Tricyclic compounds, methods for their preparation, pharmaceutical composition and method of treatment

 

Describes the new tricyclic compounds of General formula I, where a and b independently denote CH or nitrogen; D is C-W or nitrogen; W stands for hydrogen, halogen, C1-6-alkyl or the group CH2NR6R7where R6and R7independently mean C1-6-alkyl straight chain; E and G means simultaneously CH or nitrogen; R1means alkanoyl containing 2-7 carbon atoms, a group selected from CN, CONH2or a residue selected from the groups (a), (b), (C), (d), (e), (f), (g), (h), (i), (j), (k) and (m); where R2is hydrogen or C1-6-alkyl straight chain, With3-7-cycloalkyl or CF3; R3and R5- independently hydrogen or C1-6-alkyl; R4is hydrogen, C1-6-alkyl straight chain, alkoxyalkyl containing 2-7 carbon atoms, cycloalkenyl containing 3-7 carbon atoms, benzoyl, substituted with halogen, C1-6-alkyl or phenyl, which in turn is unsubstituted or substituted CF3or thiofentanyl; X is hydrogen; Y is hydrogen, C1-6-alkyl straight chain, With1-6-alkoxy, hydroxy, halogen or CF3or their pharmaceutically acceptable salts, methods for their preparation, pharmaceutical composition having activity of vasopressin agonist, and how latestmost diabetes. 15 C. and 8 C.p. f-crystals, 1 PL.

The invention relates to new compounds acting as antagonists of vasopressin, as well as to methods of treatment and pharmaceutical compositions that utilize these compounds.

Background of the invention Vasopressin (antidiuretic hormone, ADH), which is composed of nine amino acid peptide hormone and neurotransmitter that is synthesized in the hypothalamus of the brain and transported through above the optic tract hypophyseal tract to neurohypophysis (posterior lobe of the pituitary gland, where it is stored. When the perception of increasing the osmolality of plasma osmoreceptors brain or decrease in blood volume or blood pressure, recorded by baroretseptorov and polymerization, vasopressin is released into the bloodstream and activates the V1areceptors of vasopressin in the blood vessels that leads to narrowing of blood vessels to increase blood pressure, and V2receptors of vasopressin on the kidney nephrons that the Agents, In Kirk-Othiner: Encyclopedia of Chemical Technology, 4th ed., Wiley, Volume 8, 398-432, 1993). About the presence of vasopressin in the pituitary gland was discovered in 1895 (Oliver, N. and Schaefer, J. Physiol. (London), 18: 277-279, 1895). Structure determination and total synthesis of vasopressin were carried out duVigneaud al. in 1954 (duVigneaud V., D. T. Gish and Katsoyannis, J. Am. Chem. Soc., 76: 4751-4752, 1954).

V1Areceptors of vasopressin mediasource through phosphatidylinositide way. Activation of V1areceptors of vasopressin causes contraction of the smooth muscle of blood vessels to increase blood pressure. Action V2receptors of vasopressin mediated by activation of adenylyl cyclase system and increase intracellular levels of camp. Activation of V2receptors of vasopressin, a vasopressin or vasopressine (peptide or ones) compounds increases the permeability of the collecting ducts of the nephron and makes possible re-absorption of large quantities of free water. The end result is the formation and excretion of concentrated urine, with reduction of urine volume and increased urine osmolality.

Vasopressin plays a vital role in conserving water by concentrating urine in place of the collecting ducts of the kidney. Soetoro, and, therefore, the hypotonic fluid produced after filtering through glomeruli (renal glomeruli), passing through the proximal convoluted renal tubules, Genle loop and the distal convoluted renal tubules, will be excreted in the form of diluted urine. However, during dehydration, volume depletion or loss of blood vasopressin is released from the brain and activates the V2-vasopressin receptors in the collecting ducts of the kidney, making these ducts are very permeable to water, and therefore water is re-absorbed and excreted concentrated urine. In patients and animals with Central or neurogenic diabetes insipidus synthesis of vasopressin in the brain is impaired, and therefore, they do not produce vasopressin or produce little vasopressin, but their receptors vasopressin in the kidney are normal. Because they cannot concentrate urine, they can produce 10 times more volume of urine compared with their healthy counterparts and are very sensitive to the action of vasopressin and vasopressin agonists V2. Vasopressin and desmopressin, which is a peptide analogue of natural vasopressin, are used for patients with Central nesah the polyuria), urinary incontinence and help to ensure the ability of the recipient to the temporary delay of urination, whenever it is desirable.

Vasopressin, through activation of its V1Areceptors, has a vasoconstrictor effect, thus increasing blood pressure. Antagonist V1A-receptor vasopressin will counteract this effect. Vasopressin and vasopressin agonists release factor VIII and the factor a background of Villebranda, so they are useful for treating disorders associated with bleeding, such as hemophilia. Vasopressin and vasopressine agonists release also plasminogen activator tissue type (TAL) in the bloodstream, so they are useful in dissolving blood clots, for example, in patients with myocardial infarction and other thromboembolic disorders (Jackson E. K., Vasopressin and other agents affecting the renal conservation of water. In: Goodman's and Gilmar''s The Pharmacological Basis of Therapeutics, 9th ed., Eds. Hardman, Limbird, Molinoff, Ruddon and Gilman, McGraw-Hill, New York, pp. 715-731, 1996, Lethagen, S., Ann. Hematol., 69: 173-180 (1994), Cash J. D. et al. , Brit. J. Haematol, 27:363-364, 1974, David J-L., Regulatory Peptides, 45, 311-317, 1993, and Burggraaf, J., et al., Clin. Sci., 86, 497-503 (1994).

The following links prior art describe peptide antagonists of vasopressin: M. Manning et al., J. Med. Chem., 35, 382 (1992); M. Manning et al. , J. Med. Chem., 3ive, 4(4), 217, (May 1991), P. D. Williarms et al., reported strong Hexapeptide the antagonists of oxytocin [J. Med. Chem., 35, 3905 (1992)], also show weak activity as antagonists of vasopressin when linking with V1Aand V2-receptors. The disadvantage of peptide antagonists of vasopressin is the lack of oral activity and many of these peptides are selective antagonists, as they also have a partial action as agonists.

Have been recently described ones antagonists of vasopressin. Albright et al. describe tricyclic benzodiazepines as antagonists of vasopressin and oxytocin in the US 5516774 (May 14, 1996); derivatives tetrahydrobenzaldehyde as antagonists of vasopressin described in JP 08081460 (March 26, 1996); Ogawa et al. describe benzoheterocycles derivatives as antagonists of vasopressin and oxytocin and vasopressin agonists in WO 9534540-A; Albright et al. describe tricyclic derivatives benzazepine as antagonists of vasopressin in US 5512563 (April 30, 1996) and Venkatesan et al. describe tricyclic derivatives benzazepine as antagonists of vasopressin and oxytocin in the US 5521173 (May 28, 1996).

As mentioned above, desmopressin (1-desamino-8-D-arginine-vasopres what aptidon with variable biological digestibility. Intranasal path is poorly tolerated, and oral composition for bedwetting requires 10-20 times higher dose than the dose required for intranasal.

The compounds of this invention are ones and have good oral intake. They are specific agonists of vasopressin V2and not have agonistic actions against V1Aso that they do not increase blood pressure. In contrast, compounds known level (Ogawa H. et al., WO 9534540-A) are antagonists of vasopressin/oxytocin.

Summary of the invention This invention relates to new compounds selected from the compounds of General formula (I)
where A, b, E and G independently represent CH or nitrogen;
D is independently C-W or nitrogen;
R1denotes alkanoyl of 2-7 carbon atoms, a group selected from CN, COOH, CONH2,
-CC-H-CC-R9,
or a residue selected from the group





R4denotes hydrogen, alkyl with direct chain of 1-6 carbon atoms, a branched alkyl chain of 3 to 7 carbon atoms, cycloalkyl of 3-7 carbon atoms, alkoxyalkyl of 2-7 carbon atoms or acyl Deputy selected from the group consisting of alkanoyl of 2-7 carbon atoms, alkanoyl of 3-7 carbon atoms, cycloalkenyl of 3-7 carbon atoms, Arola or arylalkyl;
X and Y independently represent hydrogen, alkyl straight chain of 1 to 6 carbon atoms, a branched alkyl chain of 3 to 7 carbon atoms, cycloalkyl of 3-7 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, alkoxyalkyl of 2-7 carbon atoms, halogen including chlorine, bromine, fluorine and iodine), alkoxy of 1-6 carbon atoms, hydroxy, CF3or perfluoroalkyl of 2 to 6 carbon atoms;
W represents hydrogen, halogen (preferably chlorine, bromine or iodine), alkyl, alkoxyalkyl of 2-7 carbon atoms, hydroxyalkyl of 1-6 carbon atoms or CH2NR6R7;
R6and R7denote independently hydrogen, alkyl straight chain of 1-6 carbon atoms, alkyl with RA>and R7form a five - or six-membered ring, optionally containing one or more additional heteroatoms, such as (but not limited to), ring group




R8denotes alkyl with direct chain of 1-6 carbon atoms;
R9means independently hydrogen, trimethylsilyl or alkyl with direct chain of 1-6 carbon atoms;
or pharmaceutically acceptable salt form, of ester or prodrug.

E and G denote preferably CH; D represents preferably N or C-W, where W denotes hydrogen, alkyl, CH2NR6R7or halogen, more preferably, W represents hydrogen, methyl, CH2NMe2or bromine.

R2, R3and R5denote preferably each independently hydrogen, alkyl straight chain of 1-6 carbon atoms, cycloalkyl of 3-7 carbon atoms or perfluoroalkyl of 1-6 carbon atoms, more preferably hydrogen or alkyl with direct chain of 1-6 carbon atoms, most preferably hydrogen or methyl.

R4represents preferably hydrogen, alkyl with straight util, methoxymethyl, acetyl, cyclopropanecarbonyl, n-propylboronic, 2-thienylboronic, 2-methyl, 5-fortuneserver, 2-methylphenylcarbinol, 2-chloro-4-fortuneserver, 2,4-diferenzierbarer or 2,4-diferenzierbarer.

X and Y denote preferably each independently hydrogen, perfluoroalkyl of 1-6 carbon atoms, halogen, alkoxy of 1-6 carbon atoms or hydroxy, more preferably hydrogen, trifluoromethyl, chlorine, bromine, fluorine, methoxy or hydroxy. Most preferably, at least one of X and Y represents hydrogen.

R6and R7both represent preferably methyl.

Preferred values of R1include CN, CONH2, acetyl or one of the following residues:
- balance and in which R2, R3and R5denote each independently hydrogen or alkyl with direct chain of 1-6 carbon atoms, more preferably alkyl represents methyl;
- the balance and where two of R2, R3and R5denote hydrogen and the third one denotes cycloalkyl of 3-7 carbon atoms or perfluoroalkyl of 1-6 carbon atoms, more preferably, where the third is cyclopropyl or trifluoromethyl;
- the balance of b, C, d, or i, where R2denotes hydrogen or alkyl, f, where R2denotes hydrogen and/or R4denotes hydrogen, alkyl with direct chain of 1-6 carbon atoms or acyl Deputy selected from the group consisting of alkanoyl of 2-7 carbon atoms, alkanoyl of 3-7 carbon atoms, cycloalkenyl of 3-7 carbon atoms, Arola or arylalkyl, more preferably where R4denotes hydrogen, methyl, ethyl, n-propyl, n-butyl, methoxymethyl or acetyl, cyclopropanecarbonyl, n-propylboronic, 2-thienylboronic, 2-methyl, 5-fortuneserver, 2-methylphenylcarbinol, 2-chloro-4-fortuneserver, 2,4-diferenzierbarer or 2,4-diferenzierbarer;
the residue is f or g, where R4denotes hydrogen and/or R2denotes alkyl with direct chain of 1-6 carbon atoms, more preferably where the alkyl is a methyl;
the residue is k or h, where R2denotes methyl;
- the balance m, where R2denotes hydrogen. Among the more preferred compounds of this invention are compounds of the formula

where a and b independently represent CH or nitrogen;
D denotes C-W or nitrogen;
R1denotes alkanoyl of 2-7 carbon atoms, or a group selected from

Used in the present description, the term alkyl in relation to the remainder of (parts) of the molecule or to a component balance (parts) of the molecule, for example alkoxy, includes alkyl groups with straight or branched chain, such as methyl groups, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, hexyl and heptyl. Used in the present description, the term cycloalkyl includes saturated and unsaturated cyclic groups, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropyl, cyclobutene, cyclopentene, cyclohexene and cycloheptene. Preferred are the ultimate cycloalkyl.

For connections that are defined above and referenced in the present description, unless otherwise specified, aroline groups include, for example, benzoyl, Naftoli, which may be independently substituted one or not is of Pereda, the branched alkyl chain of 3 to 7 carbon atoms, alkoxy of 1-6 carbon atoms, CF3or phenyl (which is optionally substituted). Heteroaryl groups in this description referred to as carbonyl (radical) directly linked to a carbon atom membered heterocyclic ring having one or two heteroatoms selected from nitrogen, oxygen, sulfur, such as 2-thienoyl. Heterocyclic ring these heteroaryl groups may include, but are not limited to, the group in which the heteroaryl portion is a group of furan, pyrrole, 2H-pyrrole, imidazole, pyrazole, isothiazol, isoxazol, thiophene, pyrazoline, imidazolidine or pyrazolidine. Heteroaryl groups may be substituted independently by one or more substituents from the group consisting of hydrogen, halogen, cyano, alkyl straight chain of 1 to 6 carbon atoms or branched alkyl chain of 3 to 7 carbon atoms.

Arylalkylamine groups in the present description is called a carbonyl group (or radical), directly related to the alkyl group of 1-6 carbon atoms, which in the limit position is substituted by an aryl group, for example phenylacetic acid. Aryl halogen, cyano, alkyl straight chain of 1-6 carbon atoms, branched alkyl chain of 3 to 7 carbon atoms, alkoxy of 1-6 carbon atoms, CF3or phenyl, or substituted phenyl, where the substituents are selected from halogen, cyano, alkyl straight chain of 1-6 carbon atoms, branched alkyl chain of 3 to 7 carbon atoms, alkoxy of 1-6 carbon atoms, CF3.

Halogen, referred to herein may be selected from fluorine, chlorine, bromine or iodine, unless otherwise indicated.

Professionals in this field, it should be clear that the definition of compounds of formula (I), when R1, R2, R3, R4, R5, R6, R7X or Y contain asymmetric carbons, encompass all possible stereoisomers and their mixtures, which are discussed below activity. In particular, it includes all optical isomers and diastereomers, and racemic and separated enantiomerically pure R and S stereoisomers, as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts, having the specified activity. The optical isomers can be obtained in pure form by using the standard methods of separation. It is also clear that the definition of R1, R2, RWindows and mixtures thereof, that possess the activity discussed below. These regioisomers can be obtained in pure form by using the standard methods of separation known to specialists in this field.

Also among the preferred groups of compounds of this invention are compounds of the following subgroups:
a) compounds having the General formula

where a, b, W, R1, R2, R3, R4, R5, R6, R7, R8, R9X and Y are defined as above;
b) compounds having the General formula

where a, b, R1, R2, R3, R4, R5, R9X and Y are defined as above, and
(C) compounds having the General formula

where a, b, R1, R2, R3, R4, R5, R9X and Y are defined as above.

It should be clear that the above sub-groups a) to C) can be further identify subgroups in which
A and b independently represent CH or nitrogen;
R1denotes alkanoyl of 2-7 carbon atoms, or a group selected from



R4X, Y, W, R6, R7and R8defined as above,
or their pharmaceutically acceptable salt.

Particularly preferred among the compounds of group (a) described above is a compound in which W represents N, a and b each represents CH, and R1denotes the group alkanoyl of 2-7 carbon atoms, or a group selected from the residues (a), (b), (e), (f), (g), (h), (i) or (k) above.

Pharmaceutically acceptable salts include salts made from such organic and inorganic acids as lactic, citric, acetic, tartaric, succinic, maleic, malonic, hydrochloric, Hydrobromic, phosphoric, nitric, sulfuric, methansulfonate and similarly known acceptable acids.

In accordance with this invention there is a method of treatment of diseases, conditions or disorders where it is desirable action of the compounds as agonist of vasopressin, and the method comprises the administration to a human or other mammal in need of this, the effective number of connections is a means of treating diseases, conditions or disorders in which it is desirable release of factor VIII and the factor a background of Villebranda in the cardiovascular system, the release of plasminogen activator tissue type (TAP) in the bloodstream or the impact on renal water conservation and concentration of urine. Such methods of treatment include, but are not limited to, methods of treatment of diabetes insipidus, nocturnal enuresis, nocturia (night polyuria, incontinence of urine or disorders associated with bleeding and blood clotting in humans or other mammals.

The described methods include relief to humans or other mammals temporary delay of urination, which can also be described as regulation or treatment inability to delay urination, in any situation where it is desirable. It is assumed that this method includes procedures that facilitate the temporary delay of urination, which is separated from the treatment condition, known as nocturnal enuresis, and do not include nocturnal enuresis.

Thus, the present invention features a pharmaceutical composition suitable for treatment of the aforementioned diseases, soy pharmaceutically acceptable salts according to this invention in combination or conjunction with a pharmaceutically acceptable carrier.

These compositions are preferably adapted for oral administration. However, they can be adapted for other routes of administration, such as parenteral administration to a patient suffering from heart failure.

To achieve constant injection is preferred that the composition of this invention was in the form of uniform (standard) dose. Suitable forms a uniform dose include tablets, capsules and powders in bags (case) or vials. Such forms of standardized doses may contain from 0.1 to 1000 mg of the compounds of this invention and preferably from 2 to 50 mg. Even more preferred form of the standardized doses contain 5-25 mg of the compound of the present invention. The compounds of this invention can be administered orally in doses ranging from ~0.01 to 100 mg/kg, or preferably in the dose range of 0.1-10 mg/kg, Such compositions can be administered 1 to 6 times per day, more typically from 1 to 4 times a day.

Compositions of the invention can be prepared with conventional carriers or excipients, such as fillers, disintegrating agents, binders, lubricants, improves the taste and the back of agents, etc., They are generally the src="https://img.russianpatents.com/chr/946.gif">-blocking agents.

In accordance with this invention also provided methods for producing the compounds of this invention.

The method of receiving according to the invention
The compounds of this invention can be obtained in accordance with one of the General methods described below.

As shown in Scheme I, tricyclic benzodiazepine of formula (1) is treated appropriately substituted acetylenyl or (heteroaryl)halide, preferably aroyl or (heteroaryl)chloride of the formula (2) in the presence of a base such as pyridine or trialkylamine, as, for example, triethylamine, in an aprotic organic solvent such as dichloromethane or tetrahydrofuran, at temperatures from -40 to 50oWith obtaining acylated derivative of the formula (3). Processing (3) dealkylation of dialkylamide formula (4) in an aprotic organic solvent such as dichloromethane, at temperatures in the range of 0oC to the boiling point of the solvent gives the exact location of the formula (5) in accordance with the method of Lin et al., J. Het. Chem., 14, 345 (1977). Treatment (5) hydroxylamine or a substituted hydrazine of the formula (6) in acetic acid at temperatures ranging from ambient temperature to the defined, as indicated above, and R1represents a heterocyclic residue selected from the group consisting of heterocycles (f), (g) or (j), defined above.



Preferred substituted acetylenyl or (heteroaryl)chlorides of the formula (2) of Scheme I, is given at the end of the description, is easily obtained by treatment of the corresponding carboxylic acid with thionyl chloride at temperatures ranging from ambient temperature to the boiling point of the solvent or oxalylamino in an aprotic solvent such as dichloromethane or tetrahydrofuran, in the presence of catalytic amounts of dimethylformamide at temperatures in the range from 0 to 40oC. Preferred dialkylamino of dialkylamide either available commercially or is known in the literature or can be easily obtained in accordance with methods similar to methodical described in the literature. Kantlehner, W. Chem. Ber., 105, 1340 (1972).

Preferred tricyclic benzodiazepine of formula (1) are 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (Albright et al., US Patent No. 5536718, issued July 16, 1996), 10,11-dihydro-5H-pyrazole[5,1-C][1,4] benzodiazepine, L. Cecchi et al., J. Het. Chem., 20, 871 (1983), and 10,11-dihydro-5H-tetrazol[5, formula (3) is illustrated in Scheme II, listed at the end of the description.

According to the scheme tricyclic benzodiazepine of formula (1) is treated appropriately substituted pomarol- (or heteroaryl)halide, preferably aroyl- (or heteroaryl)chloride of the formula (8) in the presence of an organic base such as pyridine or trialkylamine, as, for example, triethylamine, in an aprotic organic solvent such as dichloromethane or tetrahydrofuran, at temperatures from -40 to 50oWith obtaining acylated intermediate product of the formula (9). Then the intermediate product (9) is associated with acetylene, monosubstituted at the end atom such Deputy as trimethylsilyl or alkyl straight chain of 1 to 6 carbon atoms, in the presence of pyridine as catalyst, such as bis(triphenylphosphine)palladium(II)chloride and copper iodide(I), in an organic base, such as triethylamine, in a solvent in a sealed tube high pressure at temperatures in the range from ambient temperature to 100oWith, essentially, in accordance with the method of Martinez et al., J. Med. Chem., 35, 620 (1992). Then the acetylene intermediate product of the formula (10) hydratious processing 1% sulfuric acid in an aprotic organic Rostovo, in accordance with the method of Reed et al., J. Org. Chem., 52, 3491 1,1987) to obtain the target allseeingeye formula (3), where a, b, D, E, G, X to Y is defined as above, R9denotes hydrogen or alkyl with direct chain of 1-6 carbon atoms. The alternate connection 9, in which R9represents trimethylsilyl, treated with tetrabutylammonium simple ether, such as tetrahydrofuran (THF) as a solvent to obtain compound (10), where R9represents hydrogen.

Preferred alleluya agents of the formula (8) of Scheme II is easily obtained by processing appropriately substituted aryl(heteroaryl)carboxylic acids of formula (7) with thionyl chloride at temperatures ranging from ambient temperature to the boiling point of the solvent or oxalylamino in an aprotic organic solvent such as dichloromethane or tetrahydrofuran, in the presence of catalytic amounts of dimethylformamide at temperatures in the range from 0 to 40oC. Protected acetylene intermediates of Scheme II are either commercially available or known in the field or can be easily derived using techniques similar to the procedures described in this area.

To the scientists also the reaction mix Still (Stille) bromacil (or heteroaryl) compounds of the formula (9) Scheme II (-ethoxyphenyl)triamcinolonum, preferably (-ethoxyphenyl)tributiloltin, in the presence of catalytic amounts of bis(triphenylphosphine)palladium(II)chloride in an aprotic organic solvent such as toluene, at temperatures ranging from ambient temperature to the boiling point of the solvent, essentially, in accordance with the methodology Kosugi et al., Bull. Chem. Soc. Jpn., 60, 767 (1987).

Getting acetylcodeine (3) can also be done through catalyzed by palladium atilirovanie vinylalcohol simple ether, such as vinylboronic simple broadcast arylalkenes intermediate product of the formula (9) in accordance with the methodology Cabri et al., Tetrahedron Lett., 32, 1753 (1991).

Intermediates of type (-alkoxyphenyl)triamcinolone Scheme III are either commercially available or well known in this field or can be easily obtained through techniques similar to the techniques described in this field.

In the case when R4in the Diagram I represents hydrogen, heterocyclic nitrogen can be alkylated or allerban in accordance with the reactions described in scheme IV, is given at the end of the description.

According to scheme IV , as sodium hydride or potassium, and an alkylating agent such as alkylhalogenide, preferably alkylchloride (bromide or iodide), in an aprotic organic solvent such as dimethylformamide or tetrahydrofuran, at temperatures in the range from 0 to 80oWith obtaining the compound (I, R1=(f) or (g)), where a, b, D, E, G, X, Y, and R2defined as above, a R4represents an alkyl part of the molecule. The alternate connection (I) acelerou processing a carboxylic acid halide, preferably chloride, or an anhydride of carboxylic acid in the presence of an amine base such as pyridine or trialkylamine, preferably triethylamine, in an aprotic organic solvent such as dichloromethane or tetrahydrofuran, at no additional solvent when used as the basis of pyridine, at temperatures ranging from -40oWith up to ambient temperature to obtain the compound (I) in which A, b, D, E, G, X, Y, and R2defined as above, and R4represents an acyl residue. Alkylation or acylation of compounds of formula I, R4represents N) leads to a mixture of regioisomers, where R2represents hydrogen and R1predstave and illustrated below, respectively.


Compounds of General formula (I) of Scheme I, where a and b denote carbon, R2denotes N and R1denotes a heterocyclic residue selected from defined above heterocycle (g) can be obtained in accordance with the General method described in Scheme V, is given at the end of the description.

According to the scheme ether appropriately substituted halogenared(or heteroaryl)carboxylic acid, preferably bromine(or iodine)methyl ester of formula (11) connect the combination with dialkylaminoalkyl, preferably 1-dimethylaminopropanol, in the presence of a catalyst, such as bis(triphenylphosphine)palladium(II)chloride and copper iodide(I), in an organic base, such as triethylamine, in a solvent and at temperatures ranging from ambient temperature up to 80oWith, essentially, in accordance with the methods Alami et at., Tetrahedron Lett., 34, 6403 (1993), and Sanogashira et al., Tetrahedron Lett., 4467 (1975), with a substituted acetylene intermediate product of General formula (12). Then the intermediate product (12) is converted into its N-oxide by treatment with an oxidising agent using any of several standard methods of oxidation (Albini, A., Synthesis, 263 (1993), or using dioxiranes reagents (Murra the temperature of the environment. The intermediate N-oxide does not produce, and are regrouping in situ in the exact location of General formula (13) processing (preferably heated) hydroxyl-containing solvent, including any solvent or
a combination of solvents consisting of water or water-containing, any C1-8-alkilany alcohol with a straight or branched chain alkyl, ethylene glycol, polyethylene glycol, 1,2-PROPANEDIOL, polypropylenglycol, glycerol, 2-methoxyethanol, 2-ethoxyethanol, 2,2,2-triptoreline, benzyl alcohol, phenol or any other equivalent solvent, which contains one or more free hydroxyl (-OH) substituents known qualified specialists in this field.

The solvent system containing one or more co-solvents, together with one or more solvents can also be used for this process of rearrangement of the N-oxide to target enaminone. Mentioned here the cosolvent can be defined as diluents primary solvent (main solvent) and can be selected from hydrocarbons, such as pentane, hexane or heptane; aromatic hydrocarbons such as benzene, toluene or xylene; ethers, such as diethyl EF the m dichloroethane or tetrachlorethane, or other common solvents such as ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, dimethylsulfoxide, acetone, etc.,

The conversion of N-amine oxide in enamine can be performed by introduction of N-amine oxide in a suitable hydroxyl-containing solvent, preferably under stirring, at room temperature or ambient temperature or between about room temperature or ambient temperature and about the boiling point of the solvent. In other cases, the introduction of N-oxide hydroxyl amine in the solvent, preferably while stirring, can be performed in the presence of an appropriate catalyst, such as containing palladium(II) catalyst or containing copper(I) catalyst at room temperature or between room temperature and the boiling temperature of the solvent.

This technique provides a new method of synthesis of compounds of enaminone from propargylamine or their N-oxides in hydroxyl solvents, which have an impact on the final yield of this reaction. This new method of synthesis of enaminones provides a convenient alternative to existing methods and add the I exact mechanism, whereby N-oxide propargylamine turns into teminology product was not strictly defined, it seems similar to two known processes: thermal [2,3]-sigmatropic rearrangement of N-oxides propargylamine (Graig et al., Tetrahedron Lett., 4025, 1979; Hallstrom et al., Tetrahedron Lett., 667, 1980; Khuthier A-H et al., J. Chem. Soc. Chem. Commun., 9, 1979) and the conversion of some isoxazoles in enaminone (Ligouri et al., Tetrahedron, 44, 1255, 1988).

Processing (13) substituted hydrazine (6) in acetic acid at temperatures ranging from ambient temperature to the boiling temperature leads to a mixture of regioisomeric compounds of General formulas (14) and (15) in a variable ratio. Main isomer of the formula (14) is separated by means of chromatography and/or crystallization, and then hydrolyzing to the target carboxylic acid of the formula (16).

Then the intermediate product (16) is transformed into its alleluya options, preferably the acid chloride (bromohydrin or iodometric) or a mixed anhydride of the formula (17), by methods similar to those described above. Then allerease agent (l7) is used for the acylation of tricyclic benzodiazepine of formula (1) by any of the methods described above, to obtain the target compounds of formula (I), where a, b predstaviteley a heterocyclic residue, selected from a heterocyclic group (g), illustrated below.


In this way processing (13) unsubstituted hydrazine (6, R4represents N) in acetic acid at temperatures ranging from ambient temperature to the boiling point of the solvent gives the intermediate ester of pyrazole of the formula (18). In this case, the heterocyclic nitrogen can be alkylated or allyawan, as shown in Scheme VI, shown at the end of the description, to obtain the compounds of formula (I), where R2represents hydrogen and R1represents a heterocyclic residue selected from heterocyclic groups (f) defined above.

According to the scheme of the intermediate ester formula (18) alkylate the processing of a strong base such as sodium hydride or potassium, and an alkylating agent such as alkylhalogenide, preferably alkylchloride (bromide or iodide) in an aprotic solvent such as dimethylformamide or tetrahydrofuran, at temperatures in the range from 0 to 80oWith a mixture of regioisomers of formula (14) and (15) in a variable ratio. The main regioisomer formula (15) is separated by means of chromatography and/or cristallisent, preferably the acid chloride or mixed anhydride by methods similar to the methods described above. Then alleluya particles of the formula (20) is used for the acylation of tricyclic benzodiazepine of formula (1) to obtain the target compounds of formula (I), where a, b, D, E, G, X, Y, and R4defined as above, R2represents hydrogen and R1represents a heterocyclic residue selected from heterocyclic groups (f) defined above.


Compounds of General formula (I), where R1denotes a heterocyclic residue selected from the group (h) in the number of heterocycles R1defined above, can be obtained as shown in Scheme VII, listed at the end of the description.

Appropriately substituted malonic dialdehyde of the formula (21) is treated first with hydrazine in acetic acid at temperatures ranging from ambient temperature to the boiling point of the solvent, and then the intermediate pyrazole oxidized by potassium permanganate mainly aqueous solution at temperatures in the range from ambient temperature to the boiling point of the solvent to obtain an intermediate p is hydride (bromohydrin or iodometric) or a mixed anhydride, through techniques similar to the techniques described above.

Finally, this allerease agent of the formula (23) communicates with tricyclic benzodiazepine of formula (1) to form compounds of General formula (I), where a, b, D, E, G, X, Y, and R4defined as above, a R1represents a heterocyclic residue selected from a heterocyclic group (h), defined above.


In the case when R4in Scheme VII is hydrogen, heterocyclic nitrogen can be alkylated or allerban in accordance with the techniques described above.

Preferred malonic dialdehyde formulas (21) and hydrazines Scheme VII are commercially available or known in the field, or can be easily obtained by methods similar to the methods described in the literature for the known compounds, such as methods Knorr et al., J. Org. hm., 49, 1288 (1984), and l et al., J. Het. hm., 11, 51 (1974).

Alternative intermediate carboxylic acids of the formula (22) of Scheme VII, where Y is defined as above, and R4is other than hydrogen, is presented in Scheme VIII, listed at the end of the description.

ORGANOTIN reagent of formula (25) reacts in the reaction with what romida or iodide of the formula (28), in the presence of a catalyst, such as tetrakis(triphenylphosphine)palladium(0) and copper iodide(I), in an organic aprotic solvent such as dimethylformamide, at temperatures ranging from ambient temperature to 150oWith, essentially, in accordance with procedures similar to the procedures described in Farina et al., J. Org. Chem., 59, 5905 (1994). Alkaline hydrolysis of ester obtained of the formula (26) with sodium hydroxide or lithium in aqueous alcohol or tetrahydrofuran at temperatures ranging from ambient temperature to the boiling point of the solvent gives the target carboxylic acid of the formula (22).

In turn, ORGANOTIN reagents of the formula (25), where the groups R are preferably alkyl groups, easily obtained by metallation of 4-bromo-N-alkylphenol formula (24) trialkylaluminium, preferably by tributyltinchloride (or bromide) in the presence of metalliser agent, such as alkylate, for example n-utility, second-utility or tert-utility, in an aprotic organic solvent such as diethyl ether, at temperatures ranging from -40oWith up to ambient temperature in accordance with methods similar to the methods described by the C 4-bromopyrazole alkylation by alkylhalogenide, preferably alkylchloride (bromide or iodide) in the presence of a strong base such as lithium hydride, sodium or potassium, in an aprotic organic solvent such as dimethylformamide or tetrahydrofuran, at temperatures in the range from 0 to 80oC. Alternative alkylation of 4-bromopyrazole can be performed using an alkylating agent mentioned above, and a strong alkaline base, such as lithium hydroxide, sodium or potassium, in the presence of phase transfer catalyst (Jones R. A. Aldrichimica ACTA, 9(3), 35, 1976), such as benzyldimethylammonium or benzyltrimethylammonium.

Preferred aryl(heteroaryl)iodides of the formula (28) is easily obtained by diazotization of the corresponding substituted anilines of the formula (27), followed by interaction of the corresponding diazonium salts with iodine and potassium iodide in aqueous acidic medium, essentially, in accordance with the techniques of Street et al., J. Med. hm., 36, 1529 (1993), and Coffen et al., J. Org. Chem., 49, 296 (1984).

Alternative obtaining the compounds of General formula (I) is shown in Scheme IX, is given at the end of the description.

Tricyclic benzodiazepine of formula (1) is treated appropriately substituted halogenatom(or heteroaryl)halo is I, such as triethylamine or diisopropylethylamine, in an aprotic organic solvent such as dichloromethane or tetrahydrofuran, at temperatures from-40oC to the boiling point of the solvent to obtain acylated derivative (30).

Alternative alleluya particles can be a mixed anhydride of the above carboxylic acids, such as mixed anhydride obtained by the reaction of 2,4,6-trichlorobenzaldehyde in a solvent such as dichloromethane, in accordance with the methodology Inanaga et al., Bull. Chem. Soc. Jpn, 52, 1989 (1979). Processing of this mixed anhydride of General formula (29) tricyclic benzodiazepine of formula (I) in a solvent such as dichloromethane and in the presence of an organic base such as 4-dimethylaminopyridine, at temperatures in the range of 0oC to the boiling point of the solvent, gives acylated derivative (30) as an intermediate product of Scheme IX.

Then the compound of formula (30) is treated with lithium, sodium or potassium salt of the appropriately substituted heterocycle of formula (31) in a polar aprotic organic solvent such as dimethylformamide or tetrahydrofuran, at temperatures in the range of temperature OCD R2, R3and R5defined as above, and R1is a heterocyclic residue selected from the group consisting of (a), (b), (C), (d), (l), (n) or (o), defined above.





Condensation of the intermediate product of the formula (30) with an intermediate salt of the formula (31) leads to variable ratio of regioisomers General formula (I), which is divided by means of chromatography and/or crystallization.

Preferred substituted Ferrol - or fluoro(or chloro)heteroaromatic formula (29) are commercially available or known in the field, or can be easily derived using techniques similar to those described in the literature for the known compounds.

Lithium, sodium or potassium salts of compounds of formula (31) is obtained by processing the specified heterocycle strong base, such as lithium hydride, sodium hydride, potassium hydride or alcoholate of a metal, at temperatures in the range -40oWith up to ambient temperature in an aprotic organic solvent such as dimethylformamide or tetrahydrofuran.

Alternative compounds of General FD is established in the end of the description.

According to the scheme replaced accordingly ferril - or fluoro(or chloro)heteroarylboronic acid of the formula (32) etherification using methods known in this field, such as processing oxalylamino (or thionyl chloride) in an alcohol solvent such as methanol, in the presence of catalytic amounts of dimethylformamide, or by condensation with methanol in the presence of an acid catalyst such as para-toluensulfonate acid, at temperatures ranging from ambient temperature to the boiling point.

The obtained ester of the formula (33) communicates with lithium, sodium or potassium salt of the appropriately substituted heterocycle of formula (31) in a polar aprotic organic solvent, such as dimethylformamide, at temperatures ranging from ambient temperature to 150oWith the receipt of ester of the formula (34) as an intermediate product. The condensation of (33) from (31) leads to variable ratio of regioisomers of the formula (34), which is divided by means of chromatography and/or crystallization.

Subsequent hydrolysis of ester intermediate of formula (34) water base, such as hydroxide liteanu carboxylic acid (35) in turn allerease agent, preferably the acid chloride or mixed anhydride of General formula (36), using any of the procedures described above.

Subsequent reaction of the tricyclic benzodiazepine of formula (1) with intermediate allermuir agent of the formula (36) in accordance with any of the above methods gives the target compounds of formula (I) of Scheme IX.

Alternative replaced Kurbanova acid of the formula (35) as described in Scheme X, can be obtained in accordance with the method presented in Scheme XI, is given at the end of the description.

According to the scheme ferril - or fluorine(chlorine)heteroaromatic formula (37) communicates with lithium, sodium or potassium salt of the substituted heterocycle of formula (31) in a polar aprotic organic solvent, such as dimethylformamide, at temperatures ranging from ambient temperature to 150oWith the formation of an intermediate product of General formula (38). Reaction (37) (31) leads to variable ratio of regioisomers of the formula (38), which is divided by means of chromatography and/or crystallization. Hydrolysis of the intermediate NITRILES of the formula (38, YCF3) is conducted preferably with an inorganic acid, such as sulfuric acid, at a pace which should be heated in ethanol in the presence of a strong alkaline base, such as sodium hydroxide, with the phase transfer catalyst or without (Jones R. A. Acta Aldrinchimica, 9(3), 35, 1976), such as benzyldimethylammonium.

Then, the resulting carboxylic acid of formula (35) is transformed into the target compounds of formula (I) of Scheme IX, using techniques similar to the techniques described above.

Alternative substituted carboxylic acid of the formula (35) Scheme X can be obtained in accordance with the method presented in Scheme XII, listed at the end of the description, sequential processing of the nitrile of the formula (38), where a and b are CH, and R1is not alkanoyl of 2-7 carbon atoms, quinil, (b) or (d), the main hydrogen peroxide in dimethyl sulfoxide, essentially, in accordance with the method of Katritzky et al. , Synthesis, 949 (1989) and subsequent hydrolysis of the obtained amide of the formula (38) preferably by treatment with diluted sulfuric acid and sodium nitrite in accordance with the methodology Hanes et al., Tetrahedron, 51, 7403 (1995).

The preferred method of obtaining the intermediate substituted carboxylic acids of the formula (35) Scheme X, where R1is a heterocyclic residue selected from the group (a) related heterocycles R1as described above, about the aniline of formula (40) and subsequent reduction of the obtained diazonium salts of the formula (41) chloride tin (II) in concentrated hydrochloric acid in accordance with the procedure of Street et al., J. Med. Chem., 36, 1529 (1993) provides an intermediate cleaners containing hydrochloride salt of the hydrazine of formula (42). Subsequent condensation of (42) with the derived aldehyde of formula (47), where R2defined as above, R3and R5denote N, and R is dialkylamines, such as dimethylacetal of acetylaldehyde, or ketone of formula (47), where R2, R3and R5defined as above, and R represents =O or (O-alkyl)2in a solvent such as aqueous methanol, at temperatures ranging from ambient temperature to 100oGive after crystallization target intermediate ester formula (34, R1means (a) and R5denotes N), which is then converted into the compounds of formula (I), as presented in figure X above.


When Y represents co3the compounds of General formula (I) of Scheme I can be easily demeterova as shown in Scheme XIV, listed at the end of the description.

According to the scheme of the reaction of the compound (I), where Y denotes the co3with tribromide boron in an organic solvent, such as dichloromethane gives the corresponding phenol of formula (I), where Y denotes HE and a, b, D, E, G, X, R2and R3determined, as indicated Wicklow, defined above and illustrated below.


Compounds in which R1contains three heteroatoms are in accordance with the Scheme XV, listed at the end of the description.

According to the scheme tricyclic benzodiazepine of formula (1) is treated appropriately substituted canarail(or heteroaryl)halide, preferably aroyl(or heteroaryl)chloride of the formula (43), in the presence of a base in an aprotic organic solvent such as dichloromethane or tetrahydrofuran, at temperatures ranging from -40 to 80oWith intermediate nitrile of formula (46, Scheme XVI), which, in turn, hydrolyzing to the intermediate amide of General formula (44) with an inorganic acid such as sulfuric acid, at a temperature from ambient temperature up to 50oC. Processing of this amide (44) dealkylation of dialkylamide formula (4) in an aprotic organic solvent such as dichloromethane or tetrahydrofuran, at temperatures in the range from 0 to 80oTo give an intermediate product of the formula (45). Processing (45) hydroxylamine or hydrazine of formula (6) in acetic acid at temperatures ranging from ambient temperature 4
defined as above, and R1is a heterocyclic residue selected from the group (e), (i) and (k) of the composition defined above heterocycles.



Another preferred method of obtaining the intermediate amide of formula (44) (see figure XV), where a and b represent CH and D is CH, depicted in Scheme XVI, listed at the end of the description, and is the treatment of the nitrile of formula (46) the main hydrogen peroxide in dimethyl sulfoxide, essentially, in accordance with the method of Katritzky et al., Synthesis, 949 (1989).

The preferred method of obtaining compounds of General formula (I) in which R1contains four heteroatoms and R4is hydrogen, depicted in Scheme XVII, provided at the end of the description.

Processing the intermediate nitrile of formula (46) Scheme XVI sodium azide and ammonium chloride in an aprotic organic solvent such as dimethylformamide, at temperatures ranging from ambient temperature to the boiling point of the solvent gives the target compounds of formula (I), where a, b, D, E, G, X and Y are defined as above, R4represents hydrogen and R1is a heterocyclic residue selected from the General formulas (I), where D denotes CW and W is hydrogen, can be subjected to condensation manniche, as shown in Scheme XVIII, listed at the end of the description.

According to the scheme of the reaction of compounds of formula I, D denotes CH) with aqueous formaldehyde or paraformaldehyde, substituted amine of formula (47) and glacial acetic acid in an alcohol solvent such as methanol, at temperatures ranging from ambient temperature to the boiling temperature gives the corresponding Mannich bases of the General formula (I), where a, b, E, G, X, Y, R2, R3, R5, R6and R7defined as above; D is a CW; W denotes dialkylaminoalkyl residue, preferably dimethylaminomethylene residue, and R1denotes a heterocyclic residue selected from the groups (a), (C), (e), (f), (g), (h), (i), (j), (k), (1), (m), (n) and (o) included in the number of heterocycles defined above.

Similarly, compounds of General formula (I), where D denotes CH, can be subjected to galogenirovannyie, as shown in Scheme XIX, listed at the end of the description.

According to the reaction scheme (I, D denotes CH) N-halogenating, such as N-chlorine(bromine or iodine)succinimide, in a polar aprotic organic solvent, takaluoma halogenated derivatives of General formula (I), where a, b, E, G, X, R2, R3and R5defined as above, D denotes CW, W denotes halogen, such as chlorine (bromine or iodine), and R1represents a heterocyclic residue selected from the groups (a), (C), (e), (f), (g), (h), (i), (j), (k), (l), (m), (n) and (o) included in the number of heterocycles defined above.

Consider the compounds of this invention were tested for biological activity in accordance with the following methods.

The effect of the tested compounds (test compounds) as agonists of the vasopressin V2on normal in conscious rats, drunk water.

Male or female rats of Sprague-Dawley (Charles River Laboratories, Inc., Kingston, NY) with normal blood pressure, body weight 350-500 g provided standard food rodent diet (Purina Rodent Lab. Chow 5001) and water ad libitum. On the day of testing (test) rats were placed individually in metabolic cages equipped with devices to separate feces from urine and containers for collection of urine. The test compound or the control drug was given in the form of an oral dose of 10 mg/kg in a volume of 10 ml/kg Applied by the carrier was 20% dimethyl sulfoxide (DMSO) 2.5% pre-boiled corn starch. Thirty minutes to feed. In the course of the test rats were not given water or food. Urine was collected for four hours after administration of doses of the test compounds. After four hours was measured volume of urine. Osmollnosti urine was determined using osmometry Fiske One-Ten Osmometer (Fisice Associates, Norwood, MA, 02062) or advanced osmometer Advanced CRYOMATIC Osmometer, Model 3C2 (Advanced Instruments, Norwood, MA). Determination of Na+To+and Cl-was performed using ion-selective electrodes in the electric analyzer model system Deskmap synchron EL-ISE Electrolyte System. Osmollnosti urine was proportional to grow. In the qualifying test is a screening test used two rats for each connection. If the difference in the amount of urine these two rats was more than 50%, then used a third rat.

The effect of the tested compounds (test compounds) as agonists of the vasopressin V2on normal in consciousness homozygous Brattleboro rats with Central diabetes insipidus.

Males or females homozygous Brattleboro rats (Harlan Sprague-Dawley, Inc. , Indianapolis, IN) with body weight 250-350 g were provided with standard food rodent diet (Purina Rodent Lab. Chow 5001) and water ad libitum. On the day of testing (test) rats were placed individually in metabolicescomu connection or the control drug was administered in the form of an oral dose of 1-10 mg/kg in a volume of 10 ml/kg Used carrier was 20% dimethyl sulfoxide (DMSO) 2.5% pre-boiled corn starch. In the course of the test rats were provided water ad libitum. Urine was collected for six hours after a dose of the test compound. After six hours was measured volume of urine. Osmollnosti urine was determined using osmometry Fiske One-Ten Osmometer (Fiske Associates, Norwood, MA, 02062) or advanced osmometer Advanced CRYOMATIC Osmometer, Model 3C2 (Advanced Instruments, Norwood, MA). Determination of Na+To+and CL-was performed using ion-selective electrodes in the electrolytic analyzer system model Beckman SYNCH-RON EL-ISE Electrolyte System. This animal model was used to evaluate the strength and duration of action of the active compounds. The results of this study are shown in the table .

The following examples are presented to illustrate and not to limit the scope of the invention.

Example 1
(4-fluoro-2-triptoreline)-(5H, 11H-pyrrolo[2,1-C][1,4]benzodiazepine-10-yl)-methanon
Oxalicacid (2.0 g) was added to a suspension of 4-fluoro-2-triftorperasin acid (2.0 g) in dichloromethane (25 ml). Added two drops of dimethylformamide and the mixture was stirred for 18 hours at room tempera is in dichloromethane and filtered. Evaporation of this material gave a liquid which then was dissolved in hexane, filtered and evaporated to obtain the acid chloride as a pale yellow viscous liquid, which was used without further purification.

The acid chloride (of 2.26 g) in dichloromethane (25 ml) was added in portions to a mixture of 10,11-dihydro-5H-pyrrolo[2,1-C] [1,4] benzodiazepine (1.66 g), dichloromethane (10 ml) and diisopropylethylamine (1,30 g), cooled in a bath of ice. After keeping at room temperature for 18 hours the reaction mixture was washed with water and saturated aqueous sodium bicarbonate. Solution in dichloromethane was dried over anhydrous sodium sulfate and filtered through a short column with aqueous sodium silicate of magnesium, and then suirable several volumes of dichloromethane. The combined organic phase was evaporated on a hot plate with gradual addition of hexane until until crystallization occurred. After cooling, the crystals were collected by filtration to obtain to 2.57 g specified in the connection header, so pl. 154-155oC.

Example 2
[4-(3-Methylpyrazole-1-yl)-2-triptoreline)-(5H, 11H-pyrrolo[2,1-C] [1,4]benzodiazepine-10-yl)-methanon
60% sodium hydride in oil (0.15 g) was washed, hexane the ode was added (4-fluoro-2-triptoreline)-(5H,11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanon (1.0 g). The reaction mixture was heated in a sand bath at 110oC for 15 hours. The reaction mixture was poured on ice and added a saturated salt solution. The precipitate was collected by filtration. The crude reaction product was dissolved in dichloromethane and filtered through a short column with aqueous sodium silicate of magnesium, and then suirable several additional volumes of dichloromethane. The combined organic phase was evaporated on a hot plate with gradual addition of hexane. After cooling, the crystals were collected by filtration receipt of 0.77 g of the crude product. Further purification of additional filtration through a short column with aqueous sodium silicate-magnesium followed by the addition of hexane gave specified in the title compound as crystalline solid (0.66 g), so pl. 194-195oC.

Example 3
[4-(4-Methylpyrazole-1-yl)-2-triptoreline] -(5H, 11N-pyrrolo[2,1-C] [1,4]benzodiazepine-10-yl)-methanon
Similar to example 2 using (4-fluoro-2-triptoreline)-(5H, 11H-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanone (0.8 g), 60% sodium hydride in oil (0.15 g), 4-methylpyrazole (0.20 g) and dimethylformamide (25 ml) was obtained the product of 0.47 g) in the form of biscotto amorphous solid vexen-pyrrolo[2,1-C] [1,4]benzodiazepine-10-yl)-metano
Similar to example 2 using (4-fluoro-2-triptoreline)-(5H, 11N-pyrrolo[2,1-c] [1,4] benzodiazepine-10-yl)-methanone (1.0 g), 60% sodium hydride in oil (0.20 g), pyrazole (0.25 g) and dimethylformamide (35 ml) was obtained the product (of 0.62 g) as a colorless amorphous solid. MS, m/z: 423,2 (M+N)+, 445,2 (M+Na)+, 845,3 (2M+N)+.

Example 5
[4-(3-Cyclopropylmethyl-1-yl)-2-triptoreline] -(5H, 11N-pyrrolo[2,1-C][1,4]benzodiazepine-10-yl)-methanon
Similar to example 2 using (4-fluoro-2-triptoreline)-(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanone (1.42 g), 60% sodium hydride in oil (0.20 g), 3-cyclopropylethanol (0,43 g) and dimethylformamide (50 ml) was obtained the product (1.22 g) as a crystalline solid, so pl. 163-164oC.

Example 6
[4-(4-Mei-1-yl)-2-triptoreline] -(5H, 11N-pyrrolo[2,1-C] [1,4]benzodiazepine-10-yl)-methanon
Similar to example 2 using (4-fluoro-2-triptoreline)-(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanone (1.0 g), 60% sodium hydride in oil (0.20 g), 4-methylimidazole (0.25 g) and dimethylformamide (25 ml) is listed in the title compound (0.66 g) was obtained as amorphous solids. MS, m/z: 437,2 (M+N)+, to 873.2 (2M+N)+.

Example 7
(5H, 11N-Pyrrolo[2,1-C] [1,4]benzodiaz methylphenyl)-(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanone (1.0 g), 60% sodium hydride in oil (0.20 g), 1,2,4-triazole (0.20 g) and dimethylformamide (25 ml) has been specified in the title compound (0.36 g) as a colorless amorphous solid. MS, m/z: 424,2 (M+N)+, 847,3 (2M+N)+.

Example 8
(2-Chloro-4-forfinal)-(5H, 11N-pyrrolo[2,1-C] [1,4]benzodiazepine-10-yl)-methanon
Oxalicacid (2,60 g) was added to a suspension of 2-chloro-4-fermenting acid (3,44 g) in dichloromethane (50 ml). Added two drops of dimethylformamide and the mixture was stirred for 18 hours at room temperature. The resulting solution was evaporated to obtain crude 2-chloro-4-tormentilla in the form of a viscous oil (and 3.72 g).

The crude 2-chloro-4-perbenzoate (3,68 g) in dichloromethane (25 ml) was added in portions to a stirred, cooled with ice to a solution of 10,11-dihydro-5H-pyrrolo[2,1-C] [1,4] benzodiazepine (2.76 g), diisopropylethylamine (2,47 g) and dichloromethane (50 ml). After 18 hours at room temperature the reaction mixture was washed with water and saturated aqueous sodium bicarbonate. Solution in dichloromethane was dried over anhydrous sodium sulfate and filtered through a short column with aqueous sodium silicate of magnesium and then suirable several volumes of the Ana as long until crystallization occurred. After cooling, the crystals were collected by filtration to obtain specified in the connection header (3,85 g), so pl. 110-112aboutC.

Example 9
[2-Chloro-4-(3-methylpyrazole-1-yl)-phenyl] -(5H, 11N-pyrrolo[2,1-C][1,4]benzodiazepine-10-yl)-methanon (isomer a) and [2-chloro-4-(5-methylpyrazole-1-yl)-phenyl]-(5H,11N-pyrrolo[2,1-C][1,4]benzodiazepine-10-yl)-methanon (isomer B)
Method 1. 60% sodium hydride in oil (0.3 g, skim hexane) in dimethylformamide (25 ml) was added 3-methylpyrazole (0.55 g). After cessation of hydrogen was added (2-chloro-4-forfinal)-(5H, 11H-pyrrolo[2,1-C][1,4]benzodiazepine-10-yl)-methanon (1.70 g). The reaction mixture was heated for 18 hours on a sand bath (internal temperature is 125oC). Then the reaction mixture was poured into ice and optionally diluted with a saturated saline solution. The precipitated solid was removed by filtration. The crude product was dissolved in dichloromethane, dried over anhydrous sodium sulfate and then filtered through a short column with aqueous sodium silicate of magnesium, and then suirable several volumes of dichloromethane. The combined eluate was boiled under reflux on a hot plate with gradual addition of hexane until p. the ri filtering this material through the second column with the aqueous sodium silicate of magnesium and evaporation of the solvent in vacuo received a mixture of regioisomers 9A and 9B in the approximate ratio of 9:1 as an amorphous glass (1,11 g). MS, m/z: 403,2 (M+N)+.

Method 2. To pre-cooled stirred suspension washed with hexane 60% sodium hydride (3.00 g) in anhydrous dimethylformamide (250 ml) was added dropwise in a nitrogen atmosphere, 3-methylpyrazole (5.50 g) at 0oC. the Mixture was heated to room temperature. After cessation of gas was added (2-chloro-4-forfinal)-(5H, 11N-pyrrolo[2,1-C] [1,4]benzodiazepine-10-yl)-methanon (17.0 g) as a solid and the mixture was heated to 130oC for one hour. The reaction mixture was poured into ice water, the precipitate was collected by filtration and dried in the air. The residue was dissolved in dichloromethane, dried over anhydrous sodium sulfate and filtered through a short column with silica gel, elwira with ethyl acetate. The combined filtrate evaporated in vacuo to a residual foam (18.5 g). Purification and separation of regioisomers column chromatography low pressure on silica gel with elution with a gradient mixture of ethyl acetate/hexane (10:90-25:75) gave two treated Regio) as a colorless amorphous solid. MS (EI) m/z: 402 (M)+. A sample (0.5 g) was led from diethyl ether followed by recrystallization from ethanol to obtain regioisomer And (0,275 g) as a colourless crystalline solid, so pl. 141-143oC.

Isomer B, [2-chloro-4-(5-methylpyrazole-l-yl)-phenyl]-(5H,11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanon (1,93 g) as a colorless amorphous solid. The sample was led from diethyl ether followed by recrystallization from methanol to obtain regioisomer In (1.4 g) as colorless needle-like crystals, so pl. 160-163oC. MS (EI) m/z: 402 (M)+. MS (+FAB), m/z: 403 (M+N)+.

Example 10
[2-Chloro-4-(3-methylpyrazole-1-yl)-phenyl] -(5H, 11N-pyrrolo[2,1-C][1,4]benzodiazepine-10-yl)-methanon
Stage a): 2-chloro-4-(3-methylpyrazole-1-yl)benzonitrile. To a cooled (0o(C) suspension of sodium hydride (60% in oil, 2.0 g) in dimethylformamide (50 ml) was added by portions 3-methylpyrazole (3,39 g). After the termination of allocation of gaseous hydrogen was added 2-chloro-4-perbenzoate (of 5.17 g) and the mixture was stirred at room temperature for 18 hours. The mixture is poured into ice, diluted salt solution and the precipitate was collected by filtration. The crude product was dissolved in dichloromethane, filterall from ethanol gave 4.42 g of product, so pl. 148-150aboutC.

Stage b): 2-chloro-4-(3-methylpyrazole-1-yl)benzamide. A suspension of 2-chloro-4-(3-methylpyrazole-1-yl)-benzonitrile (4.35 g) from stage a) in dimethyl sulfoxide (20 ml) containing potassium carbonate (0.40 g) was cooled in a bath with ice. Was added hydrogen peroxide (30%, 2.4 ml) and the mixture was heated to room temperature over 1 hour. The precipitate was removed by filtration and recrystallized from ethanol to obtain 2,44 g of the product in the form of a thin needle-shaped crystals, so pl. 159-160oC. MS m/z: 235,9 (M+N)+.

Stage C): 2-chloro-4-(3-methylpyrazole-1-yl)benzoic acid. A solution of 2-chloro-4-(3-methylpyrazole-1-yl)benzamide (1,09 g) from step b) in water 75% sulfuric acid (25 ml) was cooled in a bath of ice was added sodium nitrite (1.73 g).

The mixture was heated to room temperature over 1 hour and poured into ice. The precipitate was collected by filtration and directly used in the next reaction.

Stage d): [2-chloro-4-(3-methylpyrazole-1-yl)-phenyl]-(5H-10,11 N-dihydropyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanon. A mixture of 2-chloro-4-(3-methylpyrazole-1-yl)benzoic acid (0,69 g), dichloromethane (25 ml) with stage C), oxalicacid (1.0 g) and 1 drop of dimethylformamide was stirred at room temperature for 18 hours. The mixture upacharamalanu (25 ml), containing diisopropylethylamine (0,76 g). The mixture was stirred at room temperature for 18 hours and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate and filtered through a short column of anhydrous sodium silicate is magnesium. The solution was evaporated and the resulting substance was led from diethyl ether obtaining of 0.67 g of the product, so pl. 137-138aboutC. MS m/z: 403,2 (M+N)+, 805,8 (2M+N)+.

Example 11
[2-Chloro-4-(4-methylpyrazole-1-yl)-phenyl]-(5H,11N-pyrrolo[2,1-C][1,4]benzodiazepine-10-yl)-methanon
Similar to method 1 of example 9 using (2-chloro-4-forfinal)-(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanone (1.0 g), 60% sodium hydride in oil (0.3 g, degreased with hexane), 4-methylpyrazole (0,48 g) and dimethylformamide (25 ml) were specified in the title compound (0.74 g) as amorphous solids. MS, m/z: 403,2 (M+N)+, 425,2 (M+Na)+, 805,3 (2M+N)+.

Example 12
[2-Chloro-4-(4-Mei-1-yl)-phenyl] -(5H,11N-pyrrolo[2,1-C][1,4]benzodiazepine-10-yl)-methanon
Similar to method 1 of example 9 using (2-chloro-4-forfinal)-(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanone (1.0 g), 60% sodium hydride in oil (0.3 g, degreased with hexane), 4-matrimid what about the substance. MS, m/z: 403,3 (M+N)+.

Example 13
[2-Chloro-4-(3-cryptomaterial-1-yl)-phenyl] -(5H, 11N-pyrrolo[2,1-C] [1,4]benzodiazepine-10-yl)-methanon
Similar to method 1 of example 9 using (2-chloro-4-forfinal)-(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepin-10-yl)-methanone (0.8 g), 60% sodium hydride in oil (0.25 g, degreased with hexane), 3-cryptomaterial (0,61 g) and dimethylformamide (25 ml) has been specified in the title compound as amorphous solid. MS, m/z: 457,2 (M+N)+.

Example 14
[2-Chloro-4-(1,2,4-triazole-1-yl)-phenyl] -(5H, 11N-pyrrolo[2,1-C] [1,4]benzodiazepine-10-yl)-methanon
Similar to method 1 of example 9 using (2-chloro-4-forfinal)-(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanone (1.7 g), 60% sodium hydride in oil (0.5 g, degreased with hexane), 1,2,4-triazole (0,70 g) and dimethylformamide (50 ml) were specified in the title compound (0.51 g) as amorphous solids. MS, m/z; 390,3 (M+N)+, 779,3 (2M+N)+.

Example 15
(2-Chloro-4-pyrrol-1-yl-phenyl)-(5H, 11N-pyrrolo[2,1-C][1,4]benzodiazepine-10-yl)-methanon
Similar to method 1 of example 9 using (2-chloro-4-forfinal)-(5H, 11N-pyrrolo[2,1-c] [1,4] benzodiazepine-10-yl)-methanone (1.7 g), 60% sodium hydride in oil (0.3 g, degreased with hexane), pyrrole (0,42 g) and dimethylformamide (25 ml) gender the emer 16
(2-Chloro-4-pyrazole-1-yl-phenyl)-(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanon
Similar to method 1 of example 9 using (2-chloro-4-forfinal)-(5H, 11N-pyrrolo[2,1-c] [1,4] benzodiazepine-10-yl)-methanone (1.0 g), 60% sodium hydride in oil (0.2 g, degreased with hexane), pyrazole (0.20 g) and dimethylformamide (25 ml) has been specified in the title compound as amorphous solid. MS, m/z: 389,2 (M+N)+, 777,1 (2M+H)+.

Example 17
[2-Chloro-4-(1H-imidazol-1-yl)-phenyl] -(5H, 11H-pyrrolo[2,1-c] [1,4]benzodiazepine-10-yl)-methanon
Similar to method 1 of example 9 using (2-chloro-4-forfinal)-(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanone (2.0 g), 60% hydride, sodium in oil (0.50 g, degreased with hexane), imidazole (0.50 g) and dimethylformamide (25 ml) has been specified in the header of the connection (or 0.57 g) as a reddish-brown amorphous solid. MS, m/z: 389 (M+N)+.

Example 18
[2-Chloro-4-(3-methylpyrazole-1-yl)-phenyl] -(3-methyl-5H, 11N-pyrrolo[2,1-C] [1,4]benzodiazepine-10-yl)-methanon
Stage a): 1-(5H, 11N-pyrrolo[2,1-C][1,4]benzodiazepine-10-yl)-2,2,2-triptoreline. It chilled with ice to a solution of 10,11-dihydro-5H-pyrrolo[2,1-C] [1,4] benzodiazepine (5,62 g) and diisopropylethylamine (4.0 g) in dichloromethane (75 ml) was added dropwise triperoxonane angeri the saturated aqueous sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate and filtered through a short column of anhydrous sodium silicate is magnesium. The combined organic phase was evaporated on a hot plate with gradual addition of hexane until crystallization occurred. After cooling, the crystals were collected by filtration receipt of 7.70 g of the product as toncic needle-shaped crystals, so pl. 134-135oC. MS m/z: 281 (M+N)+.

Stage b): 1-(3-dimethylaminomethyl-5H,11N-pyrrolo[2,1-C][1,4]benzodiazepine-10-yl)-2,2,2-triptoreline. A mixture of 1-(5H,11H-pyrrolo[2,1-C][1,4]benzodiazepine-10-yl)-2,2,2-triptoreline (2,80 g) from stage a), bidimensionality (2,04 g), paraformaldehyde (2.70 g) and acetic acid (1.20 g) in a mixture of tetrahydrofuran (50 ml) and methanol (50 ml) was stirred at room temperature for 18 hours. The mixture was evaporated in vacuo, added water and the aqueous mixture was extracted with dichloromethane. Combining the extracts were dried over anhydrous sodium sulfate and filtered through a short column of anhydrous sodium silicate is magnesium. The solution was evaporated in vacuum and the residue was led from hexane to obtain 2,05 g of the product as a colourless solid, so pl. 109-110oC. MS m/z: 338,3 (M+H)+.

Stage C): trimethyl-(omethyl-5H, 11N-pyrrolo[2,1-C][1,4]benzodiazepine-10-yl)-2,2,2-triptoreline (1,83 g) from stage b) and iodomethane (1.0 g) in dichloromethane (20 ml) was stirred at room temperature for 18 hours. Added diethyl ether and the precipitate was collected by filtration receipt of 2.54 g of the product as a colourless solid, so pl. 140-155oC (decomp.).

Stage d): 10,11-dihydro-3-methyl-5H-pyrrolo[2,1-C] [1,4]benzodiazepine. Borohydride sodium (2.6 g) was added in two portions to boiling under reflux a mixture of trimethyl-(10-TRIFLUOROACETYL-10,11-dihydro-5H-pyrrolo[2,1-C][1,4]benzodiazepine-3-yl-methyl)AMMONOIDEA (2,60 g) from step C) in ethanol. After 4 hours the mixture was evaporated in vacuum. To the residue was added water and the mixture was extracted with dichloromethane. The combined extracts were dried over anhydrous sodium sulfate and filtered through a short column of anhydrous sodium silicate is magnesium. The solution was evaporated in vacuum and the residue was led from hexane to obtain 1,14 g of the product, so pl. 150-151oC. MS m/z: 199,1 (M+N)+.

Stage (e): [2-chloro-4-(3-methylpyrazole-1-yl)-phenyl]-(3-methyl-5H,11H-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanon. A mixture of 2-chloro-4-(3-methylpyrazole-1-yl) benzoic acid (0.18 g) from stage C) of example 10, oxalicacid (0.18 g) and one mesh was evaporated in vacuum and the residue was re-dissolved in dichloromethane and re-evaporated in vacuum to obtain 2-chloro-4-(3-methylpyrazole-1-yl)benzoyl chloride. A suspension of the acid chloride in dichloromethane (25 ml) was added dropwise to a solution of 10,11-dihydro-3-methyl-5H-pyrrolo[2,1-C][1,4]benzodiazepine (0.12 g) and diisopropylethylamine (0.10 g) in dichloromethane (25 ml). This mixture was stirred at room temperature for 18 hours and washed with water and saturated aqueous sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate and filtered through a short column of anhydrous sodium silicate is magnesium. The solution was evaporated in vacuo and triturated with diethyl ether to obtain 0,115 g of the product as colorless crystals, so pl. 178-180oC. MS m/z: 417,3 (M+N)+, 833,3 (2M+N)+.

Example 19
(2-Chloro-4-cryptomaterial-5-yl)-(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanon
2-Chloro-4-(trifluoromethyl)pyrimidine-5-carbonylchloride (to 2.57 g) was added slowly to a cooled with ice to a solution of 10,11-dihydro-5H-pyrrolo[2,1-C] [1,4] benzodiazepine (1.84 g) and diisopropylethylamine (1,37 g) in dichloromethane (50 ml). After stirring at room temperature for 18 hours the reaction mixture was washed with water and saturated aqueous sodium bicarbonate. Solution in dichloromethane was dried over anhydrous sodium sulfate and filtered through a short column with water the zu was evaporated on a hot plate with gradual addition of hexane until until crystallization occurred. After cooling, the crystals were collected by filtration to obtain specified in the connection header (3,22 g), so pl. 221-223oC.

Example 20
[2-(3-Methylpyrazole-1-yl)-4-cryptomaterial-5-yl] -(5H, 11H-pyrrolo[2,1-C][1,4]benzodiazepine-10-yl)-methanon
60% sodium hydride in oil (0.15 g, degreased with hexane) in dimethylformamide (25 ml) was added 3-methylpyrazole (0.25 g). After cessation of hydrogen was added (2-chloro-4-cryptomaterial-5-yl)-(5H,11N-pyrrolo[2,1-C][1,4]benzodiazepine-10-yl)-methanon (0,98 g).

The reaction mixture was heated for 18 hours in a sand bath (internal temperature 110oC). The mixture is then poured into ice and then diluted with a saturated saline solution. The precipitate was filtered, re-dissolved in dichloromethane and dried over anhydrous sodium sulfate. Purification was performed by filtration through a short column with aqueous sodium silicate of magnesium and then suirable several volumes of dichloromethane. The combined eluate was evaporated on a hot plate with gradual addition of hexane until until crystallization occurred. After cooling, the solid was collected by filtration to obtain specified in the title compound (0.54 g) in viil] -(5H, 11N-pyrrolo[2,1-C][1,4]benzodiazepine-10-yl)-methanon
Similar to method 1 of example 9 using (2-chloro-4-cryptomaterial-5-yl)-(5H,11N-pyrrolo[2,1-C][1,4]benzodiazepine-10-yl)-methanone (0,98 g), 60% sodium hydride in oil (0.15 g), 4-methylpyrazole (0,42 g) and dimethylformamide (25 ml) were specified and the title compound (0.73 g) as a crystalline solid, so pl. 214-217oC.

Example 22
1-[4-(5H,11N-Pyrrolo[2,l-c][1,4]benzodiazepine-10-carbonyl)-phenyl]-alanon
4-Acetylbenzoic acid (5.0 g) and thionyl chloride (10 ml) was heated on a steam bath in an argon atmosphere for 0.75 hour and the volatiles were removed under reduced pressure. Added toluene and again volatile components were removed to obtain the crude acid chloride as a red-orange oil. This compound is prone to hardening and it was used as such without further transformations.

The specified acid chloride (4,56 g) in dichloromethane (25 ml) was added in portions to a cooled with ice to a solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (3,68 g) and diisopropylethylamine (3.25 g) in dichloromethane (100 ml). After stirring at room have temperature for 18 hours the reaction mixture was washed with water and saturated aqueous bicarbonate modnim sodium silicate of magnesium and then suirable several volumes of dichloromethane. The combined organic phase was evaporated on a hot plate with gradual addition of hexane until until crystallization occurred. After cooling, the crystals were collected by filtration to obtain specified in the title compound (1.75 g), so pl. 135-137oC.

Example 23
3-Dimethylamino-1-[4-(5H, 11N-pyrrolo[2,1-C] [1,4]benzodiazepine-10-carbonyl)-phenyl]-2-propen-1-it
The reaction mixture of 1-[4-(5H, 11N-pyrrolo[2,1-C] [1,4]benzodiazepine-10-carbonyl)-phenyl] -ethanone (1.40 g), tert-butoxypolyethylene (5.0 ml) and dichloromethane (10 ml) was stirred for 18 hours. Red-orange precipitate was filtered to obtain specified in the title compound (1.22 g), so pl. 203-205oC. Additional product (0.18 g) was isolated from the reaction mixture by evaporation.

Example 24
[4-(1H-Pyrazole-3-yl)-phenyl] -(5H, 11N-pyrrolo[2,1-C][1,4]benzodiazepine-10-yl)-methanon
The reaction mixture of 3-dimethylamino-1-[4-(5H,11N-pyrrolo[2,1-C][1,4]benzodiazepine-10-carbonyl)-phenyl] -2-propen-1-she (1.0 g), anhydrous hydrazine (0.20 g) and glacial acetic acid (20 ml) was heated under reflux for 7 hours and was evaporated to dryness. The crude residue was dissolved in dichloromethane, washed with saturated aqueous sodium bicarbonate and dried over besv the several volumes of dichloromethane. The combined organic phase was evaporated on a hot plate with gradual addition of hexane until until crystallization occurred. After cooling, the crystals were collected by filtration. Procedure using the column was repeated with obtaining specified in the title compound (0.65 g), so pl. 219-221oC.

Example 25
[4-(1-Methyl-1H-pyrazolyl-3-yl)-phenyl] -(5H,11N-pyrrolo[2,1-C][1,4]benzodiazepine-10-yl)-methanon
To a mixture of 6.0% sodium hydride in oil (0.35 g, degreased with hexane) and dimethylformamide (20 ml) was added [4-(1H-pyrazole-3-yl)-phenyl]-(5H,11H-pyrrolo[2,1-C] [1, 4]benzodiazepine-10-yl)-methanon (0,98 g) followed by the addition after a few minutes of iodomethane (0.50 g). The reaction mixture was stirred for 18 hours at room temperature and then poured into water and was extracted with dichloromethane. After drying the organic layer was filtered through a short column with aqueous sodium silicate of magnesium, elwira several volumes of dichloromethane. The combined organic phase was evaporated on a hot plate with gradual addition of hexane until until crystallization occurred. After cooling, the crystals were collected by filtration to obtain specified in the connection header (0,70 g), so pl. 194-195upgr example 25 using [4-(1H-pyrazole-3-yl)-phenyl]-(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanone (1.0 g), 60% sodium hydride in oil (0.27 g), dimethylformamide (25 ml) and ethyliodide (0.87 g) has been specified in the header connection (0,69 g) as a crystalline solid, so pl. 180-183oC.

Example 27
[4-(1-Propyl-1H-pyrazole-3-yl)-phenyl]-(5H,11N-pyrrolo[2,1-C][1,4]benzodiazepine-10-yl)-methanon
Similar to example 25 using [4-(1H-pyrazole-3-yl)-phenyl]-(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanone (0,98 g), 60% sodium hydride in oil (0,30 g), dimethylformamide (25 ml) and 1-iodopropane (0,60 g) has been specified in the title compound (0.32 g) as a crystalline solid, so pl. 159-161oC.

Example 28
[4-(1-Butyl-1H-pyrazole-3-yl)-phenyl] -(5H,11N-pyrrolo[2,1-C][1,4]benzodiazepine-10-yl)-methanon
Similar to example 25 using [4-(1H-pyrazole-3-yl)-phenyl]-(5H, 11-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanone (0,98 g), 60% sodium hydride in oil (0,30 g), dimethylformamide (25 ml) and 1-iodobutane (0,60 g) specified in the title compound (0.32 g) was obtained as crystalline solid, so pl. 122-123oC.

Example 29
[4-(1-Methoxymethyl-1H-pyrazole-3-yl)-phenyl] -(5H, 11N-pyrrolo[2,1-C][1,4] benzodiazepine-10-yl)-methanon
Similar to example 25 using [4-(1H-pyrazole-3-yl)-phen ml) and idletimetrigger simple ester (0.50 g) has been specified in the title compound (0.26 g) as amorphous solids. MS, m/z: 399,2 (M+N)+, 797,2 (2M+N)+.

Example 30
1-{3-[4-(5H,11N-Pyrrolo[2,1-C][1,4]benzodiazepine-10-carbonyl)-phenyl]-pyrazole-1-yl}-alanon
To a solution of [4-(1H-pyrazole-3-yl)-phenyl]-(5H,11H-pirollo[2,1-c][1, 4]benzodiazepine-10-yl)-methanone (0.50 g) in anhydrous pyridine (10 ml) was added acetic anhydride (0.20 g). After stirring at room temperature for 18 hours the reaction mixture was poured into water and the precipitate was collected by filtration. The crude product was dissolved in dichloromethane and dried over anhydrous sodium sulfate. This solution was filtered through a short column with aqueous sodium silicate of magnesium, elwira several volumes of dichloromethane. The eluate was evaporated on a hot plate with gradual addition of hexane until until crystallization occurred. After cooling, the crystals were collected by filtration to obtain specified in the connection header (0,46 g), so pl. 192-194oC.

Example 31
1-{3-[4-(5H,11H-Pirollo[2,1-C][1,4]benzodiazepine-10-carbonyl)-phenyl]-pyrazole-1-yl)-propane-1-it
Similar to example 30 using [4-(1H-pyrazole-3-yl)-phenyl]-(5H, 11N-pyrrolo[2,1-C] [1, 4]benzodiazepine-10-yl)-methanone (0.16 g) in anhydrous pyridine (10 ml) and propionic anhydride (0.10 g) has been specified in the title compound (0.17 g) in the Zol-3-yl)-phenyl]-(5H,11N-pyrrolo[2,1-C] [1,4]benzodiazepine-10-yl]-methanon
To a solution of [4-(1H-pyrazole-3-yl)-phenyl]-(5H,11N-pyrrolo[2,1-C][1,4]benzodiazepine-10-yl)-methanone (1.0 g) in anhydrous pyridine (10 ml) was added cyclopropanecarbonyl (0,44 g). After stirring at room temperature for 18 hours the reaction mixture was poured into water and the precipitate was collected by filtration. The crude product was dissolved in dichloromethane and dried over anhydrous sodium sulfate. This solution was filtered through a short column with aqueous sodium silicate of magnesium, elwira several volumes of dichloromethane. The eluate was evaporated on a hot plate with gradual addition of hexane until until crystallization occurred. After cooling, the crystals were collected by filtration to obtain specified in the title compound (0.88 g) as a crystalline solid, so pl. 197-199oC.

Example 33
1-{3-[4-(5H,11N-Pyrrolo[2,1-C][1,4]benzodiazepine-10-carbonyl)-phenyl]-pyrazole-1-yl}-butane-1-it
Similarly to example 32 using [4-(1H-pyrazole-3-yl)-phenyl]-(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanone (0.71 g) in anhydrous pyridine (10 ml) and butyrylcholine (0.32 g) was obtained is listed in the title compound (0.54 g) as a solid substance, so pl. 105-110oC. MS m/z: 424 (M)+.

Example 34
(5H, 11N-Pyrrol what Finance [4-(1H-pyrazole-3-yl)-phenyl]-(5H, 11H-pyrrolo[2,1-c] [1,4] benzodiazepine-10-yl)-methanone (0.5 g) in anhydrous pyridine (10 ml) and thiophene-2-carbonylchloride (0.25 g) has been specified in the header connection (0,41 g) as a crystalline solid, so pl. 195-197oC. MS m/z: 464 (M)+.

Example 35
{ 4-[1-(5-fluoro-2-methylbenzoyl)-1H-pyrazole-3-yl] -phenyl} -5H, 11N-pyrrolo[2,1-c][1,4]benzodiazepine-10-yl)-methanon
Similarly to example 32 using [4-(1H-pyrazole-3-yl)-phenyl]-(5H, 11N-pyrrolo[2,1-c] [1,4] benzodiazepine-10-yl)-methanone (0.35 g) in anhydrous pyridine (10 ml) and 2-methyl-5-tormentilla (0,22 g) specified in the title compound (0.11 g) was obtained as an amorphous pale yellow solid. MS, m/z: 490 (M)+.

Example 36
{ 4-[1-(2-Methylbenzoyl)-1H-pyrazole-3-yl] -phenyl} -(5H,11N-pyrrolo[2,1-c] [1,4]benzodiazepine-10-yl)-methanon
Similarly to example 32 using [4-(1H-pyrazole-3-yl)-phenyl]-(5H, 11N-pyrrolo[2,1-c] [1,4] benzodiazepine-10-yl)-methanone (0.71 g) in anhydrous pyridine (10 ml) and o-trouillard (0.39 g) has been specified in the header connection (0,59 g) as a crystalline solid, so pl. 170-173oC. MS m/z: 472 (M)+.

Example 37
{ 4-[1-(2-Chloro-4-perbenzoic)-1H-pyrazole-3-yl] -phenyl} -(5H, 11H-pyrrolo[2,1-c][1,4]benzodiazepine-10-yl)-methanon
2-Chloro-4-perbenzoate (0,82 g) Diisopropylamine (0.55 g) in dichloromethane (25 ml), which was cooled in a bath of ice. The reaction mixture was allowed to mix at room temperature over night. The reaction mixture was washed with water and saturated aqueous sodium bicarbonate and dried over anhydrous sodium sulfate. Solution in dichloromethane was passed through a short column with aqueous sodium silicate of magnesium, elwira several volumes of dichloromethane. The eluate was evaporated to dryness to obtain 1.06 g of product as a solid substance, so pl. 150-157oC. MS m/z: 510 (M)+.

Example 38
{4-[1-(2,4-Dichlorobenzoyl)-1H-pyrazole-3-yl]-phenyl}-(5H,11N-pyrrolo[2,l-c] [1,4]benzodiazepine-10-yl)-methanon
Similarly to example 32 using [4-(1H-pyrazole-3-yl)-phenyl]-(5H, 11N-pyrrolo[2,1-c] [1,4] benzodiazepine-10-yl)-methanone (0.71 g) in anhydrous pyridine (20 ml) and 2,4-dichlorobenzotrifluoride (0.52 g) was obtained is listed in the title compound (0.66 g) as a crystalline solid, so pl. 180-182oC. MS m/z: 528 (M)+.

Example 39
2-(2,4-Dichlorophenyl)-1-{ 3-[4-(5H, 11N-pyrrolo[2,1-C][1,4]benzodiazepine-10-carbonyl)-phenyl]-pyrazole-1-yl}-alanon
Similarly to example 32 using [4-(1H-pyrazole-3-yl)-phenyl]-(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanone (0.71 g) in anhydrous pyridine (25 ml) and 2,4-dichlorophenylisocyanate (0.56 g) is, re-solidifies, so pl. 180-182oC.

Example 40
{ 4-[1-(Biphenyl-2-carbonyl)-1H-pyrazole-3-yl] -phenyl} -(5H, 11N-pyrrolo[2,1-C][1,4]benzodiazepine-10-yl)-methanon
Similarly to example 32 using [4-(lH-pyrazole-3-yl)-phenyl]-(5H, 11N-pyrrolo[2,1-C] [1,4]benzodiazepine-10-yl)-methanone (0.71 g) in dry pyridine (20 ml) and 2-biphenylcarboxylic (0.65 g) has been specified in the header connection (0,49 g) as amorphous solids. MS, m/z: 534 (M)+.

Example 41
{ 4-[1-(4'-Triptorelin-2-carbonyl)-1H-pyrazole-3-yl] -phenyl}-(5H, 11N-pyrrolo[2,1-C][1,4]benzodiazepine-10-yl)-methanon
Similarly to example 32 using [4-(1H-pyrazole-3-yl)-phenyl]-(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanone (0.71 g) in anhydrous pyridine (20 ml) and 4'-trifluoromethyl-2-biphenylcarboxylic (0.71 g) has been specified in the header connection (0,59 g) as amorphous solids. MS, m/z: 602 (M)+.

Example 42
3-Dimethylamino-1-[4-(5H, 11N-pyrrolo[2,1-C] [1,4]benzodiazepine-10-carbonyl)-phenyl]-2-butene-1-it
A mixture of 1-[4-(5H,11N-pyrrolo[2,1-c][1,4]benzodiazepine-10-carbonyl)-phenyl] -ethanone (2.0 g) and dimethylacetal dimethylacetamide (15 ml) was boiled under reflux in an inert atmosphere for 15 hours and the volatile components were removed under reduced pressure. Not the m sodium-magnesium and then suirable several volumes of dichloromethane. The combined eluate was evaporated and hexane was gradually added until until crystallization occurred. The cooled solution was filtered to remove specified in the connection header (of 1.03 g) as a crystalline solid, so pl. 183-185oC.

Example 43
[4-(5-Methyl-1H-pyrazole-3-yl)-phenyl]-(5H,11N-pyrrolo[2,1-C][1,4]benzodiazepine-10-yl)-methanon
Anhydrous hydrazine (0.10 g) was added to a solution of 3-dimethylamino-1-[4-(5H, 11N-pyrrolo[2,1-C] [1,4]benzodiazepine-10-carbonyl)-phenyl]-2-butene-1-she (0.50 g) in glacial acetic acid (25 ml). The reaction mixture is boiled under reflux for 18 hours and then evaporated in vacuum. The solid was extracted with dichloromethane and washed with saturated aqueous sodium bicarbonate solution in dichloromethane was dried over anhydrous sodium sulfate and filtered through a short column with aqueous sodium silicate of magnesium, then suirable several volumes of dichloromethane. The combined organic phase was evaporated on the steam bath with the gradual addition of hexane to obtain an opaque solution. After cooling, the amorphous solid was removed by filtration product (0.33 g). MS, m/z: 368 (M)+.

Example 44
4-(5H,11H-Pyrrole on a steam bath for one hour and all volatile components were removed under reduced pressure. Added hexane and the crude crystalline acid chloride (5.30 g) was removed by filtration and used without further purification.

To the reaction mixture of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (3,68 g), dichloromethane (100 ml) and diisopropylethylamine (2,80 g) was added 4-cyanobenzoate (2,97 g). After leaving at room temperature for 18 hours the reaction mixture was washed with water and saturated aqueous sodium bicarbonate. Solution in dichloromethane was dried over anhydrous sodium sulfate and filtered through a short column with aqueous sodium silicate of magnesium, then suirable several volumes of dichloromethane. The combined organic phase was evaporated on a hot plate with gradual addition of hexane until until crystallization occurred. After cooling, the crystals were collected by filtration to obtain specified in the connection header (of 5.05 g), so pl. 184-186oC.

Example 45
4-(5H,11H-Pyrrolo[2,1-c][1,4]benzodiazepine-10-carbonyl)-benzamide
4-(5H,11N-Pyrrolo[2,1-c][1,4]benzodiazepine-10-carbonyl)-benzonitrile (0.5 g) from example 44 was added to concentrated sulfuric acid (5 ml) and the mixture was stirred for 18 hours at room temperature to obtain a bright yellow Rast the solid was filtered, was dissolved in dichloromethane and filtered through a short column with aqueous sodium silicate of magnesium and then suirable several volumes of dichloromethane. The combined organic phase was evaporated on a hot plate with gradual addition of hexane until until crystallization occurred. After cooling, the crystals were collected by filtration to obtain specified in the connection header (of 5.05 g), so pl. 226-228oC.

Example 46
N-(Dimethylaminomethylene)-4-(5H, 11N-pyrrolo[2,1-C][1,4]benzodiazepine-10-carbonyl)-benzamide
A mixture of 4-(5H,11N-pyrrolo[2,1-c][1,4]benzodiazepine-10-carbonyl)-benzamide (1.25 g) from example 45 and dimethylacetal of dimethylformamide (20 ml) was boiled under reflux for 4 hours and the volatile components were removed in vacuum to obtain a solid substance. This solid was dissolved in dichloromethane and filtered through a short column with aqueous sodium silicate of magnesium and then suirable several volumes of dichloromethane. The combined organic phase was evaporated on the steam bath with gradual addition of hexane until until crystallization occurred. After cooling, the crystals were collected by filtration to obtain specified in the title compound (1.40 g), so pl. 232-234 A mixture of 4-(5H,11N-pyrrolo[2,1-C][1,4]benzodiazepine-10-carbonyl)-benzamide (1.24 g) from example 45 and dimethylacetal dimethylacetamide (5 ml) was heated on the steam bath for 4 hours. When cooled for 18 hours was deposited crystalline solid, which was removed by filtration. The solid was washed with hexane to obtain the product (1.54 g), so pl. 210-212oS, MS, m/z: 400 (M)+.

Example 48
(5H, 11N-Pyrrolo[2,1-C][1,4]benzodiazepine-10-yl)-[4-(2H-[1,2,4]triazole-3-yl)-phenyl]-methanon
A mixture of N-(dimethylaminomethylene)-4-(5H, 11N-pyrrolo[2,1-C][1,4]benzodiazepine-10-carbonyl)-benzamide (1.0 g) from example 46, glacial acetic acid (15 ml) and anhydrous hydrazine (0.16 g) was boiled under reflux for 15 hours and the volatile components were removed in vacuum. Was added a saturated aqueous sodium bicarbonate solution and the resulting solid was removed by filtration. The solid was heated under reflux for 4 hours and the volatile components were removed in vacuum to obtain a solid substance. This solid was dissolved in dichloromethane and filtered through a short column with aqueous sodium silicate of magnesium, then suirable several volumes of dichloromethane. The combined organic phase UPA is E. cooling the crystals were collected by filtration to obtain specified in the title compound (0.39 g), so pl. 225-227oC. MS m/z: 355 (M)+.

Example 49
[4-(2-Methyl-2H-[1,2,4] triazole-3-yl)-phenyl] -(5H,11N-pyrrolo[2,1-C][1,4] benzodiazepine-10-yl)-methanon
Similar to example 48, using N-(dimethylaminomethylene)-4-(5H,11N-pyrrolo[2,1-C] [1,4]benzodiazepine-10-carbonyl)-benzamide (1.56 g) from example 46 in glacial acetic acid (75 ml) and methylhydrazine (0.32 g) was obtained is listed in the title compound (0.10 g) in the form of a solid substance, so pl. 155-158oC. MS m/z: 369 (M)+.

Example 50
[4-(5-Methyl-2H-[1,2,4] triazole-3-yl)-phenyl] -(5H,11H-pyrrolo[2,1-C][1,4] benzodiazepine-10-yl)-methanon
Similar to example 48, using N-(1-dimethylaminoethyl)-4-(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-carbonyl)-benzamide (1,00 g) from example 47 in glacial acetic acid (75 ml) and anhydrous hydrazine (0.25 g) specified in the title compound (0.20 g) was obtained as amorphous solids. MS, m/z: 369 (M)+.

Example 51
[4-(2,5-Dimethyl-2H-[1,2,4] triazole-3-yl)-phenyl] -(5H, 11N-pyrrolo[2,1-C] [1,4]benzodiazepin-10-yl)-methanon
Similar to example 48, using N-(1-dimethylaminoethyl)-4-(5H, 11N-pyrrolo[2, l-c] [1,4] benzodiazepine-10-carbonyl)-benzamide (1.18 g) from example 47 in glacial acetic acid (75 ml) and methylhydrazine (0,30 g) specified in the title compound (0.33 g) was obtained in the Nile] -(5H, 11N-pyrrolo[2,1-C][1,4] benzodiazepine-10-yl)-methanon
A solution of N-(1-dimethylaminoethyl)-4-(5H, 11N-pyrrolo[2,1-C][1,4]benzodiazepine-10-carbonyl)-benzamide (1,15 g) from example 47 in glacial acetic acid (50 ml) containing hydroxylamine hydrochloride (0.40 g) and potassium acetate (1.0 g) was boiled under reflux for 2 hours. All
volatile components were removed under reduced pressure and added a saturated aqueous solution of sodium bicarbonate. This mixture was extracted with dichloromethane and the extracts were dried over anhydrous sodium sulfate. The solution was filtered through a short column with aqueous sodium silicate of magnesium, then suirable several volumes of dichloromethane. The combined organic phase was concentrated on a steam bath with gradual addition of hexane until until crystallization occurred. After cooling, the crystals were collected by filtration to obtain specified in the connection header (0,38 g), so pl. 177-179oC. MS m/z: 371,3 (M)+, 741,3 (2M)+.

Example 53
1-Methyl-4-(4-were)-lH-pyrazole
A mixture of 2-(4-were)-malondialdehyde (3,05 g), absolute ethanol (40 ml) and methylhydrazine (1,09 g) was stirred at room temperature for 18 hours and the volatile components were removed when the sodium sulfate solution was filtered through a short column with aqueous sodium silicate-magnesium, then suirable several volumes of dichloromethane. The combined organic phase was evaporated on the steam bath with gradual addition of hexane until until crystallization occurred. After cooling, the crystals were collected by filtration to obtain specified in the title compound (2.91 in g), so pl. 107-108oC.

Example 54
4-(1-Methyl-1H-pyrazole-4-yl)-benzoic acid
A mixture of 1-methyl-4-(4-were)-1H-pyrazole (1.70 g), potassium permanganate (9,70 g) and 1 n sodium hydroxide (100 ml) was boiled under reflux for 18 hours. The suspension was filtered through diatomaceous earth and cooled. The aqueous solution was extracted with dichloromethane, which was rejected. The aqueous solution was acidified to pH 5.5. The precipitate was filtered with difficulty, and therefore it was extracted with dichloromethane. After evaporation of the solvent, the obtained solid substance was recrystallized from acetone to obtain specified in the connection header (0,60 g), so pl. 274-275oC. MS m/z: 202 (M)+.

Example 55
[4-(1-Methyl-1H-pyrazole-4-yl)-phenyl] -(5H, 11N-pyrrolo[2,1-C] [1,4]benzodiazepine-10-yl)-methanon
Oxalicacid (0,30 g) was added to a suspension of 4-(1-methyl-1H-pyrazole-4-yl)-benzoic acid (0,46 g) in dichloromethane (25 ml). Added two drops dimetil the ha to obtain the crude acid chloride (0,57 g), which was used without further purification.

This acid chloride was added to a solution of 10,11-dihydro-5H-pyrrolo[2,1-C] [1,4]benzodiazepine (0, 37 g) and diisopropylethylamine (0,58 g) in dichloromethane (50 ml). After 18 hours at room temperature the reaction mixture was washed with water and saturated aqueous sodium bicarbonate. Solution in dichloromethane was dried over anhydrous sodium sulfate and filtered through a short column with aqueous sodium silicate of magnesium, and then suirable several volumes of dichloromethane. The combined organic phase was evaporated on a hot plate with gradual addition of hexane until until crystallization occurred. After cooling, the crystals were collected by filtration to obtain specified in the connection header (0,38 g), so pl. 200-201oC. MS m/z: 368 (M)+.

Example 56
6-(1-Methyl-1H-pyrazole-4-yl)-pyridine-3-carboxylic acid
A suspension of 6-(1-formyl-2-hydroxyphenyl)pyridine-3-carboxylic acid (1,93 g) (Eastroao Chemicals) in absolute ethanol (50 ml) and methylhydrazine (0.50 g) was stirred for 18 hours at room temperature. The reaction mixture was filtered to obtain the product (1.30 grams). The filtrate was evaporated to obtain a solid substance, which paracrystalline the/sup>C.

Example 57
[6-(1-Methyl-1H-pyrazole-4-yl)-pyridin-3-yl] -(5H, 11N-pyrrolo[2,1-C][1,4] benzodiazepine-10-yl)-methanon
A suspension of 6-(1-methyl-1H-pyrazole-4-yl)-pyridine-3-carboxylic acid (0,48 g) in thionyl chloride (5.0 ml) was stirred at room temperature for 2 hours. Volatiles were removed under reduced pressure to obtain 6-(1-methyl-1H-pyrazole-4-yl)-pyridine-3-carbonylchloride in the form of a solid, which was used without further purification.

A solution of 10,11-dihydro-5H-pyrrolo[2,1-C] [1,4] benzodiazepine (0,37 g) and diisopropylethylamine (0,61 g) in dichloromethane (25 ml) was cooled to 0aboutAnd portions were added to a solution of 6-(1-methyl-1H-pyrazole-4-yl)-pyridine-3-carbonylchloride in dichloromethane (25 ml). After 18 hours at room temperature the reaction mixture was washed with water and saturated aqueous sodium bicarbonate. Solution in dichloromethane was dried over anhydrous sodium sulfate and filtered through a short column with aqueous sodium silicate of magnesium, and then suirable several volumes of dichloromethane. The combined organic phase was evaporated on a hot plate with gradual addition of hexane until until crystallization occurred. After cooling, the crystals were collected by filtration with poperator-1-yl)-phenyl] -(5H, 11N-pyrrolo[2,1-C][1,4]benzodiazepine-10-yl)-methanon
To a suspension of 4-(pyrazole-1-yl)benzoic acid (1.56 g) in dichloromethane (25 ml) was added oxalicacid (1.04 g) and one drop of dimethylformamide. The mixture was stirred at room temperature for 18 hours to obtain a transparent solution. Volatiles were removed under reduced pressure to obtain 4-(pyrazole-1-yl) benzoyl chloride as a pale yellow solid (1,58 g) which was used without further purification.

4-(Pyrazole-1-yl)benzoyl chloride (0.75 g) was added to a solution of 10,11-dihydro-5H-pyrrolo[2,1-C] [1,4] benzodiazepine (0,61 g) and diisopropylethylamine (of 0.47 g) in dichloromethane (25 ml). After 18 hours at room temperature the reaction mixture was washed with water and saturated aqueous sodium bicarbonate. Solution in dichloromethane was dried over anhydrous sodium sulfate and filtered through a short column with aqueous sodium silicate of magnesium, then suirable several volumes of dichloromethane. The combined organic phase was evaporated on a hot plate with the addition of hexane until until crystallization occurred. After cooling, the crystals were collected by filtration to obtain specified in the connection header (0,90 g), so pl. /> To a suspension of 4-(3-methylpyrazole-1-yl) benzoic acid (1.84 g) in dichloromethane (25 ml) was added oxalicacid (1,16 g) and one drop of dimethylformamide. The mixture was stirred at room temperature for 18 hours and the volatile material was removed under reduced pressure. Added dichloromethane, the solution was filtered and the solvent evaporated under reduced pressure to obtain 4-(3-methylpyrazole-1-yl)benzoyl chloride as a yellow oil (1,76 g) which was used without further purification.

4-(3-Methylpyrazole-1-yl)benzoyl chloride was added to a cooled with ice to a solution of 10,11-dihydro-5H-pyrrolo[2,1-C] [1,4] benzodiazepine (0.55 g) and diisopropylethylamine (0,44 g) in dichloromethane (25 ml). After stirring at room temperature for 18 hours the reaction mixture was washed with water and saturated aqueous sodium bicarbonate. Solution in dichloromethane was dried over anhydrous sodium sulfate and filtered through a short column with aqueous sodium silicate of magnesium and then suirable several volumes of dichloromethane. The combined organic phase was evaporated on a hot plate with gradual addition of hexane until until crystallization occurred. After cooling has been specified in the header connection] -(5H, 11H-pyrrolo[2,1-C][1,4]benzodiazepine-10-yl)-methanon
To a suspension of 4-(4-methylpyrazole-1-yl)benzoic acid (0.75 g) in dichloromethane (15 ml) was added oxalicacid (0.50 g) and one drop of dimethylformamide. The mixture was stirred at room temperature for 18 hours and the volatiles were removed under reduced pressure. The residue was dissolved in hexane and filtered through diatomaceous earth. Evaporation of the solvent in vacuo gave 4-(4-methylpyrazole-1-yl)benzoyl chloride (0,77 g) which was used without further purification.

4-(4-Methylpyrazole-1-yl)benzoyl chloride (0,72 g) was added to a cooled with ice to a solution of 10,11-dihydro-5H-pyrrolo[2,1-C][1,4]benzodiazepine (0,60 g) and diisopropylethylamine (0,48 g) in dichloromethane (25 ml). After stirring at room temperature for 18 hours the reaction mixture was washed with water and saturated aqueous sodium bicarbonate. Solution in dichloromethane was dried over anhydrous sodium sulfate and filtered through a short column with aqueous sodium silicate of magnesium, then suirable several volumes of dichloromethane. The combined organic phase was evaporated on a hot plate with gradual addition of hexane until until crystallization occurred. After cooling, the crystal is)+.

Example 61
[4-(3,5-Dimethylpyrazol-1-yl)-phenyl] -(5H, 11H-pyrrolo[2,1-C] [1,4]benzodiazepine-10-yl)-methanon
To a suspension of 4-(3,5-dimethylpyrazol-1-yl) benzoic acid (1,34 g) in dichloromethane (25 ml) was added oxalicacid (1.0 g) and one drop of dimethylformamide. The mixture was stirred at room temperature for 18 hours and the volatiles were removed under reduced pressure. The residue was dissolved in hexane and filtered through diatomaceous earth. Evaporation of the solvent in vacuo gave 4-(3,5-dimethylpyrazol-1-yl)benzoyl chloride (0,80 g) which was used without further purification.

4-(3,5-Dimethylpyrazol-1-yl)benzoyl chloride (0.75 g) was added to a cooled with ice to a solution of 10,11-dihydro-5H-pyrrolo[2,1-C][1,4]benzodiazepine (0.55 g) and diisopropylethylamine (0,42 g) in dichloromethane (25 ml). After stirring at room temperature for 18 hours the reaction mixture was washed with water and saturated aqueous sodium bicarbonate. Solution in dichloromethane was dried over anhydrous sodium sulfate and filtered through a short column with aqueous sodium silicate of magnesium, and then suirable several volumes of dichloromethane. The combined organic phase was evaporated on a hot plate with gradual addition of hexane until , in the form of amorphous solids. MS, m/z: 383 (M+H)+.

Example 62
(5H, 11N-Pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-[4-(3-cryptomaterial-1-yl)-phenyl]-methanon
A suspension of 4-(3-cryptomaterial-1-yl)benzoic acid (1.45 g) in thionyl chloride (5.0 ml) was heated under reflux for 3 hours. Volatiles were removed under reduced pressure, the residue was dissolved in dichloromethane and filtered through diatomaceous earth. Evaporation of the solvent in vacuo gave 4-(3-cryptomaterial-1-yl)benzoyl chloride (1.45 g) which was used without further purification.

To a solution of 10,11-dihydro-5H-pyrrolo[2,1-C][1,4]benzodiazepine (0.88 g) and diisopropylethylamine (0.66 g) in dichloromethane (50 ml) was added 4-(3-cryptomaterial-1-yl)benzoyl chloride (1.40 g). After stirring at room temperature for 18 hours the reaction mixture was washed with water and saturated aqueous sodium bicarbonate. Solution in dichloromethane was dried over anhydrous sodium sulfate and filtered through a short column with aqueous sodium silicate of magnesium, and then suirable several volumes of dichloromethane. The combined organic phase was evaporated on a hot plate with gradual addition of hexane until until crystallization occurred. After ohlord C. MS, m/z: 423,3 (M+N)+, 845,4 (2M+H)+.

Example 63
[4-(Imidazol-1-yl)-phenyl] -(5H,11H-pyrrolo[2,1-C][1,4]benzodiazepine-10-yl)-methanon
A suspension of 4-(imidazol-1-yl)benzoic acid (0,90 g) in thionyl chloride (2.0 ml) was heated on a steam bath in an argon atmosphere for one hour. Evaporation of volatiles under reduced pressure gave a residue, which was led by adding hexane to obtain 4-(imidazol-1-yl)benzoyl chloride in the form of cleaners containing hydrochloride salt (1,17 g), so pl. 242-247oC.

To a solution of 10,11-dihydro-5H-pyrrolo[2,1-C][1,4]benzodiazepine (0.75 g), diisopropylethylamine (1.20 g) and 4-dimethylaminopyridine in dichloromethane (50 ml) were added hydrochloride 4-(imidazol-1-yl)benzoyl chloride (1.12 g). After stirring at room temperature for 18 hours the reaction mixture was washed with water and saturated aqueous sodium bicarbonate. Solution in dichloromethane was dried over anhydrous sodium sulfate and filtered through a short column with aqueous sodium silicate of magnesium, and then suirable several volumes of dichloromethane. The combined organic phase was evaporated on a hot plate with gradual addition of hexane until until crystallization occurred. After cooling, the crystals were collected ሺ/p> Example 64
[4-(4-Mei-1-yl)-phenyl] -(5H, 11N-pyrrolo[2,1-C] [1,4]benzodiazepine-10-yl)-methanon
To a suspension of 4-(4-Mei-1-yl)benzoic acid (0,80 g) in dichloromethane (25 ml) was added oxalicacid (0.50 g) and one drop of dimethylformamide. The mixture was stirred at room temperature for 18 hours and the volatiles were removed under reduced pressure to obtain 4-(4-Mei-1-yl)benzoyl chloride (1,02 g) which was used without further purification.

4-(4-Mei-1-yl)benzoyl chloride (0,99 g) was added to a cooled with ice to a solution of 10,11-dihydro-5H-pyrrolo[2,1-C] [1,4]benzodiazepine (0.64 g) and diisopropylethylamine (0,60 g) in dichloromethane (25 ml). After stirring at room temperature for 18 hours the reaction mixture was washed with water and saturated aqueous sodium bicarbonate. Solution in dichloromethane was dried over anhydrous sodium sulfate and filtered through a short column with aqueous sodium silicate of magnesium, then suirable several volumes of dichloromethane. The combined organic phase was evaporated on a hot plate with gradual addition of hexane until until crystallization occurred. After cooling has been specified in the title compound (0.52 g) in Videology ether
Thionyl chloride (1,64 ml) was added dropwise to a suspension of 4-bromo-2-chlorbenzoyl acid (6,92 g) in methanol and heated to 60oC for 2 hours. The solvent was removed in vacuo, the residue was re-dissolved in ethyl acetate and washed sequentially with 0.5 N. sodium hydroxide (2x), water and brine. The organic phase was dried over anhydrous sodium sulfate and the solvent was removed in vacuum to obtain specified in the title compound (7.8 g).

1H-NMR (300 MHz, DMSO-d6),: a 3.87 (s, 3H), 7.68 per-7,9 (m, 3H).

Example 66
2-Chloro-4-(3-dimethylaminopropan-1-yl)benzoic acid, methyl ester
To a stirred solution of methyl ester 4-bromo-2-chlorbenzoyl acid (18,69 g) in triethylamine (110 ml) was added 1-dimethylamino-2-propyne (12.1 ml), bis(triphenylphosphine)palladium(II) chloride (1.26 g) and copper iodide(I) (0,136 g).

This mixture was slowly heated to 60oAnd the specified temperature is maintained for one hour. The reaction was cooled to room temperature, filtered through diatomaceous earth and the collected solid was washed with ethyl acetate. The solvent was removed in vacuo, the obtained solid was re-dissolved in ethyl acetate and washed with water (3x). United orchidinae product. The crude product was purified column chromatography on silica gel (225 g), elwira a mixture of 40% ethyl acetate/hexane. After removal of solvent in vacuo specified in the title compound was obtained as a viscous oil (17,7 g). MS (+FB), m/z: 252 (M+N)+.

Example 67
2-Chloro-4-(3-dimethylamino-2-propen-1-on-1-yl)-benzoic acid, methyl ester
3-Chloroperoxybenzoic acid (10,76 g) was gradually added to a solution of methyl ester of 2-chloro-4-(3-dimethylaminopropan-1-yl)benzoic acid (15,07 g) in dichloromethane (40 ml) at a rate sufficient to maintain the reaction temperature at -20oC. the Mixture was stirred for 10-15 minutes. The N-oxide was purified by chromatography on basic alumina, Activity Grade I (215 g), elwira a mixture of 10% methanol/dichloromethane. The solvent was removed in vacuum at a temperature between 12 and 18oC. the Obtained residue was dissolved in methanol (100 ml) and was heated at 60-65oWith stirring for 18 hours. After removal of the solvent in vacuo the product was purified column chromatography on silica gel (190 g), elwira a mixture of 70% ethyl acetate/hexane. Rubbing with diethyl ether containing a small amount of hexane, gave specified in the title compound in the form of a solid ve the suspension of the methyl ester of 2-chloro-4-(3-dimethylamino-2-propen-1-on-1-yl)-benzoic acid (13,67 g) in ethanol (53 ml) was added monohydrochloride hydrazine (7.0 g). This mixture was heated on an oil bath at 75-80oC for one hour. The solvent was removed in vacuum. The obtained residue was dissolved in ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate and the solvent was removed in vacuum to obtain specified in the connection header in the form of a crude solid (12 g). The purified sample was so pl. 130-131oC.

Example 69
2-Chloro-4-(1-methyl-1H-pyrazole-3-yl)-benzoic acid, methyl ester
To the suspension is washed with hexane sodium hydride (3,05 g, 60% dispersion) in dimethylformamide (6 ml) under nitrogen atmosphere was added a solution of methyl ester of 2-chloro-4-(1H-pyrazole-3-yl)-benzoic acid (12.0 g) in dimethylformamide (30 ml) for 15 minutes. The mixture was stirred at room temperature for 30 minutes. Was added dropwise itmean (9,5 ml) for 15 minutes. The mixture was allowed to mix at room temperature for 45 minutes. Added more iodomethane (5,16 ml) and the reaction was stirred for 75 minutes. The reaction was diluted with a small amount of water and evaporated in vacuum. The residue was diluted with water (500 ml) and was extracted with a small amount of ethyl acetate (5x). The combined organic omatography on silica gel (195 g), elwira a mixture of 15% ethyl acetate/hexane to obtain pure 1-methyl-regioisomer (4,29 g) followed by a mixture of 1-methyl - 2-methyl-regioisomers (4.6 g). The mixture of isomers was washed with hexane three times to obtain additional samples of pure 1-methyl-regioisomer (2.55 g), so square up to 66.5-67oC. MS (+FAB), m/z: 251 (M+N)+.

Example 70
2-Chloro-4-(1-methyl-1H-pyrazole-3-yl)-benzoic acid.

To a solution of methyl ester of 2-chloro-4-(1-methyl-1H-pyrazole-3-yl)-benzoic acid (6.85 g) in methanol (32 ml) was added 2.5 n sodium hydroxide solution (15.3 ml). The reaction was heated to 50oC for one hour. The solvent was removed in vacuum and the residue was dissolved in water (250 ml), cooled in a bath of ice and acidified 2 N. hydrochloric acid (24 ml). The precipitate was filtered and dried to obtain a colorless solid (6.3 g), so pl. 232-233oC. MS (+FAB), m/z: 236 (M+N)+.

Example 71
[2-Chloro-4-(1-methyl-1H-pyrazole-3-yl)-phenyl] -(5H,11H-pyrrolo-[2,1-C][1,4] benzodiazepine-10-yl)-methanon
Well powdered 2-chloro-4-(1-methyl-1H-pyrazole-3-yl)-benzoic acid (6.3 g) and dimethylformamide (2,16 ml) suspended in the atmosphere of nitrogen in a mixture of tetrahydrofuran (70 ml) and dichloromethane (15 ml). Was added dropwise a solution of oxalylamino-1H-pyrazole-3-yl)-benzoyl chloride was used without further purification.

To a suspension of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (4,93 g) in dichloromethane (15 ml) was added diisopropylethylamine (7 ml). A suspension of freshly prepared acid chloride was gradually added over 15 minutes under pumped a stream of nitrogen. Slightly warm the reaction mixture was stirred in nitrogen atmosphere for 50 minutes. After stirring for one hour the mixture was evaporated in vacuum. The residue was dissolved in dichloromethane, washed with water, 5% sodium bicarbonate and water. The organic phase is washed with saline, dried over anhydrous sodium sulfate and the solvent was removed in vacuum to obtain the crude product (10,95 g). The crude product was purified column chromatography on silica gel (200 g), loading the column with a mixture of 25% ethyl acetate/hexane. Less polar impurities were suirable mixture 25-30% ethyl acetate/hexane. The product was suirable a mixture of 30-40% ethyl acetate/hexane to obtain pure samples (7,42 g), which, after making the seed crystals were washed with diethyl ether containing a certain amount of hexane, within 24 hours. Filtration gave specified in the title compound as crystalline solid (6,88 g), so pl. 148,5-150oC. MS (EI) m/z: 402 (M)+.

the Association received the same as described in example 68, using methyl 2-chloro-4-(3-dimethylamino-2-propen-1-one)-benzoate (0.8 g) and methylhydrazine (0,319 ml). The main 2-methyl-regioisomer was isolated by column chromatography on silica gel.

1H-NMR (300 MHz, DMSO-d6),: a 3.87 (s, 3H), with 3.89 (s, 3H), return of 6.58 (d, 1H), 7.5 (d, 1H), 7,62-to 7.93 (m, 3H).

Example 73
2-Chloro-4-(2-methyl-1H-pyrazole-3-yl)-benzoic acid
Specified in the title compound was obtained as described in example 70, using the methyl ester of 2-chloro-4-(2-methyl-1H-pyrazole-3-yl)-benzoic acid (0,464 g) and 2.5 n sodium hydroxide (1,04 ml).

1H-NMR (300 MHz, DMSO-d6),: to 3.89 (s, 3H), 6,56 (d, 1H), 7,49 (d, 1H), to 7.59-of 7.90 (m, 3H).

Example 74
[2-Chloro-4-(2-methyl-1H-pyrazole-3-yl)-phenyl] -(5H,11N-pyrrolo-[2,1-C][1,4] benzodiazepine-10-yl)-methanon
Specified in the title compound was obtained as described in example 71, using 2-chloro-4-(2-methyl-1H-pyrazole-3-yl)-benzoic acid (3.98 g), gives the corresponding acid chloride, and the acylation 10,11-dihydro-5H-pyrrolo[2,1-C] [1,4] benzodiazepine (0,293 g) gave specified in the title compound in the form of foam, so pl. 78-79oC. MS (EI) m/z: 402 (M)+.

Example 75
2-Chloro-4-cyanobenzoic acid, methyl ester
Medievaloides acid (15.7 ml). After stirring at room temperature for 10 minutes, the suspension was cooled to 0oC. a Solution of sodium nitrite (5,71 g) in water (37 ml) was gradually added over 20 minutes, maintaining the temperature of the reaction 0aboutC. After stirring at 0oWith over 35 minutes, the reaction mixture was partially neutralized by addition of solid sodium carbonate (3,16 g) obtaining a cold solution of diazonium salts.

To a pre-cooled solution of copper cyanide(I) (8,4 g) and sodium cyanide (9,19 g) in water (112 ml) was gradually added to the above solution of diazonium salts over a period of 45-50 minutes. The temperature of the solution of diazonium salts during the addition was maintained at 0oC. the resulting mixture was stirred for 18 hours at room temperature. The precipitate was filtered, dried in air, dissolved in ethyl acetate (250 ml) and filtered to remove insoluble material. The organic phase was dried over anhydrous magnesium sulfate and the solvent was removed in vacuum to obtain the crude product as a brown solid (13,2 g). The crude product was purified column chromatography on silica gel (250 g), elwira mixture of 5-10% ethyl acetate/hexane to obtain specified the 2-Chloro-4-cyanobenzoic acid.

To a stirred solution of methyl ester of 2-chloro-4-cyanobenzoic acid (24.3 g) in methanol (150 ml) was added 2.5 n sodium hydroxide (54,5 ml). After stirring at room temperature for 45 minutes the solvent was removed in vacuum. The residue was dissolved in water, cooled in a bath of ice and acidified 2 N. hydrochloric acid (14 ml). The precipitate was filtered and dried in vacuum to obtain specified in the title compound as a solid (22,55 g), so pl. 154-158oC.

Example 77
3-Chloro-4-(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-carbonyl)-benzonitrile
To a cooled suspension of 2-chloro-4-cyanobenzoic acid (9.1 g) in a mixture of dichloromethane (40 ml) and dimethylformamide (3,88 ml) was added dropwise a solution of oxalicacid (4.6 ml) in dichloromethane (10 ml) at 0aboutC. Stir the reaction was allowed to warm to room temperature over one hour. A cloudy solution of 2-chloro-4-cyanobenzaldehyde used without further purification.

To a stirred suspension of 10,11-dihydro-5H-pyrrolo[2,1-C][1,4]benzodiazepine (7,32 g) and diisopropylethylamine (to 13.6 ml) in dichloromethane (35 ml) was added under nitrogen atmosphere turbid solution of 2-chloro-4-cyanobenzaldehyde. After one hour at room those who authorized saline. After drying over anhydrous sodium sulfate the solvent was removed in vacuum to obtain the crude product (18.0 g). Purification of column chromatography on silica gel (250 g) with elution with a mixture of 20% ethyl acetate/hexane, followed by elution with a mixture of 25% ethyl acetate/hexane gave specified in the header of the connection (of 13.56 g) as a pale-yellow foam. MS (EI) m/z: 347 (M)+.

Example 78
3-Chloro-4-(5H,11N-pyrrolo[2,1-c][1,4]benzodiazepine-10-carbonyl)-benzoic acid
To a suspension of 3-chloro-4-(5H, 11N-pyrrolo[2,1-C][1,4]benzodiazepine-10-carbonyl)-benzonitrile (90,72 g) in ethanol was added 10 n sodium hydroxide (1,02 ml) and the mixture was heated under reflux for two hours. The solvent was removed in vacuo, the residue was dissolved in water and acidified 2 N. hydrochloric acid (4,7 ml). The precipitate was extracted with ethyl acetate and the organic phase was dried over anhydrous sodium sulfate. After removal of the solvent in vacuum the foam triturated with diethyl ether for 18 hours and filtered to obtain the crude product (0,69 g). The crude product was purified by treatment with activated charcoal in methanol. Crystallization from methanol/ether gave specified in the title compound in the form of cleansing is C][1,4]benzodiazepine-10-carbonyl)-benzamide
Concentrated sulfuric acid (70 ml) was added to 3-chloro-4-(5H,11N-pyrrolo[2,1-C] [1,4]benzodiazepine-10-carbonyl)-benzonitrile (12,85 g). The mixture was stirred at 60oC for 3 hours, followed by stirring at room temperature for 18 hours. The reaction mixture was poured on ice and neutralized at 0aboutWith 30% ammonia (184 ml). The resulting suspension was extracted with ethyl acetate. Water the mixture was filtered and re-extracted with ethyl acetate. The combined organic phase was dried over anhydrous sodium sulfate and the solvent was removed in vacuum. The residue is triturated with a mixture of diethyl ether (50-60 ml) and a small amount of ethyl acetate. Filtration of the precipitate gave specified in the title compound as crystalline solid (10,44 g), so pl. 211-212oC. MS (EI) m/z: 365 (M)+.

Example 80
N-(1-Dimethylaminoethyl)-3-chloro-4-(5H, 11N-pyrrolo[2,1-C] [1,4]benzodiazepine-10-carbonyl)-benzamide
A suspension of 3-chloro-4-(5H, 11N-pyrrolo[2,1-C] [1,4]benzodiazepine-10-carbonyl)-benzamide (5,48 g) and dimethylacetal dimethylacetamide (10,97 ml) was heated at 90oC for 20 minutes. Excess reagent was removed under reduced pressure specified in the title compound was used without will add the-c] [1,4]benzodiazepine-10-carbonyl)-methanon
To a solution of N-(1-dimethylaminoethyl)-3-chloro-4-(5H,11N-pyrrolo[2,1-C][1,4] benzodiazepine-10-carbonyl)-benzamide (3,01 g) in acetic acid (4 ml) solution was added anhydrous hydrazine (0,435 ml) in acetic acid (4 ml). The reaction mixture was stirred at a temperature between 85 and 90oC for 45 minutes. After removal of the acetic acid in vacuo, the reaction mixture was diluted with water (35-40 ml), neutralized to pH 7.0 aqueous sodium bicarbonate and was extracted with ethyl acetate. The organic extract was washed with saline, dried over anhydrous sodium sulfate and the solvent was removed in vacuum to obtain the crude product (2,68 g). Purification of the crude product column chromatography on silica gel (45 g) with elution with a mixture of 70% ethyl acetate/hexane gave purified product (2.5 g), which, after trituration with diethyl ether gave specified in the title compound as a solid (2 g), so pl. 211-212oC. MS (EI) m/z: 403 (M)+.

Example 82
N-(Dimethylaminomethylene)-3-chloro-4-(5H, 11N-pyrrolo[2,1-C][1,4]benzodiazepine-10-carbonyl)-benzamide
Specified in the title compound was obtained as described in example 80, using 3-chloro-4-(5H,11H-pyrrolo[2,1-C][1,4]benzodiazepine-10-carbonyl)-benzamide (1,83 g) and d]-(5H,11H-pyrrolo[2,l-c][1,4]benzodiazepine-10-yl)-methanon
Specified in the title compound was obtained as described in example 81, using N-(dimethylaminomethylene)-3-chloro-4-(5H, 11H-pyrrolo[2,1-C] [1,4] benzodiazepine-10-carbonyl)-benzamide (2,53 g) and hydrazine (0,38 ml), so pl. 174-177oC. MS (EI) m/z: 389 (M)+.

Example 84
[2-Chloro-4-(2-methyl-2H-[1,2,4] triazole-3-yl)phenyl]-(5H,11N-pyrrolo[2,l-c] [1,4]benzodiazepine-10-carbonyl)-methanon
Specified in the title compound was obtained as described in example 48, using N-(dimethylaminomethylene)-3-chloro-4-(5H,11N-pyrrolo[2,1-c] [1,4] benzodiazepine-10-carbonyl)-benzamide (0,572 g) and methylhydrazine (0,149 ml), so pl. 141-143oC. MS (EI) m/z: 403 (M)+.

Example 85
4-[(2,5-Dimethyl-2H-[1,2,4] triazole-3-yl)-2-chlorophenyl]-(5H,11N-pyrrolo[2, l-c][1,4]benzodiazepine-10-carbonyl)-methanon
Specified in the title compound was obtained as described in example 48, using N-(1-dimethylaminoethyl)-3-chloro-4-(5H,11H-pyrrolo[2, l-c] [1,4] benzodiazepine-10-carbonyl)-benzamide (0.51 g) and methylhydrazine (0,125 ml), so pl. 197-199oC. MS (EI) m/z: 417 (M)+.

Example 86
[2-Chloro-4-(1H-tetrazol-5-yl)-phenyl] -(5H, 11N-pyrrolo[2, l-c][1,4]benzodiazepine-10-yl)-methanon
To a solution of 3-chloro-4-(5H,11N-pyrrolo[2,1-C][1,4]benzodiazepine-10-carbonyl)-benzonitrile (0,348 g) in dimethylformamide (2 ml) was added and the methylformamide was removed in vacuum. The residue was dissolved in water (approximately 8 ml) and podslushivaet to pH 9,0 2,5 N. sodium hydroxide (0.6 ml), was extracted with ethyl acetate. The aqueous extract was acidified using 2 N. hydrochloric acid (1.1 ml), re-extracted with ethyl acetate, dried over anhydrous sodium sulfate and the solvent was removed in vacuum to obtain the crude product (0,350 g) as oil. This oily product is triturated with diethyl ether, filtered through the acid-treated silica gel and was suirable a mixture of 40% ethyl acetate/hexane to obtain a more pure sample. Then triturated with diethyl ether and filtered to obtain samples (0.88 g), so pl. 218-220aboutC. MS (+FAB): 391 (M+N)+.

Example 87
[2-Chloro-4-(3-methylpyrazole-1-yl)-phenyl] -(3-dimethylaminomethyl-5H, 11N-pyrrolo[2,1-C][1,4]benzodiazepine-10-yl)-methanon
To a stirred solution of [2-chloro-4-(3-methylpyrazole-1-yl)-phenyl]-(5H, 11N-pyrrolo[2,1-C] [1, 4]benzodiazepine-10-yl)-methanone (1,61 g), N,N,N',N'-tetramethyldisilane (0,82 g) and glacial acetic acid (0,48 g) in methanol (25 ml) solution was added 37% aqueous formaldehyde (4 ml). The mixture was heated to 40oC for 10 minutes. After stirring for one hour at room temperature the reaction mixture was evaporated in vacuum, the Organic phase was dried over anhydrous sodium sulfate and filtered through a plug of silica gel, elwira with ethyl acetate. Evaporation of the solvent in vacuo gave an oil, which when crushed with hexane gave 0.36 g specified in the title compound as a colourless powder, so pl. 100-102oC. MS (+FAB), m/z: 482 (M+Na)+, 460 (M+N)+.

Example 88
(3-Bromo-5H, 11N-pyrrolo[2,1-c] [1,4] benzodiazepine-10-yl)-[2-chloro-4-(3-methylpyrazole-1-yl)-phenyl]-methanon
To mix pre-cooled solution of [2-chloro-4-(3-methylpyrazole-1-yl)-phenyl] -(5H,11H-pyrrolo[2,1-C][1,4]benzodiazepine-10-yl)-methanone (1,61 g) in dichloromethane (25 ml) was added solid N-bromosuccinimide (0,712 g) for 10 minutes at -78oC. the Reaction was allowed to warm to -40aboutWith over thirty minutes. The mixture was diluted with dichloromethane and extracted sequentially with saturated aqueous sodium bicarbonate solution (2 x 100 ml) and water (100 ml). The organic phase was dried over anhydrous sodium sulfate, filtered through a plug of silica gel and evaporated in vacuo to a residue. Crystallization from diethyl ether gave 1.47 g specified in the title compound as a colourless solid, so pl. 148-149oC (decomp.). MS (El) m/z: 480 (M)+.

Example 89
(4-Bromo-2-chlorophenyl)-(5H, 11H-pyrrolo[2,1-C] [1,4]benzodiazepine-10-yl)-methanon
Dimethylformamide oxalicacid (1,46 g) and the mixture was heated to boiling (under reflux). The resulting solution was cooled to ambient temperature, then evaporated to dryness to obtain crude 4-bromo-2-chlorobenzylchloride in the form of a viscous liquid gold, which was used without further purification.

To a mixture of 10,11-dihydro-5H-pyrrolo[2,1-C] [1,4]benzodiazepine (1.44 g) and triethylamine (0.95 g) in dichloromethane (40 ml), cooled in a bath of ice, was added dropwise a solution of 4-bromo-2-chlorobenzylchloride (2,42 g) in dichloromethane (20 ml). The cooling bath was removed and after stirring for 22 hours, the reaction mixture was washed successively with water, saturated aqueous sodium bicarbonate, and 0.5 N. hydrochloric acid and water. Solution in dichloromethane was dried over anhydrous sodium sulfate, filtered, then evaporated in vacuum to dryness to obtain whitish foam. Purification with flash chromatography on silica gel with buyowner a mixture of hexane/ethyl acetate (2: 1) resulted in a white foam (3,02 g), so pl. 77-80oC. MS m/z: 400 (M)+.

Example 90
[2-Bromo-4-(3-methylpyrazole-1-yl)-phenyl] -(5H, 11N)-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl]-methanon
Stage a): 4-fluoro-2-bromobenzoate. Dimethylformamide (2 drops) was added to a solution of 4-fluoro-2-bromobenzoyl acid (4,91 g) in anhydrous tetrahydro the initial solution was cooled to room temperature, evaporated in vacuo to obtain the crude acid chloride in the form of a viscous liquid gold, which was used without further purification.

Stage b): (4-fluoro-2-bromophenyl)-(5H,11H-pyrrolo[2,1-C][1,4]benzodiazepine-10-yl)-methanon. A solution of 4-fluoro-2-bromobenzonitrile (5.32 g) from stage a) in dichloromethane (35 ml) was added dropwise to a solution of 10,11-dihydro-5H-pyrrolo[2,1-C][1,4]benzodiazepine (3,44 g) and triethylamine (2,27 g) in dichloromethane (80 ml) and cooled in a bath of ice. The cooling bath was removed and after stirring for 16 hours the reaction mixture was washed successively with water, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. Solution in dichloromethane was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuum to obtain a pale purple foam. Purification with flash chromatography on silica gel with elution by the mixture hexane/ethyl acetate (1: 1) resulted in intermediate product - (4-fluoro-2-bromophenyl)-(5H, 11N-pyrrolo[2,1-C][1, 4]benzodiazepine-10-yl)-methanone in the form of a reddish-brown foam (6,91 g). MS, m/z: 384 (M)+. This substance was used without further purification in the next stage.

Stage C): [2-bromo-4-(3-methylpyrazole-1-yl)-phenyl] -(5H, 11N)-pyrrolo[2,1-C][1,4]Ben is whether in dimethylformamide (15 ml). To this suspension was added 3-methylpyrazole (0,41 g). After the termination of allocation of gaseous hydrogen was added (4-fluoro-2-bromophenyl)-(5H, 11N-pyrrolo[2,1-C][1,4]benzodiazepine-10-yl)-methanon (1,74 g) from step b). The reaction mixture was heated to 130oC for 6 hours. After cooling the reaction mixture to room temperature it was poured into 50% saturated aqueous solution of sodium chloride and was extracted with ethyl acetate. The solution in ethyl acetate was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuum to obtain a brown oil. Purification with flash chromatography on silica gel with elution by the mixture hexane/ethyl acetate (1: 1) gave a colorless solid (0.75 g). Recrystallization from methanol gave a crystalline solid whitish (0,53 g), so pl. 141-14,2,5aboutC. MS m/z: 446 (M)+.

Example 91
(2,4-Differenl)-(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanon
Stage a): 2,4-differentiald. A suspension of 2,4-diferential acid (3.6 g) containing a few drops of dimethylformamide in dichloromethane (40 ml) was treated dropwise under nitrogen atmosphere by oxalylamino (2.4 ml). After cessation of gas evolution, the reaction mixture is boiled under reflux for 15 ,4-differenl)-(5H,11N-pyrrolo[2,1-C][1,4]benzodiazepine-10-yl)-methanon. To a solution of the crude 2,4-differentiald stage a) in dichloromethane under nitrogen atmosphere was added solid 10,11-dihydro-5H-pyrrolo[2,1-C] [1,4] benzodiazepines (2.0 g) and diisopropylethylamine (3.4 ml). The reaction mixture became yellow-orange. After stirring at room temperature for 10 minutes the reaction mixture was washed with water, 1 N. hydrochloric acid, 1 N. sodium hydroxide and salt solution. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness to obtain a brown solid. The crude product was purified column chromatography on silica gel (Merck-60) with elution with a mixture of 20% ethyl acetate/hexane to obtain 2.9 g specified in the title compound as a white foam. MS (El) m/z: 324 (M)+.

Example 92
[2-Fluoro-4-(3-methylpyrazole-1-yl)-phenyl] -(5H, 11N-pyrrolo[2,1-C][1,4]benzodiazepine-10-yl)-methanon
The suspension is washed with hexane 60% sodium hydride (0.31 g) in anhydrous dimethylformamide was treated dropwise 3-methylpyrazole (of 0.62 ml) in nitrogen atmosphere at room temperature. Stirring is continued until, until gas evolution ceased (about 10 minutes). In one portion was added (2,4-differenl)-(5H, 11N-pyrrolo[2,1-C][1,4]benzodiazepine-10-yl)-metanephridial heated oil bath at 130oC for one hour. After cooling, the mixture was distributed between water and ethyl acetate. The organic extracts were dried over anhydrous sodium sulfate and evaporated to dryness. The crude product was purified column flash chromatography on silica gel (Merck-60), elwira a mixture of 20% ethyl acetate/hexane to obtain 0,82 g specified in the connection header in the form of a foam, which was led by sonication of a mixture of ethanol/hexane, so pl. 192-193oC. MS (EI) m/z: 386 (M)+.

Example 93
Methyl-4-(3-methylpyrazole-1-yl)-2-cryptomelane
Stage a): methyl-4-fluoro-2-cryptomelane. A suspension of 4-fluoro-2-triftorperasin acid (25.6 g) and a few drops of dimethylformamide in dichloromethane (250 ml) was treated dropwise in atmosphere nitrogen oxalylamino (11.3 ml). After cessation of gas evolution, the reaction mixture is boiled under reflux for an additional 15 minutes. The reaction was cooled and was added methanol (50 ml). After stirring for 2 hours the reaction was evaporated in vacuum and
the residue was distributed between dichloromethane and water. The organic phase is washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate and was evaporated to dryness with polucionados 2 N. hydrochloric acid to obtain a colorless solid, which was collected by filtration to obtain 7.5 g of the original benzoic acid.

Stage b): methyl-4-(3-methylpyrazole-1-yl)-2-cryptomelane. The suspension is washed with hexane 60% sodium hydride (of 3.85 g) in anhydrous dimethylformamide (150 ml) was treated by adding (dropwise) a solution of 3-methylpyrazole (of 7.75 ml) in dimethylformamide (50 ml) under nitrogen atmosphere at room temperature. Stirring was continued until gas evolution stops (10 minutes). To the clear solution was added dropwise a solution of methyl-4-fluoro-2-triftoratsetata (17.8 g) from stage a) in dimethylformamide (50 ml). After stirring for 30 minutes at room temperature the reaction was suppressed saturated ammonium chloride and was extracted with ethyl acetate. Organic extracts (3x) were dried over anhydrous sodium sulfate and evaporated to dryness. The crude product was purified column flash chromatography on silica gel (Merck-60), elwira gradient dichloromethane/hexane (50%-75%) with the receipt of 13.6 g specified in the title compound as a colourless solid, so pl. 59-61oC. MS (EI) m/z: 284 (M)+.

Example 94
4-(3-Methylpyrazole-1-yl)-2-triftorperasin acid
Mate and a solution of 2.5 N. sodium hydroxide (3.3 ml). The reaction was heated at boiling under reflux for 90 minutes, cooled to room temperature and evaporated in vacuum to dryness. The residue was distributed between ethyl acetate and 1 N. hydrochloric acid. The combined organic extracts were dried over anhydrous sodium sulfate and evaporated in vacuum to obtain 1,14 g specified in the title compound as a colourless solid. MS (+FAB), m/z: 271 (M+N)+.

Example 95
[4-(3-Methylpyrazole-1-yl)-2-triptoreline] -(5H, 11H-pyrazolo[5,1-C] [1,4]benzodiazepine-10-yl)-methanon
A solution of 4-(3-methylpyrazole-1-yl)-2-triftorperasin acid (0.26 g) from example 94 in tetrahydrofuran (5 ml) was treated with dimethylformamide (0,020 ml), then oxalylamino (0,090 ml). The solution was stirred at room temperature until gas evolution stops and then the solution was heated under reflux to boiling for 10 minutes. The sample was cooled to room temperature, evaporated to a solid, and this solid substance was dissolved in tetrahydrofuran (25 ml). This solution was added to solution (5H-10,11-dihydropyrazolo[5,1-C] [1,4] benzodiazepine (0,143 g) and triethylamine (0,150 ml) in tetrahydrofuran (20 ml). The solution was stirred in techina and then the sample was evaporated in a vacuum to about 1/3 the original volume. This sample was distributed between dichloromethane and saturated aqueous ammonium chloride. The sample was extracted with dichloromethane and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and evaporated to oil. The oil was subjected to flash chromatography on silica gel using a gradient of 40% ethyl acetate/hexane - 100% ethyl acetate to obtain specified in the title compound as a foam (0,30 g). Part of this material was recrystallized from a mixture of acetone/hexane with getting heavy plates, so pl. 100-102oC. MS m/z: 437 (M)+.

Example 96
2-Chloro-4-(3-methyl-1H-pyrazole-1-yl)-benzoic acid, methyl ester and 2-chloro-4-(5-methyl-1H-pyrazole-1-yl)-benzoic acid, methyl ester
The suspension is washed with hexane potassium hydride (0,424 g) in dimethylformamide (5 ml) was treated with a single dose of 3-methylpyrazole (0,85 ml) under stirring. After cessation of gas to the transparent solution was added methyl ether 2-chloro-4-fermenting acid (2.0 g) and was heated at 130oC for 15 minutes. The reaction mixture was cooled to room temperature and distributed between ethyl acetate and brine. The organic phase is washed with water, brine and dried over anhydrous sulfate NLI by analysis of the NMR spectrum of the crude product). Target regioisomer - methyl ester 2-chloro-4-(3-methyl-1H-pyrazole-1-yl)-benzoic acid was isolated from the other isomer (described below) column flash chromatography on silica gel (Megs-60) with elution with a mixture of dichloromethane/hexane (2:1), which gave 1.55 g specified in the title compound as a colourless solid. MS (EI) m/z: 250/252 (M)+.

5-regioisomer, namely methyl ester 2-chloro-4-(5-methyl-1H-pyrazole-1-yl)-benzoic acid was isolated by using column flash chromatography on silica gel (Merck-60) further elution with a mixture of dichloromethane/hexane (2: 1) gave 0.20 g of the product as a colourless solid. MS (EI) m/z: 250/252 (M)+.

Example 97
2-Chloro-4-(3-methyl-1H-pyrazole-1-yl)-benzoic acid
A solution of methyl ester of 2-chloro-4- (3-methyl-1H-pyrazole-1-yl)-benzoic acid (1.42 g) from example 96 and 6 ml of 1 M aqueous lithium hydroxide in tetrahydrofuran (20 ml) was stirred for 18 hours at room temperature. The reaction mixture was distributed between ethyl acetate and 1 N. hydrochloric acid. The organic layer was washed with water, brine and dried over anhydrous sodium sulfate. Evaporation of the solvent in vacuo gave 1,05 g is specified in the header of the connection one-3-yl)-(5H, 11N-pyrrolo[2,1-C] [1,4]benzodiazepine-10-yl)-methanon
A solution of 2,6-dichloronicotinic acid (3,84 g), oxalicacid (2.0 g) and 1 drop of dimethylformamide in dichloromethane (25 ml) was stirred at room temperature for 18 hours. The solution was evaporated in vacuum to obtain 3.50 g of 2,6-dichloronicotinic, which was added by portions in dichloromethane (25 ml) cooled on ice to a solution of 10,11-dihydro-5H-pyrrolo[2,1-C][1,4] benzodiazepine (2.15 g) and diisopropylethylamine (2,03 g) in dichloromethane (50 ml). The mixture was stirred at room temperature for 18 hours and washed with saturated aqueous sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate and filtered through a short column of anhydrous sodium silicate is magnesium. The combined organic phase was evaporated on a hot plate with gradual addition of hexane until until crystallization occurred. After cooling, the crystals were collected by filtration to obtain 2.65 g of the specified header connection in the form of amorphous solids, so pl. 115-130oC. MS m/z: 358,1 (M+N)+.

Example 99
(2-Chloro-6-pyrazole-1-yl-pyridine-3-yl)-(5H,11N-pyrrolo[2,1-C][1,4]benzodiazepine-10-yl)-methanon
To a suspension of 60% sodium hydride in oil (0.1 g) is Yes, was added 2,6-dichloropyridine-3-yl)-(5H,11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanon (0,67 g) and the reaction mixture was heated in a sand bath at 110aboutC for 18 hours. The mixture is poured into ice, diluted saline solution and was extracted with dichloromethane. The combined extracts were dried over anhydrous sodium sulfate and filtered through a short column of anhydrous sodium silicate is magnesium. The solution was evaporated in vacuo and triturated with diethyl ether to obtain 0.18 g specified in the title compound as a colourless solid, so pl. 133-l35oC. MS m/z: 390,8 (M+N)+, 779,1 (2M+N)+.

Example 100
[2-Chloro-6-(3-methylpyrazole-1-yl)-pyridin-3-yl] -(5H, 11N-pyrrolo[2,1-C] [1,4]benzodiazepine-10-yl)-methanon
To a suspension of 60% sodium hydride in oil (0.1 g) in dimethylformamide (25 ml) was added dropwise 3-methylpyrazole (0.15 g). After the termination of allocation of gaseous hydrogen was added 2,6-dichloropyridine-3-yl)-(5H, 11H-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanon (0,67 g) and the reaction mixture was heated in a sand bath at 110oC for 18 hours. The mixture is poured into ice, diluted saline solution and was extracted with dichloromethane. The combined extracts were dried over anhydrous sodium sulfate and filtered through a short column of anhydrous sodium silicate is magnesium. The crude product was purified preparative HPLC (cassette duaringa silicon Dynamax C60 404,2 (M+N)+, 807,1 (2M+N)+.

Example 101
[2-Chloro-6-(4-methylpyrazole-1-yl)-pyridin-3-yl] -(5H, 11N-pyrrolo[2,1-C] [1,4]benzodiazepine-10-yl)-methanon
To a suspension of 60% sodium hydride in oil (0.1 g) in dimethylformamide (25 ml) was added dropwise 3-methylpyrazole (0.45 g). After the termination of allocation of gaseous hydrogen was added 2,6-dichloropyridine-3-yl)-(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanon (1,79 g) and the reaction mixture was heated in a sand bath at 110AboutC for 18 hours. The mixture is poured into ice, diluted saline solution and was extracted with dichloromethane. The combined extracts were dried over anhydrous sodium sulfate and filtered through a short column of anhydrous sodium silicate is magnesium. The crude product was purified preparative HPLC (cassette tape silicon dioxide Dynamax c60 silica cartridge) with elution with 40% ethyl acetate in hexano that gave 0.26 g of colorless crystals, so dps, 155-156oC. MS m/z: 404,2 (M+N)+, 807,0 (2M+N)+.

Example 102
[2-Chloro-4-(3-methyl-1,2,4-triazole-1-yl)-phenyl] -(5H, 11N-pyrrolo[2,1-C] [1,4]benzodiazepine-10-yl)-methanon
To a suspension of 60% sodium hydride in oil (0.3 g) in dimethylformamide (50 ml) was added dropwise 3-methyl-1,2,4-triazole (0.45 g). After the termination of allocation of gaseous hydrogen was added to the offered bath at 110oC for 18 hours. The mixture is poured into ice, diluted saline solution and was extracted with dichloromethane. The combined extracts were dried over anhydrous sodium sulfate and filtered through a short column of anhydrous sodium silicate is magnesium. The solution was evaporated in vacuo and the residue triturated with diethyl ether to obtain 1.25 g specified in the title compound as colourless crystals, so pl. 191-193oC. MS m/z: 404,1 (M+N)+.

Example 103
[4-(3-Methyl-1,2,4-triazole-1-yl)-2-triptoreline] -(5H, 11N-pyrrolo[2,1-C][1,4]benzodiazepine-10-yl)-methanon
To a suspension of 60% sodium hydride in oil (0.3 g) in dimethylformamide (50 ml) was added dropwise 3-methyl-1,2,4-triazole (0.45 g). After the termination of allocation of gaseous hydrogen was added 4-fluoro-2-triptoreline-(5H, 11N-pyrrolo[2,1-C] [1, 4]benzodiazepine-10-yl)-methanon (1,76 g) and the reaction mixture was heated in a sand bath at 110oC for 18 hours. The mixture is poured into ice, diluted saline solution and was extracted with dichloromethane. The combined extracts were dried over anhydrous sodium sulfate and filtered through a short column of anhydrous sodium silicate is magnesium. The solution was evaporated in vacuo and the residue triturated with diethyl ether to obtain 0,81 g University)+.

Example 104
4 Hydrazino-2-methoxybenzoic acid, methyl ester, hydrochloride (1: 1), hydrate (2:1)
Stir a suspension of methyl ester of 4-amino-2-methoxybenzoic acid (21,74 g) in concentrated hydrochloric acid (110 ml) which was cooled to -10oC, was treated with pre-cooled solution of sodium nitrite (8.5 g) in water (45 ml) at a speed necessary to maintain the reaction temperature below 0oC. After complete addition, the reaction mixture was stirred at -2oC for 10 minutes. The obtained turbid orange solution was added dropwise to vigorously stir pre-cooled solution of chloride dihydrate tin(II) (101 g) in concentrated hydrochloric acid (67 ml) at -10oC. the Rate of addition was controlled so as to maintain the reaction temperature below -5oC. After adding the cream-colored suspension was heated to room temperature and the solid was filtered. This solid is washed with diethyl ether and dried over anhydrous sodium sulfate to obtain 52 g of the crude product. The crude product (20 g) was distributed between water and 2.5 N. HYDROFORM and dried over anhydrous magnesium sulfate. Filtration and evaporation of solvent in vacuo gave a solid cream color (7,1 g), which on treatment with one equivalent of a solution of anhydrous hydrogen chloride in diethyl ether gave specified in the title compound in the form of monohydrochloride salt, so pl. 76-79oC. MS m/z: 197 (M+N)+.

Example 105
2-Methoxy-4-(3-methylpyrazole-1-yl)-benzoic acid, methyl ester
To a stirred solution of methyl ester hydrochloride 4-hydrazino-2-methoxybenzoic acid (0.88 g) from example 104 and one drop of concentrated hydrochloric acid in a mixture of 1:1 water/methanol (10 ml) was added dimethylacetal of acetylaldehyde (0,53 g). The reaction was heated to 90oC for 5 minutes, the reaction was evaporated in vacuum and distributed between 1 N. sodium hydroxide (10 ml) and ethyl acetate (50 ml). The organic phase was removed and washed with saline, dried over anhydrous magnesium sulfate and filtered. Evaporation of the solvent in vacuo gave a brown oil which was combined with the previous batch (0.54 g) and recrystallized three times from isopropyl ether to obtain methyl ester 2-methoxy-4-(3-methylpyrazole-1-yl)-benzoic acid (0.5 g), so pl. 167-169oC. MS m/z: 246 (M)+<-4-(3-methylpyrazole-1-yl)-benzoic acid (0.5 g) from example 105 in tetrahydrofuran (2.5 ml) was treated with 1 N. the lithium hydroxide (2,13 ml) at room temperature. After 14 hours the solvent was removed in vacuum and is listed in the title compound was besieged taken at 0oWith 1 N. hydrochloric acid. After drying in vacuum at 0.42 g specified in the title compound was obtained as a solid substance. MS, m/z: 232 (M)+.

Example 107
[2-Methoxy-4-(3-methylpyrazole-1-yl)-phenyl] (5H,11N-pyrrolo[2,1-C][1,4]benzodiazepine-10-yl)-methanon
Oxalicacid (0.17 ml) was added to a stirred solution of 2-methoxy-4-(3-methylpyrazole-1-yl)-benzoic acid (0,41 g) from example 106 and dimethylformamide (0,004 ml) in anhydrous tetrahydrofuran (10 ml). The reaction was heated at 35oWith in ten minutes. The resulting solution was evaporated in vacuum to obtain the crude carbonylchloride 2-methoxy-4-(3-methylpyrazole-1-yl)-benzoic acid. After evaporation in conjunction with dichloromethane acid chloride was dissolved in dichloromethane (10 ml) and added 10,11-dihydro-5H-pyrrolo[2,1-C] [1,4]benzodiazepine (0.31 g). Added diisopropylethylamine (0,37 ml) and the reaction was stirred at room temperature for 2 hours. The reaction was diluted with dichloromethane and washed with water and then with 1 N. hydrochloric acid. The organic phase is washed salt ROI flash chromatography on silica gel, elwira a mixture of hexane/ethyl acetate (2: 1) to obtain 0.35 g specified in the title compound as a colourless solid, so pl. 92-94oC.

Example 108
(3-Dimethylaminomethyl-5H, 11N-pyrrolo[2,1-C][1,4]benzodiazepine-10-yl)[2-methoxy-4-(3-methylpyrazole-1-yl)phenyl]-methanon
To a stirred solution of [2-methoxy-4-(3-methylpyrazole-1-yl)-phenyl](5H, 11N-pyrrolo[2,1-C][1,4]benzodiazepine-10-yl)-methanone of example 107 (0,57 g) in warm methanol (10 ml) was added N,N,N',N'-tetramethylguanidine (0,392 ml) and acetic acid (0,164 ml). After addition of 37% aqueous formalin solution (2.9 ml) the reaction was stirred for fifteen minutes. The mixture was evaporated in vacuum and was distributed between dichloromethane and sodium bicarbonate. The organic phase was removed, washed with saline and dried over anhydrous magnesium sulfate. The solution was filtered and the solvent was removed in vacuum. The residue was purified column flash chromatography on silica gel, elwira a mixture of chloroform/methanol (50: 1) to obtain a solid substance. Recrystallization of this solid from acetone gave specified in the title compound as a colourless solid, so pl. 196-198oC.

Example 109
[2-Hydroxy-4-(3-methylpyrazole-1-yl] (5H, 11N-pyrrolo[2,1-C]-yl)-methanon (0,82 g) from example 107 was dissolved in dichlormethane (20 ml) and cooled to -78oC. was Added tribromide boron (6.2 ml) and the reaction was stirred at 0aboutWith in five minutes. Was added ammonium hydroxide (15 ml) and was extracted with dichloromethane. The organic phase is washed with saline and dried over anhydrous magnesium sulfate. The solid was removed by filtration and the solvent was removed in vacuum. The residue was purified column flash chromatography on silica gel, elwira a mixture of hexane/ethyl acetate (3:1, then 2:1) to obtain the 0,19 g specified in the title compound as a colourless solid, so pl. 134-136oC.

Example 110
2-Chloro-4-identia acid, methyl ester
Methyl ester of 4-amino-2-methoxybenzoic acid (22,97 g) was cooled to an internal temperature of -10oWith concentrated hydrochloric acid (110 ml) and stirred in suspension. To this mixture was added a pre-cooled solution of sodium nitrite (98,71 g) in water (45 ml) at such a speed that allows you to maintain the reaction temperature below 0oC. After stirring for 25 minutes at 0oThe reaction was treated with a solution of potassium iodide (24,44 g) and iodine (18,37 g) in water (50 ml) at such a speed that allows you to maintain the reaction temperature below -4oC. In PR is an increase of one hour. The organic layer was diluted with ethyl acetate and well washed with saturated aqueous sodium thiosulfate. The obtained orange solution was washed with saline and dried over anhydrous magnesium sulfate. The solvent is evaporated in vacuum to obtain an oil, which was purified by filtration with suction through silica gel, elwira a mixture of hexane/ethyl acetate (50:1). The obtained oil was purified aterials while cooling with education 33,71 g specified in the connection header. MS, m/z: 296 (M)+.

Example 111
4-Bromo-1-methyl-1H-pyrazole
To a suspension of pre-washed (tetrahydrofuran) of 60% sodium hydride in oil (11,67 g) in tetrahydrofuran (200 ml) was added dropwise a solution of 4-bromopyrazole (39,77 g) in tetrahydrofuran (50 ml). The solution was stirred at room temperature for two hours. Added excess iodomethane (33 ml) in tetrahydrofuran (50 ml) at such a speed that was necessary to maintain a small increase in temperature. The reaction was stirred additionally for two hours. The solvent was removed in vacuum and the residue was stirred in diethyl ether. The precipitate was removed by filtration with suction and washed with diethyl ether. The combined organic phase is Example 112
1-Methyl-4-tributylstannyl-1H-pyrazole
To pre-cooled (internal temperature <-10C) a solution of 1.6 M n-utility in hexano (100 ml) in anhydrous diethyl ether (100 ml) in an argon atmosphere was added a solution of 4-bromo-1-methyl-1H-pyrazole (23,42 g) from example 111 in diethyl ether (50 ml) at a speed necessary to maintain this temperature. The reaction was allowed to mix for 20 minutes before adding the presence of TBT chloride (43,4 ml) in diethyl ether (50 ml). The reaction temperature was allowed to rise to 20oC. the Reaction was diluted with diethyl ether and the insoluble material was removed by filtration with suction. Evaporation of the solvent in vacuo gave 56 g specified in the connection header in the form of oil. MS, m/z: 373 (M+N)+. The residual amount of residual tin was removed from the oil by distillation using an apparatus with ball refrigerator in a high vacuum at 170oC.

Example 113
2-Chloro-4-(1-methyl-1H-pyrazole-4-yl)-benzoic acid, methyl ester
Degassed with argon a solution in dimethylformamide (70 ml) methyl ether 3-chloro-4-iodobenzoyl acid (25.4 g) from example 110, 1-methyl-4-tributylstannyl-1H-pyrazole (31,77 g), tetrakis(triphenylphosphine)palladium(0) (1.8 g) and catalyt who was armirovali on silica gel. Purification by filtration with suction through a bed of silica gel with elution successively with hexane and then hexane/ethyl acetate (2:1) gave, after evaporation of the solvent the solid residue, which was recrystallized from diisopropyl ether to obtain of 7.82 g specified in the connection header. MS, m/z: 250 (M)+.

Example 114
2-Chloro-4-(1-methyl-1H-pyrazole-4-yl)-benzoic acid
To a solution of methyl ester of 2-chloro-4-(1-methyl-1H-pyrazole-4-yl)-benzoic acid (6.25 g) from example 113 in methanol (80 ml) was added 1 n sodium hydroxide (30 ml). The reaction was heated under reflux for one hour. The volume of solvent was reduced in vacuo by three quarters, and the residue was treated, 2 N. hydrochloric acid at 0oC. the Precipitate was filtered and was dried over anhydrous sodium sulfate in a vacuum with the receipt of 5.84 g specified in the connection header. MS, m/z: 237 (M+N)+.

Example 115
[2-Chloro-4-(1-methyl-1H-pyrazole-4-yl)phenyl] -(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanon
Oxalicacid (0,49 ml) was added to a solution of 2-chloro-4-(1-methyl-1H-pyrazole-4-yl)-benzoic acid (0,41 g) from example 114 and dimethylformamide (0,012 ml) in anhydrous tetrahydrofuran (20 ml). The reaction was heated at 35oWith more than what-chloro-4-(1-methyl-1H-pyrazole-4-yl)-benzoic acid. After evaporation together with anhydrous dichloromethane acid chloride was dissolved in dichloromethane (20 ml), then added 10,11-dihydro-5H-pyrrolo[2,1-C] [1,4]benzodiazepine (0,888 g) and diisopropylethylamine (1,06 ml). The resulting solution was stirred at room temperature for 2 hours. The reaction was diluted with dichloromethane and washed with water, then with 1 N. hydrochloric acid. The organic phase is washed with saline and dried over anhydrous magnesium sulfate. Solution in dichloromethane was filtered and was evaporated to dryness in vacuum. The residue was purified column flash chromatography on silica gel, elwira a mixture of hexane/ethyl acetate (2:1) to obtain 1.4 g specified in the title compound as a colourless solid, so pl. 105-109oC.

Example 116
[2-Chloro-4-(3-methylpyrazole-1-yl)-phenyl] -(4H, 10H-pyrazolo[5,1-C] [1,4]-benzodiazepine-5-yl)-methanon
To a solution of 2-chloro-4-(3-methylpyrazole-1-yl)-benzoyl chloride (0,214 g) stage f) of example 18 in dichloromethane (10 ml) was added 5H-10,11-dihydropyrazolo[5,1-C] [1,4]benzodiazepine (0,153 g) and diisopropylethylamine (0,173 ml). The reaction was stirred at room temperature for 2 hours. The reaction was diluted with dichloromethane and washed with water, then with 1 N. hydrochloric acid. Organicism is Ali and evaporated in vacuum to dryness. The residue was purified column flash chromatography on silica gel, elwira under pressure with a mixture of hexane/ethyl acetate (1:1), with 0.3 g specified in the title compound as a colourless solid, so pl. 187-188oC.

Example 117
2-Chloro-4-(3-methylpyrazole-1-yl)-phenyl] -(5,10-dihydro-4H-tetrazolo[5,1-C] [1,4]benzodiazepine-5-yl)-methanon
To a solution of 2-chloro-4-(3-methylpyrazole-1-yl)-benzoyl chloride (0.18 g) stage f) of example 18 in dichloromethane (10 ml) was added 10,11-dihydro-5H-tetrazol[5,1-C] [1,4] benzodiazepine (0,13 g) and diisopropylethylamine (0,145 ml). The reaction was stirred at room temperature for 2 hours. The reaction was diluted with dichloromethane and washed with water, and then 1 N. hydrochloric acid. The organic phase is washed with saline and dried over anhydrous magnesium sulfate. Solution in dichloromethane was filtered and evaporated in vacuum to dryness. The residue was purified column flash chromatography on silica gel, elwira a mixture of hexane/ethyl acetate (1:1), to obtain 0.14 g specified in the title compound as a colourless solid, so pl. 110-114oC.

Example 118
1-[4-(4H,10H-Pyrazolo[5,1-C][1,4]benzodiazepine-5-carbonyl)-phenyl]-alanon
A mixture of 5,10-dihydro-4H-pyrazolo[5,1-c][1,4]benzodiazepine (0,555 g), 4-acetylene for 4 hours. The mixture was poured into water and was extracted with dichloromethane. The dichloromethane extract was washed with saturated sodium bicarbonate, water and brine and dried over anhydrous sodium sulfate. The extract was filtered through a thin cushion of water magnesium silicate and the filter cushion washed with dichloromethane. The filtrate was evaporated in vacuum to obtain 1,53 g yellow solid. Rubbing this solids with ethyl acetate gave of 0.741 g specified in the title compound as a glassy product, so pl. 201-210oC. Uterine solutions remaining after grinding, was evaporated and the residue (0,30 g) was chromatographically on the plates with a thick layer of silica gel (200 microns) using a mixture of hexane/ethyl acetate (1:1) as solvent. The solid is triturated with ethyl acetate and combined with 0,747 g initially selected product. The combined solids were besieged from a mixture of dichloromethane/hexane to obtain 0.73 g of product as a glassy substance.

Example 119
1-[4-(4H, 10H-Pyrazolo[5,1-c] [1,4] benzodiazepine-5-carbonyl)-phenyl]-3-(dimethylamino)-prop-2-EN-1-it
A mixture of 1-[4-(4H, 10H-pyrazolo[5,1-c][1,4]benzodiazepine-5-carbonyl)phenyl] -ethanone (0.73 g), tert-butoxybis(dimethylamino)methane (koume and the residue was led from a mixture of dichloromethane/hexane to obtain 0.65 g specified in the title compound as yellow crystals, so pl. 225-230oC.

Example 120
[4-(1-Methyl-1H-pyrazole-3-yl)phenyl]-(4H,10H-pyrazolo[5,1-C][1,4]benzodiazepine-5-yl)methanon (isomer a) and [4-(2-methyl-1H-pyrazole-3-yl)phenyl] -(4H, 10H-pyrazolo[5,1-C][1,4]benzodiazepine-5-yl)methanon (isomer B)
A mixture of 1-[4-(4H,10H-pyrazolo[5,1-C][1,4]-benzodiazepine-5-carbonyl)phenyl] -3-(dimethylamino)-prop-2-EN-1-it (0,83 g), hydrazine (0,198 g) and acetic acid (0,336 g) in 10 ml of ethanol was boiled under reflux for 4 hours. Volatile components were removed in vacuum and the residue was dissolved in dichloromethane. The solution was washed with water, 1 N. sodium bicarbonate, water and brine and dried over anhydrous sodium sulfate. The solution was filtered through a thin cushion of water magnesium silicate and the filter cushion washed with ethyl acetate. The filtrate was evaporated in vacuum to obtain 0.56 g of light yellow solid. The solid was chromatographically on the plates with a thick layer of silica gel (200 microns) with ethyl acetate as solvent to obtain 0.35 g of a white solid substance in the form of a mixture of a and b (1: 4). Multiple fractionated (fractional) crystallization from ethyl acetate to give 89 mg of the crystals, so pl. 155-156oWith, in the form of a mixture of a and b (9:1) and 65 mg of a glassy product in the form of a mixture of a and b (1:6).o
With over 80 hours. The solution was cooled to room temperature, the solvent was removed in vacuum and the residue was distributed between dichloromethane and water. The dichloromethane extract was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a brown foam. Purification with flash chromatography on silica gel with elution by the mixture hexane/ethyl acetate (1: 1) resulted in acetylene intermediate product in the form of whitish foam (2,11). MS, m/z: 418 (M)+. This product was used without further purification in the next stage.

Stage b). 1% solution of sulfuric acid in tetrahydrofuran saturated sulfate mercury(II). Intermediate acetylene (1,00 g) in tetrahydrofuran (5 ml) was stirred for 50 hours with 30 ml of the above solution of sulphate of mercury(II) in tetrahydrofuran. Added additional amount of sulfate mercury(II) (0.01 g) smetana. The dichloromethane solution was washed successively with saturated aqueous sodium bicarbonate solution and water. The dichloromethane solution was dried over anhydrous magnesium sulfate, filtered and evaporated to dryness to obtain a brown solid. Purification with flash chromatography on silica gel with elution by the mixture hexane/ethyl acetate (1:1) gave a white solid (0,30 g), so pl. 98-100oC. MS m/z: 364 (M)+.

Example 122
1-[4-(5H, 11H-Pyrrolo[2,1-C][1,4]benzodiazepine-10-carbonyl)-3-chlorophenyl] -alanon
Tributyl(ethoxyphenyl)tin (1,17 g) was added to a solution of (4-bromo-2-chlorophenyl)-(5H, 11N-pyrrolo[2,1-C] [1,4]benzodiazepine-10-yl)-methanone (1.24 g) in toluene (10 ml). The resulting solution was purged with nitrogen for 10 minutes, then was added bis(triphenylphosphine)palladium(II)chloride (0.11 g). The reaction mixture was heated under reflux to boiling for 24 hours. The solution was cooled to room temperature and was added 5% aqueous hydrochloric acid (10 ml). After stirring for one hour the mixture was filtered through a bed of diatomaceous earth. To the filtrate was added diethyl ether (5 ml) and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filter is imagele with elution by the mixture hexane/ethyl acetate (1:1) gave a white solid (0,30 g). MS, m/z: 364 (M)+.

Example 123
[2-Chloro-4-(3-methyl-4-ethynylphenyl)-(5H, 11N-pyrrolo[2,1-C] [1,4]benzodiazepine-10-yl)-methanon
Treatment of intermediate stage acetylene And example 121 1 M solution of tetrabutylammonium in tetrahydrofuran at room temperature was provided when the solvent is 84% yield specified in the title compound as an orange-yellow solid, so pl. 84-86oC. MS m/z: 346 (M)+.


Claims

1. Tricyclic compounds of General formula (I)

where a and b independently denote CH or nitrogen;
D means C-W or nitrogen;
W stands for hydrogen, halogen, C1-6-alkyl or the group CH2NR6R7;
where R6and R7independently mean C1-6-alkyl straight chain;
E and G means simultaneously CH or nitrogen;
R1denotes alkanoyl containing 2-7 carbon atoms, a group selected from CN, CONH2or a residue selected from the groups (a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k) and (m)





r />R3and R5mean hydrogen or C1-6alkyl straight chain,
R4denotes hydrogen, C1-6alkyl straight chain, alkoxyalkyl containing 2-7 carbon atoms, cycloalkenyl containing 3-7 carbon atoms, benzoyl, substituted with halogen, C1-6cycloalkyl or phenyl, which in turn is unsubstituted or substituted CF3or thiofentanyl;
X denotes hydrogen;
Y denotes hydrogen, C1-6alkyl straight chain, With1-6alkoxy, hydroxy, halogen or CF3,
or their pharmaceutically acceptable salts.

2. Connection on p. 1, having the formula (I)

where a and b independently denote CH or nitrogen;
D means C-W or nitrogen;
E and G means simultaneously CH or nitrogen;
R1means alkanoyl containing 2-7 carbon atoms, or a residue selected from the groups (a), (b), (e), (f), (g), (h), (i) and (K):




R2, R3, R4, R5X, Y, W, R6and R7determined as specified in paragraph 1,
or its pharmaceutically acceptable salt.

3. Connection on p. 2 having the formula




R2, R3, R4, R5, X, Y, W, R6R7determined as specified in paragraph 1,
or its pharmaceutically acceptable salt.

4. Connection on p. 1 having the formula

where a, b, W, R1, R2, R3, R4, R5, R6, R7X and Y are defined as indicated in paragraph 1,
or its pharmaceutically acceptable salt.

5. Connection on p. 4, where W denotes H; a and b each represent CH and R1, R2, R3, R4, R5X and Y are defined as indicated in paragraph 1, or its pharmaceutically acceptable salt.

6. Connection on p. 1 formula

where a, b, R1, R2, R3, R4, R5X and Y are defined as indicated in paragraph 1,
or its pharmaceutically acceptable salt.

7. Connection on p. 1 formula

where a, b, R1, R2, R3, R4, R5X and Y are defined as indicated in paragraph 1,
or its pharmaceutically acceptable salt.

8. enzodiazepin-10-yl)-methanon,
[4-(4-methylpyrazole-1-yl)-2-triptoreline] -(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanon,
(4-pyrazole-1-yl-2-triptoreline)-(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanon,
[4-(3-cyclopropylmethyl-1-yl)-2-triptoreline] -(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanon,
[4-(4-Mei-1-yl)-2-triptoreline] -(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanon,
(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-(4-[1,2,4] -triazole-1-yl-2-triptoreline)-methanon,
[2-chloro-4-(3-methylpyrazole-1-yl)-phenyl] -(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanon,
[2-chloro-4-(5-methylpyrazole-1-yl)-phenyl] -(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanon,
[2-chloro-4-(4-methylpyrazole-1-yl)-phenyl] -(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanon,
[2-chloro-4-(4-Mei-1-yl)-phenyl] -(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanon,
[2-chloro-4-(3-cryptomaterial-1-yl)-phenyl] -(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanon,
[2-chloro-4-(1,2,4-triazole-1-yl)-phenyl] -(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanon,
(2-chloro-4-pyrrol-1-ylphenyl)-(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanon,
(2-chloro-4-pyrazole-1-ylphenyl)-(5H, 11H-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanon,
[2-chloro-4-(1H-imidazol-1-yl)-Hairdryer the olo[2,1-C] [1,4] benzodiazepine-10-yl)-methanon,
[2-(3-methylpyrazole-1-yl)-4-cryptomaterial-5-yl] -(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanon,
[2-(4-methylpyrazole-1-yl)-4-cryptomaterial-5-yl] -(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanon,
1-[4-(5H, 11H-pyrrolo[2,1-C] [1,4] benzodiazepine-10-carbonyl)phenyl] -Etalon,
[4-(1H-pyrazole-3-yl)-phenyl] -(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanon,
[4-(1-methyl-1H-pyrazole-3-yl)-phenyl] -(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanon,
[4-(1-ethyl-1H-pyrazole-3-yl)-phenyl] -(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanon,
[4-(1-propyl-1H-pyrazole-3-yl)-phenyl] -(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanon,
[4-(1-butyl-1H-pyrazole-3-yl)-phenyl] -(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanon,
[4-(1-methoxymethyl-1H-pyrazole-3-yl)-phenyl] -(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanon,
1-{ 3-[4-(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-carbonyl)-phenyl] -pyrazole-1-yl} -Etalon,
1-{ 3-[4-(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-carbonyl)-phenyl] -pyrazole-1-yl} -propane-1-he,
[4-(1-cyclopropanecarbonyl-1H-pyrazole-3-yl)-phenyl] -(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanon,
1-{ 3-[4-(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-carbonyl)-phenyl] -pyrazole-1-yl} -butane-1-he,
(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-{ 4-[1-(thiophene-2-[1,4] benzodiazepine-10-yl)-methanon,
{ 4-[1-(2-methylbenzoyl)-1H-pyrazole-3-yl] -phenyl} -(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanon,
{ 4-[1-(2-chloro-4-perbenzoic)-1H-pyrazole-3-yl] -phenyl} -(5H, 11N-pyrrolo[2,1-C] [1,4] -benzodiazepine-10-yl)-methanon,
{ 4-[1-(2,4-dichlorobenzoyl)-1H-pyrazole-3-yl] -phenyl} -(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanon,
2-(2,4-dichlorophenyl)-1-{ 3-[4-(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-carbonyl)-phenyl] -pyrazole-1-yl} -Etalon,
{ 4-[1-(biphenyl-2-carbonyl)-1H-pyrazole-3-yl] phenyl} -(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanon,
{ 4-[1-(4'-triptorelin-2-carbonyl)-1H-pyrazole-3-yl] -phenyl} -(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)methanon,
[4-(5-methyl-1H-pyrazole-3-yl)-phenyl] -(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanon,
(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-[4-(2H-[1,2,4] triazole-3-yl)-phenyl] -methanon,
[4-(2-methyl-2H-[1,2,4] triazole-3-yl)-phenyl] -(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanon,
[4-(5-methyl-2H-[1,2,4] triazole-3-yl)-phenyl] -(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanon,
[4-(2,5-dimethyl-2H-[1,2,4] triazole-3-yl)-phenyl] -(5H, 11H-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanon,
[4-(3-methyl[1,2,4] oxadiazol-5-yl)-phenyl] -(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanon,
[4-(1-methyl-1H-pyrazole-4-yl)-phenyl] -(5H, 11N-pyrrolo[2,1-C] [1,4] growing presence is,
[4-(pyrazole-1-yl)-phenyl] -(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanon,
[4-(3-methylpyrazole-1-yl)-phenyl] -(5H, 11N-pyrrolo[2,1-C] [1,4] -benzodiazepine-10-yl)-methanon,
[4-(4-methylpyrazole-1-yl)-phenyl] -(5H, 11N-pyrrolo[2,1-C] [1,4] -benzodiazepine-10-yl)-methanon,
[4-(3,5-dimethylpyrazol-1-yl)-phenyl] -(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanon,
(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-[4-(3-cryptomaterial-1-yl)-phenyl] -methanon,
[4-(imidazol-1-yl)-phenyl] -(5H, 11H-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanon,
[4-(4-Mei-1-yl)-phenyl] -(5H, 11H-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanon,
[2-chloro-4-(1-methyl-1H-pyrazole-3-yl)-phenyl] -(5H, 11H-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanon,
[2-chloro-4-(2-methyl-1H-pyrazole-3-yl)-phenyl] -(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanon,
3-chloro-4-(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-carbonyl)-benzonitrile,
3-chloro-4-(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-carbonyl)-benzoic acid,
3-chloro-4-(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-carbonyl)-benzamide,
[2-chloro-4-(5-methyl-2H-[1,2,4] triazole-3-yl)phenyl] -(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-carbonyl)-methanon,
[2-chloro-4-(2H-1,2,4-triazole-3-yl)-phenyl] -(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanon,
[2-chloro-4-(2-methyl-2H-[1,2,4] triazole-3-yl)-Fe-(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepin-10-carbonyl)-methanon,
[2-chloro-4-(1H-tetrazol-5-yl)-phenyl] -(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanon,
[2-chloro-4-(3-methylpyrazole-1-yl)-phenyl] -(3-dimethylaminomethyl-5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanon,
(3-bromo-(5H, 11H-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)[2-chloro-4-(3-methylpyrazole-1-yl)-phenyl] -methanon,
[2-bromo-4-(3-methylpyrazole-1-yl)-phenyl] -(5H, 11H-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanon,
(2,4-differenl)-(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanon,
[2-fluoro-4-(3-methylpyrazole-1-yl)-phenyl] -(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanon,
[4-(3-methylpyrazole-1-yl)-2-triptoreline] -(5H, 11N-pyrazolo[5,1-C] [1,4] benzodiazepine-10-yl)-methanon,
(2-chloro-6-pyrazole-1-yl-pyridine-3-yl)-(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanon,
(2-chloro-6-(3-methylpyrazole-1-yl)-pyridin-3-yl] -(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanon,
[2-chloro-6-(4-meilleret-1-yl)-pyridin-3-yl] -(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanon,
[2-chloro-4-(3-methyl-1,2,4-triazole-1-yl)-phenyl] -(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanon,
[4-(3-methyl-1,2,4-triazole-1-yl)-2-triptoreline] -(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanon,
[2-methoxy-4-(3-methylpyrazole-1-yl)-phenyl] -(5H, 11N-is[2-methoxy-4-(3-methylpyrazole-1-yl)-phenyl] -methanon,
[2-hydroxy-4-(3-methylpyrazole-1-yl] -(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanon,
[2-chloro-4-(1-methyl-1H-pyrazole-4-yl)phenyl] -(5H, 11H-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanon,
[2-chloro-4-(3-methylpyrazole-1-yl)-phenyl] -(4H, 10H-pyrazolo[5,1-C] [1,4] benzodiazepine-5-yl)-methanon,
2-chloro-4-(3-methylpyrazole-1-yl)-phenyl] -(5,10-dihydro-4H-tetrazolo[5,1-C] [1,4] benzodiazepin-5-yl)-methanon,
1-[4-(4H, 10H-pyrazolo[5,1-C] [1,4] benzodiazepine-5-carbonyl)-phenyl] -Etalon,
[4-(1-methyl-1H-pyrazole-3-yl)phenyl] -(4H, 10H-pyrazolo[5,1-C] [1,4] -benzodiazepine-5-yl)-methanon,
[4-(2-methyl-1H-pyrazole-3-yl)phenyl] -(4H, 10H-pyrazolo[5,1-C] [1,4] -benzodiazepine-5-yl)-methanon,
1-[4-(5H, 11N-pyrrolo[2,1-C] [1,4)benzodiazepine-10-carbonyl)-3-chlorophenyl] -Etalon,
or[2-chloro-4-(3-methyl-4-ethynylphenyl)(5H, 11N-pyrrolo[2,1-C] [1,4] benzodiazepine-10-yl)-methanon.

9. Pharmaceutical composition having agonist activity of vasopressin and containing an effective amount of a compound or pharmaceutically acceptable salt according to any one of paragraphs. 1-8 and a suitable pharmaceutical carrier.

10. The method of treatment of a disease or condition of the mammal, wherein the desired activity of the vasopressin agonist, providing an introduction to the needy in the mammal an effective amount of the El.

11. The method according to p. 10, where the disease or condition of the mammal, wherein the desired activity of the vasopressin agonist, is a diabetes insipidus.

12. The method of obtaining the compounds of formula I, including interaction formula 5

where a, b, D, E, G, X, Y, and R2determined as specified in paragraph 1,
with hydroxylamine to obtain the desired compounds of formula 1, where R1represents a heterocyclic residue group j as defined in paragraph 1.

13. The method of obtaining the compounds of formula I, including the interaction of the compounds of formula 5

where each of a, b, D, E, G, X, Y, and R2determined as specified in paragraph 1,
with an appropriately substituted hydrazine of the formula
R4-NHNH2,
where R4determined as specified in paragraph 1,
obtaining a mixture of two isomers of the compounds of formula I in which R1represents one of the two isomeric heterocyclic residue, as defined in paragraph 1 as group f and group g.

14. The method of obtaining the compounds of formula I, including the interaction of the compounds of formula 1

where each of D, E, G and X are defined as specified in paragraph 1,
with Conn who is alleluya group;
R10is1-6is an alkyl group,
obtaining the compounds of formula I, where each of a, b, D, E, G, X and Y are defined as indicated in paragraph 1;
R1is2-7-alkanoyloxy group.

15. The method of obtaining the compounds of formula I, including the conversion of the compounds of formula

where each of a, b, D, E, G, X and Y are defined as indicated in paragraph 1,
into the corresponding compound of formula I, where each of a, b, D, E, G, X and Y are defined as indicated in paragraph 1, and R1is2-7-alkanoyloxy group.

16. The method of obtaining the compounds of formula I, including the interaction of the compounds of formula 1

where D, E, G and X are defined as specified in paragraph 1,
with allermuir agent of formula 9

where a and b denote carbon;
J means acelerou group;
R is a heterocyclic residue selected from the group g defined in paragraph 1;
R2denotes hydrogen,
to obtain the target compounds of formula I, where a and b are carbon;
R1represents a heterocyclic residue selected from the group g defined in paragraph 1, and R2represents hydrogen.

17. The method obtained where D, E, G and X are defined as specified in paragraph 1,
with allermuir agent of formula 9

where a and b are defined as indicated in paragraph 1;
J means acelerou group;
R1means a heterocyclic residue selected from the group f, as defined in paragraph 1;
R2means hydrogen,
to obtain the target compounds of formula I, where R1represents a heterocyclic residue selected from the group f, as defined in paragraph 1, and R2represents hydrogen.

18. The method of obtaining the compounds of formula I, including the interaction of the compounds of formula

where a, b, D, E, G, X and Y are defined as indicated in paragraph 1,
with the appropriate compound of the formula
R1N
where R1is a heterocyclic residue selected from the groups a, b, C and d defined in paragraph 1,
to obtain the target compounds of formula I, where R1represents a heterocyclic residue selected from the groups a, b, C and d defined in paragraph 1.

19. The method of obtaining the compounds of formula I, including the interaction of the compounds of formula 1

where D, E, G and X are defined as specified in paragraph 1,
with allermuir agent of formula 9

20. The method of obtaining the compounds of formula I, including the interaction of the compounds of formula 45

where each of A, B, D, E, G, X, Y, and R2determined as specified in paragraph 1,
with hydroxylamine to obtain the desired compounds of formula 1, where R1represents a heterocyclic residue group k defined in paragraph 1.

21. The method of obtaining the compounds of formula I, including the interaction of the compounds of formula 45

where each of A, B, D, E, G, X, Y, and R2determined as specified in paragraph 1,
with an appropriately substituted hydrazine of the formula
R4-NHNH2,
where R4determined as specified in paragraph 1,
to obtain the target compounds of formula I in which R1represents a heterocyclic residue selected from the group e and group i defined in paragraph 1.

22. The method of obtaining the compounds of formula I, including the interaction of the compounds of formula 1

where D, E, G and X are defined, kazano in p. 1;
J is alleluya group,
to obtain the desired compounds of formula 1, where R1represents CN, and optionally its subsequent conversion in accordance with standard methods in the target compound of formula I, where R1represents NH2.

23. The method of obtaining the compounds of formula I, including the conversion of the compounds of formula I, which is a free acid, to the corresponding pharmaceutically acceptable salt.

 

Same patents:

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

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

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

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

The invention relates to new compounds having formula I or formula II:

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< / BR>
where R1represents H, lower alkylthio or R1together with R2form a-CH2-; each of R2and R3independently represents H or lower alkyl; R4represents Oh or H2; R5is H, unsubstituted lower alkyl, cyclohexyl - lower alkyl; each of R6and R7independently represents hydrogen, phenyl, naphthyl, -C(O)-NHCHR13CO2R14or substituted phenyl, where the Deputy represents halogen, lower alkyl, lower alkoxy, hydroxy, or phenyl - lower alkoxy; R8represents H or lower alkyl; R9represents H or lower alkyl; R12is NR9or S; R13is lower alkylthio; R14represents H or lower alkyl; or their pharmaceutically acceptable salts, with the exception of 4,5-bis(4-methoxyphenyl)-2-(4-thiazolidinediones)thiazole and its hydrochloride

The invention relates to sulfonamidnuyu to the compound of formula I, where R1- alkyl, alkenyl, quinil; a represents optionally substituted heterocyclic group, excluding benzimidazolyl, indolyl, 4,7-dehydrobenzperidol and 2,3-dihydrobenzofuranyl; X - alkylene, oxa, oxa(lower) alkylene; R2- optional substituted aryl, substituted biphenyl, its salts and pharmaceutical compositions comprising this compound

The invention relates to new derivatives of 4-oxo-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-ndimethylacetamide formula I

< / BR>
where X= H, halogen, methyl, methoxy, phenylmethoxy-; Y Is H, 1 or 2 halogen atom, HE, CH3OH, NO2-, CH3; R1-H, C1-C4alkyl; R2and R3each, independently of one another, is H, C1-C4alkyl, phenylmethylene group, or R2and R3form together with the nitrogen atom which carries them, azetidinone, pyrrolidinyloxy, 3-ethoxypyrrolidine, piperidinyloxy, morpholinyl, 4-methylpiperidino or 1,3-thiazolidinedione group

The invention relates to a new pyrimido[5,4-d]pyrimidines of General formula I and medicines with the properties of an inhibitor of protein tyrosine kinase receptors of epidermal growth factor on the basis of their

The invention relates to the class of heterocyclic metallocenes and containing catalytic systems, as well as the method of polymerization joining the polymerized monomers using a given catalytic system, and these heterocyclic metallocene correspond to the formula (I), YjRiZjjMeQkP1,

where Y represents a coordinating group containing the Central radical with six-electrons, directly coordinating IU, which condensed one or more rings containing at least one atom that is not carbon atom and is selected from S; R" represents a divalent bridging communication between the groups Y and Z; Z is a coordinating group having the same meaning as Y; Me represents a transition metal of group 3, 4, 5, 6; Q is halogen or linear or branched C1-C6-alkyl; R represents a counterion; i=0 or 1; j=1-3; jj=0-2; k=1-3 and 1= 0-2

The invention relates to new pyrazole[3,4-d]pyrimidines having anticonvulsant and anti-allergic/asthma action methods for their preparation (options) and pharmaceutical compositions based on them

The invention relates to new derivatives of purine of formula I, II, III and IV, pharmaceutical compositions and method of treatment of a pathological state characterized by thrombotic activity

The invention relates to substituted 3,5-diphenyl-1,2,4-triazole and their use as pharmaceutical agents, which form chelate complexes with metal

The invention relates to aryl - and getelemen carboalkoxylation acids of formula 1

< / BR>
where R1selected from the group of arrow or getarrow, R2selected from the group of Akilov

The invention relates to new crystalline modifications of a and a', to a method for their production and to their use in pharmaceutical compositions comprising such crystalline modification

The invention relates to new substituted phenyl derivatives, which are strong blockers chlorine ion channels and as such are useful in the treatment of sickle cell anemia, cerebral edema that accompanies ischemia or tumor, diarrhea, hypertension (diuretic), osteoporosis and to reduce the intraocular pressure for the treatment of disorders such as glaucoma

The invention relates to new substituted phenyl derivatives, which are strong blockers chlorine ion channels and as such are useful in the treatment of sickle cell anemia, cerebral edema that accompanies ischemia or tumor, diarrhea, hypertension (diuretic), osteoporosis and to reduce the intraocular pressure for the treatment of disorders such as glaucoma

The invention relates to the modification 1-(2,6-diferensial)-1H-1,2,3-triazole-4-carboxamide, characterized by the following characteristic absorption in the infrared spectrum (method of transmission in KBr pellets): band at 1678 cm-1

The invention relates to new derivatives of kalaidjieva, fungicides, method of combating fungal diseases of crops and intermediate compounds for obtaining

The invention relates to new amide derivatives of General formula (I) or their salts, where a means thiazolidin, imidazoline, triazoline, benzimidazolyl, benzothiazolyl, thiadiazolyl, imidazopyridine or imidazothiazole; X is a bond, -NR5-, -NR5CO-, -NR5CONH-, NR5SO2-, -NR5C(= NH)NH-; R1means H, lower alkyl, aryl, pyridyl, thienyl, furyl, thiazolyl, benzimidazolyl, imidazopyridine, triazolyl, thiadiazolyl, imidazolyl, imidazothiazoles, benzothiazolyl, cyclohexyl, which may be optionally substituted with halogen, lower alkyl, -OH, -CN, -NO2, -CF3, -NH2, -O-lower alkyl, and the Deputy of the lower alkyl may be substituted by phenyl, naphthyl, fullam, tanila or pyridium;2a, R2bmean H or lower alkyl; R3means hydrogen or lower alkyl; R4a, R4bmean H or HE, or taken together form a group =O or =N-O-lower alkyl; R5means H or lower alkyl
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