Non-steroidal modulators of progesterone receptor

FIELD: organic chemistry, pharmaceuticals.

SUBSTANCE: invention relates to compounds of general formula I and pharmaceutically acceptable salt thereof, wherein R1, R3, R4, R5, and R10 are independently H, halogen, C1-C4-alkyl, etc.; R2 is H, halogen, NO2, etc.; R6 is H, C1-C6-alkyl, C1-C6-alkoxy-substituted C1-C4-alkyl, etc.; R7 is H, C1-C4-alkyl or C2-C4-alkenyl, optionally substituted with halogen; R8 and R9 are H, R11 and R12; meanings of the rest substituents are as define in specification.

EFFECT: new compounds with value biological properties and useful as drug having activity in relates to progesterone receptor.

15 cl, 3 tbl, 80 ex

 

The present invention relates to compounds for modulation of the progesterone receptor, as well as to the use of these compounds in therapy.

Intracellular receptors are a class of structurally related proteins involved in the regulation of gene proteins. Steroid receptors are a subset of these receptors, including the progesterone receptor (PR), androgen receptor (AR), estrogen receptor (ER), glucocorticoid receptor (GR) and mineralocorticoid receptor (MR). Regulation of the gene such factors requires intracellular receptor and the corresponding ligand, which has the ability to selectively bind to the receptor in a way that affects transcription of the gene.

Modulators of progesterone receptor (Progestogens)is known to play an important role in ensuring the health of the woman. The natural ligand for the receptor PR is a steroid hormone progesterone, but received and synthetic compounds, which can also serve as ligands (see, for example, Jones et al., U.S. patent No. 5688810).

Progestogens are now widely used for hormonal contraception and HRT (hormone replacement therapy). Other important clinical applications of Progestogens are the treatment of gynecological disorders (for example, &is matriosha, dysmenorrhea, dysfunctional uterine bleeding, acute premenstrual syndrome), cancer of the breast and lucianna support during IVF (in vitro fertilization). The PR agonists are used in drugs for birth control, while PR antagonists may be used for contraception, hormone dependent cancers, hormone-replacement therapy, endometriosis, and the like.

Currently used steroid Progestogens, as shown, are completely safe and well tolerated. There are times, however, reported side effects (e.g., chest pain, headaches, depression and weight gain), ascribed to these steroid Progestogens, either by itself or in combination with estrogenic compounds.

Steroid ligands to one of the receptors often exhibit cross-reactivity to interact with other steroid receptors. Many Progestogens are also linked, for example, with the glucocorticoid receptor. Nonsteroidal Progestogens have no similarity of molecular structures with steroids, and for this reason you can expect differences in physicochemical properties, pharmacokinetic (PK) parameters in the distribution in tissues (for example, in the Central and peripheral nervous force is the topic), and, more importantly, non-steroidal Progestogens may exhibit less cross-reactivity towards other steroid receptors or its absence. For this reason, with these points of view, non-steroidal Progestogens will be evaluated differently.

The present invention provides non-steroidal compounds that modulate the activity of the progesterone receptor. More specifically, the present invention provides non-steroidal compounds with high affinitiy, which are agonists, partial agonists or antagonists of the progesterone receptor. Preferably, these compounds are highly specific with respect to the progesterone receptor. In accordance with the present invention provides compounds having the General formula I, prodrugs or pharmaceutically acceptable salts or compounds, or prodrugs.

where R1, R3, R4, R5 and R10 independently are selected from the group consisting of H, halogen, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)quinil, OH, CN, O(1-4C)alkyl, S(O)m(1-4C)alkyl (optionally substituted by one or more halogen atoms), C(O)(1-4C)alkyl, OC(O)(1-4C)alkyl and NR19R20,

R2 is selected from the group consisting of H, halogen, NO2, NR11R12, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)quinil, OH, (1-4C)alkyl, (1-4C)alkyl and OC(O)(1-4C)alkyl,

R6 you Iraida from the group consisting of H, C(Y)R15, C(O)OR16, C(S)NR17, (1-6C)alkyl, (1-6C)alkoxy-substituted (1-4C)alkyl and (CH2)nC(O)OR21,

R7 is selected from the group consisting of (1-4C)alkyl, (2-4C)alkenyl and (2-4C)quinil, all of which are optionally substituted by one or more halogen atoms, or R7 represents H,

R8 and R9 independently are selected from the group consisting of H and (1-4C)alkyl,

R11 and R12 independently are selected from the group consisting of H, (1-4C)alkyl, (2-4C)alkenyl or (2-4C)quinil, (1-6C)alkoxycarbonyl, (1-4C)alkylsulfonyl and (6-10C)arylsulfonyl,

R15 represents H or R15 is selected from the group consisting of (1-6C)alkyl, (3-6C)cycloalkyl, (2-4C)alkenyl, (2-4C)quinil, (6-10C)aryl, 1,4-bisaria, amino(1-4C)alkyl, hydroxy(1-4C)alkyl and carboxy(1-4C)alkyl, all of which are optionally substituted by one or more halogen atoms,

R16 represents (1-6C)alkyl, optionally substituted by one or more halogen atoms,

R17 is selected from the group consisting of (1-4C)alkyl, (2-4C)alkenyl, (2-4C)quinil and (3-6C)cycloalkyl, all of which are optionally substituted by one or more halogen atoms,

X is selected from the group consisting of O, S, CH2and NR18,

Y is selected from the group consisting of O, S, and NH,

R18 is selected from the group consisting of H and (1-4C)alkyl,

R19 is selected from the group consisting of H and (1-4C)alkyl,

R20 is selected and the group, consisting of H, (1-4C)alkyl, CH2(6-10C)aryl, C(O)(1-6C)alkyl and C(O)NH(1-4C)alkyl,

R21 is selected from the group consisting of H and (1-6C)alkyl,

m is 0, 1 or 2,

n is 1, 2 or 3, provided that

(i) when X represents O, R1-R5 are H, R8-R10 are H and R6 represents ethyl or C(O)CH3then R7 is not H;

(ii) when X represents O, R1-R5 are H, R8-R10 are H and R6 represents methyl, then R7 is not a stands;

(iii) when X represents O, R1-R5 are H, R8-R10 are H and R6 represents H, then R7 is not H, ethyl or (CO)CH3.

The term "(1-4C)alkyl", as used in the definition of the present invention, refers to an alkyl group branched or non-branched chain having 1-4 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, sec-btil and tert-butyl.

The term "(1-6C)alkyl", as used in the definition of the present invention, refers to an alkyl group branched or unbranched chain having 1-6 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, sec-btil, tert-butyl and hexyl. (1-5C)Alkyl groups are preferred, (1-4C)alkyl is preferable.

The term "halogen" denotes fluorine, chlorine, bromine or iodine.

The term "(1-6C)alcox the means alkoxygroup, having 1-6 carbon atoms, and the alkyl residue has the same formula as defined previously. (1-2C)Alkoxygroup are preferred.

The term "(1-6C)alkoxycarbonyl" means alkoxycarbonyl group, and alkoxygroup it contains 1-6 carbon atoms and has the same meaning as defined previously. (1-4C)Alkoxycarbonyl group are preferred.

The term "(1-4C)alkylsulfonyl" denotes alkylsulfonyl group, an alkyl group which contains 1-4 carbon atoms and has the same meaning as defined previously. (1-2C)Alkylsulfonyl group are preferred.

The term "(6-10C)aryl" means an aromatic hydrocarbon group having 6-10 carbon atoms, such as phenyl, naphthyl, tetrahydronaphthyl or indanyl, which may optionally be substituted by one or more substituents selected from hydroxy, amino, halogen, nitro, trifloromethyl, cyano or (1-4C)alkyl, and the alkyl residue has the same meaning as defined previously. The preferred aromatic hydrocarbon group is a phenyl.

The term(6-10)arylsulfonyl" means arylsulfonyl group, aryl group which contains 6 to 10 carbon atoms and has the same meaning as defined previously. Phenylsulfonyl is preferred.

the Term "(2-4C)alkenyl" means alkenylphenol group, branched or unbranched chain, having 2-4 carbon atoms, such as ethynyl and 2-butenyl.

The term "(2-4C)quinil" means alkylamino group, branched or unbranched chain having 2-4 carbon atoms, such as ethinyl and PROPYNYL.

The term "amino(1-4C)alkyl" denotes aminoalkyl group, an alkyl group which contains 1-4 carbon atoms and has the same meaning as previously defined. Amino(1-2C)alkyl groups are preferred.

The term "hydroxy(1-4C)alkyl" denotes a hydroxyalkyl group, an alkyl group which contains 1-4 carbon atoms and has the same meaning as previously defined. Hydroxy(1-2C)alkyl groups are preferred.

The term "1,4-biaryl" refers to two phenyl groups, in which the second phenyl group attached at the 4-position of the first phenyl group.

The term "carboxy(1-4C)alkyl" denotes carboxialkilnuyu group, an alkyl group which contains 1-4 carbon atoms and has the same meaning as previously defined. Carboxy(1-2C)alkyl groups are preferred.

The term "(3-6C)cycloalkyl" means cycloalkyl group having 3-6 carbon atoms, represents cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term "pharmaceutically acceptable salt" represents those salts which are, within the framework of the European medical is to be placed, are suitable for use in contact with the tissues of humans and/or animals without undue toxicity, irritation, allergic response and the like, and are correlated with a reasonable ratio of win/risk. Pharmaceutically acceptable salts are well known in this field. They can be obtained during the final isolation and purification of the compounds of the present invention or separately by reacting a functional group of the free base with the appropriate mineral acid, such as hydrochloric acid, phosphoric acid or sulfuric acid, or with organic acids, such as ascorbic acid, citric acid, tartaric acid, lactic acid, maleic acid, malonic acid, fumaric acid, glycolic acid, succinic acid, propionic acid, acetic acid, methanesulfonate acid and the like. Functional group of the acid can interact with organic or mineral base such as sodium hydroxide, potassium hydroxide or lithium hydroxide.

For the purposes of the present invention, the term "trance"when it is used for the name of the condensed polycyclic compounds, understood as denoting such relative stereochemistry, where the substituents on the ring in position 1, in the formula I, n is located on the side of this ring, opposite the connection ring with anilinophenol ring system in position 14b. As a consequence, the substituent in position 1 is on the same side of the ring system, which is part of the bridge hydrogen atom occupying the position 14b. In addition, the use of the term "TRANS" will be clear to experts in this field from illustrations in a variety of charts, figures and diagrams reactions.

Prodrugs are compounds that are rapidly transformed in vivo into the parent compound of the above formula, for example by hydrolysis in blood.

The compounds of formula I exist as a mixture of stereochemical isomers; is preferred absolute stereochemistry of (1S,14bR).

The preferred compounds are such compounds where R2 is selected from the group consisting of H, halogen, NO2and NR11R12, where R11 and R12 independently are selected from the group consisting of H, (1-6C)alkoxycarbonyl, (1-4C)alkylsulfonyl and (6-10C)arylsulfonyl.

Especially preferred are the compounds of formula I, where R1 and R5 are H and R3 and R4 are independently selected from H or halogen.

X preferably represents O, S or CH2more preferably O or CH2. Other interest compounds are such compounds where R6 represents the t a H or C(Y)R15 and R15 represents H or (1-4C)alkyl, preferably (1-2C)alkyl, and alkyl groups optionally substituted by one or more halogen atoms.

Also preferred are compounds where R2 represents H, halogen or NO2. Most preferred as R2 are H and F.

The most preferred compounds are compounds where R11 represents H and R12 represents (1-6C)alkoxycarbonyl, (1-4C)alkylsulfonyl or (6-10C)arylsulfonyl.

Also highly preferred are compounds where R2 represents H, R3 represents halogen, R15 is a methyl, optionally substituted by 1 to 3 halogen atoms, and Y represents O or S, more specifically, those compounds where R4 represents H and X represents O. Connections with some of the preferences mentioned above in connection with General formula I, or more, are highly preferred.

Additional preferred compounds are those where R2 represents H or halogen, R3 and/or R4 are independently selected from the group consisting of H, CN, halogen, (2-4C)alkenyl and C(O)(1-4C)alkyl and R5 and/or R10 are independently selected from H or halogen.

More preferred are compounds where X is selected from the group consisting of O, S and NCH3.

Pre who are respectful connection where R8 and R9 are H.

Also preferred are compounds where R6 represents H or C(Y)R15 and R15 represents H or (1-4C)alkyl, optionally substituted by one or more halogen atoms.

Also preferred are compounds where Y is O or S and R15 is a methyl, optionally substituted by one or more halogen atoms.

Scheme I

The sequence of steps for the synthesis of compounds of the present invention is shown in schemes I-XVIII. In each of the schemes group R correspond to the structures of substitution mentioned in the examples and the formula I.

The tetracyclic system (such as structure 11) is created by using routine methods of synthesis as described in scheme I. Nucleophilic aromatic substitution of 2-ftorirovaniem respectively substituted phenols, thiophenolate or aniline gives dearlove ethers, simple thioethers or amines 1, respectively. In the case of X = CH2structure 1 is commercially available. The restoration of the nitro group using SnCl2gives derivatives of aniline 2. The acylation of the functional group of aniline 5-chlorovaleronitrile gives amides 3. The following ring closure is carried out by treating the amide PPA (polyparaben acid) with 10° C. Processing eminovic structures 4 sodium methoxide leads to intramolecular cyclization and gives the tetracyclic system 5. Interaction enaminones functional groups with trichloroacetamido gives trichloroethylene derivative 6. Trichloroethylene functional group is converted to complex derivatives methyl ester 7 in the processing of sodium methoxide. Subsequent recovery in alkinoos functional group of unsaturated carboxylates 7 borane gives exclusively the CIS-isomers, such as structure 8. The epimerization to the TRANS-isomers 9 is carried out when processing 8 with sodium methoxide. Saponification of ester gives carboxylate 10, which is subsequently converted by means of the classical reaction of kurzius in the amine functional group leads to the production of derivatives of TRANS-1-amino-tetrahydropyrimidines(ACS/ti/di)azepine 11. The racemic mixture is separated into its pure enantiomers by means of chiral HPLC (OJ column (25 x 0,46 cm)).

Tetracyclic compounds (11) are used as starting materials in schemes II and III. In scheme II shows the acylation amine functional group patterns 11 through many various routine methods of synthesis (e.g., acid chlorides, anhydrides, carboxylic acids with binding reage the Tami or amidation). The obtained amide of structure 12 are targeted to the following further modifications. Processing amides, such as structure 12, pentasulfide phosphorus gives thioamides 13. Alkylation of the amide structure 12 alkylating agents in the presence of sodium hydride gives the structure 14. Structure 15 get through the education of amidine amine functional group 11 by treating the nitrile derivatives such as triptoreline.

Scheme III describes the formation of urethane structures 16 on the basis of the structures 11, via interaction with chloroformate in the presence of sodium bicarbonate. Processing patterns 11 isothioscyanates gives derivatives of thiourea structure 17. Reductive alkylation of amine functional groups in the structure 11 aldehydes in the presence of triacetoxyborohydride sodium network structure 18. Alkylation of amine functional group 2-methoxyethylamine network structure 26. Patterns 27 are obtained by treatment of tert-butylbromide.

Direct electrophilic aromatic substitution in the frame structures give different alternative aromatic substituted derivatives (scheme IV-V).

In scheme IV describes the chlorination of the structure 12, where R3 isone Cl, N-chlorosuccinimide in the presence of catalytic amounts of HCl; this leads to the formation of two different substituted structures 19A and 19B, which are easily separated. In contrast, bromination structure 12 with N-bromosuccinimide under identical conditions gives only connection with the structure 20. Restoration of dihalogenoalkane chlorine-substituted compounds (12) is achieved by treatment with hydrogen in the presence of Pd/C and HCl, to obtain the hydrogen-substituted derivative 21. Narisovanie structure 12 with nitric acid gives a completely selective mono-substituted derivative 22.

Direct chlorination on the structure 21 (scheme V) N-herakleidon gives two regioisomer 23A and 23B, two compounds, which are easily separated by chromatographic methods.

As shown in scheme VI, the restoration of the nitro functional group structures, such as structure 22, SnCl2·2H2O in ethanol, gives the aniline derivative 24. The sulfonation or this acylation of aniline functional group gives substituted compounds such as structure 25.

As depicted in scheme VII, processing dichloroethylene 19B K2CO3leads to the formation of the corresponding amine 28, and then formirovanie the ethyl formate gives structure is ru 29.

Schemes VIII and IX describe the synthesis of bromo derivatives 36, where R4 = Br. The imine formation by processing a mixture of amine and salicylaldehyde p-toluensulfonate acid and subsequent ring closure by the esterification gives the tricyclic intermediate 31.

Scheme IX describes the sequence of stages of the synthesis of compounds 36, on the basis of tricyclic intermediates such as compound 31. Treatment tricyclic imine 31 glutaric anhydride gives tetracycli 32. Rearrangement of kurzius using DPPA and alcohol leads to the formation of urethane structures 33. The restoration of the amide functional group is carried out through the use of borane in THF. Processing of urethane structures 34 HBr in acetic acid gives amines 35. The acylation amine functional group triperoxonane anhydride gives the corresponding amides 36.

Bromo derivatives 36 are used as starting materials in scheme X. the Reaction Stille give compounds with acetyl (structure 37) or vinyl functional group (structure 39). Treatment of bromo derivatives 36 CuCN gives the corresponding cyanocobalamine 38. The connection 40 is synthesized using the Negishi reaction with a palladium catalyst and methylenchloride. Clicks the processing of bromo derivatives 36 CuI and NaOMe gives methoxypropane 41.

The synthesis of compounds 46 carried out similarly to the method described for the bromo derivatives 36. Tricyclic intermediate connection 45 synthesize way other than described in scheme XI. The synthesis starts from the esterification, with subsequent recovery of the nitro functional group and formirovanie amine 43. Then processing PPA provides a closure ring to tricyclic compounds 45.

Bromo derivatives 46 is used as a starting material in scheme XII, where the vinyl (structure 49) and acetyl derivative (structure 47) is formed through the reaction of Style. Nitrile functional group is introduced by treatment with CuCN. Benzylamine is entered using the Buchwald reaction; the following further hydrogenation of this product generates Amin 51. Interaction with propionylcarnitine gives the corresponding amide (structure 52).

The synthesis of derivatives with R5 ≠ H described in schemes XIII and XIV. Tricyclic intermediate compound obtained by imine formation and the next next ring closure through esterification.

Cyanoderivatives 56, methyl derivative 57 and dichloroethylene 58 is obtained by processing the connection 55 CuCN, methylenchloride or NC, respectively, as described in scheme X.

The method of synthesis of obtaining porpoising 61 (R5 and/or R10 = F) is depicted in scheme XV and is similar to the synthesis method of obtaining derivatives with R5 ≠ H (scheme XIII). In this case, the ring closure by the esterification is carried out using a microwave oven.

Derivatives with X = N-Me (structure 67, 68 and 69) synthesized in accordance with scheme XVI. Tricyclic intermediate connection 65 synthesize by combining 4-chloro-1-fluoro-2-nitrobenzene and N-methylaniline, followed by reduction of the nitro functional group and formirovanie Amin. Ring closure to obtain the intermediate compound 65 is carried out by processing the PPA. Sequence the stages of the synthesis of compound 66 of the connection 65 is described in scheme IX. Amine functional group of compound 66 alleroed, to obtain the amide 67, or alkiliruya getting connection 68. The following saponification gives compound 69.

The method of obtaining derivatives with X = N-H carry a tricyclic amide 72, which are obtained by the intramolecular condensation. Restore using LiAlH4and then oxidation with MnO2gives the tricyclic intermediate connection 74. Rela is ejstvujuschij amide 75 synthesize, as described in scheme IX.

The use of 3-methylglutaric anhydride in obtaining the tetracyclic intermediate compounds 78 and following receipt of the urethane yields a mixture of isomers, 80, 81 and 82, as shown in scheme XVIII. Processing HBr in acetic acid, with the following acylation and separation of isomers leads to the production of amides 86, 87 and 88.

Methods for determining the receptor binding and in vitro and in vivo to determine the biological activity of compounds is well known. Typically, the downregulation of the receptor is treated with a compound of the present invention to determine the binding, or stimulation or inhibition of a functional response.

To measure the functional response of isolated DNA encoding a gene of progesterone receptor, preferably the receptor of the person, expressed in appropriate host cells. Such a cell can be a cell in the ovary of the Chinese hamster (CHO), but other cells are also suitable for use. Preferably the cells are in a mammal.

Methods construction of recombinant cell lines expressing progesterone receptors, are well known in the art (Sambrook et al., Molecular Cloning: a aboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, latest edition). The receptor expression is achieved by the expression of DNA that encodes a desired protein.

Methods for site-based mutagenesis, ligation of additional sequences, PCR (polymerase chain reaction) and construction of appropriate expression systems today are all well known in this field. Part of the DNA or the DNA encoding the desired protein can be constructed synthetically using standard solid-phase methods, preferably with the inclusion of restriction sites for ease of ligation. The corresponding control elements for transcription and translation included the coding sequence may be generated by the coding DNA sequences. As is well known, is now available expression systems that are compatible with a wide variety of hosts, including prokaryotic hosts, such as bacteria, and eukaryotic hosts such as yeast, plant cells, insect cells, mammalian cells, bird cages and the like.

Cells expressing the receptor are then brought into contact with the connection of the present invention to observe binding, or stimulation or inhibition of a functional response.

Alternatively, the selected cytosol containing the expressed receptor, can be used to measure the binding compounds of the present invention.

To measure the binding can be used with radioactive or fluorescencebased connection. As a reference compound can be used native hormone or other compounds that bind to the receptor. Alternatively, can also be carried out analyses of competitive binding.

Other analysis includes screening for compounds agonists of the progesterone receptor of the present invention by determining the regulation of natural mRNA of the target gene, mediarama receptor, that is, genes regulated by the receptor through binding of the receptor to the promoter region of the gene. The levels of mRNA of the target gene will decrease or increase, depending on inhibitory or stimulating effect of the compounds of the present invention, when the binding with the receptor.

In addition to the direct measurement of mRNA levels in exposed cells can be used in cells, which, in addition to transfetsirovannyh DNA encoding the receptor, transfairusa a second DNA that encodes a reporter gene whose expression is responsible for the binding of receptor sensitive elements in the promoter of a specific reporter gene. Such sensitive element may be a classic hormone-sensitive elements, well known in this field and are described, for example, Beato, M., Chalepakis, G., Schauer, M., Slater, E.P. (1989) J. Steroid Biochem. 5:737-47 or may be constructed in such a way that they connect with new sensors. Typically, the reporter gene expression can be controlled by any sensor that is responsive to the binding of the progesterone receptor. Appropriate reporter genes are, for example, LacZ, alkaline phosphatase, luciferase Firefly and protein with green fluorescence (GFP).

To select the active compounds are agonists of the progesterone receptor study in 10-5M should lead to activity, more than 30% of maximum activity when (16α)-16-ethyl-21-hydroxy-19-norpregna-4-ene-3,20-dione (Org 2058) is used as a reference. To select compounds for antagonists of the progesterone receptor study in 10-5M should lead to activity that exceeds by more than 10% of maximum activity when (6β,11β,17β)-11-[4-(dimethylamino)phenyl]-4',5'-dihydro-6-methylspiro[östra-4,9-Dien-17,2'(3'H)-furan]-3-one (Org 31710) is used as a reference. Another criterion may be a value of EC50that should be <10-5M, preferably <10-7M.

The person skilled in the art will recognize that the desired value of EC50hung is t, what compounds the present invention investigated. For example, the connection with EC50that is less than 10-5M, usually considered as a candidate for the choice of drug. Preferably, this value is less than 10-7M. However, the connection that has a higher value of EC50but is selective for a particular receptor may still be a candidate for the search of drugs.

Basically, any analysis of transactionware of mammalian cells (cell line or primary culture), which can give information about the possible activation of the receptor, can be used for the purposes of selection of potent ligands. The total value of using multiple systems of cells with cells derived from different organs, can provide the necessary information on potential tissue specificity of ligands, which is obtained by this. Examples of cells are often used for this purpose are, along with CHO cells, cells, among others, T47D, MCF7 cells, cells of the ECC-1, HeLa cells, primary cultures of endometrial cells and pituitary cells.

The present invention also relates to pharmaceutical compositions containing a compound of General formula I or its salt.

Thus, the connection nastasemarian can be used in therapy.

Compounds of the present invention can be used clinically in those modes where the use of Progestogens.

Therefore, the present invention is the use of compounds having the General formula I for the manufacture of medicaments for the modulation of the health conditions in women, mediarama the progesterone receptor, more specifically hormonal dependent cancers such as breast, ovary and uterus; control endometriosis and fertility. The present invention also relates to the treatment of conditions defined above, by introducing the compounds of the present invention.

Appropriate routes of administration of compounds of the formula I or their pharmaceutically acceptable salts, also referred to here as active ingredient, are intramuscular injection, subcutaneous injection, intravenous injection or intraperitoneal injection, oral and intranasal administration. Preferably the compounds can be administered orally. The specific dose and mode of administration of the active ingredient or pharmaceutical composition necessarily will depend on therapeutic effects that should be achieved (for example, treatment of infertility; contraception, endometriosis), and may vary with the particular compound, the route of administration and the age and status is eat an individual entity, which must be a drug.

Generally, parenteral administration requires lower doses than other routes of administration that are more dependent on acquisitions. However, the dosage for people preferably contains 0,0001-25 mg per kg of body weight. The desired dose may be presented as a single dose or as multiple podos, administered at appropriate intervals throughout the day or, in the case of female patients, the dose that must be administered through the appropriate (daily) intervals during the menstrual cycle. Dosage, and mode of administration may vary for patients, male and female.

The present invention also relates to pharmaceutical compositions containing a compound of formula I in a mixture with pharmaceutically acceptable excipients and optionally other therapeutic agents. The excipient must be "acceptable"in the sense of, to be compatible with other ingredients of the composition and to be harmless to patients.

Pharmaceutical compositions include compositions suitable for oral, rectal, nasal, local (including transdermal, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration or in which edenia through the implant. The composition can be obtained by using any of the methods well known in the field of pharmacy, for example, using techniques such as described in Gennaro et al., Remington''s Pharmaceutical Sciences (18th ed., Mack Publishing company, 1990, see specific Part 8: Pharmaceutical Preparations and Their Manufacture).

Such methods include the stage of bringing into Association the active ingredient with any auxiliary substance. Auxiliary substance (substances), also referred to as additional ingredients include ingredients that are conventional in the art (Gennaro, above), such as fillers, binders, diluents, disintegrators, lubricants, colorants, flavoring agents and wetting agents.

Pharmaceutical compositions suitable for oral administration may be presented as discrete dosage units such as pills, tablets or capsules or as a powder or granules or as a solution or suspension. The active ingredient may also be presented as a bolus or pasta. In addition, the composition can be included in a suppository or enema for rectal administration.

In addition, the present invention includes a pharmaceutical composition, as described above, in combination with packaging material, including instructions for applying the composition for such use as described above.

For Parente the real introduction of appropriate compositions include aqueous and non-aqueous sterile solutions for injection. The compositions can be presented in a single dose or mnogochasovykh containers, such as sealed vials and vials, and can be stored in dried by freezing (lyophilized) condition requiring only the addition of sterile liquid carrier, for example water, before use.

Compositions or preparations suitable for administration by nasal inhalation include fine powders or aerosols, which can be generated by aerosol inhalers, nebulizers or insufflators high pressure with measured doses.

Derivative of the present invention can also be administered in the form of devices, consisting of a core of active material surrounded by a membrane that regulates the rate of release. Such implants should be applied subcutaneously or local way, they will release the active ingredient at about a constant speed for a relatively long time periods, for example from weeks to years. Methods for the manufacture of implantable pharmaceutical devices as such are known in this field, for example as described in European patent 0303306 (AKZO N.V.).

The present invention is illustrated using the following examples.

EXAMPLES

Example 1

TRANS-7-Fluoro-2,3,4,14b-tetrahydro-1H-di is Enzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine

(Structure 11 of scheme I, where R1 = H, R2 = H, R3 = F, R4 = H, R5 = H, R6 = H, R7 = H, X = O)

5-fluoro-2-Phenoxyethanol

Cs2CO3(12.1 g, a 62.9 mmol) are added to a solution of phenol (5.9 g, a 62.9 mmol) in 400 ml THF, in an atmosphere of N2. After stirring for 15 minutes, add 2.5-diplomarbeit (6,82 ml, with 62.9 mmol) in 50 ml of THF. The resulting mixture is heated at 40°C for 25 hours. The reaction is followed by means of HPLC to detect the disappearance of 2,5-deformirovannoe. Add water and ethyl acetate, followed by extraction with ethyl acetate (2x). The combined organic layers are successively washed with saturated aqueous sodium bicarbonate (3x), water and saturated saline solution, dried (Na2SO4) and evaporated. The crude compound is subjected to chromatography on silica gel to remove excess phenol. Elution with toluene/ethyl acetate, 95:5, gives specified in the header connection (12,6 g, 86%). Data: (m/z = 234 (M+H)+.

5-fluoro-2-fenoxedilom

General method 1: restore the nitro compounds of structure 1 to aniline structure 2.

SnCl2·2H2O (88.0 g, 390 mmol) are added to a solution of 5-fluoro-2-Phenoxyethanol (22,3 g, or 95.7 mmol) in 450 ml of ethanol, in an atmosphere of N2. The resulting mixture was stirred at 40°C, for 30 minutes, and optionally by cooling for 2 hours. The ethanol is removed PU is eat evaporation under reduced pressure and add 300 ml of ethyl acetate. The organic layer is washed with water and cold 1 N. NaOH. The emulsion is filtered through dekalim, washed with water, extracted with ethyl acetate, dried (Na2SO4) and evaporated to obtain crude compound as a dark brown oil (19.6 g, 100%). Data: (m/z = 204 (M+H)+.

5-Chloro-N-(5-fluoro-2-phenoxyphenyl)pentanone

General method 2: Acylation of aniline structure 2 to the amide structure 3.

A solution of 5-chlorphentermine (13,0 ml, 100 mmol) in 13 ml of CH2Cl2added dropwise within 30 minutes to a solution of 5-fluoro-2-phenoxyimino (19.6 g, or 95.7 mmol) in 88 ml of CH2Cl2and 7 ml of pyridine at <25°C. After stirring the mixture for 1 hour at room temperature add100 ml of ice water at 0°C. After 18 hours stirring at room temperature, the two layers are separated. The organic layer was washed with cold 2 N. NaOH and water, dried (Na2SO4) and evaporated to obtain crude compound as a brown oil (31.0 g, 100%). Data: (m/z = 322 (M+H)+.

8-Fluoro-11-(4-chlorobutyl)dibenzo[b,f][1,4]oxazepine

General method 3: Closure ring amide structure 3 to the imine structure 4.

PPA (190 g, 84%) are added to a solution of 5-chloro-N-(5-fluoro-2-phenoxyphenyl)pentanolide (31.0 g, or 95.7 mmol). The resulting mixture was stirred at 150°C, for 2.5 hours and then cooled to 50°C. Add 500 ml of ethyl acetate and 300 ml of the odes with ice. The mixture is stirred for 1 hour. The organic layer was washed with cold 1 N. NaOH and water, dried (Na2SO4) and evaporated to obtain crude compound as a black oil (26,3 g, 90%). Data: (m/z = 304 (M+H)+.

7-Fluoro-3,4-dihydro-2H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine

General method 4: Closure of the imine ring structure of 4 to tetracyclo patterns 5.

A solution of 8-fluoro-11-(4-chlorobutyl)dibenzo[b,f][1,4]oxazepine (26,3 g, 86,6 mmol) in 45 ml of methanol are added to a solution of sodium methoxide (9.6 g, 177 mmol) in 115 ml of methanol, in an atmosphere of N2. The resulting mixture is heated at the boil under reflux for 5 hours, cooled to room temperature and stirred over night. Add water and CH2Cl2and the mixture is then poured into 500 ml of water and extracted with CH2Cl2. The organic layer was washed with water, dried (Na2SO4) and evaporated and the crude compound is subjected to chromatography on silica gel. Elution with toluene gives specified in the title compound as a brown oil (16.5 g, 77%). Data: (m/z = 268 (M+H)+.

7-Fluoro-1-(trichloroacetyl)-3,4-dihydro-2H-d]dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine

General method 5: the Transformation of the enamine structure 5 to trichloroacetimidates patterns 6.

Trichloroethylene (8,75 ml, 78.5 per mmol) are added to a solution of 7-fluoro-3,4-dihydro-2H-dibenzo[b,f]n the Rideau[1,2-d][1,4]oxazepine (16.5 g, for 61.9 mmol) in 125 ml of toluene in an atmosphere of N2. After stirring for 15 minutes within 15 minutes, add triethylamine (7.7 ml). The obtained brown suspension is heated to 120°C for 75 minutes After cooling to 5°C add 100 ml of ice water. After stirring for 1 hour the mixture was poured into 500 ml of water and extracted with ethyl acetate. The organic layer was washed with cold saturated aqueous sodium bicarbonate and water, dried (Na2SO4) and evaporated to obtain crude compound in the form of black foam (19,1 g, 75%). Data: (m/z = 412 (M+H)+.

Methyl-7-fluoro-3,4-dihydro-2H-d]dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-carboxylate

General method 6: Transforming trichloroethylidene patterns 6 to complicated methyl ester of structure 7.

A solution of sodium methoxide (of 7.64 g, 141,6 mmol) in 60 ml of methanol is added to a suspension of 7-fluoro-1-(trichloroacetyl)-3,4-dihydro-2H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine (19,1 g of 46.4 mmol) in 60 ml of methanol. The resulting mixture was stirred for 30 min at room temperature, and heated at the boil under reflux for 1 hour. After cooling to room temperature the mixture was poured into 700 ml of ice water and extracted with CH2Cl2. The organic layer was washed with water, dried (Na2SO4) and evaporated, to obtain specified in the header is the connection in the form of black foam (13,9 g, 92%). Data: (m/z = 326 (M+H)+.

Methyl-CIS-7-fluoro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-carboxylate

General method 7: the Recovery of the unsaturated carboxylate structure 7 to the saturated carboxylate structure 8.

Complex BH3-THF (1 M, 40 ml, 40.0 mmol) added dropwise within 45 minutes to a solution of methyl 7-fluoro-3,4-dihydro-2H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-carboxylate (14.0 g, 42.8 mmol) in 84 ml of THF, in an atmosphere of N2(T<5°C). The resulting mixture was stirred for 105 minutes at 20°C. After cooling to 0°C, after 2 hours, add 20 ml of acetic acid. The reaction mixture is poured into 500 ml ice water, extracted with CH2Cl2, washed with water, dried (Na2SO4) and evaporated. The crude product is subjected to chromatography on silica gel. Elution with heptane/ethyl acetate, 7:3, gives specified in the title compound as a light brown foam (10.0 g, 71%). Data: (m/z = 328 (M+H)+.

Methyl-TRANS-7-fluoro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-carboxylate

General method 8: Epimerization of CIS-carboxylate structure 8 to the TRANS-carboxylate structure 9.

The sodium methoxide (1,00 g of 1.85 mol) are added to a suspension of methyl-CIS-7-fluoro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-carboxylate (10.0 g, 30,6 mmol) in 100 ml of methanol, in an atmosphere of N2. Recip is nnow mixture for 4.5 hours heated at the boil under reflux. After cooling, the clear brown solution was poured into 700 ml of ice water and extracted with CH2Cl2. The organic layer was washed with water, dried (Na2SO4) and evaporated, to obtain specified in the title compound (9.1 g, 91%). Data: (m/z = 328 (M+H)+.

TRANS-3-Fluoro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-carboxylic acid

General method 9: Saponification of carboxylate structure 9-carboxylic acid of structure 10.

65 ml of 2 N. NaOH are added to a solution of methyl TRANS-7-fluoro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-carboxylate (9,10 g, 27.8 mmol) in 280 ml of dioxane and 110 ml of water. The resulting mixture for 2 hours, heated to 70°C. the Cooled mixture was poured into 1.5 l of ice water and 100 ml of 2 N. HCl and extracted with CH2Cl2(3x). The organic layer was washed with water, dried (Na2SO4) and evaporated. Crystallization from CH2Cl2/simple ether, 1:3, gives specified in the title compound (5.3 g, 61%). Data: (m/z = 314 (M+H)+.

TRANS-7-Fluoro-2,3,4,14b-tetrahydro-1H-d]-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine

(Structure 11 of scheme 1, where R1 = H, R2 = H, R3 = F, R4 = H, R5 = H, R6 = H, R7 = H, X = O)

A common way 10: amination of carboxylic acids of structure 10 to amine structure 11.

2,60 ml of triethylamine added dropwise within 5 minutes at 0°C, in an atmosphere of N2to a suspension of TRANS-7-fluoro-2,3,4,14b-is etrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-carboxylic acid (4.0 g, 12.8 mmol) in 30 ml of acetone and 1 ml of water. Additionally type of 1.80 ml ethylchloride and the mixture was stirred at 0°C for 30 minutes Added to the resulting emulsion sodium azide (1.65 g, to 26.3 mmol) in 8 ml of water and continue stirring for 2.5 hours at 0°C. the Mixture is then poured into 500 ml of water and extracted with CH2Cl2. The organic layer was washed with water, dried (Na2SO4) and evaporated to obtain crude compound. This crude product is dissolved in 90 ml of 1,2-dichloropropane and heated to 100°C, for 4 hours. The mixture is then evaporated under reduced pressure. The residue is dissolved in 45 ml of methoxyethanol. Add a solution of sodium hydroxide (2,72 g, 84,7 mmol) in 6 ml of water. The resulting mixture was heated to 120°C for 2.5 hours, after which it is cooled and poured into 400 ml of ice water. The aqueous layer was extracted with CH2Cl2and the organic layer washed with water, dried (Na2SO4), evaporated and subjected to chromatography on aluminium oxide. Elution with toluene/ethyl acetate, 3:7, gives specified in the title compound as a brown oil (1.45 g, 34%). Data: (m/z = 285 (M+H)+.

Example 2

TRANS-7-Chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]diazepin-1-amine

(Structure 11 of scheme I, where R1 = H, R2 = H, R3 = Cl, R4 = H, R5 = H, R6 = H, R7 = H, X = S)

5-Chloro-2-(phenylthio)aniline

This connection get on with OSU General method 1 at room temperature, to obtain 5-chloro-2-(phenylthio)aniline (6.8 g, 77%). Data: (m/z = 236 (M+H)+.

5-Chloro-N-[5-chloro-2-(phenylthio)phenyl]pentanone

This compound is obtained using the General method 2, to obtain 5-chloro-N-[5-chloro-2-(phenylthio)phenyl]pentanolide (11,0 g, 100%). Data: (m/z = 354 (M+H)+.

8-Chloro-11-(4-chlorobutyl)dibenzo[b,f][1,4]diazepin

This compound is obtained using the General method 3, to obtain 8-chloro-11-(4-chlorobutyl)dibenzo[b,f][1,4]diazepine in the form of a black resin (4.0 g, 45%). Data: (m/z = 338 (M+H)+.

7-Chloro-3,4-dihydro-2H-dibenzo[b,f]pyrido[1,2-d][1,4]diazepin

This compound is obtained using General method 4, followed by chromatography on silica gel. Elution with toluene gives 7-chloro-3,4-dihydro-2H-dibenzo[b,f]pyrido[1,2-d][1,4]diazepine in the form of a red-brown oil (1.2 g, 47%). Data: (m/z = 300 (M+H)+.

7-Chloro-1-(trichloroacetyl)-3,4-dihydro-2H-dibenzo[b,f]pyrido[1,2-d][1,4]diazepin

This compound is obtained using General method 5, to obtain 7-chloro-1-(trichloroacetyl)-3,4-dihydro-2H-dibenzo[b,f]pyrido[1,2-d][1,4]diazepine in the form of a black resin (1.6 g, 93%). Data: (m/z = 446 (M+H)+.

Methyl-7-chloro-3,4-dihydro-2H-dibenzo[b,f]pyrido[1,2-d][1,4]diazepin-1-carboxylate

This compound is obtained using the General method 6, to obtain methyl 7-chloro-3,4-dihydro-2H-dibenzo[b,f]pyrido[1,2-d][1,4]diazepin-1-carboxylate in the form of black foam (1.2 g, 94%).

u> Methyl-CIS-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]diazepin-1-carboxylate

This compound is obtained using the General method 7, obtaining methyl-CIS-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]diazepin-1-carboxylate as a brown foam (1.0 g, 100%). Data: (m/z = 360 (M+H)+.

Methyl-TRANS-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]diazepin-1-carboxylate

This compound is obtained using the General method 8, obtaining methyl-TRANS-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]diazepin-1-carboxylate (0,77 g, 73%). Data: (m/z = 360 (M+H)+.

TRANS-7-Chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]diazepin-1-carboxylic acid

This compound is obtained using the General method 9, to obtain TRANS-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]diazepin-1-carboxylic acid (0.24 g, 32%). Data: (m/z = 346 (M+H)+.

TRANS-7-Chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]diazepin-1-amine

(Structure 11 of scheme I, where R1 = H, R2 = H, R3 = Cl, R4 = H, R5 = H, R6 = H, R7 = H, X = S)

This compound is obtained using the General method 10, to obtain TRANS-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo-[b,f]pyrido[1,2-d][1,4]diazepin-1-amine as a brown solid (165 mg, 75%). Data: (m/z = 317 (M+H)+.

Example 3

TRANS-7-Chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine

(Struct the RA 11 of scheme I, where R1 = H, R2 = H, R3 = Cl, R4 = H, R5 = H, X = O)

5-Chloro-N-(5-chloro-2-phenoxyphenyl)pentanone

This compound is obtained using the General method 2, to obtain 5-chloro-N-(5-chloro-2-phenoxyphenyl)pentahalide in the form of a brown oil (24,1 g, 100 %). Data:1H-NMR (400 MHz, CDCl3) to 1.83 (m, 4H), 2.40 a (t, J=7,0, 2H), 3,54 (t, J=7,0, 2H), 6,76 (d, J=8,0, 1H), 6,97 (DD, J=8.0 a, 2,0, 1H), 6,99 (s, 1H), 7,02 (s, 1H), 7,17 (t, J=8,0, 1H), 7,37 (d, J=8,0, 1H), 7,39 (d, J=8,0, 1H), 7,72 (user., 1H), 8,54 (d, J=2,0, 1H). (m/z = 338 (M+H)+.

8-Chloro-11-(4-chlorobutyl)dibenzo[b,f][1,4]oxazepine

This compound is obtained using the General method 3, to obtain 8-chloro-11-(4-chlorobutyl)dibenzo[b,f][1,4]oxazepine in thick brown-greenish oil (21,6 g, 94%). Data:1H-NMR (400 MHz, CDCl3) 1,90 (m, 4H), 2,96 (t, J=8,0, 2H), to 3.58 (t, J=8,0, 2H),? 7.04 baby mortality-of 7.48 (7 Aran). (m/z = 320 (M+H)+.

7-Chloro-3,4-dihydro-2H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine

This compound is obtained using General method 4, followed by chromatography on aluminium oxide. Elution with toluene gives 7-chloro-3,4-dihydro-2H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine in the form of a dark brown oil (to 3.92 g, 83%). Data:1H-NMR (400 MHz, CDCl3) to 2.06 (dt, J=16,0, 8,0, 2H), 2,32 (m, 2H), 3,69 (t, J=8,0, 2H), 4,87 (t, J=4,0, 1H), 6.73 x (DD, J=8.0 a, 3,0, 1H), make 6.90 (d, J=3,0, 1H), 7,02 (d, J=8,0, 1H), to 7.09 (m, 2H), 7,22 (m, 1H), was 7.36 (DD, J=8,0, 2,0, 1H). (m/z = 284 (M+H)+.

7-Chloro-1-(trichloroacetyl)-3,4-dihydro-2H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine

This connection get help is using General method 5, to obtain 7-chloro-1-(trichloroacetyl)-3,4-dihydro-2H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine in the form of a black resin (5,70 g, >100% crude). Data:1H-NMR (400 MHz, CDCl3) 2,19 (dt, J=16,0, 8,0, 2H), 2.95 and (m, 2H), 3,90 (m, 2H), of 6.96 (DD, J=8.0 a, 3,0, 1H),? 7.04 baby mortality-7,37 (7 Aran). (m/z = 430 (M+H)+.

Methyl-7-chloro-3,4-dihydro-2H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-carboxylate

This compound is obtained using the General method 6 followed by chromatography on silica gel. Elution with toluene/ethyl acetate, 9:1, gives methyl-7-chloro-3,4-dihydro-2H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-carboxylate (2,75 g, 65%). Data:1H-NMR (400 MHz, CDCl3) 2,11 (dt, J=16,0, 8,0, 2H), 2,65 (m, 2H), 3,38 (s, 3H), 3,82 (m, 2H), to 6.88 (DD, J=8.0 a, 3,0, 1H), 7,06 (m, 3H), 7,14 (d, J=8,0, 1H), 7.23 percent (DD, J=8.0 a, 2,0, 1H), 7,30 (dt, J=8,0, 2,0, 1H). (m/z = 342 (M+H)+.

Methyl-CIS-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-carboxylate

This compound is obtained using the General method 7, obtaining methyl-CIS-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-carboxylate as a yellow-brown foam (10.2 g, 100%). Data:1H-NMR (400 MHz, CDCl3), and 2.27 (m, 4H), to 3.02 (dt, J=12,0, 4,0, 1H), and 3.16 (m, 2H), 3,53 (s, 3H), 5,06 (user., 1H), 6.75 in (DD, J=8.0 a, 3,0, 1H), make 6.90 (d, J=3,0, 1H), 7,00 (d, J=8,0, 1H), 7,05 (dt, J=8,0, 2,0, 1H), 7,17 (dt, J=8,0, 2,0, 2H), 7,20 (dt, J=8,0, 2,0, 1H). (m/z = 344 (M+H)+.

Methyl-TRANS-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-carboxylate

This connection get with what omashu General method 8, obtaining methyl-TRANS-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-carboxylate (9.5 g, 93%). Data: (m/z = 344 (M+H)+.

TRANS-7-Chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-carboxylic acid

This compound is obtained using the General method 9. Crystallization from CH2Cl2/simple ether, 1:3, gives TRANS-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-carboxylic acid (to 3.89 g, 51%) Data: (m/z = 302 (M+H)+.

TRANS-7-Chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine

(Structure 11 of scheme I, where R1 = H, R2 = H, R3 = Cl, R4 = H, R5 = H, X = O)

This compound is obtained using the General method 10. Crystallization of simple ether gives TRANS-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine in the form of a whitish solid product (2,97 g, 68%). Data: (m/z = 301 (M+H)+.

Example 4

TRANS-7-Chloro-1,2,3,4,10,14b-hexahydrobenzo[c,f]pyrido[1,2-a]azepin-1-amine

(Structure 11 of scheme I, where R1 = H, R2 = H, R3 = Cl, R4 = H, R5 = H, R6 = H, R7 = H, X = CH2)

5-Chloro-N-[5-chloro-2-(phenylmethyl)phenyl]pentanone

This compound is obtained using the General method 2, to obtain 5-chloro-N-[5-chloro-2-(phenylmethyl)phenyl]pentahalide in the form of a whitish solid product (2,90 g, 100%). Data: (m/z = 336 (M+H)+.

3-Chloro-6-(4-chlorobutyl)-11H-dibenzo[b,e]azepin

This connection get with p the power of the General method 3, with 3-chloro-6-(4-chlorobutyl)-11H-dibenzo[b,e]azepine (scheme I, structure 4, where R1 = R2 = R4 = R5 = H, R3 = Cl, X = CH2and n = 4) in the form of a black resin (2,60 g, 97%). Data: (m/z = 318 (M+H)+.

7-Chloro-2,3,4,10-tetrahydrobenzo[c,f]pyrido[1,2-a]azepin

This compound is obtained using General method 4, followed by chromatography on silica gel. Elution with toluene gives 7-chloro-2,3,4,10-tetrahydrobenzo[c,f]pyrido[1,2-a]azepin in the form of an orange-brown oil (0,89 g, 39%). Data: (m/z = 282 (M+H)+.

7-Chloro-1-(trichloroacetyl)-2,3,4,10-tetrahydrobenzo[c,f]pyrido[1,2-a]azepin

This compound is obtained using General method 5, to obtain 7-chloro-1-(trichloroacetyl)-2,3,4,10-tetrahydrobenzo[c,f]pyrido[1,2-a]azepine in the form of dark brown foam (1,34 g, 99%).

Methyl-7-chloro-2,3,4,10-tetrahydrobenzo[c,f]pyrido[1,2-a]azepin-1-carboxylate

This compound is obtained using the General method 6, to obtain methyl 7-chloro-2,3,4,10-tetrahydrobenzo[c,f]pyrido[1,2-a]azepin-1-carboxylate as a dark brown foam (1.01 g, 95%). Data: (m/z = 340 (M+H)+.

Methyl-CIS-7-chloro-1,2,3,4,10,14b-hexahydrobenzo[c,f]pyrido[1,2-a]azepin-1-carboxylate

This compound is obtained using the General method 7, obtaining methyl-CIS-7-chloro-1,2,3,4,10,14b-hexahydrobenzo[c,f]pyrido[1,2-a]azepin-1-carboxylate as a dark brown foam (1,00 g, 98%). Data: (m/z = 342 (M+H)+.

Methyl-what Rance-7-chloro-1,2,3,4,10,14b-hexahydrobenzo[c,f]pyrido[1,2-a]azepin-1-carboxylate

This compound is obtained using the General method 8, obtaining methyl-TRANS-7-chloro-1,2,3,4,10,14b-hexahydrobenzo[c,f]pyrido[1,2-a]azepin-1-carboxylate (0,93 g, 93%).

TRANS-7-Chloro-1,2,3,4,10,14b-hexahydrobenzo[c,f]pyrido[1,2-a]azepin-1-carboxylic acid

This compound is obtained using the General method 9. Crystallization from CH2Cl2/simple ether, 1:3, gives TRANS-7-chloro-1,2,3,4,10,14b-hexahydrobenzo[c,f]pyrido[1,2-a]azepin-1-carboxylic acid (to 3.89 g, 51%) Data: (m/z = 302 (M+H)+.

TRANS-7-Chloro-1,2,3,4,10,14b-hexahydrobenzo[c,f]pyrido[1,2-a]azepin-1-amine

(Structure 11 of scheme I, where R1 = H, R2 = H, R3 = Cl, R4 = H, R5 = H, R6 = H, R7 = H, X = CH2)

This compound is obtained using the General method 10, to obtain TRANS-7-chloro-1,2,3,4,10,14b-hexahydrobenzo[c,f]pyrido[1,2-a]azepin-1-amine (104 mg, 86%). Data: (m/z = 299 (M+H)+.

Example 5

TRANS-2,2,2-Cryptor-N-(7-fluoro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)ndimethylacetamide

(Structure 12 of scheme II, where R1 = H, R2 = H, R3 = F, R4 = H, R5 = H, R15 = CF3X = O)

General method 11: N-acylation of amine structure 11 to triptolide structure 12.

Triperoxonane anhydride (1 ml) was added to TRANS-7-fluoro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine (0.6 g, 2.1 mmol) in 5 ml of CH2Cl2and 2 ml of pyridine. The resulting suspension is stirred for 18 hours at room temperature. Measles is Navy the solution is poured into 100 ml of ice water and extracted with CH 2Cl2. The organic layer was washed with water, dried (Na2SO4) and evaporated. To the obtained solid product add a simple diethyl ether and heated at the boil under reflux for 30 minutes. The residue is dissolved in CH2Cl2and heated at the boil under reflux for 30 minutes. The precipitate is filtered off, washed with CH2Cl2and dried, to obtain TRANS-2,2,2-Cryptor-N-(7-fluoro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)ndimethylacetamide in the form of a whitish solid (0.2 g, 25.6 percent). Data: (m/z = 381 (M+H)+.

Example 6

TRANS-2,2,2-Cryptor-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]diazepin-1-yl)ndimethylacetamide

(Structure 13 of scheme II, where R1 = H, R2 = H, R3 = Cl, R4 = H, R5 = H, R15 = CF3X = S)

This compound is obtained using the General method 11, followed by chromatography on silica gel. Elution with toluene → toluene/ethyl acetate, 95:5, followed by crystallization from a simple ether, which gives TRANS-2,2,2-Cryptor-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]diazepin-1-yl)ndimethylacetamide in the form of a whitish solid (3.0 mg, 12%). Data: (m/z = 413 (M+H)+.

Example 7

TRANS-N-(7-Chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-triptorelin

(Structure 12 of scheme II, where R1 = H, R2 = H, R3 = Cl, R4 = H, R5 = H, R15 = CF3X = O)

p> Consistently add ethyltryptamine (1,41 ml of 11.8 mmol) and triethylamine (628 μl, 4.5 mmol) of TRANS-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine (291 mg, 0.97 mmol) in 11.8 ml of methanol. The resulting mixture was heated to 50°C for 18 hours. A precipitate. The mixture is evaporated under reduced pressure to remove volatile reagents, and add 5 ml of methanol. After 30 minutes of stirring the precipitate is filtered off, washed with simple diethyl ether and dried, to obtain TRANS-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-trifurcated in the form of a whitish solid (330 mg, 86%). Data:1H-NMR (400 MHz, CDCl3) of 1.85 (m, 2H), and 2.26 (m, 1H), 3,12 (m, 1H), 3,20 (m, 1H), 3,62 (dt, J=12,0, 4,0, 1H), to 4.38 (d, J=8,0, 1H), and 4.68 (m, 1H), 6,76 (DD, J=8.0 a, 3,0, 1H), 6,93 (d, J=3,0, 1H),? 7.04 baby mortality (d, J=8,0, 1H), was 7.08 (dt, J=8,0, 2,0, 1H), 7,17 (DD, J=8.0 a, 2,0, 2H), 7,29 (dt, J=8,0, 2,0, 1H). (m/z = 397 (M+H)+.

Example 8

TRANS-N-(7-Chloro-1,2,3,4,10,14b-hexahydrobenzo[c,f]pyrido[1,2-a]azepin-1-yl)-2,2,2-triptorelin

(Structure 12 of scheme II, where R1 = H, R2 = H, R3 = Cl, R4 = H, R5 = H, R15 = CF3X = CH2)

This compound is obtained using the General method 11, followed by chromatography on silica gel. Elution with toluene → toluene/ethyl acetate, 95:5, gives TRANS-N-(7-chloro-1,2,3,4,10,14b-hexahydrobenzo[c,f]pyrido[1,2-a]azepin-1-yl)-2,2,2-triptorelin (34,0 mg, 12%). Data: (m/z = 395 (M+H)+.

Example

TRANS-N-(1,2,3,4,10,14b-Hexahydrobenzo[c,f]pyrido[1,2-a]azepin-1-yl)-2,2,2-triptorelin

(Structure 12 of scheme II, where R1 = H, R2 = H, R3 = H, R4 = H, R5 = H, R15 = CF3X = CH2)

This compound is obtained using the General method 11 on the basis of TRANS-1,2,3,4,10,14b-hexahydrobenzo[c,f]pyrido[1,2-a]azepin-1 linnaleht, followed by chromatography on silica gel. Elution with toluene → toluene/ethyl acetate, 9:1, gives TRANS-N-(1,2,3,4,10,14b-hexahydrobenzo[c,f]pyrido[1,2-a]azepin-1-yl)-2,2,2-triptorelin (3.6 mg, 76%). Data: (m/z = 359 (M+H)+.

Example 10

TRANS-N-(7-Chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)ndimethylacetamide

(Structure 12 of scheme II, where R1 = R2 = H, R3 = Cl, R4 = R5 = H, R15 = CH3X = O)

TRANS-7-Chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-linnaleht (10 mg, 0.02 mmol), 50 μl of pyridine and 25 μl of acetic anhydride in 1 ml of CH2Cl2stirred for 18 hours at room temperature. The mixture was washed with 5% aqueous sodium bicarbonate solution and H2O, dried (Na2SO4) and evaporated, to obtain TRANS-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)ndimethylacetamide (9.0 mg, 65%). Data: (m/z = 343 (M+H)+.

Example 11

TRANS-N-(7-Chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2-foracademic

(Structure 12 of scheme II, where R1 = R2 = H, R3 = Cl, R4 = R5 = H, R15 = CH2F, X = O)

t the ANS-7-Chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine (10 mg, 0.03 mmol) dissolved in 1 ml of ethylformate. The resulting mixture is heated at the boil under reflux for 2 hours. Evaporation followed by crystallization from methanol gives TRANS-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2-peracetate (4,7 mg, 39 %). Data: (m/z = 361 (M+H)+.

Example 12

TRANS-N-(7-Chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-4-phenylbenzene

(Structure 12 of scheme II, where R1 = R2 = H, R3 = Cl, R4 = R5 = H, R15 = C6H4C6H5X = O)

General method 12: N-acylation of amine structure 11 to the amide structure 12.

DIPEA (to 18.6 μl, 0.14 mmol) and 4-phenylbenzophenone (15.2 mg, 0.07 mmol) are added to a solution of TRANS-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1 linnaleht (9.6 mg, 0.02 mmol) in 1 ml of CH2Cl2. The resulting mixture is stirred for 18 hours at room temperature. The organic layer was washed with 5% aqueous sodium bicarbonate solution and H2O, dried (Na2SO4) and evaporated. Additional chromatography on silica gel (elution with toluene/ethyl acetate, 9:1 → toluene/ethyl acetate, 1:1) to give TRANS-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-4-phenylbenzene (4.6 mg, 44%). Data: (m/z = 350 (M+H)+.

The following amides listed in table 1, are extracted using the General method 12 using the appropriate starting materials. For example 15 instead of DIPEA is triethylamine and the compound crystallized from simple diethyl ether.

Table 1
Etc.R1R2R3R4R5R6R7R15X(m/z)Output (%)
13HHClHHC(O)R15HCHF2O37935
14HHClHHC(O)R15HCH2ClO37752
15HHClHHC(O)R15HCH2BrO42250

Example 16

TRANS-2-Amino-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)ndimethylacetamide

(Structure 12 of scheme II, where R1 = R2 = H, R3 = Cl, R4 = R5 = H, R15 = CH2NH2X = O)

Complex 1,1-dimethylethylene ether [[[(TRANS-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)amino]carbonyl]methyl]to raminosoa acid

General method 13: N-acylation of amine structure 11 to the amide structure 12.

DIPEA added (pH=9) to TRANS-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine (10 mg, 0.03 mmol) in 1 ml of CH2Cl2with HATU (12.5 mg, 0.03 mmol) and Boc-Gly-OH (10,3 mg, 0.03 mmol). The resulting mixture is stirred for 3 hours, washed with 5% aqueous sodium bicarbonate solution and H2O, dried (Na2SO4) and evaporated, to obtain the complex of 1,1-dimethylethylene ether [[[(TRANS-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)amino]carbonyl]methyl]carbamino acid (14.3 mg, 100%). Data: (m/z = 405 (M+H)+.

TRANS-2-Amino-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)ndimethylacetamide

(Structure 12 of scheme II, where R1 = R2 = H, R3 = Cl, R4 = R5 = H, R15 = CH2NH2X = O)

Complex 1,1-dimethylethyleneether [[[(TRANS-7-Chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)amino]carbonyl]methyl]carbamino acid (10 mg, 0.02 mmol) in 2 ml of ethyl acetate purge gaseous HCl at 0°C for 2 hours. The mixture is evaporated under reduced pressure to obtain TRANS-2-amino-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)ndimethylacetamide (9,2 mg, 100%). Data: (m/z = 358 (M+H)+.

Example 17

TRANS-4-[(7-Chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)amino]-2,2,3,3-titrator-4-oxalate the OIC acid

(Structure 12 of scheme II, where R1 = R2 = H, R3 = Cl, R4 = R5 = H, R15 = CF2CF2C(O)OH, X = O)

Tetrafluorethane anhydride (5,35 μl, 0.05 mmol) are added to TRANS-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine (10 mg, 0.03 mmol) in 1 ml of dioxane. The resulting mixture was stirred at room temperature for 30 minutes. The dioxane is removed by evaporation under reduced pressure and add ethyl acetate and 2% citric acid. The organic layer was washed with saturated saline solution, dried (Na2SO4) and evaporated, to obtain TRANS-4-[(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)amino]-2,2,3,3-titrator-4-oxobutanoic acid (10,6 mg, 51%). Data: (m/z = 472 (M+H)+.

Example 18

TRANS-N-(7-Chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)meantioned

(Structure 13 of scheme II, where R1 = R2 = H, R3 = Cl, R4 = R5 = H, R15 = H, X = O)

TRANS-N-(7-Chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)formamide

TRANS-7-Chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine (10 mg, 0.03 mmol) dissolved in 1 ml of ethylformate. The resulting mixture is heated at the boil under reflux for 18 hours. The cooled mixture is evaporated, to obtain TRANS-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)formamide (12.0 mg, 100 %). Data: (m/z = 329 (M+H)+.

TRANS-N-(7-the ENT-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)meantioned

(Structure 13 of scheme II, where R1 = R2 = H, R3 = Cl, R4 = R5 = H, R15 = H, X = O)

General method 14: Sulfonylamine amide structure 12 to thioamide structure 13.

Pentasulfide phosphorus (5 mg, 0.01 mmol) are added to TRANS-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)formamide (5 mg, 0.015 mmol) in dioxane. The resulting mixture is heated at the boil under reflux for 3 hours. After evaporation under reduced pressure the crudethe connection is subjected to chromatography on silica gel. Elution with toluene/ethyl acetate, 85:15, gives TRANS-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)meantioned (2.8 mg, 51%). Data: (m/z = 345 (M+H)+.

The following thioamides, listed in table 2, are generally using General method 14, using the appropriate starting materials. They are listed as examples 19-27.

Table 2
Etc.R1R2R3R4R5R6R7R15X(m/z)Output (%)
19HHClHHC(S)R15HCF3O41398
20HHClHHC(S)R15HCF3CH241162
21HHClHHC(S)R15HCH3O35911
22HHClHHC(S)R15HCH2FO37863
23HHClHHC(S)R15HCHF2O39580
24HHClHHC(S)R15CH3CF3O42849
25HHNHHC(S)R15HCF3O37924
26HHClClHC(S)R15 HCF3O44847
27HHClHHC(S)R15HCH2NH2O37475

Example 28

TRANS-N-(7-Chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-Cryptor-N-methylacetamide

(Structure 14 of scheme II, where R1 = R2 = H, R3 = Cl, R4 = R5 = H, R7 = CH3, R15 = CF3X = O)

Sodium hydride (1.6 mg, 60% in oil) are added to TRANS-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d]-[1,4]oxazepine-1-yl)-2,2,2-triptorelin (15 mg, 0.04 mmol) in 1 ml DMF. After 10 minutes of stirring, add methyliodide (2,47 μl, 0.04 mmol). The resulting mixture was stirred at room temperature for 18 hours. After evaporation the crude compound purified using chromatography on silica gel. Elution with toluene/ethyl acetate, 7:3, gives TRANS-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-Cryptor-N-methylacetamide (14 mg, 90%). Data: (m/z = 411 (M+H)+.

Example 29

TRANS-N-(7-Chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-triptoreline

(Structure 15 of scheme II, where R1 = H, R2 = H, R3 = Cl, R4 = H, R5 = H, R15 = CF3X = O)

Triptoreline within 2 hours are added to a solution of TRANS-N-(7-the ENT-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-trifurcated (10 mg, 0.03 mmol) in 2 ml of THF. The mixture is stirred at room temperature for 16 hours. After evaporation the crudethe connection is subjected to chromatography on silica gel. Elution with toluene gives TRANS-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-triptoreline (7,14 mg, 55%). Data: (m/z = 396 (M+H)+.

Example 30

Complex CHLOROTHALONIL ether of TRANS-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)carbamino acid

(Structure 16 of scheme III, where R1 = R2 = H, R3 = Cl, R4 = R5 = H, R16 = CH2Cl, X = O)

A common way 15: N-acylation of amine structure 11 to the carbamate structure 16.

100 µl of a saturated aqueous solution of sodium bicarbonate is added to TRANS-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine (9.5 mg, 0.03 mmol) and chloromethylphosphonate (64,2 μl, 0.42 mmol) in 250 μl of CH2Cl2. The resulting mixture was stirred at room temperature for 18 hours. Then add ethyl acetate and the organic layer washed with water, dried (Na2SO4) and evaporated to obtain complexchlormethiazoleester, TRANS-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)carbamino acid (9,9 mg, 88%). Data: (m/z = 393 (M+H)+.

Example 31

Complex 2-bromatology ether of TRANS-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxaze the Jn-1-yl)carbamino acid

(Structure 16 of scheme III, where R1 = R2 = H, R3 = Cl, R4 = R5 = H, R16 = CH2CH2Br, X = O)

This compound is obtained using the General method 15, obtaining a complex 2-bromatologia ester, TRANS-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)carbamino acid (yield 80%). Data: (m/z = 452 (M+H)+.

Example 32

TRANS-N-(7-Chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-N'-(2-methylpropyl)thiourea

(Structure 17 of scheme III, where R1 = R2 = H, R3 = Cl, R4 = R5 = H, R17 = CH2CH(Me)2X = O)

A common way 16: Isobutylthiazole (3,35 mg, 0.03 mmol) are added to TRANS-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine (5 mg, 0.02 mmol) in 1 ml THF. The resulting mixture was stirred at room temperature for 18 hours. The mixture is evaporated under reduced pressure. Crystallization from methanol gives TRANS-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-N'-(2-methylpropyl)thiourea (1 mg, 12%). Data: (m/z = 416 (M+H)+.

The following thiourea listed in table 3, are generally using General method 16, using the appropriate starting materials. They are listed as examples 33-35.

Table 3
Etc.R1R2R3R4R5/td> R6R7XR17(m/z)Output

(%)
33HHClHHC(S)NR17HOcC6H1144220
34HHClHHC(S)NR17HOCH2CH=CH240026
35HHClHHC(S)NR17HOC(Me)341612

Example 36

TRANS-N-(2-Methylpropyl)-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine

(Structure 18 of scheme III, where R1 = R2 = H, R3 = Cl, R4 = R5 = H, R18 = CH(CH3)2X = O)

A common way 17: N-alkylation of an amine of structure 11 to N-Aquila structure 18.

After 10 min of stirring triacetoxyborohydride sodium (11 mg, 0.05 mmol) are added to TRANS-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine (10 mg, 0.03 mmol) and isobutyramide the aldehyde (3,45 mg, 0.03 mmol) in 1 ml of CH2Cl2(pH=4). The resulting mixture was stirred at room temperature for 18 hours. CME is ü evaporated and subjected to chromatography on silica gel. Elution CH2Cl2/methanol, 8:2, gives TRANS-N-(2-methylpropyl)-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine (13 mg, 100%). Data: (m/z = 357 (M+H)+.

Example 37

TRANS-N-Propyl-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine

(Structure 18 of scheme III, where R1 = R2 = H, R3 = Cl, R4 = R5 = H, R18 = CH2CH3X = O)

This compound is obtained using the General method 17, to obtain TRANS-N-propyl-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine (10 mg, 97%). Data: (m/z = 343 (M+H)+.

Examples 38A and B

TRANS-N-(7,8-Dichloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-triptorelin (Example 38A)

(Structure 19A of scheme IV, where R1 = H, R4 = R5 = H, R15 = CF3X = O)

TRANS-N-(6,7-Dichloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-triptorelin (Example 38B)

(Structure 19B scheme IV, where R1 = R2 = H, R5 = H, R15 = CF3X = O)

N-chlorosuccinimide (6,87 mg, 0.05 mmol) and 0.5 μl of 1 N. HCl is added to TRANS-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-triptorelin (20 mg, 0.05 mmol) in 102 μl of acetone. The resulting mixture was stirred at room temperature for 18 hours. No response was observed. The reaction is repeated under the same conditions. The resulting mixture was stirred at room temperature for 1.5 hours. The organic layer is washed with saturated aqueous sodium bicarbonate and water, dried (Na2SO4) and evaporated and the crude compound purified using preparative HPLC, to obtain TRANS-N-(6,7-dichloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-trifurcated (3.6 mg, 17%) and TRANS-N-(7,8-dichloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-trifurcated (1.6 mg, 7%). Data: (m/z = 431 (M+H)+.

Example 39

TRANS-N-(8-Bromo-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-triptorelin

(Structure 20 of scheme IV, where R1 = H, R4 = H, R5 = H, R15 = CF3X = O)

N-bromosuccinimide (9,2 mg, 0.05 mmol) and 0.5 μl of 1 N. HCl is added to TRANS-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-triptorelin (20 mg, 0.05 mmol) in 512 μl of acetone. The resulting mixture was stirred at room temperature for 30 minutes the Mixture is diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate and water, dried (Na2SO4) and evaporated, to obtain TRANS-N-(8-bromo-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-trifurcated in the form of a white solid product (31 mg, 100%). Data:1H-NMR (400 MHz, CDCl3) of 1.85 (m, 4H), and 2.27 (m, 2H), 3,20 (m, 1H), to 3.64 (m, 1H), of 4.44 (d, J=8,0, 1H)and 4.65 (m, 1H), 6,26 (user., 1H), 7,02 (s, 1H), 7,10 (dt, J=8,0, 2,0, 1H), 7,16 (m, 2H), 7,30 (dt, J=8.0 a, 3,0, 1H), 7,35 (s, 1H). (m/z = 477 (M+H)+.

Example 40

TRANS-N-(2,3,4,14b-Tetrahydro-1H-dibenzo[b,f]Piri is about[1,2-d][1,4]oxazepine-1-yl)-2,2,2-triptorelin

(Structure 21 of scheme IV, where R1 = R2 = R4 = R5 = H, R15 = CF3X = O)

10 mg Pd/C 10% are added to a solution of TRANS-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-trifurcated (100 mg, 0.25 mmol) in 5 ml of DMF. The suspension is shaken in an atmosphere of H2within 2 days. The mixture is filtered, poured into water and extracted with a simple diethyl ether. The organic layer was washed with water, dried (Na2SO4) and evaporated, to obtain TRANS-N-(2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-trifurcated (89 mg, 98%). Data:1H-NMR (400 MHz, CDCl3) of 1.85 (m, 3H), 2,99 (m, 1H), 3,18 (m, 1H, in), 3.75 (m, 1H), 4,50 (d, J=8, 1H), 4.72 in (m, 1H), 6,62 (user., 1H), 6,84-7,30 (8 Aran). (m/z = 362 (M+H)+.

Example 41

TRANS-N-(7-Chloro-8-nitro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-triptorelin

(Structure 22 of scheme IV, where R1 = H, R4 = H, R5 = H, R15 = CF3X = O)

Nitric acid (50 μl, 1.10 mmol) is added at 0°C to a suspension of TRANS-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-trifurcated (210 mg, of 0.53 mmol) in 4 ml of CH2Cl2. After mixing, the mixture is extracted with ethyl acetate and the organic layer washed with 5% aqueous sodium bicarbonate solution, dried (Na2SO4) and evaporated, to obtain TRANS-N-(7-chloro-8-nitro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-trifurcata the IDA (219 mg, 90%). Data:1H-NMR (400 MHz, DMSO) 1,64-of 1.94 (m, 3H), 2.05 is (user., 1H), 3,26 (t, J=8,0, 1H), 4,20 (d, J=8,0, 1H), 4,35 (d, J=8,0, 1H), 4,60 (DQC., J=8,0, 3,0, 1H), 7,15 (m, 1H), 7,11-of 9.21 (6 Aran). (m/z = 443 (M+H)+.

Examples 42A and B

TRANS-N-(6-Chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-triptorelin (Example 42A)

(Structure 23A of scheme V, where R1 = H, R4 = R5 = H, R15 = CF3X = O)

TRANS-N-(8-Chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-triptorelin (Example 42B)

(Structure 23B of scheme V, where R1 = R2 = R5 = H, R15 = CF3X = O)

N-chlorosuccinimide (charged 8.52 mg, 0.06 mmol) and 0.67 μl of 1N HCl is added to TRANS-N-(2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-triptorelin (21 mg, 0.06 mmol) in 1 ml of acetone. The resulting mixture was stirred at room temperature for 2 hours. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and evaporated. The crude compound is subjected to chromatography on silica gel. Elution with heptane/ethyl acetate, 8:2, gives two compounds, one of which is a TRANS-N-(6-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-triptorelin (9.8 mg, 41%). Data:1H-NMR (400 MHz, CDCl3) of 1.84 (m, 3H), 2,22 (m, 1H), 3,17 (m, 1H), 3,52 (m, 1H), of 4.44 (d, J=8,0, 1H), 4,69 (m, 1H), 6.48 in (user., 1H), make 6.90 (d, J=8,0, 1H), 6,97 (DD, J=8.0 a, 3,0, 1H), 7,10 (dt, J=8,0, 2,0, 1H), 7,13 (d, J=3,0, 1H, 7,19 (d, J=8,0, 2H), 7,29 (dt, J=8,0, 2,0, 1H). (m/z = 397 (M+H)+.

8-chlorine substituted compound containing 6,8-dichlorsilane connection, purify using preparative HPLC, to obtain TRANS-N-(8-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-trifurcated (1.2 mg, 5%). Data:1H-NMR (400 MHz, CDCl3) of 1.84 (m, 3H), 2,00 (m, 1H), 2,93 (DD, J=8.0 a, 3,0, 1H), 3,28 (dt, J=8.0 a, 3,0, 1H), 4,39 (s, 1H), 4,89 (m, 1H), 7,07-7,33 (7 Aran), 8,07 (user., 1H). (m/z = 397 (M+H)+.

Example 43

TRANS-N-(7-Chloro-2,3,4,14b-tetrahydro-8-[bis(phenylsulfonyl)amino]-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-triptorelin

(Structure 25 of scheme VI, where R1 = H, R4 = H, R5 = H, R11 = R12 = S(O)2Ph, R15 = CF3X = O)

TRANS-N-(8-Amino-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-triptorelin

80 μl of 36% HCl and SnCl2·2H2O (600 mg, of 2.66 mmol) are added to TRANS-N-(7-chloro-8-nitro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-triptorelin (215 mg, 0.49 mmol) in 10 ml of ethanol. The resulting mixture was stirred at 60°C for 18 hours. After cooling, the mixture is evaporated and dissolved in ethyl acetate. An aqueous solution of sodium bicarbonate are added to a solution (formation of salts Sn), and then dekalim and the mixture filtered. The filtrate is extracted with ethyl acetate and the organic layer was washed with saturated saline solution, dried (Na2SO4) and evaporated,to obtain specified in the title compound (194 mg, 82%). Data: (m/z = 413 (M+H)+.

TRANS-2,2,2-Cryptor-N-(7-chloro-2,3,4,14b-tetrahydro-8-[bis(phenylsulfonyl)amino]-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)ndimethylacetamide

(Structure 25 of scheme VI, where R1 = H, R4 = H, R5 = H, R11 = R12 = S(O)2Ph, R15 = CF3X = O)

A common way 18: N-acylation of amine structure 25 to the amide structure 26.

Benzosulphochloride (5 μl, 0.04 mmol) is added in an atmosphere of N2to TRANS-N-(8-amino-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-triptorelin (5.0 mg, 0.01 mmol) in a mixture of 1 ml of CH2Cl2and 25 μl of triethylamine. The resulting mixture was stirred at 40°C for 4 hours. After cooling, the mixture is evaporated and the crude compound purified by chromatography on silica gel. Elution with toluene/ethyl acetate, 1:0 → 0:1 (gradient)gives TRANS-N-(7-chloro-2,3,4,14b-tetrahydro-8-[bis(phenylsulfonyl)-amino]-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-triptorelin (7,3 mg, 83%). Data: (m/z) = 692 (M+H)+.

Example 44

TRANS-N-(7-Chloro-2,3,4,14b-tetrahydro-8-[bis(methylsulphonyl)amino]-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-triptorelin

(Structure 25 of scheme VI, where R1 = H, R4 = H, R5 = H, R11 = R12 = S(O)2CH3, R15 = CF3X = O)

This compound is obtained using the General method 18, using the appropriate starting material, to obtain TRANS-N-(7-chloro-2,3,4,14b-tetrahydro-8-[bis(ethylsulfonyl)amino]-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-trifurcated (6,8 mg, 92%). Data: (m/z = 568 (M+H)+.

Example 45

TRANS-N-(7-Chloro-2,3,4,14b-tetrahydro-8-[(phenylsulfonyl)-amino]-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-triptorelin

(Structure 25 of scheme VI, where R1 = H, R4 = H, R5 = H, R11 = H, R12 = S(O)2Ph, R15 = CF3X = O)

Benzosulphochloride (10 μl, 0.08 mmol) is added in an atmosphere of N2to TRANS-N-(8-amino-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-triptorelin (5.0 mg, 0.01 mmol) in 1 ml of CH2Cl2and 2 μl (1.1 EQ.) of triethylamine. The resulting mixture was stirred at 35°C for 4 hours. After cooling, the mixture is evaporated and the crude compound purified by chromatography on silica gel. Elution with toluene/ethyl acetate, 1:0 → 0:1 (gradient)gives TRANS-N-(7-chloro-2,3,4,14b-tetrahydro-8-[(phenylsulfonyl)amino]-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-triptorelin (2.4 mg, 32%). Data: (m/z = 552 (M+H)+.

Example 46

Complex1,1-dimethylethylene ether of TRANS-N-(7-chloro-2,3,4,14b-tetrahydro-1-(2,2,2-triptoreline)-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-8-yl)carbamino acid

(Structure 25 of scheme VI, where R1 = H, R4 = H, R5 = H, R11 = H, R12 = C(O)OC(CH3)3, R15 = CF3X = O)

Di-tert-BUTYLCARBAMATE (20,55 mg, 0.09 mmol) is added at 5°C, in an atmosphere of N2to TRANS-N-(8-amino-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-triptorelin the (10,8 mg, 0.03 mmol) in 1 ml THF and 6 ml (1.1 EQ.) of triethylamine. The resulting mixture was stirred at 50°C for 72 hours. After cooling, the mixture is evaporated and subjected to chromatography on silica gel. Elution with heptane/ethyl acetate, 1:0 → 0:1 (gradient)gives specified in the title compound (2.7 mg, 15%). Data: (m/z = 512 (M+H)+.

Example 47

TRANS-N-(6,7-Dichloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)ndimethylacetamide

(Structure 19B scheme IV, where X = O, R1 = H, R2 = H, R5 = H, R15 = CH3).

To a solution of TRANS-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)ndimethylacetamide (structure 12 of scheme II, where R1 = H, R2 = H, R3 = Cl, R4 = R5 = H, R15 = CH3X = O) (0,63 g of 1.84 mmol) in acetone (15 ml) is added N-chlorosuccinimide (246 mg, of 1.84 mmol) and 6 N. (aq. solution) HCl (3.1 ml). The resulting suspension is stirred at room temperature for 20 hours. Add the second part of the N-chlorosuccinimide (246 mg, of 1.84 mmol), and then the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was extracted with ethyl acetate (3x), washed with saturated (aq. solution) NaHCO3(3x), 10% (aq. solution) NaCl (2x) and dried (Na2SO4). The solvents are removed under reduced pressure. The solid product was then purified using column chromatography (silica gel, toluene/ethanol = 9/1). Subsequent purification by HPLC gives specified is in the title compound (137 mg, 36,4%). Data:1H-NMR (400 MHz, CDCl3) of 1.55 (m, 1H), equal to 1.82 (m, 2H), 1,94-of 2.20 (m, 1H), 2,10 (s, 3H), of 2.92 (m, 1H), 3,11 (TD, J=12,6, 4,2, 1H), 4,39 (d, J=1,9, 1H), a 4.86 (m, 1H), 7,02 and 7.36 (m, 6 Aran).

Example 48

TRANS-7-Chloro-2,3,4,14b-tetrahydro-N-(2-methoxyethyl)-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine

(Structure 26 of scheme III, where R1 = H, R2 = H, R3 = Cl, R4 = H, R5 = H)

To a solution of TRANS-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine (84 mg, 0.28 mmol) in DMF (400 μl) is added 2-methoxyethylamine (37 μl, 0,39 mmol) and triethylamine (47 μl, 0.36 mmol). The resulting reaction mixture was stirred at 60°C for 18 hours. After cooling, add ethyl acetate. The mixture was washed with saturated (aq. solution) NaHCO3and water. The organic layer is dried and evaporated. The crude compound purified by HPLC and dried by freezing (lyophilizer), with specified title compound (32 mg, 32 %). Data (m/z = 359 (M+H)+.

Example 49

1,1-Dimethylethyl-TRANS-2-[(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]diazepin-1-yl)amino]acetate

(Structure 27 of scheme III, where R1 = H, R2 = H, R3 = Cl, R4 = H, R5 = H).

To a solution of HBr salt and TRANS-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]diazepin-1-amine (200 mg, 0.5 mmol) in DMF (10 ml) is added DIPEA (219 μl, 1.3 mmol) and tert-butylbromide (89 μl, 0.6 mmol). The reaction mixture was stirred at room temperature for 5.5 hours. On the Le pouring the reaction mixture into water, it is extracted with ethyl acetate (3x). The combined organic layers washed with saturated salt solution, dried (Na2SO4) and evaporated. The crude product is purified on silica gel with heptane/ethyl acetate, 8:2, to obtain the pure product (90 mg, 41%). Data: (m/z = 431 (M+H)+.

Example 50

TRANS-N-(6,7-Dichloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)formamide

(Structure 29 of scheme VII)

TRANS-6,7-Dichloro-2,3,4,14b-tetrahydro-N-(2-methoxyethyl)-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine

(Structure 28 of scheme VII)

K2CO3(537 mg, 3.9 mmol) are added to a solution of TRANS-N-(6,7-dichloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-trifurcated (322 mg, 0.75 mmol) in methanol (28 ml) and water (1.7 ml). The reaction mixture is stirred at the boiling temperature under reflux for 2 hours, after which the methanol is removed under reduced pressure. Water added to the remaining product and the aqueous layer was extracted with CH2Cl2(3x). The combined organic layers washed with saturated salt solution, dried (Na2SO4) and evaporated to obtain crude specified in the title compound (266 mg, 100%).

TRANS-N-(6,7-Dichloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)formamide

(Structure 29 of scheme VII)

A solution of TRANS-6,7-dichloro-2,3,4,14b-tetrahydro-N-(2-methoxyethyl)-1H-dibenzo[b,f]pyrido[1,2-d][1,4]ox who sepin-1-amine (122 mg, 0.36 mmol) in ethyl formate is stirred over night at the boiling point under reflux. After removal of the solvent under reduced pressure, the remaining product was then purified using preparative LC-MS, obtaining specified in the title compound (40 mg, 30%). Data (m/z = 397 (M+H)+.

Example 51

TRANS-N-(6-Bromo-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-triptorelin

(Structure 36 of scheme IX, where X = O, R1 = H, R2 = H, R3 = H, R4 = Br, R5 = H, R10 = H)

2-[(2,6-Dibromophenyl)iminomethyl]phenol

(Structure 30 of scheme VIII, where R2 = H)

A common way 19: Education imine structure 30 of the amine and aldehyde.

A solution of 2,6-dibromoanisole (9 g, or 35.9 mmol), salicylaldehyde (and 2.79 ml, compared with 35.9 mmol) and p-toluensulfonate acid (20 mg, 0.1 mmol) in toluene (180 ml) is heated at boiling under reflux in an apparatus of the Dean-stark for 2 hours. After adding a certain number of triethylamine, the reaction mixture is evaporated to obtain crude compound 2-[(2,6-dibromophenyl)iminomethyl]phenol (14 g, 100%).

9 Bromobenzo[b,f][1,4]oxazepine

(Structure 31 of scheme VIII, where X = O, R1 = H, R2 = H, R3 = H, R4 = Br, R5 = H, R10 = H)

A common way 20: ring Closure by the esterification of the structure 31.

To a solution of 2-[(2,6-dibromophenyl)iminomethyl]phenol (14.1 g, or 35.9 mmol) in 350 ml of DMSO add K2CO3(9,9 g, 71,8 mmol) and 18-crown-6 (95 is g, 0.36 mmol). The resulting mixture was stirred at 140°C for 1.5 hours and then allow to coolto the ambient temperature during the night. The mixture is then poured into ice water and extracted with ethyl acetate (3x). The organic solution is washed with water and saturated saline, and then dried (MgSO4). Removal of solvent in vacuo yields a crude 9-bromobenzo[b,f][1,4]oxazepine (9,79 g, 99%). Data: (m/z = 274 + 276 (M+H)+.

TRANS-6-Bromo-2,3,4,14b-tetrahydro-4-oxo-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-carboxylic acid

(Structure 32 of scheme IX, where X = O, R1 = H, R2 = H, R3 = H, R4 = Br, R5 = H, R10 = H)

A common way 21: Attach glutaric anhydride with a cyclic amine, resulting in the formation of tetracyclo structure 32.

Glutaric anhydride (5,22 g, with 45.8 mmol) is added to a stirred solution of 9-bromobenzo[b,f][1,4]oxazepine (9,29 g, to 33.9 mmol) in xylene (9 ml). The mixture is heated to 140°C for 72 hours. Add equal parts of simple ether and ethyl acetate, after which the product is collected by filtration. The crystals are dried at 50°C under reduced pressure, to obtain specified in the title compound as a single isomer (5.5 g, 39%, TRANS). Eluent extracted with 2 N. NaOH (aq. solution). By adding 3 N. HCl (aq. solution) to the aqueous layer pH was adjusted to pH 2. The aqueous layer was extracted with ethyl acetate, the m washed with saturated saline solution and dried. After removing ethyl acetate under reduced pressure to obtain a mixture of isomers (6,1 g, 47%). Data: (m/z = 388 + 390 (M+H)+.

Complex 1-ethylpropyl ether (TRANS-6-bromo-2,3,4,14b-tetrahydro-4-oxo-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)carbamino acid

(Structure 33 of scheme IX, where X = O, R1 = H, R2 = H, R3 = H, R4 = Br, R5 = H, R10 = H, R22 = CH(C2H5)2)

A common way 22: Rearrangement of kurzius and the subsequent formation of carbamate structure 33.

To a solution of TRANS-6-bromo-2,3,4,14b-tetrahydro-4-oxo-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-carboxylic acid (5.1 g, of 13.1 mmol) in toluene (185 ml), add triethylamine (3.3 ml, 23.6 mmol) and DPPA (3,67 ml of 17.0 mmol). The reaction mixture is heated at the boil under reflux for 1 hour. Then add 3-pentanol (2.8 ml, 26,2 mmol) and stirring is continued for 1.5 hours at 110°C. After cooling, the reaction mixture is poured into ice water, extracted with ethyl acetate, washed with water and saturated saline solution, dried (MgSO4) and evaporated, the resulting crude specified in the title compound (7.4 g, 100%). Data: (m/z = 473 + 475 (M+H)+.

Complex 1-ethylpropyl ether (TRANS-6-bromo-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)carbamino acid

(Structure 34 of scheme IX, where X = O, R1 = H, 2 = H, R3 = H, R4 = Br, R5 = H, R10 = H, R22 = CH(C2H5)2)

A common way 23: Education structure 34 by reduction with borane amide functional group.

Borane (1,0 M in THF, 60 ml, 60 mmol) is added dropwise to a mixed solution of complex 1-ethylpropyl ester, TRANS-(6-bromo-2,3,4,14b-tetrahydro-4-oxo-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)carbamino acid (7.4 g, of 13.1 mmol) in THF (90 ml). The resulting mixture was stirred at ambient temperature for 1 hour. Then added dropwise hydrochloric acid (1 n aq. solution) as long as you do not stop the gas. To the mixture add a solution of sodium hydroxide (2 n aq. solution) to bring the pH to 8. The reaction mixture is extracted with ethyl acetate and then the extract is washed with water and saturated salt solution. After drying (MgSO4) the solvent is evaporated under reduced pressure, to obtain crude specified in the title compound (7 g, 100%). Data: (m/z = 459 + 461 (M+H)+.

TRANS-6-Bromo-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-ylamine

(Structure 35 of scheme IX, where X = O, R1 = H, R2 = H, R3 = H, R4 = Br, R5 = H, R10 = H)

A common way 24: Hydrolysis of amide functional groups, leading to the amine structure 35.

A mixture of acetic acid (100 ml) and HBR(48%, 50 ml) are added to difficult the 1-ethylpropylamine ether of TRANS-(6-bromo-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)carbamino acid and stirred for 1 hour at 100° C. After cooling, the reaction mixture was poured into a cold solution of 1 N. NaOH (aq.). It is extracted with ethyl acetate and the organic layer washed with 1 N. NaOH (aq. solution) 4x, saturated NaHCO3(aq. solution), dried (MgSO4) and the solvent is evaporated. The crude compound purified on silica gel with toluene/acetone, 9:1, to obtain specified in the title compound (2.4 g, 53%). Data: (m/z = 345 + 347 (M+H)+.

TRANS-N-(6-Bromo-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-triptorelin

(Structure 36 of scheme IX, where X = O, R1 = H, R2 = H, R3 = H, R4 = Br, R5 = H, R10 = H)

A common way 25: Connection triperoxonane anhydride to amine getting trifurcated structure 36.

To a solution of TRANS-6-bromo-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-ylamine (2.4 g, 6.95 mmol) in a mixture of CH2Cl2(10 ml) and pyridine (10 ml), add triperoxonane anhydride (5 ml, of 35.4 mmol). The resulting reaction mixture was stirred at ambient temperature for 0.5 hours. Then add water while cooling in an ice bath. The mixture is extracted with CH2Cl2(2x). The combined organic layers washed with saturated salt solution, dried (MgSO4), evaporated and extracted with toluene (2x) obtaining specified in the title compound (1.54 g, 50%). Data:1H-NMR (400 MHz, DMSO) 1,59-2,05 (m, 4H), 3,09-3,17 (m, 1H), a 3.87 (d,J=14,0, 1H), 4,14 (d, J=10, 1H), 4,40-of 4.49 (m, 1H), 6,70-7,28 (m, 7 Aran), 9,13 (d, J=10, 1 NH). (m/z = 441 + 443 (M+H)+.

Example 52

TRANS-N-(6-Acetyl-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-triptorelin

(Structure 37 of scheme X, where R2 = H)

A common way 26: Conversion of acetyl bromide in structure 37.

(1-Ethoxyphenyl)tributylamine (182 μl, 0.54 mmol) are added to a solution of TRANS-N-(6-bromo-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-trifurcated (200 mg, 0.45 mmol) and PdCl2(PPh3)2(6 mg, 9 μmol) in toluene (12 ml)in an atmosphere of N2. The reaction mixture is heated at boiling under reflux and stirred for 3 hours. Added slowly at room temperature for 3 H. (aq. solution) HCl and the reaction mixture stirred for an additional ten minutes. Then it was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated NaHCO3(aq. solution and saturated saline solution, dried (MgSO4) and the solvents evaporated. The crude product was then purified, dissolved in THF (10 ml), and then add 3 N. HCl (aq. solution (4 ml). The mixture is stirred at room temperature for 1 hour, poured into water and extracted with ethyl acetate. The organic layer was washed with saturated NaHCO3and saturated saline solution, dried and evaporated. After cleaning with the LC get mentioned in the title compound (49 mg, 27%). Data:1H-NMR (400 MHz, CDCl3) 1,50 (m, 1H), 1,65 is 1.75 (m, 1H), 1,79-of 1.93 (m, 2H), 2,50 (d, J=3, 3H), 2,82 (m, 1H), 3,38 (dt, J=12,4, 1H), 4,5 (d, J=3, 1H), a 4.83 (m, 1H), 7,09-7,34 (7 Aran).

Example 53

TRANS-2,3,4,14b-Tetrahydro-1-[(TRIFLUOROACETYL)amino]-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepan-6-carbonitrile

(Structure 38 of scheme X, where R2 = H)

A common way 27: Conversion of bromide in the cyano-derivative structure 38.

The copper cyanide (I) (142 mg, 1.6 mmol) are added to a solution of TRANS-N-(6-bromo-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-trifurcated (700 mg, 1.6 mmol) in 1-methyl-2-pyrrolidinone (28 ml) and heated to 200°C and stirred for 24 hours at 190°C. At room temperature water is added and the mixture extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried (MgSO4) and concentrate under reduced pressure. Purification on silica gel with heptane/ethyl acetate, 1:1, gives specified in the title compound (450 mg, 75 %). Data:1H-NMR (400 MHz, CDCl3) 1,69 is 1.75 (m, 1H), 1,87-of 1.93 (m, 1H), 2,01-of 2.16 (m, 2H), 3,14-3,29 (m, 2H), br4.61 (d, J=3,2, 1H), 4,91 (m, 1H), 7,11-7,37 (7 Aran).

Example 54

TRANS-N-(6-Ethynyl-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-triptorelin

(Structure 39 of scheme X, where R2 = H)

A common way 28: Conversion to vinyl bromide-derived structure 39.

To a solution of TRANS-N-(6-bromo-2,3,4,14b-tetrahydro-1H-dibenz is[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-trifurcated (50 mg, 0.11 mmol) in toluene (3 ml) is added PdCl2(PPh3)2and vinyltrimethylsilane (38 μl, 0.13 mmol). The resulting reaction mixture is heated to 110°C and stirred for 2 hours at 110°C. After cooling to room temperature, water is added and the mixture extracted with ethyl acetate. The organic layer is washed with water and saturated saline solution, dried (MgSO4), and the solvent is evaporated. After purification by HPLC receive specified in the title compound (23 mg, 52%). Data:1H-NMR (400 MHz, CDCl3) to 1.60 (m, 1H), 1,78 (m, 1H), 1,83 is 1.96 (m, 2H), 2,93 (m, 1H), 3.43 points (dt, J=12, 4, 1H), 4,35 (d, J=2,5, 1H), 4,84 (m, 1H), of 5.40 (d, J=11, 1H), 5,67 (DD, J=18, 1,8, 1H), 7,07-7,31 (7 Aran), 7,55 (NH, 1H).

Example 55

TRANS-N-(2,3,4,14b-Tetrahydro-6-methoxy-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-triptorelin

(Structure 41 of scheme X, where R2 = H)

The copper iodide (I) (21 mg, 0.11 mmol) is added to a stirred solution of TRANS-N-(6-bromo-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-trifurcated (100 mg, 0.22 mmol) in DMF (1.5 ml), in the office of Dean-stark. Then add a solution of NaOMe (1.2 ml, 1.2 mmol) in methanol and stirring is continued at 135°C for 4 hours. After cooling, the reaction mixture was poured into saturated (aq. solution) NH4Cl and extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried (MgSO4) is evaporated. After purification on a column of SPE (solid phase extraction) and by HPLC receive specified in the title compound (11 mg, 13%). Data:1H-NMR (400 MHz, CDCl3) 1,50 (m, 1H), 1,76 (m, 1H), 1,87 (m, 1H), was 1.94 (m, 1H), 2,87 (m, 1H), 3,29 (dt, J=12, 3,2, 1H), 3,86 (s, 3H), 4,28 (d, J=3,2, 1H), to 4.81 (m, 1H), (arene.) of 6.66 (d, J=12, 1H), 6,78 (d, J=12, 1H), 7,10 (m, 1H), 7,20-7,31 (m, 4H), 8,18 (m, 1H, NH).

Example 56

TRANS-N-(6-Bromo-8-fluoro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-triptorelin

(Structure 36 of scheme IX, where X = O, R1 = H, R2 = F, R3 = H, R4 = Br, R5 = H, R10 = H)

2-[(2,6-Dibromo-4-forfinal)iminomethyl]phenol

(Structure 30 of scheme VIII, where R2 = F)

This compound is obtained using the General method 19, to obtain the crude specified in the title compound (15.2 g, 100%). Data: (m/z = 372 + 374 + 376 (M+H)+.

9-Bromo-7-Ferdinando[b,f][1,4]oxazepine

(Structure 31 of scheme VIII, where X = O, R1 = H, R2 = F, R3 = H, R4 = Br, R5 = H, R10 = H)

This compound is obtained using the General method 20. 9-Bromo-7-Ferdinando[b,f][1,4]oxazepine (6.7 g, 64%) collected by filtration after pouring the reaction mixture into ice water. Data: (m/z = 292 + 294 (M+H)+.

TRANS-6-Bromo-8-fluoro-2,3,4,14b-tetrahydro-4-oxo-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-carboxylic acid

(Structure 32 of scheme IX, where X = O, R1 = H, R2 = F, R3 = H, R4 = Br, R5 = H, R10 = H)

This compound is obtained using the General method 21, obtaining specified in the connection header in VI is e crystals of only one isomer (4,2 g, 45%). Data: (m/z = 406 + 408 (M+H)+.

Complex 1-ethylpropyl ether (TRANS-6-bromo-8-fluoro-2,3,4,14b-tetrahydro-4-oxo-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)carbamino acid

(Structure 33 of scheme IX, where X = O, R1 = H, R2 = F, R3 = H, R4 = Br, R5 = H, R10 = H)

This compound is obtained using the General method 22, obtaining specified in the title compound (4.6 g, 100%). Data: (m/z = 435 + 437 (M+H)+.

Complex 1-ethylpropyl ether (TRANS-6-bromo-8-fluoro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)carbamino acid

(Structure 34 of scheme IX, where X = O, R1 = H, R2 = F, R3 = H, R4 = Br, R5 = H, R10 = H)

This compound is obtained using the General method 23. The product (1.2 g, 30%) is obtained by crystallization from diethyl simple ether. Data: (m/z = 421 + 423 (M+H)+.

TRANS-6-Bromo-8-fluoro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine

(Structure 35 of scheme IX, where X = O, R1 = H, R2 = F, R3 = H, R4 = Br, R5 = H, R10 = H)

This compound is obtained using the General method 24, with the receipt of the net specified in the title compound (2.1 g, 72%) after purification on a column of the SPE. Data: (m/z = 363 + 365 (M+H)+.

TRANS-N-(6-Bromo-8-fluoro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-triptorelin

(Structure 36 of scheme IX, where X = O, R1 = H, R2 = F, R3 = H, R4 = Br, R5 = H, R10 = H)

This compound is obtained using the General method 25, with obtaining the specified reception in the e connection. After purification by HPLC obtain 79 mg (91%). Data:1H-NMR (400 MHz, CDCl3) 1,54-to 1.61 (m, 1H), 1,67-to 1.77 (m, 1H), 1,82-1,90 (m, 1H), 1.93 and e 2.06 (m, 1H), 2,85 of 2.92 (DD, J=12,2, J=5,0, 1H), 3.27 to the 3.35 (TD, J=12,0, J=3,0, 1H), 4,33 is 4.35 (d, J=2,2, 1H), 4,87 to 4.92 (m, 1H), 6,88-7,34 (6 Aran), (OSiR., 1H). (m/z = 459 + 461 (M+H)+.

Example 57

TRANS-N-(6-Acetyl-8-fluoro-2,3,4,14b-tetrahydro-1H-dibenzo-[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-triptorelin

(Structure 37 of scheme X, where R2 = F)

This compound is obtained using the General method 26, obtaining specified in the title compound (103 mg, 42,9%) after purification by HPLC. Data:1H-NMR (400 MHz, CDCl3) a 1.46-1.69 in (m, 2H), 1,76-of 1.93 (m, 2H), 2,58 (s, 3H), was 2.76-2.82 from (m, 1H), 3,34-of 3.43 (dt, J=12,0, 3,2, 1H), of 4.44-4,47 (d, J=2,2, 1H), 4.80 to a 4.86 (m, 1H), 6,99-7,32 (6 Aran), 8,5-8,58 (user., 1H). (m/z = 423 (M+H)+.

Example 58

TRANS-8-Fluoro-2,3,4,14b-tetrahydro-1-[(TRIFLUOROACETYL)amino]-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepan-6-carbonitrile

(Structure 38 of scheme X, where R2 = F)

This compound is obtained using the General method 27. After purification by HPLC receive specified in the title compound (78 mg, 55.7 per cent, TRANS). Data:1H-NMR (400 MHz, CDCl3) 1,65-1,72 (m, 1H), 1.85 to of 1.92 (m, 1H), 1,95-2,02 (m, 1H), 2.05 is with 2.14 (m, 1H), 3,06-3,11 (m, 1H), 3,17-of 3.23 (TD, J=8,0, J=2,0, 1H), 4,55-of 4.57 (d, J=1,7, 1H), 4,90-4,94 (m, 1H), 7,06 and 7.36 (6 Aran), 7,47-7,56 (user., 1H). (m/z = 406 (M+H)+.

Example 59

TRANS-N-(6-Ethynyl-8-fluoro-2,3,4,14b-tetrahydro-1H-dibenzo-[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-Triforce the MFA

(Structure 39 of scheme X, where R2 = F)

This compound is obtained using the General method 28, obtaining specified in the title compound (141 mg, 53%) after purification by HPLC. Data:1H-NMR (400 MHz, CDCl3) of 1.57-1.77 in (m, 2H), 1,82-of 1.95 (m, 2H), 2,86 of 2.92 (m, 1H), 3,40-of 3.48 (dt, J=12,0, J=3,0, 1H), 4,27-4,30 (d, J=2,5, 1H), 4,82-to 4.87 (m, 1H), 5,43-vs. 5.47 (d, J=11,4, 1H), 5,64-5,70 (DD, J=18,0, 1,1, 1H), for 6.81-7,32 (6 Aran + 1H), 7,49-EUR 7.57 (user., 1H). (m/z = 407 (M+H)+.

Example 60

TRANS-2,2,2-Cryptor-N-(8-fluoro-2,3,4,14b-tetrahydro-6-methyl-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)ndimethylacetamide

(Structure 40 of scheme X, where R2 = F)

To a solution of TRANS-N-(6-bromo-8-fluoro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-trifurcated (300 mg, of 0.65 mmol) in THF (7 ml) is added ferrocene PdCl2(10 mg, 14 μmol) and the reaction mixture is stirred for 10 minutes. Add dropwise methylenchlorid (0,81 ml), after which the reaction mixture is heated to 60°C. After 3 hours, add ferrocene PdCl2(20 mg, 28 μmol) and methylenchlorid (0.3 ml) and the reaction mixture is heated at 80°C for one hour. Water is added at room temperature and the reaction mixture is extracted with simple ether and water. Solutionin simple ether washed with saturated salt solution, dried (Na2SO4) and volatile products are removed under reduced pressure. After purification by HPLC, get the specified reception in the e compound (108 mg, 39%). Data:1H-NMR (400 MHz, CDCl3) 1,56-1,72 (m, 2H), 1,79-of 1.93 (m, 2H), is 2.37 (s, 3H), 2,79-2,86, (m, 1H), 3,44-to 3.52 (TD, J=12,0, J=3,0, 1H), 4,27-the 4.29 (d, J=2,5, 1H), 4,85-4,91 (m, 1H), 6,70-7,32 (6 Aran), 7,63-7,70 (user., 1H). (m/z = 395 (M+H)+.

Example 61

TRANS-N-(7-Bromo-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-triptorelin

(Structure 46 of scheme XI)

4-Bromo-2-nitro-1-phenoxybenzoyl

(Structure 42 of scheme XI)

Cs2CO3(4 g, 12.3 mmol) are added to a solution of phenol (1 g, 10.6 mmol) in 50 ml of THF, in an atmosphere of N2. After stirring for 15 minutes add 1,4-dibromo-2-nitrobenzene (of 2.81 g, 10 mmol). The resulting mixture is heated to the boiling temperature under reflux and stirred for overnight at the boiling temperature under reflux. Add water and ethyl acetate, followed by extraction with ethyl acetate (3x). The combined organic layers washed with water and saturated saline solution, dried (Na2SO4) and evaporated to obtain crude compound (3.2 g, 75%).

5-Bromo-2-phenoxybenzamine

(Structure 43 scheme XI)

Iron powder (3 g, with 53.4 mmol) and acetic acid (10 ml) is added to a stirred suspension of 4-bromo-2-nitro-1-phenoxybenzene (3.1 g, 9.5 mmol) in water (25 ml) at 60°C. the Reaction mixture is heated to 80°C and stirred for 30 minutes. After cooling to room temperature reaction the second mixture is filtered and extracted with toluene. The toluene solution is washed with water (3x) and saturated saline solution, dried (Na2SO4) and evaporated to obtain crude compound (2.3 g, 87%). Data: (m/z = 264 + 266 (M+H)+.

N-(5-Bromo-2-phenoxyphenyl)formamid

(Structure 44 of scheme XI)

A common way 29: Addition of formic acid to the amine with getting formamido structure 44.

A mixture of 5-bromo-2-phenoxybenzamine (68,4 g, 260 mmol) and formic acid (180 ml) is heated at boiling under reflux and stirred for 2 hours. The product is collected by filtration and dried at 50°C, under reduced pressure, to obtain the compound in the form of whitish crystals (60 g, 79%). Data: (m/z = 292 + 294 (M+H)+.

8 Bromobenzo[b,f][1,4]oxazepine

(Structure 45 of scheme XI)

A common way 30: ring Closure using PPA, deriving patterns 45.

PPA (207,5 g) are added to N-(5-bromo-2-phenoxyphenyl)formamide (20 g, of 68.7 mmol) and the reaction mixture is heated to 140°C with vigorous stirring for 2 hours. After cooling to room temperature the reaction mixture was poured into ice water. The mixture is filtered and the solid product washed with water and 25% ammonia and dried at 50°C, under reduced pressure, to obtain specified in the connection header (9,9 g, 52%). Data: (m/z = 274 + 276 (M+H)+.

TRANS-7-Bromo-2,3,4,14b-tetrahydro-4-oxo-1H-diben what about[b,f]pyrido[1,2-d][1,4]oxazepine-1-carboxylic acid

(Structure 32 of scheme IX, where X = O, R1 = H, R2 = H, R3 = Br, R4 = H, R5 = H, R10 = H)

Glutaric anhydride (5,48 g, 48.1 mmol) is added to a stirred solution of 8-bromobenzo[b,f][1,4]oxazepine (8,1 g, 29.6 mmol) in xylene (20 ml). To the reaction mixture are added-CH2Cl2and all of this is extracted with 2 N. (aq. solution) NaOH (3x). All water layers neutralized by adding 2 N. (aq. solution) HCl and extracted with CH2Cl2. The combined organic layers are dried (Na2SO4) and evaporated, to obtain specified in the title compound (9.7 g, 85%) as a mixture of TRANS and CIS-isomers. Data: (m/z = 388 + 390 (M+H)+.

Complex 1-ethylpropyl ether of TRANS-(7-bromo-2,3,4,14b-tetrahydro-4-oxo-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)carbamino acid

(Structure 33 of scheme IX, where X = O, R1 = H, R2 = H, R3 = Br, R4 = H, R5 = H, R10 = H, R22 = CH(C2H5)2)

By applying a General method 22 and through the use of 3-pentanol as alcohol get mentioned in the title compound (6.0 g, 99%). Data: (m/z = 470 + 472 (M+H)+.

Complex 1-ethylpropyl ether of TRANS-(7-bromo-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)carbamino acid

(Structure 34 of scheme IX, where X = O, R1 = H, R2 = H, R3 = Br, R4 = H, R5 = H, R10 = H, R22 = CH(C2H5)2)

Borane (1,0 M in THF, 55 ml, 55 mmol) is added dropwise to a mixed solution of complex 1-ethylpropyl the ether of TRANS-(7-bromo-2,3,4,14b-tetrahydro-4-oxo-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)carbamino acid (6,01 g, 12.7 mmol) in THF (63 ml). The resulting mixture was stirred at ambient temperature for 1 hour. Then water is added and the resulting mixture extracted with ethyl acetate. The organic layers washed with water and saturated saline solution, dried (Na2SO4) and evaporated. The crude product is subjected to chromatography on silica gel with heptane/ethyl acetate, 1:1, which gives specified in the header of the product as a mixture of CIS - and TRANS-isomers. After adding ethyl acetate to the mixture of pure TRANS product (1,41 g, 24.2 per cent) may be collected by filtration. Data: (m/z = 459 + 461 (M+H)+

TRANS-7-Bromo-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine

(Structure 35 of scheme IX, where X = O, R1 = H, R2 = H, R3 = Br, R4 = H, R5 = H, R10 = H)

This compound is obtained using the General method 24, obtaining specified in the connection header (of 1.05 g, 99%). Data: (m/z = 345 + 347 (M+H)+.

TRANS-N-(7-Bromo-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-triptorelin

(Structure 46 of scheme XI)

This compound is obtained using the General method 25, obtaining specified in the title compound (76 mg, 92%). Data:1H-NMR (400 MHz, DMSO) 1,58-of 2.09 (m, 4H), is 3.08 (t, J=12,8, 1H), 3,81 (d, J=14,0, 1H), 4,11 (d, J=10,4, 1H), to 4.38 (m, 1H), 6,83-7,28 (7 Aran), 9,13 (d, J=10,0, 1H). (m/z = 441 + 443 (M+H)+.

Example 62

TRANS-N-(7-Acetyl-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]-PI is IDO[1,2-d][1,4]oxazepine-1-yl)-2,2,2-triptorelin

(Structure 47 of scheme XII)

(1-Ethoxyphenyl)tributylamine (90 μl, 0.23 mmol) are added to a solution of TRANS-N-(7-bromo-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-trifurcated (100 mg, 0.23 mmol) and PdCl2(PPh3)2(3 mg, 4.3 mmol) in toluene (6 ml)in an atmosphere of N2. The reaction mixture is heated to 140°C and stirred for 3 hours. After cooling to room temperature, add 2 N. (aq. solution) HCl (450 ml) and the reaction mixture is stirred for 1 hour. The reaction is quenched with saturated NaHCO3(aq. solution) and extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried (Na2SO4) and evaporated. The crude compound is subjected to chromatography with heptane/ethyl acetate, 1:1. Purification by HPLC gives specified in the title compound (43 mg, 47%). Data:1H-NMR (400 MHz, DMSO) 1,60-of 2.09 (m, 4H), 3,21 (t, J=11,2, 1H), 3,90 (d, J=14,0, 1H), 4.16 the (d, J=10,4, 1H), of 4.44 (m, 1H),? 7.04 baby mortality-rate of 7.54 (m, 10H), 9,20 (d, J=10,0, 1H). (m/z = 405 (M+H)+.

Example 63

TRANS-2,3,4,14b-Tetrahydro-1-[(TRIFLUOROACETYL)amino]-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepan-7-carbonitrile

(Structure 48 of scheme XII)

This compound is obtained using the General method of 27, which gives specified in the title compound (491 mg, 50%). Data:1H-YAR (400 MHz, DMSO) 1,58-of 2.09 (m, 4H), and 3.16 (t, J=13,2, 1H), 3.96 points (d, J=13,6, 1H), 4,18 (d, J=10,4, 1H), 4,47 (m, 1H), 7,06-7,53 (m, 7 Aran), 9,18 (d, J=9,6, 1H). (m/z = 388(M+H) +.

Example 64

TRANS-N-(7-Ethynyl-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-triptorelin

(Structure 49 of scheme XII)

This compound is obtained using the General method 28, which gives specified in the title compound (15 mg, 34%). Data:1H-YAR (400 MHz, DMSO) 1,59-2,07 (m, 4H), 3,14 (t, J=12, 1H), 3,90 (d, J=13,6, 1H), 4,23 (d, J=10,0, 1H), of 4.44 (m, 1H), 5,15 (d, J=12,0, 1H), 5,50 (d, J=18,4, 1H), 6,60 (square, 1H) 6,84-7,26 (m, 7 Aran), 9,17 (d, J=9,6, 1H). (m/z = 389 (M+H)+.

Example 65

TRANS-2,2,2-Cryptor-N-[2,3,4,14b-tetrahydro-7-[(phenylmethyl)amino]-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl]ndimethylacetamide

(Structure 50 of scheme XII)

To a solution of TRANS-N-(7-bromo-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-trifurcated (0.5 g, 1.1 mmol) in DME (16 ml), add Pd2(dba)3(12.5 mg, 13.5 mmol), 2-(di-tert-butylphosphino)biphenyl (25 mg, 80 μmol), tert-piperonyl sodium (218 mg, 2.3 mmol) and benzylamine (243 mg, 2.3 mmol). The resulting reaction mixture is heated to 75°C and stirred at this temperature for 48 hours. The reaction mixture was quenched with saturated NaHCO3(aq. solution) and extracted with ethyl acetate. The organic layer is washed with water and saturated saline solution, dried (Na2SO4) and evaporated. The crude product is subjected to chromatography with heptane/ethyl acetate, 8:2, and purified using HPLC, obtaining specified in the title compound (21 mg,32%). Data:1H-NMR (400 MHz, DMSO) 1,54-2,02 (m, 4H), 2.95 points (t, J=9,2, 1H), 3,68 (d, J=14,0, 1H), was 4.02 (d, J=10,0, 1H), 4,17 (d, J=6,0, 2H), 4,37 (m, 1H), 5,90-7,33 (12 Aran, 1 NH), 9,11 (d, J=10,0, 1H). (m/z = 468 (M+H)+.

Example 66

TRANS-N-(7-Amino-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-triptorelin

(Structure 51 of scheme XII)

To a solution of TRANS-2,2,2-Cryptor-N-[2,3,4,14b-tetrahydro-7-[(phenylmethyl)amino]-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl]ndimethylacetamide (944 mg, 2.0 mmol) in ethanol (16 ml) is added Pd/C 10% (111 mg) and a solution of 4 M HCl in dioxane (778 μl, 3.11 mmol). The resulting reaction mixture hydronaut at 3 bar for 6 hours. The reaction mixture was quenched with saturated NaHCO3(aq. solution) and diluted with ethanol. After filtration through dekalim and thorough washing with ethyl acetate, volatile products are removed under vacuum. Part of the crude product purified by HPLC, to obtain the specified title compound (29 mg, 53%). Data (m/z = 378 (M+H)+.

Example 67

TRANS-N-[2,3,4,14b-Tetrahydro-7-[(1-oxopropyl)amino]-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl]-2,2,2-triptorelin

(Structure 52 of scheme XII)

To a solution of TRANS-N-(7-amino-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-trifurcated (50 mg, 0.13 mmol) in CH2Cl2(2 ml) add propionate (11 μl, 0.13 mmol) and triethylamine (20 μl, 0.14 mmol). The reaction mixture was stirred for 1.5 cha is s at room temperature. The reaction mixture was quenched with saturated NaHCO3(aq. solution) and extracted with CH2Cl2. The organic layer is dried and evaporated. The crude product is purified on silica gel and HPLC, obtaining specified in the title compound (27 mg, 48%). Data (m/z = 434 (M+H)+.

Example 68

TRANS-N-(12-Bromo-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-triptorelin

(Structure 55 of scheme XIII)

4-Bromo-2-[(4-bromo-2-forfinal)methylamino]phenol

(Structure 53 of scheme XIII)

5-Chloro-2-hydroxyanisol (9,8 g, 48 mmol) and 4-bromo-2-forbindelse (7.0 g, 48 mmol) dissolved in ethanol (400 ml). The reaction mixture is heated to 60°C and stirred for 1 hour. Then the ethanol is evaporated and receive specified in the header of the connection a (17.4 g, 100%).

3-Bromo-8-chlorodibenzo[b,f][1,4]oxazepine

(Structure 54 of scheme XIII)

To a solution of 4-bromo-2-[(4-bromo-2-forfinal)methylamino]-phenol a (17.4 g of 48.5 mmol) in DMSO (200 ml) add K2CO3(13,4 g, with 97.1 mmol). The resulting reaction mixture was stirred at 140°C for 1 hour. Add water at 45°C. the Product is collected by filtration in the form of a whitish solid product. The solid product is washed with water, dissolved in ethyl acetate and washed with saturated (aq. solution) NaCl and dried (Na2SO4). Volatile products is evaporated, with the receipt indicated the data in the title compound (14.3 g, 95,5%).

TRANS-12-Bromo-7-chloro-2,3,4,14b-tetrahydro-4-oxo-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-carboxylic acid

(Structure 32 of scheme IX, where X = O, R1 = H, R2 = H, R3 = Cl, R4 = H, R5 = 12-Br, R10 = H)

This compound is obtained using the General method 21, obtaining crystals in the form of a mixture of CIS - and TRANS-isomers, 1/1 (16.4 g, 83.6 percent), and, after extraction eluent, a mixture of CIS - and TRANS-isomers, 1/1 (1,91 g, 9.7 per cent).

Complex 1-metaliteracy ether of TRANS-(12-bromo-7-chloro-2,3,4,14b-tetrahydro-4-oxo-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)carbamino acid

(Structure 33 of scheme IX, where X = O, R1 = H, R2 = H, R3 = Cl, R4 = H, R5 = 12-Br, R10 = H, R22 = CH(CH3)2)

To a solution of TRANS-12-bromo-7-chloro-2,3,4,14b-tetrahydro-4-oxo-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-carboxylic acid (18.3 g, a 43.3 mmol) in toluene added triethylamine (10,8 ml, up 77.9 mmol) and DPPA (12,2 ml, 56,3 mmol). The reaction mixture is heated at the boil under reflux for 3 hours. At 100°C is added 2-propanol (6,6 ml, 86,5 mmol) and stirring is continued for 3 hours at 110°C. the Reaction mixture was poured into water and extracted with ethyl acetate. The organic layer is washed with water and saturated saline solution, dried (Na2SO4) and evaporated, the resulting crude specified in the connection header (25.4 g, 100%) as a mixture of CIS - and TRANS-isomers, 20:80. Data: (m/z = 479 + 481 (M+H)+.

u> Complex 1-metaliteracy ether of TRANS-(12-Bromo-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)carbamino acid

(Structure 34 of scheme IX, where X = O, R1 = H, R2 = H, R3 = Cl, R4 = H, R5 = 12-Br, R10 = H, R22 = CH(CH3)2)

Borane (1,0 M in THF, 216,5 ml, 216,5 mmol) is added dropwise to a mixed solution of complex 1-mutilative ester, TRANS-(12-bromo-7-chloro-2,3,4,14b-tetrahydro-4-oxo-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)carbamino acid (25.4 g, a 43.3 mmol) in THF. The resulting mixture was stirred at ambient temperature for 1 hour. Water is added to the mixture until then, until there is no further gas evolution. Add more water and the product collected by filtration. The solid product is dried at 40°C, under reduced pressure, within 48 hours of obtaining crystals in the form of a mixture of TRANS (86%) and CIS (14%). The filtrate is extracted with CH2Cl2. The organic layer was washed with saturated saline solution, dried (Na2SO4) and evaporated to obtain crude product (9.5 g, 47.2%) of as a mixture of isomers, CIS/TRANS = 1/2. CH2Cl2add tothe crystals discussed above, and the pure TRANS-isomer (5.9 g, 29.3 percent) is collected by filtration and dried under reduced pressure. Eluent concentrate with a mixture of CIS - and TRANS-products (7.9 g, 39.2 per cent). Data: (m/z = 465 + 467 (M+H)+.

TRANS-12-Bromo-7-chloro-2,3,4,14b-tetrahed is about-4-oxo-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine

(Structure 35 of scheme VIII, where X = O, R1 = H, R2 = H, R3 = Cl, R4 = H, R5 = 12-Br, R10 = H)

A mixture of acetic acid (30 ml) and HBR(48%, 15 ml) is added to the complex 1-methylethylamine ether of TRANS-(12-bromo-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)carbamino acid (5.9 g, 12.7 mmol, pure TRANS-isomer) and stirred for 1 hour at 100°C, in nitrogen atmosphere. After cooling, the product is collected by filtration and dissolved in CH2Cl2. The organic layer was washed with 2 N. NaOH (aq. solution), saturated NaHCO3(aq. solution), saturated salt solution, dried (Na2SO4) and evaporated, to obtain specified in the title compound (4.0 g, 83%).

TRANS-N-(12-Bromo-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo-[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-triptorelin

(Structure 55 of scheme XIII)

This compound is obtained using the General method 25, obtaining specified in the connection header (2,45 g, 90%). Data:1H-NMR (400 MHz, DMSO) 1,6-to 1.86 (m, 4H), 2,1 (m, 1H), 3,12 (TD, J=2,8, 13,4, 1H), 3,86 (d, J=14, 1H), 4,12 (d, J= 10,4, 1H), 4,4 (m, 1H), 6.73 x-7,49 (6 Aran), of 9.21 (d, J=10, 1 NH). (m/z = 475 + 477 (M+H)+.

Example 69

TRANS-7-Chloro-2,3,4,14b-tetrahydro-1-[(TRIFLUOROACETYL)amino]-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-12-carbonitrile

(Structure 56 of scheme XIV)

This compound is obtained using the General method of 27, with obtaining the specified reception in the e connection (4,7 mg, a 3.5%). Data:1H-NMR (400 MHz, DMSO) 1,60-of 1.88 (m, 4H), 2,03 (m, 1H), 3,14 (TD, J=3,2, 13,2, 1H), 3,85 (d, J=13,6, 1H), 4,21 (d, J=10, 1H), 4,4 (m, 1H), 6,77-7,70 (7 Aran), 9,26 (d, J=9,6, 1 NH).

Example 70

TRANS-N-(7-Chloro-2,3,4,14b-tetrahydro-12-methyl-1H-dibenzo-[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-triptorelin

(Structure 57 of scheme XIV)

To a solution of TRANS-N-(12-bromo-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-trifurcated (80 mg, 0,17 mmol) in THF (2 ml) is added ferrocene PdCl2(5 mg, 7 μmol) and the reaction mixture is stirred for 5 minutes. Add methylenchlorid dropwise, then the reaction mixture is heated to 60°C and stirred over night at 60°C. the Mixture was poured into saturated (aq. solution) NH4Cl and extracted with ethyl acetate (3x). The combined organic layers washed with saturated salt solution, dried (Na2SO4) and evaporated. After purification on silica gel and HPLC receive specified in the title compound (13.2 mg, 19%). Data:1H-NMR (400 MHz, DMSO) 1,60-of 1.85 (m, 3H), 2.0 (m, 1H), of 2.23 (s, 3H), 3,11 (TD, J=2,8, 13,2, 1H), 3,85 (d, J=14, 1H), 4,10 (d, J=10, 1H), and 4.40 (m, 1H), 6,69-7,10 (6 Aran), 9,16 (d, J=10, 1H).

Example 71

TRANS-N-(12-Bromo-6,7-dichloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-triptorelin

(Structure 58 of scheme XIV)

To a suspension of TRANS-N-(12-bromo-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine--yl)-2,2,2-trifurcated (100 mg, 0.21 mmol) in acetone added NCS (or 28.7 mg, 0.21 mmol) and 6 N. (aq. solution) HCl (0.4 ml, 2.4 mmol). The resulting reaction mixture is stirred over night. Add the second portion of NCS (or 28.7 mg, 0.21 mmol) and continue stirring overnight. Add the additional number of NCS (or 28.7 mg, 0.21 mmol) and stirring is continued for 5 hours. The reaction mixture was poured into saturated (aq. solution) NaHCO3and extracted with ethyl acetate (2x). The combined organic layers washed with saturated salt solution, dried (Na2SO4) and evaporated. After purification of the crude product by HPLC receive three products:TRANS-N-(12-bromo-6,7-dichloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-triptorelin(structure 53 of scheme XIII) (13.9 mg, 13%),TRANS-N-(12-bromo-7,8-dichloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-triptorelin(15.7 mg, 14.1%) andTRANS-N-(12-bromo-6,7,8-trichloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-triptorelin(20.4 mg, 17.8 per cent). Data (structure 53):1H-NMR (400 MHz, DMSO) of 1.55 (m, 1H), 1,78 (m, 2H), 1,99 (m, 1H), 3,20 (t, J=12, 1H), 3.46 in (d, J=14, 1H), 4,30 (d, J=8,8, 1H), 4,45 (users, 1H), 7,16-7,55 (6 Aran), 9,26 (d, J=6, 1 NH).

Example 72

TRANS-N-(7-Chloro-11-fluoro-2,3,4,14b-tetrahydro-1H-dibenzo-[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-triptorelin

(Structure 61 of scheme XV, where R5 = 11-F, R10 = H)

4-Bromo-2-[(2,3-difthe Il)methylamino]phenol

(Structure 59 of scheme XV, where R5 = 3-F and R10 = H)

2,3-Differentally (with 0.55 ml, 5 mmol) is added to a stirred solution of 5-chloro-2-hydroxyanisole (0,72 g, 5 mmol) in ethanol (5 ml). Within a few minutes, a solid product and add an additional amount of ethanol (10 ml). The solid product produce by filtration and dried, to obtain specified in the connection header (1,09 g, 81%).

8-Chloro-4-Ferdinando[b,f][1,4]oxazepine

(Structure 60 of scheme XV, where R5 = 4-F, R10 = H)

A solution of 4-bromo-2-[(2,3-differenl)methylamino]phenol (1,09 g, 4.1 mmol) in DMSO (2.4 ml) and diethylamine (1.2 ml) is heated in a microwave oven at 160°C. Within 5 minutes of the reaction mixture, allow to cool and add water. Filtration and drying give specified in the header connection (0,59 g, 57%).

TRANS-7-Chloro-11-fluoro-2,3,4,14b-tetrahydro-4-oxo-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-carboxylic acid

(Structure 32 of scheme IX, where X = O, R1 = H, R2 = H, R3 = Cl, R4 = H, R5 = 11-F, R10 = H)

A solution of 8-chloro-4-Ferdinando[b,f][1,4]oxazepine (0,59 g, 2.4 mmol) and glutaric anhydride (0.36 g, 3.2 mmol) in xylene (1.3 ml) was stirred at 140°C. After 72 hours the reaction mixture allow to cool to room temperature and add a simple ether. Filtration gives a solid material. This solid product is dissolved in ethyl acetate and extracted with an aqueous solution of the m 2 N. of sodium hydroxide. Water extract add 3 N. hydrochloric acid to obtain a pH of3, and then extracted with ethyl acetate. The organic extract is washed with water and saturated saline solution, dried (Na2SO4) and concentrated, obtaining specified in the connection header (0,44 g, 50%).

Complex 1-metaliteracy ether of TRANS-(7-chloro-11-fluoro-2,3,4,14b-tetrahydro-4-oxo-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)carbamino acid

(Structure 33 of scheme IX, where X = O, R1 = H, R2 = H, R3 = Cl, R4 = H, R5 = 11-F, R10 = H, R22 = CH(CH3)2)

In a General way 22 use of TRANS-7-chloro-11-fluoro-2,3,4,14b-tetrahydro-4-oxo-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-carboxylic acid (of 0.44 g, 1.2 mmol), and 2-popoola instead of 3-pentanol gives a complex 1-metaliteracy ether of TRANS-(7-chloro-11-fluoro-2,3,4,14b-tetrahydro-4-oxo-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)carbamino acid (0,63 g, 82%).

Complex 1-metaliteracy ether of TRANS-(7-chloro-11-fluoro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)carbamino acid

(Structure 34 of scheme IX, where X = O, R1 = H, R2 = H, R3 = Cl, R4 = H, R5 = 11-F, R10 = H, R22 = CH(CH3)2)

General method 23 is used for complex 1-mutilative ester, TRANS-(7-chloro-11-fluoro-2,3,4,14b-tetrahydro-4-oxo-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)carbamino acid (0,63 g, 0.98 mmol), to obtain the crude specified in zag is lowke connection. Purification using column chromatography on silica gel with heptane/ethyl acetate (heptane/ethyl acetate = 4/1) gives specified in the title compound (0.14 g, 35%).

TRANS-7-Chloro-11-fluoro-2,3,4,14b-tetrahydro-4-oxo-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine

(Structure 35 of scheme VIII, where X = O, R1 = H, R2 = H, R3 = Cl, R4 = H, R5 = 11-F, R10 = H)

General method 24 is used for complex 1-mutilative ester, TRANS-(7-chloro-11-fluoro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)carbamino acid (0.14 g, 0.35 mmol), to obtain the crude specified in the connection header. Purification using column chromatography on silica gel with heptane/ethyl acetate to give TRANS-7-chloro-11-fluoro-2,3,4,14b-tetrahydro-4-oxo-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine (0.14 g, 35%).

TRANS-N-(7-Chloro-11-fluoro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-triptorelin

(Structure 61 of scheme XV, where R5 = 11-F and R10 = H)

Receive in accordance with the General method 25 using TRANS-7-chloro-11-fluoro-2,3,4,14b-tetrahydro-4-oxo-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine (94 mg, 0.29 mmol) to give crude specified in the header connection. This compound is purified by column chromatography on silica gel with heptane/ethyl acetate, and subsequent column chromatography on silica gel with toluene/ethyl acetate (toluene/ethyl acetate = 9/1), obtaining specified in the header the compound (58 mg, 48%). Data:1H-NMR (400 MHz, DMSO d6) 1,60-of 1.92 (m, 3H), 1,99-2,07 (m, 1H), 3,10-3,18 (m, 1H), 3,90 (userd, J=14, 1H), 4,19 (d, J=10 Hz, 1H), 4,39-of 4.49 (m, 1H), 6.75 in (DD, J=3, 9, 1H), 6,98-7,11 (m, 4H), 7,20-7,27 (m, 1H), which 9.22 (d, J=9, 1H).

Example 73

TRANS-N-(7-Chloro-14-fluoro-2,3,4,14b-tetrahydro-1H-dibenzo-[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-triptorelin

(Structure 61 of scheme XV, where R5 = 14-F and R10 = H)

Receive in accordance with the procedures described in example 72, TRANS-N-(7-chloro-11-fluoro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-trifurcated based on 2,6-diferentialglea (0.54 ml, 5 mmol), givescrude specified in the header connection. This compound is purified by column chromatography on silica gel with heptane/ethyl acetate, column chromatography on silica gel with toluene/ethyl acetate (toluene/ethyl acetate = 9/1), and the final crystallization from acetonitrile, to obtain the specified title compound (136 mg, 6% of the total output). Data:1H-NMR (400 MHz, DMSO d6) of 1.57 to 1.76 (m, 2H), 1,89-2,04 (m, 2H), 3,09-3,18 (m, 1H), 3,93 (userd, J=14, 1H), 4,42 (d, J=10, 1H), to 4.52-to 4.62 (m, 1H), 6,74 (DD, J=9, 3, 1H), 6,95-7,16 (m, 4H), 7,27-7,33 (m, 1H), of 9.30 (d, J=9, 1H).

Example 74

TRANS-N-(7-Chloro-12-fluoro-2,3,4,14b-tetrahydro-1H-dibenzo-[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-triptorelin

(Structure 61 of scheme XV, where R5 = 12-F and R10 = H)

Receive in accordance with the procedures described in example 72, TRANS-N-(7-chloro-11-fluoro-2,3,4,14b-tetrahydro-1H-di is Enzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-trifurcated, based on 2,4-diferentialglea (with 0.55 ml, 5 mmol), givescrude specified in the header connection. This compound is purified by column chromatography on silica gel with heptane/ethyl acetate and HPLC on a column ofLuna (10u C(18(2), 250x50 mm) using a gradient from acetonitrile/water to acetonitrile for 30 minutes, at a flow rate of 50 ml/min, obtaining specified in the title compound (62 mg, 3% of the total output). Data:1H-NMR (400 MHz, DMSO d6) 1,59 is 1.86 (m, 3H), 1,98-to 2.06 (m, 1H), is 3.08-3,17 (m, 1H), a 3.87 (userd, J=13, 1H), 4,13 (d, J=10, 1H), 4,35 is 4.45 (m, 1H), 6,76 (DD, J=8, 3, 1H), 6,92-6,98 (m, 1H), was 7.08 (s, 1H), 7,12-7.23 percent (m, 3H), 9,18 (d, J=9, 1H).

Example 75

TRANS-N-(7-Chloro-12,13-debtor-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-triptorelin

(Structure 61 of scheme XV, where R1 = H, R2 = H, R3 = Cl, R4 = H, R5 = 12-F, R10 = 13-F)

4-Bromo-2-[(2,4,5-tryptophanyl)methylamino]phenol

(Structure 59 of scheme XV, where R5 = 4-F, R10 = 5-F)

2,4,5-Tripersonality high (0.56 ml, 5 mmol) is added to a stirred solution of 5-chloro-2-hydroxyanisole (0,72 g, 5 mmol) in ethanol (5 ml). Within a few minutes, a solid product, and add an additional amount of ethanol (10 ml). The solid product produce by filtration and dried to give the desired product (1,17 g, 82%)

8-Chloro-2,3-Divertimento[b,f][1,4]oxazepine

(Structure 60 of scheme XV, where R5 = 3-F, R10 = 2-F)

A solution of 4-bromo-2-[(2,4,5-cryptorf the Nile)methylamino]phenol (1,17 g, 4.1 mmol) in DMSO (2.4 ml) and N,N-diisopropylethylamine (1.2 ml) is heated in a microwave oven at 160°C. After 5 minutes the reaction mixture allow to cool and add water. Filtration and drying gives specified in the header connection (1,03 g, 95%).

TRANS-N-(7-Chloro-12,13-debtor-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-triptorelin

(Structure 61 of scheme XV, where R5 = 12-F and R10 = 13-F)

The procedure described in example 72, to obtain TRANS-N-(7-chloro-11-fluoro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-trifurcated (structure 61 of scheme XV, where R5 = 11-F, R10 = H) of intermediate compound 8-chloro-4-Ferdinando[b,f][1,4]oxazepine (structure 60 of scheme XV)applies for the 8-chloro-2,3-Divertimento[b,f][1,4]oxazepine (structure 60 of scheme XV, where R5 = 3-F and R10 = 2-F) (1,03 g, a 3.87 mmol). The crude product is purified by column chromatography on silica gel with toluene/ethyl acetate (toluene/ethyl acetate = 9/1), with specified title compound (44 mg, 3% of the total output). Data:1H-NMR (400 MHz, CDCl3) 1,66 (DQC., J=12 and 4.5, 1H), 1,80-of 1.92 (m, 2H), 2,28-of 2.34 (m, 1H), 3,19 (m, 1H), 3,86 (m, 1H), 4,30 (d, J=10, 1H), of 4.66 (m, 1H), 6,02 (m, 1H), 6,59 (m, 1H), 6,72 (DD, J=8,8, 3,2, 1H), 6,79 (m, 1H), make 6.90 (d, J=3,2, 1H), 7,02 (d, J=8, 1H).

Example 76

TRANS-N-(7-Chloro-1,2,3,4,10,14b-hexahydro-10-methyldibenzo[b,f]pyrido[1,2-d][1,4]diazepin-1-yl)-2,2,2-triptorelin

(Structure 67 of scheme XVI)

4-Chloro-N-methyl-2-neath the o-N-phenylfenesin

(Structure 62 of scheme XVI)

4-Chloro-1-fluoro-2-nitrobenzene (20,0 g, 0.11 mol) and K2CO3(15.7 g, 0.11 mol) is dissolved in N-methyl-aniline production (37 ml, 0.34 mol)and then heated to 180°C. After 5 hours the reaction mixture is cooled to room temperature, diluted with CH2Cl2(750 ml) and washed with H2O (500 ml), aqueous citric acid solution (5%, 500 ml) and saturated brine (500 ml). The organic layer is dried (Na2SO4) and concentrate under reduced pressure. The remaining oil is subjected to chromatography on silica gel (cyclohexane/CH2Cl2, 9/1, volume/volume), with the specified header compounds containing ˜30% of the source material. The connection is then stirred into cold hexane and the resulting red crystals are filtered, resulting in a pure crystalline product (16.5 g, 57% yield). Data: melting point: 59-62°C, Rf of 0.65 (cyclohexane/ ethyl acetate, 4/1, volume/volume).

4-Chloro-N1N-methyl-N1-phenylbenzo-1,2-diamine

(Structure 63 of scheme XVI)

To a solution of 4-chloro-N-methyl-2-nitro-N-phenylenediamine (12.5 g, with 46.3 mmol) in ethanol (250 ml) is added SnCl2·2H2O (37,5 g to 0.17 mol). The solution is heated to 40°C and stirred for 6 hours. The reaction mixture was concentrated in vacuo, and then diluted with ethyl acetate (500 ml) and PR is myauth H 2O (500 ml), cold (0° (C) aqueous solution of NaOH (1 M, 200 ml), H2O (500 ml) and saturated brine (500 ml). The organic layer is dried (Na2SO4), filtered and concentrated under reduced pressure. The crude compound was placed on a column of silica gel and elute with heptane/ethyl acetate (8/2, volume/volume), getting mentioned in the title compound (9.3 g, 87% yield). Data: Rf of 0.65 (heptane/ethyl acetate, 7/3, volume/volume). (m/z = 233 (M+H)+.

N-[5-chloro-2-(methylpentylamino)phenyl]formamide

(Structure 64 of scheme XVI)

4-Chloro-N1N-methyl-N1-phenylbenzo-1,2-diamine (9.3 g, 40,1 mmol) is dissolved in formic acid (60 ml) and heated at the boil under reflux. After 2 hours the reaction mixture was concentrated in vacuo. The residue is dissolved in ethyl acetate (500 ml) and washed with aqueous solution of NaHCO3(5%, 500 ml). The organic layer is dried, filtered and concentrated under reduced pressure. The remaining oil is subjected to chromatography on silica gel (cyclohexane/CH2Cl2, 9/1, volume/volume), with the net specified in the title compound (10.4 g, 100% yield). Data: Rf 0.25 in (heptane/ethyl acetate, 3/1, volume/volume). (m/z = 261 (M+H)+.

3-Chloro-5-methyl-5H-dibenzo[b,f][1,4]diazepin

(Structure 65 of scheme XVI)

In a three-neck flask add PPA (150 g), which is then heated to 120°C and vigorously stirred POCl 3added dropwise within 90 minutes (caution: foaming), and then added to the reaction mixture formamid (10.4 g, 40,1 mmol) in 4 consecutive portions. The reaction mixture is stirred for 2 hours at 120°C, and then cooled to room temperature, carefully added to the reaction mixture an aqueous solution of NaHCO3(300 ml) and neutralized reaction mixture by further adding NaHCO3(rich) until then, until the pH ˜ 8. Then add ethyl acetate (1 l) and remove the salt by filtration. The organic layer was washed with H2O (500 ml) and saturated brine (500 ml), dried (Na2SO4), filtered and concentrated in vacuo. Purification using column chromatography on silica gel (heptane/ethyl acetate, 8/2, volume/volume) gives pure 3-chloro-5-methyl-5H-dibenzo[b,f][1,4]diazepin (8.8 g, 91% yield). (m/z = 243 (M+H)+.

TRANS-7-Chloro-1,2,3,4,10,14b-hexahydro-10-methyl-4-oxidant[b,f]pyrido[1,2-d][1,4]diazepin-1-carboxylic acid

(Structure 32 of scheme IX, where X = N(Me), R1 = H, R2 = H, R3 = Cl, R4 = H, R5 = H, R10 = H)

A solution of 3-chloro-5-methyl-5H-dibenzo[b,f][1,4]diazepine (1.0 g, 4.1 mmol) and glutaric anhydride (0.64 g, 5.6 mmol) in xylene (2.5 ml) was stirred at 140°C. After 48 hours the reaction mixture allow to cool to room temperature and add a simple ether. Filter what their network is listed in the title compound (1.1 g, 72%) as a solid product.

Methyl ester of TRANS-(7-chloro-1,2,3,4,10,14b-hexahydro-10-methyl-4-oxidant[b,f]pyrido[1,2-d][1,4]diazepin-1-yl)carbamino acid

(Structure 33 of scheme IX, where X = N(Me), R1 = H, R2 = H, R3 = Cl, R4 = H, R5 = H, R10 = H, R22 = CH3)

A common way 22 is used for TRANS-7-chloro-1,2,3,4,10,14b-hexahydro-10-methyl-4-oxidant[b,f]pyrido[1,2-d][1,4]diazepin-1-carboxylic acid (1.1 g, 3.0 mmol), and the use of methanol as the alcohol gives crude specified in the title compound (1.4 g, 100%), which is used in the next stage of the synthesis without further purification.

Methyl ester of TRANS-7-chloro-1,2,3,4,10,14b-hexahydro-10-methyldibenzo[b,f]pyrido[1,2-d][1,4]diazepin-1-yl)carbamino acid

(Structure 34 of scheme IX, where X = N(Me), R1 = H, R2 = H, R3 = Cl, R4 = H, R5 = H, R10 = H, R22 = CH3)

General method 23 is used for complex methyl ester of TRANS-7-chloro-1,2,3,4,10,14b-hexahydro-10-methyl-4-oxidant[b,f]pyrido[1,2-d][1,4]diazepin-1-yl)carbamino acid (1.4 g, 100%), with crude specified in the connection header. The residue is triturated with simple ether, obtaining specified in the connection header (0,67 g, 61%) as a solid product.

TRANS-7-Chloro-1,2,3,4,10,14b-hexahydro-10-methyldibenzo[b,f]pyrido[1,2-d][1,4]diazepin-1-amine

(Structure 35 of scheme IX, where X = N(Me), R1 = H, R2 = H, R3 = Cl, R4 = H, R5 = H, R10 = H)

General method 24 is used for complex m is delovogo ester of TRANS-7-chloro-1,2,3,4,10,14b-hexahydro-10-methyldibenzo[b,f]pyrido[1,2-d][1,4]diazepin-1-yl)carbamino acid (0,67 g, 1.8 mmol), to obtain the crude specified in the connection header in the form of a solution in ethyl acetate (100 ml). The solid material formed during storage at 5°C for 16 hours. This solid product highlight (0.15 g, 21%) and uterine fluid concentrate. The residue is treated with simple ether. The obtained solid products are removed by filtration and the filtrate is concentrated, with the additional amount specified in the title compound (0.32 g, 56%). Both parts specified in the connection header is used in the next stage without additional purification.

TRANS-N-(7-Chloro-1,2,3,4,10,14b-hexahydro-10-methyldibenzo-[b,f]pyrido[1,2-d][1,4]diazepin-1-yl)-2,2,2-triptorelin

(Structure 67 of scheme XVI)

Gettingin accordance with the General method 25, using TRANS-7-chloro-1,2,3,4,10,14b-hexahydro-10-methyldibenzo[b,f]pyrido[1,2-d][1,4]diazepin-1-amine (0.25 g, 0.69 mmol), gives crude specified in the header connection. The residue is triturated with simple ether, obtaining specified in the title compound (0.17 g, 60%) as a solid product. Data:1H-NMR (400 MHz, CDCl3) 1,62-1,89 (m, 3H), and 2.27 (DQC., J=5,0, 5,0, 12,4, 1H), 3,20 (m, 1H), 3,30 (s, 3H), 3,63 (m, 1H), 4,08 (m, 1H), 4,80 (m, 1H), 6,07 (user., 1 NH), of 6.71 -7,27 (m, 7 Aran).

Example 77

TRANS-[(7-Chloro-1,2,3,4,10,14b-hexahydro-10-methyldibenzo-[b,f]pyrido[1,2-d][1,4]diazepin-1-yl)amino]acetic acid

(Structure 69 of scheme XVI

Ethyl TRANS-[(7-chloro-1,2,3,4,10,14b-hexahydro-10-methyldibenzo[b,f]pyrido[1,2-d][1,4]diazepin-1-yl)amino]acetate

(Structure 68 scheme XVI)

To a suspension of TRANS-7-chloro-1,2,3,4,10,14b-hexahydro-10-methyldibenzo[b,f]pyrido[1,2-d][1,4]diazepin-1-ylamine (100 mg, 0.25 mmol) in DMF (2 ml) add ethylbromoacetate (56 μl, 0.51 mmol) and triethylamine (107 μl, from 0.76 mmol). The resulting reaction mixture is heated to 60°C and stirred for 5 hours. The mixture was poured into water and extracted with ethyl acetate (3x). The organic layers washed with saturated (aq. solution) NaHCO3and saturated salt solution. After drying (MgSO4) the solvents are removed under reduced pressure. The crude product is purified on silica gel with heptane/ethyl acetate, 8:2, to obtain 80 mg (80%) specified in the connection header.

TRANS-[(7-Chloro-1,2,3,4,10,14b-hexahydro-10-methyldibenzo-[b,f]pyrido[1,2-d][1,4]diazepin-1-yl)amino]acetic acid

(Structure 69 of scheme XVI)

To a solution of ethyl TRANS-[(7-chloro-1,2,3,4,10,14b-hexahydro-10-methyldibenzo[b,f]pyrido[1,2-d][1,4]diazepin-1-yl)amino]acetate (35 mg, 0.09 mmol) in dioxane (1 ml) is added 4 N. (aq. solution) NaOH (250 ml). The reaction mixture was stirred at 65°C for 1.5 hours. It is diluted with water (25 ml), after which the pH was adjusted to pH 2 2 N. (aq. solution) HCl. The mixture is extracted with ethyl acetate (2x), washed with water and saturated saline solution, dried (MgSO4and the flash steam is granted. The crude product is purified LC-MS, obtaining specified in the title compound (4 mg, 12%). Data (m/z = 372 (M+H)+.

Example 78

TRANS-N-(7-chloro-1,2,3,4,10,14b-hexahydrobenzo[b,f]pyrido[1,2-d][1,4]diazepin-1-yl)-2,2,2-triptorelin

(Structure 75 scheme XVII)

2-[(4-Chloro-2-nitrophenyl)amino]benzoic acid

(Structure 70 scheme XVII)

A solution of 4-chloro-1-fluoro-2-nitrobenzene (20 g, 114 mmol) and Anthranilic acid (17,4 g, 127 mmol) in pentanol (250 ml) is heated to 120°C in the apparatus of the Dean-stark. Add copper (126 mg, 2 mmol)and then potassium carbonate (12.7 g, 92 mmol). The resulting reaction mixture was stirred at 120°C for 0.5 hours and at 140°C for 2 hours. Then add water and 1 N. (aq. solution) NaOH to dissolve the product. Then pH was adjusted to pH 5 and the aqueous layer was extracted with ethyl acetate (3x). The combined organic layers washed with water and saturated saline solution, dried and evaporated. To the resulting product added ethanol. Specified in the title compound (14.4 g, 43%) collected by filtration ethanol mixture.

2-[(2-Amino-4-chlorophenyl)amino]benzoic acid

(Structure 71 of scheme XVI)

To a solution of 2-[(4-chloro-2-nitrophenyl)amino]benzoic acid (12.8 g, 43,7 mmol) in ethyl acetate (300 ml) is added 5% platinum sulfide on charcoal grill. The reaction mixture hydronaut at 2 bar for 5 hours. After filtrowanie is through dekalim, washing with ethyl acetate and removal of the solvent under reduced pressure, get mentioned in the title compound (11.8 g, 100%).

8-Chloro-5,10-dihydrobenzo[b,f][1,4]diazepin-11-he

(Structure 72 of scheme XVII)

A solution of 2-[(2-amino-4-chlorophenyl)amino]benzoic acid (11.8 g, 45 mmol) in xylene (150 ml) is heated at boiling under reflux in an apparatus of the Dean-stark. The reaction mixture is stirred at the boiling temperature under reflux for 31 hours. After removal of the xylene in vacuo receive specified in the header connection. If this is still present original material. For this reason, the product is again dissolved in xylene (150 ml) and continue stirring overnight at boiling point under reflux in an apparatus of the Dean-stark. After removal of the xylene under reduced pressure get mentioned in the title compound (12.4 g, and 50.6 mmol).

8-Chloro-10,11-dihydro-5H-dibenzo[b,f][1,4]diazepin

(Structure 73 scheme XVII)

THF (250 ml) cooled to 0°C, then add portions LiAlH4(6.7 g, 177 mmol). After that add portions of 8-chloro-5,10-dihydrobenzo[b,f][1,4]diazepin-11-he (12.4 g, 45 mmol), and then THF (100 ml). The resulting reaction mixture is heated at boiling under reflux and stirred for overnight at the boiling temperature under reflux. After the OHL is born of the mixture to 0° C is added dropwise a saturated (aq. solution) Na2SO4. Stirring is continued for 15 minutes, after which the reaction mixture is filtered through dekalim. Volatile products are removed under reduced pressure, to obtain crude product. To the crude product add a mixture of toluene and ethyl acetate. The solid material (5,4 g, 52%) collected by filtration, followed by drying overnight at 40°C, under reduced pressure.

8-Chloro-5H-dibenzo[b,f][1,4]diazepin

(Structure 74 scheme XVII)

To a solution of 8-chloro-10,11-dihydro-5H-dibenzo[b,f]-[1,4]diazepine (of 8.75 g of 37.9 mmol) in CH2Cl2(375 ml) add MnO2(14.5 g, 166 mmol). The reaction mixture was stirred at room temperature for 1.5 hours. After filtration through dekalim, rinsing, CH2Cl2volatile products are removed under vacuum. The crude product is dissolved in ethanol (250 ml), then add 2 N. (aq. solution) NaOH (20 ml). This mixture was stirred at room temperature for 2.5 hours. The reaction mixture was filtered through dekalim and washed with CH2Cl2. After removal of the solvent under reduced pressure the residue is dissolved in ethanol (350 ml). Add NaOH (2 N., 20 ml) and stirred the mixture for 3 hours. Water is added and the mixture extracted with ethyl acetate (3x). The combined organic layers washed with saturated saline is Astrom, dried and evaporated, to obtain specified in the connection header (8,9 g of 38.9 mmol).

TRANS-7-Chloro-1,2,3,4,10,14b-hexahydro-4-oxidant[b,f]pyrido[1,2-d][1,4]diazepin-1-carboxylic acid

(Structure 32 of scheme IX, where X = N(H), R1 = H, R2 = H, R3 = Cl, R4 = H, R5 = H, R10 = H)

This compound is obtained using the General method 21, after acidic/basic extraction of the reaction mixture get soggy specified in the title compound (4.4 g, 34%).

Methyl ester of TRANS-7-chloro-1,2,3,4,10,14b-hexahydro-4-oxidant[b,f]pyrido[1,2-d][1,4]diazepin-1-yl)carbamino acid

(Structure 33 of scheme IX, where X = N(H), R1 = H, R2 = H, R3 = Cl, R4 = H, R5 = H, R10 = H, R22 = CH3)

This compound is obtained using the General method 22. As alcohol is methanol, to obtain the crude specified in the title compound (437 mg, >100%).

Methyl ester of TRANS-7-chloro-1,2,3,4,10,14b-hexahydrobenzo[b,f]pyrido[1,2-d][1,4]diazepin-1-yl)carbamino acid

(Structure 34 of scheme IX, where X = N(H), R1 = H, R2 = H, R3 = Cl, R4 = H, R5 = H, R10 = H, R22 = CH3)

This compound is obtained using the General method of 23, with raw is specified in the title compound (0.51 g, 100%).

TRANS-7-Chloro-1,2,3,4,10,14b-hexahydrobenzo[b,f]pyrido-[1,2-d][1,4]diazepin-1-amine

(Structure 35 of scheme IX, where X = N(H), R1 = H, R2 = H, R3 = Cl, R4 = H, R5 = H, R10 = H)

To a solution of complex methyl ester of TRANS-7-chloro-1,2,3,4,10,14b-hexage is dibenzo[b,f]pyrido[1,2-d][1,4]diazepin-1-yl)carbamino acid (0.51 g, 0.95 mmol) in ethylene glycol (6 ml) is added KOH (0,37 g, 6.6 mmol). The reaction mixture is heated to 100°C and stirred overnight at 140°C. After cooling, the reaction mixture are added water and ethyl acetate. The mixture is extracted with ethyl acetate (3x). The organic layers washed with water and saturated saline solution, dried (Na2SO4) and evaporated to obtain crude product (350 mg, 100%).

TRANS-N-(7-Chloro-1,2,3,4,10,14b-hexahydrobenzo[b,f]pyrido[1,2-d][1,4]diazepin-1-yl)-2,2,2-triptorelin

(Structure 75 scheme XVII)

To a solution of TRANS-7-chloro-1,2,3,4,10,14b-hexahydrobenzo-[b,f]pyrido[1,2-d][1,4]diazepin-1-amine (structure 35 of scheme IX, where X = N(H), R1 = H, R2 = H, R3 = Cl, R4 = H, R5 = H, R10 = H) (350 mg, at 1.17 mmol) in methanol (22 ml) and triethylamine (0.7 ml) add ethyltryptamine (1.5 ml). The reaction mixture was stirred at room temperature for 3 hours. Add water and extracted with a mixture of ethyl acetate (3x). The organic layers washed with saturated salt solution, dried (Na2SO4) and evaporated. After purification on silica gel with heptane/ethyl acetate, 6:4, receive specified in the title compound (90 mg, 19%). Data:1H-NMR (400 MHz, CDCl3) was 1.69 (m, 1H), 1,86-of 1.94 (m, 2H), 2,11 (m, 1H), 2,99-to 3.09 (m, 2H), 4,47 (d, 1H), a 4.86 (m, 1H), 5,79 (s, 1H, NH), 6,62 (d, J=8,2, 1H), 6.75 in (DD, J=7,8, 1H), 6.89 in (t, J=7,8, 1H), 6,91 (DD, J=8,2, J=2,7, 1H), 7,10 (d, J=2,7, 1H), 7,18 (t, J=7,8, 1H), 7,24 (d, J=7,8, 1H).

Examples 79A and B

(1α,2; ,14bα)-N-(7-Chloro-2,3,4,14b-tetrahydro-2-methyl-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-triptorelin (structure 86 of scheme XVIII)

(1α,2α,14bα)-N-(7-Chloro-2,3,4,14b-tetrahydro-2-methyl-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-triptorelin (structure 87 of scheme XVIII)

N-(5-Chloro-2-phenoxyphenyl)formamid

(Structure 76 of scheme XVIII)

This compound is obtained using the General method 29 from 5-choir-2-phenoxybenzamine, to obtain N-(5-chloro-2-phenoxyphenyl)formamide (29.5 g, 94%). (m/z = 248 (M+H)+.

8 Chlorodibenzo[b,f][1,4]oxazepine

(Structure 77 scheme XVIII)

This compound is obtained using the General method 30, obtaining 8 chlorodibenzo[b,f][1,4]oxazepine (24.5 g, 89%). (m/z = 230 (M+H)+.

TRANS-7-Chloro-2-methyl-2,3,4,14b-tetrahydro-4-oxo-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-carboxylic acid

(Structure 78 scheme XVIII)

This compound is obtained using the General method 21, using 3-methylglutaric anhydride (4). A mixture of two isomers (1/1) (2.2 g, 66%) was obtained by crystallization from simple diethyl ether. Data: (m/z = 358 (M+H)+.

Methyl ester of TRANS-(7-chloro-2-methyl-2,3,4,14b-tetrahydro-4-oxo-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)carbamino acid

(Structure 79 of scheme XVIII)

This compound is obtained using the General method 22, by use of methanol as the alcohol, with what rucenim crude specified in the title compound (2.6 g, >100%). (m/z = 387 (M+H)+.

Methyl ester of TRANS-(7-chloro-2-methyl-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)carbamino acid

(Patterns 80, 81 and 82 of scheme XVIII)

This compound is obtained using the General method 23. The crude product is subjected to chromatography with heptane/ethyl acetate, 6:4, to obtain the complex methyl ester (1α,2β,14bα)-(7-chloro-2-methyl-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)carbamino acid (structure 82 of scheme XVII) (301 mg, 11%, TRANS) and a mixture of the other two isomers of complex methyl ester (1α,2α,14bα)-(7-chloro-2-methyl-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)carbamino acid (structure 80 scheme XVIII) and compound with methyl ether (1α,2α,14bβ)-(7-chloro-2-methyl-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)carbamino acid (structure 81 scheme XVIII) (1.6 g, 63%, TRANS and CIS). (m/z = 373 (M+H)+.

TRANS-7-Chloro-2-methyl-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine

(Patterns 83 and 84 of scheme XVIII)

This compound is obtained using the General method 24, starting from a complex mixture methyl ester (1α,2α,14bα)-(7-chloro-2-methyl-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)carbamino acid (structure 80 scheme XVII) and compound with methyl ether (1α,2α,14bβ)-(7-chloro-2-methyl-2,3,4,14b-those whom rehydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)carbamino acid (structure 81 scheme XVII), obtaining a mixture of two isomers (1α,2α,14bα)-7-chloro-2-methyl-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine (structure 83 of scheme XVII) and (1α,2α,14bβ)-7-chloro-2-methyl-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine (structure 84 scheme XVII) (1.3 g, 96%).

(1α,2β,14bα)-7-Chloro-2-methyl-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine

(Structure 85 of scheme XVII)

This compound is obtained from the complex with methyl ether (1α,2β,14bα)-(7-chloro-2-methyl-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)carbamino acid using General method 24, obtaining specified in the connection header (structure 85 of scheme XVII) (130 mg, 51%, TRANS).

(1α,2β,14bα)-N-(7-Chloro-2,3,4,14b-tetrahydro-2-methyl-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-triptorelin

(Structure 86 of scheme XVII)

This compound is obtained using the General method 25, based on the connection 85, obtaining specified in the connection header. After purification by HPLC receive (53 mg, 31%, TRANS). Data:1H-NMR (400 MHz, CDCl3) 1,02 was 1.04 (d, J=6,4, 3H), 1,58 (m, 1H), 1,78 (m, 1H), up to 1.98 (m, 1H), 3,22-of 3.31 (dt, J=12,2, J=2,2, 1H), 3,91 (m, 1H), 4,13-4,18 (d, J=10,0, 1H), 4,23-4,30 (t, J=10,0, 1H), 6,64-7,27 (7 Aran). (m/z = 411 (M+H)+.

(1α,2α,14bα)-N-(7-Chloro-2,3,4,14b-tetrahydro-2-methyl-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-yl)-2,2,2-triptorelin

This compound is obtained using the General method 25, on the basis ofmixture of isomers 83 and 84, to obtain a mixture of products 87 and 88. After purification by HPLC receive specified in the title compound (115 mg, 13%). Data:1H-NMR (400 MHz, DMSO) of 1.00 was 1.04 (d, J=7,0, 3H), 1,73-1,79 (sq, J=6,0, 2H), 2,24 to 2.35 (m, 1H), 3,31-to 3.52 (m, 2H), 4,55-4,60 (d, J=8,3, 1H)and 4.65-4.72 in (m, 1H), of 6.71-7,38 (7 Aran), 9,07-9,12 (d, J=9,8, NH). (m/z = 411 (M+H)+.

Example 80

The activity of the receptor-B of progesterone in transactionbean

(Anti-)progestogenic activity of the compounds of the present invention (EC50and own activity) is determined in a biological in vitro assays cells Chinese hamster ovary (CHO)stably transfected with a plasmid expressing the receptor-B progesterone person, and a reporter plasmid in which the MMTV-promoter linked to reporter gene luciferase. This cell line is known under the name CHO-PRB-pMMTV-LUC 1E2-A2 (Dijkema R et al. (1998) J. Steroid Biochem. Mol. Biol., 64:147-56). Cells were cultured in a modified environment Dulbecco-Needle/nutrient mixture F-12 (DMEM/HAM F12, 1:1 ratio) from Gibco (Paisley, UK), supplemented with purified calf serum, treated with activated charcoal, from Hyclone (Utah, USA).

Antiprogesterone activity of the compounds of the present invention is determined by the inhibition of TRANS-activation by receptor-B progesterone enzyme l is referaty in the presence of 1 nm (16α )-16-ethyl-21-hydroxy-19-norpregna-4-ene-3,20-dione and compared with a reference antiprogestogens (6β,11β,17β)-11-[4-(dimethylamino)phenyl]-4',5'-dihydro-6-methylspiro[östra-4,9-Dien-17,2'(3'H)-furan]-3-one, the activity of which is taken as 100%. Agonistic ligands do not inhibit the transactivation of luciferase activity induced by 0.1 nm Org 2058, while strong and weak antiprogestogen can inhibit transactivation, depending on the level of applied dose.

Progestogenic activity with EC50in the range between 10000 and 100 nm found for the compounds of examples 1, 3, 5, 9, 10, 12, 14, 15, 16, 17, 18, 27, 28, 30, 31, 36, 37, 39, 40, 42B, 43, 44, 48, 49, 50, 56, 64 and 67. Connection examples 11, 13, 21, 24, 29, 38A, 45, 46, 55, 62, 68, 69, 70, 72, 74, 78 and 79B show EC50in the range between 100 and 10 nm, whereas the compounds of examples 6, 7, 8, 13 (1S,14bR isomer), 19, 20, 22, 23, 25, 26, 38B, 41, 42A, 47, 51, 52, 53, 54, 57, 58, 59, 60, 61, 63, 71, 73, 75, 76 and 79A exhibit EC50< 10 nm. Own activity in relation to (16α)-16-ethyl-21-hydroxy-19-norpregna-4-ene-3,20-dione is >10% in all the investigated compounds.

Antiprogesterone activity with EC50in the range between 10000 and 100 nm found for the compounds of examples 5, 9, 10, 15, 21, 32, 33, 35, 38A, 39 and 41. The compounds of examples 7, 8, 11, 22 (1S,14bR isomer), 29, 48 and 49 show EC50in the range between 100 and 10 nm, while the compound of example 13 (1S,14bR isomer) demonstrates EC 50< 10 nm. Own activity in relation to (6β,11β,17β)-11-[4-(dimethylamino)phenyl]-4',5'-dihydro-6-methylspiro[östra-4,9-Dien-17,2'(3'H)-furan]-3-ONU is >15% in all the investigated compounds.

1. The compound of General formula I

or its pharmaceutically acceptable salt,

where R1, R3, R4, R5 and R10 independently are selected from the group consisting of H, halogen, (1-4C)alkyl, (2-4C)alkenyl, CN, O(1-4C)alkyl, C(O)(1-4C)alkyl and NR19R20,

R2 is selected from the group consisting of H, halogen, NO2and NR11R12,

R6 is selected from the group consisting of H, C(Y)R15, C(O)OR16, C(S)NR17, (1-6C)alkyl, (1-6C)alkoxy-substituted (1-4C)alkyl and (CH2)nC(O)OR21,

R7 represents H or R7 is selected from the group consisting of (1-4C)alkyl and (2-4C)alkenyl, all of which are optionally substituted by one or more halogen atoms,

R8 and R9 represent H,

R11 and R12 independently are selected from the group consisting of H, (1-6C)alkoxycarbonyl, (1-4C)alkylsulfonyl and (6-10C)arylsulfonyl,

R15 represents H or R15 is selected from the group consisting of (1-6C)alkyl, (6-10C)aryl, 1,4-bisaria, amino(1-4C)alkyl, hydroxy(1-4C)alkyl and carboxy(1-4C)alkyl, all of which are optionally substituted by one or more halogen atoms,

R16 represents (1-6C)Alky is, optionally substituted by one or more halogen atoms,

R17 is selected from the group consisting of (1-4C)alkyl, (2-4C)alkenyl,

(2-4C)quinil and (3-6C)cycloalkyl, all of which are optionally substituted by one or more halogen atoms,

X is selected from the group consisting of O, S, CH2and NR18,

Y is selected from the group consisting of O, S, and NH,

R18 is selected from the group consisting of H and (1-4C)alkyl,

R19 is selected from the group consisting of H and (1-4C)alkyl,

R20 is selected from the group consisting of N, CH2(6-10C)aryl and C(O)(1-6C)alkyl,

R21 represents H,

m is 0, 1 or 2, and

n is 1, 2 or 3, provided that

(i) when X represents O, R1-R5 are H, R8-R10 represent H, R6 represents ethyl or C(O)CH3then R7 is not H;

(ii) when X represents O, R1-R5 are H, R8-R10 represent H, R6 represents methyl, then R7 is not a stands;

(iii) when X represents O, R1-R5 are H, R8-R10 are H, and R6 represents H, then R7 is not H, ethyl or (CO)CH3.

2. The compound according to claim 1, where R2 is selected from the group consisting of H, halogen, NO2and NR11R12 and

R11 and R12 independently are selected from the group sotoyama is from N, (1-6C)alkoxycarbonyl, (1-4C)alkylsulfonyl and (6-10C)arylsulfonyl.

3. The compound according to claim 1 or 2, where R1 and R5 are H, and R3 and R4 are selected from H or halogen.

4. The compound according to claim 1 or 2, where X is selected from the group consisting of O, S and CH3.

5. The compound according to claim 1 or 2, where R6 is selected from H or C(Y)R15, and R15 represents (1-4C)alkyl, optionally substituted by one or more halogen atoms, or N.

6. The compound according to claim 1 or 2, where X represents O or CH3R2 is selected from the group consisting of H, halogen and NO2and R15 represents (1-2C)alkyl, optionally substituted by one or more halogen atoms.

7. Compounds according to claim 1 or 2, where R11 is H, R12 is selected from the group consisting of (1-6C)alkoxycarbonyl, (1-4C)alkylsulfonyl and (6-10C)arylsulfonyl.

8. The compound according to claim 1 or 2, where R2 represents H, R3 represents halogen, R15 is a methyl, optionally substituted by 1-3 halogen atoms, Y represents O or S.

9. The compound according to claim 1 or 2, where R4 represents H, X represents O.

10. The compound according to claim 1, where R2 represents H or halogen,

R3 and/or R4 independently are selected from the group consisting of H, CN, halogen, (2-4C)alkenyl and C(O)(1-4C)alkyl, R5 and/or R10 are independently selected from H or halogen.

11. The compound according to claim 1 ili, where X is selected from the group consisting of O, S and NCH3.

12. The compound according to claim 1 or 10, where R8 and R9 represent N.

13. The compound according to claim 1 or 10, where R6 represents H or C(Y)R15, and R15 represents (1-4C)alkyl, optionally substituted by one or more halogen atoms, or N.

14. The compound according to claim 1 or 10, where Y is O or S, R15 represents methyl, optionally substituted by one or more halogen atoms.

15. The compound according to any one of claims 1 to 14 for use as a drug with activity against progesterone receptor.



 

Same patents:

FIELD: organic chemistry.

SUBSTANCE: invention relates to bicyclic 1,4-piridotiazine-1,1-dioxides of general formula I wherein R1 is chlorine or fluorine; R2 is linear or branched alkyl, cycloalkyl, optionally reduced aryl or heteroaryl, etc. Method for production of said compounds includes reaction of acyclic sulfones with primary alcohols, preferably in presence of inorganic or organic such as carbonates or alkali metal hydroxides tertiary organic amines or base mixtures, preferably in aprotic bipolar media without solvents, or mixture thereof with water.

EFFECT: safe method for production of new compounds useful as drugs.

2 cl, 2 ex

FIELD: medicine.

SUBSTANCE: compound is represented by structural formula

or its pharmaceutically permissible salts, where R1 is the hydrogen atom (1), C1-8acyl(2), hydroxyl (3), halogen atom (5), C2-8acyl (3), C1-8-alcocsy (4), substituted with phenyl or C2-8acyl, substituted with NR2R3; R2R3 independently represent hydrogen atom (1) or C1-8acyl(2), X and Y each independently representing C (1), CH (2) or N (3). is (1) single or (2) double bond. is 5-7-member carbocyclic group or 5-7-member partially or fully saturated heterocyclic group defined in claim 1 of invention. A is one of A1 to A5 groups defined by claim 1 of the invention. The compounds show inhibiting properties relative to poly(ADP-ribose)polymerase are usable as prophylactic and/or curative drugs for treating ischemic diseases (in brain, spinal cord, heart, digestive tract, skeletal muscle, eye retina, e.t.c.), inflammatory diseases (intestinal inflammation, disseminated sclerosis, arthritis, e.t.c.), neurodegenerative disorders (extrapyramidal disorder, Alzheimer disease, muscle dystrophy, cerebrospinal canal stenosis in lumbar segment of the vertebral column, e.t.c.), diabetes, stroke, cerebral injury, hepatic insufficiency, hyperalgesia, e.t.c. The compounds are also of use in struggling against retroviruses (HIV and others), as sensitizing agents for treating cancer cases and immunodepressant agents.

EFFECT: enhanced effectiveness of treatment.

19 cl, 90 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel lactam compounds of the formula (I) or their pharmaceutically acceptable salts wherein A means phenyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl; R2, R3 and R4 can be similar or different and mean independently of one another hydrogen atom (H), halogen atom, -OH, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, -NH2, -NO2, -CF3, phenyl that can comprise substitute(s), benzyloxy-group that can comprise substitute(s), pnehylvinyl, and one among R2, R3 and R4 means -CF3-O- and others mean H; B means phenyl that can comprises substitute(s), monocyclic aliphatic (C3-C8)-ring, dihydropyrane ring; -X- and -Y- xan be similar or different and they mean independently -O-, -NH-, -NR5-, -S-; Z means -CH2-, -NH-; W means -NR1-, -CR8R9- wherein R1 means H; R8 and R9 are similar or different and mean H; wherein R5 represents a linear alkyl group that can comprise substitute(s), (C1-C8)-linear or branched alkoxycarbonyl group, acyl group chosen from formyl group, acyl group comprising (C1-C6)-alkyl, (C1-C6)-alkenyl or (C1-C6)-alkynyl group that can comprise substitute(s), carbamoyl group comprising (C1-C6)-alkyl group at nitrogen atom that can comprise substitutes, sulfonyl group comprising (C1-C6)-alkyl group at sulfur atom that can comprise substitute(s); each among a, b and c represents position of carbon atom under condition that: (i) substitute(s) is chosen from the group comprising halogen atom, -OH, (C1-C6)-alkyl, mercapto-group, (C1-C6)-alkoxy-group, -NO2, -COOH, -CF3, phenyl, -NH2, (C1-C8)-linear or branched alkoxycarbonyl group, (C1-C8)-linear or branched acyl group, (C1-C8)-linear or branched acyloxy-group; (ii) when B represents benzene ring, each among -X- and -Y- represents -NH-, -Z- represents -CH2- and -W- represents -NH- then R2, R3 and R4 can not mean phenyl group, 4-bromophenyl group, 4-hydroxyphenyl group, 4-methoxyphenyl group, 2-hydroxyphenyl group, 3,4-dimethoxyphenyl group or 3-methoxy-4-hydroxyphenyl group. Compounds of the formula (I) show the enhanced capacity for transport of sugar and can be used in pharmaceutical compositions for prophylaxis and/or treatment of diabetes mellitus and diabetic nephropathy.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

19 cl, 21 tbl, 54 ex

FIELD: organic chemistry, herbicides.

SUBSTANCE: invention relates to a compound of the general formula [I]: wherein R1 and R2 can be similar or different and each represents (C1-C10)-alkyl group; each among R3 and R4 represents hydrogen atom; R5 and R6 can be similar or different and each represents hydrogen atom or (C1-C10)-alkyl group; Y represents 5-6-membered aromatic heterocyclic group or condensed aromatic heterocyclic group comprising one or some heteroatoms chosen from nitrogen atom, oxygen atom and sulfur atom wherein heterocyclic group can be substituted with 0-6 of similar or different groups chosen from the following group of substitutes α, and so on; n means whole values from 0 to 2; [Group of substitutes α]: hydroxyl group, halogen atoms, (C1-C10)-alkyl groups, (C1-C10)-alkyl groups wherein each group is monosubstituted with group chosen from the following group of substitutes β, (C1-C4)-halogenalkyl groups, (C3-C8)-cycloalkyl groups, (C1-C10)-alkoxy-groups, (C1-C10)-alkoxy-groups wherein each group is monosubstituted with group chosen from the following group of substitutes and so on; [Group of substitutes β]: hydroxyl group, (C3-C8)-cycloalkyl groups that can be substituted with halogen atom or alkyl group, (C1-C10)-alkoxy-group, (C1-C10)-alkylthio-groups, (C1-C10)-alkylsulfonyl groups, (C1-C10)-alkoxycarbonyl groups, amino-group, carbamoyl group (wherein its nitrogen atom can be substituted with similar or different (C1-C10)-alkyl groups), (C1-C6)-acyl groups, (C1-C10)-alkoxyimino-groups, cyano-group, optionally substituted phenyl group; [Group of substitutes γ]: optionally substituted phenyl group, optionally substituted aromatic heterocyclic groups, cyano-group. Also, invention relates to herbicide comprising derivative of isoxazoline of the formula [I] as an active component or its pharmaceutically acceptable salt. Invention provides the development of isoxazoline derivative possessing the herbicide activity with respect to resistant weeds, selectivity for cultural crop and weed.

EFFECT: valuable herbicide properties of substances.

18 cl, 24 tbl, 106 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new 2-amino-4-acetyl-7-bromo-8b-hydroxy-3a,8b-dihydroxytiazolo[5,4-b]indole of formula useful in liver protection from poisoning with carbon tetrachloride. Said compound has boiling point of 174-175°C (decomposition) and LD50 of 1950±180 mg/kg. Method for production of claimed compound also is disclosed.

EFFECT: new compound for liver protection from poisoning with carbon tetrachloride.

2 ex, 1 tbl

FIELD: organic chemistry, medicine, pulmonology.

SUBSTANCE: invention relates to a new chemical compound, namely, 7-bromo-4-acetylthiazolo[5,4-b]indol-2-succinimide of the formula: that is able to protect body against hypoxia and possesses the curative effect in lung toxic edema. The melting point of this compound is 267-269°.

EFFECT: valuable medicinal properties of compound.

2 tbl, 1 ex

FIELD: organic chemistry, medicine, pulmonology.

SUBSTANCE: invention relates to a new chemical substance, namely, 4-acetylthiazolo[5,4-b]indol-2-succinimide of the formula: that is able to protect body against hypoxia and possesses the prophylactic effect in lung toxic edema. The melting point of this substance is 264-265°C.

EFFECT: valuable medicinal properties of compound.

2 tbl, 1 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a new 2-amino-4-acetyl-7-bromo-8b-hydroxy-3a,8b-dihydrothiazolo[5,4-b]indole hydrobromide of the formula (1) that is able to protect body against hypoxia and liver against poisoning with carbon tetrachloride. The melting point of this compound is 266-267°C (with decomposition). The compound is synthesized from 1-acetyl-5-bromo-3-indolinone and elemental bromine in dioxane medium followed by addition of thiourea in isopropyl alcohol.

EFFECT: valuable medicinal properties of compound.

2 tbl, 1 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel anellated carbamoylazaheterocycles of the general formula (1) that possess inhibitory property of kinase activity and eliciting, for example, an anticancer activity. Also, compounds can be used as agonists, antagonists, receptor modulating agents, antiparasitic and antibacterial agents. Also, invention relates to a method for synthesis of compounds of the formula (1), a pharmaceutical composition based on thereof and a focused library for assay of leader-compounds. In compounds of the general formula (1) W represents 6-oxopiperazine, [1,4]-thiazepane, [1,4]-oxazepane or [1,4]-diazepane cycle anellated with at least one optionally substituted and optionally condensed heterocycle or carbocycle Q; Q represents optionally substituted thiophene, optionally substituted pyrrole, optionally substituted imidazole, optionally substituted thiazole, optionally substituted pyrrolidine, optionally substituted indole, optionally substituted benzofuran, optionally substituted pyridine, optionally substituted quinoline, optionally substituted benzene or optionally substituted naphthalene cycle; R1, R2 and R represent independently of each another hydrogen atom, inert substitute, optionally substituted (C1-C6)-alkyl, optionally substituted (C3-C8)-cycloalkyl, optionally substituted phenyl, optionally substituted aryl, optionally substituted heterocyclyl.

EFFECT: improved preparing method, valuable biological and medicinal properties of compounds and pharmaceutical composition.

15 cl, 5 tbl, 6 ex

FIELD: medicine, pharmacology, organic chemistry.

SUBSTANCE: invention relates to using 2-amino-4-acetyl-8b-hydroxy-3a,8b-dihydrothiazole[5,4-d]indole as a substance protecting body against hypoxia effect. Invention provides enhanced effectiveness of the protection effect.

EFFECT: enhanced effectiveness of effect of agent.

1 tbl, 1 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new method for production of E-2-aroylmethylene-1-phenyl-1,2,3,4-tetrahydroquinazolin-4-ones of general formula I wherein R represents H, methyl, Cl. Claimed method includes interaction of 5-aryl-2,3-dihydro-2,3-furandiones with N-phenylanthranyl acid amide in medium of inert aprotic solvent (preferably benzene) followed by isolation of target products. Process is carried out preferably at 79-80°C. Claimed compounds have fluorescent properties and are useful in labeling and copying agents, intermediates for synthesis of new heterocyclic compounds, etc.

EFFECT: new fluorescent compounds.

3 cl, 1 dwg, 3 ex

FIELD: organic chemistry, antibacterial agents.

SUBSTANCE: invention relates to an agent used against acid-resistant microorganisms containing derivative of pyridone carboxylic acid as an active component, its pharmaceutically acceptable salt or its hydrate that elicits high antibacterial activity against Mycobacterium tuberculosis and atypical acid-resistant microorganisms. Invention describes agent used against acid-resistant microorganisms containing compound represented by the following formula (I) its salt or its hydrate as an active component wherein R1 represents cyclic alkyl group comprising 3-6 carbon atoms that can comprise substitute(s) chosen from halogen atom; R2 represents hydrogen atom; R3 represents hydrogen atom; A1 represents incomplete structure represented by the formula (2): wherein X2 represents halogen atom, alkyl group comprising 1-6 carbon atoms or alkoxy-group comprising 1-6 carbon atoms; A1, A2 and A3 form incomplete structure of the formula: in common with carbon atoms combined with them; X1 represents halogen atom; Y represents hydrogen atom; Z represents phenylpiperazine substitute. Invention provides synthesis of pyridone carboxylic acid eliciting high antibacterial activity against Mycobacterium tuberculosis and atypical acid-resistant microorganisms in combination with good pharmacokinetics indices and safety.

EFFECT: valuable biological property of agent.

10 cl, 9 tbl, 10 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to a synthetic quinolone agent that is effective as medicinal agents, veterinary preparations, drugs used in fishing industry or as antibacterial preserving agents. Invention describes compound represented by the following general formula (I): as its separate isomers or their mixture, its salt and their hydrates wherein R1 represents cyclic alkyl group comprising 3-6 carbon atoms that can comprise a substitute chosen from halogen atom; R2 represents hydrogen atom; R3 represents hydrogen atom; R4 represents hydrogen atom, amino-group, hydroxyl group; A represents nitrogen atom or part of structure as given in the invention claim; each R5 and R6 represents independently alkyl group comprising 1-6 carbon atoms or hydrogen atom; n means a whole number 1 or 2. Also, invention describes antibacterial agent and therapeutic agent based on compounds of the formula (I) used in treatment of infectious disease, a method for preparing antibacterial agent, a method for preparing a medicinal agent used in treatment of infectious disease and using compound of the formula (I) for preparing an antibacterial agent and using compound of the formula (I) for preparing a medicinal agent used in treatment of infectious disease. Invention provides novel compounds possessing useful biological properties.

EFFECT: improved preparing method of agents, valuable medicinal properties of compounds and agents.

35 cl, 2 tbl, 15 ex

FIELD: chemistry of heterocyclic compounds, antibacterial agents.

SUBSTANCE: invention relates to agent used against acid-resistant microorganisms. Invention describes agent against acid-resistant microorganisms containing as an active component the compound represented by the general formula (1) or its hydrate wherein R2 represents hydrogen atom; R3 represents hydrogen atom; A1, A2 and A3 form incomplete structure of the formula: wherein A1 represent incomplete structure of the formula: wherein X2 and above described R1 can be combined to form six-membered cyclic structure comprising part of the parent nucleus wherein formed ring can comprise oxygen atom and, except for, can comprise alkyl group having 1-6 carbon atoms as a substitute; X1 represents halogen atom, hydrogen atom or amino-group; Y represents hydrogen atom; Z represents incomplete structure of the formula: . Agent elicits high antibacterial activity of broad spectrum and possesses good pharmacokinetics and safety also.

EFFECT: improved and valuable properties of agent.

3 cl, 9 tbl, 10 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel lactam compounds of the formula (I) or their pharmaceutically acceptable salts wherein A means phenyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl; R2, R3 and R4 can be similar or different and mean independently of one another hydrogen atom (H), halogen atom, -OH, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, -NH2, -NO2, -CF3, phenyl that can comprise substitute(s), benzyloxy-group that can comprise substitute(s), pnehylvinyl, and one among R2, R3 and R4 means -CF3-O- and others mean H; B means phenyl that can comprises substitute(s), monocyclic aliphatic (C3-C8)-ring, dihydropyrane ring; -X- and -Y- xan be similar or different and they mean independently -O-, -NH-, -NR5-, -S-; Z means -CH2-, -NH-; W means -NR1-, -CR8R9- wherein R1 means H; R8 and R9 are similar or different and mean H; wherein R5 represents a linear alkyl group that can comprise substitute(s), (C1-C8)-linear or branched alkoxycarbonyl group, acyl group chosen from formyl group, acyl group comprising (C1-C6)-alkyl, (C1-C6)-alkenyl or (C1-C6)-alkynyl group that can comprise substitute(s), carbamoyl group comprising (C1-C6)-alkyl group at nitrogen atom that can comprise substitutes, sulfonyl group comprising (C1-C6)-alkyl group at sulfur atom that can comprise substitute(s); each among a, b and c represents position of carbon atom under condition that: (i) substitute(s) is chosen from the group comprising halogen atom, -OH, (C1-C6)-alkyl, mercapto-group, (C1-C6)-alkoxy-group, -NO2, -COOH, -CF3, phenyl, -NH2, (C1-C8)-linear or branched alkoxycarbonyl group, (C1-C8)-linear or branched acyl group, (C1-C8)-linear or branched acyloxy-group; (ii) when B represents benzene ring, each among -X- and -Y- represents -NH-, -Z- represents -CH2- and -W- represents -NH- then R2, R3 and R4 can not mean phenyl group, 4-bromophenyl group, 4-hydroxyphenyl group, 4-methoxyphenyl group, 2-hydroxyphenyl group, 3,4-dimethoxyphenyl group or 3-methoxy-4-hydroxyphenyl group. Compounds of the formula (I) show the enhanced capacity for transport of sugar and can be used in pharmaceutical compositions for prophylaxis and/or treatment of diabetes mellitus and diabetic nephropathy.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

19 cl, 21 tbl, 54 ex

FIELD: organic chemistry, herbicides.

SUBSTANCE: invention relates to a compound of the general formula [I]: wherein R1 and R2 can be similar or different and each represents (C1-C10)-alkyl group; each among R3 and R4 represents hydrogen atom; R5 and R6 can be similar or different and each represents hydrogen atom or (C1-C10)-alkyl group; Y represents 5-6-membered aromatic heterocyclic group or condensed aromatic heterocyclic group comprising one or some heteroatoms chosen from nitrogen atom, oxygen atom and sulfur atom wherein heterocyclic group can be substituted with 0-6 of similar or different groups chosen from the following group of substitutes α, and so on; n means whole values from 0 to 2; [Group of substitutes α]: hydroxyl group, halogen atoms, (C1-C10)-alkyl groups, (C1-C10)-alkyl groups wherein each group is monosubstituted with group chosen from the following group of substitutes β, (C1-C4)-halogenalkyl groups, (C3-C8)-cycloalkyl groups, (C1-C10)-alkoxy-groups, (C1-C10)-alkoxy-groups wherein each group is monosubstituted with group chosen from the following group of substitutes and so on; [Group of substitutes β]: hydroxyl group, (C3-C8)-cycloalkyl groups that can be substituted with halogen atom or alkyl group, (C1-C10)-alkoxy-group, (C1-C10)-alkylthio-groups, (C1-C10)-alkylsulfonyl groups, (C1-C10)-alkoxycarbonyl groups, amino-group, carbamoyl group (wherein its nitrogen atom can be substituted with similar or different (C1-C10)-alkyl groups), (C1-C6)-acyl groups, (C1-C10)-alkoxyimino-groups, cyano-group, optionally substituted phenyl group; [Group of substitutes γ]: optionally substituted phenyl group, optionally substituted aromatic heterocyclic groups, cyano-group. Also, invention relates to herbicide comprising derivative of isoxazoline of the formula [I] as an active component or its pharmaceutically acceptable salt. Invention provides the development of isoxazoline derivative possessing the herbicide activity with respect to resistant weeds, selectivity for cultural crop and weed.

EFFECT: valuable herbicide properties of substances.

18 cl, 24 tbl, 106 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to using phenylethenyl- or phenylethynyl-derivatives as antagonists of glutamates receptors. Invention describes using compound of the general formula (I):

wherein each among R1, R2, R3, R4 and R5 means independently of one another hydrogen atom, (C1-C6)-alkyl, -(CH2)n-halogen, (C1-C6)-alkoxy-group, -(CH2)n-NRR', -(CH2)n-N(R)-C(O)-C1-C6)-alkyl, phenyl or pyrrolyl that can be unsubstituted or substituted with one or more (C1-C6)-alkyl; each among R, R' and R'' means independently of one another hydrogen atom or (C1-C6)-alkyl; A means -CH=CH- or C≡C; B means ,, , , or wherein R6 means hydrogen atom, (C1-C)-alkyl, -(CH2)n-C(O)OR, or halogen atom; R7 means hydrogen atom, (C1-C6)-alkyl, -(CH2)n-C(O)OR', halogen atom, nitro-group or oxodiazolyl group that can be unsubstituted or substituted with (C1-C6)-alkyl or cycloalkyl; R8 means hydrogen atom, (C1-C6)-alkyl, -(CH2)n-OH, -(CH2)n-C(O)OR'' or phenyl; R9 means (C1-C6)-alkyl; R10 and R11 mean hydrogen atom; R12 means -(CH2)n-N(R)-C(O)-(C1-C6)-alkyl; R13 means hydrogen atom; each R14, R15, R16 and R17 independently of one another means hydrogen atom or (C1-C6)-alkoxy-group; each R18, R19 and R20 independently of one another means hydrogen atom; R21 means hydrogen atom or (C1-C6)-alkyl; R22 means hydrogen atom, (C1-C6)-alkyl or (C1-C6)-alkyl comprising one or more substitutes chosen from groups hydroxy- or halogen atom; R23 means hydrogen atom, (C1-C6)-alkanoyl or nitro-group; each among R24, R25 and R26 independently of one another means hydrogen atom or (C1-C6)-alkyl; n = 0, 1, 2, 3, 4, 5 or 6; X means -O- or -S-; Y means -CH= or -N=, and its pharmaceutically acceptable salts used in preparing medicinal agents designates for treatment or prophylaxis of disorders mediated by mGluR5-receptors. Also, invention describes compounds of the formula (I-A), compound of the formula (I-B-1) given in the invention description, and a medicinal agent used in treatment or prophylaxis of disorders mediated by mGluR5-receptors.

EFFECT: valuable medicinal properties of compounds.

44 cl, 1 tbl, 44 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel anellated carbamoylazaheterocycles of the general formula (1) that possess inhibitory property of kinase activity and eliciting, for example, an anticancer activity. Also, compounds can be used as agonists, antagonists, receptor modulating agents, antiparasitic and antibacterial agents. Also, invention relates to a method for synthesis of compounds of the formula (1), a pharmaceutical composition based on thereof and a focused library for assay of leader-compounds. In compounds of the general formula (1) W represents 6-oxopiperazine, [1,4]-thiazepane, [1,4]-oxazepane or [1,4]-diazepane cycle anellated with at least one optionally substituted and optionally condensed heterocycle or carbocycle Q; Q represents optionally substituted thiophene, optionally substituted pyrrole, optionally substituted imidazole, optionally substituted thiazole, optionally substituted pyrrolidine, optionally substituted indole, optionally substituted benzofuran, optionally substituted pyridine, optionally substituted quinoline, optionally substituted benzene or optionally substituted naphthalene cycle; R1, R2 and R represent independently of each another hydrogen atom, inert substitute, optionally substituted (C1-C6)-alkyl, optionally substituted (C3-C8)-cycloalkyl, optionally substituted phenyl, optionally substituted aryl, optionally substituted heterocyclyl.

EFFECT: improved preparing method, valuable biological and medicinal properties of compounds and pharmaceutical composition.

15 cl, 5 tbl, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of benzoxazepine and describes derivative of benzoxazepine of the general formula (I): wherein X represents -CO or -SO2; R1, R2, R3 and R4 are chosen independently from hydrogen atom (H), (C1-C4)-alkyl, (C1-C4)-alkoxy-group, (C1-C4)-alkyloxy-(C1-C4)-alkyl, -CF3, halogen atom, nitro-group, cyano-group, -NR8R9, -NR8COR10 and -CONR8R9; R5, R6 and R7 represent independently hydrogen atom (H) or (C1-C4)-alkyl; R8 and R9 represent independently hydrogen atom (H) or (C1-C4)-alkyl; or R8 and R9 in common with nitrogen atom to which they are bound form 5- or 6-membered saturated heterocyclic ring comprising optionally the additional heteroatom chosen from oxygen atom (O), sulfur atom (S) or the group -NR11; R10 represents (C1-C4)-alkyl; R11 represents (C1-C4)-alkyl; A represents residue of 4-7-membered saturated heterocyclic ring comprising optionally oxygen atom wherein ring is substituted optionally with 1-3 substitutes chosen from (C1-C4)-alkyl, (C1-C4)-alkoxy-, hydroxy-group, halogen atom and oxo-group, or to its pharmaceutically acceptable salt under condition that compounds of the formula (I) are excluded wherein X represents -CO, and each among R1-R7 represents hydrogen atom (H), and A represents -(CH2)3 or -(CH2)4; compounds of the formula (I) wherein X represents -CO; R1 represents hydrogen atom (H); R2 represents methyl (CH3); each among R3-R7 represents hydrogen atom (H), and A represents -(CH2)3; compounds of the formula (I) wherein X represents -CO; R1 and R2 represent hydrogen atom (H); R3 represents methyl; each among R4-R7 represents hydrogen atom (H), and A represents -(CH2)3; compounds of the formula (I) wherein X represents -CO; each among R1-R3 represents hydrogen atom (H); R4 represents methyl; each among R5-R7 represents hydrogen atom (H), and A represents -(CH2)3, and compounds of the formula (I) wherein X represents -CO; each among R1-R4 represents hydrogen atom (H); R5 represents methyl; R6 and R7 represent hydrogen atom (H), and A represents -(CH2)3. Also, invention describes pharmaceutical compositions comprising indicated derivatives and using these benzoxazepine derivatives in treatment of neurological diseases and psychotic disorders sensitive to enhancing responses mediated by AMPA receptors in the central nervous system. Invention provides preparing new compounds possessing the useful biological properties.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

8 cl, 1 tbl, 31 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new amide derivatives of carboxylic acid that are antagonists of NMDA receptors of the formula (I): , wherein one radical among R1, R2, R3 and R4 represents -OH or NH2-group and others are hydrogen atoms; or two adjacent groups R1, R2, R3 and R4 in this case in common with one or more similar or different additional heteroatoms and -CH= and/or -CH2-groups form 5-6-membvered homo- or heterocyclic ring but preferably pyrrole, pyrazole, imidazole, oxazole, oxooxazolidine or 3-oxo-1,4-oxazine ring; two other groups among R1, R2, R3 and R4 radicals represent hydrogen atoms; R5 and R6 in common with nitrogen atom between them form saturated or unsaturated 4-6-membered heterocyclic ring that is substituted with phenoxy-, phenyl-[(C1-C4)-alkoxy]-, phenoxy-[(C1-C4)-alkyl]-, benzoyl-group optionally substituted in aromatic ring with one or more halogen atoms, (C1-C4)-alkyl or (C1-C4)-alkoxy-group; X and Y mean independently oxygen, nitrogen atom or group -CH=, and to their salts formed with acids and bases. Also, invention relates to a method for preparing compounds of the formula (I) and pharmaceutical compositions showing activity as selective antagonists of NR2B receptor based on these compounds. Invention provides preparing new compounds and pharmaceutical compositions based on thereof for aims in treatment of the following diseases: chronic neurodegenerative diseases, chronic painful states, bacterial and viral infections.

EFFECT: improved preparing method, valuable medicinal properties of compounds and compositions.

11 cl, 2 tbl, 27 ex

FIELD: organic chemistry, pharmaceuticals.

SUBSTANCE: invention relates to compounds of formula I , wherein substituents meanings are as defined in specification, and pharmaceutically acceptable salts or individual diastereomers thereof. Claimed compounds are useful as CGRP receptors antagonists in treatment or prophylaxis of headache, migraine, etc. Also disclosed are pharmaceutical compositions containing such compounds and uses thereof in treatment or prophylaxis of abovementioned diseases mediated by CGRP.

EFFECT: new CGRP receptor antagonists.

5 cl, 6 tbl, 40 ex

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