/ml suspended in RPMI medium 1640 (obtained from the company GIBC(OH), Grand island, NY). This medium contained 25 mmol S (N-2-hydroxyethylpiperazine-N'-2-econsultancy acid) and L-glutamine (to which was added 1%solution of penicillin/streptomycin). Poem is this to the RPMI medium was added deactivated by 10% (as a result of heating at 56° C for 30 min) serum bovine embryo. 200 μl of the suspension RWM were placed in sterilized 96 cells with a flat bottom (Petri dishes) (obtained from Becton Dickinson Labware, Lincoln Park, new Jersey).

Preparation connections

The connection was solubilizers in ethanol, dimethyl sulfoxide (DMSO) or an aqueous solution of tissue culture, followed by dilution with an aqueous solution of a tissue culture, a 0.01 N solution of sodium hydroxide or 0.01 N solution of hydrochloric acid. (The choice of solvent depends on the chemical properties of the compounds). Adding to the samples of culture the final concentration of ethanol or DMSO should not exceed 1%. At the initial stage of the study compounds, their concentration was in the range of from 0.1 to 5 μg/ml of the Compounds proved effective at a concentration of 0.5 μg/ml, were further investigated in a broader concentration range.

Incubation

A solution of the compound in the amount not exceeding 50 μl, were placed in Petri dishes, which were 200 ál of diluted whole blood or RWM in the medium of culture. In the control Petri dishes were added to the solvent and(or) environment (but did not add the analyzed connection) and, if necessary, brought the total sample in each Petri dish to 250 ál. The Petri dishes were closed with plastic covers, neatly p is remedial samples and kept them in for 48 hours at 37° C in an atmosphere containing 5% carbon dioxide.

Division

After the end of the incubation period of the lid on the Petri dishes with the samples were filled with wax and the samples were centrifuged for 10-15 minutes at a rotation speed of 1000 rpm and a temperature of 4° C. Used a centrifuge Dsmon IEC dl RU-5000. About 200 ál of medium was collected from 4-8 cells and transferred into a sterile tube with a volume of 2 ml, designed for operation at cryogenic temperatures. Before analysis, the samples were stored at -70° C.

Analysis of Interferon/Calculations

For analysis of interferon used method of determining biological activity, using A cell lung cancer person with signs of encephalomyocarditis. Detail the method of determining the biological activity described Gulbransen (G.L.ennan) and Lchkeria (L.H.Kronenberg) in the article "Automated determination of the biological activity of interferons in microstuttering cells", Biotechniques, June/July, 78, 1983, cited in the references. In brief, this method consists in the following. Cells A cells were cultured with the test samples and standard solutions of interferon at 37° With in 12-24 hours. Then subjected to incubation, the cells were infected by inoculation of virus encephalomyocarditis. Before quantifying cytopathol the environmental effect of the virus infected cells were additionally cultured for some time at 37° C. For the quantitative determination cytopathological effect of the viruses studied system were stained and then spectrophotometrically determined the absorption of light. The results are expressed in units of alpha, units/ml, the number of which was estimated based on the data obtained for the standard sample NIH HU IF-L. analysis method for the elimination of interferon was identified almost completely, as α -interferon, at the same time when using A cells with virus encephalomyocarditis was detected by anti-human interferon rabbit (β -inteferon) and anti-human interferon goats (α -interferon).

Using the above testing methods, we studied the ability described in the present invention, chemical compounds stimulate the production of interferon in human cells. The results are shown in table 1, in which the sign "+" indicates that the compound stimulates α -interferon at the given concentration, the sign "-" indicates that the compound does not stimulate education α -interferon, and the sign "±" indicates that the concentration of the studied compound does not show explicit action.

STIMULATION of CYTOKINE SYNTHESIS IN HUMAN CELLS

Determination of the activity obtained in the invention compounds to stimulate the formation of cytokines was performed using human cells in vitro. Activity was determined based on the number of interferon α and tumor necrosis factor (α )(IFN and TNF, respectively)secreted into the medium of culture. For this assessment used the method described by Testerman and others in the article "Stimulation of cytokine under the action of immunomodulators Imiquimod and S-27609", Journal of Leukocyte iology, 58, p.65-372 (September, 1995).

Preparation of blood cells for culture

Whole blood from healthy donors was collected by venipuncture and placed in special vials containing EDTA. Mononuclear cells from peripheral blood (RVMS) were separated from whole blood by centrifugation using the apparatus of Histopaque® -1077 (Sigma Chemicals, St. Louis, PCs Missouri). RVMS suspended in the environment RI 1640 containing 10% serum bovine embryo, 2 mmol/l L-glutamine and 1%solution of penicillin/streptomycin (complete set RI). The concentration of blood cells in this suspension was (3-4)× 106cells in 1 ml of suspension. Suspension RVMS were placed in 48 sterilized cells with a flat bottom (Petri dishes) (str, Cambridge, Minnesota, or Bector Dickinson Labware, Lincol Park, new Jersey)containing an equal volume RI with this connection.

Preparation connections

The connection was solubilizers in dimethyl sulfoxide (DMSO). Adding to the samples of culture the final concentration of DMSO should not exceed 1%. The concentration of the test compounds is usually in the range from 0.12 to 30 µmol/L.

Incubation

The solution used for test compounds with a concentration of 60 mmol/l were first added to the Petri dish, in which was set RL, and then repeatedly performed a serial dilution of the sample 3 times. After this was added an equal volume of suspension RMS; the concentration of the compounds that were kept in the range from 0.12 to 30 μmol/l Final concentration suspensions RWMS was (1,5-2)· 106cells/ml Petri dishes were closed with plastic covers, neatly mixed samples and kept them within 18-24 hours at 37° C in an atmosphere containing 5% carbon dioxide.

Division

After the end of the incubation period, the cell samples were centrifuged for 5-10 minutes at a rotation speed of 1000 rpm (approximately 200 g) and a temperature of 4° C. the Obtained upper layer was collected with a sterile polypropylene pipette and transferred into a sterile polypropylene tube. Before analysis, the samples were stored at a temperature of from -30 to -70° C. Analysis of samples in the possession of interferon (α were any way LISA, or by using the quantitative determination of biological activity; analysis of samples for the content of tumor necrosis factor (α ) was performed using the method LISA.

Quantitative determination of biological activity of interferon

For analysis of interferon used method of determining biological activity, using A cell lung cancer person with signs of encephalomyocarditis. Details of the method of determining the biological activity described Gulbransen (G.L.rennan) and Lchkeria (L.H.ronenberg) in the article "Automated determination of the biological activity of interferons in microstuttering cells", Biotechniques, June/ July, 78, 1983. In brief, this method consists in the following. Cells A cells were cultured with diluted investigated samples and standard solutions of interferon at 37° C for 24 hours. Then subjected to incubation, the cells were infected by inoculation of virus encephalomyocarditis. Before quantification cytopathological effect of virus-infected cells were additionally cultured for 24 hours at 37° C. For the quantitative determination cytopathological effect of the viruses studied system were stained with kristallwelten and then visually observed for culture. The results you who awives in units of alpha, units/ml, the number of which was estimated based on the data obtained for the standard sample NIH human leukocyte interferon.

Analysis of interferon (α ) and tumor necrosis factor (α ) by the way ELISA

The concentration of interferon (α ) was determined by the method LISA, using a standard set of Human Multi-Sis (supplied by the company L iomedical Laboratories, new Brunswick, new Jersey). The determination was carried out according to the attached manufacturer's instructions.

The concentration of tumor necrosis factor (α ) was determined by the method LISA, using kits supplied by companies Genzime, Cambridge, Minnesota, R&αμπ; D Systems, Minneapolis, Minneapolis, or harmingen, San Diego, California. The determination was carried out according to the attached manufacturer's instructions.

In the following table 2, the mark "+" indicates that the connection has stimulated the formation of the indicated cytokine at the given concentration; the sign "-" indicates that the compound does not stimulate the formation of the indicated cytokines at concentrations, and the sign "±" indicates that when used in the concentration of the studied compound does not show explicit action.

The above description of several applications of the present invention. D is the detailed description of the invention and the examples given here only to achieve full clarity in understanding the invention and areas of its application. For specialists in this field will be obvious that the described embodiments of the invention can be modified in various ways without violating the essence of the invention. However, this invention is not limited to the exact details of the compositions and structures illustrated in the various examples, but encompasses all aspects listed in the following claims.

1. Oxazolo and thiazolo-[4,5-C]-quinoline-4-amines of formula I

characterized in that

Deputy R1selected from the group consisting of oxygen atoms, and sulfur;

Deputy R2selected from the group consisting of

- hydrogen atom;

- alkyl;

- alkyl-HE (hydroxyalkyl);

- alkyl-S-alkyl;

- alkyl-O-C(O)-N(R5)2;

- morpholinyl, pyrrolidinyl;

- alkyl-X-aryl radical;

alkenyl-X-aryl radical;

moreover, each of the substituents R3and R4independently represents a hydrogen atom;

or taken together substituents R3and R4form a condensed aromatic or [1,5] naphthyridine system;

X represents-O - or a simple bond; R5represents a hydrogen atom; and pharmaceutically acceptable the e salt based on these compounds.

2. The compound according to claim 1, characterized in that the substituents R3and R4taken together, form a substituted or unsubstituted benzene ring, the substituents selected from C1-4alkyl group, a C1-4CNS group, galactography, amino and triptorelin group.

3. The compound according to claim 1, characterized in that the substituents R3and R4taken together, form an unsubstituted pyridine ring.

4. The compound according to claim 1, characterized in that the substituent R2is1-4alkyl group.

5. The compound according to claim 1, characterized in that the substituent R1is a sulfur atom.

6. The compound according to claim 5, characterized in that the substituents R3and R4taken together, form a substituted or unsubstituted benzene ring, the substituents selected from C1-4alkyl group, a C1-4CNS group, galactography, amino and triptorelin group.

7. The connection according to claim 6, characterized in that the substituent R2is1-4alkyl group.

8. The connection according to claim 6, characterized in that the substituent R2is n-through the group.

9. 2-n-Propitiatio[4,5-C]quinoline-4-amine or pharmaceutically acceptable salt based on it.

10. A compound selected from the group consisting of

2-methylthiazole[4,5-C]quinoline-4-am is h;

thiazolo[4,5-C]quinoline-4-amine;

2-utilizalo[4,5-C]quinoline-4-amine;

2-propitiatio[4,5-C]quinoline-4-amine;

2-intellisol[4,5-C]quinoline-4-amine;

2-butylthiazole[4,5-C]quinoline-4-amine;

2-(1-methylethyl)thiazolo[4,5-C]quinoline-4-amine;

2-(2-phenyl-1-ethynyl)thiazolo[4,5-C]quinoline-4-amine;

2-(2-phenyl-1-ethyl)thiazolo[4,5-C]quinoline-4-amine;

2-(4-aminothiazolo[4,5-C]quinoline-2-yl)-1,1-dimethylthiocarbamate;

2-(ethoxymethyl)thiazolo[4,5-C]quinoline-4-amine;

2-(methoxymethyl)thiazolo[4,5-C]quinoline-4-amine;

2-(2-methylpropyl)thiazolo[4,5-C]quinoline-4-amine;

2-benzilate[4,5-C]quinoline-4-amine;

8-methyl-2-propitiatio[4,5-C]quinoline-4-amine;

(4-aminothiazolo[4,5-C]quinoline-2-yl)methanol;

2-methoxazole[4,5-C]quinoline-4-amine;

2-ethyloxazole[4,5-C]quinoline-4-amine;

2-butylanisole[4,5-C]quinoline-4-amine;

2-propitiatio[4,5-C]quinoline-4,8-diamine;

2-propiconazole[4,5-C]quinoline-4-amine;

8-bromo-2-propitiatio[4,5-C]quinoline-4-amine;

7-methyl-2-propitiatio[4,5-C]quinoline-4-amine;

2-butyl-7-methoxazole[4,5-C]quinoline-4-amine;

7-methyl-2-propiconazole[4,5-C]quinoline-4-amine;

7-fluoro-2-propiconazole[4,5-C]quinoline-4-amine;

7-fluoro-2-propitiatio[4,5-C]quinoline-4-amine;

2-propyl-7-(trifluoromethyl)thiazolo[4,5-C]hee the Olin-4-amine;

2-(4-morpholino)thiazolo[4,5-C]quinoline-4-amine;

2-(1-pyrrolidino)thiazolo[4,5-C]quinoline-4-amine;

2-butylthiazole[4,5-C] [1,5]naphthiridine-4-amine;

2-propitiatio[4,5-C] [1,5]naphthiridine-4-amine;

7-chloro-2-propitiatio[4,5-C]quinoline-4-amine;

7-methoxy-2-propitiatio[4,5-C]quinoline-4-amine;

and pharmaceutically acceptable salts based on these compounds.

11. Pharmaceutical composition for stimulating the formation of cytokines in human cells containing a therapeutically effective amount of the compounds of General formula I(a)

where substituent R1selected from the group consisting of oxygen atoms, and sulfur;

Deputy R2selected from the group consisting of

- hydrogen atom;

- alkyl;

- alkyl-HE (hydroxyalkyl);

- alkyl-S-alkyl;

- alkyl-O-C(O)-N(R5)2;

- morpholinyl, pyrrolidinyl;

- alkyl-X-aryl radical;

alkenyl-X-aryl radical;

each of the substituents R3and R4independently represents a hydrogen atom;

or taken together substituents R3and R4form a condensed aromatic or [1,5] naphthyridine system;

X represents-O - or a simple bond, R5 represents a hydrogen atom; and pharmaceutically acceptable salts on the basis of these compounds with pharmaceutically acceptable carrier.

12. The way to promote tsitogeneticheskogo biosynthesis in mammals, which consists in the introduction of the composition according to claim 11 in the body of a mammal.

13. The method according to item 12, wherein the cytokine contains interferon-α.

14. The method according to item 12, wherein the cytokine contains the tumor necrosis factor-α.

15. The method according to item 12, wherein the composition is administered locally.

16. A method of treating a viral disease in a mammal, which consists in the introduction of the composition according to claim 11 in the body of a mammal.

17. The method according to item 16, wherein the composition is administered locally.

18. A method of treating neoplastic disease in a mammal, which consists in the introduction of the composition according to claim 11 in the body of a mammal.

19. The method according to p, wherein the composition is administered locally.

20. The compound of formula II

characterized in that

Deputy R1selected from the group consisting of oxygen atoms and sulfur; Deputy R2selected from the group consisting of

- alkyl;

- alkyl-HE;

- alkyl-S-alkyl;

- alkyl-X-aryl;

- morpholinyl;

- SO2CH3;

each of the substituents R3and R4independently represents a hydrogen atom;

or taken together substituents R3and R4form a condensed aromatic or [1,5] naphthyridine system;

X represents-O - or a simple link.

21. A compound selected from the group consisting of

2-methylthiazole[4,5-C]quinoline-5N-oxide;

2-utilizalo[4,5-C]quinoline-5N-oxide;

2-propitiatio[4,5-C]quinoline-5N-oxide;

2-intellisol[4,5-C]quinoline-5N-oxide;

2-butylthiazole[4,5-C]quinoline-5N-oxide;

2-(1-methylethyl)thiazolo[4,5-C]quinoline-5N-oxide;

2-(2-phenyl-1-ethynyl)thiazolo[4,5-C]quinoline-5N-oxide;

2-fenilatilamina[4,5-C]quinoline-5N-oxide;

2-methyl-1-thiazolo[4,5-C]quinoline-2-yl-2-propanol-5N-oxide;

2-(ethoxymethyl)thiazolo[4,5-C]quinoline-5N-oxide;

2-(methoxymethyl)thiazolo[4,5-C]quinoline-5N-oxide;

2-(2-methylpropyl)thiazolo[4,5-C]quinoline-5N-oxide;

2-benzilate[4,5-C]quinoline-5N-oxide;

8-methyl-2-propitiatio[4,5-C]quinoline-5N-oxide; and

2-butylanisole[4,5-C]quinoline-5N-oxide.

Priority points and features:

28.08.1998 according to claims 1-21;

27.07.1999 according to claims 1-21 varieties radicals.



 

Same patents:

The invention relates to organic chemistry and can find application in medicine

The invention relates to an improved process for the preparation of 6,8-dimethyl-2-piperidinomethyl-2,3-dihydrothiazolo[2,3-f] xanthine of the formula I, causing the induction of microsomal liver enzymes

The invention relates to organic chemistry and can find application in medicine

The invention relates to the field of production of new heterocyclic o-dicarbonitriles

The invention relates to a new method for the preparation of 3-substituted cephalosporins of the formula (I):

where R1is a para-nitrobenzyl or allyl, X is a halogen; comprising the stage of: a) cyclization trimethylphosphine the compounds of formula (IIIA):

where R1is a para-nitrobenzyl or allyl, R2selected from the group comprising FROM1-6alkyl, C6-10aryl, C6-10arils1-6alkyl and dithienyl; in a solvent to form compounds of the formula (II):

where R1is a para-nitrobenzyl or allyl; R2selected from the group comprising FROM1-6alkyl, C6-10aryl, C6-10arils1-6alkyl and dithienyl; and (b) interaction of the compounds of the formula (II) with acid

The invention relates to polycyclic, thiazolidin-2 - ildenafil amines and their physiologically acceptable salts and physiologically functional derivatives

The invention relates to a method for producing [1,2,4]triazolo[3,4-b][1,3]benzothiazol-3(2H)-thione of the formula

including fusion [1,2,4]triazolo[3,4-b][1,3]benzothiazole with excess sulfur in for 5-20 minutes at a temperature of 180-200With subsequent isolation of the target product

The invention relates to 4-hydroxy-3-chinainternational and hydrazides of General formula (I), where a represents a-CH2- or-NH-, a R1, R2, R3and R4such as defined in the claims

The invention relates to tetrahydro-gamma carbolines formula (I), where R1, R2D, Alk and n are such as defined in the claims

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The invention relates to novel ortho-sulfonamidophenylhydrazine heteroaryl hydroxamic acids of the formula

< / BR>
where W and X are both carbon, T is nitrogen, U represents CR1where R1represents hydrogen, or alkyl containing 1-8 carbon atoms, R represents-N(CH2R5)-SO2Z, Q represents -(C=O)-NHOH, with

< / BR>
is a benzene ring, or is a heteroaryl ring of 5 to 6 atoms in the cycle, which may contain 0-2 heteroatoms selected from nitrogen, oxygen and sulfur, in addition to the heteroatom of nitrogen, denoted as W, where benzene or heteroaryl ring may optionally contain one or two substituent R1where permissible; Z is phenyl, which is optionally substituted by phenyl, alkyl with 1-8 carbon atoms, or a group OR2; R1represents halogen, alkyl with 1-8 carbon atoms, alkenyl with 2-6 carbon atoms, perfluoroalkyl from 1 to 4 carbon atoms, phenyl, optionally substituted by 1-2 groups OR2group-NO2group -(CH2)nZ, where Z is a phenyl which allows an alkyl with 1-8 carbon atoms, phenyl, optionally substituted with halogen, or heteroaryl radical containing 5 to 6 atoms in the cycle, including 1-2 heteroatoms selected from nitrogen, oxygen and sulfur; R5represents hydrogen, alkyl with 1-8 carbon atoms, phenyl, or heteroaryl containing 5 to 6 atoms in the cycle, including 1-2 heteroatoms selected from nitrogen, oxygen and sulfur; or their pharmaceutically acceptable salts

FIELD: organic chemistry, chemical technology, herbicides.

SUBSTANCE: invention describes a method for preparing compounds of the formula (I):

wherein each R1, R2, R3 means independently of one another (C-C6)-alkyl; R can represent also pyridyl; R4 and R5 in common with nitrogen atoms to which they are joined form unsaturated 5-8-membered heterocyclic ring that can be broken by oxygen atom; G means hydrogen atom. Method involves interaction of compound of the formula (II):

wherein R1, R2 and R3 have above given values; R6 is a group RR9N-; R7 is a group R10R11N-; each among R8, R, R10 and R11 means independently of one another hydrogen atom or (C1-C6)-alkyl in inert organic solvent being optionally with the presence of a base with compound of the formula (IV) ,

(IVa)

or (IVb) ,

wherein R4 and R have above given values; H x Hal means hydrogen halide. The prepared compound of the formula (I) wherein G represents ammonium cation is converted to the corresponding compound of the formula (I) by treatment with Brensted's acid wherein G represents hydrogen atom. Also, invention describes compound of the formula (II) wherein R1, R2, R3, R6 and R7 have above indicated values.

EFFECT: improved preparing method.

9 cl, 12 ex

The invention relates to the field of organic chemistry, namely to new individual compounds of class benzoxazines that exhibit fluorescent properties and can be used as starting products for the synthesis of new heterocyclic systems, as well as substances for sample labeling and additives for reflective paints

The invention relates to new nitrogen-containing aromatic 6-membered cyclic compounds of the formula (I) or their pharmaceutically acceptable salts, demonstrating excellent selective PDE V inhibitory activity

The invention relates to new physiologically active substituted oxazolo[4,5-d]pyridazine General formula (1), (2) or (3) and combinatorial library designed to search among them physiologically active substances, compounds leaders and candidates (drug-candidates) on the basis of screening

The invention relates to new cyclic diamine compounds of the formula I, where

< / BR>
represents an optionally substituted divalent residue of benzene, where the substituents are selected from unsubstituted lower alkyl groups, unsubstituted lower alkoxygroup, unsubstituted lower acyl group, a lower allylthiourea, lower alkylsulfonyl group, halogen atom, etc. or unsubstituted pyridine; Ar represents a phenyl group which may be substituted by one to four groups selected from unsubstituted lower alkyl group, the unsubstituted alkoxygroup, low allylthiourea, lower alkylsulfonyl group, and so on, optional substituted amino group, alkylenedioxy; X is-NH-, oxygen atom or sulfur atom; Y is a sulfur atom, sulfoxide or sulfon; Z represents a single bond or-NR2-; R2- the atom of hydrogen or unsubstituted lower alkyl group; l = 2 or 3; m = 2 or 3; n = 1, 2, or 3, or their salts, or their solvate

The invention relates to new heterocyclic o-dicarbonitrile formula (I), where

< / BR>
The compounds obtained can be used to obtain hexatriene-fluorophores

The invention relates to a new 1.8-fused derivative of 2-Hinayana formula (I), where A, X, R1, R2, R3, R4, R5, R6such as defined in the claims
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