Derivatives diazabicyclo and pharmaceutical composition

 

(57) Abstract:

Derivatives diazabicyclo formula 1, where R1group of the formula (11) or (111); R11and R12is lower alkyl or taken together form a lower alkylenes group; R13is hydroxyl, lower acyloxy; R14is a hydrogen atom or lower alkyl; And a is a nitrogen atom or C-R16, R16is hydrogen, cyano, nitro, triptoreline, pentafluoroethyl, sulfonyl, possibly substituted aryl, carbarnoyl-methyl or sulfamoyl; R15is hydrogen, nitro; R21and R22is lower alkyl; R23is hydroxyl; R24and R25is hydrogen; X is oxygen or N-R31, R31is hydrogen; R2is hydrogen, alkenyl, quinil, alkyl, or R2optionally substituted alkylphenyl; R3and R4is hydrogen or alkyl; n = 1, or its pharmaceutically acceptable salt. The compound of formula 1 possess excellent activity, increasing potassium exchange by opening potassium channels. 2 C. and 7 C.p. f-crystals. 13 table.

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The invention relates to a new diisobutylaluminum connection, which has an excellent activity, which increases potassium exchange by opening potassium channels and therapeutic agents for the treatment of hyperten is SS="ptx2">

Treatment of hypertension (hypertonia) hold, maintaining the patient on antihypertensive medicines for a long time and therefore to antihypertensive medicines show not only potent antihypertensive activity, and the absence of undesirable side effects during long-term use. Thus antihypertensive drugs have the following requirements: 1) they must have the potential and long-lasting antihypertensive activity, 2) they must find a slow onset of antihypertensive action, as the rapid onset of this action significantly alters the homeostasis of the circulatory organs (Life Science, Vol. 47, S. 1693 - 1705 (1990)), easily causing reflex tachycardia (Japanese Journal of Pharm acology, Vol. 58 (Suppl.I) S. 36 (1992)), and preferably 3) increase renal blood flow, as a violation of blood flow in the kidney is closely connected with the preservation and development of hypertension and increase in renal blood flow thus facilitates hypertension (Circulation, Vol. 69, c. 1142 - 1145 (1984)).

Know the connection represented by the General formula

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where R represents a hydrogen atom, alkyl group, aryl group, aracelio group and so on the potassium channels and is therefore suitable as an antihypertensive medications (JP-A-2-145584, JP-A-3-20275 and Journal of Medicinal Chemistry Vol. 33, S. 2759 - 2767 (1990)); the term "JP-A" as used here, refers to published that has not passed the examination for Japanese application.

Although the compounds of formula IV almost qualify for intensity and duration of antihypertensive activity, they are still unsatisfactory from the point of view of the nature of the onset of antihypertensive action and activity increase renal blood flow.

The aim of the invention is the provision of a compound that has a powerful and long-lasting antihypertensive activity, shows a slow onset of action, and also detects a excellent activity in increasing renal blood flow.

Another aim of the invention is the provision of pharmaceutical preparations containing the compound.

Received various diazabicyclo compounds and investigated their pharmacological activity. Found that diazabicyclo compound of formula I, shown below, has an excellent activity, which increases potassium currency, and a strong and long-lasting antihypertensive activity with slow onset of action and has a highly the hypertensia. Also found that the compound of formula I is suitable as an agent for the treatment of other diseases caused by narrowing of the blood vessels or bronchial smooth muscle, such as angina and asthma. The invention is based entirely on these studies.

The invention relates to diisobutylaluminum connection formulas

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where R1represents a group of formula (II) or (III)

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where R11and R12each represents lower alilou group, or taken together form a lower alanovoy group;

R13represents a hydroxyl group, a lower alkoxygroup or lower alloctype;

R14represents a hydrogen atom or a lower alkyl group;

A represents a nitrogen atom or C-R16;

R15and R16each represent a hydrogen atom, a halogen atom, a cyano, a nitro-group, cryptometer, panafcortelone group, a lower alkyl group, lower alkenylphenol group, lower alkylamino group, a lower acyl group, carboxyl group, lower alkoxycarbonyl group, carbomoyl group which may be substituted by a lower alkyl group containing 1-2 carbon atoms, sulfonyloxy iroppoi or sulfamoyl group, which may be substituted by a lower alkyl group containing 1-2 carbon atoms;

R21and R22each represent a lower alkyl group or taken together, form the lower alkylenes group;

R23represents a hydroxyl group, a lower alloctype or lower alkoxygroup;

R24represents a hydrogen atom or a lower alkyl group;

R25represents a hydrogen atom, a lower alkyl group, lower alkenylphenol group, lower alkylamino group, aracelio group or aracelio group containing at least one heteroatom in the aryl part;

X represents an oxygen atom, a sulfur atom or N-R31where R31represents a hydrogen atom, a lower alkyl group, lower alllow group or aracelio group;

R2represents a hydrogen atom, a lower alkenylphenol group, lower alkylamino group, substituted or substituted lower alkyl group, a substituted or unsubstituted aryl group, substituted or unsubstituted aracelio group, or aracelio group containing at least one heteroatom in the aryl part;

R3and R4each represent a hydrogen atom or a halogen atom or the dispositions for the treatment of hypertension and angina or asthma, which contain diazabicyclo compound of formula (I) as an active ingredient.

In the formula (I) and in the following discussion of the formula (I), each of these groups is unsubstituted group, unless expressly agreed on the inclusion of the substituted groups.

Various groups referred to in the formula (I), are described below in detail.

"Lower alkyl group" includes an unbranched or branched alkyl group containing 1 to 6 carbon atoms, such as methyl group, ethyl group, through the group, isopropyl group, boutelou group and tert-boutelou group.

"Lower Alchemilla group" includes an unbranched or branched alkeneamine group containing from 2 to 6 carbon atoms, such as vinyl group or propenyloxy group.

"Lower Alchemilla group" includes an unbranched or branched alkyline group containing from 2 to 6 carbon atoms, for example etinilnoy group, 1-propenyloxy group and 2-propenyloxy group.

"Lower Allenova group" includes those groups which contain from 2 to 6 carbon atoms, for example propylene group, butylene group, pentico group and naphthylmethyl group.

"Kalkilya group containing at least one heteroatom in the aryl part, includes 5 or 6 membered heterocyclic ring containing at least one heteroatom (preferably, 1 to 3 heteroatoms) selected from the group comprising a nitrogen atom, an oxygen atom or a sulfur atom, the ring of which is connected with alkalinous group containing from 1 to 4 carbon atoms. The ring may contain, for example, from one to three nitrogen atoms. Specific examples of these groups are pyridylmethylene, pyridylmethylene, pyrimidinetrione, pyrimidinetrione, piperazinylmethyl, piperazinylmethyl, triazolylmethyl, triazinetrione, parasaissetia, pyrazolidine, personalproperty, imidazolylidene, imidazolylalkyl, imidazolylalkyl, oxazolidinedione, oxazolidinone, oxazolepropionic, triazolylmethyl, thienylmethyl, aziridination and aziridination group.

"Aryl group" include phenyl group, naftalina group and biphenylene group.

"Lower alkoxy group" includes groups that contain from 1 to 4 carbon atoms, such as methoxy group, ethoxypropan, propoxylate and butoxypropan.

PU, acetyl group, propanolol group and butanoyloxy group.

"Lower acyloxy group" includes groups that contain from 1 to 8 carbon atoms, for example, formyloxy group, acetoxy group, propenyloxy group, and butanoyloxy.

"Lower alkoxycarbonyl group" includes groups that contain from 2 to 6 carbon atoms, for example methoxycarbonyl group, ethoxycarbonyl group and propoxycarbonyl group.

"Sulfonylurea group which may be substituted by a lower alkyl group, i.e., the lower alkylsulfonyl group includes groups that contain from 1 to 5 carbon atoms, for example methylsulfinyl group, ethylsulfinyl group and propylsulfonyl group.

"Sulfonylurea group which may be substituted by a lower alkyl group, i.e., the lower alkylsulfonyl group includes groups that contain from 1 to 5 carbon atoms, for example methylsulfonyl group, ethylsulfonyl group and propylsulfonyl group.

"Sulfonylurea group which may be substituted by lower alkoxygroup", i.e. the lowest alkoxycarbonyl group includes groups that contain from 1 to 5 at which the UPP.

"Sulfonylurea group which may be substituted by lower alkoxy group" includes groups that contain from 1 to 5 carbon atoms, for example methoxyaniline group, ethoxysulfuron group or propoxycarbonyl group.

"Sulfonylurea group which may be substituted aryl group" includes phenylsulfonyl group and naphthylmethyl group.

"Sulfonylurea group which may be substituted aryl group" includes phenylsulfinyl group and naphthylmethyl group.

"Sulfonylurea group which may be substituted by arroceros" includes phenylenesulfonyl group and naphthalenesulfonyl group.

"Sulfonylurea group which may be substituted, aryloxy group" includes phenylenesulfonyl group and naphthalenesulfonyl group.

"Halogen atom" includes fluorine atom, chlorine atom, bromine atom and iodine atom.

When R2represents a substituted lower alkyl group, specific examples of it include formylamino lower alkyl group, carboxylterminal-lower alkyl group, hydroxylamino-lower alkyl group, Nissho urbanization-lower alkyl group, lower allacciamento-lower alkyl group, alojamiento-lower alkyl group, nitrosamino-lower alkyl group, lanzamiento-lower alkyl group, lower alkylsulfonamides-lower alkyl group, lower alkylsulfonamides-lower alkyl group, arylsulfonamides-lower alkyl group, arylsulfonamides-lower alkyl group, sulfanilamide-lower alkyl group, mono-lower alkylsulfonamides-lower alkyl group, di-lower alkylsulfonamides-lower alkyl group, carbamoylmethyl-lower alkyl group, mono-lower allylcarbosilane-lower alkyl group, di-lower carbamoylmethyl-lower alkyl group, aminosilane-lower alkyl group, mono-lower alkylaminocarbonyl-lower alkyl group, di-lower alkylaminocarbonyl-lower alkyl group, mercaptopyridine-lower alkyl group, lower alkylthiomethyl-lower alkyl group, aristotlean-lower alkyl group, lower acrylamidoethyl-lower alkyl group and triftormetilfosfinov-lower alkyl group.

When R2is substituted axially group, lower acelerou group, lower alkoxycarbonyl group, lower aryloxyalkyl group, helodrilus group, nitroaniline group, cyanoaniline group, lower alkylsulfonyl group, lower alkylsulfonyl group, arylsulfonyl group, arylsulfenyl group, sulfonylamino group, mono-lower alkylsulfonyl group, di-lower alkylsulfonyl group, carbamoylation group, mono-lower alkylcarboxylic group, di-lower alkylcarboxylic group, aminoaryl group, mono-lower alkylaminocarbonyl group, di-lower alkylaminocarbonyl group, mercaptopyridine group, lower alkylaryl group, alltoallw group, lower acylaminoalkyl group and cryptomaterial group.

When R2represents a substituted aracelio group, typical examples include those containing aryl part, replaced by halogen atom, lower alkyl group, a hydroxyl group, a lower alkoxy group, cyano, a lower acyl group, a lower alkoxycarbonyl group, a nitrogroup, cryptomaterial, lower alkylsulfonyl group, lower ALK is safe group, mono-lower alkylcarboxylic group, di-lower alkylcarboxylic group, sulfamoyl group, mono - or di-lower alkylsulfonyl group or a carboxyl group.

The compound of formula (1) can be converted in the usual way in pharmaceutically acceptable salt by treatment with inorganic acid (e.g. hydrochloric acid, sulfuric acid, Hydrobromic acid, phosphoric acid or nitric acid) or organic acid (e.g. acetic acid, propionic acid, succinato acid, glycolic acid, lactamases acid, maleic acid, tartaric acid, citric acid, maleic acid, fumaric acid, methanesulfonic acid, p-toluensulfonate acid or ascorbic acid) or hydrate or solvate.

The compounds of formula (I) in which R1represents a group of formula (II) are preferred. In the formula (II) R11and R12each represents preferably a methyl group; R13is preferably a hydroxyl group or a lower alloctype; R14represents preferably a hydrogen atom or methyl group; R15the submission is respectfully a cyano, the nitrogroup or panafcortelone group.

R2represents preferably a hydrogen atom, methyl group, ethyl group, through the group, 2-through group, 2-propenyloxy group, isobutylene group, allyl group, unsubstituted benzyl group, or benzyl group containing as a substituent a lower alkyl group containing from 1 to 4 carbon atoms, halogen atom, alkoxy group, or cyano attached to the phenyl part of the benzyl group.

R3and R4each are preferably a hydrogen atom. X is preferably an oxygen atom, n is preferably 1.

The compounds of formula (I), each includes optical isomers represented by formulas (Ia) -(Id) shown below, attributed to asymmetric carbon atoms.

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where R2, R13, R14, R15, A, X and n have the above for formula I values.

These optically active compounds and their mixtures are also included in the scope of the present invention. Particularly preferred optically active compounds are those represented by formula Ia or Ib. For example, the connection polutemnyh compounds are racemic mixture of compounds of formula (Ia) and compounds of formula (Ic), and the racemic mixture of the compounds (Ib) and compounds of formula (Id), where R2, R13, R14, R15, A, X and n represent values as defined above in formula (I).

Specific examples of compounds of formula (I) shown below.

1) 3,4-TRANS-4-/3-benzyl-2-oxo-3,4-diazabicyclo/4.1.0/-hept-4-ene-5 - yloxy/-3,4-dihydro-2,2-dimethyl-3-hydroxy-2H-1-benzopyran-6-carbonitrile:

the racemate (Ia) and (Ic) or a racemate (Ib) and (Id), where R2=benzyl, R13=OH, R14= R15=H, A=C-CN, n=1 and X=0.

2) 3,4 - TRANS-3,4-dihydro-2,2-dimethyl-3-hydroxy-4-/3-methyl-2-oxo-3,4 - diazabicyclo/4.1.0/hept-4-ene-5-yloxy/-2H-1-benzopyran-6-carbonitrile:

the racemate (Ia) and (Ic) or a racemate (Ib) and (Id), where

R2=CH3, R13=OH, R14=R15=H, A=C-CN, n=1 and X=0.

3) 3,4-TRANS-3,4-dihydro-2,2-dimethyl-3-hydroxy-4-/3-methyl-2-oxo - 3,4-diazabicyclo/4.1.0/hept-4-ene-5-yloxy/-2H-1-benzopyran-6,7-dicarboxy - imide:

the racemate (Ie), (Ig) or a racemate (If) and (Ih):

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4) /3S, 4R,1'S,6'R/-4-/3-benzyl-2-oxo-3,4-diazabicyclo/4.1.0/hept - 4-ene-5-yloxy/-3,4-dihydro-2,2-dimethyl-3-hydroxy-2H-1-benzopyran-6 - carbonitrile:

optically active compound (Ia), where R2=benzyl, R13=OH, R14, R15=H, A=C-CN, n=1 and X=0.

5) /3S,4R,1'R*,6'S*/3,4-dig the BR> optically active compound (Ia) or (Ib), where R2=CH3, R13=OH, R14= R15=H, A=C-CN, n=1 and X=0.

6) /3S,4R,1'R*,6'S*/-4-/3-allyl-2-oxo-3,4 - diazabicyclo/4.1.0/hept-4-ene-5-yloxy/-3,4-dihydro-2,2-dimethyl - 3-hydroxy-2H-1-benzopyran-6-carbonitrile:

optically active compound (Ia) or (Ib), where R2=allyl, R13=OH, R14= R15=H, A=C-CN, n=1 and X=0.

7) /3S, 4R,1'R*,6'S*/-3,4-dihydro-2,2-dimethyl-3 - hydroxy-4-/2-oxo-3-/2-propyne-1-yl/-3,4-diazabicyclo/4.1.0/hept-4-ene - 5-yloxy/-2H-1-benzopyran-6-carbonitrile:

optically active compound (Ia) or (Ib), where R2=2-propyne-1-yl, R13= OH, R14=R15=H, A=C-CN, n=1 and X=0.

8) /3S, 4R, 1'R*, 6'S*/-3,4-dihydro-2,2-dimethyl-3 - hydroxy-4-/3-/2-methoxyethyl/-2-oxo-3,4-diazabicyclo/4.1.0/hept-4-ene - 5-yloxy/-2H-1-benzopyran-6-carbonitrile:

optically active compound (Ia) or (Ib), where R2=2-methoxyethyl, R13= OH, R14=R15=H, A=C-CN, n=1 and X=0.

9) /3S, 4R, 1'R*,6'S*/-3,4-dihydro-2,2-dimethyl-3 - hydroxy-4-/3-/2-hydroxyethyl/-2-oxo-3,4-diazabicyclo/4.1.0/hept-4-ene - 5-yloxy/-2H-1-benzopyran-6-carbonitrile:

optically active compound (Ia) or (Ib), where R2=2-methoxyethyl, R13= OH, R14=R15=H, A=C-CN, n=1 and X=0.

-yloxy/-2H-1-benzopyran-6-carbonitrile:

optically active compound (Ia) or (Ib), where R2=isobutyl, R13=OH, R14=R15=H, A=C-CN, n=1 and X=0.

11) /3S,4R,1'R*,6'S*/-4-/3-n-butyl-2-oxo-3,4 - diazabicyclo/4.1.0/hept-4-ene-5-yloxy/-3,4-dihydro-2,2-dimethyl-3 - hydroxy-2H-1-benzopyran-6-carbonitrile:

optically active compound (Ia) or (Ib), where R2=n-butyl, R13=OH, R14=R15=H, A=C-CN, n=1 and X=0.

12) /3S, 4R, 1'R*, 6'S*/-4-/3-/2-Chlorobenzyl/-2-oxo-3,4 - diazabicyclo/4.1.0/hept-4-ene-5-yloxy/-3,4-dihydro-2,2-dimethyl-3 - hydroxy-2H-1-benzopyran-6-carbonitrile:

optically active compound (Ia) or (Ib), where R2=2-Chlorobenzyl, R13= OH, R14=R15=H, A=C-CN, n=1 and X=0.

13) /3S, 4R, 1'R*,6'S*/-4-/3-/2,6-dichlorobenzyl/-2-oxo - 3,4-diazabicyclo/4.1.0/hept-4-ene-5-yloxy/-3,4-dihydro-2,2-dimethyl-3 - hydroxy-2H-1-benzopyran-6-carbonitrile:

optically active compound (Ia) or (Ib), where R2=2,6-dichlorobenzyl, R13=OH, R14=R15=H, A=C-CN, n=1 and X=0.

14) /3S, 4R, 1'R*,6'S*/-4-/3-/2,4-dichlorobenzyl/-2-oxo - 3,4-diazabicyclo/4.1.0/hept-4-ene-5-yloxy/-3,4-dihydro-2,2-dimethyl-3 - hydroxy-2H-1-benzopyran-6-carbonitrile:

optically active compound (Ia) or (Ib), where R2=2,4-dichlorobenzyl, R13=OH, R14=R15=H, A=C-CN,bicyclo/4.1.0/hept-4-ene - 5-yloxy/-2H-1-benzopyran-6-carbonitrile:

optically active compound (Ia) or (Ib), where R2=2-methylbenzyl, R13= OH, R14=R15=H, A=C-CN, n=1 and X=0.

16) /3S, 4R, 1'R*,6'S*/-3,4-dihydro-2,2-dimethyl-3 - hydroxy-4-/2-oxo-3,4-diazabicyclo/4.1.0/hept-4-ene-5-yloxy/-2H-1 - benzopyran-6-carbonitrile:

optically active compound (Ia) or (Ib), where R2=H, R13=OH, R14=R15= H, A=C-CN, n=1 and X=0.

17) /3S,4R,1'R*,6'S*/-4-/3-cyanomethyl-2-oxo-3,4 - diazabicyclo/4.1.0/hept-4-ene-5-yloxy/-3,4-dihydro-2,2-dimethyl-3 - hydroxy-2H-1-benzopyran-6-carbonitrile:

optically active compound (Ia) or (Ib), where R2=cyanomethyl, R13=OH, R14=R15=H, A=C-CN, n=1 and X=0.

18) /3S, 4R,1'R*,6'S*/-3,4-dihydro-2,2-dimethyl-4- /3-etoxycarbonyl-methyl-2-oxo-3,4-diazabicyclo/4.1.0/hept-4-ene - 5-yloxy/-3-hydroxy-2H-1-benzopyran-6-carbonitrile:

optically active compound (Ia) or (Ib), where R2=ethoxycarbonylmethyl, R13=OH, R14=R15=H, A=C-CN, n=1 and X=0.

19) /3S, 4R, 1'R*,6'S*/-3,4-dihydro-3-hydroxy-4- /3-methyl-2-oxo-3,4-diazabicyclo/4.1.0/hept-4-ene-5-yloxy/-2,2,3 - trimethyl-2H-1-benzopyran-6-carbonitrile:

optically active compound (Ia) or (Ib), where R2=R14=CH3, R13=OH, R15=H, A=C-CN, n=1 and X=0.

The UP>2, R3, R4, R11, R12, R14, R15, R21, R22, R24, R25, n and A have the above in formula I values.

(The compound (Ii) or the compound (Ij) can be obtained by the interaction of the compound (V) with compound (VIa) or compound (VII), respectively.

The reaction is usually carried out in an inert solvent such as a lower aliphatic alcohol (for example, methyl alcohol or ethyl alcohol), acetonitrile or dimethylformamide (DMF), preferably in ethanol or DMF, in the presence of organic bases (e.g. pyridine) or inorganic bases (e.g. sodium hydroxide or potassium carbonate), preferably pyridine as catalyst at 50 to 150oC, preferably 80-110oC for 5-48 hours, preferably 10-20 hours

Depending on whether the original compound (VIa) or (VII) a racemate or an optically active compound in the resulting compound (Ii) or (Ij) be a racemate or optically active compound.

The racemate of the compound (VIa) can be obtained by a known method (JP-A-52-122372 or JP-A-61-293984). Compound (VIa), the compound (VIb) with (3S, 4S) configuration can be obtained by known spnge, the compound of formula (Ik) are obtained as follows:

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where R2, R3, R4, R11, R12, R14, R15, n and A are the values as they are defined above in formula (I).

The compound (Ii) obtained by using the compounds (VIa), includes 4 optical isomers, referred to the TRANS-configuration at position 3,4-Pyrenophora rings and CIS - or configuration of hydrogen atoms associated with 1-and 6-positions diazabicyclo rings. Four optical isomers are two pairs of diastereomers. The racemates each of the two pairs of diastereomers can be easily separated by chromatography on silikagelevye column.

Compound (Ik), which is obtained using the compound (VIb), includes 2 diastereoisomer related to the configuration of the hydrogen atoms associated with 1 - and 6-positions diazabicyclo rings. Two diastereoisomer can be easily separated through column chromatography with silica gel.

The compound (V), which is used in the reaction scheme above, is obtained by reaction of the compound (VIII) shown below, with a derivative of hydrazine in a lower aliphatic alcohol (for example, methyl alcohol or ethyl alcohol), acetonitrile, MC what about the above in the formula (I).

The compound (VIII) obtained by method known in the literature. For example, the compound (VIII), where n= 1 receive according to Justus Liebigs Annalen der Chemie, Vol. 606, S. 1 (1957), Tetrahedron Letters, Vol. 21, S. 1847 (1978) or in print, Vol. 28, S. 267 (1987) and the compound (VIII), where n=2 receive according to Tetrahedron Letters, Vol. 28, S. 267 (1987).

Replacement of a substituent R2in particular the compound of the formula (V) other desired substituents, in a known manner, for example by catalytic regeneration or dialkylammonium.

Method b

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where R2, R3, R4, R11, R12, R14, R15, R21, R22, R24, R25, n and A have the above for formula I values.

The compound (Il) or (Im) can be obtained by reaction of the compound (IX) with compound (VIa) or (VII).

The reaction is carried out in an inert solvent such as a lower aliphatic alcohol (for example, methyl alcohol or ethyl alcohol), acetonitrile or DMF, preferably DMF, in the presence of organic bases (e.g. pyridine) or inorganic bases (e.g. sodium hydroxide, or potassium carbonate, or sodium hydride, preferably sodium hydride as a catalyst at 20 to 150oC, site what about the known method (Journal of Heteroyclic Chemistry, Vol. 21, c. 961 - 968 (1984), Journal of Organic Chemistry, Vol. 36, S. 3356 - 3361 (1971) or Chemische Berichte, Vol. 100, C. 2719 - 2729) (1967)).

Like the method (a), where the original connection (VIa) or (VII) represents the racemate or optically active compound, determines whether the target compound (Il) or (Im) to represent a racemate or optically active compound. Using as a starting compound, the racemate, the target compound (Il) includes 4 optical isomers related to the TRANS configuration 3,4-position Pyrenophora rings and CIS - or / configuration of hydrogen atoms associated with I' - and 6'-positions diazabicyclo rings. Four optical isomers consist of two pairs of antipodes. The racemates each of the two pairs of antipodes can be easily separated by chromatography on silikagelevye column.

On the other hand, the connection, which is obtained from the compound (VIb), includes 2 diastereoisomer related to the configuration of the hydrogen atoms associated with the 1'- and 6'-positions. Two diastereoisomer can be easily separated using a chromatographic column with silica gel.

In each of the methods (a) and (b) the substituent R2end connections can be replaced, if desired, another Deputy, known spasoobydennaya, where R2is usually applied dismissed the group, such as n-methoxybenzyloxy group, by reaction with a releasing reagent, for example 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DBH). In addition, the connection, where R2represents a hydrogen atom, can be converted into the corresponding compounds having different substituents, such as R2interacting with various halide compounds.

Method (c):

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where R2, R3, R4, R11, R12, R14, R15, X, A and n represent values, as defined above in formula (I);

R17represents a lower alkyl group;

R18represents a hydrogen atom or a lower alkyl group;

V represents a halogen atom.

That is, the compound (Io) is produced by interaction of the compound (In), obtained by the method (a) or (b) with allermuir agent in accordance with the method disclosed in patent JP-A-3-20275. Appropriate alleluya agents that can be used preferably include anhydrides of lower alkylcarboxylic acids, halides lower alkylcarboxylic acid and formic acid. The acylation reaction is carried out in an inert solvent (for example, constituent base (for example, potassium carbonate) or organic bases (e.g. pyridine or triethylamine), preferably triethylamine as catalyst at 20 to 150oC, for 1 to 48 hours, preferably 3 to 20 hours

In method (c), where the starting compound is used as a compound (Ij) or (Im) are obtained the compounds of formula (I), where R1has the structure of formula (III).

The compound of the present invention can be obtained in the form of pure optical isomers by methods (a) - (c), where the source of the connections are optically active compound or racemate and the resulting isomeric mixture divided by the appropriate combination of cues, such as column chromatography, optical separation using optical separating agents, using the differences of the two diastereomers in solubility in solvent and liquid chromatography high pressure.

The compounds of formula (I) sometimes emit in the form of a hydrate or MES or in the form of amorphous compounds, and all such modifications are included in the scope of the present invention.

Thus, the compound of formula (I) has excellent activity increase potassium exchange and is therefore effective is the example of coronary heart disease, an example of which is angina, asthma, pollakiuria, a complication of subarachnoid hemorrhage, peripheral arteriopathy etc. Connection has potential and long-lasting antihypertensive activity with slow onset of action, and shows excellent activity in increasing renal blood flow. In addition, the connection has a high stability. Thus, the compound is particularly useful as an agent for the treatment of hypertension.

The compound of the present invention may be administered orally or nearline in any desired dosage form such as tablets, granules, powders, capsules, solutions, syrups, oily or aqueous suspensions, and the like. In the preparation of dosage forms and compositions containing the compound can be added commonly used binders or adjuvants, such as lubricants, solvents and surface-active agents.

Usually the dose of a compound is 0.001 to 1.0 mg, more preferably 0.01 to 0.5 mg per day per adult human in oral introduction, although to some extent the changes depend on the route of administration, symptoms and period of use.

Present izobreteniem, but it is clear that the present invention is not limited to these examples.

Referential example 1. ()-3-benzyl-3,4-diazabicyclo/4.1.0/heptane-2,5-dione.

In 150 ml of acetonitrile are dissolved in 42 g (374 mmol) of anhydride 1,2-cyclopropanedicarboxylic acid and to the solution is added dropwise a solution of 45.8 g (374 mmol) of benzylpiperazine in 50 ml of acetonitrile and the mixture is heated to boiling under reflux for 15 hours the Solvent is removed by distillation under reduced pressure and the residue is purified through column chromatography with silica gel. Crystallization of their acid ethyl ester gives 24,1 g (29,7%) specified in the connection name.

Melting point: 186 - 188oC.

NMR (CDCl3, TMS) M. D.: 1,15 (1H, m), 1.69 in (1H, m), 2,10 (1H, m), 2,28 (1H, m), of 4.66 (1H, d, J=15.6 Hz), 4,84 (1H, d, J=15.6 Hz), to 7.32 (5H, s).

Reference examples 2 to 24. The compounds listed in the table. 1 below, in the same way? as in referential example 1.

Reference example 25. ()-3,7,7-trimethyl-3,4-diazabicyclo /4.1.0/heptane-2,5-dione.

In 5 ml of ethyl alcohol add 949 mg (6,77 mmol) of anhydride is 3,3-dimethyl-1,2-cyclopropanedicarboxylic acid and 0.36 ml (6,77 mmol) methylhydrazine and the mixture is heated at boiling for 16 hours the Solvent is removed othona is a mixture of ethyl acetate/hexane gives 312 mg (27,3%) specified in the connection name.

Melting point: 151 - 154oC.

NMR (CDCl3, TMS) (M. D.): to 1.21 (3H, s) of 1.34 (3H, s) to 1.98 (1H, d, J = 7,3 Hz), 2,10 (1H, d, J = 7,3 Hz), 3,24 (3H, s).

Reference example 26. ()-3-/4-hydroxybenzyl/-3,4 - diazabicyclo/4.1.0/heptane-2,5-dione.

To 5 ml of methylene chloride add 462 mg (of 1.87 mmol) of ()-3-/4-methoxybenzyl/-3,4-diazabicyclo/4.1.0/heptane-2,5-dione, obtained in comparative example 19. The mixture is cooled in a bath of dry ice/methanol and then added dropwise 0.1 ml (1.1 mmol) of tribromide. The temperature was raised to room temperature and the mixture is stirred for 2 hours, water is Added to the reaction mixture and the mixture is extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate, the solvent is removed by distillation under reduced pressure and the residue is recrystallized from a mixture of ethanol/chloroform to obtain 120 mg (29.6 per cent) specified in the connection name.

NMR (DMCO-d6, TMS) (M. D.): 0,87 - of 0.91 (1H, m), 1.56 to of 1.62 (1H, m), 1,97 - 2,02 (1H, m), 2,07 - 2,12 (1H, m), 4,43 (1H, d, J = 15.1 Hz), of 4.57 (1H, d, J = 15.1 Hz), of 6.71 (2H, d, J = 8,3 Hz), 7,05 (2H, d, J = 8,3 Hz), 9,01 (1H, br, s).

Reference example 27. ()-3-isobutyl-3,4-diazabicyclo /4.1.0/heptane-2,5-dione.

To 40 ml of ethyl alcohol add 2,03 g (11,28 mmol) of ()-3-methyl-2-propen-1-yl/-3,4-diazabicyclo/4.1.0 I conduct catalytic reduction under normal pressure. After the reaction, the catalyst was removed by filtration, the filtrate is concentrated under reduced pressure and the residue is crystallized from a mixture of ethyl acetate/hexane to obtain 1.6 g (80%) specified in the connection name.

Melting point: 150 - 152oC.

NMR (CDCl3, TMS) (M. D.): of 0.91 (3H, d, J = 6.4 Hz), of 0.95 (3H, d, J = 6.8 Hz), 1,17 (1H, m), 1,71 (1H, m), is 2.05 (1H, m) to 2.13 (1H, m), of 2.25 (1H, m), 3,23 (1H, DD, J = 6,8 Hz, of 14.2 Hz), 3,68 (1H, DD, J = 7,8, of 14.2 Hz), 10,14 (1H, br, C).

Reference example 28. ()-3,4-diazabicyclo/4.1.0/- heptane-2,5-dione.

In 1 liter of methyl alcohol was dissolved 20,0 g (of 92.5 mmol) of ()-3-benzyl-3,4-diazabicyclo/4.1.0/-heptane-2,5-dione, obtained in comparative example 1, and added to the mixture 29,2 g (462 mmol) of ammonium formate and 29.2 g (10%) (weight. /weight.) the catalyst is palladium on carbon, followed by heating at boiling under reflux for 2 hours, the Catalyst was removed by filtration and the solvent is removed by distillation under reduced pressure with the release of 12.33 g (100%) specified in the connection name.

Melting point: 193 - 195oC.

NMR (DMSO-d6, TMS) (M. D.): 0,99 (1H, m) to 1.59 (1H, m), at 1.91 (2H, m), of 10.05 (2H, br, s).

Reference example 29. ()-2-amino-4-methyl-3,4-diazabicyclo/4.1.0/-heptane-2-EN-5-he.

25 ml of rodrigopoppe-1,2-in primary forms, which is obtained by a known method (Journal of Organic Chemistry, Vol. 36 p. 3356-3361 (1971)). The mixture is stirred on an oil bath at 60oC for 30 minutes After cooling, to the mixture of 13.6 ml (176 mmol) of DMF, followed by stirring for 30 minutes To the mixture, water is added and the reaction mixture is extracted with benzene. The organic layer is washed successively with water and saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure and the residue dispersed under reduced pressure to obtain 6,14 g (55.7 per cent) methyl-CIS-2-councilapproved.

Boiling point: 94 - 98oC (4 mm Hg column).

NMR (CDCl3, TMS) (M. D.): USD 1.43 (1H, m), 1.69 in (1H, m) to 1.86 (1H, m) to 2.15 (1H, m), of 3.80 (3H, s).

In 150 ml of methyl alcohol was dissolved 2.2 g (96 mmol) of sodium and to the solution add a solution 6,01 g (48 mmol) obtained above compound in 5 ml of methyl alcohol and the solution of 2.21 g (48 mmol) of methylhydrazine in 5 ml of methanol, followed by stirring at room temperature for 67 hours, the Reaction mixture was concentrated under reduced pressure and the concentrate is cleaned by chromatographytandem on silikagelevye column. Recrystallization from ethir>C.

NMR (CDCl3, TMS) (M. D.): 0,84 (1H, m), and 1.54 (1H, m) of 1.97 (1H, m), 2,17 (1H, m), 3,18 (3H, s), 4,18 (2H, br, s).

Reference example 30. 3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-1 - benzopyran-6,7-dicarboximide

1) Dimethyl-3,4-dihydro-2,2-dimethyl-4-oxo-2H-1-benzopyran-6,7 - in primary forms:

In 100 ml of acetone is dissolved to 4.2 g of dimethyl 4-acetyl-5-hydroxyproline received in accordance with the method described in Bulletin of the Chemical Society of Japan, Vol. 57, S. 3221 (1984). To the solution add 1.0 ml of pyrrolidine and a small amount of molecular sieves (3A), followed by stirring at room temperature for 3 days. Any insoluble compound is removed by filtration and the solvent is removed by distillation under reduced pressure. The remainder of the chromatographic clean on silikagelevye column to obtain 4.6 g (86,3%) of a yellow oily substance.

NMR (CDCl3, TMS) (M. D.): to 1.48 (6H, s), 2,77 (2H, s), 3,88 (3H, s), 3,93 (3H, s), to 7.09 (1H, s), to 8.41 (1H, s).

2) Dimethyl-3,4-dihydro-2,2-dimethyl-4-hydroxy-2H-benzopyran-6,7 - dicarboxylate:

In 4 ml of methyl alcohol was dissolved 0.15 g (0.51 mmol) of the compound obtained above in (1), and to the solution was added 23 mg of sodium borohydride under ice cooling, followed by stirring at the same temperature for 10 minutes Orme. The extract is dried over anhydrous sodium sulfate and the solvent is removed by distillation under reduced pressure to obtain 0,141 g (93,8%) of a pale yellow oily substance.

NMR (CDCl3, TMS) (M. D.): 1,30 (3H, s) to 1.45 (2H, s) to 1.86 (1H, DD, J = 9,5, and 13.4 Hz), 2,19 (1H, DD, J = 6,4, and 13.4 Hz), 3,85 (3H, s), 3,88 (3H, s), a 4.83 (1H, DD, J = 6,4, 9.5 Hz), of 6.96 (1H, s), to 7.99 (1H, s).

3) Dimethyl-2,2-dimethyl-2H-benzopyran-6,7-dicarboxylate:

In 5 ml of benzene was dissolved 0.14 g (0.475 mmol) of the compound obtained above in (2), and to the solution was added 10 mg of p-toluensulfonate acid, followed by heating at boiling under reflux for 1 h After allow the reaction mixture to cool, add ethyl acetate and the reaction mixture is washed successively with a saturated solution of sodium bicarbonate and saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. Remove by distillation of the solvent, getting 0,123 g (93,5%) of a pale yellow oily substance.

NMR (CDCl3, TMS) (M. D.): the 1.44 (6H, s), 3,85 (3H, s), 3,88 (3H, s), 5,71 (1H, d, J = 9.8 Hz), 6,32 (1H, d, J = 9.8 Hz), of 6.96 (1H, s), 7,45 (1H, s).

4) Anhydride 2,2-dimethyl-2H-1-benzopyran-6,7-dicarboxylic acid:

In 10 ml of ethanol was dissolved 2.0 g (7.2 mmol) of the compound, poluchaetsya at room temperature for 1.5 hours Ethyl alcohol is removed by distillation under reduced pressure and the residue acidified with 50 ml of 10% (wt./weight.) hydrochloric acid and extracted with diethyl ether. A layer of diethyl ether is dried over anhydrous sodium sulfate and the solvent is removed by distillation under reduced pressure to obtain 2.2 g of a brown oily substance, which is then dissolved in 10 ml of acetic anhydride and the solution is heated at boiling for a period of 7.5 hours Then the reaction mixture was allowed to cool, remove the solvent by distillation under reduced pressure to obtain of 1.62 g (79,4%) of yellow solid product.

NMR (CDCl3, TMS) (M. D.): is 1.51 (6H, s), 5,90 (1H, d, J = 10,2 Hz), to 6.43 (1H, d, J = 10,2 Hz), 7,26 (1H, s), 7,54 (1H, s).

5) 2,2-dimethyl-2H-1-benzopyran-6,7-dicarboximide:

To a solution of 0.50 g (2,17 mmol) of the compound obtained above in (4), in 10 ml of dioxane add 5 ml of concentrated aqueous ammonia, followed by heating at boiling under reflux for a period of 7.5 hours Then the reaction mixture was allowed to cool, the solvent is removed by distillation and the residue is cleaned chromatography on silikagelevye column to obtain 0,23 g (46%) of white crystals.

Melting point: 201-202oC.

NMR (CDCl3T the Tyl-4-hydroxy-2H - 1-benzopyran-6,7-dicarboximide:

In a mixed solvent of 3 ml of dimethyl sulfoxide and 0.1 ml of water is dissolved to 99.6 mg (0.43 mmol) of the compound obtained above in (5), and to the solution was added 150 mg (0.84 mmol) of N-bromosuccinimide, followed by stirring at room temperature for 4 days. The reaction mixture was poured into water and extracted with ethyl acetate. The extract is washed with water and then with diluted hydrochloric acid and dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure and the residue was washed with chloroform and filtered to obtain 0,114 g (80,5%) of white crystals.

Melting point: 230-232oC.

NMR (DCO-d6, TMS) (M. D.): to 1.42 (3H, s), 1,58 (3H, s), 4,34 (1H, d, J = 8,3 Hz), 4,88 (1H, DD, J = 8,3, 6,8 Hz), 6,50 (1H, d, J = 6.8 Hz), 7,13 (1H, s), 7,83 (1H, s).

7) 3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-1-benzopyran-6,7-dicarboximide;

In 20 ml of DMF is dissolved 1,02 g (3,13 mmol) of the compound obtained above in (6), and to the mixture of 0.27 g (of 6.75 mmol) of 60% (wt./weight.) (oil) of sodium hydride, followed by stirring at room temperature for 2 hours, the Reaction mixture was poured into a mixture of saturated aqueous solution of ammonium chloride in ethyl acetate, followed by stirring. The organic layer is extracted with ethylacetate washed with hexane to obtain of 0.62 g (80,8%) specified in the connection name.

NMR (CDCl3, TMS) (M. D.): 1,32 (3H, s), and 1.63 (2H, s) and 3.59 (1H, d, J = 4.4 Hz), was 4.02 (1H, d, J = 4.4 Hz), 7,24 (1H, s), 7,86 (1H, s).

The compound obtained in each of examples 1 to 19, described later, is recement connection (Ip), shown below, where the configuration at positions 3-, 4-, 1'- and 6'- represents S, R, S and R, respectively, and their organic antipode or racemate comprising the compound shown below, where the configuration at the 3-, 4-, 1' and 6'- positions is S, R, R and S, respectively, and their optical antipodes. The compounds obtained in each of examples 21-57, described later, are optically active compound (Ip), where the configuration at positions 3-, 4-, 1'- and 6' -represents S, R, S and R, respectively, or S, R, R and S, respectively

< / BR>
where R2, R3, R4, R11, R12, R13, R14, R15A n and X represent values, as defined above.

Example 1. 3.4-TRANS-4-/3-benzyl-2-oxo-3,4-diazabicyclo/4.1.0/hept-4-ene-5-yloxy/ 3,4-dihydro-2,2-dimethyl-3-hydroxy-2H-1-benzopyran-6-carbonitrile

In 100 ml of ethyl alcohol add 3.0 g (to 13.8 mmol) of ()-3-benzyl-3,4-diazabicyclo/4.1.0/heptane-2,5-dione, obtained in reference example 1, and 2.79 g (to 13.8 mmol) ()-3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-1 - benzopyran-6-Carboni is ritel removed by distillation under reduced pressure and to the residue is added ethyl alcohol. Recrystallization of the insoluble crude crystals from methyl alcohol gives 1,41 g (24.3 per cent) specified in the connection name.

Melting point 242-245oC (decomposition).

The value of Rf= 0,50 (thin layer chromatography on silica gel (TLC), the solvent for the manifestation: chloroform /methyl alcohol = 20:1 (volume/volume).

NMR (CDCl3, TMS) (M. D.): 1,01 (1H, s), 1,25 (3H, s) of 1.44 (3H, s) of 1.73 (1H, m) to 2.18 (1H, m), 2,33 (1H, m) of 3.00 (1H, d, J = 4.3 Hz), 3,76 (1H, DD, J = 4,3, 7,3 Hz), and 4.75 (1H, d, J = 14.4 Hz), is 4.85 (1H, d, J = 14.4 Hz), the ceiling of 5.60 (1H, d, J = 7.8 Hz), to 6.88 (1H, d, J = 8,3 Hz), 7,30 (5H, m), of 7.48 (1H, DD, J = 2.0 a, 8,3 Hz), 7,52 (1H, s).

Examples 2-8. The compounds shown in the table. 2 below, obtained in the same manner as in example 1. The melting temperature (i.e. square), the value of Rfaccording to TLC on silica gel and NMR data of the compounds are also shown in the table. 2. NMR spectra were taken with CDCl3except as disclosed. In table. 2 EtOAc means ethyl acetate and MeOH denote methyl alcohol (hereinafter the same).

Example 9. 3,4-TRANS-3,4-dihydro-2,2-dimethyl-4-/3-methyl-2-oxo-3,4 - diazabicyclo/4.1.0/hept-4-ene-5-yloxy/6 triptoreline-2H-1 - benzopyran-3-ol.

In 20 ml of ethanol was dissolved 1.0 g (of 3.84 mmol) ()-3,4-dihydro-2,2-dimethyl-3,4-epoxy-6-triptoreline-2H-1-benzopyrane examination published Japanese patent application") and to the solution was added 0.6 g (728 mmol) of ()-3-methyl-3,4-diazabicyclo/4.1.0/heptane-2,5-dione and 0.35 ml (4,34 mmol) of pyridine. The mixture is heated at the boil under reflux for 16 hours the Solvent is removed by distillation under reduced pressure. The remainder of the chromatographic clean on silikagelevye column and recrystallized from a mixture of ethyl acetate/hexane to obtain 0.32 g (20.6 per cent) specified on the connection name.

Melting point: 189-190oC.

The value of Rf:0,33 (CHCl3) MeOH=20:1 vol./about.

NMR (CDCl3, TMS) (M. D.): 0,99 (1H, m), 1,32 (3H, s) and 1.51 (3H, s), 1,68 (1H, m), 2,15-of 2.30 (2H, m) of 3.25 (3H, s), 3,90-of 3.96 (2H, m), 5,71 (1H, d, J = 7,3 Hz), 6,85 (1H, d, J = 9.3 Hz), 7,10 (1H, d, J = 9.3 Hz), to 7.15 (1H, s).

Example 10. 3,4-TRANS-3,4-dihydro-2,2-dimethyl-4-/3-methyl-2-oxo-3,4-diazabicyclo /4.1.0/hept-4-ene-5-yloxy/-6-phenylsulfonyl-2H-1-benzopyran-3-ol.

In 15 ml of ethanol is suspended 0.96 g (3.03 mmol) of ()-3,4-dihydro-2,2-dimethyl-3,4-epoxy-6-phenylsulfonyl-2H-1 - benzopyran, which is obtained according to the method of JP-B-1-287083 and 0.81 g (5,78 mmol) of ()-3-methyl-3,4-diazabicyclo/4.1.0/heptane - 2,5-dione and suspension add 0.3 ml (3.9 mmol) of pyridine. The mixture is heated at the boil under reflux for 6 hours the Solvent is removed by distillation under reduced pressure. The remainder of the chromatographic clean on silikagelevye column. Recrystallization from a mixture of ethyl acetate/Huck/P> The value of Rf: 0,24 (CHCl3) MeOH=20:1 V/V.

NMR (CDCl3, TMS) (M. D.) : 0,99 (1H, m), 1,32 (3H, s) and 1.51 (3H, s), 1,66-1,72 (1H, m), 2,14-of 2.26 (2H, m), 3,23 (3H, s) to 3.92 (1H, DD, J = 3,4, 7,3 Hz) to 4.23 (1H, br, s), USD 5.76 (1H, d, J = 7,3 Hz) 6,91 (1H, d, J = 8,8 Hz), of 7.48-7,58 (3H, m), 7,74 (1H, DD, J = 2,4, 8,8 Hz), 7,88-7,94 (3H, m).

Example 11. 3,4-TRANS-3,4-dihydro-2,2-dimethyl-3-hydroxy-4-/3-methyl-2-oxo-3,4 - diazabicyclo/4.1.0/hept-4-ene-5-yloxy/-2H-1-benzopyran-6-sulfonamide.

To 20 ml of DMF added 2.5 g (7,44 mmol) of TRANS-3-bromo-3,4-dihydro-2,2-dimethyl-4-hydroxy-2H-1-insipiron - 6-sulfonamida, which is obtained according to the method of JP-B-2-300182 and 0.75 g (of 18.75 mmol) of 60% (wt./weight.) the sodium hydride is added to the mixture, followed by stirring at room temperature for 20 minutes, the Reaction mixture was poured into a saturated aqueous solution of ammonium chloride and adjusted to pH 5 with hydrochloric acid. The reaction mixture was extracted with ethyl acetate, the extract was washed with a saturated solution of ammonium chloride and the organic layer is dried over anhydrous sodium sulfate. Remove the solvent by distillation under reduced pressure and obtain 2.6 g of a pale brown oily substance. The oily substance was dissolved in 40 ml of ethanol and added to 1.05 g (7,50 mmol) of ()-3-methyl-3,4-diazabicyclo/4.1.0/heptane-2,5-dione and 1,including The solvent is removed by distillation under reduced pressure and the residue cleaned chromatography on silikagelevye column and recrystallization from chloroform gives 0,262 g (8.9 per cent) specified in the connection name.

Melting point: 236-238oC.

The value of Rf: 0,40 (CHCl3) MeOH=10:1 V/V.

NMR (DMSO-d6, TMS) (M. D.): 0,86 to 0.92 (1H, m) of 1.27 (3H, s) of 1.40 (3H, s), 1,62 - to 1.67 (1H, m), 2,15 - of 2.24 (2H, m), of 3.13 (3H, s), of 3.78 (1H, DD, J = 5,4, 6.4 Hz), 5,73 (1H, d, J = 5.4 Hz), 5,88 (1H, d, J = 5.4 Hz), to 6.95 (1H, d, J = 8,3 Hz), of 6.65 (1H, DD, J = 8,3, 2.0 Hz), 7,72 (1H, d, J = 2.0 Hz).

Example 12. 3,4-TRANS-3,4-dihydro-2,2-dimethyl-3-hydroxy-4/3 - methyl-2-oxo-3,4-diazabicyclo/4.1.0/-hept-4-ene-5-yloxy-7-nitro-2H-1 - benzopyran-6-ndimethylacetamide.

To 20 ml of ethyl alcohol add 556 mg (2.0 mmol) ()-3,4-dihydro-2,2-dimethyl-3,4-epoxy-7-nitro-2H-1-benzopyran-6 - ndimethylacetamide, which is obtained according to the method of JP-B-59-1475, 280 mg (2.0 mmol) of ()-3-methyl-3,4-diazabicyclo/4.1.0/heptane-2,5-dione and 0.16 ml (2.0 mmol) pyridine and the mixture is heated to boiling under reflux for 16 hours the Solvent is removed by distillation under reduced pressure and the residue cleaned chromatography on a column of silica gel followed by recrystallization from ethyl acetate with the formation of 123 mg (14.8 per cent) mentioned in the title soedinenii CLASS="ptx2">

NMR (CDCl3, TMS) (M. D.): 1,17 (1H, m), 1,32 (3H, s), and 1.56 (3H, s) to 1.70 (1H, m), of 2.21 (2H, m), of 2.25 (3H, s) of 3.25 (3H, in), 3.75 (1H, d, J = 3,4 Hz), of 3.96 (1H, DD, J = 3,4, 7,8 Hz), 5,79 (1H, d, J = 7.8 Hz), 7,68 (1H, C) 8,76 (1H, s), 10,00 (1H, br, s).

Example 13. 3,4-TRANS-3,4-dihydro-2,2-dimethyl-4-/3-methyl-2 - oxo-3,4-diazabicyclo/4.1.0/hept-4-ene-5-yloxy/-7-nitro-2H-1 - benzopyran-3-ol.

To 20 ml of ethyl alcohol add 442 mg (2.0 mmol) ()-3,4-dihydro-2,2-dimethyl-3,4-epoxy-7-nitro-2H-1-benzopyran, which is obtained according to the method of J. Med. Chem., Vol. 26, S. 1582 - 1589 (1983), 280 mg (2.0 mmol) of ()-3-methyl-3,4-diazabicyclo/4.1.0/heptane-2,5-dione and 0.16 ml (2.0 mmol) of pyridine and the mixture is heated to boiling under reflux for 16 hours the Solvent is removed by distillation under reduced pressure and the residue cleaned chromatography on a column of silica gel and recrystallized from ethanol to obtain 127 mg (17.5 percent) specified in the connection name.

Melting point: 236 - 237oC.

The value of Rf: to 0.29 (ethyl acetate).

NMR (CDCl3, TMS) (M. D.): 1,00 (1H, m) of 1.34 (3H, s), and 1.54 (3H, s), 1.69 in (1H, m), of 2.21 (1H, m), 2,28 (1H, m) of 3.25 (3H, s), a-3.84 (1H, d), J = 3,4 Hz), of 3.97 (1H, DD, J = 3,4 7,3 Hz), 5,78 (1H, d, J = 7,3 Hz), 7,45 (1H, d, J = 8,3 Hz), 7,71 (1H, d, J = 2.0 Hz), 7,78 (1H, DD, J = 2.0 a, 8,3 Hz).

Example 14. 3,4-TRANS-3,4-dihydro-3-hydroxy-4-/3-methyl-2-oxo - RTA add 266 (1,23 mmol) ()-3,4-dihydro-3,4-epoxy-2,2,3-trimethyl-2H-1-benzopyran-6 - carbonitrile, which is obtained according to a known method (J. Med. Chem., Vol. 34, S. 3074 - 3085 (1991)), 133 mg (1,23 mmol) of ()-3-methyl-3,4-diazabicyclo/4.1.0/heptane-2,5-dione and 0.1 ml (0.13 mmol) of pyridine and the mixture is heated to boiling under reflux for 7 days. The solvent is removed by distillation under reduced pressure. The residue is cleaned chromatography on a column of silica gel. Recrystallization from ethyl acetate to give 125 mg (28,4%) specified in the connection name.

Melting point 226 - 227oC.

The value of Rf: 50,21 (ethyl acetate).

NMR (CDCl3, TMS) (M. D.): 1,03 (1H, m), 1,24 (3H, s) of 1.42 (3H, s) of 1.50 (3H, s) of 1.73 (1H, m), 2,22 - 2,31 (2H, m), 3,24 (3H, s), 3,95 (1H, s), of 5.83 (1H, s), make 6.90 (1H, d, J = 8,3 Hz), 7,51 (1H, DD, J = 2.0 a, 8,3 Hz), the 7.65 (1H, d, J = 2.0 Hz).

Example 15. 3,4-TRANS-3,4-dihydro-3-hydroxy-4-/3-methyl-2-oxo - 3,4-diazabicyclo/4.1.0/hept-4-ene-5-yloxy/-2,2-tetramethylene 2H-1 - benzopyran-6-carbonitrile 1/2 hydrate.

Indicated in the name of the connection will receive the same manner as in example 1, except that use ()-3,4-dihydro-3,4-epoxy-2,2-tetramethylene 2H-1-benzopyran-6 - carbonitrile obtained according to the method of JP-B-294677.

Melting point: 207 - 210oC.

The value of Rf: 0,30 (CHCl3) MeOH = 20:1 V/V.

NMR (CDCl<6,91 (1H, d, J = 8,3 Hz) to 7.50 (1H, DD, J = 8,3, 2.0 Hz) a 7.62 (1H, d, J = 2.0 Hz).

Example 16. 3,4-Tran-3,4-dihydro-2,2-dimethyl-4-/3-methyl-2-oxo - 3,4-diazabicyclo/4.1.0/hept-4-ene-5-yloxy/2H-pyrano/3,2-C/pyridine-3 - ol.

Indicated in the name of the connection will receive the same manner as in example 1, except that use ()-3,3-dihydro-2,2-dimethyl-3,4-epoxy-2H-pyrano/3,2-C/pyridine, obtained according to the method of JP-B-61-293984 instead of ()-3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-1-benzopyran-6 - carbonitrile.

The value of Rf: 0,46 (CHCl3) MeOH = 10:1 V/V.

NMR (CDCl3, TMS) : 0,97 - 1,01 (1H, m), 1,32 (3H, s), and 1.54 (3H, s), 1,67 - of 1.73 (1H, m), 2,24 - is 2.37 (2H, m), 3,26 (3H, s), 3,93 (1H, DD, J = 2.0 a, 7,8 Hz), 4,82 (1H, d, J = 2.0 Hz), to 5.66 (1H, d, J = 7.8 Hz), 6,77 (1H, d, J = 5.4 Hz), at 8.36 (1H, d, J = 5.4 Hz), and 8.50 (1H, s).

Example 17. 3,4-TRANS-4-/3-/2-amino-ethyl/-2-oxo - 3,4-diazabicyclo/4.1.0/hept-4-ene-5-yloxy/-3,4-dihydro-2,2 - dimethyl-3-hydroxy-2H-1-benzopyran-6-carbonitrile.

To 10 ml of THF added 303 mg (0.8 mmol) of 3,4-TRANS-3,4-dihydro-2,2-dimethyl-3-hydroxy-4-/3-/2-hydroxyethyl-2 - oxo-3,4-diazabicyclo/4.1.0/hept-4-ene-5-yloxy/-2H-1-benzopyran-5 - carbonitrile obtained in example 6, 456 mg (1.6 mmol) of dibenzyldithiocarbamate and 419 mg (1.6 mmol) triphenylphosphine and a solution of 278 mg (1.6 mmol) diethylazodicarboxylate in 2 ml of THF are added dropwise nom pressure. The residue is cleaned chromatography on a column of silica gel and recrystallized from a mixture of ethyl acetate/hexane to obtain 312 mg (61,1%) of 3,4-TRANS-4-/3-/2-N,N-bis/benzyloxycarbonyl/aminoacyl/-2-oxo - 3,4-diazabicyclo/4.1.0/hept-4-ene-5-yloxy/-3,4-dihydro-2,2-dimethyl-3 - hydroxy-2H-1-benzopyran-4-carbonitrile.

Melting point: 148 - 149oC.

NMR (CDCl3, TMS) (M. D.): 0,91 (1H, m) to 1.37 (3H, s) of 1.47 (3H, s), and 1.54 (1H, m), at 1.91 (2H, m), of 3.46 (1H, m), with 3.79 (1H, DD, J = 6,4, 6,8 Hz), 3,85 (1H, d, J = 6.8 Hz), 3,91 (1H, m), 4,14 (1H, m), 4.26 deaths (1H, m), by 5.18 (2H, d, J = 12,2 Hz in), 5.25 (2H, d, J = and 12.2 Hz), 5,71 (1H, d, J = 6.4 Hz), make 6.90 (1H, d, J = 8,8 Hz), 7,26 (10H, m), 7,44 (1H, d, J = 2.0 Hz), 7,49 (1H, DD, J = 2.0 a, 8,8 Hz).

In 20 ml of methyl alcohol was dissolved 291 mg (0,455 mmol) of the compound obtained above and 30 mg (10% (wt./weight.) catalyst palladium on carbon added to the mixture for carrying out the hydrogenolysis under normal pressure. After the reaction, the catalyst was removed by filtration and the solvent is removed by distillation under reduced pressure to obtain 168 mg (100%) specified in the connection name.

The value of Rf: 0,15 (CHCl3) MeOH = 4:1, vol/about.

NMR (CDCl3, TMS) (M. D.): 1,03 (1H, m), 1,32 (3H, s) of 1.50 (3H, s) of 1.73 (1H, m), 1.60 - to 2,70 (3H), of 2.21 (1H, m), is 2.30 (1H, m) of 3.00 (2H, m), of 3.54 (1H, m), 3,88 (1H, d, J = 7,3 Hz) to 3.89 (1H, m), of 5.82 (1H, d, J = 7,3 Hz), 6.90 to (abicyclo/4.1.0/hept-4-ene-5-yloxy/-3,4-dihydro-2,2-dimethyl-3 - hydroxy-2H-1-benzopyran-6-carbonitrile.

To 10 ml of methylene chloride added 108 mg (0.29 mmol) of 3,4-TRANS-4-/3-/2-amino-ethyl/-2-oxo-3,4 - diazabicyclo/4.1.0/hept-5-EN-5-yloxy/-3,4-dihydro-2,2-dimethyl-3 - hydroxy-2H-1-benzopyran-6-carbonitrile obtained in example 17, and 0.04 ml (0.29 mmol) of triethylamine and the mixture added dropwise a solution of 23 mg (0.29 mmol) acetylchloride in 2 ml of methylene chloride, followed by stirring at room temperature for 2 hours to Remove the solvent by distillation under reduced pressure, followed by chromatographic purification on a column of silica gel and recrystallization and ethyl acetate to obtain 55 mg (45.8 per cent) specified in the connection name.

Melting point: 230 - 231oC.

The value of Rf: 0,58 (CHCl3) MeOH = 5:1, vol/about.

NMR (CDCl3, TMS) (M. D.): 1,08 (1H, m) to 1.37 (3H, s), and 1.54 (3H, s) of 1.73 (1H, m), 1,95 (3H, in), 2.25 (2H, m) to 3.09 (1H, m), up 3.22 (1H, m), 3,85 (1H, DD, J = 7,3, 7,8 Hz), 4,13 (1H, m), 4,32 (1H, m), with 4.64 (1H, d, J = 7,3 Hz), of 5.75 (1H, br, s), the 6.06 (1H, d, J = 7.8 Hz), 6.89 in (1H, d, J = 8,3 Hz), of 7.48 (1H, DD, J = 2.0 a, 8,3 Hz), 7,56 (1H, d, J = 2.0 Hz).

Example 19. 3,4-TRANS-3,4-dihydro-2,2-dimethyl-4-/3-methyl-2 - oxo-3,4-diazabicyclo/4.1.0/hept-4-ene-5-yloxy/-6-pentafluoroethyl-2H-1 - benzopyran-3-ol.

To 1.5 l of diethyl ether type 12,63 g (33,67 mmol) 3-bromo-3,4-dihydro-2,2-dimethyl-6-pentafluoroethyl-2H-1-benzop what asianam at room temperature for 54 PM Insoluble compound is removed by filtration and the solvent is removed by distillation under reduced pressure to yield 9.5 g (96,2%) of 3,4-dihydro-2,2-dimethyl-3,4-epoxy-6-pentafluoroethyl-2H-1-benzopyran.

NMR (CDCl3, TMS) (M. D.): 1,30 (3H, s) to 1.60 (3H, s), of 3.54 (1H, d, J = 4.4 Hz), of 3.94 (1H, d, J = 4.4 Hz), make 6.90 (1H, d, J = 8,3 Hz), 7,46 (1H, DD, J = 2.0 a, 8,3 Hz), EUR 7.57 (1H, d, J = 2.0 Hz).

To 100 ml of ethanol added 2.50 g (8.50 mmol) of the compound obtained above, 1.20 g (8,56 mmol) of ()-3-methyl-3,4-diazabicyclo/4.1.0/heptane-2,5-dione and 0,672 g (8.50 mmol) of pyridine and the mixture is heated to boiling under reflux for 20 hours the Solvent is removed by distillation under reduced pressure. Purify the residue is chromatographically on a column of silica gel to obtain 1.22 g (33,0%) specified in the connection name.

Melting point: 190 - 191oC.

The value of Rf: 0,31 (ethyl acetate).

NMR (CDCl3, TMS) (M. D.): 0,99 (1H, m) of 1.35 (3H, s) of 1.53 (3H, s), 1.69 in (1H, m), 2,17 - of 2.30 (2H, m) of 3.25 (3H, s), with 3.79 (1H, d, J = 3,4 Hz), of 3.96 (1H, DD, J = 3,4, and 7.3 Hz), of 5.75 (1H, d, J = 7,3 Hz), to 6.95 (1H, d, J = 8,8 Hz), was 7.45 (1H, d, J = 8,8 Hz), 7,53 (1H, s).

Example 20. 3,4-TRANS-3,4-dihydro-2,2-dimethyl-3-hydroxy-/4-/3 - methyl-2-oxo-3,4-diazabicyclo/4.1.0/hept-4-ene-5-yloxy/-2H-1 - benzopyran-6,7-dicarboximide.

The compound obtained in the 3-, 4-, 1' - and 6' are S, R, S and R, respectively, and their optical antipodes or the racemate consisting of the compound (1q), where the configuration of the provisions mentioned above, is S, R, R and S, respectively, and their optical antipodes.

< / BR>
In 20 ml of DMF is dissolved 0,76 g (3.10 mmol) of 3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-1-benzopyran-6,7 - dicarboximide obtained in comparative example 30, and 0.44 g (3.14 mmol) of ()-3-methyl-3,4-diazabicyclo/4.1.0/heptane-2,5-dione, and to the solution was added 0.6 ml (7,43 mmol) of pyridine. The mixture was stirred at 90oC for 38 h, the Reaction mixture was concentrated under reduced pressure and to the mixture are added ethyl acetate and water, followed by stirring. The organic layer is separated and the aqueous layer further extracted with ethyl acetate. The organic layers are combined and dried. The solvent is removed under reduced pressure and the residue cleaned chromatography on a column of silica gel and recrystallized from a mixed solvent of methyl alcohol and isopropyl ether to obtain 62 mg specified in the connection name.

Melting point: 250 - 253oC.

The value of Rf: 0,40 (CHCl3) MeOH = 20:1 V/V.

NMR (DMSO-d6, TMS) (M. D.): 0,8 - 1,1 (1H, m) of 1.30 (3H, s) of 1.43 (3H, s), 1,5 -/P> Example 21. /3S,4R,1'S,6'R/-4-/3-benzyl-2-oxo-3,4-diazabicyclo /4.1.0/hept-4-ene-5-yloxy/-3,4-dihydro-2,2-dimethyl-3-hydroxy-2H-1 - benzopyran-6-carbonitrile.

To 20 ml of ethanol is added 800 mg (3.7 mmol) of ()-3-benzyl-3,4-diazabicyclo/4.1.0/heptane-2,5-dione, obtained in reference example 1, 774 mg (3.7 mmol) -(-)-/3S,4S/-3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-1-benzopyran-6 - carbonitrile and 0.4 ml of pyridine and the mixture is heated to boiling under reflux for 16 hours the Solvent is removed by distillation under reduced pressure and the residue is purified chromatographically on a column of silica gel and recrystallized from isopropyl ether to obtain 490 mg (31,7%) specified in the connection name.

These x-ray analysis confirm S and R configuration at positions 1'- and 6', respectively.

Melting point: 118 - 120oC.

The value of Rf: 0,50 (CHCl3) MeOH = 20:1 V/V.

[]2D5:-212,8(M. D.): 1,01 (1H, m), 1,25 (3H, s) of 1.44 (3H, s) of 1.73 (1H, m) to 2.18 (1H, m), 2,33 (1H, m) of 3.00 (1H, d, J = 4.3 Hz), 3,76 (1H, DD, J = 4,3, 7,3 Hz), and 4.75 (1H, d, J = 14.4 Hz), is 4.85 (1H, d, J = 14.4 Hz), the ceiling of 5.60 (1H, d, J = 7.8 Hz), to 6.88 (1H, d, J = 8,3 Hz), 7,30 (5H, m), of 7.48 (1H, DD, J = 2.0 a, 8,3 Hz), 7,52 (1H, s).

Examples 22-46. The compounds shown in the table. 3, taken in the same SP chromatography on silica gel, specific rotation data and NMR spectra obtained in CDCl3except as disclosed. Specific rotation measured at 25oC, except where noted.

Example 47. /3S,4R,1'R*,6'S*/-3,4-dihydro-2,2 - dimethyl-3-hydroxy-4-/2-oxo-3,4-diazabicyclo/4.1.0/hept-4-ene-5 - yloxy/2H-1-benzopyran-6-carbonitrile.

Method a:

To 500 ml of ethanol type of 12.33 g (97 mmol) of ()-3,4-diazabicyclo-/4.1.0/heptane-2,5-dione, obtained in reference example 28, and 18.6 g (of 92.5 mmol) /3S, 4S/-3,4-dihydro-2,2 - dimethyl-3,4-ethoxy-2H-1-benzopyran-6-carbonitrile and 7.5 ml (92,5 mmol) of pyridine, followed by heating at boiling under reflux for 14 hours, the Solvent is removed by distillation under reduced pressure and the residue is purified chromatographically on a column of silica gel and liquid chromatography high resolution to obtain 2.4 g (7.9 per cent) specified in the connection name.

The value of Rf: to 0.29 (ethyl acetate).

[]2D5:-168,1(M. D.): 1,18 (1H, m) of 1.33 (3H, s), of 1.52 (3H, s), 1,60-2,10 (1H, br, s), is 1.81 (1H, m), of 2.21 (2H, m), 3,92 (1H, d, J = 7,3 Hz), 5,71 (1H, d, J = 7,3), 6,91 (1H, d, J = 8,3 Hz) to 7.50 (1H, DD, J = 2.0 a, 8,3 Hz), to 7.59 (1H, d, J = 2.0 Hz), 7,71 (1H, s).

Method B:

To 450 ml of 1,2-dichloroethane add 5,91 g (13,2 mmol) of (3S,4R,1'R*, 6'S*/-3,4-carbonitrile, obtained in example 40, and 17.7 g (78 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and to the mixture is added 0.9 ml (50 mmol) of water followed by heating at boiling under reflux for 8 hours, the Insoluble matter is removed by filtration, the filtrate is concentrated under reduced pressure. Chromatographic purification on a column of silica gel gives 2,81 g (65,1%) specified in the connection name.

Example 48. /3S, 4R, 1'R*,6'S*/-4-/3-cyanomethyl-2 - oxo-3,4-diazabicyclo/4.1.0/hept-4-ene-5-yloxy/-3,4-dihydro-2,2 - dimethyl-3-hydroxy-2H-1-benzopyran-6-carbonitrile.

To 3 ml of acetone added 200 mg (0.61 mmol) /3S,4R,1'R*,6'S*/-3,4-dihydro-2,2-dimethyl-3-hydroxy - 4-/2-oxo-3,4-diazabicyclo/4.1.0/hept-4-ene-5-yloxy/-2H-1 - benzopyran-6-carbonitrile obtained in example 47, and 85 mg (0.61 mmol) of potassium carbonate, followed by stirring. To the mixture add a solution of 147 mg (1,22 mmol) bromoacetonitrile in 2 ml of acetonitrile, followed by heating at boiling under reflux for 4 hours To the mixture then add 585 mg (4,88 mmol) bromoacetonitrile and 170 mg (1,22 mmol) of potassium carbonate followed by heating at boiling under reflux for 3 hours, the Insoluble matter is removed by filtration and Rast. The organic layer was washed with water and then saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure and the residue cleaned chromatography on a column of silica gel to obtain 81 mg (36.3 per cent) specified in the connection name.

The value of Rf: to 0.47 (ethyl acetate).

[]2D5:-168,4(M. D.): 1,18 (1H, m) of 1.39 (3H, s) of 1.50 (3H, s), equal to 1.82 (1H, m), and 2.26 (1H, m), of 2.34 (1H, m), 2,82 (1H, d, J = 5.4 Hz), of 3.97 (1H, DD, J = 5,4 and 6.9 Hz), 4,36 (1H, d, J = 17,1 Hz), 4,79 (1H, d, J = 17,1 Hz), of 5.82 (1H, d, J = 6.9 Hz), 6,93 (1H, d, J = 8,8 Hz), 7,52 (1H, DD, J = 2.0 a, 8,8 Hz), 7,60 (1H, d, J = 2.0 Hz).

Examples 49-52. The compounds shown in the table. 4, obtained in the same manner as in example 48. Also shown are the data of the melting temperature (i.e. square), the value of Rfaccording to thin-layer chromatography on silica gel, specific rotation and NMR data of the compounds. NMR spectra are taken in CDCl3except as disclosed cases. Specific rotation measured at 25oC except as noted.

Example 53. /3S,4R,1'R*,6'S*/-3,4-dihydro-2,2 - dimethyl-3-hydroxy-4-/3-methyl-2-oxo-3,4-diazabicyclo/4.1.0/hept-4 - ene-5-ylamino/-2H-1-benzopyran-6-carbonitrile.

In 25 ml of dimethyl sulfoxide restore the oru added 160 mg (4 mmol) of 60% sodium hydride and 885 mg (4.4 mmol) /3S, 4S/-3,4-dihydro-2,2-dimethyl-3,4-epoxy-4H-1-benzopyran-6 - carbonitrile, followed by stirring at room temperature for 4 hours To the reaction mixture, water is added, followed by extraction with ethyl acetate. The organic layer is washed with water and then saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure and the residue cleaned chromatography on a column of silica gel and recrystallized from ethyl acetate to obtain 152 mg (11,1%) specified in the connection name.

Melting point: 157-158oC.

The value of Rf: 0,24 (CHCl3) MeOH = 10:1 V/V.

[]2D5:-217,0(M. D.): 1,00 (1H, m) of 1.28 (3H, s), of 1.52 (3H, s) of 1.66 (1H, m), from 2.00 (1H, m), of 2.21 (1H, m), up 3.22 (3H, s), of 3.73 (1H, DD, J = 2.0 a, 8,3 Hz), 4,39 (1H, d, J = 7.8 Hz), 4,82 (1H, d, J = 2.0 Hz), 4,91 (1H, DD, J = 7,8, and 8.3 Hz), 6.90 to (1H, q, j = 8,3 Hz), 7,49 (1H, DD, J = 2.0 a, 8,3 Hz), to 7.67 (1H, br, s).

Example 54. /3S,4R,1'S,6'R/-3-acetoxy-4-/3-benzyl-2-oxo - 3,4-diazabicyclo/4.1.0/hept-4-ene-5-yloxy/-3,4-dihydro-2,2 - dimethyl-2H-1-benzopyran-6-carbonitrile.

To 10 ml of methylene chloride added 0.31 g (0,74 mmol) /3S,4R,1'S,6'R/-4-/3-benzyl-2-oxo-3,4-diazabicyclo/4.1.0/hept-4-ene - 5-yloxy/-3,4-dihydro-2,2-dimethyl-3-hydroxy-2H-1-benzopyran-6 - carborid, followed by stirring at room temperature for 1 day. The solvent is removed by distillation under reduced pressure and the residue cleaned chromatography on a column of silica gel and recrystallized from diisopropyl ether to obtain 0,145 g (42.6 per cent) specified in the connection name.

Melting point: 149-151oC.

The value of Rf: 0,74 (ethyl acetate).

[]2D5:-92,9(M. D.): 0,94 (1H, m) of 1.35 (3H, s) of 1.42 (3H, s) of 1.64 (1H, m) to 1.99 (3H, s) to 2.06 (1H, m) to 2.29 (1H, m), to 4.62 (1H, d, J = 14.1 Hz), equal to 4.97 (1H, d, J = 14.1 Hz), of 5.34 (1H, d, J = 5,9 Hz), 5,74 (1H, d, J = 5,9 Hz), 6,92 (1H, d, J = 8,3 Hz), 7,25-to 7.35 (5H, m) to 7.50 (1H, DD, J = 2.0 a, 8,3 Hz), 7,52 (1H, d, J = 2.0 Hz).

Example 55. /3S,4R,1'S,6'S*/-3-acetoxy-4-/3-/2-Chlorobenzyl/-2-oxo-3,4 - diazabicyclo/4.1.0/-hept-4-ene-5-yloxy/-3,4-dihydro-2,2-dimethyl-2H - 1-benzopyran-6-carbonitrile.

Indicated in the name of the connection will receive the same manner as in example 54, except that they use /3S,4R,1'R*,6'S*/-4-/3-/2-Chlorobenzyl-2-oxo-3,4 - diazabicyclo/4.1.0/hept-4-ene-5-yloxy/-3,4-dihydro-2,2-dimethyl-3 - hydroxy-2H-1-benzopyran-6-carbonitrile obtained in example 33, instead of the compound obtained in example 21.

The value of Rf: 0,64 (CHCl3) MeOH=20:1 V/V.

[]2D

Example 56. /3S,4R,1'R*,6'S*/-3,4-dihydro-3-hydroxy-4-/3-methyl-2 - oxo-3,4-diazabicyclo/4.1.0/hept-4-ene-5-yloxy/-2,2,3-trimethyl-2H-1 - benzopyran-6-carbonitrile.

In 15 ml of methyl alcohol was dissolved 300 mg (0.85 mmol) of 3,4-TRANS-3,4-dihydro-3-hydroxy-4-/3-methyl-2-oxo-3,4 - diazabicyclo/4.1.0/hept-4-ene-5-yloxy/-2,2,3-trimethyl-2H-1 - benzopyran-6-carbonitrile obtained in example 14, and is divided into the enantiomers by high performance liquid chromatography ("CHIR AI PAK AD"; Daicel Chemical Industries, LTD., ethanol/hexane = 15:85, V/V). Recrystallization from a mixture of ethyl acetate (hexane give 102 mg (34,0%) specified in the connection name.

Melting point: 192-193oC.

The value of Rf: of 0.21 (ethyl acetate).

[]2D5:-162,2(M. D.): 1,04 (1H, m), 1,25 (3H, s) of 1.42 (3H, s) of 1.50 (3H, s), of 1.74 (1H, m), 2,22 to 2.35 (2H, m) of 3.25 (3H, s), 3,90 (1H, s), of 5.83 (1H, s) 6,91 (1H, d, J = 8,30 Hz), 7,51 (1H, DD, J = 1,95, 8,30 Hz), 7,66 (1H, C).

Example 57. /3S, 4R,1'R*,6'S*/-4-/3-/2- Chlorobenzyl/-2-oxo-3,4-diazabicyclo/4.1.0/hept-4-ene-5-yloxy/ 3,4-dihydro-2,2-dimethyl-3-formyloxy-2H-1-benzopyran-6-carbonitrile.

To 15 ml of benzene is added 1.5 g (3.3 mmol) /3S,4R, 1'R*,6'S

The value of Rf: 0,64 (CHCl3)MeOH = 20 : 1 vol./about.

[]1D7:-100,6(M. D.): 1,00 of - 1.04 (1H,m) of 1.33 (3H, s) of 1.43 (3H, s), 1,65 - 1,71 (1H, m), of 2.08 and 2.13 (1H, m), 2,29 to 2.35 (1H, m), 4,70 (1H, d, J = 15.1 Hz), 5,18 (1H, d, J = 15.1 Hz), of 5.40 (1H, d, J = 6.3 Hz), 5,78 (1H, d, J = 6.3 Hz), 6.89 in (1H, d, J = 8,3 Hz), 7,20 - 7,34 (5H, m), 7,47 (1H, d, J = 8,3 Hz), 8,00 (1H, s).

Example test 1. Activity against potassium exchange (open potassium channels).

1) the Activity of potassium metabolism of the tested compounds are shown below in table. 5, was determined according to a known method (Naunyn-Schmiedeberg''s Archives of Pharmacology, Vol. 338, S. 319 - 326 (1988)).86Rbwas introduced in the segment isecheno aorta of Wistar rats, and segment potassium exchange of test compounds was expressed as the effective concentration when the area under the peak speed of release of 86Rbreached a value of 0.2 (ECAUCO.2).

The results obtained are shown in table. 5.

2) Dvadtsatidvuhletny male rats with spontaneous hypertension (weight rats 350 - 420 g) received an intravenous injection of 30 mg/kg of glibenclamide (Sigma Chemical Compahy) having antagonistic activity on the disclosure potassium channel, or the control solvent. After 10 min was injected intravenously (0.1 mg/kg of the compound of example 1 and were observed change in blood pressure after 6 h after injection (Journal of Pharmacology and Experimental Therapeutics, Vol. 248, S. 1261 (1989). The results obtained are shown below in table. 6.

From these results it is seen that each of the compounds of examples 1, 22, 23, 47 and 56, have activity against disclosure potassium channels potassium exchange.

Example test 11. Antihypertensive activity in spontaneous hypertension rats.

Male rats with spontaneous hypertension (16 - 20 weeks of age weight: 300 - 400 g) were fed on a needs were heavily exposed to the oral introduction of the test compounds suspended in 0.5% (weight/volume) aqueous solution of carboxymethylcellulose. Beats, ol. 18, page 1285 - 1287 (1968)).

Antihypertensive activity of the test compounds was obtained as a dose effective to reduce the blood pressure of 50 mm RT.article (ED50mmRT.article.). In addition, the measured time of occurrence of maximum activity and maximum increase in heart rate at the dose lower blood pressure by 50 - 60 mm RT.article The results obtained are shown below in table. 7.

The statistical difference between the test compound and AMD 57283 were analyzed according to t-Student tests.

Each of the compounds of examples 21, 24, 32, 33, 36, 37 56 shows a high antihypertensive activity, compared with medication compare a slower onset of action and reduced side effects increased heart rate. In addition, these compounds have a long activity.

Example of test 3. Effect on renal blood flow.

20-week-old male rats with spontaneous hypertension (weight 350 - 430 g) were subjected to anesthesia by pentobarbital (30 mg kg, EXT. the bruche.). An incision was made in the left part of the abdominal cavity, and the Doppler probe for measuring blood flow was placed on the left renal artery, and a code transmitter (Provo the d was associated with a Doppler meter the flow of blood and began measuring renal blood flow. After renal blood flow has reached steady state, the test compound was administered orally, and observed changes in renal blood flow up to 9 hours of Test compound used in doses that reduce blood pressure by 50 mm RT.article The results obtained are shown below in table. 8.

As you can see from the table. 8, each of the compounds of examples 2, 21, 33, 36 and 47 have more potent activity in increasing renal blood flow than the remedy selected for comparison.

Example of test 4. Acute toxicity.

The test compound suspended in 1% (weight/volume) aqueous solution of methyl cellulose and administered orally three male mice in a single dose of 2 g/kg and observed survival and overall condition within 14 days for receipt of magnitude LD50. The results obtained are shown below in table. 9.

Thus, each of the compounds of examples 1, 2 and 33 show a high security.

The test example 5. Antiangina activity.

The tests were carried out in accordance with the method Hiramatsu and others (Japanese Journal of Pharmcology, Vol. 20, S. 313 (1970)).

Electrodes for ECG were attached to the limbs of male rats HOS-Donryu (weight 30 is diagramme. Cannula for measuring blood pressure was introduced into the left femoral artery, and a cannula for drug administration was introduced into the left femoral vein. After 30 min after administration of the compound of example 47 and after 5 min after administration of nifedipine or cromakalim were injected intravenously with 0.5 U/kg vasopressin (Sigma Chemical Company). Then recorded ECG every 30 s for 5 min to observe the reduction of ST segment. The control group was given solvent for drugs (a solution in which 5% DMSO, 5% polyethylene glycol 200 and 1% cremophor was dissolved in saline solution). The decrease in ST segment (V), obtained every 30 s, connected by a straight line and the square, surrounded by the end of the curve (S value; V/ min), was chosen as the degree of decrease for 5 minutes Each test compound was administered at a dose that reduces the value of blood pressure by 30 mm Hg column.

As shown in the table. 10, the compound of example 47 significantly reduces's value effectively reduces ST depression and, thus, shows antianginal activity.

Reference example 6. A relaxing activity against relaxation of Guinea-pig trachea.

Male Guinea pigs were killed by exsanguination and dissected the Cut the trachea was placed in the bath for organs filled with Tyrode solution (37oC with aeration 95% O2/5% CO2mixed gas). Tracheal response was measured isometrically using the Converter "EF-601G" (produced by Nihon Kagyo Co., Ltd.) and recorded on the recorder R-64GP" (manufactured by Rika benki Co., Ltd.). The initial pressure in the prepared trachea was set when the content of 1 g after equilibration cooking after 60 min, in order to cause the reduction, was added 30 mmol of potassium chloride. After reduction, when the pressure has reached a plateau, was added to test the connection. Were used for comparison of cromakalim, which, as you know, has a relaxing activity for bronchial smooth muscle (Japanese Journal of Pharmacology, Vol. 56, S. 13-21 (1991)).

Relaxing activity was expressed as the concentration inducing 50% relaxation (EC50taking relaxation 10-8g/ml isoproterenol (Sigma Chemical Company) in 100%. The results obtained are shown in table. 11.

Each of the compounds of examples 23, 29 and 32 see big potential activity in the relaxation of tracheal smooth muscle than cromakalim.

Although the invention is described in detail and with reference to specific examples, any qualified who change the nature and scope of the invention.

In the attached materials of comparative experiment used here, the compounds of the invention are (1-1) DY-9708, (2-1) DX-9015 (racemate) and DX-9348 (connection with optical resolution), (3-1) DX-9275 (racemate) and DY-9535 (connection with optical resolution), and the compounds used here as compounds analogues are (1-2) EMD-NH, (2-2) EMD-57283 (racemate) and EMD-57283 (connection with optical resolution and (3-2) EMD-Bzl (racemate) and EMD-Bzl (connection with optical resolution). Structural formulas of these tested compounds are presented in the end of the description.

From the above comparison results, you can see that the antihypertensive activity of the compounds of the invention is approximately equal to the activity of the compounds analogues, but the compounds of the invention are far superior connection-analogues from the viewpoint of reducing the side effect of increasing heart rate. Thus, the superiority of the compounds of the invention above compounds, analogs also can be seen from figures comparative data maximum increase in heart rate (%).

A comparative experiment was performed in the same manner as in the example above tests.

Example formulations 1.

An example of the formulation 2. The capsules are filled with the following ingredients, which after sealing the vials sealing sterilized at 115oC for 30 min:

Composition (1 ml)

The compound of example 47 - 50 mcg

Sodium chloride - 9 mg

Distilled water for injection to Relax. to 1 ml

The compound of example 47 DY-9709 has the structural formula:

t

1. Derivatives diazabicyclo General formula I:

< / BR>
where R1represents a group of formula (II) or (III)

< / BR>
< / BR>
where R11and R12each represents a lower alkyl group or taken together they form the lower alkylenes group;

R13is a hydroxyl group, a lower acyloxy group;

R14is a hydrogen atom or a lower alkyl group;

And a nitrogen atom or C-R16,

where R16represents a hydrogen atom, cyano, nitro, triptoreline, pentafluoroethyl, sulfonyl, possibly substituted aryl, t lower alkyl;

R23is hydroxyl;

R24and R25each is a hydrogen atom;

X is an oxygen atom or N-R31where R31is hydrogen;

R2is hydrogen, lower alkenyl, lower quinil, lower alkyl, optionally substituted by a group selected from lower alkoxygroup, hydroxy-group, ceanography, alkylcarboxylic, amino, carbamoyl, pyridyl, lower alkoxycarbonyl, phenyl, or R2optionally substituted lower alkylphenyl, where one or more substituents of the phenyl portion is independently selected from sulfamoyl groups, halogen atoms, lower alkyl, CN, OH, lower alkoxy;

R3and R4each is a hydrogen atom or lower alkyl;

n =1,

or its pharmaceutically acceptable salt.

2. Connection on p. 1, wherein R1represents a group represented by the formula (II).

3. Connection on p. 1, wherein R1represents a group represented by the formula (II), where a represents C-R16; X represents an oxygen atom; n represents 1.

4. Connection on p. 1, characterized in that it is optically active compound represented by formula (Ia), (Ib), (IC) or (Id) or a racemate, where R2
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
where R1, R2, R3, R4, X and n are defined in paragraph 1, in an effective amount.

6. The pharmaceutical composition according to p. 5, characterized in that the active compound is a compound represented by formula (Ia), (Ib), (Ic) or (Id) or a racemate, as defined in paragraph 4 of the formula.

7. The pharmaceutical composition according to p. 5, possessing antihypertensive effect.

8. The pharmaceutical composition under item 5 that has effect in relation to angina pectoris.

9. The pharmaceutical composition according to p. 5 with anti-asthma effect.

 

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< / BR>
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