RU2122000C1 - Benzopyranes, intermediate compounds, pharmaceutical composition and method of treatment - Google Patents

Abstract

FIELD: organic chemistry, pharmacy. SUBSTANCE: invention relates to benzopyranes of the formula (I)

where X is O or NH; R, R¹ and R² - H or C₁-cyanoalkyl; R³ is (a) 6-membered heterocyclic ring containing 1 or 2 N atoms being yhis ring is bound with X through carbon atom in ring, optionally fused with benzene ring and optionally substituted with alkyl, halogen or oxo-group at condition that R³ is not -N-(C_1-6-alkyl)-pyridonyl group; (b) when X is NH then group (i) R⁴ or (c) when X is NH then group (j) R⁵; C_1-6 is phenyl substituted with 1 or 2 hydroxy-groups; R⁶ is SR⁵-alkyl; R⁷ is R⁸-OR⁵;

is cyano-group;

Description

 The present invention relates to benzopyranes. More specifically, it relates to derivatives of 6- (hydroxyphenyl) sulfonylbenzo (b) pyran and compositions containing them, their uses, methods of preparation and intermediates used in the preparation of such derivatives.

 The proposed derivatives have activity, manifested in the relaxation of smooth muscles, the mechanism of which includes the opening of potassium channels. Therefore, they are useful in the treatment or prevention of diseases associated with changes in the tone and / or contractility of the smooth muscle, which may, for example, happen in the lung, bladder, intestine, uterus, or cardiovascular system. Such diseases include chronic airway obstruction, asthma, urinary incontinence, irritable bowel syndrome, diverticulum disease, achalasia (impaired ability to relax smooth muscle sphincters) of the esophagus, and hypertension. In addition, the derivatives of the present invention can be useful in the treatment of peripheral vascular disease, congestive heart failure, pulmonary hypertension, myocardial and cerebral ischemia, angina pectoris, spotted baldness in men, cardiac arrhythmias, skeletal muscle fatigue or paralysis (myotonic muscular dystrophy), glaucoma , epilepsy, tinnitus, dizziness and dysmenorrhea (menstrual cycle disorder).

 Patents EP-A-0547522, EP-A-0351720, EP-A-0450415 and EP-A-0400430 describe benzopyranes with pharmacological activity. EP-A-0553679 describes the epoxylation of chromenes.

и их фармацевтически приемлемые соли,
где X представляет O, S или NH,
R и R¹ каждый независимо выбран из H и C₁-C₄-алкила или взятые вместе представляют C₂-C₆-алкилен;
R² представляет H или C₁-C₄-алкил;
R³ представляет: (a) 6-членное гетероциклическое кольцо, содержащее 1 или 2 гетероатома N, причем указанное кольцо связано с X посредством атома углерода в кольце, необязательно сконденсированное с бензольным кольцом и необязательно замещенное (в том числе в конденсированной бензильной части) C₁-C₆-алкилен, гидрокси, -OR⁵, галогеном, -S(O)_mR⁵, оксо, амино, -NHR⁵, -N(R⁵)₂, циано, -CO₂R⁵, -CONH₂, -CONHR⁵ или CO(R⁵)₂, при условии, что R³ не является N-(C₁-C₆-алкил)-пиридонильной группой, (b) когда X-NH-группу формулы

(c) когда X-NH-группу формулы

R⁴ представляет фенил, замещенный гидроксигруппой и необязательно замещенный 1 или 2 заместителями, каждый из которых независимо выбран из гидрокси, C₁-C₆-алкила, -OR⁵, галогена, циано и нитро;
R⁵ - C₁-C₆-алкил;
R⁶ представляет -OR⁵, -NHR⁵, -N(R⁵)₂, -SR⁵ или -NHR⁹;
R⁷-циано;
R⁸ - -OR⁵, -NHR⁵, -N(R⁵)₂ или -NHR⁹;
R⁹ - фенил, необязательно замещенный C₁-C₆-алкилом, гидрокси, -OR⁵, галогеном, циано или нитро;
m = 0, 1 или 2.The present invention provides compounds of formula I

and their pharmaceutically acceptable salts,
where X represents O, S or NH,
R and R ^{1 are} each independently selected from H and C ₁ -C ₄ alkyl or taken together are C ₂ -C ₆ alkylene;
R ² represents H or C ₁ -C ₄ alkyl;
R ³ represents: (a) a 6-membered heterocyclic ring containing 1 or 2 N heteroatoms, said ring being attached to X via a carbon atom in the ring, optionally fused to the benzene ring and optionally substituted (including in the fused benzyl part) C ₁ -C ₆ -alkylene, hydroxy, -OR ⁵ , halogen, -S (O) _m R ⁵ , oxo, amino, -NHR ⁵ , -N (R ⁵ ) ₂ , cyano, -CO ₂ R ⁵ , -CONH ₂ , -CONHR ⁵ or CO (R ⁵ ) ₂ , provided that R ^{3 is} not an N- (C ₁ -C ₆ alkyl) pyridonyl group, (b) when an X-NH group of the formula

(c) when the X-NH group of the formula

R ⁴ is phenyl substituted with hydroxy and optionally substituted with 1 or 2 substituents, each independently selected from hydroxy, C ₁ -C ₆ alkyl, —OR ⁵ , halogen, cyano and nitro;
R ⁵ is C ₁ -C ₆ alkyl;
R ⁶ is —OR ⁵ , —NHR ⁵ , —N (R ⁵ ) ₂ , —SR ^5, or —NHR ⁹ ;
R ^{7 is} cyano;
R ⁸ is —OR ⁵ , —NHR ⁵ , —N (R ⁵ ) _2, or —NHR ⁹ ;
R ⁹ is phenyl optionally substituted with C ₁ -C ₆ alkyl, hydroxy, -OR ⁵ , halogen, cyano or nitro;
m = 0, 1 or 2.

 In the above definitions, the term “halogen” means fluoro, chloro, bromo or iodo. Alkyl groups containing three or more carbon atoms may be unbranched or branched.

 Preferably X is O or NH.

 Most preferably, X is O.

Preferably, R, R ¹ and R ^{2 are} each C ₁ -C ₄ alkyl.

Most preferably, R, R ¹ and R ^{2 are} each methyl.

или (c) группу формулы

Более предпочтительно R³ представляет 1,2-дигидро-2- оксо-1H-пиридин-4-ил, 1,2-дигидро-5,6-диметил-2-оксо-1H- пиридин-4-ил, 3-гидроксипиридазин-6-ил, 2,3-дигидро-2-метил- 3-оксопиридазин-6-ил, 2,3-дигидро-2-этил-3-оксопиридазин-6-ил, 1,2-дигидро-1-оксо-2H-фталазин-4-ил, 1,2-дигидро-2-метил-1-оксо-фталазин-4-ил, 2-хлорпиримидин-4-ил, 3,4-диоксо-2-этоксициклобут-1-ен-1-ил или 3-циано-2-метилизотиоурендо.Preferably, R ³ is: (a) a 6-membered heterocyclic ring containing 1 or 2 N heteroatoms, said ring being optionally fused to a benzene ring and optionally substituted with C ₁ -C ₄ alkyl, hydroxy, halogen or oxo, and more preferably said the ring is not completely saturated, (b) a group of the formula

or (c) a group of the formula

More preferably, R ³ is 1,2-dihydro-2-oxo-1H-pyridin-4-yl, 1,2-dihydro-5,6-dimethyl-2-oxo-1H-pyridin-4-yl, 3-hydroxypyridazine -6-yl, 2,3-dihydro-2-methyl-3-oxopyridazin-6-yl, 2,3-dihydro-2-ethyl-3-oxopyridazin-6-yl, 1,2-dihydro-1-oxo -2H-phthalazin-4-yl, 1,2-dihydro-2-methyl-1-oxo-phthalazin-4-yl, 2-chloropyrimidin-4-yl, 3,4-dioxo-2-ethoxycyclobut-1-ene -1-yl or 3-cyano-2-methylisothiourendo.

Most preferably, R ³ is 1,2-dihydro-2-oxo-1H-pyridin-4-yl or 2,3-dihydro-2-methyl-3-oxopyridazin-6-yl.

Preferably, R ⁴ is phenyl substituted with one or two hydroxy groups. More preferably, R ⁴ is 2-, 3- or 4-hydroxyphenyl or 3,4-dihydroxyphenyl. Most preferably, R is 3-hydroxyphenyl or 4-hydroxyphenyl.

Preferably R ⁶ is - SR ⁵ . Most preferably, R ⁶ is methylthio.

Preferably R ⁸ is —OR ⁵ . Most preferably, R ⁸ is ethoxy.

 Pharmaceutically acceptable salts of the compounds of formula I include their acid addition and base salts.

 Suitable acid addition salts are obtained from acids that form methoxy salts, and examples of such salts are hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, phosphate, hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, benzoate, methanesulfonate, benzenesulfonate and para-toluenesulfonate.

 Suitable base salts are derived from bases that form non-toxic salts, and examples of such salts are aluminum, calcium, magnesium, zinc and diethanolamine salts.

 A review of suitable salts is given by Berge et al., J. Pharm. Sci., 1977, 66, 1-19.

 The compounds of formula I may contain one or more asymmetric carbon atoms and therefore may exist in two or more stereoisomeric forms. The present invention includes both individual stereoisomers of compounds of formula I, and mixtures thereof and, where appropriate, all tautomeric forms of compounds of formula I.

 The separation of diastereoisomers can be carried out by conventional methods, for example, fractional crystallization, chromatography or HPLC of a stereoisomeric mixture of a compound of formula I or a suitable salt or derivative thereof. A single enantiomer of a compound of formula I can also be prepared from the corresponding optically pure intermediate, either by resolution, for example by HPLC of the corresponding racemate using a suitable chiral support or by fractional crystallization of diastereoisomeric salts formed by reacting the corresponding racemate with a suitable optically active acid or base.

где
X, R, R¹, R², R³ и R⁴ - такие, как указаны выше для соединения формулы I.A preferred group of compounds of formula I is of formula IA

Where
X, R, R ¹ , R ² , R ³ and R ⁴ are as defined above for the compound of formula I.

где
R¹⁰ представляет фенил, замещенный защищенной гидроксигруппой и необязательно еще замещенный 1 или 2 заместителями, каждый из которых независимо выбран из защищенной гидроксигруппы, гидрокси, C₁-C₆-алкила, -OR⁵, галогена, циано и нитро;
X, R, R¹, R², R³ и R⁵ - такие, как указаны выше для соединения формулы (I).The compounds of formula I of the present invention can be obtained in the following ways:
1) All compounds of formula I can be obtained by deprotecting a compound of formula II

Where
R ¹⁰ represents phenyl substituted with a protected hydroxy group and optionally further substituted with 1 or 2 substituents, each independently selected from a protected hydroxy group, hydroxy, C ₁ -C ₆ alkyl, -OR ⁵ , halogen, cyano and nitro;
X, R, R ¹ , R ² , R ³ and R ⁵ are as defined above for the compound of formula (I).

 A variety of suitable hydroxy protecting groups and methods for their removal are well known to those skilled in the art, for example, see T.W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Second Edition, Wiley-Interscience, 1991.

Some alkyl groups, for example methyl and tert-butyl, can be attributed to hydroxy protecting groups. It should be understood that when the phenyl group R ^{10 is} substituted with C ₁ -C ₄ alkoxy (for example, methoxy or tert-butoxy), it can also be converted to hydroxyphenyl by using certain deprotection conditions.

 In a conventional method for removing a methyl hydroxy protecting group, a methoxyphenyl sulfone of formula II is treated with boron tribromide in a suitable organic solvent, for example, dichloromethane at room temperature.

 A trialkylsilyl group may also be used as a hydroxy protecting group. Preferred is a tert-butyldimethylsilyl group, which can be removed by treatment with fluorine ions using, for example, tetrabutylammonium fluoride or hydrofluoric acid.

 When the resulting compound of formula I is a 1,2-diode, it can be obtained from a compound of formula II, where both hydroxy groups are protected together, for example, as a ketal.

Compounds of formula II, wherein R ³ has the definition (a) above for R ^{3 of a} compound of formula I, may be prepared from a compound of formula VI by a conventional method similar to that described in method (2) for preparing compounds of formula I.

Compounds of formula II where R ³ has the definition (o) or (c) above for R ^{3 of a} compound of formula I can be prepared by first converting a compound of formula VI to the corresponding 4-amino-3-hydroxybenzopyran derivative in a manner analogous to that described to obtain a compound of formula VII from a compound of formula III in method (4), followed by the additional introduction of the required 4-substituent by a procedure similar to that described in any one or more (which are suitable) of methods (4), (5) and (7).

где
R, R¹, R² и R⁴ - такие, как указаны выше для этого способа, либо с соединением формулы
R³XH
или, где это уместно, с его таутомером в присутствии основания, либо с основной солью соединения формулы
R³XH
где X и R³ - такие, как указаны выше для этого способа.2) Compounds of formula I, where R ³ has the definition of (a), as defined above for R ^3, compounds of formula I, and X, R, R ¹ , R ² and R ⁴ , such as those described above for compounds of formula I, may be obtained by reacting a compound of formula III

Where
R, R ¹ , R ² and R ⁴ are as defined above for this method, or with a compound of the formula
R ³ XH
or, where appropriate, with its tautomer in the presence of a base, or with a basic salt of a compound of the formula
R ³ XH
where X and R ³ are as described above for this method.

Preferred basic salts of the compounds of formula R ³ XH include alkali metal salts, for example sodium and potassium salts. When using a basic salt, it can be formed in situ from the corresponding compound of formula R ³ XH using a suitable base, for example sodium hydride.

If a basic salt of the compound of formula R ³ XH is not used, the presence of a suitable base, for example pyridine or triethylamine, is also necessary, although usually only a catalytic amount thereof is necessary.

 The reaction can be carried out in a suitable solvent, for example ethanol or 1,4-dioxane, at a temperature ranging from room temperature to (preferably) the boiling point of the solvent.

где
R^10a - фенил, замещенный защищенной гидроксигруппой и необязательно далее замещенный 1 или 2 заместителями, каждый из которых независимо выбран из защищенной гидроксигруппы, C₁-C₆ алкила, - OR⁵, галогена, циано и нитро;
R, R¹, R², R⁴ и R⁵ - такие, как указаны выше для соединения формулы I для способа (2).The compounds of formula III can be obtained according to the following scheme:

Where
R ^10a is phenyl substituted with a protected hydroxy group and optionally further substituted with 1 or 2 substituents, each independently selected from a protected hydroxy group, C ₁ -C ₆ alkyl, —OR ⁵ , halogen, cyano and nitro;
R, R ¹ , R ² , R ⁴ and R ⁵ are as defined above for the compound of formula I for method (2).

In a conventional procedure, a compound of formula VI is reacted with a thiol of formula
R ^10a SH
Where
R ^10a is the same as above for this method,
in the presence of sodium tert-butoxide and tetrakis (triphenylphosphine) -palladium (O) in a suitable solvent (e.g. ethanol) at boiling point.

 The resulting compound of formula V can be converted to the oxirane (ethylene oxide) of formula VI by oxidation using sodium hypochlorite in the presence of [(R, R) -or (S, S) -1,2-bis (3,5-di-tert-butylsalicylidamino )] cyclohexane-manganese (III) chloride (see JACS, 1991, 113, 7063).

 The hydroxy protecting group (s) can then be removed from the compound of formula VI in the usual manner, resulting in a compound of formula III.

A compound of formula V can be prepared from a compound of formula IV using methyl as the hydroxy protecting group in R ^10a to dealkylate this compound to produce the corresponding phenol, and then protecting the phenol again with a second hydroxy protecting group, for example benzyl, before carrying out the oxidation reaction.

All compounds of formula IV and R ^10a SH can be obtained by known methods.

где
R^10b - фенил, замещенный три(C₁-C₄-алкил)силилоксигруппой (т. е. три(C₁-C₄-алкил)силил-защищенной гидроксигруппой) и необязательно далее замещенный 1 или 2 заместителями, каждый из которых независимо выбран из три(C₁-C₄-алкил)силилокси, гидрокси, C₁-C₆-алкила, -OR⁵, галогена, циано и нитро, и R, R¹, R² и R⁵ - такие, как указаны выше для соединения формулы I, либо с соединением формулы
R³XH
или, где это уместно, его таотомером в присутствии основания, либо с основной солью соединения формулы:
R³XH
где
X и R³ - такие, как указаны для этого способа.3) Compounds of formula I, wherein R ³ is as defined in (a) above for R ^{3 of a} compound of formula I and X, R, R ¹ , R ² and R ⁴ are as defined above for a compound of formula I can be obtained by reacting a compound of formula VIA

Where
R ^10b is phenyl substituted with three (C ₁ -C ₄ -alkyl) silyloxy group (i.e., three (C ₁ -C ₄ -alkyl) silyl-protected hydroxy group) and optionally further substituted with 1 or 2 substituents, each independently selected from tri (C ₁ -C ₄ -alkyl) silyloxy, hydroxy, C ₁ -C ₆ -alkyl, -OR ⁵ , halogen, cyano and nitro, and R, R ¹ , R ² and R ⁵ are as indicated above for a compound of formula I, or with a compound of formula
R ³ XH
or, where appropriate, its ta isomer in the presence of a base, or with a basic salt of a compound of the formula:
R ³ XH
Where
X and R ³ are as indicated for this method.

A preferred tri (C ₁ -C ₄ alkyl) silyloxy protecting group is tert-butyldimethylsilyloxy.

Preferred basic salts of the compounds of formula R ³ XH include alkali metal salts, for example, sodium and potassium salts. When using a basic salt, it can be formed in situ from the corresponding compound of formula R ³ XH using a suitable base, for example sodium hydrate.

If a basic salt of a compound of formula R ³ XH is not used, the presence of a suitable base, for example pyridine or triethylamine, is also necessary, although usually only a catalytic amount thereof is necessary.

In a conventional procedure where the basic salt of the compound of formula R ³ XH is not used, the reaction is carried out in a suitable organic solvent (e.g., 1,4-dioxane, ethanol, isopropanol or diethylene glycol) and at elevated temperature, for example, at or near the boiling point of the solvent temperature.

R, R¹, R², R⁴, R⁵ и R⁷ - такие, как указаны выше для соединения формулы I, могут быть получены взаимодействием соединения формулы VII

где
R, R¹, R² и R⁴ - такие, как указаны выше для этого способа,
с соединением формулы:
(R⁵S)₂C=NR⁷
где
R⁵ и R⁷ - такие, как указаны выше для этого способа.4) The compounds of formula I, where X represents NH, R ³ represents a group of the formula

R, R ¹ , R ² , R ⁴ , R ⁵ and R ⁷ are as defined above for the compound of formula I, can be prepared by reacting a compound of formula VII

Where
R, R ¹ , R ² and R ⁴ are as described above for this method,
with a compound of the formula:
(R ⁵ S) ₂ C = NR ⁷
Where
R ⁵ and R ⁷ are as described above for this method.

 In a conventional procedure, the reactants are heated together in the presence of a basic catalyst, for example pyridine, in a suitable solvent, for example ethanol.

Compounds of formula VII can be prepared by treating a compound of formula III with an ethanol solution of aqueous ammonia, usually at a temperature of from 40 to 50 ^° C.

где
R⁶ представляет -OR⁵, -NHR⁵, -N(R⁵)₂ или -NHR⁹ и R, R¹, R², R⁴, R⁵, R⁷ и R⁹ - такие, как указаны выше для соединения формулы I, могут быть получены взаимодействием соединения формулы I, где X, R, R¹, R², R³, R⁴, R⁵ и R⁷ - такие, как указаны для способа (4) получения соединений формулы I, с подходящей основной солью соединения формулы R⁵OH (т.е. алкоксидного производного) или с соединением формулы R⁵NH₂, (R⁵)₂NH или R⁹NH₂ (или, когда это уместно, подходящей его основной солью), где R⁵ и R⁹ - такие, как указаны для этого способа.5) The compounds of formula I, where X represents NH, R ³ represents a group of the formula

Where
R ⁶ is —OR ⁵ , —NHR ⁵ , —N (R ⁵ ) _2, or —NHR ⁹ and R, R ¹ , R ² , R ⁴ , R ⁵ , R ^7, and R ⁹ are as defined above for the compound of formula I can be prepared by reacting a compound of formula I, wherein X, R, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁷ are as specified for process (4) for preparing compounds of formula I with a suitable a base salt of a compound of formula R ⁵ OH (i.e., an alkoxide derivative) or with a compound of formula R ⁵ NH ₂ , (R ⁵ ) ₂ NH or R ⁹ NH ₂ (or, when appropriate, a suitable base salt thereof), where R ⁵ and R ⁹ are as indicated for this method.

Suitable base salts of compounds of the formula R ⁵ OH, R ⁵ NH ₂ , (R ⁵ ) ₂ NH and R ⁹ NH ₂ include alkali metal salts, for example, sodium and potassium salts.

 The reaction is usually carried out in a suitable solvent, for example tetrahydrofuran, at boiling point.

6) Compounds of formula I, where X is NH, R ³ is a 6-membered heterocyclic ring containing 1 or 2 heteroatoms N, which is optionally substituted as defined in definition (a) above for R ³ for a compound of formula I, and R, R ¹ , R ² and R ⁴ , such as those indicated above for the compound of formula I, can be prepared by reacting a compound of the formula VII, R, R ¹ , R ² and R ⁴ , such as those indicated above for the compound of formula VII, with heterocyclic a compound with a 6-membered nucleus containing 1 or 2 N heteroatoms, which is substituted on the leaving carbon atom in the ring th group, e.g. halo (preferably chloro or bromo) or a group of formula (C ₁ -C ₄ alkyl) S (O) _n -, where n = 0, 1 or 2 and optionally further substituted as described above for R ³ for this method.

 In a conventional procedure where halogen is used as the leaving group, the reaction is carried out in the presence of a suitable acid acceptor (e.g. diisopropylethylamine) in a suitable solvent (e.g. 1,4-dioxane) at a temperature approximately equal to the boiling point of this solvent.

R, R¹, R², R⁴ и R⁸ - такие, как указаны выше для соединения формулы I, могут быть получены взаимодействием соединения формулы VII, где R, R¹, R² и R⁴ - такие, как указаны выше для соединения формулы VII, с соединением формулы

где
Z представляет подходящую уходящую группу (например, этокси);
R⁸ - такой, как указан выше для этого способа.7) The compounds of formula I, where X represents NH, R ³ represents a group of the formula

R, R ¹ , R ² , R ⁴ and R ⁸ are as described above for the compound of formula I, can be obtained by the interaction of the compounds of formula VII, where R, R ¹ , R ² and R ⁴ are as described above for compounds of formula VII, with a compound of the formula

Where
Z represents a suitable leaving group (e.g. ethoxy);
R ⁸ is the same as above for this method.

 In a conventional procedure, the compounds are heated together in a suitable solvent (e.g. ethanol) at a temperature approximately equal to its boiling point.

 The compounds of formula VIII can be obtained by known methods.

 All of the above reactions and the preparation of new starting materials used in the preceding methods are traditional, and suitable reagents and reaction conditions for their fulfillment or preparation, as well as methods for isolating target products well-known to those skilled in the art, including from the preceding materials and those cited in them are examples and methods of preparation.

 A pharmaceutically acceptable salt of a compound of formula I can be easily prepared by mixing together solutions of a compound of formula I and the desired acid or the desired base. Salt can be precipitated from the solution and filtered or recovered by evaporation of the solvent.

 The compounds of formula I exhibit activity in smooth muscle relaxation, because they are able to open potassium channels in such tissue. They can be tested for the indicated activity by the method described below, including the measurement of in vitro relaxation of electrically stimulated tracheal rings of guinea pigs.

Adult male guinea pigs (Porcellus, 500–900 g) were killed by a blow to the head, followed by bleeding. Each trachea was excised and placed in a Krebs solution (the composition of the Krebs solution was as follows (millimoles):
NaCl (119), KCl (4.7), NaHCO ₃ (25), KH ₂ PO ₄ (1,2), MgSO ₄ (1,2), CaCl ₂ (2,5), glucose (11), and to eliminate the effect of endogenous prostanoids, indomethacin (2.8 μM) was added, the solution being aerated with a mixture of 95% oxygen - 5% carbon dioxide, and the temperature was kept constant at 37 ^° C). The attached connective tissue was cut off, and the tracheal tube was opened by cutting through the cartilage on the side opposite to the smooth muscle bundle. A long cotton thread was attached to the cartilage at one end of the tracheal strip to connect to the isometric transducer, and the other thread was attached to the other end of the strip to connect to the electrode for stimulation. The preparation was kept under constant tension of 1 g in a bath with 15 ml of physiological saline at a temperature of 37 ^o C with a gaseous mixture of 95% oxygen and 5 carbon dioxide. The tissue was washed at intervals of 15 minutes, and allowed it to come into equilibrium for 1 hour.

 At the end of the period of establishment of the equilibrium state, the tissue was stimulated at a frequency of 1 Hz, a pulse duration of 0.1 ms, and a supermaximum voltage of 25-30 V for 10 seconds at intervals of 100 seconds. After stabilization of the contractile reactions, a single dose of a compound of formula I or a pharmaceutically acceptable salt thereof was added to the bath, and tissue stimulation was continued for 2 hours.

 Next, the minimum dose of the compound of formula I was determined, which caused the maximum inhibition of cholinergic contraction compared with the control.

 When used for human use, the compounds of formula I and their salts can be administered separately, but usually they are administered in a mixture with a pharmaceutical carrier, selected taking into account the intended route of administration and normal pharmaceutical practice.

 For example, they can be administered orally in the form of tablets containing excipients such as starch or lactose, or in capsules, alone or in a mixture with excipients, or in the form of elixirs, solutions or suspensions containing substances that add taste and smell, or coloring substances.

 They can be injected parenterally, for example intravenously, intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution, which may contain other substances, for example, a sufficient amount of salts or glucose to make the solution isotonic with blood.

 For oral and parenteral administration to sick people, the daily dose of the compounds of formula I is from 0.01 to 20 mg / kg (in single or divided doses), and preferably from 0.1 to 5 mg / kg.

 Therefore, tablets or capsules contain from 1 mg to 5 g of the active compound for administration one, two or more at a time according to need. In each case, the doctor determines the necessary dose, the most suitable for a particular patient, which he changes depending on the age, weight and sensitivity of the patient. The indicated doses are given as averaged, but in some cases wider or narrower dosage limits may be required, which are included in the scope of the present invention.

 The compounds of formula I can also be administered by inhalation, usually with an aerosol stream, from a vessel (nebulizer) under pressure using a suitable nebulizing agent, for example dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, hydrofluoroalkane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, a single dose can be provided by using a valve dispensing a metered amount. The pressure vessel (nebulizer) may contain a solution or suspension of the active compound. Administration by inhalation may also be carried out using a dry powder inhaler. Capsules and sleeves (made, for example, from gelatin) for use in an inhaler or insufflator may contain a powder mixture of a compound of formula I and a suitable powder base, such as lactose or starch.

 Aerosol dosage forms are preferably performed so that each metered dose (or "release") of the aerosol contains from 20 μg to 1000 μg of a compound of formula I or a pharmaceutically acceptable salt thereof for administration to a patient. The total daily dose administered with an aerosol is in the range of 20 μg to 10 mg and can be administered in a single dose or, more commonly, in separate doses throughout the day.

 In other embodiments, compounds of Formula I may be administered in the form of a suppository, rectal or vaginal, or topically in the form of a lotion, solution, cream, ointment, or nebulized powder. For example, they can be included in a cream consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin, or can be included (at a concentration of 1 to 10%) in an ointment consisting of white wax or white petrolatum as a base together with suitable stabilizers and preservatives .

In accordance with the present invention also provides:
i) a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable diluent or carrier,
ii) A compound of formula I or a pharmaceutically acceptable salt or composition thereof useful as a medicine,
iii) the use of a compound of formula I or a pharmaceutically acceptable salt or composition thereof for the manufacture of a medicament for the treatment or prevention of a disease associated with a change in the tone and / or contractility of smooth muscle,
iv) Use as specified in III when the disease is chronic airway obstruction, asthma, urinary incontinence, irritable bowel syndrome, diverticulum disease, achalasia (impaired relaxation of smooth muscle sphincters) of the esophagus or hypertension,
v) A method for treating or preventing a disease in a person associated with a change in the tone and / or contractility of the smooth muscle, comprising treating a person with an effective amount of a compound of formula I or a pharmaceutically acceptable salt or composition thereof,
vi) a method as specified in V, when the disease is chronic airway obstruction, asthma, urinary incontinence, irritable bowel syndrome, diverticulum disease, esophageal achalasia or hypertension, and
vii) intermediates of formulas II, III, VIA and VII.

 The following examples illustrate the preparation of compounds of formula I.

(3S, 4R)-4-(2-Хлорпиримидин-4-ил)амино-3,4-дигидро-3- гидрокси-6-(3-метоксифенил)-сульфонил-2,2,3-триметил-2H-бензо(b)пиран (0,23 г) (см. получение 19) растворяли в дихлорметане (25 мл) (колба была снабжена осушительной хлоркальциевой трубкой), и к полученному раствору добавляли трибромид бора. Смесь перемешивали при комнатной температуре в течение 24 часов, в результате чего образовался осадок. Декантировали дихлорметан, и твердое вещество растворяли в 1 н. водном растворе гидроксида натрия и промывали этилацетатом. Подкислив водную фазу, получили смолу, которую собирали и высушивали при пониженном давлении при 70^oC, что дало в результате (3S,4R)-4-(2-хлорпиримидин-4-ил)амино-3,4-дигидро-3-гидрокси-6- (3-гидроксифенил)сульфонил-2,2,3-триметил-2H-бензо(b)пиран (0,123 г) в виде белого твердого вещества, т.пл. > 280^oC.Example 1. (3S, 4R) -4- (2-Chloropyrimidin-4-yl) amino-3,4-dihydro-3-hydroxy-6- (3-hydroxyphenyl) sulfonyl-2,2,3-trimethyl- 2H-benzo (b) pyran

(3S, 4R) -4- (2-Chloropyrimidin-4-yl) amino-3,4-dihydro-3-hydroxy-6- (3-methoxyphenyl) sulfonyl-2,2,3-trimethyl-2H-benzo (b) pyran (0.23 g) (see Preparation 19) was dissolved in dichloromethane (25 ml) (the flask was equipped with a calcium chloride drying tube), and boron tribromide was added to the resulting solution. The mixture was stirred at room temperature for 24 hours, resulting in a precipitate. Dichloromethane was decanted and the solid was dissolved in 1N. aqueous sodium hydroxide solution and washed with ethyl acetate. By acidifying the aqueous phase, a resin was obtained which was collected and dried under reduced pressure at 70 ^° C., resulting in (3S, 4R) -4- (2-chloropyrimidin-4-yl) amino-3,4-dihydro-3- hydroxy-6- (3-hydroxyphenyl) sulfonyl-2,2,3-trimethyl-2H-benzo (b) pyran (0.123 g) as a white solid, mp > 280 ^o C.

MCHP: m / 2 = 475 (m) ⁺ .

¹ H-NMR (d ₆ -DMCO): δ = 10.20 (1H, s), 8.15 (1H, d), 8.05 (1H, d), 7.65 (1H, m), 7 50 (1H, d), 7.15-7.40 (3H, m), 7.00 (2H, m), 6.75 (1H, d), 5.50 (1H, d), 1, 40 (3H, s), 1.30 (3H, s), 1.10 (3H, s) ppm.

(3S, 4R)-4-Амино-3,4-дигидро-3-гидрокси-6-(3-гидроксифенил)сульфонил- 2,2,3-триметил-2H-бензо(b)пиран (0,62 г) (см. получение 20) и 1,2-диэтокси-3,4-диоксоциклобут-1-ен (0,15 г) растворяли в этаноле (10 мл) (колба снабжена осушительной хлоркальциевой трубкой), и смесь нагревали с обратным холодильником в течение 90 минут. Растворитель удаляли при пониженном давлении, после чего остаток подвергали азеотропной перегонке с дихлорметаном, и неочищенный продукт хроматографировали на диоксиде кремния, использовав в качестве элюента смесь (5:95) метанол:дихлорметан, что дало (3S,4R)-3,4-дигидро-4-(3,4-диоксо-2-этоксициклобут-1-ен-1-ил) амино-3-гидрокси-6-(3-гидроксифенил)сульфонил-2,2,3-триметил-2H- бензо(b)пиран в виде желтого твердого вещества.Example 2. (3S, 4R) -3,4-Dihydro-4- (3,4-dioxo-2-ethoxycyclobut-1-en-1-yl) amino-3-hydroxy-6- (3-hydroxyphenyl) sulfonyl -2,2,3-trimethyl-2H-benzo (b) pyran

(3S, 4R) -4-amino-3,4-dihydro-3-hydroxy-6- (3-hydroxyphenyl) sulfonyl-2,2,3-trimethyl-2H-benzo (b) pyran (0.62 g) (see Preparation 20) and 1,2-diethoxy-3,4-dioxocyclobut-1-ene (0.15 g) was dissolved in ethanol (10 ml) (the flask was equipped with a calcium chloride drying tube) and the mixture was heated under reflux in for 90 minutes. The solvent was removed under reduced pressure, after which the residue was subjected to azeotropic distillation with dichloromethane, and the crude product was chromatographed on silica using (5:95) methanol: dichloromethane as an eluent to give (3S, 4R) -3,4-dihydro -4- (3,4-dioxo-2-ethoxycyclobut-1-en-1-yl) amino-3-hydroxy-6- (3-hydroxyphenyl) sulfonyl-2,2,3-trimethyl-2H-benzo (b ) pyran as a yellow solid.

^1- H-NMR (d ₆ -DMCO) (two rotamers detected): δ / = 10.20 (1H, broad), 9.25 (0.5H, broad), 9.00 (0.5H, broad), 7.75 (2H, m), 7.38 (2H, m), 7.25 (1H, s), 7.00 (2H, m), 5.45 (0.5H, d) , 5.38 (0.5H, s), 5.30 (0.5H, s), 4.95 (1H, d), 4.75 (1H, q), 4.60 (1H, broad), 1.45 (1.5H, t), 1.38 (3H, s), 1.29 (1.5H, br), 1.22 (3H, s), 0.98 (3H, s), m .d.

(3S, 4R)-4-Амино-3,4-дигидро-3-гидрокси-6-(3-гидроксифенил) сульфонил-2,2,3-триметил-2H-бензо/b/пиран (0,6 г) (см. получение 20) и диметил N-циандитиоминокарбонат (0,24 г) растворяли в пиридине (10 мл) (колба снабжена хлоркальциевой осушительной трубкой, и смесь нагревали при 50-60^oC в течение 24 часов. Удаляли растворитель при пониженном давлении, и остаток хроматографировали на диоксиде кремния, использовав в качестве элюента смесь этилацетата: дихлорметан = 1:1, что дало в результате неочищенный продукт, который подвергали азеотропной перегонке с этилацетатом, а затем дихлорметаном, после чего растирали с диэтиловым эфиром (для удаления остаточного пиридина), и в результате получили (3S,4R)-4-(3-циан-2-метилизотиоуреидо)-3,4-дигидро-3-гидрокси- 6-(3-гидроксифенил)сульфонил-2,2,3-триметил-2H-бензо(b)пиран (0,276 г) в виде твердого вещества.Example 3. (3S, 4R) -4- (3-Cyan-2-methylisothioureido) -3,4-dihydro-3-hydroxy-6- (3-hydroxyphenyl) sulfonyl-2,2,3-trimethyl-2H- benzo (b) pyran

(3S, 4R) -4-amino-3,4-dihydro-3-hydroxy-6- (3-hydroxyphenyl) sulfonyl-2,2,3-trimethyl-2H-benzo / b / pyran (0.6 g) (see Preparation 20) and dimethyl N-cyanedithiominocarbonate (0.24 g) was dissolved in pyridine (10 ml) (the flask was equipped with a calcium chloride drying tube, and the mixture was heated at 50-60 ^° C. for 24 hours. The solvent was removed under reduced pressure and the residue was chromatographed on silica using an ethyl acetate: dichloromethane = 1: 1 mixture as eluent, resulting in a crude product which was subjected to azeotropic distillation with ethyl acetate, a then with dichloromethane, after which it was triturated with diethyl ether (to remove residual pyridine), and as a result, (3S, 4R) -4- (3-cyan-2-methylisothioureido) -3,4-dihydro-3-hydroxy-6- (3-Hydroxyphenyl) sulfonyl-2,2,3-trimethyl-2H-benzo (b) pyran (0.276 g) as a solid.

¹ H-NMR (d ₆ -DMCO): δ = 10.25 (1H, s), 8.50 (1H, d), 7.70 (1H, d), 7.50 (1H, s), 7 30-7.45 (2H, m), 7.25 (1H, d), 6.98-7.05 (2H, m), 5.45 (1H, d), 5.40 (1H, s ), 2.72 (3H, s), 1.37 (3H, s), 1.25 (3H, s), 1.07 (3H, s) ppm.

(3S, 4R)-6-(4-трет-Бутилдиметилсилилоксифенил)сульфонил-3,4-дигидро- 3,4-эпокси-2,2,3-триметил-2H-бензо(b)пиран (0,35 г) (см. получение 14) и 3,6-дигидроксипиридазин (0,273 г) суспендировали в абсолютном этаноле (3 мл), к полученной суспензии добавляли сухой пиридин (0,065 мл), и смесь нагревали с обратным холодильником в течение 4 дней. Затем удаляли при пониженном давлении растворитель, и остаток хроматографировали на диоксиде кремния, использовав в качестве элюента смесь метанол:этилацетат = 1:99, и в результате получили (3S, 4R)-3,4-дигидро-3-гидрокси-6-(4-гидроксифенил)-сульфонил- 4-(3-гидроксипиридазин-6-ил)окси-2,2,3-триметил-2H-бензо(b)пиран (0,155 г) в виде белого твердого вещества, т.пл. >200^oC. Найдено: C 57,54, H 5,35, N 5,57. Вычислено для C₂₂H₂₂N₂O₇S, 0,20 этилацетата C 57,50, H 4,99, N 5,88%.Example 4. (3S, 4R) -3,4-Dihydro-3-hydroxy-6- (4-hydroxyphenyl) sulfonyl-4- (3-hydroxypyridazin-6-yl) oxy-2,2,3-trimethyl-2H -benzo (b) pyran

(3S, 4R) -6- (4-tert-butyldimethylsilyloxyphenyl) sulfonyl-3,4-dihydro-3,4-epoxy-2,2,3-trimethyl-2H-benzo (b) pyran (0.35 g) (see Preparation 14) and 3,6-dihydroxypyridazine (0.273 g) were suspended in absolute ethanol (3 ml), dry pyridine (0.065 ml) was added to the resulting suspension, and the mixture was heated under reflux for 4 days. Then, the solvent was removed under reduced pressure, and the residue was chromatographed on silica using a methanol: ethyl acetate = 1:99 mixture as the eluent to give (3S, 4R) -3,4-dihydro-3-hydroxy-6- ( 4-hydroxyphenyl) sulfonyl-4- (3-hydroxypyridazin-6-yl) oxy-2,2,3-trimethyl-2H-benzo (b) pyran (0.155 g) as a white solid, mp > 200 ^o C. Found: C 57.54, H 5.35, N 5.57. Calculated for C ₂₂ H ₂₂ N ₂ O ₇ S, 0.20 ethyl acetate C 57.50, H 4.99, N 5.88%.

¹ H-NMR (d ₆ -DMCO): δ / = 12.38 (1H, s), 7.16 (4H, m), 7.25 (1H, d), 6.80-7.00 (4H , m), 5.80 (1H, s), 5.38 (1H, s), 1.38 (3H, s), 1.30 (3H, s), 1.15 (3H, s) m. d.

(3S, 4R)-6-(4-трет-Бутилдиметилсилилоксифенил)сульфонил-3,4-дигидро- 3,4-эпокси-2,2,3-триметил- 2H-бензо(b)пиран (1,618 г) (см. получение 14) и 2,3-дигидро-2-метил-3-оксо-6-гидроксипиридазин (1,33 г) (см. J.Org.Chem., 1971, 36, 3372) суспендировали в сухом 1,4-диоксане (15 мл), к полученной суспензии добавляли пиридин (0,275 мл), и смесь нагревали с обратным холодильником (колба снабжена хлоркальциевой осушительной трубкой) в течение 3 дней. Растворитель удаляли под пониженным давлением, и остаток распределяли между этилацетатом и водой. Органическую фазу отделяли и осушали (безводный сульфат натрия), удаляли растворитель при пониженном давлении, и неочищенный продукт хроматографировали на диоксиде кремния, использовав в качестве элюента смесь метанол:этилацетат = 1:99, что дало в результате (3S,4R)-3,4-Дигидро-4-(2,3-дигидро-2-метил-3-оксопиридазин- 6-ил)окси-3-гидрокси-6-(4-гидроксифенил)сульфонил-2,2,3-триметил- 2H-бензо(b)пиран (0,352 г) в виде белого твердого вещества. Найдено: C 58,13, H 5,00, N 5,70. Вычислено для C₂₃H₂₄N₂O₇S C 58,46, H 5,12, N 5,93%.Example 5. (3S, 4R) -3,4-Dihydro-4- (2,3-dihydro-2-methyl-3-oxopyridazin-6-yl) hydroxy-3-hydroxy-6- (4-hydroxyphenyl) sulfonyl -2,2,3-trimethyl-2H-benzo (b) pyran

(3S, 4R) -6- (4-tert-butyldimethylsilyloxyphenyl) sulfonyl-3,4-dihydro-3,4-epoxy-2,2,3-trimethyl-2H-benzo (b) pyran (1.618 g) (cm preparation 14) and 2,3-dihydro-2-methyl-3-oxo-6-hydroxypyridazine (1.33 g) (see J. Org. Chem., 1971, 36, 3372) were suspended in dry 1.4 -dioxane (15 ml), pyridine (0.275 ml) was added to the resulting suspension, and the mixture was heated under reflux (the flask was equipped with a calcium chloride drying tube) for 3 days. The solvent was removed under reduced pressure, and the residue was partitioned between ethyl acetate and water. The organic phase was separated and dried (anhydrous sodium sulfate), the solvent was removed under reduced pressure, and the crude product was chromatographed on silica using methanol: ethyl acetate = 1:99 as an eluent, which gave (3S, 4R) -3, 4-dihydro-4- (2,3-dihydro-2-methyl-3-oxopyridazin-6-yl) hydroxy-3-hydroxy-6- (4-hydroxyphenyl) sulfonyl-2,2,3-trimethyl-2H- benzo (b) pyran (0.352 g) as a white solid. Found: C, 58.13; H, 5.00; N, 5.70. Calculated for C ₂₃ H ₂₄ N ₂ O ₇ SC 58.46, H 5.12, N 5.93%.

¹ H-NMR (d ₆ -DMCO): δ = 7.65-7.75 (4H, m), 7.27 (1H, d), 6.82-7.05 (4H, m), 5, 78 (1H, s), 5.36 (1H, s), 3.34 (3H, s), 1.39 (3H, s), 1.30 (3H, s), 1.20 (3H, s ) ppm

(3S, 4R)-6-(4-трет-Бутилдиметилсилилоксифенил)сульфонил-3,4-дигидро- 3,4-эпокси-2,2,3-триметил-2H-бензо(b)пиран (1,664 г) (см. получение 14) и 2,3-дигидро-2-этил-3-оксо-6-гидроксипиридазин (1,52 г) (см. J.Org.Chem., 1971, 36, 3372) суспендировали в сухом 1,4-диоксане (15 мл), к полученной суспензии добавляли пиридин (0,282 мл), и смесь нагревали с обратным холодильником (колба снабжена хлоркальциевой осушительной трубкой) в течение 3 дней. Растворитель удаляли при пониженном давлении, и остаток распределяли между этилацетатом и водой. Органическую фазу отделяли и сушили (безводный сульфат натрия), удаляли растворитель при пониженном давлении, и неочищенный продукт хроматографировали на диоксиде кремния, использовав в качестве элюента смесь метанол:этилацетат = 1:99, что дало в результате (3S,4R)-3,4-дигидро-4-(2,3-дигидро-2-этил-3-оксопиридазин- 6-ил)окси-3-гидрокси-6-(4-гидроксифенил)сульфонил-2,2,3-триметил- 2H-бензо(b)пиран (0,340 г) в виде белого твердого вещества, т.пл. 186-188^oC. Найдено: C 59,16, H 5,27, N 5,10. Вычислено для C₂₄H₂₆N₂O₇S, 0,10 этилацетата: C 59,16, H 5,45, N 5,65%.Example 6. (3S, 4R) -3,4-Dihydro-4- (2,3-dihydro-2-ethyl-3-oxopyridazin-6-yl) oxy-3-hydroxy-6- (4-hydroxyphenyl) sulfonyl -2,2,3-trimethyl-2H-benzo (b) pyran

(3S, 4R) -6- (4-tert-butyldimethylsilyloxyphenyl) sulfonyl-3,4-dihydro-3,4-epoxy-2,2,3-trimethyl-2H-benzo (b) pyran (1,664 g) (cm preparation 14) and 2,3-dihydro-2-ethyl-3-oxo-6-hydroxypyridazine (1.52 g) (see J. Org. Chem., 1971, 36, 3372) were suspended in dry 1.4 -dioxane (15 ml), pyridine (0.282 ml) was added to the resulting suspension, and the mixture was heated under reflux (the flask was equipped with a calcium chloride drying tube) for 3 days. The solvent was removed under reduced pressure, and the residue was partitioned between ethyl acetate and water. The organic phase was separated and dried (anhydrous sodium sulfate), the solvent was removed under reduced pressure, and the crude product was chromatographed on silica using methanol: ethyl acetate = 1:99 as an eluent, which gave (3S, 4R) -3, 4-dihydro-4- (2,3-dihydro-2-ethyl-3-oxopyridazin-6-yl) hydroxy-3-hydroxy-6- (4-hydroxyphenyl) sulfonyl-2,2,3-trimethyl-2H- benzo (b) pyran (0.340 g) as a white solid, mp 186-188 ^o C. Found: C 59.16, H 5.27, N 5.10. Calculated for C ₂₄ H ₂₆ N ₂ O ₇ S, 0.10 ethyl acetate: C 59.16, H 5.45, N 5.65%.

¹ H-NMR (d ₆ -DMCO): δ / = 7.52-7.70 (4H, m), 7.16 (1H, d), 6.72-6.98 (4H, m), 5 , 72 (1H, s), 5.30 (1H, s), 4.97 (1H, m), 4.80 (1H, m), 1.28 (3H, s), 1.18 (6H, m), 1.08 (3H, s) ppm.

(3S, 4S)-6-(3-трет-Бутилдиметилсилилоксифенил)сульфонил-3,4-дигидро- 3,4-эпокси-2,2,3-триметил-2H-бензо(b)пиран (2 г) (см. получение 15) и 2,3-дигидро-2-метил-3-оксо-6-гидроксипиридазин (1,5 г) (см. J.Org.Chem., 1971, 36, 3372) суспендировали в этаноле (30 мл), к полученной суспензии добавляли пиридин (0,31 г), и смесь нагревали с обратным холодильником (колба снабжена хлоркальциевой осушительной трубкой) в течение 100 часов. После охлаждения реакционную смесь фильтровали, и фильтрат упаривали, что дало твердое вещество, которое растворяли в смеси 0,5% метанол/дихлорметан, и раствор опять фильтровали. Фильтрат опять упаривали, и остаток хроматографировали на диоксиде кремния, использовав в качестве элюента градиент смеси метанол:дихлорметан от 0,5: 99,5 до 3,75:96,25, что дало в результате (3S,4R)-3,4-дигидро-4-(2,3-дигидро-2-метил-3-оксопиридазин-6-ил)окси- 3-гидрокси-6-(4-гидроксифенил)сульфонил-2,2,3-триметил-2H-бензо(b)пиран (1 г) в виде белого твердого вещества. Найдено: C 53,20, H 4,79, N 5,22. Вычислено для C₂₃H₂₄N₂O₇S, 0,75 CH₂Cl₂: C 53,00, H 4,79, N 5,10%.Example 7. (3S, 4R) -3,4-Dihydro-4- (2,3-dihydro-2-methyl-3-oxopyridazin-6-yl) hydroxy-3-hydroxy-6- (3-hydroxyphenyl) sulfonyl -2,2,3-trimethyl-2H-benzo (b) pyran

(3S, 4S) -6- (3-tert-Butyldimethylsilyloxyphenyl) sulfonyl-3,4-dihydro-3,4-epoxy-2,2,3-trimethyl-2H-benzo (b) pyran (2 g) (cm preparation 15) and 2,3-dihydro-2-methyl-3-oxo-6-hydroxypyridazine (1.5 g) (see J. Org. Chem., 1971, 36, 3372) were suspended in ethanol (30 ml ), pyridine (0.31 g) was added to the resulting suspension, and the mixture was heated under reflux (the flask was equipped with a calcium chloride drying tube) for 100 hours. After cooling, the reaction mixture was filtered, and the filtrate was evaporated, giving a solid, which was dissolved in a mixture of 0.5% methanol / dichloromethane, and the solution was filtered again. The filtrate was again evaporated, and the residue was chromatographed on silica using a gradient of methanol: dichloromethane from 0.5: 99.5 to 3.75: 96.25 as an eluent, resulting in (3S, 4R) -3.4 -dihydro-4- (2,3-dihydro-2-methyl-3-oxopyridazin-6-yl) oxy-3-hydroxy-6- (4-hydroxyphenyl) sulfonyl-2,2,3-trimethyl-2H-benzo (b) pyran (1 g) as a white solid. Found: C, 53.20; H, 4.79; N, 5.22. Calculated for C ₂₃ H ₂₄ N ₂ O ₇ S, 0.75 CH ₂ Cl ₂ : C 53.00, H 4.79, N 5.10%.

¹ H-NMR (CDCl ₃ ): δ = 8.04 (1H, s), 7.75-7.85 (2H, m), 7.30-7.45 (3H, m), 6.90- 7.10 (4H, m), 5.91 (1H, s), 3.72 (3H, s), 3.32 (1H, s), 1.45 (3H, s), 1.40 (3H , s), 1.30 (3H, s) ppm.

(3S, 4S)-6-(3-трет-Бутилдиметилсилилоксифенил)сульфонил-3,4-дигидро- 3,4-эпокси-2,2,3-триметил-2H-бензо(b)пиран (0,5 г) (см. получение 16) и 2,3-дигидро-2-метил-3-оксо-6-гидроксипиридазин (0,41 г) (см. J.Org.Chem., 1971, 36, 3372) суспендировали в сухом 1,4-диоксане (8 мл), к полученной суспензии добавляли пиридин (0,085 г), и смесь нагревали с обратным холодильником (колба снабжена хлоркальциевой осушительной трубкой) в течение 20 часов. Растворитель выпаривали под пониженным давлением, остаток перемешивали с дихлорметаном (30 мл) и фильтровали. Фильтрат упаривали, и остаток хроматографировали на диоксиде кремния, использовав в качестве элюента смесь гексан: этилацетат = 1:1, что дало смесь целевого продукта и эпоксидного исходного материала. Эту смесь вновь растворяли в сухом 1,4-диоксане (7 мл), добавляли 2,3-дигидро-2-метил-3-оксо-6-гидроксипиридазин (0,2 г) и пиридин (0,08 г), и реакционную смесь нагревали с обратным холодильником еще 18 часов. Растворитель удаляли при пониженном давлении, и остаток растворяли в смеси 5% метанолдихлорметан и фильтровали. Фильтрат упаривали, и остаток хроматографировали на диоксиде кремния, использовав в качестве элюента смесь метанол: дихлорметан 2,5:97,5, что дало в результате (3S,4R)-3,4-дигидро-4-(2,3-дигидро-2-метил- 3-оксо-пиридазин-6-ил)окси-3-гидрокси-6-(2-гидроксифенил)сульфонил- 2,2,3-триметил-2H-бензо(b)пиран (0,17 г) в виде желтой пены. Найдено: C 54,19, H 4,95, N 5,21. Вычислено для C₂₃H₂₄N₂O₇S, 0,625 CH₂Cl₂: C 54,06, H 4,73, N 5,21%.Example 8. (3S, 4R) -3,4-Dihydro-4- (2,3-dihydro-2-methyl-3-oxopyridazin-6-yl) hydroxy-3-hydroxy-6- (2-hydroxyphenyl) sulfonyl -2,2,3-trimethyl-2H-benzo (b) pyran

(3S, 4S) -6- (3-tert-Butyldimethylsilyloxyphenyl) sulfonyl-3,4-dihydro-3,4-epoxy-2,2,3-trimethyl-2H-benzo (b) pyran (0.5 g) (see Preparation 16) and 2,3-dihydro-2-methyl-3-oxo-6-hydroxypyridazine (0.41 g) (see J. Org. Chem., 1971, 36, 3372) were suspended in dry 1 , 4-dioxane (8 ml), pyridine (0.085 g) was added to the resulting suspension, and the mixture was heated under reflux (the flask was equipped with a calcium chloride drying tube) for 20 hours. The solvent was evaporated under reduced pressure, the residue was stirred with dichloromethane (30 ml) and filtered. The filtrate was evaporated, and the residue was chromatographed on silica using hexane: ethyl acetate = 1: 1 as an eluent, which gave a mixture of the target product and epoxy starting material. This mixture was redissolved in dry 1,4-dioxane (7 ml), 2,3-dihydro-2-methyl-3-oxo-6-hydroxypyridazine (0.2 g) and pyridine (0.08 g) were added, and the reaction mixture was heated under reflux for another 18 hours. The solvent was removed under reduced pressure, and the residue was dissolved in a mixture of 5% methanol dichloromethane and filtered. The filtrate was evaporated, and the residue was chromatographed on silica using a methanol: dichloromethane 2.5: 97.5 mixture as eluent, resulting in (3S, 4R) -3,4-dihydro-4- (2,3-dihydro -2-methyl-3-oxo-pyridazin-6-yl) oxy-3-hydroxy-6- (2-hydroxyphenyl) sulfonyl-2,2,3-trimethyl-2H-benzo (b) pyran (0.17 g ) in the form of a yellow foam. Found: C, 54.19; H, 4.95; N, 5.21. Calculated for C ₂₃ H ₂₄ N ₂ O ₇ S, 0.625 CH ₂ Cl ₂ : C 54.06, H 4.73, N 5.21%.

¹ H-NMR (CDCl ₃ ): δ / = 9.15 (1H, s), 7.90 (1H, d), 7.75 (1H, dd), 7.62 (1H, dd), 7, 45 (1H, m), 6.94-7.10 (5H, m), 5.89 (1H, s), 3.69 (1H, s), 3.48 (1H, s), 1.51 (3H, s), 1.42 (3H, s), 1.25 (3H, s) ppm.

Смесь (3S, 4S)-6-(4-трет-бутилдиметилсилилоксифенил)сульфонил- 3,4-дигидро-3,4-эпокси-2,2,3-триметил-2H-бензо(b)пирана (0,81 г) (см. получение 14), фталгидразида (0,88 г), пиридина (0,5 мл) и диэтиленгликоля (10 мл) нагревали при 120^oC в течение 210 минут. Реакционную смесь выливали в воду и экстрагировали этилацетатом. Органический экстракт сушили (безводный сульфат магния), выпаривали растворитель, и полученную в результате смолу хроматографировали на диоксиде кремния, использовав в качестве элюента смесь дихлорметан: метанол: 35%-ный водный раствор аммиака = 180:20:1, в результате чего получили (3S, 4R)-3,4-дигидро-4-(1,2-дигидро-1-оксо- 2H-фталазин-4-ил)-окси-3-гидрокси-6-(4-гидроксифенил)сульфонил- 2,2,3-триметил-2H-бензо(b)пиран (0,091 г) в виде твердого вещества.Example 9. (3S, 4R) -3,4-Dihydro-4- (1,2-dihydro-1-oxo-2H-phthalazin-4-yl) -oxy-3-hydroxy-6- (4-hydroxyphenyl) sulfonyl-2,2,3-trimethyl-2H-benzo (b) pyran

Mixture of (3S, 4S) -6- (4-tert-butyldimethylsilyloxyphenyl) sulfonyl-3,4-dihydro-3,4-epoxy-2,2,3-trimethyl-2H-benzo (b) pyran (0.81 g ) (see Preparation 14), phthalhydrazide (0.88 g), pyridine (0.5 ml) and diethylene glycol (10 ml) were heated at 120 ^° C. for 210 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The organic extract was dried (anhydrous magnesium sulfate), the solvent was evaporated, and the resulting resin was chromatographed on silica using a mixture of dichloromethane: methanol: 35% aqueous ammonia = 180: 20: 1 as an eluent, to give ( 3S, 4R) -3,4-dihydro-4- (1,2-dihydro-1-oxo-2H-phthalazin-4-yl) -oxy-3-hydroxy-6- (4-hydroxyphenyl) sulfonyl-2, 2,3-trimethyl-2H-benzo (b) pyran (0.091 g) as a solid.

¹ H-NMR (d ₆ DMCO): δ = 8.28 (1H, d), 7.80-7.95 (4H, m), 7.55-7.70 (3H, m), 6.95 (1H, d), 6.90 (1H, d), 6.80 (1H, d), 5.41 (1H, s), 1.50 (3H, s), 1.48 (3H, s) , 1.28 (3H, s) ppm.

Смесь (3S, 4S)-6-(4-трет-бутилдиметилсилилоксифенил)сульфонил- 3,4-дигидро-3,4-эпокси-2,2,3-триметил-2H-бензо(b)пирана (0,71 г) (см. получение 14), 1,2-дигидро-4-гидрокси-2-метил-1-оксофталазина (0,846 г) (см. получение 21), пиридина (0,4 мл) и 1,4-диоксана (10 мл) нагревали с обратным холодильником в течение 4 дней. Растворитель удаляли под пониженным давлением, остаток растворяли в этилацетате и промывали сначала разбавленным водным раствором лимонной кислоты и затем солевым раствором. Органическую фазу осушали (безводный сульфат магния), удаляли растворитель, и неочищенный продукт хроматографировали на диоксиде кремния, использовав в качестве элюента градиент смеси дихлорметан:метанол:35%-ный водный раствор от 100:1:0,15 до 180: 20: 1, в результате чего получили (3S,4R)-3,4-дигидро-4-(1,2-дигидро-2-метил-1-оксофталазин-4-ил)окси- 3-гидрокси-6-(4-гидроксифенил)сульфонил-2,2,3-триметил-2H-бензо(b)пиран (0,12 г) в виде твердого вещества.Example 10. (3S, 4R) -3,4-Dihydro-4- (1,2-dihydro-2-methyl-1-oxophthalazin-4-yl) oxy-3-hydroxy-6- (4-hydroxyphenyl) sulfonyl - 2,2,3-trimethyl-2H-benzo (b) pyran

Mixture of (3S, 4S) -6- (4-tert-butyldimethylsilyloxyphenyl) sulfonyl-3,4-dihydro-3,4-epoxy-2,2,3-trimethyl-2H-benzo (b) pyran (0.71 g ) (see Preparation 14), 1,2-dihydro-4-hydroxy-2-methyl-1-oxophthalazine (0.846 g) (see Preparation 21), pyridine (0.4 ml) and 1,4-dioxane ( 10 ml) was heated under reflux for 4 days. The solvent was removed under reduced pressure, the residue was dissolved in ethyl acetate and washed first with a dilute aqueous solution of citric acid and then with brine. The organic phase was dried (anhydrous magnesium sulfate), the solvent was removed, and the crude product was chromatographed on silica using a gradient of dichloromethane: methanol: 35% aqueous solution from 100: 1: 0.15 to 180: 20: 1 as eluent resulting in (3S, 4R) -3,4-dihydro-4- (1,2-dihydro-2-methyl-1-oxophthalazin-4-yl) oxy-3-hydroxy-6- (4-hydroxyphenyl) ) sulfonyl-2,2,3-trimethyl-2H-benzo (b) pyran (0.12 g) as a solid.

¹ H-NMR (CDCl ₃ ): δ / = 8.40 (1H, d), 8.26 (1H, s), 7.78-7.95 (5H, m), 7.68 (2H, d ), 6.95 (1H, d), 6.90 (2H, d), 6.09 (1H, s), 3.73 (3H, s), 1.60 (3H, s), 1.50 (3H, s), 1.32 (3H, s) ppm.

(3S, 4S)-6-(3-трет-Бутилдиметилсилилоксифенил)сульфонил-3,4-дигидро- 3,4-эпокси-2,2,3-триметил-2H-бензо(b)пиран (0,70 г) (см. получение 15) и 2,4-дигидроксипиридин (0,44 г) суспендировали в этаноле (15 мл), к полученной суспензии добавляли пиридин (0,15 г), и смесь нагревали с обратным холодильником (колба снабжена хлоркальциевой осушительной трубкой) в течение 5 дней. Растворитель удаляли при пониженном давлении, остаток перемешивали со смесью 5%-ный метанол/дихлорметан и затем фильтровали. Фильтрат упаривали, и остаток хроматографировали на диоксиде кремния, использовав в качестве элюента смесь дихлорметан: метанол = 19:1, в результате чего получили (3S, 4R)-3,4-дигидро-4-(1,2-дигидро-2-оксо-1H-пиридин-4-ил)окси- 3-гидрокси-6-(2-гидроксифенил)сульфонил-2,2,3-триметил-2H-бензо(b)пиран (0,118 г) в виде белой пены. Найдено:: C 60,58, H 5,04, N 2,67. Вычислено для C₂₃H₂₃NO₇S, 0,30 диэтилового эфира: C 60,60, H 5,46, N 2,92%.Example 11. (3S, 4R) -3,4-Dihydro-4- (1,2-dihydro-2-oxo-1H-pyridin-4-yl) oxy-3-hydroxy-6- (3-hydroxyphenyl) sulfonyl -2,2,3-trimethyl-2H-benzo (b) pyran

(3S, 4S) -6- (3-tert-Butyldimethylsilyloxyphenyl) sulfonyl-3,4-dihydro-3,4-epoxy-2,2,3-trimethyl-2H-benzo (b) pyran (0.70 g) (see Preparation 15) and 2,4-dihydroxypyridine (0.44 g) was suspended in ethanol (15 ml), pyridine (0.15 g) was added to the resulting suspension, and the mixture was heated under reflux (the flask was equipped with a calcium chloride drying tube ) within 5 days. The solvent was removed under reduced pressure, the residue was stirred with 5% methanol / dichloromethane, and then filtered. The filtrate was evaporated and the residue was chromatographed on silica using a dichloromethane: methanol = 19: 1 mixture as eluent, whereby (3S, 4R) -3,4-dihydro-4- (1,2-dihydro-2- oxo-1H-pyridin-4-yl) oxy-3-hydroxy-6- (2-hydroxyphenyl) sulfonyl-2,2,3-trimethyl-2H-benzo (b) pyran (0.118 g) as a white foam. Found :: C, 60.58; H, 5.04; N, 2.67. Calculated for C ₂₃ H ₂₃ NO ₇ S, 0.30 diethyl ether: C 60.60, H 5.46, N 2.92%.

¹ H-NMR (d ₆ -DMCO): δ = 10.20 (1H, broad), 7.71 (1H, dd), 7.62 (1H, s), 7.30 - 7.40 (2H , m), 7.25 (1H, dd), 7.15 (1H, d), 6.95 - 7.05 (2H, m), 6.20 (1H, s), 6.06 (1H, dd), 5.45 (1H, s), 5.40 (1H, s), 1.48 (3H, s), 1.34 (3H, s), 1.10 (3H, s) ppm .

 Further elution afforded (3S, 4R) -3,4-dihydro-4- (1,2-dihydro-2-oxo-4-hydroxypyridin-1-yl) -3-hydroxy-6- (3-hydroxyphenyl) sulfonyl- 2,2,3-trimethyl-2H-benzo (b) pyran (0.142 g) as a foam.

¹ H-NMR (d ₆ -DMCO): δ = 10.50 (1H, broad), 7.96 (1H, d), 7.62 - 7.72 (2H, m), 7.35 (1H , m), 7.20 (1H, d), 6.94 - 7.00 (2H, m), 6.65 (1H, dd), 6.20 (2H, m), 5.50 (1H, s), 1.40 (3H, s), 1.32 (3H, s), 1.15 (3H, s) ppm.

(3S, 4S)-6-(3-трет-Бутилдиметилсилилоксифенил)сульфонил-3,4- дигидро-3,4-эпокси-2,2,3-триметил-2H-бензо(b)пиран (0,70 г) (см. получение 15) и 2,4-дигидрокси-5,6-диметилпиридин (0,42 г) (см. получение 23) суспендировали в этаноле (15 мл), к полученной суспензии добавляли пиридин (0,12 г). Смесь нагревали с обратным холодильником (колба снабжена хлоркальциевой осушительной трубкой) в течение 20 дней. Растворитель удаляли при пониженном давлении, остаток перемешивали в смеси 20%-ный метанол/дихлорметан (50 мл), фильтровали, и фильтрат упаривали, что дало неочищенный продукт, который хроматографировали на диоксиде кремния, использовав в качестве элюента градиент смеси дихлорметан:метанол от 19 : 1 до 9 : 1, в результате чего получили (3S, 4R)-3,4-дигидро-4-(1,2-дигидро- 5,6-диметил-2-оксо-1H-пиридин-4-ил)окси-3-гидрокси-6- (3-гидроксифенил)сульфонил-2,2,3-триметил-2H-бензо(b)пиран (0,143 г) в виде твердого вещества.Example 12. (3S, 4R) -3,4-Dihydro-4- (1,2-dihydro-5,6-dimethyl-2-oxo-1H-pyridin-4-yl) oxy-3-hydroxy-6- (3-hydroxyphenyl) sulfonyl- 2,2,3-trimethyl-2H-benzo (b) pyran

(3S, 4S) -6- (3-tert-Butyldimethylsilyloxyphenyl) sulfonyl-3,4-dihydro-3,4-epoxy-2,2,3-trimethyl-2H-benzo (b) pyran (0.70 g) (see Preparation 15) and 2,4-dihydroxy-5,6-dimethylpyridine (0.42 g) (see Preparation 23) were suspended in ethanol (15 ml), pyridine (0.12 g) was added to the resulting suspension. The mixture was heated under reflux (the flask was equipped with a calcium chloride drying tube) for 20 days. The solvent was removed under reduced pressure, the residue was stirred in a mixture of 20% methanol / dichloromethane (50 ml), filtered, and the filtrate was evaporated to give a crude product, which was chromatographed on silica using a gradient of dichloromethane: methanol from 19 : 1 to 9: 1, whereby (3S, 4R) -3,4-dihydro-4- (1,2-dihydro-5,6-dimethyl-2-oxo-1H-pyridin-4-yl) was obtained hydroxy-3-hydroxy-6- (3-hydroxyphenyl) sulfonyl-2,2,3-trimethyl-2H-benzo (b) pyran (0.143 g) as a solid.

¹ H-NMR (d ₆ -DMCO): δ / = 10.30 (1H, s), 6.96 - 7.85 (8H, m), 6.18 (1H, s), 5.45 (1H , s), 5.36 (1H, s), 2.20 (3H, s), 1.84 (3H, s), 1.38 (3H, s), 1.33 (3H, s), 1 12 (3H, s) ppm.

(3S, 4R)-3,4-Дигидро-4-(2,3-дигидро-2-метил-3-оксопиридазин- 6-ил)окси-6-(2,4-дигидроксифенил)сульфонил-3-гидрокси-2,2,3-триметил- 2H-бензо(b)пиран (0,50 г) (см. получение 26) растворяли в дихлорметане (12 мл) (в атмосфере азота), и к полученному раствору добавляли трибромид бора (4 мл 1M раствора в дихлорметане). Смесь перемешивали при комнатной температуре в течение часа, в результате чего образовался осадок. После добавления воды (20 мл) и дихлорметана (15 мл) образовалась нерастворимая смола, после чего декантировали растворители. Затем смолу хроматографировали на диоксиде кремния, использовав в качестве элюента смесь метанол:дихлорметан = 1:9, и в результате получили (3S, 4R)-3,4-дигидро-4-(2,3-дигидро-2-метил-3- оксопиридазин-6-ил)окси-6-(3,4-дигидроксифенил)сульфонил-3-гидрокси- 2,2,3-триметил-2H-бензо(b)пиран (0,33 г) в виде белой пены, которую затем растирали с диэтиловым эфиром и сушили, что дало белое твердое вещество.Example 13. (3S, 4R) -3,4-Dihydro-4- (2,3-dihydro-2-methyl-3-oxopyridazin-6-yl) oxy-6- (3,4-dihydroxyphenyl) sulfonyl-3 -hydroxy- 2,2,3-trimethyl-2H-benzo (b) pyran

(3S, 4R) -3,4-Dihydro-4- (2,3-dihydro-2-methyl-3-oxopyridazin-6-yl) oxy-6- (2,4-dihydroxyphenyl) sulfonyl-3-hydroxy- 2,2,3-trimethyl-2H-benzo (b) pyran (0.50 g) (see Preparation 26) was dissolved in dichloromethane (12 ml) (under nitrogen atmosphere), and boron tribromide (4 ml) was added to the resulting solution. 1M solution in dichloromethane). The mixture was stirred at room temperature for one hour, resulting in a precipitate. After adding water (20 ml) and dichloromethane (15 ml), an insoluble resin formed, after which the solvents were decanted. Then, the resin was chromatographed on silica using a methanol: dichloromethane = 1: 9 mixture as the eluent to obtain (3S, 4R) -3,4-dihydro-4- (2,3-dihydro-2-methyl-3 - oxopyridazin-6-yl) oxy-6- (3,4-dihydroxyphenyl) sulfonyl-3-hydroxy-2,2,3-trimethyl-2H-benzo (b) pyran (0.33 g) as a white foam, which was then triturated with diethyl ether and dried to give a white solid.

¹ H-NMR (d ₆ -DMCO): δ = 10.10 (1H, s), 9.75 (1H, s), 7.75 (1H, s), 7.65 (1H, m), 7 30 (1H, d), 7.15 (2H, m), 7.05 (1H, d), 6.95 (1H, d), 6.85 (1H, d), 5.80 (1H, s), 5.72 (1H, s), 3.60 (3H, s), 1.40 (3H, s), 1.31 (3H, s), 1.15 (3H, s) ppm .

 The following preparation examples illustrate the preparation of some of the starting materials used in the preceding examples.

Production Example 1. 4-Bromophenylpropionate
4-Bromophenol (259 g) and 4-dimethylaminopyridine (1.5 g) were dissolved in dichloromethane (1000 ml), the resulting solution was cooled in an ice bath, and triethylamine (219 ml) was added dropwise, so that the reaction temperature was kept lower 20 ^o C. Then propionyl chloride (137 ml) was added over an hour, and the resulting mixture was stirred at room temperature for 2 hours. The mixture was washed with water and then with brine, dried (anhydrous magnesium sulfate), and the solvent was removed under reduced pressure, resulting in 4-bromophenylpropionate (344 g) as a green oil.

¹ H-NMR (CDCl ₃ ): δ = 7.43 (2H, d), 6.94 (2H, d), 2.52 (2H, q), 1.20 (3H, t) ppm.

 Production Example 2. 1- (5-Bromo-2-hydroxyphenyl) propan-1-one.

4-Bromophenide propionate (115 g) (see Preparation 1) and aluminum chloride (150 g) were heated together at approximately 90 ^° C. for 15 minutes. The solution darkened, and gaseous hydrogen chloride was released. After cooling, the dark mass was carefully added to ice, resulting in a brown solid. The mixture was extracted with dichloromethane. The organic phase was separated, washed with brine, dried (anhydrous magnesium sulfate), and removing the solvent under reduced pressure gave 1- (5-bromo-2-hydroxyphenyl) propan-1-one (110 g) as a yellow solid.

¹ H-NMR (CDCl ₃ ): δ = 12.28 (1H, s), 7.88 (1H, d), 7.55 (1H, dd), 6.89 (1H, d), 3.02 (2H, q), 1.27 (3H, t) ppm.

 Production Example 3. 6-Bromo-3,4-dihydro-4-oxo-2,2,3-trimethyl-2H-benzo (b) pyran.

 1- (5-Bromo-2-hydroxyphenyl) propan-1-one (375 g) (see Preparation 2) was dissolved in a mixture of dry toluene (1700 ml) and acetone (2040 ml). Piperidine (748 ml) was added to the resulting solution, after which the solution was heated under reflux for 7 days. The solvent was removed under reduced pressure, and the residue was dissolved in diethyl ether and washed successively with an aqueous solution (x4) of citric acid, a 0.5 M aqueous solution (x4) of sodium hydroxide and then with brine (x3). The organic phase was separated and the solvent was removed under reduced pressure, resulting in 6-bromo-3,4-dihydro-4-oxo-2,2,3-trimethyl-2H-benzo (b) pyran (408 g) as an orange oils. Found: C, 53.59; H, 1.84.

Calculated for C ₁₂ H ₁₃ BrO ₂ : C 53.55, H 4.87%.

¹ H-NMR (CDCl ₃ ): δ = 7.90 (1H, d), 7.50 (1H, dd), 6.79 (1H, d), 2.70 (1H, q), 1.50 (3H, s), 1.28 (3H, s), 1.17 (3H, s) ppm.

 Production Example 4. 6-Bromo-2,2,3-trimethyl-2H-benzo (b) pyran.

 6-Bromo-3,4-dihydro-4-oxo-2,2,3-trimethyl-2H-benzo (b) pyran (407 g) (see Preparation 3) was dissolved in ethanol (1500 ml), cooled in ice-cold bath, and sodium borohydride (61.4 g) was added dropwise to the solution over 20 minutes. The mixture was stirred at room temperature for 3 hours, the solvent was removed under reduced pressure, the residue was dissolved in diethyl ether, and the mixture was washed first with water and then with brine. The organic layer was dried (anhydrous magnesium sulfate), and by removing the solvent, crude alcohol was obtained. It was dissolved in toluene (1000 ml), para-toluenesulfonic acid (40 g) was added to the resulting solution, and the mixture was heated under reflux (to remove water) for 2 hours. The volume of the solvent was reduced to approximately 500 ml, and the solution was washed with an aqueous solution of sodium carbonate and then with brine. The organic phase was dried (anhydrous magnesium sulfate), and removing the solvent under reduced pressure, 6-bromo-2,2,3-trimethyl-2H-benzo (b) pyran (350 g) was obtained as an orange oil.

¹ H-NMR (CDCl ₃ ): δ = 7.10 (1H, dd), 6.96 (1H, d), 6.59 (1H, d), 5.96 (1H, s), 1.78 (3H, s), 1.35 (6H, s) ppm.

 Production Example 5. 6- (4-Methoxyphenyl) thio-2,2,3-trimethyl-2H-benzo (b) pyran.

 6-Bromo-2,2,3-trimethyl-2H-benzo (b) pyran (9.637 g) (see Preparation 4) was dissolved in absolute ethanol (200 ml), sodium tert-butoxy (11.029 g) was added to the resulting solution. , 4-methoxybenzenethiol (4.9 ml) and tetrakis (triphenylphosphine) -palladium (O) (0.454 g), and the mixture was heated under reflux in a nitrogen atmosphere for 48 hours. The solvent was removed under reduced pressure, and the residue was dissolved in dichloromethane and washed with water. The organic layer was dried (anhydrous sodium sulfate), the solvent was removed under reduced pressure, and the crude product was chromatographed on silica using hexane: dichloromethane = 1: 1 as an eluent, whereby 6- (4-methoxyphenyl) thio-2 was obtained , 2,3-trimethyl-2H-benzo / b / pyran (7.823 g) as a yellow oil.

¹ H-NMR (CDCl ₃ ): δ = 7.28 (2H, d), 7.05 (1H, dd), 6.92 (1H, d), 6.84 (2H, d), 6.70 (1H, d), 6.00 (1H, s), 3.80 (3H, s), 1.81 (3H, s), 1.40 (6H, s) ppm.

Production Example 6. 6- (3-Methoxyphenyl) thio-2,2,3-trimethyl-2H-benzo (b) pyran
6-Bromo-2,2,3-trimethyl-2H-benzo (b) pyran (6.5 g) (see Preparation 4) was dissolved in absolute ethanol (135 ml), sodium tert-butoxide was added to the resulting solution (7 5 g), 3-methoxybenzenethiol (3.6 g) and tetrakis (triphenylphosphine) palladium (0) (0.35 g), and the mixture was heated under reflux in a nitrogen atmosphere for 48 hours. Then tetrakis (triphenylphosphine) palladium (0) (0.3 g) was added, and heating was continued for another 48 hours. The solvent was removed under reduced pressure, and the residue was dissolved in dichloromethane and washed with water. The organic layer was dried (anhydrous sodium sulfate), the solvent was removed under reduced pressure, and the crude product was chromatographed on silica using hexane: dichloromethane = 1: 1 as an eluent, whereby 6- (3-methoxyphenyl) thio-2 was obtained , 2,3-trimethyl-2H-benzo (b) pyran (7.2 g) as an oil.

¹ H-NMR (CDCl ₃ ): δ = 7.05 - 7.20 (3H, m), 6.63-6.78 (4H, m), 6.05 (1H, s), 3.72 ( 3H, s), 1.83 (3H, s), 1.45 (6H, s), ppm.

 Production Example 7. 6- (2-Methoxyphenyl) thio-2,2,3-trimethyl-2H-benzo (b) pyran.

 6-Bromo-2,2,3-trimethyl-2H-benzo (b) pyran (9.6 g) (see Preparation 4) was dissolved in absolute ethanol (200 ml), sodium tert-butoxide was added to the resulting solution (11 , 0 g), 2-methoxybenzoylthiol (5.3 g) and tetrakis (triphenylphosphine) -palladium (0) (0.45 g), and the mixture was heated under reflux in a nitrogen atmosphere for 74 hours. The solvent was removed under reduced pressure, and the residue was dissolved in dichloromethane and washed with water. The organic layer was dried (anhydrous sodium sulfate), the solvent was removed under reduced pressure, and the crude product was chromatographed first on silica using hexane: dichloromethane = 1: 1 as an eluent, and then on silica using hexane as an eluent: ethyl acetate = 24: 1, whereby 6- (2-methoxyphenyl) thio-2,2,3-trimethyl-2H-benzo (b) pyran (8.12 g) was obtained as an oil.

¹ H-NMR (CDCl ₃ ): δ = 7.10-7.23 (3H, m), 6.76 - 6.85 (4H, m), 6.05 (1H, s), 3.90 ( 3H, s), 1.83 (3H, s), 1.45 (6H, s) ppm.

Production Example 8. 6- (4-Hydroxyphenyl) thio-2,2,3-trimethyl-2H-benzo (b) pyran
6- (4-Methoxyphenyl) thio-2,2,3-trimethyl-2H-benzo (b) pyran (7.816 g) (see Preparation 5) was dissolved in dry 2,4,6-collidine (30 ml), anhydrous lithium iodide (10.04 g) was added to the resulting solution, and the mixture was heated under reflux in nitrogen for 48 hours. An additional portion of lithium iodide (0.09 g) was then added and heating continued for another 72 hours. After cooling, the mixture was dissolved in dichloromethane and washed with 2 N. aqueous solution (x3) of hydrochloric acid. The organic layer was separated, dried (anhydrous sodium sulfate), the solvent was removed under reduced pressure, and the residue was chromatographed on silica using dichloromethane as an eluent, to give 6- (4-hydroxyphenyl) thio-2,2,3- trimethyl-2H-benzo (b) pyran (5.799 g) as an oil.

¹ H-NMR (CDCl ₃ ): δ = 7.25 (2H, d), 7.05 (1H, dd), 6.92 (1H, d), 6.70-6.80 (3H, m) 6.02 (1H, s), 4.92 (1H, s), 1.85 (3H, s), 1.40 (6H, s), ppm.

Production Example 9. 6- (3-Hydroxyphenyl) thio-2,2,3-trimethyl-2H-benzo (b) pyran
6- (3-Methoxyphenyl) thio-2,2,3-trimethyl-2H-benzo (b) pyran (3.5 g) (see Preparation 6) was dissolved in dry 2,4,6-collidine (15 ml) , anhydrous lithium iodide (3 g) was added to the resulting solution, and the mixture was refluxed under nitrogen for 24 hours. After cooling, the mixture was dissolved in dichloromethane and washed with 2 N. aqueous solution (x3) of hydrochloric acid. The organic layer was dried (anhydrous sodium sulfate), the solvent was removed under reduced pressure, and the residue was chromatographed on silica using a gradient varying from a mixture of hexane: dichloromethane = 1: 1 to dichloromethane, resulting in 6- (3- hydroxyphenyl) thio-2,2,3-trimethyl-2H-benzo (b) pyran (2.25 g) as an oil.

¹ H-NMR (CDCl ₃ ): δ = 7.05-7.21 (3H, m), 6.75 (2H, m), 6.60 (2H, m), 6.04 (1H, s) 4.60 (1H, broad), 1.86 (3H, s), 1.45 (6H, s), ppm.

Production Example 10. 6- (2-Hydroxyphenyl) thio-2,2,3-trimethyl-2H-benzo (b) pyran
6- (2-Methoxyphenyl) thio-2,2,3-trimethyl-2H-benzo (b) pyran (3.5 g) (see Preparation 7) was dissolved in dry 2,4,6-collidine (15 ml) , anhydrous lithium iodide (9.0 g) was added to the resulting solution, and the mixture was heated at 150 ^° C. for 40 hours. After cooling, the mixture was dissolved in dichloromethane and washed with 2 N. aqueous solution (x3) of hydrochloric acid. The organic layer was dried (anhydrous sodium sulfate), the solvent was removed under reduced pressure, and the residue was chromatographed on silica using hexane: dichloromethane = 1: 1 as an eluent, whereby 6- (2-hydroxyphenyl) thio-2 was obtained. 2,3-trimethyl-2H-benzo (b) pyran (1.2 g) as an oil.

¹ H-NMR (CDCl ₃ ): δ = 7.50 (1H, d), 7.31 (1H, t), 7.05 (1H, d), 6.90 (2H, m), 6.75 (1H, d), 6.65 (1H, d), 6.55 (1H, s), 5.99 (1H, s), 1.80 (3H, s), 1.37 (6H, s) ppm

Production Example 11. 6- (4-tert-Butyldimethylsilyloxyphenyl) thio-2,2,3-trimethyl-2H-benzo (b) pyran
6- (4-Hydroxyphenyl) thio-2,2,3-trimethyl-2H-benzo (b) pyran (5.799 g) (see Preparation 8) was dissolved in dry dimethylformamide (12 ml), and imidazole was added to the resulting solution ( 2.768 g) and tert-butyldimethylsilyl chloride (2.923 g). The flask was equipped with a calcium chloride drying tube, and the mixture was stirred at 40 ^° C. for 18 hours. Then, the solvent was removed under reduced pressure, and the residue was partitioned between an aqueous sodium bicarbonate solution and dichloromethane. The organic layer was dried (anhydrous sodium sulfate), the solvent was removed under reduced pressure, and the crude product was chromatographed on silica using hexane: dichloromethane = 1: 1 as an eluent to give 6- (4-tert-butyldimethylsilyloxyphenyl) thio -2,2,3-trimethyl-2H-benzo (b) pyran (6.681 g) as an oil. MCHP: m / z = 413 (+1) ⁺ .

¹ H-NMR (CDCL ₃ ): δ = 7.20 (2H, d), 7.05 (1H, dd), 6.95 (1H, d), 6.70-6.80 (3H, m) 6.02 (1H, s), 1.85 (3H, s), 1.41 (6H, s), 0.97 (9H, s), 0.21 (6H, s) ppm.

Production Example 12. 6- (3-tert-Butyldimethylsilyloxyphenyl) thio-2,2,3-trimethyl-2H-benzo (b) pyran
6- (3-Hydroxyphenyl) thio-2,2,3-trimethyl-2H-benzo / b / pyran (2.2 g), (see Preparation 9) was dissolved in dry dimethylformamide (4 ml), and the resulting solution imidazole (1.1 g) and tert-butyldimethylsilyl chloride (1.2 g) were added. The flask was equipped with a calcium chloride drying tube, and the mixture was stirred at 40 ^° C. for one hour. Water was added and the mixture was extracted with diethyl ether. The organic extract was washed with an aqueous solution of (x2) sodium bicarbonate, dried (anhydrous sodium sulfate), the solvent was removed under reduced pressure, and the crude product was chromatographed on silica using hexane: dichloromethane = 4: 1 as an eluent, resulting in 6 - (3-tert-butyldimethylsilyloxyphenyl) thio-2,2,3-trimethyl-2H-benzo (b) pyran (2.84 g) as an oil.

¹ H-NMR (CDCl ₃ ): δ = 7.00-7.18 (3H, m), 6.74 (2H, d), 6.58 (2H, m), 6.00 (1H, s) 1.80 (3H, s), 1.40 (6H, s), 0.88 (9H, s), 0.10 (6H, s) ppm.

Production Example 13. 6- (2-tert-Butyldimethylsilyloxyphenyl) thio-2,2,3-trimethyl-2H-benzo (b) pyran
6- (2-Hydroxyphenyl) thio-2,2,3-trimethyl-2H-benzo (b) pyran (1.1 g), (see Preparation 10) was dissolved in dry dimethylformamide (2 ml), and the resulting solution imidazole (0.55 g) and tert-butyldimethylsilyl chloride (0.61 g) were added. The flask was equipped with a calcium chloride drying tube, and the mixture was stirred at 40 ^° C. for 90 minutes. Water was added and the mixture was extracted with diethyl ether. The organic extract was washed with an aqueous solution of (x2) sodium bicarbonate, dried (anhydrous sodium sulfate), the solvent was removed under reduced pressure, and the crude product was chromatographed on silica using 4: 1 hexane: dichloromethane mixture as an eluent, resulting in 6 - (2-tert-butyldimethylsilyloxyphenyl) thio-2,2,3-trimethyl-2H-benzo (b) pyran (1.43 g) as an oil.

¹ H-NMR (CDCl ₃ ): δ = 7.20 (1H, dd), 7.00 (2H, m), 6.78 (4H, m), 6.05 (1H, s), 1.83 (3H, s), 1.45 (6H, s), 1.05 (9H, s), 0.28 (6H, s) ppm.

Production Example 14. (3S, 4S) -6- (4-tert-butyldimethylsilyloxyphenyl) sulfonyl-3,4-dihydro-3,4-epoxy-2,2,3-trimethyl-2H-benzo (b) pyran
6- (4-tert-Butyldimethylsilyloxyphenyl) thio-2,2,3-trimethyl-2H-benzo (b) pyran (2.182 g) (see Preparation 11) and [(S, S) -1,2-bis ( 3,5-di-tert-butylsalicylidamino)) cyclohexane manganese (111) chloride (see J. Am. Chem. Soc., 1991, 113, 7063) (0.25 g) was dissolved in dichloromethane (10 ml), and to the resulting solution was added a 3 M aqueous solution of sodium hypochlorite (50 ml, obtained from 4 M commodity bleaching solution). The biphasic system was vigorously stirred for 20 hours and then, until the two layers were separated, diluted with dichloromethane (30 ml). The organic layer was dried (anhydrous sodium sulfate), the solvent was removed under reduced pressure, and the residue was chromatographed on silica using dichloromethane as an eluent to give (3S, 4S) -6- (4-tert-butyldimethylsilyloxyphenyl) sulfonyl-3 , 4-epoxy-2,2,3-trimethyl-2H-benzo (b) pyran (1.907 g). HPLC confirmed that this product consisted of the same enantiomer.

MCHP: m / z = 478 (M + NH ₄ ) ⁺ .

¹ H-NMR (CDCl ₃ ): δ = 7.90 (1H, d), 7.75 (3H, m), 6.90 (3H, m), 3.70 (1H, d), 1.56 (3H, s), 1.51 (3H, s), 1.26 (3H, s), 0.98 (9H, s) 0.25 (6H, s) ppm.

 Production Example 15. (3S, 4S) -6- (3-tert-Butyldimethylsilyloxyphenyl) sulfonyl-3,4-dihydro-3,4-epoxy-2,2,3-trimethyl-2H-benzo (b) pyran.

 6- (3-tert-Butyldimethylsilyloxyphenyl) thio-2,2,3-trimethyl-2H-benzo / b / pyran (21.0 g) (see Preparation 12), 4-phenylpyridine N-oxide (2.2 g ) and [(S, S) -1,2-bis (3,5-di-tert-butylsalicylidamino)] cyclohexane manganese (111) -chloride (see J. Am. Chem. Soc., 1991, 113, 7063) (2.25 g) was dissolved in dichloromethane (120 ml), and a 3 M aqueous solution of sodium hypochlorite (500 ml obtained from 4 M salable bleach solution) was added to the resulting solution. The biphasic system was stirred vigorously for 24 hours and then, before the separation of the two layers, was diluted with dichloromethane and filtered through a cellulose filter accelerator. Then, the organic layer was washed with brine, dried (anhydrous sodium sulfate), the solvent was removed under reduced pressure, and the residue was chromatographed on silica using dichloromethane as the eluent to give (3S, 4S) -6- (3-tert- butyldimethylsilyloxyphenyl) sulfonyl-3,4-dihydro-3,4-epoxy-2,2,3-trimethyl-2H-benzo (b) - pyran (23.6 g). HPLC confirmed that this product consisted of a single enantiomer.

MCHP: m / z = 461 (M + 1) ⁺ .

¹ H-NMR (CDCl ₃ ): δ = 7.90 (1H, dd), 7.78 (1H, d), 7.45 (1H, d), 7.35 (2H, m), 7.00 (1H, dd), 6.88 (1H, d), 3.70 (1H, s), 1.55 (3H, s), 1.50 (3H, s) 1.30 (3H, s), 0.97 (9H, s), 0.21 (6H, s) ppm.

 Production Example 16. (3S, 4S) -6- (2-tert-Butyldimethylsilyloxyphenyl) sulfonyl-3,4-dihydro-3,4-epoxy-2,2,3-trimethyl-2H-benzo (b) pyran.

6- (2-tert-Butyldimethylsilyloxyphenyl) thio-2,2,3-trimethyl-2H-benzo (b) pyran (1.4 g) (see Preparation 13), and [(S, S) -1.2 bis (3,5-di-tert-butylsalicylidamino)] cyclohexane manganese (111) chloride (see J. Am. Chem. Soc., 1991, 113, 7063) (0.15 g) was dissolved in dichloromethane (7 ml ), and to the resulting solution was added a 3 M aqueous solution of sodium hypochlorite (32 ml, obtained from 4 M salable bleaching solution). The biphasic system was stirred vigorously for 24 hours and then, until the two layers were separated, diluted with dichloromethane. The organic layer was dried (anhydrous sodium sulfate), the solvent was removed under reduced pressure, and the residue was chromatographed on silica using dichloromethane as an eluent to give (3S, 4S) -6- (2-tert-butyldimethylsilyloxyphenyl) sulfonyl-3 4-dihydro-3,4-epoxy-2,2,3-trimethyl-2H-benzo (b) pyran (1.2 g),
MCHP: m / z = 461 (M + 1) ⁺ .

¹ H-NMR (CDCl ₃ ): δ = 8.10 (1H, dd), 7.85 (1H, d), 7.72 (1H, dd), 7.45 (1H, t), 7.10 (1H, t), 6.82 (2H, m), 3.68 (1H, s), 1.57 (3H, s), 1.50 (3H, s), 1.28 (3H, s) , 0.95 (9H, s), 0.30 (6H, s) ppm.

 Production Example 17. (3S, 4S) -3,4-Dihydro-3,4-epoxy-6- (3-methoxyphenyl) sulfonyl-2,2,3-trimethyl-2H-benzo (b) pyran.

 6- (3-Methoxyphenyl) thio-2,2,3-trimethyl-2H-benzo (b) pyran (4.2 g) (see Preparation 6), and [(S, S) -1,2-bis (3,5-di-tert-butylsalicylidamino)] cyclohexane manganese (111) chloride (see J. Am. Chem. Soc., 1991, 113, 7063) (0.60 g) was dissolved in dichloromethane (30 ml), and to the resulting solution was added a 3 M aqueous solution of sodium hypochlorite (130 ml, obtained from 4 M salable bleaching solution). The biphasic system was vigorously stirred for 24 hours and then diluted with dichloromethane. The mixture was filtered through a cellulose filtration accelerator until two layers were diluted. Then, the organic layer was dried (anhydrous sodium sulfate), the solvent was removed under reduced pressure, and the residue was chromatographed on silica using dichloromethane as the eluent to give (3S, 4S) -3,4-dihydro-3,4-epoxy -6- (3-methoxyphenyl) sulfonyl-2,2,3-trimethyl-2H-benzo (b) - pyran (2.0 g) as a pale yellow foam.

MCHP: m / z = 361 (M + 1) ⁺ .

¹ H-NMR (CDCl ₃ ): δ = 7.90 (1H, d), 7.78 (1H, dd), 7.40-7.50 (3H, m), 7.08 (1H, dd) 6.89 (1H, d), 3.85 (3H, s), 3.72 (1H, s), 1.55 (3H, s), 1.50 (3H, s), 1.27 ( 3H, s) ppm

 Production Example 18. (3S, 4R) -4-amino-3,4-dihydro-3-hydroxy-6- (3-methoxyphenyl) sulfonyl-2,2,3-trimethyl-2H-benzo (b) pyran.

(3S, 4S) -3,4-Dihydro-3,4-epoxy-6- (3-methoxyphenyl) sulfonyl-2,2,3-trimethyl-2H-benzo (b) pyran (2.0 g) (cm Preparation 17) was dissolved in ethanol (15 ml), and a 35% aqueous ammonia solution (10 ml) was added to the resulting solution. The mixture was heated at 50 ^° C. for 48 hours, after which another ammonia solution (5 ml) was added and it was heated for another 8 hours. The solvent was removed under reduced pressure and the residue was chromatographed on silica using a methanol: dichloromethane mixture of 5:95 as eluent to give (3S, 4S), -4-amino-3,4-dihydro-3-hydroxy -6- (3-methoxyphenyl) sulfonyl-2,2,3-trimethyl-2H-benzo (b) pyran (1.9 g) as a foam. Found: C, 58.65; H, 5.77; N, 3.29. Calculated for C ₁₉ H ₂₃ NO ₅ S, 0.22 CH ₂ Cl ₂ : C 58.28, H 5.96, N 3.53%.

¹ H-NMR CDCl ₃ ): δ = 8.00 (1H, s), 7.70 (1H, dd), 7.38-7.52 (3H, m), 7.08 (1H, dd), 6.85 (1H, d), 3.90 (1H, s), 3.85 (3H, s), 2.60 (1H, broad), 1.55 (2H, broad), 1.49 ( 3H, s) 1.30 (3H, s), 1.01 (3H, s) ppm.

 Production Example 19. (3S, 4R) -4- (2-Chloropyrimidin-4-yl) amino-3,4-dihydro-3-hydroxy-6- (3-methoxyphenyl) sulfonyl-2,2,3-trimethyl- 2H-benzo (b) pyran and (3S, 4R) -4- (4-chloropyrimidin-2-yl) amino-3,4-dihydro-3-hydroxy-6- (3-methoxyphenyl) sulfonyl-2,2, 3-trimethyl-2H-benzo (b) pyran.

 (3S, 4R) -4-amino-3,4-dihydro-3-hydroxy-6- (3-methoxyphenyl) sulfonyl -2,2,3-trimethyl-2H-benzo (b) pyran (0.95 g) (see Preparation 18) was dissolved in dry 1,4-dioxane, 2,4-dichloropyrimidine (0.45 g) and diisopropylethylamine (0.39 g) were added to the resulting solution, and the mixture was heated under reflux for 25 hours. Solvent 6 was removed under reduced pressure and the residue was subjected to azeotropic distillation with dichloromethane, after which it was chromatographed on silica using a mixture of dichloromethane: ethyl acetate = 4: 1 and (3S, 4R) -4- (4-chloropyrimidine) -2-yl) amino-3,4-dihydro-3-hydroxy-6- (3-methoxyphenyl) sulfonyl-2,2,3-trimethyl-2H-benzo (b) pyran (0.25 g) as foam.

MCHP: m / z = 490 (m) ⁺ .

¹ H-NMR (CDCl ₃ ): δ = 8.01 (1H, d), 7.80 (1H, dd), 7.38-7.50 (4H, m), 7.05 (1H, dd) 6.90 (1H, dd), 6.80 (1H, broad), 5.75 (1H, broad), 5.47 (1H, d), 4.95 (1H, broad), 3 80 (1H, s), 1.50 (3H, s), 1.45 (3H, s), 1.13 (3H, s) ppm.

Further elution with a mixture of dichloromethane: ethyl acetate = 1: 1 gave (3S, 4R) -4- (2-chloropyrimidin-4-yl) amino-3,4-dihydro-3-hydroxy-6- (3-methoxyphenyl) sulfonyl-2 , 2,3-trimethyl-2H-benzo (b) pyran (0.64 g) as a white solid, and so pl. 228-230 ^o C. MCHP: m / z = 490 (m) ⁺ .

¹ H-NMR (CDCl ₃ ): δ = 8.07 (1H, d), 7.85 (1H, s), 7.70 (1H, dd), 7.35-7.45 (3H, m) 7.08 (1H, dd), 6.90 (1H, dd), 6.61 (1H, dd), 5.79 (1H, d), 5.50 (1H, broad), 4.65 (1H, broad), 3.85 (3H, s), 1.50 (3H, s), 1.40 (3H, s), 1.15 (3H, s) ppm.

 Production Example 20. (3R, 4R) -4-amino-3,4-dihydro-3-hydroxy-6- (3-hydroxyphenyl) sulfonyl-2,2,3-trimethyl-2H-benzo (b) pyran.

(3S, 4S) -6- (3-tert-Butyldimethylsilyloxyphenyl) sulfonyl-3,4-dihydro-3,4-epoxy-2,2,3-trimethyl-2H-benzo (b) pyran (2.2 g) (see Preparation 15) was dissolved in ethanol (25 ml), and a 35% aqueous ammonia solution (25 ml) was added to the resulting solution. The mixture was heated at 40-50 ^o C for 24 hours. The solvent was removed under reduced pressure, and the residue was chromatographed on silica using a methanol: dichloromethane = 7.5: 92.5 mixture as eluent to give (3S, 4R) -4-amino-3,4-dihydro-3 -hydroxy-6- (3-hydroxyphenyl) sulfonyl-2,2,3-trimethyl-2H-benzo (b) pyran (1.42 g) as a foam. Found: C, 54.39; H, 5.22; N, 3.19. Calculated for C ₁₈ H ₂₁ NO ₅ S, 0.50 CH ₂ Cl ₂ : C 54.57, H 5.46, N 3.45%.

¹ H-NMR (CDCl ₃ ): δ = 8.07 (1H, s), 7.70 (1H, dd), 7.50 (1H, s), 7.41 (1H, d), 7.30 (1H, d), 6.99 (1H, dd), 6.81 (1H, d), 3.99 (1H, s), 3.50 (2H, broad), 1.48 (3H, s ), 1.28 (3H, s), 1.00 (3H, s) ppm.

 Production Example 21. 1,2-Dihydro-4-hydroxy-2-methyl-1-oxophthalazine.

Phthalic anhydride (7.4 g) was dissolved in hot acetic acid (50 ml), and a solution of methyl hydrazine (2.7 ml) in water (50 ml) was added to the resulting solution. The mixture was refluxed for 15 minutes and allowed to cool overnight. The resulting precipitate was filtered off, washed with water and dried under reduced pressure to obtain 1,2-dihydro-4-hydroxy-2-methyl-1-oxophthalazine (7.6 g) as a white solid, mp. 243-244 ^o C.

¹ H-NMR (CDCl ₃ ): δ = 8.28 (1H, m), 8.05 (1H, m), 7.85 (2H, m), 4.87 (1H, s), 3.66 (3H, s) ppm

 Production Example 22. 1,2-Dihydro-4-hydroxy-1-methyl-2-oxopyridine.

2,4-dihydroxypyridine (3.0 g) was dissolved in 2 N. aqueous sodium hydroxide solution (30 ml), and dimethyl sulfate (3.7 g) was added dropwise to the resulting solution over 90 minutes. The mixture was stirred at room temperature overnight, acidified with concentrated hydrochloric acid, the solvent was removed under reduced pressure, and the residue was stirred in 5% methanol / dichloromethane and filtered. The filtrate was evaporated and the resulting crude product was chromatographed on silica using a methanol: dichloromethane = 7:93 mixture as eluent to give 1,2-dihydro-4-hydroxy-1-methyl-2-oxopyridine (0.77 g) in the form of a yellow solid, so pl. 165-169 ^o C. Found: C 57.28, H 5.47, N 10.89. Calculated for C ₆ H ₇ NO ₂ : C 57.59, H 5.64, N 11.19%.

¹ H-NMR (d ₆ -DMCO): δ = 10.50 (1H, d), 7.50 (1H, d), 5.82 (1H, dd), 5.55 (1H, d), 3 30 (3H, s) ppm.

 An example of obtaining 23. 2,4-Dihydroxy-5,6-dimethylpyridine.

5,6-Dimethyl-4-hydroxy-2-oxo-2H-pyran (11.92 g) (see JCS Perkin Trans 1, 1980, 2272) was dissolved in 1,4-dioxane (80 ml), to the resulting solution aqueous 35% ammonia solution (40 ml) was added, and the mixture was heated under reflux for 90 minutes. The solution was allowed to cool overnight, after which the precipitate was filtered off and dried under reduced pressure at 90 ^° C. for 24 hours, resulting in 2,4-dihydroxy-5,6-dimethylpyridine (3.47 g) as a white solid .

¹ H-NMR (d ₆ -DMCO): δ = 10.75 (1H, broad), 5.42 (1H, s), 2.09 (3H, s), 1.78 (3H, s) m .d.

 Production Example 24. 6- (3,4-Dimethoxyphenyl) thio-2,2,3-trimethyl-2H-benzo (b) pyran.

 6-Bromo-2,2,3-trimethyl-2H-benzo (b) pyran (7.4 g) (see Preparation 4) was dissolved in absolute ethanol (150 ml), sodium tert-butoxide was added to the resulting solution (8 5 g), 3,4-dimethoxybenzenethiol (5 g) and tetrakis (triphenylphosphine) -palladium (0) (0.5 g), and the mixture was heated under reflux in the atmosphere for 24 hours. Then an additional portion of tetrakis (triphenylphosphine) -palladium (0) (0.5 g) was added and heating was continued for another 24 hours. The solvent was removed under reduced pressure, and the residue was dissolved in dichloromethane and washed with water. The organic layer was dried (anhydrous sodium sulfate), the solvent was removed under reduced pressure, and the obtained crude product was chromatographed on silica using hexane: dichloromethane = 1: 4 as an eluent, resulting in 6- (3,4-dimethoxyphenyl) thio -2,2,3-trimethyl-2H-benzo (b) pyran (7.4 g) as a yellow oil.

¹ H-NMR (CDCl ₃ ): δ = 7.20 (1H, dd), 6.85-7.00 (3H, m), 6.80 (1H, d), 6.72 (1H, d) 6.03 (1H, s), 3.85 (3H, s), 3.80 (3H, s), 1.85 (3H, s), 1.41 (6H, s) ppm.

 Production Example 25. (3S, 4S) -3,4-Dihydro-6- (3,4-dimethoxyphenyl) sulfonyl-3,4-epoxy-2,2,3-trimethyl-2H-benzo (b) pyran.

 6- (3,4-Dimethoxyphenyl) thio-2,2,3-trimethyl-2H-benzo (b) -pyran (3.1 g) (see Preparation 24), 4-phenylpyridine-N-oxide (0, 4 g) and [(S, S) -1,2-bis (3,5-di-tert-butylsalicyldamino)] cyclohexane manganese (III) chloride (0.4 g) was dissolved in dichloromethane (35 ml), and the resulting solution was added 3 M aqueous sodium hypochlorite solution (100 ml, obtained from 4 M commodity bleaching solution). The biphasic system was vigorously stirred for 24 hours and then, before separation into two layers, was diluted with dichloromethane. The organic layer was dried (anhydrous sodium sulfate), the solvent was removed under reduced pressure, and the residue was chromatographed on silica using dichloromethane: ethyl acetate = 19: 1 as an eluent, and (3S, 4S) -3,4-dihydro was obtained -6-) 3,4-dimethoxyphenyl) sulfonyl-3,4-epoxy-2,2,3-trimethyl-2H-benzo (b) pyran (3.0 g) as a yellow foam.

MCHP: m / z = 408 (m + NH ₄ ) ⁺ .

¹ H-NMR (CDCl ₃ ): δ = 7.89 (1H, d), 7.75 (1H, dd), 7.53 (1H, dd), 7.35 (1H, d), 6.80 -7.00 (2H, m), 3.92 (6H, s), 3.71 (1H, s), 1.59 (3H, s), 1.52 (3H, s), 1.29 ( 3H, s) ppm

 Production Example 26. (3S, 4R) -3,4-Dihydro-4- (2,4-dihydro-2-methyl-3-hydroxypyridazin-6-yl) oxy-6- (3,4-dimethoxyphenyl) sulfonyl- 3-hydroxy-2,2,3-trimethyl-2H-benzo (b) pyran.

 (3S, 4S) -3,4-Dihydro-6- (3,4-dimethoxyphenyl) sulfonyl-3,4-epoxy-2,2,3-trimethyl-2H-benzo (b) pyran (3.0 g) (see Preparation 25) and 2,3-dihydro-2-methyl-3-oxo-6-hydroxypyridazine (2.0 g) (see J. Org. Chem., 1971, 36, 3372) were suspended in dry 1 , 4-dioxane (30 ml), pyridine (0.61 g) was added to the resulting suspension, and the mixture was heated under reflux (the flask was equipped with a calcium chloride drying tube) for 2 days. The solvent was removed under reduced pressure, and the residue was stirred with 5% methanol / dichloromethane and filtered. The filter was evaporated, and the obtained crude product was chromatographed on silica using a methanol: dichloromethane = 2.5: 97.5 mixture as eluent, whereby (3S, 4R) -3,4-dihydro-4- was obtained (2, 3-dihydro-2-methyl-3-oxopyridazin-6-yl) oxy-6- (3,4-dimethoxyphenyl) sulfonyl-3-hydroxy-2,2,3-trimethyl-2H-benzo (b) pyran (1 7 g) in the form of a yellow foam.

¹ H-NMR (CDCl ₃ ): δ = 7.90 (1H, d), 7.75 (1H, dd), 7.52 (1H, dd), 7.35 (1H, s), 7.10 (2H, m), 6.90 (2H, m), 3.92 (3H, s), 3.90 (3H, s), 3.70 (3H, s), 1.50 (3H, s) 1.40 (3H, s); 1.25 (3H, s) ppm.

Production Example 27. 6-Bromo-3,4-dihydro-4-oxo-2,2,3-trimethyl-2H-benzo (b) pyran (Alternative procedure for the preparation of the compound from preparation 3)
a) 1- (5-Bromo-2-hydroxyphenyl) propan-1-one.

 To a stirred mixture of aluminum trichloride (2.5 kg) in dichloromethane (5000 ml), propanoyl chloride (864 g) was added over 5 minutes. The mixture was stirred for 45 minutes at room temperature, after which a solution of 4-bromoanisole (875 g) in dichloromethane (1000 ml) was added over 15 minutes. The reaction mixture was refluxed for 6 hours and then cooled and stirred at room temperature overnight.

The reaction mixture was sharply cooled by slowly (over 40 minutes) it was poured onto ice (11 kg). The mixture was stirred for 30 minutes, followed by separation of the layers. The aqueous layer was then extracted with dichloromethane (2 x 1000 ml), and the combined organic extracts were washed with water (2 x 2000 ml). Two-thirds of the solvent was removed from the organic layer by distillation at atmospheric pressure. Continuing the distillation, methanol (3750 ml) was slowly added. Distillation was continued until a temperature of 64 ^° C of the distillation apparatus body and a temperature of 62 ^° C of its head were reached. Then, water (270 ml) was added to the solution at this temperature, and the reaction mixture was cooled until a precipitate of a non-white solid precipitated. After cooling the reaction mixture to 20 ^° C., additional water (270 ml) was slowly added, and the mixture was granulated at about 10 ^° C. for 2 hours.

The solid was filtered and washed gently on a soft pad with methanol: water (6: 1 by volume), then dried under reduced pressure at 50 ^° C., and the title compound (960 g) was obtained.

 b) 6-Bromo-3-dihydro-4-oxo-2,2,3-trimethyl-2H-benzo (b) pyran.

 To a stirred solution of the product obtained in stage (a) (1.46 kg) in acetone (7300 ml) and xylene (6570 ml) was added piperidine (3.04 kg), and the reaction mixture was heated under reflux for 5 days.

 The reaction mixture was cooled and washed successively with water (2 • 3000 ml), and then 2 N. aqueous solution of hydrochloric acid (2 • 5000 ml) (with ice-cooling), 2 n. aqueous sodium hydroxide solution (3000 ml) and water (2 • 3000 ml).

 The organic layer was concentrated under reduced pressure to give the title compound as a brown oil (1.46 kg).

 Pharmacological data.

 The selected compounds obtained in the preceding examples were tested for activity, manifested in relaxation (relaxation) of smooth muscles, by a method involving measuring in vitro relaxation with a preparation of electrically stimulated tracheal rings of guinea pigs.

The results are presented in the table below, which shows the minimum dose of ¹ compound, causing maximum inhibition of cholinergic reduction relative to the control.

Claims (21)

1. Benzopyranes of the general formula I

where X represents O or NH;
R and R ^{1 are} each independently selected from H and C ₁ -C ₄ alkyl;
R ² is H or C ₁ -C ₄ alkyl,
R ³ represents: a) a 6-membered heterocyclic ring containing 1 or 2 N heteroatoms, said ring being connected to X via a carbon atom in the ring, optionally fused to the benzene ring and optionally substituted (including in the fused benzene part) C ₁ -C ₆ -alkyl, hydroxy, halogen, or oxo, provided that R ^{3 is} not a -N- (C ₁ -C ₆ -alkyl) -pyridonyl group, b) when X is an NH-group of the formula

or c) when X represents an NH group of the formula

R ⁴ represents phenyl substituted with one or two hydroxy groups;
R ⁵ is C ₁ -C ₆ alkyl;
R ⁶ is SR ⁵ ;
R ⁷ is cyano;
R ⁸ - OR ⁵ .  or a pharmaceutically acceptable salt thereof. 2. Benzopyranes according to claim 1, in which X represents O or NH; R, R ¹ and R ² each is C ₁ -C ₄ alkyl; R ³ represents: (a) a 6-membered heterocyclic ring containing 1 or 2 nitrogen heteroatoms, said ring being optionally fused to the benzene ring and optionally substituted (including in the fused benzene moiety) C ₁ -C ₄ -alkyl, hydroxy, halogen or oxo, b) a group of the formula

or (c) is a group of the formula

R ⁴ is phenyl substituted with 1 or 2 hydroxy groups;
R ⁶ is SR ⁵ ;
R ⁸ is —OR ⁵ ;
R ⁵ and R ⁷ take the values indicated in claim 1. 3. Benzopyranes according to claim 2, in which X is O; R, R ¹ and R ^{2 are} each methyl; R ³ - 1,2-dihydro-2-oxo-1H-pyridin-4-yl, 1,2-dihydro-5,6-dimethyl-2-oxo-1H-pyridin-4-yl, 3-hydroxypyridazin-6 -yl, 2,3-dihydro-2-methyl-3-oxopyridazin-6-yl, 2,3-dihydro-2-ethyl-3-oxopyridazin-6-yl, 1,2-dihydro-1-oxo-2H -phthalazin-4-yl, 1,2-dihydro-2-methyl-1-oxophthalazin-4-yl, 2-chloropyrimidin-4-yl, 3,4-dioxo-2-ethocyclobut-1-en-1-yl or 3-cyano-2-methylisothioureido;
R ⁴ is 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl or 3,4-dihydroxyphenyl. 4. Benzopyranes according to claim 3, in which R ³ - 1,2-dihydro-2-oxo-1H-pyridin-4-yl or 2,3-dihydro-2-methyl-3-oxopyridazin-6-yl and R ⁴ - 3-hydroxyphenyl or 4-hydroxyphenyl. 5. Benzopyranes according to claims 1 to 4, which have the general formula IA

where X, R, R ¹ - R ⁴ are indicated in claim 1.  6. The benzopyranes according to claim 1, which are selected from the group consisting of 3,4-dihydro-4- (2,3-dihydro-2-methyl-3-oxopyridazin-6-yl) oxy-3-hydroxy-6- (3-hydroxyphenyl) sulfonyl-2,2,3-trimethyl-2H-benzo (b) pyran and 3,4-dihydro-4- (2,3-dihydro-2-methyl-3-oxopyridazin-6-yl) oxy-3-hydroxy-6- (4-hydroxyphenyl) sulfonyl-2,2,3-trimethyl-2H-benzo (b) pyran, or a pharmaceutically acceptable salt of one or the other of these compounds, or (3S, 4R) -stereoisomeric the shape of any of them.  7. A pharmaceutical composition having smooth muscle relaxant activity, comprising an active agent and a pharmaceutically acceptable diluent or carrier, characterized in that the composition contains, as an active agent, a compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, in an effective quantity.  8. Benzopyranes of formula I according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, useful as a medicine.  9. Benzopyranes of the formula I according to any one of claims 1 to 6, having smooth muscle relaxant activity.  10. The composition according to claim 7, characterized in that it is intended for the treatment of a disease associated with a change in the tone and / or contractility of the smooth muscle.  11. The composition according to claim 7, characterized in that it is intended for the treatment of diseases selected from the following group: chronic airway obstruction, asthma, urinary incontinence, irritable bowel syndrome, disease associated with the formation of diverticula, achalasia (impaired relaxation smooth muscle sphincter) of the esophagus or hypertension.  12. A method of treating a disease associated with a change in the tone and / or contractility of the smooth muscle, characterized in that an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 is administered.  13. The method according to p. 12, characterized in that the said disease is chronic obstruction of the respiratory tract, asthma, urinary incontinence, irritable bowel syndrome, a disease associated with the formation of diverticula, achalasia (impaired ability to relax smooth muscle sphincters) of the esophagus or hypertension. 14. Benzopyranes of the general formula II

where R ¹⁰ is phenyl substituted with 1 or 2 hydroxy protecting groups;
X, R, R ¹ , R ² and R ³ take the values specified in paragraph 1. 15. Benzopyranes of the general formula VIA

where R ^10b is phenyl substituted with a tri (C ₁ -C ₄ alkyl) silyloxy group;
R, R ¹ and R ² take the values specified in claim 1. 16. Benzopyranes of the general formula VII

where R, R ¹ , R ² and R ⁴ takes the values specified in claim 1. 17. The benzopyranes of formula VIA according to claim 15, wherein the tri- (C ₁ -C ₄ -alkyl) silyloxy group in the definition of the symbol R ^10b is a tert-butyldimethylsilyloxy group. 18. The benzopyranes of formula II of claim 14, wherein the protected hydroxy group in the definition of R ¹⁰ is C ₁ -C ₄ alkoxy, preferably methoxy.  19. The benzopyran according to claim 1, which is (3S, 4R) -3,4-dihydro-4- (2,3-dihydro-2-methyl-3-oxopyridazin-6-yl) oxy-3-hydroxy- 6- (3-hydroxyphenyl) sulfonyl-2,2,3-trimethyl-2H-benzo (b) pyran, or a pharmaceutically acceptable salt thereof.  20. The benzopyran according to claim 1, which is (3S, 4R) -3,4-dihydro-4- (2,3-dihydro-2-methyl-3-oxopyridazin-6-yl) -oxy-3-hydroxy -6- (4-hydroxyphenyl) sulfonyl-2,2,3-trimethyl-2H-benzo (b) pyran, or a pharmaceutically acceptable salt thereof.  21. The composition according to claim 7, characterized in that it is useful for the treatment of diseases selected from the following group: peripheral vascular disease, congestive heart failure, pulmonary hypertension, myocardial and cerebral ischemia, angina pectoris, spotted baldness in men, cardiac arrhythmia, fatigue or skeletal muscle paralysis (myotonic muscular dystrophy), glaucoma, epilepsy, tinnitus, dizziness and dysmenorrhea (menstrual cycle disorder).

Images