The method of deriving 8-cyclopentyl-6-ethyl-3- (substituted)-5,8-dihydro-4h-1,2,3 and 7,8-pentasa - as - indacene (options) and intermediate compounds

 

(57) Abstract:

Describes an improved method of obtaining (and its variants) derivatives of 8-cyclopentyl-6-ethyl-3-(substituted)-5,8-dihydro-4H-1,2,3 a, 7,8-pentasa-as-indacene formula (1.0.0) and its pharmaceutically acceptable salts, R1is (C1-C6) alkyl, or saturated or unsaturated (C4-C7) heterocyclyl containing one atom S, and the above-mentioned alkyl and heterocyclic group optionally is substituted from 1 to 3 substituents, independently selected from (C1-C2) alkyl, trifloromethyl and halogen, wherein on the basis of caprolactone and n-methoxybenzylamine multistage synthesis through the new intermediate compounds of formula (8.1.0), (8.1.1) and (10.0.0). Target product, obtained by the described method is an inhibitor of type IV (PDE4) phosphodiesterase and production of tumor necrosis factor (TNF) and are useful for the treatment of asthma, bronchitis, allergic rhinitis, psoriasis, dermatitis and other inflammatory, allergic and immunologic diseases. 5 S. and 2 C.p. f-crystals, 1 PL.

< / BR>
< / BR>
< / BR>

Link to consider simultaneously the application

Reference is made to the considered Okara 1996, which discloses tricyclic 5,6-dihydro-N-pyrazolo[3,4-C] -1,2,4-triazolo[4,3-a] pyridine having a biological activity as inhibitors of type IV (PDE4) phosphodiesterase and production of tumor necrosis factor (TNF), are useful for the treatment of asthma, bronchitis, chronic obstructive pulmonary disease, allergic rhinitis, psoriasis, dermatitis, rheumatoid arthritis and other inflammatory, allergic and immunologic diseases and conditions. Several methods for obtaining the tricyclic compounds described in them, but nothing that describes not would an ordinary specialist in the improved method of the present invention.

PRIOR ART

The class of compounds obtained in accordance with the present invention, has been named here as an 8-cyclopentyl-6-ethyl-3-[substituted]-5,8-dihydro-4H-1,2,3 a, 1,8-pentasa-as-indacene, although this class of compounds, which is tricyclic, was named in the art 5,6-dihydro-N-pyrazolo[3,4-C]-1,2,4-triazolo[4,3-a]pyridine. What would be the preferred way specified class of compounds was not called, however, the compounds obtained in accordance with the method of the present invention represented by the following formula (1.0.0):
1-C4)alkoxy; a (C1-C4)alkoxy(C1-C6)alkyl, (C2-C8)alkenyl; (C3-C7)cycloalkyl and 1'-methyl; (C4-C7)cycloalkyl(C1-C2)alkyl; a saturated or unsaturated (C4-C7)heterocyclic-(CH2)m-group where m is 0, 1 or 2, comprising one or two heteroatoms selected from 0, S, S(=0)2, N, NR3, O and N, or NR3, S, or S(=O)2and N or NR3and N or NR3and N or NR3where R3is hydrogen or (C1-C4)alkyl; and groups of formula (1.1.0):

< / BR>
where a equals 1-5, and b and C are 0 or 1; R5represents hydrogen, hydroxy, (C1-C4)alkyl, (C2-C4)alkenyl, (C1-C4)alkoxy, (C3-C6) cycloalkane, halogen, trifluoromethyl, CO2R3a, CONR3aR3b, NR3aR3b, NO2or SO2NR3aR3b; where R3aand R3bare independently hydrogen or (C1-C4)alkyl; Z is O, S, S(=O)2With(=O) or NR3; and Y represents - (C1-C4)alkylen - or - (C2-C4)albaniles, any of which is optionally monosubstituted hydroxy; where each of the above alkyl, alkenylamine, selected from (C1-C2)alkyl, trifloromethyl and halogen.

The above pentasa-as-indacene are known compounds having biological activity as inhibitors of type IV (PDE4) phosphodiesterase and production of tumor necrosis factor (TNF). This biological activity makes these pentasa-as-indacene useful for the treatment of various inflammatory, allergic and immunologic diseases and conditions which include asthma, bronchitis, chronic obstructive pulmonary disease, allergic rhinitis, psoriasis, dermatitis, and rheumatoid arthritis. The above-mentioned therapeutic applications of these pentasa-AU-indacene well established and accepted in the art as shown, for example, in published application WO 96/39408, already noted above. The use of inhibitors of PDE4 and TNF for the treatment of inflammatory, allergic and immunologic diseases and conditions well known in the art. Cm. for example, WO 95/01980 published January 19, 1995 (case attorney RSA) and WO 96/12720, published may 2, 1996 (case attorney RSS).

The way to obtain 8-cyclopentyl-6-ethyl-3-[substituted] -5,8-dihydro-4H-1,2,3 a, 7,8-pentasa-AU-indacene that WPI is xianling N-protective group in the initial stages of the synthesis. The full method of obtaining depicted for the case where R1is a 2-tanila represented by reaction scheme 1, is provided at the end of the description.

On stage and total synthesis of 2-pyrrolidinone and 4-iodoanisole heated in the presence of copper powder and potassium carbonate, giving N-(4-methoxyphenyl)pyrrolidin-2-it, which at the stage b is processed by the Grignard reagent, ethylmagnesium, giving aliphatic ketone after the opening of the ring of pyrrolidinone. This ketone is highlighted and then subjected to cyclization with the formation of the intermediate compound 3-hydroxy-1,2,5,6-tetrahydropyridine-2-it is in the stages C and d using ethyl ether chloranhydride oxalic acid and sodium hydroxide on stage and ethylate sodium and ethyl alcohol at the stage d. The corresponding 3-metaxylene intermediate compound obtained in stage e processing 3-methyl-n-tolyltriazole, after which stage f is obtained intermediate 4,5,6,7-tetrahydro-7-oxo-1H-pyrazolo [3,4-C] pyridine by cyclization using hydrochloride cyclopenthiazide. 4-metoksifenilny N-protective group is removed at the stage on the processing of nitric acid, cerium(1U)ammonium obtaining lactam intermediate compounds, after kotoe connection processing pentasulfide phosphorus.

Tricyclic final product is obtained at stages i, j and k by treatment with anhydrous hydrazine at stage i, followed by treatment of the 2-thiophenecarbonitrile at stage j and boiling in the flask with reflux condenser at stage k.

However, the above-described method of the prior art has several disadvantages. Stage and, for example, the reaction is conducted without solvent, in the presence of copper powder and potassium carbonate at a temperature of approximately 150oC. When the reaction is carried out on a larger scale than that used for research synthesis, the reaction stage and becomes exothermic and after cooling can be formed of difficult-to-solid mass, if the solvent is, for example, ethyl acetate, do not immediately add to the crude melt comprising the reaction mixture. Next, at stage s of the cost triazine reagent, 3-methyl-n-tolyltriazole is quite high, which creates the problem of the General economy of the method according to scheme 1, especially when considered in light of the fact that the outputs of virtually all stages of the method of scheme 1 are not optimal.

In addition, the phase b which receive aliphatic ketone by using a Grignard reagent, FL the CSOs are less problematic solvent, there is a tendency of occurrence of side reactions leading to products and possible stability problems. Aminoketone protected n-methoxyphenyl obtained at stage b, can be fragile, so it can be stored. Other problems can occur during the synthesis and purification cyclopentylpropionic agent; and removing the n-methoxybenzylamine protective group nitrate by aryamanya.

Further problems can be found in the procedures associated with the use of thiolactone chemistry for the introduction of the triazole component of the tricyclic core of the final products. They include the use of anhydrous hydrazine with the introduction of the triazole ring with toenailed. Anhydrous hydrazine is a dangerous chemical, fuming in the air and can explode during distillation, if there are traces of air. Accordingly, at present in the art a need for a method of obtaining 8-cyclopentyl-6-ethyl-3-[substituted]-5,8-dihydro-4H-1,2,3 a, 7,8-pentasa-AU-indacene, which is less problematic, more simple and has a large economic feasibility. Meeting this need is a method of obtaining nastoyenie relates to the field of methods, used for synthetic obtain 8-cyclopentyl-6-ethyl-3-[substituted]-5,8-dihydro-4H-1,2,3 a, 7,8-pentasa-AU-datenov, which are known compounds which possess biological activity as selective inhibitors of type IV phosphodiesterase (PDE) and the production of tumor necrosis factor (TNF). Therefore, the method of the present invention advantageously provides the prior art improved method of producing compounds, which are known to, in turn, are used in the treatment of asthma, arthritis, bronchitis, chronic obstructive airway disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory diseases, AIDS, septic shock and other diseases in mammals, especially humans.

Since the establishment of that circular adenosintriphosphate (AMR) is an intracellular secondary messenger, for example, in E. W. Sutherland, and T. W. Rail, Pharmacol. Rev. 12, 265, (1960), the inhibition of phosphodiesterase was a target for modulation and, accordingly, therapeutic intervention in the area of disease processes. Recently separate classes of PDE have been installed, for example, in J. A. Beavo at al.,TiPS, 11, 150, (1990), and their selective inhibition has led to improved drug therapy. See, for example, to Finance the release of mediators of inflammation, for example, in M. W. Verghese at al., J. Mol.Cell Car-diol., 12(Suppi. II), S 61, (1989) and relaxation of smooth muscles of the respiratory tract, for example, in T. J. Torphy, "Direction for New Anti-Asthma Drugs, eds C. P. O'donnell and C. G. A. Persson, 1988, 37 Birkhauser-Vertag.

Thus, compounds such as the aforementioned 8-cyclopentyl-6-ethyl-3-[substituted] -5,8-dihydro-4H-, 2,3 and 7,8-pentasa-as-indacene that inhibit type IV PDE, but have little activity against other types of PDE, is able to inhibit the release of mediators of inflammation and reduce the tension of smooth muscles of the respiratory tract, without causing undesirable cardiovascular or antithrombotic effects. 8-cyclopentyl-6-ethyl-3-[substituted] -5,8-dihydro-4H-1,2,3 a, 7,8-pentasa-as-indacene also useful as inhibitors of TNF production, which, as installed, is involved in many infectious and autoimmune diseases. See, for example, W. Friers, FEBS Letters, 285, 199, (1991). In addition, it is shown that TNF is the primary mediator of the response to the inflammation observed in sepsis and septic shock. See, for example, C. E. Spooner et al., Clinical Immunology and Immunopathology, 62, Sll, (1992).

SUMMARY OF THE INVENTION

The present invention relates to an improved method of producing a derivative of 8-cyclopentyl-6-ethyl-3-(substituted)-5,8-dihydro-4H-1,2,3 a, 7,8-is-R1is a member independently selected from the group consisting of hydrogen; (C1-C6)alkyl, (C1-C4)alkoxy; a (C1-C4)alkoxy (C1-C4)alkyl, (C2-C8)alkenyl; (C3-C7) cycloalkyl and 1'-methyl; (C3-C7) cycloalkyl (C1-C2)alkyl; a saturated or unsaturated (C4-C7)heterocyclic-(CH2)ngroup, where n is an integer selected from 0, 1 or 2, comprising one or two heteroatoms independently selected from O, S, S(=O)2, N, NR3O with N or NR3, S, or 3(=O)2together with N or NR3and N or NR3together with N or NR3; where:

-R3is hydrogen or (C1-C4)alkyl; or

-R1is a group of formula (1.1.0);

< / BR>
where:

is an integer selected from 1 to 5, inclusive;

- b and C are each independently an integer selected from 0 and 1;

- R5is a member independently selected from the group consisting of hydrogen, hydroxy, (C1-C4)alkyl, (C2-C4)alkenyl, (C1-C4)alkoxy, (C3-C6)cycloalkane, halogen, trifloromethyl, CO2R3a, CONR3aR3b, NR, selected from the group consisting of hydrogen and (C1-C4)alkyl;

- Z is O, S, S(=O)2c(=O) or MR3;

-Y represents - (C1-C4)alkylen - or - (C2-C4)albaniles-, any of which is optionally monosubstituted hydroxy; where

each of the above alkyl, Alchemilla, cycloalkyl, alkoxyalkyl or heterocyclic group is substituted by from 0 to 3 substituents, including a member independently selected from the group consisting of (C1-C2)alkyl, trifloromethyl and halogen;

including:

(a) heating a reaction mixture of caprolactone and p-methoxybenzylamine without solvent, whereby is obtained a derived amide, N-protected n-methoxybenzyl, formula (2.0.0):

< / BR>
(C) the restoration of a specified derivative of formula (2.0.0), whereby is obtained a derived amerosport, N-protected n-methoxybenzyl, formula (3.0.0.):

< / BR>
(C) acylation of a particular derived amerosport formula (3.0.0) ethyl ester, acid chloride oxalic acid, whereby is obtained a derivative of ethyl ether examinados acid, N-protected n-methoxybenzyl, formula (4.0.0):

< / BR>
(d) OK is derived by oxalidaceae, N-protected n-methoxybenzyl, formulas (5.0.0):

< / BR>
(e) the cyclization of the specified derivative oxalidaceae formulas (5.0.0) through which it is obtained by the derivative of pyridinone, N-protected n-methoxybenzyl, formula (6.0.0):

< / BR>
(f) O-methylation of the specified derivative of pyridinone formula (6.0.0), whereby is obtained the derived 3-methoxypyridine, N-protected n-methoxybenzyl, formula (7.0.0):

< / BR>
(q) processing the specified derived 3-methoxypyridine formula (7.0.0) cyclopentanemethanol, whereby is obtained a derivative of pyrazolopyrimidinone, N-protected n-methoxybenzyl, formula (8.0.0):

< / BR>
(h) removing the protective group with ukazannogo derived pyrazolopyrimidinone formula (8.0.0) remove the specified p-methoxybenzyloxy group from it, by which it is obtained by the derivative of the lactam of formula (9.0.0):

< / BR>
(i) the esterification of a particular derived lactam of formula (9.0.0), whereby is obtained the corresponding derived aminoether (imidate) formula (10.0.0):

< / BR>
(j) processing the specified derived aminoether (imidate) formula (10.0.0) derivatives of the carboxylic acid hydrazide of the formula (11.0.0):

< / BR>
where R1has the same value, K5,8-dihydro-4H-1,2,3 and 7,8-pentasa-as-indacene formula (1.0.0).

The present invention also relates to several different groups of new intermediates used in the above-described production method of a derivative of 8-cyclopentyl-6-ethyl-3-[substituted] -5,8-dihydro-4H-1,2,3 a, 7,8-pentasa-as-indacene formula (1.0.0). One group of such new intermediate compounds includes toiletries and besylate salt derived pyrazolopyrimidinone, N-protected n-methoxybenzyl, formula (8.1.0) and (8.1.1), respectively:

< / BR>
< / BR>
Another group of new intermediate compounds of the present invention includes the derived aminoether (imidate) formula (10.0.0):

< / BR>
and its pharmaceutically acceptable salt forms, including especially its tosylate and besylate salt.

DETAILED DESCRIPTION OF THE INVENTION

An improved method of obtaining the present invention relates to the creation of therapeutically useful compounds of formula (1. 0. 0):

< / BR>
and their pharmaceutically acceptable salt forms, where R1is, incidentally, a member independently selected from the group consisting of hydrogen; (C1-C6)alkyl, (C1-C4)alkoxy; a (C1-C4)alkoxy (C1-C4)alkyl, (C2-C<)alkyl; saturated or unsaturated (C4-C7)heterocyclic-(CH2)ngroup, where n is an integer selected from 0, 1 or 2, comprising one or two heteroatoms independently selected from O, S, S(=O)2, N, NR3O with N or NR3, S, or S(=O)2together with N or NR3and N or NR3together with N or NR3;

where R3is hydrogen or (C1-C4)alkyl.

The above compounds of formula (1.0.0) are called together here as an 8-cyclopentyl-6-ethyl-3-[substituted] -5,8-dihydro-4H-1,2,3 and 7,8-pentasa-as-indacene, and as already discussed, have biological activity as inhibitors of PDE4 and TNF production. An improved method of obtaining of the present invention is suitable for obtaining the above compounds, where R1the fragment has the value (C1-C6)alkyl, (C1-C4)alkoxy(C1-C4)alkyl, (C2-C8)alkenyl; (C3-C7)cycloalkyl and 1'-methyl; or (C3-C7)cycloalkyl(C1-C2)alkyl.

The expression "and 1'-methyl", used in connection with the definition of R1as (C3-C7)cycloalkyl means possible methyl group attached to the same atom of carbon is th of formula (1.0.0). It should be noted that this definition of R1easily distinguished from values "(C3-C7)cycloalkyl(C1-C2)alkyl", in which Allenby bridge, for example, methylene, located between specified (C3-C7)cycloalkyl group and the specified tricyclic core. Accordingly, when (C3-C7)cycloalkyl has a value of cyclohexyl, and is 1'-metal group, R1will be determined as part of a formula (1.2.0):

< / BR>
and will be called as 3-methyl-3-cyclohexyl.

In preferred embodiments of implementing the method of the present invention is particularly suitable for producing compounds of formula (1.0.0) where R1has the meaning of methyl, ethyl, n-propyl, ISO-propyl, tert-butyl, cyclopentyl, cyclohexyl, and 3-methyl-3-cyclohexyl.

Improved method for the present invention is further suitable for producing compounds of formula (1.0.0) where R1the fragment has the meaning of saturated or unsaturated (C4-C7) heterocyclic-(CH2)ngroup, where n is an integer selected from 0, 1 or 2, comprising one or two heteroatoms independently selected from O, S, S(=O)23; where R3is hydrogen or (C1-C4)alkyl.

In preferred embodiments of implementing the method of the present invention is particularly suitable for producing compounds of formula (1.0.0) where R1has the value of one of the following unsaturated (C5-C6)heterocyclic -(CH2)n-groups:

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
An improved method of obtaining of the present invention is further suitable for producing compounds of formula (1.0.0) where R1a fragment is a group of formula (1.1.0):

< / BR>
in which a is an integer selected from 1 to 5, inclusive, b and C are each independently an integer selected from 0 and 1; R5is a member independently selected from the group consisting of hydrogen; hydroxy; (C1-C4)alkyl, (C2-C4)alkenyl; (C1-C4)alkoxy; a (C3-C6)cycloalkane; halogen; trifloromethyl; CO2R3a; CONR3aR3b; NR3aR3b; NO2and SO2NR3aR3b; where R3aand R3bare, each independently, selected from the group consisting of hydrogen and (C1-C4)alkyl; Z represents O, S, S(=O)2With(=O) or NR3; and Y is positive monosubstituted hydroxy.

In preferred embodiments of implementing the method of the present invention is particularly suitable for producing compounds of formula (1.0.0), where a is 1 or 2; b is 1; C is 0; Y is -(C1-C2)alkylene-; and R5represents methyl, methoxy, hydroxyl, chlorine, iodine or trifluoromethyl. Accordingly, in preferred embodiments, the implementation of the compounds which are especially suitable for receipt by the method of the present invention, R1is set to one of the following groups:

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
The improved method of the present invention to obtain the compounds of formula (1.0.0) may be illustrated by reaction scheme 2 (see the end of the description), which indicates the receipt of representatives of the compounds of formula (1.0.0) where R1is 2-thienyl.

In the first stage, stage (a) in vyshepoimenovannoj scheme 2, is formed reaction mixture at-caprolactone and p-methoxybenzylamine, which is heated to obtain the derived amerosport, N-protected n-methoxybenzyl, formula (2.0.0). The sequence of reactions that stage (a) can be illustrated as follows:

< / BR>
-caprolacton formula (2.1.0)ature in the range from 70o95oC, preferably from 80oup to 85oWith, and maintained at that temperature for 12 to 24 hours, preferably 16 hours. Amide product of formula (2.0.0) obtained by using conventional separation procedures as a crystalline solid. This stage is improved on the basis of procedures such as, for example, the recovery of caprolactone formula (2.1.0) using di-isobutyleneisoprene (DiBAl-H) in methylene chloride, followed by reductive amination received lactol p-methoxybenzylamine and nutritioninformation [NaHB(OAc)3] in the sense of elimination of the reducing agent and solvent, which otherwise would be required in the first stage.

The second stage also leads to more sustainable aminopyrrolo intermediate product of formula (3.0.0). It should be noted that as the reagent is better to use p-methoxybenzylamine formula (2.2.0) than the corresponding p-methoxybenzylamine. It is found that, if such p-metoksifenilny group replaces n-methoxybenzyloxy group attached to the nitrogen atom aminopyrrolo intermediate compounds of formula (3.0.0), the compound obtained is unstable when ultraviol the public below.

Amide intermediate product of formula (2.0.0) obtained in the above described first stage of the method of the present invention, is then reduced with formation of the corresponding amerosport formula (3.0.0), which is N-protected n-methoxybenzyl, as already described. Reaction stage (b) can be illustrated as follows:

< / BR>
Vyshepoimenovannoe recovery is performed at the stage (b), is the restoration of the N-substituted amide to the corresponding amine and is carried out using a reducing agent for amides. Such reducing agents are known to the specialist in the art and usually consist of a hydride reducing agent type, for example, the complex of borane with ammonia, NR3.NH3; complex with borane tert-butylamine, (CH3)3N2NR3; complex with borane-trimethylamine, (CH3)3N. NR3; hydrate of aluminum, l3; athribis(2 methoxyethoxy)aluminiumhydride, [(CH3OCH2CH2O)2AlH2] Na or borhydride sodium, NaBH4.

The preferred reducing agent is sodium borohydride, NaBH4, while other reducing agents are less PR is Yu. The reducing agent used in conjunction with a source of protons, which is added later and is preferably a weak acid or THF solution of such an acid, for example acetic acid. The reducing agent and a source of protons are added in a suitable solvent such as methanol, ethanol, diethyl ether, formic acid, acetic acid, formamide and tetrahydrofuran THF. The preferred solvent is THF.

In the preferred method of execution stage (b) detribalizing the reducing agent is added in THF solvent, after which 4-benzylated 4-hydroxyhexanoic acid of formula (2.0.0) obtained in stage (a) is added in the form of solids. The reaction mixture is then cooled, added acetic acid in THF and the reaction mixture is heated to a temperature weak flavobacteria in the range 60oup to 70oWith over a period of time from 14 to 18 hours, preferably 16 hours. The hydrogen gas is removed during the reaction, and neproreagirovavshimi amide is removed by extraction with ethyl acetate after adding 1N HCL to decompose excess reagent. After that, the pH of the reaction mixture rises to 11, to enable aminopeptidase stage (C).

Stage (C) of the present invention can be illustrated by the following reaction scheme:

< / BR>
Vyshepoimenovannoe acylation at the stage (C) is an amine acylation with acid chloride in aqueous alkaline solution in accordance with known conditions "reactions of Schotten's-Bauman". Cm. Schotten, Ber. 17, 2544 (1884): and Georg, Bioorg. Med. Chem. Letters.. 4, 335 (1994). Aqueous alkali is added to bind model HC1 which is released during the reaction. In the preferred method of execution stage (C) reaction of acylation for this purpose, applied aqueous solution of sodium bicarbonate. Additional solvent, preferably ethyl acetate, is applied to obtain the solution of the ethyl ester of the acid chloride oxalic acid reagent of the formula (3.1.0) as the reaction mixture originated as an ethyl acetate solution aminopyrrolo intermediate compounds of formula (3.0.0) obtained in stage (b).

Acylchlorides reagent used in stage (C) is the ethyl ester of oxalic acid chloride of the acid of formula (3.1.0). The reaction is exothermic; therefore, the ethyl ester of the acid chloride oxalic acid is added over time, preferably, from 20 to 30 minutes >the. The reaction is completed within a short period of time from 1 to 2 hours, but the reaction mixture is optionally stirred at a room temperature of 20oup to 25oC for an additional period of time of 14 to 18 hours, preferably 16 hours to allow any remaining unreacted quantity of the ethyl ester of the acid chloride oxalic acid to be removed by decomposition. The product of formula (4.0.0), oil, obtained by using the conventional methods of separation and is structurally ethyl ester examinados acid, N-protected n-methoxybenzyloxy group. This intermediate compound is used as the starting material in the next stage, essentially without additional purification.

Stage (d) of the method of the present invention can be illustrated by the following reaction scheme:

< / BR>
Vyshepoimenovannoe oxidation carried out at the stage (d), is oxidation fragment of the secondary alcohol in keto fragment, which can be accomplished using a strong oxidizing agent under suitable oxidation conditions in accordance with the ways that specialists in the art are well aware. Nab is one of sulfuric acid and acetone, See,for example, Bowden et. al., J. Chem. Soc., 39 (1946); or Ley and Madin, Comp. Org. Syn, 7, 253-256(1991). The method is particularly useful, as it flows quickly with high yields and without prejudice to any of the other double bonds present. The method is very straightforward, as it only requires that the secondary alcohol of the formula (4.0.0) was dissolved in acetone and then titrated "Jones reagent", consisting of a solution of chromic acid and sulfuric acid in water.

Another type of oxidative method, suitable for use in stage (d) of the present invention is the oxidation involving the use of acid chromate H2CrO4; and various other catalytic compositions. oxidation, including chromium, such as chromium oxide, Cr2O3; chromium hydroxide, CR(OH)3mo2O; chromium acetate, SGSN3SOO)3. Cm. Cainelli; Cardillo Chromium Oxidations in Organic Chemistry', Springer: New York, 1984 for further details on chromium oxidation catalysts and methods for their use. Another well-known method of oxidation of secondary alcohols to ketones, which is suitable to perform the stage (d), is oxidation reaction Saretta" using SGAs3-pyridine complex as the oxidation catalyst. Alization oxidation and methods for their use for the conversion of the secondary alcohol, such as an alcohol of the formula (4.0.0) into the corresponding ketone such as a ketone of formula (5.0.0) include, but are not limited to, potassium permanganate, KMPO4; bromine, Br2; and the ruthenium tetroxide, RUO Li4.

A further example of suitable oxidation catalysts and procedures for their application for the conversion of the secondary alcohol of the formula (4.0.0) to the corresponding ketone of formula (5.0.0) and of a catalyst which is preferred for use in stage (d) of the method of the present invention, includes, but is not limited to, the use of an oxidizing agent, sodium hypochlorite, in the presence of a catalyst 2,2,6,6-tetramethyl-1-piperidinyloxy, free radical (TEMPO). The structure of the TEMPO of the catalyst may be represented by the following formula (4.1.0):

< / BR>
In this preferred method of carrying out the oxidation of the secondary alcohol of the formula (4.0.0) to turn it into a ketone of formula (5.0.0) is also preferred that the sodium hypochlorite solution was made fresh at the execution stage (d) dissolution of calcium hypochlorite and sodium carbonate in water and regulation of pH of the final solution from 9.0 to 10.0, preferably of 9.5, sodium bicarbonate, followed by filtration of the specified races of doctitle method execution stage (d), the reaction mixture includes a secondary alcohol of the formula (4.0.0), dissolved in methylene chloride, CH2CL2; and potassium bromide, KBR dissolved in water. TEMPO catalyst is added to the reaction mixture, which is then cooled to a temperature of from 0oup to 10oWith, preferably, from 0oto 5oWith, and then oxidizing agent, sodium hypochlorite, is slowly added to the reaction mixture, which is supported

temperature of 10o20oWith, preferably between 10o15oC. the Product is oil, which is obtained using conventional separation methods and used in the next stage of the process without further purification.

Even more preferred method of execution stage (d), than the above, includes the use of the polymer to maintain an oxidizing agent, sodium hypochlorite as the active ion l-and/or TEMPO of the catalyst. Cm. McKillop; Young, Synthesis, 401-422 (1979).

Specified even more preferred method of execution stage (d) also includes the use of phase transfer catalysis, since the reaction taking place is a nucleophilic substitution in which the substrate is relatively insoluble in water and other polar solvents, while nuclei the Phase Transfer Catalysis, 2nded.; Verlag Chemie: Deerfield Beach. FL (1983).

Stage (e) of the method of the present invention can be illustrated by the following reaction scheme:

< / BR>
Vyshepoimenovannoe cyclization played on the stage (e), includes a base catalyzed cyclization of esters of dicarboxylic acids with the formation of keeeper. The asterisk ("*") in the dicarboxylic acid of formula (5.0.0) indicates the point of separation of one of the esters with the formation of ethanol by-product, not shown in the above scheme of reaction. Included cyclization is registered organic reaction called condensation reaction of Dickman". Cm. Dieckmann, Ber. 27, 102, 965 (1894); or Davis and Garrett, Comp. Org. Syn. 2, 806-829 (1991).

The reaction is performed in the presence of a relatively strong base such as sodium ethylate or tert-butyl potassium, and in a suitable solvent such as dry tetrahydrofuran, di-ISO-propyl ether, methyl tert-butyl ether and toluene. The base is added gradually over a period of from 15 to 45 minutes, preferably 30 minutes, while the temperature of the reaction mixture remains below the 30o40oWith, preferably below 35oC. After that the reaction proceeds d is the temperature, for example, 20oup to 25oC. the Product, a solid substance that is secreted by filtration.

Stage (f) of the method of the present invention can be illustrated by the following reaction scheme:

< / BR>
Vyshepoimenovannoe reaction includes O-methylation derived pyridinone formula (6.0.0), whereby is obtained a derivative of 3-methoxy-pyridinone N-protected n-methoxybenzyl, formula (7.0.0). It is desirable to carry out the selective O-methylation of the alcohol group without a corresponding S-methylation; therefore, some of the reaction was determined to be inappropriate, for example, the processing iodide stands in acetone with potassium carbonate.

One successful approach, which is preferred variant of the method of the present invention is the alkylation of an alcohol of the group of inorganic complex ether, in particular, methylation of dimethylsulfate. In the preferred embodiment, this reaction is performed in dimethylformamide (DMF) as a solvent in the presence of cesium carbonate, Cs2CO3gradual addition of dimethylsulfate during the period from 15 to 45 minutes, preferably 30 minutes, while the temperature, R the reaction mixture is maintained at this temperature and stirred for 12 to 20 hours, typically 16 hours. The product oil obtained by applying the conventional separation procedures.

Phase (q) of the method of the present invention can be illustrated by the following reaction scheme:

< / BR>
Vyshepoimenovannoe reaction includes obtaining pirateradio the compounds of formula (8.0.0) processing the derived 3-methoxypyridine formula (7.0.0) of the dihydrochloride of cyclopenthiazide formula (7.1.0). In the preferred embodiment, this reaction is performed in tertrahydrofuran ring (THF) solvent by heating the reaction mixture from the 75o95oWith, preferably 88oWith over 8 to 16 hours, preferably 12 hours, while the reaction mixture is blown with nitrogen to remove methanol, THF and HCl. The product is a thick, dark oil, which can be used in the next stage of the method of the present invention without further processing, or, alternatively, it may be purified as salt p-toluensulfonate acid or benzosulfimide acid when using conventional separation procedures.

When the compound of the formula (8.0.0) should be cleaned as salt p-toluensulfonate acid or benzosulfimide acid, in predpochtitel what isatou or the anhydrous benzosulfimide acid, dissolved in ethyl acetate. The corresponding salt crystallizes from the reaction mixture, which is then cooled and filtered, providing clean tosylate or benzosulfimide salt.

The key reagent of the above stage (q) is the dihydrochloride of cyclopenthiazide formula (7.1.0), which can be obtained according to several methods known in the literature. In the preferred embodiment applies the method described in Syn. Comrn. 11, 43 (1981), in which Cyclopentanol processed di-tert-utilizadorescialis and triphenylphosphine in accordance with reaction scheme, which can be illustrated as follows:

< / BR>
The above reaction is based on organic personal reaction, called "reaction Mitsunobu", which includes the condensation of alcohols and acid components in the processing of dialkyldithiocarbamato and trialkyl or triarylphosphine primarily with inversion of configuration through an intermediate oxyphosphate salt. Cm. Mitsunobu etal.. Bull. Chem. Soc. Japan 40, 935 (1967);

Brown etal.. Tetrahedron 50, 5469 (1994); Edwards et al., ibid. 5579; and Hughes, Org. React. 42, 335-656(1992).

In the preferred embodiment, to obtain digital the right solvent such as tetrahydrofuran (THF), and then the reaction mixture is cooled to a temperature of from 2oup to 8oWith, preferably, 5oC. Di-tert-utilisationbased dissolved in THF, and then added to the reaction mixture over a period of from 1 hour to 3 hours, preferably 2 hours, while the temperature of the reaction mixture remains below 6oC. the Reaction mixture are given the opportunity to warm to room temperature, i.e. 20o-25oWith, and it is stirred for 4 hours to 6 hours, preferably 5 hours, then 6N HCL is added to the reaction mixture to remove the BOC group of the product. The reaction mixture was then stirred for an additional period of 18 to 30 hours, preferably 24 hours. The solid product is then allocated as dihydrochloride salt when using conventional separation procedures. It should be noted that the main product may be or dihydrochloride salt, or monohydrochloride salt depending on the stoichiometry of the number of added 6N Hcl. Any salt works well in the reaction described above stage(q).

Stage (h) of the method of the present invention can be illustrated by the following reaction scheme:
the formulas (8.0.0) removing the p-methoxybenzyloxy group, whereby is formed a derived lactam of formula (9.0.0). Removal of p-methoxybenzyloxy group is performed in accordance with known methods for removing the protective group with amines, where the protective group is p-methoxybenzo school group. Further, it is noted that the reaction of stage (q), described in detail above, and removing the protective group stage (h) can be performed without isolation of the product of stage (q), that is, both reactions can be carried out together in the same reaction vessel.

In accordance with a preferred embodiment of the method of the present invention stage (h) is performed at a temperature of from 50o60oWith, preferably, 55oWith that usually requires cooling of the reaction mixture after the completion of stage (q). After that, the reaction mixture is slowly added triperoxonane acid (TFA), while its temperature is maintained at from 50o60oS, and the initial load of TFA causes the terms exothermic reaction, which require external cooling. Methane-sulfonic acid, CH3SO3H, then added to the reaction mixture, the temperature now rises to 65o-75oWith, predpochtitel the aces. After that the reaction mixture is cooled to a temperature of 15o-30oWith, preferably, 20o-25oC, after which the solid product lactam of formula (9.0.0) is obtained by conventional separation procedures.

Stage (i) of the method of the present invention can be illustrated by the following reaction scheme:

< / BR>
Vyshepoimenovannoe the reaction involves the esterification derived lactam of formula (9.0.0) in the appropriate aminoether, i.e. derived imidate formula (10.0.0). This esterification is performed in the application of tetrafluoroborate trityloxy, (CH3CH2)3F4agent, used in obtaining the amino esters of the lactam. Cm. Synth. Commun. 18, 1625 (1988).

In a preferred embodiment of the method of the present invention to perform the stage (i) solution tetrafluoroborate trityloxy, (CH3CH2)3F4), in methylene chloride is slowly added to a suspension derived lactam of formula (9.0.0) in methylene chloride over a period of from 30 to 50 minutes, preferably 40 minutes. After that, the reaction mixture is maintained at a temperature of from 15oup to 25oC, preferably from 18o22oS, s separation procedures.

Stage (j) of the method of the present invention can be illustrated by the following reaction scheme:

< / BR>
In a preferred embodiment of the method of the present invention to perform the stage (j) solution of the compounds of formula (10.0.0) in 1-butanol and hydrazide 2-thiophencarboxylic acid, or alternatively, the hydrazide 2,2-dimethylpropionic acid, is heated at a temperature of from 85o95oWith, preferably, 90oWith over a period of 36 to 60 hours, preferably 48 hours. The product, a white solid and not quite white solid, respectively, obtained by applying the conventional separation procedures.

The choice of solvent for dissolving the compounds of formula (9.0.0) and a specific carboxylic acid hydrazide, which must be applied to obtain the desired compounds of formula (1.0.0) depends largely on the ability of the candidate to the appropriate solvent to dissolve the above-mentioned reagents, as well as to have the desired low boiling point so that the reaction mixture could be heated under reflux for long periods of time without danger of decomposition or reagents, or the ending produo appropriate in the form of a solution of 63% alcohol and 37% water, which forms an azeotropic mixture boiling at 92oC. Other suitable solvents include solvents selected from the group consisting of n-amyl simple ether, ISO-amylacetate, ISO-pentalofos alcohol and ISO-propyl alcohol.

It should be noted that the stages (a) to(i) inclusive method of the present invention described in detail above, all and each is specific to an individual connection, turn through each of the reactions described in the above-mentioned stages. These stages, respectively, do not have any generalized sense. The nearest and vyshepoimenovannoe the last stage, stage (j), on the other hand, is a point in the method of the present invention, where different substituents defining the group R1are introduced into the structure of the final product is defined by the formula (1.0.0). Thus, the intermediate connection of the last stage and, therefore, a key intermediate compound in the method of the present invention includes the derived aminoether (imidate) formula (10.1.0):

< / BR>
and its pharmaceutically acceptable salt forms, including especially its tosylate and besylate salt.

The key intermediate compound of formula (10.0.0) last hundred is x product formula (1.0.0). The reaction not only serves to introduce the desired substituent R1in the compound of formula (10.0.0), but it also serves to provide further cyclization with the formation of "triazolines" component three-cyclical final product of formula (1.0.0). As mentioned above, the end products of the formula (1.0.0) was called before 5,6-dihydro-N-pyrazolo[3,4-C] -1,2,4-triazolo[4,3-a]pyridine, although it is preferable to call these compounds of formula (1.0.0) 8-cyclopentyl-6-ethyl-3-[substituted] -5,8-dihydro-4H-1,2,3 a, 7,8-pentasa-as-indacene.

The above-mentioned hydrazine appropriate structure to ensure the required values of R1is a derivative of the carboxylic acid hydrazide of the formula (11.0.0):

< / BR>
where R1has the same meaning as above. In preferred embodiments of implementing the present invention, a suitable derivative of the carboxylic acid hydrazide of the formula (11.0.0) represents a member selected from the group consisting of those set forth as follows (see table).

Many of the above compounds, carboxylic acid hydrazides of the formula (11.0.0), available commercially. For example, hydrazide 2-thiophencarboxylic acid available from ldrich C the measures hydrazide tert-butylcarbamoyl acid, it can be obtained using methods published in the technical literature and known to those of ordinary skill in the field of technology of synthesis of such organic compounds. This method is developed to obtain the hydrazide tert-butylcarbamoyl acid, which is more suitably be called a hydrazide 2,2-dimethylpropionic acid. This method is described below.

The method developed to obtain the hydrazide 2,2-dimethylpropionic acid, is a modification of the method described in published European application EP 653419 (1995) transferred Shell Oil [Chem. Abs. 123: 32678b (1995)], which applies trimethyloxonium acid, hydrazine hydrate and catalytic TiO2. The reaction was carried out with the use of n-propanol as solvent along with 1 mol% of Ti(i-PrO)4that hydrolyses immediately when added to the reaction mixture, giving an amorphous active catalyst TiO2. After the reaction mixture is heated under reflux for 24 hours, n-profanely solvent Argonauts of reaktsionnogo vessel, azeotropic removing water from the reaction mixture. After diluting the reaction mixture with fresh n-propanol solid TiO2the active catalyst, it could ether, giving the desired hydrazide 2,2-dimethyl-propenylboronic acid of high purity and with 88% yield.

The present invention also relates to novel intermediate compounds used in the above stages of the method for deriving 8-cyclopentyl-6-ethyl-3-[substituted] -5,8-dihydro-4H-1,2,3 a, 7,8-pentasa-as-indacene formula (1.0.0). One group of such new intermediate compounds include a member selected from the group consisting of tosylate and besylate salts derived pyrazolidine Nona N-substituted n-methoxybenzyl, formulas (8.1.0) and (8.1.1), respectively:

< / BR>
< / BR>
The above intermediate salt of the formula (8.1.0) and formula (8.1.1) are used in stage (h), as described in detail above.

Another group of new intermediate compounds of the present invention includes a derived (imediat) formula (10.0.0):

< / BR>
and its pharmaceutically acceptable salt forms, including especially its tosylate and besylate salt. Tosylate and besylate salts can be represented by the formula (10.1.0) and (10.2.0) as follows:

< / BR>
Further preferred implementation of the present invention relates to a method for producing compounds of formula (1.0.0), consisting of tolcv figure 1 in detail above. This two-stage method can be represented by scheme 3 (see end of description).

Accordingly, the present invention further relates to an improved method of producing a derivative of 8-cyclopentyl-6-ethyl-3-[substituted] -5,8-dihydro-4H-1,2,3 and 7,8, pentasa-as-indacene formula (1.0.0):

< / BR>
and its pharmaceutically acceptable salt form, in which R1as defined above;

including:

(a) the substantial derivative of the lactam of formula (9.0.0):

< / BR>
whereby is obtained the corresponding derived aminoether (imediat) formula (10.0.0):

< / BR>
(b) processing the specified derived aminoether (imidiate) formula (10.0.0) hydrazide derivative of carboxylic acid of the formula (11.0.0):

< / BR>
where R1has the same meaning as described above; whereby is obtained the specified derived 8-cyclopentyl-6-ethyl-3-[substituted]-5,8-dihydro-4H-1,2,3 and 7,8-pentasa-as-indacene formula (1.0.0).

Following the preferred implementation of the present invention relates to a method for producing compounds of formula (1.0.0), consisting of a single stage, starting with a new intermediate compounds of formula (10.0.0), which can be obtained in accordance with Soi 4 (see at the end of the description).

Accordingly, the present invention still further relates to an improved method of producing a derivative of 8-cyclopentyl-6-ethyl-3-[substituted]-5,8-dihydro-4H-1,2,3 and 7,8-pentasa-as-indacene formula (1.0.0).

< / BR>
and its pharmaceutically acceptable salt form, in which R1is as defined above; including:

processing the derived knoeber (imidate) formula (10.0.0):

< / BR>
derivative of the carboxylic acid hydrazide of the formula (11.0.0);

< / BR>
where R1has the same meaning as described above; whereby is obtained the specified derived 8-cyclopentyl-6-ethyl-3-[substituted]-5,8-dihydro-4H-1,2,3 and 7,8-pentasa-as-indacene formula (1.0.0).

Preferred embodiments of to perform various stages of the method of the present invention have been described here. Accordingly, there are preferred options for implementation to perform the complete method of the present invention. One of the most preferred of these preferred embodiments is described below.

An improved method of deriving 8-cyclopentyl-6-ethyl-3-[substituted] -5,8-dihydro-4H-1,2,3 a, 7,8-pentasa-as-indacene formula (1.0.0).


(a) heating a reaction mixture of caprolactone and p-methoxybenzylamine without solvent to a temperature in the range from 70o95oWith, preferably, from 80oup to 85oWith and wydarzenie at this temperature for 12 to 24 hours, preferably, 16 hours, whereby is obtained a derived amide, N-protected n-methoxybenzyl, formula (2.0.0):

< / BR>
(b) recovering the specified derived Amida formula (2.0.0) using reducing agents selected from the group consisting of a complex of borane with ammonia, NR3. NH3; complex with borane tert-butylamine, (CH3)3N2NR3; complex with borane-trimethylamine, (CH3)3NBH3; aluminum hydride l3; athribis(2 methoxyethoxy)aluminiumhydride, [(CH3OCH2CH2O)2AlH2] Na and sodium borohydride NaBH4preferably, sodium borohydride;

the specified reducing agent used in conjunction with a source of protons, including a weak acid or THF solution of such an acid, preferably acetic acid; and with the specified reducing agent and a source of protons added to the solvent is selected from the group consisting of melanotaenia, THF;

in which after the specified reducing agent is added to the specified solvent specified amide of formula (2.0.0) is added in the form of solid substances specified in the reaction mixture, which is then cooled and the specified source of protons in the specified solvent is added to the specified reaction mixture, which is then heated to a temperature weak flavobacteria in the range 60oup to 70oWith over a period of time from 14 to 18 hours, preferably 16 hours, and the hydrogen gas is removed as a byproduct and unreacted amide is removed by extraction with ethyl acetate after adding 1N HCl to decompose excess reagent; and then raise the specified pH of the reaction mixture from 10 to 12, preferably 11 to give the opportunity to proektirovanii product of formula (3.0.0) to ethyl acetate and save for use in the next stage;

whereby is obtained a derived amerosport N-protected n-methoxybenzyl, formula (3.0.0);

< / BR>
(C) acylation of a particular derived amerosport formula (3.0.0) in accordance with the reaction conditions of Schotten's-Bauman for processing the amine acid chloride of the acid in aqueous alkaline solution, the preferred ethyl ester of the acid chloride oxalic acid, is added as a solution in a solvent, which is, preferably, ethyl acetate:

where the reaction that takes place is exothermic, resulting in the specified acid chloride acid, preferably ethyl ester of the acid chloride oxalic acid is added over time, preferably, from 20 to 30 minutes, the reaction temperature is maintained between 0oto 5oWith until this reaction will not be completed in 1-2 hours; after that the reaction mixture is optionally stirred at a temperature of 20oup to 25oC for 14 to 18 hours, preferably 16 hours, to give the opportunity to remove unreacted acid chloride acid, preferably ethyl ester of the acid chloride oxalic acid decomposition;

whereby is obtained a derivative of ethyl ether examinados acid, N-protected n-methoxybenzyl, formula (4.0.0);

< / BR>
(d) oxidation of the specified derivative ethyl ester examinados acid of the formula (4.0.0) using a strong oxidizing agent under suitable oxidizing conditions; at which this oxidation is performed;

(i) under the conditions of the oxidation reaction Jones, made in the presence, sodium hypochlorite, in the presence of a catalyst 2,2,6,6-tetramethyl-1-piperidinyloxy, free radical (TEMPO), wherein said sodium hypochlorite solution is made fresh when implementing the oxidation, including: dissolution of calcium hypochlorite and sodium carbonate in water and bringing the pH of the resulting solution from 9.0 to 10.0, preferably 9.5 with sodium bicarbonate, followed by filtration of the specified solution to remove any remaining by-product, calcium carbonate, from the specified solution, and then

where the reaction mixture is formed in the form of a solution of the compounds of formula (4.0.0) in methylene chloride, CH2Cl2; addition of potassium bromide, KBR dissolved in water, to which is added the specified TEMPO catalyst, the reaction mixture is cooled to a temperature of from 0oup to 10oWith, preferably, from 0oto 5oWith; after which the specified oxidizing agent, sodium hypochlorite, is slowly added, while indicated, the reaction mixture is maintained at a temperature of from 10o20oWith, preferably, from 10o15oC;

whereby is obtained the derived oxalidaceae N-protected n-methoxsalen the condensation reaction of Dickman, where the reaction is carried out in the presence of a relatively strong base selected from the group consisting of ethylate of sodium and of potassium tert-butylate, in a suitable solvent, including dry tetrahydrofuran, di-ISO-propyl simple ether, methyl tert-butyl simple ether or toluene; where the specified radix is added gradually over a period of from 15 to 45 minutes, preferably 30 minutes, while the temperature specified reaction mixture is kept below 30o-40oC, preferably below 35oWith, and this reaction proceeds to completion from 0.5 to 1.5 hours, usually 1.0 hour, while the specified reacciona mixture is at a temperature of 20oup to 25oWITH:

whereby is obtained a derivative of pyridinone, N-protected n-methoxybenzyl, formula (6.0.0):

< / BR>
(f) O-methylation of the specified derivative of pyridinone formula (6.0.0) methylation of dimethylsulfate; where the reaction mixture is formed dimethylformamide (DMF) solvent in the presence of cesium carbonate, Cs2CO3gradual addition of the specified dimethylsulfate during the period from 15 to 45 minutes, preferably 30 minutes, while the temperature specified reaction smeego specified, the reaction mixture is maintained at the same temperature and stirred for 12 to 20 hours, usually 16 hours;

whereby is obtained the derived 3-methoxypyridine, N-protected n-methoxybenzyl, formula (7.0.0):

< / BR>
(q) processing the specified derived 3-methoxypyridine formula (7.0.0) of the dihydrochloride of cyclopenthiazide; where the reaction mixture is formed tetrahydrofuranyl (THF) solvent and heating the specified reaction mixture to a temperature of 75o95oWith, preferably 88oWith over 8 to 16 hours, preferably 12 hours, as indicated, the reaction mixture is blown with nitrogen to remove methanol, THF and HCI;

whereby is obtained a derivative of pyrazolopyrimidinone, N-protected n-methoxybenzyl, formula (8.0.0):

< / BR>
where the aforementioned compound of formula (8.0.0) can be used in the next stage of the process without further processing, or alternatively, it may be purified as salt p-toluensulfonate acid or benzosulfimide acid, by dissolving the compounds of formula (8.0.0) in ethyl acetate, and then the processing of anhydrous n-toluensulfonate acid, dissolved in ethyl acetate, or the anhydrous benzosulfimide acid, dissolved in ethyl acetate; then the corresponding salt crystallizes Oh tosylates or benzosulfimide salt;

(h) removing the protective group derived from the specified pyrazolopyrimidinone formula (8.0.0) remove the specified p-methoxybenzyloxy group, where the reaction mixture is maintained at a temperature of from 50o60oWith, preferably, 55oC; then triperoxonane acid (TFA) is added slowly, with initial addition of TFA causes the terms exothermic reaction, which require external cooling; after that methansulfonate acid, CH3SO3N, is added to the specified reaction mixture, the temperature of which rises up from 65oup to 75oWith, preferably, 70oC, at which the reaction mixture is maintained for 1 1/2 to 2 1/2 hours, preferably 2 hours, and afterwards, the reaction mixture is cooled to a temperature of from 15o30oC, preferably from 20oup to 25oC;

whereby is obtained the derived lactam of formula (9,0.0):

< / BR>
(i) the esterification of a particular derived lactam of formula (9.0.0) when using tetrafluoroborate triethyloxonium (CH3CH2)3F4; where the reaction mixture is created by the slow addition of a solution of tetrafluoroborate triethyloxonium (With the methylene chloride over a period of from 30 to 50 minutes, preferably, 40 minutes; and thereafter maintaining the reaction mixture at the specified temperature from the 15oup to 25oWith, preferably, from the 18o22oSince, during the period from 18 to 24 hours, preferably 21 hours;

whereby is obtained the corresponding

derived aminoether (imidate) formula (10.0.0)

< / BR>
(j) processing the specified derived aminoether (imidate) formula (10.0.0) hydrazide carboxylic acid of the formula (11.0.0);

< / BR>
where R1represents 2-thiophene or tert-butyl; where the reaction mixture formed a solution of the compounds of formula (9.0.0) in 1-butanol and the hydrazide 2-thiophencarboxylic acid, or alternatively, the hydrazide 2,2-dimethylpropionic acid; the reaction mixture is heated at a temperature of from 85o95oWith, preferably, 90oWith over a period of 36 to 60 hours, preferably 48 hours;

whereby is obtained 8-cyclopentyl-6-ethyl-3-thiophene-2-yl-5,8-dihydro-4H-1,2,3 a, 7,8-pentasa-as-indocin formula (1.0.1) and 8-cyclopentyl-6-ethyl-3-t-butyl-5,8-di-hydro-4H-1,2,3 a, 7,8-pentasa-as-indocin formula (1.0.2):

< / BR>
< / BR>
ILLUSTRATED BY THE EXAMPLES OF THE PREFERRED EMBODIMENTS OF THE INVENTION

Ania for the purpose of illustration and for to make it even more understandable specialist technique method of producing the present invention. However, the examples are intended only for the purpose of demonstrating the present invention specified specialist and should not be interpreted any way limiting the scope and content of the present invention, which is completed by the claims.

EXAMPLE 1 4-methoxybenzylamine-hydroxyhexanoic acid (2.0.0)

< / BR>
Gamma caprolacton (28,745 kg, 251,8 mol) and 4-methoxy-benzylamine (38,0 kg, 277 moles) were placed in glass 100 galley lined tank. The solution was heated to 80-850C and was maintained at this temperature for 16 hours. TLC thin layer chromatography on silikagelevye records showed that the reaction was completed. TLC system included: ethyl acetate with detection at 254 nm. Ethyl acetate (18 gallons, 68 l) was slowly loaded into the reaction vessel after cooling to 60oC. Hexane (total number of 18 gallons, 68 l) was added until turbidity was not reached. After 1/2 hour, to allow you to start crystallization, was added to the residue of the hexane suspension was cooled to 25oWith and was granulated for 3 hours. Solid collect points and the C additional heating to obtain 46,05 kg (72.8%) of the desired amide; so pl. 81 -82oC.

'TMR (Dl3, 300 MHz) to 7.18 (d, 2), at 6.84 (d, 2), 6,27 (Shir.with a, 1), 4,32 (d, 2), 3,79 (s, 3), 3,50 (m, 1), 3,19 (Shir. with a, 1), 2,35 (t, 2), of 1.85 (m, 1), 1,67 (m, 1), for 1.49 (m, 2), to 0.92 (t, 3).

Anal. Vices. for C14H21MO3: C, 66,91; N, 8,42; N, 5,57. Found: C, 67,26; N, 8,71; N, 5,55.

EXAMPLE 2 6-(4-methoxybenzylamine)hexane-3-ol (3.0.0)

< / BR>
Tetrahydrofuran (121 gallon, 458 l) and sodium borohydride (22,154 kg, 585,6 moles) was loaded into filled with pure and dry nitrogen 500 gallon glass lined tank. The suspension was allowed to mix for 30 minutes at 20-25oWith, then 4-methoxybenzylamine 4-hydroxyhexanoic acid (45,75 kg, 182 mole) were added as solids. After 30 minutes the reaction was cooled to 5-10oWith and for 4 to 8 hour period was added a solution of acetic acid (9.1 gallons, 34,4 l) in tetrahydrofuran (12 gallons, 45,4 l) while maintaining the temperature at 0 -10oC. a Small bleed of nitrogen was maintained in the tank to help remove the hydrogen. When the addition was completed, the reaction was warmed to 20-25oC and stirred for one hour. The reaction temperature was slowly increased to weak flavobacteria (~ 66oC) and maintained there for 16 Casablanca by distillation at atmospheric pressure. Ethyl acetate was added to the obtained aqueous solution to extract the unreacted amide. The acidic aqueous solution is then brought to pH 11, to allow the obtained amine to proektirovaniya in ethyl acetate and stored for use in the next stage. An aliquot of an ethyl acetate solution of the product was selected for the preliminary determination of the final output and concentration. The solution for this large-scale series was 55.0%, which was less than the yield achieved in small-scale experiments (78.8%). When large-scale procedure was 12,8% unrestored original amide after cooling, which partly explained the lower output.

'TMR (Dl3,300 MHz) 7,21(d,2), 6,83 (d, 2), of 3.78 (s, 3), of 3.69 (s, 2), to 3.41 (m , 2), 2,78 (m, 1), 2,58 (m, 1), 1,71 (m, 2), a 1.45 (m,4), of 0.95 (t,3). GC mass spectrum: m/e 237 (M+).

EXAMPLE 3 Ethyl ester of N-(4-hydroxyhexyl)-N-(4-methoxybenzyl) examinados acid (4.0.0).

< / BR>
6-(4-Methoxybenzylamine)hexane-3-ol (24 kg, 101,1 mol) in ethyl acetate (158 gallons, 598 l) was loaded into a clean and dry nitrogen-filled 500 gallon tank. This solution was cooled to 0-5oC, then a solution of sodium bicarbonate (16,988 kg, 202,2 mole 51 gallon (193 l) of water) was added in support of the ethyl acetate (20 gallons, to 75.7 l) was added while maintaining the temperature from 0oto 5oWith over a period of time approximately 25 minutes. The reaction was allowed to warm to a temperature of 20-25oWith in which it was completed according to HPLC (liquid chromatography high resolution). The reaction stirred for an additional 16 hours to allow to decompose any remaining ethyl ether, the acid chloride oxalic acid. The lower aqueous layer was removed, and the ethyl acetate was washed 49 gallons (185,5 l) of water. The layers were separated. The remaining ethyl acetate was washed with a solution of 2n Hcl (5.6 gallon (21.2 l) of concentrated HCI plus 28.4 gallon (107,5 l) of water). The remaining ethyl acetate was evaporated under vacuum to obtain the resulting crude amide in the form of oil, 29,296 kg (85,9% of theory).

'TMR (Dl3, 400 MHz) to 7.18 (m, 2), 6,83 (m, 2), to 4.41 (m, 1), or 4.31 (m, 3), 3,76 (d, 3), of 3.43 (m, 1) at 3.25 (m, 1), 3,13 (t, 1), 2,00 (Shir. with a, 1), 1,80 - of 1.26 (m , 8), of 0.87 (t, 3). IR (without solvent) 3456, 1739, 1654, 1513 cm-1.13CMP (CDCl3, 100 MHz) 163,5, 162,1, 159,7, 159,0, 129,6, 129,2, 128,0, 127,1, 114,2, 114,1, 72,6, 72,5, 62,1, 55,3, 50,9, 47,0, 46,3, 43,6, 33,5, 33,4, 30,3, 30,2, 24,3, 22,9, 14,0, 9,9, GC mass spectrum: m/e 337 (M+).

EXAMPLE 4

Ethyl ester of N-(4-methoxybenzyl)-N-(4-oxohexyl) examinados acid (5.0.0)

< / BR>
Bromide Kali is alcohol (33,62 kg, 99,6 moles) in methylene chloride (34 gallon, 128,7 l). 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), the free radical catalyst (150 g) was added and the reaction was cooled to 0-5oC. a Fresh solution of sodium hypochlorite (derived from calcium hypochlorite (12,11 kg) and sodium carbonate (17,96 kg) in water (100 gallons, 378.5 l), brought to pH 9.5 sodium bicarbonate (1.7 kg) and filtered to remove calcium carbonate) was added slowly maintaining the temperature at 10-15oC. After the reaction, the layers were separated, and the aqueous layer was extracted with 8 gallons added methylene chloride. The combined organic layers were washed with a solution formed of concentrated HCI (5.4 l) and potassium iodide (331 g) in water (3.84 gallon, 14.5 l). The organic layer was then washed with sodium thiosulfate solution (1197 g) in water (5.3 gallons, 20 l). Methylene chloride was filtered 10 gallon (37.85 l) of water and then supariwala without vacuum up the oil. The oil was further Perivolos after moving in a 50 l reactor. It turned out 33,407 kg of product, but this material contained 15 % by weight methylene chloride (NMR). Fixed output was 28,396 kg (85.0% of theoretical).

'TMR (Dl3, 300 MHz) to 7.18 (DD, 2), 6.82 (dd, 2), 4,49 (s, 1), 4,27 (m , 3), 3,74 (d, 3), 3,22 (the 127,1, 114,2, 114,1, 112,1, 62,1, 55,2, 50,6, 46,1, 46,1, 42,7, 39,0, 38,1, 35,8, 21,5, 20,6, 13,9, 7,7. GC mass spectrum: m/e 335(M+).

EXAMPLE 5 3-hydroxy-1-(4-methoxybenzyl)-4-propionyl 5,6-dihydro-1H-pyridine-2-he (6.0.0)

< / BR>
Oxalidaceae (28,296 kg, 84,4 mol) was dissolved in dry tetrahydrofuran (28 gallons, 106 l) in a clean and dry 100 gallon tank. This solution was added to a solution of potassium tert-butylate (over 10,392 kg) in tetrahydrofuran (42 gallons, 159 l) 300 gallon tank over a 30 minute period while maintaining the temperature <35 oC. After 1 hour at 20-25oThe reaction was terminated by HPLC. Water (98 gallons, 371 l) was added to the reaction, followed by addition of ISO-propyl ether (24 gallon, 90,8 l). The layers were separated, and the water-containing product in the form of its potassium salt, was filtered a second time ISO-propyl ether. The aqueous layer was partially evaporated under vacuum to remove any remaining THF and pagkilala to pH 2.1 adding 6N HCI (4 Gal 15.1 l). The obtained suspension was filtered, and the solids were washed with water. The product was dried in air at 50oWith the giving of 17.9 kg of product (73%); so pl. 102-103oC.

'PMR (CDCl3, 300 MHz) 7,20 (d, 2), 6,86 (d, 2), 4,60 (s, 2), 3,70 (s, 3), to 3.33 (t, 2), 2,69 (K, 2), of 2.56 (t, 2), of 1.13 (t, 3).

-methoxybenzyl)-4-propionyl 5,6-dihydro-1H-pyridine-2-he (of 17.35 kg, 60 moles) and cesium carbonate (22,126 kg, 67.9 moles) was added to dry dimethylformamide (24 gallon, 90,8 l) in a clean, dry 100 gallon tank. The suspension was mixed for half an hour to ensure dispersion. Dimethylsulfate (8,552 kg, 67,8 moles) was added in pure form in the course of 30 minutes while maintaining a temperature of 20-25oC. When the download has completed, the funnel was opolaskivatel in the tank additional DMF (500 ml). The reaction was stirred at 20-25oC for 16 hours. The reaction was diluted with ethyl acetate (108 gallons, 408,8 l) and washed with water (h gallon (83,3 l)). An ethyl acetate solution was washed with a solution prepared from 6.94 liters of 50% sodium hydroxide in 22 gallons (83,3 l) of water, followed by rinsing with a solution formed 6,94 liters of concentrated HCI in 22 gallons (83,3 l) of water. The organic solution was dried by washing with brine (14 gallons, 53 l). The ethyl acetate was evaporated under vacuum to an oil, which was suitable for use in the next stage. Yield was estimated on the basis of NMR analysis of the residual solvent was 89%. A small sample was allocated to characterize.

'Poland (CDCl3, 300 MHz) 7,14 (d, 2), is 6.78 (d, 2), 4,51 (s, 2), 3,88 (s, 3), 3,71 (s, 3), and 3.2 (t, 2), 2,81 (K, 2), 2,42 (t, 2), of 1.02 (t, 3).13IDA (CDCl
The dihydrochloride of cyclopenthiazide

< / BR>
Cyclopentanol (6,127 kg, 71.1 mol) and triphenylphosphine (18,667 kg, 71,25 mol) was dissolved in tetrahydrofuran (40 gallons) in a clean, dry, nitrogen-filled 100 gallon tank, and the reaction mixture was cooled to 5oC. a Solution of di-tert-utilization.bacteria (14.9 kg, or 64.7 mol) in tetrahydrofuran (36 l) was added over about 2 hours while maintaining the temperature <6C. the Reaction was stirred for 5 hours while the temperature was given to increase slowly to 20-25oC. 6N HCl (26.5 l) was added to reaktsionnoi mixture at 20oC. the Reaction was stirred 24 hours at 20-25oWith in which the starting material has reacted. Water (10 gallons, 37.85 l) was added, and the tetrahydrofuran was removed by vacuum distillation. During concentration of the triphenylphosphine oxide was deposited, and added an additional 20 gpm (75,7 l) of water. The reaction was cooled, and methylene chloride (30 gallons, 113,6 l) was added. The layers were separated, and the aqueous was extracted twice more methylene chloride (10 gallons, 37.85 l). The aqueous layer was moved to remove the water. As the volume decreased, isopropyl alcohol (3h20 gallons (75,7 l)) was added to the azeotropic distillation of the Cabinet, giving 7,682 kg (68.6% of theoretical) on multiple parties. This material was characterized as being dichloride salt; so pl. 189-194oC.

'PMR (DMSO-d6, 300 MHz) of 3.48 (m, 1), to 1.79 (m, 2), of 1.64 (m, 4), for 1.49 (m, 2).

EXAMPLE 8

1-cyclopentyl-3-ethyl-6-(4-methoxybenzyl)-1,4,5,6-tetrahydropyrazolo[3,4-C]pyridine-7-he (8.0.0)

< / BR>
3-methoxy-1-(4-methoxybenzyl)-4-propionyl 5,6-dihydro-1H-pyridine-2-he (14,471 kg, 47,76 moles) was dissolved in tetrahydrofuran (10.5 gallons, 39,7 l) in a clean and dry 100 gallon tank. The dihydrochloride of cyclopenthiazide (7,664 kg, 44,3 mol) was added and the reaction mixture was heated slowly to ~ 88oWith, while nitrogen was flushed through the reaction mixture to remove methanol, THF and HCI. The reaction was monitored by HPLC until the transformation was not completed, which required heating during the night in most cases. The reaction product in the tank was a thick dark oil. Sample 1-cyclopentyl-3-ethyl-6-(4-methoxybenzyl)-1,4,5,6-tetrahydropyrazolo[3,4-C]pyridine-7-she stood out for characterization.

'TMR (Dl3, 300 MHz) of 7.23 (d, 2), 6,85 (d, 2), 5,72 (m, 1), to 4.62 (s, 2), of 3.77 (s, 3), 3,44 (t, 2). 2,62 (tick 4), to 2.06 (m, 4), 1,89 (m, 2), a rate of 1.67 (m , 2), 1,17 (so 3).13IDA (Dl3, 100 MHz) 159,5, 159,0, 148,0, 1 the Hai could be used directly in the next step or purified as salt p-toluensulfonate acid or benzosulfimide acid, as described.

EXAMPLE 9

Obtaining p-toluensulfonate acid or benzosulfimide acid salts of 1-cyclopentyl-3-ethyl-6-(4-methoxybenzyl)-1,4, 5,6-tetrahydropyrazolo[3,4-C]pyridine-7-it

The crude lactam (1 g, 2.83 mmole) was dissolved in ethyl acetate (5 ml) and was treated with a solution of anhydrous p-toluensulfonate acid (0.487 g, and 2.83 mmole) in ethyl acetate (2 ml). Salt was crystallized from a mixture, which is then cooled and filtered, giving 1,21 g of pure tosylate salt as a white solid with 81% yield; so pl. 110-113.8oC.

Analysis. Calculated for C28H35N3O5S: C, 63,98; N, OF 6.71; N, 7,99; S, 6,10. Found: C, 63,83; N, 6,69; N, 8,02; S, 6,14.

Salt benzosulfimide acid was formed in the same manner; so pl. 126,6-to 131.4'S.

Analysis. Calculated for C27H33N3O5S: C, 63,38; N, OF 6.50; N, 8,21. Found: C, 63,09; N, 6,48; N, 8,21.

Any of these crystalline salts may be used in the reaction of removing the protective group with triperoxonane acid and methanesulfonic acid, described in the following example.

EXAMPLE 10

1-cyclopentyl-3-ethyl-1,4,5,6-tetrahydropyrazolo[3,4-C] pyridine-7-he (9.0.0)

< / BR>
The reaction mixture from the previous example albertoni between 50 - 60oC. the First 1/3 of the boot was exothermic and required external cooling. Methansulfonate acid (6342 ml of 97.7 mol) was added and the reaction was heated to ~70oC for two hours. The reaction was cooled to 20-25oWith, and methylene chloride (17 gallons, 64 l) was added, followed by slow addition of water (17 gallons, 64 l). The layers were separated, and the aqueous layer was further diluted with water (6 gallons, 22.7 litres) and then extragonadal methylene chloride (6 gallons, 22.7 litres). United methylenchloride layers mixed with water (29 gallons, 110 l) and then brought to pH~to 7.0 by the addition of saturated sodium bicarbonate (approximately 45 gallons 170 liters). The layers were separated, and the methylene chloride was distilled under atmospheric pressure to about 9 gallons (35 liters). Ethyl acetate (13 gallons, 49 l) was added and the reaction mixture was converted to about 9 gallons (35 liters). The resulting suspension was cooled n was granulated. The solids were collected by filtration, rinsed with ethyl acetate and dried under vacuum at 40oWith under a full vacuum. The solution was to $ 7.91 kg, 71.2 percent; so pl. 152-153oC.

'TMR (Dl3, 300 MHz) 5,61 (m, 2), 3,51 (dt, 2), of 2.72 (t, 2), 2,62 (K, 2), of 2.08 (m, 4), 1,90 (m, 2), of 1.65 (m, 2), of 1.40 (t, 3).

WHEN is orata triethyloxonium (3,371 kg, 17,74 moles) in methylene chloride (10,8 l) was slowly added to a suspension of 1-cyclopentyl-3-ethyl-1,4,5,6-tetrahydropyrazolo[3,4-C] pyridine-7-she (3.6 kg, 15,43 moles) in methylene chloride (7.2 l) over a period of about 40 minutes. The solution is then allowed to react for about 21 hours at 18-22oC. After completion of the reaction the organic solution was filtered aqueous 10% sodium carbonate (36 l) and evaporated to an oil, which was used directly in the next stage. The output for this stage was 92.9%.

'TMR (Dl3, 300 MHz) 5,14 (quintet, 1), 4,25 (K, 2), 3,62 (t, 2), 2,58 (m , 4), 2,07 (m, 4), a 1.88 (m, 2), to 1.61 (m, 2), of 1.35 (t, 3), to 1.19 (t, 3). GC mass spectrum: m/e 261 (M+).

EXAMPLE 12

8-cyclopentyl-6-ethyl-3-thiophene-2-yl-5,8-dihydro-4H-1,2,3 a, 7,8-pentasa-as-indocin

< / BR>
A solution of 1-cyclopentyl-7-ethoxy-3-ethyl-4,5-dihydro-1H-pyrazolo[3,4-C] pyridine (3,739 kg of 14.3 mol) and hydrazide 2-thiophencarboxylic acid (2,237 kg 15,8 mole) was heated in a solution of 1-butanol (37 l) to ~90oC in a 50 gallon tank for 48 hours. At this temperature, some amount of 1-butanol was distilled to remove water azeotrope. The reaction was concentrated to a small volume, and 4 gallons of methylene chloride (4 gallon, 15 l) was added. Organic widespreadly alcohol (16 l) was added to the concentrate, and the resulting suspension was cooled and granulated. The product was collected by filtration and dried in a vacuum drying Cabinet at 40oC. the solution was 3.25 kg (67%) of white solids; so pl. 126oC.

'TMR (Dl3, 300 MHz) 7,51 (m, 2), 7,28 (s, 1), 7,20 (DD, 1), 5,61 (m , 1), 4,35 (t, 2), of 3.00 (t, 2), 2,70 (K, 2), to 2.18 (m, 4), of 1.97 (m, 2), of 1.62 (m, 2), of 1.29 (t, 3).

Analysis. Calculated for C18H21N5S: C, 63,69; N, 6,24; N, 20,63. Found: C, 63,82; N, 6,30; N, 20,77.

EXAMPLE 13

3-tert-butyl-8-cyclopentyl-6-ethyl-5,8-dihydro-4H-1,2,3 a, 7,8-pentasa-as-indocin

< / BR>
A solution of 1-cyclopentyl-7-ethoxy-3-ethyl-4,5-dihydro-1H-pyrazolo[3,4-C] pyridine (5 g, and 19.4 mmole) and hydrazide 2,2-dimethylpropionic acid (2,48 g, 21,4 mmol) was heated in a solution of 1-butanol (30 ml) under reflux for 48 hours. The solvent was evaporated under reduced pressure and the residual oil was dissolved in methylene chloride. The organic solution was washed 1N HCL (50 l) and dried over calcium chloride. The solution was filtered, evaporated in vacuum and the crude product was precrystallization from isopropyl alcohol. The solution was 2.76 g (45%) not quite white solids; so pl. 150-151oC.

'TMR (Dl3, 300 MHz) of 5.50 (m,1), of 4.49 (t, 2) and 3.15 (t, 2), 68,97; N, 8,68; N, 22,34. Found: C, 69,05; N, 8,89; N, 22,46.

1. The method of deriving 8-cyclopentyl-6-ethyl-3-(substituted)-5,8-dihydro-4H-1,2,3 a, 7,8-pentasa-as-indacene formula (1.0.0)

< / BR>
and its pharmaceutically acceptable salts, where R1is (C1-C6)alkyl, or saturated or unsaturated (C4-C7)heterocyclyl containing one atom S, and the above-mentioned alkyl and heterocyclic group optionally is substituted from 1 to 3 substituents, independently selected from (C1-C2)alkyl, trifloromethyl and halogen, wherein (a) a mixture of caprolactone and p-methoxybenzylamine without solvent heated to a temperature in the range from 80 to 85oC for 16 h to obtain amide derivative of the formula (2.0.0)

< / BR>
derived amide of formula (2.0.0) is subjected to recovery using sodium borohydride in tetrahydrofuran in the presence of acetic acid or its solution in tetrahydrofuran, and sodium borohydride are added to a tetrahydrofuran, and the amide of formula (2.0.0) is added in the form of solids in the reaction mixture, which is then cooled and mixed with acetic acid or its solution, the resulting mixture is heat is removed by extraction with ethyl acetate after adding 1N. HCl, and after adjusting the pH of the specified reaction mixture to 11 extracted amerosport formula (3.0.0) acetate

< / BR>
(C) the resulting aminoplast formula (3.0.0) acelerou by gradually adding within 20 to 30 minutes ethyl ester acid chloride of oxalic acid in ethyl acetate in accordance with the reaction conditions of Schotten's-Bauman in the presence of an aqueous solution of sodium bicarbonate at a temperature of from 0 to 5oWith, followed by keeping the reaction mixture at the specified temperature for 1-2 h, after which specified the reaction mixture is stirred at a temperature of from 20 to 25oC for 16 h, to obtain the ethyl ester examinados acid of the formula (4.0.0)

< / BR>
(d) is obtained ethyl ester examinados acid of the formula (4.0.0) is subjected to oxidation in methylene chloride using a freshly prepared aqueous solution of sodium hypochlorite, in the presence of a catalyst 2,2,6,6-tetramethyl-1-piperidinyloxy, and the sodium hypochlorite solution obtained by dissolution of calcium hypochlorite and sodium carbonate in water and bring the pH of the resulting solution to 9.5 with sodium bicarbonate, followed by the separation of by-product calcium carbonate by filtration, and the catalyst SN(4.0.0) in methylene chloride, the reaction mixture is cooled to a temperature of from 0 to 5oWith, then slowly add the sodium hypochlorite, keeping the temperature between 10 and 15oWith obtaining oxalidaceae formulas (5.0.0)

< / BR>
(e) oxalidaceae formulas (5.0.0) is subjected to cyclization in the reaction conditions of the condensation of Dickman, where the reaction is carried out in the presence of a relatively strong base, comprising of potassium tert-butylate in tetrahydrofuran, di-ISO-propyl simple ether, methyl tert-butyl simple ether or toluene, and the base is added gradually over a period of over 30 minutes, maintaining the temperature of the reaction mixture below 35oWith, followed by keeping the reaction mixture at a temperature of 20-25oC for 1 h and obtain pyridinone formula (6.0.0)

< / BR>
(f) pyridine formula (6.0.0) is subjected to O-methylation in the environment of dimethylformamide as a solvent in the presence of cesium carbonate, gradual addition of dimethylsulfate during over 30 min, maintaining the temperature of the reaction mixture from 20 to 25oWith, followed by keeping the reaction mixture at the same temperature and stirring for 16 h and 3 of methoxypyridine formula in the environment of tetrahydrofuran by heating the reaction mixture up to 88oC for 12 h and blowing it with nitrogen, followed by obtaining pyrazolopyrimidinone formula (8.0.0)

< / BR>
which, if necessary, can be purified and isolated in the form of a salt of p-toluensulfonate acid or benzosulfimide acid by dissolving the compounds of formula (8.0.0) in ethyl acetate and subsequent processing of anhydrous n-toluensulfonate acid or anhydrous benzosulfimide acid, dissolved in ethyl acetate, followed by crystallization of these salts from the cooled reaction mixture; (h) then carry out the removal of the protective n-methoxybenzyloxy group of pyrazolopyrimidinone formula (8.0.0) by slowly adding triperoxonane acid at a temperature of 55oWith supported by external cooling, and then adding methanesulfonic acid in the reaction mixture at a temperature of 70oWith, maintaining at this temperature the reaction mixture for 2 h and obtain a lactam of formula (9.0.0) while cooling the reaction mixture to a temperature of from 20 to 25oWITH:

< / BR>
(i) the suspension of the lactam of formula (9.0.0) in methylene chloride is subjected to esterification by slow addition of a solution of tetrafluoroborate triethyloxonium in chloritoid 18 to 22oC for 21 h, and receiving aminoether (imidate) formula (10.0.0)

< / BR>
(j) a solution of aminoether (imidate) formula (10.0.0) is treated with 1-butanol-carboxylic acid hydrazide of the formula (11.0.0)

< / BR>
where R1have the above meanings;

and the reaction mixture is heated at a temperature of 90oC for a period of more than 48 h, followed by separation of the target product.

2. The method according to p. 1, where R1represents 2-thiophene or tertbutyl; and the source connections on the stage (j) are compounds of the formula (10.0.0) and hydrazide 2-thiophencarboxylic acid or hydrazide 2,2-dimethylpropionic acid, the desired product of formula (1.0.0) is an 8-cyclopentyl-6-ethyl-3-thiophene-2-yl-5,8-dihydro-4H-1,2,3 a, 7,8-pentasa-as-indocin formula (1.0.1) or 8-cyclopentyl-6-ethyl-3-tert-butyl-2-yl-5,8-dihydro-4H-1,2,3 a, 7,8-pentasa-as-indocin formula (1.0.2)

< / BR>
< / BR>
3. The method of deriving 8-cyclopentyl-6-ethyl-3-(substituted)-5,8-dihydro-4H-1,2,3 a, 7,8-pentasa-as-indacene formula (1.0.0)

< / BR>
and its pharmaceutically acceptable salts, where R1is as defined in paragraph 1, characterized in that (a) the covenants of the formula (9.0.0)

< / BR>
subjected to esterification in the conditions of stage (i) p. 1 with obtaining kinabukasay acid of the formula (11.0.0)

< / BR>
where R1is as defined in paragraph 1,

in the conditions of stage (j) (1, followed by separation of the target product.

4. The method of deriving 8-cyclopentyl-6-ethyl-3-(substituted)-5,8-dihydro-4H-1,2,3 a, 7,8-pentasa-as-indacene formula (1.0.0)

< / BR>
and its pharmaceutically acceptable salts, where R1is as defined in paragraph 1, characterized in that aminoether (imidate) formula (10.0.0)

< / BR>
processed by the hydrazide carboxylic acid of the formula (11.0.0)

< / BR>
where R1is as defined in paragraph 1,

in the conditions of stage (j) (1, followed by separation of the target product.

5. Compounds selected from the group consisting of tosylate and besilate salts of pyrazolopyrimidinone formula (8.1.0) and (8.1.1)

< / BR>
< / BR>
6. Aminoether (imidate) formula (10.0.0)

< / BR>
and its pharmaceutically acceptable salts.

7. Connection under item 6, selected from his toiletry and besylate salts of formula (10.1.0) and (10.2.0)

< / BR>


 

Same patents:

The invention relates to the field of medicine

The invention relates to new alkaloids of the formula I

< / BR>
present in various parts of Mappia foetida, and their pharmaceutical use and use them as the new synthons for preparing compounds with antitumor and antiviral activity, the same products are new synthons for new analogues of camptothecin and palidino

--carboline" target="_blank">

The invention relates to bellrowan-carbolines, formula I, where R3denotes-CO-R1or group (a); R1- C1-C6alkoxy; R2- N2C1-C4alkyl, C1-C4alkoxy - C1-C2alkyl; And -- 5-6-membered unsaturated cycle, in which 1-2 carbon atoms may be replaced by N, O and/or S, which may be substituted with one R5or R6; R5and R6identical or different, denote H, C1-C6alkyl, NR7R8C1-C6alkyl which may be substituted by hydroxyl or C1-C4alkoxyl, phenyl, 5-6-membered heteroaryl residue, which contains one or two atoms of N, O or S, and phenyl and heteroaryl residue may be substituted C1-C4the alkyl, C1-C4alkoxyl, halogen, or R5and R6together,- CH2)nwhere n = 4; R7and R8- H, C1-C4alkyl, acyl, as well as their isomers, tautomers and salts

The invention relates to tricyclic 5,6-dihydro-N-pyrazolo [3,4-c] -1,2,4-triazolo[4,3-a]pyridinium, which have a selective inhibitory activity against phosphodiesterase (PDE) type IV or tumor-specific factor necrosis (TNF) and therefore effective in the treatment of asthma, arthritis, bronchitis, chronic obstructive Airways disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory diseases, such as AIDS, sepsis, septic shock and other diseases, in particular cachexia, causing the formation of tumor-specific factor necrosis

The invention relates to novel pyrido[3,2-e]pyrazinone f-ly I, where X,Y and Z Is N or CR3and at least one of X,Y and Z must be N, R1- C1-C10-alkyl which can be substituted by aryl, R2- H, C5-C7-cycloalkyl, C1-C10-alkyl which can be substituted by the Deputy selected from the group comprising aryl, aryloxy, hydroxyl, SO3H-group, pyridinyl, chinoline, A - CH2N - R3or Oh, R3is hydrogen, C1-C6-alkyl, or their physiologically tolerable salts, which possess anti-asthma and anti-allergic effect

The invention relates to new derivatives dipyridodiazepinone possessing biological activity, and more particularly to 2-heteroaryl-5,11-dihydro-6H-dipyrido[3,2-b: 2', 3'-e] [1,4] diazepin-6-Onam, their pharmaceutically acceptable salts and pharmaceutical composition having inhibitory activity against reverse transcriptase of HIV-1

The invention relates to a new process for the preparation of 2,3-pyridinecarboxamide formula (I), where R is hydrogen, C1-C6alkyl or C1-C6alkoxymethyl, R1means hydrogen, C1-C6alkyl, C(O)R2, phenyl, benzyl, R2means C1-C6alkyl, benzyl or phenyl, which is that the compound of formula (II), where R has the above meaning, R6means C1-C6alkyl, R7means OR8or NR9R10, R8means hydrogen, C1-C6alkyl, C(O)R11, phenyl, benzyl, R11means C1-C6alkyl, OR12, NR12, R13, benzyl or phenyl, R12and R13denote hydrogen, C1-C6alkyl, benzyl or phenyl, R9and R10denote hydrogen, C1-C6alkyl, benzyl or phenyl, is subjected to the interaction with the imide of maleic acid of the formula (III), where R1have the above values

The invention relates to compounds of General formula (I) in which X represents hydrogen or halogen or alkyl, CNS, triptorelin or phenylmethoxy, R1represents hydrogen or alkyl, cyclopropyl or phenylmethylene group, R2represents either an alkyl group, possibly substituted, or phenylalkyl group, possibly substituted, or cyclohexylmethyl group, or thienylmethyl group, or pyridinylmethyl group, or phenyl group, possibly substituted, or pyridinyl group, or 5-methyl-1,2-oxazolidinyl group, or 5-methyl-1,3,4-thiadiazolyl group, or naphthalenyloxy group, R3and R4each represents hydrogen or alkyl, 2-methoxyaniline, hydroxyalkyl, carboxialkilnuyu, alkoxycarbonylmethyl or phenylalkyl group, or together with the nitrogen atom which carries them, form or pyrrolidinyloxy group, possibly substituted, or piperidinyl group, or morpholinyl group, or 4-methylpiperidino group, or azetidinol group, or thiazolidinedione group, and the bond between carbon atoms at positions 3 and 4 is a simple or double

The invention relates to an inhibitor semipretioase - derived imidazo [1,5-a] pyridine, containing containing structural unit (link) of General formula (I), where R1and R2represent hydrogen, R3and R4independently represent hydrogen, (1-6C) alkyl or together form =CH-NR5R6and R5and R6represent (1-6C) alkyl; X is hydrogen, R7, acetyl, PMC, R7-SO2N-protecting group, where R7is (1-12C) alkyl or (1-14C) aryl; R3represents a bond, D-Tig, Atc, D - amino acid with a hydrophobic side chain; R2is Pro, Gly, Val, Jle, 2,4-Me P2O, 3,3-Dmp, Jlc, Thr, Hyp, 2,2-Dmt or 5,5-Dmt; or R2is the link in case when R3is a bond, and X is R7-SO2-; or R2and R3together represent a structure similar to a dipeptide having the formula (II), in which the positions marked with asterisks may be condensed with a benzene ring and in which R9is hydrogen; or its pharmaceutically acceptable salt

The invention relates to new bicyclic pyrimidine derivative or its pharmaceutically acceptable salts, methods of inhibiting tyrosine kinase receptor, epidermal growth factor, in particular in the treatment of cancer, the pharmaceutical composition having inhibitory to tyrosinekinase factor receptor epidermal growth activity, as well as composition having contraceptive action

The invention relates to methods of reducing the level of TNFin mammals and connections that are applicable for this purpose

The invention relates to new derivatives naphthiridine formula I, where R1denotes phenyl, benzyl, 3-nitrophenyl, 3-chlorophenyl, 3-tianfeng, 3-(tetrazolyl)phenyl or benzofuranyl; R2denotes a hydroxy-group, tripterocalyx, allyl, alkyl, alkenyl, quinil, alkoxygroup, phenyl, phenyloxy, carboxyphenyl, carboxymethyl, carbamoylmethyl, phenylamino, diphenylamino-, amino-, elcamino, Alcaidaria, where "ALK" refers to aliphatic fragment having up to 8 carbon atoms and optionally including carboxylate, ether carboxylic acid or a hydroxy-group and/or optionally containing ether and/or ester bond, or its N-oxide in free form or in the form of a pharmaceutically acceptable salt

The invention relates to new compounds of General formula (I), where R1is hydrogen, alkyl with 1 to 4 carbon atoms, R2hydrogen, (5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl, residues of formula-CH=CH-COOR3CH2CH2COOR3, -CH2CH2CN, -CH2CH2COCH3, -CH2PINES3where R3means methyl or ethyl, or a residue of the General formula R4- NH-CHR5-CO-, where R4denotes hydrogen, alkyl with 1 to 3 atoms wereda R5denotes hydrogen, alkyl with 1 to 4 carbon atoms, or benzyl, the Invention also concerns a pharmaceutical composition having antibacterial activity, containing the compounds of formula (I)

The invention relates to dipeptide compounds, which are stimulators of growth hormone and can be used for the treatment and prevention of osteoporosis

The invention relates to new heterobicyclic derivatives and their pharmaceutically acceptable salts, useful as a drug

The invention relates to amide derivative of the General formula I, the symbols in the formula have the following meanings: D is pyrazolidine group which may have 1-3 halogenated derivatives or unsubstituted lower alkyl group as the Deputy(I)her is fenelonov or topendialog group, X represents a group of formula-NH-CO - or-CO-NH -, and a represents a phenyl group which may be substituted by one or more halogen atoms, or a five - or six-membered monocyclic heteroaryl group which may be substituted by one or more of lower alkyl groups
Up!