Tricyclic compounds of benzopyran as antiarrhythmic agents

FIELD: chemistry.

SUBSTANCE: invention relates to benzopyran derivatives of formula or

or their pharmaceutically acceptable salts, where R¹ and R² independently represent a hydrogen atom or a C_1-6alkyl group, R³ is a hydroxyl group, R⁴ is a hydrogen atom, m is an integer ranging from 1 to 4, n is an integer ranging from 0 to 4, V is a single bond, CR⁷R⁸ or NR⁹, R⁵ is a hydrogen atom, R⁶ is a hydrogen atom, C_1-6alkyl group, C_3-8cycloalkyl group, C_3-8cycloalkenyl group, amino group, C_1-6alkylamino group, C_6-14aryl group, C_2-9heteroaryl group or C_2-9heterocyclic group, A is a 5- or 6-member ring condensed with a benzene ring, and the ring can contain an oxygen atom, a nitrogen atom or a sulphur atom numbering from 1 to 3 or separately, or combined, the number of unsaturated bonds in the ring equals 1, 2 or 3, including the unsaturated bond in the condensed benzene ring, carbon atoms in the ring can represent carbonyl or thiocarbonyl.

EFFECT: compounds can be used as antiarrhythmic agents.

47 cl, 1 tbl, 98 ex

The technical field

The present invention relates to the derivatives of benzopyran providing prolonging effect on the refractory period, which is used to treat arrhythmia in mammals, including humans.

The level of technology

As derived benzopyran known derivatives of 4-aceraminophen illustrated example, Cromakalim (for example, published patent application Japan No. Sho. 58-67683). It is known that these derivative 4-aceraminophen, such as Cromakalim, open ATP-sensitive K⁺the channel and, therefore, are effective for the treatment of hypertension and asthma, but there was no mention of their effectiveness for the treatment of arrhythmia due to a prolonging effect on the refractory period.

In addition, it was reported that derivatives of 4-aminobenzophenone that have β3-receptor-stimulating effect, as expected, are effective for the treatment of obesity (e.g., WO 03/014113), but this document does not include any mention of their effectiveness for the treatment of arrhythmia due to a prolonging effect on the refractory period.

Disclosure of invention

Meanwhile, conventional antiarrhythmic agents providing prolonging effect on the refractory period as the primary mechanism is ZMA (such as medicines of the class I according to the classification of antiarrhythmic agents according to Vaughan Williams or d-sotalol, or dofetilide belonging to class III), cause therapeutic problems inducyruya fibrillation with a high degree of risk, leading to sudden death, among other things, from such causes as Torsade de pointes (ventricular) due to prolongation of the action potential venticular muscles, which correlates with a prolonged effect on the refractory period. Thus, there is a need for medicines with fewer side effects.

To solve this problem the authors of the present invention investigated the connection, providing a prolonging effect on the refractory period selective in relation to the muscles of the Atria and not venticular muscles, and found that the compound of formula (I) or (II) has a prolonging effect on the refractory period selective in relation to the muscles of the Atria and not have any effect on the refractory period and action potential venticular muscles. Thus was accomplished the present invention.

Thus, the present invention includes the following aspects:

(1) derived benzopyran formula (I) or (II) or its pharmaceutically acceptable salt

where R¹and R²independently represent a hydrogen atom, a C_1-6alkyl group (where alkyl the second group may be optionally substituted by a halogen atom, C_1-6alkoxygroup (where alkoxygroup may be optionally substituted by a halogen atom) or hydroxy-group), or C_6-14aryl group (where the aryl group can be optionally substituted by halogen atom, hydroxy-group, a nitrogroup, cyano, C_1-6alkyl group (where the alkyl group can be optionally substituted by a halogen atom, a C_1-6alkoxygroup (where alkoxygroup may be optionally substituted by a halogen atom) or hydroxy-group) or C_1-6alkoxygroup (where alkoxygroup may be optionally substituted by a halogen atom));

R³represents a hydroxy-group or C_1-6alkylcarboxylic, or R³forms a bond together with R⁴;

R⁴represents a hydrogen atom, or R⁴forms a bond together with R³;

m is an integer from 0 to 4;

n is an integer from 0 to 4;

V represents a simple bond, CR⁷R⁸where R⁷represents a C_1-6alkyl group (where the alkyl group can be optionally substituted by halogen atom, hydroxy-group, C_1-6alkoxygroup (where C_1-6alkoxygroup may be optionally substituted by halogen atom), C_6-14aryl group, a C_2-9heteroaryl group (where each aryl group Il the heteroaryl group may be optionally substituted by 1-3 substituents R ¹⁰where R¹⁰represents a halogen atom; a hydroxy-group; C_1-6alkyl group (where the alkyl group can be optionally substituted by halogen atom, hydroxy-group or C_1-6alkoxygroup (where alkoxygroup may be optionally substituted by a halogen atom)); C_1-6alkoxygroup (where alkoxygroup may be optionally substituted by halogen atom), a nitro-group; a cyano; formyl group; formamido group; sulfonylamino; sulfonyloxy group; an amino group; C_1-6alkylamino; di-C_1-6alkylamino; C_1-6alkylcarboxylic; C_1-6alkylsulfonamides; aminocarbonyl group; C_1-6alkylaminocarbonyl group; di-C_1-6alkylaminocarbonyl group; C_1-6alkylcarboxylic group; C_1-6alkoxycarbonyl group; aminosulfonyl group; C_1-6alkylsulfonyl group; a carboxyl group or a C_6-14arylcarbamoyl group, and when there are several groups of R¹⁰they can be the same or different from each other); C_1-6alkylcarboxylic; the nitro-group; a cyano; formyl group; formamide group; amino group; C_1-6alkylaminocarbonyl; di-C_1-6alkylaminocarbonyl; C_1-6alkylcarboxylic; C_1-6alkylsulfonamides who sing; aminocarbonyl group; C_1-6alkylaminocarbonyl group; di-C_1-6alkylaminocarbonyl group; C_1-6alkylcarboxylic group; C_1-6alkoxycarbonyl group; aminosulfonyl group; C_1-6alkylsulfonyl group; a carboxyl group or sulfonyloxy group);

- C_6-14aryl group, a C_2-9heteroaryl group, where each aryl group or heteroaryl group may be optionally substituted by 1-3 substituents R¹⁰where R¹⁰have the above values);

the hydroxy - group;

- C_1-6alkoxygroup (where alkoxygroup may be optionally substituted by halogen atom), or

- the nitro-group; a cyano; formyl group; formamido group; sulfonylamino; sulfonyloxy group; an amino group; C_1-6alkylamino; di-C_1-6alkylamino; C_1-6alkylcarboxylic; C_l-6alkylsulfonamides; aminocarbonyl group; C_1-6alkylaminocarbonyl group; di-C_1-6alkylaminocarbonyl group; C_1-6alkylcarboxylic group; C_1-6alkoxycarbonyl group; aminosulfonyl group; C_1-6alkylsulfonyl group; carboxyl group, a C_6-14arylcarbamoyl group or a C_2-9heteroarylboronic group (where each kilcarbery gr is the PAP or heteroarylboronic group may be optionally substituted by 1-3 substituents R ¹⁰where R¹⁰have the above values), and

R⁸represents a

is a hydrogen atom,

- C_1-6alkyl group (where C_1-6the alkyl group may be optionally substituted by halogen atom, hydroxy-group, C_1-6alkoxygroup (where alkoxygroup may be optionally substituted by halogen atom), C_6-14aryl group, a C_2-9heteroaryl group (where each aryl group or heteroaryl group may be optionally substituted by 1-3 substituents R¹⁷where R¹⁷has the same meaning as R¹⁰), C_1-6alkylcarboxylic; the nitro-group; a cyano; formyl group; formamide group; amino group; C_1-6alkylaminocarbonyl; di-C_1-6alkylaminocarbonyl; C_1-6alkylcarboxylic; C_1-6alkylsulfonamides; aminocarbonyl group; C_1-6alkylaminocarbonyl group; di-C_1-6alkylaminocarbonyl group; C_1-6alkylcarboxylic group; C_1-6alkoxycarbonyl group; aminosulfonyl group; C_1-6alkylsulfonyl group; a carboxyl group or sulfonyloxy group);

- C_6-14aryl group, a C_2-9heteroaryl group, where each aryl group or heteroaryl group may be optionally substituted by 1-3 substituents R^{17 where R17has the same meaning as R10);}

the hydroxy - group;

- C_1-6alkoxygroup (where alkoxygroup may be optionally substituted by halogen atom), or

- the nitro-group; a cyano; formyl group; formamido group; sulfonylamino; sulfonyloxy group; an amino group; C_1-6alkylamino; di-C_1-6alkylamino; C_1-6alkylcarboxylic; C_l-6alkylsulfonamides; aminocarbonyl group; C_1-6alkylaminocarbonyl group; di-C_1-6alkylaminocarbonyl group; C_1-6alkylcarboxylic group; C_1-6alkoxycarbonyl group; aminosulfonyl group; C_1-6alkylsulfonyl group; carboxyl group, a C_6-14arylcarbamoyl group or a C_2-9heteroarylboronic group (where each arylcarbamoyl group or heteroarylboronic group may be optionally substituted by 1-3 substituents R¹⁷where R¹⁷has the same meaning as R¹⁰), or

R⁷together with R⁸can be a =O or =S, or

V represents NR⁹where R⁹represents a hydrogen atom, a C_1-6alkyl group (where the alkyl group can be optionally substituted by a halogen atom, a C_1-6alkoxygroup (where alkoxygroup may be optional for esena a halogen atom), hydroxy-group, C_6-14aryl group, a C_2-9heteroaryl group (where each aryl group or heteroaryl group may be optionally substituted by 1-3 substituents R¹⁷where R¹⁷has the same meaning as R¹⁰); C_{1 6}alkylaminocarbonyl group, di-C_1-6alkylaminocarbonyl group, C_1-6alkylcarboxylic group, C_3-8cycloalkylcarbonyl group, C_1-6alkoxycarbonyl group, C_1-6alkylsulfonyl group, a carboxyl group, a C_6-14arylcarbamoyl group or a C_2-9heteroarylboronic group), C_1-6alkylaminocarbonyl group, di-C_1-6alkylaminocarbonyl group, C_1-6alkylcarboxylic group,

C_3-8cycloalkylcarbonyl group, C_1-6alkoxycarbonyl group, C_1-6alkylsulfonyl group, C_6-14arylsulfonyl group, C_2-9heteroarylboronic group (where each arylsulfonyl group or heteroarylboronic group may be optionally substituted by 1-3 substituents R¹⁷where R¹⁷has the same meaning as R¹⁰), carboxyl group; C_6-14arylcarbamoyl group or a C_2-9heteroarylboronic group (where each arylcarbamoyl group or heteroarylboronic group can be neobyazatel is substituted by 1-3 substituents R ¹⁷where R¹⁷has the same meaning as R¹⁰), or

V represents O, S, SO or SO₂;

R⁵represents a hydrogen atom or a C_1-6alkyl group (where the alkyl group can be optionally substituted by a halogen atom, a C_1-6alkoxygroup (where alkoxygroup may be optionally substituted by a halogen atom) or hydroxy-group) and

R⁶represents a

is a hydrogen atom,

- C_1-6alkyl group (where the alkyl group can be optionally substituted by a halogen atom, a C_1-6alkoxygroup (where alkoxygroup may be optionally substituted by halogen atom), amino group, carboxyl group or hydroxy-group),

- C_3-8cycloalkyl group, C_3-8cycloalkenyl group (where cycloalkyl group or cycloalkenyl group may be optionally substituted by a halogen atom, a C_1-6alkyl group (where the alkyl group can be optionally substituted by a halogen atom, a C_1-6alkoxygroup (where alkoxygroup may be optionally substituted by halogen atom), amino group, carboxyl group or hydroxy-group), C_1-6alkoxygroup (where alkoxygroup may be optionally substituted by halogen atom), amino group, carboxyl group or hydroxy-group),

- an amino group, a C_{1-6 alkylamino, di-C1-6alkylamino,6-14killingray, C2-9geteroarilsulfoksidu (where each killingray or literarymonographic may be optionally substituted by 1-3 substituents R¹⁸where R¹⁸has the same meaning as R¹⁰);}

- C_6-14aryl group_2-9heteroaryl group, where each aryl group or heteroaryl group may be optionally substituted by 1-3 substituents R¹⁸where R¹⁸has the same meaning as R¹⁰or

- C_2-9heterocyclic group, where the heterocyclic group may be optionally substituted by a halogen atom, a C_1-6alkyl group (where the alkyl group can be optionally substituted by a halogen atom, a C_1-6alkoxygroup (where alkoxygroup may be optionally substituted by halogen atom), amino group, carboxyl group or hydroxy-group), C_1-6alkoxygroup (where alkoxygroup may be optionally substituted by halogen atom), C_6-14aryl group, With_2-9heteroaryl group (where each aryl group or heteroaryl group may be optionally substituted by 1-3 substituents R¹⁸where R¹⁸has the same meaning as R¹⁰), hydroxy-group, a nitrogroup, cyano, formyl group, formamide the th group, amino group, a C_1-6alkylaminocarbonyl, di-C_1-6alkylaminocarbonyl, C_1-6alkylcarboxylic, C_1-6alkylsulfonamides, aminocarbonyl group, C_1-6alkylaminocarbonyl group, di-C_1-6alkylaminocarbonyl group, C_1-6alkylcarboxylic group, C_1-6alkoxycarbonyl group; aminosulfonyl group, C_1-6alkylsulfonyl group, a carboxyl group or C_6-14arylcarboxylic group);

A represents a 5-, 6 - or 7-membered ring condensed with a benzene ring (where the 5-, 6 - or 7-membered ring may be optionally substituted by 1-6 substituents R²¹where R²¹has the same meaning as R¹⁰and when there are multiple substituents R²¹they can be the same or different from each other), the ring may contain oxygen atom, nitrogen atom or sulfur atom number of from 1 to 3 individually or in combination with each other, the number of unsaturated bonds in the ring is 1, 2 or 3, including unsaturated bond condensed with him benzene ring, the carbon atoms comprising the ring may be carbonyl or thiocarbonyl;

(2) derived benzopyran or its pharmaceutically acceptable salt p. 1, where A is a

where R¹¹and R¹²independently represent a hydrogen atom, a C_1-6alkyl group (where the alkyl group can be optionally substituted by a halogen atom, a C_1-6alkoxygroup (where alkoxygroup may be optionally substituted by halogen atom), a hydroxy-group, C_6-14aryl group, a C_2-9heteroaryl group (where each aryl group or heteroaryl group may be optionally substituted by 1-3 substituents R¹⁹where R¹⁹has the same meaning as R¹⁰), C_1-6alkylaminocarbonyl group, di-C_1-6alkylaminocarbonyl group, C_1-6alkylcarboxylic group, C_3-8cycloalkylcarbonyl group,

C_1-6alkoxycarbonyl group, C_1-6alkylsulfonyl group, a carboxyl group, a C_6-14arylcarbamoyl group or a C_2-9heteroarylboronic group), C_6-14aryl group, a C_2-9heteroaryl group, where each aryl group or heteroaryl group may be optionally substituted by 1-3 substituents R¹⁹where R¹⁹has the same meaning as R¹⁰), C_1-6alkylaminocarbonyl group, di-C_1-6alkylaminocarbonyl group,

C_1-6alkylcarboxylic group, C_3-8cycloalkylcarbonyl group, C_1- alkoxycarbonyl group, C_1-6alkylsulfonyl group, C_6-14arylsulfonyl group, C_2-9heteroarylboronic group (where each arylsulfonyl group or heteroarylboronic group may be optionally substituted by 1-3 substituents R¹⁹where R¹⁹has the same meaning as R¹⁰), carboxyl group; C_6-14arylcarbamoyl group or a C_2-9heteroarylboronic group (where each arylcarbamoyl group or heteroarylboronic group may be optionally substituted by 1-3 substituents R¹⁹where R¹⁹has the same meaning as R¹⁰),

R¹³, R¹⁴, R¹⁵and R¹⁶independently represent a hydrogen atom, halogen atom,

C_1-6alkyl group (where the alkyl group can be optionally substituted by a halogen atom, a C_1-6alkoxygroup (where alkoxygroup may be optionally substituted by halogen atom), amino group, hydroxy-group, C_6-14aryl group, a C_2-9heteroaryl group (where each aryl group or heteroaryl group may be optionally substituted by 1-3 substituents R²⁰where R²⁰has the same meaning as R¹⁰), C_1-6alkylaminocarbonyl group, di-C_1-6alkylaminocarbonyl group, C_1-6alkylcarboxylic group is Oh, C_3-8cycloalkylcarbonyl group, C_1-6alkoxycarbonyl group, C_1-6alkylsulfonyl group, a carboxyl group, a C_6-14arylcarbamoyl group or a C_2-9heteroarylboronic group), C_1-6alkoxygroup (where alkoxygroup may be optionally substituted by a halogen atom, a C_1-6alkoxygroup (where alkoxygroup may be optionally substituted by halogen atom), a carboxyl group, an amino group, a hydroxy-group, C_6-14aryl group or a C_2-9heteroaryl group (where each aryl group or heteroaryl group may be optionally substituted by 1-3 substituents R²⁰where R²⁰has the same meaning as R¹⁰)), C_1-6dialkoxy (where Tolkacheva may be optionally substituted by a halogen atom, a C_1-6alkoxygroup (where alkoxygroup may be optionally substituted by halogen atom), a carboxyl group, a hydroxy-group, C_6-14aryl group or a C_2-9heteroaryl group (where each aryl group or heteroaryl group may be optionally substituted by 1-3 substituents R²⁰where R²⁰has the same meaning as R¹⁰)), the hydroxy-group, C_6-14aryl group, a C_2-9heteroaryl group, where each aryl group or heteroaryl group m which may be optionally substituted by 1-3 substituents R ²⁰where R²⁰has the same meaning as R¹⁰), C_1-6alkylcarboxylic, a nitrogroup, cyano, formyl group, formamide group, amino group, sulfonyloxy group, C_1-6alkylamino, di-C_1-6alkylamino, C_6-14killingray, C_2-9geteroarilsulfoksidu (where each killingray or literarymonographic may be optionally substituted by 1-3 substituents R²⁰where R²⁰has the same meaning as R¹⁰), C_1-6alkylcarboxylic, C_1-6alkylsulfonamides, aminocarbonyl group, C_1-6alkylaminocarbonyl group, di-C_1-6alkylaminocarbonyl group, C_1-6alkylcarboxylic group, C_6-14arylcarbamoyl group, C_2-9heteroarylboronic group (where each arylcarbamoyl group or heteroarylboronic group may be optionally substituted by 1-3 substituents R²⁰where R²⁰has the same meaning as R¹⁰), C_1-6alkoxycarbonyl group, aminosulfonyl group, C_1-6alkylsulfonyl group, C_6-14arylsulfonyl group, C_2-9heteroarylboronic group (where each arylsulfonyl group or heteroarylboronic group may be optionally substituted by 1-3 substituents R²⁰where R²⁰has t is some set to the same value and R¹⁰), a carboxyl group, sulfonyloxy group or_2-9heterocyclic group, where the heterocyclic group may be optionally substituted by a halogen atom, a C_1-6alkyl group (where the alkyl group can be optionally substituted by a halogen atom, a C_1-6alkoxygroup (where alkoxygroup may be optionally substituted by halogen atom), amino group, carboxyl group or hydroxy-group), C_1-6alkoxygroup (where alkoxygroup may be optionally substituted by halogen atom), C_6-14aryl group, With_2-9heteroaryl group (where each aryl group or heteroaryl group can be optionally substituted with 1-3 substituents R²⁰where R²⁰has the same meaning as R¹⁰), hydroxy-group, nitrogroup, ceanography, formalnoe group, formamide group, amino group, C_1-6alkylaminocarbonyl, di-C_1-6alkylaminocarbonyl, C_1-6alkylcarboxylic, C_1-6alkylsulfonamides, aminocarbonyl group, C_1-6alkylaminocarbonyl group, di-C_1-6alkylaminocarbonyl group, C_1-6alkylcarboxylic group, C_1-6alkoxycarbonyl group, aminosulfonyl group, C_1-6alkylsulfonyl group, a carboxyl group or_{6-14 arylcarboxylic group)}

_{X represents O, S, SO or SO2;}

(3) derived benzopyran or its pharmaceutically acceptable salt as described in (2), where R¹and R²represent a methyl group, R³represents a hydroxy-group, and R⁴represents a hydrogen atom;

(4) derived benzopyran or its pharmaceutically acceptable salt as described in (3), where R⁵represents a hydrogen atom, m is an integer from 0 to 3 and n is an integer from 0 to 2;

(5) derived benzopyran or its pharmaceutically acceptable salt as described in (4), where V represents a simple bond;

(6) derived benzopyran or its pharmaceutically acceptable salt as described in (5), where m is an integer from 1 to 3, n is 0 and R⁶represents a C_6-14aryl group, where the aryl group can be optionally substituted with 1-3 substituents R¹⁸where R¹⁸has the same meaning as R¹⁰;

(7) derived benzopyran or its pharmaceutically acceptable salt as described in (6), where m is 2;

(8) derived benzopyran or its pharmaceutically acceptable salt as described in (7), where R⁶represents a C_6-14aryl group, where the aryl group can be optionally substituted by 1-3 atoms is halogen or amino group, and when there is a lot of substituents, they may be the same or different from each other;

(9) derived benzopyran or its pharmaceutically acceptable salt as described in (5), where m is an integer from 1 to 3, n is 0, and R⁶represents a C_2-9heteroaryl group, where the heteroaryl group may be optionally substituted by 1-3 substituents R¹⁸where R¹⁸has the same meaning as R¹⁰;

(10) derived benzopyran or its pharmaceutically acceptable salt as described in (9), where m is 2;

(11) derived benzopyran or its pharmaceutically acceptable salt as described in (10), where R⁶is a 2-pyridyloxy group, 3-pyridyloxy group or 4-pyridyloxy group;

(12) derived benzopyran or its pharmaceutically acceptable salt as described in (5), where m is an integer from 1 to 3, n is 0 and R⁶represents a C_2-4alkyl group (where the alkyl group can be optionally substituted by a halogen atom, a C_1-6alkoxygroup (where alkoxygroup may be optionally substituted by halogen atom), amino group, carboxyl group or hydroxy-group), C_3-8cycloalkyl group, C_3-8cycloalkenyl group (where cycloalkyl group or cycloalkenyl group can be neo is Astelin substituted by halogen atom, C_1-6alkyl group (where the alkyl group can be optionally substituted by a halogen atom, a C_1-6alkoxygroup (where alkoxygroup may be optionally substituted by halogen atom), amino group, carboxyl group or hydroxy-group), C_1-6alkoxygroup (where alkoxygroup may be optionally substituted by halogen atom), amino group, carboxyl group or hydroxy-group), or C_2-9heterocyclic group, where the heterocyclic group may be optionally substituted by a halogen atom, a C_1-6alkyl group (where the alkyl group can be optionally substituted by a halogen atom, a C_1-6alkoxygroup (where alkoxygroup may be optionally substituted by halogen atom), amino group, carboxyl group or hydroxy-group), C_1-6alkoxygroup (where alkoxygroup may be optionally substituted by halogen atom), a hydroxy-group or amino group);

(13) derived benzopyran or its pharmaceutically acceptable salt as described in (12), where m is 2;

(14) derived benzopyran or its pharmaceutically acceptable salt as described in (13), where R⁶is a n-sawn group, isopropyl group, t-pentelow group, C-hexoloy group, 1-C-pentanediol group, 2-C-pentanediol group, 3-C-pentanediol group, 1-C-g is kinilow group, 2-C-hexenyl group or 3-C-hexenyl group;

(15) derived benzopyran or its pharmaceutically acceptable salt as described in (4), where V represents CR⁷R⁸;

(16) derived benzopyran or its pharmaceutically acceptable salt as described in (15), where R⁷represents a hydroxy-group, C_1-6alkyl group (where the alkyl group can be optionally substituted by a halogen atom, a C_1-6alkoxygroup (where alkoxygroup may be optionally substituted by halogen atom), amino group, carboxyl group or hydroxy-group), C_1-6alkoxygroup (where alkoxygroup may be optionally substituted by halogen atom), C_1-6alkylamino, di-C_1-6alkylamino or carboxyl group, and R⁸represents a hydrogen atom or a C_1-6alkyl group (where the alkyl group can be optionally substituted by a halogen atom, a C_1-6alkoxygroup (where alkoxygroup may be optionally substituted by halogen atom), amino group, carboxyl group or hydroxy-group), or R⁷and R⁸together are =O or =S;

(17) derived benzopyran or its pharmaceutically acceptable salt as described in (16), where R⁷represents a hydroxy-group, C_1-6alkyl group (where the alkyl group mo is et to be optionally substituted by a halogen atom, hydroxy-group or a carboxyl group or carboxyl group, and R⁸represents a hydrogen atom or a C_1-6alkyl group (where the alkyl group can be optionally substituted by halogen atom, hydroxy-group or a carboxyl group), or R⁷and R⁸together represent =O;

(18) derived benzopyran or its pharmaceutically acceptable salt as described in (17), where R⁷represents a hydroxy-group, and R⁸represents a hydrogen atom;

(19) derived benzopyran or its pharmaceutically acceptable salt as described in (15), where m is an integer from 1 to 2, n is 0 and R⁶represents a C_6-14aryl group or a C_2-9heteroaryl group, where each aryl group or heteroaryl group may be optionally substituted by 1-3 substituents R¹⁸where R¹⁸has the same meaning as R¹⁰;

(20) derived benzopyran or its pharmaceutically acceptable salt as described in (19), where R⁷represents a hydroxy-group, C_1-6alkyl group (where the alkyl group can be optionally substituted by a halogen atom, a C_1-6alkoxygroup (where alkoxygroup may be optionally substituted by halogen atom), amino group, carboxyl group or hydroxy-group), C_1-6Alcock is the group (where alkoxygroup may be optionally substituted by halogen atom), C_1-6alkylamino, di-C_1-6alkylamino or carboxyl group, and R⁸represents a hydrogen atom or a C_1-6alkyl group (where the alkyl group can be optionally substituted by a halogen atom, a C_1-6alkoxygroup (where alkoxygroup may be optionally substituted by halogen atom), amino group, carboxyl group or hydroxy-group), or R⁷and R⁸together are =O or =S;

(21) derived benzopyran or its pharmaceutically acceptable salt as described in (20), where R⁷represents a hydroxy-group, C_1-6alkyl group (where the alkyl group can be optionally substituted by halogen atom, hydroxy-group or a carboxyl group or carboxyl group, and R⁸represents a hydrogen atom or a C_1-6alkyl group (where the alkyl group can be optionally substituted by halogen atom, hydroxy-group or a carboxyl group), or R⁷and R⁸together represent =O;

(22) derived benzopyran or its pharmaceutically acceptable salt as described in (21), where R⁷represents a hydroxy-group, and R⁸represents a hydrogen atom.

(23) derived benzopyran or its pharmaceutically acceptable salt as described in (22), where m is 1, n is 0 and R⁶before the hat is C _6-14aryl group, where the aryl group can be optionally substituted with 1-3 halogen atoms or amino groups, and if there are multiple substituents, they may be identical or different from each other;

(24) derived benzopyran or its pharmaceutically acceptable salt as described in (15), where m is an integer from 1 to 2, n is 0 and R⁶represents a C_1-4alkyl group (where the alkyl group can be optionally substituted by a halogen atom, a C_1-6alkoxygroup (where alkoxygroup may be optionally substituted by halogen atom), amino group, carboxyl group or hydroxy-group), C_3-8cycloalkyl group, C_3-8cycloalkenyl group (where cycloalkyl group or cycloalkenyl group may be optionally substituted by a halogen atom, a C_1-6alkyl group (where the alkyl group can be optionally substituted by a halogen atom, a C_1-6alkoxygroup (where alkoxygroup may be optionally substituted by halogen atom), amino group, carboxyl group or hydroxy-group), C_1-6alkoxygroup (where alkoxygroup may be optionally substituted by halogen atom), amino group, carboxyl group or hydroxy-group), or C_2-9heterocyclic group, where the heterocyclic group can in order to be optionally substituted by a halogen atom, C_1-6alkyl group (where the alkyl group can be optionally substituted by a halogen atom, a C_1-6alkoxygroup (where alkoxygroup may be optionally substituted by halogen atom), amino group, carboxyl group or hydroxy-group), C_1-6alkoxygroup (where alkoxygroup may be optionally substituted by halogen atom), amino group, carboxyl group or hydroxy-group);

(25) derived benzopyran or its pharmaceutically acceptable salt as described in (24), where R⁷represents a hydroxy-group, C_1-6alkyl group (where the alkyl group can be optionally substituted by a halogen atom, a C_1-6alkoxygroup (where C_1-6alkoxygroup may be optionally substituted by halogen atom), amino group, carboxyl group or hydroxy-group), C_1-6alkoxygroup (where C_1-6alkoxygroup may be optionally substituted by halogen atom), C_1-6alkylamino, di-C_1-6alkylamino or carboxyl group, and R⁸represents a hydrogen atom or a C_1-6alkyl group (where the alkyl group can be optionally substituted by a halogen atom, a C_1-6alkoxygroup (where C_1-6alkoxygroup may be optionally substituted by halogen atom), amino group, carboxyl group or hydrox the group), or R⁷and R⁸together are =O or =S;

(26) derived benzopyran or its pharmaceutically acceptable salt as described in (25), where R⁷represents a hydroxy-group, C_1-6alkyl group (where the alkyl group can be optionally substituted by halogen atom, hydroxy-group or a carboxyl group or carboxyl group, and R⁸represents a hydrogen atom or a C_1-6alkyl group (where the alkyl group can be optionally substituted by halogen atom, hydroxy-group or a carboxyl group), or R⁷and R⁸together represent =O;

(27) derived benzopyran or its pharmaceutically acceptable salt as described in (26), where R⁷represents a hydroxy-group, and R⁸represents a hydrogen atom;

(28) derived benzopyran or its pharmaceutically acceptable salt as described in (27), where R⁶is a n-sawn group, isopropyl group, t-pentelow group, C-hexoloy group, 1-C-pentanediol group, 2-C-pentanediol group, 3-C-pentanediol group, 1-C-hexenyl group, 2-C-hexenyl group or 3-C-hexenyl group;

(29) derived benzopyran or its pharmaceutically acceptable salt as described in (15), where R⁷and R⁸together are =O or =S and R⁶PR is dstanley an amino group, C_1-6alkylamino, di-C_1-6alkylamino, C_6-14killingray, C_2-9geteroarilsulfoksidu (where each killingray or literarymonographic may be optionally substituted by 1-3 substituents

R¹⁸where R¹⁸has the same meaning as R¹⁰), or C_2-9heterocyclic group, where the heterocyclic group may be optionally substituted by a halogen atom, a C_1-6alkyl group (where the alkyl group can be optionally substituted by a halogen atom, a C_1-6alkoxygroup (where alkoxygroup may be optionally substituted by halogen atom), amino group, carboxyl group or hydroxy-group), C_1-6alkoxygroup (where alkoxygroup may be optionally substituted by halogen atom), amino group, carboxyl group or hydroxy-group);

(30) derived benzopyran or its pharmaceutically acceptable salt as described in (4), where V represents NR⁹;

(31) derived benzopyran or its pharmaceutically acceptable salt as described in (30), where m is an integer from 1 to 3, n is 0 and R⁶represents a C_6-14aryl group or a C_2-9heteroaryl group, where each aryl group or heteroaryl group may be optionally substituted by 1-3 substituents R¹⁸where R 18has the same meaning as R¹⁰;

(32) derived benzopyran or its pharmaceutically acceptable salt as described in (31), where m is 2;

(33) derived benzopyran or its pharmaceutically acceptable salt as described in (30), where m is an integer from 1 to 3, n is 0 and R⁶represents a hydrogen atom, a C_2-4alkyl group (where the alkyl group can be optionally substituted by a halogen atom, a C_1-6alkoxygroup (where alkoxygroup may be optionally substituted by halogen atom), amino group, carboxyl group or hydroxy-group), C_3-8cycloalkyl group, C_3-8cycloalkenyl group (where cycloalkyl group or cycloalkenyl group may be optionally substituted by a halogen atom, a C_1-6alkyl group (where the alkyl group can be optionally substituted by a halogen atom, a C_1-6alkoxygroup (where alkoxygroup may be optionally substituted by halogen atom), amino group, carboxyl group or hydroxy-group), C_1-6alkoxygroup (where alkoxygroup may be optionally substituted by halogen atom), amino group, carboxyl group or hydroxy-group), or C_2-9heterocyclic group, where the heterocyclic group may be optionally substituted by a halogen atom, a C_{1-6 alkyl group (where the alkyl group can be optionally substituted by a halogen atom, a C1-6alkoxygroup (where alkoxygroup may be optionally substituted by halogen atom), amino group, carboxyl group or hydroxy-group), C1-6alkoxygroup (where alkoxygroup may be optionally substituted by halogen atom), amino group, carboxyl group or hydroxy-group);}

(34) derived benzopyran or its pharmaceutically acceptable salt as described in (33), where m is 2;

(35) derived benzopyran or its pharmaceutically acceptable salt as described in (3), which is a compound of formula (I);

(36) derived benzopyran or its pharmaceutically acceptable salt as described in (3), which is a compound of formula (II);

(37) derived benzopyran or its pharmaceutically acceptable salt as described in(8), (11), (14), (23), (28) or (35), where the ring structure And is a

where R¹¹, R¹³, R¹⁴and R¹⁵have the above meanings;

(38) derived benzopyran or its pharmaceutically acceptable salt, as indicated in (37), where R¹¹represents a hydrogen atom or a C_1-6alkyl group (where the alkyl group can be optionally substituted by a halogen atom, a C_1-6ALCO is syrupy (where alkoxygroup may be optionally substituted tomoshalarida), the amino group or hydroxy-group) and R¹³, R¹⁴and R¹⁵independently represent a hydrogen atom, a halogen atom, a C_1-6alkyl group (where the alkyl group can be optionally substituted by a halogen atom, an amino group, a C_1-6alkoxygroup (where alkoxygroup may be optionally substituted by a halogen atom) or hydroxy-group), C_3-8cycloalkyl group (where cycloalkyl group may be optionally substituted by a halogen atom, a C_1-6alkoxygroup (where alkoxygroup may be optionally substituted by halogen atom), amino group or hydroxy-group), C_1-6alkoxygroup (where alkoxygroup may be optionally substituted by a halogen atom, an amino group, a C_1-6alkoxygroup (where alkoxygroup may be optionally substituted by a halogen atom) or hydroxy-group), C_1-6alkylcarboxylic group, aminocarbonyl group, amino group, carboxyl group, or cyano;

(39) derived benzopyran or its pharmaceutically acceptable salt as described in (38), where R¹¹represents a hydrogen atom or a C_1-6alkyl group (where the alkyl group can be optionally substituted with halogen atom, amino group or hydroxy-group) and R¹³, R¹⁴and R¹⁵independently represent a hydrogen atom, the atom halog is on, C_1-6alkyl group (where the alkyl group can be optionally substituted with halogen atom, amino group or hydroxy-group), carboxyl group, amino group or cyano;

(40) derived benzopyran or its pharmaceutically acceptable salt as described in (39), where R¹¹represents a hydrogen atom, R¹³represents a hydrogen atom, halogen atom, carboxyl group or C_1-6alkyl group (where the alkyl group can be optionally substituted with halogen atom, amino group or hydroxy-group), R¹⁴represents a hydrogen atom and R¹⁵represents a hydrogen atom, halogen atom or C_1-6alkyl group (where the alkyl group can be optionally substituted with halogen atom, amino group or hydroxy-group);

(41) derived benzopyran or its pharmaceutically acceptable salt as described in(8), (11), (14), (23), (28) or (35), where the ring structure And is a

where R¹¹, R¹², R¹³and R¹⁴have the above meanings;

(42) derived benzopyran or its pharmaceutically acceptable salt as described in (41), where R¹¹and R¹²independently represent a hydrogen atom or a C_1-6alkyl group (where the alkyl group can be optionally substituted atom g is lagena, C_1-6alkoxygroup (where alkoxygroup may be optionally substituted by halogen atom), amino group or hydroxy-group) and

R¹³and R¹⁴independently from each other represent a hydrogen atom, a halogen atom, a C_1-6alkyl group (where the alkyl group can be optionally substituted by a halogen atom, an amino group, a C_1-6alkoxygroup (where alkoxygroup may be optionally substituted by a halogen atom) or hydroxy-group), C_1-6alkoxygroup (where alkoxygroup may be optionally substituted by a halogen atom, an amino group, a C_1-6alkoxygroup (where alkoxygroup may be optionally substituted by a halogen atom)or hydroxy-group), C_1-6alkylcarboxylic group, amino group or cyano;

(43) derived benzopyran or its pharmaceutically acceptable salt as described in (42), where R¹¹and R¹²independently represent a hydrogen atom or a C_1-6alkyl group (where the alkyl group can be optionally substituted with halogen atom, amino group or hydroxy-group) and R¹³and R¹⁴independently represent a hydrogen atom, a halogen atom, a C_1-6alkyl group (where the alkyl group can be optionally substituted with halogen atom, amino group or hydroxy-group), amino group or cyano;

(4) derived benzopyran or its pharmaceutically acceptable salt, as indicated in (43), where R¹¹, R¹², R¹³and R¹⁴represent a hydrogen atom;

(45) derived benzopyran or its pharmaceutically acceptable salt as described in(8), (11), (14), (23), (28) or (35), where the ring structure And is a

where R¹¹, R¹³and R¹⁴have the above meanings;

(46) derived benzopyran or its pharmaceutically acceptable salt as described in (45), where R¹¹represents a hydrogen atom or a C_1-6alkyl group (where the alkyl group can be optionally substituted by a halogen atom, a C_1-6alkoxygroup (where alkoxygroup may be optionally substituted by halogen atom), amino group or hydroxy-group), R¹³and R¹⁴independently represent a hydrogen atom, a halogen atom, a C_1-6alkyl group (where the alkyl group can be optionally substituted by a halogen atom, an amino group, a C_1-6alkoxygroup (where alkoxygroup may be optionally substituted by a halogen atom) or hydroxy-group), C_1-6alkoxygroup (where alkoxygroup may be optionally substituted by a halogen atom, an amino group, a C_1-6alkoxygroup (where alkoxygroup may be optionally substituted by a halogen atom) or hydroxy-group), amino group or cyano, and X submitted is an O, S, SO or SO₂;

(47) derived benzopyran or its pharmaceutically acceptable salt as described in (46), where R¹¹represents a hydrogen atom or a C_1-6alkyl group (where the alkyl group can be optionally substituted with halogen atom, amino group or hydroxy-group), R¹³and R¹⁴independently represent a hydrogen atom, halogen atom or C_1-6alkyl group (where the alkyl group can be optionally substituted with halogen atom, amino group or hydroxy-group) and X represents O;

(48) derived benzopyran or its pharmaceutically acceptable salt as described in (47), where R¹¹represents a hydrogen atom or a C_1-6alkyl group (where the alkyl group can be optionally substituted with halogen atom, amino group or hydroxy-group), R¹³and R¹⁴represent a hydrogen atom, and X represents O;

(49) derived benzopyran or its pharmaceutically acceptable salt as described in(8), (11), (14), (23), (28) or (35), where the ring structure And is a

where R¹¹, R¹², R¹³and R¹⁴have the above meanings;

(50) derived benzopyran or its pharmaceutically acceptable salt as described in (49), where R¹¹and R¹²independently represent an atom is odorata or C _1-6alkyl group (where the alkyl group can be optionally substituted by a halogen atom, a C_1-6alkoxygroup (where alkoxygroup may be optionally substituted by halogen atom), C_6-14aryl group (where the aryl group can be optionally substituted by a halogen atom, or hydroxy-group

C_1-6alkoxygroup (where alkoxygroup may be optionally substituted by halogen atom), amino group or hydroxy-group), and R¹³and R¹⁴independently represent a hydrogen atom, a halogen atom, a C_1-6alkyl group (where the alkyl group can be optionally substituted by a halogen atom, an amino group, a C_1-6alkoxygroup (where alkoxygroup may be optionally substituted by a halogen atom) or hydroxy-group), C_1-6alkoxygroup (where alkoxygroup may be optionally substituted by a halogen atom, an amino group, a C_1-6alkoxygroup (where alkoxygroup may be optionally substituted by a halogen atom)or hydroxy-group), amino group or cyano;

(51) derived benzopyran or its pharmaceutically acceptable salt as described in (50), where R¹¹and R¹²independently represent a hydrogen atom or a C_1-6alkyl group (where the alkyl group can be optionally substituted with halogen atom, amino group or HYDR what syruppy) and R ¹³and R¹⁴represent a hydrogen atom;

(52) derived benzopyran or its pharmaceutically acceptable salt, which is a

2,2,7,9-tetramethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

2,2,7-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

3-hydroxy-2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-7-carbonitrile,

3-hydroxy-2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-7-carboxamide,

{3-hydroxy-2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-7-yl}Etalon,

3,3-dimethyl-1-[(2-phenylethyl)amino]-2,3-dihydro-1H-pyrano[3,2-f]quinoline-2-ol,

7-hydroxymethyl-2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

7-chloro-2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

3-hydroxy-2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-7-carboxylic acid,

4-(benzylamino)-7-chloro-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

4-{[(1,3-benzodioxol-5-yl)methyl]amino}-7-chloro-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

7-chloro-2,2,9-trimethyl-4-[(3-phenylpropyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

7-chloro-4-{[2-(4-forfinal)ethyl]amino}-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

7-chloro-4-{[2-(2-forfinal)ethyl]amino}-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3g]quinoline-3-ol,

7-chloro-4-{[2-(4-chlorophenyl)ethyl]amino}-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

4-{[2-(4-AMINOPHENYL)ethyl]amino}-7-chloro-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

7-chloro-4-[(2-hydroxy-2-phenylethyl)amino]-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

7-chloro-2,2,9-trimethyl-4-[(2-phenylbutyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

4-{[2-(1,3-benzodioxol-5-yl)ethyl]amino}-7-chloro-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

7-chloro-2,2,9-trimethyl-4-{[2-(1-piperidinyl)ethyl]amino}-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

7-chloro-2,2,9-trimethyl-4-{[2-(1-methyl-2-pyrrolidinyl)ethyl]amino}-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

4-[(2-anilinomethyl)amino]-7-chloro-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

7-chloro-4-({2-[ethyl(3-were)amino]ethyl}amino)-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

7-chloro-4-{[(1-ethyl-(R)-2-pyrrolidinyl)methyl]amino}-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

7-chloro-4-[(2,2-diatexite)amino]-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

7-chloro-2,2,9-trimethyl-4-{[2-(3-thienyl)ethyl]amino}-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

7-chloro-2,2,9-trimethyl-4-[2-(1-personility)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

7-chloro-2,2,9-trimethyl-4-{[2-(4-methylpyrazole-1-yl)ethyl]amino}-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

7-chloro-4-{[2-(4-chloropyrazole-1-yl)ethyl]amino}-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-the l

7-chloro-2,2,9-trimethyl-4-{[2-(2-pyridyl)ethyl]amino}-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

7-chloro-2,2,9-trimethyl-4-{[2-(3-pyridyl)ethyl]amino}-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

7-chloro-2,2,9-trimethyl-4-{[2-(4-pyridyl)ethyl}amino}-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

7-chloro-4-ethylamino-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

7-chloro-4-isobutylamino-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

7-chloro-4-[(cyclopropylmethyl)amino]-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

7-chloro-4-isobutylamino-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

7-chloro-4-[(2-cyclopentylacetyl)amino]-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

7-chloro-4-{[2-(1-cyclopentenyl)ethyl]amino}-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

7-chloro-2,2,9-trimethyl-4-[(5-methylhexan-2-yl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

7-chloro-2,2,9-trimethyl-4-pentylamine-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

7-chloro-4-[(2-cyclohexylethyl)amino]-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

7-chloro-4-{[2-(tetrahydropyran-4-yl)ethyl]amino}-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

7-chloro-2,2,9-trimethyl-4-[{2-(4-tanil)ethyl}amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

7-chloro-4-({[6-(4-chlorophenyl)-3-pyridinyl]methyl}amino)-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

4-[(2-benzofuranyl)amino]-7-chloro-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-a]quinoline-3-ol,

7-chloro-4-[(2-hydroxyphenyl)amino]-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

2,2-dimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]cinoxacin-3-ol,

4-{[2-(2-forfinal)ethyl]amino}-2,2-dimethyl-Z,4-dihydro-2H-pyrano[2,3-g]cinoxacin-3-ol,

4-{[2-(4-forfinal)ethyl]amino}-2,2-dimethyl-Z,4-dihydro-2H-pyrano[2,3-g]cinoxacin-3-ol,

4-[(2-hydroxy-2-phenylethyl)amino]-2,2-dimethyl-Z,4-dihydro-2H-pyrano[2,3-g]cinoxacin-3-ol,

2,2-dimethyl-4-pentylamine-3,4-dihydro-2H-pyrano[2,3-g]cinoxacin-3-ol,

2,2,7,8-tetramethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-1-pyrano[2,3-g]cinoxacin-3-ol,

7,8-diethyl-2,2-dimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]cinoxacin-3-ol,

2,2,8-trimethyl-7-phenyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]cinoxacin-3-ol,

2,2,7-trimethyl-8-phenyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]cinoxacin-3-ol,

2,2,8-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]cinoxacin-3-ol,

4-[(2-cyclohexylethyl)amino]-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-g]cinoxacin-3-ol,

3-hydroxy-2,2-dimethyl-4-[(2-phenylethyl)amino]-2,3,4,6-tetrahydropyrido[2,3-f]benzimidazole-7-he,

7-hydroxy-6,6-dimethyl-8-[(2-phenylethyl)amino]-4,6,7,8-tetrahydro-1,5-dioxa-4-azaanthracene-3-one,

7-hydroxy-4,6,6-trimethyl-8-[(2-phenylethyl)amino]-4,6,7,8-tetrahydro-1,5-dioxa-4-azaanthracene-3-one,

6,6-dimethyl-8-[(2-phenylethyl)amino]-2,3,4,6,7,8-hexahydro-1,5-dioxa-4-azaanthracene-7-ol,

7-HYDR the XI-6,6-dimethyl-8-[(2-phenylethyl)amino]-1,6,7,8-tetrahydro-4,5-dioxo-1-azaanthracene-2-it,

6,6-dimethyl-8-[(2-phenylethyl)amino]-1,2,3,6,7,8-hexahydro-4,5-dioxo-1-azaanthracene-7-ol,

9-hydroxymethyl-2,2-dimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3,7-diol,

7-aminomethyl-2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

7-chloro-2,2,9-trimethyl-6λ5-hydroxy-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3g]quinoline-3-ol,

7-chloro-4-{[2-(4-forfinal)ethyl]amino}-2,2,9-trimethyl-6λ5-hydroxy-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

7-chloro-2,2,9-trimethyl-6λ5-hydroxy-4-pentylamine-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

4-{[2-(4-forfinal)ethyl]amino}-7-hydroxymethyl-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol or

2,2-dimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol.

(53) Derived benzopyran or its pharmaceutically acceptable salt, which is a

2,2,7-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

3,3-dimethyl-1-[(2-phenylethyl)amino]-2,3-dihydro-1H-pyrano[3,2-f]quinoline-2-ol,

7-hydroxymethyl-2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

7-chloro-2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

7-chloro-4-{[2-(4-forfinal)ethyl]amino}-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

7-chloro-4-{[2-(2-forfinal)ethyl]amino}-2,2,9-trimethyl-3,4-dihydro-2H-Piran is[2,3-g]quinoline-3-ol,

7-chloro-4-{[2-(4-chlorophenyl)ethyl]amino}-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3g]quinoline-3-ol,

3-hydroxy-2,2,9-trimethyl-4-[2-(phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-7-carboxylic acid,

4-{[2-(4-AMINOPHENYL)ethyl]amino}-7-chloro-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

7-chloro-4-[(2-hydroxy-2-phenylethyl)amino]-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

7-chloro-2,2,9-trimethyl-4-{[2-(1-piperidinyl)ethyl]amino}-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

7-chloro-4-{[2-(4-chloropyrazole-1-yl)ethyl]amino}-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

7-chloro-2,2,9-trimethyl-4-{[2-(2-pyridyl)ethyl]amino}-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

7-chloro-2,2,9-trimethyl-4-{[2-(3-pyridyl)ethyl]amino}-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

7-chloro-2,2,9-trimethyl-4-{[2-(4-pyridyl)ethyl]amino}-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

7-chloro-4-isobutylamino-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

7-chloro-4-[(2-cyclopentylacetyl)amino]-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

7-chloro-4-{[2-(1-cyclopentenyl)ethyl]amino}-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

7-chloro-2,2,9-trimethyl-4-pentylamine-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

7-chloro-4-[(2-cyclohexylethyl)amino]-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

7-chloro-4-[(2-hydroxyphenyl)amino]-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

2,2-dimethyl-4-[(2-phenylethyl)amino]-3,4-Digi the ro-2H-pyrano[2,3-g]cinoxacin-3-ol,

4-{[2-(2-forfinal)ethyl]amino}-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-g]cinoxacin-3-ol,

4-{[2-(4-forfinal)ethyl]amino}-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-g]cinoxacin-3-ol,

4-[(2-hydroxy-2-phenylethyl)amino]-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-g]cinoxacin-3-ol,

2,2-dimethyl-4-pentylamine-3,4-dihydro-2H-pyrano[2,3-g]cinoxacin-3-ol,

4-[(2-cyclohexylethyl)amino]-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-g]cinoxacin-3-ol,

7-hydroxy-6,6-dimethyl-8-[(2-phenylethyl)amino]-4,6,7,8-tetrahydro-1,5-dioxa-4-azaanthracene-3-one,

7-hydroxy-4,6,6-trimethyl-8-[(2-phenylethyl)amino]-4,6,7,8-tetrahydro-1,5-dioxa-4-azaanthracene-3-one,

7-hydroxy-6,6-dimethyl-8-[(2-phenylethyl)amino]-7,8-dihydro-1H,6H-4,5-dioxo-1-azaanthracene-2-it,

9-hydroxymethyl-2,2-dimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3,7-diol,

7-aminomethyl-2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

7-chloro-2,2,9-trimethyl-6λ5-hydroxy-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

7-chloro-4-{[2-(4-forfinal)ethyl]amino}-2,2,9-trimethyl-6λ5-hydroxy-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

7-chloro-2,2,9-trimethyl-6λ5-hydroxy-4-pentylamine-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,

4-{[2-(4-forfinal)ethyl]amino}-7-hydroxymethyl-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol or

2,2-dimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-chinolin-3-ol;

(54) medicinal product, including derivative benzopyran or its pharmaceutically acceptable salt as described in any of paragraphs (1)to(53), as the active ingredient, and

(55) a drug for the treatment of arrhythmias, including derived benzopyran or its pharmaceutically acceptable salt as described in any of paragraphs (1)to(53), as the active ingredient.

The connection according to the present invention has a strong prolonging effect on the refractory period and can be used as a drug for the treatment of arrhythmia.

The best way of carrying out the invention

Appropriate substituents in the compounds (I) or (II) according to the present invention specifically defined below.

Meanwhile, in this specification, "n" means normal, "from" means " from, "Deuteronomy" means secondary, "t" means tertiary, "C" means cyclo, "o" means ortho, "m" means meta, "p" means para; "Ph" means phenyl, "Py" means pyridyl, "Bn" means benzyl, "Me" means methyl, "Et" means ethyl, "Pr" means propyl, "Bu" means butyl, "Pen" means pencil, "Hex" means hexyl, "Ac" means acetyl, "Boc" means tertiary butoxycarbonyl and "MOM" means methoxymethyl.

Examples of C_2-4alkyl groups are groups such as ethyl, n-propyl, isopropyl, nbutyl, isobutyl, t-butyl, tert-butyl and the like.

Examples of C_1-4alkyl groups are groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, tert-butyl and the like.

Examples of C_1-6alkyl groups are groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, tert-butyl, 1-pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl, 2,2-dimethylpropyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-methyl-n-pentyl, 1,1,2-trimethyl-n-propyl, 1,2,2-trimethyl-n-propyl, 3,3-dimethyl-n-butyl and the like.

Preferably can be mentioned methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl and isopentyl.

Examples of C_3-8cycloalkyl groups are groups such as C-propyl, C-butyl, 1-methyl-C-propyl, 2-methyl-C-propyl, C-pentyl, 1-methyl-C-butyl, 2-methyl-C-butyl, 3-methyl-C-butyl, 1,2-dimethyl-C-propyl, 2,3-dimethyl-C-propyl,1-ethyl-C-propyl, 2-ethyl-C-propyl, t-hexyl, t-heptyl, t-octyl, 1-methyl-C-hexyl, 2-methyl-C-hexyl, 3-methyl-C-hexyl, 1,2-dimethyl-C-hexyl, 2,3-dimethyl-C-propyl, 1-ethyl-C-propyl, 1-methyl-C-pentyl, 2-methyl-C-pentyl, 3-methyl-C-pentyl, 1-ethyl-t-butyl, 2-ethyl-t-butyl, 3-ethyl-t-butyl, 1,2-dimethyl-C-butyl, 1,3-dimethyl-C-butyl, 2, 2-dimethyl-C-butyl, 2,3-dimethyl-C-butyl, 2,4-dimethyl-C-butyl, 3,3-dimethyl-C-butyl, 1-n-propyl-C-propyl, 2-n-propyl-C-propyl, 1-isopropyl-C-propyl, 2-isopropyl-C-propyl, 1,2,2-trimethyl-C-propyl, ,2,3-trimethyl-C-propyl, 2,2,3-trimethyl-C-propyl, 1-ethyl-2-methyl-C-propyl, 2-ethyl-1-methyl-C-propyl, 2-ethyl-2-methyl-C-propyl, 2-ethyl-3-methyl-C-propyl, and the like.

Preferably you can mark C-pentyl and t-hexyl.

Examples_3-8cycloalkenyl groups are groups such as 1-C-pentenyl, 2-C-pentenyl, 3-C-pentenyl, 1-methyl-2-C-pentenyl, 1-methyl-3-C-pentenyl, 2-methyl-1-C-pentenyl, 2-methyl-2-C-pentenyl, 2-methyl-3-C-pentenyl, 2-methyl-4-C-pentenyl, 2-methylene-C-pentyl, 3-methyl-1-C-pentenyl, 3-methyl-2-C-pentenyl, 3-methyl-3-C-pentenyl, 3-methyl-4-C-pentenyl, 3-methylene-C-pentyl, 1-C-hexenyl, 2-C-hexenyl, 3-C-hexenyl, 1-C-heptenyl, 2-C-heptenyl, 3-C-heptenyl, 4-C-heptenyl, 1-C-octenyl, 2-C-octenyl, 3-C-octenyl, 4-C-octenyl and the like.

Preferably it is possible to note 1-C-pentenyl, 2-C-pentenyl, 3-C-pentenyl, 1-C-hexenyl, 2-C-hexenyl and 3-C-hexenyl.

Examples of the halogen atom include fluorine atom, chlorine atom, bromine atom and iodine atom. Preferably it can be noted fluorine atom, chlorine atom and bromine atom.

Examples of C_1-6alkoxygroup are such groups as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, C-butoxy, tert-butoxy, 1-pentyloxy, 2-pentyloxy, 3-pentyloxy, isopentylamine, neopentylene, 2,2-DIMETHYLPROPANE, 1 hexyloxy, 2-hexyloxy, 3 hexyloxy, 1-methyl-n-pentyloxy, 1,1,2-trimethyl-n-propoxy, 1,2,2-trimethyl-n-propoxy, 3,3-dimethyl-n-b is toxi and the like.

Preferably can be mentioned methoxy, ethoxy, n-propoxy, isopropoxy.

Examples of C_1-6toolcategory are groups such as methylthio, ethylthio, n-propylthio, isopropylthio, C-propylthio, n-butylthio, isobutyric, C-butylthio, tert-butylthio, n-pentylthio, isopentyl, neopentyl, tert-pentylthio, n-hexylthio, C-hexylthio and the like.

Examples of C_1-6alkylcarboxylic are such groups as methylcarbonate, ethylcarbonate, n-propylmalonate, isopropylcarbonate, n-BUTYLCARBAMATE, isobutyryloxy, C-BUTYLCARBAMATE, tert-BUTYLCARBAMATE, 1 intercorporate, 2-intercorporate, 3 intercorporate, isopentylamine, neopentylene, tert-intercorporate, 1 hexylcaine, 2-hexylcaine, 3 hexylcaine, 1-methyl-n-intercorporate, 1,1,2-trimethyl-n-propylmalonate, 1,2,2-trimethyl-n-propylmalonate, 3,3-dimethyl-n-BUTYLCARBAMATE and the like.

Preferably may be noted methylcarbonate, ethylcarbonate, n-propylmalonate, isopropylcarbonate, n-BUTYLCARBAMATE and tert-BUTYLCARBAMATE.

Examples of C_6-14aryl groups are groups such as phenyl, o-biphenylyl, m-biphenylyl, p-biphenylyl, α-naphthyl, β-naphthyl, 1-antrel, 2-antrel, 9-antrel, 1-phenanthrol, 2-phenanthrol, 3-financr is l, 4-phenanthrol, 9-phenanthrol and the like.

Preferably can be mentioned phenyl, o-biphenylyl, m-biphenylyl, p-biphenylyl, α-naphthyl and β-naphthyl.

C_2-9heteroaryl group includes C_2-6heterocyclic group having one 5-7-membered ring, and C_5-9heterocyclic group having two condensed rings with the number of members from 8 to 10, which may contain 1 to 3 heteroatoms selected from the group consisting of oxygen atom, nitrogen atom and sulfur atom individually or in combination.

Examples of C_2-6heterocyclic group having one 5-7-membered ring, are groups such as 2-thienyl group, 3-thienyl group, 2-furilla group, 3-furilla group, 2-Pernilla group, 3-Pernilla group, 4-Pernilla group, 1-pyrrolidine group, 2-pyrrolidine group, 3-pyrrolidine group, 1-imidazolidinyl group, 2-imidazolidinyl group, 4-imidazolidinyl group, 1-pyrazolidine group, 3-pyrazolidine group, 4-pyrazolidine group, 2-thiazolidine group 4-thiazolidine group, 5-thiazolidine group, 3-isothiazolinone group, 4-isothiazoline group; 5-isothiazolinone group, 2-oxazolidinyl group, 4-oxazolidinyl group, 5-oxazolidinyl group, 3-isoxazolyl group, 4-isoxazolyl group, 5-isoxazolyl group, 2-Peregrina group, 3-Peregrina group, 4-pyridi the other group, 2-pyridinoline group, 2-pyrimidinyl group, 4-pyrimidinyl group, 5-pyrimidinyl group, 3-pyridazinyl group, 4-pyridazinyl group, 2-1,3,4-oxadiazolyl group, 2-1,3,4-thiadiazolyl group, 3-1,2,4-oxadiazolyl group, 5-1,2,4-oxadiazolyl group, 3-1,2,4-thiadiazolyl group, 5-1,2,4-thiadiazolyl group, a 3-1,2,5-oxadiazolyl group, a 3-1,2,5-thiadiazolyl group and the like.

Examples_5-9heterocyclic group having two condensed rings with the number of members from 8 to 10 are 2-benzofuranyl group, 3-benzofuranyl group, 4-benzofuranyl group, 5-benzofuranyl group, 6-benzofuranyl group, 7-benzofuranyl group, 1-isobenzofuranyl group, 4-isobenzofuranyl group, 5-isobenzofuranyl group, 2-benzothiazoline group, 3-benzothiazoline group, 4-benzothiazoline group, 5-benzothiazoline group, 6-benzothiazoline group, 7-benzothiazoline group, 1-isobenzofuranyl group, 4-isobenzofuranyl group A 5-isobenzofuranyl group, 2-chromadorina group, 3-chromadorina group, 4-chromadorina group, 5-chromadorina group, 6-chromadorina group, 7-chromadorina group, 8-chromadorina group, 1-indolizinyl group, 2-indolizinyl group, 3-indolizinyl group, 5-indolizinyl group, 6-indolizinyl group, 7-indole ininna group, 8-indolizinyl group, 1-isoindolyl group, 2-isoindolyl group, 4-isoindolyl group, 5-isoindolyl group, 1-indlela group, 2-indlela group, 3-indlela group, 4-indlela group, 5-indlela group, 6-indlela group, 7-indlela group, 1-indazolinone group, 2-indazolinone group, 3-indazolinone group, 4-indazolinone group, 5-indazolinone group, 6-indazolinone group, 7-indazolinone group, 1-polylina group, 2-polylina group, 3-polylina group, 6-polylina group, 7-polylina group, 8-polylina group, 2-kinolinna group, 3-kinolinna group, 4-kinolinna group, 5-kinolinna group, 6-kinolinna group, 7-kinolinna group, 8-kinolinna group, 1-izochinolina group, 3-izochinolina group, 4-izochinolina group, 5-izochinolina group, 6-izochinolina group, 7-izochinolina group, 8-izochinolina group, 1-phthalazinone group, 5-phthalazinedione group, 6-phthalazinedione group, 1-2,7-naphthyridinone group, 3-2,7-naphthyridinone group, 4-2,7-naphthyridinone group, 1-2,6-naphthyridinone group, 3-2,6-naphthyridinone group, 4-2,6-naphthyridinone group, 2-1,8-naphthyridinone group, 3-1,8-naphthyridinone group, 4-1,8-naphthyridinone group, 2-1,7-naphthyridinone group, 3-1,7-naphthyridinone group, 4-1,7-naphthyridinone group, 5-1,7-atteridgeville group, 6-1,7-naphthyridinone group, 8-1,7-naphthyridinone group, 2-,6-naphthyridinone group, 3-1,6-naphthyridinone group, 4-1,6-naphthyridinone group, 5-1,6-naphthyridinone group, 7-1,6-naphthyridinone group, 8-1,6-naphthyridinone group, 2-1,5-naphthyridinone group, 3-1,5-naphthyridinone group, 4-1,5-naphthyridinone group, 6-1,5-naphthyridinone group, 7-1,5-naphthyridinone group, 8-1,5-naphthyridinone group 2-khinoksalinona group, 5-khinoksalinona group, 6-khinoksalinona group, 2-chinadaily group, 4-chinadaily group, 5-chinadaily group, 6-chinadaily group, 7-chinadaily group, 8-chinadaily group, 3-indolenine group, 4-indolenine group, 5-indolenine group, 6-indolenine group, 7-indolenine group, 8-indolenine group, 2-pteridinyl group, 4-pteridinyl group, 6-pteridinyl group, 7-pteridinyl group and the like.

Preferably can be mentioned 2-pyridyloxy group, 3-pyridyloxy group and 4-pyridyloxy group.

C_2-9the heterocyclic group includes a heterocyclic group having one ring or two condensed rings containing 1 or more atoms chosen from oxygen atom, nitrogen atom and sulfur atom, and 2 to 9 carbon atoms, and specifically includes the following groups:

.

Examples of C_1-6alkylamino are groups such as methylamino, ethylamino, n-propylamino, isopropylamino, C-propylamino, n-butylamino, isobutylamino, sec-butylamino, tert-butylamino, C-butylamino, 1 pentylamine, 2-pentylamine, 3 pentylamine, isopentylamine, neopentylene, tert-pentylamine, C-pentylamine, 1 hexylamino, 2-hexylamino, 3 hexylamino, C-hexylamine, 1-methyl-n-pentylamine, 1,1,2-trimethyl-n-propylamino, 1,2,2-trimethyl-n-Propylamine, 3,3-dimethyl-n-butylamino and the like.

Preferably, you can mark methylamino, ethylamino, n-propylamino, isopropylamino and n-butylamine.

Examples of di-C_1-6alkylamino are groups such as dimethylamino, diethylamino, di-n-propylamino, di Isopropylamine, di-t-propylamino, di-n-butylamino, di isobutylamine, di-sec-butylamino, di-tert-butylamino, di-t-butylamino, di-1-pentylamine, di-2-pentylamine, di-3-pentylamine, di isopentylamine, di neopentylene, di-tert-pentylamine, di-t-pentylamine, di-1-hexylamino, di-2 hexylamino, di-3-hexylamino, di-t-hexylamino, di-(1-methyl-n-pentyl)amino, di-(1,1,2-trimethyl-n-propyl)amino, di-(1,2,2-trimethyl-n-propyl)amino, di-(3,3-dimethyl-n-butyl)amino, methyl(ethyl)amino, methyl(n-propyl)amino, methyl(isopropyl)amino, methyl(C-propyl)amino, methyl(n-butyl)amino, methyl(isobutyl)am is but methyl(sec-butyl)amino, methyl(tert-butyl)amino, methyl(t-butyl)amino, ethyl(n-propyl)amino, ethyl(isopropyl)amino, ethyl(C-propyl)amino, ethyl(n-butyl)amino, ethyl(isobutyl)amino, ethyl(sec-butyl)amino, ethyl(tert-butyl)amino, ethyl(sec-butyl)amino, n-propyl(isopropyl)amino, n-propyl(C-propyl)amino, n-propyl(n-butyl)amino, n-propyl(isobutyl)amino, n-propyl(sec-butyl)amino, n-propyl (tert-butyl)amino, n-propyl(t-butyl)amino, isopropyl(C-propyl)amino, isopropyl(n-butyl)amino, isopropyl(isobutyl)amino, isopropyl(sec-butyl)amino, isopropyl(tert-butyl)amino, isopropyl(C-butyl)amino, C-propyl(n-butyl)amino, C-propyl(isobutyl)amino, C-propyl(sec-butyl)amino, C-propyl(tert-butyl)amino, C-propyl(t-butyl)amino, n-butyl(isobutyl)amino, n-butyl(sec-butyl)amino, n-butyl(tert-butyl)amino, n-butyl(C-butyl)amino, isobutyl(sec-butyl)amino, isobutyl(tert-butyl)amino, isobutyl(C-butyl)amino, sec-butyl(tert-butyl)amino, sec-butyl(C-butyl)amino, tert-butyl(C-butyl)amino and the like.

Preferably it can be noted dimethylamino, diethylamino, di-n-propylamino, di Isopropylamine and di-n-butylamino.

Examples of C_1-6alkylcarboxylic are groups such as methylcobalamin, ethylcarbodiimide, n-propylnitrosamine, isopropylcarbodiimide, n-BUTYLCARBAMATE, isobutylamino, second-BUTYLCARBAMATE is, tert-BUTYLCARBAMATE, 1 intelcorporation, 2-intelcorporation, 3 intelcorporation, isopentenyladenine, neopentylene, tert-intelcorporation, 1 paxilonline, 2-paxilonline, 3 paxilonline and the like.

Preferably may be noted methylcobalamine, ethylcarbodiimide, n-propylnitrosamine, isopropylcarbodiimide and n-BUTYLCARBAMATE.

Examples of C_1-6alkylsulfonamides are groups such as methylsulfonylamino, ethylsulfonyl, n-propylsulfonyl, isopropylaniline, n-butylmethylamine, isobutylamino, sec-butylsulfonyl, tert-butylsulfonyl, 1 pentylaniline, 2-pentylaniline, 3 pentylaniline, isopentenyladenine, neopentylene, tert-pentylaniline, 1 hexylaniline, 2-hexylaniline, 3 hexylaniline and the like.

Preferably may be noted methylsulfonylamino, ethylsulfonyl, n-propylsulfonyl, isopropylacrylamide and n-butylmethylamine.

Examples of C_1-6alkylaminocarbonyl groups are groups such as methylaminomethyl, ethylaminomethyl, n-propylaminosulfonyl, isopropylaminocarbonyl, n-butylaminoethyl, isobutylparaben, second-butylamine boil, tert-butylaminoethyl, 1-intramyocardial, 2-intramyocardial, 3-intramyocardial, isopentylamine, neopentylglycol, tert-intramyocardial, 1-mexiletineciclovir, 2-mexiletineciclovir, 3-mexiletineciclovir and the like.

Preferably, you can mark methylaminomethyl, ethylaminomethyl, n-propylaminosulfonyl, isopropylaminocarbonyl and n-butylaminoethyl.

Examples of di-C_1-6alkylaminocarbonyl groups are groups such as dimethylaminoethyl, diethylaminoethyl, di-n-propylaminoethyl, di-isopropylaminocarbonyl, di-t-propylaminoethyl, di-n-butylaminoethyl, di-isobutylparaben, di-t-butylaminoethyl, di-tert-butylaminoethyl, di-t-butylaminoethyl, di-1-intramyocardial, di-2-intramyocardial, di-3-intramyocardial, di-isopentylamine, di-neopentylglycol, di-tert-intramyocardial, di-t-intramyocardial, di-1-mexiletineciclovir, di-2-mexiletineciclovir, di-3-mexiletineciclovir, di-t-mexiletineciclovir, di-(1-methyl-n-pentyl)aminocarbonyl, di-(1,1,2-trimethyl-n-propyl)aminocarbonyl, di-(1,2,2-trimethyl-n-propyl)aminocarbonyl, di-(3,3-dimethyl-n-butyl)aminocarbonyl, methyl(ethyl)aminocarbonyl, methyl(n-propyl)aminocarbonyl, methyl(isopropyl)aminocarbonyl, methyl(C-propyl)aminocarbonyl, METI is(n-butyl)aminocarbonyl, methyl(isobutyl)aminocarbonyl, methyl(sec-butyl)aminocarbonyl, methyl(tert-butyl)aminocarbonyl, methyl(t-butyl)aminocarbonyl, ethyl(n-propyl)aminocarbonyl, ethyl(isopropyl)aminocarbonyl, ethyl(C-propyl)aminocarbonyl, ethyl(n-butyl)aminocarbonyl, ethyl(isobutyl)aminocarbonyl, ethyl(sec-butyl)aminocarbonyl, ethyl(tert-butyl)aminocarbonyl, ethyl(t-butyl)aminocarbonyl, n-propyl(isopropyl)aminocarbonyl, n-propyl(C-propyl)aminocarbonyl, n-propyl(n-butyl)aminocarbonyl, n-propyl(isobutyl)aminocarbonyl, n-propyl(sec-butyl)aminocarbonyl, n-propyl(tert-butyl)aminocarbonyl, n-propyl(t-butyl)aminocarbonyl, isopropyl(t-butyl)aminocarbonyl, isopropyl(n-butyl)aminocarbonyl, isopropyl(isobutyl)aminocarbonyl, isopropyl(sec-butyl)aminocarbonyl, isopropyl(tert-butyl)aminocarbonyl, isopropyl(t-butyl)aminocarbonyl, C-propyl(n-butyl)aminocarbonyl, butyl)aminocarbonyl, n-propyl(tert-butyl)aminocarbonyl, n-propyl(t-butyl)aminocarbonyl, isopropyl(C-propyl)aminocarbonyl, isopropyl(n-butyl)aminocarbonyl, isopropyl(isobutyl)aminocarbonyl, isopropyl(sec-butyl)aminocarbonyl, isopropyl(tert-butyl)aminocarbonyl, isopropyl(t-butyl)aminocarbonyl, C-propyl(n-butyl)aminocarbonyl, C-propyl(isobutyl)aminocarbonyl, C-propyl(sec-butyl)aminocarbonyl, C-propyl(tert-butyl)aminocarbonyl, C-propyl(t-butyl)aminocarbonyl, n-butyl(Isobe is Il)aminocarbonyl, n-butyl(sec-butyl)aminocarbonyl, n-butyl(tert-butyl)aminocarbonyl, n-butyl(C-butyl)aminocarbonyl, isobutyl(sec-butyl)aminocarbonyl, isobutyl(tert-butyl)aminocarbonyl, isobutyl(t-butyl)aminocarbonyl, sec-butyl (tert-butyl)aminocarbonyl, sec-butyl(C-butyl)aminocarbonyl, tert-butyl(C-butyl)aminocarbonyl and the like.

Preferably, you can mark dimethylaminoethyl, diethylaminoethyl, di-n-propylaminoethyl, di-isopropylaminocarbonyl, di-t-propylaminoethyl and di-n-butylaminoethyl.

Examples of C_1-6alkylcarboxylic groups are groups such as methylcarbamoyl, ethylcarbazole, n-propylboronic, isopropylcarbonate, n-butylcarbamoyl, isobutylketone, C-butylcarbamoyl, tert-butylcarbamoyl, 1-internabonal, 2-internabonal, 3-internabonal, isopentylamine, neopentylene, tert-internabonal, 1-hexylcaine, 2-hexylcaine, 3-hexylcaine and the like.

Preferably, you can mark methylcarbamyl, ethylcarbazole, n-propylboronic, isopropylcarbonate and n-butylcarbamoyl.

Examples of C_3-8cycloalkylcarbonyl groups are groups such as t-propylboronic, C-butylcarbamoyl, 1-methyl-C-propylboronic, 2-methyl-C-propylboronic, C-internabonal, 1-methyl-C-butylcarbamoyl, 2-methyl-C-butylcarbamoyl, 3-methyl-C-butylcarbamoyl, 1,2-dimethyl-C-propeller is of IMT, 2,3-dimethyl-C-propylboronic, 1-ethyl-C-propylboronic, 2-ethyl-C-propylboronic, C-hexylcaine, C-heptylammonium, C-octigabay, 1-methyl-C-hexylcaine, 2-methyl-C-hexylcaine, 3-methyl-C-hexylcaine, 1,2-dimethyl-C-hexylcaine, 2,3-dimethyl-C-propylboronic, 1-ethyl-C-propylboronic, 1-methyl-C-internabonal, 2-methyl-C-internabonal, 3-methyl-C-internabonal, 1-ethyl-C-butylcarbamoyl, 2-ethyl-C-butylcarbamoyl, 3-ethyl-C-butylcarbamoyl, 1,2-dimethyl-C-butylcarbamoyl, 1,3-dimethyl-C-butylcarbamoyl, 2,2-dimethyl-C-butylcarbamoyl, 2,3-dimethyl-C-butylcarbamoyl, 2,4-dimethyl-C-butylcarbamoyl, 3,3-dimethyl-C-butylcarbamoyl, 1-n-propyl-C-propylboronic, 2-n-propyl-C-propylboronic, 1-isopropyl-C-propylboronic, 2-isopropyl-C-propylboronic, 1,2,2-trimethyl-C-propylboronic, 1,2,3-trimethyl-C-propylboronic, 2,2,3-trimethyl-C-propylboronic, 1-ethyl-2-methyl-C-propylboronic, 2-ethyl-1-methyl-C-propylboronic, 2-ethyl-2-methyl-C-propylboronic, 2-ethyl-3-methyl-C-propylboronic and the like.

Preferably you can mark C-internabonal and C-hexylcaine.

Examples of C_1-6alkoxycarbonyl groups are groups such as methoxycarbonyl, etoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxide, second-butoxycarbonyl, tert-butoxycarbonyl, 1-pentyloxybenzoyl, 2-pentyloxybenzoyl, 3-pentyloxy ronil, isopentylamine, neopentylglycol, tert-pentyloxybenzoyl, 1-hexyloxyphenyl, 2-hexyloxybenzoyl, 3-hexyloxybenzoyl and the like.

Preferably, you can mark methoxycarbonyl, etoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxide, C-butoxycarbonyl and tert-butoxycarbonyl.

Examples of C_1-6alkylsulfonyl groups are groups such as methanesulfonyl, trifloromethyl, econsultancy and the like.

Examples of C_6-14arylcarboxylic groups are groups such as benzoyl, o-biphenylcarboxylic, m-biphenylcarboxylic, p-biphenylcarboxylic, α-afterburner, β-afterburner, 1-anticarbon, 2-anticarbon, 9-anticarbon, 1-financecarbon, 2-financecarbon, 3-financecarbon, 4-financecarbon, 9-financecarbon and the like.

Preferably can be mentioned benzoyl, o-biphenylcarboxylic, m-biphenylcarboxylic, p-biphenylcarboxylic, α - and β-afterburner.

C_2-9heteroarylboronic group includes C_2-6heterocyclic carbonyl group having one 5-7-membered ring, and C_5-9heterocyclic carbonyl group having two condensed rings, with the number of members from 8 to 10, which may contain 1 to 3 heteroatoms, selected from the group consisting whom her from oxygen atom, the nitrogen atom and sulfur atom individually or in combination.

Examples of C_2-6heterocyclic carbonyl group having one 5-7-membered ring, are groups such as 2-taylorsville group, 3-taylorsville group, 2-forelornly group, 3-forelornly group, 2-pernikarly group, 3-pernikarly group, 4-pernikarly group, 1-pyrrolidinedione group, 2-pyrrolidinone group, 3-pyrrolidinone group, 1-imidazoledicarbonitrile group, 2-imidazoledicarbonitrile group, 4-imidazolecarboxamide group, 1-pyrazolecarboxylate group, 3-pyrazolecarboxylate group, 4-pyrazolecarboxylate group, 2-thiazolecarboxamide group, 4-thiazolecarboxamide group, 5-thiazolecarboxamide group, 3-isothiazolinone group, 4-isothiazolinone group, 5-isothiazolinone group, 2-oxazolidinyl group, 4-oxazolidinyl group, 5-oxazolidinyl group, 3-isoxazolecarboxylic group, 4-isoxazolecarboxylic group, 5-isoxazolecarboxylic group, 2-pyridylcarbonyl group, 3-pyridylcarbonyl group, 4-pyridylcarbonyl group, 2-pyridinecarboxylic group, 2-pyrimidinecarbonitrile group, 4-pyrimidinecarbonitrile group, 5-pyrimidinecarbonitrile group, 3-pyridazinyl nilina group, 4-pyridinecarboxylic group, 2-1,3,4-oxadiazoline group, 2-1,3,4-thiadiazolidine group, 3-1,2,4-oxadiazolidine group, 5-1,2,4-oxadiazolidine group, 3-1,2,4-thiadiazolidine group, 5-1,2,4-thiadiazolidine group, a 3-1,2,5-oxadiazolidine group, a 3-1,2,5-thiadiazolidine group and the like.

Examples_5-9heterocyclic carbonyl group having two condensed rings, with the number of members from 8 to 10 are 2-benzofurazanyl group, 3-benzofurazanyl group, 4-benzofurazanyl group, 5-benzofurazanyl group, 6-benzofurazanyl group, 7-benzofurazanyl group, 1-isobenzofuranyl group, 4-isobenzofuranyl group, 5-isobenzofuranyl group, 2-benzothiadiazole group, 3-benzothiadiazole group, 4-benzothiadiazole group, 5-benzothiadiazole group, 6-benzothiadiazole group, 7-benzothiadiazole group, 1-isobenzofuranyl group, 4-isobenzofuranyl group, 5-isobenzofuranyl group, 2-chromenickel group, 3-chromenickel group, 4-chromenickel group, 5-chromenickel group, 6-chromenickel group, 7-romanilor Vilna group, 8-chromenickel group, 1-indonesiamalaysia group, 2-indonesiamalaysia group, 3-indonesiamalaysia group, 5-indonesiamalaysia group, 6-indonesiamalaysia group, 7-indonesiamalaysia group, 8-indonesiamalaysia group, 1-soundararaja group, 2-soundararaja group, 4-soundararaja group, 5-soundararaja group, 1-indolocarbazole group, 2-indolinecarboxylic group, 3-indolocarbazole group, 4-indolocarbazole group, 5-indolocarbazole group, 6-indolocarbazole group, 7-indolocarbazole group, 1-indotricarbocyanine group, 2-indotricarbocyanine group, 3-indotricarbocyanine group, 4-indotricarbocyanine group, 5-indotricarbocyanine group, 6-indotricarbocyanine group, 7-indotricarbocyanine group, 1-painikkeella group, 2-painikkeella group, 3-painikkeella group, 6-painikkeella group, 7-painikkeella group, 8-painikkeella group, 2-hinolincarbonova group, 3-hinolincarbonova group, 4-hinolincarbonova group, 5-hinolincarbonova group, 6-hinolincarbonova group, 7-hinolincarbonova group, 8-hinolincarbonova group, 1-isopinolcamphone group, 3-isopinolcamphone group, 4-ethanolic arborina group, 5-isopinolcamphone group, 6-isopinolcamphone group, 7-isopinolcamphone group, 8-isopinolcamphone group, 1-phthalazinedione group, 5-phthalazinedione group, 6-phthalazinedione group, 1-2,7-naturalenvironment group, 3-2,7-naturalenvironment group, 4-2,7-naturalenvironment group, 1-2,6-naturalenvironment group, 3-2,6-naturalenvironment group, 4-2,6-naturalenvironment group, 2-1,8-naturalenvironment group, 3-1,8-naturalenvironment group, 4-1,8-naturalenvironment group, 2-1,7-naturalenvironment group, 3-1,7-naturalenvironment group, 4-1,7-naturalenvironment group, 5-1,7-naturalenvironment group, 6-1,7-naturalenvironment group, 8-1,7-naturalenvironment group, 2-1,6-naturalenvironment group, 3-1,6-naturalenvironment group, 4-1,6-naturalenvironment group, 5-1,6-naturalenvironment group, 7-1,6-naturalenvironment group, 8-1,6-naturalenvironment group, 2-1,5-naturalenvironment group, 3-1,5-naturalenvironment group, 4-1,5-naturalenvironment group, 6-1,5-naturalenvironment group, 7-1,5-naturalenvironment group, 8-1,5-naturalenvironment group, 2-inoxidizability group, 5-hinoklidilkarbinola the th group, 6-inoxidizability group, 2-girasolereale group, 4-girasolereale group, 5-girasolereale group, 6-girasolereale group, 7-girasolereale group, 8-girasolereale group, 3-indolinecarboxylic group, 4-indolinecarboxylic group, 5-indolinecarboxylic group, 6-indolinecarboxylic group, 7-indolinecarboxylic group, 8-indolinecarboxylic group, 2-peridiniella group, 4-peridiniella group, 6-peridiniella group, 7-peridiniella group and the like.

Preferably can be mentioned 2-pyridylcarbonyl group, 3-pyridylcarbonyl group and 4-pyridylcarbonyl group.

Examples of C_6-14arylsulfonyl groups are groups such as phenylsulfonyl, o-biventricular, m-biventricular, p-biventricular, α-naphthylmethyl, β-naphthylmethyl, 1-antisoliton, 2-antisoliton, 9-antisoliton, 1-ventriculitis, 2-ventriculitis, 3-ventriculitis, 4-ventriculitis, 9-ventriculitis and the like.

Preferably it can be noted phenylsulfonyl, o-biventricular, m-biventricular, p-biventricular, α-naphthylmethyl and β-naphthylmethyl.

C_2-9heteroarylboronic group R is t C _2-6heterocyclic sulfonyloxy group having one 5-7-membered ring, and C_5-9heterocyclic sulfonyloxy group having two condensed rings, with the number of members from 8 to 10, which may contain 1 to 3 heteroatoms selected from the group consisting of oxygen atom, nitrogen atom and sulfur atom individually or in combination.

Examples of C_2-6heterocyclic sulfonyloxy group having one 5-7-membered ring, are such groups as 2-tierralinda group, 3-tierralinda group, 2-fenilalanina group, 3-fenilalanina group, 2-piranishvili group, 3-piranishvili group, 4-piranishvili group, 1-pyrrolylacetylenes group, 2-pyrrolylacetylenes group, 3-pyrrolylacetylenes group, 1-imidazolylalkyl group, 2-imidazolylalkyl group, 4-imidazolylalkyl group, 1-pyrazolecarboxylate group, 3-pyrazolecarboxylate group, 4-pyrazolecarboxylate group, 2-triazolylmethyl group, 4-triazolylmethyl group, 5-triazolylmethyl group, 3-isothiazolinone group, 4-isothiazolinone group, 5-isothiazolinone group, 2-occasionally group, 4-occasionally group, 5-occasionally group, 3-isoxazolecarboxylic the group, 4-isoxazolecarboxylic group, 5-isoxazolecarboxylic group, 2-pyridylsulfonyl group, 3-pyridylsulfonyl group, 4-pyridylsulfonyl group, 2-pyridinesulfonamide group, 2-pyrimidinemethanol group, 4-pyrimidinemethanol group, 5-pyrimidinemethanol group, 3-pyridinylmethyl group, 4-pyridinylmethyl group, 2-1,3,4-oxadiazolyl group, 2-1,3,4-thiadiazolidine group, 3-1,2,4-oxadiazolyl group, 5-1,2,4-oxadiazolyl group, 3-1,2,4-thiadiazolidine group, 5-1,2,4-thiadiazolidine group, a 3-1,2,5-oxadiazolyl group, a 3-1,2,5-thiadiazolidine group and the like.

Examples_5-9heterocyclic sulfonyloxy group having two condensed rings with the number of members from 8 to 10 are 2-benzofurazanyl group, 3-benzofurazanyl group, 4-benzofurazanyl group, 5-benzofurazanyl group, 6-benzofurazanyl group, 7-benzofurazanyl group, 1-isobenzofuranyl group, 4-isobenzofuranyl group, 5-isobenzofuranyl group, 2-benzothiazolesulfonamide group, 3-benzothiazolesulfonamide group, 4-benzothiazolesulfonamide group, 5-benzothiazolone the other group, 6-benzothiazolesulfonamide group, 7-benzothiazolesulfonamide group, 1-isobenzofuranyl group, 4-isobenzofuranyl group, 5-isobenzofuranyl group, 2-chromelalumel group, 3-chromelalumel group, 4-chromelalumel group, 5-chromelalumel group, 6-chromelalumel group, 7-chromelalumel group, 8-chromelalumel group, 1-indonesiamalaysia group, 2-indonesiamalaysia group, 3-indonesiamalaysia group, 5-indonesiamalaysia group, 6-indonesiamalaysia group, 7-indonesiamalaysia group, 8-indonesiamalaysia group, 1-isoindoloannulated group, 2-isoindoloannulated group, 4-isoindoloannulated group, 5-isoindoloannulated group, 1-indolylmaleimide group, 2-indolylmaleimide group, 3-indolylmaleimide group, 4-indolylmaleimide group, 5-indolylmaleimide group, 6-indolylmaleimide group, 7-indolylmaleimide group, 1-indotricarbocyanine group, 2-indotricarbocyanine group, 3-indotricarbocyanine group, 4-indotricarbocyanine group, 5-indotricarbocyanine group, 6-indotricarbocyanine group, 7-indotricarbocyanine group, 1-puenylalanine group, 2-puenylalanine groups who, 3-puenylalanine group, 6-puenylalanine group, 7-puenylalanine group, 8-puenylalanine group, 2-hinolincarbonova group, 3-hinolincarbonova group, 4-hinolincarbonova group, 5-hinolincarbonova group, 6-hinolincarbonova group, 7-hinolincarbonova group, 8-hinolincarbonova group, 1-ethynodiolthinyl group, 3-ethynodiolthinyl group, 4-ethynodiolthinyl group, 5-ethynodiolthinyl group, 6-ethynodiolthinyl group, 7-ethynodiolthinyl group, 8-ethynodiolthinyl group, 1-phthalazinedione group, 5-phthalazinedione group, 6-phthalazinedione group, 1-2,7-naturalistically group, 3-2,7-naturalistically group, 4-2,7-naturalistically group, 1-2,6-naturalistically group, 3-2,6-naturalistically group, 4-2,6-naturalistically group, 2-1,8-naturalistically group, 3-1,8-naturalistically group, 4-1,8-naturalistically group, 2-1,7-naturalistically group, 3-1,7-naturalistically group, 4-1,7-naturalistically group, 5-1,7-naturalistically group, 6-1,7-naturalistically group, 8-1,7-naturalistically group, 2-1,6-naturalistically group, 3-1,6-arthritisrarely group, 4-1,6-naturalistically group, 5-1,6-naturalistically group, 7-1,6-naturalistically group, 8-1,6-naturalistically group, 2-1,5-naturalistically group, 3-1,5-naturalistically group, 4-1,5-naturalistically group, 6-1,5-naturalistically group, 7-1,5-naturalistically group, 8-1,5-naturalistically group, 2-chynoxalinilmethylen group, 5-chynoxalinilmethylen group, 6-chynoxalinilmethylen group, 2-chineselearnonline group, 4-chineselearnonline group, 5-chineselearnonline group, 6-chineselearnonline group, 7-chineselearnonline group, 8-chineselearnonline group, 3-indolinecarboxylic group, 4-indolinecarboxylic group, 5-indolinecarboxylic group, 6-indolinecarboxylic group, 7-indolinecarboxylic group, 8-indolinecarboxylic group, 2-peridiniella group, 4-peridiniella group, 6-peridiniella group, 7-peridiniella group and the like.

Preferably can be mentioned 2-pyridylsulfonyl group, 3-pyridylsulfonyl group and 4-pyridylsulfonyl group.

Examples of C_6-14killingray are groups such as phenylamino, o-biphenylamine, m-biphenylyl the Mino, p-biphenylamine, α-naphthylamine, β-naphthylamine, 1 andilamena, 2-antillano, 9 andilamena, 1 phenanthroline, 2-phenanthroline, 3 phenanthroline, 4-phenanthroline, 9 phenanthroline and the like.

Preferably may be noted phenylamino, o-biphenylamine, m-biphenylamine, p-biphenylamine, α-naphthylamine and β-naphthylamine.

C_2-9literarymonographic includes C_2-6the heterocyclic amino group having one 5-7-membered ring, and C_5-9the heterocyclic amino group having two condensed rings with the number of members from 8 to 10, which may contain 1 to 3 heteroatoms selected from the group consisting of oxygen atom, nitrogen atom and sulfur atom individually or in combination.

Examples of C_2-6heterocyclic amino group containing a single 5-7-membered ring, are such groups as 2-trilaminar, 3-trilaminar, 2-filmikauppa, 3-filmikauppa, 2-pernilleborup, 3-pernilleborup, 4-pernilleborup, 1-pyrrolidinone, 2-pyrrolidinone, 3-pyrrolidinone, 1-imidazolidinone, 2-imidazolidinone, 4-imidazolidinone, 1-pyrazolidinone, 3-pyrazolidinone, 4-pyrazolidinone, 2-thiazolidinone, 4-thiazolidinone, 5-thiazolidinone, 3-isothiazolinone, 4-isothiazolinone is a, 5-isothiazolinone, 2-oxazolidinone, 4-oxazolidinone, 5-oxazolidinone, 3-isoxazolidinone, 4-isoxazolidinone, 5-isoxazolidinone, 2-pyridylamino, 3-pyridylamino, 4-pyridylamino, 2-pyridinylamino, 2-pyrimidinamine, 4-pyrimidinamine, 5-pyrimidinediamine, 3-pyridinylamino, 4-pyridinylamino, 2-1,3,4-oxadiazoline, 2-1,3,4-thiadiazolidine, 3-1,2,4-oxadiazolidine, 5-1,2,4-oxadiazolidine, 3-1,2,4-thiadiazolidine, 5-1,2,4-thiadiazolidine, 3-1,2,5-oxadiazolyl, 3-1,2,5-thiadiazolidine and the like.

Examples of C_5-9heterocyclic amino group with two condensed rings with the number of atoms of 8 to 10 are 2-benzoguanamine, 3-benzoguanamine, 4-benzoguanamine, 5-benzoguanamine, 6-benzoguanamine, 7-benzoguanamine, 1-isobenzofurandione, 4-isobenzofurandione, 5-isobenzofurandione, 2-benzothiazolinone, 3-benzothiazolinone, 4-benzothiazolinone, 5-benzothiazolinone, 6-benzothiazolinone, 7-benzothiazolinone, 1-isobenzofuranone, 4-isobenzofurandione, 5-isobenzofurandione, 2-hermanellonota, 3-chromen luminograph, 4-hermanellonota, 5-hermanellonota, 6-hermanellonota, 7-hermanellonota, 8-hermanellonota, 1-indolizinium, 2-indolizinium, 3-indolizinium, 5-indolizinium, 6-indolizinium, 7-indolizinium, 8-indolizinium, 1-isoindoline, 2-isoindoline, 4-isoindoline, 5-isoindoline, 1-indoleamines, 2-indoleamines, 3-indoleamines, 4-indoleamines, 5-indoleamines, 6-indoleamines, 7-indoleamines, 1-indazolinone, 2-indazolinone, 3-indazolinone, 4-indazolinone, 5-indazolinone, 6-indazolinone, 7-indazolinone, 1-polylaminate, 2-polylaminate, 3-polylaminate, 6-polylaminate, 7-polylaminate, 8-polylaminate, 2-chinarating, 3-chinarating, 4-chinarating, 5-chinarating, 6-chinarating, 7-chinarating, 8-chinarating, 1-ethanolamine, 3-ethanolamine, 4-ethanolamine, 5-ethanolamine, 6-ethanolamine, 7-ethanolamine, 8-ethanolamine, 1-palatinolinotype, 5-palatinolinotype, 6-palatinolinotype, 1-2,7-naphthyridinone, 3-2,7-naphthyridinone is a, 4-2,7-naphthyridinone, 1-2,6-naphthyridinone, 3-2,6-naphthyridinone, 4-2,6-naphthyridinone, 2-1,8-naphthyridinone, 3-1,8-naphthyridinone, 4-1,8-naphthyridinone, 2-1,7-naphthyridinone, 3-1,7-naphthyridinone, 4-1,7-naphthyridinone, 5-1,7-naphthyridinone, 6-1,7-naphthyridinone, 8-1,7-naphthyridinone, 2-1,6-naphthyridinone, 3-1,6-naphthyridinone, 4-1,6-naphthyridinone, 5-1,6-naphthyridinone, 7-1,6-naphthyridinone, 8-1,6-naphthyridinone, 2-1,5-naphthyridinone, 3-1,5-naphthyridinone, 4-1,5-naphthyridinone, 6-1,5-naphthyridinone, 7-1,5-naphthyridinone, 8-1,5-naphthyridinone, 2-hinoklidilkarbinola, 5-khinoksalinona, 6-hinoklidilkarbinola, 2-hiazolidinedione, 4-hiazolidinedione, 5-hiazolidinedione, 6-hiazolidinedione, 7-hiazolidinedione, 8-hiazolidinedione, 3-sinolingua, 4-sinolingua, 5-sinolingua, 6-sinolingua, 7-sinolingua, 8-sinolingua, 2-peridiniella, 4-peridiniella, 6-peridiniella, 7-peridiniella and the like.

Preferably can be mentioned 2-pyridylamino, 3-Piri is luminograph and 4-pyridylamino.

Specific examples of substituents in the compounds used in this invention are as follows.

Specific examples of R¹and R²preferably represent methyl.

Specific examples of R³preferably is hydroxy-group.

Specific examples of R⁴are preferably hydrogen atoms.

Specific examples of R⁵are preferably hydrogen atoms.

Specific examples of the groups-N-(CH₂)_m-V-(CH₂)_n-R⁶preferred are the following groups 1)to (4):

1)

2)

3)

4)

Specific examples And preferable are listed in the following items 1) and 2):

2)

Preferred compounds used in the present invention include the following:

(2) derived benzopyran or its pharmaceutically acceptable salt, as described in paragraph (1), which is a compound of formula (I);

(3) derived benzopyran or its pharmaceutically acceptable salt, as described in paragraph (2), where V is a bond, m is an integer from 1 to 3, n is 0 or 1 and R⁶represents a benzene ring;

(4) derived benzopyran or its pharmaceutically acceptable salt, as described in paragraph (3), where V represents CR⁷R⁸where R⁷represents a hydroxy-group, and R⁸represents a hydrogen atom and m is 0 or 1;

(5) derived benzopyran or its pharmaceutically acceptable salt, as described in paragraph (3), where R⁶represents an alkyl group, cycloalkyl group or cycloalkenyl ring;

(6) derived benzopyran or its pharmaceutically acceptable salt, as described in paragraph (5), where V represents CR⁷R⁸where R⁷represents a hydroxy-group, and R⁸represents a hydrogen atom and m is 0 or 1;

(7) proizvodnje of benzopyran or its pharmaceutically acceptable salt, as indicated in paragraph (3), where a represents a group of formula (VIII)

;

(8) derived benzopyran or its pharmaceutically acceptable salt, as described in paragraph (4), where a represents a group of formula (VIII);

(9) derived benzopyran or its pharmaceutically acceptable salt, as described in paragraph (5), where a represents a group of formula (VIII);

(10) derived benzopyran or its pharmaceutically acceptable salt, as described in paragraph (6), where a represents a group of formula (VIII).

At the end of the description presents specific examples of compounds that can be used in the present invention, but the present invention is not limited. In this case, "Me" means methyl, "Et" means ethyl, "Pr" means propyl, "Bu" means butyl, "Ac" means acetyl (PINES₃) and "-" means the connection.

Compounds according to the present invention contain asymmetric carbon atoms at the 3-position and 4-position, thus, there are optical isomers based on asymmetric atmagupta, and optically active substances can also be used in the application of the present invention along with racemic modifications. Additionally, there may be included CIS - and TRANS-isomers on the basis of the configuration at the 3-position and 4-position, but the TRANS-isomer is preferred.

Further, when the compounds can form salts, their pharmaceutically acceptable salts can also be used as active ingredients.

Examples of pharmaceutically acceptable salts are those salts, as hydrochloride, hydrobromide, sulphates, methansulfonate, acetates, benzoate, tartratami, phosphates, lactates, maleate, fumarate, malate, gluconate, salicylates and the like.

Preferably, you can mark hydrochloride, maleate and methansulfonate.

The compounds of formula (I-a) or (II-a), i.e. the compounds of formula (I) or (II)where R⁴represents a hydrogen atom and R³represents a hydroxy-group, can be obtained by the coupling of compounds of formula (1) or (2) with the compound of the formula (3) in an inert solvent, as shown in the diagram below.

As solvents used in the reaction of compounds of formula (1) or (2) with the compound of the formula (3), we can note the following.

It can be noted solvents sulfoxide type, such as dimethyl sulfoxide; races is Writely amide type, for example dimethylformamide and dimethylacetamide; type solvents ethers, for example diethyl ether, dimethoxyethane, tetrahydrofuran and dioxane; halogenated solvents such as dichloromethane, chloroform and dichloroethane; nitrile solvents of the type, for example acetonitrile and propionitrile; solvents such as aromatic hydrocarbons such as benzene and toluene; the solvent of the hydrocarbon type, such as hexane and heptane; solvents, ester type, such as ethyl acetate; alcohol solvents of the type, for example methanol, ethanol, 1-propanol, 2-propanol and ethylene glycol; and water. Furthermore, the reaction can be carried out in the absence of any solvent. Preferably it can be noted solvents of the type of ester, nitrile solvents and alcohol solvents type.

The reaction temperature is usually from -80°C to the boiling point of the solvent used in the reaction, preferably from -10 to 100°C.

The molar ratio of the reacting substances is in the range of 0.5 to 4.0, preferably 1.0 to 2.0, the ratio between the compound (3)/compound (1) or (2).

The reaction can be used as acid catalysts.

Used acid catalysts include inorganic acids such as hydrochloric acid and sulfuric acid, a Lewis acid such as aluminium chloride, those whom rochloride titanium, complex epirate boron TRIFLUORIDE, Perlina acid, lithium perchlorate, lithium bromide and triftorbyenzola ytterbium.

Preferred acid catalysts are lithium bromide, and lithium perchlorate.

Synthesis of optically active compounds of formula (I) or (II) carried out using the method of optical separation of the racemate (published patent application Japan No.Hei 3-141286, U.S. patent No. 5097037 and patent EP No. 409165).

In addition, the synthesis of the compounds of formula (1) or (2) is conducted using the following method of synthesis.

General method of synthesis benzopyrano rings

Benzopyrrole ring can be synthesized in accordance with known methods (the methods described in J. M. Evans et al., J. Med. Chem. 1984, 27, 1127; J. Med. Chem. 1986, 29, 2194; J. T. North et al., J. Org. Chem. 1995, 60, 3397, as well as in tiled applications for Japan patent No. Sho 56-57785, Sho 56-57786, Sho 58-188880, Hei 2-141, Hei 10-87650 and Hei 11-209366 and the like);

- Indole or oxyindole

T. Sakamoto et al., Heterocycles, 1986, 24, 31,

.Belley et. al., Synthesis, 2001, 222,

A. D. Cross et al., J. Chem. Soc., 1961, 2714;

Imidazolinone

J. Kitteringham et. al., Synthetic Commun., 2000, 30, 1937;

- Quinoline

C.Imor et al., Synthetic Commun., 1996, 26, 2197,

Y. Kitahara et al., Tetrahedron, 1997, 53, 6001,

A. G. Osborne et al., J. Chem. Soc. Perkin Trans. 1, 1993, 181,

R.. Shuman et al., J. Org. Chem., 1990, 55, 738,

T. Sakamoto et al., Chem. Pharm. Bull., 1981, 29, 2485,

Y. Tsuji et al., J. Org. Chem., 1987, 52, 1673,

Z. Song et al., J. Heterocyclic Chem., 1993, 30, 17;

- X is nainon

M. R. Sabol et al., Synthetic Commun., 2000, 30, 427,

Z-Y. Yang et al., Tetrahedron Lett., 1999, 40, 4505,

H-B. Sun et al., Synthesis, 1997, 1249,

A.Guiotto et al., J. Heterocyclic Chem. 1989, 26, 917,

K. Konno et al., Heterocycles 1986, 24, 2169,

E. Fernandez et al., Synthesis 1995, 1362;

- Benzothiazole or a triazole

N. B. Ambati et al., Synthetic Commun., 1997, 27, 1487,

D. E. Burton. et al., J. Chem. Soc (C), 1968, 1268;

- Cinoxacin or khinoksalinona

J.H.Liu et al., J. Org. Chem., 2000, 65, 3395,

J.J.Li et al., Tetrahedron Lett., 1999, 40, 4507,

Y.Ahmed et al., Bull. Chem. Soc. Jpn., 1987, 60, 1145;

Benzocaine

G.H.Jones et al., J. Med. Chem., 1987, 30, 295,

J.L.Wright et al., J. Med. Chem., 2000, 43, 3408,

M.Kluge et al., J. Heterocyclic Chem., 1995, 32, 395,

The compound of the formula (1) or (2-a), i.e. the compound of formula (I) or (II)where a represents a group of the formula

(5), R⁴represents a hydrogen atom and R³represents a hydroxy-group, can be obtained from compounds of formula (6) or (7) in accordance with known methods (the methods described in J.M.Evans et al., J. Med. Chem. 1984, 27, 1127; J. Med. Chem. 1986, 29, 2194; J.T.North et al., J. Org. Chem. 1995, 60, 3397, and paved applications for Japan patent No.. Sho 56-57785, Sho 56-57786, Sho 58-188880, Hei 2-141, Hei 10-87650 and Hei 11-209366 and the like).

The compound of formula (6) or (7) can be obtained by interaction of the compound (8) with compound (9) (see Y.Tsuji et al., J. Org. Chem., 1987, 52, 1673).

The catalyst of the transition metal is the lia

As solvents used in the reaction of compounds of formula (8) with the compound of the formula (9), we can note the following.

It can be noted solvents sulfoxide type, such as dimethylsulfoxide; an amide type solvents, such as dimethylformamide and dimethylacetamide; type solvents ethers, for example diethyl ether, dimethoxyethane, tetrahydrofuran, dioxane and dimethyl ether of diethylene glycol; halogenated solvents such as dichloromethane, chloroform and dichloroethane; nitrile solvents of the type, for example acetonitrile and propionitrile; solvents such as aromatic hydrocarbons such as benzene and toluene; the solvent of the hydrocarbon type, such as hexane and heptane; solvents, ester type, such as ethyl acetate; alcohol solvents of the type, for example methanol, ethanol, 1-propanol, 2-propanol and ethylene glycol; water. Furthermore, the reaction can be carried out in the absence of any solvent. Preferably it can be noted solvents of the type of ester, nitrile solvents and alcohol solvents type.

The reaction temperature usually ranges from -80°C to the boiling point of the solvent used in the reaction, preferably from -10 to 200°C.

The molar ratio of the reacting substances is in the range of 0.1 to 4.0, preferred is entrusted 0.5 to 2.0, for the ratio of the compound (8)/connection (9).

In the reaction it is possible to use catalysts of transition metals and ligands.

The catalysts of transition metals include ruthenium chloride, dichlorotris(triphenylphosphine)ruthenium, librates(triphenylphosphine)ruthenium, digitalmetrics (triphenylphosphine) ruthenium, (η4-cyclooctadiene) (η6-cyclooctadiene)ruthenium dimer of dichlorocarbene ruthenium, dodecacarbonyl, (η5-pentamethylcyclopentadienyl)chloro (η4-cyclooctadiene) ruthenium, palladium acetate, palladium chloride, dichlorobis(triphenylphosphine)palladium, tetranitropentaerithrite, bis(dibenzylideneacetone)palladium, rhodium chloride, chlorotris(triphenylphosphine)rhodium, hybridcarsaustintexasrent, geriatric(triphenylphosphine)rhodium, di-µ-chlortetracycline, chlorocarbonic(triphenylphosphine)iridium dimer (η5-pentamethylcyclopentadienyl)dichloride, nicelydecorated.although, diaballickall, (η5-cyclopentadienyl)dicarbonyl and the like.

Preferably it can be noted chloride ruthenium.

Ligands include monodentate phosphine ligands, such as trimethylphosphine, triethylphosphine, tri-n-propylphosphine, triisopropylphosphine, tri-n-butylphosphine, three-tert-butylphosphine, tricyclohexylphosphine, triphenylphosphine and three(tolyl)phosphine, bidentate phosphine ligands such as 1,2-besdie inforination, 1,3-bidimensional, 1,4-bidimensionality and 1,2-diethylphosphonate, fosfatnye ligands, such as triethylphosphite, tributylphosphite, triphenylphosphite and three(o-tolyl)FOSFA.

Preferred are triphenylphosphine, tri-n-butylphosphine and three-tert-butylphosphine.

The compound of formula (6) or (7) can also be obtained by the interaction of compound (8) with compound (10) in the presence of an acid catalyst (see Y. Kitahara et al., Tetrahedron lett., 1997, 53, 6001, Z. Song et al., J. Heterocyclic Chem., 1993, 30, 17).

As solvents used in the reaction of compounds of formula (8) with the compound of the formula (10), we can note the following.

It can be noted solvents sulfoxide type, such as dimethylsulfoxide; an amide type solvents, such as dimethylformamide and dimethylacetamide; type solvents ethers, for example diethyl ether, dimethoxyethane, tetrahydrofuran, dioxane and dimethyl ether of diethylene glycol; halogenated solvents such as dichloromethane, chloroform and dichloroethane; nitrile solvents of the type, for example acetonitrile and propionitrile; solvents such as aromatic hydrocarbons such as benzene and toluene; the solvent of the hydrocarbon type, such as hexane and heptane; solvents, ester type, such as ethyl acetate; alcohol solvents of the type, e.g. the methanol, ethanol, 1-propanol, 2-propanol and ethylene glycol; solvents of the type of organic acids, such as acetic acid and triperoxonane acid, and water. Furthermore, the reaction can be carried out in the absence of any solvent. Preferably, you can mention the type solvents ethers, solvents, nitrile-type solvents, alcohol type and solvent type organic acids.

Used acid catalysts include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid, organic sulfonic acid, for example methanesulfonate acid and p-toluensulfonate acid, a Lewis acid such as aluminum chloride, titanium tetrachloride, complex epirate boron TRIFLUORIDE, perchloro acid, zinc chloride, zinc bromide, zinc iodide, chloride, iron(III)chloride iron(II)chloride copper(I) chloride copper(II). Preferably can be mentioned hydrochloric acid and zinc chloride.

The reaction temperature usually ranges from -80°C to the boiling point of the solvent used in the reaction, preferably from -10 to 200°C.

The molar ratio of the reacting substances is in the range of 1-10, preferably 1-3, the ratio between the compound (10)/the compound (8).

In addition, synthesis of optically active compounds for compounds of formula (1)or (2) may be carried out using the method of asymmetric synthesis (translated PCT publication Japan patent No. Hei 5-507645, laid claim to the Japan patent No. Hei 5-301878 and Hei 7-285983 tiled an application for a European patent No. 535377 and U.S. patent No. 5420314).

The compound of the formula (I-a) or (II-a), i.e. the compound of formula (I) or (II)where R⁴represents a hydrogen atom and R³represents a hydroxy-group, can be obtained by carrying out reductive amination of compounds of formula (11) or (12) and the compounds of formula (13) in an inert solvent, as shown in the diagram below.

As solvents used in the reaction of compounds of formula (11) or (12) with the compound of the formula (13), we can note the following.

It can be noted solvents sulfoxide type, such as dimethylsulfoxide; an amide type solvents, such as dimethylformamide and dimethylacetamide; type solvents ethers, for example diethyl ether, dimethoxyethane, tetrahydrofuran and dioxane; halogenated solvents such as dichloromethane, chloroform and dichloroethane; nitrile solvents of the type, for example acetonitrile and propionitrile; solvents such as aromatic hydrocarbons such as benzene and toluene; the solvent of the hydrocarbon type, such as hexane and heptane; solvents, ester type, such as ethyl acetate; alcohol solvents of the type, for example methanol, ethanol, 1-propanol, 2-disappear to the ol and ethylene glycol; and the water. Furthermore, the reaction can be carried out in the absence of any solvent. Preferably it can be noted solvents of the type of ester and alcohol solvents type.

The compound of the formula (I-b) or (II-b), i.e. the compound of formula (I) or (II)where R⁴represents a hydrogen atom and R³represents a hydroxy-group, m is 1, V is a CR⁷OH, can be obtained by the coupling of compounds of formula (11) or (12) with the compound of the formula (14) in an inert solvent, as shown in the diagram below.

As solvents used in the reaction of compounds of formula (11) or (12) with the compound of the formula (14), we can note the following.

It can be noted solvents sulfoxide type, such as dimethylsulfoxide; an amide type solvents, such as dimethylformamide and dimethylacetamide; type solvents ethers, for example diethyl ether, dimethoxyethane, tetrahydrofuran and dioxane; halogenated solvents such as dichloromethane, chloroform and dichloroethane; nitrile solvents of the type, for example acetonitrile and propionitrile; solvents such as aromatic hydrocarbons such as benzene and toluene; the solvent of the hydrocarbon type, such as hexane and heptane; solvents, ester type, such as ethyl acetate; dissolve Italy alcohol type, for example, methanol, ethanol, 1-propanol, 2-propanol and ethylene glycol; and water. Furthermore, the reaction can be carried out in the absence of any solvent. Preferably it can be noted solvents of the type of ester, nitrile solvents and alcohol solvents type.

The reaction temperature usually ranges from -80°C to the boiling point of the solvent used in the reaction, preferably from -10 to 100°C.

The molar ratio of the reacting substances is in the range of 0.5 to 4.0, preferably 1.0 to 2.0, the ratio between the compound (14)/the compound (11) or (12).

In the reaction it is possible to use an acid catalyst.

Used acid catalysts include inorganic acids such as hydrochloric acid and sulfuric acid, Lewis acid, for example aluminium chloride, titanium tetrachloride, complex epirate boron TRIFLUORIDE, perchloro acid, lithium perchlorate, lithium bromide and triftorbyenzola ytterbium.

Preferred acid catalysts are lithium bromide, and lithium perchlorate.

The compounds of formula (I-c) or (II-c), i.e. the compounds of formula (I) or (II)where R⁴represents a hydrogen atom, R³represents a hydroxy-group and A represents a group of formula (15)can also be obtained by the coupling of compounds of formula (16) or (17) with what Obedinenie formula (18) in an inert solvent, as shown in the diagram below.

As solvents used in the reaction of compounds of formula (16) or (17) with the compound of the formula (18), we can note the following.

It can be noted solvents sulfoxide type, such as dimethylsulfoxide; an amide type solvents, such as dimethylformamide and dimethylacetamide; type solvents ethers, for example diethyl ether, dimethoxyethane, tetrahydrofuran and dioxane; halogenated solvents such as dichloromethane, chloroform and dichloroethane; nitrile solvents of the type, for example acetonitrile and propionitrile; solvents such as aromatic hydrocarbons such as benzene and toluene; the solvent of the hydrocarbon type, such as hexane and heptane; solvents, ester type, such as ethyl acetate; alcohol solvents of the type, for example methanol, ethanol, 1-propanol, 2-propanol and ethylene glycol; and water. Furthermore, the reaction can be carried out in the absence of any solvent. Preferably, you can mark the solvent of alcohol type.

The reaction temperature usually ranges from -80°C to the boiling point of the solvent used in the reaction, preferably from -10 to 50°C.

The molar ratio of the reacting substances is in the range of 0.5 to 4.0, preferably from 0.8 to 2.0, the ratio of the giving (18)/the compound (16) or (17).

The compound of the formula (I-d) or (II-d), i.e. the compound of formula (I) or (II)where R⁴represents a hydrogen atom, R³represents a hydroxy-group and A represents a group of formula (19)can also be obtained by reduction of compounds of formula (20) or (21) in an inert solvent, as shown in the diagram below.

The compound of the formula (I-e) or (II-e), i.e. the compound of formula (I) or (II)where R⁴represents a hydrogen atom, R³represents a hydroxy-group and A represents a group of formula (22) (X represents the SO₂or CO-and Y represents S or O)can also be obtained by cyclization of compounds of formula (23) or (24) in an inert solvent in the basic conditions, as shown in the diagram below.

The compounds of formula (I) or (II)that are not included in the compounds of formula (I-a through I-e), and (II-a to II-e), i.e. the compounds of formula (I) or (II)where R³and R⁴together represent a bond, or R⁴represents a hydrogen atom, and R³represents a C_1-6alkylcarboxylic can be obtained by a method similar to that described in tiled applications for Japan patent No. Sho 52-91866 and Hei 10-87650.

As described above, the authors of the present invention have found that the compounds of formula (I)or (II) have a strong prolonging effect on the refractory period. The effect of prolongation of the refractory period represents one of the mechanisms of anti-arrhythmic action and is an important indicator that can be used to conclude about the effectiveness of the clinical arrhythmia. Conventional antiarrhythmic agents providing prolonging effect on the refractory period as the primary mechanism (such as d-sotalol belonging to the class III according to the classification of antiarrhythmic agents according to Vaughan Williams) was therapeutic problems inducyruya fibrillation with a high degree of risk, leading to sudden death from such causes as Torsade de pointes (ventricular) among other things due to prolongation of the action potential venticular muscles, which correlates with a prolonged effect on the refractory period and, therefore, becomes a therapeutic problem in adults mainly the muscles of the Atria (such as supraventricular tachycardia, atrial fibrillation, atrial fibrillation and the like).

To solve the problems the authors of the present invention conducted a study of compounds that have a prolonging effect on the refractory period selective in relation to the muscles of the Atria compared to venticular muscle, and found that the compounds of formula (I) or (II) have prolonger is its effect on the refractory period selective in relation to the muscles of the Atria and not have any effect on the refractory period and action potential venticular muscles. The difference between the opening of the authors of the present invention and prior art is to provide a prolonging effect on the refractory period selective for the muscles of the Atria, when using this group of compounds, which may be demonstrated by such facts as the absence of influence on the duration of the action potential of isolated venticular muscles and lack of effect on QT on electrocardiogram analiziropany animals. As follows from vysheizlozhennomu, the compounds of the present invention do not exhibit inducing action on the arrhythmia venticular muscle, so they can contribute to safer use in arrhythmia mainly the muscles of the Atria compared to the previous technology. The present invention provides advantages for therapeutic or prophylactic use as agents against atrial fibrillation, agents against the atrial flutter and agents from and against tachycardia atrial against paroxysmal, chronic, before surgery, during surgery and post-operative atrial fibrillation to prevent development of the disease, provodyaschego to embolism due to atrial fibrillation origin, prevent disease progression leading to ventricular fibrillation or tachycardia due to arrhythmia or tachycardia atrial and to avoid threatening the life of the forecast due to the preventive effect on the fibrillation or tachycardia atrial, leading to ventricular fibrillation or tachycardia.

The authors of the present invention has developed a pharmaceutical composition and veterinary pharmaceutical composition containing an effective amount of a compound of formula (I) or (II) for the treatment of these conditions.

As a form of introduction of the compounds of the present invention may be noted the parenteral forms of administration, such as injection (subcutaneous, intravenous, intramuscular and intraperitoneal injections), ointments, suppositories, aerosols or the like, and oral forms of administration, such as tablets, capsules, granules, pills, syrups, solutions, emulsions, suspensions and the like.

The above-described pharmaceutical or veterinary pharmaceutical composition containing the compound according to the present invention in an amount of about 0.01 to 99.5%pure, preferably about 0.1-30%, based on the total weight of the composition.

In addition to the compound according to the present invention in the compositions containing the compound may contain other pharmaceutical or veterinary pharmaceutically active compounds.

In addition, these compositions can contain a variety of compounds according to the present invention.

The number of compounds according to the present invention for use in clinical introduction can izmenyatsa depending on age, the weight and sensitivity of the patient, symptomatic status, and the like, but the effective amount when the clinical introduction is typically about 0.003 to 1.5 g, preferably 0.01 to 0.6 g, per day for an adult. However, if necessary you can use a number outside the range indicated above.

The connection according to the present invention is introduced into the composition of preparative forms for administration using a conventional pharmaceutical methods.

I.e. tablets, capsules, granules and pills for oral administration are obtained from the use of excipients such as sucrose, lactose, glucose, starch and mannitol, binders such as hydroxypropylcellulose, syrup, Arabian gum, gelatin, sorbitol, tragacanth gum, methylcellulose and polyvinylpyrrolidone; dezintegriruetsja agents, such as starch, carboxymethylcellulose and its calcium salt, microcrystalline cellulose and polyethylene glycol; lubricants, such as talc, magnesium stearate or calcium and silicon dioxide; lubricating agents such as sodium laurate and glycerol, and the like.

Preparative forms for injections, solutions, emulsions, suspensions, syrups and aerosols obtained using solvents for the active compounds, such as water, ethyl alcohol, isopropyl Speer is, propylene glycol, 1,3-butyleneglycol and polyethylene glycol; surfactants, such as ester sorbitan and fatty acids, polyoxyethylene ester sorbitan and fatty acids, polyoxyethylene ester of fatty acid, polyoxyethylene simple ester of hydrogenated castor oil and lecithin; suspendida agents, such as carboxymethylate sodium salt, cellulose derivatives such as methylcellulose or the like, and natural rubbers, such as the Arabian gum, tragacanth gum or the like, and preservatives such as esters of p-hydroxybenzoic acid, benzalkonium chloride, salts of sorbic acid and the like.

For ointments, which are percutaneous adsorbed pharmaceutical formulation, use white petrolatum, liquid paraffin, higher alcohols, macrosolve ointment, hydrophilic ointment base, water base gel type, and the like.

Suppositories is obtained using, for example, coconut fat, polyethylene glycol, lanolin, triglycerides of fatty acids, coconut oil, Polysorbate and the like.

Examples

The present invention is further illustrated in detail with examples, but the present invention is not limited to these examples.

[Examples of synthesis]

In addition, Ph,Ph Sal is a new complex of manganese (XX) and Cyc,Ph selenoviy complex of manganese (XY) denote optically active compounds, having the following formula, which were synthesized according to a method similar to that described in application laid on the Japan patent No. Hei 7-285983.

Example of synthesis 1

3/2 maleate (±)-TRANS-2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

2,2,9-Trimethyl-2H-pyrano[2,3-g]quinoline

To a solution of 6-amino-2,2-DIMETHYLPROPANE (10.1 g, 57,7 mmol) in ethanol (500 ml) was added at room temperature, methyl vinyl ketone are (33,0 ml, 404 mmol), m-nitrobenzenesulfonic acid (21.1 g, 104 mmol), zinc chloride (1.97 g, 14.4 mmol) and 35% hydrochloric acid (24 ml, 289 mmol) and the resulting mixture was stirred at 110°C for 5 hours. Upon completion of the reaction, ethanol drove, was added water and the resulting solution was neutralized with sodium bicarbonate and was extracted with ethyl acetate. The organic phase was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After removal of the solvent the residue was column purified by medium pressure chromatography (hexane/ethyl acetate=3/1) and received a target product (yield: 38%).

Brown amorphous product

¹H-NMR (CDCl₃) δ: 1,51 (C, 6N), 2,59 (d, J=0.6 Hz, 3H), 5,90 (d, J=9.9 Hz, 1H), 6,59 (d, J=9.9 Hz, 1H), 7,11 (d, J=3.6 Hz, 1H), 7,25 (s, 1H), 7,68 (s, 1H), to 8.57 (d, J=4, 4 Hz, 1H).

Mass spectrum(ESI ⁺) m/z: 226 [M+1]⁺.

(±)-TRANS-2,2,9-Trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

To a solution of 2,2,9-trimethyl-2H-pyrano[2,3-g]quinoline (530 mg of 2.35 mmol) in dimethyl sulfoxide (8 ml) was added at room temperature N-bromosuccinimide (920 mg, 5.17 mmol) and water (1.6 ml) and the resulting mixture was stirred at room temperature for 3 hours. Upon completion of the reaction, to the reaction solution were added water and the resulting solution was extracted with ethyl acetate. To the aqueous phase was added an aqueous solution of sodium bicarbonate and the resulting solution was additionally extracted with ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate and the solvent drove, getting the crude product (±)-TRANS-3-bromo-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-4-ol. To this mixture was added at room temperature, 1,4-dioxane (30 ml) and 1 mol/l aqueous solution of sodium hydroxide (5,64 ml) and the resulting solution was stirred at room temperature for 2.5 hours. Upon completion of the reaction, to the reaction solution were added water and the resulting solution was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and the solvent drove, getting the crude product is 3,4-epoxy-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline. To the residue was added at room themes is the temperature value 1,4-dioxane (3.2 ml), the lithium perchlorate (250 mg, of 2.35 mmol) and 2-phenylethylamine (0.35 ml, 2.82 mmol) and the resulting mixture was stirred at 75°C for 5 hours. Upon completion of the reaction, to the reaction solution was added aqueous sodium hydrogen carbonate solution, the resulting solution was extracted with ethyl acetate, the organic phase is washed with an aqueous solution of sodium bicarbonate then with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After removal of the solvent the residue was purified column chromatography (hexane/ethyl acetate= 1/1) and the received target product (3 stages, yield: 26%).

¹H-NMR (CDCl₃) δ: 1.26 in (c, 3H), 1.55V (c, 3H), 2,59 (c, 3H), and 2.83 (t, J=6,8 Hz, 2H), 2,96-of 3.12 (m, 3H), 3,60 (d, J=10.5 Hz, 1H), 3,88 (DD, J=1.1 Hz, 10.5 Hz, 1H), 7,13 (d, J=4,2 Hz, 1H), 7.18 in-7,32 (m, 6H), 7,98 (d, J=1,1 Hz, 1H), at 8.60 (d, J=4.4 Hz, 1H).

Mass spectrum (ESI⁺) m/z: 363 [M+1]⁺

To a solution of (±)-TRANS-2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol (219 mg, of 0.60 mmol) in ethyl acetate (3 ml) was added dropwise a solution of maleic acid (77 mg, 0.66 mmol) in ethyl acetate (1 ml), the resulting reaction solution was cooled to 0°C, was added hexane (10 ml) and precipitated precipitated solid was filtered, receiving 3/2 maleate (±)-TRANS-2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol (yield: 72%).

Yellow crystals

TPL:172-174°C (decomposition)

¹H-NMR (DMSO-d₆) δ: 1,17 (c, 3H), and 50 (c, 3H), 2,59 (c, 3H), 2,94-3,37 (m, 4H), 4,10 (DD, J=6,1 Hz and 9.4 Hz, 1H), 4.72 in (d, J=9.4 Hz, 1H), 6,09 (c, 3H), 6,33 (d, J=6,1 Hz, 1H), 7.23 percent-to 7.35 (m, 6H), 7,42 (c, 1H), 8,43 (c, 1H), 8,66 (d, J=4,1 Hz, 1H).

Example of synthesis 2

(±)-TRANS-2,2,7,9-Tetramethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

This compound was synthesized according to the method of synthesis example 1.

2,2,7,9-Tetramethyl-2H-pyrano[2,3-g]quinoline

(Yield: 59%)

Black-brown oily product

¹H-NMR (CDCl₃) δ: 1,49 (c, 6H), 2,54 (c, 3H), 2,62 (c, 3H), 5,86 (d, J=9.9 Hz, 1H), 6,55 (d, J=9.9 Hz, 1H), 7,00 (c, 1H), 7,20 (c, 1H), 7,60 (c, 1H)

Mass spectrum (ESI⁺) m/z: 240 [M+1]⁺

(±)-TRANS-3-Bromo-2,2,7,9-tetramethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-4-ol

(Yield: 82%)

¹H-NMR (CDCl₃) δ: 1,47 (c, 3H), 1,68 (c, 3H), 2,58 (c, 3H), 2,70 (c, 3H), 4,28 (d, J=9.6 Hz, 1H), 5,14 (d, J=9.6 Hz, 1H), 7,08 (c, 1H), 7,28 (c, 1H), of 8.37 (c, 1H).

Mass spectrum (ESI⁺) m/z: 336, 338 [M+1]⁺

(±)-TRANS-2,2,7,9-Tetramethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol (yield: 17%)

White crystals TPL:144-147°C

¹H-NMR (CDCl₃) δ: 1,25 (c, 3H), and 1.54 (c, 3H), 1,90 (user. c, 1H), 2,55 (c, 3H), 2,65 (c, 3H), of 2.81 (t, J=6,8 Hz, 2H), 2,97-3,10 (m, 2H), 3,19 (users, 1H), to 3.58 (d, J=10.5 Hz, 1H), 3,85 (d, J=10.5 Hz, 1H),? 7.04 baby mortality (c, 1H), 7,17-7,31 (m, 6H), to $ 7.91 (c, 1H).

Mass spectrum (ESI⁺) m/z: 377 [M+1]⁺

Mass spectrum (ESI^-) m/z: 421 [M+45]⁺(HCOOH adduct)

Example of synthesis 3

This compound was synthesized according to the method of synthesis example 1.

2,2,8,9-Tetramethyl-2H-pyrano[2,3-g]quinoline

(Yield: 50%)

¹H-NMR (CDCl₃) δ: 1.50 in (c, 6H), 2.50 each (c, 3H), 2,66 (c, 3H), by 5.87 (d, J=9.9 Hz, 1H), to 6.57 (d ,J=9.9 Hz, 1H), 7,26 (c, 1H), 7,63 (c, 1H), 8,48 (c, 1H)

Mass spectrum (ESI⁺) m/z: 240 [M+1]⁺

(±)-TRANS-3-Bromo-2,2,7,9-tetramethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-4-ol

(Yield: 65%)

¹H-NMR (CDCl₃) δ: 1,48 (c, 3H), 1.69 in (c, 3H), 1,80 (user. c, 1H), 2,46 (c, 3H), 2,56 (c, 3H), 4,28 (d, J=9.6 Hz, 1H), 5,15 (d, J=9.6 Hz, 1H), 7,25 (c, 1H), 8,42 (c, 1H), 8,57 (c, 1H)

Mass spectrum (ESI+) m/z: 336, 338 [M+1]⁺

1 maleate (±)-TRANS-2,2,8,9-tetramethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

(Yield: 4%)

White crystals

TPL: 199-203°C

¹H-NMR (DMSO-d₆) δ: 1,17 (c, 3H), 1.50 in (c, 3H), 2,41 (c, 3H), 2.49 USD (c, 3H), 2,89 is 3.40 (m, 4H), 4,07 (DD, J=5.5 Hz, 9.4 Hz, 1H), 4,66 (d, J=9.4 Hz, 1H), 6,05 (c, 2H), 6,28 (d, J=5.5 Hz, 1H), 7,22-to 7.35 (m, 5H), 7,43 (c, 1H), at 8.36 (c, 1H), 8,59 (c, 1H)

Mass spectrum (ESI⁺) m/z: 377 [M+1]⁺

Mass spectrum (ESI^-) m/z: 421 [M+45]⁺(HCOOH adduct)

Example of synthesis 4

3/2 maleate (±)-TRANS-2,2,7-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

2,2,7-Trimethyl-2H-pyrano[2,3-g]hinali the

To 6-amino-2, 2-DIMETHYLPROPANE (1,00 g, 5,71 mmol) was added at room temperature of 35% hydrochloric acid (1,43 ml of 17.1 mmol), p-chloranil (1.40 g, 5,71 mmol) and n-butanol (1.3 ml) and the temperature was raised to 120°C. the solution was Added catelouge aldehyde (0,567 ml, at 6.84 mmol) in n-butanol (0,52 ml) and the resulting mixture was stirred at 120°C for 20 minutes. Was added a solution of zinc chloride (0,777 g, 5,71 mmol) in tetrahydrofuran (10 ml) and the resulting mixture was stirred at 120°C for 20 minutes. Upon completion of the reaction was added aqueous sodium hydrogen carbonate solution the resulting solution was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. After removal of the solvent the residue was purified column chromatography (hexane/ethyl acetate= 2/1) and recrystallized from ethyl acetate, obtaining the target product (yield: 22%).

Grey solid

¹H-NMR (CDCl₃) δ: 1,48 (c, 6H), 2,67 (c, 3H), by 5.87 (d, J=9.9 Hz, 1H), 6,55 (d, J=9.9 Hz, 1H), 7,05 (c, 1H), 7,16 (d, J=8.5 Hz, 1H), to 7.64 (c, 1H), 7,86 (d, J=8.5 Hz, 1H)

Mass spectrum (ESI⁺) m/z: 226 [M+1]⁺

Mass spectrum (ESI^-) m/z: 225 [M]⁺

(±)-TRANS-3-Bromo-2,2,7-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-4-ol

This compound was synthesized according to the method of synthesis example 1.

(Yield: 24%)

3/2 maleate (±)-TRANS-2,2,7-trimethyl-4-[(2-phenylethyl)amino]-3,4-dig the DRO-2H-pyrano[2,3-g]quinoline-3-ol

(Yield: 12%)

White crystals

¹H-NMR (DMSO-d₆) δ: 1,15 (c, 3H), 1, 48 (c, 3H), 2.63 in (c, 3H), 2,70-to 3.38 (m, 4H), 4.09 to (DD, J=5.8 Hz, 9.4 Hz, 1H), and 4.68 (d, J=9.4 Hz, 1H), between 6.08 (c, 3H), of 6.29 (d, J=5.8 Hz, 1H), 7,22-7,35 (m, 6H), 7,40 (c, 1H), 8,10 (d, J=8.5 Hz, 1H), 8,33 (c, 1H)

Mass spectrum (ESI+) m/z: 363 [M+1]⁺

Mass spectrum (ESI-) m/z: 407 [M+45]⁺(HCOOH adduct)

Example of synthesis of 5

2 maleate (±)-TRANS-2,2,8-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

This compound was synthesized according to the method of synthesis example 1.

2,2,8-Trimethyl-2H-pyrano[2,3-g]quinoline

(Yield: 17%)

¹H-NMR (CDCl₃) δ: 1,48 (c, 6H), 2,45 (c, 3H), by 5.87 (d, J=9.9 Hz, 1H), 6,56 (d, J=9.9 Hz, 1H), 7,00 (c,1H), to 7.64 (c, 1H), 7,70 (c, 1H), 8,54 (d, J=8.5 Hz, 1H)

Mass spectrum (ES⁺) m/z: 226 [M+1]⁺

(±)-TRANS-3-Bromo-2,2,8-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-4-ol

(Yield: 54%)

Mass spectrum (ESI+) m/z: 322, 324 [M+1]⁺

2 maleate (±)-TRANS-2,2,8-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

(Yield: 20%)

White crystals

¹H-NMR (DMSO-d₆) δ: 1,15 (c, 3H), 1,49 (c, 3H), 2,45 (c, 3H), 2,97-3,39 (m, 4H), 4.09 to (DD, J=6,1 Hz and 9.4 Hz,1H), 4,71 (d, J=9.1 Hz, 1H), 6,15 (c, 4H), 6,32 (d, J=6.3 Hz, 1H), 7,19 and 7.36 (m, 5H), 7,97 (c, 1H), 8,39 (c, 1H), 8,67 (c, 1H).

Example of synthesis 6

1 maleate (±)-TRANS-7-chloro-2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3g]quinoline-3-ol

To a solution of 2,2,9-trimethyl-2H-pyrano[2,3-g]quinoline (1.56 g, 6,92 mmol) in chloroform (15.6 ml) was added dropwise at room temperature a solution of m-chloroperbenzoic acid (2,61 g of 15.2 mmol) in a mixture of chloroform (6,4 ml)-methanol (1.6 ml) and the resulting mixture was stirred at room temperature for 1.5 hours. Upon completion of the reaction, the reaction solution was extracted with aqueous sodium thiosulfate solution and the organic phase was washed with an aqueous solution of sodium bicarbonate, then with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After removal of the solvent the residue was added at room temperature, chloroform (33 ml), p-toluensulfonate (1,32 g, 6,92 mmol) and potassium carbonate (0,954 g, 6,92 mmol) and the resulting mixture was stirred at 70°C for 3 hours. Upon completion of the reaction, to the reaction solution was added water and was extracted with him chloroform. The organic phase was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After removal of the solvent the residue was purified column chromatography (hexane/ethyl acetate = 2/1) and received a target product (yield: 67%).

Pale yellow solid

¹H-NMR (CDCl₃) δ: 1,42 (c, 6H), 2,48 (d, J=0.8 Hz, 3H), of 5.83 (d, J=9.9 Hz, 1H), 6,47 (d, J=9.9 Hz, 1H), 7,03 (d, J=3.6 Hz, 1H), 7,11 (c, 1H), 7,50 (c, 1H).

Mass is the range (ESI ⁺) m/z: 260 [M+1]⁺

(±)-TRANS-3-Bromo-7-chloro-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-4-ol

Next, the target compound was synthesized in accordance with the method of synthesis example 1.

(Yield: 44%)

Mass spectrum (ESI⁺) m/z: 356, 358 [M+1]⁺

1 maleate (±)-TRANS-7-chloro-2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

(Yield: 58%)

White crystals

TPL: 221-226°C (decomposition)

¹H-NMR (DMSO-d₆) δ: 1,17 (c, 3H), 1,49 (c, 3H), 2,60 (c, 3H), 2,93-of 3.32 (m, 4H), of 4.05 (m, 1H)and 4.65 (d, J=9.4 Hz, 1H), 6,05 (c, 2H), 6,28 (user. c, 1H), 7,22-7,34 (m, 5H), 7,43 (c, 2H), 8,32 (c, 1H).

Mass spectrum (ESI⁺) m/z: 397 [M+1]⁺

Mass spectrum (ESI^-) m/z: 441 [M+45]⁺(HCOOH adduct)

Example of synthesis of 7

1 maleate (±)-TRANS-3-hydroxy-2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-7-carbonitrile

2,2,9-Trimethyl-2H-pyrano[2,3-g]quinoline-7-carbonitrile

To a solution of 2,2,9-trimethyl-2H-pyrano[2,3-g]quinoline (4,36 g, and 19.3 mmol) in chloroform (43,6 ml) was added dropwise at room temperature a solution of m-chloroperbenzoic acid (7,35 g of 42.6 mmol) in a mixture of chloroform (17,4 ml) - methanol (4,36 ml) and the resulting mixture was stirred at room temperature for 1 hour. Upon completion of the reaction, the reaction solution was extracted with aqueous solution of thiosulfate soda is I and the organic phase was washed with an aqueous solution of sodium bicarbonate, then an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After removal of the solvent was added to the residue at room temperature, acetonitrile (19.3 ml), trimethylsilylacetamide (7,27 ml, to 57.9 mmol) and triethylamine (5,38 ml, and 38.6 mmol) and the resulting solution was stirred at 70°C for 3.5 hours. Upon completion of the reaction was added to the reaction solution, an aqueous solution of sodium bicarbonate, extracted it with chloroform and dried over anhydrous magnesium sulfate. After removal of the solvent the residue was purified column chromatography (hexane/ethyl acetate = 2/1) and received a target product (yield: 55%).

Pale yellow solid

¹H-NMR (CDCl₃) δ: 1.52m (c, 6H), 2,62 (d, J=0.6 Hz, 3H), 5,97 (d, J=9.9 Hz, 1H), return of 6.58 (d, J=9.9 Hz, 1H), 7.23 percent (c, 1H), 7,40 (c, 1H), 7,71 (c, 1H).

Mass spectrum (ESI⁺) m/z: 251 [M+1]⁺

(±)-TRANS-3-Bromo-4-hydroxy-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-7-carbonitrile

Next, the target compound was synthesized in accordance with the method of synthesis example 1.

(Yield: 36%)

Mass spectrum (ESI⁺) m/z: 349 [M+1]⁺

1 maleate (±)-TRANS-3-hydroxy-2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-7-carbonitrile

White crystals

TPL: 218-220°C (decomposition)

¹H-NMR (DMSO-d₆) δ: 1,20 (c, 3H)and 1.51 (c, 3H), 2,65 (c, 3H), 2,96-to 3.33 (m, 4H), 4.04 the-4,06 (m, 1H), with 4.64 (user. c, 1H), 6,05 (c,2H), 6,29 (user. c, 1H), 7,25-7,31 (m, 5H), 7,50 (c, 1H), 7,85 (c, 1H), 8,49 (c, 1H).

Mass spectrum (ESI⁺) m/z: 388 [M+1]⁺

Mass spectrum (ESI^-) m/z: 432 [M+45]⁺(HCOOH adduct)

Example of synthesis 8

(±)-TRANS-3,3-Dimethyl-1-[(2-phenylethyl)amino]-2,3-dihydro-1H-pyrano

[3,2-f]quinoline-2-ol

6-[(1,1-dimethyl-2-PROPYNYL)oxy]quinoline

A solution of 2-methyl-3-butyn-2-ol (2,45 ml of 25.1 mmol) and 1,8-diazabicyclo-[5,4,0]-7-undecene (4,25 ml, 28.4 mmol) in acetonitrile (15,5 ml) was stirred at 0°C for 30 minutes and added dropwise triperoxonane anhydride (3.55 ml of 25.1 mmol). The resulting mixture was added dropwise to a solution of a mixture of 6-hydroxyquinoline solution (2,43 g, and 16.7 mmol), copper chloride (I) (8,3 mg, 0,0835 mmol), acetonitrile (15,5 ml) and 1,8-diazabicyclo-[5,4,0]-7-undecene (4,25 ml, 28.4 mmol) at 0°C and stirred at 0°C for 3 hours. The resulting solution was acidified with 1 mol/l HCl and was extracted with ethyl acetate, the resulting aqueous phase was neutralized with an aqueous solution of sodium bicarbonate, extracted with ethyl acetate and dried over anhydrous magnesium sulfate. After removal of the solvent the residue was purified column chromatography (hexane/ethyl acetate = 1/1 to 1/3) and received the target product.

Pale yellow solid

TPL: 65-67°C

¹H-NMR (CDCl₃) δ: 1,86 (c, 6H), 2,70 (c, 1H), 7,69-7,71 (2H), 7,80 (c, 1H), with 8.33 (d, J=8,3 Hz, 1H), 8,45 (d, J=8,3 Hz, 1H), 9,01 (from the er. s, 1H)

Mass spectrum (El) m/z: 211 [M]⁺

3,3-Dimethyl-3H-pyrano[3,2-f]quinoline

A solution of 6-[(1,1-dimethyl-2-PROPYNYL)oxy]quinoline (of 16.7 mmol) in 1,2-dichlorobenzene (10 ml) was stirred at 180°C for 1 hour. Upon completion of the reaction the solvent is kept off and the residue was recrystallized from a mixture of hexane-ethyl acetate, obtaining the target compound (2 stage, quantitative.).

Green crystals

TPL: 104-107°C

¹H-NMR (CDCl₃) δ: 1,54 (C, 6N), of 5.89 (d, J=10,2 Hz, 1H), 6,93 (d, J=10,2 Hz, 1H), 7,50 (d, J=9.1 Hz, 1H), 7,73 (user. s, 1H), 8,31 (d, J=9.1 Hz, 1H), total of 8.74 (d, J=8.5 Hz, 1H), 9,03 (user. s, 1H).

Mass spectrum (EI) m/z: 211 [M]⁺.

(±)-TRANS-3,3-Dimethyl-1-[(2-phenylethyl)amino]-2,3-dihydro-1H-pyrano[3,2-f]quinoline-2-ol

Next, the target compound was synthesized in accordance with the method of synthesis example 1.

TPL: 180-182°C

¹H-NMR (CDCl₃) δ: 1.32 to (s, 3H), of 1.44 (s, 3H), 1,63 (user. s, 1H), 2,43 (user. s, 1H), 2,69-2,84 (m, 3H), 2,92-of 2.97 (m, 1H), 3,83 (d, J=5.0 Hz, 1H), 4.09 to (d, J=5.5 Hz, 1H), 7,10-7,29 (m, 6H), 7,86 (d, J=9.1 Hz, 1H), 8,13 (d, J=7.7 Hz, 1H), 8,71 (DD, J=1.7 Hz, 4,1 Hz, 1H)

Mass spectrum (ESI⁺) m/z: 349 [M+1]⁺

Mass spectrum (ESI^-) m/z: 393 [M+45]⁺(HCOOH adduct)

Example 9 synthesis

(±)-TRANS-8-Chloro-3,3-dimethyl-1-[(2-phenylethyl)amino]-2,3-dihydro-1H-pyrano[3,2-quinoline-2-ol

Using 3,3-dimethyl-3H-pyrano[3,2-f]quinoline target compound was synthesized analogs is ichno way of example of synthesis 6.

8-Chloro-3,3-dimethyl-3H-pyrano[3,2-f]quinoline

(Yield: 82%)

Red-brown oily product

¹H-NMR (CDCl₃) δ: 1,49 (c, 6H), 5,77 (d, J=9.9 Hz, 1H), 6.87 in (d, J=9.9 Hz, 1H), 7,27 (d, J=9.1 Hz, 1H), 7,34 (d, J=8,8 Hz, 1H), 7,80 (d, J=9.1 Hz, 1H), 8,19 (d, J=8,8 Hz, 1H).

Mass spectrum (ESI⁺) m/z: 246 [M+1]⁺

(±)-TRANS-2-Bromo-8-chloro-3,3-dimethyl-2,3-dihydro-1H-pyrano[3,2-f]quinoline-1-ol

(Yield: 45%)

(±)-TRANS-8-Chloro-3,3-dimethyl-1-[(2-phenylethyl)amino]-2,3-dihydro-1H-pyrano[3,2-f]quinoline-2-ol

(Yield: 60%)

White crystals

TPL: 141-143°C

¹H-NMR (CDCl₃) δ: 1.28 (in c, 3H), 1,44 (c, 3H), 1,64 (user. c, 2H), 2,65-2,78 (m, 3H), 2,86-2,96 (m, 1H), 3,84 (d, J=6,1 Hz, 1H), 4,06 (d, J=5.8 Hz, 1H), 7,08-7,30 (m, 7H), 7,98 (d, J=9.1 Hz, 1H), they were 8.22 (d, J=8,8 Hz, 1H).

Mass spectrum (ESI⁺) m/z: 383 [M+1]⁺

Mass spectrum (ESI^-) m/z: 427 [M+45]⁺(HCOOH adduct)

Example 10 synthesis

(±)-TRANS-2-Hydroxy-3,3-dimethyl-1-[(2-phenylethyl)amino]-2,3-dihydro-1H-pyrano[3,2-phenalen-8-carbonitrile

Using 3,3-dimethyl-3H-pyrano[3,2-f]quinoline target compound was synthesized similarly to the method of synthesis example 7.

3,3-Dimethyl-3H-pyrano[3,2-f]quinoline-8-carbonitrile

(Yield: quantitative)

Yellow solid

¹H-NMR (CDCl₃) δ: 1.52m (c, 6H), 5,80 (d, J=9.9 Hz, 1H), 6.89 in (d, J=10,2 Hz, 1H), 7,37 (d, J=9.4 Hz, 1H), 7,65 (d, J=8,8 Hz, H), of 7.95 (d, J=9.4 Hz, 1H), 8,64 (d, J=8,8 Hz, 1H).

Mass spectrum (ESI⁺) m/z: 237[M+1]⁺

Mass spectrum (ESI^-) m/z: 235 [M-1]⁺

(±)-TRANS-2-Bromo-1-hydroxy-3,3-dimethyl-2,3-dihydro-1H-pyrano[3,2-f]quinoline-8-carbonitrile

(Yield: 49%)

¹H-NMR (CDCl₃) δ: 1.50 in (c, 3H), 1.69 in (c, 3H), of 2.72 (d, J=4,1 Hz, 1H), 4,35 (d, J=7.2 Hz, 1H), 5,43 (DD, J=3,9 Hz, 7.2 Hz, 1H), was 7.36 (d, J=9.1 Hz, 1H), of 7.70 (d, J=8,8 Hz, 1H), 8,03 (d, J=9.4 Hz, 1H), 8,72 (d, J=8,5 Hz, 1H)

Mass spectrum (ESI⁺) m/z: 333, 335 [M+1]⁺

Mass spectrum (ESI^-) m/z: 379 [M+45]⁺(HCOOH adduct)

(±)-TRANS-2-Hydroxy-3,3-dimethyl-1-[(2-phenylethyl)amino]-2,3-dihydro-1H-pyrano[3,2-f]quinoline-8-carbonitrile

(Yield: 72%)

White crystals

TPL: 93-96°C

¹H-NMR (CDCl₃) δ: 1.30 on (c, 3H), 1,46 (c, 3H), 1,60 (user. c, 3H), 2.13 and (users, 1H), 2,66-and 2.79 (m, 3H), 2,88 are 2.98 (m, 1H), a 3.87 (d, J=5.8 Hz, 1H), 4,08 (d, J=6,1 Hz, 1H), to 7.09 (d, J=6.3 Hz, 1H), 7,10 (d, J=7,4 Hz, 1H), 7.23 percent-7,27 (m, 3H), 7,30 (d, J=9.1 Hz, 1H), 7,41 (d, J=8,8 Hz, 1H), 7,92 (d, J=9.1 Hz, 1H), scored 8.38 (d, J=8.5 Hz, 1H)

Mass spectrum (ESI⁺) m/z: 374 [M+1]⁺

Mass spectrum (ESI^-) m/z: 418 [M+45]⁺(HCOOH adduct)

Example 11 synthesis

(±)-TRANS-2-Hydroxy-3,3-dimethyl-1-[(2-phenylethyl)amino]-2,3-dihydro-1H-pyrano[3,2-f]quinoline-8-carboxamide

To a solution of (±)-TRANS-2-hydroxy-3,3-dimethyl-1-[(2-phenylethyl)amino]-2,3-dihydro-1H-pyrano[3,2-f]quinoline-8-carbonitrile (400 mg, 1.07 mmol) in tert-butanol (40 ml) was added at room temperature, g is droxia potassium (800 mg, of 14.3 mmol) and the resulting mixture was stirred at 90°C for 2 hours. Upon completion of the reaction, to the reaction solution was added an aqueous solution of sodium chloride, was extracted with him ethyl acetate and the organic phase was dried over anhydrous magnesium sulfate. After removal of the solvent the residue was purified column chromatography (hexane/ethyl acetate = 1/1) and recrystallized from a mixture of hexane-ethyl acetate, obtaining the target product (yield: 54%).

White crystals

TPL: 197-199°C

¹H-NMR (CDCl₃) δ: 1.32 to (c, 3H), 1,47 (c, 3H), 1,71 (users, 2H), 2,29 (users, 1H), 2,69 was 2.76 (m, 3H), 2,89-of 2.97 (m, 1H), 3,86 (users, 1H), 4,13 (d, J=5.8 Hz, 1H), 5,62 (users, 1H), 7,10 (d, J=6,9 Hz, 1H), 7,10 (d, J=7,4 Hz, 1H), 7,20-7,28 (m, 4H), 7,89 (d, J=9.4 Hz, 1H), 7,98 (user. c, 1H), 8,07 (d, J=8,8 Hz, 1H), 8,31 (d, J=8,8 Hz, 1H).

Mass spectrum (ESI⁺) m/z: 392 [M+1]⁺

Mass spectrum (ESI^-) m/z: 436 [M+45]⁺(HCOOH adduct)

Example 12 synthesis

1 maleate (3R*,4S*)-2,2,7,9-tetramethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

(3R*,4R*)-3,4-epoxy-2,2,7,9-tetramethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline

To a solution of 2,2,7,9-tetramethyl-2H-pyrano[2,3-g]quinoline (with 4.64 g of 19.4 mmol) in ethyl acetate (70 ml) was added at room temperature N-Mei (0,303 ml, 3.88 mmol) and Ph,Ph selenoviy complex of manganese (XX) (201 mg, 0,194 mmol), was added dropwise an aqueous solution of hypochlorite n is Tria (25.6 g, 1,513 mol/kg, to 38.8 mmol) and the resulting mixture was stirred for 1 hour. Next, in a water bath was added an aqueous solution of sodium hypochlorite (25.6 g, 1,513 mol/kg, to 38.8 mmol) and the resulting mixture was stirred on a water bath for 1 hour. Upon completion of the reaction was added to the reaction solution, an aqueous sodium thiosulfate solution, the resulting mixture was filtered through celite and extracted. The organic phase was washed with an aqueous solution of sodium bicarbonate, then with an aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. After removal of the solvent the residue was purified column chromatography (hexane/ethyl acetate = 1/3) and received a target product (yield: 68%).

> 99.9% of ee; CHIRALPAKAD-RH 20 mm phosphate buffer (pH 8.0)/acetonitrile = 60/40, retention time: 5,7 minutes

¹H-NMR (CDCl₃) δ: 1.30 on (c, 3H), 1,64 (c, 3H), 2,56 (c, 3H), 2,66 (c, 3H)and 3.59 (d, J=4.4 Hz, 1H), 4,14 (d, J=4.4 Hz, 1H), 7,08 (c, 1H), 7,29 (c, 1H), 8,04 (c, 1H)

Mass spectrum (ESI⁺) m/z: 256 [M+1]⁺

1 maleate (3R*,4S*)-2,2,7,9-tetramethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

To a solution of (3R*,4R*)-3,4-epoxy-2,2,7,9-tetramethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline (0,80 g, 3.14 mmol) in 1,4-dioxane (1.6 ml) was added at room temperature, lithium perchlorate (334 mg, 3.14 mmol) and 2-phenylethylamine (0,473 ml of 3.77 mmol) and the resulting mixture was stirred at 70°C for 1 hour. Upon completion of the reaction was added to R. the promotional solution is an aqueous solution of sodium bicarbonate, were extracted its ethyl acetate and the organic phase was washed with an aqueous solution of sodium bicarbonate, then with an aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. After removal of the solvent the residue was purified column chromatography (ethyl acetate). Next, after removal of the solvent was added ethyl acetate (2 ml) was added dropwise a solution of maleic acid (376 mg, 3,23 mmol) in ethyl acetate (8 ml). The obtained precipitated precipitated solid was filtered, obtaining the target product (yield: 86%).

White crystals

TPL: 215-219°C (decomposition)

¹H-NMR (DMSO-d₆) δ: 1,16 (c, 3H), 1,49 (c, 3H), 2,55 (c, 3H), 2,58 (c, 3H), 2,93-3,39 (m, 4H), 4,07 (DD, J=6,4 Hz, 9.4 Hz, 1H), with 4.64 (d, J=9.4 Hz, 1H), 6,05 (c, 2H), 6,27 (d, J=5.8 Hz, 1H), 7.24 to 7,26 (m, 4H), 7,30 (c, 1H), 7,33 (c, 1H), was 7.36 (c, 1H), 8,31 (c, 1H)

Mass spectrum (ESI⁺) m/z: 377 [M+1]⁺

Mass spectrum (ESI^-) m/z: 421 [M+45]⁺(HCOOH adduct)

Example of synthesis 13

1 maleate (3R*,4S*)-2,2,7-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

This compound was synthesized according to the method of example 12 synthesis.

(3R*,4R*)-3,4-Epoxy-2,2,7-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline

99,3% ee; CHIRALPAKAD-RH 20 mm phosphate buffer (pH 8.0)/acetonitrile = 60/40, retention time: 6,2 minutes

¹H-NMR (CDCl₃) δ: 1.28 (in c, 3H), 1,64 (c, 3H), 2,71 (c, 3H, 3,59 (d, J=4.4 Hz, 1H), 4,15 (d, J=4.4 Hz, 1H), 7,13 (c, 1H), 7.23 percent (d, J=8.5 Hz, 1H), to $ 7.91 (d, J=8.5 Hz, 1H), 8,05 (c, 1H)

Mass spectrum (ESI⁺) m/z: 242 [M+1]⁺

1 maleate (3R*,4S*)-2,2,7-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

White crystals

TPL: 214-217°C (decomposition)

¹H-NMR (DMSO-d₆) δ: 1,15 (c, 3H), 1,48 (c, 3H), 2,62 (c, 3H), 2,93-3,14 (m, 4H), 4,03-4,07 (m, 1H), br4.61 (user. c, 1H), 6,04 (c, 2H), 6,23 (user. c, 1H), 7.23 percent-7,39 (m, 7H), of 8.09 (d, J=8.5 Hz, 1H), 8,31 (c, 1H).

Mass spectrum (ESI⁺) m/z: 363 [M+1]⁺

Mass spectrum (ESI^-) m/z: 407 [M+45]⁺(HCOOH adduct)

Example 14 synthesis

1 maleate (3R*,4S*)-3-hydroxy-2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-7-carbonitrile

This compound was synthesized according to the method of example 12 synthesis.

(3R*,4R*)-3,4-Epoxy-3-hydroxy-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-7-carbonitrile

(Yield: 33%)

of 99.1% ee; CHIRALCEL OJ-R acetonitrile/methanol/0.01 M aqueous solution of sodium chloride =1/3/3, retention time: 18,6 minutes

¹H-NMR (CDCl₃) δ: 1,33 (c, 3H), 1,66 (c, 3H), 2,65 (c, 3H), of 3.64 (d, J=4,1 Hz, 1H), 4,17 (d, J=4.4 Hz, 1H), 7,33 (c, 1H), 7,47 (c, 1H), 8,18 (c, 1H)

Mass spectrum (ESI⁺) m/z: 267 [M+1]⁺

Mass spectrum (ESI^-) m/z: 265 [M-1]⁺

1 maleate (3R*,4S*)-3-hydroxy-2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-7-carbonitrile

(Yield: 23%)

Pale-max is the first crystals

¹H-NMR (DMSO-d₆) δ: 1,20 (c, 3H), 1,52 (c, 3H), 2,66 (c, 3H), 2,98-to 3.33 (m, 4H), 4.09 to (m, 1H), 4,71 (user. c, 1H), 6,09 (c, 2H), 6,33 (user. c, 1H), 7.23 percent-7,34 (m, 5H), 7,51 (c, 1H), 7,86 (c, 1H), 8,51 (c, 1H)

Mass spectrum (ESI⁺) m/z: 388 [M+1]⁺

Mass spectrum (ESI^-) m/z: 432 [M+45]⁺(HCOOH adduct)

Example 15 synthesis

(3R*,4S*)-3-Hydroxy-2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-7-carboxamide

This compound was synthesized from (3R*,4S*)-3-hydroxy-2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-7-carbonitrile similar to the method of example 11 synthesis (yield: 9%).

White crystals

TPL:168-169°C

¹H-NMR (CDCl₃) δ: 1.26 in (c, 3H), 1.57 in (c, 3H), 1,83 (user. c, 3H), 2,65 (c, 2H), 2,90-and 3.16 (m, 4H), 3,66 (d, J=10,2 Hz, 1H), 3,95 (d, J=10.5 Hz, 1H), 5,61 (users, 1H), 7,24 and 7.36 (m, 5H), 7,85 (c, 1H), 8,00 (user. c, 1H), 8,04 (c, 1H)

Mass spectrum (ESI+) m/z: 406 [M+1]⁺

Mass spectrum (ESI-) m/z: 450 [M+45]⁺(HCOOH adduct)

Example 16 synthesis

1 maleate (3R*4S*)-{3-hydroxy-2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-7-yl}ethanone

This compound was synthesized according to the method of example 12 synthesis.

(3R*,4S*)-{3-Hydroxy-2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-7-yl}alanon

To a solution of (3R*,4S*)-3-hydroxy-2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]h is the nolin-7-carbonitrile (120 mg, 0,309 mmol) in a mixture of benzene (1.6 ml) -diethyl ether (1.4 ml) was added dropwise at 0-5°C 3.0 M solution methylacrylamide in diethyl ether (0,30 ml) and the resulting mixture was stirred for 2 hours. Was added dropwise a solution of 3.0 M methylmagnesium in diethyl ether (0,50 ml) at 0-5°C and the resulting mixture was additionally stirred for 30 minutes. Upon completion of the reaction was added an aqueous solution of ammonium chloride and the resulting solution was extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate. After removal of the solvent the residue was purified column chromatography and obtained target product (yield: 25%).

¹H-NMR (CDCl₃) δ: 1,19 (c, 3H), 1,49 (c, 3H), 2,53 (d, J=0.8 Hz, 3H), was 2.76 (c, 3H), 2.77-to a 3.06 (m, 5H), 3,55 (d, J=10.5 Hz, 1H), 3,81 (DD, J=1.4 Hz, 10.5 Hz, 1H), 7,15-7,29 (m, 6H), 7,78 (c, 1H), a 7.85 (d, J=1.4 Hz, H)

Mass spectrum (ESI⁺) m/z: 405 [M+1]⁺

1 maleate (3R*,4S*)-{3-hydroxy-2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-7-yl}ethanone

To a solution of (3R*,4S*)-{3-hydroxy-2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-7-yl)ethanone (31,3 mg, 0,077 mmol) in ethyl acetate (2 ml) was added dropwise a solution of maleic acid (10.0 mg, 0,086 mmol) in ethyl acetate (2 ml) and precipitated precipitated solid was filtered, obtaining the target product (yield: 80%).

White crystals

TPL: 230-234°C (decomposition)

¹H-I Is R (DMSO-d ₆) δ: 1,18 (c, 3H)and 1.51 (c, 3H), 2,66 (c, 3H), 2,74 (c, 3H), 2,98-to 3.34 (m, 4H), 4,10 (m, 1H), 4,66 (user. c, 1H), 6,05 (c, 2H), 6,29 (user. c, 1H), 7,25 was 7.36 (m, 5H), of 7.48 (c, 1H), 7,87 (c, 1H), 8,56 (c, 1H).

Example 17 synthesis

(1S*,2R*)-3,3-Dimethyl-1-[(2-phenylethyl)amino]-2,3-dihydro-1H-pyrano[3,2-f]quinoline-2-ol

This compound was synthesized according to the method of example 12 synthesis.

(Output 2 stages 4%)

White crystals

TPL:170-171°C

¹H-NMR (CDCl₃) δ: 1,31 (c, 3H), 1,45 (c, 3H), 1,61 (user. c, 6H), 2.71 to 2,84 (m, 3H), 2.91 in-of 2.97 (m, 1H), 3,83 (d, J=5.5 Hz, 1H), 4,11 (d, J=5.5 Hz, 1H), 7,12 (d, J=7,98 Hz, 1H), 7.18 in-7,25 (m, 5H), of 7.90 (d, J=9.1 Hz, 1H), 8,15 (d, J=8.5 Hz, 1H), 8,73 (DD, J=1.4 Hz by 4.1 Hz, 1H).

Mass spectrum (ESI⁺) m/z: 349 [M+1]⁺

Mass spectrum (ESI^-) m/z: 393 [M+45]⁺(HCOOH adduct)

Epoxy-shape, with 97.1% ee; CHIRALCEL OJ-R acetonitrile/methanol/0.01 M aqueous solution of sodium chloride = 1/3/3, retention time: 7,0 minutes

Example 18 synthesis

1 maleate (3R*,4S*)-7-hydroxymethyl-2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

This compound was synthesized according to the method of example 12 synthesis.

(2,2,9-Trimethyl-2H-pyrano[2,3-g]quinoline-7-yl)acetate

To a solution of 2,2,7,9-tetramethyl-2H-pyrano[2,3-g]quinoline (3.0 g, 12.5 mmol) in chloroform (30,0 ml) was added dropwise at room temperature a solution of m-chloroperbenzoic acid (4,76 g, 27.6 mmol who) in a mixture of chloroform (12 ml)-methanol (3 ml) and the resulting mixture was stirred at room temperature for 30 minutes. Upon completion of the reaction was added to the reaction solution, an aqueous sodium thiosulfate solution and was extracted. The organic phase is washed with sodium bicarbonate, then with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After removal of the solvent the residue was added acetic anhydride (12 ml) and the resulting mixture was stirred at 150°C for 1 hour. Upon completion of the reaction, acetic angered drove away, the residue was neutralized with an aqueous solution of sodium carbonate, was extracted with chloroform, the organic phase is washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After removal of the solvent the residue was column purified by medium pressure chromatography (hexane/ethyl acetate = 2/1) and received a target product (yield: 64%).

Black oily product

¹H-NMR (CDCl₃) δ: 1.50 in (c, 6H), 2,17 (c, 3H), 2,61 (c, 3H), and 5.30 (c, 2H), 5,90 (d, J=to 9.91 Hz, 1H), to 6.57 (d, J=9.9 Hz, 1H), 7,19 (c, 1H), 7,24 (c, 1H), 7,70 (c, 1H).

Mass spectrum (ESI⁺) m/z: 298 [M+1]⁺

(3R*,4R*)-(3,4-Epoxy-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-7-yl)acetate

> 99.9% of ee; CHIRALPAKAD-RH 20 mm phosphate buffer (pH 8.0)/acetonitrile = 60/40, retention time: 5,4 minutes

Mass spectrum (ESI⁺) m/z: 314 [M+1]⁺

(3R*,4S*)-7-Hydroxymethyl-2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-ol

To a solution of (3R*4R*)-(3,4-epoxy-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-7-yl)acetate (403 mg, 1,29 mmol) in 1,4-dioxane (1 ml) was added at room temperature, lithium perchlorate (137 mg, 1,29 mmol) and 2-phenylethylamine (of € 0.195 ml, 1.55 mmol) and the resulting mixture was stirred at 70°C for 1.5 hours. After completion of the reaction to the reaction solution was added an aqueous solution of sodium bicarbonate and was extracted with him ethyl acetate. The organic phase was washed with an aqueous solution of sodium bicarbonate, then with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After removal of the solvent the residue was column purified by medium pressure chromatography (hexane/ethyl acetate = 1/1) and received a target product (yield: 32%).

¹H-NMR (CDCl₃) δ: 1,24 (c, 3H), 1.55V (c, 3H), 2,58 (c, 3H), 2,87-is 3.08 (m, 5H), 3,63 (d, J=10,2 Hz, 1H), 3,81 (d, J=10.5 Hz, 1H), 4,82 (c, 2H), 7,02 (c, 1H), 7.23 percent and 7.36 (m, 6H), 7,75 (c, 1H).

Mass spectrum (ESI⁺) m/z: 393 [M+1]⁺

Mass spectrum (ESI^-) m/z: 437 [M+45]⁺(HCOOH adduct)

1 maleate (3R*,4S*)-7-hydroxymethyl-2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

To a solution of (3R*'4S*)-7-hydroxymethyl-2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol (157 mg, 0,407 mmol) in ethyl acetate (4 ml) was added dropwise a solution of maleic acid (52 mg, 0,448 mmol) in ethyl acetate (2 ml) and precipitated precipitated solid was filtered, receiving the target compound (yield: 80%).

Pale-yellow crystals

TPL: 216-221°C

¹H-NMR (DMSO-d₆) δ: 1,17 (s, 3H), 1,50 (s, 3H), 2,60 (s, 3H), 2,98 is 3.40 (m, 4H), 4,06-4,11 (m, 1H), 3,81 (d, J=10.5 Hz, 1H), 4,66-4,69 (3H), 5,50 (user. s, 1H), the 6.06 (s, 2H), 6.30-in (user. s, 1H), 7.23 percent-to 7.35 (m, 5H), 7,40 (s, 1H), 7,47 (s, 1H), 8,35 (s, 1H).

Example 19 synthesis

1 maleate (3R*,4S*)-7-chloro-2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

This compound was synthesized according to the method of example 12 synthesis.

(3R*,4R*)-7-Chloro-3,4-epoxy-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline

(Yield: 78%)

99,1%; CHIRALCEL OJ-R acetonitrile/methanol/0.01 M aqueous solution of sodium chloride = 1/3/3, retention time: 18,9 minutes Yellow amorphous product.¹H-NMR (CDCl₃) δ: 1.28 (in c, 3H), 1,65 (c, 3H), 2,59 (d, J=0.8 Hz, 3H), 3,60 (d, J=4.4 Hz, 1H), 4,13 (d, J=4.4 Hz, 1H), 7,19 (c, 1H), 7,29 (d, 1H), 8,02 (c, 1H)

Mass spectrum (ESI⁺) m/z: 276 [M+1]⁺

1 maleate (3R*,4S*)-7-chloro-2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol (output 2 stages: 34%)

Examples of the synthesis of 20-49

Examples of the synthesis of 20-49 were performed similarly to the method of example 19 synthesis.

Connection #	optically active
Example 21 synthesis
Example 22 synthesis
Example 23 synthesis
Example 24 synthesis
Example 25 synthesis
Example 26 synthesis
Example 27 synthesis
Example 28 synthesis
Example 29 synthesis
Connection #	optically active
Example 30 synthesis
the example of the synthesis 31
Example 32 synthesis
Example 33 synthesis
Example 34 synthesis
Example 35 synthesis
Connection #	optically active
Example 36 synthesis
Example 37 synthesis
Example 38 synthesis
Example 39 synthesis
Example 40 synthesis
Example 41 synthesis
Example 42 synthesis
Connection #	optically active
Example 43 synthesis
Example 44 synthesis
Example 45 synthesis
Example 46 synthesis
Example 47 synthesis
Example 48 synthesis
Example 49 synthesis

Example 20 synthesis

(3R*,4S*)-4-(Benzylamino)-7-chloro-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

(Yield: 81 %)

Colourless amorphous product

¹H-NMR (CDCl₃) δ: 1.28 (in c, 3H), 1,58 (c, 3H), 1,60 (user. c, 1H), 2,60 (c, 3H), 3,12 (c, 1H), and 3.72 (d, J=10.3 Hz, 1H), 3,91 (d, J=10.3 Hz, 1H), 3,85 to 4, 00 (m, 2H), 7,17 (c, 1H), 7,30-7,40 (m, 6H), 8,08 (c, 1H)

Mass spectrum (ESI⁺) m/z: 383 [M+1]⁺

Mass spectrum (ESI^-) m/z: 427 [M+45]⁺(HCOOH hell is SPS)

Example 21 synthesis

(3R*,4S*)-4-{[(1,3-Benzodioxol-5-yl)methyl]amino}-7-chloro-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

(Yield: 92%)

Pale yellow amorphous product

¹H-NMR (CDCl₃) δ: 1.28 (in s, 3H), of 1.57 (s, 3H), at 2.59 (s, 3H), 3,70 (d, J=10.3 Hz, 1H), 3,82 (ABq, J=12,8 Hz, 2H), 3,97 (DD, J=10,3, 1.2 Hz, 1H), 5,96 (s, 2H), 6,77 (d, J=8.0 Hz, 1H), PC 6.82 (DD, J=8.0 a, and 1.6 Hz, 1H), 6.89 in (l, J=l,6 Hz, 1H), 7,13 (s, 1H), 7,30 (s, 1H), 8,04 (s, 1H).

Mass spectrum (ESI⁺) m/z: 427 [M+1]⁺

Example 22 synthesis

(3R*,4S*)-7-Chloro-2,2,9-trimethyl-4-[(3-phenylpropyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

(Yield: 72%)

Colourless amorphous product

¹H-NMR (CDCl₃) δ: 1.28 (in s, 3H), of 1.57 (s, 3H), 1,80-of 1.95 (m, 2H), 2,59 (s, 3H), 2,65-to 2.85 (m, 5H), 3,24 (s, 1H), 3,61 (d, J=10.4 Hz, 1H), 3,86 (d, J=10.4 Hz, 1H), 7,10-7,20 (m, 3H), 7,25-7,35 (m, 3H), 7,94 (s, 1H)

Mass spectrum (ESI⁺) m/z: 411 [M+1]⁺

Mass spectrum (ESI^-) m/z: 455 [M+45]⁺(HCOOH adduct)

Example 23 synthesis

(3R*,4S*)-7-Chloro-4-{[2-(4-forfinal)ethyl]amino}-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

(Yield: 96%)

Colourless amorphous product

¹H-NMR (CDCl₃) δ: 1,25 (s, 3H), of 1.55 (s, 3H), 1.57 in (user. s, 1H), 2,58 (s, 3H), 2,80 (t, J=6.9 Hz, 2H), 2,90-3,10 (m, 3H), to 3.58 (d, J=10.4 Hz, 1H), 3,86 (d, J=10.4 Hz, 1H), 6,95-7,05 (m, 2H), 7,15-7,20 (m, 3H), 7,26 (s, 1H), 7,89 (s, 1H)

Mass spectrum (ESI⁺) m/z: 415[M+1]⁺

Example 24 synthesis

(3R*,4S*)-7-Chloro-4-{[2-(2-forfinal)ethyl]amino}-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

(Yield: 79%)

ascutney amorphous product

¹H-NMR (CDCl₃) δ: 1,25 (s, 3H), and 1.54 (s, 3H), 1,61 (user. s, 1H), 2.57 m (s, 3H), of 2.86 (t, J=6.9 Hz, 2H), 2.95 and-3,10 (m, 3H), of 3.56 (d, J=10.4 Hz, 1H), 3,85 (d, J=10.4 Hz, 1H), 7,00-7,25 (m, 6N), of 7.90 (s, 1H)

Mass spectrum (ESI⁺) m/z: 415 [M+1]⁺

Example 25 synthesis

(3R*,4S*)-7-Chloro-4-{[2-(4-chlorophenyl)ethyl]amino}-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

(Yield: 78%)

Colourless amorphous product

Example 26 synthesis

(3R*,4S*)-4-{[2-(4-AMINOPHENYL)ethyl]amino}-7-chloro-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

(Yield: 40%)

Colourless amorphous product

¹H-NMR (CDCl₃) δ: 1,23 (c, 3H), 1.55V (c, 3H), 1,58 (user. c, 3H), 2.57 m (c, 3H), 2,71 (t, J=7.4 Hz, 2H), 2,85 was 3.05 (m, 2H), 3,11 (user. c, 1H), 3,57 (d, J=10.4 Hz, 1H), 3,84 (d, J=10.4 Hz, 1H), 6,65 (d, J=8.5 Hz, 2H), 7,01 (d, J=8.5 Hz, 2H), 7,11 (c, 1H), 7,25 (c, 1H), 7,81 (c, 1H)

Mass spectrum (ESI⁺) m/z: 412 [M+1]⁺

Mass spectrum (ESI^-) m/z: 456 [M+45]⁺(HCOOH adduct)

Example 27 synthesis

(3R*,4S*)-7-Chloro-4-[(2-hydroxy-2-phenylethyl)amino]-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

(Yield: 72%)

Colourless amorphous product

¹H-NMR (CDCl₃) δ: 1,27 (c, 1,5H), 1.28 (in c, 1,5H), and 1.56 (c, 3H), 1.77 in (user. c, 2H), 2.57 m (c, 3H), 2,85 is 3.15 (m, 2H), 3,68 (d, J=10,2 Hz, 1H, in), 3.75 (d, J=10,2 Hz, 1H), 4.75 V-is 4.85 (m, 1H), 7,25 (c, 1H), 7,27-7,40 (c, 6H), 7,99 (c, 0,5H), 8,00 (c, 0,5H)

Mass spectrum (ESI⁺) m/z: 413 [M+1]⁺

Mass spectrum (ESI^-) m/z: 457 [M+45]⁺(HCOOH adduct)

Example 28 synthesis

(3R*,4S*)-7-Chloro-2,2,9-trimethyl-4-[(2-phenylbutyl)amino]-3,4-dihydro-2H-feast is about[2,3-g]quinoline-3-ol

(Yield: 50%)

Pale brown amorphous product

¹H-NMR (CDCl₃) δ: 0,86 (t, J=7,3 Hz, 3H), 1,20 (c, 3H), 1,53 (c, 3H), 1,51-1,71 (m, 2H), 2.57 m (c, 3H), 2.57 m-of 2.64 (m,1H), 2,86 (DD, J=11,6, and 9.1 Hz, 1H), 2,86 (DD, J=11,6, 5,2 Hz, 1H), 3,55 (d, J=10,2 Hz, 1H), 3,74 (d, J=10,2 Hz, 1H), 7,15 (c,1H), 7,20-to 7.32 (m, 4H), 7,35-7,41 (m, 2H), 7,74 (c, 1H)

Mass spectrum (ESI⁺) m/z: 425 [M+1]⁺

Example 29 synthesis

(3R*,4S*)-4-{[2-(1,3-Benzodioxol-5-yl)ethyl]amino}-7-chloro-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

(Yield: 62%)

Pale brown amorphous product

¹H-NMR (CDCl₃) δ: 1.26 in (c, 3H), and 1.56 (c, 3H), 1,66 (user., 1H), 2.57 m (c, 3H), 2,74 (t, J=6.9 Hz, 2H), 2,89-3,00 (m, 2H), 3,1 (user., 1H), 3,60 (d, J=10.4 Hz, 1H), 3,86 (d, J=10.4 Hz, 1H), 5,95 (AB Quartet, 2H), 6,66-6,77 (m, 3H), 7,15 (c, 1H), 7,26 (c, 1H), 7,83 (c, 1H)

Mass spectrum (ESI⁺) m/z: 441 [M+1]⁺

Example 30 synthesis

(3R*,4S*)-7-Chloro-2,2,9-trimethyl-4-{[2-(1-piperidinyl)ethyl]amino}-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

(Yield: 61 %)

Pale yellow amorphous product

¹H-NMR (CDCl₃) δ: 1,29 (c, 3H), 1,58 (c, 3H), 1,60 (user. c, 2H), 1,50-1,70 (m, 6H), 2,30-2,60 (m, 6H), 2,58 (c, 3H), 3,06 (t, J=5.8 Hz, 2H), 3,54 (d, J=10.4 Hz, 1H), 3,80 (d, J=10.4 Hz, 1H), 7,13 (c, 1H), 7.23 percent (c, 1H), 8,06 (c, 1H)

Mass spectrum (ESI⁺) m/z: 404 [M+1]⁺

Mass spectrum (ESI^-) m/z: 448 [M+45]⁺(HCOOH adduct)

Example 31 synthesis

(3R*,4S*)-7-Chloro-2,2,9-trimethyl-4-{[2-(1-methyl-2-pyrrolidinyl)ethyl]amino}-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

(Yield: 55%)

Colourless amorphous product

¹H-NMR (CDCl₃) δ: 129 (c, 3H), 1,58 (c, 3H), 1,49 is 2.00 (m, 8H), 2,10-of 2.25 (m, 2H), 2,34 (c, 1,5H), 2,35 (c, 1,5H), 2,58 (c, 3H), 2,65-to 2.85 (m, 2H), 3.00 and is 3.15 (m, 1H), 3,62 (d, J=10.4 Hz, 0,5H), 3,70 (d, J=10.4 Hz, 0,5H), 3,85 (d, J=10.4 Hz, 0,5H), 3,88 (d, J=10.4 Hz, 0,5H), 7,15 (c, 1H), 7,27 (c, 1H), of 7.96 (c, 1H)

Mass spectrum (ESI⁺) m/z: 404 [M+1]⁺

Mass spectrum (ESI^-) m/z: 448 [M+45]⁺(HCOOH adduct)

Example 32 synthesis

(3R*,4S*)-4-[(2-Anilinomethyl)amino]-7-chloro-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

(Yield: 78%)

Pale yellow amorphous product

¹H-NMR (CDCl₃) δ: 1,27 (c, 3H), and 1.56 (c, 3H), 1.77 in (users, 3H), 2,58 (c, 3H), 2.95 and-3,10 (m, 2H), 3,30 (t, J=5.5 Hz, 2H), 3,64 (d, J=10,2 Hz, 1H), 3,93 (d, J=10,2 Hz, 1H), 6,65-to 6.80 (m, 3H), 7,15-7,20 (m, 3H), 7,28 (c, 1H), 7,98 (c, 1H)

Mass spectrum (ESI⁺) m/z: 412 [M+1]⁺

Mass spectrum (ESI^-) m/z: 456 [M+45]⁺(HCOOH adduct)

Example 33 synthesis

(3R*,4S*)-7-Chloro-4-({2-[ethyl(3-were)amino]ethyl}amino)-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

(Yield: 90%)

Pale yellow amorphous product

¹H-NMR (CDCl₃) δ: of 1.23 (t, J=6.9 Hz, 3H), 1.26 in (s, 3H), of 1.55 (s, 3H), 1,62 (user. s, 1H), and 2.27 (s, 3H), 2.57 m (s, 3H), 2,80-3,00 (m, 2H), 3,30-to 3.50 (m, 5H), 3,61 (d, J=10.1 Hz, 1H), 3,91 (d, J=10.1 Hz, 1H), 6,60-6,70 (m, 4H), 7,05-to 7.15 (m, 2H), of 7.96 (s, 1H)

Mass spectrum (ESI⁺) m/z: 454 [M+1]⁺

Mass spectrum (ESI^-) m/z: 498 [M+45]⁺(HCOOH adduct)

Example 34 synthesis

(3R*,4S*)-7-Chloro-2,2,9-trimethyl-4-{[1-ethyl-(R)-2-pyrrolidinyl)methyl]amino}-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

(Yield: 93%)

Pale yellow amorphous product</>

¹H-NMR (CDCl₃) δ: 1,27 (s, 1H), 1,32 (t, J=7,1 Hz, 2H), and 1.56 (s, 3H), 1,95-2,12 (user., 4H), of 2.56 (s, 3H), 2.71 to 2,81 (user., 2H), 2,98-3,37 (m, 4H), 3,64-4,01 (m, 5H), 7,12 (s, 1H), 7,22 (s, 1H), 8,01 (s, 1H)

Mass spectrum (ESI⁺) m/z: 405 [M+1]⁺

Mass spectrum (ESI⁺) m/z: 448 [M+45]⁺(HCOOH adduct)

Example 35 synthesis

1-maleate (3R*,4S*)-7-chloro-4-[(2,2-diatexite)amino]-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

(Yield: 88%)

White solid

¹H-NMR (CDCl₃) δ: 1,23-of 1.30 (m, N), of 1.57 (s, 3H), of 2.64 (s, 3H), 3,50-of 3.85 (m, 4H), was 4.02 (d, J=10,2 Hz, 1H), 6,27 (s, 1H), 7,37 (s, 1H), 7,49 (s, 1H), 8,13 (s, 1H)

Free form

(3R*,4S*)-7-chloro-2,2,9-trimethyl-4-[(2,2-diatexite)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

Pale yellow amorphous product

Mass spectrum (ESI⁺) m/z: 410 [M+1]⁺

Mass spectrum (ESI^-) m/z: 453 [M+45]⁺(HCOOH adduct)

Example 36 synthesis

(3R*,4S*)-7-Chloro-2,2,9-trimethyl-4-{[2-(3-thienyl)ethyl]amino}-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

(Yield: 57%)

Pale yellow amorphous product

¹H-NMR (CDCl₃) δ: 1,24 (s, 3H), of 1.55 (s, 3H), of 2.56 (s, 3H), 2,84 (t, J=6,8 Hz, 2H), 2,90-to 3.09 (m, 2H), 3,60 (d, J=10.5 Hz, 1H), 3,86 (d, J=10.5 Hz, 1H), 6,94-7, 01 (m, 2H), 7,13 (s, 1H), 7.24 to 7,29 (m, 2H), 7,89 (s, 1H)

Mass spectrum (ESI⁺) m/z: 404 [M+1]⁺

Mass spectrum (ESI^-) m/z: 447 [M+45]⁺(HCOOH adduct)

Example 37 synthesis

(3R*,43*)-4-[2-(1H-Pyrazole-1-yl)ethylamino]-7-chloro-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

(Yield: 59%)

Pale yellow amorphous product

¹H-NMR (CDCl₃) δ: 1.28 (in s, 3H), 1,58 (s, 3H), 1,86 (user. s, 1H), 2.57 m (c, 3H), 3,26-of 3.31 (m, 2H), 3,63 (d, J=10.1 Hz, 1H), a 3.87 (d, J=10.1 Hz, 1H), 4,24-4,32 (m, 2H), 5,00 (user. c, 1H), 6,32 (DD, J=1,7, and 3.4 Hz, 1H), 7,14 (c, 1H), 7,25 (c, 1H), 7,45 (d, J=1.7 Hz, 1H), 7,58 (d, J=1.7 Hz, 1H), 8,00 (c, 1H)

Mass spectrum (ESI⁺) m/z: 387 [M+1]⁺

Example 38 synthesis

(3R*,4S*)-7-Chloro-2,2,9-trimethyl-4-{[2-(4-methylpyrazole-1-yl)ethyl]amino}-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

(Yield: 70%)

Colourless amorphous product

¹H-NMR (CDCl₃) δ: 1.28 (in c, 3H), 1,58 (c, 3H), 2.00 (evens users, 1H), 2,10 (c, 3H), 2.57 m (c, 3H), 3,16-of 3.31 (m, 2H), 3,64 (d, J=10,2 Hz, 1H), a 3.87 (d, J=10,2 Hz, 1H), 4,11-4,30 (m, 2H), 5,20 (users, 1H), 7,13 (c, 1H), 7,21 (c, 1H), 7,24 (c, 1H), was 7.36 (c, 1H), 7,98 (c, 1H)

Mass spectrum (ESI⁺) m/z: 401 [M+1]⁺

Example 39 synthesis

(3R*,4S*)-7-Chloro-4-{[2-(4-chloropyrazole-1-yl)ethyl]amino}-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

(Yield: 89%)

Pale yellow amorphous product

¹H-NMR (CDCl₃) δ: 1.28 (in c, 3H), 1,58 (c, 3H), 1,84 (users, 1H), 2,58 (c, 3H), 3,26-3,29 (m, 2H), 3,61 (d, J=10.4 Hz, 1H), a 3.87 (d, J=10.4 Hz, 1H), 4,16-the 4.29 (m, 2H), 4,51 (users, 1H), 7,15 (c, 1H), 7,26 (c, 1H), 7,45 (c, 1H), of 7.48 (c, 1H), 7,97 (c, 1H)

Mass spectrum (ESI⁺) m/z: 421 [M+1]⁺

Example 40 synthesis

(3R*,4S*)-7-Chloro-2,2,9-trimethyl-4-{[2-(2-pyridyl)ethyl]amino}-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

(Yield: 83%)

Yellow amorphous product

¹H-NMR (CDCl₃) δ: 1.32 to (c, 3H), 1.61 of (c, 3H), 1,82 (users, 1H), 2.57 m (c, 3H), 2,92-of 3.12 (m, 2H), 3,26-3,30 (m, 2H), 3,74 (d, J=10,2 Hz, 1H), 3,92 (d, J=10,2 Hz, 1H), 7,13 (c, 1H), 7,17-7,27 (m, 3H), of 7.64-of 7.70 (m, 1H), 8,06 (c, 1H), 8,56 (d, J=5.0 Hz, 1H)

Mass spectrum (ESI⁺) m/z: 398 [M+1]⁺

Example 41 synthesis

(3R*,4S*)-7-Chloro-2,2,9-trimethyl-4-{[2-(3-pyridyl)ethyl]amino}-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

(Yield: 61%)

Brown amorphous product

¹H-NMR (CDCl₃) δ: 1.26 in (c, 3H), 1.55V (c, 3H), 1,73 (users, 1H), 2,58 (c, 3H), 2,80-to 2.85 (m, 2H), 2,92-of 3.07 (m, 2H), 3,23 (users, 1H), 3,61 (d, J=10.4 Hz, 1H), 3,89 (d, J=10.4 Hz, 1H), 7,16 (c, 1H), 7,22-7,27 (m, 2H), 7,55 (d, J=7.7 Hz, 1H), 7,93 (c, 1H), of 8.47-8,48 (m, 2H)

Mass spectrum (ESI⁺) m/z: 398 [M+1]⁺

Example 42 synthesis

(3R*,4S*)-7-Chloro-2,2,9-trimethyl-4-{[2-(4-pyridyl)ethyl]amino}-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

(Yield: 47%)

Pale brown amorphous product

¹H-NMR (CDCl₃) δ: 1.26 in (c, 3H), 1.55V (c, 3H), 1,89 (users, 1H), 2,58 (c, 3H), 2,80-to 2.85 (m, 2H), 2,94-3,11 (m, 2H), 3,60 (users, 1H), 3,63 (d, J=10.4 Hz, 1H), 3,90 (d, J=10.4 Hz, 1H), 7,15 (d, J=5.7 Hz, 1H), 7,16 (c, 1H), 7,27 (c, 1H), of 7.96 (c, 1H), of 8.47 (d, J=5.7 Hz, 2H)

Mass spectrum (ESI⁺) m/z: 398 [M+1]⁺

Example 43 synthesis

(3R*,4S*)-7-Chloro-4-ethylamino-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

(Yield: 95%)

Pale yellow amorphous product

¹H-NMR (CDCl₃) δ: of 1.18 (t, J=7,1 Hz, 3H), 1,29 (c, 3H), 1,58 (c, 3H), 2,58 (c, 3H), 2,68-only 2.91 (m, 2H), 3,63 (d, J=10.4 Hz, 1H), a 3.87 (DD, J=10,4, 1.2 Hz, 1H), 7,15 (d, J=1.1 Hz, 1H), 7,27 (c, 1H), to 7.93 (d, J=1.1 Hz, 1H)

Mass spectrum (ESI⁺) m/z: 321 [M+1]⁺

Example 44 synthesis

(3R*,4S*)-7-Chloro-4-isobutylamino-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-on the Sabbath.

(Yield: 96%)

Pale brown amorphous product

¹H-NMR (CDCl₃) δ: of 0.94-0.98 (m, 6H), 1,29 (c, 3H), 1,58 (c, 3H), by 1.68 to 1.76 (m, 1H), 2,50-2,62 (m, 2H), 2,58 (c, 3H), 3,36 (users, 1H), 3,63 (d, J=10,2 Hz, 1H), 3,88 (DD, J=10,2, 1.1 Hz, 1H), 7,15 (c, 1H), 7,28 (c, 1H), 7,93 (c, 1H)

Mass spectrum (ESI⁺) m/z: 239 [M+1]⁺

Example 45 synthesis

(3R*,4S*)-7-Chloro-4-[(cyclopropylmethyl)amino]-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

(Yield: 85%)

Pale brown amorphous product

¹H-NMR (CDCl₃) δ: 0,13-0,20 (m, 2H), 0,48-of 0.54 (m, 2H), 0,95-1,01 (m, 1H), 1,29 (c, 3H), 1,58 (c, 3H), 1,8 (user. c, 1H), 2,53 (m, 1H), 2,58 (c, 3H), 2,70 (m, 1H), 3,63 (d, J=10.4 Hz, 1H), 3,91 (d, J=10.4 Hz, 1H), 7,15 (c, 1H), 7,27 (c, 1H), of 7.90 (c, 1H)

Mass spectrum (ESI⁺) m/z: 347 [M+1]⁺

Example 46 synthesis

(3R*,4S*)-7-Chloro-4-isobutylamino-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

(Yield: 64%)

Pale yellow amorphous product

¹H-NMR (CDCl₃) δ: from 0.90 (d, 6H), 1,29 (c, 3H), 1,39-1, 46 (m, 2H), 1,58 (c, 3H), 1,62-of 1.74 (m, 2H), 2,58 (c, 3H), 2,64-to 2.85 (m, 2H), 3,64 (d, J=10.4 Hz, 1H), a 3.87 (d, J=10.4 Hz, 1H), 7,15 (c, 1H), 7,28 (c, 1H), 7,93 (c, 1H)

Mass spectrum (ESI⁺) m/z: 363 [M+1]⁺

Example 47 synthesis

(3R*,4S*)-7-Chloro-4-[2-(cyclopentylmethyl)amino]-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

(Yield: 78%)

Pale yellow solid

¹H-NMR (CDCl₃) δ: 1,08-1,11 (m, 2H), 1,29 (c, 3H), 1,49-of 1.62 (m, 6H), and 1.54 (c, 3H), 1,71 of-1.83 (m, 3H), 2,58(c, 3H), 2,67-2,82 (m, 2H), 3,63 (d, J=10.4 Hz, 1H), 3,86 (d, J=10.4 Hz, 1H), 7,15 (c, 1H), 7,27 (c, 1H), 7,93 (c, 1H)

Mass spectrum (ESI⁺)m/z: 389 [M+1] ⁺

Example 48 synthesis

(3R*,4S*)-7-Chloro-4-{[2-(1-cyclopentenyl)ethyl]amino]}-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

(Yield: 70%)

Pale brown amorphous product

¹H-NMR (CDCl₃) δ: 1.28 (in c, 3H), 1,58 (c, 3H), 1,86-of 1.94 (m, 2H), 2,22-of 2.34 (m, 7H), 2,58 (c, 3H), 2,79-2,96 (m, 2H), 3,63 (d, J=10.5 Hz, 1H), a 3.87 (DD, J=10,5, 1.2 Hz, 1H), 5,44 (c, 1H), 7,15 (c, 1H), 7,27 (c, 1H), 7,92 (c, 1H)

Mass spectrum (ESI⁺) m/z: 387 [M+1]⁺

Example 49 synthesis

(3R*,4S*)-7-Chloro-2,2,9-trimethyl-4-[(5-methylhexan-2-yl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

(Yield: 83%)

Pale yellow amorphous product

¹H-NMR (CDCl₃) δ: 0,91 (DD, J=6,6 Hz, 9.6 Hz, 6H), of 1.13 to 1.34 (m, 9H), 1.56 to (c, 6H), 2.57 m (c, 3H), 3,22-3,44 (m, 2H), 3,80-3,85 (users, 1H), 7,14 (c, 1H), 7,26 (c, 1H), of 7.96-7,98 (user. c, 1H)

Mass spectrum (ESI⁺) m/z: 392 [M+2]⁺

Mass spectrum (ESI^-) m/z: 435 [M+45]⁺(HCOOH adduct)

Example of synthesis 50

1 maleate (3S*,4R*)-7-chloro-2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

This compound was synthesized using the enantiomer Ph,Ph sleevage complex of manganese (XX) (hereinafter referred to as ent-Ph,Ph selenoviy complex of manganese).

(3S*,4S*)-7-Chloro-3,4-epoxy-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline

To a solution of 7-chloro-2,2,9-trimethyl-2H-pyrano[2,3-g]quinoline (200 mg, 0.77 mmol) in ethyl acetate (3.0 ml) was added at room temperature N-marked idazole (0,012 ml, 0,154 mmol) and ent-Ph,Ph selenoviy complex of manganese (8.0 mg, 0,0077 mmol) was added dropwise an aqueous solution of sodium hypochlorite (1.0 g, 1,513 mol/kg, 1.54 mmol) and the resulting mixture was stirred for 40 minutes. Was added dropwise an aqueous solution of sodium hypochlorite (1.0 g, 1,513 mol/kg, 1.54 mmol) and the resulting mixture was further stirred at room temperature for 30 minutes. Upon completion of the reaction was added to the reaction solution, an aqueous sodium thiosulfate solution, the resulting solution was filtered through celite and extracted. The organic phase was washed with an aqueous solution of sodium bicarbonate, then with an aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. After removal of the solvent the residue was purified column chromatography (hexane/ethyl acetate = 10/1)to give (3S*,4S*)-7-chloro-3,4-epoxy-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline (yield: 94%).

>99.9% of ee; CHIRALCEL OJ-R acetonitrile/methanol/0.01 M aqueous solution of sodium chloride = 1/3/3, retention time: 44,3 minutes

1 maleate (3S*,4R*)-7-chloro-2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

To a solution of (3S*,4S*)-7-chloro-3,4-epoxy-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline (199 mg, to 0.72 mmol) in 1,4-dioxane (0.4 ml) was added at room temperature, lithium perchlorate (77.0 mg, to 0.72 mmol) and 2-phenylethylamine (of 0.11 ml, 0.87 mmol) and the resulting mixture was stirred at 0°C for 3 hours. Upon completion of the reaction was added to the reaction solution, an aqueous solution of sodium bicarbonate, extracted it with ethyl acetate, the organic phase is washed with an aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. After removal of the solvent the residue was column purified by medium pressure chromatography (hexane/ethyl acetate = 3/1). Next, after removal of the solvent was added ethyl acetate (2 ml) was added dropwise a solution of maleic acid (50,3 mg, 0.43 mmol) in ethyl acetate (2 ml). Precipitated precipitated solid was filtered, receiving 1 maleate (3S*,4R*)-7-chloro-2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol (yield: 41%).

White crystals

TPL: 240-242°C

¹H-NMR (DMSO-d₆) δ: 1,18 (s, 3H), 1,50 (s, 3H), 2,60 (s, 3H), 2,97-of 3.32 (m, 4H), Android 4.04-4.09 to (m, 1H)and 4.65 (d, J=9, 6 Hz, 1H), equal to 6.05 (s, 2H), 6,29 (user. s, 1H), 7.23 percent-to 7.35 (m, 5H), 7,44 (s, 2H), 8,32 (s, 1H)

Mass spectrum (ESI⁺) m/z: 397 [M+1]⁺

Mass spectrum (ESI^-) m/z: 441 [M+45]⁺(HCOOH adduct)

Example 51 synthesis

1 maleate (3S*4R*)-2,2,7,9-tetramethyl-4-[(2-phenethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

This compound was synthesized according to the method of synthesis example 50.

(Output 2 stages: 25%)

Epoxide of 99.1% EE, CHIRALPAK AD-RH 20 mm phosphate buffer (pH 8.0)/acetonitrile 60/40, retention time: 10,3 minutes

the white crystals

TPL: 215-216°C (decomposition)

¹H-NMR (DMSO-d₆) δ: 1,16 (s, 3H), 1,49 (s, 3H), by 2.55 (s, 3H), 2,58 (s, 3H), 2,97-of 3.32 (m, 4H), was 4.02-Android 4.04 (m, 1H), 4,62 (user. s, 1H), 6,04 (s, 2H), 6,25 (user. s, 1H), 7,24 and 7.36 (m, 7H), 8,31 (s, 1H)

Mass spectrum (ESI⁺) m/z: 377 [M+1]⁺

Example 52 synthesis

Hydrochloride, (3R*,4S*)-7-chloro-2,2,9-trimethyl-4-pentylamine-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

(3R*,4S*)-4-Amino-7-chloro-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

To a solution of (3R*,4R*)-7-chloro-3,4-epoxy-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline (2.0 g, of 7.25 mmol) in ethanol (20 ml) was added aqueous ammonia (10 ml) and the resulting mixture was stirred in a sealed tube at 90°C for 3 hours. Upon completion of the reaction, the reaction solution was concentrated and added to it the ethyl acetate. The resulting solution was washed with water and then saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated. The resulting mixture was purified column chromatography on silica gel (hexane/ethyl acetate= 1/2)to give the target product (yield: 86%).

White crystals

¹H-NMR (CDCl₃) δ: 1.30 on (c, 3H), 1,58 (c, 3H), 1,67 (user. c, 2H), 2,59 (c, 3H), 3,28 (user. c, 1H), 3.45 points (d, J=10.4 Hz, 1H), 3,85 (d, J=10.4 Hz, 1H), 7,15 (c, 1H), 7,26 (c, 1H), 8,02 (c, 1H)

(3R*,4S*)-7-Chloro-2,2,9-trimethyl-4-pentylamine-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

To a solution of (R*,4S*)-4-amino-7-chloro-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol (60 mg, 0,205 mmol) in methanol (1.2 ml) was added butyl aldehyde (35 mg, 0,041 mmol) and the resulting mixture was stirred at room temperature for 20 minutes. Was added to the mixture cyanoborohydride sodium (52 mg, 0.82 mmol) and the resulting mixture was stirred at room temperature for 1 hour. Upon completion of the reaction was added to a mixture of saturated aqueous sodium hydrogen carbonate solution, the resulting solution was extracted with ethyl acetate, washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated. The resulting mixture was purified column chromatography on silica gel (hexane/ethyl acetate = 3/1)to give the target product (yield: 41%).

Colourless amorphous product

¹H-NMR (CDCl₃) δ: from 0.90 (t, J=6.9 Hz, 3H), 1,29 (c, 3H), 1,20-of 1.45 (m, 4H), 1,55-1,70 (m, 4H), 2,58 (c, 3H), 2,60-2,82 (m, 2H), 3,63 (d, J=10.4 Hz, 1H), 3,86 (d, J=10.4 Hz, 1H), 7,15 (c, 1H), 7,28 (c, 1H), 7,93 (c, 1H)

Mass spectrum (ESI⁺) m/z: 363 [M+1]⁺

Mass spectrum (ESI^-) m/z: 407 [M+45]⁺(HCOOH adduct)

Hydrochloride, (3R*,4S*)-7-chloro-2,2,9-trimethyl-4-pentylamine-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

To a solution of (3R*,4S*)-7-chloro-2,2,9-trimethyl-4-pentylamine-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol (28 mg, 0.77 mmol) in a simple ether (560 ml) was added dropwise 4 M solution of hydrogen chloride in a simple ether (56 μl) and the resulting mixture was stirred at 0°C for 15 minutes. The solid product was filtered, amywali with ether, and dried, receiving target product (yield: 88%).

Colourless crystals

TPL: 291-294°C (decomposition)

Examples of syntheses 53-57

Connection examples of syntheses 53-57 were synthesized according to the method of example 52 synthesis.

Connection #	-optically active
Example 53 synthesis
Example 54 synthesis
Example 55 synthesis
Example 56 synthesis
Example 57 synthesis

Example 53 synthesis

Hydrochloride, (3R*,4S*)-7-chloro-4-[(2-cyclohexylethyl)amino]-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

Free form

(3R*,4S*)-7-Chloro-4-[(2-cyclohexylethyl)amino]-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

(Yield: 31%)

Colourless amorphous product

¹H-NMR (CDCl₃) δ: 0,90-1,00 (m, 2H), 1,05-1,25 (m, 6H), 1,29 (c, 3H), 1,58 (c, 3H) 1,60-1,70 (m, H), 2,58 (c, 3H), of 2,75 2,85 (m, 2H), 3,63 (d, J=10.4 Hz, 1H), 3,86 (d, J=10.4 Hz, 1H), 7,15 (c, 1H), 7,27 (c, 1H), 7,93 (c, 1H)

Hydrochloride

Hydrochloride, (3R*,4S*)-7-chloro-4-[(2-cyclohexylethyl)amino]-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

(Yield: 76%)

Colourless crystals

TPL:294-295°C (decomposition)

Mass spectrum (ESI⁺) m/z: 403 [M+1]⁺

Mass spectrum (ESI^-) m/z: 447 [M+45]⁺(HCOOH adduct)

Example 54 synthesis

Hydrochloride, (3R*,4S*)-7-chloro-4-[{2-(tetrahydropyran-4-yl)ethyl}amino]-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

Free form

(3R*,4S*)-7-Chloro-4-[{2-(tetrahydropyran-4-yl)ethyl}amino]-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

(Yield: 65%)

Colourless amorphous product

¹H-NMR (CDCl₃) δ: 1,29 (s, 3H), 1,20-1,40 (m, 4H), 1,58 (s, 3H), 1,50-1,80 (m, 4H), at 2.59 (s, 3H), 2,65-2,90 (s, 2H), 3,20-3,40 (m, 3H), of 3.64 (d, J=10.4 Hz, 1H), 3,70 of 3.75 (m, 1H), 3,85 (d, J=10.4 Hz, 1H), 3,80-4,00 (m, 3H), 7,16 (s, 1H), 7,28 (s, 1H), 7,92 (s, 1H)

Mass spectrum (ESI⁺) m/z: 405 [M+1]⁺

Mass spectrum (ESI^-) m/z: 449[M+45]⁺(HCOOH adduct)

Hydrochloride

Hydrochloride, (3R*,4S*)-7-chloro-4-[{2-(tetrahydropyran-4-yl)ethyl}amino]-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

(Yield: 72%)

Colourless crystals

TPL: 318-320°C (decomposition)

Example 55 synthesis

(3R*,4S*)-7-Chloro-2,2,9-trimethyl-4-{[2-(4-tanil)ethyl]amino}-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

(Output; 63%)

Colourless amorphous product

¹H-NMR (CDCl ₃) δ: 1.28 (in s, 3H), 1,40-1,60 (m, 5H), and 1.56 (s, 1H), 1,90-2,00 (m, 2H), 2,59 (s, 3H), 2,50-to 2.85 (m, 6N), 3,23 (s, 1H), 3,63 (d, J=10.4 Hz, 1H), a 3.87 (d, J=10.4 Hz, 1H), 7,16 (s, 1H), 7,28 (s, 1H), to $ 7.91 (s, 1H)

Mass spectrum (ESI⁺) m/z: 421 [M+1]⁺

Mass spectrum (ESI^-) m/z: 465 [M+45]⁺(HCOOH adduct)

Example 56 synthesis

Hydrochloride, (3R*,4S*)-7-chloro-4-({[6-(4-chlorophenyl)-3-pyridinyl]methyl}amino)-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

Free form

(3R*,4S*)-7-Chloro-4-({[6-(4-chlorophenyl)-3-pyridinyl]methyl}amino)-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

(Yield: 16%)

¹H-NMR (CDCl₃) δ: 1.30 on (c, 3H), 1,59 (c, 3H), 1,60 (user. c, 1H), 2,60 (c, 3H), 2,98 (c, 1H), 3.75 to 4,10 (m, 4H), 7,19 (c, 1H), 7,34 (c, 1H), 7,45 (d, J=8,8 Hz, 2H), 7,71 (d, J=9.0 Hz, 1H), 7,80 (DD, J=9,0, 2.2 Hz, 1H), of 7.96 (d, J=8,8 Hz, 2H), 8,09 (c, 1H), 8,66 (d, J=2.2 Hz, 1H)

Mass spectrum (ESI⁺) m/z: 494 [M+1]⁺

Mass spectrum (ESI^-) m/z: 538 [M+45]⁺(HCOOH adduct)

Hydrochloride

Hydrochloride, (3R*,4S*)-7-chloro-4-({[6-(4-chlorophenyl)-3-pyridinyl]methyl}amino)-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

(Yield: 67%)

Pale yellow solid

Example 57 synthesis

(3R*,4S*)-4-[(2-Benzofuranyl)amino]-7-chloro-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

(Yield: 74%)

Colourless amorphous product

¹H-NMR (CDCl₃) δ: 1.28 (in c, 3H), 1,58 (c, 3H), 2,0 (OSiR.), 2,59 (c, 3H), 3,35 (user.,1H, in), 3.75 (d, J=10,2 Hz, 1H), Android 4.04 (DD, J=10,2, 1.1 Hz, 1H), 4,06 (c, 2H), 6,60 (c, 1H), 7,16 (c, 1H), 7.18 in-7,27 (m, 2H), 7,30 (c, 1H), 7,46 (d, J=8,3 Hz, 1H), 7,49-7,52 (m, 1), 8,08 (d, J=1.1 Hz, 1H)

Mass spectrum (ESI⁺) m/z: 423 [M+1]⁺

Example 58 synthesis

(3R*,4S*)-7-Chloro-4-[(2-hydroxyphenyl)amino]-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

In a stream of nitrogen 1,2-epoxybutane (71 μl, 0,682 mmol) was added to a solution of (3R*,4S*)-4-amino-7-chloro-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol (100 mg, 0,343 mmol) and lithium perchlorate (36 mg, 0,343 mmol) in dioxane (0,50 ml) at room temperature and the resulting mixture was stirred at 70°C for 25 hours. Upon completion of the reaction, to the mixture was added ethyl acetate, the resulting reaction solution was washed with saturated aqueous solution of sodium bicarbonate and then saturated aqueous sodium chloride, then dried over magnesium sulfate and concentrated. The resulting mixture was purified column chromatography on silica gel (hexane/ethyl acetate = 1/1)to give the target product (yield: 59%).

Pale yellow amorphous product

¹H-NMR (CDCl₃) δ: 0,93 (t, J=6.9 Hz, 3H), 1.28 (in s, 3H), 1,30-1,50 (m, 4H), of 1.57 (s, 3H), 1.91 a (user. s, 3H), at 2.59 (s, 3H), 2,60-2,70 (m, 1H), 2,85-3,00 (m, 1H), 3,60 of 3.75 (m, 2H), 3,90-4,00 (m, 1H), 7,16 (s, 1H), 7,28 (s, 1H), 7,99 (s, 0,5H), 8,00 (s, 0,5N)

Mass spectrum (ESI⁺) m/z: 379 [M+1]⁺

Mass spectrum (ESI^-) m/z: 423 [M+45]⁺(HCOOH adduct)

Example 59 synthesis

1 maleate (8R*,9S*)-7,7-dimethyl-9-[(2-phenylethyl)amino] - 8.9bn-dihydro-7H-pyrano[2,3-g]cinoxacin-8-ol

(3R*,43*)-6,7-Diamino-3,4-dihydro-2,2-dimethyl-4-(2-phenylethylamine)-2H-1-benzopyran-3-ol

In a stream of hydrogen at 1 atmosphere, a solution of (3R*4S*)-6-amino-3,4-dihydro-2,2-dimethyl-7-nitro-4-(2-phenylethylamine)-2H-benzopyran-3-ol (10.0 g, of 28.0 mmol) and 5% palladium-on-coal (type AER, 1 g) in ethanol (200 ml) was stirred at room temperature for 6 hours. Upon completion of the reaction, the reaction solution was filtered through celite and concentrated, obtaining the target product (yield: 98%).

Black amorphous product

¹H-NMR (CDCl₃) δ: 1,13 (s, 3H), USD 1.43 (s, 3H), 2,60-3,00 (m, 4H), 2,5-3,5 (user., 6N), 3,47 (d, J=9, 6 Hz, 1H), 3,51 (d, J=9.6 Hz, 1H), 6,12 (s, 1H), 6,14 (s, 1H), 7,15-to 7.50 (m, 5H)

Mass spectrum (ESI) m/z: 400 [M+1]⁺, 327 (bp).

(8R*,9S*)-7,7-Dimethyl-9-[(2-phenylethyl)amino] - 8.9bn-dihydro-7H-pyrano[2,3-g]cinoxacin-8-ol

To a solution of (3R*,4S*)-6,7-diamino-3,4-dihydro-2,2-dimethyl-4-(2-phenylethylamine)-2H-benzopyran-3-ol (1.5 g, 4,58 mmol) in ethanol (30 ml) was added 40% aqueous solution of glyoxal (997 mg, 6,87 mmol) and the resulting mixture was stirred at room temperature for 30 minutes. Upon completion of the reaction, to the mixture was added ethyl acetate, the resulting solution was washed with saturated aqueous solution of sodium bicarbonate and then saturated aqueous sodium chloride, then dried over magnesium sulfate and concentrated. The resulting mixture was purified colonoscopy because it allows the Noah chromatography on silica gel (hexane/ethyl acetate = 1/1), receiving target product (yield: 74%).

¹H-NMR (CDCl₃) δ: 1.26 in (s, 3H), and 1.56 (s, 3H), 1,60 (user. s, 1H), 2,86 (t, J=6,9 Hz, 1H), 2,90-3,10 (m, 3H), 3,62 (d, J=10.4 Hz, 1H), 3,90 (d, J=10.4 Hz, 1H), 7.24 to 7,40 (m, 5H), 7,42 (s, 1H), 7,94 (s, 1H), with 8.05 (d, J=l,7 Hz, 1H), 8,72 (d, J=1.7 Hz, 1H)

Mass spectrum (ESI⁺) m/z: 350 [M+l]⁺

Mass spectrum (ESI^-) m/z: 349 [M-1]⁺

1 maleate (8R*,9S*)-7,7-dimethyl-9-[(2-phenylethyl)amino] - 8.9bn-dihydro-7H-pyrano[2,3-g]cinoxacin-8-ol

To a solution of (8R*,9S*)-7,7-dimethyl-9-[(2-phenylethyl)amino] - 8.9bn-dihydro-7H-pyrano[2,3-g]cinoxacin-8-ol (1.18 g, to 3.38 mmol) in ethyl acetate (22 ml) was added at room temperature maleic acid (471 mg, 4,06 mmol) and the resulting mixture was stirred for 10 minutes. Upon completion of the reaction, the solid product was filtered, washed with ethyl acetate and dried, obtaining the target product (yield: 61%).

Light gray crystals

TPL: 176-179°C (decomposition)

¹H-NMR (DMSO-d₆) δ: 1,20 (s, 3H), of 1.52 (s, 3H), 2,90-3,70 (m, 6N), 4,00-to 4.15 (m, 1H), 4,71 (d, J=9.1 Hz, 1H), 6,07 (s, 2H), 6,34 (user. s, 1H), 7,15 was 7.45 (m, 5H), the 7.43 (s, 1H), and 8.50 (s, 1H), 8,84 (s, 1H), 8,88 (s, 1H)

Example 60 synthesis

Hydrochloride (8R*,9S*)-9-{[2-(2-forfinal)ethyl]amino}-7,7-dimethyl-8,9-dihydro-7H-pyrano[2,3-g]cinoxacin-8-ol

Example 60 synthesis was carried out analogously to the method of example 59 synthesis.

(3R*,4S*)-6,7-Diamino-4-{[2-(2-forfinal)ethyl]amino}-2,2-dimethyl-3,4-dihydro-2H-benzopyran-3-ol

(Yield: 87%)

Black amorphous product

Mass spectrum (ESI⁺) m/z: 346 [M+1]⁺

Mass spectrum (ESI^-) m/z: 380 [M+45]⁺(HCOOH adduct)

(8R*,9S*)-9-{[2-(2-Forfinal)ethyl]amino}-7,7-dimethyl-8,9-dihydro-7H-pyrano[2,3-g]cinoxacin-8-ol

(Yield: 25%)

Grey amorphous product

¹H-NMR (CDCl₃) δ: 1.26 in (s, 3H), of 1.57 (s, 3H), 1,74 (user. s, 2H), 2,85 is 3.15 (m, 4H), 3,61 (d, J=10.4 Hz, 1H), 3,91 (d, J=10.4 Hz, 1H), 7,00-to 7.15 (m, 3H), 7,15-7,35 (m, 2H), 7,42 (s, 1H), 7,98 (s, 1H), 8,66 (d, J=1.7 Hz, 1H), 8,72 (d, J=1.7 Hz, 1H)

Mass spectrum (ESI⁺) m/z: 368 [M+1]⁺

Mass spectrum (ESI^-) m/z: 412 [M+45]⁺(HCOOH adduct)

Hydrochloride (8R*,9S*)-9-{[2-(2-forfinal)ethyl]amino}-7,7-dimethyl-8,9-dihydro-7H-pyrano[2,3-g]cinoxacin-8-ol

(Yield: 95%)

Colourless crystals

TPL: 265-268°C (decomposition)

Example 61 synthesis

Hydrochloride (8R*,9S*)-9-{[2-(4-forfinal)ethyl]amino}-7,7-dimethyl-8,9-dihydro-7H-pyrano[2,3-g]cinoxacin-8-ol

Example 61 synthesis was performed analogously to the synthesis method of example 59.

(3R*,4S*)-6,7-Diamino-4-[{2-(4-forfinal)ethyl}amino]-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-3-ol

(Yield: 87%)

Black amorphous product

^lH-NMR (CDCl₃) δ: 1,13 (s, 3H), 1,45 (s, 3H), 1,90 (user. s, 4H), 2,75-3,00 (m, 6N), 3,50-3,70 (m, 2H), 6,16 (s, 1H), 6,29 (s, 1H), 7,02 (t, J=8.5 Hz, 2H), 7,17 (t, J=8.5 Hz, 2H)

(8R*,9S*)-9-{[2-(4-Forfinal)ethyl]amino}-7,7-DIMET the l-8,9-dihydro-7H-pyrano[2,3-g]cinoxacin-8-ol

(Yield: 23%)

Pink oily product

¹H-NMR (CDCl₃) δ: 1,27 (s, 3H), of 1.57 (s, 3H), 1.69 in (user. s, 2H), and 2.83 (t, J=6.9 Hz, 2H), 2,90-3,10 (m, 4H), to 3.64 (d, J=10.4 Hz, 1H), 3,92 (d, J=10.4 Hz, 1H), 6,95-7,05 (m, 2H), 7,15-7,25 (m, 2H), 7,42 (s, 1H), 7,94 (s, 1H), 8,66 (d, J=1.7 Hz, 1H), 8,73 (d, J=the 1.7 Hz, 1H)

Hydrochloride (8R*,9S*)-9-{[2-(4-forfinal)ethyl]amino}-7,7-dimethyl-8,9-dihydro-7H-pyrano[2,3-g]cinoxacin-8-ol

(Yield: 95%)

Brown crystals

TPL: 191-197°C (decomposition)

Example 62 synthesis

(8R*,9S*)-9-[(2-Hydroxy-2-phenylethyl)amino]-7,7-dimethyl-8,9-dihydro-7H-pyrano[2,3-g]cinoxacin-8-ol

Example 62 synthesis was carried out analogously to the method of example 59 synthesis.

(3R*,4S*)-6,7-Diamino-4-[(2-hydroxy-2-phenylethyl)amino]-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-3-ol

(Yield: 92%)

Two diastereoisomer, which cannot be separated

Black amorphous product

¹H-NMR (CDCl₃) δ: 1,16 (s, 3H), USD 1.43 (s, 3H), 2,31 (user. s, 7H), 2,70 was 3.05 (m, 3H), 3,50-3,70 (m, 2H), 4,70-4,80 (m, 1H), 6,16 (s, 1H), 6,53 (s, 0,5H), to 6.58 (s, 0,5H), 7,20-7,40 (s, 5H)

(8R*,9S*)-9-[(2-Hydroxy-2-phenylethyl)amino]-7,7-dimethyl-8,9-dihydro-7H-pyrano[2,3-g]cinoxacin-8-ol

(Yield: 66%)

Two diastereoisomer, which cannot be separated

Grey amorphous product

¹H-NMR (CDCl₃) δ: 1.30 on (s, 3H), 1,58 (s, 1,5H), to 1.59 (s, 1,5H), 1,70 (user. s, 3H), 2,90-3,10 (m, 2H), 3,71 (d, J=10.5 Hz, 1H), 3.95 to of 4.05 (m, 1H), 7,207,45 (m, 6N), 8,10 (s, 0,5H), to 8.12 (s, 0,5H), 8,64 (d, J=1.9 Hz, 1H), 8,73 (d, J=1.9 Hz, 1H)

Mass spectrum (ESI⁺) m/z: 366 [M+1]⁺

Mass spectrum (ESI^-) m/z: 410 [M+45]⁺(HCOOH adduct)

Example 63 synthesis

Hydrochloride (8R*,9S*)-7,7-dimethyl-9-pentylamine-8,9-dihydro-7H-pyrano[2,3-g]cinoxacin-8-ol

Example 63 synthesis was carried out analogously to the method of example 59 synthesis.

(3R*,4S*)-6,7-Diamino-2,2-dimethyl-4-pentylamine-3,4-dihydro-2H-1-benzopyran-3-ol

(Yield: 98%)

Brown amorphous product

¹H-NMR (CDCl₃) δ: 0,80-0,90 (m, 3H), 0,99 (s, 3H), 1.26 in (s, 3H), 1,30-1,50 (m, 5H), 2,20-of 2.30 (m, 1H), 2,40-of 2.50 (m, 4H), 3,30-of 3.60 (m, 4H), 3,90 (user. s, 2H), 4,34 (user. s, 2H), is 4.93 (d, J=4.4 Hz, 1H), of 5.89 (s, 1H), 6,59 (s, 1H).

(8R*,9S*)-7,7-Dimethyl-9-pentylamine-8,9-dihydro-7H-pyrano[2,3-g]cinoxacin-8-ol

(Yield: 36%)

Orange amorphous product

¹H-NMR (CDCl₃) δ: from 0.90 (t, J=7.4 Hz, 3H), 1,32 (s, 3H), 1,20-1,40 (m, 3H), 1,60-1,70 (m, 3H), of 1.61 (s, 3H), 1,81 (user. s, 2H), 2,60-2,90 (m, 2H), 3,68 (d, J=10,2 Hz, 1H), 3,93 (d, J=10,2 Hz, 1H), 7,44 (s, 1H), 8,04 (s, 1H), 8,66 (d, J=1.9 Hz, 1H), total of 8.74 (d, J=1.9 Hz, 1H)

Hydrochloride (8R*,9S*)-7,7-dimethyl-9-pentylamine-8,9-dihydro-7H-pyrano[2,3-g]cinoxacin-8-ol

(Yield: 96%)

Pale-yellow crystals

TPL: 209-212°C (decomposition)

Mass spectrum (ESI⁺) m/z: 316 [M+1]⁺

Example 64 synthesis

1 maleate (8R*,9S*)-2,3,7,7-tetramethyl-9-[(2-phenylethyl)amino] - 8.9bn-dig the draw-7H-pyrano[2,3-g]cinoxacin-8-ol

Example 64 synthesis was carried out analogously to the method of example 59 synthesis.

(8R*,9S*)-2,3,7,7-Tetramethyl-9-[(2-phenylethyl)amino] - 8.9bn-dihydro-7H-pyrano[2,3-g]cinoxacin-8-ol

(Yield: 80%)

White amorphous product

¹H-NMR (CDCl₃) δ: 1,24 (s, 3H), and 1.54 (s, 3H), 2,68 (C, 6N), 2,84 (t, J=6.9 Hz, 2H), 2,90-3,10 (m, 4H)and 3.59 (d, J=10,2 Hz, 1H), 3,86 (d, J=10,2 Hz, 1H), 7,20-7,40 (m, 6N), of 7.82 (s, 1H).

Mass spectrum (ESI⁺) m/z: 378 [M+1]⁺

Mass spectrum (ESI^-) m/z: 380 [M+45]⁺(HCOOH adduct)

Example 65 synthesis

(8R*,9S*)-2,3-Diethyl-7,7-dimethyl-9-[(2-phenylethyl)amino] - 8.9bn-dihydro-7H-pyrano[2,3-g]cinoxacin-8-ol

Example 65 synthesis was carried out analogously to the method of example 59 synthesis.

(Yield: 79%)

White solid

¹H-NMR (CDCl₃) δ: 1,23 (s, 3H), 1.39 in (q, J=6, 6 Hz, 6N), and 1.54 (s, 3H), 2,80-2,90 (m, 2H), 2.95 and-3,10 (m, 10H), 3,60 (d, J=10.4 Hz, 1H), 3,85 (d, J=10.4 Hz, 1H), 7,20-7,40 (m, 6N), 7,81 (s, 1H).

Mass spectrum (ESI⁺) m/z: 406 [M+1]⁺

Example 66 synthesis

(8R*,9S*)-3,7,7-Trimethyl-9-[(2-phenylethyl)amino]-2-phenyl-8,9-dihydro-7H-pyrano[2,3-g]cinoxacin-8-ol

Example 66 synthesis was carried out analogously to the method of example 59 synthesis.

(Yield: 33%, iskopaemye component)

White amorphous product

¹H-NMR (CDCl₃) δ: 1,27 (s, 3H), of 1.57 (s, 3H), 1,66 (user. C. 2N), of 2.72 (s, 3H), and 2.83 (t, J=6, 9 Hz, 2H), 2,90 is 3.15(m, 4H), 3,61 (d, J=10,2 Hz, 1H), 3,88 (d, J=10,2 Hz, 1H), 7,15-to 7.35 (m, 5H), was 7.36 (s, 1H), 7,50-of 7.60 (m, 3H), 7,60-of 7.70 (m, 2H), of 7.97 (s, 1H)

Mass spectrum (ESI⁺) m/z: 440 [M+1]⁺

Example 67 synthesis

(8R*,9S*)-2,7,7-Trimethyl-9-[(2-phenylethyl)amino]-3-phenyl-8,9-dihydro-7H-pyrano[2,3-g]cinoxacin-8-ol

Example 67 synthesis was carried out analogously to the method of example 59 synthesis.

(Yield: 29%, a highly polar component)

¹H-NMR (CDCl₃) δ: 1.26 in (s, 3H), of 1.55 (s, 3H), of 2.72 (s, 3H), of 2.86 (t, J=6.9 Hz, 2H), 2.95 and-of 3.12 (m, 4H), 3,62 (d, J=10,2 Hz, 1H), 3,91 (d, J=10,2 Hz, 1H), 7,20-to 7.35 (m, 5H), 7,42 (s, 1H), 7,45-of 7.55 (m, 3H), 7,60-of 7.70 (m, 2N), of 7.90 (s, 1H)

Mass spectrum (ESI⁺) m/z: 440 [M+1]⁺

Example 68 synthesis

1 maleate (8R*,9S*)-3,7,7-Trimethyl-9-[(2-phenylethyl)amino] - 8.9bn-dihydro-7H-pyrano[2,3-g]cinoxacin-8-ol

Example 68 synthesis was carried out analogously to the method of example 59 synthesis.

(8R*,9S*)-3,7,7-Trimethyl-9-[(2-phenylethyl)amino] - 8.9bn-dihydro-7H-pyrano [2,3-g]cinoxacin-8-ol

(Yield: 52%)

White amorphous product

¹H-NMR (CDCl₃) δ: 1,25 (s, 3H), of 1.55 (s, 3H), of 2.72 (s, 3H), 2,84 (t, J=6.9 Hz, 2H), 2,90-3,10 (m, 4H), 3,61 (d, J=10.4 Hz, 1H), a 3.87 (d, J=10.4 Hz, 1H), 7,15-7,40 (m, 6N), 7,89 (s, 1H), 8,54 (s, 1H)

1 maleate (8R*,9S*)-3,7,7-trimethyl-9-[(2-phenylethyl)amino] - 8.9bn-dihydro-7H-pyrano[2,3-g]cinoxacin-8-ol

Colourless crystals, TPL: 189-192°C (decomposition)

Example 69 synthesis

Hydrochloride (8R*,9S*)-9-[(2-cyclohexyl what Tyl)amino]-7,7-dimethyl-8,9-dihydro-7H-pyrano[2,3-g]cinoxacin-8-ol

(8R*,9S*)-9-Amino-7,7-dimethyl-8,9-dihydro-7H-pyrano[2,3-g]cinoxacin-8-ol

To a solution of (3R*,4S*)-4,6,7-triamino-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-3-ol (280 mg, 1.25 mmol) in ethanol (5.6 ml) was added 40% aqueous solution of glyoxal (226 mg, 1.56 mmol) and the resulting mixture was stirred at room temperature for 1 hour. Upon completion of the reaction was added to a mixture of 1 mol/l hydrochloric acid, the resulting solution was washed with ethyl acetate, the resulting aqueous phase was brought to pH 14 using 1 mol/l aqueous solution of sodium hydroxide. Then the resulting solution was extracted with ethyl acetate, washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated. The resulting mixture was purified column chromatography on silica gel (ethyl acetate/methanol = 10/1)to give the target product (yield: 35%).

Pale brown amorphous product

¹H-NMR (CDCl₃) δ: 1.26 in (s, 3H), 1,58 (s, 3H), 2,17 (user. s, 3H), 3,49 (d, J=10,7 Hz, 1H), 3,92 (d, J=10,7 Hz, 1H), 7,41 (s, 1H), 8,13 (s, 1H), 8,65 (s, 1H), 8,72 (s, 1H).

Mass spectrum (ESI⁺) m/z: 246 [M+1]⁺

(8R*,9S*)-9-[(2-Cyclohexylethyl)amino]-7,7-dimethyl-8,9-dihydro-7H-pyrano[2,3-g]cinoxacin-8-ol

To a solution of (8R*,93*)-9-amino-7,7-dimethyl-8,9-dihydro-7H-pyrano[2,3-g]cinoxacin-8-ol (100 mg, 0,408 mmol) in methanol (2 ml) was added, the CEC is alexispetridis aldehyde (103 mg, 0,816 mmol) and the resulting mixture was stirred at room temperature for 20 minutes. Was added to the mixture cyanoborohydride sodium (51 mg, 0,816 mmol) and the resulting mixture was stirred at room temperature for 1 hour. Upon completion of the reaction was added to a mixture of saturated aqueous sodium hydrogen carbonate solution, the resulting solution was extracted with ethyl acetate, washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated. The resulting mixture was purified column chromatography on silica gel (hexane/ethyl acetate = 2/1)to give the target product (yield: 48%).

Yellow oily product

¹H-NMR (CDCl₃) δ: 0,80-1,00 (m, 2H), 1,10-1,40 (m, 4H), to 1.31 (s, 3H), of 1.44 (t, J=7,1 Hz, 1H), 1,60 (s, 3H), of 1.65 and 1.80 (m, 6N), 2,65-2,90 (m, 2H), 3,68 (d, J=10.4 Hz, 1H), 3,93 (d, J=10.4 Hz, 1H), 7,44 (s, 1H), 8,04 (s, 1H), 8,67 (d, J=l,9 Hz, 1H), 8,73 (d, J=l,9 Hz, 1H)

Hydrochloride (8R*,9S*)-9-[(2-cyclohexylethyl)amino]-7,7-dimethyl-8,9-dihydro-7H-pyrano[2,3-g]cinoxacin-8-ol

(Yield: 89%)

Yellow crystals, TPL: 258-259°C (decomposition)

Mass spectrum (ESI⁺) m/z: 356 [M+1]⁺

Mass spectrum (ESI^-) m/z: 400 [M+45]⁺(HCOOH adduct)

Example 70 synthesis

(±)-TRANS-7-Hydroxy-6,6-dimethyl-8-[(2-phenylethyl)amino]-3,6,7,8-tetrahydroharmine[7,6-d]imidazol-2(1H)-he

To a solution of (±)-TRANS-6,7-diamino-2,2-dimethyl-4-(2-phenylethylamine)-3,4-dihydro-2H-1-benzopyran-3-ol(500 mg, 1.53 mmol) in dioxane (7 ml) was added 4 mol/l solution of hydrogen chloride/dioxane (0,38 ml) and the resulting mixture was stirred at room temperature for 15 minutes. Then added to this mixture phenylcarbamate (of 0.21 ml, 1.53 mmol) and triethylamine (of 0.21 ml, 1.53 mmol) and the resulting mixture was stirred at room temperature for 1 hour. It was further added thereto triethylamine (0.63 ml, 4,58 mmol) and the resulting mixture was stirred at room temperature for 2 hours. Upon completion of the reaction was added to a mixture of 1 mol/l hydrochloric acid and brought thus to pH 7-8. After that, the obtained reaction solution was extracted with ethyl acetate, washed with saturated aqueous sodium chloride, then dried over sodium sulfate and concentrated. The resulting mixture was purified column chromatography on silica gel (methanol/chloroform = 1/20)to give the target product (yield: 4%).

Yellow amorphous product

¹H-NMR (CDCl₃) δ: 1,15 (s, 3H), 1.30 and 1.41 for (user., 1H), 1,45 (s, 3H), 2.71 to of 3.96 (m, 4H), 3,51 (d, J=9.9 Hz, 1H), to 3.67 (d, J=9.9 Hz, 1H), 6,51 (s, 1H), 7,12-of 7.48 (m, 7H), 7,76 (s, 1H)

Mass spectrum (ESI⁺) m/z: 354 [M+1]⁺

Example 71 synthesis

(7R*,8S*)-7-Hydroxy-6,6-dimethyl-8-[(2-phenylethyl)amino]-4,6,7,8-tetrahydro-1,5-dioxa-4-azaanthracene-3-one

4-(1,1-Dimethyl-2-propenyloxy)anisole

To a solution of 4-methox the phenol (15.0 g, 121 mmol) in acetonitrile (75 ml) was added under ice cooling 1,8-diazabicyclo[5,4,0]undecene (23.9 g, 157 mmol) and the resulting mixture was stirred at 0°C for 30 minutes (Solution 1). To a solution of 2-methyl-3-butyn-2-ol (11.7 g, 139 mmol) in acetonitrile (75 ml) was added under ice cooling 1,8-diazabicyclo[5,4,0]undecene (23.9 g, 157 mmol), the mixture was stirred at 0°C for 30 minutes, then added triperoxonane anhydride (25.4 g, 121 mmol) and the resulting mixture was stirred at 0°C for 30 minutes (Solution 2). To a Solution of 1 was added copper chloride(I) (36 mg, 0.36 mmol) and then was added dropwise a Solution of 2 within 15 minutes. After completion of adding dropwise, the temperature was raised to room temperature and the mixture was stirred over night. Upon completion of the reaction was added to the reaction solution, an aqueous solution of ammonium chloride and the solvent is kept at reduced pressure. To the residue was added 1 mol/l aqueous solution of hydrochloric acid, the resulting mixture was extracted with ethyl acetate, the organic phase is washed once with 1 mol/l aqueous solution of hydrochloric acid, twice with saturated aqueous sodium hydrogen carbonate solution and once with saturated aqueous sodium chloride. Then the organic phase was dried over anhydrous magnesium sulfate. After removal of the solvent the residue is directly used in the next reaction.

A solution of 4-(1,1-dimethyl-2-propenyloxy)anisole in 1,2-dichlorobenzene (50 ml) was stirred at 190°C for 2 hours. Upon completion of the reaction the solvent is kept at reduced pressure. The residue was purified column chromatography (hexane/chloroform = 3/1) and got the desired product as a red oily substance (yield 2 stages: 61%).

¹H-NMR (CDCl₃) δ: 1,41 (c, 6H), 3.75 to (c, 3H), 5,64 (d, J=9.9 Hz, 1H), 6,28 (d, J=9.9 Hz, 1H), 6,55 (d, J=2.7 Hz, 1H), 6,64-of 6.73 (m, 2H)

LC/mass spectrum (ESI⁺): 191 [M⁺+1]

6-Methoxy-2,2-dimethyl-7-nitro-2H-1-benzopyran

The solution mixture of acetic acid (6.2 ml) and acetic anhydride (6.2 ml)containing 6-methoxy-2,2-dimethyl-2H-1-benzopyran (3.1 g, 16.4 mmol) was cooled in ice, was added dropwise nitric acid (to 1.37 ml, 18.0 mmol) and the mixture is then stirred at 0°C for 1 hour. Upon completion of the reaction was added to the reaction solution 1 mol/l aqueous solution of sodium hydroxide, the resulting solution was extracted with ethyl acetate (150 ml). The organic phase was washed twice with 1 mol/l aqueous sodium hydroxide solution and once with saturated aqueous sodium chloride. Then the organic phase was dried over anhydrous magnesium sulfate. After removal of the solvent the residue was purified column chromatography (hexane/ethyl acetate= 6/1) and received the target product of the t in the form of yellow crystals (yield: 79%).

¹H-NMR (CDCl₃) δ: 1,44 (c, 6H), 3,91 (c, 3H), of 5.85 (d, J=9.6 Hz, 1H), 6,33 (d, J=9.6 Hz, 1H), 6,69 (c, 1H), 7,34 (c, 1H)

LC/mass spectrum (ESI⁺): 236 [M⁺+1]

(3R*,4R*)-3,4-Epoxy-6-methoxy-2,2-dimethyl-7-nitro-3,4-dihydro-2H-1-benzopyran

To a solution (300 ml) of acetonitrile, containing 6-methoxy-2,2-dimethyl-7-nitro-2H-1-benzopyran (10.0 g, 42,5 mmol)was added at room temperature N-Mei (0,678 ml, 8.50 mmol), Ph,Ph selenoviy complex of manganese (XX)

(880 mg, 0,850 mmol) and iodosobenzene (18.7 mg, 85,0 mmol) and the mixture was stirred for 2 hours. Upon completion of the reaction was added to the reaction solution, an aqueous sodium thiosulfate solution, the resulting solution was filtered through celite. The obtained filtrate was extracted with ethyl acetate. The organic phase is washed with water and sodium chloride solution, and then dried over anhydrous magnesium sulfate. After removal of the solvent the residue was purified column chromatography (hexane/ethyl acetate = 4/1) and got the desired product as yellow crystals (yield: 75%, optical purity: 99,7% ee).

¹H-NMR (CDCl₃) δ: 1.26 in (c, 3H), 1,58 (c, 3H), 3,53 (d, J=4.3 Hz, 1H), 3,90 (d, J=4.3 Hz, 1H), 3,95 (c, 3H), 7,08 (c, 1H), 7,33 (c, 1H)

Mass spectrum (EI): 251 [M⁺]

HPLC: 18,6 min (enantiomer 24,1 min)

The HPLC conditions: CHIRALCEL OJ-RH, MeCN/MeOH/0.01 M NaCl aq. =1/3/5, 1.0 ml/min, 40° C, 256 nm

(3R*,4S*)-6-Methoxy-2,2-dimethyl-7-nitro-4-[(2-phenylethyl)amino]-3,4-di is Idro-2H-1-benzopyran-3-ol

To a solution of (3R*,4R*)-3,4-epoxy-6-methoxy-2,2-dimethyl-7-nitro-3,4-dihydro-2H-1-benzopyran (2.50 g, for 9.95 mmol) in 1,4-dioxane (5.0 ml) was added at room temperature, lithium perchlorate (1.06 g, for 9.95 mmol) and 2-phenylethylamine (1.50 ml, with 11.9 mmol) and the mixture was stirred at 80°C for 1 hour. Upon completion of the reaction was added to the reaction solution, a saturated aqueous solution of ammonium chloride and the resulting solution was extracted with ethyl acetate. The organic phase is washed with saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate. After removal of the solvent the residue was purified column chromatography (hexane/ethyl acetate = 6/4) and got the desired product as an orange amorphous substance (quantitative yield).

¹H-NMR (CDCl₃) δ: 1,15 (c, 3H), 1,47 (c, 3H), 2,73-2,95 (m, 4H), 3,60 (d, J=10.0 Hz, 1H), 3,68 (d, J=10.0 Hz, 1H), of 3.73 (c, 3H), 6,78 (c, 1H), 7,21-7,35 (m, 6H)

Mass spectrum (EI): 372 [M⁺]

tert-Butyl(2-phenylethyl)(3R*,4S*)-3-hydroxy-6-methoxy-2,2-dimethyl-7-nitro-3,4-dihydro-2H-1-benzopyran-4-ylcarbamate

To a solution of (3R*,4S*)-6-methoxy-2,2-dimethyl-7-nitro-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-1-benzopyran-3-ol (407 mg, of 1.09 mmol) and di-tert-BUTYLCARBAMATE (477 mg, 2,19 mmol) in tetrahydrofuran (6.0 ml) was added at 0°C triethylamine (305 ml, 2,19 mmol) and the mixture was stirred over night at room temp is the temperature. After completion of the reaction to the reaction solution was added saturated aqueous solution of sodium carbonate and the resulting solution was extracted with ethyl acetate. The organic phase is washed with 1 mol/l aqueous solution of hydrochloric acid and a saturated solution of sodium chloride and then dried over anhydrous sodium sulfate. After removal of the solvent the residue was purified column chromatography (hexane/ethyl acetate = 4/1) and received the target product as a yellow amorphous substance (yield: 88%).

Mass spectrum (EI): 473 [M⁺+1]

tert-Butyl(2-phenylethyl)(3R*,4S*)-7-amino-3-hydroxy-6-methoxy-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-4-ylcarbamate

A solution of tert-butyl(2-phenylethyl)(3R*,4S*)-3-hydroxy-6-methoxy-2,2-dimethyl-7-nitro-3,4-dihydro-2H-1-benzopyran-4-ylcarbamate (1,32 g, 2,80 mmol) and 5% palladium-on-corner (132 mg) in methanol (26 ml) was stirred overnight in a hydrogen atmosphere. After completion of the reaction, the reaction solution was filtered through celite. After removal of the solvent the residue was purified column chromatography (hexane/ethyl acetate = 4/1) and received a target product (yield: 94%).

Colorless solid.

LC/mass spectrum (ESI) m/z: 443 [M⁺+1]

tert-Butyl(2-phenylethyl)(3R*,4S*)-[7-(2-chloroacetamido)-3-hydroxy-6-methoxy-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-4-yl]carbamate

To the R. is the target of tert-butyl(2-phenylethyl)(3R*,4S*)-7-amino-3-hydroxy-6-methoxy-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-4-ylcarbamate (270 mg, 0.61 mmol) in tetrahydrofuran was added at room temperature triethylamine (128 μl, of 0.92 mmol) and chlorocatechol (73 μl, of 0.92 mmol) and the resulting mixture was stirred at room temperature for 2.5 hours. Upon completion of the reaction was added to the reaction solution ethanol (1 ml) and a saturated aqueous solution of ammonium chloride and the resulting solution was extracted with ethyl acetate, washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated. The resulting mixture was purified column chromatography on silica gel (hexane/ethyl acetate = 5/1) and received a target product (yield: 91%).

Colorless oily product

2-Chloro-N-[(3R*,4S*)-3,6-dihydroxy-2,2-dimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-1-benzopyran-7-yl]ndimethylacetamide

To a solution of tert-butyl (2-phenylethyl)(3R*,4S*)-[7-(2-chloroacetamido)-3-hydroxy-6-methoxy-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-4-yl]carbamate (251 mg, 0.48 mmol) in methylene chloride (5 ml) was added at 0°C trichloride boron (1 M solution in methylene chloride, to 2.42 ml, 2,42 mmol) and the resulting mixture was stirred for 2 hours. Upon completion of the reaction was added to a mixture of water, the resulting solution was extracted with ethyl acetate, washed with saturated aqueous solution of sodium bicarbonate and then saturated aqueous sodium chloride, dried over sulfate m is fester and concentrated. The resulting mixture was purified column chromatography on silica gel (hexane/ethyl acetate = 2/1) and received a target product (yield: 70%).

Pale pink amorphous product

¹H-NMR (CDCl₃) δ: 1,33 (c, 3H), 1,44 (c, 3H), 2,75-3,00 (m, 4H), 3,50 (d, J=9.6 Hz, 1H), 3,60 (d, J=9.6 Hz, 1H), 4,23 (c, 2H), 6,58 (c, 1H), 6,83 (c, 1H), 7,20-to 7.35 (m, 5H), of 8.47 (c, 1H)

Mass spectrum (ESI⁺) m/z: 405 [M+1]⁺

Mass spectrum (ESI^-) m/z: 403 [M-1]⁺

(7R*,8S*)-7-Hydroxy-6,6-dimethyl-8-[(2-phenylethyl)amino]-4,6,7,8-tetrahydro-1,5-dioxa-4-azaanthracene-3-one

To a solution of 2-chloro-N-[(3R*4S*)-3,6-dihydroxy-2,2-dimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-1-benzopyran-7-yl]ndimethylacetamide (120 mg, 0.30 mmol) in methanol (1.2 ml) was added at room temperature an aqueous solution of peroxide sodium (1 mol/l, 1.5 ml) and the resulting mixture was stirred for 4 hours. Upon completion of the reaction was added to a mixture of saturated aqueous solution of ammonium chloride, the resulting solution was extracted with ethyl acetate, washed with saturated aqueous solution of sodium hydroxide (1 mol/l) and then saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated. The resulting mixture was purified column chromatography on silica gel (hexane/ethyl acetate = 1/1) and received a target product (yield: 72%).

Colourless solid

¹H-NMR (CDCl₃) δ: 1.14 in (c, 3H), 1,44 (c, 3H), 2,75-3,00 (m, 4H), 3,47 (d, J=9,9 G is, 1H), of 3.56 (d, J=9.9 Hz, 1H), 4,50 (d, J=to 15.4 Hz, 1H), 4,55 (d, J=to 15.4 Hz, 1H), 6,27 (c, 1H), 6,68 (c, 1H), 7,20-to 7.35 (m, 5H), 7,74 (c, 1H)

Mass spectrum (ESI⁺) m/z: 369 [M+1]⁺

Mass spectrum (ESI^-) m/z: 367 [M-1]⁺

Example 72 synthesis

Maleate (7R*,8S*)-6,6-dimethyl-8-[(2-phenylethyl)amino]-2,3,4,6,7,8-hexahydro-1,5-dioxa-4-azaanthracene-7-ol

To a solution of (7R*,8S*)-7-hydroxy-6,6-dimethyl-8-[(2-phenylethyl)amino]-4,6,7,8-tetrahydro-1,5-dioxa-4-azaanthracene-3-one (42 mg, 0.11 mmol) in tetrahydrofuran (1.2 ml) was added at room temperature sociallyengaged (1 M solution in tetrahydrofuran, 570 μl, or 0.57 mmol) and the resulting mixture was stirred at 90°C for 1.5 hours. Upon completion of the reaction was added to a mixture of saturated aqueous sodium hydrogen carbonate solution, the resulting solution was extracted with ethyl acetate, washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated. To a solution of mixture in ethyl acetate (600 ml) was added maleic acid (13 mg, 0.11 mmol) and hexane (1 ml) at room temperature and the resulting mixture was stirred at room temperature for 15 minutes. The obtained crystals were filtered off and got the target product (yield: 60%).

Pale brown solid

¹H-NMR (DMSO-d₆) δ: 1,04 (c, 3H), 1,36 (c, 3H), 2,85-3,30 (m, 6H), 3,80-of 3.85 (m, 1H), 4,11 (d, J=4,2 Hz, 2H), 4,15-4,20 (m, 1H), 6,05 (c, 2H), 6,18 (c, 1H), 676 (c, 1H), 7,20-7,40 (m, 5H)

Example 73 synthesis

Hydrochloride (7R*,8S*)-7-hydroxy-4,6,6-trimethyl-8-[(2-phenylethyl)amino]-4,6,7,8-tetrahydro-1,5-dioxa-4-azaanthracene-3-one

tert-Butyl(2-phenylethyl)(7R*,8S*)-[7-hydroxy-6,6-dimethyl-3-oxo-4,6,7,8-tetrahydro-1,5-dioxa-4-azaanthracene-8-yl]carbamate

To a solution of (7R*,8S*)-7-hydroxy-6,6-dimethyl-8-[(2-phenylethyl)amino]-4,6,7,8-tetrahydro-1,5-dioxa-4-azaanthracene-3-one (150 mg, 0.41 mmol) in tetrahydrofuran (3 ml) was added at room temperature triethylamine (85 μl, 0.61 mmol) and di-tert-BUTYLCARBAMATE (178 mg, 0.81 mmol) and the resulting mixture was stirred at 90°C for 1.5 hours. Upon completion of the reaction, to the mixture was added saturated aqueous solution of ammonium chloride, the resulting solution was extracted with ethyl acetate, washed with a saturated solution of sodium chloride, dried over magnesium sulfate and concentrated. The resulting mixture was purified column chromatography on silica gel (hexane/ethyl acetate = 3/1) and received a target product (yield: 85%).

Mass spectrum (ESI⁺) m/z: 469 [M+1]⁺

Mass spectrum (ESI^-) m/z: 467 [M-1]⁺

tert-Butyl(2-phenylethyl)(7R*,8S*)-[7-hydroxy-4,6,6-trimethyl-3-oxo-4,6,7,8-tetrahydro-1,5-dioxa-4-azaanthracene-8-yl]carbamate

To a solution of tert-butyl(2-phenylethyl)(7R*,8S*)-[7-hydroxy-6,6-dimethyl-3-oxo-4,6,7,8-tetrahydro-1,5-di the KSA-4-azaanthracene-8-yl]carbamate (106 mg, 0.23 mmol) in dimethylformamide (2 ml) was added at room temperature potassium carbonate (79 mg, or 0.57 mmol) and modesty methyl (28 μl, 0.46 mmol) and the resulting mixture was stirred at room temperature for 4 hours. Upon completion of the reaction, to the mixture was added saturated aqueous solution of ammonium chloride, the resulting solution was extracted with ethyl acetate, washed with a saturated solution of sodium chloride, dried over magnesium sulfate and concentrated. The resulting mixture was purified column chromatography on silica gel (hexane/ethyl acetate = 2/1) and received a target product (yield: 100%).

Mass spectrum (ESI⁺) m/z: 505 [M+23]⁺(Na adduct)

Mass spectrum (ESI^-) m/z: 527 [M+45]⁺(HCOOH adduct)

(7R*8S*)-7-Hydroxy-4,6,6-trimethyl-8-[(2-phenylethyl)amino]-4,6,7,8-tetrahydro-1,5-dioxa-4-azaanthracene-3-one

To a solution of tert-butyl(2-phenylethyl)(7R*,8S*)-[7-hydroxy-4,6,6-trimethyl-3-oxo-4,6,7,8-tetrahydro-1,5-dioxa-4-azaanthracene-8-yl]carbamate (115 mg, 0.24 mmol) in a simple ether (2.2 ml) was added at room temperature 4 mol/l solution of hydrogen chloride in dioxane (500 μl) and the resulting mixture was stirred at room temperature for 5 hours and then at 50°C for 30 minutes. Upon completion of the reaction was added to a mixture of saturated aqueous sodium hydrogen carbonate solution, the resulting solution was extracted with ethyl acetate, amywali saturated aqueous sodium chloride, was dried over magnesium sulfate and concentrated. The resulting mixture was purified column chromatography on silica gel (hexane/ethyl acetate = 1/2) and received a target product (yield: 76%).

Colorless oily product

¹H-NMR (CDCl₃) δ: 1,17 (c, 3H), 1,47 (c, 3H), 2,75-3,00 (m, 4H), 3,29 (c, 3H), 3,49 (d, J=9.9 Hz, 1H), to 3.58 (d, J=9.9 Hz, 1H), to 4.52 (d, J=15.1 Hz, 1H), 4,58 (d, J=15.1 Hz, 1H), 6.42 per (c, 1H), 6,68 (c, 1H), 7,20-7,35 (m, 5H)

Mass spectrum (ESI⁺) m/z: 383 [M+1]⁺

Mass spectrum (ESI^-) m/z: 427 [M+45]⁺(HCOOH adduct)

Hydrochloride (7R*,8S*)-7-hydroxy-4,6,6-trimethyl-8-[(2-phenylethyl)amino]-4,6,7,8-tetrahydro-1,5-dioxa-4-azaanthracene-3-one

To a solution of (7R*8S*)-7-hydroxy-4,6,6-trimethyl-8-[(2-phenylethyl)amino]-4,6,7,8-tetrahydro-1,5-dioxa-4-azaanthracene-3-one (65 mg, 0,17 mmol) in a simple ether (2.2 ml) was added at room temperature 4 mol/l hydrogen chloride in dioxane (200 μl) and the resulting mixture was stirred at room temperature for 10 minutes. Upon completion of the reaction, the obtained crystals otfiltrovana and received a target product (yield: 93%).

Pale pink solid

Example 74 synthesis

(±)-TRANS-7-Hydroxy-6,6-dimethyl-8-[(2-phenylethyl)amino]-1,6,7,8-tetrahydro-4,5-dioxo-1-azaanthracene-2-he

2 Methoxyethoxy-4-(1,1-dimethyl-2-propionyloxy)-1-nitrobenzene

To a solution of 4-fluoro-2-NITROPHENOL (1.6 g, 10.2 mmol) in Tetra is hydrofuran (32 ml) was added at room temperature chloromethylation ester (1.23 g, of 15.3 mmol) and diisopropylethylamine (2.66 ml of 15.3 mmol) and the resulting mixture was stirred at room temperature for 1 hour. Upon completion of the reaction was added to a mixture of saturated aqueous solution of ammonium chloride, the resulting solution was extracted with ethyl acetate, washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated. To a solution of mixture in dimethylacetamide (17 ml) at 0°C was added sodium hydride (553 mg, 12.3 mmol) and 1-methyl-2-buten-1-ol (1.23 ml, 12.7 mmol) and the resulting mixture was stirred for 7 hours. Upon completion of the reaction, to the mixture was added saturated aqueous solution of ammonium chloride, the resulting solution was extracted with ethyl acetate, washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated. The resulting mixture was purified column chromatography on silica gel (hexane/ethyl acetate = 5/1) and received a target product (yield: 94%).

Yellow oily product

7 Methoxyethoxy-2,2-dimethyl-6-nitro-2H-1-benzopyran

A solution of 2-methoxyethoxy-4-(1,1-dimethyl-2-propionyloxy)-1-nitrobenzene (2.1 g, a 7.92 mmol) in dichlorobenzene (21 ml) was stirred at 200°C for 0.5 hours. Upon completion of the reaction, the mixture was concentrated and was purified column chromatography on silica gel (hexane/ethyl acetate = 5/1). So the m was obtained mixture (1:1) of the target product and regioisomer (yield: 77%).

Yellow oily product

¹H-NMR (CDCl₃) δ: 1,46 (c, 6H), 3,53 (c 1,5 H)to 3.58 (c, 1,5H), 5,10 (c, 1H), 5,27 (c, 1H), 5,64 (d, J=10.4 Hz, 0,5H), 5,74 (d, J=10.4 Hz, 0,5H), 6,27 (d, J=10.4 Hz, 0,5H), 6,60-6,70 (m, 1,5H), to 7.67 (c, 0,5H), to 7.77 (d, J=9.1 Hz, 0,5H).

(±)-TRANS-3-Bromo-7-methoxyethoxy-2,2-dimethyl-6-nitro-3,4-dihydro-2H-1-benzopyran-4-ol

To a water solution of a mixture of 7-methoxyethoxy-2,2-dimethyl-6-nitro-2H-1-benzopyran and regioisomer (1.5 g, the 5.65 mmol) in dimethyl sulfoxide (17 ml) was added at room temperature N-bromosuccinimide (1,21 g of 6.78 mmol) and the resulting mixture was stirred for 3 hours. Upon completion of the reaction was added to a mixture of saturated aqueous solution of ammonium chloride, the resulting solution was extracted with ethyl acetate, washed with saturated aqueous solution of sodium bicarbonate and then saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated. The resulting mixture was purified column chromatography on silica gel (hexane/ethyl acetate = 7/1) and received a target product (yield: 27%).

Yellow solid

¹H-NMR (CDCl₃) δ: 1,45 (c, 3H), 1,63 (c, 3H), 2,73 (d, J=4.4 Hz, 1H), 3,52 (c, 3H), 4,08 (d, J=9.4 Hz, 1H), 4,88 (DD, J=9,4, 4,4 Hz, 1H), of 6.71 (c, 1H), 8,16 (c, 1H).

3,4-Epoxy-7-methoxyethoxy-2,2-dimethyl-6-nitro-3,4-dihydro-2H-1-benzopyran

To a solution of (±)-TRANS-3-bromo-7-methoxyethoxy-2,2-dimethyl-6-nitro-3,4-dihydro-2H-1-be supiran-4-ol (550 mg, of 1.52 mmol) in dioxane (5.5 ml) was added at room temperature, 1 mol/l aqueous solution of sodium hydroxide (to 1.82 ml, 1.82 mmol) and the resulting mixture was stirred for 2 hours. Upon completion of the reaction was added to a mixture of water, the resulting solution was extracted with ethyl acetate, washed with saturated aqueous sodium thiosulfate and then with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated. The resulting mixture was purified column chromatography on silica gel (hexane/ethyl acetate = 4/1) and received a target product (yield: 78%).

Yellow oily product

¹H-NMR (CDCl₃) δ: 1.32 to (c, 3H), 1,59 (c, 3H), 3,51 (c, 3H), 3,52 (d, J=3,9 Hz, 1H), 3,91 (d, J=3,9 Hz, 1H), 5,26 (c, 2H), 6.73 x (c, 1H), 8,05 (c, 1H)

(±)-TRANS-7-Methoxyethoxy-2,2-dimethyl-6-nitro-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-1-benzopyran-3-ol

To a solution of 3,4-epoxy-7-methoxyethoxy-2,2-dimethyl-6-nitro-3,4-dihydro-2H-1-benzopyran (332 mg, 1.18 mmol) in dioxane (1.3 ml) was added at room temperature, lithium perchlorate (126 mg, 1.18 mmol) and 2-phenylethylamine (214 mg, 1.77 mmol) and the resulting mixture was stirred for 2 hours. Upon completion of the reaction was added to a mixture of saturated aqueous sodium hydrogen carbonate solution, the resulting solution was extracted with ethyl acetate, washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated. The resulting mixture was purified column chromatography on silica gel (hexane/ethyl acetate = 3/1) and received a target product (yield: 73%).

Yellow oily product

¹H-NMR (CDCl₃) δ: 1,19 (c, 3H), 1,47 (c, 3H), 2,75-3,00 (m, 4H), 3,45-3,55 (m, 2H), 3,50 (c, 3H), 5,24 (c, 2H), 6,66 (c, 1H), 7,15-7,40 (m, 5H), 7,72 (c, 1H)

(±)-TRANS-6-Amino-7-methoxyethoxy-2,2-dimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-1-benzopyran-3-ol

To a solution of (±)-TRANS-7-methoxyethoxy-2,2-dimethyl-6-nitro-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-1-benzopyran (265 mg, 0.66 mmol) in ethanol (5 ml) was added at room temperature with 5% palladium-on-coal (type AER, 13 mg) and the resulting mixture was stirred in a stream of hydrogen during the night. Upon completion of the reaction, the resulting solution was filtered through celite, concentrated and obtained target product (yield: 98%).

Brown oily product

¹H-NMR (CDCl₃) δ: 1,13 (c, 3H), 1,43 (c, 3H), 2,70 was 3.05 (m, 8H), 3,51 (c, 3H), 3,52-of 3.60 (m, 2H), 5,12 (c, 2H), 6,21 (c, 1H), 6,51 (c, 1H), 7,20 is 7.50 (m, 5H).

2-Chloro-N-{(±)-TRANS-3-hydroxy-7-methoxyethoxy-2,2-dimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-1-benzopyran-6-yl}ndimethylacetamide

To TRANS-6-amino-7-methoxyethoxy-2,2-dimethyl-4-[(2-phenylethyl)amino]-

3,4-dihydro-2H-1-benzopyran-3-Olu (242 mg, of 0.65 mmol) in a solution mixture of ethyl acetate-dimethylformamide (5 ml)was added at 0°C 4 M solution of hydrogen chloride in dioxane (194 MK is, 0.78 mmol) and the resulting mixture was stirred for 5 minutes. Was added to a mixture of chloroacetyl chloride (88 mg, 0.78 mmol) and the resulting mixture was stirred for 15 minutes. Upon completion of the reaction was added to this mixture of ethanol and saturated aqueous sodium hydrogen carbonate solution, the resulting solution was extracted with ethyl acetate, washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated. The resulting mixture was purified column chromatography on silica gel (hexane/ethyl acetate = 1/1) and received a target product (yield: 79%).

Pale pink oily product

¹H-NMR (CDCl₃) δ: 1,17 (c, 3H), 1,45 (c, 3H), 2,75-3,00 (m, 4H), 3.43 points (d, J=9.9 Hz, 1H), 3,50 (c, 3H)and 3.59 (d, J=9.9 Hz, 1H), 4,20 (c, 2H), 5,19 (c, 2H), 6,61 (c, 1H), 7,15-7,30 (m, 5H), 8,14 (c, 1H), 8,73 (c, 1H).

Mass spectrum (ESI⁺) m/z: 449 [M+1]⁺

Mass spectrum (ESI^-) m/z: 447 [M-1]⁺

2-Chloro-N-{(±)-TRANS-3,7-dihydroxy-2,2-dimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-1-benzopyran-6-yl}ndimethylacetamide

To a solution of 2-chloro-N-{(±)-TRANS-hydroxy-7-methoxyethoxy-2,2-dimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-1-benzopyran-6-yl}ndimethylacetamide (228 mg, 0.51 mmol) in methylene chloride (6 ml) was added at 0°C tribromide boron (1 M solution in methylene chloride, to 2.42 ml, 2,42 mmol) and the resulting mixture was stirred for 2 hours. Upon completion of the reaction was added to this mixture, the methanol and acadeny aqueous solution of sodium bicarbonate, the resulting solution was extracted with ethyl acetate, washed with saturated aqueous sodium bicarbonate and then saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated, obtaining the target product (yield: 100%).

Beschetny amorphous product

Mass spectrum (ESI⁺) m/z: 405 [M+1]⁺

Mass spectrum (ESI^-) m/z: 403 [M-1]⁺

(±)-TRANS-7-Hydroxy-6,6-dimethyl-8-[(2-phenylethyl)amino]-1,6,7,8-tetrahydro-4,5-dioxo-1-azaanthracene-2-he

To a solution of 2-chloro-N-{(±)-TRANS-3,7-dihydroxy-2,2-dimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-1-benzopyran-6-yl}ndimethylacetamide (187 mg, 0.46 mmol) in methanol (2 ml) was added at room temperature an aqueous solution of sodium hydroxide (1 mol/l, 1.8 ml) and the resulting mixture was stirred for 3 hours. Upon completion of the reaction was added to a mixture of saturated aqueous solution of ammonium chloride, the resulting solution was extracted with ethyl acetate, washed with 1 mol/l aqueous solution of sodium hydroxide and then saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated. The resulting mixture was purified column chromatography on silica gel (hexane/ethyl acetate = 1/3) and received a target product (yield: 61%).

Colorless oily product

¹H-NMR (CDCl₃) δ: 1.14 in (c, 3H), 1,45 (c, 3H), 2,65-3,00 (m, 4H), 3,53 (d, J=9.9 Hz, 1H), 3,57 (d, J=9,9 G is, 1H), 4,50 (d, J=to 15.4 Hz, 1H), 4,56 (d, J=to 15.4 Hz, 1H), 5,99 (c, 1H), 6,40 (c, 1H), 7,15-7,40 (m, 5H).

Mass spectrum (ESI⁺) m/z: 369 [M+1]⁺

Example of synthesis 75

1 maleate (±)-TRANS-6,6-dimethyl-8-[(2-phenylethyl)amino]-1,2,3,6,7,8-hexahydro-4,5-dioxo-1-azaanthracene-7-ol

(±)-TRANS-6,6-Dimethyl-8-[(2-phenylethyl)amino]-1,2,3,6,7,8-hexahydro-4,5-dioxo-1-azaanthracene-7-ol

To (±)-TRANS-7-hydroxy-6,6-dimethyl-8-[(2-phenylethyl)amino]-1,6,7,8-

tetrahydro-4,5-dioxo-1-azaanthracene-2-she (67 mg, 0.18 mmol) was added at room temperature sociallyengaged (1 M solution in tetrahydrofuran, 910 μl, of 0.91 mmol) and the resulting mixture was stirred at 90°C for 0.5 hours. Upon completion of the reaction was added to a mixture of saturated aqueous sodium hydrogen carbonate solution, the resulting solution was extracted with ethyl acetate, washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated. The resulting mixture was purified column chromatography on silica gel (ethyl acetate) and received a target product (yield: 59%).

Colorless oily product

¹H-NMR (CDCl₃) δ: 1,13 (c, 3H), 1,43 (c, 3H), 2,75-3, 00 (m, 4H), 3,30-to 3.35 (m, 2H), 3,50-3,70 (m, 2H), 4,15-of 4.25 (m, 2H), 6,12 (c, 1H). 6,25 (c, 1H), 7,20-to 7.35 (m, 5H)

Mass spectrum (ESI⁺) m/z: 355 [M+1]⁺

Mass spectrum (ESI^-) m/z: 389 [M+45]⁺(HCOOH adduct)

1 maleate (±)-TRANS-6,6-dimethyl-8-[(2-phenyl what Tyl)amino]-1,2,3,6,7,8-hexahydro-4,5-dioxo-1-azaanthracene-7-ol

To a solution of (±)-TRANS-6,6-dimethyl-8-[(2-phenylethyl)amino]-1,2,3,6,7,8-hexahydro-4,5-dioxo-1-azaanthracene-7-ol in ethyl acetate (800 ml) was added at room temperature maleic acid (14 mg, 0.12 mmol) and the resulting mixture was stirred for 10 minutes. Was added to the mixture hexane (1 ml) and the resulting mixture was stirred at 0°C for 30 minutes. The obtained crystals were filtered off and got the target product (yield: 73%).

Pale gray crystals

TPL:162-162°C (decomposition)

¹H-NMR (DMSO-d₆) δ: 1,04 (c, 3H), 1,36 (c, 3H), 2,85-3,30 (m, 6H), 3,80-of 3.85 (m, 1H), 4,11 (d, J=4,2 Hz, 2H), 4,15-4,20 (m, 1H), 6,05 (c, 2H), 6,18 (c,1H), 6,76 (c, 1H), 7,20-7,40 (m, 5H).

Example 76 synthesis

(3R*,4S*)-4-{[2-(4-Forfinal)ethyl]amino}-7-hydroxymethyl-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

This compound was synthesized according to the method of example 18 synthesis. (Yield: 42%).

White crystals

TPL:147-152°C

¹H-NMR (CDCl₃) δ: 1.26 in (c, 3H), and 1.56 (c, 3H), 2,59 (c, 3H), 2,84-of 2.86 (m, 2H), 2,92-to 3.09 (m, 2H), 3,64 (d, J=10.5 Hz, 1H), 3,89 (d, J=10,2 Hz, 1H), a 4.83 (c, 2H), 6,99-7,05 (m, 3H), 7,12-of 7.23 (m, 2H), 7,29 (c, 1H), 7,81 (c, 1H)

Mass spectrum (ESI⁺) m/z: 411 [M+1]⁺

Mass spectrum (ESI^-) m/z: 455 [M+45]⁺(HCOOH adduct)

Example 77 synthesis

1 maleate (3R*,4S*)-2,2-dimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

2,2-Dimethyl-2H-pyrano[2,3-g]quinoline

In a nitrogen atmosphere to a solution of 6-amino-2,2-DIMETHYLPROPANE (3.88 g, 22,1 mmol) and trichloride ruthenium (55,0 mg, 0,265 mmol) in dimethyl ether of diethyleneglycol (8 ml) was added at room temperature, 1,3-propandiol (0,639 ml, 8,84 mmol) and tri-n-butylphosphine (0,132 ml, 0,530 mmol) and the resulting mixture was stirred at 180°C for 5 hours. Upon completion of the reaction, the ruthenium complex was removed on a column with Florisil and drove the solvent. The residue was column purified by medium pressure chromatography (hexane/ethyl acetate = 5/1) and received a target product (yield: 59%).

Brown amorphous product

¹H-NMR (CDCl₃) δ: 1,49 (c, 6H), 5,91 (d, J=9.9 Hz, 1H), 6,59 (d, J=9.9 Hz, 1H), 7,08 (c, 1H), 7.24 to 7,28 (m, 1H), to 7.67 (c, 1H), to 7.93 (d, J=8.0 Hz, 1H), 8,70 (DD, J=4,1 Hz and 1.7 Hz, 1H).

Mass spectrum (ESI⁺) m/z: 212 [M+1]⁺

(3R*,4R*)-3,4-Epoxy-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline

This compound was synthesized according to the method of example 12 synthesis.

(Yield: 65%)

CHIRALPAKAD-RH 20 mm phosphate buffer (pH 8.0)/acetonitrile = 60/40, retention time: 7,3 min).

Brown solid

¹H-NMR (CDCl₃) δ: 1.30 on (c, 3H), 1,65 (c, 3H), 3,61 (d, J=4.4 Hz, 1H), 4,18 (d, J=4.4 Hz, 1H), 7,17 (c, 1H), 7,34 (DD, J=8,5 Hz, 4.4 Hz, 1H), 8,01 (d, J=7.7 Hz, 1H), 8,12 (c, 1H), 8,79 (DD, J=4,1 Hz and 1.7 Hz, 1H)

Mass spectrum (ESI⁺) m/z: 228 [M+1]⁺

(3R*,4S*)-2,2-Dimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-ol

(Yield: 58%)

Mass spectrum (ESI⁺) m/z: 349[M+1]⁺

Mass spectrum (ESI^-) m/z: 393 [M+45]⁺(HCOOH adduct)

1 maleate (3R*,4S*)-2,2-dimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

(Yield: 79%)

White crystals

TPL:187-192°C (decomposition)

¹H-NMR (DMSO-d₆) δ: 1,16 (c, 3H), 1.50 in (c, 3H), 2,94-3,00 (m, 1H), 3,09-3,20 (m, 2H), 3,34-3,37 (m, 1H), 4,07-4,11 (m, 1H), 4,69 (d, J=9.4 Hz, 1H), 6,05 (c, 2H), 6,32 (user. c, 1H), 7.23 percent-7,39 (m, 6H), 7,49 (DD, J=8,3 Hz, 4,1 Hz, 1H), they were 8.22 (d, J=8,3 Hz, 1H), 8,44 (c, 1H), 8,80 (d, J=3,9 Hz, 1H)

Example 78 synthesis

(3R*,4S*)-7-Chloro-2,2,9-trimethyl-4-{[2-(1-pyrrolidinyl)ethyl]amino}-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

This compound was synthesized according to the method of example 19 synthesis.

(Yield: 30%)

Orange amorphous product

¹H-NMR (CDCl₃) δ: 1,19 (c, 3H), 1.50 in (c, 3H), 2.05 is-2,15 (user., 2H), 2.49 USD (c, 3H), 3,09-of 3.32 (m, 10H), 4,60-5,20 (user., 2H), 7,06 (c, 1H), 7,11 (c, 1H), 7, 88 (c, 1H)

Mass spectrum (EI⁺) m/z: 390 [M+1]⁺.

Example 79 synthesis

(3R*,4S*)-7-Chloro-2,2,9-trimethyl-4-{[2-(1,2,4-triazole-1-yl)ethyl]amino}-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

This compound was synthesized according to the method of example 19 synthesis.

(Yield: 32%)

Pale yellow solid

¹H-NMR (CDCl₃) δ: 1.28 (in c, 3H), 1.57 in (c, 3H), 2.00 (evens of usher.), 2,58 (c, 3H), 3,23-to 3.35 (m, 2H), 3,63 (d, J=10,2 Hz, 1H), 3,90 (d, J=10,2 Hz, 1H), 4,9-to 4.38 (m, 2H), 7,15 (c, 1H), 7,27 (c, 1H), 7,99 (m, 2H), 8,18 (c, 1H).

Mass spectrum (ESI⁺) m/z: 388 [M+1]⁺

Example 80 synthesis

(3R*,4S*)-7-Hydroxymethyl-2,2,9-trimethyl-4-pentylamine-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

This compound was synthesized according to the method of example 18 synthesis.

(Yield: 38%)

Pale-yellow crystals

¹H-NMR (CDCl₃) δ: 0.88 to 0,93 (m, 3H), 1,29 (c, 3H), of 1.33 to 1.37 (m, 4H), 1,59 (c, 3H), 1,60 (m, 2H), 2,60 (c, 3H), 2,66-2,84 (m, 2H), 3,68 (d, J=10.5 Hz, 1H), 3,94 (d, J=10.5 Hz, 1H), a 4.83 (c, 2H),? 7.04 baby mortality (c, 1H), 7,31 (c, 1H), 7,99 (c, 1H).

Mass spectrum (ESI⁺) m/z: 359 [M+1]⁺

Example 81 synthesis

(3R*,4S*)-4-[(2-Cyclopentylacetyl)amino]-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-g]cinoxacin-3-ol

This compound was synthesized according to the method of example 59 synthesis.

(3R*,4S*)-6,7-Diamino-4-[(2-cyclopentylacetyl)amino]-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-3-ol

Black amorphous product

(3R*,4S*)-4-[(2-Cyclopentylacetyl)amino]-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-g]cinoxacin-3-ol

¹H-NMR (CDCl₃) δ: 1,05 (m, 2H), 1,31 (s, 3H), 1,50-1,90 (m, N), to 1.59 (s, 3H), 2,60-2,90 (m, 2H), 3,37 (users, 1H), 3,68 (d, J=10.4 Hz, 1H), 3,93 (d, J=10.4 Hz, 1H), 7,44 (s, 1H), 8,03 (s, 1H), 8,66 (d, J=1.7 Hz, 1H), total of 8.74 (d, J=1.7 Hz, 1H).

Example 82 synthesis

(3R*,4S*)-3-Hydroxy-2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-7-carboxylic acid

To a solution of (3R*,4S*)-3-hydroxy-2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-7-carbonitrile described in synthesis example 14 (465 mg, 1.20 mmol), in ethanol (5 ml) was added at room temperature an aqueous solution of sodium hydroxide (3 mol/l, 5 ml) and the resulting mixture was stirred for 2 hours at the boil under reflux. After cooling to room temperature the resulting solution was neutralized with 1 mol/l hydrochloric acid, precipitated precipitated brown solid was filtered and obtained target product (yield: 90%).

Brown solid

¹H-NMR (CDCl₃) δ: 1,07 (c, 3H), 1.41 to (c, 3H), 2,46 (c, 3H), 2,89-is 3.08 (user., 2H), 3,10-3,28 (user., 2H), a 4.03-4,22 (user., 1H), 4,30-of 4.44 (user., 1H), 7,01-rate of 7.54 (m, 7H), 7,86 (c, 1H), 8,51-8,73 (user., 1H).

Mass spectrum (ESI⁺) m/z: 407 [M+1]⁺

Example 83 synthesis

2 maleate (3R*,4S*)-7-aminomethyl-2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

(3R*,4S*)-7-Aminomethyl-2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

To a solution of (3R*,4S*)-3-hydroxy-2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-7-carbonitrile described in synthesis example 14 (110 mg, 0,283 mmol)in acetic acid (5 ml) was added at room temperature, 10% Pd/C (22 mg) and the mixture was mixed in ECENA 2 hours in hydrogen atmosphere. Upon completion of the reaction, the resulting solution was filtered through celite, the solvent drove away, then added to the residue aqueous solution of sodium carbonate and the resulting solution was extracted with chloroform, dried over anhydrous magnesium sulfate, the solvent drove, getting the crude product (3R*,4S*)-7-aminomethyl-2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol (75,1 mg).

¹H-NMR (CDCl₃) δ: 1.14 in (c, 3H), 1,46 (c, 3H), 2,48 (c, 3H), by 2.73 (t, J=6.6 Hz, 2H), 2,88-2,95 (m, 2H), 3,53 (d, J=10.5 Hz, 1H), of 3.77 (d, J=10,2 Hz, 1H), 3,98 (c, 2H),? 7.04 baby mortality (c, 1H), 7,12-of 7.23 (m, 6H), 7,84 (c, 1H).

Mass spectrum (ESI⁺) m/z: 392 [M+1]⁺

2 maleate (3R*, 4S*)-7-aminomethyl-2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

(output 2 stages: 14%)

Brown crystals

TPL: 136-140°C

¹H-NMR (DMSO-d₆) δ: 1,18 (c, 3H), 1,49 (c, 3H), 2,60 (c, 3H), 2,90-3,00 (m, 2H), 3,24-to 3.35 (m, 2H), was 4.02 (users, 1H), 4,33 (c, 2H), 4,51 (users, 1H), 6,04 (c, 4H), 7,21-7,42 (m, 7H), 8,32 (users, 2H), at 8.36 (c, 1H)

Example 84 synthesis

1 maleate (3R*,4S*)-9-hydroxymethyl-2,2-dimethyl-4-[(2-phenylethyl)amino)]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

This compound was synthesized according to the method of example 18 synthesis.

(2,2-Dimethyl-2H-pyrano[2,3-g]quinoline-9-yl)acetate

To a solution of 2,2,9-trimethyl-2H-pyrano[2,3-g]quinoline described in example of synthesis 1 (3,30 mg, 14.6 mmol)in which hloroform (33 ml) was added dropwise at room temperature a solution of m-chloroperbenzoic acid (5,54 g, a 19.5 mmol) in a mixture of chloroform (13,2 ml) - methanol (3.3 ml) and the resulting mixture was stirred at room temperature for 1 hour. Upon completion of the reaction was added to a mixture of aqueous sodium thiosulfate solution and the resulting solution was extracted. The organic phase was washed with an aqueous solution of sodium bicarbonate, then with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After removal of the solvent was added to the residue at room temperature, acetic anhydride (46 ml) and the resulting mixture was stirred at 150°C for 1 hour. Upon completion of the reaction, acetic anhydride drove away, the residue was neutralized with an aqueous solution of sodium carbonate, was extracted with chloroform, the organic phase is washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After removal of the solvent the residue was column purified by medium pressure chromatography (hexane/ethyl acetate = 1/1) and received a target product (yield: 34%).

¹H-NMR (CDCl₃) δ: 1,41 (c, 6H), 2,09 (c, 3H), lower than the 5.37 (c, 2H), of 5.84 (d, J=9.9 Hz, 1H), of 6.49 (d, J=9.9 Hz, 1H), 7,09 (c, 1H), 7,24 (d, J=4.4 Hz, 1H), 7,66 (c, 1H), 8,61 (d, J=4.4 Hz, 1H).

Mass spectrum (ESI⁺) m/z: 284 [M+1]⁺

(3R*, 4R*)-(3,4-Epoxy-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-9-yl)acetate

(Yield: 58%)

of 99.5% ee; CHIRALPAK AD-RH 20 mm phosphate buffer (pH 8.0)/acetonitrile 60/40, retention time: 9,5 minutes

Pale yellow solid

¹H-NMR (CDCl₃) δ: 1,31 (c, 3H), 1,66 (c, 3H), 2,18 (c, 3H), 3,62 (d, J=4.4 Hz, 1H), 4,18 (d, J=4.4 Hz, 1H), vs. 5.47 (d, J=2.2 Hz, 2H), 7,28 (c, 1H), 7,38 (d, J=4,1 Hz, 1H), 8,16 (c, 1H), 8,78 (d, J=4.4 Hz, 1H).

Mass spectrum (ESI⁺) m/z: 300 [M+1]⁺

(3R*,4S*)-9-Hydroxymethyl-2,2-dimethyl-4-[(2-phenylethyl)amino)]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

(Yield: 80%)

Brown amorphous product

¹H-NMR (CDCl₃) δ: 1,23 (c, 3H), 1,52 (c, 3H), 2.77-to of 2.81 (m, 2H), 2,90 totaling 3.04 (m, 2H), to 3.58 (d, J=10.5 Hz, 1H), 3,83 (d, J=10.4 Hz, 1H), 5,08 (c, 2H), 7,17-7,21 (m, 4H), 7,26-7,31 (m, 2H), 7,44 (d, J=4.4 Hz, 1H), 7,98 (c, 1H), 8,65 (t, J=4,7 Hz, 1H).

Mass spectrum (ESI⁺) m/z: 379 [M+1]⁺

Mass spectrum (ESI^-) m/z: 423 [M+45]⁺(HCOOH adduct)

1 maleate (3R*,4S*)-9-hydroxymethyl-2,2-dimethyl-4-[(2-phenylethyl)amino)]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

(Yield: 88%)

White crystals

TPL:163-169°C (decomposition)

¹H-NMR (DMSO-d) δ: 1,17 (c, 3H), 1.50 in (c, 3H), 2,94-a 3.01 (m, 1H), 3,09-is 3.21 (m, 2H), 3,35-to 3.38 (m, 2H), 4.09 to (DD, J=9.6 Hz, 6.3 Hz, 1H), 4.72 in (d, J=9.4 Hz, 1H), 4,91 (c, 2H), 5,57 (users, 1H), between 6.08 (c, 2H), 6,34 (d, J=5.5 Hz, 1H), 7.23 percent-7,39 (m, 6H), 7,52 (d, J=4.4 Hz, 1H), 8,45 (c, 1H), 8,77 (d, J=4.4 Hz, 1H)

Example 85 synthesis

3/2 maleate (3R*,4S*)-2,2,9-trimethyl-4-[(2-phenylethyl)amino)]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3,7-diol

This compound was synthesized according to the method of example 18 synthesis.

(2,2,9-Trimethyl-2H-pyrano[2,3-g]Hina the n-7-yl)acetate

To a solution of 2,2,9-trimethyl-2H-pyrano[2,3-g]quinoline described in example of synthesis 1 (3,30 g, 14.6 mmol)in chloroform (33 ml) was added dropwise at room temperature a solution of m-chloroperbenzoic acid (5,54 g of 19.5 mmol) in a mixture of chloroform (13,2 ml) - methanol (3.3 ml) and the resulting mixture was stirred at room temperature for 1 hour. Upon completion of the reaction was added to a mixture of aqueous sodium thiosulfate solution and the resulting solution was extracted. The organic phase was washed with an aqueous solution of sodium bicarbonate, then with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After removal of the solvent was added to the residue at room temperature, acetic anhydride (46 ml) and the resulting mixture was stirred at 150°C for 1 hour. Upon completion of the reaction drove acetic anhydride, the residue was neutralized with an aqueous solution of sodium carbonate, was extracted with chloroform, the organic phase is washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After removal of the solvent the residue was column purified by medium pressure chromatography (hexane/ethyl acetate = 1/1) and received a target product (yield: 23%).

Red oily product

¹H-NMR (CDCl₃) δ: 1,49 (c, 6H), 2,395 (c, 3H), 2,404 (c, 3H), 5,90 (d, J=9.9 Hz, 1H), return of 6.58 (d, J=9.9 Hz, 1H), and 7.3 (c, 1H), 7,74 (c, 1H), 8,48 (c, 1H).

Mass spectrum (ESI⁺) m/z: 284 [M+1]⁺

[(3R*,4R*)-3,4-Epoxy-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-7-yl]acetate

(Yield: 37%)

CHIRALPAKAD-RH 20 mm phosphate buffer (pH 8.0)/acetonitrile = 60/40, retention time: 6,6 minutes

Brown amorphous product

¹H-NMR (CDCl₃) δ: 1,29 (c, 3H), 1,64 (c, 3H), 2,41 (c, 6H), 3,60 (d, J=4.4 Hz, 1H), 4,15 (d, J=4,1 Hz, 1H), 7,31 (c, 1H), 8,10 (c, 1H), of 8.47 (c, 1H).

Mass spectrum (ESI⁺) m/z: 300 [M+1]⁺

(3R*,4S*)-2,2,9-Trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3,7-diol

(Yield: 46%)

Brown amorphous product

¹H-NMR (CDCl₃) δ: 1,25 (c, 3H), 2.05 is (c, 3H), 2,48 (c, 3H), 2,80 (t, J=6.6 Hz, 2H), 2,93-of 3.12 (m, 2H), to 3.58 (d, J=10,2 Hz, 1H), 3,84 (d, J=10,2 Hz, 1H), 7,12-7,25 (m, 6H), 8,02 (c, 1H), 8,66 (c, 1H).

Mass spectrum (ESI⁺) m/z: 379 [M+1]⁺

Mass spectrum (ESI^-) m/z: 377 [M-1]⁺

3/2 maleate (3R*,4S*)-2,2,9-trimethyl-4-[(2-phenylethyl)amino)]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3,7-diol

(Yield: 70%)

White crystals

TPL: 184-188°C (decomposition)

¹H-NMR (DMSO-d₆) δ: 1,16 (c, 3H), 1,49 (c, 3H), 2,35 (c, 3H), 2,94-3,00 (m, 1H), 3,10-up 3.22 (m, 2H), 3,36-of 3.42 (m, 1H), 4.04 the-4,10 (m, 1H), 4,66 (d, J=9.4 Hz, 1H), 6,12 (c, 3H), 6,33 (d, J=5.8 Hz, 1H), 7.23 percent and 7.36 (m, 6H), 8,30 (c, 1H), 8,49 (c, 1H), 10,12 (c, 1H).

Example 86 synthesis

Hydrochloride, (3R*,4S*)-7-chloro-2,2,9-trimethyl-6λ5-hydroxy-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

tert-Butyl(2-phenylethyl)[(3R*,4S*)-7-chloro-3-hydroxy-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-4-yl]carbamate

To a solution of (3R*,4S*)-7-chloro-2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol as described in example 19 synthesis (391 mg, 0,99 mmol)and di-tert-BUTYLCARBAMATE (430 mg, 1.97 mmol) in tetrahydrofuran (8 ml) was added dropwise triethylamine (600 μl, the 4.29 mmol) and the resulting mixture was stirred at room temperature for 2 hours. It was further added to the mixture at room temperature, di-tert-BUTYLCARBAMATE (430 mg, 1.97 mmol) and the resulting mixture was stirred over night. Upon completion of the reaction was added to a mixture aqueous solution of sodium carbonate and the resulting solution was extracted with ethyl acetate. The organic phase was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After removal of the solvent the residue was column purified by medium pressure chromatography (hexane/ethyl acetate = 10/1) and received a target product (yield: 87%).

Mass spectrum (ESI⁺) m/z: 497 [M+1]⁺

Mass spectrum (ESI^-) m/z: 541 [M+45]⁺(HCOOH adduct)

tert-Butyl(2-phenylethyl)[(3R*,4S*)-7-chloro-3-hydroxy-2,2,9-trimethyl-6λ5-hydroxy-3,4-dihydro-2H-pyrano[2,3-g]quinoline-4-yl]carbamate

To a solution of tert-butyl(2-phenylethyl)[(3R*,4S*)-7-chloro-3-hydroxy-2,,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-4-yl]carbamate (100 mg, 0.20 mmol) in chloroform (1 ml) was added dropwise at room temperature a solution of m-chloroperbenzoic acid (75,9 mg, 0.44 mmol) in a mixture of chloroform (0.4 ml)-methanol (0.1 ml) and the resulting mixture was stirred at room temperature for 30 minutes. At room temperature, additional solution was added m-chloroperbenzoic acid (75,9 mg, 0.44 mmol) in chloroform (0.4 ml) and the resulting mixture was stirred over night. Upon completion of the reaction was added to a mixture of aqueous sodium thiosulfate solution and the resulting solution was extracted. The organic phase was washed with an aqueous solution of sodium bicarbonate, then with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After removal of the solvent the residue was column purified by medium pressure chromatography (hexane/ethyl acetate = 3/1 to 1/1) and received a target product (yield: 41%).

Mass spectrum (ESI⁺) m/z: 513 [M+1]⁺

Mass spectrum (ESI^-) m/z: 557 [M+45]⁺(HCOOH adduct)

Hydrochloride, (3R*,4S*)-7-chloro-2,2,9-trimethyl-6λ5-hydroxy-4-[(2-phenylethyl)amino)]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

To a solution of tert-butyl(2-phenylethyl)[(3R*,4S*)-7-chloro-3-hydroxy-2,2,9-trimethyl-6λ5-hydroxy-3,4-dihydro-2H-pyrano[2,3-g]quinoline-4-yl]carbamate (41.7 mg, of 0.081 mmol) in 1,4-dioxane (0.2 ml) was added at room temperature 4 mol/l solution of hydrogen chloride in dioxane (0,42 ml) and received the th mixture was stirred at 80°C for 1 hour. Upon completion of the reaction, precipitated precipitated solid was filtered and washed with diisopropyl ether, obtaining the target product (yield: 72%).

White crystals

TPL: 174-179°C (decomposition)

¹H-NMR (DMSO-d₆) δ: 1.14 in (c, 3H), 1,49 (c, 3H), 2,53 (c, 3H), 3.00 and-3,55 (m, 4H), 4,21 (d, J=9.1 Hz, 1H), 4,76 (users, 1H), 7.23 percent-7,31 (m, 6H), 7,45 (c, 1H), 7,65 (c, 1H), remaining 9.08 (c, 1H), 9,37 (users, 1H), 10,16 (users, 1H).

Mass spectrum (ESI⁺) m/z: 413, 415 [M+1]⁺

Mass spectrum (ESI^-) m/z: 457, 459 [M+45]⁺(HCOOH adduct)

Example 87 synthesis

Hydrochloride, (3R*,4S*)-7-chloro-4-{[2-(4-forfinal)ethyl]amino}-2,2,9-trimethyl-6λ5-hydroxy-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

This compound was synthesized using the compound of example 23 synthesis similar to the method of example 86 synthesis.

tert-Butyl[2-(4-forfinal)ethyl][(3R*,4S*)-7-chloro-3-hydroxy-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-4-yl]carbamate

Mass spectrum (ESI⁺) m/z: 515, 517 [M+1]⁺

Mass spectrum (ESI^-) m/z: 559, 561 [M+45]⁺(HCOOH adduct)

tert-Butyl[2-(4-forfinal)ethyl][(3R*,4S*)-7-chloro-3-hydroxy-2,2,9-trimethyl-6λ5-hydroxy-3,4-dihydro-2H-pyrano[2,3-g]quinoline-4-yl]carbamate

(output 2 stages: 30%).

Mass spectrum (ESI⁺) m/z: 531, 533 [M+1]⁺

Mass spectrum (ESI^-) m/z: 575, 577 [M+45]⁺(HCOOH adduct)

Hydrochloride, (3R*,4S*)-7-chloro-4-{[2-(4-f is arvanil)ethyl]amino}-2,2,9-trimethyl-6λ5-hydroxy-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

(yield: 71%).

Pale-yellow crystals

TPL: 193-198°C (decomposition)

¹H-NMR (DMSO-d₆) δ: 1.14 in (c, 3H), 1,49 (c, 3H), 2,53 (c, 3H), 2,96-of 3.06 (m, 1H), 3,16-3,18 (m, 2H), 3,36 (users, 1H), 4,19-4,22 (m, 1H), 4.75 V-4,78 (m, 1H), 7,13 (t, J=remaining 9.08 Hz, 2H), 7,26-7,31 (m, 2H), 7,45 (c, 1H), 7,65 (c, 1H), 9,06 (c, 1H), 9,37 (users, 1H), 10,16 (users, 1H).

Mass spectrum (ESI⁺) m/z: 431, 433 [M+1]⁺

Mass spectrum (ESI^-) m/z: 475, 477 [M+45]⁺

Example 88 synthesis

Hydrochloride, (3R*,4S*)-7-chloro-2,2,9-trimethyl-6λ5-hydroxy-4-pentylamine-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol

This compound was synthesized using the compound of example 52 synthesis similar to the method of example 86 synthesis.

tert-Butyl(pencil)[(3R*,4S*)-7-chloro-3-hydroxy-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-4-yl]carbamate

Mass spectrum (ESI⁺) m/z: 463, 465 [M+1]⁺

Mass spectrum (ESI^-) m/z: 507, 509 [M+45]⁺(HCOOH adduct)

tert-Butyl(pencil)[(3R*,4S*)-7-chloro-3-hydroxy-2,2,9-trimethyl-6λ5-hydroxy-3,4-dihydro-2H-pyrano[2,3-g]quinoline-4-yl]carbamate

(output 2 stages: 23%).

Mass spectrum (ESI⁺) m/z: 479, 481[M+1]⁺

Mass spectrum (ESI^-) m/z: 523, 525 [M+45]⁺(HCOOH adduct)

Hydrochloride, (3R*,4S*)-7-chloro-

2,2,9-trimethyl-6λ5-hydroxy-4-pentylamine-3,4-dihydro-2H-pyrano[2,3g]quinoline-3-ol

(yield: 60%).

Pale-yellow crystals

TPL: 226-230°C (decomposition

¹H-NMR (DMSO-d₆) δ: 0,86 (t, J=6.3 Hz, 3H), 1,16 (c, 3H), 1,27-of 1.29 (m, 4H), 1.50 in (c, 3H), 1.60-to 1,72 (m, 2H), 2,54 (c, 3H), 2,86 (users, 1H), 3,07 (users, 1H), 4,07-4,10 (m, 1H), 4,71 (d, J=8.5 Hz, 1H), 6,51 (d, J=4,7 Hz, 1H), 7,47 (c, 1H), to 7.67 (c, 1H), 9,04 (c, 1H), 9,19 (users, 1H), 9,74 (users, 1H).

Mass spectrum (ESI⁺) m/z: 379, 381 [M+1]⁺

Mass spectrum (ESI^-) m/z: 423, 425 [M+45]⁺(HCOOH adduct)

Example 89 synthesis

(6S*,7R*)-8,8-Dimethyl(-6-[(2-phenylethyl)amino)]-1,6,7,8-tetrahydroharman[7,6-e][1,3,4]oxadiazine-7-ol-2,2-dioxide

tert-Butyl(2-phenylethyl)[(3R*,4S*)-7-{[(chloromethyl)sulfonyl]amino}-3-hydroxy-6-methoxy-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-4-yl]carbamate

To a solution of tert-butyl(2-phenylethyl)[(3R*,4S*)-7-amino-3-hydroxy-6-methoxy-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-4-yl]carbamate described in the synthesis example 71 (1.04 g, 2,35 mmol)in pyridine (1.90 ml, 23.5 mmol) was added chloromethanesulfonyl (0,31 ml, to 3.52 mmol) and the resulting mixture was stirred at room temperature for 10 hours. Upon completion of the reaction was added to a mixture of 1 mol/l aqueous solution of hydrochloric acid (30 ml) to bring the pH to about 7 and then the resulting solution was extracted with ethyl acetate, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated. The resulting mixture was purified column chromatography (hexane/ethyl is Etat = 3/1) and received a target product (yield: 81%).

Colorless oily product

LC/mass spectrum (ESI⁺) m/z: 555 [M+1]⁺

LC/mass spectrum (ESI^-) m/z: 553 [M-1]⁺

1-Chloro-N-{(3R*,4S*)-3,6-dihydroxy-2,2-dimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-1-benzopyran-7-yl}methanesulfonamide

To a solution of tert-butyl(2-phenylethyl)[(3R*,4S*)-7-{[(chloromethyl)sulfonyl]amino}-3-hydroxy-6-methoxy-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-4-yl]carbamate (400 mg, to 0.72 mmol) in dichloromethane (4.0 ml) was added under cooling in an ice bath, 1 mol/l solution trichromate boron in dichloromethane (3,61 ml, 3.61 mmol) and the resulting mixture was stirred at 0°C for 1 hour. Added water and the resulting mixture was additionally stirred for 30 minutes. The obtained solid was filtered, washed with water and then with chloroform. The solid was dried at 60°C for 3 hours under reduced pressure and obtained the desired product in quantitative yield.

LC/mass spectrum (ESI⁺) m/z: 441 [M+1]⁺

LC/mass spectrum (ESI^-) m/z: 439 [M-1]⁺

2,2-Dioxide (6S*,7R*)-8,8-dimethyl-6-[(2-phenylethyl)amino]-1,6,7,8-tetrahydroharman[7,6-e][1,3,4]oxadiazine-7-ol

To a solution of 1-chloro-N-{(3R*,4S*)-3,6-dihydroxy-2,2-dimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-1-benzopyran-7-yl}methanesulfonamide (220 mg, 0.50 mmol) in methanol (2.2 ml) was added 1 mol/l aqueous sodium hydroxide solution (of 1.00 ml, 1.00 mmol who) and the resulting mixture was stirred at room temperature for 3 hours. Then the temperature was raised to 50°C and the mixture was additionally stirred for 2 hours. Upon completion of the reaction the solution was cooled during storage, neutralized with a saturated aqueous solution of ammonium chloride, was extracted 4 times with chloroform, and dried over anhydrous sodium sulfate. The solvent drove and got the target product (yield: 37%).

Yellow solid

¹H-NMR (CDCl₃) δ: 1,13 (c, 3H), 1,44 (c, 3H), 2,54 (users, 3H), 2,79-to 3.02 (m, 4H), 3,49 (d, J=10.0 Hz, 1H)and 3.59 (d, J=10.0 Hz, 1H), 4,86 (c, 2H), 6,23 (c, 1H), 6,78 (c, 1H), 7,21-to 7.35 (m, 5H).

LC/mass spectrum (ESI⁺) m/z: 405 [M+1]⁺

LC/mass spectrum (ESI^-) m/z: 403 [M-1]⁺

Example 90 synthesis

(±)-TRANS-6-Benzyl-3-hydroxy-2,2-dimethyl-4-[(2-phenylethyl)amino]-2,3,4,6-tetrahydropyrido[2,3-f]indole-7-he

N-Benzyl-5-methoxyisatin

To a solution of 5-methoxyisatin (15.0 g, 84,7 mmol) in DMF (100 ml) was added at 0°C, sodium hydride (5,1 g, 127 mmol) and benzyl bromide (12.1 ml, 101,6 mmol) and the resulting mixture was stirred for 1 hour. Added water and the resulting solution was extracted with ethyl acetate. The organic phase was washed with a saturated aqueous solution of ammonium chloride and then saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated, obtaining the target product (yield: 96%).

Brown t is ardoe substance

¹H-NMR (CDCl₃) δ: of 3.77 (c, 3H), 4,91 (c, 2H), to 6.67 (d, J=8.5 Hz, 1H), between 7.0 and 7.1 (m, 1H), 7,15 (m, 1H), 7,25 was 7.45 (m, 5H)

N-Benzyl-5-hydroxyvitamin

To a solution of N-benzyl-5-methoxyisatin (3.0 g, and 11.2 mmol) in dichloromethane (60 ml) was added aluminium chloride (3.7 g, 28.1 mmol) and the resulting mixture was stirred at 100°C for 1 hour. Added water and the resulting solution was extracted with ethyl acetate. The organic phase is washed with saturated aqueous solution of sodium bicarbonate and then saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated, obtaining the target product (yield: 78%).

Red solid

Mass spectrum (ESI⁺) m/z: 254[M+1]⁺

Mass spectrum (ESI^-) m/z: 252[M-1]⁺

6-Benzyl-2,2-dimethyl-2H-pyrano[2,3-f]indole-7,8-dione

In a stream of nitrogen a solution of N-benzyl-5-hidroxizina (4,74 g, to 18.7 mmol), potassium iodide (5,09 g of 31.8 mmol), potassium carbonate (5,17 g, or 37.4 mmol), copper iodide (71 mg, and 0.37 mmol) and 3-chloro-3-methyl-1-butyne (a 4.83 ml, 43,0 mmol) in DMF (47 ml) was stirred at 70°C for 2 hours. Upon completion of the reaction was added to a mixture of saturated aqueous solution of ammonium chloride, the resulting solution was extracted with ethyl acetate. The organic phase is washed with saturated aqueous sodium chloride, dried over anhydrous sulfa what Ohm sodium, concentrated and was purified column chromatography on a short column with silica gel (chloroform).

Added 1,2-dichlorobenzene (9 ml) and the resulting mixture was stirred at 200°C for 30 minutes. After concentrating the reaction solution, the residue was purified column chromatography on silica gel (hexane/ethyl acetate = 5/1)to give the target product (yield: 8%).

Red oily product

Mass spectrum (ESI⁺) m/z: 320 [M+1]⁺

6-Benzyl-2,2-dimethyl-2H-pyrano[2,3-f]indole-7-he

To a solution of 6-benzyl-2,2-dimethyl-2H-pyrano[2,3-f]indole-7,8-dione (500 mg, 1.57 mmol) in DMF (5 ml) was added hydrazine monohydrate (2.5 ml) and the resulting mixture was stirred at 100°C for 1.5 hours. Was added to a mixture of water and the resulting solution was extracted with ethyl acetate. The organic phase was washed with a saturated aqueous solution of ammonium chloride and then saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated and purified column chromatography on silica gel (hexane/ethyl acetate = 3/1)to give the target product (yield: 65%).

Yellow amorphous product

Mass spectrum (ESI⁺) m/z: 306 [M+1]⁺

(±)-TRANS-6-Benzyl-3-hydroxy-2,2-dimethyl-4-[(2-phenylethyl)amino]-2,3,4,6-tetrahydropyrido[2,3-f]indole-7-he

6-benzyl-2,2-dimethyl-2H-pyrano[2,3-f]indole-7-ONU (210 mg, 0.69 mmol) in RAS is the thief of a mixture of chloroform-water was added sodium hydrogen carbonate (115 mg, 1.38 mmol) and m-chloroperbenzoic acid (237 mg, 1.38 mmol) and the resulting mixture was stirred at room temperature for 3.5 hours. Was added to the reaction solution, an aqueous solution of sodium bicarbonate and saturated aqueous sodium thiosulfate solution, the resulting solution was extracted with chloroform, washed with a saturated solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated. To the obtained residue was added 2-phenylethylamine (173 μl, 1.38 mmol), lithium perchlorate (73 mg, 0.69 mmol) and dioxane (1 ml) and the resulting mixture was stirred at 70°C for 2 hours. To the reaction solution were added water and the resulting solution was extracted with ethyl acetate. The organic phase is washed with saturated aqueous solution of sodium bicarbonate and then saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated, purified column chromatography on silica gel (hexane/ethyl acetate = 1/1) and recrystallized from ethyl acetate, obtaining the target product (yield 2 stages: 16%).

Pale pink crystals

TPL:195°C (decomposition)

¹H-NMR (CDCl₃) δ: 1,16 (c, 3H), 1,45 (c, 3H), 2,8-3,2 (m, 4H), 3,51 (c, 2H)and 3.59 (d, J=4.4 Hz, 1H), to 3.73 (m, 1H), and 4.75 (d, J=15.7 Hz, 1H), 4,84 (d, J=15.7 Hz, 1H), 6,51 (c, 1H), 6.73 x (c, 1H), 7,2-7,4 (m, 10H).

Mass spectrum (ESI⁺) m/z: 443 [M+1]⁺

Mass spectrum (ESI^-) m/z: 441[M-1]⁺

^{Example 91 synthesis}

^{(±)-TRANS-4-{[2-(Cyclohexa-1,3-Dien-2-yl)ethyl]amino}-3-hydroxy-2,2-dimethyl-2,3,4,6-tetrahydropyrido[2,3-f]indole-7-he}

^{In a stream of nitrogen to liquid ammonia (5 ml) was added sodium (90 mg, 3,91 mmol) at -78°C and stirred the mixture. Was added dropwise at -45°C a solution of (±)-TRANS-6-benzyl-3-hydroxy-2,2-dimethyl-4-[(2-phenylethyl)amino]-2,3,4,6-tetrahydropyrido[2,3-f]indole-7-it (173 mg, 0,39 mmol) in THF (2 ml) and the resulting mixture was stirred for 15 minutes. Upon completion of the reaction was added to a mixture of saturated aqueous solution of ammonium chloride, the resulting solution was extracted with ethyl acetate. The organic phase is washed with water and then saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, concentrated and purified column chromatography on silica gel (ethyl acetate)to give the target product (yield: 19%).}

^{White solid}

^{1H-NMR (CDCl₃) δ: 1,21 (c, 3H), 1,49 (c, 3H), and 2.27 (t, J=6.9 Hz, 2H), 2,6-2,8 (m, 4H), 2,82-to 3.02 (m, 2H), 3,44 (m, 2H), 3,63 (d, J=4.4 Hz, 1H), 3,81 (d, J=4.4 Hz, 1H), 5,54 (c, 1H), 5,74 (c, 2H), 6,72 (c, 1H), 6,86 (c, 1H), 8,78 (c, 1H).}

[Examples of compositions]

Example compositions 1

Tablet:

The above ingredients are mixed in the usual way and then get 10000 covered sugar tablets, each containing 1 mg of active ingredient per tablet.

Example composition 2

Capsule:

The above ingredients are mixed in the usual way and then fill with a mixture of gelatin capsules, receiving 1000 capsules each containing 1 mg of active ingredient per capsule.

An example of the composition 3

Soft capsule:

The above ingredients are mixed in the usual way and then fill with a mixture of soft gelatin capsules No. 3, receiving 10,000 capsules each containing 1 mg of active ingredient per capsule.

An example of the composition 4

Ointment:

The above ingredients are mixed in the usual way, getting 1%ointment.

An example of the composition 5

Suppository:

(* trade name for the connection triglyceride type).

The above ingredients were mixed in the molten state in the usual way, then poured into containers for suppositories, cooled to solidification and received 1000 suppositories (1 g), each of which contained 1 mg of the active ingredient on the suppository.

An example of a composition of 6

Injection composition:

[Example pharmacological test]

Effect on the effective refractory period

Method

Beagle was anestesiologi pentobarbital sodium, thoracotomy was performed along the middle line under light and made an incision on pericardia for exposure of the heart. The electrocardiogram (ECG) were recorded using bipolar electrodes attached to the surface of the free wall of the right atrium, right atrium and free wall of the right ventricle. Vanaskie nerves were stimulated using the device for electrostimulation with nichrome wire, is inserted in vagusnye nerves on both sides of the neck. Conditions for the stimulation vagusnye nerves have set in such a way that the RR intervals in the ECG were increased by approximately 10 msec compared with intervals before stimulation.

Effective refractory periods of the atrium and ventricle were determined using the S1-S2 method extrastimulation if the length of the main loop 300 msec during bilateral stimulation vagusnye nerve using programmable electrical stimulator. For the next 10 main stimulus (S1) was followed by premature extrastimuli (S2), 2 times the diastolic threshold. The interval S1-S2 sequentially reduced to 2 MS and determined effective refra the even period as a moment, when S2 could not give increased response.

For evaluating the effect of medicines has identified effective refractory periods of the atrium and ventricle before the introduction of drugs, then intravenously injected corresponding connection at a dose of 0.3 mg/kg or 0.6 mg/kg was determined after 5 minutes after the introduction of effective refractory periods of the atrium and ventricle.

The results are presented in the form of time, prolongation of the effective refractory periods of the atrium and ventricle, i.e. the [effective refractory period after administration of the medicinal product]- [effective refractory period before the introduction of the medicinal product] (msec).

Results

Compounds of the present invention showed a prolonging effect on the effective refractory period selective for atrium, as shown in the table below.

The effect of the invention

Thus, the compounds according to the present invention, providing a prolonging effect on the effective refractory period selective for atrium, can be used as agents against atrial fibrillation and supraventricular antiaris the practical agents and are useful as medicines. In addition, since the compounds according to the present invention have an insignificant effect on the ventricles, they can contribute to the safe treatment of the above arrhythmic conditions.

1. Derived benzopyran formula (I) or (II) or its pharmaceutically acceptable salt

where R¹and R²independently represent a hydrogen atom or a C_1-6alkyl group;
R³represents a hydroxy group;
R⁴represents a hydrogen atom;
m is an integer from 1 to 4;
n is an integer from 0 to 4;
V represents a simple bond, CR⁷R⁸where R⁷represents a
With_1-6alkyl group;
hydroxy group Il is
C_1-6alkoxy group, and
R⁸represents a
a hydrogen atom,
With_1-6alkyl group;
hydroxy group, or
C_1-6alkoxy group, or
V represents NR⁹where R⁹represents a hydrogen atom or a C_1-6alkyl group;
R⁵represents a hydrogen atom;
R⁶represents a
a hydrogen atom,
With_1-6alkyl group,
With_3-8cycloalkyl group_3-8cycloalkenyl group,
an amino group, a C_1-6alkylamino;
With_6-14aryl group, a C_2-9heteroaryl group, or a C_2-9heterocyclic group (each of the aryl group, heteroaryl group, or heterocyclic group may be optionally substituted by a halogen atom, a C_1-6alkyl group, a C_6-14aryl group (where the aryl group can be optionally substituted by 1 to 3 halogen atoms), or an amino group);
But a
or
where R¹¹and R¹²independently represent a hydrogen atom, a C_1-6alkyl group (where the alkyl group can be optionally substituted phenyl group), R¹³, R¹⁴, R¹⁵and R¹⁶independently represent a hydrogen atom, a halogen atom, a C_1-6alkyl group (where the alkyl group can be optionally substituted amino group or hydroxy group), hydroxy group, phenyl group, cyano, aminocarbonyl group, C_1-6alkylcarboxylic group or carboxyl group, and
X represents O, S, SO or SO₂.

2. Derived benzopyran or its pharmaceutically acceptable salt according to claim 1, where
R¹and R²represent a methyl group.

3. Derived benzopyran or its pharmaceutically acceptable the ol according to claim 2, where m is an integer from 1 to 3, and n is an integer from 0 to 2.

4. Derived benzopyran or its pharmaceutically acceptable salt according to claim 3, where V is a simple link.

5. Derived benzopyran or its pharmaceutically acceptable salt according to claim 4, where n is 0, and R⁶represents a C_6-14aryl group, where the aryl group can be optionally substituted with 1-3 halogen atoms or amino groups, and when there is a lot of substituents, they may be the same or different from each other.

6. Derived benzopyran or its pharmaceutically acceptable salt according to claim 5, where m is equal to 2.

7. Derived benzopyran or its pharmaceutically acceptable salt according to claim 4, where n is 0, and R⁶represents a C_2-9heteroaryl group, where the heteroaryl group may be optionally substituted by 1 to 3 halogen atoms.

8. Derived benzopyran or its pharmaceutically acceptable salt according to claim 7, where m is equal to 2.

9. Derived benzopyran or its pharmaceutically acceptable salt of claim 8, where
R⁶is a 2-pyridyloxy group, 3-pyridyloxy group or 4-pyridyloxy group.

10. Derived benzopyran or its pharmaceutically acceptable salt according to claim 4, where n is 0, and R⁶represents a C_2-4alkyl group, a C_3-8the CEC is olkalou group, With_3-8cycloalkenyl group or_3-8heterocyclic group, where the heterocyclic group may be optionally substituted C_1-6alkyl group).

11. Derived benzopyran or its pharmaceutically acceptable salt of claim 10, where m is equal to 2.

12. Derived benzopyran or its pharmaceutically acceptable salt according to claim 11, where R⁶is a n-sawn group, isopropyl group, t-pentelow group, C-hexoloy group, 1-C-pentanediol group, 2-C-pentanediol group, 3-C-pentanediol group, 1-C-hexenyl group, 2-C-hexenyl group or 3-C-hexenyl group.

13. Derived benzopyran or its pharmaceutically acceptable salt according to claim 3, where V represents CR⁷R⁸.

14. Derived benzopyran or its pharmaceutically acceptable salt according to clause 13, where R⁷represents a hydroxy group, and R⁸represents a hydrogen atom.

15. Derived benzopyran or its pharmaceutically acceptable salt according to clause 13, where m is an integer from 1 to 2, n is 0, and R⁶represents a
With_6-14aryl group or_2-9heteroaryl group, where each aryl group or heteroaryl group may be optionally substituted by 1 to 3 halogen atoms or amino groups, and when there is a lot of substituents, they can be the ut to be the same as or different from each other.

16. Derived benzopyran or its pharmaceutically acceptable salt according to clause 15, where R⁷represents a hydroxy group, and R⁸represents a hydrogen atom.

17. Derived benzopyran or its pharmaceutically acceptable salt according to clause 16, where m is 1, n is 0, and R⁶represents a C_6-14aryl group, where the aryl group can be optionally substituted with 1-3 halogen atoms or amino groups, and if there are multiple substituents, they may be identical or different from each other.

18. Derived benzopyran or its pharmaceutically acceptable salt according to clause 13, where m is an integer from 1 to 2, n is 0, and R⁶represents a C_1-4alkyl group, a C_3-8cycloalkyl group_3-8cycloalkenyl group or_2-9heterocyclic group, where the heterocyclic group may be optionally substituted by a halogen atom or C_1-6alkyl group).

19. Derived benzopyran or its pharmaceutically acceptable salt p, where R⁷represents a hydroxy group, and R⁸represents a hydrogen atom.

20. Derived benzopyran or its pharmaceutically acceptable salt according to claim 19, where R⁶is a n-sawn group, isopropyl group, t-pentelow group, C-hexoloy group, 1-the-pentanediol group, 2-C-pentanediol group, 3-C-pentanediol group, 1-C-hexenyl group, 2-C-hexenyl group or 3-C-hexenyl group.

21. Derived benzopyran or its pharmaceutically acceptable salt according to claim 3, where V represents NR⁹.

22. Derived benzopyran or its pharmaceutically acceptable salt according to item 21, where n is 0, and R⁶represents a C_6-14aryl group or_2-9heteroaryl group, where each aryl group or heteroaryl group may be optionally substituted by 1 to 3 halogen atoms or amino groups, and when there is a lot of substituents, they may be the same or different from each other.

23. Derived benzopyran or its pharmaceutically acceptable salt according to item 22, where m is equal to 2.

24. Derived benzopyran or its pharmaceutically acceptable salt according to claim 2, which is a compound of formula (I).

25. Derived benzopyran or its pharmaceutically acceptable salt according to claim 2, which is a compound of formula (II).

26. Derived benzopyran or its pharmaceutically acceptable salt p, 9, 12, 17, 20 or 24, where the ring structure And is a
or
where R¹¹, R¹³, R¹⁴and R¹⁵have the above values.

27. Derived benzopyran or its pharmaceutically acceptable salt p, where R¹¹represents a hydrogen atom, R¹³represents a hydrogen atom, halogen atom, carboxyl group or C_1-6alkyl group (where the alkyl group can be optionally substituted amino group or hydroxy group),
R¹⁴represents a hydrogen atom, and R¹⁵represents a hydrogen atom or a C_1-6alkyl group (where the alkyl group can be optionally substituted amino group or hydroxy group).

28. Derived benzopyran or its pharmaceutically acceptable salt p, 9, 12,17, 20 or 24, where the ring structure And is a
or
where R¹¹, R¹², R¹³and R¹⁴have the above values.

29. Derived benzopyran or its pharmaceutically acceptable salt p, where R¹¹and R¹²independently represent a hydrogen atom or a C_1-6alkyl group, and R¹³and R¹⁴independently from each other represent a hydrogen atom or a C_1-6alkyl group (where the alkyl group can be optionally substituted amino group or hydroxy group).

30. Derived benzopyran or its pharmaceutically acceptable salt according to clause 29, the de R ¹¹, R¹², R¹³and R¹⁴represent a hydrogen atom.

31. Derived benzopyran or its pharmaceutically acceptable salt p, 9, 12, 17, 20 or 24, where the ring structure And is a
or
where R¹¹, R¹³and R¹⁴have the above values.

32. Derived benzopyran or its pharmaceutically acceptable salt p, where R¹¹represents a hydrogen atom or a C_1-6alkyl group, R¹³and R¹⁴independently represent a hydrogen atom, halogen atom or C_1-6alkyl group (where the alkyl group can be optionally substituted amino group or hydroxy group) and X represents O.

33. Derived benzopyran or its pharmaceutically acceptable salt p, where R¹¹, R¹³and R¹⁴represent a hydrogen atom.

34. Derived benzopyran or its pharmaceutically acceptable salt p, 9, 12, 17, 20 or 24, where the ring structure And is a
or
where R¹¹, R¹², R¹³and R¹⁴have the above values.

35. Derived benzopyran or its pharmaceutically acceptable salt according to clause 34, where R¹¹and R¹²independently represent sobo is a hydrogen atom or a C _1-6alkyl group (where the alkyl group can be optionally substituted phenyl group), and R¹³and R¹⁴independently represent a hydrogen atom, halogen atom or C_1-6alkyl group (where the alkyl group can be optionally substituted amino group or hydroxy group.

36. Derived benzopyran or its pharmaceutically acceptable salt p, where R¹¹and R¹²independently represent a hydrogen atom or a C_1-6alkyl group, and R¹³and R¹⁴represent a hydrogen atom.

37. Derived benzopyran or its pharmaceutically acceptable salt, which is a
2,2,7,9-tetramethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
2,2,7-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
3-hydroxy-2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-7-carbonitrile,
3-hydroxy-2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-7-carboxamide,
{3-hydroxy-2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-7-yl}Etalon,
3,3-dimethyl-1-[(2-phenylethyl)amino]-2,3-dihydro-1H-pyrano[3,2-f]quinoline-2-ol,
7-hydroxymethyl-2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
7-chloro-2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
3-hydroxy-2,2,9-trimet the l-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-7-carboxylic acid
4-(benzylamino)-7-chloro-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
4-{[(1,3-benzodioxol-5-yl)methyl]amino}-7-chloro-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
7-chloro-2,2,9-trimethyl-4-[(3-phenylpropyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
7-chloro-4-{[2-(4-forfinal)ethyl]amino}-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
7-chloro-4-{[2-(2-forfinal)ethyl]amino}-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
7-chloro-4-{[2-(4-chlorophenyl)ethyl]amino}-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
4-{[2-(4-AMINOPHENYL)ethyl]amino}-7-chloro-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
7-chloro-4-[(2-hydroxy-2-phenylethyl)amino]-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
7-chloro-2,2,9-trimethyl-4-[(2-phenylbutyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
4-{[2-(1,3-benzodioxol-5-yl)ethyl]amino}-7-chloro-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
7-chloro-2,2,9-trimethyl-4-{[2-(1-piperidinyl)ethyl]amino}-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
7-chloro-2,2,9-trimethyl-4-{[2-(1-methyl-2-pyrrolidinyl)ethyl]amino}-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
4-[(2-anilinomethyl)amino]-7-chloro-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
7-chloro-4-({2-[ethyl(3-were)amino]ethyl}amino)-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
7-chloro-4-{[(1-ethyl-(R)-2-pyrrolidinyl)methyl]amino}-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
7-chloro-4-[(2,2-diatexite)and the eno]-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
7-chloro-2,2,9-trimethyl-4-{[2-(3-thienyl)ethyl]amino}-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
4-[2-(1H-pyrazole-1-yl)ethylamino]-7-chloro-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
7-chloro-2,2,9-trimethyl-4-{[2-(4-methylpyrazole-1-yl)ethyl]amino}-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
7-chloro-4-{[2-(4-chloropyrazole-1-yl)ethyl]amino}-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
7-chloro-2,2,9-trimethyl-4-{[2-(2-pyridyl)ethyl]amino}-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
7-chloro-2,2,9-trimethyl-4-{[2-(3-pyridyl)ethyl]amino}-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
7-chloro-2,2,9-trimethyl-4-{[2-(4-pyridyl)ethyl}amino}-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
7-chloro-4-ethylamino-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
7-chloro-4-isobutylamino-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
7-chloro-4-[(cyclopropylmethyl)amino]-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
7-chloro-4-isobutylamino-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
7-chloro-4-[(2-cyclopentylacetyl)amino]-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
7-chloro-4-{[2-(1-cyclopentenyl)ethyl]amino}-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
7-chloro-2,2,9-trimethyl-4-[(5-methylhexan-2-yl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
7-chloro-2,2,9-trimethyl-4-pentylamine-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
7-chloro-4-[(2-cyclohexylethyl)amino]-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
7-chloro-4-{[2-(tetrahydropyran-4-yl)ethyl]amino}2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
7-chloro-2,2,9-trimethyl-4-[{2-(4-tanil)ethyl}amino]-3,4-dihydro-2H-pyrano [2,3-g]quinoline-3-ol,
7-chloro-4-([6-(4-chlorophenyl)-3-pyridinyl]methyl}amino)-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
4-[(2-benzofuranyl)amino]-7-chloro-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
7-chloro-4-[(2-hydroxyphenyl)amino]-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
7,7-dimethyl-9-[(2-phenylethyl)amino] - 8.9bn-dihydro-7H-pyrano[2,3-g]cinoxacin-8-ol,
9-{[2-(2-forfinal)ethyl]amino}-7,7-dimethyl-8,9-dihydro-7H-pyrano[2,3-g]cinoxacin-8-ol,
9-{[2-(4-forfinal)ethyl]amino}-7,7-dimethyl-8,9-dihydro-7H-pyrano[2,3-g]cinoxacin-8-ol,
9-[(2-hydroxy-2-phenylethyl)amino]-7,7-dimethyl-8,9-dihydro-7H-pyrano[2,3-g]cinoxacin-8-ol,
7,7-dimethyl-9-pentylamine-8,9-dihydro-7H-pyrano[2,3-g]cinoxacin-8-ol,
2,2,7,7-tetramethyl-9-[(2-phenylethyl)amino] - 8.9bn-dihydro-7H-pyrano[2,3-g]cinoxacin-8-ol,
2,3-diethyl-7,7-dimethyl-9-[(2-phenylethyl)amino] - 8.9bn-dihydro-7H-pyrano[2,3-g]cinoxacin-8-ol,
3,3,7-trimethyl-9-[(2-phenylethyl)amino]-2-phenyl-8,9-dihydro-7H-pyrano[2,3-g]cinoxacin-8-ol,
2,7,7-trimethyl-9-[(2-phenylethyl)amino]-3-phenyl-8,9-dihydro-7H-pyrano[2,3-g]cinoxacin-8-ol,
3,3,7-trimethyl-9-[(2-phenylethyl)amino] - 8.9bn-dihydro-7H-pyrano[2,3-g]cinoxacin-8-ol,
9-[(2-cyclohexylethyl)amino]-7,7-dimethyl-8,9-dihydro-7H-pyrano[2,3-g]quinoline-8-ol,
7-hydroxy-6,6-dimethyl-8-[(2-phenylethyl)amino]-3,6,7,8-tetrahydroharmine[7,6-d]imidazol-2(1H)-he,
7-hydroxy-6,6-dimethyl-8-[(2-phenylethyl)amino]-4,6,7,8-tetrahydro-5-dioxa-4-azaanthracene-3-one,
7-hydroxy-4,6,6-trimethyl-8-[(2-phenylethyl)amino]-4,6,7,8-tetrahydro-1,5-dioxa-4-azaanthracene-3-one,
6,6-dimethyl-8-[(2-phenylethyl)amino]-2,3,4,6,7,8-hexahydro-1,5-dioxa-4-azaanthracene-7-ol,
7-hydroxy-6,6-dimethyl-8-[(2-phenylethyl)amino]-1,6,7,8-tetrahydro-4,5-dioxo-1-azaanthracene-2-it,
6,6-dimethyl-8-[(2-phenylethyl)amino]-1,2,3,6,7,8-hexahydro-4,5-dioxo-1-azaanthracene-7-ol,
9-hydroxymethyl-2,2-dimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3,7-diol,
7-aminomethyl-2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
7-chloro-2,2,9-trimethyl-6λ5-hydroxy-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
7-chloro-4-{[2-(4-forfinal)ethyl]amino}-2,2,9-trimethyl-6λ5-hydroxy-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
7-chloro-2,2,9-trimethyl-6λ5-hydroxy-4-pentylamine-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
4-{[2-(4-forfinal)ethyl]amino}-7-hydroxymethyl-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol or
2,2-dimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol.

38. Derived benzopyran or its pharmaceutically acceptable salt, which is a
2,2,7-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
3,3-dimethyl-1-[(2-phenylethyl)amino]-2,3-dihydro-1H-pyrano[3,2-g]quinoline-2-ol,
7-hydroxymethyl-2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
7-chloro-2,2,9-Tr is methyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
7-chloro-4-{[2-(4-forfinal)ethyl]amino}-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
7-chloro-4-{[2-(2-forfinal)ethyl]amino}-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
7-chloro-4-{[2-(4-chlorophenyl)ethyl]amino}-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
3-hydroxy-2,2,9-trimethyl-4-[2-(phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-7-carboxylic acid
4-{[2-(4-AMINOPHENYL)ethyl]amino}-7-chloro-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
7-chloro-4-[(2-hydroxy-2-phenylethyl)amino]-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
7-chloro-2,2,9-trimethyl-4-{[2-(1-piperidinyl)ethyl]amino}-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
7-chloro-4-([2,3-chloropyrazole-1-yl)ethyl]amino}-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
7-chloro-2,2,9-trimethyl-4-{[2-(2-pyridyl)ethyl]amino}-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
7-chloro-2,2,9-trimethyl-4-{[2-(3-pyridyl)ethyl]amino}-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
7-chloro-2,2,9-trimethyl-4-{[2-(4-pyridyl)ethyl]amino}-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
7-chloro-4-isobutylamino-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
7-chloro-4-[(2-cyclopentylacetyl)amino]-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
7-chloro-4-{[2-(1-cyclopentenyl)ethyl]amino}-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
7-chloro-2,2,9-trimethyl-4-pentylamine-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
7-chloro-4-[(2-cyclohexylethyl)amino]-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,-g]quinoline-3-ol,
7-chloro-4-[(2-hydroxyphenyl)amino]-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
7,7-dimethyl-9-[(2-phenylethyl)amino] - 8.9bn-dihydro-7H-pyrano[2,3-g]cinoxacin-8-ol,
9-{[2-(2-forfinal)ethyl]amino}-7,7-dimethyl-8,9-dihydro-7H-pyrano[2,3-g]cinoxacin-8-ol,
9-{[2-(4-forfinal)ethyl]amino}-7,7-dimethyl-8,9-dihydro-7H-pyrano[2,3-g]cinoxacin-8-ol,
9-[(2-hydroxy-2-phenylethyl)amino]-7,7-dimethyl-8,9-dihydro-7H-pyrano[2,3-g]cinoxacin-8-ol,
7,7-dimethyl-9-pentylamine-8,9-dihydro-7H-pyrano[2,3-g]cinoxacin-8-ol,
9-[(2-cyclohexylethyl)amino]-7,7-dimethyl-8,9-dihydro-7H-pyrano[2,3-g]cinoxacin-8-ol,
7-hydroxy-6,6-dimethyl-8-[(2-phenylethyl)amino]-4,6,7,8-tetrahydro-1,5-dioxa-4-azaanthracene-3-one,
7-hydroxy-4,6,6-trimethyl-8-[(2-phenylethyl)amino]-4,6,1,8-tetrahydro-1,5-dioxa-4-azaanthracene-3-one,
7-hydroxy-6,6-dimethyl-8-[(2-phenylethyl)amino]-7,8-dihydro-1H,6N-4,5-dioxo-1-azaanthracene-2-it,
9-hydroxymethyl-2,2-dimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3,7-diol,
7-aminomethyl-2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
7-chloro-2,2,9-trimethyl-6λ5-hydroxy-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
7-chloro-4-{[2-(4-forfinal)ethyl]amino}-2,2,9-trimethyl-6λ5-hydroxy-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
7-chloro-2,2,9-trimethyl-6λ5-hydroxy-4-pentylamine-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol,
4-{[2-(4-forfinal)ethyl]amino}-7-hydroxymethyl-2,2,9-t is imethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol or
2,2-dimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol.

39. Derived benzopyran or its pharmaceutically acceptable salt, which is a 2,2,7-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol.

40. Derived benzopyran or its pharmaceutically acceptable salt, which is a 7-hydroxymethyl-2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol.

41. Derived benzopyran or its pharmaceutically acceptable salt, which is 7-chloro-2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol.

42. Derived benzopyran or its pharmaceutically acceptable salt, which is 7-chloro-2,2,9-trimethyl-4-{[2-(3-pyridyl)ethyl]amino}-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol.

43. Derived benzopyran or its pharmaceutically acceptable salt, which is 7-chloro-4-[(2-cyclohexylethyl)amino]-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline-3-ol.

44. Derived benzopyran or its pharmaceutically acceptable salt, which is a 7,7-dimethyl-9-[(2-phenylethyl)amino] - 8.9bn-dihydro-7H-pyrano[2,3-g]cinoxacin-8-ol.

45. Derived benzopyran or its pharmaceutically acceptable salt, which is a 9-{[2-(4-forfinal)ethyl]amino}-7,7-dimethyl-8,9-dihydro-7H-pyrano[2,3-g]cinoxacin-8-ol.

One of benzopyran or its pharmaceutically acceptable salt, which is 7-hydroxy-6,6-dimethyl-8-[(2-phenylethyl)amino]-7,8-dihydro-1H,6N-4,5-dioxo-1-azaanthracene-2-it.

47. Drug for the treatment of arrhythmias, including derived benzopyran or its pharmaceutically acceptable salt according to any one of claims 1 to 46 as the active ingredient.