Tricyclic diazepine vasopressin antagonists and antagonists of oxytocin, the method of production thereof, pharmaceutical composition, method of treatment

 

(57) Abstract:

The present invention relates to tricyclic diazepines antagonists of vasopressin and oxytocin General formula I, where Y represents -(CH2)n- where n = 0 or 1, And-represents a-NR3-(CH2)m- where m = 1 or 2, and fragment

< / BR>
represents a condensed phenyl, 5-membered aromatic (unsaturated) heterocyclic ring containing one heteroatom sulfur. Fragment

< / BR>
represents a 5-membered heterocyclic (unsaturated) condensed ring containing a nitrogen atom, where D, E and F are selected from carbon atoms or nitrogen, and where the carbon atoms may be optionally substituted by substituents selected from a halogen atom, -COCF3, -C(O)O-lower(C1-C3)-alkyl and the other, a substituent R3represents a fragment of formula

,

where Ar represents the balance

< / BR>
where R5and R7are hydrogen, lower-(C1-C3)-alkyl, lower -(C1-C3-alkoxygroup and a halogen atom; R6is selected from the fragments of the formula-NRaCOAr', -CONRaAr', -NRaCOCH2Ar' and others, where Rais hydrogen, CH2and>/BR>where W' is S; R8or R9independently selected from a hydrogen atom, lower (C1-C3)-alkyl, -S-lower-(C1-C3)-alkyl, halogen atom, OH, NO2, -O-lower(C1-C3)-alkyl, CF3; R10is selected from among hydrogen atoms, halogen, lower-(C1-C3)-alkyl, and pharmaceutically acceptable salts and problemata. The method of obtaining the compounds of formula I by reacting the compounds of formula II with the compound of the formula Ar-C(O)-Q, where the substituents Z, Y, D, E, F, Ar and n are described above, and Deputy Q represents a halogen atom or an activating group, which is obtained by converting arylcarbamoyl acid mixed anhydride or activated using peptide reagent mates with the formation of compounds of formula I. the Pharmaceutical composition having an antagonistic activity against vasopressin for the treatment of diseases characterized by excess renal reabsorption of water, congestive heart failure, cirrhosis of the liver, nephrotic syndrome, damage to the Central nervous system and other treatment vasopressinergic diseases.

< / BR>
4 c. and 9 C.p. f-crystals, 13 tables.

is used in the treatment of conditions when reduced content of vasopressin, such as congestive heart failure, painful conditions with excessive renal water reabsorption and conditions with increased vascular resistance and coronary vasoconstriction.

Vasopressin is released from the posterior lobe of the pituitary gland or in response to increased plasma osmotic pressure, defined osmoreceptors brain, or at a reduced blood volume and blood pressure, perceived nitroprusside aluminization or arterial baroretseptorov. The hormone exerts its activity through two well-established subspecies receptors: vascular (vascular) V1and renal epithelial V2the receptors. Caused by vasopressin inhibition of the excretion of urine by the kidneys mediated renal epithelial V2receptors, contributes to maintaining normal plasma osmotic pressure of the circulating blood volume and blood pressure.

Vasopressin is involved in some cases of congestive heart failure, which increases peripheral resistance. Antagonists V1can reduce systems the m coronary vasoconstriction. Consequently, when conditions are caused by vasopressin elevated total peripheral resistance and altered local blood flow V1antagonists may be of therapeutic agents.

Blockade of V2receptors may be useful in the treatment of diseases characterized by excessive renal reabsorption of free water. Inhibition of excretion of urine by the kidneys is regulated by the release of the hypothalamic vasopressin (antidiuretic hormone), which binds to a specific receptor cells direct renal tubules. This binding stimulates adenylylcyclase and promotes cyclic amp-mediated introduction of water pores to the surface gleams of these cells. V2antagonists can adjust the liquid resistance in congestive heart failure, liver cirrhosis, nephrotic syndrome, damage to the Central nervous system, diseases of the lungs and hyponatremia.

Elevated levels of vasopressin are in congestive heart failure, which occurs most frequently in older patients with chronic heart failure. In patients with gipokaliemichesky congestive heart failure and free water by suppressing the action antiaritmicheskogo hormone. On the basis of biochemical and pharmacological effects of hormones, vasopressin antagonists are expected to be useful in the treatment and/or prevention of arterial hypotension, cardiac insufficiency, coronary vasospasm, ischemia of the heart, renal vasospasm, congestive heart failure, nephrotic syndrome, cerebral ischemia, cerebral hemorrhage-stroke, blood clots-bleeding, abnormal retention of water.

The following work prior describes peptide antagonists of vasopressin: M. Manning et al., J. Med. Chem. 35, 382 (1992); M. Manning et al., J. Med. Chem. 35, 3895 (1992); H> Gavras and B. Lammek, U.S. patent 5070187 (1991); M. Manning and W. H. Sawyer, U.S. patent 5055448 (1991); F. E. Ali, U.S. patent 4766108 (1988); R. R. Ruffolo et al., Drug News and Perspective, 4, (4), 217, (may, 1991). P. D. William et al., report potential Hexapeptide the antagonists of oxytocin (J. Med. Chem. 35, 3905, (1992)), also show weak activity in the suppression of vasopressin when linking with V1and V2- receptors. Peptide antagonists of vasopressin have drawbacks or oral activity, and many of these peptides are selective antagonists, as they also have partial agonistic activity.Premature birth can cause health problems in infants and to their death, as a key mediator in the mechanism of labor is a peptide hormone oxytocin. With regard to the pharmacological actions of oxytocin can be assumed that antagonists of this hormone can be used to prevent premature births, B. E. Evans et al., J. Med. Chem. 35, 3919 (1992), J. Med. Chem., 36, 3993 (1993). The compounds of this invention are antagonists of the peptide hormone oxytocin and can be used to control premature birth.

The present invention relates to new tricyclic derivatives, which have antagonistic activity with respect to V1and V2receptors and exhibit in vivo antagonistic activity against vasopressin. The compounds also possess antagonistic activesyn from among the compounds of General formula I

< / BR>
where Y represents -(CH2)n- where n = 0, 1;

A-B represents the

< / BR>
where m = 1, 2;

fragment

< / BR>
represents: (1) condensed phenyl, (2) a 5-membered aromatic (unsaturated) heterocyclic ring containing one heteroatom S,

fragment

< / BR>
represents a 5-membered aromatic (unsaturated) condensed heterocyclic ring containing a nitrogen atom, where D, E and F are selected from carbon atoms or nitrogen, and where the carbon atoms may be optionally substituted by substituents selected from a halogen atom, -COCF3,

< / BR>
< / BR>
< / BR>
< / BR>
-(CH2)q-OH,

< / BR>
-CHO, where q = 1; the substituents Rbindependently of one another are selected from-CH3or-C2H5;

Deputy R3represents a fragment of formula

< / BR>
where the Deputy Ar represents the balance

< / BR>
where R5and R7independently selected from a hydrogen atom, lower(C1-C3)-alkyl, lower-(C1-C3-alkoxygroup and halogen atom;

Deputy R6chosen from:

(a) fragments of formulas

< / BR>
< / BR>
< / BR>
(C1-C4)-alkyl, linear or razvitka C6-cycloalkyl,

the substituents Raindependently from each other selected from hydrogen atom, CH3or

< / BR>
q = 1;

Rbtakes the values defined above;

R1and R2independently of each other selected from hydrogen atom, lower(C1-C3)-alkyl, lower(C1-C3-alkoxygroup and halogen atom;

(b) a fragment of the formula

< / BR>
where substituent Rcis selected from a halogen atom, OH group,

< / BR>
< / BR>
< / BR>
where the substituents Raand Rbtake the above specified values;

Ar' is selected from fragments formula

< / BR>
< / BR>
where W' is S,

Deputy R8and R9independently from each other selected from hydrogen atom, lower (C1-C3)alkyl, -S-lower-(C1-C3)-alkyl, halogen atom, - OH, -NO2, -O-lower (C1-C3)-alkyl, CF3;

Deputy R10is selected from among hydrogen atoms, halogen, lower (C1-C3)-alkyl,

and its pharmaceutically acceptable salts and proletarienne form.

Among the group of compounds defined by formula I some subgroups of compounds are most preferred. Most prepost Titel Ar is selected from fragments

< / BR>
where the substituents R5, R6and R7take the values defined above.

Especially preferred are such compounds where the substituent R3is a fragment:

< / BR>
and Deputy Ar is selected from fragments

< / BR>
where substituent R6represents a

< / BR>
< / BR>
< / BR>
linear or branched,

linear or branched.

where cycloalkyl is defined as C3-C6-cycloalkyl,

the substituents Raand Rbtake the values defined above;

Deputy Ar' represents a fragment of formula

< / BR>
where the substituents R5, R8and R9and W' take the values defined above.

The most preferred compounds of formula I are compounds where the Deputy Y represents -(CH2)nand n = 1; fragment A-B represents

< / BR>
Deputy Ar represents

< / BR>
where the Deputy Ar represents a residue of the formula

< / BR>
where substituent R6represents a

< / BR>
< / BR>
< / BR>
linear or branched,

linear or branched,

where cycloalkyl is defined as C6SJ from among the fragments of formulas

< / BR>
where the substituents R5, R8and R9take the values defined above.

The most preferred compounds of formula I are compounds where the Deputy represents -(CH2)nand n = 0 or 1; where is the rest

< / BR>
represents a condensed phenyl or thiophene ring; fragment A-B is a

< / BR>
where m = 1 when n = 1 one, and m = 2 when n = 0; D, E, F, the substituents R1, R2, R4, R7, R8, R9and R10take the values defined above; Deputy R3represents a residue of the formula

< / BR>
where the Deputy Ar represents a residue of the formula

< / BR>
where substituent R6represents a

< / BR>
< / BR>
< / BR>
linear or branched,

linear or branched,

where the Deputy Ar' is selected from the group of residues

< / BR>
where the substituents W', Raand Rband cycloalkyl take the values defined above.

More preferred compounds of the present invention are the compounds of formula

< / BR>
where the fragment

< / BR>
is selected from among phenyl and thiophene rings;

Deputy R3is up>6represents a

< / BR>
< / BR>
< / BR>
linear or branched,

linear or branched,

where the Deputy Ar' is selected from the group of residues

< / BR>
where the substituents Ra, Rb, R5, R7, R8, R9cycloalkyl and W' take the values defined above,

Deputy R11is selected from hydrogen atom, halogen atom,

< / BR>
< / BR>
-CHO group

Also preferred compounds are compounds having formula

< / BR>
where m = 1 or 2

fragment

< / BR>
is selected from phenyl and tiofenolov rings;

Deputy R3represents a residue of the formula

< / BR>
where the Deputy Ar represents a residue of the formula

< / BR>
where substituent R6represents a

< / BR>
< / BR>
< / BR>
linear or branched,

linear or branched,

where the Deputy Ar' is selected from the group of residues

< / BR>
where the substituents Ra, Rb, R5, R6, R8, R9cycloalkyl and W' take the values defined above;

Deputy R11is selected from hydrogen atom, halogen atom,

< / BR>
and-CHO groups.

More preferred are the " Ar represents a residue of the formula

< / BR>
where substituent R6represents a

< / BR>
< / BR>
< / BR>
linear or branched,

linear or branched,

where cycloalkyl is defined as C6-cycloalkyl,

Deputy Rais selected and a hydrogen atom, -CH3or -(CH2)qN(CH3)2;

Deputy Ar' is selected from the group of residues

< / BR>
where q, the substituents Ra, Rb, R5, R7,R8, R9, R11and W' accept Zn treatment, opredeleniya.

Also preferred compounds are compounds, imeadiately

< / BR>
where m= 1 or 2;

Deputy R3represents a residue of the formula

< / BR>
where the Deputy Ar represents a residue of f rmula

< / BR>
where substituent R6represents a

< / BR>
< / BR>
< / BR>
linear or branched,

linear or branched,

where cycloalkyl is defined as C6-cycloalkyl,

Deputy Ravybere Xia from hydrogen atom, -CH3or -(CH2)qN(CH3)2;

and Deputy Ar' is selected from the group of residues

< / BR>
where q, the substituents R5, R7, R8, R9,R11and W' are set op Ilichevsky derivatives of formulas 3a and 3b substituted with LineSegment 4-nitrobenzotrifluoride 4 with the formation of promezhutochnoyee 5a and 5b. Restore itagroup intermediates 5a and 5b to 4-aminobenzoyl derivatives 6a and 6b. Vosstanovleniya intermediates 5a and 5b may be performed in slaveholding recovery (hydrogen-Pd/C, Pd/C-hydrazine-ethanol or chemical recovery (SnCl2-ethanol, Zn-acetic acid, TiCl3), and in such conditions that horoscopist to convert the nitro group to the amino group. Conditions preferencearray in the amino group vybiraut based on compatibility and sokhrannosti functional groups in the molecule.

The reaction of compounds of formula 6a and 6b with aroylchlorides erisoodustuste activated carboxylic acids in a solvent, such cochleariform, methylene chloride, dioxane, tetrahydrofuran, toluene and pogonarthria, in the presence of a tertiary base such as triethylamine diisopropylethylamine or pyridine and similar compounds, leads to soedineniya 8a and 8b, which are antagonists of vasopressin (scheme 1, relogin at the end of the description).

Interaction of tricyclic derivatives of formula 6a and 6b or carbamoyl derivative 9 or isocyanate derivative 10 dataelement (CX is et fragmentarily

< / BR>
(scheme 2 attached at the end of the description).

Interaction of tricyclic derivatives of formula 6a and 6b or siloxane acids, activated as the acid chloride 12,mixed CSOs anhydride or activated by other known reagents, prevadid compounds 13a and 13b (scheme 3, attached at the end of the description).

Connection formula I, where Deputy Y, fragment A-B, Z, zamestitel R1, R2and R3take up values, opredeleniya, and the remainder of the Ar substituent R3(-COAr) is aboyfriend

< / BR>
can be obtained in accordance with scheme 4 reacreational ether indole-5-carboxylic acid 14 with tricyclic derivatives of a and 3b. Indole-5-carboxylic acid 14 can be activated parempilaatuisia anhydride, mixed anhydride or by reaction with diethylthiophosphate, N,N-carbonyldiimidazole or relevant peptidenanoparticle reagents. For example, a derivative 15 can be obtained provzaimodeystvuet acid 14 with N, N-carbonyl diimidazol in tetrahydrofuran;the solvent is evaporated and the resulting derivative is introduced into the reaction by soedineniya 3a and 3b at 100-120oC without solvent. On the one hand,compounds 3 and 3b can vzaimode reagents of indolencia 14 is chosen on the basis of their compatibility with R4and their reaction abilities compared to tricyclohexylphosphine 3a and 3b in the formation vasopressinergic antagonista and 16b (scheme 4, is attached at the end of the description.)

The compounds of formula I, where Deputy Y, fragment A-B, Z zamestitel R1, R2and R3take the values opredeleniya, and the remainder of the Ar substituent R3(-COAr) is aboyfriend

< / BR>
where substituent R6represents a residue of the formula

< / BR>
can be obtained according to scheme 5 by PR rotation first of all derivatives 8a and 8b intermediate compounds 17a and 17b posleduyushim the interaction of these intermediates with azionaria or lithium education products 18a and 18b.(scheme 5 attached to the end of the description.)

On the other with the parties, the products 18a and 18b can be obtained peracchi combinations derived tetrazole formula 19 with tricyclohexylphosphine 3a and 3b (scheme 6). Tetrazole carboxylic acid activates sprovedene reaction combination with tricyclic connected s 3a and 3b with peptide conjugate reagents, by turning their chloranhydride or mixed anhydrides (scheme 6 attached at the end of the description).

Alternative SPO is F and Z values, as described earlier, and the substituent R3represents a

< / BR>
lies in the combination of arylcarboxylic acids with 20 tricyclohexylphosphine 3a and 3b with the formation of compounds 2 a and 21b.

For the reaction of a combination of arylcarbamoyl acid aktiviruyut turn them into acid chlorides, bromohydrin or anhydrides repersonalize reaction with an activating reagent, as an N-disclocation, dieticians at or corresponding antivirusagent "peptide." The method of activation acids 20 to providentially combination with tricyclic derivatives 3a and 3b is selected from acetamidomalonate reagents with other substituents in the molecule. Wybran sposobem is turning alkylcarboxylic acids 20 to sootvetstvuiushchie. The acid chlorides arylcarboxylic acids 22 can be polucheniya standard techniques, well known in this field, for example,by reaction with thionyl chloride, oxalyl Reid and other podobnyesayty. The reaction mix is carried out in a solvent such as galogenirovannyie, toluene, xylene, tetrahydrofuran, dioxane, prisutstviya or tertiary bases such as triethylamine, etc. (scheme shall 3a and 3b in pyridine or bis-(dimethylamino)pyridine.

In General, when arylcarbamoyl acid 20 are activated using N, N-carbonized ash and other activating agents "peptidnogo", requires a higher temperature than when ispolzovanpokoleniya. The reaction can be carried out in xylene with more vysokotemperaturnoi boiling or without solvent (100 - 150oC) (scheme and prilozheniy at the end of the description).

The initial compounds 3a and 3b in the above schemes 1-7 mouthbut prepared as follows. In accordance with the scheme alkilirovanie heterocycles structure 24 alkylating fragment, such as 23,leads to the intermediate connection 25. A heterocycle 24 may contain-carbaldehyde function or carboxyl and/or essential functions, kakato shown in scheme 8. When the intermediate connection 25 contains carbaldehyde group, hydrogenation on pall Dios-on-coal leads to vosstanovlenie and closing cycle in one stage, with the formation of soedineniya.

In derivative 25 in which present - carboxyl and/or ester function, first allocate intermediate aminocyclopropane 7, and then carry out the cyclization. The cyclization of derivatives hassetsu when heated or by activating the development with the formation of Premiata nogo connection 29.Reaction of tricyclic derivatives of 29 with aroylchloride (ArCOCl), designtitle Ar accepts the above specified values, leads to diazepam.

Tricyclic derivatives of structural type 26 can bytevalue in accordance with scheme 9. Formirovanie connection 32 izvestnjakovyjj, such as, for example, formirovanie on Vilsmeier, depropagation connection 35, which when restoring and cyclization of obrazytesya 37.

When Z represents condenser annoy substituted renesemee phenyl group, according to this method get pyrrolo-[1,2-a]honokalani 36. Derivatives 36 and 37 can react with aroylchloride(ArCOCl) where the Deputy Ar takes a predetermined value, or samemanner or tamaseni 4-nitrobenzofurazan or protective for tomasita group, such as benzyloxycarbonylamino, obrazovanie.mozet 38 and 39. Compounds 38 and 39 can interact with chlorine,bromine or halogenation reagents such K N-chlorosuccinimide,N-bromosuccinimide and the like compounds, with the formation of compounds 40 I, where the substituent R17represents a halogen atom.Derivatives 38 and 39 can be formirovany or azetilirovanny from sidelineapparel.com 40 and 41, de substituent R17predstavki 1-substituted pyrrolo-[1,2 - a]kinocilium. Derivative 38, 39, 40 and 41, where the substituent R16pre is abousleiman or unsubstituted 4-nitrobenzoyl group, restored AR4-aminobenzoyl derivatives 42d and 43d, which interact with reagenti Ar COCl, Ar CH2COCl or Ar'-N(Rb)COCl, designtitle Ar or Rbtake the above specified values, the research of tricyclic benzodiazepines 44 and 45 (scheme 9 applied in concepisse).

Compounds of the present invention, where the substituent R3represents a residue of the formula

< / BR>
and the group Ar PR dstanley a residue of the formula

< / BR>
where substituent R6represents a residue of the formula

< / BR>
where the substituents Ra, R5, R7and Ar' prinimayushchie defined above, can be obtained in accordance with scheme EU. Tricyclic derivatives 46 and 47 communicate with monomethylethanolamine 48 education arilirovaniya methyl Selenomethionine 49 and 50. Hydrolysis of methyl esters leads 49 and 50 to kislota 51 and 52, which activate camping for the reaction of a combination of potenprivate in activated esters or becoming chlorohydrination 53 and 54. The reaction of the acid chlorides of the acids 53 and 54 with amines of the FD in the end of the description).

Getting some of tricyclic benzodiazepines, which can be used too as starting materials for the synthesis of soedineniya of the invention presented in schemes 8 and 9. Other t illiciaceae receive in accordance with literature methods,or known in this field techniques, or methodologies kotoraya synthesis of specific known of tricyclic benzodiazepines. Takadiastase cyclic system volumes below when processing conditions described in schemes 1 to 7, 9 and 10, are compounds of nastoyascheevremya.

Tricyclic diazepinone cyclic system,10,11-dihydro-5H-imidazo[2,1-c]benzodiazepine,

< / BR>
< / BR>
where X = , OCH3, -OCH2C6H5;

Y = H, Cl, -OCH3;

X, Y = O-CH2-O-,

described G. Stefancich, R. Silveatri, M. Artico, J. Het Chem. 30,529 (1993); the same cyclic system substituents in the ring described G. Stefa cich, M. Artico, F. Carelli, R. Silveatri, G. deFeo, G. Mazzanti,I. Durando, M. Palmery, IL Farmaco, Ed. Sc., 40, 429 (1985).

Sintes,10-dihydro-4H-furo[2,3-e]pyrrolo[1,2-a][1,4]diazepin-9-it

< / BR>
< / BR>
described F. Povazunec, B . Decroix, J. Morel, J. Het. Chem. 29,1507, (1992), the restoration of which leads to tricyclic heterocycle,10-dihydro-4H-furo[2,3-e]pyrrolo[1,2-a][1,4]Sana L. Cecchi G. Filacchioni, J. Het. Chem.20, 871 (1983);

< / BR>
Sintez-oxo-9,10-dihydro-4H-pyrrolo[1,2-a] thieno[2,3-e] -[1,4]diazepino described A. Daich, B. Decroix, Bull. Soc. Chem. Fr 129, 360 (1992);

< / BR>
< / BR>
and no, the boron-dimethyl sulfide gives 9,10-dihydro-4H-pyrrolo[1,2-e]thieno[2,3-e][1,4]diazepin.

A. Daich and B. Decroix described takze-oxo-4,5-dihydropyrrolo[1,2-a]thieno[3,2-e][1,4]diazepin

< / BR>
< / BR>
which when restoring day,5-dihydro-Pierre lo[1,2-a]thieno[3,2-e] [1,4]diazepin.

B. Decroix and J. Morel in the journal J. Het. Chem., 28, 81 (1991)described pyrrolo[1,2-a] thieno[3,2-e] [1,4] diazepin ibarrola[1,2-a]thieno[2,3-e][1,4] diazepin.

< / BR>
The reduction with hydrogen on palladium-on-coal sludge hemidesmosomal such reagents as cyanoborohydride sodium and acetic cicloturista to dihydro-tricyclic heterocycles

< / BR>
Synthesis of tricyclic 1,5-benzodiazepine cyclic system,6,7-dihydro-5H-pyrrolo[1,2-a] [1,5]benzo of diazepine described F. Chimenti, S. Vomero, R. Giuliano & M. Artico, IR Farmaco, Ed. Sc., 32, 339 (1977).Kannelirovannye 1,5-benzodiazepine-containing 5-membered ring,considered in the review A. Chimirri, R. Gitto, S. A. Grasso , M. Monforte, G. Romeo &M. Za pala, Heterocycles, 36, N 3, 604 (1993) also described tsiklicheskaya - 6,7-dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepine.

< / BR>
Getting 5,6-dihydro-4oma, G. Grossi, M. Ghia, & F. Mattioli, Eur. J. Med.Chem. 26, 489 (1991). Vosstanovlenie,6-dihydro-4H-[1,2,4] -triazolo[4,3-a][1,5]benzodiazepine-5-ones with DIBORANE or lithium hydride leads christliches 5,6 dihydrophosphate.

< / BR>
< / BR>
R21= H, CH3< / BR>
Compounds of the present invention and obtaining them can bitopological illustrated in the following examples, which are not dominatesdebate as examples of limiting this invention.

Example 1. N-[4-(5H-Pyrrolo[2,1-c] [1,4]benzodiazepine-10(11H)-ylcarbonyl)phenyl]-2,3-diflorasone.

With stirring to a solution of 0.350 g of 2,3-differentiald in 5 ml of methylene chloride add 0.346 ml of triethylamine. After peremeci project within 3 min add 0.500 g,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c] [2,4]benzodiazepine and stirred for 72 h, the Reaction mass is filtered and the solids washed with methylene chloride. Tverdyate lay. The combined filtrates washed with water, 2 N. citric acid solution, 1 m solution of NaHCO3and brine. Reactionuses dried with sodium sulfate, filtered and evaporated in vacuum, poluchaut g of solid product. Two solids are combined and dried.We have 790 mg of the desired product as a solid with oxybenzone.

To a solution of 0.362 g of 2-methoxybenzylamine in 5 ml methylenchloride stirring at 0oC added 0.346 g of triethylamine. Poluparallelnye for 3 min add 0.500 g,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c] [1,4] benzodiazepine and stirred for 18 CPRI room temperature. The reaction MES diluted with 45 miltilingual and washed with water, 2 N. citric acid solution, 1 M NaHCO3and brine, filtered through water magnesium silicate iprivate in vacuum. Get a solid product, which ciscaucasica of ethyl acetate and get 0.430 g of the desired product in viderestilling substances, so pl. 185 - 188oC.

Example 3. 2-Methyl-N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepine-10(11H)-ylcarbonyl)phenyl]benzamide.

To a mixture of 1.93 g of 4-[(2-methylbenzoyl)amino] benzoylchloride 15 miltilingual at 0oC added 1.13 ml of triethylamine, stirred during 3 min and add a mixture of 1.0 g,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine and 5 ml of methylene chloride. The cooling bath is removed priblisitelno chere h 30 min get the solution. The reaction mixture peremeshivayte room temperature for 48 hours and evaporated in vacuum.The residue is dissolved in 100 ml of ethyl acetate, Patria, evaporated in vacuum and obtain 3.0 g of residue. 300 megablasta residue purified by thin-layer chromatography (eluent 10% syatiletiya-methylene chloride), allocate 160 mg of the desired product. Ostalnoyye the product was then purified by rapid chromatography (eluent 10% ethyl acetate-metalenclosed obtain the desired product, which is then cristallisation ethyl acetate, allocate 800 mg of the desired compound in the form of belovorotnichkovoi substances, so pl. 212 - 215oC.

Example 4. N-[4-(5H-Pyrrolo[2,1-c] [1,4-] benzodiazepine-10(11H)-ylcarbonyl)phenyl]-2,5-dichlorobenzamide.

To a solution of 414.5 mg of 2,5-dichlorobenzonitrile in 5 ml methylenchloride 276 μl of triethylamine, stirred for 3 min PIoC and then add 400 m g,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine. The cooling bath is removed and the reaction semipermissive at room temperature for 3 hours. The mixture is evaporated vacuume, the residue is dissolved in ethyl acetate, washed with water, 2 N. citric acid solution, 1 m solution of NaHCO3and brine. Organicheskikh dried with sodium sulfate, evaporated in vacuo, the residue of acidalcohol chromatography (eluent ethyl acetate: hexane, 1: 1). Vydelenijami crystallized from EB lazette Example 5. N-[4-(5H-Pyrrolo[2,1-c] [1,4]benzodiazepine-10(11H)-ylcarbonyl)phenyl]-3-methyl-2-thiophencarboxylic.

To a solution of 318 mg of 3-Mei-2-thiophenecarbonitrile 5 miltilingual at 0oC add 346 μl of triethylamine, stirred in 3 min and add 500 mg of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine. The cooling bath is removed and the reaction cm spiremedia at room temperature for 18 hours. Mesyuarat in vacuum, the residue is crystallized from ethyl acetate, get 800 mgmmirage substances. The solid is dissolved in methylene chloride, promyvayut, 2 N. a solution of lemon sour s, 1 m solution of NaHCO3yasalam. The organic layer is filtered through water magnesium silicate, swatantrata sodium and evaporated in vacuum. The residue is crystallized of satellitedata receive 400 mg of the desired compound as a white kristallicheskogo society, so pl. 232 - 235oC.

Example 6. N-[4-(5H-Pyrrolo[2,1-C] [1,4]benzodiazepine-10(11H)-ylcarbonyl)phenyl]-2,4-dichlorobenzamide.

To a solution of 415 ml of 2,4-dichlorobenzotrifluoride in 5 ml methylenchloride 0oC add 346 μl of triethylamine, var're asked for 3 mini add 500 mg of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-C] [1,4]benzodiazepine evaporated vacuume, the remainder astonaut in ethyl acetate, washed with water, 2 H. restorational acid, 1M solution of NaHCO3and brine. Organicheskikh dried with sodium sulfate, filtered and evaporated in vacuum. Statictically of ethyl acetate, allocate 420 mg of the desired compound in viderestilling solids, so pl. 210-212oC.

Example 7. N-[4-(5H-Pyrrolo[2,1-C] [1,4]benzodiazepine-10(11H)-ylcarbonyl)phenyl]-2-chlorobenzamide.

To a solution of 347 mg of 2-chlorobenzylchloride in 5 ml of methylene chloride prioC d billaut 346 μl of triethylamine, stirred for 3 min dobavlaut 500 mg of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-C][1,4]benzodiazepine. The cooling bath is removed and the reaction semipermissive at room temperature for 18 hours the Mixture is evaporated vacuume, the residue is dissolved in methylene chloride, washed with water, 2 H. restorational acid, 1M solution of NaHCO3and brine. Organicheskikh dried with sodium sulfate, filtered and evaporated in vacuum. Statictically from milenaria, allocate 525 mg of the desired compound as a white crystalline substance, so pl. 228-230oC.

Example 8. N-[4-(5H-Pyrrolo[2,1-C] [1,4]benzodiazepine-10(11H)-ylcarbonyl)phenyl]-2-perbenzoic.

Example 9. 3-Chloro-N-[4-(5H-pyrrolo[2,1-C][1,4]benzodiazepine-10(11H)-ylcarbonyl)phenyl]-benzazimide.

The mixture 0,273 g 2-chloranilic usnei acid (and ) peremeshivayte room temperature for 2 hours, evaporated in vacuo several times subjected to the distillation residue with toluene. The remainder restauraut 10 ml of methylene chloride containing of 0.26 ml of triethylamine and dobavlaut,485 g 1 ,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-C][1,4]benzodiazepine. The reaction mixture was stirred at room temperature techenie hours. The mixture is evaporated in vacuo, the residue is dissolved in ethyl acetate,washed with water, 1N. hydrochloric sour s, 1M NaHCO3and brine. The organic layer is dried and evaporated, the residue Ciscaucasia chromatography (eluent ethyl acetate: hexane, 1: 1), receive treb what-1H-pyrrole-2-carbaldehyde.

To a solution 3,76 g of 1-(2-nitrophenyl)pyrrole in 20 N,N-dimethylformamide at 0oC and stirring is added dropwise 3 ml of CHLOROACETATE. The mixture is stirred for 30 min and incubated at 90oC during 1 hour. Upon cooling to room temperature the mixture obrabatyvaimym ice and adjusted to pH 2 to 12 N. solution of sodium hydroxide.The resulting suspension is filtered, washed with water, dried, get 5,81 Griboedova connection in the form of a pale yellow substance, so pl. 119-122oC.

Example 11. 4,5-Dihydro-pyrrolo[1,2-a]cinoxacin.

To a solution of 1.0 g of 1-(2-nitrophenyl)-1H-pyrrole-2-carbaldehyde in 40 ml of ethanol and 40 ml of ethyl acetate in an argon atmosphere add 40mg 10% Pd/C. Mas hydronaut under pressure of 40 pounds per square inch within 2 hours and filtered through diatomaceous earth. The filtrate is evaporated in vacuo,the residue is dissolved in ether, treated with hexane, get 0,35 Griboedova connection in the form of solid beige color so pl. 108-110oC.

Example 12. 4-[(2-Methylbenzoyl)amino]benzoic acid.

The mixture 43,42 g ethyl-4-aminobenzoate and 40.8 g of 2-methylbenzothiazol 150 ml of methylene chloride cooled in an ice bath and added dropwise dobavlaut,56 g of trialanine. by the end of the research Institute dopaminergically layer washed with water, 1H. hydrochloric acid, mastaram NaHCO3and dried by sodium sulfate. The solvent is evaporated vacuume, the solid residue triturated with ethyl acetate, filtered, receive g ethyl-4[(2-mailasail)amino] benzoate in the form of crystals, so pl. 110-115oC. a Mixture of 50.7 g of the obtained compound in 280 ml of ethanol I ml of 10 n NaOH solution is boiled for 5 minutes the Mixture is cooled decanates temperature, diluted with 200 ml of water and acidified with solenoidality to pH 1-2. The mixture is filtered, the precipitate washed with water, dried, poluchaut g of the desired compound as a white crystalline substance, so pl. 270-275oC.

Example 13. 4-[(2-Methylbenzoyl)amino]benzoyl chloride.

A mixture of 10.3 g of 4-[(2-methylbenzoyl)aminobenzoic acid and 32 methioninamide boiled for 1.5 hours and evaporated in vacuum. To ostadalova toluene and evaporated the solvent in vacuo. Add toluene,zakolerovat and filtered receive the desired compound in the form of Targovishte yellow, so pl. 135-141oC.

Example 14. 2-Methyl-N-[4-(pyrrolo[1,2-a] cinoxacin-5(4H)-ylcarbonyl)phenyl]benzamide.

A mixture of 0.51 g of 4 [(2-methylbenzoyl)amino]benzoyl chloride and 0.36 G1,1'-carbonyldiimidazole in 6 ml of tetrahydrofuran was stirred at connatation 60 hours . Mesyuarat in vacuum, the residue is dissolved in ethyl acetate, washed with water, 1N.hydrochloric acid, 1M solution of NaHCO3, dried with sodium sulfate filterout water through magnesium silicate. The solvent is evaporated in vacuo,the residue chromatographic (e uent ethyl acetate-hexane, 1: 2), receive 0,14 Griboedova product in the form of a white solid substance, so pl. 206-207oC. Mass spectrum (CHI - chemical ionization) : 408 (MH+).

Table I

Connection examples 15-37 obtained by the method of example 14 application of the appropriate substituted Aronhold (see conatact).

Example 38. N-(2-Nitrobenzoyl)pyrrole-2-carbaldehyde.

To a solution of 5.6 g of 2-errorcorrected in 40 ml tetrahydrofurane cooling in an ice bath, add 2.4 g of 60% sodium hydride mineralna oil, the temperature is increased to 40oC. Semipermissive for 20 min and added dropwise a solution of 11.0 G2-nitrobenzotrifluoride in 20 ml of tetrahydrofuran for 20 minutes Semipermissive PR cooling for 45 min, poured into ice bath with epitomi filtered. The two-phase filtrate is separated, the ether layer is dried,evaporated in vacuo, get 10 g of a dark syrupy residue, which dscreet, so pl. 95-99oC.

Example 39.10,11-Dihydro-5H-pyrrolo[2,1-C][1,4]benzodiazepine-5-he.

A mixture of 1.5 g of N-(2-nitrobenzoyl)pyrrole-2-carbaldehyde in 50 platelett, 2 drops to zentrierung hydrochloric acid and 0.3 g of 10% Pd/Sostragivajut in a Parr apparatus in a hydrogen atmosphere for 1.75 hours.The mixture is filtered, add 0.4 g 10% Pd/C and shaken in Apparatebau in an atmosphere of hydrogen for 2 hours. Reacciona specificeret through kieselguhr, the filtrate is evaporated in vacuum, obtain 1.0 g relegable. The residue is purified by thin-layer chromatography (allinterracial-hexane, 4: 1) obtain 107 mg of the desired compound in the form of masloobrazovatelyah substances.

example 40.2-Methyl-N-[4-[(5-oxo-5H-pyrrolo[2,1-c] [1,4] benzodiazepine - 10(11H)-yl)carbonyl]phenyl]benzamide.

To a solution of 107 mg,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine - 5-she and 0.084 ml of triethylamine in 3 ml of methylene chloride at peremeshivaniya Aut 165 mg of 4-[(2-methylbenzoyl)amino]benzoyl chloride and prodolzhitelnaya within 6 hours. The mixture is evaporated in vacuum, statomat thin-layer chromatography (eluent hexane-ethyl acetate, 7:3), poluchatelyam connection in the form of foam.

The application 41. N-[4-(3-Chloro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-10(11H)-ylcarbonyl)phenyl] benzamide in 5 ml of tetrahydrofuran pereohlajdenia on aq-ice bath, added 67 mg of N-chlorosuccinimide peremeshivayte when cooled for 10 minutes The cooling is removed and semipermissive another 2.25 hours. The reaction mixture was poured into water with ice extravert ether. The organic layer is dried and evaporated vacuum, poluchatelu, which is crystallized from a mixture of ethyl acetate-hexane, allocate 157 magtrabaho connection in the form of a pink-orange solid substance, so pl. 185-187oC.

Example 42. 2-Methyl-N-[4-(1-harperone[2,1-a]cinoxacin-5(4H)-ylcarbonyl phenyl]benzamide.

To a suspension of 5 mmol of 2-methyl-N-[4-(pyrrolo[2,1-a]cinoxacin-5(4H)-ylcarbonyl)phenyl]benzamide in 5 ml of tetrahydrofuran, cooled smenubody-ice, add 5.5 mmol of N-chlorosuccinimide with posledeistviem when it is cooled during their 10 minutes the Cooling bath is removed peremeshivanie continued for 2.25 hours, the Reaction was poured into maciwoda-ice and extracted with ether. The organic layer is dried and concentrated vacuume, get the desired product in the form of solids. Table II

Connection examples 43-48 obtained by the method of example 42 (see end of text).

Example 49. 3-Chloro-10,11-dihydro-10-(4-nitrobenzoyl-5H-pyrrolo[2,1-c] [1,4]-benzodiazepine.

To a chilled mixture of water and ice to a solution of 250 mg,11-dig draw-10-(4-nitrobenzoyl-5H-pyrrolo[2,1-c] [1,4] -benzodiazepine-6 m is 30 min and at room temperature within 2 hours The reaction was poured into ice water, stirred for 5 hours and extracted with ether. The organic layer is dried and evaporated in a vacuum,get 0.2 g of yellow foam. When grinding with ethanol 66 mulamula product as a yellow solid connection, so pl. 119-125oC.

Example 50. 3-Chloro-10,11-dihydro-10-(4-aminobenzoyl-5H-pyrrolo[2,1-c] [1,4]-benzodiazepine.

A mixture of 1 mmol of 3-chloro-10,11-dihydro-10-(4-nitrobenzoyl-5H-pyrrolo[2,1-c] [1,4] -benzodiazepine, 2.5 mmol of anhydrous hydrazine, 50 gallade-on-coal and 1 ml of ethanol is boiled for 1.5 hours Specificeret through diatomaceous earth and the filtrate is concentrated to dryness, poluchatelej product in the form of solids.

Example 51. N-[4-(3-Chloro-5H-pyrrolo[2,1-c][1,4]-benzodiazepine-10(11H)-ylcarbonyl )phenyl-2-methylbenzamide.

A mixture of 1 mmol of 3-chloro-10,11-dihydro-10-(4-aminobenzoyl-5H-pyrrolo[2,1-c] [1,4] -benzodiazepine, 2 mmol of triethylamine and 1.1 mmol-methylbenzylamine in 8 ml of methylene chloride was stirred at room temperature throughout the night. The mixture is washed with water, 1 m solution of NaHCO3icesat sodium sulfate. The solvent is evaporated in vacuum and get twentypound, which is recrystallized from a mixture of methylene chloride-hexane,recip is by the method of example 51 the application of the appropriate substituted aroylchlorides (see at the end of text).

Example 77. 1-(2-Nitrobenzyl)-2-errorcorrected.

To 5.56 g of a 60% aqueous hydride three in mineral oil, washed Teresa hexane in an argon atmosphere add 300 N,N-dimethylformamide. The reaction mass is cooled in the ice bath and slowly add 13.2 pyrrol-3-carbaldehyde. The reaction mixture is a solution and endopelvic) is stirred for 10 minutes Under stirring midlandodessa 30.0 g of 2-nitrobenzylamine. After adding reactionwas stirred for 30 min, the ice bath is removed and peremeshivayte room temperature for another 24 h N,N-Di ethylformate concentrate vacuume receive the remainder, which is stirred with ice water during 1 h resulting solid product is collected, air-dried, then vacuume and get 30.64 g of the desired product as a yellowish-coricnevatogo product, so pl. 128 - 132oC.

Example 78. 10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine.

A mixture of 30.6 g of 1-(2-nitrobenzyl)-2-errorcorrected and 3.06 g% Pd/C in 400 ml of ethyl acetate and 400 ml of ethyl alcohol hydronaut within 18 hours the Reaction mass is filtered through diatomaceous earth, filterformat activated carbon and filtered, contains ethyl alcohol. Dissolve miss cherspalace with silica gel and the pad was washed with a solution of hexane-ethyl acetate,7:1, get 16.31 g of the desired product as a solid substance, so pl. 145 - 148oC.

Example 79. 10,11-Dihydro-10-(4-nitrobenzoyl)-5H-pyrrolo[2,1-c][1,4 benzodiazepine.

To a solution of 3.3 g of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 50 ml of methylene chloride under nitrogen atmosphere add 5.0 metrically and cooled the reaction mass an ice bath. Then dropwise dobavlyautsya 4.0 g of 4-microbe of taillored in 20 ml of methylene chloride. Pokonanie add ice bath removed and the reaction mass is stirred pikantnoi temperature for 2 hours remove Volatile components vacuume, get a residue, which was dissolved in ethyl acetate. Solution raybaudi, 1 N. hydrochloric acid, NaHCO3brine, swatantrata sodium and filtered. The filtrate was concentrated in vacuo, polukulturnye product, which is dissolved in methylene chloride, miss caressingly and washed utilized. The combined filtrates contentresult vacuum, obtain 5.3 g of the desired product as yellow tverdokopchenaya, so pl. 188 - 190oC.

Example 80. 10,11-Dihydro-10-(4-am) - Rev.] benzodiazepine in 15 ml of ethanol and 15 ml of ethyl acetate containing 0.2 g of 10% Pd/C, hydronaut for 5 hours the Reaction misspeltyouth through diatomaceous earth. The filtrate is concentrated in vacuo e, tverdyate dissolved in methylene chloride, passed through silica gel promyvayut a mixture of ethyl acetate-hexane, 3: 1. The filtrate was concentrated in vacuo,to obtain 1.5 g of the desired product as a yellow solid, so pl. 166 - 168oC.

Example 81. 10,11-Dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine.

To a solution 21.58 g of 10,11-Dihydro-10-(4-nitrobenzoyl)-5H-pyrrolo[2,1-c] [1,4] benzodiazepine in 325 ml of ethyl acetate added 2.15 g of 10% Pd/C and 5.16 g of hydrazine, and then p remediat and boiled for 15 hours Cooled to room temperature and filtered through diatomaceous earth.The filtrate was concentrated in vacuo and the resulting solid residue restauraut the methylene chloride and passed through a substrate with magnesium silicate.The filtrate is evaporated in vacuum, obtain 19.2 g of the desired product in widiastuti brown solid. The solid product was then purified by bystroprokhodahaya using as eluent a mixture of ethyl acetate-hexane,7:1, get 17.97 g of the desired product, so pl. 166 - 168oC.

Example 82. N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepine-10,(11H)-ylcarbonyl)phenyl]-3-chlorobenzo[b]TIF is mesheanii to relax ut 0.33 ml of triethylamine. Poluparallelnye for 15 min add 0.485 g,11-dihydro-10-(4-aminobenzoyl)- 5H-pyrrolo[2,1-c] [1,4]benzodiazepine is added and stirred during 18 hours the Reaction mass is washed with water, 1 N. solution solenoidality, NaHC3and brine. The reaction mixture is dried with sodium sulfate,filtered and evaporated in vacuum, get a solid product, motoryacht fast chromatography, eluent ethyl acetate : hexane, 1: 1, obtain 0.49 g of the solid product, so pl. 220 - 222oC. 2 Example 83. N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepine-10(11H)-ylcarbonyl)phenyl]-2,3-dimethylbenzamide.

To a solution of 0.320 g of 2,3-dimethylbenzylamine 10 miltilingual add 0.33 ml of triethylamine. After stirring for 15 indomable t 0.485 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c] [1,4]benzodiazepine and stirred for 5 hours the Reaction cosplaywhat water, 1 N. hydrochloric acid, NaHCO3and brine.The reaction mass is dried with sodium sulfate, filter Ute and evaporated in vacuum.Get a solid product, which was purified by rapid chromatography the application of a mixture of ethyl acetate : hexane, 1:1. Obtain 0.93 g of tverdokopchenaya, so pl. 168 - 170oC.

Example 84. N-[4-(5H-Pyrrolo[2,1-c] [1,4]benzodiazep in-10(11H)-ylcarbonyl)phenyl]-2-atakebune added 0.346 g of triethylamine. Poluparallelnye for 3 min add 0.500 g,11-dihydro-10-(4 - aminobenzoyl)-5H-pyrrolo[2,1-c] [1,4]benzodiazepine and stirred for 72 CPRI room temperature. The reaction mixture is diluted with 45 miltilingual and washed with water, 2 N. citric acid solution, NaHCO3and brine. The reaction mass tub sodium sulfate, filtered iprivate in vacuum. Get a solid product, which was purified by bystroprokhodahaya using a mixture of ethyl acetate : hexane, 1:1. Get 0.890 g of solid compound, which is recrystallized from ethyl acetate. are square-0.540 g of the desired product, so pl. 160 - 176oC.

Example 85. N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepine-10(11H)-ylcarbonyl)phenyl]-2-(methylthio)benzamide.

To a solution of 0.364 g of 2-(methylthio)benzoyl chloride in 5 miltilingual when paramashiva AI and 0oC added 0.346 g of triethylamine.Stirred for 3 min and add 0.500 g,11-dihydro-10-(4-aminobenzoyl)- 5H-pyrrolo[2,1][1,4]benzodiazepine and stirring is continued during 72 h at room temperature. The reaction mass is diluted with 45 miltilingual and washed with water, 2 N. citric acid solution,NaHCO3and brine. The reaction mass is then dried with sodium sulfate,filtered and UPA is acetat-hexane, 1: 1.Get a solid product, which was crystallized with ethyl alcohol.Allocate 0.480 g of the desired compound in the form of a white solid product, so pl. 171 - 174oC.

Example 86. 3 Methylbenzo[b]thiophene-2-azet chlorid.

A mixture of 2.0 g of 3-methylbenzo[b]thiophene-2-acetic acid and 19.4 methioninamide boiled for 1 h Evaporated volatile components of vacuume obtained residue contentresult in toluene three times and dried in vacuum.Obtain 2.25 g of the desired soybean inane.

Example 87. N-[4-(5H-Pyrrolo[2,1] [1,4] benzodiazepine-10(11H)-ylcarbonyl)phenyl]-3-methylbenzo[b]thiophene-2-ndimethylacetamide.

To a solution of 0.445 g of 3-methylbenzo[b]thiophene-2-acetylchloride 5 miltilingual under stirring and at 0oC add 0.3 6 triethylamine. Stirred for 3 min and add 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1] [1,4] benzodiazepine and stirring is continued at techenie h at room temperature. Add 0.445 G3-methylbenzo[b]thiophene-2-acetylchloride, 0.346 g of triethylamine and 30 mg dimethylaminopyridine poluchennuyu mass is stirred for 18 hours the Reaction mass is diluted with 45 miltilingual and washed with water, 2 N. citric acid solution,NaHCO3and brine. The reaction mass is then dried sulfate NAT Oia,filtered and OptimizeIT-hexane, 1:1.Allocate 0.320 g of the desired compound as a yellow foam.

Example 88. 4-Chloro-2-methoxybenzoate. 2 a Solution of 2.0 g of 2-chloro-o-anisimovas acid in 22 ml of thionylchloride within 1 h of the Evaporated volatile components in vacuo, polojenieto concentrate in toluene three times and dried in vacuum. Obtain 2.0 g of the desired compound.

Example 89. N - [4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepine-10(11H)-ylcarbonyl)phenyl]-4-chloro-2-methoxybenzamide.

To a solution of 0.406 g of 4-chloro-2-methoxybenzonitrile 5 miltilingual under stirring and at 0oC added 0.346 g of triethylamine.Stirred for 3 min and add 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine and stirring is continued for 18 CPRI room temperature. Add another 0.G-chloro-2-methoxybenzonitrile and 0.346 g of triethylamine is stirred for 2 hours of Reaction Yu mastersbilt 45 ml of methylene chloride and washed with water, 2 N. solution limnoecology, NaHCO3and brine. The reaction mass is then dried solfatare, filtered and evaporated in vacuum. Get a solid product that cleans fast chrome ografia using mesitylacetate-hexane, 1: 1, get a solid product, which is crystallized from ethyl acetate rmutil)benzoyl chloride. 2 a Solution of 2.0 g of o-triftorperasin acid in 21 methioninamide boiled for 1 h Evaporated volatile components in vacuo,the obtained residue was concentrated in toluene three times and dried in vacuum. Poluchaut.1 g of the desired compound.

Example 91 N-[4-(5H-Pyrrolo[2,1-c] [1,4] benzodiazepine-10(11H)-ylcarbonyl)phenyl]-2-(trifluoromethyl)benzamid.

To a solution of 0.413 g of 2-(trifluoromethyl)benzoyl chloride in 5 miltilingual under stirring and at 0oC added 0.346 g of triethylamine.Mix 3 mi and add 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine and stirring is continued for 18 CPRI room temperature. The reaction mass is diluted with 50 ml ethylacetate washed with water, 2 N. citric acid solution, N HCO3yasalam. The reaction mass is then dried with sodium sulfate, filtered iprivate in vacuum. Get a solid product, which crystallized satellitedata. Obtain 0.5 g of solid product, which is dissolved metalenclosed and miss che ez layer of water magnesium silicate. The filtrate pariwat vacuum, get a solid residue, which kristallizuyutsya. Allocate 0.210 g of the desired compound as white crystals, so pl. 226 - 228oC.

Example 92. 2-Methylphenylacetonitrile. 2 a Solution of 2.0 g of o-tolyloxy acid in 27 ml tenille three times, dried in vacuum. Get 2.1 galamaga compound as light-brown, CSOs oil.

Example 93. N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepine-10(11H)-ylcarbonyl)phenyl]-2-methylphenylacetic.

To a solution of 0.334 g of 2-methylphenylacetonitrile in 5 ml methylenchloride stirring and at 0oC added 0.346 g of triethylamine.P remediat 3 min and add 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine and stirring is continued for 72 h pikantnoi temperature. The reaction mass is diluted with 45 ml of methylene chloride promyvayut water, 2 N. citric acid solution, NaHCO3yasalam. The reaction mass is then dried with sodium sulfate, filtered carassai water magnesium silicate and evaporated in vacuum. Get twentypound that cleanse fast chromatography using kachestve went a mixture of ethyl acetate-hexane, 1:1, get a solid product, catherinetterings with ethyl acetate. Allocate 0.385 g of the desired compound in videbaek crystals, so pl. 198 - 200oC.

Example 94. 10,11-Dihydro-10-(3-methyl-4-nitrobenzoyl)-5H-pyrrolo 2,1-c] [1,4]benzodiazepine.

A mixture of 1.81 g of 3-methyl-4-nitrobenzoic acid and 1.25 thionylchloride in 75 ml of chloroform is boiled in an argon atmosphere in those who PM The obtained residue partially dissolve metalenclosed and filtered, the filtrate evaporated in vacuum, get 1.47 galamaga the carboxylic acid. A mixture of 1.36 g of the acid chloride, 0.90 N,N-Diisopropylamine and 1.25 g,11-Dihydro-5H-pyrrolo[ ,1-c][1,4]benzodiazepine in 25 ml of methylene chloride maintained at room temperature within 8 hours To the reaction mass, water is added, the organic layer otdelyayut dried with sodium sulfate, filter and add to the boiling filtrates. Obtain 1.4 g of the desired compound in the form of crystals, so pl. 246 - 248oC.

Example 95. 10,11-Dihydro-10-(4-amino-3-methylbenzoyl)-5H-pyrrolo[2,1-c] [1,4]benzodiazepine.

A mixture of 1.22 g 10,11-Dihydro-10-(3-methyl-4-nitrobenzoyl)-5H-pyrrolo[2,1-c] [1,4] benzodiazep ina, 0.2 g of 10% Pd/C and 0.35 g of messageposition in 50 ml of absolute ethanol is heated on a steam bath during 1 h, the Reaction mass was filtered hot through diatomaceous earth iprivate in vacuum. The resulting residue is crystallized mixture of methylene chloride-hexane to obtain 0.95 g of the desired compound in the form of crystals, so pl. 232 - 234oC.

Example 96. N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepine-10(11H)-ylcarbonyl)-2-were]-2-methylbenzamide.

A solution of 0.83 g of 10,11-dihydro-10-(4-am-but-3-IU the chloride is stirred at ControlTemplate within 18 PM The reaction mass is washed with water, organic closeout Sul blockhead sodium and passed through a water layer of magnesium silicate.To the filtrate at the boil add hexane to obtain 0.75 g of tverdokoraya, which is crystallized with a mixture of methylene chloride-hexane. Allocate 0.61 galamaga connection, so pl. 125 - 130oC. 2 table IV

Connection examples 97-115 obtained by the method of example 96 the application of the appropriate substituted Aronhold (see conatact).

Example 116.10,11-Dihydro-10[4-[[[(2-were)aminocarbonyl] amino] - benzoyl]-5H-pyrrolo[2 1-c][1,4]benzodiazepine.

A mixture of 0.93 g of 10,11-Dihydro-10-(4-amino-3-methylbenzoyl)-5H-Pyrrolo[2,1-c] [1,4]benzodiazepine and 0.37 g of o-trilinoleate 50 metamagician boil in an argon atmosphere for 24 hours of Flying componentiality in vacuum , get a residue, which is dissolved in methylenechloride passed through a water layer of magnesium silicate. To the filtrate kipriyanova hexane to obtain 0.68 g of the desired compound in whitecrystal, so pl. 155 - 158oC.

Example 117. N-[4-(5H-P Rolo[2,1-c][1,4]benzodiazepine-10(11H)-ylcarbonyl)phenyl]-1H-indol-5-carboxamide.

To a solution of 0.319 mg indole-5-carboxylic acid in 5 metamagician in the atmosphere th mysupermarket at room temperature for 2 hours Volatile componentiality in vacuum and the resulting residue is dissolved in 3 ml of xylene dobavlaut 500 mg,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c] [1,4] be zodiazepine and maintained at 120oC for 18 hours Flying componentiality in vacuum and the resulting residue partitioned between 40 platelett and water. The organic layer is separated, dried with magnesium sulfate iprivate in vacuum. Received estato clear chromatographytandem apreparation plates, eluent ethyl acetate: hexane, 1:1. Allocate 140 mulamula compound as an orange solid substance, so pl. 130 -170oC.

Example 118. 1-(o-Nitrobenzyl)-imidazole-2-carbaldehyde.

UAI SKU hydride sodium 2.0 g (60% in oil) was washed with two rajaputana. To the residue in an argon atmosphere add 110 N,N-dimethylformamide. With stirring and external cooling, add 4.80 G2-imidazolecarboxaldehyde and cooling stop. When some m Chaumes external nagrevaniya yellow solution. The reaction mass is then cooled with ice and dobavlaut.8 g of 2-nitrobenzylamine. The resulting reaction mass is stirred PIoC for 18 h the Volatile components removed in vacuo, poluchitstso to th is stirred with ice water, filtered and ostogo product, so pl. 141 - 144oC;MH+232.

Example 119. 10,11-Dihydro-5H-imidazo 2,1-c][1,4]benzodiazepine.

In 150 ml of hot ethanol dissolve 5.0 G1-(o-nitrobenzyl)-imidazole-2-carbaldehyde, the resulting solution is cooled to CONTROLTEMPLATES and filtered. The filtrate is added to 0.5 g of 10% Pd/C ismes hydronaut p and a pressure of 48 psig for 4 hours Add EXE.5 g of 10% Pd/C and the mixture hydronaut at a pressure of 65 pounds per square inch within 25 hours the Mixture is filtered through diatomaceous earth and the residue of nofilter washed with ethyl acetate. The filtrate is evaporated in the Vake me and polojenieto dissolved in methylene chloride, treated with activated charcoal,filtered through diatomaceous earth, the filtrate at the boil add hexane.Obtain 1.86 g of the desired compound in the form of crystalline tverdokoraya, so pl. 164 - 170oC.

Example 120. 10,11-Dihydro-5H-imidazo[2,1-c][1,4]benzodiazepine.

To a suspension of 4 mmol of lithium aluminum hydride in 20 ml of besttravelerinsurance add 1 mmol restora,11-Dihydro-11-oxo-5H-imidazo[2,1-c][1,4] benzodiazepine and receive nnuu the mixture is boiled for 24 h ohlajdaet to 0oC. To the mixture are added dropwise 0.12 ml of water and 6 ml of 1 n sodium hydroxide solution. A mixture of extracranially from a mixture of methylene chloride-hexane procalcitonine product, so pl. 164 - 170oC.

Example 121. N-[4-(5H-imidazo[2,1-c][1,4]benzodiazepine-10(11H)-ylcarbonyl)phenyl]-2-methylbenzamide.

To a mixture of 1.37 g (5 mmol) 4-[(2-methyl entail)amino]benzoyl chloride 15 ml of methylene chloride, cooled to 0oC add 1.5 metrically. Stirred for 3 min and add 5 mmol 10,11-dihydro-5H-imidazo[2,1-c][1,4]benzodiazepine in 5 ml of methylene chloride. Cooling clean priblizitel about 30 minutes get the solution. The reaction mysupermarket at room temperature for 1 h and the volatile components pariwat vacuum. The residue is dissolved in 100 ml ethyl acetate and washed with water, 2n. the citric acid solution and brine. Rast'or dried surfacematerial and concentrated in vacuo. Get the desired connection in videotage product.

Example 122. 10,11-Dihydro-10-(4-nitrobenzoyl)-5H-imidazo[2,1-c][1,4]benzodiazepine.

To a solution of 10 mmol,11-dihydro-5H-imidazo[2,1-c][1, ]benzodiazepine in 50 ml of methylene chloride in an argon atmosphere add 15 militiamen then cooled by an ice bath. Then Calendarist a solution of 10 mmol of 4-nitrobenzaldehyde in 10 ml of methylene chloride. Pokonanie add cooling is removed and the reaction mass is stirred pikantnoi testate. Restorelayout water and brine. The organic layer is dried with sodium sulphate,f trout and evaporated in vacuum. The obtained solid residue is distilled bystroprokhodahaya and produce the desired compound in the form of solids.

Example 123. 10,11-Dihydro-10-(4-aminobenzoyl)-5H-imidazo[2,1-c][1,4]benzodiazepine.

A mixture of 5 mmol of 0.11-dihydro-10-(4-nitrobenzoyl)-5H-imidazo[2,1-c][1,4]benzodiazepine in 10 ml of ethanol and 10 ml of ethyl acetate with 0.2 g% Pd/C hydronaut for 5 h in a Parr apparatus at galleriesadult 35 pounds per square inch. The reaction mass is filtered across slidetoplay land. The filtrate was concentrated in vacuo, get a solid product,which was purified by rapid chromatography. Get the desired connection.

Example 124. 10,11-Dihydro-10-(4-aminobenzoyl)-5H-imidazo[2,1-c] [1,4] benzodiazepine.

To Rast ru 5 mmol 10,11-dihydro-10-(4-nitrobenzoyl)-5H-imidazo[2,1-c] [1,4]benzodiazepine in 100 ml of ethyl alcohol add 0.5 g% Pd/C and 10 mmol of hydrazine followed by boiling for 3 hours the Reaction mass is filtered through diatomaceous earth. F. ltrate evaporated vacuume and the resulting residue is dissolved in methylene chloride and proposalthat layer of water magnesium silicate. The filtrate is concentrated the society.

Example 125. N-[4-(5H-imidazo[2,1-c][1,4]benzodiazepine-10(11H)-ylcarbonyl)phenyl]-2-methylbenzamide.

To a solution of 1 mmol of 2-metabisulphite in 10 ml methylenchloride stirring, 1.5 mmol of triethylamine. Stirred for 15 min dobavlaut 1 mmol 1,11-dihydro-10-(4-aminobenzoyl)-5H-imidazo[2,1-c][1,4]benzodiazepine and the resulting mixture is stirred for 5 hours the Reaction mass is washed with water and brine, dried with sodium sulfate, filtrate the filtrate evaporated in vacuum. The floor indicate the solid residue, motoryacht fast chromatography and produce the desired compound in the form of Targovishte.

Table V

Connection examples 126-150 obtained by the method of example 125 the application of the appropriate substituted Aronhold (see conatact).

Example 151. N-[4-(7-chloro-5H-imidazo[2,1-c][1,4]benzodiazepine-10(11H)-ylcarbonyl)phenyl]-2-methylbenzamide.

By the method similar to the method of example 125, a mixture of 1 mmol-chloro-10,11-dihydro-5H-imidazo[2,1-c] [1,4] benzodiazepine , 1.1 mmol-[(2-methylbenzoyl)] aminobenzoylamino and 1.5 mmol of triethylamine in 10 miltilingual stirred at room temperature for 3 h and post-receive the desired compound in the form of solids.

codice, analogous to the methods of example 125, a mixture of 1 mmol-methoxy-10,11-dihydro-5H-imidazo[2,1-c] [1,4] benzodiazepine, 1.1 mmol-[(2-methylbenzoyl)] aminobenzoyl chloride and 1.5 mmol of triethylamine in 10 miltilingual stirred at room temperature for 3 h and post-receive the desired compound in the form of solids.

Example 153. N-[4-(7,8-methylenedioxy-5H-imidazo[2,1-c] [1,4] is the growing presence of EPIN-10(11H)-ylcarbonyl)phenyl]-2-methylbenzamide.

By the method similar to the method of example 125, a mixture of 1 mmol,8-methylenedioxy-10,11-dihydro-5H-imidazo[2,1-c] [1,4] benzodiazepine, 1.1 mmol of 4-[(2-methylbenzoyl)] aminobenzoylamino and 1.5 mmol of Treaty amine in 10 ml of methylene chloride is stirred at room temperature for 3 Chi after treatment receive the desired compound in the form of Targovishte.

Example 154. 4,5-Dihydro-5-(4-nitrobenzoyl)pyrrolo[1,2-a]cinoxacin.

To a solution of 5 mmol of 4,5 dihydro-pyrrolo[1,2-a]finokalia 50 miltilingual in the atmosphere of argon added 10 mmol of triethylamine posleduyushim cooling ice bath. Then added dropwise a solution of mmol 4-nitrobenzaldehyde in 10 ml of methylene chloride. On okonchaniyam of the ice bath removed and the reaction mass stirred at contrarotate. The resulting solution was promyvayut, 1 N. hydrochloric keys, the notes, NaHCO3and brine. Smashcast sodium sulfate, filtered evaporated in vacuum, get twentypound that cleanse fast chromatography. Allocate Telemanagement (from ethyl acetate) in the form of a solid substance, so pl. 174 - 178oC. 2 Example 155. 4,5-Dihydro-5-(4-aminobenzoyl)pyrrolo[1,2-a] cinoxacin.

A mixture of 1 mmol of 4,5-dihydro-5-(4-nitrobenzoyl)pyrrolo[1,2-a]-chinoline in 10 ml of ethanol and 10 ml of ethyl acetate with 0.2 g of 10% Pd/Shinryuu for 5 hours the Reaction mA su filtered through slidetoplay land. The filtrate was concentrated in vacuo, get a solid product,which was purified by rapid chromatography and highlight the desired connection,so pl. 225 - 228oC.

Example 156. 4,5-Dihydro-5-(4-aminobenzoyl)pyrrolo[1,2 a]cinoxacin.

To a solution of 1 mmol of 4,5-dihydro-5-(4-nitrobenzoyl)pyrrolo[1,2-a]finokalia in 20 ml of ethyl alcohol add 0.2 g of 10% Pd/C and 2.5 mmol of hydrazine, and then stirred and boiled for 2 hours Oracollection mass is filtered via diatomaceous earth, the precipitate filteredrowset hot chloroform and the filtrate was concentrated in vacuo. Polojenieto triturated with ethyl acetate and filtered, flogged[1,2-a] cinoxacin-5(4H)-ylcarbonyl)phenyl]-2-methylbenzamide.

To a solution of 1.5 mmol of 2-methylbenzylamine in 10 ml methylenchloride stirring, 3 mmol of triethylamine. Mix in techenie min and add 1.5 m ol,5-dihydro-5-(4-aminobenzoyl)pyrrolo[1,2-a]cinoxacin. The resulting reaction mixture is stirred for 5 h, asetem washed with water, 1 N. hydrochloric acid, NaHCO3yasalam, dried with sodium sulfate, filtered and evaporated in vacuo that is, Get a solid residue, which is purified by rapid chromatography. Vydelenijami connection in the form of a solid substance, so pl. 206 - 207oC.

Table VI

Connection examples 158-180 obtained by the method of example 157 the application of relevant existing substituted Aronhold (see conatact).

Example 181. 9,10-Dihydro-4H-furo[2,3-e]pyrrolo[1,2-a][1,4]diazepin.

To a suspension of 4 mmol of lithium aluminum hydride in 25 ml of besttravelerinsurance add 1 mmol,10-dihydro-4H-furo[2,3-e]feast olo[1,2-a][1,4]diazepin-9-it. The mixture is boiled for 12 h and incubated in techeneenii. To the resulting reaction mass added dropwise 0.12 ml of water, the click 6 ml of 1 n sodium hydroxide solution. The mixture extrahypothalamic and the extract is dried Sul atom of sodium. Volatile components are removed vacuume get the LASS="ptx2">

A solution of 1 mmol 4H-furo[2,3-e]pyrrolo[1,2-a][1,4]diazepine and 0.2 g% Pd/C in 10 ml of ethyl acetate and 10 ml of ethanol hydronaut in techenie hours the Reaction mass is filtered through diatomaceous earth and filtrative in vacuum, get the desired compound in the form of solids.

Example 183. N-[4-(4H-Furo[2,3-e] pyrrolo 1,2-a] [1,4]diazepin-10(9H)- ylcarbonyl)phenyl]-2-methylbenzamide.

To a mixture of 1.1 mmol of 4-[(2-methylbenzoyl)amino]benzoyl chloride in 10 miltilingual POI 0oC add 1 mmol,10-dihydro-4H-furo[2,3-e]pyrrolo[1,2-a] [1,4] diazepine and the mixture paramashiva t when ControlTemplate within 2 hours the Reaction mass was concentrated in vacuo, osteoclastoma in 100 ml ethyl acetate and washed with water, 2 N. solution limnoecology, aqueous solution of NaHCO3and brine. The resulting rastvoryat sodium sulfate and vacuum evaporated volatile components.Get a solid residue, which is purified by rapid chromatography and vydelenijami connection.

Example 184. 9,10-Dihydro-10-(4-nitrobenzoyl)-4H-furo[2,3-e] pyrrolo-[1,2-a][1,4]diazepin.

To dissolve in 1.0 mmol,10-dihydro-4H-furo[2,3-e]pyrrolo-[1,2-e]diazepine in 10 ml of methylene chloride in an argon atmosphere add 1.5 militiamen and then cooled in the ice banaana bath removed and the reaction mass is stirred pikantnoi temperature for 2 hours Volatile components are removed under vacuum poluchenii the residue is dissolved in ethyl acetate. The solution is washed with water, 1 N. hydrochloric acid, in dnim solution of NaHCO3and brine. Satelections the mass is dried with sodium sulfate, filtered and evaporated in vacuum.The obtained solid residue purified by rapid chromatography on silica gel,to obtain the desired compound in the form of solids.

Example 185. 9,10-Dihydro-10-(4-aminobenzoyl)-4H-furo[2,3-e] pyrrolo[1,2-a][1,4]diazepin.

A mixture of 1 mmol of 9,10-dihydro-10-(4-nitrobenzoyl)-4H-furo[2,3-e] pyrrolo[1,2-a] [1,4] diazepine in 10 ml of ethanol and 10 ml of ethyl acetate and 0.2 g of 10% Pd/C hydronaut for 5 hours the Reaction mass is filtered through a layer of diatomaceous earth. The filtrate was concentrated in vacuo, get a solid residue, which is purified by rapid chromatography on silica gel and produce the desired connection.

Example 186. 9,10-Dihydro-10-(4-aminobenzoyl)-4H-furo[2,3-e] pyrrolo[1,2-a][1,4] diazepin.

To a solution of 1 mmol of 9,10-dihydro-10-(4-nitrobenzoyl)-4H-furo[2,3-e]pyrrolo[1,2-a] [1,4] diazepine in 20 ml of ethyl alcohol add 0.2 g of 10% Pd/C and 2.5 mmol of hydrazine, and then boiled and stirred for 3 hours At room temperature, the reaction mixture was filtered through datamodule of magnesium silicate. The filtrate was concentrated in vacuo and get the desired compound which is purified by rapid chromatography on silica gel, separating the solid product.

Example 187. N-[4-(4H-furo[2,3-e] pyrrolo[1,2-a][1,4]diazepin-10 (9H)-ylcarbonyl)phenyl]-2-methylbenzamide.

To a solution of 1.1 mmol of 2-methylbenzylamine in 10 ml of methylene chloride was added with stirring 1.5 mmol of triethylamine. To the obtained mixture is added 1.1 mmol of 9,10-dihydro-10-(4 - aminobenzoyl)-4H-furo[2,3-e] pyrrolo[1,2-a] [1,4] diazepine and stirred for 5 hours the Reaction mass is washed with water, 2 N. citric acid solution, aqueous solution of NaHCO3and brine. The resulting solution was dried with sodium sulfate and evaporated in vacuum to Obtain a solid residue, which is purified by rapid chromatography on silica gel, eluent ethyl acetate-hexane. Highlight the desired compound in the form of solids.

Table VII (end of text)

Connection examples 188 - 209 obtained by the method of example 187 using the appropriate substituted Aronhold.

Example 210. N-[4-(4H-Pyrazolo[5,1-c] [1,4]benzodiazepine-5(10H)- ylcarbonyl)phenyl]-2-methylbenzamide.

To a mixture of 1.37 g of 4-[(2-methylbenzoyl)amino]benzoyl chloride in 15 ml of methylene chloride at 0oC add the Assu stirred at room temperature for 48 h and the volatile components evaporated in vacuum. The resulting residue is dissolved in 100 ml ethyl acetate and washed with water, 2 N. citric acid solution, aqueous solution of NaHCO3and brine. The resulting solution was dried with sodium sulfate and evaporated in vacuum. Get a solid residue, which is purified by rapid chromatography on silica gel, eluent ethyl acetate-hexane. Highlight the desired compound in the form of a solid substance, so pl. 142-146oC.

Example 211. 5,10-Dihydro-5-(4-nitrobenzoyl)-4H-pyrazolo[5,1-c][1,4]benzodiazepine.

To a solution of 10 mmol 5,10-dihydro-4H-pyrazolo[5,1-c][1,4]benzodiazepine in 50 ml of methylene chloride in an argon atmosphere is added 15 mmol of triethylamine and cooled in the ice bath. Then added dropwise a solution of 11 mmol of 4-nitrobenzaldehyde in 10 ml of methylene chloride. At the end of the addition the ice bath removed and the reaction mixture was stirred at room temperature for 2 h the Volatile components are evaporated in vacuo and the resulting residue is dissolved in ethyl acetate. The solution is washed with water, aqueous solution of NaHCO3and brine. Then the reaction mass is dried with sodium sulfate, filtered and evaporated in vacuum. Get a solid residue, which is purified by rapid chromatography on silica gel. Highlight the desired compound in the form of zodiazepine.

A mixture of 5 mmol 5,10-dihydro-5-(4-nitrobenzoyl)-4H-pyrazolo[5,1-c][1,4]-benzodiazepine in 25 ml of ethanol and 10 ml of ethyl acetate and 0.2 g of 10% Pd/C hydronaut for 5 hours the Reaction mass is filtered through diatomaceous earth. The filtrate was concentrated in vacuo, the obtained residue is purified by rapid chromatography on silica gel. Highlight the desired compound in the form of solids.

Example 213. 5,10-Dihydro-5-(4-aminobenzoyl)-4H-pyrazolo[5,1-c][1,4]-benzodiazepine.

To a solution of 5 mmol 5,10-dihydro-5-(4-nitrobenzoyl)-4H-pyrazolo[5,1-c] [1,4] -benzodiazepine in 25 ml of ethyl alcohol add 0.3 g 10% Pd/C and 15 mmol of hydrazine. The mixture is boiled for 3 h and then filtered through diatomaceous earth. The filtrate was concentrated in vacuo, the obtained residue is purified by rapid chromatography on silica gel. Highlight the desired compound in the form of solids. Mass spectrum: 305.1402 (M+H).

Example 214. N-[4-(4H-Pyrazolo[5,1-c] [1,4]benzodiazepine-5(10H)- ylcarbonyl)phenyl]-2-methylbenzamide.

To a solution of 3 mmol of 2-methylbenzylamine in 10 ml of methylene chloride was added with stirring 5 mmol of triethylamine and 3 mmol 5,10-dihydro-5-(4-aminobenzoyl)-4H-pyrazolo[5,1-c][1,4]-benzodiazepine. The resulting mixture was stirred at room Tempe is a sodium atom, filtered and evaporated in vacuum. Get a solid residue, which is purified by rapid chromatography on silica gel. Highlight the desired compound in the form of a solid substance, so pl. 142-146oC.

Table VIII (end of text)

Connection examples 215 - 237 obtained by the method of example 214 using the appropriate substituted Aronhold.

Example 238. 9,10-Dihydro-4H-pyrrolo[1,2-a]thieno[2,3-e][1,4] diazepin.

To a solution of 7.0 g of 9-oxo-9,10-dihydro-4H-pyrrolo[1,2-a]thieno[2,3-e][1,4] diazepine in 25 ml of anhydrous tetrahydrofuran (THF) add 9 ml of 10 M solution of boron-dimethyl sulfide in tetrahydrofuran. The mixture is boiled for 6 hours the Solution is cooled to room temperature and added dropwise 25 ml of methanol. Volatile components are evaporated in vacuum. To the obtained residue was added 100 ml of 2 n NaOH solution. The mixture is boiled for 5 h and filtered. The solid residue is extracted with methylene chloride and the extract washed with 2 N. citric acid solution, water and brine, dried with sodium sulfate. The solvent is evaporated in vacuum, get the desired compound in the form of solids.

Example 239. N-[4-(4H-Pyrazolo[1,2-a]thieno[2,3-e][1,4]diazepin - 10(9H)-ylcarbonyl)phenyl]-2-methylbenzamide.

To a mixture of 1.37 g (5 mmol) 4-military mixture is added 5 mmol of 9,10-dihydro-4H-pyrazolo[1,2-a]thieno[2,3-e][1,4]diazepine. The cooling is removed and the reaction mass was stirred at room temperature for 48 hours, Volatile components are evaporated in vacuo and the resulting residue is dissolved in 100 ml of ethyl acetate. The solution is washed with water, 2 N. citric acid solution, aqueous solution of NaHCO3and brine. Then the solution is dried with sodium sulfate, filtered and evaporated in vacuum. Get a solid residue, which is purified by rapid chromatography on silica gel. Highlight the desired compound in the form of solids.

Example 240. 9,10-Dihydro-10-(4-nitrobenzoyl)-4H-pyrazolo[1,2-a] thieno[2,3-e][1,4] diazepin.

To a solution of 10 mmol of 9,10-dihydro-4H-pyrrolo[1,2-a]thieno[2,3-e][1,4]diazepine in 50 ml of methylene chloride under nitrogen atmosphere is added 15 mmol of triethylamine and cooled in the ice bath. Then added dropwise a solution of 11 mmol of 4-nitrobenzaldehyde in 10 ml of methylene chloride. At the end of the addition the ice bath removed and the reaction mixture was stirred at room temperature for 2 h the Volatile components are evaporated in vacuo and the resulting residue is dissolved in ethyl acetate. The solution is washed with water, 1 N. hydrochloric acid, aqueous solution of NaHCO3and brine. The organic layer is dried with sodium sulfate, filtered and upravujeme connection in the form of a solid substance.

Example 241. 9,10-Dihydro-10-(4-aminobenzoyl)-4H-pyrrolo[1,2-a] thieno-[2,3-e][1,4]diazepin.

A mixture of 2 g of 9,10-dihydro-10-(4-nitrobenzoyl)-4H-pyrrolo[1,2-a] thieno-[2,3-e] [1,4] diazepine in 20 ml of ethanol and 20 ml of ethyl acetate and 0.2 g of 10% Pd/C hydronaut for 5 hours the Reaction mass is filtered through a layer of diatomaceous earth. The filtrate was concentrated in vacuo, the resulting solid residue is purified by rapid chromatography. Highlight the desired connection.

Example 242. 9,10-Dihydro-10-(4-aminobenzoyl)-4H-pyrrolo[1,2-a]thieno-[2,3-e][1,4] diazepin.

To a solution of 5 mmol of 9,10-dihydro-10-(4-nitrobenzoyl)-4H-pyrrolo[1,2-a] thieno-[2,3-e] [1,4] diazepine in 25 ml of ethanol is added 0.13 g of 10% Pd/C and 15 mmol of hydrazine. The mixture is stirred and boiled for 3 h, and then cooled and filtered through diatomaceous earth. The filtrate was concentrated in vacuo, the obtained residue is dissolved in methylene chloride and passed through a water layer of magnesium silicate. The filtrate was concentrated in vacuo, the residue is purified by rapid chromatography on silica gel. Highlight the desired compound in the form of solids.

Example 243. N-[4-(4H-pyrrolo[1,2-a]thieno-[2,3-e][1,4]diazepin-10(9H)-ylcarbonyl) phenyl]-2-methylbenzamide.

To a solution of 5 mmol of 2-methylbenzoyl who yl)-4H-pyrrolo[1,2-a]thieno[2,3-e][1,4] diazepine and the resulting mixture is stirred for 5 hours The reaction mass is washed with water, 2 N. citric acid solution, aqueous solution of NaHCO3and brine. Then the organic layer dried with sodium sulfate, filtered and evaporated in vacuum. Get a solid residue, which is purified by rapid chromatography on silica gel. Highlight the desired compound in the form of solids.

Table IX (end of text)

Connection examples 244 - 265 obtained by the method of example 243, using the appropriate substituted Aronhold.

Example 266. 4,10-Dihydro-5H-pyrrolo[1,2-a]thieno[3,2-e][1,4] diazepin.

To a suspension of 7.0 g of 5-oxo-4,5-dihydro-4H-pyrrolo[1,2-a]thieno[3,2-e][1,4] diazepine in 25 ml of anhydrous tetrahydrofuran (THF) add 9 ml of 10 M solution of boron-dimethyl sulfide in tetrahydrofuran. The mixture is boiled for 6 hours the Solution is cooled to room temperature and added dropwise 25 ml of methanol. Volatile components are evaporated in vacuum. To the obtained residue was added 100 ml of 2 n NaOH solution. The mixture is boiled for 5 h and filtered. The solid residue is extracted with methylene chloride and the extract washed with 2 N. citric acid solution and water, dried with sodium sulfate. The solvent is evaporated in vacuum, get the desired compound in the form of solids.

Found: C, 69.5; H, 5.2; N, 9.6; S 7.0.

Example 268. 4,10-Dihydro-4-(4-nitrobenzoyl)-5H-pyrrolo[1,2-a] thieno[3,2-e][1,4]diazepin.

To a solution of 3 mmol 4,10-dihydro-5H-pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine in 10 ml of metilenhloride in the atmosphere of nitrogen is added 5 mmol of triethylamine and cooled in the ice bath. Then added dropwise a solution of 3.3 mmol 4-nitrobenzotrifluoride in 3 ml of methylene chloride. At the end of the addition the ice bath removed and the reaction mixture was stirred at room temperature for vodou, 2 N. citric acid solution, aqueous solution of NaHCO3and brine. The organic layer is dried with sodium sulfate, filtered and evaporated in vacuum. Get a solid residue, which is purified by rapid chromatography on silica gel. Highlight the desired compound in the form of solids.

Example 269. 4,10-Dihydro-4-(4-aminobenzoyl)-5H-pyrrolo[1,2-a] thieno[3,2-e][1,4]diazepin.

A mixture of 5 mmol 4,10-dihydro-4-(4-aminobenzoyl)-5H-pyrrolo[1,2-a] thieno[3,2-e] [1,4] diazepine in 25 ml of ethanol and 20 ml of ethyl acetate and 0.2 g of 10% Pd/C hydronaut for 5 hours the Reaction mass is filtered through a layer of diatomaceous earth. The filtrate was concentrated in vacuo, the resulting solid residue is purified by rapid chromatography. Highlight the desired connection.

Example 270. 4,10-Dihydro-4-(4-aminobenzoyl)-5H-pyrrolo[1,2-a]thieno[3,2-e] [1,4] diazepin.

To a solution of 5 mmol 4,10-dihydro-4-(4-nitrobenzoyl)-5H-pyrrolo[1,2-a]thieno[3,2-e] [1,4] diazepine in 25 ml of ethyl alcohol add 0.3 g 10% Pd/C and 15 mmol of hydrazine. The mixture is stirred and boiled for 3 h, and then cooled and filtered through diatomaceous earth. The filtrate was concentrated in vacuo, the obtained residue is dissolved in methylene chloride and passed through a water layer of magnesium silicate. Voudintie in the form of a solid substance.

Example 271. N-[4-(5H-pyrrolo[1,2-a]thieno[3,2-e][1,4] diazepin-4(10H)-ylcarbonyl)phenyl]-2-methylbenzamide.

To a solution of 3 mmol of 2-methylbenzylamine in 10 ml of methylene chloride was added with stirring 5 mmol of triethylamine and 3 mmol 4,10-dihydro-4-(4-aminobenzoyl)-5H-pyrrolo[1,2-a] thieno[3,2-e] [1,4] diazepine and the resulting mixture is stirred for 5 hours the Reaction mass is washed with water, 2 N. citric acid solution, aqueous solution of NaHCO3and brine. Then the reaction mass is dried with sodium sulfate, filtered and evaporated in vacuum. Get a solid residue, which is purified by rapid chromatography on silica gel. Highlight the desired compound in the form of a solid substance, so pl. 162-188oC (Amorin. ).

Table X (end of text)

Connection examples 272 - 293 obtained by the method of example 271 using the appropriate substituted Aronhold.

Example 294. 6,7-dihydro-5-(4-nitrobenzoyl)-5H-pyrrolo[1,2-a] [1,5]-benzodiazepine.

To a solution of 10 mmol of 6,7-dihydro-5-(4-nitrobenzoyl)-5H-pyrrolo[1,2-a] [1,5] -benzodiazepine in 30 ml of methylene chloride under nitrogen atmosphere is added 15 mmol of triethylamine and cooled in the ice bath. Then added dropwise a solution of 11 mmol of 4-nitrobenzaldehyde in 10 ml methylene within 2 hours Volatile components are evaporated in vacuo and the resulting residue is dissolved in ethyl acetate. The solution is washed with water, 2 N. citric acid solution, aqueous solution of NaHCO3and brine. The reaction mass is dried with sodium sulfate, filtered and evaporated in vacuum. Get a solid residue, which is purified by rapid chromatography on silica gel. Highlight the desired compound in the form of solids.

Example 295. 6,7-dihydro-5-(4-aminobenzoyl)-5H-pyrrolo[1,2-a] [1,5]-benzodiazepine.

A mixture of 2 g of 6,7-dihydro-5-(4-nitrobenzoyl)-5H-pyrrolo[1,2-a] [1,5]-benzodiazepine, 25 ml of ethanol and 20 ml of ethyl acetate and 0.2 g of 10% Pd/C hydronaut for 5 hours the Reaction mass is filtered through a layer of diatomaceous earth. The filtrate was concentrated in vacuo, the resulting solid residue is purified by rapid chromatography. Highlight the desired connection.

Example 296. 6,7-dihydro-5-(4-aminobenzoyl)-5H-pyrrolo[1,2-a][1,5]-benzodiazepine.

To a solution of 5 mmol of 6,7-dihydro-5-(4-aminobenzoyl)-5H-pyrrolo[1,2-a][1,5] -benzodiazepine in 25 ml of ethyl alcohol add 0.3 g 10% Pd/C and 15 mmol of hydrazine. The mixture is stirred and boiled for 3 h, and then cooled and filtered through diatomaceous earth. The filtrate was concentrated in vacuo, poluchayut in vacuum, the residue is purified by rapid chromatography on silica gel. Highlight the desired compound in the form of solids.

Example 297. N-[4-[(6,7-dihydro-5H-pyrrolo[1,2-a][1,5] benzodiazepine-5-yl)carbonyl]phenyl]-2-methylbenzamide.

To a mixture of 1.37 g (5 mmol) 4-[(2-methylbenzoyl)amino]benzoyl chloride in 10 ml of methylene chloride at 0oC add 7 mmol of triethylamine and 5 mmol of 6,7-dihydro-5H-pyrrolo[1,2-a] [1,5] benzodiazepine. The cooling is removed and the reaction mass was stirred at room temperature for 48 hours, Volatile components are evaporated in vacuo and the resulting residue is dissolved in 100 ml of ethyl acetate. The solution is washed with water, 2 N. citric acid solution, aqueous solution of NaHCO3and brine. Then the solution is dried with sodium sulfate, filtered and evaporated in vacuum. Get a solid residue which is triturated with a mixture of ether-hexane to produce the desired compound mass spectrum: 422 (M+H).

Example 298. N-[4-[(6,7-dihydro-5H-pyrrolo[1,2-a][1,5] benzodiazepine-5-yl)carbonyl]phenyl]-2-methylbenzamide.

To a solution of 5 mmol of 2-methylbenzylamine in 10 ml of methylene chloride was added with stirring 7 mmol of triethylamine and 3 mmol of 6,7-dihydro-5-(4-aminobenzoyl)-5H-pyrrolo[1,2-a] [1,5] benzodiazepine and the resulting mixture premesis the UB> and brine. Then the reaction mass is dried with sodium sulfate, filtered and evaporated in vacuum. Get a solid residue, which is purified by rapid chromatography on silica gel. Highlight the desired compound in the form of a solid; mass spectrum (chemical ionization): 422 (M+H).

Table XI (end of text)

Connection examples 299 - 320 obtained by the method of example 298, using the appropriate substituted Aronhold.

Example 321. 5,6-Dihydro-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepine.

To 7.0 g of 5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepine-5-it in 25 ml of tetrahydrofuran, add 9 ml of 10 M solution of boron-dimethyl sulfide in tetrahydrofuran. The mixture is boiled for 6 h, cooled to room temperature and added dropwise 25 ml of methanol. Volatile components are removed in vacuo and to the residue was added 100 ml of 2 n sodium hydroxide solution. The mixture is boiled for 5 hours, cooled and extracted with chloroform. The extract was washed with 2 N. citric acid, water and dried with sodium sulfate. The solvent is evaporated in vacuum and get a solid product, which was purified by chromatographytandem on silica gel. Highlight the desired connection.

Example 322. N-[4-(4H-[1,2,4]triazolo[4,3-is lo[4,3-a] [1,5] benzodiazepine in 20 ml of methylene chloride added 5.5 mmol of 4-[(2-methylbenzoyl)amino] benzoyl chloride and then 7.5 mmol of triethylamine. The mixture is stirred at room temperature for 8 h, and then washed with water, aqueous solution of NaHCO3and brine. Then the solution is dried with sodium sulfate, filtered and evaporated in vacuum. Get a solid residue, which is purified by rapid chromatography on silica gel, eluent ethyl acetate-hexane to produce the desired compound in the form of a glassy mass.

Example 323. 5,6-Dihydro-6-(4-nitrobenzoyl)-4H-[1,2,4] triazolo[4,3-a] [1,5]benzodiazepine.

To a solution of 3 mmol of 5,6-dihydro-4H-[1,2,4]triazolo[4,3-a] [1,5]benzodiazepine in 10 ml of methylene chloride under nitrogen atmosphere add 5 mmol of triethylamine. Then to the mixture is added dropwise a solution of 3.3 mmol 4-nitrobenzotrifluoride in 3 ml of methylene chloride. The reaction mixture was stirred at room temperature for 3 h, washed with water, aqueous solution of NaHCO3and brine. The organic layer is dried with sodium sulfate, filtered and evaporated in vacuo of the solvent. Get a solid residue, which is purified by rapid chromatography on silica gel. Highlight the desired compound in the form of solids.

Example 324. 5,6-Dihydro-6-(4-aminobenzoyl)-4H-[1,2,4]triazolo [4,3-a] [1,4]benzodiazepine.

To a solution of 5 mmol of 5,6-dihydro-6-(4-aminobenzoyl)-4H- [1,2,4]three is more and boiled for 3 h, and then cooled and filtered through diatomaceous earth. The filtrate was concentrated in vacuo, the obtained residue is dissolved in methylene chloride and passed through a water layer of magnesium silicate. The filtrate was concentrated in vacuo, the residue is purified by rapid chromatography on silica gel. Highlight the desired compound in the form of solids.

Table XII (end of text)

Connection examples 325 - 351 obtained by the method of example 322, using the appropriate substituted Aronhold.

Example 352. N-[4-(1-Methyl-4H-[1,2,4] triazolo[4,3-a] [1,5]benzodiazepine-6(5H)-yl)carbonyl]phenyl]-2-methylbenzamide.

To a solution of 5 mmol of 5,6-dihydro-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,5] benzodiazepine in 20 ml of methylene chloride added 5.5 mmol of 4-[(2-methylbenzoyl)amino] benzoyl chloride and then 7.5 mmol of triethylamine. The mixture is stirred at room temperature for 8 h, and then washed with water, aqueous solution of NaHCO3and brine. Then the organic layer dried with sodium sulfate, filtered and evaporated in vacuum. Get a solid residue, which is purified by rapid chromatography on silica gel, eluent ethyl acetate-hexane to produce the desired connection.

Example 353. N-[4-(1-Methyl-4H-[1,2,4]triazolo[4,3-a][1,5]benzo,3-a][1,5]benzodiazepine in 20 ml of methylene chloride added 5.5 mmol of 4-[(2,4-dichlorobenzoyl)amino] benzoyl chloride and then 7.5 mmol of triethylamine. The mixture is stirred at room temperature for 8 h, and then washed with water, aqueous solution of NaHCO3and brine. Then the organic layer dried with sodium sulfate, filtered and evaporated in vacuum. Get a solid residue, which is purified by rapid chromatography on silica gel, eluent ethyl acetate-hexane to produce the desired connection.

Example 354. N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepine-10(11H)-ylcarbonyl-phenyl]-3 - cyclohexenecarboxylic.

A mixture of 0.50 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4] benzodiazepine, being 0.286 g of 3-cyclohexanecarbonitrile and 346 μl of triethylamine in 5 ml of methylene chloride is stirred at room temperature for 16 hours the Reaction mass is diluted with 50 ml of methylene chloride and the solution washed with 20 ml of water, 2 N. citric acid solution, 1 N. aqueous solution of NaHCO3and brine. Then the organic layer dried with sodium sulfate, filtered through a thin layer of water magnesium silicate and the filtrate evaporated in vacuum. Get a solid residue, which is purified by thin-layer chromatography on plates, get a solid residue which is crystallized from ethyl acetate. Allocate 0.34 g of crystalline compounds, so pl. 216-218oC.

Example 355. N-[4-(5H-Pyrrolo[opencellid in 5 ml of methylene chloride at 0oC add 0.50 g of 10,11-dihydro-10-(4-benzoyl)-5H-pyrrolo[2,1-c][1,4] benzodiazepine and 346 μl of triethylamine. The resulting mixture was stirred at room temperature for 16 h and diluted with 50 ml of methylene chloride and the solution washed with 20 ml of water, 2 N. citric acid solution, 1 M aqueous solution of NaHCO3and brine. Then the organic layer dried with sodium sulfate, filtered through a thin layer of water magnesium silicate and the filtrate evaporated in vacuum. Get a solid residue which is crystallized from ethyl acetate. Allot of 0.53 g of crystalline compounds, so pl. 235-238oC.

Example 356. N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepine-10(11H)-ylcarbonyl)phenyl]- cyclohexylacetate.

To a solution of 0.318 g of cyclohexylethylamine in 5 ml of methylene chloride at 0oC add 0.50 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c] [1,4] benzodiazepine and 346 μl of triethylamine. The resulting mixture was stirred at room temperature for 16 h, diluted with 50 ml of methylene chloride and the solution washed with 20 ml of water, 2 N. citric acid solution, 1 M aqueous solution of NaHCO3and brine. Then the organic layer dried with sodium sulfate, filtered through a thin layer of water magnesium silicate and the filtrate evaporated in vacuum. Recip is -234oC.

Example 357. N-[4-(5H-Pyrrolo[{ 2,1-c][1,4]benzodiazepine-1-(11H)-ylcarbonyl)phenyl] -2-perbenzoate.

To a solution of 0.342 g of 2-perforazione in 5 ml of methylene chloride at 0oC add 0.50 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c] [1,4] benzodiazepine and 346 μl of triethylamine. The resulting mixture was stirred at room temperature for 16 h and diluted with 50 ml of methylene chloride. The solution is washed with 20 ml of water, 2 N. citric acid solution, 1 M aqueous solution of NaHCO3and brine and dried with sodium sulfate. Then the solution is filtered through a thin layer of water magnesium silicate and the filtrate evaporated in vacuum. Get tverdyate, which is crystallized from ethyl acetate. Allocate 0.43 g of crystalline compounds, so pl. 204-207oC.

Example 358. N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepine-10(11H)-ylcarbonyl)phenyl]- cyclohexanecarboxylic.

To a solution of 0.342 g cyclohexanecarbonitrile in 5 ml of methylene chloride at 0oC add 0.50 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c] [1,4] benzodiazepine and 346 μl of triethylamine. The resulting mixture was stirred at room temperature for 16 h and diluted with 50 ml of methylene chloride. The solution is washed with 20 ml of water, 2 N. a solution of citric key layer of water magnesium silicate and the filtrate evaporated in vacuum. Get a solid residue which is crystallized from ethyl acetate. Allocate 0.54 g of crystalline compounds, so pl. 202-204oC.

Example 359. 4-[N-Methyl-N-(2-methylbenzoyl)amino]benzoyl chloride.

The solution 6,72 g of 4-[N-methyl-N-(2-methylbenzylamino]benzoic acid in 20 ml thionylchloride boil 1 tsp of Volatile components removed in vacuo. To the obtained residue is added toluene and then it evaporated in vacuo (repeated several times). Obtain 7.3 g of product as a brown oil.

Example 360. 4-[N-Methyl-N-(2-methylbenzoyl)amino]benzoic acid.

A portion of 1.51 g of sodium hydride (60% in oil) is washed with hexane in an argon atmosphere to remove the oil. It washed the sodium hydride add 5 ml of N, N-dimethylformamide. To this mixture is added dropwise a solution of 8.69 g of ethyl ester of 4-[(2-methylbenzoyl)amino] benzoic acid in 20 ml of N, N-dimethylformamide. The mixture is stirred at room temperature for 0.5 h and then add 5.23 g under the conditions. The resulting reaction mass was stirred at room temperature for 16 hours the Mixture is diluted with water and extracted with methylene chloride. The extract is dried with sodium sulfate, concentrated to reduce the volume and the solution is filtered through a thin,N-dimethylformamide, 1:1). Previous product - ethyl ester 4-[N-methyl-N-(2-methylbenzoyl)amino] benzoic acid (11 g) is dissolved in 30 ml of methanol and add 25 ml of 2 N. aqueous sodium hydroxide solution. The mixture is boiled for 2 h and evaporated the solvent. The residue is extracted with ether (discarded) and the remaining residue is dissolved in 50 ml of water. Basically the solution is acidified with 2 N. citric acid solution and filtered off the solid product which is washed with water. The product is dried in the air, get 6.72 g of crystalline substances, so pl. 187-190oC.

According to the method described in example 360, but when using the corresponding ethyl ester 4-[(N-aroyl)amidoamine]benzoic acid, the following compounds.

Example 361. 4-[N-Methyl-N-(2-chlorobenzoyl)amino]benzoic acid.

Example 362. 4-[N-Methyl-N-(2,5-dichlorobenzoyl)amino]benzoic acid.

Example 363. 4-[N-Methyl-N-(2,4-dichlorobenzoyl)amino]benzoic acid.

Example 364. 4-[N-Methyl-N-(2-chloro-4-methylbenzoyl)amino]benzoic acid.

Example 365. 4-[N-Methyl-N-(2-methyl-4-chlorobenzoyl)amino]benzoic acid.

Example 366. 4-[N-Methyl-N-(2,4-dichlorobenzoyl)amino]benzoic acid.

Example 367. 4-[N-Methyl-N-(2,3-dichlorobenzoyl) is>Example 369. 4-[N-Methyl-N-(2-trifloromethyl)amino]benzoic acid.

Example 370. 4-[N-Methyl-N-(2,4-dimethoxybenzoyl)amino]benzoic acid.

Example 371. 4-[N-Methyl-N-(2-methoxy-4-chlorobenzoyl)amino]benzoic acid.

Example 372. 4-[N-Methyl-N-(2-methylbenzoyl)amino]benzoic acid.

Example 373. 4-[N-Methyl-N-(2-methylthiophene-3-ylcarbonyl)amino] benzoic acid.

Example 374. 4-[N-Methyl-N-(3-methylthiophene-2-ylcarbonyl)amino] benzoic acid.

Example 375. 4-[N-Methyl-N-(2-methylfuran-3-ylcarbonyl)amino]benzoic acid.

Example 376. 4-[N-Methyl-N-(3-methylfuran-2-ylcarbonyl)amino]benzoic acid.

Example 377. 4-[N-Methyl-N-(phenylacetyl)amino]benzoic acid.

Example 378. 4-[N-Methyl-N-(2-chlorophenylacetyl)amino]benzoic acid.

Example 379. 4-[N-Methyl-N-(2-methoxyphenylacetyl)amino]benzoic acid.

Example 380. 4-[N-Methyl-N-(2-methylphenylacetic)amino]benzoic acid.

Example 381. 4-[N-Methyl-N-(cyclohexylcarbonyl)amino]benzoic acid.

Example 382. 4-[N-Methyl-N-(3-cyclohexanecarbonyl)amino]benzoic acid.

Example 383. 4-[N-Methyl-N-(cyclopentylacetyl)amino]benzoic acid.

Example 384. N-4-[5H-Pyrrol the lo[2,1-c][1,4]benzodiazepine 0.518 g of 4-[N-methyl-N-(2-methylbenzoyl)amino] benzoyl chloride, 0.182 g of triethylamine and 7 ml of tetrahydrofuran is stirred at room temperature for 3 hours To the resulting mixture is added 0.29 g of 4-[N-methyl-N-(2-methylbenzoyl)amino]benzoyl chloride and 0.10 g of triethylamine in 2 ml of methylene chloride and stirred for 2 days. The mixture was poured into water and extracted with methylene chloride. The extract is washed with water, 1 N. hydrochloric acid, 1 N. solution of NaHCO3, brine and dried with sodium sulfate. The solution is filtered through a thin layer of water magnesium silicate. The filtrate is evaporated in vacuo, the residue is crystallized with a mixture of methylene chloride-hexane. Obtain 0.38 g of crystalline product, so pl. 168-170oC.

According to the method described in example 384, but using the corresponding Aronhold obtained the following compounds.

Example 385. N-[4-(5H-Pyrrolo[2,1-c] [1,4]benzodiazepine-10(11H)- ylcarbonyl)phenyl]-N-methyl-2-chlorobenzamide.

Example 386. N-[4-(5H-Pyrrolo[2,1-c] [1,4]benzodiazepine-10(11H)- ylcarbonyl)phenyl]-N-methyl-2,5-dichlorobenzamide.

Example 387. N-[4-(5H-Pyrrolo[2,1-c] [1,4]benzodiazepine-10(11H)- ylcarbonyl)phenyl]-N-methyl-2-chloro-4-methylbenzamide.

Example 388. N-[4-(5H-Pyrrolo[2,1-c] [1,4]benzodiazepine-10(11H)- ylcarbonyl)FeNi is]-N-methyl-2,4-dimethylbenzamide.

Example 390. N-[4-(5H-Pyrrolo[2,1-c] [1,4]benzodiazepine-10(11H)- ylcarbonyl)phenyl]-N-methyl-2,3-dimethylbenzamide.

Example 391. N-[4-(5H-Pyrrolo[2,1-c] [1,4]benzodiazepine-10(11H)- ylcarbonyl)phenyl]-N-methyl-2-methoxybenzamide.

Example 392. N-[4-(5H-Pyrrolo[2,1-c] [1,4]benzodiazepine-10(11H)- ylcarbonyl)phenyl]-N-methyl-2-cryptomaterial.

Example 393. N-[4-(5H-Pyrrolo[2,1-c] [1,4]benzodiazepine-10(11H)- ylcarbonyl)phenyl]-N-methyl-2,4-dimethoxybenzamide.

Example 394. N-[4-(5H-Pyrrolo[2,1-c] [1,4]benzodiazepine-10(11H)- ylcarbonyl)phenyl]-N-methyl-2-methoxy-4-chlorobenzamide.

Example 395. N-[4-(5H-Pyrrolo[2,1-c] [1,4]benzodiazepine-10(11H)- ylcarbonyl)phenyl]-N-methyl-2-methylthiomethyl.

Example 396. N-[4-(5H-Pyrrolo[2,1-c] [1,4]benzodiazepine-10(11H)- ylcarbonyl)phenyl]-N-methyl-2-methyl-3-thiophencarboxylic.

Example 397. N-[4-(5H-Pyrrolo[2,1-c] [1,4]benzodiazepine-10(11H)- ylcarbonyl)phenyl]-N-methyl-3-methyl-2-thiophencarboxylic.

Example 398. N-[4-(5H-Pyrrolo[2,1-c] [1,4]benzodiazepine-10(11H)- ylcarbonyl)phenyl]-N-methyl-2-methyl-3-furancarboxylic.

Example 399. N-[4-(5H-Pyrrolo[2,1-c] [1,4]benzodiazepine-10(11H)- ylcarbonyl)phenyl]-N-methylbenzamide.

Example 400. N-[4-(5H-Pyrrolo[2,1-c] [1,4]benzodiazepine-10(11H)- ylcarbonyl)phenyl]-N-methyl-2-chlorobenzoate.

Example 402. N-[4-(5H-Pyrrolo[2,1-c] [1,4]benzodiazepine-10(11H)- ylcarbonyl)phenyl]-N-methyl-2-methylbenzoate.

Example 403. N-[4-(5H-Pyrrolo[2,1-c] [1,4]benzodiazepine-10(11H)- ylcarbonyl)phenyl]-N-methyl-2-methyl-3-thiopheneacetic.

Example 404. N-[4-(5H-Pyrrolo[2,1-c] [1,4]benzodiazepine-10(11H)- ylcarbonyl)phenyl]-N-methylcyclohexanecarboxylic.

Example 405. N-[4-(5H-Pyrrolo[2,1-c] [1,4]benzodiazepine-10(11H)- ylcarbonyl)phenyl]-N-methylcyclohexylamine.

Example 406. N-[4-(5H-Pyrrolo[2,1-c] [1,4]benzodiazepine-10(11H)- ylcarbonyl)phenyl]-N-methyl-3-cyclohexenecarboxylic.

Example 407. N-[4-(5H-Pyrrolo[2,1-c] [1,4]benzodiazepine-10(11H)- ylcarbonyl)-2-were]-2,3-dichlorobenzoate.

A mixture of 0.40 g of 10,11-dihydro-10-(3-methyl-4-aminobenzoyl)-5H - pyrrolo[2,1-c][1,4]benzodiazepine, 0.40 g of 2,4-dichlorobenzotrifluoride and 0.75 g of diisopropylethylamine in 50 ml of methylene chloride is stirred at room temperature for 16 hours the Mixture was washed with water, dried with magnesium sulfate and the solution is passed through a thin layer of water magnesium silicate. The filtrate is concentrated and add hexane to the formation of crystals. After recrystallization from hexane obtain 0.52 g of crystalline product, so pl. 213-215oC.

Example 408. 1-(2-Nitrophenyl)-1H-pyrrole-2-carbaldehyde.

oC. To the mixture in small portions add 10.11 g pyrrole-2-carbaldehyde. The mixture is stirred for 10 min and added dropwise 1-fluoro-2-nitrobenzene. After the addition the mixture is stirred at room temperature for 16 h and then concentrated (65oC) under high vacuum. To the obtained residue, add 400 ml of methylene chloride and the mixture is washed with 150 ml of water and brine, dried with sodium sulfate. The solvent is evaporated in vacuum and get a solid yellow color. Crystallization from a mixture of ethyl acetate-hexane (9:1) leads to 17.0 g of pale yellow crystalline product, so pl. 119-122oC.

Example 409. 4,10-Dihydro-5H-pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepin.

To ice a mixture of 2.1 g of pyrrole-2-carboxylic acid and 3.2 g of methyl ester of 3-aminothiophene-2-carboxylic acid in 40 ml of dry methylene chloride add 4 g of N,N-dicyclohexylcarbodiimide. The mixture is stirred at room temperature for 3 h and filtered. The filter cake is washed with methylene chloride and then extracted twice with 60 ml of acetone. The acetone extract was concentrated to dryness, to obtain 0.8 g of the solid product, so pl. 214-218oC. To a suspension of the obtained compound (1.19 g) in 20 ml dry tetrahydrofuran added 0.2 g Hydra poured into a mixture of water-ice. The precipitate is filtered off and the solid residue triturated with petroleum ether (so Kip. 30-60oC). Obtain 0.75 g of 4,10-dihydro-4,10-dioxo-5H-pyrrolo-[1,2-a] thieno[3,2-e] [1,4] diazepine in the form of a solid substance, so pl. 280-290oC. the compound Obtained (0.362 g) is added to ice 1 M solution of DIBORANE in tetrahydrofuran. The mixture is stirred at room temperature for 65 hours the Solution is concentrated to dryness and to the residue is added a mixture of water and ice. The mixture is acidified with diluted hydrochloric acid, stirred and then alkalinized with solid NaHCO3. The mixture is filtered, receive 0.223 g of solid foam, so pl. 80-85oC.

Example 410. 10,11-Dihydro-5H-1,2,4-triazolo[3,4-C][1,4]benzodiazepine.

A mixture of 2.2 g of 2-cyanoaniline, 2.0 g of methylpropanoate and 1.3 g of potassium carbonate in 12 ml of dry N,N-dimethylformamide maintained at 150-155oC for 40 minutes the Cold mixture was poured into ice water and the mixture filtered. Receive 2 g of methyl-[N-(2-cyanophenyl)-amino]acetate as a yellow solid product, so pl. 70-78oC. the resulting compound (2.0 g) are added to a solution of 0.5 g of sodium methoxide in 50 ml of methanol. The mixture is shaken in an atmosphere of hydrogen with a catalyst of Ni-Raney within 1 h the Mixture is filtered through diatomaceous 1H-1,4-benzodiazepine-3-one as a yellow solid, so pl. 167-170oC.

A mixture of the obtained compound (1.6 g) and 0.84 g of pentasulfide phosphorus in 10 ml of dry pyridine (dried KOH) and incubated under stirring and at 80-85oC within 30 minutes After filtration obtain 1.0 g of 1,2,4,5-tetrahydro-3H-1,4-benzodiazepine-3-thione in the form of a yellow solid, so pl. 150-153oC.

The compound obtained (0.5 g) and 0.5 g of N-formylhydrazine in 6 ml. N.-butanol is boiled for 16 h and then the solvent evaporated. Resinous residue triturated with cold water and the mixture filtered. The obtained solid product is triturated with acetone and obtain 0.19 g of yellow solid, so pl. 232-237oC.

Example 411. 4,5-Dihydro-6H-[1,2,4]triazolo[4,3-a][1,5] benzodiazepine.

A mixture of 2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-2-thione (0.8 g) and 0.80 g of N-formylhydrazine in 8 ml of ad-butanol is stirred and boiled for 18 hours, and then vacuum evaporated solvent. To the resulting solid residue is added ice water and the mixture filtered. Get 0.312 g of gray solid substance, so pl. 162 to 165 of theoC.

Example 412. 4,5-Dihydro-6H-imidazo[1,2-a][1,5]benzodiazepine.

A mixture of 30 g of acrylic acid and 33 g of o-phenylenediamine is heated on a steam bath for 1.5 h and cooled black sid ammonium. The resulting mixture was extracted with methylene chloride and the extract was concentrated to dryness. The residue is triturated with carbon tetrachloride and filtered. The oily product is triturated with a small amount of ethanol, to obtain 9.7 g of solid substance. When grinding the latter with ethyl acetate receive 2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-2-it, so pl. 75-107oC.

A mixture of the obtained compound (11.3 g) and 5.9 g of pentasulfide phosphorus in 70 ml of dry pyridine is maintained with stirring and at approximately 80oC for 20 minutes the Mixture was poured into water and stirred for 3 min After filtration allocate 8.6 g of 2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-2-thione in the form of a solid substance, so pl. 154-157oC.

A mixture of the obtained compound (0.70 g), 1.0 g of dimethylacetal of aminoacetaldehyde and 15 mg of the monohydrate of 4-methylbenzenesulfonate in 6 ml of dry ad-butanol boiled for 4 h and the solvent evaporated in vacuum. The residue is boiled with 10 ml of 3 n hydrochloric acid for 55 minutes To the cold mixture is added ice and the mixture is alkalinized with solid NaHCO3. The mixture is extracted with methylene chloride and the extract is dried with sodium sulfate. The solvent is evaporated, get orange syrup, which when stoan.185 g), so pl. 119-122oC.

Example 413. Ethyl ester of 1-(2-nitrophenyl)-2-pyrrolysine acid.

To a mixture of 1.88 g of 1-(2-nitrophenyl)pyrrole, 4.80 g of atlidzinat and 2.22 g of FeSO47H2O in 40 ml of dimethyl sulfoxide with stirring, added dropwise 10 ml of 30% hydrogen peroxide, maintaining the temperature of the reaction mixture to about room temperature. The mixture is stirred at room temperature for one day. Then to the mixture add 2.4 g of atlidzinat, 1.1 g of FeSO47H2O and 5 ml of 30% hydrogen peroxide and the resulting mixture was stirred at room temperature for one day. The mixture is diluted with water and extracted with diethyl ether. The organic extract was washed with water, brine and dried with sodium sulfate. The solvent is evaporated and the residue (2.12 g) chromatographic on silica gel, eluent ethyl acetate-hexane (1:4). Allocate 0.30 g of product as a brown resin.

Example 414. 6,7-dihydro-5H-pyrrolo[1,2-a][1,5]diazepin-6-he.

To a solution of 0.8 mmol of ethyl ester 1-(2-nitrophenyl)-2-pyrrolysine acid in 3 ml ethanol add dihydrate tin chloride (SnCl22H2O) in 2 ml of concentrated hydrochloric acid (cooling water bath). The mixture is stirred at room temperature in the decomposing solid precipitate is filtered and washed with water, and then extracted with ethyl acetate. The extract is dried with sodium sulfate and the solvent evaporated, to obtain 0.16 g of solid product, which was triturated with ether, isolated 0.11 g of the product as an almost white solid.

Example 415. 6,7-dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepine.

To a solution of 0.070 g of 6,7-dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepine-6-she's in 2 ml of tetrahydrofuran, add 0.45 ml of a 2.0 M solution of dibor-dimethyl sulfide in tetrahydrofuran. The mixture is boiled for 3 h, poured into water and alkalinized with 2 n NaOH solution. The tetrahydrofuran evaporated in vacuum and the obtained residue aqueous mixture is extracted with diethyl ether. The extract was washed with brine, dried with sodium sulfate and the solvent evaporated. Get 0.065 g of a colorless oil; according to thin-layer chromatography (silica gel, eluent ethyl acetate: hexane, 1:2) the product is a individual connection (Rf= 0; 81).

Example 416. 10,11-Dihydro-10-(2-chloro-4-aminobenzoyl)-5H-pyrrolo[1,2-C]- [1,4]benzodiazepine.

A mixture of 5.0 g of 10,11-dihydro-10-(2-chloro-4-nitrobenzoyl)-5H-pyrrolo[1,2-C] [1,4] benzodiazepine, 15 g of tin chloride and 170 ml of ethanol maintained at 70-80oC for 1 h the Mixture is cooled (ice bath) and alkalinized the pH 5 with acetic acid and extracted with 500 ml and 300 ml of ethyl acetate. The combined extract was washed with 250 ml of brine and dried with sodium sulfate. The solution is filtered through a thin layer of water magnesium silicate and the filter bed washed with ethyl acetate. Filter and concentrate the resulting residue is dissolved in 200 ml of hot mixture of chloroform-methanol (1:) and the solution is filtered through a layer of water magnesium silicate. The filtrate is evaporated in vacuum, receive 4.36 g (after drying in vacuum at 60oC during the night) of product as a white solid. A sample recrystallized from a mixture of chloroform-methanol, isolated white crystalline product, so pl. 210-212oC.

Example 417. 4-[(5-fluoro-2-methylbenzoyl)amino]benzoic acid.

A mixture of 0.60 g of ethyl-4-[(5-fluoro-2-methylbenzoyl)amino]benzoate, 0.60 ml of 10 n NaOH solution, 25 ml of water and 50 ml of absolute ethanol is heated on a steam bath for 1 h, cooled and acidified with acetic acid. The obtained solid residue is filtered off and dried in vacuum at 60-80oC, obtain 0.47 g of the desired product as a solid substance, so pl. 272-275oC.

According to the method of example 417, the compounds of examples 418 -428 (see end of text).

Example 429. 4-[(2,4-Dichlorobenzoyl)amino]-2-chlorbenzene acid.

is militiamen and at 12.67 g of 2,4-dichlorobenzotrifluoride and stirring is continued for 18 hours Add water and the organic layer dried with sodium sulfate, and then concentrated in vacuo. Get 13.68 g of the desired product, so pl. 171-175oC.

According to the method of example 429, the compounds of examples 430 - 442 (see end of text).

Example 443.

Ethyl ether is a 10.1-dihydro-10-(2-chloro-4-nitrobenzoyl)-5H-pyrrolo[2,1-C] [1,4] benzodiazepine-3-carboxylic acid.

To 25 ml of absolute ethanol is added 0.12 g of metallic sodium and added with stirring 0.68 g of 10,11-dihydro-10-(2 - chloro-4-nitrobenzoyl)-[3-(trichloroacetyl)] -5H-pyrrolo-[2,1-C] [1,4] -benzodiazepine. Stirring is continued for 18 hours, Volatile components are evaporated in vacuum, get the remainder, which is distributed between methylene chloride and water. The organic layer is separated, dried with sodium sulfate and the filtrate is heated on the steam bath with simultaneous addition of hexane. Obtain 0.45 g of the desired compound in the form of a solid substance, so pl. 165 - 166oC.

According to the method of example 443 receive connection examples 444 - 447 (see end of text).

Example 448. 10,11-Dihydro-10-(3-methyl-4-nitrobenzoyl)-[3 - trichloroacetyl)]-5H-pyrrolo[2,1-C][1,4]benzodiazepine.

To a solution of 3.47 g of 10,11-dihydro-10-(3-methyl-4-nitrobenzoyl)- 5H-pyrrolo-[the ect is stirred for 18 hours Then add water, the organic layer is separated, washed with saturated sodium bicarbonate solution, dried with sodium sulfate and passed through a thin layer of water magnesium silicate. To the filtrate at the boil add hexane to obtain the desired compound in the form of solids. Mass spectrum (chem. ionization): 491 (MH+).

According to the method of example 448, the compounds of examples 449 - 450 (see end of text).

Example 451. 10,11-Dihydro-10-(4-nitrobenzoyl)-[3-TRIFLUOROACETYL)-5H-pyrrolo [2,1-C][1,4]benzodiazepine.

A mixture of 0.50 g of 10.1-dihydro-10-(4-nitrobenzoyl)-5H-pyrrolo- [2,1-C][1,4] benzodiazepine in 10 ml of methylene chloride cooled in the ice bath and add 2.0 g triperoxonane anhydride. Bath is removed and the mixture stirred for 18 h, add saturated aqueous sodium bicarbonate solution and the separated organic layer is dried with sodium sulfate and then passed through an aqueous magnesium silicate. To the boiling filtrate add hexane to obtain 0.4 g of the desired product, so pl. 169 - 170oC.

According to the method of example 451, the compounds of examples 452 - 454 (see end of text).

Example 455. 10,11-Dihydro-10-(3-methoxy-4-nitrobenzoyl)-5H - pyrrolo[2,1-C][1,4]benzodiazepine.

SMA components are removed in vacuo, obtain 2.85 g of 3-methoxy-4 - nitrobenzonitrile which is dissolved in 50 ml of methylene chloride. To the resulting solution was added with stirring 1.84 g of 10,11-dihydro-5H-pyrrolo[2,1-C][1,4]benzodiazepine. The reaction mass is stirred in an argon atmosphere for 18 h and diluted with saturated sodium bicarbonate solution. The organic layer is dried with sodium sulfate and passed through a thin layer of an aqueous sodium silicate. To the filtrate at the boil add hexane and after cooling, get 3.39 g of the desired product as a solid substance, so pl. 191 - 192oC.

According to the method of example 455, the compounds of examples 456 - 459 (see end of text).

Example 460.10,11-Dihydro-10-(4-amino-3-methoxybenzoyl)-5H - pyrrolo[2,1-C][1,4]benzodiazepine.

A mixture of 3.24 g of 10,11-dihydro-10-(4-nitro-3-methoxybenzoyl)- 5H-pyrrolo[2,1-C] [1,4]benzodiazepine, 0.35 g of 10% Pd/C and 0.60 g of anhydrous hydrazine in 100 ml of absolute ethanol is heated on a steam bath for 1 h Hot reaction mass is filtered through diatomaceous earth and the filtrate evaporated in vacuum. The resulting residue is distributed between methylene chloride and water. The organic layer is dried with sodium sulfate and passed through a water layer of magnesium silicate. To the filtrate when the heating is By the method of example 460 receive connection examples 461 - 464 (see end of text).

Example 465. N-[4-(5H-Pyrrolo[2,1-C][1,4]benzodiazepine-10- (11H)-ylcarbonyl)phenyl]-5-fluoro-2-methylbenzamide.

To a solution of 500 mg of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-C] [1,4] benzodiazepine in 3 ml of methylene chloride at 0oC in argon atmosphere add 346 μl of triethylamine, and then added 340 mg of 2-methyl-5-tormentilla in 2 ml of methylene chloride. Remove the cooling bath and stirring is continued for 18 hours After cooling to 0oC add 342 mg of 2-methyl-5-tormentilla in 2 ml of methylene chloride. clean bath and stirred the reaction mass for 18 h the Volatile components are evaporated in vacuo, the obtained residue is dissolved in 50 ml of methylene chloride and washed with 20 ml water, 20 ml of 2 n citric acid solution, 20 ml of 1 M sodium bicarbonate solution and 20 ml of brine. The organic layer is dried with sodium sulfate and passed through a water layer of magnesium silicate. The filtrate is evaporated in vacuo and the resulting residue is crystallized with a mixture of ethyl acetate-hexane, get 295 g of the desired product as a white solid, so pl. 170 - 180oC.

According to the method of example 465, using the appropriate substituted Aronhold get connection examples 466 - 480, 26-fluoro-2-methylbenzamide.

To a solution of 1.50 g of 10,11-dihydro-5H-pyrrolo[2,1-C][1,4] benzodiazepine in 25 ml of methylene chloride add to 1.23 g of N,N-diisopropylethylamine. The mixture is cooled with an ice bath and add a solution is 3.08 g of [4-[(2-methyl-5-perbenzoic)amino]-2-chlorobenzylchloride in 50 ml of methylene chloride. Homogeneous reaction mass was stirred at room temperature for 18 hours. Add water, the organic layer is separated and washed with saturated aqueous sodium bicarbonate, dried with sodium sulfate and twice passed through a layer of water magnesium silicate. The methylene chloride evaporated in vacuum and get 3,81 g glassy product. A sample crystallized by ethyl acetate. Get crystal product, so pl. 200-205oC.

Example 482. N-[4-(5H-Pyrrolo[2,1-C] [1,4]benzodiazepine-10(11H)- ylcarbonyl)-3-chlorophenyl]-5-fluoro-2-methylbenzamide.

To a solution of 1.84 g of 10,11-dihydro-5H-pyrrolo[2,1-C][1,4] benzodiazepine in 25 ml of methylene chloride added to 1.30 g of N,N-diisopropylethylamine. The mixture is cooled with an ice bath and add a solution of 3.45 [4-[(2-methyl-5-perbenzoic)amino]-2-chlorobenzylchloride in 50 ml of methylene chloride. Homogeneous reaction mass obtained after 5 min, stirred at room temperature for 18 hours, water is Added, the organic C through the layer of water magnesium silicate. The methylene chloride evaporated in vacuum and get 4,60 g glassy product. A sample crystallized by ethyl acetate, to obtain crystalline product, so pl. 191-195oC.

Example 483. 4-(5H-Pyrrolo[2,1-C] [1,4] benzodiazepine-10(11H)- ylcarbonyl)benzoic acid.

A solution of 0.92 g of 10,11-dihydro-5H-pyrrolo[2,1-C][1,4]benzodiazepine and 1.19 g of monomethylethanolamine in 20 ml of pyridine is boiled for 2 hours. The mixture cool and add 1 N. hydrochloric acid to obtain a pH of 5. The mixture is filtered and the precipitate washed with water, get 1,53 g of solid product. After recrystallization from a mixture of methylene chloride-hexane get crystalline product, so pl. 186-188oC - methyl ester 4-(5H-Pyrrolo[2,1-C][1,4] benzodiazepine-10(11H)-ylcarbonyl)benzoic acid.

A mixture of 1.83 g of the obtained ether, 8 ml of 2 n NaOH solution and 14 ml of methanol is boiled for 0.5 h and then concentrated in vacuo. The concentrate residue with ether and the aqueous layer was acidified with 2 N. citric acid. The mixture is filtered and the solid residue washed with water and dried (in vacuo at 60oC). Get to 1.61 g of crystalline product, so pl. 210-214oC.

Example 484. N-(2-Were)-4-(5H-pyrrolo[2,1-C][1,4] benzodiazepine-10(11H)-ylcarbonyl)benzamide.

Change and 0.15 ml of gettingstarted in 20 ml of methylene chloride is heated on a steam bath overnight. The mixture is washed with water, 1M sodium bicarbonate solution, 1N. hydrochloric acid, brine and dried with sodium sulfate. The solution is filtered through a thin layer of water magnesium silicate and the filtrate evaporated to dryness. The residue is crystallized from a mixture of methylene chloride-hexane, get to 0.23 g of white crystals, so pl. 228-231oC.

Example 485. N-(2,5-Dimetilfenil)-4-(5H-pyrrolo[2,1-C][1,4] benzodiazepine-10(11H)-ylcarbonyl)benzamide.

A mixture of 0.332 g of 4-(5H-pyrrolo[2,1-C][1,4]benzodiazepine-10(11H)- ylcarbonyl)benzoic acid, 0,222 g of triethylamine, of) 0.157 g of 2,5-dimethylaniline and 0.15 ml of diethylphosphoramidite in 20 ml of methylene chloride is heated on a steam bath for 3 hours the Mixture was washed with water, 1M sodium bicarbonate solution, 1 N. hydrochloric acid, brine and dried with sodium sulfate. The solution is filtered through a thin layer of water magnesium silicate and the filter cake washed with methylene chloride. The filtrate is concentrated to dryness. The residue is crystallized from a mixture of methylene chloride-hexane to obtain 0.11 g of white crystals, so pl. 239-240oC.

Example 486. N-[4-[(4,5-Dihydro-6H-[1,2,4]triazolo[4,3-a][1,5] benzodiazepine-6-yl)carbonyl)phenyl]-2-methylbenzoate.

The mixture 0,246 g of [4-(2-methylbenzoyl)amino]benzoyl chloride, 0.14 g of 4,5-dihydro-6H-[1,2,4] triazolo[4,3-a] [1,5]benzodia throughout the night. The mixture is neutralized 1 N. hydrochloric acid and filtered. The solid product is washed with methylene chloride and the filtrate evaporated in vacuum. Get 0,151 g of the product. Mass spectrum (FAB): 424,2 (M + H).

Example 487. N-[4-(Pyrrolo[1,2-a]cinoxacin-5(4H)-yl)carbonyl)phenyl]-2,3 - dichlorobenzamide.

In accordance with the method of Example 157 of 0.47 g of 4,5-dihydro-5-(4 - aminobenzoyl)pyrrolo[1,2-a] finokalia, 346 μl of triethylamine and 5 ml of methylene chloride cooled in the ice bath and add 0,415 g of 2,3-dichlorobenzonitrile in 2 ml of methylene chloride. After stirring over night to the reaction mass add 346 μl of triethylamine and 0,415 g of 2,3-dichlorobenzonitrile. The mixture is stirred for 2 h, diluted with 50 ml of methylene chloride and the solution washed with water, 2 N. solution of citric acid, 1M aqueous solution of sodium bicarbonate and brine (20 ml each). The organic layer is dried with sodium sulfate and filtered through a thin layer of water magnesium silicate. The filtrate is concentrated to dryness. The obtained residue chromatographic on a thin layer silica gel, eluent ethyl acetate-hexane (1:1), receive 0,100 g of a white solid connection, so pl. 230-240oC.

Example 488. 10-[4-[[(2-Chlorophenyl)sulfonyl] amino] benzoyl]-10,11 - dihydro-5H-pyrrolo[2,1-C][1,4]be the keys of 0.50 g of 10,11-dihydro-10- (4-aminobenzoyl)-5H-pyrrolo[2,1-C] [1,4]benzodiazepine and 346 μl of triethylamine. The mixture is stirred at room temperature overnight and diluted with 50 ml of methylene chloride. The mixture is washed with water, 2 N. solution of citric acid, 1M aqueous solution of sodium bicarbonate and brine (20 ml each). The organic layer is dried with sodium sulfate and filtered through a thin layer of water magnesium silicate. The filtrate is concentrated to dryness. The obtained residue chromatographic on a thin layer of silica gel (4 plates), eluent ethyl acetate-hexane (1:1) get a solid product. Crystallization from ethyl acetate leads to 0,165 g of white crystalline product, so pl. 206-210oC.

Example 489. Methyl ester of 4-(5H-pyrrolo[2,1-C] [1,4]benzodiazepine-10(11H)-ylcarbonyl)benzoic acid.

To a cold solution of 0.50 g of 10,11-dihydro-10-(4-aminobenzoyl) (5H-pyrrolo[2,1-C] [1,4]benzodiazepine and 346 μl of triethylamine in 5 ml of methylene chloride add 0,394 g monomethylethanolamine. The mixture is stirred overnight in an argon atmosphere and diluted with 50 ml of methylene chloride. The mixture is washed with water, 2 N. solution of citric acid, 1M aqueous solution of sodium bicarbonate and brine (20 ml each). The organic layer is dried with sodium sulfate and filtered through a thin layer of water magnesium silicate, and the balance of the filtrate are square-0.50 g of white crystalline product, so pl. 224-228oC.

Example 490. N-[(Dimethylamino)methyl]-N-(5H-pyrrolo[2,1-C][1,4] benzodiazepine-10(11H)-ylcarbonyl)phenyl]-2,4-dichlorobenzamide.

To a suspension 0,072 g of sodium hydride (60% in oil) in 10 ml of tetrahydrofuran in an argon atmosphere added 0.71 g of N-[4-(5H - pyrrolo[2,1-C][1,4]benzodiazepine-10(11H)-ylcarbonyl)phenyl] -2,4 - dichlorobenzamide and the resulting mixture was stirred at room temperature for 1 h Then added to the mixture N,N-dimethylmethyleneammonium and the mixture is stirred for further 20 hours the Reaction mass is diluted with diethyl ether (30 ml), filtered and the filtrate concentrated in vacuo. The residue is triturated with hexane and get 0,76 g of white solid product, so pl. 126-128oC.

Example 491. 10-[4-[(Diphenylphosphanyl)amino]benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-C][1,4]benzodiazepine.

A mixture of 0.10 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo [2,1-C][1,4] benzodiazepine, 0.06 g of triethylamine and 0.12 g of diphenylphosphinylchloride in 2 ml of methylene chloride is stirred at room temperature for 2 h and then was added 1 n sodium hydroxide solution. The mixture is extracted with ethyl acetate and the extract washed with brine and dried with sodium sulfate. The solvent is evaporated and the residue triturated in a mixture of ether-hexane to obtain 0.16 g t the olo[2,1-c][1,4]benzodiazepine.

To a solution of 0.10 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H - pyrrolo[2,1-c] [1,4] benzodiazepine, 0.06 g of triethylamine in 2 ml of methylene chloride added 0.14 g of diphenoxyethane and the resulting mixture was stirred at room temperature for 2 h and then was added 1 n sodium hydroxide solution. The mixture is extracted with ethyl acetate and the extract washed with brine and dried with sodium sulfate. The solvent is evaporated and the residue triturated in a mixture of ether-hexane to obtain 0.20 g of a solid white product.

Example 493. 10-[4-[[2,5-(Dichlorophenyl)sulfonyl] amino] benzoyl]-10,11 - dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine.

A mixture of 0.10 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H - pyrrolo[2,1-c][1,4] benzodiazepine, 0.05 g of triethylamine and 0.083 g of dichlorobenzenesulfonate in 2 ml of methylene chloride is stirred at room temperature for 1 h and then added to 4 mg of 4-(N,N-dimethylamino)pyridine. After stirring for one hour add 93 mg dichlorobenzenesulfonate and 50 mg of triethylamine. The mixture is stirred at room temperature for 2 days and then add 1 n NaOH solution. The mixture is extracted with ethyl acetate and the extract washed with 50% solution of ammonium chloride, brine and dried with sodium sulfate. The solvent is evaporated, Astara NaOH and the resulting mixture stirred for 18 h at room temperature. The organic solvent is evaporated and the mixture is extracted with ethyl acetate. The extract is washed with sodium bicarbonate, brine and dried with sodium sulfate. Obtained after evaporation of the solvent the residue (0.16 g) triturated with ether, isolated 0.14 g of the yellow solid product.

Example 494. 10-[4[[(Phenylmethyl)sulfonyl] amino]benzoyl]-10,11 - dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine.

To a solution of 0.10 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c] [1,4] benzodiazepine, 0.06 g of triethylamine in 2 ml of methylene chloride add 0.10 g of o-toluensulfonate and the resulting mixture was stirred at room temperature for 2 h and then was added 1 n sodium hydroxide solution. The mixture is extracted with ethyl acetate and the extract washed with brine and dried with sodium sulfate. The solvent is evaporated and the residue (0.20 g) chromatographic on silica gel, eluent ethyl acetate: hexane, (3:2). Get 0.080 g of white solid product and 0.08 g of 10-[4-[[bis(phenyl-methyl)sulfonyl]amino]benzoyl-10,11-dihydro-5H - pyrrolo[2,1-c] [1,4]benzodiazepine in the form of a white solid. The latter compound is dissolved in methanol, is added 2 n NaOH solution and heated on the steam bath, the solvent evaporated and the alkaline aqueous residue extracted with ethyl acetate. Kind of what antinoi acid.

A mixture of 8.26 g of ethyl ester of 4-aminobenzoic acid, 8.26 g of N-chlorosuccinimide in 50 ml of methylene chloride is boiled for the night. The mixture was washed with a saturated solution of NaHCO3and dried by sodium sulfate. The solution is passed through a thin layer of water magnesium silicate and the filter cake washed with methylene chloride. The filtrate is concentrated and add hexane. When cooled receive 7.38 g of ethyl ester of 3-chloro-4-aminobenzoic acid, so pl. 82 - 83oC.

The last compound (3.66 g) and 3.0 g of diisopropylethylamine in 50 ml of methylene chloride add 3.55 g of 2-methylbenzylamine in 10 ml of methylene chloride. The mixture is stirred at room temperature overnight, washed with water, NaHCO3and dried with magnesium sulfate. The solution is passed through a thin layer of water magnesium silicate and the filter cake washed with methylene chloride. The filtrate is concentrated and diluted with hexane. After cooling, get 4.71 g of crystalline product, 129 - 130oC.

According to the method of example 495 receive connection examples 496 - 516 (see end of text).

Example 517. N-[4-(4H-Pyrazolo[5,1-c][1,4]benzodiazepine-5(10H)- ylcarbonyl)phenyl]-3-fluoro-2-methylbenzamide.

A solution of 2.87 g of 3-fluoro-2-methylbenzoic acid in 25 ml tinnevelt in vacuum (repeat several times) get 3-fluoro-2-methylbenzoate.

To a solution of 0.25 g of 5,10-dihydro-5-(4-aminobenzoyl)-4H-pyrazolo[5,1-c] [1,4] benzodiazepine and 0.0914 g of triethylamine in 6 ml of methylene chloride in the atmosphere of argon is added a solution of 0.156 g of 3-fluoro-2-methylbenzonitrile in 1.5 ml of methylene chloride. The mixture is stirred over night at room temperature and washed with water and saturated sodium bicarbonate solution. The organic layer is treated with activated charcoal and filtered through magnesium sulfate. The filtrate is evaporated, add ethyl acetate and the solvent evaporated. Obtain 0.38 g of white crystalline product, so pl. 245 - 250oC. Mass spectrum: 441.1720 (M+H).

Example 518. N-[4-(4H-Pyrazolo[5,1-c][1,4]benzodiazepine-5(10H)- ylcarbonyl)phenyl]-3-chlorophenyl]-5-fluoro-2-methylbenzamide.

A mixture of 0.185 g of 5,10-dihydro-4H-pyrazolo[5,1-c][1,4]benzodiazepine, 0.391 g of 4-[(5-fluoro-2-methylbenzoyl)amino]-2-chlorobenzylchloride and 0.158 g of diisopropylethylamine in 10 ml of methylene chloride is stirred at room temperature overnight. The mixture is washed with water, 1 N. hydrochloric acid, water, 1 M sodium bicarbonate solution, brine and dried with sodium sulfate. The solution is passed through a thin layer of water magnesium silicate and the filter cake washed with methylene chloride. the tallitot with ethyl acetate, get crystal product, so pl. 137-140oC.

Example 519. N-[4-(4H-Pyrazolo[5,1-c][1,4]benzodiazepine-5(10H)- ylcarbonyl)-3-chlorophenyl)-2-methylbenzamide.

According to the method of example 518 mixture of 0.185 g of 5,10-dihydro-4H-pyrazolo [5,1-c] [1,4]benzodiazepine, 0.369 g of 4-[(2-methylbenzoyl)amino]-2 - chlorobenzylchloride and 0.158 g of diisopropylethylamine in 10 ml of methylene chloride is stirred at room temperature overnight. Get crystalline product (from ethyl acetate), so pl. 241-244oC.

Example 520. N-[4-(4H-Pyrazolo[5,1-c] [1,4]benzodiazepine-5(10H)- ylcarbonyl)-3-chlorophenyl)-2,4-dichlorobenzamide.

According to the method of example 518 mixture of 0.185 g of 5,10-dihydro-4H-pyrazolo[5,1-c] [1,4] benzodiazepine, 0.472 g of 4-[(2,4-dichlorobenzoyl)amino]-2-chlorobenzylchloride and 0.158 g of diisopropylethylamine in 10 ml of methylene chloride is stirred at room temperature overnight. Get crystalline product (0.27 g) as a pale yellow glassy mass.

Elemental analysis: Calculated: C, 58.7; H, 3.4; N, 11.0; Cl 20.8;

Found: C, 57.3; H, 3.3; N, 9.5; Cl 21.3;

Example 521. 5,10-Dihydro-5-(4-nitro-2-chlorbenzoyl)-4H-pyrazolo[5,1-c] [1,4] benzodiazepine.

To a solution of 1.85 g of 5,10-dihydro-4H-pyrazolo[5,1-c][1,4] benzodiazepine and 1.60 g of diisopropylethylamine in 50 ml methylenchloride. The mixture is stirred at room temperature overnight and poured into water. The organic layer is washed with water, saturated sodium bicarbonate solution, water and dried with magnesium sulfate. The solution is passed through a thin layer of water magnesium silicate and the filtrate evaporated. The residue is crystallized with a mixture of methylene chloride-hexane to obtain 3.0 g of crystalline product, so pl. 197 - 199oC.

Example 522. 5,10-Dihydro-5-(4-amino-2-chlorbenzoyl)-4H - pyrazolo[5,1-c] [1,4]benzodiazepine.

A mixture of 0.553 g of 5,10-dihydro-5-(4-amino-2-chlorbenzoyl)-4H-pyrazolo[5,1-c] [1,4] benzodiazepine, 1.70 g of dihydrate of tin chloride in 20 ml of ethanol is heated at 70-80oC for 1 h the Mixture is cooled, alkalinized 1 m solution of NaHCO3and then stirred at room temperature for 0.5 hours, the Mixture is brought to pH 5 with acetic acid and extracted with (several times) with ethyl acetate. The combined extracts are dried with sodium sulfate, the filtrate evaporated and the residue is dissolved in methylene chloride and the resulting solution was passed through a thin layer of water magnesium silicate. The filtrate is evaporated in vacuum, obtain 0.40 g of a glassy mass, so pl. 98-117oC.

Elemental analysis: Calculated: C, 62.9; H, 4.7; N, 16.3; Cl 11.6;

Found: C, 62.4; H, 4.3; N 15S="ptx2">

Example 530 N-[4-(5H-Pyrrolo [2,1-c][1,4] benzodiazepine-10(11H)-ylcarbonyl)-2-chlorophenyl]-methylbenzamide.

To a mixture of 1.38 g of 5,10-dihydro-5H-pyrrolo [2,1-c][1,4] benzodiazepine of 1.11 g of N,N - diisopropylethylamine in 50 ml of methylene chloride add 2,61 g of 4-[(2-methylbenzoyl)amino] -3-chlorobenzylchloride in 25 ml of methylene chloride. The mixture is stirred at room temperature overnight and then washed with water and a saturated solution of NaHCO3. The organic layer is dried with sodium sulfate and passed through a water layer of magnesium silicate. The filtrate is evaporated, get stekloobrazovanie product (3.62 in). A sample of 1.8 g of the product is crystallized by ethyl acetate, to obtain 1.4 g of crystalline product, so pl. 176-178oC.

In accordance with the method of example 530, the compounds of examples 531 - 579 (see end of text).

Example 580. 2,4-Dichloro-N-[4-[(3-formyl-5H-pyrrolo[2,1-c][1,4]benzodiazepine - 10(11N)-yl)carbonyl]phenyl]benzamide.

To a solution of 0.48 g of 2,4-dichloro-N-[4-(5H-pyrrolo[2,1-c][1,4]-benzodiazepine - 10(11H)-yl)carbonyl)phenyl]benzamide in 2 ml of N,N-dimethylformamide at 0oC slowly add 0.3 ml of POCl3. The reaction mass was stirred at 0oC for 30 min and at room temperature for 1 h the Final mixture extinguish koume. Obtain 0.55 g of solid product. After additional washing with a mixture of ether-isopropanol, 1:1, receive 0.5 g of white solid product. Mass spectrum (chemical ionization) - calculated: 503.0774;

found: 503.- 789.

Example 581. 2,4-Dichloro-N-[4-[[[3-hydroxymethyl)-5H-pyrrolo[2,1-c][1,4]- benzodiazepine-10(11H)-yl]carbonyl]phenyl]benzamide.

To a suspension of 0.3 g of NaBH4in 1 ml of tetrahydrofuran added 0.42 g of 2,4-dichloro-N-[4[(3-formyl-5H-pyrrolo[2,1-c] [1,4] benzodiazepine-10(11H)-yl) carbonyl] phenyl] benzamide and the reaction mass stirred at room temperature for 18 h and then quenched with water. The tetrahydrofuran evaporated in vacuum and the aqueous residue is treated with 5 ml of 1 n NaOH solution and extracted with 50 ml ethyl acetate. The organic extract was washed with brine, dried with sodium sulfate and evaporated. Obtain 0.47 g of foam. Using preparative thin-layer chromatography with elution with a mixture of ethyl acetate: hexane, 2:1, obtain 0.24 g of white solid product. Mass sectr (FAB): 488 MH+-OH).

Example 582. 2,4-Dichloro-N-[4-[[3-(1H-imidazol-1-ylmethyl))-5H-pyrrolo-[2,1-c][1,4] benzodiazepine-10(11H)-yl]carbonyl]phenyl]benzamide

To a suspension of 0.28 g of the hydrochloride of N,N-dimethylglycine in 5 ml of tetrahydrofuran added 0.21 g of triethylamine and 0.35 g carbonitridation evaporated in vacuum and the residue is dissolved in ethyl acetate and washed with water, a saturated solution of NaHCO3and brine, dried with sodium sulfate, filtered and evaporated in vacuum. The obtained residue is washed with a mixture of ether-hexane (1:1) obtain 0.17 g of a white solid. Mass spectrum (FAB):556 (M+H).

Example 583. -Chloro-N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepine-10(11H)-ylcarbonyl)phenyl] benzazimide.

To a solution of 0.61 g of 10,11-dihydro-1-(4-aminobenzoyl)-5H-pyrrolo[2,1-c] [1,4] benzodiazepine in 8 ml of methylene chloride added 0.30 g of triethylamine, and then 0.47 g of 2-chloro-2-phenylacetylamino in 2 ml of methylene chloride. The mixture is stirred at room temperature for 1 h and then diluted with 10 ml of a 50% aqueous solution of NaHCO3. The methylene chloride evaporated and the residue extracted with ethyl acetate. The organic layer is separated and washed with saturated solution of NaHCO3and brine, and then dried with sodium sulfate and filtered through a thin layer of water magnesium silicate. The filtrate is evaporated and the resulting residue is stirred with a mixture of ether-hexane to obtain 0.98 g of pink solid. Mass spectrum (chemical ionization): 456 (M+H).

Example 584 -[[2-(Dimethylamino)ethyl]thio]-N-[4-(5H-pyrrolo[2,1-c][1,4]- benzodiazepine-10(11H)-ylcarbonyl)phenyl]benzazimide

A mixture of 0.14 g-chloro-N-[4[(5H-pyrrolo[2,1-c][1,4]benzodiazepine-10(11H) ilkar the a and 3 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-1(1H)-pyrimidinone incubated at 60oC within 48 h of the Methyl alcohol is evaporated and the residue diluted with water. The resulting suspension is filtered and the residue washed with water. The solid residue is dissolved in ethyl acetate and washed with saturated solution of NaHCO3, brine and dried with sodium sulfate. The mixture is filtered and the filtrate evaporated in vacuum to get the residue which is stirred with a mixture of ethyl acetate-hexane. Obtain 0.15 g of a beige solid product. Mass spectrum (chemical ionization): 525 (M+H).

Example 585. - [N-(Acetamido)amino]-N-[4-(5H-pyrrolo[2,1-c][1,4]-benzodiazepine-10(11H)- ylcarbonyl)phenyl]benzazimide.

A mixture of 0.14 g-chloro-N-[4[(5H-pyrrolo[2,1-c] [1,4] benzodiazepine-10(11H)ylcarbonyl)phenyl] benzeneamine, 0.17 g of the hydrochloride of glycinamide, 0.15 g of triethylamine and 3 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-1(1H)-pyrimidinone maintained at 75oC for 2 days. Methyl alcohol is evaporated and the residue diluted with water. The resulting suspension is filtered and the precipitate washed with water and then dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution, brine and dried with sodium sulfate. The mixture is filtered and the filtrate evaporated in vacuum. Get a residue, which was stirred with a mixture of ether-hexane to obtain 0.13 g of yellowish-brown product. Min - 10(11H)-ylcarbonyl)phenyl]benzazimide.

Mix-chloro-N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepine - 10(11H)ylcarbonyl)phenyl] benzazimide and 1 ml of methanol is treated with 0.5 ml of dimethylamine and 1 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-1(1H)-pyrimidinone and stirred for 20 hours, the Methyl alcohol is evaporated and the residue diluted with water. The resulting suspension is filtered and the precipitate washed with water and then dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution, brine and dried with sodium sulfate. The mixture is filtered and the filtrate evaporated in vacuum. Get a residue, which was stirred with a mixture of ether-hexane to obtain 0.15 g of a beige solid product. Mass spectrum (chemical ionization): 465 (M+H).

Example 587. (Atomic charges)-N-[4-(5H-pyrrolo[2,1-c][1,4]- benzodiazepine-10(11H)-ylcarbonyl)phenyl]benzazimide.

To a solution of 0.30 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H - pyrrolo[2,1-c] [1,4] -benzodiazepine in 5 ml of methylene chloride add 0.15 g of triethylamine, and then 0.27 g of acid chloride of O-acetylindole acid. The mixture is stirred at room temperature for 1 h and then diluted with 50% sodium bicarbonate solution. The methylene chloride evaporated and the resulting residue extracted with ethyl acetate. The organic layer is separated and washed with a saturated solution bicarbonate evaporated, get a residue, which was stirred with a mixture of ether-hexane to obtain 0.54 g of beige solid product. Mass spectrum (chemical ionization): 480 (M+H).

Example 588. () -- Hydroxy-N-[4-(5H-pyrrolo[2,1-c][1,4]- benzodiazepine-10(11H)-ylcarbonyl)phenyl]benzazimide.

A solution of 0.34 g (atomic charges)-N-[4-(5H-pyrrolo[2,1-c][1,4]- benzodiazepine-10(11H)-ylcarbonyl)phenyl] benzeneamine in 2 ml of 1 n NaOH and 4 ml of methyl alcohol is stirred at room temperature for 30 min, diluted with 2 ml of water and evaporated in vacuum. The aqueous suspension is extracted with 30 ml ethyl acetate and the extract washed with brine, dried with sodium sulfate and filtered through a layer of water magnesium silicate. The filtrate is evaporated in vacuo and the resulting residue is stirred with a mixture of ether-hexane, allocate 0.26 g of a cream solid color. Mass spectrum (chemical ionization): 438 (M+H).

Example 589. 2-Chloro-N-[4-(5H-pyrrolo[2,1-c][1,4]-benzodiazepine - 10(11H)-ylcarbonyl)phenyl]ndimethylacetamide.

To a solution of 0.91 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H - pyrrolo[2,1-c] [1,4]-benzodiazepine in 10 ml of methylene chloride was added with stirring 0.46 g of triethylamine and 36 mg of dimethylaminopyridine, and then slowly added 0.42 g of chloroacetanilide in 15 ml of methylene chloride. Received sa sodium and the methylene chloride evaporated under vacuum. The resulting suspension is filtered, the precipitate washed with 50% sodium bicarbonate solution, water, ethyl acetate (2 x 2 ml), ether (2 x 5 ml) and dried in vacuum. Obtain 1.14 g of beige solid product. Mass spectrum (chemical ionization): 380 (M+H).

Example 590. N-[4-(5H-Pyrrolo[2,1-c][1,4]-benzodiazepine-10(11H)- ylcarbonyl)phenyl]-4-morpholinoethyl.

To a suspension of 0.19 g of 2-chloro-N-[4-(5H-pyrrolo[2,1-c][1,4]- benzodiazepine-10(11H)-ylcarbonyl)phenyl] ndimethylacetamide in 1 ml of methylene chloride was added with stirring 0.44 g of the research, and then 1 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyridinone and stirred for 20 hours, the methylene chloride evaporated, the residue diluted with water. The resulting suspension is filtered and the residue is dissolved in 15 ml ethyl acetate and washed with saturated sodium bicarbonate solution. The mixture is filtered, the filtrate evaporated in a vacuum, getting 0.23 g of a colourless resin, which is stirred with a mixture of ethyl acetate-hexane. Allocate 0.21 g of white solid product. Mass spectrum (chemical ionization): 431 (M+H).

Example 591. N-[(2-Chlorophenyl)methyl] -N-[4-(5H-pyrrolo[2,1-c][1,4]- benzodiazepine-10(11H)-ylcarbonyl)phenyl]-4-morpholinoethyl.

A mixture of 0.11 g of N-[4-(5H-pyrrolo[2,1-c] [1,4]-benzodiazepine-10(11H)- ylcarbonyl)phenyl] -4-morpholinoethyl, 56 mg O-Harbin is romida and 0.4 mmole of sodium hydride and heated for 24 hours The reaction mass is diluted with water and extracted with ethyl acetate. The organic layer is dried with sodium sulfate and evaporated. Obtain 0.18 g of residue, which is distilled chromatographytandem on silica gel, eluent ethyl acetate-methylene chloride (1:1). Allocate 80 mg almost white solid product. Mass spectrum (chemical ionization): 555 (M+H).

Example 592. Ethyl ester of 10-[4-[(2,4-dichlorobenzoyl)amino]-3-methylbenzoyl] -10,11-dihydro-5H - pyrrolo[2,1-c][1,4]-benzodiazepine-3-carboxylic acid.

To a solution of 0.30 g of ethyl ester of 10,11-dihydro-10-(4-amino-3-methylbenzoyl-5H-pyrrolo[2,1-c] [1,4] - benzodiazepine-3-carboxylic acid in 20 ml of methylene chloride add 0.15 g of N,N-diisopropylethylamine and 0.24 g of 2,4-dichlorobenzotrifluoride. The reaction mass is washed with water, saturated sodium bicarbonate solution and dried with sodium sulfate. The organic layer is passed through a water layer of magnesium silicate. To the filtrate at the boil add hexane, allocate 0.24 g of the solid product, so pl. 174-184oC.

Example 593. Methyl ester of 10-[4-[(2,4-dichlorobenzoyl)amino]- benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]-benzodiazepine-3-carboxylic acid.

To 50 ml of absolute methyl alcohol added 0.15 g of metallic sodium. After restonica and the resulting reaction mass was stirred at room temperature overnight. Add methylene chloride, and then Na2SO4. The organic layer is filtered through water magnesium silicate. To the filtrate at the boil add hexane, allocate 0.29 g of solid product.

Example 594. N-[4-[[3-(TRIFLUOROACETYL)-5H-pyrrolo[2,1-c][1,4]- benzodiazepine-10(11H)-yl)]carbonyl]phenyl]-2-(trifluoromethyl)benzamid.

To a solution of 1.0 g of N-[4-(5H-pyrrolo[2,1-c][1,4]-benzodiazepine-10(11H)- ylcarbonyl)phenyl]-2-(trifluoromethyl)benzamide in 10 ml of methylene chloride add 1.0 ml triperoxonane anhydride, and then stirred at room temperature for 18 hours the Reaction mass is washed with saturated sodium bicarbonate solution, dried with sodium sulfate, filtered, and when boiling add hexane. Produce a solid product, which crystallized from a mixture of methylene chloride-hexane to obtain 0.89 g of the solid product, so pl. 248-250oC.

Example 595. N-[4-[[3-(TRIFLUOROACETYL)-5H-pyrrolo[2,1-c][1,4]- benzodiazepine-10(11H)-yl)]carbonyl-3-chlorophenyl]-2-methylbenzamide.

To a solution of 0.30 g of N-[4-(5H-pyrrolo[2,1-c][1,4]-benzodiazepine - 10(11H)-yl)carbonyl-3-chlorophenyl] -2-methylbenzamide in 25 ml of methylene chloride add 0.5 ml triperoxonane anhydride and stirred at room temperature for 18 hours the Reaction mass is washed with saturated is this to guard Rath when boiling add hexane, obtain 0.22 g of a colorless solid product. Mass spectrum (chemical ionization): M+551.

Example 596. Ethyl ester of 10-[4-[(2,4-dichlorobenzoyl)amino]-benzoyl]-10,11-dihydro-5H - pyrrolo[2,1-c][1,4]-benzodiazepine-3-carboxylic acid.

To 50 ml of absolute ethyl alcohol is added 0.30 g of metallic sodium. After complete dissolution of the added 2.0 g of N-[[3-(trichloroacetyl)-5H-pyrrolo[2,1-c] [1,4]-benzodiazepine-10(11H)- yl)]carbonyl] phenyl] -2,4-dichlorobenzamide and the resulting reaction mass was stirred at room temperature for 18 h the Volatile components are evaporated in vacuum and the residue is dissolved in methylene chloride and washed with water. The organic layer is dried with sodium sulfate and filtered through water magnesium silicate. To the filtrate at the boil add hexane to produce a solid product, which is crystallized with a mixture of methylene chloride-hexane to obtain 0.57 g of solid compound. Mass spectrum: (M+) - 548.2.

Example 597. N-[4-[[3-Trichloroacetyl)-5H-pyrrolo[2,1-c][1,4]- benzodiazepine-10(11H)-yl)]carbonyl]phenyl]-2-(trifluoromethyl)benzamid.

To a solution of 0.48 g of N-[4-(5H-pyrrolo[2,1-c][1,4]-benzodiazepine - 10(11H)-ylcarbonyl)phenyl]-2-(trifluoromethyl)benzamide in 20 ml of methylene chloride add 0.4 g triperoxonane anhydride, and then rbonate sodium, dried sodium sulfate, passed through a water layer of magnesium silicate. To the filtrate at the boil add hexane. Allocate 0.37 g of the solid product, so pl. 219-221oC.

Example 598. N-[4-[[3-Trichloroacetyl)-5H-pyrrolo[2,1-c][1,4]- benzodiazepine-10(11H)-yl)]carbonyl]phenyl]-2,4-dichlorobenzamide.

To a solution of 4.76 g of N-[4-(5H-pyrrolo[2,1-c][1,4]-benzodiazepine - 10(11H)-ylcarbonyl)phenyl] -2,4-dichlorobenzamide in 150 ml of methylene chloride was added with stirring 3.75 g of trichloroacetic anhydride, and then stirred for 18 hours the Reaction mass is washed with water and a saturated solution of NaHCO3, dried with sodium sulfate and passed through a water layer of magnesium silicate. The filtrate is evaporated in vacuum, obtain 2.91 g of solid product.

Example 599. N-[4-(5H-pyrrolo[2,1-c][1,4]-benzodiazepine-10(11H)- ylcarbonyl)phenyl]-2,3,5-trichlorobenzene.

According to the method of example 8 0.50 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H - pyrrolo[2,1-c] [1,4] -benzodiazepine is treated 0.483 g of 2,3,5-trichlorobenzaldehyde get glassy mass which is crystallized by ethyl acetate. Allocate 0.686 g of crystalline product, so pl. 231-234oC.

Example 600. N-[4-(5H-Pyrrolo[2,1-c][1,4]-benzodiazepine-10(11H)- ylcarbonyl)phenyl]tetrahydrofuran-2-carboxamide.

According to the method of example 297, using the appropriate substituted Aronhold the compounds of examples 601 - 659 (see end of text).

Example 660. N-[4-[[[3-[(Dimethylamino)methyl]-5H-pyrrolo[2,1-c] [1,4]-benzodiazepine-10(11H)yl-]carbonyl]phenyl]-2-Marylebone.

To a solution of 0.842 g 2-methyl-N-[4-5H-pyrrolo[2,1-c][1,4]-benzodiazepine-10(11H)yl-] carbonyl] phenyl]benzamide in 25 ml of a mixture of methanol-tetrahydrofuran, 1:1, with stirring and at 0oC add 10 ml of 35% formaldehyde and 10 ml of 30% aqueous N,N-dimethylamine. Then add 2 drops of acetic acid and the reaction mass stirred at room temperature for 16 hours, the Reaction mixture was concentrated in vacuo and the resulting residue is dissolved in chloroform and washed with water. The organic layer is dried with sodium sulfate and evaporated in vacuum. The obtained residue chromatographic on silica gel, eluent ethyl acetate: gesan, 10:1, get 0.800 g of the desired product, M+H - 479.

According to the method of example 660, using the appropriate substituted benzamide get connection examples 661 - 669 (see end Tex is D.

A solution of 0.954 g of N-[4-(5H-pyrrolo[2,1-c][1,4]-benzodiazepine-10(11H)-yl] carbonyl]phenyl]- 2,4-dichlorobenzamide in 25 ml of methylene chloride and 5 ml of acetic anhydride with stirring boiled for 24 hours, Volatile components are evaporated in vacuo, the obtained residue is purified column chromatography on silica gel, eluent ethyl acetate: hexane, 7:1, get 0.800 g of white solid product. Mass spectrum: M+H - 519.

Example 671. 1-[2-Nitro-5-(etoxycarbonyl)benzyl]-pyrrole-2 - carbaldehyde.

To a suspension of 2.2 g of sodium hydride (60% in oil, washed with hexane) in tetrahydrofuran with stirring and at 0oC add 4.5 g of pyrrole-2-carbaldehyde in 25 ml of tetrahydrofuran. After adding in the atmosphere of nitrogen is added slowly a solution of 15 g of ethyl ester 4-nitro-3-bromomethylphenyl acid. The reaction mass is stirred at 20oC for 8 h and carefully quenched with water. Then the reaction mass is extracted with chloroform, washed with water, dried with sodium sulfate and concentrated in vacuo. Obtain 12 g of the desired solid product. Mass spectrum: M+H - 349.

Example 672. 1-[2-Nitro-5-(etoxycarbonyl)benzyl]-pyrrole-2 - carbaldehyde.

According to the method of example 671 using the ethyl ester of 3-neath the>H - 349.

Example 673. Ethyl ester of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine - 7-carboxylic acid.

A solution of 10.0 g of 1-[2-nitro-5-(etoxycarbonyl)benzyl]- pyrrole-2-carbaldehyde in 150 ml of absolute ethanol containing 1.0 g of 10% Pd/C, hydronaut in a Parr apparatus for 16 h under hydrogen pressure of 40 pounds per square inch. The reaction mass is filtered through diatomaceous earth and the filtrate concentrated in vacuo. Obtain 5.5 g of the desired solid product. Mass spectrum: M+H - 255.

Example 674. Ethyl ester of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine - 8-carboxylic acid.

Hydrogenation under the conditions of example 673 1-[2-nitro-4-(etoxycarbonyl)benzyl] -pyrrole-2-carbaldehyde leads to 5.0 g of the desired solid product. Mass spectrum: M+H - 255.

Example 675. Ethyl ester of 10,11-dihydro-10-[4-[(2-methylbenzoyl)amino]-benzoyl]- 5H-pyrrolo[2,1-c][1,4]benzodiazepine-7-carboxylic acid.

A solution of 1.2 g of ethyl ester of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-7-carboxylic acid in 100 ml of methylene chloride cooled to 0oC and add 10 ml of triethylamine, and then 1.5 g of 4-[(2-methylbenzoyl)amino]benzoyl chloride. The reaction mass was stirred at room temperature for 18 h and concentator sodium and concentrated in vacuo. The resulting residue is purified column chromatography on silica gel, eluent of 40% ethyl acetate-hexane. Produce 1.0 g of the desired compound in the form of a solid substance. Mass spectrum: M+H - 494.

Example 676. Ethyl ester of 10,11-dihydro-10-[4-[(2-methylbenzoyl) amino] -benzoyl]-5H-pyrrolo[2,1-c][1,4]benzodiazepine-8-carboxylic acid.

According to the method of example 675 using ethyl ether 10,11-dihydro-5H-pyrrolo[2,1-c] [1,4] benzodiazepine-8-carboxylic acid obtain 1.2 g of the above compound in the form of a solid substance. Mass spectrum: M+H - 494.

Example 677. 10,11-Dihydro-10-(4-nitrobenzoyl)-5H-imidazo[2,1-c] [1,4] benzodiazepine

A sample of 292 g of sodium hydride in oil in an atmosphere of argon, washed with pentane. The residue was diluted with 17 ml of dioxane and then added 1.35 g of 10,11-dihydro-5H-imidazo[2,1-c] [1,4] benzodiazepine. The reaction mass is slowly heated until the evolution of hydrogen. To the cooled reaction mass is added a solution of 1.36 g of p-nitrobenzaldehyde in 45 ml of dioxane and the mixture is stirred at room temperature for 18 hours In a vacuum evaporated the solvent and the residue is heated in chloroform and filtered hot, the residue on the filter is washed with hot chloroform. The combined chloroform of soeulmate magnesium and the filtrate evaporated in vacuum, obtain 1.82 g of brown solid residue, which is purified by rapid chromatography, eluent chloroform-methanol. Allocate 630 mg of the desired compound in the form of a solid substance. Mass spectrum (HR FAB): (M+H) = 335.3433.

Example 678. 10,11-Dihydro-10-(4-aminobenzoyl)-5H-imidazo[2,1-c] [1,4] benzodiazepine.

The mixture 0.550 g of 10,11-dihydro-10-(4-nitrobenzoyl)-5H-imidazo[2,1-c][1,4] benzodiazepine and 1.86 g of SnCl22 H2O in 22 ml of ethanol is boiled in an argon atmosphere for 1 h the Mixture is diluted with water and then add 10% solution of NaHCO3to obtain an alkaline reaction mass. Add a further quantity of ethyl alcohol and the reaction mass is evaporated in vacuum. The resulting residue is triturated several times in a mixture of chloroform-methanol, 1: 1, and filtered. The filtrates are combined treated with activated charcoal and filtered through diatomaceous earth. The filtrate is evaporated in vacuum and get 680 g of a beige crystalline product. The latter is stirred in ethanol, in water and in 10% solution of NaHCO3to pH 8 for 5 hours and extracted with chloroform three times. The combined extracts are treated with activated carbon, filtered through magnesium sulfate and evaporated in vacuum, get 370 mg beige crystallizes the 1-c] [1,4]benzodiazepine-10(11H)- ylcarbonyl)phenyl]-2,4-dichlorobenzamide.

Suspension 0.330 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-imidazo[2,1-c] [1,4]benzodiazepine in 15 ml of dioxane is stirred and slightly heated to obtain almost complete dissolution. The reaction mixture is cooled to room temperature and added 43 mg of sodium hydride in oil. The mixture is slightly heated. The evolution of gas ceases in a few minutes. The reaction mass is then cooled to room temperature and add 153 μl of 2,4-dichlorobenzotrifluoride in 2.5 ml of dioxane. Add 3.5 ml of dioxane and the reaction mass was stirred at room temperature for 2 days. Volatile components are evaporated and the resulting residue partitioned between water and chloroform. The organic layer is separated and the aqueous phase is extracted twice with chloroform. The combined organic layers treated with activated charcoal and filtered through magnesium sulfate. The filtrate is evaporated in vacuum, get a beige foam which is purified by rapid chromatography on silica gel, eluent chloroform containing 3-7% methanol. Allocate 310 mg of a beige foam.

Example 680. 6,7-dihydro-5-(2-chloro-4-nitrobenzoyl)-5H-pyrrolo [1,2-a] [1,5]benzodiazepine.

To a solution of 0.28 6,7-dihydro-5H-pyrrolo[1,2-a][1,4]benzodiazepine in 6 ml of methylene chloride added 0.30 g Tr is room temperature for 1 h, and then quenched with 5 ml saturated solution of NaHCO3. The methylene chloride evaporated in vacuo and the resulting residue was diluted with 5 ml of water and extralight 20 ml of ethyl acetate. The organic layer was separated, washed with saturated solution of NaHCO3and evaporated in vacuum. Obtain 0.59 g of a yellow foam which is triturated with a mixture of ether-hexane. Allocate 0.56 g of the desired almost white solid product. Mass spectrum (chemical ionization):

368 (M+H) (Cl35)

370 (M+H) (Cl37).

Example 681. 6,7-dihydro-5-(4-amino-2-chlorbenzoyl)-5H-pyrrolo [1,2-a] [1,5]benzodiazepine.

To a solution of 0.50 g of 6,7-dihydro-5-(2-chloro-4-nitrobenzoyl)-5H-pyrrolo[1,2-a] [1,5] benzodiazepine in 10 ml of ethanol and 2 ml of tetrahydrofuran added 2.35 g of SnCl22 H2O and the resulting mixture was stirred at 55oC for 30 minutes the Solvent is evaporated in vacuo, the resulting residue is stirred with 20 ml of 1 n NaOH solution and 40 ml of ethyl acetate for 15 minutes, the Filtrate is passed through diatomaceous earth. The filter layer is washed with ethyl acetate (2 x 10 ml) and the combined extracts washed with brine, dried with sodium sulfate and evaporated in vacuum. Allocate 0.47 g of the solid residue, which is triturated with a mixture of ether-hexane. Obtain 0.43 g of light yellow crystalmir 682. N-[4-[(6,7-dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepine-5-yl)carbonyl]-3-chlorophenyl]-3-fluoro-2-methylbenzamide.

To a mixture of 0.10 g of 6,7-dihydro-5-(4-amino-2-chlorbenzoyl)-5H-pyrrolo[1,2-a] [1,5] benzodiazepine and 0.06 g of triethylamine in 6 ml of methylene chloride added 0.08 g of 3-fluoro-2-methylbenzonitrile in 5 ml of methylene chloride. The mixture is stirred for 2 h at room temperature and then add 2 ml of 1 n NaOH solution. Volatile components are evaporated in vacuum and the residue is dissolved in 2 ml of tetrahydrofuran and 1 ml of methanol. The mixture is stirred for 2 h and evaporated. The resulting residue is dissolved in 2 ml of 1 n NaOH solution and 5 ml of water. The mixture is extracted with ethyl acetate (15 ml) and the extract washed with brine and dried with sodium sulfate. The solvent is evaporated in vacuo and the residue triturated with a mixture of diethyl ether-hexane. Obtain 0.15 g of a white solid product. Mass spectrum (chemical ionization: 474 (M+H, Cl35); 476 (M+H) (Cl37).

Example 683. N-[4-(6,7-dihydro-5H-pyrrolo[1,2-a][1,5] benzodiazepine-5-yl)carbonyl]-3-chlorophenyl]-2,4-dichlorobenzamide,

To a mixture of 0.10 g of 6,7-dihydro-5-(4-amino-2-chlorbenzoyl)-5H-pyrrolo[1,2-a] [1,5] benzodiazepine and 0.06 g of triethylamine in 5 ml of methylene chloride add 0.10 g of 2,4-dihlorbenzolovy in 0.5 ml of methylene chloride. The mixture is stirred is to the residue add 2 ml of tetrahydrofuran and 1 ml of methanol. The mixture is stirred at room temperature for 2 h and the volatiles evaporated. To the obtained residue, add 2 ml of 1 n NaOH solution and 5 ml of water. The mixture is extracted with ethyl acetate (15 ml) and the extract washed with brine and dried with sodium sulfate. The solvent is evaporated in vacuo and the residue triturated with a mixture of diethyl ether-hexane. Obtain 0.15 g of a white solid product. Mass spectrum (chemical ionization): 510 (M+H, Cl35).

Example 684. N-[4-(5H-pyrrolo[2,1-C][1,4]benzodiazepine-10(11H)-ylcarbonyl)phenyl]-2- (1H-[1,2,4]-triazole-1-yl)ndimethylacetamide.

To a suspension of 0.20 g of 1,2,4-triazoline in 1 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone add 0.10 g of 2-chloro-N-[4-(5H-pyrrolo[2,1-C] [1,4] benzodiazepine-10(11H)-ylcarbonyl) phenyl]ndimethylacetamide in 1 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, and then stirred at room temperature for 3 hours, the Reaction mixture was quenched with 15 ml of water and the resulting solid residue is collected, washed with water and hexane. Get 0.70 mg of the desired compound in the form of a solid, yellowish-brown. Mass spectrum (chemical ionization): 413 (M+H).

Example 685. N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepine-10(11H)- ylcarbonyl)phenyl]-2-(2-formyl-1-pyrrolo)ndimethylacetamide.

To a suspension of 72 g of wrath 1 h at room temperature and add 984 mg of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone and 0.19 g of 2-chloro-N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepine-10(11H)- ylcarbonyl)phenyl] ndimethylacetamide. The mixture is stirred at room temperature, add water and evaporated in vacuum tetrahydrofuran. The resulting suspension is filtered and the residue washed with water and hexane. The collected residue is purified column chromatography on silica gel, eluent ethyl acetate:hexane, 3:2. Receive 50 mg of a pink solid. Mass spectrum (chemical ionization): 439 (M+H).

Example 686. N-[4-(3-Chloro-4H-pyrazolo[5,1-c] [1,4]benzodiazepine-5(10H)- ylcarbonyl)phenyl]-2-methyl-5-perbenzoic.

A mixture of 356 mg of N-[4H-pyrazolo[5,1-c][1,4]benzodiazepine-5(10H)- ylcarbonyl)-3-chlorophenyl] -5-fluoro-2-methylbenzamide and 122 mg of N-chlorosuccinimide in 5 ml of methylene chloride is boiled on a steam bath for 3 hours, the Reaction mixture was washed with a saturated solution of NaHCO3, water and brine, then dried with magnesium sulfate and passed through a water layer of magnesium silicate. The filtrate is evaporated in vacuum and obtain 190 mg of the desired product as a solid.

Connection examples 687 -707 obtained according to the method of example 465 (see end of text).

Example 708. Methyl ester 4-[2-(2-chlorophenyl)-2-cyano-2-(4-morpholinyl)-ethyl]benzoic acid.

Sample 0.876 g of 60% sodium hydride in oil was washed with hexane, and then add 60 ml creature after adding -(2-chlorophenyl)-4-morpholinylmethyl. Then to the reaction mixture are added 4.8 g of methyl ester of 4-(methyl bromide)benzoic acid and continue stirred for 3 hours Add a few drops of acetic acid to ice water and quenched the reaction. The reaction mass has a pH of 3-4 and with a saturated solution of NaHCO3the pH is brought to 6-7. After cooling, a solid precipitate, which is filtered, washed with water and dried. Get 5.92 g of the yellow solid product. Crystallization in methylene chloride leads to 2.10 g of the desired compound as a crystalline substance, so pl. 116 - 118oC.

Example 709. Methyl ester 4-[2-(2-chlorophenyl)-2-oxoethyl] benzoic acid.

A mixture of 1.0 g of methyl ester [4-(2-chlorophenyl)-2-cyano-2- (4-morpholinyl)ethyl]benzoic acid and 14 ml of water is boiled for 20 min and then poured into crushed ice. After stirring for 15 min the precipitate is collected, washed with water and dried in air. Allocate 0.63 g of beige solid product, so pl. 40-42oC.

Example 710. 4-[2-(2-Chlorophenyl)-2-oxoethyl]benzoic acid.

The mixture 18.78 g of methyl ester 4-[2-(2-chlorophenyl)-2-oxoethyl]benzoic acid in 288.8 ml of methyl alcohol, 72.7 ml of water and 5.2 g of NaOH boiled for 3 h, and then Podkolodnaya and acidified with 1 N. the hydrochloric acid. The obtained solid residue is collected and dried in vacuum. Get 17.72 g of the desired product, so pl. 168 - 172oC.

Example 711. 3-Methoxy-4-nitrobenzoate.

A suspension of 1.0 g of 3-methoxy-4-nitrobenzoic acid and 1.40 ml of thionyl chloride is boiled for 2 hours the Mixture is cooled at room temperature, add 2 ml of ISO-octane and the mixture is evaporated in vacuum. Get a solid residue, which is washed with ISO-octane (2 x 2 ml), dried in vacuum, allocate 1.08 solid cream color.

Example 712. 10,11-Dihydro-10-(4-nitro-3-methoxybenzoyl)-5H - pyrrolo[2,1-c][1,4]benzodiazepine.

To a solution of 0.55 g of 10,11-dihydro-5H - pyrrolo[2,1-c][1,4] benzodiazepine in 8 ml of methylene chloride added 0.55 g of triethylamine, and then 0.97 g of 3-methoxy-4-nitrobenzonitrile. The resulting mixture was stirred at room temperature for 2 h and then quenched with 10 ml of 1 n NaOH solution. Methylenchloride layer evaporated and the resulting suspension is filtered. The precipitate was washed with 1 N. NaOH solution (2 x 5 ml), water (3 x 5 ml) and hexane (2 x 5 ml). The collected solid product is dried in a vacuum, isolated 1.13 g of an almost white product. Mass spectrum (chemical ionization): 364 (M+H).

Example 713. 10,11-Dihydro-10-(4-amino-3-methoxybenzoyl)4]benzodiazepine 4.51 g of SnCl 2 H2O, 6 ml of ethanol, 6 ml of tetrahydrofuran and 16 ml of methylene chloride is stirred at 50oC for 2 h the Solvent is evaporated in vacuum and the residue is dissolved in 80 ml of ethyl acetate. The solution is treated with 50 ml of 1 n NaOH solution and stirred for 30 minutes, the resulting suspension is filtered through diatomaceous earth and the filter bed washed with ethyl acetate (3 x 15 ml). United an ethyl acetate solution is washed with brine, dried with sodium sulfate, filtered water through magnesium silicate and evaporated in vacuum. Obtain 0.99 g of residue which is stirred with a mixture of ether-hexane. Allocate 0.90 g of cream colored solid product. Mass spectrum (chemical ionization): 334 (M+H).

Example 714. 10,11-Dihydro-10-[4-[(3-methylpropionitrile)amino]benzoyl]-5H - pyrrolo-[2,1-c][1,4]benzodiazepine.

To a solution of 0.15 g of 10,11-dihydro-10-[4-[(3-methylpropionitrile) -5H-pyrrolo[2,1-c][1,4]benzodiazepine in 2 ml of methylene chloride with stirring, add 0.10 g of triethylamine, and then 0.10 g of isobutylacetate. The reaction mass is stirred for 3 h and then quenched with 1 N. NaOH solution. The organic layer is evaporated in vacuo and the resulting residue is stirred in 5 ml of tetrahydrofuran for 1 h, and then evaporated in vaqueria, filtered through a layer of water of magnesium silicate and evaporated in vacuum. Get a residue, which was stirred with a mixture of ethyl acetate-methylene chloride. Will provide 0.22 g of solid cream color. Mass spectrum (chemical ionization): 404 (M+H).

Example 715. 10,11-Dihydro-10-[4-(pentanoyl)aminobenzoyl)-5H - pyrrolo-[2,1-c][1,4]benzodiazepine.

To a solution of 0.15 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo-[2,1-c] [1,4]benzodiazepine in 2 ml of methylene chloride with stirring, add 0.10 g of triethylamine, and then 0.09 g of acid chloride of valerianic acid. The resulting reaction mass is stirred for 3 h and then quenched with 4 ml of 1 n NaOH solution. The methylene chloride evaporated in vacuum and the residue is dissolved within 1 h in 5 ml of tetrahydrofuran and evaporated in vacuum. The residue is extracted with a mixture of ethyl acetate-methylene chloride, washed with brine and the organic layer dried with sodium sulfate, filtered through water magnesium silicate, evaporated in vacuum. Obtain 0.23 g of residue, which is triturated with a mixture of ether-hexane. Allocate 0.19 g of a white solid product.

Example 716. 10,11-Dihydro-10-[4-[3-methylbutanoyl)amino-3-methoxybenzoyl] - 5H-pyrrolo[2,1-c][1,4]benzodiazepine.

To a solution of 0.10 g of 10,11-dihydro-10-(4-aminobenzoyl]-5H-pyrrolo[2,1-c] [the IDA ISO-valerianic acid. The resulting reaction mass is stirred for 3 h and then quenched with 1 N. NaOH solution. The organic layer is evaporated in vacuum and the residue is stirred for 1 h in 5 ml of tetrahydrofuran and evaporated in vacuum. The residue is extracted with a mixture of ethyl acetate-methylene chloride, washed with brine and the organic layer dried with sodium sulfate, filtered through water magnesium silicate, evaporated in vacuum. Obtain 0.15 g of a residue which is stirred with a mixture of ether-hexane. Allocate 0.13 g of light yellow solid product. Mass spectrum (chemical ionization): 418 (M+H).

Example 717. 10,11-Dihydro-10-[3-methoxy-4-[(butylsulfonyl)amino]benzoyl]- 5H-pyrrolo[2,1-c][1,4]benzodiazepine.

To a solution of 0.10 g of 10,11-dihydro-10-(4-amino-3-methoxybenzoyl]-5H-pyrrolo[2,1-c] [1,4] benzodiazepine in 2 ml of methylene chloride was added with stirring 60 mg of triethylamine, and then 56 mg N.-butylsulfonyl. After stirring the obtained reaction mixture for 2 h the solvent is evaporated in vacuum, the residue is dissolved in methyl alcohol, stirred for 1 h and evaporated in vacuum. Get a residue, which is treated with 2 ml of a solution of NH4Cl and extracted with 15 ml of ethyl acetate. The organic extract was washed with a saturated solution of NaHCO3 the residue is stirred with a mixture of ether-hexane. Allocate 0.14 g of light yellow solid product. Mass spectrum (chemical ionization): 418 (M+H).

Evaluation of biological activity.

Assessment of binding to hepatic V1receptors in rats.

Membranes of rat liver cells, which are vasopressive V1the subtypes of receptors, isolated by the method of density gradient of sucrose, which is described Lesko et al., (1973). These membranes are quickly suspended in 50.0 mm Tris.HCl buffer, pH 7.4, containing 0.2% bovine serum albumin (BSA) and 0.1 mm phenylmethylsulfonyl (PMSF), and before use in the experiments kept frozen at -70oC. To study the binding to the wells of 96-well microtiter tablet add the following components: 100 ál 100.0 mm Tris.HCl buffer containing 10 mm MgCl2, 0.2% inactivated when heated BSA and a mixture of protease inhibitors: leupeptin, 1.0 mg %; Aprotinin, 1.0 mg %; 1,10-phenanthroline, 2.0 mg %; tripcony inhibitor, 10.0 mg % and 0.1 mm PMSF, 20 μl of [phenylalanine-3,4,5-3H]vasopressin (S.A. 45.1 Ci/mmol) at 0.8 nm, and the reaction initiated by addition of 80 μl of tissue membranes containing 20 μg of tissue protein. Tablets stand alone on the bench at room temperature for 120 m is animalanimalesannemie, added in a volume of 20.0 μl.

The compounds solubilizer in 50% dimethyl sulfoxide (DMSO) and added in a volume of 20.0 μl to a final incubation volume of 200 μl. After binding the contents of each well was filtered using a collector cells Brandela (Brandel, Gairhersburg, MD). The radioactivity retained for disk filtrate complex ligand-receptor evaluated using the acquired scintillation counter Packard LS efficiency for tritium 65%. The received data is analyzed to estimate the IC50with the help of the program for the competition LUNDON-2 (LUNDON SOFTWARE, OH).

Assessment of binding to renal modulatory V2receptors in rats.

Modulatory the kidneys of rats cut off, cut into small pieces and soaked 0.154 mm sodium chloride solution containing 1.0 mm EDTU, with repeated replacement of the liquid phase, as long as the solution does not contain blood. The tissue is homogenized in 0.25 M sucrose solution containing 1.0 mm EDTU and 0.1 mm PMSF, by using a homogenizer (Potter-Elvehjem Teflon pestle. The homogenate was filtered through a multi-layer (layer 4) gauze. The filtrate is again homogenized using Dounce ??) homogenizer with good ground glass pestle. Received g is ova centrifuged at 40,000 g for 30 minutes The resulting pellet contains dark inner part and light pink outer part. Pink outer part is suspended in a small amount of 50.0 mm Tris.HCl buffer, pH 7.4 protein Content determined by the method of Lowry (Lowry et al., J. Biol. Chem., 1953). Prior to the experiment, the suspension of membranes stored at -70oC 50.0 mm Tris. HCl containing 0.2% inactivated BSA and 0.1 mm PMSF, 1.0 ml aliquot containing 10.0 mg of protein per 1 ml of suspension.

To study the binding to the wells of 96-well microtiter tablet add the following components: 100 ál 100.0 mm Tris.HCl buffer containing 10 mm MgCl2, 0.2% inactivated when heated BSA and a mixture of protease inhibitors: leupeptin, 1.0 mg %; Aprotinin, 1.0 mg %; 1,10-phenanthroline, 2.0 mg %; tripcony inhibitor, 10.0 mg % and 0.1 mm PMSF, 20 μl of [3H] Arginine8, vasopressin (S.A. 75/0 Ci/mmol) at 0.8 nm, and the reaction initiated by addition of 80 μl of tissue membranes (200.0 μg tissue protein). Tablets stand alone on the bench at room temperature for 120 min to establish equilibrium. Non-specific binding is estimated in the presence of 0.1 μm unlabeled ligand added in a volume of 20.0 μl.

The compounds solubilizing 50% dimetilan the keep of each well was filtered using a collector cells Brandela (Brandel, Gaithersburg, MD). The radioactivity retained for disk filter complex ligand-receptor evaluated using the acquired scintillation counter Packard LS efficiency for tritium 65%. The received data is analyzed to estimate the IC50with the help of the program for the competition LUNDON -2(LUNDONSOFTWARE, OH). The results of the study are presented in Table XIII.

Assessment of binding of labeled ligand to the membranes of human platelets.

(a) Preparation of the membranes of platelets.

Frozen platelet-rich plasma (CCP) (Source platelets: Hudson Valley Blood Services, Westchester Medical center, Valhalla, NV) and thawed at room temperature. The G containing OTP centrifuged at 16000 g for 10 min at 4oC and the supernatant liquid is discharged. Platelets resuspended in equal volume of 50.0 mm Tris HCl buffer, pH 7.5, containing 120 mm NaCl and 20.0 mm EDTU. The suspension is again centrifuged at 16000 g for 10 minutes Such a stage of washing is repeated more than once. The wash liquid is thrown away, and lysed palette homogenized in Tris buffer.HCl low ionic strength, 5.0 mm, pH 5.5, containing 5.0 mm EDTU. The homogenate was centrifuged at 39000 g for 10 minutes the resulting palette again suspended in Tris buffer.HCl, 70.0 mm pH 7.4, containing 120 mm NaCl and 5.0 mm KCl. Get 1.0 - 2.0 mg protein per 1 ml of suspension.

(b) Binding vasopressin V-a receptor in the membrane of human platelets.

Membrane platelet

In wells of 96-well microtiter tablet add 100 ál 50.0 mm Tris.HCl buffer containing 10 mm MgCl2, 0.2% BSA and a mixture of protease inhibitors (leupeptin, Aprotinin, and others). Then add 20 μl of [3H] Ligand. (Manning or Arg8Vasopressin) to obtain a final concentration in the range of from 0.01 to 10.0 nm. Linking initiate the addition of 80.0 μl of the suspension of platelets (approximately 100 µg of protein). All reagents are mixed by sucking pipette several times up and down. Nonspecific binding measured in the presence of 1.0 μm unlabeled ligand (Manning or Arg8Vasopressin). The mixture was kept at rest at room temperature for 90 minutes After this incubat quickly filtered with vacuum suction through the filters GF/B cell manifold Brandela. Determine contained in the filtered drive radioactivity by adding scintillate with acquired scintillation counter.

Binding to membranes of muscle cells fibroblast line (LV-2), transfemed.

Flask 175 ml, containing enlarged to merge cells, purified from culture medium by suction. The flask containing the expanded cells, pour (2x5 ml) of phosphate saline buffer (FSB) and each time the liquid is sucked off. Finally, in the flask add 5 ml present and degrades the free enzymes of the basic solution Hank (Speciflity Media, Inc., Lafayette, NJ) and the flask is left alone for 2 hours, the Contents of all flasks poured into a centrifuge tube and centrifuged at 300 g for 15 minutes a Solution of Hank sucked off and the cells homogenized with Poltrona when defending # 6 for 10 sec to 10.0 mm Tris.HCl buffer, pH 7.4, containing 0.25 M sucrose and 1.0 M EDTU. The homogenate was centrifuged at 1500 g for 10 min to remove the shattered membranes. The supernatant centrifuged at 100000 g for 60 min before the formation of the pellets receptor protein. Then the pellets resuspended in a small volume of 50.0 mm Tris.HCl buffer, pH 7.4. the protein content determined by the method of Lowry and receptor membrane suspended in 50.0 mm Tris.HCl buffer containing 0.1 mm FSMP and 0.2% bovine serum albumin (BSA). Get the content of the receptor protein 27: mg per ml of suspension.

(b) receptor Binding.

To study the binding in rasego 10 mm MgCl, 0.2% inactivated when heated BSA and a mixture of protease inhibitors: leupeptin, 1.0 mg %; Aprotinin, 1.0 mg %; 1,10-phenanthroline, 2.0 mg %; tripcony inhibitor, 10.0 mg % and 0.1 mm PMSF, 20 μl of [3H] Arginine8vasopressin (S.A. 75/0 Ci/mmol) at 0.8 nm, and the reaction initiated by addition of 80 μl of tissue membranes (200.0 μg tissue protein). Tablets stand alone on the bench at room temperature for 120 min to establish equilibrium. Non-specific binding is estimated in the presence of 0.1 μm unlabeled ligand added in a volume of 20.0 μl.

The compounds solubilizer in 50% dimethyl sulfoxide (DMSO) and added in a volume of 20.0 μl to a final incubation volume of 200 μl. After binding the contents of each well was filtered using a collector cells Brandela (Brandel, Gaithercburg, MD). The radioactivity retained for disk filter complex ligand-receptor evaluated using the acquired scintillation counter Packard LS efficiency for tritium 65%. The received data is analyzed to estimate the IC50with the help of the program for the competition LUNDON-2 (LUNDON SOFTWARE, OH) (table XIII attached at the end of the description.)

Vasopressive V2-antagonistic activity at finding what soedineniya in a dose of from 0.01 to 100 mg/kg orally or with a carrier. In each experiment used two to four rats. After an hour at a dose of 0.4 mcg/kg intraperitoneally administered arginine vasopressin (AVP, antidiuretic hormone, ADH), dissolved in peanut oil. Two rats in each experiment is introduced only media (peanut butter) without arginine vasopressin, and use them as control water. After 12 min each give a rat 30 mg/kg of deionized water orally using gastric tube and placed separately in a sealed chamber for the study of metabolism, equipped with a funnel and a graduated glass cylinder to collect the urine within 4 hours Measure urine volume and analyze the osmolarity using osmometry Fiske One-Ten (Fiske Assoc. Norwood., MA, USA). Sodium, potassium and chloride in the urine is analyzed using ion-specific electrodes in the analyzer Beckman Beckman E3 (Electrolyte 3).

The following test results decreased urine volume and reduced osmolarity relative to the WUAs control indicates the presence of activity. The results of this experience for specific compounds of the present invention are shown in table XIV (attached at the end of the description).

Vasopressive V1-antagonistic activity of asnload at the base of the tail locally anaesthetize by subcutaneous injection of 2% procaine (0.2 ml). Using aseptic technique remove the ventral tail artery and in the lower abdominal artery miss cannula, made of pipes of PE 10 and 20 (thermal compound). The cannula is fixed, heparinized (u/cm3), seal and the wound closed with one or two surgical sutures Dexon 4 - 0. Tail vein also kanyoro similar way for intravenous medications. The duration of surgery is approximately 5 minutes is carried out where necessary additional local anesthesia (2% procaine or lidocaine).

Animals are placed in the bounding plastic camera in a vertical position. The cannula is attached to the pressure sensor Statham P23Db and record changes in blood pressure. The increase in systolic blood pressure in response to injections of arginine vasopressin 0.01 and 0.2 international units (m units ) is recorded before the introduction of any drug (connection), then each rat is injected dose of the studied compounds or orally 0.1 - 100 mg/kg (10 cm3/kg) or intravenously 0.1 - 30 mg/kg (1 cm3/kg). Injection of vasopressin, follow through 30, 60, 90, 120, 180, 240 and 300 minutes, the degree of suppression of the compound is calculated from the calculation, CTTA for specific compounds of the present invention are presented in Table XV.

The results of this experience for specific compounds of the present invention, the dose, the maximum percentage of inhibition and the time in minutes, are presented in table XVI (attached at the end of the description).

Receptor binding of oxytocin.

(a) Preparation of membranes.

The female rats of Sprague-Damley weighing approximately 200 - 250 g intramuscularly (C. M.) 0.3 mg/kg diethylstilbestrol (DPP). Rats killed after 18 h under anesthesia by pentobarbital. Then open the uterus, cleaned of fat and connective tissue and washed with 5 ml of normal saline. Tissues from six rats was homogenized in 50 ml of 0.01 mm Tris.HCl containing 0.5 mm dithiothreitol and 1.0 mm EDTU with pH 7.4, using Polytron when vyedanii 6 with the three phases of 10 s each. The homogenate was passed through two (2) layers of cheesecloth and the filtrate centrifuged at 1000 g for 10 minutes Clean the supernatant is removed and centrifuged again at 165000 g for 30 minutes the resulting pellets containing receptors oxytocin, again suspended in 50.0 mm Tris.HCl containing 5.0 mm MgCl2at pH 7.4, get a protein concentration of 2.5 mg/ml susepnsion tissues. This drug is used in subsequent assessments of binding with [3H]Oxytocin.

(Boutet in microtiter tablets using the [3H]OT at various concentrations of 50.0 mm buffer to assess Tris.HCl, pH 7.4, containing 5.0 mm MgCl2and the mixture protease inhibitors: BSA, 0.1 mg; Aprotinin, 1.0 mg; 1,10-phenanthroline, 2.0 mg; trypsin, 10.0 mg; and PMSF, 0.3 mg per 100 ml of buffer solution. The nonspecific binding determined in the presence of 1.0 its OT. The binding reaction is stopped after 60 min, 22oC, by filtration through filters of fiberglass using the collector cells Brandela (Brandel, Gaithersburg, MD). Competitive experiments carried out at the equilibrium state using 1.0 nm [3H]OT at various concentrations showing agents. Concentration of agents exhibiting 50% [3H]OT on its websites (IC50) estimated using a computer program LUNDON - 2 (LUNDON SOFTWARE INC., Ohio, USA).

The results of this analysis for the specific compounds shown in table XVII (attached at the end of the description).

Compounds of the present invention can be used in the form of salts derived from a physiologically and pharmaceutically acceptable acids or bases. These salts include, but are not limited to, salts of inorganic acids such as hydrochloric, sulfuric, nitric, phosphoric acid and such organical or alkaline earth metals, such as sodium, potassium, calcium or magnesium, or salts of organic bases. The connection can also be used in the form of esters, carbamates and other familiar "proletarienne forms", which when introduced into the body become active residue in vivo.

When connections are used for the above purposes, they can be mixed with one or more pharmaceutically acceptable carriers, for example, solvents, diluents and other media, and they can be administered orally in such forms as tablets, capsules, dispergirujutsja powders, granules, or suspensions containing from about 0.05 to 5% suspending agent, syrups containing, for example, from about 20 to 50% ethanol, etc. or parenterally in the form of sterile injectable solutions or suspensions containing from about 0.05 to 5% a suspending agent in an isotonic medium. Such pharmaceutical preparations may contain, for example, from about 0.05 to 0% of the active ingredient with the carrier, more preferably from about 5 to 60 wt.%.

The effective dose of active ingredient can vary depending on the specific compound and the method is implement compounds of the present invention at a daily dosage of from about 0.5 to 500 mg/kg animal body, preferably, when divided into two or four doses a day, or in a form with a gradual release of active ingredient. For most large animals total daily dosage is from about 1 to 100 mg, preferably from about 2 to 80 mg Dosing form, acceptable for internal use contains from about 0.5 to 500 mg of active compound, thoroughly mixed with solid or liquid pharmaceutically acceptable carrier. The interval between doses can be adjusted to obtain the optimum therapeutic response. For example, there may be several separate doses per day, or the dose may be proportionally reduced depending on therapeutic situation.

The active compounds may be administered orally as well as intravenously, intramuscularly or subcutaneously. Solid carriers can be starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers are water, glycol, non-ionic surfactants and edible oils such as corn, peanut and sesame oils, depending on the nature of the active ingredient and the desired way BB is a odorants, coloring agents, preserving agents, as well as the antioxidant, for example, vitamin E, ascorbic acid, BHT and BHA.

The preferred pharmaceutical compositions from the standpoint of ease of preparation and the application is solid compositions, particularly tablets and filled with solid or liquid capsules. Preferably oral introduction connections.

The considered compounds may be introduced parenterally or intraperitoneally. Solutions or suspensions of the active compounds as free base or pharmaceutically acceptable salts can be obtained in water, mixed with a surface-active substance, such as hydroxypropylcellulose. The dispersion can also be prepared in glycerol, liquid polyethylene glycols and their mixtures in oils. Under normal conditions of storage and use, these preparations contain a preservative agents that prevent the growth of microorganisms.

Pharmaceutical form that is suitable for injection include sterile water solutions or dispersions or sterile powders for unplanned preparation of sterile solutions or dispersions. In all cases the form must be sterile and must be iwtsth and storage, and must be protected from contamination by microorganisms, such as bacteria or fungi. The carrier can be a solvent or dispersion medium, for example, it may be water, ethanol, polyol (e.g. glycerol, propylene glycol, liquid polyethylene glycol), acceptable mixture of these compounds, as well as vegetable oils.

1. Tricyclic diazepine antagonists of vasopressin and oxytocin General formula I

< / BR>
where Y represents -(CH2)n- where n = 0 or 1;

A - b represents the

< / BR>
where m = 1, 2;

fragment

< / BR>
represents: (1) condensed phenyl, (2) a 5-membered aromatic (unsaturated) heterocyclic ring containing one heteroatom S;

fragment

< / BR>
represents a 5-membered aromatic (unsaturated) condensed heterocyclic ring containing a nitrogen atom,

where D, E and F are selected from carbon atoms or nitrogen, and where the carbon atoms may be optionally substituted by substituents selected from a halogen atom, -COCF3,

< / BR>
< / BR>
< / BR>
-CHO, where q = 1, the substituents Rbindependently of one another are selected from-CH3or-C2H5; Deputy R3representation>and R7independently selected from a hydrogen atom, lower(C1-C3)-alkyl, lower (C1-C3-alkoxygroup and halogen atom;

Deputy R6is selected from (a) fragments of formulas

< / BR>
< / BR>
< / BR>
< / BR>
linear or branched,

linear or branched,

where cycloalkyl is defined as6-cycloalkyl;

the substituents Randindependently from each other selected from hydrogen atom, CH3or

< / BR>
q = 1;

Rbtakes the values defined above;

R1and R2independently from each other selected from hydrogen atom, lower (C1-C3)-alkyl, lower (C1-C3-alkoxygroup and halogen atom;

(b) a fragment of the formula

< / BR>
where substituent Rwithis selected from a halogen atom, OH group,

< / BR>
< / BR>
< / BR>
where the substituents Raand Rbtake the above specified values;

Ar' is selected from fragments of formulas

< / BR>
where W' is S;

the substituents R8and R9independently of one another chosen from hydrogen atom, lower (C1-C3)-alkyl, -S-lower-(C1-C3)-alkyl, halogen atom, HE, NO2, O-lower (C1-C3)-alkyl, CF<-alkyl,

and its pharmaceutically acceptable salts and proletarienne form.

2. Connection on p. I of the formula

< / BR>
where the fragment

< / BR>
is selected from among phenyl, or thiophene ring;

Deputy R3represents the balance

< / BR>
where the Deputy Ar represents a residue of the formula

< / BR>
where substituent R6is selected from (a) fragments of formulas

< / BR>
< / BR>
< / BR>
< / BR>
linear or branched,

linear or branched,

where cycloalkyl is a C6-cycloalkyl;

the substituents Raindependently from each other selected from hydrogen atom, CH3or

< / BR>
q = 1;

the substituents Rbindependently from each other selected from CH3- 2H5;

(b) a fragment of the formula

< / BR>
where substituent Rwithis selected from a halogen atom, Oh group,

< / BR>
< / BR>
< / BR>
where Randand Rbtake the above specified values;

Ar' is selected from fragments of formulas

< / BR>
where W' is S;

the substituents R5and R7selected from a hydrogen atom, lower (C1-C3)-alkyl, lower (C1-C3-alkoxygroup and halogen atom;

the substituents R8and R
-C3)-alkyl, halogen atom, HE, NO2, -O-(C1-C3)-lower alkyl, -CF3;

Deputy R11is selected from hydrogen atom, halogen, COCF3,

< / BR>
< / BR>
< / BR>
< / BR>
-CHO,

where q = 1,

and its pharmaceutically acceptable salts.

3. Connection on p. 1, selected from compounds of the formula

< / BR>
where m = 1, 2;

Deputy R3represents a residue of the formula

< / BR>
where the Deputy Ar represents a residue of the formula

< / BR>
where substituent R6choose from (a) fragments of formulas

< / BR>
< / BR>
< / BR>
< / BR>
linear or branched,

linear or branched, where cycloalkyl takes the values C6-cycloalkyl;

the substituents Randindependently from each other selected from hydrogen atom, CH3or

< / BR>
q = 1;

the substituents Rbindependently of one another are selected from-CH3C2H5;

the substituents R1and R2independently from each other selected from hydrogen atom, lower (C1-C3)-alkyl, lower (C1-C3-alkoxygroup or halogen atom;

(b) a fragment of the formula

< / BR>
where substituent Rcis selected from a halogen atom, OH group,

< / BR>
the substituents R5and R7selected from a hydrogen atom, lower (C1-C3)-alkyl, lower (C1-C3-alkoxygroup and halogen atom;

the substituents R8and R9independently of one another chosen from hydrogen atom, lower (C1-C3)-alkyl, -S-lower (C1-C3)-alkyl, halogen atom, - OH, -NO2, O-lower (C1-C3)-alkyl, CF3;

Deputy R11is selected from a halogen atom, COCF3;

< / BR>
< / BR>
< / BR>
-(CH2)q-OH, -CHO;

q = 1;

W' represents S;

and its pharmaceutically acceptable salts.

4. Connection on p. 1, selected from compounds of the formula

< / BR>
where Y represents -(CH2)n-;

n = 1 if m = 1 and m = 1 or 2, if n = 0;

Deputy R5represents a fragment of formula

,

where the Deputy Ar represents a residue selected from

< / BR>
where substituent R6is selected from (a) fragments of formulas

< / BR>
< / BR>
< / BR>
< / BR>
linear or branched,

linear or branched,

where cycloalkyl takes the values C6-cycloalkyl;

the substituents Randindependently from each other selected from hydrogen atom, CHH5;

the substituents R1and R2independently from each other selected from hydrogen atom, lower (C1-C3)-alkyl, lower (C1-C3-alkoxygroup or halogen atom;

(b) a fragment of the formula

< / BR>
where substituent Rwithis selected from a halogen atom, OH group,

< / BR>
< / BR>
< / BR>
where the substituents Randand Rbtake the above specified values;

Ar' is selected from fragments of formulas

< / BR>
the substituents R5and R7selected from a hydrogen atom, lower (C1-C3)-alkyl, lower (C1-C3-alkoxygroup and halogen atom;

the substituents R8and R9independently from each other selected from hydrogen atom, lower (C1-C3)-alkyl, -S-lower (C1-C3)-alkyl, halogen atom, - OH, - NO2, O-lower (C1-C3)-alkyl, CF3;

Deputy R11is selected from hydrogen atom, halogen atom, COCF3,

< / BR>
< / BR>
< / BR>
< / BR>
and its pharmaceutically acceptable salts.

5. Connection on p. 1 chosen from among compounds of the formula

< / BR>
where Y represents -(CH2)n;

n = 1 if m = 1 and m = 2, if n = 0;

the substituents R3and R11mautalen formula

< / BR>
where R3and R11have the meanings specified above,

and its pharmaceutically acceptable salts.

7. Connection on p. 1, which is N-[4-(5H-pyrrolo[2,1-c] [1,4]benzodiazepine-10(11H)-ylcarbonyl)phenyl]-2,4-dichlorobenzamide.

8. Connection on p. 1, which is N-[4-(5H-pyrrolo[2,1-c] [1,4]benzodiazepine-10(11H)-ylcarbonyl)-3-chlorophenyl]-5-fluoro-2-methylbenzamide.

9. Connection on p. 1, which is N-[4-[[3-[(dimethylamino)methyl] -5H-pyrrolo[2,1-c] [1,4] benzodiazepine-10(11H)-yl]carbonyl]-3-chlorophenyl]-5-fluoro-2-methylbenzamide.

10. The method of obtaining the compounds of formula I on p. 1, wherein interact compounds of the formula

< / BR>
with the compound of the formula

< / BR>
where the substituents Z, Y, D, E, F, Ar, and n described in paragraph 1;

Deputy Q represents a halogen atom or an activating group, which is obtained by converting arylcarbamoyl acid mixed anhydride or activated using peptide reagent mates,

with the formation of compounds of formula I.

11. Pharmaceutical composition having antagonistic activity against vasopressin for the treatment of diseases characterized eroticheskoe syndrome, damage to the Central nervous system, lung diseases and hyponatremia in a mammal, characterized in that it contains a pharmaceutical carrier and an effective amount of the compounds under item 1.

12. The method of treatment vasopressinergic diseases by introducing ones vasopressin antagonist, characterized in that use connections under item 1 in the amount effective to facilitate the disease.

13. The method according to p. 12, characterized in that these diseases are conditions characterized by excess renal reabsorption of water, congestive heart failure, liver cirrhosis, nephrotic syndrome, damage to the Central nervous system, lung disease and hyponatremia in mammals.

 

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The invention relates to new triazolo[4,3-a][1,4] benzodiazepine or a thieno[3,2-f][1,2,4]triazolo[4,3-a]benzodiazepines of General formula I

< / BR>
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I,

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