Derivatives of 1,2,4,5-tetrahydrobenzo[d]azepine and medicinal products based on them

 

(57) Abstract:

The invention relates to organic chemistry and can find application in medicine. Describes derivatives of 1,2,4,5-tetrahydrobenzo[d]azepine General formula I

where X represents-N=, =N-, -N<, >= or =<, Y represents-N=, =N-, -NH-, -CH= or =CH-, the dotted line can represent the relationship, and the radicals R1-R16such as described in the claims, as well as their pharmaceutically acceptable salts in their racemic and optically active form. It also describes the drug, which may find use in the treatment or prevention of acute and/or chronic neurological disorders. The technical result obtained new compounds with useful biological properties. 2 N. and 11 C.p. f-crystals, 1 table.

The invention relates to 1,2,4,5-tetrahydrobenzo[d]azepino derivative of General formula

where R1denotes hydrogen, (ness.)alkyl, oxygen, halogen or-OR-,

-O(C3-C6)cycloalkyl, -O(R)n-(C3-C6)cycloalkyl, -O(CHR)nCN,

-O(R)nCF3, -O(CHR)(CHR)nNR2, -O(CHR)(CHR)nOR, -O(CHR)n-(ness.)alkenyl, -F3, HR)nCF2Br,

-O(R)n-phenyl, where the phenyl group optionally may be substituted by one to three substituents, independently of one another selected from the series comprising (ness.)alkyl, (ness.)alkoxygroup, halogen, nitro or cyano,

-O(CHR)(R)n-morpholino, -O(CHR)(R)n-pyrrolidino,

-O(CHR)(R)n-piperidine, -O(CHR)(R)n-imidazole,

-O(CHR)(R)n-triazole, -O(R)n-pyridine,

-O(R)(R)n-OSi-(ness.)alkyl, -O(CHR)(CHR)n-OS(O)2-(ness.)alkyl, -O(CH2)nCH=CF2, -O(R)n-2,2-dimethyl[1,3]dioxolane,

-O(CHR)n-CHOR-CH2OR, -O(CHR)n-CHOR-(CHR)n-CH2OR, or

-SR, or-S(CHR)nCOOR, or

-NR2, -N(R)(CHR)(CHR)nOR, -N(R)(CHR)nCF3,

-N(R)(CHR)(R)n-morpholino, -N(R)(CHR)(R)n-imidazole,

-N(R)(CHR)(R)n-pyrrolidino,

-N(R)(CHR)(R)n-pyrrolidin-2-it,

-N(R)(CHR)(R)n-piperidino, -N(R)(CHR)(R)n-triazole,

-N(R)n-pyridine,

n is 1-6,

R denotes hydrogen, (ness.)alkyl or (ness.)alkenyl selected independently from each other, if there is more than one radical R,

- (ness.)alkyl,

-(C3-C6)cycloalkyl or piperazine derivatives, optionally substituted (ness.)the alkyl, or

-CONR2, -(CHR)nCONR2, -(CHR)nOR, -(CH2)n-CF3, -CF3,

-(R)nOS(O)CF3, -(CHR)nCOOR, -(R)nSC6H5where the phenyl group optionally may be substituted by one to three substituents, independently of one another selected from the series comprising (ness.)alkyl, (ness.)alkoxygroup, halogen, nitro or cyano, -(R)n-1,3-dioxo-1,3-dihydroindol,

-(R)n-tetrahydropyran-2-yloxy or(R)n-S-(ness.)alkyl, or

-NR2, -NR-(ness.)alkyl, -NRCHO, -N(R)(CHR)nCN,

-N(R)(CHR)nCF3, -N(R)(CHR)(CHR)n-OR, -N(R)C(O)(CHR)nO-(ness.)alkyl, -N(R)(CHR)n-(ness.)alkyl, -NR(CHR)(CHR)n-OR,

-N(R)(R)(R)n-O-phenyl, where the phenyl group optionally may be substituted by one to three substituents, independently of one another selected from the series comprising (ness.)alkyl, (ness.)alkoxygroup, halogen, nitro or cyano,

-NR(CHR)n-(ness.)alkenyl, -N(R)(CHR)(CHR)n-O-(CHR)nOR,

-N(R)(CHR)nC(O)O-(ness.)alkyl, -N(R)(CHR)nC(O)NR-(ness.)alkyl, -N(

-N(R)(CHR)(R)n-piperidino, -N(R)(CHR)(CHR)n-pyrrolidino, -N(R)(CHR)(R)n-O-pyridine,

-N(R)(R)(R)n-imidazole, -N(R)(CHR)n-CR2-(CHR)n-OR,

-N(R)(CHR)n-CR2-OR, -N(R) (R)n-R-CH2OR,

-N(R)(CHR)n-CHOR-(CHR)n-CH2OR, or-OR, -O(R)nCF3,

-F3, -O(R)(R)n-O-phenyl, where the phenyl group optionally may be substituted by one to three substituents, independently of one another selected from the series comprising (ness.)alkyl, (ness.)alkoxygroup, halogen, nitro or cyano, -O(CHR)(R)n-O-(ness.)alkyl,

-O(R)n-pyridine or-O(R)(R)n-morpholino and

R4denotes hydrogen, (ness.)alkyl, (ness.)alkenyl or nitro, or

-OR, -F3, -OCF2-R, -F2-(ness.)alkenyl, -OCHRF, -OCHF-(ness.)alkenyl, -O(R)nCF3or

-(CHR)nCHRF, -(R)nCF2R, -(R)nCF3-(C3-C6)cycloalkyl,

-(R)n(C3-C6)cycloalkyl, -(CHR)nCN, -(R)n-phenyl, where the phenyl group optionally may be substituted by one to three substituents, independently of one another selected from the series comprising (ness.)Ala is CHR)(CHR)nNR2,

-(CHR)nCOOR, -(R)(R)nOSi(ness.)alkyl, -(CHR)(CHR)n-OS(O)2-(ness.)alkyl, -(CH2)n-CH=CF2, -CF3, -CF3-R, -CF2-(ness.)alkenyl, -CHRF, -F-(ness.)alkenyl, -(R)n-2,2-dimethyl[1,3]dioxolane, -(CH2)n-2-oxazepan-1-yl,

-(R)(R)n-morpholino, -(R)n-pyridine, -(CHR)(CHR)n-imidazole, -(R)(R)n-triazole, -(R)(R)n-pyrrolidino, optionally substituted -(CH2)nHE, -(CHR)(CHR)n-3-hydroxypyrrolidine or(R)(R)n-piperidino, or

-NR2, -N(R)(R)n-pyridine, -N(R)C(O)O-(ness.)alkyl,

-N(CH2CF3)C(O)O-(ness.)alkyl, -N[C(O)O-(ness.)alkyl]2, -NR-

NR-C(O)O-(ness.)alkyl or-N(R)(CHR)nCF3, -NRF3, -NRCF2-

R-RF2-(ness.)alkenyl, -NRRF,-NRF-(ness.)alkenyl,

or

no, if X represents-N= or =N-, or

R4and R1or R3and R4interconnected groups -(CH2)-3-5,

-(CH2)2-N=, -CH=N-N=-, -CH=CH-N=, -NH-CH=CH -, or-NR-CH2-CH2and form with N atoms and to which they are attached, an additional ring,

R5, R6on the 5 and R6connected with group,- O-CH2-O - to form together with the atoms to which they are attached, an additional 5-membered ring,

R7, R8denote hydrogen, (ness.)alkyl, (ness.)alkoxy, amino, nitro or halogen,

R9, R10denote hydrogen or (ness.)alkyl,

R11, R12denote hydrogen, (ness.)alkyl, hydroxy, (ness.)alkoxy, (ness.) alkoxycarbonyl or (ness.) alkanoyloxy,

R13, R14denote hydrogen, tritium or (ness.)alkyl,

R15, R16denote hydrogen, tritium, (ness.)alkyl, hydroxy, (ness.)alkoxy, (ness.)alkoxycarbonyl or (ness.)alkanoyloxy or together form oxoprop;

X represents-N=, =N-, -N<, >C= or =<,

Y represents-N=, =N-, -NH-, -CH= or =CH - and

the dotted line can represent a bond,

and their pharmaceutically acceptable salts in artemichenko and optically active form.

It has been unexpectedly found that compounds of General formula I are antagonists of metabotropic glutamate receptors.

In the Central nervous system (CNS), the transmission of nerve impulses occurs by interaction naibolee common neurotransmitter in the Central nervous system, plays a crucial role in numerous physiological processes. Dependent glutamate receptors of nerve impulses are divided into two main groups. In the first group are controlled by the ligand ion channels. Metabotropic glutamate receptors (mGluR) are the second main group, in particular, to the family associated with G-protein receptors.

At the present time famous eight different representatives of these mGluR, some of which are subdivided into subtypes. On the basis of structural parameters, various secondary signal transduction pathways and their various epinasty chemical compounds with a low molecular weight of these eight receptors can be subdivided into the following three subgroups: receptors mGluR1 and mGluR5 belong to group I, mGluR2 and mGluR3 belong to group II, a mGluR4, mGluR6, mGluR7 and mGluR8 belong to group III.

The ligands of metabotropic glutamate receptors belonging to the first group, can be used for the treatment or prevention of acute and/or chronic neurological disorders such as epilepsy, stroke, chronic and acute pain, psychosis, schizophrenia, Alzheimer's disease, impairment of cognitive abilities and memory deficiency.

Drugoplasirani bypass or graft inadequate blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycaemia. The following indications treatable, are Huntington's chorea, amyotrophic lateral sclerosis (als), dementia caused by AIDS, eye injuries, retinopathy, idiopathic parkinsonism or parkinsonism caused by drugs, as well as the condition in which due to the deficit of glutamate functions, such as, for example, muscle spasms, convulsions, migraine, urinary incontinence, addiction to nicotine, addiction to drugs, anxiety, vomiting, dyskinesia and depression.

Objects of the present invention are the compounds of formula I and their pharmaceutical salts, individually and as pharmaceutically active compounds, methods for their preparation, pharmaceuticals based on compounds according to the invention and the method of their preparation and the use of compounds according to the invention for the control or prevention of the above diseases, respectively, to prepare the drugs. In addition, an object of the present invention is also the use of radioactively-labeled anteroom of the present invention are compounds in which R1represents =O or hydroxy and R2indicates NO2.

Examples of such compounds are:

3-ethyl-2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-3H-pyrimidine-4-one,

3-(2-foradil)-2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-3H-pyrimidine-4-one,

2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-3-(2,2,2-triptorelin)-3H-pyrimidine-4-one, or

2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-4-ol.

Are also preferred compounds of formula I in which R1represents =O or hydroxy and R2refers to-CN.

Examples of such compounds are:

2-amino-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril,

6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril,

2 ethylamino-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril,

1,2-dimethyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril,

1-ethyl-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril,

2-amino-1-ethyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril,

1-allyl-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril,

1-lanmeter-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril,

1-(2-dimethylaminoethyl)-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo-zo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril,

1-isopropyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril,

1-(2-hydroxyethyl)-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril,

2-(2-hydroxyethyl)-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril,

2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1-(2,2,2-triptoreline)-1,6-dihydropyrimidin-5-carbonitril,

2-methyl-1-methylamino-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile or

1-amino-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile.

Preferred compounds of formula I in the scope of the present invention are compounds in which R1means 2,2,2-triptoreline and R2refers to-CN.

Examples of such compounds are:

2-LASS="ptx2">2-(3-morpholine-4-ylpropionic)-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile,

2-(2-hydroxyethylamino)-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile or

(3-imidazol-1-ylpropionic)-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile.

Preferred compounds of formula I in the scope of the present invention are compounds in which R1denotes 3-[1,2,4]triazole-1-ylpropionic and R2means-NO2or-CN.

The following is an example of such connection is:

3-[2-methyl-5-nitro-6-(3-[1,2,4]triazole-1-ylpropionic)pyrimidine-4-yl]-2,3,4,5-tetrahydro-1H-benzo[d]azepin.

Preferred compounds of formula I in the scope of the present invention are compounds in which R3and R4connected with the group -(CH2)5and form together with the N atoms and to which they are attached, an extra 7-membered ring, and R2means-NO2or-CN.

The following is an example of such connection is:

4-oxo-2-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-4,6,7,8,9,10-hexahydropyrazino[1,2-a] azepin-3-carbonitrile.

The term "(ness.)alkyl in which APU, having 1-4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, etc.,

The term "(ness.)alkylen" in the context of the present invention refers to an unsaturated hydrocarbon radical with a straight or branched chain having 2 to 7 carbon atoms, preferably 2-4 carbon atoms.

The term "(ness.)alkoxy" means (ness.)alkyl radical, as defined above linked to an oxygen atom.

The term "halogen" includes fluorine, chlorine, bromine and iodine.

Compounds of General formula I and their pharmaceutically acceptable salts can be obtained by

a) interaction of the compounds of formula

with the compound of the formula

obtaining the compounds of formula

where the substituents have the above values, or

b) interaction of the compounds of formula

obtaining the compounds of formula

or obtaining the compounds of formula

where the radicals R2-R16have the above meanings and RI’means (ness.)alkyl, -(C3-C6)cycloalkyl, -(R)n-(C3-C6)cycloalkyl,

-(CHR)nCN, -(R)n-(ness.)alkenyl, -CHRF, -CHF-(ness.)alkenyl, -CF2CRF2, -CF2Br, -(CHR)nCF2Br, -(R)n-phenyl, where the phenyl group optionally may be substituted by one to three substituents, independently of one another selected from the series comprising (ness.)alkyl, (ness.)alkoxygroup, halogen, nitro or cyano,

-(CHR)(R)n-morpholino, -(CHR)(R)n-pyrrolidino, -(CHR)(CHR)n-piperidino, -(R)(R)n-imidazole, -(R)(R)n-triazole, -(R)n-pyridine, -(R)(R)n-OSi-(ness.)alkyl, -(CHR)(CHR)nOS(O)2-(ness.)alkyl, -(CH2)nCH=CF2, -(R)n-2,2-dimethyl[1.3]dioxolane,

-(CHR)n-CHOR-CH2Or, or -(CHR)n-CHOR-(CHR)n-CH2OR,

in the interaction between the compounds of formula

with the compound of the formula

obtaining the compounds of formula

where the substituents have the above values,

or

d) interaction of the compounds of formula

with alcohol, thiol, primary or secondary amine to obtain the compounds of formula

where the substituents have the above values, or

d) interaction of soy is sulfone-oxygraph, with the compound of the formula

obtaining the compounds of formula

where the substituents have the above values, or

(e) interaction of the compounds of formula

where RIVdenotes fluorine, chlorine, bromine or triftormetilfullerenov, with the compound of the formula

obtaining the compounds of formula 1-5

where the substituents have the above values,

and, if necessary, by the introduction and removal of the protective groups in the compounds of formula I, alkylation of the functions HE or NH in the compounds of formula I, the cleavage of the functions of a simple ester, conversion of the functional group in the compound of formula I into another functional group, direct or by means of suitable activating group and, if necessary, by turning the compounds of formula I in a pharmaceutically acceptable salt or in optically active form.

In schemes I-VIII (see the end of the description and in the examples 1-273 phase reactions and reactions a) to (e) described in more detail.

Chlorotoxin or teenpilipina formula II (scheme I) are known [e.g., 6-chloro-4-methoxy-2-methyl-5-nitropyrimidin: Helv. (1958), enviromedia [Monatshefte Chemie (1965), 96, 1573-1578] and sodium methoxide in methanol at a low temperature, preferably at a temperature of from -20°C to +20°C. They are subjected to interaction with optionally substituted amines III in the presence of a base such as triethylamine in solvents such as N,N-dimethylformamide, dimethylsulfoxide, acetone, methyl ethyl ketone or tetrahydrofuran, at temperatures from 0°C to 100°With tertiary amines of the formula 1-3A; however, at elevated temperatures, preferably at 100 to 150°C, in the presence of potassium carbonate in solvents such as N,N-dimethylformamide or N-organic, are formed tertiary amines of formula 1-1, at the same time, the methoxy group into a hydroxy-group. Known analogs of compounds of formula II bearing a carbonyl function instead metoxygroup, for example 2-amino-6-chloro-5-nitro-4(2H)-pyrimidine [J. Chem. Soc. 1964, 4769-4774], is subjected to the interaction with optionally substituted secondary amines of the formula III preferably at elevated temperatures, preferably at 100 to 150°C, in the presence of potassium carbonate, triethylamine or ethyldiethanolamine in solvents such as N,N-dimethylformamide or N-organic, with the receipt of the adducts of formula 1-1. Alkylation Nifontov in such solvents, as ethanol, methanol, dichloromethane, chloroform, N,N-dimethylformamide, dimethylsulfoxide, acetone, methyl ethyl ketone or tetrahydrofuran, in the presence of such bases, as the carbonates of alkali metals such as sodium carbonate, potassium or cesium, tertiary amines, such as triethylamine or ethyldiethanolamine, hydrides of alkali metals such as sodium hydride or potassium, or interphase catalysts, such as chloride designed, in the presence of solid or concentrated aqueous solution of sodium hydroxide results in various mixtures of N - and/or O-alkyl products of formula 1-2, and 1-3. The products of formula 1-2 and 1-3 can contain N - or O-alkyl features functional groups in protected form, to allow for further structural modification after removal of the protective functions.

To introduce such substituent R4as HE or NH2in pyrimidinone formula 1-1 (scheme I) using suitable reagents migration of oxygen or nitrogen. For introduction of the group NH2suitable agents are chloramine or preferably more stable mesitylsulfonylhydroxylamine [Synthesis, 1972, 140]. Both agent penaut in solvents, which are simple utstein such grounds, as sodium hydride or potassium carbonate, at temperatures in the range from room temperature up to 60°C. the Transformation of pyrimidinones formula I-1 in their O-siciliane analogues by processing suitable similitudine agents such as hexamethyldisilazane and trimethylchlorosilane, with subsequent processing oxopiperidine (pyridine) (NMRA) complex [J. Org. Chem. 43 (197), 188-196] in solvents such as dichloromethane or chloroform, at temperatures in the range from room temperature up to 60°With results pyrimidinone formula 1-2, where R4IT denotes. The compounds of formula 1-2, where R4indicates HE may be subjected to further derivatization known methods, such as alkylation, using suitable haloalkyl, tosilata or triflate in the presence of such a base as potassium carbonate or sodium hydride in solvents such as tetrahydrofuran, acetonitrile or N,N-dimethylformamide, at temperatures in the range from room temperature up to 100°C. the compounds of formula 1-2, where R4denotes NH2preferably converted into a mono-BOC-protected derivative (by obtaining di-BOC-protected derivative with di-tert-BUTYLCARBAMATE, 4-dimethylaminopyridine in dichloromethane at counterimages) and then alkylate in terms similar to that described for compounds of formula 1-2, where R4IT denotes. After that, the BOC group can easily be removed by known methods.

Bis(methylthio)acrylate of the formula IX is subjected to interaction with optionally substituted secondary amines of the formula III in the presence of such(to them) reason(s) as potassium carbonate and/or triethylamine in solvents such as ethanol, methanol, acetone, or methyl ethyl ketone, at temperatures in the range from room temperature up to 100°with the receipt of the adducts of the formula IV, which can be represented in the form Z-isomers, mixtures of E - and Z-isomers or in the form of E-isomer (scheme II). The adducts of the formula IV can be subjected to interaction with amidine derivative of urea or thiourea of formula V or in the presence of 1,8-diazabicyclo [5.4.0] undec-7-ene in N,N-dimethylformamide or dimethylsulfoxide at temperatures between 70°C to 140°C or in the presence of ateleta sodium in ethanol, preferably at the reflux that results in pyrimidinone formula 1, 1A or pyrimidinone formula 1-2A. After that pyrimidinone formula 1-1A can be alkylated in accordance with the sequence of reactions I-1I-2 and I-3, is presented in scheme I. If R3and the subsequent removal of the N-allyl functions using lithium borohydride in the presence of palladium (II) acetate and triphenylphosphine in an inert solvent, such as tetrahydrofuran or 1,2-dimethoxyethane, at temperatures in the range from room temperature up to 60°C. In an alternative embodiment, the adducts of the formula IV can be subjected to interaction with substituted amidinami derivative of formula Va, in which R3and R4optionally together form a 5-, 6 - or 7-membered ring, or in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene in N,N-dimethylformamide or dimethylsulfoxide at temperatures between 70°C to 140°C or in the presence of ateleta sodium in ethanol, preferably at reflux, resulting in pyrimidinone formula (I-2A.

Electoral monozameschennaya of dichloropyrimidine formula X (scheme III) optionally substituted secondary amines of the formula III can be carried out in solvents such as N,N-dimethylformamide or dimethylsulfoxide, in the presence of such a base as triethylamine, at temperatures between -10°C to room temperature to obtain monoglucuronide formula VI. After that, the remaining chlorine atom in the compounds phemom as solvent, or in an inert solvent, such as tetrahydrofuran, N,N-dimethylformamide or dimethylsulfoxide, at temperatures ranging from room temperature to 100°C, II) aminobenzene by treatment with amine in an inert solvent, such as tetrahydrofuran, N,N-dimethylformamide or dimethylsulfoxide, at temperatures ranging from room temperature to 100°C, III) tofunction by treatment with thiol in the presence of such a base as triethylamine or sodium hydride, in alcohol, N,N-dimethylformamide or dimethyl sulfoxide, at temperatures in the range from room temperature up to 100°C. the Substitution of the chlorine group by hydroxypoly preferably carried out in two stages: first, enter the 4-methoxybenzenesulfonyl by reacting the compounds of formula VI with the corresponding alcoholate according to the above method, and then treated with a methanol solution of hydrogen chloride at temperatures from 0°C to 50°C.

Compounds of General formula X (scheme III), where R3means methylthio and R2denotes cyano [J. Heterocycl. Chem. (1971), 8(3), 445] or where R2denotes nitro [Aust. J. Chem. (1990), 43(1), 55], are well-known. Selective monozameschennaya optionally substituted secondary amines of General formula III with a receipt with the date above method of obtaining compounds of General formula I-4. After transformation of 2-methylthiopyrimidine already replaced accordingly in the 6th position of the pyrimidine, 2-methylsulfonyl derivatives according to known methods of oxidation of the corresponding O-, N - or S-substituted pyrimidine derivatives can be obtained by processing the alcoholate, amines and thiolate in tetrahydrofuran, 1,2-dimethoxyethane, dimethylformamide or dimethyl sulfoxide at temperatures in the range from room temperature up to about 150°C.

Compounds of General formula I-4, where R2denotes cyano, R1means methylthio and R3denotes amino, can also be synthesized by reacting 2-amino-4-bromo-6-methylsulfonylamino-5-carbonitrile obtained similarly to the method of obtaining 4-chlorinated described in J. Chem. Soc. Chem. Commun. 1974, 9, 350, optionally substituted secondary amines of General formula III. In addition, compounds of General formula I-4, where R2denotes cyano, R1indicates alkylthio, can be synthesized using as initial products of compounds of General formula VI, where R3means methylthio, by their conversion into 2-methylsulfonyl derivatives according to known methods of oxidation with amide or dimethyl sulfoxide at temperatures in the range from room temperature up to about 150°C. After this substitution the remaining chlorine atom alkylsilane in tetrahydrofuran, 1,2-dimethoxyethane, dimethylformamide or dimethyl sulfoxide at temperatures in the range from room temperature up to about 150°With the results of O-, N - or S-substituted 6-alkyldiphenylamine derivatives.

Alpha aminosilane nitro - or canbesold the compounds of formula 1-5 (scheme IV) is obtained from the corresponding known benzene derivative of the formula VII, where RIIdenotes fluorine, chlorine, bromine or triftoratsetilatsetonom, by treatment with secondary amines at temperatures preferably in the range from room temperature up to 100°C in the presence of such a base as potassium carbonate or triethylamine in solvents such as methanol, ethanol, acetonitrile, tetrahydrofuran, acetone, methyl ethyl ketone, N,N-dimethylformamide or dimethylsulfoxide. Cyan - or nitropyridine formula XIII are known or can be obtained from the unsaturated ketones of formula XI (scheme V) having a leaving group, RIIIor RIVrepresenting ONa or S-alkyl function, along with the second functional group, RIIIor RIVrepresenting hydride or alkoxyphenyl. Takenaga acid-base catalysis with the use of mixtures of such bases, as piperidine or pyrrolidine with acetic or formic acid, in solvents such as water, ethanol, and tetrahydrofuran, or in the presence of such bases as sodium hydride or a sodium alcoholate or potassium hydroxide, in solvents such as ethanol, methanol, tert-butanol, N,N-dimethylformamide or dimethylsulfoxide, at temperatures ranging from room temperature to 100°With obtaining Spiridonov formula XIII, where RIIImeans hydride or alkoxyphenyl. The radical RIIIin compounds of formula XIII, which is alkoxyphenyl, optional can be converted into the radical RIIIrepresenting the IT-group, using known methods such as treatment with tribromide boron in dichloromethane. The transformation of peredonov formula XIII in pyridine formula VIIIa with a group of chlorine as RVIand optional second group of chlorine as RVyou can implement known methods, such as processing clean pentachloride phosphorus, mixtures of pentachloride phosphorus oxychloride and phosphorus in the presence of additional bases and solvents, such as ethyldiethanolamine and acetonitrile, with or without at temperatures from 80°C to 140°C. alternatively, pyridine formula VIIIa, Is B> the connection is known: US 5352784 (1994)] can be obtained from Spiridonov formula XIII (R111IT denotes) and anhydride triftormetilfullerenov acid and base as triethylamine, in an inert solvent, such as dichloromethane, at temperatures from -40°C to 60°C. the compounds of formula VIIIa, having two leaving groups RVand RVIthat represents chlorine or triftormetilfullerenov, is subjected to the interaction with nucleophiles such as primary and secondary alcoholate, in solvents such as tetrahydrofuran or N,N-dimethylformamide, water (pH 8-14), in the presence of mixing with the water solvent, such as tetrahydrofuran, or with primary or secondary amines in solvents such as dichloromethane, tetrahydrofuran or N,N-dimethylformamide, preferably at room temperature, first replacing RValkoxy-, hydroxy-group or aminosubstituted R1and thus obtaining the compounds of formula VIIIb. Then the compounds of formula VIIIb with only one leaving group, RVIcan be subjected to interaction with secondary amines of the formula III preferably from room temperature to 100°C in the presence of such an OS is return, acetone, methyl ethyl ketone, N,N-dimethylformamide or dimethyl sulfoxide, to obtain the derivatives of formula 1-6.

Benzazepine formula III-1 with different schemas substitution in the benzene fragment, optional with additional alkyl substituents in Asenova ring (for example 1,1,5,5-tetramethyl-2,3,4,5-tetrahydro-1H-3-benzazepin [Ger. Offen., DE 1921861 691120; CAS 72: 31646]) are known [see, for example, J. Heterocycl. Chem. (1971), 8(5), 779-83]. Alternatively, they can be obtained according to the method shown in scheme VI [see J. Med. Chem. (1984) 27, 918-921, which describes a similar sequence of reactions]: conversion of optionally substituted phthalic anhydrides of the formula XIV in the corresponding complex of dimethyl esters with sulfuric acid in methanol at reflux, followed by reduction of the ester of dibasic acid with lithium aluminum hydride in diethyl ether or tetrahydrofuran at a temperature in the range from room temperature up to 60°C and the transformation resulting from this diode formula XVI using thionyl chloride in a solvent such as toluene or dichloromethane, in the presence of such bases as pyridine, at a temperature in the range from room temperature up to 60°With the s XVIII can be carried out using sodium cyanide or potassium hydroxide in solvents such as dimethyl sulfoxide or N,N-dimethylformamide at a temperature in the range from room temperature up to 80°C. After this can be done reductive cyclization of dinitriles formula XVIII in benzazepine formula III-1 using Raney Nickel in a mixture of concentrated aqueous ammonia and ethanol at a temperature of approximately 100°C according to the method described in J. Heterocycl. Chem. (1971), 8(5), 779-83.

Benzazepine formula III-2 and III-3, having a keto-, respectively hydroxypoly in the benzyl position azepino rings can be obtained almost similar to the method described for obtaining thieno[2,3-d]azepino [J. Heterocyclic Chemistry 22, 1011 (1985)] (scheme VII): precursors of acid chlorides of formula XIX, preferably having a protective totalexpense on the function of the secondary nitrogen, cyclist in such an inert solvent as 1,2-dichloroethane, dichloromethane or nitrobenzene, in the presence as catalyst of such Lewis acids as trichloride aluminum, the tin tetrachloride or pentachloride phosphorus at temperatures from -40°C to 80°C receives the protected ketone of formula XX. After that klobenstein formula III-3 is produced by cleavage of the N-toiley functions using Hydrobromic acid in when the AK hydroxybenzamide formula III-2 can be obtained by simultaneous recovery of metafunction and removal of the protective N-toiley function by treatment of bis(methoxyethoxy)aluminum hydride, sodium in toluene at reflux.

Labeled amine, such as 1,1,2-Tricity-2,3,4,5-tetrahydro-1H-benzo[d]azepin formula III-4, suitable as predecessor in obtaining labeled compounds of formula I according to the synthesis schemes I-V, can be obtained according to the method presented in scheme VIII. 1-(5-bromo-1,2-dihydrobenzo[d]azepin-3-yl)Etalon formula XXII can be obtained by reacting 1-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)ethanone formula XXI [J. Heterocycl. Chem. (1971), 8(5), 779-83] with N-bromosuccinimide in carbon tetrachloride in the presence of such radical initiator, as Dibenzoyl peroxide or 1,1’-azobis(cyclohexanecarbonitrile), preferably at reflux. Hydrogenation of 1-(5-bromo-1,2-dihydrobenzo[d]azepin-3-yl) ethanone formula XXII with gaseous tritium with a palladium or platinum catalyst in solvents such as methanol, ethanol or ether, such as tetrahydrofuran, in the presence of such a base as triethylamine, leads to the production of 1-(1,1,2-Tricity-1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)ethanone formula XXIII, which can be converted into 1-(1,1,2-Tricity-1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)ethanone formula III-4 using concentrated aqueous solution of hydrochloric acid what is the nature of the connection, destined to become Sol. For the formation of pharmaceutically acceptable salts of basic compounds of formula I suitable inorganic or organic acid, such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid or citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonate acid, paratoluenesulfonyl acid, etc., For the formation of pharmaceutically acceptable salts of acidic compounds of formula I suitable compounds containing alkali metals or alkaline-earth metals, for example sodium, potassium, calcium, or magnesium, etc., basic amines or basic amino acids.

The compounds of formula I and their pharmaceutically acceptable salts, as mentioned above, are antagonists of metabotropic glutamate receptors and can be used for the treatment or prevention of acute and/or chronic neurological disorders such as epilepsy, stroke, chronic and acute pain, psychosis, schizophrenia, Alzheimer's disease, impairment of cognitive abilities and memory deficiency. Other indications of preventable by retransplantation, inadequate blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycaemia. The following indications treatable, are Huntington's chorea, amyotrophic lateral sclerosis (als), dementia caused by AIDS, eye injuries, retinopathy, idiopathic parkinsonism or parkinsonism caused by medicaments, as well as the condition in which due to the deficit of glutamate functions, such as, for example, muscle spasms, convulsions, migraine, urinary incontinence, addiction to nicotine, addiction to drugs, anxiety, vomiting, dyskinesia and depression.

Compounds according to the invention are receptor antagonists of group I mGluR.

a) Functional analysis of receptor antagonists of group I mGluR

cDNA that encodes a receptor mGluR1a rats, obtained from Professor S. Nakanishi (Kyoto, Japan), was transfectional within a short period of time the cell line HEK-EBNA according to the method described by Schlager and others, New Dev. New Appl. Anim. Cell Techn., Proc. ESACT Meet., 15th ed., (1998), 105-112 and 117-120. Level measurement of [CA2+]i was performed on the cell line HEK-EBNA, transfection mGluR1a, after incubation of the cells with Fluo-3 AM (Konechnaya salt Khanka and 20 mm HEPES). Level measurement of [CA2+]i was performed using fluorometrically tomographic tablet reader (type FLIPR, the company Molecular Devices Corporation, La Jolla, PCs California, USA). To evaluate the effectiveness of the antagonists used 10 μm glutamate as an agonist.

For 5 min before making agonist cells were treated with increasing concentrations of antagonists. Based inhibition (antagonists) were approximatively 4-parametric logarithmic equation, obtaining the values of the IC50and hill coefficient using the program Origin (firm Microcal Software Inc., Northampton, PCs Minnesota, USA), designed for iterative non-linear curve approximation.

Preferred compounds are the values of the IC50in the range of 0.001 to 1.00 μm (F-IC50).

b) study of the characteristics of the connection as antagonists of mGluR1 by analyzing binding

Analysis of the binding titrovannam 1-ethyl-2-methyl-6-oxo-4-(1,1,2-Tricity-1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile: Cell line SOME 293 was transfectional within a short period of time the receptor mGluR1a rats. The cells were collected and washed three times SFR. Cellular debris was frozen at -80°With the I in the buffer for binding HEPES, containing 20 mm NaOH, pH of 7.4, was used in experiments on the binding of 10 µg of protein for analysis. 1-Ethyl-2-methyl-6-oxo-4-(1,1,2-tritio-1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (S. A. 33,4 CI/mmol) was used at a final concentration of 3 nm. Incubation with various concentrations of potential inhibitors was carried out for 1 h at room temperature, after which incubat filtered through glass fiber filter GF/B, pre-incubated for 1 h in 0.1% PEI and washed three times with 1 ml of cold buffer for binding. The radioactivity remaining on the filter type unifilter 96, counted by a counter-radiation type Topcount. After correction for nonspecific binding data were standardized and calculated the value of the IC50using a 4-parametric logarithmic equations, which were approximatively inhibition curve.

Preferred compounds are the values of the IC50in the range of 0.001 to 1.00 μm (B-IC50).

The following table presents some data on the specific activity of the preferred compounds are:

The compounds of formula I and their pharmaceutically acceptable salts can PE compositions can be administered by oral, for example, in the form of tablets, coated tablets, pills, gelatin capsules, hard and soft coating, solutions, emulsions or suspensions. However, the introduction can also be rectal route, for example, in the form of suppositories, or parenterally, for example in the form of solutions for injection.

To prepare the pharmaceutical compositions of the compounds of formula I and their pharmaceutically acceptable salts can be processed together with pharmaceutically inert, inorganic or organic carriers. As such carriers for tablets, coated tablets, coated tablets and gelatin capsules with a hard coating can be applied, for example, lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc., are Suitable carriers for gelatin capsules with a soft coating are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols etc., however in the case of gelatin capsules, soft coated depending on the nature of the active substance carriers usually are not required. Suitable carriers in the preparation of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose, etc., For aqueous solutions is Lily, glycerin, vegetable oil, etc., but, as a rule, they are not necessary. Suitable carriers for suppositories are, for example, natural or hydrogenated oils, waxes, fats, semi-solid or liquid polyols etc.,

In addition, the pharmaceutical compositions can contain preservatives, soljubilizatory, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, corrigentov, salts for modifying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain other valuable in therapeutic relationship substance.

As mentioned above, an object of the present invention are also medicinal product containing a compound of formula I or its pharmaceutically acceptable salt and a therapeutically inert excipient, as well as the method of preparation of such medicines, including obtaining a galenical dosage form based on the one or more compounds of the formula I or their pharmaceutically acceptable salts and optionally one or more other securities in therapeutic ratio of nutrients in combination with one or more pharmaceutically inert carrier.

Finally, as noted earlier, the object of the present invention is also the use of compounds of the formula I and their pharmaceutically acceptable salts for the preparation of drugs, primarily for the control or prevention of acute and/or chronic neurological diseases specified type.

Example 1

2-Methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-4-ol

The suspension containing 2.0 g (9.8 mmole) of 2-methyl-4-methoxy-5-nitro-6-chloropyrimidine [Helv. (1958), 41, 1806], 1,98 g (10.8 mmole) of the hydrochloride 2,3,4,5-tetrahydro-1H-benzo[C1]azepino [J. Heterocycl. Chem. (1971), 8(5), 779-83] and 4,08 g (to 29.5 mmole) of potassium carbonate in 40 ml of N,N-dimethylformamide, was stirred for 2 h at 120°C. Then the reaction mixture was allowed to cool to room temperature, was poured into 150 ml of a mixture of ice/water and was extracted three times with 200 ml dichloromethane. United organicism high vacuum. After crystallization from ethyl acetate/methanol received 1,95 g (6.5 mmole), 66,1%, 2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-4-ol in the form of a solid yellow; tPL>200°C; MS: [M+H]+=301.

Example 2

3-Ethyl-2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-3H-pyrimidine-4-one

Using as initial products of 2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-4-ol and Iodate, potassium carbonate in N,N-dimethylformamide (at room temperature) were specified in the title compound in the form of solid yellow; tPL145-147°C; MS: [M+H]+=329; see example 3.

Example 3

3-(6-Ethoxy-2-methyl-5-nitropyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin

The suspension containing of 0.30 g (1.0 mmol) of 2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-4-ol (example 1), 0.24 g (1.5 mmole) of ethyliodide and 0.28 g (2.0 mmole) of potassium carbonate in 10.0 ml of N,N-dimethylformamide, was stirred at room temperature for 24 h Then the reaction mixture was poured into 50 ml of a mixture of ice/water and was extracted three times with 100 ml dichloromethane. The combined organic phases are washed twice with 50 ml water, dried over magnesium sulfate, oparians by chromatography on silica gel, using as eluent a mixture of hexane and ethyl acetate (9:1 to 1:1 vol./vol.), resulting received 0,245 g (0,746 mmole), 74,6%, 3-ethyl-2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-3H-pyrimidine-4-it is in the form of a solid yellow; tPL145-147°C; MS: [M+H]+=329; and 0,070 g (mmole 0,213), 21,3%, 3-(6-ethoxy-2-methyl-5-nitropyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine in the form of a yellow oil; MS: [M+H]+=329.

Example 4

3-(6-Methoxy-2-methyl-5-nitropyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin

The solution containing 0,204 g (1.0 mmol) of 2-methyl-4-methoxy-5-nitro-6-chloropyrimidine [Helv. (1958), 41, 1806], 0,20 g (1.1 mmole) of the hydrochloride 2,3,4,5-tetrahydro-1H-benzo[d]azepine [J. Heterocycl. Chem. (1971), 8(5), 779-83] and 0.30 g (3.0 mmole) of triethylamine in 10.0 ml of N,N-dimethylformamide, was stirred at room temperature for 60 hours and Then the reaction mixture was poured into 50 ml of a mixture of ice/water and was extracted three times with 60 ml of dichloromethane. The combined organic phases are washed twice with 50 ml water, dried over magnesium sulfate, evaporated under reduced pressure and dried in high vacuum. Then, the thus obtained residue was led from dichloromethane/hexane, getting 0.28 g (0.9 mmole), 90%, 3-(6-methoxy-2-methyl-5-nitropyrimidin-Rimer 5

2,3-Dimethyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-3H-pyrimidine-4-one

According to the method described in example 3, 2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-4-ol was treated with methyliodide in N,N-dimethylformamide in the presence of potassium carbonate, resulting in the obtained 2,3-dimethyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-3H-pyrimidine-4-one in the form of a yellow foam; MS: [M+H]+=315.

Example 6

3-Butyl-2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-3H-pyrimidine-4-one

Using as initial products of 2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-4-ol and 1-idbutton, potassium carbonate in DMF at room temperature) were specified in the title compound in the form of solid yellow; tPL158-161°C; MS: [M+H]+=357; see example 7.

Example 7

3-(6-Butoxy-2-methyl-5-nitropyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo [d] azepin

According to the method described in example 3, 2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-4-ol was treated with 1-igbotako in N,N-dimethylformamide in the presence of potassium carbonate, resulting in the received 3-butyl-2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-3H-p is-5-nitropyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin in the form of a yellow oil MS: [M+H]+=357.

Example 8

3-Isobutyl-2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-3H-pyrimidine-4-one

According to the method described in example 3, 2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-4-ol was treated with 1-iodine-2-methylpropanol in N,N-dimethylformamide at 80°C in the presence of potassium carbonate, resulting in the received 3-isobutyl-2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-3H-pyrimidine-4-one in the form of butter, light brown MS: [M+H]+=357.

Example 9

3-Isopropyl-2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-3H-pyrimidine-4-one

According to the method described in example 3, 2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-4-ol was treated with 2-jumprope in N,N-dimethylformamide in the presence of potassium carbonate, resulting in the received 3-isopropyl-2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-3H-pyrimidine-4-one as yellow oil MS: [M+H]+=343.

Example 10

3-(2-Foradil)-2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-3H-pyrimidine-4-one

According to the method described in example 3, 2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-4-ol was treated with 1-bromo-2-floridanum in N,N-dimethylformamide in obeso[d]azepin-3-yl)-3H-pyrimidine-4-one as yellow oil MS: [M+H]+=347.

Example 11

2-Methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-3-(2,2,2-triptorelin)-3H-pyrimidine-4-one

According to the method described in example 3, 2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-4-ol was treated with 2,2,2-triptoreline in N,N-dimethylformamide in the presence of potassium carbonate at 80°C, resulting in a received 2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-3-(2,2,2-triptorelin)-3H-pyrimidine-4-one in the form of butter, light brown MS: [M+H]+=383.

Example 12

2-Methyl-5-nitro-3-propyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-3H-pyrimidine-4-one

According to the method described in example 3, 2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-4-ol was treated with 1-chloropropanol in N,N-dimethylformamide in the presence of potassium carbonate at 50°C, resulting in a received 2-methyl-5-nitro-3-propyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-3H-pyrimidine-4-one in the form of a solid yellow MS: tPL164-170°C; [M+H]+=343.

Example 13

2-Amino-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril

a) a Solution containing 2,13 g (9,80 mmole) ethyl-2-cyan-3,3-bis(methylthio)acrylate and of 1.80 g (9,80 mmole) of hydrocarbonate potassium in 15 ml of ethanol, was kept at reflux for 8 hours Then the reaction mixture was evaporated and the residue was chromatographically on silica gel, using as eluent a mixture of dichloromethane and simple ether (97:3.vol.). The result was obtained 2.0 g (6.3 mmole), 64% of E - and/or Z-isomer ethyl ester 2-cyan-3-methylsulfanyl-3-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)acrylic acid in the form of a solid yellowish; tPL88-93°C; MS: [M]+=316.

b) a Solution containing 0,253 g (0,80 mmole) E - and/or Z-isomer ethyl ester 2-cyan-3-methylsulfanyl-3-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)acrylic acid, 0,199 g (1,60 mmole) of guanidine nitrate and 0,376 g (2,40 mmole) of 1,8-diazabicyclo[5,4,0]undec-7-ene in 1.0 ml of N,N-dimethylformamide, kept at 100°C for 2 h then the reaction mixture was poured into 10 ml of ice-cold water, acidified 1H. hydrochloric acid, the precipitate was filtered and washed with water, and then a simple ether. Thus received 0,180 g (of 0.64 mmole), 80%, 2-amino-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile in the form of colorless solids; tPL>200°C; MS: [M]+=281.

Example 14

2,4-Dioxo-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl) is on ether 2-cyan-3-methylsulfanyl-3-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)acrylic acid [example 13 a)], 0,142 g (of 0.50 mmole) sulfate S-methylthymidine and 0,228 g (1.50 mmole) of 1,8-diazabicyclo [5,4,0] undec-7-ene in 1.0 ml of N,N-dimethylformamide, was stirred for 3 h at 100°C. After the reaction mixture was poured into 10 ml of ice water and filtered, the filtrate was acidified using 1N. hydrochloric acid and again filtered. The combined residues were chromatographically on silica gel, using as eluent a mixture of dichloromethane and ethyl acetate (2:1 vol./vol.). The result has been 0,063 g (0,192 mmole), 38%, Z and/or E-isomer ethyl ester 2-cyan-3-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-3-raidoactive acid as colorless solids; tPL183-186°C; MS: [M]+=328; and 0,0087 g (0,031 mmole), 6.1%, and 2,4-dioxo-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,2,3,4-tetrahydropyrimidin-5-carbonitrile in the form of colorless solids; tPL>200°C; MS: [M+H]+=283.

Example 15

6-Oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril

0,070 g (3.0 mmole) of sodium was dissolved in 8.0 ml of ethanol, then added 0,316 g (1.0 mmol) of Z and/or E-isomer ethyl ester 2-cyan-3-methylsulfanyl-3-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)acrylic acid [example 13 a)] and 0,164 g (2.0 mmole) of the hydrochloride of formamidine and the reaction mixture Abbatiale 30 ml of ice water, and then 1H. hydrochloric acid and was extracted three times with 50 ml of a mixture of dichloromethane and methanol (95:5 vol./vol.). The combined organic extracts were dried over magnesium sulfate and evaporated again. Thereafter, the resulting residue was chromatographically on silica gel, using as eluent a mixture of dichloromethane and methanol (98:2 vol./vol.). The result has been 0,144 g (0,054 mmole), 54%, 6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile in the form of colorless solids; tPL>200°C; MS: [M]+=266.

Example 16

4-Oxo-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-2-thioxo-1,2,3,4-tetrahydropyrimidin-5-carbonitril

According to the method described in example 15, Z and/or E-isomer ethyl ester 2-cyan-3-methylsulfanyl-3-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)acrylic acid [example 13A)] and thiourea dissolved in ethanol, kept at the reflux in the presence of ateleta sodium, resulting in the received 4-oxo-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-2-thioxo-1,2,3,4-tetrahydropyrimidin-5-carbonitrile in the form of colorless solids; tPL>200°C; MS: [M]+=299.

Example 17

2-Methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-digial-3-methylsulfanyl-3-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)acrylic acid [example 13A)], 0,0975 g (1.0 mmol) of the hydrochloride of acetamidine and 0,235 g (1.5 mmole) of 1,8-diazabicyclo[5.4.0]undec-7-ene in 1.0 ml of N,N-dimethylformamide, was stirred for 2 h at 100°C. After the reaction mixture was poured into 30 ml of ice water and acidified using 1N. the hydrochloric acid. The resulting residue was filtered and then was chromatographically on silica gel, using as eluent a mixture of dichloromethane and methanol (95:5 vol. /about.). The result has been 0,0965 g (0,34 mmole), 69%, 2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile in the form of colorless solids; tPL>200°C; MS: [M]+=281.

Example 18

2-Cyclopropyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril

According to the method described in example 15, Z and/or E-isomer ethyl ester 2-cyan-3-methylsulfanyl-3-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)acrylic acid [example 13A)] was treated with the hydrochloride of cyclopropylamine in ethanol at reflux in the presence of ateleta sodium, resulting in a received 2-cyclopropyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile in the form of colorless solids; tPL>200°C; MS: [M]+=Itemid

According to the method described in example 17 the Z and/or E-isomer ethyl ester 2-cyan-3-methylsulfanyl-3-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)acrylic acid [example 13A)] was treated with the hydrochloride of malonamide and 1,8-diazabicyclo[5.4.0]undec-7-Yong in N,N-dimethylformamide at 100°C the result that was obtained 2-[5-cyan-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-2-yl] ndimethylacetamide in the form of a solid of light yellow color; tPL>200°C; MS: [M]+=324.

Example 20

6-Oxo-2-phenylsulfonyl-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril

According to the method described in example 17 the Z and/or E-isomer ethyl ester 2-cyan-3-methylsulfanyl-3-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl) acrylic acid [example 13A)] was treated with the hydrochloride of 2-(phenylthio)acetamidine and 1,8-diazabicyclo[5.4.0]undec-7-Yong in N,N-dimethylformamide at 100°C as a result, we obtained 6-oxo-2-phenylsulfonyl-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile in the form of colorless solids; tPL189-194°C; MS: [M+H]+=389.

Example 21

2-Dimethylamino-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrides[d]azepin-3-yl)acrylic acid [example 13 a)] was treated with sulfate 1,1-dimethylguanidine and 1,8-diazabicyclo[5.4.0]undec-7-Yong in N,N-dimethylformamide at 100°C as a result, we got 2-dimethylamino-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile in the form of colorless solids; tPL>200°C; MS: [M+H]+=310.

Example 22

2-[2-(1,3-Dioxo-1,3-dihydroindol-2-yl)ethyl]-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril

According to the method described in example 17 the Z and/or E-isomer ethyl ester 2-cyan-3-methylsulfanyl-3-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl) acrylic acid [example 13A)] was treated with the hydrochloride of 3-(1,3-dioxo-1,3-dihydroindol-2-yl)propionamide [international patent application PCT WO 9503305 A1 950202; SA 123:256545] and 1,8-diazabicyclo[5.4.0]undec-7-Yong in N,N-dimethylformamide at 100°C, the result of which was obtained 2-[2-(1,3-dioxo-1,3-dihydroindol-2-yl)ethyl]-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile in the form of colorless solids; tPL>200°C; MS: [M+H]+=440.

Example 23

6-Oxo-2-propyl-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril

According to the method described in example 17 the Z and/or E-isomer ethyl ester 2-cyan-3-methylsulfanyl-3-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl) acrylic acid [pri°C as a result, we obtained 6-oxo-2-propyl-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile in the form of colorless solids; tPL191-193°C; MS: [M+H]+=309.

Example 24

2-(2-Hydroxyethyl)-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril

According to the method described in example 17 the Z and/or E-isomer ethyl ester 2-cyan-3-methylsulfanyl-3-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl) acrylic acid [example 13A)] was treated with the hydrochloride of 3-hydroxypropionitrile (1:1) [Tetrahedron Lett. (1990), 31(14), 1969-72] and 1,8-diazabicyclo[5.4.0]undec-7-Yong in N,N-dimethylformamide at 100°C, the result of which was obtained 2-(2-hydroxyethyl)-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile in the form of a solid of light yellow color; tPL183,5-188°C; MS: [M+H]+=311.

Example 25

2 Ethylamino-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril

According to the method described in example 15, Z and/or E-isomer ethyl ester 2-cyan-3-methylsulfanyl-3-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)acrylic acid [example 13A)] and sulfate 1-ethylguanidine, dissolved in ethanol, was passed by heating with obratilsa[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile in the form of colorless amorphous solid; MS: [M]+=310.

Example 26

1,2-Dimethyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril

According to the method described in example 3, 2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 17) was treated with methyliodide in N,N-dimethylformamide in the presence of potassium carbonate, resulting in a received 1,2-dimethyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile in a solid pink color; tPL155-158°C; MS: [M]+=295.

Example 27

1-Ethyl-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril

Using as initial products of 2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril, Iodate, N,N-dimethylformamide, potassium carbonate, has been specified in the title compound as colorless solids; tPL154,5-158°C; see example 28.

Example 28

4 Ethoxy-2-methyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile

According to the method described in example 3, 2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 17) about the-2-methyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile in the form of colorless solids; tPL106-109°C; MS: [M+H]+=309; and 1-ethyl-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile in the form of colorless solids; tPL154,5-158°C.

Example 29

2-Amino-4-ethoxy-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile

Using as initial products 2-amino-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril, potassium carbonate, Iodate, N,N-dimethylformamide, potassium carbonate, has been specified in the title compound as colorless amorphous solid; MS: [M+H]+=310; see example 31.

Example 30

2-Amino-1-ethyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril

Using as initial products 2-amino-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril, potassium carbonate, Iodate, N,N-dimethylformamide, got mentioned in the title compound as colorless solids; tPL195-203°C; MS: [M+H]+=310; see example 31.

Example 31

1-Ethyl-2-ethylamino-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril

According to the method described in atively jumatano in N,N-dimethylformamide in the presence of potassium carbonate, as a result, we obtained 2-amino-4-ethoxy-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile in the form of colorless amorphous solid; MS: [M+H]+=310; 2-amino-1-ethyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile in the form of colorless solids; tPL195-203°C; MS: [M+H]+=310; and 1-ethyl-2-ethylamino-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile in the form of colorless amorphous solid; MS: [M+H]+=338.

Example 32

1-Cyclopropylmethyl-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril

Using as initial products of 2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril, bromelicola, potassium carbonate, N,N-dimethylformamide, got mentioned in the title compound as colorless solids; tPL157-161°C; MS: [M+H]+=335; see example 33.

Example 33

4 Cyclopropylmethoxy-2-methyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl) pyrimidine-5-carbonitrile

According to the method described in example 3, 2-amino-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril (the ATA which received 1-cyclopropylmethyl-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile in the form of colorless solids; tPL157-161°C; MS: [M+H]+=335; and 4 cyclopropylmethoxy-2-methyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile in the form of colorless solids; tPL119-122°C; MS: [M+H]+=335.

Example 34

1-Allyl-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril

According to the method described in example 3, 2-amino-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 17) was treated with allylbromide in N,N-dimethylformamide in the presence of potassium carbonate, which was obtained 1-allyl-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile in the form of colorless solids; tPL141-144°C; MS: [M+H]+=321.

Example 35

1-Lanmeter-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril

Using as initial products of 2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril, bromoacetonitrile, potassium carbonate, N,N-dimethylformamide, got mentioned in the title compound as colorless solids; tPL>200°C; MS: [M+H]+=320; see example 36.

Example 36

<, is written in example 3, 2-amino-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 17) was treated with bromoacetonitrile in N,N-dimethylformamide in the presence of potassium carbonate, resulting in the received 1-lanmeter-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile in the form of colorless solids; tPL>200°C; MS: [M+H]+=320; and 4 cyanotoxin-2-methyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile in the form of colorless amorphous solid; MS: [M+H]+=320.

Example 37

1-(2-Dimethylaminoethyl)-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril

According to the method described in example 3, 2-amino-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 17) was treated with the hydrochloride of 1-chloro-2-dimethylaminoethanol in N,N-dimethylformamide in the presence of potassium carbonate, which was obtained 1-(2-dimethylaminoethyl)-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile in the form of colorless solids; tPL134-139°C; MS: [M+H]+=352.

Example 38

1-Ethyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d] is tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril, Iodate, potassium carbonate, N,N-dimethylformamide, received specified in the title compound in the form of solids yellowish; tPL138-140°C; MS: [M+H]+=295; see example 39.

Example 39

1 Ethoxy-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile

According to the method described in example 3, 6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 15) were treated with jumatano in N,N-dimethylformamide in the presence of potassium carbonate, which was obtained 1-ethyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile in the form of a solid yellowish; tPL138-140°C; MS: [M+H]+=295; and 1 ethoxy-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile in the form of colorless amorphous solid; MS: [M+H]+=295.

Example 40

1-Isopropyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril

According to the method described in example 3, 6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 15) was treated with 2-jumprope in N,N-dimethylformamide in the presence of potassium carbonate, which was obtained 1-isopropyl-6-oxo-4-(1,2,4,5-then it is carbonated is FROM: [M+H]+=309.

Example 41

1-(2-Hydroxyethyl)-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril

According to the method described in example 3, 6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 15) was treated with 2-bromoethanol in N,N-dimethylformamide in the presence of potassium carbonate, which was obtained 1-(2-hydroxyethyl)-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile in the form of a solid light pink color; tPL167-171°C; MS: [M+H]+=311.

Example 42

Methyl ester [5-cyan-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6N-pyrimidine-1-yl]acetic acid

According to the method described in example 3, 6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 15) were treated with methylbromide in N,N-dimethylformamide in the presence of potassium carbonate, resulting in the obtained methyl ester [5-cyan-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6N-pyrimidine-1-yl]acetic acid in the form of a solid of light yellow color; tPL156 TO 160°C; MS: [M+H]+=339.

Example 43

1-Methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-ka is kidin-5-carbonitrile (example 15) were treated with methyliodide in N,N-dimethylformamide in the presence of potassium carbonate, the result that was obtained 1-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile in the form of colorless solids; tPL197-203°C; MS: [M+H]+=281.

Example 44

2-Amino-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-3H-pyrimidine-4-one

According to the method described in example 1, 2-amino-6-chloro-5-nitropyrimidin-4-ol [J. Chem. Soc. 1964, 4769-4774] processed hydrochloride 2,3,4,5-tetrahydro-1H-benzo[d]azepine [J. Heterocycl. Chem. (1971), 8(5), 779-83] in N,N-dimethylformamide/potassium carbonate at 140°C, resulting in the obtained 2-amino-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-3H-pyrimidine-4-one in the form of a solid yellow; tPL275°C (decomp.).

Example 45

N-[5-nitro-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-2-yl]ndimethylacetamide

A solution containing of 0.30 g (1.0 mmol) 2-amino-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-3H-pyrimidine-4-it (example 44) in 1.0 ml of acetic anhydride and 1.0 ml of pyridine was stirred for 2 h at 60°C. the Reaction mixture was poured into 25 ml of ice water and acidified using 1N. solution of hydrochloric acid. The resulting residue was filtered and washed with water and simple ether. The result has been 0,302 g (from 0.88 mmole), 88%and yellow; tPL>200°C; [M]+=344.

Example 46

3-(6-Methoxy-5-nitropyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin

a) a Solution containing 0,396 g (2.0 mmole) of 4,6-dichloro-5-nitropyrimidine and 0,367 g (2.0 mmole) of the hydrochloride 2,3,4,5-tetrahydro-[d]-benzo[d]azepine [J. Heterocycl. Chem. (1971), 8(5), 779-83] in 30 ml of N,N-dimethylformamide was slowly treated at a temperature of 0-5°With 0.70 ml (5.0 mmole) of triethylamine and the reaction mixture was stirred at the same temperature for 2 hours Then it was poured into 50 ml of a mixture of ice/water and was extracted three times with 100 ml dichloromethane. The combined organic phases are washed twice with 50 ml water, dried over magnesium sulfate, evaporated under reduced pressure and dried in high vacuum. Thus obtained crude product was purified by chromatography on silica gel, using as eluent a mixture of dichloromethane and methanol (99:1.vol.), as a result, received 0,54 g (1,78 mmole), 88,9%, 3-(6-chloro-5-nitropyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine in the form of a solid yellow; tPL165-171°C; [M+H]+=305.

b) 0,305 g (1.0 mmol) 3-(6-chloro-5-nitropyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine suspended in 15 ml of methanol and treated with 0.93 ml (5 mmol) of the bromide solution is for 4 h at room temperature, then was filtered. The obtained crystals were washed with hexane and dried in high vacuum. Thus received is 0.260 g (0,866 mmole) of 3-(6-methoxy-5-nitropyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine in the form of a solid yellow; tPL147-150°C; [M+H]+=301.

Example 47

5-Nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-4-ol

a) 0,183 g (1.3 mmole) 4-methoxybenzylthio alcohol was dissolved in 10 ml of tetrahydrofuran, then added 0,048 g (1.1 mmole) of a dispersion of sodium hydride (55% in mineral oil), and then 0,305 g (1.0 mmol) 3-(6-chloro-5-nitropyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine [example 46a)], dissolved in 5 ml of tetrahydrofuran. Then the reaction mixture was stirred at room temperature, was poured into 50 ml of a mixture of ice/water and was extracted three times with 50 ml of ethyl acetate. The combined organic phases are washed twice with 50 ml water, dried over magnesium sulfate, evaporated under reduced pressure and was purified by chromatography on silica gel, using as eluent dichloromethane, resulting in received 0,41 g (1.3 mmole), 100%, 3-[6-(4-methoxybenzyloxy)-5-nitropyrimidin-4-yl]-2,3,4,5-tetrahydro-1H-benzo[d]azepin in the form of a solid yellow; tPLthe DRO-1H-benzo[d]azepine was dissolved in 5.0 ml of methanol and was treated with 0.63 ml of 1.5 M solution of hydrochloric acid in methanol and the reaction mixture was stirred at room temperature for 2 hours The resulting crystals were filtered off, washed with hexane and dried in high vacuum, receiving 0,069 g (0,241 mmole), 98%, 5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-4-ol in the form of a solid yellow; tPL>200°C; [M-H]-=285.

Example 48

5-Nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-4-ylamine

0,305 g (1.0 mmol) 3-(6-chloro-5-nitropyrimidin-4-yl)-2,3,4,5-tetrahydro-[d]-benzo[d]azepine [example 46a)] was dissolved in 15 ml of tetrahydrofuran and treated to 0.22 ml of 25% aqueous ammonia solution and stirred at room temperature for 60 hours and Then the reaction mixture was evaporated to dryness and the thus obtained crude product was purified by chromatography on silica gel, using as eluent a mixture of dichloromethane and methanol (98:2 vol./vol.), resulting received 0,219 g (0,768 mmole), with 76.8%, 5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-4-ylamine in the form of a solid yellow; tPL>200°C; [M+H]+=286.

Example 49

Methyl-[5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-4-yl]amine

According to the method described in example 48, 3-(6-chloro-5-nitropyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine [example 46a)] processing the received methyl-[5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-4-yl]amine in the form of a solid yellow; tPL144-146°C; [M+H]+=300.

Example 50

Cyclopropyl-[5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl) pyrimidine-4-yl] amine

According to the method described in example 48, 3-(6-chloro-5-nitropyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine [example 46a)] were treated with cyclopropylamine in tetrahydrofuran at room temperature, resulting in a received cyclopropyl-[5-nitro-6-(1,2,4,5-tetrahydrobenzo-zo[d]azepin-3-yl)pyrimidine-4-yl]amine in the form of a solid of light yellow color; tPL135-138°C; [M+H]+=326.

Example 51

Methyl ester [5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-4-ylsulphonyl]acetic acid

According to the method described in example 48, 3-(6-chloro-5-nitropyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine [example 46a)] were treated with methylthioribose and triethylamine in methanol at reflux, resulting in the obtained methyl ester [5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-4-ylsulphonyl]acetic acid in the form of a solid yellow; tPL113-115°C; [M+H]+=375.

Example 52

6-Methyl-2-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)nicotinamide

0,509 g (3.3 mmole) of 2-chloro-3-qi is(6.6 mmole) of potassium carbonate was dissolved in 3.0 ml of acetonitrile and kept at reflux for 16 hours Then the reaction mixture was allowed to cool to room temperature, was poured into 30 ml of a mixture of ice/water and was extracted three times with 50 ml dichloromethane. The combined organic phases are washed twice with 50 ml water, dried over magnesium sulfate, evaporated under reduced pressure and dried in high vacuum. Thus obtained crude product was purified by chromatography on silica gel, using as eluent a mixture of hexane and ethyl acetate (4:1 vol./vol.), resulting received 0,724 g (to 2.75 mmole) of 6-methyl-2-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)nicotinanilide in the form of colorless solids; tPLOF 78.5 80,7°C; [M]+=263.

Example 53

2-(1,2,4,5-Tetrahydrobenzo[d]azepin-3-yl)benzonitrile

According to the method described in example 52, 2-Lanthenay ether triftormetilfullerenov acid [J. Org. Chem. (1992), 57(5), 1481-6] and hydrochloride 2,3,4,5-tetrahydro-1H-benzo[d]azepine [J. Heterocycl. Chem. (1971), 8(5), 779-83] was treated with potassium carbonate in acetonitrile at reflux, receiving 2-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)benzonitrile in the form of a solid yellowish; tPL68-74°C; [M]+=248.

Example 54

3-(3-Nitropyridine-2-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azaserine [J. Heterocycl. Chem. (1971), 8(5), 779-83] was treated with potassium carbonate in acetonitrile at reflux, getting 3-(3-nitropyridine-2-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin in the form of a solid yellow; tPL129-136°C.

Example 55

2-(1,2,4,5-Tetrahydrobenzo[d]azepin-3-yl)nicotinamide

According to the method described in example 52, chloronicotinamide and hydrochloride 2,3,4,5-tetrahydro-1H-benzo[d]azepine [J. Heterocycl. Chem. (1971), 8(5), 779-83] was treated with potassium carbonate in acetonitrile at reflux, receiving 2-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)nicotine-nitrile as a colorless solids; tPL110-112,5°C; [M]+=249.

Example 56

3-(2-Nitrophenyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin

According to the method described in example 52, 2-nitrophenyloctyl ether triftormetilfullerenov acid [J. Org. Chem. (1992), 57(5), 1481-6] and hydrochloride 2,3,4,5-tetrahydro-1H-benzo[d]azepine [J. Heterocycl. Chem. (1971), 8(5), 779-83] was treated with potassium carbonate in acetonitrile at reflux, getting 3-(2-nitrophenyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin in the form of an orange oil; [M+H]+=269.

Example 57

3-Methyl-2,4-dioxo-6-(1,2,4,5-tetrahydrobenzo[d]azepin-OIC ester 2-cyan-3-methylsulfanyl-3-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)acrylic acid [example 13A)] were treated with hemisulfate O-methylisoleucine and 1,8-diazabicyclo[5.4.0]undec-7-Yong in N,N-dimethylformamide at 100°C getting 3-methyl-2,4-dioxo-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,2,3,4-tetrahydropyrimidin-5-carbonitrile in the form of a solid of light yellow color; tPL>200°C; MS: [M+H]+=297.

Example 58

3-(3,5-Dinitropyridine-2-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin

According to the method described in example 4, 2-chloro-3,5-dinitropyridine and hydrochloride 2,3,4,5-tetrahydro-1H-benzo[d]azepine [J. Heterocycl. Chem. (1971), 8(5), 779-83] was treated with N,N-dimethylformamide in the presence of triethylamine at room temperature, obtaining 3-(3,5-dinitropyridine-2-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin in the form of a solid of light yellow color; tPL137-140°C; MS: [M+H]+=315.

Example 59

1-Methoxymethyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril

Using as initial products 6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril, simple methylchlorosilanes ether, sodium hydride, N,N-dimethylformamide, got mentioned in the title compound as colorless solids; tPL160-162,5°C; MS: [M]+=310; see example 60.

Example 60

4-Methoxy-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile

PL160-162,5°C; MS: [M]+=310; and 0,021 g (0,076 mmole), 24%, 4 magocsi-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile in the form of colorless solids; tPL119-124,5°C; MS: [M]+=280.

Example 61

6-Oxo-1-[3-(2-oxazepan-1-yl)propyl]-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril

According to the method described in example 17 the Z and/or E-isomer ethyl ester 2-cyan-3-IU is rimidine and 1,8-diazabicyclo[5.4.0]undec-7-Yong in N,N-dimethylformamide at 100°C getting 6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 15) and 6-oxo-1-[3-(2-oxazepan-1-yl)propyl]-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile in the form of colorless solids; tPL139-140°C; MS: [M+H]+=420.

Example 62

6-(7,8-Dimethoxy-1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-2-methyl-5-nitro-3H-pyrimidine-4-one

According to the method described in example 1, 2-methyl-4-methoxy-5-nitro-6-chloropyrimidine [Helv. (1958), 41 1806] processed hydrochloride 7,8-dimethoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine [Ann. Chim. (Paris) (1966), 1(5/6), 221-54] in N,N-dimethylformamide/potassium carbonate at 120°C receives 6-(7,8-dimethoxy-1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-2-methyl-5-nitro-3H-pyrimidine-4-one in the form of a solid yellow; tPL268-270°C (decomp.); MS: [M+H]+=361.

Example 63

2-methyl-5-nitro-6-(5,6,8,9-tetrahydro-1,3-dioxa-7-azacycloheptan[f]inden-7-yl)-3H-pyrimidine-4-one

According to the method described in example 1, 2-methyl-4-methoxy-5-nitro-6-chloropyrimidine [Helv. (1958), 41 1806] processed hydrochloride 6,7,8,9-tetrahydro-5H-1,3-dioxa-7-azacycloheptan[f]indene [J. Heterocycl. Chem. (1972), 9(3), 617-21] in N,N-dimethylformamide/potassium carbonate at 120°C receives 2-methyl-5-nitro-6-(5,6,8,9-then it is carbonated is 258-262°C (sec.); MS: [M+H]+=345.

Example 64

2-methyl-5-nitro-6-(7-nitro-1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-3H-pyrimidine-4-one

According to the method described in example 4, 6-bromo-2-methyl-5-nitro-3H-pyrimidine-4-one (obtained from 2-methyl-4-methoxy-5-nitro-6-chloropyrimidine [Helv. (1958), 41 1806] and Hydrobromic acid (48% solution in water) in acetic acid at room temperature) was treated with 7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine [J. Heterocycl. Chem. (1971), 8(5), 779-83] in N,N-dimethylformamide in the presence of N-ethyl-N,N-Diisopropylamine at room temperature, obtaining 2-methyl-5-nitro-6-(7-nitro-1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-3H-pyrimidine-4-one in the form of a solid yellow; tPL237-238°C (decomp.); MS: [M+H]+=346.

Example 65

Amide 3-(2-methyl-5-nitro-6-oxo-1,6-dihydropyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-sulfonic acid

According to the method described in example 4, 6-bromo-2-methyl-5-nitro-3H-pyrimidine-4-one (obtained from 2-methyl-4-methoxy-5-nitro-6-chloropyrimidine [Helv. (1958), 41 1806] and Hydrobromic acid (48% solution in water) in acetic acid at room temperature) were treated with Amida 2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-sulfonic acid [Ger. Offen. DE 1921737] in N,N-DIMET is-oxo-1,6-dihydropyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-sulphonic acid in the form of a solid of light yellow color; tPL268-270°C (sec.); MS: [M+H]+=380.

Example 66

6-(7-Amino-1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-2-methyl-5-nitro-3H-pyrimidine-4-one

According to the method described in example 4, 6-bromo-2-methyl-5-nitro-3H-pyrimidine-4-one (obtained from 2-methyl-4-methoxy-5-nitro-6-chloropyrimidine [Helv. (1958), 41 1806] and Hydrobromic acid (48% solution in water) in acetic acid at room temperature) was treated 2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-aluminum [J. Heterocycl. Chem. (1971), 8(5), 779-83] in N,N-dimethylformamide in the presence of N-ethyl-N,N-Diisopropylamine at room temperature, receiving 6-(7-amino-1,2,4,5-tetrahydrobenzo[d] azepin-3-yl)-2-methyl-5-nitro-3H-pyrimidine-4-one in the form of a solid yellow; tPL218-220°C (decomp.); MS: [M+H]+=316.

Example 67

6-Oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-2-[2-(tetrahydropyran-2-yloxy)ethyl]-1,6-dihydropyrimidin-5-carbonitril

0,160 g (0,516 mmole) of 2-(2-hydroxyethyl)-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 24), 0,084 g (1.0 mmol) of 3,4-dihydro-2H-Piran and 0,130 g (0,516 mmole) (toluene-4-sulfonate) pyridinium was dissolved in 5.0 ml dichloromethane and stirred for 18 h at room temperature. Then the reaction mixture of Sliven. The combined organic phases are washed twice 1H. the Hcl solution, twice with diluted aqueous sodium bicarbonate solution, dried over magnesium sulfate and evaporated under reduced pressure. Thus received 0,176 g (0,446 mmole), 87% 6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-2-[2-(tetrahydropyran-2-yloxy)ethyl]-1,6-dihydropyrimidin-5-carbonitrile in the form of colorless solids; tPL185-187°C.

Example 68

4 Ethoxy-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-2-[2-(tetrahydropyran-2-yloxy)ethyl]pyrimidine-5-carbonitrile

Using as initial products 6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril, ethyliodide, potassium carbonate, N,N-dimethylformamide, got mentioned in the title compound as colorless amorphous solid; MS: [M+H]+=423; see example 69.

Example 69

1-Ethyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-2-[2-(tetrahydropyran-2-yloxy)ethyl]-1,6-dihydropyrimidin-5-carbonitril

According to the method described in example 3, 6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-2-[2-(tetrahydropyran-2-yloxy)ethyl]-1,6-dihydropyrimidin-5-carbonitrile (example 67) was treated with ethyliodide in N,N-dimethylformamide in prisutstvie the RAS-2-yloxy)ethyl]-1,6-dihydropyrimidin-5-carbonitrile in the form of colorless amorphous solid; MS: [M+H]+=423; and 4 ethoxy-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-2-[2-(tetrahydropyran-2-yloxy)ethyl]pyrimidine-5-carbonitrile in the form of colorless amorphous solid; MS: [M+H]+=423.

Example 70

1-Ethyl-2-(2-hydroxyethyl)-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril

0,144 g (0,341 mmole) of 1-ethyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-2-[2-(tetrahydropyran-2-yloxy)ethyl]-1,6-dihydropyrimidin-5-carbonitrile (example 69) was dissolved in 2.5 ml of methanol and was treated with 0.45 ml of 1.5 M solution of Hcl in methanol. After stirring at room temperature for 30 min was added 250 mg of solid powdered sodium bicarbonate and the reaction mixture was evaporated to dryness.

Thus obtained crude product was purified by chromatography on silica gel, using as eluent a mixture (95:5 vol./about.) dichloromethane and methanol, resulting in a received 0,115 g (0,341 mmole), 100%, 1-ethyl-2-(2-hydroxyethyl)-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile in the form of a colourless solid; MS: [M+H]+=339; tPL114-115°C.

Example 71

4 Ethoxy-2-(2-hydroxyethyl)-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimido tragedian-2-yloxy)ethyl]-1,6-dihydropyrimidin-5-carbonitrile (example 68) was treated with 1,5 N. a solution of Hcl in methanol, receiving 4 ethoxy-2-(2-hydroxyethyl)-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile in the form of a colourless solid; MS: [M+H]+=339; tPL108-111°C.

Example 72

4-(2-Hydroxyethoxy)-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-2-[2-(tetrahydropyran-2-yloxy)ethyl]pyrimidine-5-carbonitrile

Using as initial products 6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-2-[2-(tetrahydropyran-2-yloxy)ethyl] -1,6-dihydropyrimidin-5-carbonitrile, 2-bromoethanol, potassium carbonate, N,N-dimethylformamide, got mentioned in the title compound as a colourless foam; MS: [M+H]+=439; see example 73.

Example 73

1-(2-Hydroxyethyl)-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-2-[2-(tetrahydropyran-2-yloxy)ethyl]-1,6-dihydropyrimidin-5-carbonitril

According to the method described in example 3,6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-2-[2-(tetrahydropyran-2-yloxy)ethyl]-1,6-dihydropyrimidin-5-carbonitrile (example 67) was treated with 2-bromoethanol in N,N-dimethylformamide in the presence of potassium carbonate, resulting in the received 4-(2-hydroxyethoxy)-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-2-[2-(tetrahydropyran-2-yloxy)ethyl]pyrimidine-5-carbonitrile as Biran-2-yloxy)ethyl]-1,6-dihydropyrimidin-5-carbonitrile in the form of a yellow foam; MS: [M+H]+=439.

Example 74

1,2-Bis(2-hydroxyethyl)-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril

According to the method described in example 70, 1-(2-hydroxyethyl)-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-2-[2-(tetrahydropyran-2-yloxy)ethyl]-1,6-dihydropyrimidin-5-carbonitrile (example 73) was treated with a solution of Hcl in methanol, receiving 1,2-bis(2-hydroxyethyl)-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile in the form of a colourless solid; MS: [M+H]+=355; tPL164°C.

Example 75

4-(2-Hydroxyethoxy)-2-(2-hydroxyethyl)-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile

According to the method described in example 70, 4-(2-hydroxyethoxy)-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-2-[2-(tetrahydropyran-2-yloxy)ethyl]pyrimidine-5-carbonitrile (example 72) was treated with a solution of Hcl in methanol, receiving 4-(2-hydroxyethoxy)-2-(2-hydroxyethyl)-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile in the form of a colourless solid; MS: [M+H]+=355; tPL118-120°C.

Example 76

4-(1,2,4,5-Tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile

According to the method described in example 4, 4-chlorpyrifos and N-ethyl-N,N-Diisopropylamine in acetonitrile at reflux) was treated with the hydrochloride 2,3,4,5-tetrahydro-1H-benzo[d]azepine [J. Heterocycl. Chem. (1971), 8(5), 779-83] in N,N-dimethylformamide in the presence of N-ethyl-N,N-Diisopropylamine at room temperature, resulting in a received 4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile in the form of a solid whitish; MS: [M+H]+=251; tPL148-150°C.

Example 77

6-(7-Chloro-1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-2-methyl-5-nitro-3H-pyrimidine-4-one

According to the method described in example 4, 6-bromo-2-methyl-5-nitro-3H-pyrimidine-4-one (obtained from 2-methyl-4-methoxy-5-nitro-6-chloropyrimidine [Helv. (1958), 41, 1806] and Hydrobromic acid (48% solution in water) in acetic acid at room temperature) was treated with 7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine [J. Heterocycl. Chem. (1971), 8(5), 779-83] in N,N-dimethylformamide in the presence of N-ethyl-N,N-Diisopropylamine at room temperature, resulting in the received 6-(7-chloro-1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-2-methyl-5-nitro-3H-pyrimidine-4-one in the form of a solid yellow; tPL218°C (decomp.); MS: [M+H]+=335.

Example 78

2-Methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1-(2,2,2-triptorelin)-1,6-dihydropyrimidin-5-carbonitril

Using as initial products of 2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]zapisanie in the title compound in the form of a solid substance of a yellowish color; tPL186-188°C; MS: [M+H]+=463; see example 79.

Example 79

2-Methyl-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile

According to the method described in example 3, 2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 17) was treated with 2,2,2-triptoreline in N,N-dimethylformamide in the presence of potassium carbonate at 80°C receives 2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1-(2,2,2-triptorelin)-1,6-dihydropyrimidin-5-carbonitrile in the form of a solid yellowish; tPL186-188°C; MS: [M+H]+= 463; and 2-methyl-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile in the form of colorless solids; tPL108-110°C; MS: [M+H]+=363.

Example 80

2-(2-Methylsulfonylmethyl)-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril

According to the method described in example 17 the Z and/or E-isomer ethyl ester 2-cyan-3-methylsulfanyl-3-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)acrylic acid [example 13A)] was treated with the hydrochloride of 3-hydroxypropionitrile (1:1) and 1,8-diazabicyclo[5.4.0]undec-7-Yong in N,N-dimethylformamide at 100°With, in addition to receiving 2-(2-HYDR shall animetal)-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile in the form of colorless solids; tPL215-218°C (decomp.); MS: [M+H]+=341.

Example 81

1-Ethyl-2-(2-methylsulfonylmethyl)-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril

Using as initial products of 2-(2-methylsulfonylmethyl)-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril, ethyliodide, potassium carbonate, N,N-dimethylformamide, got mentioned in the title compound as colorless solids; tPL154-159°C; MS: [M+H]+=369; see example 82.

Example 82

4 Ethoxy-2-(2-methylsulfonylmethyl)-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl) pyrimidine-5-carbonitrile

According to the method described in example 3, 2-(2-methylsulfonylmethyl)-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 80) was treated with ethyliodide in N,N-dimethylformamide in the presence of potassium carbonate at 80°C receives 1-ethyl-2-(2-methylsulfonylmethyl)-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile in the form of colorless solids; tPL154-159°C; MS: [M+H]+=369; and 4 ethoxy-2-(2-methylsulfonylmethyl)-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile in the form of colorless solids; tPL-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril

Using as initial products of 2-(2-methylsulfonylmethyl)-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril, potassium carbonate, N,N-dimethylformamide, biomethanol got mentioned in the title compound as amorphous solid yellow; MS: [M+H]+=385; see example 84.

Example 84

4-(2-Hydroxyethoxy)-2-(2-methylsulfonylmethyl)-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile

According to the method described in example 3, 2-(2-methylsulfonylmethyl)-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 80) was treated with 2-bromoethanol in N,N-dimethylformamide in the presence of potassium carbonate, obtaining 1-(2-hydroxyethyl)-2-(2-methylsulfonylmethyl)-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile in the form of amorphous solids yellowish; MS: [M+H]+=385; and 4-(2-hydroxyethoxy)-2-(2-methylsulfonylmethyl)-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl) pyrimidine-5-carbonitrile in the form of a solid yellowish; tPL93-99°C; MS: [M+H]+=385.

Example 85

3-(2-Hydroxyethyl)-2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-3H-pyrimidine-4-one

the potassium carbonate in N,N-dimethylformamide, got mentioned in the title compound in the form of solid yellow; tPL151-155°C; MS: [M+H]+=345; see example 86.

Example 86

2-[2-Methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-4-yloxy]-ethanol

According to the method described in example 3, 2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-4-ol (example 1) was treated with 2-bromoethanol in N,N-dimethylformamide in the presence of potassium carbonate, getting 3-(2-hydroxyethyl)-2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-3H-pyrimidine-4-one in the form of a solid yellow; tPL151-155°C; MS: [M+H]+=345; and 2-[2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-4-yloxy]-ethanol in the form of a solid of light yellow color; tPL113°C (decomp.); MS: [M+H]+=345.

Example 87

3-(5-Methyl-3-nitropyridine-2-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin

According to the method described in example 4, 2-chloro-5-methyl-3-nitropyridine [J. were obtained. (1996), 517(1-2), 25-36] processed hydrochloride 2,3,4,5-tetrahydro-1H-benzo[d]azepine [J. Heterocycl. Chem. (1971), 8(5), 779-83] in N,N-dimethylformamide in the presence of N-ethyl-N,N-Diisopropylamine at room temperature, resulting in the received 3-(5-methyl-3-nitropyridine-2-yl)-2,3,4,5-tetr">Example 88

2-(2-Methylsulfonylamino)-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile

According to the method described in example 3, 2-(2-methylsulfonylmethyl)-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 80) was treated with 2,2,2-triftoratsetilatsetonom in N,N-dimethylformamide in the presence of potassium carbonate, obtaining 2-(2-methylsulfonylamino)-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile in the form of colorless solids; tPL97-100°C; MS: [M+H]+=423.

Example 89

2-Methylsulfanyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril

a) value (0.475) g (1.50 mmole) E - and/or Z-isomer ethyl ester 2-cyan-3-methylsulfanyl-3-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)acrylic acid [example 13 a)] was dissolved in 8.0 ml of dichloromethane and treated 0,712 g (3,30 mmole) of meta-chloroperbenzoic acid. After stirring for 18 h at room temperature the reaction mixture was poured into 30 ml of a mixture of ice/dilute aqueous solution of sodium carbonate and was extracted three times with 20 ml dichloromethane. The combined organic phases were dried over magnesium sulfate and pariva the Le, using as eluent a mixture (1:1 vol./about.) ethyl acetate and hexane, resulting after crystallization from a simple broadcast received 0,115 g (0,330 mmole), 22%, E/Z-isomer ethyl ester 2-cyan-3-methanesulfonyl-3-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)acrylic acid in the form of a solid yellowish; tPL80°C; MS: [M+H]+=349.

b) 0,100 g (0,287 mmole) E - and/or Z-isomer ethyl ester 2-cyan-3-methanesulfonyl-3-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)acrylic acid, 0,082 mg (0,287 mmole) sulfate S-methylisothiazoline and 0,107 mg (equivalent to 1.03 mmole) of triethylamine were dissolved in 2.0 ml of ethanol and kept at reflux for 6 hours After cooling to room temperature the reaction mixture was evaporated to dryness, poured into 1N. the Hcl solution and was extracted three times with 20 ml dichloromethane. The combined organic phases were dried over magnesium sulfate and evaporated under reduced pressure. Thus obtained crude product was purified by chromatography on silica gel, using as eluent a mixture (95:5 vol./about.) dichloromethane and methanol, resulting after crystallization from ethyl acetate received 0,012 g (0,039 mmole), 14%, 2-methylsulfanyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-is>P CLASS="ptx2">Example 90

6-(7-Methoxy-1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-2-methyl-5-nitro-3H-pyrimidine-4-one

According to the method described in example 4, 6-bromo-2-methyl-5-nitro-3H-pyrimidine-4-one (obtained from 2-methyl-4-methoxy-5-nitro-6-chloropyrimidine [Helv. (1958), 41, 1806] and Hydrobromic acid (48% solution in water) in acetic acid at room temperature) was treated with 7-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine [J. Heterocycl. Chem. (1971), 8(5), 779-83] in N,N-dimethylformamide in the presence of N-ethyl-N,N-Diisopropylamine at room temperature, resulting in the received 6-(7-methoxy-1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-2-methyl-5-nitro-3H-pyrimidine-4-one in the form of a solid yellow; tPL243°C (decomp.); MS: [M+H]+=331.

Example 91

Dimethyl-{2-[2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-4-yloxy]ethyl}amine

Using as initial products of 2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-4-ol hydrochloride and 1-chloro-2-dimethylaminoethanol, potassium carbonate, N,N-dimethylformamide, got mentioned in the title compound as yellow oil; MS: [M+H]+=372; see example 92.

Example 92

3-(2-Dimethylaminoethyl)-2-methyl-5-nitro-6-(1,2,4,5-then it is carbonated is hydrobenzo[d]azepin-3-yl)pyrimidine-4-ol (example 1) was treated with the hydrochloride of 1-chloro-2-dimethylaminoethanol in N,N-dimethylformamide in the presence of potassium carbonate at 50°C getting dimethyl-{2-[2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl) pyrimidine-4-yloxy]ethyl}amine as yellow oil; MS: [M+H]+=372; and 3-(2-dimethylaminoethyl)-2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-3H-pyrimidine-4-one as an amorphous solid yellow; MS: [M+H]+=372.

Example 93

3-[2-Methyl-6-(2-morpholine-4-ylethoxy)-5-nitropyrimidin-4-yl]-2,3,4,5-tetrahydro-1H-benzo[d]azepin

Using as initial products of 2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-4-ol hydrochloride and 4-(2-chloroethyl)of the research, potassium carbonate, N,N-dimethylformamide, got mentioned in the title compound as yellow oil; MS: [M+H]+=414; see example 94.

Example 94

2-Methyl-3-(2-morpholine-4-retil)-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-3H-pyrimidine-4-one

According to the method described in example 3, 2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-4-ol (example 1) was treated with the hydrochloride of 4-(2-chloroethyl)the research in N,N-dimethylformamide in the presence of potassium carbonate at 50°C receives 3-[2-methyl-6-(2-morpholine-4-ylethoxy)-5-nitropyrimidin-4-yl]-2,3,4,5-tetrahydro-1H-benzo [d] azepin in the form of a yellow oil; MS: [M+H]+=414; and 2 met logo color; tPL143-145°C; MS: [M+H]+=414.

Example 95

4-(1,2,4,5-Tetrahydrobenzo[d]azepin-3-yl)-2-[2-(tetrahydropyran-2-yloxy)ethyl]-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile

According to the method described in example 3, 6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-2-[2-(tetrahydropyran-2-yloxy)ethyl]-1,6-dihydropyrimidin-5-carbonitrile (example 67) was treated with 2,2,2-triftoratsetilatsetonom in N,N-dimethylformamide in the presence of potassium carbonate, receiving 4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-2-[2-(tetrahydropyran-2-yloxy)ethyl]-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile in the form of a yellow oil; MS: [M+H]+=477.

Example 96

2-(2-Hydroxyethyl)-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile

According to the method described in example 70, 4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-2-[2-(tetrahydropyran-2-yloxy)ethyl]-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile (example 95) was treated with 1,5 N. a solution of Hcl in methanol, obtaining 2-(2-hydroxyethyl)-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline) pyrimidine-5-carbonitrile in the form of colorless solids; tPL114-116°C; MS: [M+H]+=393.

Example 97

2-Hydroxymethyl-6-oxo-4-(1,2,4,5-t and/or Z-isomer ethyl ester 2-cyan-3-methylsulfanyl-3-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl) acrylic acid [example 13A)] was treated with the hydrochloride of glycolamide [J. Amer. Chem. Soc. 68, 2393-2395 (1946)] and 1,8-diazabicyclo[5.4.0]undec-7-Yong in N,N-dimethylformamide at 110°C receives 2-hydroxymethyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile in the form of colorless solids; tPL196-198°C; MS: [M]+=296.

Example 98

2,3-Diethyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-3H-pyrimidine-4-one

Using as initial products 3-ethyl-2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-3H-pyrimidine-4-one and methyliodide, amide bis(trimethylsilyl)lithium in tetrahydrofuran, got mentioned in the title compound as yellow oil; MS: [M+H]+=343; see example 99.

Example 99

3-Ethyl-2-isopropyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-3H-pyrimidine-4-one

0,328 g (1.0 mmol) of 3-ethyl-2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-3H-pyrimidine-4-it (example 2) was dissolved in 10.0 ml of tetrahydrofuran, the solution was cooled in an atmosphere of argon to -70°C and was treated with 1.2 ml of 1.0 M solution of amide bis(trimethylsilyl)lithium in tetrahydrofuran, stirred at -70°C for 120 min and treated 0,095 ml (1.5 mmole) methyliodide. Then the reaction mixture was allowed to warm to room temperature and stirring obyedinenie the organic phase was twice washed with 50 ml water, was dried over magnesium sulfate, evaporated under reduced pressure and dried in high vacuum. Thus obtained crude product was purified by chromatography on silica gel, using as eluent a mixture (9:1 to 1:1 vol./about.) hexane and ethyl acetate, which was obtained by 0.055 g (0,161 mmole), 16.1 per cent, 2,3-diethyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-3H-pyrimidine-4-it is in the form of a yellow oil; MS: [M+H]+=343; and 0,012 g (0,034 mmole), 3,4%, 3-ethyl-2-isopropyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-3H-pyrimidine-4-one as yellow oil; MS: [M+H]+=357.

Example 100

3-(4-Butyl-5-methyl-3-nitropyridine-2-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin

0,283 g (1.0 mmole) of 3-(5-methyl-3-nitropyridine-2-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (example 87) was dissolved in 10.0 ml of tetrahydrofuran, the solution was cooled in an atmosphere of argon to -70°C and was treated to 0.94 ml of a 1.6 M solution of n-utility in n-hexane, stirred at -70°C for 120 min, after which the reaction mixture was allowed to warm to room temperature and stirring continued overnight. Then the mixture was poured into 50 ml of a mixture of ice/water and was extracted three times with 100 ml of ethyl acetate. The combined organic phases are washed twice with 50 ml water, sushi is the way the crude product was purified by chromatography on silica gel, using as eluent a mixture (98:2 to 9:1 vol./about.) hexane and ethyl acetate, resulting in a received 0,071 g (of 0.21 mmole), 21%, 3-(4-butyl-5-methyl-3-nitropyridine-2-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine in the form of a yellow oil; MS: [M+H]+=340.

Example 101

6-(6-Methoxy-1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-2-methyl-5-nitro-3H-pyrimidine-4-one

According to the method described in example 4, 6-(7-amino-1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-2-methyl-5-nitro-3H-pyrimidine-4-one (see example 66) was treated with 6-methoxy-2,3,4,5-tetrahydrobenzo[d]azepine [J. Med. Chem. (1984), 27(7), 918-21] in N,N-dimethylformamide in the presence of N-ethyl-N,N-Diisopropylamine at room temperature, receiving 6-(6-methoxy-1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-2-methyl-5-nitro-3H-pyrimidine-4-one in the form of a solid yellow; tPL>200°C; MS: [M+H]+=331.

Example 102

2-[2-Methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-4-yloxy]ethylamine

a) 0,300 g (1.00 mmole) of 2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-4-ol (example 1), 0,194 g (1.20 mmole) of N-tert-butoxycarbonylmethyl and 0,371 g (1,40 mmole) of triphenylphosphine was dissolved in 15.0 ml of tetrahydrofuran, the solution was cooled to 2°C and processed 0,306 g (1,30 mmole) of di-tert-prodoljali for 22 PM After that, the mixture was poured into 50 ml of a mixture of ice/water and was extracted three times with 100 ml of ethyl acetate. The combined organic phases are washed twice with 50 ml water, dried over magnesium sulfate, evaporated under reduced pressure and dried in high vacuum. Thus obtained crude product was purified by chromatography on silica gel, using as eluent a mixture of from 95:5 to 4:1 vol./about.) hexane and ethyl acetate, which was obtained is not fully purified tert-butyl ether {2-[2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-4-yloxy]ethyl]carbamino acid in the form of a solid yellow; MS: [M+H]+=444.

b) Not fully purified tert-butyl ether {2-[2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-4-yloxy]ethyl} carbamino acid obtained in stage a), was dissolved in 10.0 ml of methanol and treated 5,96 ml of 1.56 M solution of hydrochloric acid in methanol and the reaction mixture was stirred at room temperature for 72 hours then it was poured into 50 ml of a mixture of ice/water, was neutralized with sodium bicarbonate solution and was extracted three times with 100 ml dichloromethane. The combined organic phases are washed twice with 50 ml water, dried over magnesium sulfate, upar is Ali chromatography on silica gel, using as eluent a mixture (9:1 to 0:1/about.) hexane and ethyl acetate, resulting in a received 0,058 g (0,169 mmole), two stages of 16.9%, 2-[2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-4-yloxy]ethylamine in the form of oil is light yellow in color; MS: [M+H]+=344.

Example 103

4-(Bromodifluoromethane)-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile

According to the method described in example 60, 6-oxo-4-(1,2,4,5-tetrahydrobenzo-zo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 15) were treated with dibromodifluoromethane in N,N-dimethylformamide in the presence of sodium hydride at room temperature, obtaining 4-(bromodifluoromethane)-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile in the form of colorless solids; tPL95-100°C; MS: [M+H]+=396.

Example 104

6-Oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-2-(tetrahydropyran-2-intoximeter)-1,6-dihydropyrimidin-5-carbonitril

According to the method described in example 67, 2-hydroxymethyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 97) was treated with 3,4-dihydro-2H-Piran and (toluene-4-sulfonate) pyridinium in dichloromethane at room temperature, received in the form of colorless solids; tPL179,5-183°C; MS: [M+H]+=381.

Example 105

4-(1,2,4,5-Tetrahydrobenzo[d]azepin-3-yl)-2-(tetrahydropyran-2-intoximeter)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile

Using as initial products 6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-2-(tetrahydropyran-2-intoximeter)-1,6-dihydropyrimidin-5-carbonitrile (example 104) and 2,2,2-cryptanalytical-methanesulfonate in N,N-dimethylformamide in the presence of potassium carbonate, has been specified in the title compound as colorless amorphous solid; MS: [M+H]+=463; see example 106.

Example 106

6-Oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-2-(tetrahydropyran-2-intoximeter)-1-(2,2,2-triptorelin)-1,6-dihydropyrimidin-5-carbonitril

According to the method described in example 3, 6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-2-(tetrahydropyran-2-intoximeter)-1,6-dihydropyrimidin-5-carbonitrile (example 104) was treated with 2,2,2-triftoratsetilatsetonom in N,N-dimethylformamide in the presence of potassium carbonate, receiving 4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-2-(tetrahydropyran-2-intoximeter)-6-(2,2,2-triptoreline) pyrimidine-5-carbonitrile in the form of colorless amorphous solid; MS: [M+H]+=463; and 6-oxo-4-(1,2,4,5-tel in the form of colorless amorphous solid; MS: [M+H]+=463.

Example 107

2-Hydroxymethyl-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile

According to the method described in example 70, 4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-2-(tetrahydropyran-2-intoximeter)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile (example 105) were treated with hydrochloric acid in methanol at room temperature, obtaining 2-hydroxymethyl-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile in the form of colorless solids; tPL106-110°C; MS: [M+H]+=378.

Example 108

2-Hydroxymethyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1-(2,2,2-triptorelin)-1,6-dihydropyrimidin-5-carbonitril

According to the method described in example 70, 6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-2-(tetrahydropyran-2-intoximeter)-1-(2,2,2-triptorelin)-1,6-dihydropyrimidin-5-carbonitrile (example 106) were treated with hydrochloric acid in methanol at room temperature, obtaining 2-hydroxymethyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1-(2,2,2-triptorelin)-1,6-dihydropyrimidin-5-carbonitrile in the form of colorless solids; tPL181-185°C; MS: [M+H]+=378.

Example 109

1-AB as the original products 2-amino-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 13) and allylbromide in N,N-dimethylformamide in the presence of potassium carbonate at room temperature, got mentioned in the title compound as colorless solids; tPL>200°C; MS: [M]+=321; see example 111.

Example 110

1-Allyl-2-allylamino-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril

Using as initial products 2-amino-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 13) and allylbromide in N,N-dimethylformamide in the presence of potassium carbonate at room temperature, has been specified in the title compound as colorless solids; tPL181-182,5°C; MS: [M]+=361; see example 111.

Example 111

4 Allyloxy-2-amino-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile

According to the method described in example 3, 2-amino-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 13) were treated with allylbromide in N,N-dimethylformamide in the presence of potassium carbonate at room temperature, obtaining 1-allyl-2-amino-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile in the form of colorless solids; tPL>200°C; MS: [M]+=321; 1-allyl-2-allylamino-6-oxo-4-(1,2,4,5-tetrahydrobenzo: [M]+=361; and 4 allyloxy-2-amino-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile in the form of colorless amorphous solid; MS: [M+H]+=322.

Example 112

1-Allyl-2-ethylamino-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril

According to the method described in example 3, 1-allyl-2-amino-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 109) were treated with ethyliodide in N,N-dimethylformamide in the presence of potassium carbonate at room temperature, obtaining 1-allyl-2-ethylamino-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile in the form of colorless solids; tPL172-177°C; MS: [M+H]+=350.

Example 113

1-Allyl-2-(allylamino)-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril

According to the method described in example 3, 1-allyl-2-allylamino-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 110) were treated with ethylbromide in N,N-dimethylformamide in the presence of potassium carbonate at room temperature, obtaining 1-allyl-2-(allylamino)-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-LASS="ptx2">1-Cyclopropyl-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril

According to the method described in example 17 the Z and/or E-isomer ethyl ester 2-cyan-3-methylsulfanyl-3-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)acrylic acid [example 13A)] was treated with the hydrochloride of N-1 cyclopropylacetylene (obtained from the hydrochloride of ethylacetamide and cyclopropylamine in ethanol under reflux, which was used in the form of the crude reaction product) and 1,8-diazabicyclo[5.4.0]undec-7-Yong in N,N-dimethylformamide at 100°C receives 1-cyclopropyl-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile in the form of a solid of light yellow color; tPL177-179°C; MS: [M+H]+=321.

Example 115

5-Ethyl-6-methyl-2-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)nicotinamide

According to the method described in example 1, 2-chloro-5-ethyl-6-methylnicotinamide [J. Med. Chem. (1992), 35(21), 3784-91] processed hydrochloride 2,3,4,5-tetrahydro-1H-benzo[d]azepine [J. Heterocycl. Chem. (1971), 8(5), 779-83] in N,N-dimethylformamide in the presence of potassium carbonate at 120°C receives 5-ethyl-6-methyl-2-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)nicotinamide in the form of oil is light yellow in color; MS:zo[1,2-a]pyrimidine-6-carbonitrile

According to the method described in example 17 the Z and/or E-isomer ethyl ester 2-cyan-3-methylsulfanyl-3-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)acrylic acid [example 13A)] was treated with hydrogen bromide to 2-iminoimidazolidine and 1,8-diazabicyclo[5.4.0]undec-7-Yong in N,N-dimethylformamide at 100°C receives 5-oxo-7-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-6-carbonitrile in the form of colorless solids; tPL>200°C; MS: [M+H]+=308.

Example 117

5-Oxo-7-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,5-dihydroimidazo[1,2-a] pyrimidine-6-carbonitrile

According to the method described in example 17 the Z and/or E-isomer ethyl ester 2-cyan-3-methylsulfanyl-3-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)acrylic acid [example 13A)] was treated with sulfate 2-aminoimidazole and 1,8-diazabicyclo[5.4.0]undec-7-Yong in N,N-dimethylformamide at 100°C receives 5-oxo-7-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1.5-dihydroimidazo[1,2-a]pyrimidine-6-carbonitrile in the form of a solid brownish; tPL> 200° C; MS: [M+H]+=306.

Example 118

1-Methyl-5-oxo-7-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,2,3,5-tetrahydroimidazo[1,2-a] pyrimidine-6-carbonitrile

According to the method described in example sativali dimethylsulfate in N,N-dimethylformamide in the presence of potassium carbonate at room temperature, getting 1-methyl-5-oxo-7-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-6-carbonitrile in the form of colorless solids; tPL174-177°C; MS: [M+H]+=322.

Example 119

3-[2-Methyl-5-nitro-6-(2,2,2-triptoreline)pyrimidine-4-yl]-2,3,4,5-tetrahydro-1H-benzo[d]azepin

According to the method described in example 3, 2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-4-ol (example 1) was treated with 2,2,2-triptoreline in N,N-dimethylformamide in the presence of potassium carbonate at 80°With, in addition to receiving 2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-3-(2,2,2-triptorelin)-3H-pyrimidine-4-it (example 11) 3-[2-methyl-5-nitro-6-(2,2,2-triptoreline)pyrimidine-4-yl]-(2,3,4,5-tetrahydro-1H-benzo[d]azepin in the form of oil is light yellow in color; MS: [M+H]+=383.

Example 120

1-Allyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-2-(2,2,2-triptoreline)-1,6-dihydropyrimidin-5-carbonitril

According to the method described in example 3, 1-allyl-2-amino-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 109) was treated with 2,2,2-triftoratsetilatsetonom in N,N-dimethylformamide in the presence of potassium carbonate at room temperature, obtaining 1-allyl-6-oxo-4-(1 solids; tPL186-191°C; MS: [M+H]+=404.

Example 121

6-Oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1-(2,2,2-triptorelin)-2-(2,2,2-trichoroethylene)-1,6-dihydropyrimidin-5-carbonitril

Using as initial products 2-amino-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 13) and 2,2,2-triftoratsetilatsetonom in N,N-dimethylformamide in the presence of potassium carbonate at room temperature, has been specified in the title compound as colorless solids; tPL>200°C; MS: [M]+=446; see example 122.

Example 122

2-Amino-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile

According to the method described in example 3, 2-amino-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 13) was treated with 2,2,2-triftoratsetilatsetonom in N,N-dimethylformamide in the presence of potassium carbonate at room temperature, obtaining 2-amino-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile in the form of colorless solids; tPL145,3-146,9°C; MS: [M+H]+=364; and 6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1-(2,2,2-Treptow> >200°C; MS: [M+H]+=446.

Example 123

6-(7-Fluoro-1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-2-methyl-5-nitro-3H-pyrimidine-4-one

According to the method described in example 4, 6-(7-amino-1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-2-methyl-5-nitro-3H-pyrimidine-4-one (see example 66) was treated with 7-fluoro-2,3,4,5-tetrahydro-1H-benzo[d]azepine in N,N-dimethylformamide in the presence of N-ethyl-N,N-Diisopropylamine at room temperature, receiving 6-(7-fluoro-1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-2-methyl-5-nitro-3H-pyrimidine-4-one as solid of light yellow color; tPL>200°C; MS: [M+H]+=319.

Getting 7-fluoro-2,3,4,5-tetrahydro-1H-benzo[d]azepine

Used 7-fluoro-2,3,4,5-tetrahydro-1H-benzo[d]azepin received, carrying out the reaction in the following sequence: (I) catalytic recovery of 1-(7-nitro-1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)ethanone [J. Heterocycl. Chem. (1971), 8(5), 779-83] using hydrogen in methanol in the presence of palladium on coal was obtained 1-(7-amino-1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)Etalon; (II) the processing of 1-(7-amino-1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)ethanone tetrafluoroborate microzone in dichloromethane and decomposition of the resulting of tetrafluoroborate the page in boiling 1,2-dichlorobenzene at EN-3-yl) ethanone by removing the acetyl function using hydrochloric acid (37% solution in water) in methanol at the reflux was obtained 7-fluoro-2,3,4,5-tetrahydro-1H-benzo[d]azepin.

Example 124

1-(2-Hydroxyethyl)-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril

Using as initial products of 2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 17) and 2-bromoethanol in acetonitrile in the presence of potassium carbonate at reflux, has been specified in the title compound as colorless solids; tPL164-167,5°C; MS: [M]+=325; see example 125.

Example 125

4-(2-Hydroxyethoxy)-2-methyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl) pyrimidine-5-carbonitrile

According to the method described in example 3, 2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 17) was treated with 2-bromoethanol in acetonitrile in the presence of potassium carbonate at reflux, receiving 4-(2-hydroxyethoxy)-2-methyl-6-(1,2,4,5-tetrahydro-1H-benzo[d]azepin-3-yl)pyrimidine-5-carbonitrile in the form of a solid yellow; tPL86,7-92,3°C; MS: [M]+=325; and 1-(2-hydroxyethyl)-2-methyl-6-oxo-4-(1,2,4,5-tetrahydro-1H-benzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile in the form of colorless solids; tPL

According to the method described in example 17 the Z and/or E-isomer ethyl ester 2-cyan-3-methylsulfanyl-3-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl) acrylic acid [example 13 a)] was treated with the hydrochloride of 2-aminopyrrolidine [J. Med. Chem. (1996), 39, 669-672] and 1,8-diazabicyclo[5.4.0]undec-7-Yong in N,N-dimethylformamide at 100°C receives 4-oxo-2-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-3-carbonitrile in the form of colorless solids; tPL184,5-TO 190.5°C; MS: [M+H]+=307.

Example 127

4-Oxo-2-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-4,6,7,8,9,10-hexahydropyrazino[1,2-a]azepin-3-carbonitril

According to the method described in example 17 the Z and/or E-isomer ethyl ester 2-cyan-3-methylsulfanyl-3-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)acrylic acid [example 13 a)] was treated with hydroiodide 2-aminoguanidine [J. Med. Chem. (1996), 39, 669-672] and 1,8-diazabicyclo[5.4.0]undec-7-Yong in N,N-dimethylformamide at 100°C receives 4-oxo-2-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-4,6,7,8,9,10-hexahydropyrazino[1,2-a]azepin-3-carbonitrile in the form of colorless amorphous solid; MS: [M+H]+=335.

Example 128

4-Oxo-2-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carbonitrile

On the Sabbath.] azepin-3-yl)acrylic acid [example 13 a)] was treated with the hydrochloride of 2-aminopiperidine [J. Med. Chem. (1996), 39, 669-672] and 1,8-diazabicyclo[5.4.0]undec-7-Yong in N,N-dimethylformamide at 100°C receives 4-oxo-2-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6,7,8,9-tetrahydro-4H-pyrido[1,2-a] pyrimidine-3-carbonitrile in the form of a solid yellow; tPL136,5-139,5°C; MS: [M+H]+=321.

Example 129

5-Ethyl-6-hydroxymethyl-2-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)nicotinamide

Using as initial products 5-ethyl-6-methyl-1-hydroxy-2-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl) nicotinamide and triperoxonane anhydride in dichloromethane, at the reflux has been specified in the title compound in the form of butter, light brown; MS: [M+H]+=308; see example 130.

Example 130

5-Cyano-3-ethyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyridine-2-ymetray ether triperoxonane acid

The solution containing 0,30 g (0,98 mmole) of 5-ethyl-6-methyl-1-hydroxy-2-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)nicotinanilide and 3.0 g (14.2 mmole) triperoxonane anhydride in 3.0 ml of dichloromethane, kept under reflux for 20 hours Then the reaction mixture is evaporated and the residue was chromatographically, using as eluent a mixture (99:1.about.) dichloromethane and metrovogo ether triperoxonane acid in the form of a yellow oil; MS: [M+H]+=308; and 0,053 g (0,17 mmole), 18%, 5-ethyl-6-hydroxymethyl-2-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)nicotinanilide in the form of butter, light brown; MS: [M]+=308.

Getting 5-ethyl-6-methyl-1-hydroxy-2-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)nicotinanilide

Used above 5-ethyl-6-methyl-1-hydroxy-2-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)nicotinamide received, carrying out the reaction in the following sequence: I) treatment of 2-chloro-5-ethyl-6-methylnicotinamide [J. Med. Chem. (1992), 35(21), 3784-91] hydrogen peroxide in triperoxonane acid by heating under reflux was obtained 2-chloro-5-ethyl-6-methyl-1-oxycotingenocide; (II) treatment of 2-chloro-5-ethyl-6-methyl-1-oxycotingenocide according to the method described in example 4, hydrochloride 2,3,4,5-tetrahydro-1H-benzo[d]azepine [J. Heterocycl. Chem. (1971), 8(5), 779-83] in the presence of N-ethyl-N,N-Diisopropylamine at room temperature was obtained 5-ethyl-6-methyl-1-hydroxy-2-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)nicotinanilide in the form of a solid yellow; tPL162-166°C; MS: [M]+=307.

Example 131

3-(6-Ethoxy-2-methyl-5-nitropyrimidin-4-yl)-7-fluoro-2,3,4,5-tetrahydro-1H-benzo[d]azepin

Using as initial products 6-(7-fluoro-1,2,4,5-Tetra is e, at room temperature has been specified in the title compound in the form of an amorphous solid of light yellow color; MS: [M+H]+=347; see example 132.

Example 132

3-Ethyl-6-(7-fluoro-1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-2-methyl-5-nitro-3H-pyrimidine-4-one

According to the method described in example 3 6-(7-fluoro-1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-2-methyl-5-nitro-3H-pyrimidine-4-one (example 123) were treated with jumatano in N,N-dimethylformamide in the presence of potassium carbonate at room temperature, resulting in the received 3-ethyl-6-(7-fluoro-1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-2-methyl-5-nitro-3H-pyrimidine-4-one as yellow oil; MS: [M+H]+=347; and 3-(6-ethoxy-2-methyl-5-nitropyrimidin-4-yl)-7-fluoro-2,3,4,5-tetrahydro-1H-benzo[d]azepin in the form of an amorphous solid of light yellow color; MS: [M+H]+=347.

Example 133

1-Allyl-6-oxo-2-(2-phenoxyethylamine)-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril

The suspension containing 0,100 g (0,311 mmole) of 1-allyl-2-amino-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 109), 0,0738 g (0,367 mmole) of 2-phenoxyethylamine and 0,0887 g (to 0.662 mmole) of potassium carbonate in 1.0 ml of N,N-dimethylformamide, paramasivan. solution of hydrochloric acid and was extracted three times with 50 ml of ethyl acetate. United an ethyl acetate phase was dried over magnesium sulfate and evaporated under reduced pressure. The residue was chromatographically on silica gel, using as eluent a mixture (1:1 vol./about.) dichloromethane and ethyl acetate, and then were led out of a simple ester. Thus received 0,063 g (0,143 mmole), 46%, 1-allyl-6-oxo-2-(2-phenoxyethylamine)-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile in the form of colorless solids; tPL157-160°C; MS: [M+H]+=442.

Example 134

6-Oxo-2-(2-phenoxyethylamine)-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril

To a suspension containing 0,050 g (0,113 mmole) of 1-allyl-6-oxo-2-(2-phenoxyethylamine)-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 133), 0.0005 g (0,0023 mmole) of palladium (II) acetate and 0,0012 g (0,0045 mmole) of triphenylphosphine in 2.0 ml of tetrahydrofuran, was added 0,0065 g (0,283 mmole) of lithium borohydride and the reaction mixture was stirred at room temperature for 1 h then it was treated with a few drops of acetone was poured into 30 ml of ice water and was extracted three times with 50 ml of ethyl acetate. Obyedinenny the residue was chromatographically on silica gel, using as eluent a mixture (95:5 vol./about.) dichloromethane and methanol, and then was led from ethyl acetate/simple ether. Thus received 0,028 g (0,070 mmole), 62%, 6-oxo-2-(2-phenoxyethylamine)-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile in a solid beige; tPL> 200°C; MS: [M+H]+=402.

Example 135

1 Allyloxy-2-diallylamine-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile

According to the method described in example 3, 2-amino-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile [example 13 (b)] was treated with 3-bromo-1-propene in N,N-dimethylformamide in the presence of potassium carbonate, receiving 1 allyloxy-2-diallylamine-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile in the form of colorless solids; tPL125,9-130,0°C; MS: [M+H]+=402.

Example 136

(S)-1-(2,2-Dimethyl[1,3]dioxolane-4-ylmethyl)-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril

Using as initial products of 2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 17) and (R)-(-)-2,2-dimethyl-4-(hydroxymethyl)-1,3-dioxolane-paratoluidine in the form of colorless solids; tPLTO 166.2-168,3°C; MS: [M+H]+=395; see example 137.

Example 137

(R)-4-(2,2-Dimethyl[1,3]dioxolane-4-ylethoxy)-2-methyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile

According to the method described in example 3, 2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 17) was treated with (R)-(-)-2,2-dimethyl-4-(hydroxymethyl)-1,3-dioxolane-paratoluenesulfonyl in N,N-dimethylformamide in the presence of potassium carbonate, resulting in the obtained (R)-4-(2,2-dimethyl-[1,3]dioxolane-4-ylethoxy)-2-methyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile in the form of colorless solids; tPL109,8-111,5°C; MS: [M+H]+=395; and (S)-1-(2,2-dimethyl-[1,3]dioxolane-4-ylmethyl)-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile in the form of colorless solids; tPLTO 166.2-168,3°C; MS: [M+H]+=395.

Example 138

N-[1-Allyl-5-cyan-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-2-yl]formamide

Using as initial products 1-allyl-2-amino-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 109) and potassium carbonate in N,N-dimethylformamide at 130°C, received the decree/P>

Example 139

2-Amino-6-oxo-1-[Z]-propenyl-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril

By keeping 1-allyl-2-amino-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 109) in the presence of potassium carbonate in N,N-dimethylformamide at 130°With the received N-[1-allyl-5-cyan-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-2-yl]formamid in the form of an amorphous solid yellow; MS: [M]+=349; and 2-amino-6-oxo-1-[Z]-propenyl-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile in the form of colorless solids; tPL>200°C; MS: [M+H]+=322.

Example 140

1-Allyl-6-oxo-2-(3-phenoxypropylamine)-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril

According to the method described in example 133, 1-allyl-2-amino-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 109) was treated with 3-phenoxypropylamine in N,N-dimethylformamide in the presence of potassium carbonate at room temperature, obtaining 1-allyl-6-oxo-2-(3-phenoxypropylamine)-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile in the form of colorless Tverdov is)-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril

According to the method described in example 134, 1-allyl-6-oxo-2-(3-phenoxypropylamine)-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 140) was treated with lithium borohydride, palladium (II) acetate and triphenylphosphine in tetrahydrofuran, getting 6-oxo-2-(3-phenoxypropylamine)-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile in the form of colorless solids; tPL175-180°C; MS: [M+H]+=416.

Example 142

4 Allyloxy-2-(3-phenoxypropylamine)-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile

According to the method described in example 133, 4 allyloxy-2-amino-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile (example 111) was treated with 3-phenoxypropylamine in N,N-dimethylformamide in the presence of potassium carbonate at 130°C receives 4 allyloxy-2-(3-phenoxypropylamine)-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile in the form of colorless amorphous solid; MS: [M+H]+=456.

Example 143

4 Allyloxy-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-2-(2,2,2-triptoreline)pyrimidine-5-carbonitrile

According to the method described in example 133, 4 allyloxy-2-amino-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile sodium at room temperature, getting 4 allyloxy-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-2-(2,2,2-triptoreline)pyrimidine-5-carbonitrile in the form of colorless amorphous solid; MS: [M+H]+=404.

Example 144

(S)-1-(2,3-Dihydroxypropyl)-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril

According to the method described in example 70, (S)-1-(2,2-dimethyl-[1,3]dioxolane-4-ylmethyl)-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 136) was treated with 1,5 N. solution of hydrochloric acid in methanol at room temperature, obtaining (S)-1-(2,3-dihydroxypropyl)-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile in the form of colorless amorphous solid; MS: [M+H]+=355.

Example 145

(R)-4-(2,3-Dihydroxypropane)-2-methyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile

According to the method described in example 70, (R)-4-(2,2-dimethyl-[1,3]dioxolane-4-ylethoxy)-2-methyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile (example 137) was treated with 1,5 N. solution of hydrochloric acid in methanol at room temperature, obtaining (R)-4-(2,3-dihydroxypropane)-2-methyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimi the ASS="ptx2">1-Allyl-2-(cyanomethylene)-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril

According to the method described in example 3, 1-allyl-2-amino-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 109) were treated with bromoacetonitrile in N,N-dimethylformamide in the presence of sodium hydride at room temperature, obtaining 1-allyl-2-(cyanomethylene)-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile in the form of colorless solids; tPL198-203°C; MS: [M+H]+=361.

Example 147

4-Amino-2-methyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile

a) According to the method described in example 13 (a), [bis(methylthio)methylene] propanedinitrile processed hydrochloride 2,3,4,5-tetrahydro-1H-benzo[d]azepine [J. Heterocycl. Chem. (1971), 8(5), 779-83] in dimethyl sulfoxide in the presence of potassium carbonate at 80°C receives 2-[methylsulfonyl-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)methylene]malononitrile in the form of a solid yellowish; tPL129-132,5°C; MS: [M+H]+=270.

a) According to the method described in example 13 (b), 2-[methylsulfonyl-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)methylene] malononitrile processed hydrochloride and is hydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile in the form of a solid of light yellow color; tPL>200°C; MS: [M+H]+=280.

Example 148

2-Methyl-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile

a) According to the method described in example 133, 4-amino-2-methyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile (example 147) was treated with 2,2,2-triftoratsetilatsetonom in N,N-dimethylformamide in the presence of sodium hydride at 60°C receives 2-methyl-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile in the form of colorless amorphous solid; MS: [M+H]+=362.

Example 149

4-Chloro-2-methylsulfanyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile

According to the method described in example 46 (a), 4,6-dichloro-2-methylsulfanyl-rimidine-5-carbonitrile [J. Heterocycl. Chem. (1971), 8, 445-453] processed hydrochloride 2,3,4,5-tetrahydro-1H-benzo[d]azepine [J. Heterocycl. Chem. (1971), 8(5), 779-83] in N,N-dimethylformamide in the presence of potassium carbonate at 50°C receives 4-chloro-2-methylsulfanyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile in the form of colorless solids; tPL144-150°C; MS: [M+H]+=331.

Example 150

3-[2-Ethyl-5-nitro-6-(2,2,2-triptoreline)pyrimidine-4-yl]XI)pyrimidine-4-yl]-(2,3,4,5-tetrahydro-1H-benzo[d]azepine (example 119) was treated with Amida bis(trimethylsilyl)lithium and methyliodide in tetrahydrofuran at a temperature in the range from -70°C to room temperature, getting 3-[2-ethyl-5-nitro-6-(2,2,2-triptoreline)pyrimidine-4-yl]-2,3,4,5-tetrahydro-1H-benzo[d]azepin in the form of a colourless oil; MS: [M+H]+=397.

Example 151

1-Allyl-6-oxo-2-[(pyridine-3-ylmethyl)amino]-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril

According to the method described in example 133, 1-allyl-2-amino-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 109) was treated with the hydrochloride of 3-(chloromethyl) pyridine and sodium hydride in N,N-dimethylformamide at room temperature, obtaining 1-allyl-6-oxo-2-[(pyridine-3-ylmethyl)amino]-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile in the form of a solid yellowish; tPL>200°C; MS: [M+H]+=413.

Example 152

1-Allyl-2-(2-ethoxyethylene)-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril

According to the method described in example 133, 1-allyl-2-amino-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 109) was treated with 2-amoxicillinwithout and potassium carbonate in N,N-dimethylformamide at 100°C receives 1-allyl-2-(2-ethoxyethylene)-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyran 153

2-(Cyanomethylene)-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril

According to the method described in example 134, 1-allyl-2-(cyanomethylene)-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 146) was treated with lithium borohydride, palladium (II) acetate and triphenylphosphine in tetrahydrofuran at room temperature, obtaining 2-(cyanomethylene)-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile in the form of a solid brownish; tPL>200°C; MS: [M+H]+=321.

Example 154

N-[5-Cyan-1-ethyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-2-yl] formamide

The suspension containing 0.104 g g (0,336 mmole) of 2-amino-1-ethyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 30), 0.6 ml of ethylformate and 0,093 g (0.67 mmole) of potassium carbonate in 1.2 ml of N,N-dimethylformamide was stirred at 120°C for 30 hours and Then the reaction mixture was poured into 30 ml of a mixture of ice/1N. a solution of hydrochloric acid and filtered. The residue was chromatographically on silica gel, using as eluent a mixture (1:1 vol./about.) dichloromethane and ethyl acetate, and then was led from simple afropolitan-2-yl] formamide as a colourless solid; tPL>200°C; MS: [M+H]+=338.

Example 155

4-(2-Hydroxyethylamino)-2-methylsulfanyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl) pyrimidine-5-carbonitrile

According to the method described in example 48, 4-chloro-2-methylsulfanyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile (example 149) was treated with ethanolamine in ethanol at 80°C receives 4-(2-hydroxyethylamino)-2-methylsulfanyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile in the form of a colourless foam; MS: [M+H]+=356.

Example 156

4-(3-Imidazol-1-ylpropionic)-2-methylsulfanyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile

According to the method described in example 48, 4-chloro-2-methylsulfanyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile (example 149) was treated with 1-(3-aminopropyl)imidazole in dioxane in the presence of potassium carbonate at 90°C receives 4-(3-imidazol-1-ylpropionic)-2-methylsulfanyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile in the form of colorless solids; tPL131,0-133,5°C; MS: [M+H]+=420.

Example 157

Hydrochloride 5-methylsulfanyl-7-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-2,3-dihydroimidazo[1,2-C] pyrimidine-8-carbonite what about the[d]azepin-3-yl)pyrimidine-5-carbonitrile (example 155) and 0.5 ml (6.8 mmole) of thionyl chloride in 5.0 ml of chloroform, was stirred for 2 h at 90°C. Then the reaction mixture was evaporated under reduced pressure, suspended in dichloromethane and filtered insoluble crystals. Thus received 0,050 g (0,134 mmole), 33%, hydrochloride 5-methylsulfanyl-7-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-2,3-dihydroimidazo[1,2-C]pyrimidine-8-carbonitrile in the form of a solid yellow; tPL>200°C; MS: [M+H]+=374.

Example 158

3-(2-Methyl-5-nitro-6-oxo-1,6-dihydropyrimidin-4-yl)-2,3,4,5-tetrahydrobenzo[d]azepin-1-he

According to the method described in example 4, 6-(7-amino-1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-2-methyl-5-nitro-3H-pyrimidine-4-one (see example 66) was treated with the hydrochloride 2,3,4,5-tetrahydrobenzo[d]azepin-1-it (1:1) [J. Chem. Soc., Perkin Trans. 1 (1975), (7), 622-6] in N,N-dimethylformamide in the presence of N-ethyldiethanolamine at room temperature, obtaining 3-(2-methyl-5-nitro-6-oxo-1,6-dihydropyrimidin-4-yl)-2,3,4,5-tetrahydrobenzo[d]azepin-1-it is in the form of an amorphous solid of light yellow color; MS: [M+H]+=315.

Example 159

[rat]-6-(1-Hydroxy-1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-2-methyl-5-nitro-3H-pyrimidine-4-one

According to the method described in example 4, 6-(7-amino-1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-2-methyl-5-(1975), (7), 622-6] in N,N-dimethylformamide in the presence of N-ethyldiethanolamine at room temperature, receiving [rat]-6-(1-hydroxy-1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-2-methyl-5-nitro-3H-pyrimidine-4-one as solid of light yellow color; tPL>200°C; MS: [M-N]-=315.

Example 160

2-Methylsulfanyl-4-(3-pyridin-2-ylpropionic)-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile

According to the method described in example 47 (a), 4-chloro-2-methylsulfanyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile (example 149) was treated with 3-(3-pyridyl)-1-propanol in tetrahydrofuran in the presence of sodium hydride at room temperature, obtaining 2-methylsulfanyl-4-(3-pyridin-2-ylpropionic)-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile in the form of butter, light brown; MS: [M+H]+=432.

Example 161

2-Methylsulfanyl-4-[2-(2-oxopyrrolidin-1-yl)ethoxy]-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile

According to the method described in example 47 (a), 4-chloro-2-methylsulfanyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile (example 149) was treated with 1-(2-hydroxyethyl)-2-pyrrolidone in tetrahydrofuran in the presence of sodium hydride at comnl)pyrimidine-5-carbonitrile in the form of colorless solids; tPL126-128,5°C; MS: [M+H]+=424.

Example 162

4-(4-Methylpentylamino)-2-methylsulfanyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile

According to the method described in example 47 (a), 4-chloro-2-methylsulfanyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile (example 149) was treated with 4-methyl-1-pentanol in tetrahydrofuran in the presence of sodium hydride at room temperature, obtaining 4-(4-methylpentylamino)-2-methylsulfanyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile in the form of colorless solids; MS: [M+H]+=397.

Example 163

2-Methylsulfanyl-4-(2-morpholine-4-ylethoxy)-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile

According to the method described in example 47 (a), 4-chloro-2-methylsulfanyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile (example 149) was treated with 4-(2-hydroxyethyl)morpholine in tetrahydrofuran in the presence of sodium hydride at room temperature, obtaining 2-methylsulfanyl-4-(2-morpholine-4-ylethoxy)-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile in the form of a colourless oil; MS: [M+H]+=426.

Example 164

4-Amino-2-methylsulfanyl-6-(1,2,4,5-tetrahydrobenzo[d]separatamente[d]azepin-3-yl)pyrimidine-5-carbonitrile (example 149) was treated with an aqueous solution of ammonia at room temperature, getting 4-amino-2-methylsulfanyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile in the form of colorless solids; tPL>200°C;MS: [M+H]+=312.

Example 165

4 Allyloxy-2-methylsulfanyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile

According to the method described in example 47 (a), 4-chloro-2-methylsulfanyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile (example 149) was treated with allyl alcohol in tetrahydrofuran in the presence of sodium hydride at room temperature, receiving 4 allyloxy-2-methylsulfanyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl) pyrimidine-5-carbonitrile in the form of colorless solids; tPL102,6-104,8°C; MS: [M+H]+=353.

Example 166

2-Methylsulfanyl-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile

According to the method described in example 47 (a), 4-chloro-2-methylsulfanyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile (example 149) was treated with triptorelin in tetrahydrofuran in the presence of sodium hydride at room temperature, obtaining 2-methylsulfanyl-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile as lesconil-4-(2-morpholine-4-ylethylamine)-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl) pyrimidine-5-carbonitrile

According to the method described in example 48, 4-chloro-2-methylsulfanyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile (example 149) was treated aminoacylation in dioxane in the presence of potassium carbonate at 90°C receives 2-methylsulfanyl-4-(2-morpholine-4-ylethylamine)-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile in the form of colorless amorphous solid; MS: [M+H]+=425.

Example 168

4-(2-Methoxyethoxy)-2-methylsulfanyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl) pyrimidine-5-carbonitrile

According to the method described in example 47 (a), 4-chloro-2-methylsulfanyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile (example 149) was treated monometallism ether of diethylene glycol in tetrahydrofuran in the presence of sodium hydride at room temperature, obtaining 4-(2-methoxyethoxy)-2-methylsulfanyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile in the form of colorless amorphous solid; MS: [M+H]+=371.

Example 169

[rat]-3-(6-ethoxy-2-methyl-5-nitropyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-ol

Using as initial products [rat] -6-(1-hydroxy-1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-2-2-methyl-5-nitro-3H-Piri is TES in the title compound in the form of oil is light yellow in color; MS: [M+H]+=345; see example 170.

Example 170

[rat]-3-ethyl-6-(1-hydroxy-1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-2-methyl-5-nitro-3H-pyrimidine-4-one

According to the method described in example 3, [rat]-6-(1-hydroxy-1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-2-2-methyl-5-nitro-3H-pyrimidine-4-one (example 159) were treated with jumatano in N,N-dimethylformamide in the presence of potassium carbonate at room temperature, receiving [rat]-3-ethyl-6-(1-hydroxy-1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-2-methyl-5-nitro-3H-pyrimidine-4-one as an amorphous solid yellow; MS: [M+H]+=345; [rat]-3-(6-ethoxy-2-methyl-5-nitropyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-ol in the form of oil is light yellow in color; MS: [M+H]+=345.

Example 171

4-Chloro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-2-(2,2,2-triptoreline)pyrimidine-5-carbonitrile

According to the method described in example 47 (a), 4-chloro-2-methanesulfonyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile was treated with 2,2,2-triptorelin in tetrahydrofuran in the presence of sodium hydride at room temperature, receiving 4-chloro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-2-(2,2,2-triptoreline)pyrimidine-5-carbonitrile in the form of colorless solids; tPL165-167°C; MS: bontril

By oxidation of 4-chloro-2-methylsulfanyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile (example 149) meta-chloroperbenzoic acid in dichloromethane at room temperature was obtained 4-chloro-2-methanesulfonyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile in the form of a colourless solid; MS: [M+H]+=363.

Example 172

2-(3-Phenoxypropane)-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile

According to the method described in example 47 (a), 2-methanesulfonyl-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile was treated with 3-phenoxypropanol in tetrahydrofuran in the presence of sodium hydride at room temperature, obtaining 2-(3-phenoxypropane)-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile in the form of a colourless oil; MS: [M+H]+=499.

Getting 2-methanesulfonyl-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile

By oxidation of 2-methylsulfanyl-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile (example 166) meta-chloroperbenzoic acid in dichloromethane at room tempera is in the form of colorless solids; tPL166-169°C; MS: [M+H]+=427.

Example 173

2-(3-Pyridin-2-ylpropionic)-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile

According to the method described in example 47 (a), 2-methanesulfonyl-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile (example 172) was treated with 3-(3-pyridyl)-1-propanol in tetrahydrofuran in the presence of sodium hydride at room temperature, obtaining 2-(3-pyridin-2-ylpropionic)-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile in the form of a colourless oil; MS: [M+H]+=484.

Example 174

2-(3-Morpholine-4-ylpropionic)-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile

According to the method described in example 48, 2-methanesulfonyl-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile (example 172) was treated with 4-(3-aminopropyl)morpholine in tetrahydrofuran at 50°C receives 2-(3-morpholine-4-ylpropionic)-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile in the form of a colourless oil; MS: [M+H]+=491.

Example 175

5-Methylsulfanyl-7-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl is robinso[d]azepin-3-yl)pyrimidine-5-carbonitrile suspended in 1.0 ml of triethylorthoformate and the reaction mixture was stirred at 110°C for 24 hours Then it was evaporated under reduced pressure and the obtained residue was purified by chromatography on silica gel, using as eluent a mixture (95:5 vol./about.) dichloromethane and methanol, resulting in a received 0,183 g (0.54 mmole), 66%, 5-methylsulfanyl-7-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-[1,2,4]triazole[4,3-C]pyrimidine-8-carbonitrile in the form of a solid light brown color; tPL>200°C; MS: [M]+=336.

Getting 4-hydrazino-2-methylsulfanyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile

4-Chloro-2-methylsulfanyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile (example 149) and hydrazine hydrate was kept in a mixture of dioxane and water at 100°C receives 4 hydrazino-2-methylsulfanyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile in a solid orange; tPL>200°C; MS: [M+H]+=327.

Example 176

2-Methyl-4-(1,1,2,2-tetrafluoroethoxy)-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile

3.0 ml of tetrafluoroethylene are condensed at -180°C in a mixture containing 0.20 g (of 0.71 mmole) of 2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 17) and 0.037 g (0,86 mmole) di is supported in an autoclave at 120°C for 16 hours Then it was poured into 50 ml of a mixture of ice/1N. the Hcl solution and was extracted three times with 50 ml dichloromethane. The combined organic phases are washed twice with 50 ml water, dried over magnesium sulfate, evaporated under reduced pressure and dried in high vacuum. The resulting crude product was purified by chromatography on silica gel, using as eluent a mixture of hexane/ethyl acetate, getting 0.025 g (of 0.066 mmole), and 9.3%, 2-methyl-4-(1,1,2,2-tetrafluoroethoxy)-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile in the form of an amorphous solid yellow; MS: [M+H]+=381.

Example 177

1-Dimethylamino-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril

According to the method described in example 17 the Z and/or E-isomer ethyl ester 2-cyan-3-methylsulfanyl-3-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)acrylic acid [example 13 a)] was treated with dimethylhydrazone of ndimethylacetamide [J. Heterocycl. Chem. 18, 319 (1981)] and 1,8-diazabicyclo[5.4.0]undec-7-Yong in N,N-dimethylformamide at 100°C receives 1-dimethylamino-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile in the form of colorless solids; tPLRUR 134.4-136,3°C; MS: [M]+=324.

Perforation are condensed at -180°C in the mixture, containing 0.40 g (of 1.42 mmole) of 2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 17) and 0,296 g (2,14 mmole) of potassium carbonate in 3.0 ml of N,N-dimethylformamide, and then the reaction mixture was stirred in an autoclave at 100°C for 72 hours then it was poured into 50 ml of a mixture of ice/1N. the Hcl solution and was extracted three times with 50 ml dichloromethane. The combined organic phases are washed twice with 50 ml water, dried over magnesium sulfate, evaporated under reduced pressure and dried in high vacuum. The resulting crude product was purified by chromatography on silica gel, using as eluent dichloromethane, getting 0,097 g (0,034 mmole), 2,4%, 4-fluoro-2-methyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile in the form of amorphous solids yellowish; MS: [M]+=282.

Example 179

2-Cyclopropyl-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile

Using as initial products 2-cyclopropyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 18) and 2,2,2-triftoratsetilatsetonom in N,N-dimethylformamide, in the presence of potassium carbonate has been specified in the boot>

Example 180

2-Cyclopropyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1-(2,2,2-triptorelin)-1,6-dihydropyrimidin-5-carbonitril

According to the method described in example 3, 2-cyclopropyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 18) was treated with 2,2,2-triftoratsetilatsetonom in N,N-dimethylformamide in the presence of potassium carbonate, receiving 2-cyclopropyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1-(2,2,2-triptorelin)-1,6-dihydropyrimidin-5-carbonitrile in the form of colorless solids; tPL176-179,5°C; MS: [M+H]+=389; and 2-cyclopropyl-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile in the form of colorless solids; tPL116,5-118°C; MS: [M+H]+=389.

Example 181

2-(2-Morpholine-4-ylethylamine)-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile

According to the method described in example 48, 2-methanesulfonyl-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile (example 172) was treated with 2-morpholine-4-ylethylamine in tetrahydrofuran at 80°C receives 2-(2-morpholine-4-ylethylamine)-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)p is 2

2-Oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)-1,2-dihydropyrimidin-5-carbonitril

0,050 g (0.12 mmole) 2-methanesulfonyl-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile (example 172) was dissolved in 3.0 ml of dioxane, and treated with 0.04 ml of 6 M aqueous solution of potassium hydroxide and the reaction mixture was stirred for 16 h at 80°C. then it was evaporated under reduced pressure, was added 50 ml of water and the mixture was extracted three times with 50 ml dichloromethane. The combined organic phases are washed twice with 50 ml water, dried over magnesium sulfate, evaporated under reduced pressure and dried in high vacuum. The obtained residue was led from dichloromethane, getting 0,030 g (0,082 mmole), 69%, 2-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)-1,2-dihydropyrimidin-5-carbonitrile in the form of colorless solids; tPL196-198°C; MS: [M]+=365.

Example 183

6-Oxo-2-propyl-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1-(2,2,2-triptorelin)-1,6-dihydropyrimidin-5-carbonitril

Using as initial products 6-oxo-2-propyl-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 23) and 2,2,2-triptoreline in the form of colorless solids; tPL165-167°C; MS: [M+H]+=391, see example 184.

Example 184

2-Propyl-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline) pyrimidine-5-carbonitrile

According to the method described in example 3, 6-oxo-2-propyl-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 23) was treated with 2,2,2-triftoratsetilatsetonom in N,N-dimethylformamide in the presence of potassium carbonate at room temperature, receiving 6-oxo-2-propyl-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1-(2,2,2-triptorelin)-1,6-dihydropyrimidin-5-carbonitrile in the form of colorless solids; tPL165-167°C; MS: [M+H]+=391; and 2-propyl-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile in the form of colorless solids; tPL104-106°C; MS: [M+H]+=391.

Example 185

[rat]-3-(1-Ethyl-2-methyl-5-nitro-6-oxo-1,6-dihydropyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1 silt ether acetic acid

By processing [rat]-3-ethyl-6-(1-hydroxy-1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-2-methyl-5-nitro-3H-pyrimidine-4-it (example 170) of acetic anhydride and triethylamine in dichloromethane at room temperature was obtained [rat]-3-(1-ethyl-2-methyl-5-nitro-6-oxo-1,6-digit is a; MS: [M+H]+=387.

Example 186

3-(3-Hydroxypropyl)-2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-3H-pyrimidine-4-one

Using as initial products of 2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-4-ol (example 1) and 3-chloro-1-propanol, potassium iodide, potassium carbonate in N,N-dimethylformamide at 50°With the received specified in the title compound as yellow oil; MS: [M+H]+=359, see example 187.

Example 187

3-[2-Methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-4-yloxy]propane-1-ol

According to the method described in example 3, 2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-4-ol (example 1) was treated with 3-chloro-1-propanol, potassium iodide and potassium carbonate in N,N-dimethylformamide at 50°C receives 3- [2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-4-yloxy]propane-1-ol as yellow oil; MS: [M+H]+=359; and 3-(3-hydroxypropyl)-2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-3H-pyrimidine-4-one as yellow oil; MS: [M+H]+=359.

Example 188

2-(2-Morpholine-4-ylethoxy)-4-(2-morpholine-4-ylethylamine)-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile

According to the method, operatively 4-(2-amino-ethyl) - morpholine in dioxane at 80°C for 15 h, getting 2-(2-morpholine-4-ylethoxy)-4-(2-morpholine-4-ylethylamine)-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl) pyrimidine-5-carbonitrile in the form of an amorphous solid orange; MS: [M+H]+= 508.

Getting 4-chloro-2-(2-morpholine-4-ylethoxy)-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl) pyrimidine-5-carbonitrile

According to the method described in example 47 (a), 4-chloro-2-methanesulfonyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile (example 171) was treated with 4-(2-gadoxetic)morpholine in tetrahydrofuran in the presence of sodium hydride at 40°C receives 4-chloro-2-(2-morpholine-4-ylethoxy)-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile in the form of colorless amorphous solid; MS: [M+H]+=414.

Example 189

2-[2-(Pyridine-2-yloxy)ethylamino]-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile

According to the method described in example 48, 2-methanesulfonyl-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile (example 172) was treated with 2-(pyridine-2-yloxy)ethylamine in dioxane at 80°C receives 2-[2-(pyridine-2-yloxy)ethylamino]-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile in the form of colorless am is rogerebert[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile

According to the method described in example 48, 2-methanesulfonyl-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile (example 172) was treated with ethanolamine in dioxane at 80°C receives 2-[2-hydroxyethylamino]-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile in the form of colorless amorphous solid; MS: [M+H]+=408.

Example 191

(3-Imidazol-1-ylpropionic)-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile

According to the method described in example 48, 2-methanesulfonyl-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile (example 172) was treated with 1-(3-aminopropyl)imidazole in dioxane at 80°C receives (3-imidazol-1-ylpropionic]-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile in the form of colorless amorphous solid; MS: [M+H]+=472.

Example 192

5-Methylsulfanyl-7-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)imidazo[1,2-C]pyrimidine-8-carbonitrile

The suspension containing 0,120 g (a 0.27 mmole) of 4-amino-2-methylsulfanyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile (example 164) 0,390 ml (2.7 mmole) solution PI is igenom pressure, suspended in a simple mixture of ether and hexane and was filtered, the insoluble crystals. The resulting residue was purified by chromatography on silica gel, using as eluent a mixture (95:5 vol./about.) dichloromethane and methanol, resulting in a received 0,065 g (0,194 mmole), 72,3%, 5-methylsulfanyl-7-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)imidazo[1,2-C]pyrimidine-8-carbonitrile in the form of an amorphous solid light brown color; MS: [M+H]+=336.

Example 193

3-[2-Methyl-5-nitro-6-(3-phenylpropoxy)pyrimidine-4-yl]-2,3,4,5-tetrahydro-1H-benzo [d] azepin

Using as initial products of 2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-4-ol (example 1) and 3-chloro-1-phenylpropane in N,N-dimethylformamide, in the presence of potassium carbonate at 50°With the received specified in the title compound in the form of oil is light yellow in color; MS: [M+H]+=419; see example 194.

Example 194

2-Methyl-5-nitro-3-(3-phenylpropyl)-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-3H-pyrimidine-4-one

According to the method described in example 3, 2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-4-ol (example 1) was treated with 3-chloro-1-phenylpropane in N,N-dimethylformamide in the presence of potassium carbonate PLA yellow; MS: [M+H]+=419; and 3-[2-methyl-5-nitro-6-(3-phenylpropoxy)pyrimidine-4-yl]-2,3,4,5-tetrahydro-1H-benzo[d]azepin in the form of oil is light yellow in color; MS: [M+H]+=419.

Example 195

(2-Pyrrolidin-1 ylethylamine)-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile

According to the method described in example 48, 2-methanesulfonyl-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile (example 172) was treated with N-(2-amino-ethyl)pyrrolidine in dioxane at 80°C receives (2-pyrrolidin-1 ylethylamine)-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile in the form of an amorphous solid of light yellow color; MS: [M+H]+=461.

Example 196

2-Methyl-5-nitro-3-(3-pyridin-3-ylpropyl)-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-3H-pyrimidine-4-one

Using as initial products of 2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-4-ol (example 1) and 3-(3-pyridyl)propyl ester toluene-4-sulfonic acid in N,N-dimethylformamide, in the presence of potassium carbonate at 120°With the received specified in the title compound as yellow oil; MS: [M+H]+=420; see example 197.

Example 197

3-[2-METI the mu in example 3, 2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-4-ol (example 1) was treated with 3-(3-pyridyl)propyl ester, toluene-4-sulfonic acid in N,N-dimethylformamide in the presence of potassium carbonate at 120°C receives 3-[2-methyl-5-nitro-6-(3-pyridin-3-ylpropionic)pyrimidine-4-yl]-2,3,4,5-tetrahydro-1H-benzo[d]azepin in the form of a yellow oil; MS: [M+H]+=420; and 2-methyl-5-nitro-3-(3-pyridin-3-ylpropyl)-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-3H-pyrimidine-4-one as yellow oil; MS: [M+H]+=420.

Example 198

3-(6-Chloro-2-methyl-5-nitro-pyrimidine-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin

To a suspension containing of 0.30 g (1.0 mmol) of 2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-4-ol (example 1) of 0.66 g (5.0 mmole) of N-ethyldiethanolamine, was added in an argon atmosphere at 0°With 0,266 g (1.25 mmole) of pentachloride phosphorus. Then added to 0.63 g (4.0 mmole) of phosphorus oxychloride and the reaction mixture was stirred at 100°C for 3 hours then it was poured into 50 ml of a mixture of ice/water and was extracted three times with 100 ml dichloromethane. The combined organic phases are washed twice with 50 ml water, dried over magnesium sulfate, evaporated under reduced pressure and dried in high vacuum. Such newcitizenua, getting 0,161 g (mmole worn: 0.505), 50,5%, 3-(6-chlor-2-methyl-5-nitro-pyrimidine-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine in the form of a solid light brown color; tPL161 TO 165°C; MS: [M+H]+=319.

Example 199

1-Hydroxy-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril

The suspension containing 0,30 g (1,07 mmole) of 2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 17) in 10 ml hexamethyldisilazane and 3.0 ml of trimethylchlorosilane, kept at a temperature of delegacia for 3 hours and Then the resulting solution was evaporated under reduced pressure. The residue was dissolved in 10 ml dichloromethane and treated with 0.93 g (2,14 mmole) of complex oxopiperidin (pyridine) (NMR) [J. Org. Chem. 43 (1978), 188-196] and the reaction mixture was stirred at room temperature for 20 hours then added to 0.63 g (2,14 mmole) ethylendiaminetetraacetic acid, and 8.4 ml of 1N. the sodium hydroxide solution and continued to stir for 30 minutes and Then the pH value of the aqueous phase was brought to 7 with 1N. hydrochloric acid and the reaction mixture was extracted three times with 50 ml dichloromethane. The combined organic phases are washed twice with 50 ml water, dried m the crude product was led from simple ester, getting 0,115 g (0,388 mmole), 36.3 per cent, 1-Hydroxy-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile in the form of a solid yellowish; tPL168,5-172°C; MS: [M+H]+=297.

Example 200

1-Amino-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril

According to the method described in example 3, 2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 17) was treated with O-mesitylsulfonylhydroxylamine [Synthesis 1972, 140] in N,N-dimethylformamide in the presence of potassium carbonate at room temperature, obtaining 1-amino-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile in the form of colorless solids; tPL137-142°C; MS: [M+H]+=296.

Example 201

2-(4-Ethylpiperazin-1-yl)-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-twittorati)pyrimidine-5-carbonitrile

According to the method described in example 48, 2-methanesulfonyl-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile (example 172) was treated with ethylpiperazine in dioxane at 80°C receives 2-(4-ethylpiperazin-1-yl)-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptorelin the ptx2">Example 202

3-(3-Imidazol-1-ylpropyl)-2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-3H-pyrimidine-4-one

The solution containing 0,437 g (1.0 mmol) 3-[2-methyl-5-nitro-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6N-pyrimidine-1-yl]propyl ester methanesulfonic acid [obtained from 3-(3-hydroxypropyl)-2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-3H-pyrimidine-4-one (example 186) and methanesulfonanilide/triethylamine in dichloromethane, at a temperature of from -70°C to room temperature], 0,103 g (1.5 mmole) of imidazole and 0,396 g (3.0 mmole) of N-ethyldiethanolamine in 10.0 ml of N,N-dimethylformamide was stirred at 80°C for 16 hours Then the reaction mixture was poured into 50 ml of a mixture of ice/water and was extracted three times with 60 ml of dichloromethane. The combined organic phases are washed twice with 50 ml water, dried over magnesium sulfate, evaporated under reduced pressure and dried in high vacuum. Thus obtained crude product was purified by chromatography on silica gel, using as eluent a mixture of from 10:1 to 9:1 vol./about.) dichloromethane and methanol, getting 0,134 g (mmole 0,328), 33%, 3-(3-imidazol-1-ylpropyl)-2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-3H-pyrimidine-4-it is in the form of oil is light yellow in color; MS: [M-N]+=-pyrimidine-4-one

According to the method described in example 202, 3-[2-methyl-5-nitro-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6N-pyrimidine-1-yl]propyl ether methanesulfonate acid (example 202) was treated with morpholine (excess) at room temperature, obtaining 2-methyl-3-(3-morpholine-4-ylpropyl)-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-3H-pyrimidine-4-one as an amorphous solid light yellow color; MS: [M+H]+=428.

Example 204

2-Methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-3-(3-[1,2,4]triazole-1-ylpropyl)-3H-pyrimidine-4-one

According to the method described in example 202, 3-[2-methyl-5-nitro-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6N-pyrimidine-1-yl]propyl ether methanesulfonate acid (example 202) was treated with 1,2,4-triazole and sodium hydride in N,N-dimethylformamide at room temperature, obtaining 2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-3-(3-[1,2,4]triazole-1-ylpropyl)-3H-pyrimidine-4-one as an amorphous solid light yellow color; MS: [M+H]+=410.

Example 205

3-[3-(2-(R)-Hydroxyethylpyrrolidine-1-yl)propyl-2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-3H-pyrimidine-4-one

According to the method described in example 202, 3-[2-methyl-5-nitro-6-oxo-4-(1,2,4,5 Ali (R)-(-)-2-hydroxyethylpyrrolidine and N-ethyldiethanolamine in tetrahydrofuran under reflux, getting 3-[3-(2-(R)-hydroxyethylpyrrolidine-1-yl)propyl-2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-3H-pyrimidine-4-one in the form of oil is light yellow in color; MS: [M+H]+=442.

Example 206

3-[2-Methyl-5-nitro-6-(3-[1,2,4]triazole-1-ylpropionic)pyrimidine-4-yl]-2,3,4,5-tetrahydro-1H-benzo[d]azepin

According to the method described in example 202, 3-[2-methyl-5-nitro-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6N-pyrimidine-1-yl]propyl ether methanesulfonate acid [obtained from 3-[2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl) pyrimidine-4-yloxy]propane-1-ol (example 187) and methanesulfonanilide/triethylamine in dichloromethane at a temperature from -70°C to room temperature] was treated with 1,2,4-triazole and N-ethyldiethanolamine in N,N-dichloromethane at 50°C receives 3-[2-methyl-5-nitro-6-(3-[1,2,4]triazole-1-ylpropionic)pyrimidine-4-yl]-2,3,4,5-tetrahydro-1H-benzo[d]azepin in the form of oil is light yellow in color; MS: [M-H]+=408.

Example 207

3-[6-(3-Imidazol-1-ylpropionic)-2-methyl-5-nitropyrimidin-4-yl]-2,3,4,5-tetrahydro-1H-benzo[d]azepin

According to the method described in example 202, 3-[2-methyl-5-nitro-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6N-pyrimidine-1-yl]propyl ether methanesulfonate acid (example 206) obrabecim is l-5-nitropyrimidin-4-yl]-2,3,4,5-tetrahydro-1H-benzo[d]azepin in the form of an amorphous solid of light yellow color; MS: [M+H]+=409.

Example 208

3-[2-Methyl-5-nitro-6-(3-pyridin-2-ylpropionic)pyrimidine-4-yl]-2,3,4,5-tetrahydro-1H-benzo[d]azepin

According to the method described in example 47 (a), 3-(6-chloro-2-methyl-5-nitro-pyrimidine-4-yl) -2,3,4,5-tetrahydro-1H-benzo[d]azepine (example 198) was treated with 3-pyridine-2-ispropanol in N,N-dimethylformamide in the presence of sodium hydride at 50°C receives 3-[2-methyl-5-nitro-6-(3-pyridin-2-ylpropionic) pyrimidine-4-yl]-2,3,4,5-tetrahydro-1H-benzo[d]azepin in the form of butter, light brown; MS: [M+H]+=420.

Example 209

3-[2-Methyl-5-nitro-6-(3-pyridin-4-ylpropionic)pyrimidine-4-yl]-2,3,4,5-tetrahydro-1H-benzo[d]azepin

According to the method described in example 47 (a), 3-(6-chloro-2-methyl-5-nitro-pyrimidine-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (example 198) was treated with 3-pyridine-4-ylpropyl in N,N-dimethylformamide in the presence of sodium hydride at room temperature, obtaining 3-[2-methyl-5-nitro-6-(3-pyridin-4-ylpropionic)pyrimidine-4-yl]-2,3,4,5-tetrahydro-1H-benzo[d]azepin in the form of butter, light brown; MS: [M+H]+=420.

Example 210

[2-Methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-4-yl]-(3-morpholine-4-ylpropyl)Amin

According to the method described in example 48, 3-(6-chlorine is nom (excess) at room temperature, receiving [2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-4-yl]-(3-morpholine-4-ylpropyl)amine in the form of a yellow oil; MS: [M+H]+=427.

Example 211

(3-Imidazol-1-ylpropyl)-[2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-4-yl]amine

According to the method described in example 48, 3-(6-chloro-2-methyl-5-nitro-pyrimidine-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (example 198) was treated with 1-(3-aminopropyl)imidazole (excess) at room temperature, obtaining (3-imidazol-1-ylpropyl)-[2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-4-yl]amine as yellow oil; MS: [M+H]+=408.

Example 212

4-[2-Methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-4-ylamino]butane-1-ol

According to the method described in example 48, 3-(6-chloro-2-methyl-5-nitro-pyrimidine-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (example 198) was treated with 4-amino-1-butanol (excess) at room temperature, obtaining 4-[2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-4-ylamino]butane-1-ol in the form of oil is light yellow in color; MS: [M-N]-=370.

Example 213

3-[2-Methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-4-ylamino]propane is[d]azepine (example 198) was treated with 3-amino-1-propanol (excess) at room temperature, getting 3-[2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-4-ylamino] propane-1-ol in the form of a solid of light yellow color; tPL104-108°C; MS: [M-N]-=356.

Example 214

2-Methyl-1-methylamino-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril

Using as initial products 1-amino-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 200), methyliodide, potassium carbonate in N,N-dimethylformamide, got mentioned in the title compound as colorless solids; tPL>200°C; MS: [M+H]+=310; see example 215.

Example 215

Methyl ester [5-cyan-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6N-pyrimidine-1-yl]methylcarbamate acid

The solution containing 0,110 g (0.37 mmole) of 1-amino-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 200), 0,112 ml (4.8 mmole) of methyliodide and rate £ 0.162 g (1,17 mmole) of potassium carbonate in 1.0 ml of N,N-dimethylformamide, was stirred at room temperature for 60 hours then it was poured into 25 ml of a mixture of ice/water and was extracted three times with 50 ml of ethyl acetate. The combined organic phases are double PE. Thus obtained crude product was purified by chromatography on silica gel, using as eluent a mixture (1:1 vol./about.) hexane and ethyl acetate, getting 0,034 g (0,094 mmole), 25%, methyl ester [5-cyan-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6N-pyrimidine-1-yl] methylcarbamate acid as colorless solids; tPL120-122,5°C; MS: [M+H]+=368; and 0.008 g (0.026 mmole), 7%, 2-methyl-1-methylamino-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile in the form of colorless solids; tPL>200°C; MS: [M+H]+=310.

Example 216

Ethyl ester of [5-cyan-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6N-pyrimidine-1-yl]ethylcarbamate acid

According to the method described in example 215, 1-amino-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 200) were treated with jumatano in N,N-dimethylformamide in the presence of potassium carbonate at room temperature, obtaining the ethyl ester of [5-cyan-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6N-pyrimidine-1-yl]ethylcarbamate acid as colorless amorphous solid; MS: [M+H]+=396.

Example 217

tert-Butyl ester of [5-stwora, containing 0,100 g (0,34 mmole) of 1-amino-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 200) and 0,141 mg (0.65 mmole) of di-tert-BUTYLCARBAMATE in 1.5 ml dichloromethane, was added 4.2 mg (0,034 mmole) of 4-dimethylaminopyridine and the reaction mixture was stirred at room temperature for 16 hours Then evaporated under reduced pressure and dried in high vacuum. Thus obtained crude product was purified by chromatography on silica gel, using as eluent a mixture (9:1 vol./about.) dichloromethane and diethyl ether, receiving 0,074 g (0.015 mmole), 44%, tert-butyl ester [5-cyan-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6N-pyrimidine-1-yl]dicarbamate acid as colorless solids; tPL148-150°C; MS: [M+H]+=496.

Example 218

tert-Butyl ester of [5-cyan-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6N-pyrimidine-1-yl]carbamino acid

670 mg (of 1.35 mmole) of tert-butyl ester [5-cyan-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6N-pyrimidine-1-yl]dicarbamate acid (example 217) and 3.5 g of silica gel was suspended in 10 ml of dichloromethane and the suspension was stirred for 16 hours Then it was made in chromatographies-what about the ether, getting 0,395 g (1.0 mmol), 74%, tert-butyl ester [5-cyan-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6N-pyrimidine-1-yl] carbamino acid as colorless solids; tPL150-152°C; MS: [M+H]+=396.

Example 219

2-(2-Pyridin-3-ylethylamine)-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile

According to the method described in example 48, 2-methanesulfonyl-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile (example 172) was treated with 2-pyridine-3-ylethylamine in dioxane at 80°C receives 2-(2-pyridin-3-ylethylamine)-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile in the form of an amorphous solid of light yellow color; MS: [M+H]+=469.

Example 220

2-Methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1-(2,2,2-triptoreline)-1,6-dihydropyrimidin-5-carbonitril

According to the method described in example 3, 1-hydroxy-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 199) was treated with 2,2,2-triftoratsetilatsetonom in N,N-dimethylformamide in the presence of potassium carbonate, obtaining 2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1-(2,2 is From: [M+H]+=379.

Example 221

1-{3-[2-Methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-4-ylamino]propyl}pyrrolidin-2-he

According to the method described in example 48, 3-(6-chloro-2-methyl-5-nitro-pyrimidine-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (example 198) was treated with 1-(3-aminopropyl)-2-pyrrolidinone in tetrahydrofuran at room temperature, obtaining 1-{3-[2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-4-ylamino]propyl}pyrrolidin-2-it is in the form of oil is light yellow in color; MS: [M+H]+=425.

Example 222

3-[3-(3-(R)-Hydroxypyrrolidine-1-yl)propyl]-2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-3H-pyrimidine-4-one

According to the method described in example 202, 3-[2-methyl-5-nitro-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6N-pyrimidine-1-yl]propyl ether methanesulfonate acid (example 202) was treated with (R)-3-hydroxypyrrolidine and N-ethyldiethanolamine in tetrahydrofuran at a temperature in the range from room temperature up to the boiling temperature under reflux, getting 3-[3-(3-(R)-hydroxypyrrolidine-1-yl)propyl]-2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-3H-pyrimidine-4-one in the form of oil is light yellow in color; MS: [M+H]+=428.

Example 223

tert-Butylate

According to the method described in example 3, 2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 17) was treated with a mixture of O-mesitylsulfonylhydroxylamine [Synthesis 1972, 140] and tert-butyl-N-mesitylenesulfonyl [Synthesis 1972, 140] in N,N-dimethylformamide in the presence of potassium carbonate at room temperature, in addition to receiving 1-amino-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 200) tert-butyl ether N’-[5-cyan-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6N-pyrimidine-1-yl]hydrazinecarboxamide acid as colorless solids; tPL170-171,5°C; MS: [M+H]+=411.

Example 224

1-Methoxy-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril

According to the method described in example 3, 1-hydroxy-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 199) were treated with methyliodide in N,N-dimethylformamide in the presence of potassium carbonate, getting 1-methoxy-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile in the form of colorless solids; tPL144-145°C; MS: [M]+=310.

Approx

According to the method described in example 3, 1-hydroxy-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 199) were treated with ethyliodide in N,N-dimethylformamide in the presence of potassium carbonate, receiving 1 ethoxy-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile in the form of colorless solids; tPL149-152°C; MS: [M]+=324.

Example 226

2-Methyl-6-oxo-1-propoxy-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril

According to the method described in example 3, 1-hydroxy-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 199) was treated with n-propyliodide in N,N-dimethylformamide in the presence of potassium carbonate at room temperature, obtaining 2-methyl-6-oxo-1-propoxy-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile in the form of colorless solids; tPL132,5-134°C; MS: [M]+=338.

Example 227

4-Methoxy-2-methyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile

According to the method described in example 3, 2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 17) amrabat-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 26) 4-methoxy-2-methyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile in the form of colorless amorphous solid; MS: [M]+=294.

Example 228

2-Methyl-4-propoxy-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile

Using as initial products of 2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 17) and n-propyliodide in N,N-dimethylformamide, in the presence of potassium carbonate has been specified in the title compound as colorless amorphous solid; MS: [M+H]+=323; see example 229.

Example 229

2-Methyl-6-oxo-1-propyl-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril

According to the method described in example 3, 2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 17) was treated with n-propyliodide in N,N-dimethylformamide in the presence of potassium carbonate, obtaining 2-methyl-6-oxo-1-propyl-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile in the form of colorless amorphous solid; MS: [M+H]+=323; and 2-methyl-4-propoxy-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl) pyrimidine-5-carbonitrile in the form of colorless amorphous solid; MS: [M+H]+=323.

Example 230

1,2-Diamino-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6 the site, located between[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 13) was treated with O-mesitylsulfonylhydroxylamine [Synthesis 1972, 140] in N,N-dimethylformamide in the presence of potassium carbonate at room temperature, obtaining 1,2-diamino-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile in the form of colorless solids; tPL>200°C; MS: [M+H]+=297.

Example 231

3-{6-[4-(tert-Butyldimethylsilyloxy)butoxy]-2-methyl-5-nitropyrimidin-4-yl}-2,3,4,5-tetrahydro-1H-benzo[d] azepin

Using as initial products of 2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-4-ol (example 1) and tert-butyl(4-chloroethoxy)dimethylsilane in N,N-dimethylformamide, in the presence of potassium carbonate at 120°With the received specified in the title compound in the form of oil is light yellow in color; MS: [M-C4H9]+=429; see example 232.

Example 232

3-[4-(tert-Butyldimethylsilyloxy)butyl]-2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-3H-pyrimidine-4-one

According to the method described in example 3, 2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-4-ol (example 1) was treated with tert-butyl(4-chloroethoxy)dimethylsilanol in N,N-dimethylformamide in the presence of potassium carbonate at 120°C receives 3-[4-(tert-butultimately-silyloxy)butyl]-2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo the t-butyldimethylsilyloxy)butoxy]-2-methyl-5-nitropyrimidin-4-yl}-2,3,4,5-tetrahydro-1H-benzo[d]azepin in the form of oil is light yellow in color; MS: [M-C4H9]+=429.

Example 233

4-[2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-4-yloxy]butane-1-ol

The solution containing 4,01 g (8,23 mmole) 3-{6-[4-(tert-butyldimethylsilyl-enyloxy)butoxy]-2-methyl-5-nitropyrimidin-4-yl}-2,3,4,5-tetrahydro-1H-benzo[d]azepine (example 231) in 45 ml of a mixture (2:1 vol./about.) acetonitrile and dichloromethane, was treated under stirring with 5.2 ml of a solution of hydrogen fluoride (40% in water) and the reaction mixture was stirred for 1 h at room temperature. Then it was poured into 150 ml of a mixture of ice/water and was extracted three times with 150 ml of dichloromethane. The combined organic phases are washed twice with 50 ml water, dried over magnesium sulfate, evaporated under reduced pressure and dried in high vacuum. The resulting crude product was purified by chromatography on silica gel, using as eluent a mixture of hexane and ethyl acetate (9:1 to 1:1 vol./vol.), getting to 2.18 g (5,85 mmole), 71%, 4-[2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-4-yloxy]butane-1-ol as yellow oil; MS: [M+H]+=373.

Example 234

3-(4-Hydroxybutyl)-2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-3H-pyrimidine-4-one

On meth who EPIN-3-yl)-3H-pyrimidine-4-one (example 232) was treated with a solution of hydrogen fluoride (40% in water) in a mixture (2:1 vol./about.) acetonitrile and dichloromethane at room temperature, getting 3-(4-hydroxybutyl)-2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-3H-pyrimidine-4-one as yellow oil; MS: [M+H]+=373.

Example 235

4-[2-Methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-4-yloxy]butyl ether methanesulfonate acid

By treating 4-[2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-4-yloxy]butane-1-ol (example 233) methanesulfonanilide in dichloromethane (at a temperature of from -70°C to room temperature) was obtained 4-[2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-4-yloxy]butyl ether methanesulfonate acid as an amorphous solid yellow; MS: [M+H]+=451.

Example 236

4-[2-Methyl-5-nitro-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6N-pyrimidine-4-yl]butyl ether methanesulfonate acid

By treating 3-(4-hydroxybutyl)-2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-3H-pyrimidine-4-it (example 234) methanesulfonanilide in dichloromethane (at a temperature of from -70°C to room temperature) was obtained 4-[2-methyl-5-nitro-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6N-pyrimidine-4-yl]butyl ether methanesulfonate acid as an amorphous solid substances is l)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-4-ylamino]propane-1-ol

According to the method described in example 4 4-(3-hydroxypropylamino)-3-nitro-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-2-silt ether triftormetilfullerenov acid was treated with the hydrochloride 2,3,4,5-tetrahydro-1H-benzo[d]azepine [J. Heterocycl. Chem. (1971), 8(5), 779-83] in N,N-dimethylformamide in the presence of N-ethyl-N,N-Diisopropylamine at room temperature, obtaining 3-[3-nitro-2-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-4-ylamino]propane-1-ol as yellow oil; MS: [M+H]+=411.

Getting 4-(3-hydroxypropylamino)-3-nitro-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-2-silt ether triftormetilfullerenov acid

Used above 4-(3-hydroxypropylamino)-3-nitro-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-2-silt ether triftormetilfullerenov acid was obtained by reaction in the following sequence: (I) the processing of 3-nitro-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-2,4-diol [US 5352784 A (1994)] triftormetilfullerenov anhydride and triethylamine in dichloromethane at 3°With the received 3-nitro-2-tripterocalyx-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-4-silt ether triftormetilfullerenov acid; (II) the processing of 3-nitro-2-tripterocalyx-6,7,8,9-tetrahydro - dichloromethane at room temperature was obtained 4-(3-hydroxypropylamino)-3-nitro-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-2-silt ether triftormetilfullerenov acid.

Example 238

3-Nitro-2-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-4-ol

According to the method described in example 4, 4-hydroxy-3-nitro-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-2-silt ether triftormetilfullerenov acid [obtained from 3-nitro-2-tripterocalyx-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-2-silt ether triftormetilfullerenov acid (example 237), and potassium carbonate in a mixture of tetrahydrofuran and water at room temperature] was treated with the hydrochloride 2,3,4,5-tetrahydro-1H-benzo[d]azepine [J. Heterocycl. Chem. (1971), 8(5), 779-83] in N,N-dimethylformamide in the presence of N-ethyl-N,N-Diisopropylamine at 50°C receives 3-nitro-2-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-4-ol in the form of a solid of light yellow color; tPL>200°C; MS: [M+H]+=354.

Example 239

tert-Butyl ester of [5-cyan-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6N-pyrimidine-1-yl]methylcarbamate acid

According to the method described in example 3 tert-butyl ester of [5-cyan-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6N-pyrimidine-1-yl]carbamino acid (example 218) were treated with methyliodide in N,N-dimethylformamide in parahydrogen[d]azepin-3-yl)-6N-pyrimidine-1-yl]methylcarbamate acid as colorless solids; tPL164-166°C; MS: [M+H]+=410.

Example 240

tert-Butyl ester of [5-cyan-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6N-pyrimidine-1-yl]ethylcarbamate acid

According to the method described in example 3 tert-butyl ester of [5-cyan-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6N-pyrimidine-1-yl] carbamino acid (example 218) were treated with ethyliodide in N,N-dimethylformamide in the presence of potassium carbonate at room temperature, obtaining tert-butyl ester of [5-cyan-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6N-pyrimidine-1-yl] ethylcarbamate acid as colorless solids; tPL86-88°C; MS: [M+H]+=424.

Example 241

tert-Butyl ester of [5-cyan-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6N-pyrimidine-1-yl]-(2,2,2-triptorelin)carbamino acid

According to the method described in example 3 tert-butyl ester of [5-cyan-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6N-pyrimidine-1-yl] carbamino acid (example 218) was treated with 2,2,2-triptoreline-formetocoupon.com in N,N-dimethylformamide in the presence of potassium carbonate at room temperature, getting tert-butyl ester of [5-cyan-2-methyl-6-oxo-4-(1,2,4,5-UB>PL86-88°C; MS: [M+H]+=478.

Example 242

tert-Butyl ester of [5-cyan-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6N-pyrimidine-1-yl] isopropylcarbamate acid

According to the method described in example 3 tert-butyl ester of [5-cyan-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6N-pyrimidine-1-yl] carbamino acid (example 218) was treated with 2-jumprope in N,N-dimethylformamide in the presence of potassium carbonate at room temperature, obtaining tert-butyl ester of [5-cyan-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6N-pyrimidine-1-yl]isopropylcarbamate acid as colorless amorphous solid; MS: [M+H]+=438.

Example 243

1 Isopropylamino-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril

According to the method described in example 70, tert-butyl ester of [5-cyan-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6N-pyrimidine-1-yl] isopropylcarbamate acid (example 242) was treated with 1,5 N. solution of hydrochloric acid in methanol at room temperature, receiving 1 isopropylamino-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile in the form of a colorless solid ventuellement[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril

According to the method described in example 70, tert-butyl ester of [5-cyan-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6N-pyrimidine-1-yl] ethylcarbamate acid (example 240) was treated with 1,5 N. solution of hydrochloric acid in methanol at room temperature, receiving 1 ethylamino-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile in the form of colorless solids; tPL172-174°C; MS: [M+H]+=324.

Example 245

2-Methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1-(2,2,2-triptoreline)-1,6-dihydropyrimidin-5-carbonitril

According to the method described in example 70, tert-butyl ester of [5-cyan-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6N-pyrimidine-1-yl]-(2,2,2-triptorelin)carbamino acid (example 241) was treated with 1,5 N. solution of hydrochloric acid in methanol at room temperature, obtaining 2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1-(2,2,2-triptoreline)-1,6-dihydropyrimidin-5-carbonitrile in the form of colorless solids; tPL146-146°C; MS: [M+H]+=378.

Example 246

2-(2-Methoxyethoxy)-4-methylsulfanyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl) pyrimidine-5-carbonitrile

To a solution containing 0,019 g (0.25 m is a mineral oil) and the reaction mixture was stirred at room temperature for 15 minutes Then was added a solution containing 0.10 g (0.25 mmole) 2-methylsulfanyl-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile (example 166) in 3.0 ml of tetrahydrofuran, and continued the stirring for 16 h at 40°C. After the reaction mixture was poured into 150 ml of a mixture of ice/water and was extracted three times with 150 ml of dichloromethane. The combined organic phases are washed twice with 50 ml water, dried over magnesium sulfate, evaporated under reduced pressure and dried in high vacuum. The resulting crude product was purified by chromatography on silica gel, using as eluent a mixture of hexane and ethyl acetate (9:1 vol./vol.), resulting received 0,051 g (of 0.14 mmole), 55%, 2-(2-methoxyethoxy)-4-methylsulfanyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile in the form of colorless solids; tPL108-111°C; MS: [M+H]+=371.

Example 247

4-Amino-2-methanesulfonyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile

By oxidation of 4-amino-2-methylsulfanyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile (example 164) using meta-chloroperbenzoic acid in dichloromethane at room temperature was obtained 4-Eminescu; tPL184-185,5°C; MS: [M+H]+=344.

Example 248

4-(1,2,4,5-Tetrahydrobenzo[d]azepin-3-yl)-2,6-bis-(2,2,2-triptoreline) pyrimidine-5-carbonitrile

According to the method described in example 47 (a), 4-chloro-2-methylsulfanyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile (example 149) was treated with triptorelin in tetrahydrofuran in the presence of sodium hydride at room temperature, in addition to receiving 2-methylsulfanyl-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile (example 166) 4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-2,6-bis-(2,2,2-triptoreline)pyrimidine-5-carbonitrile in the form of colorless solids; tPL130-133,5°C; MS: [M+H]+=447.

Example 249

2-Amino-4-methylsulfanyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile

According to the method described in example 4, 2-amino-4-bromo-6-methylsulfanyl-pyrimidine-5-carbonitrile[obtained from the sodium salt of 2,2-dicyan-1-methylsulfonylmethane [EP 244360 A2 (1987)] using excess hydrogen bromide in acetic acid at a temperature in the range of 0°C to room temperature] was treated with the hydrochloride 2,3,4,5-tetrahydro-1H-benzo[d]azepine [J. Heterocycl. Chem. (1971), 8(5)4-methylsulfanyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile in the form of colorless solids; tPL164-168°C; MS: [M]+=311.

Example 250

N-[5-Cyan-4-methylsulfanyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-2-yl]-2-methoxyacetate

A solution containing 0.10 g (0,32 mmole) of 2-amino-4-methylsulfanyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile (example 249) in 5 ml of pyridine, was treated 0,072 g (of 0.64 mmole) of methoxyacetanilide and the reaction mixture was stirred at 60°C for 16 hours then it was poured into 150 ml of a mixture of ice/water and was extracted three times with 150 ml of dichloromethane. The combined organic phases are washed three times with 50 ml of 1N. hydrochloric acid, washed twice with 50 ml water, dried over magnesium sulfate, evaporated under reduced pressure and dried in high vacuum. The resulting crude product was purified by chromatography on silica gel, using as eluent a mixture of hexane and ethyl acetate (1:1 vol./vol.), resulting received 0,070 g (0,18 mmole) of N-[5-cyan-4-methylsulfanyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-2-yl]-2-methoxyacetate in the form of an amorphous solid of light yellow color; MS: [M+H]+=384.

Example 251

[rat]-2-(2-Hydroxypropylamino)-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile (example 172) was treated with [rat]-1-amino-2-hydroxypropane in dioxane at 60°C getting [rat]-2-(2-hydroxypropylamino)-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile in the form of colorless solids; tPL141-147°C; MS: [M+H]+=422.

Example 252

2-[2-(2-Hydroxyethoxy)ethylamino]-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile

According to the method described in example 48, 2-methanesulfonyl-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile (example 172) was treated with 2-(2-aminoethoxy)ethanol in dioxane at 40°C receives 2-[2-(2-hydroxyethoxy)ethylamino]-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile in the form of colorless amorphous solid; MS: [M+H]+=452.

Example 253

[pan]-2-[(2,2-Dimethyl[1,3]dioxolane-4-ylmethyl)amino]-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile

According to the method described in example 48, 2-methanesulfonyl-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-trithorax)pyrimidine-5-carbonitrile (example 172) was treated with [rat]-2,2-dimethyl-1,3-dioxolane-4-methanamine in dioxane at 40°C receives [rat]-2-[(2,2-dimethyl[1,3]dioxolane-4-ylmethyl)amino)-4-(1,2,4,5-tetrahydrobenzo[d]azepin SUP>=478.

Example 254

tert-Butyl ester 3-[5-cyan-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-2-ylamino]propionic acid

According to the method described in example 48, 2-methanesulfonyl-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile (example 172) was treated with tert-butyl ether-alanine in dioxane at 50°C receives tert-butyl ester 3-[5-cyan-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-2-ylamino]propionic acid as colorless amorphous solid; MS: [M+H]+=492.

Example 255

Methyl ester [5-cyan-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-2-ylamino]acetic acid

According to the method described in example 48, 2-methanesulfonyl-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile (example 172) was treated with methyl ester hydrochloride of glycine and N-ethyl-N,N-diisopropylamino in dioxane at 50°C receives methyl ester [5-cyano-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-2-ylamino]acetic acid as colorless solids; tPL136-140°C; MS: [M+H]+=436.

Example 256

+=354.

Example 257

N-[5-Cyan-4-methylsulfanyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-2-yl]-3-methylbutyrate

According to the method described in example 250, 2-amino-4-methylsulfanyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile (example 249) was treated with chloride of isovalerianic acid in pyridine at 60°C receives N-[5-cyan-4-methylsulfanyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-2-yl]-3-methylbutyrate in the form of colorless amorphous solid; MS: [M+H]+=396.

Example 258

4-(4-Methoxybenzyloxy)-3-nitro-2-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyridine

According to the method described in example 4, 4-(4-methoxybenzyloxy)-3-nitro-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-2-silt ether triftormetilfullerenov acid (derived from 3-nitro-2-tripterocalyx-6,7,8,9-tetrahydro-5H-cyclohepta[atrium in tetrahydrofuran at room temperature was treated with the hydrochloride 2,3,4,5-tetrahydro-1H-benzo[d]azepine [J. Heterocycl. Chem. (1971), 8(5), 779-83] in N,N-dimethylformamide in the presence of N-ethyl-N,N-Diisopropylamine at room temperature, obtaining 4-(4-methoxybenzyloxy)-3-nitro-2-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine in the form of an amorphous solid yellow; MS: [M+H]+=474.

Example 259

[glad]-2-[(2,3-dihydroxypropyl)-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile

According to the method described in example 70, [rat]-2-[(2,2-dimethyl[1,3]dioxolane-4-ylmethyl)amino)-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile (example 253) was treated with a solution of hydrochloric acid in tetrahydrofuran at room temperature, receiving [rat]-2-[(2,3-dihydroxypropyl)-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile in the form of colorless amorphous solid; MS: [M+H]+=438.

Example 260

4-Amino-2-(2-hydroxyethylamino)-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile

According to the method described in example 48, 4-amino-2-methanesulfonyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile (example 247) were treated with ethanolamine in dioxane at 80°C, poluchasa solids; MS: [M+H]+=325.

Example 261

2-(3-Hydroxypropylamino)-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile

According to the method described in example 48, 2-methanesulfonyl-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile (example 172) was treated with 3-aminopropanol in dioxane at 40°C receives 2-(3-hydroxypropylamino)-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile in the form of colorless amorphous solid; MS: [M+H]+=422.

Example 262

2-(2-Methoxyethoxy)-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile

According to the method described in example 47 (a), 2-methanesulfonyl-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile (example 172) was treated with 2-methoxyethanol in tetrahydrofuran in the presence of sodium hydride at 40°C receives 2-(2-methoxyethoxy)-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline) pyrimidine-5-carbonitrile in the form of colorless amorphous solid; MS: [M+H]+=423.

Example 263

1 Isopropoxy-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-in-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 199) were treated with isopropylidene in N,N-dimethylformamide in the presence of potassium carbonate at room temperature, getting 1 isopropoxy-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile in the form of colorless solids; tPL127-128°C; MS: [M]+=339.

Example 264

3-[2-Methyl-5-nitro-6-(4-[1,2,4]triazole-1-albucosi)pyrimidine-4-yl]-2,3,4,5-tetrahydrobenzo[d]azepin

According to the method described in example 202, 4-[2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-4-yloxy]butyl ether methanesulfonate acid (example 235) was treated with 1,2,4-triazole and sodium hydride in N,N-dimethylformamide at room temperature, obtaining 3-[2-methyl-5-nitro-6-(4-[1,2,4]triazole-1-albucosi)pyrimidine-4-yl]-2,3,4,5-tetrahydrobenzo[d]azepin in the form of a solid of light yellow color; tPL88-91°C; MS: [M+H]+=424.

Example 265

2-Methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-(4-[1,2,4]triazole-1-libutil)-3H-pyrimidine-4-one

According to the method described in example 202, 4-[2-methyl-5-nitro-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6N-pyrimidine-4-yl]butyl ether methanesulfonate acid (example 236) was treated with 1,2,4-triazole and sodium hydride in N,N-dimethylformamide at room temperature, obtaining 2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-(4-[1,2,4]triazole-1-libutil)-3H-6

1-(3,3-Littoralis)-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril

Using as initial products of 2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 17) and 3-bromo-3,3-ditropan, potassium carbonate in N,N-dimethylformamide at room temperature has been specified in the title compound in the form of an amorphous solid of light yellow color; tPL158-159°C; MS: [M]+=356; see example 267.

Example 267

4-(3,3-Deferasirox)-2-methyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile

According to the method described in example 3, 2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 17) was treated with 3-bromo-3,3-differpromises in N,N-dimethylformamide in the presence of potassium carbonate at room temperature receiving 4-(3,3-deferasirox)-2-methyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile in the form of colorless amorphous solid; MS: [M+H]+=356; and 1-(3,3-littoralis)-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile in the form of an amorphous solid of light yellow color; tPL158-15 is drobenko[d]azepin-3-yl)pyrimidine-5-carbonitrile

Using as initial products of 2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 17) and 3-bromo-3,3-ditropan, silver carbonate in 1,2-dichloroethane, at the reflux has been specified in the title compound in the form of an amorphous solid of light yellow color; MS: [M]+=356; see example 269.

Example 269

1-(1,1-Littoralis)-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril

According to the method described in example 3, 2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 17) was treated with 3-bromo-3,3-differpromises in 1,2-dichloroethane in the presence of silver carbonate at reflux, in addition to receiving 4-(3,3-deferasirox)-2-methyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile (example 267) 1-(1,1-littoralis)-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile in the form of colorless amorphous solid; MS: [M]+=356; and 4-(1,1-deferasirox)-2-methyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile in the form of an amorphous solid of light yellow color; MS: [M]

Using as initial products of 2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 17) and 1-chloro-1,1-diformate, potassium carbonate in N,N-dimethylformamide, at 145°C in the autoclave had been specified in the title compound as colorless solids; tPL143°C; MS: [M+H]+=331; see example 271.

Example 271

1 Deformedarse-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril

According to the method described in example 3, 2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 17) was treated with 1-chloro-1,1-deformation in N,N-dimethylformamide in the presence of potassium carbonate at 145°C in an autoclave for 30 min, receiving 1 deformedarse-2-methyl-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile in the form of a solid yellowish; tPL217°C; MS: [M]+=330; and 4 deformedarse-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-5-carbonitrile in the form of colorless solids; tPL143°C; MS: [M+H]+=331.

Example 272

1 Deformedarse-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydrobis[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile (example 199) was treated with 1-chloro-1,1-deformation in N,N-dimethylformamide in the presence of potassium carbonate at 50°C in an autoclave for 60 h, getting 1 deformedarse-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile in the form of colorless amorphous solid; MS: [M]+=346.

Example 273

1-Ethyl-2-methyl-6-oxo-4-(1,1,2-Tricity-1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril

1-Ethyl-2-methyl-6-oxo-4-(1,1,2-Tricity-1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile was obtained from ethyl-2-cyan-3,3-bis(methylthio)acrylate and 1,1,2-Tricity-2,3,4,5-tetrahydro-1H-benzo[d]azepine according to the method described in examples 13 and 17 and 27/28. 1,1,2-Tricity-2,3,4,5-tetrahydrobenzo[d]azepin received the following way:

I) the interaction of 1-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)ethanone [J. Heterocycl. Chem. (1971), 8(5), 779-83] with Dibenzoyl peroxide and N-bromosuccinimide in carbon tetrachloride at reflux was obtained 1-(5-bromo-1,2-dihydrobenzo[d]azepin-3-yl)Etalon;

II) hydrogenation of 1-(5-bromo-1,2-dihydrobenzo[d]azepin-3-yl)ethanone using tritium using Pd/C in methanol in the presence of triethylamine was obtained 1-(1,1,2-Tricity-1,2,4,5-tetrahydrobenzo[d]azepin-3-yl) Etalon;

III) processing 1-(1,1,2-Tricity-1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)ethanone concentre

Example

Tablets of the following composition were prepared generally accepted method, mg/tablet:

Active substance 100

Powdered lactose 95

White corn starch 35

Polyvinylpyrrolidone 8

Na-carboximetilkrahmal 10

Magnesium stearate 2

Weight tablets 250

Example B

Tablets of the following composition were prepared generally accepted method,mg/tablet:

Active ingredient 200

Powdered lactose 100

White corn starch 64

Polyvinylpyrrolidone 12

Na-carboximetilkrahmal 20

Magnesium stearate 4

Weight tablets 400

The Example In

To prepare capsules of the following composition (mg/capsule:

Active substance 50

Crystalline lactose 60

Microcrystalline cellulose 34

Talc 5

Magnesium stearate 1

The weight of the contents of the capsule 150

The active ingredient having the desired particle size, crystalline lactose and microcrystalline cellulose are mixed with each other to a homogeneous state, sieved and then mixed into casmera.

1. Compounds of General formula

where R1denotes hydrogen, (ness.)alkyl, oxygen, halogen or-OR-, -O(C3-C6)cycloalkyl, -O(R)n-(C3-C6)cycloalkyl, -O(CHR)nCN, -O(R)nCF3, -O(CHR)(CHR)nNR2, -O(CHR)(CHR)nOR, -O(R)n-(ness.)alkenyl, -F3, -OCF2-R, -F2-(ness.)alkenyl, -OCHRF, -F-(ness.)alkenyl, -F2CRF2, -OCF2Br, -O(CHR)nCF2Br, -O(R)n-phenyl, where the phenyl group optionally may be substituted by one to three substituents, independently of one another selected from the series comprising (ness.)alkyl, (ness.)alkoxygroup, halogen, nitro or cyano, -O(CHR)(R)n-morpholino, -O(R)(R)n-pyrrolidino, -O(CHR)(CHR)n-piperidine, -O(CHR)(CHR)n-imidazole, -O(R)(R)n-triazole, -O(R)n-pyridine, -O(CHR)(CHR)n-OSi-(ness.)alkyl, -O(R)(R)n-OS(O)2-(ness.)alkyl, -O(CH2)nCH=CF2, -O(R)n-2,2-dimethyl[1,3]dioxolane, -O(CHR)n-CHOR-CH2OR, -O(CHR)n-CHOR-(CHR)n-CH2OR, or-SR, or-S(R)nR, or-NR2, -N(R)(CHR)(CHR)nOR, -N(R)(-N(R)(CHR)(CHR)n-pyrrolidin-2-Oh, -N(R)(CHR)(R)n-piperidino, -N(R)(R)(R)n-triazole, -N(R)n-pyridine, where n = 1-6;

R denotes hydrogen, (ness.)alkyl or (ness.)alkenyl selected independently from each other, if there is more than one radical R;

R2represents nitro or cyano;

R3denotes hydrogen, (ness.)alkyl, =O, =S, -SR, -S(O)2-(ness.)alkyl, -(C3-C6)cycloalkyl or piperazine derivatives, optionally substituted (ness.)the alkyl, or-CONR2, -(CHR)nCONR2, -(CHR)nOR, -(CH2)n-CF3, -CF3, -(R)nOS(O)CF3, -(CHR)nCOOR, -(R)nSC6H5where the phenyl group optionally may be substituted by one to three substituents, independently of one another selected from the series comprising (ness.)alkyl, (ness.)alkoxygroup, halogen, nitro or cyano, -(R)n-1,3-dioxo-1,3-dihydroindol, -(R)n-tetrahydropyran-2-yloxy or(R)n-S-(ness.)alkyl or-NR2, -NR-(ness.)alkyl, -NRCHO, -N(R)(CHR)nCN, -N(R)(CHR)nCF3, -N(R)(CHR)(CHR)n-OR, -N(R)C(O)(CHR)nO-(ness.)alkyl, -N(R)(CHR)n-(ness.)alkyl, -NR(CHR)(CHR)n-OR, -N(R)(R)(R)n-O-phenyl, where the phenyl group optionally may be substituted is a group, halogen, nitro or cyano, -NR(R)n-(ness.)alkenyl, -N(R) (CHR) (CHR)n-O-(CHR)nOR, -N(R)(CHR)nC(O)O-(ness.)alkyl, -N(R)(CHR)nC(O)NR-(ness.)alkyl, -N(R)(CH2)n-2,2-dimethyl[1,3]dioxolane, -N(R)(CHR)(R)n-morpholino, -N(R)(R)n-pyridine, -N(R)(CHR)(R)n-piperidino, -N(R)(CHR)(CHR)n-pyrrolidino, -N(R) (CHR)(R)n-O-pyridine, -N(R)(CHR)(CHR)n-imidazole, -N(R)(CHR)n-CR2-(CHR)n-OR, -N(R)(CHR)n-CR2-OR, -N(R)(CHR)n-CHOR-CH2OR, -N(R)(CHR)n-CHOR-(CHR)n-CH2OR, or-OR, -O(CHR)nCF3, -F3, -O(R)(R)n-O-phenyl, where the phenyl group optionally may be substituted by one to three substituents, independently of one another selected from the series comprising (ness.)alkyl, (ness.)alkoxygroup, halogen, nitro or cyano, -O(R)(R)n-O-(ness.)alkyl, -O(R)n-pyridine or-O(R)(R)n-morpholino;

R4denotes hydrogen, (ness.)alkyl, (ness.)alkenyl or nitro, or-OR, -F3, -F2-R, -F2-(ness.)alkenyl, -OCHRF, -OCHF-(ness.)alkenyl, -O(R)nCF3or -(CHR)nCHRF, -(CHR)nCF2R, -(R)nCF3-(C3-C6)cycloalkyl, -(R)n(C3-C6)cycloalkyl, -(CHR)nCN, -(R)n-phenyl, where the conservation of number, includes (ness.)alkyl, (ness.)alkoxygroup, halogen, nitro or cyano, -(CHR)(CHR)nOR, -(CHR)nCHORCH2OR, -(CHR)(CHR)nNR2, -(CHR)nCOOR, -(R)(R)nOSi-(ness.)alkyl, -(CHR)(CHR)n-OS(O)2-(ness.)alkyl, -(CH2)n-CH=CF2, -CF3, -CF2-R, -CF2-(ness.)alkenyl, -CHRF, -F-(ness.)alkenyl, -(CHR)n-2,2-dimethyl[1,3]dioxolane, -(CH2)n-2-oxazepan-1-yl, -(R)(R)n-morpholino, -(R)n-pyridine, -(CHR)(CHR)n-imidazole, -(CHR)(R)n-triazole, -(CHR)(CHR)n-pyrrolidino, optionally substituted -(CH2)nHE(R)(R)n-3-hydroxypyrrolidine or(R)(R)n-piperidino, or-NR2, -N(R)(CHR)n-pyridine, -N(R)C(O)O-(ness.)alkyl, -N(CH2CF3)C(O)O-(ness.)alkyl, -N[C(O)O-(ness.)alkyl]2, -NR-NR-C(O)O-(ness.)alkyl or-N(R)(CHR)nCF3, -NRCF3, -NRCF2-R, -NRCF2-(ness.)alkenyl, -NRCHRF, -NRCHF-(ness.)alkenyl, or is absent if X is-N= or =N-, or

R4and R1or R3and R4interconnected groups -(CH2)-3-5, -(CH2)2-N=, -CH=N-N=-, -CH=CH-N=, -NH-CH=CH -, or-NR-CH2-CH2and form with N atoms and to which they are attached, an additional ring;

RR5and R6connected with group,- O-CH2"Oh - to form together with the atoms to which they are attached, an additional 5-membered ring;

R7, R8denote hydrogen, (ness.)alkyl, (ness.)alkoxy, amino, nitro or halogen;

R9, R10denote hydrogen or (ness.)alkyl;

R11, R12denote hydrogen, (ness.)alkyl, hydroxy, (ness.)alkoxy, (ness.)alkoxycarbonyl or (ness.)alkanoyloxy;

R13, R14denote hydrogen, tritium or (ness.)alkyl;

R15, R16denote hydrogen, tritium, (ness.)alkyl, hydroxy, (ness.)alkoxy, (ness.)alkoxycarbonyl or (ness.)alkanoyloxy or together form oxoprop;

X represents-N=, =N-, -N<, >C= or =<;

Y represents-N=, =N-, -NH-, -CH= or =CH - and

the dotted line can represent a bond,

and their pharmaceutically acceptable salts in their racemic and optically active form.

2. Connection on p. 1, where R1represents =O or hydroxy and R2indicates NO2and their pharmaceutically acceptable salts.

3. Connection PP.1 and 2, representing

3-ethyl-2-methyl-5-nitro-6-(1,2,4,5-tetrahit)-3H-pyrimidine-4-one,

2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-3-(2,2,2-triptorelin)-3H-pyrimidine-4-one, or

2-methyl-5-nitro-6-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)pyrimidine-4-ol.

4. Connection on p. 1, where R1means =O and R2represents-CN, and their pharmaceutically acceptable salts.

5. Connection PP.1 and 4, representing

2-amino-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril,

6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril,

2 ethylamino-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril,

1,2-dimethyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril,

1-ethyl-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril,

2-amino-1-ethyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril,

1-cyclopropylmethyl-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril,

1-allyl-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril,

1-lanmeter-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo [is benzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril,

1-isopropyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril,

1-(2-hydroxyethyl)-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril,

2-(2-hydroxyethyl)-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril,

2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1-(2,2,2-triptoreline)-1,6-dihydropyrimidin-5-carbonitril,

2-methyl-1-methylamino-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitril,

1-amino-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidin-5-carbonitrile.

6. Connection on p. 1, where R1means 2,2,2-triptoreline and R2refers to-CN.

7. Connection PP.1 and 6, representing

2-(2-morpholine-4-ylethylamine)-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile,

2-(3-morpholine-4-ylpropionic)-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile,

2-(2-hydroxyethylamino)-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-6-(2,2,2-triptoreline)pyrimidine-5-carbonitrile or

(3-imidazol-1-ylpropionic)-4-(1,2,4,5-tetrahydrobenzo[d]AZE,2,4]triazole-1-ylpropionic and R2means-NO2or-CN.

9. Connection PP.1 and 8, representing 3-[2-methyl-5-nitro-6-(3-[1,2,4]triazole-1-ylpropionic)pyrimidine-4-yl]-2,3,4,5-tetrahydro-1H-benzo[d]azepin.

10. Connection on p. 1, where R3and R4interconnected groups -(CH2)-3-5and form together with the N atoms and to which they are attached, an extra ring and R2means-NO2or-CN.

11. Connection PP.1 and 10, representing 4-oxo-2-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-4,6,7,8,9,10-hexahydropyrazino [1,2-a] azepin-3-carbonitrile.

12. Drug containing the compound according to any one of paragraphs.1-11, as well as its pharmaceutically acceptable salts in racemic and optically active form, and pharmaceutically acceptable excipients.

13. Drug under item 12, intended for the treatment or prevention of acute and/or chronic neurological disorders such as epilepsy, stroke, chronic and acute pain, psychosis, schizophrenia, Alzheimer's disease, impairment of cognitive abilities and memory deficit, restricted brain function caused by operations bypass surgery or transplants, poor blood supply to hypoglycemia, Huntington's chorea, amyotrophic lateral sclerosis (als), dementia caused by AIDS, eye injuries, retinopathy, idiopathic parkinsonism or parkinsonism caused by drugs, as well as the condition in which due to the deficit of glutamate functions, such as e.g. muscle spasms, convulsions, migraine, urinary incontinence, addiction to nicotine, psychosis, addiction to drugs, anxiety, vomiting, dyskinesia and depression.



 

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